Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-15
2001-11-27
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S491000, C548S483000, C548S484000, C548S181000, C548S312100, C514S357000, C514S314000, C514S397000, C546S278100, C546S164000
Reexamination Certificate
active
06323228
ABSTRACT:
TECHNICAL FIELD
The instant invention relates to 3-substituted indole carbohydrazides which are useful for treating angiogenesis, methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
BACKGROUND OF THE INVENTION
Angiogenesis, the process by which new blood vessels are formed, is essential for normal body activities including reproduction, development, and wound repair. Although the process is not completely understood, it is believed to involve a complex interplay of molecules which regulate the growth of endothelial cells (the primary cells of capillary blood vessels). Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e., one of no capillary growth) for prolonged periods which may last for weeks or, in some cases, decades. When necessary (such as during wound repair), these same cells can undergo short bursts of growth and rapid proliferation (
J. Biol. Chem
. 1992, 267,10931-10934, and
Science
1987, 235, 442-447.
While it is normally a regulated process, many diseases (characterized as angiogenic diseases) are driven by persistent, unregulated angiogenesis. Ocular neovascularization has been implicated as the most common cause of blindness and is responsible for approximately twenty different eye diseases. In certain existing conditions, such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. The growth and metastasis of solid tumors are also dependent on angiogenesis (
Cancer Res
. 1986, 46, 467-473, and
J. Natl. Cancer Inst
. 1989, 82, 4-6). It has been shown that solid tumors cannot grow beyond 1 to 2 cubic millimeters without inducing the formation of new blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites such as the liver, the lungs, or the bones (
N. Engl. J. Med
. 1991, 324, 1-8).
Several angiogenesis inhibitors are currently under development for use in treating angiogenic diseases, but there are disadvantages associated with these compounds. Fumagillin, a compound secreted by the fungus
Aspergillus fumigatis fresenius
, has demonstrated angioinhibitory effects, but has not been developed clinically due to the dramatic weight loss suffered by laboratory animals after prolonged exposure. TNP-470, a synthetic analog of fumagillin, also inhibits endothelial growth, but has been shown to induce asthenial and neurocortical toxicity in humans, limiting allowable dosages (
J. Clin. Oncology
1999, 17, 2541).
As shown by these examples, there is still a need for compounds useful in treating angiogenic diseases which have improved profiles of activity. More specifically, there is a need for angiogenesis inhibitors which are safe for therapeutic use and which exhibit selective toxicity with respect to the pathological condition such as by selectively inhibiting the proliferation of endothelial cells while exhibiting no or a low degree of toxicity to normal (i.e. non-cancerous) cells. Such compounds should also be easily and cost-effectively made.
SUMMARY OF THE INVENTION
In its principle embodiment, therefore, the instant invention provides angiogenesis inhibitors of formula (I)
or therapeutically acceptable salts thereof, wherein
a is 0, 1, 2, 3, or 4;
each R
1
is independently selected from the group consisting of alkoxy, amino, halo, hydroxy, and nitro;
R
2
is selected from the group consisting of alkenyl, alkyl, alkynyl, aryl, and heterocycle;
R
3
is selected from the group consisting of hydrogen, alkyl, and a nitrogen protecting group; and
R
4
and R
5
are independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycle, and (heterocycle)alkyl; with the proviso that one of R
4
and R
5
is hydrogen.
In another embodiment, the instant invention provides a pharmaceutical composition comprising a compound of formula (I) or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
In another embodiment, the instant invention provides a method of inhibiting angiogenesis in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of formula (I), or a therapeutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the instant invention comprise 3-substituted indole carbohydrazides which are useful for the treatment of angiogenesis-mediated diseases.
As used in the instant specification the following terms have the meanings indicated:
The term “alkanoyl,” as used herein, represents an alkyl group attached to the parent molecular moiety through a carbonyl group.
The term “alkenyl,” as used herein, represents a monovalent straight or branched chain group of two to six carbon atoms containing at least one carbon-carbon double bond.
The term “alkoxy,” as used herein, represents an alkyl group attached to the parent molecular moiety through an oxygen atom.
The term “alkoxyalkyl,” as used herein, represents an alkoxy group attached to the parent molecular moiety through an alkyl group.
The term “alkoxycarbonyl,” as used herein, represents an alkoxy group attached to the parent molecular moiety through a carbonyl group.
The term “alkyl,” as used herein, represents a monovalent group of one to six carbon atoms derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom.
The term “alkylsulfonyl,” as used herein, represents an alkyl group attached to the parent molecular moiety through a sulfonyl group.
The term “alkynyl,” as used herein, represents a monovalent straight or branched chain group of two to six carbon atoms containing at least one carbon-carbon triple bond.
The term “amido,” as used herein, represents an amino group attached to the parent molecular moiety through a carbonyl group.
The term “amino,” as used herein, represents —NR
6
R
7
, wherein R
6
and R
7
are independently selected from the group consisting of hydrogen, alkanoyl, alkenyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, a nitrogen protecting group, and phenyl; or R
6
and R
7
, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, and thiomorpholinyl dioxide.
The term “aminosulfonyl,” as used herein, represents an amino group attached to the parent molecular moiety through a sulfonyl group.
The term “aminosulfonyloxy,” as used herein, represents an aminosulfonyl group attached to the parent molecular moiety through an oxygen atom.
The term “aryl,” as used herein, represents dihydronaphthyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. Aryl groups having an unsaturated or partially saturated ring fused to an aromatic ring can be attached through the saturated or the unsaturated part of the group. The aryl groups of this invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkanoyl, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulfonyl, amido, amino, aminosulfonyl, aminosulfonyloxy, carbonyloxy, cyano, cycloalkyl, (cycloalkyl)alkyl, formyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, perfluoroalkoxy, perfluoroalkyl, and thioalkoxy.
The term “arylalkyl,” as used herein, represents an aryl group attached to the parent molecular moiety through an alkyl group.
The term “carbonyl,” as used herein, represents —C(O)—.
The term “carbonyloxy,” as used herein, represents an alkanoyl group attached to the parent molecular moiety through an oxygen atom.
The term “carbonyloxyalkyl,” as used herein, represents a carbonyloxy group attached to the parent molecular moiety through an alkyl group.
The term “cyano,” as used herein, represents —CN.
The term “cycloalkyl,” as used herein, represents a saturated cyclic, bicyclic, or tricyclic hydrocarbon
Ba-Maung Nwe Y.
Craig Richard A.
Kawai Megumi
Wang Jieyi
Abbott Laboratories
D'Souza Andrea M
Donner B. Gregory
McKane Joseph K.
Steele Gregory
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