CB1R RECEPTOR BLOCKERS WITH ACYCLIC BACKBONES

Abstract

The invention generally concerns a novel class of CB 1 receptor binding molecules and uses thereof.

Claims

1-234. (canceled)

235. A compound of the general formula (I): ##STR00069## wherein each of R.sub.1 and R.sub.2, independently of the other, is a group selected from —H, halide, —CN, —C.sub.1-C.sub.5alkyl-OH and —OH; each of n and m, independently of the other, is an integer between 0 and 5, designating the number of substituents on the ring; X is selected from nitrogen and —CH—; or X—R.sub.4 may optionally be N═R.sub.4 or C═R.sub.4; R.sub.3 is selected from H, a carbon containing group comprising between 1 and 3 carbon atoms, being optionally substituted, and a nitrogen atom or a nitrogen containing group; R.sub.4 is selected from a carbon containing group comprising between 1 and 3 carbon atoms, being optionally substituted, and a nitrogen atom or a nitrogen containing group; or R.sub.3 and R.sub.4 together with atoms to which they are bonded (carbon atom and X, respectively) form a 5- or 6-membered carbocyclic ring optionally containing between 1 and 3 heteroatoms selected from N, O and S; or R.sub.3 and R.sub.4 together with the atoms to which they are bonded form a fused ring system optionally containing between 1 and 6 heteroatoms selected from N, O and S.

236. The compound according to claim 235, wherein the compound is selected from compounds: (A) of the general formula (II): ##STR00070## wherein one of L, L.sub.1 and L.sub.2 is a nitrogen atom and the others of L, L.sub.1 and L.sub.2 are each a carbon atom; each of R.sub.5, R.sub.6 and R.sub.7, independently of the other, may be selected from —H, —C.sub.1-C.sub.3alkyl, —C(═O)—OH, —C(═O)—O—R.sub.8, —C(═O)—NR′R.sub.8, halide, —CN, —OH, and —NR′R″; or one of R5 and R6 or R6 and R7 together with the atoms to which they bond form a 5-, 6-, 7- or 8-membered carbocyclic ring optionally containing between 1 and 3 heteroatoms selected from N, O and S; the 5-, 6-, 7- or 8-membered carbocyclic ring is optionally substituted by at least one functionality selected from —H, —C.sub.1-C.sub.25alkyl, —C.sub.2-C.sub.25alkenyl, —C.sub.2-C.sub.25alkynyl, —C.sub.6-C.sub.10aryl, an hydroxyl, an amine, a halide, —ONO.sub.2, —NO.sub.2, —S—, —S—C.sub.1-C.sub.5alkyl, —S—C.sub.2-C.sub.5alkenyl, —S—C.sub.2-C.sub.5alkynyl, —C(═O)—, —C(═O)—C.sub.1-C.sub.25alkyl, —C(═O)—O—C.sub.1-C.sub.5alkyl, —C(═O)—O—C.sub.2-C.sub.5alkenyl, —C(═O)—O—C.sub.2-C.sub.5alkynyl, —C(═O)—NR′R″R′″, —C(═O)—NR′—C(═O)—C.sub.1-C.sub.25alkyl, —C(═O)—NR′—C(═O)—C.sub.2-C.sub.25alkenyl, —C(═O)—NR′—C(═O)—C.sub.2-C.sub.25alkynyl, —C(═O)—OR.sub.10, —O—C.sub.1-C.sub.5alkyl, —O—C.sub.1-C.sub.5alkenyl, —O—C.sub.1-C 5alkynyl, —NH—NH.sub.2, —NH—NH—C(═O)—C.sub.1-C.sub.25alkyl, —NH—NH—C(═O)—C.sub.2-C.sub.25alkenyl, —NH—NH—C(═O)—C.sub.2-C.sub.25alkynyl, —NH—NH—C(═O)—C.sub.6-C.sub.10aryl, —NH—NH—C(═O)—C.sub.3-C.sub.10heteroaryl, —NH—C.sub.1-C.sub.25alkyl-C(═O)—OH, —NH—C.sub.2-C.sub.25alkenyl-C(═O)—OH, —NH—C.sub.2-C.sub.25alkynyl-C(═O)—OH, —NH—C.sub.1-C.sub.25alkyl-C(═O)—NR′R″R′″, —NH—C.sub.2-C.sub.25alkenyl-C(═O)—NR′R″R′″, —NH—C.sub.2-C.sub.25alkynyl-C(═O)—NR′R″R′″, —NH—C.sub.1-C.sub.25alkyl-NH.sub.2, —NH—C.sub.2-C.sub.25alkenyl-NH.sub.2, —NH—C.sub.2-C.sub.25alkynyl-NH.sub.2, —NH—C.sub.1-C.sub.25alkyl-NH—C(═O)—C.sub.1-C.sub.25alkyl, —NH—C.sub.2-C.sub.25alkenyl-NH—C(═O)—C.sub.1-C.sub.25alkyl, —NH—C.sub.2-C.sub.25alkynyl-NH—C(═O)—C.sub.1-C.sub.25alkyl, —NH—C.sub.1-C.sub.25alkyl-NH—C(═O)—C.sub.6-C.sub.10aryl, —NH—C.sub.2-C.sub.25alkenyl-NH—C(═O)—C.sub.6-C.sub.10aryl, —NH—C.sub.2-C.sub.25alkynyl-NH—C(═O)—C.sub.6-C.sub.10aryl, —NH—C.sub.1-C.sub.25alkyl-NH—C(═O)—C.sub.3-C.sub.10heteroaryl, —NH—C.sub.2-C.sub.25alkenyl-NH—C(═O)—C.sub.3-C.sub.10heteroaryl, —NH—C.sub.2-C.sub.25alkynyl-NH—C(═O)—C.sub.3-C.sub.10heteroaryl, —NH—C.sub.1-C.sub.25alkylene-C(═O)—NR′R″R′″, —NH—C.sub.2-C.sub.25alkenylene-C(═O)—NR′R″R′″, —NH—C.sub.2-C.sub.25alkynylene-C(═O)—NR′R″R′″, —NH—C.sub.1-C.sub.25alkylene-C(═O)—O—C.sub.1-C.sub.25alkyl, —NH—C.sub.2-C.sub.25alkenylene-C(═O)—O—C.sub.1-C.sub.25alkyl, —NH—C.sub.2-C.sub.25alkynylene-C(═O)—O—C.sub.1-C.sub.25alkyl, —NHC(═O)C.sub.1-C.sub.25alkyl, —NHC(═O)C.sub.2-C.sub.25alkenyl, —NHC(═O)C.sub.2-C.sub.25alkynyl, —NHC(═O)C.sub.1-C.sub.25alkylene-NR′R″R′″, —NHC(═O)C.sub.2-C.sub.25alkenylene-NR′R″R′″, —NHC(═O)C.sub.2-C.sub.25alkynylene-NR′R″R′″, —NHC(═O)C.sub.1-C.sub.25alkylene-OH, —NHC(═O)C.sub.2-C.sub.25alkenylene-OH, —NHC(═O)C.sub.2-C.sub.25alkynylene-OH, —NHC(═O)C.sub.6-C.sub.10aryl, —NHC(═O)C.sub.3-C.sub.10heteroaryl, —NHC(═O)C.sub.1-C.sub.25alkylene-C.sub.6-C.sub.10aryl, —NHC(═O)C.sub.2-C.sub.25alkenylene-C.sub.6-C.sub.10aryl, —NHC(═O)C.sub.2-C.sub.25alkynylene-C.sub.6-C.sub.10aryl, —NHC(═O)C.sub.3-C.sub.10heteroaryl, —NHC(═O)C.sub.1-C.sub.25alkylene-C.sub.3-C.sub.10heteroaryl, —NHC(═O)C.sub.2-C.sub.25alkenylene-C.sub.3-C.sub.10heteroaryl, —NHC(═O)C.sub.2-C.sub.25alkynylene-C.sub.3-C.sub.10heteroaryl, 2,2,6,6-tetramethylpiperidin-1-ol-4-yl free radical, —NHC(═O)C(CH.sub.3).sub.2—O-aryl-Cl, —NHC(═O)CH.sub.2C(CH.sub.3).sub.2—O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(═O)—OH and —NR′R″R′″; the 5-, 6-, 7- or 8-membered carbocyclic ring is optionally substituted by at least one functionality selected from structures (A) through (H): ##STR00071## wherein in each functionality (A) through (H), the wavy line indicates point or bond of connectivity, j is 0 or 1 and Ra is selected from H, —C.sub.1-C.sub.25alkyl, —C.sub.2-C.sub.25alkenyl, —C.sub.2-C.sub.25alkynyl, C(═O)—C.sub.6-C.sub.10aryl and C(═O)—C.sub.3-C.sub.10heteroaryl, wherein in functionalities (G) and (H) the pendant -NH—Ra group may appear between 1 and 11 times at any position along the carbocycle; one of R.sub.5, R.sub.6 and R.sub.7 may be absent; R.sub.8 is selected from H, —C.sub.1-C.sub.25alkyl, —C.sub.2-C.sub.25alkenyl, —C.sub.2-C.sub.25alkynyl, —C.sub.6-C.sub.10aryl and C.sub.3-C.sub.10heteroaryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, —ONO.sub.2, —NO.sub.2, —S—, —S—C.sub.1-C.sub.5alkyl, —S—C.sub.2-C.sub.5alkenyl, —S—C.sub.2-C.sub.5alkynyl, —C(═O)—, —C(═O)—C.sub.1-C.sub.25alkyl, —C(═O)—O—C.sub.1-C.sub.5alkyl, —C(═O)—O—C.sub.2-C.sub.5alkenyl, —C(═O)—O—C.sub.2-C.sub.5alkynyl, —C(═O)—NR′R″R′″, —C(═O)—NR′—C(═O)—C.sub.1-C.sub.25alkyl, —C(═O)—NR′—C(═O)—C.sub.1-C.sub.25alkenyl, —C(═O)—NR′—C(═O)—C.sub.1-C.sub.25alkynyl, —C(═O)—OR.sub.10, —O—C.sub.1-C.sub.5alkyl, —O—C.sub.1-C.sub.5alkenyl, —O—C.sub.1-C.sub.5alkynyl, —NH—NH.sub.2, —NH—NH—C(═O)—C.sub.1-C.sub.25alkyl, —NH—NH—C(═O)—C.sub.2-C.sub.25alkenyl, —NH—NH—C(═O)—C.sub.2-C.sub.25alkynyl, —NH—NH—C(═O)—C.sub.6-C.sub.10aryl, —NH—NH—C(═O)—C.sub.3-C.sub.10heteroaryl, —NH—C.sub.1-C.sub.25alkyl-C(═O)—OH, —NH—C.sub.2-C.sub.25alkenyl-C(═O)—OH, —NH—C.sub.2-C.sub.25alkynyl-C(═O)—OH, —NH—C.sub.1-C.sub.25alkyl-C(═O)—NR′R″R′″, —NH—C.sub.2-C.sub.25alkenyl-C(═O)—NR′R″R′″, —NH—C.sub.2-C.sub.25alkynyl-C(═O)—NR′R″R′″, —NH—C.sub.1-C.sub.25alkyl-NH.sub.2, —NH—C.sub.2-C.sub.25alkenyl-NH.sub.2, —NH—C.sub.2-C.sub.25alkynyl-NH.sub.2, —NH—C.sub.1-C.sub.25alkyl-NH—C(═O)—C.sub.1-C.sub.25alkyl, —NH—C.sub.2-C.sub.25alkenyl-NH—C(═O)—C.sub.1-C.sub.25alkyl, —NH—C.sub.2-C.sub.25alkynyl-NH—C(═O)—C.sub.1-C.sub.25alkyl, —NH—C.sub.1-C.sub.25alkyl-NH—C(═O)—C.sub.6-C.sub.10aryl, —NH—C.sub.2-C.sub.25alkenyl-NH—C(═O)—C.sub.6-C.sub.10aryl, —NH—C.sub.2-C.sub.25alkynyl-NH—C(═O)—C.sub.6-C.sub.10aryl, —NH—C.sub.1-C.sub.25alkyl-NH—C(═O)—C.sub.3-C.sub.10heteroaryl, —NH—C.sub.2-C.sub.25alkenyl-NH—C(═O)—C.sub.3-C.sub.10heteroaryl, —NH—C.sub.2-C.sub.25alkynyl-NH—C(═O)—C.sub.3-C.sub.10heteroaryl, —NH—C.sub.1-C.sub.25alkylene-C(═O)—NR′R″R′″, —NH—C.sub.2-C.sub.25alkenylene-C(═O)—NR′R″R′″, —NH—C.sub.2-C.sub.25alkynylene-C(═O)—NR′R″R′″, —NH—C.sub.1-C.sub.25alkylene-C(═O)—O—C.sub.1-C.sub.25alkyl, —NH—C.sub.2-C.sub.25alkenylene-C(═O)—O—C.sub.1-C.sub.25alkyl, —NH—C.sub.2-C.sub.25alkynylene-C(═O)—O—C.sub.1-C.sub.25alkyl, —NHC(═O)C.sub.1-C.sub.25alkyl, —NHC(═O)C.sub.2-C.sub.25alkenyl, —NHC(═O)C.sub.2-C.sub.25alkynyl, —NHC(═O)C.sub.1-C.sub.25alkylene-NR′R″R′″, —NHC(═O)C.sub.2-C.sub.25alkenylene-NR′R″R′″, —NHC(═O)C.sub.2-C.sub.25alkynylene-NR′R″R′″, —NHC(═O)C.sub.1-C.sub.25alkylene-OH, —NHC(═O)C.sub.2-C.sub.25alkenylene-OH, —NHC(═O)C.sub.2-C.sub.25alkynylene-OH, —NHC(═O)C.sub.6-C.sub.10aryl, —NHC(═O)C.sub.3-C.sub.10heteroaryl, —NHC(═O)C.sub.1-C.sub.25alkylene-C.sub.6-C.sub.10aryl, —NHC(═O)C.sub.2-C.sub.25alkenylene-C.sub.6-C.sub.10 aryl, —NHC(═O)C.sub.2-C.sub.25alkynylene-C.sub.6-C.sub.10aryl, —NHC(═O)C.sub.3-C.sub.10heteroaryl, —NHC(═O)C.sub.1-C.sub.25alkylene-C.sub.3-C.sub.10heteroaryl, —NHC(═O)C.sub.2-C.sub.25alkenylene-C.sub.3-C.sub.10heteroaryl, —NHC(═O)C.sub.2-C.sub.25alkynylene-C.sub.3-C.sub.10heteroaryl, 2,2,6,6-tetramethylpiperidin-1-ol-4-yl free radical, —NHC(═O)C(CH.sub.3).sub.2—O-aryl-Cl, —NHC(═O)CH.sub.2C(CH.sub.3).sub.2—O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(═O)—OH and —NR′R″R′″; R.sub.10 is selected from —H, —C.sub.1-C.sub.25alkyl, —C.sub.2-C.sub.25alkenyl, —C.sub.2-C.sub.25alkynyl, —C.sub.6-C.sub.10aryl, each of which being optionally substituted by at least one functionality selected from an hydroxyl, an amine, a halide, —C.sub.1-C.sub.5alkyl, —C.sub.2-C.sub.5alkenyl, —C.sub.2-C.sub.5alkynyl, —C(═O)—, —C(═O)—C.sub.1-C.sub.25alkyl, —C(═O)—O—C.sub.1-C.sub.5alkyl, —C(═O)—O—C.sub.1-C.sub.5alkenyl, —C(═O)—O—C.sub.1-C.sub.5alkynyl, —C(═O)—NR′R″R′″, —O—C.sub.1-C.sub.5alkyl, —O—C.sub.1-C.sub.5alkenyl, —O—C.sub.1-C.sub.5alkynyl, —S—, —S—C.sub.1-C.sub.5alkyl, —S—C.sub.1-C.sub.5alkenyl, —S—C.sub.1-C.sub.5alkynyl, —ONO.sub.2, —NO.sub.2, 2,2,2,6,6-tetramethylpiperidin-1-ol-4-yl, —NHC(═O)CH.sub.2C(CH.sub.3).sub.2-O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(═O)—OH and —NR′R″R′″; each of R′, R″ and R′″ is independently selected from H, C.sub.1-C.sub.5alkyl, C.sub.2-C.sub.5alkenyl, C.sub.2-C.sub.5alkynyl, —C(═O)—C.sub.2-C.sub.25alkyl, —C(═O)—C.sub.2-C.sub.25alkenyl and C.sub.5-C.sub.25alkynyl; or wherein one of R′, R″ and R′″ is absent; and wherein each bond between N-L, L-L.sub.1, L.sub.1-L.sub.2 and L.sub.2-C(designated -) is a single or double bond; (B) of formula (III): ##STR00072## wherein - designates a single or a double bond and wherein, in case it is a double bond, the carbon atom bearing variant R.sub.7 does not carry a bond to a hydrogen atom; (C) of general formula (IV): ##STR00073## (D) of the formula (V): ##STR00074## (E) of the general formula (VI): ##STR00075## (F) of general formula (VII): ##STR00076## (G) of the general formula (VIII): ##STR00077## (H) of the formula (IX): ##STR00078## (I) of the general formula (XI): ##STR00079## optionally excluding compounds wherein R.sub.8 is C.sub.7-C.sub.12alkyl; (J) of the general formula (XII): ##STR00080## (K) of the formula (XIII): ##STR00081## wherein k is an integer between 0 to 25; (L) of the general formula (XIV): ##STR00082## (M) of the formula (XVI): ##STR00083## (N) of the general formula (XVII): ##STR00084## (O) of the general formula (XVIII): ##STR00085## (P) of the general formula (XIX): ##STR00086## (Q) of the general formula (XX): ##STR00087## (R) of the general formula (XXI): ##STR00088## (S) of the general formula (XXII): ##STR00089## (T) of the general formula (XXIII) ##STR00090## (U) of the general formula (XXV): ##STR00091## (V) of the general formula (XXVI): ##STR00092##

237. A compound of the formula selected from (A) general formula (XXVII): ##STR00093## wherein each of R.sub.1, R.sub.2, n, m is as defined in claim 236; R5 is absent or selected from H, —C.sub.1-C.sub.3alkyl, —C(═O)—O—R.sub.8, —C(═O)—NR′—R.sub.8, halide, CN, and OH; and R.sub.9 is selected from —C(═O)—O—R.sub.8, —C(═O)—NR′—R.sub.8, —NH—C(═O)—O—R.sub.8, —NH—C(═O)—NR′—R.sub.8, —O—C(═O)—O—R.sub.8 and —O—C(═O)—NR′—R.sub.8; where R.sub.8 is as defined in claim 236; (B) general formula (XXVIII): ##STR00094## (C) general formula (XXIX): ##STR00095## (D) general formula (XXX): ##STR00096## wherein one of L.sub.1 and L.sub.2 is a nitrogen atom and the other of L1 and L.sub.2 is a carbon atom being selected from C, CH or CH.sub.2; each of R.sub.5, R.sub.6 and R.sub.7, independently of the other, may be absent or selected from —H, C.sub.1-C.sub.3alkyl, —C(═O)—O—R.sub.8, —C(═O)—NR′—R.sub.8, halide, CN, OH, and NR′R″; and wherein each bond between C—N, N-L.sub.1, L.sub.1-L.sub.2 and L.sub.2-C(designated -) is a single bond or double bond; (E) general formula (XXXI): ##STR00097## (F) general formula (XXXII): ##STR00098## or (G) general formula (XXXIII) ##STR00099## wherein R.sub.9 is selected from —O-R.sub.8 and —NR′—R.sub.8.

238. The compound according to claim 235 being a compound of formula (XXXIV): ##STR00100## wherein R.sub.9 is selected from —O—R.sub.8 and NR′—R.sub.8; or a compound of (XXXV): ##STR00101## wherein R.sub.9 is selected from —O—R.sub.8 and NR′—R.sub.8 or a compound of formula (XXXVI): ##STR00102## wherein R.sub.9 is selected from O-R.sub.8 and NR′—R.sub.8; or a compound of formula (XXXVII): ##STR00103## or a compound of formula (XXXVIII): ##STR00104## wherein, ring A is a 5-, 6-, 7- or 8-membered carbocyclic ring optionally containing between 1 and 3 heteroatoms selected from N, O and S, and optionally substituted by a group B selected from H, —C.sub.1-C.sub.25alkyl, —C.sub.2-C.sub.25alkynyl, —C.sub.6-C.sub.10aryl, an hydroxyl, an amine, a halide, —ONO.sub.2, —NO.sub.2, —S—, —S—C.sub.1-C.sub.5alkyl, —S—C.sub.1-C.sub.5alkenyl, —S—C.sub.1-C.sub.5alkynyl, —C(═O)—, —C(═O)—C.sub.1-C.sub.25alkyl, —C(═O)—O—C.sub.1-C.sub.5alkyl, —C(═O)—O—C.sub.2-C.sub.5alkenyl, —C(═O)—O—C.sub.2-C.sub.5alkynyl, —C(═O)—NR′R″R′″, —C(═O)—NR′—C(═O)—C.sub.1-C.sub.25alkyl, —C(═O)—NR′—C(═O)—C.sub.2-C.sub.25alkenyl, —C(═O)—NR′—C(═O)—C.sub.2-C.sub.25alkynyl, —C(═O)—OR.sub.10, —O—C.sub.1-C.sub.5alkyl, —O—C.sub.1-C.sub.5alkenyl, —O—C.sub.1-C.sub.5alkynyl, —NH—NH.sub.2, —NH—NH—C(═O)—C.sub.1-C.sub.25alkyl, —NH—NH—C(═O)—C.sub.2-C.sub.25alkenyl, —NH—NH—C(═O)—C.sub.2-C.sub.25alkynyl, —NH—NH—C(═O)—C.sub.6-C.sub.10aryl, —NH—NH—C(═O)—C.sub.3-C.sub.10heteroaryl, —NH—C.sub.1-C.sub.25alkyl-C(═O)—OH, —NH—C.sub.2—C.sub.25alkenyl-C(═O)—OH, —NH—C.sub.2-C.sub.25alkynyl-C(═O)—OH, —NH—C.sub.1-C.sub.25alkyl-C(═O)—NR′R″R′″, —NH—C.sub.2-C.sub.25alkenyl-C(═O)—NR′R″R′″, —NH—C.sub.2-C.sub.25alkynyl-C(═O)—NR′R″R′″, —NH—C.sub.1-C.sub.25alkyl-NH.sub.2, —NH—C.sub.2-C.sub.25alkenyl-NH.sub.2, —NH—C.sub.2-C.sub.25alkynyl-NH.sub.2, —NH—C.sub.1-C.sub.25alkyl-NH—C(═O)—C.sub.1-C.sub.25alkyl, —NH—C.sub.2-C.sub.25alkenyl-NH—C(═O)—C.sub.1-C.sub.25alkyl, —NH—C.sub.2-C.sub.25alkynyl-NH—C(═O)—C.sub.1-C.sub.25alkyl, —NH—C.sub.1-C.sub.25alkyl-NH—C(═O)—C.sub.6-C.sub.10aryl, —NH—C.sub.2-C.sub.25alkenyl-NH—C(═O)—C.sub.6-C.sub.10aryl, —NH—C.sub.2-C.sub.25alkynyl-NH—C(═O)—C .sub.6-C.sub.10aryl, —NH—C.sub.1-C.sub.25alkyl-NH—C(═O)—C.sub.3-C.sub.10heteroaryl, —NH—C.sub.2-C.sub.25alkenyl-NH—C(═O)—C.sub.3-C.sub.10heteroaryl, —NH—C.sub.2-C.sub.25alkynyl-NH—C(═O)—C.sub.3—C.sub.10heteroaryl, —NH—C.sub.1-C.sub.25alkylene-C(═O)—NR′R″R′″, —NH—C.sub.2-C.sub.25alkenylene-C(═O)—NR′R″R′″, —NH—C.sub.2-C.sub.25alkynylene-C(═O)—NR′R″R′″, —NH—C.sub.1-C.sub.25alkylene-C(═O)—O—C.sub.1-C.sub.25alkyl, —NH—C.sub.2-C.sub.25alkenylene-C(═O)—O—C.sub.1-C.sub.25alkyl, —NH—C.sub.2-C.sub.25alkynylene-C(═O)-O—C.sub.1-C.sub.25alkyl, —NHC(═O)C.sub.1-C.sub.25alkyl, —NHC(═O)C.sub.2-C.sub.25alkenyl, —NHC(═O)C.sub.2-C.sub.25alkynyl, —NHC(═O)C.sub.1-C.sub.25alkylene-NR′R″R′″, —NHC(═O)C.sub.2-C.sub.25alkenylene-NR′R″R′″, —NHC(═O)C.sub.2-C.sub.25alkynylene-NR′R″R′″, —NHC(═O)C.sub.1-C.sub.25alkylene-OH, —NHC(═O)C.sub.2-C.sub.25alkenylene-OH, —NHC(═O)C.sub.2-C.sub.25alkynylene-OH, —NHC(═O)C.sub.6-C.sub.10aryl, —NHC(═O)C.sub.3-C.sub.10heteroaryl, —NHC(═O)C.sub.1-C.sub.25alkylene-C.sub.6-C.sub.10aryl, —NHC(═O)C.sub.2-C.sub.25alkenylene-C.sub.6-C.sub.10aryl, —NHC(═O)C.sub.2-C.sub.25alkynylene-C.sub.6-C.sub.10aryl, —NHC(═O)C.sub.3-C.sub.10heteroaryl, —NHC(═O)C.sub.1-C.sub.25alkylene-C.sub.3-C.sub.10heteroaryl, —NHC(═O)C.sub.2-C.sub.25alkenylene-C.sub.3-C.sub.10heteroaryl, —NHC(═O)C.sub.2-C.sub.25alkynylene-C.sub.3-C.sub.10heteroaryl, 2,2,6,6-tetramethylpiperidin-1-ol-4-yl free radical, —NHC(═O)C(CH.sub.3).sub.2—O-aryl-Cl, —NHC(═O)CH.sub.2C(CH.sub.3).sub.2—O-aryl-Cl, idebenonyl-derivative, -pyridine-3-C(═O)—OH and —NR′R″R′″; the 5-, 6-, 7- or 8-membered carbocyclic ring is optionally substituted by at least one functionality selected from structures (A) through (H): ##STR00105## wherein in each functionality (A) through (H), the wavy line indicates point or bond of connectivity, j is 0 or 1 and Ra is selected from H, —C.sub.1-C.sub.25alkyl, —C.sub.2-C.sub.25alkenyl, —C.sub.2-C.sub.25alkynyl, C(═O)—C.sub.6-C.sub.10aryl and C(═O)—C.sub.3-C.sub.10heteroaryl, wherein in functionalities (G) and (H) the pendant —NH—Ra group is present between 1 and 11 times at any position along the carbocycle; or a compound of the formula (XXXIX): ##STR00106## or a compound of formula (XXXX): ##STR00107## or a compound of formula (XXXXI): ##STR00108## or a compound of formula (XXXXII): ##STR00109## or any one compound of: ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118##

238. A compound having any one of the structures: ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128##

239. The compound according to claim 235, wherein the compound is a modulator of peripheral cannabinoid receptors.

240. The compound according to claim 239, wherein the peripheral cannabinoid receptors is selected from peripherally restricted CB.sub.1 receptors and peripherally restricted CB.sub.2 receptors.

241. The compound according to claim 235, wherein the compound is a neutral antagonist of peripheral cannabinoid receptors.

242. The compound according to claim 235, wherein the compound is an inverse agonist of peripheral cannabinoid receptors.

243. The compound according to claim 235, wherein the compound is an inhibitor of peripheral cannabinoid receptors.

244. A compound according to claim 235, being a peripherally restricted CB.sub.1 receptor inverse agonist.

245. A pharmaceutical composition comprising a compound according to claim 235.

246. A nanocarrier comprising at least one compound of claim 235.

247. A method of preventing or treating a metabolic syndrome and disorders, the method comprises administering to a human or animal subject an amount of a compound of claim 235.

248. The method according to claim 247, wherein the metabolic syndrome or disorders are selected from obesity, insulin resistance, diabetes, coronary heart disease, liver cirrhosis and cancer.

249. A method of treating a subject to reduce body fat, or to reduce body weight, or to treat insulin resistance, or to treat diabetes, or to reduce or control high blood pressure, or to improve a poor lipid profile with elevated LDL cholesterol, low HDL cholesterol, and elevated triglycerides, or to treat a metabolic syndrome, the method comprising administering to the subject at least one compound according to claim 235.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0370] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0371] FIGS. 1A-C depict the results of radioligand displacement assays. BNS-002 is more lipid soluble than rimonabant (estimated partition coefficient [log P], 17 vs. 6.4 for rimonabant) but retains high affinity and selectivity for CB.sub.1 receptor. In radioligand displacement assays, BNS-002 has a Ki of 4.96 nM for CB.sub.1 receptor, which is similar to that of rimonabant (FIG. 1A). Like rimonabant, BNS-002 reduces GTPγS binding in mouse brain membranes (FIG. 1B) and is able to ameliorate the action of the potent CB.sub.1 receptor agonist HU-210 (FIG. 1C), suggesting that it is an inverse agonist.

[0372] FIGS. 2A-B demosnstare reduced brain penetrance of BSN002. BSN002 displays markedly reduced brain penetrance, as reflected by its reduced brain levels and increased serum levels following an administration of the compound in two different doses (3 and 10 mg/kg, ip).

[0373] FIGS. 3A-E provide comparison of the effects of BNS002 and rimonabant on ambulation. Whether the reduced brain penetrance of BNS-002 is associated with an attenuation of behavioral effects was tested. To that end, the effects of BNS-002 and rimonabant were evaluated in antagonizing cannabinoid-induced hypomotility. The marked increase in immobility induced in mice by the cannabinoid agonist HU-210 (30 μg/kg, ip) was completely blocked by rimonabant (10 mg/kg, ip) but was unaffected by a similar dose and even higher doses of BNS-002 (10, 20, and 50 mg/kg; FIGS. 3A-E).

[0374] FIGS. 4A-D show the increased activity profile of rimonabant as compared with BNS002. Rimonabant (10 mg/kg, ip), but not BNS-002 (at 10, 20 and 50 mg/kg, ip), induced a marked increase in the activity profile in mice (FIGS. 4A-D).

[0375] FIGS. 5A-B show the metabolic profile of BNS002 and rimonabant. The metabolic profile of BNS-002 and rimonabant was examined in mice with diet-induced obesity (DIO). Male C57BL/6 mice fed a high-fat diet (HFD) for 14 weeks became obese and were then started on daily ip injections of vehicle, rimonabant, or BNS002 (both at 10 mg/kg/d) for an additional 28 days. Age- and sex-matched mice on standard chow served as controls. The overweight and increased adiposity of mice on HFD were significantly reduced by rimonabant only (FIGS. 5A-B).

[0376] FIGS. 6A-C show that both rimonanbant and BNS002 upregulate HFD-induced reduction in VO.sub.2, total energy expenditure, and fat oxidation, as measured by using an indirect calorimetry assessment.

[0377] FIGS. 7A-B demonstrate the efficacy of rimonabant over BNS002 in reducing food intake. The greater efficacy of rimonabant over BNS-002 in reducing body weight is probably related to its ability to reduce total caloric intake (FIGS. 7A-B).

[0378] FIGS. 8A-C show the efficacy of rimonabant and BNS-002 in ameliorating HFD-induced hyperglycemia and glucose tolerance. HFD-induced hyperglycemia and glucose intolerance were completely reversed by BNS-002 in a similar fashion as rimonabant (FIGS. 8A-B). A trend toward reduction in serum insulin levels was also documented by both compounds (FIG. 8C).

[0379] FIG. 9 shows the efficacy of rimonabant and BNS-002 in reversing HFD-induced hepatic steatosis. HFD-induced hepatic steatosis, as reflected in elevated fat vacuoles in the liver, was completely reversed by rimonabant and partially by BNS-002.

[0380] FIG. 10 shows efficacy of rimonabant and BNS-002 in reversing HI-D-induced kidney hyperfiltration. In addition, HFD-induced kidney hyperfiltration was completely normalized by BNS-002 (FIG. 10), suggesting increased ability of the novel compound to ameliorate obesity-induced kidney dysfunction.

[0381] FIGS. 11A-B demonstrate the efficacy of higher doses of BNS002 in DIO mice. The efficacy of higher doses of BNS-002 (15 and 30 mg/kg, ip for 7 days) was next tested in DIO mice in comparison with rimonabant (10 mg/kg/d). Age- and sex-matched mice on standard chow served as controls. The overweight of mice on HFD were significantly reduced by rimonabant and BNS-002 at a dose of 30 mg/kg (FIG. 11A and 11B), whereas no effect on body weight reduction was observed in the group treated with BNS-002 at 15 mg/kg.

[0382] FIG. 12 provide Ki values determined for TMP using [.sup.3H]CP-55,940 radioligand displacement assay.

[0383] FIG. 13 provide Ki values determined for EST using [.sup.3H]CP-55,940 radioligand displacement assay.

[0384] FIG. 14 provide Ki values determined for IDB using [.sup.3H]CP-55,940 radioligand displacement assay.

[0385] FIG. 15 shows the ability of IDB, EST, TMP and rimonabant (as a positive control) to induce centrally-mediated hyperactivity in mice. Wild-type, male, C57Bl/6J mice received a single dose of rimonabant (10 mg/kg, IP), IDB, EST, TMP (at 20, 40 and 35 mg/kg, IP respectively) or vehicle. Ambulatory activity was measured by the Promethion Metabolic System (Sable Instruments, Inc). Data represent the mean±SEM from 4-8 mice per group. *P<0.05 vs. Vehicle-treated control.

[0386] FIG. 16 demonstrates the ability of IDB, EST, TMP and rimonabant (as a positive control) to inhibit the hypomotility-induced by a CB.sub.1 receptor agonist (HU210). Wild-type, male, C57Bl/6J mice received a single dose of rimonabant (10 mg/kg, IP), IDB, EST, TMP (at 20, 40 and 35 mg/kg IP, respectively) or vehicle. A half an hour after, mice received a single dose of HU210 (30 μg/kg, IP) and their locomotor activity was evaluated by the Promethion Metabolic System (Sable Instruments, Inc). Data represent the mean±SEM from 4-10 mice per group. *P<0.05 vs. Vehicle-treated control #P<0.05 vs. HU210.

[0387] FIGS. 17A-B show that IDB has a CB.sub.1 binding affinity of 256.3 nM (Ki) (A), and shows an inverse agonism profile, as tested by GTPγS binding (B). Data represent the mean±SEM of at least three independent experiments done in triplicates.

[0388] FIGS. 18A-F show that IDB (20 mg/kg/day for 20 days) reduced body weight (A, B), daily and total food intake (C, D) as well as reduced fat mas and increased lean mass (E, F) in DIO mice. Data represent the mean±SEM from 5 mice per group. *P<0.05 vs. Vehicle-treated control.

[0389] FIGS. 19A-F demonstrate that chronic IDB administration (20 mg/kg/day for 20 days) induces significant changes in metabolic parameters measured by the Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc.) over a 24 hr period. Respiratory quotient (A), VO2 (B), VCO2 (C), total energy expenditure (D), fat oxidation (E), and carbohydrate oxidation (F). Data are mean±SEM from 4 mice per group. *P<0.05 vs. Vehicle-treated control.

[0390] FIGS. 20A-D demonstrates that chronic IDB administration (20 mg/kg/day for 20 days) affects ambulation in DIO mice. Ambulatory activity (A), ability to run on a wheel (B), voluntary activity (C), and total meter (D). Method: Mice were monitored by the Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc.) over a 24 hr period. Data are mean±SEM from 4 mice per group.

[0391] FIGS. 21A-I show the effect of chronic IDB administration (20 mg/kg/day for 20 days) on glycemic control. Mice on high-fat diet for 20 weeks were treated chronically with IDB or vehicle, and glucose homeostasis was assessed. Note that IDB reduced glucose tolerance (A-B), improved insulin sensitivity (C-F) as well as reduced fasting (G) and fed (H) glucose levels. In addition, IDB increases glycosuria (I). Data represent the mean±SEM from 5 mice per group. *P<0.05 vs. Vehicle-treated control.

[0392] FIGS. 22A-B show that chronic IDB administration (20 mg/kg/day for 20 days) reduces HFD-induced hepatic steatosis and liver injury in mice. An elevated in fat vacuoles deposition, measured by H&E staining, was evident in the DIO mice treated with vehicle compared with the IDB-treated animals on the same diet (A). Furthermore, a decrease in liver weight (B) as well as a reduction in liver enzymes (AST, ALT, and ALP), measured by the COBAS Chemistry analyzer, was noticeable in the IDB-treated mice. Data represent the mean±SEM from 5 mice per group. *P<0.05 vs. Vehicle-treated control.

[0393] FIGS. 23A-E show that chronic IDB administration (20 mg/kg/day for 20 days) improves dyslipidemia in DIO mice. IDB was able to reduce total cholesterol (A), triglycerides (B), HDL (C), and LDL (D) as well as to increase HDL-to-LDL ratio (E). Data represent the mean±SEM from 5 mice per group. *P<0.05 vs. Vehicle-treated control.

DETAILED DESCRIPTION OF EMBODIMENTS

[0394] As disclosed herein, “EST” is herein identified compound “I”. “TMP” is herein identified compound “H”. “IDB” is herein identified compound “K”. “BNS-002” is herein identified compound “D”.

Synthesis and characterization of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-octadecyl-1H-pyrazole-3-carboxamide (BNS-002)

[0395] Synthesis procedure. A solution of Ethyl chloroformate (0.25 mL, 2.6 mmol) in dichloromethane (10 mL) were added to a 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 g, 2.6 mmol) in dry THF (150 mL). The mixture was added to a solution of stearylamine (0.7 g, 2.6 mmol) and triethylamine (0.38 ml, 2.8 mmol) in dry THF (200 mL). The addition performed slowly and in drop-wise at room temperature, rate 10 ml/min. The reaction mixture was stirred at room temperature over 4 hours. A pale-yellow solution and a white precipitate were formed. The mixture was filtered on white paper filter and washed with dry THF (50 ml). Following filtration, the THF was evaporated, and the crude was dissolved in hexane (150 ml), poured into separatory funnel, washed with DDW (100 ml) three times. The hexane layer was collected and dried over anhydrous sodium sulfate, filtered through white paper filter, and removed via evaporation forming a pale-yellow liquid. A 70% yield before column chromatography was obtained. The precipitate was dissolved again in 10 ml of dichloromethane and incorporated with silica powder (silica gel 60), dried and load to pre-prepared silica column (radius 5 cm, length 25 cm). The separation and the purification were completed as follows: 2 fold volumes of column capacity were washed with hexane; followed by 2 volumes of column capacity with hexane.

##STR00061##

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-octadecyl-1H-pyrazole-3-carboxamide (BNS-002)

[0396] Characterization. The LC-MS and the H-NMR spectrum confirmed the structure of the title compound. The HPLC shows purity above 98%.

[0397] Compounds having longer or shorter alkyl chains may be similarly prepared. Non-limiting examples of such compounds include:

##STR00062##

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-hexyl-4-methyl-1H-pyrazole-3-carboxamide

[0398] ##STR00063##

5-(4-chlorophenyl)-N-decyl-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamide

[0399] ##STR00064##

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-hexadecyl-4-methyl-1H-pyrazole-3-carboxamide

[0400] ##STR00065##

(E)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(octadec-9-en-1-yl)-1H-pyrazole-3-carboxamide

[0401] Radioligand binding assays. BNS-002 binding to CB.sub.1 receptor was assessed in competition displacement assays using [.sup.3H]CP-55,940 as the radioligand and crude membranes from mouse brain for CB.sub.1 receptor. All data were in triplicates with Ki values determined from three independent experiments.

[0402] [.sup.35S] G-TPγS binding. Mouse brains were dissected and P2 membranes prepared and resuspended at ˜6 μg protein/μL in 1 ml assay buffer (50 mM Tris HCl, 9 mM MgCl.sub.2, 0.2 mM EGTA, 150 mM NaCl; pH 7.4). Ligand-stimulated [.sup.35S]GTPγS binding was assayed as described previously (Tam et at, JCI 2010). Briefly, membranes (10 μg protein) were incubated in assay buffer containing 100 μM GDP, 0.05 nM [.sup.35S] GTPγS, test compounds at 1 nM-1 μM, and 1.4 mg/mL fatty acid-free BSA in siliconized glass tubes. Bound ligand was separated from free by vacuum filtration. Non-specific binding was determined using 10 μM GTPS. Basal binding was assayed in the absence of the ligand and in the presence of GDP.

[0403] Tissue levels of antagonists. Mice received a single dose (3 or 10 mg/kg ip) of BNS-002 or rimonabant and were sacrificed 1 hour later. Blood was collected, and the mice were perfused with phosphate buffered saline for 1 min to remove drug from the intravascular space before removing the brain and liver. Drug levels in tissue homogenates and plasma were determined by using LC-MS/MS.

[0404] Locomotor activity. Locomotor activity was quantified by the number of disruptions of infrared XYZ beam arrays with a beam spacing of 0.25 cm in the Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc., Las Vegas, Nev., USA).

[0405] Mice. The experimental protocol used was approved by the Institutional Animal Care and Use Committee of the Hebrew University, which is an AAALAC International accredited institute. Male 6 week old C57Bl/6J mice were obtained from Harlan Laboratories. Mice were maintained under a 12-h light/dark cycle and fed ad libitum. To generate diet-induced obesity, C57Bl6/J mice were fed either a high-fat diet (HFD) (60% of calories from fat, 20% from protein, and 20% from carbohydrates; Research Diet, D12492) or a standard laboratory diet (STD, 14% fat, 24% protein, 62% carbohydrates; NIH-31 rodent diet) for 14 weeks.

[0406] HFD-fed obese mice received vehicle (1% Tween80, 4% DMSO, 95% Saline), BNS-002, IDB or rimonabant daily for 7-28 days by intraperitoneal (ip) injections of 10, 15, 20, and 30 mg/kg as indicated in the figures. Age-matched control mice on STD received vehicle daily. Body weight and food intake were monitored daily. Total body fat and lean masses were determined by EchoMRI-100H™ (Echo Medical Systems LLC, Houston, Tex., USA). 24 h urine was collected one week before euthanasia using mouse metabolic cages (CCS2000 Chiller System, Hatteras Instruments, N.C., USA). At weeks 20 mice were euthanized by a cervical dislocation under anesthesia, the kidneys, brain, liver, fat pads, and muscles were removed and weighed, and samples were either snap-frozen or fixed in buffered 4% formalin Trunk blood was collected for determining the biochemical parameters.

[0407] Multi-parameter metabolic assessment. Metabolic profile of the mice was assessed by using the Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc., Las Vegas, Nev., USA). Data acquisition and instrument control were performed using MetaScreen software version 2.2.18.0, and the obtained raw data were processed using ExpeData version 1.8.4 using an analysis script detailing all aspects of data transformation. Mice with free access to food and water were subjected to a standard 12 h light/12 h dark cycle, which consisted of a 48 h acclimation period followed by 24 h of sampling. Respiratory gases were measured by using the GA-3 gas analyzer (Sable Systems, Inc., Las Vegas, Nev., USA) using a pull-mode, negative-pressure system. Air flow was measured and controlled by FR-8 (Sable Systems, Inc., Las Vegas, Nev., USA), with a set flow rate of 2000 mL/min. Water vapor was continuously measured and its dilution effect on O.sub.2 and CO.sub.2 was mathematically compensated. Effective mass was calculated by [body mass].sup.0.75. Fat oxidation (FO) and carbohydrate oxidation (CHO) were calculated as FO=1.69×VO.sub.2−1.69×VCO.sub.2 and CHO=4.57×VCO.sub.2−3.23×VO.sub.2 and expressed as g/d/kg.sup.eff.Mass.

[0408] Glucose tolerance (ipGTT) test and insulin sensitivity tests (ipIST). Mice that fasted overnight were injected with glucose (1.5 g/kg, ip), followed by a tail blood collection at 0, 15, 30, 45, 60, 90, and 120 minutes. Blood glucose levels were determined using the Elite glucometer (Bayer, Pittsburgh, Pa.). On the following day, mice were fasted for 6 h before receiving insulin (0.75 U/kg, i.p.; Eli Lilly, D.C., USA or Actrapid® vial, novo nordisk A/S, Denmark), and blood glucose levels were determined at the same intervals as above.

[0409] Blood and urine biochemistry. Serum and urine levels of creatinine as well as serum levels of ALT, AST, ALP, HDL, LDL, TG and cholesterol were determined by using the Cobas C-111 chemistry analyzer (Roche, Switzerland). Creatinine clearance was calculated using urine and serum creatinine levels (CCr mL/h=Urine creatinine mg/dL×Urine volume/Serum creatinine mg/dL×24 hrs). Serum insulin levels were measured by an ELISA kit (Crystal Chem, Inc., Downers Grove, Ill., USA). Fasting blood glucose was measured using the Elite glucometer (Bayer, Pittsburgh, Pa.).

[0410] Histopathological Analyses. 5 μm paraffin-embedded liver sections from 5 animals per group were stained with hematoxylin-eosin staining. Liver images were captured with a Zeiss AxioCam ICc5 color camera mounted on a Zeiss Axio Scope.A1 light microscope and taken from 10 random 40× fields of each animal.

[0411] Results:

[0412] BNS-002 is more lipid soluble than rimonabant (estimated partition coefficient [log P], 17 vs. 6.4 for rimonabant) but retains high affinity and selectivity for CB1 receptor. In radioligand displacement assays, BNS-002 has a Ki of 4.96 nM for CB1 receptor, which is similar to that of rimonabant (FIG. 1A). Like rimonabant, BNS-002 reduces GTPγS binding in mouse brain membranes (FIG. 1B) and is able to ameliorate the action of the potent CB1 receptor agonist HU-210 (FIG. 1C), suggesting that it is an inverse agonist.

[0413] Importantly, BSN002 displays markedly reduced brain penetrance, as reflected by its reduced brain levels and increased serum levels following an administration of the compound in two different doses (3 and 10 mg/kg, ip; FIGS. 2A-B).

[0414] Next the inventors tested whether the reduced brain penetrance of BNS-002 is associated with an attenuation of behavioral effects. To that end, we compared the effects of BNS-002 and rimonabant in antagonizing cannabinoid-induced hypomotility. The marked increase in immobility induced in mice by the cannabinoid agonist HU-210 (30 μg/kg, ip) was completely blocked by rimonabant (10 mg/kg, ip) but was unaffected by a similar dose and even higher doses of BNS-002 (10, 20, and 50 mg/kg; FIGS. 3A-E).

[0415] In addition, rimonabant (10 mg/kg, ip), but not BNS-002 (at 10, 20 and 50 mg/kg, ip), also induced a marked increase in the activity profile in mice (FIGS. 4A-D).

[0416] The metabolic profile of BNS-002 and rimonabant was next examined in mice with diet-induced obesity (DIO). Male C57BL/6 mice fed a high-fat diet (HFD) for 14 weeks became obese and were then started on daily ip injections of vehicle, rimonabant, or AM6545 (both at 10 mg/kg/d) for an additional 28 days. Age- and sex-matched mice on standard chow served as controls. The overweight and increased adiposity of mice on HFD were significantly reduced by rimonabant only (FIGS. 5A-B).

[0417] Yet, significant increase in the metabolic profile of the DIO mice treated with both antagonists was demonstrated using an indirect calorimetry assessment. As shown in FIGS. 6A-C, both rimonabant and BNS-002 were able to upregulate the HFD-induced reduction in VO.sub.2, total energy expenditure, and fat oxidation.

[0418] The greater efficacy of rimonabant over BNS-002 in reducing body weight is probably related to its ability to reduce total caloric intake (FIGS. 7A-B).

[0419] Nevertheless, HFD-induced hyperglycemia and glucose intolerance were completely reversed by BNS-002 in a similar fashion as rimonabant (FIGS. 8A-B). A trend toward reduction in serum insulin levels was also documented by both compounds (FIG. 8C).

[0420] Moreover, HFD-induced hepatic steatosis, as reflected in elevated fat vacuoles in the liver, was completely reversed by rimonabant and partially by BNS-002 (FIG. 9).

[0421] In addition, HFD-induced kidney hyperfiltration was completely normalized by BNS-002 (FIG. 10), suggesting increased ability of the novel compound to ameliorate obesity-induced kidney dysfunction.

[0422] The efficacy of higher doses of BNS-002 (15 and 30 mg/kg, ip for 7 days) was next tested in DIO mice in comparison with rimonabant (10 mg/kg/d). Age- and sex-matched mice on standard chow served as controls. The overweight of mice on HFD were significantly reduced by rimonabant and BNS-002 at a dose of 30 mg/kg (FIG. 11A and 11B), whereas no effect on body weight reduction was observed in the group treated with BNS-002 at 15 mg/kg.

Synthesis and characterization of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(2,2,6,6-tetramethyl-1-oxo-1-piperidin-4-yl)-1H-pyrazole-3-carboxamide (BB1+TMP)

[0423] Synthesis procedure. N,N′-Dicyclohexylcarbodiimide (DCC, 1.08g, 5.24mmol) was added to 544-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (BB1, 1 g, 2.26mmol) in CH.sub.2Cl.sub.2 (70 ml). The resultant mixture was stirred for 10 min and then, 4-Amino TEMPO (free radical) (TMP, 0.45 g, 2.62 mmol) was added. The reaction mixture was stirred at room temperature over 24 h. An orange solution and a white precipitate were formed. The mixture was filtered on white paper filter and washed with CH.sub.2Cl.sub.2 (50 ml). Following filtration, the CH.sub.2Cl.sub.2 was evaporated, and the crude was dissolved in CH.sub.2Cl.sub.2 again (50 ml). An orange solution and a white precipitate were formed. The mixture was filtered on white paper filter and washed with CH.sub.2Cl.sub.2 (50 ml). Following filtration, the CH.sub.2Cl.sub.2 was evaporated.

[0424] A 74% yield before column chromatography was obtained. The orange viscous oil was dissolved again in 10 ml of CH.sub.2Cl.sub.2 and incorporated with silica powder (silica gel 60), dried and load to pre-prepared silica column (radius 5 cm, length 25 cm). The separation and the purification were completed as follows: 2 fold volumes of column capacity were washed with hexane; followed by 2 volumes of column capacity with hexane:ethyl acetate (90:10) and ended after 4 volumes of column capacity with hexane: ethyl acetate (80:20).

##STR00066##

[0425] Characterization. The LC-MS and the Elemental analysis confirmed the structure of the title compound. The HPLC shows purity above 98%.

[0426] Elemental Analysis

TABLE-US-00001 TABLE 1 Batch Sample Code Sample % C % H % N 6-6956 BB1 + TMP 58.31 5.23 10.46 57.27 5.44 9.91

Synthesis and characterization of 2,2,6,6-tetramethyl-1-piperidin-4-yl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate (BB1+EST)

[0427] Synthesis procedure. N,N′-Dicyclohexylcarbodiimide (DCC, 1.08 g, 5.24mmol) was added to 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (BB1, 1 g, 2.26 mmol) in CH.sub.2Cl.sub.2 (70 ml). The resultant mixture was stirred for 10 min and then, 4-Hydroxy TEMPO (free radical) (EST, 0.45 g, 2.62 mmol) was added. The reaction mixture was stirred at room temperature over 24 h. An orange solution and a white precipitate were formed. The mixture was filtered on white paper filter and washed with CH.sub.2Cl.sub.2 (50 ml). Following filtration, the CH.sub.2Cl.sub.2 was evaporated, and the crude was dissolved in CH.sub.2Cl.sub.2 again (50 ml). An orange solution and a white precipitate were formed. The mixture was filtered on white paper filter and washed with CH.sub.2Cl.sub.2 (50 ml). Following filtration, the CH.sub.2Cl.sub.2 was evaporated.

[0428] A 70% yield before column chromatography was obtained. The orange viscous oil was dissolved again in 10 ml of CH.sub.2Cl.sub.2 and incorporated with silica powder (silica gel 60), dried and load to pre-prepared silica column (radius 5 cm, length 25 cm). The separation and the purification were completed as follows: 2 fold volumes of column capacity were washed with hexane; followed by 2 volumes of column capacity with hexane:ethyl acetate (90:10) and ended after 4 volumes of column capacity with hexane:ethyl acetate (80:20).

##STR00067##

[0429] Characterization. The LC-MS and the Elemental analysis confirmed the structure of the title compound. The HPLC shows purity above 98%.

[0430] Elemental Analysis

TABLE-US-00002 TABLE 2 Batch Number Date Code Sample % C % H % N 6-7154 58.20 5.22 7.83 30 Jul. 2019 BB1_EST 57.71 5.17 7.54

Synthesis and characterization of 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)decyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4methyl1H-pyrazole-3-carboxylate (BB1+IDB)

[0431] Synthesis procedure. N,N′-Dicyclohexylcarbodiimide (DCC, 1.3 g, 5.91 mmol) was added to 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (BB1, 1.12 g, 2.95 mmol) in CH.sub.2Cl.sub.2 (70 ml). The resultant mixture was stirred for 10 min and then, Idebenone (IDB, 1, 2.95 mmol) was added. The reaction mixture was stirred at room temperature over 24 h. An orange solution and a white precipitate were formed. The mixture was filtered on white paper filter and washed with CH.sub.2Cl.sub.2 (50 ml). Following filtration, the CH.sub.2Cl.sub.2 was evaporated, and the crude was dissolved in CH.sub.2Cl.sub.2 again (50 ml). An orange solution and a white precipitate were formed. The mixture was filtered on white paper filter and washed with CH.sub.2Cl.sub.2 (50 ml). Following filtration, the CH.sub.2Cl.sub.2 was evaporated.

[0432] A 70% yield before column chromatography was obtained. The orange viscous oil was dissolved again in 10 ml of CH.sub.2Cl.sub.2 and incorporated with silica powder (silica gel 60), dried and load to pre-prepared silica column (radius 5 cm, length 25 cm). The separation and the purification were completed as follows: 2 fold volumes of column capacity were washed with hexane; followed by 2 volumes of column capacity with hexane: ethyl acetate (90:10) and ended after 4 volumes of column capacity with hexane:ethyl acetate (80:20).

##STR00068##

[0433] Characterization. The LC-MS and the H-NMR confirmed the structure of the title compound. The HPLC shows purity above 98%.

[0434] TMP, EST and IDB-In Vitro Binding Report

[0435] Radioligand binding assay. Binding of the tested compounds to CB1 receptor was assessed in competition displacement assays using [3H]CP-55,940 as the radioligand and crude membranes from mouse brain for CB1 receptor. Membranes were extracted according to an established protocol previously described by Catani V. M. and Gasperi V. [8]. Compounds were tested at different concentrations (10-5M -10-11M) and their ability to displace [3H]CP-55,940 was evaluated. Membranes with bound [3H]CP-55,940 were separated and washed from free ligand by vacuum filtration and bound [3H]CP-55,940 radioactivity was measured using a 13 counter. All data were in triplicates with Ki values extracted by nonlinear regression analysis using GraphPad Prism software.

[0436] Results

[0437] In radioligand displacement assays, all three tested compounds were found active with high affinity to CB.sub.1 receptor. Ki values were varying for each substance, ranging from 1.69 nM-446 nM for TMP (FIG. 12), 0.37 nM-7.81 nM for EST (FIGS. 13) and 1.9 nM-134.6 nM for IDB (FIG. 14).

[0438] TMP, EST and IDB-In Vivo Safety Report (Lack of CNS Central Activity)

[0439] Centrally-mediated hyperactivity profile. Wild-type, male, C57Bl/6J mice (n=4-8) received a single dose of rimonabant (10 mg/kg, IP), TMP (35 mg/kg, IP), EST (40 mg/kg, IP), IDB (20 mg/kg, IP) or vehicle only (IP). Mice were placed in metabolic cages and their activity profile was evaluated. Locomotor activity was quantified by the number of disruptions of infrared XYZ beam arrays with a beam spacing of 0.25 cm in the Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc., Las Vegas, Nev., USA).

[0440] Antagonizing cannabinoid-induced hypomotility. The ability of the different compounds to inhibit the hypomotility induced by HU210 (cannabinoid agonist) was evaluated. Wild-type, male, C57Bl/6J mice (n=4-10) received a single dose of rimonabant (10 mg/kg, IP), TMP (35 mg/kg, IP), EST (40 mg/kg, IP), IDB (20 mg/kg, IP) or vehicle only (IP). A half an hour thereafter, mice received a single dose of HU210 (30 ug/kg, IP) and their locomotor activity was evaluated as described above.

[0441] Results

[0442] Rimonabant (10 mg/kg) induced a marked increase in the activity profile in mice (FIG. 15), but no significant hyperactivity was recorded, compare to the vehicle group, following TMP (35 mg/kg, IP), EST (40 mg/kg, IP) and IDB (20 mg/kg, IP) injections (FIG. 15). The marked hypomotility induced in mice by the cannabinoid agonist HU210 (30 ug/kg, IP) was significantly blocked by rimonabant but was unaffected by the tested compounds (FIG. 16).

[0443] FIG. 17 shows that IDB has a CB1 binding affinity of 256.3 nM (Ki) (A), and shows an inverse agonism profile, as tested by GTPγS binding (B). Data represent the mean±SEM of at least three independent experiments done in triplicates.

[0444] IDB (20 mg/kg/day for 20 days) reduced body weight (A, B), daily and total food intake (C, D) as well as reduced fat mas and increased lean mass (E, F) in DIO mice is shown in FIG. 18. Data represent the mean±SEM from 5 mice per group. *P<0.05 vs. Vehicle-treated control.

[0445] In FIG. 19 chronic IDB administration (20 mg/kg/day for 20 days) is shown to induce significant changes in metabolic parameters measured by the Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc.) over a 24 hr period. Respiratory quotient (A), VO2 (B), VCO2 (C), total energy expenditure (D), fat oxidation (E), and carbohydrate oxidation (F). Data are mean±SEM from 4 mice per group. *P<0.05 vs. Vehicle-treated control.

[0446] In FIG. 20 chronic IDB administration (20 mg/kg/day for 20 days) is shown not to affect ambulation in DIO mice. Ambulatory activity (A), ability to run on a wheel (B), voluntary activity (C), and total meter (D). Method: Mice were monitored by the Promethion High-Definition Behavioral Phenotyping System (Sable Instruments, Inc.) over a 24 hr period. Data are mean±SEM from 4 mice per group.

[0447] In FIG. 21 the effect of chronic IDB administration (20 mg/kg/day for 20 days) on glycemic control is demonstrated. Mice on high-fat diet for 20 weeks were treated chronically with IDB or vehicle, and glucose homeostasis was assessed. Note that IDB reduced glucose tolerance (A-B), improved insulin sensitivity (C-F) as well as reduced fasting (G) and fed (H) glucose levels. In addition, IDB increases glycosuria (I). Data represent the mean±SEM from 5 mice per group. *P<0.05 vs. Vehicle-treated control.

[0448] In FIG. 22 chronic IDB administration (20 mg/kg/day for 20 days) is shown to reduce HFD-induced hepatic steatosis and liver injury in mice. An elevated in fat vacuoles deposition, measured by H&E staining, was evident in the DIO mice treated with vehicle compared with the IDB-treated animals on the same diet (A). Furthermore, a decrease in liver weight (B) as well as a reduction in liver enzymes (AST, ALT, and ALP), measured by the COBAS Chemistry analyzer, was noticeable in the IDB-treated mice. Data represent the mean±SEM from 5 mice per group. *P<0.05 vs. Vehicle-treated control.

[0449] In FIG. 23 chronic IDB administration (20 mg/kg/day for 20 days) is shown to improve dyslipidemia in DIO mice. IDB was able to reduce total cholesterol (A), triglycerides (B), HDL (C), and LDL (D) as well as to increase HDL-to-LDL ratio (E). Data represent the mean±SEM from 5 mice per group. *P<0.05 vs. Vehicle-treated control.

[0450] One very important difference between BNS-002 and IDB reside in the different impact on the liver and kidney functions. As can be seen in FIG. 10, HFD-induced kidney hyperfiltration was completely normalized by BNS-002, suggesting increased ability of the novel compound to ameliorate obesity-induced kidney dysfunction. Whereas IDB has no effect compared to the control. Furthermore, HFD-induced hepatic steatosis, as reflected in elevated fat vacuoles in the liver, was completely reversed by rimonabant and partially by BNS-002 (FIG. 9). Whereas chronic IDB administration (20 mg/kg/day for 20 days) of IDB reduces HFD-induced hepatic steatosis and liver injury in mice. An elevated in fat vacuoles deposition, measured by H&E staining, was evident in the DIO mice treated with vehicle compared with the IDB-treated animals on the same diet (FIG. 22A). Furthermore, a decrease in liver weight (FIG. 22B) as well as a reduction in liver enzymes (AST, ALT, and ALP), measured by the COBAS Chemistry analyzer, was noticeable in the IDB treated mice. Data represent the mean±SEM from 5 mice per group. *P<0.05 vs. Vehicle-treated control.