Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-19
2003-11-18
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S300000, C514S912000
Reexamination Certificate
active
06649625
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an agent for the prophylaxis and treatment of glaucoma. More specifically, the present invention relates to an agent for the prophylaxis and treatment of glaucoma, which comprises a compound having a Rho kinase inhibitory activity as an active ingredient.
BACKGROUND ART
Glaucoma is caused by an abnormally high internal pressure of the eyeball, wherein the abnormally high pressure makes the eye grow dim or hurts the eye, which in turn fails the eyesight little by little possibly into blindness. Normally, an aqueous humor continuously circulates in the eyeball and maintains a constant intraocular pressure (10-20 mmHg). The pressure is maintained by the circulation of the blood and lymphocytes, elasticity of the eyeball wall, the performance of the control nerves and the like. An abnormality in any of them results in a rise of the intraocular pressure, which may develop glaucoma.
With the aim of preventing the intraocular pressure from rising or lowering an intraocular pressure that went up, for the prophylaxis and treatment of glaucoma, various drugs have been used. Known eye drops for the therapy of glaucoma include sympathetic agonists such as epinephrine, dipivefrine and the like. Due to mydriatic action, however, these eye drops enhance angle closure when administered to treat narrow angle glaucoma, and may cause not only an acute rise of the intraocular pressure, but also hypertension and pigmentation deposit. In addition, the parasympathetic agonists such as pilocarpine and the like cause side effects such as dark visual field due to miosis and congested eye, iris cyst, posterior synechia, cataract, retinal detachment and the like after a long-term use. Moreover, &bgr;-adrenalin blockers such as timolol, pindolol and the like have been widely used, because they lower intraocular pressure by inhibiting the production of aqueous humor without acting on pupils. However, their use is limited, because &bgr;-adrenalin blockers have been reported to cause side effects such as local dry feeling of the eye, allergic blepharitis, superficial keratitis and the like, as well as systemic side effects such as bradycardia, heart failure, asthmatic fit and the like. These side effects prevent application of the blockers to patients suffering from such symptoms. A recent suggestion of an aqueous humor outflow promoting effect of &agr;1-adrenalin blockers also suggests potential use of bunazosin hydrochloride and the like as a new therapeutic agent of glaucoma (Ikuo Azuma, Folia Ophthalmol. Jpn.,42,710-714,1991). However, the &agr;1-adrenalin blockers are inevitably associated with conjunctival injection and miosis due to their vasodilating action.
In the meantime, a compound having a Rho kinase inhibitory activity has been reported to show a hypotensive effect on various hypertension model animals (Masayoshi Uehata, et al., Nature 389, 990-994, 1997). The Rho kinase has been confirmed to be present in corneal epithelial cells (Nirmala SundarRaj. et al., IOVS, 39(7) 1266-1272, 1998). However, it is unknown if Rho kinase is present in other ophthalmic tissues.
The pharmaceutical use of the compound having a Rho kinase inhibitory activity is disclosed in WO98/06433, and, as a use in the ophthalmic area, is taught to be useful for retinopathy. However, WO98/06433 does not disclose its usefulness against glaucoma or description suggestive of the effect.
As a compound having a Rho kinase inhibitory activity, a compound of formula (I) to be mentioned later has been reported (WO98/06433). The compound of formula (I) has been already known to be useful as an agent for the prophylaxis and treatment of disorders of circulatory organs such as coronary, cerebral, renal, peripheral artery and the like (e.g., a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a therapeutic agent of renal and peripheral circulation disorder, a suppressive agent of cerebrovascular contraction and the like), which is potent and long lasting, and also as a therapeutic agent of asthma (JP-A-62-89679, JP-A-3-218356, JP-A-4-273821, JP-A-5-194401, JP-A-6-41080 and WO95/28387).
However, these compounds of the formula (I) are not disclosed to be useful for glaucoma, and there is no description suggestive of such usefulness.
DISCLOSURE OF THE INVENTION
The present invention aims at solving the above-mentioned problems and provides a novel agent for the prophylaxis and treatment of glaucoma, which is superior in a prophylactic and therapeutic effect on glaucoma.
The present inventors have conducted intensive studies and found that a compound having a Rho kinase inhibitory activity also has an intraocular pressure lowering action, an optic disc blood flow improving action and an aqueous outflow promoting action, and that it is useful for the prophylaxis and treatment of various types of glaucoma, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following.
(1) An agent for the prophylaxis and treatment of glaucoma, which comprises a compound having a Rho kinase inhibitory activity.
(2) The agent for the prophylaxis and treatment of glaucoma of (1) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (I)
wherein
Ra is a group of the formula
in the formulas (a) and (b),
R is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring, or a group of the formula
wherein R
6
is hydrogen, alkyl or formula: —NR
8
NR
9
wherein R
8
and R
9
are the same or different and each is hydrogen, alkyl, aralkyl or phenyl, R
7
is hydrogen, alkyl, aralkyl, phenyl, nitro or cyano, or R
6
and R
7
in combination show a group forming a heterocycle optionally having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R
1
is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring, or R and R
1
in combination form, together with the adjacent nitrogen atom, a group forming a heterocycle optionally having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R
2
is hydrogen or alkyl,
R
3
and R
4
are the same or different and each is hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or azide, and
A is a group of the formula
wherein R
10
and R
11
are the same or different and each is hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, or R
10
and R
11
show a group which forms cycloalkyl in combination and l, m and n are each 0 or an integer of 1-3,
in the formula (c),
L is hydrogen, alkyl, aminoalkyl, mono- or dialkylaminoalkyl, tetrahydrofurfuryl, carbamoylalkyl, phthalimidoalkyl, amidino or a group of the formula
wherein B is hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxycarbonylalkyl, &agr;-aminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridyl,
Q
1
is hydrogen, halogen, hydroxy, aralkyloxy or thienylmethyl,
W is alkylene,
Q
2
is hydrogen, halogen, hydroxy or aralkyloxy,
X is alkylene,
Q
3
is hydrogen, halogen, hydroxy, alkoxy, nitro, amino, 2,3-dihydrofuryl or 5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl;
and Y is a single bond, alkylene or alkenylene, and
in the formula (c),
a broken line is a single bond or a double bond, and
R
5
is hydrogen, hydroxy, alkoxy, alkoxycarbonyloxy, alkanoyloxy or aralkyloxycarbonyloxy;
Rb is a hydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono- or dialkylaminoalkyl; and
Rc is an optionally substituted heterocycle containing nitrogen,
an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(3) The agent for the prophylaxis and treatment of glaucoma of (1) or (2) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of
Azuma Mitsuyoshi
Uehata Masayoshi
Waki Mitsunori
Yoshida Yukuo
Fay Zohreh
Senju Pharmaceutical Co. Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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