IE61755B1 - [7-(3-disubsituted amino)phenyl]pyrazolo[1,5 delta]pyrimidines - Google Patents

[7-(3-disubsituted amino)phenyl]pyrazolo[1,5 delta]pyrimidines

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Publication number
IE61755B1
IE61755B1 IE124786A IE124786A IE61755B1 IE 61755 B1 IE61755 B1 IE 61755B1 IE 124786 A IE124786 A IE 124786A IE 124786 A IE124786 A IE 124786A IE 61755 B1 IE61755 B1 IE 61755B1
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Ireland
Prior art keywords
phenyl
alkyl
cyanopyrazolo
pyrimidin
acid
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IE124786A
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IE861247L (en
Inventor
John Paul Dusza
Andrew Stephen Tomcufcik
Jay Donald Albright
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American Cyanamid Company A Co
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Priority claimed from US06/732,986 external-priority patent/US4626538A/en
Application filed by American Cyanamid Company A Co filed Critical American Cyanamid Company A 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)PHENYL]PYRA20L0[1,5-a]PYRIMIDINES SUMMARY OF THE INVENTION This invencion relates co new organic compounds which are [7-(3-disubscituted amino)phenyl]pyra2olo= [1,5-a]pyrimidines. which are useful as anxiolytic and antiepilepcic agencs as well as sedacive-hypnotic agenes and skeletal muscle relaxants. This invention also relates co che methods of using the novel compounds, to compositions of matter containing them as che active ingredient and to processes for their production.
DETAILED DESCRIPTION OF THE INVENTION The novel compounds of this invention are represented by che following structural formula; wherein Ri is selected from the group consisting of; -2Ο II hydrogen, halogen, cyano and -C~R4; R2 is selected from the group consisting of hydrogen and alkyl (Ci -C3) ;· R3 is ; R4 is selected from che group consisting R5-N-C-R6 of hydrogen, alkyl(Ci-Cg) and alkoxy(Οχ-C5): R5 is selected from che group consisting of hydrogen, alkyl(Ci-Cg), alkenyl (C2-Cg), "CHpCsCH, cycloalkyl(C3~Cg)methyl, «CK2OCH3 and -CH2CH2OCH3; and Rg is selected fro» the group consisting of alkyl(Ci-Cg), cycloalkyl(C3-Cg), -0-alkyl(Cj-Cg), -NH-alkyl(C1-C3) , ~N~dialkyl(Ci-C3) , -(CH2)n~O~aIkyl(Ci-C3) , -2)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 R| is 0 II cyano or -C-R4; R2 is hydrogen; R4 is alkyl(Ci-Cg); R5 is alkyl(C^-Cg), alkenyl(C2-Cg) or -CH2-CH; and Rg is alkyl(Ci-Cg), cycloalkyl(C3-Cg) or -O-alkyl(Ci-Cg).
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 che compounds.
The novel compounds of this invention may be readily prepared as set forth in che following reaction scheme: In accordance with the above reaction scheme a l-acetylphenyl-3-amide (1), where Rg is as described above is reacted with dimethylformamide dimechylacetal at reflux giving an N-[3~[3~(dimethylamino)~1-oxo~2-propenyl]phenyl]alkanamide, which is then reacted wich sodium hydride, and -4•J che anion generated is reacted with an alkyl halide, where R5 is as described^above giving the N~[3~[3~(dimethylamino) -l-oxo-2-propenylJpbenyl]-N-slkylalkanamide (2). This compound is then reacted with a 3-aminopyrazole (3), where Rl and R2 are as described above, in glacial acetic acid at reflux, giving the product (4).
Alternatively,, N-[3-[3-(dialkylamino)-1 -oxo-2propenylJphenyl]alkanamide (5) is reacted with a 3-aminopyrazole (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).
(A (GH3)pNCH^CHC H2I4 -Rt HN-C~R0 8" R^-hclide (3) -5The performance of che novel compounds of che presenc invention in standard casts 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 co be useful as antiepileptic agents, particularly in che treatment of grand mal epilepsy seizures, 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 antiepileptic activity by the measure of protection they provide from convulsions resulting frcm che administration of pentylenetetrazole. Single or graded dose levels of che test compounds were administered orally or intraperitoneally 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 pentylenetetrazole 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 Screening Procedures in Evaluating Psychotropic Drugs in An Introduction to Psychopharmacology, Eds. R. R. Rech and Κ. E. Moore, Raven Press, New York, p„ 237-288 (1971)] that there is a high degree of correlation between the ability of compounds co inhibit the seizure-inducing effect of pentylenetetrazole in rats and the effectiveness of those compounds as anxiolytic and anticonvulsive agents in higher warm-blooded animals. The results of this test on representative compounds of che presenc invention are shown in Table I. -6TABLE I Protection Against Clonic_Seisures Caused by Pentylenetetrazole in Rats Compound Dose (mg/kg) % of Rats Protected N~i3-(3-cyanopyrazoloE1,5-a]pyrimidin7-yl)phenylj-N-ethylpropanamxde 25.0 100 N- [ 3- (3-cyanopyrasolo (1,5-aJpyriraxdin7-y1)phenylj-N-ethylacetamide 25.0 100 N~i 3-(3-chloropyrazoloE1,5~ajpyrimi~ dxn-7-yl)phenyl]-N-ethylacetaraide 25.0 100 N-(3-(3-cyanopyrazolo[1? 5-a]pyrimxdxn7-y 1)phenyl]-N-propylacetamide 6.25 100 E 3-(3-cyanopyrazolo[1e5-a]pyrimidin-7- yl)phenylJmethylcarbamic acid? methyl ester 3.1 25 [3-(3-cvanopyrazolo[1? 5-a]pyrimidin-7yl)phenyl]ethylcarbamic acid? methyl ester 12.6 75 N-butyl-M-[3-(3~cyanopyrazolo[1? 5-a]pyrimidxn-7-yl)phenyl Jacetamide 25.0 50 (3-(3-cyanopyrazolo(l?5-a]pyrimidin-7yl)phenylJethylcarbamic acid? ethyl ester 25.0 25 [3-(3-chloropyrazolo[1? 5-a]pyrimidin7-yl)phenylJethylcarbamic acid? ethyl ester 25.0 25 N~[3-(3-cyanopyrazolo[1?5-aJpyrimidin7-yllphenylj-N-2-propenylacetamide 25.0 100 N—(3-(3-cyanopyrazolof1? 5~a]pyrimidin7-yl) phenyl]-N-2-propynylacetamide 6.25 100 -7TABLB I (continued) Compound Dose (mg/kg) % of Rats Protected N-[3-(3"cyanopyrasolo[l,5--ajpyrimidin- 7-yl,phenyl J-N-methyIcyclobutanecar- boxamide 25.0 50 N- (3-(3-cyanopyrazolo(1,5-a]pyrimidin7-yl)phenyl]-N-methylcyclopropanecarboxamide 25.0 75 N-(3-(3-cyanopyrazolo(1,5-a]pyrimidin7-yl)pheny1]-N-methylacetamide 25.0 75 N-(3-(3-chloropyrasolo[1„5-aJpyrimidin-7-yl)phenyl]-N-methylacetamide 12.5 50 7-(3-(acetylmethylamino) phenyl]pyrazolo (1 ,5-ajpyrimidine-3-carhoxylie acid, ethyl ester 25.0 100 N-[3-(3-cyanopyrazolo(1,5-a]pyrimidin7-yl)phenyl]-N-methylpropanamide 12.5 50 N-[3- (3-cyano-2-methylpyraso1o [ 1,5 - a ] pyrimidin-7-yl)phenyl]-N-methylpropanamide 25.0 100 Another test which has been used to assess antianxiety effects is a noneondicloned 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'9. Psychopharmacologia, 21,, 1-7 (1971). A conflict situation is induced in rats by a modification of this method.
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 test compounds were admjnisrered in single or graded, oral or intraperitoneal doses, suspended in a 27, search vehicle containing 0.57, v/v polyethylene glycol and one drop of polysorbate 80. Control animals received the vehicle alone. At 30 co 60 minutes -85 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 ϋ test. Results of this test on representative compounds of this invention appear in Table II.
TABLE II Nonqonditioned Passive Avoidance Test in Rats Compound Dose (mg/kg) Result N-[3-(3-cyanopyrasolo(1,5-aJpyrimidin7-yl) phenyl]-N-ethylpropanamide 0.4 Active N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin7-v 1)phenyl]-N-ethylacetamide 0.8 Active N-ethyl-N-(3-pyrazoloi1,5-aJpyrintxdin7-ylpheny1)acetamide 25.0 Active N-[3-(3-chloropyrasoloi1?5-a]pyrimidin-7-y1) phenyl]-N-ethylacetamide 3.1 Active N-[3-(3-cyanopyrazalo(1,5-a]pyrimidin7-yl) phenyl]-N-propylacetamide 1.5 Active [3-(3-cyanopyrazoIo(1, 5-a]pyrimidin-7yl)phenyl]methylcarbamic acid, methyl ester 3.1 Active -9TA3LE II (continued) Compound Dose (mg/kg) Result [3-(3-cyanopyrazoloi1,5-a]pyrimidin-7yl )phenyl Jethyl carbamic acid,» methyl ester 12.5 Active (3-(3-chloropyrazolo(1,5-aJpyrimidin7-y1)phenyl Jethylcarbamic acid, ethyl ester 25.0 Active N-[3-(3-cyanopyrazolo(1,5-aJpyrimidin7-yl)phenyl]-N-2-propenylacetamide 3.1 Active N~[3»(3-cyanopyrazolo[1,5-aJpyrimidin7-yl)phenyl]-N-2-propynylacetamide 1.5 Active N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin7-y1)phenyl]-N-methy1propanamide 6.2 Active N-[3"(3-cyano-2-methylpyrazolo(l,5-a Jpyrimidin-7-yl) phenyl]-N-methylpropanamide 25.0 Active 7-[3-(acetyImethylamino)phenylJpyrazoloi 1,5-a]pyrimidine-3-cartooxylic acid, ethyl ester 25.0 Active N~[3-(3-cyanopyrazolo(l,5-aJpyrimidin7-yl)phenyl]-N-methylacetamide 1.5 Active N-[3-(3-chloropyrazolo[l,5-a]pyrimidin-7-yl)phenyl]-N-methylacetamide 3.1 Active N-[3-(3-cyanopyrazolo[l,5-aJpyrimidin7-yl)phenyl]-N-methyIcyclobutanecar- boxamide 25.0 Active Another test utilized for che determination of anxiolytic activity is the measurement of the ability of test compounds to inhibit the binding of tritiated benzodiazepines to brain-specific receptors of warm-blooded animals. A modification of the method described by R. F. Squires, etal.. Nature, 266, No. 21, p. 732 (April -101977) and H. Mohler, et al., Science. 198, p. 849 (1977) was employed.
Male albino rats (Miscar strain, weighing 150200 g each) were obtained from Royalhart Farms. 3H-Methyldiazepam (79.9 Ci/mmol) and 3H-methylflunitrazepam (84.3 Ci/mmol) were obtained from New England Nuclear.
The test compounds were solubilized in either dimethylforraaraide, acetic acid, ethanol or hydrochloric acid.
Whole cortex of rats was homogenized gently in 20 volumes of ice-cold 0.32 M sucrose, centrifuged twice at 1000 g for 10 minutes and then recentrifuged at 30,000 g for 20 minutes to produce a crude P2~synapcosomal fraction. The P?~£raccion was either: (1) resuspended in twice the original volume in hypotonic 50 mM Tris.HCl (pH 7.4), or (2) resuspendedin one-half the original volume in hypotonic 10 mM Tris.HCl (pH 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.
The binding assay consisted of 300yl of the P2"fraction suspension (0.2-0.4 mg protein), 100 yl of test drug and 100 yl of 3H-diazepam (1.5 nM, final concentration) or 3H-flunitrazepam (1.0 nM, final concentration) which was added to 1.5 ml of 50 mM Tris.HCl (pH 7.4). Nonspecific binding controls and total binding controls received 100 yl of diazepam (3 M, final concentration) and 100 yl 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 Whatman GF/C glass fiber filters. The filters were washed twice wich 5 ml of ice-cold 50 mM Tris.HCl (pH 7.4) and placed in scintillation vials. After drying at 5O~6O°C for 30 minutes, 10 ml of Beckman Ready-SolvT^ HP (a high performance pre-mix scintillation cocktail, registered trademark of Beckman Instruments, Inc., Irvine, CA 92713) was added and che radioactivity determined in a scintillation counter. -11Inhibition 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.
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-7y1)phenyl]-N-ethylpropanamide* 83 N-[3-(3-cyanopyrazolo(1 * 5-a3 pyrimidin-7yliphenyl]-N-qthylacetaraide 79 N-[3"(3-chloropyrazolo[1, 5-a]pyrimidin-/yliphenylJ-N-ethylacetarnide 97 N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-7v1i phenyl]-N-propylacetaraide 64 7-[3-[ethyl(1-oxopropy1)amino]phenyl]pyrazolo[lg5-a]pyriraidine~3-carboxylic acid, ethyl ester 100 [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl) phenyl lmethyl carbamic acid, niethyl ester 87 7-(3-[(methoxycarbonyl)methylamino]phenyl]pyrazoloE1,5-a]pyrimidine~3-carboxylic acid, ethyl ester 98 [3-(3-cyanopyrazolo[1„5-a]pyrimidin-7~yl)phenyllethyIcarbamic acid, methyl ester 55 7-[3-[ethyl (methoxycarbonyl)amino]phenyl]- pyrazoloi1,S-alpyrimidine-3-carboxylic acid, ethyl ester 99 -12TABLE III (continued) Compound % Inhibition [3-(3-cyanopyrazolo(1,5-aj pyriraidin-7-y1)phenyl]methylcarbamic acid, ethyl ester 41 ethyl (3-pyrazolo(1,5-a]pyrimidin-7-yl~ phenyl)carbamic acid,, ethyl ester 61 (3-(3-cyanopyrazolo[1e5-aJpyrimidin-7-yl)phenylJethylcarbaxnic acid, ethyl ester 63 (3-(3-chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]ethylcarbamic acid, ethyl ester 78 N-[3-( 3-cyanopyrazoloi 1,5-ajpyrimidin-7yl) phenyl]-N-2-propenylacetamide 78 N-[3-(3-cyanopyrazolo(1,5-a]pyrimidin-7~ yl)phenyl]-N-2-propynylacetamide 91 N-[3-(3~cyano~2-methylpyrazolo(1,5-a ] pyrimidiri-7-yl) phenyl]propanamide 42 N-[3-(3-cyanopyrazolo[1e5-ajpyrimidin-7yl) phenyl]-N-methylpropanamide 79 N-[3-(3-cyano-2-methylpyrazolo[1,5-aJpyrimidin-7-yl)phenylj-N-methyIpropanamide 95 N-methyl-N-(3-pyrazolo[1,5-ajpyrimidin-7yIpheny1)acetamide 54 7-(3-( acetyImethylamino)phenyl]pyrazoΙοί 1,5~a]pyrimidine-3~carboxylic acid, ethyl ester 100 N-[3-(3-cyanopyrazolai1,5-a]pyrimidin-7y1) phenyl]-N-methylacetaraide 73 N-[3-(3-chloropyrasolo(1,5-a]pyriraidin-7yl)phenyl]-N-methylacetamide 71 N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7- yI) phenyl]-N-methylcyclobutanecarboxamide 81 -13TABLE III (continued) Compound % Inhibition N-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-7yl)phenyl]-N-methylcyclopropanecarboxamide 83 7-(3-( (cyclopropylcarbonyl)methylamino]phenylpyrazolofl„5-a]pyrimidine-3-carboxylic acid, ethyl ester 95 7-(3-(acetylethylamino)phenyl]pyrazolo[1.5-ajpyrimidihe-3-carboxylic acid, ethyl ester 97 7-[3-(acetylamino)phenyl]pyrazolo[1,5-a ] ~ pyrimidine-3-carboxylic acid, ethyl ester 85 7-[3-[(methoxycarbonyl)amino]phenyl]pyrazolofl,5-a]pyrimidine-3-carboxylic acid, ethyl alter 76 methyl(3~pyrazolo[1,5-e]pyr imidin-7-y1phenyl)carbamic acid, methyl ester 45 7 -(3-(acecyIpropylamino)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester 97 [3-(3-chloropyrazolo[1,5-a]pyrimidin-7 yl) phenylJmethylcarbamic acid, methyl ester 92 7-(3-((cyclobutylcarbonyl)amino]phenyl]pyrazolofl.5-aJpyrimidine-3-carboxylic acid, ethyl ester 82 The novel compounds of this invention have also been shown to have skeletal muscle relaxant activity through 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 treated orally with graded doses of test compounds or vehicle and placed on a wire mesh screen (inclined at an angle of 60° from a horizontal level) 65 minutes later.
The number of rats falling off the screen within 30 minutes -14was recorded. Tne ED50 (dose necessary co cause 50% of the animals tested to fall off) was calculated according to the linear arcsine transformation method of Finney.
D. J.»’’Statistical Methods in Biological Assay, 2nd Ed.» Hafner, Ν. 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 ED 50 (mg/kg) ..... N-[3 ~(3-cyanopyr azolo[l,5-a]pyrimidin7-y1)pheny1]-N-ethy1pr opanam i de 4.6 N-[3~(3~cyanopyrazolo[l,5-a]pyrimidxn7-yl)phenyl]-W-ethylacetamTde 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 compounds on the locomotor activity in rats. 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 linear regression equation. The -15test 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-7yl)phenyl]~N-echylpropanamTde 2.0 N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7= yl)phenyl]-N-echylacetamide 1.4 Tbe 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 0.1 mg co about 20.0 mg/kg of body weight per day. A preferred dosage regimen for optimum results would be from about 0.5 mg co about 10.0 mg/kg of body weight per day.
Dosage units are employed such that a total of from about 10 co about 700 rag of active compound for a subject of 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 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 co the present invention having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from 0.107, co 10.OX by weight of active compound in a vehicle consisting of a polyhydric aliphatic alcohol or mixtures thereof. Especially satisfactory are glycerin, propylene glycol, and polyethylene glycols. The polyethylene glycols consist of a mixture of nonvolatile, normally liquid, polyethylene -16glycols which are soluble in both water and organic liquids and which have molecular weights of from about 200 to 1500. Although the 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% to 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 frora 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, myriscyl-gamma-picolinius chloride, benzalkonium chloride, phenethyl alcohol, pchlorophenyl-alpha-glycerol ether, methyl and propyl parabens, and thimerosal. As a practical matter, 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, Che 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 intra venous 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 che -17food of the diet. For oral therapeutic administration, the active compounds may ba incorporated wich excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Additionally, the active ingredient may be incorporated wich che proper pharmaceutical carrier or carriers known in the art co produce a sustained-release tablec 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 chat a suitable dosage will be obtained.
The tablets, troches, pills, capsules and the like may also contain one or more of che following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients 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 agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of che above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify che physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially nontoxic in the amounts employed. -18The following non-limiting examples illustrate J th® preparation of representative compounds of the present invention. <> Example 1 Ν-[3-(3-(Dimethylamino)-l-oxo-2-propenyl]phenyl]5 propanamide A 20 g portion of 3-acetylphenyl)propanamide in 50 ml of dimethylformamide dimethylacetal was refluxed for 8 hours? then evaporated. The residue was taken up in 200 ml of dichloromethane? passed through hydrous magnesium 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 VI? were prepared.
TABLE VI Ex. Starting Material Amide 2 N-(3-acetylphenyl)ethanamide N-[3-(3-dimethylamino)-1oxo-2-propeny1) phenyl]acetamide 3 (3-aeetylphenyl)carbamic acid? methyl ester [3-(3-(dimethylamino)-1oxo-2-propeny1]phenyl]carbamic acid? methyl ester 4 (3-acetylphenyl)carbamic acid? butyl ester [3-(3-(dimethylamino)-1oxo-2-propenyl]phenyl]carbamic acid? butyl ester 5 N-(3-acetylphenyl )- butanamide M~[3-(3-(dimethylamino)-1oxo-2-propenyl]phenyl]- butanamide -19Example 6 N~[3-[3-(Dimethylamino)-l-oxo-2-propenyl]phenyl-Nethylptopanamide A mixture of 3.47 g of N~[3-[3"(dimechylamino)l-oxo-2-propenyl]phenylIpropanamide and 0.68 g of 60% sodium hydride in oil in dimethylformamide was stirred for 0.5 hour under argon, then cooled in an ice bach and a solution of 2.4 g of ethyl iodide in 10 ml of dimethylformamide was added in small portions. The mixture was then stirred ac room temperature for 0.5 hour and extracted three times with hexane. The extracts were discarded, water was added and this mixture extracted with dichloromethane. This extract was evaporated and the residue crystallized from hexane giving the desired compound, mp 105-107°C.
Following the procedure of Example 6 using the compounds of Examples 1-5 and appropriate alkyl halides. 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)-1-OXO-2propenyl]phenyl]-N-echylacetamide 110-113 8 1 N-[3-[3-(dimethylamino)-1-oxo-2propenyl]phenyl]-N-mechylpropanamide 148-149 9 2 N-[3-[3-(dimethylamino)-l~oxo-2propenyl]phenyl]-N-propylacetamide 110-112 -20TABLE VII (continued) Ex. Starting Material of Ex. Alkylated Amide MP °C 10 3 [3-[3-(dimethylamino)-l-oxo-2-propenyl ]phenyljmechylcarbamic acid, methyl ester 93-95 11 3 [3-[3-(dimethylamino)-1-oxo-2-propenyl Iphenyl]ethylcarbamic acid, methyl ester 95-97 12 L 2 N-[3-[3-(dimethylamino)-1-oxo-2propenyl]phenyl]-N-methylacetamide 140-148 Example 13 M-[3-(3~Cyanopyrazolo[l,5-a]pyrimidin-7-yl)pheny1]-Nethylpropanamide A mixture of 0.54 g of 3-araxno-4~pyrazolecarbonitrile and 1.37 g of N-[3-[3-(dimethylamino)-l-oxo-2propenylJ phenyl]-N-ethylpropanamxde in 50 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed. The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was separated, dried, passed through a pad of hydrous magnesium silicate and hexane was added to the refluxing filtrate. The mixture was then cooled and the solid collected, giving 1.3 g of the desired product, mp 161-162°C.
Following che procedure of Example 13 and using appropriately substituted 3-amino-pyrazoles together with the indicated intermediates, che products of Examples 14-37 found in Table VIII were prepared.
TABLE VIII Ex . Intermediate of Ex. 3-Amino- pyrazole Product MP°C 14 7 3- aminopyra2ole- 4- carbon!trile N-( 3-i 3-cyanopyrazoloi 1., 5-a Ipyrimidin-7-yl)phenyl]-Nethylacetaraide 186.-1 Θ 7 15 7 3-aminopyrazole N-ethyl-N-ί3-pyrazolo(1, 5-aJ- pyrimidin-7-yIphenyl)acetamide 115-11.7 16 9 3-aminopyrazole N-propyi-N-i3-pyrazolo[1, 5-aJpyrimidin-7-y1pheny1)ace tam i de 90-92 17 9 3- aminopyrazole- 4- carbonitrile N-f 3-(3-cyanopyrazolo[1,5-a]pyrimidi.n-7-yi iphenyl ]-N- propylacetami.de .151-153 1.8 6 ethyl-3-amino- pyrazole-4- carboxylate 7-(3-{ethylί Ϊ-oxopropyl )aminoIphenyl Jpyrazolo( 1., 5-ajpyrinidine-3-carboxylie acid, ethyl ester 124-126 19 10 3- aminopyrazole- 4- carbonitrile ί3-(3-cyanopyrazoloi1,5-a]pyrimidin-7-y1 iphenyl ] me thylcarbamic acid, methyl ester 160-1.70 TABLE VIII (continued) EX a Intermediate of Ex. 3-Aml.R0- pyrazole Product MP°C 20 10 ethy1-3-aminopyrazole-4- carboxylate 7-(3-((methoxycarbonylJmethylamino(phenyl(pyrazolof1,5-a(pyr im id i ne-3-carboxy11c acid, ethyl ester 115-116 21 3 3- aminopyrazole- 4- carbonitrile ( 3-( 3-cyanopyrazolof 1 , 5-a (pyrim.idin-?-yl}phenyl (carbamic acid, methyl ester 256-250 22 4 3- aminopyrazole- 4- carbonitrile (3-(3-cyanopyrazoloi1,5-aJpyrimidin-7-yl) phenyl(carbamic acid, butyl ester 13.1-133 23 1 3-aminopyrazole N-[3-(pyrazolol1,5-a(pyrimidin-7-yl)phenyl(propanamide 177-170 24 I 3- aminopyrazole- 4- carbonitrile N-( 3-( 3-cyanopyrazoloi .1,5-a (pyrimidin-7-yl(phenyl(propanamide 202-204 25 1 3-amino-5-methylpyrazole-4- carboni trile N-(3-(3-cyano-2-methylpyrazoIqJ1,5-a(pyrimidin-7-yl)phenyl(propanamide 177-178 TABLE VIII (continued) Ex . j ; intermediate i of Ex. 3-Amino- pyrazole Product MP°C 2 6:! 8 i 3- aminopyrazole- 4- carbonitri1e N-[3-(3-cyancpyrazoloi1,5-a)pyrimidin-7-yl) phenyl ]-Mime thy lpropanamide 27 8 3-amino-5-meth- ylpyrazole-4- carbonitrile N-(3-(3-cyano—2-methyipyrazolofl,5-aJpyrimidin-7-yl)phenyl]-M-methylpropanamide 184-166 2 05 3- aminopyrazole- 4- ca rbonitri1e N-{3-{3-cyanopyrazoloI1,5-a)pyrimidin-7-yi) phenylJbutanamide 138-140' 29 12 3- aminopyrazole- 4- carbonitrile 3-( 3-cyanopyrazolo[ .1., 5-a ] pyrimidin-7-y1)phenyl)-Nmethylacetamide 195-197 30 2 3- aminopyrazole- 4- carbonitrile N-[3-(3-cyancpyrazoloi1,5-a Jpyrimidine-7-yl) phenyl )acetamide 257-259 31 12 3-aminopyrazole N-methyl-N-(3-pyrazolof1,5-afpyrimidin-7-ylphenyl)acetamide 116-120 TABLE VIII (continued) EX ε Intermediate of Ex. 3-Amino- pyrazole Product MP°C 32 12 ethy1-3-amino- pyrazole-4- carboxylate 7-f 3-{ace tyIme thy1ami no)phenyl]pyrazolo(1,5-aJpyrimidine-3-carboxyiic acid, ethyl ester 155-156 33 7 3-amino-4-carboe thoxypyrazole 7-(3-{acetylethylamino)phenyl Jpyrazolot 1,5-a J pyr imi.dine-3-carboxylic acid, ethyl ester 147-140 34 2 3-amino-4-carbo- e thoxy py ra zo 1. e 7-f3-(acetylaminoiphenyl]pyrazolof .1,5-a]pyrimidine-3carboxylic acid, ethyl ester 202-204 35 3 3-amino-4-carboethoxypyrazole 7-(3-((methoxycarbonyliamino]phenyl(pyrazolofϊ,5-aJpyrimidine-3-carboxylic acid, ethyl, ester 107-188 36 1.Q 3-aminopyrazole methyl (3-pyrazolo{1,5-aJpyrimidin-7-ylphenyl.)carbamic acid, methyl ester 107-109 37 9 3-amino-4-carboethoxypyrazole 7-[3-{ace ty1propy1am i no 1phenylfpyrazoloj1,5-aJpyrimidine-3-carboxylic acid, ethyl ester 156-157 -25Example 38 Ν- [ 3-(3-Chloropyrazolo[1,5-a]pyrimidin-7-y1)phenyl]-Nethylacetamide A mixture of 1.0 g of N-ethyl-N-(3-pyrazolo(1,5-aJpyrimidin-7-yIpheny1)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 157-15S°G.
Example 39 7-(3-(Ethy1(me thoxycarbony1)amino]pheny1Ίpyrazo1o [1,5-a]pyrimidine-3-carboxylic acid, ethyl ester A 12.41 g portion of (3-[3~(dimethylamino)-l-oxo2- propenylIphenyl]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 Jethylcarbamic 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 117-119Oc.· Example 40 (3-(3~Cyanopyrazolo(1,5-a]pyrimidin-7-ylIphenyl]ethylcarbamic, acid, methyl ester A 2.76 g portion of (3-[3-(dimethylamino)-1-oxo2-propenylIphenyl]ethylcarbamic acid, methvl 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 1S2~164°C. -26Example 41 [3-(3-Cyanopyrazolo{1? 5-aJpyrimidin-7-yl)phenyl]methylcarbamic acid? ethyl _ester l-Acetylphenyl-3-carbaraic acid? ethyl ester was converted to E3"(3"(dimethylaraino)"l-oxo-2--prapenyl jphenyl Jcarbamic acid? ethyl ester by the procedure of Example 1 and this ester was then reacted with methyl iodide? again by the procedure of Example 6? giving (3-(3-(dimethylamino)-1-oxo-2-propenyl]phenyljmethy1carbamic 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 2.09 g of the.desired compound? mp 140-142°C.
Example 42 Ethyl (3-pyrazolo[l?5-aJpyrimidin-7-ylphenyl)carbaroic acid? ethyl ester [3-(3-(Dimethylamino)-1-oxo-2-propenylJphenyI]carbamic acid was rented with ethyl iodide by the procedure of Example 6? giving (3-[3-(dimethylamino)-l-oxo2-propenyl]phenylJethylcarbamic acid? ethyl ester.
A 2.9 g portion of the above ester was reacted with 0.83 g of 3-aminopyrazole by the procedure of Example 13? giving 2.27 g of the desired product? mp 7981°CExample 43 (3-(3-Cyanopyrazolo(1?S-aJpyrimidin-7-yl)phenyl ]25 ~--- ’ --~------"ethylcarbamic acid? ethyl ester A 2.0 g portion of [3-[3-(dimethylamino)-1-oxo2-propenylJ phenylJethylcarbamic acid? ethyl ester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13? civinc 2.52 g of the desired 30 product? mp 133-135°C. -27Example 44 ' (3-(3-Chloropyrazolo(1e5-a]pyrimidin-7-y1) phenyl]ethyl carbamic acid,, ethyl eater A 1.55 g portion of ethyl ( 3-pyrazolo( 1 k. 5-a] pyriraidin-7-ylphenyI)carbamic acid„ ethyl ester in 50 ml of dichloromethane was reacted with 1-chlorobenzotrxazole for 30 minutes^ giving 1.29 g of the, desired products mp 100-102©C.
Example 45 N- [3-(3-Cyanopyrazolo[1? 5-a]pyrimidin-7-yl)phenyl]-N2-propenylacetamide An 11.61 g portion of N-[3-[3-(dimethylamino)l-oxo-2-propenyl3phenyl]acetamide was reacted with 7.26 g of allyl bromide as described in Example 6„ giving 13.34 g of N-(3-[3-(diraethylamxno)-l-oxo-2-propenyl]phenyl]-N-2propenylacetamide(, 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 tha desired compounds, mp 135~137°C.
Example 46 N-[3-(3-Cyanapyrazolo(l,5~a]pyrimidin-7-yl)pheny1]-N-2-propynylace tam ide An 11.61 g portion of Ht-( 3-[3-(dimethylamino)1-oxo-2-propenyl]phenyl]acetamide was reacted with propy nyl bromide as described in Example 6, giving N-[3-(3(dimethylamino)-l-oxo-2-propenyl]phenyl]-N-2-propynylacetamide,, mp 98-101°C.
A 2.7 g portion of the above intermediate was reacted with 1.08 g of 3-aminopyrazole"4-carbonitrile as described in Example 13, giving 1.90 g of the desired product,, mp 193-195°C. -28Example 47 N-Butyl»N-[3-(3~cyanopyrazolo[1,5~a]pyrimidin-7-yl)phenyl]acetamide An 11.61 g portion of [3-[3-(dimethylamino)-1oxo-2-propenyljphenyl]carbamic acid, methyl ester 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-(dimethylamino) -l-oxo~2-propenyl]phenyljacetamide.
A 2.88 g portion of the above intermediate was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile by the procedure of Example 13, giving 1.61 g of the desired product, mp I46~148°C.
Example 48 N-[3-(3-Cyanopyrazolo[1,5-a] pyrimidin-7-yl)phenyl]-Nmethylearbamic acid, butyl ester An 11.61 g portion of [3-[3-(dimethylamino)-loxo-2-propenyl]phenyl]carbamic acid, butyl ester was reacted with 6.82 g of methyl iodide by che procedure of Example 6, giving 11.67 g of [3-[3-(dimethylamino)-1-oxo2-propenyl]phenyl]methylcarbamic acid, butyl ester.
A 3.04 g portion of the above ester was reacted with 1.08 g of 3-aminopyrazole-4-carbontirile as described in Example 13, giving 2.3 g of the desired product, mp 96-97°C.
Example 49 N-[3-(3-Chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-Nmethylacetamide 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 163165OC. -29Example 50 [3-(3-Chloropyrazolo[1,5-a]pyr imidin-/-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.
Example 51 7-[3~[(Cyclopropylcarbonyl)methylamino]phenylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester N-(3-Acetylphenyl)cyclopropanecarboxamide was prepared by che reaction of m-aminoacetophenone, diisopropylethylamine and cyclopropanecarboxylic acid chloride in dichloromethane.
This compound was then converted to N~[3~[3(dimethylamino)-l-oxo-2-propenyl(phenyl(cyclopropanecarboxamide by che procedure of Example 1 and then alkylated by che procedure of Example 6, using methyl iodide, giving 10.17 g of N~[3~(3-diraechylamino)-l-oxo-2-propenyl)phenyl]N-raethylcyclopropanecarboxamide, mp 120~122°C.
A 0.54 g portion of this compound was reacted as described in Example 13 with 3-aminopyrazole-4-carbonitrile, giving 1.08 g of che desired product, mp 178180°C.
Example 52 7-[3-[(Cyclopropylcarbonyljmethylamino]phenyIpyrazolo[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester A 0.73 g portion of ethyl 3-aminopyrazole-4-carboxylate and 1.36 g of N-[3-[(3-(dimethylamino)-l-oxo-2propenyl(phenyl]-N-methyIcyclopropanecarboxamide were reacted as described in. Example 13, giving 0.52 g of the desired product, mp 122-124°C. -30Example 53 N-ί 3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-y1) phenyl 1-Nme t hy 1 cy c l obu tanecarboxami de m-Aminoacetophenone, cyclobutanecarboxylic acid, chloride and diisopropylethylamine in dichloromethane were reacted, giving N-(3-acetylphenyl) cyclobutanecarboxasnide.
This compound was then converted to N-[3-[35 (dimethylamino)-1-oxo-2-propenylIphenylJcyclobutanecarboxamide, mp 155~X57°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)X-oxo-2-propenyl]phenyl)-N-methylcyclobutanecarboxamide, mp 117-119°C.
A 0.54 g portion of 3~aminopyrazole-4~carbonitrile 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-(3-((Cyclobutylcarbonyl) aminoIphenylJpyrazolo[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester A 0.78 g portion of 3-amino-4-carboethoxypyrazole and 1.36 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]20 phenylIcyclobutanecarboxamxde were reacted as described in Example 13, giving 1.52 g of the desired product, mp 123125°C.

Claims (9)

1.CLAIMS 1. A compound of the formula: wherein R^ is selected frcm the group consisting of hydrogen, halogen, cyano and - C ·· R ‘4 R 2 is selected from the group consisting of hydrogen and alkyl(Cj-Cg); Rg is li R^ is selected from the group consisting of hydrogen, alkyl(C^-Cg) and alkoxy^-Cg); R 5 is selected from the group consisting of hydrogen, alkyl(C^-Cg), alkenyl(C^-Cq), -CH 2 C=CH, cycloalkvl(C 3 -C 6 )methyl, -C^OCHg and -CH 2 CH 2 0CHg; and Rg is selected from the group consisting of alkyl (CpCg), cvcloalkyl (Cg-Cg) , -O-alkyl(Cj-Cg), -HHalkyl(C 1 -Cg) „ -N-dialkyKq-Cg). -(CH^-O-alkyUCpCg). -(CH 2 ) n -NH~alkyl(Cj-C 3 ) and -(CH^-H-dialkyKCpCg), - 32
2. A compound according to Claim 1, wherein Rj is cyano or 5 - C - R 4 ; R 2 is hydrogen, R^ is alkyl(Cj-Cg); Rg is alkyl(C-pCgj, alkenyl(C 2 »Cg) or -CH 2 C=,CH; and Rg is alkyl(Cj-Cg), cycloalkyl(Cg-Cg) or -0-alkyl(C^-Cg).
3. The compound according to Claim 2, which is selected from the group consisting of: jT~[3-(3-cyanopyrazolo[l ,5-a.]pyrimidin-7~yl)phenyl]“N~ethylpropanamide; IM-[3-(3~cyanopyrazolo[X,5~a]pyrimidin-7-yl)phenyl]-N-ethylacetamide: N~[3-(3-cyanopyrazolo[l,5-a]pyrimidin~7-yl)phenyl]~ji-propylacetamide: 20 [3-(3-cyanopyrazolo[l s 5-a.]pyrimidin-7yl)phenyl]methylcarbamic acid, methyl ester; 7-[3-[methoxycarbonyl)methylamino]phenyl]pyrazolo[l ,5-aJpyrimidine3-carboxylic acid, ethyl ester; [3-(3-cyanopyrazolo[l,5-aJpyrimidin-7-yl)phenyl]ethylcarbamic acid, methyl ester; ethyl(3-pyrazolo[l,5-a]pyrimidin-7-yl-phenyl)carbamic acid, ethyl ester; 30 [3-(3-chloropyrazolo[l,5~a]pyriniidin-7-yl)phenyl]ethylcarbamic acid, ethyl ester; N.-[3-(3-cyanopyrazolo[l,5-a]pyrimidin-7-yl ) phenyl]~N-2-propenylacetamide; - 33 N-[3-(3-cyanopyrazolo[l ,5-a]py rilT, idin-7-yl)phenyl]-N-2-propynv]acetamide; and N-[3-(3-cyanopyrazolo[l, 5-aJpyrimidin-7-yl )phenyl ]-N-methylacetamide. 5
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 1 for the manufacture of a 10 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. 15
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 20 pharmaceutically acceptable carrier.
9. A process for producing the product of Claim 1, which comprises the steps of 25 (a) reacting a 1-acetylphenyl-3-amide of the formula: with dimethylformamide, dimethylacetal at reflux, which produces an 35 N-[3-[3-(dimethylamino)-l-oxo-2-propeny 1 lphenyl ]alkanamide; (b) reacting the N.-[3-[3-(dimethylamino)-l-oxo-2-propenyl] phenyl]alkanamide with sodium hydride, which produces an anion; (c) reacting the anion generated with an alkyl halide of the formula R^-X, wherein X is Br or I, which produces an N_-[3-[3-(dimethylamino)l-oxo-2-propenyl]phenyl]-N-alkylalkanamide of the formula: (d) reacting the N-[3-[3-dimethylamino)-l-oxo-2-propenyl]phenyl]-N.alkvlalkanamide with a 3-aminopyrazole of the formula: in glacial acetic acid at reflux, which reaction gives the desired products. ί ' 25 IO- 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
IE124786A 1985-05-13 1986-05-12 [7-(3-disubsituted amino)phenyl]pyrazolo[1,5 delta]pyrimidines IE61755B1 (en)

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