IMIDAZOPYRIDINE DERIVATIVES, PROCESS FOR THE PREPARATION
THEREOF AND THERAPEUTIC USE THEREOF
The present invention relates to imidazopyridine derivatives which are inhibitors of
FGFs (Fibroblast Growth Factors), to the process for the preparation thereof and to
the therapeutic use thereof.
FGFs are a family of polypeptides synthesized by a large number of cells during
embryonic development and by cells of adult tissues in various pathological
conditions.
Indolizine derivatives, which are antagonists of the binding of FGFs to their
receptors, are described in international patent applications WO 03/084956 and
WO 2005/028476. lmidazo[1 ,5-a]pyridine derivatives which are FGF antagonists
are described in international patent application WO 2006/097625. Novel
imidazopyridine derivatives, which are antagonists of the binding of FGFs to their
receptors, have now been identified.
The subject of the present invention is thus compounds, imidazopyridine
derivatives, corresponding to formula (I):
in which:
- R represents
. a hydrogen or halogen atom,
. an alkyl group optionally substituted with -COOR 5,
. an alkenyl group optionally substituted with -COOR 5,
. a -COOR5 or -CONR5R6 group,
. an -NR5COR6 or -NR5-S0 2R6 group,
or
. an aryl group, in particular phenyl, or a heteroaryl group, said aryl or
heteroaryl group being optionally substituted with one or more groups selected
from: halogen atoms, alkyl groups, cycloalkyl groups, -COOR5, -CF3, -OCF3, -CN, -
C(NH2)NOH, -OR5, -O-Alk-COORs, -0-Alk-NR 5R6, -0-Alk-NR 7R8, -Alk-OR5, -
Alk-COOR 5, -CONR5R6, -CO-NR5-OR6, -CO-NR5-S0 2R7, -CONR5-Alk-NR5R6, -
CONR5-Alk-NR7R8, -Alk-NR5R6, -NR5R6, -NC(0)N(CH 3)2, -CO-Alk, -CO(OAIk) OH,
COO-Alk-NR5R6, COO-Alk-NR7R8 and 5-membered heteroaryl groups, said
heteroaryl groups being optionally substituted with one or more groups selected
from halogen atoms and alkyl, -CF3, -CN, -COOR5, -Alk-OR5, -Alk-COOR5,
-CONR5R6, -CONR7R8, -CO-NR5-OR6, -CO-NR5-S0 2R6, -NR 5R6 and
-Alk-NR5R6 groups, or with a hydroxyl group or with an oxygen atom,
n is an integer ranging from 1 to 3,
- R2 and R3 together form, with the carbon atoms of the phenyl nucleus to
which they are attached, a 6-membered nitrogenous heterocycle corresponding to
one of formula (A), (B) or (C) below:
(A) (B) (C)
in which the wavy lines represent the phenyl nucleus to which R2 and R3 are
attached and:
. Ra represents a hydrogen atom or an alkyl, haloalkyl, -Alk-CF3,
-Alk-COORs, -Alk'-COOR 5 , -Alk-CONR5R6, -Alk'-CONR 5R6, -Alk-CONR7R8, -Alk-
NR5R6, -AlkCONR5-OR6, -Alk-NR R8, -Alk-cycloalkyl, -Alk-0-R 5, -Alk-S-R5, -Alk-CN,
-OR5, -OAlkCOORs, -NR5R6, -NR5-COOR6, -Alk-aryl, -Alk-O-aryl, -Alk-O-heteroaryl,
-Alk-heteroaryl or heteroaryl group, where the aryl or heteroaryl group is optionally
substituted with one or more halogen atoms and/or alkyl, cycloalkyl, -CF3, -OCF3,
-O-R5 or -S-R5 groups,
. Ra' represents a hydrogen atom or a linear, branched, cyclic or
partially cyclic alkyl group, or an -Alk-OR 5, -Alk-NR 5R6 or -Alk-NR 7R8 group, Ra'
being optionally substituted with one or more halogen atoms,
. Rb represents a hydrogen atom or an alkyl or -Alk-COOR 5 group,
. Rb' represents a hydrogen atom or an alkyl, haloalkyl, cycloalkyl,
phenyl or -Alk-COOR 5 group,
. Rc represents a hydrogen atom or an alkyl, -CN, -COOR5,
-CO-NR5R6, -CONR7R8 -CO-NR5-Alk-NR5R6, -CONR5-Alk-OR 5, -CONR5S0 2R5, -Alkaryl
or -Alk-heteroaryl group, where the aryl or heteroaryl group is optionally
substituted with one or more halogen atoms and/or alkyl, cycloalkyl, -CF3, -OCF3,
-O-alkyl or -S-alkyl groups,
. RC' represents a hydrogen atom or an alkyl group,
. RC" represents a hydrogen atom or an alkyl, alkenyl, haloalkyl,
cycloalkyl, -Alk-NR 5R6, -Alk-NR 7R8, -Alk-OR 5 or -Alk-SR 5 group,
- R4, located on position 6, 7 or 8 of the imidazopyridine nucleus,
represents:
. a hydrogen atom,
. a -COOR5 group,
. a -CO-NR5-Alk-NR5R6 group,
. a -CO-NR5-Alk-NR7R8 group, or
. a -CO-NR5-Alk-OR6 group,
- R5 and R6, which may be identical or different, represent hydrogen atoms,
haloalkyl groups or alkyl groups, cycloalkyl groups or an Ms (mesyl) group,
- R7 and R8, which may be identical or different, represent hydrogen atoms
or alkyl or phenyl groups, or else R7 and R8 together form a 3- to 8-membered
saturated ring which can optionally contain a heteroatom,
- Alk represents a linear or branched alkylene chain, and
- Alk' represents a linear, branched, cyclic or partially cyclic alkylene chain,
these compounds being optionally present in the form of a pharmaceutically
acceptable salt thereof.
The compounds of formula (I) may comprise one or more asymmetric carbon
atoms. They can therefore exist in the form of enantiomers or of diastereoisomers.
These enantiomers and diastereoisomers, and also mixtures thereof, including
racemic mixtures, are part of the invention.
The compounds of formula (I) can exist in the form of bases or of acids or can be
salified with acids or bases, in particular pharmaceutically acceptable acids or
bases. Such addition salts are part of the invention. These salts are
advantageously prepared with pharmaceutically acceptable acids or bases, but the
salts of other acids or bases that are of use, for example, for purifying or isolating
the compounds of formula (I) are also part of the invention.
The compounds of formula (I) can also exist in the form of hydrates or of solvates,
namely in the form of associations or combinations with one or more molecules of
water or with a solvent. Such hydrates or solvates are also part of the invention.
In the context of the invention, and unless otherwise mentioned in the text, the
term:
- "alkyl" is intended to mean: a linear or branched, saturated hydrocarbonbased
aliphatic group containing from 1 to 6 carbon atoms;
- "cycloalkyl" is intended to mean: a cyclic alkyl group comprising from 3 to 8
ring members, containing between 3 and 6 carbon atoms and optionally comprising
one or more heteroatoms, for example 1 or 2 heteroatoms, such as nitrogen and/or
oxygen, said cycloalkyl group being optionally substituted with one or more
halogen atoms and/or alkyl groups. By way of examples, mention may be made of
cyclopropyl, cyclopentyl, piperazinyl, pyrrolidinyl and piperidinyl groups;
- "partially cyclic alkyl group" is intended to mean: an alkyl group of which
only a part forms a ring;
- "alkylene" is intended to mean: a linear or branched divalent alkyl group
containing from 1 to 6 carbon atoms;
- "halogen" is intended to mean: a chlorine, fluorine, bromine or iodine atom;
- "haloalkyl" is intended to mean: an alkyl chain in which all or some of the
hydrogen atoms are replaced with halogen atoms, such as fluorine atoms;
- "aryl" is intended to mean: a cyclic aromatic group containing between 5
and 10 carbon atoms, for example a phenyl group;
- "heteroaryl" is intended to mean: a cyclic aromatic group containing
between 3 and 10 atoms, including one or more heteroatoms, for example between
1 and 4 heteroatoms, such as nitrogen, oxygen or sulphur, this group comprising
one or more, preferably one or two, rings. The heterocycles may comprise several
condensed rings. The heteroaryls are optionally substituted with one or more alkyl
groups or an oxygen atom. By way of examples, mention may be made of thienyl,
pyridinyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl groups; and
- "5-membered heteroaryl" is intended to mean: a heteroaryl group
consisting of a 5-membered ring comprising 1 to 4 heteroatoms (such as oxygen
and/or nitrogen atoms), optionally substituted with one or more alkyl groups or a
hydroxyl group or with an oxygen atom. Mention may, for example, be made of
oxadiazolyl and tetrazolyl groups;
- the halogens are preferably selected from F and CI.
Among the compounds of formula (I) according to the invention, mention may be
made of a subgroup of compounds in which R represents:
a hydrogen or halogen atom,
an alkyl group which is unsubstituted or substituted with -COOR5,
an alkenyl group which is unsubstituted or substituted with -COOR5,
a -COOR5 group,
a -CONR5R6 group,
an -NR5-SO2R6 group, or
a phenyl group optionally substituted with one or two groups selected
from
halogen atoms;
alkyl groups optionally substituted with -COOR5;
-CN (cyano), -C(NH2)NOH, -COOR5, -CONR5R6,
NR5-OR6, -CO-NR5-S0 2R6, -COAlk, -CO(OAIk) OH, -OR5,
-OCF 3 , -0-Alk-COOR 5, -Alk-ORs, -NR5R6 or -
NC(0)N(CH 3)2 groups,
5-membered heteroaryls optionally substituted with an
alkyl group and/or a hydroxyl group or an oxygen atom,
in which R5 and R6, which may be identical or different, represent hydrogen
atoms, or alkyl groups optionally substituted with an -NR 7R8 group,
R7 represents a hydrogen atom, an alkyl group containing 1 or 2 carbon
atoms or a phenyl group, n is an integer ranging from 1 to 3, or
. a heteroaryl group which is optionally condensed and/or optionally
substituted with one or two groups selected from alkyl groups, OR5, -COOR5, -
NR5R6 and cycloalkyl groups, and an oxygen atom, in which R5 and R6, which may
be identical or different, represent hydrogen atoms or alkyl groups containing 1 or 2
carbon atoms.
Among the compounds of formula (I) according to the invention, mention may be
made of another subgroup of compounds in which R2 and R3 together form, with
the carbon atoms of the phenyl nucleus to which they are attached, a 6-membered
nitrogenous heterocycle corresponding to either of formulae (A) and (B) defined
above, preferably corresponding to formula (A).
Formula (A) or (B) is advantageously such that:
. Ra represents a hydrogen atom or an alkyl group, optionally substituted
with one or more halogens; -AlkCONR5R6; haloalkyl; -CH2-COOR5; -Alk-heteroaryl,
-Alk-O-phenyl or -Alk-phenyl, where the phenyl group is optionally substituted with
one or two alkyl groups and/or OR5 and/or halogen atoms; -Alk-cycloalkyl,
. Ra' represents a hydrogen atom or a linear, branched, cyclic or partially
cyclic alkyl group, or a -CH2-OR5 or -Alk-NR5R6 group,
. Rb represents a hydrogen atom or an alkyl group,
. Rb' represents a hydrogen atom or an alkyl, phenyl or -CH2-COOR5 group,
in which the alkyl groups contain 1 to 6 carbon atoms, R5 being as defined
above.
Among the compounds of formula (I) according to the invention, mention may be
made of another subgroup of compounds in which R4 represents a hydrogen atom
or a -COOH, -CO-NH-Alk-NR7R8 or -CO-NH-Alk-OH group, in which Alk, R7 and R8
are as defined above, or else an alkyl group, preferably containing 1 to 3 carbon
atoms, which is unsubstituted.
In the compounds of formula (I) according to the invention, R4 is advantageously
located on position 6 or 7 of the imidazopyridine nucleus.
Among the compounds which are subjects of the invention, mention may be
made of the following compounds:
5-{3-[(2,4-dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1-yl}-2-fluorobenzoic acid
3-{3-[(2,4-dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1-yl}benzoic acid
3-{3-[(1-methyl-2,4-dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1-yl}benzoic acid
3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazolin-6-
yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzoic acid
3-(3-{[3-(4-fluorobenzyl)-1-(methoxymethyl)-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1 -yl)benzoic acid
3-(3-{[3-(4-fluorobenzyl)-1 -propyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazolin-6-
yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzoic acid
3-[3-({3-[2-(4-fluorophenyl)ethyl]-1-methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl}carbonyl)imidazo[1 ,5-a]pyridin-1 -yl]benzoic acid
3-[3-({1-methyl-3-[(5-methylthiophen-2-yl)methyl]-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl}carbonyl)imidazo[1 ,5-a]pyridin-1 -yl]benzoic acid
3-[3-({3-[(5-methylthiophen-2-yl)methyl]-2,4-dioxo-1-propyl-1 ,2,3,4-
tetrahydroquinazolin-6-yl}carbonyl)imidazo[1 ,5-a]pyridin-1 -yl]benzoic acid
3-(3-{[2,4-dioxo-1 -propyl-3-(thiophen-2-ylmethyl)-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1 -yl)benzoic acid
3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1 -propyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl}carbonyl)imidazo[1 ,5-a]pyridin-1 -yl]benzoic acid
In the following text, the term "protective group" is intended to mean a group which
makes it possible, firstly, to protect a reactive function such as a hydroxyl or an
amine during a synthesis and, secondly, to regenerate the intact reactive function
at the end of synthesis. Examples of protective groups and also methods of
protection and deprotection are given in "Protective Groups in Organic Synthesis",
Green et al., 3rd Edition (John Wiley & Sons, Inc., New York).
In the remainder of the text, the term "leaving group" is intended to mean a group
that can be readily cleaved from a molecule by breaking a heterolytic bond, with
the departure of a pair of electrons. This group can thus be readily replaced with
another group during a substitution reaction, for example. Such leaving groups are,
for example, halogens or an activated hydroxyl group, such as a mesyl, tosyl,
triflate, acetyl, para-nitrophenyl, etc. Examples of leaving groups and also methods
for the preparation thereof are given in "Advances in Organic Chemistry", J. March,
3rd Edition, Wiley Interscience, p. 310-316.
In accordance with the invention, the compounds of general formula (I)
prepared according to the processes hereinafter.
The compounds of formula (IV) are obtained by methods known in the literature,
starting from the suitably substituted corresponding 2-aminomethylpyridines,
according to the following reaction scheme, described in J. Chem. Soc. (1955),
2834-2836
When R4 represents COOR5, the compounds of formula (II) are obtained according
to the reaction scheme described in WO 06/097625.
Scheme 1 presents a pathway for obtaining the compounds of formula (I) in which
R2 and R3 together form a nitrogenous heterocycle of formula (A) as defined
above, and in which R and Ra' represent hydrogen atoms.
Scheme 1 (Method 1):
(IX)
The compound of formula (IV), in which R4 is as defined for the compound of
formula I, is condensed with the compound of formula V in order to obtain the
compound of formula VI. The compound of formula VI is subjected to a basic
hydrolysis reaction in order to obtain the compound of formula VII. The
esterification of the compound of formula VII produces the compound of formula
VIII. By reacting triphosgene, the isocyanate corresponding to the compound of
formula VIII is formed, which is condensed with an amine of formula RaNH2 in order
to obtain the urea of formula IX. The compound of formula IX is subjected to a
cyclization reaction in a basic medium in order to obtain the compound of formula I
in which R4 and Ra are as defined above.
Scheme 2 presents a pathway for obtaining the compounds of formula (I) in which
R2 and R3 together form a nitrogenous heterocycle of formula (A) as defined
above, and in which R represents a group as defined in the general formula,
except for a hydrogen atom.
Scheme 2 (Method 2):
The compound of formula VIII is subjected to a bromination reaction in order to
obtain the compound of formula X. By reacting triphosgene, the isocyanate
corresponding to the compound of formula X is formed, which is condensed with
an amine of formula RaNH2 in order to obtain the urea of formula XI. The
compound of formula XI is subjected to a cyclization reaction in a basic medium, in
order to obtain the compound of formula XII. The compound XII is subjected to an
alkylation reaction in the presence of a base and of a halogenated derivative Ra'X
in order to obtain the compound of formula XIII. The compound of formula XIII is
subjected, in the presence of a palladium catalyst, of a ligand and of a base,
- to a reaction with phenylboronic or heteroarylboronic or phenylboronate ester or
heteroarylboronate ester derivatives according to a Suzuki coupling,
- or else to an imination reaction with benzophenoneimine followed by an acid
hydrolysis and by an alkylation reaction with a sulphonyl chloride of formula
R6S0 2CI,
- or else to a cyanation reaction with zinc cyanide, followed by an acid hydrolysis
and by an esterification or a peptide coupling with an amine R5R6NH2,
in order to obtain the compound of formula I in which R R4, Ra and Ra' are as
defined above.
Scheme 3 presents a pathway for obtaining the compounds of formula (I) in which
R2 and R3 together form a nitrogenous heterocycle of formula (A) as defined
above, and in which R represents a group as defined in the general formula,
except for a hydrogen atom, and in which R4 is as defined above.
Scheme 3 (Method 3):
The compound of formula X is subjected, in the presence of a palladium catalyst,
of a ligand and of a base,
- to a reaction with phenylboronic or heteroarylboronic or phenylboronate ester or
heteroarylboronate ester derivatives according to a Suzuki coupling,
- or else to an imination reaction with benzophenoneimine, followed by an acid
hydrolysis and by an alkylation reaction with a sulphonyl chloride of formula
R6S0 2CI,
- or else to a cyanation reaction with zinc cyanide, followed by an acid hydrolysis
and by an esterification or a peptide coupling with an amine R5R6NH2, R 5 and R6
being defined above,
in order to obtain the compound of formula XIV in which R is as defined above. By
reacting triphosgene, the isocyanate corresponding to the compound of formula
XIV is formed, which is condensed with an amine of formula RaNH2 in order to
obtain the urea of formula XV. The compound of formula XV is subjected to a
cyclization reaction in a basic medium in order to obtain the compound of formula
XVI. The compound XVI is subjected to an alkylation reaction in the presence of a
base and of a halogenated derivative RaX in order to obtain the compound of
formula I.
Scheme 4 presents a pathway for obtaining the compounds of formula ( I) in which
R2 and R3 together form a nitrogenous heterocycle of formula (A) as defined
above, and in which R represents a group as defined in the general formula,
except for a hydrogen atom , and in which R4 is as defined above.
Scheme 4 (Method 4):
The compound of formula XII is subjected , in the presence of a palladium catalyst,
of a ligand and of a base,
- to a reaction with phenylboronic or heteroarylboronic or phenylboronate ester or
heteroarylboronate ester derivatives according to a Suzuki coupling,
- or else to an imination reaction with benzophenoneimine, followed by an acid
hydrolysis and by a sulphonylation reaction with a sulphonyl chloride of formula
R6S0 2CI,
- or else to a cyanation reaction with zinc cyanide, followed by an acid hydrolysis
and by an esterification or a peptide coupling with an amine R5R6NH2,
in order to obtain the compound of formula XVI in which R is as defined above.
The compound XVI is subjected to an alkylation reaction in the presence of a base
and of a halogenated derivative Ra'X in order to obtain the compound of formula I.
Scheme 5 presents a pathway for obtaining the compounds of formula ( I) in which
R2 and R3 together form a nitrogenous heterocycle of formula (B) as defined
above, in which Ri represents a hydrogen atom and in which R4 is as defined
above.
Scheme 5 (Method 5):
(XXIV)
(I)
The compound VIII is subjected to a saponification reaction in order to obtain the
compound XXIV. The compound XXIV is subsequently subjected to a
condensation reaction with an alkyl or aryl anhydride (Rb'CO)20 in order to obtain
the compound of formula XVII. The compound of formula XVII is subjected to a
condensation reaction with an amine R NH2 in order to obtain a compound of
formula I in which R and Rb' are as defined above.
Scheme 6 presents a pathway for obtaining the compounds of formula (I) in which
R2 and R3 together form a nitrogenous heterocycle of formula (B) as defined above
and in which R is as defined above, except for a hydrogen, and in which R4 is as
defined above.
Scheme 6 (Method 6)
(I)
The compound XIV is subjected to a saponification reaction in order to obtain the
compound XXV. The compound XXV is subsequently subjected to a condensation
reaction with an alkyl or aryl anhydride (Rb'CO)20 in order to obtain the compound
of formula XVIII. The compound of formula XVIII is subjected to a condensation
reaction with an amine R NH2 in order to obtain a compound of formula I in which
Rb and Rb' are as defined above.
Scheme 7 presents a pathway for obtaining the compounds of formula (I) in which
R2 and R3 together form a nitrogenous heterocycle of formula (C) as defined above
and in which RC" and also R and R4 are as defined above.
Scheme 7 (Method 7):
The compound X is subjected to a saponification reaction in order to obtain the
compound XIX. The compound XIX is subjected to a condensation reaction in the
presence of triphosgene, in order to obtain the compound XX. The compound XX
is subjected to an alkylation reaction in the presence of a halogenated derivative
RCX or of a protective group in order to obtain the compound XXI. The compound
XXI is subjected to a condensation reaction with a malonic derivative in order to
obtain the compound XXII in which Rc and Rc are as defined above. The
compound XXII is subjected, in the presence of a palladium catalyst, of a ligand
and of a base,
- to a reaction with phenylboronic or heteroarylboronic or phenylboronate ester or
heteroarylboronate ester derivatives according to a Suzuki coupling,
- or else to an imination reaction with benzophenoneimine, followed by an acid
hydrolysis and by a sulphonylation reaction with a sulphonyl chloride of formula
R6S0 2CI,
- or else to a cyanation reaction with zinc cyanide, followed by an acid hydrolysis
and by an esterification or a peptide coupling with an amine R5R6NH2,
in order to obtain the compound of formula XXIII in which R is as defined above.
The compound XXIII is subjected to a deprotection reaction in order to obtain the
compounds of formula I in which RC" is a hydrogen atom.
In the preceding schemes, the starting compounds and the reactants, when the
method for preparing them is not described, are commercially available or
described in the literature, or else can be prepared according to methods which are
described therein or which are known to those skilled in the art.
A subject of the invention, according to another of its aspects, is also the
compounds of formulae I I to XXIII defined above. These compounds are of use as
synthesis intermediates for the compounds of formula (I).
The following examples describe the preparation of certain compounds in
accordance with the invention. These examples are not limiting and merely
illustrate the present invention. The numbers of the compounds exemplified refer
back to those given in the table hereinafter, which illustrates the chemical
structures and the physical properties of some compounds according to the
invention.
The reactants and intermediates, when their preparation is not explained, are
known in the literature or commercially available. Some intermediates that are of
use for preparing the compounds of formula I may also serve as final products of
formula (I), as will become apparent in the examples given hereinafter. Similarly,
some compounds of formula (I) of the invention can serve as intermediates that are
of use for preparing other compounds of formula (I) according to the invention.
By way of example, the derivatives of formula (I) are selected from the following
compounds:
6-(imidazo[1 ,5-a]pyridin-3-ylcarbonyl)-3-propylquinazoline-2,4(1 /-/,3/-/)-dione,
3-{3-[(2,4-dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-
a]pyridin-1-yl}benzoic acid,
3-[(2,4-dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-
a]pyridine-6-carboxylic acid,
3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazolin-6-
yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzoic acid,
3-{3[(2,4-dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-
a]pyridin-1 -yl}benzamide,
6-({1 -[3-(5-methyl-1 ,3,4-oxadiazol-2-yl)phenyl]imidazo[1 ,5-a]pyridin-3-yl}carbonyl-3-
propylquinazoline-2,4(1 H, 3/-/)-dione,
6-({1 -[3-(3-methyl-1 ,2,4-oxadiazol-5-yl)phenyl]imidazo[1 ,5-a]pyridin-3-yl}carbonyl)-
3-propylquinazoline-2,4(1 H, 3H)-dione,
N-{3-[(2,4-dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-
a]pyridin-1 -yl}methanesulphonamide,
2-morpholin-4-yl-ethyl 3-(3-{[3-(4-fluorobenzyl)-1 -methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzoate,
N-[2-(dimethylamino)ethyl]-3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzamide,
3-(3-{[3-(4-fluorobenzyl)-1 -propyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazolin-6-
yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzoic acid,
3-(4-fluorobenzyl)-1 -methyl-6-[(1 -pyridin-3-ylimidazo[1 ,5-a]pyridin-3-
yl)carbonyl]quinazoline-2,4(1 H, 3H)-dione,
3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-
a]pyridin-1-yl}benzoic acid,
3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-
a]pyridin-1 -yl}benzamide,
6-(imidazo[1 ,5-a]pyridin-3-ylcarbonyl)quinazolin-4(3/-/)-one,
L/ ,L/,1 ,2-tetramethyl-4-oxo-6-{[1-(pyridin-3-yl)imidazo[1 ,5-a]pyridin-3-yl]carbonyl}-
1,4-dihydroquinoline-3-carboxamide,
3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazolin-
6-yl}carbonyl)imidazo[1 ,5-a]pyridin-1-yl]benzoic acid.
Abbreviations
TOTU: 0-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium
tetrafluoroborate
NMP: N-Methylpyrrolidone
DME: Ethylene glycol dimethyl ether
DMF: Dimethylformamide
THF: Tetrahydrofuran
Binap: 2,2'-bis(diphenylphosphino)-1 , '-binaphthyl
The NMR analyses were carried out on Bruker Avance 250MHz, 300MHz and
400MHz instruments.
- The melting points were measured on a Buchi B-450 instrument.
- The mass spectrometry analyses were carried out on a Waters Alliance 2695
(UV: PDA996, MS: LCZ), Alliance 2695 (UV: PDA 996, MS: ZQ (simple Quad)
ZQ1), Alliance 2695 (UV: PDA 996, MS: ZQ (simple Quad) ZQ2), Waters UPLC
Acquity (UV: Acquity PDA, MS: SQD (simple Quad) SQW), Agilent MSD, Waters
ZQ, or Waters SQD instrument.
Example 1: (compound No. 1)
6-(lmidazo[1,5-a]pyridin-3-ylcarbonyl)-3-propylquinazoline-2,4(1H,3H)-dione
Methyl 2-amino-5-(imidazo[1 ,5-a]pyridin-3-ylcarbonyl)benzoate
13.4 ml (96 mmol) of triethylamine are added to 3.5 g (30 mmol) of
imidazo[1 ,5-a]pyridine [described in J. Chem. Soc; (1955), 2834-2836] in 250 ml of
1,2-dichloroethane, followed, under a nitrogen atmosphere at 0°C, by 13.7 g (48
mmol) of 4-oxo-2-phenyl-4H-3,1-benzoxazine-6-carbonyl chloride (described in
WO 05/028476). After stirring for 4.5 hours at ambient temperature, the reaction
medium is filtered. The residue obtained is washed with 1,2-dichloroethane. After
drying overnight at 40°C under reduced pressure, 3 g of a yellow solid are
obtained.
The residue obtained is dissolved in 100 ml of NMP. A solution of 8.4 g
(0.15 mol) of KOH in 10 ml of water is added dropwise, under a nitrogen
atmosphere, at ambient temperature. The reaction medium is heated at 80°C for 6
hours and then poured, at ambient temperature, into a 1N aqueous solution of
hydrochloric acid. The precipitate obtained is filtered off, rinsed with water and then
dried at 40°C under reduced pressure overnight. After silica gel column
chromatography, elution being carried out with a dichloromethane/methanol/0.1%
triethylamine mixture, 5.5 g of a yellow solid are obtained.
7 g (0.022 mol) of caesium carbonate and then, dropwise, 1.34 ml
(0.022 mol) of methyl iodide are added, under a nitrogen atmosphere at ambient
temperature, to 5.5 g (0.02 mol) of the residue obtained, in 100 ml of DMF. After
stirring for 24 hours at ambient temperature, the reaction medium is poured into
water. The precipitate obtained is filtered off, rinsed with water and then dried
overnight at 40°C under reduced pressure. 5.1 g of a yellow solid are obtained.
Melting point: 192°C
MH+: 296
Methyl 5-(imidazo[1 ,5-a]pyridin-3-ylcarbonyl)-2-
[(propylcarbamoyl)amino]benzoate
0.35 g ( 1 .2 mmol) of triphosgene is added, at ambient temperature under a
nitrogen atmosphere, to a suspension of 0.5 g ( 1 .7 mmol) of methyl 2-amino-5-
(imidazo[1 ,5-a]pyridin-3-ylcarbonyl)benzoate in 20 ml of anhydrous dioxane. After
heating for 2 hours at 100°C, 0.28 ml (3.4 mmol) of n-propylamine and then 0.71 ml
(5 mmol) of triethylamine are added to the reaction medium at ambient
temperature. After stirring for 18 hours at ambient temperature, H20 is added. The
aqueous phase is extracted with dichloromethane. The organic phase is dried over
sodium sulphate, filtered, and concentrated under reduced pressure. The yellow
solid obtained is purified by silica gel column chromatography, elution being carried
out with a dichloromethane/methanol (98/2) mixture. 0.410 g of a yellow solid is
obtained.
Melting point: 205°C
MH+: 381
6-(lmidazo[1 ,5-a]pyridin-3-ylcarbonyl)-3-propylquinazoline-2,4(1 H,3H)-dione
1.38 ml ( 1 .38 mmol) of a 1N aqueous solution of sodium hydroxide are
added, at ambient temperature, to a suspension of 0.436 g ( 1 .15 mmol) of methyl
5-(imidazo[1 ,5-a]pyridin-3-ylcarbonyl)-2-[(propylcarbamoyl)amino]benzoate in 10 ml
of methanol. After refluxing for 2 hours, the methanol is concentrated under
reduced pressure. A 1N aqueous solution of hydrochloric acid is added. The
precipitate obtained is filtered off, rinsed with water and then dried overnight at
40°C under reduced pressure. 0.27 g of a yellow solid is obtained.
Melting point: 304°C
H-NMR (D6-DMSO, 400 MHz):
0.91 (t, J=7.17Hz, 3H), 1.63 (q, J=7.59Hz, 2H), 3.89 (t, J=7.17Hz, 2H), 7.25-7.37
(m, 2H), 7.39-7.43 (m, 1H), 7.82 (s, 1H), 7.97 (d, J=8.86Hz, 1H), 8.59 (d, J=8.86Hz,
1H), 9.18 (s, 1H), 9.74 (d, J=7.17Hz, 1H), 11.8 (s, 1H).
Example 2: (compound No. 10)
Sodium salt of 3-{3-[(2,4-dioxo -3-propyl-1,2 ,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1 -yl}benzoic acid
Methyl 2-amino-5-[(1-bromoimidazo[1,5-a]pyridin -3-
yl)carbonyl]benzoate
0.42 g (2.4 mmol) of N-bromosuccinimide is added, under a nitrogen
atmosphere at ambient temperature, to a solution of 0.67 g (2.4 mmol) of methyl 2-
amino-5-(imidazo[1 ,5-a]pyridin-3-ylcarbonyl)benzoate in 20 ml of dichloromethane.
After stirring for 2 h 30, water is added. The precipitate formed is filtered off, rinsed
with water, and dried overnight at 40°C under reduced pressure. 0.77 g of a yellow
solid is obtained.
Melting point: 230°C
MH+: 375, 377
Methyl 2-amino-5-({1 -[3-(methoxycarbonyl)phenyl]imidazo[1 ,5-
a]pyridin-3-yl}carbonyl)benzoate
0.248 g ( 1 .38 mmol) of [4-(methoxycarbonyl)phenyl]boronic acid, 0.57 g
(2.30 mmol) of potassium carbonate in 2 ml of water, and 0.027 g (0.02 mmol) of
tetrakis(triphenylphosphine)palladium are added to a solution of 0.43 g ( 1 .15 mmol)
of methyl 2-amino-5-[(1-bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]benzoate in 10 ml
of DME, under an inert argon atmosphere. The reaction medium is heated at 90°C
for 2 hours. The reaction medium is acidified with a 1N aqueous solution of
hydrochloric acid, and extracted with dichloromethane. The organic phase is
washed with water, dried over sodium sulphate, filtered, and concentrated under
reduced pressure. The solid obtained is dissolved in 5 ml of DMF. 30 m I (0.5 mmol)
of methyl iodide and 0.052 g (0.16 mmol) of caesium carbonate are added. After
stirring for 24 hours at ambient temperature, the reaction medium is hydrolysed
with water and then extracted with ethyl acetate. The organic phase is dried over
sodium sulphate, filtered, and then concentrated under reduced pressure. The
solid obtained is taken up in methanol. After filtration and drying overnight at 50°C
under reduced pressure, 0.379 g of a yellow powder is obtained.
Melting point: 203°C
MH+: 430
Methyl 5-({1 -[3-(methoxycarbonyl)phenyl]imidazo[1 ,5-a]pyridin-3-
yl}carbonyl)-2-[(propylcarbamoyl)amino]benzoate
0.181 g (0.61 mmol) of triphosgene is added, under an inert atmosphere, to
0.75 g (0.87 mmol) of methyl 2-amino-5-({1-[3-
(methoxycarbonyl)phenyl]imidazo[1 ,5-a]pyridin-3-yl}carbonyl)benzoate in 10 ml of
dioxane. The reaction medium is heated at 100°C for 3 hours. 0.14 ml ( 1.75 mmol)
of propylamine and 0.37 ml (2.62 mmol) of triethylamine are added at ambient
temperature. After stirring for 2 hours at ambient temperature, the reaction medium
is hydrolysed with water. The medium is filtered, washed with water, and dried
under reduced pressure at 50°C overnight. The solid obtained is purified by silica
gel column chromatography with a dichloromethane/methanol (95/5) mixture.
0.27 g of a yellow powder is obtained.
Melting point: 212°C
MH+: 515
3-{3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1 -yl}benzoic acid
1.31 ml ( 1 .31 mmol) of a 1N aqueous solution of sodium hydroxide are
added to 0.27 g (0.52 mmol) of methyl 5-({1-[3-
(methoxycarbonyl)phenyl]imidazo[1 ,5-a]pyridin-3-yl}carbonyl)-2-
[(propylcarbamoyl)amino]benzoate in 8 ml of methanol. The reaction medium is
heated at 70°C for 5.5 hours. The methanol is concentrated under reduced
pressure. The residue is taken up in water. The aqueous phase is acidified with a
1N aqueous solution of hydrochloric acid, and then extracted with dichloromethane.
The organic phase is dried over sodium sulphate, filtered, and then concentrated
under reduced pressure. The solid obtained is taken up in methanol and then
filtered, and dried at 50°C under reduced pressure overnight. 0.245 g of a yellow
solid is obtained.
Melting point: 365°C
MH+: 469
Sodium salt of 3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1 -yl}benzoic acid
0.51 ml (0.51 mmol) of a 1N aqueous solution of sodium hydroxide is added
to 0.245 g (0.52 mmol) of 3-{3-[(2,4-dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1-yl}benzoic acid in 5 ml of methanol. The
reaction medium is stirred for 1.5 hours at ambient temperature. After the addition
of diisopropyl ether, the precipitate formed is filtered off, rinsed with diisopropyl
ether, and dried at 50°C under reduced pressure overnight. 0.242 g of a yellow
powder is obtained.
Melting point: 383°C
MH+: 469
H NMR (D6-DMSO, 400 MHz):
0.90 (t, J=7.82Hz, 3H), 1.58-1 .67 (m, 2H), 3.88 (t, J=7.07Hz, 1H), 7.32-7.35 (m,
2H), 7.45 (t, J=7.82, 1H), 7.53 (t, J=7.82Hz, 1H), 7.88-7.94 (m, 2H), 8.22 (d,
J=8.94Hz, 1H), 8.44 (t, J=1.7Hz, 1H), 8.74 (d, J=8.7Hz, 1H), 9.14 (d, J=1 .9Hz, 1H),
9.82 (d, J=7Hz, 1H), 11.9 (bs, 1H).
Examp le 3 (compound No. 8)
3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-
a]pyridine-6-carboxylic acid
3-[(4-Amino-3-carboxyphenyl)carbonyl]imidazo[1,5-a]pyridine-6-
carboxylic acid
3.68 ml (0.026 mol) of triethylamine and then, under a nitrogen atmosphere
at ambient temperature, 1.5 g (8.5 mmol) of methyl imidazo[1 ,5-a]pyridine-6-
carboxylate [described in WO 06/097625] are added to 4.02 g (0.014 mol) of 4-
oxo-2-phenyl-4H-3,1-benzoxazin-6-carbonyl chloride in 60 ml of 1,2-
dichloroethane. After stirring for 24 hours at ambient temperature, the reaction
medium is filtered, and washed with 1,2-dichloroethane, then with a 1N aqueous
solution of hydrochloric acid and then with water. After drying overnight under
reduced pressure at 40°C, the product obtained is dissolved in 60 ml of NMP.
3.59 g (6.4 mmol) of potassium hydroxide dissolved in 11 ml of water are added.
The reaction medium is heated at 100°C for 4 hours and then poured into a 1N
aqueous solution of hydrochloric acid. After filtration, the solid obtained is rinsed
with water and then dried overnight in an oven under reduced pressure at 40°C.
5.45 g of a yellow solid are obtained.
MH+: 326
Methyl 3-{[4-amino-3-(methoxycarbonyl)phenyl]carbonyl}imidazo[1,5-
a]pyridine-6-carboxylate
9.4 g (2.9 mmol) of caesium carbonate and then 1.8 ml (2.9 mmol) of methyl
iodide, at ambient temperature are added, under an inert atmosphere, to 4.2 g
( 1 .3 mmol) of 3-[(4-amino-3-carboxyphenyl)carbonyl]imidazo[1 ,5-a]pyridine-6-
carboxylic acid in 60 ml of DMF. After stirring for 4.5 hours at ambient temperature,
the reaction medium is hydrolysed with water. The precipitate obtained is filtered
off, rinsed with water, and then dried at 40°C under reduced pressure overnight.
The solid obtained is purified by silica gel column chromatography, elution being
carried out with dichloromethane. 1.3 g of a yellow solid are obtained.
MH+: 354
Methyl 3-({3-(methoxycarbonyl)-4-[(propylcarbamoyl)amino]imidazo[1,5-
a]pyridine-6-carboxylate
0.14 g (0.49 mmol) of triphosgene is added, at ambient temperature under a
nitrogen atmosphere, to 0.3 g (0.7 mmol) of methyl 3-{[4-amino-3-
(methoxycarbonyl)phenyl]carbonyl}imidazo[1 ,5-a]pyridine-6-carboxylate in 10 ml of
anhydrous dioxane. After heating for 1 h 15 at 100°C, 0.12 ml ( 1 .4 mmol) of
n-propylamine and 0.29 ml (2 mmol) of triethylamine are added to the reaction
medium at ambient temperature. After stirring for 4 hours at ambient temperature,
the reaction medium is hydrolysed with water. The precipitate obtained is filtered
off, rinsed with water, and then dried under reduced pressure at 40°C overnight.
The solid obtained is triturated from THF and then filtered and dried under reduced
pressure at 40°C overnight. 0.21 g of a yellow solid is obtained.
Melting point: 266°C
MH+: 439
3-[(2,4-Dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridine-6-carboxylic acid
1.2 ml ( 1 .2 mmol) of a 1N aqueous solution of sodium
hydroxide are added, at ambient temperature, to 0.21 g of methyl 3-({3-
(methoxycarbonyl)-4-[(propylcarbamoyl)amino]imidazo[1 ,5-a]pyridine-6-carboxylate
in 5 ml of methanol. After refluxing for 4 hours, the reaction medium is acidified
with a 1N aqueous solution of hydrochloric acid. The precipitate obtained is filtered
off and then rinsed with water and dried under reduced pressure at 40°C overnight.
The solid obtained is recrystallized while hot from methanol and then dried under
reduced pressure at 40°C overnight. 0.1 18 g of a yellow solid is obtained.
Melting point: 384°C
MH+: 393
H-NMR (D6-DMSO, 400 MHz) :
0.92 (t, J=7.2Hz, 3H), 1.59-1 .68 (m, 2H), 3.87-3.94 (m, 2H), 7.33 (d, J=8.2Hz, 1H),
7.72 (d, J=9.3Hz, 1H), 7.98 (s, 1H), 8.06 (d, J=9.3Hz, 1H), 8.59 (d, J=8.51 Hz, 1H),
9.20(d, J=2.03Hz, 1H), 11.8 (s, 1H), 13.7 (s, 1H).
Example 4 : (compound No. 49)
Sodium salt of 3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1 -yl)benzoic acid
Methyl 2-{[(4-fluorobenzyl)carbamoyl]amino}-5-({1 -[3-
(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoate
2.14 g (7.2 mmol) of triphosgene are added, at ambient temperature under
an inert atmosphere, to 2.58 g (6 mmol) of methyl 2-amino-5-({1-[3-
(methoxycarbonyl)phenyl]imidazo[1 ,5-a]pyridin-3-yl}carbonyl)benzoate in 50 ml of
dioxane. After refluxing for 7 hours, 2.25 g (18 mmol) of 4-fluorobenzylamine and
1.82 g (18 mmol) of triethylamine are added at ambient temperature. The reaction
medium is refluxed for 3 hours and then concentrated under reduced pressure.
The residue is triturated from water. After filtration, the solid is rinsed with methanol
and then dried under reduced pressure at 40°C overnight. 3.3 g of a yellow solid
are obtained.
MH+: 581
3-(3-{[3-(4-Fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-
yl]carbonyl}imidazo[1 ,5-a]pyridin-1 -yl)benzoic acid
2.85 ml (0.0285 mol) of a 1N aqueous solution of sodium hydroxide are
added to 3.3 g (5.7 mmol) of methyl 2-{[(4-fluorobenzyl)carbamoyl]amino}-5-({1-[3-
(methoxycarbonyl)phenyl]imidazo[1 ,5-a]pyridin-3-yl}carbonyl)benzoate dissolved in
250 ml of methanol. After refluxing for 2 hours, the reaction medium is acidified
with 50 ml of a 1N aqueous solution of hydrochloric acid and then diluted with 700
ml of water. The precipitate obtained is filtered off, and dried under reduced
pressure at 40°C overnight. 3.01 g of a yellow solid are obtained.
MH+: 535
Methyl 3-(3-{[ 3-(4-fluorobenzyl)-1 -methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoate
2.44 g (7.5 mmol) of caesium carbonate and 1.06 g (7.5 mmol) of methyl
iodide are added, under an inert atmosphere, to 1.3 g (2.5 mmol) of 3-(3-{[3-(4-
fluorobenzyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-
a]pyridin-1-yl)benzoic acid in 50 ml of DMF. The reaction medium is stirred for 3
hours at ambient temperature under a nitrogen atmosphere and then concentrated
under reduced pressure. The residue obtained is washed with 200 ml of water and
then dried under reduced pressure at 40°C overnight. 1.35 g of a yellow solid are
obtained.
MH+: 563
Sodium salt of 3-(3-{[ 3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1 -yl)benzoic acid
24 ml (24 mmol) of a 1N aqueous solution of lithium hydroxide are added to
1.3 g (2.4 mmol) of methyl 3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzoate in 120 ml of
THF. The reaction medium is refluxed for 5 hours and then acidified at 5°C with
45 ml of a 1N aqueous solution of hydrochloric acid and, finally, diluted with 200 ml
of water. After filtration, the residue obtained is dried under reduced pressure at
40°C overnight.
0.62 ml (0.62 mmol) of a 1N aqueous solution of sodium hydroxide is added to
0.35 g (0.64 mmol) of the yellow solid obtained, in 20 ml of methanol. After
filtration, the residue obtained is dried under reduced pressure at 40°C overnight.
0.38 g of a yellow solid is obtained.
MH+: 549
H-NMR (D6-DMSO, 500 MHz):
3.62 (s, 3 H), 5.17 (s, 2 H), 7.1 1-7.18 (ps t , J = 8.9 Hz, 2 H), 7.35 - 7.40 (ps t , 8.9
Hz, 1 H), 7.42 - 7.48 (m, 3 H), 7.54 - 7.60 (ps t , J = 8.9 Hz, 1 H), 7.70 - 7.74 (ps d,
J = 8.9 Hz, 1 H), 7.89 - 7.95 (ps t , J = 8.9 Hz, 2 H), 8.26 - 8.30 (ps d, J = 8.9 Hz, 1
H), 8.44 - 8.48 (m, 1 H), 8.96 - 9.01 (ps d, J = 8.9 Hz, 1 H), 9.22 - 9.24 (m, 1 H),
9.88 - 9.91 (ps d, J = 7.2 Hz, 1 H).
Example 5: (compound No. 29)
3-{3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1 -yl}benzamide
10.7 mg (0.2 mmol) of ammonium chloride, 5.17 mg (0.4 mmol) of N,Ndiisopropylethylamine
and 49.2 mg (0.2 mmol) of TOTU are added, at 0°C, under
an inert atmosphere, to 46.8 mg (0.1 mmol) of 3-{3-[(2,4-dioxo-3-propyl-1 ,2,3,4-
tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-a]pyridin-1-yl}benzoic acid in 2 ml of
DMF. The reaction medium is stirred for 12 hours at ambient temperature and then
poured into 30 ml of a saturated solution of sodium hydrogen carbonate. The
precipitate obtained is filtered off, washed with water, and dried under reduced
pressure at 40°C overnight. 0.042 g of a yellow solid is obtained.
MH+: 468
H-NMR (D6-DMSO, 500 MHz):
d = 0.92 (t, 3 H, J = 7.7 Hz), 1.66 (tq, 2 H, J = 7.7 Hz, 7.3 Hz), 3.94 (t, 2 H, J = 7.3
Hz), 7.34-7.42 (2 m, 2 H), 7.52-7.61 (2m, 2 H), 7.69 (t, 1 H, J = 7.6 Hz), 7.96 ( m, 1
H), 8.10 -8.23 (2 m, 2 H), 8.41- 8.46 (m, 2 H), 8.80 (dd, 1 H, J = 8.9 Hz, 2.2 Hz),
9.27 (d, 1 H, 1.9 Hz), 9.88 (d, 1 H, J = 7.1 Hz), 11.83 (s, 1 H).
Examp le 6 : (compound No. 34)
6-({1 -[3-(5-Methyl-1 ,3,4-oxadiazol-2-yl)phenyl]imidazo[1 ,5-a]pyridin-3-
yl}carbonyl-3-propylquinazoline-2,4(1 H, 3H)-dione
N'-Acetyl-3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1 -yl}benzohydrazide
29.6 mg (0.4 mmol) of acetohydrazide, 98.4 mg (0.3 mmol) of TOTU and 0.104 ml
(0.6 mmol) of N,N-diisopropylethylamine are added, under an inert atmosphere, at
0°C, to 93.7 mg (0.2 mmol) of 3-{3-[(2,4-dioxo-3-propyl-1 ,2,3,4-
tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-a]pyridin-1-yl}benzoic acid in 6 ml of
DMF. The reaction medium is stirred for 1 hour at 0°C and then for 6 hours at 50°C
and then concentrated under reduced pressure. The residue is taken up in 10 ml of
methanol. The precipitate obtained is filtered off, washed with dyethyl ether and
with pentane, and then dried under reduced pressure at 40°C overnight. 45 mg of a
yellow solid are obtained.
MH+: 525
6-({1 -[3-(5-Methyl-1 ,3,4-oxadiazol-2-yl)phenyl]imidazo[1 ,5-a]pyridin-3-
yl}carbonyl-3-propylquinazoline-2,4(1 H, 3H)-dione
35 mg (0.066 mmol) of N'-acetyl-3-{3-[(2,4-dioxo-3-propyl-1 ,2,3,4-
tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-a]pyridin-1 -yl}benzohydrazide in
1 ml of phosphorus oxychloride are heated at 100°C for 15 minutes. The reaction
medium is concentrated under reduced pressure. The residue obtained is
hydrolysed with water and with a saturated solution of sodium hydrogen carbonate.
The aqueous phase is extracted with dichloromethane. The organic phase is
concentrated under reduced pressure. The residue obtained is purified by silica gel
column chromatography, elution being carried out with methanol. 0.025 g of a
yellow solid is obtained.
MH+: 507
H-NMR (D6-DMSO, 500MHz):
0.91 (t, J = 7.5 Hz, 3H), 1.65 (qt, J = 7.5 Hz, 7.5 Hz, 2 H), 2.67 (s, 3 H), 3.93 (t, J =
7.5 Hz, 2 H), 7.33 - 7.43 (m, 2 H), 7.58 - 7.64 (m, 1H), 7.77 - 7.84 (m, 1 H), 8.04 -
8.06 (m, 1 H), 8.28 - 8.32 (m, 1H), 8.39 - 8.43 (m, 1 H), 8.59 (s, 1 H), 8.71 - 8.74
(m, 1 H), 9.37 (s, 1 H), 9.86 - 9.90 (s, 1 H), 11.85 (br s, 1H).
Example 7: (compound No. 36)
6-({1 -[3 -(3-Methyl-1 ,2,4-oxadiazol-5-yl)phenyl]imidazo[1 ,5-a]pyridin-3-
yl}carbonyl)-3-propylquinazoline-2,4(1 H, 3H)-dione
3-{3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1 -yl}-N-[(1 E)-
hydroxyethanimidoyl]benzamide
39 mg (0.24 mmol) of 1, 1 '-carbonyldiimidazole are added, at ambient temperature
under an inert atmosphere, to 94 mg (0.2 mmol) of 3-{3-[(2,4-dioxo-3-propyl-
1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-a]pyridin-1-yl}benzoic acid in
5 ml of DMF. After stirring for 12 hours at ambient temperature, 22.2 mg (0.3 mmol)
of acetamidoxime are added. The reaction medium is stirred for 5 hours at ambient
temperature and then concentrated under reduced pressure. The residue is
triturated from dyethyl ether, filtered, and then dried under reduced pressure at
40°C overnight. 0.101 g of a yellow solid is obtained.
MH+: 525
6-({1 -[3 -(3-Methyl-1,2,4-oxadiazol-5-yl)phenyl]imidazo[1 ,5-a]pyridin-3-
yl}carbonyl)-3-propylquinazoline-2,4(1 H, 3H)-dione
A solution of 0.1 g (0.19 mmol) of 3-{3-[(2,4-dioxo-3-propyl-1 ,2,3,4-
tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-a]pyridin-1 -yl}-N-[(1 E)-
hydroxyethanimidoyl]benzamide in 3 ml of DMF is heated at 120°C for 5 hours.
The reaction medium is concentrated under reduced pressure. The residue
obtained is taken up in dyethyl ether, filtered, and then dried under reduced
pressure at 40°C overnight. 0.083 g of a yellow solid is obtained.
MH+: 507
H-NMR (D6-DMSO):
0.91 (t, J = 7.5 Hz, 3H), 1.65 (qt, J = 7.5 Hz, 7.5 Hz, 2 H), 2.47 (s, 3 H), 3.94 (t, J =
7.5 Hz, 2 H), 7.36 - 7.45 (m, 2 H), 7.59 - 7.66 (m, 1H), 7.82 - 7.89 (m, 1H), 8.13 -
8.19 (m, 1H), 8.36 - 8.45 (m, 2H), 8.68 (s, 1H), 8.75 - 8.79 (m, 1H), 9.25. 9.28 (m,
1 H), 9.85 - 9.90 (m, 1 H), 11.85 (br s, 1 H).
Examp le 8 : (Compound No. 13)
N-{3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1 -yl}methanesulphonamide
Methyl 5-[(1 -bromoimidazo(1 ,5-a)pyridin-3-yl)carbonyl]-2-
[(propylcarbamoyl)aminobenzoate
0.55 g (0.0019 mol) of triphosgene is added, at ambient temperature under
an inert atmosphere, to 1 g (2.7 mmol) of methyl 2-amino-5-[1-bromo(imidazo[1 ,5-
a]pyridin-3-yl)carbonyl)]benzoate in 30 ml of anhydrous dioxane. The reaction
medium is heated for 1.5 hours at 100°C. 0.44 ml (5.3 mmol) of n-propylamine and
1.12 ml (8 mmol) of triethylamine are added at ambient temperature. After 2 h 30,
the reaction medium is hydrolysed with water. The aqueous phase is extracted with
dichloromethane. The organic phase is dried over sodium sulphate, filtered, and
then concentrated under reduced pressure. The solid obtained is triturated from
dichloromethane, filtered, and then dried under reduced pressure at 40°C
overnight.
MH+: 459, 461
Melting point: 236°C
6-[(1-Bromoimidazo(1,5-a)pyridin-3-yl)carbonyl]-3-propylquinazoline-
2,4(1 H,3H)-dione
3.14 ml (3.1 mmol) of a 1N aqueous solution of sodium hydroxide are added,
at ambient temperature, to 1.2 g (2.6 mmol) of methyl 5-[(1-bromoimidazo(1 ,5-
a)pyridin-3-yl)carbonyl]-2-[(propylcarbamoyl)aminobenzoate in 20 ml of methanol.
After refluxing for 3 hours, the reaction medium is hydrolysed with a 1N aqueous
solution of hydrochloric acid. The precipitate obtained is filtered off, rinsed with
methanol, and then dried under reduced pressure at 40°C overnight. 1.09 g of a
yellow solid are obtained.
MH+: 427, 429
Melting point: 322°C
6-[(1 -Aminoimidazo(1 ,5-a)pyridin-3-yl)carbonyl]-3-propylquinazoline-
2,4(1 H,3H)-dione
1.45 g (4.7 mmol) of caesium carbonate, 1.13 ml (6.7 mmol) of
benzophenoneimine, 0.278 g (0.45 mmol) of binap and 0.204 g (0.22 mmol) of
dibenzylideneacetone dipalladium are added, at ambient temperature under an
argon atmosphere, to 0.955 g (2 mmol) of 6-[(1-bromoimidazo(1 ,5-a)pyridin-3-
yl)carbonyl]-3-propylquinazoline-2,4(1/-/,3/-/)-dione in 20 ml of DMSO. The reaction
medium is heated at 110°C for 18 hours. The reaction medium is extracted with
ethyl acetate. The organic phase is dried over sodium sulphate, filtered and
concentrated under reduced pressure.
The residue obtained is dissolved in 40 ml of THF. 4.5 ml (9 mmol) of a 2N
aqueous solution of hydrochloric acid are added at ambient temperature. After
stirring for 4 hours at ambient temperature, the reaction medium is concentrated
under reduced pressure. The residue obtained is washed with dichloromethane
and with methanol, and then dried under reduced pressure at 40°C overnight.
0.558 g of a red solid is obtained.
MH+: 364
N-{3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1 -yl}methanesulphonamide
0.1 ml ( 1 .2 mmol) of mesyl chloride is added, at 0°C under an inert
atmosphere, to 0.25 g (0.4 mmol) of 6-[(1-aminoimidazo(1 ,5-a)pyridin-3-
yl)carbonyl]-3-propylquinazoline-2,4(1/-/,3/-/)-dione in 5 ml of pyridine. After the
addition of methanol, the reaction medium is concentrated under reduced pressure.
The residue is taken up with dichloromethane. The organic phase is washed with a
1N aqueous solution of hydrochloric acid and then with water, dried over sodium
sulphate, filtered, and concentrated under reduced pressure. The residue is
recrystallized while hot from methanol, purified on a silica gel frit, elution being
carried out with DMF. 0.057 g of an orange solid is obtained.
Melting point: 334°C
MH+: 442
H-NMR (D6-DMSO, 400 MHz):
0.88 (t, J=7.37Hz, 3H), 1.55-1 .65 (m, 2H), 3.29 (s, 3H), 3.87-3.90 (m, 2H), 7.27-
7.31 (m, 2H), 7.40-7.44 (m, 1H), 7.92 (d, J=9Hz, 1H), 8.52 (d, J=8.46Hz, 1H), 9.15
(d, J=2.18Hz, 1H), 9.71 (d, J=7.1 Hz, 1H), 10.2 (s, 1H), 11.8 (s, 1H).
Examp le 9 : (Compound No. 82)
2-Morpholin-4-yl-ethyl 3-(3-{[3-(4-fluorobenzyl)-1 -methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoate
hydrochloride
0.022 g (0.61 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.189 g
( 1 .37 mmol) of potassium carbonate are added, under an inert atmosphere, to
0.3 g (0.55 mmol) of 3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzoic acid in 8 ml of
DMF. After stirring for 18 h at ambient temperature and then for 8 hours at 50°C,
the reaction medium is hydrolysed with water, and extracted with ethyl acetate. The
organic phase is washed with water, dried over sodium sulphate, filtered, and then
concentrated under reduced pressure. The yellow solid obtained is purified by silica
gel column chromatography, elution being carried out with a
dichloromethane/methanol (95/5) mixture. 0.61 ml of a 1N aqueous solution of
hydrochloric acid is added to 0.334 g of the yellow solid obtained, in 5 ml of
methanol. The reaction medium is stirred for 1 hour at ambient temperature.
Dyethyl ether is added and then the reaction medium is filtered. The precipitate
obtained is rinsed with dyethyl ether and then dried under reduced pressure at
50°C overnight. 0.298 g of a yellow solid is obtained.
Melting point: 215°C
MH+: 662
H-NMR (D6-DMSO, 500 MHz):
3.21-3.31 (m, 2H), 3.31 (s, 3H), 3.46-3.54 (m, 2H), 3.6-3.7 (m, 2H), 3.61 (s, 3H),
3.70-3.80 (m, 2H), 3.90-4 (m, 2H), 4.65-4.75 (m, 2H), 5.16 (s, 2H), 7.1 1-7.16 (m,
2H), 7.37-7.39 (m, 1H), 7.42-7.45 (m, 2H), 7.55-7.58 (m, 1H), 7.67 (d, J=9.28Hz,
1H), 7.73 (t, J=7.69Hz, 1H), 8.07 (d, J=7.69Hz, 1H), 8.29-8.34 (m, 2H), 8.55 (s,
1H), 8.82 (d, J=9.01 Hz, 1H), 9.27 (d, J=1.85Hz, 1H), 9.83 (d, J=7.16Hz, 1H), 10.9
(s, 1H).
Examp le 10: (Compound No. 117)
N-[2-(Dimethylamino)ethyl]-3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1 -yl)benzamide
hydrochloride
0.06 ml (0.55 mmol) of N,N-dimethylethylenediamine, 0.134 g (0.41 mmol) of
TOTU and 0.14 ml (0.82 mmol) of diisopropylethylamine are added to 0.15 g
(0.27 mmol) of 3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzoic acid in 5 ml of
DMF. The reaction medium is heated at 80°C for 16 hours. The reaction medium is
hydrolysed with water, and extracted with ethyl acetate. The organic phase is
washed with water, dried over sodium sulphate, filtered, and concentrated under
reduced pressure. The yellow solid obtained is purified by silica gel column
chromatography, elution being carried out with a dichloromethane/methanol (95/5)
mixture. 0.23 ml of a 1N solution of hydrochloric acid in dyethyl ether is added to
0.095 g of the yellow solid obtained. After stirring for 1 hour, dyethyl ether is added.
The precipitate obtained is filtered off, rinsed with water, and then dried under
reduced pressure at 50°C overnight. 0.1 g of a yellow solid is obtained.
Melting point: 247°C
MH+: 619
H-NMR (D6-DMSO, 400 MHz):
2.50(m, 6H), 2.84 (s, 2H), 3.31 (s, 3H), 3.61 (s, 1H), 3.64-6.70 (m, 1H), 5.16 (s,
2H), 7.7.1 1-7.17 (m, 2H), 7.37-7.46 (m, 3H), 7.55-7.60 (m, 1H), 7.67-7.71 (m, 2H),
7.93 (d, J=8.19Hz, 1H), 8.19 (d, J=7.51 Hz, 1H), 8.38-8.43 (m, 2H), 8.87 (d,
J=8.88Hz, 1H), 8.92 (t, J=5.12Hz, 1H), 9.27 (d, J=2Hz, 1H), 9.81 (s, 1H), 9.84 (d,
J=7.1 Hz, 1H).
Example 11: (Compound No. 72
Sodium salt of 3-(3-{[3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1 -yl)benzoic acid
Propyl 3-(3-{[3-(4-fluorobenzyl)-1 -propyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1 -yl)benzoate
1.371 g (4.21 mmol) of caesium carbonate and 0.715 g (4.21 mmol) of propyl
iodide are added, under an inert atmosphere, to 0.75 g ( 1.4 mmol) of 3-(3-{[3-(4-
fluorobenzyl)-2,4-dioxo-1 ,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-
a]pyridin-1-yl)benzoic acid in 30 ml of DMF. The reaction medium is stirred for
3 hours at ambient temperature under a nitrogen atmosphere, and then
concentrated under reduced pressure. The residue obtained is washed with 100 ml
of water and then dried under reduced pressure at 40°C overnight. The solid
obtained is purified by silica gel column chromatography, elution being carried out
with a dichloromethane/methanol (75/1 ) mixture. 0.55 g of a yellow solid is
obtained.
MH+: 619
Sodium salt of 3-(3-{[3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1 -yl)benzoic acid
8.9 ml (8.9 mmol) of a 1N aqueous solution of lithium hydroxide are added to
0.55 g (0.889 mmol) of propyl 3-(3-{[3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzoate in 50 ml of
THF. The reaction medium is refluxed for 6 hours and then acidified at 5°C with
17 ml of a 1N aqueous solution of hydrochloric acid and, finally, diluted with 100 ml
of water. After filtration, the residue obtained is dried under reduced pressure at
40°C overnight.
0.408 ml (0.408 mmol) of a 1N aqueous solution of sodium hydroxide is added to
0.24 g (0.416 mmol) of the yellow solid obtained, in 20 ml of methanol. After
filtration, the residue obtained is dried under reduced pressure at 40°C overnight.
0.24 g of a yellow solid is obtained.
MH+: 577
1H-NMR (D6-DMSO, 500 MHz):
0.97 (t, J = 7.5 Hz, 3H, 1.71 (tq, J1/J2= 7.5 Hz, 2 H), 4.18 (t, J = 7.5 Hz, 2 H), 5.20
(s, 2 H), 7.17 (ps t , J = 9.3 Hz, 2 H), 7.37 - 7.41 (m, 1 H), 7.44 - 7.49 (3 m, 3 H),
7.59 (m, 1 H), 7.78 (ps d, J = 8.5 Hz, 1 H), 7.91 (2 m, 2 H), 8.28 (ps d, J = 9.8 Hz, 1
H), 8.45 (m, 1 H), 8.99 - 9.02 (m, 1 H), 9.23 (m, 1 H), 9.90 (ps d, J = 7.5 Hz, 1 H).
Examp le 12: (Compound No. 113)
3-(4-Fluorobenzyl)-1 -methyl-6-[(1 -pyridin-3-ylimidazo[1 ,5-a]pyridin-3-
yl)carbonyl]quinazoline-2,4(1 H, 3H)-dione
Methyl 5-[(1 -bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-2-{[(4-
fluorobenzyl)carbamoyl]amino}benzoate
3 g (10.4 mmol) of triphosgene diluted in 40 ml of dioxane are added to
5.57 g (14.9 mmol) of methyl 2-amino-5-[1-bromo(imidazo[1 ,5-a]pyridin-3-
yl)carbonyl]benzoate in 160 ml of dioxane, under an inert atmosphere. The reaction
medium is refluxed for 1 hour. 3.7 g (0.030 mol) of 4-fluorobenzylamine and
6.22 ml (0.045 mol) of triethylamine are added at ambient temperature. The
reaction medium is stirred for 4 hours at ambient temperature and then hydrolysed
with water. The precipitate obtained is filtered off, rinsed with water, and dried
under reduced pressure at 50°C overnight. The solid obtained is taken up with
methanol, filtered, rinsed with methanol, and dried under reduced pressure
overnight.
12 g of a yellow solid are obtained (yield=95.5%).
MH+: 525, 527
Melting point: 203°C
6-[(1 -Bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-3-(4-
fluorobenzyl)quinazoline-2,4(1H, 3H)-dione
22.33 ml (22.33 mmol) of a 1N aqueous solution of sodium hydroxide are
added to 7.8 g (0.0149 mol) of methyl 5-[(1-bromoimidazo[1 ,5-a]pyridin-3-
yl)carbonyl]-2-{[(4-fluorobenzyl)carbamoyl]amino}benzoate in 100 ml of methanol.
The reaction medium is refluxed for 2.5 hours. After hydrolysis with water, the
precipitate obtained is filtered off, rinsed with water, and dried under reduced
pressure at 50°C overnight.
The solid obtained is taken up in a 0.1 N aqueous solution of hydrochloric acid,
filtered, rinsed with water, and dried under reduced pressure at 50°C overnight.
5.4 g of a yellow solid are obtained.
Melting point: 325°C
MH+: 494, 496
6-[(1 -Bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)-1 -
methylquinazoline-2,4(1 H, 3H)-dione
1.87 g (5.7 mmol) of caesium carbonate and 0.39 ml (6.2 mmol) of methyl
iodide are added, at anbient temperature under an inert atmosphere, to 2.6 g
(5.17 mmol) of 6-[(1-bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-3-(4-
fluorobenzyl)quinazoline-2,4(1/-/,3/-/)-dione in 50 ml of anhydrous DMF. The
reaction medium is stirred for 18 hours at ambient temperature and then filtered.
The precipitate is rinsed with water and then dried under reduced pressure at 50°C
overnight. 2.54 g of a yellow solid are obtained.
Melting point: 280°C
MH+: 507, 509
3-(4-Fluorobenzyl)-1 -methyl-6-[(1 -pyridin-3-ylimidazo[1 ,5-a]pyridin-3-
yl)carbonyl]quinazoline-2,4(1 H, 3H)-dione
0.04 g (0.32 mmol) of 3-pyridylboronic acid, 0.2 g (0.81 mmol) of potassium
phosphate dihydrate dissolved in 0.29 ml of water, and 6.2 mg (0.01 mmol) of
tetrakis(triphenylphosphine)palladium are added to 0.15 g (0.27 mmol) of 6-[(1-
bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)-1 -methylquinazoline-
2,4(1/-/, 3/-/)-dione in 3 ml of DMF under an inert argon atmosphere. The reaction
medium is microwave-heated at 150°C for 20 minutes. After filtration over talc, the
reaction medium is concentrated under reduced pressure. The residue obtained is
purified by silica gel column chromatography, elution being carried out with a
dichloromethane/methanol (95/5) mixture. 0.12 g of a yellow solid is obtained.
Melting point: 207°C
MH+: 506
3-(4-Fluorobenzyl)-1 -methyl-6-[(1 -pyridin-3-ylimidazo[1 ,5-a]pyridin-3-
yl)carbonyl]quinazoline-2,4(1H, 3H)-dione hydrochloride
0.35 ml (0.35 mmol) of a 1N solution of hydrochloric acid in dyethyl ether is
added to 0.12 g (0.23 mmol) of 3-(4-fluorobenzyl)-1-methyl-6-[(1-pyridin-3-
ylimidazo[1 ,5-a]pyridin-3-yl)carbonyl]quinazoline-2,4(1/-/, 3/-/)-dione in 3 ml of
methanol. After stirring for 1 hour at ambient temperature, the reaction medium is
filtered. The precipitate obtained is rinsed with dyethyl ether, and dried under
reduced pressure at 50°C overnight. 0.12 g of a yellow solid is obtained.
MH+: 506
Melting point: 267°C
H-NMR (D6-DMSO, 400 MHz):
3.60 (s, 3H), 5.16 (s, 2H), 7.14 (t, J=8.34Hz, 2H), 7.36-7.47 (m, 3H), 7.60 (t,
J=7.05Hz, 1H), 7.65 (d, J=8.98Hz, 1H), 7.83 (t, J=7.05Hz, 1H), 8.43 (d, J=8.98Hz,
1H), 8.66-8.75 (m, 2H), 8.83 (d, J=8.98Hz, 1H), 9.30(m, 2H), 9.81 (d, J=7.05Hz,
1H).
Examp le 13: (Compound No. 53)
3-{3-[(2-Methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-
a]pyridin-1-yl}benzoic acid
2-Amino-5-(1 -bromoimidazo[1 ,5-a]pyridin-3-ylcarbonyl)benzoic acid
60 ml (60 mmol) of a 1N aqueous solution of sodium hydroxide are added, at
ambient temperature, to 3.74 g (10 mmol) of methyl 2-amino-5-[1-
bromo(imidazo[1 ,5-a]pyridin-3-yl)carbonyl]benzoate in 300 ml of methanol and
125 ml of water. The reaction medium is refluxed for 6 hours and then 140 ml of a
1N aqueous solution of hydrochloric acid are added. After concentration of the
methanol under reduced pressure, the precipitate obtained is filtered off, washed
with water, and then dried under reduced pressure at 40°C for 18 hours. 3.53 g of
a yellow solid are obtained.
MH+: 360, 362
36
2-(Acetylamino)-5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]benzoic
acid
0.92 g (2.56 mmol) of 2-amino-5-(1-bromoimidazo[1 ,5-a]pyridin-3-
ylcarbonyl)benzoic acid in 30 ml of acetic anhydride are refluxed for 5.5 hours. The
reaction medium is concentrated under reduced pressure. The residue is taken up
in water and then filtered and dried under reduced pressure overnight at 40°C.
1. 1 g of a yellow solid are obtained.
MH+: 402, 404
6-[(1 -Bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-2 -methyl-3-
propylquinazolin-4(3H)-one
1.32 g (22.4 mmol) of n-propylamine are added, at 0°C under an inert
atmosphere, to 0.9 g (2.2 mmol) of 6-[(1-bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-
2-methyl-4/-/-3,1-benzoxazin-4-one in 15 ml of glacial acetic acid. The reaction
medium is microwave-heated for 45 minutes at 160°C. The reaction medium is
concentrated under reduced pressure. The residue obtained is taken up with a
saturated aqueous solution of sodium carbonate. The precipitate obtained is
filtered off and then dried under reduced pressure at 50°C overnight. 0.67 g of a
yellow solid is obtained.
MH+: 425, 427
Methyl 3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1 -yl}benzoate
0.35 g ( 1 .95 mmol) of 3-methoxycarbonylphenylboronic acid, 0.689 g
(3.24 mmol) of potassium phosphate dissolved in 3 ml of water, and 0.037 g
(0.032 mmol) of tetrakis(triphenylphosphine)palladium are added to 0.69 g
( 1 .62 mmol) of 6-[(1-bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-2-methyl-3-
propylquinazolin-4(3/-/)-one in 15 ml of NMP. The reaction medium is microwaveheated
for 15 minutes at 150°C and then concentrated under reduced pressure.
After the addition of 100 ml of water, the precipitate is filtered off and then dried
under reduced pressure at 50°C overnight. The solid obtained is purified by silica
gel column chromatography, elution being carried out with a
dichloromethane/methanol (50/1 ) mixture.
MH+: 481
3-{3-[(2-Methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1 -yl}benzoic acid
7.65 ml of a 1N aqueous solution of sodium hydroxide are added to 0.735 g
( 1 .53 mmol) of methyl 3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-
yl)carbonyl]imidazo[1 ,5-a]pyridin-1-yl}benzoate in 30 ml of THF. The reaction
medium is refluxed for 2.5 hours. After acidification with 10 ml of a 1N aqueous
solution of hydrochloric acid, the reaction medium is concentrated under reduced
pressure. The residue is taken up in 20 ml of water. The precipitate obtained is
filtered off, and dried under reduced pressure at 50°C overnight. 0.52 g of a yellow
solid is obtained.
MH+: 467
H-NMR (D6-DMSO, 500 MHz):
0.97 (t, J = 7.6 Hz, 3 H), 1.69 - 1.76 (m, 2 H), 2.71 (s, 3H), 4.07 - 4.1 1 (m, 2 H),
7.40 - 7.44 (m, 1H), 7.59 - 7.66 (m, 1H), 7.71 - 7.80 (m, 2 H), 8.01 - 8.05 (m, 1
H), 8.28 - 8.39 (2 m, 2 H), 8.55 - 8.58 (m, 1 H), 8.79 - 8.82 (m, 1 H), 9.30 - 9.34
(m, 1 H), 9.88 - 9.22 (m, 1 H), 13.23 (br s, 1H).
Examp le 14: (Compound No. 55)
3-{3-[(2-Methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-
a]pyridin-1 -yl}benzamide
0.107 g (2 mmol) of ammonium chloride, 0.328 g ( 1 mmol) of TOTU and
0.517 g (4 mmol) of N,N-diisopropylethylamine are added, at ambient temperature
under an inert atmosphere, to 0.233 g (0.5 mol) of 3-{3-[(2-methyl-4-oxo-3-propyl-
3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-a]pyridin-1-yl}benzoic acid in 30 ml
of DMF. The reaction medium is stirred for 5 hours at ambient temperature and
then concentrated under reduced pressure. 50 ml of a saturated solution of sodium
hydrogen carbonate are added to the residue. The precipitate obtained is filtered
off, and then dried under reduced pressure at 50°C overnight. 0.230 g of a yellow
solid is obtained.
MH+: 466
H-NMR (D6-DMSO, 500 MHz):
0.98 (t, J = 8 Hz, 3H), 1.74 (m, 2 H), 2.71 (s, 3 H), 4.10 (t, J = 8.1 Hz, 2H), 7.40 -
7,45 (m, 1H), 7.54 - 7.64 (m, 2 H), 7.67 - 7.71 (m, 1 H), 7.75 - 7.80 (m, 1 H), 7.96
- 8.00 (m, 1 H), 8.19 - 8.23 (m, 2 H), 8.42 - 8.48 (m, 2H), 8.82 - 8.85 (m, 1H), 9.39
- 9.41 (m, 1 H), 9.90 - 9.95 (m, 1 H).
Example 15: (Compound No. 3)
6-(lmidazo[1 ,5-a]pyridin-3-ylcarbonyl)quinazolin-4(3H)-one
0.36 g (3.6 mmol) of formamidine acetate is added to 0.2 g (0.72 mmol) of 2-
amino-5-(imidazo[1 ,5-a]pyridin-3-ylcarbonyl)benzoic acid (described in
WO 06/097625) in 7 ml of ethanol. The reaction medium is microwave-heated at
150°C for 25 minutes. The reaction medium is hydrolysed with a 1N aqueous
solution of sodium hydroxide. The aqueous phase is extracted with
dichloromethane. The heterogeneous organic phase is filtered. The solid obtained
is purified by silica gel column chromatography, elution being carried out with a
dichloromethane/methanol (90/10) mixture. 54 mg of a yellow solid are obtained.
MH+: 291
Melting point: 289°C
H-NMR (D6-DMSO, 400 MHz):
7.29-7.47 (m, 2H), 7.80-7.82 (m, 1H), 7.96 (s, 1H), 8.04-8.07 (m, 1H), 8.23 (s, 1H),
8.67-8.70 (m, 1H), 9.29 (s, 1H), 9.52-9.53 (m, 1H), 12.5 (s, 1H).
Example 16: (Compound No. 177)
L,LM ,2-Tetramethyl-4-oxo-6-{[1 -(pyridin-3-yl)imidazo[1 ,5-a]pyridin-3-
yl]carbonyl}-1,4-dihydroquinoline-3-carboxamide
6-[(1-Bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2H-3,1-benzoxazine-
2,4(1 H)-dione
1.30 g (4.37 mmol) of triphosgene dissolved in 10 ml of dioxane are added,
under an inert atmosphere at ambient temperature, to 1.05 g (2.91 mmol) of 2-
amino-5-(1-bromoimidazo[1 ,5-a]pyridin-3-ylcarbonyl)benzoic acid. The reaction
medium is refluxed for 4 hours, and then concentrated under reduced pressure.
100 ml of water are added to the residue. The precipitate obtained is filtered off
under reduced pressure at 40°C for 18 hours. 1. 1 g of a yellow solid are obtained.
MH+: 386, 388
6-[(1 -Bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-1 -methyl-2H-3,1 -
benzoxazine-2,4(1 H)-dione
808 mg (5.7 mmol) of methyl iodide and 164 mg (3.42 mmol) of 50% sodium
hydride are added, at ambient temperature under an inert atmosphere, to 1. 1 g
(2.85 mmol) of 6-[(1-bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-2H-3,1-
benzoxazine-2,4(1 H)-dione in 20 ml of DMF. After stirring for 3 hours, the reaction
medium is poured into 200 ml of ice-cold water. The precipitate is filtered off, rinsed
with water, and then dried under reduced pressure for 18 hours at 40°C. 1.13 g of
a yellow solid are obtained.
MH+: 402, 403.95
6-[(1 -Bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-N,N-1 ,2-tetramethyl-4-
oxo-1,4-dihydroquinoline-3-carboxamide
1.25 ml of a 2N aqueous solution of sodium hydroxide are added, at ambient
temperature, to 333 mg (2.5 mmol) of N ,N-dimethylacetoacetamide in 3 ml of DMF.
After stirring for 1 hour, 400 mg ( 1 mmol) of 6-[(1-bromoimidazo[1 ,5-a]pyridin-3-
yl)carbonyl]-1-methyl-2H-3,1-benzoxazine-2,4(1 H)-dione dissolved in 25 ml of DMF
are added. The reaction medium is heated for 6 hours at 50°C under an inert
atmosphere. The reaction medium is concentrated under reduced pressure. The
residue obtained is purified by silica gel column chromatography, elution being
carried out with a dichloromethane/methanol 20/1 mixture. 220 mg of a yellow oil
are obtained.
MH+: 467, 469
L ,LM ,2-Tetramethyl-4-oxo-6-{[1 -(pyridin-3-yl)imidazo[1 ,5-a]pyridin-3-
yl]carbonyl}-1,4-dihydroquinoline-3-carboxamide
115 mg (0.37 mmol) of 3-pyridinylboronic acid, 331 mg ( 1.56 mmol) of
potassium phosphate dissolved in 1 ml of water, and 18 mg (15.6 mhhoI ) of
tetrakis(triphenylphosphine)palladium are added, at ambient temperature under an
inert atmosphere, to 365 mg (0.78 mmol) of 6-[(1-bromoimidazo[1 ,5-a]pyridin-3-
yl)carbonyl]-N,N-1 ,2-tetramethyl-4-oxo-1 ,4-dihydroquinoline-3-carboxamide in
20 ml of N-methylpyrolidone. The reaction medium is microwave-heated at 150°C
for 25 minutes and then concentrated under reduced pressure. The residue
obtained is purified by silica gel column chromatography, elution being carried out
with a dichloromethane/methanol 9/1 mixture. 0.290 g of a yellow oil is obtained.
MH+: 466
H-NMR (D6-DMSO, 500 MHz):
2.44 (s, 3 H), 2.89 (s, 3 H), 3.03 (s, 3 H), 3.89 (s, 3 H), 7.39 - 7.43 (m, 1 H),
7.59 - 7.64 (2 m, 2 H), 8.07 (d, J = 9.7 Hz, 1 H), 8.44 - 8.49 (2 m, 2 H), 8.67 (d, J =
4.8 Hz, 1 H), 8.86 (dd, J = 9.7 Hz and 2.2 Hz, 1 H), 9.32 - 9.34 (m, 1 H), 9.55 (d, J
= 2.2 Hz, 1 H), 9.93 (d, J = 7.4 Hz, 1 H).
Example 17: (Compound No. 223)
Sodium salt of 3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl}carbonyl)imidazo[1 ,5-a]pyridin-1 -yl]benzoic acid
Methyl 5-[(1 -bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-2-({[2-(4-
fluorophenoxy)ethyl]carbamoyl}amino)benzoate
4.75 g (16 mmol) of triphosgene are added, at ambient temperature under
an inert atmosphere, to 4.99 g (13.33 mmol) of methyl 2-amino-5-({1-[3-
(methoxycarbonyl)phenyl]imidazo[1 ,5-a]pyridin-3-yl}carbonyl)benzoate in 220 ml of
dioxane. After refluxing for 5 hours, 6.21 g (40 mmol) of 2-(4-fluorophenoxy)-1-
ethylamine and 4.05 g (40 mmol) of triethylamine are added at ambient
temperature. The reaction medium is refluxed for 3 hours and then concentrated
under reduced pressure. The residue is triturated from water. After filtration, the
solid is rinsed with methanol and then dried under reduced pressure at 40°C
overnight. 6.67 g of a yellow solid are obtained.
MH+: 555
6-[(1 -Bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-
fluorophenoxy)ethyl] quinazoline-2,4(1H,3H)-dione
60.1 ml (60.1 mmol) of a 1N aqueous solution of sodium hydroxide are added
to 6.67 g (12 mmol) of methyl 5-[(1-bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-2-
({[2-(4-fluorophenoxy)ethyl]carbamoyl}amino)benzoate dissolved in 600 ml of
methanol. After refluxing for 2 hours, the reaction medium is acidified with 120 ml
of a 1N aqueous solution of hydrochloric acid and then diluted with 2000 ml of
water. The precipitate obtained is filtered off, and dried under reduced pressure at
40°C overnight. 5.83 g of a yellow solid are obtained.
MH+: 523.2, 525.2
6-[(1 -Bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-
fluorophenoxy)ethyl]-1 -propylquinazoline-2,4(1 H,3H)-dione
7.22 g (22.1 6 mmol) of caesium carbonate and 5.65 g (33.24 mmol) of propyl
iodide are added, under an inert atmosphere, to 5.6 g ( 1 1.08 mmol) of 6-[(1-
bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-fluorophenoxy)ethyl]quinazoline-
2,4(1 H,3H)-dione in 300 ml of DMF. The reaction medium is stirred for 12 hours at
ambient temperature under a nitrogen atmosphere and then concentrated under
reduced pressure. The residue obtained is washed with 700 ml of water and then
dried under reduced pressure at 40°C overnight. 5.74 g of a yellow solid are
obtained.
MH+: 565, 567
Methyl 3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1 -propyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoate
2.178 g (12.1 mmol) of 3-methoxycarbonylphenylboronic acid, 4.279 g
(20.16 mmol) of potassium phosphate dissolved in 30 ml of water, and 582.4 g
(0.504 mmol) of tetrakis(triphenylphosphine)palladium are added to 5.7 g
(10.08 mmol) of 6-[(1-bromoimidazo[1 ,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-
fluorophenoxy)ethyl]-1-propylquinazoline-2,4(1 H,3H)-dione in 180 ml of NMP. The
reaction medium is microwave-heated for 15 minutes at 120°C and then
concentrated under reduced pressure. The solid obtained is purified by silica gel
column chromatography, elution being carried out with a dichloromethane/methanol
( 100/1 ) mixture. 4.32 g of a yellow solid are obtained.
MH+: 621 .3
Sodium salt of 3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-dioxo-
1,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1 ,5-a]pyridin-1 -yl]benzoic
acid
69.6 ml (69.6 mmol) of a 1N aqueous solution of lithium hydroxide are added
to 4.32 g (6.96 mmol) of methyl 3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-
dioxo-1 ,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1 ,5-a]pyridin-1 -
yl]benzoate in 500 ml of THF. The reaction medium is refluxed for 3 hours and then
acidified at ambient temperature with 150 ml of a 1N aqueous solution of
hydrochloric acid and, finally, diluted with 700 ml of water. After filtration, the
residue obtained is dried under reduced pressure at 40°C overnight.
5.88 ml (5.88 mmol) of a 1N aqueous solution of sodium hydroxide are added to
4.1 1 g (6 mmol) of the yellow solid obtained, in 100 ml of methanol. After filtration,
the residue obtained is dried under reduced pressure at 40°C overnight. 3.46 g of a
yellow solid are obtained.
MH+: 607.3
Mp: 190-205°C (decomposition)
1H-NMR (D6-DMSO, 500 MHz):
0.98 (t, J=7.7Hz, 3H), 1.71 (tq, J 1=J2=7.7Hz, 2H), 4.17 (t, J=7.7Hz, 2H), 4.24
(t, J=6.6Hz, 2H), 4.39 (t, J=6.6Hz, 2H), 6.97-7.00 (2m, 2H), 7.10-7.16 (2m, 2H),
7.38-7.41 (m, 1H), 7.47- 7.52 (m, 1H), 7.57-7.61 (m, 1H), 7.75-7.79 (m, 1H), 7.94-
7.98 (2m, 2H), 8.26-8.30 (m, 1H), 8.49-8.52 (m, 1H), 8.97-9.02 (m, 1H), 9.26-9.28
(m, 1H), 9.89-9.93(m, 1H).
The table which follows illustrates the chemical structures and the physical
properties of some compounds according to the invention. In this table:
- Me and Et represent, respectively, methyl and ethyl groups;
- the wavy lines indicate the bond attached to the rest of the molecule;
- "Mp" represents the melting point of the compound, expressed in degrees
Celsius;
- "M+H+" represents the mass of the compound, obtained by LC-MS (Liquid
Chromatography - Mass Spectroscopy).
Table
(I)

1

J

The compounds according to the invention were the subject of
pharmacological assays for determining their FGF-inhibiting effect.
Example 18 : FGF-2-induced in vitro angiogenesis of HUVEC cells
In order to demonstrate the ability of the FGF-R antagonists of the present
invention to inhibit FGF-induced angiogenesis, in vitro angiogenesis experiments
were carried out with human endothelial cells of HUVEC type stimulated with FGF-
2 or b-FGF.
To do this, matrices composed of matrigel (growth factor reduced matrigel,
Becton Dickinson 356230) and collagen (rat tail collagen type I , Becton Dickinson
354236) are deposited, at a rate of 160 m I, into each chamberslide well (Biocoat
Cellware collagen, Type I, 8-well culturesides: Becton Dickinson 354630), or 60 m I
per well of 96-well plates (Biocoat collagen I cellware, Becton Dickinson 354407).
The matrix is prepared by mixing 1/3 of matrigel, 1 mg/ml final concentration of
collagen, 0.1 N NaOH (0.026x the volume of collagen in m I) and 1x PBS, and the
volume is then adjusted with water. The gels are kept at 37°C for 1 hour so as to
allow them to polymerize. Next, the human vein endothelial cells (HUVECs ref:
C-1 2200 - Promocell) were seeded at 15 103 or 6 103 cells/well in 400 or 120 m I
(for the 8-well or 96-well plates respectively) of EBM medium (Clonetics C3121) +
2% FBS + 10 mg/ml hEGF. They were stimulated with 1 or 3 ng/ml of FGF-2 (R&D
systems, 133-FB-025; Invitrogen, PHG0026) for 24 h at 37°C in the presence of
5% C0 2. After 24 hours, the length of the network of microtubules formed was
measured using a computer-assisted image analysis system (Imagenia Biocom,
Courtaboeuf, France) and the total length of the pseudotubules in each well was
determined. The average total length of the microcapillary network was calculated
in m h for each condition corresponding to the average of 6 replicates.
Stimulation with FGF2 makes it possible to induce the formation of new
tubules. An FGF-R antagonist is considered to be active in this test as long as it is
capable of partially inhibiting this angiogenesis at a dose less than or equal to
300 nM.
Example of screening for FGF-R antagonists
In this experiment, the molecules are evaluated at 3 and 30 nM on induction
of the angiogenesis of HUVEC human cells by FGF-2. Compounds No. 7 1, 72
(example 11) and 68 are declared active since they exhibit an inhibitory activity of
pseudotubule formation which is greater than or equal to 20% at a dose less than
or equal to 300 nM.
Table 1: In vitro angiogenesis of HUVEC cells stimulated with FGF-2 and effect of
FGF-R antagonists (inhibition of angiogenesis as a percentage of the control)
Example 19 : FGF-2-induced in vitro proliferation of HUVEC cells
In order to demonstrate the ability of the FGF-R antagonists of the present
invention to inhibit FGF-induced cell proliferation, in vitro proliferation experiments
were carried out with human endothelial cells of HUVEC type stimulated with FGF-
2 or b-FGF.
To do this, HUVEC human vein endothelial cells (promocell, C-12200) are
seeded at a rate of 5000 cells per well of a 96-well plate (Biocoat collagen I
cellware, Becton Dickinson 354650) in 100 m I of RPMI 1640 deprivation medium
(Invitrogen, 31872-025) supplemented with 0.5% or 1% FCS, 2 mM glutamine, 1x
sodium pyruvate (Invitrogen, 11360-039) and 1x NEAA (Invitrogen, 11140-035),
overnight at 37°C in the presence of 5% C0 2. The following morning, the medium
is suctioned-off and replaced with 50 m I of deprivation medium containing the
antagonists at a 2x concentration, to which are added 50 m I of FGF-2 (R&D
systems, 133-FB-025; Invitrogen, PHG0026) at 0.2 ng/ml (i.e. 2x). After 48 or 72 h,
100 m I of Cell Titer-GLO™ Luminescent Cell Viability Assay (Promega, G7571 ) are
added for 10 min in order to measure, by means of a luminometer, the amount of
ATP present in the cells and which is in relation to the number of cells per well
corresponding to the cell proliferation.
The antagonists of the present invention are considered to be active as long
as they are capable of inhibiting FGF-2-induced proliferation of HUVEC cells at a
dose less than or equal to 300 nM.
Example of HUVEC cell proliferation induced by FGF-2 and inhibited by
FGF-R antagonists
Compounds No. 49 (example 4), 7 1 and 72 (example 11) are capable of
inhibiting the FGF-2-induced cell proliferation since, in their presence, a reduction
in proliferation of greater than or equal to 20% is observed for doses less than or
equal to 300 nM.
Table 2: Cell proliferation of HUVEC cells stimulated with FGF-2 and effect of
FGF-R antagonists (inhibition of proliferation as percentage of the control)
More generally, all the compounds according to the invention are active, at
the dose of 300 nM, in in vitro angiogenesis of HUVEC cells induced by FGF-2 or
in in vitro proliferation of HUVEC cells induced by FGF-2.
Example 20: Model of inflammatory angiogenesis in mice
Angiogenesis is required for the development of chronic inflammatory
diseases such as rheumatoid arthritis. The formation of new vessels allows not only
the perfusion of pathological tissues, but also the transport of cytokines responsible
for establishing the chronicity of the disease.
The model described by Colville-Nash et al., in 1995, makes it possible to
study pharmacological agents capable of modulating the occurrence of
angiogenesis in an inflammatory context. The model is developed on OF1 female
mice (Charles River Laboratories) weighing approximately 25 g, and by groups of
12. The animals are anaesthetized with sodium pentobarbital (60 mg/kg; Sanofi
Nutrition Sante animale)) intraperitoneally. An air pocket is created on the back of
the mouse by subcutaneous injection of 3 ml of air. After they have awoken, the
animals receive a treatment generally by gavage, and receive an injection of 0.5 ml
of Freund's adjuvant (Sigma) with 0.1% of croton oil (Sigma) in the pocket. Seven
days later, the mice are again anaesthetized and placed on a hot plate at 40°C.
One ml of carmine red (Aldrich Chemicals, 5% in 10% of gelatin) is injected into the
tail vein. The animals are then placed at 4°C for 2-3 hours. The skins are then
taken and dried for 24 h in an oven at 56°C. The dry tissues are weighed and
placed in 1.8 ml of digestion solution (2 mM dithiothreitol, 20 mM Na2HP0 4, 1 mM
EDTA, 12 U/ml papain) for 24 h. The dye is then dissolved in 0.2 ml of 5M NaOH.
The skins are centrifuged at 2000 rpm for 10 min at ambient temperature. The
supernatants are filtered through 0.2 m h cellulose acetate membranes. The
filtrates are read in a spectrophotometer at 492 nm against a carmine red
calibration range. Two parameters are studyed: the dry weight of the granuloma
and the amount of dye after digestion of the tissues. The results are expressed as
mean values (± sem). The differences between the groups are tested with an
ANOVA followed by a Dunnett's test, of which the reference group is the "solvent
control" group.
The FGF-R antagonists are evaluated between 1 and 50 mg/kg using
methylcellulose/tween (0.6% v/v) as vehicle or any other vehicle which allows the
active ingredyent to be solubilized. The molecules are administered daily, orally
(one or two times a day) by gavage. The antagonists of the present invention are
considered to be active as long as they enable a significant reduction in the
angiogenic parameter, i.e. a reduction in the amount of carmine red dye in the
skins of the animals tested.
Example of evaluation of FGF-R antagonists in the model of inflammatory
angiogenesis in mice. Compounds No. 49 (example 4) and 72 (example 11) at
10 mg/kg, after one week of daily treatment, significantly reduce the two
parameters measured: the weight of the granuloma (dry weight of the skin)
corresponding to the inflammation part of the model, and the dye content
corresponding to the angiogenesis.
Table 3: Effect of the FGF-R antagonists, in a model of inflammatory angiogenesis,
on the dry weight of the skins or on their content of carmine red dye.
Model of inflammatory angiogenesis % inhibition of the % inhibition of
inflammatory the angiogenic
parameter (mass parameter (dye
of the granuloma) content)
Compound No. 49 (example 4); 10 mg/kg 40 46
Compound No. 223 (example 17); 25 43
10 mg/kg
Compound No. 72 (example 11) ; 38 43
10 mg/kg
Compound No. 7 1; 30 mg/kg 28 40
Compound No. 149; 10 mg/kg 14 30
Compound No. 215; 10 mg/kg 2 1 39
Compound No. 10 (example 2); 30 mg/kg 19 19
Example 2 1: 4T1 orthotopic mammary carcinoma model in mice
In order to evaluate the effect of the FGF-R antagonists in a murine tumour
model, 4T1 mouse mammary carcinoma cells are injected into the mammary gland.
The cells proliferate until the formation of a tumour after infiltration of the cells of
the tumour microenvironment.
The 4T1 cells are cultured in RPMI 1640 medium containing 10% FCS and
1% glutamine, supplemented with 1 mg/ml of geneticin. On the day of the injection
into the mouse, the 4T1 cell concentration is adjusted to 2 106 cells/ml in PBS in
order to inject 1 105 cells in 50 m I.
Mice (Balb/c, female, Charles River, approximately 8+/-2 weeks old) are
anaesthetized by intraperitoneal injection of a mixture of 5% Rompun (xylazine),
10% Imalgene (ketamine) and 85% NaCI, in a proportion of 10 ml/kg. The injection
zone (top-right nipple) is disinfected with hexomedine. After having vortexed the
cells, 50 m I are removed in a syringe and injected into the nipple with a 26G needle.
The day of injection corresponds to D 1. There are 15 mice in each group of mice
(10 mice will be devoted to the ELISA assays and 5 mice to the histology). The
FGF-R antagonists are evaluated at between 1 and 50 mg/kg in
methylcellulose/tween (0.6% v/v) or any other vehicle which makes it possible to
solubilize the active ingredyent. The molecules are administered daily, orally (one
or two times a day) by gavage, this taking place from D5 to D21 , which is the day
before the samples are taken. From D5, the tumours are measured as soon as
possible, every two days, or even every day at the end of the experiment, using a
caliper (sliding caliper). It is done in the following way: the longest length (L) and
the perpendicular to the centre (I) are measured in mm. The volume in mm3 is then
defined by means of the mathematical formula which determines the volume of an
ellipsoid: ( I2 L) 0.52. On the day the samples are taken, generally D22, the mice
are sacrificed by means of an excess of sodium pentobarbital after having
measured the volume of the tumours. The tumours are then cleared, photographed
and weighed. The lungs are also removed and the metastases are counted after
boin staining.
The antagonists of the present invention are considered to be active as long
as they allow a significant reduction in the volume of the tumour and/or any number
of lung metastases.
Example of 4T1 mammary carcinoma in mice
The compounds considered to be active in the inflammatory angiogenesis
model are evaluated in the 4T1 mammary carcinoma model in mice at between 1
and 50 mg/kg and showed a reduction in tumour volume of up to 49% and a
decrease in the number of lung metastases of up to 33%.
It therefore appears that the compounds of formula (I) according to the present
invention, by virtue of their FGF antagonist effect, reduce in vitro and in vivo,
angiogenesis, tumour growth and metastasization.
Generally, FGFs and their receptors play an important role, by means of autocrine,
paracrine or juxtacrine secretions, in phenomena where there is dysregulation of
the stimulation of cancer cell growth. Furthermore, FGFs and their receptors affect
tumour angiogenesis which plays a predominant role both on tumour growth and
also on metastasization phenomena.
Angiogenesis is a process in which new capillary vessels are generated from pre
existing vessels or by mobilization and differentiation of bone marrow cells. Thus,
both uncontrolled proliferation of endothelial cells and mobilization of angioblasts
from the bone marrow are observed in tumour neovascularization processes. It has
been shown, in vitro and in vivo, that several growth factors stimulate endothelial
proliferation, and in particular FGF-1 or a-FGF and FGF-2 or b-FGF. These two
factors induce proliferation, migration and protease production by endothelial cells
in culture and neovascularization in vivo. a-FGF and b-FGF interact with
endothelial cells by means of two classes of receptors, high-affinity receptor
tyrosine kinases (FGF-Rs) and low-affinity receptors of heparin sulphate
proteoglycan type (HSPGs) located at the surface of cells and in extracellular
matrices. Although the paracrine role of these two factors on endothelial cells is
widely described, these FGFs could also intervene on the cells through an
autocrine process. Thus, FGFs and their receptors represent very relevant targets
for therapies aimed at inhibiting angiogenesis processes (Keshet E, Ben-Sasson
SA., J. Clin. Invest, (1999), Vol. 501 , pp. 104-1497; Presta M, Rusnati M, Dell'Era
P, Tanghetti E, Urbinati C, Giuliani R et al, New York: Plenum Publishers, (2000),
pp. 7-34, Billottet C, Janji B, Thiery J.P., Jouanneau J, Oncogene, (2002) Vol. 2 1,
pp. 8128-8139).
Moreover, systematic studyes aimed at determining the expression due to FGFs
and their receptors (FGF-Rs) of various types of tumour cells demonstrate that a
cell response to these two factors is functional in a large majority of human tumour
lines studyed. These results support the hypothesis that an FGF receptor
antagonist could also inhibit tumour cell proliferation (Chandler LA, Sosnowski BA,
Greenlees L, Aukerman SL, Baird A, Pierce GF., Int.J. Cancer, (1999), Vol. 58,
pp. 81-451 ) .
FGFs play an important role in the growth and maintenance of prostate cells. It has
been shown, both in animal models and in humans, that an impairment in the cell
response to these factors plays an essential role in the progression of prostate
cancer. Specifically, in these pathological conditions, both an increase in the
production of a-FGF, b-FGF, FGF-6, FGF-8 etc., by the fibroblasts, stromal cells,
residual basal cells and endothelial cells present in the tumour and an increase in
the expression of FGF receptors and ligands by the tumour cells are recorded.
Thus, a paracrine stimulation of prostate cancer cells takes place, and this process
appears to be a major component of this pathological condition. A compound which
has an FGF receptor antagonist activity, such as the compounds of the present
invention, may represent a therapy of choice in these pathological conditions (Giri
D, Ropiquet F., Clin.Cancer Res., (1999), Vol. 7 1, pp. 5-1063; Doll JA, Reiher FK,
Crawford SE, Pins MR, Campbell SC, Bouck NP., Prostate, (2001 ) , Vol. 305,
pp. 49-293) (Sahadevan et al., 2007) (Kwabi-Addo et al., 2004).
Several studyes show the presence of FGFs and of their receptors, FGF-Rs, both
in human breast tumour lines (in particular MCF7) and in tumour biopsies. These
factors appear to be responsible, in this pathological condition, for the appearance
of the very aggressive phenotype and induce a strong metastasization. Thus, a
compound which has FGF-R receptor antagonist activity, such as the compounds
of formula I, may represent a therapy of choice in these pathological conditions
(Vercoutter-Edouart A-S, Czeszak X, Crepin M, Lemoine J, Boilly B, Le Bourhis X
et al., Exp.Cell Res., (2001 ) , Vol. 262, pp. 59-68) (Schwertfeger, 2009).
Cancerous melanomas are tumours which induce metastases with a high
frequency and which are very resistant to the various chemotherapy treatments.
The angiogenesis processes play a predominant role in the progression of a
cancerous melanoma. Furthermore, it has been shown that the probability of the
occurrence of metastases increases very greatly with the increase in the
vascularization of the primary tumour. Melanoma cells produce and secrete various
angiogenic factors, including a-FGF and b-FGF. Moreover, it has been shown that
inhibition of the cellular effect of these two factors by means of the soluble FGF-R1
receptor blocks melanoma tumour cell proliferation and survival in vitro and blocks
tumour progression in vivo. Thus, a compound which has an FGF receptor
antagonist activity, such as the compounds of the present invention, may represent
a therapy of choice in these pathological conditions (Rofstad EK, Halsor EF.,
Cancer Res., (2000); Yayon A, Ma Y-S, Safran M, Klagsbrun M, Halaban R.,
Oncogene, (1997), Vol. 14, pp. 2999-3009).
Glyoma cells produce a-FGF and b-FGF in vitro and in vivo, and have various FGF
receptors at their surface. This therefore suggests that these two factors play a
pivotal role, by means of an autocrine and paracrine effect, in the progression of
this type of tumour. Furthermore, like most solid tumours, the progression of
gliomas and their ability to induce metastases is highly dependent on the
angiogenic processes in the primary tumour. It has also been shown that FGF-R1
receptor antisenses block human astrocytoma proliferation. In addition,
naphthalenesulphonate derivatives are described for inhibiting the cellular effects
of a-FGF and b-FGF in vitro and the angiogenesis induced by these growth factors
in vivo. An intracerebral injection of these compounds induces a very significant
increase in apoptosis and a considerable decrease in angiogenesis, reflected by a
considerable regression of gliomas in rats. Thus, a compound which has an a-FGF
antagonist and/or b-FGF antagonist and/or FGF receptor antagonist activity, such
as the compounds of the present invention, may represent a therapy of choice in
these pathological conditions (Yamada SM, Yamaguchi F, Brown R, Berger MS,
Morrison RS, Glia , (1999), Vol. 76, pp. 28-66; Auguste P, Gursel DB, Lemiere S,
Reimers D, Cuevas P, Carceller F et al., Cancer Res., (2001 ) , Vol. 26, pp. 61-1717)
(Loilome et al., 2008).
Active angiogenesis is also described for hepatocarcinomas or hepatocellular
carcinoma (HCC). In vivo, tumour progression in HCCs requires a considerable
supply of oxygen and nutrients. Hepatocarcinomas are tumours which are typically
angiogenic, because a drastic modification is observed with respect to arterial
vascularization, and this results in the acquisition of an uvasive and metastatic
potential (Tanaka et al., 2006). FGFs participate actively in the development of
tumour angiogenesis within HCCs and are frequently associated with the
inflammatory process. They are also overexpressed in the context of chronic
hepatitis and liver sclerosis (Uematsu et al., 2005) and the serum FGF level has
been correlated with the clinicopathological progression of HCCs. Furthermore, the
FGF-R4 receptor, and also FGF-R1 , have been described as participating actively
in HCC tumour genesis (Huang et al., 2006) (Nicholes et al., 2002). The
antagonists of the present invention may therefore be a treatment of choice for
hepatocellular carcinomas or hepatocarcinomas.
In lung cancers of NSCLC (Non-Small Cell Lung Cancer) type, recent studyes
show that b-FGF, FGF-9, FGF-R1 and FGF-R2 are regularly coexpressed in
NSCLC cancer lines and especially in those resistant to anti-EGFR treatment such
as gefitinib. These expressions are connected to the capacity for proliferation via
autocrine cell signalling and anchorage-independent growth of tumours of NSCLC
type and mainly the type insensitive to treatment with gefitinib (Marek et al., 2008).
Furthermore, b-FGF has been suggested as playing an important role in the
survival of NSCLC cells during treatment by chemotherapy, by inducing the
overexpression of the anti-apoptotic proteins BCL-2, BCL-X, XIAP or BIRC3 (Pardo
et al., 2002, 2003 and 2006). Thus, an FGF receptor antagonist, such as those of
the present invention, may represent a therapy of choice for lung cancers of
NSCLC type, alone or in combination with EGF receptor inhibitors or
chemotherapies.
In approximately 10% of gastric cancers, this FGF-R2 gene amplification is
observed. This amplification is associated with a poor vital prognosis for cancers of
diffuse type. The proliferation of tumour cells may be ligand-independent or
dependent on paracrine activation by FGF-7 (Turner et al., 2010). The antagonists
of the present invention may therefore be a treatment of choice for gastric cancers.
More recently, the potential role of pro-angiogenic agents in leukaemias and
lymphomas has been documented. Indeed, in general, it has been reported that
cell clones in these pathological conditions can be destroyed naturally by the
immune system or switch into an angiogenic phenotype which promotes their
survival and then their proliferation. This change in phenotype is induced by an
overexpression of angiogenic factors, in particular by macrophages, and/or a
mobilization of these factors from the extracellular matrix (Thomas DA, Giles FJ,
Cortes J, Albitar M, Kantarjian HM., Acta Haematol, (2001 ) , Vol. 207, pp. 106-1 90).
Among the angiogenic factors, b-FGF has been detected in many lymphoblastic
and hematopoietic tumour cell lines. FGF receptors are also present on the
majority of these lines, suggesting a possible autocrine cellular effect of a-FGF and
b-FGF inducing proliferation of these cells. Moreover, it has been reported that
bone marrow angiogenesis via paracrine effects is correlated with the progression
of some of these pathological conditions.
More particularly, it has been shown, in CLL (chronic lymphocytic leukaemia) cells,
that b-FGF induces an increase in anti-apoptotic protein (Bcl2) expression,
resulting in an increase in the survival of these cells, and that it therefore
participates considerably in their cancerization. In addition, the b-FGF levels
measured in these cells are very well-correlated with the stage of clinical
advancement of the disease and the resistance to the chemotherapy applied in this
pathological condition (fludarabine). Thus, a compound which has an FGF receptor
antagonist activity, such as the compounds of the present invention, may represent
a therapy of choice, either alone or in combination with fludarabine or other
products that are active in this pathological condition (Thomas DA, Giles FJ, Cortes
J, Albitar M, Kantarjian HM., Acta Haematol, (2001 ) , Vol. 207, pp. 106-190;
Gabrilove JL, Oncologist, (2001 ) , Vol. 6, pp. 4-7).
Furthermore, it has been shown in many recent studyes that FGFs and FGF-Rs
participate actively in the resistance of tumour and/or endothelial cells to
treatments by chemotherapy, radiotherapy or else anti-VEGF treatments. These
resistances use various cell mechanisms, such as protection against apoptosis by
positive regulation of the Bcl-xl protein by FGF-R4 in the case of breast cancer
resistance to doxorubicin (Roidl et al., 2009) or by FGF-2 production in the case of
resistance of bladder tumours to cisplatin (Miyake et al., 1998), by activation of the
Pi3K/AKT pathway by the FGF2/FGF-R1 couple in the case of resistance of acute
myeloidal leukaemia cells to cytarabin (Karajannis et al., 2006), by stimulation of
the RAS/MAP-K, PI3-K and mTOR pathway by FGF-1 for certain breast tumours
resistant to anti-oestrogen treatments (Manuvakhova et al., 2006). The
FGFs/FGF-Rs couple is also involved in resistance to anti-VEGF treatments in the
case of pancreatic carcinomas (Casanovas et al., 2005) or of glioblastomas
(Batchelor et al., 2007) or else in radiotherapy resistance phenomena (Gu et al.,
2004; Moyal et al., 2009). Thus, the compounds of the present invention could be
combined with existing therapies in order to limit the appearance of resistance
phenomena.
Furthermore, tumour invasion, which is one of the marks of malignancy, consists of
the translocation of tumour cells from the initial neoplastic locus to the surrounding
host tissues, allowing the tumour to penetrate into the vascular endothelium in
order to circulate and to form metastatic loci remote from the primary tumour. An
increasing number of recent articles suggest that changes in the tissue architecture
at the peripherary of the tumour appear to be responsible for the epithelialmesenchymal
transition (EMT) process. EMT is a cell process by which epithelial
cells modulate their phenotype and acquire mesenchymal cell properties through
the disruption of intercellular adhesion and an increase in cell motility, thus playing
an essential role in tumour progression by conferring an invasive and metastatic
phenotype on carcinomas. Growth factors such as FGFs participate in this cell
process by virtue of their stimulatory activity on cell migration and invasion, but
also, as regards FGF receptors, by virtue of their ability to interact with cadherins,
thus facilitating tumour cell migration (Cowin et al., 2005). The FGF-R antagonists
described herein may be used for preventing these metastatic phases in a large
number of cancers.
A correlation exists between the bone marrow angiogenesis process and
"extramedullar disease" in CML (chronic myelomonocytic leukaemia). Various
studyes demonstrate that the inhibition of angiogenesis, in particular by means of a
compound which has an FGF receptor antagonist activity, could represent a
therapy of choice in this pathological condition.
The proliferation and migration of vascular smooth muscle cells contributes to
intimal hypertrophy of the arteries and thus plays a predominant role in
atherosclerosis and in restenosis after angioplasty and endoarterectomy.
In vivo studyes show, after lesion of the carotid "balloon injury", a local production
of a-FGF and of b-FGF. In this same model, an anti-FGF2 neutralizing antibody
inhibits vascular smooth muscle cell proliferation and thus decreases intimal
hypertrophy.
A chimeric protein consisting of FGF2 linked to a molecule such as saporin inhibits
vascular smooth muscle cell proliferation in vitro and intimal hypertrophy in vivo
(Epstein CE, Siegall CB, Biro S, Fu YM, FitzGerald D., Circulation, (1991 ) , Vol. 87,
pp. 84-778; Waltenberger J., Circulation, (1997), pp. 96-4083).
Thus, FGF receptor antagonists, such as the compounds of the present invention,
represent a therapy of choice, either alone or in combination with compounds that
are antagonists of other growth factors involved in these pathological conditions,
such as PDGF, in the treatment of pathological conditions related to vascular
smooth muscle cell proliferation, such as atherosclerosis, post-angioplasty
restenosis or restenosis following the implantation of endovascular prostheses
(stents) or during aortocoronary bypasses.
Cardiac hypertrophy occurs in response to a stress of the ventricular wall induced
by an overload in terms of pressure or volume. This overload can be the
consequence of numerous physiopathological states, such as hypertension, AC
(aortic coarctation), myocardial infarction, and various vascular disorders. The
consequences of this pathological condition are morphological, molecular and
functional changes such as cardiac myocyte hypertrophy, matrix protein
accumulation and foetal gene reexpression. b-FGF is implicated in this pathological
condition. Specifically, the addition of b-FGF to cultures of newborn rat
cardiomyocytes modifies the profile of the genes corresponding to the contractile
proteins, resulting in a foetal-type gene profile. In a complementary manner, adult
rat myocytes show a hypertrophic response under the effect of b-FGF, this
response being blocked by anti-b-FGF neutralizing antibodyes. Experiments
carried out in vivo in b-FGF-knock-out transgenic mice show that b-FGF is the
major factor stimulating cardiac myocyte hypertrophy in this pathological condition
(Schultz JeJ, Witt SA, Nieman ML, Reiser PJ, Engle SJ, Zhou M et al., J.Clin.
Invest., (1999), Vol. 19, pp. 104-709). Thus, a compound, such as the compounds
of the present invention, which has an FGF receptor antagonist activity represents
a therapy of choice in the treatment of heart failure and any other pathological
condition associated with cardiac tissue degeneration. This treatment could be
carried out alone or in combination with the common treatments (beta-blockers,
diuretics, angiotensic antagonists, antiarrythmics, anti-calcium agents,
antithrombotics, etc.).
Vascular disorders due to diabetes are characterized by an impairment of vascular
reactivity and of blood flow, hyperpermeability, an exacerbated proliferative
response and an increase in matrix protein deposits. More specifically, a-FGF and
b-FGF are present in the preretinol membranes of patients having diabetic
retinopathies, in the membranes of the underlying capillaries and in the vitreous
humour of patients suffering from proliferative retinopathies. A soluble FGF
receptor capable of binding both a-FGF and b-FGF is developed in diabetesrelated
vascular disorders (Tilton RG, Dixon RAF, Brock TA., Exp. Opin. Invest.
Drugs, (1997), Vol. 84, pp. 6-1671 ) . Thus, a compound, such as the compounds of
formula I, which has an FGF receptor antagonist activity represents a therapy of
choice, either alone or in combination with compounds that are antagonists of other
growth factors involved in these pathological conditions, such as VEGF.
Fibrosis is the abnormal formation of scar tissues following a tissue lesion, and
results in a chronic and progressive impairment of the affected organs that can
result in serious dysfunction of the affected organ. It can occur in all tissues, but is
mainly prevalent in organs exposed to chemical or biological attacks, such as the
lungs, the skin, the kidneys, the digestive tract, the liver, etc. FGFs participate in
this cell process by promoting the production and accumulation of extracellular
matrices by fibroblasts, the proliferation of said fibroblasts and infiltration into many
organs such as the kidneys or the lungs (Khalil et al., 2005) (Strutz et al., 2003).
Antagonists of the activity of these FGFs, such as the molecules of the present
invention, may be used alone or in combination in the treatment of fibrosis.
Rheumatoid arthritis (RA) is a chronic disease with an unknown etiology. Although
it affects many organs, the most serious form of RA is a progressive synovial
inflammation of the joints resulting in destruction. Angiogenesis appears to
considerably affect the progression of this pathological condition. Thus, a-FGF and
b-FGF have been detected in the synovial tissue and in the joint fluid of patients
suffering from RA, indicating that this growth factor is involved in the initiation
and/or the progression of this pathological condition. In models of AIA (adjuvantinduced
model of arthritis) in rats, it has been shown that the overexpression of b-
FGF increases the severity of the disease, whereas an anti-b-FGF neutralizing
antibody blocks the progression of RA (Malemud, 2007) (Yamashita A, Yonemitsu
Y, Okano S, Nakagawa K, Nakashima Y, Irisa T et al., J.Immunol., (2002), Vol. 57,
pp. 168-450 ; Manabe N, Oda H, Nakamura K, Kuga Y, Uchida S, Kawaguchi H,
Rheumatol, (1999), Vol. 20, pp. 38-714). Thus, the compounds according to the
invention represent a therapy of choice in this pathological condition.
Recent scientific articles document the involvement of b-FGF in neuropathic pain.
Specifically, an increase in astroglial b-FGF production is observed in astrocytes
following a spinal cord lesion (Madiai et al., 2003). This b-FGF contributes to
neuropathic pain due to contact or allodynia. Treatment using an anti-FGF2
neutralizing antibody reduces this mechanical allodynia (Madiai et al., 2005). The
antagonists of the present invention are treatments of choice for pain by inhibiting
the effect of FGF-2 on these receptors.
It has also been described that the level of growth factors having a pro-angiogenic
activity, such as FGF-1 and -2, are greatly increased in the synovial fluid of patients
suffering from osteoarthritis. In this type of pathological condition, a considerable
modification is recorded in the balance between the pro- and anti-angiogenic
factors inducing the formation of new vessels, and consequently, the
vascularization of nonvascularized structures, such as joint cartilages or
intervertebral discs. Thus, angiogenesis represents a key factor in bone formation
(osteophytes), thus contributing to the progression of the disease. Additionally, the
inervation of the new vessels can also contribute to the chronic pain associated
with this pathological condition (Walsh DA., Curr Opin Rheumatol. 2004
Sep;16(5):609-15). Thus, the compounds according to the invention represent a
therapy of choice in this pathological condition.
oo
9
IBD (inflammatory bowel disease) includes two forms of chronic inflammatory
diseases of the intestine: UC (ulcerative colitis) and Crohn's disease (CD). IBD is
characterized by an immune dysfunction reflected by an inappropriate production
of inflammatory cytokines inducing the establishment of a local microvascular
system. This angiogenesis of inflammatory origin results in an intestinal ischemia
induced by vasoconstriction. High circulating and local levels of b-FGF have been
measured in patients suffering from these pathological conditions (Kanazawa S,
Tsunoda T, Onuma E, Majima T, Kagiyama M, Kkuchi K., American Journal of
Gastroenterology, (2001 ) , Vol. 28, pp 96-822 ; Thorn M, Raab Y, Larsson A, Gerdin
B, Hallgren R., Scandinavian Journal of Gastroenterology, (2000), Vol. 12, pp. 35-
408). The compounds of the invention which exhibit a high anti-angiogenic activity
in an inflammatory angiogenesis model represent a therapy of choice in these
pathological conditions.
Another disease which has a considerable inflammatory component and for which
a strong implication of FGFs and FGF-Rs is described is benign prostatic
hyperplasia (BPH). BPH is a disease related to ageing which is characterized by
hyperplasia of the glandular tissues and of the stroma around the urethra until it
becomes obstructed. At the cellular level, this pathological condition involves
hyperplasia of the basal cells, an increase in the stromal mass, amplified matrix
deposit or else a reduction in tissue elasticity (Untergasser et al., 2005). FGFs
participate in the development of this disease by stimulating the proliferation of the
prostatic stroma and epithelial cells, and in particular FGF-7 or KGF, but also FGF-
2 or FGF-17 (Wang 2008 , Boget 2001 , Giri 2001 ) . In addition, FGFs promote the
transdifferentiation step by modifying epithelial cell/stromal cell interactions, in
combination with TGF-b (Untergasser 2005). Finally, certain receptors, such as
FGF-R1 , are overexpressed in BPH, promoting induction of the pathological
condition and potentiating the paracrine effects of FGF-2 (Boget 2001). An
antagonist of the effect of these FGFs is therefore a treatment of choice for benign
prostatic hyperplasia.
Psoriasis is a chronic skin disease caused by a hyperproliferation of the epidermal
keratinocytes, while clear cell acanthoma (CCA) is a benign neoplasm of the
epidermis which also involves an abnormal proliferation of keratinocytes. These
two skin diseases have similar histological characteristics despite different
underlying causes: a thickening of the epidermis, inflammatory infiltrations of
lymphocytes and neutrophils, dilation and tortuosity of the papillary capillaries. In
both cases, KGF or FGF-7 plays a predominant role in the development of the
pathological condition (Kovacs et al., 2006) (Finch et al., 1997). The use of the
antagonists of the present invention may make it possible to slow down the
development of such skin diseases.
FGF-R1 , -R2 and -R3 receptors are involved in chronogenesis and osteogenesis
processes. Mutations resulting in the expression of FGF-Rs that are always
activated have been connected to a large number of human genetic diseases
reflected by malformations of the skeleton, such as Pfeiffer syndrome, Crouzon
syndrome, Apert syndrome, Jackson-Weiss syndrome and Bear-Stevenson cutis
gyrate syndrome. Some of these mutations affect more particularly the FGF-R3
receptor, resulting in particular in achondroplasias (ACH), hyperchondroplasias
(HCH) and TD (thanatophoric dysplasia); ACH being the most common form of
dwarfism. From a biochemical point of view, the sustained activation of these
receptors takes place via a dimerization of the receptor in the absence of ligand
(Chen L , Adar R. , Yang X. Monsonego E.O., L I C , Hauschka P.V, Yagon A. and
Deng C.X., (1999), The Journ. Of Clin. Invest, Vol. 104, n° 11, pp. 1517-1525).
Thus, the compounds of the invention which exhibit an FGF antagonist or FGF
receptor antagonist activity and which inhibit FGF-R-dependent intracellular
signalling represent a therapy of choice in these pathological conditions.
It is also known that adipose tissue is one of the rare tissues that, in adults, can
develop or regress. This tissue is highly vascularized and a very dense network of
microvessels surrounds each adipocyte. These observations have resulted in the
testing of the effect of anti-angiogenic agents on adipose tissue development in
adults. Thus, it appears that, in pharmacological models in ob/ob mice, the
inhibition of angiogenesis is reflected by significant weight loss in the mice
(Rupnick MA et al, (2002), PNAS, Vol. 99, n°16, pp. 10730-10735). Furthermore,
FGFs appear to be key regulators of adipogenesis in humans (Hutley et al., 2004).
Thus, an FGF receptor antagonist compound which has a powerful anti-angiogenic
activity may represent a therapy of choice in obesity-related pathological
conditions.
By virtue of their low toxicity and their pharmacological and biological properties,
the compounds of the present invention are of use in the treatment and prevention
of any carcinoma which has a high degree of vascularization, such as lung, breast,
prostate, oesophageal, pancreatic, liver, colon or kidney carcinomas, or which
induces metastases, such as colon, breast, liver or stomach carcinomas, or
melanomas, or which is sensitive to a-FGF or to b-FGF in an autocrine manner or
else in pathological conditions of glioma type, lymphomas and leukaemias or,
finally, in any therapy-resistance phenomenon. These compounds represent a
therapy of choice, either alone or in combination with a chemotherapy, a
radiotherapy or any other suitable treatment. The compounds according to the
invention are also of use in the treatment and prevention of cardiovascular
diseases, such as atherosclerosis, or restenosis post-angioplasty, in the treatment
of diseases related to complications occurring following the implantation of
endovascular stents and/or aortocoronary bypasses or other vascular grafts, and
cardiac hypertrophy or vascular complications of diabetes, such as diabetic
retinopathies. The compounds according to the invention are also of use in the
treatment and prevention of chronic inflammatory diseases such as rheumatoid
arthritis, IBD or benign prostatic hyperplasia. Finally, the compounds according to
the invention can be used in the treatment and prevention of achondroplasias
(ACH), hypochondroplasias (HCH) and TD (thanatophoric dysplasia), as also in the
treatment of obesity.
The products according to the invention are also of use in the treatment and
prevention of macular degeneration, in particular age-related macular degeneration
(or ARMD). A major characteristic of the loss of sight in adults is the
neovascularization and the subsequent haemorrhages which cause considerable
functional disorders in the eye and which are reflected by early blindness.
Recently, studying the mechanisms involved in ocular neovascularization
phenomena has made it possible to demonstrate the involvement of proangiogenic
factors in these pathological conditions. By using a laser-induced
choroidial neoangiogenesis model, it has been possible to confirm that the
products according to the invention also make it possible to modulate
neovascularization of the choroid.
Moreover, the products of the invention can be used in the treatment or prevention
of thrombopenias due in particular to anticancer chemotherapy. It has in fact been
demonstrated that the products of the invention can improve circulating platelet
levels during chemotherapy.
Finally, the products according to the invention are of use in the treatment and
prevention of skin diseases, such as psoriasis or clear cell acanthoma, in
combating the progression of liver, kidney or lung fibrosis, and also in the treatment
of neuropathic pain.
A subject of the invention is, according to another of its aspects, medicaments
which comprise a compound of formula (I), or an addition salt thereof with a
pharmaceutically acceptable acid or base, or else a hydrate or a solvate of the
compound of formula (I).
According to another of its aspects, the present invention relates to pharmaceutical
compositions comprising, as active ingredyent, a compound of formula (I)
according to the invention. These pharmaceutical compositions contain an effective
dose of at least one compound according to the invention, or a pharmaceutically
acceptable salt or a hydrate or solvate of said compound, and also at least one
pharmaceutically acceptable excipient. Said excipients are selected, according to
the pharmaceutical form and the method of administration desired, from the usual
excipients which are known to those skilled in the art.
In the pharmaceutical compositions of the present invention for oral, sublingual,
subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal,
transdermal or rectal administration, the active ingredyent of formula (I) above, or
optional salt, solvate or hydrate thereof, can be administered in unit administration
form, as a mixture with conventional pharmaceutical excipients, to animals and to
human beings for the prophylaxis or the treatment of the disorders or the diseases
mentioned above.
The suitable unit administration forms comprise forms for oral administration, such
as tablets, soft or hard gel capsules, powders, granules and oral solutions or
suspensions, sublingual, buccal, intratracheal, intraocular or intranasal
administration forms, forms for administration by inhalation, topical, transdermal,
subcutaneous, intramuscular or intravenous administration forms, rectal
administration forms, and implants. For topical application, the compounds
according to the invention can be used in creams, gels, ointments or lotions.
The pharmaceutical compositions according to the present invention are preferably
administered orally.
By way of example, a unit administration form of a compound according to the
invention in tablet form may comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Sodium croscaramellose 6.0 mg
Maize starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
The present invention also relates to a pharmaceutical composition as defined
above, as a medicament.
A subject of the present invention is also the use of a compound of formula (I), as
defined above, for use thereof in the treatment and prevention of diseases
requiring a modulation of FGFs.
A subject of the present invention is also the use of a compound of formula (I), as
defined above, for use thereof in the treatment and prevention of cancers, in
particular carcinomas which have a high degree of vascularization, such as lung,
breast, prostate, pancreatic, colon, kidney and oesophageal carcinomas, cancers
which induce metastases, such as colon cancer, liver cancer and stomach cancer,
melanomas, gliomas, lymphomas and leukaemias.
A compound of formula (I) according to the present invention can be administered
alone or in combination with one or more compound(s) which has (have) an antiangiogenic
activity or with one or more cytotoxic compound(s) (chemotherapy), or
else in combination with a radiation treatment. Thus, a subject of the present
invention is also the use of a compound of formula (I), as defined above, in
combination with one or more anticancer active ingredyent(s) and/or with
radiotherapy.
A subject of the present invention is also the use of a compound of formula (I), as
defined above, in the treatment and prevention of cardiovascular diseases, such as
atherosclerosis or post-angioplasty restenosis, diseases related to complications
occurring following the implantation of endovascular stents and/or aortocoronary
bypasses or other vascular grafts, cardiac hypertrophy, or vascular complications
of diabetes, such as diabetic retinopathies.
A subject of the present invention is also the use of a compound of formula (I), as
defined above, in the treatment or prevention of chronic inflammatory diseases
such as rheumatoid arthritis or IBD.
A subject of the present invention is also the use of a compound of formula (I), as
defined above, in the treatment or prevention of osteoarthritis, achondroplasias
(ACH), hypochondroplasias (HCH) and TD (thanatophoric dysplasia).
A subject of the present invention is also the use of a compound of formula (I), as
defined above, in the treatment or prevention of obesity.
A subject of the present invention is also the use of a compound of formula (I), as
defined above, in the treatment or prevention of macular degeneration, such as
age-related macular degeneration (ARMD).
The compositions according to the invention, for oral administration, contain
recommended doses of 0.01 to 700 mg. There may be particular cases where
higher or lower dosages are appropriate; such dosages do not depart from the
context of the invention. According to the usual practice, the dosage appropriate
for each patient is determined by the physician according to the method of
administration and the age, weight and response of the patient, and also according
to the degree of progression of the disease.
According to another of its aspects, the present invention also relates to a method
for treating the pathological conditions indicated above, which comprises the
administration, to a patient, of an effective dose of a compound according to the
invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
CLAIMS
1. Compound of formula (I):
in which:
- R represents
. a hydrogen or halogen atom,
. an alkyl group optionally substituted with -COOR 5,
. an alkenyl group optionally substituted with -COOR 5,
. a -COOR5 or -CONR5R6 group,
. an -NR5COR6 or -NR5-S0 2R6 group,
or
. an aryl group, in particular phenyl, or a heteroaryl group, said aryl or
heteroaryl group being optionally substituted with one or more groups selected
from: halogen atoms, alkyl groups, cycloalkyl groups, -COOR 5, -CF3, -OCF3, -CN, -
C(NH2)NOH, -OR 5, -O-Alk-COORs, -0-Alk-NR 5R6, -0-Alk-NR 7R8, -Alk-OR5, -
Alk-COOR 5, -CONR5R6, -CO-NR5-OR6, -CO-NR5-S0 2R7, -CONR5-Alk-NR5R6, -
CONR5-Alk-NR7R8, -Alk-NR5R6, -NR5R6, -NC(0)N(CH 3)2, -CO-Alk, -CO(OAIk) OH,
COO-Alk-NR5R6, COO-Alk-NR7R8 and 5-membered heteroaryl groups, said
heteroaryl groups being optionally substituted with one or more groups selected
from halogen atoms and alkyl, -CF3, -CN, -COOR5, -Alk-OR5, -Alk-COOR5,
-CONR5R6, -CONR7R8, -CO-NR5-OR6, -CO-NR5-S0 2R6, -NR 5R6 and -Alk-NR5R6
groups, or with a hydroxyl group or with an oxygen atom,
n is an integer ranging from 1 to 3,
- R2 and R3 together form, with the carbon atoms of the phenyl nucleus to
which they are attached, a 6-membered nitrogenous heterocycle corresponding to
one of formula (A), (B) or (C) below:
in which the wavy lines represent the phenyl nucleus to which R2 and R3 are
attached and:
. Ra represents a hydrogen atom or an alkyl, haloalkyl, -Alk-CF3,
-Alk-COORs, -Alk'-COORs , -Alk-CONR5R6, -Alk'-CONR 5R6, -Alk-CONR R8, -Alk-
NR5R6, -AlkCONR 5-OR6, -Alk-NR R8, -Alk-cycloalkyl, -Alk-0-R 5, -Alk-S-R5, -Alk-CN,
-OR5, -OAlkCOORs, -NR5R6, -NR5-COOR6, -Alk -aryl, -Alk -O-aryl, -Alk -O-heteroaryl,
-Alk-heteroaryl or heteroaryl group, where the aryl or heteroaryl group is optionally
substituted with one or more halogen atoms and/or alkyl, cycloalkyl, -CF3, -OCF3,
-O-R5 or -S-R5 groups,
. Ra' represents a hydrogen atom or a linear, branched, cyclic or
partially cyclic alkyl group, or an -Alk-OR5, -Alk-NR5R6 or -Alk-NR7R8 group, Ra'
being optionally substituted with one or more halogen atoms,
. Rb represents a hydrogen atom or an alkyl or -Alk-COOR 5 group,
. Rb' represents a hydrogen atom or an alkyl, haloalkyl, cycloalkyl,
phenyl or -Alk-COOR 5 group,
. Rc represents a hydrogen atom or an alkyl, -CN, -COOR5,
-CO-NR5R6, -CONR7R8 -CO-NR5-Alk-NR5R6, -CONR5-Alk-OR5, -CONR5S0 2R5, -Alkaryl
or -Alk-heteroaryl group, where the aryl or heteroaryl group is optionally
substituted with one or more halogen atoms and/or alkyl, cycloalkyl, -CF3, -OCF3,
-O-alkyl or -S-alkyl groups,
. RC' represents a hydrogen atom or an alkyl group,
. RC" represents a hydrogen atom or an alkyl, alkenyl, haloalkyl,
cycloalkyl, -Alk-NR5R6, -Alk-NR7R8, -Alk-OR5 or -Alk-SR5 group,
- R4, located on position 6, 7 or 8 of the imidazopyridine nucleus,
represents:
. a hydrogen atom,
. a -COOR5 group,
. a -CO-NR5-Alk-NR5R6 group,
. a -CO-NR5-Alk-NR7R8 group, or
. a -CO-NR5-Alk-OR6 group,
- R5 and R6, which may be identical or different, represent hydrogen atoms,
haloalkyl groups or alkyl groups, cycloalkyl groups or an Ms group,
- R7 and R8, which may be identical or different, represent hydrogen atoms
or alkyl or phenyl groups, or else R7 and R8 together form a 3- to 8-membered
saturated ring which can optionally contain a heteroatom,
- Alk represents a linear or branched alkylene chain, and
- Alk' represents a linear, branched, cyclic or partially cyclic alkylene chain,
optionally in the form of a pharmaceutically acceptable salt thereof.
2. Compound according to Claim 1, in which R represents:
. a hydrogen or halogen atom,
. an alkyl group which is unsubstituted or substituted with -COOR5,
. an alkenyl group which is unsubstituted or substituted with -COOR5,
. a -COOR5 group,
. a -CONR5R6 group,
. an -NR5-SO2R6 group, or
. a phenyl group optionally substituted with one or two groups selected
• halogen atoms;
• alkyl groups optionally substituted with -COOR5;
• -CN, -C(NH2)NOH, -COORs, -CONR5R6, -CO-NR5-OR6, -
CO-NR5-S0 2R6, -COAlk, -CO(OAIk) OH, -OR5, -OCF3 , -
0-Alk-COOR 5, -Alk-OR5, -NR5R6 or -NC(0)N(CH 3)2
groups,
• 5-membered heteroaryls optionally substituted with an
alkyl group and/or a hydroxyl group or an oxygen atom,
in which R5 and R6, which may be identical or different, represent hydrogen
atoms, or alkyl groups optionally substituted with an -NR 7R8 group,
R7 represents a hydrogen atom, an alkyl group containing 1 or 2 carbon
atoms or a phenyl group, n is an integer ranging from 1 to 3, or
. a heteroaryl group which is optionally condensed and/or optionally
substituted with one or two groups selected from alkyl groups, OR5, -COOR5, -
NR5R6 and cycloalkyi groups, and an oxygen atom, in which R5 and R6, which may
be identical or different, represent hydrogen atoms or alkyl groups containing 1 or 2
carbon atoms,
optionally in the form of a pharmaceutically acceptable salt thereof.
3. Compound according to Claim 1, in which R2 and R3 together form,
with the carbon atoms of the phenyl nucleus to which they are attached, a
6-membered nitrogenous heterocycle corresponding to either of formulae (A) and
(B) as defined in Claim 1, optionally in the form of a pharmaceutically acceptable
salt thereof.
4. Compound according to Claim 1, in which R2 and R3 together form,
with the carbon atoms of the phenyl nucleus to which they are attached, a
6-membered nitrogenous heterocycle corresponding to formula (A) as defined in
Claim 1, optionally in the form of a pharmaceutically acceptable salt thereof.
5. Compound according to any one of the preceding claims, in which
formula (A) or (B) is such that:
. Ra represents a hydrogen atom or an alkyl group, optionally substituted
with one or more halogens; -AlkCONR5R6; haloalkyl; -CH2-COOR5; -Alk-heteroaryl,
-Alk-O-phenyl or -Alk-phenyl, where the phenyl group is optionally substituted with
one or two alkyl groups and/or OR5 and/or halogen atoms; -Alk-cycloalkyl,
. Ra' represents a hydrogen atom or a linear, branched, cyclic or partially
cyclic alkyl group, or a -CH2-OR5 or -Alk-NR5R6 group,
. Rb represents a hydrogen atom or an alkyl group,
. Rb' represents a hydrogen atom or an alkyl, phenyl or -CH2-COOR5 group,
in which the alkyl groups contain 1 to 6 carbon atoms, R5 being as described in
Claim 1,
optionally in the form of a pharmaceutically acceptable salt thereof.
6. Compound according to any one of the preceding claims, in which
R4 represents a hydrogen atom or a -COOH, -CO-NH-Alk-NR 7R8 or -CO-NH-Alk-OH
group, or else an alkyl group, preferably containing 1 to 3 carbon atoms, which is
unsubstituted, in which Alk, R7 and R8 are as described in Claim 1.
7. Compound according to one of the preceding claims, selected from
the following compounds:
6-(imidazo[1 ,5-a]pyridin-3-ylcarbonyl)-3-propylquinazoline-2,4(1/-/,3/-/)-dione,
3-{3-[(2,4-dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-
a]pyridin-1-yl}benzoic acid,
3-[(2,4-dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-
a]pyridine-6-carboxylic acid,
3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazolin-6-
yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzoic acid,
3-{3[(2,4-dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-
a]pyridin-1 -yl}benzamide,
6-({1 -[3-(5-methyl-1 ,3,4-oxadiazol-2-yl)phenyl]imidazo[1 ,5-a]pyridin-3-yl}carbonyl-3-
propylquinazoline-2,4(1 H, 3/-/)-dione,
6-({1 -[3-(3-methyl-1 ,2,4-oxadiazol-5-yl)phenyl]imidazo[1 ,5-a]pyridin-3-yl}carbonyl)-
3-propylquinazoline-2,4(1 H, 3H)-dione,
N-{3-[(2,4-dioxo-3-propyl-1 ,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-
a]pyridin-1-yl}methanesulphonamide,
2-morpholin-4-yl-ethyl 3-(3-{[3-(4-fluorobenzyl)-1 -methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1 -yl)benzoate,
N-[2-(dimethylamino)ethyl]-3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1 ,2,3,4-
tetrahydroquinazolin-6-yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzamide,
3-(3-{[3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazolin-6-
yl]carbonyl}imidazo[1 ,5-a]pyridin-1-yl)benzoic acid,
3-(4-fluorobenzyl)-1 -methyl-6-[(1 -pyridin-3-ylimidazo[1 ,5-a]pyridin-3-
yl)carbonyl]quinazoline-2,4(1 H, 3H)-dione,
3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-
a]pyridin-1-yl}benzoic acid,
3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1 ,5-
a]pyridin-1 -yl}benzamide,
6-(imidazo[1 ,5-a]pyridin-3-ylcarbonyl)quinazolin-4(3/-/)-one,
L/ ,L/,1 ,2-tetramethyl-4-oxo-6-{[1 -(pyridin-3-yl)imidazo[1 ,5-a]pyridin-3-yl]carbonyl}-
1,4-dihydroquinoline-3-carboxamide,
3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1 -propyl-2,4-dioxo-1 ,2,3,4-tetrahydroquinazolin-
6-yl}carbonyl)imidazo[1 ,5-a]pyridin-1-yl]benzoic acid,
optionally in the form of a pharmaceutically acceptable salt thereof.
8. Process for preparing the compounds of formula (I) according to any
one of Claims 1 to 7 in which R2 and R3 together form a nitrogenous heterocycle of
formula (A) as defined in Claim 1, in which R and Ra' represent hydrogen atoms,
characterized in that:
- the com ound of formula (IV)
(IV)
in which R4 is as defined in Claim 1, is condensed with the compound
of formula (V)
(V)
in order to obtain the com ound of formula (VI)
(VI)
- the compound of formula (VI) is subjected to a basic hydrolysis
reaction in order to obtain the com ound of formula (VII):
(VII)
- a reaction of esterification of the compound of formula (VII) is carried
out so as to obtain the com ound of formula (VIII)
(VIII)
- the compound of formula (VIII) is subjected to the action of
triphosgene so as to form the isocyanate corresponding to the compound (VIII),
and then this isocyanate is condensed with an amine of formula RaNH2, Ra being
as defined in Claim 1, in order to obtain the urea of formula IX),
(IX)
- the urea of formula (IX) is subjected to a cyclization reaction in a basic
medium.
9. Process for preparing a derivative of formula (I) according to one of
Claims 1 to 7 in which R2 and R3 together form a nitrogenous heterocycle of
formula (A) as defined in Claim 1, R is as defined in Claim 1, with the proviso that
R does not represent a hydrogen atom, and R4 is as defined in Claim 1,
characterized in that:
- the com ound of formula (IV)
(IV)
in which R4 is as defined in Claim 1, is condensed with the compound of
formula (V)
(V)
in order to obtain the com ound of formula (VI)
(VI)
- the compound of formula (VI) is subjected to a basic hydrolysis reaction in
order to obtain the com ound of formula (VII):
(VII)
a reaction of esterification of the compound of formula (VII) is carried out
obtain the com ound of formula (VIII)
(VIII)
- the compound of formula (VIII) is subjected to a bromination reaction in
order to obtain the compound of formula (X):
(X)
- the derivative of formula (X) is subjected to the action of triphosgene and
the isocyanate corresponding to the compound of formula (X) is formed, which is
condensed with an amine of formula RaNH2, Ra being as defined in Claim 1, in
order to obtain the urea of formula (XI):
u
- the compound of formula (XI) is subjected to a cyclization reaction in a
basic medium in order to obtain the compound of formula (XII),
- the compound of formula (XII) is subjected to an alkylation reaction in the
presence of a base and of a halogenated derivative RaX, a' being as defined in
Claim 1, in order to obtain the compound of formula (XIII):
- the compound of formula (XIII) is subjected, in the presence of a palladium
catalyst, of a ligand and of a base:
to a reaction with phenylboronic or heteroarylboronic or
phenylboronate ester or heteroarylboronate ester derivatives according to a Suzuki
coupling,
. or else to an imination reaction with benzophenoneimine, followed by
an acid hydrolysis and by an alkylation reaction with a sulphonyl chloride of formula
R6S0 2CI,
. or else to a cyanation reaction with zinc cyanide, followed by an acid
hydrolysis and by an esterification or a peptide coupling with an amine R5R6NH2, R5
and R6 being defined in Claim 1.
10. Process for preparing the compounds of formula (I) according
to any one of Claims 1 to 7 in which R2 and R3 together form a nitrogenous
heterocycle of formula (A) as defined in Claim 1, and in which R and R4 represent
groups as defined in Claim 1, with the proviso that R is not a hydrogen atom,
characterized in that:
- the com ound of formula (IV)
(IV)
in which R4 is as defined in Claim 1, is condensed with the compound
of formula (V)
(V)
in order to obtain the com ound of formula (VI)
(VI)
- the compound of formula (VI) is subjected to a basic hydrolysis
reaction in order to obtain the com ound of formula (VII):
(VII)
- a reaction of esterification of the compound of formula (VII) is carried
out so as to obtain the com ound of formula (VIII):
(VIII)
- the compound of formula (VIII) is subjected to a bromination reaction
in order to obtain the compound of formula (X):
- the compound of formula (X) is subjected, in the presence of a
palladium catalyst, of a ligand and of a base:
. to a reaction with phenylboronic or heteroarylboronic or phenylboronate ester or
heteroarylboronate ester derivatives according to a Suzuki coupling,
. or else to an imination reaction with benzophenoneimine, followed by an acid
hydrolysis and by an alkylation reaction with a sulphonyl chloride of formula
R6S0 2CI,
. or else to a cyanation reaction with zinc chloride, followed by an acid hydrolysis
and by an esterification or a peptide coupling with an amine R5R6NH2, R 5 and R6
being defined in Claim 1,
in order to obtain the compound of formula (XIV):
(XIV)
- the derivative of formula (XIV) is subjected to the action of triphosgene so
as to form the corresponding isocyanate, the isocyanate obtained is condensed
with an amine of formula RaNH2 in order to obtain the urea of formula (XV), Ra
being as defined in Claim 1:
the derivative of formula (XV) is subjected to a cyclization reaction in a
basic medium in order to obtain the compound of formula (XVI):
- the compound of formula (XVI) is subjected to an alkylation reaction in the
presence of a base and of a halogenated derivative RaX, a' being as defined in
Claim 1 and X being a halogen.
11. Process for preparing the compounds of formula (I) according
to Claims 1 to 7 in which R2 and R3 together form a nitrogenous heterocycle of
formula (A) and in which R represents a group as defined in Claim 1, with the
proviso that R does not represent a hydrogen atom, R4 being as defined in claim,
characterized in that:
- the com ound of formula (IV)
(IV)
in which R4 is as defined in Claim 1, is condensed with the compound
of formula (V)
(V)
in order to obtain the com ound of formula (VI)
(VI)
- the compound of formula (VI) is subjected to a basic hydrolysis
reaction in order to obtain the compound of formula (VII):
(VII)
- a reaction of esterification of the compound of formula (VII) is carried
out so as to obtain the com ound of formula (VIII)
(VIII)
- the compound of formula (VIII) is subjected to a bromination reaction
in order to obtain the compound of formula (X):
(X)
- the derivative of formula (X) is subjected to the action of triphosgene
and the isocyanate corresponding to the compound of formula (X) is formed, which
is condensed with an amine of formula RaNH2, Ra being as defined in Claim 1, in
order to obtain the urea of formula (XI):
- the compound of formula (XI) is subjected to a cyclization reaction in a
basic medium in order to obtain the compound of formula (XII)
- the compound of formula (XII) is subjected, in the presence of a palladium
catalyst, of a ligand and of a base,
- to a reaction with phenylboronic or heteroarylboronic or phenylboronate ester or
heteroarylboronate ester derivatives according to a Suzuki coupling,
- or else to an imination reaction with benzophenoneimine, followed by an acid
hydrolysis and by a sulphonylation reaction with a sulphonyl chloride of formula
R6S0 2CI,
- or else to a cyanation reaction with zinc cyanide, followed by an acid hydrolysis
and by an esterification or a peptide coupling with an amine R5R6NH2, R 5 and R6
being as defined in Claim 1, in order to obtain the compound of formula (XVI) in
which R is as defined in Claim 1, with the proviso that R does not represent a
hydrogen atom,
- the compound of formula (XVI) is subjected to an alkylation reaction in the
presence of a base and of a halogenated derivative RaX, Ra' being as defined in
Claim 1 and X being a halogen.
12. Process for preparing the compounds of formula (I) according
to Claims 1 to 7, in which R2 and R3 together form a nitrogenous heterocycle of
formula (B) as defined in Claim 1, R4 being as defined in Claim 1, and R
represents a hydrogen atom, characterized in that:
- the com ound of formula (IV)
(IV)
in which R4 is as defined in Claim 1, is condensed with the compound
of formula (V)
(V)
in order to obtain the com ound of formula (VI)
(VI)
- the compound of formula (VI) is subjected to a basic hydrolysis
reaction in order to obtain the com ound of formula (VII):
(VII)
- a reaction of esterification of the compound of formula (VII) is carried
out so as to obtain the com ound of formula (VIII)
(VIII)
- the compound (VIII) is subjected to a saponification reaction in order
to obtain the com ound (XXIV):
(XXIV)
- the compound (XXIV) is then subjected to a condensation reaction
with an alkyl or aryl anhydride (Rb'CO)20 in order to obtain the compound of
formula (XVII ,
(XVII)
- the compound of formula (XVII) is subjected to a condensation
with an amine RbNH2, b and Rb' being as defined in Claim 1.
13. Process for preparing the compounds of formula (I) according
to Claims 1 to 7, in which R2 and R3 together form a nitrogenous heterocycle of
formula (B) as defined in Claim 1, R4 being as defined in Claim 1 and R being as
defined in Claim 1, with the proviso that R does not represent a hydrogen atom,
characterized in that:
- the com ound of formula (IV)
(IV)
in which R4 is as defined in Claim 1, is condensed with the compound
of formula (V):
(V)
in order to obtain the com ound of formula (VI):
(VI)
- the compound of formula (VI) is subjected to a basic hydrolysis
reaction in order to obtain the compound of formula (VII):
(VII)
- a reaction of esterification of the compound of formula (VII) is carried
out so as to obtain the com ound of formula (VIII):
(VIII)
- the compound of formula (VIII) is subjected to a bromination reaction
in order to obtain the compound of formula (X):
(X)
- the compound of formula (X) is subjected, in the presence of a
palladium catalyst, of a ligand and of a base,
- to a reaction with phenylboronic or heteroarylboronic or
phenylboronate ester or heteroarylboronate ester derivatives according to a Suzuki
coupling,
- or else to an imination reaction with benzophenoneimine, followed by
an acid hydrolysis and by an alkylation reaction with a sulphonyl chloride of formula
R6S0 2CI,
- or else to a cyanation reaction with zinc chloride, followed by an acid
hydrolysis and by an esterification or a peptide coupling with an amine R5R6NH2, R 5
and R6 being defined in Claim 1,
- in order to obtain the compound of formula XIV:
(XIV)
- the compound (XIV) is subjected to a saponification reaction in order
to obtain the compound (XXV):
(XXV)
- the compound (XXV) is then subjected to a condensation reaction with
an alkyl or aryl anhydride (Rb'CO)20 , Rb' being as defined in Claim 1, in order to
obtain the compound of formula (XVI II) :
(XVIII)
- the compound of formula (XVI II) is subjected to a condensation
reaction with an amine RbNH2, b being as defined in Claim 1.
14. Pharmaceutical composition containing, as active ingredient,
a derivative of formula ( I) according to any one of Claims 1 to 7, optionally in
combination with one or more suitable inert excipients.
15. Compound according to any one of Claims 1 to 7, for use
thereof in the treatment and prevention of diseases requiring a modulation of
b-FGFs.
16. Compound according to any one of Claims 1 to 7, for use
thereof in the treatment and prevention of cancers, in particular carcinomas which
have a high degree of vascularization, such as lung, breast, prostate, pancreatic,
colon, kidney and oesophageal carcinomas, cancers which induce metastases,
such as colon cancer, liver cancer and stomach cancer, melanomas, gliomas,
lymphomas, leukaemias, and also thrombopenias.
17. Compound according to Claim 16, for use thereof in combination
with one or more anticancer active ingredient(s) and/or with radiotherapy and/or
with any anti-VEGF treatment.
18. Compound according to any one of Claims 1 to 7, for use thereof
in the treatment and prevention of cardiovascular diseases, such as
atherosclerosis or post-angioplasty restenosis, diseases related to complications
that occur following the implantation of endovascular stents and/or aortocoronary
bypasses or other vascular grafts, cardiac hypertrophy, vascular complications of
diabetes, such as diabetic retinopathies, liver, kidney and lung fibroses,
neuropathic pain, chronic inflammatory diseases, such as rheumatoid arthritis or
IBD, prostatic hyperplasia, psoriasis, clear cell acanthoma, osteoarthritis,
achondroplasias (ACH), hypochondroplasias (HCH), TD (thanatophoric dysplasia),
obesity, and macular degeneration, such as age-related macular degeneration
(ARMD).