Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

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
View PDF0 Cites 43 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

These compounds effectively modulate histamine H3 receptor activity, enhancing wakefulness, cognitive function, and reducing food intake while minimizing peripheral side effects, offering improved treatments for neurological and metabolic disorders.

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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)+

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
temperatureaaaaaaaaaa
temperatureaaaaaaaaaa
temperatureaaaaaaaaaa
Login to View More

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com