Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-05-04
2002-11-26
Owens, Amelia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S374000, C514S471000, C514S473000, C549S214000, C549S313000, C549S318000, C548S239000
Reexamination Certificate
active
06486196
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel anticancer agents, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. The present invention more particularly relates to novel derivatives of andrographolide, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates. The novel derivatives of andrographolide have the general formula (I),
where R
1
, R
2
and R
3
may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl group or a group —(CO)—W—R
5
where W represents O, S or NR
6
, wherein R
6
represents hydrogen or substituted or unsubstituted (C
1
-C
6
)alkyl group, R
5
represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR
2
and OR
3
together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms; R
4
represents hydrogen, halogen or XR
7
where X represents O, S, or NH and R
7
represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, aralkyl, alkenoyl, alkanoyl, aroyl, heteroaroyl, aralkenoyl, aralkanoyl, sulfonyl groups or a group —(CO)—NH—R
8
where R
8
represents substituted or unsubstituted groups selected from alkyl, aryl, or aralkyl; with provisos that (i) R
1
, R
2
and R
3
may be same except when they represent hydrogen or alkanoyl group and (ii) when R
2
and R
3
represent hydrogen, R
1
does not represent unsubstituted alkanoyl.
The andrographolide derivatives represented by general formula (I) as defined above and general formulas (X) and (XI) as defined below of the present invention are useful for treating cancer and other proliferative diseases including but not limited to herpes simplex virus types I and II (HSV I and HSV II) and human immunodeficiency (HIV). The compounds of the present invention are also useful in the treatment of psoriasis, restenosis, atherosclerosis and other cardiovascular disorders. The compounds of the present invention are also useful as antiviral, antimalarial, antibacterial, hepatoprotective, immunomodulating agents and for the treatment of metabolic disorders. The anticancer activity exhibited may be through cytotoxic activity, antiproliferation, cell cycle kinase inhibition or may be through cell differentiation.
The novel compounds of this invention are also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, body weight reduction, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders.
The present invention also relates to pharmaceutical compositions containing compounds of general formula (I), formula (X), or formula (XI), or their stereoisomers, their polymorphs, their salts or their solvates or mixtures thereof.
The present invention also relates to a process for the preparation of the compounds of general formula (I), formula (X), and formula (XI), and their stereoisomers, their polymorphs, and their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates.
BACKGROUND OF THE INVENTION
The plant
andrographis paniculata
is extensively used in medicine as a bitter tonic, febrifuge and in bowel complaints (Glossary of Indian Medicinal Plants., Ed. R. N. Chopra, S. L. Nayar, I. C. Chopra, p18, 1996. The useful plants of India, Ed. By S. B. Ambasta, p39, 1992). The plant is useful in the treatment of bacterial infections (Int. J. Crude Drug Res. 1990, 28(4), p273-283; Drugs of the Future. 1990, 15(8) p809-816). It is reported to possess antimalarial (Int. J. Pharmacognosy, 1992, 30(4), p263-274; J. Ethnopharmocol., 1999, 64(3), p249-254) and immunostimulant activity (J. Nat. Prod., 1993, 56(7), p995-999). The plant has also been shown to be antithrombotic (Chinese Medical Journal 1991, 104(9), p770-775) and inhibit stenosis and restenosis after angioplasty in the rat (Chinese Medical Journal, 1994, 107(6), p464-470). It is also known that the plant extract and its constituents exhibit promising hepatoprotective activity (Planta Medica, 1987, 53(2), p135-140). Significant attention has been paid by several research groups on
A. paniculata
in recent years due to its cytotoxic, antitumorogenic, cell differentiation inducing activities and anti-HIV activities.
Andrographolide having the formula (II),
the major constituent of the plant
A. paniculata
was first isolated by Gorter (Rec. trav. chim., 1911, 30, p151-160).
The extracts of the dried plant, which contains compounds of formula (III), have been assayed for the ability to decrease expression and phosphorylation of p34
cdc2
kinase, cyclin B and c-Mos for treating or preventing pathogenecity of diseases such as AIDS, Alzheimer's disease and hepatitis (WO 96/17605).
Cell cycle kinases are naturally occurring enzymes involved in regulation of the cell cycle (
Progress in Cell Cycle Research,
1995, 1, p351-363). Typical enzymes include the cyclin-dependent kinases (cdk) cdk1, cdk2, cdk4, cdk5, cdk6 and wee-1 kinase. Increased activity or temporarily abnormal activation of these kinases has been shown to result in development of tumors and other proliferative disorders such as restenosis. Compounds that inhibit cdks, either by blocking the interaction between a cyclin and its kinase partner or by binding to and inactivating the kinase, cause inhibition of cell proliferation and are thus useful for treating tumors or other abnormally proliferating cells.
The extract of
A. paniculata
was found to show significant cytotoxic activity against KB and P388 cells. Interestingly, Andrographolide of the formula II, has been shown for the first time to have potent cytotoxic activity against KB as well as P388 lymphocytic leukemia, where as 14-deoxy-11,12-didehydroandrographolide and neoandrographolide having the formulae IV & V
where R represents &bgr;-D-glucose moiety, have shown no cytotoxic activity in tumor cell lines (
J. Sci. Soc. Thailand,
1992, 18, p187-194).
The methanolic extract of the aerial parts of
A. paniculata
Nees showed potent cell differentiation inducing activity on mouse myeloid leukemia (M1) cells (
Chem. Pharm. Bull.
1994, 42(6) 1216-1225).
Japanese patent application JP 63-88124, discloses a mixture of at least two compounds of formula VIa, VIb,
where R
1
, R
2
, R
3
, R
4
and R
5
represent hydrogen or lower alkanoyl group and their activity as antitumorogenic agents.
DASM (dehydroandrographolide succinic acid monoester) prepared from andrographolide of the formula II is found to be inhibiting HIV virus and nontoxic to the H9 cell at the concentrations of 50-200 &mgr;g/ml and was inhibitory to HIV-1 (EIB) at the minimal concentration of 1.6-3.1 &mgr;g/ml (
Proc. Soc. Exp. Biol. Med.,
1991, 197, p59-66).
The plant
Andrographis paniculata
is also reported to inhibit proprotein convertases-1,-7 and furin possibly by suppressing the proteolytic cleavage of envelops glycoprotein gp 160 of HIV, which is known to be PC-mediated, particularly by furin and PC (
Biochem. J,
1999, 338, 107-113)
In International patent application WO 91/01742, compositions containing one or more ingredients obtained from the plants
Valeariana officinalis
and/or
A. paniculata
were disclosed to have antiviral, antineoplastic, antibacterial and immunomodulatory activity.
Although several novel andrographolide derivatives have been prepared, screened and reported in the above said prior-art literature for their anticancer activity, they are not showing interesting activity.
OBJECTIVE OF THE INVENTION
With an objective of preparing novel andrographolide derivatives useful for treating cancer, infections and diseases caused by HSV, HIV, psoriasis, restenosis, atherosclerosis, ca
Akella Venkateswarlu
Chakrabarti Ranjan
Nanduri Srinivas
Pillai Sunilkumar Bhadramma Kochunarayana
Pothukuchi Sairam
Dr. Reddy's Research Foundation
Ladas & Parry
Owens Amelia
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