Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as parp inhibitors

A technology of heterocyclyl and cycloalkyl, applied in the field of tetracyclic or pentacyclic compounds

Active Publication Date: 2014-04-02
百济神州(苏州)生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Tankyrase-2 may have an overall sequence identity of 83% and a sequence similarity of 90% to Tankyrase-1

Method used

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  • Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as parp inhibitors
  • Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as parp inhibitors
  • Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as parp inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0203] Example 1: Synthesis of Compounds 1-19.

[0204] Compound 1: 2,3,5,10-tetrahydro-[1,2]diazepine And[3,4,5,6-def]carbazol-6(1H)-one

[0205]

[0206] step 1: Methyl 2-bromo-3-((3-oxocyclohex-1-en-1-yl)amino)benzoate

[0207]

[0208] Methyl 3-amino-2-bromobenzoate (2.39 g, 10.0 mmol) and cyclohexane-1,3-dione (1.12 g, 10.0 mmol) were dissolved in acetic acid (10 mL) at 25 °C under nitrogen . The mixture was stirred at 80°C for 8 hours. The resulting solid was purified by column chromatography on silica gel (eluting with hexane and ethyl acetate) to give 2-bromo-3-((3-oxocyclohex-1-en-1-yl)amino)benzoic acid Methyl ester (2.46 g, 76%) as a tan foam. 1 H NMR (CDCl 3 -d 1 )δ7.53-7.55(m,2H),7.37(dd,1H,J=7.2,8.4Hz),6.34(broad singlet,1H),5.57(s,1H),3.95(s,3H),2.56 -2.59(m,2H),2.40-2.42(m,2H),2.08-2.11(m,2H). MS(ESI)m / e[M+1] + 324.0.

[0209] Step 2: 4-Oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylic acid methyl ester

[0210]

[0211] Methyl 2-bromo-3...

Embodiment 2

[0220] Embodiment 2: the synthesis of compound 20-21

[0221] Compound 20: 8-Oxo-3,4,8,9-tetrahydro-2,4,9,10-tetraazepine[def]fluorene -2(1H)-Benzyl carboxylate

[0222]

[0223] step 1: 3-((2-bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)- Benzyl carboxylate

[0224]

[0225] Methyl 3-amino-2-bromobenzoate (0.25 g, 1.1 mmol) and benzyl 3,5-dioxopiperidine-1-carboxylate (0.13 g, 0.55 mmol) were dissolved at 25 °C under nitrogen in acetic acid (10 mL). The mixture was stirred at 70°C for 8 hours. The resulting solid was purified by column chromatography on silica gel (eluting with hexane / ethyl acetate) to give 3-((2-bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5 , Benzyl 6-dihydropyridine-1(2H)-carboxylate (0.13 g, 51%) as a tan foam. 1 H NMR (CDCl 3 -d 1 )δ7.53-7.58(m,3H),7.42-7.48(m,5H),5.56(s,1H),5.16(s,2H),4.46(s,2H),4.13(s,2H),3.93 (s,3H). MS(ESI)m / e[M+1] + 459.0.

[0226] Step 2: 4-Oxo-3,4-dihydro-1H-pyrido[3,4-b]indole-2,5(...

Embodiment 3

[0236] Embodiment 3: the synthesis of compound 22-25

[0237] Compound 22: 10-Methyl-2,3,5,10-tetrahydro-[1,2]diazepine and [3,4,5,6-def]carbazole -6(1H)-one

[0238]

[0239] step 1: 9-Methyl-4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylic acid methyl ester

[0240]

[0241] To a solution of methyl 4-oxo-2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate (0.27 g, 1 mmol) in THF (5 ml) was added at 0 °C under nitrogen Potassium tert-butoxide (0.12 g, 1.05 mmol). After the reaction mixture was stirred for 30 minutes, iodomethane (0.76 g, 5.0 mmol) was added. After 3 hours, the reaction mixture was concentrated to give a residue and partitioned between EtOAc (40ml) and 1N HCl (5ml). Shake and separate layers. The organic layer was washed with 1N HCl (2×80ml) and brine (2×10ml), washed with Na 2 SO 4 Drying, filtration and concentration gave a solid (0.46g). The solid was directly used in the next reaction without further purification. 1 H NMR (DMSO-d 6 )δ7...

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Abstract

Provided are certain fused tetra or penta-cyclic compounds and salts thereof, compositions thereof, and methods of use thereof.

Description

technical field [0001] The present invention discloses fused tetracyclic or pentacyclic compounds which can inhibit the activity of poly(ADP-ribose) polymerases (PARPs), pharmaceutical compositions comprising at least one of said compounds and their Use in the treatment of certain diseases. Background technique [0002] Poly(ADP-ribose) polymerases (PARPs), previously recognized as poly(ADP-ribose) synthases or poly(ADP-ribose)transferases, are a family of proteins containing a PARP catalytic domain (BMC Genomics, 2005Oct.4; 6:139.). About 17 members of the PARP family have been discovered so far, including PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), PARP-5a (tankyrase-1 (Tank y rase-1)), PARP5b (tankyrase-2), PARP-6, PARP-7 (tiPARP), PARP-8, PARP-9 (BAL1), PARP-10, PARP-11, PARP-12, PARP-13(ZAP), PARP-14(CoaSt6), PARP-15 and PARP-16. The catalytic activity of PARP is to convert the ADP-ribose moiety from nicotinamide adenine dinucleotide (NAD + ) to glutamic acid resi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/06A61K31/55A61P35/00
CPCC07D487/06C07D487/14C07D471/22C07D487/04C07D471/16A61K31/551A61P29/00A61P35/00A61P37/00A61K31/5517
Inventor 周昌友任博王鹤翔
Owner 百济神州(苏州)生物科技有限公司
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