Pharmaceutical compounds

A technology of compounds and oxides, applied in drug combination, organic chemistry, antineoplastic drugs, etc., can solve problems such as arrhythmia

Inactive Publication Date: 2009-10-21
ASTEX THERAPEUTICS LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It was later discovered that the side effects of these drugs were irregular heartbeats caused by blockade of hERG channels in heart cells

Method used

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  • Pharmaceutical compounds
  • Pharmaceutical compounds
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1 to 4

[0878] The compounds of Examples 1 to 4 were prepared as described above.

[0879]

[0880]

Embodiment 5

[0882] 5A. tert-butyl 4-tert-butoxycarbonylamino-4-(4-chloro-benzylcarbamoyl)-piperidine-1-carboxylate

[0883]

[0884] Anhydrous DMF (1 mL) was added to a mixture of mono-tert-butyl 4-tert-butoxycarbonylamino-piperidine-1,4-dicarboxylate (151 mg, 0.44 mmol) and HATU (220 mg, 0.58 mmol) under nitrogen. mixture. N-Ethyldiisopropylamine (0.38 mL, 2.1 mmol) was added to the solution, and the reaction mixture was stirred for 15 minutes. 4-Chlorobenzylamine (70 uL, 0.57 mmol) was added and the solution was stirred at room temperature under nitrogen for 23 hours. The reaction mixture was partitioned between dichloromethane (10 mL) and water (10 mL). The aqueous phase was further extracted with dichloromethane (20 mL). The combined organic layers were dried (Mg 2 SO 4 ), filtered and concentrated. Elution with 4% methanol in dichloromethane and flash column chromatography on silica afforded 4-tert-butoxycarbonylamino-4-(4-chloro-benzylcarbamoyl)-piperidine-1 - tert-butyl f...

Embodiment 6

[0895] 1-thieno[3,2-d]pyrimidin-4-yl-piperidin-4-yl-amine

[0896] 6A. (1-Thieno[3,2-d]pyrimidin-4-yl-piperidin-4-yl)-tert-butyl carbamate

[0897]

[0898] The title compound (AT11980) was prepared using the method of Example 5, except piperidin-4-yl-carbamic acid tert-butyl ester was used in place of 4-amino-piperidine-4-carboxylic acid 4-chloro-benzylamide.

[0899] LC / MS: (LCT1)[M+H] + 334,R t 4.62min

[0900] 6B.1-Thieno[3,2-d]pyrimidin-4-yl-piperidin-4-yl-amine

[0901]

[0902] A solution of the product from Example 6A in 2M HCl (2ml) was stirred at room temperature for 2 hours and then evaporated to dryness. Solid-phase extraction on SCX-II acidic resin (elution with MeOH followed by 1M NH in MeOH 3 elution) to obtain the deprotected product. LC / MS (LCT1): [M+H] + 234,R t 0.85min. 1 H(250MHz, MeOD) δ8.45(1H, s), 8.04(1H, d, J=5.5Hz), 7.38(1H, d, J=5.5Hz), 4.95-4.81(2H, m), 3.34- 3.29(2H,m), 3.08-2.98(1H,m), 2.06-2.00(2H,m), 1.52-1.36(2H,m).

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Abstract

Compounds of the formula (I), and salts, solvates, tautomers and N-oxide thereof; wherein TG is selected from groups (1) and (2): wherein the asterisk (*) represents the point of attachment of the group E to the group X; Ris an optionally substituted aryl or heteroaryl group; R is hydrogen or a group Rla; X is an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 are heteroatoms selected from O, N and S; and A, E, R, R, R, Q and Q are as defined in the claims; provided that when E is aryl or heteroaryl, then Q is other than a bond; and further provided that the moiety (a) is other than a group (BG1) or (BG2); wherein (BGl) and (BG2) are each optionally substituted; T is N or CR; J-J is selected from N=C(R), (R)C=N, (R)N-C(O), (R)2C-C(O), N=N and (R)C=C(R); J-J is a group N=C(R) or a group (R)N-CO; and R is hydrogen or a substituent. The compounds of the formula (I) have PKA and PKB kinase inhibiting activity and are useful in the treatment of cancers.

Description

[0001] The present invention relates to aryl- and heteroaryl-alkylamine compounds that inhibit or modulate the activity of protein kinase B (PKB) and protein kinase A (PKA) for the treatment or prevention of PKB- and PKA-mediated Uses in diseases or disorders, and novel compounds having PKB and PKA inhibitory or modulatory activity. The present invention also provides pharmaceutical compositions and novel chemical intermediates comprising the compounds. Background of the invention [0002] Protein kinases constitute a large family of structurally related enzymes responsible for the control of various signal transduction processes in cells (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA) . Kinases can be divided into families by the substrates they phosphorylate (eg, protein-tyrosine, protein-serine / threonine, lipids, etc.). It has been determined that sequence motifs generally correspond to families of these kinases (e....

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D495/04C07D498/04A61K31/506A61P35/00
InventorG·萨克斯蒂M·L·费尔东克J·考德威尔I·科林斯K·-M·钟T·F·达丰塞卡麦哈迪
OwnerASTEX THERAPEUTICS LTD