Patent Application: US-92626107-A

Abstract:
this invention comprises antineoplastic curcumin derivatives and methods of preparation and use thereof . particular reference is made to the following isomeric compounds wherein r1 , r2 , and r3 are selected from the group consisting of h , oh , och3 , and cooh .

Description:
commercially available β - ionone ( 7 , as shown in scheme 1 ) and β - cyclocitral ( 3 ) were employed in the synthesis of 1 , 7 - bis -( 2 , 6 , 6 - trimethylcyclohex - 1 - en - 1 - yl )- 1 ( e ), 6 ( e )- heptadiene - 3 , 5 - dione ( 8 ) by the method outlined in scheme 1 . triethyl phosphonoacetate ( 2 ) was prepared in 88 % yield by heating a mixture of ethyl bromoacetate and triethyl phosphate . treatment of ( 2 ) with potassium tert - butoxide in dimethyl formamide ( dmf ) generated the phosphonate anion which subsequently effected wadsworth - emmons - horner olefination of β - cyclocitral ( 3 ). the reaction proceeded in 65 % yield with the expected e - selectivity . without being bound by any particular theory , it is believed that during the course of the reaction , migration of the double bond in the cyclohexene ring occurred and a 64 : 36 mixture of compounds ( 4 ) and ( 4a ) was obtained . see , scheme 2 . the 1 hnmr spectrum ( fig2 ) of the ( 4 - 4 - a ) mixture features a pair of doublets at 7 . 41 ( j = 16 . 0 hz ) and 5 . 79 ppm ( j = 16 . 0 hz ). these are attributed to protons 2 - and 3 - of compound ( 4 ). proton 3 - of compound ( 4a ) gives rise to a doublet of doublets at 6 . 82 ppm ( j = 16 . 0 , 9 . 5 hz ) while the neighboring proton 2 - gives rise to the doublet at 5 . 77 ppm ( j = 16 . 0 hz ). proton 3 ′- of compound ( 4a ) comes to resonance as a broad singlet at 5 . 48 ppm . a doublet at 2 . 30 ppm ( j = 9 . 5 hz ) is due to proton 1 ′ of compound ( 4a ). exposure of the mixture of olefinated products to basic conditions converted ( 4a ) into the thermodynamically more stable compound ( 4 ). base hydrolysis using “ anhydrous potassium hydroxide ” ( kobu t , dry et 2 o , h 2 o ) followed by aqueous acid workup the acids ( 5 ) and ( 5a ) ( 83 % yield ) in a ratio of 80 : 20 respectively . scheme 3 in one embodiment , the sensitivity to base of β - cyclocitral ( 3 ) under the conditions of the wadsworth - emmons - horner olefination as manifested by the double bond migration is addressed by using the masamune - roush conditions in which an organic base such as diisopropylethylamine or 1 , 8 - diazobicycloundec -[ 5 . 4 . 0 ]- ene ( dbu ) in the presence of a lithium salt effects the formation of the phosphonate anion . again , without being bound by any particular theory , it is believed that the stability gained by formation of the chelate structure ( 9 ) allows for the use of the milder organic bases and complications associated with base sensitive carbonyl substrates are thereby avoided . scheme 4 . the mixture of acids ( 5 ) and ( 5a ) was converted to the corresponding acid chlorides upon reaction with oxalyl chloride in thf in the presence of a catalytic amount of dmf . the acid chlorides were not isolated but were immediately made to react at − 78 ° c . with the enolate ( 10 ) generated from β - ionone and lithium diisopropylamide ( lda ). workup and flash chromatography on silica eluting with 1 % ethyl acetate in hexanes , followed by recrystallization from 95 % ethanol furnished in 70 % yield , the target compound , 1 , 7 - bis -( 2 , 6 , 6 - trimethylcyclohex - 1 - en - 1 - yl )- 1 ( e ), 6 ( e )- heptadiene - 3 , 5 - dione in a 86 : 14 mixture with the isomer ( 8a ). it is understood that under physiological conditions this molecule exists as an equilibrium of its keto and enol tautomers . a synthesis for this compound is presented as scheme 6 below . nmr spectra were obtained on a bruker vector 2000 - 200 or a bruker vector 2000 - 500 spectrometer using tetramethylsilane as internal standard . ir spectra were run on a bruker vector 22 ftir spectrometer . melting points are uncorrected and were determined on a thomas - hoover melting point apparatus . diethyl ether and tetrahydrofuran ( thf ) were distilled from sodium / benzophenone ketyl while dimethy formamide ( dmf ) was dried over 3 å sieves then distilled at reduced pressure . analytical thin layer chromatography ( tlc ) was performed on 250 μm silica and flash column chromatography on 230 - 400 mesh silica . a mixture of ethyl bromoacetate ( 11 . 30 g , 7 . 5 ml , 67 . 6 mmol ) and triethyl phosphate ( 11 . 63 g mmol , 12 ml , 1 . 05 equiv .) was heated with stirring in a sealed tube at 140 ° c . for 3 h . after which the crude mixture was distilled to give triethyl phosphonoacetate ( 13 . 39 g , 88 %) as a colorless liquid . b . p . 93 - 94 ° c ./ 0 . 8 mmhg ( lit 2 140 ° c ./ 9 mmhg ); 1 h nmr ( 200 mhz , cdcl 3 ) δ 4 . 12 ( m , 6h ), 3 . 05 ( s , 1h ), 2 . 90 ( s , 1h ), 1 . 20 - 1 . 30 ( m , 9h ). triethyl phosphonoacetate ( 4 . 97 g , 4 . 4 ml , 22 . 2 mmol ) was added dropwise to a slurry of potassium tert - butoxide ( 2 . 53 g , 22 . 5 mmol ) in dmf ( 15 ml ) at 0 ° c . the mixture was brought to room temperature and stirred for 1 h under an atmosphere of nitrogen . b - cyclocitral ( 3 ) ( 3 . 38 g , 3 . 52 ml , 22 . 2 mmol ) was added over a period of 15 min . with the temperature maintained below 30 ° c . the yellow suspension was stirred at room temperature for 20 h at which point tlc indicated that the reaction was not complete . an additional portion of potassium tert - butoxide ( 1 . 27 g , 11 . 3 mmol , 0 . 5 equiv .) was added and the mixture stirred for a further 27 h . the reddish - brown reaction mixture was poured into 130 ml of water and was extracted with ether . after drying over sodium sulphate , the ethereal solution was evaporated under vacuum to give a pale yellow liquid ( 4 . 15 g ). flash chromatography on silica eluting with hexanes gave a mixture of esters ( 4 ) and ( 4a ) as a pale yellow oil ( 3 . 16 g , 65 %). ethyl 2 ( e )- 3 -( 2 , 6 , 6 - trimethylcyclohex - 1 - en - 1 - yl ) propenoate ( 4 ): 64 % of mixture ; 1 h nmr ( 200 mhz , cdcl 3 ) δ 7 . 41 ( d , j = 16 . 0 hz , 1h ), 5 . 79 ( d , j = 16 . 0 hz , 1h ), 4 . 22 ( m , 2h ), 2 . 07 ( m , 2h ), 1 . 78 ( s , 3h ), 1 . 70 - 1 . 20 ( m , 7h ), 1 . 09 ( s , 6h ). ethyl 2 ( e )- 3 -( 2 , 6 , 6 - trimethylcyclohex - 2 - en - 1 - yl ) propenoate ( 4a ): 36 % of mixture ; 1 h nmr ( 200 mhz , cdcl 3 ) δ 6 . 82 ( dd , j = 16 . 0 , 9 . 5 hz , 1h ), 5 . 77 ( d , j = 16 . 0 hz , 1h ), 5 . 77 ( br s , 1h ), 4 . 22 ( m , 2h ), 2 . 30 ( d , j = 9 . 5 hz , 1h ), 1 . 78 ( s , 3h ), 2 . 07 ( m , 2h ), 1 . 70 - 120 ( m , 5h ), 0 . 92 ( s , 3h ), 0 . 82 ( s , 3h ) water ( 0 . 55 ml , 30 . 5 mmol ) was added to a suspension of potassium tert - butoxide ( 12 . 79 g , 0 . 114 mol ) in anhydrous diethyl ether ( 80 ml ) whilst cooling in an ice bath . the mixture was stirred under an atmosphere of nitrogen for 5 min . then an ethereal solution of the 64 : 36 mixture of propenoates ( 4 ) and ( 4a ) ( 3 . 14 g , 14 . 2 mmol ) was added over a period of 5 min . the reaction mixture was stirred at 0 - 5 ° c . for 1 h then at room temperature for 30 h when tlc indicated that the reaction was complete . the reaction was quenched with cold water ( 5 ml ) then was further diluted with water until two distinct layers were seen . the two phases were separated and whilst cooling in ice , the aqueous phase was acidified with 5 % hydrochloric acid to ph 6 . the white precipitate was extracted into diethyl ether . this process of acidification and extraction was repeated until the aqueous layer was ph 3 and no longer yellow but colorless . the combined ether extracts were dried over anhydrous sodium sulphate and evaporated under vacuum to give a mixture of the acids ( 5 ) and ( 5a ) as a yellow - white waxy solid ( 2 . 47 g , 90 %). ir ( kbr disc ) 3000 - 2500 br , 2929 , 2865 , 1685 , 1630 cm − 1 2 ( e )- 3 -( 2 , 6 , 6 - trimethylcyclohex - 1 - en - 1 - yl ) propenoic acid ( 5 ): 80 % of mixture ; 1 hnmr ( 200 mhz , acetone - d 6 ) δ 7 . 30 ( d , j = 16 . 0 hz , 1h ), 5 . 65 ( d , j = 16 . 0 hz , 1h ), 1 . 91 ( m , 2h , 1 . 60 ( s , 3h ), 1 . 43 ( m , 2h ), 0 . 95 ( s , 6h ). 2 ( e )- 3 -( 2 , 6 , 6 - trimethylcyclohex - 2 - en - 1 - yl ) propenoic acid ( 5a ): 20 % of mixture ; 1 hnmr ( 200 mhz , acetone - d 6 ) δ 6 . 61 ( dd , j = 16 . 0 , 9 . 5 hz , 1h ), 5 . 70 ( d , j = 16 . 0 hz , 1h ), 5 . 33 ( br s , 1h ), 2 . 23 ( d , j = 9 . 5 hz , 1h ), 1 . 91 ( m , 2h ), 1 . 60 ( s , 3h ), 1 . 36 ( m , 2h ), 0 . 75 ( s , 3h ), 0 . 66 ( s , 3h ). acid chlorides were prepared by the addition of oxalyl chloride ( 0 . 8 ml , 91 . 6 mmol ) and dmf ( 2 drops ) to a solution in thf ( 15 ml ) of the mixture of acids ( 5 ) and ( 5a ) ( 1 . 55 g , 8 . 0 mmol ). the solution was stirred at room temperature under an atmosphere of nitrogen for 3 h then was evacuated to remove solvent and excess oxalyl chloride . the dark brown residual liquid was set aside for later use . lithium diisopropylamide ( lda ) was prepared by the dropwise addition of butyl lithium ( 10 ml of a 2 . 5m solution in hexanes , 25 mmol ) to a solution of diisopropylamine ( 3 . 5 ml , 25 mmol ) in thf ( 17 ml ) at − 78 ° c . under a nitrogen atmosphere . b - ionone ( 7 ) ( 5 . 2 ml , 25 mmol ) in thf ( 5 ml ) was added dropwise to the freshly prepared solution of lda and the mixture stirred at − 78 ° c . for 5 min . a solution of the acid chlorides in thf ( 8 ml ) was then added dropwise and the mixture stirred at − 78 ° c . for 1 h . the cooling bath was brought up to 0 ° c . over a period of 45 min and the reaction mixture was stirred at this temperature for a further 1 h . after which it was poured into a mixture of crushed ice ( 18 g ) and concentrated hydrochloric acid ( 4 . 8 ml ). the organic layer was separated , diluted with diethyl ether , washed with saturated sodium bicarbonate solution followed by water and then dried over sodium sulphate . evaporation under vacuum followed by flash chromatography furnished a mixture of compounds ( 8 ) and ( 8a ) as a yellow solid ( 2 . 13 g , 70 %). recrystallization from 95 % ethanol furnished yellow crystals . m . p . 104 - 106 ° c . ; ir ( kbr disc ) 2929 , 1685 , 1630 , 1373 cm − 1 . 86 % of mixture ; 1 hnmr ( 200 mhz , cdcl 3 ) δ 7 . 35 ( d , j = 16 . 0 hz , 2h ), 5 . 98 ( d , j = 16 . 0 hz , 2h ), 5 . 58 ( s , 1h ), 2 . 09 ( m , 4h ), 1 . 80 ( s , 6h ), 1 . 62 ( m , 4h ), 1 . 48 ( m , 4h ), 1 . 09 ( s , 12h ); 13 c nmr ( 50 mhz , cdcl 3 ) δ 183 . 56 , 140 . 04 , 136 . 59 , 135 . 69 , 127 . 97 , 100 . 60 , 39 . 82 , 34 . 19 , 33 . 65 , 28 . 85 , 21 . 81 , 18 . 94 . 1 -( 2 , 6 , 6 - trimethylcyclohex - 2 - en - 1 - yl )- 7 -( 2 , 6 , 6 - trimethylcyclohex - 1 - en - 1 - yl )- 1 ( e ), 6 ( e )- heptadiene - 3 , 5 - dione ( 8a ): 14 % of mixture ; 1 hnmr ( 200 mhz , cdcl 3 ) δ 7 . 35 ( d , j = 16 . 0 hz , 1 - h ), 6 . 68 ( dd , j = 16 . 0 , 9 . 5 hz ), 5 . 98 ( d , j = 16 . 0 hz , 1h ), 5 . 90 ( d , j = 16 . 0 hz , 1h ), 5 . 58 ( s , 1h ), 5 . 45 ( br s , 1h ), 2 . 28 ( d , j = 9 . 5 hz , 1h ), 2 . 09 ( m , 4h , 1 . 80 ( s , 6h ), 1 . 48 ( m , 4h ), 0 . 93 ( s , 6h ), 0 . 85 ( s , 6h ) the chemical structure of one exemplary antineoplastic curcumin derivatives is related to the compound curcumin and other β - diketones which have been shown to have anti - cancer or antineoplastic properties . studies have demonstrated the involvement of aberrant arachidonic acid metabolism in carcinogenesis . membrane phospholipids , the major source of arachidonic acid are hydrolyzed by phospholipase a 2 ( pla 2 ); the released arachidonic acid is further metabolized by three different types of oxygenases : cyclooxygenase ( cox ), lipoxygenase ( lox ) and cytochrome p450 . modulation of arachidonic acid metabolism by inhibiting these enzymes has been considered as an effective mechanism for chemoprevention . inhibition of arachidonic acid metabolism by curcumin has been suggested to be a key mechanism for its anticarcinogenic action ( 1 - 3 ). curcumin has been reported to inhibit cox - 2 expression in gastrointestinal cancer cells and mouse skin ( 4 - 6 ). it has also been reported that curcumin affects the formation of cox - and lox - dependent metabolites and decrease activities of pla 2 and plcγ ( 7 , 8 ). it has been suggested the curcumin affects arachidonic acid metabolism by blocking the phosphorylation of cpla 2 , decreasing the expression of cox - 2 and inhibiting the catalytic activities of lox ( 9 ). in one embodiment , the new compounds are composed of two trimethyl hexame rings separated by a double - ketone . this is believed to lend itself to photoreaction that dramatically increases the anti - cancer effects of curcumin . the photoproduct of curcumin binds and inhibits lox - 3 . the portion of the photoproduct of curcumin that sits in the binding pocket of lox - 3 , would be identical to the photoproduct produced of the compound . without being bound by any particular theory , the trimethyl hexane ring in our new compound enters the cancer cell , opens with it , and destroys it without harming the surrounding , normal , cells . the toxicity level of our new chemical compound is extremely low , a key benefit for cancers patients who suffer from low immunity . the formulation of this chemical compound causes no known adverse reactions or side effects in patients . additional compounds of the present invention are also noted . according to this invention , a therapeutically or pharmaceutically effective amount of antineoplastic curcumin derivatives are administered to subjects ( with particular reference to mammals , and more particular reference to humans ) to treat or prevent neoplastic disease with particular reference to cancer . in particular embodiments the antineoplastic curcumin derivatives of this invention therapeutically treat neuroblastoma , pancreatic , ovarian , prostate , endometrial , cervical and colorectal cancers as well as lymphoma and leukemia . a therapeutically effective dose will depend upon the nature of the disease , the severity and course of the disease , previous therapy , the patient &# 39 ; s health status , response to the antineoplastic curcumin derivative and the judgment of the treating medical caregiver . typically , at least one antineoplastic curcumin derivative is administered as a sole active ingredient , or in combination with one or more other active ingredients . typically co - administered drugs are n2 - mercaptopropionylglycine , n - acetylcysteine , glutathione , dimethyl thiourea , desferrioxamine , mannitol , α - tocopherol , ascorbate , buthionine sulfoximine , allopurinol , 21 - aminosteroids , calpain inhibitors , glutamate receptor antagonists , tissue plasminogen activator , streptokinase , urokinase , nonsteroidal anti - inflammatory agent , cortisone , and carotenoids . antineoplastic curcumin derivatives are also be administered in conjunction with polypeptides having sod and / or catalase activity . the present invention includes a method of treating patients who have a neoplasticity associated disease with a prophylactically effective or therapeutically effective amount of an antineoplastic curcumin derivative . this method is useful to treat patients at various stages of their diseases or to prevent development of such diseases . in addition , the treatment can be administered to prevent or reduce the incidence of developing a neoplasm . in some instances , a dosage of about 5 to 5000 mg will be administered to a patient either in single or multiple doses . in general , for treatment of neoplastic diseases , a therapeutically effective dose of antineoplastic curcumin derivative will be in the range of about 0 . 1 to 100 milligram ( mg ) per kilogram ( kg ) of body weight of recipient per day , and particularly in the range of about 1 to 20 mg per kg of body weight per day . the desired dosage is usefully presented in one , two , three , four or more subdoses administered at appropriate intervals throughout the day . these subdoses are administered as unit dosage forms , for example , containing about 5 to 10 , 000 mg , and particularly about 10 to 2000 mg of antineoplastic curcumin derivative per unit dosage form . the composition used in these therapies can be in a variety of forms . these include , for example , solid , semi - solid and liquid dosage forms , such as tablets , pills , powders , liquid solutions or suspensions , liposome preparations , injectable and infusible solutions . the preferred form depends on the intended mode of administration and therapeutic application . typically , a sterile solution of antineoplastic curcumin derivative in an aqueous solvent ( e . g ., saline ) will be administered intravenously . the contemplated compositions also include pharmaceutically acceptable carriers and adjuvants which are known to those of skill in the art . see , e . g ., remington : the science and practice of pharmacy , ed . randy hendrickson , lippincott , williams & amp ; wilkins , 21 st edition ( 2005 ). generally , administration will be by oral or parenteral ( including subcutaneous , intramuscular , intravenous , and intradermal ) routes , or by topical application or infusion into a body cavity , or as a bathing solution for tissues during surgery . it should , of course , be understood that the methods of this invention are usefully employed in combination with antioxidant agents that have sod ( superoxide dismutase ) activity , catalase activity , glutathione peroxidase ( gsh - px )) activity , or are free radical scavengers or inhibitors of free radical formation . it is possible to administer the active ingredient of this invention as a single active pharmaceutical agent , and also as part of a pharmaceutical formulation . the pharmaceutically acceptable formulations of the present invention comprise at least one compound of this invention in a therapeutically or pharmaceutically effective dose together with , optionally , one or more pharmaceutically or therapeutically acceptable carriers and optionally other therapeutic ingredients . carriers include inert , non - toxic solids ( e . g ., mannitol , talc ) and buffered saline . various considerations are described in , for example , goodman and gilman &# 39 ; s : the pharmacological bases of therapeutics , eds . laurence brunton , john lazo , keith parker 11 th ed ., pergamon press ( 2005 ); and remington &# 39 ; s supra , each of which is hereby incorporated herein by reference . methods for administration are discussed therein , e . g ., for oral , intravenous , intraperitoneal , or intramuscular administration , and others . pharmaceutically acceptable carriers will include water , saline , buffers , and other compounds described in a number of sources including the merck index , merck & amp ; co ., rahway , n . j ., incorporated herein by reference . as used herein , the term “ pharmaceutically acceptable carrier ” encompasses any of the standard pharmaceutical carriers such as sterile solutions , tablets , coated tablets , and capsules . typically such carriers contain excipients such as starch , milk , sugar , certain types of clay , gelatin , stearic acids or salts thereof , magnesium or calcium sterate , talc , vegetable fats or oils , gums , glycols , or other known excipients . such carriers may also include flavor and color additives or other ingredients . compositions comprising such carriers are formulated by well known conventional methods . depending on the intended mode of administration and the intended use , the compositions may be in the form of solid , semi - solid , or liquid dosage forms , such , for example , as powders , granules , crystals , liquids , suspensions , liposomes , pastes , cremes , salves , etc ., and may be in unit - dosage forms suitable for administration of relatively precise dosages . for semi - solid compositions , as would be appropriate for pastes and creams intended for topical administration , the antineoplastic curcumin derivatives are provided separately or may be compounded with conventional nontoxic carriers such as , for example , aloe vera gel , squalane , glycerol sterate , polyethylene glycol , cetyl alcohol , stearic acid , and propylene glycol , among others . such compositions may contain about 0 . 005 - 100 % active ingredient , more particularly about 0 . 5 - 25 %. the concentration of antineoplastic curcumin derivatives in these formulations varies widely . selection of a specific concentration may consider intended use , viscosities , etc ., in accordance with the particular mode of administration selected . typical compositions include lotions containing water and / or alcohols and emollients such as hydrocarbon oils and waxes , silicone oils , vegetable , animal or marine fats or oils , glyceride derivatives , fatty acids or fatty acid esters or alcohols or alcohol ethers , lecithin , lanolin and derivatives , polyhydric alcohols or esters , wax esters , sterols , phospholipids and the like , and generally also emulsifiers ( nonionic , cationic or anionic ), although some of the emollients inherently possess emulsifying properties . these same general ingredients are be formulated into a cream rather than a lotion , or into gels , or into solid sticks by utilization of different proportions of the ingredients and / or by inclusion of thickening agents such as gums or other forms of hydrophillic colloids . such compositions are referred to herein as dermatologically acceptable carriers . the pharmaceutical compositions will be administered by parenteral or oral administration for prophylactic and / or therapeutic treatment . the pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration . for example , unit dosage forms suitable for oral administration include powder , tablets , pills , capsules , trochees , and dragees . the pharmaceutical compositions will often be administered intravenously . thus , this invention provides compositions for intravenous administration which comprise a solution of the compound dissolved or suspended in an acceptable carrier , with specific reference to an aqueous carrier . a variety of aqueous carriers can be used , e . g ., water , buffered water , 0 . 4 % saline , and the like . often , an antineoplastic curcumin derivative is dissolved in an organic solvent ( e . g ., dimethylsulfoxide ) and either applied directly or diluted into an aqueous solvent . typically , antineoplastic curcumin derivatives that are relatively lipophilic ( e . g ., c9 , c12 and greater than c12 ) are dissolved in an organic solvent such as dmso and , if desired , subsequently diluted into a more polar solvent , such as water . these compositions will sometimes be sterilized by conventional , well known sterilization techniques , or sterile filtered . the resulting aqueous solutions can be packaged for use as is , or lyophilized , the lyophilized preparation being combined with a sterile aqueous solution prior to administration . the compositions usefully contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions , such as ph adjusting and buffering agents , tonicity adjusting agents , wetting agents and the like , for example , sodium acetate , sodium lactate , sodium chloride , potassium chloride , calcium chloride , sorbitan monolaurate , triethanolamine oleate , and the like . for solid compositions , conventional nontoxic solid carriers can be used which include , for example , pharmaceutical grades of mannitol , lactose , starch , magnesium stearate , sodium saccharin , talcum , cellulose , glucose , sucrose , magnesium carbonate , and the like . for oral administration , a pharmaceutically acceptable nontoxic composition is formed by incorporating any of the normally employed excipients , such as those carriers previously listed , and generally 0 . 001 - 95 % of active ingredient , with particular reference to about 20 %. the compositions containing the compounds are usefully administered for prophylactic and / or therapeutic treatments . in therapeutic applications , compositions are administered to a patient already suffering from a disease , as described above , in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications . an amount adequate to accomplish this is defined as “ therapeutically effective amount or dose .” amounts effective for this use will depend on the severity of the disease and the weight and general state of the patient . in prophylactic applications , compositions containing the compounds of the invention are administered to a patient susceptible to or otherwise at risk of a particular disease . such an amount is defined to be a “ prophylactically effective amount or dose .” in this use , the precise amounts again depend on the patient &# 39 ; s state of health and weight . for solid compositions , conventional non - toxic solid excipients include , for example , pharmaceutical grades of mannitol , lactose , starch , magnesium stearate , talcum , celluloses , glucose , sucrose , magnesium carbonate , and the like may be used . the active compound as defined above may be formulated as suppositories using , for example , triglycerides , for example , any pharmaceutically acceptable hard fat nf bases ( e . g ., witepsol ®™, condea vista company , cranford , n . j . ), as the carrier . liquid pharmaceutically administerable compositions can , for example , be prepared by dissolving , dispersing , etc . an active compound as defined above and optional pharmaceutical adjuvants in a excipient , such as , for example , water , saline , aqueous dextrose , glycerol , ethanol , and the like , to thereby form a solution or suspension . if desired , the pharmaceutical composition to be administered may also contain minor amounts of inert auxiliary substances such as wetting or emulsifying agents , ph buffering agents and the like , for example , sodium acetate , sorbitan monolaurate , triethanolamine sodium acetate , triethanolamine oleate , etc . actual methods of preparing such dosage forms are known , or will be apparent , to those skilled in this art ; for example , see remington : the science and practice of pharmacy , ed . randy hendrickson , lippincott , williams & amp ; wilkins , 21 st edition ( 2005 ). the composition or formulation to be administered will , in any event , contain an effective amount of the active compound ( s ). parenteral administration is generally characterized by injection , either subcutaneously , intramuscularly or intravenously . injectables can be prepared in conventional forms , either as liquid solutions or suspensions , solid forms suitable for solution or suspension in liquid prior to injection , or as emulsions . suitable excipients are , for example , water , saline , dextrose , glycerol , ethanol or the like . in addition , if desired , the pharmaceutical compositions to be administered may also contain minor amounts of inert auxiliary substances such as wetting or emulsifying agents , ph buffering agents and the like , such as for example , sodium acetate , sorbitan monolaurate , triethanolamine oleate , etc . a more recently devised approach for parenteral administration employs the implantation of a slow - release or sustained - release system , such that a constant level of dosage is maintained . see , e . g ., u . s . pat . nos . 5 , 629 , 008 , 5 , 851 , 547 , 6 , 183 , 461 , and 3 , 710 , 795 , which are incorporated herein by reference . antineoplastic curcumin derivatives may be administered by transdermal patch ( e . g ., iontophoretic transfer ) for local or systemic application . once detectable improvement of the patient &# 39 ; s conditions has occurred , a maintenance dose is administered if necessary . subsequently , the dosage or the frequency of administration , or both , is reduced , as a function of the symptoms , to a level at which the improved condition is retained . when the symptoms have been alleviated to the desired level , treatment can cease . patients can , however , require intermittent treatment on a long - term basis upon any recurrence of the disease symptoms or as a prophylactic measure to prevent disease symptom recurrence . in particular embodiments extended release formulations are contemplated . antineoplastic curcumin derivatives are also be added to extravasated blood for transfusion to inhibit oxyradical damage to the blood cells and components during storage ; similarly , antineoplastic curcumin derivatives reduce oxyradical damage to blood cells in vivo . antineoplastic curcumin derivatives are usefully added to rinse or storage solutions for organs and tissues , such as for organ transplantation or for surgical rinses . for example , excised organs are often placed in a preservation solution prior to transplant into a recipient . inclusion of at least one antineoplastic curcumin derivatives in a preservation solution , usually at a concentration of about 0 . 01 mm to 10 mm , is useful for reducing damage due to ischemia during storage and reperfusion injury following reimplantation in the recipient . typically a antineoplastic curcumin derivatives is present in the rinse or storage solution at a concentration of about 10 microm to about 10 mm , and most usually is present at 1 mm . for example , but not to limit the invention , a suitable rinse solution comprises ringer &# 39 ; s solution ( 102 mm nacl , 4 mm kcl , 3 mm cacl 2 , 28 mm sodium lactate , ph 7 . 0 ) or ringer &# 39 ; s solution with 0 . 1 mm adenosine , and the antineoplastic curcumin derivatives at a final concentration of 1 mm . the rinse solution can further comprise additional antioxidants ( e . g ., glutathione , allopurinol ). preservation or rinse solutions containing antineoplastic curcumin derivative is used to provide enhanced storage or irrigation of organs ( e . g ., kidney , liver , pancreas , lung , fetal neural tissue , heart , vascular grafts , bone , ligament , tendon , skin ) which is believed to enhance the viability of the tissue and increase resistance to oxidative damage ( e . g ., as a consequence of ischemia / reperfusion ). 1 . cuendet , m . and pezzuto , j . m . 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