BE898512A - 5H-1,3,4-thiadiazolo (3,2-a) pyrimidine carboxamido type derivatives, process for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Compound which is derived from the carboxamido type of 5H-1,3,4-thiadiazolo 3,2-a pyrimidine, characterized in that it corresponds to the general formula (I), in which R1 = H, Hal, alkyl, - (CH) nN R4-R5 triahalomethyl, R6-S (O) P-, pyridyl, etc. R2 = H alkyl, R3 = phenyl for example, heteromonocyclic or bicyclic.

Description

       

    <Desc / Clms Page number 1>
 
 EMI1.1
 having for object: Derivatives of the carboxamido type of 5H-1, 3, thiadiazolo S ,, 2-a thiadiazolo preparation process and pharmaceutical compositions containing them Qualification proposed: PATENT OF INVENTION Priority of two patent applications filed in Great Britain on December 23, 1982 under No. 8236642 and November 8, 1983 under No. 8329746 Inventors: Gianfederico DORIA
Carlo PASSAROTTI
Ada BUTTINONI

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 EMI2.1
 The invention relates to new carboxamido type derivatives of a process for their preparation and to pharmaceutical compositions containing them and having an anti-inflammatory analgesic effect.



   The invention provides compounds having the following general formula (1)
 EMI2.2
 in which R represents: a) a hydrogen or halogen atom or a C1 to C6 alkyl group,
 EMI2.3
 unsubstituted or substituted by alkoxy in &; b) a group- (CH) -Nr in which n is equal to os 2 or 3 and cha 2 n - R5. 1 1 p cun of the symbols R4 and R, a hydrogen atom or a C 1 -C 6 alkyl group, or else R4 and R5, taken with the nitrogen atom to which they are linked, form a nucleus
 EMI2.4
 Unsubstituted N-pyrrolidinyl or a piperidino, morpholino, r- \ N-piperazinyl ring formula in which m is 0, 1 \ - im to or 2, the piperidino and morpholino rings being unsubstituted or substituted by 1 or 2 alkyl groups in C.

   & C and the ring i 6 N-piperazinyl being unsubstituted or substituted by a substituent chosen from a C 1 -C alkyl and pyridyl group; c) a trihalomethyl group or R-S p is 1 or 2 and p.



  R. a C-C alkyl group or the phenyl ring not being. substituted or being substituted by a substituent selected from halogen, a C 1 -C alkyl group, and C 1 alkoxy; 1 6 d) an unsubstituted pyridyl ring, pyridyl N-oxide or thienyl or a phenyl ring which is unsubstituted or substituted by one, two or three substituents chosen, independently, from halogen, a
 EMI2.5
 C. & C. alkyl group
C ,, C2 to Ca'nitro alkoxyalkanoyloxy, amino, formylamino, C2 to Ca alkanoylamino and dialkyl (C1 to C6) -amino;

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 EMI3.1
 represents an ao. or a C1 alkyl group;

   R3: a ') a phenyl ring, unsubstituted or substituted by one or two substituents chosen, independently, from a C 1 to C 6 alkyl group. at C, at C6 and a halogen atom; i o i b b ') an unsaturated heteromonocyclic or heterobicyclic ring containing one or more heteroatoms chosen from nitrogen and sulfur, unsubstituted or substituted by one or two substituents-
 EMI3.2
 independently selected from halogen, C 1-6 alkyl and C 1-6 alkoxy and their pharmaceutically acceptable salts.



   The present invention also encompasses the metabolic metabolites and precursors of the compounds of formula (I) and all possible isomers of the compounds of formula (1), for example optical isomers, and mixtures thereof.



   The alkyl, alkoxy, alkylthio, alkylsulfinylated, alkylsulfonyl, alkanoyloxy and alkanoylamino groups can be linear or branched groups.



   A halogen atom is, for example, chlorine, bromine or fluorine, and preferably it is chlorine or fluorine.



   A trihalomethyl group is preferably a trifluoromethyl group.



   A C1-C6 alkyl group is preferably a C1-C4 alkyl group, in particular methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.
 EMI3.3
 



  A C 6 alkoxy group preferably has a 6 C 6 alkoxy group, in particular methoxy, methoxy, propoxy and isopropoxy.



   A C 1-6 alkylthio group is, for example, a methylthio, ethylthio, propylthio, butylthio group; preferably, it is a methylthio, ethylthio and propylthio group.



   A C1-C6 alkylsulfinyl group is, for example, a methylsulfinyl, ethylsulfinyl and propylsulfinyl group.



   A C1-C6 alkylsulfonyl group is, for example, a methylsulfonyl, ethylsulfonyl and propylsulfonyl group.



   A C2 to Ca alkanoyloxy group is, for example, a

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 EMI4.1
 Lro, pe-ic.-eto> -t acLoxy group, prrpicny]; preferably, it is the acctoyy group.



  An alkanoylamino group, for example, an acetylamino, propionylamino, butyrylamino group; preferably, it is an acetylamino group.
 EMI4.2
 When R represents a C 1 alkyl group, not 1 1 D
C, substituted, is, for example, a methyl, ethyl, propyl, isopropyl, butyl or tert-butyl group, preferably it is a methyl, ethyl or isopropyl group.
 EMI4.3
 



  When R is a C alkyl group



  1 16 ′ as defined above in a), it is preferably a C 1 to C 4 alkyl group substituted by a C 1 alkoxy group even better by a methoxy or ethoxy group. When R, is a group
 EMI4.4
 / R4 -. and R-, '2n "Rc
 EMI4.5
 ticks or different, are each a C 1 to C 6 alkyl group, preferably R 4 and R 5 are each a C 1 to C 4 alkyl group and better still an ethyl, propyl and isopropyl group.



   When R4 and R5, taken with the nitrogen atom to which they are linked, form a piperidino or morpholino nucleus, this nucleus, when substituted, is preferably substituted by one or two C 4 -C 4 alkyl groups, whatever may be the same or different; even better, it is substituted by a substituent chosen from a methyl, ethyl, propyl and isopropyl group.



   When R4 and R5, taken with the nitrogen atom to which they are linked, form an N-piperazinyl ring, this ring is, when substituted, preferably substituted by a substituent chosen from a phenyl, pyridyl and alkyl group in C. a C., for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.



   When R2 represents a C1 to C6 alkyl group, it is, for example, a methyl, ethyl, propyl, isopropyl, butyl or tert-butyl group, preferably it is a methyl, ethyl or isopropyl group.



   When R. and / or R3 is a phenyl nucleus as defined above in d) and a ') respectively, this nucleus is preferably substituted by one or two substituents chosen from chlorine, fluorine, a methyl and methoxy group.

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   When R6 is a shell substituted benzyl group defined above, it is preferably substituted by a substituent chosen from chlorine, a methyl and methoxy group.



     When R is an unsaturated heteromonocyclic or heterobicyclic ring as defined above in b), it is, for example, a ring chosen from a pyridyl, thiazolyl, pyrazolyl, pyrimidinyl and benzothiazolyl ring; preferably, it is a thiazolyl or pyridyl ring, these thiazolyl and pyridyl rings being unsubstituted or being substituted by one or two substituents chosen from a methyl group, a chlorine or bromine atom and a methoxy group, or else it is a pyrazolyl ring substituted by a C1-C4 alkyl group "
Preferred compounds of the invention are the compounds of formula (1), in which R. represents a ") a hydrogen atom, a C 1 -C 6 alkyl group,

   C. b C alkylthio, benzylthio, methoxymethyl, ethoxymethyl or di (C1-c4 alkyl) amino; or b ") an unsubstituted N-pyrrolidinyl ring; a morpholino or piperidino ring, unsubstituted or substituted by a C 1 -C 2 alkyl group; or an N-piperazinyl ring substituted with a substi-
 EMI5.1
 killing chosen from an alkyl and pyridyl group; or c ") an unsubstituted pyridyl or pyridyl-N-oxide ring or a ring
 EMI5.2
 phenyl unsubstituted or substituted by one or two substituents chosen from chlorine, fluorine and a methyl group; or
 EMI5.3
 d ") a nucleus which m is 0, 1 or 2;
 EMI5.4
 R2 a hydrogen atom or a C 1 or C 6 alkyl group;

   -N 5 (0) J in 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 a methyl group and a chlorine atom and their pharmaceutically acceptable salts.



   More preferred compounds of the invention are the compounds of formula (I), [wherein R. represents

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 6 '' ') an ato. e of hydrogen or a methyl group; or b "') an unsubstituted N-pyrrolidinyl nucleus; a piperidino or morpholino nucleus, both unsubstituted or substituted by a C1-C2 alkyl group; or an N-piperazinyl nucleus substituted by a substituent chosen from a C1-alkyl group C. phenyle and pyridyle; or
 EMI6.1
 c "') an unsubstituted pyridyl or pyridyl-N-oxide ring; or
 EMI6.2
 d "') d"') formula in which m is 0, 1 or 2
 EMI6.3
 a hydrogen atom or a methyl group; an N-ring S (O) R3 is an unsubstituted benzothiazolyl ring;

   1- (C1-C2 alkyl) pyrazolyl; or a thiazolyl or pyridyl ring, both unsubstituted or substituted by one or two methyl groups] and their pharmaceutically acceptable salts.



   Examples of pharmaceutically acceptable salts are those formed with mineral acids, for example nitric, hydrochloric, hydrobromic and sulfuric acids, and with organic acids, for example citric, tartaric, maleic, malic, fumaric, methanesulfonic and ethanesulfonic acids.



   Examples of particularly preferred compounds of the invention are:
 EMI6.4
 5-oxo-5H-1, carboxamide; 5-oxo-5H-1,3,4-thiadiazol 2-a] pyrimidine-6-N-carboxamide; 2- 3, 4-thiadiazolo (2-benzothiazolyl) -carboxamide 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo3,
3,4-thiadiazolo [3, 2-a] pyrimidine-6-N- (2-pyridyl) - (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-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;

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 EMI7.1
 2- 3, 4-thiadiazoloL3, (2-pyridyl) -carboxamide;

   2-, 3,4 "(2-pyridyl) -carboxamide; 2- 3,4-thiadiazolo [3, (2-thiazolyl) -carboxamide; 2- 3, pyrimidine-6-N-; 2-pyrimidine -6-N-; 2- (4-methyl-2-thiazolyl) 2- 3, midine-6-N- 2-thiomorpholino-5-oxo-5H-1, 3, 4-thiadiazolo (2- pyridyl) -carboxamide; 7-methyl-2-morpholino-5-oxo-5H-13, 2-a] 6-N-; 7-methyl-2-morpholino-5-oxo-5H-13, 3, 6-N- 7-methyl-5-oxo-5H-1, pyridyl) -carboxamide; 7-methyl-5-oxo-5H-1, thiazolyl) -carboxsmide; 2- 6-N-; 2 - 3, 6-N-; 2-thiomorpholino-5-oxo-5H-1, 3, 4-thiadiazolo3, (2-thiazolyl) -carboxamide; 7-methyl-2- 6-N- 7-methyl -2- 3, 6-N- le 2- 3, 4-thiadiazolo3, pyrimidine-6-N-

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 EMI8.1
 pyrinjdine-6-N-; and their pharmaceutically acceptable salts.



   The compounds of the present invention can be prepared by a process comprising reacting a compound of formula (II)
 EMI8.2
 [in which
R1 and R2 are as defined above and R7 is a carboxyl group or a reactive derivative of a carboxyl group with a compound of formula (III) H2N-R3 (III) [wherein R3 is as defined above]; and, if desired, the transformation of a compound of formula (1) into another compound of formula (1) and / or, if desired, the transformation of a compound of formula (1) into a salt pharmaceutically acceptable of this compound and / or, if desired, obtaining a free compound of formula (I) from its salt and / or, if desired, the separation of a mixture of isomers into simple isomers.



   When R7 is a reactive derivative of a carboxyl group, it is preferably a carboxylic ester, for example a group
 EMI8.3
 of formula-COR'-, for example, a tri (C 1 -C) alkyl alkoxy group It is possible to kill, for example, the reaction between a compound of formula (II), in which R7 is a group -COR'7 [where R'7 is a C 1 -C 12 alkoxy or tri (C 1 -C alkyl) - silyloxy group] and a compound of formula (III) by heating with l polyphosphoric or methanesulfonic or p-toluenesulfonic acid at a temperature varying between approximately 500C and approximately 2000C, 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. fage from 50 C to about 150 "C without any acid agent and in the presence

  <Desc / Clms Page number 9>

 an organic solvent only, such as toluene or xylene, if necessary.



   As indicated above, a compound of formula (1) can be transformed into another compound of formula (I) by known methods; for example, free hydroxyl groups can be etherified by reaction with a suitable alkyl halide in the presence of a
 EMI9.1
 base such as NaH, sCQK H-, sodium or sodium ethylate in a solvent chosen from the group consisting, for example, of methanol, ethanol, dioxane, acetone, dimethylformamide, phosphoric hexamethyltriamide, tetrahydrofuran, water and their mixtures at a temperature preferably between approximately 0 ° C. and approximately 150 ° C.



   In addition, for example, a nitro group present as a substituent in the phenyl group R can be converted into an amino group by treatment, for example, with stannous chloride in concentrated hydrochloric acid using, if necessary, an organic cosolvent like acetic acid, dioxane, tetrahydrofuran at a temperature varying between room temperature and around 100oC.



   For example, an amino or hydroxyl group can be transformed into a formylamino, formyloxy, alkanoylamino (C2 to C) or alkanoyloxy (C2 to C8) group, for example, respectively, by reaction with formic acid or with anhydride of corresponding alkanoyl, 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 OOC and approximately 100 ° C.



   As another example, a thiomorpholino group can be transformed into a thiomorpholino l-oxide group or into a thiomorpholine l, l-dioxide group by reaction with suitable oxidizing agents, for example with a stoichiometric amount of peracetic acid, obtaining thus derivatives of l-oxide type or with m-ch10roperbenzoic acid in CH2C12 thereby obtaining derivatives of type l, l-dioxide, and carrying out the reaction in both cases at a temperature varying between about 0 "C and about 30 C.



   The optional salification of a compound of formula (1) can also be carried out by conventional methods, as well

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 as the transformation of a salt into a free compound and the separation of a mixture of isomers into simple isomers.



   For example, it is possible to effect the separation of a mixture of optical isomers into the individual isomers by salification using an optically active acid and subsequent fractional crystallization.



   The compounds of formula (II) can be obtained according to known methods; for example, the compounds of
 EMI10.1
 formula (II), in which Ru a group-COR * where R * 7 7 7 a C 1-6 alkoxy group or tri (C 1 & alkyl) -silyloxy by cyclization of a compound of formula (IV)
 EMI10.2
 is [in which R-andR are as defined above and R8 and Rg, which may be the same or different, each represents an alkoxy group in
 EMI10.3
 C. sorting (C 1 -C 12 alkyl 1 b to C,. Or analogous methods of preparation can be used to obtain the other esters of formula (II).



   It is for example possible to cyclize a compound of formula (IV) by treatment with an acidic condensing agent such as polyphosphoric acid, alone or in the presence of phosphorus oxychloride, or by treatment with sulfuric or hydrochloric acid or acetic, methanesulfonic acid or p-toluenesulfonic acid, at a temperature preferably between about 50 ° C. and 150 ° C .; the reaction can be carried out in an organic solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, formic acid, diglyme, toluene, xylene, ethylene glycol monomethyl ether or dichloroethane, but the operation is carried out preferably in the absence of a solvent.



   Alternatively, the compound of formula (IV) can be cyclized by heating the compound to a temperature

  <Desc / Clms Page number 11>

 between approximately 150 C and approximately 350 C, preferably between 200 C and 300oC, in an inert organic solvent with a high boiling point such as diphenyl oxide or diglyme, or in the absence of a solvent .



   The compounds of formula (IV) can be prepared, for example, by reacting a compound of formula (V):
 EMI11.1
 [in which R. is as defined above with a compound of formula (VI)
 EMI11.2
 [in which R2, R8 and Rg are as defined above; and rice is a reactive group chosen, preferably, from a hydroxyl, amino group,
 EMI11.3
 C1 to C alkoxy, tri (C. alkyl

   to C6) i \ One can carry out, for example, the reaction between a compound of formula (V) and a compound of formula (VI) by heating in solvents such as dioxane, toluene, xylene, a C alkyl alcohol with dimethylformamide, dimethylacetamide, diglyme, diphenyl oxide, or else in the absence of a solvent, at a temperature varying between approximately 50 ° C. and approximately 200 ° C.
 EMI11.4
 



  Preferably, when is a hydroxyl group, the reaction is carried out between a compound of formula (V) and a compound of formula (VI) in the presence of an acid-condensing agent such as polyphosphoric acid, methanesulfonic acid. , p-toluenesulfonic acid or acetic acid, using the same experimental conditions as those described above for the cyclization of the compounds of formula (IV).



   The reaction of a compound of formula (V) with a compound of formula (VI) can be carried out until a compound is obtained

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 of formula (II) without it being necessary to isolate the intermediate product of formula (IV) formed during the reaction. The compounds corresponding to formulas (III), (V) and (VI) are known compounds or they can be prepared by conventional methods; in some cases, these are commercially available products.



   When the reactions described above relate to compounds in which free amino or hydroxyl groups are present, it is possible to protect, if necessary, amino and hydroxyl groups by operating in a conventional manner before carrying out the reaction. Protective groups of the amino group can be, for example, the protective groups commonly used in peptide chemistry. Examples of amino protecting groups are a formyl group, an alipha- acyl group
 EMI12.1
 tick optionally substituted with preferably a chloracetyl, dichloracetyl or trifluoroacetyl group, a tert-butoxycarbonyl, p-nitrobenzyloxycarbonyl or trityl group.

   The hydroxyl groups can be protected, for example, by a formyl, acetyl, chloroacetyl, dichloroacetyl, trifluoroacetyl, tetrahydropyrannyl, trityl or silyl group, preferably a trimethylsilyl or dimethyl-tert-butyl-silyl group.



   Then the protective groups of the amino and hydroxyl groups are removed at the end of the reaction, usually in a known manner. For example, when the amino group protecting group is the monochloroacetyl group, this can be removed by treatment with thiourea; the formyl and trifluoroacetyl groups can be removed by treatment with hydrochloric acid in aqueous methanol, and the trityl group by treatment with formic or trifluoroacetic acid.



   The hydroxyl protecting groups can be removed, for example, under gentle reaction conditions, for example by carrying out acid hydrolysis.



   The compounds of the present invention have anti-inflammation activity, as shown, for example, by the fact that they are active, after oral administration, to inhibit: A) the formation of edema in the hind paw rats in response to a subplantar injection of carrageenan, using the method of

  <Desc / Clms Page number 13>

 
C. A. Winter et al. (J. Pharmac. Exp. Therap. 1963, 141, 369) and
P. Lence (Arch. Int.

   Fharmacodyn., 1962, 136. 237), and B) the passive phenomenon of inverted Arthus in the rat's paw, phenomenon caused by the interaction of an antigen and an antibody causing the formation of an antigen complex - antibody which precipitates, which is followed by the fixation of the complement and the accumulation of polymorphonuclear leukocytes at a focal point (DK Gemmell. J. Cottney and AJ Lewis,
Agents and Actions 9/1, page 107, 1979).



   Tables I and II which follow show, for example, the approximate ED50 (effective dose) values of the anti-inflammation activity in the abovementioned tests, on the rat after oral administration of a compound of the present invention: 2- (3 -pyridyl) - 5-oxo-SH-1, 3, 4-thiadiazolo [3, 2-a] pyrimidine-6-N- (2-pyridyl) -carboxamide [which will be designated here by its internal code name FCE 22914]:

  
TABLE 1
 EMI13.1
 
 <tb>
 <tb> Compound <SEP> Activity <SEP> anti-inflammation <SEP> on <SEP> a
 <tb> edema <SEP> caused <SEP> by <SEP> the <SEP> carrageenan
 <tb> FCE <SEP> 22914 <SEP> DE50 <SEP> = <SEP> 45.86 <SEP> mg / kg
 <tb>
 TABLE II
 EMI13.2
 
 <tb>
 <tb> Compound <SEP> Activity <SEP> anti-inflammation
 <tb> Phenomenon <SEP> by Arthus
 <tb> FCE <SEP> 22914 <SEP> DE50 <SEP> = <SEP> 85.2 <SEP> mg / kg
 <tb>
 
The compounds of the present invention are also endowed with analgesic activity.



   The analgesic activity is established, for example, using the phenylquinone test on mice, according to Siegmund:

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   [Sieanund et al. Proc. Soc. E:: pcr. Biol. Uh. 9S 729 (1957)].



  In this test, the compound FCE 22914, for example, gives a 30% inhibition at a dose of 50 mg / kg after oral administration.



   It is known that certain thiadiazolopyrimidine derivatives are endowed with an antiallergic and anti asthma activity, for example the compounds described in the Japanese patent application published under No. J57 142989, but such compounds do not contain anti-inflammatory activity and / or analgesic activity.



  On the contrary, the new thiadiazolo-pyrimidine derivatives of the present invention which, as indicated above, have an anti-inflammation and analgesic activity useful in therapy, are, surprisingly, devoid of any anti-allergy and anti-asthma activity.



   Due to their high therapeutic index, the compounds of the invention can be used safely in medicine. For example, the approximate acute toxicity (LD50) of 2- (3-pyridyl) -5-oxo-5H-1,3,4-thiadiazolo3,2-a] pyrimidine-6-N- (2-pyridyl) - carboxamide and 5-oxo-5H-1,3,4-thiadiazol {3,2-a] - pyrimidine-6-N- (2-pyridyl) -carboxamide in mice, effect, determined by a single administration of increasing doses and effect measured on the seventh day after treatment, is greater than 800 mg / kg orally. Similar toxicity data have been found for other compounds of the invention.



   The compounds of the invention can be administered in various dosage forms, for example orally in the form of tablets, capsules, tablets coated with sugar or a film, liquid solutions or suspensions, rectally, in the form suppositories, parenterally, for example intramuscularly or by intravenous injection or infusion.



   The dosage depends on the age, weight, condition of the patient and the method of administration; for example, a dosage suitable for oral administration to adult humans for the treatment of pain and inflammatory processes is between about 10 and about 200 mg per dose, one to five times a day.



   The invention therefore also encompasses pharmaceutical compositions comprising a compound of the invention in association with

  <Desc / Clms Page number 15>

 a pharmaceutically acceptable excipient (which may be a vehicle or diluent).



   Pharmaceutical compositions containing the compounds of the invention are usually prepared by conventional methods and administered in a pharmaceutically suitable form.



   For example, the solid oral forms may contain, with the active compound, diluents such as lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycols; binding agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents, for example a starch, alginic acid, alginates or sodium starch or starch glycolate; effervescent mixtures, colors, sweeteners;

   wetting agents such as lecithin, polysobates, laurylsulfates; and, in general, pharmacologically inactive and non-toxic substances which are used in pharmaceutical formulations. These pharmaceutical preparations can be made in known manner, for example by a mixing operation, granulation, the formation of tablets or tablets, sugar coating or film coating methods.



   The liquid dispersion for oral administration can be, for example, in the form of syrups, emulsions and suspensions.



  The syrups can contain, as a vehicle, for example, sucrose or sucrose with glycerol and / or mannitol and / or sorbitol; in particular, a syrup to be administered to diabetic patients may contain, as carriers or vehicles, only products which cannot give by metabolization of glucose, or which give only a very small amount of glucose by metabolization, for example sorbitol. The suspensions and emulsions may contain as support, for example, a natural gum, agar or agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or alcohol

  <Desc / Clms Page number 16>

 polyvinyl.

   The suspensions or solutions for intramuscular injections may contain with the active compound a pharmaceutically acceptable vehicle, for example sterile water, olive oil, ethyl oleate, glycols such as propylene glycol and, if if desired, a suitable amount of lidocaine hydrochloride.



   The solutions intended for intravenous injections or infusions may contain as vehicles, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions.



   Suppositories may contain a pharmaceutically acceptable carrier with the active compound, for example coconut butter, polyethylene glycol, an ester type surfactant
 EMI16.1
 fatty acid and polyoxyethylenesorbitan or lecithin.



  The following examples are presented A tif but not limiting of the invention.



  EXAMPLE 1
5 g of 2-amino-1,3,4-thiadiazole are reacted with 26.5 g of diethyl ethoxymethylenemalonate in 20 ml of ethanol at reflux temperature for 23 h. After cooling, the precipitate is filtered and purified with hexane, which gives 10 g of diethyl N- (1,3,4-thiadiazol-2-yl) -aminomethylenemalonate,
 EMI16.2
 F. 107 at 111oC, which is treated with 57.6 g of polyphosphoric acid (30.8 g of H3PO4 A and 26.8 g of P205) and 25 g of POOL3 with stirring 3 4 2 5 3
99% at 120 C for 30 min.



   After having cooled the reaction mixture, it is diluted with ice water and then the solution is neutralized with NaOH at 35%: the precipitate is filtered and washed with water, which gives 5.75 g of 5- ethyl oxo-5H-1, 3, 4-thiadiazolo [3,2-a] pyrimidine-6-carboxylate, F. 228-230 C, which is reacted with 4.9 g of 2-aminopyridine, in 57.5 g (31 g of 99% H3PO4 and 26.5 g of P205) of polyphosphoric acid while stirring at 120 C for 12 h. After cooling, dilution with ice water and neutralization with NaOH at 35%, the precipitate is filtered and washed with water.

   Crystallization from chloroform / methanol gives 3.3 g of 5-oxo-5H-1,3,4-thiadiazolo [3, 2-a] - pyrimidine-6-N- (2-pyridyl) -carboxamide; F. 24-245 C with decomposition

  <Desc / Clms Page number 17>

 
 EMI17.1
 sitiùn; rc-sonance rl - Qq) -iylsitifjD gnUque (d 6 from DMSO; resonance csulfo:: yde)) & ppm: 7.15 (m) (1H, C-5 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) (1H, proton at C-7), 9.57 (s) (1H, proton C-2).



   By proceeding in an analogous manner, the following compounds are prepared:
 EMI17.2
 2-methyl-5-oxo-5H-1, pyridyl) -carboxamide, F. 231-233 C; 2-ethyl-5-oxo-SH-1,3,4-thiadiazolo [3,6-N-
3, 4-thiadiazolo [3, 2-a] pyrimidine-6-N- (2-carboxamide, F. 247-248 C; 2-benzylthio-5-oxo-5H-1, 3, 4-thiadiazolo [3 , 2-a] pyrimidine-6-N- (2-
 EMI17.3
 pyridyl) -carboxamide, F. 209-211 C; 2 3, 4-thiadiazolct3, pyridyl) -carboxamide, 2-ethylthio-5-oxo-5H-1, pyridyl) -carboxamide; 2-methylsulfinyl-5-oxo-5H-1,3,4-thiadiazolo 2-a] pyrimidine-6-N- (2-pyridyl) -carboxamide 2-methylsulfonyl-5-oxo-5H-1,4 thiadiazolo {3, (2-pyridyl) -carboxamide; 2-trifluoromethyl-5-oxo-5H-1, (2-pyridyl) -carboxamide Z-methoxymethyl-S-oxo-5H-I, 3,4-thiadiazolo [3, (Z-pyridyl); 2-ethoxymethyl-5-oxo-5H-1, 3, 4-thiadiazolo [3, 2-a] (2-pyridyl) -carboxamide;

   and 2-chloro-5-oxo-5H-1,3,4-thiadiazolo [3,2-a] pyrimidine-6-N- (2-pyridyl) -carboxamide.



  EXAMPLE 2
React 3 g of 2-phenyl-5-oxo-5H-1,3, 4-thiadiazolo [3,2-a] pyrimidine-6-ethyl carboxylate (E. 172-174C) with 1.9 g of 2-amino-pyridine in 50 g (26 g of 99% H3PO4 and 24 g of P205) of polyphosphoric acid while stirring at 110 C for 6 h.



  After cooling, dilution with ice water and neutralization with NaOH at 35%, the precipitate is filtered and washed with water. A crystal-

  <Desc / Clms Page number 18>

 
 EMI18.1
 reading from chloroform / ethanol gives 2.6 g of 2-phnyl-5-oxo-5H-1, mide, F. 273-275C; Ppm NMR: 7 45-8, 10 (m) (7H, C-3 and C-5 pyridyl protons and phenyl protons), 8, 40 (m) (2H, C-4 and C pyridyl protons -6), 9, 10 (s) (1H, C-7 proton).



  By operating in an analogous manner, the following compounds are prepared 2- 4-thiadiazolo [3, 2-a] 6-N- F. 214-217OC; 2- 3, 6-N-; 2- 3, 4-thiadiazolo 6-N-; 2-pyrimidine-6-N- 2, 3, 4-thiadiazolo dine-6-N-; 2- (4-methyl-phenyl) -5-oxo-5H-1, 6-N- F. 301-303 * C; 2- 6-N-; F. 274-278cC; 2- 3, 4-thiadiazolo 6-N-; 2- N-; F. 302-305 "C le 2- 3, N- le 2- 6-N- le 2- (2-pyridyl) F. 270-272 * C. le 2- pyrimidine-6-N- le 2- 3 , 4-thiadiazolo pyrimidine-6-N- 1

  <Desc / Clms Page number 19>

    3, 4-thiadiazolo [3, 2-a] pyrimidine-6-N- (2-pyridyl) -carboy. a-EXAMPLE 3
10 g of 2-amino-5- (3-pyridyl) -1, 3, 4thiadiazole are reacted with 18 g of diethyl ethoxymethylene malonate all. shaking at the lake for 9 h.

   After cooling, the reaction mixture is crystallized from CH2Cl2 / isopropyl oxide, which gives 15.8 g of N- [5- (3-pyridyl) -1, 3,4-thiadiazol-2 -yl] -aminomethylene diethyl malonate (F. 144-145 C) which is
 EMI19.1
 treats with 6.6 g (3.5 g of 99% and 3.1 g of polyphosphoric acid and 27.8 g of POC13 while stirring for 40 min at 120 C.



   After cooling, the reaction mixture is diluted with ice water and then the solution is neutralized with 35% NaOH. The precipitate is filtered and washed with water; crystallization from CH-Cl / isopropyl alcohol gives 6.6 g
 EMI19.2
 of 2- 3, ethyl boxylate (F. 200-2020C), which is reacted with 10.02 g of 2-amino-pyridine in 330 g (176 g of and 154 g of (3-pyridyl) -5-oxo-5H-1,3,4-thiadiazolo P205) of polyphosphoric acid while stirring for 7 h at 120C. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate is filtered and washed with water.
 EMI19.3
 



  Crystallization from CHCl-methanol gives 5.3 g of. 3, 4-thiadiazolo 2- (3-pyridyl) -5-oxo-5H-1, pyridyl) -carboxamide, F. 274-277 C; NMR (CDCl3 + CF3COOD0 # ppm: 7.75 (m) (2H, C-5 pyridyl and C-5 pyridyl amide protons), 8.45 (m) (3H, C- pyridyl protons 4 and C-3 and C-4 pyridyl amide), 9, 20 (m) (2H, C-6 pyridyl and C-6 pyridylamide protons), 9.29 (s) (1H, C-7 proton), 9.67 (bs) (1H, C-2 pyridyl proton).



   By proceeding in an analogous manner, the compounds are prepared
 EMI19.4
 following: 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo [3, pyridyl) -ccarboxamide; F. 274-275'OC; NMR (CDCl ppm: 3, 4-4, 0 (m) (8H, morpholinyl protons), 7.6 (m) (2H, C-4 and C-5 pyridyl protons), 8.3-8 , 6 (m) (2H, C-3 and C-6 pyridyl protons), 8.9 (s) (1H, C-7 proton).

  <Desc / Clms Page number 20>

 
 EMI20.1
 2-3, (2-pyridyl); F. 279-280 C; 2-pyridyl); 2- 3, 4-thiadiazol [3, methyl-2-pyridyl); F. 305-307 C; 2, 4, 4-methyl-2-pyridyl) -carboxamide; 2- methyl-2-pyridyl) 2- 3,4-thiadiazolo (32-a] (4,6-dimethyl-2-pyridyl) 2- 3,4-thiadiazol 2-a] pyrimidine-6-N - (4, 6-dimethyl-2-pyridyl); 2-morpholino-5-oxo-5H-1, pyrimidine-6-N-6dimethyl-2-pyridyl);

   F. 310-313 C; 2-morpholino-5-oxo-5H-1, 3, chloro-2-pyridyl) 2-morpholino-5-oxo-5H-13, pyridyl) -carboxamide 2- 3, 4-thiadiazolo [3, ( 3-pyridyl) -carboxamide 2 3, 4-thiadiazol (3, (5-chloro-2-pyridyl) -carboxamide; F. 306-310 * C; 2-morpholino-5-oxo-5H-13,2 -a] pyrimidine-6-N- (6-methyl-2-pyridyl) 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo methyl-2-pyridyl); 2-N, N-diethylamino-5-oxo-5H-1,3, pyrimidine-6N- 2-N, N-dipropylamino-5-oxo-5H-1,3,6-N-; 2-N, N-diisopropylamino-5-oxo-5H-1, dine-6-N- 2, 3, 4-thiadiazolo 2-a] 6-N-; F. 302-3040C;

  <Desc / Clms Page number 21>

 
 EMI21.1
 2-pipridino-S-oxo-511-1, pyridyl) -carboxanide;

   F. 242-244 C; 2-dine-6-N-; 2- 3, 4-thiadiazolo dine-6-N-; 2-dine-6-N-amide; 2- (2,6-dimethyl-piperidin-5-oxo-5H-13, midine-6-N-; 3,4-thiadiazolo midine-6-N-; 2- 6-N-; 2 - 4- <midin-6-N-; F. 220-221 "C 2- 2-a] midin-6-N-; 2- [4- [3, 2-a]; 2-N, N-dibutylamino-5-oxo-5H- 1, 3, N-; 2-N, 6-N-; 2-2-a] midin-6-N-; 5-oxo-5H-1, 3, 4-thiadiazol [carboxamide; 5 -oxo-5H-1,3,4-thiadiazolo pyridyl) -carboxamide; F. 260-270oC with decomposition; 2-methyl-5-oxo-5H-1,3,4-thiadiazolo3,2-pyridyl) -carboxamide 5-oxo-5H-1,3,4-thiadiazolo [3, pyridyl) -carboxamide;

   F. 258-2680C with decomposition; 5-oxo-5H-1,3,4-thiadiazolo 2-a] pyrimidine-6-N-2-pyridyl) -carboxamide;

  <Desc / Clms Page number 22>

 2-methyl-5-oxo-5H-1,3,4-thiadiazolo [3,2-a] pyrimidine-6-N- (6methyl-2-pyridyl) -carboxamide;
 EMI22.1
 2-methyl-5-oxo-5-1, dimethyl-2-pyridyl); and 2-morpholinomethyl-5-oxo-5h-1, 3, 4-thiadiazolo [3,2-a] pyrimidine-6-N- (2-pyridyl) -carboxamide.



  EXAMPLE 4
6.25 g of 2-amino-5-morpholino-1, 3,4- are reacted
 EMI22.2
 thiadiazole with 9 g of diethyl ethoxymethylene malonate while stirring for 4 h at 120 ° C. After its treatment, the crude diethyl N- is treated with 5 g (2.6 g and 2.4 g of polyphosphoric acid and 20.5 g of POC13 while stirring for 30 min at 120.



   After cooling, the reaction mixture is diluted with ice water and then the solution is neutralized with 35% NaOH. The precipitate is filtered and washed with water. A
 EMI22.3
 crystallization from CHCl / isopropyl oxide gives 8 g of the 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo [3, ethyl carboxylate (F. 217-219 C) which is react with
2-a) pyrimidine-6-5, 2 g of 2-amino-thiazole in 120 g (64 g of H3PO4 at 997. and 56 g of P205) of polyphosphoric acid while stirring for 30 h at 110oC. After cooling, dilution with ice water and neutralization with NaOH at 35%, the precipitate is filtered and washed with water.

   Crystallization from CH Cl.-ethanol gives 5 g of 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo [3,2-a] pyrimidine-6-N- (2-thiazolyl) - carboxamide, F. 274-276 C; NMR (CDCl + CF3COOD) ppm: 3.58 (m) (4H, C-3 and C-5 morpholinyl protons), 3.85 (m) (4H, C-2 and C-6 morpholynyl protons ), 6.69 (d) (1H, C-5 thiazolyl proton), 7.75 (d) (1H, C-4 thiazolyl proton), 8.94 (s) (1H, C- proton 7).



   By proceeding in an analogous manner, the following compounds are prepared:
 EMI22.4
 5-oxo-5H-1,3,4-thiadiazolo [3, thiazolyl) -carboxamide; F. 230-240 C with decomposition; 5-oxo-5H-1,3,4-thiadiazolo [3,5-dimethyl-2thiazolyl) -carboxamide;

  <Desc / Clms Page number 23>

 
 EMI23.1
 I thyl-3pyrazolyl) -carboxamide; 3, 4-thiadiazolo thiazolyl); F. 255-275 C with decomposition; 5-oxo-5H-1, pyrimidine-6-N-carboxamide; F. 230-240 C with decomposition; 5-oxo-5H-1,3, carboxamide; F. 162-1640C; 2-methyl-5-oxo-5H-13, zolyl) -carboxamide; F. 246-249 C; 2- (2-thiazolyl) -carboxamide; 2-pyrimidine-6-N- (2-thiazolyl) -carboxamide, F. 310-3160C; 2- 3, 4-thiadiazol [3, (2-thiazolyl); 2-ethyl-5-oxo-5H-1, lyl) -carboxamide;

   F. 239-241'C; 2-methyl-5-oxo-5H-13, 3, methyl-3-pyrazolyl); 2-methyl-5-oxo-SH-I, 3, dimethyl-2-thiazolyl); 2-methyl-5-oxo-5H-1,3,4-thiadiazolo methyl-2-thiazolyl); 2 pyrimidine-6-N- (2-benzothiazolyl) 2- (4-methyl-2-thiazolyl); the 2- zolo [3.



  (1-methyl-3-pyrazolyl) -carboxamide 2-3 (methyl-2-thiazolyl); F. 276-279'C; 2- 3, 4-thiadiazolo3, (4, S-dimethyl-2-thiazolyl); F. 330-332 C; 2- (5-chloro-2-thiazolyl) -carboxamide;

  <Desc / Clms Page number 24>

 
2-a] ple2- (4-pyridyl) -5-oxo-5H-1,3,4-thiadiazolo [3,2-a] pyrimidine-6N- (2-benzothiazolyl) -carboxamide;
 EMI24.1
 2-rnoupholino-5-oxo-5H-1. 3.



  (4-methyl-2-thiazolyl); F. 259-261 C; 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo [3,2-a] pyrimidine-6-N- (2-benzothiazolyl) -carboxamide; F. 380-385 C with decomposition; 2-morpholino-5-oxo-5H-1, 3, 4-thiadiazolo [2-a] pyrimidine-6-N- (4, 5-dimethyl-2-thiazolyl) -carboxamide; F. 325-328 C;
 EMI24.2
 2-morpholino-5-oxo-5H-1. 3, (5-chloro-2-thiazolyl); F. 279-281 "C; 2-morpholino-5-oxo-5H-1,3,
3,4-thiadiazolo (1-methyl-3-pyrazolyl) -carboxamide; F. 277-279 C; 2- (pyrrolidine-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; F; 249-250 C;
 EMI24.3
 2-pyrimidine-6-N-;

   F. 264-266 C; 2-pyrimidine-6-N-; 2-morpholinomethyl-5-oxo-5H-1, 6-N-; 2-ine-6-N- (1-methyl-3-pyrazolyl); and 2- 3, 4-thiadiazol- [3, EXAMPLE 5 5 g of 2-amino-S-morpholino-l, thiadiazole are reacted with 6.2 g of diethyl (1-ethoxy-ethylidene) -malonate in 40 ml of diglyme at 150 "C for 20 h. After cooling, the reaction mixture is eluted with ice water and extracted with ethyl acetate; after evaporation to dryness under vacuum, the product is purified. residue on a 5x10 column using a 98: 2 chloroform / methanol system as eluent.

   Crystallization from isopropyl ether gives 2.6 g of 7-methyl-2-morpholino-5-oxo-5H-
 EMI24.4
 l, 3, 4-thiadiazolo

  <Desc / Clms Page number 25>

    [3, 2-a] ethyl pyrimidine-6-carboxylate (F. 196-198 C), which is reacted with 2.25 g of 2-amino-pyridine in 130 g of polyphosphoric acid while shaking at 1200C for 4 h. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate is filtered and washed with water, which gives 1.9 g of 7-methyl-2-morpholino-5-oxo- 5H-1, 3, 4-thiadiazolo [3, 2-a] - pyrimidine-6-N- (2-pyridyl) -carboxamide, F. 285-2870C.



   By following an analogous procedure, the following compounds are prepared: 7-methyl-5-oxo-5H-1, 3, 4-thiadiazolo 2-a] pyrimidine-6-N- (2-pyridyl) -carboxamide; 2,57-dimethyl-5-oxo-5H-1,3,4-thiadiazolo [3,2, -a] pyrimidine-6-N- (2-pyridyl) -carboxamide; 2-ethyl-7-methyl-5-oxo-5H-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-benzy1thio-7-methyl-S-oxo-SH-1,3,4-thiadiazolo [3,2-a] pyrimidine-6-N- (2-pyridyl) -carboxamide;
 EMI25.1
 2-methoxymethyl-7-methyl-5-oxo-5H-13, midine-6-N- 2-ethoxymethyl-7-methyl-S-oxo-SH-1,3,4-thiadiazole dine-6-N -;

   7-ethyl-5-oxo-5H-1,3,4-thiadiazolct3, carboxamide; 7-methyl-2-pyrimidine-6-N- F. 253-255 C 7-ethyl-2- 6-N-; 7-methyl-2- 6-N- F. 255-2560Ci. 2-N, N-diethylamino-7-methyl-5-oxo-5H-1, 3, 4-thiadiazolo pyrimidine-6-N-; 2-N, 4-thiadiazolo [32-a] pyrimidine-6-N-; 2-N, 32-a] pyrimidine-6-N-;

  <Desc / Clms Page number 26>

 
 EMI26.1
 7-nthyl-2-3, pyrjmidine-6-n-; 7-methyl-2- [3, 2-a]; 7-methyl-2-morpholino-S-oxo-SH-1.6-N-; 7-methyl-2-piperidino-S-oxo-SH-1,3,4-thiadiazolo [3,6-N-; 7-methyl-2-3, pyrimidine-6-N- 7-methyl-2-pyrimidine-6-N-; 7-methyl-2- [3, 2-a]; 2- [3, 2-a]; 7-methyl-2, 3, 4-thiadiazolo- [3,; 7-methyl-2-morpholinomethyl-5-oxo-5H-13, -a] pyrimidine-6-N- 7-methyl-2-3, 4-thiadiazolo [3, pyrimidine-6-N-60C;

   7-ethyl-2-morpholino-5-oxo-5H-1,3,4-thiadiazolo 6-N- 7-ethyl-2-morpholino-5-oxo-5H-1, 3, pyrimidine-6-N - (2-thiazolyl) -carboxamide; 7-methyl-2- [3, 7-methyl-2-3, diazolo 2- zolo 2- 3-4-thiadiazolo [3 7-methyl-2- dine-6-N-

  <Desc / Clms Page number 27>

 7-methyl-2-morpholino-5-oxo-5H-1,3,4-thiadiazolo [3,2-a] pyrimidine-6-N- (2-thiazolyl) -carboxamide, F. 251-254 VS ;
 EMI27.1
 7-methyl-5-oxo-5H-1, thiazolyl) -carboxamide; 2, 7-dimethyl-5-oxo-5H-1, 3, 4-thiadiazolo pyrimidine-6-N- (2-thiazolyl) -carboxamide; 7-methyl-2, 3, 4-thiadiazolo- [3, 2-a]; and 7-methyl-2, 3, 4-thiadiazolo pyrimidine-6-N- EXAMPLE 6
10 g of 2-amino-5- (2-methyl-morpholino) - 1,3, 4-thiadiazole are reacted with 11.3 g of diethyl ethoxymethylene malonate for 30 min at 120 C.

   After the reaction mixture has cooled, it is crystallized from isopropyl ether, which gives 16.4 g of N- [5- (2-methyl-morpholino) -1, 3,4-thiadiazol - 2-yl] -amino-methylene-diethyl malonate (F 89-91 "C), which are treated with 6.9 g of polyphosphoric acid and 27.15 g of POCI while stirring for 30 min at 120 C.



   After cooling, the reaction mixture is diluted with ice water, then the solution is neutralized with 35% NaOH. The precipitate is filtered and washed with water until
 EMI27.2
 neutrality. Crystallization from Cl / isopropyl oxide gives 12.5 g of ethyl X2-methyl-morpholino) -5-oxo-5H-1., CH2CIZ [3, 2-a] pyrimidine-6-carboxylate (F. 189-1910'C), which is reacted with 11.2 g of 2-amino-pyridine in 625 g of polyphosphoric acid (320 g of 99% H3PO4 and 305 g of P205). while stirring at 1200C for 8 h. After cooling, dilution with ice water and neutralization with 35% NaOH, a solution is obtained which is extracted with ethyl acetate.



   The organic phase is washed with water, then evaporated to dryness under vacuum. Crystallization from CH2Cl2 / methanol
 EMI27.3
 gives 7.6 g of 2- 3, [3, 2-a] F. 263-265 C; NMR: 1.33 (d) (3H, CH), 3.00-4.4 (m) (7H, morpholine protons), 7.6 (m) (2H, C-3 and C pyridyl protons -5), 8.4 (m) (2H, C-2 and C-6 pyridyl protons), 9 0

  <Desc / Clms Page number 28>

 
 EMI28.1
 (s) (H, C-7 proton).



  By proceeding in an analogous manner, the following are prepared 2- 3, 4-thiadiazolo 2, alpyritnidine-6-N-; 2- 3, 4-thia dine-6-N-; 2-roidine-6-N-; 2-dine-6-N-; 2-dine-6-N-; 2, 3, 3, midin-6-N-; 2-dine-6-N- 2-dine-6-N- 2-pyrimidine-6-N-; 2-pyrimidine-6-N- F. 272-2730C ,, NMR (CDC13 (d) (6H, two-CH); 2, (m) (2H, C-3 and C-5 morpholinyl axial protons ); 3.73 (m) (4H; C-3 and C-5 equatorial morpholinyl protons; C-2 and C-6 equatorial morpholinyl protons); 7, C-5 pyridyl proton); 8, 0-8, 4 (m) (2H, C-3 and C-4 pyridyl protons), 8, 60 (bd) (1H, C-6 pyridyl proton), 82 (s) (1H , proton at C-7), 12, 45 (bs) (1H, -CONH-) on 2- 3, 4-thiadiazolo pyrimidine-6-N- on 2- py on 2- 3, pyrimidine-6-N-

  <Desc / Clms Page number 29>

 
 EMI29.1
 2- (cis-2b-dimethyl-norpholjn pyrimidine;

   2- [3, 2-a] pyrimidine-6-N- 2- [3, 2-a]; 2- [3, 2-3, [3, Z-a] pyrimidine-6-N-; 2-thiomorpholino-5-oxo-5H-1,3,4-thiadiazolo [3, N-; F. 306-308 C; 2-thiomorpholino-5-oxo-5H-1, 3, N-; 2- 3, midine-6-N- F. 325-330oC (decomposition); 2- 3, midine-6-K- F. 365-370 C 2- 3, pyrimidine-6-N- F. 338-340oC (decomposition); 2-pyrimidine-6-N-; 2-pyrimidine-6-N-; 2- 4-thiadiazolo3, 6-N-;

   F. 318-320oC; 2- 4-thiadiazolo 6-N- 2- 4-thiadiazolo 6-N-; 2- 4-thiadiazolo 2-a] 6-N- 2- (4-pyridyl-N-oxide) -5-oxo-5H-13,6-N-; and

  <Desc / Clms Page number 30>

   (2-methyl-morpholino) -5-oxo-5H-l EXAMPLE 7
1.5 g of 2-thiomorpholino-5-oxo-5H-1,3,4-thiadiazolo [3,2-a] pyrimidine-6-N- (2-pyridyl) -carboxamide are reacted with acid peracetic obtained from 0.5 g of H202 at 36%. and 70 ml of acetic acid at room temperature for 1 h. The reaction mixture is diluted with ice water, neutralized with NaHCO and extracted with chloroform. The organic solution is washed with H2O, then evaporated to dryness under vacuum.

   Crystallization from CH2Cl2 / methanol gives 0.8 g of 2- (thiomorpholino-1-oxide) - 5-oxo-5H-1, 3, 4-thiadiazolo (3, 2-a] pyrimidine-6-N- (2-pyridyl) -carboxamide, F. 325-330 C (with decomposition); MN (CDC13 + CF3COOD) & ppm: 3.30 (m) (4H, thiomorpholinyl protons in C-2 and C-6), 4.00-4.70 (m) (4H, C-3 and C-5 thiomorpholinyl protons), 7.70 (m) (2H, C-3 and C-5 pyridyl protons), 8, 44 (m) (2H, pyri protons
 EMI30.1
 dyle in C-4 and C-6), 9, 11 (s) (1H, proton in).



  By proceeding in this way, the following compound is prepared: 2-midin-6-N- EXAMPLE 8
1.3 g of 2-thiomorpholino-5-oxo-5H- 1, 3, 4-thiadiazolo [3,2-a] pyrimidine-6-N- (2-thiazolyl) -carboxyamide are reacted with 1.6 g m-chloroperbenzoic acid in 50 ml of methylene chloride at room temperature for 3 h.

   The organic solution is washed with a 5% NaHCO3 solution and then with water; after
 EMI30.2
 evaporation to dryness under vacuum, crystallization from gives 0.7 g of 2-5H-1,3,4-thiadiazolo [3, F. 365-370 C (decomposition);
By proceeding in an analogous manner, the following compound is prepared:
 EMI30.3
 2- 4-thiadiazolo pyrimidine-6-N- EXAMPLE 9
4 g of 2- (4-nitro-phenyl) -5-oxo-5Hl, 3, 4-thiadiazolo [3,2-a] pyrimidine-6-N- (2-pyridyl) -carboxamide are reacted,

  <Desc / Clms Page number 31>

   prepared according to Example 2, with 22.5 of SnC12. 2H20 in 16 ml of 37% BCI and 56 ml of acetic acid while stirring: at 60 ° C for 8 h.

   After cooling, the precipitate is filtered and washed with acetic acid, then it is suspended while stirring in 2N NaOH. The product is filtered, washed with water until neutral, then it is crystallized from dioxane / ethanol, which gives 1.7 g of 2- (4-amino-phenyl) -5-oxo -5H-1, 3, 4-thiadiazolo- [3,2-a] pyrimidine-6-N- (2-pyridyl) -carboxamide, F 290-293 C; NMR (DMSO d6) ppm: 6.28 (bs) (2H) -NH2), 6, 10 (bd) (2H, phenyl protons C-3 and C-5), 7, 16 (m) ( 1H, C-5 pyridyl proton), 7.68 (bd) (2H, C-2 and C-6 phenyl protons); 7.84 (m) (1H, C-4 pyridyl proton), 8.20-8, 40 (m) (2H, C-3 and C-6 pyridyl protons), 8.84 (s. ) (1H, proton at C-7), 11, 40 (bs) (1H, -CONH-).



   By proceeding in an analogous manner, the following compounds are prepared: 2- (3-amino-phenyl) -5-oxo-5H-1, 3, 4-thiadiazolo [3,2-a] pyrimidine-6N- (2- pyridyl) -carboxamide;
 EMI31.1
 2- N-; and 2-midin-6-N- EXAMPLE 10 1.5 g of 2- 1, 3, 4-thiadiazol (2-amino-phenyl) -5-oxo-5H-1, 3, 4-tniadiazolo are reacted [3, 2-a] pyrimidine-6-prepared according to example 9, dissolved in 20 ml of dimethylformamide, with 4 ml of acetic anhydride in the presence of 2 ml of pyridine at room temperature for 20 h. The reaction mixture is diluted with ice water and the precipitate is filtered and washed with water.



  Crystallization from dimethylformamide / methanol gives 1.2 g
 EMI31.2
 of 2- pyri- (4-N-midine-6-N- (2-pyridyl) -carboxamide.



   By proceeding in an analogous manner, the following compounds are prepared:
 EMI31.3
 2-pyrimidine-6-N-;

  <Desc / Clms Page number 32>

 
 EMI32.1
 2- (2-i% '- accityl-anino-phC-nyl) -5-oyo-511-1, pyrimjdine-6-N-; 2-midin-6-N-; and 2- 4-thiadiazolo- [3, 2-a] EXAMPLE 11 2 g of 5-oxo-5H-1,3,4-thiadiazolo midine-6-N- are treated in suspension in 500 ml of hot dioxane, with stirring with a slight excess of HCl gas dissolved in dioxane for 1 h. After cooling, the precipitate is filtered and washed with dioxane, which gives 2.1 g of 5-oxo-5H-1,3,4-thiadiazolo hydrochloride 2-a] pyrimidine-6-N- ( 2-pyridyl) -carboxamide; F.> 300 C with decomposition.



   By proceeding in an analogous manner, the following compounds are prepared:
 EMI32.2
 2-methyl-5-oxo-5H-1,3,4-thiadiazol hydrochloride 2-a] pyrimidine-6-N-; 2- 2-a] pyrimidine-6-N- hydrochloride; 2-morpholino-5-oxo-5H-1,3,4-thiadiazol {3, pyrimidine-6-N- hydrochloride; 2-morpholino-5-oxo-5H-1, 3, 4-thiadiazolo3 hydrochloride, pyrimidine-6-N-; and 2- 3 hydrochloride, pyrimidine-6-N- EXAMPLE 12
2.25 g of 5-oxo-5H-1, 3, 4-thiadiazolo- [3, 2-a] pyrimidine-6-carboxylate, prepared according to Example 1, are reacted with 1.95 g of 4-chloro-aniline in 250 ml of xylene at reflux temperature, for 18 h, by carrying out a slow distillation of the solvent. After cooling, the precipitate is filtered and washed with isopropyl ether oxide.

   Crystallization from ethanol gives. 1.55 g of 5-oxo-5H-1, 3, 4-thiadiazolo [3, 2-a] pyrimidine-6-N- (4-chloro-phenyl) -carboxamide.

  <Desc / Clms Page number 33>

 



   By following an analogous procedure, the following COp05 {S are prepared: 5-oxo-515-1, 3, 4-thiadiazolo [3,2-a] pyrimidine-6-N- (4-methoxyphenyl) -carboxamide ; 5-oxo-5H-1, 3, 4-thiadiazolo [3,2-a] pyrimidine-6-N- (4-fluoro-phenyl) carboxamide; 2- (3-pyridyl) -5-oxo-5H-1,3,4-thiadiazolo [3,2-a] pyrimidine-6-N- (4-chloro-phenyl) -carboxamide;
 EMI33.1
 2- 3, 4-thiadiazolo [3, (3-pyridyl) -5-oxo-5H-1, (4-methoxy-phenyl) -carboxamide; 2-morpholino-5-oxo-5H-1,3,4-thiadiazolo [3,2-a] pyrimidine-6-N- (4-chloro-phenyl) -carboxamide; and 2-morpholino-5-oxo-5H-1,3,4-thiadiazol 2-a] pyrimidine-6-N- (4-methoxy-phenyl) -carboxamide.



  EXAMPLE 13
Tablets are produced as follows, each weighing 150 mg and containing 50 mg of the active substance: Composition (per 10,000 tablets)
 EMI33.2
 2- 3, 4-thiadiazolo pyrimidine-6-N- 500 g Lactose 710 g Corn starch 237.5 g Talcum powder. 37.5 g Magnesium stearate 15 g
 EMI33.3
 The 2- 3, 4-thiadiazolo- [3, 2-a] lactose and half of the corn starch are mixed; the mixture is then discharged through a sieve with 0.5 mm mesh opening. 18 g of corn are suspended in 180 ml of hot water. The resulting paste is used to granulate the powder. Dry the granules, brpie them on a 1.4 mm sieve, then add the remaining amount of starch, talc and magnesium stearate, mix carefully and process to obtain tablets , using punches 8 mm in diameter.



   By operating in a similar fashion, tablets are prepared having the same composition, but containing one of the following compounds as active substance:

  <Desc / Clms Page number 34>

 5-oxo-5H-1,3,4-thiadiazolo [3,2-a] pyrimidine-6-N- (2-pyridyl) carboxamide,
 EMI34.1
 2-morpholino-5-oxo-5H-1,3, (2-pyridyl) -carboxamide and 7-methyl-2-morpholino-5-oxo-5H-1,3, pyrimidine-3, 4-thiadiazolo6- N- (2-pyridyl) -carboxamide.



  EXAMPLE 14
Tablets are produced as follows, each weighing 150 mg and containing 50 mg of the active substance: Composition (per 10,000 tablets)
 EMI34.2
 2- 3, 4-thiadiazol- [3, 2-a] 500 g Lactose g Corn starch 5 g Talcum powder 37, 5 g Magnesium stearate 15 g We mix the 2- 3, 4thiadiazolo the lactose and half of corn starch. The mixture is then discharged through a sieve with a 0.5 mm mesh opening. 18 g of corn starch are suspended in 180 ml of hot water. The resulting paste is used to granulate the powder. The granules are dried, ground on a sieve with a mesh size of 1.4 mm, then the rest of the starch, talc and magnesium stearate are added, mixed carefully and treated to obtain tablets, using punches 8 mm in diameter.



   By proceeding in an analogous manner, tablets are prepared having the same composition, but containing as active substance one of the following compounds
 EMI34.3
 2-thiomorpholino-1, pyrimidine-6-N-; and 7-methyl-2- (3-pyridyl) -5-oxo-5H-1, 3, 4-thiadiazolo [3,2-a] pyrimidine-6-N- (2-pyridyl) -carboxamide.


    

Claims (6)

 CLAIMS 1 - Compound which is a carboxamido derivative of 5H-1,3,4-thiadiazolo [3,2-a] pyrimidine, characterized in that it corresponds to the general formula (I)  EMI35.1  [in which  EMI35.2  R1: a) a hydrogen or halogen atom or a C 1 -C 6 alkyl group D unsubstituted or substituted by a C 1 -C 6 alkoxy group;    EMI35.3  jazz b) R n is 0, 1, 2 or 3 and each ----- 5 ----  EMI35.4  these symooies K4 and K-represern-e of hydrogen or an alkyl group in C., in C-, well R4 and R taken together with the nitrogen atom to which they are connected, form an unsubstituted N-pyrrolidinyl nucleus or a piperidino nucleus. mor-  EMI35.5  r-1 (0) in which m is 0. pholino, N-piperazinyl or \ -i w -----  EMI35.6  or z, the nuclei not SUDS1cue or being substituted by one or two alkyl groups in the i 6 N-piperazinyl nucleus being unsubstituted or substituted by a substituent chosen from a C 1 to alkyl group and 1 6 pyridyl;  c) a trihalomethyl group or R6-S (O) -, where p is Op 1 or 2,  EMI35.7  and represents an alkyl group in which the 6 t 6 phenyl ring is not substituted or is substituted by a substituent chosen from halogens, a C1 to C6 alkyl group and a  EMI35.8  alkoxy group in or 1 bd) an unsubstituted pyridyl ring, pyridyl N-oxide or thienyl a phenyl ring unsubstituted or substituted by one, two or three substituents chosen independently from a halogen atom, a C1-C4 alkyl group C ,, C1 to C6 alkoxy, hydroxyl, formyloxy, C2 to C8 alkanoyloxy, nitro, amino, formylamino, C2 to C8 alkenoylamino and dialkyl (C to C6) -amino;    <Desc / Clms Page number 36>    EMI36.1  represents a hydrogen atom or a C 1 -C 6 alkyl group; '16 RZ R3 represents: Z! ') A phenyl ring, unsubstituted or substituted by one or  EMI36.2  two substituents independently selected from a C 1 to C 1 alkyl group and a halogen atom b ') an unsaturated ring or heterobicyclic containing one or more heteroatoms chosen from nitrogen and sulfur, unsubstituted or substituted by one or two substituents independently selected from a halogen atom, a group  EMI36.3  C1 alkyl and one alkoxy group C. 16 i 6 or in that it is a pharmaceutically acceptable salt of the above compound.  2-Derivative of the carboxamido type, characterized in that the compound corresponds to the formula (1) of claim 1, in which: R. represents a ") a hydrogen atom, a C 1 -C 6 alkyl group, C1-C6 alkylthio, benzylthio, methoxymethyl, ethoxymethyl or di (C1-C4 alkyl) amino; or b ") an unsubstituted N-pyrrolidinyl ring; a morpholino or piperidino ring, unsubstituted or substituted by an alkyl group  EMI36.4  to an N-piperazinyl ring substituted by a substituent chosen from a C 1 to C 4 alkyl group and C1 or C2; orpyridyl; or c ") an unsubstituted pyridyl or pyridyl-N-oxide ring;  or a phenyl ring which is unsubstituted or substituted by one or two substituents chosen from a chlorine or fluorine atom and a methyl group; or  EMI36.5  d ") a ring-N where m is 0, 1 or 2;  EMI36.6  represents hydrogen or an alkyl group CloU R3 is an unsubstituted benzothiazolyl ring; a C 1-4 ring) pyrazolyl; or a thiazolyl or pyridyl ring, unsubstituted or substituted by one or two substituents chosen from a methyl group and a chlorine atom; or this derivative is a pharmaceutically acceptable salt of the above compound.  <Desc / Clms Page number 37>    EMI37.1   3 of carboxa: nido type which corresponds to formula (I) according to claim 1 [in which represents a "') a hydrogen atom or a methyl or bill group) an unsubstituted N-pyrrolidinyl nucleus a nucleus piperidino or morpholino, which are unsubstituted are substituted by an & C alkyl group or an N-piperazinyl ring substituted by a substituent chosen from a C1 to C3 alkyl group, and pyridyl or c "') a pyridyl ring or unsubstituted pyridyl-N-oxide; or  EMI37.2  d "') a nucleus S (o), where m is 0, 1 or 2; Li m  EMI37.3  R2 a hydrogen atom or a group; R3 an unsubstituted benzothiazolyl ring; pyrazolyl; or a thiazolyl or pyridyl ring, unsubstituted or substituted by one or two methyl groups] or the compound is acceptable from the above. 4-Derivative of the carboxamido type, characterized in that it is chosen from the group consisting of: 5-oxo-5H-1, 3, 4-thiadiazolo carboxamide; 5-oxo-5H-1,3,4-thiadiazolo carboxamide; 2- (2-benzothiazolyl) -carboxamide; 2-morpholino-5-oxo-5H-1, 3, 4-thiadiazol {3, 2-a] (2-benzothiazolyl) -carboxamide 2-morpholino-5-oxo-5H-1, (2-thiazolyl) -carboxamide; 2-methyl-5-oxo-5H-I, 3, 4-thiadiazolo [3, -N- pyridyl) -carboxamide 2-morpholino-5-oxo-5H-1, 3, (2-pyridyl) -carboxa nest 5-oxo-5H-1, 3, 4-thiadiazol 2-a] pyrimidine-6-N-zolyl) -carboxamide;  <Desc / Clms Page number 38>  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-thiazolyf) -carboxamide; 2- (2-methyl-morpholino) -5-oxo-5H-1,3,4-thiadiazolo [3,2-a] pyrimidine-6-N- (2-pyridyl) -carboxamide;  EMI38.1  2- 3, pyrimidine-6-N-; 2- 2-a] (4-methyl-2-thiazolyl); 2- (2-methyl-morpholino) -5-oxo-5H-1,3,4-thiadiazolo 2-a] pyrimidine-6-N- (2-thiazolyl) -carboxamide; 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-thiadiazol 3, 2 -a] pyrimi. dine- 6-N- (2-pyridyl) -carboxamide;  EMI38.2  7-methyl-2-morpholino-5-oxo-SH-16-N-; 7-methyl-5-oxo-5H-1,3,4-thiadiazolo pyridyl) -carboxamide;  7-methyl-5 3,4-thiadiazolo th; 2- 6-N- 2- 3, dine-6-N-; 2-thiomorpholino-5-oxo-5H-1,3,4-thiadiazolo [3 2-a] pyrimidine-1 (2-thiazolyl) -carboxarnide; 7-methyl-2- (3-pyridyl) -5-oxo-5H-1,3,4-thiadiazolo3,2-a] pyrimidine- 6-N- (2-pyridyl) -carboxamide;  EMI38.3  pyrimidine- 7-met6-N- (2-thiazolyl) -carboxamide; 2- (thiomorpholino-1,1-dioxide) -5-oxo-5H-1,3,4-thiadiazolo [3,2-a] - pyrimidine-6-N- (2-pyridyl) -carboxamide;  <Desc / Clms Page number 39>    EMI39.1  2-pyri idine-6-N-idej or in that it is a pharmaceutically acceptable salt of a compound above.    5 - Process for the preparation of a compound of formula (1), or of a pharmaceutically acceptable salt of this compound, according to claim 1, process characterized in that a compound of formula (II) is reacted  EMI39.2    EMI39.3  z [in which: R. and R2 are as defined in claim 1, and R7 is a carboxyl group or a reactive derivative of a carboxyl group with a compound of formula (III) H2N-R3 (III) [in which R3 is as defined in claim 1] and, if desired, a compound of formula (1) is transformed into another compound of formula (1) and, optionally or alternatively, it is transformed if desired compound of formula (I) into a pharmaceutically acceptable salt thereof, optionally or alternatively,  the free compound of formula (I) is obtained from a salt and, optionally or alternatively, a mixture of isomers is separated into individual isomers if desired.  6-Pharmaceutical composition with analgesic and anti-inflammatory effect, characterized in that it contains a vehicle or diluent, or else a vehicle and a diluent; suitable, and, as active substance, a compound corresponding to the formula. (I) of claim 1, or a pharmaceutically acceptable salt of this compound.