Anticancer compounds and process for the preparation thereof

Patent metadata

Field	Value
Publication number	US-9845302-B2
Application number	US-201414768883-A
Country	US
Kind code	B2
Filing date	Feb 19, 2014
Priority date	Feb 19, 2013
Publication date	Dec 19, 2017
Grant date	Dec 19, 2017

Abstract

The invention disclosed herein relates to novel Peribysin E analogs of general formula-I. Further the invention provides simple, economical and short synthesis of Peribysin E and its analogs of Formula I, in good yield and purity leading to the identification of more potent cell adhesion inhibitors.

First claim

We claim:

1. A compound of formula I

wherein;
R is hydrogen or (C1-C8) alkyl,
R 1 and R 2 each are individually selected from the group consisting of H, OH, OR or R 1 and R 2 together may form a 4-8 membered alicyclic, or an aromatic ring which may additionally contain a hetero atom, or R 1 and R 2 together form an epoxide ring, wherein when the bond between the carbon atoms to which R 1 and R 2 are attached is a single bond, a hydrogen atom is attached to each of the carbon atoms;
R 3 is OH and the carbon atom to which R 3 is attached is also attached to a hydrogen atom;
R 4 and R 5 are selected from hydrogen, C1-C8 alkyl, CONR 2 , COOR; or
R 4 and R 5 may form a 4-8 membered alicyclic ring which may additionally contain a heteroatom, wherein the compound is not (±)-Peribysin E.

2. The compound as claimed in claim 1 , wherein said compound exhibits cell adhesion inhibition activity wherein the inhibition concentration at 50% (IC 50 ) is in the range of 2.0-20.0 μM.

3. The compound as claimed in claim 1 , wherein the compound is:
(2R,2′R,3′R,3a′S,4′R,7a′R)-2-methoxy-3a′,4′-dimethyl-4-methylene 1′,3′,3a′,4,4′, 5,5′,7a′-octahydro-2H-spiro[furan-3,2′-inden]-3′-ol (9);

(1a′R,2R,3R,3′R,3a′S,4′R,6a′S,6b′S)-2-methoxy-3′,3a′-dimethyl-4-methylenedecahydro-2H-spiro[furan-3,5′-indeno[4,5-b]oxiren]-4′-ol (10);

(1′R,2R,2′R,3a′R,5′R,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylene decahydro-2H-spiro[furan-3,2′-indene]-1′,5′-diol (11a);

(1′R,2R,2′R,3a′S,4′R,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylenedecahydro-2H-spiro [furan-3,2′-indene]-1′,4′-diol (11b);

(1′R,2R,2′R,3a′S,4′S,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylenedecahydro-2H-spiro [furan-3,2′-indene]-1′,4′-diol (11c):

(1′R,2R,2′R,3a′S,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylene decahydro-2H-spiro [furan-3,2′-inden]-1′-ol (20);

(1′R,2R,2′R,3a′S,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylene decahydro-2H-spiro[furan-3,2′-indene]-1′,4′,5′-triol (21); or

or
(1′R,2R,3R,3a′S,4′S,5′R,7′R,7a′S)-2-methoxy-7′,7a′-dimethyl-4-methylenedecahydro-2H-spiro[furan-3,2′-indene]-1′,4′,5′-triol (22):

4. A process for the preparation of a compound of formula-I, according to claim 1 , or (±)-Peribysin E, comprising:
o) reacting a compound of formula-II with a compound of formula-III in the ratio ranging between 1 to 2.5 in the presence of BF 3 .Et 2 O in a suitable organic solvent at a temperature in the range of −78 to 25° C. to obtain a compound of formula-IV, R 4 and R 5 are methyl;

p) reducing the compound of formula IV with lithium aluminum hydride (LAH) in a ratio ranging between 1 to 4 in presence of an organic solvent to obtain a diol compound (4) followed by oxidizing in presence of a Collins reagent to obtain a corresponding aldehyde, compound (5)

q) subjecting compound (5) to an intramolecular aldol reaction in presence of an aqueous metal hydroxide and an alcohol to obtain an intermediate, compound (6)

r) oxidizing compound (6) under regioselective Wacker conditions to obtain a keto-aldehyde (12) followed by selective reduction at a temperature in the range of −80° C. to 0° C. to obtain an alcohol, compound (13)

s) subjecting compound (13) to reduction in presence of a lithium amide to obtain an alcohol, compound (14), followed by oxidizing to obtain an α,β-unsaturated aldehyde, compound (15), using MnO 2 ; subsequently epoxidising compound (15) to obtain a corresponding epoxide, compound (16), which is further treated with an iodoalcohol of the formula:

to obtain a diastereomeric mixture of compound (17)

and
t) treating compound (17) with 2,6-lutidine and TMSOTf followed by reacting with methanolic HCl to obtain crude Peribysin E; optionally purifying the crude Peribysin E

u) epoxidising intermediate compound (6) as obtained in step q, to obtain oxirene-carbaldehyde compound (7)

followed by reacting compound (7) with the iodoalcohol of the formula

to obtain a diastereomeric mixture of compound (8)

v) treating compound (8) with 2,6-lutidine and TMSOTf followed by reacting with methanolic HCl to obtain crude compound (9)

w) epoxidising compound (9) in presence of mCPBA to obtain compound (10);
x) reducing oxirane compound (10) in presence of lithium aluminium hydride, to obtain three stereoisomers (11a), (11b) and (11c)

y) hydrogenating oxirene-carbaldehyde intermediate compound (7) as obtained in step

(u), to obtain saturated hydrindane (18)
z) reacting compound (18) with the iodoalcohol of the formula:

to obtain a diastereomeric mixture of compound (19)

aa) treating compound (19) with 2,6-lutidine and TMSOTf, followed by reacting with methanolic HCl, to obtain compound (20)

and
bb) subjecting compound (9) as obtained in step v) to dihydroxylation in presence of OsO 4 -catalyst to furnish mixture of triols (21) and (22)

in a chemoselective manner.

Assignees

• Council Scient Ind Res

Inventors

• Reddy Dumbala Srinivasa
• Handore Kishor Laxman

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D307/94 Primary

  spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins · CPC title

• C07C67/347

  by addition to unsaturated carbon-to-carbon bonds · CPC title

• C07D493/10

  Spiro-condensed systems · CPC title

• C07D301/00

  Preparation of oxiranes · CPC title