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Compounds and compounds for use in methods for treating diseases or conditions mediated by protein disulfide isomerase

a technology of protein disulfide isomerase and compound compound, which is applied in the direction of biocide, drug composition, extracellular fluid disorder, etc., can solve the problems of morbidity and mortality, heart attacks and strokes,

Inactive Publication Date: 2016-05-26
THE BROAD INST INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a compound of Formula I and its pharmaceutically acceptable salts and prodrugs. The compound has various structures and can inhibit protein disulfide isomerase, which is involved in various diseases such as thrombosis, infectious diseases, cancer, and inflammation. The compound can be used as a pharmaceutical composition to treat or prevent these diseases.

Problems solved by technology

Arterial thrombosis causes heart attacks and strokes and is the leading cause of morbidity and mortality in the United States.
However, potential complications of inhibiting PDI are the ubiquitous distribution and critical function of intracellular PDI.

Method used

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  • Compounds and compounds for use in methods for treating diseases or conditions mediated by protein disulfide isomerase
  • Compounds and compounds for use in methods for treating diseases or conditions mediated by protein disulfide isomerase
  • Compounds and compounds for use in methods for treating diseases or conditions mediated by protein disulfide isomerase

Examples

Experimental program
Comparison scheme
Effect test

example 1a

Preparation of Ethyl 1-(3-chloro-4-hydroxybenzyl)-4-(2-phenoxyethyl)piperidine-4-carboxylate (1)

[0067]

[0068]4-(allyloxy)-3-chlorobenzaldehyde (8a): To a solution of 3-chloro-4-hydroxybenzaldehyde (7a, 5.0 g, 31.9 mmol) in anhydrous DMF (20 mL) at rt under nitrogen atmosphere was added K2CO3 (13.2 g, 96.0 mmol) in one portion followed by addition of allyl bromide (4.2 mL, 47.9 mmol). The mixture was stirred at 65° C. for 18 hr. The mixture was cooled down to rt followed by addition of water (100 mL). The mixture was extracted with ethyl acetate (3×80 mL). The combined organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography over 80 g of silica and eluted with ethyl acetate / hexane (0-30%) to provide the 4-(allyloxy)-3-chlorobenzaldehyde (6.1 g, 97% yield) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 9.84 (s, 1H), 7.91 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H),...

example 1b

Preparation of Isopropyl 1-(3-chloro-4-hydroxybenzyl)-4-(2-phenoxyethyl)piperidine-4-carboxylate (11a)

[0074]

[0075]Iso-propyl 1-(4-(allyloxy)-3-chlorobenzyl)-4-(2-phenoxyethyl)piperidine-4-carboxylate (10a): To a solution of ethyl 1-(4-(allyloxy)-3-chlorobenzyl)-4-(2-phenoxyethyl)piperidine-4-carboxylate (6a, 1.1 g, 2.4 mmol) in MeOH (15 mL) was added LiOH (0.58 g, 24.02 mmol) in water (1.5 ml) at rt. The mixture was stirred at rt for 48h. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The crude product mixture was used in the next step without further purification. To a solution of crude 1-(4-(allyloxy)-3-chlorobenzyl)-4-(2-phenoxyethyl)piperidine-4-carboxylic acid (0.2g, 0.47 mmol) in anhydrous DCM (5 ml) at 0 ° C. under nitrogen atmosphere was added oxalyl chloride (0.08 ml, 0.93 mmol. The mixture was stirred at 0 ° C. for 30 minutes a...

example 1

C: Preparation of Tert-butyl 1-(3-chloro-4-hydroxybenzyl)-4-(2-phenoxyethyl)piperidine-4-carboxylate (12a):

[0077]

This compound was prepared similarly to compound 11a by following the procedures in EXAMPLE 1B replacing iso-propylalcohol with tert-butyl alcohol in the reaction of compound 6a. 1H NMR (300 MHz, CDCl3): δ 7.30-7.23 (m, 3H), 7.11-7.08 (m, 1H), 6.96-6.890 (m, 2H), 6.88-6.82 (m, 2H), 3.96 (t, J=7.2 Hz, 2H), 3.36 (s, 2H), 2.71-2.67 (m, 2H), 2.21-1.94 (m, 7H), 1.62-1.48 (m, 2H), 1.46 (s, 9H). LCMS (ESI+): 446.2 (M+H).

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Abstract

The invention provides compounds of formula (I) that inhibit PDI, for use in methods to treat or prevent a disease or condition in a subject that would benefit by inhibition of PDI. Formula (I)

Description

Related Applications[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 837,820, filed Jun. 21, 2013, the entire teachings of which are incorporated herein by reference.Statement Regarding Federally Sponsored Research or Development[0002]This invention was supported in part by the United States Government under National Institutes of Health grants R03 DA032476-01 and 1U54HL112302-01. The Government may have certain rights in this invention.BACKGROUND OF THE INVENTION[0003]Arterial thrombosis causes heart attacks and strokes and is the leading cause of morbidity and mortality in the United States. Recurrent thrombosis is common despite current therapies.[0004]Protein disulfide isomerase (PDI) is a member of an extended family of oxidoreductases, best known as endoplasmic reticulum-resident enzymes. These enzymes catalyze posttranslational disulfide bond formation and exchange and serve as chaperones during protein folding (Hatahet et al. Antioxid Redox Si...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D211/62
CPCC07D211/62A61K31/445A61K31/454A61P7/02A61P29/00A61P31/00A61P35/00Y02A50/30
Inventor FLAUMENHAFT, ROBERTNAG, PARTHA PRATIMPILYUGINA, TATIANAPU, JUNDANDAPANI, SIVARAMANMUNOZ, BENITO
Owner THE BROAD INST INC
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