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Thieno[3,2-b]pyridine derivatives as udp glycosyltransferase inhibitors and methods of use

An alkyl and aryl technology, applied to thieno[3,2-B]pyridine derivatives as UDP glycosyltransferase inhibitors and their application fields, can solve problems such as incurable diseases

Pending Publication Date: 2021-09-21
GENZYME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Despite awareness and research on Krabbe's and MLD, these deadly and debilitating diseases remain incurable

Method used

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  • Thieno[3,2-b]pyridine derivatives as udp glycosyltransferase inhibitors and methods of use
  • Thieno[3,2-b]pyridine derivatives as udp glycosyltransferase inhibitors and methods of use
  • Thieno[3,2-b]pyridine derivatives as udp glycosyltransferase inhibitors and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 10

[1477] Example 10: 5-(4-(2-(isopropylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b ]Pyridine-3-carboxylic acid methyl ester

[1478]

[1479] Step 1: 5-(4-(2-(Benzyloxy)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-Methyl carboxylate

[1480] To a stirred solution of Intermediate 3 (0.642 g, 2.17 mmol) in N,N-dimethylformamide (15 mL) was added benzyl 2-(piperazin-1-yl)acetate dihydrochloride (800 mg , 2.60 mmol), then potassium carbonate (0.900 g, 6.51 mmol) was added. The reaction was heated at 90 °C overnight and then concentrated. The residue was partitioned between aqueous sodium bicarbonate (about 60 mL) and ethyl acetate (about 40 mL). The organic layer was combined with the back extract of the aqueous layer (ethyl acetate, 1 x about 40 mL), dried (Na 2 SO 4 ) and concentrate. The crude product was purified by automated flash chromatography (Combiflash system; 30% to 50% ethyl acetate in heptane; 40 g silica column...

Embodiment 25

[1485] Example 25: 5-(4-(2-(Ethylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno[3 ,2-b]pyridine-3-carboxamide

[1486]

[1487] Step 1: 5-(4-(2-(Ethylamino)-2-oxoethyl)piperazin-1-yl)-7-(trifluoromethyl)thieno[3,2-b]pyridine -3-Methyl carboxylate

[1488] Using the HATU-mediated amide coupling procedure described in Example 10, Step 3, the product of Example 10, Step 2 was condensed with ethylamine hydrochloride to give the title compound as a pale yellow solid. 1 H NMR (400MHz, CDCl 3 )δ8.57(s,1H),7.12(br s,1H),7.01(s,1H),3.95(s,3H),3.83-3.75(m,4H),3.41-3.32(m,1H), 3.09 (s, 2H), 2.73-2.66 (m, 4H), 1.18 (t, J = 7.3Hz, 3H) ppm.

[1489] Step 2: 5-(4-(2-(Ethylamino)-2-oxoethyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl)thieno-[3 ,2-b]pyridine-3-carboxamide

[1490] A 20 mL microwave reaction vial equipped with a stir bar was charged with the product from Step 1 (0.150 g, 0.348 mmol) and a 2.0 N solution of methylamine in methanol (8.0 mL, 16 mmol)...

Embodiment 39

[1491] Example 39. (+ / -)-5-(4-(2-(cyclopropylmethoxy)propyl)piperazin-1-yl)-N-methyl-7-(trifluoromethyl) Thieno[3,2-b]pyridine-3-carboxamide

[1492]

[1493] Step 1: (+ / -)-tert-butyl 4-(2-(cyclopropylmethoxy)propyl)piperazine-1-carboxylate

[1494] To a stirred solution of tert-butyl 4-(2-hydroxypropyl)piperazine-1-carboxylate (0.750 g, 3.07 mmol) in tetrahydrofuran (30 mL) was added a 60% dispersion of sodium hydride in mineral oil (0.147 g, 3.68 mmol). The suspension was stirred at room temperature for one hour, then (bromomethyl)cyclopropane (0.45 mL, 4.6 mmol) was added via syringe. The reaction was heated at reflux overnight. TLC analysis indicated that the reaction contained approximately equal fractions of starting material and product as judged by relative spot intensities (visualized by iodine staining). Additional sodium hydride (0.123 g, 3.08 mmol) and alkyl bromide (0.30 mL, 3.09 mmol) were added (at approximately 30 minute intervals) to the stirred reactio...

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Abstract

Disclosed herein is a compound of Formula (I), as described herein, and pharmaceutically acceptable salts thereof. Also disclosed herein are compositions and the use of such compositions in methods of treating a variety of diseases and conditions, in particular Krabbe's Disease (KD) and Metachromatic leukodystrophy (MLD).

Description

[0001] This application is an international application claiming priority to and benefit of U.S. Provisional Application No. 62 / 739,405, filed October 1, 2018, the contents of which are hereby incorporated by reference in their entirety. Background technique [0002] UDP glycosyltransferase 8 (UGT8) is an enzyme in the UDP-glycosyltransferase enzyme family. UGT8 catalyzes the conversion of galactose to ceramide, a key enzymatic step in the biosynthesis of galactosylceramide. These molecules are abundant sphingolipids of the myelin membranes of the central and peripheral nervous systems. Galactocerebrosides also serve as precursors in the glycosphingolipid biosynthetic pathway and are further modified by cerebroside sulfotransferases (enzymes that convert galactocerebrosides to sulfatides). Sulfatides are also important components of the central nervous system (CNS) and peripheral nervous system (PNS) as a component of myelin, the vital insulating sheath that forms a double me...

Claims

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Application Information

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IPC IPC(8): C07D495/04C07D513/04C07D519/00A61P25/00A61K31/4743
CPCC07D495/04C07D513/04A61P25/00C07D519/00A61K31/4545A61K31/496A61K31/519C07D487/10
Inventor S·林R·H·小巴克M·A·克伦威尔E·马基诺B·赫斯J·江S·马尼尔M·芒森Y-M·崔S·图拉拉特南K·Y·穆西克J·普里比什M·安格拉斯特
Owner GENZYME CORP
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