Sri International

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Sloan-kettering Institute for Cancer Research

Southern Research Institute

Sloan-kettering Institute

Joseph I DeGraw

Francis M Sirotnak

William T Colwell

James R Piper

Howard L Johnson

Frank M Berger

R Lane Smith

John A Lawson

Lawrence F Kelly

Gilda H Loew

John A Montgomery

Donald A Berkowitz

Pamela H Christie

There are provided methods of making an N-demethylated derivative of morphine namely, normorphine. The normorphine can be substituted at the N&#x2014;H position with various ligands that may result in new useful morphine derivatives. These derivatives may have increased analgesic efficacy, have less addictive properties, and/or have effective anti-opiate properties capable of rescuing overdosed persons or lead to recovery from conditions caused by opiate drug abuse.

Facile conversion of morphine to normorphine

Preliminary clinical studies in humans have now been done which show both the efficacy of 10-propargyl-10dAM and a preferred dosage schedule for such treatments. In addition, it has now been determined that combinations of 10-propargyl-10-deazaaminopterin (preferably highly purified forms, substantially free of 10-deazaaminopterin) with taxols exhibit synergistic effectiveness in the treatment of tumors. 10-propargyl-10-deazaaminopterin and a taxol in therapeutically effective amounts can be administered concurrently, one right after the other, or with a period of time in between.

Combinations of 10-propargyl-10-deazaaminopterin and taxols and methods of using same in the treatment of tumors

Purified compositions of 10-propargyl-10-deazaaminopterin and methods of

Antiinflammatory and antineoplastic 5-deazaaminopterins and 5,10-dideazaaminopterins and their 5 and 10 alkyl analogs. A method for the treatment and prevention of inflammatory disease, such as rheumatoid arthritis, and for suppression and prevention of neoplastic growth in tumors and in blood forming tissues. A process for preparation of 10-deazaaminopterins.

Antiinflammatory and antineoplastic 5-deazaaminopterins and

A process is provided for the preparation of 10-deazaaminopterins and 5,10- and 8,10-dideazaaminopterins starting from the corresponding homoterephthalic acid diester coupling the corresponding dicarboxylic acid diester having the formula: ##STR1## with the corresponding diaminopterin 6-methylene halide having the formula: ##STR2## thereby forming a pteroic acid diester having the formula: ##STR3## hydrolysing the two ester groups to form the corresponding carboxylic acid groups, and then monodecarboxylating the diacid, thereby removing the carboxylic acid group attached to the carbon alpha to the A group and forming a pteroic acid.

Process for preparing 10-deazaaminopterins and 5,10-and

There is disclosed certain heteroaroyl 10-deazaaminopterin and 5, 10 and 8, 10 di deazaminopterin compounds and their use for treatment of rheumatoid arthritis and related diseases and preparative process. Also disclosed are 10 alkenyl-(and alkynyl) 10-deazaminopterins also disclosed for treatment of rheumatoid arthritis and for leukemia and ascites tumors and preparative process.

Heteroaroyl 10-deazaamino-pterine compounds and use for rheumatoid

Compounds of the formula: ##STR1## wherein R.sub.1 is at position 4 and either is an alkyl group of 1-6 C or is an --(CH.sub.2).sub.3 -- which is additionally linked to the phenyl at position 3 thereof;

Phenoxy alkanol esters for treatment of allergic conditions

8,10-Dideazatetrahydrofolic acid derivatives of the formula: ##STR1## where R.sub.1 and R.sub.2 are selected from hydrogen and alkyl having from one to about eight carbon atoms and the carboxylates and acid addition salts thereof, showing strong inhibition of L1210 murine leukemia cells in culture, modest inhibition of glycinamide ribotide transformylase and aminoimidazole carboxamide ribotide transferase, and insignificant inhibition of dihydrofolate reductase and thymidylate synthase enzymes.

8,10-dideazatetrahydrofolic acid derivatives

5,10-Dialkyl substituted 5,10-dideazaaminopterins and a cyclized derivative thereof are disclosed as potent antineoplastic agents. Also disclosed is an improved process for the preparation of 10-ethyl-10-deazaaminopterin using the intermediate methyl 4-[[2-(2,4-diamino-6-pteridinyl)-1-ethyl]ethenyl]benzoate.

Cyclized 5,10-dideazaaminopterin compounds

p-Alkyl or cycloalkyl phenoxy alkanols and esters are provided having the structure: ##STR1## in which: R.sub.1 is an alkyl group having from one to six carbon atoms, preferably tertiary, and still more preferably tertiary-butul; or a bivalent cycloalkylene group condensed with the phenyl group at adjacent ring carbons thereof, such as in indane;

P-alkyl phenoxy alkanols for the treatment of allergic conditions

Compounds of the formula ##STR1## wherein R.sup.1 is H, methyl, ethyl, or chloro and R.sup.2 is hydrocarbyl of 1-12 C are useful as antifungal agents. Compounds of this series wherein R.sup.2 is 7-12 C are novel. A new synthetic method for the compounds is also described.

Synthesis and method of use for 2, 4 diaminoquinazoline

A process and composition are provided employing 10-ethyl- 10 deazaminopterin for treating leukemia, as well as other tumor systems including of ascitic character.

Process and composition for treatment of luekemia and process for

Stereoisomerically pure forms of normorphine analogs which have superior analgesic and nonaddicting qualities are described. In addition, a method of separating diastereomeric forms of N-sec-alkyl-substituted analogs utilizes the hydrocarbyl(1-8C) diesters of the normorphine derivatives. A new method for preparing the N-methylalkylmethyl derivatives of normorphine and norcodeine and their conventional analogs is also disclosed. This method employs the corresponding methyl alkyl ketones and a reducing agent.

Orally active nonaddicting analgesics

Diastereomers of 10-alkyl-10-deazaminopterins are provided, as well as a synthesis for their preparation as the individual d,L. and l,L.-diastereomers, the d,L-10-ethyl diastereomer being three times as potent against L1210 cells as the l,L-10-ethyl diastereomer, and the l,L-10-ethyl diastereomer being approximately one-half as toxic as the d,L-10-ethyl diastereomer.

Diastereomers of 10-alkyl-10-deazaminopterins and process for preparing

p-Alkyl or cycloalkyl phenoxy alkanols and esters are provided having the structure: ##STR1## in which: R.sub.1 is an alkyl group having from one to six carbon atoms, preferably tertiary, and still more preferably tertiary-butyl; or a bivalent cycloalkylene group condensed with the phenyl group at adjacent ring carbons thereof, such as in indane;

Growing community of inventors

Sunnyvale, CA, United States of America

Joseph I DeGraw