Piperazine derivatives for treating disorders
View Patent ↗Anti-angiogenic treatments, treatments of hyperpermeability disorders, treatments of neuropathic and neurodegenerative disorders, pain treatments, methods of reducing the risk of pre-eclampsia and compounds for use in such methods are described.
1. A method of dose-dependent treatment of ocular neovascularisation, comprising administering to a subject in need thereof a compound of Formula (I)
or a pharmaceutically acceptable salt thereof;
wherein:
n=1, 2, 3 or 0;
R 1 =a 4- to 8-membered carbocyclic group, which may have one or more substituent; a 4- to 8-membered heterocyclic group comprising one oxygen atom, which may have one or more substituent; a 4- to 8-membered heterocyclic group comprising one nitrogen atom, which may have one or more substituent, a 4- to 8-membered heterocyclic group comprising one nitrogen atom and one oxygen atom which may have one or more substituent; a 4- to 8-membered heterocyclic group comprising two nitrogen atoms which may have one or more substituent; a 4- to 8-membered heterocyclic group comprising three nitrogen atoms which may have one or more substituent, or a condensed aromatic heterocyclic group, which may have one or more substituent;
X=CH, NH or N;
Y=CH, NH or N;
Z=O, S, N or NH; and
R 2 =H, a C 1-6 alkyl group; a phenyl group; a 4- to 8-membered heterocyclic group; or a condensed aromatic heterocyclic group, each of which may have one or more substituent.
2. The method according to claim 1 , wherein
n=1, 2, 3 or 0;
R 1 =a 4- to 8-membered carbocyclic group, which may have one or more substituent; a 4- to 8-membered heterocyclic group having one nitrogen atom, which may have one or more substituent, a 4- to 8-membered heterocyclic group comprising one nitrogen atom and one oxygen atom which may have one or more substituent, or a 4- to 8-membered heterocyclic group comprising two nitrogen atoms which may have one or more substituent;
X=CH or N;
Y=CH or N;
Z=O, S or NH; and
R 2 =a phenyl group; a 4- to 8-membered heterocyclic group or a condensed aromatic heterocyclic group.
3. A method of topically treating ocular neovascularisation, comprising topically administering a compound of Formula (I) to a subject in need thereof:
or a pharmaceutically acceptable salt thereof;
wherein:
n=1, 2, 3 or 0;
R 1 =a 4- to 8-membered carbocyclic group, which may have one or more substituent; a 4- to 8-membered heterocyclic group comprising one oxygen atom, which may have one or more substituent; a 4- to 8-membered heterocyclic group comprising one nitrogen atom, which may have one or more substituent, a 4- to 8-membered heterocyclic group comprising one nitrogen atom and one oxygen atom which may have one or more substituent; a 4- to 8-membered heterocyclic group comprising two nitrogen atoms which may have one or more substituent; a 4- to 8-membered heterocyclic group comprising three nitrogen atoms which may have one or more substituent, or a condensed aromatic heterocyclic group, which may have one or more substituent,
X=CH, NH or N;
Y=CH, NH or N;
Z=O, S, N or NH; and
R 2 =H, a C 1-6 alkyl group; a phenyl group; a 4- to 8-membered heterocyclic group; or a condensed aromatic heterocyclic group, each of which may have one or more substituent.
4. The method according to claim 3 , wherein the topical treatment or prevention of ocular neovascularisation is dose-dependent treatment or prevention.
5. The method according to claim 1 , wherein the ocular neovascularisation is choroidal neovascularisation or wherein the ocular neovascularisation is retinal neovascularisation.
6. A compound of Formula (I)
or a pharmaceutically acceptable salt thereof;
wherein:
n=1, 2, 3 or 0
R 1 =a 4- to 8-membered carbocyclic group, which may have one or more substituent; a 4- to 8-membered heterocyclic group comprising one oxygen atom, which may have one or more substituent; a 4- to 8-membered heterocyclic group comprising one nitrogen atom, which may have one or more substituent, a 4- to 8-membered heterocyclic group comprising one nitrogen atom and one oxygen atom which may have one or more substituent; a 4- to 8-membered heterocyclic group comprising two nitrogen atoms which may have one or more substituent; a 4- to 8-membered heterocyclic group comprising three nitrogen atoms which may have one or more substituent, or a condensed aromatic heterocyclic group, which may have one or more substituent;
X=CH, NH or N;
Y=CH, NH or N;
Z=O, S, N or NH; and
R 2 =H, a C 1-6 alkyl group; a phenyl group; a 4- to 8-membered heterocyclic group or a condensed aromatic heterocyclic group, each of which may have one or more substituent.
7. The compound according to claim 6 , wherein:
n=1, 2, 3 or 0;
R 1 =a 4- to 8-membered carbocyclic group, which may have one or more substituent; a 4- to 8-membered heterocyclic group having one nitrogen atom, which may have one or more substituent, a 4- to 8-membered heterocyclic group comprising one nitrogen atom and one oxygen atom which may have one or more substituent, or a 4- to 8-membered heterocyclic group comprising two nitrogen atoms which may have one or more substituent;
X=CH or N;
Y=CH or N;
Z=O, S or NH; and
R 2 =a phenyl group; a 4- to 8-membered heterocyclic group or a condensed aromatic heterocyclic group.
8. The compound according to claim 6 , wherein R 1 represents a 2-, 3- or -4-pyridyl group, each of which may have one or more substituent; or wherein R 1 represents pyrimidinyl group, which may have one or more substituent; or wherein R 1 represents a phenyl group, which may have one or more substituent.
9. The compound according to claim 6 , wherein R 2 represents a nitrogen- or oxygen-containing 4- to 8-membered heteroaromatic ring, which may have one or more substituent.
10. The compound according to claim 6 , wherein R 2 represents a 2- or 3- or 4-pyridyl group, each of which may have one or more substituent.
11. The compound according to claim 6 , wherein R 2 represents:
an oxygen-containing 4- to 8-membered heterocyclic ring, which may have one or more substituent; or
a 4- to 8-membered carbocyclic group, which may have one or more substituent.
12. The compound according to claim 6 , wherein R 2 represents:
a phenyl group, which may have one or more substituent; or H, or C 1-6 alkyl which may have one or more substituent; or a tetrahydropyranyl group, which may have one or more substituent.
13. The compound according to claim 6 , wherein:
X=Y=CH and Z=O;
X=Y=CH and Z=S;
X=Y=N and Z=O; or
X=N, Y=CH and Z=O.
14. The method according to claim 1 , wherein R 1 represents a 2-, 3- or -4-pyridyl group, each of which may have one or more substituent; or wherein R 1 represents pyrimidinyl group, which may have one or more substituent; or wherein R 1 represents a phenyl group, which may have one or more substituent.
15. The method according to claim 1 , wherein R 2 represents a nitrogen- or oxygen-containing 4- to 8-membered heteroaromatic ring, which may have one or more substituent.
16. The method according to claim 1 , wherein R 2 represents a 2- or 3- or 4-pyridyl group, each of which may have one or more substituent.
17. The method according to claim 1 , wherein R 2 represents:
an oxygen-containing 4- to 8-membered heterocyclic ring, which may have one or more substituent; or
a 4- to 8-membered carbocyclic group, which may have one or more substituent.
18. The method according to claim 1 , wherein R 2 represents:
a phenyl group, which may have one or more substituent; or H, or C 1-6 alkyl which may have one or more substituent; or a tetrahydropyranyl group, which may have one or more substituent.
19. The method according to claim 1 , wherein:
X=Y=CH and Z=O;
X=Y=CH and Z=S;
X=Y=N and Z=O; or
X=N, Y=CH and Z=O.
20. The method according to claim 5 , wherein the choroidal neovascularisation is macular degeneration.