PT89608B

Pt (IV) complexes.

Abstract

A Pt(IV) complex of the formula <CHEM> wherein A and A min are NH3 or an amino group; R and R<1> are hydrogen, alkyl, alkenyl, aryl, aralkyl, alkylamino or alkoxy or functionalized derivatives thereof; and X is halogen or alkyl mono- or dicarboxylate. The complexes have high antitumor activity, particularly when administered orally.

Term

No projected expiry on record.

7 claims: 1 independent, 6 dependent

1
CLAIMS REIVINDICAÇÕES 1.- Process for the preparation of platinum (IV) complexes of general formula 1.- Processo para a preparação de complexos de platina (IV) de fórmula geral 0 - C - R 0 - C - R J na qual A e A' representam, cada um, um grupo NH^ ou um grupo amino;R e R^ representam, cada um,um átomo de hidrogénio ou um grupo alquilo C^-C^Q, alcenil°' arilo, aralquilo, alquilamino ou alcoxi;J wherein A and A 'each represent an NH 4 group or an amino group;R 2 and R 4 each represent a hydrogen atom or a C 1 -C 4 alkyl groupQ, Thelcenaryl, aralkyl, alkylamino or alkoxy;and X represents a halogen atom or an alkyl monocarboxylate or dicarboxylate group, wherein an appropriate platinum (IV) compound is subjected to a carboxylation reaction. e X representa um átomo dc halogéneo ou un grupo monocarboxilato ou dicarboxilato dc alquilo, caracterizado pelo facto do se submeter um composto de platina (IV) apropriado a uma reacção de carboxilação.

632 paragraphs in 95 sections, as filed

DESCRIPTION

GIVES

PATENT OF INVENTION

No. 89 608

APPLICANT: JOHNSON MATTHEY INC., American, Industrial, established at 4 Malin Road, Malvern, Pennsylvania 19355, United States of America ca.

TITLE:

INVENTORS:

PROCESS FOR THE PREPARATION OF PLATINE (IV) COMPLEXES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Michael J. Abrams, Christen M. Gaindomenico, Barry A.Murrer and Jean F. Vollano.

Claim of right of priority under Article 4 of the Paris Convention of 20 March 1883.

United States of America on 2 February 1988 under9 . 151,674 and on January 13, 1989, under number9. 296,776.

INPI MOO 113 RF 16732

JOHNSON MATTHEY INC,

PROCESS FOR PREPARING PLATINUM COMPLEX (IV)

AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to novel Pt (IV) complexes that demonstrate powerful anti-tumor activity.

BACKGROUND OF THE INVENTION

Since the development and use of cls-platinum as an effective antitumor agent, intensive research has been done to find platinum complexes that can demonstrate identical or better antitumor activity while providing improvements in other properties, for example, reduction of toxicity and other undesirable side effects.

A variety of cis-platinum analog compounds, including Pt (IV) complexes such as cis-trans-cis-PtCl (OH) (1-prNH) fc · fc C. C, were investigated intensively. (U.S. Patent No. 4 394 319) and

PtCl4 (DACH) (U.S. Patent No. 4,550,187)

Most of the antitumor Pt compounds described so far are hydrophilic in that they dissolve more easily in water than they dissolve in ordinary organic solvents, for example acetone, methylene chloride, and the like. Examples of such hydrophilic complexes include cisplatin and carboplatin itself. Recently a variety of fat-soluble Pt complexes have been described, for example bis (caprate) DACH Pt7 which have low water solubility but easily dissolve in dis. Organic solvents. See Maeda et al., JPN, J, Cancer Res. 77,523-525 (1986).

Some platinum (II) and (IV) and 1-amino-2-aminomethyl-cyclopentane complexes are also described in U.S. Patent No. 4,466,924. This patent generally relates to the possibility of encompassing acetate substituents. oxalate, malonate or carboxylate bound to the platinum atom. However, no specific examples of such complexes have been disclosed in this patent.

DESCRIPTION OF THE INVENTION

The present invention provides Pt (1V) complexes that demonstrate a high degree of anti-tumor activity, particularly when administered orally. Many

These complexes exhibit a high degree of solubility in both water and organic solvents and this dual-type solubility property can contribute significantly to the high degree of antitumor activity demonstrated by these complexes when administered orally. See J. Blanchard, Am, J. Pharm., 135 (1975) and M. Orme, Br, J, Amaesth., 56, 59 (1984).

The complexes of the present invention may be illustrated structurally by the following general formula I:

II

(I)

Wherein A and A 'represent an NH 4 or amino group, for example a (C 1) alkyl1-Çlo) -amine (straight chain, branched or cyclic); rand R 1 is each selected from 1 hydrogen atom or an alkyl group, for example alkyl or alkenyl, aryl, aralkyl, alkylamino or alkoxy or functionalized derivatives thereof; and X represents a halogen atom or an alkyl mono- or dicarboxylate.

-4 - same or different.

The substituents A and A may be

The simplest aspect, both A and A 'can represent

However, one or both of these substituents may represent an amine, the nature of which may vary widely. This includes, for example, aromatic, heteroaromatic or heterocyclic radicals, for example anilino, pyridyl, asiridine or morpholine groups, functionalized amines such as MH (CH ..) -, CO.

λ 2 3 2 2 b

X ^ CC ^ -cC · ^ lCO2CH2CH2Í'II 2 or sinilares wherein X 3 represents a lower alkyl group such as methyl, ethyl, propyl, etc. A and / or A 'may also represent a burning diamine such as 1,2-diaraino-cyclohexane (CACH) or 2-aminomethyl-cyclo-b.exylamine (ΔHCHa). uses a quenching amine, A and A 'are joined to complete a ring provided that A and A' do not however comprise a cyclopentane ring, when R and / or R3 each represent a methyl group.

Other specific examples of A and / or A 'include primary or secondary amines such as n-propylamine (nCCH ^MH ^), isopropylamine (i-Cyl ^HN ^), cyclopropylamine (cCH HMH ^). ), cyclobutylamine (CC ^H ^ MHH ^), isobutylamine (C1 H ^H ?H??), tertiary butylamine (tC ^H MHH?)), neo-pentylamine, t-amylamine, isoamylamine (CHC lH ^ NHH?). - (1), cyclopentylamine (cC glycMH 2), cyclohexylamine (cC HCl LiH 4), cyclohexylamine C c -C6II1L3-l2), cycloheptylamine (CC ^j ^^H) and corresponding secondary alkylamines, for example di-n-oropylamine. How

Of course, the alkyl group or groups in the alkyl amine may be straight chain, branched chain or cyclic. Also included are mixed alkyl amine groups.

The substituents R1 and R2 may also be the same or different. Representative meanings for the substituents R 1 and R 3 include alkyl groups of 1 to 10 carbon atoms, straight chain or branched such as CH 3, C2H ^, Rt-C -Hq, CC ^H,,, nC4Hg, nC ^ H ^^, nC ^ H ^ or nC ^ H ^; cycloalkyl of 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; ethenyl, propenyl or other alkenyls; similar monocyclic or dicyclic phenyl, tolyl, naphthyl or aryl; benzyl or phenethyl or similar aralkyl; (lower alkyl) amino (primary amino) with up to 6 carbon atoms, for example methylamino (CH 2 NH-), ethylamino (C 1 H 4 NH-); and lower alkoxy of 1 to 6 carbon atoms such as methoxy, ethoxy, etc. R 2 and R 4 may each also represent a functionalized group such as an alkoxyalkyl (e.g. methoxymethyl), tosylamino or the like group. It is intended that the definition of R 1 and R 4 given above for general formula I encompasses such functionalized or substituted groups.

Representative substituents of X are chlorine, bromine or other halogens, or C1-10 alkyl mono-carboxylate4 such as acetate or dicarboxylate such as malonate or

-6-cyclobutane-1,1-dicarboxylate. The substituents X, such as the substituents R, R4 and A / A 'may be the same or different. They may also be linked as a chelating dicarboxylate radical.

It should be noted that the substituents indicated for A, A ', X, R and R 4 may also be substituted themselves. For example, when R and / or R 2 represent an alkyl group, that alkyl radical may be substituted by a halogen atom to provide a chloromethyl substituent.

A preferred subgroup of compounds within the scope of formula I is that wherein A represents THE'represents a C 1 -C 4 lower alkylamino group, X represents a chlorine atom and R and R 3 represent a C 1 -C 4 lower alkyl group or cycloalkyl having 3 to 7 carbon atoms. Especially preferred are compounds wherein A 'represents a cyclopentylamine (cC5HgNH2) or cyclohexylamine (cC θΗ ^ NH 2 ) and R1 and R2 each represent a propyl group.

Other subgroups of compounds encompassed by general formula I include those wherein A represents NH4, A * represents an alkylamino group, X represents a chlorine atom and R and R3 each represent a (lower alkyl) amino group or lower alkoxy.

The compounds of the present invention and the necessary starting compounds may be prepared by procedures generally known in the art. Pt (OH) type starting compounds are conveniently prepared.2, C4 AA 'and Pt (OH)2Cl2THE2 by the reaction of ^ 2 ^ 2 with the corresP °nodente species Pt (Il) -dichloro / RJ Brandon, JC Dabrowiak, J. Med, Chem. , 27: 861 (1984) J7. The synthesis of the species Pt (II) -dichlor is described in the literature (see, MJ Cleare, JD Hoeschele, Plat.

Met. Rev. 17: 2 (1973) and TA Connors et al., Chem. Biol. Interact., 11: 145 (1975). For example, it is possible to prepare complexes where X represents a halogen atom by reacting a compound Pt (OH)2X2 · P °r example, Pt (OH2) Cl2 (i-PrNH2)2with the appropriate anhydride, isocyanate or pyrocarbonate. The reaction may be effected by simply mixing the reagents at room temperature (20 ° -25 ° C) and then cooling to crystallize the desired product. A generically identical preparation of other platinum complexes of formula PtCl has been previously mentioned.2- (RCO2)2 (i-PrNH2)2 where R represents a group CF4, CF2CF3 or CF2 CF2But these complexes were found to be practically insoluble in water. See Cowens et al., Int. J. of Mass Spectrometry and Ion Physics, 48, 177-180 (1983).

Complexes of formula I wherein X represents a carboxylate group may be prepared by acylation of the intermediate compound formed by oxidation with hydrogen peroxide of P t (H 20) 2 (R2 ) (R2 ) 2 + _7 which in turn prefers from Ptl2(R1 NH2) (R2) and silver nitrate.

As noted, the complexes of the present invention demonstrate antitumor activity when administered orally for the treatment of malignant tumors. Accordingly, the complexes may be formulated into tablets, pills, capsules, sterile suspensions, solutions or the like suitable for oral administration. Conventional pharmaceutical carriers, additives, binders and / or excipients may also be used.

The present invention is illustrated without limitation, with the following examples using ctc as a vehicle opener for cis-trans-cis, in order to identify the stereochemistry of coordinate ligands around the octahedral Pt when paired together. in the written order and used. ο-0χΗγ to refer to a cyclic alkyl radical being the ring size specified by the X index.

-9Example 1 ctc-PtCl2(O2CCH3)2(NH3) (cC5H NH2) Asosto N2 33

0.31 g of ctc-? tC 12 (0H2 ) (NH3 ) (cCl2) in 7 ml of acetic anhydride until the solid dissolved. The solution was cooled to 5 ° C and the product crystallized. Addition of ether provided more product. The solid was collected, washed with ether and dried under vacuum. The yield was 0.33 g, 87% based on Pt. The product recrystallized from a hot ethyl acetate / hexane mixture.

Example 2

Ctc-PtC12(O2CCH3)2(NH3) (nC3H?NH2) Asosto N? 9th

The product was synthesized by the method described in Example 1 but using ctc-PtCl2(OH)2(NH3) (nC ^H ^N N · ^) instead of the platinum compound of Example 1.

Example 3 ctc-PtCl2(O2CCH2CH3)2(NH3) (nC ^ NH ^

Compound No. io

The product of this Example was synthesized using proplonic anhydride and 2 g of ctc-PtCl.2(OH)2(nC ^ HγΝΗ2). The reaction yielded 0.87 g of product (33%).

Example 4 ç-tc-PtCl2(O2CCH2CH3)2(NH3) (tC4HgNH2) Asosto N? 23

The method described in Example 1 was repeated using propionic anhydride and 1 g of ctc-PtCl2(OH)2(NH3) (tC4HgNH2) to provide 0.30 g of product (23%).

Example 5 ctc-PtCl2(O2CC (CH3)3)2(iC3H7NH2)2 NS 6 compound

The product was synthesized by the method described in Example 1 using pivalic anhydride and 1 g of ctc-PtCl.2(OH)2(iC3H7NH2)2 affording 0.82 g of product (59%).

Example 6 ctc-PtCl2(O2CCH2CH2CH3)2(iC3H7NH2)2 NS 5 Compound

The product was synthesized by the method described in the previous Examples and precipitated from solution by adding excess hexane and cooling to 0 ° C. The reagents were anhydrous. of butyric acid and 1 g of ctc-PtCl2(OH)2(iC3H7NH2) yielding 0.85 g of product (64%).

Example 7 ctc-PtCl2(O2CC6H5)2(iC3H7NH2)2 Compound No. 7

Ctc-PtCl dissolved2(OH)2(iC3H7NH2)2 (2 g; 0.0048 mol) in benzoic anhydride (10.82 g), pyridine (0.15 ml) and toluene (5 ml). The precipitated product was collected after a few hours, washed with copious amounts of ether to dissolve excess benzoic anhydride and dried under vacuum.

The product was recrystallized from a mixture of ethyl acetate / hexa. in the hot. The reaction provided 1.25 g (41%).

Example 8 ctc-PtCl2(O2CC2H5)2(iC3H7NH2)2 Compound N? 4

With 1 g of ctc-PtCl2(OH)2(iC3H7NH2)2 It was suspended in dichloromethane (50 ml) and triethylamine (0.72 g, 3 equivalents). Propionyl chloride (0.63 ml, 3 equivalents) was added dropwise. After 15 minutes of stirring, water (20 ml) was added, the mixture was filtered and the organic phase was washed with water (2 x 20 ml), dried over magnesium sulfate and evaporated to dryness. under empty. The residue was recrystallized from a mixture of ethyl acetate / ether. The production of ctc-PtC 12 (O2CC2Hc-) 2 (iC 3H7NH2 ) 2 was 0.18 g (14%).

Example 9 ctc-PtCl2(O2CCH (CH3) CH2CH3)2NH3(cC6H11NH2) Compound N? 2

(S) - (+) - 2-Methylbutyric acid (0.982 g) and triethylamine (0.971 g) were dissolved in anhydrous dimethylacetamide (10 ml) and cooled to 0 ° C. Isobutylchloroformate (1.3 g) in dimethylacetamide (2 ml) was added dropwise and stirred at <4 ° C for 2 hours.

-13 ctc-PtCl was added2 (OH) 2NH3 (c_C6H11NH2 ) (1 g) in suspension in dimethylacetamide (10 ml) and the mixture was stirred for 24 hours at room temperature. Water (10 ml) and methylene chloride (10 ml) were added, the organic phase was collected and the aqueous phase was extracted with more methylene chloride (10 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution (2 x 10 ml) and the solvent removed under vacuum. 0 The resulting orange oil crystallized from an ethyl acetate / ether mixture. It was found by microanalysis that the yellow crystals (500 g) of ctc-PtCl „(O „CCH (CH) -CHCH NH).£H, NH) contained one mole of dimethylacetamide / Pt. The presence of dimethylacetamide was confirmed by infrared spectroscopy.

Example 10 ctc-PtCl2(O2CH)2NH3(cC6H11NH) Compound N? 37

Ctc-PtCl (OH) NH_ (c-CNH_) (140 mg) was dissolved

Ζ Z □ D ii Z in formic acid (96%, 2 ml) and heated to 50 ° C. After 1 hour, the solution was cooled to room temperature, the resulting white solid was filtered off, washed with water (3 x 5 ml) and dried to give ctc-PtCl.2(O CH.) NH3(cC6H11NH) (80 mg, 50%).

I

Example 11 f '

-14c-tc-PtBr2(O2CnC3H7)2NH3(cC6H11NH2) Compound Ne 66

With cis-PtI2(NH3) (cC6H ^^ NH2) (8.01 g) was suspended in a mixture of water (50 ml) and ethanol (10 ml). Silver nitrate (4.7 g; 1.95 equivalents) was added and the mixture was stirred in the dark overnight. The precipitated silver iodide was filtered off and HBr (48% aqueous solution, 30 ml) was added. After stirring for 1.5 hours, it was collected by cis-PtBr filtration.2 (NH 4) (cCl 3 H) (6.9 g) and dried.

The dibromo complex (6.9 g) was oxidized by treatment with 3 equivalents of H2O2Pt in water (15 ml) and acetone (10 ml) for 3 hours at 60 ° to 70 ° C. On cooling crystallized PtBr (OH) NH 3 (cC, Η,ΊNH 4) and collected by filtration, washed with water and dried. The yield was 5.05 g, 67%. This compound (1.5 g) was stirred in butyric anhydride (15 ml) for 3 days at room temperature to afford a pale yellow solution which was partitioned between dichloromethane (20 ml) and water (20 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and the solvent was removed under vacuum. 0 The resulting yellow oil was triturated with hexane to provide ctc-PtBr_ (0 „CnCOH „) NHO (cCl 3 NH 4) 2 2 3/23 o 11 2 (0.39 g, 20%) as a yellow powder.

-Ιοί xemolo L · ctc-? TCl2 (O2CCm3) KO2Cn-Ct-L3laugh7) Nh3 (ç )

Comoosto T2 72

3.35 g of ctcP tC 1 was stirred2 (OH) 2NH3 (cCl ^H) in a mixture of dichloromethane (15 mL) and diethyl ether (15 mL). A mixture of butyric anhydride (2.29g, 1.8 equivalents / Pt) and acetic anhydride (0.164c; 0.2 equivalentss / Pt) was added and the reaction stirred for 20 hours. The resulting white solid was collected by filtration, washed with ether and dried. The yield was 3.30 g. Thin layer chromatography (TLC) (silica gel, eluting with 1: 1 ethyl acetate / dichloromethane) showed that the solid was a mixture of two compounds. 0.9 g of the above mixture was dissolved in 1: 1 ethyl acetate / dichloromethane and chromatographed; on a silica column. The first eluted compound was ctc-PtCl2 (O2CnC3H7> 2NH- (c-C) (450 mg). The second eluted compound (50 mg) was the desired product ctc-PtCl2~ (O2CCH3 ) (02CnC 3H 7) DH3 (cC 1. | _H2 ) confirmed by microanalysis, θ IR NMR spectroscopy. The TLC of this sample had a single spot R = 0.3.

example 13 ctc-PtCl (0OCCH.) (0 „CaC.Hno) (tH) - (cC(.H11KL) Compound Ne 73 2 2 J 2 49 -> 6 11 2

With ctc-PtCl (CH) (ΝΉ) (cC HJH) a suspension was made in a mixture of dichloromethane (10 ml), ether (15 ml),

Valeric anhydride (1.8 equivalents / Pt) and acetic anhydride (1.2 equivalents / Pt) and stirred at room temperature. After 24 hours, the solid was collected by filtration, washed with ether and stirred in dichloromethane (20 ml) for 30 minutes. Collected by ctc-PtCl filtration2(OH) 2 · 113 (cC 2) (0.65 g) which was unreacted and the soluble methylene chloride fraction was evaporated in vacuo. The residual oil (0.4 g) was chromatographed on a 17.5 cm x 2.5 cm silica column, eluting with a 1: 1 ethyl acetate / dichloromethane mixture. The fractions were collected. It was found that the first ctc-PtC12(O ^ CnC ^ Hg)2(NH3) (c-C6 H4 NH4)2) (0.092 g) was identical to the sample of compound 42 prepared by acylation with pure valeric anhydride. The third fraction, ctc-PtCl2 (O2CCH3 ) 2 (NH 3) (cC ^H ^ NN ^) (0.082 g) was identical to an authentic sample of compound 38. The intermediate fraction (0.168 g) was ctc-PtCl ^ ^C CC CCH ^ -Nn ^Hg) (NH3). ) (c -C 6 H 4 NH 4 NH2 ), as confirmed by microanalysis, IR and NMR spectroscopy and found to be pure by TLC.

Example 14 ctc-PtCl2(O2CNHCH3)2(NH3) (tC4H NH2) Compound No. 26

Ctc-PtCl2(OH)2(NH3) (tC4HgNH2) in n-methyl isocyanate (10 ml / g) for 2 hours. The product was collected, washed with ether and dried under vacuum. The amount of

L

-171 g ctc-PtCl (OH) starting compound2(ΝΗ ^) (tC4HgNH2) gave 1.26 g of product (97%).

Example 15 cis-Pt (o2cch3)4(nh3) (t-c3H?nh2)

NS 68 Compound

6.11 g cis-PtI was added2 (NH3) (CH 2 NH 4) to a stirred solution of silver nitrate (3.86 g, 1.95 equivalents) in water (10 ml). Stirring was continued for 1 hour and charcoal (approximately 200 mg) was added and stirred for 10 minutes. After filtration, hydrogen peroxide (30%; 20 ml) was added to the filtrate and the reaction mixture was stirred for 72 hours at room temperature. Carbon black (1 g) was added and the mixture was stirred overnight to remove excess hydrogen peroxide. The carbon was removed by filtration and acetone (200 ml) was added to the filtrate. The reaction mixture was cooled (-20 ° C) overnight. The resulting pale yellow solid was collected, washed with acetone and ether and dried under vacuum. This solid was added to acetic anhydride (20 ml) and potassium acetate (4 g) and the mixture was stirred for 24 hours at room temperature and then allowed to stand one week before pouring into water (100 ml). ml). The mixture was stirred for 5 minutes and then extracted with chloroform (4 x 25 ml). The combined chloroform extracts were washed with a saturated aqueous sodium carbonate solution.

Sodium hydrogen (2 x 50 ml), saturated aqueous sodium chloride solution (50 ml) and dried over magnesium sulfate. After rotary evaporation, some acetic anhydride remained, so ethanol (20 ml) was added, reacted for 5 minutes and removed. This process was repeated until all acetic anhydride was removed as ethyl acetate and acetic acid. 0 Resulting oil crystallized from an ether / hexane mixture affording yellow needles, 0.57 g, 11% yield.

Example 16 ctc-Pt (CBDCA) (O2CCH3)2(NH3)2 Compound N $ 6

C-Pt (CBDCA) (NH3) (4.45 g) at 80 ° C for minutes in a mixture of hydrogen peroxide (30%, 1; 20 ml). On cooling crystallized ctc-Pt (CBDCA) (OH)2(NH3The white solid was filtered off, washed with water and dried. The yield was 3.38 g, 70%.

With ctc-Pt (CBDCA) (OH)2(NH3)2 (1 g) was suspended in acetic anhydride (10 ml) and stirred for 48 hours at room temperature. Ether (20 ml) was added and the white solid was collected by filtration, washed with ether and dried to give ctc-Pt (CBDCA) (O2CCH3)2(NH3)2 (0.99 g, 82%).

(CBDCA = cyclobutane-1,1-dicarboxylate)

Example 17 ç-tc-PtCl2(O2COC2H5)2NH3(NH2-nC3H7) Compound No. 8

1.25 g suspension of ctc-PtCl (OH)2NH3(NH2-nC3H7) in 15 ml diethyl pyrocarbonate at room temperature and in the dark until an IR analysis of the solid no longer showed a PtOH line at 3520 cm 1 (10 days). The solid product was collected (1.1 g, 63% yield), washed with ether and dried.

Table I presents the microanalytical data obtained for the representative compounds of the present invention.

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<td>GRANDFATHER tfl</td><td>ASS Ul</td><td>ass grandfather</td><td>Ul tf?</td><td>ass tf?</td><td>O tfl</td><td></td><td>cn x Ul</td><td>Cl Ul</td><td>ass Ul</td><td>O Ul</td><td>O Ul</td><td>Cx</td><td>ass GRANDFATHER</td><td>Cx</td><td>03 Cl</td><td>Ul</td><td>Cx “X</td><td> 03</td>

<td>Ul</td><td>Hi</td><td>Cx</td><td></td><td>Ul</td><td>ass</td><td>U3</td><td>Cx</td><td></td><td> 01</td><td></td><td></td><td>r * »</td><td>Ul</td><td> 00</td><td>GRANDFATHER</td><td>ass</td><td>O</td><td>Hello</td>

<td></td><td></td><td>ci</td><td></td><td></td><td>Ul</td><td>Cl</td><td>Cl</td><td></td><td></td><td>tfl</td><td>tfl</td><td>Ul</td><td>grandfather</td><td>Ul</td><td>r *.</td><td>Ul</td><td>you</td><td></td>

<td>cn</td><td></td><td>grandfather</td><td></td><td> 03</td><td>GRANDFATHER</td><td>kO</td><td>"ç</td><td></td><td>G3</td><td>Cl</td><td></td><td>r * x</td><td>GRANDFATHER</td><td>Cx</td><td>cn</td><td>Cl</td><td>O</td><td>O</td>

<td>ci</td><td>rx</td><td> 03</td><td>ASS</td><td>Ul</td><td> 03</td><td> 03</td><td>O</td><td></td><td>Cx</td><td>O</td><td>O</td><td>ass</td><td>grandfather</td><td>ass</td><td>ass</td><td>Cl</td><td> 03</td><td></td>

<td>GRANDFATHER</td><td>ci</td><td></td><td> 03</td><td>wow</td><td>ass</td><td>grandfather</td><td>o></td><td>GRANDFATHER</td><td>Cl</td><td>O</td><td>O</td><td> 03</td><td>Cl</td><td>The</td><td>Hello</td><td>GRANDFATHER</td><td></td><td></td>

<td>Ul</td><td>Ul</td><td>grandfather</td><td>Ul</td><td>tfl</td><td>Ul</td><td></td><td>Ul</td><td>Ul</td><td>Ul</td><td>Ul</td><td>Ul</td><td></td><td>GRANDFATHER</td><td></td><td>Cl</td><td>* T *</td><td></td><td>Ul</td>

TABLE I (CONTINUED)

X u

<td>"ç</td><td>Hello</td><td>Ul Cl</td><td>Ul Cl</td><td>rx</td><td>ass Ul</td><td>O</td><td>The Cl</td><td>• X</td><td>O «X Ul</td><td>* x Ul</td><td>xr Ul</td><td>co Ul</td><td>* x grandfather</td><td>03 «X Ul</td><td>Ul * x Cx</td><td>Cl • X Ul</td><td>O • x grandfather</td><td>Cx «X ^ r</td>

<td>O</td><td>Cl</td><td>Cl</td><td>ci</td><td>Cx</td><td> 03</td><td></td><td>Cl</td><td>O</td><td>Cl</td><td>ass</td><td>ass</td><td>Hello</td><td> 03</td><td>cn</td><td></td><td>Ul</td><td>C * X</td><td></td>

<td>** x</td><td>Cx</td><td>Hello</td><td>Hello</td><td>Hello</td><td>Hello</td><td>Cl</td><td>«-X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>XT ·</td><td>* r</td><td>tfl</td><td>tfl</td><td>tfl</td><td>Ul</td><td>tfl</td><td>grandfather</td><td>uO</td><td>grandfather</td><td>GRANDFATHER</td><td>kO</td><td>U3</td><td>kO</td><td>kO</td><td>U3</td><td>grandfather</td><td>grandfather</td><td>grandfather</td>

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TABLE I (CONTINUED) υ

OJ

U

CL

And X OX υ ω u

<td> -</td><td>co</td><td>GRANDFATHER</td><td>co</td><td>~ r</td><td></td><td>GRANDFATHER</td><td>grandfather</td><td>GRANDFATHER</td><td>GRANDFATHER</td><td>grandfather</td><td>Hello</td><td>Hello</td><td>GRANDFATHER</td><td>GRANDFATHER</td>

<td>ci</td><td>ci</td><td>CO</td><td>co</td><td> 03</td><td>ASS</td><td></td><td>O</td><td> 03</td><td>O</td><td>GRANDFATHER</td><td></td><td>O</td><td>O</td><td>LOL</td>

<td></td><td></td><td></td><td>* r</td><td>there</td><td>O</td><td>vn</td><td>Ul</td><td><r</td><td>vn</td><td>vn</td><td>w</td><td>PS</td><td>Ul</td><td></td>

<td>r *.</td><td></td><td>grandfather</td><td>-r</td><td>Hi</td><td>GRANDFATHER</td><td>GRANDFATHER</td><td>ass</td><td></td><td>PS</td><td>-x</td><td>w</td><td>-r</td><td>LOL</td><td>LOL</td>

<td> «*·</td><td>GRANDFATHER</td><td>Cl</td><td></td><td></td><td></td><td>"Ç</td><td>Ul</td><td>vn</td><td>vn</td><td>Cl</td><td> -</td><td></td><td></td><td></td>

<td>no</td><td>O</td><td>-r</td><td>GRANDFATHER</td><td>O</td><td>O</td><td>Cl</td><td>Hello</td><td> 03</td><td>ass</td><td>O</td><td> 03</td><td>O</td><td>GRANDFATHER</td><td>LOL</td>

<td>d</td><td>O</td><td>XX</td><td>Wl</td><td>Wl</td><td></td><td>Wl</td><td>here</td><td></td><td>O</td><td></td><td>Cx</td><td>Hello</td><td>Wl</td><td>grandfather</td>

<td>ass</td><td>ass</td><td>Hello</td><td>Wl</td><td>σ</td><td>Cl</td><td></td><td></td><td>Hello</td><td>O</td><td>bs</td><td>O</td><td>O</td><td>O</td><td> 03</td>

<td>co</td><td></td><td>Wl</td><td></td><td>O</td><td> 03</td><td>GRANDFATHER</td><td> —</td><td>grandfather</td><td> 03</td><td>ass</td><td>ass</td><td>CO</td><td></td><td>co</td>

<td>*and</td><td>grandfather</td><td>Cl</td><td>w</td><td>Ul</td><td> *</td><td> ”</td><td>Ul</td><td>vn</td><td>vn</td><td>PI</td><td></td><td></td><td></td><td></td>

<td></td><td>GO</td><td></td><td>Cl</td><td>co</td><td>Cl</td><td>vn</td><td>grandfather</td><td></td><td></td><td>no</td><td></td><td>O</td><td>ç-</td><td></td>

<td>d</td><td>Hello</td><td></td><td>Ul</td><td>Wl</td><td>• r</td><td>Ul</td><td>C3</td><td></td><td>O</td><td>RT</td><td>co</td><td>Hello</td><td>Wl</td><td>GRANDFATHER</td>

<td>laugh</td><td>Cl</td><td>ass</td><td>ass</td><td>ass</td><td>ASS</td><td>ass</td><td>ass</td><td>Cl</td><td>Cl</td><td>ass</td><td>Cl</td><td>Cl</td><td>ass</td><td>ass</td>

<td></td><td>XX</td><td></td><td>xx</td><td></td><td>Hello</td><td>xx</td><td>xx</td><td></td><td></td><td></td><td>XX</td><td>XX</td><td>xX</td><td></td>

<td>GRANDFATHER</td><td>grandfather</td><td>grandfather</td><td>grandfather</td><td>grandfather</td><td>Wl</td><td>FS.</td><td>Cs.</td><td>LOL.</td><td>xx</td><td>vn</td><td>Ό</td><td>GRANDFATHER</td><td>GRANDFATHER</td><td>u.</td>

<td> •</td><td> •</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td>grandfather</td><td> 1</td><td> 1</td><td> 1</td><td></td>

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TABLE I (CONTINUED)

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grandfather

TABLE I (CONTINUED)

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TABLE I (CONTINUED)

Hello

Pt> Γ-4 ϊ 7

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PI PJ cp pi%.

ip ip

TABLE I (CONTINUED)

Ή PI

OR «

ur — 1 <CXO x \

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CP CO%>

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cp X 'cp

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PJ ~ r ~~ r TABLE I (CONTINUED)

O

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CN cr

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+ J ra

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AND

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TABLE I (CONTINUED)

<td></td><td>O</td><td>P</td><td></td><td>ASS</td><td></td><td>already</td>

The antitumor activity of the complexes according to the present invention was tested following a standard assay procedure using the ADJ / PC6 tumor in mice. The complexes were administered parenterally (PI) or orally (PO). LD values were determined5q and EDg0 θ ™ mg / kg showing the results in Table 2:

TABLE II. ANTITUMOR ACTIVITY IN ADJ / PC6

Wow

O

AND

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Praça

D (0

T3 • H>

t4 + J o

CN

X

CN

X ro CN cn cn

Γ- σ rχ χ x cn cn ro Ν 'm in χ γό m χ (_) U m χ χ oxx _ (m L ix 1. N jj

CUCCJ

Γ '

X cn cn U

X '

OC

O • P ω

The α

AND

Oυ

CDCbOHr-COrHsfinvO »—I» —Ir — 4rHCNCNCNCN

H

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O

AND

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Zs.

TABLE II (CONTINUED) ο

Ρ ra ο

ή ή Ε ο ο η co

XX υ ο υ υ

H Ο rH I— | t — i ο * aaa ή <—ι r-1

Fγ- »XfH t-γΗ PjH Mj-I Kl ►μ» J- «U- <3- μ-» aX <U- «ifl ιη ιΠ ιθ 10 ιθ u υ υ ο υ ο ι ι ι ι Ύ ι υυυουυυώ

Γ 'θ'

XX ιη m ιη <ο

ΓΟ (Ο X Ο (χ χ υ tO CO XX ΟΙ I χ 04 IX χ υ ο ο cο υ c ο υ

Γ'ΉΟΙγΠΙΌΟ'ΟΟγΟΟ 'ojmmmmmmvOO

TI values indicate useful activity for the complexes, particularly for oral administration when TI values are significantly higher than those obtained for parenteral (PI) administration.

It should be noted that various modifications may be made to the invention now described and the scope of the present invention is defined in the appended claims.

Contents95

40 members in 19 offices

This recordMember, by publication datePriority claim9 more offices are in the list below

Priority claims8

Priority claims
Document	Office	Kind	Date
15167488	United States of America	A	1988-02-02
15167488	United States of America	A	1988-02-02
29677689	United States of America	A	1989-01-13
29677689	United States of America	A	1989-01-13
151674	–	–	–
296776	–	–	–
US19880151674	–	–	–
US19890296776	–	–	–

Members40

Family members, oldest first
Document	Office	Kind
DK49189D0	Denmark	D0	1989-02-02
FI890512A0	Finland	A0	1989-02-02
NO890426D0	Norway	D0	1989-02-02
IE890319L	Ireland	L	1989-08-02
AU2897189A	Australia	A	1989-08-03
DK49189A	Denmark	A	1989-08-03
FI890512A	Finland	A	1989-08-03
FI890512L	Finland	L	1989-08-03
NO890426L	Norway	L	1989-08-03
IL89119A0	Israel	A0	1989-08-15
IL89119D0	Israel	D0	1989-08-15
EP0328274A1	European Patent Office (EPO)	A1	1989-08-16
KR890013044A	Republic of Korea	A	1989-09-21
PT89608A	Portugal	A	1989-10-04
HUT49890A	Hungary	A	1989-11-28
JPH01294684A	Japan	A	1989-11-28
ZA89831B	South Africa	B	1989-12-27
NZ227839A	New Zealand	A	1991-06-25
US5072011A	United States of America	A	1991-12-10
AU618310B2	Australia	B2	1991-12-19
HU205767B	Hungary	B	1992-06-29
MX9203596A	Mexico	A	1992-09-01
US5244919A	United States of America	A	1993-09-14
FI91260B	Finland	B	1994-02-28
IL89119A	Israel	A	1994-04-12
PT89608BThis record	Portugal	B	1994-05-31
FI91260C	Finland	C	1994-06-10
EP0328274B1	European Patent Office (EPO)	B1	1994-10-19
AT113054T	Austria	T	1994-11-15
ATE113054T1	Austria	T1	1994-11-15
DE68918878D1	Germany	D1	1994-11-24
ES2063119T3	Spain	T3	1995-01-01
DE68918878T2	Germany	T2	1995-02-23
NO177569B	Norway	B	1995-07-03
NO177569C	Norway	C	1995-10-11
IE65503B1	Ireland	B1	1995-11-01
JP2781403B2	Japan	B2	1998-07-30
KR0147270B1	Republic of Korea	B1	1998-08-17
CA1340286C	Canada	C	1998-12-22
DK175050B1	Denmark	B1	2004-05-10