USE OF POLYAMINE SITE ANTAGONIST FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF ISCHEMIC DISORDERS OF THE EYE

Abstract: The use of polyamine site antagonists in treating ischemic disorders of the retina and optic nerve head are disclosed. Especially preferred are certain 1-phenyl-2-piperidinoalkanol derivatives, such as eliprodil and ifenprodil.

Description: USE OF POLYAMINE SITE ANTAGONIST FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT OF ISCHEMIC DISORDERS OF THE EYE The present invention rciaies generally to the field of ophthalmology. In particular, the invention relates to the use of eiiprodil and related agents that prevent or attcmfflrr ischemic mediated neuronal injury and hence are useful for treating ischemia or hypoxia of the retina or optic nerve head in mammalian subjects. RArKraorrNn QFTΉE ϊNVFfVπnN It is known that oxygen debt within the tissues supplied by the retinal artery is chances to the inner retina. Acute changes include swelling of the inner nuclear, inner plexiform. and ganglion cell layers. Typically, in a matter of days pyknonc nuclei are observed, which is followed by loss of ganglion cells and a thinning of the inner retina. Many of the histological changes observed in the inner retina followmg hypoxia were elucidated using the chick embryo retina preparation. David used this model to show that when subjected to anoxia, morphological changes occurred that were similar to the toxic effects of glutamate or potassium adm_jτisτzarion (David. P., et al., "Involvement of excitatory neuroaa.srn.gers in the damage produced in chick embryo retinas by anoxia and extracellular - l - high potassium, ' ' Exp. Eye Res. 46: 657-662. 1988). Imn uorxytochemical and eiectrophysioiogicai studies have unequivocally proven that giutamate is the major excitatory neurotrarismitter in the retina as well as most other regions in the central nervous system (Massey, S.. ''Cell types using giutamate as a neuroπansinrtter in the verebrate retina, " ' Progress in Retina Research, Volume 9, edited by N. N. Osbome and G. J. Chader, Oxford: Pergammon Press, 399-425, 1990; Miller, R. F. and M. M. Slaughter, 'Εxαtatory arnino acid receptors in the vertebrate retina." Retina Transmitters end Modulators, Volume EL edited by W. W. Morgan. Boca Raton: CRC Press, Inc. 123-160, 1985). Under ∞πnal conditions neuronal release of giutamate is presynaptic and mediates an excitatory response on post-synapϋc excitatory amino acid (EAA) receptors. Dissociation from these receptors as well as uptake into presyraptic neurons and or glial cells is very rapid. Under certain conditions giutamate release can be excessive and uptake mechanisms ouiiipiuiiiised. In the central nervous system it has been demonstrated that brief periods of ischemia can rapidly increase giutamate levels. Beneviste demonstrated increases in giutamate in the adult rat brain within minutes of global cerebral ischemia (Beneviste. H. et al., 'Ηevaπon of the extracellular concenrradons of giutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by iniracerebral πticrc ialysis. " './ Neumchem. 43(5): 1369-1374, 1984.). Excessive EAA stimulation, referred to as excitotoxicity, can result in neuronal injury (Olney, J. W., "Inciting excitotoxic cytocide among central neurons." Adv. Exp. Med Biol. 203:631-645. 1986). The process of excitotoxicity has been extensively studied in the retina. Such toxicity to the inner retina has been observed following travitreal injection of EAAs, following application of EAAs to the isolated animal retina, or from exogenousiy applied giutamate to retinal ganglion cells in culture. See generally, SattayasaL et al.. "Morphology of qiiisquaiate-induced neurotoxicity in the chicken retina," Invest. Ophthdmol. Vis. Sci., 28:106-117 (1987); Tung, et al.. "A quantitative analysis of the effects of excitatory neurotoxins on retinal ganglion cells in the chick." Visit d Neumsci, 4:217-223 (1990); Sisk. et al., "Histological changes in the inner retina of albino rats following inπavitreal injection of monosodium L-glutamate." Graefe's Arch Clin. Exp. Ophthdmol, 223:250-258 (1985); Siliprandl et al., "N-methyl-D-aspartate-induced neurotoxicity in the adult rat retina," Visual Neumsci., 8:567-573 (1992); Reif-Lehrer. et al.. "Effects of monosodium giutamate on chick embryo retina in culture," Invest. Ophthdmol. Vis. ScL, 14(2): 114-124 (1975); Blanks, J. C, "Effects of monosodium giutamate on the isolated retina of the chick embryo as a function of age: A morphological study," Exp. Eye Res.. 32:105-124 (1981); Olney, etaL, "The role of specific ions in giutamate neurotoxicity," Neumsci Lett., 65:65-71 (1986); Olney, et aL, "The a_τti-ocitotσxic effects of certain anesthetics, analgesics and sed-ffrve-hyp∞tics,'' Neumsci Lett 68:29-34 (1986); Price, et al., "CNQX potently and sdectivdy blocks kainate excitotoxicity in the chick embryo retina," Soc Neumsci Abst, 14:418 (1988); David, et aL, "Involvement of excitatory neurotCTisminαs m the damage by anoxia and extracellular high potassium," Exp. Eye Res., 46:657-662 (1988); Caprioli, et aL, "Large retinal ganglion cells are more susceptible to excitotoxic and hypαxic injury than small cells," Invest Ophthdmol Vis. Sci., 34(Suppl):1429 (1993); Osnrans, et aL, 'Εlectrophysioiogy of cultured retinal ganglion cells to investigate basic rrechanics of damage," Glaucoma Updcte IV. 59-65 (1991); and Sucher, et al., antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in v ro," J. Neumsci, 11(4):966-971 (1991). EAA receptors have been characterized as n∞tabonopic or iαrrøtropic. Activation of a metabotropic receptor affects cellular processes via G-proteins; whereas ionotropic receptors affect the translocation of mono- and divalent cations across the cell iiiembraue. There are at least three ionotropic receptors that have been named for the agonist that preferentially stimulates the receptor. These receptors have been classified as: N-rnethyl-D-aspartate (NMDA); kainate; and 2-amino-3-(3-hydroxy-5- methylisoxazol- 4-yl) propanoic acid (AMPA) receptors. These EAA receptors arc differentially distributed in srxrific ceils in the retina. (See, for example, Massey. S., "Cell types using giutamate as a neMUUansiu ter in the vertebrate retina." N. N. Osbome and G. J. Chader (Eds.) Progress in Retold Research, C . 9, Pergammon Press: Oxford. 399-425 (1990); and Miller, et al., "Excitatory amino acid receptors in the vertebrate retina." Retind Tratsmitters cndModulaors: Models far the Bran, (W. W. Morgan, Ed) CRC Press. Inc., Boca Raton. 11:123-160 (1985).) The localization of such receptors accounts for the pathologies associated with ischemia of the retina or optic nerve head. For example, death of the retinal ganglion cell induced by kainate has to a large part been attributed to the NMDA receptor. (See, for example, Sucher, et aL, - 3 - SUBSTITUTE SHEET {RULE 26) '74-methyl-D-aspartate antagonists prevent kainate neurotoxicity in retinal ganglion cells in vit ," J. Neumsci, 11(4):966-971 (1991).). SI JMMAHV OF TTTC INVFTfππN The present invention is directed to methods for treating ischemic di^^ with polyamine site antagonists. Figure 1 shows the effect of euprodil on the restoration of the dectroretinogram following ischemic challenge in the pigmented rabbit nirrAiira nref πfw OF THE INVENTION Polyamine site antagonists are useful in treating ischemic disorders of the mammalian, particulariy human, retina (e.g. branch and central veinartery occlusion) or optic nerve head (e.g. anterior ischemic optic neuropathy). Unlike other NMDA antagonists, polyamine site antagonists, such as eliprodiL partition across the blood-brain barrier and produce their actions at a modulatory site without side-effects typical of non-αirπpetitive antagonists. (See, for example, Lφton, SA, "Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide," TINS, 16(12): 527-532 (1993).) Particulariy preferred polyamine site antagonists are certain l-phenyl-2-piperiάino- alkanol derivatives of formula (I), below: wherein: R, lepichcms a hydrogen atom, a halogen atom, a uiflucτoτnethyl group, an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, an alkanoyloxy group having from 1 to 16 carbon atoms or a benzoyloxy group, or, when R 2 icμeseui a hydroxyl or methoxy group in the 4-position and R j leμiesαus a hydrogen atom, R< may also represent a hydroxymethyl group, a carbamoyl group or an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkoxy part R 2 lepiesαits a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group or an alkoxy group having from 1 to 4 carbon atoms, R, represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, R, lepie enis an alkyl group having from 1 to 4 carbon atoms, in which case the confounds are in the (± erythro form, or, when R^ iqae&ent a hydrogen atom, R« may also represent a hydrogen atom, and R < 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 the 3-, 4- and 5-positions of the benzyl radicaL and phaπnaceutically acceptable acid addition salts thereof The ∞mpou ds of formula (I) above are described in U.S. Patent No. 4,690,931 (Wick, et al.); however, there is no mention in that patent of ophthalmic indications for such ∞mpounds. Wick, et al. also describe methods for synthesizing such compounds. The entire contents of U.S. Patent No. 4,690.931 are incorporated herein by reference. The most preferred ∞mpounds are: 2-[4-(4-fluorobenzyl) ipcridino]- l-(4-chlorophenyl ethanol, also known as eiiprodil; 2-(4-beπzylpiperidino l- (4-hydroxyphenyl)-propanoL also known as ifenprodil; or a pharrnaceuticaily acceptable salt thereof. The smi tires ofehprodil and ifenprod^ Eiiprodil IfeπprodU In generaL the polyamine site antagonists useful in the present invention will be administered orally. Daily dosage of these ∞mpounds will range between about 0.1 and about 500 milligrams (mg), preferably between about 5 and about 100 mg. Local administration of these ∞mpouπds will range between about 0.1 and about 500 mg, preferably between about 5 and about 100 mg. An aqueous ∞mposition will generally contain between about 0.1 and about 10 percent by weight (wt%) of the active, preferably between about 1 and about 5 wt%. The following example is presented to illustrate further various aspects of the present invention, but is not intended to limit the scope of the invention in any respect Example Studies were conducted to evaluate the effect of Eiiprodil on the recovery of the ERG (eiectroretinogram) following an ischemic challenge in the pigmented rabbit This experimental paradigm is thought to be a good model for evaluating the possible beneficial effects of therapeutic agents on retinal damage caused by interruption of blood flow (Noon. Y. H., and Marmor. M F., "Dextromethorphan Protects Retina Against Ischemic Injury In Vivo", Arch Ophthdmol. 107:409-411(1989); Gupta. L. Y., and Marmor, M F., "Mannitol, Dexαornethorphan. and Catalase Minimize Ischemic Damage to Retinal Pigment Epithelium and Retina", .4 /cλ Ophthdmol 111:384-388 (1993). Ischemia was produced by mechanically - 6 - SUBSTITUTE SHEET (RULE 26J elevating intraocular pressure above systemic blood pressure for 65 minutes. Just prior to and during the ischemic period, all rabbits were put into a surgical plane of anesthesia by administering sodium pen∞barbital. Ischemia was conπrmed by a cessation of A and B wave activity (< 15 (μV). One hour prior to ischemia, rabbits were adrmnistered iπrravenously 3 mgkg of EliprodiL 10 mgl^EliprodU was giv∞ intnφeritoneaU 12, 24 and 36 hours following the ischemic period ERG recordings were made prior to ischemia and at 24 and 48 hours post-ischemia. Results of this experiment are presented (Figure 1) as a function of percent of baseline (pre-ischemia measurement). Values are mean ± SEM; N=5 vehicle; N=6 for eiiprodil. Baseline B wave amplitude=456 + 32 and 441 + 28 μV for eiiprodil and vehicle groups. Baseline A wave amphtude= -143 + 8 and -130 + 3 μV for eiiprodil and vehicle. Panel A shows the effect of Eiiprodil on B wave amplitude ∞mpared to vehicle Heated animals. B wave amplitude is thought to be a composite of Mulle s cell and Bipolar cell activity. Drug treatment resulted in a 70.7% and 77.9% increase (p< .05) over vehicle treated amplitudes at 24 and 48 hours post ischemia, respectively. In panel B, the functionality of the outer retina was evaluated through measurement of A wave amplitude. The 24 hour increase in A wave amplitude by Eiiprodil treated rabbits (109% increase above vehicle) was proportionally greater than that seen in the B wave amplitude at this period Thus in this experiment Eiiprodil clearly improved the functional condition of the retina following an ischemic insult. The invention has been described by reference to certain μiefαied embodiments; however, it should be understood that it may be embodied in other specific forms or variations thereof without departing from its spirit or essential characteristics. The ernixx-iments described above are therefore considered to be illustrative in all respects and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description.

Claims: 71 Claims: 1. Use of a polyamine site antagonist for the manufacture of a medicament for treating ischemic disorders of the eye. 2. Use of Claim. 1, wherein the polyamine site antagonist is a compound of the formula: wherein: R, represents a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, an alkanoyloxy group having from 1 to 16 carbon atoms or a benzoyioxy group, or. when R 2 represents a hydroxyl or methoxy group in the 4-ρosition and R, represents a hydrogen atom. R, may also represent a hydroxymethyl group, a carbamoyl group or an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkoxy part R ; represents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group or an alkoxy group having from 1 to 4 carbon atoms. R j represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms. R 4 lepresαus an alkyl group having from 1 to 4 carbon atoms, in which case the compounds are in the (=>^thro form. or. when R, represents a hydrogen atom. R« may also represent a hydrogen atom, and R< represents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from I to 4 carbon atoms or a set of three methoxy groups in the 3-, 4- and 5-positions of the benzyl radical, and phaπnaceutically acceptable acid addition salts thereof. 3. Use of Claim 2, wherein the polyamine site an t agonist is selected from the group consisting of eiiprodil and ifenprodil. 4. Use of Claim 1, wherein the polyamine site antagonist is used in an amount between about 5 and about 500 mg on a daily basis. 5. use of Claim 4, wherein the polyamine site antagonist is used in an amount between about 5 and about 100 mg on a daily basis. 6. A composition for treating ischemic disorders of the eye comprising, a pharmaceutically effective amount of a polyamine site antagonist 7. The composition of Claim 6. wherein the polyamine site antagonist is a ∞mpound of the formula: wherein: R, represents a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, an alkanoyloxy group having from 1 to 16 carbon atoms or a benzoyloxy group, or. when R 2 represents a hydroxyl or methoxy group in the 4-position and Rj represents a hydrogen atom. R, may also represent a hydroxymethyl group, a carbamoyl group or an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkoxy part R : represents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group or an alkoxy group having from 1 to 4 carbon atoms. R, represents a hydrogen atom or an alkyl group having from I to 4 carbon atoms, ^ represents an aikyl group havmg J^ are in the (±><rythro form. or. when R, represents a hydrogen atom, R may also represent a hydrogen atom, and R« reprcseπis a hyctogm att ) n% a iialogm alkyl group having irom 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms or a set of three methoxy groups in the 3-, 4- and 5-positions of the benzyl radical, and pharmaceutically acceptable acid addition salts thereof 8. Thecomrxsm∞ ofClaim 7, wher^ from the group consisting of eiiprodil and tferrprodil. 9 - A method for treating ischemic disorders of the eye which comprises, administering to an affected person a pharmaceutical eff antagonist 10 • The method of Claim 9 wherein the polyamine site antagonist is a compound of the formula: wherein: R, represents a hydrogen atom, a halogen atom, a trifluoromethyl group, an aikyl group having from 1 to 4 carbon atoms, a hydroxyl group, an alkoxy group having from 1 to 4 carbon atoms, a benzyloxy group, an alkanoyloxy group having from 1 to 16 carbon atoms or a benzoyloxy group, or. when R 2 represents a hydroxyl or methoxy group in the 4-position and Rj represents a hydrogen atom, R, may also represent a hydroxymethyl group, a carbamoyl group or an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkoxy part R : represents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, a hydroxyl group or an alkoxy group having from 1 to 4 carbon atoms. R, represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms, R, represents an alkyl group having from 1 to 4 carbon atoms, in which case the compounds are in the (±}«rythro form. or. when Rj represents a hydrogen atom, R, may also represent a hydrogen atom, and R< 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 the 3-, 4- and 5-positions of the benzyl radical. and phaπnaceutically acceptable acid addition salts thereof. 11. The method of CIaim9.wherein the polyamine site antagonist is selected from the group ∞nsisting of eiiprodil and ifenprodil. 12. The method of Claim 9 , wherein the affected person is administered between about 0.1 and about 500 mg of the polyamine site antagonist on a daily basis. 13. The method of Claim 9 , wherein the affected person is adπrinistered between about 5 and about 100 mg of the polyamine site antagonist on a daily basis.

Inventors: DESANTIS LOUIS JR, KAPIN MICHAEL A, LANGER SALOMON, SCATTON BERNARD, DESANTIS, LOUIS, JR., KAPIN, MICHAEL, A., LANGER, SALOMON, SCATTON, BERNARD
Applicants: SYNTHELABO
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P27, A61P43, C07D211