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Substituted piperidines containing a heteroarylamide or heteroarylphenyl moiety

A technology of groups and substituents, applied in the field of pharmaceutical compositions containing such compounds

Inactive Publication Date: 2010-01-13
ASTEX THERAPEUTICS LTD +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] It is also clear that mutations in regulatory subunits of PKA can lead to hyperactivity in endocrine tissues

Method used

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  • Substituted piperidines containing a heteroarylamide or heteroarylphenyl moiety
  • Substituted piperidines containing a heteroarylamide or heteroarylphenyl moiety
  • Substituted piperidines containing a heteroarylamide or heteroarylphenyl moiety

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0943] 4-Aminomethyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid (6-chloro-pyridine -3-ylmethyl)-amide

[0944] 1A. tert-butyl 4-(6-chloro-pyridin-3-ylmethylcarbamoyl)-4-cyano-piperidine-1-carboxylate ester

[0945]

[0946] 5-Aminomethyl-2-chloropyridine (1.28 mmol) was added to 4-cyano-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (250 mg, 0.98 mmol), HATU (486 mg, 1.28 mmol) and Hunig's base (0.86ml, 4.92mmol) in DMF (2.5ml) and stirred at room temperature under argon atmosphere. After stirring for 17 hours, the reaction mixture was partitioned between dichloromethane and water. Then, the organic layer was dried, filtered and evaporated. The crude material can be purified by flash column chromatography on silica gel, eluting with 25% ethyl acetate-petroleum ether, to afford the title compound.

[0947] 1B. 4-Cyano-piperidine-4-carboxylic acid (6-chloro-pyridin-3-ylmethyl)-amide

[0948]

[0949] To a solution of the product ...

Embodiment 2

[0958] 4-Amino-1-(8-oxo-8,9-dihydro-7H-purin-6-yl)-piperidine-4-carboxylic acid (3-benzoxazole -2-yl-phenyl)-amide

[0959] 2A. 4-tert-butoxycarbonylamino-4-(3-benzoxazol-2-yl-phenylcarbamoyl)-piper tert-Butyl pyridine-1-carboxylate

[0960]

[0961] 3-Benzoxazol-2-yl-aniline (1.74 mmol) was added to 4-tert-butoxycarbonylamino-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (600 mg, 1.74 mmol), HATU (861 mg, 2.26 mmol) and Hunig's base (1.52 ml, 8.71 mmol) in a stirred solution in DMF (5 ml) and stirred at room temperature under an atmosphere of argon. After stirring for 17 hours, the reaction mixture was partitioned between dichloromethane and water. Then, the organic layer was dried, filtered and evaporated. The crude material can be purified by flash column chromatography on silica gel, eluting with 25% ethyl acetate-petroleum ether, to afford the title compound.

[0962] 2B. 4-Amino-piperidine-4-carboxylic acid (3-benzoxazol-2-yl-phenyl)-amide

[09...

Embodiment 3

[0975] 4-Amino-1-(8-oxo-8,9-dihydro-7H-purin-6-yl)-piperidine-4-carboxylic acid [3-(4-methyl-pyridine Pyridine-2-yl)-phenyl]-amide

[0976] 3A. 4-Amino-piperidine-4-carboxylic acid [3-(4-methyl-pyridin-2-yl)-phenyl]-amide

[0977]

[0978] The title compound was prepared according to the procedure described in Examples 2A and 2B, using 3-(4-methyl-pyridin-2-yl)-aniline in place of 3-benzoxazol-2-yl-aniline.

[0979] 3B.4-Amino-1-(8-oxo-8,9-dihydro-7H-purin-6-yl)-piperidine-4-carboxylic acid [3-(4-methanoic acid Base-pyridin-2-yl)-phenyl]-amide

[0980]

[0981] The title compound was prepared according to the procedure described in Examples 2C to 2E. LC-MS m / z445. 1 H NMR (400MHz, Me-d 3 -OD): 8.47 (1H, d), 8.21-8.13 (2H, m), 7.75-7.66 (3H, m), 7.48 (1H, t), 7.25 (1H, d), 4.26-4.15 (2H, m ), 3.59-3.47 (2H, m), 2.68 (2H, s), 2.48 (3H, s), 2.42-2.31 (2H, m), 1.74 (2H, d).

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Abstract

The invention provides compounds of the formula (I) having PKA and PKB kinase inhibiting compounds of the formula (I): GP 1 J T 2 J N 4 R N H (I) or salts, solvates, tautomers or N-oxides thereof, wherein (1) GP is a group GP1: HET 2a a Q G (HNCO)f 7 (R )x N * (GP1) (2) GP is a group GP2: 10 (R )r O 2a a QG (CH2)w N V H N * (GP2) wherein HET is a monocyclic or bicyclic heterocyclic group containing up to 4 heteroatom ring members; the ring V is a monocyclic or bicyclic heteroaryl group of 5 to 10 ring members; and J1, J2, R4, R7, R10, Q2a, Ga, x, w and f are as defined in the claims.

Description

[0001] The present invention relates to purine, purinone and deazapurine and deazapurinone compounds or structural isomers thereof which inhibit or modulate the activity of protein kinase B (PKB) and / or protein kinase A (PKA), such compounds in the treatment of or the use of preventing disease states or symptoms mediated by PKB and / or PKA, and novel compounds having PKB and / or PKA inhibitory or modulatory activity. Also provided are pharmaceutical compositions containing such compounds, as well as novel chemical intermediates. Background technique [0002] Protein kinases are a large family of structurally related enzymes responsible for the control of a wide variety of signal transduction processes in cells (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I and II, Academic Press , San Diego, CA). Such kinases can be classified into several families by the substrates they phosphorylate (eg, protein-tyrosine, protein-serine / threonine, lipids, etc.). Sequence m...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D473/34C07D471/04A61K31/519A61P35/00
Inventor S·J·伍德海C·哈姆雷特M·L·韦当克H·F·索尔D·W·沃克I·柯林斯J·科德威T·F·达方斯卡麦哈迪R·W·A·路克Z·S·马图席维克G·R·卡尔J·J·摩里斯K·M·张
Owner ASTEX THERAPEUTICS LTD