IE861247L - PYRAZOLO £1,5-a| PYRIMIDINES - Google Patents

PYRAZOLO £1,5-a| PYRIMIDINES

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Publication number
IE861247L
IE861247L IE861247A IE124786A IE861247L IE 861247 L IE861247 L IE 861247L IE 861247 A IE861247 A IE 861247A IE 124786 A IE124786 A IE 124786A IE 861247 L IE861247 L IE 861247L
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IE
Ireland
Prior art keywords
phenyl
pyrimidin
alkyl
cyanopyrazolo
acid
Prior art date
Application number
IE861247A
Other versions
IE61755B1 (en
Inventor
John Paul Dusza
Andrew Stephen Tomcufcik
Jay Donald Albright
Original Assignee
American Cyanamid Co
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Publication date
Priority claimed from US06/732,986 external-priority patent/US4626538A/en
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Publication of IE861247L publication Critical patent/IE861247L/en
Publication of IE61755B1 publication Critical patent/IE61755B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • G—PHYSICS
    • G11—INFORMATION STORAGE
    • G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
    • G11B5/00—Recording by magnetisation or demagnetisation of a record carrier; Reproducing by magnetic means; Record carriers therefor
    • G11B5/48—Disposition or mounting of heads or head supports relative to record carriers ; arrangements of heads, e.g. for scanning the record carrier to increase the relative speed
    • G11B5/58—Disposition or mounting of heads or head supports relative to record carriers ; arrangements of heads, e.g. for scanning the record carrier to increase the relative speed with provision for moving the head for the purpose of maintaining alignment of the head relative to the record carrier during transducing operation, e.g. to compensate for surface irregularities of the latter or for track following
    • G11B5/584—Disposition or mounting of heads or head supports relative to record carriers ; arrangements of heads, e.g. for scanning the record carrier to increase the relative speed with provision for moving the head for the purpose of maintaining alignment of the head relative to the record carrier during transducing operation, e.g. to compensate for surface irregularities of the latter or for track following for track following on tapes
    • G11B5/588—Disposition or mounting of heads or head supports relative to record carriers ; arrangements of heads, e.g. for scanning the record carrier to increase the relative speed with provision for moving the head for the purpose of maintaining alignment of the head relative to the record carrier during transducing operation, e.g. to compensate for surface irregularities of the latter or for track following for track following on tapes by controlling the position of the rotating heads
    • G—PHYSICS
    • G11—INFORMATION STORAGE
    • G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
    • G11B15/00—Driving, starting or stopping record carriers of filamentary or web form; Driving both such record carriers and heads; Guiding such record carriers or containers therefor; Control thereof; Control of operating function
    • G11B15/18—Driving; Starting; Stopping; Arrangements for control or regulation thereof
    • G11B15/1808—Driving of both record carrier and head
    • G11B15/1816—Programmed access in sequence to indexed parts of operating tapes cooperating with rotating heads
    • G—PHYSICS
    • G11—INFORMATION STORAGE
    • G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
    • G11B15/00—Driving, starting or stopping record carriers of filamentary or web form; Driving both such record carriers and heads; Guiding such record carriers or containers therefor; Control thereof; Control of operating function
    • G11B15/18—Driving; Starting; Stopping; Arrangements for control or regulation thereof
    • G11B15/1808—Driving of both record carrier and head
    • G11B15/1825—Driving of both record carrier and head driving or moving the head in a direction which cuts across the direction of travel of the tape, e.g. for helicoïdal scanning
    • G11B15/1833—Driving of both record carrier and head driving or moving the head in a direction which cuts across the direction of travel of the tape, e.g. for helicoïdal scanning with head driven in a plane, cyclically around an axis, e.g. on headwheel
    • G—PHYSICS
    • G11—INFORMATION STORAGE
    • G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
    • G11B15/00—Driving, starting or stopping record carriers of filamentary or web form; Driving both such record carriers and heads; Guiding such record carriers or containers therefor; Control thereof; Control of operating function
    • G11B15/18—Driving; Starting; Stopping; Arrangements for control or regulation thereof
    • G11B15/1808—Driving of both record carrier and head
    • G11B15/1875—Driving of both record carrier and head adaptations for special effects or editing
    • G—PHYSICS
    • G11—INFORMATION STORAGE
    • G11B—INFORMATION STORAGE BASED ON RELATIVE MOVEMENT BETWEEN RECORD CARRIER AND TRANSDUCER
    • G11B5/00—Recording by magnetisation or demagnetisation of a record carrier; Reproducing by magnetic means; Record carriers therefor
    • G11B5/008—Recording on, or reproducing or erasing from, magnetic tapes, sheets, e.g. cards, or wires
    • G11B5/00813—Recording on, or reproducing or erasing from, magnetic tapes, sheets, e.g. cards, or wires magnetic tapes
    • G11B5/00817—Recording on, or reproducing or erasing from, magnetic tapes, sheets, e.g. cards, or wires magnetic tapes on longitudinal tracks only, e.g. for serpentine format recording
    • G11B5/00839—Recording on, or reproducing or erasing from, magnetic tapes, sheets, e.g. cards, or wires magnetic tapes on longitudinal tracks only, e.g. for serpentine format recording using cyclically driven heads providing segmented tracks

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Signal Processing (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

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

Description

[7-(3-DISUBSTITuTED AMINO)PHENYL1- PYRAZOLO[1,5-a]PYRIMIDINES SUMMARY OF THE INVENTION This invention relates to new organic compounds which are [7»(3-disubstituted amino)phenyl]pyra:zolo-[1,5-e]pyrimidines. which are useful as anxiolytic and anciepilepcic agents as well as sedative-hypnotic agents and skeletal muscle relaxants. This invention also relates to the methods of using the novel compounds, to compositions of matter containing them as the active ingredient and to processes for their production.
DETAILED DESCRIPTION OF THE INVENTION The novel compounds of this invention are represented by the following structural formula; R, wherein Ri is selected from the group consisting of; -2- 0 II hydrogen, halogen. cyano and -C-R41 R2 is selected from the group consisting of hydrogen and alkyl(Ci-C3); R3 R5-N-C-R6 of hydrogen, alkyl(C].-Cg) and alkoxy(Ci-Cg) ; R5 is selected from the group consisting of hydrogen;, alkyl(C1-C5) » alkenyl- (C2-Cg), -CH2CSCH, cycloalkyl(C3-C5)methyl, -CK20CH3 and -CH2CH2OCH3; and Rg is selected from the group consisting of alkyl(Ci~Cq), cycloalkyl(C3-C5), -O-alkyl(C^-Cg), -NH-alkyl(Cj-C3), -M-dialkyKCi-C3), -(CH2)n-0-alkyl(Ci-C3), -(CH2)n-NH~alkyl(Cx-C3) and -(CH2)n-N-dialkyl(C1-C3), where n is an integer 1 to 3 inclusive.
The most preferred compounds of this invention are the compounds of the above formula wherein Rj is 0 II cyano or -C-R4; R2 is hydrogens R4 is alkyl (Ci -Cg) ; R5 is alkyl(C^-Cg). alkenyl(C2-C5) or -CH2-CH5 and R5 is alkyl(Ci-C§), cycloalkyl(C3-05) or -O-alkyl(Ci-C5).
The instant invention is additionally concerned with the methods which employ the above-described compounds in mammals to treat anxiety or epilepsy and to induce a sedative-hypnotic effect or relax skeletal muscles, with compositions of matter containing the above-described compounds and with processes for producing the compounds. is I R4 is selected from the group consisting „ 1 _ The novel compounds of this invention may be readily prepared as set forth in the following reaction scheme: II // \ CH3-C- n h~H~C~R6 (1) (1) DMF-acetal (z) Nan; r5-x (X = Br, I) (CH3 ) 2NCH=CHC- " ^ R5_N-C-R^ (2) Rs 0 *6 N V !2 !1 /W \ H-N ' N\ (3) ~^2 ~Ri (4) In accordance with the above reaction scheme a 1-acenylpheny1-3-amide (l)s where Rg is as described above is reacted with dimethylformamide dimethylacetal at reflux giving an N-[3-[3~(dimechylamino)-1~oxo~2-propenyl]phenyl]-alkanamide, which is then reacted with sodium hydride, and -4~ che anion generated is reacted with an alkyl halide, where R5 is as described, above giving the N~[3~[3~(dimethylamino)' -l-oso-2-propenyl]phenyl]-N-alkylalkanamide (2). This compound is then reacted with a 3-amioopytazole (3). where 5 and R2 are as described above, in glacial acetic acid at reflux, giving the produce (4).
Alternatively, H-[3-[3-(dialkylamino)-1-oxo~2-propenyl ]phenyl ]alkanamide (5) is reacted with a 3-amino-pyrazole (3) to giv© intermediates (6) which are reacted with a base such as sodium hydride, sodium alkoxide and the like and an Rj-halide to give the products (4). 0 (CH3)2NCH«CHC—(' N) + H~H ^ H2W «2 -Ri (3) -5- 10 15 The performance of the novel compounds of the present invention in standard tests with laboratory animals which are known to correlate well with relief of anxiety in man indicates that they possess central nervous system activity at nontoxic doses and thus are useful as anxiolytic agents. Furthermore, these compounds have been shown by biological data to be useful as antiepileptic agents, particularly in the treatment of grand ma1 epilepsy seizuress and as sedative-hypnotic and skeletal muscle relaxant agents.
The anti-anxiety and anticonvulsant properties of che novel compounds of the present invention have been established in a test which indicates anxiolytic and anti-epileptic activity by the measure of protection they pro-20 vide from convulsions resulting from the administration of pentylenetetrazol. Single or graded dose levels of the test compounds were administered orally or intraperitoneally 25 in a 2% starch vehicle, containing 0.5% v/v polyethylene glycol and one drop of Polysorbate 80 to groups of at least 4 rats. At 30 or 60 minutes, the rats were treated intravenously wich pentylenetetrazols at a dose of 23 mg/kg of body weight. This dose is estimated to cause clonic seizures in 99% of unprotected rats. It has been reported [R. T. Hill and D. H. Tedeschi, "Animal Testing and 35 Screening Procedures in Evaluating Psychotropic Drugs" in "An Introduction to Psychopharmacology", Eds. R. R. Rech and K. E. Moore. Raven Press, New York? p„ 237-288 (1971) ] that there is a high degree of correlation between the ability of compounds to inhibit the seizure-inducing effect of pentylenetetrazol in rats and the effectiveness of those compounds as anxiolytic and anticonvulsive agents in higher warm-blooded animals. The resulcs of this test on representative compouxids of the present invention are shown in Table I. 30 40 45 TABLE I Protection Against Clonic Seizures Caused bv Pentv1enetetrazole in Rats Compound Dose (rag/kg) % of Rats Protected N~[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl J-N~ethylpropanainide 25.0 100 N~[3-(3-cyanopyrazolo[1,5-a]pyriraidin-7-y1)phenylj-N-ethylacetamide 25.0 100 N-[3-(3-chloropyrazolo[1,5-a]pyrimi~ din-7-yl) phenyl ] -N-ethylacetaraide 25.0 100 N—[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-propylacetamide 6.25 100 [ 3~(3-cyanopyrazolo [ 1, 5-a'jpyrimidin-7-yl)phenyl]tnethylcarbamic acid, methyl ester 3.1 25 [3-(3-cyanopyrazolo[1,5«a]pyrimidin-7-yl)phenyl]ethylcarbamic acid, methyl ester 12,6 75 N-butyl~N-[3-(3-cyanopyrazolo[1,5-a]-pyrimidin-7-yl)phenyl]acetamide 25.0 50 [3-(3-cyanopyrazolo[1,5~a]pyrimidin-7~ yl)phenyl]ethylcarbamic acid1? ethyl ester 25.0 25 [3-(3-chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]ethylcarbamic acid, ethyl ester 25.0 25 N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-y1)phenyl j -N-2-propenyLacetamide 25.0 100 N~t3-(3-cyanopyrazolo[1,5~aJpyrimidin-7-yl)phenylj-N~2-propynylacetamide 6.25 100 -7- TABLS X (continued) Compound Dose (rng/kg) % of Rats Protected N-[3-(3-cyanopyrazolo[1,S-aJpyriraidin-7-yl)phenyl]-N~methyIcyclobutanecar-boxamide 25.0 50 N-|3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylcyclopropanecar~ boxamiae 25.0 75 N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-raethylacetamide 25.0 75 N-[3-(3-chloropyrazolo[1,5-a]pyrimi-din-7-yl)phenyl]-N-methylacetamide 12.5 50 7—[3—(acetylmethylamino)phenyl]pyra-zolo[1,5-alpyrimidine-3-carboxylic acid, ethyl ester 25.0 100 N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-me thy1propanami de 12.5 50 N-[3-(3-cyano-2-methylpyraaolo[l,5-a]-pyrimidin-7-yl)phenyl]-N-methy1pro-pan, amide 25.0 100 Another test which has been used to assess antianxiety effects is a noncondicloned passive avoidance procedure described by J. R. Vogel, B. Beer and D. E. Clody, "A Simple and Reliable Conflict Procedure for 5 Testing Anti-Anxiety Agents". Psychopharmacologia, 21, 1-7 (1971). A conflicc situation is induced in rats by a modification of this Method. ■jQ Groups of 6 native, Wistar strain rats, weighing 200-240 g each were deprived of water for 48 hours and food for 24 hours. The nest compounds yere administered in single or graded, oral or intraperitoneal doses, sus- 15 pended in a 2% starch vehicle containing 0.5% v/v polyethylene glycol and one drop of polysotbaca 80. Control animals received the vehicle alone. At 30 to 60 minutes each rat was placed in an individual plexiglass chamber. Water was available ad libitum from a tap located in the rear of the chamber. A 0.7 milliampere DC shocking current was established between the stainless steel grid floor and the tap. After 20 licks of non-shocked drinking, a shock was delivered for 2 seconds and then further shocks were delivered on a ratio of one shock for 2 seconds for every 20 licks. This was continued for a total of 3 minutes. The number of shocks taken by each rat during the 3 minute interval was recorded and compared to a control group. The test compounds are considered active if the number of shocks received by the test group is significantly higher than the control group by the Mann-witney U test. Results of this test on representative compounds of this invention appear in Table II.
TABLE XI Nonconditioned Passive Avoidance Test in Rats Compound Dose (mg/kg) Result■ N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenylj-N-ethylprop&naraide 0.4 Active N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-v1)phenyl]-N-ethylacetamide 0.8 Active N-ethyl-N-{3-pyrazolo[1,5~a]pyrimidin-7-ylphenyl)acetamide 25.0 Active N-[3-(3~chloropyrasolo[1,5~a]pyrimi-din-7-yl)phenyl]-N-ethylacetamide 3.1 Active N-[3-(3-cyanopyrazolo(1,5-aIpyrimidin-7-yl)phenyl]-N-propylacetamide 1.5 Active [3-(3-cyanopyrazolo(1,5~a3pyrimidin-7~ yl)phenyl]methyIcarbamic acid, methyl ester 3.1 Active TABLE II (continued) Compound Dose (mg/kg) Resul 'c [3-(3-cyanopyrazolo[1„5-a]pyrimidin-7-yl )phenyl lethylcarbaraic acid, methyl ester 12 „ 5 Active [3-(3-chloropyrazolo[1,5-a]pyrimidin~ 7 -y 1)pheny1]ethy1carbami c acid, ethyl ester 25- 0 Active N-[3-(3-cyanopyrazolo[1,5-aJpyrimidin-7-yl)phenyl]-N-2-propeny1ace tamide 3» 1 Active N-(3~( 3-cyanopyrazolo [ 1,5-a]pyrin»idin-7-yl)phenyl]-N-2-propynylacetamide X. 5 Active N-[3-(3-cyanopyrazolo[1,5-aJpyrimidin-7-yl)phenyl]-N-methylpropanamide 6. 2 Active N- [3-(3-cyano-2-methylpyrazolo(1,5-aj-pyrimidin-7-yl)phenyl]-N-me thy1propan-amide 25. 0 Active 7™[3-(acetyimethy1amino)phenylJpyra-2olo[l,5-a]pyrimidine-3-carboxyiic acid, ethyl ester 25, 0 Active N~[3~(3-cyanopyrazolo[1,5-a]pyrimidin-7-y1)phenyl]-N-raethylacetamide 1. 5 Active N~[3-(3-chloropyrazolo[1,5-a]pyrimi-din-7-yl)phenyl]-N-me thy1ace tami de 3. 1 Active N-[3-(3-cyaaopyrazolo[l,5-a]pyrimidin-7-yl)phenyl]-N-methylcyclobutanecar-boxamide 25, 0 Active Another test utilized for the determination of anxiolytic activity is che measurement of Che ability of test compounds Co inhibit the binding of CtiCiated benzodiazepines to brain-specific recepCors of warm-blooded animals. A modification of Che method described by R. F. Squires, e£ al.. Nature, 266, No. 21. p. 732 (April -10- 1977) and H. Mohler, ec al., Science. 198, p. 849 (1977) was employed.
Male albino racs (Wiscar strain, weighing 150— 200 g each) were obtained from Royalhart Farms, ^H-Meth-5 yldiazepam (79.9 Ci/mmol) and ^H-methylflunitrazepasn (84.3 Ci/mmol) were obtained from New England Nuclear. The test compounds were solubilized in either dimethyl-formamide, acetic acid, ethanol or hydrochloric acid.
Whole cortex of rats was homogenized gently in 10 20 volumes of ice-cold 0.32 M sucrose, centrifuged twice at 1000 g for 10 minutes and then recentrifuged at 30.000 g for 20 minutes to produce a crude p2~synaptosomal fraction. The P2-fraccion was either: (1) resuspended in twice the original volume in hypotonic 50 mM Tris.HCl (pH 7.4), 15 or (2) resuspended ■ in one-half the original volume in hypotonic 10 mM Tris.HCl (pK 7.4) and then was frozen (~20°C) until time of use. Frozen ?2 preparations were thawed and resuspended in four times the original homogenizing volume at time of assay. 20 The binding assay consisted of 300^1 of the P2»fraction suspension (0.2-0.4 mg protein), 100 jJ, of test drug and 100 yl of ^H~diazepam (1.5 nM, final concentration) or ^H-flunitrazepam (1.0 nM, final concentration) which was added to 1.5 ml of 50 mM Tris.HCl (pH 7.4). Non-25 specific binding controls and total binding controls received 100 pi of diazepam (3 M, final concentration) and 100 jjl of deionized water, respectively, in place of the test compound. Incubation for 30 minutes proceeded in ice and was terminated by filtration, under vacuum,, through 30 Whatman GF/C glass fiber filters. The filters were washed twice with 5 ml of ice-cold 50 mM Tris.HCl (pH 7.4) and placed in scintillation vials. After drying at 50~60°C for 30 minutes. 10 ml of Beckman Ready-SolvTM HP (a high performance pre-mix scintillation cocktail, registered trademark of Beckman Instruments. Inc., Irvine, CA 92713) was added and the radioactivity determined in a scintillation counter. -11- Inhibition of binding was calculated by the difference between total binding and binding in the presence of test compound, divided by the total binding x 100. 5 The results of this test on representative compounds of the present invention are given in Table 111.
TABLE, III Inhibition of the Binding of ^-Benzodiazepine to Brain-Specific Receptors of Rats Compound % Inhibition N~[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7- y 1) phenyl j -M-ethvIpropanamide 83 H— £ 3—(3=cyanopyra2olo[l»5-a]pyrimidin~7~ yl)phenyl]-N-ethylacetamide 79 N-[3-(3-chloropyrazolo[1, 5-a]pyrimidin-/-yl)phenyl]-N~ethylacetamide 97 N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-y1)phenyl]~N~propylacetamide £ A 0 7-(3-[ethyl(1-oxopropyl)amino]phenyl]pyra-zolo[ 1 j?5-a]pyrimidine-3-carboxy1ic acid, ethyl ester 100 [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]methylcarbamic acid, methyl ester 87 7-[3-[(methoxycarbonyl)methylamino]phenyl]-pyrazolo[1,5-a]pyrimidine-3-carboxylie acid, ethyl ester 98 [3-(3-cyanopyrazolo[1,5-a]pyrimidin~7~yl)-phenyl]ethylcarbamic acid, methyl ester 55 7-[3-[ethy1(me thoxycarbony1)amino]pheny1]-pyraaolo[l, 5~a jpyrijmidine~3-carboxylic~ acid, ethyl ester QO -12- TMBLE III (continued) Compound % Inhibition [3~(3-cyanopyrazolo[1,5-a]pyritaidin-7-yl)-phenyljmethylcarbamic acid, ethyl ester 41 ethyl(3~pyrazolo(1,5-a]pyrimidin-7-yl~ phenyl )carbamic acid,, ethyl ester 61 [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]ethylcarbamic acid,, ethyl ester 63 [3-(3-chloropyrazolo[1,5-a]pyrimidin-7~yl)-phenyl]ethylcarbamic acid, ethyl ester 78 N-[3-(3-cyanopyrazolo(1,5-a]pyrimiain-7-yl)phenyl]-N-2~propenylacetamide 78 N-[3-(3-cyanopyrazolo[1,5-a]pyriinidxn-7~ yl)phenyl]-N-2-propynylacetamide 91 N-[3-(3~cyano~2-methylpyrazolo[1,5-aj pyrimidiri~7-yl) phenyl ]propanamide 42 N—[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenylJ-N-methylpropanamide 79 N—[ 3—( 3-cvano—2—niethylpyrazolo [ 1,5-a]-pyrimidin-7-yl}phenylj-N-methy1propanamide 95 N-rnethyl~N-(3-pyrazolo[1,5-ajpyrimidin-7-ylphenyl )acetaxnide 54 7—[3—(acetylmethylamino)phenyl]pyrazolo-I1,5-a]pyrimidine-3~carboxylic acid, ethyl ester 100 N~[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-y 1) phenyl ] -N-methylacetamide 73 N-(3-{3-chloropyrazolo(1,5-a]pyrimidin-7-yl)phenyl]-N-methylacetamide 71 N-[3~(3-cyanopyrazolo[1,5-a]pyrimidin-7-y1)phenyl]-N-methylcyclobutanecarboxamide 81 -13- TABLE III (continued) Compound % Inhibition N-[3-(3-cyanopyrazolo[l,5-a]pytimidin-7-yl)phenyl ] -M-methylcyclopropanecarboxamide 83 7-[3-[(eyelopropyIcatbonyl)methy1amino]-phenylpyraaolo(1,5-a]pyrimidine-3-car- boxylic acid, ethyl ester 95 7-[3-(acetylethylamino)phenyl]pyrazolo-[1, 5-a]pyr iaudihe-3-catboxyl ic acid, ethyl ester 97 7-[3-(acetylamino)phenyl]pyrazolo[1,5-a]- pyrimidine-3-carboxylie acid, ethyl ester 85 7~[3~[(mechoxycarbonyl)amino]phenyl]-pyrasolo[l,5-a]pyrimidine-3-carboxylic acid, ethyl ester 75 methyl(3~pyrazolo[I,5-a]pyrimidin-7-yl-phenyl)carbamic acid, methyl ester 45 7-[3-(acetylpropylamino)pheny1]pyrazolo-[ 1, 5-a]pyrimidine~3-catboxylic acid, ethyl ester 97 [3~(3-ebloropyrazolo[l,5-a]pyrimidin-7-yl)phenyl ]raethylcarbainic acid, methyl ester 92 7-[3-[ (cyclobucyl'carbonyl)amino]phenyl ]-pyrazolo[l,5~a]pyrimidine-3-carboxylic acid, ethyl ester 82 The novel compounds of chis invention have also been shown to have skeletal muscle relaxant activity chrough the use of two tests. The first test measures the effect of representative compounds on the ability of rats to remain on an inclined screen. Groups of at least 6 rats were created orally with graded doses of test compounds or vehicle and placed on a uire saesh screen (inclined at an angle of 60° from a horizontal level) 65 minutes later. The number of rats falling off che screen within 30 minutes -14- was recorded. The ED50 (dose necessary to causa 50% of the anisnals tested to rail off) was calculated according Co the linear arcsine transformation method of Finney. D. J.,"Statistical Methods in Biological Assay", 2nd Ed.» Hafner, N. Y., 1964. p. 454. Compounds were dissolved or suspended in a 2% aqueous starch suspension containing 5% polyethylene glycol 400 and a drop of polysorbate 80. and administered in a constant volume of 5 ml/kg. The results of representative compounds of this invention appear in Table XV.
TABLE IV Effect on Ability of Rats to Remain on an Inclined Screen Compound ED50 (mg/kg) N-[3~(3~cyanopyrazolo[l,5-a]pyrimidin-7~y1)pheny1]-N-ethylpropanamide N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenylj-W-ethylacetamTde 4.6 3.9 The second test to illustrate that the novel compounds of the present invention possess skeletal muscle relaxant properties shows the effect of representative cosBpounds on the locomotor activity in tats. Groups of 6 rats were treated orally with vehicle (5 ml/kg) or graded doses of the test compounds. Sixty minutes later, individ ual rats were placed in Actophotometers and locomotor activity was measured for 5 minutes after a brief (30 sec.) habituation period. Motor activity counts (number of crossings of the photo cells) were recorded for each rat, and mean activity counts were calculated for each treatment group. The dose causing a 50% decrease in mean activity counts compared with the vehicle group (MDD50) was calculated from a 1inear regression equation. The -15- cest results of representative compounds appear in Table V.
TABLE V Effects on Locomotor Activity in Rats Compound MDD50 (mg/kg P.O.) N-[3~(3-cyanopyrazolo[1.5-a]pyr imidin-7- yl)phenyl]-W-ethylpropansmTde 3-(3-cyanopyrazolo[1.5-a]pyriraidin-7-yl)phenyl]-N-ethylacetamide 2.0 1.4 The novel compounds of the present invention have been found to be highly useful for drug therapy in mammals when administered in amounts ranging from about 5 0.1 mg to about 20.0 mg/kg of body weight per day. A preferred dosage regimen for optimum results would be from about 0.5 rag to about 10.0 mg/kg of body weight per day.
Dosage units are employed such that a total of from about 10 to about 700 rag of active compound for a subject of 10 about 70 kg of body weight are administered in a 24 hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the 15 exigencies of the therapeutic situation. The compounds of this invention are preferably administered orally but may be administered in any convenient manner such as by the intravenous, intramuscular, or subcutaneous routes.
Compositions according to the present invention 20 having the desired claritys stability and adaptability for parenteral use are obtained by dissolving from 0.10% to 10.0% by weight of active compound in a vehicle consisting of a polyhydric aliphatic alcohol or mixtures thereof. Especially satisfactory are glycerin, propylene glycols 25 and polyethylene glycols. The polyethylene glycols con sist of a mixture of nonvolatile, normally liquid, polyethylene -16- glycols which are soluble in both water and organic liquids and which have molecular weights of from about 200 to 1500. Although che amount of active compound dissolved in the above vehicle may vary from 0.10% to 10.0% by weight, it is preferred that the amount of active compound employed be from about 3.0% Co about 9.0% by weight. Although various mixtures of the aforementioned nonvolatile polyethylene glycols may be employed, it is preferred to use a mixture having an average molecular weight of from about 200 to about 400.
In addition to the active compound;, the parenteral solutions may also contain various preservatives which may be used to prevent bacterial and fungal contamination- The preservatives which may be used for these purposes are. for example, myristyl-gamma-picolinium chloride, benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-alpha-glycerol ether, methyl and propyl parabens, and thimerosal. As a practical matters, it is also convenient to employ antioxidants. Suitable antioxidants include, for example, sodium bisulfite, sodium metabisulfite, and sodium formaldehyde sulfoxylate. Generally, from about 0.05% to about 0.2% concentrations of antioxidant are employed.
For intramuscular injection, the preferred concentration of active compound is 0.25 to 0.50 mg/ml of the final compositions. The novel compounds of the present invention are equally adapted to intravenous administration when diluted with water or diluents employed in intravenous therapy such as isotonic glucose in appropriate quantities. For intravenous use, initial concentrations down to about 0.05 to 0.25 mg/ml of active ingredient are satisfactory.
The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or compressed into tablets, or incorporated directly into the food of the diet. For oral therapeutic administration, the active compounds may be incorporated with exeipients and used in the for® of tablets, troches, capsules, elixirs, suspensions, syrups, wafers and che like. Additionally, the active ingredient may be incorporaced with the proper pharmaceutical carrier or carriers known in the art to produce a sustained-release tablet or capsule. Such compositions and preparations should contain at least 0.1% of active compound,. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit dose. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
The tablets, troches, pills, capsules and the like may also contain one or more of the following; a binder such as gum cragacanth. acacia, corn starch or gelatin; exeipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like? a lubricant such as magnesium stearate; a wetting agent such as sodium lauryl sulfate and a sweetening agenc such as sucrose, lactose or saccharin may be added or a flavoring agent such as pepper-mints oil of wintergreen or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both. A. syrup or elixir may contain the accive compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unic form should be pharmaceutically pure and substantially nontoxic in che amounts employed. -18- The following non-limiting examples illustrate the preparation of representative compounds of the present invention.
Example 1 N-[ 3-[ 3™ (Dime thy lasi.no )-l-oxo~2~propenyl ] phenyl ]- 5 propanasnide h 20 g portion of N-{3-aeetylphenylJpropanamide in 50 ml of dime thy lformainide dimethylacetal was refluxed for 8 hours, then evaporated- The residue was taken up in 200 ml of dichlorosnethane, passed through hydrous magnesium XO silicate, diluted with hexane and concentrated, giving 21.17 g of the desired compound.
Following the procedure of Example 1 and using the indicated starting materials,, the amides of Examples 2-5, found in Table VIr were prepared.
TABLE VI EJC.
Starting Material Amide 2 N~(3-acetylphenyl)-ethanamide N-[3-(3-dimethylamino)-1-oxo-2-propeny1)phenyl]- acetamide 3 (3-acetylphenyl)carbamic acid, methyl ester [3-[3-(dimethylamino)-I-oxo-2-propenyl]phenyl]-carbamic acid, methyl ester A (3-acetylphenyl)carbamic acid, butyl ester [3-[3-(dimethylamino)-1-oxo-2-propeny1]phenyl]-carbamic acid, butyl ester 5 N-(3-acetylphenyl)-butanamide N~[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-butanamide -19- Example 6 K~[3-[3-(Dimethy1amino)-l-oxo-2-propenyl]phenyl-N~ ethylpropanamide A mixture of 3,47 g of N~[3-[3-(dimethylamino)- l-oxo-2~propeoyl]phenylIpropanaraide and 0.68 g of 60% sodium hydride in oil in diraechylformamide was scirred for 0.5 hour under argon, Chen cooled in an ice bach and a 5 solution of 2.4 g of ethyl iodide in 10 ml of dimethyl- formamide was added in small portions. The mixture was then scirred ac room temperature for 0.5 hour and extracted three times with hexane. The extracts were discarded, water was added and chis mixture extracted with 10 dichloromechane. This extract was evaporated and che residue crystallized from hexane giving che desired compound, mp 105-107°C.
Following the procedure of Example 6 using the compounds of Examples 1-5 and appropriate alkyl halides, 15 the alkylated amides of Examples 7-12, found in Table VII, were prepared.
TABLE VII Ex.
Starting Material of Ex.
Alkylated Amide MP°C 7 2 N-[3-[3«(dimethylamino)-l-oxo-2-propanyl]phenyl]-M-echylacetamide 110-113 8 I N-[3~[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-mechylpropan-amide 148-149 Q y 2 N- [ 3- [ 3- (dimethylamino) -1 -o::o- 2-propenyl]phenyl]-N-propylacetainide 110-112 -20- TABLE VII (continued) Ex.
Starting Material of Ex.
Alkylated Amide MP°C 10 3 [3-[3-(dimethylamino)-1-oxo-2-pro-penyl]phenyl]methylcarbamic acid. methyl ester 93-95 11 3 [3-[3-(dimethylamino)-l-oxo-2-pro-penyl]phenyl]ethylcarbamic acid, methyl ester 95-97 12 2 N~[3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-N-methylacetamide 146-148 Example 13 M-[3-(3~Cyaoopyrazolo[l, 5-a]pyrimidin~7-yl)phenyl] -N- ethylpropanamide A mixture of 0.54 g of 3-acaioo-4~pyrazolecarbo-nitrile and 1-37 g of N-[3-[3-(dioiethylamino)-l-oxo~2-propenyl]phenyl]-N~ethylpropanamide in 50 ml of glacial acetic acid was refluxed for 8 hours and then the solvent 5 «as removed. The residue was partitioned between satur ated aqueous sodium bicarbonate and dichloromethane. The organic layer was separated, dried, passed chrough a pad of hydrous magnesium silicate and hexane was added to che refluxing filtrate. The mixture was then cooled and the 10 solid collected, giving 1.3 g of the desired product ? sap 161-162°C.
Following the procedure of Example 13 and using appropriately substituted 3-amino-pyrazoles together with the indicated intermediates. the products of Examples 15 14-37 found in Table VIII were prepared.
TABLE VIII Ex.
Intermediate of Ex, 3-Amino- ■ pyrazole Product HP°C 14 7 3-aminopyrazcle- 4-carbon!trile N—[ 3-{ 3-cyanopyrazolo 11., 5-a 1-pyrimidin-7-yl)phenyl]-N-ethylacetamide 106-107 15 7 3-amin0py.ra20.le N-ethyl-H-|3-pyrazolo(1,5-a]-pyrimidin-7-y I phenyl Jacefcarnide 115-117 16 3 3-aminopyrazole N-propyl-N-{3-pyrazolo[1,5-a}-pyrimidin-7-y1pheny1)ace tam i de 90-92 17 9 3-aminopyrazole- 4 -carbon!., tr i Le N-f3-C3-cyanopyrazolo[1,5-a]-pyrimidin-7-yi]phenyl]-N-propylacetamide .151.-153 18 6 ethy1-3-amino- pyrazole-4- carboxylate 7-{ 3-'[ethyl (1-oxopropyl )-aminojphenyL]pyrazolo(1,5-aj-pyrimidine-3-carboxylic acid, ethyl ester 124-126 19 10 3-aminopyrazole- 4-carbonitrile [3-(3-cyanopyrazolo11,5-a J-pyrimidin-7-yl)phenyl]methyl-carbamic acid, methyl ester 168-170 TABLE VIII (continued) Ex s Intermediate of Ex, 3-AmIiro-pyrazole Product MP°C 20 10 e thy .1-3 -ami no- pyrazole-4- carboxylate 7-13 —!(me thoxycarbony1)methyl-antinojphenyl Ipyrazclof 1, 5-a f-pyrimidine-3-carboxy11c acid, ethyl ester 115-116 21 3 3-aminopyrazoie- 4-carbonitrile I 3-(3-cyanopyrazolo11,5-a ] -pyrimidin-7-yl}phenyllcarbamic acid, methyl ester 256-250 22 4 3-aminopyrazole- 4-carbon!, trile [3-(3-cyanopyrazolo11,5-aJ-pyrimidin-7-ylJ phenyllcarbamic acid, butyl ester 131-133 23 1 3-aminopyrazole N-[3-(pyrazolo(l,5-aIpyrimi-din-7-yl}phenylJpropanamide 177-178 24 I 3-aminopyrazole- 4-carbonitrile 3-(3-cyanopyrazolo(1,5-a]-pyrimidin-7-yl)phenyl}pro-panamide 202-204 25 1 3-amino-5-meth-ylpyrazole-4- carboni trile N-[3-(3-cyano-2-methylpyra-zolol1,5-ajpyrimidin-7-yl)-phenylJpropanamide 177-178 TABLE VIII (continued) Ex.
Intermediate of Ek , 3-Asnino-pyrazole Product MP°C 26 8 3-aminopyrazole- 4-carbonitrile N-[3-{3-cyanopyrazolo{1,5-a ]-pyrimidin-7-y!)phenylj-N-me thy1propanam i de 27 8 3-amino-5-meth-ylpyrazole-4-carbonitrile N-(3-(3-cyano—2-methyLpyra-zolol1,5-a]pyrimidin-7-yl)-phenyl]-N-me thylpropanamide 184-106 2 fl 5 3-aminopyrazole- 4-carbon!trile N-f 3-{ 3-cyanopyrazolo(1., 5-a J-pyrimidin-7-yi}phenyljbutan-amide 138-140' 29 12 3-aminopyrazole- 4-carbonitrile N-( 3-( 3-cyanopyrazolo[ .1,5-a ] -pyrimidin-7-y L}phenyl j -lime thy lacetamide 195-197 30 2 3-aminopyrazole- 4-carbonitrile N-[3-(3-cyanopyrazolo[1,5-aj-pyrimidine-7-ylI phenyl]-acetamide 257-259 31 .12 3-aminopyrazole N-methyl-N-(3-pyrazolof1,5-aI-pyrimidin-7-ylphenyl}acetamide 118-120 TABLE VIII {continued) Ex * Intermediate of Ex. 3-Amino-pyrazole Product HP°C 32 12 ethy1-3-am ino- pyrazole-4- carboxylate 7-13-(acetylmethylamino)-phenyljpyrazoiof1,5-aJpyriroi-dine-3-carboxylAc acid, ethyl ester 155-156 33 7 3-amino-4-carbo-e thoxypyrazole 7-(3-(acetylethylamina)-phenyl ]pyrazolo[ 1, 5-a Ipy.iri.roi-dine-3-carboxy1£c acid, ethyl ester .147-148 34 2 3-amino-4-carbo-e thoxypyrazo1e 7-13-(acetylamino)phenyl]-pyrazoloj .1, 5-a ]pyrimidine-3-carboxylic acid, ethyl ester 202-204 35 3 3-amino-4-carbo-ethoxypyrazole 7 — [3-({methoxycarbony1}amino]-phenylJpyrazolo[I,5-aJpyrimi-dine-3-carboxylic acid, ethyl ester 107-188 36 10 3-aminopyrazole methyl{3-pyrazolo[1,5-aJ-pyrimidin-7-ylphenylJcarbamic acid, methyl ester 107-109 37 9 3-amino-4-carbo-e thoxypyrazole 7-[3-{acetylpropy1amino 1-phenyl]pyrazolol1,5-aJpyrimi-dine-3-carboxylic acid, ethyl ester 156-157 -2S~ Example 38 H"[3~(3-Chloropyrasolo[1„5-a]pyrimidin~7-yl)phenyl]-N- ethylacetamide A mixture of 1.0 g of N-ethyl~N-(3-pyrazolo-[1,5-a]pyrimidin-7-ylphenyl)acetamide .and 4.57 g of 1-chlorobenzotriazole in 50 ml of dichloromethane was refluxed for 25 minutes, then cooled and poured into 50 ml of ice-cold 2.5N aqueous sodium hydroxide. The mixture was filtered through hydrous magnesium silicate,, precipitated with hexane and the solid collected,, giving 0.7 g of the desired product, mp 157-159°C„ Example 39 7-j' 3-[Ethyl (methoxycarbonyI)amino 1 phenyl 1 pyrazolo [1,5-a]pyrimidine~3-carboxylic acid, ethyl ester A 12.41 g portion of [3-[3-(dimethylamino)-1-oxo- 2-propeny1]phenyl]carbamic acid, methyl ester was reacted as described in Example 6, using 9.36 g of ethyliodide, giving 13.4 g of [3~[3-(dimethylamino)-l~oxo-2-propenyl]-phenyl]ethylcarbamic acid, methyl ester, mp 95-97oc.
A 2.76 g portion of the above ester was reacted with 1.55 g of ethyl-3-aminopyrazole-4-carboxylate as described in Example 13, giving 2.87 g of the desired product, mp 117-119<3c.- Example 40 [3~(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]~ ethylcarbamic acid, methyl ester A 2.76 g portion of [3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]ethylcarbamic acid, methyl ester was reacted with 1,08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13, giving 2.6 g of the desired product, mp 162-164°C. -26- Exaiaple 41 [3-(3-Cyanopyrazolo{1,5-a]pyrimidin-7-yl)phenyl]~ methylcarbamic acid, ethyl ester l-Acetylphenyl~3-carbaraic acid? ethyl ester was converted to l3~l3-{dimethylaiainQ)-l-oxo-2-prapenyl]-phesylJcarbamic acid, ethyl ester by the procedure of Example 1 and this ester was then reacted with methyl iodides, again by the procedure of Example 6, giving [3~(3-{dimethylamino)-l-oxo-2-propenyl]phenyl]methylcarbamic acid, ethyl ester.
A 2.6 g portion of the above ester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile by the procedure of Example 13, giving 2„Q9 g of the.desired compound, mp 140~142°C.
Example 42 Ethyl(3~pyrazolo[1,5-a]pyrimidin~7~ylphenyl)-carbamic acid, ethyl ester [3-[3-(Dimethylamino)-l-oxo-2-propeny1]phenyl]-carbamic acid Mas reated with ethyl iodide by the procedure of Exaiaple 6, giving [3-[ 3-(dimethylamino)-l-oxo™ 2~propenyl]phenyl]ethylcarbamic acid, ethyl ester.
A 2.9 g portion of the above ester was reacted with 0.83 g of 3-aminopyrasole by the procedure of Example 13, giving 2.27 g of the desired product, mp 79-81°C- Bxample 43 [3~(3-Cyanopyrazolol1,S-ajpyrimidin-7-yl)phenyl]-ethylcarbamic acid, ethyl ester A 2.0 g portion of [3~[ 3-(dimethy^amino)-l--oxo-2•~•propenyl ]phenyl]ethylcarbamic acid, ethyl ester ^as reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13, giving 2.52 g of the desired product, mp 133-135°C. -27- Bxample 44 ' [3-(3-Chloropyrazolo[1,5~a]pyriau.din-7-yl)phenyl]~ ethylcarbamic acid- ethyl ©star A 1-55 g portion of ethyl(3~pyrazolo[1,5~a]-pyrimidin-7-ylphenylJcarbamic acid, ethyl ester in. 50 ml of dichloromethane was reacted with 1-chlorobenzotriazole for 30 minutes, giving 1.29 g of the desired product, mp XQG-102©C.
Example 45 N-[3-(3-Cyanopyrazolo[1,5-a J pyrimidin-7-yl)phenyl]-N- 2-~propea v 1 ace t amide An 11.61 g portion of N-[3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]acetamide was reacted °«°ith 7.26 g of allyl bromide as described in Example 6, giving 13.34 of N-[3-[3-(dimethylamino)-l-oxo-2-propeny1]phenyl]-N-2-propeny1acetamide, mp 91-94°C.
A 1.36 g portion of the above intermediate was reacted with 0.54 g of 3-aminopyrazole~4-carbonitrile as described in Example 13, giving 1.0 g of the desired compound e, mp 135~137°C.
Example 46 N-[3-(3-Cyanopyrazolo[1,5~a]pyrimidin-7-yl)phenyl]-N- -2~propynvlacetamide An 11.61 g portion of N-[3-[3~(dimethylamino)-l-oxo-2-propeny1]phenyl]acetamide was reacted with pro-pynyl bromide as described in Example 6, giving N-[3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]-M-2-propynvlacet amide, mp 98-101°C.
A 2-7 g portion of the above intermediate was reacted with 1.08 g of 3~aminopyrazole-4-carbonitrile as described in Example 13, giving 1.90 g of the desired product, mp 193-195°C. -28- Example 47 N-Butyl-N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)- phenyllacetamide An 11.61 g portion of [3-[3-(dimethylamino)-l-oxo-2-propenyljphenylJcarbamic acid, methyl escer was reacted with 11.0 g of butyl iodide by the procedure of Example 6. giving 16,3 g of N-butyl-N-[3-[3~(dimethyl-amino)-1-oxo-2-propenyljphenyljacecamide.
A 2.38 g portion of the above intermediate was reacted with 1.08 g of 3-aminopyrazole-A-carbonitrile by the procedure of Example 13, giving 1.61 g of the desired product, mp 146~148°C.
Example 48 N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin~7-yl)phenyl]-N- methylcarbamic acid, butyl ester An 11.61 g portion of [3-[3-(dimethylamino)-I-oxo-2-propenyl]phenyl]carbamic acid, butyl ester was reacted with 6.82 g of methyl iodide by the procedure of Example 6. giving 11.67 g of [3~[3-(dimethylamino)-1-oxo~ 2-propenyl]phenyl]methylcarbamic acid, butyl ester.
A 3.04 g portion of the above ester was reacted with 1.08 g of 3~arainopyrazole-4-carbontirile as described in Example 13, giving 2.3 g of Che desired product, mp 96-97°C.
Example 49 N-[3~(3~Chloropyrazolo[l,5-a]pyrimidin-7-yl)phenyl] methylacetamide A 1.0 g portion of N-methyl-N-(3-pyrazolo[1,5-a]-pyrimidin-7-ylphenyl)acetamide was reacted as described in Example 38, giving 1.0 g of the desired product, mp 163— 165°C. -29- Example 50 [3-(3-Cbloropyrssolo[1,5-a]pyrimidin-7-yl)phenyl]-methylcarbamic acid, methyl ester A 1.4 g portion of methyl(3-pyrazolo[1,5-a]-pyrimidin-7-ylphenyl)carbamic acid,, methyl ester was reacted as described in Example 38. giving 1.42 g of che desired product, mp 132-134°C. 5 Example 51 7-[3-[(Cyclopropylearbonyl)methylamino]phenylpyrazolo-[1,5-a ]pyr imidin.e-3-carboxylic acid, ethyl ester N-(3-Acety1phenyl)eyelopropanecarboxamide was prepared by the reaction of m-aminoacetophenone, diiso-10 propylethy1amine and cyclopropanecarboxylic acid chloride in dichloromethane.
This compound was then converted to N-[3-[3-(dimethylamino)-l-oxo-2-propenylJphenyl]cyclopropanecar-boxamide by the procedure of Example 1 and then alkylated 15 by the procedure of Example 6, using methyl iodide, giving 10.17 g of N-[3-(3-dimethylamino)-l-oxo-2-propenyl)phenyl]-N-tnethylcyclopropanecarboxamide, mp 120~122°C.
A 0»54 g portion of this compound was reacted as described in Example 13 with 3-aminopyrazole-4~carbo-20 nitrile, giving 1.08 g of the desired product, mp 178- 180°C.
Example 52 7-[3-[(Cyclopropylcarbonyl)mechylamino]phenylpyrazolo-[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester 25 A 0.73 g portion of ethyl 3-aminopyrazole-4~car- boxylate and 1.36 g of N-[3-[(3-(dimethylamino)-l-oxo-2~ propenyl]phenyl]~N~methylcyelopropanecarboxamide were reacted as described in Example 13, giving 0.52 g of the desired product, mp 122-124°C. -30- Example 53 N-C 3-(3-Cyanopyrazolo[1, 5-a ]pyrimidin-7-yl) phenyl Jl -N~ methy 1 eye 1 obutanecarboxamide m-Arainoacetophenone, cyclobutanecarboxy1ic acid, chloride and diisopropylethylamine in dichloromethane were reacted, giving N-(3-acetylphenyl)cyclobutanecarboxamide.
This compound was then converted to N-[3-[3~ (dimethylamino)-l~oxo~2~propenylJphenylJcyclobutanecarbox-amide, mp 155~157°C, by the procedure of Example 1 and further alkylated by the procedure of Example 6, using methyl iodide to give 8-32 g of N-[3~[3-(dimethylamino)-l-oxo-2-propenylJ phenylJ-N-methy1eye1obutanecarboxamide, mp 117-H9°C.
A 0.54 g portion of 3~aminopyrazole~4~carbo-nitrile was reacted with 1-43 g of the above product by the procedure of Example 13, giving 1-3 g of the desired product, mp 157~158°C.
Example 54 7-1* 3-f (Cyclobutylcarbonvl) amino j phenyl Ipyrasolo-[ 1, 5-a]pyrimidine-3-carboxylic acide, ethyl ester A 0*78 g portion of 3-amino-4-carboethoxypyrazole and 1-36 g of N~[3~[3-(dimethylamino)-l-oxo-2-propenylJ-phenyl]cyclobutanecarboxamide were reacted as described in Example 13, giving 1,52 g of the desired product, mp 123-125°C. - 31 -

Claims (11)

1. CLAIMS 5 1. A compound of the formulas wherein R^ is selected from the group consisting of hydrogen, halogens cyano and 15 0 20 selsc"ted from the group consisting of hydrogen and alkyl(C^-Cg), R3 is 30 R^ is selected from the group consisting of hydrogen, alkyl(C^-Cg) and alkoxy(Cj-Cg); R5 is selected from the group consisting of hydrogen, alkyl(C^-Cg), alkenyl(C2-Cg), -CH2C=CH„ cycloalkyl(C3-Cg)methyl, -CH20CH3 and -CH2CH20CH3; and Rg is selected from the group consisting of 35 alkyl (C^-Cg), cycloalkyl(C3-Cg)3 -O-alkyl (C^-Cg), -NH-alkyl(CrC3)9 -S^dialkyl(CrC3)fl -(CH2)n-0-alkyl(CrC3). -(CH2)n-i1H»alky1(CrC3) and -(CH^-N-dialkylfC^), n "y r nr» iifonnv 1 +0 *5 inrlftr ivn - 32 -
2. A compound according to Claim 1, wherein Rj is cyano or 0 II C - j R2 is hydrogen, R^ is alkyl(C^-Cg); Rg is alkvl(C^-Cq), alkenylor -CH2C=CH; and Rg is alkyl(Cj-Cg), cycloalkylfC^-Cg) or -O-alkyl(Cj-Cg).
3. The compound according to Claim 2, which is selected from the group consisting of* jj|~[3-(3-cyanopyrazolo[l ,5-a.]pyrimidin-7»yl )phenvl ]~N~ethylpropanamide* 11-[3-(3=cvanopyrazo 1 o[l ,5-a'jpyrimid in-7-vl) phenyl ]-H-ethylacetamide* N-[3-(3-cyanopyrazolo[l, 5-a]pyrimidin-7-yl Jphenyl ]-£-propylacetamide; [3-(3-cyanopyrazolo[l85-a.]pyrimidin-7-yl)phenyl]methylcarbamic acid, methyl ester; 7-[3-[methoxycarbonyl)methylamino]phenyl]pyrazolo[l ,5-aJpyrimidine-3-carboxvlic acid, ethyl esters [3-(3-cyanopyrazolo[l,5-a.]pyrimidin-7-yl)phenyl]ethylcarbamic acid, methyl ester; ethyl(3-pyrazolo[l,5-aJpvrimidin-7-yl-phenyl)carbamic acid, ethyl ester; [3-(3-chloropyrazolo[l,5~a]pyrinridin-7-yl)phenyl]ethylcarbamic acid, ethyl ester; £-[3-(3-cyanopyrazolo[l, 5-a]pyrimidin-7-yl )phenyl ]-N.-2-propenylacetamide; - 33 - N-[3-(3-cyanopvrazolo[l,5-a]pyrimidin-7-yl )phenvl]-N-2-propynvlacetamide; and N-[3-(3-cyanopyrazolo[l, 5-a.]pyrinndin-7-yl Jphenyl ]-N-methylacetamide.
4. Use of a compound according to Claim 1 for the manufacture of a medicament for ameliorating anxiety in a mammal.
5. Use of a compound according to Claim i for the manufacture of a medicament for treating epilepsy in a mammal.
6. Use of a compound according to Claim 1 for the manufacture of a medicament for inducing sedation or hypnosis in a mammal.
7. Use of a compound according to Claim 1 for the manufacture of a medicament for inducing skeletal muscle relaxion in a mammal.
8. A composition of matter in dosage unit form comprising from 2-750 mg of a compound of Claim 1 in association with a pharmaceutical^ acceptable carrier.
9. A process for producing the product of Claim 1, which comprises the steps of (a) reacting a 1-acetvlphenyl-3-araide of the formula: with dimethylformamide, dimethylacetal at reflux, which produces an N~[3-[3-(dimethylami no) -l-oxo-2-propenyl Jphenyl ]alkanamide; (b) reacting the N-[3-[3-(dimethylamino)-l-oxo-2-propenyl] phenyl]-alkanamide with sodium hydride, which produces an anion; _ 34 - (c) reacting the anion generated with an alkyl ha Tide of the formula Rg~X, wherein X is Br or I, which produces an N.-[3-[3-(dimethylamino)-l-oxo-2-propenyl Jphenyl J-N-a Iky la Ikanarnide of the formula: (d) reacting the N-[ 3-[ 3-d imethy l ami no)-l-oxo-2-propeny'l Jphenyl J-ji~ alkvlalkanamide with a 3-aminopyrazole of the formula: in glacial acetic acid at reflux, which reaction gives the desired products.
10. A process for producing a compound as claimed in Claim 1, substantially as hereinbefore described by way of Example.
11. A compound as claimed in Claim 1 whenever prepared by a process as claimed in Claim 9 or 10. TONKINS & CO.
IE124786A 1985-05-13 1986-05-12 [7-(3-disubsituted amino)phenyl]pyrazolo[1,5 delta]pyrimidines IE61755B1 (en)

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