Benzamide 2-hydroxy-3-diaminoalkanes

• US 7,223,774 B2
• Filed: 04/21/2004
• Issued: 05/29/2007
• Est. Priority Date: 04/21/2003
• Status: Expired due to Fees

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Tucker, John, John, Varghese, Aquino, Jose, Tenbrink, Ruth, Hom, Roy, Pulley, Shon
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US10/829,106
• Publication Number:
  US 20050032848A1
• Time in Patent Office: 1,133 Days
• Field of Search: 544/406, 546/298, 546/316, 546/323, 546/163, 548/248, 548/267.2, 548/323.1, 548/374.1, 549/23, 549/72, 549/404, 564/185, 514/354, 514/355, 514/311, 514/494, 514/617, 514/432
• US Class Current: 514/311
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• 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 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 215/46 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/90 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 241/24 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 249/10 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 261/18 Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 311/68 with nitrogen atoms directly attached in position 4
• CPC Class Codes: C07D 333/38 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 335/06 Benzothiopyrans; Hydrogenated benzothiopyrans

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 also useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.

Claims

1. A compound of the formula:

2. A compound according to claim 1, wherein:

Z is aryl or heteroaryl, wherein each ring is independently optionally substituted with 1 or 2 groups independendently selected from halogen, —

OH, —

OCF₃, —

O-phenyl, —

CN, —

NR₁₀₀R₁₀₁, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, (CH₂)_0-3 (C₃-C₇ cycloalkyl), aryl, heteroaryl, or heterocyclyl wherein, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups are optionally substituted with 1 or 2 substitutents independently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halogen, —

OH, —

CN, or —

NR₁₀₀R₁₀₁.

3. A compound according to claim 1, wherein X is —

(C═

O)—

.

4. A compound according to claim 1, wherein:

R₁ is —

C₁-C₆ alkyl-aryl, —

C₁-C₆ alkyl-heteroaryl, or —

C₁-C₆ alkyl-heterocyclyl, wherein each aryl group at each occurrence is optionally substituted with 1, 2 or 3 R₅₀ groups;

wherein R₅₀ is independently selected from halogen, OH, SH, CN, —

CO—

(C₁-C₄ alkyl), —

NR₇R₈, —

S(O)_0-2—

(C₁-C₄ alkyl), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, or C₃-C₈ cycloalkyl;

wherein the alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl groups are optionally substituted with 1 or 2 substituents independently selected from the group consisting of C₁-C₄ alkyl, halogen, OH, —

NR₅R₆, CN, C₁-C₄ haloalkoxy, NR₇R₈, and C₁-C₄ alkoxy;

wherein R₅ and R₆ at each occurrence are independently H or C₁-C₆ alkyl;

or

wherein R₅ and R₆ and the nitrogen to which they are attached, at each occurrence form a 5 or 6 membered heterocycloalkyl ring; and

wherein R₇ and R₈ are independently selected from the group consisting of H;

—

C₁-C₄ alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —

OH, —

NH₂, and halogen;

—

C₃-C₆ cycloalkyl;

—

(C₁-C₄ alkyl)—

O—

(C₁-C₄ alkyl);

—

C₂-C₄ alkenyl; and

—

C₂-C₄ alkynyl;

wherein each heteroaryl at each occurrence is optionally substituted with 1 or 2 R₅₀ groups;

wherein each heterocycloalkyl group at each occurrence is optionally substituted with 1 or 2 groups that are independently R₅₀ or ═

O.

5. A compound according to claim 1, wherein R₂ and R₃ are hydrogen.

6. A compound according to claim 1, wherein R₁₅ is hydrogen.

7. A compound according to claim 1 wherein one of x₁, x₂, or x₃ is SO₂.

8. A compound according to claim 1 wherein one of x₁, x₂, or x₃ is NH.

9. A compound according to claim 8 wherein x₁, x₂, and x₃ are each CH₂.

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

N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)pyridine-2-carboxamide;

N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)pyrazine-2-carboxamide;

N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide;

3-amino-N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)-1H-1,2,4-triazole-5-carboxamide;

N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)-5-methylisoxazole-3-carboxamide;

N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)-6-hydroxypyridine-2-carboxamide;

N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)-1H-imidazole-4-carboxamide;

N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)nicotinamide;

N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)-1H-pyrazole-4-carboxamide;

N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)isonicotinamide;

5-chloro-N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-2-hydroxypropyl)thiophene-2-carboxamide;

N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-neopentyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}propyl)benzamide;

N-[(1S,2R)-3-{[(4S)-6-tert-butoxy-1,2,3,4-tetrahydroquinolin-4-yl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]benzamide;

N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-7-neopentyl-1,2,3,4-tetrahydronaphthalen-1-yl]amino}propyl)benzamide;

N-[(1S,2R)-3-{[(1S)-7-tert-butoxy-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]benzamide;

N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-([(4R)-6-neopentyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino)propyl)benzamide;

N-[(1S,2R)-3-([(4R)-6-tert-butoxy-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino)-1-(3,5-difluorobenzyl)-2-hydroxypropyl]benzamide;

N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-3,5-dimethylbenzamide; and

N-((1S, 2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-1H-isothiochromen-4-yl]amino}-2-hydroxypropyl)-4-(2-methoxyethyl)benzamide.

11. A method for the treatment 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.

12. A method of treatment as in claim 11, wherein the patient is a human.

13. A pharmaceutical composition comprising a compound according to claim 1 in combination with a physiologically acceptable carrier or excipient.