TREATMENT OF CNS DISEASES WITH sGC STIMULATORS
The present disclosure relates to the use of stimulators of soluble guanylate cyclase (sGC), pharmaceutically acceptable salts thereof and pharmaceutical formulations or dosage forms comprising them, alone or in combination with one or more additional agents, for the treatment of various CNS diseases, wherein an increase in sGC stimulation, or an increase in the concentration of nitric oxide (NO), or cyclic guanosine 3′,5′-monophosphate (cGMP) or both, or an upregulation of the NO-sGC-cGMP pathway is desirable. Compounds useful in the methods of the invention are those of Formula (I) or pharmaceutically acceptable salts thereof.
1 . A method of treating a CNS disease, health condition or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
J C is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 fluoroalkyl substituted with 1 to 3 fluoro atoms;
X is N or C(J C1 );
J C1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 fluoroalkyl substituted with 1 to 3 fluoro atoms;
each J B is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 fluoroalkyl substituted with 1 to 3 fluoro atoms;
J D is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl and C 1-6 fluoroalkyl substituted with 1 to 3 fluoro atoms; and
n is an integer selected from 0, 1, 2, 3 or 4.
2 . The method of claim 1 , wherein:
J C is selected from the group consisting of hydrogen, halogen and C 1-6 alkyl;
X is N or C(J C1 );
J C1 is selected from the group consisting of hydrogen, halogen and C 1-6 alkyl;
each J B is independently selected from the group consisting of hydrogen, halogen and C 1-6 alkyl;
J D is selected from the group consisting of hydrogen, halogen and C 1-6 alkyl; and
n is an integer selected from 0, 1, 2, 3 or 4.
3 . The method of claim 1 or 2 , wherein the compound is represented by Formula IA:
or a pharmaceutically acceptable salt thereof.
4 . The method of any one of claims 1-3 , wherein J C1 is H, F or Cl.
5 . The method of any one of claims 1-3 , wherein J C1 is H.
6 . The method of any one of claims 1-3 , wherein J C1 is F.
7 . The method of claim 1 or 2 , wherein the compound is represented by Formula IB:
or a pharmaceutically acceptable salt thereof.
8 . The method of any one of claims 1-7 , wherein n is 2 or 3.
9 . The method of any one of claims 1-7 , wherein n is 0 or 1.
10 . The method of any one of claims 1-9 , wherein each J B is independently H, F or C 1-4 alkyl.
11 . The method of claim 10 , wherein each J B is independently F or methyl.
12 . The method of claim 8 , wherein n is 2 and J B are both F or one of J B is F and the other is methyl.
13 . The method of claim 8 , wherein n is 3 and two of J B are F and the other is methyl.
14 . The method of claim 9 , wherein n is 1 and J B is F.
15 . The method of claim 9 , wherein n is 0.
16 . The method of any one of claims 1-15 , wherein J D is hydrogen.
17 . The method of any one of claims 1-15 , wherein J D is F, Cl or methyl.
18 . The method of any one of claims 1-15 , wherein J D is F.
19 . The method of any one of claims 1-18 , wherein J C is H or F.
20 . The method of any one of claims 1-18 , wherein J C is H.
21 . The method of any one of claims 1-20 , wherein the CNS disease is Alzheimer's disease.
22 . The method of claim 21 , wherein the Alzheimer's disease is mild to moderate Alzheimer's disease or moderate to severe Alzheimer's disease.
23 . The method of any one of claims 1-20 , wherein the CNS disease is cognitive impairment.
24 . The method of any one of claims 1-20 , wherein the CNS disease is dementia.
25 . The method of any one of claims 1-20 , wherein the CNS disease is subjective cognitive impairment (SCI).
26 . The method of any one of claims 1-20 , wherein the CNS disease is cognitive ageing.
27 . The method of any one of claims 1-20 , wherein the CNS disease is vascular dementia.
28 . The method of any one of claims 1-20 , wherein the CNS disease is mixed dementia.
29 . The method of any one of claims 1-20 , wherein the CNS disease is Parkinson's disease.
30 . The method of any one of claims 1-20 , wherein the CNS disease is mild cognitive impairment.
31 . The method of any one of claims 1-20 , wherein the CNS disease is traumatic (closed or open) penetrating head injuries, traumatic brain injury (TBI), nontraumatic stroke, aneurism, hypoxia, or other injuries to the brain.
32 . The method of any one of claims 1-20 , wherein the CNS disease is stroke.
33 . The method of claim 32 , wherein the CNS disease is ischemic stroke.
34 . The method of any one of claims 1-33 , wherein the method further comprising administering to the subject an additional therapeutic agent.