RU2007105141A - APPLICATION OF CYCLOSPORINS FOR TREATMENT OF ALZHEIMER'S DISEASE - Google Patents

Claims (6)

1. The use of non-immunosuppressive cyclophilin-binding cyclosporin for the manufacture of a medicament for the treatment or prevention of pathological conditions associated with the formation and / or secretion of Aβ (amyloid-beta peptides), for example, Alzheimer's disease, Parkinson's disease, tau-patium, prion diseases, frontotemporal dementia, striatonigral degeneration, dementia with Levi bodies, Huntington’s disease, Peak’s disease, amyloidosis and other neurodegenerative disorders associated with increased the development of Aβ. 2. A method of treating or preventing pathological conditions associated with the formation and / or secretion of Aβ, comprising administering to said patient an effective amount of a cyclophilin-binding cyclosporin that does not have an immunosuppressive effect. 3. The use according to claim 1 or the method according to claim 2, in which the cyclophilin-binding cyclosporin having no immunosuppressive effect is a compound of formula A

wherein B is an amino acid residue of formula B

where a denotes a bond with the remainder of αAbu at position 2; b is a bond to residue C at position 4; Alk is a straight or branched chain C ₂ -C ₆ alkylene or C ₃ -C ₆ cycloalkylene, and R is a carboxy or alkyloxycarbonyl radical; the radical —NR ₁ R ₂ in which R ₁ and R _{2 are the} same or different and are hydrogen, alkyl, C ₂ -C ₄ alkenyl, C3-C6 cycloalkyl, phenyl (optionally substituted with halogen, alkoxy, alkoxycarbonyl, amino, alkylamino or dialkylamino ) or benzyl, or a saturated or unsaturated heterocyclic radical containing 5 or 6 atoms in the cycle and 1-3 heteroatoms, or in which R ₁ and R ₂ form, together with the nitrogen atom to which they are attached, a saturated or unsaturated heterocycle containing 4 -6 atoms in the cycle and optionally additionally containing a heteroatom selected from nitrogen, oxygen or sulfur and optionally substituted with alkyl, phenyl or benzyl; radical of the formula

wherein R ₁ and R ₂ are the same as described above, R ₃ is hydrogen or an alkyl radical and n is an integer from 2 to 4, and where alkyl is straight or branched C ₁ -C ₄ alkyl; C is MeLeu or 4-hydroxy-MeLeu; and their pharmaceutically acceptable salts. 4. The use according to claim 1 or the method according to claim 2, in which the cyclophilin-binding cyclosporin having no immunosuppressive effect is a compound of formula I:

in which W is MeBmt, dihydro-MeBmt or 8'-hydroxy-MeBmt, X is αAbu, Val, Thr, Nva or O-methyltreonine (MeOThr), R is Sar or (D) -MeAla, Y is MeLeu, γ-hydroxy-MeLeu, MeIle, MeVal, MeThr, MeAla, MeTyr, MeTyr (O-PO (OH) ₂ ), MeaIle or MeaThr, or Pro; Z is Val, Leu, N-Alk-Val or N-Alk-Leu wherein Alk is Me or Me substituted with vinyl optionally substituted with phenyl or N-, S- or O-heteroaryl containing six membered rings, or phenyl optionally substituted with halogen, and Q is MeLeu, γ-hydroxy-MeLeu or MeAla. 5. The use according to claim 1 or the method according to claim 2, in which the cyclophilin-binding cyclosporin having no immunosuppressive effect is a compound selected from the group including a) [dihydro-MeBmt] ¹ - [γ-hydroxy-MeLeu] ⁴ -cyclosporin A, b) [MeVal] ⁴ -cyclosporin A, c) [MeIle] ⁴ -cyclosporin A, g) [MeThr] ⁴ -cyclosporin A, d) [γ-hydroxy-MeLeu] ⁴ -cyclosporin A, e) [Nva] ² - [γ-hydroxy-MeLeu] ⁴ -cyclosporin A, g) [γ-hydroxy-MeLeu] ⁴ - [γ-hydroxy-MeLeu] ⁶ -cyclosporin A, h) [MeVal] ⁵ -cyclosporin A, i) [MeOThr] ² - [(D) MeAla] ³ - [MeVal] ⁵ -cyclosporin A or j) [8'-hydroxy-MeBmt] ¹ -cyclosporin A. m) [N-benzyl-Val] ⁵ -cyclosporin A, o) [N-5-fluoro-benzyl-Val] ⁵ -cyclosporin A, o) [N-allyl-Val] ⁵ -cyclosporin A, p) [N-3-phenyl-allyl-Val] ⁵ -cyclosporin A, c) [Pro] ⁴ -cyclosporin A or r) [γ-hydroxy-MeLeu] ⁹ -cyclosporin A. 6. The use according to claim 1 or the method according to claim 2, in which the cyclophilin-binding cyclosporin having no immunosuppressive effect is [MeVal] ⁴ -cyclosporin A.