Derivatives of 2-(iminomethyl)amino-phenyl, their...

Details Derivatives of 2-(iminomethyl)amino-phenyl, their... Derivatives of 2-(iminomethyl)amino-phenyl, their...

1999-12-07

2002-01-01

Shah, Mukund J. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S392000, C544S374000, C544S399000, C544S402000, C544S405000, C540S553000, C546S207000, C546S212000, C548S469000, C548S950000, C549S398000, C512S014000, C512S014000, C512S014000, C512S014000, C512S014000

Reexamination Certificate

active

06335445

ABSTRACT:

A subject of the present invention is new derivatives of 2-(iminomethyl)amino-phenyl 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:
cardiovascular and cerebro-vascular disorders including for example artherosclerosis, migraine, arterial hypertension, septic shock, ischemic or hemorragic cardiac or cerebral infarctions, notably those related with complications of coronary artery bypass grafting, ischemias and thromboses.
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.
disorders of the skeletal muscle and neuromuscular joints (myopathy, myosis) as well as cutaneous diseases.
proliferative and inflammatory diseases such as for example artherosclerosis, 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).
organ transplants.
auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis.
cancer.
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).
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, their use and more recently the combination of these inhibitors with products having antioxidant or antiradicular properties have already been described in previous Patents (respectively U.S. Pat. Nos. 5,081,148; 5,360,925 and an unpublished Patent Application).
A subject of the present invention is the derivatives of 2-(iminomethyl)amino-phenyl, their preparation and their therapeutic use.
The compounds of the invention correspond to general formula (I):
in which:
A represents a hydrogen atom or:
either a
 radical in which R
1
and R
2
represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms,
R
3
represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a —COR
4
radical,
R
4
represents a linear or branched alkyl radical having from 1 to 6 carbon atoms,
or a
 radical in which R
3
represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a —COR
4
radical, R
4
represents a linear or branched alkyl radical having from 1 to 6 carbon atoms,
or a
 radical in which R
5
represents a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms;
B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing from 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms;
X represents —Z
1
—, —Z
1
—CO—, —CH═, —CH═CH—CO—, —Z
1
—NR
3
—CO—Z′
1
—, —CO—NR
3
—Z′
1
—, —Z
1
—NR
3
—CS—, —Z
1
—NR
3
—SO
2
— or a single bond;
Het does not exist or represents a heterocycle containing from 1 to 5 heteroatoms chosen from O, N, S which can be substitued by one or more substituents X′—OR
3
, X′—NR
3
, X′—S—R
3
and such as for example: oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, sulpholane, imidazole, imidazoline, dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole, oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole, thiazoline, thiazolidine, thiazolidinone, hydantoine, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine, 1,2,4-triazole-3-one, tetrazole, tetrahydropyridine, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine or 4-aminopiperidine;
Y represents a radical chosen from the —Z
2
—Q—, —Z
2
—CO—, —Z
2
—NH—CO—, —Z
2
—CH
2
—NR
3
—CO—, —NR
3
—Z
2
—Q—, —NR
3
—CO—Z
2
—Q—, —NR
3
—NH—CO—Z
2
—, —NH—NH—Z
2
—, —NR
3
—O—Z
2
—, —NR
3
—SO
2
—NR
3
—Z
2
—, —O—Z
2
—Q—, —O—CO—Z
2
—Q— or —S—Z
2
—Q— radicals, in which Q represents a single bond, O—Z
3
, R
3
—N—Z
3
or S—Z
3
;
Z
1
, Z′
1
, Z
2
and Z
3
represent independently a single bond or a linear or branched alkylene radical having from 1 to 6 carbon atoms; preferably, Z
1
, Z′
1
, Z
2
and Z
3
represent —(CH
2
)
m
—, m being an integer comprised between 0 and 6;
R
6
represents a hydrogen atom or an OH group;
it being understood that when Het is absent, then A is not a hydrogen atom and that when A is hydrogen then Het does not represent a piperidine, pyrrolidine or morpholine radical;
or are salts of the latter.
The compounds of general formula (I) containing an asymmetrical centre are of isomeric form. The racemic and enantiomeric forms of these compounds also form part of this invention.
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, hydrochlorides, dihydrochlorides, fumarates or hemifumarates.
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 alkoxy having from 1 to 6 carbon atoms is meant radicals the alkyl radical of which has the meaning indicated previously. By halogen is meant fluorine, chlorine, bromine or iodine atoms.
Preferably, the compounds of general formula (I) are such that they include at least one of the following features:
A represents a
radical in which R
1
and R
2
represent, independently, a branched alkyl radical having from 3 to 6 carbon atoms,
R
3
represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a —COR
4
radical,
R
4
represents a linear or branched alkyl radical having from 1 to 6 carbon atoms,
or A represents a
 radical in which R
3
represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms;
B represents a thiophene or phenyl radical;
X represents —Z
1
—CO— or —CO—NR
3
—Z′
1
;
Het is absent or represents a piperazine or tetrahydropyridinyl radical;
Y represents —Z
2
—Q— or —NR
3
—Z

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