U.S. patent application number 11/410659 was filed with the patent office on 2006-10-19 for inhibitors of cdc25 phosphatases.
This patent application is currently assigned to SCRAS. Invention is credited to Marie-Christine Brezak Pannetier, Bernard Ducommun, Marie-Odile Galcera Contour, Francoise Goubin Gramatica, Christophe Lanco, Gregoire Prevost, Christophe Thurieau.
Application Number | 20060235027 11/410659 |
Document ID | / |
Family ID | 8853011 |
Filed Date | 2006-10-19 |
United States Patent
Application |
20060235027 |
Kind Code |
A1 |
Prevost; Gregoire ; et
al. |
October 19, 2006 |
Inhibitors of cdc25 phosphatases
Abstract
A method of inhibiting cdc25 phosphatases in warm-blooded
animals comprising administering to warm-blooded animals in need
thereof an effective amount of a compound of the formula ##STR1##
wherein the substituents are defined as in the specification.
Inventors: |
Prevost; Gregoire; (Antony,
FR) ; Brezak Pannetier; Marie-Christine; (Antony,
FR) ; Galcera Contour; Marie-Odile; (Bondoufle,
FR) ; Thurieau; Christophe; (Paris, FR) ;
Goubin Gramatica; Francoise; (Agen, FR) ; Ducommun;
Bernard; (Belberaud, FR) ; Lanco; Christophe;
(Dourdan, FR) |
Correspondence
Address: |
Charles A. Muserlian;c/o Hedman and Costigan
1185 Avenue of the Americas
New York
NY
10036
US
|
Assignee: |
SCRAS
|
Family ID: |
8853011 |
Appl. No.: |
11/410659 |
Filed: |
April 25, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10343171 |
Jan 27, 2003 |
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PCT/FR01/02443 |
Jul 26, 2001 |
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11410659 |
Apr 25, 2006 |
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Current U.S.
Class: |
514/255.01 ;
514/255.02; 514/319; 514/618; 514/620 |
Current CPC
Class: |
C07F 9/12 20130101; A61P
35/00 20180101; A61P 21/00 20180101; A61K 31/495 20130101; A61K
31/63 20130101; A61P 25/00 20180101; A61P 35/02 20180101; A61P
25/28 20180101; C07D 233/84 20130101; A61K 31/165 20130101; A61P
31/12 20180101; C07C 311/37 20130101; A61P 43/00 20180101; C07C
229/36 20130101; C07C 217/84 20130101; C07C 311/21 20130101; A61P
33/00 20180101; A61K 31/381 20130101; C07C 311/29 20130101; C07C
235/66 20130101; C07D 333/22 20130101; C07D 295/135 20130101; C07D
295/192 20130101; C07C 311/08 20130101; A61K 31/18 20130101; A61K
31/445 20130101; C07D 295/26 20130101; C07D 333/34 20130101; A61K
31/137 20130101; C07C 311/13 20130101; A61P 17/14 20180101 |
Class at
Publication: |
514/255.01 ;
514/618; 514/620; 514/319; 514/255.02 |
International
Class: |
A61K 31/495 20060101
A61K031/495; A61K 31/445 20060101 A61K031/445; A61K 31/165 20060101
A61K031/165 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 28, 2000 |
FR |
00/09900 |
Claims
1. A method of inhibiting cdc 25 phosphatases in warm-blooded
animals comprising administering to warm-blooded animals in need
thereof an amount of a compound of the formula ##STR63## wherein A
is ##STR64## wherein two of R.sup.1, R.sup.2, R.sup.3, R.sup.4, and
R.sup.5 are hydrogen and the other three are independently selected
from the group consisting of hydrogen, halogen, alkyl, hydroxy,
alkoxy, alkylcarbonyloxy, alkylthio and --NR.sup.6R.sup.7, it being
understood that: either R.sup.1 and one of R.sup.2 and R.sup.4 are
independently selected from the group consisting of hydroxy,
alkylcarbonyloxy and --NR.sup.6R.sup.7, or R.sup.2 and one of
R.sup.3 and R.sup.5 are independently selected from the group
consisting of hydroxy, alkylcarbonyloxy and --NR.sup.6R.sup.7, or
R.sup.4 and one of R.sup.3 and R.sup.5 are independently selected
from the group consisting of hydroxy, alkylcarbonyloxy and
--NR.sup.6R.sup.7, or also one of R.sup.1, R.sup.3 and R.sup.5 is
selected from the group consisting of hydroxy, alkylcarbonyloxy and
--NR.sup.6R.sup.7, and B--N(W)--X--Y remainder is attached to A by
nitrogen, R.sup.6 and R.sup.7 are independently each time that they
occur a hydrogen or alkyl or R.sup.6 and R.sup.7 together with the
nitrogen atom form a heterocycle of 4 to 7 ring members comprising
1 to 2 heteroatoms, the members necessary to complete the
heterocycle being independently selected from the group consisting
of --CR.sup.8R.sup.9--, --O--, --S-- and --NR.sup.10--, R.sup.8 and
R.sup.9 independently are each time that they occur selected from
the group consisting of hydrogen, alkyl, alkoxy,
benzyloxycarbonylamino and dialkylamino, and R.sup.10 independently
is each time that it occurs hydrogen or alkyl, wherein either
R.sup.11 and one of R.sup.13, R.sup.14 and R.sup.15 are hydroxy
while R.sup.13, R.sup.14 and R.sup.15 as well as R.sup.16 are
hydrogen, or R.sup.12 and R.sup.16 are hydroxy while R.sup.11,
R.sup.13, R.sup.14 and R.sup.15 are hydrogen; B is
--(CH.sub.2).sub.p-- and p is an integer from 0 to 1; W is hydrogen
or alkyl; X is selected from the group consisting of
--(CH.sub.2).sub.q--, --(CH.sub.2).sub.q--NH and
--CO--(CH.sub.2).sub.r--, q is an integer from 1 to 6 and r is an
integer from 0 to 6; or B--N(W)--X--Y is ##STR65## wherein B is as
defined above, t is an integer from 0 to 2, s is an integer from 0
to 1 and R.sup.17 and R.sup.18 are independently hydrogen or alkyl;
and: when X is --(CH.sub.2).sub.q-- or --CO--(CH.sub.2).sub.r--,
then Y is ##STR66## wherein R.sup.19 is selected from the group
consisting of hydrogen, halogen, nitro, alkyl, alkylthio,
--NR.sup.21R.sup.22, --SO.sup.2--NR.sup.22R.sup.24,
--NH--SO.sup.2--R.sup.25 and --O--P(O)(OR.sup.26)(OR).sup.27,
R.sup.21 and R.sup.22 independently are hydrogen or alkyl, R.sup.23
and R.sup.24 independently are hydrogen or alkyl, or R.sup.23 and
R.sup.24 representing together with the nitrogen atom which carries
them a heterocycle with 5 to 7 ring members, the additional members
are independently selected from the group consisting of
--CHR.sup.28--, --NR.sup.29--, --O-- and --S--, R.sup.28-- and
R.sup.29 are independently each time that they occur, hydrogen or
alkyl, R.sup.25 is selected from the group consisting of alkyl,
haloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, the aryl or
heteroaryl nucleus of which is optionally substituted by at least
one member independently selected from the group consisting of
halogen, alkyl, haloalkyl, hydroxy, alkoxy and nitro, except for
the optional nitrogen atoms of the heteroaryl nucleus for which the
optional substituents are alkyl, R.sup.26 and R.sup.27 are
independently alkyl, and R.sup.20 is selected from the group
consisting of hydrogen, halogen, alkyl, alkoxy and alkylthio, when
X is --(CH.sub.2).sub.q--NH-- or when B--N(W)--X--Y is ##STR67##
then Y exclusively is --SO.sub.2--R.sup.30 wherein R.sup.30 is
selected from the group consisting of alkyl, haloalkyl, aryl,
heteroaryl, aralkyl and heteroaralkyl, the aryl or heteroaryl
nucleus of which is optionally substituted by at least one member
independently selected from the group consisting of halogen, alkyl,
haloalkyl, hydroxy, alkoxy and nitro, except for the optional
nitrogen atoms of the heteroaryl nucleus for which the optional
substituents are alkyl; it being understood that when B--N(W)--X--Y
is ##STR68## then B is --(CH.sub.2)--; or a pharmaceutically
acceptable salt thereof sufficient to inhibit cdc25
phosphatases.
2. The method of claim 1, wherein: A is ##STR69## wherein two of
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are hydrogen and the
other three are independently selected from the group consisting of
hydrogen, halogen, alkyl, alkylcarbonyloxy, hydroxy, alkoxy and
NR.sup.6R.sup.7, it being understood that: either R.sup.1 and one
of R.sup.2 and R.sup.4 are independently selected from the group
consisting of hydroxy, alkylcarbonyloxy and --NR.sup.6R.sup.7, or
R.sup.2 and one of R.sup.3 and R.sup.5 are independently selected
from the group consisting of hydroxy, alkylcarbonyloxy and
--NR.sup.6R.sup.7, or R.sup.4 and one of R.sup.3 and R.sup.5 are
independently selected from the group consisting of hydroxy,
alkylcarbonyloxy and --NR.sup.6R.sup.7, or one of R.sup.1, R.sup.3
and R.sup.5 is independently selected from the group consisting of
hydroxy, alkylcarbonyloxy and --NR.sup.6R.sup.7, and B--N(W)--X--Y
remainder is attached to A by nitrogen, R.sup.6 and R.sup.7 are
independently each time that they occur, hydrogen or alkyl or
R.sup.6 and R.sup.7 together with the nitrogen atom form a
heterocycle with 5 to 7 ring members comprising 1 to 2 heteroatoms,
the members necessary to complete the heterocycle being
independently selected from the group consisting of
--CR.sup.8R.sup.9--, --O--, --S--, and --NR.sup.10--, R.sup.8 and
R.sup.9 independently each time that they occur hydrogen or alkyl
or alkoxy, and R.sup.10 independently is each time that it occurs
hydrogen or alkyl, or A is ##STR70## wherein either R.sup.11 and
one of R.sup.13, R.sup.14 and R.sup.15 is hydroxy while the other
R.sup.13, R.sup.14 and R.sup.15 as well as R.sup.16 are hydrogen,
or R.sup.12 and R.sup.16 are hydroxy while R.sup.11, R.sup.13,
R.sup.14 and R.sup.15 are hydrogen; B is --(CH.sub.2).sub.p, p is
an integer from 0 to 1; W is hydrogen or alkyl; X is selected from
the group consisting of --(CH.sub.2).sub.q--,
--(CH.sub.2).sub.q--NH-- and --CO--(CH.sub.2).sub.r, q is an
integer from 1 to 4 and r is an integer from 0 to 5; or
B--N(W--X--Y is ##STR71## wherein B is as defined in claim 1, t is
an integer from 0 to 2, s is an integer from 0 to 1, R.sup.17 and
R.sup.18 are independently hydrogen or alkyl; when X is
--(CH.sub.2).sub.q-- or --CO--(CH.sub.2).sub.r--, Y is ##STR72##
wherein R.sup.19 is hydrogen, halogen, nitro, alkyl, alkylthio,
--NR.sup.21R.sup.22, --SO.sub.2--NR.sup.23R.sup.24,
--NH--SO.sub.2--R.sup.25 and --O--P(O)(OR.sup.26)(OR.sup.27),
R.sup.21 and R.sup.22 independently are hydrogen or alkyl, R.sup.23
and R.sup.24 independently are hydrogen or alkyl, or R.sup.23 and
R.sup.24 together with the nitrogen atom which carries them form a
heterocycle with 5 to 6 ring members, the additional members of
which are independently selected from the group consisting of
--CHR.sup.28--, NR.sup.29--, --O-- and --S--, R.sup.28 and R.sup.29
are independently each time that they occur, hydrogen or alkyl,
R.sup.25 is alkyl or aryl optionally substituted by at least one
member selected from the groups consisting of halogen, alkyl,
haloalkyl, alkoxy and nitro, except for the optional nitrogen atoms
of the heteroaryl nucleus for which the optional substituents are
alkyl, R.sup.26 and R.sup.27 are independently alkyl, and R.sup.20
is hydrogen or alkyl or alkoxy, when X is a
--(CH.sub.2).sub.q--NH-- or B--N(W)--X--Y is ##STR73## then Y is
--SO.sub.2--R.sup.30, R.sup.30 is selected from the group
consisting of alkyl, haloalkyl, aryl, heteroaryl, aralkyl and
heteroaralkyl the aryl or heteroaryl nucleus of which is optionally
substituted by at least one member independently selected from the
group consisting of halogen, alkyl, haloalkyl, alkoxy and nitro,
except for the optional nitrogen atoms of the heteroaryl nucleus
for which the optional substituents are alkyl.
3. The method of claim 1, wherein the compound is selected from the
group consisting of:
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)-phenol;
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
4-(dimethylamino)-2-methoxy-6-({[2-(4-nitrophenyl)ethyl]amino}methyl)phen-
ol;
4-(dimethylamino)-2-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
2-(dimethylamino)-6-methoxy-4-({methyl[2-(4-nitrophenyl)ethyl]amino}-meth-
yl)phenol;
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol;
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}-meth-
yl)phenyl acetate; or a pharmaceutically acceptable salt
thereof.
4. The method of claim 1 wherein Y is not (T) and the condition to
be treated is selected from the group consisting of prostate
cancer, pancreatic cancer, breast cancer, lymphoma and head and
neck cancer.
5. The method of claim 1 wherein Y is (T), and the condition being
treated is spontaneous alopecia, alopecia induced by exogenous
products, or radiation-induced alopecia.
6-8. (canceled)
9. Pharmaceutical composition characterized in that it comprises,
as active ingredient, one of the following compounds:
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)phenol;
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)phenol;
4-(4-aminophenyl)-N-[4-(4-methyl-1-piperazinyl)phenyl]butanamid- e;
4-(dimethylamino)-2-methoxy-6-({[2-(4-nitrophenyl)ethyl]amino}methyl)p-
henol;
4-(dimethylamino)-2-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
2-(dimethylamino)-6-methoxy-4-({methyl[2-(4-nitrophenyl)ethyl]amino}meth-
yl)phenol;
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol;
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)phenyl acetate;
3,7-dihydroxy-N-[2-(4-nitrophenyl)ethyl]-2-naphthamide;
N-[4-(dimethylamino)benzyl]-3,7-dihydroxy-2-naphthamide; diethyl
4-{2-[(3,7-dihydroxy-2-naphthoyl)amino]ethyl}phenylphosphate;
N-{2-[4-(aminosulphonyl)phenyl]ethyl}-3,7-dihydroxy-2-naphthamide;
3,7-dihydroxy-N-[2-(4-aminophenyl)ethyl]-2-naphthamide;
3,7-dihydroxy-N-(2-{4-[(methylsulphonyl)amino]phenyl}ethyl)-2-naphthamide-
;
N-(2-{4-[(butylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamid-
e;
3,7-dihydroxy-N-[2-(4-{[(4-methylphenyl)sulphonyl]amino}phenyl)ethyl]--
2-naphthamide;
3,7-dihydroxy-N-(2-{4-[(1-naphthylsulphonyl)amino]phenyl}ethyl)-2-naphtha-
mide;
3,7-dihydroxy-N-{2-[4-({[2-(trifluoromethyl)phenyl]sulphonyl}amino)-
phenyl]ethyl}-2-naphthamide;
N-(2-{4-[(benzylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamide-
;
3,7-dihydroxy-N-{2-[4-({[3-(trifluoromethyl)phenyl]sulphonyl}amino)phen-
yl]ethyl}-2-naphthamide;
3,7-dihydroxy-N-[2-(4-{[(4-nitrophenyl)sulphonyl]amino}phenyl)ethyl]-2-na-
phthamide;
3,7-dihydroxy-N-{2-[4-({[4-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide;
3,7-dihydroxy-N-(2-{4-[(thien-2-ylsulphonyl)amino]phenyl}ethyl)-2-naphtha-
mide;
3,7-dihydroxy-N-[2-(4-{[(4-methoxyphenyl)sulphonyl]amino}phenyl)eth-
yl]-2-naphthamide;
3,7-dihydroxy-N-[2-(4-{[(1-methyl-1H-imidazol-4-yl)sulphonyl]amino}phenyl-
)ethyl]-2-naphthamide;
N-[2-(4-{[(4-fluorophenyl)sulphonyl]amino}phenyl)ethyl]-3,7-dihydroxy-2-n-
aphthamide;
3,7-dihydroxy-N-{3-[(4-methyl-1-piperidinyl)sulphonyl]benzyl}-2-naphthami-
de;
3-({4-[(4-methylphenyl)sulphonyl]piperazin-1-yl}carbonyl)naphthalene--
2,6-diol;
3-{[4-(methylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6--
diol;
3-{[4-(butylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-diol;
or pharmaceutically acceptable salt of one of the latter.
10. Pharmaceutical composition comprising, as active ingredient,
5-(4-{[1E)-amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(dimethylamino)-
phenyl]pentanamide or one of its pharmaceutically acceptable
salts.
11. As a new industrial product, a compound of the general formula
(III) ##STR74## in which A is (A1) ##STR75## in which two of
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are hydrogen and the
other three are selected independently from the group consisting of
hydrogen, a halogen, and alkyl, hydroxy, alkoxy, alkylcarbonyloxy,
alkylthio or NR.sup.6R.sup.7, it being understood moreover that:
either R.sup.1 and one of R.sup.2 and R.sup.4 are selected
independently from the group consisting of a hydroxy,
alkylcarbonyloxy and --NR.sup.6R.sup.7, or R.sup.2 and one of
R.sup.3 and R.sup.5 are selected independently from the group
consisting of hydroxy, alkylcarbonyloxy and --NR.sup.6R.sup.7, or
R.sup.4 and one of R.sup.3 and R.sup.5 are selected independently
from the group consisting of a hydroxy, alkylcarbonyloxy and
--NR.sup.6R.sup.7, or also one of R.sup.1, R.sup.3 and R.sup.5 is
selected from the group consisting of a hydroxy, alkylcarbonyloxy
and --NR.sup.6R.sup.7, and B--N(W)--X--Y remainder is attached to A
by nitrogen, R.sup.6 and R.sup.7 being, independently each time
that they occur, a hydrogen or alkyl or R.sup.6 and R.sup.7 forming
together with the nitrogen atom form a heterocycle with 4 to 7
members comprising 1 to 2 heteroatoms, the members necessary to
complete the heterocycle being selected independently from the
group consisting of --CR.sup.8R.sup.9--, --O--, --S--, and
--NR.sup.10--, R.sup.8 and R.sup.9 independently being each time
that they occur a hydrogen or alkyl, alkoxy, benzyloxycarbonylamino
or dialkylamino, and R.sup.10 independently being each time that it
occurs a hydrogen or alkyl, or also A is (A2): ##STR76## in which:
either R.sup.11 and one of R.sup.13, R.sup.14 and R.sup.15 are
hydroxy whilst the others from R.sup.13, R.sup.14 and R.sup.15 as
well as R.sup.16 are hydrogen, or R.sup.12 and R.sup.16 are hydroxy
whilst R.sup.11, R.sup.13, R.sup.14 and R.sup.15 are hydrogen; B is
--CO--, --NH--CO--(CH.sub.2).sub.n-- or --CH.sub.2).sub.p--, n
being an integer from 0 to 3 and p being an integer from 0 to 1; W
is hydrogen or alkyl; X is --(CH.sub.2).sub.q--,
--(CH.sub.2).sub.q--NH-- or --CO--(CH.sub.2).sub.r, q being an
integer from 1 to 6 and r is an integer from 0 to 6; or also
B--N(W--X--Y is such that it represents ##STR77## in which B is as
defined above, t is an integer from 0 to 2, s is an integer from 0
to 1 and R.sup.17 and R.sup.18 selected independently from a
hydrogen and alkyl; and: when X is --(CH.sub.2).sub.q-- or
--CO--(CH.sub.2).sub.r--, then Y is ##STR78## in which R.sup.19 is
--SO.sub.2--NR.sup.23R.sup.24, --NH--SO.sub.2--R.sup.25 or
--O--P(O)(OR.sup.26)(OR.sup.27), R.sup.23 and R.sup.24
independently being hydrogen or alkyl, or R.sup.23 and R.sup.24
being together with the nitrogen atom which carries them form a
heterocycle with 5 to 7 members the additional members of which are
selected independently from the group consisting of --CHR.sup.28--,
--NR.sup.29--, --O-- and --S--, R.sup.28 and R.sup.29 being,
independently each time that they occur, a hydrogen or alkyl,
R.sup.25 being alkyl, haloalkyl or aryl, heteroaryl, aralkyl or
heteroaralkyl aryl or heteroaryl nucleus of which is optionally
substituted by one or more radicals selected independently from the
group consisting of a halogen and alkyl, haloalkyl, hydroxy, alkoxy
or nitro, except for the optional nitrogen atoms of the heteroaryl
nucleus for which the optional substituents are selected from
alkyl, R.sup.26 and R.sup.27 being selected independently from
alkyl, and R.sup.20 is hydrogen, a halogen or alkyl, or alkoxy or
alkylthio; when X is a --(CH.sub.2).sub.q--NH-- or when
B--N(W)--X--Y is such that it is ##STR79## then Y is exclusively
--SO.sub.2--R.sup.30 in which R.sup.30 is selected from the group
consisting of alkyl haloalkyl or aryl, heteroaryl, aralkyl or
heteroaralkyl aryl or heteroaryl nucleus of which is optionally
substituted by one or more members selected independently from the
group consisting of halogen and alkyl, haloalkyl, hydroxy, alkoxy
or nitro, except for the optional nitrogen atoms of the heteroaryl
nucleus for which the optional substituents are selected from alkyl
radicals; it being understood moreover that when B--N(W)--X--Y
group is such that it is ##STR80## then B exclusively is --CO-- or
--(CH.sub.2)--; or a salt of a compound of general formula
(III).
12. (canceled)
13. As a new industrial product, a compound chosen from the
following compounds of general formula (I) of the claim:
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
4-(4-aminophenyl)-N-[4-(4-methyl-1-piperazinyl)phenyl]butanamide;
4-(dimethylamino)-2-methoxy-6-({[2-(4-nitrophenyl)ethyl]amino}methyl)phen-
ol;
4-(dimethylamino)-2-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
2-(dimethylamino)-6-methoxy-4-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)phenol;
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol- ;
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}met-
hyl)phenyl acetate;
3,7-dihydroxy-N-[2-(4-nitrophenyl)ethyl]-2-naphthamide;
N-[4-(dimethylamino)benzyl]-3,7-dihydroxy-2-naphthamide; and the
salts of the latter.
14-17. (canceled)
Description
[0001] A subject of the present invention is new inhibitors of
cdc25 phosphatases, and in particular of cdc25-C phosphatase.
[0002] Control of the transition between the different phases of
the cell cycle during mitosis or meiosis is provided by a group of
proteins, the enzymatic activities of which are associated with
different states of phosphorylation. These states are controlled by
two large classes of enzymes: the kinases and the phosphatases.
[0003] Synchronization of the different phases of the cell cycle
thus allows reorganisation of the cell architecture at each cycle
in all of the living world (microorganisms, yeasts, vertebrates,
plants). Among the kinases, the cyclin-dependent kinases (CDKs)
play a major role in this control of the cell cycle. Their
activities are regulated by their molecular associations with other
proteins called cyclins. In addition, endogenous inhibitors are
capable of preventing these activities. Several inhibitors of this
family of kinases are already identified and studied in several
therapeutic fields such as oncology for preventing the division of
tumour cells (McDonald and el-Deiry, Int. J. Oncol. (2000), 16,
871-886) or also neurobiology for preventing natural or
chemically-induced apoptosis of normal cells (for example the
neurones) (cf. Maas et al., J. Neurochem. (1998), 70, 1401-1410;
Park et al., J. Neurosci. (1997) 17, 1256-1270).
[0004] Moreover, the enzymatic activity of these different CDKs is
controlled by two other families of enzymes which work in
opposition (Jessus and Ozon, Prog. Cell cycle Res. (1995), 1,
215-228). The first groups together kinases such as Wee1 and Mik1
which deactivate the CDKs by phosphorylating certain amino acids
(Den Haese et al., Mol. Biol. Cell (1995), 6, 371-385). The second
groups together phosphatases such as Cdc25 which activate the CDKs
by dephosphorylating tyrosine and threonine residues of CDKs (Gould
et al., Science (1990), 250, 1573-1576). Dephosphorylation will be
carried out in the first instance thanks to a protein/protein
interaction between the cyclin and cdc25, and this complex will in
the second instance target CDK (Morris and Divita, J. Mol. Biol.
(1999), 286, 475-487). In addition, cyclin B is itself
phosphorylated by the Cdc2 kinase (cdk1) to which it is associated
(Borgne et al., J. Biol. Chem. (1999), 274, 11977-11986).
[0005] If a single form of cdc25 is described in yeast, a family of
3 genes, cdc25-A, cdc25-B and cdc25-C, code for the human cdc25
proteins. In addition, variants originating from alternative
splicing of the cdc25B gene have been identified: they are cdc25B1,
cdc25B2 and cdc25B3 (Baldin et al., Oncogene (1997), 14,
2485-2495). The proteins coded by these variants would be localized
differently within the cell (Davezac et al., Oncogene (2000), 19,
2179-2185). cdc25 activity is regulated by the Cdc2 and Cdk2
kinases. But in the absence of cdc2 kinase, the activity of cdc25
can be activated by other kinases (Izumi and Maller, Mol. Biol.
Cell (1995), 6, 215-226). Among these, the chk1 protein
phosphorylates cdc25-C on a serine in position 216, which increases
its affinity for a chaperone protein 14-3-3. This bond neutralises
cdc25-C and consequently maintains the cdk1 enzyme in a
phosphorylated state and therefore inactive, not allowing entry
into mitosis. The chaperone protein allows the complex to pass into
the cytoplasm thanks to a protein unit of nuclear export
(Lopez-Girona et al., Nature (1999), 397, 172-175).
[0006] A chemical inhibitor of chk1 (SB-218070) allows a cell to
continue its cell cycle despite the induction of the DNA break.
This aspect allows the effectiveness of certain cytotoxic compounds
such as campthotecin to be increased (Jackson et al., Cancer Res.
(2000), 60, 566-572).
[0007] The role of cdc25 phosphatases in oncogenesis was described
initially by the Beach group showing that cdc25A and cdc25B by
co-operating with Ha-RASG12V form foci, after transfection of
normal cells (Galaktionov et al., Science (1995), 269, 1575-1577).
The transforming activity of cdc25A and cdc25B is also observed
when transfection is carried out in cells having a lack of the RB1
tumour suppressor gene. In addition, the expression of the cdc25-A
and -B genes appears to be under the direct control of the protein
coded by the c-Myc oncogene (Galaktionov et al., Nature (1996),
382, 511-517). On the other hand, cdc25-C phosphatase does not seem
to be controlled by the latter.
[0008] The overexpression of cdc25, and principally cdc25-A,
appears to prevent the cell from stopping its cell cycle in the
event of aggression on the genome and thus avoids a possible repair
process (Mailand et al., Science (2000), 288, 1425-1429).
[0009] Moreover, the overexpression of the different forms of cdc25
is now reported in many classifications of human tumors: [0010]
Breast cancer: measurement by riboprobe shows that 32% of tumors
over-express cdc25-B. The overexpression of cdc25-A is shown in
nearly 50% of cancers of the breast and is associated with a poor
prognosis (Cangi et al., Resume 2984, AACR meeting San Francisco,
2000). [0011] Lymphomas: in the circulating lymphocytes, the
expressions of the RNAs of cdc25-B1 and -B3 are detected by RT-PCR
while the expressions of cdc25-A, -B2 and -C are very weak or
undetectable. On the other hand, analysis of these genes in
non-hodgkin's lymphomas shows a strong expression of cdc25-A and
-B2 in approximately 35% of the tumors. The cdc25-B1 and -B3
variants are themselves detected in all of the tumors analysed. On
the other hand, the expression of cdc25-C remains very weak in the
sample group (Hernandez et al., Int. J. Cancer (2000), 89,
148-152). It is important to note the correlation between the
expression of proteins such as myc and cdc25. 26 of 35 (74%)
non-hodgkin's lymphomas with a raised level of cdc25-B also show an
over-expression of c-myc. On the other hand, 27 out of 28 (96%)
tumors with a low level of cdc25-B expression do not show any
detectable c-myc (P<0.0001). This suggests that the expression
of cdc25 associated with that of myc could participate in the
development of this type of lymphoma (Hernandez et al., Cancer Res.
(1998), 58, 1762-1767). [0012] Neck and head cancers: of 20 tumors
examined by quantitative RT-PCR, Gasparotto et al. note that
CDC25-A and -B are over-expressed whilst cdc25-C is expressed very
little (Gasparotto et al., Cancer Res. (1997), 57, 2366-2368).
[0013] Moreover, the E. Sausville group reports an inverse
correlation between the level of expression of cdc25-B in a panel
of 60 cell lines and their sensitivity to CDK inhibitors such as
Olumucine or Flavopiridol, suggesting that the presence of cdc25
can provide resistance to certain anti-tumor agents and more
particularly to CDK inhibitors (Hose et al., Proceedings of AACR,
Abstract 3571, San Francisco, 2000).
[0014] Vitamin K3, also called menadione, was the first selective
inhibitor of cdc25 phosphatase described (Ham et al., Bioorg. Med.
Chem. Lett. (1998) 8, 2507-2510). Other cdc25 inhibitors have since
been identified and have an inhibitory activity of micromolar order
on the recombinant enzymes. Among these products, the following can
be noted: [0015] 1. Naphthoquinone analogues derived from menadione
(Ham et al., Bioorg. Med. Chem. Lett. (1998) 8, 2507-2510). [0016]
2. Cpd5, a thioalkyl derivative of vitamin K (Tamura et al., Cancer
Res. (2000), 60, 1317-1325). The inhibition constants (Kis)
measured on cdc25-A, -B2 & -C are 15, 1.7 and 1.3 .mu.mol
respectively. [0017] 3.
4-(benzyl-(2-[(2,5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)--
2-decanoylaminobutanoic acid also called SC-alpha alpha delta 9
(Tamura et al., Oncogene (1999) 18, 6989-6996). [0018] 4. Certain
compounds originating from a Ugi library containing groups
mimicking phosphates are non-competitive inhibitors of cdc25-A
which do not act on the active site. The most active compound has
an IC.sub.50 of 0.5 .mu.M and the interaction site is in the
process of being identified (Bergnes et al., Bioorg. Med. Chem.
Lett. (1999), 9, 2849-2854). [0019] 5. Quinolin-4-one and
1,7-naphthyridin-4-one derivatives. Certain compounds are
inhibitors both of cdc25 and cdc2 (el-Subbagh et al., Arch. Pharm.
(Weinheim.) (1999), 332, 19-24). [0020] 6. Dysidiolide and
derivatives containing a .gamma.-hydroxy butenolide group. The
effectiveness of these products is discussed in Blanchard et al.,
Bioorg. Med. Chem. Lett. (1999), 9, 2537-2538. [0021] 7. Certain
5-substituted 2-bromoindolo[3,2-b]quinoxalines. Certain of these
compounds are inhibitors of both cdc25 and cdc2 (Abadi et al.,
Arch. Pharm. (Weinheim.) (1998), 331, 352-358).
[0022] The PCT Application WO 00/17190 describes amidine
derivatives which inhibit the NO synthases and trap the free
radicals. Because of this, these compounds present numerous
pharmacological properties and their use can be envisaged in the
treatment of numerous pathologies, principally in the field of
neurology. A simplified general formula of these compounds could be
general formula (ET1): ##STR2## in which A represents a radical
which traps free radicals, for example a substituted phenyl
radical; X and Y are linking chains, for example alkylene,
alkylenecarbonyl, carbonylalkylene radicals; R represents H or
alkyl; and B represents a carbocyclic or heterocyclic aryl radical,
and preferably the 2-thienyl radical.
[0023] The invention offers new inhibitors of cdc25, and in
particular of cdc25-C, which correspond to general formula (I)
defined below. These compounds are capable of being used as
medicaments, in particular in the treatment of the following
diseases/disorders: [0024] inhibition of tumorous proliferation
when used alone or in combination with other treatments; [0025]
inhibition of the proliferation of normal cells when used alone or
in combination with other treatments; [0026] the prevention of
spontaneous alopecia; [0027] the prevention of alopecia induced by
exogenous products; [0028] the prevention of radiation-induced
alopecia; [0029] the prevention of spontaneous or induced apoptosis
of normal cells; [0030] the prevention of meiosis and
fertilization; [0031] the prevention of oocyte maturation; [0032]
all of the diseases/disorders corresponding to the uses mentioned
for CDK inhibitors, and in particular non-tumorous proliferative
diseases (for example: angiogenesis, psoriasis or the recurrence of
stenosis), tumorous proliferative diseases, parasitology
(proliferation of protozoa), viral infections, neurodegenerative
diseases, myopathies; [0033] all of the diseases/disorders
corresponding to clinical uses of vitamin K and its
derivatives;
[0034] Moreover, the compounds of the present invention are also,
because of their properties of inhibiting cdc25 phosphatases,
capable of being used to inhibit the proliferation of
microorganisms, in particular yeasts. One of the advantages of
these compounds is their low toxicity on healthy cells.
[0035] At present, the Applicant has discovered in a surprising
manner, that the compounds corresponding to general formula (I)
##STR3## in which: A represents an (A1) radical ##STR4## in which
two of the R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 groups
represent hydrogen atoms and the other three are chosen
independently from a hydrogen atom, a halogen atom and an alkyl,
hydroxy, alkoxy, alkylcarbonyloxy, alkylthio or NR.sup.6R.sup.7
radical, it being understood moreover that: [0036] either R.sup.1
and one of R.sup.2 and R.sup.4 are chosen independently from a
hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7 radical, [0037] or
R.sup.2 and one of R.sup.3 and R.sup.5 are chosen independently
from a hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7 radical,
[0038] or R.sup.4 and one of R.sup.3 and R.sup.5 are chosen
independently from a hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7
radical, [0039] or also one of R.sup.1, R.sup.3 and R.sup.5 is
chosen from a hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7
radical, and the B--N(W)--X--Y remainder is attached to the A
radical by a nitrogen atom, R.sup.6 and R.sup.7 representing,
independently each time that they occur, a hydrogen atom or an
alkyl radical or R.sup.6 and R.sup.7 forming together with the
nitrogen atom a heterocycle with 4 to 7 members comprising 1 to 2
heteroatoms, the members necessary to complete the heterocycle
being chosen independently from the --CR.sup.8R.sup.9--, --O--,
--S-- and --NR.sup.10-- radicals, R.sup.8 and R.sup.9 independently
representing each time that they occur a hydrogen atom or an alkyl,
alkoxy, benzyloxycarbonylamino or dialkylamino radical, and
R.sup.10 independently representing each time that it occurs a
hydrogen atom or an alkyl radical, or also A represents an (A2)
radical ##STR5## in which: [0040] either R.sup.11 and one of
R.sup.13, R.sup.14 and R.sup.15 represent hydroxy radicals whilst
the other radicals among R.sup.13, R.sup.14 and R.sup.15 as well as
R.sup.16 represent hydrogen atoms, [0041] or R.sup.12 and R.sup.16
represent hydroxy radicals whilst R.sup.11, R.sup.13, R.sup.14 and
R.sup.15 represent hydrogen atoms; B represents a --CO--,
--NH--CO--(CH.sub.2).sub.n-- or --(CH.sub.2).sub.p-- radical, n
being an integer from 0 to 3 and p being an integer from 0 to 1; W
represents a hydrogen atom or an alkyl radical; X represents a
--(CH.sub.2).sub.q--, --(CH.sub.2).sub.q--NH-- or
--CO--(CH.sub.2).sub.r-- radical, q being an integer from 1 to 6
and r an integer from 0 to 6; or also the B--N(W)--X--Y group is
such that it represents the ##STR6## radical in which B is as
defined above, t is an integer from 0 to 2, s is an integer from 0
to 1 and R.sup.17 and R.sup.18 represent radicals chosen
independently from a hydrogen atom and an alkyl radical; and:
[0042] when X represents a --(CH.sub.2).sub.q-- or
--CO--(CH.sub.2).sub.r-- radical, then Y represents a ##STR7##
radical in which R.sup.19 represents a hydrogen atom, a halogen
atom, a nitro, alkyl, alkylthio, NR.sup.21R.sup.22,
--SO.sub.2--NR.sup.23R.sup.24, --NH--SO.sub.2--R.sup.25 or
--O--P(O)(OR.sup.26)(OR.sup.27) radical, R.sup.21 and R.sup.22
independently representing a hydrogen atom or an alkyl radical,
R.sup.23 and R.sup.24 independently representing a hydrogen atom or
an alkyl radical, or also --R.sup.23 and R.sup.24 representing
together with the nitrogen atom which carries them a heterocycle
with 5 to 7 members the additional members of which are chosen
independently from --CHR.sup.28--, NR.sup.29--, --O-- and --S--,
R.sup.28 and R.sup.29 representing, independently each time that
they occur, a hydrogen atom or an alkyl radical, R.sup.25
representing an alkyl, haloalkyl radical or one of the aryl,
heteroaryl, aralkyl or heteroaralkyl radicals the aryl or
heteroaryl nucleus of which is optionally substituted by one or
more radicals chosen independently from a halogen atom and alkyl,
haloalkyl, hydroxy, alkoxy or nitro radicals, except for the
optional nitrogen atoms of the heteroaryl nucleus for which the
optional substituents are chosen from alkyl radicals, R.sup.26 and
R.sup.27 being chosen independently from alkyl radicals, and
R.sup.20 represents a hydrogen atom, a halogen atom or an alkyl,
alkoxy or alkylthio radical, or also Y represents the (T) radical
represented below ##STR8## in which R.sup.20 represents a hydrogen
atom or an alkyl, alkoxy or alkylthio radical, [0043] when X
represents a --(CH.sub.2).sub.q--NH-- radical or when the
B--N(W)--X--Y group is such that it represents the ##STR9## radical
then Y exclusively represents an --SO.sub.2--R.sup.30 radical in
which R.sup.30 represents an alkyl, haloalkyl radical or one of the
aryl, heteroaryl, aralkyl or heteroaralkyl radicals the aryl or
heteroaryl nucleus of which is optionally substituted by one or
more radicals chosen independently from a halogen atom and alkyl,
haloalkyl, hydroxy, alkoxy or nitro radicals, except for the
optional nitrogen atoms of the heteroaryl nucleus for which the
optional substituents are chosen from alkyl radicals; it being
understood moreover that when the B--N(W)--X--Y group is such that
it represents the ##STR10## radical then B exclusively represents a
--CO-- or --(CH.sub.2)-- radical; or the pharmaceutically
acceptable salts of compounds of general formula (I) defined above
are inhibitors of cdc25 phosphatases, and in particular inhibitors
of cdc25-C phosphatase, and can therefore be used for preparing a
medicament intended to inhibit cdc25 phosphatases, and in
particular cdc25-C phosphatase.
[0044] By alkyl, unless specified otherwise, is meant a linear or
branched alkyl radical containing 1 to 12 carbon atoms, preferably
1 to 10 carbon atoms and more preferentially 1 to 6 carbon atoms.
By alkenyl, unless specified otherwise, is meant a linear or
branched alkyl radical containing 1 to 6 carbon atoms and
presenting at least one unsaturation (double bond). By alkynyl,
unless specified otherwise, is meant a linear or branched alkyl
radical containing 1 to 6 carbon atoms and presenting at least one
double unsaturation (triple bond). By carbocyclic or heterocyclic
aryl, is meant a carbocyclic or heterocyclic system comprising at
least one aromatic ring, a system being said to be heterocyclic
when at least one of the rings which forms it comprises a
heteroatom (O, N or S); when a carbocyclic or heterocyclic aryl
radical is said to be substituted unless specified otherwise, it is
meant that said carbocyclic or heterocyclic aryl radical is
substituted 1 to 3 times, and preferably 1 to 2 times by radicals
different to a hydrogen atom which, if they are not specified, are
chosen from a halogen atom and the alkyl or alkoxy radicals;
moreover, unless specified otherwise, by aryl is meant a
carbocyclic aryl exclusively. By haloalkyl, is meant an alkyl
radical of which at least one (and optionally all) of the hydrogen
atoms is replaced by a halogen atom.
[0045] By alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl,
alkenyl, alkynyl, aralkyl, is meant respectively the alkylthio,
alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl,
aralkyl radicals the alkyl radical of which has the meaning
indicated previously.
[0046] 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 carbocyclic aryl, is meant in
particular the phenyl and naphthyl radicals. By heterocyclic aryl
or heteroaryl, is meant in particular the thienyl, imidazolyl,
thiazolyl, oxazolyl and pyridyl radicals. Finally, by halogen, is
meant the fluorine, chlorine, bromine or iodine atoms.
[0047] By pharmaceutically acceptable salt, is meant in particular
the addition salts with inorganic acids such as hydrochloride,
hydrobromide, hydroiodide, sulphate, phosphate, diphosphate and
nitrate or with organic acids such as acetate, maleate, fumarate,
tartrate, succinate, citrate, lactate, methanesulphonate,
p-toluenesulphonate, pamoate, and stearate. Also included in the
scope of the present invention, when they can be used, are the
salts formed from bases such as sodium or potassium hydroxide. For
other examples of pharmaceutically acceptable salts, reference can
be made to "Salt selection for basic drugs", Int. J. Pharm. (1986),
33, 201/217.
[0048] 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. the "R" and "S" configurations. The
present invention includes the two enantiomeric forms and all
combinations of these forms, including the racemic "RS" mixtures.
For the sake of simplicity, when no specific configuration is
indicated in the structural formulae, it should be understood that
the two enantiomeric forms and their mixtures are represented.
[0049] Preferably, the compounds of general formula (I) according
to the invention will include at least one of the following
characteristics: [0050] A representing an (A1) radical ##STR11##
[0051] in which two of the R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 groups represent hydrogen atoms and the other three are
chosen independently from a hydrogen atom, a halogen atom and an
alkyl, alkylcarbonyloxy, hydroxy, alkoxy or NR.sup.6R.sup.7
radical, it being understood moreover that: [0052] either R.sup.1
and one of R.sup.2 and R.sup.4 are chosen independently from a
hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7 radical, [0053] or
R.sup.2 and one of R.sup.3 and R.sup.5 are chosen independently
from a hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7 radical,
[0054] or R.sup.4 and one of R.sup.3 and R.sup.5 are chosen
independently from a hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7
radical, [0055] or also one of R.sup.1, R.sup.3 and R.sup.5 is
chosen independently from a hydroxy, alkylcarbonyloxy and
NR.sup.6R.sup.7 radical, and the B--N(W)--X--Y remainder is
attached to the A radical by a nitrogen atom, [0056] R.sup.6 and
R.sup.7 representing, independently each time that they occur, a
hydrogen atom or an alkyl radical or R.sup.6 and R.sup.7 forming
together with the nitrogen atom a heterocycle with 5 to 7 members
comprising 1 to 2 heteroatoms, the members necessary to complete
the heterocycle being chosen independently from the
--CR.sup.8R.sup.9--, --O--, --S-- and --NR.sup.10-- radicals,
R.sup.8 and R.sup.9 independently representing each time that they
occur a hydrogen atom or an alkyl or alkoxy radical, and R.sup.10
independently representing each time that it occurs a hydrogen atom
or an alkyl radical, [0057] or also A representing an (A2) radical
##STR12## [0058] in which: [0059] either R.sup.11 and one of
R.sup.13, R.sup.14 and R.sup.15 represent hydroxy radicals whilst
the other radicals among R.sup.13, R.sup.14 and R.sup.15 as well as
R.sup.16 represent hydrogen atoms, [0060] or R.sup.12 and R.sup.16
represent hydroxy radicals whilst R.sup.11, R.sup.13, R.sup.14 and
R.sup.15 represent hydrogen atoms; [0061] B representing a --CO--,
--NH--CO--(CH.sub.2).sub.n-- or --(CH.sub.2).sub.p-- radical, n
being an integer from 0 to 2 and p being an integer from 0 to 1;
[0062] W representing a hydrogen atom or an alkyl radical; [0063] X
representing a --(CH.sub.2).sub.q--, --(CH.sub.2).sub.q--NH-- or
--CO--(CH.sub.2).sub.r radical, q being an integer from 1 to 4 and
r an integer from 0 to 5; [0064] or also the B--N(W)--X--Y group
being such that it represents the ##STR13## [0065] radical in which
B is as defined in general formula (I), t is an integer from 0 to
2, s is an integer from 0 to 1, R.sup.17 and R.sup.18 represent
radicals chosen independently from a hydrogen atom and an alkyl
radical; [0066] when X represents a --(CH.sub.2).sub.q-- or
--CO--(CH.sub.2).sub.r-- radical, Y representing a ##STR14## [0067]
radical in which R.sup.19 represents a hydrogen atom, a halogen
atom, a nitro, alkyl, alkylthio, NR.sup.21R.sup.22,
--SO.sub.2--NR.sup.23R.sup.24, --NH--SO.sub.2--R.sup.25 or
--O--P(O)(OR.sup.26)(OR.sup.27) radical, R.sup.21 and R.sup.22
independently representing a hydrogen atom or an alkyl radical,
R.sup.23 and R.sup.24 independently representing a hydrogen atom or
an alkyl radical, or R.sup.23 and R.sup.24 representing together
with the nitrogen atom which carries them a heterocycle with 5 to 6
members the additional members of which are chosen independently
from --CHR.sup.28--, --NR.sup.29--, --O-- and --S--, R.sup.28 and
R.sup.29 representing, independently each time that they occur, a
hydrogen atom or an alkyl radical, R.sup.25 representing an alkyl
or aryl radical optionally substituted by one or more radicals
chosen from a halogen atom and alkyl, haloalkyl, alkoxy or nitro
radicals, except for the optional nitrogen atoms of the heteroaryl
nucleus for which the optional substituents are chosen from alkyl
radicals, [0068] R.sup.26 and R.sup.27 being chosen independently
from alkyl radicals, [0069] and R.sup.20 represents a hydrogen atom
or an alkyl or alkoxy radical, [0070] or also Y representing the
radical of formula (T) ##STR15## [0071] in which R.sup.20
represents a hydrogen atom or an alkyl or alkoxy radical; [0072]
when X represents a --(CH.sub.2).sub.q--NH-- radical or when the
B--N(W)--X--Y group is such that it represents the ##STR16## [0073]
radical Y representing an --SO.sub.2--R.sup.30 radical in which
R.sup.30 represents an alkyl, haloalkyl radical or one of the aryl,
heteroaryl, aralkyl or heteroaralkyl radicals the aryl or
heteroaryl nucleus of which is optionally substituted by one or
more radicals chosen independently from a halogen atom and alkyl,
haloalkyl, alkoxy or nitro radicals, except for the optional
nitrogen atoms of the heteroaryl nucleus for which the optional
substituents are chosen from alkyl radicals.
[0074] More preferentially, the compounds of general formula (I)
according to the invention will include at least one of the
following characteristics: [0075] A representing an (A1) radical
##STR17## [0076] in which two of the R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 groups represent hydrogen atoms and the other
three are chosen independently from a hydrogen atom, a halogen atom
and an alkyl, alkylcarbonyloxy, hydroxy, alkoxy or NR.sup.6R.sup.7
radical, it being understood moreover that: [0077] either R.sup.1
and one of R.sup.2 and R.sup.4 are chosen independently from a
hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7 radical, [0078] or
R.sup.2 and one of R.sup.3 and R.sup.5 are chosen independently
from a hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7 radical,
[0079] or R.sup.4 and one of R.sup.3 and R.sup.5 are chosen
independently from a hydroxy, alkylcarbonyloxy and NR.sup.6R.sup.7
radical, [0080] or also one of R.sup.1, R.sup.3 and R.sup.5 is
chosen independently from a hydroxy, alkylcarbonyloxy and
NR.sup.6R.sup.7 radical, and the B--N(W)--X--Y remainder is
attached to the A radical by a nitrogen atom, [0081] R.sup.6 and
R.sup.7 representing, independently each time that they occur, a
hydrogen atom or an alkyl radical containing 1 to 3 carbon atoms or
R.sup.6 and R.sup.7 forming together with the nitrogen atom a
heterocycle with 5 to 6 members comprising 1 to 2 heteroatoms, the
members necessary to complete the heterocycle being chosen
independently from the --CR.sup.8R.sup.9--, --O-- and --NR.sup.10--
radicals, R.sup.8 and R.sup.9 independently representing each time
that they occur a hydrogen atom or an alkyl or alkoxy radical, and
R.sup.10 independently representing each time that it occurs a
hydrogen atom or an alkyl radical, [0082] or also A representing an
(A2) radical ##STR18## [0083] in which: [0084] either R.sup.11 and
R.sup.15 represent hydroxy radicals whilst R.sup.12, R.sup.13,
R.sup.14 and R.sup.16 represent hydrogen atoms, [0085] or R.sup.12
and R.sup.16 represent hydroxy radicals whilst R.sup.11, R.sup.13,
R.sup.14 and R.sup.15 represent hydrogen atoms; [0086] W
representing a hydrogen atom or a methyl or ethyl radical; [0087] X
representing a --(CH.sub.2).sub.q--, --(CH.sub.2).sub.q--NH-- or
--CO--(CH.sub.2).sub.r radical, q being an integer from 1 to 3 and
r an integer from 0 to 4; [0088] or also the B--N(W)--X--Y group
being such that it represents the ##STR19## [0089] radical in which
B is as defined in general formula (I), t is an integer from 0 to
2, s is an integer from 0 to 1, R.sup.17 and R.sup.18 represent
radicals chosen independently from a hydrogen atom and an alkyl
radical containing 1 to 3 carbon atoms; [0090] when X represents a
--(CH.sub.2).sub.q-- or --CO--(CH.sub.2).sub.r-- radical, Y
representing a ##STR20## [0091] radical in which R.sup.19
represents a nitro, NR.sup.21R.sup.22,
--SO.sub.2--NR.sup.23R.sup.24, --NH--SO.sub.2--R.sup.25 or
--O--P(O)(OR.sup.26)(OR.sup.27) radical, [0092] R.sup.21 and
R.sup.22 independently representing a hydrogen atom or an alkyl
radical, [0093] R.sup.23 and R.sup.24 independently representing a
hydrogen atom or an alkyl radical, or R.sup.23 and R.sup.24
representing together with the nitrogen atom which carries them a
heterocycle with 5 to 6 members the additional members of which are
chosen independently from --CHR.sup.28--, --NR.sup.29--, --O-- and
--S--, R.sup.28 and R.sup.29 representing, independently each time
that they occur, a hydrogen atom or an alkyl radical, [0094]
R.sup.25 representing an alkyl or aryl radical optionally
substituted by one or more radicals chosen from a halogen atom and
alkyl, haloalkyl, alkoxy or nitro radicals, except for the optional
nitrogen atoms of the heteroaryl nucleus for which the optional
substituents are chosen from alkyl radicals, [0095] R.sup.26 and
R.sup.27 being chosen independently from alkyl radicals, [0096] and
R.sup.20 represents a hydrogen atom or an alkyl radical, [0097] or
also Y representing the radical of formula (T) ##STR21## [0098] in
which R.sup.20 represents a hydrogen atom or an alkyl radical;
[0099] when X represents a --(CH.sub.2).sub.q--NH-- radical or when
the B--N(W)--X--Y group is such that it represents the ##STR22##
[0100] radical, Y representing an --SO.sub.2--R.sup.30 radical in
which R.sup.30 represents an alkyl, haloalkyl radical or one of the
aryl or aralkyl radicals the aryl nucleus of which is optionally
substituted by one or more radicals chosen independently from a
halogen atom and alkyl, haloalkyl, alkoxy or nitro radicals, except
for the optional nitrogen atoms of the heteroaryl nucleus for which
the optional substituents are chosen from alkyl radicals.
[0101] Yet more preferentially, the compounds of general formula
(I) according to the invention will include at least one of the
following characteristics: [0102] A representing an (A1) radical
##STR23## [0103] in which two of the R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and R.sup.5 groups represent hydrogen atoms and the other
three are chosen independently from a hydrogen atom, a halogen atom
and an alkyl, acetoxy, hydroxy, methoxy or NR.sup.6R.sup.7 radical,
it being understood moreover that: [0104] either R.sup.1 and one of
R.sup.2 and R.sup.4 are chosen independently from a hydroxy,
acetoxy and NR.sup.6R.sup.7 radical, [0105] or R.sup.2 and one of
R.sup.3 and R.sup.5 are chosen independently from a hydroxy,
acetoxy and NR.sup.6R.sup.7 radical, [0106] or R.sup.4 and one of
R.sup.3 and R.sup.5 are chosen independently from a hydroxy,
acetoxy and NR.sup.6R.sup.7 radical, [0107] or also one of R.sup.1,
R.sup.3 and R.sup.5 is chosen independently from a hydroxy, acetoxy
and NR.sup.6R.sup.7 radical, and the B--N(W)--X--Y remainder is
attached to the A radical by a nitrogen atom, [0108] R.sup.6 and
R.sup.7 representing, independently each time that they occur, a
hydrogen atom or an alkyl radical containing 1 to 3 carbon atoms
(this alkyl radical preferably being the methyl radical) or R.sup.6
and R.sup.7 forming together with the nitrogen atom a heterocycle
containing 6 members and comprising 1 to 2 heteroatoms, the members
necessary to complete the heterocycle being chosen independently
from the --CR.sup.8R.sup.9--, --O-- and --NR.sup.10-- radicals,
R.sup.8 and R.sup.9 independently representing each time that they
occur a hydrogen atom or an alkyl radical (this alkyl radical
preferably being the methyl radical), and R.sup.10 independently
representing each time that it occurs a hydrogen atom or an alkyl
radical (this alkyl radical preferably being the methyl radical),
[0109] or also A representing an (A2) radical ##STR24## [0110] in
which R.sup.11 and R.sup.15 represent hydroxy radicals whilst
R.sup.12, R.sup.13, R.sup.14 and R.sup.16 represent hydrogen atoms;
[0111] W representing a hydrogen atom or a methyl radical; [0112] X
representing a --(CH.sub.2).sub.q--, --(CH.sub.2).sub.q--NH-- or
--CO--(CH.sub.2).sub.r radical, q being an integer from 1 to 3 and
r an integer from 0 to 4; [0113] or also the B--N(W)--X--Y group
being such that it represents the ##STR25## [0114] radical in which
B is as defined in general formula (I), t is an integer from 0 to
2, s is an integer from 0 to 1, R.sup.17 and R.sup.18 represent
radicals chosen independently from a hydrogen atom and a methyl
radical; [0115] when X represents a --(CH.sub.2).sub.q-- or
--CO--(CH.sub.2).sub.r-- radical, Y representing a ##STR26## [0116]
radical in which R.sup.19 represents a nitro, NR.sup.21R.sup.22,
--SO.sub.2--NR.sup.23R.sup.24, --NH--SO.sub.2--R.sup.25 or
--O--P(O)(OR.sup.26)(OR.sup.27) radical, [0117] R.sup.21 and
R.sup.22 independently representing a hydrogen atom or an alkyl
radical, [0118] R.sup.23 and R.sup.24 independently representing a
hydrogen atom or an alkyl radical, or R.sup.23 and R.sup.24
representing together with the nitrogen atom which carries them a
heterocycle with 5 to 6 members the additional members of which are
chosen independently from --CHR.sup.28--, --NR.sup.29--, --O-- and
--S--, R.sup.28 and R.sup.29 representing, independently each time
that they occur, a hydrogen atom or an alkyl radical, [0119]
R.sup.25 representing an alkyl or aryl radical optionally
substituted by one or more radicals chosen from a halogen atom and
alkyl, haloalkyl, alkoxy or nitro radicals, except for the optional
nitrogen atoms of the heteroaryl nucleus for which the optional
substituents are chosen from alkyl radicals, [0120] R.sup.26 and
R.sup.27 being chosen independently from alkyl radicals, [0121] and
R.sup.20 represents a hydrogen atom or a methyl radical (and
preferably a hydrogen atom), [0122] or also Y representing the
radical of formula (T) ##STR27## [0123] in which R.sup.20
represents a hydrogen atom or a methyl radical (and preferably a
hydrogen atom); [0124] when X represents a --(CH.sub.2).sub.q--NH--
radical or when the B--N(W)--X--Y group is such that it represents
the ##STR28## [0125] radical Y representing an --SO.sub.2--R.sup.30
radical in which R.sup.30 represents an alkyl radical or one of the
aryl or aralkyl radicals the aryl nucleus of which is optionally
substituted by one or more radicals chosen independently from a
halogen atom and alkyl, haloalkyl, alkoxy or nitro radicals, except
for the optional nitrogen atoms of the heteroaryl nucleus for which
the optional substituents are methyl radicals.
[0126] For a use according to the invention, the following
compounds described (if appropriate in the form of salts) in the
examples will be particularly preferred: [0127]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)-phenol; [0128]
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
[0129]
2,7-dihydroxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl-
}-2-napthalenecarboxamide; [0130]
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[4-(dimethylam-
ino)phenyl]propanamide; [0131]
4-(4-aminophenyl)-N-[4-(4-methyl-1-piperazinyl)phenyl]butanamide;
[0132]
4-(dimethylamino)-2-methoxy-6-({[2-(4-nitrophenyl)ethyl]amino}methyl)phe-
nol; [0133]
4-(dimethylamino)-2-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
[0134]
2-(dimethylamino)-6-methoxy-4-({methyl[2-(4-nitrophenyl)ethyl]ami-
no}methyl)phenol; [0135]
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol;
[0136]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)phenyl acetate; [0137]
3,7-dihydroxy-N-[2-(4-nitrophenyl)ethyl]-2-naphthamide; [0138]
N-[4-(dimethylamino)benzyl]-3,7-dihydroxy-2-naphthamide; [0139]
diethyl
4-{2-[(3,7-dihydroxy-2-naphthoyl)amino]ethyl}phenylphosphate;
[0140]
N-{2-[4-(aminosulphonyl)phenyl]ethyl}-3,7-dihydroxy-2-naphthamide;
[0141] 3,7-dihydroxy-N-[2-(4-aminophenyl)ethyl]-2-naphthamide;
[0142]
3,7-dihydroxy-N-(2-{4-[(methylsulphonyl)amino]phenyl}ethyl)-2-naphthamide-
; [0143]
N-(2-{4-[(butylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-na-
phthamide; [0144]
3,7-dihydroxy-N-[2-(4-{[(4-methylphenyl)sulphonyl]amino}phenyl)ethyl]-2-n-
aphthamide; [0145]
3,7-dihydroxy-N-(2-{4-[(1-naphthylsulphonyl)amino]phenyl}ethyl)-2-naphtha-
mide; [0146]
3,7-dihydroxy-N-{2-[4-({[2-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide; [0147]
N-(2-{4-[(benzylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamide-
; [0148]
3,7-dihydroxy-N-{2-[4-({[3-(trifluoromethyl)phenyl]sulphonyl}am-
ino)phenyl]ethyl}-2-naphthamide; [0149]
3,7-dihydroxy-N-[2-(4-{[(4-nitrophenyl)sulphonyl]amino}phenyl)ethyl]-2-na-
phthamide; [0150]
3,7-dihydroxy-N-{2-[4-({[4-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide; [0151]
3,7-dihydroxy-N-(2-{4-[(thien-2-ylsulphonyl)amino]phenyl}ethyl)-2-naphtha-
mide; [0152]
3,7-dihydroxy-N-[2-(4-{[(4-methoxyphenyl)sulphonyl]amino}phenyl)ethyl]-2--
naphthamide; [0153]
3,7-dihydroxy-N-[2-(4-{[(1-methyl-1H-imidazol-4-yl)sulphonyl]amino}phenyl-
)ethyl]-2-naphthamide; [0154]
N-[2-(4-{[(4-fluorophenyl)sulphonyl]amino}phenyl)ethyl]-3,7-dihydroxy-2-n-
aphthamide; [0155]
3,7-dihydroxy-N-{3-[(4-methyl-1-piperidinyl)sulphonyl]benzyl}-2-naphthami-
de; [0156]
5-(4-{[(1E)-amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(dimethylamino-
) phenyl]pentanamide; [0157]
3-({4-[(4-methylphenyl)sulphonyl]piperazin-1-yl}carbonyl)naphthalene-2,6--
diol; [0158]
3-{[4-(methylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-diol;
[0159]
3-{[4-(butylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-dio-
l; or the pharmaceutically acceptable salts of such compounds.
[0160] The following compounds will quite particularly be preferred
for a use according to the invention: [0161]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)-phenol; [0162]
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
[0163]
2-(dimethylamino)-6-methoxy-4-({methyl[2-(4-nitrophenyl)ethyl]ami-
no}methyl)phenol; [0164]
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol;
[0165]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)phenyl acetate; [0166] diethyl
4-{2-[(3,7-dihydroxy-2-naphthoyl)amino]ethyl}phenylphosphate;
[0167]
N-{2-[4-(aminosulphonyl)phenyl]ethyl}-3,7-dihydroxy-2-naphthamide;
[0168]
3,7-dihydroxy-N-(2-{4-[(methylsulphonyl)amino]phenyl}ethyl)-2-nap-
hthamide; [0169]
N-(2-{4-[(butylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamide;
[0170]
3,7-dihydroxy-N-[2-(4-{[(4-methylphenyl)sulphonyl]amino}phenyl)e-
thyl]-2-naphthamide; [0171]
3,7-dihydroxy-N-{2-[4-({[3-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide; [0172]
N-[2-(4-{[(4-fluorophenyl)sulphonyl]amino}phenyl)ethyl]-3,7-dihydroxy-2-n-
aphthamide; [0173]
3,7-dihydroxy-N-{3-[(4-methyl-1-piperidinyl)sulphonyl]benzyl}-2-naphthami-
de; [0174]
3-({4-[(4-methylphenyl)sulphonyl]piperazin-1-yl}carbonyl)naphthalene-2,6--
diol; or the pharmaceutically acceptable salts of such
compounds.
[0175] Moreover,
5-(4-{[(1E)-amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(dimethylamino-
)phenyl]pentanamide and its pharmaceutically acceptable salts are
also preferred for a use according to the invention.
[0176] The following compounds will be quite particularly preferred
for a use according to the invention: [0177]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)-phenol; [0178]
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
[0179]
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol;
[0180]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]ami-
no}methyl)phenyl acetate; [0181]
3,7-dihydroxy-N-{2-[4-({[3-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide; [0182]
3,7-dihydroxy-N-{3-[(4-methyl-1-piperidinyl)sulphonyl]benzyl}-2-naphthami-
de; or the pharmaceutically acceptable salts of such compounds.
[0183] Preferably, the compounds of general formula (I) will be
used to prepare a medicament intended to treat a disease chosen
from the following diseases: tumorous proliferative diseases, and
in particular cancer, non-tumorous proliferative diseases,
parasitic diseases, viral infections, spontaneous alopecia,
alopecia induced by exogenous products and radiation-induced
alopecia.
[0184] Preferably however, the compounds of general formula (I)
used for preparing a medicament intended to treat proliferative
diseases, parasitic diseases and viral infections are such that the
Y radical does not represent the radical of formula (T). The
compounds of general formula (I) in which the Y radical represents
the radical of formula (T) will therefore be preferably used for
preparing a medicament intended to treat spontaneous alopecia,
alopecia induced by exogenous products, and radiation-induced
alopecia
[0185] Quite particularly, the compounds of general formula (I)
could be used for preparing a medicament intended to treat cancer,
and in particular cancer of the breast, lymphomas, cancers of the
neck and head, cancer of the lung, cancer of the colon, cancer of
the prostate and cancer of the pancreas.
[0186] According to a particular variant of the invention, the
compounds of general formula (I) as defined above can be used for
preparing a medicament intended to treat spontaneous alopecia,
alopecia induced by exogenous products or radiation-induced
alopecia.
[0187] The present invention also offers, as medicaments, the
compounds of general formula (II) ##STR29## in which A represents
an (A1) radical ##STR30## in which two of the R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 groups represent hydrogen atoms and
the other three are chosen independently from a hydrogen atom, a
halogen atom and an alkyl, hydroxy, alkoxy, alkylcarbonyloxy,
alkylthio or NR.sup.6R.sup.7 radical, it being understood moreover
that: [0188] either R.sup.1 and one of R.sup.2 and R.sup.4 are
chosen independently from a hydroxy, alkylcarbonyloxy and
NR.sup.6R.sup.7 radical, [0189] or R.sup.2 and one of R.sup.3 and
R.sup.5 are chosen independently from a hydroxy, alkylcarbonyloxy
and NR.sup.6R.sup.7 radical, [0190] or R.sup.4 and one of R.sup.3
and R.sup.5 are chosen independently from a hydroxy,
alkylcarbonyloxy and NR.sup.6R.sup.7 radical, [0191] or also one of
R.sup.1, R.sup.3 and R.sup.5 is chosen from a hydroxy,
alkylcarbonyloxy and NR.sup.6R.sup.7 radical, and the B--N(W)--X--Y
remainder is attached to the A radical by a nitrogen atom, R.sup.6
and R.sup.7 representing, independently each time that they occur,
a hydrogen atom or an alkyl radical or R.sup.6 and R.sup.7 forming
together with the nitrogen atom a heterocycle with 4 to 7 members
comprising 1 to 2 heteroatoms, the members necessary to complete
the heterocycle being chosen independently from the
--CR.sup.8R.sup.9--, --O--, --S-- and --NR.sup.10-- radicals,
R.sup.8 and R.sup.9 independently representing each time that they
occur a hydrogen atom or an alkyl, alkoxy, benzyloxycarbonylamino
or dialkylamino radical, and R.sup.10 independently representing
each time that it occurs a hydrogen atom or an alkyl radical, or
also A represents an (A2) radical ##STR31## in which: [0192] either
R.sup.11 and one of R.sup.13, R.sup.14 and R.sup.15 represent
hydroxy radicals whilst the other radicals from R.sup.13, R.sup.14
and R.sup.15 as well as R.sup.16 represent hydrogen atoms, [0193]
or R.sup.12 and R.sup.16 represent hydroxy radicals whilst
R.sup.11, R.sup.13, R.sup.14 and R.sup.15 represent hydrogen atoms;
B represents a --CO--, --NH--CO--(CH.sub.2).sub.n-- or
--(CH.sub.2).sub.p-- radical, n being an integer from 0 to 3 and p
being an integer from 0 to 1; W represents a hydrogen atom or an
alkyl radical; X represents a --(CH.sub.2).sub.q--,
--(CH.sub.2).sub.q--NH-- or --CO--(CH.sub.2).sub.r-- radical, q
being an integer from 1 to 6 and r an integer from 0 to 6; or also
the B--N(W)--X--Y group is such that it represents the ##STR32##
radical in which B is as defined above, t is an integer from 0 to
2, s is an integer from 0 to 1 and R.sup.17 and R.sup.18 represent
radicals chosen independently from a hydrogen atom and an alkyl
radical; and: [0194] when X represents a --(CH.sub.2).sub.q-- or
--CO--(CH.sub.2).sub.r-- radical, then Y represents a ##STR33##
radical in which R.sup.19 represents a hydrogen atom, a halogen
atom, a nitro, alkyl, alkylthio, NR.sup.21R.sup.22,
--SO.sub.2--NR.sup.23R.sup.24, --NH--SO.sub.2--R.sup.25 or
--O--P(O)(OR.sup.26)(OR.sup.27) radical, R.sup.21 and R.sup.22
independently representing a hydrogen atom or an alkyl radical,
R.sup.23 and R.sup.24 independently representing a hydrogen atom or
an alkyl radical, or R.sup.23 and R.sup.24 representing together
with the nitrogen atom which carries them a heterocycle with 5 to 7
members the additional members of which are chosen independently
from --CHR.sup.28--, --NR.sup.29--, --O-- and --S--, R.sup.28 and
R.sup.29 representing, independently each time that they occur, a
hydrogen atom or an alkyl radical, R.sup.25 representing an alkyl,
haloalkyl radical or one of the aryl, heteroaryl, aralkyl or
heteroaralkyl radicals the aryl or heteroaryl nucleus of which is
optionally substituted by one or more radicals chosen independently
from a halogen atom and alkyl, haloalkyl, hydroxy, alkoxy or nitro
radicals, except for the optional nitrogen atoms of the heteroaryl
nucleus for which the optional substituents are chosen from alkyl
radicals, R.sup.26 and R.sup.27 being chosen independently from
alkyl radicals, and R.sup.20 represents a hydrogen atom, a halogen
atom or an alkyl, alkoxy or alkylthio radical; [0195] when X
represents a --(CH.sub.2).sub.q--NH-- radical or when the
B--N(W)--X--Y group is such that it represents the ##STR34##
radical then Y exclusively represents an --SO.sub.2--R.sup.30
radical in which R.sup.30 represents an alkyl, haloalkyl radical or
one of the aryl, heteroaryl, aralkyl or heteroaralkyl radicals the
aryl or heteroaryl nucleus of which is optionally substituted by
one or more radicals chosen independently from a halogen atom and
alkyl, haloalkyl, hydroxy, alkoxy or nitro radicals, except for the
optional nitrogen atoms of the heteroaryl nucleus for which the
optional substituents are chosen from alkyl radicals; it being
understood moreover that when the B--N(W)--X--Y group is such that
it represents the ##STR35## radical then B exclusively represents a
--CO-- or --(CH.sub.2)-- radical; or the pharmaceutically
acceptable salts of compounds of general formula (II).
[0196] In particular, the invention relates, as medicaments, to the
following compounds of general formula (II): [0197]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)phenol; [0198]
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
[0199]
4-(4-aminophenyl)-N-[4-(4-methyl-1-piperazinyl)phenyl]butanamide;
[0200]
4-(dimethylamino)-2-methoxy-6-({[2-(4-nitrophenyl)ethyl]amino}me-
thyl)phenol; [0201]
4-(dimethylamino)-2-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
[0202]
2-(dimethylamino)-6-methoxy-4-({methyl[2-(4-nitrophenyl)ethyl]ami-
no}methyl)phenol; [0203]
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol;
[0204]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)phenyl acetate; [0205]
3,7-dihydroxy-N-[2-(4-nitrophenyl)ethyl]-2-naphthamide; [0206]
N-[4-(dimethylamino)benzyl]-3,7-dihydroxy-2-naphthamide; [0207]
diethyl
4-{2-[(3,7-dihydroxy-2-naphthoyl)amino]ethyl}phenylphosphate;
[0208]
N-{2-[4-(aminosulphonyl)phenyl]ethyl}-3,7-dihydroxy-2-naphthamide;
[0209] 3,7-dihydroxy-N-[2-(4-aminophenyl)ethyl]-2-naphthamide;
[0210]
3,7-dihydroxy-N-(2-{4-[(methylsulphonyl)amino]phenyl}ethyl)-2-naphthamide-
; [0211]
N-(2-{4-[(butylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-na-
phthamide; [0212]
3,7-dihydroxy-N-[2-(4-{[(4-methylphenyl)sulphonyl]amino}phenyl)ethyl]-2-n-
aphthamide; [0213]
3,7-dihydroxy-N-(2-{4-[(1-naphthylsulphonyl)amino]phenyl}ethyl)-2-naphtha-
mide; [0214]
3,7-dihydroxy-N-{2-[4-({[2-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide; [0215]
N-(2-{4-[(benzylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamide-
; [0216]
3,7-dihydroxy-N-{2-[4-({[3-(trifluoromethyl)phenyl]sulphonyl}am-
ino)phenyl]ethyl}-2-naphthamide; [0217]
3,7-dihydroxy-N-[2-(4-{[(4-nitrophenyl)sulphonyl]amino}phenyl)ethyl]-2-na-
phthamide; [0218]
3,7-dihydroxy-N-{2-[4-({[4-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide; [0219]
3,7-dihydroxy-N-(2-{4-[(thien-2-ylsulphonyl)amino]phenyl}ethyl)-2-naphtha-
mide; [0220]
3,7-dihydroxy-N-[2-(4-{[(4-methoxyphenyl)sulphonyl]amino}phenyl)ethyl]-2--
naphthamide; [0221]
3,7-dihydroxy-N-[2-(4-{[(1-methyl-1H-imidazol-4-yl)sulphonyl]amino}phenyl-
)ethyl]-2-naphthamide; [0222]
N-[2-(4-{[(4-fluorophenyl)sulphonyl]amino}phenyl)ethyl]-3,7-dihydroxy-2-n-
aphthamide; [0223]
3,7-dihydroxy-N-{3-[(4-methyl-1-piperidinyl)sulphonyl]benzyl}-2-naphthami-
de; [0224]
3-({4-[(4-methylphenyl)sulphonyl]piperazin-1-yl}carbonyl)naphthalene-2,6--
diol; [0225]
3-{[4-(methylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-diol;
[0226]
3-{[4-(butylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-dio-
l; and their pharmaceutically acceptable salts.
[0227] Moreover, the invention also relates to 5-(4-{[(1E)-amino
(2-thienyl)methylidene]amino}phenyl)-N-[2-(dimethylamino)phenyl]pentanami-
de or one of its pharmaceutically acceptable salts, as a
medicament.
[0228] In addition, the invention relates to the pharmaceutical
compositions comprising, as active ingredient, at least one of the
compounds of general formula (II) defined above or a
pharmaceutically acceptable salt of such a compound, and preferably
a compound chosen from the following compounds: [0229]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)phenol; [0230]
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
[0231]
4-(4-aminophenyl)-N-[4-(4-methyl-1-piperazinyl)phenyl]butanamide;
[0232]
4-(dimethylamino)-2-methoxy-6-({[2-(4-nitrophenyl)ethyl]amino}me-
thyl)phenol; [0233]
4-(dimethylamino)-2-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
[0234]
2-(dimethylamino)-6-methoxy-4-({methyl[2-(4-nitrophenyl)ethyl]ami-
no}methyl)phenol; [0235]
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol;
[0236]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)phenyl acetate; [0237]
3,7-dihydroxy-N-[2-(4-nitrophenyl)ethyl]-2-naphthamide; [0238]
N-[4-(dimethylamino)benzyl]-3,7-dihydroxy-2-naphthamide; [0239]
diethyl
4-{2-[(3,7-dihydroxy-2-naphthoyl)amino]ethyl}phenylphosphate;
[0240]
N-{2-[4-(aminosulphonyl)phenyl]ethyl}-3,7-dihydroxy-2-naphthamide;
[0241] 3,7-dihydroxy-N-[2-(4-aminophenyl)ethyl]-2-naphthamide;
[0242]
3,7-dihydroxy-N-(2-{4-[(methylsulphonyl)amino]phenyl}ethyl)-2-naphthamide-
; [0243]
N-(2-{4-[(butylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-na-
phthamide; [0244]
3,7-dihydroxy-N-[2-(4-{[(4-methylphenyl)sulphonyl]amino}phenyl)ethyl]-2-n-
aphthamide; [0245]
3,7-dihydroxy-N-(2-{4-[(1-naphthylsulphonyl)amino]phenyl}ethyl)-2-naphtha-
mide; [0246]
3,7-dihydroxy-N-{2-[4-({[2-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide; [0247]
N-(2-{4-[(benzylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamide-
; [0248]
3,7-dihydroxy-N-{2-[4-({[3-(trifluoromethyl)phenyl]sulphonyl}am-
ino)phenyl]ethyl}-2-naphthamide; [0249]
3,7-dihydroxy-N-[2-(4-{[(4-nitrophenyl)sulphonyl]amino}phenyl)ethyl]-2-na-
phthamide; [0250]
3,7-dihydroxy-N-{2-[4-({[4-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide; [0251]
3,7-dihydroxy-N-(2-{4-[(thien-2-ylsulphonyl)amino]phenyl}ethyl)-2-naphtha-
mide; [0252]
3,7-dihydroxy-N-[2-(4-{[(4-methoxyphenyl)sulphonyl]amino}phenyl)ethyl]-2--
naphthamide; [0253]
3,7-dihydroxy-N-[2-(4-{[(1-methyl-1H-imidazol-4-yl)sulphonyl]amino}phenyl-
)ethyl]-2-naphthamide; [0254]
N-[2-(4-{[(4-fluorophenyl)sulphonyl]amino}phenyl)ethyl]-3,7-dihydroxy-2-n-
aphthamide; [0255]
3,7-dihydroxy-N-{3-[(4-methyl-1-piperidinyl)sulphonyl]benzyl}-2-naphthami-
de; [0256]
3-({4-[(4-methylphenyl)sulphonyl]piperazin-1-yl}carbonyl)naphthalene-2,6--
diol; [0257]
3-{[4-(methylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-diol;
[0258]
3-{[4-(butylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-dio-
l; and their pharmaceutically acceptable salts.
[0259] According to a variant of the invention, a pharmaceutical
composition according to the invention will include
5-(4-{[(1E)-amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(dimethylamino-
)phenyl]pentanamide or one of its pharmaceutically acceptable
salts.
[0260] More preferentially, a pharmaceutical composition according
to the invention will include, as active ingredient, a compound
chosen from the following compounds: [0261]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)-phenol; [0262]
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
[0263]
2-(dimethylamino)-6-methoxy-4-({methyl[2-(4-nitrophenyl)ethyl]ami-
no}methyl)phenol; [0264]
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl-1,4-benzenediol;
[0265]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)phenyl acetate; [0266] diethyl
4-{2-[(3,7-dihydroxy-2-naphthoyl)amino]ethyl}phenylphosphate;
[0267]
N-{2-[4-(aminosulphonyl)phenyl]ethyl}-3,7-dihydroxy-2-naphthamide;
[0268]
3,7-dihydroxy-N-(2-{4-[(methylsulphonyl)amino]phenyl}ethyl)-2-nap-
hthamide; [0269]
N-(2-{4-[(butylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamide;
[0270]
3,7-dihydroxy-N-[2-(4-{[(4-methylphenyl)sulphonyl]amino}phenyl)e-
thyl]-2-naphthamide; [0271]
3,7-dihydroxy-N-{2-[4-({[3-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide; [0272]
N-[2-(4-{[(4-fluorophenyl)sulphonyl]amino}phenyl)ethyl]-3,7-dihydroxy-2-n-
aphthamide; [0273]
3,7-dihydroxy-N-{3-[(4-methyl-1-piperidinyl)sulphonyl]benzyl}-2-naphthami-
de; [0274]
3-({4-[(4-methylphenyl)sulphonyl]piperazin-1-yl}carbonyl)naphthalene-2,6--
diol; or a pharmaceutically acceptable salt of one of the
latter.
[0275] Also more preferentially, a pharmaceutical composition
according to the invention will include, as active ingredient, a
compound chosen from the following compounds: [0276]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)-phenol; [0277]
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
[0278]
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol;
[0279]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]ami-
no}methyl)phenyl acetate; [0280]
3,7-dihydroxy-N-{2-[4-({[3-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide; [0281]
3,7-dihydroxy-N-{3-[(4-methyl-1-piperidinyl)sulphonyl]benzyl}-2-naphthami-
de; or a pharmaceutically acceptable salt of one of the latter.
[0282] The invention relates moreover to the use of a compound of
general formula (II) as defined previously for preparing a
medicament intended to treat a disease chosen from the following
diseases: tumorous proliferative diseases, and in particular
cancer, non-tumorous proliferative diseases, parasitic diseases,
viral infections, neurodegenerative diseases, myopathies,
spontaneous alopecia, alopecia induced by exogenous products,
radiation-induced alopecia
[0283] Preferably, the compounds of general formula (II) will be
used for preparing a medicament intended to treat a disease chosen
from the following diseases: tumorous proliferative diseases and in
particular cancer, non-tumorous proliferative diseases, parasitic
diseases, viral infections, spontaneous alopecia, alopecia induced
by exogenous products and radiation-induced alopecia.
[0284] Quite particularly, the compounds of general formula (II)
could be used for preparing a medicament intended to treat cancer,
and in particular cancer of the breast, lymphomas, cancers of the
neck and head, cancer of the lung, cancer of the colon, cancer of
the prostate and cancer of the pancreas.
[0285] The invention also relates, as new industrial products, to
the compounds of general formula (III) ##STR36## in which A
represents an (A1) radical ##STR37## in which two of the R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 groups represent hydrogen
atoms and the other three are chosen independently from a hydrogen
atom, a halogen atom and an alkyl, hydroxy, alkoxy,
alkylcarbonyloxy, alkylthio or NR.sup.6R.sup.7 radical, it being
understood moreover that: [0286] either R.sup.1 and one of R.sup.2
and R.sup.4 are chosen independently from a hydroxy,
alkylcarbonyloxy and NR.sup.6R.sup.7 radical, [0287] or R.sup.2 and
one of R.sup.3 and R.sup.5 are chosen independently from a hydroxy,
alkylcarbonyloxy and NR.sup.6R.sup.7 radical, [0288] or R.sup.4 and
one of R.sup.3 and R.sup.5 are chosen independently from a hydroxy,
alkylcarbonyloxy and NR.sup.6R.sup.7 radical, [0289] or also one of
R.sup.1, R.sup.3 and R.sup.5 is chosen from a hydroxy,
alkylcarbonyloxy and NR.sup.6R.sup.7 radical, and the B--N(W)--X--Y
remainder is attached to the A radical by a nitrogen atom, R.sup.6
and R.sup.7 representing, independently each time that they occur,
a hydrogen atom or an alkyl radical or R.sup.6 and R.sup.7 forming
together with the nitrogen atom a heterocycle with 4 to 7 members
comprising 1 to 2 heteroatoms, the members necessary to complete
the heterocycle being chosen independently from the
--CR.sup.8R.sup.9--, --O--, --S-- and --NR.sup.10-- radicals,
R.sup.8 and R.sup.9 independently representing each time that they
occur a hydrogen atom or an alkyl, alkoxy, benzyloxycarbonylamino
or dialkylamino radical, and R.sup.10 independently representing
each time that it occurs a hydrogen atom or an alkyl radical, or
also A represents an (A2) radical ##STR38## in which: [0290] either
R.sup.11 and one of R.sup.13, R.sup.14 and R.sup.15 represent
hydroxy radicals whilst the other radicals from R.sup.13, R.sup.14
and R.sup.15 as well as R.sup.16 represent hydrogen atoms, [0291]
or R.sup.12 and R.sup.16 represent hydroxy radicals whilst
R.sup.11, R.sup.13, R.sup.14 and R.sup.15 represent hydrogen atoms;
B represents a --CO--, --NH--CO--(CH.sub.2).sub.n-- or
--(CH.sub.2).sub.p-- radical, n being an integer from 0 to 3 and p
being an integer from 0 to 1; W represents a hydrogen atom or an
alkyl radical; X represents a --(CH.sub.2).sub.q--,
--(CH.sub.2).sub.q--NH-- or --CO--(CH.sub.2).sub.r-- radical, q
being an integer from 1 to 6 and r an integer from 0 to 6; or also
the B--N(W)--X--Y group is such that it represents the ##STR39##
radical in which B is as defined above, t is an integer from 0 to
2, s is an integer from 0 to 1 and R.sup.17 and R.sup.18 represent
radicals chosen independently from a hydrogen atom and an alkyl
radical; and: [0292] when X represents a --(CH.sub.2).sub.q-- or
--CO--(CH.sub.2).sub.r-- radical, then Y represents a ##STR40##
radical in which R.sup.19 represents an
--SO.sub.2--NR.sup.23R.sup.24, --NH--SO.sub.2--R.sup.25 or
--O--P(O)(OR.sup.26)(OR.sup.27) radical, R.sup.23 and R.sup.24
independently representing a hydrogen atom or an alkyl radical, or
R.sup.23 and R.sup.24 representing together with the nitrogen atom
which carries them a heterocycle with 5 to 7 members the additional
members of which are chosen independently from --CHR.sup.28--,
--NR.sup.29--, --O-- and --S--, R.sup.28 and R.sup.29 representing,
independently each time that they occur, a hydrogen atom or an
alkyl radical, R.sup.25 representing an alkyl, haloalkyl radical or
one of the aryl, heteroaryl, aralkyl or heteroaralkyl radicals the
aryl or heteroaryl nucleus of which is optionally substituted by
one or more radicals chosen independently from a halogen atom and
alkyl, haloalkyl, hydroxy, alkoxy or nitro radicals, except for the
optional nitrogen atoms of the heteroaryl nucleus for which the
optional substituents are chosen from alkyl radicals, R.sup.26 and
R.sup.27 being chosen independently from alkyl radicals, and
R.sup.20 represents a hydrogen atom, a halogen atom or an alkyl,
alkoxy or alkylthio radical; [0293] when X represents a
--(CH.sub.2).sub.q--NH-- radical or when the B--N(W)--X--Y group is
such that it represents the ##STR41## radical then Y exclusively
represents an --SO.sub.2--R.sup.30 radical in which R.sup.30
represents an alkyl, haloalkyl radical or one of the aryl,
heteroaryl, aralkyl or heteroaralkyl radicals the aryl or
heteroaryl nucleus of which is optionally substituted by one or
more radicals chosen independently from a halogen atom and alkyl,
haloalkyl, hydroxy, alkoxy or nitro radicals, except for the
optional nitrogen atoms of the heteroaryl nucleus for which the
optional substituents are chosen from alkyl radicals; it being
understood moreover that when the B--N(W)--X--Y group is such that
it represents the ##STR42## radical then B exclusively represents a
--CO-- or --(CH.sub.2)-- radical; or the salts of compounds of
general formula (III).
[0294] In particular, the invention relates, as new products, to
the following compounds of general formula (III): [0295] diethyl
4-{2-[(3,7-dihydroxy-2-naphthoyl)amino]ethyl}phenylphosphate;
[0296]
N-{2-[4-(aminosulphonyl)phenyl]ethyl}-3,7-dihydroxy-2-naphthamide;
[0297]
3,7-dihydroxy-N-(2-{4-[(methylsulphonyl)amino]phenyl}ethyl)-2-nap-
hthamide; [0298]
N-(2-{4-[(butylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamide;
[0299]
3,7-dihydroxy-N-[2-(4-{[(4-methylphenyl)sulphonyl]amino}phenyl)e-
thyl]-2-naphthamide; [0300]
3,7-dihydroxy-N-(2-{4-[(1-naphthylsulphonyl)amino]phenyl}ethyl)-2-naphtha-
mide; [0301]
3,7-dihydroxy-N-{2-[4-({[2-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide; [0302]
N-(2-{4-[(benzylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamide-
; [0303]
3,7-dihydroxy-N-{2-[4-({[3-(trifluoromethyl)phenyl]sulphonyl}am-
ino)phenyl]ethyl}-2-naphthamide; [0304]
3,7-dihydroxy-N-[2-(4-{[(4-nitrophenyl)sulphonyl]amino}phenyl)ethyl]-2-na-
phthamide; [0305]
3,7-dihydroxy-N-{2-[4-({[4-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl-
]ethyl}-2-naphthamide; [0306]
3,7-dihydroxy-N-(2-{4-[(thien-2-ylsulphonyl)amino]phenyl}ethyl)-2-naphtha-
mide; [0307]
3,7-dihydroxy-N-[2-(4-{[(4-methoxyphenyl)sulphonyl]amino}phenyl)ethyl]-2--
naphthamide; [0308]
3,7-dihydroxy-N-[2-(4-{[(1-methyl-1H-imidazol-4-yl)sulphonyl]amino}phenyl-
)ethyl]-2-naphthamide; [0309]
N-[2-(4-{[(4-fluorophenyl)sulphonyl]amino}phenyl)ethyl]-3,7-dihydroxy-2-n-
aphthamide; [0310]
3,7-dihydroxy-N-{3-[(4-methyl-1-piperidinyl)sulphonyl]benzyl}-2-naphthami-
de; [0311]
3-({4-[(4-methylphenyl)sulphonyl]piperazin-1-yl}carbonyl)naphthalene-2,6--
diol; [0312]
3-{[4-(methylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-diol;
[0313]
3-{[4-(butylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-dio-
l; and the salts of the latter.
[0314] The invention also relates, as new products, to the
following compounds of general formula (I): [0315]
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
[0316]
4-(4-aminophenyl)-N-[4-(4-methyl-1-piperazinyl)phenyl]butanamide;
[0317]
4-(dimethylamino)-2-methoxy-6-({[2-(4-nitrophenyl)ethyl]amino}me-
thyl)phenol; [0318]
4-(dimethylamino)-2-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol;
[0319]
2-(dimethylamino)-6-methoxy-4-({methyl[2-(4-nitrophenyl)ethyl]ami-
no}methyl)phenol; [0320]
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol;
[0321]
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methy-
l)phenyl acetate; [0322]
3,7-dihydroxy-N-[2-(4-nitrophenyl)ethyl]-2-naphthamide; [0323]
N-[4-(dimethylamino)benzyl]-3,7-dihydroxy-2-naphthamide; and the
salts of the latter.
[0324] The invention also relates, as a new industrial product
corresponding to general formula (I), to
5-(4-{[(1E)-amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(dimethylamino-
)phenyl]pentanamide.
[0325] The invention also relates to pharmaceutical compositions
comprising, as active ingredient, a compound of general formula
(III) or a pharmaceutically acceptable salt of the latter.
[0326] Another subject of the invention is the use of compounds of
general formula (III) or of pharmaceutically acceptable salts of
the latter for preparing medicaments intended to treat a disease
chosen from the following diseases: tumorous proliferative
diseases, and in particular cancer, non-tumorous proliferative
diseases, parasitic diseases, viral infections, neurodegenerative
diseases, myopathies; spontaneous alopecia, alopecia induced by
exogenous products, radiation-induced alopecia
[0327] Preferably, the compounds of general formula (III) are used
for preparing a medicament intended to treat a disease chosen from
the following diseases: tumorous proliferative diseases, and in
particular cancer, non-tumorous proliferative diseases, parasitic
diseases, viral infections, spontaneous alopecia, alopecia induced
by exogenous products, radiation-induced alopecia
[0328] Quite particularly, the compounds of general formula (III)
could be used for preparing a medicament intended to treat cancer,
and in particular cancer of the breast, lymphomas, cancers of the
neck and head, cancer of the lung, cancer of the colon, cancer of
the prostate and cancer of the pancreas.
[0329] Generally, the same preferences as those indicated for the
compounds of general formula (I) are moreover applicable by analogy
to the compounds of general formulae (II) and (III).
[0330] The invention also relates to a process for the preparation
of a compound of general formula (I).3 ##STR43## in which A, B, W,
X, R.sup.20 and R.sup.25 have the same meaning as in general
formula (I), said process being characterized in that the compound
of general formula (I).2 ##STR44## is reacted with a compound of
general formula R.sup.25--SO.sub.2Cl in an aprotic solvent (such as
tetrahydrofuran, dichloromethane or dimethylformamide) and in the
presence of a base (such as pyridine, triethylamine or a supported
base, for example morpholinomethyl polystyrene resin; the base
being able if appropriate to also serve as reaction solvent).
[0331] The invention also relates to a process for the preparation
of a compound of general formula (I).7 ##STR45## in which A, B, W,
q and R.sup.30 have the same meaning as in general formula (I),
said process being characterized in that the compound of formula
(XXVII) ##STR46## is reacted with a compound of general formula
R.sup.30--SO.sub.2Cl (XXVIII) in an aprotic solvent (such as
tetrahydrofuran, dichloromethane or dimethylformamide) and in the
presence of a base (such as pyridine, triethylamine or a supported
base, for example morpholinomethyl polystyrene resin; the base
being able if appropriate to also serve as reaction solvent).
[0332] The invention also relates to a process for the preparation
of a compound of general formula (I).8 ##STR47## in which A, B,
R.sup.17, R.sup.18, s, t and R.sup.30 have the same meaning as in
general formula (I), said process being characterized in that the
compound of formula (XXVII)a ##STR48## is reacted with a compound
of general formula R.sup.30--SO.sub.2Cl (XXVIII) in an aprotic
solvent (such as tetrahydrofuran, dichloromethane or
dimethylformamide) and in the presence of a base (such as pyridine,
triethylamine or a supported base, for example morpholinomethyl
polystyrene resin; the base being able if appropriate to also serve
as reaction solvent).
[0333] The invention also relates to a process for the preparation
of a compound of general formula (I).9 ##STR49## in which A, W, X,
R.sup.20, R.sup.26 and R.sup.27 have the same meaning as in general
formula (I), and B represents the --CO-- or --CH.sub.2-- radical,
said process being characterized in that the amine of general
formula (IV).sub.p ##STR50## is reacted with: [0334] either, when B
represents the --CO-- radical, with an acid of general formula
A-CO.sub.2H (V) in an aprotic solvent (such as tetrahydrofuran,
dichloromethane or dimethylformamide) and in the presence of a
peptide coupling agent (such as dicyclohexylcarbodiimide (DCC),
1,1'-carbonyldiimidazole (CDI) or
1-(3-dimethylaminoproyl)-3-ethylcarbodiimide)hydrochloride; [0335]
or, when B represents the --CH.sub.2-- radical, with an aldehyde of
general formula A-CHO (VI) in an alcoholic solvent (such as, for
example, methanol) and in the presence of a reducing agent (such as
NaBH.sub.4, NaBH.sub.3CN or also a resin containing borohydride
ions).
[0336] The pharmaceutical composition can be in the form of a
solid, for example powders, granules, tablets, gelatin capsules,
liposomes or suppositories. Appropriate solid supports can be, for
example, calcium phosphate, magnesium stearate, talc, sugars,
lactose, dextrin, starch, gelatin, cellulose, methyl cellulose,
sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
[0337] The pharmaceutical compositions containing a compound of the
invention can also be presented in liquid form, for example,
solutions, emulsions, suspensions or syrups. Appropriate liquid
supports can be, for example, water, organic solvents such as
glycerol or glycols, as well as their mixtures, in varying
proportions, in water.
[0338] The administration of a medicament according to the
invention can be carried out by topical, oral, parenteral route, by
intramuscular injection, etc.
[0339] The administration dose envisaged for a medicament according
to the invention is comprised between 0.1 mg and 10 g according to
the type of active compound used.
[0340] In accordance with the invention, the compounds of general
formula (I) can be prepared for example by the processes described
below.
Preparation of the Compounds of the Invention
[0341] The preparation processes below are given by way of
illustration and a person skilled in the art will be able to
subject them to the variations that he judges useful, both as
regards to the reagents and the conditions and techniques of the
reactions.
A) Case where Y Represents a Substituted Phenyl Radical
1. Case where Y Represents a Radical of Nitrophenyl Type:
[0342] The compounds of general formula (I) in which Y represents a
radical of nitrophenyl type (hereafter designated by
<<compounds of general sub-formula (I).1>>) can be
easily prepared according to identical or similar procedures to
those described in the PCT Patent Application WO 00/17190.
2. Case where Y Represents a Radical of Aminophenyl,
Dialkylaminophenyl or, Alkylsulphonylamino Type or Also a Radical
of Formula (T):
[0343] In the case where Y represents a radical of aminophenyl,
dialkylaminophenyl, alkylsulphonylamino type or also the radical of
formula (T), the compounds of general formula (I) can be prepared
from nitrophenyl derivatives of general sub-formula (I).1 according
to the procedures represented in Diagram 1 below. ##STR51##
[0344] In the case where neither X or B represents --CH.sub.2--,
the derivatives of aminophenyl type of general sub-formula (I).2,
in which A, B, W, X and R.sup.20 are as defined above can be easily
obtained, Diagram 1, by reduction of the compounds of general
formula (I).1, for example, by the action of hydrogen in the
presence of a catalyst of the palladium on carbon type in a solvent
such as for example methanol, ethanol, dichloromethane or
tetrahydrofuran (THF). In the particular case where at least one of
X and B represents --CH.sub.2--, the reduction of the nitro
function can be carried out, 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) or in the
presence of SnCl.sub.2/Zn (Synthesis. (1996), 9, 1076-1078), using
NaBH.sub.4--BiCl.sub.3 (Synth. Comm. (1995), 25(23), 3799-3803) in
a solvent such as ethanol, or then by using Raney Ni with added
hydrazine hydrate (Monatshefte fur Chemie, (1995), 126, 725-732),
or also by using indium in a mixture of ethanol and ammonium
chloride under reflux (Synlett (1998), 9, 1028).
[0345] The compounds of general formula (I) in which Y represents
the alkylsulphonylaminophenyl radical (i.e. the compounds of
general sub-formula (I).3) can be easily prepared from the
compounds of general formula (I).2, Diagram 1, according to
standard methods of sulphonamide synthesis, by the action of a
sulphonyl halide on an aminated derivative, in an aprotic solvent
such as THF, dichloromethane or dimethylformamide (DMF), in the
presence of a base such as pyridine, triethylamine or a supported
base such as morpholinomethyl polystyrene resin or also by using
pyridine as solvent.
[0346] The compounds of general formula (I) in which Y represents
the (T) radical (i.e. the compounds of general sub-formula (I).4)
can be easily prepared from the compounds of general formula (I).2,
Diagram 1, according to identical or similar procedures to those
described in the PCT Patent Application WO 00/17190.
[0347] Finally, the derivatives of alkylaminophenyl or
dialkylaminophenyl type (the compounds of sub-general formulae
(I).5 and (I).6 respectively represented in Diagram 1) can be
obtained by mono- or dialkylation of the aminophenyl derivatives of
general sub-formula (I).2 according to standard methods known to a
person skilled in the art. Mono-alkylation is carried out by
reducing amination with an aldehyde or by nucleophilic substitution
by reacting with an R.sup.21-Hal halogenoalkyl equivalent in order
to produce the monoalkylated derivative of general sub-formula
(I).5. A second alkylation can then be carried out if appropriate
by means of an R.sup.22-Hal halogenoalkyl in order to produce the
dialkylated derivative of general sub-formula (I).6.
[0348] In the particular case where R.sup.21=R.sup.22=--CH.sub.3
and where neither X or B represents --CH.sub.2--, the nitrophenyl
derivative of general sub-formula (I).2 can be treated with
suitable quantities of paraformaldehyde under a hydrogen atmosphere
in a solvent such as ethanol and in the presence of a catalyst of
the palladium on carbon type, in order to produce the
dimethylaminophenyl derivative of general sub-formula (I).6a (cf.
Diagram 2 below). ##STR52## 3. Other Cases where Y Represents a
Radical of the Substituted Phenyl Type:
[0349] In the other cases not yet mentioned where Y represents a
radical of the substituted phenyl type, the preparation of the
compounds of general formula (I) will be carried out in a standard
manner known to a person skilled in the art.
[0350] When the compounds of general formula (I) will include a
carboxamide function (B=--CO--), they could, for example, be
prepared according to methods of peptide synthesis represented in
Diagram 3 below. ##STR53##
[0351] The carboxamides of general formula (I), Diagram 3, in which
B represents --CO-- and A, W, X, R.sup.19 and R.sup.20 are as
defined previously, are prepared by condensation of the acids of
general formula (V), with the amines of general formula (IV) under
standard conditions of peptide synthesis (M. Bodanszky, The
Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)), for
example 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-dimethylaminoproyl)-3-ethylcarbodiimide
hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of
peptides, 54 (Clarendon Press, Oxford, 1991)).
[0352] When the compounds of general formula (I) are such that
B=--CH.sub.2--, they could, for example, be prepared according to
methods of reducing amination represented in Diagram 4 hereafter.
##STR54##
[0353] The amines of general formula (I), Diagram 4, in which B
represents --CH.sub.2-- and A, W, X, R.sub.19 and R.sub.20 are as
defined previously, are prepared by reaction of the aldehydes of
general formula (VI) with amines of general formula (IV) in
reducing medium. The reaction takes place in an alcoholic solvent
such as, for example, methanol, and leads to the imine which is
then converted to amine by a reducing agent such as NaBH.sub.4 or
NaBH.sub.3CN or also an Amberlite.RTM. IRA-400 borohydride resin
(Aldrich; 2.5 mmol BH.sub.4.sup.-/g of resin).
[0354] When the compounds of general formula (I) are such that
B=--NH--CO--(CH.sub.2).sub.n--, they could, for example, be
prepared according to the synthesis methods represented in Diagram
5 below. ##STR55##
[0355] The compounds of general formula (I), Diagram 5, in which B
represents --NH--CO--(CH.sub.2).sub.n-- and A, W, X, R.sup.19,
R.sup.20 and n are as defined previously, are prepared by reacting
amines of general formula (X) with carboxylic acids of general
formula (XI) (in which X'' is such that X''--CO.dbd.X) according to
methods of peptide synthesis described above or also by reacting
the same amines of general formula (X) with aldehydes of general
formula (XII) (in which X' is such that X'--CH.sub.2.dbd.X) under
the conditions of reducing amination described above, or also by
reacting the same amines of general formula (X) with halogenated
derivatives of general formula (XIII) according to standard methods
known to a person skilled in the art. The amines of general formula
(X) are obtained by condensation of the amines of general formula
(VII) with acids of general formula (VIII) in which A, W and n are
as defined previously and Gp represents a protective group of the
amine function such as, for example, a carbamate group, under
standard conditions of peptide synthesis as described above. The
amine function is then deprotected (deprotection in acid medium in
the case where Gp represents a carbamate group such as, for
example, the tert-butoxycarbonyl group).
[0356] When the compounds of general formula (I) are such that
B=--(CH.sub.2).sub.p-- with p=0 (in other words, B represents a
bond) and X=--CO--(CH.sub.2).sub.r--, they could, for example, be
prepared according to the methods of peptide synthesis represented
in Diagram 6 below. ##STR56##
[0357] The carboxamides of general formula (I), Diagram 6, in which
B represents --(CH.sub.2).sub.p-- with p=0, X represents
--CO--(CH.sub.2).sub.r-- and A, W, R.sup.19, R.sup.20 and r are as
defined previously, are prepared by condensation of the acids of
general formula (XV), with the amines of general formula (XIV)
under standard conditions of peptide synthesis described above.
[0358] When the compounds of general formula (I) are such that
B=--(CH.sub.2).sub.p-- with p=0 (in other words, B represents a
bond) and X=--(CH.sub.2).sub.q--, they could, for example, be
prepared according to the synthesis methods represented in Diagram
7 below. ##STR57##
[0359] The compounds of general formula (I), Diagram 7, in which B
represents --(CH.sub.2).sub.p-- with p=0, X represents
--(CH.sub.2).sub.q--, A, W, R.sup.19, R.sup.20 and q are as defined
previously, are prepared by reaction of the amines of general
formula (XIV) with aldehydes of general formula (XVI) under the
conditions of reducing amination described above, or by reaction of
the same amines of general formula (XIV) with halogenated
derivatives of general formula (XVII) according to standard methods
known to a person skilled in the art.
4. Preparation of the Amines of General Formula (IV):
[0360] The amines which are not commercially available of general
formula (IV) in which X represents (CH.sub.2).sub.q--, W represents
H and R.sup.19 represents an --SO.sub.2--NR.sup.23R.sup.24 radical
(hereafter designated by amines of general formula (IV).sub.s), can
in particular be obtained in 6 stages according to methods in the
literature, and in particular according to the method represented
in Diagram 8 below. ##STR58##
[0361] For example, Diagram 8, the alcohol of general formula (XXI)
is obtained in 3 stages from the acid of general formula (XVIII),
via sulphonamide by the action of a primary or secondary amine on
sulphonyl chloride under the conditions described previously for
the synthesis of sulphonamides, followed by esterification, for
example by a treatment with trimethylsilyldiazomethane in an
alcoholic solvent such as, for example, methanol, and reduction of
the ester function by a reducing agent such as LiBH.sub.4 in a
polar aprotic solvent such as, for example, THF. The alcohol
function is then halogenated by CBr.sub.4 in the presence of
triphenylphosphine, then converted to phthalimide by treatment of
potassium phthalimidate in a polar solvent such as, for example,
acetonitrile. After cleavage of the phthalimide by addition of
hydrazine hydrate in an alcoholic solvent such as, for example,
ethanol, the amine of general formula (IV), is obtained.
[0362] The amines of general formula (IV) in which R.sup.19
represents the --O--P(O)(OR.sup.26)(OR.sup.27) group (hereafter
designated by amines of general formula (IV).sub.p) can be obtained
in 2 stages according to methods in the literature, and in
particular, when X represents a --(CH.sub.2).sub.q-- radical,
according to the method represented in Diagram 9 below.
##STR59##
[0363] According to said method, the phenol of general formula
(XXIV) is substituted, Diagram 9, using a derivative of phosphonate
type, in particular the cyanophosphonate of general formula (XXV),
in the presence of a base such as, for example, triethylamine in a
solvent such as dichloromethane. The protective group of the amine
function (Gp) of the compound of formula (XXVI) is then cleaved
under suitable conditions (for example in acid medium in the case
where Gp is a group of carbamate type, such as the
tert-butoxycarbonyl group) in order to finally produce the amine of
general formula (IV).sub.p.
[0364] For the other amines of general formula (IV), a person
skilled in the art could for example refer to the PCT Patent
Application WO 00/17190.
5. Preparation of Certain Starting Reagents:
[0365] Certain starting reagents are not commercially available and
should be prepared according to methods described in the
literature. By way of example, the preparation of
dihydroxy-2-naphthoic acids (A=naphthyl nucleus) can be carried out
according to the methods described in Marsilje et al., Bioorg. Med.
Chem. Lett. (2000), 10, 477-481.
[0366] The starting reagents in which A represents the phenyl
radical substituted by a alkylcarbonyloxy group are obtained from
corresponding phenols by the action of a corresponding acid
chloride in the presence of a base such as, for example,
diisopropylethylamine in a solvent such as dichloromethane.
[0367] The preparation of certain starting reagents will sometimes
require the use of protection and deprotection reactions well known
to a person skilled in the art who can refer, if necessary, to the
following work: T. W. Greene and P. G. M. Wuts, Protective Groups
in Organic Synthesis, Second edition (Wiley-Interscience,
1991),
B) Case where Y Represents an --SO.sub.2R.sup.30 Radical:
[0368] The compounds of general formula (I) in which Y represents
the --SO.sub.2--R.sup.30 radical (i.e. the compounds of general
sub-formula (I).7 in which X represents the
--(CH.sub.2).sub.q--NH-- radical defined previously and the
compounds of general sub-formula (I).8 in which the --N(W)--X--
group represents an optionally substituted piperazinyl nucleus) can
easily be prepared from the amines of general formulae (XXVII) and
(XXVII)a (in which A, B, W, R.sup.17, R.sup.18, q, s and t have the
same meaning as in general formula (I)) according to procedures of
sulphonamide synthesis as described above (cf. Diagram 10 below).
##STR60## Preparation of the Amines of General Formula (XXVII) and
(XYVII)a:
[0369] When B represents --CO-- or --(CH.sub.2).sub.p-- with p=1,
the amines of general formula (XXVII) and (XXVII)a could, for
example, be prepared by the procedures represented in Diagram 11
below. ##STR61##
[0370] The amines which are not commercially available of general
formula (XXVII) or (XXVII)a in which A, B, W, R.sup.17, R.sup.18,
s, t and q are as defined previously are obtained by standard
methods by condensation of carboxylic acids of general formula (V)
and aldehydes of general formula (VI) with linear diamines of
general formula (XXIX) or cyclic diamines of general formula
(XXIX)a, Diagram 11, according to methods similar to those
described above and in which the protective group Gp of the amine
can be a carbamate group such as the tert-butoxycarbonyl group.
Cleavage of the protective group is carried out according to known
methods, such as for example cleavage in hydrochloric acid medium
in the case of the tert-butoxycarbonyl group.
[0371] When the amines of general formula (XXVII) are such that
B=--(CH.sub.2).sub.p-- with p=0 (in other words, B represents a
bond), they could, for example, be prepared according to the
synthesis methods represented in Diagram 12 below. ##STR62##
[0372] The amines of general formula (XXVII), Diagram 12, in which
B represents --(CH.sub.2).sub.p-- with p=0, X represents
--(CH.sub.2).sub.q--, A, W and q are as defined previously and Gp
is a protective group for an amine function (for example a
protective group of carbamate type such as the tert-butoxycarbonyl
group), are prepared by reacting the amines of general formula
(XIV) with aldehydes of general formula (XXXI) under the conditions
of reducing amination described above, or by reacting the same
amines of general formula (XIV) with halogenated derivatives of
general formula (XXXII) according to standard methods known to a
person skilled in the art, followed by a deprotection stage of the
intermediate of general formula (XXXIII) carried out under standard
conditions known to a person skilled in the art.
[0373] Unless defined otherwise, 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 this invention
belongs. Similarly, all the publications patent applications, all
the patents and all other references mentioned here are
incorporated by way of reference.
[0374] The following examples are presented in order to illustrate
the above procedures and should in no case be considered as a limit
to the scope of the invention.
EXAMPLES
Characterisation of Certain Compounds by their Retention Time
r.t.
[0375] When a retention time r.t. is indicated for the compounds of
the examples, this was measured by high performance liquid
chromatography combined with mass spectrometry (HPLC-MS) using,
according to what is indicated, the following elution conditions:
[0376] conditions 1: passage from an
acetonitrile-water-trifluoroacetic acid 0-1000-0.2 (A) mixture to
an acetonitrile-water-trifluoroacetic acid 850-150-0.2 (B) mixture
by a linear gradient over a period of 6 minutes then elution with
the pure mixture B for 2 minutes. [0377] conditions II: passage
from an acetonitrile-water-trifluoroacetic acid mixture 100-900-0.2
(A) to an acetonitrile-water-trifluoroacetic acid mixture
850-150-0.2 (B) by a linear gradient over a period of 6 minutes
then elution with the pure mixture B for 2 minutes. [0378]
conditions III: passage from an acetonitrile-water-trifluoroacetic
acid mixture 50-950-0.2 (A) to an
acetonitrile-water-trifluoroacetic acid mixture 900-100-0.2 (B) by
a linear gradient over a period of 8.5 min then elution with the
pure mixture B for 2 minutes. [0379] conditions IV: passage from an
acetonitrile-water-trifluoroacetic acid mixture 50-950-0.2 (A) to
an acetonitrile-water-trifluoroacetic acid mixture 950-50-0 (B) by
a linear gradient over a period of 8.5 minutes then elution with
the pure mixture B for 10.5 minutes.
Example 1
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]-amino}methy-
l)phenol
[0380] It is a synthesis intermediate obtained during the
preparation of the compound of Example 80 of the Application WO
00/17190,
N'-(4-{2-[[5-(dimethylamino)-2-hydroxy-3-methoxybenzyl]-(methyl)amino]eth-
yl}-phenyl)-2-thiophenecarboximidamide, according to the procedure
described in this document.
[0381] Melting point: 91-93.degree. C.
[0382] MH+=360.30; r.t.=3.40 min (elution conditions I).
Example 2
4-(dimethylamino)-2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)phenol
[0383] 0.5 g (3 mmol) of 5-(dimethylamino)-2-hydroxybenzaldehyde
(Bull. Chem. Soc. Jpn. (1978), 51 (8), 2433-2434) and 0.72 g (3.33
mmol) of N-methyl-2-(4-nitrophenyl)ethylamine hydrochloride are
placed in solution in 30 ml of anhydrous methanol under an inert
atmosphere in the presence of 0.65 ml of triethylamine (4.5 mmol).
The reaction mixture is stirred vigorously for 18 hours before the
addition, by portions, of 126 mg (3.33 mmol) of NaBH.sub.4.
Stirring is maintained for a further 4 hours before adding 10 ml of
ice-cold water. The reaction mixture is extracted twice with 50 ml
of CH.sub.2Cl.sub.2. The organic phase is washed with 10 ml of
water, dried over sodium sulphate, filtered and concentrated under
vacuum. The residue is purified on a silica column (eluent:
CH.sub.2Cl.sub.2/MeOH: 97/3). The expected product is obtained in
the form of a brown oil with a yield of 34% (0.34 g).
[0384] NMR .sup.1H (DMSO d6, 200 MHz, .delta.): 2.23 (s, 3H,
CH.sub.3); 2.71-2.77 (m, 8H, 2CH.sub.3, CH.sub.2); 2.96 (t, 3H,
CH.sub.2); 3.6 (s, 2H, CH.sub.2); 6.48-6.53 (m, aromatic 3H's);
7.50-7.55 (m, aromatic 2H's); 8.13-8.17 (m, aromatic 2H's).
[0385] MH.sup.+=330.31; r.t.=3.20 min (elution conditions I).
Example 3
2,7-dihydroxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-2-napht-
halenecarboxamide hydrochloride
[0386] [It is the compound of Example 11 of the Application WO
00/17190]
Example 4
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[4-(dimethylami-
no)phenyl]propanamide hydrochloride
[0387] [It is the compound of Example 50 of the Application WO
00/17190]
Example 5
4-(4-aminophenyl)-N-[4-(4-methyl-1-piperazinyl)phenyl]butanamide
hydrochloride
5.1)
4-(4-nitrophenyl)-N-[4-(4-methyl-1-piperazinyl)phenyl]butanamide:
[0388] 4-(N-methylpiperazinyl)aniline (0.5 g; 2.6 mmol),
hydroxybenzotriazole (0.39 g; 2.86 mmol),
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.1
g; 5.7 mmol) and triethylamine (0.8 ml; 5.7 mmol) are added to a
solution of 0.55 g (2.6 mmol) of 4-(4-nitrophenyl)butanoic acid in
dichloromethane (30 ml). The reaction medium is stirred for 16
hours at ambient temperature, then the medium is diluted with 15 ml
of water and the product is extracted with dichloromethane. The
organic phase is dried over sodium sulphate followed by filtering
and concentrating under vacuum and the residue is purified on a
silica column (eluent: CH.sub.2Cl.sub.2/EtOH: 4/1). A clear oil is
obtained with a yield of 84% (0.84 g).
[0389] NMR .sup.1H (CDCl.sub.3, 100 MHz, .delta.): 2.0-2.3 (m, 2H,
CH.sub.2); 2.3-2.5 (m, 5H, CH.sub.2, CH.sub.3); 2.5-2.7 (m, 4H, 2
CH.sub.2); 2.7-3.0 (m, 2H, CH.sub.2); 3.1-3.3 (m, 4H, 2CH.sub.2);
6.9 (s, 1H, NH); 6.9-7.1 (m, aromatic 2H's); 7.3-7.5 (m, aromatic
4H's); 8.1-8.3 (m, aromatic 2H's).
5.2)
4-(4-aminophenyl)-N-[4-(4-methyl-1-piperazinyl)phenyl]-butanamide
hydrochloride
[0390] 0.1 g of palladium on carbon (10%) is added to a solution of
0.84 g (2.2 mmol) of intermediate 5.1 in a mixture of ethanol (150
ml) and dichloromethane (15 ml). The medium is placed under a
hydrogen atmosphere under a pressure of 1.5 bars for 30 minutes.
The catalyst is filtered and the solvent is evaporated under
reduced pressure. The free base is obtained with a yield of 71%
(0.55 g; 1.56 mmol) in the form of a white solid, then placed in
solution in ice-cold ethanol (45 ml) and 4.6 ml (4.7 mmol) of a 1N
solution of hydrochloric acid in ether is added. After stirring for
30 minutes at ambient temperature, the solvent is evaporated to
dryness, then the residue is taken up in ether in order to provide
the expected hydrochloride in the form of a clear brown solid with
a yield of 97% (0.64 g). Melting point: 156-158.degree. C.
[0391] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 1.80-1.88 (m, 2H,
CH.sub.2); 2.27 (t, 2H, CH.sub.2); 2.58 (t, 2H, --CH.sub.2); 2.78
(s, 3H, CH.sub.3); 3.00-3.80 (m, 8H, 4 CH.sub.2); 6.90-6.93 (m,
aromatic 2H's); 7.04-7.06 (m, aromatic 2H's); 7.16-7.18 (m,
aromatic 2H's); 7.47-7.49 (m, aromatic 2H's); 9.77 (s, 1H, NH).
[0392] MH.sup.+=353.23.
Example 6
4-(dimethylamino)-2-methoxy-6-({[2-(4-nitrophenyl)ethyl]amino}methyl)pheno-
l
[0393] The experimental protocol used is the same as that described
for the compound of Example 2, 2-(4-nitrophenyl)ethylamine
replacing N-methyl-2-(4-nitrophenyl)ethylamine and
2-hydroxy-3-methoxy-5-(dimethylamino)benzaldehyde replacing
2-hydroxy-5-(dimethylamino)benzaldehyde. A brown oil is obtained.
NMR .sup.1H (CDCl.sub.3, 400 MHz, .delta.): 2.85 (m, 6H,
N(CH.sub.3).sub.2); 2.97 (m, 4H, 2CH.sub.2); 3.88 (s, 3H,
OCH.sub.3); 3.96 (s, 2H, CH.sub.2); 6.06-6.07 (d, aromatic 1H);
6.36-6.37 (d, aromatic 1H); 7.36-7.37 (d, aromatic 2H's); 8.17-8.18
(d, aromatic 2H's).
[0394] MH+=346.20; r.t.=3.40 min (elution conditions I).
Example 7
4-(dimethylamino)-2-({[2-(4-nitrophenyl)ethyl]amino}methyl)phenol
[0395] The experimental protocol used is the same as that described
for the compound of Example 2, 2-(4-nitrophenyl)ethylamine
replacing N-methyl-2-(4-nitrophenyl)ethylamine. A brown oil is
obtained. NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 2.71 (m, 6H,
N(CH.sub.3).sub.2); 2.75-2.89 (m, 4H, 2CH.sub.2); 3.76 (s, 3H,
CH.sub.3); 6.55 (m, 3H, aromatic H); 7.48-7.50 (d, aromatic 2H's);
8.12-8.14 (d, aromatic 2H's).
[0396] MH+=316.26; r.t.=3.30 min (elution conditions I).
Example 8
2-(dimethylamino)-6-methoxy-4-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl-
)phenol
[0397] The experimental protocol used is the same as that described
for the compound of Example
2,5-(dimethylamino)-4-hydroxy-3-methoxybenzaldehyde, (Bull. Chem.
Soc. Jpn. (1978), 51(8), 2433-2434; replacing
5-(dimethylamino)-3-methoxy-2-hydroxybenzaldehyde. A brown oil is
obtained.
[0398] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 2.61-2.64 (m, 2H,
CH.sub.2); 2.71 (m, 6H, N(CH.sub.3).sub.2); 2.88-2.90 (m, 2H,
CH.sub.2); 3.66 (s, 2H, CH.sub.2); 7.14-7.17 (m, aromatic 2H's);
7.48-7.51 (m, aromatic 2H's); 8.13-8.15 (m, aromatic 2H's).
[0399] MH+=360.27; r.t.=3.30 min (elution conditions I);
Example 9
2-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl)-1,4-benzenediol
[0400] The experimental protocol used is the same as that described
for the compound of Example 2, 2,5-dihydroxybenzaldehyde replacing
5-(dimethylamino)-3-methoxy-2-hydroxybenzaldehyde. A brown oil is
obtained.
[0401] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 2.22 (s, 3H,
CH.sub.3); 2.74 (t, 2H, CH.sub.2); 2.95 (t, 2H, CH.sub.2); 3.57 (s,
2H, CH.sub.2); 6.48 (m, aromatic 3H's); 7.50-7.52 (d, aromatic
2H's); 8.13-8.15 (d, aromatic 2H's).
[0402] MH+=303.25; r.t.=3.80 min (elution conditions I).
Example 10
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]amino}methyl-
)phenyl acetate
[0403] 0.1 g (0.278 mmol) of
4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]-amino}meth-
yl)phenol (compound of Example 1) are placed in solution in 5 ml of
anhydrous dichloromethane in the presence of 49 .mu.l (0.42 mmol;
1.5 eq.) of diisopropylethylamine at 0.degree. C. 30 .mu.l (0.42
mmol; 1.5 eq.) of acetyl chloride are added dropwise to the
solution and the medium is stirred for 1 hour at ambient
temperature. Then 10 ml of dichloromethane is added to the reaction
medium which is then washed with 3 times 10 ml of a saturated
solution of sodium chloride. The organic phase is dried over
magnesium sulphate, followed by filtering and concentrating under
vacuum. The residue is purified on a silica column (eluent:
AcOEt/Heptane: 2/1) in order to produce a yellow oil with a yield
of 60%.
[0404] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 2.16 (m, 6H,
2N(CH.sub.3).sub.2); 2.59 (t, 2H, CH.sub.2); 2.80 (m, 6H, 2
CH.sub.3); 2.87 (t, 2H, CH.sub.2); 3.31 (s, 2H, CH.sub.2); 3.71 (s,
3H, OCH.sub.3); 6.11 (s, aromatic 1H); 6.27 (s, aromatic 1H); 7.48
(m, aromatic 2H's); 8.11 (m, aromatic 2H's).
[0405] MH+=402.19; r.t.=4.80 min (elution conditions I).
Example 11
3,7-dihydroxy-N-[2-(4-nitrophenyl)ethyl]-2-naphthamide
[0406] 125 .mu.l of 4-nitrophenethylamine (1 mmol), 1 ml of a 1M
solution of N,N'-dicyclohexylcarbodiimide in dichloromethane and
135 mg (1 mmol) of hydroxybenzotriazole monohydrate are added
successively to a solution of 204 mg (1 mmol) of
3,7-dihydroxy-2-naphthoic acid in dimethylformamide (10 ml). The
reaction mixture is stirred for two hours at ambient temperature,
followed by diluting with 100 ml of water and extracting twice with
30 ml of ethyl acetate. The organic phases are combined then washed
successively with 100 ml of water then with 50 ml of a saturated
solution of sodium chloride. The organic phase is dried over
magnesium sulphate, followed by filtering and the solvent is
eliminated by evaporation under reduced pressure. The residue is
taken up in dichloromethane followed by filtering and drying under
vacuum. 100 mg of product is obtained in the form of a yellow
powder (yield of 30%). Melting point: >250.degree. C.
[0407] MH+=353.20; r.t.=6.10 min (elution conditions I).
Example 12
N-[4-(dimethylamino)benzyl]-3,7-dihydroxy-2-naphthamide
[0408] The experimental protocol used is the same as that described
for the compound of Example 11, 4-dimethylaminobenzylamine
replacing 4-nitrophenethylamine. A yellow oil is obtained.
[0409] NMR-.sup.1H (DMSO d6, 400 MHz, .delta.): 2.86 (s, 6H); 4.42
(s, 2H); 6.70 (m, 2H); 7.04-7.20 (m, 5H); 7.58 (d, 1H); 8.29 (s,
1H); 9.32 (t, 1H); 9.55 (s, 1H); 11.78 (s, 1H).
[0410] MH+=337.20; r.t.=4.20 min (elution conditions I).
Example 13
diethyl
4-{2-[(3,7-dihydroxy-2-naphthoyl)amino]ethyl}phenylphosphate
13.1) tert-butyl
2-{4-[(diethoxyphosphoryl)oxy]phenyl}ethylcarbamate
[0411] 1.2 g (5 mmol) of N-Boc tyramine, 0.9 g (5.5 mmol) of
diethylcyanophosphonate and 1.4 ml (10 mmol) of triethylamine are
placed in solution in 5 ml of dichloromethane at 0.degree. C. under
an argon atmosphere. The reaction mixture is stirred for 30 minutes
at 0.degree. C. followed by diluting with 25 ml of water and
extracting with twice 30 ml of dichloromethane. The organic phases
are combined followed by washing with 50 ml of water then 25 ml of
a saturated solution of sodium chloride. The organic phase is dried
over magnesium sulphate, followed by filtering and concentrating
under vacuum. The expected product is obtained in the form of a
clear oil with a yield of 92% (1.73 g).
13.2) diethyl 4-(2-aminoethyl)phenylphospate
[0412] 1.7 g (4.5 mmol) of intermediate 13.1 is dissolved in 20 ml
of a 4M solution of hydrochloric acid in dioxane. The reaction
mixture is stirred for 1 hour at ambient temperature then
concentrated under reduced pressure. 20 ml of a saturated solution
of sodium hydrogen carbonate is added to the reaction mixture which
is then extracted twice with 25 ml of ethyl acetate. The desired
compound is obtained with a yield of 62% (0.76 g) and is used in
the following stage without other purification.
13.3) diethyl
4-{2-[(3,7-dihydroxy-2-naphthoyl)amino]ethyl}phenylphosphate
[0413] The experimental protocol used is the same as that described
for the compound of Example 11, intermediate 13.2 replacing
4-nitrophenethylamine. A yellow powder is obtained. Melting point:
192-194.degree. C.
[0414] MH+=460.20; r.t.=9.60 min (elution conditions I).
Example 14
N-{2-[4-(aminosulphonyl)phenyl]ethyl}-3,7-dihydroxy-2-naphthamide
[0415] The experimental protocol used is the same as that described
for the compound of Example 11, 4-(2-aminoethyl)benzenesulphonamide
replacing 4-nitrophenethyl amine. A yellow oil is obtained.
[0416] NMR-.sup.1H (DMSO d6, 400 MHz, .delta.): 2.98 (t, 2H); 3.59
(q, 2H); 7.05-7.09 (m, 2H); 7.14 (s, 1H); 7.28 (s, 2H); 7.46 (d,
2H); 7.58 (d, 1H); 7.75 (d, 2H); 8.22 (s, 1H); 9.03 (t, 1H); 9.55
(s, 1H); 11.64 (s, 1H).
[0417] MH+=387.10; r.t.=4.30 min (elution conditions I).
Example 15
3,7-dihydroxy-N-[2-(4-aminophenyl)ethyl]-2-naphthamide
[0418] It is a synthesis intermediate from obtained during the
preparation of the compound of Example 11 of the Application WO
00/17190, 2,7-dihydroxy-N-{2-[4-[(2-thienyl
(imino)methyl)amino]phenyl]ethyl}-2-naphthalenecarboxamide,
according to the procedure described in this document. A beige
solid is obtained.
[0419] MH+=323.20; r.t.=4.00 min (elution conditions I).
Example 16
3,7-dihydroxy-N-(2-{4-[(methylsulphonyl)amino]phenyl}ethyl)-2-naphthamide
[0420] 44 .mu.l (0.55 mmol) of methanesulphonyl chloride is added
to a solution of 170 mg (0.5 mmol) of the compound of Example 15 in
pyridine (1 ml). The reaction medium is stirred for 16 hours at
ambient temperature then diluted with 20 ml of water and extracted
twice with 30 ml of ethyl acetate. The organic phases are combined
followed by washing successively with 20 ml of water then 20 ml of
a saturated solution of sodium chloride. The organic phase is dried
over magnesium sulphate, followed by filtering and the solvent is
eliminated by evaporation under reduced pressure. The residue is
eluted on silica with a mixture of ethyl acetate and
dichloromethane (30/70). 65 mg of product is obtained (yield of
30%) in the form of a yellow powder. Melting point: 176-178.degree.
C.
[0421] MH+=401.10; r.t.=4.60 min (elution conditions II).
[0422] The compounds of Examples 17 to 28 are synthesized according
to the same strategy as that used for the compound of Example
16.
Example 17
N-(2-{4-[(butylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamide
[0423] Yellow powder. Melting point: 193-195.degree. C.
[0424] MH+=443.20; r.t.=5.50 min (elution conditions II).
Example 18
3,7-dihydroxy-N-[2-(4-{[(4-methylphenyl)sulphonyl]amino}phenyl)ethyl]-2-na-
phthamide
[0425] Yellow powder. Melting point: 182-184.degree. C.
[0426] MH+=477.20; r.t.=5.70 min (elution conditions II).
Example 19
3,7-dihydroxy-N-(2-{4-[(1-naphthylsulphonyl)amino]phenyl}ethyl)-2-naphtham-
ide
[0427] Yellow oil.
[0428] MH+=513.20; r.t.=9.70 min (elution conditions III).
Example 20
3,7-dihydroxy-N-{2-[4-({[2-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl]-
ethyl}-2-naphthamide
[0429] Yellow oil.
[0430] MH+=531.20; r.t.=9.60 min (elution conditions III).
Example 21
N-(2-{4-[(benzylsulphonyl)amino]phenyl}ethyl)-3,7-dihydroxy-2-naphthamide
[0431] Yellow oil.
[0432] MH+=477.20; r.t.=9.20 min (elution conditions III).
Example 22
3,7-dihydroxy-N-{2-[4-({[3-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl]-
ethyl}-2-naphthamide
[0433] Brown oil.
[0434] MH+=531.20; r.t.=9.80 min (elution conditions III).
Example 23
3,7-dihydroxy-N-[2-(4-{[(4-nitrophenyl)sulphonyl]amino}phenyl)ethyl]-2-nap-
hthamide
[0435] Orange-coloured oil.
[0436] MH+=508.20; r.t.=9.30 min (elution conditions III).
Example 24
3,7-dihydroxy-N-{2-[4-({[4-(trifluoromethyl)phenyl]sulphonyl}amino)phenyl]-
ethyl}-2-naphthamide
[0437] Brown oil.
[0438] MH+=531.20; r.t.=9.80 min (elution conditions III).
Example 25
3,7-dihydroxy-N-(2-{4-[(thien-2-ylsulphonyl)amino]phenyl}ethyl)-2-naphtham-
ide
[0439] Yellow oil.
[0440] MH+=469.20; r.t.=9.00 min (elution conditions III).
Example 26
3,7-dihydroxy-N-[2-(4-{[(4-methoxyphenyl)sulphonyl]amino}phenyl)ethyl]-2-n-
aphthamide
[0441] Yellow oil.
[0442] MH+=493.20; r.t.=9.10 min (elution conditions III).
Example 27
3,7-dihydroxy-N-[2-(4-{[(1-methyl-1H-imidazol-4-yl)sulphonyl]amino}phenyl)-
ethyl]-2-naphthamide
[0443] Yellow oil.
[0444] MH+=467.20; r.t.=7.90 min (elution conditions III).
Example 28
N-[2-(4-{[(4-fluorophenyl)sulphonyl]amino}phenyl)ethyl]-3,7-dihydroxy-2-na-
phthamide
[0445] Yellow oil.
[0446] MH+=481.20; r.t.=9.20 min (elution conditions III).
Example 29
3,7-dihydroxy-N-{3-[(4-methyl-1-piperidinyl)sulphonyl]benzyl}-2-naphthamid-
e
29.1) 3-(4-methylpiperidinosulphonyl)phenylmethanol:
[0447] 11 g (50 mmol) of 3-chlorosulphonylbenzoic acid in
suspension in dichloromethane (300 ml) is treated with 12.4 g (125
mmol) of 4-methylpiperidine and the reaction mixture is maintained
under stirring at ambient temperature overnight. The resulting
solution is washed successively with a 10% aqueous solution of
citric acid and a saturated solution of sodium chloride, followed
by drying (Na.sub.2SO.sub.4) and concentrating under reduced
pressure in order to produce a colourless viscous residue. The
latter is taken up in methanol and, whilst maintaining the
temperature between 0.degree. C. and 10.degree. C., is titrated by
trimethylsilyldiazomethane until a characteristic yellow coloration
persists. The excess reagent is destroyed with a few drops of
formic acid, and the reaction medium is concentrated under reduced
pressure. The traces of acid and methanol are eliminated by two
azeotropic evaporations under reduced pressure with toluene. The
residue, taken up in tetrahydrofuran (300 ml), is treated with
lithium borohydride (2N in THF, 30 ml). The reaction medium is
taken to reflux for 2 hours then cooled down and hydrolyzed with a
saturated solution of ammonium chloride. The resulting mixture is
extracted with ethyl acetate then the organic phase is washed with
a saturated solution of sodium chloride, followed by drying
(Na.sub.2SO.sub.4) and concentrating under reduced pressure. The
residue is purified on a silica column (eluent: 5% acetone in
dichloromethane) in order to produce the expected benzyl alcohol in
the form of a white solid.
[0448] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 0.84 (d, 3H); 1.13
(m, 2H); 1.26 (m, 1H); 1.63 (d, 2H); 2.17 (t, 2H); 3.59 (d, 2H);
4.59 (d, 2H); 5.42 (t, 1H); 7.60 (m, 3H); 7.67 (s, 1H).
29.2)
2-[3-(4-methylpiperidinosulphonyl)benzyl]-1,3-isoindolinedione
[0449] 950 mg (3.5 mmol) of benzyl alcohol, 1.5 equivalents of
triphenylphosphine and 1.5 equivalents of phthalimide in solution
in dichloromethane (50 ml) are treated with 1.5 equivalents of
diisopropyl diazadicarboxylate and the reaction mixture is stirred
overnight at ambient temperature, then treated with a saturated
solution of ammonium chloride, washed with a saturated solution of
sodium chloride, followed by drying (Na.sub.2SO.sub.4) and
concentrating under reduced pressure. The residue is purified on a
silica column (eluent: EtOAc/heptane 1/4) in order to produce a
white solid.
[0450] NMR .sup.1H (DMSO d6; 400 MHz, .delta.): 0.79 (d, 3H); 1.05
(m, 2H); 1.26 (m, 1H); 1.57 (d, 2H); 2.18 (t, 2H); 3.56 (d, 2H);
4.89 (s, 2H); 7.6 (m, 3H); 7.68 (s, 1H); 7.88 (m, 4H).
29.3) 3-(4-methylpiperidinosulphonyl)benzylamine
[0451] Intermediate 29.2 is treated with an excess of hydrazine
hydrate in methanol and the resulting mixture is maintained under
stirring at ambient temperature overnight, then concentrated under
reduced pressure. The residue taken up in dichloromethane is washed
with a saturated solution of sodium chloride. After drying and
concentrating, a white solid is obtained which is purified on a
silica column (eluent: 10% MeOH/DCM) in order to produce a white
solid.
[0452] NMR .sup.1H (DMSO-d6, 400 MHz, .delta.): 0.84 (d, 3H); 1.13
(m, 2H); 1.26 (m, 1H); 1.63 (d, 2H); 2.17 (t, 2H); 3.58 (d, 2H);
4.22 (d, 2H); 7.6 (m, 3H); 7.70 (s, 1H).
29.4)
3,7-dihydroxy-N-{3-[(4-methyl-1-piperidinyl)sulphonyl]benzyl}-2-naph-
thamide
[0453] The experimental protocol used is the same as that described
for the compound of Example 11, intermediate 29.3 replacing
4-nitrophenethylamine.
[0454] NMR .sup.13C (DMSO-d6, 100 MHz, .delta.): 21.4; 29.39;
32.90; 42.41; 46.19; 109.22; 111.06; 118.89; 121.59; 126.06;
126.14; 127.47; 127.57; 128.07; 129.58; 130.89; 132.15; 136.01;
140.98; 153.00; 153.67; 168.58.
[0455] MH+=455.20; r.t.=9.90 min (elution conditions IV).
Example 30
5-(4-{[(1E)-amino(2-thienyl)methylidene]amino}phenyl)N-[2-(dimethylamino)p-
henyl]pentanamide hydrochloride
30.1) N-[2-(dimethylamino)phenyl]-5-(4-nitrophenyl)pentanamide
[0456] The experimental protocol used is the same as that described
for intermediate 5.1), N,N-dimethyl-1,2-benzenediamine replacing
4-(N-methylpiperazinyl)aniline and 5-(4-nitropheny)pentanoic acid
replacing 4-(4-nitrophenyl)butanoic acid.
30.2) 5-(4-aminophenyl)-N-[2-(dimethylamino)phenyl]pentanamide
[0457] The experimental protocol used is the same as that described
for intermediate 5.2, intermediate 30.1 replacing intermediate
5.1.
30.3)
5-(4-{[(1E)-amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(dimethyl-
amino)phenyl]pentanamide hydrochloride
[0458] 0.071 g (0.24 mmol) of S-methyl-2-thiophenethiocarboximide
hydroiodide (Ann. Chim. (1962), 7, 303-337) is added to a solution
of 0.07 g (0.22 mmol) of intermediate 30.2 in 2-propanol (5 ml).
After heating at 60.degree. C. for 18 hours, the reaction mixture
is concentrated to dryness under reduced pressure. The residue is
taken up in ethyl acetate and a saturated solution of sodium
carbonate. After decanting, the organic phase is washed
successively with twice 25 ml of water and twice 25 ml of a
saturated solution of sodium chloride. The organic phase is dried
over magnesium sulphate followed by filtering and evaporating under
reduced pressure. The evaporation residue is purified on a silica
column (eluent: ethyl acetate/heptane: 2/1). 0.06 g (yield of 63%)
of a free base is obtained. The hydrochloride is prepared by
dissolving 0.06 g (0.14 mmol) of the previously obtained base in
acetone (10 ml) and by adding 0.43 ml of a molar solution of
hydrochloric acid in anhydrous diethyl ether to it. The crystals
obtained are filtered and rinsed with diethyl ether in order to
produce, after drying, 0.052 g of the desired product (yield of
74%) in the form of a beige solid. Melting point: 145-148.degree.
C. MH+=421.20; r.t.=3.30 min (elution conditions II).
Example 31
3-({4-[(4-methylphenyl)sulphonyl]piperazin-1-yl}carbonyl)naphthalene-2,6-d-
iol
31.1) tert-butyl
4-(3,7-dihydroxy-2-naphthoyl)piperazine-1-carboxylate
[0459] The experimental protocol used is the same as that described
for the compound of Example 11, N-tert-butyloxycarbonylpiperazine
replacing 4-nitrophenethylamine. A beige solid is obtained.
31.2) 3-(piperazin-1-ylcarbonyl)naphthalene-2,6-diol
[0460] 10 ml of a 4N solution of hydrochloric acid in dioxane is
added to a solution of 1.9 g (5 mmol) of intermediate 31.1 in
ethanol (20 ml). The solution is stirred for 2 hours at ambient
temperature, the solvent is evaporated off and the residue is taken
up in dichloromethane. The precipitate is filtered followed by
washing with dichloromethane and drying under vacuum. 1.35 g of the
expected product is obtained in the form of a white powder.
31.3)
3-({4-[(4-methylphenyl)sulphonyl]piperazin-1-yl}carbonyl)naphthalene-
-2,6-diol
[0461] The experimental protocol used is the same as that described
for the compound of Example 16, intermediate 31.2 replacing the
compound of Example 15 and paratoluene sulphonyl chloride replacing
methane sulphonyl chloride. A yellow powder is obtained.
[0462] Melting point: 135-137.degree. C.
[0463] MH+=427.20; r.t.=8.30 min (elution conditions IV).
[0464] The compounds of Examples 32 and 33 are synthesized
according to the same strategy as that used for the compound of
Example 31.
Example 32
3-{[4-(methylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-diol
[0465] Yellow powder. Melting point: 124-126.degree. C.
[0466] MH+=351.20; r.t.=6.70 min (elution conditions IV).
Example 33
3-{[4-(butylsulphonyl)piperazin-1-yl]carbonyl}naphthalene-2,6-diol
[0467] Yellow powder. Melting point: 105-110.degree. C.
[0468] MH+=393.20; r.t.=7.90 min (elution conditions IV).
Pharmacological Study of the Compounds of the Invention
Test Protocols
a) Measurement of the Phosphatase Activity of the Purified Cdc25C
Recombinant Enzyme
[0469] The phosphatase activity of the MBP-Cdc25C protein is
evaluated by the dephosphorylation of
3-O-methylfluorescein-phosphate (OMFP) to 3-O-methylfluorescein
(OMF) with determination of the fluorescence of the reaction
product at 475 nm. This test allows identification of the
inhibitors of cdc25 recombinant enzyme. The preparation of the
fusion protein MBP-cdc25C is described in PCT Patent Application WO
01/44467.
[0470] The reaction is carried out in 384-well plate format in a
final volume of 50 .mu.l. The MBP-Cdc25C protein (prepared as
described above) is stored in the following elution buffer: 20 mM
Tris-HCl pH 7.4; 250 mM NaCl; 1 mM EDTA; 1 mM DTT; 10 mM maltose.
It is diluted to a concentration of 60 .mu.M in the following
reaction buffer: 50 mM Tris-HCl pH 8.2; 50 mM NaCl; 1 mM DTT; 20%
glycerol. Measurement of the background noise is carried out with
the buffer without addition of the enzyme. The products are tested
at decreasing concentrations starting from 80 .mu.M. The reaction
is initiated by the addition of an OMFP solution at 500 .mu.M final
(prepared beforehand from a 12.5 mM stock solution in 100% DMSO
(Sigma #M2629)). After 4 hours at 30.degree. C. in a disposable
384-well plate, the fluorescence measured at OD 475 nm is read
using a Victor2 plate reader (EGG-Wallac). Determination of the 50%
inhibitory concentration of the enzymatic reaction is calculated
from three independent experiments. Only the values included in the
linear part of the sigmoid are retained for linear regression
analysis.
b) Measurement of the State of cdc2 Phosphorylation:
[0471] This relates to showing that the enzymatic activity of
cdc25-C phosphatase is inhibited in vivo on the purified enzyme in
the presence of selected inhibitors. When cdc25-C is inhibited, the
quantity of phosphorylated cdc2 protein (inactive) increases.
[0472] The cells of the Mia PaCa2 line are seeded at a rate of 450
000 cells in 10 cm Petri dishes in Dulbecco's modified Eagle medium
completed with 10% foetal calf serum 48 hours later, the cells are
treated for 1 hour with the compound to be tested or menadione at
100 .mu.M (reference inhibitor). The medium is renewed after
washing with PBS. 24 hours after the cells are scraped and lysed in
the lysis buffer (Hepes 50 mM pH 7.5; NaCl 10 mM; Triton X100 1%;
glycerol 10%; MgCl.sub.2 5 mM; EDTA 1 mM; sodium orthovanadate 1
mM; protease inhibitor cocktail 1836170 Roche Diagnostics). After
centrifugation at 13 000 rpm for 10 minutes at 4.degree. C., the
concentration of proteins is, determined in the supernatant
(Bio-Rad DC Protein assay kit) and adjusted to 10 .mu.g. The load
buffer concentrated 5 times (TrisHCl 125 mM pH 7.4; SDS 10%;
glycerol 50%; bromophenol blue 0.025%; .beta.-mercaptoethanol 7%)
is added to the samples. The samples are heated for 10 minutes at
100.degree. C. The samples are deposited in a volume of 40 .mu.l on
Tris/Glycine 12% gels (BioRad). Migration occurs over 1 hour at 180
V. The proteins are transferred onto a nitrocellulose membrane
(Hybond C, Amersham) under semi-dry conditions. The membrane is
blocked for 1 hour in milk (BioRad) at 5% with 0.1% Tween 20. Then
it is incubated for 6 hours with the primary antibody directed
against phosphorylated cdc2 (PhosphoPlus cdc2, 91115 New England
BioLabs) diluted to 1/1300.sup.th. After washing in PBS-Tween 20 at
0.1%, the membrane is incubated for 1 hour and 30 minutes with the
secondary antibody anti-rabbit Immunoglobulin G (anti-rabbit
IgG-HRP, sc2030, Santa Cruz) diluted to 1/40000.sup.th. The
proteins are revealed by electrochemical luminescence (western
blotting detection system ECL.sup.+, Amersham) which is detected
using photographic films (BioMax light, Sigma). The images are
scanned (BioProfil scanner, Vilbert Lourmat) and processed in
Powerpoint.RTM.. The result obtained is reproduced in FIG. 1 which
represents the comparative effect of menadione and the compound of
Example 1 on the phosphorylation of cdc2 in the Mia PaCa-2 line (3
hour treatment with menadione or the compound of Example 1 and
sampling 24 hours later).
c) Characterization of the Anti-Proliferative Activity:
[0473] By way of example, the effect of a treatment on two lines of
human Mia-Paca2 and DU145 cells with compounds of Examples 1-5
described previously will be studied. The cell lines DU145 (human
prostate cancer cells) and Mia-PaCa2 (human pancreatic cancer
cells) were acquired from the American Tissue Culture Collection
(Rockville, Md., USA). The cells placed in 80 .mu.l of Dulbecco's
modified Eagle medium (Gibco-Brl, Cergy-Pontoise, France) completed
with 10% foetal calf serum inactivated by heating (Gibco-Brl,
Cergy-Pontoise, France), 50000 units/l of penicillin and 50 mg/l
streptomycin (Gibco-Brl, Cergy-Pontoise, France), and 2 mM of
glutamine (Gibco-Brl, Cergy-Pontoise, France) were seeded on a
96-well plate on day 0. The cells were treated on day 1 for 96
hours with increasing concentrations of each of the compounds to be
tested up to 50 .mu.g/ml. At the end of this period, quantification
of cell proliferation is evaluated by a colorimetric test based on
the cleavage of the tetrazolium salt WST1 by mitochondrial
dehydrogenases in viable cells leading to the formation of formazan
(Boehringer Mannheim, Meylan, France). These tests are carried out
in duplicate with 8 determinations per concentration tested. For
each compound to be tested, the values included in the linear part
of the sigmoid were retained for linear regression analysis and
used to estimate the inhibitory concentration IC.sub.50. The
products are solubilized in dimethylsulphoxide (DMSO) at 10.sup.-2
M and finally used in culture with 0.5% DMSO.
Results of the Tests
[0474] a) The compounds of Examples 1 to 11, 13 to 18 and 27 to 33
present an IC.sub.50 lower than or equal to 100 .mu.M on the
phosphatase activity of the purified Cdc25-C recombinant
enzyme.
[0475] b) The inhibitory activity of the compound of Example 1 on
the endogenous cdc25C phosphatase of human cells is shown by the
growing increase of the phosphorylated form of cdc2 in the
Mia-Paca2 cells treated with increasing concentrations of this
compound. This increase is comparable to that induced by menadione
(see FIG. 1).
[0476] c) The compounds of Examples 1 to 4, 6 to 11, 13, 14, 16 to
18, 22 and 28 to 31 present an IC.sub.50 lower than or equal to 100
.mu.M on the cell proliferation of Mia-Paca2 lines.
[0477] d) The compounds of the examples 1 to 4, 8 to 10, 13, 14, 16
to 18, 22 and 28 to 30 present an IC.sub.50 lower than or equal to
100 .mu.M on the cell proliferation of DU-145 lines.
* * * * *