Isis Pharmaceuticals, Inc.

Arena Pharmaceuticals, Inc.

Center for Neurologic Study

Tonix Pharma Holdings Limited (Bermuda)

Andrew Mamoru Kawasaki

Phillip Dan Cook

Muthiah Manoharan

Thazha P Prakash

Pei Pei Kung

Charles John Guinosso

Allister S Fraser

Thomas W Bruice

Richard Holmes Griffey

Robert M Jones

Michael E Jung

Daniel J Buzard

Sun Hee Kim

Xiuwen Zhu

Juerg Lehmann

P Dan Cook

Lars Thoresen

David J Ecker

Seth Lederman

Brett Ullman

Oscar L Acevedo

Venkatraman Mohan

Kandasamy Ramasamy

Richard Alan Smith

Philip D Cook

Jeanne V Moody

Darryl C Rideout

Pei-Pei Kung

Leland J Gershell

Kathleen Myers

Darryl Rideout

Bruce Daugherty

Substituted analogs of dextromethorphan (DM) are disclosed, which are shown to have substantial binding affinity at both NMDA and sigma-1 receptors, and which are degraded by human liver enzymes more slowly than dextromethorphan. The analogs are useful as alternatives to dextromethorphan, and can provide the same benefits without requiring co-administration of a cytochrome P-450 enzyme inhibitor.

Analogs of dextromethorphan with balanced receptor activities

The invention relates to a purified Isometheptene compound comprising the structure according to Formula (I), or a hydrochloride, or a pharmaceutically acceptable addition salt thereof. In particular, the disclosure relates to the synthesis, purification and characterization of an Isometheptene isomer mucate crystal 2, wherein the Isometheptene isomer 2 is stereochemically characterized as (R)-enantiomer, respectively. The Isometheptene (R)-enantiomer activity indicates a selective centrally acting selective ligand for Imidazoline subtype 1 (I1) receptor sites; and more specifically, the disclosure provides an antihypertensive composition for treatment of migraine and other neurovascular or neurogenic pain from abdominal distress. (R)-Isometheptene enantiomer or isomer 2 may be an anti-hypertensive agent with lower side effects than the racemate form. Therefore (R)-Isometheptene is believed to be effective against episodic tension-type headaches (ETTH). The (R)-Isometheptene enantiomer or isomer 2 is believed to effectively lower blood pressure, used alone or together with other headache ameliorating drugs. Methods of synthesis and treatment are described. Regarding (R)-Isometheptene crystals data of X-ray crystallography are presented.

Isometheptene isomer

The present invention relates to certain substituted tricyclic acid derivatives of Formula (I) and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists of the S1P1 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of S1P1 -associated disorders, for example, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, acne, myocardial ischemia-reperfusion injury, hypertensive nephropathy, glomerulosclerosis, gastritis, polymyositis, thyroiditis, vitiligo, hepatitis, biliary cirrhosis, microbial infections and associated diseases, viral infections and associated diseases, diseases and disorders mediated by lymphocytes, auto immune diseases, inflammatory diseases, and cancer.

Substituted tricyclic acid derivatives as S1P1 receptor agonists useful in the treatment of autoimmune and inflammatory disorders

The present invention relates to certain substituted tricyclic acid derivatives of Formula (I) and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists of the S1P1 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of S1P1-associated disorders, for example, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, acne, myocardial ischemia-reperfusion injury, hypertensive nephropathy, glomerulosclerosis, gastritis, polymyositis, thyroiditis, vitiligo, hepatitis, biliary cirrhosis, microbial infections and associated diseases, viral infections and associated diseases, diseases and disorders mediated by lymphocytes, auto immune diseases, inflammatory diseases, and cancer. 

Compositions and methods are provided for the treatment and diagnosis of diseases amenable to modulation of the production of selected proteins. In accordance with preferred embodiments, oligonucleotides and oligonucleotide analogs are provided which are specifically hybridizable with a selected sequence of RNA or DNA wherein at least one of the 2'-deoxyfuranosyl moieties of the nucleoside unit is modified. Treatment of diseases caused by various viruses and other causative agents is provided.

Sugar modified oligonucleotides

Modified oligonucleotides containing both A-form conformation geometry and B-from conformation geometry nucleotides are disclosed. The B-form geometry allows the oligonucleotide to serve as substrates for RNase H when bound to a target nucleic acid strand. The A-form geometry imparts properties to the oligonucleotide that modulate binding affinity and nuclease resistance. By utilizing C2' endo sugars or O4&#x2032; endo sugars, the B-form characteristics are imparted to a portion of the oligonucleotide. The A-form characteristics are imparted via use of either 2&#x2032;-O-modified nucleotides that have 3&#x2032; endo geometries or use of end caps having particular nuclease stability or by use of both of these in conjunction with each other.

Oligonucleotides having A-DNA form and B-DNA form conformational geometry

Compositions comprising novel di-nitrogen heterocycle compounds containing at least one N-meta-substituted alkaryl group are prepared. The compounds of the present invention are useful as antibacterial and as other pharmaceutical agents and as intermediates for preparation of other pharmaceutical agents. In addition, compounds of the present invention are useful as research reagents.

Di-nitrogen heterocycle compositions

Nucleosidic monomers and oligomeric compounds prepared therefrom are provided which have increased nuclease resistance, substituent groups (such as 2&prime;-aminooxy groups) for increasing binding affinity to complementary strand, and regions of 2&prime;-deoxy-erythro-pentofuranosyl nucleotides that activate RNase H. Such oligomeric compounds are useful for diagnostics and other research purposes, for modulating the expression of a protein in organisms, and for the diagnosis, detection and treatment of other conditions susceptible to oligonucleotide therapeutics.

Aminooxy-modified nucleosidic compounds and oligomeric compounds prepared therefrom

Methods for the regioselective alkylation at the 2&prime;-hydroxy position over the 3&prime;-hydroxy position of nucleosides and nucleoside analogs, forming 2&prime;-O-ester modified compounds, are disclosed. Reduction and derivatization of the 2&prime;-O-ester provides 2&prime;-O-modified nucleosides and nucleoside analogs useful for the synthesis of oligomeric compounds having improved hybridization affinity and nuclease resistance.

Regioselective synthesis of 2&prime;-O-modified nucleosides

Compositions and methods for modulating the activity of RNA are disclosed. In accordance with preferred embodiments, antisense compositions are prepared comprising targeting and reactive portions. The reactive portions preferably comprise one or two imidazole functionalities conjugated to the targeting oligonucleotide via linkers with or without intervening intercalating moieties. Therapeutics, diagnostics and research methods also are disclosed, as are synthetic nucleosides and nucleoside fragments that can be elaborated into oligonucleotides.

Compositions and methods for modulating RNA

Compositions and methods are provided for the treatment and diagnosis of diseases amenable to modulation of the production of selected proteins. In accordance with preferred embodiments, oligonucleotides and oligonucleotide analogs are provided which are specifically hybridizable with a selected sequence of RNA or DNA wherein at least one of the 2&prime;-deoxyfuranosyl moieties of the nucleoside unit is modified. Treatment of diseases caused by various viruses and other causative agents is provided.

2'modified oligonucleotides

Compositions and methods for modulating the activity of RNA are disclosed, In accordance with preferred embodiments, antisense compositions are prepared targeting reactive portions. The reactive portions preferably comprise one or two imidazole functionalities conjugated to the targeting oligonucleotide via linkers with or without intervening intercalating moieties. Therapeutics, diagnostics and research methods also are disclosed, as are synthetic nucleosides and nucleoside fragments that can be elaborated into oligonucleotides.

Compositions and methods are provided for the treatment and diagnosis of diseases amenable to modulation of the production of selected proteins. In accordance with preferred embodiments, oligonucleotides and oligonucleotide analogs are provided which are specifically hybridizable with a selected sequence of RNA or DNA wherein at least one of the 2&prime;-deoxyfuranosyl moieties of the nucleoside unit is modified. Treatment of HIV, herpes virus, papillomavirus and other infections is provided.

Sugar modified oligonucleotides that detect and modulate gene expression

Methods for the alkylation of alcohols, amines and thiols by the use of cyclic sulfates are disclosed. The alkylated sulfates formed are versatile intermediates which may be further elaborated by methods of the invention. In particular, methods for the alkylation of the 2&prime;, 3&prime; or 5&prime;-hydroxy position of nucleosides and nucleoside analogs with cyclic sulfates to form the 2&prime;, 3&prime; or 5&prime;-O-alkyl sulfate modified compounds are disclosed. Displacement of the 2&prime;,3&prime; or 5&prime;-O-sulfate with a nucleophile provides 2&prime;, 3&prime; or 5&prime;-O-modified nucleosides and nucleoside analogs useful for the synthesis of oligomeric compounds having improved hybridization affinity and nuclease resistance.

Growing community of inventors

Oceanside, CA, United States of America

Andrew Mamoru Kawasaki