Anti-inflammatory uses of manzamines

Details Anti-inflammatory uses of manzamines Anti-inflammatory uses of manzamines

2000-03-24

2002-05-14

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S292000, C514S321000, C514S322000

Reexamination Certificate

active

06387916

ABSTRACT:

BACKGROUND OF THE INVENTION
The prevention and control of inflammation is often of great importance for the treatment of humans and animals. Much research has been devoted to development of compounds having anti-inflammatory properties. Certain methods and chemical compositions have been developed which aid in inhibiting or controlling inflammation, but additional anti-inflammatory methods and compositions are needed.
Neuroinflammatory conditions are complex and poorly understood disease processes which are hypothesized to involve microglia (BM&PHgr;) (Mallat, M. [1994 ]
J. Leukoc. Biol.
56:416-422). BM&PHgr; are mononuclear-phagocytes which become activated in a number of inflammatory conditions, such as neurogenic inflammation, meningitis, septic shock, Down's syndrome, postischemic brain injury, HIV encephalopathy, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis (Mayer, A. M. [1988 ]
Medicina
. (
B. Aires
.) 58:377-385), acquiring a macrophage-like phenotype and become cytotoxic to brain cells by releasing mediators, i.e., proteolytic enzymes, reactive oxygen intermediates, eicosanoids and cytokines (Mayer et al. [1999]
Shock
11(3):180-186). Present therapies for these and other inflammatory conditions are based on steroids and nonsteroidal anti-inflammatory compositions which are usually associated with a high incidence of unsatisfactory toxicity and poor efficacy (Faden, A. I. and S. Salzman [1992 ]
Trend in Pharmacological
Sciences 13:29-35).
It has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activity of great diversity. Marine sponges have proved to be such a source, and a number of publications have issued disclosing organic compounds derived from marine sponges. Such publications include Scheuer, P. J. Ed. [1978-1983]
Marine Natural Products, Chemical and Biological Perspectives
, Academic Press, New York; Faulkner, D. [1995-]
J. Nat. Prod. Rep.
12:223-269; [1994] 11:355-394; [1993] 10:497-539; [1992] 9:323-364; [1991] 8:97-147; [1990] 7:269-309; [1988] 5:613-663; [1987 ] 4:539-576; [1986] 3:1-33; [1984] O
2
−
1:551-598.
It has been suggested (Glaser, K. B., R. S. Jacobs [1987]
Biochem
. Pharmacol. 36:2079-2086) that manoalide, and other marine natural products have the potential to modulate leukocyte eicosanoid (Mayer, A. M. S., S. Oh, K. H. Ramsey et al. [1999]
Shock
11(3):180-186) and O
2
−
and thromboxane B
2
(TXB
2
) in BM&PHgr;.
Certain cyclic alkaloid compositions, e.g., manzamines A-F derived from extracts of the marine sponge Haliclona sp., have been found to possess useful antitumor activity. These compounds have been described in, for example, U.S. Pat. Nos. 4,895,854; 4,895,853; and 4,895,852. Manzamines A-F have the following structures:
These compounds have not previously been reported to play any role in inflammatory processes.
BRIEF SUMMARY OF THE INVENTION
The objects of the present invention are accomplished by the provision of anti-inflammatory manzamine compounds. Specifically exemplified herein are manzanines A-F. The subject invention further concerns the use of various derivatives and analogs of these compounds. Advantageously, these compounds have been found to possess anti-antigen driven, immune mediated inflammation and anti-neurogenic inflammation activity. Manzamine A has been found to be particularly effective because of its potent anti-inflammatory activity and low toxicity.
As described herein, the invention also comprises pharmaceutical compositions, e.g. anti-inflammatory compositions, containing as an active ingredient an effective amount of one or more compounds described herein and a non-toxic, pharmaceutically acceptable carrier or diluent. The pharmaceutical compositions of the subject invention can further comprise other active compounds. Such other active compounds include, but are not limited to, other anti-inflammatory compounds for example, steroidal compounds, including hydrocortisone and the like; or non-steroidal anti-inflammatories, including acetylsalicylic acid (aspirin), ibuprofen, acetaminophen, indomethacin, and the like. The second active ingredient can include antiviral, antibacterial, antifungal or other antimicrobial compounds or antitumor compounds as well.
As described herein, the invention further comprises processes for the production of compounds and compositions of the invention and novel methods of use thereof, e.g. methods of inhibiting an inflammatory response in a human or animal.
In accordance with the invention, methods for inhibiting inflammation comprise administering to a human or animal in need of such treatment an effective amount of the pharmaceutical compositions described herein.
DETAILED DISCLOSURE OF THE INVENTION
The subject invention pertains to novel uses as anti-inflammatory agents of manzamine compounds and compositions comprising the manzamine compounds. Surprisingly, the manzamine compounds of the subject invention can be highly effective in inhibiting antigen driven, immune-mediated inflammation and neurogenic inflammation activity.
In one embodiment, the subject invention pertains to the use of compounds having the following General Structure (I):
wherein X
1
, X
2
, X
3
, X
4
, X
5
, and X
6
are, independently, a hydrogen, halogen, hydroxy, lower alkoxy, lower acyloxy, or lower mono or dialkyl amino group; R
1
is hydrogen, lower alkyl, or lower acyl group; R
2
is hydrogen, hydroxy, lower alkoxy, or lower acyloxy group.
In a preferred embodiment of the invention, the invention pertains to anti-inflammatory compositions comprising manzamine A having the following structure:
Further embodiments of the subject invention pertain to the anti-inflammatory use of compounds having General Structures (II)-(IV):
wherein X
1
, X
2
, X
3
, X
4
, X
5
, and X
6
are the same or different and are a hydrogen, halogen, hydroxyl, lower alkoxy, lower acyloxy, thiol, lower alkylthiol, nitro, amino, lower alkylsulfonyl, aminosulfonyl, hydroxy sulfonyl (—SO
3
H), lower acylamino, lower alkyl, or lower monoalkyl- or dialkyl-amino group; R
1
and R
2
are the same or different and are a hydrogen, lower alkyl, or lower acyl group; and Y is a hydrogen, hydroxyl, lower alkoxy, or lower acyloxy group.
In more specific embodiments of the invention, the invention comprises the anti-inflammatory use of the compounds designated as manzamine B, C, or D of the formulae:
Further embodiments of the subject invention utilize General Structure V:
wherein R is a hydrogen, halogen, hydroxy, or lower acyloxy group; and X is a double bonded oxygen, or is the same or different and is any two of a hydrogen, hydroxy, lower alkyl, lower alkoxy, or lower acyloxy group wherein said lower alkyl, alkoxy, or acyloxy groups have preferably, from 1 to 5 carbon atoms.
In a specific embodiment, the subject invention concerns manzamines E and F which have the following structures:
In other embodiments of the invention, the double bonds in the composition of General Structures (I)-(V) are partially or fully reduced. In further embodiments of the invention, the composition is a mineral acid (e.g., HCl, H
2
SO
4
, H
3
PO
4
, HNO
3
, etc.) or organic salt of compositions according to the General Structures.
Methods for obtaining these compounds are described in, for example, U.S. Pat. Nos. 4,895,852; 4,895,853; and 4,895,854, which are herein incorporated in their entirety by reference thereto.
Skilled chemists having the benefit of the instant disclosure, can readily use procedures to prepare the subject compounds. In carrying out such operations, suitable filtration, chromatographic and other purification techniques can be used. These techniques could include, for example, reversed phase (RPLC), column, vacuum flash, medium pressure (MPLC) and high performance liquid chromatography (HPLC) with a su

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