Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – N-c doai
Reexamination Certificate
2000-10-11
2003-03-18
Richter, Johann (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
N-c doai
C514S478000, C514S490000, C560S136000
Reexamination Certificate
active
06534541
ABSTRACT:
This invention is in particular related to the use of rivastigmine in the manufacture of a medicament for the treatment of ocular disorders selected from glaucoma and neurodegenerative disease conditions of the retina and the optic nerve.
The term glaucoma includes symptoms of the eye which are especially to be attributed to increased intraocular pressure. Frequently, an obstruction to drainage of the aqueous humour leads to an increase in the intraocular pressure. Chronically raised intraocular pressure has a harmful effect on the optic nerve and the retina, which can terminally lead to blindness. Accordingly, for the treatment of glaucoma, active ingredients are used which are typically able to reduce the intraocular pressure (IOP). For example, increased IOP be treated with certain &bgr;-adrenoceptor blockers.
More recently, the phenomenon of so-called normal tension glaucoma (“low tension” or “normal tension glaucoma” is used synonymously) has now been clinically established in ophthalmology [J. Flammer, Fortschr. Ophthalmol. 87, 187(1990)]. Normal tension glaucoma is characterized by an intraocular pressure which is typically in the normal range, i.e. is not increased, but in which the optic disc (papilla nervi optici) is pathologically excavated and the field of vision is impaired. The pathogenetic factors are especially circulatory problems in the ocular blood vessels, which may be caused e.g. by atherosclerosis, hypotension, orthostasis, functional vasospasms and neurodegenerative factors.
It has now surprisingly been found that rivastigmine, its racemate, its analogs and/or its pharmaceutically acceptable salts are highly effective in the treatment of glaucoma and disorders of neurological pathogenesis (neurodegeneration), such as normal tension glaucoma.
Accordingly, a first aspect of the present invention is related to the use of a compound of formula (I),
wherein
R1 is hydrogen, lower alkyl, cyclohexyl, allyl or benzyl,
R2 is hydrogen, methyl, ethyl or propyl or
R1 and R2 together with the nitrogen to which they are attached form a morpholino or piperidino radical,
R3 is hydrogen or lower alkyl,
R4 and R5 are the same or different and each is a lower alkyl, and the dialkylaminoalkyl group is in the meta, ortho or para position,
in free base or pharmaceutically acceptable acid addition salt form,
in the preparation of a pharmaceutical composition for the treatment of an ocular disorder selected from the group consisting of glaucoma, normal tension glaucoma and neurodegenerative disease conditions of the retina and the optic nerve.
In a preferred embodiment the dialkylaminoalkyl group is in the meta position.
A more preferred compound in accordance to formula (I) is racemic N-ethyl-3-[(1-diethylamino)-ethyl]-N-methyl-phenyl-carbamate free base and/or acid addition salt.
An even more preferred compound in accordance to formula (I) is (S)-N-ethyl-3-[(1-diethylamino)-ethyl]-N-methyl-phenyl-carbamate free base and/or acid addition salt.
A preferred acid addition salt is derived from tartraric acid.
A highly preferred compound in accordance to formula (II) is (S)-N-ethyl-3-[(1-diethylamino)-ethyl]-N-methyl-phenyl-carbamate hydrogen tartrate (rivastigmine).
This invention is preferably related to the treatment of normal tension glaucoma and neurodegenerative disease conditions of the retina and the optic nerve, and even more preferred to neurodegenerative disease conditions of the retina and the optic nerve.
A further aspect of the present invention is a method of treating an ocular disorder, which disorder is selected from the group consisting of glaucoma, normal tension glaucoma and neurodegenerative disease conditions of the retina and the optic nerve, which method comprises the repeated administration of a pharmaceutically effective amount of a compound of formula (I), to an individual in need of such treatment,
wherein
R1 is hydrogen, lower alkyl, cyclohexyl, allyl or benzyl,
R2 is hydrogen, methyl, ethyl or propyl or
R1 and R2 together with the nitrogen to which they are attached form a morpholino or piperidino radical,
R3 is hydrogen or lower alkyl,
R4 and R5 are the same or different and each is a lower alkyl, and the dialkylaminoalkyl group is in the meta, ortho or para position,
in free base or pharmaceutically acceptable acid addition salt form.
A preferred mode of administering a compound of the present invention is the topical, and more preferably the topical ocular administration.
A preferred group of individuals are human beings.
The term repeated administration refers in particular a weekly and more preferably to a daily administration, wherein the active is administered in regular intervals from one to ten times, more preferably from one to six times, and even more preferably from one to three times.
For the purposes of the present invention, the term “lower” in connection with radicals and compounds, unless defined otherwise, denotes, in particular, radicals or compounds having up to 8 carbon atoms, preferably up to 4 carbon atoms.
Accordingly, lower alkyl has up to 8 carbon atoms, and can be straight-chain or branched, preferably up to 4 carbon atoms, and is, for example; methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl or isohexyl.
Alkyl has up to 18 carbon atoms and can be straight-chain or branched. Suitable examples are octadecyl, undecyl, octyl, hexyl, pentyl, butyl, propyl, ethyl, and the like.
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Goldblum et al., “Topical Rivastigmine, a selective Acetylcholinesterase Inhibitor, Lowers Intraocular Pressure in Rabbits”, Journal of Ocular Pharmacology and Therapeutics, vol. 16, No. 1, pp. 29-35, (Feb. 2000).
Sim, Alasdair, “Rivastigmine: a review”, Hospital Medicine, vol. 60, pp. 731-735, (1999).
Novartis AG
Richter Johann
Wildman David E.
Zucker Paul A.
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