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GB2116971A - 1H-pyrazolo [1,5-a] pyrimidines - Google Patents

1H-pyrazolo [1,5-a] pyrimidines Download PDF

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GB2116971A
GB2116971A GB08306905A GB8306905A GB2116971A GB 2116971 A GB2116971 A GB 2116971A GB 08306905 A GB08306905 A GB 08306905A GB 8306905 A GB8306905 A GB 8306905A GB 2116971 A GB2116971 A GB 2116971A
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oxo
pyrimidine
pyrazolo
carboxamide
pyridyl
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GB2116971B (en
GB8306905D0 (en
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Gianfederico Doria
Carlo Passarotti
Ada Buttinoni
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds having anti- inflammatory and analgesic activity of formula <IMAGE> wherein R1 is a) a pyridyl group, unsubstituted or substituted by a C1-C6 alkyl group; b) a phenyl ring, unsubstituted or substituted by one or more substituents chosen from halogen, trihalo-C1-C4 alkyl, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, formyloxy, C2-C6 alkanoyloxy, nitro, amino, formylamino and C2-C6 alkanoylamino; c) benzyl; or d) C1-C6 alkyl; each of R2 and R3 independently is a hydrogen of a halogen atom or C1-C6 alkyl; R4 is hydrogen, C1-C6 alkyl or phenyl; R5 is a'> <IMAGE> wherein each of R6 and R7 independently is hydrogen or C1-C6 alkyl, or R6 and R7, taken together with the nitrogen atom to which they are linked, form a morpholino, piperidino, N-pyrrolidinyl or N-piperazinyl ring, all the rings being unsubstituted or substituted by C1-C6 alkyl; b'> <IMAGE> wherein R8 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy or halogen; c') a -NH-R9 group,wherein R9 is an unsaturated heterocyclic ring containing one or two heteroatoms chosen front nitrogen and sulphur, unsubstituted or substituted by one or two substituents chosen from halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy and phenyl; d'> <IMAGE> wherein m is 1, 2 or 3 and R6 and R7 are as defined above; or e') hydroxy or C1-C6 alkoxy unsubstituted or substituted by <IMAGE> wherein R6 and R7 are as defined above; and wherein R5 is not as defined above under e') when R1 is C1-C6 alkyl; and the pharmaceutically acceptable salts thereof.

Description

SPECIFICATION Substituted 1H - pyrazolo[1,5 - a]pyrimidines and process for their preparation The present invention relates to new substituted 1 H - pyrazolofi - a]pyrlmidines, to a process for their preparation and to pharmaceutical compositions containing them.
The invention provides compounds having the following general formula (!)
wnereln R1 is a) a pyridyl group, unsubstituted or substituted by a C1-C6 alkyl group; b) a phenyl ring, unsubstituted or substituted by one or more substituents chosen from halogen, trihalo-C1C4 alkyl, C1-C8 alkyl, C1-6 alkoxy, hydroxy, formyloxy, C2-C6 alkanoyloxy, nitro, amino, formylamino and C2-C6 alkanoylamino; c) benzyl; or d) C1-C6 alkyl; each of R2 and R3 independently is a hydrogen or a halogen atom orC1-C6alkyl; R4 is hydrogen, C1-C6 alkyl or phenyl; is iS a')
wherein each of R6 and R7 independently is hydrogen or C1-C6 alkyl, or B6 and R7, taken together with the nitrogen atom to which they are linked, form a morpholino, piperidino, N-pyrrolidinyl or N-piperazinyl ring, all the rings being unsubstituted or substituted byC1-C6alkyl; b')a
group, wherein B6 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy or halogen;; c') a -NH-Rg group, wherein B8 is an unsaturated heterocyclic ring containing one or two heteroatoms chosen from nitrogen and sulphur, unsubstituted or substituted by one or two substituents chosen from halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy and phenyl; d')
wherein m is 1,20 or 3 and R6 and R7 are as defined above; or e') hydroxy or C1-C6 alkoxy unsubstituted or substituted by
wherein B6 and R7 are as defined above; and wherein R5 is not as defined above under e') when R1 is C-C6 alkyl; and the pharmaceutically acceptable salts thereof.
The present invention includes also the metabolites and the metabolic precursors of the compounds of formula (I) and all the possible isomers of the compounds of formula (I), e.g. optical isomers, and the mixtures thereof.
The alkyl, alkoxy, alkoxycarbonyl, alkanoyloxy and alkanoyiamino groups may be branched or straight chain groups. A halogen atom is, for example, chlorine, bromine or fluorine, preferably it is chlorine or bromine.
Atrihalo-01-C4 alkyl group may be, for example, a trifluoro-C1-C4 alkyl group, preterably it is trif luoromethyl. A C2-C6 alkanoyloxy group is, for example, acetoxy, propionyloxy, butyryloxy or vaieryloxy, preferably it is acetoxy.
A Cl-C6 alkyl group is preferably a C1-C4 alkyl group, in particular, methyl, ethyl, propyl ortert- butyl.
A C,-C6 alkoxy group is preferably Cs-C4 alkoxy, in particular, methoxy, ethoxy, propoxy or butoxy.
A C2-C6 alkanoylamino group is, for example, acetylamino, propionylamino, butyrylamino or valerylamino, preferably it is acetylamino.
When R1 is a C1-C6 alkyl group, it is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably it is methyl, ethyl, propyl or tert-butyl.
When R1 is a pyridyl group substituted by a C1-C6 alkyl group, the alkyl group may be, for example, methyl, ethyl or propyl, preferably it Is methyl.
When R1 is a phenyl ring substituted as defined above, it is preferably substituted by one or more substituents chosen from chlorine, fluorine, trif luoromethyi, methyl, methoxy, amino and acetyla mino.
When B2 and/or R3 is a halogen atom it is, e.g., chlorine, bromine or fluorine, preferably it is chlorine or bromine.
When R2 and/or B3 represents a C1-C6 alkyl group, it is, for example, methyl, ethyl, propyl or isopropyl, preferably it is methyl.
When R4 represents a C1-C6 alkyl group, it is, for example, methyl, ethyl, propyl, isopropyl or butyl, preferably it is methyl, ethyl, propyl or isopropyl.
When one or both of B6 and R7, being the same or different, is a C1-C6 alkyl group, it is for example methyl, ethyl, propyl, isopropyl or butyl, preferably it is methyl, ethyl, propyl or isopropyl.
When R6 and R7, taken together with the nitrogen atom to which they are linked, form a morpholino, piperidino, N-pyrrolidinyl or N-piperazinyl ring and said ring is substituted by C1-C6 alkyl, the alkyl group is preferably C1-C4 alkyl, in particular methyl or ethyl.
When B8 is halogen, it is, e.g., chlorine, bromine or fluorine, preferably it is chlorine or bromine.
When B8 is a C1-C4 alkyl group, it is preferably a methyl group.
When B8 is a C1-C4 alkoxy group, it is preferably methoxy or ethoxy.
When B9 is a heterocyclic ring as defined above under c') it may be a heteromonocyclic or heterobicyclic ring, preferably it is a pyridyl, a pyrimidinyl, a thiazolyl, a pyrazolyl or a benzothiazolyl group, each of them being preferably unsubstituted or substituted by one or two substituents chosen from methyl, chlorine, bromine and methoxy.
Preferred compounds of the invention are those of formula (I) wherein R1 is pyridyl; benzyl; C1-C6 alkyl; or phenyl unsubstituted or substituted by one or two substituents chosen from chlorine, methyi,amino and acetylamino; each of R2 and B3 independently represents hydrogen, chlorine or a methyl group; R4 is hydrogen, C1-C2 alkvl or nhenvl R5isa")
wherein each of R'6 and R'7 is independently hydrogen or C1-C4 alkyl; or R'6 and B'7, taken together with the nitrogen atom to which they are linked, form a morpholino, piperidino or N-piperazinyl ring, wherein the N-piperazinyl ring is unsubstituted or substituted by C1-C4 alkvl.
b")
,wherein R1i is hydrogen, methyl, methoxy or chlorine; c") -NHR9, wherein R9i is a pyridyl, pyrimidinyl, 2-thiazoyly or 2-benzothiazolyl group, wherein all the groups are unsubstituted or substituted by one or two substituents chosen trom chlorine, bromine, methyl and methoxy or @@@
wherein m, H'6 and R'7 are as defined above; and the pharmaceutically acceptable salts thereof.
More preferred compounds of the invention are those of formula (1) wherein : R1 is pyridyl; benzyl; or phenyl unsubstituted or substituted by one or two substituents chosen from chlorine, methyl, amino and acetylamino : each of R2 and R3i independently represents hydrogen, chlorine or a methyl group; R4 is hydrogen, C1-C2 alkylor phenyl R5isa")
wherein each of R"6ar and R"7 is independently hydrogen or C1-C3 alkyl, or R"6 and R"7 taken together with the nitrogen atom to which they are linked, form a morpholino, a piperidino or a N-piperazinyl ring, wherein the N-piperazinyl ring is unsubstituted or substituted by C1-C4 alkyl.
b")
,wherein B8 is hydrogen, methyl,methoxy or chlorine; c") -NHR9, wherein Rg is a pyridyl, pyrimidinyl, 2-thiazolyl or 2-benzothiazolyl group wherein all the groups are unsubstituted or substituted by one or two substituents chosen from chlorine, bromine, methyl and methoxv: or d")
,wherein m, R"6 and R"7 are as defined above; and the pharmaceutically acceptable salts thereof.
Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides or with organic bases, such as lysine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di - (2 - ethyl - hexyl) - amine, piperidine, N-ethylpiperidine, N,N-diethylaminoethylamine, N-ethyl-morpholine, ss-phenethylamine, N - benzyl '3- phenethylamine, N - benzyl - N,N - dimethylamine and the other acceptable organic amines, as well as the salts with inorganic acids, e.g. nitric, hydrochloric, hydrobromic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric, methanesulphonic and ethanesulphonic acids.
Examples of particularly preferred compounds of the invention are: 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5= aipyrimidine - 6 - N - (3 - pyridyl) - carboxamide 1-pnenyl-7-oxo-1H,7H-pyrazolo@@@@- a]pyrimidine-6-N-(2-pyridyl)-carboxamide ; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5 aipynmidine - 6 - N - (6 - methyl - 2 - pyridyl) carboxamide; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(5-chloro-2-pyridyl)carboxamide; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5 ajpyrimidine -6 - N - (2- pyryimidinyl) - carboxamide; 3 - methyl - 1 - phenyi - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (2 - pyridyl) - carboxamide; 1 phenyl - 7 - oxo - 1H,7H - pyrazolo[1,5 5]pyrimidine - 6 - N - (6 - methoxy- 3 - pyridyl) carboxamide; 5-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyridyl)-carboxamide ; 5-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (2 - pyrimidinyl) - carboxamide; 3,5-dimethyl-l- phenyl- 7-oxo-1H.7H- pyrazolo[1,5-a]pyrimiame-6-N-[2-pyriayl)carboxamide; 5-ethyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5 alpyrimidine - 6 - N - (2 - pyridyl) - carboxamide; 1 - (3 - chloro - phenyl) - 7 - oxo -1 H,7H - pyrazolo[1,5 -a]pyrimiaine-@-N-(2-pyriayl@-carboxam@@e; 1-(3-chloro-phenyl)-5-methyl-7-oxo-1H,7H.
pyrazolo[1,5 - a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide; 1 - (4 - chloro - phenyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - N - (2 - pyridyl) - carboxamide; @-(4-@@@@@@-p@eny@-@-me@@y@-@-oxo-@@@@@@ pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide; 1-(4-amino-phenyl)-7-oxo-1H,7H-pyrazolo[1,5 -a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-(4-acetylamino-phenyl)-7-oxo-1H,7Hyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide; 1 - (3 - pyridyl) - 7 - oxo - 1 H,7H - pyrnzolo[1,5- a]pyrimidine-@-@-(2-pyri@y@)-carpoxam@@e; 1 - (3 - pyridyl) - 7 - oxo -1 H,7H - pyrazolo[1,5 a]pyrimidine-@-N-(@0methyl)-2-yridyl)- carboxamide; 5-methyl-1 -(3-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(5-chloro-2-pyridyl)carboxamide; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-thiazolyl)-carboxamide ; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (5 - chloro - 2 - pyridyl) carboxamide; 5-methyl-1-(2-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyriminidine-6-N-(2-thiazolyl)carboxamide; 1 - benzyl - 7 - oxo - 1 H,7H - pyrazolo[1,5- a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1 - benzyl - 5 - methyl - 7 - oxo - 1 H,7H - pyrazolo[1 ,5 a]pyrimidine - 6 - N - (2 - pyridyl) - carboxamide; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5 lpyrimidine-6-N-(2-piperidino-ethyl) carboxamide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5 alpyrimidine - 6 - N - (2 - pyridyl) - carboxamide; 1-ethyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) - carboxamide; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5 a]pyrimidine-6-N-(2-pyridyl)-carboxamide ; 1 - methyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (2 - thiazolyl) - carboxamide;; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5 a1pyrimidine - 6 - N - (2 - benzothiazolyl) - carbox amide; 1 - (2 - pyridyl) - 7- oxo -1 H,7H - pyrazolo[1,5- a]pyrimidine-6-N-(2-thiazolyl)-carboxamide ; 1 - (2 - pyridyl) - 7 - oxo - 1H,7H - pyrazolo[1,5 lpyrimidine -6 - N - (2 - benzothiazolyl) - carbox amide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5 a]pyrimidine-6-N-(2-piperidino-ethyl) carboxamide; 1,5 - dimethyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (2 - pyridyl) - carboxamide; 1-(4-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5 a]pyrimidine - 6 - N - (2 - pyridyl) - carboxamide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5-a] pyrimidine - 6 - N - (5 - chloro - 2 - pyridyl) carboxamide;; 5 - methyl - 1 - (2 - pyridyl) - 7 - oxo - 1H, 7H - pyrazolo [1,5-a]pyrimidine-6-N-(2-pyridyl) carboxamide; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5-a] pyrimidine - 6 - carboxylic acid; 5-methyl-1-henyl-7-oxo-1H,7H-pyrazolo[1, 5 - a] pyrimidine - 6 - carboxylic acid; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5-a] pyrimidine - 6 - carboxylic acid; and 5-methyl-1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo [1,5 - al pyrimidine - 6 - carboxylic acid; and the pharmaceutically acceptable salts thereof.
The compounds of the invention can be prepared bya process comprising: a) cyclizing a compound of formula (11)
wnereln R1, R2, R3, R4 and B5 are as defined above and B10 is a nucleophile group able to easily remove the proton @linked to the nitrogen atom of the pyrazolyl ring, or a salt thereof; or b) reacting a compound of formula (11 1)
wherein R1, R2, B3 and R4 are as defined above and R11 is a free or esterified carboxy group, or a salt thereof, with a compound of formula (IV) H2N-B9 (IV) wherein R9 is as defined above, or an active derivative thereof, so obtaining compounds of formula (1 ) wherein R5 is as defined above under c'); or c) reacting a compound of formula (V)
wherein R1, R2, B3 and R4 are as defined above and Z is a reactive carboxy group, with a compound of formula (VI)
or of formula (VII)
or or formula (VIII) wherein
R6, R7, R8 and m are as defined above, so obtaining compounds of formula (I) wherein B5 is as defined above under a'), b') and d') respectively, and if desired, converting a compound of formula (I) into another compound of formula (I) andtor, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof and/or, if desired, obtaining a free compound of formula (I) from a salt thereof and/or, if desired, separating a mixture of isomers into the single isomers.
When R10is a nucleophiie group as defined above, it is, for example, hydroxy, tri - (C1 - C6) alkyl silyloxy, or C1 - Cg alkoxy unsubstituted or substituted by a
group, wherein B6 and B7 are as defined above.
The compounds of formula (II) may also be represented by the tautomeric formula (Ila)
wherein R1, R2, R3, R4, R5 and R1o are as defined above.
Preferred salts of the compounds of formula (II) and (III) are, for example, those with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric and sulphuric acid.
The cyclization of a compound of formula (lI) may be, for example, carried out by treatment with an acid condensing agent such as polyphosphoric acid (alone or in the presence of phosphorus oxychloride, sulphuric acid, hydrochloric acid, methanesulphonic acid or p - toluenesulphonic acid, at a temperature ranging preferably about between 50 C and 1 50 C; the reaction may be carried out in an organic solvent such as dimethylformamide, dimethylacetamide, jimethylsulphoxide, benzene, toluene, xylene, ethylene glycol monomethylether or dichloroethane, but it is preferably carried out in the absence of a solvent.
Alternatively, the cyclization of a compound of formula (II) may be carried out by heating the compound at a temperature ranging between about 15000 and about3SO0C, preferably between 200 C and 300 C, in an inert high boiling organic solvent such as diphenyl ether, or in the absence of a solvent.
When in a compound of formula (III) R11 is an esterified carboxy group, it is, for example, an alkoxy - carbonyl group or a tri - (C1-C6) alkyl - silyloxy carbonyl group.
The reaction between a compound of formula (III), or a salt thereof, and a compound of formula (IV) may be carried out, for example, by heating with polyphosphoric or methane - sulphonic or p toluenesulphonic acid at a temperature varying between about 50 C and about 200 C in the absence of a solvent or in the presence of an inert organic solvent such as dimethylformamide, dimethylacetamide, toluene orxylene; or, alternatively, by heating from about 50 C to about 15000 without any acidic agent and in the presence of an organic solvent only, e.g., toluene or xylene, if required.
An active derivative of a compound of formula (IV) is, e.g., a compound obtained by reacting a compound of formula (IV) with PCI3 in pyridine, at a temperature ranging from room temperature and about 50 C. The reaction between such active derivative of a compound of formula (IV) and a free acid of formula (III) is carried out in the same medium by heating to a temperature ranging from about 50 C to the reflux temperature.
The reactive carboxy group Z in a compound of formula (V) is, for example, a -COZ' group, wherein Z' is, e.g., halogen, preferably chlorine or bromine, or Z is a -COOCOOR12 group, wherein R12is, e.g., C1-C6 alkyl, phenyl or benzyl. The reaction between a compound of formula (V) and a compound of formula (VI), (VII) or (VIII) may be carried out, for example, in an inert organic solvent such as ben zene, toluene, xylene, dioxane, chloroform, dichlor oethane, methylene choride or tetrahydrfuran, at a temperature varying between about 0 C and about 1 20 C, preferably in the presence of a base such as triethylamine or pyridine.
A compound of formula (I) may be converted, as stated above, into another compound of formula (I) by known methods. For example, a compound of formula (I) wherein -COR5 is C1-C6 alkoxy - carbonyl, wherein the alkoxy group is unsubstituted or substituted by a
group, wherein B6 and R7 are as defined above, may be converted into a compound of formula til wherein -CORs is a free carboxy group by conventional methods, for example by acid hydrolysis using, for example, HCI, HBr, HI in water or in acetic acid or dioxane or their mixtures and operating at a temperature ranging from the room temperature to about 1 50 C;; the same hydrolysis may be also carried out e.g. by treatment with lithium bromide in dimethylformamide at a temperature higher than 50 C.
Furthermore, for example, a compound of formula (I) wherein -CORs is a free carboxy group may be converted into a compound of formula (I) wherein
group, wherein Rs, R7, B8 and m are as defined above, by converting the carboxylic acid into the corresponding halocarbonyl, preferably chlorocarbonyl, derivative, by reaction, e.g., with the desired acid halide, for example oxalyl chloride, thionyl chloride, PCI3, PC15 or POCI3, either in the absence of solvents or in an inert organic solvent such as benzene, toluene, xylene, dioxane, dichloroethane, methylene chloride or tetrahydrofuran, at a temperature ranging preferably from about 0 C to about 12000 and then reactinothe nhtained halncarhnnvl derivative with a compound of formula
wherein Rs, R7, Rsand m are as defined above, according to the same reaction conditions described aboveforthe reaction of compound of formula (V) with a compound of formula (VI), (VII), or (VIII).
A compound of formula (I), wherein -CORs is carboxy or a C1-C6 alkoxycarbonyl group, wherein the alkoxy group is unsubstituted or substituted by a
group, may be converted into a compound of formula (I), wherein -COR5 is a -CONH-Rg group, wherein Rg is as defined above, by reaction with a compound offormula NH2B9, wherein B9 is as defined above, by following, for example, the same reaction conditions described above for the reaction of a compound of formula (III) with a compound of formula (IV). Furthermore, for example, a compound of formula (I), wherein -CORs is a free carboxy group, may be converted into a compound of formula (I) wherein -CORs is C1-C6 alkoxy - carbonyl, unsubstituted or substituted by a
group, wherein B8 and R7 are as defined above, by conventional methods, for example, by converting the carboxylic acid into the corresponding chlorocarbonyl derivative, following, e.g. one of experimental methods described above and then reacting the obtained chlorocarbonyl derivative with an alcohol of formula (IX) R' 5-OH (IX) wherein R's is a C1-C6 alkyl group unsubstituted or substituted by a -N / K6 group, wherein Rg and R7 are as defined above, in the absence of a solvent or in the presence of an inert organic solvent such as benzene, toluene, dioxane, tetrahydrofuran at a temperature varying between about 0 C and about 12000.
Furthermore, for example, a nitro group as substituent in the R1 phenyl group may be converted into an amino group by treatment, for example, with stannous chloride in concentrated hydrochloric acid, using, if necessary, an organic cosolvent such as acetic acid, dioxane, tetrahydrofuran at a temperaturevarying between room temperature and about 100"C.
Furthermore, for example, an amino or hydroxy group may be converted respectively into a formyla mino, C2-C6 alkanoylamino or C2-C6 alkanoyloxy group, for example by reaction with formic acid or with the corresponding alkanoyl anhydride without any solvent or in an organic solvent such as dioxane, dimethylformamide, tetrahydrofuran, usually in the presence of a base such as pyridine or triethylamine at a temperature varying between 0 C and about 100"C.
Also the optional saiification of a compound of formula (I) as weli as the conversion of a salt into a free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods.
For example, the separation of a mixture of optical isomers into the individual isomers may be carried out by salification with an optically active base or acid and subsequent fractional crystallization.
The compounds of formula (II) may be prepared, for example, by reacting a compound of formula (X) wherein
R1, R2 and B3 are as defined above, or a salt thereof, with a compound of formula (XI) wherein
B4, R5 and R10 are as defined above and B13 is a reactive group chosen, preferably, from hydroxy, amino, C1-Cs alkoxy or tri - (C1-Cs) alkyl - silyloxy.
Preferred salts of a compounds of formula (X) are, for example, those with inorganic acids such as hydrochloric, hydrobromic, phosphoric and sulphur ic acid.
The reaction between a compound of formula (X) and a compound of formula (Xl) may be carried out, for example, by heating in solvents such as dioxane, toluene, xylene, acetonitrile, C1-C4 alkyl alcohols, acetic acid, dimethylformamide, dimethylacetamide, diphenylether or in the absence of a solvent at a temperature varying from about 50 C to about 200 C.
Preferably, when R10 is hydroxy, the reaction between a compound of formula (X) and a compound of formula (XI) is carried out in the presence of an acid condensing agent such as polyphosphoric acid, methanesulphonic acid, p-toluenesulphonic acid or acetic acid using the same experimental conditions, as described above, for the cyclization of the compounds of formula (II).
Under these specific conditions the reaction of a compound of formula (X) with a compound of formula (Xl) may be carried out till a compound of formula (I) is obtained without the need to isolate the intermediate product of formula (II) formed during the reaction.
The compounds of formula (III), wherein R1 is C1-C6 alkyi, are compounds of formula (I) which are excluded from the scope of the invention, as stated above.
The compounds of formula (III) may be prepared by cyclizing a compound of formula (XII)
R1, R2, R3, R4, Rio and B11 are as defined above, using the same experimental conditions specified above for the cyclization of a compound of formula (II).
Alternatively, for example, the compounds of formula (III), wherein R11 is a free carboxy group, may be prepared by hydrolyzing a compound of formula (III) wherein B11 is an esterified carboxy group or a tri - (C1-C6)alkyl - silyloxy - carbonyl group, bytreatment, for example, with a mineral acid such as HCI, HBr, HI in water or in acetic acid or dioxane or their mixtures at a temperature varying between room temperature and about 12000.
The compounds of formula (V), wherein Z' is halogen, preferably chlorine or bromine, may be prepared, for example, by reacting a compound of formula (III), wherein R11 is a free carboxy group, with a suitable acid halide such as oxalyl chloride, SOCI2, PCI3, POOl3, PBr3, for example, in a solvent such as benzene, toluene, dioxane, dichloroethane, at a temperature varying between room temperature and about 12000.
The compounds of formula (V), wherein Z is a group -COOCOOR12, wherein R12 is as defined above, may be prepared, for example, by reacting a compound of formula (III), wherein B11 is a free carboxy group, with a compound of formula YCOOR12, wherein B12 is as defined above and Y is a halogen atom, preferably chlorine or bromine, in a solvent such as benzene, toluene, dioxane, dichloroethane, methylene chloride, chloroform, in the presence of a base such as pyridine or triethylamine, at a temperature varying between about 0 C and about 50 C.
The compounds of formula (XII) may be prepared, for example, by reacting a compound of formula (X), as defined above, with a compound of formula (XII I)
B4, Rao, B11 and B13 are as defined above, using the same experimental conditions specified above for the reaction between a compound of formula (X) and a compound of formula (XI).
The compounds of formula (IV), (VI), (VII), (VIII), (IX), (X), (Xl) and (Xill) are known compounds or may be prepared by conventional methods: in some cases they are commercially available products.
The compounds of this invention possess anti-inflammatory activity as demonstrated e.g. by the fact that they are active, after oral administration, in inhibiting: A) the oedema formation in the hind paw of rats in response to a subplantar injection of carrageenin, according to the method of C.A. Winter et al. (J. Pharmac. Exp. Therap. 1963, 141, 369) and P.
Lence (Arch. Int. Pharmacodyn., 1962, 136,237), and B) the Reversed Passive Arthus Reaction (RPAR) in rat paw, induced by the interaction of antigen and antibody resulting in the formation of precipitating immune complex, followed by fixation of complement and accumulation of polymorphonuclear leucocytes at a focal point (D. K. Gemmell, J. Cottney and A. J. Lewis: Agents and Actions 9/1 pag. 107, 1979.
The compounds of this invention are also endowed with analgesic activity. The analgesic activity was assessed, for example, by means of phenylquinonetest in mice according to Siegmund [Sieg mund et al. Proc. Soc. Exper. Biol. Med., 95,729 (1957)].
Therefore the compounds of the invention may be used in therapy to treat pains and inflammatory processes, for example, rheumatoid arthritis and osteoarthrosis.
The following Table 1 shows, for example, the approximate ED25 values of the antiinflammatory activity in the carrageenin induced oedema test, in the rat after oral administration, for some compounds of this invention: TABLE I
Compound Antiinflammatory activity carrageenin induced oedema 1-phenyl-7-oxo-1H,7H-pyra zoloh ,5-aapyrimidine-6-N- ED = 16 mg/kg -(2-pyridyl)-carboxamide 5-methyl-1-phenyl-7-oxo -19,7H-pyrezoloJl,5-ajpy- ED25 = 9.8 mg/kg rimidine-6-N-(2-pyridyl) -carboxamide The compounds of formula (I), wherein R1 is Cl-C6 alkyl and B5 is hydroxy or C1-Cs alkoxy, are known compounds, e.g., they are described in Published Japan Patent Application 14424/66 and in Belgian Patent 847,698 and, in fact, they are excluded by the previously reported proviso.
A pharmacological comparison has shown that the compounds of this invention are more active, as anti-inflammatory agents, than those of the above cited prior art.
For example, the compound of this invention 1 methyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - N - (2 - pyridyl) - carboxamide (internal code FCE 23081) was tested versus the compound of the above prior art 1 - methyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 - aipyrimidine - 6 - carboxylic acid, ethyl ester (internal code SR 5444/50) according to the carrageenin and RPAR tests described above, and the following results were obtained: a) in the carrageenin induced oedema test in the rat, after oral administration at a dosage of 100 mg/kg body weight, the anti-inflammatory activity of the compound FCE 23081 was found to be about three times higher than that of the compound SR 5444/50; and b) in the RPAR test in the rat, after oral administration art a dosage of 100 mg/kg body weight, the compound SR 5444/50 was found to be totally inactive; on the contrary the compound FCE 23081 was found to strongly inhibit the RPAR reaction.
In view of their high therapeutic index, the com pounds of the invention can be used safely in medicine. For example, the approximate acute toxicity (LD50) of the compounds 1 - phenyl - 7 - oxo 1 H,7K - pyrazolo[l,5- - a]pyrimidine - 6 - N - (2 pyridyl) - carboxamide,1 - phenyl - 7 - oxo - 1 H,7H pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid and 5 - methyl - 1 - phenyl - 7 - oxo -1 H,7H - pyrazoloil 5 - a]pyrimidine - 6 - N - (2 - pyridyl) - carboxamide in the mouse, determined by single administration of increasing doses and measured on the seventh day after the treatment, is higher than 800 mg/kg per os.
Analogous toxicity data have been found for other compounds of the invention.
The compounds of the invention can be ad minis- tered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, e.g. intra muscularly, or by intravenous injection or infusion.
The dosage depends on the age, weight, condi tions of the patient and administration route; for example the dosage adopted for oral administration to adult humans may range from about 20 to about 200 mg pro dose, from 1 to 5 times daily.
The invention includes pharmaceutical composi tions comprising a compound of the invention in association with a pharmaceutically acceptable exci I pient (which can be a carrier or diluent).
The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are adminis tered in a pharmaceutically suitable form.
For example, the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxy methyl cellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologicaily inactive substances used in pharmaceutical formulations.
Said pharmaceutical preparations may be manufactured in Imown manner, for example, by means of mixing, granulating, tabetting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/orsorbitol; In particular a syrup to be administered to diabetic patIents can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amount to glucose, for example sorbitol.
The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, ca rboxmethylcellu- lose, or polyvinyl alcohol.
The suspensions or solutions for intramuscular injections may contain together with the active compound a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g.
propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The following examples illustrate but do not limit the invention.
Example 1 1 - phenyl - 3 - amino - pyrazole, m.p.90-91 C (18 g) was reacted with diethyl ethoxymethylenemalonate (29.3 g) in anhydrous ethanol (180 ml) at the reflux temperature for 15 hours. After cooling the solution was evaporated in vacuo to dryness: the residue was dissolved in isopropyl ether (200 ml) and decolorized by charcoal. Crystallization obtained by dilution with hexane gave diethyl N - (1 - phenyl pyrazol - 3 - yl) - aminomethylenemalonate, m.p.
81-82"C (31 g), which was reacted with polyphosphoric acid (13 g: 6.1 g of P205 and 6.9 g of H3PO4) and POOl3 (57 g) under stirring at the reflux temperature for 30 minutes. After cooling the reaction mixture was diluted with ice water and then the solution was decolorizedwith charcoal: neutraliza- tion with 35% NaOH gave a precipitate which was filtered and washed with water. Washing with hexane gave 1 - phenyl - 7 - oxo 1H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p. 187-190O (24.2 g), which was hydrolized by heating with a mixture 1:1 of 37% HCI: acetic acid (1.21) at the reflux temperature for 4 hours.After cooling the reaction mixture was neutralized to pH=6 with 35% NaOH and the precipitate was filtered and washed with water: crystallization from isopropyl alcohol gave 9.7 g of 1 - phenyl - 7 - oxo 1 H,7H - pyrazolo[1 ,5 - a]pyrimidine - 6 - carboxylic acid m.p. 185-190 C dec. N.M.R. (DMSO-d6) [p.p.m.: 6.94 (d) (1 H, C-3 proton), 7.59 (s) (5H, phenyl protons), 8.74 (d) (1H, C-2 proton), 8.81 (s) (C-5 proton).
By proceeding analogously the following ethyl esters, and after hydrolysis, the following acids were prepared: 2 - chloro - 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
196 C; 1 - (2 - methyl - phenyl) - 7 - oxo - 1H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester; 1 - (3 methyl - phenyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 - a]pynmidine - 6 - carboxylic acid, ethyl ester; 1 - (4 - methyl - phenyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 - aipyrimidine - 6 - carboxylic acid, ethyl ester; 1 -(2-methoxy-phenyl)-7-oxo-1H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester; 1 -(4-methoxy-phenyl)-7-oxo-1H,7H- pyrazoio[1 ,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester;; 11 - (4 - nitro - phenyl) - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
240-250 C; 1 - (4 - fluoro - phenyl) - 7 - oxo - 1H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
215-220 C dec.; 1 - (2 - chloro - phenyl) - 7 - oxo - 1H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester; 1 - (3 - chloro - phenyl) -7 - oxo - 1 H,7H - pyrazolot1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
200-205 C; 1 - (4 - chloro - phenyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
181-183"C; 1 - (3 - trifluoromethyl - phenyl) - 7 - oxo - 1 H,7H pyrazolo[1,5 - a] pyrimidine - 6 - carboxylic acid, ethyl ester, m.p. 181-183 C; 3 - methyl - 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
182-185 C; 1 -(3-chloro-phenyl)-3-methyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 - a] pyrimidine - 6 - carboxylic acid, ethyl ester; 1-(4-chloro-phenyl)-3-methyl-7-oxo-1H,7H pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester; 1-(4-chloro-phenyl)-2-methyl-7-oxo-1H,7H pyrazolo[1,5 - a] pyrimidine - 6 - carboxylic acid, ethyl ester; 3-methyl-1 methyl- phenyl)-7-oxo-1H,7H 1 H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester; 2 - methyl - 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
160-163 C; 3 - bromo - 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
185-187 C; 1 - (2 - methyl - phenyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; 1 - (3 - methyl - phenyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 - alpyrimidine - 6 - carboxylic acid; 1-(4-methyl-phenyl)-7-oxo-1H,7H-pyrazolo[1,5 -a]pyrimidine-6-carboxylic acid, m.p. 185-188 C dec.; 1 -(2-methoxy-phenyl)-7-oxo-1H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; 1 -(3-methoxy-phenyl)-7-oxo-1H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; 1 -(4-methoxy-phenyl)-7-oxo-1H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; 1 - (4 -fluoro - phenyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; 1 - (2 - chloro- phenyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; 1-(3-chloro-phenyl)-7-oxo-1H-7Hpyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; 1 - (4 - chloro - phenyl) - 7 - oxo - 1 H,7H - pyrazoio[1,5 - a]pyrimidine - 6 - carboxylic acid; 1 - (3 - trifluoromethyl - phenyl) - 7- oxo - 1 H,7H pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; 3 - methyl - 1 - phenyl - 7 - oxo - 1H,7H - pyrazolo[1,5- a] pyrimidine - 6 - carboxylic acid; 2 - chloro - 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid; 3-methyl-1-(4-methyl-phenyl)-7-oxo-1H,7Hpyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; 1-(3-chloro-phenyl)-3-methyl-7-oxo-1H,7Hpyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; 1-(4-chloro-phenyl)-3-methyl-7-oxo-1H,7Hpyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; and 1 - (4 - methoxy - phenyl) - 3 - methyl - 7- oxo -1 H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid.
Example 2 By proceeding according to Example 1, using diethyl (1 - ethoxy - alkylidene) - malonates or diethyl (1 - ethoxybenzylidene) - malonate, the following esters, and, after hydrolysis, the following acids were prepared: 5 - methyl - 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1 ,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
172-173 C; 5-methyl-1 -(4-methyl-phenyl)-7-oxo-1H,7H- pyrazolo[1,5 - alpyrimidine - 6 - carboxylic acid, ethyl ester; 1-(3-chloro-phenyl)-5-methyl-7-oxo-1H,7Hpyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester; 1 -(4-chloro-phenyl) -S-methyl -7-oxo-1H,7H pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester; 1-(4-fluoro-phenyl)-5-methyl-7-oxo-1H,7Hpyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p. 175-177 C; 1,5 - diphenyl - 7 - oxo - 1 H,7H - pyrazolo[1 ,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester; 5 - ethyl - 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid; 5-ethyl-1 -phenyl-7-oxo-1H,7H-pyrazolo[1,5- a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
119-120 C; 5-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - carboxylic acid; 5-methyl-1 -(4-methyl-phenyl)-7-oxo-1H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; 1-(3-chloro-phenyl)-5-methyl-7-oxo-1H.7H pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; 1 - (4 - chloro - phenyl} - 5 - methyl 7 - oxo - 1H,7H - pyrazolo[1 ,5 - a]pyrimidine - 6 - carboxylic acid; 1-(4-fluoro-phenyl)-5-methyl-7-oxo-1H.7H Pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; and 1,5 - diphenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid.
Example 3 By proceeding according to Examples 1 and 2, starting from suitable 1 - pyridyl - 3 - amino pyrazoles, the foliowing esters, and, after hydrolsis, the following acids were prepared: 1 - (2 - pyridyl) - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
138-139 C; 1 - (3 - pyridyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
203-207 C; 1 - (4 - pyridyl) - 7 - oxo - 1H,7H - pyrazolo[1,S a]pyrimidine - 6 - carboxylic acid, ethyl ester; 5-methyl-1-(2-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p. 103-104 C; 5-methyl-1-(3- pyridyl)-7-oxo-l H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester; 1 - (2 - pyridyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid; 1 - (3 - pyridyl) - 7 - oxo - 1H,7H - pyrazolo[1,S a]pyrimidine - 6 - carboxylic acid; 1 - (4 - pyridyl) - 7 - oxo -1 H,7H - pyrazolo[1 S - a]pyrimidine - 6 - carboxylic acid; 5-methyl-1-(2- pyridyl)-7-oxo-l H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid; and 5-methyl-1-(3-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid.
Example4 1 - benzyl - 3 - amino - pyrazole, m.p. 57-59 C (4 g) was reacted with diethyl ethoxymethylenemalonate (6 g) in anhydrous ethanol (40 ml) at the reflux temperature for 3 hours. After cooling the solution was evaporated in vacuo to dryness. Crystallization obtained by dilution with hexane gave diethyl N - (1 benzyl - pyrazol - 3 - yl) - aminomethylene - malonate, m.p. 60-62 C (7.5 g), which was reacted with polyphosphoric acid (3.2g: 1.5 9 of P205 and 1.7 g of H3PO4) and POCI3 (13.5 g) under stirring at 120 C for 30 minutes. After cooling the reaction mixture was diluted with ice water: neutralization with 35% NaOH gave a precipitate which was filtered and washed with water. Crystallization from methanol gave 6 9 of 1 - benzyl - 7 - oxo - 1H,7H - pyrazoio[l,5 - a]pyrimidine - 6 - carboxylic acid, ethyl ester, m.p.
172-173 C, which was hydrolized by heating with a mixture 1:1 of 37% HCI: acetic acid (300 ml) at the reflux temperature for 4 hours. After cooling the reaction mixture was neutralized to pH=6 with 35% NaOH and the precipitate was filtered and washed with water: crystallization from isopropyl alcohol gave 9.7 g of 1 - benzyl -7 - oxo I H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, m.p. 198-199 C.
By proceeding analogously, using suitable diethyl (1 - ethoxy - alkylidene) - malonates, the following esters and, after hydrolysis, the following acids were prepared: 1-benzyl-5-methyl-7-oxo-1H,7H-pyrazolop[1,5alpyrimidine - 6 - carboxylic acid, ethyl ester; 1-benzyl-5-ethyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - carboxylic acid, ethyl ester; 1-enzyl-5-phenyl-7-oxo-1H,7H-pyrazolo[1,5 alpyrimidine - 6 - carboxylic acid, ethyl ester; 1 - benzyl - 5 - methyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid; 1-benzyl-5-ethyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - carboxylic acid; and 1-benzyl-5-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - carboxylic acid.
Example 5 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - carboxylic acid (3 g), was reacted with thionyl chloride (2.8 g) in dioxane (70 ml) at the reflux temperature for 1 hour, then the mixture was evaporated in vacuoto dryness. The crude 6 chlorocarbonyl - 1 - phenyl - 7- oxo - 1 H,7H - pyrazolo[1,5 - a]pyrimidine was suspended in dioxane (60 ml) and reacted under stirring at room temperature for 30 minutes with methylamine (3.75 g).The precipitate was filtered and washed with water until neutral: crystallization from isopropyl alcohol gave 1.7 g of 1 - phenyl - 7 - oxo - 1H,7H pyrazolo[1,5 - a]pyrimidine - 6 - N - methyl carboxamide, m.p. 244-246 C, N.M.R. (CDCl3) # p.p.m.: 2.92 (d) (3H, -CH3), 6.73 (d) (1 H, C-3 proton), 7.37-7.75 (m) (5H, phenyl protons), 7.91(d) (1H, (1 H, C-2 proton), 8.70 (bs) (1H,-NHCH3), 9.10 (s) (1H, C-5 proton).
By proceeding analogously, using ammonia or suitable amines, the following compound were prepared: 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - carboxamide, m.p. 265-270 C dec.; 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - ethyl - carboxamide, m.p.
225-230 C dec.; 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine-6- N,N - diethyl - carboxamide, m.p.
146-147 C; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - ethyl - carboxamide; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - isopropyl - carboxamide, m.p.
220-225 C dec.; 5 - methyl - 1 - phenyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - phenyl - carboxamide; 3 - methyl - 1 - phenyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine-6-N-phenyl-carboxamide ; 1 - chloro - 1 - phenyl - 7 - oxo - 1H,7H - pyrazolo[1,5 alpyrimidine - 6 - N - phenyl - carboxamide; 1 -phenyl-7-oxo-1H,7H-pyrazolo[1,5- a]pyrimidine-6-N- phenyl - carboxamide, m.p.
245-247 C; 1 -phenyl-7-oxo-1H,7H-pyrazolo[1,5- a]pyrimidine-6-N- (3 - pyridyl) - carboxamide, m.p.
207-210 C; 1 -phenyl-7-oxo-1H,7H-pyrazolo[1,5- a]pyrimidine - 6 - N - (4 - methyl - phenyl) carboxamide; 1 - (3 - chloro - phenyl) - 7 - oxo - 1H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - N - methyl - carboxamide; l-(4-chloro-phenyl) -7-oxo-1H,7H- pyrazolo[l,5 - a]pyrimidine - 6 - N - methyl - carboxamide; 1 - (4 - chloro - phenyl) -7 - oxo - 1 H,7H - pyrazolo[1,5 -a]pyrimidine-6-N- ethyl - carboxamide; 1 - (4 - chloro - phenyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 -a]pyrimidine-6-N-isopropyl-carboxamide ; 1-(4-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - methyl - carboxamide; 1 - (2 - pyridyl) - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - methyl - carboxamide; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5 alpyrimidine - 6 - N - methyl - carboxamide; 1-(3-chloro-phenyl)-7-oxo-1H,7H-pyrazolo[1,5 - a]pyrimidine - 6 - N - phenyl - carboxamide; 1 - (4 - chloro - phenyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 -a]pyrimidine-6-N-phenyl-carboxamide; 1 - phenyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (4 - chloro - phenyl) carboxamide; 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine -6 - N - (6 - methoxy - 3- pyridyl) carboxamide; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5 a]pyrimidine - 6 - N - ethyl - carboxamide; 5-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-methyl-carboxamide; 5 - methyl - 1 - phenyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine-6-N-ethyl-carboxamide; 5 - methyl - 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1 ,5 - a]pyrimidine-6-N,N-diethyl-carboxamide; 5-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-isopropyl-carboxamide; 5 - methyl - 1 - phenyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (4 - chloro - phenyl) carboxamide; 5-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (4 - methoxy - phenyl) carboxamide; and 1-(4-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - ethyl - carboxamide.
Example 6 By proceeding according to Example 5, using suitable amines, the following compounds were prepared: 1-benzyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N,N - diethyl - carboxamide; 1 - benzyl - 7 - oxo - 1H,7H - pyrazolo[1,S - a]pyrimidine-6-N-ethyl-carboxamide; 1-benzyl-7-oxo-1H,7H-pyrazolo[1,5 a]pyrimidine -6 - N - isopropyl - carboxamide; 1 - benzyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine-6-N-(4-methyl-phenyl)carboxamide; 1-benzyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (4- chloro - phenyl) carboxamide; 1-benzyl-5-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-methyl-carboxamide; 1-benzyl-5-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-ethyl-carboxamide; 1 - benzyl - 5 - methyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N,N - diethyl - carboxamide; 1-benzyl-5-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - isopropyl - carboxamide; 1-benzyl-5-methyl-7-oxo-1H,7H-pyrazolo[1,5 alpyrimidine - 6 - N - (4 - chloro - phenyl) carboxamide; 1-benzyl-5-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N- (4 - methoxy - phenyl) carboxamide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5 a]pyrimidine -6 - N - isopropyl - carboxamide; 1 - methyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine-6-N,N-diethyl-carboxamide; 1,5 - dimethyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine -6 - N - methyl - carboxamide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-methyl-carboxamide; 1 - methyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - ethyl - carboxamide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine . 6 - N - (4 - chloro - phenyl) carboxamide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (4 - methoxy - phenyl) carboxamide; 1,5 - dimethyl - 7 - oxo - 1 H,7H - [pyrazolo[1,5- a]pyrimidine-6-N-isopropyl-carboxamide; 1 - ethyl - 5 - methyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - methyl - carboxamide; 1-ethyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimdine - 6 - N - isopropyl - carboxamide; 1-ethyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine - 6 - N - ethyl - carboxamide; 1,5 - dimethyl - 7 - oxo - 1 H,7H - pyrazolo[1,5- a]pyrimidine-6-N-ethyl-carboxamide; 1,5-dimethyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N,N - diethyl - carboxamide; 1-ethyl-5-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-ethyl-carboxamide; 1-ethyl-5-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-isopropyl-carboxamide; 1,5-dimethyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (4 - chloro - phenyl) carboxamide; 1,5 - dimethyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (4 - methoxy - phenyl) carboxamide; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - isopropyl - carboxamide; 1 - (3 - pyridyl) - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - isopropyl - carboxamide; 1 - (4 - pyridyl) - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimdie-6-N-isopropyl-carboxamide; 5-methyl-1 (2-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-methylcarboxamide; 5-methyl-1-(3-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-methylcarboxamide; 5-methyl-1 (4-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-methylcarboxamide; 5-methyl-1-(2-pyridyl)-7-oxo-1H,7H pyrazolo[1 ,5 - a]pyrimidine - 6 - N - ethyl - carboxamide; 5-methyl-1 (3-pyndyl)-7-oxo-1H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - N - ethyl - carboxamide; 5-methyl-1-(4-pyridyl)-7-oxo-1H,7H pyrazolo[1,5- a]pyrimidine - 6 - N - ethyl - carbox amide; 5-methyl-1 -(2-pyrdyl)-7-oxo-1H,7H- pyraazolo[1,5-a]pyrimidine-6-N-isopropyl carboxamide; 5 - methyl -(3-pyridyl)-7-oxo-1H,7H- pyrazolo[1 ,5 - a]pyrimidine - 6 - N - isopropyl carboxamide; and 5 - methyl -(4-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-isopropylcarboxamide.
Example 7 1-phenyl-7-oxo-1H,7H-yrazolo[1,5 a]pyrimidine - 6 - carboxylic acid (1.2 g) was reacted with thionyl chloride (0.8 ml) in dioxane (30 ml) at the reflux temperature for 3 hours, then the mixture was evaporated in vacuo to dryness. The residue was dissolved in dioxane (30 ml) and reacted with 2 (diethylamino) - ethanol (1.2 g) at room temperature for 24 hours. After dilution with water and alkalinization with Na2CO3 the precipitate was extracted with ethyl acetate: evaporation to dryness and crystallization from chloroform - ethanol gave 0.7 g of 1 phenyl -7 - oxo - lH,7H - pyrazolo[l,5 - a]pyrimidine 6 - carboxylic acid, 2- (diethylamino) - ethyl ester, m.p.127-130 C.
By proceeding analogously the following compounds were prepared: 1 - (4 - fluoro - phenyl) - 7- oxo - 1 H,7H - pyrazolo[l,5 - a]pyrimidine - 6 - carboxylic acid, 2 - (diethylamino) - ethyl ester; 1 - (4 - chloro - phenyl) - 7 - oxo - lH,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, 2 - (diethylamino) - ethyl ester; 1 - (3 - chloro - phenyl) -7 - oxo - 1H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, 2 - (diethylamino) - ethyl ester; 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid, 2 - (dimethylami no)-ethyl ester, m.p. 153-154 C; 1 - (4 - methyl - phenyl) - 7- oxo - 1 H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - carboxylic acid, 2 - (diethylamino) - ethyl ester;; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid, 2 - (diethylamino) - ethyl ester; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid, 2 - (diethylamino) - ethyl ester; 5-(mehtyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid, 2 - (diethylamino) - ethyl ester; 3-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5 a3pyrimidine - 6 - carboxylic acid, 2 - (diethylamino) ethyl ester; and 1-benzyl-7-oxo-1H,7H-pyrazolo[1,5 a]pyrimidine - 6 - carboxylic acid, 2 - (diethylamino) - ethyl ester.
Example 8 6 - chlorocarbonyl - 1 - phenyl - 7 - oxo - lH,7H - pyrazolo[1,5 - a]pyrimidine (2.7 g) was reacted with N - (2 - amino - ethyl) - piperidine (2.5 g) in dioxane (55 ml) at room temperature for 30 minutes. After evaporation in vacuo to dryness, the reaction pro duct was dissolved in chloroform and then purified over a SiO2 column using CHCl3: CH30H=85:15 as eluent. Crystallization from CH2CI2 - isopropyl ether gave 2.1 g of 1 - phenyl - 7 - oxo - 1H,7H - pyrazolo[1,5-a]pyrimidine-6-N-(2-piperidino ethyl)-carboxamide, m.p. 136-138=0.
By proceeding analogously the following compounds were prepared: 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (2 - morpholino - ethyl) - carboxamide, m.p. 179-180 C; 1 - phenyl - 7. oxo - 1 H,7H - pyrazolo[1 5 - a]pyrimidine - 6 - N - [2 - (pyrrolidin - 1 -yl) - ethyl] - carboxamide, m.p. 145-148 C; I -phenyl-7-oxo-1H,7H-pyrazolo[1,5- a]pyrimidine - 6 - N - [2 - (N,N - diethylamino) - ethyl] -carboxamide, m.p. 135-137 C; 1-benzyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (2 - piperidino - ethyl) carboxamide; 1 - benzyl - 7 - oxo - 1 H,7H - pyrazolo[1 5 - a]pyrimidine - 6 - N - [2 - (N,N - diethylamino) - ethyl] - carboxamide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-piperidino-ethyl)carboxamide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - [2 - (N N - diethylamino) ethyl] - carboxamide; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (2 - piperidino - ethyl) - carboxamide; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N- [2 - (N,N - diethylamino) - ethyl] - carboxamide; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (2 - piperidino - ethyl) carboxamide; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5 alpyrimidine - 6 - N - (2 - morpholino - ethyl) - carboxamide; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N- [2 - (N,N - diethylamino) - ethyl] - carboxamide; 5-methyl-1-phenyl-7-oxo-1H-7H-pyrazolo[1,5 - a]pyrimidine - 6 - N - (2 - piperidino - ethyl) carboxamide; 5-methyl-1 -(3-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - N - (2 - piperidino - ethyl) - carboxamide; and 5-methyl-1 -(2-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-piperidinoethyl) - carboxamide.
Example 9 6-chlorocarbonyl - 1 - phenyl - 7 - oxo - 1H,7H - pyrazolo[1,5 - a]pyrimidine (2.7 g), prepared according to Example 5, was reacted with piperidine (1.65 g) in dioxane (45 ml) at room temperature for 30 minutes. After evaporation in vacuo to dryness, the reaction product was dissolved in chloroform and then purified over a SiO2 column using chloroform methanol = 95:5 as eluent.
Crystallization from CH2Cl2-isopropyl ether gave 2.35 g of 1 - phenyl - 6 - piperidinocarbonyl - 1H,7H pyrazolo[1,5-a]pyrimidine-7-one, m.p. 160-161 C.
By proceeding analogously the following compounds were prepared: 6 - (4 - methyl - piperazin - 1 - yl)carbonyl - 1 - phenyl 1H,7H-pyrazolo[1,5-a]pyrimidine-7-one, m.p.
185-186 C; 6-morpholinocarbonyl-1-phenyl-1H,7Hpyrazolo[1,5-a]pyrimidine-7-one, m.p. 150-152 C; 6 - morpholinocarbonyl- 1 - (3 - pyridyl) - 1 H,7H pyrazolo[1,5-a]pyrimidine-7-one; 6 - (4 - methyl - piperazin- 1 -yl)carbonyl - 1 - (3 pyridyl)-1H,7H-pyrazolo[1,5-a]pyrimidine-7one; 6 - piperidinocarbonyl - 1 - (3 - pyridyl) -1 H,7H pyrazolo[1,5-a]pyrimidine-7-one; 5 - methyl - 6 - (4 - methyl - piperazin - 1 - yl)carbonyl -1-phenyl-1H,7H-pyrazolo[1,5-a]pyrimidine-7one; 6 - piperidinocarbonyl -1 - (2 - pyridyl) - 1 H,7H pyrazolo[1,5 - a]pyrimidine - 7 - one; 5 - methyl - 6 - morpholinocarbonyl - 1 - phenyl 1H,7H - pyrazolo[1,5 - a]pyrimidine -7 - one; 5 - methyl - 6 - morpholinocarbonyl - 1 - (3 - pyridyl) 1H,7H -pyrazolo[1,5- a]pyrimidine - 7 - one; 5 - methyl - 6 - (4 - methyl - piperazin - 1 - yl)carbonyl -1-(3-pyridyl)-1H,7H-pyrazolo[1,5-a]pyrimidine -7-one; 5 - methyl - 6 - piperidinocarbonyl - 1 - (3 - pyridyl) 1 H,7H - pyrazolo[1,5 - a]pyrimidine -7 - one; 1 - benzyl - 6 - morpholinocarbonyl - 1 H,7H pyrazolo[1,5-a]pyrimidine-7-one; 1 - benzyl - 6 - (4 - methyl - piperazin - 1 - yl)carbonyl 1 H,7H-pyrazolo[1,5- alpyrimidine - 7 - one; 1 - methyl - 6 - morpholinocarbonyl - 1 H,7H pyrazolo[1 ,5 - a]pyrimidine - 7 - one; 1 - methyl - 6 - (4 - methyl - piperazin - 1 - yl)carbonyl - 1 H,7H - pyrazolo[1,5 - a]pyrimidine - 7 - one; 6 - morpholinocarbonyl -1 - (2- pyridyl) - 1 H,7H pyrazolo[1,5 - a]pyrimidine - 7 - one; 6 - (4 - methyl - piperazin - 1 - yl)carbonyl - 1 - (2 pyridyl) - 1H,7H - pyrazolo[1,5 - a]pyrimidine -7 - one; 5 - methyl - 6 - piperidinocarbonyl - 1 - (2 - pyridyl) - 1H,7H-pyrazolo[1,5-a]pyrimidine-7-one; 5 - methyl - 6 - morpholinocarbonyl - 1 - (2 - pyridyl) 1 H,7H - pyrazolo[1 ,5 - a]pyrimidine - 7-one; and 5-methyl-6-(4-methyl-piperazin-1-yl)-1-(2pyridyl)-1H,7H-pyrazolo[1,5-a]pyrimidine-7one.
Example 10 l-phenyl-7-oxo-l H,7H- pyrazol oC1,5- alpyrimidine - 6 - carboxylic acid (5.1 g) was reacted with 2 - amino - thiazole (4 g) in polyphosphoric acid (90 g: 47.7 g of H3P04 and 42.3 g of P205) under stirring at 120 C for 20 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water: crystallization from CHCl3 - methanol gave 4.5 g of 1 phenyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine 6-N-(2-thiazolyl)-carboxamide, m.p. 245-247 C dec., N.M.R. (CDCl3)# p.p.m.: 6.72 (d) (1H, C-3 proton), 6.84 (d) (1 H, C-5 thiazolyl proton), 7.4-7.7 (m) (6H, phenyl protons and C-4 thiazolyl proton), 7.98 (d) (1 H, C-2 proton), 9.45 (s) (1 H, C-5 proton), > 11 (bs) (1H,-CONH-).
By proceeding analogously the following com pounds were prepared: 3-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (2 - thiazolyl) - carboxamide; 5-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5 alpyrimidine - 6 - N - (2 - thiazolyl) - carboxamide; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (2- pyridyl) - carboxamide, m.p.
207-210 C dec.; 5-ethyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a] pyrimidine - 6 - N - (2 - thiazolyl) - carboxamide; and 5-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (2 - pyridyl) - carboxamide, m.p.
184-187 C.
Example 11 5-methyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - carboxylic acid, ethyl ester (17 g) was reacted with 2 - amino - pyridine (10.8 g) in polyphosphoric acid (270 g) under stirring at 12000 for 2 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water: crystallization from CH2Cl2 - methanol gave 14 g of 5 methyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl) carboxamide, m.p. 186-187 C, N.M.R. (CDCl3) # p.p.m.: 2.88 (s) (3H, -OH3), 6.62(d) (1H, C-3 proton), 6.99 (m) (1 H, C-5 pyridyl proton), 7.38-7.50 (m) (5H, phenyl protons), 7.70 (ddd) (1 H, C-4 pyridyl proton), 7.82 (d) (1 H, C-2 proton), 8.26 (dd) (1 H, C-3 pyridyl proton), 8.34 (d) (1H, (1 H, C-6 pyridyl proton), > 10.5 (bs) (1H, -CONH-).
By proceeding analogously the following compounds were prepared: 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide, m.p. 207-210 C; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2pyridyl) - carboxamide, m.p. 260 C dec.; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (5 - methyl - 2 pyridyl)-carboxamide, m.p. 268-270 C; 1 - phenyl - 7 - oxo -1 H,7H - pyrazolo[1 ,5 - ]pyrimidine - 6 - N - (4 - methyl - 2 - pyridyl) - carboxamide, m.p.
210-215 C dec.; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-pyrazinyl-carboxamide; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(6-methyl-2pyridyl)-carboxamide, m.p. 235-240 C dec.; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-ajpyrimidine - 6 - N - (5 - bromo - 2 pyridyl) - carboxamide; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(6-hydroxy-2pyridyl) - carboxamide, m.p. 280-290 C dec.; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1 ,5-a]pyrimidine - 6 - N - (3 - methyl - 2 pyridyl)-carboxamide, m.p. 252-254 C; 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5-a] pyrimidine - 6 - N - (6 - methoxy -2 - benzothiazolyl) carboxamide; 1 -phenyl-7-oxo-1K,7H- pyrazolo[1,5-a]pyrimidine-6-N-(4,5-dimethyl-2thiazolyl) - carboxamide; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-1]pyrimidine-6-N-(4-methyl-2 thiazolyl) - carboxamide; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-benzothiazolyl) -carboxamide, m.p. 245-250 C;; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(4-phenyl-2thiazolyl) - carboxamide; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(1-methyl-3pyrazolyl) - carboxamide; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(1-phenyl-3pyrazolyl)-carboxamide, m.p. 248-252 C; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2thiazolyl) - carboxamide; 1 -(4-methoxy-phenyl)-7-oxo-1H,7H- pyrazolo[1 ,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide; 1 -(4-methoxy-phenyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl) - carboxamide; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-pyrimidinyl)carboxamide, m.p. 200-205 C dec.; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (3,5 - dichloro 2 pyridyl) - carboxamide, m.p. 305-310 C dec.; 1 -phenyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(4-pyridyl)carboxamide, m.p. 270-275 C dec.; 2-methyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide, m.p. 225-230 C dec.; 1 -(4-methoxy-phenyl)-7-oxo-1H,7H- pyrazolo[1,5-ajpyrimidine - 6 - N - (5 - chloro - 2 pyridyl) - carboxamide; 'I-(4-methoxy- phenyl)-7- oxo- 1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (4,5 - dimethyl - 2 - thiazolyl) - carboxamide; 1 -(4-methyl-phenyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2pyridyl) - carboxamide; 1 -(4-methyl-phenyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(4,5-dimethyl-2thiazolyl) - carboxamide; 1 -(4-methyl-phenyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide, m.p. 209-213 C dec.; 1 -(4-methyl-phenyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl) - carboxamide; 1 -(4-methyl-phenyl)-7-oxo-1H,7H- pyrazolo[1 ,5-a]pyrimidine - 6 - N - (2 - thiazolyl) carboxamide; 1 -(4-methyl-phenyl)-7-oxo-1H,7H- pyrazolo[1,5-ajpyrimidine - 6 - N - (2 - benzothiazolyl) - carboxamide; 1 -(4-methyl-phenyl)-7-oxo-1H,7H- pyrazolo[1 5-alpyrimidine - 6 - N - (4 - methyl - 2 thiazolyl) - carboxamide; 1-(4-methyl-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2 thiazolyl)-carboxamide; 1-(4-chloro-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl) carboxamide, m.p. 254-257 C; 1-(4-chloro-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(6-methyl-2 pyridyl)-carboxamide; 1-(4-chloro-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide; 1-(4-chloro-phenyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-benzothiazolyl) -carboxamide; 1-(4-chloro-pyenyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(4-methyl-2thiazolyl)-carboxamide; 1-(4-chloro-phenyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2thiazolyl)-carboxamide; 1-(4-fluoro-phenyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide. m.p. 202-210 C dec.; 1-(4-chloro-phenyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2pyridyl)-carboxamide; 1-(4-chloro-phenyl)-7-oxo-1H,7H @yrazolo[1,5-a]pyrimidine-6-N-(4,5-dimethyl-2 @hiazolyl)-carboxamide; 1-(4-nitro-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide, m.p. 305-310 C; 1-(4-fluoro-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2 pyridyl)-carboxamide; 1-(4-fluoro-henyl)-7-oxo-1H,7Hyrazolo[1,5-a]pyrimidine-6-N-(4,5-dimethyl-2thiazolyl)carboxamide; 1-(4-fluoro-phenyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(6-methyl-2pyridyl)-carboxamide; 1-(4-fluoro-phenyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide; 1-(4-fluoro-pyenyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-benzothiazolyl) -carboxamide; 1-(4-fluoro-phenyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(4-methyl-2thiazolyl)-carboxamide; 1-(4-fluoro-phenyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2thiazolyl)-carboxamide; 1-(3-chloro-phenyl)-7-oxo-1H,7H-pyrazolo[1,5 -a]pyrimidine-6-N-(2-pyridyl)-carboxamine, m.p. 284-286 C; 1-(3-trifluoromethyl-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide, m.p. 246-251 C; 1-(3-chloro-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide; 1-(3-trifluoromethyl-henyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide; 1-(2-chloro-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl) carboxamide; 1-(2-chloro-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl) carboxamide; 1-(3-methyl-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl) carboxamide; 1-(3-chloro-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2 pyridyl)-carboxamide; 5-mehtyl-1-phenyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2pyridyl)-carboxamide; 3-methyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide, m.p. 274-277 C; 3-methyl-1-henyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(6-methyl-2pyridyl)-carboxamide; 3-methyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide; 3-methyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-benzothiazolyl) -carboxamide; 3-methyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(4-methyl-2thiazolyl)-carboxamide; 3-methyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2thiazolyl)carboxamide; 3-methyl-1-phenyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2 pyridyl)-carboxamide; 3-methyl-1-phenyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(4,5-dimethyl-2thiazolyl)-carboxamide; 3-methyl-1-(4-methyl-phenyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(6-methyl-2pyridyl)-carboxamide; 2-chloro-1-phenyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide, m.p. 275-278 C; 2-chloro-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(6-methyl-2pyridyl)-carboxamide; 2-chloro-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide; 2-chloro-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2pyridyl)-carboxamide; 1-(4-fluoro-phenyl)-5-methyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide, m.p. 252-255 C; 1-(4-chloro-phenyl)-3-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide; 1-(3-chloro-phenyl)-3-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide; 3-methyl-1-(4-methyl-phenyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl) carboxamide; 1-(4-fluoro-phenyl)-3-methyl-7-oxo-1H,7H pyrazolo[1 ,5-a]pyrimidine - 6 - N - (2 - thiazolyl) - carboxamide; 1-(4-chloro-phenyl)-3-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (2 - thiazolyl) carboxamide; 1-(3-chloro-phenyl)-3-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (2 - thiazolyl) carboxamide; 3-methyl-1-(4-methyl-phenyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (2 - thiazolyl) carboxamide; 1 -(4-fluoro-phenyl).3.methyl.7.oxo.1H,7H.
pyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl) - carboxamide; 1 - (4 - chloro-phenyl) - 3 - methyl - 7 - oxo - 1 H,7H pyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl) - carboxamide; 1 - (4 - methoxy - phenyl) - 3 - methyl - 7 - oxo - 1H,7H - pyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl) - carboxamide; 1,5 - diphenyl - 7 - oxo - 1 H,7H pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide; 5-ethyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide; 1-(4-chloro-phenyl)-5-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide; 1-(3-chloro-phenyl)-5-methyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide; 5-methyl-1-(4-methyl-phenyl)-7-oxo-1H,7H pyrazolo[1,5-ajpyrimidine - 6 - N - (2 - pyridyl) carboxamide; 5-methyl-1-phenyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl) - carboxamide; 5-methyl-1-Phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyrimidinyl) carboxamide; and 3,5-dimethyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide.
Example 12 1 -benzyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - carboxylic acid, ethyl ester (3.5 g) was reacted with 2 - amino - pyridine (5.2 g) in polyphosphoric acid (87 g) under stirring at 120 C for 5 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water: crystallization from dimethylformamide gave 1.5 g of 1 benzyl - 7- oxo -1 H,7H - pyrazolo[1 ,5-alpyrimidine - 6-N-(2-pyridyl)-carboxamide, m.p. 337-340 C.
By proceeding analogously the following com pounds were prepared: 1 -benzyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (3 - pyridyl) carboxamide; 1 -benzyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (5 - chloro - 2 pyridyl) - carboxamide; 1-benzyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(6-methvl-2 pyridyl) - carboxamide; 1-benzyl-5-methyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide; 1-benzyl-5-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2pyridyl) - carboxamide; 1 -benzyl-5-methyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6 - N - (3 - pyridyl) carboxamide; and 1-benzyl-5-methyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(6-methyl-2pyridyl) - carboxamide.
Example 13 1 -methyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - carboxylic acid, ethyl ester (3.4 g) was reacted with 2 - amino - pyrimidine (2.9 g) in polyphosphoric acid (51 g) under stirring at 110 C for 3 hours. After cooling, dilution with ice water and neutralization with 35% NaOH the precipitate was filtered and washed with water: crystallization from CH2CI2/ethanol gave 2.6 g of 1 - methyl - 7 - oxo -1 H,7H - pyrazolo [1 ,5-alpyrimidine - 6 - N (2 - pyridyl) - carboxamide, m.p. 222-226 C. N.M.R.
(CDCl3-CF3COOD)# p.p.m.: 4.71 (s) (3H, CH3), 6.97 (d) (1 H, C-3 proton), 7.80 (m) (2H, C-4 and C-5 pyridyl protons) 8.50 (m) (3H, C-2 proton; C-3 and C-6 pyridyl protons),9.11 (1H, C-5 proton).
By proceeding analogously the following compounds were prepared: 1 - ethyl - 7 - oxo - 1 H,7H - pyrazolo[1 ,5-a]pyrimidine - 6 - N - (2 - pyridyl) - carboxamide; 1-tert.butyl-7-oxo-1H,7Hpyrazolo[1,5-alpyrimidine - 6 - N- (2 - pyridyl) carboxamide; 1 -tert.butyl-5-methyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide; 1,5-dimethyl-7-oxo-1H,7H pyrazolo[1,5-ajpyrimidine - 6 - N - (2 - pyridyl) carboxamide, m.p. 212-214 C; 1 - methyl - 7 - oxo - 1 H,7H - pyrazolo[1,5- a]pyrimidine -6-N-(3-pyridyl)-carboxamide; 1 -methyl-7-oxo-1H,7H- pyrazolo[1 ,5-a]pyrimidine - 6 - N - (5 - chloro -2 - pyridyl) - carboxamide, m.p. 270-273 C (dec.); 1,5-dimethyl-7-oxo- 1 H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (3 - pyridyl) carboxamide; 1 -methyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl)-carboxamide, m.p. 225-227 C; 1,5 -dimethyl -7 - oxo - 1H,7H - pyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2 pyridyl) - carboxamide, m.p. 256-259 C; 1,5-dimethyl-7-oxo- 1 H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(6-methyl-2 pyridyl)-carboxamide, m.p. 220-221 C;; 1 -ethyl-5-methyl-7-oxo-1H,7Hl- pyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 - pyridyl) - carboxamide; 1 - ethyl - 7 - oxo - 1 H,7H - pyrazolo[1 ,5-a]pyrimidine 6 - N - (5 - chloro - 2 - pyridyl) - carboxamide; 1-tert.butyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl) - carboxamide; I-ethyl-5-methyl-7- oxo-1H,7H- pyrazolo[1,5-ajpyrimidine- 6 - N - (2 - pyridyl) carboxamide; 1-ethyl-5-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (5 - chloro - 2 pyridyl) - carboxamide; and 1-tert.butyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2 pyridyl) - carboxamide.
Example 14 By proceeding according to Examples 12 and 13, using suitable heterocyclic amines, the following compounds were prepared: 1 - benzyl - 7 - oxo - 1 H,7H - pyrazolo[1 5 - a]pyrimidine 6 - N - (2 - thiazolyl) - carboxamide; 1-benzyl-7-oxo-1H-7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-benzethiazolyl) - carboxamide; 1 - benzyl-7.oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(4-methyl-2thiazolyl) - carboxamide; 1 -benzyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (5 - chloro - 2 - thiazolyl) - carboxamide; 1 -benzyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (4,5 - dimethyl - 2 - thiazolyl) - carboxamide; 1 -methyl-7-oxo-1H,7H- pyrazolo[1 ,5-a]pyrimidine - 6 - N - (2 - thiazolyl) carboxamide, m.p. 265-268 C (dec.); 1-methyl-7-oxo-1H,7H, pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - benzothiazolyl) -carboxamide, m.p. 293-298 C (dec.); 1-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(4-methyl-2 thiazolyl) - carboxamide; 1 .methyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (5 - chloro - 2 thiazolyl) - carboxamide; 1 -methyl.7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(4,5-dimethyl-2thiazolyl)-carboxamide; 1-ethyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine6-N-(2-thiazolyl)-carboxamide; 1 -tert.butyl.7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (4,5 - dimethyl - 2 thiazolyl) - carboxamide; 1 .tert.butyl.7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - thiazolyl) carboxamide; 1 -tert.butyl-7.oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - benzothiazolyl) - carboxamide; 1 - tert.butyl - 7 - pyrazolo[1 ,5-a]pyrimidine - 6 - N - (4 - methyl - 2 - thiazolyl) - carboxamide;; 1 .tert.butyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (5 - chloro - 2 - thiazolyl) - carboxamide; 1-benzyl-5-methyl-7-oxo-1H,7H pyrazolo[1 ,5-a]pyrimidine - 6 - N - (2 - thiazolyl) carboxamide; 1 .tert.butyl.5.methyl.7.oxo-1H,7K- pyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide; 1,5-dimethyl-7-oxo- 1 H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide; m.p. 243-245 C; 1-benzyl-5-methyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine - 6 - N - (5 - chloro thiazolyl) - carboxamide; 1 -ethyl-5-methyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (5 - chloro - 2 thiazolyl) - carboxamide; 1,5-dimethyl-7-oxo- 1 H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (5 - chloro - 2 thiazolyl) - carboxamide; 1-benzyl-5-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(4,5-dimethyl-2thiazolyl) - carboxamide; 1-ethyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine6 - N - (4 - methyl - 2 - thiazolyl) - carboxamide; 1 -ethyl-5-methyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(4,5-dimethyl-2thiazolyl) - carboxamide; 1,5-dimethyl-7-oxo- 1 H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(4,5-dimehtyl-2 thiazo,yl} - carboxamide; 1,S - dimethyl -7 - oxo - 1H,7H - pyrazolo[1 ,5-a]pyrimidine - 6 - N - (4 - methyl - 2 thiazolyl) - carboxamide; 1-benzyl-5-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(4-methyl-2thiazolyl) - carboxamide; 1-tertbutyl-5-methyl-7-oxo-1H,7H pyrazolo[1 ,5-a]pyrimidine - 6 - N - (4 - methyl - 2 thiazolyl) - carboxamide; 1-benzyl-5-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-benzothiazolyl) - carboxamide; 1.5-dimethyl-7-oxo- 1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - benzothiazolyl) - carboxamide; 1-tert.butyl-5-methyl-7-oxo-1H.7H pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - benzothiazolyl) - carboxamide; 1 - ethyl - 7 - oxo - 1 H,7H - pyrazolo[1 ,5-a]pyrimidine - 6 - N - (4,5 - dimethyl - 2 - thiazolyl) - carboxamide; 1 - ethyl - 7 - oxo -1 H,7H - pyrazolo[1 ,5-a]pyrimidine - 6 - N - (2 - benzothiazolyl) - carboxamide; 1 - ethyl - 7- oxo - 1 H,7H - pyrazolo[1 ,5-a]pyrimidine - 6 - N - (5 - chloro - 2 - thiazolyl) carboxamide; 1 -ethyl-5-methyl-7-oxo-1H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - N - (2 - thiazolyl) - carboxamide; 1 -ethyl-5-methyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6- N - (2 - benzothiazolyl) -carboxamide; and 1 -ethyl-5-methyl-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (4 - methyl - 2 thiazolyl) - carboxamide.
Example 15 2 - amino - pyridine (4.86 g), dissolved in anhydrous pyridine (10 ml) was reacted with PCI3 (1.24 g) at 55 C for 30 minutes: after cooling at 20 C 1 - phenyl 7 - oxo - 1 H,7H - pyrazolo[1,5-a]pyrimidine - 6 carboxylic acid (4 g) was added and the mixture was kept to the reflux temperature for 30 minutes. After cooling, dilution with ice water and neutralization with 37% NaOH the precipitate was filtered, washed with water and purified over a SiO2 column using ethyl acetate: methanol 98:2 as eluent. Crystallization from methanol gave 2 g of 1 - phenyl - 7 - oxo 1H,7H - pyrazolo[1,5-a]pyrimidine - 6 - N - (2 pyridyl) - carboxamide, m.p. 207-210 C dec., N.M.R.
(CDCl3)# p.p.m.: 6.74 (@) (1H, C-3 proton), 7.04 (m) (1 H, C-5 pyridyl proton), 7.3 - 7.9 (m) (6H, C-4 pyridyl proton and phenyl protons), 7.94 (d) (1H, C-2 pro ton), 8.2 - 8.45 (m) (2H, C-3 and C-6 pyridyl protons), 9.25 (s) (1H, C-5 proton), 11.2 (bs) (1H, CONH-).
By proceeding analogously the following compounds were prepared: 3-methyl-1-phenyl-7-oxo-1H,7H pyrazolo[1 ,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide, m.p. 274-277 C; and 5-methyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide, m.p. 184-187 C.
Example 16 By proceeding according to Examples 3, 10 and 11, the following compounds were prepared: 1 -(2-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide, m.p. 202-204 C; 1 -(2-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide, m.p. 218-220 C; 1 -(2-pyridyl)-7-oxo-1H,7H- pyrazolo[1 ,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl)-carboxamide, m.p. 212-214 C; 1 -(2-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - benzothiazolyl) - carboxamide; 1 -(3-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide, m.p. 291-293 C (dec.); l-(3-pyridyl)-7-oxo -1H,7H- pyrazolo[1 ,5-a]pyrimidine - 6 - N - (2 - thiazolyl) carboxamide; 1 .(3-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl) - carboxamide; 1-(3-pyridyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - benzothiazolyl) - carboxamide;; 1-(4-pyridyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide; 1-(4-pyridyl)-7-oxo-1H,7H pyrazolo[1 ,5-a]pyrimidine - 6 - N - (2 - thiazolyl) - carboxamide; 1-(4-pyridyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl) - carboxamide; 1-(4-pyridyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-benzothiazolyl) - carboxamide; 3-methyl-1 -(2-pyridyl).7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl) carboxamide; 3-methyl-1-(4-pyridyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl) carboxamide; 5-methyl-1-(2-pyridyl)-7-oxo-1H,7H pyrazolo[1,5-ajpyrimidine - 6 - N - (2 - pyridyl) carboxamide, m.p. 183-187 C (dec.); 5-methyl-1-(3-pyridyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide; 3-methyl-1 -(2-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide; 3 - methyl - 1 -(4-pyridyl)-7-oxo- 1H,7H - pyrazolo[1,5-a]pyrimidine - 6 - N - (2 -thiazolyl) carboxamide; 5-methyl-1 -(2-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide; 5-methyl-1 -(3-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - thiazolyl) carboxamide; 3-methyl-1 -(2-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(6-methyl-2pyridyl) - carboxamide; 3-methyl-1-(4-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl) - carboxamide; 5-methyl-1 -(2-pyridyl)-7-oxo-1H,7H- pyrazolo[1 ,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl) - carboxamide; 1 -(4-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2 pyridyl) - carboxamide; 5-methyl-1-(3-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (6 - methyl - 2- pyridyl) - carboxamide; 3 - methyl -(2-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - benzothiazolyl) - carboxamide; 3-methyl-1-(4-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (2 - benzothiazolyl) - carboxamide; 5-methyl-1 -(2-pyridyl)-7-oxo-lH,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-benzothiazolyl) - carboxamide; 5-methyl-1-(3-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (2 - benzothiazolyl) - carboxamide; 2-methyl-1-(2-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide; 2-methyl-1 -(4-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide; 1 -(2-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(3-pyridyl)carboxamide; 1 -(3-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(3-pyridyl)carboxamide; 1 -(4-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (3 - pyridyl) carboxamide; ?-(2-pyridyl)-7-oxo -1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2pyridyl) - carboxamide, m.p. 292-294 C (dec.); 1 -(3-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine-6-N-(5-chloro-2 pyridyl) - carboxamide; 1 -(4-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6 - N - (5 - chloro - 2 - pyridyl) - carboxamide; and 5-methyl-1 -(4-pyridyl)-7-oxo- pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide.
Example 17 1 -(4-nitro-phenyl)-7-oxo-1H,7H- pyrazolo[1,5-a]pyrimidine - 6-N - (2 - pyridyl) carboxamide (4.1 g), prepared according to Example 11,was reacted with SnCI2-2 H20 (25 g) in 37% HCI (15 ml) and acetic acid (45 ml) under stirring at 60 C for 3 hours. After cooling the precipitate was filtered and washed with water and then suspended under stirring in 2.5% aqueous NaHC03: the product was filtered, washed with water until neutral and then crystallized from CHCI3-methanol to give 2.9 g of 1 (4 - amino - phenyl) - 7 - oxo - 1 H,7H pyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide, m.p. 235-245 C dec.
By proceeding analogously the following compounds were prepared: 1 -(4-amino-phenyl)-7-oxo- 1 H,7H - pyrazolop1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide; 1-(4-amino-phenyl)-3-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide; 1-(4-amino-phenyl)-5-methyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide; and 1-(4-amino-phenyl)-2-methyl-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide Example 18 1-(4-amino-phenyl)-7-oxo-1H,7Hpyrazolo[1,5 - a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide (2 g), prepared according to Example 17, was reacted with acetic anhydride (2 ml) in dimethylformamide (30 ml) in the presence of pyridine (2 ml) at 120 C for 1 hour.After cooling the precipitate was filtered and washed with methanol to give 1.7 g of 1-(4-acetylamino-phenyl)-7-oxo 1 H,7H - pyrazolo[1,5- a]pyrimidine - 6 - N - (2 pyridyl) - carboxamide, m.p. 327-332=0.
By proceeding analogously the following com pounds were prepared: 1 - (4 - acetylamino - phenyl) - 7 - oxo - 1 H,7H pyrazolo[1,5 - a]pyrimidine - 6 - N - (2 - thiazolyl) - carboxamide; 1 - (4 - acetylamino - phenyl) - 3 - methyl - 7 - oxo 1H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - N - (2 pyridyl) - carboxamide; 1 - (4 - acetylamino - phenyl) - 5 - methyl - 7 - oxo 1H,7H - pyrazolo[1,5 - a]pyrimidine - 6 - N - (2 pyridyl) - carboxamide; and 1 - (4- acetylamino - phenyl) - 2 - methyl - 7 - oxo 1 H,7H-pyrazolo[1,5- a]pyrimidine - 6 - N - (2 pyridyl) - carboxamide.
Example 19 By proceeding according to Example 11 the fol lowing compounds were prepared: 5 - methyl -1 - phenyl -1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (3 - pyrazolyl) - carboxamide; 5-methyl-1-phenyl-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (1 - methyl - 3 - pyrazolyl) carboxamide; 1,5 - dimethyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (3 - pyridyl) - carboxamide; 1,5 - dimethyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine -6- N - (6 - methoxy - 3 - pyridyl) carboxamide; 1 - methyl - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (3 - pyrazolyl) - carboxamide, m.p. 300-305=0 (dec.); 1 - methyl - 7 - oxo - 1H,7H - pyrazolo[1,S - a]pyrimidine - 6 - N - (1 - methyl - 3 - pyrazolyl) carboxamide; 1,5 - dimethyl - 7 - oxo - 1 H,7H - pyrazolo[1 ,5 - a]pyrimidine - 6 - N - (1 - methyl - 3 - pyrazolyl) carboxamide; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (3 - pyrazolyl) - carboxamide, m.p. 296-298 C (dec.);
1-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (5 - bromo - 2 - pyndyl) carboxamide, m.p. 255-260=0 (dec.); 1-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (2 - pyrazinyl) - carboxamide; 1 - methyl - 7 - oxo - 1H,7H - pyrazolo[1,5- a]pyrimi- dine - 6 - N - (2 - pyrimidinyl) - carboxamide, m.p.
240-245 C; 1.5-dimethyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (2 - pyrimidinyl) - carboxamide; 1,5 - dimethyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (2 - pyrazinyl) - carboxamide; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (2 - pyrimidinyl) - carboxamide; 5-methyl-1-(2-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5 - a]pyrimidine - 6 - N - (2 - pyrimidinyl) - carboxamide; 1,5 - dimethyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (3 - pyrazolyl) - carboxamide; 5-methyl-1-(2-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5 - a]pyrimidine - 6 - N - (4 - methyl - 2 thiazolyl) - carboxamide; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (3 - pyrazolyl) - carboxamide; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine - 6 - N - (1 - methyl - 3 - pyrazolyl) carboxamide; 5-methyl-1-(2-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5 - a]pyrimidine - 6 - N - (3 - pyrazolyl) - carboxamide; 5-methyl-1-(2-pyridyl)-7-oxo-1H,7H pyrazolo[1,5-a]pyrimidine-6-N-(1-methyl-3pyrazolyl) - carboxamide; 1 - (2 - pyridyl) - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (2 - pyrazinyl) - carboxamide; 5-methyl-1-(2-pyridyl)-7-oxo 1H,7H pyrazolo[1,5 - a]pyrimidine - 6 - N - (2 - pyrazinyl) carboxamide; 1 - (3 - pyridyl) - 7 - oxo - 1H,7H - pyrazolo[1,5 a]pyrimidine - 6 - N - (3 - pyrazolyl) - carboxamide; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5 a]pyrimidine - 6 - N - (1 - methyl - 3 - pyrazolyl) carboxamide; ; 5-methyl-1-(3-pyridyl)7-oxo-1H,7H pyrazolo[1,5 - a]pyrimidine-6- N - (3 - pyrazolyl) - carboxamide; and 5-methyl-1 -(3-pyridyl)-7-oxo-1H,7H- pyrazolo[1,5 - a]pyrimidine - 6 - N - (1 - methyl - 3-' pyrazolyl) - carboxamide.
Example 20 Tablets, each weighing 100 mg and containing 50 mg of the active substance are manufactured as follows: Compositions (for 10,000 tablets) 5-methyl-1-phenyl-7-oxo-1H,7H-yrazolo[1,5a]pyrimidine - 6 - N (2 - pyridyl) - carboxamide 500 g Lactose 710 g Corn starch 237.5 g Talc powder 35.5g Magnesium stearate 15 g 5-methyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5 - a]pyrimidine - 6 - N - (2 - pyridyl) carboxamide, lactose and a half of the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm openings. Corn starch (18 g) is suspended in warm water (180 ml). The resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve of sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets using punches of 8 mm diameter.

Claims (9)

1) A compound of general formula (I)
R1 is a) a pyridyl group, unsubstituted or substituted by a C1-C6 alkyl group; b) a phenyl ring, unsubstituted or substituted by one or more substi- tuents chosen from halogen, trihalo-C1-C4 alkyl, C1-C6 alkyl, C7-C6 alkoxy, hydroxy, formyloxy, C2-C6 alkanoyloxy, nitro, amino, formylamino and C2-C6 alkanoylamino; c) benzyl; or d) C-C6 alkyl; each of B2 and B3 independently is a hydrogen or a halogen atom or C1-C6 alkyl; R4 is hydrogen, C1-C6 alkyl or phenyl; B5 is a')
wherein each of B6 and B7 independently is hydrogen or C-C6 alkyl, or R6a and R7, taken together with the nitrogen atom to which they are linked, form a morpholino, piperidino, N-pyrrolidinyl or N-piperazinyl ring, all the rings being unsubstituted or substituted by Ci-Os alkyl; b')a
group, wherein R8 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy or halogen;; c') a -NH-Rg group, wherein Rg is an unsaturated heterocyclic ring containing one or two heteroatoms chosen from nitrogen and sulphur, unsubstituted or substituted by one or two substituents chosen from halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy and phenyl d')
,wherein m is a 1,2 or 3 and B6 and B7 are as defined above; or e') hydroxy or C1-C6 alkoxy unsubstituted or substituted by
wherein R6 and R7 are as defined above; and wherein R5 is not as defined above under e') when R1 is C1-C6 alkyl; and the pharmaceutically acceptable salts thereof.
2) A compound of formula (I), according to claim 1), wherein: R1 is pyridyl; benzyl; C1-C6 alkyl; or phenyl unsubstituted or substituted by one or two substituents chosen from chlorine methyl, amino and acetylamino; each of R2 and R3 independently represents hydrogen, chlorine or a methyl group; R4 is hydrogen, C1-C2 alkyl or phenyl; B5 isa")
wherein @ each of R'6 and R'7 is independently hydrogen or C1-C4 alkyl; or R'6a and R'7, taken together with the nitrogen atom to which they are inked, from a morpholino, piperidino or N-piperazinyl ring, wherein the N-piperazinyl ring is unsubsti tuted or substituted by C1-C4 @ alkvl: b")
wherein B8 is hydrogen, methyl, methoxy or chlorine; c") -NHRg, wherein Rg is a pyridyl, pyrimidinyl, 2-thiazolyl or 2-benzothiazolyl group, wherein all the groups are unsubstituted or substituted by one or two substituents chosen from chlorine, bromine, methyl and methoxv: or, d")
wherein m, R'6 and R'7 are as defined above; and the pharmaceutically acceptable salts thereof.
3) A compound of formula (I), according to claim 1), wherein: R1 is pyridyl; benzyl; or phenyl unsubstituted or substituted by one or two substituents chosen from chlorine, methyl, amino and acetylamino; each of B2 and B3 independently represents hyd- rogen, chlorine or a methyl group; B4 is hydrogen, C1-C2 alkyl or phenyl; R5isa")
,wherein each of R"6 and R"7 is independently hydrogen or C1-C3 alkyl, or R"6 and R"7 taken together with the nitrogen atom to which they are linked, form a morpholino, a piperdino or a N-piperazinyl ring, wherein the N-piperazinyl ring is unsubstituted or substituted by C1-C4 alkyl; b")
,wherein Ra is hydrogen, methyl, methoxy or chlorine; c") -NHR9, wherein Rg is a pyridyl, pyrimidinyl.
2-thiazolyl or 2-benzothiazolyl group wherein all the groups are unsubstituted or substituted by one or two substituents chosen from chlorine, bromine, methyl and methoxy; or d")
,wherein m, R"6 and R"7 are as defined above; and the pharmaceutically acceptable salts thereof.
4) A compound selected from the group consisting of: 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(3-pyridyl)-carboxamide; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(6-methyl-2-pyridyl) carboxamide; 1 - phenyl - 7 - oxo - 1 H,7H - pyrazolo[1,5 a]pyrimidine-6-N-(5-chloro-2-pyridyl) carboxamine, 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyrimidinyl)-carboxamide; 3-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(6-methoxy-3-pyridyl)carboxamide; 5-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 5-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyrimidinyl)-carboxamide; 3,5-dimethyl-1-phenyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6N-(2-pyridyl)carboxamide; 5-ethyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-(3-chloro-phenyl)-7-oxo-1H,7H-pyrazolo[1,5 -a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-(3-chloro-phenyl)-5-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide; 1-(4-chloro-phenyl)-7-oxo-1H,7H-pyrazolo[1,5 -a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-(4-chloro-phenyl)-5-methyl-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide; 1-(4-amino-phenyl)-7-oxo-1H,7H-pyrazolo[1,5 -a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-(4-acetylamino-phenyl)-7-oxo-1H,7Hyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(6-methyl-2-pyridyl)carboxamide; 5-methyl-1-(3-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-yridyl)carboxamide; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5 -a]pyrimidine-6-N-(5-chloro-2-pyridyl)carboxamide; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(5-chloro-2-pyridyl)carboxamide; 5-methyl-1-(2-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-thiazolyl)carboxamide; 1-benzyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-benzyl-5-methyl-7-oxo-1H,7H-pyrazolo[1,5 -a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-piperidino-ethyl)carboxamide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-ethyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine -6-N-(2-pyridyl)-carboxamide; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-mehtyl-7-oxo-1H,7H-yrazolo[1,5a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-benzothiazolyl)-carboxamide; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 1-(2-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-benzothiazolyl)-carboxamide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-piperidino-ethyl)carboxamide; 1,5-dimethyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-(4-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 1-methyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-N-(5-chloro-2-pyridyl)carboxamide; 5-methyl-1-(2-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-N-(2-pyridyl)carboxamide; 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-carboxylic acid; 5-methyl-1-phenyl-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-carboxylic acid; 1-(3-pyridyl)-7-oxo-1H,7H-pyrazolo[1,5a]pyrimidine-6-carboxylic acid; and 5-methyl-1-(3-pyridyl)-7-oxo-1H,7Hpyrazolo[1,5-a]pyrimidine-6-carboxylic acid; and the pharmaceutically acceptable salts thereof.
5) A process for the preparation of a compound of formula (I), as claimed in claim 1, said process comprising: a) cyclizing a compound of formula (II)
R" R2, R3, R4 and R5 are as defined in claim 1) and R10 is a nucleophile group able to easily remove the proton linked to the nitrogen atom of the pyrazolyl ring, or a salt thereof; or b) reacting a compound of formula (III)
wherein B1, R2, B3 and R4 are as defined in claim 1) and R11 is a free or esterified carboxy group, or a salt thereof, with a compound of formula (IV) H2N-R9 (IV) wherein Rg is as defined in claim 1), or an active derivative thereof, so obtaining compounds of formula (I) wherein B5 is as defined in claim 1 under c'); or c) reacting a compound of formula (V)
R1, R2, R3 and R4 are as defined in claim 1) and Z is a reactive carboxy group, with a compound of formula (Vl)
or of formula (VII)
or of formula (VIII) wherein
R6, R7, R8 and mare as defined in claim 1), so obtaining compounds of formula (I) wherein B5 is as defined in claim 1) under a'), b') and d') respectively, and if desired, converting a compound of formula (I) into another compound of formula (I) and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof and/or, if desired, obtaining a free compound of formula (I) from a saltthereof and/or, if desired, separating a mixture of isomers into the single isomers.
6) A pharmaceutical composition containing a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) according to claim 1), or a pharmaceutically acceptable salt thereof.
7) A process according to claim 5 substantially as hereinbefore described with reference to any one of Examples 1 to 19.
8) A composition according to claim 6 substantially as hereinbefore described with reference to Example 20.
9) A compound according to claim 1 for use as an anti-inflammatory or analgesic agent.
GB08306905A 1982-03-16 1983-03-14 Substituted 1h-pyrazolo (1 5-a) pyrimidines and process for their preparation Expired GB2116971B (en)

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GB838303089A GB8303089D0 (en) 1983-02-04 1983-02-04 Substituted 1h-pyrazolo 1,5-a pyrimidines
GB08306905A GB2116971B (en) 1982-03-16 1983-03-14 Substituted 1h-pyrazolo (1 5-a) pyrimidines and process for their preparation

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0353047A2 (en) * 1988-07-26 1990-01-31 Sankyo Company Limited Use of imidazopyrazole derivatives as analgesics and anti-inflammatory agents
US5232939A (en) * 1988-07-26 1993-08-03 Sankyo Company Limited Use of imidazopyrazole derivatives as analgesics and anti-inflammatory agents
EP0671395A1 (en) * 1994-03-11 1995-09-13 Masakatsu Matsumoto 1,2-Dioxetane derivatives, intermediates for syntheses thereof and methods of producing the intermediates

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0353047A2 (en) * 1988-07-26 1990-01-31 Sankyo Company Limited Use of imidazopyrazole derivatives as analgesics and anti-inflammatory agents
EP0353047A3 (en) * 1988-07-26 1991-07-24 Sankyo Company Limited Use of imidazopyrazole derivatives as analgesics and anti-inflammatory agents
US5232939A (en) * 1988-07-26 1993-08-03 Sankyo Company Limited Use of imidazopyrazole derivatives as analgesics and anti-inflammatory agents
EP0671395A1 (en) * 1994-03-11 1995-09-13 Masakatsu Matsumoto 1,2-Dioxetane derivatives, intermediates for syntheses thereof and methods of producing the intermediates
US5936132A (en) * 1994-03-11 1999-08-10 Matsumoto; Masakatsu Alkene intermediates and synthesis thereof

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GB2116971B (en) 1985-03-27
GB8306905D0 (en) 1983-04-20

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