FIELD OF THE INVENTION
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
Polyphenols 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.
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.
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.
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.
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 halflife
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.
OBJECT OF THE INVENTION
An object of the invention is to provide novel analogues of polyphenols and a process of
preparation thereof.
SUMMARY OF THE INVENTION
The present invention is related to novel analogues of polyphenols of the formula (I).
Wherein,
A is independently deuterium, hydrogen, alkyl, F, CI
B is independently A or hydroxyl; OR 11, NR R 12
R 1 to R 10 are independently hydrogen; deuterium, NH , F, CI, hydroxyl, alkoxy, lower acyclic
or cyclic alkyl, lower acyclic or cyclic acyl, -CO-OR , -OCO-OR , -CO -NRnR 12 , -COR , -
CR ,,Ri , -O-CO -Rn, -CR Ri2, -0-CO-NRnRi 2, OCONHCHR' V 2, -OCR Ri2, -O-CORiiRi
2, -CO -aminoacid; or -CO -hydroxyacid; which may be optionally substituted with
lower alkyl, acyl, alkoxy, OR 11, NR R 12 , COOR 11, CONR R 12 , OCOR R 12 , OCONR R 12 ,
OS0 3R , OS0 2NR R 12 , NR S0 2NR 12 , NR O 12 ;
When any two adjacent R 1 to R 10 are either OH or NHR , these may be additionally be
joined together by a CR R 12 , -(C =0) , -CO(CH 2) -,-C=S, C=NR 12 or -OSO3-; wherein n=l
to 2.
R 1 and R1' 2 are independently hydrogen, OH, halo, C 1-6 alkyl, aryl, alkaryl , arylalkyl,
substituted alkyl, which may be straight, branched chain or cyclic, Ci-6 alkoxy which may be
straight, branched chain or cyclic, COOR13 , CH2COOR 3 , C(R )2OCOR ,
C(R1 )2OCOOR13 , C(Rl ) OCON(R )2, C(R1 )2N(R 1 )COOR 3 or haloalkyl, aryl, substituted
aryl, or R1 and R1 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 R6may form an oxime;
R is independently hydrogen, lower straight or branched alkyl, substituted or unsubstituted
aryl or benzyl, when two R groups are present on the same atom; they may 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.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention is related to novel analogues of polyphenols of the
formula (I).
Formula I
Wherein,
A is independently deuterium, hydrogen, alkyl, F, CI
B is independently A or hydroxyl; OR1 1, NR R12
R to R 0 are independently hydrogen; deuterium, NH , F, CI, hydroxyl, alkoxy, lower acyclic
or cyclic alkyl, lower acyclic or cyclic acyl, -CO-ORn, -OCO-OR , -CO-NRnR 12 , -COR , -
CR Ri2, -O-CO-Rn, -CRnRi2, -0-CO-NR Ri2, OCONHCHR R12 , -OCR R12 , -O-COR
R12 , -CO-aminoacid; or -CO-hydroxyacid; which may be optionally substituted with
lower alkyl, acyl, alkoxy, OR11 , NR R 2 , COOR , CONR R12 , OCOR R12 , OCONR R12 ,
OS0 3R , OS0 2NR1 R1 ,NR1 S0 2NR12 , NR S0 3R12 ;
When any two adjacent R to R6 are either OH or NHR 1, these may be additionally be joined
together by a CR R12 , -(C=0) n, -CO(CH2)„-,-C=S, C=NR12 or -OS0 3-; wherein n=l to 2.
11 12 R and R are independently hydrogen, OH, halo, C1-6 alkyl, aryl, alkaryl , arylalkyl,
substituted alkyl, which may be straight, branched chain or cyclic, Ci- alkoxy which may be
straight, branched chain or cyclic, COOR 3, CH2COOR13 , C(R1 )2OCOR13 ,
C(R1 )2OCOOR13 , C(R1 )2OCON(R1 )2, C(R )2N(R )COOR 3 or haloalkyl, aryl, substituted
aryl, or R and R 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 R6may 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..
The novel analogues of polyphenols of the present invention of Formula I that may also be
represented by compounds of Formula II;
Formula II
wherein
A is independently deuterium, hydrogen, alkyl, F, CI;
B is independently A or hydroxyl; OR1 1, NR R12 ;
R to R7 and R9 are independently; H, D, NH2, F, CI, hydroxyl, -CO-ORn, -CO-NR R12 ,
OCONHCHR R12 , -CORn, -CR R12 , -0-CO-R , -CR,iRi , -0-CO-NR -R12 , -OCR Ri2, -
0-CO-RnR 12 ;
R and R are independently hydrogen, OH, halo, C1-6 alkyl, aryl, alkaryl , arylalkyl,
substituted alkyl, which may be straight, branched chain or cyclic, C -6 alkoxy which may be
straight, branched chain or cyclic, COOR13 , CH COOR13 , C(R1 )2OCOR 3 ,
C(R13)2OCOOR13 , C(R,3)2OCON(R1 )2 C(R1 )2N(R 3)COOR13 or haloalkyl, aryl, substituted
aryl, or R and R 2 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 R6may form an oxime;
R is independently hydrogen, lower straight or branched alkyl, substituted or unsubstituted
aryl or benzyl, when two R 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:
The compounds of the present invention are illustrated but not limited to the examples as
provide in Table 1.
Table 1: Illustrative Compounds of the present invention

1041 3-((((2R,3R)-2-(3,4- C22H2oIN0 + 537.03
dihydroxyphenyl)-5,7-
dihydroxychroman-3 -
yl)oxy)carbonyl)- 1-
methylpyridin- 1-ium
1042 2-hydroxy-5-((2R,3R)- C2 H240 404.15
o 3,5,7-
trihydroxychroman-2-
OH yl)phenyl neopentyl
carbonate
¾ 7H 5 2-hydroxy-4-((2R,3R)- 23H 80 7 416.18
1043 3,5,7-
trihydroxychroman-2 -
yl)phenyl octanoate
OH
H 4-((2R,3R)-3,5,7- C23H N 0 460.18
1044 trihydroxychroman-2-yl)-
1,2-phenylene
A bis(isopropylcarbamate)
OH
1045 (2R,3R)-2-(3,4- C2 1H240 404.15
dihydroxyphenyl)-5,7-
dihydroxychroman-3 -yl
neopentyl carbonate
O O ^tBu
1046 fx" (2R,3R)-2-(3,4- C19H2 1N0 375.13
dihydroxyphenyl)-5,7-
dihydroxychroman-3 -yl
isopropylcarbamate
H

1052 dibenzyl (4-((2R,3R)- C4 H3 0i4 826.23
5,7-
bis(((benzyloxy)carbonyl
)oxy)-3- Y hydroxychronian-2-yl)-
1,2-phenylene)
bis(carbonate)
1053 (2R,3R)-2-(3,4- C18H1808 362.10
dihydroxyphenyl)-5,7-
dihydroxychroman-3 -yl
ethyl carbonate
1054 (2R,3R)-2-(3,4- C25H30O10 490.18
dihydroxyphenyl)-3-
hydroxychromane- 5,7-
diyl diisobutyl
bis(carbonate)
1055 (2R,3R)-2-(3,4- C19H20O8 376.12
dihydroxypheny 1)-5,7-
dihydroxychroman-3 -yl
isopropyl carbonate
1056 methyl ((((2R,3R)-2- C19H19N09 405.1
n r 0H (3,4-dihydroxyphenyl)-
5,7-dihydroxychroman-
3-
H 0
yl)oxy)carbonyl)glycinat
e
1057 (2R,3R)-2-(3,4- C21H22O10 434.12
dihydroxyphenyl)-3 -
hydroxychromane-5,7-
diyl diethyl
o bis(carbonate)
1058 (2R,3R)-2-(3,4- C19H18O10 406.09
dihydroxyphenyl)-3 -
hydroxychromane-5,7-
diyl dimethyl
bis(carbonate)
1059 4-((2R,3R)-3,5,7- C31H28N20 556.18
trihydroxychroman-2-yl)- 8
,2-phenylene
bis(benzylcarbamate)
1060 dibenzyl (4-((2R,3R)-3- C41H42014 758.26
hydroxy-5,7-
bis((isobutoxycarbonyl)o
xy)chroman-2-yl)- 1,2-
o phenylene)
bis(carbonate)
1061 (2R,3R)-2-(3,4- C22H2607 402.17
dihydroxyphenyl)-3 ,7-
dihydroxychroman-5-yl
O
heptanoate
1062 (2R,3R)-2-(3,4- C22H2607 402.17
dihydroxyphenyl)-3 ,5-
dihydroxychroman-7-yl
O H
heptanoate
1063 (2R,3R)-2-(3,4- C29H3808 514.26
n r dihydroxyphenyl)-3-
hydroxychromane-5,7-
O diyl diheptanoate
1064 (2R,3R)-2-(3,4- . C23H2807 416.18
dihydroxyphenyl)-3,7-
dihydroxychroman-5-yl
octanoate
1065 (2R,3R)-2-(3,4- C23H2807 416.18
dihydroxyphenyl)-3,5-
dihydroxychroman-7-yl
OH octanoate
1066 dibenzyl (4-((2R,3R)-3- C35H30O14 674.16
hydroxy-5,7-
bis((methoxycarbonyl)ox
y)chroman-2-yl)- ,2-
phenylene)
bis(carbonate)
1067 (2R,3R)-7-methoxy-2-(3- C20H24O4 328.17
methoxypheny1) -3-
propoxychromane
1068 (2R,3R)-2-(3- C19H2204 314.15
methoxyphenyl)-3-
propoxychroman-7-ol
1069 (2R,3R)-2-(3-hydroxy-4- C16H1604 272.10
methylphenyl)chromane-
3,7-diol

bis(carbonate)
The compounds of the present invention include:
I . (R,E)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-one
II. Cis (±) 3-hydroxychroman-2-yl)benzene-l,2-diol;
III. Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol;
IV. Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol;
V. Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol;
VI. Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol;
VII. Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol;
VIII. Cis (±) 2-(4-hydroxyphenyl)chroman-3,5,7-triol;
IX. (2R,3S)-2-(3,4-dihydroxyphenyl)-3-aminochroman-5,7-diol;
X. (2R,3R)-2-(3,4-dihydroxyphenyl)-3-fluorochroman-5,7-diol;
XI. Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol;
XII. Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol;
XIII. Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol;
XIV. Cis (±) 2-(3-hydroxyphenyl)chroman-3,5,7-triol;
XV. Cis (±) 2-phenylchroman-3,5,7-triol;
XVI. Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol;
XVII. Cis (±) 2-(3-methoxyphenyl)chroman-3,7-diol;
XVIII. Cis (±) 2-(3-hydroxyphenyl)-7-methoxychroman-3-ol;
XIX. Cis (±) 7-methoxy-2-(3-methoxyphenyl)chroman-3-ol;
XX. Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl)chromic;
XXI. Cis (±) 7-hydroxy-2-(4-hydroxyphenyl)chroman-3-yl acetate;
XXII. Cis (±)4-(3,7-dihydroxychroman-2-yl)phenyl acetate;
XXIII. Cis (±) 3-hydroxy-2-(3-hydroxyphenyl)chroman-7-yl acetate;
XXIV. Cis (±)4-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate;
XXV. Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate;
XXVI. 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol;
XXVII. 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;
XXVIII. 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol;
XXIX. 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol;
XXX. 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol;
XXXI. Cis (±) 2-(3,4-dihydroxy-2-methylphenyl)chroman-3,5,7-triol;
XXXII. Cis (±) 2-(2-fluoro-3,4-dihydroxyphenyl)chroman-3,5,7-triol;
XXXIII. Cis (±) 2-(2-fluoro-4,5-dihydroxyphenyl)chromane-3,5,7-triol;
XXXIV. Cis (±) 2-(3-fluoro-4-hydroxyphenyl)chromane-3,5,7-triol;
XXXV. Cis(±) (2-(3,4-dihydroxy-5-methylphenyl)chromane-3,5,7-triol;
XXXVI. (2R,3R)-2-(3,4-dihydroxyphenyl)chromane-4,4-d2-3,5,7-triol;
XXXVII. (2R,3R)-2-(3,4-dihydroxyphenyl)chromane-2-d-3,5,7-triol;
XXXVIII. (2R,3R)-2-(3,4-dihydroxyphenyl)chromane-2,4-d2-3,5,7-triol;
XXXIX. (2R,3R)-2-(3 ,4-dihydroxyphenyl)-5 ,7-dihydroxychroman-3-yl isobutyl
carbonate;
XL. tert-butyl neopentyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-
phenylene) bis(carbonate);
XLI. 3-((((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl)oxy)
carbonyl)- 1-methylpyridin- 1-ium;
XLII. 2-hydroxy-5-((2R,3R)-3,5,7-trihydroxychroman-2-yl)phenyl neopentyl
carbonate;
XLIII. 2-hydroxy-4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)phenyl octanoate;
XLIV. 4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-phenylene bis (isopropyl
carbamate);
XLV. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl neopentyl
carbonate;
XLVI. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl-isopropyl
carbamate;
XLVII. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl dimethyl
carbamate;
XLVIII. dibenzyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-phenylene)
bis(carbonate);
XLIX. dimethyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-phenylene)
bis(carbonate);
-L. (2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diisobutyl
bis(carbonate);
LI. 4-((2R,3R)-5,7-bis((benzylcarbamoyl)oxy)-3-hydroxychroman-2-yl)-l,2-
phenylene bis(benzylcarbamate);
LII. dibenzyl (4-((2R,3R)-5,7-bis(((benzyloxy)carbonyl)oxy)-3-hydroxychroman-
2-yl)-l,2-phenylene) bis(carbonate);
LIII. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl ethyl
carbonate;
LIV. (2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diisobutyl
bis(carbonate);
LV. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychronian-3-yl isopropyl
carbonate;
LVI. methyl ((((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-
yl)oxy)carbonyl)glycinate;
LVII. (2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diethyl
bis(carbonate);
LVIII. (2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl dimethyl
bis(carbonate);
LIX. 4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-phenylene bis(benzyl
carbamate);
LX. dibenzyl (4-((2R,3R)-3-hydroxy-5,7-bis((isobutoxycarbonyl)oxy)chroman-2-
yl)- 1,2-phenylene) bis(carbonate);
LXI. (2R,3R)-2-(3,4-dihydroxyphenyl)-3,7-dihydroxychroman-5-yl heptanoate;
LXII. (2R,3R)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxychroman-7-yl heptanoate;
LXIII. (2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diheptanoate;
LXIV. (2R,3R)-2-(3 ,4-dihydroxyphenyl)-3 ,7-dihydroxychroman-5-yl octanoate;
LXV. (2R,3R)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxychroman-7-yl octanoate;
LXVI. dibenzyl (4-((2R,3R)-3-hydroxy-5,7-bis((methoxycarbonyl)oxy)chroman-2-
yl)-l ,2-phenylene) bis(carbonate).
LXVII. (2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane;
LXVIII. (2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol;
LXIX. (2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3 ,7-diol;
LXX. (2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;
LXXI. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl nicotinate;
LXXII. dineopentyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-phenylene)
bis(carbonate);
LXXIII. tert-butyl ((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl)
carbonate;
LXXIV. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl (R)-3-
hydroxybutanoate;
LXXV. diisopropyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-phenylene)
bis(carbonate);
LXXVI. dineopentyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)- 1,2-phenylene)
bis(carbonate).
In another embodiment, he present invention also discloses a process of preparing
compounds of formula (I) and formula (II) as below,
Synthetic Scheme 1:
4H-chromene
7
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 of the present invention.
Synthetic Scheme 2 :
Scheme 2 comprises the following steps:
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 Os0 4, with or without chiral co-catalysts such as AD-mix-a or ADmix-
b 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.
Synthetic Scheme 3:
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.
Synthetic Scheme 4 :
15 16
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 sueh 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
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 NaCNBD 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) in hydrogen atmosphere to obtain the final
products with or without diastereoselectivity.
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 analogues of the present invention.
Salts and Isomers and counter ions
The present invention includes within its scope the salts and isomers. Compounds of the
present invention after being novel may in some cases form salts which are also within the
scope of this invention. 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 contemplated within the scope of this invention.
Composition containing the novel entities of the invention
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 agerits.
In another aspect, the present invention is also drawn to the use of the compounds for
indications wherein epicatechin and other polyphenols are found to be useful.
The compounds of the present invention 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. The compound of the present invention may be used for treating the diseases
associated with mitochondria dysfunction.
Without being limited by theory, it is submitted that the novel analogues of the present
invention 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
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 embodiments 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
embodiments. 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.
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.
EXAMPLE 1: Synthesis of (R,E)-2-(3,4-dihydroxyphenyI)-5,7-dihydroxychroman-3-one
oxime [1001]
To a stirred solution of [19] (1.0 g, 3.4 mmol) in DMF, anhydrous K2C0 3 (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]
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 NaH2C0 3 (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]
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]
Ste 4 : Synthesis of 1001 from [22]
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 lhr 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].
EXAMPLE 2 : Synthesis of (2R,3R)-2-(2,3-dihydroxyphenyl)-3-fluorochroman-5,7-diol
[1010]
Step 1: Synthesis of [1010] from catechin [19]
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 i DCM to form a solution. The stirring was continued for 2 h
before addition of saturated NaHC0 3 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].
EXAMPLE 3: Synthesis of (2R,3S)-2-(3,4-dihydroxyphenyI)-3-aminochroman-5,7-dioI
[1009]
Step 1: Synthesis of [23(A+B)J from [21]
[23A] [23B]
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 dropwise.
Further stirring at this temperature for lh, NaCNBH (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]
[23A] 1009
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++l]
Example 4: Synthesis of Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol [1004]
Step 1: Synthesis of l-(4-benzyloxy)-2-hydroxyphenyl)ethanone from l-(2,4-
dihydroxyphenyl)ethanone.
[24] [25]
To a stirred solution of [24] (10.0 g, 65.78 mmol) in DMF (60 ml) was added 2C0 3 (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].
Ste 2 : Synthesis of [27] from l-(4-benzyloxy)-2-hydroxyphenyI) ethanone and [26].
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%
HC1 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]
tep 3: Synthesis of [28] from [27]„
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% H20 (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%HC1 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].
To a stirred solution of [28] (1.6 g, 3.55 mmol) in DMF was added K2C0 3 (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].
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, 6 1 %). The mixture of [30] and [31] was used
in the next step; ESIMS: 526[M++1].
Ste 6: Synthesis of [1004] from [30] and [31].
[32]
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-l,2-diol
[1002]
Step 1: Synthesis of (E)-3-(3,4-bis-(benzyloxy)phenyl)-l-(2-hydroxyphenyI)prop-2-en-lne
[35]:
[33] [34] [35]
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]
tep 2 : Synthesis of 2-(3,4-bis(benzyloxy)phenyl)-3-hydroxy-4H-chromen-4-one (36):
[35] [36]
Compound [35] (2.5 g, 5.77 mmol) was stirred at 0 °C for 0 minute in EtOH (20 ml). Then
solution of 20% NaOH (8 ml) was added in reaction mixture followed by 30% H 0 2 (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]:
To a stirred solution of [36] (1.40 g, 3.1 1 mmol) in DMF, anhydrous K2C0 3 (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]
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 NH4C 1 (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
1002A
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 ( 0.0 lOg, 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 l-(2-(benzyloxy)-6-hydroxyphenyl)-ethanone [41]
[40] [41]
To a stirred solution of [40] (2.0 g, 1.34mmol) in DMF, anhydrous K C0 3 (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 dropwise.
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 (2x1 00ml). 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)-l-(2-(benzyloxy)-6-hydroxyphenyl)-3-(4-(benzyloxy)-phenyl)-
prop-2-en-l-one (43):
41 42 43
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 (lg 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 HC1 to pH 4,
water (50ml) was added and organic layer was extracted with ethyl acetate (2 100ml). 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):
43 44 45
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% H202 (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-(benzyIoxy)-phenyl)-4H-chromen-4-one
44 46
To a stirred solution of [44] (0.6 g, 1.33 mmol) in DMF, anhydrous C0 3 (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]
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 NH4C 1 (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):
47A 47B 1006
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 lhr 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.
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-methoxyphenyI)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-dioI, 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]
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 (±)4-(3,7-dihydroxychroman-2-yl)phenyl acetate [1022],
Cis (±) 3-hydroxy-2-(4-hydroxyphenyl)chroman-7-yl acetate [1023] and Cis (±)4-(7-
acetoxy-3-hydroxychroman-2-yl)phenyl acetate [1024]
1007 1022 1023 1024
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 lh.
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]
(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]
48 49
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]
49 1030
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
lhr 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++l]
EXAMPLE 18: Synthesis of Cis (±) 2-(4-hydroxyphenyl)chroman-3,5,7-triol [1008]
Step 1: Synthesis of l-(2,4-bis(benzyloxy)-6-hydroxyphenyI)-ethanone:
50 51
To a stirred solution of [50] (3.0 g, 16.19 mmol) in DMF, anhydrous 2C0 3 (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)-l-(2,4-bis(benzyloxy)-6
hydroxyphenyl)-prop-2-en-l-one:
51 26 52
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 HC1 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[ n +1]
Step 3: Synthesis of 5,7-bis(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-hydroxy-4H-chromen-
4-One:
52 53
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% H20 2 (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:
53 54
To a stirred solution of [53] (1.25 g, 2.24 mmol) in DMF, anhydrous K2C0 3 (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): 55A
54 55B
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 NH4C 1 (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)
55B 1008
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 lhr 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 raeemic 1008 (0.040 g, 35 %) as an off-white solid.ESIMS: 275[M++1]
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.
EXAMPLE 20: Synthesis of Cis (±) 2-phenyIchroman-3,5,7-triol [1015] was carried out
by procedure as described for 1008 with [51] and benzaldehyde as starting material.
EXAMPLE 21: Synthesis of Cis (±) 2-(3,4-dihydroxy-2-methylphenyl)chroman-3,5,7-
triol [1035]
Step 1: Synthesis of 51 from 50
50 51
To a stirred solution of [50] (5.0 g, 26.8 mmol) in DMF(50 ml) was added K2C0 3 ( 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].
51 56 57
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% HC1 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++l]
Step 3: Synthesis of [58] from [57].
57 58
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% H20 2 (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%HC1 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].
58 59
To a stirred solution of [58] (0.4 g, 0.59 mmol) in DMF was added K2C0 (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].
4H-chromene 2H-chromene
59 60 61
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].
1031 B
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 lhr 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 (0¾02 g, 20 %) and trans racemic [1031B] as a off white powder (0.01 g, 9 %).
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-fluorobenzaIdehyde as starting material. ESIMS: 309[M ++1]
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-fiuorobenzaldehyde as starting material. ESIMS: 309[M ++1]
EXAMPLE 24: Synthesis of Cis (±) 2-(3-fluoro-4-hydroxyphenyl)chromane-3,5,7-triol
[1034]
Step 1: Synthesis of [63] from [51] and [62].
51 62 63
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]
Ste 2: Synthesis of [64] from [63].
To a stirred solution of [63] (2.0g, 3.57mmol) in mixture of EtOH (20.0ml) and THF(lOml)
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
Na2C0 3 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]
(l.Og, 51%). ESIMS: 545[M++1]
Step 3: Synthesis of [65] from [64].
To a stirred solution of [64] (l.Og, 1.8mmol) in dry THF was added N-methyl morpholine
oxide (0.2g, 2.29mmol), Os0 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]
65 66
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
lh 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 NaHC0 3
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]
To a stirred solution of [66] (0.6g, l.Ommol) 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 NaHC0 3 (20ml) was added and was extracted with DCM (3x1 00ml). 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++l]
Step 6: Synthesis of [68] from [67]
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
NaHC0 3 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]
To a stirred solution of [68] (0.1 Og, 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 lhr 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
[1034] (0.028, 57%). ESIMS: 293[M++1]
EXAMPLE 25: Synthesis of Cis(±) (2-(3,4-dihydroxy-5-methyIphenyl)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]
EXAMPLE 26: Synthesis of (2R,3R)-2-(3,4-dihydroxyphenyI)chromane-4,4-d2-3,5,7-
triol [1036]
Step 1: Synthesis of [84 and 85] from [86]
69 70 71
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 HCI (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].
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]
71 1036
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) (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]
70 Cis(+)1038 trans(+)1038
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 [IvT + 1]
EXAMPLE 27 Synthesis of (2R,3R)-2-(3,4-dihydroxyphenyl)chromane-2-d-3,5,7-triol
[1037]
tep 1: Synthesis of [73 and 74] from [72]
72 73 74
To a stirred solution of [72] (0.2g, 0.25 mmol) in dry dichloromethane under nitrogen
atmosphere was added NaCNBD 3 (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]
73 1037
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) (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 [103 7]along with
minor trans isomer.. ESIMS: 292 [M++ 1]
Example 28:- Synthesis of dibenzyl (4-(3,5,7-trihydroxychroman-2-yI)-l,2-phenylene)
75 1048
To a suspension of [75] (l.Oeq, 0.1 5gm, 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 Na S0 4, 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.
Example 29:- Synthesis of 4-(3,5,7-trihydroxychroman-2-yl)-l,2-phenylene
bis(benzylcarbamate) [1059]
75 1059
To a suspension of [75] (l.Oeq, 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. ml, 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 Na2S0 4, 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++l]
Example 30:- Synthesis of (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yI
isopropylcarbamate [1046]
Step 1: Synthesis of tetrabenzylated racemic epicatechin [76] form racemic epicatechin
[75]
75 76
To a stirred of [75] (l.Ogm, 3.4mmol) in DMF was added 2C0 (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]
76 77
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 lh, 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 (2x1 00ml). 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]
Ste 3: synthesis of [1046] from [77]
77 1046
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 [ ++l]
In a similar manner the compounds [1045], [1047], [1053], [1055] and [1056] were
synthesized.
Example 31:- Synthesis of dibenzyl (4-((2R,3R)-5,7-bis(((benzyloxy)carbonyl)oxy)-3-
hydroxychroman-2-yl)-l,2-phenylene) bis(carbonate) [1052]
To a suspension of [75] (l.Oeq, l.Ogm, 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 oyer 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 Na2S0 4, filtered and evaporated to
afford [1052] transparent sticky material (2.70g, 94%]. ESIMS: 827[M++1]
In a similar manner [1051] was synthesized.
Example 32:- Synthesis of dibenzyl (4-((2R,3R)-5,7-bis(((benzyloxy)carbonyl)oxy)-3-
hydroxychroman-2-yl)-l,2-phenylene) bis(carbonate) [1066]
Step 1: synthesis of [1066] from [1048]
1048 1066
To a suspension of [1048] (0.1 gm, 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 Na S0 , 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]
1066 1058
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 Ihr. 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++l]
In a similar manner [1050], [1054] and [1057] were synthesized.
Example 33: Synthesis of [1061], [1062] and [1063]
Step 1: Synthesis of [78], [79] and [80] from [1048]
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 Na2S0 4, 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]
[80]: ESIMS: 783 [M++l]
Step 2 :
Synthesis of [1061], [1062] and [1063] was carried out as described for [1058] from [78],
[79] and [80].
In a similar manner [1064] and [1065] were synthesized.
Example 34: Testing of compounds for their AMPK activation potential:
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 flaskcontaining
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% C0 2 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% C0 2 for 30 min and l h 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 % H 0 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-AMRKa (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 mΐ TMB substrate solution for 30minutes and the reaction was stopped with 100 mΐ of 2N
H2S0 4. 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 of the
present invention, as exemplified and encompassed are found to be active. For illustrative
purpose, the activation potential of the compounds ar lOnm concentration is provided in
Table 2.
Table 2: Activiation potential of the compounds.
Compound %pAMPK(at lOnm)
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 9 1
1051 85
1052 103
1053 94
1054 9 1
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

We Claim:
1. Novel analogues of Epicatechin polyphenol of Formula (I)
wherein
A is independently deuterium, hydrogen, alkyl, F, CI;
B is independently A or hydroxyl; OR1 , NR R12 ;
R1 to R 0 are independently hydrogen; deuterium, NH2, F, CI, hydroxyl, alkoxy, lower
acyclic or cyclic alkyl, lower acyclic or cyclic acyl, -CO-ORn, -OCO-ORu, -CONR
R 2 , -CORn, -CR R 2 , -0-CO-R , -CRnR 12 , -0-CO-NR,,R 2 ,
OCONHCHR1 R12 , -OCRnR I2, -0-CO-R R12 , -CO-aminoacid; or -CO-hydroxyacid;
which can be optionally substituted with lower alkyl, acyl, alkoxy, OR1 1, NR R12 ,
COOR1 1, CONR R12 , OCOR R12 , OCONR R12 , OS0 3R , OS0 2NR R12 ,
NR S0 2NR12 ,NR S0 3R12 ;
When any two adjacent R1 to R are either OH or NHR1 1, these are additionally
joined together by a CR R12 , -(C=0) n, -CO(CH2)n-,-C=S, C=NR12 or -OS0 3-;
wherein n=l to 2.
R1 1 and R12 are independently hydrogen, OH, halo, C1-6 alkyl, aryl, alkaryl , arylalkyl,
substituted alkyl, which may be straight, branched chain or cyclic, C1- alkoxy which
may be straight, branched chain or cyclic, COORi3, CH2COORi3, C(R1 ) OCOR13 ,
C(R1 )2OCOOR 3 , C(R1 ) OCON(R13)2 C(R1 )2N(R1 )COOR13 or haloalkyl, aryl,
substituted aryl, or R1 1 and R 2 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 R6may form an oxime;
R is independently hydrogen, lower straight or branched alkyl, substituted or
unsubstituted aryl or benzyl, when two R 3 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.
2. The analogues as claim in claim 1 and represented by Formula (II),
wherein
A is independently deuterium, hydrogen, alkyl, F, CI;
B is independently A or hydroxyl; OR1 , NR R12 ;
R to R7 and R9 are independently; H, D, NH2, F, CI, hydroxyl, -CO-ORn, -CONR
R1 , OCONHCHR R12 , -COR , -CR R1 , -0-CO-R , -CRnR 1 , -0-CO-NR -
R 2 , -OCR, R12 , -O-CO-Ri iR12 ;
R1 and 12 are independently hydrogen, OH, halo, Ci- alkyl, aryl, alkaryl , arylalkyl,
substituted alkyl, which may be straight, branched chain or cyclic, Ci-6 alkoxy which
may be straight, branched chain or cyclic, COORn, CH COORi3, C(R13)2OCOR13 ,
C(R13 )2OCOOR13 , C(R1 )2OCON(R13 )2, C(R )2N(R1 )COOR13 or haloalkyl, aryl,
substituted aryl, or R and R 2 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;
R is independently hydrogen, lower straight or branched alkyl, substituted or
unsubstituted aryl or benzyl, when two R13 groups are present on the same atom,
which 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.
3. The compounds as claimed in claim 1, wherein the compound is any of:
I. (R,E)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-one oxime
II. Cis (±) 3-hydroxychroman-2-yl)benzene-l,2-diol;
III. Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,7-diol;
IV. Cis (±) 2-(4-hydroxyphenyl)chroman-3,7-diol;
V. Cis (±) 2-(3-hydroxyphenyl)chroman-3,5-diol;
VI. Cis (±) 2-(4-hydroxyphenyl)chroman-3,5-diol;
VII. Cis (±) 2-(3-hydroxyphenyl)chroman-3,7-diol;
VIII. Cis (±) 2-(4-hydroxyphenyl)chroman-3,5,7-triol;
IX. (2R,3S)-2-(3,4-dihydroxyphenyl)-3-aminochroman-5,7-diol;
X. (2R,3R)-2-(3,4-dihydroxyphenyl)-3-fluorochroman-5,7-diol;
XI. Cis (±) 2-(3-hydroxyphenyl)chroman-3-ol;
XII. Cis (±) 2-(4-hydroxyphenyl)chroman-3-ol;
XIII. Cis (±) 2-(3,4-dihydroxyphenyl)chroman-3,5-diol;
XIV. Cis (±) 2-(3-hydroxyphenyl)chroman-3,5,7-triol;
XV. Cis (±) 2-phenylchroman-3,5,7-triol;
XVI. Cis (±) 2-(4-hydroxyphenyl)-3-methoxychroman-7-ol;
XVII. Cis (±) 2-(3-methoxyphenyl)chroman-3,7-diol;
XVIII. Cis (±) 2-(3-hydroxyphenyl)-7-methoxychroman-3-ol;
XIX. Cis (±) 7-methoxy-2-(3-methoxyphenyl)chroman-3-ol;
XX. Cis (±) 3,7-dimethoxy-2-(4-methoxyphenyl)chromic;
XXI. Cis (±) 7-hydroxy-2-(4-hydroxyphenyl)chroman-3-yl acetate;
XXII. Cis (±)4-(3,7-dihydroxychroman-2-yl)phenyl acetate;
XXIII. Cis (±) 3-hydroxy-2-(3-hydroxyphenyl)chroman-7-yl acetate;
XXIV. Cis (±)4-(7-acetoxy-3-hydroxychroman-2-yl)phenyl acetate;
XXV. Cis (±) 2-(4-acetoxyphenyl)chroman-3,7-diyl diacetate;
XXVI. 2-(3-methoxy-4-methylphenyl)chromane-3,7-diol;
XXVII. 2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;
XXVIII. 2-(4-fluoro-3-methoxyphenyl)chromane-3,7-diol;
XXIX. 2-(4-fluoro-3-hydroxyphenyl)chromane-3,7-diol;
XXX. 2-(3-hydroxyphenyl)-3-propoxychroman-7-ol;
XXXI. Cis (±) 2-(3,4-dihydroxy-2-methylphenyl)chroman-3,5,7-triol;
XXXII. Cis (±) 2-(2-fluoro-3,4-dihydroxyphenyl)chroman-3,5,7-triol;
XXXIII. Cis (±) 2-(2 fluoro-4,5-dihydroxyphenyl)chromane-3,5,7-triol;
XXXIV. Cis (±) 2-(3-fluoro-4-hydroxyphenyl)chromane-3,5,7-triol;
XXXV. Cis(±) (2-(3,4-dihydroxy-5-methylphenyl)chromane-3,5,7-triol;
XXXVI. (2R,3R)-2<3,4-dihydroxyphenyl)chromane-4,4-d2-3,5,7-triol;
XXXVII. (2R,3R)-2-(3,4-dihydroxyphenyl)chromane-2-d-3,5,7-triol;
XXXVIII. (2R,3R)-2-(3,4-dihydroxyphenyl)chromane-2,4-d2-3,5,7-triol;
XXXIX. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl isobutyl carbonate;
XL. tert-butyl neopentyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-phenylene)
bis(carbonate);
XLI. 3-((((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl)oxy) carbonyl)-lmethylpyridin-
1-ium;
XLII. 2-hydroxy-5-((2R,3R)-3,5,7-trihydroxychroman-2-yl)phenyl neopentyl carbonate;
XLIII. 2-hydroxy-4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)phenyl octanoate;
XLIV. 4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-phenylene bis (isopropyl carbamate);
XLV. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl neopentyl carbonate;
XLVI. (2R,3R)-2-(3,4-dihydroxyphenyl)-5 ,7-dihydroxychroman-3 -yl-isopropyl carbamate;
XLVII. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl dimethyl carbamate;
XLVIII. dibenzyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-phenylene) bis(carbonate);
XLIX. dimethyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-phenylene) bis(carbonate);
L. (2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diisobutyl
bis(carbonate);
LI. 4-((2R,3R)-5,7-bis((benzylcarbamoyl)oxy)-3-hydroxychroman-2-yl)-l,2-phenylene
bis(benzylcarbamate);
LII. dibenzyl (4-((2R,3R)-5,7-bis(((benzyloxy)carbonyl)oxy)-3-hydroxychroman-2-yl)-
1,2-phenylene) bis(carbonate);
LIII. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl ethyl carbonate;
LIV. (2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diisobutyl
bis(carbonate);
LV. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl isopropyl carbonate;
LVI. methyl ((((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-
yl)oxy)carbonyl)glycinate;
LVII. (2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diethyl
bis(carbonate);
LVIII. (2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl dimethyl
bis(carbonate);
LIX. 4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)- 1,2-phenylene bis(benzyl carbamate);
LX. dibenzyl (4-((2R,3R)-3-hydroxy-5,7-bis((isobutoxycarbonyl)oxy)chroman-2-yl)-l,2-
phenylene) bis(carbonate);
LXI. (2R,3R)-2-(3 ,4-dihydroxyphenyl)-3 ,7-dihydroxychroman-5-yl heptanoate;
LXII. (2R,3R)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxychroman-7-yl heptanoate;
LXIII. (2R,3R)-2-(3,4-dihydroxyphenyl)-3-hydroxychromane-5,7-diyl diheptanoate;
LXIV. (2R,3R)-2-(3,4-dihydroxyphenyl)-3,7-dihydroxychroman-5-yl octanoate;
LXV. (2R,3R)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxychroman-7-yl octanoate;
LXVI. dibenzyl (4-((2R,3R)-3-hydroxy-5,7-bis((methoxycarbonyl)oxy)chroman-2-yl)-l,2-
phenylene) bis(carbonate);
LXVII. (2R,3R)-7-methoxy-2-(3-methoxyphenyl)-3-propoxychromane;
LXVIII. (2R,3R)-2-(3-methoxyphenyl)-3-propoxychroman-7-ol;
LXIX. (2R,3R)-2-(3-hydroxy-4-methylphenyl)chromane-3,7-diol;
LXX. (2R,3R)-7-methoxy-2-(4-methoxyphenyl)chroman-3-ol;
LXXI. (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl nicotinate;
LXXII. dineopentyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-phenylene)
bis(carbonate);
LXXIII. tert-butyl ((2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl) carbonate;
LXXIV. (2R,3R)-2-(3 ,4-dihydroxypheny l)-5 ,7-dihydroxychroman-3 -y1(R)-3 -
hydroxybutanoate ;
LXXV. diisopropyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l,2-phenylene)
bis(carbonate);
LXXVI. dineopentyl (4-((2R,3R)-3,5,7-trihydroxychroman-2-yl)-l ,2-phenylene)
bis(carbonate).
The compound of claim 1, when present as its stereoisomer or pharmaceutically
acceptable salt thereof.
A process for the preparation of novel analogues of polyphenols as claimed in claim 1,
comprising the steps of :
I. protecting hydroxyl groups of an acetophenone of Formula 1 with a protecting
agent in presence of a base and a solvent;
1
II. reacting compound of Formula 2 obtained from step (i) with a compound of
formula 3 in presence of a base and a solvent to obtain a chalcone of formula
1 2 3
III. converting chalcone of formula 4 to compound 5 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 presence of chiral/achiral
reducing agents to obtain a mixture of 4H-chromene and 2H-chromene
compounds of formula 6 and 7;
VI. deprotecting 4H-chromene and 2H-chromene compounds obtained in step
V to obtain polyphenol analogues of the present invention.
6. A process for the preparation of novel analogues of polyphenols as, claimed in claim 1,
comprising the steps of :
I. protecting hydroxyl groups of a flavan-3-ol of formula 8 with a protecting
agent;
II. treating the protected flavan-3-ol of step I with an oxidizing agent to obtain
compound of formula 9;
functionalisation of oxo group of compound 9 to obtain compound of formula
10;
deprotection of the compounds obtained in step III to obtain polyphenol
analogues of the present invention.
7. A process for the preparation of novel analogues of polyphenols as claimed in claim 1,
comprising the steps of :
i. optionally protecting hydroxyl groups of a flavan-3-ol of formula 11 with a
protecting agent;
ii. functionalising protected/unprotected hydroxyl group of compound 11 to obtain
compound of formula 12 ;
15 16
iii. deprotection of the compounds obtained in step ii to obtain polyphenol
analogues of the present invention.
8. A process for the preparation of novel analogues of polyphenols as claimed in claim 1,
comprising the steps of:
i . treating chalcone of formula 4 with a reducing agent in presence of a solvent at
a temperature ranging from ambient to reflux to obtain a compound of formula
13;
converting compound of formula 13 to compound of formula 14 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;
in. functionalizing hydroxyl group of compound of formula 14 with a suitable
reagent in the presence of a suitable solvent to obtain compound of formula 15;
IV. treating compound of formula 14 with an oxidizing agent to obtain compound
of formula 16;
12 13
IV. reducing the compound obtained from step iv in the presence of chiral reducing
agents at a temperature ranging from -78°C to room temperature in presence of
suitable solvents to obtain the polyphenol analogues.
9. A pharmaceutical composition comprising any compound as claimed in claims 1 to 3
along with pharmaceutically or nutraceutically acceptable excepients.
10. The compound as claimed in claim 1, for their use in treatment of diseases associated
with mitochondria dysfunction.
1. The compound as claimed in claim 1, for their use as supplements and medication in
meeting the muscle requirement by sports men/excercised muscles to meet the increasing
energy demand.