Patent EA-000897-B1 (EA)
Title: PYRIDO[2,3-d]PYRIMIDINES FOR INHIBITING PROTEIN TYROSINE KINASE MEDIATED CELLULAR PROLIFERATION
Inventor: BLANKLEY CLIFTON JOHN
IPC: A61P43/00
Filed: 1996-04-26
Abstract: 1. A compound of the formula (I)   wherein X is iminogroup , N-acyl, O, or S;  R1 is NR3R4S(O)mR3, where m is 0,1 or 2, or OR3,  R2, R3, and R4 independently are hydrogen, (CH2)nPh group, where Ph is phenyl, unsubstituted or substituted by 1-3 residues selected from the group, comprising halogen, hydroxy, carboxy, alkyl having 1-6 carbon atoms, unsubstituted or substituted by hydroxy, carboxy, alkoxycarbonyl having 1-6 carbon atoms in alkoxy portion, aminogroup, alkylaminogroup or dialkylaminogroup, having 1-6 carbon atoms in each alkyl portion, and n is 0, 1, 2, or 3, heteroaromatic residue with 4-9 ring atoms, of which 1-4 atoms are selected from the group, comprising O, N, S, cycloalkyl having 3-6 carbon atoms, alkanoyl having 1-6 carbon atoms, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, wherein alkyl, alkenyl and alkynyl can be substituted by NR5R6 group where R5 and R6 are independently hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms,(CH2)nPh where Ph and n as defined above, cycloalkyl having 3-6 carbon atoms, heteroaromatic residue having 4-9 ring atoms from which 1-4 atoms selected from the group, comprising oxygen, nitrogen and sulfur, or R5  and R6  together with nitrogen atom, they are bound with, can form a cycle, comprising 3-7 carbon atoms optionally containing 1, 2, or 3 heteroatoms selected from the group comprising nitrogen, oxygen and sulfur phenyl, unsubstituted or substituted by 1-3 residues from the above group, thioalkyl having 1-6 carbon atoms hydroxy, carboxy, halogen, or cycloalkyl having 3-6 carbon atoms, R4 can additionally be the group -C(=O)R3, -C(=O)OR3, -SO2R3, -SO2NR5R6, -C(=O)NR5R6, -C(=S)NR5R6, -C(=NH)R3, -C(=NH)NR5R6, where R3, R5 and R6  are as defined above or R3 and R4 can be taken together with the nitrogen atom, which they are attached to, can complete a cycle having 3 to 7 carbon atoms and optionally containing 1, 2, or 3 heteroatoms selected from group, comprising nitrogen, oxygen, and sulfur;  Ar is phenyl, unsubstituted or substituted by 1-3 residues selected from the group, comprising halogen, hydroxy, alkyl having 1-6 carbon atoms, thioalkyl having 1-6 carbon atoms, alkoxy having 1-6 carbon atoms, trifluoromethyl, thyogroup, cianogroup, nitrogroup, alkanoyl having 1-6 carbon atoms, alkanoyloxygroup having 1-6 carbon atoms, -COOR7 group, where R7 is alkyl having 1-6 carbon atoms or halogen, and -NR5R6 where R5 and R6  are as defined above or heteroaromatic residue with 4-9 ring atoms, of which 1-4 atoms are selected from the group, comprising O, N, S with the proviso that if R2  is hydrogen than X is not iminogroup or the pharmaceutically acceptable salts thereof. 2. Derivatives pyrido[2,3-d]pyrimidin of general formula (I) of claim 1 where Ar is phenyl di-substituted by independent residues from halogen and alkyl having 1-6 carbon atoms, having the formula wherein R7 and R8 independently are C1-C6 alkoxy and R1, R2, and X are as defined above. 3. Derivatives pyrido[2,3-d]pyrimidin of claim 2 where R2 is alkyl having 1-6 carbon atoms unsubstituted or substituted by residues as claimed in claim 1. 4. Derivatives pyrido[2,3-d]pyrimidin of claim 3 where R1 is NR3R4  group. 5. Derivatives pyrido[2,3-d]pyrimidin of claim 4 where R3 is hydrogen. 6. Derivatives pyrido[2,3-d]pyrimidin of claim 5 where R4 is hydrogen. 7. Derivatives pyrido[2,3-d]pyrimidin of claim 6 where X is iminogroup. 8. Derivatives pyrido[2,3-d]pyrimidin of general formula (I) of claim 1 where X is oxygen, R1 is NR3R4 , R3 is hydrogen or alkyl having 1-6 carbon atoms and R4 is alkyl having 1-6 carbon atoms or substituted alkyl having 1-6 carbon atoms, R2 alkyl having 1-6 carbon atoms and Ar is phenyl di-substituted by independent residues from alkyl having 1-6 carbon atoms and halogen. 9. Derivatives pyrido[2,3-d]pyrimidin of claim 6 where X is oxygen. 10. Derivatives pyrido[2,3-d]pyrimidin of claim 5 where R4 is alkyl having 1-6 carbon atoms, substituted by NR5R6  group. 11. Derivatives pyrido[2,3-d]pyrimidin of claim 10 where R5 and R6 both are alkyls having 1-6 carbon atoms. 12. Derivatives pyrido[2,3-d]pyrimidin of claim 10 where X is iminogroup. 13. Derivatives pyrido[2,3-d]pyrimidin of claim 11 where X is oxygen. 14. Derivatives pyrido[2,3-d]pyrimidin of claim 6 where X is sulfur. 15. Derivatives pyrido[2,3-d]pyrimidin of claim 4 where X is oxygen. 16. Derivatives pyrido[2,3-d]pyrimidin of claim 3 where R1 is OR3. 17. Derivatives pyrido[2,3-d]pyrimidin of claim 16 where X is iminogroup. 18. Derivatives pyrido[2,3-d]pyrimidin of claim 16 where X is oxygen. 19. Derivatives pyrido[2,3-d]pyrimidin of claim 3 where R1 is S(O)mR3. 20. Derivatives pyrido[2,3-d]pyrimidin of claim 19 where X is iminogroup or oxygen. 21. Derivatives pyrido[2,3-d]pyrimidin of claim 19 where X is N-acyl. 22. Derivatives pyrido[2,3-d]pyrimidin of general formula (I) of claim 1 where R1 is NHPh', where Ph' is defined for Ph or is pyridyl unsubstituted or substituted by residues defined for phenyl, R2 is alkyl having 1-6 carbon atoms unsubstituted or substituted by residues as defined, X is oxygen or iminogroup and Ar is phenyl di-substituted by independent residues from alkyl having 1-6 carbon atoms and halogen. 23. Derivatives pyrido[2,3-d]pyrimidin of general formula (I) of claim 1 where R1 is NHR4 group, where R4 is phenyl, unsubstituted or substituted by said residues, R2 is alkyl having 1-6 carbon atoms unsubstituted or substituted by said residues, X is iminogroup or oxygen. 24. Derivatives pyrido[2,3-d]pyrimidin of general formula (I) of claim 1 where R3 is hydrogen and R4 is cycloalkyl. 25. Derivatives pyrido[2,3-d]pyrimidin of of claim 1 where R where 6-(2,6-Dichlorophenyl)-8-methyl-2-[3-(4-methylpiperazin-1-yl)-propyiamino]- 8H-pyrido[2,3-d]pyrimidin-7-one;  6-(2,6-Dichlorophenyl)-8-methyl-2-methylamino-8H-pyrido[2,3-d]pyrimidin-7-o ne;  6-(2,6-Dichlorophenyl)-2-dimethylamino-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;  6-(2,6-Dichlorophenyl)-2-ethylamino-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;  6-(2,6-Dichlorophenyl)-2-ethylamino-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;  6-(2,6-Dichlorophenyl)-2-(2-hydroxyethylamino)-8-methyl-8H-pyrido[2,3-d]pyr imidin-7-one;  6-(2,6-Dichlorophenyl)-2-isopropylamino-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;  2-Butylamino-6-(2,6-dichlorophenyl)-8-methyl-8 H-pyrido[2,3-d]pyrimidin-7-one;  2-Benzylamino-6-(2,6-dichlorophenyl)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;  6-(2,6-Dichlorophenyl)-8-methyl-2-(3-morpholin-4-ylpropylamino)-8H-pyrido[ 2,3-d]-pyrimidin-7-one;  6-(2,6-Dichlorophenyl)-2-[2-(3,4-dimethoxyphenyl)-ethylamino]-8-methyl-8H-pyrido[2,3-d]-pyrimidin-7-one;  6-(2,6-Dichlorophenyl)-8-methyl-2-[(pyridin-2-ylmethyl)-amino]-8H-pyrido[2,3-d ]pyrimidin-7-one;  6-(2,6-Dichlorophenyl)-8-methyl-2-[(pyridin-3-ylmethyl)-amino]-8H-pyrido[2, 3-d]pyrimidin-7-one;  6-(2,6-Dichlorophenyl)-8-methyl-2-(2-pyridin-2-ylethylamino)-8H-pyrido[2,3 -d]pyrimidin-7-one;  6-(2,6-Dichlorophenyl)-2-{3-[4-(2-methoxyphenyl)-piperazin-1-yl]-propylamino}-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one;  6-(2,6-Dichlorophenyl)-8-methyl-2-[4-(4-methylpiperazin-1-yl)-butylamino]-8 H-pyrido[2,3-d]pyrimidin-7-one;  6-[6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin -2-ylamino]-hexanoic acid, tert-butyl ester;  6-[6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin -2-ylamino]-hexanoic acid;  6-(2,6-Dichlorophenyl)-8-ethyl-2-[3-(4-methylpiperazin-1-yl)-propylamino]- 8H-pyrido[2,3-d]pyrimidin-7-one;  6-(2,6-Dichlorophenyl)-8-methyl-2-[5-(4-methylpiperazin-1-yl)-pentylamino]- 8H-pyrido[2,3-d]pyrimidin-7-one;  4-{4-[6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimid in-2-ylamino]-phenyl}-butyric acid, ethyl ester; or  4-{4-[6-(2,6-Dichlorophenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimid in-2-ylamino]-phenyl}-butyric acid; 2-Amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;  2-Amino-6-phenyl-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one;  2-Amino-6-(2,6-dichlorophenyl)-8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one;  2-Amino-6-(2,6-dichlorophenyl)-8-propyl-8H-8H-pyrido[2,3-d]pyrimidin-7-one;  [2-Amino-8-butyl-6-(2,6-dichlorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one; [2-Amino-6-(2,6-dichlorophenyl)-8-isobutyl-8H-pyrido[2,3-d]pyrimidin-7 one; [2-Amino-6-(2,6-dichlorophenyl)-8-(3-dimethyllaminopropyl)8H-pyrimidine-7-one; [2-Amino-6-(2,6-dichlorophenyl)-7 oxo-7H-pyrido[2,3-d]pyrimidin-8-yl] acetic acid methyl ester; [2-Amino-6-(2,6-dichlorophenyl)-7 oxo-7H-pyrido[2,3-d]pyrimidin-8-yl] acetic acid tret butyl ester; 2-Amino-8-benzyl-6-(2,6-dichlorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one; 2-Amino-8-(3-bromobenzyl)-6-(2,6-dichlorophenyl)-8H-pyrido[2,3-d]pyrimidin- 7-one;  4-[2-Amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-ylmethy l]-benzoic acid methyl ester; 2-Amino-8-(2,6-dichlorobenzyl)-6-(2,6-dichlorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one; 2-Amino-6-(2,6-dichlorophenyl)-8-(4-methoxybenzyl)-8H-pyrido[2,3-d]pyrimidi n-7-one;  2-Amino-6-(2,6-dichlorophenyl)-8-pyridin-4-ylmethyl-8H-pyrido[2,3-d]pyrimid in-7-one; 2-Amino-6-(2,6-dichlorophenyl)-8-(3-phenylpropyl)-8H-pyrido[2,3-d]pyrimidin -7-one; [6-(2,6-dichlorophenyl))-7-imino-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]-(3-diethalaminopropyl)amine; [6-(2,6-dichlorophenyl))-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]-(3-diethalaminopropyl)amine; N-[6-(2,6-dichlorophenyl))-7-imino-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]acetamide; 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-thione; N-[[6-(2,6-dichlorophenyl)-7-oxo-8-methyl-7,8-dihydropyrido[2,3-d]-pyrimidin-2-yl]succinic acid semiamide; 1-[6-(2,6-dichlorophenyl)-7-oxo-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]pyrrolidine-2, 5-dione; 6-(2,6-dichlorophenyl)-2-hydroxy-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-ylideneamine; 6-(2,6-dichlorophenyl)-2-(2-ethoxyethoxy)-8 methyl-8H-pyrido[2,3-