Patent Application: US-1723501-A

Abstract:
the invention relates to the preparation of novel polyamines , such as derivatives of 1 , 3 - bis -- amino ] propane and 1 , 4 , 8 , 11 - tetraazacyclotetradecane , which can be used to treat mitochondrial and degenerative diseases . accordingly , in one aspect the invention is directed to compounds of the formula : wherein r 1 , r 2 , r 3 , r 4 , r 5 and r 6 may be the same or different and are hydrogen , alkyl , aryl , cycloalkyl , amino acid , glutathione , urate , ascorbate , estrogen , dehydroepiandrosterone , redox stabilizing substituents , a quinone , glutamate , succinate , — n n ] nh 2 — wherein n = 3 - 6 and x = nitrogen , sulfur , phosporous or carbon , or heterocycle wherein r 1 to r 6 taken together are — n — wherein n = 3 - 6 and x = nitrogen , sulfur , phosporous or carbon . m , n , and p may be the same or different and are bridging groups of variable length from 3 - 12 carbons . x 1 and x 2 may be the same or different and are nitrogen , sulfur , phosporous or carbon .

Description:
among the reasons for the selection of compounds to be used for these formulations are the results of a series of calculations using heats of formations of the molecules . the relative stabilities of the compounds were determined in order to predict which would lead to the most stable metal complexes when they react with metals such as copper , cobalt , iron , zinc , cadmium , manganese and chromium these metals are of particular interest due to their importance in neurological and other diseases . heats of formation ( δh °) are calculated by looking at the formation of a compound from its constituent atoms . the lower the heat of formation , the more stable is the compound . the assumption in this computational work is that the calculated heats of formation for the complexes will correlate with the ability of the organic compound to complex with metal ions in biological systems . the more strongly the binding occurs , the more likely it is that the organic molecule will interact with the metal ion of choice . there are other factors that enter into the actual binding ability of the organic molecules , but heats of formation help suggest how different organic molecules might behave . by varying the organic molecules , the heats of formation for the complexes can be compared and correlations between the stability of the complexes and the structure of the complexes can be made . the relative stabilities of a representative survey of organic compounds is shown in table i while the heats of formation for the metal complexes are shown in tables ii - viii . table i heats of formation of organic compounds compound δh 0 ( kcal / mol ) 2 , 3 , 2 - tetramine − 18 . 24 2 , 2 , 2 - tetramine − 17 . 09 3 , 3 , 3 - tetramine − 32 . 70 2 , 3 , 2 - methylated on n1 / n4 − 13 . 81 2 , 3 , 2 - methylated on n2 / n3 − 10 . 35 2 , 3 , 2 - piperidine − 32 . 47 2 , 3 , 2 - piperizine 4 . 33 2 , 3 , 2 - tetra sulfur − 26 . 25 cyclam − 15 . 65 cyclam - methylated 18 . 73 cyclam - adamantane − 40 . 02 [ 0130 ] table ii heats of formation of copper complexes compound δh 0 ( kcal / mol ) cu 2 , 3 , 2 - tetramine 244 . 10 cu 2 , 2 , 2 - tetramine 252 . 36 cu 3 , 3 , 3 - tetramine 224 . 16 cu 2 , 3 , 2 - methylated on n1 / n4 243 . 98 cu 2 , 3 , 2 - methylated on n2 / n3 241 . 42 cu 2 , 3 , 2 - isopropyl on n1 / n4 207 . 69 cu 2 , 3 , 2 - isopropyl on n2 / n3 250 . 17 cu 2 , 3 , 2 - dibenzyl on n2 / n3 314 . 08 cu 2 , 3 , 2 - tetramethyl 273 . 85 cu 2 , 3 , 2 - tetraisopropyl 229 . 83 cu 2 , 3 , 2 - benzylated 380 . 10 cu 2 , 3 , 2 - piperidine 255 . 10 cu 2 , 3 , 2 - piperizine 288 . 68 cu 2 , 3 , 2 - adamantane 269 . 53 cu 2 , 3 , 2 - methyls on carbons 5 / 7 227 . 45 cu 2 , 3 , 2 - tetra sulfur 210 . 42 cu cyclam 260 . 20 cu cyclam - methylated 298 . 97 cu cyclam - benzylated 405 . 60 cu cyclam - adamantane 254 . 55 cu cyclam - isopropyl 271 . 59 cu cyclam - s4 207 . 15 cu cyclen 285 . 10 cu cyclam 3 , 3 , 3 245 . 28 [ 0131 ] table iii heats of formation of iron complexes compound δh 0 ( kcal / mol ) fe 2 , 3 , 2 12 . 16 fe 2 , 2 , 2 37 . 16 fe 3 , 3 , 3 − 1 . 39 fe 2 , 3 , 2 - methylated on n1 / n4 − 8 . 19 fe 2 , 3 , 2 - piperidine − 54 . 23 fe 2 , 3 , 2 - piperizine − 18 . 51 fe 2 , 3 , 2 - adamantane − 19 . 16 fe 2 , 3 , 2 - methyls on carbons 5 / 7 7 . 99 fe 2 , 3 , 2 - tetra sulfur 87 . 39 fe cyclam − 5 . 75 fe cyclam - methylated − 69 . 53 fe cyclam - adamantane − 92 . 82 fe cyclam - isopropyl − 83 . 02 fe cyclam - s4 137 . 13 fe cyclen 17 . 76 fe cyclam 3 , 3 , 3 − 31 . 73 [ 0132 ] table iv heats of formation of zinc complexes compound δh 0 ( kcal / mol ) zn 2 , 3 , 2 355 . 75 zn 2 , 2 , 2 352 . 45 zn 3 , 3 , 3 328 . 73 zn 2 , 3 , 2 - methylated on n1 / n4 336 . 55 zn 2 , 3 , 2 - isopropyl on n1 / n4 316 . 18 zn 2 , 3 , 2 - isopropyl on n2 / n3 330 . 81 zn 2 , 3 , 2 - tetramethyl 351 . 00 zn 2 , 3 , 2 - benzlyated 478 . 96 zn 2 , 3 , 2 - piperizine 351 . 70 zn 2 , 3 , 2 - methyls on carbons 5 / 7 342 . 21 zn 2 , 3 , 2 - tetra sulfur 329 . 15 zn cyclam 358 . 25 zn cyclam - methylated 388 . 64 zn cyclam - benzylated 485 . 39 zn cyclam - adamantane 347 . 52 zn cyclam - isopropyl 330 . 81 zn cyclam - s4 339 . 04 zn cyclam 3 , 3 , 3 351 . 89 [ 0133 ] table v heats of formation of manganese complexes compound δh 0 ( kcal / mol ) mn 2 , 3 , 2 266 . 79 mn 2 , 2 , 2 235 . 44 mn 3 , 3 , 3 194 . 42 mn 2 , 3 , 2 - tetra sulfur 264 . 50 mn cyclam 215 . 97 mn cyclam - methylated 198 . 40 mn cyclam - s4 248 . 57 [ 0134 ] table vi heats of formation of cobalt complexes compound δh 0 ( kcal / mol ) co 2 , 3 , 2 − 1250 . 81 co 2 , 2 , 2 − 1236 . 41 co 3 , 3 , 3 − 1265 . 92 co 2 , 3 , 2 - methylated on n1 / n4 − 1269 . 13 co 2 , 3 , 2 - piperidine − 1300 . 69 co 2 , 3 , 2 - adamantane − 1250 . 92 co 2 , 3 , 2 - methyls on carbons 5 / 7 − 1268 . 45 co 2 , 3 , 2 - tetra sulfur − 1258 . 52 co cyclam − 1187 . 9 co cyclam - methylated − 1265 . 64 co cyclam - isopropyl co cyclam - s4 − 1265 . 56 [ 0135 ] table vii heats of formation of cadmium complexes compound δh 0 ( kcal / mol ) cd 2 , 3 , 2 393 . 21 cd 2 , 2 , 2 401 . 00 cd 3 , 3 , 3 382 . 04 cd 2 , 3 , 2 - isopropyl on n1 / n4 366 . 86 cd 2 , 3 , 2 - isopropyl on n2 / n3 376 . 40 cd 2 , 3 , 2 - piperidine 374 . 06 cd 2 , 3 , 2 - adamantane 354 . 51 cd 2 , 3 , 2 - tetra sulfur 357 . 79 cd cyclam 411 . 95 cd cyclam - isopropyl 376 . 40 cd cyclam - s4 356 . 13 [ 0136 ] table viii heats of formation of chromium complexes compound δh 0 ( kcal / mol ) cr 2 , 3 , 2 398 . 73 cr 2 , 3 , 2 - isopropyl on n1 / n4 379 . 87 cr 2 , 3 , 2 - piperidine 403 . 22 cr cyclam 399 . 99 cr cyclam - isopropyl 430 . 05 this tabular data can be analyzed by comparing the various structural features of the molecules as in examples 19 to 24 below . there are numerous compounds described in the invention but in general , the invention compounds are obtained by converting the starting di - or tetramine of the formula : a variety of reactions were used to prepare the compounds . compound 1 was prepared via a nucleophilic substitution reaction followed by conversion of the free amine to its hcl salt . the amine acts as the nucleophile in displacing the di - alkyl halide , a reaction of general utility . compound 2 also involved a nucleophilic substitution reaction , this time done in basic solution with a protection / deprotection sequence also involved in the synthesis . the use of acetyl groups to protect the amines could be exploited to alkylate tetramines . compounds 3 and 4 were synthesized by having 1 , 3 - diaminopropane serve as the nucleophile with displacement occurring on the a carbon to the piperidine or piperizine . the position is particularly susceptible to nucleophilic attack in molecules of this type . other heterocyclic moieties could be added in similar fashion starting from the appropriate β - ethyl heterocycle in this fashion . the theme of using amines to attack alkyl halides in nucleophilic substitution reactions was also exploited in the formation of 6 and 14 . the 1 - position in the bromoadamantane is much more reactive than expected and so the adamantane moiety could be added to numerous amines in this fashion . compound 7 involves a novel preparation of an existing compound as we reversed the nature of the nucleophile and the electrophile to lead to high yields of the product . in the case described , the 1 , 3 - substituted portion is the alkyl halide while the amine is used to form the terminal nitrogens . compounds 8 and 9 were prepared using substitution reactions rather than the previously reported ( for 8 ) imine formation reaction followed by a reduction . the α - carbon on the pyridine ring is extremely reactive due to resonance stabilization of any intermediate formed . this is a general approach and numerous other aromatic heterocycles could be added in this fashion . we have continued the take advantage of nucleophilic substitution reactions to prepare 11 with the electrophilic 2 - chloroethylamine . once again , this scheme illustrates the extreme reactivity of the β - carbon on amines when used to do substitution reactions . 2 - chloroethylamine could be added to many amines to form other tetraamines including many that are not symmetrical . compound 13 was prepared in a fashion similar to that used to synthesize 3 . the starting amine here is the macrocyclic cyclam . this reaction illustrates the power of using macrocycles in these schemes as the substitution led cleanly to the tetramine . compound 15 was prepared under strongly basic conditions using the anion of the cyclam as the nucleophile attacking an alkyl halide . certainly any primary alkyl halide could be substituted in this sequence . phosphine also can be incorporated into these molecules as been done for compound 16 . this molecule was prepared via the use of an addition / reduction sequence starting with an amine . this reaction could be used on any number of amines covered in this patent . compounds 1 - 16 can be used to make metal complexes . examples include the preparation of the vanadium complex 17 where 2 , 3 , 2 - tetramine is converted into its vanadium complex by treatment with a vanadium precursor . compound 18 was prepared in similar fashion starting with a chromium precursor . any number of metal complexes such as copper , cobalt , iron , manganese could be prepared from any of the compounds 1 - 16 by treating these compounds with the appropriate metal salt followed by isolation of the metal complex . compound 16 is a novel compound that incorporates phosphorous into the molecule in the place of two of the nitrogens . this internal substitution is done via an addition / reduction process and could be changed to include oxygen or other donors if desired . the preparation of the vanadium ( iv ) complex 17 occurs in straightforward fashion by mixing a vanadium precursor with the 2 , 3 , 2 - tetramine and isolating the complex . compound 18 is prepared in similar fashion using a chromium precursor . ( where a and b equal hydrogen or alkyl and m , n , and p may be the same or different ) to the corresponding n - substituted compound by treating these compounds with an alkyl halide under conditions that affect the conversion . there are also instances where some forms of 2 , 3 , 2 - tetramine need to be protected prior to adding on the various groups as is true for 2 and 6 . for the cyclam type molecules , nucleophilic substitution reactions were generally used to prepare the compounds ( compounds 10 - 15 ). compounds 2 , 3 , 4 , 6 , 9 , 13 , and 14 are prepared in this invention for the first time . of the known compounds described here , most ( 5 , 7 , 8 , 10 , 11 , 12 , and 15 ) have been prepared in a fashion significantly different than that found in the literature . in addition , many of the compounds covered in the invention but not used as examples have not been prepared elsewhere and will be prepared as part of this invention for the first time . the base compound 1 , 3 - bis -[( 2 ′- aminoethyl )- amino ] propane , 1 , was prepared in a fashion similar to that found in the literature ( van alphen , j . rec . trav . chim . 55 , 835 , 1936 ). however , in the original literature preparation , an impurity was found that significantly reduced the purity of the product . subsequent preparations have taken a number of tacks to lead to a pure product . we have eliminated this problem by developing a purification strategy that works through the hydrochloride salt that leads to a single product of very high purity . in order to prepare the novel compound 2 , ([ 2 -( methylethylamino ) ethyl ]( 3 -{[ 2 -( methylamino ) ethyl ] amino } propyl ) amine ), protection of the more reactive terminal nitrogens 1 and 4 as their acetyl derivatives was performed prior to methylation of nitrogens 2 and 3 . deprotection of the acetyl groups with koh led to the desired compound . compounds 3 (( 2 - piperidylethyl )-{ 3 -[( 2 - piperidylethyl ) amino ] propyl } amine ) and 4 (( 2 - piperazinylethyl )-{ 3 -[( 2 - piperazinylethyl ) amino ] propyl } amine ) were made in similar fashion through the nucleophilic substitution reaction of 1 , 3 - diaminopropane with 1 -( 2 - chloroethyl ) piperidine ( to give 3 ) or 1 -( 2 - chloroethyl ) piperizine ( to give 4 ). numerous other tetramines are accessible through similar reactions where the nature of the amine is varied . ( 2 - aminoethyl ){ 3 -[( 2 - aminoethyl ) methylamino ] propyl } methylamine , 5 , is a known compound ( barefield , e . k ., wagner , f ., hodges , k . d ., inorg . chem ., 15 , 1370 - 1377 , 1976 ) but was prepared in a novel way here . the physical properties of our compound do not match those found in the literature but the nmr data in the literature in no way fits the structure of the compound while our nmr and mass spectral data are consistent with the formulation . compound 6 , [ 2 -( bicyclo [ 3 . 3 . 1 ] non - 3 - ylamino ) ethyl ]( 3 -{ 2 -( bicyclo [ 3 . 3 . 1 ] non - 3 - ylamino ) ethyl ] amino } propyl ) amine and compound 14 , 1 , 4 , 8 , 11 ]- tetraaza - 1 , 4 , 8 , 11 - tetrabicyclo [ 3 . 3 . 1 ] non - 3 - ylcyclotetradecane were prepared in a similar way . direct amination ( krumkalns , e . v ., pfeifer , w ., jour . med . chem ., 11 , 1103 , 1968 ) of 1 - bromoadamantane with the appropriate amine led to the pure products . compound 7 , ( 2 - aminoethyl ) { 3 -[( 2 - aminoethyl ) amino ]- 1 - methylbutyl } amine , has been prepared previously through the reaction of n , n ′- bis ( chloroacetyl )- 2 , 4 - pentanediamine with methylamine ( mikukami , f ., bull . chem . soc ., japn ., 48 , 1205 - 1212 , 1975 ). we have prepared the compound in a completely different way by following a similar procedure as that used for compound 1 . ( 2 - pyridylmethyl ){ 3 -[( 2 - pyridylmethyl ) amino ] propyl } amine , 8 , is a known compound but was prepared by a completely different procedure than that found in the literature . instead of making this compound via the two step process of a schiff base condensation of pyridine - 2 - carboxaldehyde with 1 , 3 - propanediamine followed by a reduction reaction ( fischer , h . r ., hodgson , d . j ., michelsen , k ., pedersen , e ., inorg . chim . acta , 88 , 143 - 150 , 1984 ), we prepared it directly through a nucleophilic substitution of picolyl chloride with 1 , 3 - propanediamine . this results in higher overall yields since we employ a one step process . the preparation of the novel compound 9 , methyl ( 3 -[ methyl ( 2 - pyridylmethyl ) amino ] propyl }( 2 - pyridylmethyl ) amine , was performed in a fashion similar to that used to synthesize 8 . the product was of high purity and its analytical data matched the desired structure . compound 10 , [ 2 -( dimethylamino ) ethyl ]( 3 -{[ 2 -( dimethylamino ) ethyl ] methylamino } propyl ) methylamin , was prepared by the literature procedure ( golub , g ., cohen , h ., meyerstein , d ., j . chem . soc ., chem . commun ., 397 - 398 , 1992 .) and the synthesis resulted in a high yield of a pure product . although the literature did not supply physical data for the compound , our results are consistent with the structure of the compound . 2 -[ 3 -( 2 - aminoethylthio ) propylthio ] ethylamine , 11 , is a known compound ( hay , r . w ., gidney , p . m ., lawrance , g . a ., j . chem . soc ., dalton , 779 - 784 , 1975 ) but was prepared by a novel procedure here . nucleophilic substitution of 1 , 3 - dimercaptopropane with 2 - chloroethyamine resulted in formation of 11 that had physical properties similar to those reported . the preparation of 1 , 4 , 8 , 11 - tetraaza - 1 , 4 , 8 , 11 - tetramethylcyclotetradecane , 12 , was performed in a manner similar to that found in the literature ( barefield , k ., wagner , f ., inorg . chem ., 12 , 2435 - 2436 , 1973 ). the analytical data for this compound matches that found previously . compound 13 , 1 , 4 , 8 , 11 - tetraaza - 1 , 4 , 8 , 11 - tetra ( 2 - piperidylethyl ) cyclotetradecane , was prepared from cyclam through a nucleophilic substitution in a fashion similar to the one we use to prepare compound 4 . many other derivatives of cyclam could be prepared using this type of reaction . 1 , 4 , 8 , 11 - tetraaza - 1 , 4 , 8 , 11 - tetraethylcyclotetradecane , 15 , is a known compound ( oberholzer , m . r ., neuburger , m ., zehnder , m ., kaden , t . a ., helv . chim . acta , 78 , 505 , 1995 ) but was prepared here by a modified procedure using similar reagents but with different reactions conditions and purification steps . compound 16 is a novel compound that incorporates phosphorous into the molecule in the place of the two nitrogens . this internal substitution is done via addition / reduction process and could be changed to include oxygen or other donors if desired . the preparation of the vanadium ( iv ) complex 17 occurs in straightforward fashion by mixing a vanadium precursor with the 2 , 3 , 2 - tetramine and isolating the complex . compound 18 is prepared in similar fashion using a chromium precursor . compounds 1 to 18 correspond with fig1 to 18 and examples 1 to 18 . the following examples are intended to illustrate but not to limit the number of compounds within the scope of the invention . a mixture of 15 g of 1 , 3 - dibromopropane and 50 ml of absolute etoh was added slowly to 25 g of 1 , 2 - diaminoethane hydrate . the mixture immediately became warm . it was then heated to 50 ° c . for 1 hour , 20 g of kcl added and the heating continued for 30 minutes . the mixture was filtered from the kbr and distilled at reduced pressure . the residue formed two layers that were separated . the top layer was distilled and the product had a b . p . of 115 - 116 ° c ., ( 1 mm ). the compound was further purified by converting the free amine to its tetrahydrochloride salt by addition of 6m . hcl . the melting point of the salt was 278 - 283 ° c . it was converted back to its free amine by treatment with nh 4 oh . mass spectral analysis showed a m / e = 160 . 1 h nmr ( cdcl 3 ): δ 1 . 26 ( 6h , s ), 1 . 60 ( 2h , quin ), 2 . 60 ( 4h , t ), 2 . 71 ( 8h , t ). a mixture of 0 . 37 g ( 0 . 0155 mol ) of magnesium turnings , 5 . 0 g ( 0 . 031 mol ) of 1 , 3 - bis -[( 2 ′- aminoethyl )- amino ] propane , 50 ml of benzene and 3 . 76 g ( 0 . 047 mol ) of acetyl chloride is heated under reflux for 2 h . the reaction mixture is cooled in an ice bath and the liquid portion is decanted into a separatory funnel . the residue in the flask is washed twice with 50 ml portions of ether , and the ethereal solution is poured over ice . the ether - water mixture is then added to the benzene solution in the separatory funnel and separated . the organic phase is washed once with 50 ml of 5 % sodium bicarbonate and once with water and dried over cacl 2 . the solution is filtered and used without further purification . a magnetically stirred mixture of 5 . 0 g ( 8 . 67 mmol ) of the acetylated 2 , 3 , 2 - tetramine prepared above and 2 . 0 g ( 80 . 7 mmol ) of sodium hydride in 75 ml of n , n - dimethylformamide was heated at 60 ° c . under n 2 for 3 h . the resultant mixture was treated with 19 . 8 g ( 0 . 164 mol ) of iodomethane and stirred at 50 ° c . after 24 h at 50 ° c ., the reaction was quenched by the addition of 95 % etoh . volatiles were removed at reduced pressure and 50 ml of water was added to the residue . the product was extracted with three 50 ml portions of chloroform . the combined organic extracts were successively washed with water and nacl , dried over anhydrous sodium sulfate , and concentrated to give 6 . 3 g of yellowish oil . the oil was purified by flash chromatography with 1 : 4 hexanes - ethyl acetate as the eluent to give acetylated [ 2 -( methylethylamino ) ethyl ]( 3 -{[ 2 -( methylamino ) ethyl ] amino } propyl ) amine as an oil . a stirred solution of 3 . 0 g ( 4 . 54 mmol ) of acetylated [ 2 -( methylethylamino ) ethyl ]( 3 -{[ 2 -( methylamino ) ethyl ] amino } propyl ) amine , 10 . 0 g ( 0 . 178 mol ) of potassium hydroxide , 70 ml of methanol and 15 ml of water was heated under reflux for 24 h . the methanol was removed at reduced pressure and the product was extracted into 2 × 50 ml of ether . the combined extracts were washed with nacl , dried over sodium sulfate and concentrated under vacuum . the crude mixture was purified by flash chromatography with 5 : 1 hexanes - ethyl acetate as the eluent . after evaporation of the solvents , 0 . 79 g ( 71 %) of the product was obtained as a colorless oil . mass spectral analysis showed a m / e = 244 . 1 h nmr ( cdcl 3 ): δ1 . 03 ( 12 h , d ), 1 . 26 ( 6h , s ), 1 . 60 ( 2h , quin ), 2 . 60 ( 4h , t ), 2 . 71 ( 8h , t ), 3 . 23 ( 2h , m ). to a mixture of 0 . 5 g ( 6 . 75 mmol ) of 1 , 3 - diaminopropane and 50 ml of absolute etoh was added 1 . 62 g ( 40 . 5 mmol ) of naoh . to this solution was added dropwise 2 . 48 g ( 13 . 45 mmol ) of 1 -( 2 - chloroethyl ) piperidine in 50 ml of etoh over 30 min . the solution was allowed to stir for 24 h . the solvent was evaporated and the residue was extracted with 2 × 50 ml of ch 2 cl 2 , dried over na 2 so 4 , and evaporated to dryness . the compound was purified by converting it to its hydrochloride salt by addition of hcl . the melting point of the salt was & gt ; 300 ° c . it was converted back to its free amine by treatment with nh 4 oh . the resultant oil ( 1 . 04 g , 52 %) was analyzed . mass spectral analysis showed a m / e = 297 ( m + + 1 ). 1 h nmr ( cdcl 3 ): δ 1 . 40 - 1 . 82 ( 14h , m ), 2 . 40 - 2 . 58 ( 14h , quin ), 2 . 60 - 2 . 72 ( 10h , m ). to a mixture of 0 . 5 g ( 6 . 75 mmol ) of 1 , 3 - diaminopropane and 50 ml of absolute etoh was added 1 . 62 g ( 40 . 5 mmol ) of naoh . to this solution was added dropwise 2 . 48 g ( 13 . 45 mmol ) of 1 -( 2 - chloroethyl ) piperizine in 50 ml of etoh over 30 min . the solution was allowed to stir for 24 h . the solvent was evaporated and the residue was extracted with 2 × 50 ml of ch 2 cl 2 , dried over na 2 so 4 , and evaporated to dryness . the compound was purified by converting it to its hydrochloride salt by addition of hcl . the melting point of the salt was & gt ; 300 ° c . it was converted back to its free amine by treatment with nh 4 oh . the resultant oil ( 0 . 82 g , 41 %) was analyzed . mass spectral analysis showed a m / e = 299 ( m + 1 ). 1 h nmr ( cdcl 3 ): δ1 . 40 - 1 . 82 ( 10h , m ), 2 . 42 - 2 . 55 ( 14h , quin ), 2 . 58 - 2 . 77 ( 10h , m ). to a solution of 1 . 0 g ( 0 . 0128 mol ) of n , n - dimethyl - 1 , 3 - propanediamine in 50 ml of etoh was added a solution of 2 . 96 g ( 25 . 6 mmol ) of 2 - chloroethylamine in 50 ml of etoh dropwise over 40 min . the solution was stirred at room temperature for 20 h . the solvent was evaporated and the residue was extracted with 2 × 50 ml of ch 2 cl 2 , dried over na 2 so 4 , and evaporated to dryness . the resultant oil ( 1 . 52 g , 63 %) was distilled ( bp 145 - 148 , 1 mm ). mass spectral analysis showed a m / e = 189 ( m +. + 1 ). 1 h nmr ( cdcl 3 ): δ 1 . 20 ( 4h , s ), 1 . 60 ( 2h , quin ), 2 . 29 ( 6h , s ) 2 . 57 ( 4h , t ), 2 . 73 ( 8h , t ). a mixture of 0 . 06 mol of 1 - bromoadamantane and 0 . 30 mol of acetylated 2 , 3 , 2 - tetramine were heated in a stainless steel bomb at 215 ° c . for 6 h . the product was poured into a mixture of 250 ml of 2 n hcl and 200 ml of ether . the aqueous layer was separated and made alkaline with 200 ml of 50 % aqueous naoh . the mixture was extracted with ether and the extract dried over k 2 co 3 and evaporated to give an oil ( 1 . 32 g , 33 %). mass spectral analysis showed a m / e = 406 . 1 h nmr ( cdcl 3 ): δ 1 . 24 - 1 . 30 ( 4h , s ), 1 . 50 - 2 . 12 ( 32h , m ), 2 . 62 ( 4h , t ), 2 . 75 ( 8h , t ). a mixture of 2 . 34 g ( 10 mmol ) of 2 , 4 - dibromopentane and 50 ml of absolute etoh was added slowly to 1 . 2 g ( 20 mmol ) of 1 , 2 - diaminoethane hydrate . the mixture immediately became warm . it was then heated to 50 ° c . for 1 hour , 10 g of kcl added and the heating continued for 30 minutes . the mixture was filtered from the kbr and distilled at reduced pressure . the compound was purified by converting it to its hydrochloride salt by addition of hcl . the melting point of the salt was & gt ; 300 ° c . it was converted back to its free amine by treatment with nh 4 oh . mass spectral analysis of the oil (( 1 . 28 g , 68 %) showed a m / e = 188 . 1 h nmr ( cdcl 3 ): δ 1 . 12 ( 6h , d ), 1 . 30 - 1 . 37 ( 6h , s ), 1 . 60 ( 2h , t ), 2 . 60 ( 2h , m ), 2 . 74 ( 8h , t ). to a solution of 1 . 0 g ( 0 . 0135 mol ) of 1 , 3 - diaminopropane in 50 ml of etoh was added a solution of 4 . 43 g ( 27 . 0 mmol ) of 2 - chloromethylpyridine in 25 ml of water . 10 % naoh was added until the ph reached 9 . the solution was stirred at room temperature and naoh was added to keep the ph at 8 - 9 over 3 days . the solvent was evaporated and the residue was extracted with 3 × 30 ml of ch 2 cl 2 , dried over na 2 so 4 , and evaporated to dryness . the resultant oil ( 2 . 63 g , 76 %) was analyzed . mass spectral analysis showed a m / e = 257 ( m +. + 1 ). 1 hnmr ( cdcl 3 ): δ 1 . 60 ( 2h , quin ), 2 . 62 ( 4h , t ), 4 . 06 ( 4h , s ), 7 . 15 - 7 . 80 ( 6h , m ), 8 . 44 - 8 . 63 ( 2h , d ). to a solution of 1 . 0 g ( 0 . 0128 mol ) of n , n - dimethyl - 1 , 3 - propanediamine in 50 ml of etoh was added a solution of 4 . 19 g ( 25 . 6 mmol ) of 2 - chloromethylpyridine in 25 ml of water . 10 % naoh was added until the ph reached 9 . the solution was stirred at room temperature and naoh was added to keep the ph at 8 - 9 over 3 days . the solvent was evaporated and the residue was extracted with 3 × 30 ml of ch 2 cl 2 , dried over na 2 so 4 , and evaporated to dryness . the resultant oil ( 2 . 69 g , 74 %) was analyzed . mass spectral analysis showed a m / e = 285 ( m +. + 1 ). 1 hn ( cdcl 3 ): δ 1 . 55 ( 2h , quin ), 2 . 30 ( 6h , s ), 2 . 58 ( 4h , t ), 3 . 75 ( 4h , s ), 7 . 07 - 7 . 85 ( 6h , m ), 8 . 50 - 8 . 62 ( 2h , d ). a solution of 1 . 0 g ( 6 . 23 mmol ) of 2 , 3 , 2 - tetramine , 10 ml of formic acid , 10 ml of 37 % formaldehyde and 1 ml of water was refluxed for 20 h . the solvent was evaporated , the solution was made basic with 3 m naoh , and was extracted with 3 × 30 ml of ch 2 cl 2 , dried over na 2 so 4 , and evaporated to dryness . the resultant oil ( 0 . 88 g , 58 %) was analyzed . mass spectral analysis showed a m / e = 244 ( m +. + 1 ). 1 h nmr ( cdcl 3 ): δ 1 . 62 ( 2h , quin ), 2 . 24 - 2 . 30 ( 18h , s ), 2 . 60 ( 4h , t ), 2 . 71 - 2 . 75 ( 8h , t ). to a solution of 1 . 0 g ( 0 . 0128 mol ) of 1 , 3 - dimercaptopropane in 50 ml of etoh was added a solution of 1 . 48 g of naoh in 10 ml of water . to the solution was added 214 g ( 18 . 48 mmol ) of 2 - chloroethylamine in 25 ml of etoh . the solution was refluxed for 8 h . the solvent was evaporated and the residue was extracted with 3 × 25 ml of ch 2 cl 2 , dried over na 2 so 4 , and evaporated to dryness . the resultant oil was distilled at 165 - 173 ( 1 mm ) to give 1 . 81 g , 73 %. mass spectral analysis showed a m / e = 194 . 1 h nmr ( cdcl 3 ): δ 1 . 48 ( 4h , s ), 2 . 34 - 2 . 86 ( 14h , m ). a solution consisting of 1 . 0 g ( 0 . 005 mol ) of cyclam , 5 . 3 ml of formic acid , 4 . 5 ml of 37 % formaldehyde and 1 ml of water was refluxed for 18 h . the reaction mixture was transferred with 6 ml of water to a beaker and cooled to 5 ° c . in an ice bath . while stirring , a concentrated solution of naoh was slowly added to ph & gt ; 12 , the temperature was kept below 25 ° c . during the addition and then extracted with 3 × 30 ml of ch 2 cl 2 ., dried over na 2 so 4 , and evaporated to dryness . the resultant oil ( 0 . 98 g , 71 %) was analyzed . mass spectral analysis showed a m / e = 256 . 1 h nmr ( cdcl 3 ): δ 1 . 68 ( 4h , quin ), 2 . 22 ( 12h , s ), 2 . 64 ( 8h , t ), 2 . 75 ( 8h , t ). to a solution of 0 . 5 g ( 2 . 5 mmol ) of cyclam in 25 ml of ch 2 cl 2 was added a solution of 0 . 8 g of naoh in 25 ml of water . a solution of 1 . 83 g ( 9 . 98 mmol ) of1 -( 2 - chloroethyl ) piperidine in 25 ml of ch 2 cl 2 was added dropwise at room temperature . the stirring was continued for 24 h . the solvent was evaporated and the residue was extracted with 3 × 50 ml of ch 2 cl 2 , dried over na 2 so 4 , and evaporated to dryness . the resultant oil ( 0 . 725 g , 45 %) was analyzed . mass spectral analysis showed a m / e = 646 ( m +. + 1 ). 1 h nmr ( cdcl 3 ): δ 1 . 28 ( 8h , q ), 1 . 46 - 1 . 72 ( 24h , m ), 1 . 72 ( 4h , m ), 2 . 42 - 2 . 80 ( 24h , m ), 2 . 64 ( 8h , t ), 2 . 75 ( 8h , t ). to 0 . 5 g ( 2 . 5 mmol ) of cyclam in 50 ml of etoh was added 2 . 15 g ( 10 . 0 mmol ) of 1 - bromoadamantane in 50 ml of etoh dropwise over 30 min . the solution was heated to reflux and heated for 20 h . the solution was evaporated under reduced pressure , extracted with 3 × 35 ml of ch 2 cl 2 ., dried over na 2 so 4 , and evaporated to dryness . the resultant oil ( 0 . 53 g , 31 %) was analyzed . mass spectral analysis showed a m / e = 690 ( m + + 1 ). 1 h nmr ( cdcl 3 ): δ 1 . 24 - 1 . 58 ( 56h , m ), 1 . 66 ( 4h , quin ), 2 . 62 ( 8h , t ), 2 . 70 ( 8h , t ). to a stirred solution of 1 . 0 g ( 5 . 0 mmol ) of cyclam in 50 ml of dmf was added 4 . 0 g ( 0 . 1 mol ) of nah in small portions . the solution was heated under nitrogen at 60 ° c . for 3 h . 3 . 12 g ( 20 mmol ) of iodoethane was added in one portion . the solution was heated at 60 ° c . for 18 h . the reaction was quenched with 95 % etoh extracted with 3 × 35 ml of ch 2 cl 2 ., dried over na 2 so 4 , and evaporated to dryness . the resultant oil was purified by flash chromatography using ethyl acteate / meoh . mass spectral analysis of the oil ( 0 . 72 g , 46 %) showed a m / e = 312 . 1 h nmr ( cdcl 3 ): δ 1 . 38 ( 12h , t ), 2 . 16 ( 8h , q ), 3 . 38 ( 4h , quin ), 3 . 54 ( 8h , t ), 3 . 80 ( 8h , t ). propylenediamine ( 4 . 0 g ) was dissolved in 200 ml of ethanol . to the solution was added 9 . 4 g of dimethylvinylphosphine sulfide and the mixture was heated at reflux for 72 h . the solvent was evaporated under reduced pressure and the residue dissolved in 400 ml of chloroform and washed with 50 ml of 2 m naoh and dried over mgso 4 . the solvent was removed under reduced pressure to give an oil that was crystallized from ethyl acetate to give 6 . 8 g ( 51 %) of the pure product . . to a suspension of lialh4 ( 1 . 2 g ) in 125 ml of dry dioxane was added n , n ′-( 2 ′- dimethylphosphinothioethyl )- propylenediamine ( prepared as above ). the mixture was refluxed for 36 h . the mixture was cooled , dioxane / water added , 3 ml of 2 m naoh added and then the solution was filtered to give the pure phosphine . 1 h nmr ( cdcl 3 ): δ 1 . 64 ( 2h , quin ), 2 . 10 ( 12h , s ), 2 . 57 ( 4h , t ), 2 . 55 - 2 . 80 ( 8 , m ). to 1 . 0 g ( 0 . 624 mol ) of 2 , 3 , 2 tetramine in 20 ml of etoh was added 0 . 073 g ( 0 . 0624 mol ) of vanadylacetylacetonate in 20 ml of etoh . the solution was refluxed for 30 min and cooled to room temperature . overnight a red - brown solid precipitated . the complex is formulated as being [ vo ( 2 , 3 , 2 - tetramine ) acac ]. to 1 . 0 g ( 0 . 0624 mol ) of 2 , 3 , 2 - tetramine in 20 ml of etoh was added 0 . 245 g ( 0 . 0624 mol ) of chromium ( iii ) nitrate in 20 ml . of etoh . the solution was refluxed for 30 min and cooled to room temperature . overnight a solid precipitated . the complex is formulated as being [ cr ( 2 , 3 , 2 - tetramine )( no 3 ) 2 ] no 3 . referring to the heats of formation , the first modification to consider is how the heats of formation are affected by changing the metal ion . the data is quite clear here with the relative stabilities following the pattern : co & gt ; fe & gt ; mn & gt ; cu & gt ; zn & gt ; cd . occasionally the cu complexes are more stable than the mn but otherwise the trend holds consistently from one set of complexes to another . the trend in changes in stability due to changes in the metal may be exploited by recognizing the affinity that the organic compounds have for various metal ions in the body . in table iii it is apparent that fe 2 , 3 , 2 - piperidine and fe 2 , 3 , 2 - adamantane have a low heat of formation which would be attractive to address the excess iron pools in neuro degenerative disease and the excess iron released into brain tissue following lysis of dead neurons post stroke , the adamantane having additional effect on the nmda receptor . similarly from tables ii and iv it is apparent that fe cyclam methylated and fe cyclam adamanatane are very stable and zn cyclam methylated and zn cyclam adamantane not unduly stable . this behavior could be useful in treating ischemic damage post myocardial infarction where iron exerts toxic redox effects and tissue zinc stores are rapidly depleted . from tables ii and v it is apparent that there are open ring molecules binding copper and manganese , cu 2 , 3 , 2 - isopropyl on n1 / n4 and mn 3 , 3 , 3 respectively are as stable as closed ring molecules . thus open ring molecules are comparable with closed ring molecules in their capacity to address free metal excess in neurodegenerative diseases and stroke . for the 2 , 3 , 2 - tetramine compounds , formation of 6 - membered rings when binding to metal ions increases the stability of the metal complexes . this can be seen when comparing the 3 , 3 , 3 - tetramine metal complexes to the corresponding 2 , 3 , 2 - tetramine and the 2 , 2 , 2 - tetramine compounds . in all cases , the 3 , 3 , 3 - tetramine complexes are more stable than their 2 , 3 , 2 - tetramine counterparts . also , it is generally true that the 2 , 3 , 2 - tetramine complexes are more stable than the 2 , 2 , 2 - tetramine complexes . this suggests that the 3 , 3 , 3 - tetramine compounds may be of considerable interest as companions to the 2 , 3 , 2 - tetramine compounds . schugar h . and coworkers ( inorg . chem ., 19 , 940 , 1980 ) have shown through stability constants that changing the size of the chelate ring has an effect on the resultant stability of the metal complex . modification of the cyclam rings so that the rings are smaller or larger also impacts the heats of formation . the cyclen complexes are less stable than the cyclam rings , a result that has been documented elsewhere . increasing the size of the ring as was done for the cyclam 3 , 3 , 3 - tetramine complexes also leads to enhanced stability compared to cyclam . these size related changes in stability influence the design of compounds for treatment of neurodegenerative disorders , stroke , glaucoma , atherosclerosis , cardiomyopathy , ischemia , optic neuropathy , peripheral neuropathy , presbycussis and cancer . along with changing the size of the rings , various alkyl groups were put on the nitrogens or carbons to see how these modifications affected the stability of the complexes . a number of generalizations can be extracted from the data . first , putting small alkyl groups on the nitrogens generally enhances their stability . this can be seen when comparing the 2 , 3 , 2 - tetramine compounds to the ones where either n1 / n4 or n2 / n3 are substituted with methyl groups . this result also holds for isopropyl groups substituted on n1 / n4 and generally for isopropyls on n2 / n3 . there is a limit to adding large groups on the nitrogens as seen by the compounds with benzyl substituents . these complexes are very much less stable than the unsubstituted 2 , 3 , 2 - tetramine complexes . the placement of alkyl groups on the carbons was only studied in a few cases , but for all of them the addition of methyls led to enhanced stability at a level comparable to that found when the methyls were placed on the nitrogens . the trends for the heats of formation of the cyclam complexes are not as consistent as those found for the 2 , 3 , 2 - tetramine complexes . for example , putting methyl groups on the nitrogens increases the stability in some cases but decreases it in others . the same is true for the complexes where isopropyl is added to the nitrogens . once again though , benzyl groups greatly decrease the stability of the complexes showing that there is an upper limit as to how bulky the substituents can be before the stability of the complexes is greatly diminished . surprisingly , the addition of adamantane to the cyclams leads to enhanced stability in all cases . adamantane is a very large group but it is able to find ways to exist so that the structure is actually quite stable . this stability of the cyclam adamantane compounds may be useful in situations such as stroke and glaucoma where nmda receptor antagonism is required . from a biopassaging standpoint the stability of the 2 , 3 , 2 - isopropyl complexes and molecules with carbon side chains attached to the ring nitrogens or carbons is valuable toward developing compounds which are more lipophilic and thus have better passage across the gastrointestinal tract , blood brain barrier and blood retinal barrier , this being important in the treatment of parkinson &# 39 ; s , alzheimer &# 39 ; s , lou gehrig &# 39 ; s , binswanger &# 39 ; s , lewy body diseases , olivopontine cerebellar degeneration , stroke , glaucoma and optic neuropathy described herein . another important result is the one shown by changing n1 / n4 into piperidine or piperizine nitrogens . it should be noted that these compounds are somewhat different than the ones described above in that the piperidine groups are not added to n1 / n4 but rather n1 / n4 are replaced by the piperidine or piperizine . with the exception of the copper complexes , these complexes are more stable than the base 2 , 3 , 2 - tetramine complexes . no generalizations can be made regarding the adamantane compounds but it is noteworthy that they are not excessively unstable compared to the 2 , 3 , 2 - tetramine compounds ( indeed , the fe complex is more stable while the co one is equal in stability ) even though they are quite large and bulky . this suggests that even large , bulky alkyl groups placed on the nitrogens may not adversely affect their properties and they should be pursued . the piperidine , piperizine and adamantane derivative molecules are attractive because the terminal groups can substantially alter basicity , lipophilicity and passage through membranes , in addition to altering receptor binding properties . these derivatives may also be attractive where a selective bias towards iron removal versus stored copper removal is sought . this could be applicable to therapeutics for ischemia post myocardial infarction , atherosclerosis and neurodegenerative diseases . further the stability of terminally substituted derivatives provides opportunity for substitution with glutathione , uric acid , ascorbic acid , taurine , estrogen , dehydroepiandrosterone , probucol , vitamin e , hydroxytoluene , carvidilol , α - lipoic acid , α - tocopherol , ubiquinone , phylloquinone , β - carotene , meanadione , glutamate , succinate , acetyl - l - carnitine , co - enzyme q , lazeroids , and polyphenolic flavonoids or homocysteine , menaquinone , idebenone , dantrolene . these specific derivatives of polyamines may be used as compounds in the treatment of , though not limited to , the following diseases : vitamin e polyamine in peripheral neuropathy , alzheimer &# 39 ; s disease , stroke and ischemia , it is also possible to replace the nitrogens with other donors such as sulfur . as shown , these complexes excepting the iron ones are considerably more stable than the nitrogen ones . sulphur containing polyamines terminally derivatized with homocysteine could be used as anti - cancer agents . replacing the nitrogens with sulfur enhances the stability of some complexes cu , zn , co ) but not in others ( fe , mn ). this result shows that it is possible to build into the organic compounds selectivity for some metal ions over others . again a sulphur containing closed ring polyamine derivatized with homocysteine could be used as an anti - cancer agent . terminal modifications and side chain additions alter pka , lipophilicity and also the metabolism of these compounds , thus changing half life in vivo . 2 , 2 , 2 - tetramine is rapidly metabolized to acetyl 2 , 2 , 2 - tetramine and rapidly excreted with a half life in vivo of only a few hours ( kodama h . et al 1997 ). this metabolism will obviously be altered considerably in terminally derivatized compounds and to some extent in molecules with side chains attached and in internally derivatized molecules . in the treatment of the diseases mentioned above a longer half life and less frequent dosing such as once daily dosing will be highly advantageous for therapeutic effect and patient compliance . the results in tables i to viii shed light on the stability of these molecules and helps direct which ones are appropriate for particular disease situations based upon metal ion selectivity and pharmacological actions and how to enhance the bioavailablility of orally or parenterally delivered drugs , and drugs crossing particular membranes such as the blood brain barrier and blood retinal barrier . partition coefficients were determined by dissolving the compound in a 1 : 1 mixture of octanol / water and shaking the solution for 12 hours . hplc was used to determine the partition coefficient . the reported values are the log of the octanol / water partition table ix oil water partition coefficients log partition coefficient compound octanol : water 2 , 2 , 2 - tetramine 1 . 6 2 , 3 , 2 - tetramine 2 . 1 2 , 3 , 2 - pyridine 2 . 7 2 , 3 , 2 - ch 3 on n1 / n4 0 . 4 cyclam - piperidine 0 . 7 octanol : water partition log partition coefficients of 2 are optimal for passage through lipid membranes and tissue barriers . molecules within a range from 0 . 5 to 4 . 0 are potential candidates for in vivo use . thus 2 , 2 , 2 - tetramine , 2 , 3 , 2 - tetramine and 2 , 3 , 2 - pyridine have optimal lipid water partitioning to facilitate their passage through the gastrointestinal barrier and the blood brain barrier . pka &# 39 ; s were determined by standard potentiometric titration methods in aqueous solution with an ionic strength of 0 . 10 at 25 ° c . values are reported as log k values of the equilibrium constant . table x pka &# 39 ; s pka ( 1 ) pka ( 2 ) pka ( 3 ) pka ( 4 ) 2 , 2 , 2 - tetramine 9 . 7 9 . 1 6 . 6 3 . 3 2 , 3 , 2 - tetramine 10 . 3 9 . 5 7 . 3 6 . 0 2 , 3 , 2 - pyridine 8 . 3 7 . 4 2 , 3 , 2 - piperidine 9 . 9 9 . 3 6 . 4 3 . 6 2 , 3 , 2 - tetramethyl 10 . 2 9 . 4 6 . 1 2 . 9 tetramethylcyclam 9 . 7 9 . 3 3 . 1 2 . 6 2 , 3 , 2 - pyridine is less basic and thus more soluble at neutral ph than some of the other amines . selection of compounds with appropriate pka &# 39 ; s for use in various diseases where low pka &# 39 ; s would be useful . selection of compounds with appropriate pka &# 39 ; s for use in various diseases where higher pkas would be useful such as in diabetes and post myocardial infarction . neurodegenerative diseases — parkinson &# 39 ; s disease , alzheimer &# 39 ; s disease , lou gehrig &# 39 ; s disease , binswanger &# 39 ; s disease , olivopontine cerebellar degeneration , lewy body disease . a ) competitive inhibition of uptake of xenobiotics at the polyamine transport site , such organic molecules being a cause of depigmentation and dna damage ; b ) steric shielding of dna from organic molecules by compacting dna ; c ) limitation of mitochondrial dna damage by removal of free copper , iron , nickel , mercury and lead ions by the presence of a polyamine ; d ) induction of metallothionein gene transcription ; e ) induction of nerve growth factor , brain derived neuronotrophic factor and neuronotrophin - 3 gene transcription ; f ) regulation of affinity of nmda receptors and blockade of the mk801 ion channel ; g ) inhibition of protein kinase c ; h ) mitochondrial reuptake of calcium ; i ) binding and conservation of reduced glutathione ; j ) induction of ornithine decarboxylase by glutathione ; k ) maintenance of the homeostasis of the redox environment in brain ; l ) non toxic chelation of divalent metals in brain ; m ) regulation of activity of preaspartate proteases ; n ) inhibition of acetylcholinesterase and butyrylcholinesterase ; o ) blockade of muscarinic m 2 receptors ; p ) maintenance of ratio of membrane phosphatidylcholine : phosphatidylserine ratio ; q ) inhibition of superoxide dismutase , amine oxidase , monoamine oxidase b by binding of free copper ; r ) regulation of brain polyamine levels in dementias with maintenance of endogenous polyamine levels ; s ) blockade of neuronal n and p type calcium channels . to treat neurodegenerative diseases require prevention of mitochondrial dna damage , maintenance of the oxidative phosphorylation activity of cells , induction of cellular repair mechanisms , regulation of receptor and enzymatic activities . age , growth and metabolic requirements , weight and body mass , predisposition to atherosclerotic and vascular complications influence the treatment selection for diabetes mellitus patients . several drugs may be developed to treat type i and type ii diabetes mellitus and its vascular and neuronal complications , treatment choices being related to age , weight , body mass and clinical stage of disease ; compositions which provide mitochondrial protection ; compositions which additionally increase insulin output , compositions which enhance glucose tolerance , compositions which reduce insulin requirements and compositions which prevent diabetic nephropathy : a ) competitive inhibition of uptake of xenobiotics at the polyamine transport site , such organic molecules being a cause of mitochondrial dna damage ; b ) steric shielding of dna from organic molecules by compacting dna ; c ) limitation of mitochondrial dna damage by removal of free copper , iron , nickel , mercury and lead ions by the presence of a polyamine ; d ) induction of metallothionein gene transcription ; e ) inhibition of protein kinase c ; f ) mitochondrial reuptake of calcium ; g ) binding and conservation of reduced glutathione ; h ) induction of omithine decarboxylase by glutathione ; i ) maintenance of the homeostasis of the redox environment j ) inhibition of superoxide dismutase , amine oxidase by binding of free copper . succinate and glutamate derivatized polyamines can stimulate insulin release . prevention of mitochondrial dna damage , maintaining oxidative phosphorylation , maintaining mitochondrial membrane integrity from free radical induced damage and stimulating insulin secretion via exocytosis or reducing insulin secretion in states of hyperinsulinism are important objectives in the treatment of diabetes . succinate polyamines increase the supply of succinic acid and acetyl coa to the krebs cycle they stimulate insulin synthesis and release they increase insulin output at high concentrations of glucose . glutamate polyamines stimulate release of insulin by promoting exocytosis . however in forms of diabetes associated with hyperinsulinism further insulin secretion is not desired because it may further damage β islet cells thus causing islet amyloid deposition and it contributes to macrovascular damage . agents which increase glucose tolerance whilst not increasing insulin output can be helpful in managing the disease . chromium and vanadium polyamine complexes are useful in that regard . a chromium polyamine complex can deliver trivalent chromium to its target sites where it promotes glucose tolerance in instances where body mass index is greater than average . a trivalent chromium polyamine complex can enhance glucose tolerance and decrease blood cholesterol and triglycerides , and increase high density lipoprotein in diabetics with above average body mass index and in obese patients having incipient diabetes . a chromium polyamine combines mitochondrial protection with enhanced glucose tolerance and metabolic regulation of lipid and carbohydrate metabolism . tetravalent vanadium polyamine complexes may be used in type i and type ii diabetes to achieve metabolic control and diminish insulin requirement . a vanadyl polyamine complex delivers vanadium in its cationic vanadyl v ( iv ) form to the tissues and a smaller dose of vanadium is required than when administered in other salt forms . vanadium decrease blood glucose and d - 3 - hydroxybutyrate levels in diabetes , it also restores fluid intake and body weight of diabetic animals . these metabolic effects occur because vanadium a ) decreases p - enolpyruvate carboxykinase ( pepck ) transcription , thus decreasing gluconeogenesis ; b ) it decreases tyrosine aminotransferase gene expression ; c ) it increases expression of glucokinase gene ; d ) it induces pyruvate kinase ; e ) it decreases mitochondrial 3 - hydroxy - 3 - methylglutaryl - coa synthase ( hmgcoas ) gene expression ; f ) it decreases the expression of the liver and pancreas glucose - transporter glut - 2 gene in diabetic animals to the level seen in controls ; g ) it increases the amount of the insulin - sensitive glucose transporter , glut4 by stimulating its transcription ; h ) the insulin like metabolic effects of vanadium are mediated by inhibition of protein tyrosine phosphatases ( ptp ). peroxovanadium compounds irreversibly oxidize the thiol group of the essential cysteine at the ptp catalytic site . vanadium is a structural analog of phosphate . vanadium does not exhibit the growth effects and mitogenic effects of insulin and thus might avoid the macrovascular diseases consequences of hyperinsulinemia and be clinically useful in disease where insulin resistance is caused by defects in the insulin signaling pathway . vanadium mimics the effects of insulin in restoring g proteins and adenyl cyclase activity increasing cyclic amp levels ; i ) vanadyl ion suppresses nitric oxide production by macrophages ; j ) it has a positive cardiac inotropic effect ; k ) vanadium restores albumin mrna levels in diabetic animals by increasing hepatic nuclear factor 1 ( hnf 1 ); l ) it restores triiodothyronine t 3 levels . vanadyl polyamine has the advantages of mitochondrial protection combined with the ability to regulate the insulin signaling pathways , with effects on glucose , carbohydrate and fat metabolism . it can lower insulin requirements , thus overcoming the vascular consequences of hyperinsulinism , permit viable β cells to continue functioning and will exert these functions irrespective of body mass index . polyamines which more potently decrease protein kinase c activity than others may be used in the treatment of diabetic nephropathy . protein kinase c causes apoptosis in diabetic nephropathy and polyamines reduce protein kinase c activation . protein kinase c is overactivated due to excess diacylglycerol ( dag ) formation from glucose . a ) induction of metallothionein gene transcription ; b ) induction of nerve growth factor , brain derived neuronotrophic factor and neuronotrophin - 3 gene transcription ; c ) regulation of affinity of nmda receptors and blockade of the mk801 ion channel ; d ) inhibition of protein kinase c ; e ) mitochondrial reuptake of calcium ; f ) binding and conservation of reduced glutathione ; g ) induction of omithine decarboxylase by glutathione ; h ) maintenance of the homeostasis of the redox environment in brain ; i ) non toxic chelation of divalent metals in brain ; j ) inhibition of superoxide dismutase and amine oxidase k ) regulation of brain polyamine levels in dementias with maintenance of endogenous polyamine levels ; 1 ) blockade of neuronal n and p type calcium channels . prevention of oxidative damage during the reperfusion post ischemia and removal of redox metals released from dead cells , trapped in the tissue are important objectives . a ) steric shielding of dna from organic molecules by compacting dna ; b ) limitation of mitochondrial dna damage by removal of free copper , iron and cadmium ions by the presence of a polyamine ; c ) induction of metallothionein gene transcription ; d ) inhibition of protein kinase c ; e ) mitochondrial reuptake of calcium ; f ) binding and conservation of reduced glutathione ; g ) induction of omithine decarboxylase by glutathione ; h ) maintenance of the homeostasis of the redox environment ; i ) inhibition of superoxide dismutase and amine oxidase by binding of free copper . prevention of mitochondrial dna damage , maintaining oxidative phosphorylation , maintaining normal ldl : hdl lipid ratios and preserving mitochondrial membrane integrity from free radical damage are major objectives in these diseases . in atherosclerosis prevention of oxidation of low density lipoprotein is also important . the chromium and vanadium polyamines mentioned above in relation to diabetic treatment are useful with regards to improving lipoprotein ratios and preventing atherosclerotic plaque formation . a ) limitation of mitochondrial dna damage by removal of free metals by the presence of a polyamine ; b ) induction of metallothionein gene transcription ; c ) regulation of affinity of nmda receptors and blockade of the mk801 ion channel ; d ) mitochondrial reuptake of calcium ; e ) binding and conservation of reduced glutathione ; f ) induction of ornithine decarboxylase by glutathione ; g ) maintenance of the homeostasis of the redox environment ; h ) non toxic chelation of divalent metals ; i ) inhibition of superoxide dismutase and amine oxidase by binding of free copper ; j ) regulation of polyamine levels in m ganglion cells with maintenance of endogenous polyamine levels . the m ganglion cells are pigment and metal rich and very prone to glutamate toxicity . a ) steric shielding of dna from organic molecules by compacting dna ; b ) limitation of mitochondrial dna damage by removal of free copper and iron ions by the presence of a polyamine ; c ) induction of metallothionein gene transcription ; d ) inhibition of protein kinase c ; e ) mitochondrial reuptake of calcium ; f ) binding and conservation of reduced glutathione ; g ) induction of ornithine decarboxylase by glutathione ; h ) maintenance of the homeostasis of the redox environment ; i ) inhibition of superoxide dismutase and amine oxidase by binding of free copper . a , b ) and c ) prevent mitochondrial dna damage which increases in the cochlea during aging and causes deafness . polyamines form extremely stable complexes with cobalt as indicated by their heats of formation . a cobalt dihomocysteine polyamine complex can behave like thioretinaco . as a non toxic , intracellular electrophile it will promote atp formation and protect against free oxygen species produced by toxins , radiation and cancer cells . further it would diminish homocysteic acid formation , which promotes growth factor activity , and thus prevent the invasiveness and neovascularization caused by cancer cells . abraham a . s . brooks b . a ., eylath u . the effects of chromium supplementation on serum glucose and lipids in patients with and without non - 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