Pharmaceutical compounds
Tricyclic pyrazole derivatives of the following formula (I) having affinity for the cannabinoidergic CB1 and/or CB2 receptors: wherein: A represents a group selected from one of the following: (CH 2 ) t —, —(CH 2 )—S(O) z —, or —S(O) z —(CH 2 )—, B is a heteroaryl, optionally substituted; R is a group selected from the following: alkyl, aryl, arylalkyl or arylalkenyl, not substituted or having from one to four substituents, equal to or different from each other; R′ is a group selected from the following: an ether group of formula —(CH 2 )—O—(CH 2 ) v —R″, a ketonic group of formula —C(O)—Z′, wherein Z′ is as defined below; a substituent having an hydroxyl function of formula —CH(OH)—Z′; an amide substituent of formula —C(O)—NH-T′.
1. A compound of the chemical structure (I):
wherein:
A is (CH 2 ) t wherein
t is equal to 1, 2 or 3;
B is an heteroaryl with a ring having 5 or 6 atoms, selected from the following:
thiophene, furan, oxazole, thiazole, imidazole, isoxazole, isothiazole, triazole, pyridazine, pyrazine, triazine, or pyrrole, optionally substituted with a number of substituents from 1 to 4, said substituents being equal to or different from each other and selected from the following: 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, isothiocyanate, phenyl, cycloalkyl, saturated or unsaturated heterocycle, or heteroaryl;
R is
a linear or branched C 1 -C 10 alkyl, wherein the end of the main chain not linked to the nitrogen atom has —CH 2 —W termination, W being a group selected from hydrogen, halogen, isothiocyanate, CN, OH, OCH 3 , NH 2 , or —CH═CH 2 ; or
an aryl, arylalkyl or arylalkenyl, 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, a saturated or unsaturated heterocycle, or phenyl; and
R′ is
a ketonic group of formula —C(O)—Z′, wherein Z′ is a C 1 -C 8 alkyl or a C 3 -C 15 cycloalkyl, a saturated or unsaturated heterocycle, an aryl, or a heteroaryl; or
an amidic substituent of formula —C(O)—NH-T′, wherein
T′ is selected from:
C 1 -C 8 alkyl;
C 1 -C 7 haloalkyl;
an aryl, arylalkyl or arylalkenyl, optionally containing one heteroatom selected from S, N, or O, either not substituted or optionally having from one to four substituents, equal to or different from each other, said substituents selected from halogen, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 haloalkoxy, C 1 -C 7 alkylthio, or C 1 -C 7 alkoxy;
a C 3 -C 15 cycloalkyl either not substituted or substituted with one or more C 1 -C 7 alkyl chains, said chains being from one to four chains for C 5 -C 15 cycloalkyls, one to three chains for C 4 cycloalkyl, and being from one to two chains for C 3 cycloalkyl, said alkyl chains being equal to or different from each other;
a group of formula (IA):
wherein R 3 and R 4 are equal to or different from each other and are hydrogen or C 1 -C 3 alkyl, with the proviso that R 3 and R 4 are not both hydrogen;
a group of formula (IB):
wherein R 5 represents a C 1 -C 3 alkyl and k is an integer between 1 and 3 or
a group NR 1 R 2 , wherein R 1 and R 2 are equal or different and are
hydrogen;
a C 1 -C 7 alkyl; or
an aryl, arylalkyl or arylalkenyl not substituted or optionally having on the aromatic rings from one to five 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, or C 1 -C 7 alkoxy; 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, either not substituted or optionally having from one to four substituents, equal to or different from each other, selected from the group consisting of: C 1 -C 7 alkyl, phenyl and benzyl, said phenyl or benzyl 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, haloalkoxy, alkylthio, and C 1 -C 7 alkoxy;
or pharmaceutically acceptable salts or reactive derivatives thereof selected from acyl halides, anhydrides, mixed anhydrides, imidazolides, ester-amide adducts, or linear or branched C 1 -C 4 alkyl esters, thereof.
2. The compound of claim 1 , wherein:
A is —CH 2 ) t —, wherein t is defined as in claim 1 ;
B is optionally substituted with a number of substituents from 1 to 4, said substituents being equal to or different from each other and selected from the following: halogen, C 1 -C 7 alkyl, C 1 -C 7 alkylthio, C 1 -C 7 alkoxy, C 1 -C 7 haloalkyl, and C 1 -C 7 haloalkoxy;
R is a linear or branched C 1 -C 10 alkyl, wherein the end not linked to the nitrogen atom of the main chain has —CH 2 —W termination, wherein W is a halogen;
an arylalkyl or an arylalkenyl not substituted or having from one to five substituents, equal to or different from each other, said substituents 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, or phenyl;
R′ is a ketonic group of formulae —C(O)—Z′, wherein Z′ is as defined as in claim 1 , or an amide of formula —C(O)—NH-T′ wherein T′ is as defined as in claim 1 excluding the formulas (IA) and (IB).
3. The compound of claim 1 , wherein:
A is —(CH 2 ) t —, wherein t is defined as in claim 1 ;
B is optionally substituted with one, two, three or four substituents, said 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, or C 1 -C 3 haloalkoxy;
R has the following meanings:
linear or branched C 1 -C 7 alkyl, wherein the end not linked to the nitrogen atom of the main chain has —CH 2 —W termination, wherein W is a halogen;
an arylalkyl or arylalkenyl, 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, or C 1 -C 3 haloalkoxy;
R′ is
a ketonic group of formulae —C(O)—Z′, wherein Z′ is as defined as in claim 1 , or an amide of formula —C(O)—NH-T-′; wherein T′ is a group selected from the following:
C 1 -C 8 alkyl;
C 1 -C 7 haloalkyl;
an aryl, arylalkyl or arylalkenyl, optionally containing one heteroatom, 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 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 alkylthio, or C 1 -C 3 alkoxy;
an NR 1 R 2 group, wherein R 1 and R 2 are as defined as in claim 1 , and
a C 3 -C 15 cycloalkyl not substituted or substituted with one or more C 1 -C 7 alkyl chains, said chains being from one to four chains for C 5 -C 15 cycloalkyls, being from one to three chains for the C 4 cycloalkyl, and being from one to two chains for the C 3 cycloalkyl, said alkyl chains being equal to or different from each other.
4. The compound of claim 1 , wherein R′=—C(O)—NHT′.
5. The compound of claim 1 , wherein the structure of the compound is chiral.
6. The compound of claim 1 , wherein the compound is a cis-trans isomer.
7. A pharmaceutical composition comprising the compound of claim 1 and pharmaceutically acceptable additives or excipients.
8. A pharmaceutical composition comprising the compound of claim 1 , further comprising additives or excipients which allow the compound of claim 1 to pass the hematoencephalic barrier.
9. The pharmaceutical composition of claim 7 , wherein the additives or excipients comprise sodium alkyl sulfate.
10. A pharmaceutical composition comprising from about 0.5 to about 20% by weight of the compound of claim 1 , from about 0.05 to about 0.5% by weight of sodium alkyl sulfate and from about 2.5 to about 10% by weight of a disintegrating agent.
11. A compound of the chemical structure and corresponding geometric isomers and stereoisomers:
or pharmaceutically acceptable salts thereof.
12. The compound of claim 1 , wherein B is a thiophene.
13. The compound of claim 1 , wherein t is 1.
14. The compound of claim 1 , wherein t is 2.
15. The compound of claim 1 , wherein t is 3.
16. The compound of claim 1 , wherein R′ is —C(O)—NH-T′, wherein T′ is
a C 3 -C 15 cycloalkyl either not substituted or substituted with one or more C 1 -C 7 alkyl chains, said chains being from one to four chains for C 5 -C 15 cycloalkyls, being from one to three chains for C 4 cycloalkyl, and being from one to two chains for C 3 cycloalkyl, said alkyl chains being equal to or different from each other.