Millennium Pharmaceuticals Limited

Genzyme Corporation

Millenium Pharmaceuticals, Inc.

Sunil Vyankatesh Mhaskar

Mukund Shankar Chorghade

Mukund Keshao Gurjar

Alla Venkata Rama Rao

Susanta Sekhar Adhikari

Gangavaram Vasantha Madhava Sharma

Sista Venkata Sai Lalitha

Kashinath Sadalapure

Tangallapally Rajendra Prasad

Palakodety Radha Krishna

Vavilala Goverdhan Reddy

Punna Sreenivas

Aminul Islam

Andappan Murugaiah Subbaiah Murugaiah

Chittineni Hari Prasad

Batchu Venkateswara Rao

Levadala Murali Krishna

Bethi Sridhar Reddy

Hymavathi Lanka

Rayomand H Gimi

Anegondi Sreenivasa Prasad

Vemuri Venkata Kiran Rao

Amin Ul Islam

Kotakonda Shailaja

Ranga Reddy

Lalata Krishnakanth Reddy

Non-natural amino acids such as 2-alkylated amino acids allow for the synthesis of a wider variety of peptidal and non-peptidal pharmaceutically active agents. In one embodiment, the present invention relates to a method of preparing a 2-alkylcysteine comprising condensing cysteine with an aryl nitrile to form a 2-arylthiazoline-4-carboxylic acid, esterifying the 2-arylthiazoline-4-carboxylic acid using a substituted or unsubstituted alcohol group comprising one or more chiral carbons, and alkylating at the 4-position of the thiazoline ring to form a 2-aryl-4-alkyl-thiazoline-4-carboxylic acid ester. The chiral templates present in the thiazoline carboxylic acid ester can provide face selectivity, and consequently desired stereochemistry, during the delivery of an alkyl group to the 4-position of the thiazoline ring. The present invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. In one embodiment, an aryl nitrile is condensed with cysteine or a 2-alkyl cysteine.

Synthesis of 2-alkylcysteine via substituted thiazoline ester

Non-natural amino acids such as 2-alkylated amino acids allow for the synthesis of a wider variety of peptidal and non-peptidal pharmaceutically active agents. In one embodiment, the present invention relates to a method of preparing 2-alkylcysteine comprising condensing cysteine with an aryl nitrile to form a 2-arylthiazoline-4-carboxylic acid, forming a 2-arylthiazoline-4-amide using an amine group comprising at least one substituted or unsubstituted alkyl group that comprises one or more chiral carbon atoms, and alkylating at the 4-position of the thiazoline ring to form a 2-aryl-4-alkyl-thiazoline-4-amide. The present invention also discloses a method of preparing a class of iron chelating agents related to desferrithiocin, all of which contain a thiazoline ring. In one embodiment, an aryl nitrile or imidate is condensed with cysteine or a 2-alkyl cysteine.

Synthesis of 2-alkylcysteine via substituted thiazoline amide

The invention provides new methods for preparation of cyclic oxygen compounds, including 2,5-disubstituted tetrahydrofurans, 2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and 2,8-oxocanes. The invention also provides new cyclic oxygen compounds and pharmaceutical compositions and therapeutic methods that comprise such compounds.

Substituted oxygen alicyclic compounds, including methods for synthesis thereof

The invention includes inter alia new methods for preparation of the pharmaceutically active compound 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1 -butynyl)-tetrahydrofuran and precursors thereof.

Methods of synthesis of substituted tetrahydrofuran compound

A method is provided for synthesizing diaryl-substituted heterocyclic compounds, particularly 2,5-diaryl-substituted tetrahydrofurans and tetrahydrothiophenes. Methods for synthesizing starting materials and intermediates are provided as well. An important application of the invention is in the synthesis of CMI-392, (&plusmn;)trans-2-&lsqb;5-N&prime;-methyl-N&prime;-hydroxyureidyl-methyl)3-methoxy-4-p-chlorophenylthioethoxyphenyl&rsqb;-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran, a highly effective agent in treating inflammatory and immune disorders. The invention also encompasses novel compounds useful as starting materials and intermediates in the synthetic processes disclosed.

Method for synthesizing diaryl-substituted heterocyclic compounds, including tetrahydrofurans

The invention includes inter alia new methods for preparation of the pharmaceutically active compound 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran and precursors thereof.

Methods for synthesis of substituted tetrahydrofuran compound

The invention provides new methods for preparation of cyclic oxygen compounds, including 2,5-disubstituted tetahydrofurans, 2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and 2,8-oxocanes. The invention also provides new cyclic oxygen compounds and pharmaceutical compositions and therapeutic methods that comprise such compounds.

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Natick, MA, United States of America

Sunil Vyankatesh Mhaskar