WO1990006118A1 - Utilisation therapeutique de dihydropyrimidones et de derives de benzazepine et de benzothiazepine dans le disfonctionnement du nerf optique ou retinien - Google Patents

Utilisation therapeutique de dihydropyrimidones et de derives de benzazepine et de benzothiazepine dans le disfonctionnement du nerf optique ou retinien Download PDF

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WO1990006118A1
WO1990006118A1 PCT/US1989/005505 US8905505W WO9006118A1 WO 1990006118 A1 WO1990006118 A1 WO 1990006118A1 US 8905505 W US8905505 W US 8905505W WO 9006118 A1 WO9006118 A1 WO 9006118A1
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alkyl
aryl
hydrogen
cycloalkyl
alkoxy
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PCT/US1989/005505
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English (en)
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Craig E. Crosson
David E. Potter
Miguel A. Ondetti
David Floyd
Gunner Aberg
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Houston Biotechnology Incorporated
E.R. Squibb & Sons, Inc.
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Publication of WO1990006118A1 publication Critical patent/WO1990006118A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds

Definitions

  • the subject invention is drawn to the use of dihydropyrimidones and benzazepine and benzothiazepine derivatives as calcium channel antagonists in the treatment of retinal and optic nerve dysfunction.
  • Retinal vascular disease and ischemia are associated with malfunction of neuroendocrine regulation and autoregulation of the choroidal and retinal circulations, respectively. It has been postulated that excessive elevation of intracellular calcium (calcium overload) in retinal blood vessels and neurons may be involved in the pathogenesis of retinal vasculopathy, ischemia and ultimately, retinal damage.
  • Some specific pathologic events triggered by excess intracellular calcium ions include: generation of free radicals, activation of proteases, endonucleases and Upases, and interference with energy production in mitochondria.
  • Blood flow to the retina is supplied by two separate vascular systems: the retinal vessels supplying the inner retinal layers and choroidal vessels supplying the outer retinal layers.
  • the retinal vessels supplying the inner retinal layers
  • choroidal vessels supplying the outer retinal layers.
  • approximately 35% of the total retinal blood flow is derived from the retinal vessels, while 65% is from the choroidal vessels.
  • the choroidal blood flow is of greater magnitude, retinal ischemia is usually associated with a reduction of flow in the inner retinal vessels.
  • This greater propensity for ischemia in the inner retina may result from several factorsr (1) the high rate of choroidal blood flow over that required to meet the metabolic needs of the outer retina; (2) the large diameter capillaries in the choroid are less likely to be occluded by emboli; (3) the lack of anastomoses in the retinal vessels; and (4) the larger percentage of oxygen extracted from the retinal arterioles/capillaries (35%) as compared to the choroidal circulation (3-4%).
  • metabolic oxygen and carbon dioxide
  • myogenic and possibly local hormonal (paracrine and autocrine) factors are highly autoregulated by metabolic (oxygen and carbon dioxide), myogenic and possibly local hormonal (paracrine and autocrine) factors.
  • systemic and ocular disorders have been associated with ischemic conditions of the retina or optic nerve.
  • Ocular manifestations of systemic disorders include: diabetes, atherosclerosis, hyperlipidemia, and hypertension.
  • Specific ocular disorders include:
  • retinitis of AIDs macular degeneration, anterior ischemic optic neuropathy, ocular hypertension, glaucoma, retinopathy of prematurity, retinal vessel occlusion, diabetic retinopathy and hypertensive retinopathy.
  • edemic conditions of the retina or optic nerve are evidenced in diabetes, hypertension and cystoid macular edema. Newer evidence also suggests that excessive influx of calcium ions into vascular and neuronal tissue is a primary contributor to the pathogenesis of ischemic injury and the development of vascu-lopathy and neuropathy.
  • Desirable characteristics of such a bioassay are the use of relatively small animals with ocular vasculature and neural retina similar to that of humans, particularly rodentiae, which provides for constitutive retinal dysfunction or the ability to reproducibly induce such dysfunction, ease of access to the major arteries supplying the retina, ease of identifying the existence of the dysfunction and the effect of addition of a candidate compound on occurrence of such dysfunction or the effect on progression of such dysfunction.
  • Azaheterocycle calcium entry blockers are useful in the treatment of subjects, such as mammals, including man, suffering from ischemia or edema of the retina or optic nerve.
  • Such calcium entry blockers may be grouped as calcium channel antagonists and excitatory amino acid receptor antagonists.
  • Associated with retinal dysfunction are techniques for assessing neural retinal function. In addition, such compounds exhibit prophylactic effects in preventing such conditions. Methods are further provided for screening compounds associated with regulation of calcium channels by employing in vivo bioassays using rats with inducible retinal dysfunction. DESCRIPTION OF THE SPECIFIC EMBODIMENTS
  • dihydropyrimidones diphenylpiperazines, benzazepines and benzothiazepines derivatives.
  • the second category are excitatory amino acid antagonists, which include NMDA, quisqualate and kainate receptor antagonists.
  • nifedipine having the structural formula:
  • nimodipine having the structural formula:
  • nisoldipine having structural formula:
  • nitrendipine having structural formula:
  • dihydropyrimidones are those of the formula:
  • X is oxygen or sulfur
  • R' is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R' 1 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclo,
  • R' 2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
  • R' 3 is hydrogen, alkyl, cycloalkyl, aryl, heterocyclo, or halo substituted alkyl
  • R' 4 is aryl or heterocyclo
  • R' 5 and R' 6 are each independently hydrogen, alkyl
  • Y 1 is cycloalkyl, aryl, heterocyclo, hydroxyl, alkoxy, aryl —(CH 2 ) m —O— , mercapto, alkylthio,
  • Y 2 is cycloalkyl, aryl, heterocyclo, carbamoyl, (substituted amino)- —, carboxyl, alkoxycarbonyl, alkyl- —, aryl-(CH 2 ) m —C— or heterocyclo-(CH 2 )
  • Y 3 is hydroxyl, alkoxy, aryl—(CH 2 ) m —O—, mercapto, alkylthio, aryl—(CH 2 ) m —S—, alkyl- —O—, aryl-(CH 2 )m— —O—,
  • q O, 1, 2 or 3;
  • n O or an integer of 1 to 6;
  • n O or an integer of 1 to 5;
  • p is an integer of 1 to 5.
  • diphenylpiperazines of interest are cinnarizine and flunarizine, having structural formula:
  • the calcium entry blockers of this invention may include such calcium channel antagonists as phenylalkylamines, such as verapamil and adipamil, benzothiazepines, such as diltiazem, clentiazem and naltiazem and benzazepines.
  • phenylalkylamines such as verapamil and adipamil
  • benzothiazepines such as diltiazem, clentiazem and naltiazem and benzazepines.
  • Benzazepine and benzothiazepine derivatives of interest include those of the formula:
  • R 3 and R 4 are each independently hydrogen, halogen, alkyl, alkoxy, aryloxy, arylalkoxy, arylalkyl, cyano, hydroxy, alkanoyloxy,
  • n or n' are independently 0, 1, 2, or 3;
  • n 0, 1 or 2;
  • Y 1 and Y 2 are independently hydrogen or alkyl, Y 1 is hydrogen and Y 2 is alkenyl, alkynyl, aryl, heteroaryl, or cycloalkyl, or Y 1 and Y 2 together with the carbon atom to which they are attached are cycloalkyl;
  • Y 3 is hydrogen, alkyl, alkanoyl, alkenyl, arylcarbonyl, heteroarylcarbonyl, or - -NY 8 Y 9 ;
  • Y 4 and Y 5 are each independently hydrogen, alkyl, aryl or arylalkyl, provided that when both are present they are not both hydrogen, and provided further that when both are attached to the same carbon atom neither of them is hydrogen;
  • Y 6 and Y 7 are each independently hydrogen, alkyl, cycloalkyl or arylalkyl or Y 6 and Y 7 together with the nitrogen atom to which they are attached are azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl;
  • Y 8 and Y 9 are each independently hydrogen, alkyl, aryl or heteroaryl, or Y 8 and Y 9 together with the nitrogen atom to which they are attached are pyrrolidinyl, piperidinyl or morpholinyl;
  • Y 10 and Yii are each independently hydrogen, alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl, or - -NY 8 Y 9 ;
  • Y 12 is hydroxy, alkoxy, aryloxy, amino, alkylamino or dialkylamino
  • Y 13 is alkyl, alkoxy, or aryloxy
  • Y 14 is hydrogen, hydroxy, alkoxy, aryloxy or arylalkoxy.
  • alkyl and “alkoxy” refer to both straigh and branched chain groups. Those groups having 1 to 10 carbon atoms are preferred.
  • alkenyl refers to both straight and branched chain groups. Those groups having 2 to 10 carbon atoms are preferred.
  • aryl refers to phenyl and substituted phenyl.
  • exemplary substituted phenyl groups are phenyl groups substituted with 1, 2 or 3 amino (-NH 2 ), alkylamino, dialkylamino, nitro, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), alkylthio, (of 1 to 4 carbon atoms), alkanoyloxy, carbonyl, or carboxyl groups.
  • alkanoyl refers to groups having the formula alkyl- -. Those alkanoyl groups having 2 to 11 carbon atoms are preferred.
  • heteroaryl refers to an aromatic heterocyclic group having at least one heteroatom in the ring.
  • Preferred groups are pyridinyl, pyrrolyl, imidazolyl, furyl, thienyl, oxazolyl or thiazolyl.
  • cycloalkyl refers to groups having 3, 4, 5, 6 or 7 carbon atoms.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • fluoro substituted alkyl and “fluoro substituted alkoxy” refer to alkyl and alkoxy groups (as described above) in which one or more hydrogens have been replaced by fluorine atoms.
  • exemplary groups are trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, fluoromethoxy, difluoromethoxy, etc.
  • the compounds of formula I form acid-addition salts with inorganic and organic acids. These acid-addition salts frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble.
  • the free base may then be obtained by neutralization, e.g., with a base such as sodium hydroxide. Any other salt may then be formed from the free base and the appropriate inorganic or organic acid.
  • a base such as sodium hydroxide.
  • Any other salt may then be formed from the free base and the appropriate inorganic or organic acid.
  • the hydrohalides especially the hydrochloride and hydrobromide, sulfate, nitrate, phosphate, borate, acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, salicylate, methanesulfonate, benzenesulfonate, toluenesulfonate and the like.
  • the carbon atoms in the 3 and 4-positions of the benzazepine nucleus and, carbon atoms in the 2 and 3-positions of the benzothiazepine nucleus, of the compounds of the formula I are asymmetric carbons.
  • the compounds of formula I therefore, exist in enantiomeric and diastereomeric forms and as racemic mixtures thereof. All are within the scope of this invention. It is believed that those compounds of formula I which have the cis configuration are the most potent and are therefore preferred.
  • Calcium channel antagonists which may be employed in this invention are produced by conventional methods well known in the art.
  • benzothiazepine and benzazepine derivatives can be prepared from the corresponding compounds having the formula:
  • the compounds of formula II where R 1 is OH can be prepared in nonracemic form by reacting the racemic compound of formula II where R 1 is OH with a nonracemic acid or ammo acid H where Z and Z 1 are different using conventional acylation techniques such as carbodiimide with a catalyst such as
  • a compound of formula I can be prepared by reacting a compound of formula II with one of formula III under phase transfer conditions in a mixture of water and dichloromethane or toluene in the presence o an appropriate base (e.g., barium hydroxide or sodium hydroxide) and catalyst (e.g., benzyl trimethy1ammonium chloride or tetra-n-butylammonium hydrogen sulfate).
  • an appropriate base e.g., barium hydroxide or sodium hydroxide
  • catalyst e.g., benzyl trimethy1ammonium chloride or tetra-n-butylammonium hydrogen sulfate.
  • the products of formula I wherein R 1 is -OH can be alkylated or acylated (using conventional techniques) to obtain those products of formula I wherein
  • R 1 is -O-Y 3 and Y 3 is other than hydrogen.
  • a compound of formula Ii comprises treating a compound of formula Ii with an alkali metal hydride (e.g., sodium hydride) in an inert solvent (e.g., dimethylformamide or dimethylsulfoxide) followed by reaction with a compound of the formula:
  • an alkali metal hydride e.g., sodium hydride
  • an inert solvent e.g., dimethylformamide or dimethylsulfoxide
  • a compound of formula Il can be prepared by first treating a compound of formula Il with an alkali metal hydride (e.g., sodium hydride) in an inert organic solvent (e.g., dimethylformamide or dimethylsulfoxide) followed by reaction with the appropriate compound having the formula:
  • an alkali metal hydride e.g., sodium hydride
  • an inert organic solvent e.g., dimethylformamide or dimethylsulfoxide
  • an inert solvent e.g., a halogenated hydrocarbon
  • reduction e.g., using a chemical reducing agent such as dimethylsulfide
  • a compound of formula X can be treated with the appropriate amine having the formula:
  • a reducing agent e.g., hydrogen using a catalyst such as palladium on carbon, or a chemical reducing agent such as sodium cyanoborohydride
  • a reducing agent e.g., hydrogen using a catalyst such as palladium on carbon, or a chemical reducing agent such as sodium cyanoborohydride
  • Illustrative compounds within this invention are those wherein R 3 is located in the 6- or 7- position of the benzazepine nucleus or the 8- or 9- position of the benzothiazepine nucleus and is halogen, trifluoromethyl or methoxy; and R 4 is located in the 4-position of the phenyl ring to which it is attached and is alkoxy. Include herein are compounds wherein R 3 is 6-trifluoromethyl or 7-methoxy on the benzazepine nucleus, or 8-methoxy on the benzothiazepine nucleus, and R 4 is methoxy.
  • Excitatory amino acid receptor antagonists include MK-801, 2-APV and CNQX, having the structural formula:
  • the pharmaceutically acceptable salts of any of the above-designated compounds may be employed as the calcium entry blocker in accordance with the invention. Combinations of the aforementioned compounds may likewise be used.
  • Calcium entry blockers of this invention may be administered orally, parenterally or topically.
  • parenteral and/or topical administration is preferred in order to more rapidly introduce the calcium entry blocker to the target site.
  • oral administration is normally preferred since it is more easily administered.
  • the compounds for use in this invention are administered in their pure form or in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient (depending on the desired administration).
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient (depending on the desired administration).
  • the pharmaceutical preparations may thus be administered as a solid, semi-solid, lyophilized powder, liquid dosage form, tablets, pills, capsules, powders, solutions, suspensions, emulsions, creams, lotions, ointments, or granules, as well as injectable solutions.
  • the nature of the composition in the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration.
  • examples of appropriate pharmaceutical carriers or diluents include for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, olive oil, syrup, cottonseed oil, peanut oil, sesame oil, parafins and mixtures thereof with water; and for solid systems, lactose, kaolin, mannitol, sucrose, gelatin and agar.
  • the pharmaceutical compositions may include other medicinal agents, pharmaceutical agents, adjuvants, stabilizers, anti-oxidents, preservatives, lubricants, suspending agents, and viscosity modifiers, etc.
  • the dosage level of the calcium entry blocker within this invention is dependent upon the conditions of the disease to be treated, the administration route employed, the subject and the pharmacokinetic and pharmacodynamic characteristics of the active ingredient.
  • the dosage of the active ingredient is generally within the range from about 0.1 to about 100 mg/kg administered orally, parenterally or topically.
  • the physiological pH is generally in the range of about pH 6.5 to 8.
  • Specific compounds for treating retinal dysfunction are provided associated with modulation of calcium channel activity and/or the activation of excitatory amino acid receptors.
  • calcium channel antagonists or other compounds having equivalent effect can be used in the treatment of retinal vasculopathy.
  • SS rats Dahl salt-sensitive rats which are available from Harlan Sprague-Dawley.
  • the rats will generally be in the age group of three to twenty weeks, usually in the age group of four to twelve weeks. When placed on a high salt diet, the animals rapidly develop (2-4 weeks) a systemic hypertension.
  • Other rats which may be used are normal Sprague-Dawley (albino) rats, Long-Evans pigmented rats or spontaneously hypertensive (SHR) (albino) rats.
  • All of these rats may be employed as models by creation of acute retinal ischemia in their eyes.
  • the ischemia may be created by reversibly occluding the short posterior ciliary arteries and the central retinal artery. Electroretmograms are recorded prior to, during and after occlusion. The occlusion is reversed after a brief period, usually one minute to three hours, preferably five minutes to two hours and reperfusion occurs. During reperfusion ERGs are taken to provide an index of retinal function, followed by a histologic examination to determine changes in normal retinal structure.
  • Ophthalmoscopic examination of the eyes is also performed to document the absence of retinal blood flow and gross ischemic damage.
  • Drug efficacy is related to the ability of the candidate composition to reduce or prevent pathologic changes noted in ERG and histologic examinations.
  • the eyes may be fixed by cardiac perfusion with a fixative, such as a combination of paraformaldehyde and glutaraldehyde in an appropriate buffer.
  • a fixative such as a combination of paraformaldehyde and glutaraldehyde in an appropriate buffer.
  • the globe may be opened at the ora serrata and fixation continued for four to twenty-four hours. Segments of the central and peripheral retinal are then dissected free, the tissue washed and then post fixed in an appropriate fixative, e.g., osmium tetroxide. Following dehydration, the sample may be sectioned in accordance with conventional techniques for light and electron microscopy.
  • Changes in thickness on the retinal layer or number of cell bodies per unit area in the inner and outer nuclear layers may then be observed and reported.
  • the retinas may be reported as "normal”, if all layers are intact with no abnormalities; “mild degeneration”, if thinning of the inner and outer segments or visible reduction in cell bodies of the inner and outer nuclear layers has occurred; and “severe degeneration”, if extensive loss of any individual or multiple layers of the retina has occurred.
  • an electroretinogram may be employed.
  • Functional assessment of the inner and outer layers of the neural retina and the non-neural retina (RPE) is made by means of full field ERGs.
  • the wave forms of the ERG result from the electrophysiological processes involved in visual transduction in the retina. Reduction in these waves provides a direct measurement of retinal function.
  • the initial negative deflection, termed the "a-wave” originates in the photoreceptors.
  • the subsequent b-wave is produced by the Muller and bipolar cells from the inner retina.
  • the much slower positive c-wave arises from the RPE but is generally reduced or absent in adult albino rats.
  • the photoreceptors and RPE are nourished by the choroidal circulation
  • the Muller and bipolar cells are nourished primarily by the retinal vessels.
  • An initial indication as to the site of retinal ischemia may be related to selective reductions in the individual wave forms.
  • Base-line ERGs may be obtained prior to induction of retinal ischemia. Thereafter, ERGs are determined at convenient intervals, e.g. hourly, daily or weekly. These subsequent ERGs are then normalized to preischemic values and are expressed as the percent of control (i.e.
  • Rats Prior to dark adaptation, the rat host receives an ophthalmoscopic examination to ensure the absence of cataracts or other gross abnormalities. Since rats are primarily a rod-dominated (98%) animal, ERGs are performed under dark-adapted conditions (12-14 hours). Rats are anesthetized and placed on a heating pad to maintain normal body temperature.
  • ERGs small agar-Ag/AgCl electrodes are placed on the cornea and tongue.
  • a reference ground electrode is placed under the scalp.
  • ERG signals may be amplified by an appropriate differential amplifier and recorded.
  • Light stimulation is provided by an appropriate photostimulator in conjunction with a series of neutral density filters.
  • Single flash (10 ⁇ sec duration) of white light is used to generate individual ERGs.
  • the amplitude of the b-waves is measured from base line to peak in the absence of an a-wave or from the trough of the a-wave to the peak of the b-wave.
  • a-Waves are measured form the base line to the peak of the a-wave.
  • the time interval from the onset of the flash to the peak of the a- and b-waves is used for measurements of latency.
  • Group data are compared by means of a two-way analysis of variance. Comparisons involving two means employ Students t-test for non-paired data. Differences between groups (control vs. drug-treated) are regarded as significant if P-values are ⁇ 0.05.
  • the following examples are offered by way of illustration and not by way of limitation.
  • the methodology involves the creation of acute retinal ischemia in the eyes of normal Sprague-Dawley (albino) or Long-Evans (pigmented) rats, which are available from Harlan Sprague-Dawley.
  • Adult rats were used, ranging in weight from 175 g to 250 g. These rats were housed under normal conditions and fed standard rat chow. Rats were anesthetized with 50 mg/kg sodium pentobarbital intraperitoneally (i.p.) and the iris of th eye dilated with one drop of 10% atropine solution.
  • Total retinal ischemia in these animals was created by reversibly occluding the short posterior ciliary arteries and the central retinal artery.
  • the duration of the occulsions varied from five to 120 minutes. Prior to the occlusion, baseline ERGs were recorded and used as an index of normal retinal function. Complete retinal occlusion was determined by the absence of ERG. At the end of the occlusion period, the retina was allowed to reperfuse, and changes in normal retinal structure and function determined by histological observations and ERGs. During the reperfusion period, ERGs were evaluated at one to two minute intervals for the first 30 minutes and thereafter at ten minute intervals through 120 minutes. Additional, ERG evaluations in selected animals were made at 24 hours.
  • Drug efficacy was based on the ability of a compound to minimize or prevent the pathologic changes in retinal structure and/or function induced by acute retinal ischemia (e.g. the appearance of necrotic cells within the retina or a significant reduction or loss of normal wave forms in the ERG. )
  • Example 1 illustrates an in vivo bioassay which can be employed for determining the efficacy of compounds in the treatment of retinal dysfunction.
  • Examples 2-4 conducted in accordance with the procedure of Example 1, demonstrate that pretreatment with Ca ++ channel antagonists can protect retinal function (as measured by ERG recovery) from ischemic injury. Values are means ⁇ standard errors and "have been normalized (0-100%) to preocclusion control values. At each time point tested, significant improvement in b-wave recovery when compared to control-treated animals is exhibited.
  • Example 5 is drawn to the use of an excitatory amino acid antagonist.
  • the subject invention provides for retinal degeneration models as evidenced by both structural and functional changes. Associated with the retinal dysfunction and/or degeneration is a dramatic reduction in retinal perfusion. These rats are therefore good models for screening compounds having activities as calcium channel antagonists or excitatory amino acid antagonists and their use in preventing or ameliorating retinal degeneration.
  • the initial appearance of the b-wave also occurred at 16 to 22 minutes of reperfusion, but the magnitude of the a-wave recovery at 90 minutes and 24 hours was 61% and 100% of control levels (as compared to 26% and 40%, respectively, for the 30 minute occlusion). These data indicate that total retinal ischemia for 30 minutes results in the partial loss of retinal function. This loss appears to be permanent, as the b-wave recovery was only 40% of control values after 24 hours of reperfusion. The rapid return of the a-wave and gradual return of the b-wave indicates that the primary site of acute retina ischemic injury is the inner retinal layer.
  • Table I shows the effect of nifedipine i.p. on b-wave recovery following 30 minutes of total retinal ischemia (*P ⁇ 0.05).
  • the ability of the 3.3 mg/kg dose to provide apparently better protection of retinal function than the 10 and 33 mg/kg dose likely reflects cardiovascular side effects of nifedipine, as significantly greater reductions in heart rate and blood pressure were observed in these animals.
  • the resulting dose-related reduction in cardiac output and peripheral vasodilation likely reduces retinal perfusion in the ischemic eye and reduces functional recovery (e.g. ERG's) of the retina.
  • Chick retinas were isolated from a day 14 embryo. Isolated retinas were then incubated for 40 or 60 minutes in a control Ringer's solution (5 mM glucose under an atmosphere of 95% air, 5% CO 2 ) or in a test Ringer's solution (0 mM glucose under an atmosphere of 95% N 2 , 5% CO 2 ).
  • the NMDA antagonist, MK 801 (10 -6 to 10 -4 M) was added to retinas incubated in the test Ringer's solution. At the end of the incubation period retinas were fixed in 4% paraformaldehyde, dehydrated in ethanol and embedded in paraffin. Thick (4 ⁇ m) cross-section of the retina were then cut, stained with haematoxylin and eosin, and evaluated by light microscopy to determine the degree of retinal degeneration.
  • Control retinas i.e. incubate in Ringer's with glucose under 95% air
  • Retinas incubated in the test Ringer's solution showed signs of cellular degeneration in the ganglionic and inner plexiform layers and edema in the inner nuclear, outer plexiform and inner plexiform layers.
  • the administration of 10 -6 M to 10 -4 M MK 801 to retinas incubated in test Ringer's caused a dose related improvement in these structural integrity of the retina, with all layers present in the MK 801-treated retinas, when compared to nontreated retinas.
  • the edema noted in retinas incubated in the test Ringer's was reduced by the administration of MK 801.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'ischémie ou l'÷dème de la rétine ou du nerf optique se traduit par un disfonctionnement rétinien. Ce disfonctionnement rétinien peut être associé à l'activation des canaux de calcium. L'administration prophylactique ou thérapeutique de composés permettant d'arrêter ces processus peut améliorer ou prévenir le disfonctionnement rétinien. Ces composés comprennent les dihydropyrimidones, des classes de dérivés de benzazépine et de benzothiazapine sélectionnés parmi des antagonistes des canaux de calcium. Le traitement thérapeutique est effectué avec des composés comprenant lesdits hydropyrimidones et les dérivés de benzazépines et de benzothiazépine en tant qu'antagonistes des canaux de calcium. De tels composés ont un effet prophylactique contre l'ischémie et l'÷dème de la rétine et du nerf optique.
PCT/US1989/005505 1988-12-05 1989-12-05 Utilisation therapeutique de dihydropyrimidones et de derives de benzazepine et de benzothiazepine dans le disfonctionnement du nerf optique ou retinien WO1990006118A1 (fr)

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PCT/US1989/005487 WO1990006123A1 (fr) 1988-12-05 1989-12-05 Utilisation therapeutique d'agents bloquant l'entree de calcium dans le dysfonctionnement du nerf retinie ou optique

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Cited By (7)

* Cited by examiner, † Cited by third party
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WO1998050065A2 (fr) * 1997-05-05 1998-11-12 Marion Sangster Eckmiller Utilisation de principes actifs a effet biologique pour influer sur l'espace extracellulaire de cellules sensorielles et procede de commande d'administration de principe actif et dispositif approprie
WO1999025350A1 (fr) * 1997-11-14 1999-05-27 Alcon Laboratories, Inc. Traitement de la retinopathie diabetique
US6037354A (en) * 1997-06-18 2000-03-14 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
EP0986553A1 (fr) * 1997-02-04 2000-03-22 Bristol-Myers Squibb Company Derives de dihydropyrimidone comme antagonistes du neuropeptide y (npy)
EP0994709A1 (fr) * 1997-06-30 2000-04-26 Evan B. Dreyer Antagonistes du calcium servant a traiter la vitreoretinopathie proliferative
US8557855B2 (en) * 2002-07-03 2013-10-15 Allergan, Inc. Methods of using ryanodine antagonists in treating neural injury
US10111873B1 (en) 2018-01-17 2018-10-30 King Saud University Dihydropyrimidinone derivatives

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US5525601A (en) * 1990-09-07 1996-06-11 Universidad De Alicante Composition for treating ocular pain
ATE129890T1 (de) * 1990-09-07 1995-11-15 Univ Alicante Komposition für die behandlung von augenschmerzen.
ES2224597T3 (es) 1998-01-29 2005-03-01 Akzo Nobel N.V. Agentes que mejoran la circulacion optica papilar.
BR9914254A (pt) 1998-10-02 2001-07-03 Sucampo Ag Composição para o tratamento de doença de degeneração retinal lesada por luz
FR2784030B1 (fr) 1998-10-02 2002-12-20 Inst Nat Sante Rech Med Utilisation de bloqueurs des canaux calciques et/ou cgmp-dependants pour le traitement de pathologies de la retine

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AM J CARDIOL 1987; 59: 11B-23B, GODFRAIND, THEPHILE, "Classification of calcium Antagonists". See page 12B, table 1 and page 13B, figure 2. *
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0986553A1 (fr) * 1997-02-04 2000-03-22 Bristol-Myers Squibb Company Derives de dihydropyrimidone comme antagonistes du neuropeptide y (npy)
EP0986553A4 (fr) * 1997-02-04 2000-12-27 Bristol Myers Squibb Co Derives de dihydropyrimidone comme antagonistes du neuropeptide y (npy)
WO1998050065A3 (fr) * 1997-05-05 1999-06-10 Marion Sangster Eckmiller Utilisation de principes actifs a effet biologique pour influer sur l'espace extracellulaire de cellules sensorielles et procede de commande d'administration de principe actif et dispositif approprie
WO1998050065A2 (fr) * 1997-05-05 1998-11-12 Marion Sangster Eckmiller Utilisation de principes actifs a effet biologique pour influer sur l'espace extracellulaire de cellules sensorielles et procede de commande d'administration de principe actif et dispositif approprie
US6037354A (en) * 1997-06-18 2000-03-14 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
US6255315B1 (en) 1997-06-18 2001-07-03 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
EP0994709A1 (fr) * 1997-06-30 2000-04-26 Evan B. Dreyer Antagonistes du calcium servant a traiter la vitreoretinopathie proliferative
EP0994709A4 (fr) * 1997-06-30 2006-02-01 Allergan Inc Antagonistes du calcium servant a traiter la vitreoretinopathie proliferative
US7230032B2 (en) 1997-06-30 2007-06-12 Allergan, Inc. Calcium blockers to treat proliferative vitreoretinopathy
US8101635B2 (en) 1997-06-30 2012-01-24 Allergan, Inc. Calcium blockers to treat proliferative vitreoretinopathy
WO1999025350A1 (fr) * 1997-11-14 1999-05-27 Alcon Laboratories, Inc. Traitement de la retinopathie diabetique
US8557855B2 (en) * 2002-07-03 2013-10-15 Allergan, Inc. Methods of using ryanodine antagonists in treating neural injury
US10111873B1 (en) 2018-01-17 2018-10-30 King Saud University Dihydropyrimidinone derivatives

Also Published As

Publication number Publication date
AU4754790A (en) 1990-06-26
CA2004617A1 (fr) 1990-06-05
CA2004616A1 (fr) 1990-06-05
AU4807790A (en) 1990-06-26
WO1990006123A1 (fr) 1990-06-14

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