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Haloallylamine sulfone derivative inhibitors of lysyl oxidases and uses thereof

A halogen and compound technology, applied in the direction of amide active ingredients, medical preparations containing active ingredients, organic chemistry, etc., can solve problems such as poor tolerance of BAPN

Active Publication Date: 2021-03-19
PHARMAXIS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies in human scleroderma patients found BAPN to be poorly tolerated and highlighted the need for safer alternatives (Clin.Pharmacol.Ther. 1967:593–602)

Method used

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  • Haloallylamine sulfone derivative inhibitors of lysyl oxidases and uses thereof
  • Haloallylamine sulfone derivative inhibitors of lysyl oxidases and uses thereof
  • Haloallylamine sulfone derivative inhibitors of lysyl oxidases and uses thereof

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0278] The preparation of formula I compound

[0279] Compounds of formula I can be prepared by those skilled in the art using methods and materials known in the art and with reference to standard textbooks such as "Advanced Organic Chemistry" by Jerry March (Third Edition, 1985, John Wiley and Sons) or Richard C. . Larock's "Comprehensive Organic Transformations (Comprehensive Organic Transformations)" (1989, VCH Press) to easily prepare.

example 1

[0431] Preparation of tert-butyl (Z)-(4-bromo-3-fluorobut-2-en-1-yl)carbamate

[0432]

[0433] Procedure A: Preparation of tert-butyl 2-oxoethylcarbamate

[0434]

[0435] To a stirred solution of 3-amino-1,2-propanediol (20.0 g, 0.22 mol) in water (200 mL) was added di-tert-butyl dicarbonate (55.5 mL, 0.24 mol) at 0-5°C . After adjusting the alkalinity of the solution to pH about 9 by addition of aqueous solution, the mixture was stirred at room temperature (rt) for 18 hours by addition of NaOH (6N). The reaction mixture was cooled to 0-5°C, then acidified to pH about 6, then sodium metaperiodate (56.3 g, 0.26 mol) was added. The resulting suspension was stirred at room temperature for 2 hours. The mixture was filtered to remove all solids, and the filtrate was transferred to a separatory funnel and extracted with ethyl acetate (200 mL). Sodium chloride was added to the aqueous layer until a saturated solution was obtained. The aqueous layer was then further ext...

example 2

[0446] The following compounds were prepared according to Procedures E, F, G, H and I.

[0447] Preparation of (Z)-4-((2-((4-amino-2-fluorobut-2-en-1-yl)sulfonyl)phenoxy)methyl)-N,N-diisopropylbenzene Sulfonamide hydrochloride (compound 11)

[0448]

[0449] Procedure E: Preparation of 4-(bromomethyl)-N,N-diisopropylbenzenesulfonamide

[0450]

[0451] To stirred 4-(bromomethyl)benzenesulfonyl chloride (500 mg, 1.86 mmol) in CH at 0 °C 2 Cl 2 (10 mL) was added dropwise diisopropylamine (0.65 mL, 4.63 mmol). After the addition, the resulting mixture was stirred at this temperature for 30 minutes, then allowed to warm to room temperature and stirred for a further 48 hours. The reaction mixture was dissolved in HCl (1M, 20mL) and CH 2 Cl 2 (20mL). The organic layer was washed with aqueous HCl (1M; 20 mL) and water (20 mL), washed with Na 2 SO 4 Drying and concentration in vacuo afforded the title compound (yellow oil, 190 mg) in a mixture with 4-(chloromethyl)-N,...

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PUM

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Abstract

The present invention relates to novel compounds which are capable of inhibiting certain amine oxidase enzymes. These compounds are useful for treatment of a variety of indications, e.g., fibrosis, cancer and / or angiogenesis in human subjects as well as in pets and livestock. In addition, the present invention relates to pharmaceutical compositions containing these compounds, as well as various uses thereof.

Description

technical field [0001] The present invention relates to novel compounds capable of inhibiting certain amine oxidases. These compounds are useful in the treatment of various indications such as fibrosis, cancer and / or angiogenesis in human subjects as well as in pets and livestock. In addition, the present invention relates to pharmaceutical compositions containing these compounds and various uses thereof. Background technique [0002] The enzymes are the first described family members lysyl oxidase (LOX) as well as LOX-like 1 (LOXL1), LOXL2, LOXL3 and LOXL4 (J Cell Biochem 2003;88:660- 672). Lysyl oxidase isozyme is a copper-dependent amine oxidase that initiates covalent crosslinking of collagen and elastin. The main function of lysyl oxidase isoenzymes is to promote cross-linking of collagen and elastin by oxidative deamination of lysine and hydroxylysine amino acid side chains to aldehydes that react spontaneously with neighboring residues. The resulting cross-linked ...

Claims

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Application Information

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IPC IPC(8): C07C317/28C07D209/10C07D213/71C07D215/36C07D277/64A61P9/00A61P11/00A61P13/12A61P17/02A61P35/00A61K31/145A61K31/166A61K31/18A61K31/4402A61K31/4406A61K31/4409A61K31/47
CPCC07C317/28C07D213/71C07D215/36C07D277/64A61P13/12A61P11/00A61P17/02A61P35/00A61P9/00C07D209/10C07C2603/74C07C317/44A61K45/06C07B2200/05C07C317/32A61K31/145A61K31/18A61P43/00C07C2602/10C07C2601/16A61P19/04A61P35/04A61K31/4409A61K31/47C07C311/29C07D209/08
Inventor 艾莉森·桃乐丝·芬得利克雷格·伊旺·特纳曼达·迪奥达强纳森·史都华·甫特沃尔夫冈·杰洛利梅克周文斌A·布森A·E·格雷克
Owner PHARMAXIS LTD
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