Intra-cellular Therapies, Inc.

Sandoz Pharm. Corp.

Sandoz Gmbh

John Charles Tomesch

Lawrence P Wennogle

Qiang Zhang

Peng Li

Andrew S Thompson

Wei Yao

James David Beard

Hua Cheng

Youyi Peng

Robert E Davis

Sharon Mates

William J Houlihan

J David Beard

Mahavir Prashad

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 present invention provides methods for the preparation of substituted heterocycle fused gamma-carbolines, such as 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: 

Hydrochloric acid salt of (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4&#x2032;:4,5]pyrrolo[1,2,3-de]quinoxaline

The present invention relates to toluenesulfonic acid addition salt crystals of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4&#x2032;: 4,5]pyrrolo[1,2,3 -de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone, and methods of using such crystals as 5-hydroxytryptamine 2 receptor agonists and antagonists in treating disorders of the central nervous system.

4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4&#x2032;:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid salt crystal forms

The present invention provides methods for the preparation of certain optionally substituted heterocycle fused gamma-carbolines of Formula 2F, as shown below and as further defined herein: 

Preparation of certain substituted 1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalines and pharmaceutically acceptable salts thereof

The present invention provides methods for the preparation of certain optionally substituted heterocycle fused gamma-carbolines of Formula 2J, as shown below and as further defined herein: 

Preparation of certain substituted 1-(4-fluorophenyl)-4-(2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4&#x2032;:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-YL)butan-1-ones and pharmaceutically acceptable salts thereof

The present invention provides pharmaceutical compositions comprising certain optionally substituted heterocycle fused gamma-carbolines of Formula 2J, as shown below, and as further defined herein: 

Pharmaceutical compositions comprising ((6bR,10aS)-1-(4-fluorophenyl)-4-(3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4&#x2032;:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)butan-1-one or pharmaceutically acceptable salts thereof

The present invention provides methods for the preparation of substituted heterocycle fused gamma-carbolines of Formula 2F, as shown below, intermediates useful in producing them and methods for producing such intermediates and such heterocycle fused gamma-carbolines, such methods comprising the preparation of a Compound of Formula 2F, as shown below and as further defined herein: 

Preparation of certain substituted [((6bR,10aS)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4&#x2032;:4,5]pyrrolo[1,2,3-de]quinoxalines and pharmaceutically acceptable salts thereof

The invention provides novel compounds, composition comprising said compounds and methods for inhibiting CK1 as well as methods of treating CK1 related disorders such as Alzheimer's disease comprising administering a therapeutically effective amount of a CK1 inhibitor to a patient in need thereof.

Organic compounds

The present invention provides methods for the preparation of substituted heterocycle fused gamma-carbolines of Formula 2J, as shown below, intermediates useful in producing them and methods for producing such intermediates and such heterocycle fused gamma-carbolines, such methods comprising the preparation of a Compound of Formula 2G, as shown below, and use of said compound to produce the fused gamma-carbolines of Formula 2J, as defined herein: 

Preparation of certain [((6BR,10AS)-2,3,6B,7,8,9,10, 10A-octahydro-1H-pyrido[3',4&#x2032;:4,5]pyrrolo [1,2,3-de]quinoxalines and pharmaceutically acceptable salts thereof

The invention relates to compounds and methods of treatment relating to nicotinic receptor antagonists. For example, the compounds and methods of treatment function block the activity of certain acetylcholine receptors and subtypes therein, and are useful treating diseases and conditions mediated by nicotinic receptor stimulation, e.g., small cell lung cancer.

The present invention relates to toluenesulfonic acid addition salt crystals of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4&#x2032;: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone, and methods of using such crystals as 5-hydroxytryptamine 2 receptor agonists and antagonists in treating disorders of the central nervous system.

4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4&#x2032;:4,5]pyrrolo[1,2,3-de] quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid salt crystal forms

It is an object of the present invention that the novel nicotinic receptor antagonists disclosed herein may be used in a broad array of clinical or medicinal facets. For example, it is a contemplated use of the present invention that the novel nicotinic receptor antagonists be used to inhibit the growth cycle of non-small cell lung cancer cells. Without being bound by theory, it is an object of the present invention that the nicotinic receptor antagonists disclosed herein are believed to possess reversible binding properties. Moreover, the compounds of the present invention are selective for 0.7 nAChR. For example, the compounds of the present invention are not believed to bind to 0.4 (32 nAChR neuromuscular receptors. It is also contemplated that the nicotinic receptor antagonists of the present invention will be used as a counter measure to treat exposure, or potential exposure, to a wide array of potential neurotoxins.

Compounds and methods of prophylaxis and treatment regarding nicotinic receptor antagonists

The invention relates to particular substituted heterocycle fused gamma-carbolines, of Formula I as described herein, 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 Dreceptor signaling systems, such as diseases of the central nervous system. 

Substituted pyrido[3',4&#x2032;:4,5]pyrrolo[1,2,3-de]quinoxalines for the treatment of nervous system disorders

The present invention provides methods for the preparation of 4-(3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3',4&#x2032;:4,5]-pyrrolo[1,2,3-de]quinoxalin-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone in free form or a salt thereof.

Preparation of 4-((6BR,10AS)-3-methyl-2,3,6B,9,10, 10A-hexahydro-1H-pyrido[3',4&#x2032;:4,5]pyrrolo [1,2,3-de]quinoxalin-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone or a pharmaceutically acceptable salt thereof

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Succasunna, NJ, United States of America

John Charles Tomesch