Novel non-psychotropic cannabinoids

Abstract

Novel non-psychotropic cannabinoids are disclosed and pharmaceutical compositions comprising these novel compounds are described for preventing neurotoxicity, neuroinflammation, immune or inflammatory disorders comprising as active ingredient the stereospecific (+) enantiomer, having (3S,4S) configuration of Δ 6 tetrahydrocannabinol type compounds. The compositions are particularly effective in alleviating and even preventing neurotoxicity due to acute injuries to the central nervous system, including mechanical trauma, compromised or reduced blood supply as may occur in cardiac arrest or stroke, or poisonings. They are also effective in the treatment of certain inflammatory disorders and chronic degenerative diseases characterized by neuronal loss and chronic pain including neuropathic pain.

1 . A method for treating or preventing inflammatory diseases or disorders, damage resulting from ischemia, injuries to the central nervous system and neurodegenerative disorders, pain, autoimmune diseases, cardiovascular disorders, or drug abuse, tolerance or dependence, by administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of the formula (I):  
     
       
         
         
             
             
         
       
     
     having the (3S,4S) configuration and being essentially free of the (3R,4R) enantiomer, wherein A═B indicates an optional 1(2) or 6(1) double bond, 
 R 1  is 
 A) R 3  where R 3  is selected from the group consisting of 
 a) a linear or branched, saturated or unsaturated, carbon side chain comprising 1-8 carbon atoms and 1-3 heteroatoms, at least one heteroatom being placed between two carbon atoms; or  
 b) a saturated or unsaturated cyclic moiety or an aromatic or heterocyclic moiety having from 5-20 atoms comprising one or two-ringed structures, wherein each ring comprises 3-8 carbons and 0-4 heteroatoms,  
 said heteroatoms each independently selected from the group consisting of N, O, and S; wherein each ring optionally is further substituted with one or more groups selected from 
 i) C 1-6  alkyl,  
 ii) C 1-6  alkoxy,  
 iii) C 1-6  alkylthio,  
 iv) halo,  
 v) carboxyl,  
 vi) —CO 2 -C 1-4  alkyl,  
 vii) keto,  
 viii) nitro, and  
 ix) a saturated or unsaturated cyclic moiety, or an aromatic or a heterocyclic moiety comprising one or two ringed structures wherein each ring comprises 3-8 carbons interrupted by 0-4 heteroatoms, said heteroatoms each independently selected from the group consisting of N, O, and S; wherein each ring optionally is further substituted with one or more groups selected from i)-viii) as defined above;  
 
 
 B) an amine or an amide substituted with at least one substituent as defined in R 3  above;  
 C) a thiol, a sulfide, a sulfoxide, a sulfone, a thioester or a thioamide optionally substituted with one substituent as defined in R 3  above; or  
 D) an ether —OR 3  wherein R 3  is as defined above;  
 G is (a) halogen, (b) C 1 -C 6  alkyl, or (c) —OR wherein R is (a′) —R″, wherein R″ is hydrogen or C 1 -C 6  alkyl optionally containing a terminal —OR′″ or —OC(O)R′″ moiety wherein R′″ is hydrogen or C 1 -C 6  alkyl, or (b′) —C(O)R′″ wherein R′″ is as previously defined, and  
 R 2  is (a) C 1 -C 12  alkyl, (b) —OR″″, in which R″″ is a straight chain or branched C 2 -C 9  alkyl which may be substituted at the terminal carbon atom by a phenyl group, or (c) —(CH 2 ) n OR′″ wherein n is an integer of 1 to 7 and R′″ is hydrogen or C 1 -C 6  alkyl; with the proviso that R 1  is other than a heterocyclic moiety having a labile hydrogen atom so that said moiety acts as a carboxylic acid analogue.  
 
 
   
   
       2 . The method according to  claim 1  wherein R 1  is a saturated or unsaturated cyclic moiety, an aromatic moiety or a heterocyclic moiety having from 5-20 atoms comprising one or two-ringed structures, wherein each ring comprises 3-8 carbons and 0-4 heteroatoms, said heteroatoms each independently selected from the group consisting of N, O, and S; optionally further substituted with at least one substituent selected from the group consisting of lower alkyl, halogen, nitro, cyano, —SR′″, —NHR′″, —N(R′″) 2 , —OR′″, —COR′″, —C(O)OR′″ or NH—COR′″ moiety wherein R′″ is hydrogen or C 1 -C 6  alkyl.  
   
   
       3 . The method according to  claim 1  wherein R 1  is a heterocyclic moiety selected from the group consisting of an imidazolyl, an imidazolinyl, a morpholino, a piperidyl, a piperazinyl, a pyrazolyl, a pyrrolyl, a pyrrolidinyl, a triazolyl, and a tetrazolyl, optionally further substituted wherein the substituent is selected from the group consisting of C 1-6  alkyl, C 1-6  alkyloxy, C 1-6  alkylthio, keto, carboxy, or nitro, wherein C 1-6  alkyl, C 1-6  alkoxy and C 1-6  alkylthio are intended to include saturated and unsaturated linear, branched and cyclic structures.  
   
   
       4 . The method according to  claim 1  wherein R 1  is imidazolyl, pyrazolyl, 2-methyl thio-2-imidazolinyl, or 4-methylpiperidinyl.  
   
   
       5 . The method according to  claim 1  wherein A═B is a 6(1) double bond, and G is —OH or lower acyloxy.  
   
   
       6 . The method according to  claim 5  wherein R 2  is 1,1-dimethylheptyl or 1,2-dimethylheptyl and wherein R 1  is selected from the group consisting of imidazole, pyrazole, oxazole, isoxazole, tetrahydropyridine, pyrazoline, oxazoline, pyrrolidine, imidazoline, 2-thio-imidazole, 2-methylthio-imidazoline, 4-methyl-2-imidazoline, 4,4-dimethyl-2-imidazoline, methyl sulfide, methylsulfoxide, acetamido, benzamide, cyano, 1,2,4-triazole, 1,3,4-triazole, 1,2,3,4-tetrazole, 1,2,3,5-tetrazole, thiophene, phenyl, morpholine, thiomorpholine, thiazolidine, glycerol, piperazine, piperidine and tetrahydropyran, optionally further substituted wherein the substituent is selected from the group consisting of C 1-6  alkyl, C 1-6  alkyloxy, C 1-6  alkylthio, keto, carboxy, or nitro, wherein C 1-6  alkyl, C 1-6  alkoxy and C 1-6  alkylthio are intended to include saturated and unsaturated linear, branched and cyclic structures.  
   
   
       7 . The method according to  claim 6  wherein R 1  is imidazole, pyrazole, 2-methyl thio-2-imidazoline, or 4-methylpiperidine.  
   
   
       8 . The method according to  claim 1  wherein A═B is absent and G is —OH or lower acyloxy.  
   
   
       9 . The method according to  claim 1  wherein said compound is selected from the group consisting of: (+)-(3S ,4S)-6,6-Dimethyl-(1,1-dimethylheptyl)-1-hydroxy-9-(imidazolo methyl)-6a,7, 10,10a-tetrahydro-6H-dibenzo[b,d]pyran; (+)-(3S,4S)-6,6-Dimethyl-(1,1-dimethylheptyl)-1-hydroxy-9-(pyrazolomethyl)-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d]pyran; (+)-(3S,4S)-6,6-Dimethyl-( 1,1-dimethylheptyl)-1-hydroxy-9-(1H-imidazol-2-ylsulfanylmethyl)-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d]pyran; (+)-(3S,4S)-6,6-Dimethyl-(1,1-dimethylheptyl)-1-hydroxy-9-(4-piperidinopiperidinemethyl)-6a,7,10,10 a-tetrahydro-6H-dibenzo [b,d]pyran; and (+)-(3S,4S)-6,6-Dimethyl-(1,1-dimethylheptyl)-1-hydroxy-9-(4-methylpiperidine methyl)-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d]pyran.  
   
   
       10 . The method according to  claim 1  wherein said compound is administered in a manner to protect against excitatory amino acid-mediated neurotoxicity.  
   
   
       11 . The method according to  claim 1  which comprises administering said compound to a patient who exhibits the symptoms associated with tolerance or dependence to opioids, cocaine, psychostimulants or alcohol.  
   
   
       12 . The method according to  claim 1  which comprises administering said compound to a patient who exhibits the symptoms associated with neural injury due to edema, neural injury due to cerebral ischemia, neural injury due to head trauma, poisoning of the central nervous system, cardiac arrest, stroke, optic neuropathy, or spinal cord injury.  
   
   
       13 . The method according to  claim 1  which comprises administering said compound to a patient who exhibits the symptoms associated with epilepsy, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or Alzheimer's disease.  
   
   
       14 . The method according to  claim 1  which comprises administering said compound to a patient who exhibits the symptoms associated with chronic, neuropathic or other pain.  
   
   
       15 . The method according to  claim 1  which comprises administering said compound to a patient who exhibits the symptoms associated with multiple sclerosis, rheumatoid arthritis, systemic  lupus erythematosis,  Graves disease, Hashimoto's thyroiditis, or inflammatory bowel.  
   
   
       16 . The method according to  claim 1  which comprises administering said compound to a patient who exhibits the symptoms associated with myocardial infarction, atheroma, unstable angina, restenosis, or ischemic damage to the cardiovascular system.  
   
   
       17 . The method according to  claim 1  which comprises administering said compound to a patient who exhibits the symptoms associated with ischemic and/or inflammatory damage to body organs including the lungs, liver, kidney or joints related to pulmonary, hepatic, or renal ischemias, rheumatoid arthritis or septic shock.  
   
   
       18 . The method according to  claim 1  which comprises administering said compound to a patient who exhibits the symptoms associated with glaucoma, retinal degeneration or emesis.  
   
   
       19 . The method according to  claim 1  wherein the daily dosage of said compound is between 0.01 and 25 mg/kg.  
   
   
       20 . The method according to  claim 1  wherein the composition is administered orally, parenterally, intravenously, intramuscularly, intralesionally, subcutaneously, transdermally, intratechally, rectally or intranasally.  
   
   
       21 . A method for treating or alleviating an inflammatory condition; excitatory amino acid-mediated neurotoxicity; tolerance to or dependence on opioids, cocaine, psychostimulants or alcohol; symptoms associated with chronic, neuropathic or other pain; neural injury caused by edema, cerebral ischemia, head trauma, stroke or spinal cord injury; Parkinson's disease; or myocardial infarction by administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of the formula (I):  
     
       
         
         
             
             
         
       
     
     having the (3S,4S) configuration and being essentially free of the (3R,4R) enantiomer, wherein A═B is a 6(1) double bond; R 1  is imidazolyl, pyrazolyl, 2-methyl thio-2-imidazolinyl, or 4-methylpiperidinyl; G is —OH or lower acyloxy; and R 2  is C 1 -C 12  alkyl.  
   
   
       22 . The method according to  claim 21 , wherein G —OH and R 2  is 1,1-dimethylheptyl.