Heterocyclic compounds and their use as medicines

Details Heterocyclic compounds and their use as medicines Heterocyclic compounds and their use as medicines

2002-04-30

2004-06-08

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S226200, C544S037000, C544S038000, C544S039000

Reexamination Certificate

active

06747024

ABSTRACT:

The present invention relates to new heterocyclic derivatives having an:,inhibitory activity on calpains and/or a trapping activity on reactive oxygen species (ROS's). The invention also relates to methods for their preparation, pharmaceutical preparations containing them and their use for therapeutic purposes, in particular as inhibitors of calpains and selective or non-selective ROS traps.
Given the potential role of calpains and ROS's in physiopathology, the new derivatives according to the invention can produce beneficial or favourable effects in the treatment of pathologies involving these enzymes and/or these radicular species, and in particular:
inflammatory and immunological diseases such as for example rheumatoid arthritis, pancreatitis, multiple sclerosis, inflammation of the gastro-intestinal tract (ulcerative or non-ulcerative colitis, Crohn's disease),
cardiovascular and cerebrovascular diseases including for example arterial hypertension, septic shock, cardiac or cerebral infarctions of ischemnic or hemorrhagic origin, ischemia as well as disorders linked to platelet aggregation,
disorders of the central or peripheral nervous system such as for example neurodegenerative diseases where there can in particular be mentioned trauma to the brain or spinal cord, sub-arachnoid haemorrhages, epilepsy, ageing, senile dementia, including Alzheimer's disease, Huntington's chorea, Parkinson's disease, peripheral neuropathies,
osteoporosis,
muscular dystrophies,
proliferative diseases such as for example atherosclerosis or recurrence of stenosis,
cataracts,
organ transplants,
auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes and its complications, multiple sclerosis,
cancer,
all the pathologies characterized by an excessive production of ROS's and/or activation of calpains.
In all these pathologies, there is experimental evidence demonstrating the involvement of ROS's (Free Radic. Biol. Med. (1996) 20, 675-705; Antioxid. Health. Dis. (1997) 4 (Handbook of Synthetic Antioxidants), 1-52) as well as the involvement of calpains (Trends Pharmacol. Sci. (1994) 15, 412419; Drug News Perspect (1999) 12, 73-82). For example, cerebral lesions associated with cerebral infarction or experimental cranial trauma are reduced by antioxidants (Acta Physiol. Scand. (1994) 152, 349-350; 1. Cereb. Blood Flow Metabol. (1995) 15, 948-952; J Pharmacol Exp Ther (1997) 2, 895-904) as well as by inhibitors of calpains (Proc Natl Acad Sci USA (1996) 93, 3428-33; Stroke, (1998) 29, 152-158; Stroke (1994) 25, 2265-2270).
A subject of the present invention is therefore compounds of general formula (I)
in which
R
1
represents a hydrogen atom, an —OR
3
, —SR
3
, oxo or cyclic acetal radical,
in which R
3
represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or —NR
4
R
5
;
R
4
and R
5
represent, independently, a hydrogen atom or an alkyl radical, or R
4
and R
5
together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R
2
represents a hydrogen atom, an alkyl, aryl or aralkyl radical, the aryl group being optionally substituted by one or more identical or different radicals chosen from: —OR
6
, —NR
7
R
8
, halogen, cyano, nitro or alkyl,
in which R
6
, R
7
and R
8
represent, independently, a hydrogen atom, an alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical;
A represents
either an A1 or A′1 radical
 in which R
9
, R
10
, R
11
, R
12
, R
13
represent, independently, a hydrogen atom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitro or —NR
15
R
16
radical,
R
15
and R
16
represent, independently, a hydrogen atom, an alkyl radical or a —COR
17
group, or R
15
and R
16
together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R
17
represents a hydrogen atom, an alkyl, alkoxy or —NR
18
R
19
radical,
R
18
and R
19
represent, independently, a hydrogen atom or an alkyl radical, or R
18
and R
19
together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R
14
represents a hydrogen atom, an alkyl radical or a —COR
20
group,
R
20
represents a hydrogen atom, an alkyl, alkoxy, aryl, aralkyl, heterocycloalkyl or —NR
21
R
22
radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or —NR
4
R
5
;
R
21
and R
22
represent, independently, a hydrogen atom or an alkyl radical, or R
21
and R
22
together with the nitrogen atom to which they are, attached form an optionally substituted heterocycle,
W represents a bond, O or S or also an —NR
23
radical, in which R
23
represents a hydrogen atom or an alkyl radical;
or an A2 radical
 in which
R
24
, R
25
and R
26
represent, independently, a hydrogen, a halogen, the OH or SR
27
group, an alkyl, alkenyl, alkoxy radical or an —NR
28
R
29
radical,
R
27
represents a hydrogen atom or an alkyl radical,
R
28
and R
29
represent, independently, a hydrogen atom, an alkyl radical or a —COR
30
group, or R
28
and R
29
form together with the nitrogen atom to which they are attached an optionally substituted heterocycle,
R
30
represents a hydrogen atom, an alkyl, alkoxy or —NR
31
R
32
radical,
R
31
and R
32
represent, independently, a hydrogen atom or an alkyl radical, or R
31
and R
32
together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
Q represents —OR
33
, —SR
33
, —NR
34
R
35
or an aryl radical substituted by one or more identical or different substituents chosen from: halogen, the OH group, an alkyl, alkoxy, cyano, nitro or —NR
15
R
16
radical,
R
33
represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or —NR
4
R
5
;
R
34
and R
35
represent, independently, a hydrogen atom, an alkyl radical or a —CO—R
36
radical, or together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
R
36
representing an alkyl radical;
or an A3 radical
 in which R
37
represents a hydrogen atom, an alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl radical,
in which the alkyl, aryl or heterocycloalkyl radicals are optionally substituted by one or more identical or different substituents chosen from: alkyl, OH, alkoxy, nitro, cyano, halogen or —NR
4
R
5
;
T represents a —(CH
2
)
m
— radical with m=1 or 2;
or an A4 radical
in which R
38
represents a hydrogen atom, an alkyl, —(CH
2
)
q
—NR
39
R
40
or aralkyl radical, the aryl group being optionally substituted by one or more identical or different substituents chosen from: OH, alkyl, halogen, nitro, alkoxy or —NR
39
R
40
,
q being an integer comprised between 2 and 6;
or an A5 radical
 in which R′
38
and R″
38
represent independently a hydrogen atom, nitro, —NR′
39
R′
40
, an alkyl or arylalkyl radical, the aryl group being optionally substituted by one or more identical or different substituents chosen from: OH, the alkyl, halogen, nitro, alkoxy or —NR
39
R
40
radicals,
R′
39
, R′
40
, R
39
and R
40
represent, independently, a hydrogen atom, an alkyl radical or a —COR
41
group, or R
39
and R
40
or R′
39
and R′
40
together with the nitrogen atom form an optionally substituted heterocycle,
R
41
represents a hydrogen atom, an alkyl, alkoxy or —NR
42
R
43
radical,
R
42
and R
43
represen

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