Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-01-19
2001-08-07
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S912000, C514S913000
Reexamination Certificate
active
06271224
ABSTRACT:
BACKGROUND OF THE INVENTION
Although the underlying causes of glaucoma are not fully understood at this time, glaucoma is characterized by damage to the optic nerve head, accompanied by a decrease in the normal visual field. One risk factor for glaucomatous visual field loss is elevated IOP. In fact, glaucoma has historically been treated by drug and/or surgical therapy to lower elevated IOP. While elevated IOP has been positively correlated with the rate of progression of visual field loss in glaucoma, visual field loss may occur at levels of IOP which are considered within the normal range. Thus, other factors, alone or in addition to elevated IOP, may influence the occurrence and rate of progression of visual field loss.
To remain healthy and function normally, the retina and the optic nerve head fibers (neurons) must receive a proper supply of nutrients and oxygen, and must have their carbon dioxide and other metabolic waste products removed. This is accomplished by the microcirculation in these tissues. As used herein, the term “microcirculation” refers to the blood flow through the nutritive blood vessels, across whose walls nutrients, gases and waste products move. Blood flow to the eye depends upon the pension pressure (the systemic blood pressure may the IOP). Some tissues have the ability to maintain (i.e., autoregulate) blood flow through a range of perfusion pressures such that an increase in systemic blood pressure may cause a reduction in the caliber of the blood vessel lumen. Conversely, reduction in systemic pressure in such tissues can result in vessel dilation; however, there is a point where perfusion pressure falls to such a level that the vessel is maximally dilated. Any further fall in perfusion pressure results in a reduction of blood flow to the tissue (ischemia). Ischemia may also result from obstruction, vasospasm, increased vascular resistance, or other interference with microcirculation. Prolonged ischemia ultimately can result in tissue necrosis or neuronal cellular apoptosis. In the case of the optic nerve head or retina, a state of visual dysfunction may precede the death of the neurons. Hence, if ischemia is involved in the death of optic nerve fibers due to glaucoma or some other ischemic-borne retinopathies or optic neuropathies, then its prevention could protect the neurons from death or loss of function.
The vasodilatory and spasmolytic activities of certain isoquinolinesulfonyl compounds have been described with respect to non-ocular tissues. See, e.g., EP 0 187 371 B1, which corresponds to U.S. Pat. No. 4,678,783. These vascular attributes are likely associated with inhibitition of myosin-light chain kinase activity. Myosin-light chain kinase is an enzyme necessary for the excitation-contraction coupling of contractile activity in vascular smooth muscle. Inhibition of this enzyme results in vascular smooth muscle relaxation (i.e., vasodilation) which can produce an increased blood flow.
SUMMARY OF THE INVENTION
The inventors believe that microcirculatory disturbances that restrict nutritive blood flow to the choroid, retina and optic nerve head are likely involved in the progression of visual field loss. While bound by no theories, the inventors postulate that compounds which enhance oxygen and nutrient delivery by enhancing ocular blood flow may be beneficial in preventing optic nerve head injury and may subsequently prevent or alter the rate of progression of visual field loss associated with glaucoma and ischemic optic neuropathies.
The present invention provides compositions and methods useful in the treatment of glaucoma (with or without ocular hypertension) and ocular ischemia, which may result in retinopathies and optic neuropathies. The compositions contain an isoquinolinesulfonyl compound which is effective in reducing or preventing optic nerve head or retinal damage as well as reducing IOP toward normal levels and thus, in reducing or preventing visual field loss.
In an alternative embodiment of the compositions and methods of the present invention, the above compositions may further include a mucomimetic polymer, a gelling polysaccharide, a finely divided drug carrier substrate (defined below), or a combination of these components. These additional components provide compositions which enhance comfort and provide sustained release and delivery of the drug to the eye.
DETAILED DESCRIPTION OF THE INVENTION
Elevation of IOP is associated with clinical manifestations characteristic of glaucomatous optic neuropathy. Optic nerve dysfunction may be the result of pressure-induced changes in the structure of the optic nerve head and/or reduced circulation to the optic nerve head and retina. In addition to affecting vascular resistance and blood flow, the inventors have discovered that certain isoquinolinesulfonyl compounds also lower intraocular pressure.
The isoquinolinesulfonyl compounds of the present invention are the compounds of formula (I) shown below, as well as their pharmaceutically acceptable salts.
wherein
R
1
represents a hydrogen atom, a chlorine atom or a hydroxyl group; and when R
1
represents a hydrogen atom,
A represents an ethylene group unsubstituted or substituted with an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group,
R
2
and R
3
are directly bonded with each other, thereby forming a trimethylene group unsubstituted or substituted with an alkyl group having 1 to 6 carbon atoms, a phenyl group or a benzyl group, and
R
4
represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and
when
R
1
represents a chlorine atom or a hydroxyl group,
A represents an alkylene group having 2 to 6 carbon atoms, said group being unsubstituted or substituted with an alkyl group having 1 to 6 carbon atoms,
R
2
and R
3
are not bonded with each other and each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or R
2
and R
3
are directly bonded with each other, thereby forming an ethylene group unsubstituted or substituted with an alkyl group having 1 to 6 carbon atoms or a trimethylene group unsubstituted or substituted with alkyl group having 1 to 6 carbon atoms, and
R
4
represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an amidino group;
and pharmaceutically acceptable salts thereof. With respect to the above-mentioned alkyl groups, they may be a straight chain group or a branched chain group. These compounds and methods of their syntheses are disclosed in U.S. Pat. No 4,678,783, the entire contents of which are incorporated herein by this reference. Other isoquinolinesulfonyl derivatives and methods of their syntheses are disclosed in U.S. Pat. No. 4,525,589, the entire contents of which are likewise incorporated herein by this reference.
The preferred isoquinohnesulfonyl compound of the present invention is hexahydro-1-(5-isoquinolinylsulfonyl)-1H-1,4-diazepine, also known as 1-(5-isoquinolinesulfonyl)-homopiperazine, and shown below as Compound (II), as well as its pharmaceutically acceptable salts.
Most preferred is the hydrochloride salt of Compound (II). The hydrochloride salt of Compound (II), known as fasudil, AT-877, and HA-1077 is manufactured by Asahi Chemical Industry Co., Ltd. (Japan).
Alternatively, Compound (II) and a preferred metabolite thereof may be represented the following formula:
wherein R=H or OH.
In general, for topical administration an amount of an isoquinolinesulfonyl compound between about 0.001 and about 10.0 percent by weight (wt %) is used in the compositions of the present invention. It is preferred that between about 0.01 and about 3.0 wt % is used, and it is especially preferred to use an amount between about 0.1 and about 2.0 wt %.
The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. No. 4,911,920 issued Mar. 27, 1990 and in U.S. Pat. No. 5,2
Desantis, Jr. Louis M.
Kapin Michael A.
Alcon Laboratories Inc.
Copeland Barry L.
Fay Zohreh
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