Method of treating inflammation with glutaminyl cyclase inhibitors

1. A method of treating an inflammatory disease or condition, comprising:

administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a glutaminyl cyclase (QC) inhibitor;

wherein the QC inhibitor has a K i for QC inhibition of 1 μM or less.

2. The method of treating according to claim 1 , wherein the disease is mild cognitive impairment (MCI).

3. The method of treating according to claim 2 , wherein said pharmaceutical composition comprises a further agent, selected from the group consisting of nootropic agents, neuroprotectants, antiparkinsonian drugs, amyloid protein deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs and anti-multiple sclerosis drugs.

4. The method of treating according to claim 1 , wherein the disease is a chronic or acute inflammation, selected from rheumatoid arthritis, atherosclerosis, restenosis and pancreatitis.

5. The method of treating according to claim 4 , wherein the disease is selected from restenosis and pancreatitis.

6. The method of treating according to claim 4 , wherein the disease is restenosis.

7. The method of treating according to claim 4 , wherein the disease is selected from rheumatoid arthritis and atherosclerosis.

8. The method of treating according to claim 4 , wherein said pharmaceutical composition comprises a further agent, selected from the group consisting of inhibitors of the angiotensin converting enzyme (ACE); angiotensin II receptor blockers; diuretics; calcium channel blockers (CCB); beta-blockers; platelet aggregation inhibitors; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high density lipoprotein (HDL) increasing compounds; renin inhibitors; IL-6 inhibitors; antiinflammatory corticosteroids; antiproliferative agents; nitric oxide donors; inhibitors of extracellular matrix synthesis; growth factor or cytokine signal transduction inhibitors; MCP-1 antagonists and tyrosine kinase inhibitors.

9. The method of treating according to claim 1 , wherein the disease and/or condition afflicts a human being.

10. The method of treating according to claim 1 , wherein said QC inhibitor is a compound of formula I including pharmaceutically acceptable salts, solvates and stereoisomers thereof:

wherein,

A is either

(i) selected from an alkyl chain, alkenyl chain or alkynyl chain; or

(ii) a group selected from

wherein,

R 6 , R 7 , R 8 , R 9 and R 10 are independently H or an alkyl chain, alkenyl chain, alkynyl chain, cycloalkyl, a carbocycle, aryl, heteroaryl, or a heterocycle;

n and n 1 are independently 1-5;

m is 1-5;

o is 0-4; and

B is a group selected from

wherein,

D and E independently represent an alkyl chain, alkenyl chain, alkynyl chain, a cycloalkyl, carbocycle, aryl, -alkylaryl, heteroaryl, -alkylheteroaryl, acyl or a heterocycle;

Z is CH or N;

X represents CR 20 R 21 , O, S, NR 19 , with the proviso for formulas (VIII) and (IX) that, if Z=CH, X is O or S;

R 19 is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, -oxyalkyl, -oxyaryl, carbonyl, amido, hydroxy, NO 2 , NH 2 , CN;

R 20 and R 21 are independently selected from H, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, -oxyalkyl, -oxyaryl, carbonyl, amido, NO 2 , NH 2 , CN, CF 3 ;

X 1 , X 2 and X 3 are independently O or S provided that X 2 and X 3 are not both O;

Y is O or S, with the proviso that Y may not by O, when the carbocycle formed by R 17 and R 18 has 3 members in the ring;

R 11 , R 12 , R 13 and R 14 can be independently selected from H, an alkyl chain, an alkenyl chain, an alkynyl chain, cycloalkyl, carbocycle, aryl, heteroaryl, a heterocycle, halo, alkoxy-, -thioalkyl, carboxyl, carboxylic acid ester, carbonyl, carbamide, carbimide, thiocarbamide, thiocarbonyl, NH 2 , or NO 2 ;

R 15 and R 16 are independently of each other H or a branched alkyl chain, an unbranched alkyl chain, a branched alkenyl chain or an unbranched alkenyl chain;

R 17 and R 18 are independently selected from H, an alkyl chain, alkenyl chain, alkynyl chain, carbocycle, aryl, heteroaryl, or heteroalkyl, or can be connected to form a carbocycle with up to 6 ring atoms; and

n 3 is 0 or 1.

11. The method of treating according to claim 1 , wherein said QC inhibitor or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is selected from:

(i) a compound of formula 1*,

(ii) a compound of formula 1a,

wherein R is selected from Methyl; tert-Butyl; Benzyl; Phenyl; 4-(fluoro)-phenyl; 4-(chloro)-phenyl; 4-(ethyl)-phenyl; 4-(trifluoromethyl)-phenyl; 4-(methoxy-carbonyl)-Phenyl; 4-(acetyl)-phenyl; 4-(methoxy)-phenyl; bicyclo[2.2.1]hept-5-en-2-yl; 3,4-(dimethoxy)-phenyl; 2,4-(dimethoxy)-phenyl; 3,5-(dimethoxy)-phenyl; 2-(methoxy-carbonyl)-Phenyl; 4-(oxazol-5-yl)-phenyl; 4-(pyrazol-1-yl)-phenyl; 4-(isopropyl)-phenyl; 4-(piperidine-1-sulfonyl)-Phenyl; 4-(morpholin-4-yl)-phenyl; 4-(cyano)-phenyl; 2,3-dihydro-benzo[1,4]benzo[1,3]dioxol-5-yl; 3,4,5(trimethoxy)-phenyl; 3-(methoxy)-phenyl; 4-(ethoxy)-phenyl; 4-(benzyloxy)-phenyl; 4-(methoxy)-benzyl; 3,4-(dimethoxy)-benzyl; 2-(methoxy-carbonyl)-thiophene-3-yl; 3-(ethoxy-carbonyl)-4,5,6,7-tetrahydrobenzo[b]thio-phene2-yl; 2-(methoxy-carbonyl)-4-(methyl)-thiophene-3-yl; Benzo[c][1,2,5]thiazol-4-yl; Benzo[c][1,2,5]thiazol-5-yl; 5-(methyl)-3-(phenyl)-isooxazol-4-yl; 3,5-(dimethyl)-isooxazol-4-yl; 4-(iodo)-phenyl; 4-(bromo)-phenyl; 4-(methyl)-phenyl; Naphthalen-1-yl; 4-(nitro)-phenyl; Butyl; Cyclooctyl; Furan-2-ylmethyl; Tetrahydrofuran-2-ylmethyl; Benzo[1,3]dioxol-5-ylmethyl; 2-(morpholin-4-yl)-ethyl; 4-(methylsulfanyl)-phenyl; 4-(dimethylamino)-phenyl; 4-(trifluoromethoxy)-phenyl; Benzoyl; or Pyridin-4-yl;

(iii) a compound of formula 1b,

wherein

R 1 is Cyano and R 2 is Methyl;

R 1 is Cyano and R 2 is 3,4-(dimethoxy)-phenyl;

R 1 is Cyano and R 2 is 2,4-(dimethoxy)-phenyl;

R 1 is Cyano and R 2 is 3,5-(dimethoxy)-phenyl;

R 1 is Cyano and R 2 is 2,3-dihydrobenzo[b][1,4]dioxin-7-yl;

R 1 is Cyano and R 2 is Benzo[d][1,3]dioxol-6-yl;

R 1 is Cyano and R 2 is 3,4,5-(trimethoxy)-phenyl;

R 1 is Cyano and R 2 is 3-(methoxy)-phenyl;

R 1 is Cyano and R 2 is 4-(ethoxy)-phenyl;

R 1 is Cyano and R 2 is 4-(benzyloxy)-phenyl;

R 1 is Cyano and R 2 is Phenyl;

R 1 is Cyano and R 2 is 4-(methoxy)-phenyl;

R 1 is Cyano and R 2 is 4-(acetyl)-phenyl;

R 1 is Cyano and R 2 is 4-(nitro)-phenyl;

R 1 is Cyano and R 2 is Benzyl;

R 1 is Cyano and R 2 is Naphthalen-1-yl;

R 1 is Cyano and R 2 is 4-(fluoro)-phenyl;

R 1 is Cyano and R 2 is 4-(iodo)-phenyl;

R 1 is Cyano and R 2 is 4-(bromo)-phenyl;

R 1 is Cyano and R 2 is Cyclooctyl;

R 1 is Cyano and R 2 is tert-butyl;

R 1 is Cyano and R 2 is 4-(methyl)-phenyl;

R 1 is Cyano and R 2 is 4-(methylthio)-phenyl;

R 1 is Cyano and R 2 is 4-(ethyl)-phenyl;

R 1 is Cyano and R 2 is 4-(dimethylamino)-phenyl;

R 1 is Cyano and R 2 is Butyl;

R 1 is Cyano and R 2 is Trityl;

R 1 is Cyano and R 2 is (Benzo[d][1,3]dioxol-6yl)methyl;

R 1 is Cyano and R 2 is (tetrahydrofuran-2-yl)methyl;

R 1 is Cyano and R 2 is 4-(trifluoromethyl)-phenyl;

R 1 is Cyano and R 2 is (furan-2-yl)methyl;

R 1 is Cyano and R 2 is 2-(morpholin-4-yl)-ethyl;

R 1 is Cyano and R 2 is 4-(oxazol-5-yl)-phenyl;

R 1 is Cyano and R 2 is Pyridin-3-yl;

R 1 is Cyano and R 2 is 4-(cyano)-phenyl;

R 1 is Cyano and R 2 is 4-(trifluoromethoxy)-phenyl;

R 1 is Cyano and R 2 is 4-(piperidinosulfonyl)-phenyl;

R 1 is Cyano and R 2 is 4-(1H-pyrazol-1-yl)phenyl;

R 1 is H and R 2 is 3,4-(dimethoxy)-phenyl;

R 1 is Methyl and R 2 is 3,4-(dimethoxy)-phenyl;

R 1 is Cyano and R 2 is 2,3,4-(trimethoxy)-phenyl; or

R 1 is Cyano and R 2 is Cycloheptyl;

(iv) a compound of formula 1c,

wherein R 3 is selected from Ethyl; 6-fluoro-4H-benzo[d][1,3]dioxin-8-yll; 3-(cylopentyloxy)-4-(methoxy)-phenyll; 4-(heptyloxy)-phenyll; 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yll; 4-(butoxy)-phenyll; or 3,4-(dimethoxy)-phenyll;

(v) a compound of formula 1d,

wherein the substitution position on the benzyl ring is selected from 2, 3, or 4;

(vi) a compound of formula 1e,

wherein

R 4 is H and R 5 is Methyl;

R 4 is Methyl and R 5 is H;

R 4 is Methyl and R 5 is Methyl; or

R 4 is —CH 2 —CH 2 — and R 5 is —CH 2 —CH 2 —;

(vii) a compound of formula 1f,

wherein R 6 is selected from H, Chloro, or Methoxy;

(viii) a compound of formula 1g,

wherein

R 7 is Phenyl, R 8 is H, and R 9 is H;

R 7 is Thiophen-2-yl, R 8 is H, and R 9 is H;

R 7 is Phenyl, R 8 is Methyl, and R 9 is H;

R 7 is Phenyl, R 8 is H, and R 9 is Methyl;

R 7 is Phenyl, R 8 is H, and R 9 is Ethyl;

R 7 is Phenyl, R 8 is H, and R 9 is Phenyl;

R 7 is 3,4-(dimethoxy)-Phenyl, R 8 is H, and R 9 is H;

R 7 is 3,4-(dimethoxy)-Phenyl, R 8 is Methyl, and R 9 is Methyl;

R 7 is 4-(chloro)-phenyl, R 8 is —CH 2 —CH 2 —CH 2 —, and R 9 is —CH 2 —CH 2 —CH 2 —;

R 7 is 4-(chloro)-phenyl, R 8 is —CH 2 —C 2 H 4 —CH 2 —, and R 9 is —CH 2 —C 2 H 4 —CH 2 —;

R 7 is 4-(methoxy)-phenyl, R 8 is —CH 2 —C 3 H 6 —CH 2 —, and R 9 is —CH 2 —C 3 H 6 —CH 2 —;

R 7 is 4-(methoxy)-phenyl, R 8 is —CH 2 —CH 2 —, and R 9 is —CH 2 —CH 2 —;

R 7 is 3,4-(dimethoxy)-Phenyl, R 8 is —CH 2 —CH 2 —, and R 9 is —CH 2 —CH 2 —;

R 7 is 3,4,5-(trimethoxy)-Phenyl, R 8 is —CH 2 —CH 2 —, and R 9 is —CH 2 —CH 2 —;

R 7 is 2,3,4-(trimethoxy)-Phenyl, R 8 is —CH 2 —CH 2 —, and R 9 is —CH 2 —CH 2 —;

R 7 is 2-(methoxy)-phenyl, R 8 is —CH 2 —CH 2 —, and R 9 is —CH 2 —CH 2 —;

R 7 is 3-(methoxy)-phenyl, R 8 is —CH 2 —CH 2 —, and R 9 is —CH 2 —CH 2 —;

R 7 is 2,3-(dimethoxy)-Phenyl, R 8 is —CH 2 —CH 2 —, and R 9 is —CH 2 —CH 2 —;

R 7 is 3,5-(dimethoxy)-Phenyl, R 8 is —CH 2 —CH 2 —, and R 9 is —CH 2 —CH 2 —; or

R 7 is 2,5-(dimethoxy)-Phenyl, R 8 is —CH 2 —CH 2 —, and R 9 is —CH 2 —CH 2 —;

(ix) a compound of formula 1h,

wherein n is selected from 3, 4, or 5;

(x) a compound of formula 1i,

wherein m is selected from 2 or 4; or

(xi) a compound selected from

12. The method of treating according to claim 11 , wherein said QC inhibitor is 1-(3-(1H-imidazole-1-yl)propyl)-3-(3,4-dimethoxy-phenyl)thiourea hydrochloride.

13. The method of treating according to claim 1 , wherein administering said pharmaceutical composition comprises parenteral, enteral or oral administration.

14. The method of treating according to claim 12 , wherein the disease is restenosis.

15. The method of treating according to claim 12 , for the treatment of an inflammatory disease or condition.

16. The method of treating according to claim 1 , wherein the QC inhibitor has a Ki for QC inhibition of 0.1 μM or less.