Compounds to treat alzheimer's disease

• US 20020143177A1
• Filed: 06/29/2001
• Published: 10/03/2002
• Est. Priority Date: 06/30/2000
• Status: Active Grant

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC), Pharmacia & Upjohn Company (Pfizer Inc.)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC), Pharmacia & Upjohn Company (Pfizer Inc.)
• Inventors: Maillard, Michel, Jagodzinska, Barbara, John, Varghese, Gailunas, Andrea, Beck, James P., Hom, Roy
• Granted Patent: US 6,846,813 B2
• Time in Patent Office: Days
• US Class Current: 544/60
• 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: C07C 215/28 and containing six-membered aromatic rings
• CPC Class Codes: C07C 233/78 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07C 235/84 with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 239/20 having oxygen atoms of hydroxylamino groups etherified
• CPC Class Codes: C07C 243/22 having nitrogen atoms of hydrazine groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 243/28 to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
• CPC Class Codes: C07C 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 271/18 to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 311/03 having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 311/08 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/13 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 311/16 having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 311/37 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 323/60 with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 215/12 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 223/10 attached in position 2
• CPC Class Codes: C07D 277/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 303/36 : with hydrocarbon radicals, substituted by nitrogen atoms nitro, nitroso radicals C07D303/08
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/54 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 333/24 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The present invention is disubstituted amines of formula (I)

and disubstituted amines of formula (II)

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

Claims

1. A disubstituted amine of formula I

2. A disubstituted amine of claim 1, wherein R₁ is:

—

(CH₂)_0-1—

(R_1-aryl), or

—

(CH₂)₁—

(R_1-heteroaryl).

3. A disubstituted amine of claim 2, wherein R₁ is:

—

(CH₂)—

(R_1-aryl), or

—

(CH₂)—

(R_1-heteroaryl).

4. A disubstituted amine of claim 3, wherein R₁ is —

(CH₂)—

(R_1-aryl) where R_aryl is phenyl.

5. A disubstituted amine of claim 4, wherein R₁ is substituted with two —

F.

6. A disubstituted amine of claim 5, wherein the —

F substitutions is on the -3 and -5 positions.

7. A disubstituted amine of claim 1, wherein R₂ and R₃ are both —

H.

8. A disubstituted amine of claim 1, wherein R_C is:

—

C₁-C₈ alkyl,

—

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

—

(CR_C-xR_C-y)_0-4—

R_CC-aryl,

—

(CR_C-xR_C-y)_0-4—

R_C-heteroaryl,

—

(CR_C-xR_C-y)_0-4—

R_{C-heterocycle}, or

-cyclopentyl or -cyclohexyl ring fused to R_C-aryl or R_C-heteroaryl or R_{C-heterocycle}.

9. A disubstituted amine of claim 8, wherein R_C is:

—

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

—

(CR_C-xR_C-y)_0-4—

R_C-aryl,

—

(CR_C-xR_C-y)_0-4—

R_C-heteroaryl,

—

(CR_C-xR_C-y)_0-4—

R_{C-heterocycle},

-cyclopentyl or -cyclohexyl ring fused to a R_C-aryl or R_C-heteroaryl or R_{C-heterocycle}.

10. A disubstituted amine of claim 9, wherein R_C is:

—

(CR_C-xR_C-y)_0-4—

R_C-aryl,

—

(CR_C-xR_C-y)_0-4—

R_C-heteroaryl, —

-cyclopentyl or -cyclohexyl ring fused to a R_C-aryl or R_C-heteroaryl or R_{C-heterocycle}.

11. A disubstituted amine of claim 10, wherein R_C is:

—

(CR_C-xR_C-y)_0-4—

R_C-aryl where R_C-aryl is phenyl.

12. A disubstituted amine of claim 11, wherein said phenyl is substituted in the 3-position or 3,5-positions.

13. A disubstituted amine of claim 1, wherein R_C-A is:

-methyl, or

-ethyl.

14. A disubstituted amine of claim 1, wherein Z is:

—

C(O)—

, or

—

C(O)—

X_N-1—

where X_N-1 is selected from the group consisting of —

O—

, —

S—

and —

NR′

—

.

16. A disubstituted amine of claim 15, wherein R₁ is:

—

(CH₂)_0-1(R_1-aryl), or

—

(CH₂)_n1-(R_1-heteroaryl).

17. A disubstituted amine of claim 16, wherein R₁ is:

—

(CH₂)—

(R_1-aryl), or

—

(CH₂)—

(R_1-heteroaryl).

18. A disubstituted amine of claim 17, wherein R₁ is —

(CH₂)—

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

19. A disubstituted amine of claim 18, wherein R₁ is substituted with two —

F.

20. A disubstituted amine of claim 19, wherein the —

F substitutions are on the −

3 and −

5 positions.

21. A disubstituted amine of claim 15, wherein R₂ and R₃ are both —

H.

22. A disubstituted amine of claim 15, wherein R_C is:

—

C₁-C₈ alkyl,

—

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

—

(CR_C-xR_C-y)_0-4—

R_C-aryl,

—

(CR_C-xR_C-y)_0-4—

R_C-heteroaryl,

—

(CR_C-xR_C-y)_0-4—

R_{C-heterocycle}, or

-cyclopentyl or -cyclohexyl ring fused to R_{C-aryl or RC-heteroaryl} or R_{C-heterocycle}.

23. A disubstituted amine of claim 22, wherein R_C is:

—

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

—

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

—

(CR_C-xR_C-y)_0-4—

R_C-heteroaryl,

—

(CR_C-xR_C-y)_0-4—

R_{C-heterocycle},

-cyclopentyl or -cyclohexyl ring fused to a R_C-aryl or R_C-heteroaryl or R_{C-heterocycle}.

24. A disubstituted amine of claim 23, wherein R_C is:

—

(CR_C-xR_C-y)_0-4—

R_C-aryl,

—

(CR_C-xR_C-y)_0-4—

R_C-heteroaryl,

—

cyclopentyl or -cyclohexyl ring fused to a R_C-aryl or R_C-heteroaryl or R_{C-heterocycle}.

25. A disubstituted amine of claim 24, wherein R_C is:

—

(CR_C-xR_C-y)_0-4—

R_C-aryl where R_C-aryl is phenyl.

26. A disubstituted amine of claim 25, wherein said phenyl is substituted in the 3-position or 3,5-positions.

27. A disubstituted amine of claim 15, wherein R_C-A is:

-methyl, or

-ethyl.

28. A disubstituted amine of claim 15, wherein Z is:

—

C(O)—

, or

—

C(O)—

X_N-1—

where X_N-1 is selected from the group consisting of —

O—

, —

S— and

—

NR′

—

.

29. A disubstituted amine of claim 15, wherein R_N is:

—

R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl or R_N-heteroaryl where R_N-aryl is phenyl where the substitution on phenyl is 1,3-, and where R_N-aryl or R_N-heteroaryl, are substituted with one —

CO—

NR_N-2R_N-3,

—

R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl or R_N-heteroaryl where R_N-aryl is phenyl substituted with one C₁ alkyl where the substitution on the phenyl is 1,3,5-, and where R_N-aryl or R_N-heteroaryl are substituted with one —

CO—

NR_N-2R_N-3, or

—

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.

30. A disubstituted amine of claim 29, wherein R_N-2 and R_N-3 are the same and are C₃ alkyl.

31. A disubstituted amine of claim 29, wherein R_N-1-X_N- where X_N is —

CO—

, where R_N-1 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-.

32. A disubstituted amine of claim 29, wherein R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl where R_N-aryl is phenyl substituted with one C₁ alkyl and with one —

CO—

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

33. A disubstituted amine of claim 29, wherein X_N is —

CO—

, or —

SO₂—

.

34. A disubstituted amine of claim 29, wherein X_N is —

CO—

.

35. A compound according to claim 1 or claim 15 selected from the group consisting of:

6-({[[(2S,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]benzoyl}amino)-2hydroxybutyl](ethyl)amino]carbonyl}amino)hexanoic acid,

N¹-((1S,2S)-1-(3,5-difluorobenzyl)-3-{ethyl[(isobutylamino)carbonyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,

N¹-[(1S,2S)-3-[(butylsulfonyl)(ethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,

N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{(2S)-2-[(isobutylamino)carbonyl]piperidinyl}propyl)-5-methyl-N³,N³dipropylisophthalamide,

N¹-[(1S,2R)-1 -(3,5-difluorobenzyl)-2-hydroxy-3-(4-methyl-1-piperazinyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,

N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[[2-(isobutylamino)-2-oxoethyl](methyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,

N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[[(1S)-2-(isobutylamino)-1-methyl-2-oxoethyl](methyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,

N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(1,3-thiazolidin-3-yl)propyl]-N³,N³-dipropylisophthalamide, and

N¹-{(1S,2R)-1-benzyl-3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide.

37. A method of treatment according to claim 36, wherein the disease is Alzheimer'"'"'s disease.

38. A method of treatment according to claim 36, wherein the method is helping prevent or delay the onset of Alzheimer'"'"'s disease.

39. A method of treatment according to claim 36, wherein the disease is mild cognitive impairment.

40. A method of treatment according to claim 36, wherein the disease is Down'"'"'s syndrome.

41. A method of treatment according to claim 36, wherein the disease is Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.

42. A method of treatment according to claim 36, wherein the disease is cerebral amyloid angiopathy.

43. A method of treatment according to claim 36, wherein the disease is degenerative dementias.

44. A method of treatment according to claim 36, wherein the disease is diffuse Lewy body type of Alzheimer'"'"'s disease.

45. A method of treatment according to claim 36, wherein the method is treating an existing disease.

46. A method of treatment according to claim 36, wherein the method is preventing a disease from developing.

47. A method of treatment according to claim 36, wherein the therapeutically effective amount for oral administration is from about 0.1 mg/day to about 1,000 mg/day;

for parenteral, sublingual, intranasal, intrathecal administration is from about 0.5 to about 100 mg/day;

for depo administration and implants is from about 0.5 mg/day to about 50 mg/day;

for topical administration is from about 0.5 mg/day to about 200 mg/day;

for rectal administration is from about 0.5 mg to about 500 mg.

48. A method of treatment according to claim 47, wherein the therapeutically effective amount for oral administration is from about 1 mg/day to about 100 mg/day and for parenteral administration is from about 5 to about 50 mg daily.

49. A method of treatment according to claim 48 where the therapeutically effective amount for oral administration is from about 5 mg/day to about 50 mg/day.

50. A method of treatment according to claim 36, wherein R₁ is:

—

(CH₂)_0-1—

(R_1-aryl), or

—

(CH₂)_n1—

(R_1-heteroaryl).

51. A method of treatment according to claim 50, wherein R₁ is:

—

(CH₂)—

(R_1-aryl), or

—

(CH₂)—

(R_1-heteroaryl).

52. A method of treatment according to claim 51, wherein R₁ is —

(CH₂)—

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

53. A method of treatment according to claim 52, wherein R₁ is substituted with two —

F.

54. A method of treatment according to claim 53, wherein the —

F substitutions are on the -3 and -5 positions.

55. A method of treatment according to claim 36, wherein R₂ and R₃ are both —

H.

56. A method of treatment according to claim 36, wherein R_C is:

—

C₁-C₈ alkyl,

—

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

—

(CR_C-xR_C-y)_0-4—

R_C-aryl,

—

(CR_C-xR_C-y)_0-4—

R_C-heteroaryl,

—

(CR_C-xR_C-y)_0-4—

R_{C-heterocycle}, or

-cyclopentyl or -cyclohexyl ring fused to R_C-aryl or R_C-heteroaryl or R_{C-heterocycle}.

57. A method of treatment according to claim 56, wherein R_C is:

—

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

—

(CR_C-xR_C-y)_0-4—

R_C-aryl,

—

(CR_C-xR_C-y)_0-4—

R_C-heteroaryl,

—

(CR_C-xR_C-y)_0-4—

R_{C-heterocycle}, or

-cyclopentyl or -cyclohexyl ring fused to a R_C-aryl or R_C-heteroaryl or R_{C-heterocycle}.

58. A method of treatment according to claim 57, wherein R_C is:

—

(CR_C-xR_C-y)_0-4—

R_C-aryl,

—

(CR_C-xR_C-y)_0-4—

R_C-heteroaryl,

-cyclopentyl or -cyclohexyl ring fused to a R_C-aryl, or R_C-heteroaryl or R_{C-heterocycle}.

59. A method of treatment according to claim 58, wherein R_C is:

—

(CR_C-xR_C-y)_0-4—

R_C-aryl where R_C-aryl is phenyl.

60. A method of treatment according to claim 59, wherein said phenyl is substituted in the 3-position or 3,5-positions.

61. A method of treatment according to claim 36, wherein RCA is:

-methyl, or

-ethyl.

62. A method of treatment according to claim 36, wherein Z is:

—

C(O)—

, or

—

C(O)—

XN_N-1—

where X_N-1 is selected from the group consisting of —

O—

, —

S—

and —

NR′

—

.

63. A method of treatment according to claim 36 where the pharmaceutically acceptable salt is selected from the group consisting of salts of the following acids:

acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, phthalic, polygalactouronic, propionic, salicylic, stearic, succinic, succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic.

98. A method of treatment according to claim 36 or 64 where the disubstituted amine is selected from the group consisting of:

6-({[[(2S,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]benzoyl}amino)-2-hydroxybutyl](ethyl)amino]carbonyl}amino)hexanoic acid,

N¹-((1S,2S)-1-(3,5-difluorobenzyl)-3-{ethyl[(isobutylamino)carbonyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,

N¹-[(1S,2S)-3-[(butylsulfonyl)(ethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³,N³-dipropylisophthalamide,

N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{(2S)-2-[(isobutylamino)carbonyl]piperidinyl}propyl)-5-methyl-N³,N³-dipropylisophthalamide,

N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(4-methyl-1-piperazinyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,,

N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[[2-(isobutylamino)-2-oxoethyl](methyl)amino]propyl}-5-methyl-N³, N³-dipropylisophthalamide,

N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[[(1S)-2-(isobutylamino)-1-methyl-2-oxoethyl](methyl)amino]propyl}-5-methyl-N³, N³-dipropylisophthalamide,

N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(1,3-thiazolidin-3-yl)propyl]-N³,N³-dipropylisophthalamide, and

N¹-{(1S,2R)-1-benzyl-3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide.

99. A method for inhibiting beta-secretase activity, comprising exposing said beta-secretase to an effective inhibitory amount of a compound according to claim 1.

100. The method of claim 99, wherein said beta-secretase is exposed to said compound in vitro.

101. The method of claim 99, wherein said beta-secretase is exposed to said compound in a cell.

102. The method of claim 101, wherein said cell is in an animal.

103. The method of claim 102, wherein said animal is a human.

104. A method for inhibiting beta-secretase activity, comprising exposing said beta-secretase to an effective inhibitory amount of a compound according to claim 15.

105. The method of claim 104, wherein said beta-secretase is exposed to said compound in vitro.

106. The method of claim 104, wherein said beta-secretase is exposed to said compound in a cell.

107. The method of claim 106, wherein said cell is in an animal.

108. The method of claim 107, wherein said animal is a human.

109. The method of claims 99 or 104, wherein the compound is selected from the group consisting of:

6-({[[(2S,3S)-4-(3,5-difluorophenyl)-3-({3-[(dipropylamino)carbonyl]benzoyl}amino)-2-hydroxybutyl](ethyl)amino]carbonyl}amino)hexanoic acid,

N¹-((1S,2S)-1-(3,5-difluorobenzyl)-3-{ethyl[(isobutylamino)carbonyl]amino}-2-hydroxypropyl)-N³,N³-dipropylisophthalamide,

N¹-[(1S,2S)-3-[(butylsulfonyl)(ethyl)amino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]-5-methyl-N³, N³-dipropylisophthalamide,

N¹-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{(2S)-2-[(isobutylamino)carbonyl]piperidinyl}propyl)-5-methyl-N³, N³-dipropylisophthalamide,

N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(4-methyl-1-piperazinyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide,,

N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[[2-(isobutylamino)-2-oxoethyl](methyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,

N¹-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[[(1S)-2-(isobutylamino)-1-methyl-2-oxoethyl](methyl)amino]propyl}-5-methyl-N³,N³-dipropylisophthalamide,

N¹-[(1S,2R)-1-benzyl-2-hydroxy-3-(1,3-thiazolidin-3-yl)propyl]-N³,N³-dipropylisophthalamide, and

N¹-{(1S,2R)-1-benzyl-3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxypropyl}-N³,N -dipropylisophthalamide.

110. A method for inhibiting cleavage of amyloid precursor protein (APP), 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 compound according to claim 1.

111. The method of claim 110, 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.

112. The method of claim 110, wherein said reaction mixture is exposed in vitro.

113. The method of claim 110, wherein said reaction mixture is exposed in a cell.

114. The method of claim 113, wherein said cell is an animal cell.

115. The method of claim 114, wherein said cell is a human cell.

116. A method for inhibiting cleavage of amyloid precursor protein (APP), 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 compound according to claim 15.

117. The method of claim 116, 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-75 1 Swedish Mutation;

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

118. The method of claim 116, wherein said reaction mixture is exposed in vitro.

119. The method of claim 116, wherein said reaction mixture is exposed in a cell.

120. The method of claim 118, wherein said cell is an animal cell.

121. The method of claim 120, wherein said cell is a human cell.

122. A method for inhibiting production of amyloid beta peptide (A beta) in a cell, comprising administering to said cell an effective inhibitory amount of a compound according to claim 1.

123. The method of claim 122, wherein said administering is to an animal.

124. The method of claim 123, wherein said administering is to a human.

125. A method for inhibiting production of amyloid beta peptide (A beta) in a cell, comprising administering to said cell an effective inhibitory amount of a compound according to claim 15.

126. The method of claim 125, wherein said administering is to an animal.

127. The method of claim 126, wherein said administering is to a human.

128. A method for inhibiting the production of beta-amyloid plaque in an animal, comprising administering to said animal an effective inhibitory amount of a compound according to claim 1.

129. The method of claim 128, wherein said animal is a human.

130. A method for inhibiting the production of beta-amyloid plaque in an animal, comprising administering to said animal an effective inhibitory amount of a compound according to claim 15.

131. The method of claim 130, wherein said animal is a human.

132. 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 compound according to claim 1.

133. The method of claim 132, wherein said therapeutic amount is in the range of from about 0.1 to about 1000 mg/day.

134. The method of claim 132, wherein said therapeutic amount is in the range of from about 15 to about 1500 mg/day.

135. The method of claim 133, wherein said therapeutic amount is in the range of from about 1 to about 100 mg/day.

136. The method of claim 135, wherein said therapeutic amount is in the range of from about 5 to about 50 mg/day.

137. The method of claim 133, wherein said disease is Alzheimer'"'"'s disease.

138. The method of claim 132, wherein said disease is Mild Cognitive Impairment, Down'"'"'s Syndrome, or Hereditary Cerebral Hemmorrhage with Amyloidosis of the Dutch Type.

139. 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 compound according to claim 15.

140. The method of claim 139, wherein said therapeutic amount is in the range of from about 0.1 to about 1000 mg/day.

141. The method of claim 139, wherein said therapeutic amount is in the range of from about 15 to about 1500 mg/day.

142. The method of claim 140, wherein said therapeutic amount is in the range of from about 1 to about 100 mg/day.

143. The method of claim 142, wherein said therapeutic amount is in the range of from about 5 to about 50 mg/day.

144. The method of claim 139, wherein said disease is Alzheimer'"'"'s disease.

145. The method of claim 139, wherein said disease is Mild Cognitive Impairment, Down'"'"'s Syndrome, or Hereditary Cerebral Hemmorrhage with Amyloidosis of the Dutch Type.

146. A composition comprising beta-secretase complexed with a compound according to claim 1.

147. A composition comprising beta-secretase complexed with a compound according to claim 15.

148. A method for producing a beta-secretase complex comprising:

exposing beta-secretase to a compound according to claim 1, or a pharmaceutically acceptable salt thereof in a reaction mixture under conditions suitable for the production of said complex.

149. The method of claim 148, where said exposing is in vitro.

150. The method of claim 149, wherein said reaction mixture is a cell.

151. A method for producing a beta-secretase complex comprising:

exposing beta-secretase to a compound according to. claim 15, or a pharmaceutically acceptable salt thereof in a reaction mixture under conditions suitable for the production of said complex.

152. The method of claim 151, where said exposing is in vitro.

153. The method of claim 152, wherein said reaction mixture is a cell.

154. A kit comprising component parts capable of being assembled, wherein at least one component part comprises a compound according to claim 1, enclosed in a container.

155. The kit of claim 154, wherein said compound is lyophilized and at least one further component part comprises a diluent.

156. A kit comprising component parts capable of being assembled, wherein at least one component part comprises a compound according to claim 15, enclosed in a container.

157. The kit of claim 156, wherein said compound is lyophilized and at least one further component part comprises a diluent.

158. A kit comprising a plurality of containers, each container comprising one or more unit dose of a compound according to claim 1.

159. The kit of claim 158, wherein each container is adapted for oral delivery and comprises a tablet, gel, or capsule.

160. The kit of claim 158, wherein each container is adapted for parenternal delivery and comprises a depot product, syringe, ampoule, or vial.

161. The kit of claim 158, wherein each container is adapted for topical delivery and comprises a patch, medipad, ointment, or cream.

162. A kit comprising a plurality of containers, each container comprising one or more unit dose of a compound according to claim 1.

163. The kit of claim 162, wherein each container is adapted for oral delivery and comprises a tablet, gel, or capsule.

164. The kit of claim 162, wherein each container is adapted for parenternal delivery and comprises a depot product, syringe, ampoule, or vial.

165. The kit of claim 162, wherein each container is adapted for topical delivery and comprises a patch, medipad, ointment, or cream.

166. A kit comprising a compound according to claim 1;

and

one or more therapeutic agent selected from the group consisting of an antioxidant, an anti-inflamatory, a gamma secretase inhibitor, a neurotrophic agent, an acetylcholinesterase inhibitor, a statin, an A beta peptide, and an anti-A beta antibody.

167. A kit comprising a compound according to claim 15;

and

one or more therapeutic agent selected from the group consisting of an antioxidant, an anti-inflamatory, a gamma secretase inhibitor, a neurotrophic agent, an acetylcholinesterase inhibitor, a statin, an A beta peptide, and an anti-A beta antibody.

168. A composition comprising a compound according to claim 1;

and an inert diluent or edible carrier.

169. The composition of claim 168, wherein said carrier is an oil.

170. A composition comprising a compound according to claim 1;

and an inert diluent or edible carrier.

171. The composition of claim 170, wherein said carrier is an oil.

172. A composition comprising a compound according to claim 1;

and a binder, excipient, disintegrating agent, lubricant, or gildant.

173. A composition comprising a compound according to claim 15;

and a binder, excipient, disintegrating agent, lubricant, or gildant.

174. A composition comprising a compound according to claim 1 disposed in a cream, ointment, or patch.

175. A composition comprising a compound according to claim 15 disposed in a cream, ointment, or patch.

15. A disubstituted amine of formula II

36. A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer'"'"'s disease, for helping prevent or delay the onset of Alzheimer'"'"'s disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer'"'"'s disease in those who would progress from MCI to AD, for treating Down'"'"'s syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson'"'"'s disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer'"'"'s disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of a disubstituted amine of formula (I)

64. A method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from the group consisting of Alzheimer'"'"'s disease, for helping prevent or delay the onset of Alzheimer'"'"'s disease, for treating patients with mild cognitive impairment (MCI) and preventing or delaying the onset of Alzheimer'"'"'s disease in those who would progress from MCI to AD, for treating Down'"'"'s syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson'"'"'s disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer'"'"'s disease and who is in need of such treatment which comprises administration of a therapeutically effective amount of a compound selected from the group consisting of a disubstituted amine of formula II

65. A method of treatment according to claim 64, wherein the disease is Alzheimer'"'"'s disease.

66. A method of treatment according to claim 64, wherein the method is helping prevent or delay the onset of Alzheimer'"'"'s disease.

67. A method of treatment according to claim 64, wherein the disease is mild cognitive impairment.

68. A method of treatment according to claim 64, wherein the disease is Down'"'"'s syndrome.

69. A method of treatment according to claim 64, wherein the disease is Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.

70. A method of treatment according to claim 64, wherein the disease is cerebral amyloid angiopathy.

71. A method of treatment according to claim 64, wherein the disease is degenerative dementias.

72. A method of treatment according to claim 64, wherein the disease is diffuse Lewy body type of Alzheimer'"'"'s disease.

73. A method of treatment according to claim 64, wherein the method is treating an existing disease.

74. A method of treatment according to claim 64, wherein the method is preventing a disease from developing.

75. A method of treatment according to claim 64, wherein the therapeutically effective amount for oral administration is from about 0.1 mg/day to about 1,000 mg/day;

for parenteral, sublingual, intranasal, intrathecal administration is from about 0.5 to about 100 mg/day;

for depo administration and implants is from about 0.5 mg/day to about 50 mg/day;

for topical administration is from about 0.5 mg/day to about 200 mg/day;

for rectal administration is from about 0.5 mg to about 500 mg.

76. A method of treatment according to claim 75, wherein the therapeutically effective amount for oral administration is from about 1 mg/day to about 100 mg/day and for parenteral administration is from about 5 to about 50 mg daily.

77. A method of treatment according to claim 76 where the therapeutically effective amount for oral administration is from about 5 mg/day to about 50 mg/day.

78. A method of treatment according to claim 64, wherein RI is:

—

(CH₂)_0-1—

(R_1-aryl), or

—

(CH₂)_n1—

(R_1-heteraoyl).

79. A method of treatment according to claim 78, wherein R₁ is:

—

(CH₂)—

(R_1-aryl), or

—

(CH₂)—

(R_1-heteroaryl).

80. A method of treatment according to claim 79, wherein R₁ is —

(CH₂)—

R_1-aryl) where R_1-aryl is phenyl.

81. A method of treatment according to claim 80, wherein R₁ is substituted with two —

F.

82. A method of treatment according to claim 81, wherein the —

F substitutions are on the -3 and -5 positions.

83. A method of treatment according to claim 64, wherein R₂ and R₃ are both —

H.

84. A method of treatment according to claim 64, wherein R_C is:

—

C₁-C₈ alkyl,

—

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

—

(CR_C-xR_C-y)_0-413 R_C-aryl,

—

(CR_C-xR_C-y)_0-4—

R_C-heteroaryl,

—

(CR_C-xR_C-y)_0-4—

R_{C-heterocycle}, or

-cyclopentyl or -cyclohexyl ring fused to R_C-aryl or R_C-heteroaryl or R_{C-heterocycle}.

85. A method of treatment according to claim 84, wherein R_C is:

—

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

—

(CR_C-xR_C-y)_0-4—

R_C-aryl,

—

(CR_C-xR_C-y)_0-4—

R_C-heteroaryl,

—

(CR_C-xR_C-y)_0-4—

R_{C-heterocycle},

-cyclopentyl or -cyclohexyl ring fused to a R_C-aryl or R_C-heteroaryl or R_{C-heterocycle}.

86. A method of treatment according to claim 85, wherein R_C is:

—

(CR_C-xR_C-y)_0-4—

R_C-aryl,

(CR_C-xR_C-y)_0-4—

R_C-heteroaryl,

-cyclopentyl or -cyclohexyl ring fused to a R_C-aryl or R_C-heteroaryl or R_{C-heterocycle}.

87. A method of treatment according to claim 86, wherein R_C is:

—

(CR_C-xR_C-y)_0-4—

R_C-aryl where R_C-aryl is phenyl.

88. A method of treatment according to claim 87, wherein said phenyl is substituted in the 3-position or 3,5-positions.

89. A method of treatment according to claim 64, wherein R_C-A is:

-methyl, or

-ethyl.

90. A method of treatment according to claim 64, wherein Z is:

—

C(O)—

, or

—

C(O)—

X_N-1—

where X_N-1 is selected from the group consisting of —

O—

, —

S— and

—

NR′

—

.

91. A method of treatment according to claim 64, wherein R_N is:

—

R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl or R_N-heteroaryl where R_N-aryl is phenyl where the substitution on phenyl is 1,3, and where R_N-aryl or R_N-heteroaryl are substituted with one —

CO—

NR_N-2R_N-3,

—

R_N-1—

X_N—

where X_N is—

CO—

, where R_N-1 is R_N-aryl or R_N-heteroaryl where R_N-aryl is phenyl substituted with one C₁ alkyl where the substitution on the phenyl is 1,3,5, and where R_N-aryl or R_N-heteroaryl are substituted with one —

CO—

NR_N-2R_N-3, or

—

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.

92. A method of treatment according to claim 91, wherein R_N-2 and R_N-3 are the same and are C₃ alkyl.

93. A method of treatment according to claim 91, wherein R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 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.

94. A method of treatment according to claim 91, wherein R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl where R_N-aryl is phenyl substituted with one C₁ alkyl and with one —

CO—

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

95. A method of treatment according to claim 91, wherein X_N is —

CO—

, or —

SO₂—

.

96. A method of treatment according to claim 95, wherein X_N is —

CO—

.

97. A method of treatment according to claim 64 where the pharmaceutically acceptable salt is selected from the group consisting of salts of the following acids:

acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, phthalic, polygalactouronic, propionic, salicylic, stearic, succinic, succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic.