C-9 oxygen functionalized labdane derivates

Patent metadata

Field	Value
Publication number	US-9527827-B2
Application number	US-201214237235-A
Country	US
Kind code	B2
Filing date	Aug 6, 2012
Priority date	Aug 5, 2011
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

Abstract

This invention relates to diterpenes of general formula (1) belonging to labdane class, isolated from Leucas stelligera , being useful for prevention, treatment, inhibition or controlling growth and proliferation of mycobacterial activity in mammals. The invention further discloses process for isolation of the fractions containing the same.

First claim

We claim:

1. A composition comprising a compound of formula:

wherein R 1 and R 2 are together:

and a pharmaceutically acceptable carrier, enclosed in a capsule.

2. A composition comprising a compound of formula:

wherein R 1 is:

and R 2 is OH
and a pharmaceutically acceptable carrier, enclosed in a capsule.

3. A method for inhibition, control of growth or proliferation of tubercular bacteria selected from the group consisting of M. tuberculosis and M. smegmatis comprising contacting said tubercular bacteria with an amount of the composition of claim 1 , or 2 sufficient to inhibit, control growth, or control proliferation of said tubercular bacteria.

4. The method of claim 3 , carried out in vitro.

5. A process for the extraction of a compound of formula:

wherein R 1 is:

and R 2 is OH
comprising
i) powdering aerial parts of Leucas steiligera followed by extraction with acetone at room temperature in the range of 25 to 30° C., filtering acetone solubles and concentrating under reduced pressure in the range of 50-100 mm Hg to obtain a greenish acetone extract,
ii) separating the extract of step i) by using column chromatography (CC) with gradient increasing polarity of 10-50% acetone in petroleum ether to obtain 11 fractions (LS1 to LS-11),
iii) subjecting fraction LS7 of step ii) to CC with a gradient of acetonitrile from 1% to 3% in chloroform to give 18 sub-fractions (LS7a-4),
iv) subjecting sub-fraction LS7i of step iii) to CC in 15% acetone in petroleum ether to obtain said compound.

6. A process for the extraction of a compound of formula:

wherein R 1 and R 2 are together:

comprising:
i) powdering aerial parts of Leucas stelligera followed by extraction with acetone at room temperature in the range of 25 to 30° C., filtering acetone solubles and concentrating under reduced pressure in the range of 50-100 mm Hg to obtain a greenish acetone extract,
ii) separating the extract of step i) by using column chromatography (CC) with gradient increasing polarity of the 10-50% acetone in petroleum ether to obtain 11 fractions (LS-1 to LS-11),
iii) subjecting fraction LS7 of step ii) to CC with gradient of acetonitrile from 1% to 3% in chloroform to give 18 sub-fractions (LS7a-r),
iv) subjecting sub-fraction LS7i of step iii) to CC in 15% acetone in petroleum ether,
v) subjecting fraction LS4 of step ii) to CC in 6% acetonitrile in chloroform to give 10 (LS4a-j) sub-fractions,
vi) subjecting fraction LS5 of step ii) to CC in 6% acetonitrile in chloroform to give 13(LS5a-m) sub-fractions, and
vii) combining fractions LS4f, LS4h, LS4i of step v) and LS5j, LS5k of step vi) and subjecting to CC in 15% acetone-petroleum ether to obtain the compound of claim 1 .

7. A process for the extraction of a compound of formula

wherein R 1 is;

and R 2 is OH
comprising:
i) powdering aerial parts of Leucas stelligera followed by extraction with acetone at room temperature in the range of 25 to 30° C., filtering acetone solubles and concentrating under reduced pressure in the range of 50-100 mm Hg to obtain a greenish acetone extract,
ii) separating the extract of step i) by using column chromatography (CC) with gradient increasing polarity of the 10-50% acetone in petroleum ether to obtain 11 fractions (LS-1 to LS-11),
iii) subjecting fraction LS7 of step ii) to CC with gradient of acetonitrile from 1% to 3% in chloroform to give 18 sub-fractions (LS7a-r),
iv) subjecting sub-fraction LS7i of step iii) to CC in 15% acetone in petroleum ether,
v) subjecting fraction LS4 of step ii) to CC in 6% acetonitrile in chloroform to obtain 10 (LS4a-j) sub-fractions,
vi) subjecting fraction LS5 of step ii) to CC in 6% acetonitrile in chloroform to obtain 13 (LS5a-m) sub-fractions,
vii) combining fractions LS4f, LS4h, LS4i of step v) and LS5j, LS5k of step vi) and subjecting to CC in 15% acetone-petroleum ether,
viii) subjecting fraction LS11 of step ii) to CC in gradient of methanol from 5-20% in chloroform to obtain 8 fractions (LS11a-h),
ix) subjecting sub-fraction LS11b of step viii) to CC in gradient of methanol in chloroform from 1-3% to give 6 (LS11bi-bvi) sub-fractions,
x) subjecting sub-fraction LS11bvi of step ix) to CC in gradient of acetone from 5-50% in petroleum ether,
xi) subjecting fraction 1 of step x) to successive preparative thin layer chromatographies (PTLC) in 25% acetonitrile in chloroform and 35% ethyl acetate in chloroform to obtain the compound of claim 2 .

8. The composition of claim 1 , wherein said pharmaceutically acceptable carrier is mannitol.

9. The composition of claim 2 , wherein said pharmaceutically acceptable carrier is mannitol.

10. The composition of claim 1 , wherein said pharmaceutically acceptable carrier is magnesium stearate.

11. The composition of claim 2 , wherein said pharmaceutically acceptable carrier is magnesium stearate.

12. A method for inhibition, control of growth or proliferation of tubercular bacteria selected from the group consisting of M. tuberculosis and M. smeginatis comprising contacting said tubercular bacteria with a compound selected from the group consisting of:

wherein R 1 is

and R 2 is OH,

wherein R 1 and R 2 are together:

and

wherein R 1 is:

and R 2 is OH
sufficient to inhibit, control growth, or control proliferation of said tubercular bacteria.

Assignees

• Joshi Swati
• Kulkarni Roshan Rajan
• Shurpali Ketaki Dilip
• Sarkar Sampa
• Sarkar Dhiman
• Council Scient Ind Res

Inventors

• Joshi Swati
• Kulkarni Roshan Rajan
• Shurpali Ketaki Dilip
• Sarkar Sampa
• Sarkar Dhiman

Classifications

• C07D493/10

  Spiro-condensed systems · CPC title

• C07D307/58

  One oxygen atom, e.g. butenolide · CPC title

• A61P31/06

  for tuberculosis · CPC title

• C07D307/94 Primary

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

• C07C35/36

  the condensed ring system being a [4.4.0] system, e.g. hydrogenated naphthols · CPC title