Burroughs Wellcome Co.

Charles A Nichol

David Stanley Duch

Carl W Sigel

Eric C Bigham

Gertrude B Elion

Gary Keith Smith

George H Hitchings

John F Reinhard, Jr

Dwight R Stickney

William S Simmons

Potent antiproliferative activity in combination with low inhibition of histamine N-methyltransferase has been found in a class of 2,4-diamino-6-(2,5-dialkoxybenzyl)-5-methylpyrido[2,3-d]pyrimidines.

Treatment with dialkoxy pyridopyrimidines

This invention provides the pterin compounds of formula (I) and use in human and veterinary medicine. ##STR1## wherein R represents lower alkyl groups (straight or branched) of 1-8 carbons (for this formula and all other formulas herein) including all stereo isomers thereof or a pharmaceutically acceptable salt thereof.

Biopterin analogs

The compounds of formula (I) ##STR1## wherein R.sup.1 is hydrogen, lower alkyl of 1-4 carbons, lower alkenyl of 2-4 carbons, --B--X--R.sup.5).sub.n, or --B--Z--B--X--R.sup.5 --.sub.n ; n=0 when X is halogen or n=1 when X is --O--, --NR.sup.6 -- (where R.sup.6 is hydrogen or lower alkyl of 1-4 carbons) or --S(O)q-- (where q=0 to 2); B is lower alkanyl (straight or branched) of 1-5 carbons; R.sup.5 is hydrogen, aralkyl of 7 to 12 carbons or alkyl of 1-10 carbons; Z is --O--, NR.sup.6 --, or --S(O)q--; R.sup.2 is hydrogen or lower alkyl of 1-4 carbons or lower alkenyl of 2-4 carbons or either R.sup.1 and R.sup.2 together with the carbon atom in the pteridine ring structures to which they are attached, form a spirocycloalkyl ring system having 3 to 7 carbon atoms; R.sup.3 and R.sup.4 are hydrogen or methyl; R.sup.2 and R.sup.3, together with the carbon atoms in the pteridine ring structure to which they are attached, form a cycloalkyl ring system having 5 to 7 carbon atoms; provided that at least one of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is hydrogen, and further provided that one of R.sup.1, R.sup.2 and R.sup.3, R.sup.4 represents gem disubstitution; have been found to selectively cofactor the biological conversion of tyrosine to dopamine, and are useful in the treatment of diseases resulting from a deficiency of dopamine in the brain such as Parkinson's disease. A further aspect of this invention comprises novel compounds of formula (I) defined above with the proviso that when both R.sup.3 and R.sup.4 are methyl neither R.sup.1 and R.sup.2 may be methyl, and R.sup.1 and R.sup.2 may not both be hydrogen, or a pharmaceutically acceptable salt thereof.

This invention provides the intermediates of formula II-A below, useful to make the pterin compounds of formula I below. The pterin compounds are used in human and veterinary medicine. ##STR1## wherein R represents a lower alkyl of 1 to 8 carbons.

This application is directed to treatment of psoriasis with a pyrido pyrimidine compound such as 2,4-diamino-6-(3,4-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine.

Treatment with dialkoxy pyridopyrimidine compounds

Potent psoriasis activity in combination with low inhibition of histamine N-methyltransferase has been found in a class of 2,4-diamino-6-(2,5-dialkoxybenzyl)-5-methylpyrido[2,3-d]pyrimidines.

Method and pharmaceutical preparations for treating meningeal leukemia, CNS lymphoma and neoplasms in the brain which comprises treating an infected mammal such as a human with a dose of an effective treatment amount of a compound of Formula I ##STR1## where R is a straight or branched chain lower alkyl of 1 to 4 carbon atoms, and X is a halogen atom (fluorine, chlorine, bromine or iodine) and pharmaceutically acceptable salts thereof. Preferred compounds for treatment of the aforementioned diseases are 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methyl-pyrimidine and 2,4-diamino-5-(3',4'-dichlorophenyl)-6-ethyl-pyrimidine.

Treating CNS lymphoma

Method and pharmaceutical preparations for treating meningeal leukemia, CNS Iymphoma and neoplasma in the brain which comprises treating an infected mammal such as a human with a dose of an effective treatment amount of a compound of Formula I ##STR1## where R is a straight or branched chain lower alkyl of 1 to 4 carbon atoms, and X is a halogen atom (fluorine, chlorine, bromine or iodine) and pharmaceutically acceptable salts thereof. Preferred compounds for treatment of the aforementioned diseases are 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine and 2,4-diamino-5-(3',4'-dichlorophenyl)-6-ethylpyrimidine.

Treatment of meningeal leukemia with diamino dichlorophenyl pyrimidine

Method and pharmaceutical preparations for treating meningeal leukemia, CNS Iymphoma and neoplasms in the brain which comprises treating an infected mammal such as a human with a dose of an effective treatment amount of a compound of Formula I ##STR1## where R is a straight or branched chain lower alkyl of 1 to 4 carbon atoms, and X is a halogen atom (fluorine, chlorine, bromine or iodine) and pharmaceutically acceptable salts thereof. Preferred compounds for treatment of the aforementioned diseases are 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine and 2,4-diamino-5-(3',4'-dichlorophenyl)-6-ethylpyrimidine.

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Durham, NC, United States of America

Charles A Nichol