U.S. patent application number 11/272304 was filed with the patent office on 2006-04-06 for product comprising a transduction inhibitor of heterotrimeric g protein signals combined with another anti-cancer agent for therapeutic use in the treatment of cancer.
This patent application is currently assigned to S.C.R.A.S.. Invention is credited to Thomas Gordon, Marie-Odile Lonchampt, Barry Morgan, Gregoire Prevost.
Application Number | 20060074078 11/272304 |
Document ID | / |
Family ID | 26212071 |
Filed Date | 2006-04-06 |
United States Patent
Application |
20060074078 |
Kind Code |
A1 |
Prevost; Gregoire ; et
al. |
April 6, 2006 |
Product comprising a transduction inhibitor of heterotrimeric G
protein signals combined with another anti-cancer agent for
therapeutic use in the treatment of cancer
Abstract
A composition for treating cancer comprising an anti-tumorally
effective amount of a product comprising at least one transduction
inhibitor of heterotrimeric G protein signals and at least one
other anti-cancer agent selected from the group consisting of
prenyltransferase inhibitors, taxol and its analogues, gemcitabine
and camptothecin and its analogues, administered simultaneously,
separately or spread over a period of time and a pharmaceutical
carrier.
Inventors: |
Prevost; Gregoire; (Antony,
FR) ; Lonchampt; Marie-Odile; (Chevilly-Larue,
FR) ; Gordon; Thomas; (Medway, MA) ; Morgan;
Barry; (Franklin, MA) |
Correspondence
Address: |
Charles A. Muserlian;c/o Hedman and Costigan
1185 Avenue of the Americas
New York
NY
10036
US
|
Assignee: |
S.C.R.A.S.
|
Family ID: |
26212071 |
Appl. No.: |
11/272304 |
Filed: |
November 10, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10129569 |
Jun 21, 2002 |
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PCT/FR00/03098 |
Nov 8, 2000 |
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11272304 |
Nov 10, 2005 |
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Current U.S.
Class: |
514/221 ;
514/249; 514/312; 514/365; 514/374; 514/400; 514/449; 514/49 |
Current CPC
Class: |
A61K 31/70 20130101;
A61K 45/06 20130101; A61K 31/55 20130101; A61K 31/70 20130101; A61K
31/70 20130101; A61P 43/00 20180101; A61K 31/55 20130101; A61K
31/495 20130101; A61K 31/495 20130101; A61K 31/495 20130101; A61K
31/495 20130101; A61K 2300/00 20130101; A61K 31/335 20130101; A61K
2300/00 20130101; A61K 31/47 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61P 35/00 20180101; A61K 31/55 20130101; A61K
31/4985 20130101; A61K 31/495 20130101; A61K 31/495 20130101; A61K
31/4985 20130101 |
Class at
Publication: |
514/221 ;
514/312; 514/249; 514/400; 514/365; 514/374; 514/449; 514/049 |
International
Class: |
A61K 31/7072 20060101
A61K031/7072; A61K 31/5513 20060101 A61K031/5513; A61K 31/4704
20060101 A61K031/4704; A61K 31/498 20060101 A61K031/498; A61K
31/426 20060101 A61K031/426; A61K 31/421 20060101 A61K031/421; A61K
31/4172 20060101 A61K031/4172; A61K 31/337 20060101
A61K031/337 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 9, 1999 |
FR |
99/14037 |
Jan 6, 2000 |
FR |
00/00104 |
Claims
1. A composition for treating cancer comprising an anti-tumorally
effective amount of a product comprising at least one transduction
inhibitor of heterotrimeric G protein signals and at least one
other anti-cancer agent selected from the group consisting of
prenyltransferase inhibitors, taxol and its analogues, gemcitabine
and camptothecin and its analogues, administered simultaneously,
separately or spread over a period of time and a pharmaceutical
carrier.
2. The composition of claim 1 wherein the other anti-cancer agent
is a prenyltransferase inhibitor.
3. The composition of claim 2 wherein the prenyltransferase
inhibitor is a farnesyltransferase inhibitor.
4. The composition of claim 1 comprising at least one transduction
inhibitor of heterotrimeric G protein signals of the formula
##STR16## corresponding to the sub-formulae ##STR17## wherein X is
R.sub.12 and Y is R.sub.8, or X and Y together complete a ring with
6 members, the X--Y mnixture is --CH(R.sub.8)--CH(R.sub.9)--
radical; R.sub.1 is selected from the group consisting of H, alkyl
and alkylthio; R.sub.2 and R.sub.3 are individually H or alkyl;
R.sub.4 is H.sub.2 or O; R.sub.5 is selected from the group
consisting of H, alkyl, alkenyl, alkynyl, aryl, aralkyl,
heterocyclyl and heterocyclylalkyl unsubstituted or substituted by
a member selected from the group consisting of alkyl,
--O--R.sub.10--S(O).sub.mR.sub.10 (m is 0, 1, or 2),
--N(R.sub.10)R(.sub.11), --N--C(O)--R.sub.10,
--NH--(SO.sub.2)--R.sub.10, --CO.sub.2--R.sub.10, C(O)--N(R.sub.10)
(R.sub.11), and --(SO.sub.2)--N(R.sub.10) (R.sub.11); R.sub.6 and
R.sub.7 are individually selected from the group consisting of H,
--C(O)--NH--CHR.sub.13--CO.sub.2R.sub.14, alkyl, aryl, aralkyl,
heterocyclyl and heterocyclylalkyl, the latter four unsubstituted
or substituted by a member selected from the group consisting of
OH, alkyl, alkoxy, --N(R.sub.10)(R.sub.11), --COOH, --CON(R.sub.11)
(R.sub.11), and halo, or R.sub.6 and R.sub.7 together form aryl or
heterocycle; R.sub.8 and R.sub.9 are individually selected from the
group consisting of H, alkyl, aryl, aralkyl, heterocyclyl and
heterocyclylalkyl unsubstituted or substituted by a member of the
group consisting of --OH, alkyl, alkoxy --N(R.sub.10)(R.sub.11),
--COOH, --CONR(.sub.10)(R.sub.11) and halo; or R.sub.8 and R.sub.9
together form aryl or heterocycle; R.sub.10 and R.sub.11 are
individually selected from the group consisting of H, aryl,
heterocyclyl, alkyl, aralkyl and heterocyclylalkyl; R.sub.12 is
selected from the group consisting of NR.sub.9, S, or O; R.sub.13
is alkyl unsubstituted or substituted by a member selected from the
group consisting of alkyl, --OR.sub.10, --S(O).sub.mR.sub.10 (m is
0, 1, or 2) and --N(R.sub.10) (R.sub.11) R.sub.14 is H or alkyl;
combined with at least one other anti-cancer agent selected from
the group consisting of gemcitabine, taxol, taxol analogues and
farnesyltransferase inhibitor selected from the group consisting
of: a compound of the formula ##STR18## wherein n1 is 0 or 1; X, is
independently, each time that it occurs, (CHR.sup.11).sub.n3
(CH.sub.2).sub.n4Z (CH.sub.2).sub.n5; Z is selected from the group
consisting of O, N(R.sup.12), S, and a bond; n3 is, independently,
each time that it occurs, 0 or 1; each of n4 and n5 are,
independently, each time that they occur, 0, 1, 2 or 3; Y is,
independently, each time that it occurs, selected from the group
consisting of CO, CH.sub.2, CS, and a bond; R.sup.1 is selected
from the group consisting of ##STR19## and N(R.sup.24R.sup.25) each
of R.sup.2, R.sup.11, and R.sup.12 are individually, each time that
it occurs, selected from the group consisting of H,
--(C.sub.1-6)alkyl and an aryl unsubstituted or substituted by at
least one member selected from the group consisting of R.sup.8 or
R.sup.30, each substituent being chosen independently of the
others; R.sup.3 is, independently, each time that it occurs,
selected from the group consisting of H, --(C.sub.1-6)alkyl,
--(C.sub.2-6)alkenyl, --(C.sub.2-6)alkynyl,
--(C.sub.3-6)cycloalkyl, --(C.sub.3-6)cycloalkyl(C.sub.1-6)alkyl,
--(C.sub.5-7)cycloalkenyl,
--(C.sub.5-7)cycloalkenyl(C.sub.1-6)alkyl, aryl,
aryl(C.sub.1-6)alkyl, heterocyclyl, and
heterocyclyl(C.sub.1-6)alkyl unsubstituted or substituted by at
least one R.sup.30, each substituent being chosen independently of
the others; each of R.sup.1 and R.sup.5 are, independently, each
time that it occurs, selected from the group consisting of H,
--(C.sub.1-6)alkyl, --(C.sub.3-6)cycloalkyl, aryl and heterocyclyl
unsubstituted or substituted by at least one R.sup.30, each
substituent being chosen independently of the others, or R.sup.4
and R.sup.5 when taken together with the carbon atoms to which they
are attached together form aryl; R.sup.6 is, independently, each
time that it occurs, selected from the group consisting of H,
--(C.sub.1-6)alkyl, --(C.sub.2-6)alkenyl, --(C.sub.3-6)cycloalkyl,
--(C.sub.3-6) cycloalkyl(C.sub.1-6)alkyl, --(C.sub.5-7)
cycloalkenyl, --(C.sub.5-7) cycloalkenyl(c.sub.1-6)alkyl, aryl,
aryl(C.sub.1-6)alkyl, heterocyclyl and heterocyclyl(C.sub.1-6)alkyl
unsubstituted or substituted by at least one member selected from
the group consisting of --OH, --(C.sub.1-6)alkyl,
--(C.sub.1-6)alkoxy, --N(R.sup.8R.sup.9), --COOH,
--CON(R.sup.8R.sup.9) and halo, each substituent being chosen
independently of the others; R.sup.7 is, independently, each time
that it occurs, selected from the group consisting of H, .dbd.O,
.dbd.S, H --(C.sub.1-6)alkyl, --(C.sub.2-6)alkenyl,
--(C.sub.3-6)cycloalkyl, --(C.sub.3-6)cycloalkyl(C.sub.1-6)alkyl,
--(C.sub.5-7) cycloalkenyl,
--(C.sub.5-7)cycloalkenyl(C.sub.1-6)alkyl, aryl,
aryl(C.sub.1-6)alkyl, heterocyclyl and heterocyclyl(C.sub.1-6)alkyl
unsubstituted or substituted with at least one member selected from
the group consisting of --OH, --(C.sub.1-6)alkyl,
--(C.sub.1-6)alkoxy, --N(R.sup.8R.sup.9), --COOH,
--CON(R.sup.8R.sup.9) and halo, each substituent being chosen
independently of the others; each of R.sup.8 and R.sup.9 are,
independently, each time that it occurs, selected from the group
consisting of H, (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.2-6)alkynyl, aryl, and aryl(C.sub.1-6)alkyl; R.sup.10 is C;
or, when n1=0, R.sup.6 and R.sup.7 can be taken together with the
carbon atoms to which they are attached form aryl or cyclohexyl;
R.sup.21 is, independently, each time that it occurs, selected from
the group consisting of (C.sub.1-6)alkyl and aryl(C.sub.1-6)alkyl
unsubstituted or substituted by at least one R.sup.8 or R.sup.30,
each substituent being chosen independently of the others; R.sup.22
is selected from the group consisting of H, (C.sub.1-6)alkylthio,
(C.sub.3-6)cycloalkylthio, R.sup.8--CO--, and ##STR20## each of
R.sup.24 and R.sup.25 is independently, each time that it occurs,
selected from the group consisting of H, (C.sub.1-6)alkyl and aryl
(C.sub.1-6) alkyl; R.sup.30 is, independently, each time that it
occurs, selected from the group consisting of --(C.sub.1-6)alkyl,
--O--R.sup.8, --S(O).sub.n6R.sup.8, --S(O).sub.n7N(R.sup.8R.sup.9),
--N(R.sup.8R.sup.9), --CN, --NO.sub.2, --CO.sub.2R.sup.8,
--CON(R.sup.8R.sup.9), --NCO--R.sup.8, and halogen, each of n6 and
n7 is, independently, each time that it occurs, 0, 1 or 2; said
heterocyclyl is selected from the group consisting of azepinyl,
benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,
benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,
benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,
dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl,
imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl,
isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,
isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl,
2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl,
pyridyl-N-oxide, quinoxalinyl, tetrahydrofuryl,
tetrahydroisoquinolinyl, tetahydro-quinolinyl, thiamorpholinyl,
thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl,
thienothienyl and thienyl; said aryl radical being phenyl or
naphthyl; with the proviso that when n1=1, R.sup.10 is C and
R.sup.6 is H, then R.sup.10 and R.sup.7 can, taken together, form
##STR21## or when n1=1, R.sup.10 is C, and R.sup.7 is .dbd.O, H, or
.dbd.S, then R.sup.10 and R.sup.6 can, taken together, form
##STR22## with each of X.sup.1, X.sup.2, and X.sup.3 is
independently selected from the group consisting of H, halogen,
--NO.sub.2, --NCO--R.sup.8, --CO.sub.2R.sup.8, --CN, and
--CON(R.sup.8R.sup.9); and when R.sup.1 is N(R.sup.24R.sup.25),
then n3 is 1, each of n4 and n5 is 0, Z is a bond, and R.sup.3 and
R.sup.11 can, taken together, form ##STR23## n2 is an integer from
1 to 6, and each of X.sup.4 and X.sup.5 is independently selected
from the group consisting of H, --(C.sub.1-6)alkyl and aryl, or
X.sup.4 and X.sup.5 taken together, form (C.sub.3-6)cycloalkyl, a
compound of the formula ##STR24## wherein R.sup.1 is selected from
the group consisting of H, --OR.sup.10 and --NR.sup.11R.sup.12;
R.sup.2 is H or alkyl; R.sup.3, R.sup.4 and R.sup.5 are
independently selected from the group consisting of H, halogen,
alkyl, trihalomethyl, hydroxy, cyano and alkoxy; R.sup.6 is H or
alkyl; R.sup.7 is selected from the group consisting of halogen,
alkyl, hydroxyalkyl, amino, and hydroxycarbonyl; R.sup.8 and
R.sup.9 are independently selected from the group consisting of H,
halogen, cyano, alkyl, trihalomethyl, alkoxy, alkylthio and
dialkylamino; R.sup.10 is selected from the group consisting of H,
alkyl and alkylcarbonyl; R.sup.11 is H or alkyl; R.sup.12 is
selected from the group consisting of H, alkyl and alkylcarbonyl;
and Y is O or S; and of a pharmaceutically acceptable salt of a
compound of formula (II) or a compound of formula (III).
5. A composition of claim 4, wherein the transduction inhibitor of
heterotrimeric G protein signals is a compound of sub-formula
(I.sub.A) wherein: R.sub.1 is H; R.sub.2 and R.sub.3 are
independently H or lower alkyl; R.sub.4 is O; R.sub.5 is selected
from the group consisting of H, lower alkyl, cycloalkyl and
cycloalkylalkyl; R.sub.6 is aryl unsubstituted or substituted by a
member selected from the group consisting of OH, alkyl, lower
alkoxy, --N(R.sub.10) (R.sub.11), --COOH, --CON(R.sub.10)
(R.sub.11) and halo; R.sub.10 and R.sub.11 are independently H or
lower alkyl; and a pharmaceutically acceptable salt thereof.
6. A composition of claim 4 wherein the anti-cancer agent combined
with the transduction inhibitor of heterotrimeric G protein signals
is a compound of the formula ##STR25## wherein R.sup.1 is ##STR26##
R.sup.21 is aralkyl unsubstituted or substituted by at least one
member selected from the group consisting of halogen, cyano,
hydroxy, alkoxy, amino, alkylamino and dialkylamino; R.sup.4 is
aryl unsubstituted or substituted by at least one member of the
group consisting of halogen, hydroxy, alkoxy, amino, alkylamino and
dialkylamino; X is alkylene of 1 to 6 carbon atoms; Y is CO; n1=1,
R.sup.10 is C, R.sup.6 is H and R.sup.10 and R.sup.7 taken
together, form ##STR27## each of X.sup.1, X.sup.2, and X.sup.3 is
independently H or halogen and a pharmaceutically acceptable salt
thereof.
7. The composition of claim 4 wherein the anti-cancer agent
combined with the transduction inhibitor of heterotrimeric G
protein signals is a compound of the formula ##STR28## wherein
R.sup.1 is OH or NH.sub.2; R.sup.2 is alkyl; one of R.sup.3,
R.sup.4 and R.sup.5 is halogen; R.sup.6 is alkyl; one of R.sup.8
and R.sup.9 is halogen; Y is O; and a pharmaceutically acceptable
salt thereof.
8. A composition of claim 1 wherein the inhibitor of G proteins is
selected from the group consisting of
-7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5-
,6,7,8-tetrahydroimidazo[1,2a]pyrazine; and
-7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tet-
rahydroimidazo[1,2a]pyrazine; and pharmaceutically acceptable salts
thereof.
9. The composition of claim 1, wherein the anti-cancer agent is
selected from the group consisting of
1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-
-methoxyphenyl)imidazo[1,2c][1,4]benzodiazepine,4-(2-bromophenyl)-1-(2-(1--
((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-1-oxoethyl)-1,2-dihydro-8--
fluoroimidazo[1,2a](1,4)-benzodiazepine;
(.+-.)-4-(3-chlorophenyl)-6-[(4-chloro-phenyl)-amino-(1-methyl-1H-imidazo-
l-5-yl)methyl]-1-methyl-2(1H)quinolinone, taxol and
gemcitabine.
10. The composition of claim 1 wherein an additional anti-cancer
compound, different from the anti-cancer agent combined with the
transduction inhibitor of heterotrimeric G protein signals, is
selected from the group consisting of
-1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(-
2-methoxyphenyl)imidazo[1,2c][1,4)benzodiazepine;
-4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl-
-1-oxoethyl)-1,2-dihydro-8-fluoro-imidazo[1,2a](1,4]-benzodiazepine;
-.+-.-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-amino-(1-methyl-1H-imidazol--
5-yl)methyl]-1-methyl-2(1H)quinolinone; taxol; gemcitabine; and a
pharmaceutically acceptable salt thereof.
11. The composition of claim 7 wherein R.sup.2 is methyl.
12. A method of treating cancer in warm-blooded animals comprising
administering to warm-blooded animals in need thereof an
antitumorally effective amount of a composition of claim 1.
13. A method of treating cancer in warm-blooded animals comprising
administering to warm-blooded animals in need thereof an
antitumorally effective amount of a composition of claim 4.
14. A method of treating cancer in warm-blooded animals comprising
administering to warm-blooded animals in need thereof an
antitumorally effective amount of a composition of claim 10.
Description
[0001] The present invention relates to a product comprising at
least one transduction inhibitor of heterotrimeric G protein
signals, that preferably corresponds to general formula (I) defined
below, combined with at least one other anti-cancer agent,
preferably chosen from the group comprising taxol, taxol analogues,
gemcitabine and prenyltransferase inhibitors, particularly the
compounds of general formulae (II) or (III) defined below, for
therapeutic use, simultaneously, separately or spread over a period
of time, in the treatment of cancer.
[0002] The development of new anti-cancer treatments occurs largely
by the discovery of effective combinations between different
therapeutic classes to accentuate the antitumorous effect of each
class.
[0003] The combination of the anti-Her-2/neu antibody and cisplatin
or etoposide inhibits the proliferation of mammary tumor cells in a
more significant manner than the simple addition of the effects of
each product (cf. Pegram, M., et al., Oncogene, 18(1999):
2241-2251). The combination ofrthis antibody with taxol or
methotrexate shows an addition of the effects whilst its
combination with 5-fluorouracyl shows an antagonism of the products
(McGuire W. P. et al., Semin. Oncol. 1997 Feb. 24 (1 Suppl
2):S2-13-S2-16).
[0004] The farnesyltransferase inhibitors act in synergy with
agents which depolymerise microtubules (taxol, epothilones) (cf.
Moasser et al., Proc. Natl. Acad. Sci. U.S.A. (1998), 95,
1369-1374). The combination of farnesyltransferase inhibitors with
cytotoxic doxorubicin, cisplatin or 5-fluorouracyl shows only an
addition of the effects.
[0005] The heterotrimeric G proteins are, in fact, the structural
association of three distinct sub-units called .alpha., .beta. and
.gamma., but function as dissociable entities constituted by
sub-units .alpha. on the one hand and .beta./.gamma. dimers on the
other. Different forms of sub-units of .alpha., .beta. and .gamma.
type are described.
[0006] The G proteins participate in the transmission of signals
outside the cell, thanks to its interaction with receptors with
seven transmembrane domains, inside using different effectors
including adenylate cyclase, phospholipase C or also the ionic
channels. The adenylate cyclase enzyme generates cyclic adenosine
monophosphate (cAMP) (cf. Gilman, Biosci. Rep. (1995), 15, 65-97).
Thus it is known, that in order to activate adenylate cyclase, it
is necessary form the G proteins to be transitionally in a
heterotrimeric form, in which form the monomer constituted by an a:
sub-unit is associated with the dimer constituted by the .beta. and
.gamma. sub-units. It is also known that for the G proteins to be
found in their heterotrimeric form, they must be fixed by their
.gamma. sub-units to the membrane. It is only in this situation
that the signal outside the cell can activate the .alpha. sub-unit
of a G protein, which can, after disassociation, modulate the
effectors such as adenylate cyclase and modulate the production of
cAMP.
[0007] It is also known that the .beta./.gamma. dimers can directly
activate the effectors leading to the activation of kinases
regulated by extracellular signals (ERKs) or MAP kinases. A direct
link between the .beta./.gamma. sub-units and the src or src-like
kinases has been demonstrated (cf. Gutkind, J. Biol. Chem. (1998),
273, 1839-1842).
[0008] The harmful effects of an abnormal cAMP level are also known
and occur in particular at the level of the following biological
functions or disorders: smell, taste, light perception,
neurotransmission, neurodegeneration, endocrine and exocrine gland
functions, autocrine and paracrine regulation, arterial tension,
embryogenesis, benign cell proliferation, oncogenesis, viral
infection and immunological functions, diabetes and obesity.
[0009] The Applicant has itself already described in PCT Patent
Application WO 00/02881 the use of the compounds of general formula
(I) as defined hereafter as G protein inhibitors. Certain products
had been described previously in the PCT Patent Application WO
97/30053.
[0010] Prenyltransferase inhibitors are already used in the field
of cancer treatment (cf. Sebti et al., Pharmacol. Ther. (1997), 74,
103-114; Sepp-Lorenzino et al., Cancer Res. (1997), 55, 5302-5309).
The usefulness of prenyltransferase inhibitors in this type of
treatment comes from their action which prevents prenylation at the
level of the Ras substrate. However, the prenylation of certain
forms of Ras is not modified by the prenylation inhibitors (Lerner
et al., Oncogene (1997), 15, 1283-1288).
[0011] As far as the anti-cancer agents are concerned,
prenyltransferase inhibitors are in particular described in the
following Patent Applications: PCT Applications WO 97/21701, WO
97/16443, WO 98/00409, WO 96/21456, WO 97/24378, WO 97/17321, WO
97/18813, WO 95/00497; U.S. Pat. No. 5,532,359, U.S. Pat. No.
5,523,430, U.S. Pat. No. 5,510,510 and U.S. Pat. No. 5,627,202.
Moreover, the compounds of general formula (II) have been described
in PCT Patent Application WO 00/39130. Taxol is in particular
described in Merck Index, 11th ed., 1989, under heading number 9049
and in the references cited. Camptothecin analogues have in
particular been described in the U.S. Pat. No. 4,894,456 and in the
PCT Patent Applications WO 94/11376, WO 97/00876, WO 98/28304, WO
98/28305, WO 99/11646 and WO 99/33829.
[0012] A product according to the invention offers the advantage of
being able to use lower doses of the anti-cancer agents chosen,
which has the main effect of reducing the toxicity of the treatment
whilst obtaining a pharmacological effect with a minimum of
additive.
[0013] A subject of the invention is therefore a product comprising
at least one transduction inhibitor of heterotrimeric G protein
signals combined with at least one anti-cancer agent, preferably
chosen from the group comprising taxol, taxol analogues,
gemcitabine and prenyltransferase inhibitors, for therapeutic use
simultaneously, separately or spread over a period of time, in the
treatment of cancer.
[0014] Preferably, the prenyltransferase inhibitor combined with
the transduction inhibitor of heterotrimeric G protein signals is a
farnesyltransferase inhibitor.
[0015] Although taxol, taxol analogues, gemcitabine and
prenyltransferase inhibitors are preferred, a number of other
anti-cancer agents can be also combined, according to the
invention, with a transduction inhibitor of heterotrimeric G
protein signals, for example: enzyme inhibitors such as
topoisomerase inhibitors such as camptothecin and camptothecin
analogues (in the form of analogues comprising an E lactonic ring
with six members such as for example the compounds described in PCT
Patent Application WO 94/11376, in the form of analogues comprising
an E lactonic ring with seven members such as for example the
compounds described in PCT Patent Application WO 97/00876 or also
in the form of open tetracyclic analogues such as for example the
compounds described in the PCT Patent Application WO 99/33829),
Cdc25 phosphatase inhibitors, MAP kinase or MAP kinase kinase
inhibitors, protein kinase C inhibitors, tyrosine kinase
inhibitors, telomerase inhibitors; inductors of apoptosis;
alkylating agents such as cisplatin; anti-metabolic agents such as
5-fluorouracil; differentiation agents; cell spindle poisons;
angiogenesis inhibitors; anti-hormones or antagonists of the
steroid receptors; antioxidants; antisense agents; anti-p53 agents
(gene therapy); chemo-prevention agents; anti-viral agents;
immuno-therapeutic agents; antibodies such as heregulin.
[0016] Preferably, the transduction inhibitor of heterotrimeric G
protein signals is a compound of general formula (I) ##STR1##
corresponding to sub-formulae (I.sub.A) or (I.sub.B): ##STR2## in
which:
[0017] X represents R.sub.12 and Y represents R.sub.8, or X and Y
complete a ring with 6 members, the X--Y mixture representing the
--CH(R.sub.8)--CH(R.sub.9)-- radical;
[0018] R.sub.1 represents H, an alkyl or alkylthio radical;
[0019] R.sub.2 and R.sub.3 independently represent H or an alkyl
radical;
[0020] R.sub.4 represents H.sub.2 or O;
[0021] R.sub.5 represents H, or one of the alkyl, alkenyl, alkynyl,
aryl, aralkyl, heterocyclyl or heterocyclylalkyl radicals, these
radicals being able to be optionally substituted by radicals chosen
from the group comprising an alkyl radical, --O--R.sub.10,
--S(O).sub.mR.sub.10 (m representing 0, 1, or 2),
--N(R.sub.10)(R.sub.11), --N--C(O)--R.sub.10,
--NH--(SO.sub.2)--R.sub.10, --CO.sub.2--R.sub.10,
C(O)--N(R.sub.10)(.sub.11), and
--(SO.sub.2)--N(R.sub.10)(R.sub.11);
[0022] R.sub.6 and R.sub.7 independently represent H, a
--C(O)--NH--CHR.sub.13--CO.sub.2R.sub.14 radical, or one of the
alkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl radicals,
these radicals being optionally substituted by radicals chosen from
the group comprising OH, alkyl or alkoxy, N(R.sub.10)(R.sub.11),
COOH, CON(R.sub.10)(R.sub.11), and halo radicals,
or R.sub.6 and R.sub.7 together form an aryl radical or a
heterocycle;
[0023] R.sub.8 and R.sub.9 independently represent H or one of the
alkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl radicals,
these radicals being able to be optionally substituted by radicals
chosen from the group comprising OH, alkyl or alkoxy,
N(R.sub.10)(R.sub.11), COOH, CON(R.sub.10)(R.sub.11) and halo
radicals,
or R.sub.8 and R.sub.9 together form an aryl radical or a
heterocycle;
[0024] R.sub.10 and R.sub.11, independently represent H, an aryl or
heterocyclyl, or an alkyl, aralkyl or heterocyclylalkyl
radical;
[0025] R.sub.12 represents NR.sub.9, S, or O;
[0026] R.sub.13 represents an alkyl radical optionally substituted
by a radical chosen from the alkyl, --OR.sub.10,
--S(O).sub.mR.sub.10 (m representing 0, 1, or 2) and
--N(R.sub.10)(R.sub.11) radicals;
[0027] R.sub.14 represents H or an alkyl radical;
or a pharmaceutically acceptable salt of such a compound.
[0028] By lower alkyl radical, is meant a linear or branched alkyl
radical containing 1 to 6 carbon atoms, and in particular the
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and
tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals.
By heterocycle radical, is meant a radical constituted by one or
more rings and including at least one heteroatom. By lower
arylalkyl, heterocycle alkyl, alkylthio or alkoxy radical, is meant
the radicals of which the alkyl radical has the meaning as
indicated previously.
[0029] Preferably, the compounds of general formula (I) are such
that:
[0030] X and Y complete a ring with 6 members, the X--Y combination
representing the --CH(R.sub.8)--CH(R.sub.9)-- radical;
[0031] R.sub.1 represents an alkyl radical or lower;
[0032] R.sub.2 and R.sub.3 represent H;
[0033] R.sub.4 represents O;
[0034] R.sub.5 represents H, or one of the lower alkyl, cycloalkyl,
cycloalkylalkyl, lower arylsulphonylalkyl, lower aralkoxyalkyl
radicals, these radicals being able to be optionally substituted by
radicals chosen from the group comprising a lower alkyl or
--O--R.sub.10 radical;
[0035] R.sub.6 and R.sub.7 independently represent H or an aryl
radical optionally substituted by radicals chosen from the group
comprising the OH, alkyl or lower alkoxy radicals,
[0036] R.sub.8 and R.sub.9 represent H;
[0037] and R.sub.10 and R.sub.11, independently represent H or a
lower alkyl radical.
[0038] The following compounds of general formula (1) are in
particular preferred for the invention: [0039]
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,-
6,7,8-tetrahydroimidazo[1,2a]pyrazine; [0040]
7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrah-
ydro-imidazo[1,2a]pyrazine; [0041]
bis-1,1'-[7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-methylp-
ropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine]disulphide; [0042]
bis-1,1'-7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxy-
-phenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine disulphide; [0043]
bis-1,1'-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-
-5,6,7,8-tetrahydroimidazo[1,2a]pyrazin-7-yl) disulphide; [0044]
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetr-
ahydroimidazo[1,2a]pyrazine; [0045]
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylmethoxy)methy-
l-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; [0046]
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-phenylmethoxy)eth-
yl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine; [0047]
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7-
,8-tetrahydroimidazo[1,2a]pyrazine; [0048]
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7-
,8-tetrahydro-imidazo[1,2a]pyrazine, or its dimeric form; [0049]
and
7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylsulphonylethy-
l) -5,6,7,8-tetrahydro-imidazo[1,2a]pyrazine; or a pharmaceutically
acceptable salt of one of the latter.
[0050] Preferably, when the anti-cancer agent combined with a
transduction inhibitor of heterotrimeric G protein signals is a
prenyltransferase inhibitor, it is a farnesyltransferase
inhibitor.
[0051] More preferentially, the farnesyltransferase inhibitor is
chosen from the group composed: [0052] of a compound of general
formula (II) ##STR3## in which:
[0053] n1 represents 0 or 1;
[0054] X represents, independently, each time that it occurs,
(CHR.sup.11).sub.n3(CH.sub.2).sub.n4Z(CH.sub.2).sub.n5;
[0055] Z representing O, N(R.sup.12), S, or a bond;
[0056] n3 representing, independently, each time that it occurs, 0
or 1;
[0057] each of n4 and n5 representing, independently, each time
that they occur, 0, 1, 2, or 3;
[0058] Y represents, independently, each time that it occurs, CO,
CH.sub.2, CS, or a bond;
[0059] R.sup.1 represents one of the ##STR4## or
N(R.sup.24R.sup.25) radicals;
[0060] each of R.sup.2, R.sup.11, and R.sup.12 representing,
independently, each time that it occurs, H or an optionally
substituted radical chosen from the group consisting of a
(C.sub.1-6)alkyl radical and an aryl radical, said optionally
substituted radical being optionally substituted by at least one
radical chosen from the R.sup.8 and R.sup.30 radicals, each
substituent being chosen independently of the others;
[0061] R.sup.3 represents, independently, each time that it occurs,
H or an optionally substituted radical chosen from the group
consisting of the (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.2-6)alkynyl, (C.sub.3-6)cycloalkyl,
(C.sub.3-6)cycloalkyl(C.sub.1-6)alkyl, (C.sub.5-7)cycloalkenyl,
(C.sub.5-7)cycloalkenyl(C.sub.1-6)alkyl, aryl,
aryl(C.sub.1-6)alkyl, heterocyclyl, and
heterocyclyl(C.sub.1-6)alkyl radicals, said optionally substituted
radical being optionally substituted by at least one radical chosen
from the R.sup.30 radicals, each substituent being chosen
independently of the others;
[0062] each of R.sup.4 and R.sup.5 represents, independently, each
time that it occurs, H or an optionally substituted radical chosen
from the group consisting of the (C.sub.1-6)alkyl,
(C.sub.3-6)cycloalkyl, aryl and heterocyclyl radicals, said
optionally substituted radical being optionally substituted by at
least one radical chosen from the R.sup.30 radicals, each
substituent being chosen independently of the others, or R.sup.4
and R.sup.5 taken together with the carbon atoms to which they are
attached together form an aryl radical;
[0063] R.sup.6 represents, independently, each time that it occurs,
H or an optionally substituted radical chosen from the group
consisting of the (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.3-6)cycloalkyl, (C.sub.3-6)cycloalkyl(C.sub.1-6)alkyl,
(C.sub.5-7)cycloalkenyl, (C.sub.5-7)cycloalkenyl(C.sub.1-6)alkyl,
aryl, aryl(C.sub.1-6)alkyl, heterocyclyl and
heterocyclyl(C.sub.1-6)alkyl radicals, said optionally substituted
radical being optionally substituted by at least one radical chosen
from the OH, (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy,
--N(R.sup.8R.sup.9), --COOH, --CON(R.sup.8R.sup.9) and halo
radicals, each substituent being chosen independently of the
others;
[0064] Each time that it occurs, R.sup.7 represents, independently,
H, .dbd.O, .dbd.S, H or an optionally substituted radical chosen
from the group consisting of the (C.sub.1-6)alkyl,
(C.sub.2-6)alkenyl, (C.sub.3-6)cycloalkyl,
(C.sub.3-6)cycloalkyl(C.sub.1-6)alkyl, (C.sub.5-7)cycloalkenyl,
(C.sub.5-7)cycloalkenyl(C.sub.1-6)alkyl, aryl,
aryl(C.sub.1-6)alkyl, heterocyclyl and heterocyclyl(C.sub.1-6)alkyl
radicals, said optionally substituted radical being optionally
substituted by at least one radical chosen from the OH,
(C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, --N(R.sup.8R.sup.9), --COOH,
--CON(R.sup.8R.sup.9) and halo radicals, each substituent being
chosen independently of the others;
[0065] each of R.sup.8 and R.sup.9 representing, independently,
each time that it occurs, H, (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl,
(C.sub.2-6)alkynyl, aryl, or aryl(C.sub.1-6)alkyl;
[0066] R.sup.10 represents C;
[0067] or, when n1=0, R.sup.6 and R.sup.7 can be taken together
with the carbon atoms to which they are attached to form an aryl or
cyclohexyl radical;
[0068] R.sup.21 represents, independently, each time that it
occurs, H or an optionally substituted radical chosen from the
group consisting of the (C.sub.1-6)alkyl and aryl(C.sub.1-6)alkyl
radicals, said optionally substituted radical being optionally
substituted by at least one radical chosen from the R.sup.8 and
R.sup.30 radicals, each substituent being chosen independently of
the others;
[0069] R.sup.22 represents H, (C.sub.1-6)alkylthio,
(C.sub.3-6)cycloalkylthio, R.sup.8--CO--, or a substituent of
formula ##STR5##
[0070] each of R.sup.24 and R.sup.25 represents, independently,
each time that it occurs, H, (C.sub.1-6)alkyl or
aryl(C.sub.1-6)alkyl;
[0071] R.sup.30 represents, independently, each time that it
occurs, (C.sub.1-6)alkyl, --O--R.sup.8, --S(O).sub.n6R.sup.8,
--S(O).sub.n7N(R.sup.8R.sup.9), --N(R.sup.8R.sup.9), --CN,
--NO.sub.2, --CO.sub.2R.sup.8, --CON(R.sup.8R.sup.9),
--NCO--R.sup.8, or halogen, each of n6 and n7 representing,
independently, each time that it occurs, 0, 1 or 2;
[0072] said heterocyclyl radical being azepinyl, benzimidazolyl,
benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,
benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,
cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,
dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulphone, furyl,
imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl,
isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,
isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,
oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,
2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl,
pyridyl-N-oxide, quinoxalinyl, tetrahydrofuryl,
tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl,
thiamorpholinyl sulphoxide, thiazolyl, thiazolinyl, thienofuryl,
thienothienyl or thienyl;
[0073] said aryl radical being phenyl or naphthyl;
[0074] it being understood that: when n1=1, R.sup.10 is C and
R.sup.6 represents H, then R.sup.10 and R.sup.7 can, taken
together, form the ##STR6## or when n1=1, R.sup.10 is C, and
R.sup.7 is .dbd.O, --H, or .dbd.S, then R.sup.10 and R.sup.6 can,
taken together, form the ##STR7## with each of X.sup.1, X.sup.2,
and X.sup.3 representing, independently, H, a halogen atom,
--NO.sub.2, --NCO--R.sup.8, --CO.sub.2R.sup.8, --CN, or
--CON(R.sup.8R.sup.9); and when R.sup.1 is N(R.sup.24R.sup.25),
then n3 represents 1, each of n4 and n5 represents 0, Z is a bond,
and R.sup.3 and R.sup.11 can, taken together, form the ##STR8##
with n2 representing an integer from 1 to 6, and each of X.sup.4
and X.sup.5 representing, independently, H, (C.sub.1-6)alkyl or
aryl, or X.sup.4 and X.sup.5 taken together, forming a
(C.sub.3-6)cycloalkyl radical; [0075] of a compound of general
formula (III) ##STR9## in which:
[0076] R.sup.1 represents H or an alkyl, OR.sup.10, SR.sup.10 or
NR.sup.11R.sup.12 radical;
[0077] R.sup.2 represents H or an alkyl radical;
[0078] R.sup.3, R.sup.4 and R.sup.5 represent, independently, H, a
halogen atom or an alkyl, trihalomethyl, hydroxy, cyano or alkoxy
radical;
[0079] R.sup.6 represents H or an alkyl radical;
[0080] R.sup.7 represents H, a halogen atom or an alkyl,
hydroxyalkyl, amino, hydroxycarbonyl radical;
[0081] R.sup.8 and R.sup.9 represent, independently, H, a halogen
atom or a cyano, alkyl, trihalomethyl, alkoxy, alkylthio or
dialkylamino radical;
[0082] R.sup.10 represents H or an alkyl or alkylcarbonyl
radical;
[0083] R.sup.11 represents H or an alkyl radical;
[0084] R.sup.12 represents H or an alkyl or alkylcarbonyl
radical;
[0085] and Y represents O or S; [0086] and a pharmaceutically
acceptable salt of a compound of general formula (II) or of a
compound of general formula (III).
[0087] In certain cases, compounds which are of use in the
composition of a product according to the present invention can
comprise asymmetrical carbon atoms. As a result, said compounds
have two possible enantiomeric forms, i.e. the "R" and "S"
configurations. The present invention includes the two enantiomeric
forms and all combinations of these forms, including the racemic
mixtures "RS". In an effort to simplify matters, when no specific
configuration is as indicated in the structural formulae, it should
be understood that both enantiomeric forms and their mixtures are
represented.
[0088] By alkyl, unless specified otherwise, is meant a linear or
branched alkyl radical containing 1 to 6 carbon atoms. By
alkylcarbonyl, alkylthio, alkoxy, alkylamino, dialkylamino,
alkenyl, alkynyl, aralkyl, heterocyclylalkyl radicals, is meant
respectively the alkylcarbonyl, alkylthio, alkoxy, alkylamino,
dialkylamino, alkenyl, alkynyl, aralkyl, heterocyclylalkyl radicals
of which the alkyl radical has the meaning indicated
previously.
[0089] 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. Finally, by halogen, is meant the
fluorine, chlorine, bromine or iodine atoms.
[0090] When a chemical structure such as used here has an arrow
emanating from it, the arrow indicates the attachment point. For
example, the structure ##STR10## is a pentyl radical. When a value
in brackets appears close to the arrow, the value indicates where
the attachment point can be found in the compound. For example, in
general formula (II) ##STR11## as defined previously, when R.sup.10
and R.sup.7 are taken together to form the ##STR12## the following
structure results: ##STR13##
[0091] Finally, by pharmaceutically acceptable salt, is meant in
particular the addition salts of inorganic acids such as
hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate,
diphosphate and nitrate or organic acids such as acetate, maleate,
fumarate, tartrate, succinate, citrate, lactate, methanesulphonate,
p-toluenesulphonate, pamoate and stearate. The salts formed from
bases such as sodium or potassium hydroxide also fall within the
scope of the present invention, when they can be used. For other
examples of pharmaceutically acceptable salts, reference can be
made to "Salt selection for basic drugs", Int. J. Pharm. (1986),
33, 201-217.
[0092] In particular, transduction inhibitors of heterotrimeric G
protein signals could, according to the invention, be usefully
combined with the following compounds:
[0093] Prenyltransferase inhibitors, and in particular
farnesyltransferase inhibitors such as
1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-
-methoxy-phenyl)imidazo[1,2c][1,4]benzodiazepine,
4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-
-1-oxoethyl)-1,2-dihydro-8-fluoro-imidazo[1,2a][1,4]-benzodiazepine
or
(.+-.)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-amino-(1-methyl-1H-imidazol-
-5-yl)methyl]-1-methyl-2(1H)quinolinone;
[0094] cell spindle poisons such as taxol;
[0095] alkylating agents such as cisplatin;
[0096] anti-metabolic agents such as gemcitabine or
5-fluorouracyl.
[0097] Preferably, the transduction inhibitors of heterotrimeric G
protein signals used in the invention are such that they correspond
to general sub-formula (IA) as defined previously in which:
[0098] R.sub.1 represents H;
[0099] R.sub.2 and R.sub.3 represent, independently, H or a lower
alkyl radical;
[0100] R.sub.4 represents O;
[0101] R.sub.5 represents H, or one of the lower alkyl, cycloalkyl
or cycloalkylalkyl radicals;
[0102] R.sub.6 represents an aryl radical optionally substituted by
radicals chosen from the group comprising the OH, alkyl or lower
alkoxy, N(R.sub.10)(R.sub.11), COOH, CON(R.sub.10)(R.sub.11) and
halo radicals;
[0103] R.sub.10 and R.sub.11, representing independently H or a
lower alkyl radical;
[0104] or are salts of these same compounds.
[0105] Preferably, when they are used for the invention, the
compounds of general formula (II) are those in which are found,
independently, the radicals presenting the following
characteristics:
[0106] R.sup.1 representing the ##STR14##
[0107] R.sup.21 representing an aralkyl radical the aryl group of
which can be optionally substituted by a radical or radicals chosen
from a halogen atom and the cyano, hydroxy, alkoxy, amino,
alkylamino and dialkylamino radicals;
[0108] R.sup.4 representing an aryl radical optionally substituted
by a radical or radicals chosen from a halogen atom and the
hydroxy, alkoxy, amino, alkylamino and dialkylamino radicals;
[0109] X representing an alkylene radical containing 1 to 6 carbon
atoms;
[0110] Y representing CO;
[0111] n1=1, R.sup.10 being C, R.sup.6 representing H and R.sup.10
and R.sup.7 taken together, forming the ##STR15##
[0112] each of X.sup.1, X.sup.2, and X.sup.3 representing,
independently, H or a halogen atom.
[0113] Preferably, when they are used for the invention, the
compounds of general formula (III) are those in which are found,
independently, the radicals presenting the following
characteristics: [0114] R.sup.1 representing OH or NH.sub.2; [0115]
R.sup.2 representing alkyl and preferably methyl; [0116] one of
R.sup.3, R.sup.4 and R.sup.5 representing a halogen atom; [0117]
R.sup.6 representing alkyl and preferably methyl; [0118] one of
R.sup.8 and R.sup.9 representing a halogen atom; [0119] Y
representing O.
[0120] According to a particularly preferred variant of the
invention, the transduction inhibitors of heterotrimeric G protein
signals are chosen from the group composed of: [0121]
-7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5-
,6,7,8-tetrahydroimidazo[1,2a]pyrazine; and [0122]
-7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tet-
rahydro-imidazo[1,2a]pyrazine; and pharmaceutically acceptable
salts of the latter.
[0123] Still according to a particularly preferred variant of the
invention, the anti-cancer agents combined with said transduction
inhibitors of heterotrimeric G protein signals are chosen from the
group composed of: [0124]
1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-
-methoxyphenyl)imidazo[1,2c][1,4]benzodiazepine; [0125]
4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-
-1-oxoethyl)-1,2-dihydro-8-fluoro-imidazo[1,2a][1,4]-benzodiazepine;
[0126]
(.+-.)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-amino-(1-methyl-1H--
imidazol-5-yl) methyl]-1-methyl-2(1H)quinolinone; [0127] taxol;
[0128] gemcitabine; and of the pharmaceutically acceptable salts of
the latter.
[0129] Optionally, an additional anti-cancer compound can also be
used, different from the anti-cancer agent combined with the
transduction inhibitor of heterotrimeric G protein signals, in the
composition of the product of the invention. Preferably, said
additional compound is chosen from the group composed: [0130]
1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-
-methoxyphenyl)imidazo[1,2c][1,4]benzodiazepine; [0131]
4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-
-1-oxoethyl)-1,2-dihydro-8-fluoro-imidazo[1,2a][1,4]-benzodiazepine
[0132]
(.+-.)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-amino-(1-methyl-1H--
imidazol-5-yl)methyl]-1-methyl-2(1H)quinolinone; [0133] taxol;
[0134] gemcitabine; and pharmaceutically acceptable salts of the
latter.
[0135] A subject of the invention is also a pharmaceutical
composition comprising at least one of the products according to
the invention.
[0136] The pharmaceutical compositions comprising a product
according to the invention can be in the form of a solid, for
example powders, granules, tablets, gelatin capsules, liposomes or
suppositories. The 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.
[0137] The pharmaceutical compositions comprising a product
according to the invention can also be presented in liquid form,
for example, solutions, emulsions, suspensions or syrups. The
appropriate liquid supports can, for example, be water, organic
solvents such as glycerol or glycols, and similarly their mixtures,
in varying proportions, in water.
[0138] The administration of a medicament according to the
invention can be done by topical, oral, parenteral route, by
injection (intramuscular, sub-cutaneous, intravenous, etc.), etc.
The administration route will depend of course on the type of
disease to be treated.
[0139] The following administration doses (daily, except for
contra-indication) could be envisaged for the different compounds
used in the composition of a product according to the
invention:
[0140] compound of general formula (I): from 50 to 200 mg/m.sup.2
by intraperitoneal route;
[0141] compound of general formula (II): from 50 to 500 mg/m.sup.2
per os;
[0142] taxol: 1 to 10 mg/kg (intraperitoneal route) or 1 to 3 mg/kg
(intravenous route);
[0143] cisplatin: 50 to 80 mg/m.sup.2;
[0144] 5-fluorouracil: 400 to 800 mg/rn.sup.2 by intravenous route,
the administrations being repeated from 1 to 4 times per month;
[0145] gemcitabine: 100 to 500 mg/m.sup.2 by intravenous route
(perfusions lasting approximately 6 hours).
Preparation of Certain Compounds Used in the Composition of the
Products of the Invention:
[0146] I) The compounds of general formula (I) are prepared
according to methods similar to those described in PCT Patent
Application WO 97/30053.
[0147] However, the following compounds have been described
previously in Patent Application WO 00/02881: [0148]
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,-
6,7,8-tetrahydroimidazo[1,2a]pyrazine; and [0149]
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetr-
ahydro-imidazo[1,2a]pyrazine.
[0150] II) The compounds of general formula (II), of which
1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-
-methoxyphenyl) imidazo[1,2c][1,4]benzodiazepine and
4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)imidazo-5-yl)--
1-oxoethyl)-1,2-dihydro-8-fluoroimidazol
[1,2a][1,4]-benzodiazepine, are prepared according to the
procedures described in PCT Patent Application WO 00/39130.
[0151] C) The compounds of general formula (III) are prepared
according to the methods described in PCT Patent Application WO
97/21701.
[0152] Unless they are defined differently, all the technical and
scientific terms used here have the same meaning as that usually
understood by an ordinary specialist in the field to which this
invention belongs. Similarly, all the publications, patent
applications, all the patents and all other references mentioned
here are incorporated by way of reference.
[0153] The following examples are presented in order to illustrate
the above procedures and should in no event be considered as a
limit to the scope of the invention.
EXAMPLES
[0154] In order to illustrate the usefulness of the invention, the
effect of a treatment on a tumor line of Mia-Paca2 pancreatic human
cells with
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,-
6,7,8-tetrahydroimidazo[1,2a]pyrazine or
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetr-
ahydroimidazo[1,2a]pyrazine (described in PCT Application WO
00/02881) combined with different anti-cancer agents will be
studied.
[0155] By convention, the products inhibiting the transduction of
heterotrimeric G protein signals used in the tests are identified
by the letter A, and the other anti-cancer agents used in the tests
by the letter B.
1) Procedures
Material
[0156] The following compounds (prepared according to the methods
described previously) are of use in the composition of the products
tested: [0157]
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,-
6,7,8-tetrahydroimidazo[1,2a]pyrazine (compound A.sub.1); [0158]
7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetr-
ahydroimidazo[1,2a]pyrazine (compound A.sub.2); [0159]
1-(2-(1-((4-cyano)phenylmethyl)imidazol-4-yl)-1-oxoethyl-2,5-dihydro-4-(2-
-methoxyphenyl)imidazo[1,2c][1,4]benzodiazepine (compound B.sub.1);
[0160] taxol (compound B.sub.2); [0161] gemcitabine (compound
B.sub.3); [0162]
(.+-.)-4-(3-chlorophenyl)-6-[(4-chlorophenyl)-amino-(1-methyl-1H-imidazol-
-5-yl)methyl]-1-methyl-2(1H)quinolinone (compound B.sub.4); [0163]
4-(2-bromophenyl)-1-(2-(1-((4-cyano-3-methoxy)phenylmethyl)-imidazo-5-yl)-
-1-oxoethyl)-1,2-dihydro-8-fluoro-imidazo[1,2a][1,4]-benzodiazepine
(compound B.sub.5). Cell Line
[0164] The cell line Mia-Paca2 (human pancreatic cancer cells) was
acquired from the American Tissue Culture Collection (Rockville,
Md., USA).
Measurement of Cell Proliferation In Vitro
[0165] The Mia-Paca2 cells (1500 cells/wells) are cultured in
96-well plates pre-coated with polyhema (Sigma) which allows only
the growth of cells presenting a tumorigenic phenotype.
[0166] On day 0, these cells are seeded in 90 .mu.l of Dulbecco's
modified Eagle medium (Gibco-Brl, Cergy-Pontoise, France) completed
with 10% of foetal calf serum inactivated by heating (Gibco-Brl,
Cergy-Pontoise, France), 50000 units/l of penicillin and 50 mg/l
streptomycin (Gibco-Brl, Cergy-Pontoise, France), and 2 mM of
glutamin (Gibco-Brl, Cergy-Pontoise, France).
[0167] The cells were treated with increasing concentrations of two
products alone or combined in a matrix, i.e.: on day 1, with the
first product for 96 hours and on day 2 with the second product for
72 hours. According to method (t, the transduction inhibitor of
heterotrimeric G protein signals with which the anti-cancer agent
is combined is administered before the latter, then according to
method A, it is done so after.
[0168] At the end of this period, quantification of cell
proliferation is evaluated by a colorimetric test based on the
cleavage of the tetrazolium salt WST1 by mitochondrial
dehydrogenases in the living cells leading to the formation of
formazan (Boehringer Mannheim, Meylan, France). These tests are
carried out in duplicate with 4 measurements for each single
product and for each combination tested. This allows the number of
living cells at the end of each treatment to be determined, i.e.
the observed value. The calculated value of the living cells for
each treatment corresponds to the multiplication of the observed
values of the effects of separate products. These observed and
calculated values are compared for each combination. When the
observed value of living cells is lower than the calculated value
of the living cells, a synergy is considered to exist. When the
observed value is equal to the calculated value, a additive effect
is considered to exist. When the observed value is greater than the
calculated value, an antagonism is considered to exist.
2) Results:
[0169] The results obtained are given in the tables shown
below.
[0170] The results given in Tables I, II, III, IV and IV show that
the products comprising compound A.sub.1 combined with compound
B.sub.1, compound B.sub.2 or compound B.sub.3 or those comprising
compound A.sub.2 combined with compound B.sub.4 or compound B.sub.5
are capable of inhibiting the proliferation in vitro of Mia-Paca2
human tumor cells. The combined effect of the combination,
evaluated by the method described in Cote, S. and Momparler, R. L.,
Anticancer Drugs (1993), 4, 327-333, allows a synergy in
combinations A.sub.1+B.sub.1, A.sub.1+B.sub.2, A.sub.1+B.sub.3,
A.sub.2+B.sub.4 and A.sub.2+B.sub.5 to be noted. TABLE-US-00001
TABLE I Observed values (method .alpha. - n = 4) Calculated values
Compound A.sub.1 Compound A.sub.1 Doses of Compound B.sub.1 (20
.mu.M) + (20 .mu.M) + compound B.sub.1 alone compound B.sub.1
compound B.sub.1 0 .mu.M 100 51 .+-. 8.9 0.04 .mu.M 94 .+-. 2.3 39
.+-. 8.4 47 .+-. 7.1 0.2 .mu.M 80 .+-. 4.2 23 .+-. 5.9 38 .+-. 4.9
1 .mu.M 68 .+-. 2.3 23 .+-. 6.5 34 .+-. 5.0
[0171] TABLE-US-00002 TABLE II Observed values (method .alpha. - n
= 3) Calculated values Compound A.sub.1 Compound A.sub.1 Doses of
Compound B.sub.2 (20 .mu.M) + (20 .mu.M) + compound B.sub.2 alone
compound B.sub.2 compound B.sub.2 0 nM 100 49 .+-. 7.7 0.8 nM 100
.+-. 5.8 34 .+-. 2.4 48 .+-. 6.7 4 nM 100 .+-. 0.3 32 .+-. 2.2 49
.+-. 7.5 20 nM 60 .+-. 10.6 17 .+-. 4.5 30 .+-. 7.2
[0172] TABLE-US-00003 TABLE III Observed values (method .alpha. - n
= 3) Calculated values Compound A.sub.1 Compound A.sub.1 Doses of
Compound B.sub.3 (20 .mu.M) + (20 .mu.M) + compound B.sub.3 alone
compound B.sub.3 compound B.sub.3 0 nM 100 65 .+-. 7.3 4 nM 95 .+-.
9.8 48 .+-. 2.1 59 .+-. 1.3 20 nM 72 .+-. 11.5 27 .+-. 6.8 45 .+-.
4.0 100 nM 62 .+-. 1.9 30 .+-. 4.0 40 .+-. 3.1
[0173] TABLE-US-00004 TABLE IV Observed values (method .beta. - n =
2) Calculated values Compound A.sub.2 Compound A.sub.2 Doses of
Compound B.sub.4 (20 .mu.M) + (20 .mu.M) + compound B.sub.4 alone
compound B.sub.4 compound B.sub.4 0 nM 100 42 .+-. 11.0 40 nM 104
.+-. 2.0 28 .+-. 3.0 44 .+-. 12.0 0.2 .mu.M 90 .+-. 9.0 13 .+-. 2.0
37 .+-. 6.0 1 .mu.M 72 .+-. 3 14 .+-. 1.0 30 .+-. 7.0
[0174] TABLE-US-00005 TABLE V Observed values (method .beta. - n =
3) Calculated values Compound A.sub.2 Compound A.sub.2 Doses of
Compound B.sub.5 (20 .mu.M) + (20 .mu.M) + compound B.sub.5 alone
compound B.sub.5 compound B.sub.5 0 .mu.M 100 44 .+-. 6.4 0.2 .mu.M
86 .+-. 0.9 17 .+-. 2.7 38 .+-. 5.2 1 .mu.M 63 .+-. 2.6 11 .+-. 1.4
27 .+-. 3.0
* * * * *