Europaisches Patentamt ® European Patent Office @ Publication number: 0 220 107 Office europeen des brevets A2

EUROPEAN PATENT APPLICATION

(§) Application number: 86402219.9 © Int.CI.": A 61 K 31/47 A 61 K 31/55, A 61 K 31/505, © Date of filing: 07.10.86 A 61 K 31/195, A 61 K 31/66, A 61 K 31/40, A 61 K 31/495, A 61 K 31/405

® Priority: 09.10.85 US 785925 © Applicant: MERCK & CO. INC. 126, East Lincoln Avenue P.O. Box 2000 @ Date of publication of application : Rahway New Jersey 07065 (US) 29.04.87 Bulletin 87/18 @ Inventor: Veber, Daniel F. Designated Contracting States: 290 Batleson Road CH DE FR GB IT LI NL Ambler Pennsylvania 19002 (US) Baldwin, John J. 621 Gypsy Hill Circle Gwynedd Valley Pennsylvania 19437 (US)

@ Representative: Warcoin, Jacques et al Cabinet Regimbeau 26, avenue Kleber F-75116 Paris (FR)

The title of the invention has been amended (Guidelines for Examination in the EPO. A-lll, 7.3). @ Use of -convertlng enzyme inhibitors in macular degeneration. @ Angiotensin converting enzyme inhibitors are useful in the treatment of senile macular degeneration.

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Bundesdruckerei Berlin 0 220 107

Description

ACE INHIBITORS IN MACULAR DEGENERATION

SUMMAHY OF THE INVENTION 5 This invention is concerned with the use of angiotensin converting enzyme (ACE) inhibitors in the treatment of senile macular degeneration, a leading cause of visual diminution in the elderly BACKGROUND OF THE INVENTION Senile macular degeneration is a poorly characterized disease state of the elderly which appears to result 10 from a poor blood supply to the macular region of the eye. As a result, vision is lost in the central region of the eye while partial peripheral vision is retained. The disease progresses with increased vision loss, one eye at a time. Until the present invention, there was no known treatment of the disease or its symptoms although vasodilators and antihypercholesterolemics have been tried without success. Experience with ACE inhibitors as antihypertensive agents has shown a tendency for them to accumulate in 15 the eye resulting in unexpectedly high concentrations in ocular tissue [Igic et ai., Exp. Eye Res. 30, 299 (I980)]. These high concentrations result in selective ocular vasodilation thereby increasing local blood flow to the otherwise ischemic tissue thus preventing damage to the eye. It is therefore an object of this invention to provide a novel method of treating senile macular degeneration by the administration of an ACE inhibitor. 20 it is a further object of this invention to provide pharmaceutical formulations comprising an ACE inhibitor as an active ingredient for use in the novel method of treatment.

DETAILED DESCRIPTION OF THE INVENTION The novel method of treatment of senile macular degeneration of this invention comprises the 25 administration to a patient in need of such treatment of an effective amount of an angiotensin converting enzyme inhibitor. The angiotensin converting enzyme inhibitor useful as the active ingredient in the novel method of treatment and pharmaceutical formulations of this invention is selected from: , , , , ranipril, , , , pentopril, cilazaprii, pivopril, fosenopril, indolapril, indalapril, 30 phenacein, fentiapril, alacepril, perindopril, murgenic acid, ancovenin, CI 925, CGS 14824a, CGS 14831, WY 44221, CI 928, SQ 28853, SQ 27786, CGS 16617, MC 838, K 26. The company codes used above serve to identify the compounds designated in the following table: vVi»K»P4ijr ^uuc ^nemicai name

CI-925 2-[2-[ [l-(l-(ethoxycarbonyl)-3- phenylpropyl]amino]-l-oxopropyl-6,7-

dimethoxy-1 , 2 , 3 , 4-tet rahydro-3- isoquinolinecarboxylic acid.

CGS-14824a 3-[ [l-ethoxycarbonyl-3-phenyl-(lS> propyl] amino] -2,3/4, 5-tetrahydro-2- oxo-l-(3S)-benzazepine-l-acetic acid HC1.

CGS-14831 3- t I l-carboxylate-3-phenyl-l(S) -pro- pyl] amino] -2,3,4, 5-tet rahydro-2-oxo- l(3S)-benzazepine-l-acetic acid HC1.

:i~928 2t2-[[l-carbonyl-3-phenylpropyl]- amino] -1-oxopropyl] -1 , 2 , 3 , 4-tet ra- hydro-3-isoquinoline-carboxylic acid.

3Q-28853 [l-(S)-4S]-4-[ [2-[6-

&U-2//B6 il-(S)-4S]-4-[4-[6-(aminosulfonyl)- 7-chloro-l , 2,3, 4-tetrahydro-4-oxo-2- quinazolinyl]phenoxy]-l-(3-mercapto- 2-methyl-l-oxopropyl)-L-proline.

Calcium N-[(S)-3-(N-cyclohexane- carbonyl-D-alanylthio)-2-methylpro- panoyl]-L-prolinate.

MeCO-Ile-Tyr-NH-CH-PO(OH) 2

wy-44221 (-)-(S)-l-[ (S) -3-mercaptc~2-methyl- 1-oxopropyl] indoline-2-carboxylic acid.

CGS-16617 3-[(5-amino-l-carboxy-lS-pentyl)- amino] -2,3,4, 5-tetrahydro-2-oxo-3S- lH-l-benzazepine-l-acetic acid.

The preferred inhibitors are captopril, disclosed in U.S. Patent 4,046,889, enalapril, enalaprilat or lisinapril disclosed in U.S. Patent 4,374,829, which patents are incorporated herein by reference. The route of administration can be orally; parenteral injection, for example intravenously, intramuscularly or subcutaneously; or transdermally. An effective amount of angiotensin converting enzyme inhibitor in the novel method of treatment of this nvention is the same as the effective amount normally employed for the treatment of hypertension, i.e. about ).l mg to about I g and preferably about 5 to 500 mg per day. The dosage regimen can be one to four times a Jay depending on the daily total required and the unit dosage. The novel pharmaceutical formulations of this invention for oral administration can be in the form of tablets in ;ombination with other compounding ingredients customarily used, such as, talc, vegetable oils, polyols, jenzylalcohols, gums, gelatins, starches or other carriers; dissolved, dispersed or emulsified in a suitable iquid carrier; or in capsules in a suitable encapsulating material. For transdermal administration, the active ngredient can be in the form of an ointment, a gel, a solution, suspension or emulsion in a suitable vehicle or in he form of a patch. For parenteral administration the active ingredient may be dissolved, dispersed, suspended or emulsified with an appropriate injectable vehicle. A further object of the present invention is the jse of an angiotesin converting enzyme inhibitor as listed above for the manufacture of a pharmaceutical ;omposition useful for the treatment of senile macular degeneration. 0 220 107

Pry Fiueo capsule

Per Capsule

cnaiaprn 50 mg

149 mg

nagnesium bcearate

capsule (size no. l) 200 mg

■ ne it. uve oompouna is reaucea to a no. wj Kowaer and then lactose and magnesium stearate are passed through a No. 60 bolting cloth onto the powder and the combined ingredients are mixed for 10 minutes and filled into the No. I dry gelatin capsule. Any of the other ACE inhibitors can be substituted for enalapril in the above Example I. -AfAiyiri_c: c

« lypi^ci wuiei domains capiopni izo mgj, pregeiatinized starch USP (82 mg), microcrystalline cellulose (82 rig) and magnesium stearate (I mg). In like manner, for example, N-(l(S)-carboxy-3-phenylpropyl)-L-lysyl-L- jroline (20 mg) may be formulated in place of N-(l(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline with he composition of pregeiatinized starch, microcrystalline cellulose and magnesium stearate described above. Any of the other ACE inhibitors can be substituted for captopril in the above Example 2.

n ly^ai iiijei;iiiuie lormuiaxion contains enaiapniat (o.4k! mg), sodium phosphate diabasic anhydrous (li.4 ng), benzyl alcohol (0.01 ml), and water for injection (1.0 ml). Similarly, this formulation can be Prepared smploying, for example, N-(l(S)-carboxy-3-phenyfpropyl)-L-lysyl-L-proline in place of N-(l(S)-ethoxycarbonyl- l-phenylpropyl)-L-alanyl-L-proline.

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1. « pndrmaceuucai composition userui tor the treatment of senile macular degeneration which lomprises, as an active substance, an angiotensin converting enzyme inhibitor which is selected from : malapril, enalaprilat, lisinopril, captopril, ranipril, perindopril, zofenopril, quinapril, pentopril, , •ivopril, fosenopril, indolapril, indaiapril, phenacein, fentiapril, alacepril, perindopril, murgenic acid Jicovenin, CI 925, CGS 14824a, CGS 14831, WY 44221, CI 928, SQ 28853, SQ 27786, CGS 16617 MC 838 K 6. 2. Ihe pharmaceutical composition of Claim I wherein the angiotensin converting enzyme inhibitor is nalapril. 3. The pharmaceutical composition of Claim I wherein the angiotensin converting enzyme inhibitor is sinopril. 4. The pharmaceutical composition of Claim I wherein the angiotensin converting enzyme inhibitor is nalaprilat. 5. The pharmaceutical composition of Claim I wherein the angiotensin converting enzyme inhibitor is aptopril. 6. The pharmaceutical composition of Claims 1-5, which comprises an appropriate vehicle for an oral a ansdermal or a parenteral administration. 7. Use of an angiotensin converting enzyme inhibitor as listed in claim I for the manufacture of a harmaceutical composition useful for the treatment of senile macular degeneration.