GB2132200A - Carboxamido-derivatives of 5H-1,3,4-thiadiazolo[3,2-a]-pyrimidines and process for their preparation - Google Patents

Carboxamido-derivatives of 5H-1,3,4-thiadiazolo[3,2-a]-pyrimidines and process for their preparation Download PDF

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GB2132200A
GB2132200A GB08333535A GB8333535A GB2132200A GB 2132200 A GB2132200 A GB 2132200A GB 08333535 A GB08333535 A GB 08333535A GB 8333535 A GB8333535 A GB 8333535A GB 2132200 A GB2132200 A GB 2132200A
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pyridyl
oxo
thiadiazolo
pyrimidine
carboxamide
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GB8333535D0 (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
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Novel compounds of general formula (I> <IMAGE> wherein R1 represents: (a) hydrogen, halogen or C1-C6 alkyl unsubstituted or substituted by C1-C6 alkoxy; (b> <IMAGE> wherein n is zero, 1, 2 or 3 and each of R4 and R5 is, independently, hydrogen or C1-C6 alkyl, or R4 and R5, taken together with the nitrogen atom to which they are linked, form an unsubstituted N- pyrrolidinyl ring or a piperidino, morpholino, N-piperazinyl or <IMAGE> ring, wherein m is zero, 1 or 2, the piperidino and morpholino rings are unsubstituted or substituted by one or two C1-C6 alkyl groups and the N-piperazinyl ring is unsubstituted or substituted by a substituent chosen from C1-C6 alkyl, phenyl and pyridyl; (c) trihalomethyl or R6-S(O)p-, wherein p is zero, 1 or 2 and R6 is C1-C6 alkyl or benzyl, wherein the phenyl ring is unsubstituted or substituted by a substituent chosen from halogen, C1-C6 alkyl and C1-C6 alkoxy; or (d) an unsubstituted pyridyl, pyridyl-N-oxide or thienyl ring or a phenyl ring unsubstituted or substituted by one, two or three substituents independently chosen from halogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, formyloxy, C2-C8 alkanoyloxy, nitro, amino, formylamino, C2-C8 alkanoylamino and di-(C1-C6) alkylamino; R2 represents hydrogen or C1-C6 alkyl; R3 represents: (a') phenyl unsubstituted or substituted by one or two substituents independently chosen from C1-C6 alkyl, C1-C6 alkoxy and halogen; (b') an unsaturated heteromonocyclic or heterobicyclic ring, containing one or more heteroatoms chosen from nitrogen and sulphur, unsubstituted or substituted by one or two substituents independently chosen from halogen, C1-C6 alkyl and C1-C6 alkoxy; and the pharmaceutically acceptable salts thereof; are useful as anti-inflammatory and analgesic agents.

Description

SPECIFICATION Carboxamido-derivatives of 5H-1 ,3,4-thiadiazolo (3,2-a pyrimidines and process for their preparation The present invention relates to new carboxamido-derivatives of 5H-1,3,4-thiadiazolo[3,2-a] pyrimidines, to a process for their preparation and to pharmaceutical compositions containing them.
The invention provides compounds having the fol!owing general formula (I)
wherein R, represents: (a) a hydrogen or halogen atom or a C1 -C6 alkyl group unsubstituted or substituted by C-C6 alkoxy; (b) a
group, wherein n is zero, 1, 2 or 3 and each of R4 and R6 is, independently, hydrogen or C,-C6 alkyl, or R4 and R5, taken together with the nitrogen atom to which they are linked, form an unsubstituted N-pyrrolidinyl ring or a piperidino, morpholino, N-piperazinyl or
ring, wherein m is zero, 1 or 2, the piperidino and morpholino rings are unsubstituted or substituted by one or two C,-C6 alkyl groups and the N-piperazinyl ring is unsubstituted or substituted by a substituent chosen from C,-C6 alkyl, phenyl and pyridyl; (c) trihalomethyl or a R6-S(O)p- group, wherein p is zero, 1 or 2 and R6 is C,-C6 alkyl or benzyl, wherein the phenyl ring is unsubstituted or substituted by a substituent chosen from halogen, C,-C6 alkyl and C,-C6 alkoxy; or (d) an unsubstituted pyridyl, pyridyl-N-oxide or thienyl ring or a phenyl ring unsubstituted or substituted by one, two or three substituents independently chosen from halogen, C,-C6 alkyl, C,-C6 alkoxy, hydroxy, formyloxy, C2-C8 alkanoyloxy, nitro, amino, formylamino, C2-C8 alkanoyamino and di-(C,-C6) alkyl-amino; R2 represents a hydrogen atom or a C,-C6 alkyl group; R3 represents: (a') a phenyl ring, unsubstituted or substituted by one or two substituents independently chosen from C1-C6 alkyl, C1-C6 alkoxy and halogen; (b') an unsaturated heteromonocyclic or heterobicyclic ring, containing one or more heteroatoms chosen from nitrogen and sulphur, unsubstituted or substituted by one or two substituents independently chosen from halogen, C,-C6 alkyl and C,-C6 alkoxy; 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 mixtures thereof.
The alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyloxy and alkanoylamino groups may be branched or straight chain groups.
A halogen atom is, for example, chlorine, bromine or fluorine, preferably it is chlorine or fluorine.
A trihalomethyl group is preferably trifluoromethyl.
A C,-C6 alkyl group is preferably a C,-C4 alkyl group, in particular methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.
A C,-C6 alkoxy group is preferably a C,-C4 alkoxy group, in particular, methoxy, ethoxy, propoxy and isopropoxy.
A C,-C6 alkylthio group is, for example, methylthio, ethylthio, propylthio, butylthio; preferably it is methylthio, ethylthio and propylthio.
A C,-C6 alkylsulfinyl is, for example, methylsulfinyl, ethylsulfinyl and propylsulfinyl.
A C,-C6 alkylsulfonyl, is for example, methylsulfonyl, ethylsulfonyl and propylsulfonyl.
A C2-C8 alkanoyloxy group is, for example, acetoxy, propionyloxy, butyryloxy and valeryloxy; preferably it is acetoxy.
A C2-C8 alkanoylamino group is, for example, acetylamino, propionylamino, butyrylamino; preferably it is acetylamino. When R, represents an unsubstituted C,-C6 alkyl group, it is, e.g.
methyl, ethyl, propyl, isopropyl, butyl or tert-butyl; preferably it is methyl, ethyl or isopropyl.
When R, is a substituted C1-C6 alkyl group, as defined above under (a), it is preferably C,-C4 alkyl substituted by C1-C4 alkoxy, more preferably by methoxy or ethoxy.
When R1 is a
group, wherein n is as defined above and R4 and 115, being the same or different, are C1 -C6 alkyl, preferably R4 and Rs are C1 -C4 alkyl, more preferably ethyl, propyl and isopropyl.
When R4 and R,, taken together with the nitrogen atom to which they are linked, form a piperidino or morpholino ring, said ring, when substituted, is preferably substituted by one or two C1-C4 alkyl groups, which may be the same or different; more preferably it is substituted by a substituent chosen from methyl, ethyl, propyl and isopropyl.
When R4 and R,, taken together with the nitrogen atom to which they are linked, form a Npiperazinyl ring, said ring, when substituted, is preferably substituted by a substituent chosen from phenyl, pyridyl and C1-C4 alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.
When R2 represents a C,-C6 alkyl group, it is, e.g. methyl ethyl, propyl, isopropyl, butyl or tert-butyl, preferably it is methyl, ethyl or isopropyl.
When R, and/or R3 is a phenyl ring as defined above under (d) and (a'), respectively, said ring is preferably substituted by one or two substituents chosen from chlorine, fluorine, methyl and methoxy.
When R6 is a benzyl group substituted as defined above, it is preferably substituted by a substituent chosen from chlorine, methyl and methoxy.
When 113 is an unsaturated heteromonocyclic or heterobicyclic ring as defined above under (b'), it is, for example, a ring chosen from pyridyl, thiazolyl, pyrazolyl, pyrimidinyl and benzothiazolyl; preferably it is a thiazolyl or pyridyl ring wherein the thiazolyl and pyridyl rings are unsubstituted or substituted by one or two substituents chosen from methyl, chlorine, bromine and methoxy or it is a pyrazolyl ring substituted by a C1 -C4 alkyl group.
Preferred compounds of the invention are the compounds having formula (I), wherein R, is (a") hydrogen C,-C3 alkyl, C,-C3 alkylthio, benzylthio, methoxymethyl, ethoxymethyl or di (C,-C4 alkyl)-amino; or (b") an unsubstituted N-pyrrolidinyl ring; a morpholino or piperidino ring, both unsubstituted or substituted by C,-C2 alkyl; or a N-piperazinyl ring substituted by a substituent chosen from C,-C3 alkyl, phenyl and pyridyl; or (c") an unsubstituted pyridyl or pyridyl-N-oxide ring; or a phenyl ring unsubstituted or substituted by one or two substituents chosen from chlorine, fluorine and methyl; or (d") a
ring, wherein m is zero, 1 or 2; R2 is hydrogen or C,-C2 alkyl; R3 is an unsubstituted benzothiazolyl ring; 1 -(C1-C4 alkyl)-pyrazolyl; or a thiazolyl or pyridyl ring, both unsubstituted or substituted by one or two substituents chosen from methyl and chlorine; and the pharmaceutically acceptable salts thereof.
More preferred compounds df the invention are the compounds having formula (I), wherein R, is (a"') hydrogen or methyl; or (b"') an unsubstituted N-pyrrolidinyl ring; a piperidino or a morpholino ring, both unsubstituted or substituted by C,-C2 alkyl; or a N-piperazinyl ring substituted by a substituent chosen from C,-C3 alkyl, phenyl and pyridyl; or (c"') an unsubstituted pyridyl or pyridyl-N-oxide ring; or (d"') a
ring, wherein m is zero, 1 or 2; R2 is hydrogen or methyl; R3 is an unsubstituted benzothiazolyl ring; 1-(C,-C2-alkyl)-pyrazolyl; or a thiazolyl or pyridyl ring, both unsubstituted or substituted by one or two methyl groups; and the pharmaceutically acceptable salts thereof.
Examples of pharmaceutically acceptable salts are those 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: 5-oxo-5 H-I 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 5-oxo-SH-I ,3,4.thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-(4-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-benzothiazolyl)-carboxamide; 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-benzothiazolyl)-carboxamide; 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3, 2-ajpyrimidine-6-N-(2-pyridyl)-carboxamide; 2-morpholino-5-oxo-5 H-I , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-benzothiazolyl)-carboxamide; 2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(4-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine.6-N-(pyridyl)-carboxamide; 2-(4-pyridyl)-5-oxo-5H-1 ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-(2-methyl-morpholino)-5-oxo-5H-l 3,4-thiadiazolo(3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxam- ide; 2-(4-methyl-piperazin- 1 -yl)-5-oxo-5 H-i , 3, 4-thiadiazolo[3, 2-a]pyri m idine-6-N-(2-pyridyl)-carboxamide; 2-(4-pyridyl)-5-oxo-5 H- ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4-methyl-2-thiazolyl)-carboxamide; 2-(2-methyl-morpholino)-5-oxo-5 H- 1,3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-thiazolyl)-carboxam- ide; 2-thiomorpholino-5-oxo-SH-l , 3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 7-methyl-2-morpholino-5-oxo-5 H- 1, ,3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 7-methyl-2-morpholino-5-oxo-5 H-i 3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxam- ide; 7-methyl-5-oxo-SH-I ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide;; 7-methyl-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-(3-pyridyl-N-oxide)-5-oxo-5H-1 ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(4-pyridyl-N-oxide)-5-oxo-5H-1 ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-thiomorpholino-5-oxo-SH- 1 ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 7-methyl-2-(3-pyridyl)-5-oxo-5 H-i ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 7-methyl-2-(4-pyridyl)-5-oxo-5H-1, 3, 4-thiadiazolo[3, 2-a]pyrimid ine-6-N-(2-th iazolyl)-carboxam ide; 2-(thiomorpholino-l , 1 -dioxide)-5-oxo-SH-1 , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide; 2-(thiomorpholino-1 1 -dioxide)-5-oxo-5H-1 ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-car- boxamide; and the pharmaceutically acceptable salts thereof.
The compounds of this invention can be prepared by a process comprising reacting a compound of formula (II)
wherein R1 and R2 are as defined above and R7 is carboxy or a reactive derivative of a carboxy group, with a compound of formula (III) H2N-R3 (III) wherein R3 is as defined above; 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 salt thereof and/or, if desired, separating a mixture of isomers into the single isomers.
When R7 is a reactive derivative of a carboxy group, it is preferably a carboxylic ester, for example, a group of formula -COR'7, wherein R'7 is, e.g., C,-C,2 alkoxy or tri(C1-C6)-alkylsilyloxy.
The reaction between a compound of formula (II), wherein R7 is a -COR'7 group wherein R'7 is C1-C,2 alkoxy or tri(C,-C6)-alkyl-silyloxy, and a compound of formula (III) may be carried out, for example, by heating with polyphosphoric or methanesulphonic or p-toluensulphonic 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 or xylene; or alternatively by heating from 50"C to about 1 50 C without any acidic agent and in the presence of an organic solvent only, e.g. toluene or xylene, if required.
A compound of formula (I) may be converted, as stated above, into another compound of formula (I) by known methods; for example, free hydroxy groups may be etherified by reaction with a suitable alkyl halide in the presence of a base such as NaH, Na2CO3, K2CO3,NaNH2, sodium methoxide or sodium ethoxide in a solvent selected from the group consisting, for example, of methanol, ethanol dioxane, acetone, dimethylformamide, hexamethylphosphorotriamide, tetrahydrofuran, water and their mixtures at a temperature ranging preferably between about and about 150"C.
Furthermore, for example, a nitro-group as substituent in the R, phenyl group may be converted into an amino group by treatment, for example, with stannous chloride in connected hydrochloric acid, using, if necessary, an organic cosolvent such as acetic acid, dioxane, tetrahydrofuran at a temperature varying between room temperature and about 1 00 C.
For example, an amino or an hydroxy group may be converted into a formylamino, formyloxy, C2-C8 alkanoylamino or C2-C8 alkanoyloxy group, for example, respectively, 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 1 00 C.
As further example, a thiomorpholino group may be converted into a thiomorpholino 1-oxide group or into a thiomorpholino 1 ,1-dioxide group by reaction with suitable oxidizing agents, for example, with a stoichiometric amount of peracetic acid thus obtaining the 1-oxide derivatives or with m-chloroperbenzoic acid in CH2CI2 thus obtaining the 1,1-dioxide derivatives, and carrying out the reaction in both the cases at a temperature varying between about 0 C and about 30"C.
Also the optional salification of a compound of formula (I) as well 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 acid and subsequent fractional crystallization.
The compounds of formula (II) may be obtained according to known methods; for example, the compounds of formula (II) wherein R7 is a -COR'7 group, wherein R'7 is C,-C,2 alkoxy or tri(C,-C6)alkyl-silyloxy, may be prepared, by cyclizing a compound of formula (IV)
wherein R, and R2 are as defined above and R8 and Rg, which may be the same or different, are C,-C,2 alkoxy or tri(C,-C6) alkyl-silyloxy.
Analogous methods of preparation may be carried out for the other esters of formula (II).
The cyclization of a compound of formula (1V) 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, or by treatment with sulphuric or hydrochloric or acetic acid, methanesulphonic acid or p-toluenesulphonic acid, at a temperature ranging preferably between about 50"C and 1 50 C; the reaction may be carried but in an organic solvent such as dimethylformamide, dimethylacetamide, dimethylsulphoxide, formic acid, diglyme, 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 (IV) may be carried out by heating the compound at a temperature ranging between about 1 50 C and about 350"C, preferably between 200 C and 300"C, in an inert high boiling organic solvent such a diphenyl ether or diglyme, or in the absence of a solvent.
The compounds of formula (IV) may be prepared, for example, by reacting a compound of formula (V)
wherein R, is as defined above, with a compound of formula (Vl)
wherein R2, R8 and 119 are as defined above and 1110 is a reactive group chosen, preferably, from hydroxy, amino, C,-C6 alkoxy or tri(C,-C6) alkyl-silyloxy.
The reaction between a compound of formula (V) and a compound of formula (Vl) may be carried out, for example, by heating in solvents such as dioxane, toluene, xylene, C,-C4 alkyl alcohol, dimethylformamide, dimethylacetamide, diglyme, diphenylether or in the absence of a solvent at a temperature varying from about 50"C to about 200"C.
Preferably, when R,o is hydroxy, the reaction between a compound of formula (V) and a compound of formula (Vl) 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 (iV).
The reaction of a compound of formula (V) witha compound of formula (Vl) may be carried out till a compound of formula (II) is obtained without the need to isolate the intermediate product of formula (IV) formed during the reaction.
The compounds of formula (III), (V) and (Vl) are known compounds or may be prepared by conventional methods: in some cases they are commercially available products. When the reactions hereabove described concern compounds wherein free amino or hydroxy groups are present, the amino and hydroxy groups may be protected, if necessary, in a conventional manner, before the reaction takes place. Amino protecting groups may be, for example, the protecting groups usually employed in the chemistry of peptides. Examples of amino protecting groups are formyl, an optional halo-substituted C2-C6 aliphatic acyl, preferably chloroacetyl, dichloroacetyl or trifluoroacetyl, tert-butoxycarbonyl, p-nitrobenzyloxy-carbonyl or trityl.The hydroxy groups may be protected, for example, by a formyl, acetyl, chloroacetyl, dichloroacetyl, trifluoroacetyl, tetrahydropyranyl, trityl or silyl group, preferably trimethylsilyl or dimethyltert.butyl silyl. The amino and hydroxy protecting groups are then removed at the end of the reaction usually in a known manner. For example, when- the amino protecting group is the monochloroacetyl group, it may be removed by treatment with thiourea; the formyl and the trifluoroacetyl groups may be removed by treatment with hydrochloric acid in aqueous methanol and the trityl group by treatment with formic or trifluoroacetic acid.
The hydroxy protecting groups, for instance, may be removed by mild reaction conditions, e.g. acid hydrolysis. The compounds of the present invention possess anti-inflammatory activity, as demonstrated e.g. by the fact that they are active, after oral adminstration, in inhibiting: (A) the edema 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 following Tables I and ll show, for example, the approximate ED60 values of tha antiinflammatory activity in the above mentioned tests, in the rat after oral administration, for a compound of this invention: 2-(3-pyridyl)-5-oxo-5 H-l ,3,4-thiadiazolo[3, 2-a]pyri m idine-6-N-(2- pyridyl)-carboxamide (internal code FCE 22914): TABLE I Compound Anti-inflammatory activity Carrageenin induced oedema FCE 22914 End50=45.86 mg/kg TABLE II Compound Anti-inflammatory activity RPAR reaction FCE 22914 ED60 = 85.2 mg/kg The compounds of this invention are also endowed with analgesic activity.
The analgesic activity was assessed, for example, by means of this phenylquinone test in mice according to Siegmund: iegmund et al. Proc. Soc. Exper. Biol Med. 95, 729 (1 957)].
In this test the compound FCE 22914, for example, gives a 30% inhibition at 50 mg/kg after oral administration.
It is known that certain thiadiazolo-pyrimidine derivatives are endowed with anti-allergic and anti-asthma activity, e.g. those described in Published Japan Patent Application J57 142989, but such compound are devoid of any anti-inflammatory and/or analgesic activity. On the contrary the new thiadiazolo-pyrimidine derivatives of the present invention, which, as stated above, possess a therapeutically useful anti-inflammatory and analgesic activity, are surprisingly devoid of any anti-allergic and anti-asthma activity.
In view of their high therapeutic index, the compounds of the invention can be used safely in medicine. For example, the approximate acute toxicity (LD50) of the compounds 2-(3-pyridyl)-5oxo-5 H-l ,3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide and 5-oxo-5 H-l ,3,4-thia- diazolo[3,2-aipyrimidine-6-N-(2-pyridyl)-carboxamide in the mouse, determined by single adminstration of increasing doses and measured on the seventh day after 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 administered 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. intramuscularly or by intravenous injection or infusion.
The dosage depends on the age, weight, conditions of the patient and administration route; for example the dosage suitable for oral administration to adult humans for the treatment of pains and inflammatory processes ranges from about 10 to about 200 mg per dose, from 1 to 5 times daily. The invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent).
The pharmaceutical compositions containing the compounds of the invenntion are usually prepared following conventional methods and are administered 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, carboxymethylcellulose or polyvinyl pyrrolidone; disagregating 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 pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating or film-coating processes.
The liquid dispersion 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/or sorbitol; 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, carboxymethylcellulose 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 carriers, 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 2-amino-1 ,3,4-thiadiazole (5 g) was reacted with diethyl ethoxymethylenemalonate (26.5 g) in ethanol (20 ml) at the reflux temperature for 23 hours. After cooling the precipitate was filtered and purified with hexane to give diethyl N-(1 ,3,4-thiadiazol-2-yl)-aminomethylenemalonate, m.p.
107-111 C (10 g), which was treated with polyphosphoric acid (57.6 g : 30.8 g of 99% H3PO4 and 26.8 g of P205) and POCI3 (25 g) under stirring at 120"C for 30 minutes.
After cooling the reaction mixture was diluted with ice water and then the solution was neutralized with 35% NaOH: the precipitate was filtered and washed with water to give 5-oxo5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid, ethyl ester, m.p. 228-230 C, (5.75 g), which was reacted with 2-amino-pyridine (4.9 9) in polyphosphoric acid (57.5 g: 31 g of 99% H3PO4 and 26.5 g of P205) under stirring at 120"C for 12 hours.After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water: crystallization from chloroform-methanol gave 3.3 g of 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimi- dine-6-N-(2-pyridyl)-carboxamide, m.p. 240-245"C dec., NMR (DMSO d 6) 8 p.p.m.: 7.15 (m) (1H, C-S pyridyl proton), 7.84 (dt) (1H, C-4 pyridyl proton), 8.15-8.40 (m) (2H, C-3 and C-6 pyridyl protons), 8.92 (s) (1 H, C-7 proton), 9.57 (s) (1 H, C-2 proton).
By proceeding analogously the following compounds were prepared: 2-methyl-S-oxo-5H- 1, 3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p.
231 -233'C; 2-ethyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m p.
247-248"C; 2-benzylthio-5-oxo-5 H- 1 , 3 ,4-thiad iazolo[3, 2-a]pyrim idine-6-N-(2-pyridyl)-carboxamide, m p.
209-211 C; 2-methylthio-5-oxo-5H-l ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p.
239-240"C; 2-ethylthio-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-methylsulfinyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-methylsulfonyl-5-oxo-5 H-l , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-trifluoromethyl-5-oxo-5 ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-methoxymethyl-5-oxo-5H-1 , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p.
218-220"C; 2-ethoxymethyl-5-oxo-5 H-l , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; and 2-chloro-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide.
EXAMPLE 2 2-phenyl-5-oxo-5 , 3,4-thiadiazoIo3, 2-a]pyrimidine-6-carboxylic acid, ethyl ester, m.p.
172-174"C (3 g) was reacted with 2-amino-pyridine (1.9 g) in polyphosphoric acid (50 g : 26 g of 99% H3PO4 and 24 g of P205) under stirring at 110"C for 6 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water: crystallization from chloroform-ethanol gave 2.6 g of 2-phenyl-S-oxo-5H-l 3,4-thiadiazo- lO[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p. 273-275"C, NMR (CDCI3-CF3COOD) 8 p.p.m.: 7.45-8.10 (m) (7H, C-3 and C-S pyridyl protons and phenyl protons), 8.40 (m) (2H, C-4 and C-6 pyridyl protons), 9.10 (s) (1 H, C-7 proton).
By proceeding analogously the following compounds were prepared: 2-(4-fluoro-phenyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p. 214-217 C; 2-(4-chloro-phenyl)-5-oxo-5H-1,3,4-thiadiazol[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p.
294-297 C; 2-(3-chloro-phenyl)-5-oxo-5H-1,3,4-thiadiazol[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(2-chloro-phenyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(3,4-dichloro-phenyl)-5-oxo-5 H- 1,3,4thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(4-methyl-phenyl)-5-oxo-5H-1 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p. 301-303 C; 2-(4-methoxy-phenyl)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(pyridyl)-carboxamide, m.p. 274-278 C; 2-(3-methoxy-phenyl)-5-oxo-5 H- 1,3, 4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(4-nitro-phenyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p.
302-305'C; 2-(3-nitro-phenyl)-5-oxo-SH-l ,3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(2-nitro-phenyl)-5-oxo-5 H- , 3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(2-thienyl)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p.
270-272"C; 2-(4-N,N-dimethylamino-phenyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide; and 2-(3-N, N-dimethylamino-phenyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide.
Example 3 2-amino-5-(3-pyridyl)-1,3,4-thiadiazole (10 g) was reacted with diethyl ethoxymethylene-malonate (18 g) under stirring at 120"C for 9 hours. After cooling the reaction mixture was crystallized from CH2CI2-isopropyl ether to give diethyl N-[5-(3-pyridyl)-1,3,4-thiadiazol-2-yl]- aminomethylene-malonate, m.p. 144-145"C (15.8 g) which was treated with polyphosphoric acid (6.6 g: 3.5 g of 99% H3PO4 and 3.1 g of P205) and POCI3 (27.8 g) under stirring at 1 20'C for 40 minutes.
After cooling the reaction mixture was diluted with ice water and then the solution was neutralized with 35% NaOH. The precipitate was filtered and washed with water: crystallization from CH2CI2-isopropyl alcohol gave 2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6- carboxylic acid, ethyl ester, m.p. 200-202 C, (6.6 g), which was reacted with 2-amino-pyridine (10.02 g) in polyphosphoric acid (330 g: 176 g of 99% H3PO4 and 154 g of P205) under stirring at 120"C for 7 hours.After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water: crystallization from CH2CI2-methanol gave 5.3 g of 2-(3-pyridyl)-5-oxo-5 H-i, 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carbox- amide, m.p. 274-277"C, NMR (CDCI3 + CF3COOD) S ppm: 7.75 (m) (2H, C-S pyridyl and C-S pyridyl-amide protons), 8.45 (m) (3H, C-4 pyridyl and C-3 and C-4 pyridyl-amide protons), 9.20 (m) (2H, C-6 pyridyl and C-6 pyridyl-amide protons), 9.29 (s) (1 H, C-7 proton), 9.67 (bs) (1 H, C-2 pyridyl proton).
By proceeding analogously the following compounds were prepared: 2-morpholino-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p.
274-275"C, NMR (CDCI3 + CF3COOD) 8 ppm: 3.4-4.0 (m) (SH, morpholinyl protons), 7.6 (m) (2H, C-4 and C-S pyridyl protons), 8.3-8.6 (m) (2H, C-3 and C-6 pyridyl protons), 8.9 (s) (1 H, C-7 proton); 2-(4-pyridyl)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m p.
279-280"C; 2-(2-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(3-pyridyl)-5-oxo-5 H- 1,3,4-th iad iazolo[3,2-a]pyrimidine-6-N-(6-methyl-2-pyridyl)-carboxamide, m.p. 305-307 C; 2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(5-methyl-2-pyridyl)-carboxamide; 2-(4-pyridyl)-5-oxo-5 H- , 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(6-methyl-2-pyridyl)-carboxamide; 2-(4-pyridyl)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4,6-dimethyl-2-pyridyl)-carboxam- ide; 2-(3-pyridyl)-5-oxo-5 H-i , 3,4-thiadiazolo[3, 2-a]pyrim idine-6-N-(4, 6-dimethyl-2-pyridyl)-carboxam- ide; 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4,6-dimethyl-2-pyridyl)-carbox- amide, m.p. 310-313 C; 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(5-chloro-2-pyridyl)-carboxamide, 2-morpholino-5-oxo-5H-l ,3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(3-pyridyl)-carboxami 2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(3-pyridyl).carboxamide; 2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(5-chloro-2-pyridyl)-carboxamide, m.p. 306-310 C; 2-morpholino-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(6-methyl-2-pyridyl)-carboxamide; 2-morpholino-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(5-methyl-2-pyridyl)-carboxamide; 2-N, N-diethylamino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-N,N-dipropylamino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-N,N-diisopropylamino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxam- ide; ; 2-(pyrrolidin- 1 -yl)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m p.
302-304 C; 2-piperidino-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p.
242-244 C; 2-(2-methyl-piperidino)-5-oxo-S H-i , 3, 4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(3-methyl-piperidino)-5-oxo-SH-i , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(4-methyl-piperidino)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(2,6-dimethyl-piperidino)-5-oxo-5H-1,3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carbox- amide; 2-(3,5-dimethyl-piperidino)-5-oxo-5H-1,3,4-thiadiazolo-[3,2-a]pyrimidine-6-N-(2-pyridyl)-carbox- amide; 2-(2-ethyl-piperidino)-5-oxo-5H-1 , 3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(4-methyl-piperazin- 1 -yl)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxam- ide, m.p. 220-221 C; 2-(4-phenyl-piperazin- 1 -yl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxam- ide; 2-[4-(2-pyridyl)-piperazin- 1 -ylj-5-oxo-S H-i ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide; 2-N, N-dibutylamino-5-oxo-5 H-i , 3,4-thiadiazolo[3,2-a]pyrimidine-6-N.(2-pyridyl)-carboxamide; 2-N, N-diisobutylamino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(4-ethyl-piperazin-1-yl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxam- ide; 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(3-pyridyl)-carboxamide; 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(5-chloro-2-pyridyl)-carboxamide, m.p.
260-270 C dec.; 2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(5-chloro-2-pyridyl)-carboxamide; 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(6-methyl-2-pyridyl)-carboxamide,m.p.
258-268 C dec.; 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4,6-dimethyl-2-pyridyl)-carboxamide; 2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(6-methyl-2-pyridyl)-carboxamide; 2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4, 6-dimethyl-2-pyridyl)-carboxamide; and 2-morpholinomethyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide.
Example 4 2-amino-5-morpholino-1,3,4-thiadiazole (6.25 g) was reacted with diethyl ethoxymethylenemalonate (9 g) under stirring at 120"C for 4 hours. After cooling the crude diethyl N-(5morpholino-1,3,4-thiadiazol-2-yl)-aminomethylene-malonate was treated with polyphosphoric acid (5 g: 2.6 g of 99% H3PO4 and 2.4 9 of P2O6) and POCI3 (20.5 g) under stirring at 120"C for 30 minutes.
After cooling the reaction mixture was diluted with ice water and then the solution was neutralized with 35% NaOH. The precipitate was filtered and washed with water: crystallization from CH2CI2-isopropyl ether gave 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6- carboxylic acid, ethyl ester, m.p. 217-219"C, (8 g), which was reacted with 2-amino-thiazole (5.2 g) in polyphosphoric acid (120 g: 64 g of 99% H3PO4 and 56 g of P205) under stirring at 110 C for 30 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 5 g of 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide, m.p.
274-276 C, NMR (CDCI3 + CF3COOD) 8 ppm: 3.58 (m) (4H, C-3 and C-S morpholinyl protons), 3.85 (m) (4H, C-2 and C-6 morpholinyl protons), 6.69 (d) (1 H, C-S thiazolyl proton), 7.75 (d) (1 H, C-4 thiazolyl proton), 8.94 (s) (1 H, C-7 proton).
By proceeding analogously the following compounds were prepared: 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4-methyl-2-thiazolyl)-carboxamide, m.p.
230-240 C dec.; 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4,5-dimethyl-2-thiazolyl)-carboxamide; 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(1-methyl-3-pyrazolyl)-carboxamide; 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(5-chloro-2-thiazolyl)-carboxamide, m.p.
255-275 C dec.; 5-oxo-5H-1,3,4thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide, m.p. 230-240 C dec.; 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-benzothiazolyl)-carboxamide, m p.
162-164"C; 2-methyl-S-oxo-5 H-i , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide, m. p.
246-249 'C; 2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo,[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide, m.p.
322-326 C; 2-(4-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide,m.p.
310-316"C; 2-(2-pyridyl)-S-oxo-5 H-I , 3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-ethyl-5-oxo-5H-I , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide, m p.
239-241 C; 2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(1-methyl-3-pyrazolyl)-carboxamide; 2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4,5-dimethyl-2-thiazolyl)-carboxam- ide; 2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4-methyl-2-thiazolyl)-carboxamide; 2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-benzothiazolyl)-carboxamide; 2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(4-methyl-2-thiazolyl)-carboxamide; 2-(3-pyridyl)-5-oxo-5 H- , 3, 4-thiadiazoIo3, 2-a]pyrimidine-6-N-( 1 -methyl-3-pyrazolyl)-carboxamide; 2-(4-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4-methyl-2-thiazolyl)-carboxamide, m.p. 276-279 C; 2-(4-pyridyl)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4,5-dimethyl-2-thiazolyl)-carbox- amide, m.p. 330-332 C; 2-(4-pyridyl)-5-oxo-5H-1,3,4thiadiazolo[3,2-a]pyrimidine-6-N-(5-chloro-2-thiazolyl)-carboxamide; 2-(4-pyridyl)-5-oxo-5 H- , 3, 4-th iadiazolor3, 2-a]pyri mid ine-6-N-(2-benzothiazolyl)-carboxamide; 2-morpholino-5-oxo-5 H- ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4-methyl-2-thiazolyl)-carboxam- ide, m.p. 259-261 C; 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-benzothiazolyl)-carboxamide; m.p. 380-385"C dec.; 2-morpholino-5-oxo-5H-l , 3,4-thiadiazoloC3,2-a]pyrimidine-6-N-(4, 5-dimethyl-2-thiazolyl)-carbox- amide, m.p. 325-328 C; 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(5-chloro-2-thiazolyl)-carboxam- ide, m.p. 279-281 C; 2-morpholino-5-oxo-5 H- , 3,4-thiadiazoloE3, 2-a]pyrimidine-6-N-( 1 -methyl-3-pyrazolyl)-carboxamide, m.p. 277-279 C; 2-(pyrrolidin-1 -yl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-piperidino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide, m.p.
249-250 C; 2-(4-methyl-piperazin- 1 -yl)-5-oxo-5 H- , 3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carbox- amide, m.p. 264-266 C; 2-(4-phenyl-piperazin- 1 -yl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carbox- amide; 2-morpholinomethyl-5-oxo-SH-l ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-(4-pyridyl)-5-oxo-5 H- , 3,4-thiadiazolo(3, 2-a]pyrimid ine-6-N-( 1 -methyl-3-pyrazolyl)-carboxamide; and 2-[4-(2-pyridyl)-piperazin- 1 -yl]-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-car- boxamide.
Example 5 2-amino-5-morphilino-1,3,4-thiadiazole (5g) was reacted with diethyl (1-ethoxy-ethylidene)malonate (6.2 g) in diglyme (40 ml) at 150"C for 20 hours. After cooling the reaction mixture was diluted with ice water and extracted with ethyl acetate; after evaporation in vacuo to dryness, the residue was purified over a SiO2 column using chloroform-methanol 98:2 as eluent.
Crystallization from isopropyl ether gave 7-methyl-2-morpholino-5-oxo-5H-l ,3,4-thiadiazolo[3,2- a]pyrimidine-6-carboxylic acid, ethyl ester, m.p. 196-198 C (2.6 g), which was reacted with 2amino-pyridine (2.25 g) in polyphosphoric acid (130 g) under stirring at 120"C for 4 hours.
After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water to give 1.9 g of 7-methyl-2-morpholino-5-oxo-5H-1,3,4thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m. p. 285-287"C.
By proceeding analogously the following compounds were prepared: 7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2,7-dimethyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N -(2-pyridyl)-carboxamide; 2-ethyl-7-methyl-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 7-methyl-2-methylthio-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-benzylthio-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-methoxymethyl-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carbox- amide; 2-ethoxymethyl-7-methyl-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxam- ide; 7-ethyl-5-oxo-S H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 7-methyl-2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl).carboxamide; m.p 253-255"C 7-ethyl-2-(3-pyridyl)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 7-methyl-2-(4-pyridyl)-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; m.p. 255-256"C 2-N,N-diethylamino-7-methyl-5-oxo-5H-oxo-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)- carboxamide; 2-N, N-dipropylamino-7-methyl-5-oxo-SH- 1, 3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide; 2-N,N-diisopropylamino-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)- carboxamide; 7-methyl-2-(pyrrolidin-1-yl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carbox- amide; 7-methyl-2-(3-pyridyl-N-oxide)-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide; 7-methyl-2-morpholino-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-benzothiazolyl)-car- boxamide; 7-methyl-2-piperidino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 7-methyl-2-(2-methyl-piperidino)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide; 7-methyl-2-(3-methyl-piperidino)-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide; 7-methyl-2-(4-methyl-piperidino)-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide; 2-(2,6-dimethyl-piperidino)-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)- carboxamide; 7-methyl-2-(4-methyl-piperazin-1-yl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)- carboxamide; 7-methyl-2-morpholinomethyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide; 7-methyl-2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; m.p. 322-326 C.
7-ethyl-2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 7-ethyl-2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyi)-carboxamide; 7-methyl-2-(4-methyl-piperazin-l -yl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazo- lyl)-carboxamide; 7-methyl-2-[4-(2-pyridyl)-piperazin-1-yl]-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyri- dyl)-carboxamide; 2-(thiomorpholino-1,1-dioxide)-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyri- dyl)-carboxamide; 2-(thiomorpholino-l , 1 -dioxide)-7-methyl-5-oxo-5 H-l ,3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-thia- zolyl)-carboxamide; 7-methyl-2-(4-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; m.p. 275-277 C 7-methyl-2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxam- ide; m.p. 251-254 C 7-methyl-5-oxo-SH- 1 , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2, 7-dimethyl-5-oxo-5H- 1 , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 7-methyl-2-(2-methyl-morpholino)-5-oxo-5 ,3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)- carboxamide; and 7-methyl-2-(4-pyridyl-N-oxide)-5-oxo-5 H- , 3,4-thiadiazolo[3, i pyri m id i ne-6-N -(2-th iazolyl)-car- boxamide.
Example 6 2-amino-5-(2-methyl-morpholino)-1,3,4-thiadiazole (10 g) was reacted with diethyl ethoxymethylene-malonate (11.3 g) at 120"C for 30 minutes: after cooling the reaction mixture was crystallised from isopropyl ether to give diethyl N-[5-(2-methyl-morpholino)-1,3,4-thiadiazol-2-yl]- aminomethylene-malonate, m.p. 89-91 'C (16.4 g), which was treated with polyphosphoric acid (6.9 g) and POCI3 (27.15 g) under stirring at 120"C for 30 minutes.
After cooling the reaction mixture was diluted with ice water and then the solution was neutralized with 35% NaOH: the precipitate was filtered and washed with water until neutral.
Crystallization from CH2CI2-isopropyl ether gave 2-(2-methyl-morphilino)-5-oxo-1,3,4-thiadiazo- 10[3,2-a]pyrimidine-6-carboxylic acid, ethyl ester, m.p. 189-191 C (12.5 g), which was reacted with 2-amino-pyridine (11.2 g) in polyphospheric acid (625 g : 320 g of 99% H3PO4 and 305 g of P205) under stirring at 120 C for 8 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the obtained solution was extracted with ethyl acetate.
The organic phase was washed with water and then evaporated in vacuo to dryness: crystallization from CH2CI2-methanol gave 7.6 g of 2-(2-methyl-morpholino)-5-oxo-5H-1,3,4thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide,m.p. 263-265 C, NMR (CDCl3 + CF3COOD) 8 ppm: 1.33 (d) (3H, CH3), 3.00-4.4 (m) (7H, morpholine protons), 7.6 (m) (2H, C-3 and C-S pyridyl protons), 8.4 (m) (2H, C-2 and C-6 pyridyl protons), 9.0 (s) (1 H, C-7 proton).
By proceeding analogously the following compounds were prepared: 2-(2-methyl-morpholino)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(6-methyl-2-pyridyl)- carboxamide; 2-(2-methyl-morpholino)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(5-methyl-2-pyridyl)- carboxamide; 2-(2-methyl-morphol i no)-5-oxo-5 H-I , 3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4,6-dimethyl-2-pyri- dyl)-carboxamide; 2-(2-methyl-morpholino)-5-oxo-5 H- , 3,4-thiadiazolo[3, 2-a]pyri midine-6-N-( 1 -methyl-3-pyrazolyl)carboxamide; 2-(2-methyl-morpholino)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxam- ide;; 2-(2-methyl-morpholino)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-benzothiazolyl)-car- boxamide; 2-(2-methyl-morpholino)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4-methyl-2-thiazolyl)- carboxamide; 2-(2-methyl-morpholino)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4,5-dimethyl-2-thiazo- lyl)-carboxamide; 2-(trans-2, 6-dimethyl-morpholino)-5-oxo-S H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)- carboxamide; 2-(cis-2, 6-dimethyl-morpholino)-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide, m.p. 272-273"C, NMR (CDCI3 + CF3COOD) S:1.26 (d) (6H, two -CH3), 2.95 (m) (2H, C-3 and C-S morpholinyl axial protons), 3.70 (m) (4H;C-3 and C-S morpholinyl equatorial protons; C-2 and C-6 morpholinyl equatorial protons), 7.46 (dd) (1 H, C-S pyridyl proton), 8.0-8.4 (m) (2H, C-3 and C-4 pyridyl protons), 8.60 (bd) (1 H, C-6 pyridyl proton), 8.82 (s) (1H, C-7 proton), 12.45 (bs) (iH, -CONH-) ppm; 2-(cis-2,6-dimethyl-morpholino)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(6-methyl-2-py- ridyl)-carboxamide; 2-(cis-2, 6-dimethyl-morpholino)-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(5-methyl-2-py- ridyl)-carboxamide; 2-(cis-2,6-dimethyl-morpholino)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(1 -methyl-3-pyrazolyl)-carboxamide; 2-(cis-2, 6-dimethyl-morpholino)-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4,6-dimethyl- 2-pyridyl)-carboxamide; 2-(cis-2, 6-d imethyl-morpholino)-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-car- boxamide; 2-(cis-2, 6-dimethyl-morpholino)-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-benzothiazo- lyl)-carboxamide; 2-(cis-2, 6-dimethyl-morpholino)-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4-methyl-2-thi- azolyl)-carboxamide; 2-(cis-2, 6-dimethyl-morphol ino)-5-oxo-5 H-I , 3,4-thiadiazolo(3, 2-a]pyrimidine-6-N-(4, 5-dimethyl- 2-thiazolyl)-carboxamide; 2-thiomorpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p.
306-308"C; 2-thiomorpholino-5-oxo-SH-l , 3,4-thiadiazolo[3,2-a]pyrimidine.6.N-(2-thiazolyl)-carboxamide; 2-(thiomorphol ino- 1 -oxide)-5-oxo-5 H- , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carbox- amide, m.p. 325-330"C (dec.); 2-(thiomorpholino- 1 -oxide)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carbox- amide; m.p. 365-370"C (dec.).
2-(thiomorpholino-1,1-dioxide)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide; m.p. 338-340"C (dec.); 2-(thiomorpholino-1,1-dioxide)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-benzothiazo lyl)-carboxamide; 2-(thiomorpholino-i ,1 -dioxide)-5-oxo-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carbox- amide; 2-(3-pyridyl-N-oxide)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, m.p. 318-320 C; 2-(3-pyridyl-N-oxide)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(6-methyl-2-pyridyl)-car- boxamide; 2-(3-pyridyl-N-oxide)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-(4-pyridyl-N-oxide)-5-oxo-5 H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-(4-pyridyl-N-oxide)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-benzothiazolyl)-carbox- amide; and 2-(4-pyridyl-N-oxide)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide.
Example 7 2-thiomorpholino-5-oxo-SH-l , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide (1.5 g) was reacted with peracetic acid obtained from 36% H202 (0.5 g) and acetic acid (70 ml) at room temperature for 1 hour. The reaction mixture was diluted with ice water, neutralized with NaHCO3 and extracted with chloroform: the organic solution was washed with H20 and then evaporated in vacuo to dryness.Crystallization from CH2CI2-methanol gave 0.8 g of 2 (thiomorpholino-1 -oxide)-5-oxo-5 1 1,3,4-thiad iazolo[3,2-a]pyri mid i ne-6-N-(2-pyridyl)-carboxam- ide, m.p. 325-330"C (dec.), NMR (CDCI3 + CF3COOD) S ppm: 3.30 (m) (4H, C-2 and C-6 thiomorpholinyl protons), 4.00-4.70 (m) (4H, C-3 and C-S thiomorpholinyl protons), 7.70 (m) (2H, C-3 and C-S pyridyl protons), 8.44 (m) (2H, C-4 and C-6 pyridyl protons), 9.11 (s) (1 H, C7 proton).
By proceeding analogously the following compound was prepared: 2-(thiomorpholino- 1 -oxide)-5-oxo-5 H- , 3, 4-thiadiazolo[3, 2-a]pyrim idine-6-N-(2-thiazolyl)-carbox- amide.
Example 8 2-thiomorpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide (1.3 g) was reacted with m-chloroperbenzoic acid (1.6 g) in methylene chloride (50 ml) at room temperature for 3 hours. The organic solution was washed with 5% NaHCO3 solution and then with water: after evaporation in vacuo to dryness, crystallization from CH2CI2-methanol gave 0.7 g of 2-(thiomorpholino-1,1-dioxide)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)- carboxamide; m.p. 365-370"C (dec.).
By proceeding analogously the following compound was prepared: 2-(thiomorpholino-I 1 -dioxide)-5-oxo-5H- 1 ,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-benzothiazo- lyl)-carboxamide.
Example 9 2-(4-nitro-phenyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide(4 g), prepared according to Example 2, was reacted with SnCl2.2H20 (22.5 g) in 37% HCI (16 ml) and acetic acid (56 ml) under stirring at 60"C for 8 hours.After cooling the precipitate was filtered and washed with acetic acid and then suspended under stirring in 2N NaOH: the product was filtered, washed with water until neutral and then crystallized from dioxane-ethanol to give 1.7 g of 2-(4-amino-phenyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)- carboxamide, m.p. 290-293"C, NMR (DMSO d6) 8 ppm: 6.28 (bs) (2H, -N H2), 6.70 (bd) (2H, C-3 and C-S phenyl protons), 7.16 (m) (1 H, C-S pyridyl proton), 7.68 (bd) (2H, C-2 and C-6 phenyl protons), 7.84 (m) (1 H, C-4 pyridyl proton), 8.20-8.40 (m) (2H, C-3 and C-6 pyridyl protons), 8.84 (s) (1 H, C-7 proton), 11.40 (bs) (1 H, -CONH-).
By proceeding analogously the following compounds were prepared.
2-(3-amino-phenyl)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(2-amino-phenyl)-5-oxo-5H- 1 , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; and 2-(4-amino-phenyl)-7-methyl-5-oxo-5 H-I , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carbox- amide.
Example 10 2-(4-amino-phenyl)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide (1.5 g), prepared according to Example 9, dissolved in dimethylformamide (20 ml), was reacted with acetic anhydride (4 ml) in the presence of pyridine (2 ml) at room temperature for 20 hours. The reaction mixture was diluted with ice water and the precipitate was filtered and washed with water: crystallization from dimethylformamide-methanol gave 1.2 g of 2-(4-Nacetyl-amino-phenyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide.
By proceeding analogously the following compounds were prepared: 2-(3-N-acetyl-amino-phenyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6.N-(2-pyridyl)-carbox- amide; 2-(2-N-acetyl-amino-phenyl)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carbox- amide; 2-(4-N-formyl-amino-phenyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carbox- amide; and 2-(4-N-acetyl-amino-phenyl)-7-methyl-5-oxo-5 H-i, 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyri- dyl)-carboxamide.
Example 11 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide (2 g) suspended in hot dioxane (500 ml) under stirring was treated with a slight excess of gaseous HCI dissolved in dioxane for 1 hour: after cooling the precipitate was filtered and washed with dioxane to give 2.1 g of 5-oxo-SH-i ,3,4-thiadiazolo3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, hydrochloride, m.p. > 300 C dec.
By proceeding analogously the following compounds were prepared: 2-methyl-5-oxo-5 H- , 3, 4-thiad iazolo(3, 2-a]pyri midine-6-N-(2-pyridyl)-carboxamide, hydrochloride; 2-(3-pyridyl)-5-oxo-5 H- , 1,3,4-th iadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, hydrochloride; 2-morpholino-5-oxo-5 H- , 3,4-thiad iazolo[3, 2-a]pyri midine-6-N-(2-pyridyl)-carboxamide, hydrochloride; 2-morpholino-S-oxo-5 H-i , 3,4-thiadiazolo(3, 2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide, hydrochloride; and 2-(4-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide, hydrochloride.
Example 12 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-carboxylic acid, ethyl ester (2.25 g), prepared according to Example 1, was reacted with 4-chloro-aniline (1.95 g) in xylene (250 ml) at the reflux temperature for 18 hours carrying out a slow distillation of the solvent. After cooling the precipitate was filtered and washed with isopropyl ether: crystallization from ethanol gave 1.55 g of 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4-chloro-phenyl)-carboxamide.
By proceeding analogously the following compounds were prepared: 5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4-methoxy-phenyl)-carboxamide; 5-oxo-5H-1,3,4thiadiazolo[3,2-a]pyrimidine-6-N-(4-fluoro-phenyl)-carboxamide; 2-(3-pyridyl)-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4-chloro-phenyl)-carboxamide; 2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo(3,2-a]pyrimidine-6-N-(4-methoxy-phenyl)-carboxamide; 2-morpholino-5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4-chloro-phenyl)-carboxamide; and 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(4-methoxy-phenyl)-carboxamide.
Example 13 Tablets, each weighing 150 mg and containing 50 mg of the active substance were manufactured as following: Compositions (for 10000 tablets) 2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine- 6-N-(2-pyridyl)-carboxamide 500 g Lactose 710 g Corn starch 237.5 g Talc powder 37.5 g Magnesium stearate 15 g 2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide, lactose and a half of the corn starch were mixed; the mixture was then forced through a sieve of 0.5 mm openings. Corn starch (18 g) was suspended in warm water (180 ml). The resulting paste was used to granulate the powder. The granules were dried, comminuted on a sieve of sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate was added, carefully mixed and processed into tablets using punches of 8 mm diameter.
By proceeding analogously tablets were prepared having the same composition, but containing as active substance one of the following compounds: 5-oxo-5H-1,3,4-thiadiazolo[3,2- a]pyrimidine-6-N-(2-pyridyl)-carboxamide, 2-morpholino-5-oxo-5 H- , 3,4-thiadiazolo[3,2-a]pyrimi- dine-6-N-(2-pyridyl)-carboxamide and 7-methyl-2-morpholino-5-oxo-5 H- , 3,4-thiadiazolo(3, 2-ajp- yrimidine-6-N-(2-pyridyl)-carboxamide.
Example 14 Tablets, each weighing 150 mg and containing 50 mg of the active substance were manufactured as following: Composition (for 10000 tablets) 2-(2-methyl-morpholino)-5-oxo-5 H-I ,3,4-thiadiazolo(3, 2-a] pyrimidine-6-N-(2-pyridyl)-carboxamide 500 g Lactose 710 g Corn starch 237.5 g Talc powder 37.5 g Magnesium stearate 15 g 2-(2-methyl-morpholino).5-oxo-5 H-i , 3, 4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-pyridyl)-carbox- amide, lactose and a half of the corn starch were mixed; the mixture was then forced through a sieve of 0.5 mm openings. Corn starch (18 g) was suspended in warm water (180 ml). The resulting paste was used to granulate the powder. The granules were dried, comminuted on a sieve of sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate was added, carefully mixed and processed into tablets using punches of 8 mm diameter.
By proceeding analogously, tablets were prepared having the same composition, but containing as active substance one of the following compounds: 2-(thiomorpholino- ,1 -dioxide)-5-oxo-5 H-i , 3,4-thiadiazolo(3,2-a]pyrimidine-6-N-(2-pyridyl).car boxamide and 7-methyl-2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)- carboxamide.

Claims (10)

1. A compound of general formula (I)
wherein R, represents: (a) a hydrogen or halogen atom or a C1 -C6 alkyl group unsubstituted or substituted by C,-C6 alkoxy;
group, wherein n is zero, 1, 2 or 3 and each of R4 and 116 is, independently, hydrogen or C,-C6 alkyl, or R4 and R5, taken together with the nitrogen atom to which they are linked, form an unsubstituted N-pyrrolidinyl ring or a piperidino, morpholino, N-piperazinyl or
ring, wherein m is zero, 1 or 2, the piperidino and morpholino rings are unsubstituted or substituted by one or two C,-C6 alkyl groups and the N-piperazinyl ring is unsubstituted or substituted by a substituent chosen from C,-C6 alkyl, phenyl and pyridyl; (c) trihalomethyl or a R6-S(O)p-group, wherein p is zero, 1 or 2 and R6 is C,-C6 alkyl or benzyl, wherein the phenyl ring is unsubstituted or substituted by a substituent chosen from halogen, C,-C6 alkyl and C,-C6 alkoxy; or (d) an unsubstituted pyridyl, pyridyl-N-oxide or thienyl ring or a phenyl ring unsubstituted or substituted by one, two or three substituents independently chosen from halogen, C,-C6 alkyl, C,-C6 alkoxy, hydroxy, formyloxy, C2-C8 alkanoyloxy, nitro, amino, formylamino, C2-C8 alkanoylamino and di-(C,-C6) alkyl-amino; R2 represents a hydrogen atom or a C,-C6 alkyl group; R3 represents:: (a') a phenyl ring, unsubstituted or substituted by one or two substituents independently chosen from C,-C6 alkyl, C,-C6 alkoxy and halogen; (b') an unsaturated heteromonocyclic or heterobicyclic ring, containing one or more heteroatoms chosen from nitrogen and sulphur, unsubstituted or substituted by one or two substituents independently chosen from halogen, C,-C6 alkyl and C,-C6 alkoxy; and the pharmaceutically acceptable salts thereof.
2. A compound of formula (I), according to claim 1, wherein R, is (a") hydrogen, C,-C3 alkyl, C,-C3 alkylthio, benzylthio, methoxymethyl, ethoxymethyl or di (C,-C4 alkyl)-amino; or (b") an unsubstituted N-pyrrolidinyl ring; a morpholino or piperidino ring, both unsubstituted or substituted by C1-C2 alkyl; or a N-piperazinyl ring substituted by a substituent chosen from C,-C3 alkyl, phenyl and pyridyl; or (c") an unsubstituted pyridyl or pyridyl-N-oxide ring; or a phenyl ring unsubstituted or substituted by one or two substituents chosen from chlorine, fluorine and methyl; or (d") a
ring, wherein m is zero, 1 or 2; R2 is hydrogen or C,-C2 alkyl; R3 is an unsubstituted benzothiazolyl ring; 1-(C,-C4 alkyl)-pyrazolyl; or a thiazolyl or pyridyl ring, both unsubstituted or substituted by one or two substituents chosen from methyl and chlorine; and the pharmaceutically acceptable salts thereof.
3. A compound of formula (I), according to claim 1, wherein R, is '(a"') hydrogen or methyl; or (b"') an unsubstituted N-pyrrolidinyl ring; a piperidino or a morpholino ring, both unsubstituted or substituted by C,-C2 alkyl; or a N-piperazinyl ring substituted by a substituent chosen from C,-C3 alkyl, phenyl and pyridyl; or (c"') an unsubstituted pyridyl or pyridyl-N-oxide ring; or (d"') a
ring, wherein m is zero, 1 or 2; R2 is hydrogen or methyl; R3 is an unsubstituted benzothiazolyl ring; 1-(C,-C2-alkyl)-pyrazolyl; or a thiazolyl or pyridyl ring, both unsubstituted or substituted by one or two methyl groups; and the pharmaceutically acceptable salts thereof.
4. A compound selected from the group consisting of: 5-oxo-5 H- 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 5-oxo-5H- 1 , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-(4-pyridyl)-5-oxo-5 H- , 3 ,4-th iad iazolo[3,2-a]pyri midine-6-N-(2-benzothiazolyl)-carboxamide; 2-morpholino-5-oxo-5 H-I , 3,4-thiadiazolo[3, 2-a]pyrimidine-6-N-(2-benzothiazolyl)-carboxamide; 2-morphol ino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 5-oxo-5H 1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-benzothiazolyl)-carboxamide; 2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(4-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(4-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-(2-methyl-morpholino)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxam- ide; 2-(4-methyl-piperazin-1-yl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxam- ide; 2-(4-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine6-N-(4-methyl-2-thiazolyl)-carboxamide; 2-(2-methyl-morpholino)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxam- ide; 2-thiomorpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 7-methyl-2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 7-methyl-2-morpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxam- ide; 7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-(3-pyridyl-N-oxide)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 2-(4-pyridyl-N-oxide)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-thiomorpholino-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 7-methyl-2-(3-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-carboxamide; 7-methyl-2-(4-pyridyl)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-carboxamide; 2-(thiomorpholino-1,1-dioxide)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-pyridyl)-car- boxamide; 2-(thiomorpholino-1,1-dioxide)-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-6-N-(2-thiazolyl)-car- boxamide; and the pharmaceutically acceptable salts thereof.
5. A process for the preparation of a compound of formula (I) and the pharmaceutically acceptable salts thereof, as claimed in claim 1, said process comprising reacting a compound of formula (II)
wherein R, and R2 are as defined in claim 1 and R7 is carboxy or a reactive derivative of a carboxy group, with a compound of formula (III) H2N-R3 (Ill) wherein R3 is as defined in claim 1; 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 salt thereof 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 compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof specifically mentioned hereinbefore other than a compound of formula (I) or pharmaceutically acceptable salt thereof claimed in claim 4.
8. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof for use as an anti-inflammatory or analgesic agent.
9. A process for the preparation of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, said process being substantially as hereinbefore described in any one of Examples 1 to 1 2.
10. A pharmaceutical composition substantially as hereinbefore described in Example 1 3 or 14.
GB08333535A 1982-12-23 1983-12-16 Carboxamido-derivatives of 5h-1,3,4-thiadiazolo]3, 2-a-pyrimidines and process for their preparationn Expired GB2132200B (en)

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GB08333535A GB2132200B (en) 1982-12-23 1983-12-16 Carboxamido-derivatives of 5h-1,3,4-thiadiazolo]3, 2-a-pyrimidines and process for their preparationn

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GB838329746A GB8329746D0 (en) 1983-11-08 1983-11-08 Carboxamido-derivatives
GB08333535A GB2132200B (en) 1982-12-23 1983-12-16 Carboxamido-derivatives of 5h-1,3,4-thiadiazolo]3, 2-a-pyrimidines and process for their preparationn

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4548938A (en) * 1981-07-15 1985-10-22 Janssen Pharmaceutica N.V. 5-H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4548938A (en) * 1981-07-15 1985-10-22 Janssen Pharmaceutica N.V. 5-H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one compounds

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