Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-18
2001-04-10
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06214819
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to staurosporine derivatives for treating ocular neovascular disease. More specifically, the invention relates to a method for treating ocular neovascular disease, e.g., retinal neovascularization and choroidal neovascularization, with staurosporine derivatives.
The retina of the eye receives its blood supply from two vascular beds, the retinal vessels which supply the inner two thirds of the retina, and the choroidal vessels which supply the outer one third. Damage to retinal blood vessels resulting in closure of retinal capillaries occurs in several disease processes including diabetic retinopathy, retinopathy of prematurity, branch retinal vein occlusion, and central retinal vein occlusion; they are collectively referred to as ischemic retinopathies. Retinal ischemia results in release of one or more angiogenic factors that stimulate neovascularization. The new vessels break through the internal limiting membrane (ILM) that lines the inner surface of the retina and grow along the outer surface of the vitreous. They recruit many other cells and produce sheets of vessels, cells, and extracellular matrix that exert traction on the retina, often leading to retinal detachment and severe loss of vision.
Choroidal neovascularization occurs in a number of disease processes, the most common of which is age-related macular degeneration. In this condition, the macula, which is especially adapted for acute and detailed vision, is damaged by gradual death of photoreceptor and RPE cells. This constitutes the degeneration part of the disease which results in the gradual loss of central vision. The reason for the cell death is unknown and there is currently no treatment. As the degeneration occurs, there is a tendency for new blood vessels to grow from the choroid to invade the sub-RPE and subretinal spaces. This process is called choroidal neovascularization (CNV) and it often leads to rapid and severe loss of vision from bleeding and scarring. If the CNV is well-delineated and not beneath the center of the fovea, which is true for a small minority of patients, laser treatment can sometimes help. Even when laser is initially successful, there is a high rate of recurrent CNV and loss of vision. A treatment directed at the stimuli for blood vessel growth is needed and would benefit patients with either retinal or choroidal neovascularization.
SUMMARY OF THE INVENTION
There is provided in accordance with the present invention a method for treating or preventing ocular neovascular diseases, including retinal neovascularization and choroidal neovascularization. The method has the step of administering an effective amount of a staurosporine derivative or a salt thereof.
The staurosporine treatment of the present invention is highly effective in inhibiting and preventing ocular neovascularization, unlike prior art laser treatment that has a limited efficacy. In addition, the staurosporine treatment is simple to administer, unlike prior art treatment methods, e.g., laser treatment, that are invasive and require complex equipment.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method for treating ocular neovascular diseases. The method uses a medicament containing a staurosporine derivative. It has now surprisingly been found that the compounds of formula (I) are highly useful for treating ocular neovascularization, including retinal neovascularization and choroidal neovascularization.
Suitable staurosporine derivatives for the present invention have the formula (I):
wherein R represents a hydrocarbyl radical R
o
or an acyl radical Ac. Suitable hydrocarbyl radicals include acyclic, carbocyclic and carbocyclic-acyclic hydrocarbyl radicals having a maximum total number of carbon atoms of preferably 30, especially 18. Additionally suitable hydrocarbyl radicals are heterocyclic radicals and heterocyclic-acyclic radicals. The hydrocarbyl radicals (R
o
) may be saturated or unsaturated and substituted or unsubstituted. Suitable acyl radicals include optionally functionally modified carboxylic acid and organic sulfonic acid, and optionally esterified phosphoric acid, e.g., pyro- or ortho-phosphoric acid.
Preferred acyclic hydrocarbyl radicals include C
1
-C
20
-alkyl radicals; C
2
-C
20
hydroxyalkyl radicals of which the hydroxy group is in any position other than the 1-position; cyano-[C
1
-C
20
]-alkyl radicals; carboxy-[C
1
-C
20
]-alkyl radicals of which the carboxy group; and C
3
-C
20
-alkenyl radicals of which the free valency is not at the same carbon atom as the double bond. Exemplary acyclic hydrocarbyl radicals are radicals of lower alkyl, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl; lower alkenyl, e.g., propenyl, 2- or 3-methallyl and 2- or 3-butenyl; lower alkadienyl, e.g., 1-penta-2,4-dinyl; and lower alkynyl, e.g., propargyl or 2-butynyl. Preferred carbocyclic hydrocarbyl radicals are radicals of mono-, bi- or polycyclic cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2,2,2]octyl, 2-bycyclo[2,2,1]heptyl and adamantyl; cycloalkenyl; cycloalkandienyl; and corresponding aryl. Aryl radicals include radicals of phenyl, napthyl (e.g., 1- or 2-napthyl), biphenylyl (e.g., 4-biphenylyl), anthryl, fluorenyl, azulenyl, and aromatic analogues thereof having one or more saturated rings. Preferred carbocyclic-acyclic radicals are acyclic radicals that carry one or more of carbocyclic radicals. Heterocyclic radicals and heterocyclic-acyclic radicals include monocyclic, bicyclic, polycyclic, aza-, thia-, oxa-, thaza-, oxaza-, diaza-, triaza-, and tetraza-cyclic radicals of aromatic character.
Exemplary acyl radicals derived from an optionally functionally modified carboxylic acid (Ac
1
) have the formula Z—C(═W)— in which W is oxygen, sulfur, or imino and Z is hydrogen, hydrocarbyl R
o
, hydrocarbyloxy R
o
O, or amino. Preferably, W is oxygen or sulfur, and Z is C
1
-C
7
alkyl, especially C
1
-C
4
alkyl, which is optionally substituted by halogen, carboxy or C
1
-C
4
alkoxycarbonyl. Additionally preferred Z is phenyl, pyridyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl, each of which is unsubstituted or substituted by C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogen, nitro, trifluoromethyl, carboxy, C
1
-C
4
alkoxycarbonyl, methylenedioxy, cyano and/or a salt thereof. Preferred Ac
1
acyl radicals have the formula R
b
o
—CO—, in which R
b
o
is hydrogen, benzoyl, or a hydrocarbyl radical, e.g., C
1
-C
19
alkyl radical which is optionally substituted by a carboxy group, cyano group, ester group, amino group or helogen. Another group of preferred Ac
1
acryl radicals have the formula R
o
—O—CO—. Yet another group of preferred Ac
1
acryl radicals have the formula
in which R
1
and R
2
are independently selected from hydrogen and unsubstituted acyclic C
1
-C
7
hydrocarbyl, preferably C
1
-C
4
alkyl and C
3
-C
7
alkenyl. R
1
and R
2
, independently, can be monocyclic aryl, aralkyl or aralkenyl having a maximum of 10 carbon atoms, each of which is optionally substituted by C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogen and/or nitro. Particularly desirable radicals of this group have hydrogen as R
1
and optionally substituted C
1
-C
4
alkyl, C
3
-C
7
alkenyl, phenyl, pyridyl, pyrimidyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl as R
2
.
Exemplary acyl radicals derived from an organic sulfonic acid (Ac
2
) have the formula R
o
—SO
2
— in which R
o
is a hydrocarbyl radical. Preferably, R
o
of the sulfonic acid acyl radicals is C
1
-C
7
alkyl, phenyl, pyridyl, pyrimidyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl, each of which is unsubstituted or is substituted by C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halogen, nitro, trifluoromethyl, carboxy, C
1
-C
4
alkoxycarbonyl, methylenedioxy, cyano and/or a salt thereof.
Exemplary acyl radicals derived from optionally esterified phosphoric acid (Ac
3
) have the formula
in which R
1
and
Brazzell Romulus Kimbro
Campochiaro Peter Anthony
Kane Frances Elizabeth
Wood Jeanette Marjorie
Gorman Robert J.
Novartis AG
Reamer James H.
Wildman David E.
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