Hydroxypropyl amides for the treatment of Alzheimer's disease

• US 20040039034A1
• Filed: 04/30/2003
• Published: 02/26/2004
• Est. Priority Date: 04/30/2002
• Status: Active Grant

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC), Pharmacia & Upjohn Company (Pfizer Inc.)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: John, Varghese, Beck, James P., Brogley, Louis, Pulley, Shon R., Tucker, John A., Sherer, Brian A., Xu, Ying Zi, Jacobs, Jon S.
• Granted Patent: US 7,262,208 B2
• Time in Patent Office: Days
• US Class Current: 514/357
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 235/10 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 235/34 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/74 of a saturated carbon skeleton
• CPC Class Codes: C07C 237/20 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/10 the ring being unsaturated
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 279/28 having nitrogen atoms of guanidine groups bound to cyano groups, e.g. cyanoguanidines, dicyandiamides
• CPC Class Codes: C07C 311/05 to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07D 209/46 with an oxygen atom in position 1
• CPC Class Codes: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 261/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/33 in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 333/22 Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
• 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
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention relates to compounds of formula (I):

useful in treating Alzheimer'"'"'s disease and other similar diseases. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer'"'"'s disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.

Claims

1. A compound of formula I:

2. A compound according to claim 1 wherein

R₁ and Y together form —

C₁-C₆ alkyl-aryl, —

C₁-c₆ alkyl-heteroaryl, or —

C₁-C₆ alkyl-heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —

OH, —

SH, —

C≡

N, —

NO₂, —

NR₁₀₅R′

₁₀₅, —

CO₂R, —

N(R)COR′

, or —

N(R)SO₂R′

, —

C(═

O)—

(C₁-C₄) alkyl, —

SO₂-amino, —

SO₂-mono or dialkylamino, —

C(═

O)-amino, —

C(═

O)-mono or dialkylamino, —

SO₂—

(C₁-C₄)alkyl, or

C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which are independently selected from halogen, or

C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, amino, —

C₁-C₆ alkyl and mono- or dialkylamino, or

C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

OH, —

SH, —

C≡

N, —

CF₃, —

C₁-C₃ alkoxy, amino, mono- or dialkylamino and —

C₁-C₃ alkyl, or

C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- or dialkylamino; and

the heterocyclyl group is optionally further substituted with oxo.

3. A compound according to claim 1 wherein

R₂ is —

(CRR′

)_0-6R₁₀₀; and

R₁₀₀ represents aryl, heteroaryl, or heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, or 3 groups independently selected from

—

OR, —

NO₂, C₁-C₆ alkyl, halogen, —

C≡

N, —

OCF₃, —

CF₃, —

(CH₂)_0-4—

O—

P(═

O)(OR)(OR′

), —

(CH₂)_0-4—

CO—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

O—

(CH₂)_0-4—

CONR₁₀₂R₁₀₂′

, —

(CH₂)_0-4—

CO—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

CO—

(C₂-C₁₂ alkenyl), —

(CH₂)_0-4—

CO—

(C₂-C₁₂ alkynyl), —

(CH₂)_0-4—

CO—

(CH₂)_0-4(C₃-C₇ cycloalkyl), —

(CH₂)_0-4—

R₁₁₀, —

(CH₂)_0-4—

R₁₂₀, —

(CH₂)_0-4—

R₁₃₀, —

(CH₂)_0-4—

CO—

R₁₁₀, —

(CH₂)_0-4—

CO—

R₁₂₀, —

(CH₂)_0-4—

CO—

R₁₃₀, —

(CH₂)_0-4—

CO—

R₁₄₀, —

(CH₂)_0-4—

CO—

O—

R₁₅₀, —

(CH₂)_0-4—

SO₂—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

SO—

(C₁-C₈ alkyl), —

(CH₂)_0-4—

SO₂—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

SO₂—

(CH₂)_0-4—

(C₃-C₇ cycloalkyl), —

(CH₂)_0-4—

N(R₁₅₀)—

CO—

O—

R₁₅₀, —

(CH₂)_0-4—

N (R₁₅₀)—

CO—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀)—

CS—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀)—

CO—

R₁₀₅, —

(CH₂)_0-4—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

R₁₄₀, —

(CH₂)_0-4—

O—

CO—

(C₁-C₆ alkyl), —

(CH₂)_0-4—

O—

P(O)—

(O—

R₁₁₀)₂, —

(CH₂)_0-4—

O—

CO—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

CS—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

(R₁₅₀), —

(CH₂)_0-4—

O—

R₁₅₀′

—

COOH, —

(CH₂)_0-4—

S—

(R₁₅₀), —

(CH₂)_0-4—

N(R₁₅₀)—

SO₂—

R₁₀₅, —

(CH₂)_0-4—

C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, or (C₂-C₁₀)alkynyl.

4. A compound according to claim 1 wherein R₃, R₃′

, R₄ and R₅ are each hydrogen.

5. A compound according to claim 1 wherein

X is

6. A compound according to claim 1 wherein

R₆ is —

(CR₂₄₅R₂₅₀)_0-4-aryl, —

(CR₂₄₅R₂₅₀)_0-4-heteroaryl, —

(CR₂₄₅R₂₅₀)_0-4-heterocyclyl, —

(C₁-C₆ alkyl)—

O—

(C₁-C₆ alkyl)—

OH;

—

(C₁-C₆ alkyl)—

O—

(C₁-C₆ alkenyl);

—

(C₁-C₆ alkyl)—

O—

(C₁-C₆ alkyl)—

O—

(C₁-C₆ alkyl);

—

(C₁-C₆ alkyl)—

O—

(C₀-C₆ alkyl)-aryl;

—

(C₁-C₆ alkyl)—

O—

(C₀-C₆ alkyl)-cycloalkyl;

—

CH₂—

NH—

CH₂—

CH(—

O—

CH₂—

CH₃)₂, —

(CH₂)_0-6—

C(═

NR₂₃₅)(NR₂₃₅R₂₄₀), —

(C₂-C₆ alkenyl)-heteroaryl, —

(CR₂₄₅R₂₅₀)_1-4—

N(R₂₃₅)—

C(═

O)—

O—

(C₁-C₃ alkyl)-aryl, —

(CR₂₄₅R₂₅₀)_1-4—

N(R₂₃₅)—

C(═

O)—

(C₀-C₃ alkyl)-aryl, —

(CR₂₄₅R₂₅₀)_1-4—

N(R₂₃₅)—

C(═

O)—

(C₀-C₃ alkyl)-heteroaryl, —

(CR₂₄₅R₂₅₀)_1-4—

C(═

O)-aryl, —

(CR₂₄₅R₂₅₀)_1-4—

C(═

O)-heteroaryl, or

C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R₂₀₅, cyclopentenyl, —

OC═

ONR₂₃₅R₂₄₀, —

S(═

O)_0-2(C₁-C₆ alkyl), —

SH, —

NR₂₃₅C═

ONR₂₃₅R₂₄₀, —

C═

ONR₂₃₅R₂₄₀, —

NR₂₃₅—

C(═

O)—

O—

R₂₀₅, and —

S(═

O)₂NR₂₃₅R₂₄₀, —

NR₂₃₅C(═

O)—

(C₁-C₆ alkyl), ═

O, or

—

(CH₂)_0-3—

(C₃-C₈) cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R₂₀₅, —

CO₂H, —

CO₂—

(C₁-C₄ alkyl), —

CO—

NH₂, —

CO—

NH(C₁-C₆ alkyl) and —

CO—

N—

(C₁-C₆ alkyl) (C₁-C₆ alkyl), or

C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl, each of which is optionally substituted with 1, 2, or 3 independently selected R₂₀₅ groups, wherein

each aryl and heteroaryl is optionally substituted with 1, 2, or 3 R₂₀₀, and wherein each heterocyclyl is optionally substituted with 1, 2, 3, or 4 independently selected R₂₁₀, and each cycloalkyl is optionally substituted with 1 or 2 R₂₀₅ groups.

7. A compound according to claim 1 selected from the group consisting of:

5-({5-[(tert-butoxycarbonyl)amino]pentanoyl}amino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[(propylamino)carbonyl]amino}-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3E)-pent-3-enoylamino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(ethoxyacetyl)amino]-D-erythro-pentitol;

5-[(3-cyclopentylpropanoyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-(pentanoylamino)-D-erythro-pentitol;

5-({6-[(tert-butoxycarbonyl)amino]hexanoyl}amino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-{[(benzyloxy)acetyl]amino}-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(4-phenylbutanoyl)amino]-D-erythro-pentitol;

5-({3-([1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}amino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(methoxyacetyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-5-(3,5-difluorophenyl)-4-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-1-[(4-methylpentanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-5-{[4-(3,4-dimethoxyphenyl)butanoyl]amino}-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[4-(4-methoxyphenyl)butanoyl]amino}-D-erythro-pentitol;

5-{[3-(1-(6-[(tert-butoxycarbonyl)amino]hexanoyl}piperidin-4-yl)propanoyl]amino}-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-[(3-cyclohexylpropanoyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-({3-[1-(3-hydroxypropanoyl)piperidin-4-yl]propanoyl}amino)-D-erythro-pentitol;

5-{[(1E)-N-cyanobutanimidoyl]amino}-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-diflubrophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(4-phenoxybutanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[(2E)-3-(2-thienyl)prop-2-enoyl]amino}-D-erythro-pentitol;

5-(butyrylamino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-[(butoxyacetyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(4,4,4-trifluoro-3-methylbutanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(2-hydroxy-4-methylpentanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[4-(2-thienyl)butanoyl]amino}-D-erythro-pentitol;

5-[(cyclopropylacetyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-({3-[1-(tert-butoxycarbonyl)piperidin-3-yl]propanoyl}amino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-hydroxybutanoyl)amino]-D-erythro-pentitol;

5-({3-[1-(6-aminohexanoyl)piperidin-4-yl]propanoyl}amino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-({4-[(tert-butoxycarbonyl)amino]butanoyl}amino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(5-methylhexanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-(hept-6-ynoylamino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-(pent-4-enoylamino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-({3-[1-(1H-imidazol-5-ylacetyl)piperidin-4-yl]propanoyl}amino)-D-erythro-pentitol;

1-[(3-carboxypropanoyl)amino]-1,2,4,5-tetradeoxy-5-(3,5-difluorophenyl)-4-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[(2-methoxyethoxy)acetyl]amino}-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-{1-[3-(1H-imidazol-5-yl)propanoyl]piperidin-4-yl}propanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-(pent-4-ynoylamino)-D-erythro-pentitol;

5-[(cyclopent-2-en-1-ylacetyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-methylpentanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-phenylpropanoyl)amino]-D-erythro-pentitol;

5-[(4-{[(benzyloxy)carbonyl]amino}-3-hydroxybutanoyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3Z)-hex-3-enoylamino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(2-thienylacetyl)amino]-D-erythro-pentitol;

5-{[N-(cyclohexa-2,4-dien-1-ylacetyl)glycyl]amino}-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-({3-[1-(tert-butoxycarbonyl)piperidin-4-yl]butanoyl}amino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-{[4-(benzyloxy)butanoyl]amino}-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-methoxypropanoyl)amino]-D-erythro-pentitol;

5-[(N-acetylglycyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(6-oxoheptanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(5-oxohexanoyl)amino]-D-erythro-pentitol;

5-[(cycloheptylacetyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-5-[(3-{1-[4-(dimethylamino)butanoyl]piperidin-4-yl}propanoyl)amino]-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[(3R)-3-hydroxy-3-phenylpropanoyl]amino}-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[N-(pyridin-3-ylcarbonyl)glycyl]amino}-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(5-oxo-5-phenylpentanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-5-({3-[1-(N,N-dimethylglycyl)piperidin-4-yl]propanoyl}amino)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-({N-[(benzyloxy)carbonyl]-β

-alanyl}amino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-[(N-benzoyl-N-methylglycyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-[(4-cyclohexylbutanoyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol

5-{[(4R)-4-amino-5-phenylpentanoyl]amino}-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-pyridin-3-ylpropanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(propylsulfonyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[3—

(2-thienyl)propanoyl]amino}-D-erythro-pentitol;

5-{[N-(tert-butoxycarbonyl)-β

-alanyl]amino}-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-{[(2-butoxyethoxy)acetyl]amino}-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-5-{[4-(dimethylamino)butanoyl]amino}-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[(3S)-3-hydroxy-3-phenylpropanoyl]amino}-D-erythro-pentitol;

1,2,4,5-tetradeoxy-5-[(N,N-diethyl-β

-alanyl)amino]-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl }amino)-D-erythro-pentitol;

5-{[N-(tert-butoxycarbonyl)glycyl]amino}-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[3-(1H-imidazol-5-yl)propanoyl]amino}-D-erythro-pentitol;

5-{[3-(4-chlorophenoxy)propanoyl]amino}-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-5-({3-[1-(N,N-diethyl-β

-alanyl)piperidin-4-yl]propanoyl}amino)-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-piperidin-3-ylpropanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-piperidin-4-ylpropanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(1H-tetrazol-1-ylacetyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(1H-imidazol-5-ylacetyl)amino]-D-erythro-pentitol;

5-{[4-(acetylamino)butanoyl]amino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-hydroxypropanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[(3-methylisoxazol-5-yl)acetyl]amino}-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-5-{[4-(dimethylamino)-4-oxobutanoyl]amino}-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-5-[(N,N-dimethylglycyl)amino]-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-[(4-aminobutanoyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-[(5-aminopentanoyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

5-[(6-aminohexanoyl)amino]-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-L-threo-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(N-methylglycyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(phenoxyacetyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-(quinolin-2-ylamino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[(1-oxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]amino}-D-erythro-pentitol;

5-{[3-(allyloxy)propanoyl]amino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(2-hydroxyhexanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-D-erythro-pentitol;

5-(β

-alanylamino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-(2-oxo-3,4,5,6-tetrahydrocyclopenta[b]pyrrol-1(2H)-yl)-D-erythro-pentitol;

5-{[N-(tert-butoxycarbonyl)-N-methylglycyl]amino}-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[(2S)-2-hydroxy-4-methylpentanoyl]amino}-D-erythro-pentitol;

5-({(4S)-4-[(tert-butoxycarbonyl)amino]-5-phenylpentanoyl}amino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-(glycylamino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[({[(1S,2R,5S)-2-isopropyl-5-methylcyclohexyl]oxy}acetyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[({[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]oxy}acetyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(phenylacetyl)amino]-D-erythro-pentitol;

5-(butanimidoylamino)-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(4-oxo-4-phenylbutanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(3-phenoxypropanoyl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[4-oxo-4-(2-thienyl)butanoyl]amino}-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(4-methylpyridin-2-yl)amino]-D-erythro-pentitol;

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-[(4-ethylpyridin-2-yl)amino]-D-erythro-pentitol;

(S,S)-N-[1-(3,5-Difluorobenzyl)-2-hydroxy-4-(propane-1-sulfonylamino)-butyl]-5-methyl-N′

,N′

-dipropyl-isophthalamide;

(S,S)-N-[1-(3,5-Difluorobenzyl)-2-hydroxy-4-(3-propylureido)-butyl]-5-methyl-N′

,N′

-dipropyl-isophthalamide;

(S,S)-N-[4-Butyrylamino-1-(3,5-difluorobenzyl)-2-hydroxybutyl]-5-methyl-N′

,N′

-dipropyl-isophthalamide;

3-[(3R,4S)-6-({3-[1-(6-aminohexanoyl)piperidin-4-yl]propanoyl}amino)-3-(3,5-difluorobenzyl)-4-hydroxyhexanoyl]-5-methyl-N,N-dipropylbenzamide;

5-{[(1Z)-N-cyanobutanimidoyl]amino}-1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-L-threo-pentitol; and

1,2,4,5-tetradeoxy-1-(3,5-difluorophenyl)-2-({3-[(dipropylamino)carbonyl]-5-methylbenzoyl}amino)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-L-threo-pentitol.

8. A method for the treatment or prevention of Alzheimer'"'"'s disease, mild cognitive impairment Down'"'"'s syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, other degenerative dementias, 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 comprising administration of a therapeutically effective amount of a compound or salt according to claim 1, to a patient in need thereof.

9. A method of treatment as in claim 8, wherein the patient is a human.

10. A method of treatment according to claim 8, wherein the disease is dementia.

11. A method for making a compound of claim 1.

13. The use of a compound or salt according to claim 1 for the manufacture of a medicament.

14. The use of a compound or salt according to claim 1 for the manufacture of a medicament for use in the treatment or prevention of Alzheimer'"'"'s disease, mild cognitive impairment Down'"'"'s syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, other degenerative dementias, 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, or diffuse Lewy body type of Alzheimer'"'"'s disease.

12. An intermediate of the formula 23: