(19)
(11)EP 2 812 333 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
03.10.2018 Bulletin 2018/40

(21)Application number: 13708897.7

(22)Date of filing:  08.02.2013
(51)International Patent Classification (IPC): 
C07D 471/04(2006.01)
A61K 31/517(2006.01)
A61K 31/4745(2006.01)
A61P 31/06(2006.01)
(86)International application number:
PCT/IB2013/000164
(87)International publication number:
WO 2013/117986 (15.08.2013 Gazette  2013/33)

(54)

PYRROLOQUINOLINE ALKALOIDS AS ANTIMALARIAL AGENTS AND PROCESS FOR THE PREPARATION THEREOF

PYRROLOCHINOLINALKALOIDE ALS ANTIMALARIAMITTEL UND HERSTELLUNGSVERFAHREN DAVON

ALCALOÏDES DE TYPE PYRROLOQUINOLINE COMME AGENTS ANTIPALUDIQUES ET PROCÉDÉ DE PRÉPARATION ASSOCIÉ


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 08.02.2012 IN 356DE2012

(43)Date of publication of application:
17.12.2014 Bulletin 2014/51

(73)Proprietor: Council of Scientific & Industrial Research
New Delhi 110 001 (IN)

(72)Inventors:
  • MHASKE, Santosh, Baburao
    Maharashtra Pune-411008 (IN)
  • LANDE, Jyoti, Reveji
    Maharashtra Pune-411008 (IN)

(74)Representative: AWA Sweden AB 
P.O. Box 5117
200 71 Malmö
200 71 Malmö (SE)


(56)References cited: : 
  
  • ANTHONY R. CARROLL ET AL: "Aplidiopsamine A, an Antiplasmodial Alkaloid from the Temperate Australian Ascidian, Aplidiopsis confluata", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 75, no. 23, 3 December 2010 (2010-12-03), pages 8291-8294, XP055059546, ISSN: 0022-3263, DOI: 10.1021/jo101695v cited in the application
  • PATRICK W. OKANYA ET AL: "Marinoquinolines A-F, Pyrroloquinolines from Ohtaekwangia kribbensis (Bacteroidetes)", JOURNAL OF NATURAL PRODUCTS, vol. 74, no. 4, 25 April 2011 (2011-04-25) , pages 603-608, XP055059571, ISSN: 0163-3864, DOI: 10.1021/np100625a
  • LIJUN NI ET AL: "Concise total syntheses of Marinoquinolines AC", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 53, no. 10, 30 December 2011 (2011-12-30), pages 1271-1274, XP028454579, ISSN: 0040-4039, DOI: 10.1016/J.TETLET.2011.12.124 [retrieved on 2012-01-05]
  • THIBAUD GERFAUD ET AL: "Palladium-Catalyzed Annulation of Acyloximes with Arynes (or Alkynes): Synthesis of Phenanthridines and Isoquinolines", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 48, no. 3, 5 January 2009 (2009-01-05), pages 572-577, XP055059596, ISSN: 1433-7851, DOI: 10.1002/anie.200804683 cited in the application
  • CRISTIANE STORCK SCHWALM ET AL: "Divergent total synthesis of the natural antimalarial marinoquinolines A, B, C, E and unnatural analogues", TETRAHEDRON LETTERS, vol. 53, no. 36, 2 July 2012 (2012-07-02), pages 4836-4840, XP055059574, ISSN: 0040-4039, DOI: 10.1016/j.tetlet.2012.06.115
  • JYOTI P. MAHAJAN ET AL: "Pd-Catalyzed Imine Cyclization: Synthesis of Antimalarial Natural Products Aplidiopsamine A, Marinoquinoline A, and Their Potential Hybrid NCLite-M1", ORGANIC LETTERS, vol. 14, no. 22, 16 November 2012 (2012-11-16), pages 5804-5807, XP055059577, ISSN: 1523-7060, DOI: 10.1021/ol302676v
  • JOSEPH D. PANARESE ET AL: "Biomimetic Synthesis and Biological Evaluation of Aplidiopsamine A", ORGANIC LETTERS, vol. 14, no. 22, 16 November 2012 (2012-11-16), pages 5808-5810, XP055059578, ISSN: 1523-7060, DOI: 10.1021/ol3024665
  • MA, XINGHUA ET AL: "Total Synthesis of Marinoquinoline A Using a Palladium(0)-Catalyzed Ullmann Cross-Coupling Reaction", ASIAN JOURNAL OF ORGANIC CHEMISTRY , 1(2), 160-165 CODEN: AJOCC7; ISSN: 2193-5807, 2012, XP002695465,
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description

FIELD OF THE INVENTION:



[0001] The present invention relates to field of novel compounds of the pyrroloquinoline alkaloids group and process for the preparation thereof. Particularly, the present invention relates to novel anti-malarial compounds and process of synthesis thereof. Further, the present invention also discloses the process for the synthesis of known antimalarial natural products and their potential antimalarial analogues.

Background and prior art:



[0002] Alkaloids are highly important pharmacophores and currently available methods for the synthesis of substituted pyridine based alkaloids are tedious, lengthy and low yielding.

[0003] The natural products Marinoquinoline A-F, Aplidiopsamine A and related natural products have very good antimalarial activity but till date their synthesis is not known.

[0004] Sangoi et al in Marine Drugs, 2008, 6, 578-586 reports the acetylcholinerase-inhibiting activity of pyrrole derivatives obtained from a novel marine gliding bacterium, Rapithidix thailandica.

[0005] Gerfaud et al in Angew Chem Int, 2009, 48, 572-577 reported a process which leads to a rapid constriction of functionalized phenanthridines and isoquinolines by a domino aminopalladation/C-H functionalization sequence.

[0006] Carroll et al in JOC, vol 75, No: 23, 2010, 8291 describes Aplidiopsamine A isolated from the temperate Australian ascidian Aplidiopsis confluata and its anti-malarial properties.

[0007] But there is a need in the art to provide synthetic routes of synthesis of anti-malarial compounds isolated from natural resources such that therapies are available for drug resistant strains of plasmodium. It would be advantageous if such processes are simple, with reactants freely available and result in good yields and selectivity.

[0008] Further there is a continuous need for novel compounds that possess anti-malarial properties, such that clinicians have alternatives available to combat drug resistance in subjects infected with malaria.

Object of invention:



[0009] The main object of the present invention is to provide novel compounds of the pyrroloquinoline alkaloids group and process for the preparation thereof.

[0010] Another object of the invention is to provide novel compounds of the pyrroloquinoline alkaloids group that possess therapeutic activity.

[0011] Another object of the invention is to provide novel and efficient palladium catalyzed C-H activation methodology for the synthesis of substituted Pyrroloquinoline based alkaloids.

SUMMARY OF THE INVENTION



[0012] Accordingly, the present invention provides a compound of formula I,

wherein R, R1, R2 are selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,

X is selected from halide or hydrogen

R3 is of formula III, and

R4 is selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,



and pharmaceutically acceptable salt thereof.

[0013] In one embodiment of the present invention, a process for the preparation of compound of formula I is provided,

said process comprising the following steps:
  1. a. refluxing ketone of formula

    wherein R, is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl with aniline of formula

    wherein R is selected from H, halide, alkyl, aryl and hetero alkyl/aryl,

    X is either halide or an activating group selected from the group consisting of OTf, OTs, B(OR)2, SnR3 and SiR3 in mole ratio 1:1 in a solvent preferably dry toluene for a period ranging between 12-24 hours followed by work up to obtain corresponding imine of formula



    wherein R is selected from H, halide, alkyl, aryl and hetero alkyl/aryl,

    X is either halide or an activating group selected from the group consisting of OTf, OTs, B(OR)2, SnR3 and SiR3,

  2. b. Catalyzing the conversion of corresponding imine of step (a) in the presence of Pd catalyst, ligand, base and solvent at temperature ranging between 100-120°C for a period between 8-24 hrs to obtain corresponding quinoline of formula;

    wherein R is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl,
  3. c. Catalyzing the conversion of quinoline compound of step (b) to obtain corresponding substituted quinoline of formula

  4. d. reacting substituted quinoline obtained in step (d) with substituted or unsubstituted quinazolin-4(3H)-one compound to obtain a product of formula I.

    R' is of formula III, and

    R4 is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl,

  5. e. optionally deprotecting the -SO2Ph group by methanol and K2CO3.


[0014] One embodiment of the present invention relates to the process according to claim 2, wherein the yield is in the range of 40 % to 98 %.

[0015] In another embodiment of the present invention the catalyst is preferably Pd(OAc)2 in the range of 1 mol% to 20 mol%, and the catalyst is used in the presence of a ligand.

[0016] In still another embodiment of the present invention the ligand is selected from triphenyl phosphate, PPh3, Neocuproine, Tricyclohexylphosphine PCy3, preferably PPh3 in the range of 1 mol% to 40 mol%.

[0017] In yet another embodiment of the present invention the base is selected from K2CO3, Cs2CO3, Ag2CO3, KOtBu, preferably Ag2CO3 in the range of 1 mol% to 200 mol%.

[0018] In yet another embodiment of the present invention the solvent is chosen from 1,4-dioxane, dry toluene, dimethylformamide DMF, Benzene, tetrahydrofuran THF, preferably 1,4-dioxane.

[0019] In yet another embodiment of the present invention the catalyst is N-bromo succinimide NBS and radical initiators are Aza iso butyro nitrile (AIBN), Aza Bis cyanide (ABCN), Benzyl peroxide (BPO).

[0020] Also described is a compound of formula I,



wherein R, R1, -R2 are selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,

X is selected from halide or hydrogen,

R3 is of formula III, and

wherein R4 is selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,



and pharmaceutically acceptable salt thereof useful as antimalarial agents.

[0021] Further described is a compound of formula I,

wherein R, R1, -R2 are selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,

X is selected from halide or hydrogen,

R3 is of formula III,

wherein R4 is selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,.



and pharmaceutically acceptable salt thereof useful as antimycobacterial agents.

BRIEF DESCRIPTION OF THE DRAWINGS



[0022] 

Figure 1: 1H NMR spectra of compound 8

Figure 2: 13C NMR spectra of compound 8

Figure 3: DEPT NMR spectra of compound 8

Figure 4: 1H NMR spectra of compound of table 2, entry 1

Figure 5: 13C NMR spectra of compound of table 2, entry 1

Figure 6: DEPT NMR spectra of compound of table 2, entry 1

Figure 7: 1H NMR spectra of compound of table 2, entry 2

Figure 8: 13C NMR spectra of compound of table 2, entry 2

Figure 9: DEPT NMR spectra of compound of table 2, entry 2

Figure 10: 1H NMR spectra of compound of table 2, entry 3

Figure 11: 13C NMR spectra of compound of table 2, entry 3

Figure 12: DEPT NMR spectra of compound of table 2, entry 3

Figure 13: 1H NMR spectra of compound of table 2, entry 4

Figure 14: 13C NMR spectra of compound of table 2, entry 4

Figure 15: DEPT NMR spectra of compound of table 2, entry 4

Figure 16: 1H NMR spectra of compound of table 2, entry 5

Figure 17: 13C NMR spectra of compound of table 2, entry 5

Figure 18: DEPT NMR spectra of compound of table 2, entry 5

Figure 19: 1H NMR spectra of compound of table 2, entry 6

Figure 20: 13C NMR spectra of compound of table 2, entry 6

Figure 21: DEPT NMR spectra of compound of table 2, entry 6


DETAILED DESCRIPTION OF THE INVENTION



[0023] With the view to provide novel alternatives in antimalarial therapy,, the present invention provides herein novel compounds of general formula I, referred hereinafter as NCLite-M1.

[0024] The present invention provides the novel compounds and pharmaceutically acceptable salt thereof. of general formula I

wherein R, R1, R2 are selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,

X is selected from halide or hydrogen,

R3 is of formula III, wherein R4 is selected from H, halide, alkyl, aryl, and hetero alkyl/aryl,.



[0025] In the present invention compound of formula I consists of NCLite-M1 as depicted herein.



[0026] The present invention provides a process for preparation of novel compounds of formula I beginning from compound 2, 2-Iodo-N-(1-(1-(phenylsulfonyl)-1H-pyrrol-2-yl)ethylidene)aniline,

said process comprising:
  1. a. Refluxing a compound containing a carbonyl group selected from ketone and an aniline in dry solvent, particularly, toluene followed by work-up to obtain compound 2;

  2. b. Catalyzing the conversion of compound 2 of step (a) in the presence of Pd catalyst, ligand, base and solvent to obtain corresponding quinolone compound 3;



[0027] The process for the preparation of compound I & II is depicted in Scheme 1.



[0028] The process of preparation of compound of formula II is depicted below in Scheme 2 which leads to the formation of Aplidiopsamine A and Marinoquinoline A.



[0029] The process of Scheme 1 may lead to formation of NCLite-M1 is depicted below in the Scheme 3.



[0030] In an aspect of invention, the yield of compound of formula I may be in the range of 25% to 98%.

[0031] In an aspect of invention, the yield of compound of formula II may be in the range of 40% to 98%.

[0032] In a preferred embodiment, the Pd catalyst used in the process above is Pd(OAc)2 in the range of 1 mol% to 20 mol%.

[0033] In a preferred embodiment, the ligand used in the process above is selected from PPh3, Neocuproine, and PCy3 in the range of 1 mol% to 40 mol%, and is preferably PPh3 in the range of 1 mol% to 40 mol%.

[0034] In a preferred embodiment, the base used in the process above is selected from K2CO3, Cs2CO3, Ag2CO3, KOtBu in the range of 1 mol% to 200 mol%, and is preferably Ag2CO3 in the range of 1 mol% to 200 mol%.

[0035] In a preferred embodiment, the solvent used in the process above is chosen from 1, 4-dioxane, dimethyl formamide, DMF, Benzene, tetrahydrofuran THF and is preferably 1,4-dioxane.

[0036] The catalyst used for the process of step (c) may be NBS and radical initiator like AIBN, ABCN and is preferably BPO catalyzed NBS.

[0037] In an aspect of the invention, the compound of formula I & II may possess activity against other known or unknown pathogens and are useful in treating a subject in need of a treatment against such pathogens.

[0038] The compound NCLite-M1 was tested for anti-malarial activity against a known parasite Plasmodium falciprum 3D7, which is chloroquine sensitive strain and the results are tabulated herein.

[0039] The compound of formula I are useful as antimycobacterial agents, Compound formula I may be used for treatment of infections caused by Mycobacteria in subjects in the need of the same. Brent Copp et al in Natural product growth inhibitors of Mycobacterium tuberculosis, Nat. Prod. Rep., 2007, 24, 278-297 discusses the antimycobacterial activity and anti tumour of compounds 225-23, which are alkaloids isolated from various natural sources.

[0040] Described is also a pharmaceutical composition comprising a compound of formula (I & II), or a stereoisomer, or ester or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0041] The pharmaceutical compositions described can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels and microspheres,

[0042] Accordingly, compound of formula I and pharmaceutical compositions containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.

[0043] Pharmaceutical compositions described are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient may take the form of one or more dosage units. The dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms.

[0044] The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention in any manner.

Examples:


Example 1


1-(1-(methylsulfonyl)-1H-pyrrol-2-yl)ethanone (1):



[0045] 


Procedure:



[0046] To a solution of acetic anhydride (1.3 mL, 0.13 mmol) in 5 mL of 1,2-dichloroethane at 25 °C was added BF3-OEt2 (3.4 mL, 0.27 mmol). The mixture was stirred for 10 min, a solution of methylsulfonyl protected pyrrole (500 mg, 0.61 mmol) in 2 mL of 1,2-dichloroethane was added, and the mixture was stirred at 25 °C for 90 min. The reaction was quenched with cold water, and the reaction products were extracted into dichloromethane. The residue remaining after concentration at reduced pressure was chromatographed in a column of silica gel (70-230 mesh), eluting with ethyl acetate-petroleum ether (1:9) to afford 1-(1-(methylsulfonyl)-1H-pyrrol-2-yl)ethanone (440 mg, 68%).
Rf = 0.50 (4:1 PE:EtOAc); MP 62-64 °C; IR(Nujol) : vmax 2925, 2854, 1711, 1679, 1539, 1459, 1375, 938, 847, 768 cm-1; 1H NMR (500 MHz, CDCl3): δ 2.49 (s, 3H), 3.72 (s, 3H), 6.28 (t, J = 3.7 Hz, 1H), 7.11 (dd, J = 1.7, 3.7 Hz, 1H), 7.56 (dd, J = 1.8, 3.2 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 27.2, 43.1, 110.1, 124.8, 129.9, 133.2, 187.3; HRMS-ESI(m/z): calcd for [C7H9O3NS+H]+, 188.0376; found 188.0379.

Example 2


2-Iodo-N-(1-(1-(phenylsulfonyl)-1H-pyrrol-2-yl)ethylidene)aniline (2):


Procedure:



[0047] To a dry two

neck round bottom flask, equipped with Dean-Stark apparatus, containing freshly activated 4Å molecular sieves, ketone 1 (100 mg, 0.40 mmol), Iodoaniline (439 mg, 2.00 mmol) and p-toluenesulphonic acid (8 mg, 0.04 mmol), was added dry toluene under argon atmosphere and the reaction mixture was refluxed for 18 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. Ethyl acetate was added and the organic layer was washed with saturated sodium bicarbonate solution, brine and dried over sodium sulphate. Evaporation of ethyl acetate followed by silica gel chromatography (49:1 PE:EtOAc) furnished 2 as yellow solid (145 mg, 80%).
Rf = 0.50 (19:1 PE:EtOAc); MP 145-147 °C; IR(Nujol): vmax 2928, 2851, 1456, 1374, 721 cm-1; 1H NMR (400 MHz, Acetone-D6): δ 2.03 (s, 3H), 6.49 (t, J = 3.1 Hz, 1H), 6.70 (dd, J = 1.5, 7.8 Hz, 1H), 6.85 (ddd, J = 1.5, 7.8 Hz, 1H), 7.03 (dd, J = 1.8, 3.7 Hz, 1H), 7.36-7.48 (m, 3H), 7.63 (t, J = 7.5 Hz, 1H), 7.75-7.81 (m, 4H); 13C NMR (100 MHz, Acetone-D6): δ 19.5, 89.1, 111.9, 119.6, 120.5, 125.6, 127.8, 129.0, 129.6, 129.8, 134.1, 135.7, 139.5, 141.4, 152.3, 158.5; HRMS-ESI(m/z): calcd for [C18H15O2N2IS+H]+, 450.9972; found 450.9960.

Example 3


4-Methyl-3-(phenylsulfonyl)-3H-pyrrolo[2,3-c]quinoline (3):



[0048] 


Procedure A (in round bottom flask with reflux condenser):



[0049] To a two neck round bottom flask, equipped a with a water condenser, was added Pd(OAc)2 (2 mg, 0.01 mmol), PPh3 (6 mg,0.02 mmol) and Ag2CO3 (61 mg, 0.22 mmol). To this was added solution of 2 (50 mg, 0.11 mmol) in 1,4-dioxane (1 ml) by means of a syringe and the reaction mixture was refluxed for 2 h. After cooling to room temperature the reaction mixture was filtered through celite and 1,4-dioxane was evaporated. The residue was dissolved in ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. After evaporation of the solvent, the crude product was purified by using column chromatography on silica gel (4:1 PE:EtOAc) to yield 3 as a brown solid (32 mg, 91%).

Procedure B (in sealed tube):



[0050] To a sealed tube containing magnetic stirring bar was added Pd(OAc)2 (1 mg, 2 mol%), PPh3 (2 mg, 4 mol%) and Ag2CO3 (24 mg, 0.09 mmol). To this was added solution of 2 (100 mg, 0.22 mmol) in 1,4-dioxane (1 ml) by means of a syringe and the tube was sealed and heated at 120 °C for 10 h. After cooling to room temperature the reaction mixture was filtered through celite and 1,4-dioxane was evaporated. The residue was dissolved in ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. After evaporation of the solvent, the crude product was purified by using column chromatography on silica gel (4:1 PE:EtOAc) to yield 3 as a brown solid (67 mg, 93%).
Rf = 0.50 (7:3 PE:EtOAc); MP 143-145 °C; IR(CHCl3) : vmax 3148, 3060, 2928, 2851, 1618, 1577, 1366, 1176, 990, 751, 685, 592 cm-1; 1H NMR (500 MHz, CDCl3): δ 2.90 (s, 3H), 7.22 (d, J = 3.7 Hz, 1H), 7.43 (t, J = 7.9 Hz, 2H), 7.54 (q, J = 7.0 Hz, 2H), 7.62 (m, 1H), 7.68 (d, J = 7.3 Hz, 2H), 8.02 (d, J = 8.2 Hz, 1H), 8.05-8.09 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 26.1, 105.6, 121.5, 122.8, 126.1, 126.4, 128.0, 128.53, 128.55, 129.5, 131.8, 134.1, 134.7, 139.3, 143.3, 146.7; HRMS-ESI(m/z): calcd for [C18H14O2N2S+H]+, 323.0849; found 323.0839.

Example 4


Marinoquinoline A:



[0051] 


Procedure:



[0052] To the solution of 3 (50 mg, 0.15 mmol) in MeOH (2 ml) was added K2CO3 (42 mg, 0.31 mmol). The reaction mixture was refluxed for 1 h. Then it was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. After evaporation of the solvent, the crude product was purified by using silica gel column chromatography (1:1 PE:EtOAc) to obtain Marinoquinoline A as a white solid (27 mg, 96%).
Rf = 0.30 (1:1 PE:EtOAc); MP 237-239 °C; IR(Nujol): vmax 3379, 2917, 2857, 1465, 1451, 1377, 751 cm-1; 1H NMR (500 MHz, Acetone-D6): δ 2.87 (s, 3H), 7.15 (d, J = 2.8 Hz, 1H), 7.50-7.57 (m, 2H), 7.62 (d, J = 2.7 Hz, 1H), 8.05 (dd, J = 2.1, 7.3 Hz 1H), 8.25 (dd, J = 2.1, 7.3 Hz, 1H), 11.29 (br s, 1H); 13C NMR (125 MHz, Acetone-D6): δ 21.0, 101.9, 123.7, 124.1, 125.7, 126.1, 127.4, 128.5, 129.5, 129.7, 143.3, 146.8; HRMS-ESI(m/z): calcd for [C12H10N2+H]+, 183.0917; found 183.0914.

Example 5


4-(Bromomethyl)-3-(phenylsulfonyl)-3H-pyrrolo[2,3-c]quinoline (4):



[0053] 


Procedure:



[0054] To the solution of 3 (60 mg, 0.18 mmol) in dry carbon tetrachloride (3 ml) was added NBS (132 mg, 0.74 mmol) and radical initiator benzoyl peroxide (9 mg, 0.03 mmol). The reaction mixture was refluxed for an 8 h and then cooled to room temperature. The precipitated solid was filtered of and the filtrate was concentrated. Crude product was rapidly passed through silica gel column (7:1.5 PE:EtOAc) to obtain 4 (56 mg, 75%). The purity of the obtained product was more than 90% and it was used for further reaction as soon as possible to avoid decomposition.
Rf = 0.60 (7:3 PE:EtOAc); IR (Nujol): vmax 2923, 2862, 1459, 1374, 1185, 1083, 727, 587 cm-1; 1H NMR (400 MHz, CDCl3): δ 5.30 (s, 2H), 7.28 (d, J = 3.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.54 (d, J = 7.5, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.65-7.71 (m, 1H), 7.75 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 3.8 Hz, 1H), 8.10 (t, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 33.9, 106.9, 122.1, 122.9, 126.6, 127.4, 128.6, 129.3, 129.6, 129.8, 132.9, 134.3, 136.6, 138.1, 143.5, 144.9; HRMS-ESI(m/z): calcd for [C18H13O2N2SBr(79)+H]+, 400.9959; found 400.9942 and [C18H13O2N2SBr(81)+H]+, 402.9939; found 402.9917.

Example 6


4-((6-Chloro-9H-purin-9-yl)methyl)-3-(phenylsulfonyl)-3H-pyrrolo[2,3-c]quinoline (5):



[0055] 


Procedure:



[0056] A two neck dry round bottom flask containing 6-chloropurine (38 mg, 0.24 mmol), K2CO3 (43 mg, 0.31 mmol) and dry DMF (0.5 ml) was stirred at 50 °C under argon atmosphere for 1 h. It was then cooled to room temperature and to the reaction mixture was added a solution of 4 (50 mg, 0.12 mmol) in dry DMF (0.5 ml). The reaction mixture was heated to 50 °C and stirred at the same temperature for 6 h. The reaction mixture was cooled to room temperature and quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. After evaporation of the solvent the crude compound was purified using silica gel column chromatography (4:1 PE:EtOAc) to yield 5 as off white solid (42 mg, 70%).
Rf = 0.40 (3:2 PE:EtOAc); MP 223-225 °C; IR(Nujol): vmax 2923, 1462, 1376, 1176, 727 cm-1; 1H NMR (500 MHz, CDCl3): δ 6.17 (s, 2H), 7.31 (d, J = 3.7 Hz, 1H), 7.52 (t, J = 7.9 Hz, 2H), 7.54-7.58 (m, 2H), 7.64 (t, J = 7.3, 1H), 7.70-7.74 (m, 1H), 7.82(d, J = 7.6, 2H), 8.05 (d, J = 3.7 Hz, 1H), 8.06-8.09 (m, 1H), 8.31(s, 1H), 8.58 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 47.9, 107.2, 121.9, 122.8, 126.4, 126.5, 127.4, 128.5, 129.5, 129.9, 131.2, 132.3, 134.6, 136.2, 138.4, 141.1, 142.8, 147.6, 150.5, 151.7, 152.5; HRMS-ESI(m/z): calcd for [C23H15O2N6ClS+H]+, 475.0738; found 475.0727.

Example 7


Aplidiopsamine A (6):



[0057] 


Procedure:



[0058] To a dry sealed tube containing 5 (20 mg, 0.04 mmol) was added saturated methanolic ammonia solution (5 ml). The tube was sealed with Teflon cap and the reaction mixture was refluxed at 150 °C for 24 h. After cooling to room temperature ammonia was allowed to escape and methanol was evaporated. The crude product was purified using column chromatography on silica gel (49:1 DCM:MeOH) to yield Aplidiopsamine A as an off white solid (9 mg, 69%).
Rf = 0.40 (19:1 DCM:MeOH); MP 229-231 °C; IR(Nujol): vmax 3351, 2923, 1684, 1462, 1374, 1116, 1152, 735, 716 cm-1; 1H NMR (400 MHz, DMSO-D6): δ 5.94 (s, 2H), 7.20 (s, 1H), 7.25 (br s, 2H), 7.43-7.55 (m, 2H), 7.75 (d, J = 7.8 Hz, 2H), 8.07(s, 1H), 8.26 (d, J = 7.8, 1H), 8.33 (s, 1H), 12.39 (br s, 1H); 13C NMR (100 MHz, DMSO-D6): δ 44.8, 101.6, 118.7, 123.4, 125.9, 126.9 (2 C), 128.2, 128.4, 129.2(2 C), 141.7, 142.5, 143.6, 150.1, 152.7, 156.2; HRMS-ESI(m/z): calcd for [C17H13N7+H]+, 316.1305; found 316.1304.

Example 8


3-((3-(Phenylsulfonyl)-3H-pyrrolo[2,3-c]quinolin-4yl)methyl)quinazolin-4(3H)-one(7):



[0059] 


Procedure:



[0060] To a two neck dry round bottom flask was added 6 (50 mg, 0.34 mmol), K2CO3 (60 mg, 0.43 mmol) and dry DMF (0.5 ml) under argon atmosphere. The reaction mixture was stirred at 50 °C for 1 h, then cooled to room temperature followed by addition of a solution of 4 (70 mg, 0.17 mmol) in dry DMF (0.5 ml). It was heated to 50 °C and stirred at same temp for 6 h. The reaction mixture was cooled to room temperature and quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. After evaporation of the solvent, the crude compound was purified using silica gel column chromatography (7:3 PE:EtOAc) to yield 7 as a white solid (60 mg, 73%).
Rf = 0.50 (1:1 PE:EtOAc); MP 201-203 °C; IR(Nujol): vmax 2925, 2854, 1675, 1612, 1461, 1376, 1176, 726, cm-1; 1H NMR (500 MHz, CDCl3): δ 5.85 (s, 2H), 7.26 (d, J = 3.8 Hz, 1H), 7.43-7.55 (m, 5H), 7.60 (t, J = 7.3 Hz, 1H), 7.72-7.79 (m, 3H), 7.85 (d, J = 7.3 Hz, 2H), 8.00 (d, J = 3.8 Hz, 1H), 8.01-8.05 (m, 1H), 8.11 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 49.9, 107.1, 121.9, 122.3, 122.6, 126.5, 126.8, 126.9, 127.4, 128.1, 129.7, 129.8,131.9, 134.0, 134.5, 135.8, 138.4, 142.2, 142.9, 148.4, 161.3; HRMS-ESI(m/z): calcd for [C26H18O3N4S+Na]+, 489.0992; found 489.0980.

Example 9


NCLite-M1 (8):



[0061] 

3-((3H-pyrrolo[2,3-c]quinolin-4-yl)methyl)quinazolin-4(3H)-one

Procedure:



[0062] To a two neck round bottom flask was added 7 (20 mg, 0.04 mmol), K2CO3 (17 mg, 0.12 mmol) and methanol (1 ml). The reaction mixture was refluxed for 1 h, brought to room temperature and quenched with water. Extraction with dichloromethane, drying over sodium sulphate and evaporation gave the crude compound, which was purified using column chromatography on silica gel (1:1 PE: EtOAc) to yield NCLite-M1 as white solid (12 mg, 90%).
Rf = 0.30 (1:1 PE:EtOAc); MP 211-213 °C; IR(Nujol): vmax 3286, 2925, 2855, 1668, 1614, 1464, 1375, 766, 739 cm-1; 1H NMR (400 MHz, DMSO-D6): δ 5.78 (s, 2H), 7.20 (t, J = 2.5 Hz, 1H), 7.43(t, J = 8.3, 1H), 7.48-7.58 (m, 2H), 7.70 (d, J = 8.3, 1H), 7.74-7.80 (m, 2H), 7.88 (t, J = 8.5, 1H), 8.12 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.6 (s, 1H), 12.39 (br s, 1H); 13C NMR (100 MHz, DMSO-D6): 47.1, 101.5, 121.87, 121.94, 123.3, 125.7, 125.8, 126.4, 126.9, 127.2, 127.5, 127.9, 128.2, 129.1, 134.7, 141.6, 143.7, 148.5, 149.6, 160.5; HRMS-ESI(m/z): calcd for [C20H14ON4+H]+, 327.1240; found 327.1231.

Example 10:


General Procedure for imine formation and cyclization (Table 2, entry 1-6):



[0063] To a dry two neck round bottom flask, equipped with Dean-Stark apparatus, containing freshly activated 4Å molecular sieves, ketone (1.2 equiv.), Iodoaniline (1 equiv.) and p-toluenesulphonic acid (0.1 equiv.), was added dry toluene under argon atmosphere and the reaction mixture was refluxed for 12-24 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure. Ethyl acetate was added and the organic layer was washed with saturated sodium bicarbonate solution, brine and dried over sodium sulphate. Evaporation of ethyl acetate provided crude imine, which was used further without any purification.

[0064] To a sealed tube containing magnetic stirring bar was added Pd(OAc)2 (0.02 equiv.), PPh3 (0.04 equiv.) and Ag2CO3 (0.4 equiv.). To this was added solution of crude imine (1 equiv.) in 1,4-dioxane by means of a syringe and the tube was sealed and heated at 120 °C for 8-24 h. After cooling to room temperature the reaction mixture was filtered through celite and 1,4-dioxane was evaporated. The residue was dissolved in ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate. After evaporation of the solvent, the crude product was purified by using column chromatography on silica gel (PE:EtOAc) to yield cyclized product in 51-90% yield over two steps.
Table 1. Optimization studies on cyclization of iodo-imine 2 to pyrroloquinoline 3.


 
entr ycatalyst (equiv)ligand (equiv)base (equiv)solventtemptimeyield
01 - Neocuproine (0.50) KOtBu (2.5) Benzene 100 °C 18h trace
02 Pd(OAc)2 (0.10) PPh3 (0.20) Ag2C03 (2.0) DMF 100 °C 02 h 51%
03 Pd(OAc)z (0.20) PPh3 (0.40) Ag2C03 (4.0) DMF 100 °C 02 h 64%
04 Pd(OAch (0.20) PPh3 (0.40) Ag2C03 (2.0) THF reflux 04 h 63%
05 Pd(OAch (0.10) PPh3 (0.20) Ag2C03 (2.0) 1,4-dioxane reflux 03 h 91%
06 Pd(OAc)2 (0.04) PCy3 (0.08} Cs2C03 (2.0) THF 110°C 24 h 23%
07 Pd(OAc)2 (0.04) PCy3 (0.08) K1C03(2.0) DMF 110 °C 24 h 35%
08 Pd(0Ac)2 (0.10) PCy3 (0.20) Ag2C03 (2.0) DMF 110°C 24 h 31%
09 Pd(0Ac)2 (0.05) PPh3 (0.10) Ag2C03 (1.0) 1,4-dioxane 120°c 07 h 90%
10 Pd(0Ac)2 (0.03) PPh3 (0.06) Ag2C03 (0.6) 1,4-dioxane 120°c 08 h 89%
11 Pd(0Ac)2 (0.02) PPh3 (0.04) Ag2C03 (0.4) 1,4-dioxane 120°C 10h 93%
 
12 Pd(O Ac)z PPh3 (0.02) AgzC03 (0.2) 1,4-dioxane 120°C 24 h 72%
Note: Reactions shown in entries 1 and 6-12 were carried out in a sealed tube

Example 11



[0065] 
Table 2. Generalization studies of the optimized Pd-catalyzed intramolecular imine cyclization protocol
entryimine substrateproducttimeyield
         
01



08 h 82%
02



10 h 70%
03



05 h 62%
04



10 h 90%
05



10 h 85%
06



24 h 51%
Reaction condition: imine substrate (1 equiv), Pd(OAc)2 (0.02 equiv), PPh3 (0.04 equiv), Ag2CO3(0.4 equiv), 1,4-dioxane, sealed tube, 120 °C

4-methyl-3-(methylsulfonyl)-3H-pyrrolo[2,3-c]quinoline (Table 2, entry 1):



[0066] 



[0067] Reaction Time: 8 h, Rf = 0.50 (7:3 PE:EtOAc); MP 152-154 °C, 82%; IR(Nujol) : vmax 2928, 1459, 1377, 995, 743 cm-1; 1H NMR (500 MHz, CDCl3): δ 3.19 (s, 3H), 3.36 (s, 3H), 7.21 (d, J = 3.6 Hz, 1H), 7.58 (t, J = 8.1 Hz, 1H), 7.68 (t, J = 8.3 Hz, 1H), 7.84 (d, J = 3.7 Hz, 1H), 8.12 (t, J = 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 26.2, 43.4, 105.6, 121.7, 122.9, 126.4, 128.2, 128.3, 128.7, 131.0, 139.3, 143.4, 145.9; HRMS-ESI(m/z): calcd for [C13H12O2N2S+H]+, 261.0692; found 261.0696.
Imine: HRMS-ESI(m/z): calcd for [C13H13O2N2SI+H]+, 388.9815; found 388.9812.

7-chloro-4-methyl-3-(phenylsulfonyl)-3H-pyrrolo[2,3-c]quinoline (Table 2, entry 2):



[0068] 



[0069] Reaction Time: 10 h, Rf = 0.30 (9:1 PE:EtOAc); MP 178-180 °C, 70%; IR(Nujol) : vmax 2924, 2854, 2725, 1614, 1462, 1376, 822, 726, 685 cm-1; 1H NMR (500 MHz, CDCl3): δ 2.88 (s, 3H), 7.21 (d, J = 3.7 Hz, 1H), 7.46-7.52 (m, 3H), 7.60 (t, J = 7.6 Hz, 1H), 7.71 (d, J = 8.5, 2H), 8.02 (s, 1H), 8.03 (d, J = 6.7 Hz, 1H), 8.10 (d, J = 3.7, 1H); 13C NMR (125 MHz, CDCl3): δ 26.1, 105.5, 120.0, 124.2, 126.5, 126.9, 127.8, 128.6, 129.7, 132.3, 133.7, 134.3, 134.6, 139.2, 143.9, 147.9; HRMS-ESI(m/z): calcd for [C18H13ClN2SO2+H]+, 357.0459; found 357.0462.
Imine: HRMS-ESI (m/z): calcd for [C18H14N2O2ClSI+H]+, 484.9582; found 484.9580.

4-methyl-1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]quinoline (Table 2, entry 3):



[0070] 



[0071] Reaction Time: 5 h, Rf = 0.40 (4:1 PE:EtOAc); semi-solid, 62%; IR(Nujol) : vmax 2925, 1642, 1542, 1458, 1376, 1175, 761, 726, 686 cm-1; 1H NMR (400 MHz, CDCl3): δ 2.85 (s, 3H), 6.93 (d, J = 3.8 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 7.42-7.51 (m, 2H), 7.52-7.61 (m, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.98 (d, J = 3.8 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 8.93 (d, J = 8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 22.5, 107.1, 117.1, 123.2, 124.5, 125.9, 126.8, 127.7, 129.0, 129.45, 129.50, 134.3, 134.6, 138.0, 145.7, 153.9; HRMS-ESI(m/z): calcd for [C18H14O2N2S+H]+, 323.0849; found 323.0853.
Imine: HRMS-ESI (m/z): calcd for [C18H15N2IO2S+H]+, 450.9972; found 450.9972.

6-phenylphenanthridine (Table 2, entry 4):



[0072] 



[0073] Reaction Time: 10 h, Rf = 0.40 (19:1 PE:EtOAc); MP 104-106 °C, 90%; IR(Nujol) : vmax 2923, 2945, 2851, 1607, 1459, 1374, 760, 718, 697, 672 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.50-7.58 (m, 3H), 7.61 (t, J = 7.6 Hz, 1H), 7.65-7.80 (m, 4H), 7.86 (t, J = 7.9 Hz, 1H), 8.10 (d, J = 8.2, 1H), 8.26 (d, J = 7.9 Hz, 1H), 8.62 (d, J = 7.9 Hz, 1H), 8.71 (d, J = 8.2 Hz, 1H);
13C NMR (125 MHz, CDCl3): δ 121.9, 122.2, 123.8, 125.2, 126.9, 127.1, 128.4, 128.7, 128.8, 128.9, 129.7, 130.3, 130.6, 133.5, 139.6, 143.7, 161.3; HRMS-ESI(m/z): calcd for [C19H13N+H]+, 256.1121; found 256.1121.
Imine: HRMS-ESI (m/z): calcd for [C19H14NI+H]+, 384.0244; found 384.0244.

6-phenylphenanthridine-2-carbonitrile (Table 2, entry 5):



[0074] 



[0075] Reaction Time: 10 h, Rf = 0.50 (19:1 PE:EtOAc); MP 233-235 °C, 85%; IR(Nujol) : vmax 2924, 2224, 1609, 1462, 1377, 961, 829, 776, 688, 670 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.52-7.62 (m, 3H), 7.60-7.76 (m, 3H), 7.90-7.98 (m, 2H), 8.16 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.66 (d, J = 8.3 Hz, 1H), 8.95 (d, J = 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 110.2, 119.1, 122.2, 123.9, 125.5, 127.8, 128.5, 128.6, 129.4, 129.7, 130.4, 131.5, 131.6, 132.4, 138.9, 145.5, 164.3; HRMS-ESI(m/z): calcd for [C20H12N2+H]+, 281.1073; found 218.1075.
Imine: HRMS-ESI (m/z): calcd for [C20H13N2I+H]+, 409.0196; found 409.0193.

2-phenyl-1H-indole-5-carbonitrile (Table 2, entry 6):



[0076] 



[0077] Reaction Time: 24 h, Rf = 0.40 (4:1 PE:EtOAc); MP 194-196 °C, 51%; 1H NMR (500 MHz, CDCl3): δ 6.87 (d, J = 1.5 Hz, 1H), 7.37-7.50 (m, 5H), 7.66 (d, J = 8.5 Hz, 2H), 7.96 (s, 1H), 8.73 (brs, 1H); 13C NMR (125 MHz, CDCl3): δ 100.2, 103.4, 111.7, 120.7, 125.2, 125.4, 126.0, 128.6, 129.0, 129.2, 131.2, 138.4, 140.2; HRMS-ESI(m/z): calcd for [C15H10N2+H]+, 219.0917; found 219.0917. Imine: HRMS-ESI (m/z): calcd for [C15H11N2I+H]+, 347.0040; found 347.0042.

Example 3:


Antimalarial activity:



[0078] This study was performed in vitro on Plasmodium falciparum at erythrocyte stage. The test protocol for testing antimalarial activity is from R. E. Desjardins, C. J. Canfield, J. D. Haynes and J. D. Chulay Antimicrob. Agents Chemother. 1979, 16, 710.

[0079] A known parasite 3D7 was used, which is Chloroquine sensitive strain. 2 mg of the compound NCLite-M1 which has a molecular weight of 326.35, was dissolved in 10 mL of EtOH and used as a stock. The results are tabulated in Table 3. As seen from table 3, the compound is active at concentration as low as 2 µMoles in crude form. Further studies using highly pure compound and its soluble salts are planned.
Table 3: Antimalarial activity of NCLite-M1
Sr NoConcentration 
  % inhibition by NCLite-M1
1 2-5 µM 17.6%
2 25 µM 19.5 %
3 50 µM 77.2 %
4 75 µM 89.4 %

Advantages of invention:



[0080] 
  1. a. Novel anti-malarial agents
  2. b. Novel and simple synthetic process of synthesis of novel and known anti-malarial agents provided.
  3. c. Process applicable for synthesis of other natural products



Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein R, R1, R2 are selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl,

X is halide or hydrogen,

R3 is formula III and

R4 is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl,


 
2. A process for the preparation of compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1,
said process comprises of following steps;

a. refluxing ketone of formula

wherein R, is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl.
with aniline of formula

wherein R is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl,

X is either halide or an activating group selected from the group consisting of OTf, OTs, B(OR)2, SnR3 and SiR3

in mole ratio 1:1 in a solvent for a period ranging between 12-24 hours followed by work up to obtain corresponding imine of formula



wherein R is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl,

X is either halide or an activating group selected from the group consisting of OTf, OTs, B(OR)2, SnR3 and SiR3,

b. Catalyzing the corresponding imine of step (a) in the presence of a Pd catalyst, a ligand, a base and a solvent at temperature ranging between 100 -120°C for a period between 8-24 hrs to obtain corresponding quinoline of formula

wherein R is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl.

c. Catalyzing the conversion of quinoline compound of step (b) to obtain corresponding substituted quinoline of formula

d. reacting substituted quinoline obtained in step (c) with substituted or unsubstituted quinazolin-4(3H)-one compound to obtain a product of formula I.

R' is of formula III, and

R4 is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl,

e. optionally deprotecting the -SO2Ph group by methanol and K2CO3.


 
3. The process as claimed in claim 2, wherein the yield is in the range of 40 % to 98 %.
 
4. The process as claimed in claim 2, wherein the catalyst used in step (b) is Pd(OAc)2 in the range of 1 mol% to 20 mol%.
 
5. The process as claimed in claim 2, wherein the ligand used in step (b) is selected from the group consisting of triphenyl phosphate, PPh3, Neocuproine and Tricyclohexyl- phosphine PCy3.
 
6. The process as claimed in claim 2, wherein the ligand used in step (b) is PPh3 in the range of 1mol% to 40 mol%.
 
7. The process as claimed in claim 2, wherein the base used in step (b) is selected from the group consisting of K2CO3, Cs2CO3, Ag2CO3 and KOtBu.
 
8. The process as claimed in claim 2, wherein the base used in step (b) is Ag2CO3 in the range of 1 mol% to 200 mol%.
 
9. The process as claimed in claim 2, wherein the solvent used in step (b) is selected from the group consisting of 1,4-dioxane, dry toluene, dimethylformamide, Benzene and tetrahydrofuran.
 
10. A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein R, R1, R2 are selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl ,

X is halide or hydrogen,

R3 is formula III, and

R4 is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl.



for use as anti malarial agents.


 
11. A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein R, R1, -R2 are selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl,

X is halide or hydrogen

R3 is formula III, and

R4 is selected from the group consisting of H, halide, alkyl, aryl and hetero alkyl/aryl

for use as anti mycobacterial agents.


 


Ansprüche

1. Verbindung der Formel I oder ein pharmazeutisch unbedenkliches Salz davon,

wobei R, R1, R2 aus der Gruppe bestehend aus H, Halogenid, Alkyl, Aryl und Heteroalkyl/-aryl ausgewählt sind,

X für Halogenid oder Wasserstoff steht,

R3 für die Formel III steht und

R4 aus der Gruppe bestehend aus H, Halogenid, Alkyl, Aryl und Heteroalkyl/-aryl ausgewählt ist,


 
2. Verfahren zur Herstellung einer Verbindung der Formel I oder eines pharmazeutisch unbedenklichen Salzes davon nach Anspruch 1,
wobei das Verfahren folgende Schritte umfasst:

a. Refluxieren eines Ketons der Formel

wobei R aus der Gruppe bestehend aus H, Halogenid, Alkyl, Aryl und Heteroalkyl/-aryl ausgewählt ist, mit einem Anilin der Formel

wobei R aus der Gruppe bestehend aus H, Halogenid, Alkyl, Aryl und Heteroalkyl/-aryl ausgewählt ist,

X entweder für Halogenid oder eine aktivierende Gruppe, die aus der Gruppe bestehend aus OTf, OTs, B(OR)2, SnR3 und SiR3 ausgewählt ist, steht,

in einem Molverhältnis von 1:1 in einem Lösungsmittel über einen Zeitraum im Bereich zwischen 12-24 Stunden mit anschließender Aufarbeitung zum Erhalt eines entsprechenden Imins der Formel

wobei R aus der Gruppe bestehend aus H, Halogenid, Alkyl, Aryl und Heteroalkyl/-aryl ausgewählt ist,

X entweder für Halogenid oder eine aktivierende Gruppe, die aus der Gruppe bestehend aus OTf, OTs, B(OR)2, SnR3 und SiR3 ausgewählt ist, steht,

b. Katalysieren des entsprechenden Imins aus Schritt (a) in Gegenwart eines Pd-Katalysators, eines Liganden, einer Base und eines Lösungsmittels im Temperaturbereich zwischen 100-120 °C über einen Zeitraum zwischen 8-24 Stunden zum Erhalt eines entsprechenden Chinolins der Formel

wobei R aus der Gruppe bestehend aus H, Halogenid, Alkyl, Aryl und Heteroalkyl/-aryl ausgewählt ist,

c. Katalysieren der Umwandlung der Chinolinverbindung aus Schritt (b) zum Erhalt eines entsprechenden substituierten Chinolins der Formel

d. Umsetzen des in Schritt (c) erhaltenen substituierten Chinolins mit einer substituierten oder unsubstituierten Chinazolin-4(3H)-on-Verbindung zum Erhalt eines Produkts der Formel I,

wobei R' die Formel III aufweist und

R4 aus der Gruppe bestehend aus H, Halogenid, Alkyl, Aryl und Heteroalkyl/-aryl ausgewählt ist,

e. gegebenenfalls Entschützen der -SO2Ph-Gruppe mit Methanol und K2CO3.


 
3. Verfahren nach Anspruch 2, bei dem die Ausbeute im Bereich von 40 % bis 98 % liegt.
 
4. Verfahren nach Anspruch 2, bei dem es sich bei dem in Schritt (b) verwendeten Katalysator um Pd(OAc)2 im Bereich von 1 Mol-% bis 20 Mol-% handelt.
 
5. Verfahren nach Anspruch 2, bei dem der in Schritt (b) verwendete Ligand aus der Gruppe bestehend aus Triphenylphosphat, PPh3, Neocuproin und Tricyclohexylphosphin PCy3 ausgewählt wird.
 
6. Verfahren nach Anspruch 2, bei dem es sich bei dem in Schritt (b) verwendeten Liganden um PPh3 im Bereich von 1 Mol-% bis 40 Mol-% handelt.
 
7. Verfahren nach Anspruch 2, bei dem die in Schritt (b) verwendete Base aus der Gruppe bestehend aus K2CO3, Cs2CO3, Ag2CO3 und KOtBu ausgewählt wird.
 
8. Verfahren nach Anspruch 2, bei dem es sich bei der in Schritt (b) verwendeten Base um Ag2CO3 im Bereich von 1 Mol-% bis 200 Mol-% handelt.
 
9. Verfahren nach Anspruch 2, bei dem das in Schritt (b) verwendete Lösungsmittel aus der Gruppe bestehend aus 1,4-Dioxan, trockenem Toluol, Dimethylformamid, Benzol und Tetrahydrofuran ausgewählt wird.
 
10. Verbindung der Formel I oder ein pharmazeutisch unbedenkliches Salz davon,

wobei R, R1, R2 aus der Gruppe bestehend aus H, Halogenid, Alkyl, Aryl und Heteroalkyl/-aryl ausgewählt sind,

X für Halogenid oder Wasserstoff steht,

R3 für die Formel III steht und

R4 aus der Gruppe bestehend aus H, Halogenid, Alkyl, Aryl und Heteroalkyl/-aryl ausgewählt ist,

zur Verwendung als Antimalariamittel.


 
11. Verbindung der Formel I oder ein pharmazeutisch unbedenkliches Salz davon,

wobei R, R1, R2 aus der Gruppe bestehend aus H, Halogenid, Alkyl, Aryl und Heteroalkyl/-aryl ausgewählt sind,

X für Halogenid oder Wasserstoff steht,

R3 für die Formel III steht und

R4 aus der Gruppe bestehend aus H, Halogenid, Alkyl, Aryl und Heteroalkyl/-aryl ausgewählt ist,

zur Verwendung als antimykobakterielle Mittel.


 


Revendications

1. Composé de formule I ou sel pharmaceutiquement acceptable de celui-ci,

dans lequel R, R1, R2 sont choisis dans le groupe constitué de H, halogénure, alkyle, aryle et hétéroalkyle/aryle,

X est halogénure ou hydrogène,

R3 est de formule III et

R4 est choisi dans le groupe constitué de H, halogénure, alkyle, aryle et hétéroalkyle/aryle,


 
2. Procédé de préparation d'un composé de formule I ou un sel pharmaceutiquement acceptable de celui-ci selon la revendication 1,
ledit procédé comprenant les étapes suivantes ;

a. chauffage à reflux d'une cétone de formule

dans laquelle R est choisi dans le groupe constitué de H, halogénure, alkyle, aryle et hétéroalkyle/aryle, avec une aniline de formule

dans laquelle R est choisi dans le groupe constitué de H, halogénure, alkyle, aryle et hétéroalkyle/aryle,

X est halogénure ou un groupe activateur choisi dans le groupe constitué de OTf, OTs, B(OR)2, SnR3 et SiR3 dans un rapport molaire 1:1 dans un solvant pendant une durée dans la plage comprise entre 12 et 24 heures suivie par un travail jusqu'à l'obtention d'une imine correspondante de formule

dans laquelle R est choisi dans le groupe constitué de H, halogénure, alkyle, aryle et hétéroalkyle/aryle,

X est halogénure ou un groupe activateur choisi dans le groupe constitué de OTf, OTs, B(OR)2, SnR3 et SiR3,

b. catalyse de l'imine correspondante de l'étape (a) en présence d'un catalyseur à Pd, un ligand, une base et un solvant à une température dans la plage comprise entre 100 et 120 °C pendant une durée comprise entre 8 et 24 h pour obtenir une quinoléine correspondante de formule

dans laquelle R est choisi dans le groupe constitué de H, halogénure, alkyle, aryle et hétéroalkyle/aryle,

c. catalyse de la conversion du composé de quinoléine de l'étape (b) pour obtenir une quinoléine substituée de formule

d. réaction de la quinoléine substituée obtenue dans l'étape (c) par un composé de quinazolin-4(3H)-one substitué ou non substitué pour obtenir un produit de formule I,

R' est de formule III, et

R4 est choisi dans le groupe constitué de H, halogénure, alkyle, aryle et hétéroalkyle/aryle,

e. facultativement la déprotection du groupe -SO2Ph par du méthanol et K2CO3.


 
3. Procédé selon la revendication 2, dans lequel le rendement est dans la plage de 40 % to 98 %.
 
4. Procédé selon la revendication 2, dans lequel le catalyseur utilisé dans l'étape (b) est Pd(OAc)2 dans la plage de 1 % en moles à 20 % en moles.
 
5. Procédé selon la revendication 2, dans lequel le ligand utilisé dans l'étape (b) est choisi dans le groupe constitué du phosphate de triphényle, PPh3, la néocuproïne et la tricyclohexylphosphine PCy3.
 
6. Procédé selon la revendication 2, dans lequel le ligand utilisé dans l'étape (b) est PPh3 dans la plage de 1 % en moles à 40 % en moles.
 
7. Procédé selon la revendication 2, dans lequel la base utilisée dans l'étape (b) est choisie dans le groupe constitué de K2CO3, Cs2CO3, Ag2CO3 et KOtBu.
 
8. Procédé selon la revendication 2, dans lequel la base utilisée dans l'étape (b) est Ag2CO3 dans la plage de 1 % en moles à 200 % en moles.
 
9. Procédé selon la revendication 2, dans lequel le solvant utilisé dans l'étape (b) est choisi dans le groupe constitué des 1,4-dioxane, toluène anhydre, diméthylformamide, benzène et tétrahydrofurane.
 
10. Composé de formule I ou sel pharmaceutiquement acceptable de celui-ci,

dans lequel R, R1, R2 sont choisis dans le groupe constitué de H, halogénure, alkyle, aryle et hétéroalkyle/aryle,

X est halogénure ou hydrogène,

R3 est de formule III, et

R4 est choisi dans le groupe constitué de H, halogénure, alkyle, aryle et hétéroalkyle/aryle,

pour utilisation en tant qu'agents antipaludéens.


 
11. Composé de formule I ou sel pharmaceutiquement acceptable de celui-ci,

dans lequel R, R1, -R2 sont choisis dans le groupe constitué de H, halogénure, alkyle, aryle et hétéroalkyle/aryle,

X est halogénure ou hydrogène

R3 est de formule III, et

R4 est choisi dans le groupe constitué de H, halogénure, alkyle, aryle et hétéroalkyle/aryle

pour utilisation en tant qu'agents antimycobactériens.


 




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Cited references

REFERENCES CITED IN THE DESCRIPTION



This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Non-patent literature cited in the description