Methods of treatment of fatty liver disease by pharmacological activation of cholinergic pathways

1. A method of treating a fatty liver disease in a subject in need thereof, comprising administering to the subject, as monotherapy, a pharmaceutical composition comprising an inert excipient, diluent, or carrier and an effective amount of a cholinergic pathway stimulating agent, wherein the fatty liver disease is selected from a non-alcoholic fatty liver (NAFL), alcoholic fatty liver (AFL), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), NASH-associated liver fibrosis, ASH-associated liver fibrosis, non-alcoholic cirrhosis and alcoholic cirrhosis.

2. The method of claim 1 , wherein the fatty liver disease is alcoholic fatty liver (AFL).

3. The method of claim 1 , wherein the fatty liver disease is alcoholic steatohepatitis (ASH).

4. The method of claim 1 , wherein the cholinergic pathway stimulating agent is selected from the group consisting of a nicotinic receptor agonist, a muscarinic receptor agonist, a cholinesterase inhibitor and an antagonist of presynaptic acetylcholine autoreceptors.

5. The method of claim 4 , wherein the cholinergic pathway stimulating agent is a cholinesterase inhibitor selected from the group consisting of galantamine, tacrine, fasciculin, metrifonate, heptyl-physostigmine, norpyridostigmine, norneostigmine, huperzine A, physostigmine, velnacrine, citicoline, donepizil, 7-methoxytacrine, eptastigmine, icopezil, ipidacrine, zifrosilone, anseculin, suronacrine, linopiridine, rivastigmine, neostigmine, edrophonium, demacarium, ambenonium, arecoline, xanomeline, subcomeline, cevimeline, alvameline, milameline, talsaclidine, and compounds of the following structural formulae:

or a pharmaceutically acceptable salt thereof.

6. The method of claim 5 , wherein the cholinesterase inhibitor is galantamine.

7. The method of claim 4 , wherein the cholinergic pathway stimulating agent is a nicotinic receptor agonist.

8. The method of claim 7 , wherein the nicotinic receptor agonist is a compound of structural formula (III):

wherein:

R is hydrogen or methyl; and

n is 0 or 1; or

a pharmaceutically acceptable salt thereof.

9. The method of claim 8 , wherein the nicotinic receptor agonist is (−)-spiro-[1-azabicyclo[2.2.2]octane-3,5′-octane-3,5′oxazolidin-2′-one].

10. The method of claim 7 , wherein the nicotinic receptor agonist is a compound of structural formula (IV):

wherein:

1 is 1 or 2;

m is 0 or 1;

Y is CH, N, or NO;

X is oxygen or sulfur;

W is oxygen, H 2 , or F 2 ;

A is N or C(R 2 );

G is N or C(R 3 );

D is N or C(R 4 );

R 2 , R 3 , and R 4 are independently hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, aryl, heteroaryl, OH, OC 1 -C 4 alkyl, CO 2 R 1 , —CN, —NO 2 , —NR 5 R 6 , —CF 3 or —OSO 2 CF 3 ; or

R 2 and R 3 , or R 3 and R 4 , respectively, may together form another six membered aromatic or heteroaromatic ring sharing A and G, or G and D, respectively, containing between zero and two nitrogen atoms, and substituted with one to two of the following substitutents: independently hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, aryl, heteroaryl, OH, OC 1 -C 4 alkyl, CO 2 R 1 ′, —CN, —NO 2 , —NR 5 ′R 6 ′, —CF 3 or —OSO 2 CF 3 ;

R 1 and R 1 ′ are independently hydrogen or C 1 to C 4 alkyl;

R 5 , R 5 ′, R 6 and R 6 ′ are independently hydrogen, C 1 -C 4 alkyl, C(O)R 7 , C(O)NHR 8 , C(O)OR 9 , SO 2 R 10 or may together be (CH 2 ) j Q(CH 2 ) k ; where Q is O, S, NR 11 , or a bond;

j is 2 to 7;

k is 0 to 2; and

R 7 , R 8 , R 9 , R 10 , and R 11 are independently C 1 -C 4 , alkyl, aryl, or heteroaryl, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

11. The method of claim 10 wherein the nicotinic receptor agonist is (R)-(−)-5′-phenylspiro[1-azabicyclo[2.2.2]octane-3,2′octane-3,2′(3′H)-furo[2,3-b]pyridine].

12. The method of claim 7 , wherein the nicotinic receptor agonist is a compound of structural formula (V):

wherein:

R 21 is hydrogen or C 1 -C 4 alkyl, R 26 , and R 27 are independently selected from hydrogen, or C 1 -C 4 alkyl or may be absent; and

R 22 is:

wherein:

R 23 , R 24 and R 25 are independently hydrogen, C 1 -C 4 alkyl optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, C 1 -C 6 alkoxy optionally substituted with N, N-dialkylamino having 1 to 4 carbons in each of the alkyls, carboalkoxy having 1 to 4 carbons in the alkoxy, amino, amido having 1 to 4 carbons in the acyl, cyano, and N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, halo, hydroxyl, or nitro.

13. The method of claim 12 wherein the nicotinic receptor agonist is 3-(4-hydroxy-2-methoxybenzylidene)anabaseine.

14. The method of claim 12 , wherein the nicotinic receptor agonist is 3-(2,4-dimethoxybenzylidene)anabaseine (DMXB-A).

15. The method of claim 7 , wherein the nicotinic receptor agonist is (1-aza-bicyclo [2.2.2]oct-3-yl)-carbamic acid 1-(2-fluorophenyl)-ethyl ester.

16. The method of claim 7 , wherein the nicotinic receptor agonist is cocaine methiodide.

17. The method of claim 7 , wherein the nicotinic receptor agonist is choline.

18. The method of claim 7 , wherein the nicotinic receptor agonist is a compound of structural formula (VI):

wherein:

X 2 is O or S;

R 30 is H, OR 31 , NHC(O)R 31 , or a halogen; and

R 31 is a C 1 -C 4 alkyl; or

a pharmaceutically acceptable salt thereof.

19. The method of claim 4 , wherein the cholinergic pathway stimulating agent is a muscarinic receptor agonist.

20. The method of claim 19 , wherein the muscarinic receptor agonist is muscarine, McN-A-343, or MT-3.

21. The method of claim 19 , wherein the muscarinic receptor agonist is an aromatic amidinohydrazone.

22. The method of claim 21 , wherein the muscarinic receptor agonist is a compound having the structural formula (I):

wherein

X 1 , X 2 , X 3 and X 4 is each independently GhyCH, GhyCCH 3 , redGhyCH 2 , or redGhyCHCH 3 , or H, provided at least one of X 1 , X 2 , X 3 and X 4 is not H,

wherein GhyCH is NH 2 (CNH)—NH—N═CH—, GhyCCH 3 is NH 2 (CNH)—NH—N═C(CH 3 )—, redGhyCH 2 is NH 2 (CNH)—NH—NH—CH 2 — and redGhyCHCH 3 is NH 2 (CNH)—NH—NH—CH(CH 3 )—,

or a pharmaceutically acceptable salt thereof.

23. The method of claim 21 , wherein the muscarinic agonist is N,N′-bis(3,5-diacetylphenyl) decanediamide tetrakis (amidinohydrazone) tetrahydrochloride (CNI-1493).

24. The method of claim 1 , wherein the cholinergic pathway stimulating agents is an antagonist of a presynaptic acetylcholine autoreceptor.

25. The method of claim 24 , wherein the antagonist of a presynaptic acetylcholine autoreceptor is selected from

26. The method of claim 1 , wherein the subject does not have diabetes.

27. The method of claim 1 , wherein the fatty liver disease is non-alcoholic fatty liver (NAFL).

28. The method of claim 1 , wherein the fatty liver disease is non-alcoholic steatohepatitis (NASH).

29. The method of claim 1 , wherein the fatty liver disease is selected from NASH-associated liver fibrosis and ASH-associated liver fibrosis.