Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-02-19
2001-09-18
Gerstl, Robert (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S312100
Reexamination Certificate
active
06291501
ABSTRACT:
FIELD OF THE INVENTION
The subject invention pertains to compounds which are useful as anti-inflammatory agents and to compositions containing such compounds as active ingredients. More particularly, the invention concerns novel biologically active bis-heterocyclic compounds, e.g. bis-indoles, novel uses of the compounds, pharmaceutical compositions containing these compounds, and methods of producing the compounds. The novel uses of the compounds relate to the anti-neurogenic inflammatory properties of the disclosed bis-heterocyclic compounds. Specifically exemplified herein are dragmacidin f, topsentin d and topsentin e, and their salts, analogs and derivatives.
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.
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) 1:551-598.
Indole compounds of marine origin have also been described in Moquin, C., M. Guyot (1984) Tetrahedron Letters 25 (44):5047-5048; Norton, R. S., R. J. Wells (1982)
J. Am. Chem. Soc.
104: 3628-3635; Roll, D. M., C. M. Iireland, H. S. M. Lu, J. Clardy (1988)
J. Org. Chem,
53:3276; Kobayashi, H., T. Ohta, S. Nozoe (1990)
Tetrahedron
46:7699; Jiminez C., E. Quinoa, P. Crews, (1991)
Tetrahedron Lett.
32:1843; Jiminez, C., E. QUinoa, M. Adamczeski, L. M. Hunter, P. Crews (1991)
J. Org. Chem.
56:3403; Bifulco, G., I. Bruno, L. .Minale, R. Riccio, A. Calignano, C. Debitus (1994)
J. Nat. Prod.
57:1294; and Bifulco, G., I. Bruno, R. Riccio, J. Lavayre, G. Bourdy (1995)
J. Nat. Prod.
58:1254.
Utilizing sponges as a source material and supplemented by synthetic production methods, new classes of biologically active compounds and new pharmaceutical compositions useful as antitumor and antiviral agents have been provided to the art. For example, bis-heterocyclic compounds such as bis-indoles have been previously described as having antimicrobial, antitumoror antiviral activity. Specifically, the bis-indole compounds known as topsentins are disclosed in U.S. Pat. No. 4,866,084. Dragmacidin and its related compounds isolated from the marine sponge of the Dragmacidon sp. are disclosed in U.S. Pat. No.4,895,844. These patents are herein incorporated by reference. These compounds as well as the homocarbonyltopsentins and hamacanthins have also been described as having inhibitory activity against cellular inflammatory responses. See U.S. Pat. Nos. 5,290,777 and 5,464,835, which are also hereby incorporated by reference. The present invention provides additional related compounds which have improved water solubility characteristics and which have a novel utility as anti-neurogenic inflammatory compositions.
Other advantages and further scope of applicability of the present invention will become apparent from the detailed descriptions given herein; it should be understood, however, that the detailed descriptions, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent from such descriptions.
BRIEF SUMMARY OF THE INVENTION
The objects of the present invention are accomplished by the provision of novel anti-inflammatory bis-heterocyclic compounds that have a general structure according to the formula:
A
1
—M—A
2
wherein each of A
1
and A
2
is a heterocycle; and M is a core moiety linking the heterocycles, A
1
and A
2
. In a specific embodiment, the compound comprises an indole as the A
1
and A
2
moieties. Thus, the compound can be a bis-indole. Other compounds of the subject invention can comprise heterocycles such as pyridyl or purine as the A
1
and A
2
moieties. The core moiety M can be a linear or cyclic group comprising at least three atoms.
Specifically exemplified herein are the novel compounds which have been designated as dragmacidin f, topsentin d, and topsentin e. Advantageously,these compounds have been found to possess anti-neurogenic inflammation activity.
As described herein, the invention also comprises pharmaceutical compositions, e.g. anti-neurogenic inflammatory compositions, containing as an active ingredient an effective amount, of one or more compounds according to the formula expressed above 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, 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 a neurogenic 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 composition
DETAILED DISCLOSURE OF THE INVENTION
The subject invention pertains to novel uses as anti-inflammatory agents of bis-heterocyclic compounds and compositions comprising the bis-heterocyclic compounds. Surprisingly, the bis-heterocycle compounds of the subject invention can be highly effective in inhibiting neurogenic inflammation.
A specific embodiment of the subject invention is a bis-indole compound, wherein one of the indole rings has been reduced and an internal cyclization has taken place between a 2-aminoimidazolyl-ethylamine side chain and one of the indole rings as shown in structure (I) below:
R
1-4
are the same or different selected from —H, —OH, halogen, —R, —OR, —OCOR, —OA, or NZZ (wherein the Zs can be the same or different);
Y is the single group ═O, or the single group ═NZ, or two groups, same or different, selected from —H, —OH, —OR, —OCOR, NZZ (wherein the Zs can be the same or different);
Z is independently selected from —H, —R, —OH, or —COR;
R is C1-C8 alkyl or C1-C8 alkoxyl, mesyl, or tosyl; and A is —R-phenyl.
A particularly preferred embodiments the compound called dragmacidin f (structure (II), below), and salts thereof. In this compound, R
1
═R
2
═R
4
═Z═H; R
3
═Br; Y is the single group ═O.
A specific embodiment of the invention includes compounds in which alkylation of the imidazole ring of the topsentins has occurred as shown in structure (III) below:
wherein
R
1-8
are the same or different selected from —H, —OH, halogen, —R, —OR, —OCOR, —OA, or NZZ (wherein the Zs can be the same or different);
R
9
is C
1-8
alkyl or aryl;
Z is independently selected from —H, —R, —OH, or —COR;
R is C
1-8
alkyl or C
1-8
alkoxyl, mesyl, or tosyl; and
A is —R-phenyl.
A particularly preferred embodiment is the compound in which R
1
═R
2
═R
4
═Z═H and R
3
═Br and R
6
═OH, and salts thereof, as
Jacobs Robert S.
Pomponi Shirley A.
Wright Amy E.
Gerstl Robert
Harbor Branch Oceanographic Institution Inc.
Saliwanchik Lloyd & Saliwanchik
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