Therapeutic compounds and methods

Details Therapeutic compounds and methods Therapeutic compounds and methods

2002-11-08

2004-03-23

Solola, Taofiq (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S468000, C549S379000, C549S458000

Reexamination Certificate

active

06710075

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to compounds having a cyclopentabenzofuran core. More particularly, the present invention relates to cyclopentabenzofuran compounds having a bulky substituent at the 6-oxy position, such as where the cyclopentabenzofuran core is substituted by a dioxanyloxy moiety. The invention also relates to the use of these compounds in therapy and compositions comprising said compounds.
BACKGROUND
Aglaia is a large genus of the family Meliaceac comprising over 100 (mostly woody) species in Indo-Malaysia and the Western Pacific region. Uses include treatment of fever, fractures, parturition and inflammation. Extracts are also used as bactericides, insecticides, in perfumery, as an astringent, tonic, a refrigerant (
Dr Duke's Phytochemical and Ethnobotanical Databases
) and for the treatment of abdominal tumours (Pannel, et al, 1992, Kew Bull., (16) 273-283).
More recently, a number of 1H-cyclopenta[b]benzofuran lignans have been isolated from Aglaia species (see for example, WO97/08161; JP 97171356; Ohse, et al,
J Nat Prod,
1996, 59(7):650-52; Lee et al, Chem. Biol. Interact., 1998, 115(3):215-28; Wu et al,
J. Nat. Prod.,
1997, 60(6):606-08; Bohnenstengel et al,
Z. Naturforsch,
1999, 54
c
(12):55-60 and Bohnenstengel et al,
Z. Naturforsch,
1999, 54
c
(12):1075-83, Xu, Y. J., et al, 2000,
J. Nat. Prod.,
63, 4732-76, the entire contents of which are incorporated herein by reference). A number of these compounds have also been noted for their insecticidal activity (Janpraseri, et al, 1993,
Phytochemistry,
32 (1): 67-69; Ishibashi et al, 1993,
Phytochemistry,
32 (2): 307-310; Hiort, et al, 1999
, J. Nat. Prod.,
62 (12): 1632-1635). Insecticidal compounds with a closely related core structure were isolated from Aglaia roxburghiana and are described in WO 9604284 for use as active ingredients in agrochemical formulations.
New compounds (Compounds A and B), as described herein) have now been isolated from Aglaia leptantha, Miq. (Meliaceae) which uniquely possess a dioxanyloxy group at the 6-position of the cyclopenta[b]benzofuran core. Compounds A and B have been shown to exhibit potent cytotoxic and cytostatic effects on cancer cell growth and viability and thus the compounds of the invention and derivatives thereof, may be useful as therapeutic agents in the treatment of cancer and cancerous conditions or other diseases associated with cellular hyperproliferation.
SUMMARY OF THE INVENTION
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
In a first aspect, the invention relates to compounds of Formula (I) or a salt or prodrug thereof.
wherein
each R
4
-R
10
is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylacyl, optionally substituted cycloalkylacyl and a C-1 linked saccharide;
X is OR
8
or NR
9
R
10
;
R
11
and R
12
are preferably each independently hydrogen or, alternatively, OR
4
and R
11
, and/or OR
5
and R
12
together form a methylenedioxy group; and
Y is selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, optionally substituted benzoyl, optionally substituted C
3
-C
8
cycloalkyl, (preferably optionally substituted C
5
-C
6
cycloalkyl) optionally substituted CH
2
-(C
3
-C
8
cycloalkyl) (preferably optionally substituted CH
2
-(C
5
-C
6
cycloalkyl), optionally substituted 5-6 membered heterocyclyl, and optionally substituted CH
2
-(5-6 membered heterocyclyl).
In a preferred embodiment, the invention relates to compounds (including steroisomers within the dioxanyl group) of formula (i) or a salt or prodrug thereof.
wherein
and each R
1
-R
10
is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylacyl, optionally substituted cycloalkylacyl and a C-1 linked saccharide; and
X is OR
8
or NR
9
R
10
);
R
11
and R
12
are each independently hydrogen or, OR
4
and R
11
, and/or OR
5
and R
12
together form a methylenedioxy group. In one preferred embodiment, R
11
and R
12
are both hydrogen.
In one preferred embodiment, compounds of the present invention have the Formula (ii):
or a salt or prodrug thereof.
Formula (ii) has 4 chiral centres in the dioxanyl moiety. Two isomers (isomeric in the dioxanyl group) of Formula (ii) have now been isolated—Compounds A and B as described in Example 1.
In another aspect, the invention provides a composition comprising a compound of Formula (I), such as Formula (i), or a salt or prodrug thereof, together with a pharmaceutically acceptable carrier, excipient or diluent.
In still a further aspect, the present invention provides a method for the treatment of cancer or a cancerous condition or a disease state or condition associated with cellular hyperproliferation comprising the administration of a treatment effective amount of a compound of Formula (I), such as Formula (i), or a salt, derivative or prodrug thereof, to a subject in need thereof. Some particular cancerous conditions which may be treated by the compounds of the invention may include lung, prostate, colon, brain, melanoma, ovarian, renal and breast tumours and leukemia. Disease states or conditions associated with cellular hyperproliferation which may be treated by compounds of the invention may include atherosclerosis, restinosis, rheumatoid arthritis, osteoarthritis, inflammatory arthritis, psoriasis, peridontal disease or virally induced cellular hyperproliferation.


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patent: WO 96/04284 (1996-02-01), None
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patent: WO 00/7579 (2000-02-01), None
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Bohnenstengel, F. et al., “1H-Cyclopental[b ]Benzofuran Lignans from Aglaia Species Inhibit Cell Proliferation and Alter Cell Cycle Distribution in Human Monocytic Leukemia Cell Lines,”Z. Naturforsch, 54c, pp. 1075-1083, 1999.
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Cui, B. et al., “Novel Cytotoxic 1H-Cyclopenta[b]Benzofuran Lignans from Aglaia Elliptica,”Tetrahedron, 53(52):17625-17632, 1997.
Davey, A. et al., “Synthesis of the Novel Anti-Leukaemic Tetrahydrocyclopenta[b]Benzofuran, Rocaglamide and Related Synthetic Studies,”J. Chem. Soc. Perkin Trans 1, 1992.
Dreyer, M. et al., “New Insecticidal Rocaglamide Derivatives and Related Compounds from Aglaia Oligophylla, ”J. Nat. Prod., vol. 64, pp. 415-420, 2001.
Dr. Duke, “Phytochemical and Ethnobotanical Databases,”Agricultural Research Service; Ethnobotany Query, pp. 1-2, Retrieved from <http://www.ars-grin.gov/cgi-bin/duke/ethnobot.p1> on Apr. 27, 2000.
Engelmeier, D. et al., “Cyclopenta[b]Benzofurans from Aglaia Species with Pronouned Antifungal

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