QUINAZOLINEDIONE DERIVATIVES, PREPARATION THEREOF AND VARIOUS
THERAPEUTIC USES THEREOF.
The invention relates to quinazolinedione derivatives, to processes for obtaining
them, to synthetic intermediates thereof and to the therapeutic uses thereof.
The invention relates to quinazolinedione derivatives that may be inhibitors of
phosphodiesterase 7 (abbreviated as PDE7). Some of these derivatives may also
inhibit phosphodiesterase 8 (abbreviated as PDE8).
The invention also relates to the use of such quinazolinedione derivatives,
which are capable of acting as inhibitors of phosphodiesterase 7 (PDE7), or even, for
some of these derivatives, which are also capable of acting as inhibitors of
phosphodiesterase 8 (PDE8), given that it is not excluded for these same
quinazolinedione derivatives also to be capable of acting via other
biological/biochemical pathways.
Phosphodiesterases (PDEs) are intracellular enzymes responsible for the
hydrolysis of the secondary messengers cAMP (cyclic adenosine-3',5'-
monophosphate) and cGMP (cyclic guanosine-3',5'-monophosphate) into inactive 5'-
monophosphate nucleotides. cAMP and cGMP play an essential role in cell signalling
pathways and intervene in many physiological processes.
The inhibition of phosphodiesterases is reflected by an increase in the
intracellular concentrations of cAMP and cGMP, producing the specific activation of the
phosphorylation pathways involved in varied functional responses. Increasing the
intracellular concentrations of cAMP or cGMP with the aid of selective
phosphodiesterase inhibitors appears to be a promising approach for the treatment of
various diseases (Bender and Beavo, Pharmacol. Rev. (2006) 58, 488-520).
Phosphodiesterase inhibitors are thus of interest as therapeutic agents and as
pharmacological tools.
At the present time, eleven families of phosphodiesterases have been
identified. They are distinguished by their primary structure, their substrate specificity
and their sensitivity towards various specific PDE effectors and inhibitors. Each family
is formed from one or more genes that are expressed in different issues in the form of
splicing variants (Bender and Beavo, Pharmacol. Rev. (2006) 58, 488-520; Lugnier,
Pharmacol. Therapeut. (2006) 109, 366-398).
PDE4, 7 and 8 specifically hydroiyse cAMP, and PDE5, 6 and 9cGMP.
The PDE7 family is represented by the isoforms PDE7A and PDE7B,
originating from two distinct genes.

Human PDE7A (Michaeli et al., J. Biol. Chem. (1993) 268, 12925-12932; Han
et al., J. Biol. Chem. (1997) 272, 16152-16157; Wang et al., Biochem. Biophys. Res.
Commun. (2000) 276, 1271-1277) and human PDE7B (Sasaki et al., Biochem.
Biophys. Res. Commun. (2000), 271, 575-583; Gardner et al., Biochem. Biophys. Res.
Commun. (2000) 272, 186-192) selectively hydrolyse cAMP with Michaelis constants
(Km) of 0.1 to 0.2 uM and of 0.13 to 0.2 uM, respectively. The catalytic part of PDE7B
shows about 67% homology with that of PDE7A.
Three splicing variants are known for PDE7A. PDE7A1 and PDE7A3 are mainly
expressed in the cells of the immune system and the lungs, whereas PDE7A2 is
essentially expressed in skeletal muscle, the heart and the kidneys. For PDE7B, three
variants have also been recently identified (Giembycz and Smith, Drugs Future (2006)
31,207-229).
The tissue distribution profiles of PDE7A and PDE7B are very different,
suggesting that these two isoforms have different physiological functions. Whereas
PDE7A is abundantly expressed in haematopoietic cells, the lungs, the placenta,
Leydig cells, the spleen, the collecting tubes of the kidneys and the adrenal glands,
strong expression of PDE7B is detected in the pancreas, the heart, the thyroid and
skeletal muscle (Giembycz and Smith, Drugs Future (2006) 31, 207-229).
The localization of PDE7 in the organs mentioned above suggests that
selective PDE7 inhibitors might have uses in the field of muscular, renal, cardiac and
pancreatic diseases, such as in the treatment and/or prevention of diabetes.
A co-expression of messenger RNA (mRNA) and of PDE7A and PDE7B is,
however, observed in certain tissues. This is the case for osteoblasts (Ahlstrom et al.,
Cell. Mol. Biol. Lett. (2005) 10, 305-319) and for certain regions of the brain: several
zones of the cortex, the dentate gyrus, most of the components of the olfactory
system, the striatum, many thalamic nuclei and the pyramidal cells of the hippocampus
(Miro et al., Synapse (2001) 40, 201-214; Reyes-lrisarri et al., Neuroscience (2005)
132, 1173-1185). On the other hand, in certain regions of the brain, only one of the two
isoforms is expressed. Thus, only the mRNAs of PDE7A and are present in many
nuclei of the brain stem. Similarly, mRNAs and PDE7B are present in high
concentrations in the nucleus accumbens and the dorsal motor nucleus of the vagus
nerve, whereas the mRNAs of PDE7A and are not detected therein (Miro et al.,
Synapse (2001) 40, 201-214; Reyes-lrisarri et al., Neuroscience (2005) 132, 1173-
1185).
The protein PDE7A1 is clearly expressed in blood T lymphocytes, epithelial cell
lines of the bronchi, lung fibroblasts and eosinophils (Smith et al., Am. J. Physiol. Lung

Cell. Mol. Physiol. (2003) 284: L279-L289). Several reports suggest that PDE7A might
play a role in activating T lymphocytes (Li et al., Science (1999) 283, 848-851; Glavas
et al., PNAS (2001) 98, 6319-6324; Nakata et al., Clin. Exp. Immunol., (2002) 128,
460-466; Smith et al., Mol. Pharmacol. (2004) 66, 1679-1689). The protein PDE7A1 is
also expressed in cells that play a central role in the pathogenesis of asthma and
chronic obstructive pulmonary disease (COPD), such as the T lymphocytes (CD4+ and
CD8+), monocytes, neutrophils, alveolar macrophages, and smooth muscle cells of the
airways and of pulmonary vessels (Smith et al., Am. J. Physiol. Lung Cell Mol. Physiol.
(2003) 284: L279-L289). The localization of PDE7A in the pro-inflammatory cells and
the cells of the immune system and its potential role in activating T lymphocytes
suggest that selective PDE7 inhibitors might have applications in the field of diseases
associated with the T lymphocytes and in that of diseases of the lung pathways.
The protein PDE7A is also present in the B lymphocytes and in the cell line of B
WSU-CLL lymphocytes originating from a patient suffering from a chronic lymphocytic
leukaemia. Treatment of the WSU-CLL cells with IC242, a specific PDE7 inhibitor,
increases the expression of PDE7A (Lee et al., Cell Signal (2002) 14, 277-284).
Moreover, it has been shown that expression of the protein PDE7B is about 5 to 90
times higher in peripheral blood mononuclear cells (PBMC) of patients suffering from
chronic lymphocytic leukaemia (CLL-PBMC) than in PBMC isolated from the blood of
normal individuals (WO 2007/067 946). BRL-50481, a selective PDE7 inhibitor,
induces dose-dependent apoptosis of CLL-PBMCs, but it has no effect on the PBMCs
of normal individuals. These observations suggest that selective PDE7 inhibitors might
be effective in treating this type of leukaemia.
Selective PDE4 inhibitors increase bone mineral density in rats and mice, and
their effects appear to be associated with a reduction in the activity of osteoclasts and
an increase in that of osteoblasts (Miyamoto et al., Biochem. Pharmacol. (1997) 54,
613-617; Waki et al., Jpn J. Pharmacol. (1999) 79, 477-483; Kinoshita et al., Bone
(2000) 27, 811-817). PDE7 activity has been detected in osteoblasts (Ahlstrom et al.,
Cell Mol. Biol. Lett. (2005) 10, 305-319). By increasing the intracellular concentration of
cAMP, PDE7 inhibitors and PDE4 inhibitors might prove to be effective in the treatment
of osteopenia and osteoporosis.
Moreover, recent studies (WO 2006/092 691, WO 2006/092 692) report the
pharmacological activities of various PDE7 inhibitors in models of neuropathic pain in
rats, suggesting applications in the treatment of various types of pain and more
particularly in that of neuropathic pain.
Moreover, document WO 2008/119 057 describes a method for treating

movement anomalies associated with a neurological movement disorder pathology,
such as Parkinson's disease, the treatment method comprising the administration to a
patient of an amount of PDE7 inhibitor that is effective for inhibiting the enzymatic
activity of PDE7.
One subject of the invention is a compound of general formula (I) below:

in which A represents either an oxygen or sulfur atom, or a sulfoxide function (SO
function) or a sulfone function (SO2 function);
> n represents the value 0, 1 or 2;
> R2 represents an atom or a group chosen from:

• a hydrogen atom,
• a halogen atom,
• a cyano group,
• a nitro group,
• an aryl, arylalkyl or heteroaryl group,
• a group (CrC6)alkyl, optionally substituted with a function -NH2, with one
or more halogen atoms, with one or more hydroxyl groups, with an
alkynyl group, with an alkenyl group, with a group -NHC(0)Rb and/or
with a group -NHC(0)-NRbRc, Rb and Rc being defined below,
• a group -ORa, Ra being defined below,
• a group NRbRc, Rb and Rc being defined below,
• a group C(0)(CrC6)alkyl,
• an alkenyl group or an alkynyl group, the said groups being optionally
substituted with at least one hydroxyl or with at least one halogen atom;
• a group alkyl-S-,
• alkyl-S(O)-, and
• alkyl-S(0)r,
> p represents the value 1, 2 or 3, it being understood that when p is equal to 2 or 3,

then the atoms R2 or the groups R2 may be, respectively, identical or different;
> Ri represents an aryl, arylalkyl or heteroaryl group, the said groups being optionally
substituted with (i) an atom R3 or a group R3> or with (ii) 2 or 3 atoms and/or groups R3,
the said atoms or groups R3 being, respectively, identical or different,
given that R3 represents:
■ a hydrogen atom,
■ a halogen atom,
■ a hydroxyl group,
■ a cyano group,
■ a group -SCF3,
■ a nitro group,
■ a group -S(O)0-2-alkyl, a group -S(0)o.2-heterocycloalkyl, a group -0-SO2-aryl
or 0-SO2-arylalkyl optionally substituted with one or more halogen atoms;
■ an alkyl-amino-alkyl group or a -cycloalkyl-amino-alkyl group, the said groups
being optionally substituted on the terminal alkyl,
■ an optionally substituted sulfonamide group,

■ an aryl, arylalkyl or heteroaryl group, the said group being monocyclic or
polycyclic and moreover being optionally substituted with a group (d-C6)alkyl,
with one or more hydroxyl groups, with one or more halogen atoms, with one or
more cyano groups and/or with one or more groups (CrC6)alkoxy,
■ a heterocycloalkyl group optionally substituted with a group (C1-C6)alkyl,
■ a group (CrC6)alkyl optionally substituted with:

- one or more halogen atoms,
- an aryl or arylalkyl group that may be substituted with one or more
halogen atoms, with one or more groups (CrC6)alkoxy, with one or more
groups (CrC6)alkyl, with one or more cyano groups and/or with one or more
hydroxyl groups,
- a heteroaryl group,
- one or more hydroxyl groups that may be substituted with an aryl or
arylalkyl group, which is itself optionally substituted with one or more halogen
atoms, or
- a heterocycloalkyl group optionally substituted with a group CO(0)Ra,
or with a group (CrC6)alkyl, Ra being defined below,

■ a group -C(0)NRbRc, Rb and Rc being defined below,
■ a group -C(0)ORc, or a group -0-C(0)ORc, Rc being defined below,
■ a group (CrC6)alkoxy, optionally substituted with:

- an amino-alkyl group, an amino-cycloalkyl group,
- a cycloalkyl group,
- a heterocycloalkyl group,
- a monocyclic or polycyclic heteroaryl group,
- one or more hydroxyl groups,
- one or more halogen atoms,
- a group (CrC6)alkoxy,
- a group -C(0)ORc, Re being defined below,
- a group -C(0)NRbRc, Rb and Rc being defined below, and/or
- an aryl or arylalkyl group, which is itself optionally substituted with at
least one atom and/or at least one group, the said atoms and groups being
chosen from halogen atoms, a cyano group, groups (CrC6)alkoxy, -O-haloalkyl
groups and haloalkyl groups,
■ a group -O-cycloalkyl, -O-aryl or -O-arylalkyl, or a group -O-heterocycloalkyl,
the said groups being optionally substituted with:
- an aryl or arylalkyl group, which is itself optionally substituted with one
or more halogen atoms, or with a group (Ci-C6)alkyl,
- one or more halogen atoms, and/or
- a group (CrC6)alkyl, which may itself be substituted with an aryl or
arylalkyl group,

■ a group -NH-CO-NH-aryl, a group -NH-CO-NH-arylalkyl, a group -NH-CO-
NH-heteroaryl, or a group -NH-CO-NH-(Ci-C6)alkyl, the said aryl, arylalkyl, heteroaryl
and alkyl being optionally substituted with at least one atom and/or at least one group,
the said atoms and groups being chosen from halogen atoms, a cyano group, a nitro
group, a hydroxyl group and groups (d-C6)alkoxy,
■ a group -N-(CrC6)alkyl, the group (CrC6)alkyl possibly being substituted with
at least one aryl or arylalkyl group optionally substituted with at least one halogen atom
and/or with at least one group SO2, or
■ a group -NH-C(0)-aryl, a group -NH-C(0)-aralkyl or a group -NH-C(O)-
heteroaryl, the said groups being optionally substituted with at least one halogen atom;
> Ra represents:
o a hydrogen atom,
o a group (CrC6)alkyl or a group (CrC6)cycloalkyl, the said groups
being optionally substituted with one or more halogen atoms,
with one or more hydroxyl groups, with an aryl or arylalkyl group,
with one or more cyano groups and/or with a group

-C(0)NRbRc, Rb and Rc being defined below,
o a group (C2-C6)alkynyl,
o an aryl or arylalkyl group,
> Rb represents:
o a hydrogen atom,
o a group (CrC6)alkyl optionally substituted with one or more halogen
atoms, with one or more hydroxyl, cyano, amino, heterocycloalkyl or
(CrC6)alkoxy groups, or with an aryl or arylalkyl group optionally
substituted with one or more halogen atoms,
o a group (C3-C6) cycloalkyl,
o a group (C2-C6) alkenyl or alkynyl,
o a group (CrC6)alkoxy,
o an aryl or arylalkyl group optionally substituted with one or more halogen
atoms;
> Rc represents a hydrogen atom, or a group (Ci-Cejalkyl optionally substituted with
one or more halogen atoms;
> given that in the groups -NRbRc, Rb and Rc may form with the nitrogen atom a
heteroaryl or a heterocycloalkyl, the latter groups being optionally substituted;
in the form of the base or of an acid-addition salt.
According to one embodiment, the compound according to the invention is
characterized in that n is equal to 1; in the form of the base or of an acid-addition salt.
According to one embodiment, the compound according to the invention is
characterized in that p represents the value 1 or 2, it being understood that when p is
equal to 2, then the possible combinations are either (i) two identical or different atoms
R2, or (ii) an atom R2 and a group R2, or (iii) two identical or different groups R2; in the
form of the base or of an acid-addition salt.
According to one embodiment, the compound according to the invention is
characterized in that R2 represents an atom or a group chosen from:
• a halogen atom,
• a hydrogen atom,
• a nitro group,
• a cyano group,
• an aryl, arylalkyl or heteroaryl group,
• a group (CrC6)alkyl, optionally substituted with a function -NH2, with one
or more hydroxyl groups, with an alkynyl group, with one or more
halogen atoms, with a group -NHC(0)Rb with Rb being an optionally

substituted group (Ci-C6)alkyl. with a group -NHC(0)-NRbRc with Rb
and Re being hydrogen atoms and/or with an alkenyl group,
• a group -ORa, Ra being chosen from:
o a hydrogen atom,
o a group (CrC6)alkyl optionally substituted with one or more
halogen atoms, with one or more hydroxyl groups, with an aryl or
arylalkyl group, with one or more cyano groups and/or with a
group -C(0)NRbRc,
o a group (C1-C6)cycloalkyl,
o a group (C2-C6)alkynyl,
o an aryl group,
o an arylalkyl group,
• a group NRbRc, Rb being chosen from a hydrogen atom and a group
(Ci-C6)alkyl optionally substituted with a group (C2-C6)alkynyl and Re
being a hydrogen atom, or Rb and Re form with the nitrogen atom a
heterocycloalkyl, optionally substituted with a hydroxyl group;
• a group C(0)(C1-C6)alkyl, and
• an alkenyl group optionally substituted with at least one halogen atom;
in the form of the base or of an acid-addition salt.
According to another embodiment, the compound according to the invention is
characterized in that R2 represents an atom or a group chosen from:
• a halogen atom chosen from bromine, fluorine and iodine,
• a hydrogen atom,
• a nitro group,
• a cyano group,
• an aryl or heteroaryl group chosen from phenyl and pyridyl,

• a group (d-C6)alkyl, optionally substituted with a function -NH2l with one
or more hydroxyl groups, with an alkynyl group, with one or more
fluorine atoms, with a group -NHC(0)Rb with Rb being an optionally
substituted group (CrC6)alkyl, with a group -NHC(0)-NRbRc with Rb
and Re being hydrogen atoms and/or with an alkenyl group,
• a group -ORa, Ra being chosen from:
o a hydrogen atom,
o a group (CrC6)alkyl optionally substituted with one or more
halogen atoms, with one or more fluorine atoms, with one or
more hydroxyl groups, with a benzyl or phenyl group, with one or

more cyano groups and/or with a group -C(0)NRbRc, Rb and Rc
being hydrogen atoms,
o a group (C-pCe^ycloalkyl,
o a group (C2-C6)alkynyl,
o a benzyl,
• a group NRbRc, Rb being chosen from a hydrogen atom and a group
(CrC6)alkyl optionally substituted with a group (C2-C6)alkynyl and Rc
being a hydrogen atom, or Rb and Rc form with the nitrogen atom a
heterocycloalkyl, optionally substituted with a hydroxyl group;
• a group C(0)(CrC6)alkyl, and
• an alkenyl group optionally substituted with at least one fluorine atom;
in the form of the base or of an acid-addition salt.
According to another embodiment, the compound according to any one of the
preceding claims is characterized in that p is equal to 2 and the two groups and/or
atoms R2 are chosen from:
• a halogen atom, and
• a group -ORa, Ra being chosen from:
o a hydrogen atom, and
o a group (CrC6)alkyl optionally substituted with one or more
halogen atoms or with an aryl group;
in the form of the base or of an acid-addition salt.
According to another embodiment, the compound according to the invention is
characterized in that p is equal to 2 and the two groups and/or atoms R2 are chosen
from:
• a fluorine atom, and
• a group -ORa, Ra being chosen from:
o a hydrogen atom, and
o a group (CrC6)alkyl optionally substituted with one or more
fluorine atoms or with a phenyl group;
in the form of the base or of an acid-addition salt
According to another embodiment, the compound according to the invention is
characterized in that R, is a phenyl or a pyridyl, optionally substituted with (i) an atom
R3 or a group R3 or (ii) with two atoms and/or groups R3, the possible combinations
then being:
o either two identical or different atoms R3,
o or an atom R3 and a group R3,

o or two identical or different groups R3)
R3 being chosen from hydroxyl and (CrC6)alkoxy groups, the said groups (d-
C6)alkoxy being optionally substituted with an aryl or arylalkyl group, the said aryl or
arylalkyl group itself being optionally substituted with at least one halogen atom;
in the form of the base or of an acid-addition salt.
According to another embodiment, the compound according to the invention is
characterized in that Ri is a phenyl or a pyridyl, optionally substituted with (i) an atom
R3 or a group R3 or (ii) with two atoms and/or groups R3, the possible combinations
then being:
o either two identical or different atoms R3,
o or an atom R3 and a group R3,
o or two identical or different groups R3,
R3 being chosen from hydroxyl and (CrC6)alkoxy groups, the said groups (d-
C6)alkoxy being optionally substituted with a benzyl group, the said benzyl group itself
being optionally substituted with at least one chlorine atom;
in the form of the base or of an acid-addition salt.
Among the compounds of formula (I) that are subjects of the invention, mention
may be made of the following compounds:
- compound 1: 3-(3,4-dimethoxybenzyl)-6-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione;
- compound 2: {[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile;
- compound 3: 3-(3,4-dimethoxybenzyl)-6-pyridin-4-yl-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1H,3H)-dione hydrochloride;
- compound 4: 3-[(6-methoxypyridin-3-yl)methyl]-6-pyridin-4-yl-1-(tetrahydro-2H-pyran-
4-yl)quinazoline-2,4(1H,3H)-dione;
- compound 5: 6-bromo-3-[(6-methoxypyridin-3-yl)methyl]-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione;
compound 6: 6-bromo-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 7: 2-({3-[(6-methoxypyridin-3-yl)methyl]-2,4-dioxo-1-(tetrahydro-2H-pyran-
4-yl)-1,2,3,4-tetrahydroquinazolin-6-yl}oxy)propanenitrile
- compound 8: 2-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}propanenitrile
- compound 9: ({3-[(6-methoxypyridin-3-yl)methyl]-2,4-dioxo-1-(tetrahydro-2H-pyran-4-
yl)-1,2,3,4-tetrahydroquinazolin-6-yl}oxy)acetonitrile

- compound 10: 3-(3,4-dimethoxybenzyl)-6-hydroxy-1-(tetrahydro-2H-thiopyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 11: {[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile
- compound 12: 2-{[3-(3,4-dimethoxybenzyl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-
yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}propanenitrile
- compound 13: 3-(3,4-dimethoxybenzyl)-6-hydroxy-1-(1-oxidotetrahydro-2H-thiopyran-
4-yl)quinazoline-2,4(1H,3H)-dione
- compound 14: {[3-(3,4-dimethoxybenzyl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-
2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile

- compound 15: 2-{[3-(3,4-dimethoxybenzyl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-
2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}propanenitrile (isomer 1)
- compound 16: 2-{[3-(3,4-dimethoxybenzyl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-
2,4-dioxo-1,2,3,4-tetrahydroquinazoiin-6-yl]oxy}propanenitrile (isomer 2)
- compound 17: {[3-(3,4-dimethoxybenzyl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-2,4-
dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile (isomer 1)
- compound 18: {[3-(3,4-dimethoxybenzyl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-2,4-
dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile (isomer 2)

- compound 19: 2-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}propanenitrilemethane (1:1) (enantiomer 1)
- compound 20: 2-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}propanenitrilemethane (1:1) (enantiomer 2)
- compound 21:3-(3,4-dimethoxybenzyl)-6-(prop-2-yn-1-yloxy)-1-(tetrahydro-2H-pyran-
4-yl)quinazoline-2,4(1H,3H)-dione

- compound 22: 2-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}-2-methylpropanenitrile
- compound 23: 2-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}-2-methylpropanamide
- compound 24: 3-(3,4-dimethoxybenzyl)-6-(2-hydroxyethoxy)-1-(tetrahydro-2H-pyran-
4-yl)quinazoline-2,4(1H,3H)-dione
- compound 25: 6-(cyclopropylmethoxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 26: 3-(3,4-dimethoxybenzyl)-6-[(1-methylprop-2-yn-1-yl)oxy]-1-(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 27: 3-(3,4-dimethoxybenzyl)-6-(3-hydroxyazetidin-1-yl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione

- compound 28: 3-(3,4-dimethoxybenzyl)-6-(prop-2-yn-1-ylamino)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 29: 3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazoline-6-carbonitrile
- compound 30: N-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]methyl}acetamide
- compound 31: 1-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]methyl}urea

- compound 32: 3-(3,4-dimethoxybenzyl)-6-[(1-methylprop-2-yn-1-yl)oxy]-1-(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione (enantiomer 1)
- compound 33: 3-(3,4-dimethoxybenzyl)-6-[(1-methylprop-2-yn-1-yl)oxy]-1-(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione (enantiomer 2)
compound 34: 3-(3,4-dimethoxybenzyl)-6-iodo-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
compound 35: 3-(3,4-dimethoxybenzyl)-6-[(1-methylprop-2-yn-1-yl)amino]-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 36: 3-(3,4-dimethoxybenzyl)-6-propoxy-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 37: 3-(3,4-dimethoxybenzyl)-6-(2-methylpropoxy)-1-(tetrahydro-2H-pyran-
4-yl)quinazoline-2,4(1H,3H)-dione
- compound 38: 3-(3,4-dimethoxybenzyl)-6-(1-methylethoxy)-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione
- compound 39: 3-(3,4-dimethoxybenzyl)-6-(1-hydroxyethyl)-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione
compound 40: 6-acetyl-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 41: 6-(2,3-dihydroxypropoxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 42: 3-(3,4-dimethoxybenzyl)-6-(2-hydroxypropoxy)-1-(tetrahydro-2H-
1 pyran-4-yl)quinazoline-2,4(1 H,3H)-dione
- compound 43: 3-(3,4-dimethoxybenzyl)-6-(1-hydroxy-1-methylethyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 44: 3-(3,4-dimethoxybenzyl)-6-ethenyl-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
i - compound 45: 3-(3,4-dimethoxybenzyl)-6-(hydroxymethyl)-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione

- compound 46: 3-(3,4-dimethoxybenzyl)-6-(1-hydroxy-1-methylbut-3-yn-1-yl)-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 47: 3-(3,4-dimethoxybenzyl)-6-(2-hydroxyethyl)-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione
- compound 48: 3-(3,4-dimethoxybenzyl)-6-[(1R)-2-hydroxy-1-methylethoxy]-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 49: 3-(3,4-dimethoxybenzyl)-6-ethoxy-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 50: 3-(3,4-dimethoxybenzyl)-6-(2-fluoroethoxy)-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione
- compound 51: 3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-
trifluoroethoxy)quinazoline-2,4(1H,3H)-dione
compound 52: 3-(3,4-dimethoxybenzyl)-6-[(1S)-2-hydroxy-1-methylethoxy]-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
i - compound 53:: 6-(2,2-difluoroethoxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
compound 54: 3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-6-(3,3,3-
trifluoropropoxy)quinazoline-2,4(1H,3H)-dione
- compound 55: 3-(3,4-dimethoxybenzyl)-6-{[(1R)-1-methylpropyl]oxy}-1-(tetrahydro-
i 2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 56: 3-(3,4-dimethoxybenzyl)-6-{[(1S)-1-methylpropyl]oxy}-1-(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
compound 57: 3-(3,4-dimethoxybenzyl)-6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
i - compound 58: 3-(3,4-dimethoxybenzyl)-6-[(1S)-2-fluoro-1-methylethoxy]-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 59: 6-(2,2-difluoroethenyl)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 60: 3-(3,4-dimethoxybenzyl)-6-(fluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)-
) quinazoline-2,4(1H,3H)-dione
- compound 61: 3-(3,4-dimethoxybenzyl)-7-fluoro-6-hydroxy-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione
- compound 62: 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-7-fluoro-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
5 - compound 63: 6-(2,2-difluoroethoxy)-3-(3,4-dimethoxybenzyl)-7-fluoro-1-(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione

- compound 64: 3-[4-(benzyloxy)-3-methoxybenzyl]-6-[(1,3-difluoropropan-2-yl)oxy]-7-
fluoro-1-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
compound 65: 3-{4-[(3,4-dichlorobenzyl)oxy]-3-methoxybenzyl}-6-[(1,3-
difluoropropan-2-yl)oxy]-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-
dione
compound 66: 3-(3,4-dimethoxybenzyl)-6-nitro-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 67: 6-amino-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
compound 68: 6-[(1,3-difluoropropan-2-yl)oxy]-7-fluoro-3-(4-hydroxy-3-
methoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione;
in the form of the base or of an acid-addition salt.
The quinazolidinedione derivatives that are the subject of the invention, which
may prove to be powerful PDE7 inhibitors or PDE7 and PDE8 inhibitors depending on
the derivatives, or which may act via other biological pathways, may be used as
medicaments or for the preparation of medicaments.
The compounds of general formula (I) may comprise one or more asymmetric
centres. 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 pure enantiomers of the compounds of the invention may be obtained from
enantiomerically pure precursors or by chromatography on chiral phases, or
alternatively, when the compounds comprise acid or amine functions, via selective
crystallization of the diastereoisomeric salts obtained by reacting the compounds (I)
with, respectively, chiral amines or acids.
By virtue of their structure, the compounds of general formula (I) may also exist
in the form of isomers of rotamer or atropoisomer type.
The compounds of formula (I) may also exist in the form of bases or of acid-
addition salts. Such addition salts form part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable
acids, but the salts of other acids that are useful, for example, for purifying or
separating the compounds of general formula (I) also form part of the invention.
The compounds of general formula (I) may also be in crystalline, amorphous or
oily form, these forms forming part of the invention.
The compounds of general formula (I) may also be in the form of hydrates or
solvates, i.e. in the form of associations or combinations with one or more water

molecules or with a solvent. Such hydrates and solvates also form part of the
invention.
According to the present invention, the N-oxides of the compounds comprising
an amine also form part of the invention.
The compounds of formula (I) according to the present invention also include
those in which one or more hydrogen, carbon or halogen, especially chlorine or
fluorine, atoms have been replaced with the radioactive isotopes thereof, for example
tritium or deuteriurm for replacing hydrogen, or carbon-14 for replacing carbon-12.
Such labelled compounds may be useful in research, metabolism or pharmacokinetic
studies or in biological and pharmacological trials as tools, or even as medicaments, in
particular for compounds comprising deuteriurm.
In the context of the invention, the following definitions apply:
> in (CrC6), the numerical indices determine the possible number of carbon
atoms present in the group that it defines. Thus, for example, (CrCeJalkyl represents a
group as defined previously, which may contain from 1 to 6 carbon atoms;
> the term "alkyl" means a linear or branched, saturated aliphatic group; for
example, a linear or branched carbon-based chain of 1 to 6 carbon atoms, especially a
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl; when an
alkyl group is substituted with one or more halogen atoms or with one or more groups
as indicated in the definitions, these substitutions may be borne by the same carbon
atom and/or by different carbon atoms;
> an alkynyl group means a linear or branched, monounsaturated or
polyunsaturated aliphatic group comprising, for example, one or two acetylenic
unsaturations. For example, a C2-C6 alkynyl group may represent an ethynyl, propynyl,
etc.;
> an alkenyl group means a linear or branched, monounsaturated or
polyunsaturated aliphatic group comprising, for example, one or two ethylenic
unsaturations. For example, a group C2-C6 alkenyl may represent an ethenyl, propenyl,
butenyl, etc.;
i > the terms "alkoxy" and "alkyloxy" mean a group -O-alkyl containing a saturated,
linear or branched aliphatic chain. Thus, by way of example, (CrCeJalkoxy represents
a group -0-(C1.C6)alkyl, the group (dAJalkyl being defined previously;
> the term "halogen atom" means a fluorine, a chlorine, a bromine or an iodine;
> the term "heterocycloalkyl" means an optionally substituted saturated ring
> comprising from 3 to 8 atoms and comprising at least one heteroatom such as
nitrogen, sulfur or oxygen, or several identical or different heteroatoms. For example, a

heterocycloalkyl may be a monocyclic heterocycloalkyl such as: an azetidine, a
pyrrolidine, a piperidine, a tetrahydropyran, a morpholine, a piperazine, an azepine,
etc.;
> the term "cycloalkyl" means a carbon-based ring preferably containing from 3 to
8 carbon atoms, the said ring being saturated and optionally substituted. By way of
example, mention may be made of cyclopropyl, methylcyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl groups;
> the term "aryl" means a cyclic aromatic group containing between 6 and 10
carbon atoms. Examples of aryl groups that may be mentioned phenyl and naphthyl;
> an arylalkyl group: an aryl group, as defined above, substituted with at least one
alkyl group, as defined above. Advantageously, they are -alkylene-aryl radicals. An
example that may be mentioned is benzyl, i.e. the radical -CH2-Ph;
> the term "heteroaryl" means an aromatic system comprising one or more
heteroatoms such as nitrogen, oxygen or sulfur atoms and possibly being monocyclic
or polycyclic, i.e. comprising from 2 to 5 rings. When the system is polycyclic, at least
one of the rings is aromatic. The nitrogen atoms may be in the form of N-oxides.
Examples of monocyclic heteroaryl groups that may be mentioned include
monocyclic heteroaryls such as thiazole, thiadiazole, thiophene, imidazole, triazole,
tetrazole, pyridine, furan, oxazole, isoxazole, oxadiazole, pyrrole, pyrazole, pyrimidine
and pyridazine.
Examples of polycyclic heteroaryl groups that may be mentioned include
bicyclic heteroaryls, such as indole, benzofuran, benzimidazole, benzothiophene,
benzotriazole, benzothiazole, benzoxazole, quinoline, isoquinoline, indazole,
quinazoline, phthalazine, quinoxaline, naphthyridine, 2,3-dihydro-1H-indole, 2,3-
dihydrobenzofuran, 2,3-dihydroindene, tetrahydroquinoline, tetrahydroisoquinoline or
tetrahydroisoquinazoline;
> a sulfonamide group means a group corresponding to the formula SO2-N-alkyl
or SO2-N-cycloalkyl, alkyl and cycloalkyl being as defined above;
> a trifluoromethylthio group is defined by the formula -S-CF3,
> the terms "phenoxy group" and "benzyloxy group" mean, respectively, groups
C6H5-0- and C6H5-CH2-0-, in which the group C6H5 (also represented by the
abbreviation Ph).
Among the compounds that are subjects of the invention, mention may be
made of a group of compounds of formula (I) in which R1 represents an aryl group, in
particular a phenyl, or a heteroaryl group, in particular a pyridyl group, all the other
substituents and indices being as defined in the general formula (I) defined above.

In the text hereinbelow, the term "leaving group" means a group that can be
readily replaced, with loss of an electron pair, by breaking a heterolytic bond. This
group may thus be readily replaced with another group, for example during a
substitution reaction. Such leaving groups are, for example, halogens or an activated
hydroxyl group such as a mesylate, tosylate, triflate, etc. Examples of leaving groups
and references for preparing them are given in "Advanced Organic Chemistry", J.
March, 3rd edition, Wiley Interscience, pp. 310-316.
The term "protecting group PG" means a group that prevents the reactivity of a
function or position during a chemical reaction liable to affect it, and which restores the
function after cleavage according to methods known to those skilled in the art.
The term "temporary protecting group for amines or alcohols" means protecting
groups such as those described in Protective Groups in Organic Synthesis, Greene
T.W. and Wuts P.G.M., published by Wiley Interscience, 1999, and in Protecting
Groups, Kocienski P.J., 1994, Georg Thieme Verlag.
Examples that may be mentioned of temporary protecting groups for amines
include: benzyls, carbamates, (such as tert-butyloxycarbonyl, which is cleavable in
acidic medium, or benzyloxycarbonyl, which is cleavable by hydrogenolysis), temporary
protecting groups for carboxylic acids: alkyl esters (such as methyl, ethyl or tert-butyl,
which may be hydrolysed in basic or acidic medium) and hydrogenolysable benzyl
groups, temporary protecting groups for alcohols or phenols such as tetrahydropyranyl,
methyloxymethyl or methylethoxymethyl, fert-butyl and benzyl groups, temporary
protecting groups for carbonyl derivatives such as linear or cyclic acetals, for instance
1,3-dioxan-2-yl or 1,3-dioxolan-2-yl; and reference may be made to the well-known
general methods described in Protective Groups, mentioned above.
Depending on the case, a person skilled in the art will be capable of selecting
the appropriate protecting groups.
In the general synthetic schemes that follow, the starting materials and the
reagents, when their preparation method is not described, are commercially available
or described in the literature, or else may be prepared according to the described
l methods or methods known to those skilled in the art.
The compounds of formula (I) may comprise protecting groups for other
functions that are generated subsequently in one or more other steps.
The compounds of the present invention may be prepared according to
schemes 1 to 7 that follow. These synthetic routes serve merely as illustrations and are
> not in any way limiting. A person skilled in the art can without difficulty adapt the
teaching below to the compounds of formula (I) for which A, Ri, R2, n, p and optionally

R3> Ra, Rb and Re are defined in the general formula (I). He will be capable of
selecting, in the light of his knowledge and of the literature, the appropriate protecting
groups allowing the introduction of all the groups or functions described in the present
invention.
For the sake of clarity, n and p = 1 and the position of R2 have been chosen as
indicated in the schemes.

The compounds corresponding to formula (la), in which A, Ri and R2 are as
defined in the general formula (I), may be prepared according to Scheme 1.
The compounds of formula (IV) are obtained via a reductive amination reaction
by reacting a compound of formula (II) in which R2 is as defined in the general formula
(I) and R' represents a group (Ci-C6)alkyl, with a compound of formula (III), in which A
is as defined in the general formula (I), in acidic medium and in the presence of a
reducing agent such as sodium triacetoxyborohydride. The compounds of formula (IV)
thus formed are then acylated according to methods that are well known to those
skilled in the art, with an alkyl or aryl chloroformate to give the compound of formula
(V) in which R" represents a group (CrC6)alkyl or a substituted aryl group. A
hydrogenolysis reaction in basic medium gives the compounds of formula (VI), which,
via a coupling reaction with a compound of formula (VII), in which Ri is as defined for
the compounds of general formula (I), leads to the compounds of formula (VIII). An
i intramolecular cyclization reaction in basic medium gives the quinazolinedione
derivatives of formula (la).


Alternatively, the compounds corresponding to formula (la), in which A, F^ and
R2 are as defined in the general formula (I), may be prepared according to Scheme 2.
A reductive amination reaction between the compound of formula (IX), in which F^ and
R2 are as defined in the general formula (I), and a compound of formula (III), in which
A is as defined in the general formula (I), in acidic medium and in the presence of a
reducing agent such as sodium triacetoxyborohydride, gives the compounds of formula
(X). The compounds of formula (X) are then acylated with an alkyl or aryl
chloroformate to give the compounds of formula (VIII) in which R" represents a group
(C1-C6)alkyl or a substituted aryl group, which, via an intramolecular cyclization
reaction in basic medium, gives, as previously, the quinazolinedione derivatives of
formula (la).


The compounds of formula (lb) for which R2 represents -ORa, Ra being as
defined for the compounds of general formula (I), may be prepared according to
Scheme 3.
The compounds of formula (XII) are obtained via an aromatic nucleophilic
substitution reaction involving a compound of formula (XI) in which R' represents a
group (CrC6)alkyl, and benzyl alcohol in the presence of a base. Reduction of the nitro
group of the compounds of formula (XII) leads to the corresponding anilino derivatives
(XIII). A reductive amination reaction with a compound of formula (III) in which A is as
defined in the general formula (I), in acidic medium and in the presence of a reducing
agent such as sodium triacetoxyborohydride, gives the compounds of formula (XIV),
which, via a hydrogenolysis reaction in basic medium, gives the compounds of formula
(XV). This is followed by an acylation reaction with a compound of formula (VII),
leading to the production of compounds of formula (XVI) and then a second acylation

reaction with an alkyl or aryl chloroformate leads to the production of compounds of
formula (XVII), and finally an intramolecular cyclization reaction in the presence of a
base gives the compounds of formula (XVIII). The compounds of formula (XIX),
obtained by deprotection of the benzyloxy group of the compounds of formula (XVIII),
are then subjected, for example, to an alkylation reaction with an alkylating agent of
the type Ra-X in which Ra is as defined for the compounds of general formula (I) and
X represents a leaving group (for instance a halogen atom), in the presence of a base
such as caesium carbonate (Cs2CO3), or alternatively to a Mitsunobu reaction
(Synthesis 1981, 1) with an alcohol of the type Ra-OH, Ra being as defined for the
compound of general formula (I), to give the compounds of formula (lb).

The compounds of formula (Ic) in which R2 represents -NHRa, Ra, A and Ri
being as defined for the compound of general formula (I), may be prepared according
to Scheme 4.
A nucleophilic substitution reaction between a compound of formula (XX) and a
compound of formula (XXI) leads to the compounds of formula (XXII), which are then
converted into compounds of formula (XXV) via the sequence of reactions equivalent
to those described in the preceding schemes, namely (i) a first acylation reaction of the
compounds of formula (XXII) with an amine of formula (VII), with R^ as defined for the
general formula (I), leading to the production of the compounds of formula (XXIII), (ii) a
second acylation reaction with an alkyl or aryl chloroformate to form the compounds of

formula (XXIV) and then (iii) a cyclization reaction leading to the formation of the said
compounds of formula (XXV). The compounds of formula (XXVI), obtained via
reduction of the nitro group of the compounds of formula (XXV) to amine, are then
subjected to an alkylation reaction with an alkylating agent of the type Ra-X in which
Ra is as defined for the compounds of general formula (I) and X represents a leaving
group (for instance a halogen atom) in the presence of a base such as caesium
carbonate (Cs2CO3) to give the compounds of formula (Ic).

The compounds of formulae (Id), (le), (If), (Ig) and (Ih) in which A, Ri, Rb and
Re are as defined for the compound of general formula (I) may be prepared according
to Scheme 5. They are obtained from the compounds of formula (XXVII) in which R2
represents a halogen atom, preferably a bromine or iodine atom.
The compounds of formula (XXVIII) are obtained from the compounds of
formula (XXVII) via a reaction of Stille type (see, for example, Chemical Review 2007,
107, 133-173). Reduction or alkylation of the carbonyl group makes it possible to
obtain the compounds of formulae (Id) and (le), respectively.
The compounds of formulae (If) and (Ig) are obtained from the compounds of
formula (XXVII) via a reaction of Buchwald or Suzuki type (see, for example, Chemical
Review 2007, 107, 133-173), respectively.

The compounds of formula (XXIX), obtained via a cyanation reaction (see, for
example, Chemical Review 2007, 107, 133-173) on compounds of formula (XXVII),
lead to the compounds of formula (XXX) via a reduction reaction. Finally, an acylation
reaction of the compounds of formula (XXX) leads to the compounds of formula (Ih).

The compounds of formulae (li) and (Ij) in which A and Ri are as defined in the
general formula (I) and R2 is as indicated in Scheme 6 may be prepared according to
Scheme 6.
The compounds of formula (XXXI), obtained from the compounds of formula
(XXVII) via a Stille reaction, lead to the aldehydes of formula (XXXII) via an ozonolysis
reaction. The compounds of formula (XXXIII) are obtained via a reduction reaction on
the said aldehydes of formula (XXXII) using, for example, boron hydrides as reducing
i agent. The compounds of formula (li) are obtained from the compounds of formula
(XXXIII) via a fluorination reaction using, for example, DAST as fluorinating agent. The

compounds of formula (XXXIV) are obtained from the compounds of formula (XXXII)
via a reaction of Wittig type.
Finally, the compounds of formula (XXXV), obtained from the compounds of
formula (XXXI) via a hydroboration/oxidation reaction, are converted into compounds
of formula (Ij) via a fluorination reaction.

The compounds of formulae (Ik) and (Im) for which A represents a group SO or
SO2, respectively, may be prepared according to Scheme 7. For the sake of clarity, the
group R2 of general formula (I) has been chosen as indicated in Scheme 7.
Oxidation of the compounds of formula (XXXVI) in the presence of potassium
periodate leads to the sulfoxide derivatives of formula (XXXVII). The benzyloxy group
is deprotected, for example via a hydrogenolysis reaction, to give the compounds of
formula (XXXVIII), which, via an alkylation reaction with an alkylating agent of the type
Ra-X in which Ra is as defined for the compound of general formula (I) and X
represents a leaving group (for instance a halogen atom) in the presence of a base

such as caesium carbonate (Cs2CO3), leads to the compounds of formula (Ik).
By analogy, the sulfone derivatives of formula (Im) may be prepared according
to the same synthetic scheme, with the exception of the oxidation step, which may be
performed with Oxone® to give the compounds of formula (XXXIX).
The numbers of the illustrated compounds refer to those given in Table 1
below, which illustrates the chemical structures and the physical properties of a
number of compounds according to the invention.
The software used for the nomenclature of the named compounds in the
present invention is ACD/Name® (www.acdlabs.com).

EXAMPLES
The procedures and examples that follow describe the preparation of certain
compounds in accordance with the invention. These procedures and examples are not
limiting, and serve merely to illustrate the present invention.
A person skilled in the art can without difficulty adapt the teaching below to the
compounds of general formula (I). He will be capable of selecting, in the light of his
general knowledge and of the literature, the appropriate protecting groups for
introducing all the groups or functions described in the present invention.
In the procedures and examples below:
- the mass spectra are acquired on a quadrupolar spectrometer of Platform
LCZ type (Waters) or of ZQ 4000 type (Waters) in positive electrospray ionization
mode;
- the NMR (nuclear magnetic resonance) spectra are acquired on a Fourier
transform spectrometer (Bruker), at a temperature of 300 K (exchangeable protons not
recorded);
- s = singlet;
- d = doublet;
- m = multiplet;

- br = broad signal;
-1 = triplet;
- q = quartet;
- DMSO-d6 = deuterated dimethyl sulfoxide;
- CDCI3 = deuterated chloroform.
The solvent mixtures are quantified as volume ratios.
The NMR and mass spectra confirm the structures of the compounds obtained
according to the examples below.
In the examples that follow, the following abbreviations are used:
ACN: acetonitrile
EtOAc: ethyl acetate
AcOH: acetic acid
DAST: (diethylamino)sulfur trifluoride
DBU: 1,8-diazabicyc!o[5.4.0]undec-7-ene
DCM: dichloromethane
DCE: 1,2-dichloroethane
< DEAD: diethyl azodicarboxylate
DIAD: diisopropyl azodicarboxylate

DIEA: diisopropylamine
DMF: N.N-dimethylformamide
PE: petroleum ether
Et20: diethyl ether
EtOH: ethanol
HBTU: 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
IBCF: isobutyl chloroformate
MeOH: methanol
NaBH(OAc)3: sodium triacetoxyborohydride
RT: room temperature
min: minute
THF: tetrahydrofuran
NEt3: triethylamine
TFA: trifluoroacetic acid
EXAMPLE 1: Compound 6
Synthesis of 6-bromo-3-(3,4-dimethoxybenzyl)-1 -(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione

Step 1.1:
5-bromo-2-(tetrahydro-2H-pyran-4-ylamino)benzoicacid

A mixture of 5 g of 2-amino-5-bromobenzoic acid, 9.27 g of tetrahydro-4H-
pyran-4-one and 32 g of Na2SO4 in 50 ml of acetic acid is stirred overnight at room
i temperature. The reaction mixture is filtered. A further 9.27 g of tetrahydro-4/-/-pyran-4-
one and 32 g of Na2SO4 are added and the resulting mixture is stirred overnight at
room temperature. This mixture is filtered and 9.81 g of NaBH(OAc)3 are added. The

resulting mixture is allowed to cool to room temperature over 2 hours. The reaction
medium is evaporated under reduced pressure and the residue is taken up in EtOAc. It
is washed with aqueous 1N HCI solution. The organic phase is dried over Na2SO4,
filtered and evaporated under reduced pressure to give 3.35 g of the expected product.
Step 1.2:
5-bromo-A/-(3,4-dimethoxybenzyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide

A mixture of 1 g of the compound obtained in Step 1.1, 0.646 g of
veratrylamine, 1.152 g of DIEA and 1.69 g of HBTU in 50 ml of DMF is stirred for
2 days at room temperature. The reaction medium is evaporated under reduced
pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc
mixture from (100/0, v/v) to (80/20, v/v) to give 1.2 g of a solid, which is used without
purification in the following step.
Step 1.3:
6-bromo-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)quinazoline-
2,4(1 H,3H)-dione

A mixture of 1.67 g of IBCF, 1.1 g of the compound obtained in Step 1.2, 3.23 g
of NaOH and 0.83 g of tetrabutylammonium hemisulfate in 150 ml of DCE is stirred
overnight. The reaction medium is filtered and evaporated under reduced pressure.
The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from
(100/0, v/v) to (80/20, v/v) to give 0.649 g of the expected product.

EXAMPLE 2: Compound 34
Synthesis of 3-(3,4-dimethoxybenzyl)-6-iodo-1 -(tetrahydro-2H-pyran-4-yl)-
quinazoiine-2,4(1 W,3H)-dione

Step 2.1:
A/-(3,4-dimethoxybenzyl)-5-iodo-2-(tetrahydro-2H-pyran-4-ylamino)benzamide

A mixture of 14.22 g of 5-iodo-2-(tetrahydro-2H-pyran-4-ylamino)benzoic acid,
18.4 g of HBTU, 21.28 g of DIEA and 9.18 g of veratrylamine in 200 ml of DMF is
stirred overnight at room temperature. The reaction medium is evaporated under
reduced pressure. The residue is taken up in 3000 ml_ of EtOAc. The solution is
washed with aqueous 0.5N HCI solution, with saturated aqueous NaHCO3 solution,
and then with saturated aqueous NaCI solution. The organic phase is dried over
MgSO4, filtered and evaporated under reduced pressure to give 18 g of the expected
product.
Step 2.2:
3-(3,4-dimethoxybenzyl)-6-iodo-1-(tetrahydro-2H-pyran-4-yl)quinazoline-
2,4(1 H,3H)-dione

I 2.9 g of NaOH are added to a solution of 18 g of the compound obtained in
Step 2.1 in 200 ml of DCE and the mixture is left to react for 30 minutes at room
temperature. 1.5 g of NaH are added and the mixture is left to react for 30 minutes at

room temperature. 51.1 g of IBCF are added and the reaction mixture is heated for
4 hours at 80°C. The resulting mixture is evaporated under reduced pressure and the
residue is taken up in 200 ml of DMF. 8.7 g of NaOH and 12.3 g of tetrabutyl-
ammonium hemisulfate are added. The mixture is heated for 4 hours at 80°C and then
overnight at room temperature. The residue is chromatographed on silica gel, eluting
with a DCM/EtOAc mixture from (100/0, v/v) to (80/20, v/v) to give 9 g of the expected
product.
EXAMPLE 3: Compound 11
Synthesis of {[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1 -(tetrahydro-2H-thiopyran-4-
yl)-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile

Step 3.1:
5-(benzyloxy)-W-(3,4-dimethoxybenzyl)-2-(tetrahydro-2H-thiopyran-4-ylamino)-
benzamide

A mixture of 0.235 g of 2-amino-5-(benzyloxy)-A/-(3,4-dimethoxybenzyl)-
benzamide, 0.090 g of tetrahydro-4H-thiopyran-4-one and 0.78 g of sodium triacetoxy-
borohydride in 0.5 ml of acetic acid is irradiated in a microwave field for 5 minutes at
130°C. 1N HCI is added and the mixture is extracted with EtOAc. The organic phase is
dried over MgSO4 and filtered, and the filtrate is evaporated under reduced pressure.
The residue is chromatographed on silica gel, eluting with a heptane/EtOAc mixture
from (90/10, v/v) to (20/80, v/v) to give 0.2 g of the expected product.

Step 3.2:
6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-thiopyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione

A mixture of 2.5 g of the compound obtained in Step 3.1, and 6.7 g of NaOH in
100 ml of DCE is stirred for 30 minutes at room temperature. 2.77 g of IBCF are then
added and the mixture is stirred for 2 hours at room temperature. The same amounts
of NaOH and IBCF are again added and the resulting mixture is stirred overnight at
room temperature. Since the reaction is not complete, 6.7 g of NaOH, 1.39 g of IBCF
and 0.05 g of tetrabutylammonium sulfate are added, and the mixture is then stirred for
3 days at room temperature. The resulting mixture is filtered, and the filtrate is
evaporated under reduced pressure. The residue is chromatographed on silica gel,
eluting with a DCM/EtOAc mixture from (100/0, v/v) to (80/20, v/v) to give 2.07 g of the
expected product.
Step 3.3:
S-tS^-dimethoxybenzyO-B-hydroxy-l-ttetrahydro^H-thiopyran^-ylJquinazoline-
2,4(1 H,3H)-dione

A mixture of 0.200 g of the compound obtained in Step 3.2, and 1.22 g of
formic acid is irradiated in a microwave field for 2 minutes at 180°C. The reaction
mixture is taken up in EtOAc and then evaporated under reduced pressure. The
residue is chromatographed on silica gel, eluting with a CH2CI2/MeOH mixture from
(100/0, v/v) to (97/3, v/v) to give the expected product.

Step 3.4:
{^-(a^-dimethoxybenzylJ^^-dioxo-l-ttetrahydro-ZH-thiopyran^-ylJ-l^.a^-
tetrahydroquinazolin-6-yl]oxy}acetonitrile

A mixture of 0.16 g of the compound obtained in Step 3.3, 0.054 g of
bromoacetonitrile and 0.243 g of Cs2CO3 in 1 ml of DMF is irradiated in a microwave
field for 15 minutes at 100°C. The reaction mixture is evaporated under reduced
pressure. The residue is taken up in DCM, washed with water, dried over Na2SO4 and
filtered, and the filtrate is evaporated under reduced pressure. The residue is
chromatographed on silica gel, eluting with an EtOAc/DCM mixture from (10/90, v/v) to
(20/80, v/v) to give 0.138 mg of the expected product.
EXAMPLE 4: Compound 63
Synthesis of 6-(2,2-difluoroethoxy)-3-(3,4-dimethoxybenzyl)-7-fIuoro-1 -
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
i
Step 4.1:
ethyl 5-(benzyloxy)-4-fluoro-2-nitrobenzoate

8.25 g of Verkade base are added to a solution of 2.61 g of benzyl alcohol in
) 20 ml of THF. The mixture is stirred for 10 minutes at room temperature, and a solution
of 5.3 g of ethyl 4,5-difluoro-2-nitrobenzoate and 2.55 g of Et3N in 150 ml of THF is
added to this solution. The mixture is stirred for 1 hour at room temperature. The
reaction medium is evaporated under reduced pressure. The residue is taken up in
DCM and washed three times with aqueous 1N HCI solution, and then with water. The

organic phase is dried over MgSO4 and filtered, and the filtrate is evaporated under
reduced pressure. The residue is chromatographed on silica gel, eluting with a
PE/DCM mixture from (100/0, v/v) to (0/100, v/v) to give 4.5 g of the expected product.
Step 4.2:
ethyl 2-amino-5-(benzyloxy)-4-fluorobenzoate

1.76 g of NH4CI dissolved in 21 ml of water are added to a mixture heated to
90°C of 7.0 g of the compound obtained in Step 4.1, and 4.44 g of Fe(0) in 400 ml of
isopropanol and 100 ml of THF. The reaction mixture is heated for 4 hours at 90°C. A
i further 0.88 g of NH4CI is added and the mixture is heated for 2 hours at 90°C. The
resulting mixture is filtered while hot and the filtrate is evaporated under reduced
pressure. The residue is taken up in EtOAc and washed twice with saturated NaHCO3
solution. The organic phase is dried over MgSO4 and filtered, and the filtrate is
evaporated under reduced pressure. The residue is chromatographed on silica gel,
> eluting with a PE/EtOAc mixture from (100/0, v/v) to (40/60, v/v) to give 5.2 g of the
expected product.
Step 4.3:
ethyl 5-(benzyloxy)-4-fluoro-2-(tetrahydro-2A/-pyran-4-ylamino)benzoate

} A mixture of 10.5 g of the compound obtained in Step 4.2, 29.07 g of
tetrahydro-4H-pyran-4-one and 51.56 g of Na2SO4 in 360 ml of acetic acid is stirred
overnight at room temperature. 34.62 g of sodium triacetoxyborohydride are then
added and the mixture is stirred for 3 hours at room temperature. The resulting mixture
is evaporated under reduced pressure and the residue is taken up in EtOAc. This
5 solution is washed with water and then 4 times with saturated aqueous NaHCO3
solution. The resulting solution is dried over MgSO4 and filtered, and the filtrate is
evaporated under reduced pressure. The residue is chromatographed on silica gel,
eluting with a PE/EtOAc mixture from (100/0, v/v) to (50/50, v/v) to give 10.55 g of the
expected product.

Step 4.4:
5-(benzyloxy)-4-fluoro-2-(tetrahydro-2H-pyran-4-ylamino)benzoic acid

A mixture of 1.0 g of the compound obtained in Step 4.3 and 0.45 g of KOH in
16 ml of isopropanol and 4 ml of water is irradiated in a microwave field for 20 minutes
at 130°C. The reaction medium is evaporated under reduced pressure. Water is
added, the resulting mixture is acidified with aqueous 1N HCI solution to pH 3 and this
mixture is extracted with EtOAc. The organic phase is dried over Na2SO4 and filtered,
and the filtrate is evaporated under reduced pressure to give 0.91 g of the expected
product.
Step 4.5:
5-(benzyloxy)-W-(3,4-dimethoxybenzyl)-4-fluoro-2-(tetrahydro-2H-pyran-4-
ylamino)benzamide

A mixture of 14 g of the compound obtained in Step 4.4, 7.46 g of
veratrylamine, 19.99 g of HBTU and 13.1 g of DIEA in 300 ml of DMF is stirred for
2 hours at room temperature. The solvent is evaporated off under reduced pressure
and the residue is taken up in DCM. The resulting solution is washed twice with
saturated aqueous NaHCO3 solution. The organic phase is dried over Na2SO4 and
filtered, and the filtrate is evaporated under reduced pressure. The residue is
chromatographed on silica gel, eluting with a PE/EtOAc mixture from (90/10, v/v) to
(40/60, v/v) to give 16 g of the expected product.

Step 4.6:
6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione

A mixture of 1.0 g of the compound obtained in Step 4.5, 1.223 g of 4-
nitrophenyl chloroformate and 0.915 g of DIEA in 15 ml of THF is irradiated in a
microwave field for 15 minutes at 80°C. 0.616 g of DBU is then added and the mixture
is stirred for 1 hour at room temperature. The reaction medium is evaporated under
reduced pressure. The residue is taken up in EtOAc and washed twice with saturated
aqueous NaHCO3 solution, then with aqueous 1M KHSO4 solution and then with water.
The organic phase is dried over Na2SO4 and filtered, and the filtrate is evaporated
under reduced pressure. The residue is chromatographed on silica gel, eluting with a
DCM/EtOAc mixture from (100/0, v/v) to (60/40, v/v) to give 0.74 g of the expected
product.
Step 4.7:
3-(3,4-dimethoxybenzyl)-7-fluoro-6-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-d\one

A mixture of 0.2 g of the compound obtained in Step 4.6, 0.036 g of ammonium
formate and 0.041 g of Pd/C (10%) in 4 ml of EtOH is irradiated in a microwave field
for 5 minutes at 60°C. DCM is added, the mixture is filtered and the filtrate is
evaporated under reduced pressure. The residue is chromatographed on silica gel,
eluting with a PE/EtOAc mixture from (95/5, v/v) to (0/100, v/v) to give 0.11 g of the
expected product.

Step 4.8:
6-(2,2-difluoroethoxy)-3-(3,4-dimethoxybenzyl)-7-fluoro-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione

0.125 g of difluoroethanol, 0.47 g of tributylphosphine and 0.38 g of DIAD are
successively added to a solution of 0.4 g of the compound obtained in Step 4.7 in
15 ml of THF. This mixture is stirred overnight at room temperature. The reaction
medium is evaporated under reduced pressure. The residue is chromatographed on
silica gel, eluting with a PE/EtOAc mixture from (100/0, v/v) to (30/70) to give 0.38 g of
the expected product.
EXAMPLE 5: Compound 50
Synthesis of 3-(3,4-dimethoxybenzyl)-6-(2-fluoroethoxy)-1 -(tetrahydro-2H-pyran-
4-yl)quinazoline-2,4(1H,3H)-dione

A mixture of 0.2 g of 3-(3,4-dimethoxybenzyl)-6-hydroxy-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione and 0.32 g of Cs2CO3 in 10 ml of DMF is
irradiated in a microwave field for 1 minute at 100°C. 0.169 g of fluoroethanol are then
added and the mixture is irradiated in a microwave field for 5 minutes at 140°C. The
reaction medium is evaporated under reduced pressure. The residue is taken up in
EtOAc and washed with water and then with saturated NaCI solution. The resulting
solution is dried over Na2SO4, filtered and evaporated under reduced pressure. The
residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from
(80/20, v/v) to give 0.212 g of the expected product.

EXAMPLE 6: Compound 28
3-(3,4-dimethoxybenzyl)-6-(prop-2-yn-1-ylamino)-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione

Step 6.1:
5-nitro-2-(tetrahydro-2H-pyran-4-ylamino)benzoicacid

A mixture of 5.1 g of 2-fluoro-5-nitrobenzoic acid and 6.21 g of tetrahydro-2H-
pyran-4-amine in 5 ml of DMF is irradiated in a microwave field for 15 minutes at
100°C. The mixture is irradiated a second time for 15 minutes at 100°C. The same
reaction is repeated on identical amounts of reagents. All the reaction mixtures are
pooled and the solvent is evaporated off under reduced pressure. The residue is
recrystallized from EtOAc to give 6 g of expected product.
Step 6.2:
W-(3,4-dimethoxybenzyl)-5-nitro-2-(tetrahydro-2H-pyran-4-ylamino)benzamide

A mixture of 5.8 g of the compound obtained in Step 6.1, 7.02 g of DIEA and
12.38 g of HBTU is stirred for 30 minutes at room temperature. 4.37 g of veratrylamine
are then added and the resulting mixture is stirred overnight at room temperature. The
resulting mixture is evaporated under reduced pressure and the residue is taken up in
EtOAc. This solution is washed with water and then sequentially with 1N HCI solution,
with water, with saturated NaHCO3 solution, with water and with saturated NaCI
solution. The resulting solution is dried over Na2SO4 and filtered, and the solvent is

evaporated off under reduced pressure. The residue is chromatographed on silica gel,
eluting with an EtOAc/heptane mixture from (50/50, v/v) to (70/30, v/v) to give 7.7 g of
the expected product.
Step 6.3:
3-(3,4-dimethoxybenzyl)-6-nitro-1-(tetrahydro-2H-pyran-4-yl)quinazoline-
2,4(1 W,3H)-dione

15.19 g of IBCF are added to a mixture of 7.7 g of the compound obtained in
Step 6.2, 29.65 g of NaOH and 3.14 g of tetrabutylammonium sulfate in 618 ml of
DCE. This mixture is stirred overnight at room temperature. The resulting mixture is
filtered and the filtrate is washed with 1N HCI solution, with water and with saturated
NaCI solution. The resulting solution is dried over Na2SO4 and filtered, and the solvent
is evaporated off under reduced pressure. The residue is chromatographed on silica
gel, eluting with an EtOAc/DCM mixture from (5/95, v/v) to (100/0, v/v) to give 7.35 g of
the expected product.
Step 6.4:
6-amino-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)quinazoline-
2,4(1 W,3H)-dione

A mixture of 1 g of the compound obtained in Step 6.3, 0.36 g of ammonium
formate and 0.24 g of Pd/C (10%) in 10ml of EtOH purged beforehand with nitrogen is
irradiated in a microwave field for 10 minutes at 80°C. The resulting mixture is filtered
and the filtrate is evaporated under reduced pressure. The residue is chromatographed
on silica gel, eluting with an EtOAc/DCM mixture from (0/100, v/v) to (100/0, v/v) to
give the expected product.
Step 6.5:
3-(3,4-dimethoxybenzyl)-6-(prop-2-yn-1-ylamino)-1-(tetrahydro-2H-pyran-4-yl)-

quinazoiine-2,4(1 H,3H)-dione

A mixture of 0.25 g of the compound obtained in Step 6.4, 0.094 g of propargyl
bromide, 0.12 g of K2CO3 and 0.009 g of sodium iodide in 8.25 ml of DMF is irradiated
in a microwave field for 3 hours at 100°C. The resulting mixture is evaporated under
reduced pressure. The residue is chromatographed on silica gel, eluting with an
MeOH/DCM mixture from (0/100) to (2/98, v/v) to give 0.155 g of the expected product.
EXAMPLE 7: Compound 39
Synthesis of 3-(3,4-dimethoxybenzyl)-6-(1 -hydroxyethyl)-1 -(tetrahydro-2H-pyran-
4-yl)quinazoline-2,4(1H,3H)-dione

Step 7.1:
6-acetyl-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)quinazoline-
2,4(1 H,3H)-dione

A mixture of 1 g of 3-(3,4-dimethoxybenzyl)-6-iodo-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1H,3H)-dione, 1.3 ml of tributyl(1-ethoxyvinyl)tin and 0.04 g of
Pd(PPh3)4 in 20 ml of toluene is heated for 1 hour at 130°C and then stirred for
48 hours at room temperature. The solvent is evaporated off under reduced pressure.
The residue is taken up in EtOAc and washed four times with 4N HCI and then with
water. The organic phase is dried over Na2SO4, filtered and evaporated under reduced
pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc

mixture from (80/20, v/v) to give 0.84 g of the expected product.
Step 7.2:
3-(3,4-dimethoxybenzyl)-6-(1-hydroxyethyl)-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1H,3H)-dione

A mixture of 0.154 of the compound obtained in Step 7.1 and 0.026 g of NaBH4
in 30 ml of MeOH is stirred for 2 hours at room temperature. Water is added and the
mixture is neutralized with 1N HCI. The resulting mixture is evaporated under reduced
pressure and the residue is taken up in DCM. This solution is filtered and evaporated
under reduced pressure. The residue is chromatographed on silica gel, eluting with
EtOAc to give 0.14 g of the expected product.
EXAMPLE 8: Compound 43
Synthesis of 3-(3,4-dimethoxybenzyl)-6-(1 -hydroxy-1 -methylethyl)-1 -(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione

0.1 g of 6-acetyl-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1H,3H)-dione is added to a solution of 0.143 g of methylmagnesium
iodide in 1 ml of Et20. This mixture is stirred for 30 minutes at 0°C and then overnight
at room temperature. The reaction mixture is evaporated under reduced pressure. The
residue is chromatographed on silica gel, eluting with EtOAc to give 0.01 g of the
expected product.

EXAMPLE 9: Compound 46
Synthesis of 3-(3,4-dimethoxybenzyl)-6-(1-hydroxy-1-methylbut-3-yn-1 -yl)-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione

Step 9.1:
3-(3,4-dimethoxybenzyl)-6-[1 -hydroxy-1 -methyl-4-(trimethylsilyl)but-3-yn-1 -yl]-1 -
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione

A mixture of 0.1 g of 6-acetyl-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-
4-yl)quinazoline-2,4(1H,3H)-dione, 0.057 g of potassium iodide, 0.01 g of lithium
chloride, 0.019 g of gallium and 0.065 g of trimethylsilylpropargyl bromide in 1 ml of
THF is refluxed for 2 hours and then left for 2 days at room temperature. The reaction
mixture is filtered through Celite and evaporated under reduced pressure. The residue
is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (70/30, v/v)
to give 0.112 g of the expected product.
Step 9.2:
3-(3,4-dimethoxybenzyl)-6-(1 -hydroxy-1 -methylbut-3-yn-1 -yl)-1 -(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione

A mixture of 0.112 g of the compound obtained in Step 9.1, 0.031 g of caesium
fluoride and 0.003 g of tetrabutylammonium fluoride in 5 ml of DMF is stirred overnight

at room temperature. The resulting mixture is evaporated under reduced pressure. The
residue is taken up in DCM. This solution is washed with water, and the organic phase
is dried over MgSO4, filtered and evaporated under reduced pressure. The residue is
chromatographed on silica gel, eluting with EtOAc to give 0.084 g of the expected
product.
EXAMPLE 10: Compound 27
Synthesis of 3-(3,4-dimethoxybenzyl)-6-(3-hydroxyazetidin-1 -yl)-1 -(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione

Step 10.1:
6-[3-(benzyloxy)azetidin-1-yl]-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione

A mixture of 0.2 g of 6-bromo-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione, 0.096 g of 3-benzyloxyazetidine, 0.006 g of
palladium acetate, 0.055 g of sodium tert-butoxide and 0.01 ml of tributylphosphine in
4 ml of DMF is stirred for 4 days at room temperature. The reaction mixture is filtered
and evaporated under reduced pressure. The residue is chromatographed on silica
gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (20/80, v/v) to give 0.041 g
of the expected product.

Step 10.2:
3-(3,4-dimethoxybenzyl)-6-(3-hydroxyazetidin-1-yl)-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione

A mixture of 0.04 g of the compound obtained in Step 10.1, 0.007 g of
ammonium formate and 0.008 g of Pd/C (10%) in 7.2 ml of EtOH is irradiated in a
microwave field for 1 hour at 120°C. The reaction mixture is filtered and evaporated
under reduced pressure. The residue is chromatographed on silica gel, eluting with a
DCM/MeOH mixture from (100/0, v/v) to (95/5, v/v) to give 0.017 g of the expected
product.
EXAMPLE 11: Compound 3
Synthesis of 3-(3,4-dimethoxybenzyl)-6-pyridin-4-yl-1 -(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione hydrochloride

A mixture of 0.25 g of 6-bromo-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione, 0.0776 g of 4-pyridineboronic acid, 1 ml of
aqueous 2N K2CO3 solution and 0.025 g of tetrakis(triphenylphosphine)palladium(0) in
10 ml of DMF is heated for 3 hours at 90°C. The reaction mixture is filtered and then
evaporated under reduced pressure. The residue is chromatographed on silica gel,
eluting with an MeOH/EtOAc mixture from (0/100, v/v) to (5/95, v/v) to give 0.17 g of
the expected product in free base form. The product is dissolved in 1 ml of EtOAc, and
1 ml of Et20 is added, followed by addition of 0.5 ml of a 2N solution of HCI in Et20.
0.193 g of the hydrochloride of the expected product is obtained.

EXAMPLE 12: Compound 30
Synthesis of N-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1 -(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]methyl}acetamide

Step 12.1:
3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-
tetrahydroquinazoline-6-carbonitrile

A mixture of 1.22 g of 6-bromo-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione, 0,3 g of zinc cyanide and 0.089 g of
tetrakis(triphenylphosphine)palladium(0) in 10 ml of DMF is irradiated in a microwave
field for 3 minutes at 170°C. EtOAc is added and the mixture is washed six times with
water. The resulting solution is dried over Na2SO4, filtered and evaporated under
reduced pressure. The residue is chromatographed on silica gel, eluting with a
DCM/EtOAc mixture from (100/0, v/v) to (80/20, v/v) to give 0.804 g of the expected
product.
Step 12.2:
6-(aminomethyl)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione

A mixture of 0.55 g of the compound obtained in Step 12.1, and 2.94 ml of a
2M borane/dimethyl sulfide complex in THF, in 15 ml of THF is irradiated in a

microwave field for 1 minute at 100°C. The reaction medium is taken up in DCM. 50 ml
of 1N HCI are added and the mixture is stirred for 2 hours at room temperature. The
resulting mixture is neutralized with 2N sodium hydroxide solution. This resulting
mixture is extracted with DCM, dried over Na2SO4, filtered and evaporated under
reduced pressure. The residue is chromatographed on an RP18 column, eluting with a
water/ACN mixture from (90/10, v/v) to (50/50, v/v) to give 0.23 g of the expected
product.
Step 12.3:
N-{[3-(3,4-dimethoxybenzyl)-2,4-dIoxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-
tetrahydroquinazolin-6-yl]methyl}acetamide

0.066 g of acetic anhydride is added at 0°C to a solution of 0.23 g of the
compound obtained in Step 12.2 and 0.11 g of Et3N in 5 ml of DCM. The mixture is
stirred at room temperature for 2 hours. The organic phase is washed with saturated
NH4CI solution, filtered and evaporated under reduced pressure. The residue is
chromatographed on silica gel, eluting with a DCM/MeOH mixture from (99/1, v/v) to
(95/5, v/v) to give 0.195 g of the expected product.
EXAMPLE 13: Compound 31
Synthesis of 1 -{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1 -(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]methyl}urea

A mixture of 0.1 g of 6-(aminomethyl)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione and 0.025 g of potassium cyanate in 2 ml
of acetic acid is irradiated in a microwave field for 4 minutes at 120°C. The resulting
mixture is evaporated under reduced pressure. The residue is chromatographed on
silica gel, eluting with a DCM/MeOH mixture from (100/0, v/v) to (93/7, v/v) to give
0.06 g of the expected product.

EXAMPLE 14: Compound 60
Synthesis of 3-(3,4-dimethoxybenzyl)-6-(fluoromethy!)-1 -(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1H,3H)-dione

Step 14.1:
3-(3,4-dimethoxybenzyl)-6-ethenyl-1-(tetrahydro-2H-pyran-4-yl)quinazoline-
2,4(1 H,3H)-d\one

A mixture of 3.0 g of 3-(3,4-dimethoxybenzyl)-6-iodo-1-(tetrahydro-2H-pyran-
4-yl)quinazoline-2,4(1H,3H)-dione, 3.64 g of tributylvinyltin and Pd(PPh3)4 in 2 ml of
toluene is irradiated in a microwave field for 30 minutes at 130°C. The reaction mixture
is filtered and evaporated under reduced pressure. The residue is chromatographed on
silica gel, eluting with a DCM/EtOAc mixture from (100/0, v/v) to (80/20, v/v) to give
1.4 g of the expected product.
Step 14.2:
3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-
tetrahydroquinazoline-6-carbaldehyde

A stream of ozone is passed for 10 minutes through a solution of 1.4 g of the
compound obtained in Step 14.1 in 100 ml of DCM cooled to -78°C. The reaction
medium is degassed with nitrogen, 40 ml of dimethyl sulfide are added and the

resulting mixture is stirred overnight at room temperature. The reaction medium is
evaporated under reduced pressure. The residue is chromatographed on silica gel,
eluting with a DCM/EtOAc mixture from (100/0, v/v) to (60/40, v/v) to give 0.58 g of the
expected product.
Step 14.3:
3-(3,4-dimethoxyben2yl)-6-(hydroxymethyl)-1-(tetrahyclro-2H-pyran-4-yl)quin-
azoline-2,4(1H,3H)-dione

A mixture of 0.575 g of the compound obtained in Step 14.2 and 0.077 g of
NaBH4 in a mixture of 20 ml of MeOH and 10 ml of THF is stirred for 30 minutes at
room temperature. The reaction medium is evaporated under reduced pressure. The
residue is taken up in DCM. This solution is washed with saturated NH4CI solution. The
organic phase is dried over Na2SO4, filtered and evaporated under reduced pressure to
give 0.554 g of the expected product.
Step 14.4:
3-(3,4-dimethoxybenzyl)-6-(fluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)quin-
azoline-2,4(1 «,3H)-dione

0.11 ml of DAST is added dropwise to a solution of 0.1 g of the compound
obtained in Step 14.3 in 2 ml of DCM cooled to -78°C. The reaction medium is stirred
for 2 hours at -78°C and then allowed to warm to room temperature. It is neutralized
with saturated NaHCO3 solution. The resulting mixture is extracted with DCM. The
organic phase is dried over Na2SO4, filtered and evaporated under reduced pressure.
The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from
(95/5, v/v) to (30/70, v/v) to give 0.032 g of the expected product.

EXAMPLE 15: Compound 59
Synthesis of 6-(2,2-difluoroethenyl)-3-(3,4-dimethoxybenzyl)-1 -(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione

A solution of 0.121 mg of CBr2F2 and 0.096 g of HMPT in 0.5 ml of DME is
added, at 0°C, to a solution of 0.12 g of 3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-
(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinazoline-6-carbaldehyde and 0.096 g
of HMPT in 0.5 ml of DMF. This mixture is stirred overnight at room temperature.
Aqueous 10% NaHCO3 solution is added at 0°C. The resulting mixture is extracted
with DCM. The organic phase is dried over Na2SO4, filtered and evaporated under
reduced pressure. The residue is chromatographed on silica gel, eluting with a
DCM/EtOAc mixture from (80/20, v/v) to give 0.023 g of the expected product.
EXAMPLE 16: Compound 24
Synthesis of 3-(3,4-dimethoxybenzyl)-6-(2-hydroxyethyl)-1 -(tetrahydro-2H-pyran-
4-yl)quinazoline-2,4(1H,3H)-dione

0.95 ml of a 1N solution of BH3-THF complex in THF is added, at 0°C, to a
mixture of 0.1 g of 3-(3,4-dimethoxybenzyl)-6-ethenyl-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1H,3H)-dione in 2 ml of THF. The reaction medium is allowed to warm
to room temperature and is stirred for 1 hour. 2 ml of 1N sodium hydroxide and then
2 ml of 30% aqueous hydrogen peroxide solution are added. The resulting mixture is
refluxed for 1 hour and then extracted with DCM. The organic phase is dried over
Na2SO4, filtered and evaporated under reduced pressure. The residue is
chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (80/20, v/v) to
(40/60) to give 0.057 g of the expected product.

EXAMPLE 17: Isomers 17 and 18
Synthesis of {[3-(3,4-dimethoxybenzyl)-1 -(1 -oxidotetrahydro-2H-thiopyran-4-yl)-
2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile

Step 17.1:
6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-
quinazoline-2,4(1 H,3H)-d\one

A mixture of 0.9 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-
thiopyran-4-yl)quinazoline-2,4(1H,3H)-dione and 0.445 g of sodium periodate in 20 ml
of an MeOH/EtOH/water mixture (5/5/1, v/v/v) is stirred overnight at room temperature.
The resulting mixture is evaporated under reduced pressure. Water is added and the
resulting mixture is extracted with DCM. The organic phase is dried over Na2SC>4. The
resulting mixture is filtered, and the filtrate is evaporated under reduced pressure. The
residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from
(100/0, v/v) to (95/5, v/v) to give 0.99 g of the expected product.

Step 17.2:
3-(3,4-dimethoxybenzyl)-6-hydroxy-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione

A mixture of 0.57 g of the compound of Step 17.1 and 10 ml of formic acid is
irradiated in a microwave field for 3 minutes at 140°C. The reaction mixture is
evaporated under reduced pressure. The residue is chromatographed on an RP18
column, eluting with an ACN/water mixture from (10/90, v/v) to (50/50, v/v) to give
0.443 g of the expected product in the form of a mixture of two isomers.
Step 17.3:
{[3-(3,4-dimethoxybenzyl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-2,4-dioxo-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile

A mixture of 0.265 g of the compound obtained in Step 17.2, 0.086 g of
bromoacetonitrile and 0.39 g of Cs2CO3 in 1 ml of DMF is irradiated in a microwave
field for 15 minutes at 100°C. The reaction mixture is evaporated under reduced
pressure. The residue is taken up in DCM, washed with water, dried over Na2SO4 and
filtered, and the filtrate is evaporated under reduced pressure. The residue is
chromatographed on silica gel, eluting with an MeOH/DCM mixture from (0.5/99.5, v/v)
to (5/95, v/v) to give 128 mg of the less polar isomer (compound 17) and 98 mg of the
more polar isomer (compound 18).

EXAMPLE 18: Compound 14
Synthesis of {[3-(3,4-dimethoxybenzyl)-1 -(1,1 -dioxidotetrahydro-2H-thiopyran-4-
yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile

Step 18.1:
6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1 -(1,1 -dioxidotetrahydro-2H-thiopyran-4-
yl)quinazoline-2,4(1 W,3H)-dione

0.55 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-thiopyran-4-
yl)quinazoline-2,4(1H,3H)-dione and 0.196 g of Oxone® in 100 ml of an MeOH/water
mixture (10/1) (v/v) is stirred at room temperature overnight. The resulting mixture is
evaporated under reduced pressure. Water is added and the resulting mixture is
extracted with DCM. The organic phase is dried over Na2SO4. The resulting solution is
filtered and the filtrate is then evaporated under reduced pressure. The residue is
chromatographed on silica gel, eluting with a heptane/EtOAc mixture from (50/50, v/v)
to (0/100, v/v) to give 0.454 g of the expected product.
Step 18.2:
3-(3,4-dimethoxybenzyl)-1 -(1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-6-
hydroxyquinazoline-2,4(1H,3H)-dione

A mixture of 0.42 g of the compound obtained in Step 18.1 and 3.66 g of formic

acid is irradiated in a microwave field for 10 minutes at 180°C. The reaction mixture is
evaporated under reduced pressure. The residue is chromatographed on silica gel,
eluting with a DCM/MeOH mixture from (100/0, v/v) to (90/10, v/v), to give the
expected product.
Step 18.3
{[3-(3,4-dimethoxybenzyl)-1 -(1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-2,4-dioxo-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile

A mixture of 0.055 g of the compound obtained in Step 18.2, 0.017 g of
bromoacetonitrile and 0.078 g of Cs2CO3 in 2 ml of DMF is irradiated in a microwave
field for 15 minutes at 100°C. The reaction mixture is evaporated under reduced
pressure. The residue is taken up in DCM, washed with water, dried over Na2SO4 and
filtered, and the filtrate is evaporated under reduced pressure. The residue is
chromatographed on silica gel, eluting with an MeOH/DCM mixture from (0.5/99.5, v/v)
to (5/95, v/v), to give 0.043 g of the expected product.
The invention relates to a process for synthesizing a compound of general
formula (I), the said process using an intermediate of formula (VIII), (X), (XVI), (XVII),
(XVIII) and/or (XXIV), and also such synthetic intermediates defined previously.
The compounds according to the invention underwent pharmacological trials
that showed their value as therapeutically active substances.
1) Measurement of the inhibitory activity of the compounds according to the
invention with respect to PDE7
The capacity of the compounds of formula (I) to inhibit PDE7 is measured by
means of an enzymatic test based on separating radioactive cAMP (substrate of
PDE7) from radioactive 5'-AMP (product of the enzymatic reaction) by thin-layer
chromatography on polyethyleneimine (PEI) cellulose, after stopping the enzymatic
reaction. The 5'-AMP is quantitatively extracted from the PEI cellulose and its
radioactivity is measured using a liquid scintillation counter.
The inhibitory activity of the compounds of formula (I) on PDE7 is represented
by the inhibition constant IC50, defined as the concentration of test compound
(inhibitor) in the trial that can reduce the enzymatic activity of PDE7 by 50%. The lower

the IC50 values, the greater the inhibitory power of the compounds.
o Materials
[3H]-cAMP (NET 275; 25 to 40 Ci/mmol) was purchased from Perkin-Elmer
(NEN Life Sciences, Boston, United States), rolipram was purchased from Sigma (St
Louis, MO, United States), and the plastic polyethyleneimine cellulose F sheets for
thin-layer chromatography were purchased from Merck (Darmstadt, Germany). All the
other products are of commercial origin,
o Enzyme
Human PDE7 was partially purified from the cell line HUT-78 by following a
method similar to that described by Bloom and Beavo (Proc. Natl Acad. Sci. USA,
(1996) 93, 14188-14192). The enzyme preparation obtained is stored at -80°C in a
buffer containing 20 mM of Tris-HCI (pH 7.0), 5 mM of MgCI2, 4 mM of EDTA, 1 mM of
dithiothreitol and 20% glycerol. Since the partially purified PDE7 is contaminated with
PDE4, it is necessary to add 10 urn of rolipram (selective PDE4 inhibitor) in the
enzymatic test to totally inhibit the PDE4 activity. The Michaelis constant (Km) of PDE7
for cAMP, measured using the radiochemical test described hereinbelow, is 21 nM.
o Solutions of compounds in accordance with the invention
The compounds of formula (I) to be tested as PDE7 inhibitors are dissolved in
DMSO to a concentration of 10 mM. These solutions are then serially diluted in DMSO
to obtain solutions of desired concentrations. These solutions are then diluted 20-fold
in the test buffer to give solutions containing 5% DMSO. These solutions are finally
diluted 5-fold in the enzymatic test.
The solution of rolipram (added to the test to totally inhibit the contaminant
PDE4 activity) is prepared in an identical manner and provides 1% of DMSO to the
enzymatic test.
o PDE7 enzymatic test
The test is performed in 1.5-ml Eppendorf tubes containing 40 mM of Tris-HCI
(pH 7.5), 15 mM of MgCI2, 1 mM of EGTA, 0.5 mg/ml of bovine serum albumin,
0.25 uCi of [3H]-cAMP (corresponding to a cAMP concentration of between 60 and
100 nM), 10 uM of rolipram and PDE7 in a final volume of 100 ul. The test is
performed in the absence (control sample) or in the presence (treated sample) of
compounds tested as PDE7 inhibitors. The final concentration of DMSO in the test is
2%. The reaction is initiated by adding enzyme and the samples are maintained at
room temperature for 30 minutes. The enzymatic dilution is adjusted so as to obtain a
degree of conversion of 10% to 15%. The enzymatic reaction is stopped by immersing
the stoppered Eppendorf tubes in a water bath at 100°C for 3 minutes. Blanks

(reaction stopped immediately after adding the enzyme) are included in each
experiment. The samples are then centrifuged at 10 000 * g for 1 minute and a 10 ul
aliquot portion of the supernatant is deposited 2 cm from the bottom edge of a sheet of
PEI cellulose onto which 10 ug of cAMP and 10 ug of 5'-AMP have previously been
deposited. To facilitate the migration and the subsequent cutting of the PEI cellulose
strips containing the 5'-AMP, 18 migration paths 1 cm wide are delimited per plate by
scraping the cellulose with a spatula over a width of 1 mm. The plates are developed
over their entire length with a 0.30 M solution of LiCI in water by ascending
chromatography. The 5'-AMP (Rf = 0.20) and the cAMP (Rf = 0.47) are visualized
under UV light at 254 nm. The PEI cellulose bands containing the 5'-AMP are cut out
and the nucleotide is extracted quantitatively into counting flasks with 2 ml of a solution
containing 16 M of formic acid and 2 M of ammonium formate in water (rotary stirring
for 15 minutes). After adding 10 ml of scintillation liquid (OptiPhase HiSafe 3 from
Perkin-Elmer/Wallac), the radioactivity is counted using a liquid scintillation counter
(Perkin-Elmer/Wallac model 1414). Each test is performed in duplicate. The
radioactivity specifically associated with the 5'-AMP formed in the enzymatic reaction is
obtained by subtracting the mean value of the blanks from the mean value of the
controls (or of the treated samples).
The percentage of inhibition of PDE7 at a given concentration of the test
compound (inhibitor) is calculated using the equation: l% = [mean value of the controls
- mean value of the treated samples] * 100/[mean value of the controls - mean value
of the blanks].
The IC50 is the concentration of test compound (inhibitor) in the test that can
reduce the enzymatic activity of PDE7 by 50%.
o Results
As non-limiting illustrative examples, the IC50 values for the following PDE7-
inhibiting quinazolinediones are indicated hereinbelow in Table 2. In these examples,
the IC50 values were measured at a cAMP concentration equal to about 4 times the
value of the Km of the enzyme for cAMP.

therapeutic substances. The compound(s) of formula (I) according to the invention
may thus be useful as medicaments or for the preparation of medicaments.
According to another of its aspects, the invention relates to medicaments or
pharmaceutical compositions comprising at least one compound of formula (I)
according to the invention or an addition salt of this compound with a pharmaceutically
acceptable acid and optionally with at least one pharmaceutically acceptable excipient.
The compounds of formula (I) according to the invention may be useful as
medicaments or for the preparation of a medicament intended especially for treating
and/or preventing inflammatory or immuno-inflammatory diseases.
The compounds of formula (I) according to the invention may be useful as
medicaments or for the preparation of a medicament especially for treating and/or
preventing asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis,
allergies, Crohn's disease, ulcerative colitis, myasthenia gravis, atopic dermatitis,
psoriasis, disseminated lupus erythematosus, rheumatoid arthritis, diabetes and
multiple sclerosis.
The compounds according to the invention may be useful in the context of
treating and/or preventing organ graft rejection, in particular for preventing rejection
and/or in the treatment of immuno-inflammatory reactions following such grafts, in the
treatment and/or prevention of certain types of cancer, for instance osteosarcoma and
i adenocarcinoma, in the treatment and/or prevention of bone diseases, for instance
osteopenia and osteoporosis, in the treatment and/or prevention of acute renal
insufficiency, or in the treatment and/or prevention of pain, in particular neuropathic
pain and visceral pain.
The compounds of formula (I) according to the invention may also be used as
i medicaments or for the preparation of a medicament intended for treating at least a
cardiovascular disease and/or for preventing the onset of at least a cardiovascular
disease.
Examples of cardiovascular diseases that may be mentioned include (i)
coronary diseases, (ii) heart muscle diseases, (Hi), heart valve diseases, (iv)
) pericardium diseases, (v) heart rhythm diseases and heart conduction diseases, and
(vi) blood vessel diseases.
According to the invention, the compounds of formula (I) in accordance with the
invention may be used as medicaments or for the preparation of a medicament for
treating and/or preventing the onset of myocardial infarction, diseases associated with
5 reperfusion lesions of heart muscle and/or skeletal muscle, pulmonary hypertension,
hepatic fibrosis, arterial restenosis after angioplasty, with or without the insertion of a

stent, atherosclerosis and complications thereof, for instance plaque rupture,
aneurysm and coronary diseases, cardiac insufficiency, dilated cardiopathies and
myocarditis of viral and/or bacterial origin.
The compounds of formula (I) according to the invention may be useful as
medicaments or for the preparation of a medicament especially for treating and/or
preventing disorders related to the central nervous system (abbreviated as CNS)
and/or related to the peripheral nervous system (abbreviated as PNS).
The compounds of formula (I) according to the invention may be more
particularly useful as medicaments or for the preparation of a medicament for treating
and/or preventing psychiatric disorders and/or neurological disorders.
According to the invention, the compounds of formula (I) in accordance with the
invention may be used as medicaments or for the preparation of a medicament for
treating and/or preventing psychiatric disorders chosen from anxiety, depression,
mood disorders, insomnia, delirium disorders, obsessive disorders, psychoses,
schizophrenia-related disorders, attention deficit hyperactivity disorder (ADHD) in
hyperkinetic children, disorders associated with the use of psychotropic substances,
especially in the case of substance abuse and/or substance dependency, including
alcohol dependency and/or nicotine dependency, migraine, stress, disorders related to
diseases of psychosomatic origin, panic attacks, epilepsy, memory disorders, cognitive
disorders, in particular senile dementia, disorders related to Alzheimer's disease, and
also attention or vigilance disorders, ischaemia, disorders related to cranial trauma,
and disorders related to acute or chronic neurodegenerative diseases, including
chorea and Huntington's chorea.
According to the invention, the compounds of formula (I) in accordance with the
invention may be used as medicaments or for the preparation of a medicament for
treating and/or preventing neurological diseases, which may be reflected by movement
anomalies or motor disorders, associated with a pathology chosen from dyskinesia,
Parkinson's disease, post-encephalitic Parkinson's syndrome, dopa-sensitive dystonia,
Shy-Drager's syndrome, periodic limb movement disorder (PLMD), periodic limb
movements in sleep (PLMS), Tourette's syndrome, and restless leg syndrome (RLS).
According to the invention, the compounds of formula (I) may be used as
medicaments or for manufacturing a medicament for treating at least one movement
anomaly or motor disorder related to Parkinson's disease, the said movement anomaly
or the said motor disorder being chosen in particular from resting tremor, rigour,
bradykinesia and postural reflex deficiency.
According to the invention, the compounds of formula (I) may be used as

medicaments or for the manufacture of a medicament for preventing and/or treating
neurological disorders reflected by movement anomalies or motor disorders,
associated with spinal column trauma, in particular in the treatment of spinal trauma.
For the purposes of the present invention, the term "spinal column trauma" means
acute or chronic pathologies with an external origin, which destroy the spinal tract
and/or neurones, and which occur, for example, during a fall, a knock, crushing or a
circulatory accident.
The compounds of formula (I) according to the invention may be used
especially as medicaments or for the manufacture of a medicament for preventing
and/or treating disorders:
- associated with schizophrenia, in particular (i) in the prevention and/or
treatment of positive or negative symptoms and/or (ii) in the prevention and/or
treatment of memory deficiency;
- associated with Parkinson's disease, in particular (i) in the symptomatic
prevention and/or treatment of motor disorders, depression and/or cognitive disorders,
and/or (ii) in its fundamental treatment (neuroprotective); and/or
- related to Alzheimer's disease, in particular (i) in the symptomatic prevention
and/or treatment of cognitive disorders and/or behavioural disorders (aggressiveness,
depression) and/or (ii) in its fundamental treatment (neuroprotective).
The use of the compounds of general formula (I) as medicaments or for the
preparation of a medicament for treating the conditions, diseases or syndromes
mentioned above forms an integral part of the invention, and in particular the
compounds of formula (I) chosen from compounds 1 to 68 of Table 1 above.
According to another of its aspects, the present invention relates to
pharmaceutical compositions comprising, as active principle, at least one compound of
formula (I) according to the invention. These pharmaceutical compositions contain an
effective dose of at least one compound of formula (I) according to the invention, and
also at least one pharmaceutical^ acceptable excipient.
The said excipients are chosen, according to the pharmaceutical form and the
desired mode of administration, from the usual excipients 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 principle of formula (I) above, or the
i possible salt, solvate or hydrate thereof, may be administered in unit administration
form, as a mixture with standard pharmaceutical excipients, to man and animals for the

prophylaxis or treatment of the complaints, disorders, syndromes or diseases
mentioned above.
The appropriate unit forms of administration include oral-route forms such as
tablets, soft or hard gel capsules, powders, granules and oral solutions or
suspensions, sublingual, buccal, intratracheal, intraocular, intranasal and inhalation
administration forms, topical, transdermal, subcutaneous, intramuscular or intravenous
administration forms, rectal administration forms and implants. For topical application,
the compounds according to the invention may be used in creams, gels, ointments or
lotions.
By way of example, a unit administration form of a compound according to the
invention, in particular a compound of formula (I) chosen from compounds 1 to 68 of
Table 1 above, in tablet form may comprise the following components:
Compound of formula (I) according to the invention 50.0 mg
Mannitol 223.75 mg
Sodium croscarmellose 6.0 mg
Corn starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg
Magnesium stearate 3.0 mg
The said unit forms are dosed to allow a daily administration of from 0.5 mg to
800 mg of active principle per individual, and more particularly from 0.5 mg to 200 mg,
according to the pharmaceutical form.
There may be cases where higher or lower dosages are appropriate: such
dosages do not depart from the scope of the invention. According to the usual
practice, the dosage that is appropriate to each patient is determined by the doctor
according to the mode of administration and the weight and response of the said
patient.
According to another of its aspects, the present invention also relates to a
method for treating and/or preventing the complaints, disorders, syndromes or
diseases mentioned above, which comprises the administration to patient of an
effective amount of at least one compound of formula (I) according to the invention
and/or at least one salt, hydrate or solvate thereof.

CLAIMS
1. Compound of general formula (I) below:

in which A represents either an oxygen or sulfur atom, or a sulfoxide function (SO
function) or a sulfone function (SO2 function);
> n represents the value 0,1 or 2;
> R2 represents an atom or a group chosen from:

• a hydrogen atom,
• a halogen atom,
• a cyano group,
• a nitro group,
• an aryl, arylalkyl or heteroaryl group,
• a group (CrC6)alkyl, optionally substituted with a function -NH2, with one
or more halogen atoms, with one or more hydroxyl groups, with an
alkynyl group, with an alkenyl group, with a group -NHC(0)Rb and/or
with a group -NHC(0)-NRbRc, Rb and Rc being defined below,
• a group -ORa, Ra being defined below,
• a group NRbRc, Rb and Rc being defined below,
• a group C(0)(C1-C6)alkyl,
• an alkenyl group or an alkynyl group, the said groups being optionally
substituted with at least one hydroxyl or with at least one halogen atom;
• a group alkyl-S-,
• alkyl-S(O)-, and
• alkyl-S(0)2-,
> p represents the value 1, 2 or 3, it being understood that when p is equal to 2 or 3,

then the atoms R2 or the groups R2 may be, respectively, identical or different;
> R-i represents an aryl, arylalkyl or heteroaryl group, the said groups being optionally
substituted with (i) an atom R3 or a group R3, or with (ii) 2 or 3 atoms and/or groups R3,
the said atoms or groups R3 being, respectively, identical or different,
given that R3 represents:
■ a hydrogen atom,
■ a halogen atom,
■ a hydroxyl group,
■ a cyano group,
■ a group -SCF3,
■ a nitro group,
■ a group -S(0)o-2-alkyl, a group -S(0)o-2-heterocycloalkyl, a group -0-SO2-aryl
or 0-SO2-arylalkyl optionally substituted with one or more halogen atoms;
■ an alkyl-amino-alkyl group or a -cycloalkyl-amino-alkyl group, the said groups
being optionally substituted on the terminal alkyl,
■ an optionally substituted sulfonamide group,

■ an aryl, arylalkyl or heteroaryl group, the said group being monocyclic or
polycyclic and moreover being optionally substituted with a group (CrC6)alkyl,
with one or more hydroxyl groups, with one or more halogen atoms, with one or
more cyano groups and/or with one or more groups (CrC6)alkoxy,
■ a heterocycloalkyl group optionally substituted with a group (CrC6)alkyl,
■ a group (CrC6)alkyl optionally substituted with:

- one or more halogen atoms,
- an aryl or arylalkyl group that may be substituted with one or more
halogen atoms, with one or more groups (CrCeJalkoxy, with one or more
groups (CrC6)alkyl, with one or more cyano groups and/or with one or more
hydroxyl groups,
- a heteroaryl group,
- one or more hydroxyl groups that may be substituted with an aryl or
arylalkyl group, which is itself optionally substituted with one or more halogen
atoms, or
- a heterocycloalkyl group optionally substituted with a group CO(0)Ra,
or with a group (CrC6)alkyl, Ra being defined below,

■ a group -C(0)NRbRc, Rb and Rc being defined below,
■ a group -C(0)ORc, or a group -0-C(0)ORc, Rc being defined below,
■ a group (CrCeJalkoxy, optionally substituted with:

- an amino-alkyl group, an amino-cycloalkyl group,
- a cycloalkyl group,
- a heterocycloalkyl group,
- a monocyclic or polycyclic heteroaryl group,
- one or more hydroxyl groups,
- one or more halogen atoms,
- a group (Ci-C6)alkoxy,
- a group -C(0)ORc, Re being defined below,
- a group -C(0)NRbRc, Rb and Rc being defined below, and/or
- an aryl or arylalkyl group, which is itself optionally substituted with at
least one atom and/or at least one group, the said atoms and groups being
chosen from halogen atoms, a cyano group, groups (CrC6)alkoxy, -O-haloalkyl
groups and haloalkyl groups,
■ a group -O-cycloalkyl, -O-aryl or -O-arylalkyl, or a group -O-heterocycloalkyl,
the said groups being optionally substituted with:
- an aryl or arylalkyl group, which is itself optionally substituted with one
or more halogen atoms, or with a group (CrC6)alkyl,
- one or more halogen atoms, and/or
- a group (CrC6)alkyl, which may itself be substituted with an aryl or
arylalkyl group,

■ a group -NH-CO-NH-aryl, a group -NH-CO-NH-arylalkyl, a group -NH-CO-
NH-heteroaryl, or a group -NH-CO-NH-(CrC6)alkyl, the said aryl, arylalkyl, heteroaryl
and alkyl being optionally substituted with at least one atom and/or at least one group,
the said atoms and groups being chosen from halogen atoms, a cyano group, a nitro
group, a hydroxyl group and groups (C-i-C6)alkoxy,
■ a group -N-(CrC6)alkyl, the group (CVCeJalkyl possibly being substituted with
at least one aryl or arylalkyl group optionally substituted with at least one halogen atom
and/or with at least one group SO2, or
■ a group -NH-C(0)-aryl, a group -NH-C(0)-aralkyl or a group -NH-C(O)-
heteroaryl, the said groups being optionally substituted with at least one halogen atom;
> Ra represents:
o a hydrogen atom,
o a group (CrC6)alkyl or a group (CrC6)cycloalkyl, the said groups
being optionally substituted with one or more halogen atoms,
with one or more hydroxyl groups, with an aryl or arylalkyl group,
with one or more cyano groups and/or with a group

-C(0)NRbRc, Rb and Rc being defined below,
o a group (C2-C6)alkynyl,
o an aryl or arylalkyl group,
> Rb represents:
o a hydrogen atom,
o a group (CrC6)alkyl optionally substituted with one or more halogen
atoms, with one or more hydroxyl, cyano, amino, heterocycloalkyl or
(CrC6)alkoxy groups, or with an aryl or arylalkyl group optionally
substituted with one or more halogen atoms,
o a group (C3-C6) cycloalkyl,
o a group (C2-C6) alkenyl or alkynyl,
o a group (Ci-C6)alkoxy,
o an aryl or arylalkyl group optionally substituted with one or more halogen
atoms;
> Rc represents a hydrogen atom, or a group (CrCeJalkyl optionally substituted with
one or more halogen atoms;
> given that in the groups -NRbRc, Rb and Rc may form with the nitrogen atom a
heteroaryl or a heterocycloalkyl, the latter groups being optionally substituted;
in the form of the base or of an acid-addition salt.
2. Compound according to the preceding claim, characterized in that n is equal
to1;
in the form of the base or of an acid-addition salt.
3. Compound according to either of the preceding claims, characterized in that
p represents the value 1 or 2, it being understood that when p is equal to 2, then the
possible combinations are either (i) two identical or different atoms R2, or (ii) an atom
R2 and a group R2, or (iii) two identical or different groups R2;
in the form of the base or of an acid-addition salt.
4. Compound according to any one of the preceding claims, characterized in
that R2 represents an atom or a group chosen from:
• a halogen atom,
• a hydrogen atom,
• a nitro group,
• a cyano group,
• an aryl, arylalkyl or heteroaryl group,
• a group (C1-C6)alkyl, optionally substituted with a function -NH2, with one
or more hydroxyl groups, with an alkynyl group, with one or more

halogen atoms, with a group -NHC(0)Rb with Rb being an optionally
substituted group (C1-C6)alkyl, with a group -NHC(0)-NRbRc with Rb
and Rc being hydrogen atoms and/or with an alkenyl group,
• a group -ORa, Ra being chosen from:
o a hydrogen atom,
o a group (C1-C6)alkyl optionally substituted with one or more
halogen atoms, with one or more hydroxyl groups, with an aryl or
arylalkyl group, with one or more cyano groups and/or with a
group -C(0)NRbRc,
o a group (C1-C6)cycloalkyl,
o a group (C2-C6)alkynyl,
o an aryl group,
o an arylalkyl group,
• a group NRbRc, Rb being chosen from a hydrogen atom and a group
(C1-C6)alkyl optionally substituted with a group (C2-C6)alkynyl and Rc
being a hydrogen atom, or Rb and Rc form with the nitrogen atom a
heterocycloalkyl, optionally substituted with a hydroxyl group;
• a group C(O)(C1-C6)alkyl, and
• an alkenyl group optionally substituted with at least one halogen atom;
in the form of the base or of an acid-addition salt.
5. Compound according to any one of the preceding claims, characterized in
that R2 represents an atom or a group chosen from:
• a halogen atom chosen from bromine, fluorine and iodine,
• a hydrogen atom,
• a nitro group,
• a cyano group,
• an aryl or heteroaryl group chosen from phenyl and pyridyl,

• a group (C1-C6)alkyl, optionally substituted with a function -NH2, with one
or more hydroxyl groups, with an alkynyl group, with one or more
fluorine atoms, with a group -NHC(0)Rb with Rb being an optionally
substituted group (C1-C6)alkyl, with a group -NHC(0)-NRbRc with Rb
and Rc being hydrogen atoms and/or with an alkenyl group,
• a group -ORa, Ra being chosen from:
o a hydrogen atom,
o a group (C1-C6)alkyl optionally substituted with one or more
halogen atoms, with one or more fluorine atoms, with one or

more hydroxyl groups, with a benzyl or phenyl group, with one or
more cyano groups and/or with a group -C(0)NRbRc, Rb and Rc
being hydrogen atoms,
o a group (C1-C6)cycloalkyl,
o a group (C2-C6)alkynyi,
o a benzyl,
• a group NRbRc, Rb being chosen from a hydrogen atom and a group
(C1-C6)alkyl optionally substituted with a group (C2-C6)alkynyl and Rc
being a hydrogen atom, or Rb and Rc form with the nitrogen atom a
heterocycloalkyl, optionally substituted with a hydroxyl group;
• a group C(O)(C1-C6)alkyl, and
• an alkenyl group optionally substituted with at least one fluorine atom;
in the form of the base or of an acid-addition salt.
6. Compound according to any one of the preceding claims, characterized in
that p is equal to 2 and the two groups and/or atoms R2 are chosen from:
• a halogen atom, and
• a group -ORa, Ra being chosen from:
o a hydrogen atom, and
o a group (C1-C6)alkyl optionally substituted with one or more
halogen atoms or with an aryl group;
in the form of the base or of an acid-addition salt.
7. Compound according to any one of the preceding claims, characterized in
that p is equal to 2 and the two groups and/or atoms R2 are chosen from:
• a fluorine atom, and
• a group -ORa, Ra being chosen from:
o a hydrogen atom, and
o a group (C1-C6)alkyl optionally substituted with one or more
fluorine atoms or with a phenyl group;
in the form of the base or of an acid-addition salt.
8. Compound according to any one of the preceding claims, characterized in
that R1 is a phenyl or a pyridyl, optionally substituted with (i) an atom R3 or a group R3
or (ii) with two atoms and/or groups R3, the possible combinations then being:
o either two identical or different atoms R3,
o or an atom R3 and a group R3,
o or two identical or different groups R3,
R3 being chosen from hydroxyl and (C1-C6)alkoxy groups, the said groups (C1

C6)alkoxy being optionally substituted with an aryl or arylalkyl group, the said aryl or
arylalkyl group itself being optionally substituted with at least one halogen atom;
in the form of the base or of an acid-addition salt.
9. Compound according to any one of the preceding claims, characterized in
that R1 is a phenyl or a pyridyl, optionally substituted with (i) an atom R3or a group R3
or (ii) with two atoms and/or groups R3, the possible combinations then being:
o either two identical or different atoms R3,
o or an atom R3 and a group R3l
o or two identical or different groups R3,
R3 being chosen from hydroxyl and (C1-C6)alkoxy groups, the said groups (C1
C6)alkoxy being optionally substituted with a benzyl group, the said benzyl group itself
being optionally substituted with at least one chlorine atom;
in the form of the base or of an acid-addition salt.
10. Compound according to any one of the preceding claims, characterized in
that it is:
compound 1: 3-(3,4-dimethoxybenzyl)-6-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione;
- compound 2: {[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile;
- compound 3: 3-(3,4-dimethoxybenzyl)-6-pyridin-4-yl-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1H,3H)-dione hydrochloride;
- compound 4: 3-[(6-methoxypyridin-3-yl)methyl]-6-pyridin-4-yl-1-(tetrahydro-2H-pyran-
4-yl)quinazoline-2,4(1H,3H)-dione;
- compound 5: 6-bromo-3-[(6-methoxypyridin-3-yl)methyl]-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione;
compound 6: 6-bromo-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 7: 2-({3-[(6-methoxypyridin-3-yl)methyl]-2,4-dioxo-1-(tetrahydro-2H-pyran-
4-yl)-1,2,3,4-tetrahydroquinazolin-6-yl}oxy)propanenitrile
- compound 8: 2-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}propanenitrile
- compound 9: ({3-[(6-methoxypyridin-3-yl)methyl]-2,4-dioxo-1-(tetrahydro-2H-pyran-4-
yl)-1,2,3,4-tetrahydroquinazolin-6-yl}oxy)acetonitrile
- compound 10: 3-(3,4-dimethoxybenzyl)-6-hydroxy-1-(tetrahydro-2H-thiopyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 11: {[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-

1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile
- compound 12: 2-{[3-(3,4-dimethoxybenzyl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-
yl)-2,4-dioxo-1,2,3,4-tetrahydroquina2olin-6-yl]oxy}propanenitrile
- compound 13: 3-(3,4-dimethoxybenzyl)-6-hydroxy-1-(1-oxidotetrahydro-2H-thiopyran-
4-yl)quinazoline-2,4(1H,3H)-dione
- compound 14: {[3-(3,4-dimethoxybenzyl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-
2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile

- compound 15: 2-{[3-(3,4-dimethoxybenzyl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-
2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}propanenitrile (isomer 1)
- compound 16: 2-{[3-(3,4-dimethoxybenzyl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-
2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}propanenitrile (isomer 2)
- compound 17: {[3-(3,4-dimethoxybenzyl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-2,4-
dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile (isomer 1)
- compound 18: {[3-(3,4-dimethoxybenzyl)-1-(1-oxidotetrahydro-2H-thiopyran-4-yl)-2,4-
dioxo-1 ,2,3,4-tetrahydroquinazolin-6-yl]oxy}acetonitrile (isomer 2)

- compound 19: 2-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}propanenitrilemethane (1:1) (enantiomer 1)
- compound 20: 2-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yI)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}propanenitrilemethane (1:1) (enantiomer 2)
- compound 21:3-(3,4-dimethoxybenzyl)-6-(prop-2-yn-1-yloxy)-1-(tetrahydro-2H-pyran-
4-yi)quinazoline-2,4(1H,3H)-dione

- compound 22: 2-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}-2-methylpropanenitrile
- compound 23: 2-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]oxy}-2-methylpropanamide
- compound 24: 3-(3,4-dimethoxybenzyl)-6-(2-hydroxyethoxy)-1-(tetrahydro-2H-pyran-
4-yl)quinazoline-2,4(1H,3H)-dione
- compound 25: 6-(cyclopropylmethoxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 26: 3-(3,4-dimethoxybenzyl)-6-[(1-methylprop-2-yn-1-yl)oxy]-1-(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 27: 3-(3,4-dimethoxybenzyl)-6-(3-hydroxyazetidin-1-yl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 28: 3-(3,4-dimethoxybenzyl)-6-(prop-2-yn-1-ylamino)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 29: 3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-

1,2,3,4-tetrahydroquinazoline-6-carbonitrile
- compound 30: N-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]methyl}acetamide
- compound 31: 1-{[3-(3,4-dimethoxybenzyl)-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-
1,2,3,4-tetrahydroquinazolin-6-yl]methyl}urea

- compound 32: 3-(3,4-dimethoxybenzyl)-6-[(1-methylprop-2-yn-1-yl)oxy]-1-(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione (enantiomer 1)
- compound 33: 3-(3,4-dimethoxybenzyl)-6-[(1-methylprop-2-yn-1-yl)oxy]-1-(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione (enantiomer 2)
compound 34: 3-(3,4-dimethoxybenzyl)-6-iodo-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
compound 35: 3-(3,4-dimethoxybenzyl)-6-[(1-methylprop-2-yn-1-yl)amino]-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 36: 3-(3,4-dimethoxybenzyl)-6-propoxy-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 37: 3-(3,4-dimethoxybenzyl)-6-(2-methylpropoxy)-1-(tetrahydro-2H-pyran-
4-yl)quinazoline-2,4(1H,3H)-dione
- compound 38: 3-(3,4-dimethoxybenzyl)-6-(1-methylethoxy)-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione
- compound 39: 3-(3,4-dimethoxybenzyl)-6-(1-hydroxyethyl)-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione
compound 40: 6-acetyl-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 41: 6-(2,3-dihydroxypropoxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 42: 3-(3,4-dimethoxybenzyl)-6-(2-hydroxypropoxy)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 43: 3-(3,4-dimethoxybenzyl)-6-(1-hydroxy-1-methylethyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 44: 3-(3,4-dimethoxybenzyl)-6-ethenyl-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 45: 3-(3,4-dimethoxybenzyl)-6-(hydroxymethyl)-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione
- compound 46: 3-(3,4-dimethoxybenzyl)-6-(1-hydroxy-1-methylbut-3-yn-1-yl)-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 47: 3-(3,4-dimethoxybenzyl)-6-(2-hydroxyethyl)-1-(tetrahydro-2H-pyran-4-

yl)quinazoline-2,4(1 H,3H)-dione
compound 48: 3-(3,4-dimethoxybenzyl)-6-[(1R)-2-hydroxy-1-methylethoxy]-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 49: 3-(3,4-dimethoxybenzyl)-6-ethoxy-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 50: 3-(3,4-dimethoxybenzyl)-6-(2-fluoroethoxy)-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione
- compound 51: 3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-6-(2,2,2-
trifluoroethoxy)quinazoline-2,4(1H,3H)-dione
compound 52: 3-(3,4-dimethoxybenzyl)-6-[(1S)-2-hydroxy-1-methylethoxy]-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 53:: 6-(2,2-difluoroethoxy)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
compound 54: 3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-6-(3,3,3-
trifluoropropoxy)quinazoline-2,4(1H,3H)-dione
- compound 55: 3-(3,4-dimethoxybenzyl)-6-{[(1R)-1-methylpropyl]oxy}-1-(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 56: 3-(3,4-dimethoxybenzyl)-6-{[(1S)-1-methylpropyl]oxy}-1-(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
compound 57: 3-(3,4-dimethoxybenzyl)-6-[2-fluoro-1-(fluoromethyl)ethoxy]-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
compound 58: 3-(3,4-dimethoxybenzyl)-6-[(1S)-2-fluoro-1-methylethoxy]-1-
(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 59: 6-(2,2-difluoroethenyl)-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 60: 3-(3,4-dimethoxybenzyl)-6-(fluoromethyl)-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
- compound 61: 3-(3,4-dimethoxybenzyl)-7-fluoro-6-hydroxy-1-(tetrahydro-2H-pyran-4-
yl)quinazoline-2,4(1 H,3H)-dione
- compound 62: 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-7-fluoro-1-(tetrahydro-2H-
pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 63: 6-(2,2-difluoroethoxy)-3-(3,4-dimethoxybenzyl)-7-fluoro-1-(tetrahydro-
2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
- compound 64: 3-[4-(benzyloxy)-3-methoxybenzyl]-6-[(1,3-difluoropropan-2-yl)oxy]-7-
fluoro-1-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione
compound 65: 3-{4-[(3,4-dichlorobenzyl)oxy]-3-methoxybenzyl}-6-[(1,3-

difluoropropan-2-yl)oxy]-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-
dione
compound 66: 3-(3,4-dimethoxybenzyl)-6-nitro-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
compound 67: 6-amino-3-(3,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-
quinazoline-2,4(1 H,3H)-dione
compound 68: 6-[(1,3-difluoropropan-2-yl)oxy]-7-fluoro-3-(4-hydroxy-3-
methoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione;
in the form of the base or of an acid-addition salt.
11. Medicament, characterized in that it comprises at least one compound
according to any one of the preceding claims, or an addition salt of this compound with
a pharmaceutically acceptable acid.
12. Pharmaceutical composition, characterized in that it comprises at least one
compound according to any one of Claims 1 to 10, or an addition salt of this compound
with a pharmaceutically acceptable acid, and also at least one pharmaceutically
acceptable excipient.
13. Use of at least one compound according to any one of Claims 1 to 10, as a
medicament or for the preparation of a medicament.

14. Use of a compound according to any one of Claims 1 to 10, as a
medicament or for the preparation of a medicament for treating and/or preventing at
least one inflammatory or immuno-inflammatory disease.
15. Use of a compound according to any one of Claims 1 to 10, as a
medicament or for the preparation of a medicament for treating and/or preventing
asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, allergies,
Crohn's disease, ulcerative colitis, myasthenia gravis, atopic dermatitis, psoriasis,
disseminated lupus erythematosus, rheumatoid arthritis, diabetes and multiple
sclerosis.
16. Use of a compound according to any one of Claims 1 to 10, as a
medicament or for the preparation of a medicament for treating and/or preventing graft
rejection and/or immuno-inflammatory reactions following grafting, in the treatment
and/or prevention of certain types of cancer, for instance osteosarcoma and
adenocarcinoma, in the treatment and/or prevention of bone diseases, for instance
osteopenia and osteoporosis, in the treatment and/or prevention of acute renal
insufficiency, or in the treatment and/or prevention of pain, in particular neuropathic
pain and visceral pain.

17. Use of a compound according to any one of Claims 1 to 10, as a
medicament or for the preparation of a medicament for treating and/or preventing at
least a cardiovascular disease and/or for preventing the onset of at least a
cardiovascular disease.
18. Use according to the preceding claim, characterized in that the
cardiovascular disease is chosen from (i) coronary diseases, (ii) heart muscle
diseases, (iii), heart valve diseases, (iv) pericardium diseases, (v) heart rhythm
diseases and heart conduction diseases, and (vi) blood vessel diseases.
19. Use of a compound according to any one of Claims 1 to 10, as a
medicament or for the preparation of a medicament for treating and/or preventing the
onset of myocardial infarction, diseases associated with reperfusion lesions of heart
muscle and/or skeletal muscle, pulmonary hypertension, hepatic fibrosis, arterial
restenosis after angioplasty, with or without the insertion of a stent, atherosclerosis and
complications thereof, for instance plaque rupture, aneurysm and coronary diseases,
cardiac insufficiency, dilated cardiopathies and myocarditis of viral and/or bacterial
origin.
20. Use of a compound according to any one of Claims 1 to 10, as a
medicament or for the preparation of a medicament for treating and/or preventing
disorders associated with the central nervous system and/or associated with the
peripheral nervous system.
21. Use of a compound according to any one of Claims 1 to 10, as a
medicament or for the preparation of a medicament for treating and/or preventing
psychiatric disorders and/or neurological disorders.
22. Use according to the preceding claim, characterized in that (i) the
psychiatric disorder is chosen from anxiety, depression, mood disorders, insomnia,
delirium disorders, obsessive disorders, psychoses, schizophrenia-related disorders,
attention deficit hyperactivity disorder (ADHD) in hyperkinetic children, disorders
associated with the use of psychotropic substances, especially in the case of
substance abuse and/or substance dependency, including alcohol dependency and/or
nicotine dependency, migraine, stress, disorders related to diseases of psychosomatic
origin, panic attacks, epilepsy, memory disorders, cognitive disorders, in particular
senile dementia, disorders related to Alzheimer's disease, and also attention or
vigilance disorders, ischaemia, disorders related to cranial trauma, and disorders
related to acute or chronic neurodegenerative diseases, including chorea and
Huntington's chorea, and in that (ii) the neurological disorder, which may be reflected
by movement anomalies or motor disorders, is associated with a pathology chosen

from dyskinesia, Parkinson's disease, post-encephalitic Parkinson's syndrome, dopa-
sensitive dystonia, Shy-Drager's syndrome, periodic limb movement disorder (PLMD),
periodic limb movements in sleep (PLMS), Tourette's syndrome, and restless leg
syndrome (RLS).
23. Use of a compound according to any one of Claims 1 to 10, as a
medicament or for the preparation of a medicament for treating and/or preventing
neurological disorders reflected by movement anomalies or motor disorders,
associated with spinal cord trauma.
24. Process for synthesizing a compound according to any one. of Claims 1 to
10, characterized in that it uses an intermediate of formula:

characterized in that R2 and A are as defined in Claim 1 and in that R" is a group

(CrC6)alkyl or a substituted aryl group.
26. Compound of formula:

characterized in that R1, R2 and A are as defined in Claim 1.
27. Compound of formula:

characterized in that R1 and A are as defined in Claim 1.
28. Compound of formula:

characterized in that R1 and A are as defined in Claim 1 and R" is a group (Cr
C6)alkyl or a substituted aryl group.
29. Compound of formula:


characterized in that R1 and A are as defined in Claim 1.
30. Compound of formula:

characterized in that R1 and A are as defined in Claim 1 and R" is a group (C1-C6)alkyl
or a substituted aryl group.

The subject matter of the invention is
quinazolinedione derivatives of formula (I) with A
being a sulphur or oxygen atom or a sulphoxide or a
sulphone group, methods for obtaining same and
therapeutic uses thereof, such as cancer, diabetes,
muscle diseases, bone diseases, cardiovascular
diseases, central nervous system diseases, peripheral
nervous system diseases, inter alia.