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Novel cyclosporin derivatives and uses thereof

A halogen, compound technology, applied in the field of novel cyclosporine derivatives, can solve problems such as cell death and mitochondrial swelling

Pending Publication Date: 2019-03-15
S&T GLOBAL INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unregulated opening of mPTP leads to mitochondrial swelling and cell death

Method used

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  • Novel cyclosporin derivatives and uses thereof
  • Novel cyclosporin derivatives and uses thereof
  • Novel cyclosporin derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0370] [α-Methylene-Sar]-3-cyclosporine

[0371]

[0372] To a solution of [α-hydroxymethyl-Sar]-3-cyclosporin (246mg, 0.20mmol) in THF (15ml) was added sodium hydride (120mg, 60% in mineral oil, 3mmol) and dichlorophosphoric acid Ethyl ester (412 mg, 2.40 mmol). The resulting mixture was stirred overnight at room temperature. After disappearance of starting material, methanol (10 mL) and potassium tert-butoxide (33 mg, 26.00 mmol) were added. The mixture was stirred at room temperature for 3 hours, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (50ml). The dichloromethane layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. Purification of the residue by flash chromatography using dichloromethane / methanol as eluent afforded 205 mg of the product [molecular formula: C 63 h 111 N 11 o 12 ; Exact mass: 1213.84; MS (m / z): 1214.59 (M+1) + ; HPLC RT: 17.47 min. (C8 reverse-phas...

Embodiment 2

[0374] [(3R,4R)-3-Hydroxy-4-methyl-6-(4-methoxycarbonylbenzyl)-N-MeNle]-1-[(S)-(4-Hydroxybutyl Thio)methyl-Sar]-3-cyclosporine

[0375] [3-Acetyl-MeBmt]-1-cyclosporin

[0376]

[0377] To a dry flask under nitrogen was added cyclosporine (12.00 g, 9.98 mmol), N,N-dimethylaminopyridine (0.12 g, 0.10 mmol), anhydrous pyridine (120 ml) and acetic anhydride (54 ml, 0.54mol). After stirring overnight at room temperature, the mixture was poured into ice water (600ml) and stirred until the ice melted. Ethyl acetate (100ml) was added, and the mixture was separated. The ethyl acetate layer was washed with 1.0N hydrochloric acid solution (100ml x 2), saturated sodium bicarbonate solution (100ml), brine (100ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane / acetone) to obtain 11.40 g of pure [3-acetyl-MeBmt]-1-cyclosporine [molecular formula: C 64 h 113 N 11 o 13 ; Exact mass: 1243.85; MS (m / z): 1244.5...

Embodiment 3

[0400] [(3R,4R)-3-Hydroxy-4-methyl-6-(4-carboxybenzyl)-N-MeNle]-1-[(S)-(4-hydroxybutylthio) Methyl-Sar]-3-cyclosporine

[0401]

[0402] To [(3R,4R)-3-hydroxy-4-methyl-6-(4-methoxycarbonylbenzyl)-N-MeNle]-1-[(S)-(4-hydroxybutylthio) To a solution of methyl-Sar]-3-cyclosporin (85mg, 0.06mmol) in methanol (5ml) was added a solution of lithium hydroxide (15mg) in water (5ml). The reaction mixture was stirred overnight at room temperature. Most of the methanol was evaporated under reduced pressure. The pH of the mixture was adjusted to 6 with 1.0N hydrochloric acid. Ethyl acetate (60ml) and brine (10ml) were added, and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. Purification of the residue afforded pure [(3R,4R)-3-hydroxy-4-methyl-6-(4-carboxybenzyl)-N-MeNle]-1-[(S)-(4-hydroxybutyl Thio)methyl-Sar]-3-cyclosporine [molecular formula: C 73 h 125 N 11 o 15 S; Exact mass: 1427.91; MS (m / z): 1428.6...

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PUM

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Abstract

A compound of the Formula (I) is disclosed: (I) or pharmaceutically acceptable salt thereof, wherein the symbols are as defined in the specification. Also described are a pharmaceutical composition comprising the same and a method for treating or preventing viral infections, inflammation, dry eye, central nervous disorders, cardiovascular diseases, cancer, obesity, diabetes, muscular dystrophy, lung, and liver, and kindey diseases, and hair loss using the same.

Description

[0001] related application [0002] This application is related to US Application Serial No. 13 / 840,088, filed March 15, 2013. This application claims U.S. Provisional Application No. 62 / 337,377, filed May 17, 2016, U.S. Provisional Application No. 62 / 339,464, filed May 20, 2016, and U.S. Provisional Application No. 62 / 384,822 priority. The entire contents of these applications are expressly incorporated herein by reference in their entirety. technical field [0003] The present invention relates to novel cyclosporine derivatives, their pharmaceutical compositions containing them, and their use in the treatment or prevention of viral infections, inflammation, dry eye, central nervous disorders, liver diseases, lung and kidney diseases, cardiovascular diseases, cancer, Methods for obesity, diabetes, muscular dystrophy, hair loss, etc. Background technique [0004] Cyclosporins are essentially poly-N-methyl cyclic undecaptides isolated from fungi. Cyclosporin A has immuno...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64
CPCC07K7/645A61P31/20A61P31/18A61P31/14A61P19/02A61P29/00A61P11/00A61P27/02A61P25/28A61P25/16A61P25/14A61P25/00A61P9/10A61P9/00A61P35/00A61P3/04A61P3/10A61P1/16A61P13/12A61P17/14A61P21/00A61K38/00A61K38/13
Inventor 苏壮杨遂周龙正宇
Owner S&T GLOBAL INC
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