Substituted pyrazolo[3,4-
The present invention relates to new substituted pyrazolo[3,4-d]pyrimidine compounds, having a great affinity for sigma receptors, especially sigma-1 receptor, as well as to the process for the preparation thereof, to compositions comprising them, and to their use as medicaments.
1. A compound of general formula (I):
wherein
n is 1, 2, 3 or 4;
R 1 represents a carbon-linked substituted or unsubstituted aryl or heteroaryl radical;
R 2 and R 3 independently represent a hydrogen atom;
a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted, aliphatic radical C 1-10 ;
a substituted or unsubstituted cycloalkyl radical C 3-9 ; a branched or unbranched cycloalkyl-alkyl radical C 1-10 group in which either the alkyl group and/or the cycloalkyl group is optionally at least mono-substituted; a substituted or unsubstituted cycloalkyl C 3-9 or cycloalkylalkyl C 1-10 group in which the cycloalkyl group is condensed with another substituted or unsubstituted mono- or polycyclic ring system;
a substituted or unsubstituted aryl radical; a substituted or unsubstituted, branched or unbranched arylalkyl radical C 1-10 ;
a substituted or unsubstituted heteroaryl radical; a substituted or unsubstituted, branched or unbranched heteroarylalkyl radical C 1-10 ; a substituted or unsubstituted non-aromatic heterocyclyl radical C 3-9 ; a substituted or unsubstituted, branched or unbranched heterocyclylalkyl radical C 3-9 ;
a substituted or unsubstituted heterocyclyl C 3-9 or heterocyclyl-alkyl radical C 1-10 group in which the heterocyclyl group is condensed with another substituted or unsubstituted mono- or polycyclic ring system;
or R 2 and R 3 together with the bridging nitrogen form a substituted or unsubstituted heterocycloalkyl radical C 3-9 ; or a substituted or unsubstituted heteroaryl radical C 3-9 ;
or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
2. The compound according to claim 1 , wherein R 1 represents a group selected from:
wherein Ra independently represents a hydrogen atom, an alkyl radical C 1 -C 6 , a halogen atom, an haloalkyl radical C 1 -C 6 , —CN, —OR or —SO 2 R where R is hydrogen or an alkyl C 1 -C 6 .
3. The compound according to claim 1 , wherein R 2 and R 3 independently represent a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted, aliphatic radical C 1-10 ; a substituted or unsubstituted aryl radical; a substituted or unsubstituted, branched or unbranched arylalkyl radical C 1-10 or an optionally monosubstituted benzhydryl group; or R 2 and R 3 together with the bridging nitrogen form a substituted or unsubstituted heterocycloalkyl radical C 3-9 ; or a substituted or unsubstituted heteroaryl radical C 3-9 .
4. The compound according to claim 3 , wherein R 2 and R 3 together with the bridging nitrogen form a piperidine which is optionally substituted by at least one halogen atom.
5. The compound according to claim 1 , wherein n is 2.
6. The compound according to claim 1 , which is selected from:
4-phenyl-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
1-(2-(piperidin-1-yl)ethyl)-4-o-tolyl-1H-pyrazolo[3,4-d]pyrimidine,
1-(2-(piperidin-1-yl)ethyl)-4-m-tolyl-1H-pyrazolo[3,4-d]pyrimidine hydrochloride,
1-(2-(piperidin-1-yl)ethyl)-4-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(2-methylpyridin-3-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
3,5-dimethyl-4-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isoxazole hydrochloride,
4-(4-methoxypyridin-3-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride,
4-(4-methylpyridin-3-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride,
4-(1-methyl-1H-pyrazol-5-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(2-methoxypyridin-3-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(2-methoxypyridin-3-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine (L)-tartrate,
4-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isoquinoline,
4-(2-ethoxyphenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride,
4-(4-fluorophenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(4-methoxyphenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)benzonitrile,
4-(5-methylpyridin-3-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
1-(2-(piperidin-1-yl)ethyl)-4-(pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(5-chlorothiophen-2-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(4-chlorophenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(6-methylpyridin-2-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(4-(methylsulfonyl)phenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
1-(2-(piperidin-1-yl)ethyl)-4-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(2-chloro-5-methylphenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(2,5-dimethylphenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(1-methyl-1H-pyrrol-2-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(4-fluoro-2-methoxyphenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(4-fluoro-2-methylphenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(1-methyl-1H-imidazol-4-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(1-methyl-1H-pyrazol-4-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
2-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)oxazole,
2-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thiazole,
4-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(2-chlorophenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)isothiazole,
4-(1-isopropyl-1H-pyrazol-4-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
1-(2-(piperidin-1-yl)ethyl)-4-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(2,4-difluorophenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
1-(2-(piperidin-1-yl)ethyl)-4-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(1-methyl-1H-imidazol-5-yl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(2-chloro-4-fluorophenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(2-chlorophenyl)-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(2-chloro-4-fluorophenyl)-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(4-chloro-2-fluorophenyl)-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-(4-chloro-2-fluorophenyl)-1-(2-(piperidin-1-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine,
2-(4-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(4-fluorobenzyl)-N-methylethanamine,
N-(4-fluorobenzyl)-N-methyl-2-(4-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethanamine, or
2-(4-(2-chloro-4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(4-fluorobenzyl)-N-methylethanamine,
or a pharmaceutically acceptable salt or solvate thereof.
7. A method of treating a condition selected from the group consisting of pain, diarrhea, addiction to cocaine, stroke, depression, anxiety, and schizophrenia in a subject in need thereof comprising administration of an effective amount of the compound according to claim 1 .
8. The method according to claim 7 , wherein the condition is pain which is selected from the group consisting of neuropathic pain, inflammatory pain, allodynia, and hyperalgesia.
9. The method according to claim 8 , wherein the allodynia is mechanical allodynia or thermal allodynia.
10. The method according to claim 8 , wherein the neurophatic pain is hyperpathia.
11. The method according to claim 7 , wherein the condition is selected from the group consisting of diarrhea, addiction to cocaine, stroke, depression, anxiety, and schizophrenia.
12. A process for the preparation of a compound of general formula (I):
comprising the reaction between a compound of general formula (III):
with a boronic acid of formula (V):
R 1 B(OH) 2 (V)
a corresponding ester or a corresponding organoborane thereof,
or with an organotin derivative of formula (VI):
R 1 Sn(R 4 ) 3
wherein
n is 1, 2, 3 or 4;
R 1 represents a carbon-linked substituted or unsubstituted aryl or heteroaryl radical;
R 2 and R 3 independently represent a hydrogen atom;
a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted, aliphatic radical C 1-10 ;
a substituted or unsubstituted cycloalkyl radical C 3-9 ; a branched or unbranched cycloalkyl-alkyl radical C 1-10 group in which either the alkyl group and/or the cycloalkyl group is optionally at least mono-substituted; a substituted or unsubstituted cycloalkyl C 3-9 or cycloalkylalkyl C 1-10 group in which the cycloalkyl group is condensed with another substituted or unsubstituted mono- or polycyclic ring system;
a substituted or unsubstituted aryl radical; a substituted or unsubstituted, branched or unbranched arylalkyl radical C 1-10 ;
a substituted or unsubstituted heteroaryl radical; a substituted or unsubstituted, branched or unbranched heteroarylalkyl radical C 1-10 ; a substituted or unsubstituted non-aromatic heterocyclyl radical C 3-9 ; a substituted or unsubstituted, branched or unbranched heterocyclylalkyl radical C 3-9 ;
a substituted or unsubstituted heterocyclyl C 3-9 or heterocyclyl-alkyl radical C 1-10 group in which the heterocyclyl group is condensed with another substituted or unsubstituted mono- or polycyclic ring system;
or R 2 and R 3 together with the bridging nitrogen form a substituted or unsubstituted heterocycloalkyl radical C 3-9 ; or a substituted or unsubstituted heteroaryl radical C 3-9 ;
X is a halogen atom; and
R 4 represents a C 1 -C 10 alkyl radical.
13. The process according to claim 12 , wherein the compound of formula (III):
is prepared by a reaction between a compound of general formula (II):
with a compound of formula general (IV):
wherein
n is 1, 2, 3 or 4;
R 2 and R 3 independently represent a hydrogen atom;
a branched or unbranched, saturated or unsaturated, optionally at least mono-substituted, aliphatic radical C 1-10 ;
a substituted or unsubstituted cycloalkyl radical C 3-9 ; a branched or unbranched cycloalkyl-alkyl radical C 1-10 group in which either the alkyl group and/or the cycloalkyl group is optionally at least mono-substituted; a substituted or unsubstituted cycloalkyl C 3-9 or cycloalkylalkyl C 1-10 group in which the cycloalkyl group is condensed with another substituted or unsubstituted mono- or polycyclic ring system;
a substituted or unsubstituted aryl radical; a substituted or unsubstituted, branched or unbranched arylalkyl radical C 1-10 ;
a substituted or unsubstituted heteroaryl radical; a substituted or unsubstituted, branched or unbranched heteroarylalkyl radical C 1-10 ; a substituted or unsubstituted non-aromatic heterocyclyl radical C 3-9 ; a substituted or unsubstituted, branched or unbranched heterocyclylalkyl radical C 3-9 ;
a substituted or unsubstituted heterocyclyl C 3-9 or heterocyclyl-alkyl radical C 1-10 group in which the heterocyclyl group is condensed with another substituted or unsubstituted mono- or polycyclic ring system;
or R 2 and R 3 together with the bridging nitrogen form a substituted or unsubstituted heterocycloalkyl radical C 3-9 ; or a substituted or unsubstituted heteroaryl radical C 3-9 ;
X is a halogen atom or triflate; and
Y is a suitable leaving group, including a halogen atom or a hydroxyl group.
14. A pharmaceutical composition comprising the compound according to claim 1 , and at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle.