WO1997033582A1

WO1997033582A1 - Polyamine site antagonist compositions

Info

Publication number: WO1997033582A1
Application number: PCT/FR1997/000447
Authority: WO
Inventors: Michael A. Kapin; Stephen M. Goode; Bernard Scatton; Salomon Langer
Original assignee: Synthelabo
Priority date: 1996-03-14
Filing date: 1997-03-13
Publication date: 1997-09-18
Also published as: AU2164797A

Abstract

(NMDA) polyamine site antagonist compositions for treating optical neuritis, and specifically the use of eliprodil or ifenprodil for treating said disease, are disclosed.

Description

COMPOSITIONS OF POLYAMINE SITE ANTAGONISTS

SUMMARY OF THE INVENTION

The present invention relates to polyamine site antagonist compositions for treating or controlling optic neuritis. Methods of treating people with optic neuritis are also contemplated.

DETAH T FF DESCRIPTION OF THE EMBODIMENTS

The invention relates to the use of polyamine site antagonists for neuronal cytoprotection by preventing neuronal death due, for example, to demyelination. Since the neurons in the test strip are affected by this disorder, agents that promote remyelination are believed to delay neuronal damage and prevent deterioration of visual function.

Unlike other NMDA antagonists, polyamine site antagonists, such as epriprodile, separate through the blood-brain barrier and act at a modulatory site without the side effects typical of other non-antagonists. competitors. (See, for example, SA Lipton, "Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide -, TINS, 16 (12): 527-532 (1993).) Polyamine site antagonists particularly preferred are certain l-phenyl-2-piperidinoalkanol derivatives of formula (I) below:

in which : R 1 represents a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group comprising from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group comprising from 1 to 4 carbon atoms, a benzyloxy group, an alkanoyloxy group comprising from 1 to 16 carbon atoms or a benzoyloxy group or, when R ₂ represents a hydroxyl or methoxy group in position 4 and when R ₃ represents a hydrogen atom, Ri may also represent a hydroxymethyl group, a group carbamoyl or an alkoxycarbamoyl group comprising from 1 to 4 carbon atoms in the alkoxy part, R ₂ represents a hydrogen atom, a halogen atom, an alkyl group comprising from 1 to 4 carbon atoms, a hydroxyl group or a alkoxy group containing from 1 to 4 carbon atoms,

R ₃ represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms,

R ₄ represents an alkyl group comprising from 1 to 4 carbon atoms, in which case the compounds are in (±) erythro form or, when R ₃ represents a hydrogen atom, R ₄ can also represent a hydrogen atom, and R ₅ represents a hydrogen atom, a halogen atom, an alkyl group comprising from 1 to 4 carbon atoms, an alkoxy group comprising from 1 to 4 carbon atoms, or a set of three methoxy groups in positions 3, 4 and 5 of the benzyl radical, and their pharmaceutically acceptable acid addition salts.

The compounds of formula (1) above are described in US Patent No. 4,690,931 (Wick et al.); however, there is no mention in this patent of ophthalmic indications for these compounds. Wick et al. also describe methods of synthesizing these compounds. The full content of U.S. Patent No. 4,690,931 is cited here for reference.

European patent 0676 200 A2 describes the use of epriprodile for the treatment of peripheral neuropathies and central neurodegenerative diseases. The very particularly preferred compounds are 2- [4- (4-fluorobenzyl) -piperidino] -1- (4-chlorophenyl) -ethanol also known under the name eliprodile; 2- (4-benzylpiperidino) -1- (4-hydroxyphenyl) - propanol, also known as ifenprodile; or a pharmaceutically acceptable salt thereof. The structures of eipriprodile and ifenprodile are presented below.

Eliprodile Ifenprodile

In general, the polyamine site antagonists useful in the present invention will be administered generally, preferably orally, to a person suffering from optic neuritis. The dosage of these compounds will be in the range between about 0.1 and about 500 milligrams (mg), preferably between about 5 and about 100 mg. Local, eg intravitreal, retrobulbar, and periocular administration of these compounds will range from about 0.1 to about 500 mg, preferably from about 5 to about 100 mg. A local ophthalmic composition will generally contain between about 0.1 and about 10% by weight of the active substance, preferably between about 1 and about 5% by weight.

Claims

1. A composition for controlling optic neuritis comprising a pharmaceutically effective amount of a polyamine site antagonist.

2. Composition according to claim 1, in which the polyamine site antagonist is a compound of formula

in which: R 1 represents a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group comprising from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group comprising from 1 to 4 carbon atoms, a benzyloxy group, an alkanoyloxy group comprising from 1 to 16 carbon atoms or a benzoyloxy group or, when R ₂ represents a hydroxyl or methoxy group in position 4 and when R ₃ represents a hydrogen atom,

may also represent a hydroxymethyl group, a carbamoyl group or an alkoxycarbamoyl group comprising from 1 to 4 carbon atoms in the alkoxy part, R ₂ represents a hydrogen atom, a halogen atom, an alkyl group comprising of

1 to 4 carbon atoms, a hydroxyl group or an alkoxy group comprising from 1 to 4 carbon atoms, R ₃ represents a hydrogen atom or an alkyl group comprising from 1 to 4 carbon atoms, R represents an alkyl group comprising from 1 to 4 carbon atoms, in which case the compounds are in (±) erythro form or, when R represents a hydrogen atom, R can also represent a hydrogen atom, and R ₅ represents a hydrogen atom, a halogen atom, an alkyl group comprising from 1 to 4 carbon atoms, an alkoxy group comprising from 1 to 4 carbon atoms, or a set of three methoxy groups at positions 3, 4 and 5 of the benzyl radical, and their pharmaceutically acceptable acid addition salts.

3. The composition of claim 2, wherein the polyamine site antagonist is eliprodile.

4. A method of controlling optic neuritis which comprises administering a pharmaceutically effective amount of a polyamine site antagonist to a person suffering from this disorder.

5. Method according to claim 4, in which the polyamine site antagonist is a compound of formula:

in which:

R 1 represents a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group comprising from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group comprising from 1 to

4 carbon atoms, a benzyloxy group, an alkanoyloxy group comprising from 1 to 16 carbon atoms or a benzoyloxy group or, when R ₂ represents a hydroxyl or methoxy group in position 4 and when R ₃ represents a hydrogen atom, Ri may also represent a hydroxymethyl group, a carbamoyl group or an alkoxycarbamoyl group comprising from 1 to 4 carbon atoms in the alkoxy part, R ₂ represents a hydrogen atom, a halogen atom, an alkyl group comprising of

1 to 4 carbon atoms, a hydroxyl group or an alkoxy group comprising from 1 to 4 carbon atoms,

R ₄ represents an alkyl group containing from 1 to 4 carbon atoms, in which case the compounds are in (±) erythro form or, when R ₃ represents a hydrogen atom, R ₄ can also represent a hydrogen atom, and R ₅ represents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, or a set of three methoxy groups in positions 3, 4 and 5 of the benzyl radical, and their pharmaceutically acceptable acid addition salts.

6. The method of claim 5, wherein the polyamine site antagonist is eliprodile.