WO2012107934A1 - Analogues de flinderole et leur procédé de synthèse - Google Patents

Analogues de flinderole et leur procédé de synthèse Download PDF

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Publication number
WO2012107934A1
WO2012107934A1 PCT/IN2011/000899 IN2011000899W WO2012107934A1 WO 2012107934 A1 WO2012107934 A1 WO 2012107934A1 IN 2011000899 W IN2011000899 W IN 2011000899W WO 2012107934 A1 WO2012107934 A1 WO 2012107934A1
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Prior art keywords
och
chc0
conh
ococh
nhme
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PCT/IN2011/000899
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English (en)
Inventor
Dattatraya Hanumant DETHE
Rohan Diliprao ERANDE
Alok RANJAN
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Council of Scientific and Industrial Research CSIR
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Council of Scientific and Industrial Research CSIR
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Priority to CN2011800697848A priority Critical patent/CN103476775A/zh
Priority to EP11817423.4A priority patent/EP2673276A1/fr
Publication of WO2012107934A1 publication Critical patent/WO2012107934A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides a compound of general formula I and analogues thereof. Particularly, the present invention further discloses a highly stereo- and regioselective [3 +2] cycloaddition process for the preparation of Flinderole compound/analogues of general formula 1.
  • the present invention further provides compounds of general formula 1 which are useful as antimalarial compounds.
  • Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium.
  • Four strains of the parasite are responsible for malaria in humans, Plasmodium falciparum, P. vivax, P. ovale, and P. malariae.
  • Plasmodium falciparum the most severe form of malaria, is responsible for the vast majority of deaths associated with the disease.
  • Malaria is commonly associated with poverty, and can indeed be a cause of poverty and a major hindrance to economic development.
  • Nitrogen-containing heterocycles have been used as medicinal compounds for centuries, and form the basis for many common drugs such as Morphine (analgesic), Captopril (treatment of hypertension) and Vincristine (cancer chemotherapy).
  • Morphine analgesic
  • Captopril treatment of hypertension
  • Vincristine cancer chemotherapy
  • the chemical structure of the flinderoles is based on the nitrogen-containing indole ring system; however, these compounds have a novel structure not reported in the literature, due to the attachment of the two indole rings.
  • the flinderoles are related to the borreverine compounds, such as isoborreverine,
  • FIG. 1 Proposed routes for coupling Fragments A and B.
  • flinderoles disclosed in the prior art are either isolated from the natural sources which have the limitations in view of environmental, biodiversity issues etc. or are synthesized by lengthy, non-economical processes.
  • the inventors proposed to further research into these novel compounds for use as an agent against potent and resistant P.falciparum.
  • the inventors have also perceived the need to evolve a synthetic process for such effective compounds, such that the process fulfills the market needs for such effective compounds and also leads to compounds with enhanced bioactivity.
  • the main object of the present invention is to provide flinderole compounds /analogues of general formula I, excluding the proviso which comprises known Flinderoles A, B and C, as effective antimalarials.
  • the another object of the invention is to provide a feasible, cost effective process for the preparation of Flinderoles and its analogues of general formula I as antimalarials especially for effective treatment against Plasmodium falciparum.
  • Another object of the invention is to provide a highly stereo- and regioselective [3 +2] cycloaddition process for the preparation of Flinderole compound/analogues of general formula 1.
  • Yet another object of the present invention is to provide a process for the synthesis of compounds of formula I such that the process is useful for production of commercial quantities of such compounds with improved level of bioactivity.
  • the present invention provides flinderole compounds /analogues of formula I, , excluding the provisos which comprises known Flinderoles A, B and C, as effective antimalarials.
  • R 6 is -CH 2 CH 2 NHMe and R 7 is -H;
  • R 6 is -CH 2 CH 2 NMe 2 and R 7 is -H are known compounds in the art and represent Flinderoles A, B and C.
  • R 9 represents -H, -CH 3
  • R 7 -H, -CH 3 , -COCH 3 , -S02Ph, -(BOC), -(Ph-F), -(Bn), -(C 5 Hi 0 F), -(C0 2 Et), -(MOM).
  • R 8 represents -H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -Br, -CI, -F, -I, -CH 2 OH, -CH 2 OCH 3 , -CH 2 OBn -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 Br.
  • R 3 is -H
  • R 5 is CH 3 ,
  • R 6 is -CH 2 CH 2 NHMe and R 7 is -H;
  • R 6 is -CH 2 CH 2 NMe 2 and R 7 is -H are excluded.
  • said compounds are useful as anti-malarial compound.
  • step (d) e. reacting alcohol (la') as obtained in step (d) optionally with sulphonated diene (lb') as obtained in step (b) or desulphonated diene (le') as obtained in step (c) in presence of Lewis acid and a non- polar solvent at temperature in the range of 25 to 32°C to obtain sulphonated or desuphonated compound of general formula 1;
  • step (e) desulfonylating sulphonated compound of general formula 1 as obtained in step (e) using methanoiic NaOH to obtain desulphonated Flinderole A-C and compounds of general formula I .
  • Lewis acid used in step (e) is selected from Cu(OTf)2 or BF 3 OEt 2 .
  • reaction mixture 50 to 70 minutes at temperature in the range of 25 to 32°C followed by adding water to obtain reaction mixture;
  • step (b) extracting the reaction mixture as obtained in step (a) with non-polar solvent, washing with brine, drying followed by evaporating the solvent;
  • Lewis acid used in step (a) is selected from Cu(OTf)2 or BF 3 OEt 2 .
  • compositions for the treatment of malaria comprising compounds of general formula I optionally along with pharmaceutically acceptable excipients.
  • Scheme 1 represents the cycloaddition reaction between a tertiary alcohol (la') and an olefin (lb') to obtain compound of general formula 1.
  • Scheme 2 represents the structures of flinderoles A-C and the proposed biosynthetic pathway.
  • Scheme 3 represents flow chart for the preparation of compound of general formula 1.
  • Scheme 4 represents process steps for the preparation of intermediate compounds.
  • Scheme 5 represents compound 11 to 17 and process steps for the preparation of compound 9a, 9b, 10a and 10b.
  • Scheme 6 represents process steps for the preparation of compound 17-28 and flinderole B and C.
  • Figure 1' represents proposed stereo chemical model for the [3+2] cycloaddition.
  • the present invention provides Flinderole compounds/ analogues of general formula I,
  • the present invention also relates to a highly stereo- and regioselective [3 +2] cycloaddition reaction between a tertiary alcohol (la') and a diene (lb') (olefin) in presence of Lewis acid and a non-polar solvent at room temperature (25 to 32°C). (Scheme 1).
  • the process for the preparation of flinderoles of compounds/ analogues of formula I by the instsnt invention includes Flinderoles A, B and C.
  • Flinderoles A, B and C contain an unprecedented rearranged skeleton compared to their related isomers of the borreverine class of compounds. (Scheme 2)
  • diene (lb') Mesylation of alcohol (la') and subsequent elimination yielded diene (lb'), which give the required diene (le') upon desulfonylation using methanolic NaOH.
  • the diene (le') is found to polymerize with different Lewis acids under various reaction conditions employed, resulting in intractable mixtures. It is reasonably concluded that the actual site of protonation in 4 is at C3 of the indole nucleus to produce a conjugated enamine, which could undergo cationic polymerization.
  • the pesent invention discloses the preparation of flinderoles 9a and 9b by dimerization of alcohol (8) in presence of various Lewis acids as shown in Scheme 4 nd Table 1 below. Various Lewis acids were screened for the proposed dimerization of the alcohol 8 and results are summarized in Table 1.
  • the present invention provides a highly stereo- and regioselective [3 +2] cycloaddition reaction between a tertiary alcohol (la') and a sulphonated diene (lb') in presence of Lewis acid selected from Cu(OTf)2 or BF 3 Et 2 for the synthesis of flinderole compounds and its analogues of formula I comprising;
  • Dehydration of the hydroxyl group of alcohol 24 is achieved via its mesylate followed by elimination to furnish the requisite olefin 19.
  • Deprotection of the phenylsulfonyl group in alcohol 24 with sodium amalgam gives the other coupling partner, alcohol 18 (Scheme 6).
  • An equimolar mixture of the tert alcohol 18 and the diene 19 are treated with catalytic amount of copper(ll) triflate, which lead to the adduct 25a in 62% yield with diastereoselectivity.
  • TFA salt of synthetic flinderoles B and C possess physical properties (IR, mass, H, 13 C) identical to those reported in the literature.
  • compound of formula 9a and 9b are obtained by desulphonation of compounds of formula 10a and 10b using sodium amalgam as shown in Scheme 6.
  • the flinderole compounds/analogues of formula I finds use in pharmaceutical industry, in agriculture; preferably in pharmaceutical industry for the treatment of malaria especially against Plasmodium falciparum.
  • the present invention provides a method of treatment or prevention of malaria to a subject by administering an effective amount of the compound of Formula I along with one or more suitable pharmaceutical carriers/excipients.
  • the dosage forms include solid dosage forms such as tablets, powders, capsules, liquid dosage forms as well as parenteral dosage forms.
  • the dosage forms can also be prepared as sustained, controlled, modified and immediate release dosage forms. Active ingredient(s) and excipients can be formulated into compositions and dosage forms according to methods known in the art.
  • Reaction were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm Merck silica gel plates (60F-254) using UV light as a visualizing agent and an p- anisaldehyde or ninhydrine stain, and heat as developing agents.
  • TLC thin-layer chromatography
  • Merck silica gel particle size 100-200 and 230-400 mesh
  • Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated.
  • methylmagnesium iodide [prepared from magnesium turnings (3.4 g, 138.1 mmol), methyl iodide (11.5 ml, 184.4 mmol) and few crystals of iodine in anhydrous ether (50 ml)] was added slowly a mixture of the ester lOf (13 g, 46.1 mmol ) in anhydrous ether (50 ml) .
  • the reaction mixture was stirred for 2 h at RT. It was then quenched with aq .
  • methylmagnesium iodide [prepared from magnesium turnings (6.4 g, 29.2 mmol), methyl iodide (18.2 ml, 292.4 mmol) and few crystals of iodine in anhydrous ether (50 ml)] was added slowly a mixture of the ester 23' (15 g, 269.1 mmol) in anhydrous ether (50 ml).
  • the reaction mixture was stirred for 2 h at RT. It was then quenched with aq. NH 4 CI solution (50 ml), extracted with ethyl acetate (3 x 15 ml), washed with brine and dried over Na 2 S0 4 . Evaporation of the solvent and purification of the residue on a silica gel column using EtOAc-hexane (3:7) as eluent furnished the alcohol 24 (13 g, 89%) as a white solid;
  • Flinderole C (10 mg) was treated with 0.5 solution of TFA in acetonitrile to obtain the TFA salt of flinderole C;
  • Flinderole B (30 mg) was treated with 0.5M solution of TFA in acetonitrile to obtain the TFA salt of flinderole B;

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés/analogues de flinderole de formule I et leur procédé de préparation, comprenant une réaction de cycloaddition stéréo- et régiosélective [3+2] d'un alcool tertiaire (1a') et d'un diène sulfoné (1b') en présence d'acide de Lewis choisi parmi Cu(OTf)2 ou BF3OEt2 et un solvant non polaire à la température ambiante. Les composés/analogues de flinderole selon la présente invention et préparés par le procédé selon l'invention sont représentés par la formule I, dans laquelle R1-R4 sont tels que définis dans la description.
PCT/IN2011/000899 2011-02-10 2011-12-28 Analogues de flinderole et leur procédé de synthèse Ceased WO2012107934A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN2011800697848A CN103476775A (zh) 2011-02-10 2011-12-28 Flinderole类似物及其合成方法
EP11817423.4A EP2673276A1 (fr) 2011-02-10 2011-12-28 Analogues de flinderole et leur procédé de synthèse

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Application Number Priority Date Filing Date Title
IN336DE2011 2011-02-10
IN0336/DEL/2011 2011-02-10

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102964352A (zh) * 2012-11-23 2013-03-13 华中师范大学 具有生物活性的手性2，3-二氢吡咯［1，2-a］吲哚衍生物及其不对称合成方法

Families Citing this family (1)

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CN118955508B (zh) * 2024-07-30 2026-01-30 浙江大学 α-吲哚基吡咯并[1,2-a]吲哚衍生物及其制备方法

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WO2006046949A1 (fr) * 2004-10-22 2006-05-04 Walter Reed Army Institute Of Research (Wrair) SYNTHÈSE ET ACTIVITÉ ANTIMALARIALE DE DÉRIVÉS DE PYRROLO[3,2-f]QUINAZOLINE-1,3-DIAMINE
WO2009094157A1 (fr) * 2008-01-25 2009-07-30 Arena Pharmaceuticals, Inc. Dérivés carboxyliques dihydro-1h-pyrrolo[1,2-a]indol-1-yle agissant comme des agonistes de s1p1
WO2009153516A1 (fr) * 2008-06-16 2009-12-23 Sanofi-Aventis Nouveaux derives de pyrroloindole inhibiteurs d'hsp90, compositions les contenant et utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006046949A1 (fr) * 2004-10-22 2006-05-04 Walter Reed Army Institute Of Research (Wrair) SYNTHÈSE ET ACTIVITÉ ANTIMALARIALE DE DÉRIVÉS DE PYRROLO[3,2-f]QUINAZOLINE-1,3-DIAMINE
WO2009094157A1 (fr) * 2008-01-25 2009-07-30 Arena Pharmaceuticals, Inc. Dérivés carboxyliques dihydro-1h-pyrrolo[1,2-a]indol-1-yle agissant comme des agonistes de s1p1
WO2009153516A1 (fr) * 2008-06-16 2009-12-23 Sanofi-Aventis Nouveaux derives de pyrroloindole inhibiteurs d'hsp90, compositions les contenant et utilisation

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Title
DATTATRAYA H D ET AL: "Biomimetic Total Synthesis of Flinderoles B and C", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 133, no. 9, 11 February 2011 (2011-02-11), pages 2864 - 2867, XP002671884 *
FERNANDEZ L S ET AL: "Antiparasitic activity of alkaloids from plant species of Papua New Guinea and Australia", INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, vol. 36, no. 3, 1 September 2010 (2010-09-01), ELSEVIER SCIENCE, AMSTERDAM, NL, pages 275 - 279, XP027147676, ISSN: 0924-8579, [retrieved on 20100716] *
FERNANDEZ L S ET AL: "Flinderoles A-C: Antimalarial Bis-indole Alkaloids from Flindersia Species", ORGANIC LETTERS, vol. 11, no. 2, 17 December 2008 (2008-12-17), pages 329 - 332, XP002671883 *
LIZA S. FERNANDEZ: "Flinderoles A-C: Antimalarial Bis-indole Alkaloids from Flindersia Species", ORG. LETT., vol. 11, no. 2, 2009, pages 329 - 332, XP002671883, DOI: doi:10.1021/OL802506N

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102964352A (zh) * 2012-11-23 2013-03-13 华中师范大学 具有生物活性的手性2，3-二氢吡咯［1，2-a］吲哚衍生物及其不对称合成方法

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EP2673276A1 (fr) 2013-12-18

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