Patent Abstract:
compositions of the formulae , and ; where r1 , r2 and r3 are residues of amino acids such as , but not limited to , valine , sarcosine , leucine , glutamine , tryptophan , tyrosine , alanine and 4butyric acid or combination thereof , and salts thereof . methods of preparation of these compositions and methods of treating any disease condition responsive to thc comprising administration of at least one these compositions in a pharmaceutically acceptable carrier using a pharmaceutically acceptable formulation .

Detailed Description:
thc - amino acid esters as prodrugs for thc were prepared in this invention by coupling of thc with allyl protected different amino acids to generate the thc - allyl protected amino acid esters which on deprotection produced thc - amino acid esters . thc ( fig1 ) is used as the starting material for all thc - amino acid esters . fig1 : schematic representation of the utility of the prodrug / tmp system concept . prodrug ( pd ) derivatization of the parent drug thc ( d ), in combination with the tmp system improves overall permeability . transbuccal permeability and bioreversion are illustrated by arrows . line thickness represents the extent and higher or lower rates of permeability . fig3 : representative peaks in carbon spectroscopy for compound 6 fig4 : gc / ms analysis of the hydrolysis product of 6 confirming a δ 9 - thc derivative . fig7 hreims of compound 9 (+ ive mode ) m + h = 443 . 29 and m + na = 465 . 27 fig8 : representative peaks in carbon spectroscopy for compound 9 fig9 : hreims of compound 10 (+ ive mode ) m + h = 501 . 6 , m + na = 523 . 6 and m + k = 539 . 3 fig1 : representative peaks in carbon spectroscopy for compound 13 fig1 : lcms of compound 14 (+ ive mode ) m + nh 4 + = 593 . 7 fig1 : representative peaks in carbon spectroscopy for compound 14 fig1 : lcms of compound 15 (+ ive mode ) m + nh 4 + = 531 . 7 fig1 representative peaks in carbon spectroscopy for compound 15 chemical modification of a therapeutic agent by way of prodrug design has become an important drug delivery tool [ 22 - 24 ] . this is one of the most widely accepted and successful strategies for modifying physicochemical characteristics , aqueous solubility , chemical and enzymatic stability and mucosal permeability of drug candidates through linkage of appropriate promoieties . a significant positive aspect of the prodrug approach is that it does not induce any change in the membrane structure , fluidity or characteristics . the prodrugs are cleaved in vivo to generate the active drug and the harmless pro - moiety , which is eliminated from the body ( fig1 ). in the past decade amino acids have taken center stage as promoieties for transporter targeted prodrug derivatization of hydrophilic drug molecules [ 25 - 31 ] . some studies exploiting this mechanism for circumvention of efflux proteins have also been published [ 32 - 35 ] . a few studies exploring the use of single amino acid based prodrug derivatization to enhance hydrophilicity of lipophilic molecules and improve oral absorption have also been reported [ 28 , 36 - 46 ] . however , to date , transbuccal delivery of mono -, di - or tri - amino acid conjugated prodrugs of lipophilic compounds has not been investigated . indeed , a major gap in the understanding of the structural and physicochemical characteristics of any molecule necessary for transbuccal penetration exists . this route of administration holds tremendous untapped potential for the delivery of many therapeutic agents with limited permeability and metabolic stability . compounds whose systemic bioavailability is limited by hepatic metabolism , as in the case of thc , will necessitate preparation of more permeable prodrugs , such as the mono -, di - and tri - amino acid esters to be formulated in non - oral formulations such as the transmucosal matrix patch ( tmp ) system with a multitude of advantages . however , the above - cited prodrugs could also be incorporated into an oral delivery system and other compositions using processing techniques , including , but not limited to , hot - melt extrusion to enhance bioavailability . the highlight of this invention is the ability , for the first time , to prepare amino acid esters of thc , without affecting the basic structure of thc . increasing the bioavailability of thc , through the use of the amino acid esters prodrugs and incorporating these prodrugs in a formulation such as the transmucosal matrix patch ( tmp ), or a more efficient oral delivery system , could have a significant influence on many chronically ill patients , such as those infected with the hiv virus , those undergoing chemotherapy , as well as other conditions known to be ameliorated by thc , such as pain , spasticity and multiple sclerosis . the pharmacologically acceptable compounds of the present invention can be used , for example , for the manufacture of pharmaceutical compositions useful in treatment of chronic states treatable with thc and which contain an effective amount of the active substance together or in admixture with inorganic or organic , solid or liquid , pharmaceutically acceptable carriers . the pharmaceutical compositions according to the invention are those which are suitable for enteral , such as oral , administration and for parenteral , such as subcutaneous , administration to warm - blooded animals , especially humans , and which contain the pharmacologically active substance on its own or together with a pharmaceutically acceptable carrier . a preferred method of use for the present compositions is by transmucosal patch . the dosage of the active substance depends on the species of warm - blooded animal and on the age and individual condition the illness to be treated and also on the mode of administration . computational analysis of the amino acid based thc prodrugs : based on the previous findings , computational analysis , using molecular modeling pro ® software , was utilized to predict the physicochemical properties of various promoiety candidates . computational analysis was subsequently performed with some of the amino acids classified under the hydrophobic amino acid group ( e . g . alanine , leucine , valine ), as well as with the hydrophilic amino acids ( e . g . glycine , serine , sarcosine , esparto acid , tyrosine and glutamine ), and their combinations . these results are depicted in table 1 . the results predict a significant decrease in the log p values and increase in hydrophilicity with both hydrophilic and hydrophobic amino acid prodrugs evaluated . the polar surface area and the % hydrophilic surface area are also significantly improved . additionally the di - and tri - amino acid ( peptide ) linkages will allow significant modulation of the physicochemical properties . thus depending on the type of amino acid selected and the number of amino acids linked to thc , a wide range of hydrophilicities can be generated and permeabilities determined . thus the correlation of log p and permeability can be determined . several procedures were attempted for the preparation of the δ 9 - thc amino acid derivatives using the t - boc and f - moc protected amino acids . while the formation of the esters with the protected amino groups was not problematic for all of the amino acid derivatives attempted , deprotection of the t - boc or the f - moc groups under various deprotection conditions always resulted in conversion of the δ 9 - thc ( at least in part ) to δ 8 - thc , in case of the t - boc , or reversion to δ 9 - thc in the case of the f - moc . in this invention , we have developed allyl protected amino acids prepared in house ( scheme i ) to overcome the problems associated with the commonly available protected amino acids . this approach proved to be successful and promises viability in the preparation of any amino acid derivative or small chain peptide derivatives of δ 9 - thc without any effect on the rest of the structure . the di - amino acid derivative could be converted to the tri - amino acid derivative following the same procedure as for the conversion of the mono - to the di - derivative . general scheme for the preparation of mono , di and tri - amino acid thc derivatives . scheme i . examples of amino acid esters prepared according to scheme i , are : δ 9 - thc - valinate ( 6 ), thc - sarcosinate ( 7 ), thc - leucinate ( 8 ), thc - glutaminate ( 9 ) thc - tryptophinate ( 10 ), thc - tyrosinate ( 11 ) and thc - b - alaninate ( 12 ) were prepared . the compounds thc - 4 -( 4 - amino - phenyl ) butyrate ) ( 13 ), and thc - 4 -( 4 - amino - phenyl ) butyrate ) hemisuccinate ( 14 ) and thc - valinate - hemisuccinate ( 15 ) were prepared using scheme ii . their structures were confirmed by mass ( lc / ms and hreims ) and spectroscopic analysis ( 1 h - nmr and 13 c - nmr ). following the general procedure outlined in scheme i , where compound i is valine , δ 9 - thc - valinate 6 was synthesized to test the validity of the synthetic protocol . valine ( 5 g ) was dissolved in 34 ml of distilled water and 5 . 8 gram of sodium carbonate was added in several portions . allyl chloroformate ( 10 ml ) was added at once after the bubbling stopped . the solution was stirred for 24 hours at 22 ° c . concentrated hydrochloric acid was then used to adjust the ph to 1 . the solution was extracted with ethyl acetate 8 times and the organic layer was rinsed with brine and dried over sodium sulfate . the solvent was evaporated to dryness to give 6 . 5 g of the crude product as a colorless syrup . a 1 . 1 equivalent of this product was dissolved in dichloromethane and 1 . 1 equivalent of dcc was added to it ( solution a ). δ 9 - thc ( 1 equivalent ) was dissolved in dichloromethane along with a catalytic amount of dmap ( dimethyl amino pyridine ) which was added drop - wise to solution a . the reaction mixture was stirred at room temperature for 1 hour and the reaction progress was monitored through tlc . after one hour the reaction mixture was worked up and the product was purified using silica gel column chromatography . fractions having the product were combined and evaporated to obtain the protected δ 9 - thc - valine ester ( 95 % yield ), which was confirmed by mass spectroscopy . the latter was dissolved in dichloromethane and 0 . 05 mmol of tetrakis ( triphenylphosphine ) palladium was added along with 0 . 01 mmol of phenyl silane . the reaction was allowed to stir at room temperature for 30 minutes . the solvent was then evaporated and the product 6 was purified using column chromatography (& gt ; 87 % yield ) and confirmed by mass spectroscopy in the positive ionization mode ( m + h = 414 . 5 ) ( fig2 ). the structure of product 6 was also confirmed by spectral analysis 1 h - nmr and 13 c - nmr ( see fig3 for 13 c - nmr assignments ). for confirmation that the product 6 is the derivative of e - thc and not converted to e - thc , compound 6 was base hydrolyzed followed by gc / ms analysis of the hydrolysis product . the analysis confirmed that it is pure δ 9 - thc as shown in fig4 . following the general procedure outlined in scheme i , where compound i is sarcosine , δ 9 - thc — sarcosinate 7 was synthesized . product 7 was purified using column chromatography (& gt ; 80 % yield ) and confirmed by mass spectroscopy in the positive ionization mode ( m + h = 386 ) ( fig5 ). the structure of product 7 was also confirmed by spectral analysis 1 h - nmr and 13 c - nmr . following the general procedure outlined in scheme i , where compound i is leucinine , δ 9 - thc - leucinate 8 was synthesized . product 8 was purified using column chromatography (& gt ; 81 % yield ) and confirmed by mass spectroscopy in the positive ionization mode ( m + h = 428 ) ( fig6 ). the structure of product 6 was also confirmed by spectral analysis 1 h - nmr and 13 c - nmr . following the general procedure outlined in scheme i , where compound i is glutamine , δ 9 - thc - glutaminate 9 was synthesized . product 9 was purified using column chromatography (& gt ; 85 % yield ) and confirmed by mass spectroscopy in the positive ionization mode ( m + h = 443 ) ( fig7 ). the structure of product 9 was also confirmed by spectral analysis ( 1 h - nmr and 13 c - nmr ( see fig8 for 13 c - nmr assignments ). following the general procedure outlined in scheme i , where compound i is tryptophan , δ 9 - thc - tryptophinate 10 was synthesized . product 10 was purified using column chromatography (& gt ; 86 % yield ) and confirmed by mass spectroscopy in the positive ionization mode ( m + h = 501 ) ( fig9 ). the structure of product 10 was also confirmed by spectral analysis 1 h - nmr and 13 c - nmr ( see fig1 for 13 c - nmr assignments ). following the general procedure outlined in scheme i , where compound i is tyrosine , δ 9 - thc - tyrosinate 11 was synthesized . product 11 was purified using column chromatography (& gt ; 82 % yield ) and confirmed by mass spectroscopy in the positive ionization mode ( m + h = 478 . 3 ) ( fig1 ). the structure of product 10 was also confirmed by spectral analysis 1 h - nmr and 13 c - nmr . following the general procedure outlined in scheme i , where compound i is b - alanine , δ 9 - thc - β - alaninate 12 was synthesized . product 12 was purified using column chromatography (& gt ; 82 % yield ) and confirmed by mass spectroscopy in the positive ionization mode ( m + h = 386 . 3 ) ( fig1 ). the structure of product 6 was also confirmed by spectral analysis 1 h - nmr and 13 c - nmr . following the general procedure outlined in scheme i , compound 12 was synthesized , where compound i was 4 -( 4 - aminophenyl ) butyrate and was used without any protection . product 12 was purified using column chromatography (& gt ; 90 % yield ) and confirmed by mass spectroscopy in the positive ionization mode ( m + h = 476 ) ( fig1 ). the structure of product 12 was also confirmed by spectral analysis 1 h - nmr and 13 c - nmr ( see fig1 for 13 c - nmr assignments ). thc - 4 ( 4 - aminophenyl ) butyrate ( 13 ) was dissolved in 50 ml of dichloromethane and 1 . 1 eq of succinic anhydride was added along with catalytic amount of dmap ( di - methyl amino pyridine ). 1 . 1 eq . of triethyl amine was added drop wise with a syringe and reaction was allowed to run overnight at room temperature . in the morning , tlc indicated complete conversion of the starting material to product . solvent was evaporated up to approximately one third of volume on rotavap , and then 1 ml of dcm was added in it . a column was packed with silica gel ( 10 eq .) in dcm and the reaction mixture , which was dissolved in dcm , was loaded at the top of the column . fractions were collected initially in dcm and then increased to 50 % etoac . product came in 40 % etoac in dcm . fractions containing pure product were combined and the solvent was evaporated to dryness to get the product ( 14 ) ( 95 % yield ). product 14 was confirmed by mass spectroscopy in the positive ionization mode ( m + nh 4 + = 593 ) ( fig1 ). the structure of product 14 was also confirmed by spectral analysis 1 h - nmr and 13 c - nmr ( see fig1 for 13 c - nmr assignments ). compound 15 was also prepared using scheme ii , where the starting material was compound 6 ( thc - valinate ). product 15 was purified using column chromatography (& gt ; 85 % yield ) and confirmed by mass spectroscopy in the positive ionization mode ( m + nh 4 + = 531 ) ( fig1 ). the structure of product 15 was also confirmed by spectral analysis 1 h - nmr and 13 c - nmr ( see fig1 for 13 c - nmr assignments ). spectral analysis of δ 9 - thc prodrugs prepared above : identity and purity of the synthesized prodrugs was established by spectral means including 1 h - nmr , 13 c - nmr and 2d - nmr such as cosy , hmqc , hmbc , as well as other spectroscopic means ( ir , uv and ms ). the synthetic protocols outlined above yielded prodrugs with ≧ 95 % purity . 1 . marijuana and medicine : assessing the science base , ed . j . e . joy , s . j . watson , and j . a . benson , 1999 , washington , d . c . : national academy press . 2 . martin , b . r ., the use of cannabinoids in patients with chronic illness . u . s . pharmacist , 2002 , 1 : p . 61 - 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