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Histamine H3 Receptor Agents, Preparation and Therapeutic Uses

a technology of histamine h3 receptor and histamine, applied in the field of new drugs, can solve the problems of poor blood-brain barrier penetration of imidazole-containing compounds, unsatisfactory side effects, and hepatic and ocular toxicities, and achieve selective and high affinity binding.

Inactive Publication Date: 2010-02-04
FINLEY DON RICHARD +5
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0003]The histamine H3 receptor is relatively neuron specific and inhibits the release of a number of monoamines, including histamine. The histamine H3 receptor is a presynaptic autoreceptor and hetero-receptor located both in the central and the peripheral nervous system. The histamine H3 receptor regulates the release of histamine and other neurotransmitters, such as serotonin and acetylcholine. These are examples of histamine H3 receptor mediated responses. Recent evidence suggests that the H3 receptor shows intrinsic, constitutive activity, in vitro as well as in vivo (i.e. it is active in the absence of an agonist). Compounds acting as inverse agonists can inhibit this activity. A histamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of H3 receptor-regulated neurotransmitters in the brain. A histamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis of histamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists, and antagonists could be important mediators of neuronal activity, and the activities of other cells that may express this receptor. Inverse agonism or selective antagonism of the histamine H3 receptor raises brain levels of histamine, and other monoamines, and inhibits activities such as food consumption while minimizing non-specific peripheral consequences. By this mechanism, H3R inverse agonists or antagonists induce a prolonged wakefulness, improved cognitive function, reduction in food intake, and normalization of vestibular reflexes. Accordingly, the histamine H3 receptor is an important target for new therapeutics in Alzheimer's disease, mood and attention adjustments, cognitive deficiencies, obesity, dizziness, schizophrenia, epilepsy, sleeping disorders, narcolepsy, and motion sickness.

Problems solved by technology

Activation or inhibition of this receptor could result in undesirable side effects when targeting antagonism of the H3R receptor.
These imidazole-containing compounds have the disadvantage of poor blood-brain barrier penetration, interaction with cytochrome P-450 proteins, and hepatic and ocular toxicities.

Method used

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  • Histamine H3 Receptor Agents, Preparation and Therapeutic Uses
  • Histamine H3 Receptor Agents, Preparation and Therapeutic Uses
  • Histamine H3 Receptor Agents, Preparation and Therapeutic Uses

Examples

Experimental program
Comparison scheme
Effect test

internediate preparation 1

2.(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine

[0143]

[0144](S) BOC proline (CAS 15761-39-4) and 2-(R)Methyl-pyrrolidine hydrochloride (CAS 135324-85-5) are coupled in a manner substantially analogous to General Procedure D in dichloromethane to give 2(S)-(2(R)-Methyl-pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester(233179). The material is deprotected by stirring in dichloromethane at 5-10° C. while trifluoroacetic acid (10 eq,) is added and then stirred at room temperature for 18 hours. Reaction is concentrated and dissolved in H2O. The pH is adjusted to 8-9 with K2CO3, and the aqueous layer is extracted several times with CH2Cl2. The extracts are combined, dried (Na2SO4) and concentrated in vacuo to give (2(R)-Methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone. A 1 M Lithium Aluminum Hydride / THF solution (3 eq.) is diluted with an equal volume of THF and stirred under N2. A THF solution of (2(R)-methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone is added dr...

example 1

S-[4-(2(S)-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl)-thiophene-2-carbonitrile

[0209]

[0210]The title compound is prepared in a manner substantially analogous to General Procedure D in 100 mL 10% DMF / dichloromethane using 4(5-cyano-thiophen-2-yl)-benzoic acid (CAS 402765-55-9)(2.75 g, 12.0 mmol), EDC—HCl (3.44 g, 18.0 mmol), HOBt (2.43 g, 18.0 mmol), DIEA (5.22 mL, 30 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.54 g, 10.0 mmol) to give the title compound (2.33 g, 64% yield). MS (ES+) 366.2 (M+H)+

example 2

5-{4-[2-(2(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-phenyl}-thiophene-2-carbonitrile

[0211]

[0212]The title compound is prepared in a manner substantially analogous to General Procedure D in 10 mL 10% DMF / dichloromethane using 4-(5-cyano-thiophen-2-yl)-benzoic acid (CAS 402765-55-9)(360 mg, 1.57 mmol), EDC—HCl (451 mg, 2.36 mmol), HOBt (319 mg, 2.36 mmol), DIEA (1.14 mL, 6.5 mmol) and 2-(R)Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine di HCl(314 mg, 1.31 mmol) to give the title compound (60 mg, 13% yield). MS (ES+) 380.3 (M+H)+

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Abstract

The present invention provides a novel compound of Formula (I) or a pharmaceutically acceptable salt thereof, having histamine-113 receptor antagonist or inverse agonist activity, as well as methods for preparing such compounds. In another, embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula (I) as well as methods of using them to treat obesity, cognitive deficiencies, narcolepsy, and other histamine H3 receptor-related diseases.

Description

[0001]This patent application claims the benefit of U.S. Provisional Patent Application No. 60 / 603,628 filed Aug. 23, 2004.[0002]The present invention relates to novel heteroaromatic aryl compounds, and to the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions comprising the compounds, to methods of treatment employing these compounds and compositions, and to intermediates and methods for making these compounds.[0003]The histamine H3 receptor is relatively neuron specific and inhibits the release of a number of monoamines, including histamine. The histamine H3 receptor is a presynaptic autoreceptor and hetero-receptor located both in the central and the peripheral nervous system. The histamine H3 receptor regulates the release of histamine and other neurotransmitters, such as serotonin and acetylcholine. These are examples of histamine H3 receptor mediated responses. Recent evidence suggests that the H3 receptor shows intrinsic, constitutive activi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/397A61K31/4025A61K31/421A61K31/4436A61K31/426A61K31/4439A61K31/428A61K31/433A61K31/454A61P25/00
CPCC07D207/327C07D401/14C07D403/10C07D405/10C07D417/14C07D409/14C07D413/14C07D417/10C07D409/10A61P25/00A61P3/04A61P43/00
Inventor FINLEY, DON RICHARDFINN, TERRY PATRICKHIPSKIND, PHILIP ARTHURHORNBACK, WILLIAM JOSEPHJESUDASON, CYNTHIA DARSHINITAKAKUWA, TAKAKO
Owner FINLEY DON RICHARD
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