CA1270825A - ¬7-(3-disubstituted amino)phenyl|-pyrazolo¬1,5- a|pyrimidines - Google Patents
¬7-(3-disubstituted amino)phenyl|-pyrazolo¬1,5- a|pyrimidinesInfo
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- CA1270825A CA1270825A CA000508783A CA508783A CA1270825A CA 1270825 A CA1270825 A CA 1270825A CA 000508783 A CA000508783 A CA 000508783A CA 508783 A CA508783 A CA 508783A CA 1270825 A CA1270825 A CA 1270825A
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- Prior art keywords
- phenyl
- alkyl
- pyrimidin
- cyanopyrazolo
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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
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- 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
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- 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
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- 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
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- 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
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- 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)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
[7-(3-DISUBSTITUTED AMINO)-PHENYL]PYRAZOLO[1,5-a]-PYRIMIDINES
ABSTRACT OF THE DISCLOSURE
Novel [7-(3-disubstituted amino)phenyl]pyrazolo-[1,5-a]pyrimidines useful as anxiolytic, antiepileptic and sedative-hypnotic agents as well as skeletal muscle relaxants, methods of using these compounds, compositions of matter containing them and processes for their production.
ABSTRACT OF THE DISCLOSURE
Novel [7-(3-disubstituted amino)phenyl]pyrazolo-[1,5-a]pyrimidines useful as anxiolytic, antiepileptic and sedative-hypnotic agents as well as skeletal muscle relaxants, methods of using these compounds, compositions of matter containing them and processes for their production.
Description
~ ~e~
29,~95 [7-(3-DISUBSTITUTED
AMINO)PHENYL~-PYRAZOLO[1,5-a]PYRIMIDINES
SUMMARY OF THE INVENTION
-This invention relates to new organic compounds which are [7-(3-disubstituted amino)phenyl]pyrazolo-[1,5-a~pyrimidines, which are useful as anxiolytic and antiepileptic agents as well as sedative-hypnotic agents and skeletal muscle relaxants. This invention also re-lates to the methods of using the novel compounds, to compositions of matter containing them as the active in-gredient and to processes for their production.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of this invention are repre-sented by the following structural formula:
,~\N~R2 I R
:S ~J,_~ L
~i~
wherein Rl is select~d from the group consisting of:
hydrogen, halogen, cyano and -C-R4; R2 is selected from the group consisting of hydrogen and alkyl(Cl-C3); R3 ; ~4 is selected from the group consisting of hydrogen, alkyl(Cl-C6) and ~lkoxy(Cl-C6); Rs is selected from the group consisting of hydrogen, alkyl(Cl-C6), alkenyl-S (C2-C6), -CH~C-CH, cycloalkyl(C3-C6)methyl, -CH20CH3 and -C~2CH20CH3; and R6 is selectet from the group consisting of alkyl(Cl-C6), cycloalkyl(C3-C6), -0-alkyl(Cl-C6), -NH-alkyl(Cl-C3), -N-dialkyl(Cl-C3), -(CH~)n-O-alkyl(Cl-C3), (cH2)n-NH-alkyl(cl-c3) and ~~CH2)n~N~dialkYl(cl 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 Rl is cyano or -C-R4; R2 is hydrogen; R4 is alkyl(Cl-C6);
~0 Rs is alkyl(Cl-C6), alkenyl(C2-C6) or -CH2~CH; and Rs is alkyl(Cl-C6), cycloalkyl(C3-C6) o~ -0-alkyl(Cl-C6).
The instant invention is additionally concerned with ehe 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 ^ompositions of matter containing the above-described compounds and with processes for producing the compounds.
~7~t~tP
The novel compounds of this invention may be readily prepared as set ~orth in the following reaction scheme:
o CH3-~ (/ ~> (1) I~MF-acetal \ _ ~0 ( 2 ) NaH; Rs-X
~ (X = Br, I ) (1) (CH3)2NC~=CHC ~
o
29,~95 [7-(3-DISUBSTITUTED
AMINO)PHENYL~-PYRAZOLO[1,5-a]PYRIMIDINES
SUMMARY OF THE INVENTION
-This invention relates to new organic compounds which are [7-(3-disubstituted amino)phenyl]pyrazolo-[1,5-a~pyrimidines, which are useful as anxiolytic and antiepileptic agents as well as sedative-hypnotic agents and skeletal muscle relaxants. This invention also re-lates to the methods of using the novel compounds, to compositions of matter containing them as the active in-gredient and to processes for their production.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of this invention are repre-sented by the following structural formula:
,~\N~R2 I R
:S ~J,_~ L
~i~
wherein Rl is select~d from the group consisting of:
hydrogen, halogen, cyano and -C-R4; R2 is selected from the group consisting of hydrogen and alkyl(Cl-C3); R3 ; ~4 is selected from the group consisting of hydrogen, alkyl(Cl-C6) and ~lkoxy(Cl-C6); Rs is selected from the group consisting of hydrogen, alkyl(Cl-C6), alkenyl-S (C2-C6), -CH~C-CH, cycloalkyl(C3-C6)methyl, -CH20CH3 and -C~2CH20CH3; and R6 is selectet from the group consisting of alkyl(Cl-C6), cycloalkyl(C3-C6), -0-alkyl(Cl-C6), -NH-alkyl(Cl-C3), -N-dialkyl(Cl-C3), -(CH~)n-O-alkyl(Cl-C3), (cH2)n-NH-alkyl(cl-c3) and ~~CH2)n~N~dialkYl(cl 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 Rl is cyano or -C-R4; R2 is hydrogen; R4 is alkyl(Cl-C6);
~0 Rs is alkyl(Cl-C6), alkenyl(C2-C6) or -CH2~CH; and Rs is alkyl(Cl-C6), cycloalkyl(C3-C6) o~ -0-alkyl(Cl-C6).
The instant invention is additionally concerned with ehe 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 ^ompositions of matter containing the above-described compounds and with processes for producing the compounds.
~7~t~tP
The novel compounds of this invention may be readily prepared as set ~orth in the following reaction scheme:
o CH3-~ (/ ~> (1) I~MF-acetal \ _ ~0 ( 2 ) NaH; Rs-X
~ (X = Br, I ) (1) (CH3)2NC~=CHC ~
o
(2) R5 o R 6 ~ R 2 \1~ H2 R
N ~ ~ R2 (3) Rl N
(4) In accordance with the above reaceion scheme a 1-acetylphenyl-3-amide (1~, where R6 is as described above is reacted with dimethylformamide dimethylacetal at reflux giving an N-[3-~3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-alkanamide, which is then reacted with sodium hydride, and ~ 2~ Z.~i the anion generated is reacted with an alkyl halide, where Rs is as described,~bove giving the N-[3-[3-(dimethylamino)--l-oxo-2-propenyl]phenyl]-N-alkylalkanamide (2). This compound is then reacted with a 3-aminopyrazole (3), wher~
Rl and R2 are as described above, in glacial acetic acid at reflux, giving tbe product (4).
Alternatively, N-[3-~3-(dialkylamino)-1-oxc-2-propenyl]phenyl~alkanamide (5) i5 reacted with a 3-amino-pyrazole (3) to give intermediate~ (6) which are reacted with a base such as sodium hyd~ide, sodium alkoxide and the like and an Rs^halide to give the products (4).
o (CH3)2NCH-CHC ~ +H-N ~ \ ~ R2 \=1/ H 2 ~ - R 1 (5) I
~ R6 ~ H_ I I R 6 Rs-halide y 21 ~N R
'~ ~'7~
The perrormance of the novel compounds of the present inventio~ in standard tests with laboratory ani-mals 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 agen~s. Furthermore, these compounds have been shown by biological data to be useful as antiepileptic agents, particularly in the treatment of grand mal epilepsy seizures~ and as sedative-hypnotic and skeletal muscle relaxant agents.
The an~i-anxiety and anticonvulsant properties of the novel compounds of the present invention have been established in a test which indicates anxiolytic and anti-epilep~ic activity by the measure of protection they pro-vide from convulsions resulting from the administration of pentylenetetrazole. Single or graded dose levels of the 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 with pentylenetetrazole at a dose of 23 mg/kg of body weight. This dose is estimated to cause clonic sei~ures 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 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 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 the present invention are shown in Table I.
TABLE I
_~tecti~ Linst Clon _ Seizures Caused by PentylenetetrazoLe in Rats . _ _ _ .
Dose ~ of Rats Compound(mg/kg) Protected , _ ~ . I
N-[3-(3~yanopyrazolo[1,5-a]py~imidin- 25.0 100 7-yl)phenyl]-N ethylpropanamide N-[3-(3-cyanopyrazolo[1,5-a~pyrimidin- 25.~ lO0 7-yl)phenyl]-N-ethylacetamide N-~3-(3-chloropyrazolo[l,5-a]pyrimi- 25.0 lOQ
din-7-yl)phenyl]-N-ethylacetamide N-[3 (3-cyanopyra~olo[1,5-a]pyrimidin- 6.25 100 7-yl)phenyl]-N-propylacetamide [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7- 3.1 25 yl)phenyl]methylcarbamic acid, methyl ester [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7- 12.6 75 yl)phenyljethylcarbamic acid, methyl ester N-butyl-N-[3-(3-cyanopyrazolo[l,5-a]- 25.0 50 pyrimidin-7-yl)phenyl]acetamide [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7- 25.0 25 yl)phenyl~ethylcarbamic acid, ethyl ester [3-(3-chloropyra2010[1,5-a]pyrimidin- 25.0 25 7-yl)phenyl]ethylcarbamic acid, ethyl ester N-[3-(3-cyanopyrazolo~1,5-a]pyrimidin- 25.0 100 7-yl)phenyl]-N-2-propenylacetamide N-[3-(3 cyanopyra2010[1,5-a3pyrimidin 6.25 100 7-yl)phenyl]-N-2-propynylacetamide TABLE I (continued) . ,. ..... , Dose ~ of Rats Compound (mg/kg) Protected ~,.,_ _ __ N-[3-(3-cyanopyrazolo~1,5-a]pyrimidin- 25.0 50 7-yl)phenyl]-N-methylcyclobutanecar-boxamide N-[3-(3-cyanopyrazolo~1,5-a]pyrimidin- 25.0 75 7-yl)phenyl]-N-methylcyclopropanecar-boxamide N- ~ 3 - ( 3-cyanopyrazolo[l,5~a]pyrimidin- 25.0 75 7-yl)phenyl]-N-methylacetamide N- ~ 3- t 3-chloropyrazolo[1,5-a3pyrimi- 12.5 50 din-7-yl)phenyl~-N-methylacetamide 7-~3-(acetylmethylamino)phenyllpyra- 25.0 100 zolo~l,5-a]pyrimidine-3-carboxylic acid, ethyl ester N- [ 3- ( 3-cyanopyrazolo[1,5-a]pyrimidin- 12.s 50 7-yl~phenyl]-N-~ethylpropanamide N-[3-(3-cyano-2-methylpyrazolo[l,5 a]- 25.0 lO0 pyrimidin-7-yl)phenyl]-N-methylpro-panamide Another test which has been used to assess anti-anxiety effects is a nonconditioned passive avoidance procedure described by J. R. Vogel, B. Beer and D. E.
Clody, "A Simple and Reliable Conflict Procedure for Testing Anti-Anxiety Agents", Psychopharmacologia, 21, 1-7 (1971). A conflict situation is induced in rats by a modifica~ion 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 administered in single or graded, oral or intraperitoneal doses, sus-pended in a 2% starch vehicle containing 0.5% v/v poly-ethylene glycol and one drop of polysorbate 80. Control animals received the vehicle alone. At 30 to 60 minutes each rat was placed in an individual plexiglass chamber.
Water ~as available ad libitum from a tap located in the rear of the chamber. A 0.7 milliampere DC shocking cur-rent wa~ 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 we~e 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 representa-tive compounds of this invention appear in Table II.
TABLE II
Noncondition d _ sive Avoidance Test in Rats Compound ~mg/kg) ~e~ul~
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin- 0.4 Active 7-yl)phenyl]-N-ethylpropanamide N-[3-~3-cyanopyrazolo[1,5-a]pyrimidin- 0.8 Active 7-yl)phenyl]-N-ethylacetamide N-ethyl-N-(3-pyrazolo[l,S-a]pyrimidin- 25.0 Active 7-ylphenyl)acetamide N-[3-(3-chloropyrazolo[1,5~a]pyrimi- 3.1 Ac~ive din-7-yl)phenyl]-N-ethylacetamide N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin- 1.5 Active 7-yl)phenyl]-N-propylacetamide [3 (3-cyanopyrazolo~1,5-a]pyrimidin-7- 3.1 Active yl)phenyl~methylcarbamic acid, methyl ~l~t7~
TA~LE I I ( c:ontinued) _ _.__ r Compound ~(mg/kg)~ Result ~ _ [3-~3-cyanopyra~olo[1,5-a]pyrimidin-7- 12.5 Active yl)phenyl]ethylcarbamiG acid, methyl ester [3-(3-chloropyrazolo~l,S-a]pyrimidin- 25.0 Active 7-yl)phenyl]ethylcarbamic acid, ethyl e~ter N~3-(3-cyanopyrazolotl,5-a]pyrimidin- 3.1 Active 7-yl)phenyl]-N-2-propenylacetamide N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin- 1.5 Active 7-yl)phenyl]-N-2-propynylacetamide N-13-(3-cyanopyrazolo[1,5-a]pyrimidin- 6.2 Active 7-yl)phenyl]-N-methylpropanamide N-[3-(3-cyano-2-methylpyrazolo[1,5-a]- 25.0 Active pyrimidin-7-yl)phenyl]-N-methylpropan-amide 7-[3-(acetylmethylamino)phenyl]pyra- 25.0 Active ~olo[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester N-[3-(3-cyanopyrazolo~1,5-a]pyrimidin- 1.5 Active 7-yl)phenyl]-N-methylacetamide N-[3-(3-chloropyrazolo[1,5-a]pyrimi- 3.1 Active din-7-yl)phenyl]-N-methylacetamide N-[3-~3-cyanopyrazolo[1,5-a]pyrimidin- 25.0 Active 7-yl)phenyl]-N-methylcyclobutanecar-boxamide . _ Another test utilized for the determination of anxiolytic activity is the measurement of the ability of test compounds to inhibit the binding of tritiated benzo-diazepines to brain-specific receptors of warm-blooded animals. A modification of the method described by R. F. Squires~ et al., Nature, 256, No. 21, p. 732 ~Aprll ~!l2~
1977) and H. ~ohler, et al., Science, 198, p. 849 ~1977 was employed.
Male albino rats (Wistar ~train, weighing 150-200 g each) were obtained Çrolm Royalhart Farms. 3H-Meth-yldiazepam (79.9 Ci/mmol) and 3H-methylflunitrazepam (84.3 Ci/m~ol) ~ere obtained from New England Nuclear.
The ~es~ compounds were solubilized in either dimethyl-formamide, 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 lO00 g for lO minutes and then recentrifuged at 30,000 g for 20 minutes to produce a crude P2-synaptosomal fraction.
The P2-fraction was either: ~l) resuspended in twice the original volume in hypotonic 50 mM Tris.HCl (pH 7.4), or (2) resuspended in one-half the original volume in hypotonic lO mM Tris.HCl (pH 7.4) and then was frozen (-20C) until time of use. Frozen P2 preparations were thawed and resuspended in four times the original homo-genizing volume at time of assay.
2Q The binding assay consisted of 300~1 of the P2-fraction suspension ~0.2-0.4 mg protein), lO0 ~ of test drug and lO0 ~l 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). Non-specific binding controls and total binding controls received lO0 ~l of diazepam (3 M, final concentration) and 100 ~l 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 l~hatman 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 50-60C
for 30 minutes, 10 ml of Beckman Ready-Solv~l 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.
Inhibition of binding was calculated by the di~ference between total bind.ing 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 pres~nt invention are given in Table TABL
Inhibition of the ~inding of 3H-Benzodi.azepine to Brain-SPecific ReceDtors of Rats . , . , . . --Compound ~ Inhibition _ _ _ N-~3-(3-cyanopyrazolo[l,S-a]pyrimidin-7- 83 yl)phenyl]-N-ethylpropanamide N-13-~3-cyanopyrazolo[1,5-a]pyrimidin-7- 79 yl)phenyl]-N-ethylacetamide N-[3-(3-chloropyrazolo[l,S-a]pyrimidin-7- 97 yl)phenyl]-N-ethylacetamide N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7- 64 yl)phenyl]-N-propylacetamide 7-~3-[ethyl(l-oxopropyl)amino]phenyl]pyra- 100 zolorl,S-a]pyrimidine-3-carboxylic acid, ethyl ester [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)- 87 phenyl]methylcarbamic acld, methyl ester 7-[3-[~methoxycarbonyl)methylamino]phenyl]- 9 pyrazolo[l,5-a]pyrimidine-3-carboxylic acid, ethyl ester [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)- SS
phenyl]ethylcarbamic acid, methyl ester 7-[3-~ethyl~methoxycarbonyl)amino3phenyl]- 99 pyrazolo~l,5-a]pyrimidine-3-carboxylic .
acid, ethyl ester . ._ ~7~18 ~
TABLE III ~continued) Compound ~ Inhibition¦
. . ~
r3-(3-cyanopyrazolo[1,5-a~py~rimidin-7-yl)- 41 phenyl]methylcarbamic acid, ethyl ester ethyl(3-pyrazolo[1,5-a]pyrimidin-7-yl-61 phenyl)carbamic acid, ethyl ester [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)- 63 phenyl]ethylca~bamic acid, ethyl ester [3-(3-chloropyrazolo[1~5-a]pyrimidin-7-yl~- 78 phenyl]ethylcarbamic acid, ethyl ester N [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7- 78 yl)phenyl]-N-2-propenylacetamide N [3-(3-cyanopyrazolo[1,5-a~pyrimidin-7- 31 yl)phenyl]-N-2-propynylacetamide N-i3-(3-cyano-~-methylpyrazolo[l,S-a] 42 pyrimidin-7-yl)phenyl]propanamide N-[3-(3 cyanopyrazolo[l,5-a]pyrimidin-7- 79 yl)phenyl]-N-methylpropanamide N-[3-(3-cyano-2 methylpyrazolo[l,5-a]- 95 pyrimidin-7-yl)phenyl~-N-methylpropanamide N-methyl-N-(3-pyrazolo~1,5-a]pyrimidin-7- 54 ylphenyl)acetamide 7-[3-(acetylmethylamino)phenyl]pyrazolo- 100 [1,5-a]pyrimidine-3-carboxylic acid, ethyl ester N-[3-~3-cyanopyrazolo~1,5-a]pyrimidin-7- 73 yl)phenyl]-N~methylacetamide N-[3-(3-chloropyrazolo[1,5-a]pyrimidin-7- 71 yl)phenyl]-N-methylacetamide N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-81 ¦yl)phenyl]-N-methylcyclobutanecarboxamide ~ _ r-- . __.___ 127~8~
TABLE III (continued ?
___ _ .
Compound 7~ Inhibition _ _ . _ _ _ N-[3-~3 cyanopyrazolo[l,5-a]F)yrimidin-7- 83 yl)phenyl]-N-methylcyclopropanecarboxamide 7-[3-[(cyclQpropylcarbonyl)methylamino]- 95 phenylpyrazolo[l,5-a]pyrimidine-3-car-boxylic ~cid, ethyl~ester 7-[3-(acetylethylamino)phenyl]pyrazolo- 97 [1,5-a]pyri~idine-3-carboxylic acid, ethyl ester 7-~3-(ace~ylamino)phenyl]pyrazolo[1,5-a]- 85 pyrimidine-3-carboxylic acid, ethyl ester 7-[3-[(methoxycarbonyl)amino]phenyl]- 76 py~azolo[l,5-a]pyrimidine-3-carboxylic acid, ethyl ester methyl(3-pyrazolo[1,5-a]pyrimidin-7-yl- 45 phenyl)carbamic acid, methyl ester 7-[3-(acetylpropylamino)phenyl]pyrazolo- 97 [1,5-a]pyrimidine-3-carboxylic acid, ethyl ester [3-(3-chloropyrazolo[1,5-a]pyrimidin 7- 92 yl)phenyl]methylcarbamic acid, methyl ester 7-[3-[(cyclobutylcarbonyl)amino]phenyl]- 82 pyrazolo[l,5-a~pyrimidine-3-carboxylic acid, ethyl ester 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
N ~ ~ R2 (3) Rl N
(4) In accordance with the above reaceion scheme a 1-acetylphenyl-3-amide (1~, where R6 is as described above is reacted with dimethylformamide dimethylacetal at reflux giving an N-[3-~3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-alkanamide, which is then reacted with sodium hydride, and ~ 2~ Z.~i the anion generated is reacted with an alkyl halide, where Rs is as described,~bove giving the N-[3-[3-(dimethylamino)--l-oxo-2-propenyl]phenyl]-N-alkylalkanamide (2). This compound is then reacted with a 3-aminopyrazole (3), wher~
Rl and R2 are as described above, in glacial acetic acid at reflux, giving tbe product (4).
Alternatively, N-[3-~3-(dialkylamino)-1-oxc-2-propenyl]phenyl~alkanamide (5) i5 reacted with a 3-amino-pyrazole (3) to give intermediate~ (6) which are reacted with a base such as sodium hyd~ide, sodium alkoxide and the like and an Rs^halide to give the products (4).
o (CH3)2NCH-CHC ~ +H-N ~ \ ~ R2 \=1/ H 2 ~ - R 1 (5) I
~ R6 ~ H_ I I R 6 Rs-halide y 21 ~N R
'~ ~'7~
The perrormance of the novel compounds of the present inventio~ in standard tests with laboratory ani-mals 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 agen~s. Furthermore, these compounds have been shown by biological data to be useful as antiepileptic agents, particularly in the treatment of grand mal epilepsy seizures~ and as sedative-hypnotic and skeletal muscle relaxant agents.
The an~i-anxiety and anticonvulsant properties of the novel compounds of the present invention have been established in a test which indicates anxiolytic and anti-epilep~ic activity by the measure of protection they pro-vide from convulsions resulting from the administration of pentylenetetrazole. Single or graded dose levels of the 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 with pentylenetetrazole at a dose of 23 mg/kg of body weight. This dose is estimated to cause clonic sei~ures 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 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 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 the present invention are shown in Table I.
TABLE I
_~tecti~ Linst Clon _ Seizures Caused by PentylenetetrazoLe in Rats . _ _ _ .
Dose ~ of Rats Compound(mg/kg) Protected , _ ~ . I
N-[3-(3~yanopyrazolo[1,5-a]py~imidin- 25.0 100 7-yl)phenyl]-N ethylpropanamide N-[3-(3-cyanopyrazolo[1,5-a~pyrimidin- 25.~ lO0 7-yl)phenyl]-N-ethylacetamide N-~3-(3-chloropyrazolo[l,5-a]pyrimi- 25.0 lOQ
din-7-yl)phenyl]-N-ethylacetamide N-[3 (3-cyanopyra~olo[1,5-a]pyrimidin- 6.25 100 7-yl)phenyl]-N-propylacetamide [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7- 3.1 25 yl)phenyl]methylcarbamic acid, methyl ester [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7- 12.6 75 yl)phenyljethylcarbamic acid, methyl ester N-butyl-N-[3-(3-cyanopyrazolo[l,5-a]- 25.0 50 pyrimidin-7-yl)phenyl]acetamide [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7- 25.0 25 yl)phenyl~ethylcarbamic acid, ethyl ester [3-(3-chloropyra2010[1,5-a]pyrimidin- 25.0 25 7-yl)phenyl]ethylcarbamic acid, ethyl ester N-[3-(3-cyanopyrazolo~1,5-a]pyrimidin- 25.0 100 7-yl)phenyl]-N-2-propenylacetamide N-[3-(3 cyanopyra2010[1,5-a3pyrimidin 6.25 100 7-yl)phenyl]-N-2-propynylacetamide TABLE I (continued) . ,. ..... , Dose ~ of Rats Compound (mg/kg) Protected ~,.,_ _ __ N-[3-(3-cyanopyrazolo~1,5-a]pyrimidin- 25.0 50 7-yl)phenyl]-N-methylcyclobutanecar-boxamide N-[3-(3-cyanopyrazolo~1,5-a]pyrimidin- 25.0 75 7-yl)phenyl]-N-methylcyclopropanecar-boxamide N- ~ 3 - ( 3-cyanopyrazolo[l,5~a]pyrimidin- 25.0 75 7-yl)phenyl]-N-methylacetamide N- ~ 3- t 3-chloropyrazolo[1,5-a3pyrimi- 12.5 50 din-7-yl)phenyl~-N-methylacetamide 7-~3-(acetylmethylamino)phenyllpyra- 25.0 100 zolo~l,5-a]pyrimidine-3-carboxylic acid, ethyl ester N- [ 3- ( 3-cyanopyrazolo[1,5-a]pyrimidin- 12.s 50 7-yl~phenyl]-N-~ethylpropanamide N-[3-(3-cyano-2-methylpyrazolo[l,5 a]- 25.0 lO0 pyrimidin-7-yl)phenyl]-N-methylpro-panamide Another test which has been used to assess anti-anxiety effects is a nonconditioned passive avoidance procedure described by J. R. Vogel, B. Beer and D. E.
Clody, "A Simple and Reliable Conflict Procedure for Testing Anti-Anxiety Agents", Psychopharmacologia, 21, 1-7 (1971). A conflict situation is induced in rats by a modifica~ion 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 administered in single or graded, oral or intraperitoneal doses, sus-pended in a 2% starch vehicle containing 0.5% v/v poly-ethylene glycol and one drop of polysorbate 80. Control animals received the vehicle alone. At 30 to 60 minutes each rat was placed in an individual plexiglass chamber.
Water ~as available ad libitum from a tap located in the rear of the chamber. A 0.7 milliampere DC shocking cur-rent wa~ 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 we~e 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 representa-tive compounds of this invention appear in Table II.
TABLE II
Noncondition d _ sive Avoidance Test in Rats Compound ~mg/kg) ~e~ul~
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin- 0.4 Active 7-yl)phenyl]-N-ethylpropanamide N-[3-~3-cyanopyrazolo[1,5-a]pyrimidin- 0.8 Active 7-yl)phenyl]-N-ethylacetamide N-ethyl-N-(3-pyrazolo[l,S-a]pyrimidin- 25.0 Active 7-ylphenyl)acetamide N-[3-(3-chloropyrazolo[1,5~a]pyrimi- 3.1 Ac~ive din-7-yl)phenyl]-N-ethylacetamide N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin- 1.5 Active 7-yl)phenyl]-N-propylacetamide [3 (3-cyanopyrazolo~1,5-a]pyrimidin-7- 3.1 Active yl)phenyl~methylcarbamic acid, methyl ~l~t7~
TA~LE I I ( c:ontinued) _ _.__ r Compound ~(mg/kg)~ Result ~ _ [3-~3-cyanopyra~olo[1,5-a]pyrimidin-7- 12.5 Active yl)phenyl]ethylcarbamiG acid, methyl ester [3-(3-chloropyrazolo~l,S-a]pyrimidin- 25.0 Active 7-yl)phenyl]ethylcarbamic acid, ethyl e~ter N~3-(3-cyanopyrazolotl,5-a]pyrimidin- 3.1 Active 7-yl)phenyl]-N-2-propenylacetamide N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin- 1.5 Active 7-yl)phenyl]-N-2-propynylacetamide N-13-(3-cyanopyrazolo[1,5-a]pyrimidin- 6.2 Active 7-yl)phenyl]-N-methylpropanamide N-[3-(3-cyano-2-methylpyrazolo[1,5-a]- 25.0 Active pyrimidin-7-yl)phenyl]-N-methylpropan-amide 7-[3-(acetylmethylamino)phenyl]pyra- 25.0 Active ~olo[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester N-[3-(3-cyanopyrazolo~1,5-a]pyrimidin- 1.5 Active 7-yl)phenyl]-N-methylacetamide N-[3-(3-chloropyrazolo[1,5-a]pyrimi- 3.1 Active din-7-yl)phenyl]-N-methylacetamide N-[3-~3-cyanopyrazolo[1,5-a]pyrimidin- 25.0 Active 7-yl)phenyl]-N-methylcyclobutanecar-boxamide . _ Another test utilized for the determination of anxiolytic activity is the measurement of the ability of test compounds to inhibit the binding of tritiated benzo-diazepines to brain-specific receptors of warm-blooded animals. A modification of the method described by R. F. Squires~ et al., Nature, 256, No. 21, p. 732 ~Aprll ~!l2~
1977) and H. ~ohler, et al., Science, 198, p. 849 ~1977 was employed.
Male albino rats (Wistar ~train, weighing 150-200 g each) were obtained Çrolm Royalhart Farms. 3H-Meth-yldiazepam (79.9 Ci/mmol) and 3H-methylflunitrazepam (84.3 Ci/m~ol) ~ere obtained from New England Nuclear.
The ~es~ compounds were solubilized in either dimethyl-formamide, 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 lO00 g for lO minutes and then recentrifuged at 30,000 g for 20 minutes to produce a crude P2-synaptosomal fraction.
The P2-fraction was either: ~l) resuspended in twice the original volume in hypotonic 50 mM Tris.HCl (pH 7.4), or (2) resuspended in one-half the original volume in hypotonic lO mM Tris.HCl (pH 7.4) and then was frozen (-20C) until time of use. Frozen P2 preparations were thawed and resuspended in four times the original homo-genizing volume at time of assay.
2Q The binding assay consisted of 300~1 of the P2-fraction suspension ~0.2-0.4 mg protein), lO0 ~ of test drug and lO0 ~l 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). Non-specific binding controls and total binding controls received lO0 ~l of diazepam (3 M, final concentration) and 100 ~l 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 l~hatman 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 50-60C
for 30 minutes, 10 ml of Beckman Ready-Solv~l 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.
Inhibition of binding was calculated by the di~ference between total bind.ing 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 pres~nt invention are given in Table TABL
Inhibition of the ~inding of 3H-Benzodi.azepine to Brain-SPecific ReceDtors of Rats . , . , . . --Compound ~ Inhibition _ _ _ N-~3-(3-cyanopyrazolo[l,S-a]pyrimidin-7- 83 yl)phenyl]-N-ethylpropanamide N-13-~3-cyanopyrazolo[1,5-a]pyrimidin-7- 79 yl)phenyl]-N-ethylacetamide N-[3-(3-chloropyrazolo[l,S-a]pyrimidin-7- 97 yl)phenyl]-N-ethylacetamide N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7- 64 yl)phenyl]-N-propylacetamide 7-~3-[ethyl(l-oxopropyl)amino]phenyl]pyra- 100 zolorl,S-a]pyrimidine-3-carboxylic acid, ethyl ester [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)- 87 phenyl]methylcarbamic acld, methyl ester 7-[3-[~methoxycarbonyl)methylamino]phenyl]- 9 pyrazolo[l,5-a]pyrimidine-3-carboxylic acid, ethyl ester [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)- SS
phenyl]ethylcarbamic acid, methyl ester 7-[3-~ethyl~methoxycarbonyl)amino3phenyl]- 99 pyrazolo~l,5-a]pyrimidine-3-carboxylic .
acid, ethyl ester . ._ ~7~18 ~
TABLE III ~continued) Compound ~ Inhibition¦
. . ~
r3-(3-cyanopyrazolo[1,5-a~py~rimidin-7-yl)- 41 phenyl]methylcarbamic acid, ethyl ester ethyl(3-pyrazolo[1,5-a]pyrimidin-7-yl-61 phenyl)carbamic acid, ethyl ester [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)- 63 phenyl]ethylca~bamic acid, ethyl ester [3-(3-chloropyrazolo[1~5-a]pyrimidin-7-yl~- 78 phenyl]ethylcarbamic acid, ethyl ester N [3-(3-cyanopyrazolo[1,5-a]pyrimidin-7- 78 yl)phenyl]-N-2-propenylacetamide N [3-(3-cyanopyrazolo[1,5-a~pyrimidin-7- 31 yl)phenyl]-N-2-propynylacetamide N-i3-(3-cyano-~-methylpyrazolo[l,S-a] 42 pyrimidin-7-yl)phenyl]propanamide N-[3-(3 cyanopyrazolo[l,5-a]pyrimidin-7- 79 yl)phenyl]-N-methylpropanamide N-[3-(3-cyano-2 methylpyrazolo[l,5-a]- 95 pyrimidin-7-yl)phenyl~-N-methylpropanamide N-methyl-N-(3-pyrazolo~1,5-a]pyrimidin-7- 54 ylphenyl)acetamide 7-[3-(acetylmethylamino)phenyl]pyrazolo- 100 [1,5-a]pyrimidine-3-carboxylic acid, ethyl ester N-[3-~3-cyanopyrazolo~1,5-a]pyrimidin-7- 73 yl)phenyl]-N~methylacetamide N-[3-(3-chloropyrazolo[1,5-a]pyrimidin-7- 71 yl)phenyl]-N-methylacetamide N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-81 ¦yl)phenyl]-N-methylcyclobutanecarboxamide ~ _ r-- . __.___ 127~8~
TABLE III (continued ?
___ _ .
Compound 7~ Inhibition _ _ . _ _ _ N-[3-~3 cyanopyrazolo[l,5-a]F)yrimidin-7- 83 yl)phenyl]-N-methylcyclopropanecarboxamide 7-[3-[(cyclQpropylcarbonyl)methylamino]- 95 phenylpyrazolo[l,5-a]pyrimidine-3-car-boxylic ~cid, ethyl~ester 7-[3-(acetylethylamino)phenyl]pyrazolo- 97 [1,5-a]pyri~idine-3-carboxylic acid, ethyl ester 7-~3-(ace~ylamino)phenyl]pyrazolo[1,5-a]- 85 pyrimidine-3-carboxylic acid, ethyl ester 7-[3-[(methoxycarbonyl)amino]phenyl]- 76 py~azolo[l,5-a]pyrimidine-3-carboxylic acid, ethyl ester methyl(3-pyrazolo[1,5-a]pyrimidin-7-yl- 45 phenyl)carbamic acid, methyl ester 7-[3-(acetylpropylamino)phenyl]pyrazolo- 97 [1,5-a]pyrimidine-3-carboxylic acid, ethyl ester [3-(3-chloropyrazolo[1,5-a]pyrimidin 7- 92 yl)phenyl]methylcarbamic acid, methyl ester 7-[3-[(cyclobutylcarbonyl)amino]phenyl]- 82 pyrazolo[l,5-a~pyrimidine-3-carboxylic acid, ethyl ester 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
3~7~ 5 was recorded. The EDso (dose necessary to cause 50% of the animals tested to fall off) was calculated according to the linear arcsine transformation method of Finney9 D. J. ? Statistical Methods in Biological Assay",2nd Ed., Hafner, N. Y., 1964, p. 454, Compounds were dissolved or suspended in a 2~/o aqueous starch suspen5ion 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 IV.
TABLE IV
Effect_on Ability of Rats to Remain on an Inclined Screen Compound (mg~kg) N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin- 4.6 7-yl)phenyl]-N-ethylpropanamide N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin- 3.9 7-yl)phenyl~-N-ethylacecamide _ 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 ~est compouods. Sixty minutes later, individ-ual rats were placed in Actophotometers and locomotor activity was measured ~or 5 minutes after a brie~ (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 activ;ty counts compared with the vehicle group (MDDso) was calculated rom a linear regression equation. The test results of representative compounds appear in Table V.
TABLE V
Effects on Locomotor Activi~y in Raes . _ _ _ Compound (mg/kg PØ) _ _ _ _ N-[3-(3-cyanopyrazolo[1~5-a]pyrimidin-7- 2.0 yl)phenyl]-N-ethylpropanamlde N-[3-(3 cyanopyrazolo[l~5-a]pyrimidin-7- 1.4 yl)phenyl]-N-ethylacetamide The novel compounds of ~he present invention have been found to be highly useful for drug therapy in mammals when administered in amoun~s ranging from about 0.1 mg ~o about 20.0 mg/kg of body t~eight per day. A
preferred dosage regimen for optimum results would be from about 0.5 mg to about 10.0 mg/kg of body weight per day.
Dosage units are employed such that a total oÇ from about 10 to about 700 mg 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 proportlonally 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 to the present invention having the desired clarity, 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 glycol, and polyethylene glycols. The polyethylene glycols con-sist of a mixture of nonvolatile, normally liquid, polyethylene 31.;2'7~t~3~D~
glycols which are soluble in both water and organic liqulds and which have molecu:Lar 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 nonvola-tile 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, ~he paren-teral sol~tions may also contain various preservatives which may be used to prevent bacterial and fun~al contam-ination. 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 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, the preferred con-centration 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 administra-tion 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 the ~7~ 8 food of ~he diet. For oral therapeutic administration, the active compounds may be incorporated with excipients and used ;n the form of tablets ! troches, capsules, elixirs, suspensions, syrups, wafers and the like Additionally, the active ingredient may be incorporaeed with the proper pharmaceutical carrier or carriers known in the art to produce a sustained-release eablet or capsule. Such compo~ition~ and prepara~ions should contain at least O.I% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 27~ 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 tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a dis-integrating 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 sul~ate and a sweetening agent such as sucrose, lactose or sac-charin may be added or a flavoring agent such as pepper-mint, 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 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.
8~
The following non-limiting examples il lustrate the preparation of representati~e compounds of the present invention.
Exam~)le 1 N-~3-[3-(Dimet.hylaminoJ-l-oxo-2-propenyl]phenyl]-~opanamide A 20 g portion of N-(3-acetylph~nyl)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 ~hrough hydr~us magnesium sili~ate, 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 cf Examples 2-S, found in Table VI, were prepared.
TABLE VI
. ........... ~ , ¦EX. Starting Material Amide ~ _ 2 N-(3~acetylphenyl)- N-[ 3-(3-dimethylamino)-1-ethanamide oxo-2-propenyl)phenyl]-acetamide 3 (3-acetylphenyl)carbamic [3-[3-(dimethylamino)-1-acid, methyl ester oxo-2-propenyl]phenyl]-carbamic acid, methyl ester
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 IV.
TABLE IV
Effect_on Ability of Rats to Remain on an Inclined Screen Compound (mg~kg) N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin- 4.6 7-yl)phenyl]-N-ethylpropanamide N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin- 3.9 7-yl)phenyl~-N-ethylacecamide _ 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 ~est compouods. Sixty minutes later, individ-ual rats were placed in Actophotometers and locomotor activity was measured ~or 5 minutes after a brie~ (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 activ;ty counts compared with the vehicle group (MDDso) was calculated rom a linear regression equation. The test results of representative compounds appear in Table V.
TABLE V
Effects on Locomotor Activi~y in Raes . _ _ _ Compound (mg/kg PØ) _ _ _ _ N-[3-(3-cyanopyrazolo[1~5-a]pyrimidin-7- 2.0 yl)phenyl]-N-ethylpropanamlde N-[3-(3 cyanopyrazolo[l~5-a]pyrimidin-7- 1.4 yl)phenyl]-N-ethylacetamide The novel compounds of ~he present invention have been found to be highly useful for drug therapy in mammals when administered in amoun~s ranging from about 0.1 mg ~o about 20.0 mg/kg of body t~eight per day. A
preferred dosage regimen for optimum results would be from about 0.5 mg to about 10.0 mg/kg of body weight per day.
Dosage units are employed such that a total oÇ from about 10 to about 700 mg 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 proportlonally 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 to the present invention having the desired clarity, 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 glycol, and polyethylene glycols. The polyethylene glycols con-sist of a mixture of nonvolatile, normally liquid, polyethylene 31.;2'7~t~3~D~
glycols which are soluble in both water and organic liqulds and which have molecu:Lar 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 nonvola-tile 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, ~he paren-teral sol~tions may also contain various preservatives which may be used to prevent bacterial and fun~al contam-ination. 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 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, the preferred con-centration 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 administra-tion 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 the ~7~ 8 food of ~he diet. For oral therapeutic administration, the active compounds may be incorporated with excipients and used ;n the form of tablets ! troches, capsules, elixirs, suspensions, syrups, wafers and the like Additionally, the active ingredient may be incorporaeed with the proper pharmaceutical carrier or carriers known in the art to produce a sustained-release eablet or capsule. Such compo~ition~ and prepara~ions should contain at least O.I% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 27~ 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 tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a dis-integrating 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 sul~ate and a sweetening agent such as sucrose, lactose or sac-charin may be added or a flavoring agent such as pepper-mint, 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 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.
8~
The following non-limiting examples il lustrate the preparation of representati~e compounds of the present invention.
Exam~)le 1 N-~3-[3-(Dimet.hylaminoJ-l-oxo-2-propenyl]phenyl]-~opanamide A 20 g portion of N-(3-acetylph~nyl)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 ~hrough hydr~us magnesium sili~ate, 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 cf Examples 2-S, found in Table VI, were prepared.
TABLE VI
. ........... ~ , ¦EX. Starting Material Amide ~ _ 2 N-(3~acetylphenyl)- N-[ 3-(3-dimethylamino)-1-ethanamide oxo-2-propenyl)phenyl]-acetamide 3 (3-acetylphenyl)carbamic [3-[3-(dimethylamino)-1-acid, methyl ester oxo-2-propenyl]phenyl]-carbamic acid, methyl ester
4 (3-acetylphenyl)carbamic ~3-[3-(dimethylamino)-1-acid, butyl ester oxo-2-propenyl]phenyl]-carbamic acid, butyl ester
5 N-(3-acetylphenyl)- N-[3-[3-(dimethylamino)-1-butanamide oxo-2-propenyl]phenyl]
butanamide __ __ _ ~
.~7~
~le 6 N-[3-[3-(Dimethylamino)-1 -oxQ-2-propenyl]phenyl-N
ethylpropanamide A mixture of 3.47 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]propanamide and 0.68 g o~ 60%
sodium hydride in oil in dimethylformamide was stirred for 0.5 hour under argon, then cooled in an ice bath and a solution of 2.4 g of ethyl iodide in 10 ml of dimethyl-formamide was added in small portions. The mix~ure was then stirred at room ~emperature for 0.5 hour and ex-tracted three times with hexane. The extracts were dis-carded, water was added and this mixture extracted with dichloromethane. This exeract was evaporated and the residue crystallized from hexane giving the desired com-pound, mp 105-lQ7C.
Followin~ 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
- Starting _ Material Ex. of Ex. Alkylated Amide ~PC
7 2 N-~3-[3-(dimethylamino)-1-oxo-2- 110-113 propenyl]phenyl]-N-ethylacetamide 8 1 N-[3-[3-(dimethylamino)-1-oxo-2- 148-149 prodpenyl]phenyl]-N-methylpropan-9 2 N-[3-[3-(dimethylamino)-1-oxo-2- 110-112 _ Dropenyl]phenyl3-N-propylacetamide :~2~18 TABLE VII (continued) Stareing _ ~ _ _ _ Material Ex. of Ex. Alkylated Amide MPC
__ . __ _ _ 3 ~3-[3-(dimethylamino)-1-oxo-2-pro~93-95 penyl]phenyl]methylcarbamic acid, methyl ester 11 3 [3-[3-~dimethylamino~-1-oxo-2-pro- 95-97 penyl]phenyl]ethylcarbamic acid, methyl ester 12 2 N-[3-[3-(dimethylamino)-1-oxo-2- 146-148 propenyl]phenyl]-N-methylacetamide _ _ ~___ ., _ Example 13 N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylp opanamide A mixture of 0.54 g of 3-amino-4-pyrazolecarbo-nitrile and 1.37 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylpropanamide in 50 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed. The residue was partitioned between satur ated 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 ~hen cooled and the solid collected, giving 1.3 g of the desired product, mp 161-162C.
Following the procedure of Example 13 and USillg appropriately substituted 3-amino-pyrazoles together with the indicated intermediates, the products of Examples 14-37 found in Table VIII were prepared.
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.~7~
~le 6 N-[3-[3-(Dimethylamino)-1 -oxQ-2-propenyl]phenyl-N
ethylpropanamide A mixture of 3.47 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]propanamide and 0.68 g o~ 60%
sodium hydride in oil in dimethylformamide was stirred for 0.5 hour under argon, then cooled in an ice bath and a solution of 2.4 g of ethyl iodide in 10 ml of dimethyl-formamide was added in small portions. The mix~ure was then stirred at room ~emperature for 0.5 hour and ex-tracted three times with hexane. The extracts were dis-carded, water was added and this mixture extracted with dichloromethane. This exeract was evaporated and the residue crystallized from hexane giving the desired com-pound, mp 105-lQ7C.
Followin~ 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
- Starting _ Material Ex. of Ex. Alkylated Amide ~PC
7 2 N-~3-[3-(dimethylamino)-1-oxo-2- 110-113 propenyl]phenyl]-N-ethylacetamide 8 1 N-[3-[3-(dimethylamino)-1-oxo-2- 148-149 prodpenyl]phenyl]-N-methylpropan-9 2 N-[3-[3-(dimethylamino)-1-oxo-2- 110-112 _ Dropenyl]phenyl3-N-propylacetamide :~2~18 TABLE VII (continued) Stareing _ ~ _ _ _ Material Ex. of Ex. Alkylated Amide MPC
__ . __ _ _ 3 ~3-[3-(dimethylamino)-1-oxo-2-pro~93-95 penyl]phenyl]methylcarbamic acid, methyl ester 11 3 [3-[3-~dimethylamino~-1-oxo-2-pro- 95-97 penyl]phenyl]ethylcarbamic acid, methyl ester 12 2 N-[3-[3-(dimethylamino)-1-oxo-2- 146-148 propenyl]phenyl]-N-methylacetamide _ _ ~___ ., _ Example 13 N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylp opanamide A mixture of 0.54 g of 3-amino-4-pyrazolecarbo-nitrile and 1.37 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylpropanamide in 50 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed. The residue was partitioned between satur ated 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 ~hen cooled and the solid collected, giving 1.3 g of the desired product, mp 161-162C.
Following the procedure of Example 13 and USillg appropriately substituted 3-amino-pyrazoles together with the indicated intermediates, the products of Examples 14-37 found in Table VIII were prepared.
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Example 38 N-[3-(3-Chloropyxazolo[1,5-~]pyrimidin-7-yl)phenyl]-N-ethylacetamide A ~ixture of 1.0 g of N-ethyl-N-(3-pyrazolo~
[1,5-a]pyrimid.in-7~ylphenyl)~ce~amide and 4.57 g of l-chlorobenzotriazole in 50 ml o~ dichloromethane was refluxed for 25 minutes, then cooled and poured into 50 ml of ic~-cold 2.5N aqueous sodium hydroxide. The ~ixture was filtered through hydrous magnesium silicate, precipi-tat~d with hexane and the solid collected, giving 0.7 g of the desired product, mp 157-159C.
Example 39 ~ ~
[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester , A 12.41 g portion of [3-[3-tdimethylamino)-1-oxo-2-propenyl]phenyl]carbamic acid, methyl ester was reacted as described in Example 6, using 9.36 g of ethyliodide, giving 13.~ g of [3-[3-(dimethylamino)-1-oxo-2-propenyl]-phenyl]ethylcarbami.c acid, methyl ester, mp 95-~7C.
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, ~p 117-119C.
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 reac~ed with 1~08 g of 3 aminopyrazole-~-carbonitrile as described in Example 13, giving 2.6 g o~ the desired product, mp 162~164C.
~ ;~7~
-26~
xample 41 [3 (3~Cyanopyrazolo~1,5 2!]pyrimidin-7-yl)phenyl]-. . .
meth~lcarbamic acid, ethyl ester -l-Acetylphenyl-3-carbamic acid, ethyl ester was converted to ~3- r 3-(dimethylamino)-1-oxo-2-propenyl]-phenyl]carbamic acid, ethyl ester by the procedure of Example 1 and this e~ter was then reacted with methyl S iodide, again by the procedure of Example 6, giving [3~[3-[dimethylamino)-1-oxo-2-propenyl~phenyl]methylcar-bamic 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 ~xample 13, giving 2.09 g of the desired compound, mp 140-142C.
xample 42 Ethyl(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)-carbamic acid, ethyl ester [3-[3-(Dimethylamino)-l-oxo-2-propenyl]phenyl]-carbamic acid was reated with ethyl iodide by the pro-cedure of Example 6, giving [3-~3-(dimethylamino)-1-oxo-2-propenyl~phenyl]ethylcarbamic acid, ethyl ester.
A 2.9 g portion o f 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 79-~1C.
Example 43 [3-(3-Cyanopyrazolo[1,5-a~pyrimidin-7-yl)phenyl]-- _ _ ethylcarbamic acid, ethvl e~ter A 2.0 g portion of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]ethylcarbamic acid, ethyl ester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13, giving 2.52 g of the desired product, mp 133-135C.
8~1~
.
Exam~le 44 [3 (3~Chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-ethylcarbamic acidL_ethyl ester A 1.55 g portion of ethyl(3-pyrazolol1,5-al-pyrimidih-7-ylphenyl)carbamic acid, ethyl ester in 50 ml of dichloromethane was reacted wi~h l-chlorobenzotriazole for 30 minutes, giving 1~29 g of ~he desired product, ~p 100-102Co Example 45 N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-~ .
2-proPenylace~amide An 11~61 g portion of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide was reacted with 7.26 g of allyl bromide as d~scribed in Example 6, giving 13.34 g of N-[3~[3-(dimethylamino~-1-oxo-2-propenyl]phenyl]-N-2-propenylacetamide, mp 91-94C.
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 com-pound, mp 135-137C.
Example 46 N-[3-t3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl~-N-2Q -2-propynylacetamide An 11.61 g portion of N-[3- r 3-(dimethylamino)-l-oxo-2-propenyl]phenyl]acetamide was reacted with pro-pynyl bromide as described in Example 6, giving N-[3-[3-tdimethylamino)-l-oxo-2-propenyl]phenyl]-N-2-propynylacet-amide, mp 98-101C.
A 2.7 g portion of the above intermedia~e 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 193-195C.
~L2t~
-2~-Example 47 N-Butyl N-~3~(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)-~ . .. . _ . .. _ ~ cetamide An 11.$1 g portion of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]carbamic acid, methyl ester was reacted wlth 11.0 g of butyl iodide by the procedure of Example 6, giving 16.3 g of N~butyl-N-[3-[3 (dimethyl-S amino)-l-oxo-2-propenyl]phenyl]acetamide.
A 2.88 g portion of the above intermediate was reacted with 1.0-8 g of 3-aminopyrazole-4-carbonitrile by the procedure of Example 13, giving 1.61 g of the desired product, mp 146-148C.
Example 48 N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylcarbam_c acid, butyl ester An 11.61 g portion of [3-[3-(dimethylamino)-1-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-aminopyrazole-4-carbontirile as described in Example 13, giving 2.3 g of the desired product, mp 96-97C.
Example 49 N-[3-(3-Chloropyrazolo[1,5-alpyrimidin-7-yl)phenyl] N-methylacetamide A 1.0 g por~ion of N-methyl-N-(3-pyrazolo[1,5-a]-pyrimidin-7-ylphenyl)acetamide ~as reacted as described in Example 38, giving 1.0 g of the desired product, mp 163-165C.
-29~
Example 50 [3-~3-Chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-methylcarbamic ac:id,_methyl ester ~ 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 the desired product, mp 132-134C.
Example 51
:~7 O X C ~ C :~ C ~ C -1 ~ a. _ N O ~_1 X --~ X -1 X ~ X
:~ ~ ~ E o E o E O E E o ,C ~ h t~ S aJ C 1~ S a~
I ~J I ~ I ~) I I ~J
~ ~ u - __ ._~ .
~ X
h ~ _ ~ ~ O ~
CO
_ _ X
1~ r~
_ _ 2~
Example 38 N-[3-(3-Chloropyxazolo[1,5-~]pyrimidin-7-yl)phenyl]-N-ethylacetamide A ~ixture of 1.0 g of N-ethyl-N-(3-pyrazolo~
[1,5-a]pyrimid.in-7~ylphenyl)~ce~amide and 4.57 g of l-chlorobenzotriazole in 50 ml o~ dichloromethane was refluxed for 25 minutes, then cooled and poured into 50 ml of ic~-cold 2.5N aqueous sodium hydroxide. The ~ixture was filtered through hydrous magnesium silicate, precipi-tat~d with hexane and the solid collected, giving 0.7 g of the desired product, mp 157-159C.
Example 39 ~ ~
[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester , A 12.41 g portion of [3-[3-tdimethylamino)-1-oxo-2-propenyl]phenyl]carbamic acid, methyl ester was reacted as described in Example 6, using 9.36 g of ethyliodide, giving 13.~ g of [3-[3-(dimethylamino)-1-oxo-2-propenyl]-phenyl]ethylcarbami.c acid, methyl ester, mp 95-~7C.
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, ~p 117-119C.
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 reac~ed with 1~08 g of 3 aminopyrazole-~-carbonitrile as described in Example 13, giving 2.6 g o~ the desired product, mp 162~164C.
~ ;~7~
-26~
xample 41 [3 (3~Cyanopyrazolo~1,5 2!]pyrimidin-7-yl)phenyl]-. . .
meth~lcarbamic acid, ethyl ester -l-Acetylphenyl-3-carbamic acid, ethyl ester was converted to ~3- r 3-(dimethylamino)-1-oxo-2-propenyl]-phenyl]carbamic acid, ethyl ester by the procedure of Example 1 and this e~ter was then reacted with methyl S iodide, again by the procedure of Example 6, giving [3~[3-[dimethylamino)-1-oxo-2-propenyl~phenyl]methylcar-bamic 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 ~xample 13, giving 2.09 g of the desired compound, mp 140-142C.
xample 42 Ethyl(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)-carbamic acid, ethyl ester [3-[3-(Dimethylamino)-l-oxo-2-propenyl]phenyl]-carbamic acid was reated with ethyl iodide by the pro-cedure of Example 6, giving [3-~3-(dimethylamino)-1-oxo-2-propenyl~phenyl]ethylcarbamic acid, ethyl ester.
A 2.9 g portion o f 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 79-~1C.
Example 43 [3-(3-Cyanopyrazolo[1,5-a~pyrimidin-7-yl)phenyl]-- _ _ ethylcarbamic acid, ethvl e~ter A 2.0 g portion of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]ethylcarbamic acid, ethyl ester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13, giving 2.52 g of the desired product, mp 133-135C.
8~1~
.
Exam~le 44 [3 (3~Chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-ethylcarbamic acidL_ethyl ester A 1.55 g portion of ethyl(3-pyrazolol1,5-al-pyrimidih-7-ylphenyl)carbamic acid, ethyl ester in 50 ml of dichloromethane was reacted wi~h l-chlorobenzotriazole for 30 minutes, giving 1~29 g of ~he desired product, ~p 100-102Co Example 45 N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-~ .
2-proPenylace~amide An 11~61 g portion of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide was reacted with 7.26 g of allyl bromide as d~scribed in Example 6, giving 13.34 g of N-[3~[3-(dimethylamino~-1-oxo-2-propenyl]phenyl]-N-2-propenylacetamide, mp 91-94C.
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 com-pound, mp 135-137C.
Example 46 N-[3-t3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl~-N-2Q -2-propynylacetamide An 11.61 g portion of N-[3- r 3-(dimethylamino)-l-oxo-2-propenyl]phenyl]acetamide was reacted with pro-pynyl bromide as described in Example 6, giving N-[3-[3-tdimethylamino)-l-oxo-2-propenyl]phenyl]-N-2-propynylacet-amide, mp 98-101C.
A 2.7 g portion of the above intermedia~e 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 193-195C.
~L2t~
-2~-Example 47 N-Butyl N-~3~(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)-~ . .. . _ . .. _ ~ cetamide An 11.$1 g portion of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]carbamic acid, methyl ester was reacted wlth 11.0 g of butyl iodide by the procedure of Example 6, giving 16.3 g of N~butyl-N-[3-[3 (dimethyl-S amino)-l-oxo-2-propenyl]phenyl]acetamide.
A 2.88 g portion of the above intermediate was reacted with 1.0-8 g of 3-aminopyrazole-4-carbonitrile by the procedure of Example 13, giving 1.61 g of the desired product, mp 146-148C.
Example 48 N-[3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylcarbam_c acid, butyl ester An 11.61 g portion of [3-[3-(dimethylamino)-1-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-aminopyrazole-4-carbontirile as described in Example 13, giving 2.3 g of the desired product, mp 96-97C.
Example 49 N-[3-(3-Chloropyrazolo[1,5-alpyrimidin-7-yl)phenyl] N-methylacetamide A 1.0 g por~ion of N-methyl-N-(3-pyrazolo[1,5-a]-pyrimidin-7-ylphenyl)acetamide ~as reacted as described in Example 38, giving 1.0 g of the desired product, mp 163-165C.
-29~
Example 50 [3-~3-Chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-methylcarbamic ac:id,_methyl ester ~ 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 the desired product, mp 132-134C.
Example 51
7-[3-[(Cyclopropylcarbonyl?methylamino]phenyl~yrazolo-[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester , _ _ N-(3-Acetylphenyl~cyclopropanecarboxamide was prepared by the reaction of m-aminoacetophenone, diiso~
propylethylamine and cyclopropanecarboxylic acid chloride in dichloromethane.
This compound was then converted to N-[3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]cyclopropanecar-boxamide by the procedure of Example 1 and ehen alkylated by the procedure of Example 6, using methyl iodide, giving 10.17 g of N-[3-(3-dimethylamino)-1-oxo-2-propenyl)phenyl]-N-methylcyclopropanecarboxamide, mp 120-122C.
A 0.54 g portion of this compound was reacted as described in Example 13 with 3-aminopyrazole-4-carbo-nitrile, giving 1.08 g of the desired product, mp 178-180C.
Example 52 7-~3-[(Cyclopropylcarbonyl)methylamino]phenylpyrazolo-[1,5-a]pyrimidine-3-carboxylic acid7 ethyl ester A 0.73 g portion of ethyl 3-aminopyrazole-4-car-boxylate and 1.36 g of N-[3-[(3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methylcyclopropanecarboxamide were reacted as described in Example 13, giving 0.52 g of the desired product, mp 122-124C.
Example 53 N-~3~(3-Cyanopyrazolo~1,5-a~pyrimidin-7 yl)phenyl]-N-methylcyclobutanecarboxamide m Aminoacetophenone, cyclobutanecarboxylic acid, chloride and diisopropylethylamine in dichloromethane were reacted, giving N-(3-acetylphenyl)cyclobutanecar30xamide.
This compound was then converted to N-[3-[3-(dimet~ylamino)-1-oxo-2-propenyl]phenyl]cyclobu~anecarbox-amide, mp 155-157C, by the procedure of Example 1 and further alkylated by the procedure o Example 6, using methyl iodide to give 8.32 g of N [3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl ! -N-methylcyclobutanecarboxamide, mp 117~119C.
~ 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 q of the desired product, mp 157-158C.
Example 54 7-~3-[~Cyclobutylcarbonyl)amino]phenyl~pyrazolo-[l,S-a]pyrimidine-3-carboxylic acid, ethyl este.r _ ~ 0.78 g portion of 3-amino-4-carboethoxypyrazole and 1.36 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]-phenyl]cyclobutanecarboxamide were reacted as described in Example 13, giving 1.52 g of the desired product, mp 123-125C.
propylethylamine and cyclopropanecarboxylic acid chloride in dichloromethane.
This compound was then converted to N-[3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl]cyclopropanecar-boxamide by the procedure of Example 1 and ehen alkylated by the procedure of Example 6, using methyl iodide, giving 10.17 g of N-[3-(3-dimethylamino)-1-oxo-2-propenyl)phenyl]-N-methylcyclopropanecarboxamide, mp 120-122C.
A 0.54 g portion of this compound was reacted as described in Example 13 with 3-aminopyrazole-4-carbo-nitrile, giving 1.08 g of the desired product, mp 178-180C.
Example 52 7-~3-[(Cyclopropylcarbonyl)methylamino]phenylpyrazolo-[1,5-a]pyrimidine-3-carboxylic acid7 ethyl ester A 0.73 g portion of ethyl 3-aminopyrazole-4-car-boxylate and 1.36 g of N-[3-[(3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methylcyclopropanecarboxamide were reacted as described in Example 13, giving 0.52 g of the desired product, mp 122-124C.
Example 53 N-~3~(3-Cyanopyrazolo~1,5-a~pyrimidin-7 yl)phenyl]-N-methylcyclobutanecarboxamide m Aminoacetophenone, cyclobutanecarboxylic acid, chloride and diisopropylethylamine in dichloromethane were reacted, giving N-(3-acetylphenyl)cyclobutanecar30xamide.
This compound was then converted to N-[3-[3-(dimet~ylamino)-1-oxo-2-propenyl]phenyl]cyclobu~anecarbox-amide, mp 155-157C, by the procedure of Example 1 and further alkylated by the procedure o Example 6, using methyl iodide to give 8.32 g of N [3-[3-(dimethylamino)-l-oxo-2-propenyl]phenyl ! -N-methylcyclobutanecarboxamide, mp 117~119C.
~ 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 q of the desired product, mp 157-158C.
Example 54 7-~3-[~Cyclobutylcarbonyl)amino]phenyl~pyrazolo-[l,S-a]pyrimidine-3-carboxylic acid, ethyl este.r _ ~ 0.78 g portion of 3-amino-4-carboethoxypyrazole and 1.36 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]-phenyl]cyclobutanecarboxamide were reacted as described in Example 13, giving 1.52 g of the desired product, mp 123-125C.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the formula:
wherein R1 is selected from the group consisting of hydrogen, halogen, cyano and ; R2 is selected from the group consisting of hydrogen and alkyl(C1-C3); R3 is ; R4 is selected from the group consisting of hydrogen, alkyl(C1-C6) and alkoxy(C1-C6); R5 is selected from the group consisting of hydrogen, alkyl(C1-C6), alkenyl(C2-C6), -CH2C?CH, cycloalkyl(C3-C6)methyl, -CH2OCH3 and -CH2CH2OCH3; and R6 is selected from the group consisting of alkyl(C1-C6), cycloalkyl(C3-C6), -O-alkyl(C1-C6), -NH-alkyl(C1-C3), -N-dialkyl(C1-C3), -(CH2)n-O-alkyl(C1-C3), -(CH2)n-NH-alkyl(C1-C3) and -(CH2)n-N-dialkyl(C1-C3), where n is an integer 1 to 3 inclusive.
wherein R1 is selected from the group consisting of hydrogen, halogen, cyano and ; R2 is selected from the group consisting of hydrogen and alkyl(C1-C3); R3 is ; R4 is selected from the group consisting of hydrogen, alkyl(C1-C6) and alkoxy(C1-C6); R5 is selected from the group consisting of hydrogen, alkyl(C1-C6), alkenyl(C2-C6), -CH2C?CH, cycloalkyl(C3-C6)methyl, -CH2OCH3 and -CH2CH2OCH3; and R6 is selected from the group consisting of alkyl(C1-C6), cycloalkyl(C3-C6), -O-alkyl(C1-C6), -NH-alkyl(C1-C3), -N-dialkyl(C1-C3), -(CH2)n-O-alkyl(C1-C3), -(CH2)n-NH-alkyl(C1-C3) and -(CH2)n-N-dialkyl(C1-C3), where n is an integer 1 to 3 inclusive.
2. A compound according to Claim 1, wherein R1 is cyano or ; R2 is hydrogen; R4 is alkyl(C1-C6), alkenyl(C2-C6) or -CH2?CH; and R6 is alkyl(C1-C6), cycloalkyl(C3-C6) or -O-alkyl(C1-C6).
3. The compound according to Claim 2, which is selected from the group consisting of:
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]]-N-ethylpropanamide;
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]]-N-ethylacetamide;
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]]-N-propylacetamide;
[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]methyl-carbamic acid, methyl ester;
7-[3-[(methoxycarbonyl)methylamino]phenyl]pyrazolo-[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester;
[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]
ethylcarbamic acid, methyl ester;
ethyl(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)carbamic acid, ethyl ester;
[3-(3-chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]ethyl-carbamic acid, ethyl ester;
N-[3-(3-cyanopyrazolo[1,5-alpyrimidin-7-yl)phenyl]-N-2-propenylacetamide;
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-2-propynylacetamide; and N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylacetamide.
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]]-N-ethylpropanamide;
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]]-N-ethylacetamide;
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]]-N-propylacetamide;
[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]methyl-carbamic acid, methyl ester;
7-[3-[(methoxycarbonyl)methylamino]phenyl]pyrazolo-[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester;
[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]
ethylcarbamic acid, methyl ester;
ethyl(3-pyrazolo[1,5-a]pyrimidin-7-ylphenyl)carbamic acid, ethyl ester;
[3-(3-chloropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]ethyl-carbamic acid, ethyl ester;
N-[3-(3-cyanopyrazolo[1,5-alpyrimidin-7-yl)phenyl]-N-2-propenylacetamide;
N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-2-propynylacetamide; and N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylacetamide.
4. A composition of matter in dosage unit form comprising from 2-750 mg of a compound of Claim 1 in association with a pharmaceutically acceptable carrier.
5. A process for producing a compound of the formula:
wherein R1 is selected from the group consisting of hydrogen, halogen, cyano and ; R2 is selected from the group consisting of hydrogen and alkyl(C1-C3); R3 is ; R4 is selected from the group consisting of hydrogen, alkyl(C1-C6) and alkoxy(C1-C6); R5 is selected from the group consisting of hydrogen, alkyl(C1-C6), alkenyl(C2-C6), -CH2C?CH, cycloalkyl(C3-C6)methyl, -CH2OCH3 and -CH2CH2OCH3; and R6 is selected from the group consisting of alkyl(C1-C6), cycloalkyl(C3-C6), -O-alkyl(C1-C6), -NH-alkyl(C1-C3 ), -N-dialkyl(C1-C3), -(CH2)n-O-alkyl(C1-C3), -(CH2)n-NH-alkyl(C1-C3) and -(CH2)n-N-dialkyl(C1-C3), where n is an integer from 1 to 3 inclusive, which comprises the steps of (a) reacting a 1-acetylphenyl-3-amide of the formula:
with dimethylformamide, dimethylacetal at reflux, which produces an N-[3-[3-(dimethylamino)-1 oxo-2-propenyl]phenyl]-alkanamide;
(b) reacting the N-[3-[3-(dimethylamino)-1-oxo-2-propeny]
phenyl]alkanamide with sodium hydride, which produces an anion;
(c) reacting the anion generated with an alkyl halide of the formula R5-X, wherein X is Br or I, which produces an N-[3-[3-(dimethylamino)-1-oxo 2-propenyl]phenyl]-N-alkyl-alkanamide of the formula:
;
(d) reacting the N-[3-[3-(dimetbylamino)-1-oxo-2-propenyl]-phenyl]-N-alkylalkanamide with a 3-aminopyrazole of the formula:
in glacial acetic acid at reflux, which reaction gives the desired products.
wherein R1 is selected from the group consisting of hydrogen, halogen, cyano and ; R2 is selected from the group consisting of hydrogen and alkyl(C1-C3); R3 is ; R4 is selected from the group consisting of hydrogen, alkyl(C1-C6) and alkoxy(C1-C6); R5 is selected from the group consisting of hydrogen, alkyl(C1-C6), alkenyl(C2-C6), -CH2C?CH, cycloalkyl(C3-C6)methyl, -CH2OCH3 and -CH2CH2OCH3; and R6 is selected from the group consisting of alkyl(C1-C6), cycloalkyl(C3-C6), -O-alkyl(C1-C6), -NH-alkyl(C1-C3 ), -N-dialkyl(C1-C3), -(CH2)n-O-alkyl(C1-C3), -(CH2)n-NH-alkyl(C1-C3) and -(CH2)n-N-dialkyl(C1-C3), where n is an integer from 1 to 3 inclusive, which comprises the steps of (a) reacting a 1-acetylphenyl-3-amide of the formula:
with dimethylformamide, dimethylacetal at reflux, which produces an N-[3-[3-(dimethylamino)-1 oxo-2-propenyl]phenyl]-alkanamide;
(b) reacting the N-[3-[3-(dimethylamino)-1-oxo-2-propeny]
phenyl]alkanamide with sodium hydride, which produces an anion;
(c) reacting the anion generated with an alkyl halide of the formula R5-X, wherein X is Br or I, which produces an N-[3-[3-(dimethylamino)-1-oxo 2-propenyl]phenyl]-N-alkyl-alkanamide of the formula:
;
(d) reacting the N-[3-[3-(dimetbylamino)-1-oxo-2-propenyl]-phenyl]-N-alkylalkanamide with a 3-aminopyrazole of the formula:
in glacial acetic acid at reflux, which reaction gives the desired products.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/732,986 US4626538A (en) | 1983-06-23 | 1985-05-13 | [7-(3-disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidines |
| US732,986 | 1985-05-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1270825A true CA1270825A (en) | 1990-06-26 |
Family
ID=24945743
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000508783A Expired - Lifetime CA1270825A (en) | 1985-05-13 | 1986-05-09 | ¬7-(3-disubstituted amino)phenyl|-pyrazolo¬1,5- a|pyrimidines |
Country Status (16)
| Country | Link |
|---|---|
| JP (1) | JPH0784468B2 (en) |
| KR (1) | KR900001887B1 (en) |
| AT (1) | ATE97414T1 (en) |
| AU (1) | AU587617B2 (en) |
| CA (1) | CA1270825A (en) |
| DE (2) | DE19975048I2 (en) |
| DK (1) | DK170534B1 (en) |
| ES (1) | ES8900165A1 (en) |
| FI (1) | FI83324C (en) |
| HK (1) | HK127795A (en) |
| IE (1) | IE61755B1 (en) |
| IL (1) | IL78700A (en) |
| NZ (1) | NZ216052A (en) |
| PH (1) | PH24037A (en) |
| SG (1) | SG30590G (en) |
| ZA (1) | ZA863499B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1198824C (en) * | 1999-09-02 | 2005-04-27 | 纽罗克里恩生物科学有限公司 | Polymorphs of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide and compositions and methods related thereto |
| DE10004790B4 (en) * | 2000-02-01 | 2004-09-09 | Lts Lohmann Therapie-Systeme Ag | Method for producing sewn or embroidered three-dimensional textile structure utilized for e.g. table cloth, involves connecting points on lattice structure with threads to form thread arrangement under which lattice structure is not visible |
| ES2222813B1 (en) * | 2003-07-24 | 2005-12-16 | Ferrer Internacional, S.A. | N- (3- (3-SUBSTITUTES-PIRAZOLO (1,5-A) PIRIMIDIN-7-IL) -PENYL) -SULPHONAMIDS AND RELATED COMPOSITIONS AND METHODS |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4178449A (en) * | 1978-04-17 | 1979-12-11 | American Cyanamid Company | Pyrazolo[1,5-a]pyrimidines and imidazo-[1,5-a]pyrimidines |
| NZ208554A (en) * | 1983-06-23 | 1987-06-30 | American Cyanamid Co | (aryl and heteroaryl)-(7-(aryl and heteroaryl)-pyrazolo (1,5-a) pyrimidin-3-yl)-methanone derivatives and pharmaceutical compositions |
-
1986
- 1986-04-21 SG SG1995905097A patent/SG30590G/en unknown
- 1986-04-21 AT AT86105477T patent/ATE97414T1/en active
- 1986-04-21 DE DE1999175048 patent/DE19975048I2/en active Active
- 1986-04-21 DE DE3689294T patent/DE3689294T2/en not_active Expired - Lifetime
- 1986-05-05 NZ NZ216052A patent/NZ216052A/en unknown
- 1986-05-06 IL IL78700A patent/IL78700A/en not_active IP Right Cessation
- 1986-05-07 PH PH33742A patent/PH24037A/en unknown
- 1986-05-09 CA CA000508783A patent/CA1270825A/en not_active Expired - Lifetime
- 1986-05-12 ZA ZA863499A patent/ZA863499B/xx unknown
- 1986-05-12 AU AU57360/86A patent/AU587617B2/en not_active Expired
- 1986-05-12 JP JP61106883A patent/JPH0784468B2/en not_active Expired - Lifetime
- 1986-05-12 ES ES554887A patent/ES8900165A1/en not_active Expired
- 1986-05-12 IE IE124786A patent/IE61755B1/en not_active IP Right Cessation
- 1986-05-12 FI FI861973A patent/FI83324C/en not_active IP Right Cessation
- 1986-05-12 DK DK218286A patent/DK170534B1/en not_active IP Right Cessation
- 1986-05-12 KR KR1019860003674A patent/KR900001887B1/en not_active IP Right Cessation
-
1995
- 1995-08-10 HK HK127795A patent/HK127795A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PH24037A (en) | 1990-02-09 |
| NZ216052A (en) | 1989-04-26 |
| SG30590G (en) | 1995-09-18 |
| FI83324B (en) | 1991-03-15 |
| IL78700A (en) | 1989-06-30 |
| DE19975048I2 (en) | 2001-06-13 |
| JPS61260083A (en) | 1986-11-18 |
| IE61755B1 (en) | 1994-11-30 |
| FI83324C (en) | 1991-06-25 |
| JPH0784468B2 (en) | 1995-09-13 |
| IL78700A0 (en) | 1986-08-31 |
| KR860009017A (en) | 1986-12-19 |
| ES8900165A1 (en) | 1989-03-01 |
| AU587617B2 (en) | 1989-08-24 |
| ES554887A0 (en) | 1989-03-01 |
| DK170534B1 (en) | 1995-10-16 |
| KR900001887B1 (en) | 1990-03-26 |
| FI861973A (en) | 1986-11-14 |
| DK218286D0 (en) | 1986-05-12 |
| DK218286A (en) | 1986-11-14 |
| AU5736086A (en) | 1986-11-20 |
| ATE97414T1 (en) | 1993-12-15 |
| HK127795A (en) | 1995-08-18 |
| IE861247L (en) | 1986-11-13 |
| ZA863499B (en) | 1987-11-12 |
| DE3689294D1 (en) | 1993-12-23 |
| FI861973A0 (en) | 1986-05-12 |
| DE3689294T2 (en) | 1994-06-09 |
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