U.S. patent application number 12/849573 was filed with the patent office on 2010-12-16 for 4,7-dioxobenzothiazole-2-carboxamide derivatives, their preparation and their therapeutic uses.
This patent application is currently assigned to Ipsen Pharma S.A.S.. Invention is credited to Marie-Odile Galcera-Contour, Gregoire Prevost, Alban Sidhu.
Application Number | 20100317658 12/849573 |
Document ID | / |
Family ID | 34952837 |
Filed Date | 2010-12-16 |
United States Patent
Application |
20100317658 |
Kind Code |
A1 |
Galcera-Contour; Marie-Odile ;
et al. |
December 16, 2010 |
4,7-Dioxobenzothiazole-2-Carboxamide Derivatives, Their Preparation
And Their Therapeutic Uses
Abstract
A subject of the present invention is
4,7-dioxobenzothiazole-2-carboxamide derivatives, which inhibit the
cdc25 phosphatases, in particular cdc25-C phosphatase. These
compounds can in particular be used in the treatment of cancer.
Inventors: |
Galcera-Contour; Marie-Odile;
(Bondoufle, FR) ; Prevost; Gregoire; (Antony,
FR) ; Sidhu; Alban; (Palaiseau, FR) |
Correspondence
Address: |
HUNTON & WILLIAMS LLP;INTELLECTUAL PROPERTY DEPARTMENT
1900 K STREET, N.W., SUITE 1200
WASHINGTON
DC
20006-1109
US
|
Assignee: |
Ipsen Pharma S.A.S.
Paris
FR
|
Family ID: |
34952837 |
Appl. No.: |
12/849573 |
Filed: |
August 3, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11718791 |
May 7, 2007 |
7795284 |
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PCT/FR05/02763 |
Nov 7, 2005 |
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12849573 |
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Current U.S.
Class: |
514/233.8 ;
514/253.1; 514/254.02; 514/314; 514/367 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 31/00 20180101; A61P 33/00 20180101; A61P 29/00 20180101; C07D
417/12 20130101; A61P 9/10 20180101; A61P 17/06 20180101; C07D
277/68 20130101; A61P 3/02 20180101; A61P 31/12 20180101; A61P
17/14 20180101; A61P 43/00 20180101; A61P 25/28 20180101; A61P
21/00 20180101; A61P 37/00 20180101; A61P 15/18 20180101; A61P
37/08 20180101; A61P 9/00 20180101; A61P 37/06 20180101; A61P 35/00
20180101 |
Class at
Publication: |
514/233.8 ;
514/367; 514/254.02; 514/253.1; 514/314 |
International
Class: |
A61K 31/428 20060101
A61K031/428; A61K 31/5377 20060101 A61K031/5377; A61K 31/496
20060101 A61K031/496; A61K 31/4725 20060101 A61K031/4725; A61P
35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 5, 2004 |
FR |
0411802 |
Claims
1-10. (canceled)
11. A method of treating a disease or disorder comprising
administering a compound of formula (I) ##STR00050## in racemic,
enantiomeric form or a combination thereof, wherein: R.sup.1 is a
hydrogen atom, alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl,
--(CH.sub.2)--X--Y, --(CH.sub.2)--Z--NR.sup.6R.sup.7 radical or a
--CHR.sup.8R.sup.9 radical, X is a bond or a linear or branched
alkylene radical comprising 1 to 5 carbon atoms, Y is a saturated
cyclic carbon system comprising 1 to 3 condensed rings, wherein
each ring independently comprises 3 to 7 members, or Y is a
saturated heterocycle comprising 1 to 2 heteroatoms including O, N
or S and attached to X by an N or CH member, said saturated
heterocycle comprising 2 to 6 additional members, each
independently including --CHR.sup.10--, --CO--, --NR.sup.11--,
--O-- or --S--, R.sup.10 is a hydrogen atom or an alkyl radical and
R.sup.11 is a hydrogen atom or an alkyl or aralkyl radical, or Y is
a carbocyclic or heterocyclic aryl radical optionally substituted
by 1 to 3 substituents including a halogen atom, an alkyl radical,
a haloalkyl radical, an alkoxy radical, a haloalkoxy radical, a
hydroxy radical, a nitro radical, a cyano radical, a phenyl
radical, an SO.sub.2NHR.sup.12 radical or NR.sup.13R.sup.14
radical, R.sup.12 is a hydrogen atom or an alkyl or phenyl radical,
and R.sup.13 and R.sup.14 are each independently-alkyl radicals, Z
is a bond or a linear or branched alkylene radical comprising 1 to
5 carbon atoms, R.sup.6 and R.sup.7 are each independently a
hydrogen atom, an alkyl, aralkyl or --(CH.sub.2).sub.n--OH radical,
wherein n is an integer from 1 to 6, or R.sup.6 is an
alkoxycarbonyl, haloalkoxycarbonyl or aralkoxycarbonyl radical and
R.sup.7 is a hydrogen atom or a methyl radical, or R.sup.6 and
R.sup.7, together with the nitrogen atom to which they are
attached, form a heterocycle with 4 to 7 members comprising 1 to 2
heteroatoms, wherein the members necessary for completing the
heterocycle are each independently --CR.sup.15R.sup.16--, --O--,
--S-- or --NR.sup.17-- radicals, R.sup.15 and R.sup.16 are each
independently a hydrogen atom or an alkyl radical, and R.sup.17 is
a hydrogen atom, Of an alkyl, or aralkyl radical, or R.sup.17 is a
phenyl radical optionally substituted by 1 to 3 substituents
including a halogen atom, an alkyl or alkoxy radical, R.sup.8 and
R.sup.9, together with the carbon atom to which they are attached,
form an indanyl or tetralinyl radical, or R.sup.8 and R.sup.9,
together with the carbon atom to which they are attached, form a
saturated heterocycle comprising 5 to 7 members and 1 to 2
heteroatoms including O, N or S, wherein the nitrogen atoms of said
heterocycle are optionally substituted by alkyl radicals or a
benzyl radical; R.sup.2 is a hydrogen atom, an alkyl radical, or an
aralkyl radical; or R.sup.1 and R.sup.2, together with the nitrogen
atom to which they are attached, form a heterocycle with 4 to 8
members comprising 1 to 2 heteroatoms, wherein the members
necessary for completing the heterocycle are each independently
--CR.sup.18R.sup.19--, --O--, --S-- or --NR.sup.20-- radicals,
R.sup.18 and R.sup.19 are each independently a hydrogen atom or an
alkyl radical, and R.sup.20 is a hydrogen atom, an alkyl radical,
or an aralkyl radical; R.sup.3 is a hydrogen atom or a halogen
atom; R.sup.4 is an alkyl radical, a haloalkyl radical, a
cycloalkyl radical, a cycloalkylalkyl radical, an alkoxyalkyl
radical, carbocyclic or heterocyclic aryl radicals or carbocyclic
or heterocyclic aralkyl radicals the aryl nucleus of which is
optionally substituted by 1 to 3 substituents independently
including a halogen atom, an alkyl radical, an alkoxy radical, a
haloalkyl radical or --SO.sub.2--NH.sub.2 radical, or R.sup.4 is
--(CH.sub.2).sub.m--[O--(CH.sub.2).sub.p].sub.q--O-Alk,
--(CH.sub.2).sub.r--[O-(CH.sub.2).sub.s].sub.t--NR.sup.21R.sup.22
or --(CH.sub.2).sub.v-A, wherein m, p and s are each independently
an integer from 2 to 4, q is an integer from 1 to 4, t is an
integer from 0 to 4, r is an integer from 2 to 12 and v is an
integer from 1 to 12, Alk is an alkyl radical, R.sup.21 is a
hydrogen atom, an alkyl, alkoxycarbonyl, or aralkoxycarbonyl
radical, R.sup.22 is a hydrogen atom or an alkyl radical and A is a
saturated heterocycle comprising 1 to 2 heteroatoms independently
including O, N or S and attached to the --(CH.sub.2).sub.v-- group
by an N or CH member, said saturated heterocycle including 2 to 6
additional members independently including --CHR.sup.23--, --CO--,
--NR.sup.24--, --O-- or --S--, R.sup.23 is a hydrogen atom or an
alkyl radical and R.sup.24 is a hydrogen atom, an alkyl radical, an
alkoxycarbonyl, or aralkoxycarbonyl group, or R.sup.4 is
##STR00051## wherein R.sup.1, R.sup.2, and R.sup.3 are as defined
above, and L is
--(CH.sub.2).sub.g--[O--(CH.sub.2).sub.w].sub.x--[O--(CH.sub.2).sub.y].su-
b.z-- or --(CH.sub.2).sub.a--.OMEGA.--(CH.sub.2).sub.b--, wherein
g, w and y are integers from 2 to 4, x is an integer from 1 to 3
and z is 0 or 1, a and b are independently integers from 2 to 6 and
.OMEGA. is --O--, --S--, --NR.sup.25--, --CO--, --CO--NR.sup.26--,
--CR.sup.27R.sup.25--, a cycloalkylene radical containing 3 to 7
carbon atoms, or a carbocyclic aryl radical, R.sup.25 is an alkyl
radical, R.sup.26 is a hydrogen atom or a methyl radical, R.sup.27
and R.sup.25 are each independently a hydrogen atom or a methyl
group; or R.sup.4 is ##STR00052## R.sup.5 is a hydrogen atom, an
alkyl, or aralkyl radical, or R.sup.5 is the same as R.sup.4 when
R.sup.4 is an alkyl, haloalkyl, alkoxyalkyl, carbocyclic or
heterocyclic aralkyl radical, the aryl nucleus of which is
optionally substituted by 1 to 3 substituents independently
including a halogen atom, an alkyl radical, an alkoxy radical, a
haloalkyl radical or a --SO.sub.2--NH.sub.2 radical; or R.sup.4 and
R.sup.5, together with the nitrogen atom to which they are
attached, form a saturated heterocycle with 4 to 7 members
comprising 1 to 2 heteroatoms, wherein the members necessary for
completing the heterocycle are each independently
--CR.sup.29R.sup.30--, --O--, --S-- or --NR.sup.31--, R.sup.29 and
R.sup.30 are a hydrogen atom, an alkyl, or aralkyl radical and
R.sup.31 is --COR.sup.32 or --SO.sub.2R.sup.33, R.sup.32 is an
alkyl radical, a carbocyclic aryl radical optionally substituted by
1 to 3 substituents including a halogen atom, an alkyl radical, or
an alkoxy radical, or R.sup.32 is a heterocyclic aryl radical or a
saturated heterocycle comprising 5 to 7 members and 1 to 2
heteroatoms including O, N or S, R.sup.33 is a hydrogen atom or an
alkyl radical, or R.sup.4 and R.sup.5, together with the nitrogen
atom to which they are attached, form a heterocyclic aryl radical
including ##STR00053## the aromatic ring of which may be
substituted by 1 to 3 substituents including an alkyl radical or an
alkoxy radical; or a salt thereof, wherein the disease or disorder
is a tumorous proliferative disease, non-tumorous proliferative
disease, neurodegenerative disease, parasitic disease, viral
infection, spontaneous alopecia, alopecia induced by exogenous
products, radiation-induced alopecia, auto-immune disease,
transplant rejection, inflammatory disease or allergy.
12. The method according to claim 11, wherein R.sup.4 is not
##STR00054## or salt thereof.
13. The method according to claim 11, wherein R.sup.4 is
##STR00055## or a salt thereof.
14. The method according to claim 11, wherein the compound is:
5-{[2-(dimethylamino)ethyl]amino}-2-(morpholin-4-ylcarbonyl)-1,3-benzothi-
azole-4,7-dione;
tert-butyl{2-[2-(2-{[(5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dih-
ydro-1,3-benzothiazol-2-yl)carbonyl]amino}ethoxy)ethoxy]ethyl}carbamate;
N,N-dibenzyl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydro-1,3--
benzothiazole-2-carboxamide;
5-{[2-(dimethylamino)ethyl]amino}-N,N-bis(2-methoxyethyl)-4,7-dioxo-4,7-d-
ihydro-1,3-benzothiazole-2-carboxamide;
5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-N-[3-(2-oxopyrrolidin-1-yl)pr-
opyl]-4,7-dihydro-1,3-benzothiazole-2-carboxamide;
4,7-dioxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-5-[(2-pyrrolidin-1-ylethyl)a-
mino]-4,7-dihydro-1,3-benzothiazole-2-carboxamide;
5-{[2-(dimethylamino)ethyl]amino}-N-isobutyl-4,7-dioxo-4,7-dihydro-1,3-be-
nzothiazole-2-carboxamide; tert-butyl
(4-{[(5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzoth-
iazol-2-yl)carbonyl]amino}butyl)carbamate;
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(2-furoyl)piperazin-1-yl]carbonyl-
}-1,3-benzothiazole-4,7-dione;
5-{[2-(dimethylamino)ethyl]amino}-N-(2-methoxyethyl)-4,7-dioxo-4,7-dihydr-
o-1,3-benzothiazole-2-carboxamide;
N-butyl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzo-
thiazole-2-carboxamide;
N-benzyl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benz-
othiazole-2-carboxamide;
N-(cyclohexylmethyl)-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihy-
dro-1,3-benzothiazole-2-carboxamide;
N,N'-(oxydiethane-2,1-diyl)bis(5-([2-(dimethylamino)ethyl]amino}-4,7-diox-
o-4,7-dihydro-1,3-benzothiazole-2-carboxamide);
N,N'-[ethane-1,2-diylbis(oxyethane-2,1-diyl)]bis(5-{[2-(dimethylamino)eth-
yl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazole-2-carboxamide);
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(morpholin-4-ylcarbonyl)piperazin-
-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione;
2-{[4-(morpholin-4-ylcarbonyl)piperazin-1-yl]carbonyl}-5-[(2-pyrrolidin-1-
-ylethyl)amino]-1,3-benzothiazole-4,7-dione;
5-{[2-(dimethylamino)ethyl]amino}-N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihyd-
ro-1,3-benzothiazole-2-carboxamide;
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(methylsulphonyl)piperazin-1-yl]c-
arbonyl]-1,3-benzothiazole-4,7-dione;
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(tetrahydrofuran-2-ylcarbonyl)pip-
erazin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione;
6-bromo-5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(tetrahydrofuran-2-ylcarb-
onyl)piperazin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione;
5-{[2-(dimethylamino)ethyl]amino}-2-(pyrrolidin-1-ylcarbonyl)-1,3-benzoth-
iazole-4,7-dione;
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(2-thienylcarbonyl)piperazin-1-yl-
]carbonyl}-1,3-benzothiazole-4,7-dione;
5-{[2-(dimethylamino)ethyl]amino}-N-ethyl-4,7-dioxo-4,7-dihydro-1,3-benzo-
thiazole-2-carboxamide;
N-(4-chlorophenyl)-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydr-
o-1,3-benzothiazole-2-carboxamide;
N-1,3-benzodioxol-5-yl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-di-
hydro-1,3-benzothiazole-2-carboxamide;
5-[(2-methoxyethyl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-
-yl]carbonyl}-1,3-benzothiazole-4,7-dione;
5-(4-methylpiperazin-1-yl)-2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazin--
1-yl]carbonyl}-1,3 -benzothiazole-4,7-dione;
5-[(2-pyridin-2-ylethyl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)pipera-
zin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione;
5-[(3-morpholin-4-ylpropyl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)pip-
erazin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione;
5-[(1-benzylpyrrolidin-3-yl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)pi-
perazin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione;
5-[(2-cyclohexylethyl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazi-
n-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione;
5-{[2-(dimethylamino)ethyl]amino}-N-(4-fluorophenyl)-4,7-dioxo-4,7-dihydr-
o-1,3-benzothiazole-2-carboxamide;
6-{[2-(dimethylamino)ethyl]amino}-2-(pyrrolidin-1-ylcarbonyl)-1,3-benzoth-
iazole-4,7-dione;
5-{[2-(dimethylamino)ethyl]amino}-N-(3-fluoro-4-methoxyphenyl)-4,7-dioxo--
4,7-dihydro-1,3-benzothiazole-2-carboxamide;
5-{[2-dimethylamino)ethyl]amino}-2-[(6-methoxy-3,4-dihydroquinolin-1(2H)--
yl)carbonyl]-1,3-benzothiazole-4,7-dione;
5-{(2-(dimethylamino)ethyl]amino}-2-{[4-(4-methoxybenzoyl)piperazin-1-yl]-
carbonyl}-1,3-benzothiazole-4,7-dione;
5-{[2-(dimethylamino)ethyl](methyl)amino]-N-ethyl-4,7-dioxo-4,7-dihydro-1-
,3-benzothiazole-2-carboxamide;
N-ethyl-5-{[2-(4-fluorophenyl)ethyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benz-
othiazole-2-carboxamide; or a salt thereof.
15. The method according to claim 11, wherein the disease or
disorder is cancer.
16. The method according to claim 15, wherein the cancer is breast
cancer, lymphomas, cancers of the neck or head, lung cancer, cancer
of the colon, cancer of the prostate or cancer of the pancreas.
17. The method according to claim 11, wherein the compound
is--5-{[2-(dimethylamino)ethyl]amino}-2-{[4(2-furoyl)piperazin-1-yl]carbo-
nyl}-1,3-benzothiazole-4,7-dione or a salt thereof.
18. The method according to claim 11, wherein the compound
is--6-{[2-(dimethylamino)ethyl]amino}-2-(pyrrolidin-1-ylcarbonyl)-1,3-ben-
zothiazole-4,7-dione or a salt thereof.
Description
[0001] A subject of the present invention is novel
4,7-dioxobenzothiazole-2-carboxamide derivatives, which inhibit the
cdc25 phosphatases, in particular cdc25-C phosphatase.
[0002] Control of the transition between the different phases of
the cell cycle during mitosis or meiosis is ensured by a set of
proteins the enzymatic activities of which are associated with
different states of phosphorylation. These states are controlled by
two major classes of enzymes: the kinases and the phosphatases.
[0003] The synchronization of the different phases of the cell
cycle thus allows the reorganization of the cell architecture at
each cycle throughout the living world (microorganisms, yeast,
vertebrates, plants). Among the kinases, the cycline-dependent
kinases (CDKs) play a major role in this control of the cell cycle.
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 includes
kinases such as Weel and Mik1 which deactivate the CDKs by
phosphorylating certain amino acids (Den Haese et al., Mol. Biol.
Cell (1995), 6, 371-385). The second includes phosphatases such as
Cdc25 which activate the CDKs by dephosphorylatying the tyrosine
and threonine residues of CDKs (Gould et al., Science (1990), 250,
1573-1576).
[0004] The phosphatases are classified in 3 groups: the
serine/threonine phosphatases (PPases), the tyrosine phosphatases
(PTPases) and the dual-specificity phosphatases (DSPases). These
phosphatases play an important role in the regulation of numerous
cell functions.
[0005] As regards human cdc25 phosphatases, 3 genes (cdc25-A,
cdc25-B and cdc25-C) code for the cdc25proteins. Moreover, variants
originating from the alternative splicing of the gene cdc25B have
been identified: these are cdc25B1, cdc25B2 and cdc25B3 (Baldin et
al., Oncogene (1997), 14, 2485-2495).
[0006] The role of the Cdc25 phosphatases in oncogenesis is now
better known and the action mechanisms of these phosphatases are
illustrated in particular in the following references: Galaktionov
et al., Science (1995), 269, 1575-1577; Galaktionov et al., Nature
(1996), 382, 511-517; and Mailand et al., Science (2000), 288,
1425-1429.
[0007] In particular, the overexpression of the different forms of
cdc25 is now reported in numerous series of human tumors: [0008]
Breast cancer: cf. Cangi et al., Resume 2984, AACR meeting San
Francisco, 2000); [0009] Lymphomas: cf. Hernandez et al., Int. J.
Cancer (2000), 89, 148-152 and Hernandez et al., Cancer Res.
(1998), 58, 1762-1767; [0010] Cancers of the neck and the head: cf.
Gasparotto et al., Cancer Res. (1997), 57, 2366-2368.
[0011] Moreover, E. Sausville's group reports an inverse
correlation between the level of expression of cdc25-B in a panel
of 60 lines and their sensitivities to CDK inhibitors, suggesting
that the presence of cdc25 can provide resistance to certain
antineoplastic agents and more particularly to CDK inhibitors (Hose
et al., Proceedings of AACR, Abstract 3571, San Francisco,
2000).
[0012] Among other targets, the pharmaceutical industry is
therefore currently researching compounds capable of inhibiting the
Cdc25 phosphatases in order to use them in particular as
anti-cancer agents.
[0013] The Cdc25 phosphatases also play a role in the
neurodegenerative diseases such as Alzheimer's disease (cf. Zhou et
al., Cell Mol. Life Sci. (1999), 56(9-10), 788-806; Ding et al.,
Am. J. Pathol. (2000), 157(6), 1983-90; Vincent et al.,
Neuroscience (2001), 105(3), 639-50) so that it is also possible to
envisage using compounds possessing an inhibition activity on these
phosphatases for treating these diseases.
[0014] Another problem addressed by the invention is research into
medicaments intended to prevent or treat the rejection of organ
transplants or also to treat auto-immune diseases. In these
disorders/diseases, the non-appropriate activation of the
lymphocytes and the monocytes/macrophages is involved.
Immunosuppressive medicaments known at present have side-effects
which could be reduced or modified by products specifically
targeting the signalling routes in the haematopoietic cells which
initiate and maintain inflammation.
[0015] Firstly, a subject of the invention is novel inhibitors of
cdc25 phosphatases (in particular of cdc25-C phosphatase), which
are 4,7-dioxobenzothiazole-2-carboxamide derivatives and correspond
to the general formula (I) defined hereafter. Given the above,
these compounds are capable of being used as medicaments, in
particular in the treatment and/or the prevention of the following
diseases or disorders: [0016] inhibition of tumor proliferation
alone or in combination with other treatments; [0017] inhibition of
normal cell proliferation alone or in combination with other
treatments; [0018] neurodegenerative diseases such as Alzheimer's
disease; [0019] prevention of spontaneous alopecia; [0020]
prevention of alopecia induced by exogenous products; [0021]
prevention of radiation-induced alopecia; [0022] prevention of the
spontaneous or induced apoptosis of normal cells; [0023] prevention
of meiosis and/or fertilization; [0024] prevention of the
maturation of the oocytes; [0025] all the diseases/all the
disorders corresponding to uses reported for CDK inhibitors, and in
particular non-tumorous proliferative diseases (for example:
angiogenesis, psoriasis or restenosis), tumorous proliferative
diseases, parasitology (proliferation of protozoans), viral
infections, neurodegenerative diseases, myopathies; and/or [0026]
all diseases/all disorders corresponding to clinical uses of
vitamin K and its derivatives.
[0027] Moreover, the compounds of the present invention are also,
because of their inhibition properties on the cdc25 phosphatases,
capable of being used for inhibiting or preventing the
proliferation of microorganisms, in particular yeasts. One of the
advantages of these compounds is their low toxicity on healthy
cells.
[0028] Firstly, a subject of the invention is the compounds
corresponding to general formula (I)
##STR00001##
in racemic, enantiomeric form or any combination of these forms, in
which:
[0029] R.sup.1 represents a hydrogen atom or an alkyl, alkoxyalkyl,
alkylthioalkyl, cycloalkyl, --(CH.sub.2)--X--Y,
--(CH.sub.2)--Z--NR.sup.6R.sup.7 radical or a --CHR.sup.8R.sup.9
radical,
[0030] X representing a bond or a linear or branched alkylene
radical containing 1 to 5 carbon atoms,
[0031] Y representing a saturated cyclic carbon system containing 1
to 3 condensed rings chosen independently from rings with 3 to 7
members, or Y representing a saturated heterocycle containing 1 to
2 heteroatoms chosen independently from O, N and S and attached to
the X radical by an N or CH member, said saturated heterocycle
moreover containing 2 to 6 additional members chosen independently
from --CHR.sup.10--, --CO--, --NR.sup.11--, --O-- and --S--,
R.sup.10 representing a hydrogen atom or an alkyl radical and
R.sup.11 representing a hydrogen atom or an alkyl or aralkyl
radical, or also Y representing a carbocyclic or heterocyclic aryl
radical optionally substituted 1 to 3 times by substituents chosen
independently from the group constituted by a halogen atom, an
alkyl radical, a haloalkyl radical, an alkoxy radical, a haloalkoxy
radical, a hydroxy radical, a nitro radical, a cyano radical, the
phenyl radical, an SO.sub.2NHR.sup.12 radical and an
NR.sup.13R.sup.14 radical, R.sup.12 representing a hydrogen atom or
an alkyl or phenyl radical, and R.sup.13 and R.sup.14 independently
representing alkyl radicals,
[0032] Z representing a bond or a linear or branched alkylene
radical containing 1 to 5 carbon atoms,
[0033] R.sup.6 and R.sup.7 being chosen independently from a
hydrogen atom, an alkyl, aralkyl radical or --(CH.sub.2).sub.n--OH
in which n represents an integer from 1 to 6,
[0034] or R.sup.6 representing an alkoxycarbonyl,
haloalkoxycarbonyl or aralkoxycarbonyl radical and R.sup.7
representing a hydrogen atom or a methyl radical,
[0035] or also 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 for completing the heterocycle
being chosen independently from the .sup.--CR.sup.15R.sup.16--,
--O--, --S-- and --NR.sup.17-- radicals, R.sup.15 and R.sup.16
independently representing each time that they occur a hydrogen
atom or an alkyl radical, and R.sup.17 representing a hydrogen atom
or an alkyl or aralkyl radical, or also R.sup.17 representing a
phenyl radical optionally substituted 1 to 3 times by substituents
chosen independently from a halogen atom and an alkyl or alkoxy
radical,
[0036] R.sup.8 and R.sup.9 forming together with the carbon atom
which carries them an indanyl or tetralinyl radical, or also
R.sup.8 and R.sup.9 forming together with the carbon atom which
carries them a saturated heterocycle containing 5 to 7 members and
1 to 2 heteroatoms chosen from O, N and S, the nitrogen atoms of
said heterocycle being optionally substituted by radicals chosen
from the alkyl radicals and the benzyl radical;
[0037] R.sup.2 representing a hydrogen atom or an alkyl or aralkyl
radical;
[0038] or also R.sup.1 and R.sup.2 forming together with the
nitrogen atom a heterocycle with 4 to 8 members comprising 1 to 2
heteroatoms, the members necessary for completing the heterocycle
being chosen independently from the --CR.sup.18R.sup.19--, --O--,
--S-- and --NR.sup.20-- radicals, R.sup.18 and R.sup.19
independently representing each time that they occur a hydrogen
atom or an alkyl radical, and R.sup.20 representing a hydrogen atom
or an alkyl or aralkyl radical;
[0039] R.sup.3 represents a hydrogen atom or a halogen atom;
[0040] R.sup.4 represents an alkyl radical, a haloalkyl radical, a
cycloalkyl radical, a cycloalkylalkyl radical, an alkoxyalkyl
radical, one of the carbocyclic or heterocyclic aryl or carbocyclic
or heterocyclic aralkyl radicals the aryl nucleus of which is
optionally substituted 1 to 3 times by substituents chosen
independently from the group constituted by a halogen atom, an
alkyl radical, an alkoxy radical, a haloalkyl radical and an
--SO.sub.2--NH.sub.2 radical,
[0041] or also R.sup.4 represents one of the
--(CH.sub.2).sub.m--[O--(CH.sub.2).sub.p].sub.q--O-Alk,
--(CH.sub.2).sub.r[O--(CH.sub.2).sub.s].sub.t--NR.sup.21R.sup.22 or
--(CH.sub.2).sub.v-A radicals in which m, p and s are each
independently an integer from 2 to 4, q is an integer from 1 to 4,
t is an integer from 0 to 4, r is an integer from 2 to 12 (and
preferably an integer from 2 to 8 and in particular an integer from
2 to 6) and v is an integer from 1 to 12 (and preferably an integer
from 1 to 8 and in particular an integer from 1 to 6), Alk is an
alkyl radical, R.sup.21 is a hydrogen atom or an alkyl,
alkoxycarbonyl or aralkoxycarbonyl radical, R.sup.22 is a hydrogen
atom or an alkyl radical and A is a saturated heterocycle
containing 1 to 2 heteroatoms chosen independently from O, N and S
and attached to the --(CH.sub.2).sub.v-- group by an N or CH
member, said saturated heterocycle containing moreover 2 to 6
additional members chosen independently from --CHR.sup.23--,
--CO--, --NR.sup.24--, --O-- and --S--, R.sup.23 representing a
hydrogen atom or an alkyl radical and R.sup.24 representing a
hydrogen atom, an alkyl radical or an alkoxycarbonyl or
aralkoxycarbonyl group,
[0042] or also R.sup.4 represents a radical of formula
##STR00002##
in which R.sup.1, R.sup.2, R.sup.3 and R.sup.5 are identical to the
R.sup.1, R.sup.2, R.sup.3 radicals mentioned previously and R.sup.5
mentioned hereafter, and L is chosen from the
--(CH.sub.2).sub.g--[O--(CH.sub.2).sub.w].sub.x--[O--(CH.sub.2).sub.y].su-
b.z-- and --(CH.sub.2).sub.a--.OMEGA.--(CH.sub.2).sub.b-- radicals
in which g, w and y are integers from 2 to 4 (and preferably 2 to
3), x is an integer from 1 to 3 and z is 0 or 1, a and b are
independently integers from 2 to 6 (and preferably 2 to 4) and
.OMEGA. is chosen from the group constituted by --O--, --S--,
--NR.sup.25--, --CO--, --CO--NR.sup.26--, --CR.sup.27R.sup.28--, a
cycloalkylene radical containing 3 to 7 carbon atoms and finally a
carbocyclic aryl radical, R.sup.25 representing an alkyl radical,
R.sup.26 representing a hydrogen atom or a methyl radical, R.sup.27
and R.sup.28 each being chosen independently from a hydrogen atom
and a methyl group;
[0043] or also R.sup.4 represents a radical of formula
##STR00003##
R.sup.5 represents a hydrogen atom or an alkyl or aralkyl radical,
R.sup.5 also being able to represent a radical identical to R.sup.4
when R.sup.4 represents a carbocyclic or heterocyclic alkyl,
haloalkyl, alkoxyalkyl or aralkyl radical, the aryl nucleus of
which is optionally substituted 1 to 3 times by substituents chosen
independently from the group constituted by a halogen atom, an
alkyl radical, an alkoxy radical, a haloalkyl radical and an
--SO.sub.2--NH.sub.2 radical;
[0044] or also R.sup.4 and R.sup.5 form together with the nitrogen
atom which carries them a saturated heterocycle with 4 to 7 members
comprising 1 to 2 heteroatoms in total, the members necessary for
completing the heterocycle being chosen independently from the
--CR.sup.29R.sup.30--, --O--, --S-- and --NR.sup.31-- radicals,
R.sup.29 and R.sup.30 representing a hydrogen atom or an alkyl or
aralkyl radical and R.sup.31 representing --COR.sup.32 or
--SO.sub.2R.sup.33,
[0045] R.sup.32 representing an alkyl radical, a carbocyclic aryl
radical optionally substituted 1 to 3 times by substituents chosen
independently from the group constituted by a halogen atom, an
alkyl radical and an alkoxy radical, or also R.sup.32 representing
a heterocyclic aryl radical or a saturated heterocycle containing 5
to 7 members and 1 to 2 heteroatoms chosen independently from O, N
and S (and in particular one of the piperidino, piperazino,
morpholino, thiomorpholino or 2-tetrahydrofuryl radicals),
[0046] R.sup.33 representing a hydrogen atom or an alkyl
radical,
[0047] or finally R.sup.4 and R.sup.5 form together with the
nitrogen atom which carries them a heterocyclic aryl radical chosen
from the radicals
##STR00004##
the aromatic ring of which can be substituted 1 to 3 times by
substituents chosen independently from the group constituted by an
alkyl radical and an alkoxy radical;
[0048] and their salts.
[0049] The Applicant has surprisingly discovered that the above
compounds corresponding to general formula (I) are powerful
inhibitors of the cdc25 phosphatases (and in particular of Cdc25C
phosphatase), which makes them suitable for use as anti-cancer
agents.
[0050] The invention therefore relates in the first place to the
compounds of general formula (I) defined previously and the salts
of such compounds.
[0051] By alkyl, unless otherwise specified, 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 8 carbon atoms
(and in particular 1 to 6 carbon atoms).
[0052] By alkylene, unless otherwise specified, is meant a linear
or branched saturated alkyl radical, containing 1 to 5 carbon
atoms, for example a --CH.sub.2-- or --CH.sub.2--CH.sub.2--
radical.
[0053] By alkoxy, unless otherwise specified, is meant a linear or
branched alkoxy radical containing 1 to 6 carbon atoms (and in
particular 1 to 4 carbon atoms).
[0054] By alkoxycarbonyl, unless otherwise specified, is meant a
radical of --CO--O-alkyl type.
[0055] By haloalkoxycarbonyl unless otherwise specified, is meant a
radical of --CO--O-haloalkyl type.
[0056] By haloalkyl, is meant an alkyl radical at least one (and
optionally all) of the hydrogen atoms of which is replaced by a
halogen atom.
[0057] By aralkoxycarbonyl unless otherwise specified, is meant a
radical of --CO--O-alkyl-aryl type.
[0058] By cycloalkyl, unless otherwise specified, is meant a
cycloalkyl radical containing 3 to 7 carbon atoms.
[0059] By cycloalkylene, unless otherwise specified, is meant a
cycloalkyl radical containing 3 to 7 carbon atoms, for example
a
##STR00005##
radical.
[0060] By alkylthioalkyl, unless otherwise specified, is meant a
radical of -alkyl-S-alkyl type.
[0061] By carbocyclic or heterocyclic aryl, is meant a carbocyclic
or heterocyclic system of 1 to 3 condensed rings comprising at
least one aromatic ring, a system being called heterocyclic when at
least one of the rings which compose it comprises at least one
heteroatom (O, N or S); when a carbocyclic or heterocyclic aryl
radical is referred to as substituted, unless otherwise specified,
it is meant that said carbocyclic or heterocyclic aryl radical is
substituted 1 to 3 times, and preferably from 1 to 2 times by
radicals different from a hydrogen atom which, unless otherwise
specified, are chosen from a halogen atom and the alkyl or alkoxy
radicals; moreover, unless otherwise specified, by aryl is
exclusively meant a carbocyclic aryl.
[0062] By halogen or atom halogen is meant a chlorine, bromine,
fluorine or iodine atom.
[0063] By cycloalkylalkyl, alkoxyalkyl, haloalkyl, haloalkoxy and
aralkyl radicals, is meant respectively the cycloalkylalkyl,
alkoxyalkyl, haloalkyl, haloalkoxy and aralkyl radicals the alkyl,
cycloalkyl and aryl radicals of which have the meanings indicated
previously.
[0064] When it is indicated that a radical is optionally
substituted 1 to 3 times, it is preferably optionally substituted 1
to 2 times and more preferentially optionally substituted once.
[0065] 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 haloalkyl, is meant in particular the
trifluoromethyl radical. By haloalkoxy, is meant in particular the
trifluoromethoxy radical. By carbocyclic aryl, is meant in
particular the phenyl and naphthyl radicals. By aralkyl, is meant
in particular the phenylalkyl radicals, and in particular the
benzyl radical. By saturated cyclic carbon system containing 1 to 3
condensed rings chosen independently from rings with 3 to 7
members, is meant in particular the cyclopropyl, cyclobutyl,
cyclohexyl and adamantyl radicals. By heterocyclic aryl or
heteroaryl, is meant in particular the thienyl, furanyl, pyrrolyl,
imidazolyl, thiazolyl, oxazolyl and pyridyl radicals. Finally, by
halogen, is meant the fluorine, chlorine, bromine or iodine
atoms.
[0066] By salt of a compound, is meant the addition salts of said
compound with an organic or inorganic acid or, if appropriate, with
a base, and in particular the pharmaceutically acceptable salts of
said compound.
[0067] By pharmaceutically acceptable salt, is meant in particular
addition salts of inorganic acids such as hydrochloride,
hydrobromide, hydroiodide, sulphate, phosphate, diphosphate and
nitrate or acids organic such as acetate, maleate, fumarate,
tartrate, succinate, citrate, lactate, methanesulphonate,
p-toluenesulphonate, pamoate and stearate. Also included within 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.
[0068] In certain cases, the compounds according to the present
invention can comprise 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 "RS" racemic mixtures.
In an effort to simplify matters, when no specific configuration is
indicated in the structural formulae, it should be understood that
the two enantiomeric forms and their mixtures are represented.
[0069] Generally, it is preferred that the saturated heterocycle A
is such that it comprises a maximum of 2--CO-- members, a maximum
of 2 members chosen independently from --NR.sup.24--, --O-- and
--S-- and a maximum of one --CHR.sup.23-- member in which R.sup.23
is not a hydrogen atom. Similarly, it is preferred, in the case
where R.sup.4 and R.sup.5 form together with the nitrogen atom
which carries them a saturated heterocycle with 4 to 7 members
comprising 1 to 2 heteroatoms, that said saturated heterocycle is
such that it comprises a maximum of two --CR.sup.29R.sup.30--
members in which at least one of R.sup.29 and R.sup.30 is not a
hydrogen atom.
[0070] According to a variant of the invention, the compounds of
general formula (I) or their salts are such that R.sup.4 does not
represent a radical of formula
##STR00006##
in the remainder of this disclosure, such compounds are called the
"compounds of general sub-formula (I).sub.M".
[0071] Among the compounds of general sub-formula (I).sub.M,
certain will correspond to general sub-formula (I).sub.M5
##STR00007##
in which R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the
same meaning as in general sub-formula (I).sub.M; whilst the other
will correspond to general sub-formula (I).sub.M6
##STR00008##
in which R.sup.l, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the
same meaning as in general sub-formula (I).sub.M.
[0072] According to another variant of the invention, the compounds
of general formula (I) or their salts are such that R.sup.4
represents a radical of formula
##STR00009##
in the remainder of this disclosure, such compounds are called the
"compounds of general sub-formula (I).sub.D".
[0073] Among the compounds of general sub-formula (I).sub.D,
certain will correspond to general sub-formula (I).sub.D5
##STR00010##
in which R.sup.1, R.sup.2, R.sup.3 and R.sup.5 have the same
meaning as in general sub-formula (I).sub.D and R.sup.4 represents
a radical of formula
##STR00011##
in which L has the same meaning as in general sub-formula
(I).sub.D; whilst the others will correspond to general sub-formula
(I).sub.D6
##STR00012##
in which R.sup.1, R.sup.2, R.sup.3 and R.sup.5 have the same
meaning as in general sub-formula (I).sub.D and R.sup.4 represents
a radical of formula
##STR00013##
in which L has the same meaning as in general sub-formula
(I).sub.D.
[0074] When the compounds of general sub-formula (I).sub.D or their
salts are such that L represents
--(CH.sub.2).sub.a--.OMEGA.--(CH.sub.2).sub.b--, .OMEGA. is
preferably --O--, --CO--, --CR.sup.27R.sup.28-- and more
preferentially --O--.
[0075] Preferably, the compounds of general formula (I) or their
salts are such that they possess independently at least one of the
following characteristics: [0076] R.sup.1 represents an alkyl,
cycloalkyl, alkoxyalkyl, --(CH.sub.2)--X--Y,
--(CH.sub.2)--Z--NR.sup.6R.sup.7 or --CHR.sup.8R.sup.9 radical; or
[0077] R.sup.2 represents a hydrogen atom or the methyl, ethyl or
benzyl radical; or [0078] R.sup.3 represents a hydrogen atom; or
[0079] R.sup.4 represents an alkyl radical, a cycloalkyl radical, a
cycloalkylalkyl radical, an alkoxyalkyl radical, one of the
carbocyclic or heterocyclic aryl or carbocyclic or heterocyclic
aralkyl radicals the aryl nucleus of which is optionally
substituted 1 to 3 times by substituents chosen independently from
the group constituted by a halogen atom, an alkyl radical, an
alkoxy radical, a haloalkyl radical and an --SO.sub.2--NH.sub.2
radical, [0080] or also R.sup.4 represents one of the
--(CH.sub.2).sub.m--[O--(CH.sub.2).sub.p].sub.q--O-Alk,
--(CH.sub.2).sub.r--[O--(CH.sub.2).sub.s].sub.t--NR.sup.21R.sup.22
or --(CH.sub.2).sub.v-A radicals in which m, p and s are each
independently 2 or 3, q is an integer from 1 to 3, t is an integer
from 0 to 3, r is an integer from 2 to 6 and v is an integer from 1
to 6, Alk is an alkyl radical, R.sup.21 is a hydrogen atom or an
alkoxycarbonyl radical, R.sup.22 is a hydrogen atom or a methyl
radical and A is a saturated heterocycle containing 1 to 2
heteroatoms chosen independently from O, N and S and attached to
the --(CH.sub.2).sub.v-- group by an N or CH member, said saturated
heterocycle containing moreover 2 to 6 additional members chosen
independently from --CHR.sup.23--, --CO--, --NR.sup.24--, --O-- and
--S--, R.sup.23 representing a hydrogen atom or a methyl radical
and R.sup.24 representing a hydrogen atom, an alkyl radical or an
alkoxycarbonyl group; [0081] or also R.sup.4 represents a radical
of formula
[0081] ##STR00014## [0082] or [0083] R.sup.5 represents a hydrogen
atom or an alkyl or aralkyl radical, R.sup.5 also being able to
represent a radical identical to R.sup.4 when R.sup.4 represents a
carbocyclic alkyl, alkoxyalkyl or aralkyl radical the aryl nucleus
of which is optionally substituted 1 to 3 times by substituents
chosen independently from the group constituted by a halogen atom,
an alkyl radical, an alkoxy radical, a haloalkyl radical and a
--SO.sub.2--NH.sub.2 radical; [0084] or also R.sup.4 and R.sup.5
form together with the nitrogen atom which carries them a saturated
heterocycle with 4 to 7 members comprising 1 to 2 heteroatoms in
total, the members necessary for completing the heterocycle being
chosen independently from the --CH.sub.2--, --O--, --S-- and
--NR.sup.31-- radicals, R.sup.31 representing --COR.sup.32-- or
--SO.sub.2R.sup.33--, [0085] R.sup.32 representing an alkyl
radical, a carbocyclic aryl radical optionally substituted 1 to 3
times by substituents chosen independently from the group
constituted by a halogen atom, an alkyl radical and an alkoxy
radical, or also R.sup.32 representing a heterocyclic aryl radical
or a saturated heterocycle chosen from the piperidino, piperazino,
morpholino, thiomorpholino and 2-tetrahydrofuryl radicals, [0086]
R.sup.33 representing a hydrogen atom or an alkyl radical, [0087]
or also R.sup.4 and R.sup.5 form together with the nitrogen atom
which carries them a heterocyclic aryl radical of formula
[0087] ##STR00015## [0088] the aromatic ring of which can be
substituted 1 to 3 times by an alkyl or alkoxy radical.
[0089] More preferentially, the compounds of general formula (I) or
their salts are such that they possess independently at least one
of the following characteristics: [0090] R.sup.1 represents a
--(CH.sub.2)--Z--NR.sup.6R.sup.7 radical, [0091] Z representing a
bond or a linear or branched alkylene radical containing 1 to 5
carbon atoms, [0092] R.sup.6 and R.sup.7 being chosen independently
from a hydrogen atom and an alkyl radical, or also 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
for completing the heterocycle being chosen independently from the
--CH.sub.2--, --O--, --S-- and --NR.sup.17-- radicals, R.sup.17
representing a hydrogen atom or an alkyl radical; or [0093] R.sup.2
represents a hydrogen atom or the methyl radical; or [0094] R.sup.4
represents an alkyl radical, a cycloalkyl radical, a
cycloalkylalkyl radical, an alkoxyalkyl radical or a carbocyclic or
heterocyclic aryl or carbocyclic or heterocyclic aralkyl radical
the aryl nucleus of which is optionally substituted 1 to 3 times by
substituents chosen independently from the group constituted by a
halogen atom, an alkyl radical, an alkoxy radical, a haloalkyl
radical and an --SO.sub.2--NH.sub.2 radical (and preferably chosen
independently from the group constituted by a halogen atom, an
alkyl radical and an alkoxy radical), [0095] or also R.sup.4
represents one of the
--(CH.sub.2).sub.m--[O--(CH.sub.2).sub.p].sub.q--O-Alk,
--(CH.sub.2).sub.r--O--(CH.sub.2).sub.s].sub.t--NR.sup.21R.sup.22
or --(CH.sub.2).sub.v-A radicals in which m, p and s are each
independently 2 or 3, q is an integer from 1 to 3, t is an integer
from 0 to 3, r is an integer from 2 to 6 and v is an integer from 1
to 6, Alk is an alkyl radical, R.sup.21 is a hydrogen atom or an
alkoxycarbonyl radical, R.sup.22 is a hydrogen atom or a methyl
radical and A is a saturated heterocycle containing 1 to 2
heteroatoms chosen independently from O, N and S and attached to
the --(CH.sub.2).sub.v-- group by an N or CH member, said saturated
heterocycle moreover containing 2 to 6 additional members chosen
independently from --CHR.sup.23--, --CO--, --NR.sup.24--, --O-- and
--S--, R.sup.23 representing a hydrogen atom or a methyl radical
and R.sup.24 representing a hydrogen atom, an alkyl radical or an
alkoxycarbonyl group; [0096] or also R.sup.4 represents a radical
of formula
[0096] ##STR00016## [0097] R.sup.5 represents a hydrogen atom,
R.sup.5 also being able to represent a radical identical to R.sup.4
when R.sup.4 represents an carbocyclic alkyl, alkoxyalkyl or
aralkyl radical the aryl nucleus of which is optionally substituted
1 to 3 times by substituents chosen independently from the group
constituted by a halogen atom, an alkyl radical, an alkoxy radical,
a haloalkyl radical and an --SO.sub.2--NH.sub.2 radical; or [0098]
or also R.sup.4 and R.sup.5 form together with the nitrogen atom
which carries them a saturated heterocycle with 4 to 7 members
comprising 1 to 2 heteroatoms in total, the members necessary for
completing the heterocycle being chosen independently from the
--CH.sub.2--, --O--, --S-- and --NR.sup.31-- radicals, R.sup.31
representing --COR.sup.32-- or --SO.sub.2R.sup.33--, [0099]
R.sup.32 representing an alkyl radical, a carbocyclic aryl radical
optionally substituted 1 to 3 times by substituents chosen
independently from the group constituted by a halogen atom, an
alkyl radical and an alkoxy radical, or also R.sup.32 representing
a heterocyclic aryl radical chosen from the 2-furyl, 2-pyrrolyl and
2-thienyl radicals, or a saturated heterocycle chosen from the
piperidino, piperazino, morpholino, thiomorpholino and
2-tetrahydrofuryl radicals, [0100] R.sup.33 representing a hydrogen
atom or a methyl radical, [0101] or also R.sup.4 and R.sup.5 form
together with the nitrogen atom which carries them a heterocyclic
aryl radical of formula
[0101] ##STR00017## [0102] the aromatic ring of which can be
substituted 1 to 3 times by an alkyl or alkoxy radical (and
preferably by an alkoxy radical).
[0103] Still more preferentially, the compounds of general formula
(I) or their salts are such that they possess independently at
least one of the following characteristics: [0104] R.sup.1
representing a --(CH.sub.2)--Z--NR.sup.6R.sup.7 radical, [0105] Z
representing a bond or a linear or branched alkylene radical
containing 1 to 3 carbon atoms (and in particular 1 carbon atom),
[0106] R.sup.6 and R.sup.7 being chosen independently from a
hydrogen atom and an alkyl radical (and in particular R.sup.6 and
R.sup.7 each representing a methyl radical), or also R.sup.6 and
R.sup.7 forming together with the nitrogen atom a pyrrolidinyl or
piperidinyl (and in particular pyrrolidinyl) ring; [0107] R.sup.2
representing a hydrogen atom; [0108] R.sup.4 representing an alkyl
radical, a cycloalkyl radical, a cycloalkylalkyl radical, an
alkoxyalkyl radical or a carbocyclic or heterocyclic aryl radical
or a carbocyclic or heterocyclic aralkyl radical the aryl nucleus
of which is optionally substituted 1 to 2 times by substituents
chosen independently from the group constituted by a halogen atom,
an alkyl radical or an alkoxy radical, [0109] or also R.sup.4
representing one of the
--(CH.sub.2).sub.m--[O--(CH.sub.2).sub.p].sub.q--O-Alk,
--(CH.sub.2).sub.r--[O--(CH.sub.2).sub.s].sub.t--NR.sup.21R.sup.22
or --(CH.sub.2).sub.v-A radicals in which m, p and s are each
independently 2 or 3, q is an integer from 1 to 3, t is an integer
from 0 to 3, r is an integer from 2 to 6 and v is an integer from 1
to 6, Alk is an alkyl radical containing 1 to 3 carbon atoms,
R.sup.21 is a hydrogen atom or an alkoxycarbonyl radical (and in
particular tert-butoxycarbonyl), R.sup.22 is a hydrogen atom and A
is a saturated heterocycle containing 1 to 2 heteroatoms chosen
independently from O, N and S and attached to the
--(CH.sub.2).sub.v-- group by an N or CH member, said saturated
heterocycle moreover containing 2 to 6 additional members chosen
independently from --CH.sub.2--, --CO--, --NR.sup.24--, --O-- and
--S--, R.sup.23 representing a hydrogen atom or a methyl radical
and R.sup.24 representing a hydrogen atom, an alkyl radical or an
alkoxycarbonyl group; [0110] or also R.sup.4 represents a radical
of formula
[0110] ##STR00018## [0111] R.sup.5 representing a hydrogen atom;
[0112] or also R.sup.4 and R.sup.5 forming together with the
nitrogen atom which carries them a saturated heterocycle with 5 to
7 members comprising 1 to 2 heteroatoms in total, the members
necessary for completing the heterocycle being chosen independently
from the --CH.sub.2--, --O--, --S-- and --NR.sup.31-- radicals,
R.sup.31 representing --COR.sup.32-- or --SO.sub.2R.sup.33--,
[0113] R.sup.32 representing an alkyl radical, a carbocyclic aryl
radical optionally substituted 1 to 3 times by substituents chosen
independently from the group constituted by a halogen atom, an
alkyl radical and an alkoxy radical, or also R.sup.32 representing
a heterocyclic aryl radical chosen from the 2-furyl, 2-pyrrolyl and
2-thienyl radicals, or a saturated heterocycle chosen from the
piperidino, piperazino, morpholino, thiomorpholino and
2-tetrahydrofuryl radicals, [0114] R.sup.33 representing an alkyl
radical; [0115] or also R.sup.4 and R.sup.5 form together with the
nitrogen atom which carries them a heterocyclic aryl radical of
formula
[0115] ##STR00019## [0116] the aromatic ring of which can be
substituted 1 to 3 times (and preferably once) by an alkoxy radical
(and preferably by a methoxy radical).
[0117] More particularly the compounds of general formula (I) or
their salts are such that they possess independently at least one
of the following characteristics: [0118] R.sup.1 represents at
least one radical chosen from the following radicals:
--(CH.sub.2).sub.2--N(CH.sub.3).sub.2, or
--(CH.sub.2).sub.2--O--CH.sub.3, or a
[0118] ##STR00020## [0119] radical; [0120] Or R.sup.1R.sup.2N--
represents a
[0120] ##STR00021## [0121] radical; [0122] Or R.sup.2 represents a
hydrogen atom or a methyl radical; [0123] Or R.sup.3 represents a
hydrogen or bromine atom; [0124] Or R.sup.4 represents at least one
radical chosen from the following radicals:
[0124] ##STR00022## [0125] or an ethyl, isobutyl, butyl or
--(CH.sub.2).sub.2--O--CH.sub.3 radical, [0126] or also R.sup.4
represents a radical of formula
[0126] ##STR00023## [0127] in which L represents a radical chosen
independently from
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2-- or
--(CH.sub.2).sub.2--O--(CH.sub.2).sub.2--, R.sup.5, R.sup.3 and
R.sup.2 represent H and R1 represents
--(CH.sub.2).sub.2--N(CH.sub.3).sub.2; [0128] Or R.sup.5 represents
a hydrogen atom or a --(CH.sub.2).sub.2--O--CH.sub.3 radical or
a
[0128] ##STR00024## [0129] radical; [0130] or also R.sup.4 and
R.sup.5 forming together with the nitrogen atom which carries them
a heterocycle chosen from the following heterocycles:
[0130] ##STR00025## [0131] it being understood that .fwdarw.*
signifies the attachment point to general formula (I).
[0132] Among the compounds of general formula (I), the following
compounds described in the examples will be preferred in
particular: [0133]
5-{[2-(dimethylamino)ethyl]amino}-2-(morpholin-4-ylcarbonyl)-1,3-benzothi-
azole-4,7-dione; [0134]
tert-butyl{2-[2-(2-{[(5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dih-
ydro-1,3-benzothiazol-2-yl)carbonyl]amino}ethoxy)ethoxy]ethyl}carbamate;
[0135]
N,N-dibenzyl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihyd-
ro-1,3 -benzothiazole-2-carboxamide; [0136]
5-{[2-(dimethylamino)ethyl]amino}-N,N-bis(2-methoxyethyl)-4,7-dioxo-4,7-d-
ihydro-1,3-benzothiazole-2-carboxamide; [0137]
5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-N-[3-(2-oxopyrrolidin-1-yl)pr-
opyl]-4,7-dihydro-1,3-benzothiazole-2-carboxamide; [0138]
4,7-dioxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-5-[(2-pyrrolidin-1-ylethyl)a-
mino]-4,7-dihydro-1,3 -benzothiazole-2-carboxamide; [0139]
5-{[2-(dimethylamino)ethyl]amino}-N-isobutyl-4,7-dioxo-4,7-dihydro-1,3-be-
nzothiazole-2-carboxamide; [0140]
tert-butyl(4-{[(5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydro-1-
,3-benzothiazol-2-yl)carbonyl]amino}butyl)carbamate; [0141]
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(2-furoyl)piperazin-1-yl]carbonyl-
}-1,3-benzothiazole-4,7-dione; [0142]
5-{[2-(dimethylamino)ethyl]amino}-N-(2-methoxyethyl)-4,7-dioxo-4,7-dihydr-
o-1,3-benzothiazole-2-carboxamide; [0143]
N-butyl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzo-
thiazole-2-carboxamide; [0144]
N-benzyl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benz-
othiazole-2-carboxamide; [0145]
N-(cyclohexylmethyl)-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihy-
dro-1,3-benzothiazole-2-carboxamide; [0146]
N,N'-(oxydiethane-2,1-diyl)bis(5-{[2-(dimethylamino)ethyl]amino}-4,7-diox-
o-4,7-dihydro-1,3-benzothiazole-2-carboxamide); [0147]
N,N'-[ethane-1,2-diylbis(oxyethane-2,1-diyl)]bis(5-{[2-(dimethylamino)eth-
yl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazole-2-carboxamide);
[0148]
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(morpholin-4-ylcarbonyl)piperazin-
-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione; [0149]
2-{[4-(morpholin-4-ylcarbonyl)piperazin-1-yl]carbonyl}-5-[(2-pyrrolidin-1-
-ylethyl)amino]-1,3-benzothiazole-4,7-dione; [0150]
5-{[2-(dimethylamino)ethyl]amino}-N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihyd-
ro-1,3-benzothiazole-2-carboxamide; [0151]
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(methylsulphonyl)piperazin-1-yl]c-
arbonyl}-1,3-benzothiazole-4,7-dione; [0152]
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(tetrahydrofuran-2-ylcarbonyl)pip-
erazin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione; [0153]
6-bromo-5-[2-(dimethylamino)ethyl]amino}-2-{[4-(tetrahydrofuran-2-ylcarbo-
nyl)piperazin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione; [0154]
5-{[2-(dimethylamino)ethyl]amino}-2-(pyrrolidin-1-ylcarbonyl)-1,3-benzoth-
iazole-4,7-dione; [0155]
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(2-thienylcarbonyl)piperazin-1-yl-
]carbonyl}-1,3-benzothiazole-4,7-dione; [0156]
5-{[2-(dimethylamino)ethyl]amino}-N-ethyl-4,7-dioxo-4,7-dihydro-1,3-benzo-
thiazole-2-carboxamide; [0157]
N-(4-chlorophenyl)-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydr-
o-1,3-benzothiazole-2-carboxamide; [0158]
N-1,3-benzodioxol-5-yl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-di-
hydro-1,3-benzothiazole-2-carboxamide; [0159]
5-[(2-methoxyethyl)amino]-2-[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1--
yl]carbonyl}-1,3-benzothiazole-4,7-dione; [0160]
5-(4-methylpiperazin-1-yl)-2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazin--
1-yl]carbonyl}-1,3-benzothiazole-4,7-dione; [0161]
5-[(2-pyridin-2-ylethyl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)pipera-
zin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione; [0162]
5-[(3-morpholin-4-ylpropyl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)pip-
erazin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione; [0163]
5-[(1-benzylpyrrolidin-3-yl)amino]-2-[4-(tetrahydrofuran-2-ylcarbonyl)pip-
erazin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione; [0164]
5-[(2-cyclohexylethyl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazi-
n-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione; [0165]
5-{[2-(dimethylamino)ethyl]amino}-N-(4-fluorophenyl)-4,7-dioxo-4,7-dihydr-
o-1,3-benzothiazole-2-carboxamide; [0166]
6-{[2-(dimethylamino)ethyl]amino}-2-(pyrrolidin-1-ylcarbonyl)-1,3-benzoth-
iazole-4,7-dione; [0167]
5-{[2-(dimethylamino)ethyl]amino}-N-(3-fluoro-4-methoxyphenyl)-4,7-dioxo--
4,7-dihydro-1,3-benzothiazole-2-carboxamide; [0168]
5-{[2-(dimethylamino)ethyl]amino}-2-[(6-methoxy-3,4-dihydroquinolin-1(2H)-
-yl)carbonyl]-1,3-benzothiazole-4,7-dione; [0169]
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(4-methoxybenzoyl)piperazin-1-yl]-
carbonyl}-1,3-benzothiazole-4,7-dione; [0170]
5-[[2-(dimethylamino)ethyl](methyl)amino]-N-ethyl-4,7-dioxo-4,7-dihydro-1-
,3-benzothiazole-2-carboxamide; [0171]
N-ethyl-5-{[2-(4-fluorophenyl)ethyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benz-
othiazole-2-carboxamide; and the salts of these compounds.
[0172] The following compounds are more particularly preferred:
[0173]
5-{[2-(dimethylamino)ethyl]amino}-2-(morpholin-4-ylcarbonyl)-1,3-benzothi-
azole-4,7-dione; [0174]
5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-N-[3-(2-oxopyrrolidin-1-yl)pr-
opyl]-4,7-dihydro-1,3-benzothiazole-2-carboxamide; [0175]
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(2-furoyl)piperazin-1-yl]carbonyl-
}-1,3-benzothiazole-4,7-dione; [0176]
5-{[2-(dimethylamino)ethyl]amino}-N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihyd-
ro-1,3-benzothiazole-2-carboxamide; [0177]
5-{[2-(dimethylamino)ethyl]amino}-2-(pyrrolidin-1-ylcarbonyl)-1,3-benzoth-
iazole-4,7-dione; [0178]
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(2-thienylcarbonyl)piperazin-1-yl-
]carbonyl}-1,3-benzothiazole-4,7-dione; [0179]
N-1,3-benzodioxol-5-yl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-di-
hydro-1,3-benzothiazole-2-carboxamide; [0180]
5-{[2-(dimethylamino)ethyl]amino}-N-(4-fluorophenyl)-4,7-dioxo-4,7-dihydr-
o-1,3-benzothiazole-2-carboxamide; [0181]
6-{[2-(dimethylamino)ethyl]amino}-2-(pyrrolidin-1-ylcarbonyl)-1,3-benzoth-
iazole-4,7-dione; [0182]
5-{[2-(dimethylamino)ethyl]amino}-N-(3-fluoro-4-methoxyphenyl)-4,7-dioxo--
4,7-dihydro-1,3-benzothiazole-2-carboxamide; [0183]
5-{[2-(dimethylamino)ethyl]amino}-2-[(6-methoxy-3,4-dihydroquinolin-1(2H)-
-yl)carbonyl]-1,3-benzothiazole-4,7-dione; [0184]
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(4-methoxybenzoyl)piperazin-1-yl]-
carbonyl}-1,3-benzothiazole-4,7-dione; and the salts of these
compounds.
[0185] The invention also relates, as medicaments, to the compounds
of general formula (I) mentioned above, or their pharmaceutically
acceptable salts.
[0186] A subject of the invention is also the pharmaceutical
compositions comprising, as active ingredient, a compound of
general formula (I) or a pharmaceutically acceptable salt of such a
compound, with at least one pharmaceutically acceptable
excipient.
[0187] Another subject of the invention is the use of the compounds
of general formula (I) or of their pharmaceutically acceptable
salts for preparing a medicament intended to treat a disease or a
disorder chosen from the following diseases or the following
disorders: tumorous proliferative diseases (and in particular
cancer), non-tumorous proliferative diseases, neurodegenerative
diseases, parasitic diseases, viral infections, spontaneous
alopecia, alopecia induced by exogenous products, radiation-induced
alopecia, auto-immune diseases, transplant rejections, inflammatory
diseases or allergies.
[0188] Quite particularly, the compounds of general formula (I) or
their pharmaceutically acceptable salts can be used for preparing a
medicament intended to treat cancer, and in particular breast
cancer, lymphomas, cancers of the neck or head, lung cancer, cancer
of the colon, cancer of the prostate or cancer of the pancreas.
[0189] The invention relates moreover to a treatment method for one
of the diseases/one of the disorders mentioned, said method
comprising the administration to the patient suffering from said
disease/said disorder of a therapeutically effective quantity of a
compound of general formula (I) or of a pharmaceutically acceptable
salt of such a compound.
[0190] The invention also offers, as novel industrial products, the
intermediates of general formula (A)
##STR00026##
in which R is an alkyl radical,
[0191] R.sup.5 has the same meaning as in general formula (I)
[0192] and R.sup.4 represents an alkyl radical, a haloalkyl
radical, a cycloalkyl radical, a cycloalkylalkyl radical, an
alkoxyalkyl radical, one of the carbocyclic or heterocyclic aryl
or, carbocyclic or heterocyclic aralkyl radicals the aryl nucleus
of which is optionally substituted 1 to 3 times by substituents
chosen independently from the group constituted by a halogen atom,
an alkyl radical, an alkoxy radical, a haloalkyl radical and an
--SO.sub.2--NH.sub.2 radical,
[0193] or also R.sup.4 represents one of the
--(CH.sub.2).sub.m--[O--(CH.sub.2).sub.p].sub.q--O-Alk,
--(CH.sub.2).sub.r--[O--(CH.sub.2).sub.s].sub.t--NR.sup.21R.sup.22
or --(CH.sub.2).sub.v-A radicals in which m, p and s are each
independently an integer from 2 to 4, q is an integer from 1 to 4,
t is an integer from 0 to 4, r is an integer from 2 to 12 (and
preferably an integer from 2 to 8 and in particular an integer from
2 to 6) and v is an integer from 1 to 12 (and preferably an integer
from 1 to 8 and in particular an integer from 1 to 6), Alk is an
alkyl radical, R.sup.21 is a hydrogen atom or an alkyl,
alkoxycarbonyl or aralkoxycarbony radical, R.sup.22 is a hydrogen
atom or an alkyl radical and A is a saturated heterocycle
containing 1 to 2 heteroatoms chosen independently from O, N and S
and attached to the --(CH.sub.2).sub.v-- group by an N or CH
member, said saturated heterocycle moreover containing 2 to 6
additional members chosen independently from --CHR.sup.23--,
--CO--, --NR.sup.24--, --O-- and --S--, R.sup.23 representing a
hydrogen atom or an alkyl radical and R.sup.24 representing a
hydrogen atom, an alkyl radical or an alkoxy carbonyl or
aralkoxycarbonyl group,
[0194] or also R.sup.4 represents a radical of formula
##STR00027##
in which R and R.sup.5 are identical to the R and R.sup.5 radicals
mentioned previously and L is chosen from the
--(CH.sub.2).sub.g--[O--(CH.sub.2).sub.w].sub.x--[O--(CH.sub.2).sub.y].su-
b.z-- and --(CH.sub.2).sub.a--.OMEGA.--(CH.sub.2).sub.b-- radicals
in which g, w and y are integers from 2 to 4 (and preferably 2 to
3), x is an integer from 1 to 3 and z is 0 or 1, a and b are
independently integers from 2 to 6 (and preferably 2 to 4) and
.OMEGA. is chosen from the group constituted by --O--, --S--,
--NR.sup.25--, --CO--, --CO--NR.sup.26--, --CR.sup.27R.sup.28--,
.sub.a cycloalkylene radical containing 3 to 7 carbon atoms and
finally a carbocyclic aryl radical, R.sup.25 representing an alkyl
radical, R.sup.26 representing a hydrogen atom or a methyl radical,
R.sup.27 and R.sup.28 each being chosen independently from a
hydrogen atom and a methyl group;
[0195] or also R.sup.4 represents a radical of formula
##STR00028##
and the salts of such compounds.
[0196] According to a variant of the invention, said compounds of
general formula (A) are such that R.sup.4 does not represent a
radical of formula
##STR00029##
in the remainder of this disclosure, such compounds are called
"compounds of general sub-formula (A).sub.M".
[0197] A particular feature of this variant of the invention
relates to the compounds of general sub-formula (A).sub.M5
##STR00030##
in which R, R.sup.4 and R.sup.5 have the same meaning as in general
formula (A).
[0198] Another feature of this variant of the invention relates to
the compounds of general sub-formula (A).sub.M6
##STR00031##
in which R, R.sup.4 and R.sup.5 have the same meaning as in general
formula (A).
[0199] According to another variant of the invention, said
compounds of general formula (A) are such that R.sup.4 represents a
radical of formula
##STR00032##
in the remainder of this disclosure, such compounds are called the
"compounds of general sub-formula (A).sub.D".
[0200] A particular feature of this variant of the invention
relates to the compounds of general sub-formula (A).sub.D5
##STR00033##
in which R and R.sup.5 have the same meaning as in general formula
(A) whilst R.sup.4 represents a radical of formula
##STR00034##
in which L, R and R.sup.5 have the same meaning as in general
formula (A).
[0201] Another feature of this variant of the invention relates to
the compounds of general sub-formula (A).sub.D6
##STR00035##
in which R and R.sup.5 have the same meaning as in general formula
(A) whilst R.sup.4 represents a radical of formula
##STR00036##
in which L, R and R.sup.5 have the same meaning as in general
formula (A).
[0202] The preferences indicated for the compounds of general
formulae (I), (I).sub.M or (I).sub.D or their salts are applicable
mutatis mutandis to these compounds or their pharmaceutically
acceptable salts as medicaments, to the pharmaceutical compositions
containing these compounds or their pharmaceutically acceptable
salts, to the uses of these compounds or of their pharmaceutically
acceptable salts, to the treatment methods according to the
invention or to the intermediates of general formulae (I),
(A).sub.M or (A).sub.D or their salts.
[0203] The pharmaceutical compositions containing a compound of the
invention can be presented in the solid form, 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.
[0204] 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, the water, organic solvents such as
glycerol or the glycols, as well as their mixtures, in varying
proportions, in water.
[0205] The administration of a medicament according to the
invention can be carried out by topical, oral, parenteral route, by
intramuscular injection, etc.
[0206] The administration dose envisaged for a medicament according
to the invention is comprised between 0.1 mg to 10 g depending on
the type of active ingredient used.
[0207] According to the invention, the compounds of general formula
(I) can be prepared by the processes described hereafter.
[0208] Preparation of the Compounds of General Formula (I)
[0209] A distinction is to be made between two cases, according to
whether the compounds of general sub-formula (I).sub.M or those of
general sub-formula (I).sub.D are concerned.
[0210] Of course, the preparation processes hereafter are given by
way of illustration and a person skilled in the art can subject
them to the variations deemed useful, both with respect to the
reagents and to the reaction conditions and techniques.
[0211] General Method:
[0212] The compounds of general formula (I).sub.M in which R.sup.3
represents a hydrogen atom can be prepared according to the
procedure summarized in Diagram 1 hereafter.
##STR00037##
[0213] According to this method, the compounds of general formula
(I).sub.M, in which R.sup.1, R.sup.2, R.sup.4 and R.sup.5 are as
described above, are obtained by treatment of the compounds of
general formula (A).sub.M, in which R.sup.4 and R.sup.5 have the
same meaning as in general formula (I).sub.M, with the amines of
general formula R.sup.1R.sup.2NH in a protic solvent such as
methanol or ethanol, at a temperature comprised between 20.degree.
C. and 80.degree. C. and optionally in the presence of a base such
as, for example, diisopropylethylamine (cf. Yasuyuki Kita et al.,
J. Org. Chem. (1996), 61, 223-227).
[0214] The compounds of general formula (I).sub.D in which R.sup.3
represents a hydrogen atom can be prepared according to the
procedure summarized in Diagram 1a hereafter.
##STR00038##
[0215] According to this method, the compounds of general
sub-formula (I).sub.D, in which R.sup.1, R.sup.2, L and R.sup.5 are
as described above, are obtained by treatment of the compounds of
general formula (A).sub.D, in which L and R.sup.5 have the same
meaning as in general sub-formula (I).sub.D, with the amines of
general formula R.sup.1R.sup.2NH in a protic solvent such as
methanol or ethanol, at a temperature comprised between 20.degree.
C. and 80.degree. C. and optionally in the presence of a base such
as, for example, diisopropylethylamine (cf. Yasuynki Kita et al.,
J. Org. Chem. (1996), 61, 223-227).
[0216] Generally, the compounds of general sub-formulae (I).sub.M
or (I).sub.D in which R.sup.3 represents a halogen atom (Hal) can
be obtained from the correspondent compounds of general
sub-formulae (I).sub.M or (I).sub.D in which R.sup.3 represents a
hydrogen atom, for example by the action of N-chlorosuccinimide or
N-bromosuccinimide in an aprotic solvent such as dichloromethane or
tetrahydrofuran (Paquette and Farley, J. Org. Chem. (1967), 32,
2725-2731), by the action of an aqueous solution of sodium
hypochlorite (Javel water) in a solvent such as acetic acid
(Jagadeesh et al., Synth Commun. (1998), 28, 3827-3833), by the
action of Cu(II) (in a CuCl.sub.2/HgCl.sub.2 mixture) in the
presence of a catalytic quantity of iodine in a solvent such as
warm acetic acid (Thapliyal, Synth. Commun. (1998), 28, 1123-1126),
by the action of an agent such as benzyltrimethylammonium
dichloroiodate in the presence of NaHCO.sub.3 in a solvent such as
a dichloromethane/methanol mixture (Kordik and Reitz, J. Org. Chem.
(1996), 61, 5644-5645), or also by the use of chlorine, bromine or
iodine in a solvent such as dichloromethane (J. Renault, S.
Giorgi-Renault et al., J. Med. Chem. (1983), 26, 1715-1719). (cf.
Diagram 1b where only the compounds of general sub-formula
(I).sub.M are represented).
##STR00039##
[0217] Preparation of the Intermediates of General Formula
(A).sub.M and (A).sub.D:
[0218] The compounds of general sub-formula (A).sub.M, in which
R.sup.4 and R.sup.5 are as defined above, can be obtained, Diagram
2, from the compounds of general formula (B).sub.M in which R.sup.4
and R.sup.5 are as defined above and one of Q and Q' represents an
amino radical whilst the other represents a hydrogen atom.
##STR00040##
[0219] In the same way, the compounds of general formula (A).sub.D,
in which L and R.sup.5 are as defined above, can be obtained,
Diagram 2a, from the compounds of general formula (B).sub.D in
which L and R.sup.5 are as defined above and one of Q and Q'
represents an amino radical whilst the other represents a hydrogen
atom.
##STR00041##
[0220] The compounds of general formula (A).sub.M or (A).sub.D are
obtained by oxidation of the compounds of general formula (B).sub.M
or (B).sub.D respectively, for example by the use of an ion
exchange resin of Dowex type in the form of hypochlorite in
anhydrous medium (Hashemi et al., J. Chem. Res., Synop. (1999), 11,
672-673) or Fremy's salt (potassium nitrosodisulphonate) (Ryu et
al., Bioorg. Med. Chem. Lett. (2000), 10, 461-464), or by the use
of a reagent comprising a hypervalent iodine such as
[bis(acetoxy)iodo]benzene or [bis(trifluoroacetoxy)iodo]benzene in
aqueous acetonitrile at a temperature preferably comprised between
-20.degree. C. and ambient temperature (i.e. approximately
25.degree. C.), and preferably at approximately -5.degree. C.
(Kinugawa et al., Synthesis, (1996), 5, 633-636).
[0221] Preparation of the Intermediates of General Formula
(B).sub.M and (B).sub.D:
[0222] The compounds of general formula (B).sub.M, in which Q, Q',
R.sup.4 and R.sup.5 are as defined above, can be obtained from the
nitro derivatives of formula (C).sub.M in which R.sup.4 and R.sup.5
are as defined above and one of Q and Q' represents a nitro radical
whilst the other is a hydrogen atom, by reduction methods well
known to a person skilled in the art such as, for example,
hydrogenation in the presence of a palladinized catalyst or
treatment by tin chloride in hydrochloric acid.
[0223] The preparation of the compounds of general formula
(B).sub.M in which the methoxy group is in position 5 is
represented in Diagram 3 below for the case where, for example,
Q=NH.sub.2 and Q'=H.
##STR00042##
[0224] The preparation of the compounds of general formula
(B).sub.M in which the methoxy group is in position 6 is
represented in Diagram 3a below for the case where, for example,
Q=H and Q'=NH.sub.2.
##STR00043##
[0225] In the same way, the compounds of general formula (B).sub.D,
in which Q, Q', L and R.sup.5 are as defined above, can be obtained
from the nitro derivatives of formula (C).sub.D in which L and
R.sup.5 are as defined above and one of Q and Q' represents a nitro
radical whilst the other represents a hydrogen atom (see Diagrams
3b and 3c below).
##STR00044##
[0226] Preparation of the Intermediates of General Formula
(C).sub.Mand (C).sub.D:
[0227] The compounds of general formula (C).sub.M in which R.sup.4
and R.sup.5 are as defined above and one of Q and Q' represents a
nitro radical whilst the other represents a hydrogen atom, can be
obtained, Diagram 4, from the compounds of general formula (D), in
which Q and Q' are as defined above, and the amines of general
formula R.sup.4R.sup.5NH.
##STR00045##
[0228] In the same way, the compounds of general formula (C).sub.D
in which L and R.sup.5 are as defined above and one of Q and Q'
represents a nitro radical whilst the other represents a hydrogen
atom, can be obtained, Diagram 4a, from the compounds of general
formula (D), in which Q and Q' are as defined above, and the
diamines of general formula R.sup.5HN-L-NHR.sup.5.
##STR00046##
[0229] The compounds of general formula (C).sub.M or (C).sub.D are
obtained as indicated above using the standard conditions for
peptide synthesis (M. Bodansky, The Practice of Peptide Synthesis,
145 (Springer-Verlag, 1984)), for example in dichlorornethane in
the presence of a coupling reagent such as
bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) in
the presence of dimethylaminopyridine (DMAP) (Corte et al.,
Tetrahedron Lett. (1990), 31, 669), or in a mixture
(dimethylformamide/dichloromethane/dioxane: 1/1/1) in the presence
of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, a
catalytic quantity of dimethylaminopyridine and
diisopropylethylamine, or also by the formation of an intermediate
acid chloride obtained by the addition of oxalyl chloride in
solution to dichloromethane.
[0230] Preparation of the Intermediates of General Formula (D):
[0231] The compounds of general formula (D), in which Q and Q' are
as defined above, can be obtained, Diagram 5, by oxidation of the
carboxaldehydes of general formula (E.i) by the action of a
oxidizing agent such as, for example sodium chlorite in a buffered
solution of sodium hydrogen phosphate (pH 3.5) and in an aqueous
solution of tert-butanol in the presence of 2-methyl-2-butene;
these aldehydes of general formula (E.i) themselves being obtained
by oxidation of the compounds of general formula (E) by the action,
for example, of selenium oxide in 1,4-dioxane at 80.degree. C. (Bu
et al., J. Med. Chem. (2001), 44, 2004-2014).
##STR00047##
[0232] Preparation of the Intermediates of General Formula (E):
[0233] The compounds of general formula (E), in which Q and Q' are
as defined above, can be obtained from the compounds of general
formula (F), in which the positions corresponding to the Q and Q'
radicals are substituted by hydrogen atoms, by nitration methods
well known to a person skilled in the art such as, for example,
treatment by a mixture of nitric acid and sulphuric acid.
[0234] The preparation of the compounds of general formula (E) in
which the methoxy group is in position 5 is represented in Diagram
6 below for the case where, for example, Q=NO.sub.2 and Q'=H.
##STR00048##
[0235] The preparation of the compounds of general formula (E) in
which the methoxy group is in position 6 is represented in Diagram
6a below for the case where, for example, Q=H and Q'=NO.sub.2.
##STR00049##
[0236] Compounds of General Formula (F):
[0237] The compounds of general formula (F) are known industrial
products available from the usual suppliers or can be synthesized
from such products according to methods familiar to a person
skilled in the art.
[0238] As regards the temperatures to which reference is made in
the present text, the term "approximately XX.degree. C." indicates
that the temperature in question corresponds to an interval within
10.degree. C. above or below the temperature of XX.degree. C., and
preferably to an interval within 5.degree. C. above or below the
temperature of XX.degree. C.
[0239] Unless otherwise defined, 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.
[0240] The following examples are presented in order to illustrate
the above procedures and should in no event be considered as
limiting the scope of the invention.
[0241] The melting points were measured using a Buchi 535 capillary
apparatus.
[0242] The NMR spectra were recorded using a Brucker ARX 400
spectrometer. The chemical shifts are expressed in parts per
million (ppm) with respect to tetramethylsilane (TMS) and the
multiplicity of the signals is given in the form of s (singlet), d
(doublet), t (triplet), m (multiplet).
EXAMPLES
[0243] Method Used for Measuring the Retention Time (r.t.) and of
the Molecular Peak (MH+)
[0244] The compounds are characterized by their retention time
(r.t.), expressed in minutes, determined by liquid chromatography
(LC), and their molecular peak (MH+) determined by mass
spectrometry (MS), single quadrupole mass spectrometer (Micromass,
Platform model) equipped with an electrospray source is used with a
resolution of 0.8 Da at 50% valley.
[0245] For Examples 1 to 15 hereafter, the elution conditions
corresponding to the results indicated are the following: elution
with the acetonitrile-water-trifluoroacetic acid mixture 50-950-0.2
(A) for 1 minute then passing from mixture (A) to an
acetonitrile-water mixture 950-50 (B) by a linear gradient over a
period of 7.5 minutes before elution with pure mixture B for 2
minutes.
Example 1
5-{[2-(dimethylamino)ethyl]amino}-2-(morpholin-4-ylcarbonyl)-1,3-benzothia-
zole-4,7-dione
1.1) 5-methoxy-4-nitro-1,3-benzothiazole-2-carboxylic acid
1.1.1) 5-methoxy-4-nitro-1,3-benzothiazole-2-carbaldehyde
[0246] 12.8 g (0.115 mol; 6 equivalents) of selenium dioxide is
added to 4.34 g (19.3 mmol) of
5-methoxy-2-methyl-4-nitro-1,3-benzothiazole in solution in 180 ml
of anhydrous dioxane. The reaction mixture is stirred at 80.degree.
C. for 18 hours then the insoluble matter is filtered and the
solvent is evaporated off under reduced pressure. The expected
aldehyde is obtained in the form of a yellow oil and purified on a
silica column (eluent: ethyl acetate/heptane: gradient of 30% to
70%). Melting point: 154-155.degree. C.
[0247] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 10.06 (s, 1H, CHO);
8.52-8.49 (d, 1H, arom H); 7.80-7.78 (d, 2H, arom H); 4.04 (s, 3H,
OCH.sub.3).
1.1.2) 5-methoxy-4-nitro-1,3-benzothiazole-2-carboxylic acid
[0248] A solution of 18 g of sodium chlorite and 18 g of sodium
hydrogen phosphate in 180 ml of water is added dropwise to the
carbaldehyde residue taken up in 420 ml of tert-butanol and 100 ml
of 2-methyl-but-2-ene. The reaction mixture is maintained under
stirring for 18 hours at ambient temperature, then the insoluble
matter is filtered, taken up in water and the aqueous solution
obtained is acidified by a 1M solution of hydrochloric acid. The
precipitate obtained is filtered and washed with water. The acid is
obtained in the form of a beige powder. (m=3.12 g; yield=64%).
Melting point: 140-142.degree. C.
[0249] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 8.45-8.43 (d, 1H,
arom H); 7.74-7.71 (d, 1H, arom H); 3.99 (s, 3H, CH.sub.3).
[0250] MS-LC: MH+=254.99; r.t.=8.20 min.
1.2)
5-Methoxy-2-(morpholin-4-ylcarbonyl)-4-nitro-1,3-benzothiazole
[0251] 980 mg (2.1 mmol; 1.1 eq.) of
bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) is
added to 500 mg (1.97 mmol) of
5-methoxy-4-nitro-1,3-benzothiazole-2-carboxylic acid and 344 .mu.l
(1.97 mmol; 1 eq.) of diisopropylethylamine in solution in 40 ml of
dichloromethane. The reaction mixture is maintained for 15 minutes
under stirring at ambient temperature, then 202 .mu.l (2.3 mmol;
1.2 eq.) of morpholine and a spatula tip's worth of
dimethylaminopyridine are added to the medium which is maintained
under stirring for 18 hours at ambient temperature. The insoluble
matter is then filtered and the solvent is evaporated off under
reduced pressure. The residue is then purified on a silica column
(eluent: ethyl acetate/heptane: gradient of 30 to 70% over 40
minutes then for 5 minutes at 70% of ethyl acetate in heptane) and
210 mg (yield=33%) of expected product is obtained in the form of
beige powder.
[0252] MS-LC: MH+=324.01; r.t.=9.63 min.
1.3)
5-Methoxy-2-(morpholin-4-ylcarbonyl)-1,3-benzothiazol-4-amine
[0253] 20 mg of 10% palladium on activated carbon is added to 210
mg (0.65 mmol) of
5-methoxy-2-(morpholin-4-ylcarbonyl)-4-nitro-1,3-benzothiazole in
solution in 10 ml of methanol. The reaction medium is then placed
under stirring under a hydrogen atmosphere for 18 hours. The
catalyst is then filtered out and the solvent is evaporated off.
173 mg of the expected product (gross yield=91%) is obtained in the
form of a yellow oil and is used in the following stage without
other purification.
[0254] MS-LC: MH+=294.04; r.t.=9.09 min.
1.4)
5-methoxy-2-(morpholin-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione
[0255] A solution of 570 mg (1.063 mmol; 1.8 eq.) of Fremy's salt
(potassium nitrosodisulphonate, containing 25 to 50% water and
methanol) in a 0.3M aqueous solution of sodium hydrogen phosphate
(12 ml) is added dropwise to 173 mg (0.6 mmol) of
5-methoxy-2-(morpholin-4-ylcarbonyl)-1,3-benzothiazol-4-amine in
solution in 5 ml of acetone. The reaction mixture is maintained
under stirring at ambient temperature for 4 hours, then the acetone
is evaporated off and the medium is taken up in 10 ml of
dichloromethane and washed twice with 7 ml of a saturated aqueous
solution of sodium chloride. The organic phases are combined, dried
over magnesium sulphate and the solvent is evaporated off under
reduced pressure. 175 mg (gross yield=99%) of expected product is
obtained in the form of a yellow powder and is used in the
following stage without other purification.
[0256] MS-LC: MH+=308.99; r.t.=8.40 min.
1.5) 5-{[2-(dimethylamino)ethyl]amino}-2-
morpholin-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione
[0257] 66 .mu.l (0.6 mmol; 1 eq.) of N,N-dimethylethylenediamine is
added to 175 mg of
5-methoxy-2-(morpholin-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione in
solution in 10 ml of anhydrous ethanol. The reaction mixture is
stirred at 80.degree. C. for 2 hours then the solvent is evaporated
off under reduced pressure. The residue is purified on a silica
column (eluent: methanol in dichloromethane: gradient of 0 to 5%
over 35 minutes then for 5 minutes at 5% methanol in
dichloromethane) and 50 mg (yield=23%) of compound expected is
obtained in the form of a red powder. Melting point=207-208.degree.
C.
[0258] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.56 (t, 1H, NH);
5.61 (s, 1H, CH); 4.24 (m, 2H); 3.69 (m, 6H); 3.26 (m, 2H,
CH.sub.2); 2.49 (m, 2H, CH.sub.2); 2.19 (s, 6H, 2CH.sub.3).
[0259] MS-LC: MH+=365.06; r.t.=7.19 min.
[0260] The compounds of Examples 2 to 13 are obtained according to
a protocol analogous to that used for Example 1, with the
appropriate amines replacing morpholine in the second stage and
with N-(2-aminoethyl)pyrrolidine replacing
N,N-dimethylethylenediamine in the last stage for Example 6.
Example 2
tert-butyl{2-[2-(2-{[(5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihy-
dro-1,3-benzothiazol-2-yl)carbonyl]amino}ethoxy)ethoxy]ethyl}carbamate
[0261] Red powder. Melting point: 55-57.degree. C.
[0262] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.10 (t, 1H, NH);
7.54 (t, 1H, NH); 6.69 (t, 1H, NH); 5.62 (s, 1H, CH); 3.56-3.43 (m,
8H); 3.37-3.35 (m, 2H); 3.29-3.25 (m, 2H); 3.04-3.02 (m, 2H,
CH.sub.2); 2.51 (m, 2H, CH.sub.2); 2.18 (s, 6H, 2CH.sub.3); 1.35
(s, 9H, 3CH.sub.3).
[0263] MS-LC: MH+=526.34; r.t.=7.80 min.
Example 3
N,N-dibenzyl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydro-1,3-b-
enzothiazole-2-carboxamide
[0264] Red powder.
[0265] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.51 (t, 1H, NH);
7.36-7.27 (m, 10H, arom H); 5.61 (s, 1H, CH); 5.26 (s, 2H,
CH.sub.2); 4.61 (s, 2H, CH.sub.2); 3.26-3.23 (m, 2H, CH.sub.2);
2.46-2.44 (m, 2H, CH.sub.2); 2.17 (s, 6H, 2CH.sub.3).
[0266] MS-LC: MH+=475.44; r.t.=8.98 min.
Example 4
5-{[2-(dimethylamino)ethyl]amino}-N,N-bis(2-methoxyethyl)-4,7-dioxo-4,7-di-
hydro-1,3-benzothiazole-2-carboxamide
[0267] Red powder. Melting point: 92-94.degree. C.
[0268] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.53-7.52 (t, 1H,
NH); 5.60 (s, 1H, CH); 4.18-4.15 (m, 2H, CH.sub.2); 3.69-3.67 (m,
2H, CH.sub.2); 3.56-3.53 (m, 4H, 2 CH.sub.2); 3.29-3.24 (m, 5H);
3.19 (m, 3H, CH.sub.3); 2.48-2.27 (m, 2H, CH.sub.2); 2.19 (s, 6H, 2
CH.sub.3).
[0269] MS-LC: MH+=411.43; r.t.=7.52 min.
Example 5
5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-N-[3-(2-oxopyrrolidin-1-yl)pro-
pyl]-4,7-dihydro-1,3-benzothiazole-2-carboxamide
[0270] Red powder. Melting point: 154-156.degree. C.
[0271] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.19 (t, 1H, NH);
7.55 (t, 1H, NH); 5.61 (s, 1H, CH); 3.37-3.18 (m, 10H); 2.51-2.49
(m, 2H, CH.sub.2); 2.20-2.19 (m, 6H, 2 CH.sub.3); 1.93-1.89 (m, 2H,
CH.sub.2); 1.74-1.69 (m, 2H, CH.sub.2).
[0272] MS-LC: MH+=420.14; r.t.=7.26 min.
Example 6
4,7-dioxo-N-[3-(2-oxopyrrolidin-1-yl)propyl]-5-[(2-pyrrolidin-1-ylethyl)am-
ino]-4,7-dihydro-1,3-benzothiazole-2-carboxamide
[0273] Red powder.
[0274] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.18 (t, 1H, NH);
7.67 (t, 1H, NH); 5.61 (s, 1H, CH); 3.37-3.18 (m, 10H); 2.68-2.67
(t, 2H, CH.sub.2); 2.49 (m, 2H, CH.sub.2); 2.20 (t, 2H, CH.sub.2);
1.93-1.89 (m, 2H, CH.sub.2); 1.74-1.68 (m, 6H).
[0275] MS-LC: MH+=446.17; r.t.=7.32 min.
Example 7
5-{[2-(dimethylamino)ethyl]amino}-N-isobutyl-4,7-dioxo-4,7-dihydro-1,3-ben-
zothiazole-2-carboxamide
[0276] Red powder. Melting point: 163-164.degree. C.
[0277] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.21 (t, 1H, NH);
7.54 (t, 1H, NH); 5.61 (s, 1H, CH); 3.28-3.23 (m, 2H, CH.sub.2);
3.11-3.08 (m, 2H, CH.sub.2); 2.49 (m, 2H, CH.sub.2); 2.18 (m, 6H, 2
CH.sub.3); 1.92-1.89 (m, 1H, CH); 0.88-0.86 (m, 6H, 2
CH.sub.3).
[0278] MS-LC: MH+=351.16; r.t.=7.71 min.
Example 8
tent-butyl
(4-{[(5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydro-1-
,3-benzothiazol-2-yl)carbonyl]amino}butyl)carbamate
[0279] Red powder.
[0280] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.21 (t, 1H, NH);
7.54 (t, 1H, NH); 6.77 (t, 1H, NH); 5.61 (s, 1H, CH); 3.28-3.24 (m,
4H, 2CH.sub.2); 2.93-2.90 (m, 2H, CH.sub.2); 2.49 (m, 2H,
CH.sub.2); 2.18 (s, 6H, 2CH.sub.3); 1.53-1.49 (m, 2H, CH.sub.2);
1.39-1.32 (m, 11H).
[0281] MS-LC: MH+=466.25; r.t.=7.75 min.
Example 9
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(2-furoyl)piperazin-1-yl]carbonyl}-
-1,3-benzothiazole-4,7-dione
[0282] Red powder.
[0283] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.86 (m, 1H, arom
H); 7.58 (t, 1H, NH); 7.06 (m, 1H, arom H); 6.64 (m, 1H, arom H);
5.62 (s, 1H, CH); 4.32 (m, 2H); 3.82-3.78 (m, 6H); 3.26-3.25 (m,
2H, CH.sub.2); 2.49 (m, 2H, CH.sub.2); 2.18 (s, 6H, 2CH.sub.3).
[0284] MS-LC: MH+=458.08; r.t.=7.39 min.
Example 10
5-{[2-(dimethylamino)ethyl]amino}-N-(2-methoxyethyl)-4,7-dioxo-4,7-dihydro-
-1,3-benzothiazole-2-carboxamide
[0285] Red powder.
[0286] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.11 (t, 1H, NH);
7.55 (t, 1H, NH); 5.61 (s, 1H, CH); 3.50-3,44 (m, 4H); 3.27-3.24
(m, 5H); 2.49 (m, 2H, CH.sub.2); 2.18 (s, 6H, 2CH.sub.3).
[0287] MS-LC: MH+=353.11; r.t.=7.27 min.
Example 11
N-butyl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzot-
hiazole-2-carboxamide
[0288] Red powder.
[0289] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.20 (t, 1H, NH);
7.54 (t, 1H, NH); 5.61 (s, 1H, CH); 3.28-3.25 (m, 4H); 2.49 (m, 2H,
CH.sub.2); 2.18 (s, 6H, 2CH.sub.3); 1.54-1.50 (m, 2H, CH.sub.2);
1.32-1.27 (m, 2H, CH.sub.2); 0.88 (t, 3H, CH.sub.3).
[0290] MS-LC: MH+=351.10; r.t.=7.78 min.
Example 12
N-benzyl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzo-
thiazole-2-carboxamide
[0291] Red powder. Melting point: 188-189.degree. C.
[0292] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.78 (t, 1H, NH);
7.55 (t, 1H, NH); 7.34-7.23 (m, 5H, arom H); 5.62 (s, 1H, CH);
4.46-4.45 (m, 2H, CH.sub.2); 3.27-3.24 (m, 2H, CH.sub.2); 2.49 (m,
2H, CH.sub.2); 2.19 (m, 6H, 2 CH.sub.3).
[0293] MS-LC: MH+=385.09; r.t.=7.89 min.
Example 13
N-(cyclohexylmethyl)-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihyd-
ro-1,3-benzothiazole-2-carboxamide
[0294] Red powder. Melting point: 171-172.degree. C.
[0295] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.17 (t, 1H, NH);
7.54 (t, 1H, NH); 5.61 (s, 1H, CH); 3.27-3.24 (m, 2H, CH.sub.2);
3.13-3.10 (m, 2H, CH.sub.2); 2.49 (m, 2H, CH.sub.2); 2.18 (m, 6H, 2
CH.sub.3); 1.67-1.60 (m, 6H); 1.22-1.13 (m, 3H); 0.95-0.89 (m,
2H).
[0296] MS-LC: MH+=391.13; r.t.=8.23 min.
Example 14
N,N'-(oxydiethane-2,1-diyl)bis(5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-
-4,7-dihydro-1,3-benzothiazole-2-carboxamide)
14.1) 5-methoxy-4-nitro-1,3-benzothiazole-2-carboxylic acid
14.1.1) 5-methoxy-4-nitro-1,3-benzothiazole-2-carbaldehyde
[0297] 12.8 g (0.115 mol; 6 equivalents) of selenium dioxide is
added to 4.34 g (19.3 mmol) of
5-methoxy-2-methyl-4-nitro-1,3-benzothiazole in solution in 180 ml
of anhydrous dioxane. The reaction mixture is stirred at 80.degree.
C. for 18 hours then the insoluble matter is filtered and the
solvent is evaporated off under reduced pressure. The expected
aldehyde is obtained in the form of a yellow oil and purified on a
silica column (eluent: ethyl acetate/heptane: gradient of 30% to
70%). Melting point: 154-155.degree. C.
[0298] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 10.06 (s, 1H, CHO);
8.52-8.49 (d, 1H, arom H); 7.80-7.78 (d, 2H, arom H); 4.04 (s, 3H,
OCH.sub.3).
14.1.2) 5-methoxy-4-nitro-1,3-benzothiazole-2-carboxylic acid
[0299] A solution of 18 g of sodium chlorite and 18 g of sodium
hydrogen phosphate in 180 ml of water is added dropwise to the
carbaldehyde residue taken up in 420 ml of tert-butanol and 100 ml
of 2-methyl-but-2-ene. The reaction mixture is maintained under
stirring for 18 hours at ambient temperature, then the insoluble
matter is filtered, followed by taking up in water and the aqueous
solution obtained is acidified with a 1M solution of hydrochloric
acid. The precipitate obtained is filtered and washed with water.
The acid is obtained in the form of a beige powder. (m=3.12 g;
yield=64%). Melting point: 140-142.degree. C.
[0300] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 8.45-8.43 (d, 1H,
arom H); 7.74-7.71 (d, 1H, arom H); 3.99 (s, 3H, CH.sub.3).
[0301] MS-LC: MH+=254.99; r.t.=8.20 min.
14.2)
N,N'-(oxydiethane-2,1-diyl)bis(5-methoxy-4-nitro-1,3-benzothiazole-2-
-carboxamide)
[0302] 3.03 g (6.5 mmol; 1.1 eq.) of
bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) is
added to 1.5 g (5.9 mmol) of
5-methoxy-4-nitro-1,3-benzothiazole-2-carboxylic acid and 1.13 ml
(6.5 mmol; 1.1 eq.) of diisopropylethylamine in solution in 100 ml
of dichloromethane. The reaction mixture is maintained for 10
minutes under stirring at ambient temperature, then 0.31 g (2.9
mmol; 0.5 eq.) of 2.2'-oxybis(ethylamine) and a spatula tip's worth
of dimethylaminopyridine are added to the medium which is
maintained under stirring for 18 hours at ambient temperature. The
insoluble matter is filtered and the solvent is evaporated off
under reduced pressure. The residue is then purified on a silica
column (eluent: ethyl acetate/heptane: 4/1) and 250 mg of expected
product (yield=8%) is obtained in the form of beige. powder.
[0303] MS-LC: MH+=577.11; r.t.=10.27 min.
14.3)
N,N'-(oxydiethane-2,1-diyl)bis(4-amino-5-methoxy-1,3-benzothiazole-2-
-carboxamide)
[0304] 0.33 g (1.5 mmol; 3.4 eq.) of dihydrated tin chloride is
added to 250 mg (0.43 mmol) of
N,N'-(oxydiethane-2,1-diyl)bis(5-methoxy-4-nitro-1,3-benzothiazole-2-carb-
oxamide) in solution in 10 ml of concentrated hydrochloric acid.
The reaction medium is maintained under stirring at 60.degree. C.
for 4 hours, then poured into iced water and neutralized with a 5N
soda solution. The expected product is then extracted with 3 times
25 ml of dichloromethane, then the organic phases are combined,
dried over magnesium sulphate and the is solvent evaporated off
under reduced pressure. 220 mg of the expected product (gross
yield=98%) is obtained in the form of a yellow oil and is used in
the following stage without other purification.
[0305] MS-LC: MH+=517.23; r.t.=9.59 min.
14.4)
N,N'-(oxydiethane-2,1-diyl)bis(5-methoxy-4,7-dioxo-4,7-dihydro-1,3-b-
enzothiazole-2-carboxamide)
[0306] A solution of 0.91 g (1.7 mmol; 4 eq.) of Fremy's salt
(potassium nitrosodisulphonate, containing 25 to 50% of water and
methanol) in a 0.3M aqueous solution of sodium hydrogen phosphate
(35 ml) is added dropwise to 220 mg (0.43 mmol) of
N,N'-(oxydiethane-2,1-diyl)bis(4-amino-5-methoxy-1,3-benzothiazole-2-carb-
oxamide) in solution in 10 ml of acetone. The reaction mixture is
maintained under stirring at ambient temperature for 2 hours, then
the acetone is evaporated off and the medium is taken up in 25 ml
of dichloromethane and washed twice with 15 ml of a saturated
aqueous solution of sodium chloride. The organic phases are
combined, dried over magnesium sulphate and the solvent is
evaporated off under reduced pressure. 230 mg of expected product
(gross yield=99%) is obtained in the form of a yellow powder and is
used in the following stage without other purification.
[0307] MS-LC: MH+=547.12; r.t.=8.76 min.
14.5)
N,N'-(oxydiethane-2,1-diyl)bis(5-{[2-(dimethylamino)ethyl]amino}-4,7-
-dioxo-4,7-dihydro-1,3-benzothiazole-2-carboxamide)
[0308] 81 .mu.l (0.73 mmol; 2 eq.) of N,N-dimethylethylenediamine
is added to 200 mg of
N,N'-(oxydiethane-2,1-diyl)bis(5-methoxy-4,7-dioxo-4,7-dihydro-1,3-benzot-
hiazole-2-carboxamide) in solution in 300 ml of anhydrous ethanol.
The reaction mixture is stirred at 60.degree. C. for 4 hours then
the solvent is evaporated off under reduced pressure. The residue
is purified on a silica column (eluent: methanol in
dichloromethane: gradient of 0 to 20% over 30 minutes then for 15
minutes with 20% of methanol in dichloromethane) and 12 mg
(yield=5%) of expected compound is obtained in the form of a red
powder.
[0309] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.04 (t, 2H, 2NH);
7.49 (t, 2H, 2NH); 5.56 (s, 2H, 2CH); 3.64-3.58 (m, 4H, 2CH.sub.2);
3.45-3.41 (m, 4H, 2CH.sub.2); 3.26-3.22 (m, 4H, 2CH.sub.2);
2.51-2.49 (m, 4H, 2CH.sub.2); 2.19 (s, 12H, 4CH.sub.3).
[0310] MS-LC: MH+=659.20; r.t.=6.99 min.
[0311] The compound of Example 15 is obtained according to a
protocol analogous to that used for Example 14, with the
appropriate amine replacing 2.2'-oxybis(ethylamine) in the second
stage.
Example 15
N,N'-[ethane-1,2-diylbis(oxyethane-2,1-diyl)]-bis(5-([2-(dimethylamino)eth-
yl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzothiazole-2-carboxamide)
[0312] Red powder.
[0313] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.07 (t, 2H, 2NH);
7.55 (t, 2H, 2NH); 5.59 (s, 2H, 2CH); 3.57-3.54 (m, 8H, 4CH.sub.2);
3.43-3.37 (m, 4H, 2CH.sub.2); 3.26-3.22 (m, 4H, 2CH.sub.2);
2.50-2.49 (m, 4H, 2CH.sub.2); 2.18 (m, 12H, 4CH.sub.3).
[0314] MS-LC: MH+=703.24; r.t.=7.14 min.
[0315] The compounds of Examples 16 to 20 are obtained according to
a protocol analogous to that used for Example 1, with the
appropriate amines replacing morpholine in the second stage and
N-(2-aminoethyl)pyrrolidine replacing N,N-dimethylethylenediamine
in the last stage for Example 17.
Example 16
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(morpholin-4-ylcarbonyl)piperazin--
1-yl]carbonyl}-1,3-benzothiazole-4,7-dione
[0316] Red powder. Melting point: 211-212.degree. C.
[0317] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.57 (t, 1H, NH);
5.62 (s, 1H, CH); 4.24 (m, 2H); 3.69 (m, 2H); 3.59-3.56 (m, 4H);
3.30 (m, 4H); 3.19-3.16 (m, 4H); 2.52 (m, 4H); 2.20 (s, 6H,
2CH.sub.3).
[0318] MS-LC: MH+=477.20; r.t.=7.23 min.
Example 17
2-{[4-(morpholin-4-ylcarbonyl)piperazin-1-yl]carbonyl}-5-[(2-pyrrolidin-1--
ylethyl)amino]-1,3-benzothiazole-4,7-dione
[0319] Red powder. Melting point: 193-194.degree. C.
[0320] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.72 (t, 1H, NH);
5.64 (s, 1H, CH); 4.24 (m, 2H); 3.69 (m, 4H); 3.59-3.56 (m, 6H);
3.19-3.16 (m, 6H); 2.66-2.60 (m, 6H); 1.73 (m, 4H).
[0321] MS-LC: MH+=503.26; r.t.=7.29 min.
Example 18
5-{[2-(dimethylamino)ethyl]amino}-N-(4-methoxyphenyl)-4,7-dioxo-4,7-dihydr-
o-1,3-benzothiazole-2-carboxamide
[0322] Red powder. Melting point: 207-208.degree. C.
[0323] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 10.96 (s, 1H, NH);
7.78-7.75 (m, 2H, arom); 7.58 (t, 1H, NH); 6.96-6.93 (m, 2H, arom);
5.65 (s, 1H, CH); 3.75 (s, 3H, OCH.sub.3); 3.27-3.26 (m, 2H);
2.53-2.50 (m, 2H); 2.20 (s, 6H, 2CH.sub.3).
[0324] MS-LC: MH+=401.11; r.t.=7.98 min.
[0325] This compound is obtained in salified form, (the salt
prepared being a methanesulphonate) according to standard methods
known to a person skilled in the art.
[0326] Orange powder.
[0327] MS-LC: MH+=401.17; r.t.=8.07 min.
Example 19
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(methylsulphonyl)piperazin-1-yl]ca-
rbonyl}-1,3-benzothiazole-4,7-dione
[0328] Red powder. Melting point: 201-202.degree. C.
[0329] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.57 (t, 1H, NH);
5.62 (s, 1H, CH); 4.32 (m, 2H); 3.78 (m, 2H); 3.28-3.25 (m, 6H);
2.91 (s, 3H, CH.sub.3); 2.53-2.50 (m, 2H); 2.18 (s, 6H,
2CH.sub.3).
[0330] MS-LC: MH+=442.15; r.t.=7.31 min.
Example 20
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(tetrahydrofuran-2-ylcarbonyl)pipe-
razin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione
[0331] Red powder. Melting point: 168-169.degree. C.
[0332] NMR .sup.1H(DMSO d6, 400 MHz, .delta.): 7.57 (t, 1H, NH);
5.62 (s, 1H, CH); 4.73-4.69 (m, 1H); 4.25-4.21 (m, 2H); 3.79-3.72
(m, 2H); 3.68-3.57 (m, 6H); 3.28-3.25 (m, 2H); 2.51-2.49 (m, 2H);
2.19 (s, 6H, 2CH.sub.3); 2.05-2.01 (m, 2H); 1.85-1.80 (m, 2H).
[0333] MS-LC: MH+=462.19; r.t.=7.22 min.
Example 21
6-bromo-5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(tetrahydrofuran-2-ylcarbo-
nyl)piperazin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione
[0334] 78 mg (0.17 mmol) of the compound of Example 20 is
solubilized in 10 mL of acetic acid. 33 mg (0.19 mmol; 1.1 eq.) of
N-bromosuccinimide is added and the reaction mixture is agitated
for 3 hours at ambient temperature. After concentration under
reduced pressure, the residue is purified by chromatography on a
silica column (eluent: dichloromethane/methanol 90/10) and the
expected product is obtained, after being taken up in ethyl ether,
in the form of a violet powder.
[0335] Melting point: 161-162.degree. C.
[0336] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.47 (t, 1H, NH);
4.73-4.69 (m, 1H); 4.25-4.21 (m, 2H); 3.79-3.72 (m, 2H); 3.68-3.57
(m, 6H); 3.28-3.25 (m, 2H); 2.51-2.49 (m, 2H); 2.19 (s, 6H,
2CH.sub.3); 2.05-2.01 (m, 2H); 1.85-1.80 (m, 2H).
[0337] MS-LC: MH+=540.09; r.t.=7.39 min.
[0338] The compounds of Examples 22 to 26 are obtained according to
a protocol analogous to that used for Example 1, with the
appropriate amines replacing morpholine in the second stage.
Example 22
5-{[2-(dimethylamino)ethyl]amino}-2-(pyrrolidin-1-ylcarbonyl)-1,3-benzothi-
azole-4,7-dione
[0339] Red powder. Melting point: 207-208.degree. C.
[0340] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.54 (t, 1H, NH);
5.61 (s, 1H, CH); 4.01 (t, 2H, CH.sub.2); 3.55 (t, 2H, CH.sub.2);
3.29-3.25 (m, 2H); 2.52-2.49 (m, 2H); 2.19 (s, 6H, 2CH.sub.3);
1.98-1.93 (m, 2H); 1.89-1.84 (m, 2H).
[0341] MS-LC: MH+=349.16; r.t.=7.45 min.
Example 23
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(2-thienylcarbonyl)piperazin-1-yl]-
carbonyl}-1,3-benzothiazole-4,7-dione
[0342] Red powder.
[0343] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.79-7.78 (m, 1H);
7.57 (t, 1H, NH); 7.50-7.49 (m, 1H); 7.16-7.13 (m, 1H); 5.62 (s,
1H, CH); 4.33 (m, 2H); 3.79 (m, 6H); 3.28-3.25 (m, 2H); 2.50-2.48
(m, 2H); 2.19 (s, 6H, 2CH.sub.3).
[0344] MS-LC: MH+=474.15; r.t.=7.55 min.
Example 24
5-{[2-(dimethylamino)ethyl]amino}-N-ethyl-4,7-dioxo-4,7-dihydro-1,3-benzot-
hiazole-2-carboxamide
[0345] Red powder. Melting point: 174-175.degree. C.
[0346] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.21 (t, 1H, NH);
7.54 (t, 1H, NH); 5.61 (s, 1H, CH); 3.27-3.24 (m, 4H); 2.52-2.49
(m, 2H); 2.19 (s, 6H, 2CH.sub.3); 1.13 (t, 3H, CH.sub.3).
[0347] MS-LC: MH+=323.12; r.t.=7.29 min.
Example 25
N-(4-chlorophenyl)-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dihydro-
-1,3-benzothiazole-2-carboxamide
[0348] Red powder.
[0349] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 11.22 (s, 1H, NH);
7.95-7.85 (m, 3H); 7.46-7.39 (m, 2H); 5.79 (s, 1H, CH); 3.50 (m,
2H); 2.66 (m, 2H); 2.19 (s, 6H, 2CH.sub.3).
[0350] MS-LC: MH+=405.03; r.t.=8.35 min.
Example 26
N-1,3-benzodioxol-5-yl-5-{[2-(dimethylamino)ethyl]amino}-4,7-dioxo-4,7-dih-
ydro-1,3-benzothiazole-2-carboxamide
[0351] Red powder. Melting point: 220-221.degree. C.
[0352] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 10.98 (s, 1H, NH);
7.58 (t, 1H, NH); 7.47 (s, 1H); 7.37-7.34 (m, 1H); 6.93-6.91 (m,
1H); 6.02 (s, 2H, CH.sub.2); 5.65 (s, 1H, CH); 3.27-3.25 (m, 2H);
2.53-2.51 (m, 2H); 2.19 (s, 6H, 2CH.sub.3).
[0353] MS-LC: MH+=415.07; r.t.=8.00 min.
[0354] The compounds of Examples 27 to 32 are obtained according to
a protocol analogous to that used for Example 20, with the
appropriate amines replacing N,N-dimethylethylenediamine in the
last stage.
Example 27
5-
[(2-methoxyethyl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-
-yl]carbonyl}-1,3-benzothiazole-4,7-dione
[0355] Red powder.
[0356] MS-LC: MH+=449.16; r.t.=8.16 min.
Example 28
5-(4-methylpiperazin-1-yl)-2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-
-yl]carbonyl}-1,3-benzothiazole-4,7-dione
[0357] Red powder.
[0358] MS-LC: MH+=474.20; r.t.=7.31 min.
Example 29
5-[(2-pyridin-2-ylethyl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperaz-
in-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione
[0359] Red powder.
[0360] MS-LC: MH+=496.20; r.t.=7.42 min.
Example 30
5-[(3-morpholin-4-ylpropyl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)pipe-
razin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione
[0361] Red powder.
[0362] MS-LC: MH+=518.22; r.t.=7.34 min.
Example 31
5-[(1-benzylpyrrolidin-3-yl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)pip-
erazin-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione
[0363] Red powder.
[0364] MS-LC: MH+=550.22; r.t.=7.70 min.
Example 32
5-[(2-cyclohexylethyl)amino]-2-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-
-1-yl]carbonyl}-1,3-benzothiazole-4,7-dione
[0365] Red powder.
[0366] MS-LC: MH+=501.21; r.t.=10.83 min.
[0367] The compound of Example 33 is obtained according to a
protocol analogous to that used for Example 1, with 4-fluoroaniline
replacing morpholine in the second stage.
Example 33
5-{[2-(dimethylamino)ethyl]amino}-N-(4-fluorophenyl)-4,7-dioxo-4,7-dihydro-
-1,3-benzothiazole-2-carboxamide
[0368] Red powder. Melting point: 208-209.degree. C.
[0369] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 11.15 (s, 1H, NH);
7.90-7.85 (m, 2H); 7.60 (t, 1H, NH); 7.26-7.20 (m, 1H); 5.66 (s,
1H, CH); 3.27-3.25 (m, 2H); 2.53-2.51 (m, 2H); 2.19 (s, 6H,
2CH.sub.3).
[0370] MS-LC: MH+=389.14; r.t.=8.11 min.
[0371] The compound of Example 34 is obtained according to a
protocol analogous to that used for Example 1, with
6-methoxy-2-methyl-7-nitro-1,3-benzothiazole replacing
5-methoxy-2-methyl-4-nitro-1,3-benzothiazole in the first stage and
pyrrolidine replacing morpholine in the second stage.
Example 34
6-{[2-(dimethylamino)ethyl]amino}-2-(pyrrolidin-1-ylcarbonyl)-1,3-benzothi-
azole-4,7-dione
[0372] Red powder. Melting point: 224-225.degree. C.
[0373] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.32 (t, 1H, NH);
5.55 (s, 1H, CH); 4.01 (t, 2H, CH.sub.2); 3.55 (t, 2H, CH.sub.2);
3.27-3.22 (m, 2H); 2.49-2.47 (m, 2H); 2.18 (s, 6H, 2CH.sub.3);
1.98-1.93 (m, 2H); 1.89-1.84 (m, 2H).
[0374] MS-LC: MH+=349.16; r.t.=7.35 min.
[0375] The compounds of Examples 35 to 37 are obtained according to
a protocol analogous to that used for Example 1, with appropriate
amine replacing morpholine in the second stage.
Example 35
5-{[2-(dimethylamino)ethyl]amino}-N-(3-fluoro-4-methoxyphenyl)-4,7-dioxo-4-
,7-dihydro-1,3-benzothiazole-2-carboxamide
[0376] Red powder. Melting point: 199-200.degree. C.
[0377] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 11.11 (s, 1H, NH);
7.80-7.76 (m, 1H); 7.68-7.66 (m, 1H); 7.60 (t, 1H, NH); 7.21-7.16
(m, 1H); 5.65 (s, 1H, CH); 3.83 (s, 3H, CH.sub.3); 3.28-3.26 (m,
2H); 2.53-2.52 (m, 2H); 2.20 (s, 6H, 2CH.sub.3).
[0378] MS-LC: MH+=419.15; r.t.=8.11 min.
Example 36
5-{[2-(dimethylamino)ethyl]amino}-2-[(6-methoxy-3,4-dihydroquinolin-1(2H)--
yl)carbonyl]-1,3-benzothiazole-4,7-dione
[0379] Red powder. Melting point: 192-193.degree. C.
[0380] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.54 (m, 2H); 6.80
(m, 1H); 6.70 (m, 1H); 5.60 (s, 1H, CH); 4.05-4.15 (m, 2H); 3.73
(s, 3H, CH.sub.3); 3.27-3.24 (m, 2H); 2.82-2.79 (m, 2H); 2.51-2.49
(m, 2H); 2.18 (s, 6H, 2CH.sub.3); 1.98-1.96 (m, 2H).
[0381] MS-LC: MH+=441.22; r.t.=8.01 min.
Example 37
5-{[2-(dimethylamino)ethyl]amino}-2-{[4-(4-methoxybenzoyl)piperazin-1-yl]c-
arbonyl}-1,3-benzothiazole-4,7-dione
[0382] Red powder. Melting point: 209-210.degree. C.
[0383] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 7.60 (t, 1H, NH);
7.44-7.42 (m, 2H); 7.01-6.99 (m, 2H); 5.61 (s, 1H, CH); 4.29-4.31
(m, 2H); 3.80 (s, 3H, CH.sub.3); 3.73-3.71 (m, 2H); 3.63-3.61 (m,
4H); 3.28-3.26 (m, 2H); 2.50-2.48 (m, 2H); 2.19 (s, 6H,
2CH.sub.3).
[0384] MS-LC: MH+=498.30; r.t.=7.73 min.
[0385] The compounds of Examples 38 to 39 are obtained according to
a protocol analogous to that used for Example 24, with the
appropriate amines replacing N,N-dimethylethylenediamine in the
last stage.
Example 38
5-[[2-(dimethylamino)ethyl](methyl)amino]-N-ethyl-4,7-dioxo-4,7-dihydro-1,-
3-benzothiazole-2-carboxamide
[0386] Red powder. Melting point: 163-164.degree. C.
[0387] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.10 (t, 1H, NH);
5.65 (s, 1H, CH); 3.77-3.74 (m, 2H); 3.34-3.32 (m, 2H); 2.98 (s,
3H, CH.sub.3); 2.35-2.33 (m, 2H); 1.93 (s, 6H, 2CH.sub.3); 1.13 (t,
3H, CH.sub.3).
[0388] MS-LC: MH+=337.19; r.t.=7.36 min.
Example 39
N-ethyl-5-{[2-(4-fluorophenyl)ethyl]amino}-4,7-dioxo-4,7-dihydro-1,3-benzo-
thiazole-2-carboxamide
[0389] Red powder. Melting point: 260-261.degree. C.
[0390] NMR .sup.1H (DMSO d6, 400 MHz, .delta.): 9.20 (t, 1H, NH);
7.96 (t, 1H, NH); 7.33-7.29 (m, 2H); 7.13-7.09 (m, 2H); 5.66 (s,
1H, CH); 3.44-3.42 (m, 2H); 3.30-3.29 (m, 2H); 2.89 (t, 2H,
CH.sub.2); 1.13 (t, 3H, CH.sub.3).
[0391] MS-LC: MH+=374.13; r.t.=10.27 min.
[0392] and the salts of these compounds.
[0393] Pharmacological Study of the Compounds of the Invention
[0394] Test Protocols
[0395] i) Measurement of the Phosphatase Activity of the Purified
Recombinant Enzyme Cdc25C
[0396] The phosphatase activity of the protein MBP-Cdc25C is
evaluated by the dephosphorylation of
3-O-methylfluorescein-phosphate (OMFP) to 3-O-methylfluorescein
(OMF) with a determination of the fluorescence at 475 nm of the
reaction product. This test makes it possible to identify
inhibitors of the recombinant enzyme cdc25. The preparation of the
fusion protein MBP-Cdc25C is described in the Patent Application
PCT WO 01/44467.
[0397] The reaction is carried out in 384-well plate format at a
final volume of 50 .mu.l. The protein MBP-Cdc25C (prepared as
described above) is preserved in following elution buffer: 20 mM
Tris-HCl pH 7.4; 250 mM NaCl; 1 mM EDTA; 1 mM of dithiothreitol
(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 40
.mu.M. The reaction is initiated by the addition of an OMFP
solution at 500 .mu.M final (prepared extemporaneously from a 12.5
mM stock solution in 100% DMSO (Sigma #M2629)). After 4 hours at
30.degree. C. in a single-use 384-well plate, the fluorescence
measured at OD 475 nm is read using a Victor.sup.2 plate reader
(EGG-Wallac). The determination of the concentration inhibiting the
enzyme reaction by 50% is calculated from three independent
experiments. Only the values contained in the linear part of the
sigmoid are retained for linear regression analysis.
[0398] ii) Characterization of Anti Proliferative Activity:
[0399] By way of example, the effect of a treatment by the
compounds of the examples described previously on two lines of
human Mia-Paca2 and DU145 cells 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), 50,000 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 at increasing concentrations of each of the compounds to be
tested up to 10 .mu.M. At the end of the of this period,
quantification of the cell proliferation is evaluated by a
colorimetric test based on the cleavage of the tetrazolium salt
WST1 by the mitochondrial dehydrogenases in the 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 in order to
estimate the inhibitory concentration IC.sub.50. The products are
solubilized in dimethylsulphoxide (DMSO) at 10.sup.-2M and finally
used in culture with 0.1% DMSO.
[0400] Results of the Tests [0401] a) The compounds of Examples 1
to 39 have an IC.sub.50 below or equal to 1.1 .mu.M on the
phosphatase activity of the purified recombinant enzyme Cdc25-C.
[0402] b) The compounds of the examples 1 to 39 have an IC.sub.50
below or equal to 10 .mu.M, more particularly below or equal to 4
.mu.M on the cell proliferation of the Mia-Paca2 lines. [0403] c)
The compounds of the examples 1 to 39 have an IC.sub.50 below or
equal to 10 .mu.M, more particularly below or equal to 6 .mu.M on
the cell proliferation of the DU-145 lines.
* * * * *