(19)
(11)EP 2 981 260 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
13.01.2021 Bulletin 2021/02

(21)Application number: 14778691.7

(22)Date of filing:  04.04.2014
(51)International Patent Classification (IPC): 
C07D 311/54(2006.01)
C07D 311/60(2006.01)
A61K 31/353(2006.01)
A61P 21/00(2006.01)
C07D 405/12(2006.01)
C07D 311/62(2006.01)
A61K 31/4433(2006.01)
A61P 9/00(2006.01)
(86)International application number:
PCT/IN2014/000213
(87)International publication number:
WO 2014/162320 (09.10.2014 Gazette  2014/41)

(54)

NOVEL ANALOGUES OF EPICATECHIN AND RELATED POLYPHENOLS

NEUARTIGE EPICATECHIN-ANALOGA UND ZUGEHÖRIGE POLYPHENOLE

NOUVEAUX ANALOGUES D'ÉPICATÉCHINE ET POLYPHÉNOLS ASSOCIÉS


(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: 04.04.2013 IN 3104DE2012

(43)Date of publication of application:
10.02.2016 Bulletin 2016/06

(73)Proprietor: Sphaera Pharma Pvt. Ltd.
Haryana 122051 (IN)

(72)Inventors:
  • DUGAR, Sundeep
    Haryana 122051 (IN)
  • MAHAJAN, Dinesh
    Haryana 122051 (IN)
  • RAI, Kumar, Santosh
    Haryana 122051 (IN)
  • SINGH, Sarbjit
    Haryana 122051 (IN)
  • PATIL, Ishwar, Rakesh
    Haryana 122051 (IN)

(74)Representative: Jacob, Reuben Ellis 
Maucher Jenkins 26 Caxton Street
London SW1H 0RJ
London SW1H 0RJ (GB)


(56)References cited: : 
WO-A1-03/101927
WO-A1-2013/020979
WO-A2-2013/022846
US-A1- 2010 048 920
WO-A1-2010/121232
WO-A2-2012/101652
US-A- 4 334 067
US-A1- 2010 266 523
  
  • JW CLARK-LEWIS ET AL: "Chemistry of 3-oxoflavans: Oxidation of (+)-catechin 5,7,3',4'-Tetramethyl ether to (+)-5,7,3',4'-Tetramethoxy-3-oxoflavan", AUSTRALIAN JOURNAL OF CHEMISTRY: AN INTERNATIONAL JOURNAL FOR CHEMICAL SCIENCE, vol. 26, no. 12, 1 January 1973 (1973-01-01), pages 2675-2682, XP055279114, AU ISSN: 0004-9425, DOI: 10.1071/CH9732675
  • BEN R. BROWN ET AL: "Reactions of flavanoids and condensed tannins with sulphur nucleophiles", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, 1 January 1974 (1974-01-01), pages 2036-2049, XP055279143, GB ISSN: 0300-922X, DOI: 10.1039/p19740002036
  • DAVID J. MALONEY ET AL: "(+)-Myristinin A, a Naturally Occurring DNA Polymerase [beta] Inhibitor and Potent DNA-Damaging Agent", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 127, no. 12, 1 March 2005 (2005-03-01), pages 4140-4141, XP055279440, US ISSN: 0002-7863, DOI: 10.1021/ja042727j
  • LI Z ET AL: "Synthesis of a library of glycosylated flavonols", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 49, no. 51, 15 December 2008 (2008-12-15), pages 7243-7245, XP025624908, ISSN: 0040-4039, DOI: 10.1016/J.TETLET.2008.10.032 [retrieved on 2008-10-11]
  • YUH-MEEI LIN ET AL: "Chalcones and flavonoids as anti-Tuberculosis agents", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 10, no. 8, 1 August 2002 (2002-08-01) , pages 2795-2802, XP055464742, GB ISSN: 0968-0896, DOI: 10.1016/S0968-0896(02)00094-9
  
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 provides novel analogues of epicatechin and related polyphenols, their variously functionalized derivatives, process for preparation of the same, composition comprising these compounds and their method of use.

BACKGROUND OF THE INVENTION



[0002] Polyphenolic natural products are of current interest because of their various biological activities, their occurrence in foodstuffs, and hence their relevance for human health. Polyphenolic natural products have two or more hydroxyl groups on their aromatic rings.

[0003] Representative examples include: (-)-epiafzelechin, (+)-catechin, (-)-epicatechin, (-)-gallocatechin, (-)-epigallocatechin, their respective 3-gallate esters, as well as two 3-(30-methyl)-gallate esters, herein referred to collectively as "catechins". (+)-Catechin, (-)-catechins, (+)-epicatechin and (-)-epicatechin are flavon-3-ols.

[0004] These flavonols are present in the human diet in chocolate, fruits, vegetables and wine and have found use in the treatment of acute coronary syndromes, including but not limited to myocardial infarction and angina; acute ischemic events in other organs and tissues, renal injury, renal ischemia and diseases of the aorta and its branches; injuries arising from medical interventions, including but not limited to coronary artery bypass grafting (CABG) procedures and aneurysm repair; cancer; and metabolic diseases, diabetes mellitus and other such disorders.

[0005] Though such polyphenols including catechins and epicatechin are used widely, they have certain drawbacks such as low potency, undesirable pharmacodymanics and pharmacokinetic profile. Hence there is a need to improve the potency, pharmacodynamics and pharmacokinetic profiles of the polyphenols.

[0006] One of the means to achieve such an effect is to have new analogues of epicatechin. The analogues of polyphenols may be used, to reduce or eliminate metabolites, increase the half-life of the parent drug, decrease the number of doses needed to achieve a desired effect, and/or create a more effective and/or a safer drug.

[0007] WO2013/022846 discloses epicatechin derivatives for treatment of conditions related to mitochondrial function.

[0008] WO2013/020979 discloses catechin and epicatechin conjugates, processes for their preparation, and food products comprising them.

[0009] US2010/048920 discloses the preparation of (+)-catechin, (-)-epicatechin, (-)-catechin, and (+)-epicatechin and their 5,7,3',4'-tetra-O-benzyl analogues.

[0010] WO2012/101652 discloses synthetic processes for preparing racemic and/or optically pure epicatechin, epigallocatechin and related polyphenols.

OBJECT OF THE INVENTION



[0011] An object of the invention is to provide novel analogues of polyphenols and a process of preparation thereof.

SUMMARY OF THE INVENTION



[0012] According to a first aspect of the present invention, there is provided a process for the preparation of a compound of formula (I):

which is selected from the group consisting of:

1002 Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol;

1003 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol;

1004 Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol;

1005 Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol;

1006 Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol;

1007 Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol;

1011 Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol;

1012 Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol;

1013 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol;

1016 Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol;

1017 Cis (±) 2-(4-methoxyphenyl)chroman-3,7-diol;

1018 Cis (±) 2-(4-hydroxyphenyl)-7-methoxychroman-3-ol;

1019 Cis (±) 7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;

1020 Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl)chromane;

1021 Cis (±) 7-hydroxy-2-(4-hydroxyphenyl)chroman-3-yl acetate;

1022 Cis (±) 3-(3,7-dihydroxychroman-2-yl)phenyl acetate;

1023 Cis (±) 3-hydroxy-2-(3-hydroxyphenyl)chroman-7-yl acetate;

1024 Cis (±) 3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate;

1025 Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate;

1026 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol;

1027 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;

1028 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol;

1029 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol;

1030 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol;

1067 (2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane;

1068 (2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol;

1069 (2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol; and

1070 (2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;
comprising the steps of:

  1. I. protecting the hydroxyl groups of an acetophenone of Formula 1, wherein X is methyl, with a protecting agent in the presence of a base and a solvent;

  2. II. reacting compound of Formula 1 obtained from step (i) with a compound of formula 2 in the presence of a base and a solvent to obtain a chalcone of formula 3;

  3. III. converting the chalcone of formula 3 to a compound 4 in the presence of an epoxidizing agent or a base;

  4. IV. optionally protecting hydroxyl group(s) of the compound obtained in step (iii);
  5. V. reducing the compounds of step (iii) or step (iv) in the presence of a chiral/achiral reducing agent to obtain a mixture of 4H-chromene and 2H-chromene compounds of formula 6 and 7; and

    hydrogenating 4H-chromene and 2H-chromene compounds obtained in step (v) to obtain the compound of Formula (I).



[0013] According to a second aspect of the invention, there is provided a compound selected from the group consisting of:

1002 Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol;

1003 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol;

1004 Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol;

1005 Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol;

1006 Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol;

1007 Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol;

1011 Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol;

1012 Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol;

1013 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol;

1016 Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol;

1017 Cis (±) 2-(4-methoxyphenyl)chroman-3,7-diol;

1018 Cis (±) 2-(4-hydroxyphenyl)-7-methoxychroman-3-ol;

1019 Cis (±) 7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;

1020 Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl)chromane;

1021 Cis (±) 7-hydroxy-2-(4-hydroxyphenyl)chroman-3-yl acetate;

1022 Cis (±) 3-(3,7-dihydroxychroman-2-yl)phenyl acetate;

1023 Cis (±) 3-hydroxy-2-(3-hydroxyphenyl)chroman-7-yl acetate;

1024 Cis (±) 3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate;

1025 Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate;

1026 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol;

1027 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;

1028 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol;

1029 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol;

1030 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol;

1067 (2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane;

1068 (2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol;

1069 (2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol; and

1070 (2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman-3-ol.


DETAILED DESCRIPTION OF EXAMPLES



[0014] One example relates to analogues of polyphenols of the formula (I). Only the compounds of formula (I) as claimed are part of the invention. Further disclosure is for reference only.

Wherein,

A is independently deuterium, hydrogen, alkyl, F, Cl

B is independently A or hydroxyl; OR11, NR11R12

R1 to R10 are independently hydrogen; deuterium, NH2, F, Cl, hydroxyl, alkoxy, lower acyclic or cyclic alkyl, lower acyclic or cyclic acyl, -CO-OR11, -OCO-OR11, -CO-NR11R12, -COR11,-CR11R12, -O-CO-R11, -CR11R12, -O-CO-NR11R12, OCONHCHR11R12, -OCR11R12, -O-CO-R11R12, -CO-aminoacid; or -CO-hydroxyacid; which may be optionally substituted with lower alkyl, acyl, alkoxy, OR11, NR11R12, COOR11, CONR11R12, OCOR11R12, OCONR11R12, OSO3R11, OSO2NR11R12, NR11SO2NR12, NR11SO3R12;

When any two adjacent R1 to R6 are either OH or NHR11, these may be additionally be joined together by a CR11R12, -(C=O)n, -CO(CH2)n-,-C=S, C=NR12 or -OSO3-; wherein n=1 to 2.



[0015] R11 and R12 are independently hydrogen, OH, halo, C1-6 alkyl, aryl, alkaryl , arylalkyl, substituted alkyl, which may be straight, branched chain or cyclic, C1-6 alkoxy which may be straight, branched chain or cyclic, COOR13, CH2COOR13, C(R13)2OCOR13, C(R13)2OCOOR13, C(R13)2OCON(R13)2, C(R13)2N(R13)COOR13 or haloalkyl, aryl, substituted aryl, or R11 and R12 taken together with the atoms to which they may attach to form a 5- to 7-member ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is optionally substituted with further substituents
or A and R6 may form an oxime;
R13 is independently hydrogen, lower straight or branched alkyl, substituted or unsubstituted aryl or benzyl, when two R13 groups are present on the same atom, they can be joined to form a 3 to 6 membered ring;
Where substitution at C2 and C3 of pyran ring is always cis (+) or cis (-) or mixture of two. In other words, absolute configuration at C2 and C3 of pyran ring may either have RR or SS stereochemistry or a racemic mixture of RR and SS..

[0016] The analogues of polyphenols of Formula I may also be represented by compounds of Formula II;

wherein

A is independently deuterium, hydrogen, alkyl, F, Cl;

B is independently A or hydroxyl; OR11, NR11R12;

R1 to R7 and R9 are independently; H, D, NH2, F, Cl, hydroxyl, -CO-OR11, -CO-NR11R12, OCONHCHR11R12, -COR11, -CR11R12, -O-CO-R11, -CR11R12, -O-CO-NR11-R12, -OCR11R12,-O-CO-R11R12;

R11 and R12 are independently hydrogen, OH, halo, C1-6 alkyl, aryl, alkaryl , arylalkyl, substituted alkyl, which may be straight, branched chain or cyclic, C1-6 alkoxy which may be straight, branched chain or cyclic, COOR13, CH2COOR13, C(R13)2OCOR13, C(R13)2OCOOR13, C(R13)2OCON(R13)2, C(R13)2N(R13)COOR13 or haloalkyl, aryl, substituted aryl, or R11 and R12 taken together with the atoms to which they may attach to form a 5- to 7-member ring optionally incorporating one or two ring heteroatoms chosen from N, O, or S, which is optionally substituted with further substituents
or A and R6 may form an oxime;

R13 is independently hydrogen, lower straight or branched alkyl, substituted or unsubstituted aryl or benzyl, when two R13 groups are present on the same atom, they can be joined to form a 3 to 6 membered ring;

Where substitution at C2 and C3 of pyran ring is always cis (+) or cis (-) or mixture of two. In other words, absolute configuration at C2 and C3 of pyran ring may either have RR or SS stereochemistry or a racemic mixture of RR and SS.


Compounds of the present invention:



[0017] The compounds of the present invention are selected from the group consisting of:

1002 Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol;

1003 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol;

1004 Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol;

1005 Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol;

1006 Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol;

1007 Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol;

1011 Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol;

1012 Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol;

1013 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol;

1016 Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol;

1017 Cis (±) 2-(4-methoxyphenyl)chroman-3,7-diol;

1018 Cis (±) 2-(4-hydroxyphenyl)-7-methoxychroman-3-ol;

1019 Cis (±) 7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;

1020 Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl)chromane;

1021 Cis (±) 7-hydroxy-2-(4-hydroxyphenyl)chroman-3-yl acetate;

1022 Cis (±) 3-(3,7-dihydroxychroman-2-yl)phenyl acetate;

1023 Cis (±) 3-hydroxy-2-(3-hydroxyphenyl)chroman-7-yl acetate;

1024 Cis (±) 3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate;

1025 Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate;

1026 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol;

1027 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;

1028 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol;

1029 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol;

1030 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol;

1067 (2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane;

1068 (2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol;

1069 (2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol; and

1070 (2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman-3-ol.



[0018] These compounds are illustrated in Table 1. The remaining compounds illustrated in Table 1 are provided as reference examples.
Table 1: Illustrative Compounds
SPR NoStructureChemical nameMolecular FormulaMol. Weight
1001

(R,E)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman- 3 -one oxime C15H13NO6 303.07
1002

Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol C15H14O4 258.09
1003

Cis (±) 2-(3,4-dihydroxyphenyl)chroma n-3,7-diol C15H14O5 274.08
1004

Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol C15H14O4 258.09
1005

Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol C15H14O4 258.27
1006

Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol C15H14O4 258.27
1007

Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol C15H14O4 258.27
1008

Cis (±) 2-(4-hydroxyphenyl)chroman-3,5,7-triol C15H14O5 274.27
1009

(2R,3S)-2-(3,4-dihydroxyphenyl)-3-methylchroman-3,5,7-triol C17H18NO7 348.11
1010

(2R,3R)-2-(2,3-dihydroxyphenyl)-3-fluorochroman-5,7-diol C15H13FO5 292.07
1011

Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol C15H14O3 242.09
1012

Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol C15H14O3 242.09
1013

Cis (±) 2-(3,4-dihydroxyphenyl)chroma n-3,5-diol C15H14O5 274.08
1014

Cis (±) 2-(3-hydroxyphenyl)chroman-3,5,7-triol C15H14O5 274.08
1015

Cis (±) 2-phenylchroman-3,5,7-triol C15H14O4 258.1
1016

Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol C16H16O4 272.1
1017

Cis (±) 2-(4-methoxyphenyl)chroman -3,7-diol C16H16O4 272.1
1018

Cis (±) 2-(4-hydroxyphenyl)-7-methoxychroman-3-ol C16H16O4 272.1
1019

Cis (±) 7-methoxy-2-(4-methoxyphenyl)chroman -3-ol C17H18O4 286.12
1020

Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl) chromane C18H20O4 300.14
1021

Cis (±) 7-hydroxy-2-(4-hydroxyphenyl)chroman-3-yl acetate C17H16O5 300.1
1022

Cis (±)3-(3,7-dihydroxychroman-2-yl)phenyl acetate C17H16O5 300.1
1023

Cis (±) 3-hydroxy-2-(4-hydroxyphenyl)chroman-7-yl acetate C17H16O5 300.1
1024

Cis (±)3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate C19H18O6 342.11
1025

Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate C21H20O7 384.12
1026

2-(3-methoxy-4-methylphenyl)chromane-3,7-diol C17H18O4 286.12
1027

2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol C16H16O4 272.10
1028

2-(4-fluoro-3-methoxyphenyl)chroman e-3,7-diol C16H15FO4 290.10
1029

2-(4-fluoro-3-hydroxyphenyl)chromane -3,7-diol C15H13FO4 276.08
1030

2-(3-hydroxyphenyl)-3-propoxychroman-7-ol C18H20O4 300.14
1031

Cis (±) 2-(3,4-dihydroxy-2-methylphenyl)chroman-3,5,7-triol C16H16O6 304.29
1032

Cis (±) 2-(2-fluoro-3,4-dihydroxyphenyl)chroma n-3,5,7-triol C15H13FO6 308.07
1033

Cis (±) 2-(2-fluoro-4,5-dihydroxyphenyl)chroma ne-3,5,7-triol C15H13FO6 308.07
1034

Cis (±) 2-(3-fluoro-4-hydroxyphenyl)chromane -3,5,7-triol C15H13FO5 292.07
1035

Cis(±) (2-(3,4-dihydroxy-5-methylphenyl)chromane-3,5,7-triol C16H16O6 304.09
1036

(2R,3R)-2-(3,4-dihydroxyphenyl)chroma ne-4,4-d2-3,5,7-triol C15H12D2O6 292.09
1037

(2R,3R)-2-(3,4-dihydroxyphenyl)chroma ne-2-d-3,5,7-triol C15H13DO6 291.09
1038

(2R,3R)-2-(3,4-dihydroxyphenyl)chroma ne-2,4-d2-3,5,7-triol C15H12D2O6 292.09
1039

(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl isobutyl carbonate C20H22O8 390.13
1040

tert-butyl (2-hydroxy-5-(2R,3R)-3,5,7-trihydroxychroman-2yl)phenyl)carbonate    
1041

3-((((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl)oxy)carbonyl)-1-methylpyridin-1-ium C22H20INO7+ 537.03
1042

2-hydroxy-5-((2R,3R)-3,5,7-trihydroxychroman-2-yl)phenyl neopentyl carbonate C21H24O8 404.15
1043

2-hydroxy-4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)phenyl octanoate C23H28O7 416.18
1044

4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene bis(isopropylcarbamate) C23H28N2O8 460.18
1045

(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl neopentyl carbonate C21H24O8 404.15
1046

(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl isopropylcarbamate C19H21NO7 375.13
1047

(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl dimethylcarbamate C18H19NO7 361.12
1048

dibenzyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) C31H26O10 558.15
1049

dimethyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) C19H18O10 406.09
1050

(2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diisobutyl bis(carbonate) C25H30O10 490.18
1051

4-((2R,3R)-5,7-bis((benzylcarbamoyl)ox y)-3-hydroxychroman-2-yl)-1,2-phenylene bis(benzylcarbamate) C47H42N4O10 822.29
1052

dibenzyl (4-((2R,3R)-5,7-bis(((benzyloxy)carbonyl )oxy)-3-hydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) C47H38O14 826.23
1053

(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl ethyl carbonate C18H18O8 362.10
1054

(2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diisobutyl bis(carbonate) C25H30O10 490.18
1055

(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl isopropyl carbonate C19H20O8 376.12
1056

methyl ((((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl)oxy)carbonyl)glycinat e C19H19NO9 405.11
1057

(2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diethyl bis(carbonate) C21H22O10 434.12
1058

(2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl dimethyl bis(carbonate) C19H18O10 406.09
1059

4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene bis(benzylcarbamate) C31H28N2O 8 556.18
1060

dibenzyl (4-((2R,3R)-3-hydroxy-5,7-bis((isobutoxycarbonyl)o xy)chroman-2-yl)-1,2-phenylene) bis(carbonate) C41H42O14 758.26
1061

(2R,3R)-2-(3,4-dihydroxyphenyl)-3,7-dihydroxychroman-5-yl heptanoate C22H26O7 402.17
1062

(2R,3R)-2-(3,4-dihydroxyphenyl) -3,5-dihydroxychroman-7-yl heptanoate C22H26O7 402.17
1063

(2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diheptanoate C29H38O8 514.26
1064

(2R,3R)-2-(3,4-dihydroxyphenyl)-3,7-dihydroxychroman-5-yl octanoate C23H28O7 416.18
1065

(2R,3R)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxychroman-7-yl octanoate C23H28O7 416.18
1066

dibenzyl (4-((2R,3R)-3-hydroxy-5,7-bis((methoxycarbonyl)ox y)chroman-2-yl)-1,2-phenylene) bis(carbonate) C35H30O14 674.16
1067

(2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane C20H24O4 328.17
1068

(2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol C19H22O4 314.15
1069

(2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol C16H16O4 272.10
1070

(2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman -3-ol C17H18O4 286.12
1071

(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl nicotinate C21H17NO7 395.10
1072

dineopentyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) C27H34O10 518.22
1073

tert-butyl ((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl) carbonate C20H22O8 390.13
1074

(2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl (R)-3-hydroxybutanoate C19H20O8 376.12
1075

diisopropyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) C23H26O10 462.15
1076

dineopentyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) C27H34O10 518.22


[0019] In one example, there is disclosed a process of preparing the compounds of formula (I) and formula (II) as below,



[0020] Scheme 1 comprises the following steps:

Step 1: Hydroxyl groups of an acetophenone of Formula 1 is optionally protected with a protecting agent in presence of a base and a solvent;

The protecting agent is preferably a benzylating agent such as benzyl bromide in presence of suitable base such as potassium carbonate in presence of suitable solvent such as dimethylformamide or acetone at ambient temperature may be converted to a compound having protected hydroxyl group. The protected compound is further converted to chalcone of formula [3] in presence of suitable base such as NaOH, KOH, or piperidine in presence of suitable solvents as such MeOH, EtOH, THF at an ambient temperature;

Step 2: Chalcone of formula [3] may be converted into compound [4] in presence of suitable base such as NaOH, in presence of suitable epoxidizing agent such as hydrogen peroxide and in presence of suitable solvent such as MEOH or EtOH.

Step 3: Compound of formula [4] may be treated with a protecting agent to protect the hydroxyl group(s) if any, preferably with a benzylating agent such as benzyl bromide in presence of suitable base such as potassium carbonate in presence of suitable solvent such as dimethylformamide or acetone at ambient temperature may be converted to a compound [5] having protected hydroxyl group;

Step 4: Compound [5] may be converted to mixture of compound [6] and [7] in presence of chiral/achiral reducing agents such as lithium aluminum hydride/deutride in solvents such as THF or ether at a temperature ranging from ambient to reflux.

Step 5: Compounds [6] and [7] may be converted to compound [8] and [9] on deprotection. 4H-chromene and 2H-chromene compounds obtained in step 4 when subjected to hydrogenation in presence of palladium on carbon in presence of hydrogen atmosphere or palladium hydroxide at a temperature ranging from ambient to 60°C is converted to polyphenol analogues.





Step 1: Chalcone 3 which may be synthesized as described in synthetic scheme 1, on treatment with a reducing reagent such as NaBH4 may be converted to 10 in presence of a suitable solvent such as EtOH or MeOH at temperature ranging from ambient to reflux.

Step 2: Compound 10 may be converted to compound of general formula 11 in presence of suitable reagents such as OsO4, with or without chiral co-catalysts such as AD-mix-α or AD-mix-β in presence of suitable solvent such as THF at a temperature ranging from ambient to reflux.

Step 3: Compound 11 may be converted to 12 when treated with suitable reducing agents such as NaCNBH3 in presence of suitable solvents as AcOH or THF at ambient temperature.

Step 4: Compound 12 may be converted to compound 13 in presence of suitable oxidizing agents such as dess-martin periodinane in presence of suitable solvents such as THF or DCM.

Step 5: Compound [13] may be converted to compound 8 in presence of suitable reducing agents such as 1-selectride at a temperature ranging from -78°C to room temperature in presence of suitable solvents such as THF.







[0021] Any flavan-3-ol (12) such as catechin with or without a suitable protecting group such as benzyl on phenolic OH can be converted to compound [13] in presence of suitable oxidizing agents such as Dess-Martin periodinane in presence of suitable solvents such as THF or DCM. Compound [13] may be further functionalized to compound 14 with or without diastereoselectivity, exploiting different transformations of ketone group known in literature such as but not limited to cyanohydrins, oximes synthesis or halogenations or when treated with different Grignard reagents to obtain tertiary alcohols.



[0022] Any flavan-3-ol (15) such as epicatechin with or without a suitable protecting groups such as benzyl on phenolic OH can be functionalized into compound of general formula [16] in presence of suitable nucleophiles such as alkylating agents like alkyl iodide or bromide or acylating agents such as acetyl chloride or alkyl chloroformate reagents in presence of suitable base such as NaH, pyridine in presence of suitable solvents such as THF, DCM. The protecting groups if present can then be removed or retained to provide the final compounds





[0023] Any flavan-3-ol intermediate such as cyanidin [17] with or without a suitable protecting group such as benzyl on phenolic OH can be converted to compound [18A] and [18B] in presence of suitable reducing agents such as NaCNBD4 in presence of suitable solvents such as THF or DCM. Compounds [18A] and [18B] may be further reduced as well as deprotected in a single step when treated with Pd(OH)2 in hydrogen atmosphere to obtain the final products with or without diastereoselectivity.

[0024] It is submitted that the synthetic schemes as disclosed herein are not meant to limit the scope of the invention, but are meant as general synthetic schemes representative for synthesizing all described analogues.

Salts and Isomers and counter ions



[0025] Examples include the salts and isomers of the compounds. Compounds may in some cases form salts. All stereoisomers of the present compounds, such as those which may exist due to asymmetric carbons on the R substituents of the compound, including enantiomeric and diastereomeric forms, are disclosed.

Composition containing the novel entities



[0026] The present invention also contemplates a composition or formulation comprising the compounds of the present invention. The composition or formulation may be used for cosmetic or nutraceutical or pharmaceutial purposes. Further the compounds of the present invention can be used in combination with other pharmaceutical or nutraceutical agents.

[0027] In another example, the compounds are used for indications wherein epicatechin and other polyphenols are found to be useful.

[0028] In another example, the compounds may be used for inducing mitochondrial biogenesis. The compounds of the present invention may be useful as supplements/medication in meeting the muscle requirement by sports men/exercised muscles to meet the increasing energy demand. In another example, the compounds may be used for treating the diseases associated with mitochondria dysfunction.

[0029] Without being limited by theory, it is submitted that the novel analogues exhibit substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles in comparison to the other polyphenols. Further, they exhibit rapid oxidations and generally produce a detectable kinetic isotope effect that affects the pharmacokinetic, pharmacological, and/or toxicological profiles of a compound.

EXAMPLES



[0030] The following examples are representative of the disclosure, and provide detailed methods for preparing the compounds of the disclosure, including the preparation of the intermediate compounds. The preparation of particular compounds of the examples is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various examples. For example, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.

[0031] For all of the following examples, standard work-up and purification methods known to those skilled in the art may be utilized. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions conducted at room temperature unless otherwise noted. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.

Reference EXAMPLE 1: Synthesis of (R,E)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-one oxime [1001]


Step 1: Synthesis of Tetrabenzylated Catechin [20] from catechin [19]



[0032] 



[0033] To a stirred solution of [19] (1.0 g, 3.4 mmol) in DMF, anhydrous K2CO3 (2.3 g, 17.0 mmol) was added at 0 °C under nitrogen atmosphere. After an additional stirring at this for 15 minutes at same temperature, benzyl bromide (2.0 ml, 17.0 mmol) was added drop-wise. The reaction temperature was allowed to increase up to 25 °C and stirring was continued for overnight. Consumption of [19] was monitored by TLC. After complete consumption of [19], water (50 ml) was added and organic layer was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified using silica gel column chromatography using 8% ethyl acetate in hexane as eluent to afford [20] as white powder (1.5 g, 68%); ESIMS: 651[M++1]

Step 2: Synthesis of [21] from tetrabenzylated catechin [20]



[0034] 



[0035] To a stirred solution of [20] (1.0 g, 1.53 mmol) in Dry DCM, Dess-Martin Periodinane (0.98 g, 2.3 mmol) was added in one portion at room temperature. After an additional stirring for 6 - 7 h, saturated NaH2CO3 (20 ml) was added and was extracted with DCM (3 x 100 ml). The combined organic layers were washed with water and dried over sodium sulphate. The organic layer was concentrated to afford light pink sticky material which was further purified using silica gel flash column chromatography using DCM as eluent to afford off [21] as a white-pinkish solid powder (0.65 g, 71%); ESIMS: 649[M++1]

Step 3: Synthesis of [22] from [21]



[0036] 



[0037] To a stirred solution of [21] (0.20 g, 0.30 mmol) in a mixture of acetonitrile (2ml) and methanol (5 ml), ammonium acetate (0.03 g, 0.36 mmol) was added in one portion at room temperature. After additional stirring at this temperature for 10 min hydroxylamine hydrochloride (0.02 g, 0.36 mmol) was added. Consumption of [21] was monitored by TLC. After complete consumption of [21], the reaction mixture was concentrated and water (50 ml) was added. The organic layer was then extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford [22] as off white sticky solid which was used as such for further steps (0.12 g, 68 %); ESIMS: 664[M++1]

Step 4: Synthesis of 1001 from [22]



[0038] 



[0039] To a stirred solution of [22] (0.15 g, 0.22 mmol) in a mixture of ethyl acetate and methanol (1;1, 5 ml), was added a slurry of 10% Pd/C (0.02 g) at room temperature. Hydrogen balloon pressure was applied and the reaction mixture was stirred for 1hr at RT, followed by additional stirring of overnight at 50°C-55°C. Reaction was monitored using TLC. The reaction mass was filtered over celite and excess of solvent was removed under vacuum to afford light brown sticky material, which was further purified using silica gel column and 6% methanol in dichloromethane as eluent to afford [1001] as off white sticky material (0.02 g, 25%); ESIMS: 304[M++1] .

Reference EXAMPLE 2: Synthesis of (2R,3R)-2-(2,3-dihydroxyphenyl)-3-fluorochroman-5,7-diol [1010]


Step 1: Synthesis of [1010] from catechin [19]



[0040] 



[0041] To a stirred solution of [19] (0.10 g, 0.34 mmol) in Dry DCM at -10 °C was added DAST (0.20 ml, 1.0 mmol) dissolved in DCM to form a solution. The stirring was continued for 2 h before addition of saturated NaHCO3 followed by extraction with DCM (2 x 50 ml). The combined organic layer was washed with brine and dried over sodium sulphate and concentrated to afford light brown sticky material. The crude reaction mixture was purified using Flash silica gel column and 1% MeOH in DCM as eluent to afford 1014 (0.01 g, 10 %) as a light yellowish sticky material; ESIMS: 293[M++1].

Reference EXAMPLE 3: Synthesis of (2R,3S)-2-(3,4-dihydroxyphenyl)-3-aminochroman-5,7-diol [1009]


Step 1: Synthesis of [23(A+B)] from [21]



[0042] 



[0043] To a stirred solution of [21] (0.50 g, 0.77 mmol) in dry THF, benzylamine (0.18 ml, 1.5 mmol) was added at room temperature under nitrogen atmosphere. After an additional stirring at this for 15 minutes at same temperature, acetic acid (3 - 4drops) was added drop-wise. Further stirring at this temperature for 1h, NaCNBH3 (0.09 g, 1.5 mmol) was added. Consumption of [21] was monitored by TLC. After complete consumption of the starting material, water (50ml) was added and organic layer was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified using silica gel column chromatography using 5% ethyl acetate in hexane as eluent to afford [23] (0.21 g, 36 %) and 15 (0.07 g, 13 %) as a light yellow sticky material. ESIMS: 740[M++1]

Step 2: Synthesis of 1009 from [23A]



[0044] 



[0045] To a stirred solution of [23A] (0.10 g, 0.13 mmol) in a mixture of ethyl acetate and methanol (1;1, 5 ml), was added a slurry of 10% Pd/C (0.02 g) at room temperature. Hydrogen balloon pressure was applied and the reaction mixture was stirred for overnight at RT. Reaction was monitored using TLC. The reaction mass was filtered over celite and excess of solvent was removed under vacuum at low temperature to afford light brown sticky material, which was further purified using Prep HPLC to afford [1009] as light brown sticky material (0.01 g, 27%). ESIMS: 290 [M++1]

Example 4: Synthesis of Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol [1004]


Step 1: Synthesis of 1-(4-benzyloxy)-2-hydroxyphenyl)ethanone from 1-(2,4-dihydroxyphenyl)ethanone.



[0046] 



[0047] To a stirred solution of [24] (10.0 g, 65.78 mmol) in DMF (60 ml) was added K2CO3 (27.2 g, 197 mmol) at 0°C under nitrogen atmosphere. After stirring at this temperature for 15min, was added Benzyl bromide drop-wise (7.2 ml, 65.7 mmol). The temperature of reaction mixture was allowed to raise to room temperature and stirred it for overnight. TLC showed complete consumption of [24]. Reaction mixture was quenched with water (500 ml) and extracted with ethyl acetate (2 x 500 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The organic layer was rotary evaporated to afford light brown sticky material. This crude product was loaded on to silica gel column and eluted with 8 % ethyl acetate/hexane to afford brown powder [25] (12 g,75 %); ESIMS: 242[M++1].

Step 2: Synthesis of [27] from 1-(4-benzyloxy)-2-hydroxyphenyl) ethanone and [26].



[0048] 



[0049] To a stirred solution of [25] (3.0 g, 12.3 mmol) in EtOH (30 ml) was added [26] (3.1 g, 14.8 mmol) and reaction mixture was heated to 50°C, then 50% aq.NaOH solution (9.0ml) was added dropwise with constant stirring to reaction mixture at 50 °C and allowed to stir at rt for overnight. Completion of reaction was monitored by checking TLC. TLC showed complete consumption of [25]. Reaction mixture was poured into crushed ice and neutralized with 5% HCl solution, crude product was obtained as yellow precipitate which was filtered through buchener funnel and crude product was recrystallised with aq.EtOH to obtained pure product [27] as a yellow powder. This pure product [27] (3.5 g, 64 %) was used for further step. ESIMS: 436[M++1]

Step 3: Synthesis of [28] from [27].



[0050] 



[0051] To a stirred solution of [27] (3.0 g, 6.88 mmol) in methanol (40 ml), was added 20% aq. NaOH(7.0 ml) . The reaction mixture was kept in an ice bath at 0°C and 30% H2O2 (3.2ml) was added dropwise with constant stirring then reaction temperature was raised to RT and stirred at this temperature for overnight. Completion of reaction was monitored by c TLC. TLC showed complete consumption of [27]. Reaction mixture was acidified with cold 5%HCl solution. The yellow precipitate formed was filtered off through Buchner funnel and crude product was recrystallized with aq. EtOH to obtained pure product [28] as a yellow powder. This pure product [28] (1.7 g, 56%) was used for the next step; ESIMS: 450[M++1]

Step 4: Synthesis of [29] from [28].



[0052] 



[0053] To a stirred solution of [28] (1.6 g, 3.55 mmol) in DMF was added K2CO3 (0.588 g, 4.26 mmol) at 0°C under nitrogen atmosphere. After stirring at this temperature for 15min, was added Benzyl bromide drop-wise (0.42 ml, 3.55 mmol). The temperature of reaction mixture was allowed to rise to room temperature and stirred it for overnight. TLC showed complete consumption of [28]. Reaction mixture was quenched with water (500 ml) and extracted with ethyl acetate (2x200ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The organic layer was rotary evaporated to afford yellow solid. This crude product was washed with diethyl ether to afford light yellow powder [29] (1.5 g, 78 %). ESIMS: 540[M++1]

Step 5: Synthesis of [30] and [31] from [29].



[0054] 



[0055] To a stirred solution of [29] (1.5g, 2.77 mmol) in MTBE (20 ml) was added LAH (0.422 g, 11.1 mmol) at 40 °C under nitrogen atmosphere. After stirring at this temperature for 5min, The temperature of reaction mixture was allowed to raise to 80 °C for 2 h. Completion of reaction as monitored by TLC showed complete consumption of [29]. Reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The organic layer was rotary evaporated to afford dark brown sticky material. This crude product was loaded on to silica gel column and eluted with 100% DCM to afford light brown sticky material as a mixture of [30] and [31] (0.90 g, 61 %). The mixture of [30] and [31] was used in the next step; ESIMS: 526[M++1].

Step 6: Synthesis of [1004] from [30] and [31].



[0056] 



[0057] To a stirred solution of [30] and [31] (0.750 g, 1.42 mmol) in 1:1 mixture ethyl acetate and methanol (10 ml), was added a slurry of 10% Pd/C (0.075 g) at room temperature. Hydrogen balloon pressure was applied and the reaction mixture was stirred at this temperature for 1 h and then reaction temperature was raised to 50 °C - 55 °C and stirred at this temperature for overnight. The reaction mass was filtered over celite and the solvent was removed under rotary evaporator to afford light brown sticky material. This crude product was purified by prep HPLC to afford cis racemic [1004] as an off white powder (0.035 g, 10%) and its trans isomer [32] as an off white powder (0.013 g, 4 %); ESIMS: 258[M++1].

EXAMPLE 5: Synthesis of Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol [1003] was carried out by procedure as described for [1004] with [25] and 3,4-bis(benzyloxy)benzaldehyde as starting material.


EXAMPLE 6: Synthesis of Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol [1007] was carried out by procedure as described for [1004] with [25] and 3-(benzyloxy)benzaldehyde as starting material.


EXAMPLE 7: Synthesis of Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol



[0058] 


Step 1: Synthesis of (E)-3-(3,4-bis-(benzyloxy)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one [35]:



[0059] 



[0060] To a stirred solution of compound [33] (2.0 g, 14.68 mmol) and compound [34] (1.75 g, 8.28 mmol) in EtOH (20 ml), were added aq. NaOH solution (2 g dissolve in 10 ml water). Reaction mixture was stirred at 50°C for 30 min and then stirred at RT for overnight. Consumption of [33] and [34] were monitored by TLC. Reaction mixture was acidified with 2N HCl to pH 4, water (50 ml) was added and organic layer was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light yellow sticky material which was further purified using recrysallisation by using EtOH to afford [35] as light yellow solid (3.04 g, 55 %).ESIMS: 437[M++1]

Step 2: Synthesis of 2-(3,4-bis(benzyloxy)phenyl)-3-hydroxy-4H-chromen-4-one (36):



[0061] 



[0062] Compound [35] (2.5 g, 5.77 mmol) was stirred at 0 °C for 10 minute in EtOH (20 ml). Then solution of 20% NaOH (8 ml) was added in reaction mixture followed by 30% H2O2 (10 ml) was added and stirred at 0°C for 4-5 hrs. Then reaction mixture was kept in freeze for overnight at 4°C. Consumption of [35] was monitored by TLC. Reaction mixture was acidified with 2N HCl to pH 3, and organic layer was extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light yellow sticky material which was further purified using recrysallisation by using EtOH to afford [36] as light yellow solid (1.56 g, 62%).ESIMS: 451[M++1]

Step 3: Synthesis of 3-(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-4H-chromen-4-one [37]:



[0063] 



[0064] To a stirred solution of [36] (1.40 g, 3.11 mmol) in DMF, anhydrous K2CO3 (0.865 g, 6.22 mmol) was added at RT under nitrogen atmosphere. After an additional stirring at this for 15 minutes at same temperature, benzyl bromide (0.57 ml, 4.66 mmol) was added drop-wise in reaction mixture. The reaction mixture was stirred continued for 2-3 h at RT. Consumption of [36] was monitored by TLC. After complete consumption of [36], water (20 ml) was added and organic layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified by crystallization using EtOH to afford [37] as light yellow solid (1.70 g, 90 %). ESIMS: 541[M++1]

Step 4: Synthesis of compound [38] and [39]



[0065] 



[0066] To a stirred solution of [37] (1.30 g, 2.41mmol) in MTBE (30 ml), LAH (0.366 g, 9.647mmol) was added at RT under nitrogen atmosphere. Reaction mixture temperature was increased to 70°C and stirred at this temperature for 1 hrs. Consumption of [37] was monitored by TLC. After complete consumption of [37], reaction mixture was cooled to 0°C and then quenched by NH4Cl (25 ml). Water (20 ml) was added and organic layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford off-white sticky material of compound [38] and compound [39] (1.20 g, 80%), which was directly used for next step. ESIMS: 527[M++1]

Step 5: Synthesis of 1002



[0067] 



[0068] To a stirred solution of [38] and [39] (0.500 g, 9.53 mmol) in a mixture of ethyl acetate and methanol (1:1, 20 ml), was added a slurry of 10% Pd/C (0.05 g) at room temperature under nitrogen atmosphere. Hydrogen balloon pressure was applied and the reaction mixture was stirred for 1 h at RT, followed by additional stirring of overnight at 50°C - 55°C. Reaction was monitored by using TLC. The reaction mass was filtered over celite bed and excess of solvent was removed under vacuum to afford light brown sticky material, which was further purified using silica gel column and 2% methanol in dichloromethane as eluent to afford cis racemic 1002 (0.090 g, 40%) as an off-white solid and 1002A (0.010g, 10%) .ESIMS: 259[M++1]

EXAMPLE 8: Synthesis of Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol [1011] was carried out by procedure as described for 1002 with [33] and 3-(benzyloxy)benzaldehyde as starting material.


EXAMPLE 9: Synthesis of Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol [1012] was carried out by procedure as described for 1002 with [33] and 4-(benzyloxy)benzaldehyde as starting material.


EXAMPLE 10: Synthesis of Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol [1006]


Step 1: Synthesis of 1-(2-(benzyloxy)-6-hydroxyphenyl)-ethanone [41]



[0069] 



[0070] To a stirred solution of [40] (2.0 g, 1.34mmol) in DMF, anhydrous K2CO3 (2.17 g, 15.77mmol) was added at RT under nitrogen atmosphere. After an additional stirring at this for 15 minutes at same temperature, benzyl bromide (1.92 ml, 15.77mmol) was added drop-wise. The reaction mixture was stirred continuously for overnight at RT. Consumption of [40] was monitored by TLC. After complete consumption of [40], water (50ml) was added and organic layer was extracted with ethyl acetate (2x100ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified using silica gel column chromatography using 5% ethyl acetate in hexane as eluent to afford [41] as white powder (2.1 g, 80%).ESIMS: 243[M++1]

Step 2: Synthesis of (E)-1-(2-(benzyloxy)-6-hydroxyphenyl)-3-(4-(benzyloxy)-phenyl)-prop-2-en-1-one (43):



[0071] 



[0072] To a stirred solution of compound [41] (2.0 g, 8.28mmol) and compound [42] (1.75 g, 8.28 mmol) in EtOH (20 ml), were added aq. NaOH solution (1g dissolve in 6 ml water). Reaction mixture was stirred at 50°C for 30 min and then stirred at RT for overnight. Consumption of [41] and [42] were monitored by TLC. Reaction mixture was acidified with 2N HCl to pH 4, water (50ml) was added and organic layer was extracted with ethyl acetate (2x100ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light yellow sticky material which was further purified using recrysallisation by using EtOH to afford [43] as light yellow solid (2.0 g, 50%).ESIMS: 437[M++1]

Step 3: Synthesis of 5-(benzyloxy)-2-(4-(benzyloxy)-phenyl)-3-hydroxy-4H-chromen-4-one (44):



[0073] 



[0074] Compound [43] (1.5 g, 3.44mmol) was stirred at 0°C for 10 minute in EtOH (20 ml). Then solution of 20% NaOH (10 ml) was added in reaction mixture followed by 30% H2O2 (10 ml) was added and stirred at 0 °C for 4-5 h. Then reaction mixture was kept in freeze for overnight at 4 °C. Consumption of [43] was monitored by TLC. Reaction mixture was acidified with 2N HCl to pH 3, and organic layer was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light yellow sticky material which was further purified using recrysallisation by using EtOH to afforded [44] and [45] as a light yellow solid (890 mg, 50 %).ESIMS: 451[M++1]

Step 4: Synthesis of 3,5-bis-(benzyloxy)-2-(4-(benzyloxy)-phenyl)-4H-chromen-4-one (46):



[0075] 



[0076] To a stirred solution of [44] (0.6 g, 1.33 mmol) in DMF, anhydrous K2CO3 (0.36 g, 2.66mmol) was added at RT under nitrogen atmosphere. After an additional stirring at this for 15 minutes at same temperature, benzyl bromide (0.325 ml, 2.66 mmol) was added drop-wise in reaction mixture. The reaction mixture was stirred continued for 2-3 hrs at RT. Consumption of [44] was monitored by TLC. After complete consumption of [44], water (20ml) was added and organic layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified by crystallization using EtOH to afford [46] as light yellow solid (0.3 g, 52%).ESIMS: 541[M++1]

Step 5: Synthesis of compound 62 (A) + 62 (B) from [61]



[0077] 



[0078] To a stirred solution of [46] (0.5 g, 9.25 mmol) in MTBE (20 ml), LAH (0.140 g, 37.03 mmol) was added at RT under nitrogen atmosphere. Reaction mixture temperature was increased to 70°C and stirred at this temperature for 1 hrs. Consumption of [46] was monitored by TLC. After complete consumption of [46], reaction mixture was cooled to 0°C and then quenched by NH4Cl (25 ml). Water (20 ml) was added and organic layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford off-white sticky material of compound 47 (A + B) (0.4 g, 80 %), which was directly used for next step. ESIMS: 527[M++1]

Step 6: Synthesis of 2-(4-hydroxyphenyl)-chroman-3,5-diol (1006):



[0079] 



[0080] To a stirred solution of 47 (A+B) (0.400 g, 0.76 mmol) in a mixture of ethyl acetate and methanol (1:1, 20 ml), was added a slurry of 10 % Pd/C (0.04 g) at room temperature under nitrogen atmosphere. Hydrogen balloon pressure was applied and the reaction mixture was stirred for 1hr at RT, followed by additional stirring of overnight at 50°C - 55°C. Reaction was monitored by using TLC. The reaction mass was filtered over celite bed and excess of solvent was removed under vacuum to afford light brown sticky material, which was further purified using silica gel column and 2% methanol in dichloromethane as eluent to afforded cis racemic 1006 (0.028 g, 30 %) as an off-white solids.ESIMS: 259[M++1]

EXAMPLE 11: Synthesis of Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol [1005] was carried out by procedure as described for 1006 with [41] and 3-(benzyloxy)benzaldehyde as starting material.


EXAMPLE 12: Synthesis of Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol [1013] was carried out by procedure as described for 1006 with [41] and 3,4-bis(benzyloxy)benzaldehyde as starting material.



[0081] EXAMPLE 13: Synthesis of 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol [1026] and 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol [1027] was carried out by procedure as described for 1004 with [25] and 3-methoxy-4-methylbenzaldehyde as starting material. [1026] ESIMS: 287[M++1][1027] ESIMS: 272[M++1]

EXAMPLE 14: Synthesis of 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol [1028] and 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol [1029] was carried out by procedure as described for 1004 with [25] and 4-fluoro-3-methoxybenzaldehyde as starting material. [1028] ESIMS: 290[M++1] [1029] ESIMS: 276[M++1]


EXAMPLE 15: Synthesis of Cis (±) 2-(3-methoxyphenyl)chroman-3,7-diol, Cis (±) 2-(3-hydroxyphenyl)-7-methoxychroman-3-ol, Cis(±)7-methoxy-2-(3-methoxyphenyl) chroman-3-ol [1017, 1018 and 1019]


Step 1: Synthesis of [1017], [1018] and [1019] from [1007]



[0082] 



[0083] To a stirred solution of [1007] (0.12g, 0.46 mmol) in DMF, anhydrous K2CO3 (0.12g, 0.93 mmol) was added at 0°C under nitrogen atmosphere. After an additional stirring for 15 minutes at same temperature, Methyl iodide (0.05 ml, 0.93 mmol) was added drop-wise. The reaction temperature was allowed to increase up to 25°C and stirring was continued for 4 h. Consumption of [1007] was monitored by TLC. After complete consumption of [1007], water (50 ml) was added and organic layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified using silica gel column chromatography using 5 % ethyl acetate/hexane as eluent to afford [1017] as light green sticky material (0.05g, 37%,), [1018] and [1019] as light yellow sticky material (0.02g, 16 %). [1019] ESIMS: 287[M++1] [1017] and [1018] ESIMS: 272[M++1]

EXAMPLE 16: Synthesis of Cis (±)3-(3,7-dihydroxychroman-2-yl)phenyl acetate [1022], Cis (±) 3-hydroxy-2-(4-hydroxyphenyl)chroman-7-yl acetate [1023] and Cis (±)3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate [1024]


Step 1: Synthesis of [1022], [1023] and [1024] from [1007]



[0084] 



[0085] To a stirred solution of [1007] (0.2g, 0.77 mmol) in DMF, pyridine (0.12ml, 1.5 mmol) was added at 0°C under nitrogen atmosphere. After an additional stirring for 5 minutes at same temperature, Acetic anhydride (0.15 ml, 1.5 mmol) was added drop-wise. The reaction temperature was allowed to increase up to 25°C and stirring was continued for 1h. Consumption of [1007] was monitored by TLC. After complete consumption of [1007], water (50 ml) was added and organic layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified using silica gel column chromatography using 5 % ethyl acetate/hexane as eluent to afford [1024] as light yellow sticky material (0.08g, 30%), [1022] and [1023] as yellow sticky material (0.04g, 17 %). [1024] ESIMS: 343[M++1] [1022] and [1023] ESIMS: 301[M++1]

EXAMPLE 17: Synthesis of 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol [1030]


Step 1: Synthesis of [48] from [1007]



[0086] 



[0087] To a stirred solution of [1007] (0.15 g, 0.58 mmol) in DMF, anhydrous K2CO3 (0.24g, 1.14 mmol) was added at RT under nitrogen atmosphere. After an additional stirring for 15 minutes at same temperature, benzyl bromide (0.13ml, 1.16 mmol) was added drop-wise in reaction mixture. The reaction mixture was stirred continued for overnight at RT. Consumption of [1007] was monitored by TLC. After complete consumption of [1007], water (20ml) was added and organic layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified using silica gel column chromatography using 5 % ethyl acetate/hexane as eluent to afford [48] as off-white sticky material (0.17g, 67%). [81] ESIMS: 439[M++1]

Step 2: Synthesis of [49] from [48]



[0088] 



[0089] To a stirred solution of [48] (0.25 g, 0.57 mmol) in DMF, Sodium hydride (0.45g, 1.1 mmol) was added at RT under nitrogen atmosphere. After an additional stirring for 15 minutes at same temperature, propyl bromide (0.13ml, 1.1 mmol) was added drop-wise in reaction mixture. The reaction mixture was stirred continued for overnight at RT. Consumption of [48] was monitored by TLC. After complete consumption of [48], water (20ml) was added and organic layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified using silica gel column chromatography using 7 % ethyl acetate/hexane as eluent to afford [49] as off-white sticky material (0.20g, 73%). [49] ESIMS: 481[M++1]

Step 3: Synthesis of [1030] from [49]



[0090] 



[0091] To a stirred solution of [49] (0.20 g, 0.4 mmol) in a mixture of ethyl acetate and methanol (1:1, 20 ml), was added a slurry of 10% Pd/C (0.02 g) at room temperature under nitrogen atmosphere. Hydrogen balloon pressure was applied and the reaction mixture was stirred for 1hr at RT, followed by additional stirring of overnight at 50 °C - 55 °C. Reaction was monitored by using TLC. The reaction mass was filtered over celite bed and excess of solvent was removed under vacuum to afford light brown sticky material, which was further purified using silica gel column and 2 % methanol in dichloromethane as eluent to afforded [1030] (0.90g, 72%) as an off-white solid. ESIMS: 301 [M++1]

Reference EXAMPLE 18: Synthesis of Cis (±) 2-(4-hydroxyphenyl)chroman-3,5,7-triol [1008]


Step 1: Synthesis of 1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)-ethanone:



[0092] 



[0093] To a stirred solution of [50] (3.0 g, 16.19 mmol) in DMF, anhydrous K2CO3 (5.56 g, 40.32 mmol) was added at 0°C under nitrogen atmosphere. After an additional stirring at this for 15 minutes at same temperature, benzyl bromide (4.92 ml, 40.32 mmol) was added drop-wise. The reaction temperature was allowed to increase up to 25°C and stirring was continued for overnight. Consumption of [50] was monitored by TLC. After complete consumption of [50], water (50 ml) was added and organic layer was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified using silica gel column chromatography using 5 % ethyl acetate/hexane as eluent to afford [51] as white powder (3.2 g, 70 %). ESIMS: 349[M++1]

Step2: Synthesis of (E)-3-(4-(benzyloxy)phenyl)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)-prop-2-en-1-one:



[0094] 



[0095] To a stirred solution of compound [51] (2.0 g, 5.74 mmol) and compound [26] (1.21 g, 5.74 mmol) in EtOH (20 ml), were added aq. NaOH solution (2 g dissolve in 10 ml water). Reaction mixture was stirred at 50 °C for 30 min and then stirred at RT for overnight. Consumption of [51] and [26] were monitored by TLC. Reaction mixture was acidified with 2N HCl to pH 4, water (50 ml) was added and organic layer was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light yellow sticky material which was further purified using recrysallisation by using EtOH to afford [52] as light yellow solid (2.0 g, 65 %).ESIMS: 543[M++1]

Step 3: Synthesis of 5,7-bis(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-hydroxy-4H-chromen-4-One:



[0096] 



[0097] Compound [52] (1.8 g, 3.32 mmol) was stirred at 0°C for 10 minute in EtOH (20 ml). Then solution of 20 % NaOH (8 ml) was added in reaction mixture followed by 30% H2O2 (20 ml) was added and stirred at 0°C for 4-5 hrs. Then reaction mixture was kept in freeze for overnight at 4°C. Consumption of [52] was monitored by TLC. Reaction mixture was acidified with 2N HCl to pH 3, and organic layer was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light yellow sticky material which was further purified using recrysallisation by using EtOH to afford [53] as light yellow solid (1.3 g, 60 %).ESIMS: 557[M++1]

Step 4: Synthesis of 3,5,7-tris(benzyloxy)-2-(4-(benzyloxy)phenyl)-4H-chromen-4-one:



[0098] 



[0099] To a stirred solution of [53] (1.25 g, 2.24 mmol) in DMF, anhydrous K2CO3 (0.370 g, 2.69 mmol) was added at RT under nitrogen atmosphere. After an additional stirring at this for 15 minutes at same temperature, benzyl bromide (0.330 ml, 2.69 mmol) was added drop-wise in reaction mixture. The reaction mixture was stirred continuously for 2-3 hrs at RT. Consumption of [53] was monitored by TLC. After complete consumption of [53], water (20 ml) was added and organic layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford light brown sticky material which was further purified by crystallization using EtOH to afford [54] as light yellow solid (0.900 g, 60 %).ESIMS: 646[M++1]

Step 5: Synthesis of compound 55(A) + 55(B):



[0100] 



[0101] To a stirred solution of [54] (0.950 g, 1.47 mmol) in MTBE (20 ml), LAH (0.223 g, 5.82 mmol) was added at RT under nitrogen atmosphere. Reaction mixture temperature was increased to 70 °C and stirred at this temperature for 1 hrs. Consumption of [54] was monitored by TLC. After complete consumption of [54], reaction mixture was cooled to 0°C and then quenched by NH4Cl (25 ml). Water (20 ml) was added and organic layer was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, brine and dried over sodium sulphate. The organic layer was concentrated to afford off-white sticky material of compound [55 (A + B)] (0.590 g, 70 %), which was directly used for next step. ESIMS: 633[M++1]

Step 6: Synthesis of 1011 from 55(A) and 55(B)



[0102] 



[0103] To a stirred solution of 55 (A+B) (0.300 g, 4.7 mmol) in a mixture of ethyl acetate and methanol (1:1, 20 ml), was added a slurry of 10% Pd/C (0.05 g) at room temperature under nitrogen atmosphere. Hydrogen balloon pressure was applied and the reaction mixture was stirred for 1hr at RT, followed by additional stirring of overnight at 50 °C - 55 °C. Reaction was monitored by using TLC. The reaction mass was filtered over celite bed and excess of solvent was removed under vacuum to afford light brown sticky material, which was further purified using silica gel column and 2 % methanol in dichloromethane as eluent to afforded cis racemic 1008 (0.040 g, 35 %) as an off-white solid.ESIMS: 275[M++1]

Reference EXAMPLE 19: Synthesis of Cis (±) 2-(3-hydroxyphenyl)chroman-3,5,7-triol [1014] was carried out by procedure as described for 1008 with [51] and 3-(benzyloxy)benzaldehyde as starting material.


Reference EXAMPLE 20: Synthesis of Cis (±) 2-phenylchroman-3,5,7-triol [1015] was carried out by procedure as described for 1008 with [51] and benzaldehyde as starting material.


Reference EXAMPLE 21: Synthesis of Cis (±) 2-(3,4-dihydroxy-2-methylphenyl)chroman-3,5,7-triol [1035]


Step 1: Synthesis of 51 from 50



[0104] 



[0105] To a stirred solution of [50] (5.0 g, 26.8 mmol) in DMF(50 ml) was added K2CO3 (11.1 g, 80.6mmol) at 0°C under nitrogen atmosphere. After stirring at this temperature for 15min, was added Benzyl bromide drop-wise (6.42 ml, 53.7 mmol). The temperature of reaction mixture was allowed to rise to room temperature and stirred it for overnight. TLC showed complete consumption of [50]. Reaction mixture was quenched with water (500 ml) and extracted with ethyl acetate (2x400ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The organic layer was rotary evaporated to afford light brown solid. This crude product was loaded on to silica gel column and eluted with 10% ethyl acetate/hexane to off-white powder [51] (3.3 g, 35 %). This pure product [51] was used for further step.ESIMS: 348[M++1]

Step 2: Synthesis of [53] from [51] and [56].



[0106] 



[0107] To a stirred solution of [51] (3.3. g, 9.48 mmol) in EtOH (35.0 ml) was added [56] (3.6 g, 11.3 mmol) and reaction mixture was heated to 50 °C, then 50 % aq.NaOH solution (10.0 ml) was added dropwise with constant stirring to reaction mixture at 50 °C and allowed to stir at room temperature for overnight. Completion of reaction was monitored TLC. TLC showed complete consumption of [56]. Reaction mixture was poured into crushed ice and neutralized with 5% HCl solution, crude product was obtained as yellow precipitate which was filtered through Buchner funnel and crude product was recrystallised with aq.EtOH to obtained pure product [57] as a yellow powder. This pure product [57] (4.2 g, 68 %) was used for further step. ESIMS: 663[M++1]

Step 3: Synthesis of [58] from [57].



[0108] 



[0109] To a stirred solution of [57] (3.0 g, 5.53 mmol) in methanol (35 ml), was added 20% aq. NaOH(5.0 ml) . The reaction mixture was kept in an ice bath at 0°C and 30% H2O2 (2.5 ml) was added dropwise with constant stirring then reaction temperature was raised to rt and stirred at this temperature for overnight. Completion of reaction was monitored by checking TLC. Reaction mixture was acidified with cold 5%HCl solution. The yellow precipitate formed was filtered off through Buchner funnel and crude product was re-crystallised with aq.EtOH to obtained pure product [58] as a yellow powder. This pure product [58] (0.4 g, 10%) was used for further step. ESIMS: 677[M++1]

Step 4: Synthesis of [59] from [58].



[0110] 



[0111] To a stirred solution of [58] (0.4 g, 0.59 mmol) in DMF was added K2CO3 (0.12 g, 0.86 mmol) at 0 °C under nitrogen atmosphere. After stirring at this temperature for 15min, was added Benzyl bromide drop-wise (0.10 ml, 0.88 mmol). The temperature of reaction mixture was allowed to raise to room temperature and stirred it for overnight. TLC showed complete consumption of [58]. Reaction mixture was quenched with water (500 ml) and extracted with ethyl acetate (2 x 200 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The organic layer was rotary evaporated to afford a yellow solid. This crude product was washed with diethyl ether to afford light yellow powder [59] (0.4 g, 88 %). ESIMS: 767[M++1]

Step 5: Synthesis of [60] and [61] from [59].



[0112] 



[0113] To a stirred solution of [59] (0.4 g, 0.52 mmol) in MTBE (10 ml) was added LAH (0.05 g, 1.56 mmol) at 40 °C under nitrogen atmosphere. After stirring at this temperature for 5min, the temperature of reaction mixture was allowed to raise to 80 °C for 2 h. Completion of reaction was monitored by checking TLC TLC showed complete consumption of [59]. Reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The organic layer was rotary evaporated to afford dark brown sticky material. This crude product was loaded on to silica gel column and eluted with 100 % DCM to afford light brown sticky material as a mixture of [60] and [61] (0.25 g, 67 %). The mixture of [60] and [61] was used for further step.ESIMS: 727[M++1]

Step 6: Synthesis of 1031 from [60] and [61].



[0114] 



[0115] To a stirred solution of [60] and [61] (0.25 g, 0.34 mmol) in 1:1 mixture ethyl acetate and methanol (10 ml), was added a slurry of 10% Pd/C (0.03 g) at room temperature under nitrogen atmosphere. Hydrogen balloon pressure was applied and the reaction mixture was stirred at this temperature for 1hr and then reaction temperature was raised to 50 °C - 55 °C and stirred at this temperature for overnight. The reaction mass was filtered over celite and the solvent was removed under rotary evaporator to afford light brown sticky material. This crude product was purified by prep HPLC to afford cis racemic [1031A] as a off-white powder (0.02 g, 20 %) and trans racemic [1031B] as a off white powder (0.01 g, 9 %).

Reference EXAMPLE 22: Synthesis of Cis (±) 2-(2-fluoro-3,4-dihydroxyphenyl)chroman-3,5,7-triol [1032] was carried out by procedure as described for 1031 with [51] and 3,4-bis(benzyloxy)-2-fluorobenzaldehyde as starting material. ESIMS: 309[M++1]


Reference EXAMPLE 23: Synthesis of Cis (±) 2-(2-fluoro-4,5-dihydroxyphenyl)chromane-3,5,7-triol [1033] was carried out by procedure as described for 1031 with [51] and 4,5-bis(benzyloxy)-2-fluorobenzaldehyde as starting material. ESIMS: 309[M++1]


Reference EXAMPLE 24: Synthesis of Cis (±) 2-(3-fluoro-4-hydroxyphenyl)chromane-3,5,7-triol


Step 1: Synthesis of [63] from [51] and [62].



[0116] [1034]



[0117] To a stirred solution of [51] (2.2g, 6.32mmol) in EtOH (35.0ml) was added [62] (1.7g, 7.58mmol) and reaction mixture was heated to 50°C, then 50% aq.NaOH solution (10.0ml) was added dropwise with constant stirring to reaction mixture at 50°C and allowed to stir at room temperature for overnight. Completion of reaction was monitored TLC. TLC showed complete consumption of [62]. Reaction mixture was poured into crushed ice and neutralized with 5% HCl solution, crude product was obtained as yellow precipitate which was filtered through Buchner funnel and crude product was recrystallised with aq.EtOH to obtained pure product [63] as a yellow powder. This pure product [63] (2.0g, 55%) was used for further step.ESIMS: 560[M++1]

Step 2: Synthesis of [64] from [63].



[0118] 



[0119] To a stirred solution of [63] (2.0g, 3.57mmol) in mixture of EtOH (20.0ml) and THF(10ml) was added NaBH4 (0.3g, 7.14mmol) and reaction mixture was heated to 80°C for 2hr, then the reaction mixture was rotary-evaporated to dryness and was added 1:2 mixture of AcOH and water(20ml) at 0°C. The reaction mixture was allowed to stir at room temperature for overnight. Reaction mixture was again rotary evaporated to dryness and saturated solution of Na2CO3 was poured and was extracted with DCM (200ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The organic layer was rotary evaporated to afford light brown sticky material. This crude product was loaded on to silica gel flash column and eluted with 100% DCM to afford light yellow sticky material [64] (1.0g, 51%). ESIMS: 545[M++1]

Step 3: Synthesis of [65] from [64].



[0120] 



[0121] To a stirred solution of [64] (1.0g, 1.8mmol) in dry THF was added N-methyl morpholine oxide (0.2g, 2.29mmol), OsO4 in t-BuOH (3%, 2ml) and water(3ml) at room temperature and the resulting solution was stirred at this temperature for 6 h. Reaction was monitored by TLC. After complete consumption of [64], saturated solution of sodium thiosulfate was added and extracted with DCM. The combined organic layer was washed with brine and dried over sodium sulphate and evaporated to afford the desired material [65] (0.9g, 86%) which was used as such for further reaction. ESIMS: 579[M++1]

Step 4: Synthesis of [66] from [65]



[0122] 



[0123] To a stirred solution of [65] (0.9g, 1.55mmol) in AcOH at 0°C was added NaCNBH3(1.4g 23.3mmol) portion-wise under constant stirring. The resulting solution was stirred at 0°C for 1h and then the temperature of reaction mixture was allowed to come to room temperature. Reaction was monitored by TLC. After complete consumption of [65], saturated NaHCO3 was added and extracted with DCM. The combined organic layer was washed with brine and dried over sodium sulphate and evaporated to afford the desired material trans [66] (0.60g, 68%) which was used as such for further reaction. ESIMS: 563[M++1]

Step 5: Synthesis of [67] from [66]



[0124] 



[0125] To a stirred solution of [66] (0.6g, 1.0mmol) in Dry DCM, Dess-Martin Periodinane (1.2g, 3.0mmol) was added in one portion at room temperature. After an additional stirring for 6-7h, saturated NaHCO3 (20ml) was added and was extracted with DCM (3x100ml). The combined organic layers were washed with water and dried over sodium sulphate. The organic layer was concentrated to afford light pink sticky material which was further purified using silica gel flash column chromatography using DCM as eluent to afford off [67] as a white-pinkish solid powder (0.40g, 71%) ESIMS: 561[M++1]

Step 6: Synthesis of [68] from [67]



[0126] 



[0127] To a stirred solution of [67] (0.2g, 0.35mmol) in dry THF at -78 °C was added L-selectride (1.78ml) drop wise under nitrogen atmosphere. The resulting solution was stirred at -78 °C for 5 h and then the temperature of reaction mixture was allowed to come to room temperature. Reaction was monitored by TLC. After complete consumption of [67], saturated NaHCO3 was added and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over sodium sulphate and evaporated to afford the desired material cis [68] (0.10g, 51%). ESIMS: 563[M++1]

Step 7: Synthesis of [1034] from [68]



[0128] 



[0129] To a stirred solution of [68] (0.10g, 0.17 mmol) in 1:1 mixture ethyl acetate and methanol (10 ml), was added a slurry of 10% Pd/C (0.010 g) at room temperature. Hydrogen balloon pressure was applied and the reaction mixture was stirred at this temperature for 1hr and then reaction temperature was raised to 50 °C - 55 °C and stirred at this temperature for overnight. The reaction mass was filtered over celite and the solvent was removed under rotary evaporator to afford light brown sticky material. This crude product was loaded on to silica gel column and eluted with 4% methanol/ Dichloromethane to afford off white powder
(0.028, 57%). ESIMS: 293[M++1]

Reference EXAMPLE 25: Synthesis of Cis(±) (2-(3,4-dihydroxy-5-methylphenyl)chromane-3,5,7-triol [1035] was carried out by procedure as described for 1031 with [51] and 3,4-bis(benzyloxy)-5-methylbenzaldehyde as starting material. ESIMS: 305[M++1]


Reference EXAMPLE 26: Synthesis of (2R,3R)-2-(3,4-dihydroxyphenyl)chromane-4,4-d2-3,5,7-triol [1036]


Step 1: Synthesis of [84 and 85] from [86]



[0130] 



[0131] To a stirred suspension of [69] (2.5g) in methyl tertiary butyl ether (75.0ml,30vol) was added lithium aluminium deuteride (0.251 mg, 3.6 eq) in small portions at room temperature under a nitrogen atmosphere. After stirring for 10 min at this temperature, the temperature of the reaction was raised from 65°C to 70°C. After stirring at the same temperature for 1 hour, reaction mass was quenched with a 1 N HCl (10 ml) solution at 0 to -5°C, then the temperature of the reaction was raised to room temperature. Ethyl acetate (10 ml) was added to the reaction and stirred for 30 min. The organic layer was decanted and removed. Ethyl acetate was added to the aqueous layer. The mixture was filtered through a celite bed, and the aqueous and organic layer was separated. The organic layers were combined and concentrated under reduced pressure to afford an off-white solid (2.5 g). The crude compound was triturated with ethyl acetate (10 ml) at room temperature for 4 h, then filtered, washed with ethyl acetate, and dried under vacuum to afford an off-white solid (1.0 g, 40% yield) [70].

[0132] After isolation of [70], the mother liquor was concentrated under reduced pressure to afford a pale yellow residue. The semi solid obtained was triturated with 50% ethyl acetate: hexane (250 ml) for 30 min at room temperature, thus solid was obtained. The solid was filtered and washed with 50% ethyl acetate: hexane (200ml). The solid obtained was dried under vacuum to obtain off white solid (0.250 g, 10% yield) [71]. ESIMS: 741 [M++ 1]

Step 2: Synthesis of [1036] from [71]



[0133] 



[0134] To a stirred solution of [71] (0.3g, 0.404 mmol) in 1:1 mixture ethyl acetate and methanol (10ml), was added a slurry of Pd(OH)2 (0.030 g) at room temperature. The reaction mixture was stirred at room temperature for 1 h then the reaction temperature was raised to 50 to 55 °C and stirred at this temperature for overnight. The reaction was filtered through celite. The collected solvent was removed with a rotary evaporator to afford a light brown sticky material. This crude product was loaded on to silica gel column and eluted with a 4% methanol/ dichloromethane to afford a light pink powder (0.055 g, 46% yield) [1036]. ESIMS: 293 [M++ 1]

Step 3: [1038] from [70]



[0135] 



[0136] To a stirred solution of [70] (0.18 g, 0.24 mmol) in a 1:1 mixture of ethyl acetate and methanol (8 ml), was added a slurry of Pd(OH)2 (0.020 g) at room temperature. The reaction mixture was stirred at this temperature for 1 h and then the reaction temperature was raised to 50 - 55 °C and stirred at this temperature for overnight. The reaction was filtered through celite. The collected solvent was removed with a rotary evaporator to afford a light brown sticky material. This crude product was loaded on to silica gel column and eluted with 4% methanol/ dichloromethane to afford an off white powder, which was then separated on prep-HPLC to afford [1038] (0.045 g, 64% yield). ESIMS: 293 [M++ 1]

Reference EXAMPLE 27 Synthesis of (2R,3R)-2-(3,4-dihydroxyphenyl)chromane-2-d-3,5,7-triol [1037]


Step 1: Synthesis of [73 and 74] from [72]



[0137] 



[0138] To a stirred solution of [72] (0.2g, 0.25 mmol) in dry dichloromethane under nitrogen atmosphere was added NaCNBD3 (0.02g, 0.25 mmol) in one portion at room temperature. Reaction mixture was allowed to stir at this temperature for 15min. After completion of reaction, the reaction mixture was quenched with water under cooling. Reaction mixture was further diluted with dichloromethane, organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to give [73] and [74] as light pink sticky material (0.16g, 85%). ESIMS: 740[M++1]

Step 2: Synthesis of [1037] from [73]



[0139] 





[0140] To a stirred solution of [73] (0.150 g, 0.20 mmol) in a 1:1 mixture of ethyl acetate and methanol (8 ml), was added a slurry of Pd(OH)2 (0.020 g) at room temperature. Hydrogen balloon pressure was applied and the reaction mixture was stirred at this temperature for 1 h and then the reaction temperature was raised to 50 - 55 °C and stirred at this temperature for overnight. The reaction was filtered through celite. The collected solvent was removed with a rotary evaporator to afford a light brown sticky material. This crude product was loaded on to silica gel column and eluted with 4% methanol/ dichloromethane to afford an off white powder, which was then separated on prep-HPLC to afford cis racemic [1037]along with minor trans isomer.. ESIMS: 292 [M++ 1]

Reference Example 28:- Synthesis of dibenzyl (4-(3,5,7-trihydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) [1048]



[0141] 



[0142] To a suspension of [75] (1.0eq, 0.15gm, 0.5mmol) in 10 ml acetonitrile at 0°C was added dropwise triethyl amine (2.0eq,0.14ml,1.0mol) and stirred for 10 minutes. To this suspension benzyl chloroformate (2.0eq, 0.16ml, 1.0 mol) was added dropwise over a period of 5 minutes. The resulting solution was stirred at 0°C for another 10 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed with water. Ethyl acetate layer was separated and dried over Na2SO4, filtered and evaporated to yield colorless gel which was subjected to column chromatography on silica gel and eluted with 2% MeOH /Dichloromethane to afforded [1048] as a colorless solid [0.135gm,46%].ESIMS: 740[M++1]
In a similar manner the compounds [1043], [1044] and [1049] were synthesized.

Reference Example 29:- Synthesis of 4-(3,5,7-trihydroxychroman-2-yl)-1,2-phenylene bis(benzylcarbamate) [1059]



[0143] 



[0144] To a suspension of [75] (1.0eq, 0.2gm, 0.68mmol) in 10 ml acetonitrile at 0°C was added dropwise triethyl amine (2.0eq, 0.14ml, 1.4mol) and stirred for 10 minutes. To this suspension benzyl isocyanate [2.0eq, 0.17ml, 1.4mol] was added dropwise over a period of 5 minutes. The resulting solution was stirred at 0°C for 10 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed with water. Ethyl acetate layer was separated and dried over Na2SO4, filtered and evaporated to yield colorless gel which was subjected to column chromatography on silica gel [100-200 mesh size] and eluted the compound by 2% MeOH/Dichloromethane to afforded [1059] as a colorless solid [0.08gm,20%]. ESIMS: 556 [M++1]

Reference Example 30:- Synthesis of (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl isopropylcarbamate [1046]


Step 1: Synthesis of tetrabenzylated racemic epicatechin [76] form racemic epicatechin [75]



[0145] 



[0146] To a stirred of [75] (1.0gm, 3.4mmol) in DMF was added K2CO3 (2.3gm, 17.0mmol) at 0°C under nitrogen atmosphere. After stirring at this temperature for 15min, was added Benzyl bromide drop-wise. The temperature of reaction mixture was allowed to raise to room temperature and stirred it for overnight. TLC showed complete consumption of [75]. Reaction mixture was quenched with water (50ml) and extracted with ethyl acetate (2x100ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The organic layer was rotary evaporated to afford to afford light brown sticky material. This crude product was loaded on to silica gel column and eluted with 8% ethyl acetate/hexane to afford white powder [76] (1.5gm, 68%). ESIMS: 651[M++1]

Step 2: Synthesis of [77] from [76]



[0147] 



[0148] To a stirred of [76] (0.20gm, 0.30mmol) in DMF was added NaH portionwise (0.017gm, 0.46mmol) at 0°C under nitrogen atmosphere. After stirring at this temperature for 1h, was added 4-nitrophenyl isopropylcarbamate (0.10gm,0.46mmol) portion-wise. The temperature of reaction mixture was allowed to raise to room temperature and stirred it for 2h. TLC showed complete consumption of [76] Reaction mixture was quenched with water (50ml) and extracted with ethyl acetate (2x100ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The organic layer was rotary evaporated to afford to afford light brown sticky material which was purified on silica gel column with 8% EtoAc/hexane as eluent to afford [77](0.07gm, 35%) as light yellow powder. ESIMS: 736[M++1]

Step 3: synthesis of [1046] from [77]



[0149] 



[0150] To a stirred solution of [77] (0.070 g, 0.09 mmol) in 1:1 mixture ethyl acetate and methanol (10 ml), was added a slurry of 10% Pd/C (0.070 g) at room temperature. Hydrogen balloon pressure was applied and the reaction mixture was stirred at this temperature for 4hr. The reaction mass was filtered over celite and the solvent was removed under rotary evaporator to afford light brown sticky material. This crude product was purified on silica gel column with 4%MeOH/ Dichloromethane as eluent to afford [1046] (0.02g, 10%) as a off white powder (0.005g, 74%). ESIMS: 376 [M++1]

[0151] In a similar manner the compounds [1045], [1047], [1053], [1055] and [1056] were synthesized.

Reference Example 31:- Synthesis of dibenzyl (4-((2R,3R)-5,7-bis(((benzyloxy)carbonyl)oxy)-3-hydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) [1052]



[0152] 



[0153] To a suspension of [75] (1.0eq, 1.0gm, 3.5mmol) in 10 ml acetonitrile at 0°C was added dropwise triethyl amine (2.9ml, 21.0mol) and stirred for 10 minutes. To this suspension benzyl chloroformate (3.61ml, 21.0mmol) was added dropwise over a period of 5 minutes. The resulting solution was stirred at 0°C for another 10 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed with water. Ethyl acetate layer was separated and dried over Na2SO4, filtered and evaporated to afford [1052] transparent sticky material (2.70g, 94%]. ESIMS: 827[M++1]
In a similar manner [1051] was synthesized.

Reference Example 32:- Synthesis of dibenzyl (4-((2R,3R)-5,7-bis(((benzyloxy)carbonyl)oxy)-3-hydroxychroman-2-yl)-1,2-phenylene) bis(carbonate) [1066]


Step 1: synthesis of [1066] from [1048]



[0154] 



[0155] To a suspension of [1048] (0.1gm, 0.17mmol) in 10 ml acetonitrile at 0°C was added dropwise to triethyl amine (0.02ml, 0.17mmol) and stirred for 10 minutes. To this suspension methyl chloroformate (0.01ml, 0.17mmol) was added dropwise over a period of 5 minutes. The resulting solution was stirred at 0°C for another 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed with water. Ethyl acetate layer was separated and dried over Na2SO4, filtered and evaporated to yield colorless gel which was subjected to column chromatography on silica gel and eluted with 20% Ethylacetate/Hexane to afforded [1066] as a off white solid [0.04gm,35%]. ESIMS: 675[M++1]
In a similar manner [1060] was synthesized

Step 2: Synthesis of [1058] from [1066]



[0156] 



[0157] To a stirred solution of [1066] (0.10 g, 0.14 mmol) in 1:1 mixture ethyl acetate and methanol (10 ml), was added a slurry of 10% Pd/C (0.01 g) at room temperature. Hydrogen balloon pressure was applied and the reaction mixture was stirred at this temperature for 1hr. The reaction mass was filtered over celite and the solvent was removed under rotary evaporator to afford light brown sticky material. This crude product was purified on silica gel column with 4% MeOH/ Dichloromethane as eluent to afford [1058] (0.05g, 83%) as a light brown powder (0.05g, 74%). ESIMS: 407 [M++1]
In a similar manner [1050], [1054] and [1057] were synthesized.

Reference Example 33: Synthesis of [1061], [1062] and [1063]


Step 1: Synthesis of [78], [79] and [80] from [1048]



[0158] 



[0159] To a suspension of [1048] (0.5gm, 0.89mmol) in 20 ml acetonitrile at 0°C was added dropwise triethyl amine (0.12ml, 0.89mmol) and stirred for 10 minutes. To this suspension hepatnoic chloride (0.13g, 0.89mmol) was added dropwise over a period of 5 minutes. The resulting solution was stirred at 0°C for another 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and washed with water. Ethyl acetate layer was separated and dried over Na2SO4, filtered and evaporated to yield colorless gel which was subjected to column chromatography on silica gel and eluted with 2% MeOH/ Dichloromethane to afforded [78] (0.07g, 11%) as off white solid, [79] (0.05, 9%) and [80] (0.18g, 25%) as a light green sticky material. [78] and [79]: ESIMS: 671[M++1]
: ESIMS: 783 [M++1]

Step 2:


Synthesis of [1061], [1062] and [1063] was carried out as described for [1058] from [78], [79] and [80].



[0160] In a similar manner [1064] and [1065] were synthesized.

Example 34: Testing of compounds for their AMPK activation potential:



[0161] AMPK activation potential of the compounds was evaluated using cell based ELISA.Hepatoma (Hep G2) liver cells were maintained in a T 75 culture flask-containing 25 mM DMEM+10% fetal calf serum. The cells were maintained in a T 75 culture flask-containing medium (DMEM+10% fetal calf serum). On reaching a confluence of 70 to 80%, the cells were seeded in a 96 well plate at a density of 40,000 cells per well in 25mM DMEM+10% FCS medium. The plates were then incubated at 37°C with 5% CO2 for 24 hours. Various concentrations of drugs were prepared in DMSO and diluted to required concentration with the medium and incubated at 37° C. with 5% CO2 for 30 min and 1h for Epicatechin analogs and 11-BHP analogs respectively. Metformin was used as positive control .Cells were fixed with 4% formaldehyde for 30 minutes at room temperature and washed three times with PBS containing 0.1% Triton X-100. Endogenous peroxidase was quenched with 1 % H2O2 in PBS-T (0.1% Tween 20) for 30 minutes and washed three times in PBS-T. Cells were blocked with 1% BSA in PBS-T for 1 hour. The cells were incubated with 1:1000 dilution primary antibody (Phospho-AMPKα (Thrl72) Rabbit mAb, Cell Signaling in PBS-T containing 5% BSA at 4° C overnight. The cells were then washed three times with PBS-T for 5 minutes and incubated with 1:1000 dilution secondary antibody (Anti-rabbit IgG, HRP-linked Antibody, Cell Signaling) in PBS-T with 1% BSA for 1 hour at RT. Cells were washed three times with PBS-T for 5 minutes The cells were incubated with 100 µl TMB substrate solution for 30minutes and the reaction was stopped with 100 µl of 2N H2SO4. Then the plate was read at 450 nM using ELISA plate reader and absorbance recorded. % activity was calculated using DMSO control as 100%. All compounds, as exemplified and encompassed are found to be active. For illustrative purpose, the activation potential of the compounds at 10nm concentration is provided in Table 2, whereby only compounds 1002-1007, 1011-1013, 1016-1030 and 1067-1070 are compounds of the invention.
Table 2: Activiation potential of the compounds.
Compound%pAMPK(at 10nm)
1002 108
1004 114
1005 102
1006 103
1007 113
1008 103
1009 101
1015 119
1017 110
1018 100
1019 101
1026 101
1027 94
1028 101
1029 93
1030 94
1032 104
1031 101
1033 107
1034 107
1035 102
1036 105
1037 110
1041 88
1042 95
1043 98
1044 96
1045 105
1046 101
1047 100
1048 103
1049 105
1050 91
1051 85
1052 103
1053 94
1054 91
1055 105
1056 112
1058 117
1059 144
1060 110
1064 110
1066 139
1068 90
1069 110
1070 126
1071 102
1072 99
1073 109



Claims

1. A process for the preparation of a compound of Formula (I):

which is selected from the group consisting of:

1002 Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol;

1003 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol;

1004 Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol;

1005 Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol;

1006 Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol;

1007 Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol;

1011 Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol;

1012 Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol;

1013 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol;

1016 Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol;

1017 Cis (±) 2-(4-methoxyphenyl)chroman-3,7-diol;

1018 Cis (±) 2-(4-hydroxyphenyl)-7-methoxychroman-3-ol;

1019 Cis (±) 7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;

1020 Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl)chromane;

1021 Cis (±) 7-hydroxy-2-(4-hydroxyphenyl)chroman-3-yl acetate;

1022 Cis (±) 3-(3,7-dihydroxychroman-2-yl)phenyl acetate;

1023 Cis (±) 3-hydroxy-2-(3-hydroxyphenyl)chroman-7-yl acetate;

1024 Cis (±) 3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate;

1025 Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate;

1026 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol;

1027 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;

1028 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol;

1029 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol;

1030 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol;

1067 (2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane;

1068 (2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol;

1069 (2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol; and

1070 (2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman-3-ol; comprising the steps of:

i. protecting the hydroxyl groups of an acetophenone of Formula 1, wherein X is methyl, with a protecting agent in the presence of a base and a solvent;

ii. reacting compound of Formula 1 obtained from step (i) with a compound of formula 2 in the presence of a base and a solvent to obtain a chalcone of formula 3;

iii. converting the chalcone of formula 3 to a compound 4 in the presence of an epoxidizing agent or a base;

iv. optionally protecting hydroxyl group(s) of the compound obtained in step (iii);

v. reducing the compounds of step (iii) or step (iv) in the presence of a chiral/achiral reducing agent to obtain a mixture of 4H-chromene and 2H-chromene compounds of formula 6 and 7; and

hydrogenating 4H-chromene and 2H-chromene compounds obtained in step (v) to obtain the compound of Formula (I).


 
2. The process of claim 1, comprising the steps of:

i. protecting hydroxyl groups of a flavan-3-ol of formula 12 with a protecting agent;

ii. treating the protected flavan-3-ol of step (i) with an oxidizing agent to obtain a compound of formula 13;

iii. functionalising the oxo group of compound 13 to obtain a compound of formula 14; and

iv. deprotecting the compound obtained in step (iii) to obtain the compound of Formula (I).


 
3. The process of claim 1, comprising the steps of:

i. optionally protecting hydroxyl groups of a flavan-3-ol of formula 15 with a protecting agent;

ii. functionalising the protected/unprotected hydroxyl group of the compound of formula 15 to obtain compound of formula 16; and

deprotecting the compound obtained in step (ii) of formula 16 to obtain the compound of Formula (I).


 
4. The process of claim 1, wherein the compound of Formula (II) is of formula 8, comprising the steps of:

i. treating a chalcone of formula 3 with a reducing agent in presence of a solvent at a temperature ranging from ambient to reflux to obtain a compound of formula 10;

ii. converting the compound of formula 10 to compound of formula 11 in the presence of a hydroxylating agent with or without chiral co-catalysts and a suitable solvent at a temperature ranging from ambient to reflux;

iii. functionalizing the hydroxyl group of compound of formula 11 with a suitable reagent in the presence of a suitable solvent to obtain a compound of formula 12;

iv. treating the compound of formula 12 with an oxidizing agent to obtain a compound of formula 13; and

iii. reducing the compound of formula 13 from step iv in the presence of a chiral reducing agent at a temperature ranging from -78°C to room temperature in presence of suitable solvents to obtain the compound of Formula (I).


 
5. A compound selected from the group consisting of:

1002 Cis (±) 3-hydroxychroman-2-yl)benzene-1,2-diol;

1003 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol;

1004 Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol;

1005 Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol;

1006 Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol;

1007 Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol;

1011 Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol;

1012 Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol;

1013 Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol;

1016 Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol;

1017 Cis (±) 2-(4-methoxyphenyl)chroman-3,7-diol;

1018 Cis (±) 2-(4-hydroxyphenyl)-7-methoxychroman-3-ol;

1019 Cis (±) 7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;

1020 Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl)chromane;

1021 Cis (±) 7-hydroxy-2-(4-hydroxyphcnyl)chroman-3-yl acctatc;

1022 Cis (±) 3-(3,7-dihydroxychroman-2-yl)phenyl acetate;

1023 Cis (±) 3-hydroxy-2-(3-hydroxyphenyl)chroman-7-yl acetate;

1024 Cis (±) 3-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate;

1025 Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate;

1026 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol;

1027 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;

1028 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol;

1029 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol;

1030 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol;

1067 (2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane;

1068 (2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol;

1069 (2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol; and

1070 (2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman-3-ol.


 
6. A pharmaceutical composition comprising a compound of claim 5 along with a pharmaceutically or nutraceutically acceptable excipient.
 
7. The compound as claimed in claim 5, for use in treating acute coronary syndromes, selected from the group comprising myocardial infarction and angina; acute ischemic events in other organs and tissues, renal injury, renal ischemia and diseases of the aorta and its branches; injuries arising from medical interventions selected from the group comprising coronary artery bypass grafting (CABG) procedures and aneurysm repair; cancer; metabolic diseases, and diabetes mellitus.
 
8. Non-therapeutic use of the compound of claim 5, as supplement in meeting the muscle requirement by sports men/exercised muscles to meet the increasing energy demand.
 
9. The compound of claim 5, when present as its stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof.
 


Ansprüche

1. Verfahren für die Herstellung einer Verbindung der Formel (I):

die aus der Gruppe ausgewählt ist, die aus Folgenden besteht:

1002 cis-(±)-3-Hydroxychroman-2-yl)benzol-1,2-diol;

1003 cis-(±)-2-(3,4-Dihydroxyphenyl)chroman-3,7-diol;

1004 cis-(±)-2-(4-Hydroxyphenyl)chroman-3,7-diol;

1005 cis-(±)-2-(3-Hydroxyphenyl)chroman-3,5-diol;

1006 cis-(±)-2-(4-Hydroxyphenyl)chroman-3,5-diol;

1007 cis-(±)-2-(3-Hydroxyphenyl)chroman-3,7-diol;

1011 cis-(±)-2-(3-Hydroxyphenyl)chroman-3-ol;

1012 cis-(±)-2-(4-Hydroxyphenyl)chroman-3-ol,

1013 cis-(±)-2-(3,4-Dihydroxyphenyl)chroman-3,5-diol;

1016 cis-(±)-2-(4-Hydroxyphenyl)-3-methoxychroman-7-ol;

1017 cis-(±)-2-(4-Methoxyphenyl)chroman-3,7-diol;

1018 cis-(±)-2-(4-Hydroxyphenyl)-7-methoxychroman-3-ol;

1019 cis-(±)-7-Methoxy-2-(4-methoxyphenyl)chroman-3-ol;

1020 cis-(±)-3,7-Dimethoxy-2-(4-methoxyphenyl)chroman;

1021 cis-(±)-7-Hydroxy-2-(4-hydroxyphenyl)chroman-3-ylacetat;

1022 cis-(±)-3-(3,7-Dihydroxychroman-2-yl)phenylacetat;

1023 cis-(±)-3-Hydroxy-2-(3-hydroxyphenyl)chroman-7-ylacetat;

1024 cis-(±)-3-(7-Acetoxy-3-hydroxychroman-2-yl)phenylacetat;

1025 cis-(±)-2-(4-Acetoxyphenyl)chroman-3,7-diyldiacetat;

1026 2-(3-Methoxy-4-methylphenyl)chroman-3,7-diol;

1027 2-(3-Hydroxy-4-methylphenyl)chroman-3,7-diol;

1028 2-(4-Fluor-3-methoxyphenyl)chroman-3,7-diol;

1029 2-(4-Fluor-3-hydroxyphenyl)chroman-3,7-diol;

1030 2-(3-Hydroxyphenyl)-3-propoxychroman-7-ol;

1067 (2R,3R)-7-Methoxy-2-(3-methoxyphenyl)-3-propoxychroman;

1068 (2R,3R)-2-(3-Methoxyphenyl)-3-propoxychroman-7-ol;

1069 (2R,3R)-2-(3-Hydroxy-4-methylphenyl)chroman-3,7-diol; und

1070 (2R,3R)-7-Methoxy-2-(4-methoxyphenyl)chroman-3-ol;
das die folgenden Schritte umfasst:

i. Schützen der Hydroxylgruppen eines Acetophenons der Formel 1, wobei X Methyl ist, mit einem Schutzmittel in Gegenwart einer Base und eines Lösungsmittels;

ii. Reagieren der Verbindung der Formel 1, die von Schritt (i) erhalten wurde, mit einer Verbindung der Formel 2 in Gegenwart einer Base und eines Lösungsmittels, um ein Chalkon der Formel 3 zu erhalten;

iii. Umwandeln des Chalkons der Formel 3 in eine Verbindung 4 in Gegenwart eines Epoxidierungsmittels oder einer Base;

iv. optionales Schützen von Hydroxylgruppe(n) der Verbindung, die im Schritt (iii) erhalten wurde;

v. Reduzieren der Verbindungen von Schritt (iii) oder Schritt (iv) in Gegenwart eines chiralen/achiralen Reduktionsmittels, um eine Mischung aus 4H-Chromen- und 2H-Chromenverbindungen der Formel 6 und 7 zu erhalten; und

Hydrieren der 4H-Chromen- und 2H-Chromenverbindungen, die im Schritt (v) erhalten wurden, um die Verbindung der Formel (I) zu erhalten.


 
2. Verfahren nach Anspruch 1, das die folgenden Schritte umfasst:

i. Schützen von Hydroxylgruppen eines Flavan-3-ols der Formel 12 mit einem Schutzmittel;

ii. Behandeln des geschützten Flavan-3-ols von Schritt (i) mit einem Oxidationsmittel, um eine Verbindung der Formel 13 zu erhalten;

iii. Funktionalisieren der Oxogruppe der Verbindung 13, um eine Verbindung der Formel 14 zu erhalten; und

iv. Entschützen der Verbindung, die im Schritt (iii) erhalten wurde, um die Verbindung der Formel (I) zur erhalten.


 
3. Verfahren nach Anspruch 1, das die folgenden Schritte umfasst:

i. optionales Schützen von Hydroxylgruppen eines Flavan-3-ols der Formel 15 mit einem Schutzmittel;

ii. Funktionalisieren der geschützten/ungeschützten Hydroxylgruppe der Verbindung der Formel 15, um die Verbindung der Formel 16 zu erhalten; und

Entschützen der Verbindung, die im Schritt (ii) erhalten wurde, der Formel 16, um die Verbindung der Formel (I) zur erhalten.


 
4. Verfahren nach Anspruch 1, wobei die Verbindung der Formel (II) die Formel 8 aufweist, das die folgenden Schritte umfasst:

i. Behandeln eines Chalkons der Formel 3 mit einem Reduktionsmittel in Gegenwart eines Lösungsmittels bei einer Temperatur im Bereich von Umgebungs- bis Rückflusstemperatur, um eine Verbindung der Formel 10 zu erhalten;

ii. Umwandeln der Verbindung der Formel 10 in die Verbindung der Formel 11 in Gegenwart eines Hydroxylierungsmittels mit oder ohne chirale Cokatalysatoren und eines geeigneten Lösungsmittels bei einer Temperatur im Bereich von Umgebungs- bis Rückflusstemperatur;

iii. Funktionalisieren der Hydroxylgruppe der Verbindung der Formel 11 mit einem geeigneten Reagenz in Gegenwart eines geeigneten Lösungsmittels, um eine Verbindung der Formel 12 erhalten;

iv. Behandeln der Verbindung der Formel 12 mit einem Oxidationsmittel, um eine Verbindung der Formel 13 zu erhalten; und

iii. Reduzieren der Verbindung der Formel 13 von Schritt iv in Gegenwart eines chiralen Reduktionsmittels bei einer Temperatur im Bereich von -78 °C bis Raumtemperatur in Gegenwart von geeigneten Lösungsmitteln, um die Verbindung der Formel (I) zur erhalten.


 
5. Verbindung, die aus der Gruppe ausgewählt ist, die aus Folgenden besteht:

1002 cis-(±)-3-Hydroxychroman-2-yl)benzol-1,2-diol;

1003 cis-(±)-2-(3,4-Dihydroxyphenyl)chroman-3,7-diol;

1004 cis-(±)-2-(4-Hydroxyphenyl)chroman-3,7-diol;

1005 cis-(±)-2-(3-Hydroxyphenyl)chroman-3,5-diol;

1006 cis-(±)-2-(4-Hydroxyphenyl)chroman-3,5-diol;

1007 cis-(±)-2-(3-Hydroxyphenyl)chroman-3,7-diol;

1011 cis-(±)-2-(3-Hydroxyphenyl)chroman-3-ol;

1012 cis-(±)-2-(4-Hydroxyphenyl)chroman-3-ol,

1013 cis-(±)-2-(3,4-Dihydroxyphenyl)chroman-3,5-diol;

1016 cis-(±)-2-(4-Hydroxyphenyl)-3-methoxychroman-7-ol;

1017 cis-(±)-2-(4-Methoxyphenyl)chroman-3,7-diol;

1018 cis-(±)-2-(4-Hydroxyphenyl)-7-methoxychroman-3-ol;

1019 cis-(±)-7-Methoxy-2-(4-methoxyphenyl)chroman-3-ol;

1020 cis-(±)-3,7-Dimethoxy-2-(4-methoxyphenyl)chroman;

1021 cis-(±)-7-Hydroxy-2-(4-hydroxyphenyl)chroman-3-ylacetat;

1022 cis-(±)-3-(3,7-Dihydroxychroman-2-yl)phenylacetat;

1023 cis-(±)-3-Hydroxy-2-(3-hydroxyphenyl)chroman-7-ylacetat;

1024 cis-(±)-3-(7-Acetoxy-3-hydroxychroman-2-yl)phenylacetat;

1025 cis-(±)-2-(4-Acetoxyphenyl)chroman-3,7-diyldiacetat;

1026 2-(3-Methoxy-4-methylphenyl)chroman-3,7-diol;

1027 2-(3-Hydroxy-4-methylphenyl)chroman-3,7-diol;

1028 2-(4-Fluor-3-methoxyphenyl)chroman-3,7-diol;

1029 2-(4-Fluor-3-hydroxyphenyl)chroman-3,7-diol;

1030 2-(3-Hydroxyphenyl)-3-propoxychroman-7-ol;

1067 (2R,3R)-7-Methoxy-2-(3-methoxyphenyl)-3-propoxychroman;

1068 (2R,3R)-2-(3-Methoxyphenyl)-3-propoxychroman-7-ol;

1069 (2R,3R)-2-(3-Hydroxy-4-methylphenyl)chroman-3,7-diol; und

1070 (2R,3R)-7-Methoxy-2-(4-methoxyphenyl)chroman-3-ol.


 
6. Pharmazeutische Zusammensetzung, die eine Verbindung nach Anspruch 5 zusammen mit einem pharmazeutisch oder nutrazeutisch verträglichen Hilfsstoff umfasst.
 
7. Verbindung nach Anspruch 5 für die Verwendung bei der Behandlung von Folgenden: akuten Koronarsyndromen, die aus der Gruppe ausgewählt sind, die Myokardinfarkt und Angina umfasst; akuten ischämischen Ereignissen in anderen Organen und Geweben, Nierenverletzung, renaler Ischämie und Erkrankungen der Aorta und ihrer Verzweigungen; Verletzungen, die durch medizinische Eingriffe entstehen, die aus der Gruppe ausgewählt sind, die Koronararterien-Bypass-Operations(CABG)-Verfahren und Aneurysmareparatur umfasst; Krebs; Stoffwechselerkrankungen und Diabetes mellitus.
 
8. Nichttherapeutische Verwendung der Verbindung nach Anspruch 5 als Ergänzungsmittel bei der Erfüllung der Anforderung an Muskeln durch Sportler/belastete Muskeln, um den zunehmenden Energiebedarf zu decken.
 
9. Verbindung nach Anspruch 5 bei Vorliegen als ihr Stereoisomer, Enantiomer oder pharmazeutisch verträgliches Salz davon.
 


Revendications

1. Procédé de préparation d'un composé de Formule (I)

qui est choisi dans le groupe constitué par :

1002 le cis-(±)-3-hydroxychroman-2-yl)benzène-1,2-diol ;

1003 le cis-(±)-2-(3,4-dihydroxyphényl)chromane-3,7-diol ;

1004 le cis-(±)-2-(4-hydroxyphényl)chromane-3,7-diol ;

1005 le cis-(±)-2-(3-hydroxyphényl)chromane-3,5-diol ;

1006 le cis-(±)-2-(4-hydroxyphényl)chromane-3,5-diol ;

1007 le cis-(±)-2-(3-hydroxyphényl)chromane-3,7-diol ;

1011 le cis-(±)-2-(3-hydroxyphényl)chroman-3-ol ;

1012 le cis-(±)-2-(4-hydroxyphényl)chroman-3-ol ;

1013 le cis-(±)-2-(3,4-dihydroxyphényl)chromane-3,5-diol ;

1016 le cis-(±)-2-(4-hydroxyphényl)-3-méthoxychroman-7-ol ;

1017 le cis-(±)-2-(4-méthoxyphényl)chromane-3,7-diol ;

1018 le cis-(±)-2-(4-hydroxyphényl)-7-méthoxychroman-3-ol ;

1019 le cis-(±)-7-méthoxy-2-(4-méthoxyphényl)chroman-3-ol ;

1020 le cis-(±)-3,7-diméthoxy-2-(4-méthoxyphényl)chromane ;

1021 l'acétate de cis-(±)-7-hydroxy-2-(4-hydroxyphényl)chroman-3-yle ;

1022 l'acétate de cis-(±)-3-(3,7-dihydroxychroman-2-yl)phényle ;

1023 l'acétate de cis-(±)-3-hydroxy-2-(3-hydroxyphényl)chroman-7-yle ;

1024 l'acétate de cis-(±)-3-(7-acétoxy-3-hydroxychroman-2-yl)phényle ;

1025 le diacétate de cis-(±)-2-(4-acétoxyphényl)chroman-3,7-diyle ;

1026 le 2-(3-méthoxy-4-méthylphényl)chromane-3,7-diol ;

1027 le 2-(3-hydroxy-4-méthylphényl)chromane-3,7-diol ;

1028 le 2-(4-fluoro-3-méthoxyphényl)chromane-3,7-diol ;

1029 le 2-(4-fluoro-3-hydroxyphényl)chromane-3,7-diol ;

1030 le 2-(3-hydroxyphényl)-3-propoxychroman-7-ol ;

1067 le (2R,3R)-7-méthoxy-2-(3-méthoxyphényl)-3-propoxychromane ;

1068 le (2R,3R)-2-(3-méthoxyphényl)-3-propoxychroman-7-ol ;

1069 le (2R,3R)-2-(3-hydroxy-4-méthylphényl)chromane-3,7-diol ; et

1070 le (2R,3R)-7-méthoxy-2-(4-méthoxyphényl)chroman-3-ol ;
comprenant les étapes consistant à :

i. protéger les groupements hydroxyle d'une acétophénone de formule 1, où X est méthyle, par un agent protecteur en présence d'une base et d'un solvant ;

ii. réagir le composé de formule 1 obtenu dans l'étape (i) avec un composé de formule 2 en présence d'une base et d'un solvant, afin d'obtenir une chalcone de formule 3 ;

iii. convertir la chalcone de formule 3 en un composé 4 en présence d'un agent d'époxydation ou d'une base ;

iv. éventuellement, protéger le ou les groupements hydroxyle du composé obtenu dans l'étape (iii) ;

v. réduire les composés de l'étape (iii) ou de l'étape (iv) en présence d'un agent réducteur chiral/achiral, afin d'obtenir un mélange de composés de 4H-chromène et de 2H-chromène de formule 6 et 7 ; et

hydrogéner les composés de 4H-chromène et de 2H-chromène obtenus dans l'étape (v) afin d'obtenir le composé de Formule (I).


 
2. Procédé selon la revendication 1, comprenant les étapes consistant à :

i. protéger les groupements hydroxyle d'un flavan-3-ol de formule 12 par un agent protecteur ;

ii. traiter le flavan-3-ol protégé de l'étape (i) par un agent oxydant, afin d'obtenir un composé de formule 13 ;

iii. fonctionnaliser le groupement oxo du composé 13, afin d'obtenir un composé de formule 14 ; et

iv. déprotéger le composé obtenu dans l'étape (iii), afin d'obtenir le composé de Formule (I).


 
3. Procédé selon la revendication 1, comprenant les étapes consistant à :

i. éventuellement, protéger les groupements hydroxyle d'un flavan-3-ol de formule 15 par un agent protecteur ;

ii. fonctionnaliser le groupement hydroxyle protégé/non protégé du composé de formule 15, afin d'obtenir un composé de formule 16 ; et

déprotéger le composé obtenu dans l'étape (ii) de formule 16, afin d'obtenir le composé de Formule (I).


 
4. Procédé selon la revendication 1, dans lequel le composé de Formule (II) répond à la formule 8, comprenant les étapes consistant à :

i. traiter une chalcone de formule 3 par un agent réducteur en présence d'un solvant à une température allant de la température ambiante au reflux, afin d'obtenir un composé de formule 10 ;

ii. convertir le composé de formule 10 en composé de formule 11 en présence d'un agent d'hydroxylation avec ou sans co-catalyseurs chiraux et d'un solvant convenable, à une température allant de la température ambiante au reflux ;

iii. fonctionnaliser le groupement hydroxyle du composé de formule 11 par un réactif convenable en présence d'un solvant convenable, afin d'obtenir un composé de formule 12 ;

iv. traiter le composé de formule 12 par un agent oxydant, afin d'obtenir un composé de formule 13 ; et

iii. réduire le composé de formule 13 de l'étape (iv) en présence d'un agent réducteur chiral à une température allant de -78°C à la température ambiante, en présence de solvants convenables, afin d'obtenir le composé de Formule (I).


 
5. Composé choisi dans le groupe constitué par :

1002 le cis-(±)-3-hydroxychroman-2-yl)benzène-1,2-diol ;

1003 le cis-(±)-2-(3,4-dihydroxyphényl)chromane-3,7-diol ;

1004 le cis-(±)-2-(4-hydroxyphényl)chromane-3,7-diol ;

1005 le cis-(±)-2-(3-hydroxyphényl)chromane-3,5-diol ;

1006 le cis-(±)-2-(4-hydroxyphényl)chromane-3,5-diol ;

1007 le cis-(±)-2-(3-hydroxyphényl)chromane-3,7-diol ;

1011 le cis-(±)-2-(3-hydroxyphényl)chroman-3-ol ;

1012 le cis-(±)-2-(4-hydroxyphényl)chroman-3-ol ;

1013 le cis-(±)-2-(3,4-dihydroxyphényl)chromane-3,5-diol ;

1016 le cis-(±)-2-(4-hydroxyphényl)-3-méthoxychroman-7-ol ;

1017 le cis-(±)-2-(4-méthoxyphényl)chromane-3,7-diol ;

1018 le cis-(±)-2-(4-hydroxyphényl)-7-méthoxychroman-3-ol ;

1019 le cis-(±)-7-méthoxy-2-(4-méthoxyphényl)chroman-3-ol ;

1020 le cis-(±)-3,7-diméthoxy-2-(4-méthoxyphényl)chromane ;

1021 l'acétate de cis-(±)-7-hydroxy-2-(4-hydroxyphényl)chroman-3-yle ;

1022 l'acétate de cis-(±)-3-(3,7-dihydroxychroman-2-yl)phényle ;

1023 l'acétate de cis-(±)-3-hydroxy-2-(3-hydroxyphényl)chroman-7-yle ;

1024 l'acétate de cis-(±)-3-(7-acétoxy-3-hydroxychroman-2-yl)phényle ;

1025 le diacétate de cis-(±)-2-(4-acétoxyphényl)chroman-3,7-diyle ;

1026 le 2-(3-méthoxy-4-méthylphényl)chromane-3,7-diol ;

1027 le 2-(3-hydroxy-4-méthylphényl)chromane-3,7-diol ;

1028 le 2-(4-fluoro-3-méthoxyphényl)chromane-3,7-diol ;

1029 le 2-(4-fluoro-3-hydroxyphényl)chromane-3,7-diol ;

1030 le 2-(3-hydroxyphényl)-3-propoxychroman-7-ol ;

1067 le (2R,3R)-7-méthoxy-2-(3-méthoxyphényl)-3-propoxychromane ;

1068 le (2R,3R)-2-(3-méthoxyphényl)-3-propoxychroman-7-ol ;

1069 le (2R,3R)-2-(3-hydroxy-4-méthylphényl)chromane-3,7-diol ; et

1070 le (2R,3R)-7-méthoxy-2-(4-méthoxyphényl)chroman-3-ol.


 
6. Composition pharmaceutique, comprenant un composé selon la revendication 5, conjointement avec un excipient acceptable sur le plan pharmaceutique ou nutraceutique.
 
7. Composé selon la revendication 5, pour une utilisation dans le traitement de syndromes coronariens aigus choisis dans le groupe comprenant l'infarctus du myocarde et l'angine ; les évènements ischémiques aigus dans d'autres organes et tissus, une lésion rénale, une ischémie rénale et les maladies de l'aorte et de ses branches ; les lésions survenant à la suite d'interventions médicales choisies dans le groupe comprenant les modes opératoires de pontage aorto-coronarien (PAC) et les réparations d'anévrismes ; le cancer ; les maladies métaboliques, et le diabète sucré.
 
8. Utilisation non thérapeutique du composé selon la revendication 5, comme complément pour répondre aux besoins musculaires des muscles à l'exercice/de sportifs, afin de répondre à la demande énergétique accrue.
 
9. Composé selon la revendication 5, lorsqu'il est présent sous forme du stéréoisomère, de l'énantiomère, ou du sel pharmaceutiquement acceptable de celui-ci.
 






Cited references

REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description