METHODS OF TREATING OR PREVENTING AN INFLAMMATORY DISEASE OR CONDITION USING GLUTAMINYL CYCLASE INHIBITORS
Methods for the treatment and/or prevention of an inflammatory disease or disorder through administration of an inhibitor of a glutaminyl peptide cyclotransferase. Inflammatory diseases or disorders treated or prevented by methods disclosed herein include mild cognitive impairment (MCI), rheumatoid arthritis, atherosclerosis, restenosis, pancreatitis, sepsis and peritonitus. Further provided are respective diagnostic methods, assays and kits.
1 . A Method of treatment and/or prevention of an inflammatory disease or condition, selected from the group consisting of mild cognitive impairment, rheumatoid arthritis, atherosclerosis, restenosis, pancreatitis, sepsis and peritonitis, wherein a pharmaceutical composition comprising an effective amount of a QC inhibitor is administered to a subject in need thereof.
2 . The method of treatment and/or prevention according to claim 1 , wherein the disease is mild cognitive impairment (MCI).
3 . The method of treatment and/or prevention 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 treatment and/or prevention according to claim 1 , wherein the disease is a chronic or acute inflammation, selected from rheumatoid arthritis, atherosclerosis, restenosis, pancreatitis, sepsis and peritonitis.
5 . The method of treatment and/or prevention according to claim 4 , wherein the disease is selected from restenosis and pancreatitis.
6 . The method of treatment and/or prevention according to claim 4 , wherein the disease is selected from sepsis and peritonitis.
7 . The method of treatment and/or prevention according to claim 4 , wherein the disease is selected from rheumatoid arthritis and atherosclerosis.
8 . The method of treatment and/or prevention 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 treatment and/or prevention according to claim 1 , wherein the disease and/or condition afflicts a human being.
10 . The method of treatment and/or prevention according to claim 1 , wherein said QC inhibitor is a compound of formula 1 including pharmaceutically acceptable salts, solvates and stereoisomers thereof:
wherein:
A is either:
an alkyl chain, alkenyl chain or alkynyl chain;
or A is 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 0, when the carbocycle formed by R 17 and R 18 has 3 members in the ring;
Z is CH or N;
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 or thiocarbonyl, NH 2 , NO 2 ;
R 15 and R 16 are independently of each other H or a branched or unbranched alkyl chain, or a branched or unbranched alkenyl chain;
R 17 and Rn are independently selected from H or an alkyl chain, alkenyl chain, a alkynyl chain, a carbocycle, aryl, heteroaryl, heteroalkyl, or can be connected to form a carbocycle with up to 6 ring atoms;
n is 0 or 1.
11 . The method of treatment and/or prevention according to claim 1 , wherein said QC inhibitor or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is selected from
a compound of formula 1*:
or
a compound of formula 1a,
wherein R is defined in examples 1 to 53:
Example
R
1
Methyl
2
tert-Butyl
3
Benzyl
4
Phenyl
5
4-(fluoro)-phenyl
6
4-(chloro)-phenyl
7
4-(ethyl)-phenyl
8
4-(trifluoromethyl)-
phenyl
9
4-(methoxy-
carbonyl)-
Phenyl
10
4-(acetyl)-phenyl
11
4-(methoxy)-phenyl
12
bicyclo[2.2.1]hept-
5-en-2-yl
13
3,4-(dimethoxy)-
phenyl
14
2,4-(dimethoxy)-
phenyl
15
3,5-(dimethoxy)-
phenyl
16
2-(methoxy-
carbonyl)-
Phenyl
17
4-(oxazol-5-y)-
phenyl
18
4-(pyrazol-1-yl)-
phenyl
19
4-(isopropyl)-phenyl
20
4-(piperidine-1-
sulfonyl)-
Phenyl
21
4-(morpholin-4-yl)-
phenyl
22
4-(cyano)-phenyl
23
2,3-dihydro-
benzo[1,4]dioxin-
6-yl
24
benzo[1,3]dioxol-5-
yl
25
3,4,5(trimethoxy)-
phenyl
26
3-(methoxy)-phenyl
27
4-(ethoxy)-phenyl
28
4-(benzyloxy)-phenyl
29
4-(methoxy)-benzyl
30
3,4-(dimethoxy)-
benzyl
31
2-(methoxy-
carbonyl)-
thiophene-3-yl
32
3-(ethoxy-carbonyl)-
4,5,6,7-
tetrahydrobenzo[b]thio-
phene2-yl
33
2-(methoxy-
carbonyl)-4-
(methyl)-thiophene-
3-yl
34
Benzo[c][1,2,5]thiazol-
4-yl
35
Benzo[c][1,2,5]thiazol-
5-yl
36
5-(methyl)-3-
(phenyl)-
isooxazol-4-yl
37
3,5-(dimethyl)-
isooxazol-
4-yl
38
4-(iodo)-phenyl
39
4-(bromo)-phenyl
40
4-(methyl)-phenyl
41
Naphthalen-1-yl
42
4-(nitro)-phenyl
43
Butyl
44
Cyclooctyl
45
Furan-2-ylmethyl
46
Tetrahydrofuran-2-
ylmethyl
47
Benzo[1,3]dioxol-5-
ylmethyl
48
2-(morpholin-4-yl)-
ethyl
49
4-(methylsulfanyl)-
phenyl
50
4-(dimethylamino)-
phenyl
51
4-
(trifluoromethoxy)-
phenyl
52
Benzoyl
53
Pyridin-4-yl
or
a compound of formula 1b,
wherein R 1 and R 2 are defined in examples 54 to 95.
Example
R 1
R 2
54
Cyano
Methyl
55
Cyano
3,4-(dimethoxy)-
phenyl
56
Cyano
2,4-(dimethoxy)-
phenyl
57
Cyano
3,5-(dimethoxy)-
phenyl
58
Cyano
2,3-
dihydrobenzo[b][1,4]dioxin-
7-yl
59
Cyano
Benzo[d][1,3]dioxol-
6-yl
60
Cyano
3,4,5-(trimethoxy)-
phenyl
61
Cyano
3-(methoxy)-phenyl
62
Cyano
4-(ethoxy)-phenyl
63
Cyano
4-(benzyloxy)-phenyl
64
Cyano
Phenyl
65
Cyano
4-(methoxy)-phenyl
66
Cyano
4-(acetyl)-phenyl
67
Cyano
4-(nitro)-phenyl
68
Cyano
Benzyl
69
Cyano
Naphthalen-1-yl
70
Cyano
4-(fluoro)-phenyl
71
Cyano
4-(iodo)-phenyl
72
Cyano
4-(bromo)-phenyl
73
Cyano
Cyclooctyl
74
Cyano
tert-butyl
75
Cyano
4-(methyl)-phenyl
76
Cyano
4-(methylthio)-phenyl
77
Cyano
4-(ethyl)-phenyl
78
Cyano
4-(dimethylamino)-
phenyl
79
Cyano
Butyl
80
Cyano
Trityl
81
Cyano
(Benzo[d][1,3]dioxol-
6yl)methyl
82
Cyano
(tetrahydrofuran-
2yl)methyl
83
Cyano
4-(trifluoromethyl)-
phenyl
84
Cyano
(furan-2-yl)methyl
85
Cyano
2-(morpholin-4-yl)-
ethyl
86
Cyano
4-(oxazol-5yl)-phenyl
87
Cyano
Pyridin-3-yl
88
Cyano
4-(cyano)-phenyl
89
Cyano
4-(trifluoromethoxy)-
phenyl
90
Cyano
4-
(piperidinosulfonyl)-
phenyl
91
Cyano
4-(1H-pyrazol-1-
yl)phenyl
92
H
3,4-(dimethoxy)-
phenyl
93
Methyl
3,4-(dimethoxy)-
phenyl
94
Cyano
2,3,4-(trimethoxy)-
phenyl
95
Cyano
Cycloheptyl
or
a compound of formula 1c,
wherein R 3 is defined in examples 96 to 102.
Example
R 3
96
Ethyl
97
6-fluoro-4H-benzo[d][1,
3]dioxin-8-yl
98
3-(cylopentyloxy)-4-
(methoxy)-phenyl
99
4-(heptyloxy)-phenyl
100
3,4-dihydro-2H-
benzo[b][1,
4]dioxepin-7-yl
101
4-(butoxy)-phenyl
102
3,4-(dimethoxy)-
phenyl
or
a compound of formula 1d,
wherein the position on the ring is defined in examples 103 to 105.
or
a compound of formula 1e,
wherein R 4 and R 5 are defined in examples 106 to 109.
Example
R 4
R 5
106(S)
H
Methyl
107(R)
Methyl
H
108
Methyl
Methyl
109
—CH 2 —CH 2 —
or
a compound of formula 1f,
wherein R 6 is defined in examples 110 to 112.
Example
R 6
110
H
111
Chloro
112
Methoxy
or
a compound of formula 1g,
wherein R 7 , R 8 and R 9 are defined in examples 113 to 132.
Example
R 7
R 8
R 9
113
Phenyl
H
H
114
Thiophen-2-yl
H
H
115(R)
Phenyl
Methyl
H
116(S)
Phenyl
H
Methyl
117
Phenyl
H
Ethyl
118
Phenyl
H
Phenyl
119
3,4-
H
H
(dimethoxy)-
Phenyl
120
3,4-
Methyl
Methyl
(dimethoxy)-
Phenyl
121
4-(chloro)-
—CH 2 —CH 2 —CH 2 —
phenyl
122
4-(chloro)-
—CH 2 —C 2 H 4 —CH 2 —
phenyl
123
4-(methoxy)-
—CH 2 —C 3 H 6 —CH 2 —
phenyl
124
4-(methoxy)-
—CH 2 —CH 2 —
phenyl
125
3,4-
—CH 2 —CH 2 —
(dimethoxy)-
Phenyl
126
3,4,5-
—CH 2 —CH 2 —
(trimethoxy)-
Phenyl
127
2,3,4-
—CH 2 —CH 2 —
(trimethoxy)-
Phenyl
128
2-(methoxy)-
—CH 2 —CH 2 —
phenyl
129
3-(methoxy)-
—CH 2 —CH 2 —
phenyl
130
2,3-
—CH 2 —CH 2 —
(dimethoxy)-
Phenyl
131
3,5-
—CH 2 —CH 2 —
(dimethoxy)-
Phenyl
132
2,5-
—CH 2 —CH 2 —
(dimethoxy)-
Phenyl
or
a compound of formula 1h,
wherein n is defined in examples 133 to 135.
Example
n
133
3
134
4
135
5
or
a compound of formula 1i,
wherein m is defined in examples 136 and 137.
Example
m
136
2
137
4
or
a compound selected from examples 138 to 141
Example
Structure
138
139
140
141
12 . The method of treatment and/or prevention according to claim 11 , wherein said QC inhibitor is 1-(3-(1H-imidazole-1-yl)propyl)-3-(3,4-dimethoxy-phenyl)thiourea hydrochloride.
13 . Diagnostic assay, comprising a QC inhibitor.
14 . Diagnostic assay according to claim 13 , wherein said QC inhibitor is a compound of formula 1 including pharmaceutically acceptable salts, solvates and stereoisomers thereof:
wherein:
A is either:
an alkyl chain, alkenyl chain or alkynyl chain;
or A is 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;
Z is CH or N;
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 or thiocarbonyl, NH 2 , NO 2 ;
R 15 and R 16 are independently of each other H or a branched or unbranched alkyl chain, or a branched or unbranched alkenyl chain;
R 17 and R 18 are independently selected from H or an alkyl chain, alkenyl chain, a alkynyl chain, a carbocycle, aryl, heteroaryl, heteroalkyl, or can be connected to form a carbocycle with up to 6 ring atoms;
n is 0 or 1.
15 . Diagnostic assay according to claim 13 , wherein said QC inhibitor or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is selected from
a compound of formula 1*:
or
a compound of formula 1a,
wherein R is defined in examples 1 to 53:
Example
R
1
Methyl
2
tert-Butyl
3
Benzyl
4
Phenyl
5
4-(fluoro)-phenyl
6
4-(chloro)-phenyl
7
4-(ethyl)-phenyl
8
4-(trifluoromethyl)-
phenyl
9
4-(methoxy-
carbonyl)-
Phenyl
10
4-(acetyl)-phenyl
11
4-(methoxy)-phenyl
12
bicyclo[2.2.1]hept-
5-en-2-yl
13
3,4-(dimethoxy)-
phenyl
14
2,4-(dimethoxy)-
phenyl
15
3,5-(dimethoxy)-
phenyl
16
2-(methoxy-
carbonyl)-
Phenyl
17
4-(oxazol-5-y)-
phenyl
18
4-(pyrazol-1-yl)-
phenyl
19
4-(isopropyl)-phenyl
20
4-(piperidine-1-
sulfonyl)-
Phenyl
21
4-(morpholin-4-yl)-
phenyl
22
4-(cyano)-phenyl
23
2,3-dihydro-
benzo[1,4]dioxin-
6-yl
24
benzo[1,3]dioxol-5-
yl
25
3,4,5(trimethoxy)-
phenyl
26
3-(methoxy)-phenyl
27
4-(ethoxy)-phenyl
28
4-(benzyloxy)-phenyl
29
4-(methoxy)-benzyl
30
3,4-(dimethoxy)-
benzyl
31
2-(methoxy-
carbonyl)-
thiophene-3-yl
32
3-(ethoxy-carbonyl)-
4,5,6,7-
tetrahydrobenzo[b]thio-
phene2-yl
33
2-(methoxy-
carbonyl)-4-
(methyl)-thiophene-
3-yl
34
Benzo[c][1,2,5]thiazol-
4-yl
35
Benzo[c][1,2,5]thiazol-
5-yl
36
5-(methyl)-3-
(phenyl)-
isooxazol-4-yl
37
3,5-(dimethyl)-
isooxazol-
4-yl
38
4-(iodo)-phenyl
39
4-(bromo)-phenyl
40
4-(methyl)-phenyl
41
Naphthalen-1-yl
42
4-(nitro)-phenyl
43
Butyl
44
Cyclooctyl
45
Furan-2-ylmethyl
46
Tetrahydrofuran-2-
ylmethyl
47
Benzo[1,3]dioxol-5-
ylmethyl
48
2-(morpholin-4-yl)-
ethyl
49
4-(methylsulfanyl)-
phenyl
50
4-(dimethylamino)-
phenyl
51
4-
(trifluoromethoxy)-
phenyl
52
Benzoyl
53
Pyridin-4-yl
or
a compound of formula 1b,
wherein R 1 and R 2 are defined in examples 54 to 95.
Example
R 1
R 2
54
Cyano
Methyl
55
Cyano
3,4-(dimethoxy)-
phenyl
56
Cyano
2,4-(dimethoxy)-
phenyl
57
Cyano
3,5-(dimethoxy)-
phenyl
58
Cyano
2,3-
dihydrobenzo[b][1,4]dioxin-
7-yl
59
Cyano
Benzo[d][1,3]dioxol-
6-yl
60
Cyano
3,4,5-(trimethoxy)-
phenyl
61
Cyano
3-(methoxy)-phenyl
62
Cyano
4-(ethoxy)-phenyl
63
Cyano
4-(benzyloxy)-phenyl
64
Cyano
Phenyl
65
Cyano
4-(methoxy)-phenyl
66
Cyano
4-(acetyl)-phenyl
67
Cyano
4-(nitro)-phenyl
68
Cyano
Benzyl
69
Cyano
Naphthalen-1-yl
70
Cyano
4-(fluoro)-phenyl
71
Cyano
4-(iodo)-phenyl
72
Cyano
4-(bromo)-phenyl
73
Cyano
Cyclooctyl
74
Cyano
tert-butyl
75
Cyano
4-(methyl)-phenyl
76
Cyano
4-(methylthio)-phenyl
77
Cyano
4-(ethyl)-phenyl
78
Cyano
4-(dimethylamino)-
phenyl
79
Cyano
Butyl
80
Cyano
Trityl
81
Cyano
(Benzo[d][1,3]dioxol-
6yl)methyl
82
Cyano
(tetrahydrofuran-
2yl)methyl
83
Cyano
4-(trifluoromethyl)-
phenyl
84
Cyano
(furan-2-yl)methyl
85
Cyano
2-(morpholin-4-yl)-
ethyl
86
Cyano
4-(oxazol-5yl)-phenyl
87
Cyano
Pyridin-3-yl
88
Cyano
4-(cyano)-phenyl
89
Cyano
4-(trifluoromethoxy)-
phenyl
90
Cyano
4-
(piperidinosulfonyl)-
phenyl
91
Cyano
4-(1H-pyrazol-1-
yl)phenyl
92
H
3,4-(dimethoxy)-
phenyl
93
Methyl
3,4-(dimethoxy)-
phenyl
94
Cyano
2,3,4-(trimethoxy)-
phenyl
95
Cyano
Cycloheptyl
or
a compound of formula 1c,
wherein R 3 is defined in examples 96 to 102.
Example
R 3
96
Ethyl
97
6-fluoro-4H-benzo[d][1,
3]dioxin-8-yl
98
3-(cylopentyloxy)-4-
(methoxy)-phenyl
99
4-(heptyloxy)-phenyl
100
3,4-dihydro-2H-
benzo[b][1,
4]dioxepin-7-yl
101
4-(butoxy)-phenyl
102
3,4-(dimethoxy)-
phenyl
or
a compound of formula 1d,
wherein the position on the ring is defined in examples 103 to 105,
or
a compound of formula 1e,
wherein R 4 and R 5 are defined in examples 106 to 109.
Example
R 4
R 5
106(S)
H
Methyl
107(R)
Methyl
H
108
Methyl
Methyl
109
—CH 2 —CH 2 —
or
a compound of formula 1f,
wherein R 6 is defined in examples 110 to 112.
Example
R 6
110
H
111
Chloro
112
Methoxy
or
a compound of formula 1g,
wherein R 7 , R 8 and R 9 are defined in examples 113 to 132.
Example
R 7
R 8
R 9
113
Phenyl
H
H
114
Thiophen-2-yl
H
H
115(R)
Phenyl
Methyl
H
116(S)
Phenyl
H
Methyl
117
Phenyl
H
Ethyl
118
Phenyl
H
Phenyl
119
3,4-
H
H
(dimethoxy)-
Phenyl
120
3,4-
Methyl
Methyl
(dimethoxy)-
Phenyl
121
4-(chloro)-
—CH 2 —CH 2 —CH 2 —
phenyl
122
4-(chloro)-
—CH 2 —C 2 H 4 —CH 2 —
phenyl
123
4-(methoxy)-
—CH 2 —C 3 H 6 —CH 2 —
phenyl
124
4-(methoxy)-
—CH 2 —CH 2 —
phenyl
125
3,4-
—CH 2 —CH 2 —
(dimethoxy)-
Phenyl
126
3,4,5-
—CH 2 —CH 2 —
(trimethoxy)-
Phenyl
127
2,3,4-
—CH 2 —CH 2 —
(trimethoxy)-
Phenyl
128
2-(methoxy)-
—CH 2 —CH 2 —
phenyl
129
3-(methoxy)-
—CH 2 —CH 2 —
phenyl
130
2,3-
—CH 2 —CH 2 —
(dimethoxy)-
Phenyl
131
3,5-
—CH 2 —CH 2 —
(dimethoxy)-
Phenyl
132
2,5-
—CH 2 —CH 2 —
(dimethoxy)-
Phenyl
or
a compound of formula 1h,
wherein n is defined in examples 133 to 135.
Example
n
133
3
134
4
135
5
or
a compound of formula 1i,
wherein m is defined in examples 136 and 137.
Example
m
136
2
137
4
or
a compound selected from examples 138 to 141.
Example
Structure
138
139
140
141
16 . Diagnostic assay according to claim 13 , wherein said QC inhibitor is 1-(3-(1H-imidazole-1-yl)propyl)-3-(3,4-dimethoxy-phenyl)thiourea hydrochloride.
17 . A method of diagnosing any one of the diseases and/or conditions as defined in claim 1 , comprising the steps of
collecting a sample from a subject who is suspected to be afflicted with said disease and/or condition,
contacting said sample with a QC inhibitor, and
determining whether or not said subject is afflicted by said disease and/or condition.
18 . The method according to claim 17 , wherein said subject is a human being.
19 . The method according to claim 17 , wherein said QC inhibitor is a compound of formula 1 including pharmaceutically acceptable salts, solvates and stereoisomers thereof:
wherein:
A is either:
an alkyl chain, alkenyl chain or alkynyl chain;
or A is 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;
Z is CH or N;
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 or thiocarbonyl, NH 2 , NO 2 ;
R 15 and R 16 are independently of each other H or a branched or unbranched alkyl chain, or a branched or unbranched alkenyl chain;
R 17 and Rn are independently selected from H or an alkyl chain, alkenyl chain, a alkynyl chain, a carbocycle, aryl, heteroaryl, heteroalkyl, or can be connected to form a carbocycle with up to 6 ring atoms;
n is 0 or 1.
20 . The method according to any of claims 17 to 19 , wherein said QC inhibitor or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is selected from
a compound of formula 1*:
or
a compound of formula 1a,
wherein R is defined in examples 1 to 53:
Example
R
1
Methyl
2
tert-Butyl
3
Benzyl
4
Phenyl
5
4-(fluoro)-phenyl
6
4-(chloro)-phenyl
7
4-(ethyl)-phenyl
8
4-(trifluoromethyl)-
phenyl
9
4-(methoxy-
carbonyl)-
Phenyl
10
4-(acetyl)-phenyl
11
4-(methoxy)-phenyl
12
bicyclo[2.2.1]hept-
5-en-2-yl
13
3,4-(dimethoxy)-
phenyl
14
2,4-(dimethoxy)-
phenyl
15
3,5-(dimethoxy)-
phenyl
16
2-(methoxy-
carbonyl)-
Phenyl
17
4-(oxazol-5-y)-
phenyl
18
4-(pyrazol-1-yl)-
phenyl
19
4-(isopropyl)-phenyl
20
4-(piperidine-1-
sulfonyl)-
Phenyl
21
4-(morpholin-4-yl)-
phenyl
22
4-(cyano)-phenyl
23
2,3-dihydro-
benzo[1,4]dioxin-
6-yl
24
benzo[1,3]dioxol-5-
yl
25
3,4,5(trimethoxy)-
phenyl
26
3-(methoxy)-phenyl
27
4-(ethoxy)-phenyl
28
4-(benzyloxy)-phenyl
29
4-(methoxy)-benzyl
30
3,4-(dimethoxy)-
benzyl
31
2-(methoxy-
carbonyl)-
thiophene-3-yl
32
3-(ethoxy-carbonyl)-
4,5,6,7-
tetrahydrobenzo[b]thio-
phene2-yl
33
2-(methoxy-
carbonyl)-4-
(methyl)-thiophene-
3-yl
34
Benzo[c][1,2,5]thiazol-
4-yl
35
Benzo[c][1,2,5]thiazol-
5-yl
36
5-(methyl)-3-
(phenyl)-
isooxazol-4-yl
37
3,5-(dimethyl)-
isooxazol-
4-yl
38
4-(iodo)-phenyl
39
4-(bromo)-phenyl
40
4-(methyl)-phenyl
41
Naphthalen-1-yl
42
4-(nitro)-phenyl
43
Butyl
44
Cyclooctyl
45
Furan-2-ylmethyl
46
Tetrahydrofuran-2-
ylmethyl
47
Benzo[1,3]dioxol-5-
ylmethyl
48
2-(morpholin-4-yl)-
ethyl
49
4-(methylsulfanyl)-
phenyl
50
4-(dimethylamino)-
phenyl
51
4-
(trifluoromethoxy)-
phenyl
52
Benzoyl
53
Pyridin-4-yl
or
a compound of formula 1b,
wherein R 1 and R 2 are defined in examples 54 to 95.
Example
R 1
R 2
54
Cyano
Methyl
55
Cyano
3,4-(dimethoxy)-
phenyl
56
Cyano
2,4-(dimethoxy)-
phenyl
57
Cyano
3,5-(dimethoxy)-
phenyl
58
Cyano
2,3-
dihydrobenzo[b][1,4]dioxin-
7-yl
59
Cyano
Benzo[d][1,3]dioxol-
6-yl
60
Cyano
3,4,5-(trimethoxy)-
phenyl
61
Cyano
3-(methoxy)-phenyl
62
Cyano
4-(ethoxy)-phenyl
63
Cyano
4-(benzyloxy)-phenyl
64
Cyano
Phenyl
65
Cyano
4-(methoxy)-phenyl
66
Cyano
4-(acetyl)-phenyl
67
Cyano
4-(nitro)-phenyl
68
Cyano
Benzyl
69
Cyano
Naphthalen-1-yl
70
Cyano
4-(fluoro)-phenyl
71
Cyano
4-(iodo)-phenyl
72
Cyano
4-(bromo)-phenyl
73
Cyano
Cyclooctyl
74
Cyano
tert-butyl
75
Cyano
4-(methyl)-phenyl
76
Cyano
4-(methylthio)-phenyl
77
Cyano
4-(ethyl)-phenyl
78
Cyano
4-(dimethylamino)-
phenyl
79
Cyano
Butyl
80
Cyano
Trityl
81
Cyano
(Benzo[d][1,3]dioxol-
6yl)methyl
82
Cyano
(tetrahydrofuran-
2yl)methyl
83
Cyano
4-(trifluoromethyl)-
phenyl
84
Cyano
(furan-2-yl)methyl
85
Cyano
2-(morpholin-4-yl)-
ethyl
86
Cyano
4-(oxazol-5yl)-phenyl
87
Cyano
Pyridin-3-yl
88
Cyano
4-(cyano)-phenyl
89
Cyano
4-(trifluoromethoxy)-
phenyl
90
Cyano
4-
(piperidinosulfonyl)-
phenyl
91
Cyano
4-(1H-pyrazol-1-
yl)phenyl
92
H
3,4-(dimethoxy)-
phenyl
93
Methyl
3,4-(dimethoxy)-
phenyl
94
Cyano
2,3,4-(trimethoxy)-
phenyl
95
Cyano
Cycloheptyl
or
a compound of formula 1c,
wherein R 3 is defined in examples 96 to 102.
Example
R 3
96
Ethyl
97
6-fluoro-4H-benzo[d][1,
3]dioxin-8-yl
98
3-(cylopentyloxy)-4-
(methoxy)-phenyl
99
4-(heptyloxy)-phenyl
100
3,4-dihydro-2H-
benzo[b][1,
4]dioxepin-7-yl
101
4-(butoxy)-phenyl
102
3,4-(dimethoxy)-
phenyl
or
a compound of formula 1d,
wherein the position on the ring is defined in examples 103 to 105,
or
a compound of formula 1e,
wherein R 4 and R 5 are defined in examples 106 to 109.
Example
R 4
R 5
106(S)
H
Methyl
107(R)
Methyl
H
108
Methyl
Methyl
109
—CH 2 —CH 2 —
or
a compound of formula 1f,
wherein R 6 is defined in examples 110 to 112.
Example
R 6
110
H
111
Chloro
112
Methoxy
or
a compound of formula 1g,
wherein R 7 , R 8 and R 9 are defined in examples 113 to 132.
Example
R 7
R 8
R 9
113
Phenyl
H
H
114
Thiophen-2-yl
H
H
115(R)
Phenyl
Methyl
H
116(S)
Phenyl
H
Methyl
117
Phenyl
H
Ethyl
118
Phenyl
H
Phenyl
119
3,4-
H
H
(dimethoxy)-
Phenyl
120
3,4-
Methyl
Methyl
(dimethoxy)-
Phenyl
121
4-(chloro)-
—CH 2 —CH 2 —CH 2 —
phenyl
122
4-(chloro)-
—CH 2 —C 2 H 4 —CH 2 —
phenyl
123
4-(methoxy)-
—CH 2 —C 3 H 6 —CH 2 —
phenyl
124
4-(methoxy)-
—CH 2 —CH 2 —
phenyl
125
3,4-
—CH 2 —CH 2 —
(dimethoxy)-
Phenyl
126
3,4,5-
—CH 2 —CH 2 —
(trimethoxy)-
Phenyl
127
2,3,4-
—CH 2 —CH 2 —
(trimethoxy)-
Phenyl
128
2-(methoxy)-
—CH 2 —CH 2 —
phenyl
129
3-(methoxy)-
—CH 2 —CH 2 —
phenyl
130
2,3-
—CH 2 —CH 2 —
(dimethoxy)-
Phenyl
131
3,5-
—CH 2 —CH 2 —
(dimethoxy)-
Phenyl
132
2,5-
—CH 2 —CH 2 —
(dimethoxy)-
Phenyl
or
a compound of formula 1h,
wherein n is defined in examples 133 to 135.
Example
n
133
3
134
4
135
5
or
a compound of formula 1i,
wherein m is defined in examples 136 and 137.
Example
m
136
2
137
4
or
a compound selected from examples 138 to 141.
Example
Structure
138
139
140
141
21 . The method according to claim 20 , wherein said QC inhibitor is 1-(3-(1H-imidazole-1-yl)propyl)-3-(3,4-dimethoxy-phenyl) thiourea hydrochloride.
22 . The method according to claim 17 , wherein said sample is a blood sample, a serum sample, a sample of cerebrospinal liquor or a urine sample.
23 . Diagnostic kit for carrying out the method of claim 17 comprising as detection means the diagnostic assay of claim 13 and a determination means.
24 . Diagnostic kit for carrying out the method of claim 17 comprising as detection means the diagnostic assay of claim 14 and a determination means.
25 . Diagnostic kit for carrying out the method of claim 17 comprising as detection means the diagnostic assay of claim 15 and a determination means.
26 . Diagnostic kit for carrying out the method of claim 17 comprising as detection means the diagnostic assay of claim 16 and a determination means.
27 . The method of treatment and/or prevention according to claim 1 , wherein said pharmaceutical composition is for parenteral, enteral or oral administration.