U.S. patent application number 10/895578 was filed with the patent office on 2005-02-03 for new derivatives of n-(iminomethyl)amines, their preparation, their use as medicaments and the pharmaceutical compositions containing them.
This patent application is currently assigned to SOCIETE DE CONSEILS DE RECHERCHES D'APPLICATIONS SCIENTIFIQUES (S.C.R.A.S.). Invention is credited to Auvin, Serge, Bigg, Dennis, Chabrier de Lassauniere, Pierre-Etienne, Harnett, Jeremiah, Ulibarri, Gerard.
Application Number | 20050027009 10/895578 |
Document ID | / |
Family ID | 9530743 |
Filed Date | 2005-02-03 |
United States Patent
Application |
20050027009 |
Kind Code |
A1 |
Bigg, Dennis ; et
al. |
February 3, 2005 |
New derivatives of N-(iminomethyl)amines, their preparation, their
use as medicaments and the pharmaceutical compositions containing
them
Abstract
N-(imino)amines and their preparation and their use as NO
synthase inhibitors and selective or non-selective traps for a
reactive oxygen species.
Inventors: |
Bigg, Dennis;
(Gif-sur-Yvette, FR) ; Chabrier de Lassauniere,
Pierre-Etienne; (Paris, FR) ; Auvin, Serge;
(Mauchamps, FR) ; Harnett, Jeremiah;
(Gif-sur-Yvette, FR) ; Ulibarri, Gerard;
(Burres-sur-Yvette, FR) |
Correspondence
Address: |
Charles A. Muserlian
c/o Muserlian, Lucas and Mercanti
475 Park Avenue South
New York
NY
10016
US
|
Assignee: |
SOCIETE DE CONSEILS DE RECHERCHES
D'APPLICATIONS SCIENTIFIQUES (S.C.R.A.S.)
|
Family ID: |
9530743 |
Appl. No.: |
10/895578 |
Filed: |
July 21, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10895578 |
Jul 21, 2004 |
|
|
|
10612646 |
Jul 1, 2003 |
|
|
|
6809090 |
|
|
|
|
10612646 |
Jul 1, 2003 |
|
|
|
10255849 |
Sep 26, 2002 |
|
|
|
6620840 |
|
|
|
|
10255849 |
Sep 26, 2002 |
|
|
|
09787466 |
Mar 16, 2001 |
|
|
|
6482822 |
|
|
|
|
09787466 |
Mar 16, 2001 |
|
|
|
PCT/FR99/02251 |
Sep 22, 1999 |
|
|
|
Current U.S.
Class: |
514/631 ;
514/524; 564/244 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
25/02 20180101; A61P 25/16 20180101; A61P 7/02 20180101; A61P 19/02
20180101; A61P 1/04 20180101; A61P 9/10 20180101; A61P 19/00
20180101; A61P 37/02 20180101; A61P 25/00 20180101; A61P 11/00
20180101; A61P 25/36 20180101; A61P 27/12 20180101; A61P 25/32
20180101; A61P 39/06 20180101; A61P 27/16 20180101; A61P 31/00
20180101; A61P 33/00 20180101; A61P 21/00 20180101; A61P 27/06
20180101; A61P 17/00 20180101; A61P 43/00 20180101; A61P 11/06
20180101; A61P 25/28 20180101; A61P 31/18 20180101; A61P 13/12
20180101; C07D 333/38 20130101; A61P 29/00 20180101; A61P 31/12
20180101; A61P 35/00 20180101; A61P 17/06 20180101; A61P 9/00
20180101; A61P 9/12 20180101 |
Class at
Publication: |
514/631 ;
564/244; 514/524 |
International
Class: |
A61K 031/275; A61K
031/155 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 23, 1998 |
FR |
9811867 |
Claims
1-14. (cancelled)
15 A compound of the formula 40wherein .phi. is phenylene with 1 to
2 substituents selected from the group consisting of hydrogen,
halogen, --OH, and alkyl or alkoxy of 1 to 6 carbon atoms, A is 41W
does not exist, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 are
individually selected from the group consisting of hydrogen,
halogen, --OH, --CN, --NO.sub.2, --NR.sub.6R.sub.7 and alkyl and
alkoxy of 1 to 6 carbon atoms, R.sub.6 and R.sub.7 are individually
selected from the group consisting of hydrogen, --OH, --COR.sub.8
and alkyl or alkoxy of 1 to 6 carbon atoms, R.sub.8 is selected
from the group consisting of hydrogen, --OH, --NR.sub.9R.sub.10 and
alkyl or alkoxy of 1 to 6 carbon atoms, R.sub.9 and R.sub.10 are
individually selected from the group consisting of hydrogen, --OH
and alkyl of 1 to 6 carbon atoms, R.sub.11 is selected from the
group consisting of hydrogen, --OH, --COR.sub.12 and alkyl or
alkoxy of 1 to 6 carbon atoms, R.sub.12 is selected from the group
consisting of hydrogen, --OH and alkyl of 1 to 6 carbon atoms, B is
selected from the group consisting of --CH.sub.2--NO.sub.2, alkyl
of 1 to 6 carbon atoms, --NR.sub.13R.sub.14 and unsubstituted and
substituted carbocyclic aryl and heterocyclic aryl of 5 to 6 ring
members containing 1 to 4 heteroatoms containing 1 to 4 heteroatoms
selected from the group consisting of oxygen, sulfur and nitrogen,
the aryl substituents being selected from the group consisting of
alkyl, alkenyl and alkoxy of up to 6 carbon atoms, R.sub.13 and
R.sub.14 are individually selected from the group consisting of
hydrogen, --CN, --NO.sub.2 and alkyl of 1 to 6 carbon atoms or
together with the nitrogen form a non-aromatic heterocycle of 5 to
6 ring members selected from the group consisting of --CH.sub.2--,
--NH--, --O-- and S--, X is selected from the group consisting of a
bond, --(CH.sub.2).sub.k--NR.sub.16--, --O--, --S--, --CO--,
--NR.sub.16--CO--, --CO--NR.sub.16--, --O--CO--, --CO--O--,
--NR.sub.16--CO--O-- and --NR.sub.16--CO--NR.sub.17--, k is 0 or 1,
Y represents a bond or a radical chosen from the
--(CH.sub.2).sub.m--, (CH.sub.2).sub.m--O--(CH.su- b.2).sub.n--,
--(CH.sub.2).sub.m--S--(CH.sub.2).sub.n--,
--(CH).sub.m--NR.sub.18(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18-- -CO--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--CO--NR.sub.18--(CH.sub.2).sub- .n--,
--(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n-radicals, Q is selected
from the group consisting of piperazine, homopiperazine,
2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine and
4-aminopiperidine, m and n are individually integers from 0 to 6,
R.sub.16, R.sub.17 and R.sub.18 are individually a hydrogen atom or
alkyl of 1 to 6 carbon atoms and its pharmaceutically acceptable
salt with acids or bases.
16 The compound of claim 15 wherein A is 42R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5 are individually selected from the group
consisting of hydrogen, halogen, --OH and alkyl and alkoxy of 1 to
6 carbon atoms, R.sub.11 is hydrogen atom or alkyl of 1 to 6 carbon
atoms, B is a substituted or unsubstituted carbocyclic aryl or
heterocyclic aryl of 5 to 6 ring members containing 1 to 4
heteroatoms selected from the group consisting of oxygen, sulfur
and nitrogen, the aryl substituents being selected from the group
consisting of alkyl, alkenyl and alkoxy of up to 6 carbon atoms, W
does not exist, X is selected from the group consisting of a bond,
--(CH.sub.2).sub.k--NR.sub.16--, --O--, --S--, --CO--,
--NR.sub.16--CO--, --CO--NR.sub.16--, --O--CO--, --CO--O--,
--NR.sub.16--CO--O-- and --NR.sub.16--CO--NR.sub.17--, k is 0 or 1,
Y is selected from the group consisting of a bond,
--(CH.sub.2).sub.m--, --(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--S--(CH).su- b.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18--CO--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--CO--NR.sub.18--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n--, Q is selected from the
group consisting of piperazine, homopiperazine, 2-methylpiperazine,
2,5-dimethylpiperazine, 4-oxypiperazine or 4-aminopiperidine and m
and n are integers from 0 to 6.
17 The compound of claim 15 wherein B is selected from the group
consisting of thiophene, furan, pyrrole and thiazole.
18 The compound of claim 15 wherein A is 43R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 are individually selected from
hydrogen, --OH and alkyl and alkoxy of 1 to 6 carbon atoms,
R.sub.11 is hydrogen or methyl, B is selected from the group
consisting of unsubstituted or substituted phenyl, thiophene,
furan, pyrrole and thiazole, the substituents being at least one
member of the group consisting of alkyl, alkenyl and alkoxy of up
to 6 carbon atoms, W does not exist, X is selected from the group
consisting of a bond, --(CH.sub.2).sub.k--NR.sub.16--, --O--,
--S--, --CO--, --NR.sub.16--CO--, --CO--NR.sub.16--, --O--CO--,
--CO--O--, --NR.sub.16--CO--O-- and --NR.sub.16--CO--NR.sub.17--, k
is 0 or 1, Y is selected from the group consisting of a bond,
--(CH.sub.2).sub.m--, --(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--S--(CH.sub- .2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18--CO--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--CO--NR.sub.18--(CH.sub.2).sub.n)-- and
--(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n--, Q is selected from the
group consisting of piperazine, homopiperazine, 2-methylpiperazine,
2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine and m
and n are integers from 0 to 6.
19 The compound of claim 15 wherein A is 44R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5 are individually hydrogen or methyl,
R.sub.11 is hydrogen or methyl, B is thiophene, W does not exist, X
does not exist or is selected from the group consisting of
--(CH.sub.2).sub.k--NR.sub.16--, --O--, --S--, --CO--,
--NR.sub.16--CO--, --CO--NR.sub.16--, --O--CO--, --CO--O--,
--NR.sub.16--CO--O-- and --NR.sub.16--CO--NR.sub.17--, k is 0 or 1,
Y is selected from the group consisting of --(CH.sub.2).sub.m--,
--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--S--(CH.sub- .2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18--CO--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--CO--NR.sub.18--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n--, Q is piperazine, m and n
are integers from 0 and 6 and R.sub.16, R.sub.17 and R.sub.18 are
hydrogen.
20 A compound of claim 15 which is
4-(4-{[amino(2-thienyl)methylidene]amin-
o}phenyl)-N-(4-phenoxyphenyl)butanamide hydrochloride or
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-4-(4-hydroxyphenoxy)b-
enzamide hydrochloride.
21 A compound of claim 20 in the form of its hydrochloride
salt.
22 A composition for inhibiting NO synthase and/or lipidic
peroxidation comprising an effective amount of a compound of claim
15 and an inert pharmaceutical carrier.
23 A method of inhibiting NO synthase in warm-blooded animals
comprising administration to said patient of a NO synthase
inhibitory amount of a compound of general formula (I) as defined
in claim 15 or a pharmaceutically acceptable salt of said
compound.
24 A method of inhibiting lipidic peroxidation in a patient in need
thereof comprising administration to said patient of a lipidic
peroxidation inhibitory amount of a compound of general formula (I)
as defined in claim 15 or of a pharmaceutically acceptable salt of
said compound.
25 A method of inhibiting both NO synthase and lipidic peroxidation
in a patient in need thereof comprising administration to said
patient of a compound of general formula (I) as defined in claim 15
or of a pharmaceutically acceptable salt of said compound, in an
amount sufficient to inhibit both NO synthase and lipidic
peroxidation.
Description
[0001] This application is a division of U.S. patent application
Ser. No. 09/787,466 filed Mar. 16, 2001, now U.S. Patent No.
______, which is a 371 of PCT/FR99/02251 filed Sept. 22, 1999.
[0002] A subject of the present invention is new derivatives of
N-(iminomethyl)amines comprising the aminodiphenylamine,
oxodiphenylamine, carbazole, phenazine, phenothiazine, phenoxazine
or oxodiphenyl unit in their skeleton. These derivatives 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.
[0003] 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:
[0004] Proliferative and inflammatory diseases such as for example
atherosclerosis, pulmonary hypertension, respiratory distress,
glomerulonephritis, portal hypertension, psoriasis, arthrosis and
rheumatoid arthritis, fibroses, angiogenisis, amyloidoses,
inflammations of the gastro-intestinal system (ulcerous or
non-ulcerous colitis, Crohn's disease), diarrhoea.
[0005] Diseases affecting the pulmonary system and airways (asthma,
sinusitis, rhinitis).
[0006] Cardio-vascular and cerebro-vascular disorders including for
example, migraine, arterial hypertension, septic shock, ischemic or
hemorragic, cardiac or cerebral infarctions, ischemias and
thromboses.
[0007] 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; ocular
neuropathies such as glaucoma but also pain, cerebral and bone
marrow traumas, addiction to opiates, alcohol and addictive
substances, cognitive disorders, encephalopathies, encephalopathies
of viral or toxic origin.
[0008] Disorders of the skeletal muscle and neuromuscular joints
(myopathy, myosis) as well as cutaneous diseases.
[0009] Cataracts.
[0010] Organ transplants.
[0011] Auto-immune and viral diseases such as for example lupus,
AIDS, parasitic and viral infections, diabetes and its
complications, multiple sclerosis.
[0012] Cancer.
[0013] 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).
[0014] all the pathologies characterized by an excessive production
or dysfunction of NO and/or ROS's.
[0015] 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).
[0016] Moreover, in earlier patents, the inventors have already
described NO Synthase inhibitors and their use (U.S. Pat. Nos.
5,081,148; 5,360,925) and more recently the combination of these
inhibitors with products having antioxidant or antiradicular
properties (Patent Application PCT WO/09653). They have also
described in not yet published Applications other derivatives of
amidines or, more recently, derivatives of aminopyridines. These
derivatives of amidines or aminopyridines have the characteristic
of being both NO Synthase inhibitors and ROS inhibitors.
[0017] A subject of the present invention is new derivatives of
amidines, their preparation and their use in therapeutics.
[0018] The compounds of the invention correspond to general formula
(I): 1
[0019] in which
[0020] .PHI. represents a bond or a phenylene radical which can
include, in addition to the two chains already represented in
general formula (I), up to two substituents chosen from a hydrogen
atom, a halogen, an OH group, and a linear or branched alkyl or
alkoxy radical having 1 to 6 carbon atoms;
[0021] A represents a 2
[0022] radical in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
represent, independently, a hydrogen atom, a halogen, the OH group,
a linear or branched alkyl or alkoxy radical having 1 to 6 carbon
atoms, or a cyano, nitro or NR.sub.6R.sub.7 radical,
[0023] R.sub.6 and R.sub.7 representing, independently, a hydrogen
atom, the OH group, a linear or branched alkyl or alkoxy radical
having 1 to 6 carbon atoms, or also a --COR.sub.8 group,
[0024] R.sub.8 representing a hydrogen atom, the OH group, a linear
or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or
NR.sub.9R.sub.10,
[0025] R.sub.9 and R.sub.10 representing, independently, a hydrogen
atom, the OH group or a linear or branched alkyl radical having 1
to 6 carbon atoms,
[0026] R.sub.11 representing a hydrogen atom, the OH group, a
linear or branched alkyl or alkoxy radical having 1 to 6 carbon
atoms, or a --COR.sub.12 radical,
[0027] and R.sub.12 representing a hydrogen atom, the OH group, a
linear or branched alkyl radical having 1 to 6 carbon atoms,
[0028] or a 3
[0029] radical in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
represent, independently, a hydrogen atom, a halogen, the OH group,
a linear or branched alkyl or alkoxy radical having 1 to 6 carbon
atoms, or a cyano, nitro or NR.sub.6R.sub.7 radical,
[0030] R.sub.6 and R.sub.7 representing, independently, a hydrogen
atom, the OH group, a linear or branched alkyl or alkoxy radical
having 1 to 6 carbon atoms, or also a --COR.sub.8 group,
[0031] R.sub.8 representing a hydrogen atom, the OH group, a linear
or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or
NR.sub.9R.sub.10,
[0032] R.sub.9 and R.sub.10 representing, independently, a hydrogen
atom, the OH group or a linear or branched alkyl radical having 1
to 6 carbon atoms,
[0033] B represents --CH.sub.2--NO.sub.2, a linear or branched
alkyl radical having 1 to 6 carbon atoms, carbocyclic or
heterocyclic aryl with 5 or 6 members containing 1 to 4 heteroatoms
chosen from O, S, N and in particular the thiophene, furan, pyrrole
or thiazole radical, the aryl radical being optionally substituted
by one or more groups chosen from linear or branched alkyl, alkenyl
or alkoxy radicals having 1 to 6 carbon atoms,
[0034] or B represents an NR.sub.13R.sub.14 radical, in which
R.sub.13 and R.sub.14 representing, independently, a hydrogen atom
or a linear or branched alkyl radical having 1 to 6 carbon atoms or
a cyano or nitro radical, or R.sub.13 and R.sub.14 form with the
nitrogen atom a non aromatic heterocycle with five to six members,
the elements of the chain being chosen from a group composed of
--CH.sub.2--, --NH--, --O-- or --S--;
[0035] W does not exist, or represents a bond, or O, S or
NR.sub.15, in which R.sub.15 represents a hydrogen atom or a linear
or branched alkyl radical having 1 to 6 carbon atoms;
[0036] X represents a bond or a (CH.sub.2).sub.k--NR.sub.16--,
--O--, --S--, --CO--, --NR.sub.16--CO--, --CO--NR.sub.16--,
--O--CO--, --CO--O--, --NR.sub.16--CO--O--,
--NR.sub.16--CO--NR.sub.17-- radical,
[0037] k representing 0 or 1;
[0038] Y represents a bond or a radical chosen from the
--(CH.sub.2).sub.m)--, --(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--S--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18-- -(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18--CO--(CH.sub.2).sub.n--- ,
--(CH.sub.2).sub.m--CO--NR.sub.18--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n-- radicals,
[0039] Q representing piperazine, homopiperazine,
2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or
4-aminopiperidine radicals,
[0040] m and n being integers from 0 to 6;
[0041] R.sub.16, R.sub.17 and R.sub.18 represent, independently, a
hydrogen atom or a linear or branched alkyl radical having 1 to 6
carbon atoms;
[0042] or are salts of the products mentioned previously.
[0043] By linear or branched alkyl having 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 1 to
6 carbon atoms, is meant the alkyl radical of which has the meaning
indicated previously. Finally, by halogen, is meant fluorine,
chlorine, bromine or iodine atoms.
[0044] Preferably, the compounds according to the invention are the
compounds of general formula (I) such that:
[0045] A represents a 4
[0046] radical in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
represent, independently, a hydrogen atom, the OH group or a linear
or branched alkyl or alkoxy radical having 1 to 6 carbon atoms,
[0047] R.sub.11 representing a hydrogen atom or a linear or
branched alkyl radical having 1 to 6 carbon atoms,
[0048] or a 5
[0049] radical in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
represent, independently, a hydrogen atom, the OH group or a linear
or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
[0050] B represents a carbocyclic or heterocyclic aryl radical with
5 or 6 members containing 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 linear or branched alkyl, alkenyl or alkoxy
radicals having 1 to 6 carbon atoms;
[0051] W does not exist, or represents a bond, S or NR.sub.15, in
which R.sub.15 represents a hydrogen atom or a linear or branched
alkyl radical having 1 to 6 carbon atoms;
[0052] X represents a bond or a --(CH.sub.2).sub.k--NR.sub.16--,
--O--, --S--, --CO--, --NR.sub.16--CO--, --CO--NR.sub.16--,
--O--CO--, --CO--O--, --NR.sub.16--CO--O--,
--NR.sub.16--CO--NR.sub.17-- radical
[0053] k representing 0 or 1;
[0054] Y represents a bond or a radical chosen from the
--(CH.sub.2).sub.m--, --(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--S--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18-- -(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18--CO--(CH.sub.2).sub.n--- ,
--CH.sub.2).sub.m--CO--NR.sub.18--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n-- radicals,
[0055] Q representing piperazine, homopiperazine,
2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or
4-aminopiperidine,
[0056] m and n being integers from 0 to 6;
[0057] or are salts of the products mentioned previously.
[0058] More preferentially, the compounds according to the
invention are compounds of general formula (I) such that:
[0059] A represents a 6
[0060] radical in which R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
R.sub.5 represent, independently, a hydrogen atom, the OH group or
a linear or branched alkyl or alkoxy radical having 1 to 6 carbon
atoms,
[0061] R.sub.11 representing a hydrogen atom or a methyl
radical,
[0062] or a 7
[0063] radical in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
represent, independently, a hydrogen atom, the OH group or a linear
or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
[0064] B represents one of the phenyl, thiophene, furan, pyrrole or
thiazole radicals optionally substituted by one or more groups
chosen from linear or branched alkyl, alkenyl or alkoxy radicals
having 1 to 6 carbon atoms;
[0065] W does not exist, or represents a bond, S or NR.sub.15, in
which R.sub.15 represents a hydrogen atom or a linear or branched
alkyl radical having 1 to 6 carbon atoms;
[0066] X represents a bond or a --(CH.sub.2).sub.k--NR.sub.16--,
--O--, --S--, --CO--, --NR.sub.16--CO--, --CO--NR.sub.16--,
--O--CO--, --CO--O--, --NR.sub.16--CO--O--,
--NR.sub.16--CO-NR.sub.17-- radical,
[0067] k representing 0 or 1;
[0068] Y represents a bond or a radical chosen from the
--(CH.sub.2).sub.m--, --(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--S--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18-- -(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18--CO--(CH.sub.2).sub.n--- ,
--(CH.sub.2).sub.m--CO--NR.sub.18--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n-- radicals,
[0069] Q representing piperazine, homopiperazine,
2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or
4-aminopiperidine,
[0070] m and n being integers comprised from 0 to 6;
[0071] or are salts of the products mentioned previously.
[0072] Yet more preferentially, the compounds according to the
invention are compounds of general formula (I) such that:
[0073] A represents a 8
[0074] radical in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
represent, independently, a hydrogen atom or a methyl radical,
[0075] R.sub.11 representing a hydrogen atom or a methyl
radical;
[0076] B represents the thiophene radical;
[0077] W does not exist, represents a single bond or S;
[0078] X represents a bond or represents a
--(CH.sub.2).sub.k--NR.sub.16--- , --O--, --S--, --CO--,
--NR.sub.16--CO--, --CO--NR.sub.16--, --O--CO--, --CO--O--,
--NR.sub.16--CO--O--, --NR.sub.16--CO--NR.sub.17-- radical;
[0079] k representing 0 or 1;
[0080] Y represents a bond or a radical chosen from the
--(CH.sub.2).sub.m--, --(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--S--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18-- -(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18--CO--(CH.sub.2).sub.n--- ,
--(CH.sub.2).sub.m--CO--NR.sub.18--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n-- radicals,
[0081] Q representing piperazine,
[0082] m and n being integers comprised between 0 and 6;
[0083] R.sub.16, R.sub.17 and R.sub.18 represent a hydrogen
atom;
[0084] or are salts of the products mentioned previously.
[0085] Quite particularly preferred are the following compounds
described in the examples:
[0086] N-[4-(phenylamino)phenyl]-2-thiophenecarboximidamide;
[0087]
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzene-
acetamide;
[0088]
{4-{[2-thienyl(imino)methyl]amino}phenoxy}-N-[4-(phenylamino)phenyl-
]-acetamide;
[0089]
4-{[2-thienyl(imino)methyl]amino}-N-[2-(phenylamino)phenyl]-benzene-
butanamide;
[0090]
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzene-
butanamide;
[0091]
4-{[2-thienyl(imino)methyl]amino}-N-[4-(4-methoxyphenylamino)phenyl-
]-benzenebutanamide;
[0092]
2-{4-{[2-thienyl(imino)methyl]amino}phenyl}-ethyl[4-(phenylamino)ph-
enyl]-carbamate;
[0093]
N-{2-{4-{[2-thienyl(imino)methyl]amino}phenyl}ethyl}-N'-[4-(phenyla-
mino)phenyl]-urea;
[0094]
4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-N-[4-(phenylamino)pheny-
l]-1-piperazine-acetamide;
[0095]
1-{[(4-phenylamino)phenylamino]carbonyl}-4-{4-{[2-thienyl(imino)met-
hyl]amino}phenyl}-piperazine;
[0096]
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzene-
butanamine;
[0097]
3-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzene-
propanamide;
[0098]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)-
phenyl]butanamide;
[0099]
4-anilinophenyl-4-(4-{[amino(2-thienyl)methylidene]amino}-phenyl)bu-
tanoate;
[0100]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)-
phenyl]butanamide;
[0101]
N'-{4-[4-(3-anilinophenoxy)butyl]phenyl}-2-thiophenecarboximidamide-
;
[0102] N'-(9H-carbazol-3-yl)-2-thiophenecarboximidamide;
[0103]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(9H-carbazol-3-y-
l)butanamide;
[0104]
N'-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximidamide;
[0105]
N'-{4-[(10-methyl-10H-phenothiazin-2-yl)oxy]phenyl}-2-thiophenecarb-
oximidamide;
[0106]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-phenothiazi-
n-3-yl)butanamide;
[0107]
N'-(4-{4-[2-(10H-phenothiazin-2-yloxy)ethyl]-1-piperazinyl}phenyl)--
2-thiophenecarboximidamide;
[0108]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(4-toluidino)-
phenyl]butanamide;
[0109] 3-anilinophenyl
4-(4-{[amino(2-thienyl)methylidene]amino}-phenyl)bu- tanoate;
[0110]
2-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(9H-carbazol--
4-yloxy)ethyl]acetamide;
[0111]
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-anilinobenzam-
ide;
[0112]
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-(2,3-dimethyl-
anilino)benzamide;
[0113]
N'-{4-[4-(2-anilinobenzoyl)-1-piperazinyl]phenyl}-2-thiophenecarbox-
imidamide;
[0114]
N'-(4-{4-[2-(2,3-dimethylanilino)benzoyl]-1-piperazinyl}phenyl)-2-t-
hiophenecarboximidamide;
[0115]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(4-phenoxyphenyl-
)butanamide;
[0116]
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-4-(4-hydroxyphe-
noxy)benzamide;
[0117]
N-[2-(9H-carbazol-4-yloxy)ethyl]-2-thiophenecarboximidamide;
[0118]
N-[3-(9H-carbazol-4-yloxy)propyl]-2-thiophenecarboximidamide;
[0119]
N-{4-[4-(10H-phenothiazin-2-yloxy)butyl]phenyl}-2-thiophenecarboxim-
idamide;
[0120]
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-anili-
nophenyl)propanamide;
[0121]
N'-(4-{2-[(10H-phenothiazin-3-ylmethyl)amino]ethyl}phenyl)-2-thioph-
enecarboximidamide;
[0122]
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-methoxy-10H-p-
henothiazine-1-carboxamide;
[0123]
N'-[4-(2-{[(2-methoxy-10H-phenothiazin-1-yl)methyl]amino}ethyl)phen-
yl]-2-thiophenecarboximidamide;
[0124]
N'-{4-[(10H-phenothiazin-2-yloxy)methyl]phenyl}-2-thiophenecarboxim-
idamide;
[0125] or their salts.
[0126] Among the exemplified compounds, the following compounds are
in particular preferred:
[0127]
{4-{[2-thienyl(imino)methyl]amino}phenoxy}-N-[4-(phenylamino)phenyl-
]-acetamide;
[0128]
4-{[2-thienyl(imino)methyl]amino}-N-[2-(phenylamino)phenyl]-benzene-
butanamide;
[0129]
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzene-
butanamide;
[0130] 2-{4-{[2-thienyl(imino)methyl]amino}phenyl}-ethyl
[4-(phenylamino)phenyl]-carbamate;
[0131]
4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-N-[4-(phenylamino)pheny-
l]-1-piperazine-acetamide;
[0132]
3-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzene-
propanamide;
[0133]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)-
phenyl]butanamide;
[0134]
N'-{4-[4-(3-anilinophenoxy)butyl]phenyl}-2-thiophenecarboximidamide-
;
[0135]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(9H-carbazol-3-y-
l)butanamide;
[0136]
N'-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximidamide;
[0137]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-phenothiazi-
n-3-yl)butanamide;
[0138]
N'-(4-{4-[2-(10H-phenothiazin-2-yloxy)ethyl]-1-piperazinyl}phenyl)--
2-thiophenecarboximidamide;
[0139]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(4-phenoxyphenyl-
)butanamide;
[0140]
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-anili-
nophenyl)propanamide;
[0141]
N'-(4-{2-[(10H-phenothiazin-3-ylmethyl)amino]ethyl}phenyl)-2-thioph-
enecarboximidamide;
[0142]
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-methoxy-10H-p-
henothiazine-1-carboxamide;
[0143] or their salts.
[0144] Also more particularly the following compounds are
preferred:
[0145]
4-{[2-thienyl(imino)methyl]amino}-N-[2-(phenylamino)phenyl]-benzene-
butanamide;
[0146]
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzene-
butanamide;
[0147]
N'-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximidamide;
[0148]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-phenothiazi-
n-3-yl)butanamide;
[0149]
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-anili-
nophenyl)propanamide;
[0150]
N'-(4-{2-[(10H-phenothiazin-3-ylmethyl)amino]ethyl}phenyl)-2-thioph-
enecarboximidamide;
[0151] or their salts.
[0152] In a general manner, the compounds of general formula (I) in
which X represents a bond or one of the --O--,
--CH.sub.2--NR.sub.16--, --NR.sub.16--CO-- or --NR.sub.16--CO--O--
radicals and Y represents one of the --(CH.sub.2).sub.m-- or
--(CH.sub.2).sub.m--NR.sub.18--(CH.sub.2).- sub.n-- radicals will
be preferred.
[0153] In certain cases, the compounds according to the present
invention can contain asymmetrical carbon atoms. As a result, the
compounds according to the present invention have two possible
enantiomeric forms, i.e. "R" and "S" configurations. The present
invention includes the two enantiomeric forms and all combinations
of these forms, including the racemic "RS" mixtures. In an effort
to simplify matters, when no specific configuration is indicated in
the structural formulae, it should be understood that the two
enantiomeric forms and their mixtures are represented.
[0154] The invention further relates, as new industrial products,
to the synthesis intermediates of general formula (IS), useful for
the preparation of products of general formula (I) defined
above,
A-X-Y-.PHI.-T (IS)
[0155] general formula (IS) in which
[0156] A represents a 9
[0157] radical in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
represent, independently, a hydrogen atom, a halogen, the OH group,
a linear or branched alkyl or alkoxy radical having 1 to 6 carbon
atoms, or a cyano, nitro or NR.sub.6R.sub.7 radical,
[0158] R.sub.6 and R.sub.7 representing, independently, a hydrogen
atom, the OH group, a linear or branched alkyl or alkoxy radical
having 1 to 6 carbon atoms, or also a --COR.sub.8 group,
[0159] R.sub.8 representing a hydrogen atom, the OH group, a linear
or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or
NR.sub.9R.sub.10,
[0160] R.sub.9 and R.sub.10 representing, independently, a hydrogen
atom, the OH group or a linear or branched alkyl radical having 1
to 6 carbon atoms,
[0161] R.sub.11 representing a hydrogen atom, the OH group, a
linear or branched alkyl or alkoxy radical having 1 to 6 carbon
atoms, or a --COR.sub.12 radical,
[0162] and R.sub.12 representing a hydrogen atom, the OH group, a
linear or branched alkyl radical having 1 to 6 carbon atoms,
[0163] or a 10
[0164] radical in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
represent, independently, a hydrogen atom, a halogen, the OH group,
a linear or branched alkyl or alkoxy radical having 1 to 6 carbon
atoms, or a cyano, nitro or NR.sub.6R.sub.7 radical,
[0165] R.sub.6 and R.sub.7 representing, independently, a hydrogen
atom, the OH group, a linear or branched alkyl or alkoxy radical
having 1 to 6 carbon atoms, or also a --COR.sub.8 group,
[0166] R.sub.8 representing a hydrogen atom, the OH group, a linear
or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or
NR.sub.9R.sub.10,
[0167] R.sub.9 and R.sub.10 representing, independently, a hydrogen
atom, the OH group or a linear or branched alkyl radical having 1
to 6 carbon atoms;
[0168] W does not exist, or represents a bond, or O, S or
NR.sub.15, in which R.sub.15 represents a hydrogen atom or a linear
or branched alkyl radical having 1 to 6 carbon atoms;
[0169] X represents a bond or a --(CH.sub.2).sub.k--NR.sub.16--,
--O--, --S--, --CO--, --NR.sub.16--CO--, --CO--NR.sub.16--,
--O--CO--, --CO--O--, --NR.sub.16--CO--O-- or
--NR.sub.6--CO--NR.sub.17-- radical,
[0170] k representing 0 or 1;
[0171] Y represents a bond or a radical chosen from the
--(CH.sub.2).sub.m--, --(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--S--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18-- -(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--NR.sub.18--CO--(CH.sub.2).sub.n--- ,
--(CH.sub.2).sub.m--CO--NR.sub.18--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n-- radicals,
[0172] Q representing piperazine, homopiperazine,
2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or
4-aminopiperidine,
[0173] m and n being integers from 0 to 6;
[0174] .PHI. represents a bond or a phenylene radical which may
comprise, in addition to the two chains already represented in
general formula (I), up to two substituents chosen from a hydrogen
atom, a halogen, an OH group and a linear or branched alkyl or
alkoxy radical having 1 to 6 carbon atoms;
[0175] T represents NO.sub.2 or NH.sub.2;
[0176] R.sub.16, R.sub.17 and R.sub.18 represent, independently, a
hydrogen atom or a linear or branched alkyl radical having 1 to 6
carbon atoms.
[0177] The invention further relates, as new industrial products,
to the synthesis intermediates of general formula (IS'), useful for
the preparation of products of general formula (I) in which X
represents the --NR.sub.16--CO-- radical and Y represents the
--(CH.sub.2).sub.m--NR.sub- .18--(CH.sub.2).sub.n-- radical, 11
[0178] general formula (IS') in which
[0179] A represents a 12
[0180] radical in which R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
R.sub.5 represent, independently, a hydrogen atom, a halogen, the
OH group, a linear or branched alkyl or alkoxy radical having 1 to
6 carbon atoms, or a cyano, nitro or NR.sub.6R.sub.7 radical,
[0181] R.sub.6 and R.sub.7 representing, independently, a hydrogen
atom, the OH group, a linear or branched alkyl or alkoxy radical
having 1 to 6 carbon atoms, or also a --COR.sub.8 group,
[0182] R.sub.8 representing a hydrogen atom, the OH group, a linear
or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or
NR.sub.9R.sub.10,
[0183] R.sub.9 and R.sub.10 representing, independently, a hydrogen
atom, the OH group, a linear or branched alkyl radical having 1 to
6 carbon atoms,
[0184] R.sub.11 representing a hydrogen atom, the OH group, a
linear or branched alkyl or alkoxy radical having 1 to 6 carbon
atoms, or also a --COR.sub.12 radical,
[0185] and R.sub.12 representing a hydrogen atom, the OH group, a
linear or branched alkyl radical having 1 to 6 carbon atoms,
[0186] or a 13
[0187] radical in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5
represent, independently, a hydrogen atom, a halogen, the OH group,
a linear or branched alkyl or alkoxy radical having 1 to 6 carbon
atoms, or a cyano, nitro or NR.sub.6R.sub.7 radical,
[0188] R.sub.6 and R.sub.7 representing, independently, a hydrogen
atom, the OH group, a linear or branched alkyl or alkoxy radical
having 1 to 6 carbon atoms, or also a --COR.sub.8 group,
[0189] R.sub.8 representing a hydrogen atom, the OH group, a linear
or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or
NR.sub.9R.sub.10,
[0190] R.sub.9 et R.sub.10 representing, independently, a hydrogen
atom, the OH group, a linear or branched alkyl radical having 1 to
6 carbon atoms;
[0191] W does not exist, or represents a bond, or O, S or NR.sub.15
in which R.sub.15 represents a hydrogen atom or a linear or
branched alkyl radical having 1 to 6 carbon atoms;
[0192] .pi. represents a hydrogen atom or a protective group of the
carbamate type;
[0193] R.sub.16, R.sub.17 and R.sub.18 represent, independently, a
hydrogen atom or a linear or branched alkyl radical having 1 to 6
carbon atoms;
[0194] and m represents an integer from 0 to 6.
[0195] A subject of the invention is also, as medicaments, the
compounds of general formula (I) described previously or their
pharmaceutically acceptable salts. It also relates to
pharmaceutical compositions containing these compounds or their
pharmaceutically acceptable salts, and the use of these compounds
or of their pharmaceutically acceptable salts for producing
medicaments intended to inhibit neuronal NO synthase or inductible
NO synthase, to inhibit lipidic peroxidation or to provide the
double function of NO synthase inhibition and lipidic peroxidation
inhibition.
[0196] By pharmaceutically acceptable salt is meant in particular
addition salts of inorganic acids such as hydrochloride,
hydrobromide, hydroiodide sulphate, phosphate, diphosphate and
nitrate, or of organic acids, such as acetate, maleate, fumarate,
tartrate, succinate, citrate, lactate, methanesulphonate,
p-toluenesulphonate, pamoate, oxalate and stearate. The salts
formed from bases such as sodium or potassium hydroxide also fall
within the scope of the present invention, when they can be used.
For other examples of pharmaceutically acceptable salts, reference
can be made to "Pharmaceutical salts", J. Pharm. Sci. 66:1
(1977).
[0197] The pharmaceutical composition can be in the form of a
solid, for example powders, granules, tablets, capsules, liposomes
or suppositories. Appropriate solid supports can be for example
calcium phosphate, magnesium stearate, talc, sugars, lactose,
dextrin, starch, gelatin, methyl cellulose, sodium carboxymethyl
cellulose, polyvinylpyrrolidine and wax.
[0198] The pharmaceutical compositions containing a compound of the
invention can also be presented in the form of a liquid, for
example, solutions, emulsions, suspensions or syrups. Appropriate
liquid supports can be, for example, water, organic solvents such
as glycerol or the glycols, as well as their mixtures, in varying
proportions, in water.
[0199] A medicament according to the invention can be administered
by topical, oral or parenteral route, by intramuscular injection,
etc.
[0200] The envisaged administration dose for a medicament according
to the invention is comprised between 0.1 mg and 10 g according to
the type of active compound used.
[0201] In accordance with the invention, the compounds of general
formula (I) can be prepared by the process described below.
[0202] Preparation of the Compounds of General Formula (I):
[0203] The compounds of general formula (I) can be prepared from
intermediates of general formula (II) according to Diagram 1 where
A, B, X, Y and .PHI. are as defined above and Gp is a protective
group of carbamate type such as for example the t-butoxycarbonyl
group. 14
[0204] The derivatives of aniline of general formula (II), can be
condensed with the compounds of general formula (III), in which L
represents a parting group (for example an alkoxy, alkylthio,
aralkylthio, sulphonic acid, halide, aryl alcohol or tosyl
radical), in order to produce the final compounds of general
formula (I) of substituted amidine type (cf. Diagram 1). For
example, for B=thiophene, the derivatives of general formula (II)
can be condensed with S-methylthiophene thiocarboxamide
hydroiodide, prepared according to a method in the literature (Ann.
Chim. (1962), 7, 303-337). The condensation can be carried out by
heating in an alcohol (for example in methanol or isopropanol),
optionally in the presence of DMF and/or pyridine at a temperature
preferably comprised between 20 and 100.degree. C. for a duration
generally comprised between a few hours and overnight.
[0205] In the case where B is an amine, the final compounds of
general formula (I) are guanidines. These can be prepared, for
example, by the condensation of the amines of general formula (II)
with the derivatives of general formula (IV) or (IV'). The reagents
of general formula (IV) in which L represents, for example, a
pyrazole ring are condensed with the amines of general formula (II)
according to the conditions described in the literature (J. Org.
Chem. (1992) 57, 2497-2502) similarly for the reagents of general
formula (IV') in which L represents, for example, a pyrazole ring
and Gp the tBuOCO group (Tetrahedron Lett. (1993) 34 (21),
3389-3392) or when L represents the --N--SO.sub.2--CF.sub.3 group
and Gp the tBuOCO group (J. Org. Chem. (1998) 63, 3804-3805).
During the final stage of the synthesis, deprotection of the
guanidine function is carried out in the presence of a strong acid
such as for example trifluoroacetic acid.
[0206] Therefore the invention also relates to a process for the
preparation of a product of general formula (I) as defined
previously, characterized in that intermediate of general formula
(II)
A-X-Y-.PHI.-NH.sub.2 (II)
[0207] in which A, B, X, Y and .PHI. are as defined above, is
reacted with intermediate of general formula (III) 15
[0208] in which B is as defined above and L represents a parting
group, for example an alkoxy, alkylthio, aralkylthio, sulphonic
acid, halide, aryl alcohol or tosyl radical.
[0209] In addition the invention relates to a process for the
preparation of a product of general formula (I) in which B is an
amine, characterized in that intermediate of general formula
(II)
A-X-Y-.PHI.-NH.sub.2 (II)
[0210] in which A, B, X, Y and .PHI. are as defined above is
reacted,
[0211] a) either with intermediate of general formula (IV) 16
[0212] in which L represents a parting group, for example an
alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl
alcohol or tosyl radical,
[0213] b) or with intermediate of general formula (IV') 17
[0214] in which L represents a parting group, for example an
alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl
alcohol or tosyl radical, and Gp a protective group of carbamate
type, for example the t-butoxycarbonyl group, this reaction being
followed, in the case where reaction with the compound of general
formula (IV') is chosen, by hydrolysis in the presence of a strong
acid, for example trifluoroacetic acid.
[0215] When -X-Y-.PHI.- Represents a Direct Bond:
[0216] Intermediates of general formula (II) in the particular case
where -X-Y-.PHI.- represents a direct bond are comparable to the
compounds of general formula (X), A-NH.sub.2, described in the
chapter "Synthesis of intermediates". In this case, these
A-NH.sub.2 amines can be directly condensed with the derivatives of
general formula (III) or (IV) as described in the preceding
chapter.
[0217] Preparation of the Compounds of General Formula (II):
[0218] The non-commercial intermediates of general formula (II),
are obtained either from detachment of a protective group, or from
reduction of a precursor of nitride or nitro type, as illustrated
in the synthesis diagrams below.
[0219] Deprotection of the Amino Group:
[0220] Intermediates of general formula (II), in which A, X, Y and
.PHI. are as defined above, can be prepared from intermediates of
general formula (V), Diagram 2, which are compounds comprising a
protected amine (N=Gp') in the form, for example, of phthalimide or
2,5-dimethylpyrrole. In the case of phthalimides, these are
deprotected in a standard fashion using hydrazine hydrate under
reflux of ethanol and in the case of pyrroles, deprotection takes
place by heating in the presence of hydroxylamine hydrochloride, in
order to finally produce to the primary amines of general formula
(II). 18
[0221] Reduction of the Precursors of Azido Type:
[0222] The synthetic intermediates of general formula (VI), Diagram
3, in which A, X, Y and .PHI. are as defined above, are azide
derivatives which are converted into a primary amine of general
formula (II), for example, using hydrogen in the presence of Pd/C
in an appropriate solvent such as ethanol. 19
[0223] Reduction of the Precursors of Nitro Type:
[0224] The reduction of the nitro function of intermediates of
general formula (VII), Diagram 4, in which A, X, Y and .PHI. are as
defined above, is generally carried out by catalytic hydrogenation,
in ethanol, in the presence of Pd/C, except in the case of
molecules sensitive to these conditions where the nitro group is
selectively reduced, for example, by heating the product in an
appropriate solvent such as ethyl acetate with a little ethanol in
the presence of SnCl.sub.2 (J. Heterocyclic Chem. (1987), 24,
927-930; Tetrahedron Letters (1984), 25 (8), 839-842), also using
SnCl.sub.2 in the presence of Zn (Synthesis (1996), (9),
1076-1078), or using NaBH.sub.4--BiCl.sub.3 (Synth. Com. (1995) 25
(23), 3799-3803) in a solvent such as ethanol, or then by using
Raney Ni with hydrazine hydrate added (Monatshefte fur Chemie,
(1995), 126, 725-732; Pharmazie (1993) 48 (11), 817-820) in the
case, for example, of the nitrocarbazoles. 20
[0225] Preparation of the Compounds of General Formula (V):
[0226] Intermediates of general formula (V), Diagram 5, contain an
amine protected in the form of phthalimide, in which X=--O--,
Y=--(CH.sub.2).sub.m-- with A, R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, W, m and .PHI. as defined above, can be prepared from the
hydroxylated aromatic rings of general formula (VIII). In the
particular case of hydroxycarbazoles, the compounds of general
formula (VIII) are prepared according to an experimental protocol
in the literature (J. Chem. Soc. (1955), 3475-3477; J. Med. Chem.
(1964) 7, 158-161) and in that of hydroxyphenothiazines the
protocol is described in J. Med. Chem. (1992) 35, 716. The
compounds of general formula (VIII) are condensed with commercial
halogenoalkyl-phthalimides in the presence of a base, for example
NaH, in a solvent such as DMF, in order to produce intermediates of
general formula (V). 21
[0227] Preparation of the Compounds of General Formula (VI):
[0228] Intermediates of general formula (VI), Diagram 6, in which
A, X, Y, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, W, m and
.PHI. are as defined above, are derivatives of azido type. They are
prepared in two stages from intermediates of general formula (VIII)
(Diagram 5). The OH radical of the compounds of general formula
(VIII) can be alkylated by dihalogenated derivatives of
dibromoalkane type, in the presence of a base, for example NaH or
NaOH, in order to produce the compounds of general formula (IX)
which are then substituted using sodium azide in DMF in order to
produce intermediates of general formula (VI). 22
[0229] Preparation of the Compounds of General Formula (VII):
[0230] The syntheses of the compounds of general formula (VII),
which carry a terminal nitro group, in which A, X, Y and .PHI. are
as described above, are illustrated in the following synthesis
diagrams.
[0231] Syntheses of the Carboxamides of General Formula (VII):
[0232] The carboxamides of general formula (VII), Diagram 7, in
which X represents --NR.sub.16--CO-- and A, Y, .PHI. and R.sub.16
are as defined above, are prepared by condensation of the
commercial amines of general formula (X) with the commercial acids
of general formula (XI). The carboxamide bonds are formed under the
standard conditions of peptide synthesis (M. Bodanszky and A.
Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag,
1984)) in THF, dichloromethane or DMF in the presence of a coupling
reagent such as dicyclohexylcarbodiimide (DCC),
1.1'-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23),
4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of
peptides, 54 (Clarendon Press, Oxford, 1991)). The syntheses of the
non-commercial amines of general formula (X) and the syntheses of
the non-commercial carboxylic acids of general formula (XI) are
described in the chapter Preparation of Intermediates. 23
[0233] The carboxamides of general formula (VII), Diagram 8, in
which X represents --CO--NR.sub.16-- and A, Y, Q, .PHI. and
R.sub.16 are as defined above, are prepared by condensation of the
commercial acids of general formula (XII) with the commercial
amines of general formula (XIII) or the amines of general formula
(XIV) under standard conditions for peptide synthesis described
previously. The syntheses of the non-commercial acids of general
formula (XII) and amines of general formula (XIV) are described in
the chapter Preparation of Intermediates. 24
[0234] The carboxamides of general formula (VII), Diagram 9, in
which X represents --O--, Y represents
--(CH.sub.2).sub.m--NR.sub.18--CO--(CH.sub- .2).sub.n-- with A,
R.sub.18, m, n and .PHI. as defined above, are prepared by standard
peptide condensation of the acids of general formula (XI) (Diagram
7) with the amines of general formula (II), the syntheses of which
have been described in Diagrams 2 and 3. 25
[0235] Synthesis of the Amines of General Formula (VII):
[0236] The amines of general formula (VII) in which X=--NR.sub.16--
and Y=--(CH.sub.2).sub.m-- with A, R.sub.16, m and .PHI. as defined
above, are prepared, Diagram 10, from the carboxamides of general
formula (VII). The reduction of the carboxamide function is carried
out in the presence of an excess (5 eq.) of diborane in THF, by
heating the mixture to reflux of the solvent in order to produce
the amines of general formula (VII). 26
[0237] Synthesis of the Carbamates of General Formula (VII):
[0238] The carbamate derivatives of general formula (VII) in which
X=--NR.sub.16--CO--O-- and Y=--(CH.sub.2).sub.m-- with A, m and
.PHI. as defined above, are prepared, Diagram 11, by condensation
of an amine of general formula (X) (Diagram 7) with a commercial
alcohol of general formula (XV) in the presence of triphosgene and
a base such as for example N,N-dimethylaniline in an inert solvent
such as, for example, dichloromethane, according to a protocol
described in Tetrahedron Lett. (1993) 34 (44), 7129-7132. 27
[0239] Synthesis of the Ureas of General Formula (VI):
[0240] The ureas of general formula (VII) in which
X=--NR.sub.16--CO--NR.s- ub.17-- and Y=--(CH.sub.2).sub.m-- or
X-Y=--NR.sub.16--CO--Q-- (in the case of a nitrogenous heterocycle)
with A, R.sub.17, m, Q and .PHI. as defined above, are prepared,
Diagram 12, from the primary amines of general formula (X) (Diagram
7) and the amines of general formula (XIII) or (XIV) (Diagram 8) in
the presence of triphosgene and a tertiary amine, such as, for
example, diisopropylethylamine, in a neutral solvent such as
dichloromethane (J. Org. Chem. (1994), 59 (7), 1937-1938). 28
[0241] Synthesis of the Esters of General Formula (VII):
[0242] The carboxylic esters of general formula (VII) in which
X=--O--CO-- or --CO--O-- and Y=--(CH.sub.2).sub.m-- with A, m and
.PHI. as defined above, are prepared in a single stage from the
alcohols of general formula (VIII) (Diagram 5) and the carboxylic
acids of general formula (XI) (Diagram 7) or the acids of general
formula (XII) (Diagram 8) and the alcohols of general formula (XV)
(Diagram 11) in the presence of a coupling agent such as, for
example carbonyldiimidazole or dicyclohexylcarbodiimide, in an
appropriate solvent such as dichloromethane, for example. 29
[0243] Synthesis of the Ethers of General Formula (VII):
[0244] The ethers of general formula (VII) in which X=--O-- and
Y=--(CH.sub.2).sub.m-- with A, m and .PHI. as defined above,
Diagram 14, are prepared in a single stage by condensation of the
aromatic alcohols of general formula (VIII) (Diagram 5) and the
alcohols of general formula (XV) (Diagram 11) under the standard
conditions of Mitsunobu (Synthesis (1981), 1) in the presence, for
example, of diethylazodicarboxylate and tributylphosphine, in a
solvent such as, for example, THF. 30
[0245] When X=--O--, Y is a bond and .PHI.=phenylene, with A and n
as defined above, the ethers of general formula (VII), Diagram 15,
can also be prepared in a single stage by condensation of the
aromatic alcohols of general formula (VIII) (Diagram 5) with the
halogenated derivatives of general formula (XVI), in which Hal
represents a halogen atom, in the presence of a base such as, for
example, K.sub.2CO.sub.3, in a polar solvent such as, for example,
THF or DMF, at a reaction temperature comprised between 20 and
140.degree. C. 31
[0246] When X=--O-- and Y=--(CH.sub.2).sub.m--Q--(CH.sub.2).sub.n--
with A, .PHI., Q and m as defined above, the ethers of general
formula (VII), Diagram 16, can also be prepared by condensation of
the aromatic alcohols of general formula (VIII) (Diagram 5) with
the halogenated derivatives of general formula (XVII), in which Hal
represents a halogen atom, in the presence of a base such as, for
example, K.sub.2CO.sub.3, in an inert solvent such as, for example,
CH.sub.2Cl.sub.2, at a temperature comprised between 40.degree. C.
and the reflux temperature of the reaction mixture. Synthesis of
the compounds of general formula (XVII) is described in the chapter
Preparation of Intermediates. 32
[0247] Synthesis of the Amines of General Formula (VII) by Reducing
Amination:
[0248] The amines of general formula (VII), in which
X=--NR.sub.16--CO-- and
Y=--(CH.sub.2).sub.m--NR.sub.18--(CH.sub.2).sub.n-- with A, .PHI.,
R.sub.16, R.sub.18, m and n as defined above, are prepared, Diagram
17, by condensation of an aldehyde of general formula (XIX) with an
amine of general formula (XVIII) in reducing medium. The reaction
is carried out in an alcoholic solvent such as, for example,
methanol in the presence of pulverulent 4 .ANG. molecular sieve,
activated beforehand, and of a reducing agent such as, for example,
NaBH.sub.4 or NaBH.sub.3CN. The syntheses of the non-commercial
amines of general formula (XVIII) are described in the chapter
Preparation of Intermediates. 33
[0249] In an analogous manner, the amines of general formula (VII),
in which X=--CH.sub.2--NR.sub.16--, with A, Y, .PHI. and R.sub.16
as defined above, are prepared, Diagram 18, by condensation of the
aldehydes of general formula (XX) with the amines of general
formula (XIII) (Diagram 8) in reducing medium under the conditions
described previously. The preparation of the non-commercial
aldehydes of general formula (XX) is described in the chapter
Preparation of Intermediates. 34
[0250] Modification of the A Radical in the Compounds of General
Formula (VII):
[0251] Intermediates of general formula (VII), in which A, X, Y,
.PHI., R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as
described above, can be subjected to chemical modifications at the
level of the A radical, Diagram 19, in particular at the level of
the nitrogen atom which can be alkylated using an R.sub.11-Hal
reagent, as defined above, and in particular using methyl iodide in
the presence of a base such as, for example, NaH, in an inert
solvent such as THF for example. 35
[0252] Preparation of the Different Synthesis Intermediates:
[0253] Synthesis of Intermediates (X):
[0254] Intermediates of general formula (X) in which A is a
diphenylamine (W does not exist), are accessible using the methods
described in the literature (Synthesis (1990) 430; Indian J. Chem.
(1981) 20B, 611-613; J. Med. Chem. (1975) 18(4), 386-391) which
operate through the reduction of a nitrodiphenylamine intermediate.
The reduction of the nitro function is carried out in a standard
fashion by hydrogenation in the presence of a catalytic quantity of
Pd/C in order to access the aminodiphenylamines of general formula
(X).
[0255] When A is a carbazole derivative (W then represents a direct
bond), the preparation methods for the aminocarbazoles of general
formula (X) operate through the synthesis of a nitrocarbazole
intermediate. These methods are described in Pharmazie (1993)
48(11), 817-820; Synth. Commun. (1994) 24(1), 1-10; J. Org. Chem.
(1980) 45, 1493-1496; J. Org. Chem. (1964) 29(8), 2474-2476; Org
Prep. Proced. Int. (1981) 13(6), 419-421 or J. Org. Chem. (1963)
28, 884. The reduction of the nitro function of the nitrocarbazole
intermediates is, in this case, preferably carried out using
hydrazine hydrate in the presence of Raney Nickel.
[0256] Intermediates of general formula (X) in which A is a
phenothiazine derivative (W represents a sulphur atom), are
accessible via methods in the literature which operate through the
synthesis of a nitrophenothiazine derivative. In particular
3-nitrophenothiazine is described in J. Org Chem. (1972) 37, 2691.
The reduction of the nitro function in order to access the
aminophenothiazines of general formula (X) is carried out in a
standard fashion by hydrogenation in the presence of a catalytic
quantity of Pd/C in a solvent such as ethanol.
[0257] Synthesis of Intermediates (XI):
[0258] The syntheses of the non-commercial acids of general formula
(XI), are described in Diagrams 7.1 and 7.2.
[0259] In the particular case where
Y=--(CH.sub.2).sub.m--Q--(CH.sub.2).su- b.n-- and .PHI. is a
phenylene radical, with Q, m and n as defined above, the carboxylic
acids of general formula (XI), Diagram 7. 1, are prepared, in 2
stages, from a heterocyclic amine of general formula (XIV) (Diagram
8), for example 4-nitrophenylpiperazine, and of a halogenoester of
general formula (XI.1) such as for example ethyl bromoacetate. The
condensation is carried out at 20.degree. C. in the presence of a
base such as, for example, triethylamine in an inert solvent such
as, for example, dichloromethane in order to produce intermediates
of general formula (XI.2). Saponification by LiOH at 20.degree. C.
produces the carboxylic acids of general formula (XI).
[0260] In the cases where
Y=--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n-- and .PHI. is a
phenylene radical, with m and n as defined above, the synthesis of
the carboxylic acids of general formula (XI), Diagram 7.1, operates
through condensation of the halogenated derivatives of general
formula (XI.1) on the alcohols of general formula (XI.3) in the
presence of a base such as, for example, triethylamine or potassium
carbonate, at reflux of a polar solvent such as, for example, THF
or DMF. Deprotection of the ester function of intermediate of
general formula (XI.4) is then carried out in a standard fashion in
the presence of a base or of a strong acid fort in the case of
tert-butyl esters. 36
[0261] The carboxylic acids of general formula (XI) in which
Y=--(CH.sub.2).sub.m-- and .PHI. represents a substituted phenylene
group, with m as defined above, are prepared in 3 stages from the
commercial alcohols of general formula (XI.3), Diagram 7.2.
Activation of the alcohol is carried out in a standard fashion
using methane sulphonyl chloride (MsCl) in the presence of a base
such as triethylamine in an inert solvent such as dichloromethane
in order to produce intermediates of general formula (XI.4). The
mesylate is then displaced by sodium cyanide in DMF in order to
produce intermediates of general formula (XI.5). The nitrile
function is then hydrolyzed by heating in a mixture of ethanol and
concentrated HCl in order to produce the acids of general formula
(XI). 37
[0262] Synthesis of Intermediates (XII):
[0263] The synthesis of the carboxylic acid derivatives of the
phenothiazines of general formula (XII) is described in literature
(J. Med. Chem. (1992) 35(4), 716-724).
[0264] Synthesis of Intermediates (XIV):
[0265] The non-commercial amines of general formula (XIV) defined
previously, in which Q represents homopiperazine,
2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, are
synthesized in three stages from the corresponding commercial
diamines. The diamines are selectively mono-protected in the form
of carbamate (Synthesis (1984), (12), 1032-1033; Synth. Commun.
(1990), 20, (16), 2559-2564) before reacting by nucleophilic
substitution with a halogenonitrobenzene, in particular
4-fluoronitrobenzene. The amines, which have been previously
protected, are released at the last stage, according to the methods
described in the literature (T. W. Greene and P. G. M. Wuts,
Protective Groups in Organic Synthesis, Second edition
(Wiley-Interscience, 1991)), in order to produce intermediates of
general formula (XIV).
[0266] Synthesis of Intermediates (XVII):
[0267] The halogenated derivatives of general formula (XVII)
defined previously, Diagram 16.1, are accessible in two stages from
the amines of general formula (XIII) or (XIV) (Diagram 8) and the
commercial halogenated derivatives of general formula (XVII.1).
Condensation in order to produce intermediates of general formula
(XVII.2) or (XVII.3) is carried out in a standard fashion in the
presence of a base such as, for example, K.sub.2CO.sub.3 in an
appropriate inert solvent such as, for example, dichloromethane.
Then the alcohol function is activated in the form of a halogenated
derivative using, for example, carbon tetrabromide in the presence
of triphenylphosphine in order to produce intermediates of general
formula (XVII). 38
[0268] Synthesis of Intermediates (XVIII):
[0269] The amines of general formula (XVIII) defined previously,
Diagram 17.1, in which A, R.sub.16, R.sub.18 and m are as defined
above, are prepared by condensation of the amines of general
formula (X) (Diagram 7) with the protected amino acids (Gp:
protective group) of general formula (XVIII.1), under the standard
conditions of peptide synthesis (see "synthesis of carboxamides"
chapter). Deprotection of the amine of the compounds of general
formula (XVIII.2) is then carried out in a standard fashion
according to the conditions described in literature (T. W. Greene
et P. G. M. Wuts, Protective Groups in Organic Synthesis, Second
edition (Wiley-Interscience, 1991)). 39
[0270] Synthesis of Intermediates (XX):
[0271] Synthesis of the aldehydes of the phenothiazines of general
formula (XX) defined previously is described in literature (J.
Chem. Soc. (1951), 1834; Bull. Soc. Chim. Fr. (1969), 1769).
[0272] Unless they are defined differently, all the technical and
scientific terms used here have the same meaning as that usually
understood by an ordinary specialist in the field to which the
invention belongs. Similarly, all publications, patent
applications, patents and other references mentioned here are
incorporated by way of reference.
[0273] The following examples are presented to illustrate the above
procedures and should in no way be considered as restricting the
scope of the invention.
EXAMPLES
Example 1
[0274] N-[4-(phenylamino)phenyl]-2-thiophene-carboximidamide
hydroiodide: 1
[0275] 0.92 g (5 mmol) of 4-aminodiphenylamine and 2.85 g (10 mmol)
of S-methyl-2-thiophene thiocarboximide hydroiodide in 15 ml of
isopropanol are mixed together in a 50 ml flask under an argon
atmosphere. The reaction mixture is heated at 70.degree. C. for 48
hours. The solvent is partially evaporated under vacuum and the
solid obtained is filtered and washed several times successively
with isopropanol and ethyl ether. A yellow powder is obtained with
a yield of 98%. Melting point: 216.3-216.8.degree. C.
[0276] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 6.90 (m, 1H,
arom.); 7.10-7.30 (m, 8H, arom.); 7.40 (m, 1H, thiophene);
8.10-8.20 (m, 2H, thiophene); 8.50 (s, 1H, NH); 8.75 (s, 1H,
NH.sup.+); 9.70 (s, 1H, NH.sup.+); 11.15 (s, 1H, NH.sup.+).
[0277] IR: .nu..sub.C.dbd.N (amidine): 1590 cm.sup.-1.
Example 2
[0278]
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzene-
acetamide hydrochloride: 2
[0279] 2.1) 4-Nitro-N-[4-(phenylamino)phenyl]-benzeneacetamide:
[0280] 1.84 g (10 mmol) of 4-aminodiphenylamine, 1.81 g (10 mmol)
of 4-nitrophenylacetic acid and 1.48 g (11 mmol) of
hydroxybenzotriazole in 40 ml of THF are dissolved successively in
a 100 ml flask. Then 2.27 g (11 mmol) of
1,3-dicyclohexylcarbodiimide (DCC) is added and the reaction
mixture is agitated for 15 hours. A precipitate of dicyclohexylurea
(DCU) forms which is filtered and rinsed with 100 ml of ethyl
acetate. The filtrate is then washed successively with 50 ml of a
saturated solution of Na.sub.2CO.sub.3, 50 ml of water, 50 ml of a
molar solution of HCl and finally 2.times.50 ml of salt water. The
organic phase is dried over magnesium sulphate, filtered and
concentrated under vacuum. The residue is purified rapidly on a
silica gel column (eluent: heptane/ethyl acetate 1/1). The purest
fractions are collected and evaporated under vacuum in order to
produce a brown powder. The product is used as it is in the
following stage.
[0281] NMR .sup.1H (100 MHz, CDCl.sub.3, .delta.): 1.61 (broad s,
1H, NH); 3.82 (s, 2H, CH.sub.2); 5.70 (broad s, 1H, NH); 6.85-7.50
(m, 10H, arom., NH--CO); 7.90 (AB, 4H, Ph--NO.sub.2).
[0282] 2.2) 4-Amino-N-[4-(phenylamino)phenyl]-benzeneacetamide:
[0283] A solution of intermediate 2.1 (0.54 g, 1.54 mmol) in 40 ml
of an ethyl acetate/ethanol mixture (1/1) as well as 0.1 g of Pd/C
at 10% are introduced into a stainless steel autoclave equipped
with a magnetic stirrer. The reaction mixture is agitated under a
hydrogen pressure (1.5 bar) for 1 hour 30 minutes at a temperature
of 20.degree. C. The Pd/C is then eliminated by filtration and the
filtrate is concentrated under vacuum. The evaporation residue is
purified on a silica gel column (eluent: heptane/ethyl acetate:
4/6), the pure fractions are collected and concentrated under
vacuum. A white powder is obtained with a yield of 90%. Melting
point: 162-163.degree. C.
[0284] NMR .sup.1H (100 MHz, CDCl.sub.3, .delta.): 1.61 (broad s,
1H, NH); 3.61 (s, 2H, CH.sub.2); 3.70 (broad s, 2H, NH.sub.2); 5.62
(broad s, 1H, NH--CO); 6.68-7.40 (m, 13H, arom.).
[0285] 2.3)
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-be-
nzeneacetamide hydrochloride: 2
[0286] 0.44 g (1.39 mmol) of intermediate 2.2 and 0.47 g (1.67
mmol) of S-methyl-2-thiophene thiocarboximide hydroiodide in 15 ml
of isopropanol are dissolved in a 50 ml flask. The reaction mixture
is agitated for 20 hours at a temperature of 60.degree. C. After
evaporation of the solvent under vacuum, the residue is taken up in
100 ml of a mixture of 1N soda and ethyl acetate (1/1). After
decantation, the organic phase is washed with 50 ml of water
followed by 50 ml of salt water. The organic solution is dried over
magnesium sulphate, filtered, concentrated under vacuum and the
residue is purified on a silica gel column (eluent: ethyl acetate).
The pure fractions are collected and concentrated under vacuum. A
white powder is obtained with a yield of 25%. The compound is then
dissolved in methanol and salified by adding a 1N solution of HCl
in ethyl ether (1 ml). After agitation for one hour at 20.degree.
C., the reaction mixture is concentrated under vacuum in order to
produce a pale yellow powder. Melting point: the product turns into
a foam.
[0287] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 3.71 (s, 2H,
CH.sub.2); 4.60 (broad s, 1H, NH); 6.75 (m, 1H, thiophene); 7.00
(m, 4H, arom.); 7.19 (m, 2H, arom.); 7.40 (m, 3H, arom.); 7.55 (m,
4H, arom.); 8.14 (m, 2H, thiophene); 8.95 (broad s, 1H, NH+); 9.86
(broad s, 1H, NH.sup.+); 10.41 (s, 1H, NH--CO); 11.60 (broad s, 1H,
NH.sup.+).
[0288] IR: .nu..sub.C.dbd.O (amide): 1649 cm.sup.-1;
.nu..sub.C.dbd.N (amidine): 1597 cm.sup.-1.
Example 3
[0289]
{4-{[2-thienyl(imino)methyl]amino}phenoxy}-N-[4-(phenylamino)phenyl-
]-acetamide hydroiodide: 3
[0290] 3.1) tertiobutyl 4-nitrophenoxyacetate:
[0291] 3 g (21.6 mmol) of paranitrophenol, 8.94 g (64.8 mmol) of
potassium carbonate and 8.42 g (43.2 mmol) of tertiobutyl
bromoacetate are introduced under a nitrogen atmosphere, into a 250
ml flask containing 100 ml of THF. The reaction mixture is agitated
at reflux for 2 hours. The solid is filtered and the filtrate is
concentrated under reduced pressure. The residue is taken up in 50
ml of ethyl acetate and washed successively with 50 ml of water and
50 ml of salt water. The organic phase is dried over sodium
sulphate, filtered and evaporated under vacuum. After purification
of the pure fractions on a silica gel column (eluent: ethyl
acetate/heptane 1:8) and concentration under vacuum, a white powder
is obtained with yield of 50%. Melting point: 81-83.degree. C.
[0292] NMR .sup.1H (100 MHz, CDCl.sub.3, .delta.): 1.50 (s, 9H,
3.times.CH.sub.3); 4.60 (s, 2H, CH.sub.2); 7.57 (AB, 4H,
Ph--NO.sub.2).
[0293] 3.2) 4-nitrophenoxyacetic acid:
[0294] 2.58 g (10.2 mmol) of intermediate 3.1 is dissolved in 45 ml
of dichloromethane in a 100 ml flask, under a nitrogen atmosphere.
The mixture is cooled down to 0.degree. C. and 7.85 ml (102 mmol)
of trifluoroacetic acid is added dropwise. The reaction mixture is
agitated for 3 and a half hours at ambient temperature. The
solution is then concentrated under reduced pressure. The
evaporation residue is taken up in 30 ml of ethyl acetate and
washed with 20 ml of water. The organic phase is dried over sodium
sulphate, filtered and concentrated under vacuum. A yellow solid is
obtained with a yield of 89%. The product obtained is sufficiently
pure to be used directly in the following stage. Melting point:
190-192.degree. C.
[0295] NMR .sup.1H (100 MHz, CDCl.sub.3, .delta.): 2.00 (broad s,
1H, COOH); 4.80 (s, 2H, CH.sub.2); 7.60 (AB, 4H, Ph--NO.sub.2).
[0296] 3.3)
(4-nitrophenoxy)-N-[(4-phenylamino)phenyl]acetamide:
[0297] 1.65 g (8.98 mmol) of 4-aminodiphenylaimine, 1.77 g (8.98
mmol) of intermediate 3.2 and 1.27 g (9.42 mmol) of
hydroxybenzotriazole are dissolved in 40 ml of THF in a 100 ml
flask, under a nitrogen atmosphere. When all have dissolved, 1.94 g
(9.42 mmol) of 1,3-dicyclohexylcarbodiimi- de is added and the
reaction medium is left under agitation for 15 hours. The
precipitate of dicyclohexylurea formed is filtered and rinsed with
ethyl acetate. The filtrate is evaporated under vacuum and the
evaporation residue is taken up in ethyl acetate, it then forms a
precipitate which is filtered and rinsed using the same solvent. A
greenish solid is obtained with a yield of 65%. The product
obtained is sufficiently pure to be used directly in the following
stage. Melting point: 192-195.degree. C.
[0298] NMR .sup.1H (100 MHz, CDCl.sub.3, .delta.): 4.75 (s, 2H,
CH.sub.2--O); 5.70 (broad s, 1H, NH); 7.10 (m, 9H, arom.); 7.85
(AB, 4H, Ph--NO.sub.2); 8.05 (broad s, 1H, NH--CO).
[0299] 3.4)
(4-aminophenoxy)-N-[(4-phenylamino)phenyl]acetamide:
[0300] 1 g (2.75 mmol) of intermediate 3.3 dissolved in 200 ml of a
mixture of solvents (ethanol/dichloromethane/THF 1:1:1) and 0.1 g
of Palladium on carbon at 10% are introduced into a 300 ml
autoclave. The mixture is placed under a hydrogen pressure of 1.5
bar and agitated at ambient temperature for 15 minutes. The
catalyst is filtered off and the solvents are concentrated under
reduced pressure in order to produce a pinkish beige solid with a
yield of 71%. Melting point: 146-148.degree. C.
[0301] NMR .sup.1H (100 MHz, CDCl.sub.3, .delta.): 3.50 (broad s,
2H, NH.sub.2); 4.50 (s, 2H, CH.sub.2--O); 5.70 (broad s, 1H, NH);
6.70 (m, 4H, arom.); 7.10 (m, 4H, arom.); 7.25 (m, 5H, arom.); 8.20
(broad s, 1H, NH--CO).
[0302] 3.5)
[4-{[imino(2-thienyl)methyl]amino}phenoxy]-N-[(4-phenylamino)p-
henyl]acetamide hydroiodide: 3
[0303] A mixture of 0.3 g (0.9 mmol) of intermediate 3.4 in the
presence of 0.25 g (0.9 mmol) of S-methyl-2-thiophene
thiocarboximide hydroiodide in solution in 20 ml of isopropanol is
heated at 50.degree. C., for 15 hours. The reaction mixture is
filtered and the solid obtained is rinsed with ethyl ether. A
yellow powder is obtained with a yield of 78%. Melting point:
163-166.degree. C.
[0304] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 4.75 (s, 2H,
CH.sub.2O); 6.77 (m, 1H, thiophene); 7.04 (m, 4H, arom.); 7.19 (m,
4H, arom.); 7.40 (m, 3H, arom.); 7.50 (m, 2H, arom.); 8.12 (m, 2H,
thiophene); 8.81 (broad s, 1H, NH.sup.+); 9.70 (broad s, 1H,
NH.sup.+); 10.01 (s, 1H, CO--NH); 11.20 (broad s, 1H,
NH.sup.+).
[0305] IR: .nu..sub.C.dbd.O (amide): 1647 cm.sup.-1;
.nu..sub.C.dbd.N (amidine): 1598 cm.sup.-1.
Example 4
[0306]
4-{[2-thienyl(imino)methyl]amino}-N-[2-(phenylamino)phenyl]-benzene-
butanamide: 4
[0307] The experimental protocol used is the same as that described
for Example 2. The product is obtained in the form of the free base
(white solid). Melting point: 164-167.degree. C.
[0308] NMR .sup.1H (400 MHz, DMSO d6,.delta.): 1.86 (m, 2H,
CH.sub.2); 2.35 (m, 2H, CH.sub.2); 2.55 (m, 2H, CH.sub.2); 6.37
(broad s, 2H, NH.sub.2); 6.76 (m, 3H, arom.); 6.87 (m, 2H, arom.);
6.96 (m, 1H, thiophene); 7.10 (m, 3H, thiophene); 7.18 (m, 2H,
arom.); 7.25 (m, 1H, arom.); 7.33 (s, 1H, NH); 7.52 (m, 1H,
thiophene); 7.73 (m, 1H, thiophene); 9.36 (s, 1H, NH--CO).
[0309] IR: .nu..sub.C.dbd.O (amide): 1627cm.sup.-1;
.nu..sub.C.dbd.N (amidine): 1591 cm.sup.-1.
Example 5
[0310]
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzene-
butanamide hydrochloride: 5
[0311] The experimental protocol used is the same as that described
for Example 2. The hydrochloride is obtained in the form of a
salmon-pink powder. Melting point: 167-170.degree. C.
[0312] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 1.90 (m, 2H,
CH.sub.2); 2.35 (m, 2H, CH.sub.2); 2.70 (m, 2H, CH.sub.2); 6.70 (m,
1H, thiophene); 7.00 (m, 4H, arom.); 7.20 (m, 2H, arom.); 7.40 (m,
5H, arom.); 7.50 (m, 2H, arom.); 8.20 (m, 2H, thiophene); 8.90 (s,
1H, NH.sup.+); 9.85 (s, 1H, NH.sup.+); 9.90 (s, 1H, NHCO); 11.55
(s, 1H, NH.sup.+).
[0313] IR: .nu..sub.C.dbd.O (amide): 1654 cm.sup.-1;
.nu..sub.C.dbd.N (amidine): 1597 cm.sup.-1.
Example 6
[0314]
4-{[2-thienyl(imino)methyl]amino}-N-[4-(4-methoxyphenylamino)phenyl-
]-benzenebutanamide hydrochloride: 6
[0315] The experimental protocol used is the same as that described
for intermediate 2.3, intermediate 6.2 replacing
4-amino-N-[4-(phenylamino)ph- enyl]-benzeneacetamide. A beige
powder is obtained with a yield of 65%. Melting point:
200-202.degree. C.
[0316] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 1.91 (m, 2H,
CH.sub.2); 2.33 (m, 2H, CH.sub.2); 2.67 (mn, 2H, CH.sub.2); 3.69
(s, 3H, O--CH.sub.3); 4.71 (broad s, 1H, NH); 6.81-7.00 (m, 6H,
arom.); 7.37-7.45 (m, 7H, arom.); 8.20 (m, 2H, thiophene); 8.90
(broad s, 1H, NH.sup.+); 9.87 (broad s, 1H, NH.sup.+); 9.92 (s, 1H,
NH--CO); 11.67 (broad s, 1H, NH.sup.+).
[0317] IR:.nu..sub.C.dbd.O (amide): 1664 cm.sup.-1;
.nu..sub.C.dbd.N (amidine): 1603 cm.sup.-1.
Example 7
[0318] 2-{4-{[2-thienyl(imino)methyl]amino}phenyl}-ethyl:
[4-(phenylamino)phenyl]-carbamate hydrochloride: 7
[0319] 7.1) 2-(4-nitrophenyl)-ethyl
[4-(phenylamino)phenyl]-carbamate:
[0320] 1.18 g (3.9 mmol) of triphosgene is dissolved in 15 ml of
dichloromethane in a 250 ml flask, under argon. Using a motorized
syringe, a solution of 2 g (12 mmol) of 4-nitrophenylethanol and
1.7 ml (13 mmol) of N,N-dimethylaniline in 40 ml of dichloromethane
is added over 1 hour. The reaction mixture is agitated for a few
minutes at 20.degree. C. before adding in one go a solution of 2.2
g (12 mmol) of 4-aminodiphenylamine and 1.7 ml (13 mmol) of
N,N-dimethylaniline in 40 ml of dichloromethane. After agitation
for one hour at 20.degree. C., the contents of the flask are poured
into 100 ml of water. The mixture is diluted with 100 ml of
dichloromethane and agitated. The organic phase is decanted, dried
over magnesium sulphate, filtered and evaporated under vacuum. The
solid obtained is taken up in ethyl ether, triturated and filtered.
After drying, a greenish powder is obtained with a yield of 22%.
Melting point: 146.4-148.degree. C.
[0321] NMR .sup.1H (400 MHz, CDCl.sub.3, .delta.): 3.10 (m, 2H,
CH.sub.2); 4.40 (m, 2H, CH.sub.2); 5.65 (s, 1H, NH); 6.50 (s, 1H,
NH); 6.80-7.60 (m, 11H, arom.); 8.20 (m, 2H, arom.).
[0322] 7.2) 2-(4-aminophenyl)-ethyl
[4-(phenylamino)phenyl]-carbamate:
[0323] The experimental protocol used is the same as that described
for intermediate 2.2, intermediate 7.1 replacing
4-nitro-N-[4-(phenylamino)ph- enyl]-benzeneacetamide. A white solid
is obtained with a yield of 48%. Melting point: 140-140.5.degree.
C.
[0324] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 2.75 (m, 2H,
CH.sub.2); 4.15 (m, 2H, CH.sub.2); 5.20 (s, 2H, NH.sub.2); 6.50 (m,
2H; arom.); 6.70 (m, 1H, arom.); 7.00 (m, 6H, arom.); 7.15 (m, 2H,
arom.); 7.30 (m, 2H, arom.); 8.00 (s, 1H, NH); 9.40 (s, 1H,
NH).
[0325] 7.3)
2-{4-{[2-thienyl(imino)methyl]amino}phenyl}-ethyl[4-(phenylami-
no)phenyl]-carbamate hydrochloride: 7
[0326] The experimental protocol used is the same as that described
for intermediate 2.3, intermediate 7.2 replacing
4-amino-N-[4-(phenylamino)ph- enyl]-benzeneacetamide. A white solid
is obtained with a yield of 34%. Melting point: 153-159.degree.
C.
[0327] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 3.00 (m, 2H,
CH.sub.2); 4.30 (m, 2H, CH.sub.2); 6.60-7.70 (m, 14H, arom.); 8.20
(m, 2H, thiophene); 8.90 (s, 1H, NH.sup.+); 9.50 (s, 1H, NH--CO);
9.90 (s, 1H, NH.sup.+); 11.70 (s, 1H, NH.sup.+).
[0328] IR: .nu..sub.C.dbd.O (carbamate): 1719 cm.sup.-1;
.nu..sub.C.dbd.N (amidine): 1598 cm.sup.-1.
Example 8
[0329]
N-{2-{4-{[2-thienyl(imino)methyl]amino}phenyl}ethyl}-N'-[4-(phenyla-
mino)phenyl]-urea hydrochloride: 8
[0330] 8.1)
N-[2-(4-nitrophenyl)-ethyl]-N'-[4-(phenylamino)phenyl]-urea:
[0331] 0.5 g (1.7 mmol) of triphosgene is dissolved in 8 ml of
dichloromethane in a 100 ml flask, under argon. Using a motorized
syringe, a solution of 0.92 g (5 mmol) of 4-aminodiphenylamine and
1.44 ml (8.2 mmol) of diisopropylethylamine in 15 ml of
dichloromethane is added over one hour. Five minutes after the
addition is finished, 1.01 g (5 mmol) of 4-nitrophenethylamine
hydrochloride followed by a solution of 1.44 ml (8.2 mmol) of
diisopropylethylamine in 10 ml of dichloromethane are added in a
single portion. After agitation for two hours at 20.degree. C., the
reaction mixture is diluted with 50 ml of dichloromethane and 20 ml
of water. The organic phase is decanted and rewashed with 20 ml of
water. After drying over MgSO.sub.4 and filtration, the organic
solution is partially concentrated under vacuum. The precipitate
formed is collected by filtration and rinsed with dichloromethane.
A yellow solid is obtained with a yield of 40%. Melting point:
204-205.degree. C.
[0332] NMR .sup.1H (100 MHz, DMSO d6, .delta.): 2.96 (m, 2H,
CH.sub.2); 3.50 (m, 2H, CH.sub.2--NH); 5.78 (m, 1H, HN--CH.sub.2);
6.45 (broad s, 1H, Ph--NH--CO); 6.72-7.49 (m, 11H, arom.); 7.81
(broad s, 1H, NH); 8.15 (m, 2H, arom.).
[0333] 8.2)
N-[2-(4-aminophenyl)-ethyl]-N'-[4-(phenylamino)phenyl]-urea:
[0334] A solution of intermediate 8.1 (0.68 g, 1.81 mmol) in 40 ml
of a THF/ethanol mixture (3/1) as well as 0.1 g of Pd/C at 10% is
introduced into a stainless steel autoclave equipped with a
magnetic stirrer. The reaction mixture is agitated under hydrogen
pressure (1.5 bar) for 1 hour at a temperature of 20.degree. C. The
Pd/C is then eliminated by filtration and the filtrate is
concentrated under vacuum. The solid obtained is washed
successively with ethyl acetate and dichloromethane. A beige powder
is obtained with a yield of 61%. Melting point>260.degree.
C.
[0335] NMR .sup.1H (100 MHz, DMSO d6, .delta.): 2.70 (m, 2H,
CH.sub.2); 3.40 (m, 2H, CH.sub.2--NH); 5.18 (broad s, 2H,
NH.sub.2); 6.07 (m, 1H, HN--CH.sub.2); 6.60-7.45 (m, 13H, arom.);
8.00 (broad s, 1H, NH); 8.41 (broad s, 1H, Ph--NH--CO).
[0336] 8.3)
N-{2-{4-{[2-thienyl(imino)methyl]amino}phenyl}ethyl}-N'-[4-(ph-
enylamino)phenyl]-urea hydrochloride: 8
[0337] 0.38 g (1.10 mmol) of intermediate 8.2 and 0.34 g (1.21
mmol) of S-methyl-2-thiophene thiocarboximide hydroiodide are
dissolved in 20 ml of isopropanol in a 50 ml flask. The reaction
mixture is agitated for 20 hours at a temperature of 60.degree. C.
After evaporation of the solvent under vacuum, the residue is taken
up in 50 ml of a 1/1 mixture of a saturated solution of
Na.sub.2CO.sub.3 and ethyl acetate. The reaction medium is
vigorously agitated and after a few moments a precipitate appears.
This is collected, filtered and rinsed successively with ethyl
acetate and water. After drying, the precipitate is purified on a
silica gel column (eluent THF). The pure fractions are collected
and concentrated under vacuum. The solid obtained (300 mg) is
redissolved in 80 ml of THF to which 2 ml of a 1N solution of HCl
in ethyl ether is added. The hydrochloride formed precipitates, it
is filtered and rinsed with THF followed by ethyl ether in order to
produce a light grey powder. Melting point: the product becomes a
foam.
[0338] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 2.80 (m, 2H,
CH.sub.2); 3.37 (m, 2H, CH.sub.2); 4.46 (broad s, 1H, NH); 6.40
(broad s, 1H, NH--CH.sub.2); 6.70 (m, 1H, thiophene); 6.94 (m, 4H,
arom.); 7.15 (m, 2H, arom.); 7.28 (m, 2H, arom.); 7.40 (m, 5H,
arom.); 8.17 (m, 2H, thiophene); 8.78 (broad s, 1H, Ph--NH--CO);
8.93 (broad s, 1H, NH.sup.+); 9.84 (broad s, 1H, NH.sup.+); 11.52
(broad s, 1H, NH.sup.+).
[0339] IR: .nu..sub.C.dbd.O (urea): 1654 cm.sup.-1;
.nu..sub.C.dbd.N (amidine): 1598 cm.sup.-1.
Example 9
[0340]
4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-N-[4-(phenylamino)pheny-
l]-1-piperazine acetamide hydrochloride: 9
[0341] 9.1) ethyl 4-(nitrophenyl)-1-piperazine acetate:
[0342] 3 g (14.5 mmol) of 1-(4-nitrophenylpiperazine) and 1.8 ml
(15.9 mmol) of bromoethyl acetate are dissolved in 60 ml of
dichloromethane in a 100 ml flask. After the addition of 2.42 ml
(17.4 mmol) of triethylamine, the reaction mixture is agitated, at
20.degree. C., for one hour. The solution is then poured into 100
ml of water and extracted with 100 ml of dichloromethane. After
decantation, the organic phase is dried over magnesium sulphate,
filtered and concentrated under vacuum. The solid obtained is taken
up in ethyl ether, triturated and filtered. A yellow powder is
obtained with a yield of 89%. Melting point: 122.1-122.5.degree.
C.
[0343] NMR .sup.1H (400 MHz, CDCl.sub.3, .delta.): 1.3 (t, 3H,
CH.sub.3, J=7 Hz); 2.75 (m, 4H, piperazine); 3.30 (s, 2H,
CO--CH.sub.2); 3.50 (m, 4H, piperazine); 4.20 (q, 2H,
CH.sub.2--CH.sub.3, J=7 Hz); 7.45 (AB, 4H, Ph--NO.sub.2).
[0344] 9.2) 4-(nitrophenyl)-1-piperazine acetic acid:
[0345] 32.4 ml of a 1M aqueous solution of LiOH is added dropwise
at 20.degree. C. into a flask containing a solution of 3.8 g (13
mmol) of intermediate 9.1 in solution in 80 ml of THF. After
agitation for one hour, the reaction mixture is acidified to pH=5
with a 2N solution of hydrochloric acid. The precipitate obtained
is filtered and rinsed with a minimum amount of THF and water. The
product is used as it is in the following stage.
[0346] NMR .sup.1H (100 MHz, D.sub.2O, .delta.): 3.30 (m, 4H,
piperazine); 3.60 (m, 6H, piperazine+CO--CH.sub.2); 7.45 (AB, 4H,
Ph--NO.sub.2).
[0347] 9.3)
4-(4-nitrophenyl)-N-[4-(phenylamino)phenyl]-1-piperazine
acetamide:
[0348] The protocol used is the same as that described for
intermediate 2.1, intermediate 9.2 replacing 4-nitrophenylacetic
acid. A yellow solid is obtained with a yield of 84%. Melting
point: 212-213.degree. C.
[0349] NMR .sup.1H (400 MHz, CDCl.sub.3, .delta.): 2.80 (m, 4H,
piperazine); 3.25 (s, 2H, CO--CH.sub.2); 3.50 (m, 4H, piperazine);
5.70 (s, 1H, NH); 6.90 (m, 3H, arom.); 7.10 (m, 4H, arom.); 7.30
(m, 2H, arom.); 7.85 (AB, 4H, Ph--NO.sub.2); 8.90 (s, 1H,
NHCO).
[0350] 9.4)
4-(4-aminophenyl)-N-[4-(phenylamino)phenyl]-1-piperazine
acetamide:
[0351] The protocol used is the same as that described for
intermediate 2.2, intermediate 9.3 replacing
4-nitro-N-[4-(phenylamino)phenyl]-benzene- acetamide. A brown oil
is obtained with a yield of 71%.
[0352] NMR .sup.1H (400 MHz, CDCl.sub.3, .delta.): 2.80 (m, 4H,
piperazine); 3.15 (m, 4H, piperazine); 3.20 (s, 2H, CO--CH.sub.2);
5.70 (s, 1H, NH); 6.70 (m, 2H, arom.); 6.90 (m, 3H, arom.); 7.10
(m, 4H, arom.); 7.30 (m, 2H, arom.); 7.50 (m, 2H, arom.); 9.10 (s,
1H, NHCO).
[0353] 9.5)
4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-N-[4-(phenylamino)-
phenyl]-1-piperazine acetamide hydrochloride: 9
[0354] The protocol used is the same as that described for
intermediate 2.3, intermediate 9.4 replacing
4-amino-N-[4-(phenylamino)phenyl]-benzene- acetamide. A yellow
solid is obtained with a yield of 30%. Melting point:
230-240.degree. C.
[0355] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 3.10-3.50 (m, 4H,
piperazine); 3.65 (m, 2H, piperazine); 3.90 (m, 2H, piperazine);
4.30 (s, 2H, CO--CH.sub.2); 6.80 (m, 1H, thiophene); 6.90-7.40 (m,
11H, arom.); 7.50 (m, 2H, arom.); 8.15 (m, 2H, thiophene); 8.75 (s,
1H, NH.sup.+); 9.80 (s, 1H, NH.sup.+); 10.9 (m, 2H, NHCO+NH.sup.+);
11.40 (s, 1H, NH.sup.+).
[0356] IR: .nu..sub.C.dbd.O (amide): 1680 cm.sup.-1;
.nu..sub.C.dbd.N (amidine): 1512 cm.sup.-1.
Example 10
[0357]
1-{[(4-phenylamino)phenylamino]carbonyl}-4-{4-{[2-thienyl(imino)met-
hyl]amino}phenyl}-piperazine hydrochloride: 10
[0358] The experimental protocol used is the same as that described
for Example 8. The product is salified under conditions which are
identical to compound 2 except that THF replaces methanol. A yellow
powder is obtained. Melting point: 239-240.degree. C.
[0359] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 3.30 (broad s, 4H,
piperazine); 3.70 (broad s, 4H, piperazine); 5.80 (broad s, 1H,
NH); 6.73 (m, 1H, thiophene); 6.98 (m, 4H, arom.); 7.17 (m, 2H,
arom.); 7.28-7.37 (m, 7H, arom.); 8.16 (m, 2H, thiophene); 8.65
(broad s, 1H, Ph--NH--CO); 8.80 (broad s, 1H, NH.sup.+); 9.80
(broad s, 1H, NH.sup.+); 11.52 (broad s, 1H, NH.sup.+).
[0360] IR: .nu..sub.C.dbd.O (urea): 1654 cm.sup.-1;
.nu..sub.C.dbd.N (amidine): 1597 cm.sup.-1.
Example 11
[0361]
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzene-
butanamine hydrochloride: 11
[0362] 11.1)
4-Nitro-N-[4-(phenylamino)phenyl]-benzenebutanamine:
[0363] 1.12 g (3 mmol) of
4-nitro-N-[4-(phenylamino)phenyl]-benzenebutanam- ide (obtained
under the same conditions as intermediate 2.1) is dissolved in 50
ml of anhydrous THF in a 250 ml three-necked flask under an argon
atmosphere. The solution is cooled down using an ice bath, before
the dropwise addition of 15 ml (15 mmol) of a solution of
diborane/THF. The reaction mixture is heated to reflux for 5 hours.
After returning the temperature to 20.degree. C., 25 ml of an HCl
solution (6N) is added slowly dropwise and the mixture is taken to
reflux for 2 hours. The solution is then cooled down using an ice
bath before the addition of a 20% soda solution until a basic pH is
reached. The product is extracted using ethyl ether (2.times.50
ml), the organic solution is washed with salt water (2.times.50 ml)
and dried over magnesium sulphate. After filtration and
concentration under vacuum, the residue is purified on a silica gel
column (eluent: heptane/AcOEt 1/1). The pure fractions are
collected and evaporated under vacuum in order to produce a brown
oil with a yield of 28%.
[0364] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 1.55 (m, 2H,
CH.sub.2); 1.71 (m, 2H, CH.sub.2); 2.75 (m, 2H, CH.sub.2-Arom);
2.98 (m, 2H, HN--CH.sub.2); 5.29 (m, 1H, NH); 6.51-7.51 (m, 12H,
Arom.+NH); 8.15 (m, 2H, Ph--NO.sub.2).
[0365] 11.2)
4-Amino-N-[4-(phenylamino)phenyl]-benzenebutanamine:
[0366] The experimental protocol used is the same as that described
for intermediate 2.2, intermediate 11.1 replacing
4-nitro-N-[4-(phenylamino)p- henyl]-benzeneacetamide. A brown oil
is obtained with a yield of 36%.
[0367] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 1.55 (m, 4H,
2.times.CH.sub.2); 2.44 (m, 2H, CH.sub.2); 2.97 (m, 2H, CH.sub.2);
4.81 (s, 2H, NH.sub.2); 5.27 (m, 1H, NH); 6.47-7.10 (m, 13H,
arom.); 7.49 (s, 1 H, NH).
[0368] 11.3)
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-b-
enzenebutanamine hydrochloride: 11
[0369] 0.10 g (0.3 mmol) of intermediate 11.2 and 0.11 g (0.37
mmol) of S-methyl-2-thiophene thiocarboximide hydroiodide are
dissolved in 5 ml of isopropanol with 0.05 ml (0.6 mmol) of
pyridine added to it, in a 50 ml flask. The reaction mixture is
agitated for 20 hours at a temperature of 23.degree. C. After
evaporation of the solvent under vacuum, the residue is taken up in
25 ml of a mixture (1/1) of a saturated solution of NaHCO.sub.3 and
dichloromethane. After decantation, the organic phase is washed
with 2.times.25 ml of salt water. The organic solution is dried
over magnesium sulphate, filtered, concentrated under vacuum and
the residue is purified on a silica gel column (eluent:
dichloromethane+5% of ethanol). The pure fractions are collected
and concentrated under vacuum. A pinkish powder is obtained which
is salified by adding a 1N solution of HCl in ethyl ether (1 ml) to
the solution of the base in acetone. After agitation for one hour
at 20.degree. C., the reaction mixture is filtered and the powder
is washed successively with 20 ml of acetone and 20 ml of ethyl
ether. Melting point: 165-166.degree. C.
[0370] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 1.71 (m, 4H,
2.times.CH.sub.2); 2.66 (m, 2H, CH.sub.2); 3.20 (m, 2H, CH.sub.2);
6.85-7.41 (m, 14H, arom.); 8.16 (m, 2H, thiophene); 8.53 (broad s,
1H, NH); 8.87 (broad s, 1H, NH.sup.+); 9.83 (broad s, 1H,
NH.sup.+); 11.19 (broad s, 2H, 2.times.NH.sup.+);c 11.56 (broad s,
1H, NH.sup.+).
[0371] IR: .nu..sub.C.dbd.N (amidine): 1595 cm.sup.-1.
Example 12
[0372]
3-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzene-
propanamide hydrochloride: 12
[0373] 12.1) 3-nitrophenylethanol mesylate:
[0374] A solution of 4.63 ml (59.8 mmol) of methane sulphonyl
chloride diluted with 20 ml of dichloromethane is added dropwise to
a solution of 10 g (59.8 mmol) of 3-nitrophenylethanol and 8.31 ml
(59.8 mmol) of triethylamine in 120 ml of dichloromethane, cooled
down with an ice bath. Agitation is maintained for 1 hour at
0.degree. C. and for 2 hours at 20.degree. C. The reaction mixture
is then concentrated under vacuum and the residue is taken up in
125 ml of ethyl acetate and 100 ml of water. After agitation and
decantation, the organic phase is washed successively with 100 ml
of water and 100 ml of salt water. The organic solution is dried
over magnesium sulphate, filtered and concentrated under vacuum.
The evaporation residue is purified on a silica column (eluent
heptane/ethyl acetate 6/4) and the pure fractions are collected and
evaporated in order to produce a yellow oil with a yield of
71%.
[0375] NMR .sup.1H (100 MHz, CDCl.sub.3, .delta.): 3.00 (s, 3H,
CH.sub.3); 3.20 (t, 2H, CH.sub.2, J=5.8 Hz); 4.50 (t, 2H,
CH.sub.2); 7.60 (m, 2H, arom.); 8.20 (m, 2H, arom.).
[0376] 12.2) 3-nitrobenzene-propanenitrile:
[0377] 0.49 g (10 mmol) of NaCN is introduced in one portion into a
100 ml flask ml, under an argon atmosphere, containing a solution
of 1.22 g (5 mmol) of intermediate 12.1 in 20 ml of dry DMF. The
reaction mixture is heated at 60.degree. C. for 3 hours and, after
allowing the temperature to return to 20.degree. C., poured into
100 ml of water. The solution is extracted with 5.times.50 ml of
ethyl acetate, the organic phases are collected and washed
successively with 100 ml of water and 100 ml of salt water. After
drying over magnesium sulphate, the organic solution is
concentrated under vacuum and the residue is purified on a silica
column (eluent: heptane/ethyl acetate: 7/3). The pure fractions are
collected and concentrated under vacuum in order to produce a light
yellow powder with a yield of 78%. Melting point: 86-88.degree.
C.
[0378] NMR .sup.1H (100 MHz, CDCl.sub.3, .delta.): 2.70 (t, 2H,
CH.sub.2, J=5.8 Hz); 3.10 (t, 2H, CH.sub.2); 7.60 (m, 2H, arom.);
8.20 (m, 2H, arom.).
[0379] 12.3) 3-nitrobenzene propanoic acid:
[0380] A solution of 2.33 g (19.2 mmol) of intermediate 12.2 in 100
ml of a 10% aqueous solution of HCl and 100 ml of ethanol is taken
to reflux for 72 hours. After allowing the temperature to return to
20.degree. C., the reaction mixture is concentrated to dryness
under vacuum. The residue is taken up in 100 ml of ethyl acetate
and washed with 3.times.100 ml of water and with 50 ml of salt
water. After drying over sodium sulphate, the organic solution is
filtered and concentrated under vacuum. The evaporation residue is
purified on a silica column (eluent: heptane/ethyl acetate 95/5 up
to 80/20). A light yellow powder is obtained with a yield of 21%.
Melting point: 107-109.degree. C.
[0381] NMR .sup.1H (100 MHz, CDCl.sub.3, .delta.): 2.70 (m, 2H,
CH.sub.2); 3.10 (m, 2H, CH.sub.2); 5.40 (broad s, 1H, 7.50 (m, 2H,
arom.); 8.10 (m, 2H, arom.).
[0382] 12.4)
3-nitro-N-[4-(phenylamino)phenyl]-benzenepropanamide:
[0383] The experimental protocol used is the same as that described
for intermediate 2.1, intermediate 12.3 replacing
4-nitrophenylacetic acid. A brown powder is obtained with a yield
of 70%. Melting point: 130-132.degree. C.
[0384] NMR .sup.1H (CDCl.sub.3, 100 MHz, .delta.): 2.70 (t, 2H,
CH.sub.2, J=5.8 Hz); 3.20 (t, 2H, CH.sub.2); 5.70 (broad s, 1H,
NH); 6.90-7.60 (m, 13H, arom.).
[0385] 12.5)
3-amino-N-[4-(phenylamino)phenyl]-benzenepropanamide:
[0386] The experimental protocol used is the same as that described
for intermediate 2.2, intermediate 12.4 replacing
4-nitro-N-[4-(phenylamino)p- henyl]-benzeneacetamide. A white
powder is obtained with a yield of 64%. Melting point:
164-166.degree. C.
[0387] NMR .sup.1H (CDCl.sub.3, 100 MHz, .delta.): 2.80 (m, 2H,
CH.sub.2); 3.50 (m, 2H, CH.sub.2); 5.10 (broad s, 2H, NH.sub.2);
6.50 (m, 3H, arom.); 6.80-7.45 (m, 8H, arom.); 7.60 (m, 2H, arom.);
8.15 (s, 1H, NH); 9.88 (s, 1H, NH--CO).
[0388] 12.6)
3-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-b-
enzenepropanamide hydrochloride: 12
[0389] The experimental protocol used is the same as that described
for intermediate 2.3, intermediate 12.5 replacing
4-amino-N-[4-(phenylamino)p- henyl]-benzeneacetamide. After
salification, a light beige powder is obtained with a yield of 78%.
Melting point: 228-230.degree. C.
[0390] NMR .sup.1H (400 MHz, DMSO d6, .delta.): 2.70 (m, 2H,
CH.sub.2); 2.96 (m, 2H, CH.sub.2); 5.20 (broad s, 1H, NH); 6.74 (m,
1H, thiophene); 7.00 (m, 4H, arom.); 7.19 (m, 2H, arom.); 7.29 (m,
1H, arom.); 7.39 (m, 3H, arom.); 7.47 (m, 3H, arom.); 8.18 (m, 2H,
thiophene); 8.96 (broad s, 1H, NH.sup.+); 9.90 (broad s, 1H,
NH.sup.+); 10.07 (s, 1H, NH--CO); 11.60 (broad s, 1H,
NH.sup.+).
[0391] IR: .nu..sub.C.dbd.O (amide): 1649 cm.sup.-1;
.nu..sub.C.dbd.N (amidine): 1596 cm.sup.-1.
Example 13
[0392]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)-
phenyl]butanamide: 13
[0393] 13.1) N'-(4-methylphenyl)-1,2-benzenediamine:
[0394] The reduction of the nitro function of
N-(4-methylphenyl)-2-nitroan- iline (Synthesis (1990) 430) is
carried out in the presence of Pd/C in ethanol, under the
conditions described previously for intermediate 2.2. A violet
product is obtained in a semi-oil semi-crystal form with a yield of
90%.
[0395] 13.2)
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-tolu-
idino)phenyl]butanamide:
[0396] The experimental protocol used is the same as that described
for Example 2, starting from 4-nitrophenylbutyric acid and
intermediate 13.1. The product is isolated in the form of a free
base. White solid. Melting point: 66-68.degree. C.
Example 14
[0397]
4-anilinophenyl-4-(4-{[amino(2-thienyl)methylidene]amino}-phenyl)bu-
tanoate: 14
[0398] 14.1) 4-anilinophenyl 4-(4-nitrophenyl)butanoate:
[0399] 0.98 g (6.02 mmol) of 1,1'-carbonyldiimidazole is slowly
added at 20.degree. C. to a solution of 1.25 g (5.96 mmol) of
4-nitrophenylbutyric acid in 25 ml CH.sub.2Cl.sub.2. The reaction
mixture is agitated for 30 minutes before the addition of 1 g (5.42
mmol) of 4-hydroxy-diphenylamine- . After agitation for 3 hours,
the reaction is stopped by the addition of 3 ml of MeOH and the
solvent is evaporated under vacuum. The evaporation residue is
purified on a silica column (eluent: Heptane/AcOEt: 100/0 to
80/20). A yellow solid is obtained with a yield of 89%.
[0400] 14.2) 4-anilinophenyl
4-(4-{[amino(2-thienyl)methylidene]amino}phen- yl)butanoate:
[0401] The experimental protocol used is the same as that described
for intermediates 2.2 and 2.3, starting from intermediate 14.1. The
product is isolated in the form of a free base. Pale yellow solid.
Melting point: 147-148.degree. C.
Example 15
[0402]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)-
phenyl]butanamide: 15
[0403] 15.1)
N-{4-[4-(4-nitrophenyl)butoxy]phenyl}-N-phenylamine:
[0404] 2.0 g (10.88 mmol) of 4-hydroxy-diphenylamine, 2.0 ml (12
mmol) of 4-(4-nitrophenyl)-1-butanol and 1.66 ml (12 mmol) of
tributylphosphine are successively introduced into a flask
containing 10 ml CH.sub.2Cl.sub.2. 1.90 ml (12 mmol) of
diethylazodicarboxylate is then added dropwise and the whole is
agitated at 20.degree. C. for 16 hours. The solvent is evaporated
off under vacuum and the residue is purified on a silica column
(eluent: heptane/AcOEt: 100/0 to 80/20). The expected product is
obtained in the form of a dark red oil with a yield of 35%.
[0405] 15.2)
N'-{4-[4-(4-anilinophenoxy)butyl]phenyl}-2-thiophenecarboximi-
damide:
[0406] The experimental protocol used is the same as that described
for intermediates 2.2 and 2.3, starting from intermediate 14.1. The
product is isolated in the form of a free base. White solid.
Melting point: 120-121.degree. C.
Example 16
[0407]
N'-{4-[4-(3-anilinophenoxy)butyl]phenyl}-2-thiophenecarboximidamide-
: 16
[0408] The experimental protocol used is the same as that described
for Example 15, starting from 3-hydroxy-diphenylamine. The product
is isolated in the form of a free base. White solid. Melting point:
73-74.degree. C.
Example 17
[0409] N'-(9H-carbazol-3-yl)-2-thiophenecarboximidamide: 17
[0410] The experimental protocol used is the same as that described
for Example 1, starting from 3-aminocarbazole (Pharmazie (1993)
48(11), 817-820). The product is isolated in the form of a free
base. Light beige solid. Melting point: 243-244.degree. C.
Example 18
[0411]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(9H-carbazol-3-y-
l)butanamide hydrochloride: 18
[0412] The experimental protocol used is the same as that described
for Example 2, starting from 3-aminocarbazole (Pharmazie (1993)
48(11), 817-820) and 4-nitrophenylbutyric acid. Light beige solid.
Melting point >250.degree. C. MS: MH.sup.+: 452.2.
Example 19
[0413]
N'-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximidamide
hydroiodide: 19
[0414] 19.1) 2-(4-nitrophenoxy)-10H-phenothiazine:
[0415] 1.1 g (5.11 mmol) of 2-hydroxy-10H-phenothiazine (J. Med.
Chem. (1992) 35, 716), 1.34 g (9.71 mmol) of K.sub.2CO.sub.3 and
0.94 g (6.64 mmol) of 4-fluoro-1-nitrobenzene are mixed in 25 ml
anhydrous DMF in a flask under argon atmosphere. The reaction
mixture is heated at 70.degree. C. for 18 hours. The solvent is
then evaporated off under vacuum and the residue is taken up in 50
ml of AcOEt and 50 ml of water. After agitation and decantation,
the organic phase is washed with 50 ml of salt water. The organic
solution is dried over MgSO.sub.4, filtered and concentrated under
vacuum. The residue is crystallized from diisopropyl ether. After
drying, a yellow solid is obtained with a yield of 83%. Melting
point: 210-211.degree. C.
[0416] 19.2)
N'-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximid-
amide hydroiodide:
[0417] The experimental protocol used is the same as that described
for intermediates 2.2 and 2.3, starting from intermediate 19.1. The
expected final product precipitates directly from the reaction
mixture, it is isolated by filtration and washed using iPrOH.
Yellow solid. Melting point: 175-180.degree. C.
Example 20
[0418]
N'-{4-[(10-methyl-10H-phenothiazin-2-yl)oxy]phenyl}-2-thiophenecarb-
oximidamide hydrochloride: 20
[0419] 20.1) 10-methyl-10H-phenothiazin-2-yl
4-nitrophenylether:
[0420] 0.014 g (0.58 mmol) of NaH (60%) is added to a flask under
argon atmosphere, containing a solution of 0.1 g (0.29 mmol) of
intermediate 19.1 in 10 ml of anhydrous DMF. Agitation is
maintained, at 20.degree. C., for 16 hours. 0.04 ml (0.58 mmol) of
MeI is then added to the reaction mixture, under agitation at
20.degree. C. At the end of the reaction, the whole is poured into
50 ml of ice-cooled water and the product is extracted using 50 ml
of AcOEt. The organic phase is decanted, washed with 50 ml of salt
water, dried over MgSO.sub.4, filtered and concentrated under
vacuum. The residue is purified on a silica column (eluent :
heptane/AcOEt: 80/20). An orange oil is obtained with a yield of
50%.
[0421] 20.2)
N'-{4-[(10-methyl-10H-phenothiazin-2-yl)oxy]phenyl}-2-thiophe-
necarboximidamide hydrochloride:
[0422] The experimental protocol used is the same as that described
for intermediates 2.2 and 2.3, starting from intermediate 20.1. A
white solid is obtained. Melting point: 256-257.degree. C.
Example 21
[0423]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-phenothiazi-
n-3-yl)butanamide hydrochloride: 21
[0424] 21.1) 3-amino-10H-phenothiazine:
[0425] Reduction of the nitro function of 3-nitro-10H-phenothiazine
(J. Org. Chem. (1972) 37, 2691) is carried out in the presence of
Pd/C in an EtOH/THF mixture under the conditions described for
intermediate 2.2. A grey solid is obtained with a yield of 97%.
Melting point: 150-156.degree. C.
[0426] 21.2)
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-pheno-
thiazin-3-yl)butanamide hydrochloride:
[0427] The experimental protocol used is the same as that described
for Example 2, starting from 4-nitrophenylbutyric acid and
intermediate 21.1. Light green solid. Melting point:
170-176.degree. C.
Example 22
[0428]
N'-(4-{4-[2-(10H-phenothiazin-2-yloxy)ethyl]-1-piperazinyl}phenyl)--
2-thiophenecarboximidamide dihydrochloride: 22
[0429] 22.1) 2-[4-(4-nitrophenyl)-1-piperazinyl]-1-ethanol:
[0430] 7.5 g (60 mmol) of 2-bromoethanol is added, under argon
atmosphere, to a mixture of 10.35 g (50 mmol) of
1-(4-nitrophenyl)piperazine, 7.6 g (55 mmol) of K.sub.2CO.sub.3 and
9 ml (65 mmol) of Et.sub.3N in 200 ml of CH.sub.2Cl.sub.2. The
whole is then heated at 45.degree. C. for 18 hours The reaction
mixture is finally diluted with 50 ml water, agitated and decanted.
The organic phase is washed with 50 ml of salt water, dried over
MgSO.sub.4, filtered and concentrated under vacuum. The residue is
crystallized from diisopropyl ether. A yellow solid is obtained
with a yield of 89%. Melting point: 98-99.degree. C.
[0431] 22.2) 1-(2-bromoethyl)-4-(4-nitrophenyl)piperazine:
[0432] 8.6 g (26 mmol) of CBr.sub.4 is added to a solution of 5 g
(20 mmol) of intermediate 22.1 in 75 ml of CH.sub.2Cl.sub.2. The
whole is cooled using an ice bath before the addition, by portions,
of 6.3 g (24 mmol) of triphenylphosphine. Agitation is maintained
for 2 hours at 20.degree. C. After the addition of 50 ml of water,
agitation and decantation, the organic phase is washed with 50 ml
of salt water, dried over MgSO.sub.4, filtered and concentrated
under vacuum. The evaporation residue is purified on a silica
column (eluent: CH.sub.2Cl.sub.2/EtOH: 95/5) and finally
crystallized from ethyl ether. A yellow-orange solid is obtained
with a yield of 40%. Melting point: 134-135.degree. C.
[0433] 22.3)
2-{2-[4-(4-nitrophenyl)-1-piperazinyl]ethoxy}-10H-phenothiazi-
ne:
[0434] The experimental protocol used is the same as that described
for intermediate 19.1, starting from intermediate 22.2. A yellow
solid is obtained with a yield of 43%. Melting point:
224-225.degree. C.
[0435] 22.4)
N'-(4-{4-[2-(10H-phenothiazin-2-yloxy)ethyl]-1-piperazinyl}-p-
henyl)-2-thiophenecarboximidamide dihydrochloride:
[0436] The experimental protocol used is the same as that described
for intermediates 2.2 and 2.3 starting from intermediate 22.3.
Light beige solid. Melting point: 198-200.degree. C.
Example 23
[0437]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(4-toluidino)-
phenyl]butanamide hydrochloride: 23
[0438] 23.1) N'-(4-methylphenyl)-1,4-benzenediamine:
[0439] Reduction of the nitro function of
N-(4-methylphenyl)-4-nitroanilin- e (Indian J. Chem. (1981) 20B,
611-613) is carried out in the presence of Pd/C in ethanol, under
the conditions described for intermediate 2.2. A grey solid is
obtained with a yield of 85%.
[0440] 23.2)
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(4-tolu-
idino)phenyl]butanamide hydrochloride:
[0441] The experimental protocol used is the same as that described
for Example 2, starting from intermediate 22.3 and
4-nitrophenylbutyric acid. Yellow solid. Melting point:
142-145.degree. C.
Example 24
[0442] 3-anilinophenyl
4-(4-{[amino(2-thienyl)methylidene]amino}-phenyl)bu- tanoate:
24
[0443] The experimental protocol used is the same as that described
for Example 14, starting from 3-hydroxy-diphenylamine and
4-nitrophenylbutyric acid. White solid. Melting point:
110-112.degree. C.
Example 25
[0444]
2-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(9H-carbazol--
4-yloxy)ethyl]acetamide hydrochloride: 25
[0445] 25.1) 3-(2-bromoethoxy)-9H-carbazole:
[0446] A mixture of 1.83 g (10 mmol) of 4-hydroxycarbazole (J.
Chem. Soc. (1955), 3475-3477; J. Med. Chem. (1964) 7, 158-161),
1.08 ml (12.5 mmol) of 1,2-dibromoethane and 2.6 ml (10.5 mmol) of
a 4 M aqueous solution of NaOH in 2 ml of water is heated under
reflux for 5 hours. After the temperature returns to 20.degree. C.,
the product is extracted using 2 times 30 ml of CH.sub.2Cl.sub.2.
The organic solutions collected are then successively washed with
20 ml of water and 20 ml of salt water. After drying over
MgSO.sub.4, filtration and concentration under vacuum, the residue
is purified on a silica column (eluent: heptane/AcOEt: 80/20). A
beige powder is obtained with a yield of 32%. Melting point:
135-136.degree. C.
[0447] 25.2) 3-(2-azidoethoxy)-9H-carbazole:
[0448] A mixture of 0.9 g (3.1 mmol) of intermediate 25.1 and 0.20
g (3.1 mmol) of NaN.sub.3 in 10 ml of DMF is heated at 70.degree.
C. for 1 hour. The whole is then poured into 30 ml of a mixture of
water and ice. After the addition of 50 ml of AcOEt and agitation,
the organic phase is decanted and washed successively with 20 ml of
water and 20 ml of salt water. The organic solution is then dried
over Na.sub.2SO.sub.4, filtered and concentrated under vacuum.
After drying, a beige powder is obtained (quantitative yield) which
is used as is in the following stage.
[0449] 25.3) 2-(9H-carbazol-3-yloxy)ethylamine:
[0450] A solution of intermediate 25.2 in 50 ml EtOH as well as 0.3
g Pd/C (10%) are introduced into a stainless steel autoclave
equipped with a magnetic stirrer. The reaction mixture is agitated
for 2 hours under 1.5 bar H.sub.2 at a temperature of 25.degree. C.
The Pd/C is then eliminated by filtration and the filtrate is
concentrated under vacuum until dryness. The residue is taken up in
ethyl ether and the crystals formed are filtered and abundantly
rinsed with ethyl ether. After drying, a white powder is obtained
with a yield of 82%. Melting point: 145-146.degree. C.
[0451] 25.4)
2-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(9H-car-
bazol-4-yloxy)ethyl]acetamide hydrochloride:
[0452] The experimental protocol used is the same as that described
for Example 2, starting from intermediate 25.3 and
4-nitrophenylbutyric acid. Light beige solid. Melting point:
233-234.degree. C.
Example 26
[0453]
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-anilinobenzam-
ide hydrochloride: 26
[0454] The experimental protocol used is the same as that described
for Example 2, starting from N-phenylanthranilic acid and
4-nitrophenethylamine. Pale yellow solid. Melting point:
163-165.degree. C.
Example 27
[0455]
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-(2,3-dimethyl-
anilino)benzamide hydrochloride: 27
[0456] The experimental protocol used is the same as that described
for Example 2, starting from mefenamic acid and
4-nitrophenethylamine. Pale yellow solid. Melting point:
168-170.degree. C.
Example 28
[0457]
N'-{4-[4-(2-anilinobenzoyl)-1-piperazinyl]phenyl}-2-thiophenecarbox-
imidamide dihydrochloride: 28
[0458] The experimental protocol used is the same as that described
for Example 2, starting from N-phenylanthranilic acid and
4-nitrophenylpiperazine. Pale yellow solid. Melting point:
168-170.degree. C.
Example 29
[0459]
N'-(4-{4-[2-(2,3-dimethylanilino)benzoyl]-1-piperazinyl}phenyl)-2-t-
hiophenecarboximidamide dihydrochloride: 29
[0460] The experimental protocol used is the same as that described
for Example 2, starting from mefenamic acid and
4-nitrophenylpiperazine. Pale yellow solid. Melting point:
166-168.degree. C.
Example 30
[0461]
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(4-phenoxyphenyl-
)butanamide hydrochloride: 30
[0462] The experimental protocol used is the same as that described
for Example 14, starting from 4-nitrophenylbutyric acid and
4-phenoxyphenol. Pale yellow solid. Melting point: 119-123.degree.
C.
Example 31
[0463]
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-4-(4-hydroxyphe-
noxy)benzamide hydrochloride: 31
[0464] The experimental protocol used is the same as that described
for Example 2, starting from 4-(4-hydroxyphenoxy)benzoic acid and
4-nitrophenethylamine. Pale yellow solid. Melting point:
155-157.degree. C.
Example 32
[0465] N-[2-(9H-carbazol-4-yloxy)ethyl]-2-thiophenecarboximidamide:
32
[0466] The experimental protocol used is the same as that described
for intermediate 2.3, starting from intermediate 25.3. The expected
product is isolated in the form of a free base. White solid.
Melting point: 180-181.degree. C.
Example 33
[0467]
N-[3-(9H-carbazol-4-yloxy)propyl]-2-thiophenecarboximidamide:
33
[0468] 33.1)
2-[3-(9H-carbazol-4-yloxy)propyl]-1H-isoindole-1,3(2H)dione:
[0469] 1 g (5.46 mmol) of 4-hydroxycarbazole (J. Chem. Soc. (1955),
3475-3477; J. Med. Chem. (1964) 7, 158-161) is added to a
suspension, under argon, of 0.23 g (5.73 mmol) of NaH (60%) in 20
ml anhydrous DMF. After agitation for 30 minutes at 20.degree. C.,
1.46 g (5.46 mmol) of 3-bromopropylphtalimide in solution in 10 ml
of anhydrous DMF is added dropwise to the reaction mixture. The
whole is heated at 80.degree. C. for 16 hours. After the
temperature returns to 20.degree. C., 5 ml of water is added and
the mixture is concentrated under vacuum. The residue is taken up
in 300 ml of CH.sub.2Cl.sub.2 and the organic solution is washed
successively with 50 ml of 1M NaOH, 100 ml of water and 100 ml of
salt water. After drying over MgS0.sub.4, filtration and
concentration under vacuum, an oily residue is obtained which
slowly crystallizes. The crystals are washed using ethyl ether. A
beige solid is obtained with a yield of 40%. Melting point:
171-172.degree. C.
[0470] 33.2) 3-(9H-carbazol-4-yloxy)propylamine:
[0471] A solution of 0.13 ml (3.24 mmol) hydrazine hydrate in 5 ml
ethanol is added dropwise to a solution of 0.8 g (2.16 mmol) of
intermediate 33.1 in 30 ml ethanol, heated to reflux. The reaction
mixture is agitated and heated under reflux for 4 hours. After the
temperature returns to 20.degree. C., the product is partitioned
between 100 ml of AcOEt and 50 ml of 1M NaOH. After decanting, the
organic phase is washed successively with 50 ml water and 50 ml
salt water. The organic solution is dried over Na.sub.2SO.sub.4,
filtered and concentrated under vacuum. A beige powder is obtained
with a yield of 41%. Melting point: 146-147.degree. C.
[0472] 33.3)
N-[3-(9H-carbazol-4-yloxy)propyl]-2-thiophenecarboximidamide:
[0473] The experimental protocol used is the same as that described
for intermediate 2.3, starting from intermediate 33.2. The expected
product is isolated in the form of a free base. Pale beige solid.
Melting point: 189-190.degree. C.
Example 34
[0474]
N-{4-[4-(10H-phenothiazin-2-yloxy)butyl]phenyl}-2-thiophenecarboxim-
idamide hydroiodide: 34
[0475] The experimental protocol used is the same as that described
for Example 15, starting from 4-(4-nitrophenyl)-1-butanol and
2-hydroxy10H-phenothiazine (J. Med. Chem. (1992) 35, 716). The
expected final product precipitates directly from the reaction
mixture, it is isolated by filtration and washed using iPrOH.
Yellow solid. Melting point: 262-270.degree. C.
Example 35
[0476]
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-anili-
nophenyl)propanamide trihydrochloride: 35
[0477] 35.1) tert-butyl 3-(4-anilinoanilino)-3-oxopropyl
carbamate:
[0478] The experimental protocol used is the same as that described
for intermediate 2.1, starting from Boc-.beta.-Alanine and
4-aminodiphenylamine. After rapid filtration on a silica column
(eluent: Heptane/AcOEt: 1/1), the expected product is obtained with
a quantitative yield.
[0479] 35.2) 3-amino-N-(4-anilinophenyl)propanamide:
[0480] 15 g (42.2 mmol) of intermediate 35.1 is dissolved in 300 ml
of AcOEt and 120 ml of an aqueous 6 N HCl solution is added. The
reaction mixture is agitated vigorously, at 20.degree. C., for 1
hour. After decantation, the aqueous phase is recovered and made
basic (pH>11) by the addition of an aqueous 2 M NaOH solution.
The product is then extracted using 2 times 50 ml of
CH.sub.2Cl.sub.2 and the organic phase is washed with 50 ml of salt
water. Afters drying over MgSO.sub.4, filtration and concentration
under vacuum, the residue is purified on a silica column (eluent :
CH.sub.2Cl.sub.2/EtOH/NH.sub.4OH (20%): 20/5/0.5). A violet powder
is obtained with a yield of 73%. Melting point: 108-110.degree.
C.
[0481] 35.3)
N-(4-anilinophenyl)-3-[(3-nitrobenzyl)amino]propanamide:
[0482] 1.40 g (5.5 mmol) of intermediate 35.2, 0.92 g (6 mmol) of
3-nitrobenzaldehyde and 3 g of 4 .ANG. pulverulent molecular sieve
which has been activated beforehand are added successively, under
inert atmosphere, into a flask containing 100 ml anhydrous MeOH.
The reaction mixture is agitated vigorously for 15 hours before the
addition, by portions, of 0.24 g (6 mmol) of NaBH.sub.4. Agitation
is maintained for another 4 hours before the addition of 10 ml of
water. After a quarter of an hour, the sieve is filtered out and
the reaction mixture is extracted twice with 100 ml
CH.sub.2Cl.sub.2. The organic phase is washed successively with 50
ml of water and 50 ml of salt water, dried over sodium sulphate,
filtered and concentrated under vacuum. The residue is purified on
a silica column (eluent: CH.sub.2Cl.sub.2/EtOH: 20/1). An orange
oil is obtained with a yield of 94%.
[0483] 35.4)
3-[(3-aminobenzyl)amino]-N-(4-anilinophenyl)propanamide:
[0484] Reduction of the nitro function of intermediate 35.3 is
carried out in the presence of Pd/C in ethanol, under the
conditions described for intermediate 2.2. After filtration of the
Pd/C and concentration under vacuum, the product is directly used
in the following stage.
[0485] 35.5)
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-
-anilinophenyl)propanamide trihydrochloride:
[0486] 0.50 g (1.40 mmol) of intermediate 35.4 and 0.50 g (1.75
mmol) of S-methyl-2-thiophene thiocarboximide hydroiodide are
dissolved in 15 ml isopropanol and 15 ml DMF in a 50 ml flask, in
the presence of 0.11 ml (1.40 mmol) of pyridine. The reaction
mixture is agitated for 20 hours at 23.degree. C. After evaporation
of the solvent under vacuum, the residue is taken up in 100 ml of a
mixture of NaOH 1N and ethyl acetate (1/1). After decantation, the
organic phase is washed with 50 ml of water followed by 50 ml of
salt water. The organic solution is dried over magnesium sulphate,
filtered, concentrated under vacuum and the residue is purified on
a silica gel column (eluent: CH.sub.2Cl.sub.2/EtOH/NH.sub.- 4OH
(20%): 20/5/0.5). The pure fractions are collected and concentrated
under vacuum. The compound is then dissolved in methanol and
salified by the addition of a 1N HCl solution in ethyl ether (10
ml). After agitation for one hour at 20.degree. C., the reaction
mixture is concentrated under vacuum to produce a pale yellow
powder. Melting point: 184-186.degree. C.
Example 36
[0487]
N'-(4-{2-[(10H-phenothiazin-3-ylmethyl)amino]ethyl}phenyl)-2-thioph-
enecarboximidamide: 36
[0488] The experimental protocol used is the same as that described
for intermediates 35.3, 35.4 and 35.5, starting from
10H-phenothiazine-3-carb- aldehyde (J. Chem. Soc. (1951), 1834 ;
Bull. Soc. Chim. Fr. (1969), 1769) and 4-nitrophenethylamine. Beige
foam. MS: MH.sup.+: 457.1.
Example 37
[0489]
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-methoxy-10H-p-
henothiazine-1-carboxamide hydrochloride: 37
[0490] The experimental protocol used is the same as that described
for Example 2, starting from
2-methoxy-10H-phenothiazine-1-carboxylic acid (J. Med. Chem. (1992)
35(4), 716-724) and 4-nitrophenethylamine. Pale yellow solid.
Melting point >200.degree. C. (decomposition).
Example 38
[0491]
N'-[4-(2-{[(2-methoxy-10H-phenothiazin-1-yl)methyl]amino}ethyl)phen-
yl]-2-thiophenecarboximidamide: 38
[0492] 38.1) 2-methoxy-10H-phenothiazine-1-carbaldehyde:
[0493] 4.6 g (20 mmol) of 2-methoxy-10H-phenothiazine are
dissolved, under an argon atmosphere, in a three-necked flask,
containing 140 ml anhydrous ethyl ether. 20 ml (50 mmol) of a
solution of nBuLi (2.5 M) in hexane is then added dropwise, at
20.degree. C. The reaction mixture is agitated for 3 hours at
20.degree. C. before the dropwise addition of 6.2 ml (80 mmol) of
anhydrous DMF. Agitation is maintained for another 15 hours at
20.degree. C. The whole is then poured into 150 ml ice-cooled water
and the product is extracted twice using 200 ml of ethyl acetate.
The organic solution is washed with 100 ml of salt water, dried
over MgSO.sub.4, filtered and concentrated under vacuum. The
evaporation residue is taken up in diisopropyl ether, filtered and
dried to produce a red solid with a yield of 30%. Melting point:
155-160.degree. C.
[0494] 38.2)
N'-[4-(2-{[(2-methoxy-10H-phenothiazin-1-yl)methyl]amino}ethy-
l)phenyl]-2-thiophenecarboximidamide:
[0495] The experimental protocol used is the same as that described
for Example 36, starting from intermediate 38.1 and
4-nitrophenethylamine. Grey solid. MS: MH.sup.+: 487.2.
Example 39
[0496]
N'-{4-[(10H-phenothiazin-2-yloxy)methyl]phenyl}-2-thiophenecarboxim-
idamide: 39
[0497] 39.1) 2-[(4-nitrobenzyl)oxy]-10H-phenothiazine:
[0498] 1.08 g (5 mmol) of 2-hydroxy10H-phenothiazine (J. Med. Chem.
(1992) 35, 716) is dissolved, under argon atmosphere, in 20 ml
anhydrous THF in a flask. The solution is then cooled down to
0.degree. C. and 0.22 g (5.5 mmol) of NaH (60%) is added by
portions. After agitation for 15 minutes, 1.2 g (5.5 mmol) of
4-nitrobenzyl bromide is added by portions and the reaction mixture
is agitated for 15 hours at 20.degree. C. before being poured into
50 ml of ice-cooled water. The product is extracted twice with 25
ml CH.sub.2Cl.sub.2 and the organic solution is washed successively
with 25 ml of water and 25 ml of salt water. After drying over
MgSO.sub.4, filtration and concentration under vacuum, the
evaporation residue is purified on a silica column (eluent:
CH.sub.2Cl.sub.2/EtOH: 99/1 to 98/2). After concentration of the
purest fractions, a maroon solid is obtained, which is
recrystallized using isopropyl acetate. A maroon solid is finally
obtained with a yield of 37%.
[0499] 39.2) 4-[(10H-phenothiazin-2-yloxy)methyl]aniline:
[0500] 1.02 g (4.52 mmol) of SnCl.sub.2.2H.sub.2O and 0.29 g (4.52
mmol) of Zn are added successively to a solution of 0.65 g (1.86
mmol) of intermediate 39.1 in a mixture of 9.3 ml of acetic acid
and 1.2 ml of HCl (12 N). The whole is agitated for 18 hours at
20.degree. C. The reaction mixture is then made basic by the
addition of a 30% aqueous NaOH solution. The product is then
extracted twice using 50 ml of CH.sub.2Cl.sub.2. The organic
solution is washed with 50 ml of salt water, dried over MgSO.sub.4,
filtered and concentrated under vacuum. The residue is purified on
a silica column (eluent: Heptane/AcOEt: 1/1). A pale yellow solid
is obtained with a yield of 20%. Melting point: >175.degree. C.
(decomposition).
[0501] 39.3)
N'-{4-[(10H-phenothiazin-2-yloxy)methyl]phenyl}-2-thiopheneca-
rboximidamide:
[0502] The experimental protocol used is the same as that described
for intermediate 2.3, starting from intermediate 39.2. Salmon-pink
solid. Melting point: 105-116.degree. C.
[0503] Pharmacological Study of the Products of the Invention
[0504] Study of the Effects on Neuronal Constitutive NO Synthase of
a Rat's Cerebellum
[0505] The inhibitory activity of the products of the invention is
determined by measuring their effects on the conversion by NO
synthase of [.sup.3H]L-arginine into [.sup.3H]L-citrulline
according to the modified method of Bredt and Snyder (Proc. Natl.
Acad. Sci. USA, (1990) 87: 682-685). The cerebellums of
Sprague-Dawley rats (300 g--Charles River) are rapidly removed,
dissected at 4.degree. C. and homogenized in a volume of extraction
buffer (HEPES 50 mM, EDTA 1 mM, pH 7.4, pepstatin A 10 mg/ml,
leupeptin 10 mg/ml). The homogenates are then centrifuged at 21000
g for 15 min at 4.degree. C. Dosage is carried out in glass test
tubes in which 100 .mu.l of incubation buffer containing 100 mM of
HEPES (pH 7.4), 2 mM of EDTA, 2.5 mM of CaCl.sub.2, 2 mM of
dithiotreitol, 2 mM of reduced NADPH and 10 .mu.g/ml of calmodulin
are distributed. 25 .mu.l of a solution containing 100 nM of
[.sup.3H]L-arginine (Specific activity: 56.4 Ci/mmol, Amersham) and
40 .mu.M of non-radioactive L-arginine is added. The reaction is
initiated by adding 50 .mu.l of homogenate, the final volume being
200 .mu.l (the missing 25 .mu.l are either water or the tested
product). After 15 min, the reaction is stopped with 2 ml of
stopping buffer (20 mM of HEPES, pH 5.5, 2 mM of EDTA). After
passing the samples through a 1 ml column of DOWEX resin, the
radioactivity is quantified by a liquid scintillation spectrometer.
The compounds of examples 3 to 5, 7, 9 to 12, 15, 16, 18, 19, 21,
22, 26, 27, 30, 31 and 35 to 37 described above show an IC.sub.50
lower than 3.5 .mu.M.
[0506] Study of the Effects on Lipidic Peroxidation of the Cerebral
Cortex of a Rat
[0507] The inhibitory activity of the products of the invention is
determined by measuring their effects on the degree of lipidic
peroxidation, determined by the concentration of malondialdehyde
(MDA). The MDA produced by peroxidation of unsaturated fatty acids
is a good indication of lipidic peroxidation (H Esterbauer and K H
Cheeseman, Meth. Enzymol. (1990) 186: 407-421). Male Sprague Dawley
rats weighing 200 to 250 g (Charles River) were sacrificed by
decapitation. The cerebral cortex is removed, then homogenized
using a Thomas potter in a 20 mM Tris-HCl buffer, pH=7.4. The
homogenate was centrifuged twice at 50000 g for 10 minutes at
4.degree. C. The pellet is stored at -80.degree. C. On the day of
the experiment, the pellet is replaced in suspension at a
concentration of 1 g/15 ml and centrifuged at 515 g for 10 minutes
at 4.degree. C. The supernatant is used immediately to determine
the lipidic peroxidation. The homogenate of rat's cerebral cortex
(500 .mu.l) is incubated at 37.degree. C. for 15 minutes in the
presence of the compounds to be tested or of solvent (10 .mu.l).
The lipidic peroxidation reaction is initiated by adding 50 .mu.l
of FeCl.sub.2 at 1 mM, EDTA at 1 mM and ascorbic acid at 4 mM.
After incubation for 30 minutes at 37.degree. C., the reaction is
stopped by adding 50 .mu.l of a solution of hydroxylated di tertio
butyl toluene (BHT, 0.2%). The MDA is quantified using a
colorimetric test, by reacting a chromogenic reagent (R),
N-methyl-2-phenylindol (650 .mu.l) with 200 .mu.l of the homogenate
for 1 hour at 45.degree. C. The condensation of an MDA molecule
with two molecules of reagent R produce a stable chromophore the
maximum absorbence wavelength of which is equal to 586 nm.
(Caldwell et al. European J. Pharmacol. (1995) 285, 203-206). The
compounds of Examples 1 to 9, 12 to 19, 21 to 23, 30 and 35 to 37
described above show an IC.sub.50 lower than 30 .mu.M.
* * * * *