Substituted hydroxyethylamine aspartyl protease inhibitors
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Abstract
The invention relates to novel compounds and also to methods of treating at least one disease, disorder, or condition associated with amyloidosis using such compounds. Amyloidosis refers to a collection of diseases, disorders, and conditions associated with abnormal deposition of A-beta protein.
36 Citations
24 Claims
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1. A compound of formula (I),
- View Dependent Claims (2, 3, 4, 5, 6, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
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2. The compound according to claim 1, wherein R1 is selected from —
- CH2-phenyl, wherein the phenyl ring is optionally substituted with at least one group independently selected from -halogen, —
C1—
C2 alkyl, -0-methyl, and —
OH.
- CH2-phenyl, wherein the phenyl ring is optionally substituted with at least one group independently selected from -halogen, —
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3. The compound according to claim 1, wherein R1 is selected from 4-hydroxy-benzyl, 3-hydroxy-benzyl, 5-chloro-thiophen-2-yl-methyl, 5-chloro-3-ethyl-thiophen-2-yl-methyl, 3,5-difluoro-2-hydroxy-benzyl, piperidin-4-yl-methyl, 2-oxo-piperidin-4-yl-methyl, 2-oxo-1,2-dihydro-pyridin-4-yl-methyl, 5-hydroxy-6-oxo-6H-pyran-2-yl-methyl, 3,5-difluoro-4-hydroxy-benzyl, 3,5-difluoro-benzyl, 3-fluoro-4-hydroxy-benzyl, 3- luoro-5-hydroxy-benzyl, and 3-fluoro-benzyl.
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4. The compound according to claim 1, wherein Rc is selected from formulae (VIa) and (VIb)
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5. The compound according to claim 1, wherein Rc is selected from 6-isobutyl-1,1-dioxo-1λ
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6-thiochroman-4-yl, 6-Isopropyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, 6-ethyl-2,2-dioxo-2λ
6-isothiochroman-4-yl, 7-ethyl-1,2,3,4-tetrahydro-naphthalen-1-yl, and 1-(3-tert-Butyl-phenyl)-cyclohexyl.
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6-thiochroman-4-yl, 6-Isopropyl-2,2-dioxo-2λ
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6. The compound according to claim 1, wherein R2 is selected from hydrogen, 3-Bromo-[1,2,4]thiadiazol-5-ylamino, [1,2,4]thiadiazol-5-ylamino, 4-Chloro-[1,2,5]thiadiazol-3-ylamino, [1,2,5]thiadiazol-3-ylamino, thiazol-2-ylamino, 5-Bromo-[1,3,4]thiadiazol-2-ylamino, [1,3,4]thiadiazol-2-ylamino, 5-Amino-[1,3,4]thiadiazol-2-ylamino, 2-Bromo-thiazol-5-ylamino, thiazol-5-ylamino, 5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamino, 5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamino, 5-Amino-[1,3,4]oxadiazol-2-ylamino, 1-trityl-1H-[1,2,4]triazol-3-ylamino, 1H-[1,2,4]triazol-3-ylamino, oxazol-2-ylamino, 5-Bromo-2-trityl-2Hl-[1,2,3]triazol-4-ylamino, 2-trityl-2H-[1,2,3]triazol-4-ylamino, 5-Bromo-2H-[1,2,3]triazol-4-ylamino, 2H-[1,2,3]triazol-4-ylamino, thiophen-2-ylamino, 3-methyl-5-nitro-3H-imidazol-4-ylamino, 4-Cyano-5-phenyl-isothiazol-3-ylamino, 4-phenyl-[1,2,5]thiadiazol-3-ylamino, 3,4-dioxo-cyclobut-1-enylamino, 2-methoxy-3,4-dioxo-cyclobut-1-enylamino, and 2-methylamino-3,4-dioxo-cyclobut-1-enylamino.
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14. A method of treating at least one condition selected from Alzheimer'"'"'s disease, dementia associated with Alzheimer'"'"'s disease, Parkinson'"'"'s disease and dementia associated with Parkinson'"'"'s disease, comprising:
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administering to a host a composition comprising a therapeutically effective amount of at least one beta-secretase inhibitor of formula (I) according to claim 1, further comprising a composition comprising a beta-secretase complexed with at least one compound of formula (I), or pharmaceutically acceptable salt thereof.
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15. A method or treating the onset of dementia associated with Alzheimer'"'"'s disease, or dementia associated with Parkinson'"'"'s disease comprising:
- administering to a patient a therapeutically effective amount of at least one compound of formula (I),
or a pharmaceutically acceptable salt thereof according to claim 1 to the patient.
- administering to a patient a therapeutically effective amount of at least one compound of formula (I),
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16. A method of inhibiting beta-secretase activity in a cell, the method comprising the step of adding to the cell an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, and Rc are defined as in claim 1.
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17. A method of prescribing a medication for Alzheimer'"'"'s disease, dementia associated with Alzheimer'"'"'s disease, Parkinson'"'"'s disease or dementia associated with Parkinson'"'"'s disease comprising:
- identifying in a patient symptoms associated with at least one disorder, condition or disease associated with amyloidosis; and
prescribing at least one dosage form of at least one compound of formula (I),
- identifying in a patient symptoms associated with at least one disorder, condition or disease associated with amyloidosis; and
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18. An article of manufacture, comprising:
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(a) at least one dosage form of at least one compound of formula (I), or a stereoisomer, or pharmaceutically acceptable salt thereof, according to claim 1; (b) a package insert providing that a dosage form comprising a compound of formula (I) should be administered to a patient in need of therapy for at least one disorder, condition selected from Alzheimer'"'"'s disease, dementia associated with Alzheimer'"'"'s disease, Parkinson'"'"'s disease and dementia associated with Parkinson'"'"'s disease; and (c) at least one container in which at least one dosage form of at least one compound of formula (I) is stored.
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19. An article of manufacture, comprising:
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(a) at least one oral dosage form of at least one compound of formula (I) or a stereoisomer, or pharmaceutically acceptable salt thereof, according to claim 1; in a dosage amount ranging from about 2 mg to about 1000 mg; (b) a package insert providing that an oral dosage form comprising;
a compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg should be administered to a patient in need of therapy for at least one disorder, condition or disease selected from Alzheimer'"'"'s disease, dementia associated with Alzheimer'"'"'s disease, Parkinson'"'"'s disease and dementia associated with Parkinson'"'"'s disease; and(c) at least one container In which at least one oral dosage form of at least one compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg is stored.
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20. An article of manufacture, comprising:
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(a) at least one oral dosage form of at least one compound of formula (I) according to claim 1, in a dosage amount ranging from about 2 mg to about 1000 mg in combination with (b) at least one therapeutically active agent;
associated with(c) a package insert providing that an oral dosage form comprising;
a compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg in combination with at least one therapeutically active agent should be administered to a patient in need of therapy for at least one disorder, condition or diseases selected from Alzheimer'"'"'s disease, dementia associated with Alzheimer'"'"'s disease, Parkinson'"'"'s disease and dementia associated with Parkinson'"'"'s disease; and(d) at least one container in which at least one dosage form of at least one compound of formula (I) in a dosage amount ranging from about 2 mg to about 1000 mg in combination with a therapeutically active agent is stored.
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21. The article of manufacture according to claim 20 wherein the therapeutically active agent, is selected from an antioxidant, an anti-inflammatory, a gamma-secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase inhibitor, a statin, an A-beta, and an anti-A-beta antibody.
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22. An article of manufacture, comprising:
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(a) at least one parenteral dosage form of at least one compound of formula (I) according to claim 1, in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL; (b) a package insert providing that a parenteral dosage form comprising;
a compound of formula (I) in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL should be administered to a patient in need of therapy for at least one disorder, condition or disease selected from Alzheimer'"'"'s disease, dementia associated with Alzheimer'"'"'s disease, Parkinson'"'"'s disease and dementia associated with Parkinson'"'"'s disease; and(c) at least one container in which at least one parenteral dosage form of at least one compound of formula (I) in a dosage amount ranging from about 0.2 mg/mL to about 50 mg/mL is stored.
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23. A kit comprising:
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(a) at least one dosage form of at least one compound according to claim 1; and (b) at least one container in which at least one dosage form of at least one compound according to claim 1 is stored.
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24. A method of manufacture of a medicament for treating Alzheimer'"'"'s disease, comprising:
- adding an effective amount of at least one compound of formula (I) as defined in claim 1, to a pharmaceutically acceptable carrier.
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2. The compound according to claim 1, wherein R1 is selected from —
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7. A method of treating at least one condition selected from Alzheimer'"'"'s disease, dementia associated with Alzheimer'"'"'s disease, Parkinson'"'"'s disease and dementia associated with Parkinson'"'"'s disease, comprising:
administering to a host a composition comprising a therapeutically effective amount of at least one compound of formula (I), - View Dependent Claims (8, 9, 10, 11, 12, 13)
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8. The method according to claim 7, wherein R1 is selected from —
- CH2-phenyl, wherein the phenyl ring is optionally substituted with at least one group independently selected from -halogen, —
C1—
C2 alkyl, —
O-methyl, and —
OH.
- CH2-phenyl, wherein the phenyl ring is optionally substituted with at least one group independently selected from -halogen, —
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9. The method according to claim 7, wherein R1 is selected from 4-hydroxy-benzyl, 3-hydroxy-benzyl, 5-chloro-thiophen-2-yl-methyl, 5-chloro-3-ethyl-thiophen-2-yl-methyl, 3,5-difluoro-2-hydroxy-benzyl, piperidin-4-yl-methyl, 2-oxo-piperidin-4-yl-methyl, 2-oxo-1,2-dihydro-pyridin-4-yl-methyl, 5-hydroxy-6-oxo-6H-pyran-2-yl-methyl, 3,5-difluoro-4-hydroxy-benzyl, 3,5-difluoro-benzyl, 3-fluoro-4-hydroxy-benzyl, 3- fluoro-5-hydroxy-benzyl, and 3-fluoro-benzyl.
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10. The method according to claim 7, wherein Rc is selected from formulae (VIa) and (VIb),
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11. The method according to claim 7, wherein Rc is selected from 6-isobutyl-1,1-dioxo-186-thiochroman-4-yl, 6-4-yl, 7-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl, and 1-(3-tert-Butyl-phenyl)-cyclohexyl.
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12. The method according to claim 7, wherein R2 is selected from hydrogen, 3-Bromo-[1,2,4]thiadiazol-5-ylamino, [1,2,4]thiadiazol-5-ylamino, 4-Chloro-[1,2,5]thiadiazol-3-ylamino, [1,2,5]thiadiazol-3-ylamino, thiazol-2-ylamino, 5-Bromo-[1,3,4]thiadiazol-2-ylamino, [1,3,4]thiadiazol-2-ylamino, 5-Amino-[1,3,4]thiadiazol-2-ylamino, 2-Bromo-thiazol-5-ylamino, thiazol-5-ylamino, 5-trifluoromethyl-[1,3,4]thiadiazol-2-ylamino, 5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamino, 5-Amino-[1,3,4]oxadiazol-2-ylamino, 1-trityl-1H-[1,2,4]triazol-3-ylamino, 1H-[1,2,4]triazol-3-ylamino, oxazol-2-ylamino, 5-Bromo-2-trityl-2H-[1,2,3]triazol-4-ylamino, 2-trityl-2H-[1,2,3]triazol-4-ylamino, 5-Bromo-2H-[1,2,3]triazol-4-ylamino, 2H-[1,2,3]triazol-4-ylamino, thiophen-2-ylamino, 3-methyl-5-nitro-3H-imidazol-4-ylamino, 4-Cyano-5-phenyl-isothiazol-3-ylamino, 4-phenyl-[1,2,5]thiadiazol-3-ylamino, 3,4-dioxo-cyclobut-1-enylamino, 2-methoxy-3,4-dioxo-cyclobut-1-enylamino, and 2-methylamino-3,4-dioxo-cyclobut-1-enylamino.
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13. The method according to claim 7, wherein the condition is Alzheimer'"'"'s disease.
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8. The method according to claim 7, wherein R1 is selected from —
Specification
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Current AssigneeElan Pharmaceuticals Incorporated (Perrigo Company PLC)
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Original AssigneeElan Pharmaceuticals Incorporated (Perrigo Company PLC)
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InventorsMaillard, Michel, Tucker, John, Aquino, Jose, Shah, Neerav, Brogley, Louis, Tung, Jay S., Bowers, Simeon, Jagodzinska, Barbara, Probst, Gary, Dressen, Darren, John, Varghese
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Primary Examiner(s)Solola; Taofiq A
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Application NumberUS12/396,989Publication NumberTime in Patent Office665 DaysField of Search514/362, 514/314, 548/128, 546/159US Class Current514/314CPC Class CodesA61P 25/00 Drugs for disorders of the ...A61P 25/16 Anti-Parkinson drugsA61P 25/28 for treating neurodegenerat...A61P 29/00 Non-central analgesic, anti...A61P 43/00 Drugs for specific purposes...C07C 215/28 and containing six-membered...C07C 215/50 with amino groups and the s...C07C 217/30 having the oxygen atom of a...C07C 217/34 by halogen atoms, by trihal...C07C 217/48 the carbon skeleton being u...C07C 217/52 having etherified hydroxy g...C07C 217/58 with amino groups and the s...C07C 225/06 and acyclicC07C 225/20 having amino groups bound t...C07C 229/16 to carbon atoms of hydrocar...C07C 229/42 with carboxyl groups linked...C07C 229/60 with amino and carboxyl gro...C07C 233/43 having the carbon atom of t...C07C 237/20 the carbon skeleton contain...C07C 237/30 having the nitrogen atom of...C07C 2601/02 : with a three-membered ringC07C 2601/14 : The ring being saturatedC07C 2602/04 : One of the condensed rings ...C07C 2602/10 : the other ring being six-me...C07C 2602/42 : the bicyclo ring system con...C07C 2603/18 : Fluorenes; Hydrogenated flu...C07C 2603/74 : AdamantanesC07C 271/12 : to hydrogen atoms or to car...C07C 311/24 : of an acyclic saturated car...C07C 317/28 : with sulfone or sulfoxide g...C07C 323/25 : the carbon skeleton being a...C07C 323/30 : having the sulfur atom of a...C07C 323/32 : having at least one of the ...C07D 207/323 : with only hydrogen atoms or...C07D 207/325 : with substituted hydrocarbo...C07D 213/38 : having only hydrogen or hyd...C07D 215/42 : attached in position 4C07D 231/12 : with only hydrogen atoms, h...C07D 231/38 : Nitrogen atoms nitro radica...C07D 233/54 : having two double bonds bet...C07D 233/64 : with substituted hydrocarbo...C07D 233/88 : Nitrogen atoms, e.g. allantoinC07D 239/42 : One nitrogen atom nitro rad...C07D 239/48 : Two nitrogen atomsC07D 249/04 : 1,2,3-Triazoles; Hydrogenat...C07D 249/06 : with aryl radicals directly...C07D 249/14 : Nitrogen atomsC07D 257/04 : Five-membered ringsC07D 263/34 : with hetero atoms or with c...C07D 271/113 : with oxygen, sulfur or nitr...C07D 275/02 : not condensed with other ringsC07D 277/42 : Amino or imino radicals sub...C07D 285/08 : 1,2,4-Thiadiazoles; Hydroge...C07D 285/10 : 1,2,5-Thiadiazoles; Hydroge...C07D 285/135 : Nitrogen atomsC07D 307/52 : Radicals substituted by nit...C07D 309/14 : Nitrogen atoms not forming ...C07D 311/74 : Benzo[b]pyrans, hydrogenate...C07D 333/36 : Nitrogen atomsC07D 335/06 : Benzothiopyrans; Hydrogenat...C07D 401/12 : linked by a chain containin...C07D 403/12 : linked by a chain containin...C07D 405/12 : linked by a chain containin...C07D 409/12 : linked by a chain containin...C07D 413/04 : directly linked by a ring-m...C07D 413/12 : linked by a chain containin...C07D 417/12 : linked by a chain containin...C07D 419/12 : linked by a chain containin...C07D 495/04 : Ortho-condensed systems