Neurogen Corporation

The United States of America, as Represented by the Secretary, Department of Health and Human Services

Georgetown University

Novartis International Pharmaceutical, Ltd.

Yang Gao

He Zhao

Andrew Y Thurkauf

Terrence R Burke, Jr

Linghong Xie

Bingsong Han

George D Maynard

Bertrand Leo Chenard

Wallace C Pringle

Zhu-jun Yao

Suoming Zhang

John M Peterson

Taeyoung Yoon

Dajun Yang

Yuelian Xu

Ping Ge

Joseph W Ochterski

Chang-Qing Wei

Alan J Hutchison

Scott A Mitchell

Kenneth Shaw

Jiong Lan

George P Luke

Johannes H Voigt

Donald P Bottaro

Timothy M Caldwell

Alan J Hutchinson

Zhen-Dan Shi

Robert Ohliger

Xiao Shu He

Diane E Breckenridge

Safiye N Atabey

Jesus V Soriano

LuYan Zhang

Andrew Thrukauf

The invention provides packaged pharmaceutical preparations of Aryl substituted imidazoles, pyrazoles, pyridizines and related compounds of the Formula where the variables are defined herein. Such compounds are ligands of C5a receptors. Preferred compounds of the invention act bind to C5a receptors with high affinity and exhibit neutral antagonist or inverse agonist activity at C5a receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating a variety of inflammatory and immune system disorders.

Aryl imidazoles and related compounds as C5a receptor modulators

Amino methyl imidazoles of Formula I are provided: wherein R, R, R, R, R, R, and Rare defined herein. Such compounds are ligands of C5a receptors. Preferred compounds of Formula I bind to C5a receptors with high affinity and exhibit neutral antagonist or inverse agonist activity at C5a receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating a variety of inflammatory, cardiovascular, and immune system disorders. Additionally, this invention provides labeled amino methyl imidazoles compounds, which are useful as probes for the localization of C5a receptors.

Amino methyl imidazoles and related compounds as C5a receptor modulators

Dipiperazinyl ketones and related analogues are provided, as are methods for their preparation and use. Such compounds may generally be used to modulate ligand binding to histamine H3 receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of disorders in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and therapeutic methods are provided, as are methods for using such ligands for detecting histamine H3 receptors (e.g., receptor localization studies).

Dipiperazinyl ketones and related analogues

The present invention provides phenylalanine derivatives that inhibit SH2 domain binding with a phosphoprotein. These derivatives include compounds of the formula: W&#x2014;Y-(AA)-Z wherein n is 0 to 15; Y is a phenylalanyl radical having a phenyl ring, an amine end, and a carboxyl end, the phenyl ring having one or more substituents, e.g., hydroxyl, carboxyl, formyl, carboxyalkyl, carboxyalkyloxy, dicarboxyalkyl, dicarboxyalkyloxy, dicarboxyhaloalkyl, dicarboxyhaloalkyloxy, and phosphonoalkyl, or phosphonohaloalkyl; W is a moiety attached to the nitrogen of Y and is, e.g., alkylcarbonyl, oxalyl, alkylaminooxalyl, arylaminooxalyl, arylalkylaminooxalyl, or alkoxyoxalyl; AA is an amino acid, the amine end of which is attached to the carboxyl end of Y; and Z is an arylalkylamino or arylheterocyclyl alkylamino; or a salt thereof; with the proviso that W is not arylalkylamino when the phenyl ring of phenylalanyl contains a phosphonoalkyl or phosphonohaloalkyl substituent at a position para to the alkylamido group and the ortho and meta positions are unsubstituted. The present invention further provides precursors suitable for preparing the phenylalanine derivatives and a method for the preparation of the precursors. The present invention further provides conjugates comprising a precursor and a conjugant that are covalently linked. These conjugates have biological and/or pharmacological properties. 

Phenylanine derivatives

Piperazinyl oxoalkyl tetrahydroisoquinolines and related analogues of the Formula: are provided, in which variables are as described herein. Such compounds may be used to modulate ligand binding to histamine H3 receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) and other disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting histamine H3 receptors (e.g., receptor localization studies).

Piperazinyl oxoalkyl tetrahydroisoquinolines and related analogues

Thiazole amides, imidazole amides and related analogues of the Formula: are provided, in which variables are as described herein. Such compounds may be used to modulate ligand binding to histamine H3 receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) and other disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting histamine H3 receptors (e.g., receptor localization studies).

Thiazole amides, imidazole amides and related analogues

Disclosed are compounds for SH2 domain binding inhibition, for example, a compound of formula (I), wherein Ris a lipophile; R, in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group; Ris hydrogen, azido, amino, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, or alkylcarbonylamino, wherein the alkyl portion of Rmay be optionally substituted with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, alkyl, alkoxy, and keto; Ris a linker; AA is an amino acid; and n is 1 to 6; or a salt thereof. The conformationally compounds provide enhanced binding affinity with SH2 domain protein. Also disclosed are a pharmaceutical compositions and a method for inhibiting an SH2 domain from binding with a phosphoprotein.

SH2 domain binding inhibitors

Substituted biaryl amides of Formula I are provided. Such compounds are ligands that may be used to modulate Creceptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological Creceptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies 

Substituted biaryl amides C5a receptor modulators

Compounds of Formula I are provided, as are methods for their preparation. The variables Z, Z, Z, R, R, R, R, Rand Ar in the above formula are defined herein. Such compounds may be used to modulate ligand binding to GABAreceptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting GABAreceptors (e.g., receptor localization studies).

Imidazo-pyrimidines and triazolo-pyrimidines: benzodiazepine receptor ligands

Disclosed herein are phenylalanine derivative compounds of the following formulaW&#x2014;Y&#x2014;(AA)&#x2014;Zwherein Y is a phenylalanyl radical, AA is an amino acid, n is an integer of 1 to 15, and substituent variables W and Z are as described herein. The compounds can be used to inhibit SH2 binding with phosphoproteins, and to inhibit proliferation of tumor cells.

Phenylalanine derivatives

The invention provides Aryl substituted imidazoles, pyrazoles, pyridizines and related compounds of the Formula where the variables are defined herein. Such compounds are ligands of C5a receptors. Preferred compounds of the invention act bind to C5a receptors with high affinity and exhibit neutral antagonist or inverse agonist activity at C5a receptos. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating a variety of inflammatory and immune system disorders.

Amino methyl imidazoles as C5a receptor modulators

Substituted biaryl amides of Formula I are provided. Such compounds are ligands that may be used to modulate C5a receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological C5a receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies 

Substituted biaryl amides as C5A receptor modulators

Disclosed are methods of inhibiting cell motility, for example, by inhibiting the binding between an intracellular transducer and a receptor protein tyrosine kinase, and more particularly by inhibiting hepatocyte growth factor (HGF) induced cell motility. The present invention also provides a method of inhibiting angiogenesis. The methods of the present invention employ peptides such as phosphotyrosyl mimetics. The present invention further provides methods of preventing and/or treating diseases, disorders, states, or conditions such as cancer, particularly metastatic cancer comprising administering to a mammal of interest one or more peptides of the present invention. Also disclosed are methods of blocking HGF, VEGF, or bFGF-stimulated migration, cell proliferation, and formation of capillary-like structures 

Inhibition of cell motility and angiogenesis by inhibitors of Grb2-SH2-domain

Disclosed are compounds for SH2 domain binding inhibition. For example, disclosed is a compound of formula (I)wherein Ris a lipophile; R, in combination with the phenyl ring, forms a phenylphosphate mimic group or a protected phenylphosphate mimic group; Ris hydrogen, azido, amino, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, or alkylcarbonylamino, wherein the alkyl portion of Rmay be optionally substituted with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, alkyl, alkoxy, and keto; Ris a linker; AA is an amino acid; and n is 1 to 6; or a salt thereof. Also disclosed are a pharmaceutical composition, a method for inhibiting an SH2 domain from binding with a phosphoprotein and a method of treating breast cancer.

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Branford, CT, United States of America

Yang Gao