Patent GB-1328679-A (GB)
Title: Pyridopyrimidines
IPC: C07D471/04
Filed: 1970-10-12
Abstract: 1328679 1,2 - Dihydro- and 1,2,3,4 - tetrahydro - pyrido[2,3-d]pyrimidin- 2 - ones SANDOZ Ltd 12 Oct 1970 [20 Oct 1969 10 Nov 1969 1 June 1970 (2)] 48289/70 Heading C2C Novel 1,2 - dihydro- and 1,2,3,4 - tetrahydro - pyrido[2,3-d]pyrimidin- 2 - ones of the general formula wherein x y is a -CR 2  = N- or -CHR 2 -NH- group, R 1  is a C 1-6  alkyl, C 3-6  cycloalkyl, allyl, methallyl or propargyl group, R 2  is a phenyl group or a substituted phenyl group of formula in which Y is a fluorine, chlorine or bromine atom or a C 1-4  alkoxy or C 1-4  alkyl group and Y 1  is as Y or a hydrogen atom, and R is a group of formula wherein Z and Z 1  are each a hydrogen, fluorine, chlorine or bromine atom or a C 1-3  alkoxy group, are prepared (a) when xy is a -CR 2 =N- group and R 1  is not a tertiary alkyl group in which the tertiary carbon atom is attached directly to the ring nitrogen atom, by reaction of a 1,2 - dihydro - pyrido[2,3-d]pyrimidin - 2 - one of the general formula wherein M<SP>1</SP> is an alkali metal atom, with a halide of the general formula R<SP>1</SP> 1 X, wherein X is a chlorine, bromine or iodine atom and R<SP>1</SP> 1  is as R 1  except that it is not a tertiary alkyl group in which the tertiary carbon atom is attached directly to the ring nitrogen atom; (b) when #x y is a -CR 2 =N- group, by reaction of a phenyl 3-(2-aminopyridyl) ketone imine of the general formula with phosgene, a C 1-2  alkyl chlorocarbonate, a C 1-5  alkyl carbamate or 1,1<SP>1</SP>-carbonyldiimidazole, provided that when R 1  is a tertiary alkyl group in which the tertiary carbon atom is directly attached to the ring nitrogen atom, the reaction is effected with phosgene or 1,1<SP>1</SP>- carbonyldiimidazole and provided that when a C 1-5  alkyl carbamate is used, the reaction is effected at a temperature of at least 140‹ C; (c) when the product is as in (a) above, by reaction of a phenyl 3-(2-aminopyridyl) ketone of the general formula with a C 1-5  alkyl carbamate, urea or isocyanic acid, provided that when a C 1-5  alkyl carbamate is used, the reaction is effected at a temperature of at least 140‹ C. and in the presence of a catalytic amount of a Lewis acid; and (d) when #x y is a -CHR 2 -NH- group, by reduction of the product of (b) above in an inert organic solvent. 1,2 - Dihydro - pyrido[2,3-d]pyrimidin - 2- ones of the second general formula above wherein M<SP>1</SP> is a hydrogen atom are prepared by reaction of a phenyl 3-(2-aminopyridyl) ketone of the general formula with a C 1-5  alkyl carbamate at a temperature of at least 140‹ C. Phenyl 3-(2-aminopyridyl) ketones of the fourth general formula above are prepared by reaction of a 2-aminonicotinonitrile of the general formula with an organometallic compound of the general formula R 2 Q, wherein Q is a lithium atom or a -MgX group, followed by hydrolysis under neutral or alkaline conditions. 2-Amino-nicotinonitriles of the seventh general formula above are prepared by (a) reaction of a 2-halonicotinonitrile of the general formula wherein X<SP>1</SP> is a chlorine or bromine atom, with an amine of the general formula R 1 NH 2 ; (b) reaction of the corresponding compound in which R 1  is a hydrogen atom with a halide of the third general formula above and (c) reaction of a 2-amino-3-halopyridine of the general formula with cuprous cyanide in an inert organic solvent and decomposition of the resulting complex. 2 - Aminonicotinonitriles of the seventh general formula above wherein R 1  is a hydrogen atom are prepared by reaction of a 2-halonicotinonitrile of the ninth general formula above with ammonia. 2-Amino-3-halopyridines of the eleventh general formula above are prepared by reaction of a 2-aminopyridine of the general formula with chlorine or bromine. Phenyl 3-(2-aminopyridyl) ketones of the fifth general formula above are prepared by the same method as described above for the production of phenyl 3 - (2 - aminopyridyl) ketones of the fourth general formula above, except that in the starting material R<SP>1</SP> 1  replaces R 1  and the final step is an acid hydrolysis. 2-(Chloro-5-phenylnicotinonitrile is prepared by reaction of phenylacetic acid with phosphorus oxychloride and dimethylformamide, reaction of the resulting 2 - phenyl - 3 - dimethyl - aminoacrolein with 2-cyanoacetamide in the presence of sodium methoxide and reaction of the resulting 3- cyano - 5 - phenyl - 2(1H) - pyridone with phosphorus oxychloride and phosphorus pentachloride. 2 - Chloro - 5 - p - chloro - phenyl - nicotinonitrile is prepared analogously. Pharmaceutical compositions having antiinflammatory activity comprise, as active ingredient, a 1,2-dihydro- or 1,2,3,4 - tetrahydropyrido[2,3-d]pyrimidin - 2 - one of the first general formula above, in association with a pharmaceutically acceptable carrier, and may be administered orally or parenterally.