Synthesis of New Pyrrolo[1,2-a]quinoxaline Derivatives as Potential Inhibitors of Akt Kinase

Figures & data

Figure 1 Structures of 2,3-diphenylquinoxaline I, pyrazinones II-III, quinoxaline IV and V (A6730), Akt kinase inhibitors.

Figure 2 General structure of synthesized substituted pyrrolo[1,2-a]quinoxaline derivatives 1.

Scheme 1 Synthesis of the 1,3-dihydro-1-{1-[4-(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]piperidin-4-yl}-2H-benzimidazol-2-ones 1a-g. Reagents and conditions: (i) DMTHF, AcOH, Δ; (ii) Method A: CuSO₄, NaBH₄, EtOH, RT for 3a-d; Method B: SnCl₂, 2H₂O, EtOH, Δ for 3e; (iii) CO(OCCl₃)₂, toluene, Δ; (iv) POCl₃, Δ; (v) Method A: OHC-C₆H₄-B(OH)₂, Pd[P(C₆H₅)₃]₄, Na₂CO₃, C₆H₆, EtOH, Δ; Method B: OHC-C₆H₄-BF₃K, PdCl₂(dppf)·CH₂Cl₂, Cs₂CO₃, THF-H₂O, Δ; (vi) 4-(2-ketobenzimidazolin-1-yl)piperidine, NaBH₃CN, MeOH, Δ; (vii) 1e, NaN₃, NH₄Cl, DMF, Δ.

Scheme 2 Synthesis of the 1,3-dihydro-1-{1-[4-(4-phenylpyrrolo[1,2-a]quinoxalin-1-yl)benzyl- or -methyl]piperidin-4-yl}-2H-benzimidazol-2-ones 1h-i. Reagents and conditions: (i) C₆H₅COCl, toluene, pyridine, Δ; (ii) POCl₃, Δ; (iii) POCl₃/DMF, DMF, Δ; (iv) 4-(2-ketobenzimidazolin-1-yl)piperidine, NaBH₃CN, MeOH, Δ; (v) NBS, CH₂Cl₂, RT; (vi) OHC-C₆H₄-B(OH)₂, Pd[P(C₆H₅)₃]₄, K₂CO₃, toluene, EtOH, Δ; (vii) 4-(2-ketobenzimidazolin-1-yl)piperidine, NaBH₃CN, MeOH, Δ.

Scheme 3 Synthesis of the 1,3-dihydro-1-{1-[4-(4-phenylpyrrolo[1,2-a]quinoxalin-2-yl)methyl]piperidin-4-yl}-2H-benzimidazol-2-ones 1j-k. Reagents and conditions: (i) C₆H₅COCOCH₃, AcOH, Δ; (ii) BrCH₂COCOOC₂H₅, EtOH, Δ; (iii) LiAlH₄, THF, Δ; (iv) MnO₂, CHCl₃, Δ; (v) 4-(2-ketobenzimidazolin-1-yl)piperidine, NaBH₃CN, MeOH, Δ.

Figure 3 The ORTEP drawing of 1,3-dihydro-1-{1-[4-(4-phenylpyrrolo[1,2-a]quinoxalin-2-yl)methyl]piperidin-4-yl}-2H-benzimidazol-2-ones 1j and 1k with thermal ellipsoids at 30% level.

Table I.  In vitro activity of compounds 1a-k on U937, K562, HL60 and MCF7 cells, and cytotoxicity on human peripheral blood mononuclear cells PBMNC + PHA.

	IC50 values (μM)^a
Compound	U937	K562	HL60	MCF7	Cytotoxicity on activated human peripheral blood mononuclear cells (PBMNC) PBMNC+PHA
A6730	8 ± 0.2	8 ± 0.3	5.5 ± 0.2	>20	n.d.^b
1a	>20	4.5 ± 0.2	14 ± 0.4	20 ± 1	10 ± 0.5
1b	>20	>20	>20	>20	43 ± 2
1c	>20	10 ± 0.3	10 ± 0.3	>20	9 *** ± 0.4
1d	>20	16 ± 0.4	>20	>20	>50
1e	>20	>20	10 ± 0.4	>20	44 ± 2
1f	>20	9 ± 0.3	>20	>20	8 ± 0.4
1g	>20	>20	>20	>20	>50
1h	5 ± 0.1	>20	20 ± 1	8 ± 0.3	9 ± 0.4
1i	>20	>20	15.5 ± 0.4	>20	>50
1j	16 ± 0.3	8 ± 0.2	14 ± 0.3	17 ± 0.4	5 ± 0.1
1k	17 ± 0.3	17 ± 0.4	>20	>20	35 ± 3

^a The IC₅₀ (μM) values correspond to the mean+/ − standard deviation from 3 independent experiments.

^b n.d. = not determined.