Proline sulfonamide derivatives as orexin receptor antagonists

A technology of amide and appetite, applied in the field of formula-proline sulfonamide compound, preventing or treating diseases or diseases related to the orexin system, and can solve problems such as the use of undisclosed compounds

Active Publication Date: 2013-05-01
IDORSIA PHARM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the use of these compounds has not been disclosed in the prior art

Method used

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  • Proline sulfonamide derivatives as orexin receptor antagonists
  • Proline sulfonamide derivatives as orexin receptor antagonists
  • Proline sulfonamide derivatives as orexin receptor antagonists

Examples

Experimental program
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preparation example Construction

[0233] Preparation of compounds of formula (I) can alternatively be carried out as depicted in Scheme 2, starting with Boc-L-proline (7), which is dissolved in a solvent such as DCM or MeCN, followed by addition of base (such as NEt 3 or DIPEA or N-methylmorpholine), activator ethyl chloroformate and aniline derivatives 5. Pure Boc-protected L-prolineaniline 8 can be isolated after aqueous work-up and chromatographic purification. Compound 9 was obtained by treating compound 8 with 4M HCl in dioxane (1,4-dioxane) at room temperature. Final compound 10 was prepared by reacting precursor 9 with sulfonyl chloride 2 in a solvent such as MeCN or DCM in the presence of a base such as DIPEA or N-methylmorpholine at room temperature, followed by aqueous work-up and purification.

[0234] Experimental part:

[0235] Abbreviations (as used here and in the specification above):

[0236] aq. Aqueous solution / water-based

[0237] BSA bovine serum albumin

[0238] CC silica gel column...

example

[0285] The example compounds listed in Table 1 below have been prepared according to Method A or B above using appropriate commercially available amine and sulfonyl chloride derivatives as starting materials.

[0286] To further characterize these compounds, antagonistic activity at two orexin receptors has been determined for each of the example compounds using the following procedure:

[0287] In Vitro Assay: Intracellular Calcium Measurement:

[0288] Chinese hamster ovary (CHO) cells expressing human orexin-1 receptor and human orexin-2 receptor were treated with 300 μg / ml G418, 100 U / ml penicillin, 100 μg / ml streptomycin and 10% heat-inactivated fetal calf serum (FCS) medium (Ham F-12 and L-glutamine) growth. Cells were seeded at 20,000 cells / well in 384-well black clear bottom sterile dishes (Greiner). at 37°C in 5% CO 2 Inoculated plates were incubated overnight in .

[0289] Human orexin-A as an agonist was prepared as a 1 mM stock solution in MeOH:water (1:1), dil...

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Abstract

The present invention relates to (S)-proline sulfonamide compounds of formula (I), wherein R1 and R2 are as described in the description, or pharmaceutically acceptable salts thereof, for use in the prevention or treatment of diseases or disorders related to the orexin system. The present invention also relates to the use of (S)-proline sulfonamide compounds of formula (II) as pharmaceuticals, to pharmaceutical compositions comprising compounds of formula (II), and especially their use in the prevention or treatment of diseases or disorders related to the orexin system.

Description

technical field [0001] The present invention relates to a (S)-proline sulfonamide compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising these compounds, which are used for the prevention or treatment of disease or condition. In particular, the present invention relates to the use of (S)-prolinesulfonamide compounds of formula (II) as medicines, pharmaceutical compositions containing one or more compounds of formula (II), and the use of these compounds or pharmaceutical compositions for prophylaxis Or use for treating diseases or conditions related to the orexin system, especially for preventing or treating sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunction, mood disorders or appetite disorders. The invention also relates to related aspects comprising processes for the preparation of these compounds. Background technique [0002] Orexins (orexin A or OX-A and orexin B or OX-B) are nove...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/401A61K31/4025A61K31/535A61P39/00A61P25/30A61P25/00A61P3/00
CPCC07D409/12C07D207/48A61K31/4025A61K31/40A61P39/00A61P25/00A61P3/00A61P25/30A61K31/401
Inventor 克里斯多夫·博斯克莉丝汀·普罗奇约翰·加特菲尔德马库斯·盖得比比安·海德曼蒂埃里·西弗朗约迪·T·威廉姆斯
Owner IDORSIA PHARM LTD
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