Pyrazolylbenzene-1,3-diols for diseases associated with g protein-coupled receptor 18 and in combination with transient receptor potential vanilloid 1
The present invention relates to pyrazolylbenzene-1,3-diols as cannabidiol derivatives, its use for the manufacture of a medicament, and more particularly, to the use of this medicament for the treatment and/or prevention of a disorder associated with the GPR18 and/or TRPV1 receptors and the use of these compounds for pharmacological assays related to GPR18 and/or TRPV1.
1. A compound represented by Formula (I)
or a tautomer, a pharmaceutically acceptable salt or solvate thereof; wherein:
R 1 is selected from the group consisting of hydrogen and a substituted or unsubstituted alkyl;
R 2 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 5 -C 20 aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclic ring; and
R 3 is selected from the group consisting of hydrogen and halogen.
2. A compound of claim 1 , wherein the compound is selected from the group consisting of a compound represented by Formula (II),
or a tautomer, a pharmaceutically acceptable salt or solvate thereof, and a compound represented by Formula (III),
or a tautomer, a pharmaceutically acceptable salt or solvate thereof,
wherein R 1 is selected from the group consisting of hydrogen and a substituted or unsubstituted alkyl;
R 2 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C5-C20 aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclic ring; and
R 3 is selected from the group consisting of hydrogen and halogen.
3. A compound of claim 1 , wherein R 1 is selected from the group consisting of hydrogen, methyl, pentyl, and 1,1-dimethyl heptyl.
4. A compound of claim 1 , wherein R 2 is selected from the group consisting of methyl, ethyl, iso-propyl, and tert-butyl.
5. A compound of claim 1 , wherein R 2 is cyclohexyl.
6. A compound of claim 1 , wherein R 2 is a phenyl.
7. A compound of claim 6 , wherein R 2 is a phenyl substituted by a hydroxyl or a methoxy group.
8. A compound of claim 1 , wherein R 2 is a substituted or unsubstituted benzyl.
9. A compound of claim 1 , wherein R 3 is selected from the group consisting of hydrogen and fluorine.
10. A compound of claim 1 , wherein the compound is selected from the group consisting of:
5-pentyl-2-(1-phenyl-1H-pyrazol-5-yl)benzene-1,3-diol,
2-(1-methyl-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
2-(1-benzyl-1H-pyrazol-3-yl)-5-pentylbenzene-1,3-diol,
2-(1-benzyl-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-5-yl)-5-(2-methyloctan-2-yl)benzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-3-yl)-5-(2-methyloctan-2-yl)benzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-3-yl)benzene-1,3-diol, 12-(1-isopropyl-1H-pyrazol-5-yl)benzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-3-yl)-5-methylbenzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-5-yl)-5-methylbenzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-3-yl)-5-pentylbenzene-1,3-diol,
2-(1-benzyl-1H-pyrazol-3-yl)-5-methylbenzene-1,3-diol,
2-(1-benzyl-1H-pyrazol-5-yl)-5-methylbenzene-1,3-diol,
2-(1-cyclohexyl-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
2-(1-(tert-butyl)-1H-pyrazol-3-yl)-5-pentylbenzene-1,3-diol,
2-(1-(tert-butyl)-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
2-(1-ethyl-1H-pyrazol-3-yl)-5-pentylbenzene-1,3-diol,
2-(1-ethyl-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
2-(1-cyclohexyl-1H-pyrazol-3-yl)-5-methylbenzene-1,3-diol,
2-(1-cyclohexyl-1H-pyrazol-5-yl)-5-methylbenzene-1,3-diol,
2-(1-ethyl-1H-pyrazol-3-yl)-5-methylbenzene-1,3-diol,
2-(1-ethyl-1H-pyrazol-5-yl)-5-methylbenzene-1,3-diol,
5-methyl-2-(1-(pyridin-4-ylmethyl)-1H-pyrazol-5-yl)benzene-1,3-diol,
2-(1-benzyl-1H-pyrazol-3-yl)-4-fluoro-5-pentylbenzene-1,3-diol,
2-(1-(3-hydroxybenzyl)-1H-pyrazol-3-yl)-5-pentylbenzene-1,3-diol,
2-(1-(3-hydroxybenzyl)-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
2-(1-(4-hydroxybenzyl)-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol, and
2-(1-(4-hydroxybenzyl)-1H-pyrazol-3-yl)-5-pentylbenzene-1,3-diol.
11. A pharmaceutical composition comprising at least one compound of claim 1 .
12. A method of treating a disease or disorder associated with GPR18 receptor, the method comprising administering the compound of claim 1 or a composition thereof,
wherein the disease or disorder associated with GPR18 receptor is selected from the group consisting of neurodegenerative diseases, endometriosis, peritonitis, metabolic dysfunction, obesity-related disease, diabetes, bacterial infection, cardiovascular disease, pain, glaucoma, metastatic melanoma, and male reproduction.
13. A method of treating a disease or disorder associated with TRPV1 receptor, the method comprising administering the compound of claim 1 or a composition thereof,
wherein the disease or disorder associated with TRPV1 receptor is selected from the group consisting of pain, diabetes type-2, epilepsy, anxiety, depression, and drug-addiction.
14. A composition comprising at least one compound of claim 1 .
15. A compound selected from the group consisting of:
5-pentyl-2-(1-phenyl-1H-pyrazol-5-yl)benzene-1,3-diol,
2-(1-methyl-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
2-(1-benzyl-1H-pyrazol-3-yl)-5-pentylbenzene-1,3-diol,
2-(1-benzyl-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
5-(2-methyloctan-2-yl)-2-(1H-pyrazol-3-yl)benzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-5-yl)-5-(2-methyloctan-2-yl)benzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-3-yl)-5-(2-methyloctan-2-yl)benzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-3-yl)benzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-5-yl)benzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-3-yl)-5-methylbenzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-5-yl)-5-methylbenzene-1,3-diol,
2-(1-isopropyl-1H-pyrazol-3-yl)-5-pentylbenzene-1,3-diol,
2-(1-benzyl-1H-pyrazol-3-yl)-5-methylbenzene-1,3-diol,
2-(1-benzyl-1H-pyrazol-5-yl)-5-methylbenzene-1,3-diol,
2-(1-cyclohexyl-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
2-(1-(tert-butyl)-1H-pyrazol-3-yl)-5-pentylbenzene-1,3-diol,
2-(1-(tert-butyl)-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
2-(1-ethyl-1H-pyrazol-3-yl)-5-pentylbenzene-1,3-diol,
2-(1-ethyl-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
5-methyl-2-(1H-pyrazol-3-yl)benzene-1,3-diol,
2-(1-cyclohexyl-1H-pyrazol-3-yl)-5-methylbenzene-1,3-diol,
2-(1-cyclohexyl-1H-pyrazol-5-yl)-5-methylbenzene-1,3-diol,
2-(1-ethyl-1H-pyrazol-3-yl)-5-methylbenzene-1,3-diol,
2-(1-ethyl-1H-pyrazol-5-yl)-5-methylbenzene-1,3-diol,
5-methyl-2-(1-(pyridin-4-ylmethyl)-1H-pyrazol-5-yl)benzene-1,3-diol,
2-(1-benzyl-1H-pyrazol-3-yl)-4-fluoro-5-pentylbenzene-1,3-diol,
2-(1-(3-hydroxybenzyl)-1H-pyrazol-3-yl)-5-pentylbenzene-1,3-diol,
2-(1-(3-hydroxybenzyl)-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol,
2-(1-(4-hydroxybenzyl)-1H-pyrazol-5-yl)-5-pentylbenzene-1,3-diol, and
2-(1-(4-hydroxybenzyl)-1H-pyrazol-3-yl)-5-pentylbenzene-1,3-diol.
16. The compound of claim 1 , wherein the substituted or unsubstituted alkyl is a substituted or unsubstituted alkyl C 1 -C 9 alkyl.
17. The compound of claim 2 , wherein the substituted or unsubstituted alkyl is a substituted or unsubstituted alkyl C 1 -C 9 alkyl.