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KDM1A INHIBITORS FOR THE TREATMENT OF DISEASE

Disclosed herein are new compounds and compositions and their application as pharmaceuticals for the treatment of diseases. Methods of inhibition of KDM1A, methods of increasing gamma globin gene expression, and methods to induce differentiation of cancer cells in a human or animal subject are also provided for the treatment of diseases such as acute myelogenous leukemia.

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NOVEL INHIBITOR COMPOUNDS OF PHOSPHODIESTERASE TYPE 10A

The present invention relates to compounds of the formula I, the N-oxides, tautomers, the prodrugs and the pharmaceutically acceptable salts thereof: In formula I the variablesHet, A, X, Y, Z, Rl, R2, R3, R4, R5 andQ are as defined in the claims. The compounds of the formula I, the N-oxides, tautomers, the prodrugs and the pharmaceutically acceptable salts thereof are inhibitors of phosphodiesterase type 10A. Thus, theinvention also relates to the use of the compounds of the formula I, the N-oxides, tautomers, the prodrugs and the pharmaceutically acceptable salts thereof for the manufacture of a medicament and which thus are suitable for treating or controlling of medical disorders selected from neurological disorders and psychiatric disorders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders.

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Design, synthesis, biological properties, and molecular modeling investigations of novel tacrine derivatives with a combination of acetylcholinesterase inhibition and cannabinoid CB1 receptor antagonism

Pyrazolines 7-10 were designed as novel CB1 receptor antagonists, which exhibited improved turbidimetric aqueous solubilities. On the basis of their extended CB1 antagonist pharmacophore, hybrid molecules exhibiting cannabinoid CB1 receptor antagonistic as well as acetylcholinesterase (AChE) inhibiting activities were designed. The target compounds 12, 13, 20, and 21 are based on 1 (tacrine) as the AChE inhibitor (AChEI) pharmacophore and two different CB1 antagonistic pharmacophores. The imidazole-based 20 showed high CB1 receptor affinity (48 nM) in combination with high CB1/CB2 receptor subtype selectivity (>20-fold) and elicited equipotent AChE inhibitory activity as 1. Molecular modeling studies revealed the presence of a binding pocket in the AChE enzyme which nicely accommodates the CB1 pharmacophores of the target compounds 12, 13, 20, and 21. 2010 American Chemical Society.

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SULFINYLAMINOBENZAMIDE AND SULFONYLAMINOBENZAMIDE DERIVATIVES

Provided is a compound of Formula (I): wherein the variable groups are defined herein.

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ARYL COMPOUNDS WITH AMINOALKYL SUBSTITUENTS AND THEIR USE

The present application relates to novel aryl compounds with aminoalkyl substituents, to processes for their preparation, to their use for treatment and/or prevention of diseases and to their use for the preparation of medicaments for treatment and/or prevention of diseases, in particular for treatment and or prevention of hyperproliferative and angiogenic diseases and those diseases which arise from metabolic adaptation to hypoxic states. Such treatments can be carried out as monotherapy or also in combination with other medicaments or further therapeutic measures.

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4-(3-Chloro-4-methoxybenzyl)aminophthalazines: Synthesis and inhibitory activity toward phosphodiesterase 5

We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1-and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2alpha (10-5 M). The preferred substituents at the 1-position of the phthalazine were 4- hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4:(3,chloro-4- methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthalazinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC50 = 0.56 nM) with > 1700-fold high selectivity over other PDE isozymes (PDE 1-4). Compound 13 exhibited the most potent vasorelaxant action (EC50 = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 ¡À 3.1% when administered intravenously at 30 mug/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.

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Pharmaceutical compositions (by machine translation)

[Problem] imidazole compound or its pharmacologically acceptable salt in the melanocortin receptor activity that operates as an active ingredient of a pharmaceutical composition comprising. “I” general formula [a]” Formula, the aryl group may be substituted A ring represents a; R1 Represents a hydrogen atom, or an alkyl group which may be substituted represented; R2 Represents a hydrogen atom, a halogen atom or represents a; R3 The alkyl group may be substituted ” represented by the imidazole compound, its pharmacologically acceptable salt as an active ingredient in a pharmaceutical composition. [Drawing] no (by machine translation)

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6H-THIENO 2,3-B PYRROLE DERIVATIVES AS ANTAGONISTS OF GONADOTROPIN RELEASING HORMONE (GNRH)

The invention relates to a group of novel thieno-pyrrole compounds of Formula (I): wherein: R1, R2, R3, R4 and R5 are as defined in the specification, which are useful as gonadotrophin releasing hormone antagonists. The invention also relates to pharmaceutical formulations of said compounds, methods of treatment using said compounds and to processes for the preparation of said compounds.

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N-PHENYL-3-QUINAZOLIN-6-YL-BENZAMIDE DERIVATIVES AS P38 KINASE INHIBITORS

There are provided compounds of formula I, wherein R1A to R1E, R2, R3, R4A to R4C, L and X have meanings given in the description, which compounds have antiinflammatory activity (e.g. through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes; Syk kinase; and members of the Src family of tyrosine kinases) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

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4,5-DIHYDRO-1H-PYRAZOLE DERIVATIVE OR SALTS THEREOF, AND PHARMACEUTICAL COMPOSITION COMPRISING SAME

The present invention provides a 4,5-dihydro-1H-pyrazole derivative or its pharmaceutically acceptable salt, a process for the preparation thereof, and a pharmaceutical composition comprising the same. The 4,5-dihydro-1H-pyrazole derivative or its pharmaceutically acceptable salt effectively increases the LXR transcriptional activity, and therefore can be usefully applied for preventing or treating a dysfunction in cholesterol metabolism, such as cholesterol gallstone, hyperlipidemia, or coronary atherosclerosis.

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