Intra-cellular Therapies, Inc.

The Rockefeller University

Lawrence P Wennogle

Peng Li

Robert E Davis

Sharon Mates

Qiang Zhang

Jun Zhao

John Charles Tomesch

Hailin Zheng

Allen Fienberg

Gretchen Snyder

Andrew S Thompson

Wei Yao

Kimberly Vanover

James David Beard

Hua Cheng

Joseph Hendrick

Youyi Peng

Jennifer O'Brien

Hailin Zeng

Robert Davis

Edwin Aret

Toru Hashimoto

Graham Buckton

Mark Hooper

David Kass

Paul Greengard

Yuhei Yamamoto

Takashi Abe

Hideaki Maruyama

Hironori Yamashita

Wenjie Luo

Gen He

Masahiro Takasuga

J David Beard

John Tomesch

Richard A Lerner

The disclosure provides methods for the acute treatment of depression and/or anxiety, for the enhancement of mTOR (e.g., mTORC1) signaling, and for the reduction of neuroinflammation, comprising administering to a patient in need thereof, a therapeutically effective amount of a 5-HT2A or 5-HT2A/D2 receptor ligand, e.g. lumateperone.

Methods of treating acute depression

The disclosure relates to the use of phosphodiesterase 1 (PDE1) inhibitors for the treatment of cancers and tumors, including for inhibiting tumor recruitment of macrophages and other cells to the tumor or cancer, for complementing and enhancing checkpoint inhibitor therapies, and for mitigating the side effects (i.e., inflammatory-related adverse events) associated with checkpoint inhibitor therapies.

Organic compounds

The disclosure provides new, stable, pharmaceutically acceptable hydrochloride salt forms of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H -pyrido[3',4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one, together with methods of making and using them, and pharmaceutical compositions comprising them.

Salts and crystals

This invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving 5-HTreceptor, serotonin transporter (SERT) and/or pathways involving dopamine D/Dreceptor signaling systems, and/or the treatment of residual symptoms.

The invention relates to pharmaceutical compositions comprising compounds of Formula Q: wherein W is —N(CH)—, and Y is —C(O)—, in free base or pharmaceutically acceptable salt form, and methods of use in the treatment of diseases involving 5-HTreceptor, serotonin transporter (SERT) pathway and/or the dopamine Dreceptor pathway, and methods of treating conditions of the central nervous system therewith.

Pharmaceutical compositions comprising 4-((6bR, 10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)butan-1-one for treating central nervous system disorders

The invention relates to pharmaceutical compositions comprising compounds of Formula Q: wherein W is —N(CH)—, and Y is —CH(OH)—, in free base or pharmaceutically acceptable salt form, and methods of use in the treatment of diseases involving 5-HTreceptor, serotonin transporter (SERT) pathway and/or the dopamine Dreceptor pathway, and methods of treating conditions of the central nervous system therewith.

Pharmaceutical compositions comprising 4-((6bR, 10aS)-3-methyl-2,3,6b,9,10, 10a-hexahydro-1H,7H-pyrido[3',4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluorophenyl)butan-1-ol for treating central nervous system disorders

The present invention provides methods for the preparation of substituted heterocycle fused gamma-carbolines, such as the compound of Formula 2J, as shown below, intermediates useful in producing them and methods for producing such intermediates and such heterocycle fused gamma-carbolines, and as further defined herein.

Process for preparing 1-(4-fluorophenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)butan-1-one

The disclosure provides methods for the acute treatment of depression and/or anxiety, for the enhancement of mTOR (e.g., mTORC1) signaling, and for the reduction of neuroinflammation, comprising administering to a patient in need thereof, a therapeutically effective amount of a 5-HT/mu-opioid receptor or 5-HT/D1 and/or D2/mu-opioid receptor ligand.

Methods

Methods of treating acute depression and/or acute anxiety

The present invention relates to use of particular substituted heterocycle fused gamma-carbolines as described herein, in free, pharmaceutically acceptable salt or prodrug form, and pharmaceutical composition comprising the same optionally in combination with one or more agents, for the prophylaxis or treatment of one or more disorders associated with dementia, particularly behavioral or mood disturbances (e.g., agitation/aggression), psychosis, depression and sleep disturbances among others in patients suffering from dementia.

Compounds and methods

The disclosure provides methods, treatments and materials for enhancing the effect of an adenosine Areceptor agonist in the treatment, mitigation or prophylaxis of a disease or condition characterized by inotropic and/or lusitropic dysfunction, and/or enhancing adenosine Areceptor function in the treatment, mitigation or prophylaxis of a disease or condition characterized by impaired adenosine Areceptor function, comprising administration of an effective amount of a PDE1 inhibitor to a patient in need thereof, for example a patient suffering from heart failure.

Methods for treating or mitigating cardiotoxicity characterized by inhibition of adenosine Asignaling and/or adenosine Areceptor expression

Uses

The invention relates to pharmaceutical compositions comprising, compounds of Formula Q: wherein W is &#x2014;N(H)&#x2014;, or &#x2014;N(CH)&#x2014;, and Y is &#x2014;C(&#x2550;O)&#x2014; or &#x2014;O&#x2014;, in free base or pharmaceutically acceptable salt form, and methods of use in the treatment of diseases involving 5-HTreceptor, serotonin transporter (SERT) pathway and/or the dopamine Dreceptor pathway, and methods of treating conditions of the central nervous system therewith.

Pharmaceutical compositions comprising 4-(6Br,10aS)-3-methyl-2, 3, 6b, 9, 10, 10a-hexahydro-1H, 7H-pyrido[3', 4&#x2032;, 5] pyrolo[1,2,3-de] quinoxalin-8YL)-1-(4-fluorophenyl)-butane-1-one and methods of treating conditions of the central nervous system

The subject matter generally relates to methods of treatment and/or prophylaxis of CNS diseases, disorders, and/or injuries. In one aspect, the subject matter relates to inhibitors of phosphodiesterase 1 (PDE1) as neuroprotective agents and/or neural regenerative agents. In a further aspect, the subject matter relates to individuals that are at risk for the development of CNS disease or disorder.

Growing community of inventors

Hillsborough, NJ, United States of America

Lawrence P Wennogle