Patent GB-897870-A (GB)
Title: s-triazolo[2, 3-c]pyrimidine derivatives
Inventor: MILLER GEORGE WILLIAM
IPC: C07D487/04
Filed: 1959-06-15
Abstract: The invention comprises resinate salts of s-triazolo [2,3-c] pyrimidine compounds of the general formula <FORM:0897870/IV (a)/1> wherein R1 represents an alkyl radical, R2 R3 represents a halogen or hydrogen, or an alkyl, hydroxyalkyl or alkenyl radical, R4 represents hydrogen or an alkyl, hydroxyalkyl or acyl radical, and R5 represents an alkyl, hydroxyalkyl, alkoxycarbonylalkyl, alkenyl or aralkyl radical, or wherein R4 and R5 are joined together to form, with the adjacent nitrogen atom, a heterocyclic ring.  The resinates may be derived from sulphonated cross-linked polystyrene resins.ALSO:The invention comprises S - triazolo [2,3 - C] pyrimidine compounds of the general formula <FORM:0897870/IV (b)/1> wherein R1 represents an alkyl radical, R2 repre sents an alkyl or halogenoalkyl radical, R3 represents a halogen, or hydrogen or an alkyl, hydroxyalkyl or alkenyl radical, R4 represents hydrogen or an alkyl, hydroxyalkyl or acyl radical, and R5 represents an alkyl, hydroxyalkyl, alkoxycarbonylalkyl, alkenyl or aralkyl radical, or wherein R4 and R5 are joined together to form, with the adjacent nitrogen atom, a heterocyclic ring such as a piperidino or morpholino ring, and salts thereof, and the following processes for the preparation of such compounds: (a) in the case wherein R1, R2, R3, R4 and R5 have the above significance, by desulphurising a pyrimidylthiosemicarbazide of the formula <FORM:0897870/IV (b)/2> wherein R1, R2, R3, R4 and R5 have the above significance, e.g. by heating with lead oxide, mercuric oxide or copper sulphate; the reactant may also be in the form of an S-alkyl or S-aralkyl derivative thereof in which case the desulphurisation may be carried out by heating alone or by heating with lead oxide; (b) in the case where R1 represents an alkyl radical, R2 represents an alkyl or halogenoalkyl radical, R3 represents hydrogen or an alkyl or alkenyl radical or a halogen atom, R4 represents hydrogen or an alkyl radical, and R5 represents an alkyl, alkenyl or aralkyl radical, or R4 and R5 are joined together to form with the adjacent nitrogen atom a heterocyclic ring, by treating a pyrimidyl-semicarbazide derivative of the formula <FORM:0897870/IV (b)/3> wherein R1, R2, R3, R4 and R5 have the meanings stated immediately above, with a dehydrating agent to remove the elements of water and ring closure takes place, e.g. by treatment with phosphorus oxychloride or pentoxide; (c) in the case where R4 represents hydrogen or an acyl radical and R1, R2, R3 and R5 have the significanc under the first general formula above, by reacting a triazolo-pyrimidine of the formula <FORM:0897870/IV (b)/4> wherein R1, R2 and R3 have the significance under the first general formula above and R6 represents a lower alkyl radical, with an alkylating, alkenylating or aralkylating agent such as dimethyl sulphate; this process may result in the removal of the acyl substituent COR6 by hydrolysis so that the acyl substituent is replaced by hydrogen-particularly in the presence of an alkali metal hydroxide; (d) in the case where R1, R2, R3 and R5 have the significance indicated under the first general formula above and R4 represents an acyl radical, by acylating, e.g. with an acid anhydride or an acid halide, a triazolo-pyrimidine of the formula <FORM:0897870/IV (b)/5> wherein R1, R2, R3 and R5 have the significance indicated under the first general formula above; (e) in the case where R1, R2, R3 and R5 have the significance indicated under the first general formula above and R4 represents hydrogen or an alkyl or hydroxyalkyl radical or R4 and R5 are joined together to form with the adjacent nitrogen atom a heterocyclic ring, by reacting a triazolopyrimidine of the formula <FORM:0897870/IV (b)/6> wherein R1, R2 and R3 have the significanc indi cated under the frist general formula above and R7 represents a reactive replaceable substituent such as a halogen or an alkylsulphonyl radical, with an amine of the formula HHR4R5 wherein R4 and R5 have the significance stated immediately above; (f) in the case where R1, R2 and R3 have the significance indicated under the first general formula above, R4 represents hydrogen and R5 represents an alkyl or an aralkyl radical, by reacting a pyrimidine compound of the formula <FORM:0897870/IV (b)/7> wherein R1, R2, R3 and R5 have the significance indicated immediately above, with hydrazine in the presence of a desulphurising agent such as lead oxide; and (g) in the case where R1, R2 and R3 have the significance indicated under the first general formula above, R4 represents hydrogen and R5 represents an alkyl radical containing at least 3 carbon atoms or a dihydroxyalkyl radical containing at least 3 carbon atoms, by reacting a triazolo-pyrimidine of the general formula <FORM:0897870/IV (b)/8> wherein R1 and R2 have the significance indicated under the first general formula above, R8 represents hydrogen or an alkyl or alkenyl radical, and R9 represents an alkyl or alkenyl radical provided that at least one of the groups R8 and R9 represents an alkenyl radical, with a reducing or oxidising agent, e.g. hydrogen in the presence of a metal catalyst or potassium permanganate.  The Provisional Specification states that the compounds of the invention obtained by the processes described in the Complete Specification are S-triazolo-[4,3-C]-pyrimidines having the structure <FORM:0897870/IV (b)/9> Pyrimidylsemicarbazide deravitives of the general formula <FORM:0897870/IV (b)/100> wherein R1, R2, R3, R4 and R5 have the significance indicated above, are prepared by reacting the corresponding hydrazinopyrimidines and the corresponding carbamyl halides.  When R4 represents hydrogen, the derivatives may be prepared by reacting the corresponding hydrazinopyrimidines with the corresponding isocyanates.  Pyrimidylthiosemicarbazide derivatives of the general formula <FORM:0897870/IV (b)/111> wherein R1, R2, R3, R4 and R5 have the significance indicated above, are prepared by reacting the corresponding hydrazinopyrimidines and the corresponding thiocarbamyl halides.  When R4 represents hydrogen, the derivatives may be prepared by reacting the corresponding hydrazinopyrididines with the corresponding isothiocyanates.  S - Triazolo - [2,3 - C] - pyrimides of the general formula <FORM:0897870/IV (b)/122> wherein R1, R2, R3 and R6 have the above significance, are prepared by reacting corresponding halopyrimidines with hydrazine to form the corresponding 6-hydrazinopyrimidines, reacting these pyrimidine derivatives with cyanogen halide to form the corresponding 2-amino-s-triazolo-[2,3-c]-pyrimidines, and acylating these pyrimidines.  2 - Bromo - 5 - n - propyl - 7 - methyl - S - triazolo - [2,3 - c] - pyrimidine is prepared either by reacting 2-amino-5-n-propyl-7-methyl-s-triazolo[2,3-c]pyrimidine with bromine and hydrobromic acid, or by treating 2-hydroxy-5-n-propyl-7-methyl-s-triazolo[2,3-c]pyrimidine with phoshporus oxybromide.  2 - n - Propyl - 4 - methyl - 6 - carbethoxy - hydrazino-pyrimidine is prepared by reacting carbethoxyhydrazine and the required 6-chloro substituted pyrimidine.  2 - methylsulphonyl - 7 - methyl - 5 - n - propyl - s - triazolo - [2,3 - c] - pyrimidine is prepared by reacting 4 - hydrazino - 6 - methyl - 2 - n - propylpyrimidine and carbon disulphide to form 2 - thiol - 7 - methyl - 5 - n - propyl - s - triazolo [2,3-c] pyrimidine, reacting this compound with dimethyl sulphate to form 2-methylthiol-7-methyl - 5 - n - propyl - s - triazolo [2,3 - c] pyrimidine, and treating this compound with concentrated sulphuric acid and ammonium persulphate. 4 - (N1 - methylthioureido - N) - 2,6 - dimethyl - pyrimidine is prepared by reacting 4-amino-2,6-dimethylpyrimidine and methylisocyanate.  5 - Ethyl - 6 - (N1 - methylthioureido - N -) - 2,4 - di - n - propylpyrimidine is prepared by reacting 6 - amino - 5 - ethyl - 2,4 - di - n - propylpyrimidine and methylisocyanate.  2 - n - Propyl - 4 - methyl - 6 - (41 - isobutyl - s - ethyl - thiosemicarbazido - 11 - ) pyrimidine hydriodide is prepared by heating ethyl iodide and 2 - n - propyl - 4 - methyl - 6 - (41 - iso - butylthiosemicarbazido-11-) pyrimidine.ALSO:A pharmaceutical preparation suitable for use as a bronchodilator or analgesic contains as an active ingredient a triazolo-pyrimidine of the general formula <FORM:0897870/VI/1> wherein R1 represents an alkyl radical, R2 represents an alkyl or halogenoalkyl radical, R3 represents a halogen or hydrogen, or an alkyl, hydroxyalkyl or alkenyl radical, R4 represents hydrogen or an alkyl, hydroxyalkyl or acyl radical, and R5 represents an alkyl, hydroxyalkyl, alkoxycarbonylalkyl, alkenyl or aralkyl radical, or wherein R4 and R5 are joined together to form, with the adjacent nitrogen atom, a heterocyclic ring, or a salt thereof, e.g. derived from an inorganic or organic acid or a resin such as a sulphonated cross-linked polystyrene resin, and a non-toxic pharmaceutical carrier therefor.  The composition may be used for oral or parenteral administration or for topical application, e.g. in the form of a tablet, capsule, aqueous solution or suspension, oily solution or suspension, emulsion, powder, spray or aerosol.  The composition may also contain one or more known drugs such as an anti-inflammatory agent -particularly an antihistamine, e.g. 9-(2-dimethylaminopropyl) - 10 - thia - 1,9 - diaza - anthracene, prednisolone, hydrocortisone, or N - 2,4 - dimethylphenylacetamidine salt, or N - amino - N1 - p - tolylguanidine, a sedative, e.g. phenobarbitone, an antibacterial agent, e.g. sulphadimidine or penicillin V, or another drug possessing bronchodilatory activity, e.g. adrenaline or isoprenaline.