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2,4-diamino-pyridopyrimidine derivatives and their use as mTOR inhibitors

A technology of uses and groups, 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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  • 2,4-diamino-pyridopyrimidine derivatives and their use as mTOR inhibitors
  • 2,4-diamino-pyridopyrimidine derivatives and their use as mTOR inhibitors
  • 2,4-diamino-pyridopyrimidine derivatives and their use as mTOR inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0212]

[0213] raw material:

[0214] 1a: X 1 =N,X 2 =CH,X 3 =CH,X 4 =CH; 2-aminonicotinic acid

[0215] 1b:X 1 =CH,X 2 =CH,X 3 =N,X 4 =CH; 3-aminoisonicotinic acid

[0216] 1c:X 1 =CH,X 2 =CH,X 3 =CH,X 4 =N; 3-Amino-pyridine-2-carboxylic acid

[0217] (i) 1-H-pyridopyrimidine-2,4-dione (2)

[0218] Suspend the appropriate amino acid (1) (1 equivalent), potassium cyanate (5 equivalents) and ammonium chloride (10 equivalents) in water. The slurry was heated (160°C) and mixed by hand for 2 hours at which time water vapor was vented from the reactor. The reaction temperature was then raised to 200°C for 40 minutes, then cooled to 90°C while adding hot water, after which the mixture was allowed to cool to room temperature. The precipitate formed during cooling was removed by filtration, washed with water (twice) and diethyl ether (once) before drying in a desiccator to give the desired product of appropriate purity which was used without further purification. ...

Embodiment 2

[0235]

[0236] To 2-(2-chloromethyl-morpholin-4-yl)-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine (4aj ) (36mg, 0.1mmol) and a solution of the appropriate amine dissolved in dimethylacetamide (2.5ml) were added NaI (3mg, 0.02mmol) and K 2 CO 3 (14 mg, 0.1 mmol). The reactor was sealed and heated under the influence of microwave radiation (low absorption setting, 200°C, 10 minutes). The crude reaction mixture was then concentrated in vacuo and purified by preparative HPLC to give the desired product (5).

[0237]

[0238]

[0239]

[0240]

[0241] To 2-(2-chloromethyl-morpholin-4-yl)-4-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidine (4aj ) (36mg, 0.1mmol) (11mg, 0.03mmol) in anhydrous dimethylacetamide (0.5ml) was added tert-BuOK (6.8mg, 06mmol) and 18-crown-6-ether (0.006mmol, 1.6 mg). The appropriate alcohol was then added to the reaction mixture and the reactions were heated to 110°C for 15 hours. The crude reaction mixture was then con...

Embodiment 3

[0244] Embodiment 3: biological test

[0245] For mTOR enzymatic activity assays, mTOR protein was isolated from HeLa cell cytoplasm by immunoprecipitation and activity was determined essentially as previously described (ref. 21 ) using recombinant cell PHAS-1 as substrate.

[0246] All tested compounds showed ICs less than 15 μM 50 value.

[0247] The following compounds exhibited ICs less than 1.5 μM 50 Values: 4c, 4d, 4h, 4n, 4o, 4y, 4ab, 4af, 4ag, 4ah, 5e, 5g, 5h, 5k, 5m, 5z.

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Abstract

Compounds of formula (I) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof one of X1, X2 and X3 is N, and the others are CH; RN1 and RN2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring having from 4 to 8 ring atoms; RN3 and RN4 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring having from 4 to 8 ring atoms and their use in treating diseases ameliorated by the inhibition of mTOR.

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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IPC IPC(8): A61K31/519C07D471/04
CPCC07D471/04A61P35/00
Inventor M·G·胡默索恩S·戈梅茨K·A·梅尼尔X·-L·F·科克罗夫特P·爱德华兹V·J·M·L·洛G·C·M·史密思
Owner MAYBRIDGE LTD GB
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