Methods to treat alzheimer's disease

• US 20020019403A1
• Filed: 03/23/2001
• Published: 02/14/2002
• Est. Priority Date: 03/23/2000
• Status: Active Grant

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Tung, Jay, John, Varghese, Gailunas, Andrea, Fang, Lawrence Y., Hom, Roy, Mamo, Shumeye S.
• Granted Patent: US 7,119,085 B2
• Time in Patent Office: Days
• US Class Current: 514/256
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 271/14 to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 271/18 to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07D 261/20 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 307/14 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/33 in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 307/52 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07K 5/0207 containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link

Abstract

The present invention is directed toward substituted hydroxyethylene compounds of formula (XII)

useful in treating Alzheimer'"'"'s disease and other similar diseases.

Claims

1. A method for inhibiting β

-secretase activity, comprising exposing said β

-secretase to an effective inhibitory amount of a hydroxyethylene compound of the formula

5. A method for inhibiting β

-secretase activity according to claim 1 where R₁ is;

—

CH₂—

(R_1-aryl) where R_1-aryl is phenyl.

6. A method for inhibiting β

-secretase activity according to claim 5 where R₁ is;

—

CH₂-(Rawyi) where RIaryi is phenyl substituted with two —

F.

7. A method for inhibiting β

-secretase activity according to claim 6 where phenyl is substituted with two —

F in the 3- and 5-positions giving 3,5-difluorophenyl.

8. A method for inhibiting β

-secretase activity according to claim 1 where R₂ is;

(I) —

H,

(II) C₁-C₆ alkyl, or

(III) —

(CH₂)_0-4-R_2-1 where R_2-1 is R_1-aryl.

9. A method for inhibiting β

-secretase activity according to claim 1 where R₂ is;

(II) C -C₆ alkyl, or

(III) benzyl.

10. A method for inhibiting β

-secretase activity according to claim 1 where R_N is

R_N-1-X_N- where X_N is —

CO—

, where R_N-, is R_N-aryl where R_N-aryl is phenyl substituted with one —

CO—

NR_N-2R_N-3 where the substitution on phenyl is 1,3-.

11. A method for inhibiting β

-secretase activity according to claim 1 where R_N-2 and R_N-3 are the same and are C₃ alkyl.

12. A method for inhibiting β

-secretase activity according to claim 1 where R_N is

R_N-1-X_N- where X_N is —

CO—

, where R_N-, is R_N-aryl where R_N aryl is phenyl substituted with one Cl alkyl and with one —

CO—

NR_N-2R_N-3 where the substitution on the phenyl is 1,3,5-.

13. A method for inhibiting β

-secretase activity according to claim 12 where R_N-2 and R_N-3 are the same and are C₃ alkyl.

14. A method for inhibiting β

-secretase activity according to claim 1 where R_N is

R_N-1-X_N- where X_N is —

CO—

, where R_N-1 is R_N-heteroaryl where R_N-heteroaryl is substituted with one —

CO—

NR_N-2R_N-3.

15. A method for inhibiting β

-secretase activity according to claim 1 where R_N-2 and R_N-3 are the same and are -C₃ alkyl.

16. A method for inhibiting β

-secretase activity according to claim 1 where R_N is;

A-X_N- where X_N is —

CO—

, where A is;

(C) C₁₀H₇-CH(OH)—

, or

(D) t-butoxy.

17. A method for inhibiting β

-secretase activity according to claim 1 where R_C is;

(V) -(CR_C-xR_C-y)_0-4-R_C-aryl,

(VI) —

(CH₂)_0-4-R_C-heteroaryl,

(VII) —

(CH₂)_0-4-R_{C-heterocycle},

(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one or two;

(A) C₁-C₃ alkyl,

(B) —

CF₃,

(C) —

F, Cl, —

Br or —

I,

(D) C₁-C₃ alkoxy,

(E) —

OCF₃, or

(XVIII) —

H.

18. A method for inhibiting β

-secretase activity according to claim 17 where R_C is;

(V) -(CR_C-xR_C-y0-4-R_C-aryl where R_C-aryl is phenyl.

19. A method for inhibiting β

-secretase activity according to claim 18 where phenyl substituted in the 3-position or 3,5-positions.

20. A method for inhibiting β

-secretase activity according to claim 17 where R_C is;

(VI) —

CH₂-R_C-heteroaryl,

21. A method for inhibiting β

-secretase activity according to claim 17 where R_C is;

(VII) -CH₂-R_{C-heterocycle}.

22. A method for inhibiting β

-secretase activity according to claim 17 where R_C is;

(X) -cyclohexyl ring fused to a phenyl ring.

24. A method for inhibiting β

-secretase activity according to claim 1 where R_C is;

(I) -(C₁-C₁₀)alkyl-K where K is H, carboxyl, carboxyl methyl ester, amino unsubstituted or substituted with C₁-C₆ alkyl,

(II) a benzy] or phenylpropyl group substituted with a carboxyl group,

(III) —

(CH₂)_0-3-(C₃-C₇) cycloalkyl where cycloalkyl is cyclohexyl, cyclohexyl substituted with 1 or 2 carboxyl groups, or cyclohexyl substituted with 1 or 2 alkoxy groups,

(V) —

(CH₂)_0-4-phenyl substituted or unsubstituted with F,

(VI) —

(CH₂)_0-4-heteroaryl, or

(VII) selected from —

(CH₂)_0-4-morpholinyl and —

(CH₂)_0-4-tetrahydrofuryl.

25. A method for inhibiting β

-secretase activity according to claim 1 where R_C is;

(I) C₅HIo-K or C₇HU₄-K where K is carboxyl or carboxyl methyl ester,

(II) a benzyl or phenylpropyl group substituted with a carboxyl group at the 5-position, or

(III) a cyclohexyl ring substituted at the 3- and 5- positions or at the 4-position with a carboxyl group.

26. A method for inhibiting β

-secretase activity according to claim 1 where R₁ is;

(I) C₁-C₅ alkyl,

(II) —

(CH₂)_1-2-S—

CH₃,

(IV) C₁-C₅ alkenyl,

(V) —

(CH₂)_0-3-(R_1-aryl) where R_1-aryl is as defined above, and

(VI) —

(CH₂) _0-3-(R_1-heteroaryl) where R_1-heteroaryl is as defined above,

wherein any of the above are unsubstituted or substituted with up to two C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, or —

CF₃;

where R₂ is;

(1) —

H,

(II) C₁-C₆ alkyl, or

(III) —

(CH₂)_0-3-R_2-1 where R_2-1 is (C₃-C₆)cycloalkyl, R_1-aryl or R_1-heteroaryl where R_1-aryl is a 5 or 6-membered aryl group and R_1-heteroaryl is as defined above;

where R_N is;

(II) A-X_N- where X_N is —

CO—

,

wherein A is

(A) TE(Q)m′

,

(1) where -T is

where

(a) x=1 when y=1 and x=2 when y=0,

(b) m is 0, 1, 2 or 3,

(c) the values of x and y vary independently on each carbon when m is 2 and 3, and

(d) R′

″

varies independently on each carbon and is H, (C₁-C₂) alkyl, phenyl, or phenyl(C₁-C₃)alkyl;

(2) -E is

(a) C₁-C₅ alkyl, but only if m′

does not equal 0,

(b) methylthioxy(C₂-C₄)alkyl,

(c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,

(d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,

(e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms,

(f) biphenyl,

(g) diphenyl ether,

(h) diphenylketone,

(i) phenyl(C₁-C₈)alkyloxyphenyl, or

(j) C₁-C₆ alkoxy;

(3) is

(a) C₁-C₃ alkyl,

(b) C₁-C₃ alkoxy,

(c) C₁-C₃ alkylthioxy,

(d) C₁-C₆ alkylacylamino,

(e) C₁-C₆ alkylacyloxy,

(f) amido (including primary, C₁-C₆ alkyl and phenyl secondary and tertiary amino moieties),

(g) C₁-C₆ alkylamino

(h) phenylamino,

(i) carbamyl (including C₁-C₆ alkyl and phenyl amides and esters),

(j) carboxyl (including C₁-C₆ alkyl and phenyl esters),

(k) carboxy(C₂-C₅)alkoxy,

(l) carboxy(C₂-C₅)alkylthioxy,

(m) heterocyclylacyl,

(n) heteroarylacyl, or

(o) hydroxyl;

(4)m is 0, 1, 2 or 3;

(B) E(Q)_m″

wherein E and -Q are as defined as above and m″

is 0, 1, 2, or 3;

(C) -T-E wherein -E and -Q are as defined as above;

or

(D) -E wherein -E is as defined as above;

where R_C is;

(I) -(C₁-C₁₀)alkyl-K_1-3

(E) the alkyl chain optionally contains a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon,

(F) each K is;

(2) C₁-C₃ alkyl,

(3) C₁-C₃ alkoxy,

(4) C₁-C₃ alkylthioxy,

(5) C₁ -C₆ alkylacylamino,

(6) C₁-C₆ alkylacyloxy,

(7) amido,

(8) C₁-C₆ alkylamino

(9) phenylamino,

(10) carbamyl,

(11) carboxyl,

(12) carboxy(C₂-C₅)alkoxy,

(13) carboxy(C₂-C5)alkylthioxy,

(14) heterocyclylacyl,

(15) heteroarylacyl,

(16) amino unsubstituted or substituted with C_l-C₆ alkyl,

(17) hydroxyl, or

(18) carboxyl methyl ester;

(II) —

(CH₂)_0-3-J-[(—

(CH₂)_0-3-K]I₃ where K is;

(2) C_l-C₃ alkyl,

(3) C_l-C₃ alkoxy,

(4) C₁-C₃ alkylthioxy,

(5) C₁-C₆ alkylacylamino,

(6) C₁-C₆ alkylacyloxy,

(7) amido,

(8) C₁-C₆ alkylamino

(9) phenylamino,

(10) carbamyl,

(11) carboxyl, (12) carboxy(C₂-C₅)alkoxy,

(13) carboxy(C₂-C₅)alkylthioxy,

(14) heterocyclylacyl,

(15) heteroarylacyl,

(16) amino unsubstituted or substituted with C₁-C₆ alkyl,

(17) hydroxyl, or

(18) carboxyl methyl ester;

J is;

(A) a 5 to 7 atom monocyclic aryl group,

(B) a 8 to 12 atom multicyclic aryl group,

(C) a 5 to 7 atom monocyclic heterocyclic group,

(D) a 8 to 12 atom multicyclic heterocyclic group, or

(E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group; and

where B is 0 or NH.

27. A method for inhibiting β

-secretase activity according to claim 1 where the pharmaceutically acceptable salt is a salt of hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, citric, methanesulfonic, CH₃—

(CH₂)_n-COOH where n is 0 thru 4, HOOC—

(CH₂)n-COOH where n is as defined above, HOOC—

CH═

CH—

COOH and φ

-COOH acid or triethanolamine, N-methylglucamine, diethanolamine, ethanolamine, tris(hydroxymethyl)aminomethane (TRIS), ammonia, or carbonate, bicarbonate, phosphonate, or hydroxide salts of an alkali or alkaline earth metal.

28. A method for inhibiting β

-secretase activity according to claim 1 wherein said compound is;

N-[(1S, 2S, 4R)-1-(3,5-Difluorobenzyl)-4-(syn, syn)-(3,5 -dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide,

6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoic acid,

5-[6-(3,5-Difluorophenyl)-5-(S)-(3 -dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-pentanoic acid,

4-[6-(3 ,5 -Difluorophenyl)-5-(S)-(3 -dipropylcarbamoylbenzoylamino)-2-(R)-7thyl-4-(S)-hydroxyhexanoylamino]-butyric acid,

3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionic acid,

8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-octanoic acid,

8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoic acid methyl ester,

N-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexyl]-N,N-dipropyl-isophthalamide,

N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5 -difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-N,N-dipropyl-isophthalamide,

4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3 -dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5 -Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamini)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5 -Difluoro-phenyl)-5 -(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[4-(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5 -methyl-N,N-dipropyl-isophthalamide,

N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[ I -(S)-(3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbamoyl-pemtyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, or

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-pentyl]-5-methy-N,N-dipropyl-isophthalamide.

30. The method of claim 1, wherein said compound inhibits 50% of the enzyme'"'"'s activity at a concentration of from about 0.1 nM to about 200 μ

M.

31. The method of claim 30, wherein said compound inhibits 50% of the enzyme'"'"'s activity at a concentration of from about 10 nM to about 100 μ

M.

32. The method of claim 31, wherein said compound inhibits 50% of the enzyme'"'"'s activity at a concentration of from about 100 nM to about 50 μ

M.

33. The method of claim 32, wherein said compound inhibits 50% of the enzyme'"'"'s activity at a concentration of from about 1 μ

M to about 10 μ

M.

34. The method of claim 1, wherein said β

-secretase is exposed to said compound in vitro.

35. The method of claim 1, wherein said β

-secretase is exposed to said compound in a cell.

36. The method of claim 35, wherein said cell is in an animal.

37. The method of claim 36, wherein said animal is a human.

39. The method of claim 38, wherein said cleavage site is between Met652 and Asp653, numbered for the APP-751 isotype;

between Met 671 and Asp 672, numbered for the APP-770 isotype,;

between Leu596 and Asp597 of the APP-695 Swedish Mutation;

between Leu652 and Asp653 of the APP-751 Swedish Mutation;

or between Leu671 and Asp672 of the APP-770 Swedish Mutation.

40. The method of claim 38, wherein said reaction mixture is exposed in vitro.

41. The method of claim 38, wherein said reaction mixture is exposed in a cell.

42. The method of claim 41, wherein said cell is in an animal.

43. The method of claim 42, wherein said animal is a human.

2. A method for inhibiting β

-secretase activity according to 1

where R₁ is;

(V) (CH₂)_0-3-(R_1-aryl), or

(VI) —

(CH₂)₁ -(R_1-heteroaryl)

where R_N is;

(I) R_N-1-X_N- where X_N is;

(A) —

CO—

, or

(B) —

SO₂—

,

where R_N-1 is;

(A) R_N-aryI, or

(B) -R_N-heteroaryl,

(VI) —

CO—

CH(—

(CH₂)_0-2-O-R_N-10)—

(CH₂)0-2-R_N-aryl/R_N-heteroaryl)

where R_C is;

(I) -C₁-C₈ alkyl,

(III) —

(CH₂)_0-3-(C₃-C₇) cycloalkyl,

(IV) —

(CH₂)₀o₃—

OH,

(V) -(CR_C-xR_C-y)_0-4-R_C-aryl,

(VI) —

(CH₂)_0-4-R_C-heteroaryl,

(VII) —

(CH₂)_0-4-R_{C-heterocycle},

(VIII) —

C(R_C-1)(R_C-2)-CO—

NH—

R_C-3, or

(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one or two;

(A) C₁-C₃ alkyl,

(B) —

CF₃,

(C) —

F, Cl, —

Br or —

I,

(D) C₁-C₃ alkoxy, or

(E) —

OCF₃

3. A method for inhibiting β

-secretase activity according to claim 85

where R₁ is;

(V) —

CH₂-(R_1-aryl), or

(VI) —

CH₂-(R_1-heteroaryl);

where R₂ is —

H;

where R_N is;

(I) R_N-1X_N- where X_N is;

(A) —

CO—

,

where R_N-1 is;

(A) R_N-aryl or

(B) R_N-heteroaryl

where R_C is;

(III) —

(CH₂)_0-3-(C₃-C₇) cycloalkyl,

(V) -(CR_C-xR_C-y)_0-4-R_C-aryl

(VI) —

(CH₂)_0-4-R_C-heteroaryl,

(VII) —

(CH₂)_0-4-R_{C-heterocycle}

(VIII) —

C(R_C-1)(R_C-2)—

CO—

NH—

R_C-3, or

(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.

4. A method for inhibiting ,B-secretase activity according to claim 3 where R_C is:

(V) —

(CR_C-xR_C-y)_0-4-R_C-aryl,

(VI) (CH_20-4-R_C-heteroaryl, or

(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.

23. A method for inhibiting β

-secretase activity according to claim I where R_C is;

(1) -(C₁-C₁₀)alkyl-K_1-3 where each K is;

(1) H,

(11) carboxyl,

(16) amino unsubstituted or substituted with C₁-C₆ alkyl;

or

(18) carboxyl methyl ester;

(II) —

(CH₂)_0-3-J-[-K] 1₃, where J is;

(A) a 5 to 7 atom monocyclic aryl group, or

(B) a 5 to 10 atom multicyclic cycloalkyl group,

and each K is;

(1) H,

(3) C₁-C₃ alkoxy, or

(11) carboxyl,

(III) —

(CH₂)_0-3-(C₃-C₇) cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three;

(B) —

CO—

OH,

(C) —

CO—

O—

(C₁-C₄ alkyl), or

(E) C₁-C₆ alkoxy,

(IV) —

(CH₂)₂₆—

OH,

(V) —

(CH₂)_0-4-R_C-aryl,

(VI) —

(CH₂)_0-4R_C-heteroaryl,

(VII) —

(CH₂)_0-4-R_{C-heterocycle}) or

(XVIII) -(C₂-C₈) alkynyl.

29. A method for inhibiting β

-secretase activity according to claim I wherein said compound is;

38. A method for inhibiting amyloid precursor protein (APP) cleavage in a reaction mixture at a site between Met596 and Asp597, numbered for the APP-695 amino acid isotype;

or at a corresponding site of an isotype or mutant thereof, comprising exposing said reaction mixture to an effective inhibitory amount of a hydroxyethylene compound of the formula

44. A method for inhibiting production of amyloid beta peptide (Aβ

) in a cell, comprising administering to said cell an effective inhibitory amount of a hydroxyethylene compound of the formula

45. The method of claim 44, wherein said administering is to and animal.

46. The method of claim 45, whererin said administering is to a human.

48. The method of claim 47, wherein said animal is a human.

50. The method of claim 49, wherein said compound inhibits 50% of the enzyme'"'"'s activity at a concentration of from about 0.1 nM to about 200 μ

M.

51. The method of claim 50, wherein said compound inhibits 50% of the enzyme'"'"'s activity at a concentration of from about 10 nM to about 100 μ

M.

52. The method of claim 51, wherein said compound inhibits 50% of the enzyme'"'"'s activity at a concentration of from about 100 nM to about 50 μ

M.

53. The method of claim 52, wherein said compound inhibits 50% of the enzyme'"'"'s activity at a concentration of from about 1 μ

M to about 10 μ

M.

54. The method of claim 49, wherein said thereapeutic amount is in the range of from about 0.1 to about 1000 mg/day.

55. The method of claim 49, wherein said thereapeutic amount is in the range of from about 15 to about 1500 mg/day.

56. The method of claim 55, wherein said thereapeutic amount is in the range of from about 1 to about 100 mg/day.

57. The method of claim 56, wherein said thereapeutic amount is in the range of from about 5 to about 50 mg/day.

58. The method of claim 49, wherein said disease is Alzheimer'"'"'s disease.

59. The method of claim 49, wherein said disease is Mild Cognitive Impairment, Down'"'"'s Syndrome, or Hereditary Cerebral Hemmorrhage with Amyloidosis of the Duvtch Type.

47. A method for inhibiting the production of beta-amyloid plaque in an animal, comprising administering to said animal an effective inhibitory amount of a hydroxyethylene compound of the formula

49. A method for treating or preventing a disease characterized by beta-amyloid deposits in the brain comprising administering to a patient an effective therapeutic amount of a hydroxyethylene compound of the formula

60. A composition comprising β

-secretase complexed with a hydroxyethylene compound of the formula

61. A method for producing a β

-secretase complex comprising exposing β

-secretase to a hydroxyethylene compound of the formula

62. The method of claim 61, where said exposing is in vitro.

63. The method of claim 61, wherein said reaction mixture is a cell.