Method for inhibiting loss of cognitive functions employing an ACE inhibitor

Claim 2

Use of an angiotensin converting enzyme inhibitor which is a phosphonate substituted amino or imino acid cr salt thereof for the preparation of a pharmaceutical drug for inhibiting loss of cog­nitive function in a mammalian species over a pro­longed period of time.

Claim 3

Use as defined in Claim 1 wherein said angiotensin converting enzyme inhibitor containing pharmaceutical drug is administered orally or par­enterally.

Claim 4

Use as defined in Claim 1 wherein said angiotensin converting enzyme inhibitor is admixed with a pharmaceutically acceptable carrier therefor.

Claim 5

Use as defined in Claim 1 wherein the angiotensin converting enzyme inhibitor has the formula and pharmaceutically acceptable salts thereof wherein: each R₈ is the same or different and is halogen or -Y-R₁₄; R₁₁ is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl; R₁₂ is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl or hydroxy; m is zero, one, two or three; p is one, two or three provided that p is more than one only if R₁₁ or R₁₂ is hydrogen, methyl, methoxy, chloro or fluoro; R₁₃ is hydrogen or lower alkyl of 1 to 4 carbons; Y is oxygen or sulfur. R₁₄ is lower alkyl of 1 to 4 carbons, or the R₁₄ groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent; R₁ is alkyl of 1 to 10 carbons, aminoalkyl, haloalkyl, wherein q is zero or an integer from 1 to 7 and R₁₁ and p are as defined above; R₁₉ and R₂₀ are independently selected from hydrogen, lower alkyl, halo substituted lower alkyl, wherein m, R₁₁, and p are as defined above; R₂ is hydrogen, lower alkyl, halo substituted lower alkyl, wherein r is an integer from 1 to 4; R₃ and R₆ are independently selected form hydrogen, lower alkyl, benzyl, benzhydryl, alkali metal or wherein R₁₅ is hydrogen, lower alkyl, cycloalkyl or phenyl, and R₁₆ is hydrogen, lower alkyl, lower alkoxy, phenyl, or R₁₅ and R₁₆ taken together are -(CH₂)₂-, -(CH₂)₃-, -CH=CH-, or R₁₇ is lower alkyl, benzyl, or phenethyl; and R₁₈ is hydrogen, lower alkyl, benzyl or phenethyl.

Claim 6

Use as defined in Claim 4 wherein in the compound employed R₄ is hydrogen, hydroxy, chloro, fluoro, lower alkyl of 1 to 4 carbons, cyclohexyl, amino, -O-lower alkyl wherein lower alkyl is of 1 to 4 carbons, 1- or 2-naphthyloxy, -S-lower alkyl wherein lower alkyl is of 1 to 4 carbons, or 1- or 2-naphthylthio; R₅ is -O-lower alkyl wherein lower alkyl is of 1 to 4 carbons, -S-lower alkyl wherein lower alkyl is of 1 to 4 carbons, R₇ is phenyl, 2-hydroxyphenyl, or 4-hydroxyphenyl; each R₈ is fluoro, chloro or -Y-R₁₄; Y is oxygen or sulfur; R₁₄ is lower alkyl of 1 to 4 carbons or the R₁₄ groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a methyl or dimethyl substituent; m is zero, one or two; R₁₁ is hydrogen, methyl, methoxy, methylthio, chloro, bromo, fluoro or hydroxy; R₂ is hydrogen, lower alkyl of 1 to 4 carbons, CF₃, or amino substituted lower alkyl of 1 to 4 carbons; R₁ is alkyl of 1 to 10 carbons, -(CH₂) q -cycloalkyl wherein cycloalkyl is of 5 or 6 carbons, wherein q is zero or an integer from 1 to 4 and R₁₁ is as defined above; R₁₉ and R₂₀ are independently selected from lower alkyl of 1 to 4 carbons or wherein q and R₁₁ are as defined above; R₃ and R₆ are independently selected from hydrogen, alkali metal salt, lower alkyl of 1 to 4 carbons, or R₁₅ is hydrogen, methyl or isopropyl; and R₁₆ is lower alkyl of 1 to 4 carbons or phenyl.

Claim 7

Use as defined in Claim 5 where­in the compound employed X is R₄ is hydrogen, cyclohexyl, lower alkoxy of 1 to 4 carbons, m is zero, one or two; R₁₁ is hydrogen, methyl, methoxy, methylthio, bromo, fluoro or hydroxy; Y is oxygen or sulfur; t is two or three; and R₆ is hydrogen, or an alkali metal salt, R₁ is R₂ is hydrogen or lower alkyl; and R₃ is hydrogen, alkali metal or phenylalkyl.

Claim 8

Use as defined in Claim 6 where in the compound employed R₁ is phenylalkyl or wherein R₁₉ is phenylalkyl and R₂₀ is phenyl; R₂ is hydrogen, methyl, or -(CH₂)₄-NH₂; and R₃ is hydrogen, phenylmethyl, or an alkali metal salt.

Claim 9

Use as defined in Claim 7 where in the compound employed R₁ is alkyl of 1 to 10 carbons.

Claim 10

Use as defined in Claim 8 where in the compound employed X is and R₄ is hydrogen.

Claim 11

Use as defined in Claim 6 where in the compound employed R₁ is phenylbutyl; R₂ is methyl; and R₃ and R₆ are an alkali metal salt.

Claim 12

Use as defined in Claim 6 where in the compound employed R₁ is R₂ is methyl; and R₃ and R₆ are an alkali metal salt.

Claim 13

Use as defined in Claim 9 where in the compound employed R₁ is R₂ is methyl; R₃ is ethyl; and R₆ is an alkali metal salt.

Claim 14

Use as defined in Claim 1 wherein said angiotensin converting enzyme inhibitor is (S)-1-[6-amino-2-[[hydroxy(4-­phenylbutyl phosphinyl]oxy]-1-oxohexyl]-L-­proline (SQ 29,852).

Claim 15

Use as defined in Claim 1 wherein said angiotensin converting enzyme inhibitor containing pharmaceutical drug is to be administered in the form of tablets, capsules or by injection.

Claim 16

Use as defined in Claim 1 wherein said angiotensin converting enzyme inhibitor is (S)-1-[6-amino-2-[[hydroxy(4-phenyl­butyl)phosphinyl]oxy]-1-oxohexyl-L-proline and the pharmaceutical drug containing the inhibitor is to be administered systemically in an amount of from about 0.1 to about 500 mg/l or 4 times a day.

Claim 17

Use of an angiotensin converting enzyme inhibitor which is a phosphonate substituted amino or imino acid or salt thereof for the preparation of a pharmaceutical drug for treating or delaying progression of Alzheimer's disease in a mammalian species.

Claim 18

Use of an angiotensin converting enzyme inhibitor which is a phosphonate substituted amino or imino acid or salt thereof for the preparation of a pharmaceutical drug for treating or delaying progression of Alzheimer's disease in a mammalian species.

Claim 19

Use according to any of Claims 1 to 15 wherein said angiotensin converting enzyme inhibitor containing drug is to be administered over a pro­longed period of treatment to inhibit loss of cog­nitive function during such period of treatment.

Claim 20

Use as defined in Claim 17 wherein the angiotensin converting enzyme inhibitor is (S)-1-[6-amino-2-[[hydroxy(4-phenyl­butyl)phosphinyl]oxy]-1-oxohexyl-L-proline.