Warner-lambert Company

Roy Thomas Winters

Haile Tecle

Helen Tsenwhei Lee

Karen Elaine Sexton

Kevin Matthew Schlosser

Stephen Alan Fakhoury

Jessica Elizabeth Reed

William Alexander Denny

Howard D Showalter

Ellen Myra Dobrusin

Mark Robert Barvian

Ronald G Micetich

Rajeshwar Singh

Gordon William Rewcastle

James S Kaltenbronn

Peter Laurence Toogood

James Marino Hamby

Andrew Mark Thompson

Zhipei Wu

Inderjit S Sidhu

Yadagiri Bathini

Howard Isaac Tjiong

H D H Showalter

This invention provides quinazoline compounds of the formula: 

4-phenylamino-quinazolin-6-yl-amides

This invention provides quinazoline compounds of the formula: wherein: Ris halo; Ris H or halo; Ris a) C-Calkyl, optionally substituted by halo; or b) &#x2014;(CH)-morpholino, &#x2014;(CH)-piperidine, &#x2014;(CH)-piperazine, &#x2014;(CH)-piperazine-N(C-Calkyl), &#x2014;(CH)-pyrrolidine, or &#x2014;(CH)-imidazole; n is 1 to 4; Ris &#x2014;(CH)-Het; Het is morpholine, piperidine, piperazine, piperazine-N(C-Calkyl), imidazole, pyrrolidine, azepane, 3,4-dihydro-2H-pyridine, or 3,6-dihydro-2H-pyridine, each optionally substituted by alkyl, halo, OH, NH, NH(C-Calkyl) or N(C-Calkyl); m is 1-3; and X is O, S or NH; or a pharmaceutically acceptable salt thereof, as well as processes and intermediate compounds for making them, useful pharmaceutical compositions and methods of using the compounds in the treatment of proliferative diseases.

This invention provides quinazoline compounds of the formula: wherein: Ris halo; Ris H or halo; Ris a) C-Calkyl, optionally substituted by halo; or b) &#x2014;(CH)-morpholino, &#x2014;(CH)-piperidine, &#x2014;(CH)-piperazine, &#x2014;(CH)&#x2014;-piperazine-N(C-Calkyl), &#x2014;(CH)-pyrrolidine, or &#x2014;(CH)-imidazole; n is 1 to 4; Ris &#x2014;(CH)-Het; Het is morpholine, piperidine, piperazine, piperazine-N(C-Calkyl), imidazole, pyrrolidine, azepane, 3,4-dihydro-2H-pyridine, or 3,6-dihydro-2H-pyridine, each optionally substituted by alkyl, halo, OH, NH, NH(C-Calkyl) or N (C-Calkyl); m is 1-3; and X is O, S or NH; or a pharmaceutically acceptable salt thereof, as well as processes and intermediate compounds for making them, useful pharmaceutical compositions and methods of using the compounds in the treatment of proliferative diseases.

This invention provides quinazolines that are useful for treating cell proliferative diseases and disorders, such as cardiovascular diseases, infections, cancers, autoimmune diseases, gout, kidney disease, and neurodegenerative diseases and disorders such as Alzheimer's disease. We have now discovered a group of 2-arylamino-7-(alkyl)oxy-8-alkylquinazolines and 8-alkyl-2-arylamino-quinazoline 2,7-diamines that are potent inhibitors of cyclin-dependent kinases (cdks). The compounds are readily synthesized and can be administered by a variety of routes, including orally, and have sufficient bioavailability. This invention also provides pharmaceutical formulations comprising at least one of the quinazoline compounds together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. The invention further provide useful intermediates generated during the production of the quinazoline compounds.

Quinazolines and their use for inhibiting cyclin-dependent kinase enzymes

A process for preparing a 2-(pyridin-4-ylamino)-pyrido[2,3-d]pyrimidine of Formula IIcomprising reacting a 4-aminopyridine of the formulawith an alkali metal amide or hydride and a 2-alkylsulfanyl-pyrido[2,3-d]pyrimidine of Formula Iwherein R, R, R' and R&#x2033;, and aryl are as defined in the specification.

Process for preparing 2-(4-pyridyl)amino-6-dialkyloxyphenyl-pyrido(2,3-d)pyrimidin-7-ones

An improved process for the preparation of 4,6-disubstituted pyrido&lsqb;3,4-d&rsqb;pyrimidines is described where 5-amino-2-fluoropyridine is converted in seven operations to the desired products, as well as other valuable intermediates used in the process.

Process for preparing 4,6-disubstituted pyrido&lsqb;3,4-d&rsqb;pyrimidines

Naphthyridinones for inhibiting protein tyrosine kinase and cell cycle

Preparation of 4-bromo-4'-demethylepipodophyllotoxin by reacting podophyllotoxin with hydrogen bromide at about -20.degree. C. New antitumor compounds of the formula: ##STR1## wherein R is A--(CH.sub.2).sub.n [A(CH.sub.2).sub.n ].sub.m (CHAH).sub.p --Q or ##STR2## each A, independently, is O, S, SO or SO.sub.2 ; n is an integer from 1 to 6, except when n and p, taken together, are zero, then n is 2 to 6; n is 0, 1, or 2; p is 0, 1, or 2; Q is H, alkyl from 1 to 6 carbon atoms which may be substituted with an NR.sub.1 R.sub.2 group wherein each R.sub.1 and R.sub.2, independently, is selected from the group of H, alkyl containing 1 to 6 carbon atoms which may be substituted with OH, alkanoyl containing 1 to 6 carbon atoms, or R.sub.1 and R.sub.2 are interconnected and together with the N to which they are connected form an N heterocyclic ring of 5 to 6 carbon atoms; R.sub.3 is hydrogen, and R.sub.4 is an alkyl, alkenyl, cycloalkyl, 2-furyl, 2-thienyl, aryl, aralkyl, and aralkenyl, wherein the aromatic ring may optionally be substituted, preferentially by one or more of hydroxyl, alkyl, alkoxy, nitro, or halogen radicals. R.sub.3 and R.sub.4 together with the carbon atom to which they are attached may form a saturated cycloaliphatic ring having 5 or 6 carbon atoms; each X and Y, individually, is OH or NR.sub.6 R.sub.7 wherein R.sub.6 and R.sub.7, independently, is H, alkyl containing 1 to 6 carbon atoms or one of R.sub.6 and R.sub.7 is acyl; and Z is ##STR3## Novel process for the preparation of the novel compounds or analogs thereof having advantageous stereoselection using alkyltin thiolates, preferably with selected solvents.

4-bromo-4'-demethylepipodophyllotoxin derivatives

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Pinckney, MI, United States of America

Roy Thomas Winters