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- Nachgewiesen in: USPTO Patent Applications
- Sprachen: English
- Document Number: 20100305091
- Publication Date: December 2, 2010
- Appl. No: 12/669843
- Application Filed: July 16, 2008
- Claim: 1. A compound of formula I: [chemical expression included] or a pharmaceutically acceptable salt or hydrate thereof; wherein: A represents a mono- or bicyclic aromatic ring system of up to 10 ring atoms, of which 0-3 are heteroatoms independently selected from O, N and S, which bears 0-3 substituents independently selected from halogen, CN, C1-4alkyl, CF3 and C1-4alkoxy; X represents a monocyclic or bicyclic ring system comprising up to 10 ring atoms, of which 1-3 are selected from N, O and S and the remainder are C, said ring system bearing 0-3 substituents independently selected from halogen, CN, R1-L, R10-L, R1R2N-L and R1CONR2; L represents a bond or a linking group selected from CO, (CO)m(CH2)n, (CO)m(CH2)nO, (CO)m(CH2)nNR2 and (CO)m(CH2)nS; m is 0 or 1; n is 0, 1, 2, 3 or 4; R1 is selected from: H; C1-6alkyl which is optionally substituted with up to 3 halogen atoms or with OH, CN, C3-6cycloalkyl, C1-4alkoxy, C1-4alkoxycarbonyl, amino, C1-4alkylamino or di(C1-4alkyl)amino; and phenyl or C3-6cycloalkyl, either of which is optionally substituted with up to 3 halogen atoms or with OH, CN, CF3, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, amino, C1-4alkylamino or di(C1-4alkyl)amino; R2 represents H or C1-4alkyl; or R1 and R2 attached to the same nitrogen atom may complete a heterocycle of up to 7 ring atoms which is optionally substituted with up to 3 halogen atoms or with OH, CN, CF3, C1-4alkyl, C1-4alkoxy, C1-4alkoxycarbonyl, amino, C1-4alkylamino or di(C1-4alkyl)amino; R3 represents H or C1-4alkyl which is optionally substituted with OH, CN, CF3, C1-4alkoxy, amino, C1-4alkylamino or di(C1-4alkyl)amino; R4 is selected from: (i) H; (ii) C1-8alkyl or C2-8alkenyl, either of which optionally bears up to 3 substituents independently selected from halogen, OH, CN, CF3, OR6, SR7, SO2R7, SO2N(R6)2, COR6, CO2R6, CON(R6)2, N(R6)2, NR6COR7 and NR6SO2R7; and (iii) C3-10cycloalkyl, C3-10cycloalkylC1-4alkyl, Het, HetC1-4alkyl, aryl or arylC1-4alkyl, any of which optionally bears up to 3 substituents independently selected from halogen, OH, oxo, CN, CF3, R7, OR6, SR7, SO2R7, SO2N(R6)2, COR6, CO2R6, CON(R6)2, N(R6)2, NR6COR7 and NR6SO2R7; where “aryl” refers to phenyl or 5- or 6-membered heteroaryl, either of which phenyl or heteroaryl is optionally fused to a 5- or 6-membered carbocycle or heterocycle, and “Het” refers to a nonaromatic mono- or bicyclic heterocyclic system of up to 10 ring atoms; or R3 and R4 together may complete a mono- or bicyclic heterocyclic system of up to 10 ring atoms which optionally bears up to 3 substituents independently selected from halogen, OH, oxo, CN, CF3, R7, OR6, SR7, SO2R7, SO2N(R6)2, COR6, CO2R6, CON(R6)2, N(R6)2, NR6COR7 and NR6SO2R7; R6 represents H or C1-6alkyl which is optionally substituted with up to 3 halogen atoms or with OH, CN, CF3, C1-4alkoxy, amino, C1-4alkylamino or di(C1-4alkyl)amino, or R6 represents phenyl, benzyl or 5- or 6-membered heteroaryl, any of which optionally bears up to 3 substituents independently selected from halogen, OH, CN, CF3, C1-4alkyl, C1-4alkoxy, amino, C1-4alkylamino and di(C1-4alkyl)amino; or two R6 groups attached to the same nitrogen atom may complete a heterocycle of up to 6 ring atoms which optionally bears up to 3 substituents independently selected from halogen, OH, oxo, CN, CF3, C1-4alkyl, C1-4alkoxy, amino, C1-4alkylamino and di(C1-4alkyl)amino; and R7 has the same definition as R6 except that R7 is not H.
- Claim: 2. A compound according to claim 1 wherein A represents phenyl, thienyl or thiazolyl.
- Claim: 3. A compound according to claim 1 wherein X represents 2-oxo-1,2-dihydropyridin-4-yl which bears a substituent R1R2N(CH2)p on the 1-position, where p is 2 or 3.
- Claim: 4. A compound according to claim 1 wherein X represents 3-pyridine which is unsubstituted or substituted in the 6-position.
- Claim: 5. A compound according to claim 4 wherein the substituent is selected from NH2, dimethylamino, piperazin-1-yl, 4-methylpiperazin-1-yl, 2-(morpholin-1-yl)ethylamino, cyclopropylmethoxy, acetylamino, 3-(dimethylamino)propoxy, methoxy, 2-hydroxy-2-methylpropylamino, morpholin-1-yl and 2-methoxyethylamino.
- Claim: 6. A compound according to claim 1 wherein X represents optionally-substituted 5-membered heteroaryl.
- Claim: 7. A compound according to claim 6 wherein X represents 1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl, 1-benzyl-1H-pyrazol-4-yl, 1H-pyrrol-2-yl, 1H-pyrazol-3-yl, 3-thienyl, 3-furyl, 2-furyl, 5-acetyl-2-thienyl or 1H-pyrazol-4-yl.
- Claim: 8. A compound according to claim 1 which is a compound of formula II: [chemical expression included] or a pharmaceutically acceptable salt or hydrate thereof; wherein: Z1 represents S or O; Z2 represents N or CR9; and R8 and R9 are independently selected from H, halogen, CN, C1-4alkyl, CF3 and C1-4alkoxy.
- Claim: 9. A compound according to claim 8 wherein Z1 is S, Z2 is CR9 and R8 is H, methyl or Cl; or Z1 is S, Z2 is N and R8 is H, methyl or Cl.
- Claim: 10. A compound of claim 8 wherein X represents 1-methylpyrazol-4-yl.
- Claim: 11. A compound according to claim 8 wherein R3 is H and R4 represents: [chemical expression included] where n is 0 or 1 and R5 represents H, C1-6alkyl, phenyl or pyridyl, said phenyl or pyridyl optionally bearing a substituent selected from halogen, CF3, C1-4alkyl and C1-4alkoxy; or R4 represents: [chemical expression included] where m is 0 or 1, V represents H, OH or NH2 and W represents CH2, CF2 or SO2.
- Claim: 12. A compound according to claim 8 wherein R4 is of formula (i) [chemical expression included] where n is 0 or 1 and R5 represents H, isopropyl, phenyl, 2-pyridyl, 5-fluoro-2-pyridyl or 6-methyl-2-pyridyl; or wherein R4 is of formula (ii) [chemical expression included] and m is 1, V is NH2 and W is CF2.
- Claim: 13. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.
- Claim: 14. A method for treating or preventing a neurodegenerative disease associated with hyperphosphorylation of tau in a human patient, said method comprising administering to said patient an effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt or hydrate thereof.
- Claim: 15. The method according to claim 14 wherein the neurodegenerative disease is Alzheimer's disease.
- Claim: 16. A method for reducing the production of hyperphosphorylated tau in a human patient, said method comprising administering to said patient an effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt or hydrate thereof.
- Claim: 17. A compound of claim 1 wherein X represents 1-methylpyrazol-4-yl.
- Claim: 18. A compound according to claim 1 wherein R3 is H and R4 represents: [chemical expression included] where n is 0 or 1 and R5 represents H, C1-6alkyl, phenyl or pyridyl, said phenyl or pyridyl optionally bearing a substituent selected from halogen, CF3, C1-4alkyl and C1-4alkoxy; or R4 represents: [chemical expression included] where m is 0 or 1, V represents H, OH or NH2 and W represents CH2, CF2 or SO2.
- Current U.S. Class: 51421/018
- Current International Class: 61; 07; 61; 07; 61
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