-AMINO-3-(IMIDAZOL-2-YL)-PYRIDIN-4-ONE DERIVATIVES AND THEIR USE AS VEGF
RECEPTOR KINASE INHIBITORS
The present invention relates to a 7-phenol or a 7-alkynyl-3-(imidazol-2-yl)-
5 l,8-naphthyridin-4-one derivatives and their possible quinolinone analogs which are
inhibitors of the kinase activity of VEGF receptor, to the preparation thereof and to the
therapeutic use thereof.
VEGF (Vascular Endothelial Growth Factor) family of proteins bind to
10 three structurally related receptor tyrosine kinases known as VEGF-R1 (Flt-1), VEGFR2
(KDR) and VEGF-R3 (Flt-4). All three receptors are vital for the development of
the vasculature during embryogenesis and during tumor-induced angiogenesis. In
addition, VEGFR-3 plays an important role in the development of the lymphatic system
and in tumor induced-lymphangiogenesis
15 Particularly WO 2009/007535 describes substituted 7-alkynyl-4-oxo-l,8-
naphthyridin-3-carboxamides derivatives which are inhibitors of the kinase activity of
VEGF receptor. The compounds of the present invention differ from these compounds
of the prior art at least by the presence of an imidazole ring in position 3 of the bicycle.
Criteria to be taken into account in the development of a drug compound are
20 the exposure of the compound to the tissues and its efficacy. These criteria could be
enhanced by improving at least one of the following items among efficacy, absorption,
distribution, metabolism, excretion and toxicology."
It remains a need to dispose of inhibitors of the kinase activity VEGF
25 receptor with an enhanced activity and this is advantageously achieved with the novel
compounds according to the invention.
A first subject of the invention concerns the compounds corresponding to
the general formula (I) hereinbelow.
30 Another subject of the invention concerns processes for preparing the
compounds of general formula (I).
Another subject of the invention concerns the use of the compounds of
general formula (I) especially in medicaments or in pharmaceutical compositions.
The compounds of the invention correspond to the general formula (I):
(I)
in which:
- W represents a nitrogen atom or a group CH;
- Y represents a group C2-C3-alkynylene, a 1,4-phenylene optionally
substituted with R which represents one or more halogen atom(s);
- Z represents a bond or a group CRiR2;
- Ri and R2, independently of each other, represent a group chosen from a
hydrogen atom, a group Ci-C6-alkyl, a trifluoromethyl group, a group (CH2) OR6, C3-
C7-cycloalkyl, an heteroaryl or an aryl optionally substituted with one or more halogen
atom(s) ;
- Ri and R2 can form together, with the carbon atom which bear them, a
C3-C7-cycloalkyl;
- R3 represents a hydrogen atom;
- R4 represents a group chosen from a group Ci-C6-alkyl, a group
(CH2) OR6, C3-C7-cycloalkyl or Ci-C6-alkyl optionally substituted by a C3-C7-
cycloalkyl;
- R represents a group chosen from a hydrogen atom or a group Ci-C -
alkyl;
- represents a group chosen from a hydrogen atom or a group Ci-C -
alkyl;
- n is equal to 1, 2 or 3.
The compounds of formula (I) may comprise one or more asymmetric
carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers.
These enantiomers and diastereoisomers, and also mixtures thereof, including racemic
mixtures, form part of the invention.
The compounds of formula (I) may exist in the form of bases or of acidaddition
salts. Such addition salts form part of the invention.
These salts may be prepared with pharmaceutically acceptable acids, but the
salts of other acids that are useful, for example, for purifying or isolating the
compounds of formula (I) also form part of the invention.
In the context of the present invention, the following definitions apply:
- a halogen atom: a fluorine, a chlorine, a bromine or an iodine atom;
- Ct-C : a carbon-based chain possibly containing from t to z carbon atoms
in which t and z may take values from 1 to 7; for example, C1-C3 is a carbon-based
chain possibly containing from 1 to 3 carbon atoms;
- an alkyl: a linear or branched saturated aliphatic group. Examples that
may be mentioned include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl,
pentyl, etc.;
- an alkylene: a bivalent radical derived from an alkane, by removal of a
hydrogen atom from each of the two terminal carbon atoms of the chain, optionally
substituted by an alkyl group; for example a group Ci-C 3-alkylene represents a linear or
branched divalent carbon-based chain of 1 to 3 carbon atoms, more particularly a
methylene, ethylene, methylethylene or propylene;
- an alkenylene: a bivalent radical derived from an alkene, by removal of a
hydrogen atom from each of the two terminal carbon atoms of the chain, optionally
substituted by an alkyl or alkenyl group; for example a group C2-C3-alkenylene
represents a linear or branched divalent carbon-based chain of 2 to 3 carbon atoms,
more particularly an ethenylene or a propenylene;
- an alkynylene: a bivalent radical derived from an alkyne, by removal of
a hydrogen atom from each of the two terminal carbon atoms of the chain, optionally
substituted by an alkyl, an alkenyl or an alkynyl group; for example a group C2-C3-
alkynylene represents a linear or branched divalent carbon-based chain of 2 to 3 carbon
atoms, more particularly an ethynylene or a propynylene;
- a cycloalkyl: a saturated or partially unsaturated cyclic alkyl group.
Examples that may be mentioned include the groups cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,
etc.;
- a cycloalkyloxy: a radical -O-cycloalkyl in which the cycloalkyl group is
as defined previously;
- a fluoroalkyl: an alkyl group, one or more hydrogen atoms of which
have been replaced with a fluorine atom;
- an alkoxy: a radical -O-alkyl in which the alkyl group is as defined
previously;
- a fluoroalkoxy: an alkoxy group, one or more hydrogen atoms of which
have been replaced with a fluorine atom;
- a thioalkyl or alkylthio: a radical -S-alkyl in which the alkyl group is as
defined previously;
- an aryl: a monocyclic or bicyclic aromatic group containing between 6
and 10 carbon atoms. Examples of aryl groups that may be mentioned include phenyl
and naphthyl groups;
- an arylene: bivalent group derived from aryl by removal of a hydrogen
atom from two ring carbon atoms. Example of arylene group that may be mentioned
include phenylene group;
- a heterocycle: a saturated or partially unsaturated 5- to 7-membered
monocyclic group, comprising from 1 to 3 heteroatoms chosen from O, S and N.
Examples of heterocycles that may be mentioned include azetidinyl, piperidyl, azepinyl,
morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, dihydrooxazolyl,
dihydrothiazolyl, dihydroimidazolyl, dihydropyrrolyl or tetrahydropyridyl,
[l,3]dioxolyl, [l,3]dioxinyl, dihydro[l,4]dioxinyl, dihydro[l,2]oxazinyl,
dihydro[l,3]oxazinyl, dihydrooxazolyl, dihydroisoxazolyl, dihydro[l,4]oxazinyl,
tetrahydro[l,3]oxazepinyl, tetrahydro[l,4]oxazepinyl, tetrahydro[l,3]diazepinyl and
tetrahydro [1,4] diazepinyl;
- a heteroaryl: a 5- to 12-membered monocyclic or bicyclic aromatic
group containing from 1 to 5 heteroatoms chosen from O, S and N. Examples of
monocyclic heteroaryls that may be mentioned include imidazolyl, pyrazolyl, thiazolyl,
oxazolyl, isothiazolyl, isoxazolyl, furyl, thienyl, oxadiazolyl, thiadiazolyl, triazolyl,
tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl. Examples of
bicyclic heteroaryls that may be mentioned include indolyl, isoindolyl, benzofuryl,
benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothienyl, isobenzofuryl,
isobenzothiazolyl, pyrrolo[2,3-c]pyridyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,2-b]pyridyl,
pyrrolo[3,2-c]pyridyl, pyrrolo[l,2-a]pyridyl, quinolyl, isoquinolyl, cinnolinyl,
quinazolinyl, quinoxalinyl, pyrrolo[l,2-a]imidazolyl, imidazo[l,2-a]pyridyl,
imidazo[l ,2-a]pyridazinyl, imidazo[l ,2-c]pyrimidinyl, imidazo[l ,2-a]pyrimidinyl,
imidazo[l,2-a]pyrazinyl, imidazo[4,5-b]pyrazinyl, imidazo[4,5-b]pyridyl, imidazo[4,5-
c]pyridyl, pyrazolo[2,3-a]pyridyl, pyrazolo[2,3-a]pyrimidinyl, pyrazolo[2,3-
ajpyrazinyl, thiazolo[5,4-b]pyridyl, thiazolo[5,4-c]pyridyl, thiazolo[4,5-c]pyridyl,
thiazolo[4,5-b]pyridyl, oxazolo[5,4-b]pyridyl, oxazolo[5,4-c]pyridyl, oxazolo[4,5-
c]pyridyl, oxazolo[4,5-b]pyridyl, isothiazolo[5,4-b]pyridyl, isothiazolo[5,4-c]pyridyl,
isothiazolo[4,5-c]pyridyl, isothiazolo[4,5-b]pyridyl, isoxazolo[5,4-b]pyridyl,
isoxazolo[5,4-c]pyridyl, isoxazolo[4,5-c]pyridyl and isoxazolo[4,5-b]pyridyl.
- "oxo" means "=0";
- "thio" means "-S-".
In the context of the present invention, the following abbreviations and
empirical formulae are used:
Boc tert-Butyloxycarbony1
Cul Copper (I) iodide
CH2C 12 Dichloromethane
HPLC High performance liquid chromatography
LC/MS Liquid chromatography/mass spectrometry
dba Dibenzylideneacetone
DCM Dichloromethane
DME Dimethoxyethane
DMF Dimethylformamide
DMSO Dimethylsulphoxide
dppf 1,1'-Bis(diphenylphosphino)ferrocene
°C degree Celsius
Et3N Triethylamine
h Hour(s)
HC1 Hydrochloric acid
IR Infrared
MeOH Methanol
min. Minutes
ml Millilitre
MgS0 4 Magnesium sulphate
NaCl Sodium chloride
NH4C 1 Ammonium chloride
NH4OH Ammonium hydroxide
NaHC0 3 Sodium hydrogen carbonate
Na2S0 4 Sodium sulphate
NMR Nuclear Magnetic Resonance
Rt Retention time
SEM [2-(trimethylsilyl)ethoxy]methyl
THF Tetrahydrofuran
TOSMIC Tosylmethylisocyanide
Trityl Triphenylmethyl
Xphos 2-Dicyclohexylphosphino-2 ' ,4 ' ,6
triisopropylbiphenyl
Among the compounds of general formula (I) that are subjects of the
invention, a first subgroup of compounds is constituted by the compounds for which W
represents a nitrogen atom or a group CH.
Among the compounds of general formula (I) that are subjects of the
invention, a second subgroup of compounds is constituted by the compounds for which
W represents a nitrogen atom.
Among the compounds of general formula (I) that are subjects of the
invention, a third subgroup of compounds is constituted by the compounds for which Y
represents a group C2 -C3 -alkynylene, more particularly ethynylene.
Among the compounds of general formula (I) that are subjects of the
invention, a fourth subgroup of compounds is constituted by the compounds for which:
- Z represents a bond, a group CRiR2;
- Ri represents a group chosen from a hydrogen atom, a group Ci-C -
alkyl, a group (CH2) OR6, C3-Cy-cycloalkyl, an aryl or a 5- or 6-membered-heteroaryl
optionally substituted with one or more halogen atom(s);
- R2 represents a group chosen from a hydrogen atom, a group Ci-C 6-alkyl
or a trifluoromethyl;
- represents a group chosen from a hydrogen atom or a group Ci-C -
alkyl;
- n is equal to 1, 2 or 3.
Among the compounds of general formula (I) that are subjects of the
invention, a fifth subgroup of compounds is constituted by the compounds for which:
- Z represents a group CRiR2;
- Ri represents a group chosen from a hydrogen atom, a group Ci-C6-alkyl,
a group (CH2) OR6, C3-Cy-cycloalkyl, an aryl or a 5- or 6-membered-heteroaryl;
- R2 represents a group chosen from a hydrogen atom, a group Ci-C 6-alkyl
or a trifluoromethyl;
- represents a group chosen from a hydrogen atom or a group Ci-C -
alkyl; and
- n is equal to 1, 2 or 3.
When Y represents a group C2-C3-alkynylene, more particularly ethynylene,
then Z represents a group CRiR2,Ri and R2 being as defined above.
Among the compounds of general formula (I) that are subjects of the
invention, a sixth subgroup of compounds is constituted by the compounds for which
R4 represents a group chosen from a group Ci-C6-alkyl, a group (CH2) OR6, C3-C7-
cycloalkyl or Ci-C6-alkyl optionally substituted by a C3-C7-cycloalkyl.
Among the compounds of general formula (I) that are subjects of the
invention, a seventh subgroup of compounds is constituted by the compounds for which
R4 represents a group Ci-C6-alkyl, more particularly an ethyl.
Among the compounds of general formula (I) that are subjects of the
invention, a eighth subgroup of compounds is constituted by the compounds for which
R represents a group chosen from a hydrogen atom or a group Ci-C6-alkyl.
Among the compounds of general formula (I) that are subjects of the
invention, a ninth subgroup of compounds is constituted by the compounds for which
R represents a hydrogen atom.
Among the compounds of general formula (I) that are subjects of the
invention, a tenth subgroup of compounds is constituted by the compounds for which
the definitions ofW, Y, Z, R3, R 4 and R given hereinabove are combined.
Among the compounds of general formula (I) that are subjects of the
invention, a eleventh subgroup of compounds is constituted by the compounds for
which:
- Wrepresents a nitrogen atom or a group CH;
- Y represents a group C2-C3-alkynylene or a 1,4-phenylene optionally
substituted with a halogen atom;
- Z represents a bond, a group CRiR2;
- Ri represents a group chosen from a hydrogen atom, a group Ci-C -
alkyl, a group (CH2) OR6, C3-C7-cycloalkyl, an aryl or a 5- or 6-membered-heteroaryl
optionally substituted with a halogen atom;
- R2 represents a group chosen from a hydrogen atom, a group Ci-C 6-alkyl
or a trifluoromethyl;
- R3 represents a hydrogen atom;
- R4 represents a group chosen from a group Ci-C 6-alkyl, a group
(CH2) OR6, C3-C7-cycloalkyl or Ci-C6-alkyl optionally substituted by a C3-C7-
cycloalkyl;
- R represents a group chosen from a hydrogen atom or a group Ci-C -
alkyl;
- R represents a group chosen from a hydrogen atom or a group Ci-C -
alkyl;
- n is equal to 1, 2 or 3.
Among the compounds of general formula (I) that are subjects of the
invention, a twelfth subgroup of compounds is constituted by the compounds for which:
- W represents a nitrogen atom or a group CH;
- Y represents a group C2-C3-alkynylene;
- Z represents a group CRiR2;
- Ri represents a group chosen from a hydrogen atom, a group Ci-C -
alkyl, a group (CH2) OR6, C3-C7-cycloalkyl, an aryl or a 5- or 6-membered-heteroaryl
optionally substituted with a halogen atom;
- R2 represents a group chosen from a hydrogen atom, a group Ci-C 6-alkyl
or a trifluoromethyl;
- R 3 represents a hydrogen atom;
- R4 represents a group chosen from a group Ci-C 6-alkyl, a group
(CH2) OR6, C3-C7-cycloalkyl or Ci-C6-alkyl optionally substituted by a C3-C7-
cycloalkyl;
- R represents a group chosen from a hydrogen atom or a group Ci-C -
alkyl;
- represents a group chosen from a hydrogen atom or a group Ci-C -
alkyl;
- n is equal to 1, 2 or 3.
Among the compounds of general formula (I) that are subjects of the
invention, a thirteenth subgroup of compounds is constituted by the compounds for
which Ri and R2 form together, with the carbon atom which bear them, a C3-C7-
cycloalkyl.
Of course, each of the subgroups mentioned above may be combined with
one or more of the others subgroups and the corresponding compounds are also subjects
of the invention.
Among the compounds of general formula (I) that are subjects of the
invention, mention may be made especially of the following compounds:
1: 2-Amino- 1-ethyl-7-((3R)-3-hydroxy-4-methoxy-3-methyl-but- 1-ynyl)-3-
(1H-imidazo 1-2-yl)- 1H-[1,8]naphthyridin-4-one
2 : 2-Amino- 1-propyl-7-((3R)-3-hydroxy-4-methoxy-3-methyl-but- 1-ynyl)-
3-(lH-imidazol-2-yl)-lH-[l,8]naphthyridin-4-one
3: 2-Amino-7-(3 ,4-dihydroxy-3 -methyl-but- 1-ynyl)- 1-ethyl-3 -(1Himidazo
1-2-yl)- 1-[1,8]naphthyridin-4-one
4: 2-Amino- 1-ethyl-7-(-3 -hydroxy-3 -pyridin-2-yl-but- 1-ynyl)-3 -(1Himidazo
1-2-yl)- 1-[1,8]naphthyridin-4-one
5: 2-Amino- 1-ethyl-7-[(3R)-3-hydroxy-4-methoxy-3-methylbut- 1-yn- 1-yl]-
3-(4-methyl- 1H-imidazo 1-2-yl)- 1,8-naphthyridin-4( 1H)-one
6: 2-Amino- 1-(cyclopropylmethyl)-7-(3 -hydroxypent- 1-yn- 1-yl)-3 -(1Himidazo
1-2-yl)- 1,8-naphthyridin-4( 1H)-one
7: 2-Amino- 1-ethyl-7- [(3R)-3-hydroxy-4-methoxy-3 -methylbut- 1-yn- 1-yl] -
3-(1H-imidazo l-2-yl)quino lin-4( 1H)-one
8: 2-Amino-7-(3 -chloro-4-hydroxyphenyl)- 1-ethyl-3 -(1H-imidazo 1-2-yl)-
1,8-naphthyridin-4(lH)-one
9: 2-Amino- 1-ethyl-7- [3-(2-fluorophenyl)-3 -hydroxybut- 1-yn- 1-yl] -3-(1Himidazo
1-2-yl)- 1,8-naphthyridin-4( 1H)-one
10: 2-Amino-l-cyclopentyl-7-(3-hydroxypent-l-yn-l-yl)-3-(lHimidazo
1-2-yl)- 1,8-naphthyridin-4( 1H)-one
11: 2-Amino-7-(3-hydroxypent-l-yn-l-yl)-3-(lH-imidazol-2-yl)-l-
(3-methoxypropyl)- 1,8-naphthyridin-4( 1H)-one
12: 2-Amino-7-(3 -hydroxypent- 1-yn- 1-yl)-3 -(1H-imidazo 1-2-yl)- 1-
(2-methoxyethyl)-l,8-naphthyridin-4(lH)-one
13: 2-Amino-l-ethyl-7-[(l-hydroxycyclobutyl)ethynyl]-3-(lHimidazo
1-2-yl)- 1,8-naphthyridin-4( 1H)-one
14: 2-Amino- 1-ethyl-7- [( 1-hydroxy cyclopentyl)ethynyl] -3-(1Himidazo
1-2-yl)- 1,8-naphthyridin-4( 1H)-one
15: 2-Amino- 1-ethyl-7-(3 -hydroxy-3 -methylbut- 1-yn- 1-yl)-3 -(1Himidazol-
2-yl)-l,8-naphthyridin-4(lH)-one
16: 2-Amino- 1-ethyl-7-(3 -hydroxy-3 -methylpent- 1-yn- 1-yl)-3 -(1Himidazo
1-2-yl)- 1,8-naphthyridin-4( 1H)-one
17: 2-Amino- 1-ethyl-7-(3 -hydroxy-3 -phenylbut- 1-yn- 1-yl)-3 -(1Himidazo
1-2-yl)- 1,8-naphthyridin-4( 1H)-one
18: 2-Amino- 1-ethyl-7- [3-(3 -fluorophenyl)-3 -hydroxybut- 1-yn- 1-yl]-
3-(1H-imidazo 1-2-yl)- 1,8-naphthyridin-4( 1H)-one
19: 2-Amino-l-ethyl-3-(lH-imidazol-2-yl)-7-(4,4,4-trifluoro-3-
hydroxy-3 -phenylbut- 1-yn- 1-yl)- 1,8-naphthyridin-4( 1H)-one
20: 2-Amino-7-(3 -cyclopropyl-3 -hydroxybut- 1-yn- 1-yl)- 1-ethyl-3 -
( 1H-imidazo 1-2-yl)- 1,8-naphthyridin-4( 1H)-one
2 1: 2-Amino- 1-ethyl-7- [3-hydroxy-3 -(thiophen-2-yl)but- 1-yn- 1-yl] -
3-(1H-imidazo 1-2-yl)- 1,8-naphthyridin-4( 1H)-one
22: 2-Amino- 1-ethyl-7-(3 -hydroxybut- 1-yn- 1-yl)-3 -(1H-imidazo 1-2-
yl)- 1,8-naphthyridin-4( 1H)-one
23: 2-Amino- 1-ethyl-7-(3 -hydroxypent- 1-yn- 1-yl)-3 -(1H-imidazo 1-2-
yl)- 1,8-naphthyridin-4( 1H)-one
24: 2-Amino- 1-ethyl-7-(3-hydroxyhex- 1-yn- 1-yl)-3-( 1H-imidazo 1-2-
yl)- 1,8-naphthyridin-4( 1H)-one
25: 2-Amino- 1-ethyl-7-(3 -hydroxy-4-methylpent- 1-yn- 1-yl)-3 -(1Himidazo
1-2-yl)- 1,8-naphthyridin-4( 1H)-one
26: 2-Amino- 1-ethyl-7-(3 -hydroxy-3 -phenylprop- 1-yn- 1-yl)-3-( 1Himidazo
1-2-yl)- 1,8-naphthyridin-4( 1H)-one
27: 2-Amino-7-((3R)3 ,4-dihydroxy-3 -methyl-but- 1-ynyl)- 1-ethyl-3 -(1Himidazo
1-2-yl)- 1,8-naphthyridin-4( 1H)-one
28: 2-Amino-7-((3 S)3 ,4-dihydroxy-3 -methyl-but- 1-ynyl)- 1-ethyl-3 -(1Himidazo
1-2-yl)- 1,8-naphthyridin-4( 1H)-one
29: 2-Amino- 1-ethyl-7-((3 S)-3-hydroxy-4-methoxy-3 -methyl-but- 1-ynyl)-3 -
(1H-imidazo 1-2-yl) - 1,8-naphthyridin-4( 1H)-one
In the text hereinbelow, the term "leaving group" means a group that can be
readily cleaved from a molecule by breaking a heterolytic bond, with loss of an electron
pair. This group may thus be readily replaced by another group during a substitution
reaction, for example. Such leaving groups are, for example, halogens or an activated
hydroxyl group such as a methanesulfonate, benzenesulfonate, p-toluenesulfonate,
triflate, acetate, etc. Examples of leaving groups and references for preparing them are
given in "Advances in Organic Chemistry", J . March, 5th Edition, Wiley Interscience,
2001.
In the text hereinbelow, the term "protecting group" (PG) means a group
that can be momentarily incorporated into a chemical structure for the purpose of
temporarily inactivating a part of the molecule during a reaction, and which may be
readily removed in a subsequent synthetic step. Examples of protecting groups and
references concerning their properties are given in "Protective Groups in Organic
Synthesis", T.W. Greene, P.G.M. Wutz, 3rd Edition, Wiley Interscience 1999.
In accordance with the invention, the compounds of general formula (I) can
be prepared according to the process illustrated by the general scheme 1, 2 and 3,
below:

Scheme 3 :
According to scheme 1, in stage (i), a 2,6-dihalogeno-nicotinic acid of
formula (II) is mono-substituted in position 2 with an amine of formula R 4-NH 2 (where
R 4 is as defined previously with reference to the compounds of formula (I)), at room
temperature, or at a temperature from 50°C to 100°C, with conventional heating or
microwave heating and in a protic solvent such as an alcohol, for example ethanol, nbutanol,
tert-butanol or water. The acid (III), resulting from stage (i), is then activated to
a derivative of formula (IV), following stage (ii) either in the form of acid fluoride by
the action of cyanuryl fluoride at room temperature, in the presence of a base such as
triethylamine or pyridine and in an aprotic solvent such as dichloromethane or THF, as
described by G. Olah et al, in Synthesis (1973), 487, or in the form of imidazolide by
the action of carbonyldiimidazole in a polar aprotic solvent such as DMF or THF or by
other methods known by a person skilled in the art, such as those described by
Mukaiyama and Tanaka in Chem. Lett. (1976), 303 or by Ishikawa and Sasaki in Chem.
Lett. (1976), 1407.
The cyanomethylimidazoles of formula (V) are prepared in two stages from
an imidazole-2-carboxaldehyde unsubstituted or substituted in position (4,5) of the
imidazole. In stage (iii) the free nitrogen of the imidazole-2-carboxaldehyde is protected
by a protecting group, designated PG in scheme 1, for example such as a SEM, Boc or
trityl group, in conventional working conditions known by a person skilled in the art, as
described for example in "Protective Groups in Organic Synthesis", Greene et al, 3rd
Edition (John Wiley & Sons, Inc., New York). If applicable, the two isomers Tau and Pi
of the protected imidazole are obtained and used without distinction in the subsequent
reactions. The protected imidazole-2-carboxaldehyde is then transformed in stage (iv)
to cyanomethylimidazole of formula (V) by reaction of the aldehyde function with the
anion of TOSMIC, formed by adding potassium tert-butylate to an anhydrous DME
solution of TOSMIC at low temperature (-50°C), followed by ring opening of the
anionic intermediate formed, 4-tosyl-2-oxazoline, then the reaction mixture is heated
under reflux in the presence of methanol to permit formation of the acetylnitrile
function following the method described by Van Leusen A. et al. (Synthetic Comm,
10(5) 1980, 399-403).
The acid fluoride or the imidazolide of formula (IV) obtained at the end of
stage (ii), very reactive but stable, is then reacted, in stage (v), with a
cyanomethylimidazole of formula (V), unsubstituted or substituted in position (4,5), in
the presence of one equivalent of a base such as sodium hydride or potassium
tert-butoxide, in a polar aprotic solvent such as THF or DMF, at a temperature from -
5°C to room temperature, then a second equivalent of the base used is added and the
compound of formula (VI) that formed is cyclized in situ, at room temperature, to give
the pyridino-pyridinone compound of formula (VII), following stage (vi).
According to scheme 2, in stage (vii), a 2,4-dihalogeno-toluene of formula
(VIII) is oxidized to the corresponding acid derivative (IX) using a strong oxidant such
as potassium permanganate at room temperature, or at a temperature from 50°C to
100°C, with conventional heating or microwave heating and in a protic solvent such as
water and in the presence of a base such as pyridine or by other methods known by a
person skilled in the art, such as those described in the following patent: US 6,187,950.
The acid (IX), resulting from stage (vii), is mono-substituted in position 2 with an
amine of formula R 4-NH 2 (where R 4 is as defined previously with reference to the
compounds of formula (I)), at room temperature, or at a temperature from 50°C to
100°C, with conventional heating or microwave heating and in a protic solvent such as
an alcohol, for example ethanol, n-butanol, tert-butanol or water. The acid (X), resulting
from stage (viii), is then cyclised in benzo-l,3-oxazine-2,4-dione (XI) by action of
carbonyldiimidazole or triphosgene at room temperature, or at a temperature from 50°C
to 120°C, with conventional heating or microwave heating and in an aprotic solvent
such as DMF, toluene, THF, dioxane. The benzo-l,3-oxazine-2,4-dione (XI) is then
treated by malononitrile at room temperature, or at a temperature from 50°C to 120°C,
with conventional heating or microwave heating and in an aprotic solvent such as DMF,
toluene, dioxane and in the presence of a base such as triethylamine, or pyridine or by
other methods known by a person skilled in the art, such as those described by Iminov
et al. in Synthesis (2008) 1535, to obtain nitrile (XII). This nitrile (XII) resulting from
stage (x) reacted with aminoacetaldehyde diethylacetal, in the presence of a copper
catalyst such as CuCl, at room temperature, or at a temperature from 50°C to 120°C,
with conventional heating or microwave heating and in an aprotic solvent such as DME,
DMF, toluene, dioxane. The acetal (XIII) resulting from stage (xi) was then cyclised
into imidazole (XIV) using strong acidic conditions such as HCl (12N) at room
temperature, or at a temperature from 50°C to 120°C, with conventional heating or
microwave heating and in a protic solvent such as an alcohol, for example ethanol, nbutanol,
tert-butanol or water.
To obtain the compounds of formula (I) according to the present invention,
two methods, described in scheme 3, can be used starting from halogenated
intermediates of formula (VII) or (XIV).
Following the first method leading to a compound of formula (I), which is
the subject of the present invention, the halogenated intermediate of formula (VII) or
(XIV) is used, in stage (xiii), either in a Sonogashira coupling reaction with a suitable
derivative of propargyl alcohol RiR2CH(OR3)CCH of formula (XVa) where Ri, R2
and R3 are as defined previously or in a Suzuki coupling reaction with a suitable aryl
boronic acid of formula (XVb). The Sonogashira reaction (xiii) is carried out in the
presence of a complex of palladium (in oxidation state (0) or (II)) for example such as
Pd(PPh3)4, PdCl2(PPh3)2, in the presence of copper iodide, triethylamine, in an aprotic
polar solvent such as THF or DMF, heating conventionally between 80 and 120°C or by
microwave heating.
The Suzuki reaction (xiii) is carried out in the presence of a complex of
palladium (in oxidation state (0) or (II)) for example such as Pd(PPh3)4, PdCl2(PPh3)2,
Pd2dba3, Xphos or PdCl2(dppf), in a protic or aprotic polar solvent such as DME,
ethanol, DMF, dioxane, or mixtures of these solvents, in the presence of a base such as
cesium carbonate, aqueous sodium hydrogen carbonate, or K3PO4, heating
conventionally between 80 and 120°C or by microwave heating between 130 and
170°C.
The Sonogashira (XVIa) or Suzuki (XVIb) product are finally deprotected,
according to conventional stage of deprotection (xiv), for example in the presence of an
acid such as HCl (4N) in dioxane or trifluoroacetic acid in a solvent such as ethanol or
dichloromethane, at a temperature between -5°C and 60°C, to yield compound of
formula (I).
Following the second method to obtain a compound of formula (I), which is
the subject of the present invention, the halogenated intermediate of formula (VII) or
(XIV) is first deprotected (xv), according to the same conventional procedure as for
stage (xiv). And the resulting unprotected compound (XVII) is used either in a
Sonogashira coupling reaction with a suitable derivative of propargyl alcohol
RiR2CH(OPv3)CCH (XVa) where Ri, R2 and R 3 are as defined previously; or in a
Suzuki coupling reaction with a suitable aryl boronic acid of formula (XVb), according
to the same conditions as described before for stage (xiii). Both coupling reactions lead
directly to compound (I).
If necessary, during the reaction steps presented in scheme 1, the hydroxyl
group or certain reactive functions located on the groups Ri, R2 and R 3 can be
temporarily protected with protective groups known to those skilled in the art and as
described in "Protective Groups in Organic Synthesis", Greene et al, 2nd Edition (John
Wiley & Sons, Inc., New York).
According to another of its aspects, a subject of the invention is also the
compounds of formula (VII) as defined in Scheme 1. These compounds can be used as
synthesis intermediates for the compounds of formula (I).
According to another of its aspects, a subject of the invention is also the
process for preparing a compound of formula (I), characterized in that a compound of
formula (VII):
in which X is a chlorine or a bromine and R 4 and R are as defined
general formula (I), is reacted with a compound of general formula (XVa):
in which Rl R2 and R3 are as defined in the general formula (I),
or is reacted with a compound of general formula (XVb):
(XVb)
in which R3 and R are as defined in the general formula (I),
a conventional stage of deprotection is carried out before or after the
reaction of the compound of formula (VII) with the compound of general formula
(XVa) or the compound of general formula (XVb).
The examples that follow describe the preparation of certain compounds in
accordance with the invention. These examples are not limiting, and serve merely to
illustrate the present invention. The illustrated compounds numbers refer to those in
Table 1. The elemental microanalyses, the LC/MS analyses and the IR or NMR
spectrum confirm the structures of the obtained compounds.
Example 1: (Compound N°l)
2-Amino-l-ethyl-7-((3R)-3-hydroxy-4-methoxy-3-methyl-but-l-ynyl)-3-
(lH-imidazol-2-yl)-lH-[l,8]-naphthyridin-4-one
1.1: 6-Chloro-2-ethylamino-nicotinic acid
A solution of 18.0 g (84.4 mmol) of 2,6-dichloronicotinic acid in 180 ml of
a solution of ethylamine (70% in water) was stirred at ambient temperature for
72 hours. The excess amine was then evaporated off under reduced pressure, and an
aqueous solution of acetic acid at 10% was added until the product precipitates. The
beige solid was spin-filter-dried, rinsed with cold water and dried in an oven. 10.5 g of
the expected product are obtained.
Melting point = 158-160°C.
Yield = 62%.
1.2: 6-Chloro-2-ethylamino-nicotinoyl fluoride
2 ml (24.8 mmol) of pyridine and 4.2 ml (49.8 mmol) of 2,4,6-
trifluorotriazine were added to a suspension of 5.0 g (24.8 mmol) of 6-chloro-2-
ethylamino -nicotinic acid in 125 ml of dichloromethane. The mixture was stirred for
3 hours at ambient temperature and then filtered. The solid was rinsed with 50 ml of
dichloromethane and the filtrate was washed twice with 60 ml of ice-cold water. The
organic phase was dried over Na2S0 4 and the solvent was evaporated off under reduced
pressure. 5.01 g of product were obtained in the form of an orange oil which was used
without further purification.
Yield = 99%.
1.3: l-(2-Trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-carbaldehyde
An oily suspension of 20.8 g sodium hydride in mineral oil (50%>, 0.52 mol)
was washed mineral oil free by stirring with hexane 3-times and suspended in 400 ml
DMF. Under stirring at ambient temperature 50.0 g (0.520 mol) imidazole-2-
carbaldehyde was added to the suspension. After 1.5 h, 101.0 ml (0.572 mol) 2-
(trimethylsilanyl)ethoxymethyl chloride was added and the reaction was stirred a
further hour. Then excess water was added to the suspension and the reaction mixture
was extracted three times with ethyl acetate. The organic phase was dried over Na2S0 4
and the solvent was evaporated off under reduced pressure. The raw material was then
purified by column chromatography (DCM) to yield 85.0 g (0.376 mol) of the SEMprotected
imidazole-2-carbaldehyde.
Yield = 72%.
MH+ = 227.1 (CioHi 20 2Si, Mr=226.35).
1H NMR (DMSO-d6, 500MHz): 9.83 (s, 1H); 7.86 (s, 1H); 7.39 (s, 1H);
5.75 (s, 2H); 3.58 (t, 2H); 0.95 (t, 2H); 0.02 (s, 9H).
1:4: [l-(2-Trimethylsilanyl-ethoxymethyl)- lH-imidazol-2-yl] -
acetonitrile
1.73 g (8.84 mmol) tosylmethylisocyanide were solved in 10 ml DME and
cooled down to -60°C. At this temperature first 1.98 g potassium tert-butoxide was
added then slowly a solution of 2.00 g (8.84 mmol) l-(2-trimethylsilanylethoxymethyl)-
lH-imidazole-2-carbaldehyde in 5 ml DME . After 2 hours stirring at -
60°C the reaction was allowed to reach 0°C and 5 ml methanol (123.60 mmol) was
added to the solution. The reaction was stirred for further 24 hours at ambient
temperature and for 2 hours at 40°C. Excess water was added and the solution was
extracted 3 times with dichloromethane. The organic phase was dried over Na2S0 4,
after evaporation of the solvent under reduced pressure the raw material was purified by
reverse phase column chromatography (water 0.1%TFA/acetonitrile = 80/20 to yield
0.87 g (0.367 mol) of the SEM-protected imidazole-acetonitrile.
Yield = 41%
MH+ = 238.1 (CnHi N3OSi, Mr =237,38).
1H NMR (DMSO-d6, 500MHz): 7.66 (s, 1H); 7.39 (s, 1H); 5.53 (s, 2H);
4.52 (s, 2H); 3.55 (t, 2H); 0.92 (t, 2H); 0.02 (s, 9H).
1.5: 3-(6-Chloro-2-ethylamino-pyridin-3-yl)-3-hydroxy-2-[l-(2-
(trimethylsilanyl-ethoxymethyl)-lH-imidazol-2-yl]-acrylonitrile
0.283 g (2.53 mmol) of potassium tert-butylate was added, in small
amounts, to a 0°C solution of 0.600 g (2.53 mmol) [l-(2-trimethylsilanylethoxymethyl)-
lH-imidazol-2-yl] -acetonitrile in 10 ml of anhydrous THF. The mixture
was stirred for 45 minutes at ambient temperature, and was then cooled again to 0°C. A
solution of 0.512 g (2.53 mmol) 6-chloro-2-ethylamino-nicotinoyl fluoride in 10 ml of
THF was then added and the medium was stirred at ambient temperature overnight,
again cooled down to 0°C and a second equivalent of potassium tert-butylate (0.283 g,
2.53 mmol) was added. After 2 h stirring at ambient temperature 50 ml saturated
ammonium chloride aqueous solution was added, the pH was adjusted to 7 with 2N HCl
thereafter then extracted three times with ethyl acetate. The combined organic phases
were dried over MgSC^ and the solvents were evaporated under reduced pressure. The
raw material is further purified by column chromatography (DCM/Methanol=90:10)
yielded 418mg (yield=38%) of the title compound as an intermediate which was
subsequently used in the next step.
MH+ = 421 (Ci H26ClN50 2Si, Mr = 419,99)
1H NMR (DMSO-d6, 500MHz): 13.35 (s, 1H); 7.70 (d, 1H); 7.46 (s, 1H);
7.23 (s, 1H); 7.08 (t, 1H); 6.58 (d, 1H); 5.59 (s, 2H); 3.58 (t, 2H); 3.34 (dq, 2H); 1.13 (t,
3H); -0.03 (3s, 9H).
1.6: 2-Amino-7-chloro-l-ethyl-3- [l-(2-trimethylsilanyl-ethoxymethyl)-
lH-imidazol-2-yl] -1H-[1,8] naphthyridin-4-one
0.112 g ( 1 mmol) of potassium tert-butylate was added, in small amounts, to
a 0°C cold solution of 418 mg ( 1 mmol) of the intermediate prepared under 1.53-(6-
chloro-2-ethylamino-pyridin-3-yl)-3-hydroxy-2-[ 1-(2-(trimethylsilanyl-ethoxymethyl)-
lH-imidazol-2-yl]-acrylonitrile in 5 ml of anhydrous THF. The mixture was stirred for
48h at ambient temperature after which 50 ml of saturated ammonium chloride aqueous
solution was added, the pH is adjusted to 7 with 2N HCl and the reaction mixture was
extracted three times with ethyl acetate. The combined organic phases were dried over
MgS04 and the solvents were evaporated under reduced pressure yielding 400 mg of
the title compound.
Yield = 38%.
MH+ = 421 (Ci H26ClN50 2Si, Mr = 419,99).
1H NMR (DMSO-d6, 500MHz): 8.50 (d, 1H); 8.03 (s, 1H); 7.98 (s, 1H);
7.78 (s, 2H); 7.60 (s, 1H); 5.49 (s, 2H); 4.58 (q, 2H); 3.57 (t, 2H); 1.42 (t, 3H); 0.85
(t, 2H); -0.03 (3s, 9H).
1.7: (±)-2-Methyl-but-3-yne-1,2-diol
A commercially available 0.5 M solution of ethynylmagnesium chloride in
tetrahydrofuran was diluted with 200 ml of tetrahydrofuran and cooled to 0°C. Then a
solution of hydroxyacetone in 200 ml of tetrahydrofuran is added and the mixture was
stirred at ambient temperature for 3 hours. The reaction mixture was cooled and an
aqueous solution of NH4C 1 was added. The mixture was extracted 3 times with ethyl
acetate and the organic phases were combined, dried over sodium sulphate, filtered, and
concentrated under vacuum (approximately 200 mbar). Finally, 20 g of expected
product were obtained in the form of a brown oil, which was used without subsequent
purification (quantitative crude yield) in the racemic form or could be separated in the
pure enantiomers by preparative HPLC on chiral HPLC columns. In order to obtain the
optically pure enantiomers, the corresponding racemic mixture was subjected to
preparative chromatography on a chiral stationary phase (Chiralpak AD-H column,
250 x 2 1 mm, 5 mm) using, as mobile phase: either C0 2/2-propanol (70%/30%) with a
flow rate of 60 ml/min at a pressure of 100 bar or an isohexane/ethanol (70/30) mixture
with 0.3% of TFA and a flow rate of 120 ml/min.
After elution and evaporation, each enantiomer was isolated, and the
chemical purity and enantiomeric purity of each are determined by analytical methods
known to those skilled in the art.
1.8: 2-Amino-l-ethyl-7-((3R)-3-hydroxy-4-methoxy-3-methyl-but-lynyl)-
3- [l-(2-trimethylsilanyl-ethoxym ethyl)-1H-imidazol-2-yl] -1H-
[1,8] naphthyridin-4-one
In an argon filled microwave reaction flask 500 mg (1.2 mmol) 2-amino-7-
chloro- 1-ethyl-3 -[1-(2-trimethylsilanyl-ethoxymethyl)- 1H-imidazo 1-2-yl] -1H-
[l,8]naphthyridin-4-one, 204 mg (1.8 mmol) (3R)-l-methoxy-2-methyl-but-3-yn-2-ol,
84 mg (0.120 mmol) bis(triphenylphosphine)palladium (II) dichloride, 30 mg
(0.16 mmol) copper (I) iodide, 2 ml DMF (degassed), 2ml triethylamine (degassed)
were given and irradiated in the microwave in such a way that the reaction mixture was
kept at 120°C for 24h. The solvents were evaporated and the solid resuspended in 3 ml
DMF and filtrated. The filtrate was then purified by HPLC yielding 430 mg
(0.702 mmol) of the TFA salt of the title compound.
Yield = 59%.
MH+ = 498.2 (C25H3 5N50 4Si, Mr =497,67).
1H NMR (DMSO-d6, 500MHz): 8.39 (d, 1H); 7.95 (s, 1H); 7.88 (s, 1H);
7.60 (s, 2H); 7.48 (d, 1H); 5.25 (s, 2H); 4.50 (broad signal, 2H); 3.52 - 3.40 (broad
signal, water peak + 4H); 1.48 (s, 3H); 1.25 (t, 3H); -0.12 (3s, 9H).
1.9: 2-Amino-l-ethyl-7-((3R)-3-hydroxy-4-methoxy-3-methyl-but-lynyl)-
3-(lH-imidazol-2-yl)-lH-[l,8]naphthyridin-4-one
240 mg (0.4 mmol) SEM protected naphthyridinone 1.8 was solved at 0°C
in 1.2 ml TFA and 1.2 ml DCM. The solution was kept at 3-5°C overnight until
analytical HPLC showed complete deprotection of the naphthyridinone. The solution is
neutralized by adding an excess of aqueous NaHC0 3 solution. The mixture was then
extracted three times with ethyl acetate. The combined organic phases were dried over
MgS0 4 and the solvents were evaporated off under reduced pressure. The so gained raw
material was purified on silica gel (DCM:MeOH = 4:1) yielding 143 mg (quantitative
yield) of the unprotected title compound.
MH+ = 368.2 (Ci9H2iN50 3, Mr =367,41).
1H NMR (DMSO-d6, 500MHz): 13.15 (s, 1H); 11.55 (b s, 1H); 8.59
(d, 1H); 8.10 (b s, 1H); 7.47 (d, 1H); 7.25 (s, 1H); 7.02 (s, 1H); 5.85 (s, 1H); 4.58
(broad signal, 2H); 3.51 - 3.370 (broad signal, water peak + 4H); 1.48 (s, 3H); 1.25
(t, 3H).
Rt (analytical HPLC): 4.806 min.
Example 2 : (Compound N°2)
2-Amino-l-propyl-7-((3R)-3-hydroxy-4-methoxy-3-methyl-but-l-ynyl)-
3-(lH-imidazol-2-yl)-lH-[l,8]naphthyridin-4-one
Using the procedure described up to step 1.6, 2-amino-7-chloro-l-propyl-3-
[1-(2-trimethylsilanyl-ethoxymethyl)- 1H-imidazo 1-2-yl] -1H-[1,8]naphthyridin-4-one
was synthesized by using n-propylamine instead of ethylamine in step 1.1. Coupling
this intermediate to (3R)-l-methoxy-2-methyl-but-3-yn-2-ol following in an analogous
manner to the detailed procedure outlined for example 1 the title compound was
accessed.
MH+ = 382.48 (C2oH23N 50 3,Mr =381,44).
1H NMR (DMSO-d6, 500MHz): broad signals: 8.45 (m, 1H); 7.4
(m, 3H); 5.85 (s, 1H); 4.58 (m, 3H); 3.51 - 3.370 (water peak + 4H); 1.70 (m, 2H);
sharp signals: 1.48 (s, 3H); 0.95 (t, 3H).
Rt (analytical HPLC): 4.98 min.
Example 3 : (Compound N°3, N°27 and N°28)
2-Amino-7-(3,4-dihydroxy-3-methyl-but-l-ynyl)-l-ethyl-3-(lHimidazol-
2-yl) -l,8-naphthyridin-4(lH)-one
2-Amino-7-((3R)3,4-dihydroxy-3-methyl-but-l-ynyl)-l-ethyl-3-(lHimidazol-
2-yl)-l,8-naphthyridin-4(lH)-one
2-Amino-7-((3S)3,4-dihydroxy-3-methyl-but-l-ynyl)-l-ethyl-3-(lHimidazol-
2-yl)-l,8-naphthyridin-4(lH)-one
3.1. 2-Amino-l-ethyl-7-(3,4-dihydroxy-3-methyl-but-l-ynyl)-l-ethyl-3-
[l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazol-2-yl] -l,8-naphthyridin-4(lH)-
one
Following the detailed procedure outlined for step 1.8 , u ing the
intermediate described under 1.6 (2-amino-7-chloro-l-ethyl-3-[l-(2-trimethylsilanylethoxymethyl)-
lH-imidazol-2-yl-l,8-naphthyridin-4(lH)-one) and the (±)-2-methylbut-
3-yne-l,2-diol, previously prepared as in procedure describe in step 1.7, was
accessed.
MH+ = 354.16 (Ci Hi N50 3, Mr = 353,38)
Rt (analytical HPLC): 4.48¾nin.
3.2. 2-Amino-l-ethyl-7-((3R)3,4-dihydroxy-3-methyl-but-l-ynyl)-lethyl
3-[l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazol-2-yl] -1,8-naphthyridin-
4(lH)-one
2-Amino-l-ethyl-7-((3S)3,4-dihydroxy-3-methyl-but-l-ynyl)-l-ethyl-3-
[l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazol-2-yl] -l,8-naphthyridin-4(lH)-
one
The racemic compound obtaines at step 3.1 was subjected to a preparative
Chiral SFC purification, using a methods, Berger prep SFC, UV detection at 230nm,
stationary phase Chiralpak IC 20x 250nm 5, mobile phase 65%/ 35% C02/ (MeOH
+ a.5% zsopropylamine), 50 ml/min, 100 bars) leading to the separation of the two
enantiomers.
For the two enantiomers the chiral purity was controled using Chiral SFC
methods, Berger SFC, UV detection at 210nm, stationary phase Chiralpak AD-H
(250mmx4.6) 5, mobile phase 65/ 35% C02/ (z ' sopropanol + 0.5% z'sopropylamine),
2.4 ml/min, 100 bars.
R enantiomer (tr= 6.9 min, enatiomeric purity = 97.9 %)
S enantiomer (tr= 5.9 min, enatiomeric purity = 96.8%)
3.3. 2-Amino-7-(3,4-dihydroxy-3-methyl-but-l-ynyl)-l-ethyl-3-(lHimidazol-
2-yl)-l,8-naphthyridin-4(lH)-one
2-Amino-7-((3R)3,4-dihydroxy-3-methyl-but-l-ynyl)-l-ethyl-3-(lHimidazol-
2-yl)-l,8-naphthyridin-4(lH)-one
2-Amino-7-((3S)3,4-dihydroxy-3-methyl-but-l-ynyl)-l-ethyl-3-(lHimidazol-
2-yl)-l,8-naphthyridin-4(lH)-one
After the deprotection step according to step 1.9 compounds 3, 27 and 28
are isolated as a yellow powder.
MH+ = 354.16 (Ci8Hi N50 3, Mr = 353,38)
Tr= 0.77 min
1H NMR (DMSO-d6, 400MHz): 13.15 (s, 1H); 11.55 (bs, 1H); 8.55
(d, 1H, J= 6.4Hz); 8.10 (bs, 1H); 7.47 (d, 1H, J= 6.4Hz); 7.15 (s, 1H); 7.02 (s, 1H); 5.6
(s, 1H); 5.1 (t, 1H, J= 6.4Hz) 4.53 (bd, 2H); 3.49 (dd, 1H, J= 6.4; 10.4 Hz); 3.41 (dd,
1H, J= 6.4; 10.4 Hz)1.48 (s, 3H); 1.27 (t, 3H, J= 7.2Hz).
For the two enantiomers the chiral purity was controled using Chiral SFC
methods, Berger SFC, UV detection at 230nm, stationary phase Chiralpak AD-H
(250mmx4.6) 5, mobile phase 60/ 40% C02/ ( zsopropanol + 0.5% zsopropylamine),
2.4 ml/min, 100 bars.
R enantiomer (tr= 8.37 min, enatiomeric purity = 99.2 %)
S enantiomer (tr= 7.29 min, enatiomeric purity = 98.5%)
Example 4 : (Compound N°4)
2-Amino-l-ethyl-7-(3-hydroxy-3-pyridin-2-yl-but-l-ynyl)-3-(lHimidazol-
2-yl)-lH-[l,8]naphthyridin-4-one
Using the intermediate described under 1.6 (2-amino-7-chloro-l-ethyl-3-[l-
(2-trimethylsilanyl-ethoxymethyl)-lH-imidazol-2-yl]-lH-[l,8]naphthyridin-4-one) and
coupling it to (±)-2-pyridin-2-yl-but-3-yn-2-ol following the detailed procedure outlined
for example 1 in an analogous manner the title compound was accessed.
MH+ = 401.21 (C22H20N6O2, Mr = 400,44).
Rt (analytical HPLC): 4.49 min.
Example 5 (Compound N°5)
2-Amino-l-ethyl-7-[(3R)-3-hydroxy-4-methoxy-3-methyl-but-l-yn-lyl]-
3-(4-methyl-lH-imidazol-2-yl)-lH-[l,8]naphthyridin-4-one
5.1: 4-Methyl-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-
carbaldehyde:
Using the same procedure as for exemple 1 stage 1.3, starting from 4 g
(36.3 mmol) 4(5)-methyl-lH-imidazole-2-carbaldehyde, 1.5g (38 mmol) of sodium
hydride and 6.7 g (40 mmol) 2-(trimethylsilanyl)ethoxymethyl chloride in 73 ml DMF,
8.7 g of the title compound was accessed as a brown oil (quantitative yield).
MH+ = 241 (C1 1H20N2O2S1, 240.377).
5.2: [4-Methyl-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazol-2-yl]-
acetonitrile
Same procedure as that described in example 1, stage 1.4, starting from
8.7 g (32.7 mmol) of 4-methyl-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazole-2-
carbaldehyde, 6.7 g (34.3 mmol) of TOSMIC and 7.3 g (65 mmol) of potassium tertbutylate
in solution in anhydrous DME (54 ml). 6.6 g of compound is obtained in the
form of a yellow oil as 70/30 mixture of regioisomers tau and Pi.
Yield = 80%.
MH+ = 252 (C12H2 1N3OS1, 251.404).
Tr = 6.38 and 6.55 min.
5.3: 2-Amino-7-chloro-l-ethyl-3-[4-methyl-l-(2-trimethylsilanylethoxymethyl)-
lH-imidazol-2-yl] -1H-[1,8] naphthyridin-4-one
Same procedure as that described in example 1, stage (1.5-1.6), starting
from 6.3 g (25 mmol) of the compound obtained at the end of stage 6.2, 5 g (25 mmol)
of the compound obtained at the end of stage 1.2 and 7.2 g (62 mmol) of potassium tertbutylate
in solution in anhydrous THF (83 ml). 4 g of product, in the form of a beige
powder, is obtained as a mixture of 80/20 of the 2 isomers Tau Dand Pi, used as a
mixture in the next step
Yield = 38%.
Melting point = 120°C.
MH+ = 435 (C2oH28ClN50 2Si, 434,013).
Tr = 10.5 and 10.6 min,
1H NMR of both isomers (500 MHz, DMSO-d6) ppm 8.45 (d, J=8.07 Hz,
2 H) 7.70 (b. s . , 2 H) 7.56 (b. s . , 2 H) 7.43 (d, J=8.07 Hz,l H) 7.42 (d, J=8.07 Hz, 1 H)
6.99 (m, 1 H) 6.84 (m, 1 H) 5.18 (s, 2 H) 5.17(s, 2 H) 4.43 (q, J=6.85 Hz, 4 H) 3.19
(m, 2 H) 3.12 (m, 2 H) 2.25 (d, J=0.98 Hz, 3 H) 2.16 (d, J=0.98 Hz, 3 H) 1.24 - 1.29
(m, 6 H) 0.57 - 0.64 (m, 4 H) -0.22 (s, 9 H) -0.22 (s, 9 H)
5.4: 2-Amino-l-ethyl-7-[(3R)-3-hydroxy-4-methoxy-3-methyl-but-l-ynl-
yl]-3-[4-methyl-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazol-2-yl]-lH-
[1,8] naphthyridin-4-one
In a argon filled microwave reaction flask 0.5 g (1.15 mmol) of the
compound obtained at the end of stage 5.3, 0.26 g (2.3 mmol) (R)-l-methoxy-2-methylbut-
3-yn-2-ol, 40 mg (0.06 mmol) bis(triphenylphosphine)palladium (II) dichloride,
22 mg (0.12 mmol) copper (I) iodide, 3 ml DMF (degassed), 3 ml triethylamine
(degassed) were heated at 80°C for 3h. The solvents were evaporated; the solid was
dissolved in ethyl acetate and washed successively with an aqueous solution of
saturated NaHC0 3 and with HC1 (IN). The organic phase was then dried over Na2S0 4,
filtrated and concentrated under reduced pressure. The residue was then purified by
flash chromatography on silica gel (DCM/THF 95/5: MeOH (1% NH4OH) from 0% to
10%) yielding 0.19 g of the title compound.
Yield: 32%.
MH+ = 512 (C26H37N50 4Si, 511.695).
1H NMR (400 MHz, DMSO-d6) ppm 8.43 (d, J=7.91 Hz, 2 H) 7.69
(br. s., 2 H) 7.55 (br. s., 2 H) 7.41 (d, J=7.79 Hz, 2 H) 6.99 (s, 1 H) 6.84 (s, 1 H) 5.81
(s, 2 H) 5.18 (s, 4 H) 4.40 - 4.58 (m, 4 H) 3.47 (d, J=9.54 Hz, 2 H) 3.37 - 3.43 (m, 8 H)
3.19 (t, J=8.02 Hz, 2 H) 3.12 (t, J=8.08 Hz, 2 H) 2.26 (s, 3 H) 2.17 (s, 3 H) 1.47 (s, 6 H)
1.26 (t, J=6.57 Hz, 6 H) 0.54 - 0.67 (m, 4 H) -0.23 (s, 18 H)
5.5: 2-Amino-l-ethyl-7-[(3R)-3-hydroxy-4-methoxy-3-methyl-but-l-ynl-
yl]-3-(4-methyl-lH-imidazol-2-yl)-lH-[l,8]naphthyridin-4-one
0.18 g (0.36 mmol) of the compound obtained at the end of stage 5.4 was
dissolved at 0°C in 1.7 ml TFA and 1.7 ml DCM. The solution was kept at 3-5°C
overnight. The solution is neutralized by adding an excess of aqueous NaHC0 3
solution. The mixture was then extracted three times with ethyl acetate. The combined
organic phases were dried over Na2S0 4 and the solvents were evaporated off under
reduced pressure. The raw material was purified by crystallization in DCM 62 mg
(yield 46%>) of the unprotected title compound.
MH+ = 382 (C20H23N5O3, 381.434).
1H NMR (DMSO-d6, 500MHz): (the 2 topoisomers on the imidazole are
detected as 60/40 ratio) = 12.9-12.8 (2s, 1H) 11.6 (brs, 1H) 8.52 (d, J=7.9 Hz, 1 H)
8.0 (brs, 1H) 7.42 (d, J=7.9 Hz, 1 H) 6.84- 6.70 (2s, 1H) 5.8 (s, 1H) 4.56 (m, 2H) 3.46
(d, J=9.5Hz, 1H) 3.3 (s, 3H) 3.4 (d, J= 9.5Hz, 1H) 2.28-2.2(2s 3H) 1.47 (s,3H) 1.28
(t, J=6.6Hz, 3H)
Example 6: (Compound N°6)
2-Amino-l-cyclopropylmethyl-7-(3-hydroxy-pent-l-ynyl)-3-(lHimidazol-
2-yl)- lH-[l,8]naphthyridin-4-one
6.1: 6-Chloro-2-(cyclopropylmethyl-amino)-nicotinic acid
In a sealable tube, 3 g (42 mmol) of cyclopropylmethylamine is added to
3 g (14 mmol) of 2,6-dichloronicotinic acid in solution in tert-butanol (14 ml), the tube
is sealed and heated at 170°C for 30 minutes in a Biotage Initiator microwave. The
reaction mixture is cooled to room temperature, diluted in dichloromethane (100 ml)
and washed with a 10% aqueous solution of acetic acid (12 ml). The organic phase is
dried over Na2S0 4, filtered, concentrated and dried under vacuum. 3.4 g of product is
obtained in the form of an orange oil.
Yield is quantitative.
MH+ = 227.
Tr = 4.54 min.
6.2: 6-Chloro-2-(cyclopropylmethyl-amino)-nicotinoyl fluoride
Same procedure as that described in example 1, stage 1.2, starting from
0.334 g ( 1.4 mmol) of the compound obtained at the end of stage 7.1 in solution in 4 ml
of dichloromethane, 0.38 g (2.8 mmol) of cyanuric fluoride, and 0.28 g (2.8 mmol) of
triethylamine. The product, obtained in the form of a green oil, is used without
purification in the next stage.
6.3: 2-Amino-7-chloro-l-(cyclopropylmethyl)-3-[l-(2-trimethylsilanylethoxymethyl)-
lH-imidazol-2-yl] -1H-[1,8] naphthyridin-4-one
Same procedure as that described in example 1, stage (1.5-1.6), starting
from the raw compound obtained at the end of stage 6.2, 0.32 g (1.4 mmol) of the
compound obtained at the end of stage 1.3 in solution in 5 ml of anhydrous THF and
0.4 g (0.35 mmol) of potassium tert-butylate. 0.56 g of product is obtained in as a
brown powder.
Yield = 90%.
Melting point = 70°C.
MH+ = 447 (C2iH28ClN 50 2Si).
Tr = 6.68 min.
1H NMR (400 MHz, DMSO-d6) ppm 8.46 (d, J=8.05 Hz, 1 H) 7.67 (br. s,
2 H) 7.43 (d, J=8.05 Hz, 1 H) 7.35 (d, J=1.37 Hz, 1 H) 7.12 (d, J=1.19 Hz, 1 H) 5.27
(s, 2 H) 4.38 (d, J=7.04 Hz, 2 H) 3.19 - 3.25 (m, 2 H) 1.21 - 1.32 (m, 1 H) 0.59 - 0.68
(m, 2 H) 0.45 - 0.57 (m, 4 H) -0.21 (s, 9 H)
6.4 : 2-Amino-l-(cyclopropylmethyl)-7-(3-hydroxy-pent- l-ynyl)-3- [l-(2-
trimethylsilanyl-ethoxymethyl)-lH-imidazol-2-yl] -1H-[1,8] naphthyridin-4-one
Same procedure as that described in example 5, stage 5.4, starting from
0.5 g (1.2 mmol) of the compound obtained at the end of stage 6.3, 0.22 g (2.5 mmol)
pent-4-yn-3-ol, 43 mg (0.06 mmol) bis(triphenylphosphine)palladium (II) dichloride,
23 mg (0.12 mmol) copper (I) iodide, 3 ml DMF (degassed), 3 ml triethylamine
(degassed) . 0.19 g of the title compound is obtained.
Yield = 30%.
MH+ = 494 (C2 6H3 5 50 3Si 493.68).
1H NMR (400 MHz, DMSO-d6) ppm 8.44 (d, J=7.87 Hz, 1 H) 7.65 (br. s,
2 H) 7.42 (d, J=7.87 Hz, 1 H) 7.33 (s, 1 H) 7.10 (s, 1 H) 5.63 (d, J=5.58 Hz, 1 H) 5.28
(s, 2 H) 4.38 - 4.52 (m, 3 H) 3.17 - 3.25 (m, 2 H) 1.67 - 1.76 (m, 2 H) 1.22 - 1.31
(m, 1 H) 1.01 (t, J=7.36 Hz, 3 H) 0.59 - 0.66 (m, 2 H) 0.44 - 0.57 (m, 4 H) -0.24 - 0.20
(m, 9 H)
6.5: 2-Amino-l-cyclopropylmethyl-7-(3-hydroxy-pent-l-ynyl)-3-(lHimidazol-
2-yl)- lH-[l,8]naphthyridin-4-one
Same procedure as that described in example 5, stage 5.5, starting from
0.18 g (0.36 mmol) of the compound obtained at the end of stage 7.4, in 1.7 ml TFA
and 1.7 ml DCM, 19 mg of the title compound is obtained.
Yield = 15 %
Melting point = 252°C.
MH+ = 364 (C2oH2iN 50 2, 363.419).
1H NMR (400 MHz, DMSO-d6) ppm 13.15 (br s, 1H) 11.5 (br s, 1H)
8.56 (d, J=7.9 Hz, 1 H) 8.0 (br. s, 1H) 7.45 (d, J=7.9 Hz, 1 H) 7.15 (m, 2 H) 5.62 (br s,
1 H) 4.62 (m, 2H+1 H) 1.75 (m, 2 H) 1.34 (m, 1 H) 1.05 (t, J=7.36 Hz, 3 H) 0.5
(m, 2 H) 0.48 - (m, 2 H).
Example 7: (Compound N°7)
2-Amino-l-ethyl-7-((R)-3-hydroxy-4-methoxy-3-methyl-but-l-ynyl)-3-
(lH-imidazol-2-yl)-lH-quinolin-4-one
7.1: 2-Fluoro-4-iodo-benzoic acid
13.39 g (84.74 mmol) potassium permanganate were added to a suspension
of 5 g (21.18 mmol) of 2-fluoro-4-iodo-toluene and 25.13 g (317.77 mmol) of pyridin
in water. The mixture was heated and stirred at 70°C during 18 hours. As the reaction
was not finished, 3.34 g (21.18 mmol) of potassium permanganate were added to the
reaction mixture at room temperature and the mixture was stirred for another 6 hours at
70°C. The reaction mixture was then filtered through a celite pad, which was then
washed with water and ethyl acetate. After decantation, the aqueous phase was acidified
to pH = 1 with an aqueous solution of HC1 6N. A white solid was first filtered and the
aqueous phase extracted three times with ethyl acetate. The combined organic phases
were dried over MgS0 4 and the solvents were evaporated off under reduced pressure.
The filtered white solid and the solid extracted with ethyl acetate were combined to give
4.1 g.
Yield = 73%.
MH+ = 266.9 (C7H4FI0 2) .
1H NMR (DMSO-d6, 400MHz): 13.49 (broad signal, 1H); 7.88 (d, 1H);
7.78 (d, 1H); 7.65 (d, 1H).
7.2: 2-Ethylamino-4-iodo-benzoic acid
3.5 g (13.16mmol) of 2-fluoro-4-iodobenzoic acid were mixed to a 16.1 1ml
solution of ethylamine (70% in water) in a sealed tube. The reaction vessel was heated
and stirred at 125°C during 24 hours. Nitrogen was bubbled through the reaction
mixture to eliminate the excess of ethylamine. The reaction mixture was than poured
into an iced water solution and the mixture acidified to pH = 3-4 with acetic acid. The
resulting white solid was then filtered off, washed with water and dried to give 2.2g
(7.55mmol).
Yield = 58%.
MH+ = 291.8 (C9H10INO2).
1H NMR (DMSO-d6, 400MHz): 12.5 (br s, 1H); 7.55 (d, 1H); 7.1 1
(s, 1H); 6.9 (d, 1H).
7.3 : l-Ethyl-7-iodo- lH-benzo [d] [1,3] oxazine-2,4-dione
0.785 g (2.65 mmol) of triphosgene were added at room temperature to
2.2 g (7.55 mmol) of 2-ethylamino-4-iodo-benzoic acid in 30 ml of dioxane. The
reaction mixture was then heated and stirred at 110°C during 2 hours. The solution was
evaporated to dryness and reevaporated twice after 2 additions of 20 ml of toluene to
give 2.39g (7.5 mmol) of a solid.
Yield = 100%.
MH+ = 317.7 (CioH IN0 3) .
1H NMR (DMSO-d6, 400MHz): 7.87 (s, 1H); 7.68 (s, 2H); 4.04 (m, 2H);
1.19 (t, 3H).
7.4 : 2-Amino- l-ethyl-7-iodo-4-oxo- 1,4-dihydro-quinoline-3-carbonitrile
0.32g (6.31mmol) of malononitrile and 1.45g (14.35mmol) triethylamine
were added to 2 g (6.31 mmol) of l-ethyl-7-iodo-lH-benzo[d][l,3]oxazine-2,4-dione
dissolved in 25 mL of DMF. The solution was stirred for 2 hours at 120°C and after
addition of 0.73 g (7. 17 mmol) of triethylamine, for another 1 hour at 110°C. The DMF
was then evaporated under reduced pressure and the residue taken over with a mixture
of water and dichloromethane. Filtration of this mixture gave a first fraction of the
expected compound: 0.55 g (1.62 mmol).
Yield = 26%.
MH+ = 339.7 (Ci0H INO3) .
1H NMR (DMSO-d6, 400MHz): 7.99 (s, 1H); 7.80 (d, 1H); 7.7 (m, 2H);
4.21 (m, 2H); 1.20 (t, 3H).
7.5: 2-Amino-N-(2,2-diethoxy-ethyl)-l-ethyl-7-iodo-4-oxo- 1,4-dihydroquinoline-
3-carboxamidine
0.38g (2.86mmol) of aminoacetaldehyde diethylacetal and 0.155g
(1.57mmol) of CuCl were added to 0.48.g (1.43mmol) of 2-amino-l-ethyl-7-iodo-4-
oxo-l,4-dihydro-quinoline-3-carbonitrile disolved in 20ml of DME. The solution was
stirred and irridiated with microwaves for 0.5 hour at 100°C.
The solution was then filtered off and evoporated to dryness. The raw
material was then purified by column chromatography (DCM/MeOH: 9/1) to yield
0.57 g (1.2mmol) of a solid.
Yield = 78%.
MH+ = 473 (Ci8H25IN40 3) .
7.6: 2-Amino-l-ethyl-3-(lH-imidazol-2-yl)-7-iodo-lH-quinolin-4-one
0.37ml of a 12N HC1 solution were added at 0°C to a suspension of 0.13.g
(0.28mmol) of 2-amino-N-(2,2-diethoxy-ethyl)- 1-ethyl-7-iodo-4-oxo- 1,4-dihydroquinoline-
3-carboxamidine. The reaction mixture was stirred at room temperature
during 16 hours. The reaction mixture was than diluted with 0.55 ml of water, basified
with 0.32ml of IN NaOH solution, and 0.134 ml of an NH4OH solution. The mixture
was then filtered and the resulting solid was washed with water, acetonitrile and
pentane to give 0.08g (0.21mmol) of a brown solid.
Yield = 76%.
MH+ = 381 (Ci4Hi3IN40).
7.7: 2-Amino-l-ethyl-7-((R)-3-hydroxy-4-methoxy-3-methyl-but-lynyl)-
3-(lH-imidazol-2-yl)-lH-quinolin-4-one
0.43mg (1.15mmol) of 2-amino-l-ethyl-3-(lH-imidazol-2-yl)-7-iodo-lHquinolin-
4-one, 0.262 (23mmol) of (R)-3-hydroxy-4-methoxy-3-methyl-but-l-yne, and
0.397g (3.45mmol) were mixed in 15ml of DMF. Argon was flushed through this
solution for 10 minutes. After addition of 0.126mg (0.17mmol) of 1,1 '-bis
(diphenylphosphino)ferrocene palladium dichloride and 0.033mg (0.17mmol) of copper
iodide, the reaction mixture was stirred at 80°C during 6 hours. The reaction mixture
was then evaporated to dryness and the residue poured into a mixture of DCM and
water. A black insoluble solid was filtered off (lOOmg). The aqueous phase was
extracted three times with dichloromethane. The combined organic phases were dried
over MgS04 and the solvents were evaporated off under reduced pressure. The residue
was then purified by column chromatography (DCM/MeOH/NH40H aq: 9/1/0.1) to
yield 0.80 g (1.2mmol) of yellow solid. This solid was recrystallized in
dichloromethane to yield 0.02g of a beige solid .
Yield = 4.5%.
MH+ = 367 (C20H22N4O3, 366.419).
1H NMR (DMSO-d6, 400MHz): 13.19 (s, 1H); 8.27 (d, 1H); 7.61 (s, 1H);
7.31 (d, 1H); 7.13 (s, 1H); 7.02 (s, 1H); 6.94 (broad signal, 2H); 4.36-4.28 (broad
signal, 2H); 3.45 - 3.25 (broad signal, water peak + 4H); 1.46 (s, 3H);1.31 (t, 3H)
Example 8: (Compound N°8)
2-Amino-7-(3-chloro-4-hydroxy-phenyl)-l-ethyl-3-(lH-imidazol-2-yl)-
1H-[1,8] naphthyridin-4-one
8.1: 2-Amino-7-(3-chloro-4-hydroxy-phenyl)-l-ethyl-3- [l-(2-
trimethylsilanyl-ethoxymethyl)-lH-imidazol-2-yl] -1H-[1,8] naphthyridin-4-one
In a round bottom flask 0.3g (0.71 mmol) 2-amino-7-chloro-l-ethyl-3-[l-(2-
trimethylsilanyl-ethoxymethyl)- 1H-imidazo 1-2-yl] -1H-[1,8]naphthyridin-4-one, 0.185g
(1.07 mmol) 3-chloro-4-hydroxy-phenylboronic acid, 0.098g (0.1 1 mmol) tris-
(dibenzylidenacetone) dipalladium (0), 0.030mg (0.0.1 lmmol) tricyclohexyl phosphine,
0.303g of potassium phosphate tribasic, and 8 mL of dioxane /water (50/50) (degassed)
were stirred and heated at 85°C for 8h. The solvents were evaporated and the residue
was purified by column chromatography (DCM/MeOH: 9/1) to yield 0.4 g of a brown
solid. This solid was engaged without further purification in the next step.
8.2: 2-Amino-7-(3-chloro-4-hydroxy-phenyl)-l-ethyl-3-(lH-imidazol-2-
yl)-1H-[1,8] naphthyridin-4-one
400 mg (0.59 mmol) of impure 2-amino-7-(3-chloro-4-hydroxy-phenyl)-lethyl-
3 -[1-(2-trimethylsilanyl-ethoxymethyl)- 1H-imidazo 1-2-yl] -1H-[1,8]naphthyridin-
4-one was dissolved in 20 ml DCM. At 0°C, 3.39g of TFA were added and the mixture
was stirred at room temperature for 24 hours. The solution is neutralized by adding an
excess of aqueous NaHC0 3 solution. The mixture was then extracted three times with
DCM. The combined organic phases were dried over MgS0 4 and the solvents were
evaporated off under reduced pressure. The so-gained raw material was purified on
silica gel (DCM:MeOH:NH 4OH = 4:10.1) yielding 0.035 g of the unprotected title
compound.
Yield for 2 steps = 13%.
MH+ = 382 (Ci H 6ClN50 2, 381.821).
1H NMR (DMSO-d6, 400MHz): 13.19 (s, 1H); 8.55 (d, 1H); 8.2 (s, 1H);
8.04 (dd, 1H); 7.9 (s, 1H); 7.15 (s, 1H); 7.09 (d, 1H); 7.3 (s, 1H); 4.72-4.66 (m, 2H);
1.37 (t, 3H).
Example 9: (Compound N°9)
2-Amino-l-ethyl-7-[3-(2-fluorophenyl)-3-hydroxy-but-l-ynyl]-3-(lHimidazol-
2-yl)-1H-[1,8] naphthyridin-4-one
9.1: 2-Amino-l-ethyl-7-chloro-3-(lH-imidazol-2-yl)-lH-
[1,8] naphthyridin-4-one
2-Amino-7-chloro- 1-ethyl-3-[ 1-(2-trimethylsilanyl-ethoxymethyl)- 1Himidazol-
2-yl]-lH-[l,8]naphthyridin-4-one (1.0 g, 2.38 mmol) was dissolved in 30mL
of dichoromethane. 30mL of trifluoroacetic acid were added and the reaction mixture
was stirred at room temperature for 3h, until analytical HPLC showed complete
consumption of the starting material. Solvents were removed under reduced pressure,
and ethyl acetate was added to the residue. The solution was washed with saturated
aqueous sodium bicarbonate. The formed precipitate was collected by filtration, then
put to dry out overnight at 40°C under vacuum, yielding 574mg of beige powder.
Yield = 83%.
1H NMR (DMSO-d6, 600 MHz): (ppm) 13.09 (s, 1H); 8.57 (d, 1H); 7.47
(d, 1H); 7.15 (s, 1H); 7.03 (s, 1H); 4.51 (bq, 2H); 1.29 (t, 3H).
9.2: 2-Amino-l-ethyl-7-[3-(2-fluorophenyl)-3-hydroxybut-l-ynyl]-3-
(lH-imidazol-2-yl)-lH-[l,8]naphthyridin-4-one
Copper (I) iodide (23.7 mg, 0.12 mmol), N-ethylmorpholine (130 , 1.04
mmol) and 2-(2-fluorophenyl)but-3-yn-2-ol (76, 0.52 mmol) were added to 2.5 mL
of DMF. The mixture was degassed with argon. [l,l'-Bis(diphenylphosphino)ferrocene]
palladium (II) chloride 1:1 complex with dichloromethane (5.6 mg, 0.01 mmol) and
intermediate 20.1 (100 mg, 0.35 mmol) were added. The mixture was stirred at 80°C
under argon atmosphere for 2h, until no remaining starting material was observed in
LCMS. Ethyl acetate was added. The organic layer was successively washed with
water, IN aqueous sodium hydroxide solution, saturated aqueous sodium chloride
solution, then dried over magnesium sulfate. The solvent was evaporated off under
reduced pressure. The residue was then purified by column chromatography
(DCM/MeOH/NH 4OH aq: 100/0/0 95/5/0.5) to yield 30 mg of off-white powder.
Yield = 21%.
MH+ = 418.
Rt = 0.57 min (C2 3H 2oFN50 2, 417.442).
1H NMR (DMSO-d6, 600 MHz): 13.10 (bs, 1H); 8.54 (d, 1H); 7.72
(dt, 1H); 7.44 (d, 1H); 7.38 (m, 1H); 7.25-7.19 (m, 2H); 7.13 (d, 1H); 7.02 (d, 1H); 6.62
(s, 1H); 4.54 (bq, 2H); 1.84 (s, 3H); 1.27 (t, 3H).
Example 10: (Compound N°12)
2-Amino-7-(3-hydroxypent-l-ynyl)-3-(lH-imidazol-2-yl)-l-(2-
methoxyethyl)-1H-[1,8] naphthyridin-4-one
Similar procedure as that described in example 6 step 1 and 2, starting step
1 from 2-methoxyethanamine instead of cyclopropylmethylamme and then following
same procedure as in example 20 step 2, starting from pent-l-yn-3-ol instead of 2-(2-
fluorophenyl)but-3-yn-2-ol. 15 mg of product is obtained as a powder.
MH+ = 368.
Rt = 0.46 min (Ci9H 2i 50 3 367,407).
Example 11: (Compound N°19)
2-Amino-l-ethyl-3-(lH-imidazol-2-yl)-7-(4,4,4-trifluoro-3-hydroxy-3-
phenyl-but- 1-ynyl)-1H-[1,8] naphthyridin-4-one
11.1: 2-Amino- l-ethyl-7-(4,4,4-trifluoro-3-hydroxy-3-phenyl-but- 1-
ynyl)-3- [l-(2-trimethylsilanyl-ethoxym ethyl)- 1H-imidazol-2-yl] -1H-
[1,8] naphthyridin-4-one
Same procedure as that described in example 5, stage 5.4, starting from
0.4 g (0.95 mmol) of 2-amino-7-chloro-l-ethyl-3-[l-(2-trimethylsilanyl-ethoxymethyl)-
lH-imidazol-2-yl]-lH-[l,8]naphthyridin-4-one, 0.4 g (1.9 mmol) l,l,l-trifluoro-2-
phenyl-but-3-yn-2-ol, 33mg (0.05 mmol), bis(triphenylphosphine)palladium(II)
dichloride, 18 mg (0.1 mmol) copper (I) iodide, 3 ml DMF (degassed), 3 ml
triethylamine (degassed) . 0.15 g of the title compound is obtained.
Yield = 30%.
MH+ = 584 (C29H32N50 3Si).
1H NMR (250 MHz, DMSO-d6) ppm 8.52 (d, J=7.91 Hz, 1 H) 8.21 (s, 1
H) 7.76 - 7.84 (m, 2 H) 7.72 (br. s, 2 H) 7.64 (d, J=7.91 Hz, 1 H) 7.46 - 7.57 (m, 3 H)
7.33 (d, J=1.34 Hz, 1 H) 7.10 (d, J=1.34 Hz, 1 H) 5.28 (s, 2 H) 4.44 - 4.57 (m, 2 H) 3.16
- 3.27 (m, 2 H) 1.28 (t, J=6.91 Hz, 3 H) 0.57 - 0.69 (m, 2 H) -0.22 (s, 9 H)
11.2: 2-Amino-l-ethyl-3-(lH-imidazol-2-yl)-7-(4,4,4-trifluoro-3-
hydroxy-3-phenyl-but-l-ynyl)-lH-[l,8]naphthyridin-4-one
Same procedure as that described in example 5, stage 5.5, starting from
0.145 g (0.25 mmol) of the compound obtained at the end of stage 21.1, in 1.2 ml TFA
and 1.2 ml DCM, 97 mg of the title compound is obtained.
Yield = 86 %.
Melting point = 260°C.
MH+ = 454 (C23Hi F3 502).
Rt= 7.29 min.
1H NMR (400 MHz, DMSO-d6), ppm 13.12 (br. s., 1 H) 11.58 (br. s.,
1 H) 8.63 (d, J=7.87 Hz, 1 H) 8.21 (s, 1 H) 8.19 (br. s, 1 H) 7.77 - 7.82 (m, 2 H) 7.66
(d, J=7.87 Hz, 1 H) 7.46 - 7.55 (m, 3 H) 7.14 (br. s., 2 H) 4.57 (q, J=6.59 Hz, 2 H) 1.30
(t, J=7.00 Hz, 3 H)
Compounds 10 and 11 are prepared with a similar procedure as that
described in example 6.
Compounds 13, 14, 15, 16, 17, 18, 20, 21, 25 are prepared with a similar
procedure as that described in example 10.
Compounds 22, 23 and 24 are prepared with a similar procedure as that
described in example 11.
Compound 29 is prepared with a similar procedure as that described in
example 1.
Equipment used for Examples 5 and 6
Microwave apparatus: Biotage, initiator
Analytical method LC/UV/MS Retention time (Rt) detection
Analytical method LC/UV/MS used to analyze compounds (Rt) 1, 2, 3 and,
Column: Merk Chromolith performance RP18e, 100 x 4.6 mm, 3.5 
Solvent A: H20/TFA (99.9/0.1)
Solvent B: ACN/TFA (99.9/0.1)
Flow rate: 2 ml/min
Gradient (A/B): 98/2 (0 min) to 0/100 (8 min) to 98/2 (10 min)
Detection: 254.16 nM
Analytical method LC/UV/MS used to analyze compound (Rt) 9, 12, 13, 14,
17, 18 and 20:
UPLC SOD Electrospray ionization, positive mode (30V)
Column: Ascentis Express 50x2. lmm 2.7, T=55°C
Solvent A: H2O+0.02% TFA
Solvent B: CH CN+0.014% TFA
Flow rate: 1 mL/min
Gradient (A B v/v): 98/2 (t=0min), 2/98 (t=lmin), 2/98 (t=1.3min), 98/2
(t=1.33min), next injection (t=1.5 min)
Detection: 220 nm
Analytical method used to analyze compounds 5, 6, 10, 11, 19, 22. 23 and
HPLC chain: Series 1100, Mass spectrometer MSD SL (Agilent)
Software: Chemstation version B.01 .03 from Agilent
Ionization mode: Electrospray positive mode ESI+
Mass range: 90-1500 uma
Column: Symmetry C18 3.5 (2. 1 x 50 mm) (Waters) T= 25°C, pH: 3
Eluents: A: H20 + 0.005% TFA / B: CH3CN + 0.005% TFA
Flow: 0.4 ml/min
Gradient: 0 to 10 min 0 to 100% B and from 10 to 15 min 100 B%
Detection: 220 nm
Analytical method LC/UV/MS used for compounds (Rt) 7. 8, 15, 16. 21. 25.
UPLC LCT Electrospray ionization, positive mode (15V30V)
Software : Masslyx V4. 1
Column: Acquity UPLC BEH CI850x2. lmm 2.7, T=40°C
Solvent A: H2O+0.05% TFA
Solvent B: CH3CN+0.035% TFA
Flow rate : 1 mL/min
Gradient (A/B v/v): 98/2 (t=0min), 0/100 (t=1.6min), 0/100 (t=2.1min),
98/2 (t=2.5min), next injection (t= 3 min)
Detection: at 220nm
NMR
The 1H NMR spectra were obtained using NMR spectrometers Bruker 250,
300, 400, or 600 MHz in DMSO-d6, using the peak of DMSO-d5 as internal reference.
The chemical shifts expressed in parts per million (ppm).
The signals observed are expressed as follows: s = singlet; d = doublet; t =
triplet; q = quadruplet; m = multiplet or large singlet; br = broad; H = proton.
Melting points
The melting points below 260°C were measured with a Kofler bench and
melting points above 260°C were measured with a Buchi B-545 instrument.
Rotatory powers
The rotatory powers were measured on a polarimeter of the type:
Polarimeter Perkin-Elmer, energy 55.
Table 1

N CC isopropyl H H Et H Rac. 352 (0.69min)
N CC phenyl H H Et H Rac. 386 (0.74min)
N CC -CH2OH Me H Et H R 354.16 (0.77min)
N CC -CH2OH Me H Et H S 354.16 (0.77min)
N CC Me H Et H S 368.2 (0.59min)
CH2OCH3
The compounds according to the invention were the subject of
pharmacological assays for determining their inhibitory effect on autophosphorylation
of VEGFR-3 as well as to evaluate their ex vivo activity described in the assay below.
Effect of compounds on VEGFR-3 auto-phosphorylation in HEK cells
The effects of compounds in blocking VEGFR-3 autophosphorylation were
quatified by ELISA after Overexpression of VEGFR-3 in HEK cells. HEK293T cells
were maintained in MEM supplemented with 10% foetal calf serum (FCS) and
glutamine. The day before transfection, 104 cells/ well were seeded on 48 wells plates
and transfection was done using Fugene-6 (Roche, Basel). Fugene-6 (18 ) was
preincubated for 5 min with 282 ΐ of optimem. Then 3 g DNA corresponding VFGR-
3-Flag was added and left at room temperature during 10 min before distributing 200 ΐ
on HEK cells. After 24h, the medium was removed and replaced by a new one without
serum and incubated for l h with different concentrations (ranging from 3 to )
of each compound. After additional 30 min incubation with Orthovanadate (0.4mM),
cells were washed with cold PBS supplemented by orthovanadate and then lysed with
300 ΐ of RIPA buffer. Lysates were then centrifuged during 10 min at 10000 g.
Supernatants (75 ΐ) were distributed in duplicate on 96 well plate precoated with the
anti-Flag and left during 1 hour at room temperature. After 3 washes with TBS buffer
containing 0.5% tween20, the anti-phospho-tyrosine conjugated to the HRP was added
and incubated for 1 hour at room temperature. Wells were then washed 3 times with
TBS buffer containing tween 20 (0.5 %) and MgCl2 (2 mM). The reaction was stopped
with 50 ΐ of H2S0 4 (2 N) and the signal was read at Envision at 485 and 530.
The concentration-response curves were analyzed with internal software
Biost@t-SPEED v2.0 using the 4-parameter logistic model according to Ratkovsky and
Reedy (Ratkovsky DA., Reedy TJ. Choosing near-linear parameters in the four
parameters logistic model radioligands and related assays. Biometrics 1986 Sep
42(3):575-82.)
The compounds according to the invention have an inhibitory activity on
the autophosphorylation of VEGFR-3 and exhibiting IC50 values of less than in
the autophosphorylation in HEK cells, particularly between 1 and 500nM, more
particularly between 1 and lOOnM.
By way of examples, the IC50 values of some compounds of Table 1 are
indicated in Table 2 below.
Table 2
No. of the compound ICso (nM)
1 25
2 18
3 125
4 40
5 45
6 85
7 19
8 73
9 16
10 37
11 334
12 166
13 4 1
14 200
15 27
16 119
17 13
18 36
19 14
2 1 24
22 38
23 19
24 85
25 303
26 120
27 47
28 153
29 145
The inhibitors of VEGFR-3 tyronise kinase according to the invention
present a good ex vivo activity using an assay measuring the inhibition of
autophosphorylation of VEGFR3, even better that the one of the inhibitors of the prior
art.
Ex vivo assay
Protocol for administration of the products to the mice:
The products are prepared in a mortar with 0.5% Tween 80 and 0.6%
methylcellulose qs final volume. The suspensions are administered by gavage
(lOml/kg) to male Balb/c mice 8 to 15 weeks old. Three hours or 6 hours after single
oral administrations of 30 mg/kg, animals were anaesthetized with pentobarbital and
blood samples (400 ) were collected from cava vein and transferred into glass tubes
containing lithium heparin. After centrifugation (1500 - 2000 g forlO minutes), plasma
samples were frozen at a temperature close to -20°C until analysis.
In order to detect the ex vivo activity of the products in the plasmas, we
have used the autophosphorylation assay in HEK cells described earlier. For this
purpose, transfected cells were incubated with plasma (10%>) instead of compounds.
Results are expressed as percent of inhibition of VEGFR-3 autophosphorylation in
comparison to untreated cells (maximum autophosphorylation) and to untransfected
cells (background).
The ex vivo activity of the compounds of the invention are summarized in
the following table 3. Results are expressed as a percentage of inhibition of VEGFR-3
auto-phosphorylation of in HEK cells, in presence of a plasma sample collected (at a
time), after per os (p.o.) administration of compounds. In order to evaluate the increase
of this activity for compounds of the invention, a comparison with compounds of the
prior art (WO 2009/007535) and subjected to the same measurement is made in table 3.
Table 3
Comparison of ex vivo activity between of compounds from this invention
and the corresponding compound of the prior art after p.o administration to male Balb/c
mice
It t ere ore appears t at compoun s accor ng to t e nvent on ave an
inhibitory activity on the autophosphorylation of VEGFR-3, they may therefore be used
5 in the preparation of medicaments, in particular of medicaments which inhibit
VEGFR-3.
The increase of exposure of the compound particularly the bioavailability is
one of the criterium for the increase in the ex vivo inhibition of the autophosphorylation
of VEGFR3 of compound of the invention.
The inhibitors of VEGFR-3 tyronise kinase according to the invention
present a good bioavaibility, even better that the one of the inhibitors of the prior art.
The bioavailability refers to the extent to and rate at which the active moiety
(drug or metabolite) enters systemic circulation, thereby accessing the site of action.
Bioavailability of a drug is largely determined by the properties of the
dosage form (which depend partly on its design and manufacture), rather than by the
drug's physicochemical properties, which determine absorption potential. Differences in
bioavailability among formulations of a given drug can have clinical significance; thus,
knowing whether drug formulations are equivalent is essential.
The bioavailability is used to describe the fraction of an administered dose
of unchanged drug that reaches the systemic circulation, one of the principal
pharmacokinetic properties of drugs. By definition, when a medication is administered
intravenously, its bioavailability is 100%. However, when a medication is administered
via other routes (such as orally), its bioavailability decreases (due to incomplete
absorption and first-pass metabolism) or may vary from patient to patient (due to interindividual
variation). Bioavailability is one of the essential tools in pharmacokinetics,
as bioavailability must be considered when calculating dosages for non-intravenous
routes of administration.
Thus, according to another of its aspects, a subject of the invention is
medicaments which comprise a compound of formula (I), or an addition salt of the
latter with a pharmaceutically acceptable acid or base, and also an enantiomer or a
diastereoisomer, including a mixture thereof, of the compound of formula (I).
Another aspect of the invention comprises a combination of at least one
compound according to the invention and at least one therapeutic agent.
Specifically, the compounds of the present invention may be used alone or
as a mixture with at least one therapeutic agent that may be selected from:
- alkylating agents,
- intercalating agents,
- antimicrotubule agents,
- antimitotics,
- antimetabolites,
- antiproliferative agents,
- antibiotics,
- immunomodulatory agents,
- anti-inflammatories,
- kinase inhibitors,
- anti-angiogenic agents,
- antivascular agents,
- oestrogenic and androgenic hormones.
It is also possible to combine the compounds according to the invention
with a radiation treatment.
The combinations of the compounds of the invention with the therapeutic
agents mentioned above and/or radiation are another subject of the present invention.
The therapeutic agents mentioned above and/or the radiation may be
administered simultaneously, separately or sequentially. The treatment will be adjusted
by the practitioner according to the patient to be treated.
These medicaments are used therapeutically, in particular in the treatment
and/or prevention:
- of cancers and metastases thereof, such as glioblastomas, multiple
myelomas, myelodysplasic syndromes, Kaposi's sarcomas, cutaneous angiosarcomas,
solid tumours, lymphomas, melanomas, breast cancers, colorectal cancers, lung cancers,
including non-small-cell cancers, pancreatic cancers, prostate cancers, kidney cancers,
head and neck cancers, liver cancers, ovarian cancers, cancers of the respiratory tract
and chest, other tumours expressing VEGFR-3 or involving a process of angiogenesis
or of lymphangiogenesis,
- of non-oncological proliferative diseases and pathological angiogenesis
linked to VEGFR-3, such as arthrosis, restenosis, psoriasis, hemangiomas,
lymphangiomas, glaucomas, glomerulonephritis, diabetic nephropathies,
nephrosclerosis, thrombotic microangiopathic syndromes, liver cirrhosis,
atherosclerosis, organ transplant rejection, eye diseases involving a process of
angiogenesis or of lymphangiogenesis, such as diabetic retinopathy or macular
degeneration,
- or else in the treatment and prevention of inflammation (chronic or nonchronic),
of infection with microorganisms and of autoimmune diseases, such as
rheumatoid arthritis,
- or else in the treatment of rare diseases such as
lymphangioleiomyomatosis.
According to another of its aspects, the present invention relates to
pharmaceutical compositions comprising, as active ingredient, a compound 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, a
hydrate or a 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 invention for oral, sublingual,
subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal,
transdermal or rectal administration, the active ingredient of formula (I) above, or
possible salt, solvate or hydrate thereof, may be administered in unit administration
form, as a mixture with conventional pharmaceutical excipients, to animals and to
human beings for the treatment or prevention of the disorders or diseases above.
The appropriate unit administration forms comprise oral administration
forms, such as tablets, soft or hard gel capsules, powders, granules and oral solutions or
suspensions, sublingual, buccal, intratracheal, intraocular and 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.
By way of example, a unit form of administration 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
Croscarmellose sodium 6.0 mg
Corn starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
According to another its aspects, the present invention also relates to a
method of treating the pathologies 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 thereof.
CLAIMS
1. Compound corresponding to formula (I):
0)
in which:
W represents a nitrogen atom or a group CH;
Y represents a group C2-C3-alkynylene, a 1,4-phenylene optionally
substituted with R which represents one or more halogen atom(s);
Z represents a bond or a group CRiR2;
- Ri and R2, independently of each other, represent a group chosen from a
hydrogen atom, a group Ci-C6-alkyl, a trifluoromethyl group, a group (CH2) OR6, C3-
C7-cycloalkyl, an heteroaryl or an aryl optionally substituted with one or more halogen
atom(s) ;
Ri and R2 can form together, with the carbon atom which bear them, a C3-
C -cycloalkyl;
R3 represents a hydrogen atom;
R4 represents a group chosen from a group Ci-C6-alkyl, a group (CH2) OR6,
C3-C7-cycloalkyl or Ci-C6-alkyl optionally substituted by a C3-C7-cycloalkyl;
R represents a group chosen from a hydrogen atom or a group Ci-C6-alkyl;
represents a group chosen from a hydrogen atom or a group Ci-C6-alkyl;
n is equal to 1, 2 or 3;
in the form of the base or of an acid-addition salt.
2. Compound of formula (I) according to Claim 1, characterized in that W
represents a nitrogen atom or a group CH, in the form of the base or of an acid-addition
salt.
3. Compound of formula (I) according to Claim 1 or 2, characterized in that W
represents a nitrogen atom, in the form of the base or of an acid-addition salt.
4. Compound of formula (I) according to any one of Claims 1 to 3,
characterized in that Y represents a group C2-C3-alkynylene„ more particularly
ethynylene, in the form of the base or of an acid-addition salt.
5. Compound of formula (I) according to any one of Claims 1 to 4,
characterized in that:
Z represents a bond, a group CRiR2;
Ri represents a group chosen from a hydrogen atom, a group Ci-C6-alkyl, a
group (CH2) OR6, C3-C -cycloalkyl, an aryl or a 5- or 6-membered-heteroaryl;
R2 represents a group chosen from a hydrogen atom, a group Ci-C6-alkyl or
a trifluoromethyl;
R represents a group chosen from a hydrogen atom or a group Ci-C6-alkyl;
n is equal to 1, 2 or 3;
in the form of the base or of an acid-addition salt.
6. Compound of formula (I) according to any one of Claims 1 to 5,
characterized in that:
Z represents a group CRiR2;
Ri represents a group chosen from a hydrogen atom, a group Ci-C6-alkyl, a
group (CH2) OR6, C3-C -cycloalkyl, an aryl or a 5- or 6-membered-heteroaryl;
R2 represents a group chosen from a hydrogen atom, a group Ci-C6-alkyl or
a trifluoromethyl;
Re represents a group chosen from a hydrogen atom or a group Ci-C6-alkyl;
and
n is equal to 1, 2 or 3;
in the form of the base or of an acid-addition salt.
7. Compound of formula (I) according to any one of Claims 1 to 6,
characterized in that R4 represents a group chosen from a group Ci-C6-alkyl, a group
(CH2) OR6, C3-C7-cycloalkyl or Ci-C6-alkyl optionally substituted by a C3-C7-
cycloalkyl, in the form of the base or of an acid-addition salt.
8. Compound of formula (I) according to any one of Claims 1 to 7,
characterized in that R4 represents a group Ci-C6-alkyl, more particularly an ethyl, in
the form of the base or of an acid-addition salt.
9. Compound of formula (I) according to any one of Claims 1 to 8,
characterized in that R represents a group chosen from a hydrogen atom or a group Ci-
C -alkyl, in the form of the base or of an acid-addition salt.
10. Compound of formula (I) according to any one of Claims 1 to 9,
characterized in that R represents a hydrogen atom, in the form of the base or of an
acid-addition salt.
11. Compound of formula (I) according to any one of Claims 1 to 10,
characterized in that:
W represents a nitrogen atom or a group CH;
- Y represents a group C2-C3-alkylyne or a 1,4-phenylene optionnally
substituted with R which represents a halogen atom;
Z represents a bond, a group CRiR2;
Ri represents a group chosen from a hydrogen atom, a group Ci-C6-alkyl, a
group (CH2) OR6, C3-C7-cycloalkyl, an aryl or a 5- or 6-membered-heteroaryl
optionally substituted with a halogen atom;
R2 represents a group chosen from a hydrogen atom, a group Ci-C6-alkyl or
a trifluoromethyl;
R 3 represents a hydrogen atom ;
R4 represents a group chosen from a group Ci-C6-alkyl, a group (CH2) OR6,
C3-C7-cycloalkyl or Ci-C6-alkyl optionally substituted by a C3-C7-cycloalkyl;
R represents a group chosen from a hydrogen atom or a group Ci-C6-alkyl;
represents a group chosen from a hydrogen atom or a group Ci-C6-alkyl;
n is equal to 1, 2 or 3;
in the form of the base or of an acid-addition salt.
12. Compound of formula (I) according to any one of Claims 1 to 11,
characterized in that Ri and R2 form together, with the carbon atom which bear them, a
C3-C7-cycloalkyl, in the form of the base or of an acid-addition salt.
13. Compound of formula (I) according to Claim 1, chosen from:
2-Amino- 1-ethyl-7-((3R)-3 -hydroxy-4-methoxy-3-methyl-but- 1-ynyl)-3 -(lHimidazol-
2-yl)- lH-[ 1,8]naphthyridin-4-one
2-Amino- 1-propyl-7-((3R)-3 -hydroxy-4-methoxy-3-methyl-but- 1-ynyl)-3 -(lHimidazol-
2-yl)- lH-[ 1,8]naphthyridin-4-one
2-Amino-7-(3 ,4-dihydroxy-3 -methyl-but- 1-ynyl)- 1-ethyl-3 -(1H-imidazo 1-2-yl)-
lH-[l,8]naphthyridin-4-one
2-Amino- 1-ethyl-7-(-3 -hydroxy-3 -pyridin-2-yl-but- 1-ynyl)-3 -(1H-imidazo 1-2-
yl)- 1H-[ 1,8]naphthyridin-4-one
2-Amino- 1-ethyl-7- [(3R)-3-hydroxy-4-methoxy-3 -methyl-but- 1-ynyl]-3-(4-
methyl- 1H-imidazo 1-2-yl)- 1-[1,8]naphthyridin-4-one
2-Amino- 1-(cyclopropylmethyl)-7-(3 -hydroxy-pent- 1-ynyl)-3 -(1H-imidazo 1-2-
yl)- 1H-[1,8]naphthyridin-4-one
2-Amino- 1-ethyl-7- [(3R)-3 -hydroxy-4-methoxy-3 -methyl-but- 1-ynyl] -3-(1Himidazo
1-2-yl)- 1H-quino lin-4-one
2-Amino-7-(3 -chloro-4-hydroxy-phenyl)- 1-ethyl-3 -(1 H-imidazo 1-2-yl)- 1H-
[1,8]naphthyridin-4-one
2-Amino- 1-ethyl-7- [3-(2-fluorophenyl)-3 -hydroxy-but- 1-ynyl]-3-(1H-imidazo 1-
2-yl)- 1H-[1,8]naphthyridin-4-one
2-Amino- 1-cyclopentyl-7-(3-hydroxy-pent- 1-ynyl)-3-( 1H-imidazo 1-2-yl)- 1H-
[1,8]naphthyridin-4-one
2-Amino-7-(3 -hydroxy-pent- 1-ynyl)-3-(l H-imidazo 1-2-yl)- 1-(3-
methoxypropyl)- 1H-[ 1,8]naphthyridin-4-one
2-Amino-7-(3-hydroxy-pent- 1-ynyl)-3-( 1H-imidazo 1-2-yl)- 1-(2-methoxyethyl)-
lH-[l,8]naphthyridin-4-one
2-Amino- 1-ethyl-7- [( 1-hydroxycyclobutyl)ethynyl] -3-(1H-imidazo 1-2-yl)- 1H-
[1,8]naphthyridin-4-one
2-Amino- 1-ethyl-7- [( 1-hydroxy cyclopentyl)ethynyl] -3-(1H-imidazo 1-2-yl)- 1H-
[1,8]naphthyridin-4-one
2-Amino- 1-ethyl-7-(3 -hydroxy-3 -methyl-but- 1-ynyl)-3 -(1H-imidazo 1-2-yl)- 1H-
[1,8]naphthyridin-4-one
2-Amino- 1-ethyl-7-(3 -hydroxy-3 -methyl-pent- 1-ynyl)-3 -(1H-imidazo 1-2-yl)-
lH-[l,8]naphthyridin-4-one
2-Amino- 1-ethyl-7-(3 -hydroxy-3 -phenyl-but- 1-ynyl)-3 -(1H-imidazo 1-2-yl)- 1H-
[l,8]naphthyridin-4-one
2-Amino- 1-ethyl-7- [3-(3 -fluorophenyl)-3 -hydroxy-but- 1-ynyl]-3-(1H-imidazo 1-
2-yl)- 1H-[1,8]naphthyridin-4-one
2-Amino-l-ethyl-3-(lH-imidazol-2-yl)-7-(4,4,4-trifluoro-3-hydroxy-3-phenylbut-
1-ynyl)- 1H-[1,8]naphthyridin-4-one
2-Amino-7-(3 -cyclopropyl-3 -hydroxy-but- 1-ynyl)- 1-ethyl-3 -(1H-imidazo 1-2-
yl)- 1H-[ 1,8]naphthyridin-4-one
2-Amino- 1-ethyl-7- [3-hydroxy-3 -(thiophen-2-yl)but- 1-ynyl]-3-(1H-imidazo 1-2-
yl)- 1H-[ 1,8]naphthyridin-4-one
2-Amino- 1-ethyl-7-(3 -hydroxy-but- 1-ynyl)-3 -(1H-imidazo 1-2-yl)- 1H-
[1,8]naphthyridin-4-one
2-Amino- 1-ethyl-7-(3 -hydroxy-pent- 1-ynyl)-3 -(1H-imidazo 1-2-yl)- 1H-
[ 1,8]naphthyridin-4-one
2-Amino- 1-ethyl-7-(3 -hydroxy- hex- 1-ynyl)-3 -(1H-imidazo 1-2-yl)- 1H-
[1,8]naphthyridin-4-one
2-Amino- 1-ethyl-7-(3 -hydroxy-4-methyl-pent- 1-ynyl)-3 -(1H-imidazo 1-2-yl)-
lH-[l,8]naphthyridin-4-one
2-Amino- 1-ethyl-7-(3 -hydroxy-3 -phenyl-prop- 1-ynyl)-3 -(1H-imidazo 1-2-yl)-
lH-[l,8]naphthyridin-4-one
2-Amino-7-((3R)3 ,4-dihydroxy-3 -methyl-but- 1-ynyl)- 1-ethyl-3 -(1H-imidazo 1-
2-yl)- 1,8-naphthyridin-4( 1H)-one
2-Amino-7-((3 S)3 ,4-dihydroxy-3 -methyl-but- 1-ynyl)- 1-ethyl-3 -(1H-imidazo 1-2-
yl)- 1,8-naphthyridin-4( 1H)-one
2-Amino- 1-ethyl-7-((3 S)-3-hydroxy-4-methoxy-3 -methyl-but- 1-ynyl)-3 -(1Himidazo
1-2-yl) -l,8-naphthyridin-4(lH)-one.
14. Process for preparing a compound of formula (I) according to any
Claims 1 to 13, characterized in that a compound of formula (VII):
in which X is a chlorine or a bromine and R 4 and R are as defined in the general
formula (I) according to any one of Claims 1 to 14, is reacted with a compound of
general formula (XVa):
in which Rl R2 and R 3 are as defined in the general formula (I) according to any
one of Claims 1 to 13,
or is reacted with a compound of general formula (XVb):
in which R3 and R7 are as defined in the general formula (I) according to any
one of Claims 1 to 13,
a conventional stage of deprotection being carried out before or after the
reaction of the compound of formula (VII) with the compound of general formula
(XVa) or the compound of general formula (XVb).
15. Medicament comprising a compound of formula (I) according to any one of
Claims 1 to 13, or a pharmaceutically acceptable salt, or an enantiomer or a
diastereoisomer, or a mixture thereof.
16. A pharmaceutical composition comprising a compound according to any
one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, or an enantiomer
or a diastereoisomer, or a mixture thereof, and also at least one pharmaceutically
acceptable excipient.
17. The combination of a compound of formula (I) according to any one of
Claims 1 to 13 with at least one therapeutic agent selected from:
- alkylating agents,
intercalating agents,
antimicrotubule agents,
antimitotics,
antimetabolites,
antiproliferative agents,
- antibiotics,
immunomodulatory agents,
anti-inflammatories,
kinase inhibitors,
anti-angiogenic agents,
- antivascular agents,
oestrogenic and androgenic hormones.
18. Compound of formula (I) according to any one of Claims 1 to 13 for use in
the preparation of a medicament for preventing and/or treating diseases in which
VEGFR-3 is involved.
19. Compound of formula (I) according to any one of Claims 1 to 13 for use in
the preparation of a medicament for preventing and/or treating cancer and metastases.
20. Compound of formula (I) according to any one of Claims 1 to 13 for use in
the preparation of a medicament for preventing and/or treating glioblastomas, multiple
myelomas, myelodysplasic syndromes, Kaposi's sarcomas, cutaneous angiosarcomas,
solid tumours, lymphomas, melanomas, breast cancers, colorectal cancers, lung cancers,
including non-small-cell cancers, pancreatic cancers, prostate cancers, kidney cancers,
head and neck cancers, liver cancer, ovarian cancers, cancers of the respiratory tract and
chest, or other tumours expressing VEGFR-3 or involving a process of angiogenesis or
of lymphangiogenesis.
21. Compound of formula (I) according to any one of Claims 1 to 13 for use in
the preparation of a medicament for preventing and/or treating non-oncological
proliferative disease or pathological angiogenesis linked to VEGFR-3.
22. Compound of formula (I) according to any one of Claims 1 to 13 for use in
the preparation of a medicament for preventing and/or treating diseases selected from
the group consisting of arthrosis, restenosis, psoriasis, hemangiomas, lymphangiomas,
glaucomas, glomerulonephritis, diabetic nephropathies, nephrosclerosis, thrombotic
microangiopathic syndromes, liver cirrhosis, atherosclerosis, organ transplant rejection,
or eye diseases involving a process of angiogenesis or of lymphangiogenesis.
23. Compound of formula (I) according to any one of Claims 1 to 13 for use in
the preparation of a medicament for preventing and/or treating chronic or non-chronic
inflammation, infection with microorganisms and of autoimmune diseases, such as
rheumatoid arthritis.
24. Compound of formula (I) according to any one of Claims 1 to 13 for use in
the preparation of a medicament for preventing and/or treating rare diseases such as
lymphagioleiomyomatosis or Gorham's Disease