Pharmaceutical compounds
Pyrazole derivatives of the following formula (I), having affinity for the cannabinoidergic CB1 and/or CB2 receptors: wherein: R is a group selected from: C 1 -C 10 alkyl; aryl, arylalkyl or arylalkenyl, not substituted or having from one to four substituents, equal to or different from each other; A is a group selected from the following: an ether group of formula —(CH 2 )—O—(CH 2 ) v —R″ wherein v is equal to 1 or 2; R″ is as defined in the present application; a ketone group of formula —C(O)—Z′, wherein Z′ is as defined in the present application; a substituent having an hydroxyl function of formula —CH(OH)—Z′, Z′ being as defined in the present application; an amide substituent of formula —C(O)—NH—T′, T′ being as defined in the present application; B is a group as defined in the present application; D is an heteroaryl optionally substituted.
1. A Pyrazole derivative of formula (I), having affinity for the cannabinoidergic CB1 and/or CB2 receptors:
R is
aryl, not substituted or having from one to five substituents, equal to or different from each other, selected from halogen, C 1 -C 7 alkyl, C 1 -C 7 alkylthio, C 1 -C 7 alkoxy, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkoxy, cyano, nitro, amino, N-alkylamino, N,N-dialkylamino, saturated or unsaturated heterocycle, and phenyl;
A is
an amidic substituent of formula —C(O)—NH-T′, wherein T′ is
a group NR 1 R 2 , wherein R 1 and R 2 are equal or different and have the following meanings:
C 1 -C 7 alkyl;
aryl, arylalkyl or arylalkenyl not substituted or optionally having on the aromatic rings from one to four substituents, equal to or different from each other, selected from halogen, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkoxy, C 1 -C 7 alkylthio, C 1 -C 7 alkoxy, wherein in the previous substituents comprising C 1 -C 7 aliphatic chains, C 1 -C 3 chains are preferably used; wherein R 1 may additionally be hydrogen;
or R 1 and R 2 together with the nitrogen atom to which they are linked form a, saturated or unsaturated, heterocycle from 5 to 10 atoms comprising carbon atoms and including the nitrogen of NR 1 R 2 , and optionally an additional S, O or N atom, not substituted or optionally having from one to four substituents, equal to or different from each other, selected from C 1 -C 7 alkyl, phenyl, and benzyl, said phenyl or benzyl optionally substituted with one or more groups, equal to or different from each other, selected from: halogen, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkoxy, C 1 -C 7 alkylthio and C 1 -C 7 alkoxy;
B is a group selected from: hydrogen and C 1 -C 4 alkyl; and
D is an heteroaryl with a ring size of from 5 to 6 atoms, selected from the group consisting of thiophene, pyridine, furan, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, pyridazine, pyrimidine, pyrazine, triazine and pyrrole; wherein the heteroaryl is optionally substituted with one, two, three or four substituents, equal to or different from each other, selected from the following: halogen, C 1 -C 3 alkyl, C 1 -C 3 alkylthio, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy.
2. A compound according to claim 1 , wherein:
R is
aryl containing from one to five substituents, equal to or different from each other, selected from halogen, C 1 -C 7 alkyl, C 1 -C 7 alkylthio, C 1 -C 7 alkoxy, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkoxy, cyano, nitro, amino, N-alkylamino, N,N-dialkylamino, saturated or unsaturated heterocycle and phenyl;
B is a
C 1 -C 4 alkyl.
3. A compound according to claim 1 , wherein:
R is
aryl, not substituted or having from one to five substituents, equal to or different from each other, selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkylthio, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy;
B is a C 1 -C 3 alkyl;
D is an heteroaryl selected from the following: thiophene, pyridine, furan, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, pyridazine, pyrimidine, pyrazine, triazine, and pyrrole; said heteroaryls optionally substituted with one, two, three or four substituents, equal to or different from each other, selected from the following: halogen, C 1 -C 3 alkyl, C 1 -C 3 alkylthio, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy.
4. A compound according to claim 1 , wherein A=—C(O)—NH—T′, wherein T′ is a group NR 1 R 2 wherein R 1 is not hydrogen.
5. A compound according to claim 4 , selected from the following:
N-piperidinyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide;
N-homopiperidinyl-5-(5-chloro-thiophen-2-yl)-1-2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carboxamide;
N-pyrrolidinyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carboxamide;
p-Methoxyphenyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carbohydrazide;
N-piperidinyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carboxamide;
N-homopiperidinyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carboxamide;
N-pyrrolidinyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carboxamide;
p-Methoxyphenyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carbohydrazide;
N-piperidinyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carboxamide;
N-homopiperidinyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carboxamide;
N-pyrrolidinyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carboxamide;
p-Methoxyphenyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-methyl-1H-pyrazol-3-carbohydrazide;
N-piperidinyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carboxamide;
N-homopiperidinyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carboxamide;
N-pyrrolidinyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carboxamide;
p-Methoxyphenyl-5-(5-chloro-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carbohydrazide;
N-piperidinyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carboxamide;
N-homopiperidinyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carboxamide;
N-pyrrolidinyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carboxamide;
p-Methoxyphenyl-5-(5-bromo-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carbohydrazide;
N-piperidinyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carboxamide;
N-homopiperidinyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carboxamide;
N-pyrrolidinyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichlorophenyl-4-ethyl-1H-pyrazol-3-carboxamide; and
p-Methoxyphenyl-5-(5-methyl-thiophen-2-yl)-1-(2′,4′-dichlorophenyl)-4-ethyl-1H-pyrazol-3-carbohydrazide.
6. A compound according to claim 1 wherein the compound comprises chiral cores.
7. A compound according to claim 1 wherein the compound is a cis isomer or a trans isomer.
8. A pharmaceutically acceptable salt of the compound:
wherein R is
aryl, not substituted or having from one to five substituents, equal to or different from each other, selected from halogen, C 1 -C 7 alkyl, C 1 -C 7 alkylthio, C 1 -C 7 alkoxy, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkoxy, cyano, nitro, amino, N-alkylamino, N,N-dialkylamino, saturated or unsaturated heterocycle and phenyl;
A is
an amidic substituent of formula —C(O)—NH—T′, wherein T′ is
a group NR 1 R 2 , wherein R 1 and R 2 are equal or different and have the following meanings:
C 1 -C 7 alkyl;
aryl, arlylalkyl or arylalkenyl not substituted or optionally having on the aromatic rings from one to four substituents, equal to or different from each other, selected from halogen, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkoxy, C 1 -C 7 alkylthio, C 1 -C 7 alkoxy, wherein in the previous substituents comprising C 1 -C 7 aliphatic chains, C 1 -C 3 chains are preferably used;
wherein R 1 may additionally be hydrogen;
or R 1 , and R 2 together with the nitrogen atom to which they are linked form a, saturated or unsaturated, heterocycle from 5 to 10 atoms, comprising carbon atoms and including the nitrogen of NR 1 R 2 , and optionally an additional S, O or N atom not substituted or optionally having from one to four substituents, equal to or different from each other, selected from C 1 -C 7 alkyl, phenyl, and benzyl, said phenyl or benzyl optionally substituted with one or more groups, equal to or different from each other, selected from: halogen, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkoxy, C 1 -C 7 alkylthio and C 1 -C 7 alkoxy;
B is a group selected from: hydrogen and C 1 -C 4 alkyl; and
D is an heteroaryl with a ring size of from 5 to 6 atoms, selected from the group consisting of thiophene, pyridine, furan, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, pyridazine, pyrimidine, pyrazine, triazine and pyrrole; wherein the heteroaryl is optionally substituted with one, two, three or four substituents, equal to or different from each other, selected from the following: halogen, C 1 -C 3 alkyl, C 1 -C 3 alkylthio, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy.
9. A pharmaceutical comprising a compound of formula (I) according to claim 1 .
10. A pharmaceutical according to claim 9 comprising sodium alkylsulphate or another surfactant.
11. A pharmaceutical composition comprising 0.5-20% by weight of a compound according to claims 1 - 8 , 0.05-0.5% by weight of sodium alkylsulphate or another surfactant, 2.5-10% by weight of a disgregating agent.