The Board of Governors for Higher Education, State of Rhode Island and

Board of Governors for Higher Education, State of Rhode Island and Providence Plantations

Cypros Pharmaceutical Corp.

Providence Plantations

The Board of Governors for Higher Education

State of Rhode Island

Elie Abushanab

Palle V Pragnacharyulu

Palle V P Pragnacharyulu

Chandra Vargeese

Hussein I El Subbagh

Raymond P Panzica

Subramaniam Arumugam

Process to prepare pyrimidine nucleosides

A process for the production of a compound of the formula:

A process for the production of a compound of the formula: ##STR1## wherein R.sub.1 is hydrogen, alkyl C.sub.1 -C.sub.16 substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyls, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyano, carboxy, carboxy esters, carboxamido, N-mono substituted and N,N-disubstituted carboxamido with alkyl, aralkyl and aryl groups; R.sub.2 is hydrogen, alkyl C.sub.1 -C.sub.16 substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyls, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl; R.sub.3 is alkyl C.sub.2 -C.sub.6, branched alkyl, aryl C.sub.2 -C.sub.6, substituted aryl and R.sub.4 is halogen or H. A condensation reaction is effected between compounds of the formulae: ##STR2## to form a novel compound of the formula: ##STR3## Compound (2) is acylated with a compound of the formula:

The high intensity natural sweetener monatin, an .alpha.-amino acid (1) is synthesized from readily available starting materials. Regiospecific ring opening of epoxide (9) with indole magnesium bromide yields lactone (11). Amination of (11) followed by saponification yields Monatin.

Synthesis of monatin-A high intensity natural sweetener

A process for the production of a compound of the formula: ##STR1## wherein R.sub.1 is hydrogen, alkyl, C.sub.1 -C.sub.16 substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyls, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyano, carboxy, carboxy esters, carboxamido, or N-mono substituted and N,N-disubstituted carboxamido with alkyl, aralkyl or aryl groups; R.sub.2 is hydrogen, alkyl C.sub.1 -C.sub.16 substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyls, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl; R.sub.3 is alkyl C.sub.2 -C.sub.6, branched alkyl, aryl C.sub.2 -C.sub.6 or substituted aryl and R.sub.4 is halogen or H. A condensation reaction is effected between compounds of the formulae: ##STR2## to form a novel compound of the formula: ##STR3## Compound (2) is acylated with a compound of the formula:

This invention disclosed (2S,3R)-3(6-aminopurin-9-yl) aralkan-2-ols, a novel class of adenine derivatives (also called 9-aralkyladenines, ARADS), which have been shown to inhibit the enzyme adenosine deaminase at therapeutically useful levels. The relevant inhibitory constant (K.sub.i) values are in the range of 10.sup.-7 -10.sup.-10 M. These compounds with potencies in this range can reversibly inhibit ADA in an effective manner, without permanently deactivating the enzyme. ADA inhibitors that have similar biological profiles have been shown to be of therapeutic value when used to protect heart muscle against ischemic damage.

Adenosine deaminase inhibitors

Enantiomerically pure glycerol derivatives, e.g. S-1,2-O-isopropylidene, S-1,2-O-benzylidene, and R-1,2-O-dibenzyl glycerol, have been prepared from 1,2R-O-protected erythritols in high yields. The latter compounds are easily obtained from erythorbic acid and are useful building blocks in the synthesis of a host of optically active compounds having biological activity.

Chiral glycerol derivatives

Sphingolipids are involved in the structure of biological membranes. There is a link between sphingolipids and signal transduction. The invention relates to the stereospecific syntheses of dihidrosphingosines using certain chiral epoxides.

Practical, cost-efficient chiral synthesis of dihydrosphingosines

This invention discloses various analogs of erythro-hydroxynonyladenine (EHNA) which have been modified by the addition of hydroxy groups or other moieties at the #8 or #9 carbon atoms of the side-chain portion of the molecule (i.e., the erythro-hydroxynonyl chain which is attached to the adenosine ring structure). It also discloses synthetic reagents and steps that can be used to create these and other analogs of EHNA which contain hydroxyl, halide, acid, ester, ether, amine, azide, or other moieties at such locations, or at other controllable locations such as the #5, #6, or #7 carbon atoms on the side-chain. Analogs containing such side-chain modifications can also be modified in the adenosine structure if desired. The hydroxylated analogs described herein have been shown to inhibit adenosine deaminase (ADA) at therapeutically useful levels. The relevant Ki values are in the range of 10.sup.-8 to 10.sup.-9, which is within a desired range of about 10.sup.-7 to about 10.sup.-10. EHNA analogs that have potencies within this range can effectively inhibit ADA activity on a reversible basis, without permanently poisoning the enzyme. It has also been discovered that some of these analogs have an additional therapeutic value when used to protect heart muscle against ischemic damage.

Hydroxylated erythro-hydroxynonyladenines and related analogs

A process for the production of a compound of the formula ##STR1## where R.sub.1 and R.sub.2 each are alkyl C.sub.1 -C.sub.16, aryl, aralkyl, alkenyl, alkynyl, cyano, carboxy and esters, carboximido, N-monosubstituted and N,N-disubstituted carboximido with alkyl, aralkyl, and aryl groups; R.sub.3 is tertiary butyldimethyl silyl, R.sub.4 is tertiarybutyldimethylsilyl, trimethylsilyl, X=O or NH comprising condensing a compound of the formula ##STR2## wherein R.sub.3 and R.sub.4 are as defined above with a compound of either the formula: ##STR3## wherein R.sub.1 and R.sub.2 are as defined above and R.sub.5 is C.sub.1 -C.sub.4 ; in the presence of a reaction-inert solvent at a temperature of from 50.degree.to about 150.degree. C. forming an intermediate and oxidizing the intermediate product, to form the desired compound of formula I. The products are antiviral.

Growing community of inventors

Peace Dale, RI, United States of America

Elie Abushanab