Derivatives of 2-aminopyridines, their use as medicaments...

Details Derivatives of 2-aminopyridines, their use as medicaments... Derivatives of 2-aminopyridines, their use as medicaments...

2003-04-02

2004-04-27

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S277000, C514S337000, C514S349000, C514S357000, C514S456000, C546S268100, C546S281700, C546S282700, C546S304000, C546S329000, C549S396000, C549S398000

Reexamination Certificate

active

06727239

ABSTRACT:

A subject of the present invention is new derivatives of 2-aminopyridines which have. an inhibitory activity on NO-synthase enzymes producing nitrogen monoxide NO and/or an activity which traps the reactive oxygen species (ROS). The invention relates to the derivatives corresponding to general formula (I) defined below, their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as NO-synthase inhibitors and selective or non selective traps for reactive oxygen species.
Given the potential role of NO and the ROS's in physiopathology, the new derivatives described corresponding to general formula (I) may produce beneficial or favourable effects in the treatment of pathologies where these chemical species are involved. In particular:
in the treatment of cardiovascular and cerebro-vascular disorders including for example atherosclerosis, migraine, arterial hypertension, septic shock, ischemic or hemorragic cardiac or cerebral infarctions, ischemias and thromboses.
in the treatment of disorders of the central or peripheral nervous system such as for example neurodegenerative diseases where there can in particular be mentioned cerebral infarctions, sub-arachnoid haemorrhaging, ageing, senile dementias including Alzheimer's disease, Huntington's chorea, Parkinson's disease, Creutzfeld Jacob disease and prion diseases, amyotrophic lateral sclerosis but also pain, cerebral and bone marrow traumas, addiction to opiates, alcohol and addictive substances, erective and reproductive disorders, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin.
in the treatment of disorders of the skeletal muscle and neuromuscular joints (myopathy, myosis) as well as cutaneous diseases.
in the treatment of proliferative and inflammatory diseases such as for example atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, portal hypertension, psoriasis, arthrosis and rheumatoid arthritis, fibroses, amyloidoses, inflammations of the gastro-intestinal system (colitis, Crohn's disease) or of the pulmonary system and airways (asthma, sinusitis, rhinitis).
in treatments related to organ transplants.
in the treatment of auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis.
in the treatment of cancer.
in the treatment of neurological diseases associated with intoxications (Cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatments (radiotherapy) or disorders of genetic origin (Wilson's disease).
in the treatment of all the pathologies characterized by an excessive production or dysfunction of NO and/or ROS's.
In all these pathologies, there is experimental evidence demonstrating the involvement of NO or ROS's (
J. Med. Chem
. (1995) 38, 4343-4362
; Free Radic. Biol. Med
. (1996) 20, 675-705
; The Neuroscientist
(1997) 3, 327-333).
Furthermore, NO Synthase inhibitors and their use have already been described by the inventors in previous Patents (U.S. Pat. No. 5,081,148; U.S. Pat. No. 5,360,925), as well as the combination of these inhibitors with products having antioxidant or antiradicular properties (Patent Application WO 98/09653). More recently, derivatives of amidines having NO Synthase inhibitory properties and/or antioxidant or antiradicular properties have been described in the Patent Applications WO 98/42696 and WO 98/58934.
The Applicant has now discovered a new class of compounds having an inhibitory activity on NO-synthases and/or an activity which traps the reactive oxygen species (ROS). These compounds, of general formula (I) defined hereafter, are derivatives of 2-aminopyridines.
The compounds according to the invention correspond to general formula (I)
in which A represents a radical which traps free radicals, and in particular:
a radical
 in which R
1
, R
2
, and R
3
represent, independently, a hydrogen atom, a halogen, the OH or SH group, a linear or branched alkyl, aralkoxy or alkoxy radical having from 1 to 6 carbon atoms, an —O—CO—R
4
, —SR
4
, —S(O)R
4
, —SO
2
R
4
, or —NR
5
R
6
radical, or also R
1
and R
2
or R
2
and R
3
together form a methylenedioxy ring,
R
4
representing a linear or branched alkyl radical having from 1 to 6 carbon atoms, and R
5
and R
6
representing independently a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or an aromatic ring optionally substituted by one or more groups chosen from a halogen atom, the OH group and a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms,
or NR
5
R
6
constitutes a heterocycle with 4 to 6 members, which contains from 1 to 2 heteroatoms chosen from O, S and N, the corresponding members being respectively —O—, —S— and —NR
7
—,
R
7
representing a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms,
or a radical
 in which R
1
, R
2
, R
3
and R
4
represent, independently, a hydrogen atom, a halogen, the OH group, or a linear or branched alkoxy radical having from 1 to 6 carbon atoms,
or also a radical
 in which R
8
represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a —CO—R
9
radical, an arylalkyl radical optionally substituted by one or more linear or branched alkyl or alkoxy radicals having from 1 to 6 carbon atoms, R
9
represents a linear or branched alkyl radical having from 1 to 6 carbon atoms;
X represents a —(CH
2
)
m
—Q—, —(CH
2
)
m
—CH═CH—Q—, —(CH
2
)
m
—C(═W)—Q—, —(CH
2
)
m
——NR
11
—C(═W)—Q—, —(CH
2
)
m
—NR
11
—C(═W)—O—Q—, —(CH
2
)
m
—N═C(═W)—NR
2
—Q—, —(CH
2
)
m
—NH—Z—NH—C(═W)—, —(CH
2
)
m
—N═C(R
16
)—NR
12
—, —(CH
2
)
m
—CH═CH—C(═W)—Q radical or a linear or branched alkenyl radical having from 1 to 6 carbon atoms,
Q representing a bond or a radical chosen from the piperazine, homopiperazine, piperidine, pyrrolidine or azetidine radicals, these radicals can be substituted by one or more linear or branched alkyl radicals having from 1 to 6 carbon atoms,
W representing one of the O or S atoms or the NH group,
Z representing a phenylene radical optionally substituted by one or more halogen atoms, m being an integer comprised between 0 and 6;
Y represents an alkyl, alkenyl or alkynyl chain, each of these chains can be linear or branched, having up to 10 carbon atoms and be optionally substituted by an NR
13
R
14
radical, or Y represents a —(CH
2
)
n
—O—(CH
2
)
p
, —(CH
2
)
n
—S—(CH
2
)
p
— or —(CH
2
)
n
—NR
13
—(CH
2
)
p
— radical,
n and p being integers comprised between 0 and 6;
R
10
represents a hydrogen atom, one of the OH, CN, NO
2
or —SR
15
radicals, or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms;
R
11
, R
12
, R
13
, R
14
and R
15
represent independently a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms;
R
16
represents independently a hydrogen atom or a linear or branched alkyl or thioalkyl radical having from 1 to 6 carbon atoms;
It being understood that —X—Y— together do not represent a single bond, a linear or branched alkylene radical or an —O—, —S—, —NH— or —NH—CO—NH-alkylene radical;
it being also understood that when A represents the phenyl radical, —X—Y— together do not represent —NH—CO—NH—;
or a salt of a product of general formula (I).
The compounds of the invention can exist in the state of bases or of addition salts in particular with organic or inorganic acids or with bases, and in particular in the state of hydrates.
By linear or branched alkyl having from 1 to 6 carbon atoms, is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By linear or branched thioalkyl radicals having from 1 to 6 carbon atoms or linear or branched alkoxy having from 1 to 6 carbon atoms, are meant the thioalkyl or alkoxy radicals, the alkyl radical of which has the mean

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