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Hydrazinomethyl, hydr zonomethyl and 5-membered heterocyclic compounds which act as mTOR inhibitors and their use as anti cancer agents

A technology of compounds and solvates, applied in the field of mTOR inhibitor compounds, can solve problems such as signal increase

Inactive Publication Date: 2008-02-20
MAYBRIDGE LTD GB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, enhanced signaling from P13K leads to increased signaling to mTOR and its downstream activators

Method used

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  • Hydrazinomethyl, hydr zonomethyl and 5-membered heterocyclic compounds which act as mTOR inhibitors and their use as anti cancer agents
  • Hydrazinomethyl, hydr zonomethyl and 5-membered heterocyclic compounds which act as mTOR inhibitors and their use as anti cancer agents
  • Hydrazinomethyl, hydr zonomethyl and 5-membered heterocyclic compounds which act as mTOR inhibitors and their use as anti cancer agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0317] Example 1a: 6-(N'-methylene-hydrazino)-[1,3,5]triazine-2,4-diamine derivative (5) preparation of

[0318]

[0319] (i) Preparation of 4,6-dichloro-[1,3,5]triazin-2-ylamine derivative (2)

[0320] To a cooled (-60°C) solution of cyanuric chloride (1) (3.00g, 16.26mmol) in ethylene glycol dimethyl ether (40ml) was added the appropriate amine (2.80ml, 32.5mmol) dissolved in water (1.4 ml) solution. The amine solution was added dropwise over 10 minutes. The mixture was removed from the cold water bath and water (25ml) was added to completely quench the reaction. The quench mixture was stirred for 5 minutes before any precipitate was filtered off. The filter cake was washed with water (250ml) and dried in a vacuum desiccator to give the desired 4,6-dichloro-[1,3,5]triazin-2-ylamine, which was then further purified by making Recrystallization from a minimal amount of hot EtOAc afforded the product.

[0321]

[0322] (iia) Synthesis of 6-chloro-[1,3,5]triazine-2...

Embodiment 1

[0338] Example 1(b): 4-[(4-chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yl)-hydrazonomethyl]-2,6- Synthesis of Dimethoxy-phenol (7)

[0339]

[0340] (i) (4-chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yl)-hydrazine (6)

[0341] Using the method of Example 1a(iii), the compound was synthesized from (2a) with a yield of 99%.

[0342] M / Z (LC-MS, ESP): 231 [M+H] + , R / T = 2.93 minutes.

[0343] (ii) 4-[(4 chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yl)-hydrazonomethyl]-2,6-dimethoxy- Phenol(7)

[0344] This compound was synthesized from (6) using the method of Example 1a(iv).

[0345] M / Z (LC-MS, ESP): 97% purity, 395 [M+H] + , R / T = 4.08 minutes.

Embodiment 2

[0346] Example 2: Synthesis of 6-(N'-methylene-hydrazino)-pyrimidine-2,4-diamine derivatives (12)

[0347]

[0348] (i) Synthesis of 2,6-dichloro-pyrimidin-4-ylamine derivative (9)

[0349] To a cooled (-5 °C) solution of 2,4,6-trichloro-pyrimidine (8) (2.73 mmol) in ethanol (6 ml) was added the appropriate amine (2.73 mmol), followed by dropwise addition of Et 3 N (0.303ml, 2.18mmol). The cooling bath was removed and the reaction was allowed to warm to room temperature. Water was then added to the mixture, resulting in the formation of a precipitate. The solid was removed by suction filtration and washed with icy EtOH (6ml) to give the desired product which was then purified by flash chromatography (eluent typically 100% hexane to 4:1-hexane:EtOAc)

[0350]

[0351] (iia) Synthesis of 6-chloro-pyrimidine-2,4-diamine derivatives (10) (wherein the amine groups are different)

[0352] To a solution of the appropriate 2,6-dichloro-pyrimidin-4-ylamine derivative (9) (0.8...

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Abstract

Compounds of formula (I): A-B-C and isomers, salts, solvates, chemically protected forms, and prodrugs thereof wherein: B is selected from the group consisting of formula (i) where RN is H or Me; or B is a divalent C5 heterocyclic residue containing one or two ring heteroatoms; A is formula (ii) RA3 and RA5 are independently selected from halo, ORO and RAC, where RO is H or Me, and RAC is H or C1-4 alkyl; XA is selected from N and CRA4, where RA4 is selected from H, ORO, CH2OH, CO2H, NHSO2Me and NHCOMe; RA2 and RA6 are independently selected from H, halo and ORO; or RA3 and RA4 together with the carbon atoms to which they are attached, or RA2 and RA3 together with the carbon atoms to which they are attached, may form a C5-6 heterocylic or heteroaromatic ring, containing at least one nitrogen ring atom; where if X is not N, 1 , 2, or 3 of RA2 to RA6 are not H; C is formula (iii) where X is selected from N and CH, Y is selected from N and CH, and Z is selected from N and CRC6; RC3 is selected from H, halo and an optionally substituted N-containing C5-7 heterocyclic group; RC5 is a group selected from formula (iv) which group may be selected by one or two C1-4 alkyl groups or a carboxy group; RC6 is H; or, when X and Y are N, RC5 and RC6 (when Z is CRC6) together with the carbon atoms to which they are attached may form a fused C6 aromatic ring selected from the group consisting of formula (v).

Description

[0001] The present invention relates to compounds useful as mTOR inhibitors, their use and their synthesis. Background technique [0002] Growth factor / mitogenic activation of the phosphatidylinositol 3-kinase (P13K) AKT signaling pathway culminates in the critical cell cycle and growth control regulator mTOR, the mammalian target of rapamycin (alternatively referred to as FRAP (FKBP 12 and rapamycin-associated protein), RAFT1 (target of rapamycin and FKBP12 1), RAPT1 (target of rapamycin 1)—all derived from the association with the FK-506-binding proteins FKBP12 and SEP (Siro Mus effector protein) interaction). mTOR is a mammalian serine / threonine kinase of approximately 289 kDa in size, which is a member of the evolutionary conserved eukaryotic TOR kinases (References 1-4). The mTOR protein is a member of the P13-kinase-like protein kinase (PIKK) family because its C-terminus is compatible with P13-kinase and other members of this family, such as DNA-PKc (DNA-dependent prot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D251/70C07D403/04A61K31/53A61K31/506A61K31/517
CPCC07D401/14C07D471/04C07D417/04C07D403/04C07D405/14C07D251/54C07D405/04C07D403/14
Inventor M·G·胡默索恩S·戈梅茨K·A·梅尼尔X·-L·F·科克罗夫特G·C·M·史密思
Owner MAYBRIDGE LTD GB
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