Massachusetts Institute of Technology

University of South Florida

Jon Clarence Antilla

Stephen L Buchwald

Artis Klapars

Gabriel E Job

Fuk Y Kwong

Gero Nordmann

Edward J Hennessy

Martina Wolter

Alison Elizabeth Willing

Javier Cuevas

Keith R Pennypacker

Pankaj Jain

Emily B Rowland

Michelle Cortes-Salva

Gerald B Rowland

Martina Uhlenbrock

Edward Hennessy

A method of treating stroke by administration of a novel sigma agonist is presented. Twenty-four hours after MCAO, systemic administration of several novel sigma agonists including: Bromo-DTG; Chloro-DTG; N,N'-di-1-Naphthylguanidine hydrochloride (NAGH); N,N&#x2032;-di-p-Nitrophenylguanidine HCL (NAD) or vehicle were injected subcutaneously daily for 3 days. Rats treated with Bromo-DTG and Chloro-DTG had no significant improvements in any of the motor or cognitive tests while NAGH treated rats showed improved vertical movement and had significantly less motor asymmetry and bias than vehicle treated rats. Sigma receptor agonist NAGH also was found to exert its long-term neuroprotective effects by preserving both gray matter and white matter tracts. Both NAD and NAGH, when administered 24 hours after experimental stroke, reduced neural damage and enhanced behavioral recovery thirty days later which suggests that NAGH and NAD potentially extend the therapeutic window of stroke several fold over the current treatments.

N,N'-di-1 naphthylguanidine HCl (NAGH) and N,N&#x2032;-di-p-nitrophenylguanidine HCl (NAD) treatment for stroke at delayed timepoints

The present invention relates to copper-catalyzed carbon-heteroatom and carbon-carbon bond-forming methods, such as the reaction of Z-X with C(L)(R)(R')in the present of a catalyst and a base, thereby forming C(Z)(R)(R&#x2032;); wherein X represents I, Cl, alkylsulfonate, or arylsulfonate; Z represents optionally substituted aryl, heteroaryl or alkenyl; L represents H or a negative charge; catalyst comprises a copper atom or ion, and a ligand, wherein the ligand is an optionally substituted aryl alcohol, alkyl amine, 1,2-diamine, 1,2-aminoalcohol, 1,2-diol, imidazolium carbene, pyridine, or 1,10-phenanthroline; the ligand is a chelating ligand; and the base represents a Bronsted base; R represents H, optionally substituted alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl; R&#x2032; represents independently for each occurrence H, alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl, formyl, acyl, &#x2014;COR&#x2033;, &#x2014;C(O)N(R), sulfonyl, &#x2014;P(O)(OR&#x2033;), &#x2014;CN, or &#x2014;NO; R&#x2033; represents independently for each occurrence optionally substituted alkyl, cycloalkyl, aralkyl, aryl, or heteroaryl; and C(R&#x2032;)(R) taken together may represent nitrile.

Copper-catalyzed formation of carbon-heteroatom and carbon&#x2014;carbon bonds

A method synthesizing homoallylic or homopropargylic alcohols was developed to react aldehydes with allyl boronates, such as allylboronic acid pinacol ester, or allenylborates in the presence of a catalytic amount of a chiral binaphthyl-derived chiral phosphoric acid. The method showed enhanced enantiocontrol and chemical yield, which increased with lower temperatures. A large series of aldehydes were tested under these catalytic conditions and wide successful substrate scope was found, including aryl, heteroaryl, aromatic aldehydes, heteroaryl aldehydes, &#x3b1;,&#x3b2;-unsaturated aldehydes and aliphatic aldehydes, and alkyl aldehydes. Likewise, the use of crotyl boronates (E and Z) were successfully reacted with aryl aldehydes under the conditions to allow for highly enantio- and diasteo-selective crotylation.

Br&#xf8;nsted acid-catalyzed asymmetric allylation and propargylation of aldehydes

A process for the preparation of a nucleophilic addition product of an aziridine and a nucleophile, the process comprising treating the arizidine with the nucleophile in the presence of a biaryl phosphoric acid catalyst.

Enantioselective ring-opening of aziridines

The present invention relates to copper-catalyzed carbon-heteroatom and carbon-carbon bond-forming methods. In certain embodiments, the present invention relates to copper-catalyzed methods of forming a carbon-nitrogen bond between the nitrogen atom of an amide or amine moiety and the activated carbon of an aryl, heteroaryl, or vinyl halide or sulfonate. In additional embodiments, the present invention relates to copper-catalyzed methods of forming a carbon-nitrogen bond between a nitrogen atom of an acyl hydrazine and the activated carbon of an aryl, heteroaryl, or vinyl halide or sulfonate. In other embodiments, the present invention relates to copper-catalyzed methods of forming a carbon-nitrogen bond between the nitrogen atom of a nitrogen-containing heteroaromatic, e.g., indole, pyrazole, and indazole, and the activated carbon of an aryl, heteroaryl, or vinyl halide or sulfonate. In certain embodiments, the present invention relates to copper-catalyzed methods of forming a carbon-oxygen bond between the oxygen atom of an alcohol and the activated carbon of an aryl, heteroaryl, or vinyl halide or sulfonate. The present invention also relates to copper-catalyzed methods of forming a carbon-carbon bond between a reactant comprising a nucleophilic carbon atom, e.g., an enolate or malonate anion, and the activated carbon of an aryl, heteroaryl, or vinyl halide or sulfonate. Importantly, all the methods of the present invention are relatively inexpensive to practice due to the low cost of the copper comprised by the catalysts.

Copper-catalyzed formation of carbon-heteroatom and carbon-carbon bonds

Growing community of inventors

Tampa, FL, United States of America

Jon Clarence Antilla