Aza-peptides
Provided are peptides comprising at least one azaamino acid and having β-sheet breaking ability, useful in the treatment and prevention of diseases such as alzheimer's disease, Dementia Pugilistica (including head trauma), Hereditary Cerebral Haemorrhage with amyloidosis of the Dutch type (HCHWA-D) and Vascular Dementia with amyloid angiopathy.
1 . A compound of the general Formula I:
wherein R 1 is selected from H, C 2 -C 6 acyl and C 1 -C 6 alkyl;
R 2 , R 3 , R 4 and R 5 are independently selected from H and C 1 -C 6 alkyl;
R 6 is selected from OH and NR 7 R 8 , wherein R 7 and R 8 are independently selected from H and C 1 -C 6 alkyl;
X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from CR 9 or N wherein R 9 is selected from H and C 1 -C 6 alkyl and with the condition that at least one among X 1 , X 2 , X 3 , X 4 and X 5 is N; as well as any chiral derivative thereof.
2 . The compound according to claim 1 , wherein R 1 is C 2 -C 6 acyl and R 6 is NR 7 R 8 wherein R 7 and R 8 are independently selected from H and C 1 -C 6 alkyl.
3 . The compound according to claim 1 , wherein X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from CH and N and with the condition that at least one among X 1 , X 2 , X 3 , X 4 and X 5 is N.
4 . The compound according to claim 1 , wherein R 2 , R 3 , R 4 and R 5 are H and R 1 is —C(O)CH 3 and R 6 is NH 2 ; wherein X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from CH and N and with the condition that at least one among X 1 , X 2 , X 3 , X 4 and X 5 is N.
5 . The compound according to claim 1 , wherein X 2 is N.
6 . The compound according to claim 1 , wherein X 3 is N.
7 . The compound according to claim 1 selected from the following group:
Ac-L-P-F a -F-D-NH2;
Ac-L-P a -F-F-D-NH 2 ; and
Ac-L-P a -F a -F-D-NH 2 .
8 . The compound according to claim 1 wherein the compound is utilized as a medicament.
9 . A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable excipient, diluent or carrier.
10 . A method for the manufacture of a medicament for the treatment or prevention of a disease or condition selected from Alzheimer's disease, Dementia pugilistica (including head trauma), Hereditary Cerebral Haemorrhage with amyloidosis of the Dutch type (HCHWA-D) and vascular dementia with amyloid angiopathy comprising adding the compound according to claim 1 to a medicament.
11 . The method according to claim 10 , wherein the disease is Alzheimer's disease.
12 . A method for the preparation of a medicament for the treatment of a disease associated with abnormal protein folding into amyloid and amyloid-like deposits comprising adding the compound according to claim 1 to a medicament.
13 . A process for the preparation of an aza-peptide comprising:
a. reacting at least one an aza-amino acid building block of Formula (II) with an amino acid, an aza-amino acid, a peptide, an aza-peptide or an azatide to form a aza-peptoidic bond through aza-peptide coupling:
wherein R is selected from H and C 1 -C 6 alkyl;
A is any functional group of an amino acid;
R and A can form a C 3 -C 6 -heterocycloalkyl ring and
b. removing the para-nitro carbobenzyloxy group.
14 . The process according to claim 13 wherein the at least one aza-amino acid building block in step a) is selected from Formulae III, IV, V and VI:
wherein R is selected from H and C 1 -C 6 alkyl;
R Z is selected from —CH 2 —CH═CH 2 and -tert-butyl.
15 . The process according to claim 14 wherein R is H.
16 . The process according to claim 13 for the preparation of an aza-peptide of a total sequence from 2 to 10 peptoid units in length.
17 . The process according to claim 13 for the preparation of an aza-peptide of a total sequence from 2 to 5 units peptoid units in length.
18 . The process according to claim 13 for the preparation of an aza-peptide having between 2 to 10 aza-amino acids.
19 . The process according to claim 13 for the preparation of an aza-peptide having between 2 to 5 aza-amino acids.
20 . The process according to claim 13 for the preparation of an aza-peptide of Formula I.
21 . A synthetic aza-peptide building block having a Formula selected from Formulae III, IV, V and VI.
22 . A synthetic aza-peptide building block of claim 21 wherein R is H.
23 . A medicament comprising the compound according to claim 1 .
24 . A method for the treatment or prevention of a disease or condition comprising administering an effective amount of the compound according to claim 1 to a patient in need thereof.
25 . A method for the treatment or prevention of a disease or condition comprising administering an effective amount of the compound according to claim 1 to a patient in need thereof, wherein the disease or condition is selected from the group consisting of Alzheimer's disease, Dementia pugilistica (including head trauma), Hereditary Cerebral Haemorrhage with amyloidosis of the Dutch type (HCHWA-D) and vascular dementia with amyloid angiopathy.
26 . The method according to claim 25 , wherein the disease is Alzheimer's disease.
27 . A method for the treatment of a disease associated with abnormal protein folding into amyloid and amyloid-like deposits comprising administering an effective amount of the compound according to claim 1 to a patient in need thereof.