BISPLATINUM COMPLEXES ACTIVE THROUGH THE ORAL ROUTE

Abstract: Compositions of formula (I), wherein X is halogen (chlorine, bromine, iodine); n, m = integer 2 to 8; p = 1, 2; A is selected from the group consisting of -B-, -B-(CH2)r-B-, -B-(CH2)r-B-(CH2)z-B-, with r and z ranging from 2-8; B is a group of formula -NR- wherein R is a group convertible into a hydrogen atom under physiological conditions, with the proviso that R is different from C1-C4 alkyl or acyl and from tert-butoxycarbonyl. Q<-p> is an anion selected from the group of chloride, bromide, iodide nitrate, sulfate, hydrogen sulfate and perchlorate.

Description: BISPLATINU COMPLEXES ACTIVE THROUGH THE ORAL ROUTE The present invention relates to novel platinum complexes having antitumor activity when administered orally. The oral administration of a medicament involves a number of advantages compared with the other administration routes commonly used, such as the intravenous or subcutaneous administrations. First, a better compliance by the patient, who does not often willingly agree with the treatment with mηectable formulations, as their administration is intrinsically inconvenient. Another remarkable advantage with the oral administration is the possibility of self -medication cy the patient himself, who conversely, has to depend on skilled personnel m the case of mjectable preparations. Only very few platinum complexes similar to cisplatin described m literature show antitumor activity when administered orally: carboplatm, J -216 and AMD-473 ( the latter described m EP 727430 A 1996) can be mentioned. The compounds have however poor effectiveness against tumors with cisplatin intrinsic or acquired resistances. The multmuclear platinum complexes disclosed m US 5,744,497 have an interesting antitumor activity profile, due to their activity against tumors with cisplatin intrinsic or acquired resistance (G. Pratesi et al , Br. J. Cancer, 1999, Aug 80:12, 1912-9; P. Perego et al . , Mol . Pharmacol., 55, 528-534, 1999). Said complexes are however poorly effective when administered through tne oral route. This may, m some cases, restrict the use thereof. - WO 98/03519 and "Proceedings of the American association for cancer research", vol 39 abstract 1096, disclose platinum (II) dmuclear complexes m which natural polyammes such as spermme and spermidme and their synthetic analogues are bridging two monofunctional platinum spheres. The in vitro most potent complexes are characterized by the presence of one or two secondary amino groups in the spacer bridging the two platinum atoms. The introduction of tert-butoxycarbonyl groups on said amino groups induces a marked decrease in both the in vitro cytotoxic activity and the in vivo antitumor activity. It has now surprisingly been found that the introduction of the spacer with suitable functional groups on the secondary nitrogen atoms leads to dinuclear platinum complexes having antitumor activity and which are absorbed through the oral route. The compounds of the invention have the following general formula (I) (I) wherein: X is halogen (chlorine, bromine, iodine) ; n, m = an integer 2 to 8; P = 1, 2; A is selected from the group consisting of —B-, -B- CCH 2 ) r -B-, -B- (CH 2 ) r -B- (CH 2 ) Z -B-, with r and z ranging from 2 to 8 ; B is a group of formula —NR- wherein R is a group convertible into a hydrogen atom under physiological conditions, with the proviso that R is different from C-,-C 4 alkyl or acyl and from ter-butoxycarbonyl . Q " P is an anion selected from the group of chloride, bromide, iodide, nitrate, sulfate, hydrogen sulfate and perchlorate . Examples of groups R comprise groups of formulae: 1) wherein: R 1# R 2 and R 3 , which can be the same or different, are hydrogen, C- ] _-C 4 alkyl, C 5 -Cg cycloalkyl, phenyl optionally substituted with one or more C 1 -C 4 alkyl, C- j _-C 4 alkoxy, halogen, hydroxy, or are C 7 -C 10 aralkyl ; or R^ , R 2 and R 3 are the residue of an α-amino acid in the D or L configuration; and R a is - j _-Cg alkyl, preferably t -butyl; 2) R 4 C0- wherein R 4 is hydrogen, C^-Cg cycloalkyl, preferably Cc-Cg, phenyl optionally substituted with C ± ~ C 4 alkyl, c ι _ C 4 alkoxy, hydroxy, nitro, cyano, halogen; alkyl C 1 -C 2 -phenyl ; ethyloxy or C 3 -C 8 alkyl interrupted by 1 to 4 oxygen atoms with the exception of —O-CI^-O- acetal groups; or R4 is a residue of a saturated or unsaturated fatty acid or a residue of a hexose or pentose sugar; 4) •CO-0-R E wherein R 5 is C 1 -C- L8 alkyl (with the exception of t- butyl) , C " 3 -C 18 alkenyl, benzyl or benzyl substituted at the phenyl position with one or more hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, cyano, acetoxy, c ι" c 3 alkylaminocarbonyloxy, c ι" C 3 alkoxycarbonyloxy groups; a residue of a hexose or pentose sugar, a group of formula: wherein Rg is methyl or phenyl; or a group of formula wherein Rg is hydrogen or C- ] _-C 4 alkyl and w is an integer 1 to 6; 5) wherein Rg is as above defined; 6) wherein Rg and R 7 , which can be the same or different, are hydrogen or C-^- ^ alkyl; 7) wherein Rg is hydrogen or C- L -C 4 alkyl; 8) wherein R 9 is hydrogen or C- j _-C 4 alkyl and RIO is C-,-C 4 alkyl; 9) wherein R 1;L and R 12 , which can be the same or different, are hydrogen, - j _-C 4 alkyl, phenyl; wherein Rb is C-^-Cg alkyl, preferably methyl 11) A group of formula C, D or E, C D E wherein R^ is as defined above and R c , R^, R e and R j , which can be the same or different, are H, CH 3 or OCH 3 ; 12) 13) 3 wherein Z is C 2" C 4 alkylene, cycloalkylene, optionally substituted phenylene, T is an oxygen atom or a —NH- or —N-R 14 group, wherein R 14 is C 1" C 4 alkyl ; Y is a bond, an oxygen atom, a NH or —N-R 14 group as defined above; R 13 is C 1 -C 4 alkyl, c s ~ C 6 cycloalkyl, phenyl; phenyl optionally substituted with C- j _-C 3 alkyl, C- j _-C 3 alkoxy, nitro, cyano, hydroxy groups. Examples of 1 -C 4 alkyl groups comprise methyl, ethyl, propyl , isopropyl, butyl, isobutyl, tert -butyl. Examples of C 5" C 6 cycloalkyl groups comprise cyclopentyl and cyclohexyl . Examples of optionally substituted phenyl groups comprise phenyl, 4-methylphenyl , 2 , 4 -dimethoxyphenyl , 4- methoxyphenyl , 4-nιtrophenyl , 3-chlorophenyl , 4- hydroxyphenyl , 3 , 5-dιmethoxy-4 -hydroxyphenyl , 3- cyanopheny1 , 2 -hydroxyphenyl , 2 -carboxypheny1. Examples of aralkyl groups comprise benzyl and phenethyl . Q is preferably nitrate. The groups ι~R are preferably hydrogen or alkyl. R 4 is preferably an alkyl group interrupted by oxygen atoms, such as polyoxyethylene, or a residue of a saturated or unsaturated fatty acid. R 5 is preferably methyl, i -butyl, n-hexyl, benzyl, p- nitro-benzyl , 4 -acetyloxy-benzyl , 4-methylammocarbonyl- oxybenzyl , 4 -methoxycarbonyloxy-benzyl . Rg and R 7 are preferably hydrogen, methyl, ter -butyl, isopropyl . R c , R^, R e and Rf in the group of formula D are preferably hydrogen or methyl, most preferably at least one of R c and R f being methyl. Z is preferably ethylene, 1, 2-cyclohexenyl, 3,4- butenyl . T and Y are preferably oxygen atoms and R 13 is preferably - | _-C 4 alkyl or phenyl. The compounds of formula (I) are prepared by reaction of intermediates of formula (II) NH 2 - (CH 2 ) n -A- (CH 2 ) m -NH 2 (ID in which A, m and n are as defined above, with platinum complexes of formula (III) (III) wherein X is as defined above and (O)DMF is a dimethylformamide molecule coordinated to the platinum atom, in an inert solvent such as dimethylformamide under conditions similar to those described in US 5,744,497. The compounds of formula (III) can be prepared "in situ" by reaction of a complex of formula trans-Pt (NH 3 ) 2 X 2 wherein X is as defined above, in dimethylformamide in the presence of equimolar amounts of silver nitrate. Usually the resulting complexes of formula (III) are not recovered but they are directly reacted with a compound of formula (ID . The compounds of formula (II) may be prepared from the corresponding polyamines in which R is hydrogen, by selective protection of the primary amino groups, followed by functionalization of the secondary amino groups with suitable R-G groups wherein R is as defined above and G is a suitable reactive group such as a halogen atom, a leaving group such as 4-nitrophenyl , mesyl, tosyl or an activated carbonyl . The protective groups for the primary amino groups will of course be stable under the reaction conditions used for the functionalization of the secondary amino groups, and they will be selected so as to be cleaved under selective conditions without removing at the same time the groups R. For example, when the groups R are base- sensitive, suitable protective groups can be tert- butoxycarbonyl groups or benzylydene derivatives which can be removed by treatment under mildly acidic conditions. On the other hand, when the groups R are sensitive to both acids and bases, suitable protective groups may be phthalimides or bromocarbobutyloxycarbonyl or other groups which can be removed under neutral conditions. Finally, when the groups R are acid-sensitive, suitable protective groups can be tπfluoroacetyls or similar acyl derivatives, which can be removed by basic hydrolysis. One exemplary synthetic scheme for the preparation of the intermediate amines of formula (II) is reported in the following (Scheme 1) , with reference to the case m which A is a NH group, n is 4 and m is 3 : Scheme 1 The compound of formula (IV), m which Z' is a protective group, is reacted with a compound of formula (V) , - m which Z' is as defined above and Hal is a halogen atom or a sulfonic ester, such as mesylate or tosylate. On the other hand, the compounds (II) m which A is a —B-(CH 2 ) r -B- group can be prepared, for example, according to the following Scheme 2 : Hal ' N H V by reacting the diamine (VI) with a compound of formula (V) as defined above. Suitable reaction conditions for introducing the R groups reported above are described, for example, in the following references: For groups 4 and 5), J.Med.Chem. 27,713-717, 1984; Chem. Pharm. Bull. 32, 2241-2248. For groups 6), J.Med.Chem. 31, 318-322, 1988. For groups 7), Synthesis 9, 824-827, 1987. For group 10), J.Org.Chem. 41,2029-2031, 1976; Chem. Pharm. Bull.32, 2241-2248; Cancer Chemotherapy Rep 59, 679- 683. For groups 11), J. Am. Chem. Soc . 9175-9182, 1972; J.Org. Chem. 54, 3303-3310, 1989; Chem. Pharm. Bull . 47, 90-95, 1999. For groups 12), Nucleic Acid Res, Vol. 22, Issue 15, 3119-3123, 1994. For groups 13), PCT/US97/03640. The compounds of formula (I) prepared as described above may optionally be subjected to further salification, separation of the enantiomers when at least one asymmetry center is present, conversion of an R group into another R group according to conventional procedures. The intermediates of formula (II) are novel and therefore are a further otject of the invention. The compounds of the invention, when administered to humans or animals bearing tumors which can be treated with cis-platmum or which are resistant to cis-plat um, at doses ranging from 0.1 mg to 1.2 g / m 2 of body area, are capable of inducing the regression of said tumors. More generally, the compounds of the invention can be used for the treatment of the same patnological conditions for which cis-platmum is used. This includes the treatment of tumors, the sensitization or enhancement of radiations [Douple et al . , Cis-plat Current Status and Developments, And. A.W. Prestayk et al . , Academic Press, 125 (1980); Douple et al . , Platinum Metals Res., 29; 118 (1985)] and the treatment of parasitic diseases such as African sleeping sickness [Farrell et al . , Biochem. Pharmacol., 33, 961 (1984) ] . Therefore, another ob ect of the present invention are pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula (I) in mixture with conventional carriers and excipients. The effective dosage of the compounds of the invention may be determined by the expert clinicians according to conventional methods. The relationship between the dosages used for animals of various species and sizes and those for humans (on the basis of mg/ body area) is described by Freirech et al . , Quantitative Comparison of Toxicity of Anticancer Agents m Mouse, Rat, Hamster, Dog, Monkey and Man, Cancer Chemother. Rep., 50. N.4, 219-244 (1986). The patient will however receive doses of the complex ranging from 0.1 to 200 mg/kg body weight, with a dosage regimen which will depend on a number of factors which are well known to the expert clinicians. The treatment regimen may be suitably varied, as it is well known to the expert clinicians, depending on the type of tumor to be treated and the conditions of the patient. The compounds of the invention may be administered through the parenteral or oral routes . The pharmaceutical compositions for the parenteral administration include sterile saline solutions, as defined below, or sterile powders for the extemporary preparation of solutions, as well as oily preparations for the intramuscular dm) or traperitoneal dp) administrations. The compounds of the invention may be preferaoly administered as sterile aqueous solution, optionally containing sodium chloride in suitable concentration (0.1 - 0.9 %) . The solutions are administered preferably through the intravenous (ιv) or mtra-arterial da) routes, although m particular cases other administration forms could be envisaged. Pharmaceutical compositions useful for the oral administration comprise, for example, syrups or similar liquid forms, as well as solid forms such as tablets, capsules and the like. The pharmaceutical compositions according to the present invention are prepared following conventional methods, such as those reported m Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A. Sometimes it can be advantageous to administer the platinum complexes of the present invention m combination with one or more agents which enhance the antitumor activity or relieve the undesirable side effects which may be associated with the therapy with platinum complexes. For example, the platinum complexes of the present invention can be administered together with reduced glutathione, as disclosed m GB 2,174,905 and in U.S. 4,871,528. Furthermore, it can be advantageous to administer the platinum complexes of the invention combination with other platinum complexes having antitumor activity. Therefore, a further OD ect of the present invention are pharmaceutical compositions containing at least one compound of formula (I) m combination with a platinum complex having antitumor activity. A further obi ect of the invention is the use of the compounds of formula (I) for the preparation of pharmaceutical compositions for the treatment of mammals bearing tumors which can be treated with cis-platmum or which are resistant to cis-platmum. The invention is further illustrated by the following examples . EXAMPLES Preparation 1 1, 12 -bis (trifluoroacetylammo) -4, 9-dιaza-4, 9-bιs- (methoxycarbonyl) dodecane A solution of 1 , 12 -bis (trifluoroacetamido) -4 , 9- diazadodecane [N 1 ,N -bis-trifluoroacetylspermme] (0.544 g, 1.379 mmol) in dry THF (12 mL) at room temperature is added with K 2 C0 3 (0.420 g, 3.03 mmol); after that, methyl chloroformate (0.34 mL, 4.4 mmol) is carefully poured therein. The reaction is slightly exothermal. After about 5 hours the reaction is completed as evidenced by TLC (CH 2 Cl 2 /MeOH/NH 4 OH 9:1:0.4, rf = 0.8). The mixture is poured into H 2 0 (15 mL) and extracted with ter -butyl methyl ether (3 x 30 mL) . The combined extracts are washed with saturated NaCl , dried over Na 2 S0 4 and concentrated under vacuum to obtain 650 mg (97% yield) . 1H-NMR (OMSO- dg) 1.4 (bs, 4H) ; 1.7 (q, 4H) ; 3.15 (m, 12H) ; 3.6 (s, 6H) ; 9.35 (bt , 2H, NHCOCF 3 ) . Preparation 2 1 , 12 -bis (trifluoroacetylamino) -4 , -diaza-4, 9-bis (n- hexyloxycarbonyl) dodecane A solution of 1 , 12 -bis (trifluoroacetamido) -4 , 9- diazadodecane [N 1 , N -bis-trifluoroacetylspermine] (0.789 g, 2 mmol) in dry CH 2 C1 2 (18 mL) cooled at 5°C is added with triethylamine (TEA: 0.3 mL, 2.2 mmol), then with n-hexyl chloroformate (0.36 mL, 2.2 mmol) dissolved in 1.5 mL of CH 2 Cl 2 . The resulting whitish suspension is stirred overnight until the starting product completely disappears (TLC: CH 2 Cl 2 /MeOH/NH 4 OH 9:1:0.4, rf = 0.9). The mixture is poured into water (40 mL) and extracted with CH 2 Ci 2 (2 x 50 mL) . The combined extracts are washed with water, dried over Na 2 S0 4 and concentrated under vacuum to obtain 585 g (45% yield) of a transparent oil which tends to solidify. 1 H-NMR (DMSO-d<?) 0.85 (bt, 6H) ; 1.25 (bs, 12H) ; 1.4 (bs, 4H) ; 1.5 (bq, 4H) ; 1.7 (bq, 4H) ; 3.15 (m, 12H) ; 4.0 (t, 4H) ; 9.4 (m, 2H, NHCOCF 3 ) . Preparation 3 1, 8-bis (trifluoroacetylamino) -4-aza-4- (p-nitrobenzyl- oxycarbonyl) octane A solution of 1 , 8-bis (trifluoroacetamido) -4-aza octane (0.5 g, 1.48 mmol) in dry THF (20 mL) is added with K 2 C0 3 (0.225 g, 1.63 mmol) then, keeping temperature at 25 °C, 4- nitrobenzyl chloroformate (0.362 g, 1.63 mmol) dissolved in 3 mL of THF is dropped therein. After 2h the reaction is completed (TLC: CHCl 3 /MeOH 8:2, rf=0.5). The mixture is concentrated to small volume under vacuum, taken up with 20 mL of water and extracted with AcOEt (2 x 20 mL) . The combined extracts are washed first with water, then with saturated NaCl , dried over Na 2 S0 4 and concentrated under vacuum, thereby obtaining a transparent oil, 0.72 g (94%). 1 H-NMR (DMSO-d^) 1.5 (bs, 4H) ; 1.75 (m, 2H) ; 3.25 (bq , 8H) ; 5 . 2 ( s , 2H) ; 7 . 6 (d , 2H) ; 8 . 25 ( d , 2H) ; 9 . 4 (m, 2H , NHCOCF 3 ) . Preparation 4 1, 8-bis (trifluoroacetylamino) -4-aza-4- (benzyloxy- carbonyl) octane A solution of 1 , 8-bis (trifluoroacetamido) -4-aza octane (0.5 g, 1.48 mmol) in dry THF (20 mL) is added with K 2 C0 3 (0.225 g, 1.63 mmol) then, keeping temperature at 25°C, benzyl chloroformate (0.24 g, 1.63 mmol) dissolved in 3 mL of THF is dropped therein. The reaction is slightly exothermal (temperature rises from 20°C to 25°C) . After lh the reaction is completed (TLC: CHCl 3 /MeOH 8:2, rf=0.5). The mixture is concentrated to small volume under vacuum, taken up with 20 mL of water and extracted with AcOEt (2 x 50 mL) . The combined extracts are washed first with water then with saturated NaCl, dried over Na 2 S0 4 and concentrated under vacuum thereby obtaining a transparent oil, 0.74 g (96%) . The product is purified by column chromatography (Si0 2 230 mesh, eluent CHCl 3 /MeOH 9:1) to yield 0.58 g of a transparent oil pure by TLC. X H-NMR (DMSO-dg-) 1.4 (bs, 4H) ; 1.75 (m, 2H) ; 3.25 (m, 8H) ; 5.0 (S, 2H) ; 7.25-7.5 (m, 5H, Ph) ; 9.4 (m, 2H, NHCOCF 3 ) . Preparation 5 1, 8-bis (trifluoroacetylamino) -4-aza-4- (p-nitrobenzene- sulfonyl) octane A solution of 1 , 8-bis (trifluoroacetamido) -4-aza octane (0.5 g, 1.48 mmol) in dry THF (10 mL) is added with K 2 C0 3 (0.225 g, 1.63 mmol) then, keeping temperature at 25°C, p- nitrobenzenesulfonyl chloride (0.4 g, 1.63 mmol) dissolved in 3 'mL of THF is dropped therein. After 3h the reaction is completed (TLC: CHCl 3 /MeOH 8:2, rf=0.7). The mixture is concentrated to small volume under vacuum, taken up with 20 mL of water and extracted with AcOEt (2 x 20 mL) . The combined extracts are washed first with water then with saturated NaCl , dried over Na 2 S0 4 and concentrated under vacuum, thereby obtaining a transparent oil, 0.8 g, which tends to solidify. Crystallization from Et 2 0 yields 0.435 g of a white solid (56%) with melting point 109-111°C. ^-H-NMR (DMSO-d^) 1.5 (bs, 4H) ; 1.75 (q, 2H) ; 3.15 (bt, 8H) ; 8.05 (d, 2H) ; 8.4 (d, 2H) ; 9.4 (m, 2H, NHC0CF 3 ) . Preparation 6 1, 8-bis (trifluoroacetylammo) -4-aza-4-oleyl octane A solution of 1 , 8-bis (trifluoroacetamido) -4-aza octane (0.5 g, 1.48 mmol) m dry THF (20 mL) is added with K 2 C0 3 (0.225 g, 1.63 mmol) then, keeping temperature at 25°C, oleyl chloride (0.495 g, 1.63 mmol) dissolved m 3 mL of THF is dropped therein. After 1 night the reaction is completed (TLC: CHCl 3 /MeOH 8:2, rf=0.9). The mixture is poured m 50 mL of water and extracted with AcOEt (2 x 20 mL) . The combined extracts are washed first with water then with saturated NaCl , dried over Na 2 S0 4 and concentrated under vacuum. The resulting oily product is chromatographed (Sι0 2 230 mesh, eluent CHCl 3 /MeOH 9:1) to yield 0.41 g (46%) of a transparent oil pure by TLC. Preparation 7 1, 12 -bis (trifluoroacetylammo) -4,9-dιaza-4,9-bιs(ι- butyloxycarbonyl) dodecane A solution of 1 , 12-bιs (trifluoroacetamido) -4 , 9- diazadodecane [N ,N -bis-tnfluoroacetylspermine] (1 g, 2.5 mmol) m dry THF (35 mL) at 25°C is added with triethylam e (TEA: 0.35 mL, 5 mmol), then with l-butyl chloroformate (0.76 g, 5.6 mmol) dissolved 5 mL of THF. The resulting whitish suspension is stirred overnight until the " starting product completely disappears (TLC: CH 2 Cl 2 /MeOH/NH 4 OH 9:1:0.4, rf = 0.9). The mixture is poured m water (80 mL) and extracted with CH 2 Cl 2 (3 x 50 mL) . The combined extracts are washed with water, dried over Na 2 S0 4 and concentrated under vacuum to obtain 1.4 g (95% yield) of a clear oil . 1 H-NMR (DMSO-d^) 0.85 (d, 12H) ; 1.4 (bs, 4H) ; 1.7 (bt, 4H) ; 1.8 ( , 2H, CH-(CH 3 ) 2 ); 3.15 (m, 12H) ; 3.75 (d, 4H, CH 2 -0) ; 9.4 (m, 2H, NHCOCF 3 ) . Preparation 8 With procedures similar to those described m Preparations 1-9 and starting from the corresponding {a, - bis (trifluoroacetylammo) -n (, m) - (bis) aza alkanes, are prepared: 1 , 16 -bis (trifluoroacetylammo) -6, ll-dιaza-6, 11 -b s (methoxy- carbonyl) hexadecane ; 1 , 16 -bis (trifluoroacetylammo) -7, 10-dιaza-7, 10 -bis (methoxy- carbonyl) hexadecane; 1, 8 -bis (trifluoroacetylammo) -3, 6-dιaza-3, 6 -bis (methoxy- carbonyl) octane; 1, 16-bis (trifluoroacetylammo) -8-aza-8-methoxycarbonyl hexadecane ; 1 , 13 -bis (trifluoroacetylammo) -7-aza-7-methoxycarbonyl tridecane; 1, 11 -bis (trif luoroacetylammo) -5-aza-5-methoxycarbonyl undecane; 1 , 8 -bis (trif luoroacetylammo) -3 -aza-3 -methoxycarbonyl octane; 1, 8-bis (trif luoroacetylammo) -4 -aza-4 -methoxycarbonyl octane ; 1 , 5-bιs (trif luoroacetylammo) -3 -aza-3 -methoxycarbonyl pentane; 1, 16 -bis (trif luoroacetylammo) -6 , ll-dιaza-6 , 11 -bis (n-hexyl - oxycarbonyl) hexadecane; 1, 16-b " is (trif luoroacetylammo) -7, 10-dιaza-7,10-bιs (n-hexyl - oxycarbonyl) hexadecane; 1 , 8-bis (trif luoroacetylammo) -3 , 6-dιaza-3 , 6-bιs (n-hexyloxy- carbonyl) octane; 1 , 16-bis (trifluoroacetylammo) -8-aza-8- (n-hexyloxycarbonyl) hexadecane ; 1 , 13-bis (trifluoroacetylammo) -7-aza-7- (n-hexyloxycarbonyl) tπdecane ; 1 , 11-bis (trifluoroacetylammo) -5-aza-5- (n-hexyloxycarbonyl) undecane ; 1 , 8 -bis (trifluoroacetylammo) -3 -aza-3- (n-hexyloxycarbonyl) octane; 1 , 8 -bis (trifluoroacetylammo) -4-aza-4- (n-hexyloxycarbonyl) octane; 1 , 5 -bis (trifluoroacetylammo) -3-aza-3- (n-hexyloxycarbonyl) pentane ; 1, 16 -bis (trifluoroacetylammo) -6, ll-dιaza-6, 11-bis (p-nitro- benzyloxycarbonyl) hexadecane; 1,16-bis (trifluoroacetylammo) -7,10-dιaza-7,10-bιs(p-nιtro- benzyloxycarbonylaza) hexadecane ; 1, 12 -bis (trifluoroacetylammo) -4, 9-dιaza-4 , 9-bιs (p-nitro- benzyloxycarbonyl) dodecane; 1, 8-bis (trifluoroacetylammo) -3 , 6-dιaza-3 , 6-bιs (p-nitro- benzyloxycarbonyl) octane; 1, 16-bis (trifluoroacetylammo) -8-aza-8- (p-mtrobenzyloxy- carbonyl) hexadecane; 1, 13-bis (trifluoroacetylammo) -7-aza-7- (p-nitrobenzyloxy- carbonyl) tridecane; 1, 11-bis (trifluoroacetylammo) -5-aza-5- (p-mtrobenzyloxy- carbonyl) undecane; 1, 8-bis (trifluoroacetylammo) -3-aza-3- (p-nitrobenzyloxy- carbonyl) octane; 1, 5-bιs (trifluoroacetylammo) -3 -aza-3- (p-nitrobenzyloxy- carbonyl) pentane; 1, 16-bis (trifluoroacetylammo) -6, ll-dιaza-6, 11-bis (p-nitro- benzenesulfonyl) hexadecane; 1, 16-bis (trifluoroacetylammo) -7 , 10-dιaza-7 , 10 -bis (p-nitrobenzenesulfonyl) hexadecane; 1, 12 -bis (trifluoroacetylammo) -4, 9-diaza-4, 9-bis (p-nitrobenzenesulfonyl) dodecane; 1, 8-bis (trifluoroacetylamino) -3 , 6-diaza-3 , 6-bis (p-nitro- benzenesulfonyl ) octane ; 1, 16-bis (trifluoroacetylamino) -8-aza-8- (p-nitrobenzene- sulfonyl) hexadecane; 1 , 13 -bis (trifluoroacetylamino) -7-aza-7- (p-nitrobenzenesulfonyl) tridecane; 1, 11-bis (trifluoroacetylamino) -5-aza-5- (p-nitrobenzene- sulfonyl) undecane ; 1 , 8-bis (trifluoroacetylamino) -3 -aza-3 - (p-nitrobenzene- sulfonyl) octane; 1 , 5-bis (trifluoroacetylamino) -3 -aza-3 - (p-nitrobenzene- sulfonyl) pentane; 1, 16-bis (trifluoroacetylamino) -6, ll-diaza-6, 11-bis (benzyl - oxycarbonyl) hexadecane; 1, 16-bis (trifluoroacetylamino) -7, 10-diaza-7, 10-bis (benzyl - oxycarbonyl) hexadecane; 1, 12 -bis (trifluoroacetylamino) -4,9-diaza-4, 9-bis (benzyl - oxycarbonyl) dodecane; 1, 8-bis (trifluoroacetylamino) -3 , 6-diaza-3 , 6-bis (benzyl - oxycarbonyl) octane; 1, 16-bis (trifluoroacetylamino) - 8 -aza- 8 -benzyloxycarbonyl hexadecane; 1, 13-bis (trifluoroacetylamino) -7-aza-7-benzyloxycarbonyl tridecane; 1, 11-bis (trifluoroacetylamino) -5 -aza- 5 -benzyloxycarbonyl undecane; 1, 8-bis (trifluoroacetylamino) -3 -aza-3 -benzyloxycarbonyl octane; 1, 5-bis (trifluoroacetylamino) -3 -aza-3 -benzyloxycarbonyl pentane; 1, 16-bis (trifluoroacetylamino) -6, ll-diaza-6, 11-bis (p-nitrobenzenesulfonyl ) hexadecane; 1, 16-bis (trifluoroacetylammo) -7, 10-dιaza-7, 10-bis (p-nitro- benzenesulfonyl) hexadecane; 1, 12 -bis (trifluoroacetylammo) -4 , 9-dιaza-4, 9-bis (p-nitrobenzenesulfonyl ) dodecane; 1, 8-bis (trifluoroacetylammo) -3 , 6-dιaza-3 , 6-bis (p-nitro- benzenesulfonyl) octane; 1, 16-bis (trifluoroacetylammo) -8-aza-8- (p-nitrobenzene- sulfonyl) hexadecane; 1, 13-bis (trifluoroacetylammo) -7-aza-7- (p-nitrobenzene- sulfonyl) tridecane; 1, 11-bis (trifluoroacetylammo) -5-aza-5- (p-nitrobenzene- sulfonyl) undecane; 1, 8-bis (trifluoroacetylammo) -3 -aza-3- (p-nitrobenzene- sulfonyl) octane; 1, 5-bis (trifluoroacetylammo) -3-aza-3- (p-nitrobenzene- sulfonyl) pentane; 1, 16-bis (trifluoroacetylamino) -6, ll-diaza-6, 11-bis (i- butyloxycarbonyl) hexadecane; 1, 16-bis (trifluoroacetylammo) -7, 10-diaza-7, 10-bis (i- butyloxycarbonyl) hexadecane; 1, 8-bis (trifluoroacetylamino) -3 , 6-dιaza-3 , 6-bis (l-butyloxy- carbonyl) octane; 1, 16-bis (trifluoroacetylammo) -8-aza-8- (i-butyloxycarbonyl) hexadecane ; 1, 13-bis (trifluoroacetylammo) -7-aza-7- (i-butyloxycarbonyl) tridecane; 1 , 11-bis (trifluoroacetylamino) -5-aza-5- (i-butyloxycarbonyl) undecane; 1, 8-bis (trifluoroacetylammo) -3-aza-3- (i-butyloxycarbonyl) octane; 1 , 8 -bi's (trifluoroacetylammo) -4 -aza-4 - ( i -butyloxycarbonyl ) octane ; 1, 5-bis (trifluoroacetylamino) -3-aza-3- (i-butyloxycarbonyl) pentane; 1, 16-bis (trifluoroacetylamino) -6, ll-diaza-6, 11-bis (α- [1,4,7, 10-tetraoxaundecanyl] acetyl) hexadecane; 1 , 16-bis (trifluoroacetylammo) -7,10-diaza-7, 10-bis ( - [1,4,7, 10-tetraoxaundecanyl] acetyl) hexadecane; 1 , 12-bis (trifluoroacetylamino) -4 , 9-diaza-4 , 9-bis (α- [1,4,7,10-tetraoxaundecanyl] acetyl ) dodecane ; 1, 8-bis (trifluoroacetylamino) -4-aza-4- (a- [1,4, 7, 10- tetraoxaundecanyl] acetyl) octane ; 1, 16-bis (trifluoroacetylamino) -6, ll-diaza-6, 11-bis (oleyl) hexadecane; 1, 16-bis (trifluoroacetylamino) -7, 10-diaza-7, 10-bis (oleyl) hexadecane; 1, 12-bis (trifluoroacetylammo) -4 , 9-diaza-4 , 9-bis (oleyl) dodecane ; 1, 8-bis (trifluoroacetylamino) -3 , 6-diaza-3 , 6-bis (oleyl) octane; 1, 16-bis (trifluoroacetylamino) -8-aza- 8-oleyl hexadecane; 1, 13-bis (trifluoroacetylamino) -7-aza-7-oleyl tridecane; 1 , 11-bis (trifluoroacetylamino) -5-aza-5-oleyl undecane ; 1, 8-bis (trifluoroacetylamino) -3-aza-3-oleyl octane ; 1, 5-bis (trifluoroacetylamino) -3 -aza-3 -oleyl pentane; 1, 16-bis (trifluoroacetylammo) -6,ll-dιaza-6,ll-bιs (stearyl) hexadecane; 1, 16-bis (trifluoroacetylamino) -7, 10-diaza-7 7 10-bis (stearyl) hexadecane; 1, 12-bis (trifluoroacetylamino) -4 , 9-diaza-4 , 9-bis (stearyl) dodecane ; 1, 8-bis (trifluoroacetylamino) -3 , 6-diaza-3 , 6-bis (stearyl) octane; 1, 16-bis (trifluoroacetylamino) -8-aza-8-stearyl hexadecane; 1, 13-bis (trifluoroacetylamino) -7-aza-7-stearyl tridecane; 1, 11-bis (trifluoroacetylamino) -5-aza-5-stearyl undecane; 1, 8-bis (trifluoroacetylamino) -3 -aza-3 -stearyl octane; 1, 5-bis (trifluoroacetylamino) -3 -aza-3 -stearyl pentane; 1, 16-bis (trifluoroacetylamino) -6, ll-diaza-6, 11-bis- (palmityl) hexadecane; 1, 16-bis (trifluoroacetylamino) -7, 10-diaza-7, 10-bis- (palmityl) hexadecane; 1, 12-bis (trifluoroacetylamino) -4 , 9-diaza-4 , 9-bis (palmityl) dodecane ; 1 , 8 -bis ( trifluoroacetylamino) - 3 , 6 -diaza- 3 , 6 -bis (palmityl ) octane ; 1, 16-bis (trifluoroacetylamino) -8-aza-8-palmityl hexadecane; 1, 13-bis (trifluoroacetylamino) -7-aza-7-palmityl tridecane; 1, 11-bis (trifluoroacetylamino) -5-aza-5-palmityl undecane ; 1,.8-bis (trifluoroacetylamino) -3-aza-3-palmityl octane; 1, 5-bis (trifluoroacetylamino) -3 -aza-3 -palmityl pentane; 1, 16-bis (trifluoroacetylamino) -6, ll-diaza-6, 11-bis (α-1- [1, 4 , 7, 10-tetraoxaundecanyl] acetyl) hexadecane; 1, 16-bis (trifluoroacetylamino) -7, 10-diaza-7, 10-bis (α-1- [1,4,7, 10-tetraoxaundecanyl] acetyl) hexadecane; 1, 12-bis (trifluoroacetylamino) -4, 9-diaza-4 , 9-bis (α-l- [1,4,7, 10-tetraoxaundecanyl] acetyl) dodecane; 1, 8-bis (trifluoroacetylamino) -4-aza-4- (of- [1,4, 7, 10- tetraoxaundecanyl] acetyl ) octane . Preparation 9 1 , 12-diamino-4 , 9-diaza- , 9-bis (methoxycarbonyl) dodecane 0.2N NaOH (14.5 mL, 2.2 mmol) is dropped in 30' into a methanolic solution (15 mL) of 1, 12- bis (trifluoroacetylamino) -4 , 9-diaza-4 , 9-bis (methoxycarbonyl) dodecane (0.64 g, 1.315 mmol) cooled to 10 °C. The mixture is stirred overnight at 25°C, then concentrated under vacuum to remove MeOH. The aqueous phase is extracted with CHCl 3 /MeOH 20:1 (3 x 30 mL) , the combined extracts are dried over Na 2 S0 4 and concentrated to dryness under vacuum, thereby yielding 0.403 g (96%) of a transparent oil. 1 H-NMR (D 2 0) 1.35 (bs, 4H) ; 1.5 (q, 4H) ; 2.4 (t, 4H) ; 3.15 (m, 8H) ; 3.55 (s, 6H) . Preparation 10 1, 12-diamino-4 , 9-diaza-4, 9-bis (n-hexyloxycarbonyl) dodecane 0.2N NaOH (9.9 mL, 2.2 mmol) is dropped in 30 'into a methanolic solution (15 mL) of 1, 12- bis (trifluoroacetylamino) -4 , 9-diaza-4, 9-bis (n-hexyloxycarbonyl) dodecane (0.584 g, 0.897 mmol) cooled to 10°C. The mixture is stirred overnight at 25°C then concentrated under vacuum to remove MeOH. The aqueous phase is then extracted with CHCl 3 /MeOH 20:1 (3 x 10 mL) , the combined extracts are dried over Na 2 S0 4 and concentrated to dryness under vacuum, thereby obtaining 0.39 g (95%) of transparent oil . 1H-NMR (DMSO-d^) 0.85 (t, 6H) ; 1,25 (bs, 12H) ; 1.4-1.6 (m, 12H + 2 NH 2 ) ; 2.5 (bt, 4H) ; 3.15 (bq, 8H) ; 3.95 (t, 4H) . Preparation 11 1, 8-diamino-4-aza-4- (p-nitrobenzyloxycarbonyl) octane 1, 8-bis (Trifluoroacetylamino) -4-aza-4- (p-nitrobenzyloxycarbonyl) octane (0.7 g, 1.35 mmol) is dissolved in MeOH (15 mL) and the solution is cooled to 0°C. 0.2N NaOH (15 mL, 2.98 mmol) is dropped in 30' then temperature is left to rise overnight. Most MeOH is removed under vacuum, then the aqueous phase is extracted with CHCl 3 /MeOH 20:1 (3 x 15 mL) . The combined extracts are dried over Na 2 S0 4 and concentrated to dryness under vacuum. Column chromatography (Si0 2 230 mesh, eluent CHCl 3 /MeOH/NH 4 OH 45:50:5) yields 0.28 g (64%) of a colourless oil. 1H-NMR (DMSO-dg- + D20) 1.25 (m, 2H) ; 1.5 (m, 4H) ; 2.4 (m, 4H) ; 3.25 (m, 4H) ; 5.15 (s, 2H) ; 7.6 (d, 2H) ; 8.25 (d, 2H) . Preparation 12 1, 8 -diamino-4-aza-4 -benzyloxycarbonyl octane 1, 8-bis (trifluoroacetylamino) -4-aza-4- (benzyloxycarbonyl) octane (0.58 g, 1.23 mmol) is dissolved in MeOH (13.5 mL) and the solution is cooled to 0°C. 0.2N NaOH (13.5 mL, 2.7 mmol) is dropped in 30' then temperature is left to rise overnight. Most MeOH is distilled off under reduced pressure, then the aqueous phase is extracted with CHCl 3 /MeOH 20:1 (3 x 50 mL) . The combined extracts are dried over Na 2 S0 4 and concentrated to dryness under vacuum, thereby obtaining 0.27 g (79%) of a pale yellow oil. 1H-NMR (OMSO- d 6 ) 1.25 (bq, 2H) ; 1.5 (m, 2H) ; 2.5 (m, 4H) ; 5.05 (s, 2H) ; 7.25-7.5 (m, 5H, Ph) . Preparation 13 1 , 8-diamino-4-aza-4- (p-nitrobenzenesulfonyl) octane 1, 8-bis (Trifluoroacetylamino) -4-aza-4- (p-nitrobenzene- sulfonyl) octane (0.451 g, 0.8 mmol) is dissolved in MeOH (9 mL) and the solution is cooled to 0°C. 0.2N NaOH (8.8 mL, 1.77 mmol) is dropped in 30' then temperature is left to rise overnight. MeOH is concentrated under reduced pressure, then the aqueous phase is extracted with CHCl 3 /MeOH 20:1 (2 x 20 mL) . The combined extracts are dried over Na 2 S0 4 and concentrated to dryness under vacuum, thereby obtaining 0.24 g (90%) of an oil. 1 H-NMR (DMSO-dg) 1.25 (q, 2H) ; 1. 5 (m, 4H) ; 2.5 (m, 4H + 2 NH2) ; 3.15 (m, 4H) ; 8.05 (d, 2H) ; 8.4 (d, 2H) . Preparation 14 1 , 8-diamino-4-aza-4-oleyl octane 1, 8-bis (Trifluoroacetylamino) -4-aza-4-oleyl octane (0.40 g, 0.68 mmol) is dissolved in MeOH (15 mL) and the solution is cooled to 0°C. 0.2N NaOH (15 mL, 1.49 mmol) is dropped in 30' then temperature is left to rise overnight. Most "MeOH is removed under reduced pressure, then the aqueous phase is extracted with CHCl 3 /MeOH 20:1 (10 x 20 mL) . The combined extracts are dried over Na 2 S0 4 and concentrated to dryness under vacuum, thereby obtaining Preparation 15 1, 12-dιammo-4, 9-dιaza-4 , 9-bis (i-butyloxycarbonyl) dodecane 0.2N NaOH (27 mL, 5.35 mmol) is dropped in 30' into a methanolic solution (45 mL) of 1,12-bιs- (trifluoroacetylammo) -4, 9-dιaza-4, 9 -bis d -butyloxycarbonyl) dodecane (1.45 g, 2.43 mmol) cooled to 10°C. After stirring overnight at 25°C, the mixture is concentrated under vacuum to remove MeOH. The aqueous phase is then extracted with CHCl 3 /MeOH 20:1 (3 x 10 mL) , the combined extracts are dried over Na 2 S0 4 and concentrated to dryness under vacuum, thereby obtaining 1 g (99%) of product as a transparent oil . 1H-NMR (DMSO-d^) 0.9 (d, 12H) ; 1.35-1.6 (m, 8H + 2 NH 2 ); 1.85 (m, 2H, CH-(CH 3 ) 2 ); 3.2 (m, 8H) ; 3.75 (d, 4H, CH 2 -0) . Preparation 16 With processes similar to those described Preparations 10-15 starting from the suitable bistrifluoroacetamides described m Preparation 9, are prepared: 1, 16-dιammo-6, ll-diaza-6, 11-bis (methoxycarbonyl) hexadecane; 1, 16-dιammo-7, 10-dιaza-7,10-bιs (methoxycarbonyl) hexadecane; 1, 8-dιammo-3 , 6-dιaza-3 , 6-bis (methoxycarbonyl) octane; 1, 16-diam o- 8 -aza-8 -methoxycarbonyl hexadecane; 1 , 13 -diammo- 7 -aza- 7 -methoxycarbonyl tridecane; 1 , ll-dιammo-5-aza-5-methoxycarbonyl undecane; 1, 8 -dιammo-3 -aza-3 -methoxycarbonyl octane; 1, 8 -dιammo-4-aza-4 -methoxycarbonyl octane; 1, 5 -diammo-3 -aza-3 -methoxycarbonyl pentane; 1, 16-diammo- 6 , ll-diaza-6 , 11 -bis (n-hexyloxycarbonyl) hexadecane; 1, 16 -diammo- 7 , 10-dιaza-7, 10 -bis (n-hexyloxycarbonyl) hexadecane ; 1 , 8 -diammo- 3 , 6-diaza-3, 6 -bis (n-hexyloxycarponyl ) octane ; 1 , 16-dιammo-8-aza-8- (n-hexyloxycarbonyl ) hexadecane; 1 , 13 -diammo- 7 -aza- 7- (n-hexyloxycarbonyl) tridecane; 1 , ll-dιammo-5-aza-5- (n-hexyloxycarbonyl) undecane; 1 , 8-dιammo-3 -aza-3 - (n-hexyloxycarbonyl ) octane ; 1 , 8 -dιammo-4 -aza-4 - (n-hexyloxycarbonyl ) octane ; 1 , 5-dιammo-3 -aza-3 - (n-hexyloxycarbonyl ) pentane; 1 , 16-dιammo-6 , ll-diaza-6 , 11-bis (p-nitrobenzyloxycarbonyl) hexadecane ; 1 , 16 -diammo- 7, lO-dιaza-7, 10- bis (p-nitrobenzyloxycarbonyl) hexadecane ; 1,12 -dιammo-4 , 9-dιaza-4 , 9-bis (p-mtrobenzyloxycarponyl) dodecane; 1 , 8 -diammo -3 , 6- di aza-3, 6 -bis (p-mtrobenzyl oxycarbonyl) octane; 1, 16-dιammo-8-aza-8- (p-nitrobenzyloxycarbonyl) hexadecane; 1 , 13 -dιammo-7-aza-7- (p-nitrobenzyloxycarbonyl) tridecane; 1 , ll-dιammo-5-aza-5- (p-mtropenzyloxycarbonyl) undecane; 1 , 8 -diammo-3 -aza-3 - (p-nitropenzyloxycarbonyl) octane; 1 , 5 -diammo-3 -aza-3 - (p-nitrobenzyloxycarbonyl) pentane ; 1, 16 -diammo- 6, 11 -diaza- 6, 11 -bis (benzyloxycarbonyl) hexadecane; 1, 16 -diammo- 7, 10-diaza-7, 10 -bis (benzyloxycarbonyl) hexadecane; 1, 12 -diammo-4 , 9-dιaza-4 , 9 -bis (benzyloxycarPonyl) dodecane; 1 , 8 -diammo-3 , 6 -diaza-3, 6-bis (benzyloxycarbonyl) octane ; 1 , 16-dιammo-8-aza-8-benzyloxycarbonyl hexadecane; 1 , 13 -diammo- 7 -aza- 7 -benzyloxycarbonyl tridecane; 1, 11-diammo-5 -aza-5 -benzyloxycarbonyl undecane; 1, 8 -diammo- 3 -aza-3 -benzyloxycarbonyl octane; 1, 5 -diammo-3 -aza-3 -benzyloxycarbonyl pentane; 1, 16-diamino-6 , ll-diaza-6, 11-bis (p-nitrobenzenesulfonyl) hexadecane ; 1, 16-diamino-7, 10-diaza-7,10-bis (p-nitrobenzenesulfonyl) hexadecane ; 1, 12-diamino-4 , 9-diaza-4 , 9-bis (p-nitrobenzenesulfonyl) dodecane ; 1, 8-diamino-3 , 6-diaza-3 , 6-bis (p-nitrobenzenesulfonyl) octane; 1, 16-diamino-8-aza-8- (p-nitrobenzenesulfonyl) hexadecane; 1, 13-diamino-7-aza-7- (p-nitrobenzenesulfonyl) tridecane; 1, ll-diamino-5-aza-5- (p-nitrobenzenesulfonyl) undecane; 1, 8-diamino-3-aza-3- (p-nitrobenzenesulfonyl) octane ; 1 , 5 -diamino-3 -aza-3 - (p-nitrobenzenesulfonyl) pentane; 1, 16-diamino-6, ll-diaza-6, 11-bis (oleyl) hexadecane; 1, 16-diamino-7, 10-diaza-7, 10-bis (oleyl) hexadecane; 1, 12-diamino-4 , 9-diaza-4, 9-bis (oleyl) dodecane; 1, 8-diamino-3 , 6-diaza-3, 6-bis (oleyl) octane; 1, 16-diamino-8-aza-8-oleyl hexadecane; 1, 13-diamino-7-aza-7-oleyl tridecane; 1, ll-diamino-5-aza-5-oleyl undecane; 1 , 8-diamino-3 -aza-3 -oleyl octane ; 1, 5-diamino-3 -aza-3 -oleyl pentane; 1, 16-diamino-6, ll-diaza-6, 11-bis (i-butyloxycarbonyl) hexadecane; 1, 16-diamino-7, 10-diaza-7, 10-bis (i-butyloxycarbonyl) hexadecane ; 1, 8-diamino-3 , 6-diaza-3 , 6-bis (i-butyloxycarbonyl) octane; 1, 16-diamino-8-aza-8- (i-butyloxycarbonyl) hexadecane; 1, 13-diamino-7-aza-7- (i-butyloxycarbonyl) tridecane; 1, ll-diamino-5-aza-5- (i-butyloxycarbonyl) undecane ; 1, 8-diamino-3-aza-3- (i-butyloxycarbonyl) octane; 1, 8-diamino-4-aza-4- (i-butyloxycarbonyl) octane; 1, 5-diammo-3 -aza-3- (i-butyloxycarbonyl) pentane; 1, 16-diamino-6, ll-diaza-6, ll-bis(c.-l- [1,4,7, 10-tetraoxa- undecanyl] acetyl) hexadecane; 1, 16 -diammo- 7, l0-dιaza-7,10-bιs(α-l- [1,4,7, 10-tetraoxaundecanyl ] acetyl ) hexadecane ; 1, 12 -diammo-4 ,9-dιaza-4,9-bιs(α;-l- [1,4,7, 10-tetraoxa- undecanyl] acetyl ) dodecane; 1, 8-dιammo-4-aza-4- (α-1- [1,4,7, 10-tetraoxaundecanyl] - acetyl) octane ; 1 , 16 -diammo- 6, ll-diaza-6, 11 -bis (stearyl) hexadecane; 1,16- diammo -7 , 10-dιaza-7 , 10-bis (stearyl ) hexadecane; 1,12- diammo -4 , 9-dιaza-4 , 9-bis (stearyl) dodecane; 1 , 8 -diammo-3 , 6 -diaza-3 , 6-bis (stearyl ) octane ; 1, 16-dιammo-8-aza-8-stearyl hexadecane ; 1, 13-dιammo-7-aza-7-stearyl tridecane; 1 , 11 -diammo- 5 -aza-5 -stearyl undecane ; 1 , 8-dιammo-3 -aza-3 -stearyl octane; 1, 5 -diammo-3 -aza-3 -stearyl pentane; 1 , 16 -diammo- 6 , 11-diaza- 6, 11-bis (palmityl) hexadecane; 1, 16 -diammo- 7, 10-dιaza-7, 10-bis (palmityl) hexadecane ; 1, 12 -diammo-4 , 9-dιaza-4 , 9 -bis (palmityl) dodecane; 1 , 8-dιammo-3 , 6-dιaza-3 , 6-bis (palmityl ) octane; 1 , 16 -diammo- 8 -aza- 8 -palmityl hexadecane , 1 , 13 -diammo- 7 -aza-7 -palmityl tridecane; 1 , 11 -diammo-5 -aza-5 -palmityl undecane; 1 , 8 -diammo-3 -aza-3 -palmityl octane ; 1 , 5-dιammo-3-aza-3-palmιtyl pentane. EXAMPLE 1 bis [ trans-diammmechloroplatmum (II) ] -μ- [1, 12-dιammo- 4 , 9-dιaza-4 , 9-bis (methoxycarbonyl) dodecane] dmitrate trans-dιammmedιchloroplatmum(II) (0.705 g, 2.35 mmol) is dissolved m dry DMF (70 mL) then a solution of AgN0 3 - (0.399 g, 2.35 mmol) m DMF (5 mL) is added and the resulting mixture is stirred for 20h at 20°C, shielded from light. The precipitated AgCl is filtered off and the clear yellow filtrate is cooled to —20°C. Then a solution of 1, 12-diamino-4 , 9-diaza-4 , 9-bis (methoxycarbonyl) dodecane (0.35 g, 1.114 mmol, in 10 mL of DMF) is dropped therein, afterwards (about 40') the resulting mixture is stirred for lh at -20°C and 3h at 25°C. The pale yellow solution is then concentrated under vacuum to an about 5 mL volume and diluted with acetone (30 mL) . The formed grey precipitate is stirred overnight, then filtered and dried under vacuum (35°C, 2h; 25°C, overnight) . The resulting solid is dissolved in MeOH/H 2 0 10:1 (165 mL) . Active charcoal Norit A (100 mg) is added then, after 35' stirring, filtered off. The clear filtrate is concentrated under vacuum to an about 5 mL volume, then MeOH (30 mL) is added and the mixture is left to crystallize for 2h. The precipitated solid is filtered and dried under vacuum (35°C, 2h; 25°C, overnight) thereby obtaining 0.6 g (55%) of the desired product. 1 H-NMR (D 2 0) 1.6 (bs, 4H) ; 1.9 (m, 4H) ; 2.75 (bt, 4H) ; 3.25-3.5 (m, 8H) ; 3.75 (s, 6H) . EXAMPLE 2 bis [ trans-diamminechloroplatinum(II) ] - μ- [1, 12-diamino- 4 , 9-diaza-4 , 9-bis (n-hexyloxycarbonyl) dodecane] dinitrate trarts-diamminedichloroplatinum(II) (0.524 g, 1.747 mmol) is dissolved in dry DMF (52 mL) then a solution of AgN0 3 (0.296 g, 1.747 mmol) in DMF (3 mL) is added and the resulting mixture is stirred for 20h at 20°C, shielded from the light. The precipitated AgCl is filtered off and the clear yellow filtrate is cooled to —18°C. Then a solution of 1, 12-diamino-4, 9-diaza-4, 9-bis (n-hexyloxycarbonyl) dodecane (0.38 g, 0.828 mmol, in 10 mL of DMF) is dropped therein, afterwards (about 40') the resulting mixture is stirred for lh at -20°C and 3h at 25°C. The pale yellow solution is then concentrated under vacuum to an about 5 mL volume and diluted with MeOH (15 mL) . The formed grey precipitate is stirred for 2h, then filtered and dried under vacuum (35°C, 2h; 25°C, overnight) . The resulting solid (0.49 g; , s dissolved m MeOH/H 2 0 2:1 (75 mL) and heated to 35°C. Active charcoal Norit A (100 mg) is added then, after 35' stirring, filtered off. The clear filtrate is concentrated under vacuum until crystallization begins, then left to crystallize for 3h at 10°C. The precipitated solid is filtered and dried under vacuum (35°C, 2h; 25°C, overnight) thereby obtaining 0.33 g (67%) of product. EXAMPLE 3 bis [ trans-diammmechloroplatmum (II) ] -μ- [1, 8 -diammo- 4-aza-4- (benzyloxycarbonyl) octane] dmitrate trans-diammmedichloroplatmum (II) (0.725 g, 2.416 mmol) is dissolved m dry DMF (75 mL) , then a solution of AgN0 3 (0.410 g, 2.416 mmol) m DMF (10 mL) is added and the resulting mixture is stirred for 20h at 20°C, shielded from the light. The precipitated AgCl is filtered off and the clear yellow filtrate is cooled to —18°C. Then a solution of 1 , 8-dιammo-4 -aza-4 - (benzyloxycarbonyl) octane (0.27 g, 0.966 mmol, m 10 mL of DMF) is dropped therein, afterwards (about 40') the resulting mixture is stirred for lh at -18°C and 3h at 25°C. The pale yellow solution is then concentrated under vacuum to an about 3 mL volume and diluted with H 2 0 (15 mL) . The formed grey precipitate is stirred for 3h, then filtered and dried under vacuum (35°C, 2h; 25°C, overnight) . The resulting solid is dissolved (0.2 g) m DMF/H 2 0 2:1 (35 mL) , heated to 35°C. Active charcoal Norit A (100 mg) is added then, after 35' stirring, is filtered off. The clear filtrate is concentrated under vacuum until crystallization begins, then left to crystallize for 3h at 10°C. The precipitated solid is filtered and dried under vacuum (35°C, 2h; 25°C, overnight) thereby obtaining 0.06 g of product. EXAMPLE 4 bis [ trans-diammmechloroplatmum (II) ] -μ- [1, 12 -diammo- 4 , 9-dιaza-4 , 9-bis ( i -butyloxycarbonyl ) dodecane] dmitrate trans-diammedichloroplatmum (II ) (0.750 g, 2.5 mmol) is dissolved dry DMF (78 mL) , then a solution of AgN0 3 (0.424 g, 2.5 mmol) m DMF (10 mL) is added and the resulting mixture is stirred for 20h at 20°C, shielded from the light. The precipitated AgCl is filtered off and the clear yellow filtrate is cooled to —18°C. Then a solution of 1 , 12-dιammo-4 , 9-bis (i-butyloxycarbonyl ) dodecane (0.402 g, 1 mmol, in 10 mL of DMF) is dropped therein, afterwards (about 40') the resulting mixture is stirred for lh at —18°C and 3h at 25°C. The pale yellow solution is then concentrated under vacuum to an about 3 mL volume and diluted with H 2 0 (15 mL) . The formed grey precipitate is stirred for 3h, then filtered and dried under vacuum (35°C, 2h; 25°C, overnight) to obtain 0.14 g of product (14%). EXAMPLE 5 With a process similar to that described m Examples 1-4, starting from the corresponding diamines, are prepared: bis [ trans-diammmechloroplatmum (II) ] -μ- [1 , 16-diammo- 6 , 11- diaza- 6, 11 -bis- (methoxycarbonyl) hexadecane] dmitrate; bis [trans-diammmechloroplatmum (II) ] -μ- [1 , 16 -diammo- 7, 10- dιaza-7 , 10-bis- (methoxycarbonyl) hexadecane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1, 8 -diammo-3 , 6- dιaza-3 , 6 -bis (methoxycarbonyl) octane] dmitrate; bis [trans-diammmechloroplatmum (II) ] -μ- [1, 16 -diammo-8- aza- 8- (methoxycarbonyl) hexadecane] dmitrate; bis [ trans-diammmechloroplatmum ( II) ] -μ- [1 , 13 -diammo- 7- aza-7- (methoxycarbonyl) tridecane] dmitrate; bis [trans-diammmechloroplatmum (II) ] -μ- [1, 11 -diammo-5- aza-5- (methoxycarbonyl) undecane] dmitrate; bis [trans-dιammmechloroplatmum(II) ] -μ- [1 , 8-dιammo-3-aza- 3- (methoxycarbonyl) octane] dinitrate; bis [ trans-diammmechloroplatmum ( II) ] -μ- [1 , 8 -diammo-4-aza- 4- (methoxycarbonyl) octane] dmitrate; bis [ trans-diamminechloroplatinum (II) ] -μ- [1, 5 -diammo-3-aza- 3- (methoxycarbonyl) pentane] dmitrate; bis [ trans-diamminechloroplatinum(II) ] -μ- [1, 16-diamino-6 , ll- diaza-6 , 11-bis (n-hexyloxycarbonyl) hexadecane] dmitrate; bis [ϋrans-diamminechloroplatinum(II) ] -μ- [1 , 16 -diammo-7, 10- diaza-7, 10-bis (n-hexyloxycarbonyl) hexadecane] dini-trate bis [ trans-diamminechloroplatinum (II) ] -μ- [1, 8 -diamino-3 , 6- diaza-3 , 6-bis (n-hexyloxycarbonyl) octane] dmitrate; bis [ rans-diamminechloroplatinum (II) ] -μ- [1, 16-diamino-8- aza- 8- (n-hexyloxycarbonyl) hexadecane] dmitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 13-diamino-7- aza- 7- (n-hexyloxycarbonyl) tridecane] dmitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1 , 11 -diammo- 5- aza-5- (n-hexyloxycarbonyl) undecane] dmitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1 , 8-diamino-3-aza- 3- (n-hexyloxycarbonyl) octane] dmitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 8-diamino-4-aza- 4- (n-hexyloxycarbonyl octane] dmitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 5 -diammo-3 -aza- 3- (n-hexyloxycarbonyl) pentane] dmitrate; bis [ trans-diamminechloroplatinum (II) ] -μ- [1 , 16-diamino-6 , ll- diaza-6, 11-bis (α- [1,4, 7, 10-tetraoxaundecanyl] acetyl) hexadecane] dmitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 16-diamino-7, 10- diaza-7, 10-bis (α- [1, 4, 7, 10-tetraoxaundecanyl] acetyl) hexadecane] dmitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 12-diamino-4 , 9- diaza-4, 9-bis(o- [1,4,7, 10-tetraoxaundecanyl] acetyl) dodecane] dmitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 8-diamino-4-aza- 4-(α--[l,4,7, 10-tetraoxaundecanyl] acetyl) octane] dmitrate; bis [ trans-diamminechloroplatinum (II) ] -μ- [1 , 16-diamino-6 , ll- diaza-6, 11-bis- (oleyl) hexadecane] dmitrate; bis [ trans-diamminechloroplatinum (II) ] -μ- [1 , 16-diamino-7 , 10- dιaza-7 , 10-bis- (oleyl) hexadecane] dmitrate; bis [ trans-dιammmechloroplatmum(II) ] -μ- [1, 12 -diammo- 4 , 9- dιaza-4 , 9-bis (oleyl) dodecane] dmitrate; bis [ trans -diammmechloropl at mum (II; ] -μ- [1 , 8 - diammo- 4 -aza - 4- (oleyl) octane] dmitrate; bis [ trans- diammmechloropl at mum (II) ] -μ- [1 , 16 -diammo- 6 ,11- dιaza-6, 11 -bis (p- nitrobenzenesulfonyl) hexadecane] dmitrate ; bis [ trans -diammmechloropl at mum (II) ] -μ- [1 , 16 -diammo- 7 ,10- dιaza-7,10-bιs (p- nitrobenzenesulfonyl) hexadecane] dmitrate ; bis [trans-diammmechloroplatmum (II) ] -μ- [1 , 12 -diammo-4 , 9- dιaza-4 , 9-bis (p-nitrobenzenesulfonyl ) dodecane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1 , 8-dιammo-4-aza- 4- (p-nitrobenzenesulfonyl) octane] dmitrate; bis [trans-diammmechloroplatmum (II) ] -μ- [1, 16-diammo- 6 , 11- dιaza-6 , 11-bis- (benzyloxycarbonyl) hexadecane] dmitrate; bis [ trans-dιammmechloroplatmum(II) ] -μ- [1, 16 -diammo- 7 ,10- dιaza-7 , 10-bis- (benzyloxycarbonyl) hexadecane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1, 12 -diammo-4 , 9- dιaza-4 , 9-bis (Penzyloxycarbonyl ) dodecane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1, 8-dιammo-4 -aza- 4- (benzyloxycarbonyl) octane] dmitrate; bis [trans-diammmechloroplatmum (II) ] -μ- [1, 8 -diammo-3 , 6- dιaza-3 , 6-bis (benzyloxycaroonyl ) octane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1 , 16 -diammo- 8- aza-8- (benzyloxycarbonyl ) hexadecane] dmitrate; bis [trans-diammmechloroplatmum (II) ] -μ- [1, 13 -diammo- 7- aza-7- (benzyloxycarbonyl) tridecane] dmitrate; bis [trans-diammmechloroplatmum (II) ] -μ- [1, 11 -diammo- 5- aza-5= (benzyloxycarbonyl) undecane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1 , 8 -diammo- 3 -aza- 3- (benzyloxycarbonyl) octane] dmitrate; is [trans-diammmechloroplatmum (II) ] -μ- [1 , 5 -diammo-3 -aza- 3- (benzyloxycarbonyl) pentane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1 , 16-diamino-6 , ll- diaza-6 , 11-bis (i-butyloxycarbonyl) hexadecane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1 , 16-diamino-7 , 10- diaza-7, 10-bis (i-butyloxycarbonyl) hexadecane] dinitrate; bis [ rans-diamminechloroplatinum (II) ] -μ- [1 , 8-diamino-3 , 6- diaza-3 , 6-bis (i-butyloxycarbonyl) octane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1 , 16-diamino-8- aza-8- (i-butyloxycarbonyl) hexadecane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1 , 13 -diamino-7- aza-7- (i-butyloxycarbonyl) tridecane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, ll-diamino-5- aza-5- (i-butyloxycarbonyl) undecane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1 , 8-diamino-3 -aza- 3- (i-butyloxycarbonyl) octane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 8 -diammo-4-aza- 4- (i-butyloxycarbonyl) octane] dinitrate; bis [trans-diamminechloroplatinu (II) ] -μ- [1, 5-diamino-3-aza- 3- (i-butyloxycarbonyl) pentane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 16-diamino-6, ll- diaza-6 , 11-bis- (stearyl) hexadecane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 16-diamino-7 , 10- diaza-7, 10-bis- (stearyl) hexadecane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 12-diamino-4 , 9- diaza-4 , 9-bis- (stearyl) dodecane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 8-diamino-3, 6- diaza-3 , 6-bis (stearyl) octane] dinitrate; bis [ rans-diamminechloroplatinum (II) ] -μ- [1 , 16-diamino-8- aza-8-stearyl hexadecane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 13-diamino-7- aza-7--stearyl tridecane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, ll-diamino-5- aza-5-stearyl undecane] dinitrate; bis [trans-diamminechloroplatinum (II) ] -μ- [1, 8-diamino-3-aza- 3-stearyl octane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1 , 5 -diammo- 3 -aza - 3-stearyl pentane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1 , 16 -diammo- 6, 11- dιaza-6 , 11-bis- (palmityl) hexadecane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1 , 16 -diammo- 7 , 10- dιaza-7 , 10-bis- (palmityl ) hexadecane] dmitrate; bis [ trans-diammmechloroplatmum (II)]-μ- [l,12 -diammo- 4 , 9- dιaza-4 , 9-bis (palmityl) dodecane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1 , 8 -diammo -3 , 6- dιaza-3 , 6-bis (palmityl) octane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1 , 16-dιammo-8- aza-8-palmιtyl hexadecane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1 , 13 -diammo- 7- aza-7-palmιtyl tridecane] dmitrate; bis [ trans-diammmechloroplatmum (II) ] -μ- [1 , 11 -diammo- 5- aza-5-palmιtyl undecane] dmitrate; bis [trans-diammmechloroplatmum (II) ] -μ- [1, 8 -diammo- 3- aza - 3 -palmityl octane] dmitrate; bis [trans-diammmechloroplatmum (II) ] -μ- [1 , 5 -diammo -3 -aza- 3 -palmityl pentane] dmitrate.

Claims: CLAIMS Compounds of formula (I) wherein: X is halogen (chlorine, bromine, iodine) ; n, m = an integer 2 to 8; p = 1, 2; A is selected from the group consisting of —B-, -B- (CH 2 ) r -B-, -B- (CH 2 ) r -B- (CH 2 ) Z -B-, with r and z ranging from 2 to 8 ; B is a group of formula —NR- wherein R is a group convertible into a hydrogen atom under physiological conditions, with the proviso that R is different from C -C 4 alkyl or acyl and from ter-butoxycarbonyl . Q ~ P is an anion selected from the group of chloride, bromide, iodide nitrate, sulfate, hydrogen sulfate and perchlorate. 2. Compounds as claimed in claim 1, wherein R is selected from the group consisting of: 1 ) wherein: R- ] _ , R 2 and R 3 , which can be the same or different, are hydrogen, C-^ - ^ alkyl, 5 -Cg cycloalkyl, phenyl optionally substituted with one or more C 1 -C 4 alkyl, C- j _-C 4 alkoxy, halogen, hydroxy, or are C 7 -C 1Q aralkyl ; or R-^ , R 2 and R 3 are the residue of an α-amino acid in the D or L configuration; and R a is C-L-Cg alkyl, preferably t-butyl; 2) R 4 CO- wherein R 4 is hydrogen, C 3 -C 8 cycloalkyl, preferably C 5 -Cg, phenyl optionally substituted with C ] _-C 4 alkyl, c ι" c 4 alkoxy, hydroxy, nitro, cyano, halogen; alkyl C 1 ~ C 2 -phenyl ; ethyloxy or C 3 -Cg alkyl interrupted by 1 to 4 oxygen atoms with the exception of —0-CH 2 -0- acetal groups; or R 4 is a residue of a saturated or unsaturated fatty acid or a residue of a hexose or pentose sugar; 3) 4 ) - CO-0-R 5 wherein R 5 is C 1 -C 18 alkyl (with the exception of t- butyl) , C 3 -C 18 alkenyl, benzyl or benzyl substituted at the phenyl position with one or more hydroxy, C- | _-C 4 alkyl, C 1 -C 4 alkoxy, nitro, cyano, acetoxy, c ι~ c 3 alkylaminocarbonyloxy, ^ι"^ 3 alkoxycarbonyloxy groups; a residue of a hexose or pentose sugar, a group of formula: wherein F is methyl or phenyl; or a group of formula wherein R g is hydrogen or C^-C ^ ^ alkyl and w is an integer 1 to 6; 5) wherein Rg is methyl or phenyl ; 6 ) wherein Rg and R 7 , which can be the same or different, are hydrogen or - j _-C 4 alkyl; 7) wherein Rg is hydrogen or C- j _-C 4 alkyl 8) wherein R 9 is hydrogen or C- j _-C 4 alkyl and R 1Q is C-,-C 4 alkyl ,- 9) wherein R-^ and R 12 , which can be the same or different, are hydrogen, C- | _-C 4 alkyl, phenyl; 10) wherein Rb is C j -Cg alkyl, preferably methyl, 11) A group of formula C, D or E, D wherein R^ is as defined above and R c , R^, R e and f, which can be the same or different, are H, CH 3 or OCH 3 ; 12) 13) wherein Z is c 2" c 4 alkylene, cycloalkylene, optionally substituted phenylene, T is an oxygen atom or a —NH- or —N-R 14 group, wherein R 14 is χ -C 4 alkyl; Y is a bond, an oxygen atom, a NH or —N-R 14 group as defined above; R 13 is c ι"C 4 alkyl, c s ~ C 6 cycloalkyl, phenyl; phenyl optionally substituted with c _C 3 alkyl, c ι~ C 3 alkoxy, nitro, cyano, hydroxy groups. 3. Compounds as claimed in claim 2, wherein R ~R 3 are hydrogen or alkyl. 4. Compounds as claimed in claim 2, wherein R 4 is an alkyl group interrupted by oxygen atoms, selected from polyoxyethylene, or a residue of a saturated or unsaturated fatty acid or a residue of a hexose or pentose sugar. 5. Compounds as claimed in claim 2, wherein R 5 is methyl, i-butyl, n-hexyl, benzyl, p-nitro-benzyl , 4-acetyloxy- benzyl, 4-methylaminocarbonyloxy-benzyl , 4 -methoxycarbonyloxy-benzyl . 6. Compounds as claimed in claim 2, wherein Rg and R 7 are hydrogen, methyl, tert-butyl, isopropyl. 7. Pharmaceutical compositions containing as active ingredient a compound of claims 1-6 in mixture with a suitable carrier. 8. Compositions as claimed in claim 7, in the form of combined preparations for the sequential or simultaneous administration, containing, in addition to a compound of claims 1-6, an antitumor drug with synergistic action. 9. The use of the compounds of claims 1-6 for the preparation of antitumor medicaments.

Inventors: DA RE GIOVANNI, MENTA ERNESTO, SPINELLI SILVANO, DA RE, GIOVANNI, MENTA, ERNESTO, SPINELLI, SILVANO
Applicants: DA RE GIOVANNI, MENTA ERNESTO, NOVUSPHARMA SPA, SPINELLI SILVANO, DA RE, GIOVANNI, MENTA, ERNESTO, NOVUSPHARMA S.P.A., SPINELLI, SILVANO
Application year: 2000
Main classification: C07F15
IPC codes: A61K33, A61P35, C07F15