Cannabinoid derivatives, methods of making, and use thereof

Abstract

1′-substituted cannabinoid derivatives of delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol, and delta-6a-10a-tetrahydrocannabinol that have affinity for the cannabinoid receptor type-1 (CB-1) and/or cannabinoid receptor type-2 (CB-2). Compounds having activity as either agonists or antagonists of the CB-1 and/or CB-2 receptors can be used for treating CB-1 or CB-2 mediated conditions.

1 . A composition comprising 
 a pharmaceutically acceptable carrier; and    a compound according to formula (I)                          wherein,    X is selected from the group of C(CH 3 ) 2 , C(—Y(CH 2 ) n Y—), CH 2 , C(O),                          Y is selected from the group of S and O;    R 1  is selected from the group of a C3 to C8 cycloalkyl, biphenyl, methyltetrazolyl,                          with the proviso that, when X is CH 2 , R 1  is not cyclohexyl or phenyl;    R 2  and R 3  are methyl for compounds containing a Δ 8  or a Δ 9  double bond, or are independently selected from the group of a C1 to C3 alkyl group and a C1 to C3 alkanol for compounds containing a Δ 6a-10a  double bond;    R 4  is selected from the group of methyl, methanol, —(CH 2 ) m COOH, and —(CH 2 ) m COH for compounds containing a Δ 8  or a Δ 9  double bond, or is methyl for compounds containing a Δ 6a-10a  double bond;    R 5  is selected from the group of H, OH, methoxy, and ethoxy;    R 6 -R 10  are independently selected from the group of H, OH, C1 to C6 alkyl, halo, amino, C1 to C2 alkylamino, C1 to C2 dialkylamino, amido, C1 to C2 alkylamido, cyano, nitro, C1 to C6 alkoxy, C1 to C6 alcohol, carboxyl containing a C1 to C6 alkyl, carbonyl containing a C1 to C6 alkyl, ester containing a C1 to C6 alkyl group, sulfoxide containing a C1 to C6 alkyl, and sulfone containing a C1 to C6 alkyl;    at least one of R 11 -R 13  is selected from the group of C1 to C6 alkyl, C1 to C6 alkoxy, fluoro, and chloro, and the other of R 11 -R 13  can optionally be H;    n is an integer from 2 to 4; and    m is an integer that is either 0 or 1.    
   
   
       2 . The composition according to  claim 1  wherein the composition is in the form of a microemulsion preparation.  
   
   
       3 . The composition according to  claim 2  wherein the liposomal preparation comprises polyethylene glycol 300, ethanol, polysorbate 80, tocopherol acetate, and disodium EDTA solution.  
   
   
       4 . The composition according to  claim 1  wherein the carrier is an oil.  
   
   
       5 . The composition according to  claim 1  wherein the carrier is a formulation comprising hydrogenated soy phosphatidyl choline, cholesterol, and distearyl phosphotidyl ethanolamine-PEG2000 conjugate.  
   
   
       6 . A method of modifying the activity of a cannabinoid receptor comprising: 
 providing a compound according to formula (I)                          wherein,    X is selected from the group of C(CH 3 ) 2 , C(—Y(CH 2 ) n Y—), CH 2 , C(O),                          Y is selected from the group of S and O;    R 1  is selected from the group of a C3 to C8 cycloalkyl, biphenyl, methyltetrazolyl,                          with the proviso that, when X is CH 2 , R 1  is not cyclohexyl or phenyl;    R 2  and R 3  are methyl for compounds containing a Δ 8  or a Δ 9  double bond, or are independently selected from the group of a C1 to C3 alkyl group and a C1 to C3 alkanol for compounds containing a Δ 6a-10a  double bond;    R 4  is selected from the group of methyl, methanol, —(CH 2 ) m COOH, and —(CH 2 ) m COH for compounds containing a Δ 8  or a Δ 9  double bond, or is methyl for compounds containing a Δ 6a-10a  double bond;    R 5  is selected from the group of H, OH, methoxy, and ethoxy;    R 6 -R 10  are independently selected from the group of H, OH, C1 to C6 alkyl, halo, amino, C1 to C2 alkylamino, C1 to C2 dialkylamino, amido, C1 to C2 alkylamido, cyano, nitro, C1 to C6 alkoxy, C1 to C6 alcohol, carboxyl containing a C1 to C6 alkyl, carbonyl containing a C1 to C6 alkyl, ester containing a C1 to C6 alkyl group, sulfoxide containing a C1 to C6 alkyl, and sulfone containing a C1 to C6 alkyl;    at least one of R 11 -R 13  is selected from the group of C1 to C6 alkyl, C1 to C6 alkoxy, fluoro, and chloro, and the other of R 11 -R 13  can optionally be H;    n is an integer from 2 to 4; and    m is an integer that is either 0 or 1; and    contacting a cannabinoid receptor of a cell with the compound, whereby said contacting modifies the activity of the cannabinoid receptor in the cell.    
   
   
       7 . The method according to  claim 6  wherein the cell is ex vivo.  
   
   
       8 . The method according to  claim 6  wherein the cell is in vivo.  
   
   
       9 . The method according to  claim 6  wherein cannabinoid receptor is a CB- 1  receptor.  
   
   
       10 . The method according to  claim 9  wherein the cell is from the central nervous system, heart, vascular endothelium, uterus, testis, vas deferens, small intestine, or urinary bladder.  
   
   
       11 . The method according to  claim 9  wherein the compound is selective for the CB-1 receptor, with a K i  ratio [CB1/CB2] that is at least 4:1.  
   
   
       12 . The method according to  claim 6  wherein cannabinoid receptor is a CB-2 receptor.  
   
   
       13 . The method according to  claim 12  wherein the cell is from the spleen, a leukocyte, a B-cell, or a macrophage.  
   
   
       14 . The method according to  claim 8  wherein the compound is selective for the CB-2 receptor, with a K i  ratio [CB2/CB1] that is at least 4:1.  
   
   
       15 . A method of treating a cannabinoid receptor-mediated condition comprising: 
 providing a compound that acts as an agonist on the cannabinoid receptor, wherein the compound is a compound according to formula (I)                          wherein,    X is selected from the group of C(CH 3 ) 2 , C(—Y(CH 2 ) n Y—), CH 2 , C(O),                          Y is selected from the group of S and O;    R 1  is selected from the group of a C3 to C8 cycloalkyl, biphenyl, methyltetrazolyl,                          with the proviso that, when X is CH 2 , R 1  is not cyclohexyl or phenyl;    R 2  and R 3  are methyl for compounds containing a Δ 8  or a Δ 9  double bond, or are independently selected from the group of a C1 to C3 alkyl group and a C1 to C3 alkanol for compounds containing a Δ 6a-10a  double bond;    R 4  is selected from the group of methyl, methanol, —(CH 2 ) m COOH, and —(CH 2 ) m COH for compounds containing a Δ 8  or a Δ 9  double bond, or is methyl for compounds containing a Δ 6a-10a  double bond;    R 5  is selected from the group of H, OH, methoxy, and ethoxy;    R 6 -R 10  are independently selected from the group of H, OH, C1 to C6 alkyl, halo, amino, C1 to C2 alkylamino, C1 to C2 dialkylamino, amido, C1 to C2 alkylamido, cyano, nitro, C1 to C6 alkoxy, C1 to C6 alcohol, carboxyl containing a C1 to C6 alkyl, carbonyl containing a C1 to C6 alkyl, ester containing a C1 to C6 alkyl group, sulfoxide containing a C1 to C6 alkyl, and sulfone containing a C1 to C6 alkyl;    at least one of R 11 -R 13  is selected from the group of C1 to C6 alkyl, C1 to C6 alkoxy, fluoro, and chloro, and the other of R 11 -R 13  can optionally be H;    n is an integer from 2 to 4; and    m is an integer that is either 0 or 1; and    administering to a patient an amount of the compound that is effective to treat a cannabinoid receptor-mediated condition.    
   
   
       16 . The method according to  claim 15  wherein said administering is carried out orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes.  
   
   
       17 . The method according to  claim 15  wherein the amount administered is between about 1 mg and about 1000 mg/per dose.  
   
   
       18 . The method according to  claim 15  further comprising: 
 periodically repeating said administering.    
   
   
       19 . The method according to  claim 15  wherein the compound is an agonist of the CB-1 receptor.  
   
   
       20 . The method according to  claim 19  wherein the compound is selective for the CB-1 receptor, with a K i  ratio [CB1/CB2] that is at least 4:1.  
   
   
       21 . The method according to  claim 19  wherein the cannabinoid receptor-mediated condition is selected from the group of neurodegenerative disorders, hypertension, peripheral vascular disease, angina pectoris, and hemorrhagic shock, and cell proliferative disorders.  
   
   
       22 . The method according to  claim 21  wherein the neurodegenerative disorder is cerebral apoplexy or craniocerebral trauma.  
   
   
       23 . The method according to  claim 21  wherein the cell proliferative disorder is breast cancer or prostate cancer.  
   
   
       24 . The method according to  claim 15  wherein cannabinoid receptor is a CB-2 receptor.  
   
   
       25 . The method according to  claim 24  herein the compound is selective for the CB-2 receptor, with a K i  ratio [CB2/CB1] that is at least 4:1.  
   
   
       26 . The method according to  claim 25  wherein the cannabinoid receptor-mediated condition is selected from the group of an immunologically-mediated immune disorder, a bone formation/resorption disorder, and renal ischemia.  
   
   
       27 . The method according to  claim 26  wherein the immunologically-mediated immune disorder is selected from the group of rheumatoid arthritis, systemic lupus erythematosus, psoriasis, eczema, multiple sclerosis, diabetes, and thyroiditis.  
   
   
       28 . The method according to  claim 26  wherein the bone formation/resorption disorder is selected from the group of osteoporosis, ankylosing spondylitis, gout, arthritis associated with gout, and osteoarthritis.  
   
   
       29 . A method of making a Δ 8 -THC or Δ 9 -THC analog, said method comprising: 
 reacting an intermediate compound having the structure of formula (II)                          with a reactant according to either formula (IIIa) or formula (IIIb)                          under conditions effective to form a compound according to formula (I)                          wherein,    X is selected from the group of C(CH 3 ) 2 , C(—Y(CH 2 ) n Y—), CH 2 , C(O),                          Y is selected from the group of S and O;    R 1  is selected from the group Of a C3 to C8 cycloalkyl, biphenyl, methyltetrazolyl,                          with the proviso that, when X is CH 2 , R 1  is not cyclohexyl or phenyl;    R 2  and R 3  are methyl for compounds containing a Δ 8  or a Δ 9  double bond, or are independently selected from the group of a C1 to C3 alkyl group and a C1 to C3 alkanol for compounds containing a Δ 6a-10a  double bond;    R 4  is selected from the group of methyl, methanol, —(CH 2 ) m COOH, and —(CH 2 ) m COH for compounds containing a Δ 8  or a Δ 9  double bond, or is methyl for compounds containing a Δ 6a-10a  double bond;    R 5  is selected from the group of H, OH, methoxy, and ethoxy;    R 6 -R 10  are independently selected from the group of H, OH, C1 to C6 alkyl, halo, amino, C1 to C2 alkylamino, C1 to C2 dialkylamino, amido, C1 to C2 alkylamido, cyano, nitro, C1 to C6 alkoxy, C1 to C6 alcohol, carboxyl containing a C1 to C6 alkyl, carbonyl containing a C1 to C6 alkyl, ester containing a C1 to C6 alkyl group, sulfoxide containing a C1 to C6 alkyl, and sulfone containing a C1 to C6 alkyl;    at least one of R 11 -R 13  is selected from the group of C1 to C6 alkyl, C1 to C6 alkoxy, fluoro, and chloro, and the other of R 11 -R 13  can optionally be H;    n is an integer from 2 to 4; and    m is an integer that is either 0 or 1;    wherein the compound contains a double bond at the Δ 8  or Δ 9  position of the C ring.    
   
   
       30 . The method according to  claim 29  further comprising: 
 reacting the compound obtained from said reacting, having a methyl group at the R 4  position, under conditions effective to replace the methyl group with either an aldehyde, a carboxyl, or a methanol.    
   
   
       31 . The method according to  claim 29  further comprising: 
 reacting the compound obtained from said reacting, having a hydroxyl group at the R 5  position, under conditions effective to replace the hydroxyl group with either a hydrogen, a methoxy, or an ethoxy.    
   
   
       32 . The method according to  claim 29  further comprising: 
 reacting the compound obtained from said reacting, having a keto group at the X position, with either an alkane-diol, an alkane-dithiol, or 1,2-phenyl-dithiol under conditions effective to replace the keto group with either C(—Y(CH 2 ) n Y—),                          respectively.