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7-heterocyclyl quinoline and thieno[2,3,-b] pyridine derivatives useful as antagonists of gonadotropin releasing hormone

A heterocycloalkyl and heteroaryl technology, applied in the field of 7-heterocyclyl quinoline and thieno[2,3-b]pyridine derivatives used as gonadotropin-releasing hormone antagonists, can solve biological problems Insufficient availability, etc.

Inactive Publication Date: 2004-04-14
ORTHO MCNEIL PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds are limited to intravenous and subcutaneous administration due to insufficient bioavailability

Method used

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  • 7-heterocyclyl quinoline and thieno[2,3,-b] pyridine derivatives useful as antagonists of gonadotropin releasing hormone
  • 7-heterocyclyl quinoline and thieno[2,3,-b] pyridine derivatives useful as antagonists of gonadotropin releasing hormone
  • 7-heterocyclyl quinoline and thieno[2,3,-b] pyridine derivatives useful as antagonists of gonadotropin releasing hormone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128] 7-bromo-6-bromomethyl-1-(2,6-difluorobenzyl)-1,4-dihydro-4-oxoquinoline

[0129] -3-Carboxylic acid ethyl ester

[0130] 7-bromo-1-(2,6-difluorobenzyl)-1,4-dihydro-methyl-4-oxoquinolinyl prepared according to the method described in PCT application WO97 / 14682 Reference Example 3 - A mixture of ethyl 3-carboxylate (3.5 g, 8 mmol), NBS (1.5 g, 8.4 mmol) and 2,2'-azobisisobutyronitrile (AIBN, 100 mg) in DCM (200 mL) was stirred at reflux 4 hours. Additional NBS (750 mg) was added and the mixture was refluxed for a further 4 hours. Column chromatography Purification by column chromatography (hexane:ethyl acetate=3:7) gave a white solid product.

[0131] Yield: 2.95g (72%)

[0132] m.p.184-187℃;

[0133] 1 H NMR (CDCl 3 ), δ1.41(t, J=8Hz, 3H), 4.40(q, J=8Hz, 2H), 4.66(s, 2H), 5.36(s, 2H), 7.03(m, 2H), 7.39(m , 1H), 7.92(s, 1H), 8.54(s, 1H), 8.68(ds, 1H);

[0134] MS (m / z): 514 (MH + ).

Embodiment 2

[0136] 6-(N-Benzyl-N-methylaminomethyl)-7-bromo-1-(2,6-difluorobenzyl)-1,4-dihydro-4-

[0137] Ethyl oxoquinoline-3-carboxylate

[0138] 7-Bromo-6-bromomethyl-1-(2,6-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (110mg, 0.21mmol), A mixture of methylbenzylamine (31 mg, 0.26 mmol) in DIPEA (0.045 ml) and DMF (15 ml) was stirred at room temperature for 16 hours. Ethyl acetate and water were added. Separate the organic phase, wash with water, wash with MgSO 4 dry. The solvent was evaporated and the residue was dried under vacuum to give the product as a white solid.

[0139] Yield: 120mg (100%)

[0140] 1 H NMR (CDCl 3 ), δ1.41(t, J=8Hz, 3H), 2.17(s, 3H), 3.62(s, 2H), 3.67(s, 2H), 4.40(q, J=8Hz, 2H), 5.36(s , 2H), 7.03(m, 2H), 7.25-7.39(m, 6H), 7.88(s, 1H), 8.59(s, 1H), 8.67(ds, 1H);

[0141] MS (m / z): 555 (MH + ).

Embodiment 3

[0143] 6-(N-Benzyl-N-methylaminomethyl)-7-(benzofuran-2-yl)-1-(2,6-difluorobenzyl

[0144] base)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester

[0145] Compound #2

[0146] 7-Bromo-6-bromomethyl-1-(2,6-difluorobenzyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (278mg, 0.5mmol), A mixture of benzofuran-2-boronic acid (97mg, 0.6mmol), tetrakis(triphenylphosphine)palladium(0) (69mg, 0.06mmol) and 2M sodium carbonate (414mg, 3mmol) in DME (20ml) was heated under reflux 16 hours. Ethyl acetate and water were added. The organic phase was separated, washed with water and washed with MgSO 4 dry. Purification by column chromatography (ethyl acetate) yielded the product as a yellow solid.

[0147] Yield: 55mg (19%)

[0148] 1 H NMR (CDCl 3 ), δ1.44(t, J=8Hz, 3H), 2.17(s, 3H), 3.63(s, 2H), 3.90(s, 2H), 4.42(q, J=8Hz, 2H), 5.49(s , 2H), 7.00(m, 2H), 7.22-7.81(m, 11H), 8.23(s, 1H), 8.62(s, 1H), 8.76(ds, 1H);

[0149]...

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Abstract

The present invention is directed to novel 7-heterocyclyl quinoline and thieno[2,3-b]pyridine derivatives of the general formula (I) or (II), wherein all variables are as herein defined, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions associated with gonadotropin releasing hormone (GnRH). The compounds of the invention are antagonists of GnRH, useful in the treatment of the infertility, prostate cancer, benign prostate hyperplasia (BPH) and as contraceptives.

Description

field of invention [0001] The present invention relates to novel 7-heterocyclylquinoline and thieno[2,3-b]pyridine derivatives, pharmaceutical compositions containing them, and their use in the treatment of gonadotropin-releasing hormone (GnRH)-related Applications in Diseases and Symptoms. The compounds of the present invention are antagonists of GnRH and are useful in the treatment of infertility, prostate cancer, benign prostatic hyperplasia (BPH) and as contraceptives. Background of the invention [0002] Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a linear decapeptide amide, pGlu-HisTrp-Ser-Tyr-GIy-Leu-Arg-Pro-Gly-NH 2 , originally from pigs (Matsuo, H., et.al., Biochem. Biophys. Res. Commun. 1972, 43, 1334-1339) and sheep (Burgus, R., et.al., PNAS, USA, 1972, 69, 278-282). GnRH plays an important role in the reproductive system. The hormone originates from the hypothalamus and acts on ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22A61K31/4365A61K31/437A61K31/4709A61K31/4745A61P13/08A61P15/00A61P15/08A61P15/16A61P35/00A61P43/00C07D405/04C07D409/04C07D471/04C07D495/04C07D495/14
CPCC07D495/14C07D495/04C07D471/04C07D409/04C07D405/04A61P13/08A61P15/00A61P15/08A61P15/16A61P35/00A61P43/00
Inventor Z·隋M·马茨拉J·C·兰特
Owner ORTHO MCNEIL PHARM INC
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