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Functionalized thieno-indole derivatives for the treatment of cancer

A technology of indole and compounds, applied in the field of functionalized thienoindole derivatives for the treatment of cancer, which can solve the problems of lack of tumor cell selectivity, non-optimal physical and chemical properties, and the impossibility of reaching tumor drug concentrations, etc.

Active Publication Date: 2014-12-10
NERVIANO MEDICAL SERVICES SRL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, it is not possible to achieve drug concentrations capable of complete tumor eradication due to the dose-limiting side effects described
[0005] In addition to lack of selectivity against tumor cells, in some cases cytotoxic drugs display sub-optimal physicochemical properties and lack suitable pharmacokinetic properties, which limits their use in patients

Method used

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  • Functionalized thieno-indole derivatives for the treatment of cancer
  • Functionalized thieno-indole derivatives for the treatment of cancer
  • Functionalized thieno-indole derivatives for the treatment of cancer

Examples

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preparation example Construction

[0236] The present invention provides the preparation method of the compound of formula (I) or (II) defined above, it is characterized in that, described method comprises the following steps:

[0237] b) reacting a compound of formula (X) with a compound of formula (XIII),

[0238]

[0239] where X, Y, R 7 , R 8 and n are as defined above, and A 1 is A, wherein A is selected from OH, NH 2 and saturated groups of COOH,

[0240]

[0241] where R 16 Absent or hydrogen, halogen, -OH or -OR 17 , where R 17 is an activated moiety of a carboxyl group, such as an activated ester, or an activated -NH group, preferably p-toluenesulfonyl, and

[0242] L, W, Z and RM are as defined above, at least one of them is present;

[0243] c) reacting the resulting compound of formula (VIII) with a compound of formula (IX),

[0244]

[0245] Where X, Y, A 1 , R 7 , R 8 , L, W, Z, RM and n are as defined above,

[0246]

[0247] where R 14 is hydrogen or a protecting group,...

Embodiment 1

[0454] {2-[(2-{[(8S)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indole -6-yl]carbonyl}-1H-indol-5-yl)carbamoyl]-1H-indol-5-yl}carbamate tert-butyl ester (XIV)

[0455] step c, step c', deprotection, step e

[0456]

[0457] step c

[0458](8S)-8-(Chloromethyl)-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-ol prepared as reported in GB2344818 A solution of ((IX), 11.4 mg, 0.045 mmol) was dissolved in dry DMF (1 mL), washed with EDCI (35 mg, 4 eq.) and 5-[({5-[(tert-butoxycarbonyl)amino]- 1H-indol-2-yl}carbonyl)amino]-1H-indole-2-carboxylic acid (VIII) (29mg, 1.5eq.) as described in J.Med.Chem.2003, (46) The preparation reported on pages 634-637, the mixture was stirred at room temperature for 16 hours and then quenched by the addition of saturated aqueous NaCl. Isolation of the product was carried out by extraction with EtOAc (x4), followed by 2M aqueous HCl (x3), saturated Na 2 CO 3 The combined organic layers were washed with aqueous solution (x3)...

Embodiment 2

[0516] Coupling, deprotection, step e

[0517]

[0518] coupling

[0519]Preparation of (8S)-8-(chloromethyl)-6-({5-[(1H-indol-2-ylcarbonyl)amino]-1H-indol-2-yl}carbonyl)-1-methanol tert-butyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-ylpiperazine-1,4-dicarboxylate

[0520]

[0521] N-(2-{[(8S)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-6H-thieno[3,2-e]indole- 6-yl]carbonyl}-1H-indol-5-yl)-1H-indole-2-carboxamide (111 mg, 0.2 mmol) (prepared as reported in GB2344818) was dissolved in dry DCM (15 mL) and added to To this solution were added tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (100 mg, 0.4 mmol) and N,N-dimethylaminopyridine (55 mg, 0.45 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. The solvent was evaporated, the residue was dissolved in EtOAc, the resulting organic layer was washed with brine (x4), dried (Na 2 SO 4 ), concentrated under vacuum. The crude residue was purified by flash chromatogr...

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Abstract

The invention relates to new functionalized thieno-indole derivatives of formula (I) or (II) which have cytotoxic activity and are useful in treating diseases such as cancer and cellular proliferation disorders. The invention also relates to the use of these functionalized thieno-indole derivatives in the preparation of conjugates. Formula (I) or (II) wherein R1 and R2 taken together form a group (D) or (G): wherein R5 is hydrogen or C1-C4 alkyl; R3 and R4 are independently hydrogen, C1-C4 alkyl or C1-C4 hydroxyalkyi; n is 0, 1 or 2; each of X is independently -O-, -S- or -NR4-; each of Y is independently -CH = or -N=; R7 and R8 are independently hydrogen, halogen, hydroxy, C1-C4 alkoxy, cyano, -NHCOOR3, -C(NH)NH2 or -NR3R4; A is -O-, -NH- or -CO-; L is null or a conditionally-cleavable moiety; W is null or a self-immolative moiety comprising one or more self-immolative groups; Z is null or a peptidic, non peptidic or hybrid peptidic and non peptidic linker; RM is null or a reactive moiety; R6 is a leaving group; A1 is null or A; L1 is hydrogen or L.

Description

technical field [0001] The present invention relates to novel functionalized thienoindole derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of certain mammalian tumors. The invention also relates to their use in the preparation of conjugates. Background technique [0002] The lack of selectivity of chemotherapeutic drugs is a major problem in cancer treatment. [0003] Anticancer therapy is mainly based on cytotoxic drugs, which act on rapidly proliferating cells by different mechanisms. Cytotoxic drugs usually inhibit the proliferation of cancer cells by directly or indirectly interfering with DNA replication. [0004] Although this treatment is effective in different tumor types, it suffers from certain limitations: Interfering with cell proliferation actually affects normal cells that proliferate frequently. These include cells of the bone marrow, gastrointestinal tract, and hair follicles. Frequen...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61K31/407A61P35/00
CPCC07D495/04C07K5/06052C07K5/0812A61K47/65A61K31/496A61P35/00A61K31/407A61K45/06
Inventor I·伯利亚M·卡鲁索V·卢皮P·奥西尼M·萨尔萨
Owner NERVIANO MEDICAL SERVICES SRL
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