1-((s)-1-(3-chloro-5-fluoro-2-((4-(1h-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-imidazolidine-2,4-dione derivatives and related compounds as bradykinin (BK) b2 receptor antagonist for treating skin diseases

A compound, C1-C3 technology, applied in skin diseases, drug combinations, diseases, etc., can solve the problems of low bioavailability, hindering practicality, low metabolic stability, etc.

Pending Publication Date: 2022-01-07
PHARVARIS GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds exhibit a number of deficiencies that hamper their utility as pharmaceuticals, including low metabolic stability, low bioavailability, formation of glutathione adducts, and bioactivation (toxicity), as described in WO 201 4 / Revealed in 159637

Method used

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  • 1-((s)-1-(3-chloro-5-fluoro-2-((4-(1h-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-imidazolidine-2,4-dione derivatives and related compounds as bradykinin (BK) b2 receptor antagonist for treating skin diseases
  • 1-((s)-1-(3-chloro-5-fluoro-2-((4-(1h-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-imidazolidine-2,4-dione derivatives and related compounds as bradykinin (BK) b2 receptor antagonist for treating skin diseases
  • 1-((s)-1-(3-chloro-5-fluoro-2-((4-(1h-pyrazol-1-yl)-2-methylquinolin-8-yloxy)methyl)phenyl)ethyl)-imidazolidine-2,4-dione derivatives and related compounds as bradykinin (BK) b2 receptor antagonist for treating skin diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0178] Example 1: Preparation of Compound No. 1

[0179]

[0180] (S)-2-(3-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinoline-8 -yloxy)methyl)phenyl)ethyl)-2,5-two-side oxyimidazolidin-1-yl)acetamide

[0181] step a. Synthesis of 3-amino-5-fluoro-2-methylbenzoic acid methyl ester

[0182] Methyl 5-fluoro-2-methyl-3-nitrobenzoate [Gillmore, A.T. et al., Org. Process Res. Dev. 2012, 16, 1897-1904] (4.69 g; 22 mmol) was dissolved in MeOH (100 mL ) and added palladium-10% Pd on charcoal (200 mg). The solution was flushed with nitrogen and vacuumed three times, then flushed with hydrogen. The reaction mixture was stirred vigorously under 1 atm of hydrogen. After completion of the reaction as indicated by TLC (21 h), the solution was filtered through silica gel. The filter cake was washed with methanol (5 x 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (eluting with EA...

example 2

[0213] Example 2: Preparation of Compound No. 2

[0214]

[0215] 1-((S)-1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy Base) methyl) phenyl) ethyl) -3-ethyl-5-methylimidazolidine-2,4-dione diastereomer B

[0216] step a. Diastereomer of methyl 2-((S)-1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethylamino)propanoate Synthesis of A and B

[0217] (S)-1-(3-Chloro-5-fluoro-2-(4-methoxyphenoxy)methyl)phenyl)ethylamine (220 mg, 710 μmol), methyl pyruvate (72.0 μL, 79.8 mg, 781 μmol) and borane-pyridine-complex (107.6 μl, 1.06 mmol) were dissolved in propan-2-ol (5 mL). About 10 μL of 0.5M aqueous HCl was added and the reaction mixture was stirred overnight at RT. After the reaction was complete (TLC), the solution was poured onto an SCX-cartridge (Phenomenex, StrataSCX, 0.6 mmol / g) and eluted with methanol. The resin was then washed with about 8M methanolic ammonia solution to give the crude product after evaporation of the solv...

example 3

[0230] Example 3: Preparation of Compound No. 3

[0231]

[0232] (S)-1-(1-(3-chloro-5-fluoro-2-((4-(4-fluoro-1H-pyrazol-1-yl)-2-methylquinolin-8-yloxy Base) methyl) phenyl) ethyl) imidazolidin-2-one

[0233] step a. Synthesis of (S)-tert-butyl 2-(1-(3-chloro-5-fluoro-2-((4-methoxyphenoxy)methyl)phenyl)ethylamino)ethylcarbamate

[0234] (S)-1-(3-chloro-5-fluoro-2-(4-methoxyphenoxy)methyl)phenyl)ethylamine (100mg, 323μmol), N-Boc-2-aminoethyl Aldehyde (113.1 μl, 355 μmol) and borane-pyridine-complex (48.9 μl, 484 μmol) were dissolved in 2-propanol (4 mL). About 10 μL of 0.5M HCl solution was added and the reaction mixture was stirred overnight at RT. After the reaction was complete (TLC), saturated NaHCO was added 3 aqueous solution and the aqueous phase was extracted with DCM (3x). Combined organic layers were passed through Na 2 SO 4 Dry and evaporate to dryness under reduced pressure after filtration. The crude product was purified by flash chromatography on sil...

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Abstract

The invention relates to a compound according to general formula (I), which acts as a bradykinin (BK) B2 receptor antagonist; to a pharmaceutical composition containing one or more of the compound(s) of the invention; to a combination preparation containing at least one compound of the invention and at least one further active pharmaceutical ingredient; and to said compound(s) for use as in a method of treating a skin disorder; eye disease; ear disease; mouth, throat and respiratory disease; gastrointestinal disease; liver, gallbladder and pancreatic disease; urinary tract and kidney disease; disease of male genitale organs and female genitale organs; disease of the hormone system; metabolic disease; cardiovascular disease; blood disease; lymphatic disease; disorder of the central nervous system; brain disorder; musculoskeletal system disease; allergy disorder; pain; infectious disease; inflammatory disorder; injury; immunology disorder; cancer; hereditary disease; or edema. (I).

Description

technical field [0001] The present invention relates to a compound according to general formula (I), which acts as a bradykinin (bradykinin; BK) B2 receptor antagonist; a pharmaceutical composition containing one or more compounds of the present invention; a A combined preparation comprising at least one compound of the present invention and at least one additional active pharmaceutical ingredient; and use of one or more of the aforementioned compounds, including use as a medicament. Background technique [0002] BK is a peptide hormone that participates in inflammatory processes by activating endothelial cells, resulting in vasodilation, increased vascular permeability, nitric oxide production, and arachidonic acid mobilization. BK also stimulates sensory nerve endings, causing burning pain to the touch. Thus, the classic parameters of inflammation such as redness, heat, swelling and pain can all be caused by BK formation. BK is a transient component of the kallikrein-kin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14C07D413/14A61P1/16A61P5/00A61P9/00A61P11/00A61P13/00A61P13/12A61P15/00A61P17/00A61P25/00A61P25/04A61P27/00A61P27/02A61P27/16A61P31/00A61P35/00A61P37/00A61K31/4709A61K31/496
Inventor C·吉布森J·索普H-D·安布罗西L·O·豪斯泰特
Owner PHARVARIS GMBH
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