NZ232959A

NZ232959A - Tetra-coordinate complexes of platinum with cyclic diamines plus either two chlorines or another bidentate ligand; preparatory processes and pharmaceutical compositions

Info

Publication number: NZ232959A
Application number: NZ232959A
Authority: NZ
Inventors: Michel Barreau; Jean-Claude Chottard; Pecq Jean-Bernard Le; Patrick Mailliet
Original assignee: Bellon Labor Sa Roger
Priority date: 1989-03-17
Filing date: 1990-03-16
Publication date: 1992-07-28
Also published as: KR900014416A; FR2644458A1; JPH032191A; FR2644458B1; HUT53659A; ZA902031B; EP0389338A1; FI901326A0; DD297825A5; AU5129590A; IL93759A0; NO901239L; PT93486A; AU632313B2; CA2012342A1; NO901239D0; HU208018B; HU901588D0

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £32959 £32 9 5 9 Compete Specification Filed: class: .C1 f'.C - : T,.:/. ^ >J.!y ' 1'' ' i /■'•'■/'> / - ■// ■/ 1 ' j( i^u,_ •' \ : v , c-Publication Date: 2-&.-UU_...t9©-- P.O. Journal, No: r*n Mpmif*© Ui inviiViUQ NEW ZEALAND No.: Date: PATENTS ACT. 1953 COMPLETE SPECIFICATION NEW PLATINUM COMPLEXES, THEIR PREPARATION ^ND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM NEW Zir ALAND PATENT OFFICL UMARI990 received We, LABORATOIRE ROGER BELLON, a French body corporate, (France) 159, Avenue Ac hi lie Peretti, 92201 Neui1ly-Sur-Seine, France, hereby declare the invention for which IX/ we pray that a patent may be granted to mt/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - Followed by page la m 232 8 5 - la - The present invention relates to platinum complexes, their preparation and pharmaceutical compositions which contain them. 5 In European Patent Application 290 169 platinum complexes of formula: 0 have been described in which: A]_ and A2 together form a radical of formula: 10 H2N — CH — CH — NH2 R5 where R4 and R5 may be hydrogen atoms or optionally substituted alkyl radicals, - r! and R2 are in particular hydrogen or optionally substituted alkyl radicals, 15 - R3 may be a hydrogen atom or a cation and n is 0 to 2. These complexes have antitumour activity. o 7 - 2 - platinum and are of the formula: Diamino complexes of which have antitumour activity ' , ..fS NH2 *1 \ / Pt 5 in which R1 and R2 together form an alkylene radical containing 3 to 6 carbon atoms and X in particular represents a halogen atom, or the 2 radicals X together form an -OCO-COO- or -OCO-CHR3-COO- radical, have also been described. The present invention provides platinum complexes of 10 formula: R2 R, \ ^ (I) ^NH2' X2 in which: - R]_ and R2 together with the carbon atom to which they are attached form a saturated or unsaturated polycyclic 15 carbocyclic radical containing 7 to 12 carbon atoms, or a saturated or partially (ie. unsaturated but non-aromatic) mono-, bi- or tricyclic heterocyclic radical which contains 5 to 11 ring atoms and a single hetero-atom chosen from nitrogen, oxygen and sulphur, the said nitrogen atom being unsubstituted or substituted by an alkoxycarbony1 radical, and the said mono-, bi- or tricyclic heterocyclic radical being otherwise unsubstituted, and and X2 represent chlorine or together form V ^ 19 MAY 1992r i1. ■>: , /19 - 3 - - either a radical of formula: — 0 — C— (cr5r7 )n — c — 0 — II II (HI) 0 0 in which n is 0, 1 or 2 and, when n is 1, Rg and R7 are identical or different and are hydrogen atoms, alkyl radicals or form, together with the carbon atom to which they are attached, a cyclobutyl radical or, when n is 2, Rg and R7 are hydrogen atoms, - or a radical of formula: OH I - 0 - C - (CR6R7)n — P - 0 — O o (IV) 10 in which n, R6 and R7 are as defined above, and their salts where such exist, and their hydrates. These platinum complexes have particularly valuable antitumour properties. In the above definition, the alkyl radicals and alkyl 15 portions are straight-chain or branched and contain 1 to 4 carbon atoms each and the halogen atoms can be chlorine, bromine, fluorine or iodine. When R^ and R2 together form a polycyclic carbocyclic divalent radical, by wav of exanple, the latter can be derived from: 20 bicyclo[2.2.l]heptane, bicyclo[3.2.1]octane, bicyclo [2 . 2 . 2] octane, bicyclo[ 3 . 2 . 2 ] nonane, ^ "I ■ 9 MAY 1992 ^'/ Cv r*' - 4 - bicyclo[3.3.1]nonane, adamantane, decahydronaphthalene, 1,2,3,4-tetrahydronaphthalene, spiro[5.5]undecane, tricyclo[5.2.1.0/2,6]decane or indane. When Rjl and R2 together form a saturated or partially 5 saturated heterocyclic radical, by way of example, the latter can be chosen from: 4-chromanyl, 3-coumaryl, 4-homopiperidinyl, 4-piperidinyl, 3-pyrrolidinyl, 3-quinuclidinyl, 4-tetrahydropyranyl, 3-tetrahydrofuryl, 4-tetrahydrothiopyranyl, 3-tetrahydrothiofuryl or 1,2,3,4-10 tetrahydroquinol-4-yl . A/ According to a feature of the invention, the complexes of formula (I) are obtained by the action of potassium tetrachloroplatinate on a diamine of formula: R1 *2 ^ nh2 nh2 (V) 15 in which R^ and R2 are defined as above, followed where appropriate, when it is desired to obtain a complex of general formula (I) in which X-± and X2 are radicals of formula (III) or (IV), by the conversion of the chlorinated complex obtained into a dicarboxylated or 20 phosphonocarboxylated complex. The action of potassium tetrachloroplatinate generally takes place under nitrogen and in the absence of ■ light on the diamine, which is optionally liberated in situ V v E N f -o\ •V tV, ,2. rA \ '8 Ma* 1992" 2 3 2 & b S - 5 - from its salt, in an aqueous or aqueous-alcoholic (for example ethanol/water in proportions which can be up to 20-80 by volume) medium, at a temperature of between 0 and 80*C. The conversion of the chlorinated complex into a-dicarboxylated or phosphonocarboxylated complex takes place via the diaqua dinitrate complex of formula: *2 R1 NH? oh2 \ / Pt2* / NH2 OH2 , 2N03" (VI) in which and R2 are defined as above, which is then converted into the dicarboxylated or phosphonocarboxylated 10 complex either by direct action of a salt of an acid of formula: OH I HOC— (CR6R7)n - COH H0C _ (CR6R7>n — P0H II II !| II 0 0 0 0 or u (Vila) (Vllb) in which Rg, R7 and n are defined as above, or by passage 15 over an anion exchange resin (OH form) followed by the addition of an acid of formula (Vila) or (Vllb). The complex of formula (VI) can be obtained by the action of silver nitrate on the dichlorinated complex, in an aqueous medium or in an alcohol/water mixture (ethanol/water 20 or methanol/water for example, in proportions which can vary, - 6 - 2 3) 2 9 5 9 preferably, to up to 10 % of methanol), the reaction being carried out under nitrogen and in the absence of light at a temperature of between 20 and 70*C. The direct action of a salt of the acid of formula 5 (Vila) or (Vllb) on the complex of general formula (VI) takes place in an aqueous or aqueous-alcoholic medium, in the absence of light and under an atmosphere of nitrogen, at a temperature of between 0 and 50"C. It is not essential to isolate the complex of formula (VI) to use it in this 10 reaction. The salt of the acid of formula (Vila) or (Vllb) is, preferably, an alkali metal salt (sodium or potassium salt for example) ; it can be formed in situ in the course of the reaction. 15 Under these conditions, the complex of formula (I) in which and X2 form a radical of general formula (IV) is obtained in the form of an alkali metal salt, which can be liberated and if desired converted into another salt by known methods. 20 When the complex of formula (VI) is converted by passage over an anion exchange resin, the reaction is generally carried out by percolating the solution of diaqua dinitrate complex through a column of 1.2 to 1.5 times the theoretical amount of Amberlite IRA 402 resin (OH form) in 25 the absence of light. The addition of the acid of formula (Vila) or (Vllb) 23 2 9 59 - 7 - takes place in an aqueous medium, in the absence of light and under an atmosphere of nitrogen, at a temperature of between 0 and 50 * C. B/ According to a further feature of the invention, the 5 products of formula (I) are also obtained via the diiodo complex of formula: «2 R1 nh2 i \ / Pt L / \ (VIII) ^ NH2 i in which R^ and R2 are defined as above, by the action of potassium tetrachloroplatinate on a diamine of formula (V), 10 in the presence of an excess of potassium iodide. The diiodo complex obtained is then treated with silver nitrate and then with an alkali metal chloride in excess and subsequently, if appropriate, if it is desired to obtain a complex of formula (I) for which and X2 are radicals of formula (III) or 15 (IV), the chlorinated complex obtained is converted into a dicarboxylated or phosphonocarboxylated complex. The preparation of the intermediate diiodo complex takes place under conditions identical to those described above for the preparation of a chlorinated platinum complex 20 of formula (I) by the action of potassium tetrachloroplatinate on an amine of formula (V). The addition of silver nitrate takes place under conditions analogous to those described above under A/. " ^ L. 0 L - 8 - The alkali metal chloride can be sodium or potassium chloride. It is not necessary to isolate the product formed as an intermediate in order to proceed to this addition. The reaction can be carried out at a temperature of between "0 and 5 70"C. The conversion of the dichlorinated complex of formula (I) to a dicarboxylated or phosphonocarboxylated complex is effected, if necessary, under the conditions described above under A/. 10 0/ According to a further feature of the invention, the complexes of formula (I) are also obtained by the action of potassium trichloro(ethylene)platinate on a diamine of formula (V), followed, if appropriate, when it is desired to obtain a product of formula (I) in which X! and X2 are 15 radicals of formula (III) or (IV), by the conversion of the chlorinated complex obtained into a dicarboxylated or phosphonocarboxylated complex. The reaction generally takes place on the diamine (optionally liberated in situ from its salt), in an alcohol 20 or in an aqueous-alcoholic medium, at a temperature of between 0 and 40"C. The conversion of the dichlorinated complex obtained into a product of formula (I) in which and X2 are radicals of formula (III) or (IV) takes place under the conditions 25 described above under A/. The diamines of formula (V) can be prepared as 23 2^59 - 9 - described below in the Examples, in particular by a Strecker reaction, in the presence of sodium cyanide or potassium cyanide and ammonium chloride, ammonia or benzylamine, on a ketone of formula: (IX) in which and R2 are defined as above, followed by catalytic hydrogenation of the aminonitrile formed and, where appropriate, the removal of the protective radical or radicals. 10 The Strecker reaction takes place in water or in an alcohol (methanol or ethanol for example) or in an aqueous-alcoholic medium, at a temperature of between 20 and 80"C. The Strecker reaction can also be carried out in the presence of trimethylsilyl cyanide on a ketone of general 15 formula (IX), in an anhydrous medium and if appropriate in the presence of a catalytic amount of Lewis acid. In this case, the reaction takes place with or without solvent, at a temperature of between -20 and +40°C. Where appropriate, the Lewis acid can be zinc iodide or 20 cobalt chloride. The solvent can be, for example, diethyl ether or dipropyl ether, tetrahydrofuran, dichloromethane or chloroform. The trimethylsilylated cyanohydrin thus obtained is 23 2 9 5 9 - 10 - treated with ammonia or benzylamine in solution in an alcohol (for example methanol or ethanol) at a temperature of between 20*C and the reflux temperature of the reaction mixture. This method for carrying out the Strecker reaction is chosen -more 5 particularly in the case of highly obstructed ketones of general formula (IX) (such as, for example, the ketones for which Rj, and R2 together form a bicyclof 2 .2. 2 ]octane or bicyclo[3.2.2]nonane cyclic radical or a quinuclidine). In the reactions described above it is understood 10 that, depending on the reactants employed, the aminonitrile obtained as an intermediate can be protected on the amine radical. The hydrogenation can be effected equally on the aminonitrile in which the amine function is free or 15 protected. It is also possible to protect the amine function before the catalytic hydrogenation. In this case, the protection is effected in particular by acylation (for example in accordance with Org. Synth., vol. IV, p. 5 and 6). The catalytic hydrogenation of the aminonitrile 20 generally takes place under a pressure of 100 to 4000 kPa in the presence of a catalyst, such as Adams platinum, Raney nickel or rhodium on alumina, at a temperature of between 20 and 80°C and the reduction is carried out in an alcohol (ethanol or methanol for example), either in the presence of 25 hydrochloric acid or in a basic medium (ammonia for example), or in acetic acid in the presence of acetic anhydride. When the reduction is carried out in an acetic medium, it is necessary to remove the acetyl groups from the diamine obtained. This is carried out by acid treatment after the hydrogenation. In the case of ketones of formula (IX) for which the ketone function is not in a plane of symmetry of the molecule, the Strecker reaction leads to a mixture of exocyclic and endocyclic racemates in which the exocyclic racemate is preponderant. It is understood that the platinum derivatives of formula (I) prepared from exocyclic or endocyclic diamines or their mixtures fall within the scope of the present invention. The diamines of formula (V) in the form of the pure exocyclic racemate can be obtained by successive recrystallizations of the intermediate aminonitrile. The diamines of formula (V) in the form of the pure endo racemate can be obtained from the corresponding endo amino acids of formula: in which and R2 are defined as above and in which the amine function has been protected beforehand, by conversion of the acid function to an amide by known methods, followed (X) - 12 - £ 3 2 9 b 9 by removal of the protective radical from the amine and reduction of the amide by the action of diborane under the conditions described in J. Org. Chem. , 38.(16), 2786 (1973) or J. Org. Chem., 12(16), 3153 (1982). 5 The amino acids of formula (X) can be obtained from ketones of formula (IX) for which Rj and R2 are defined as above, by the action of ammonium carbonate and an alkali metal cyanide, in an aqueous-alcoholic medium at a temperature of between 50 and 100'C, followed by hydrolysis 10 of the spirohydantoin thus obtained, by the action of an aqueous solution of barium hydroxide, in an autoclave at a temperature of between 120 and 200*C. The complexes of the invention in which and X2 together form a radical of formula (IV) can be converted into 15 metal salts. These salts can be obtained by the action of a metal base (for example an alkali metal or alkaline earth metal base) in an appropriate solvent. Examples of pharmaceutical^ acceptable salts which may be mentioned are the salts with the alkali metals 20 (sodium, potassium, lithium) or the salts with the alkaline earth metals (magnesium, calcium). The complexes of the present invention can be purified, if desired, by physical methods such as crystallization or chromatography. 25 The products of formula (!'■ , and also their pharmaceutical^ acceptable salts and their hydrates, are - 13 - particularly useful for the treatment of malignant tumours. ;""'s They have proved particularly active on graft tumours in mice: they are especially active at doses of between 4 and 120 mg/kg when administered intraperitoneally, against 5 leukaemia L1210. Their maximum tolerated dose is between 10 mg/kg and doses higher than 120 mg/kg when administered intraperitoneally to mice. Products of particular value are those of formula (I) in which and R2 together form a polycyclic carbocyclic 10 clival en t radical derived from: bicyclo [ 2.2.1] heptane, adainantane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane or tricyclo[5.2.1.0/2,6]decane and X^ and X2 represent chlorine atoms or a radical of formula (IV) in which R6 and R7 are hydrogen atoms or methyl radicals. 15 And amongst these products, the following products are of more particular value: cis-(2-amino-2-aminomethyl-bicyclo[2.2.l]heptane)-dichloroplatinum, cis-(2-amino-2-aminomethyl-bicyclo[3.2.1]octane)-20 dichloroplatinum, - cis-(2-amino-2-aminomethyl-adamantane)-dichloroplatinum, cis-(3-amino-3-aminomethyl-bicyclo[3.2.1]octane)-dichloroplatinum, and 25 - cis-(2-amino-2-aminomethyl-bicyclo[2 . 2. 2]octane)- dichloroplatinum. ^ 1 '/V ^ ' ^ < «. * Y 19 MAY 1992' - 0 X Q - 14 - & *3 * I a b 9 The following examples illustrate the present invention: EXAMPLE 1 Under an atmosphere of nitrogen and in the absen.ce of 5 light, 2-amino-2-aminomethyl-bicyclo[2.2.1]heptane dihydrochloride (1.49 g), in the form of the mixture of the exo and endo racemates in a ratio of (4/1), is dissolved in methanol (6 cc) and a 1 N solution (14 cc) of sodium hydroxide in water. Potassium tetrachloroplatinate (2.84 g) 10 in solution in water (14 cc) is added to the opalescent solution obtained, with stirring, in the course of 10 minutes. Stirring is continued for 20 hours at 20*C. The precipitate formed is drained, washed with water (3x5 cc) 15 and dried under reduced pressure (2.5 kPa) in the presence of phosphorus pentoxide. Cis-(2-amino-2-aminomethyl-bicyclo[2.2.l]heptane)-dichloroplatinum hydrate (2.48 g) is thus obtained, as a mixture of the exo and endo racemates in a ratio of (4/1), in the form of a yellow-beige powder which 20 melts with decomposition at 331-C. 2-Amino-2-aminomethyl-bicyclo[2.2.l]heptane dihydrochloride, as a mixture of the exo and endo racemates in a ratio of (4/1), can be obtained in the following way: 2-Acetylamino-2-acetylaminomethyl-25 bicyclo[2.2.l]heptane (3g), in the form of a mixture of the exo and endo racemates in a ratio of (4/1), in a 6 N solution (100 cc) of hydrochloric acid in water is refluxed for 8 hours. The mixture is concentrated to dryness under reduced pressure (5.2 kPa), the residue from the evaporation is taken up in ethanol (50 cc) and diisopropyl ether (150 cc) is added 5 dropwise. The precipitate obtained is drained on a glass frit, washed with a mixture of ethanol and diisopropyl ether (25/75 by volume) (20 cc) and then with diisopropyl ether (2 x 20 cc) and finally dried in an oven at 80"C. 2-Amino-2-aminomethyl-bicyclo[2.2.1]heptane dihydrochloride (2.53 g) is 10 thus obtained in the form of white crystals which melt at 262—4 * C. 2-Acetylamino-2-acetylaminomethyl-bicyclo[2.2.ljheptane, as a mixture of the exo and endo racemates in a ratio of (4/1), can be obtained in the 15 following way: A solution of 2-acetylamino-2-cyano-bicyclo[2.2.l]heptane (6.05 g), in the form of the mixture of the exo and endo racemates in a ratio of (4/1), in acetic acid (100 cc) is charged into a 250 cc autoclave and acetic 20 anhydride (6.4 cc) and Adams platinum oxide (0.6 g) are added. The mixture is subjected to catalytic hydrogenation at 500C for 5 hours, under an initial pressure of 4000 kPa. After cooling, the catalyst is filtered off on a bed of clarcel DIC and the filtrate is evaporated under reduced 25 pressure (5.2 kPa) . The residue from the evaporation is recrystallized 2 3 2 y b 9 - 16 - from a mixture of water and ethanol (90/10 by volume) (100 cc); 2-acetylamino-2-acetylaminomethyl- bicyclo[2.2.l]heptane (7.25 g) is thus obtained in the form of fine white crystals which melt at 192-4*C. 5 2-Acetylamino-2-cyano-bicyclo[2.2.1]heptane, as a mixture of the exo and endo racemates in a ratio of (4/1), can be obtained in the following way: 2-Amino-2-cyano-bicyclo[2.2.l]heptane (7.98 g), in the form of the mixture of the exo and endo racemates in a 10 ratio of (4/1), is dissolved in diethyl ether (100 cc) and acetic anhydride (5.7 cc) is added. After stirring for 20 hours at 20"C, the precipitate formed is drained and washed with diethyl ether (3 x 20 cc). 2-Acetylamino-2-cyano-bicyclo[2.2.1]heptane (9.25 g) 15 is obtained in the form of fine white crystals which melt at 152-3"C. 2-Amino-2-cyano-bicyclo[2.2.1]heptane can be obtained quantitatively, in the form of a colourless oil which crystallizes at about 0°C and corresponds to a mixture of the 20 exo and endo racemates in a ratio of (4/1), by neutralization of its hydrochloride. This hydrochloride can be obtained under the conditions described by H.S. TAGER et al., J. Amer. Chem. Soc., 94(3), 968-972 (1972). EXAMPLE 2 25 Under an atmosphere of nitrogen and in the absence of light, cis-(2-amino-2-aminomethyl-bicyclo[2.2.1]heptane) - -.{fk '7 ^ ■ w .3 / V ' •ipF <U»-w , , - 17 - dichloroplatinum (0.81 g), in the form of the mixture of the exo and endo racemates in a ratio of (4/1), is suspended in methanol (2 cc) and water (18 cc), and silver nitrate (0.68 g) in water (6.8 cc) is then added. The mixture is-5 stirred for 3 hours at 20*C, the silver chloride formed is filtered off on a glass frit and the filtrate is then clarified on a filter cartridge having a pore size of 3 /x. The solution of (2-amino-2-aminomethyl- bicyclo[2.2.1]heptane)diaqua-platinum dinitrate is percolated 10 through a column, having a diameter of 1.2 cm, containing Amberlite IRA 4 02 ion exchange resin in the OH form (0.0012 mole/cc) (6 cc). A solution of phosphonoacetic acid (0.28 g) in water (6 cc) is added to the solution of (2-amino-2-aminomethyl-bicyclo[2.2.l]octane)-aqua-15 hydroxoplatinum hydroxide thus obtained. The mixture is chromatographed on a column 1 m in height and 2.5 cm in diameter containing Sephadex LH 20 (120 g), collecting fractions of 5 cc. The fractions between 415 and 455 cc are concentrated to dryness. 20 The sodium salt hexahydrate of cis-(2-amino-2- aminomethyl-bicyclo[2.2.1]heptane)phosphonoacetatoplatinum (0.89 g), as a mixture of the exo and endo racemates in a ratio of (4/1), is thus obtained in the form of bright white crystals which melt with decomposition at 314°C. 25 EXAMPLE 3 The procedure is as in Example 2, starting from E3295 - 18 cis- (2-amino-2-aminomethyl- bicyclo[2.2.l]heptane)dichloroplatinum (0.81 g), in the form of the mixture of the exo and endo racemates in a ratio of (4/1), in methanol (2 cc) and water (18 cc), and silver ' 5 nitrate (0.68 g) in water (6.8 cc). After filtering off the silver chloride formed and clarifying the filtrate on a cartridge having a pore size of 3 n, a solution of 2,2-dimethylphosphonoacetic acid (0.35 g) in a 1 N solution (6 cc) of sodium hydroxide in water is added to the solution 10 of (2-amino-2-aminomethyl- bicyclo[2.2.1]heptane)diaquaplatinum dinitrate. The mixture is chromatographed on a colunn 2.5 cm in diameter containing Sephadex LH 20 (120 g), collecting fractions of 5 cc. The fractions between 4 10 and 465 cc are concentrated to dryness. 15 The sodium salt pentahydrate of cis-(2-amino-2- aminomethyl-bicyclo[2.2.1]heptane-(2,2- dimethylphosphonoacetato)platinum (0.89 g) is thus obtained as a mixture of the exo and endo racemates in a ratio of (4/1), in the form of bright white crystals which melt with 20 decomposition at 311°C. 2,2-Dimethylphosphonoacetic acid can be prepared under the conditions described in Patent Application EP 290169. EXAMPLE 4 25 The procedure is as in Example 1, starting from a solution of 2-amino-2-aminomethyl-adamantane dihydrochloride 232959 - 19 - (3 g) in methanol (3 cc) and a 1 N solution (24 cc) of sodium hydroxide in water, and a solution of potassium tetrachloroplatinate (4.98 g) in water (30 cc). Cis-(2-amino-2-aminomethyl-adamantane)-5 dichloroplatinum (3.9 g) is thus obtained in the form of a yellow powder which melts with decomposition at 360"C. 2-Amino-2-aminomethyl-adamantane dihydrochloride can be obtained in the following way: 2-Acetylamino-2-acetylaminomethyl-adamantane (6.45 g) 10 in a 6 N solution (180 cc) of hydrochloric acid in water is refluxed for 6 hours. The solution is concentrated to dryness under reduced pressure (5.2 kPa), the residue from the evaporation is taken up in ethanol (100 cc) and diisopropyl ether (100 cc) is added dropwise. 15 The precipitate obtained is drained on a glass frit, washed with a mixture of ethanol and diisopropyl ether (50/50 by volume) (20 cc) and dried in an oven at 80°C. 2-Amino-2-aminomethyl-adamantane dihydrochloride (3.73 g) is thus obtained in the form of white crystals which melt at 3 00CC. 20 2-Acetylamino-2-acetylaminomethyl-adamantane can be prepared in the following way: A solution of 2-acetylamino-2-cyano-adamantane (6.8 g) in acetic acid (90 cc) is charged into a 500 cc autoclave and acetic anhydride (5.8 cc) followed by Adams 25 platinum oxide (0.68 g) are added. The mixture is subjected to catalytic hydrogenation, at 50°C for 5 hours, under an initial pressure of 4000 kPa. After cooling, the catalyst is filtered off on a bed of clarcel DIC and the filtrate is evaporated under reduced pressure (5.2 kPa). The residue from the evaporation is recrystallized from water (100 cc). 2-Acetylamino-2-acetylaminomethyl-adamantane (6.95 g) is thus obtained in the form of fine white crystals which melt at 108'C. 2-Acetylamino-2-cyano-adamantane can be obtained in the following way: 2-Amino-2-cyano-adamantane (10 g) is dissolved in diethyl ether (100 cc) and acetic anhydride (5.8 cc) is added. After stirring for 20 hours at 20°C, the precipitate formed is drained and washed with diethyl ether (3 x 20 cc). 2-Acetylamino-2-cyano-adamantane (6.83 g) is thus obtained in the form of fine white crystals which melt at 14 0 * C. 2-Amino-2-cyano-adamantane can be obtained in the following way: Sodium cyanide (6.61 g) and ammonium chloride (14.44 g) are dissolved in water (150 cc) and ethanol (250 cc). A 28 % solution (30 cc) of ammonia in water is added and 2-adamantanone (20 g) is then added in portions. The mixture is refluxed for 5 hours. After cooling to 0'C, the mixture is acidified to pH 1 by the addition of a 2 N solution of hydrochloric acid in water. The adamantanone which has not reacted is drained on a glass frit and the >5 Q h 0 flm W ^ ^ - 21 - filtrate is neutralized to pH 9 by the addition of a 2 N solution of sodium hydroxide in water. The precipitate is drained on a glass frit, washed with water (5 x 20 cc) and dried under reduced pressure (2.5 kPa). 5 2-Amino-2-cyano-adamantane (16.1 g) is thus obtained in the form of white crystals which melt at 215"C. EXAMPLE 5 The procedure is as in Example 1, starting from 2-amino-2-aminomethyl-bicyclo[3.2.1]octane dihydrochloride 10 (1.31 g), in the form of the mixture of the exo and endo racemates in a ratio of (8/1), in methanol (3 cc) and a 1 N solution (12 cc) of sodium hydroxide in water, and potassium tetrachloroplatinate (2.46 g) in solution in water (12 cc). Cis-(2-amino-2-aminomethy1-15 bicyclo[3.2.1]octane)dichloroplatinum hydrate (1.23 g) is thus obtained as a mixture of the exo and endo racemates in a ratio of (8/1), in the form of a yellow-beige powder which melts with decomposition at 326°C. 2-Amino-2-aminomethyl-bicyclo[3.2.1]octane 20 dihydrochloride, as a mixture of the exo and endo racemates in a ratio of (8/1), can be obtained in the following way: The procedure is as in Example 1, but starting from 2-acetylamino-2-acetylaminomethyl-bicyclo[3.2.1]octane (4.14 g), in the form of the mixture of the exo and endo 25 racemates in a ratio of (8/1), in a 6 N solution (100 cc) of hydrochloric acid in water for 18 hours under reflux; by X 9 3 9 9 5 9 £. w u w \J - 22 - taking up the residue from the evaporation in ethanol (30 cc) and diethyl ether (100 cc), 2-amino-2-aminomethyl-bicyclo[3.2.1]octane dihydrochloride (3.1 g) is obtained in the form of white crystals which melt at 284-6*C. 5 2-Acetylamino-2-acetylaminomethyl- bicyclo[3.2.1]octane, as a mixture of the exo and endo racemates in a ratio of (8/1), can be obtained in the following way: The procedure is as in Example 1, but starting from 10 2-acetylamino-2-cyano-bicyclo[3.2.1]octane (9 g), in the form of the mixture of the exo and endo racemates in a ratio of (8/1), in acetic acid (140 cc) and acetic anhydride (8.8 cc), in the presence of Adams platinum oxide (0.9 g); by chromatographing the residue from the evaporation on a column 15 5.5 cm in diameter containing silica gel (250 g), eluting with a mixture of ethyl acetate and ethanol (7 5/25 by volume) and collecting fractions of 100 cc. The fractions between 1400 and 3100 cc are concentrated to dryness. 2-Acetylamino-2-acetylaminomethyl-bicyclo[3.2.1]octane (9.75 g) is thus 2 0 obtained in the form of fine white crystals which melt at 92-3 °C. 2-Acetylamino-2-cyano-bicyclo[3.2.l]octane, as a mixture of the exo and endo racemates in a ratio of (8/1), can be obtained in the following way: 25 The procedure is as in Example 1, but starting from 2-amino-2-cyano-bicyclo[3.2.1]octane (8.05 g) , in the form of - 23 - the mixture of the exo and endo racemates in a ratio of (8/1), in diethyl ether (150 cc) and acetic anhydride (5.6 cc); 2-acetylamino-2-cyano-bicyclo[3.2.l]octane (10.16 g) is obtained in the form of fine white crystals 5 which melt at 78-80'C. 2-Amino-2-cyano-bicyclo[3.2.l]octane, as a mixture of the exo and endo racemates in a ratio of (8/1), can be obtained quantitatively from its hydrochloride, which is itself prepared in the following way: 10 Bicyclo[3.2.l]octan-2-one (30 g) is dissolved in ethanol (300 cc) and a solution of potassium cyanide (18.2 g) and ammonium chloride (13.9 g) in water (300 cc) is added. After stirring for 6 days at 20°C, the ethanol is concentrated under reduced pressure (5.2 kPa) and the aqueous 15 phase is extracted with diethyl ether (5 x 200 cc). The ethereal phase is washed with water (2 x 50 cc), dried over sodium sulphate and concentrated under reduced pressure (5.2 kPa) to a volume of 400 cc. Hydrogen chloride gas is then bubbled through the solution until it is saturated. The 20 precipitate formed is drained, washed with diethyl ether (3 x 25 cc) and dried under reduced pressure (2.5 kPa). 2-Amino-2-cyano-bicyclo[3.2.1]octane hydrochloride (13.25 g) is thus obtained, as a mixture of the exo and endo racemates in a ratio of (8/1), in the form of fine white crystals which 25 melt with decomposition at 202-5°C. £3 2 9 u 9 - 24 - EXAMPLE 6 The procedure is as in Example 1, starting from exo-3-amino-3-aminomethyl-bicyclo[3.2.1]octane dihydrochloride (1.14 g) in methanol (10 cc) and a 1 N solution (10 cc) "of 5 sodium hydroxide in water, and potassium tetrachloroplatinate (2.08 g) in solution in water (21 cc). Cis-(exo-3-amino-3-aminomethyl-bicyclo[3.2.l]octane)dichloroplatinum (1.32 g) is thus obtained in the form of a yellow powder which melts with 10 decomposition at 332*C. Exo-3-amino-3-aminomethyl-bicyclo [3.2.1] octane dihydrochloride can be obtained in the following way: The procedure is as in Example 1, but starting from exo-3-acetylamino-3-acetylaminomethyl-bicyclo[3. 2 . l]octane 15 (4 g) in a 6 N solution (100 cc) of hydrochloric acid in water for 18 hours under reflux; by taking up the residue from the evaporation in ethanol (50 cc) and diethyl ether (100 cc), exo-3-amino-3-aminomethyl-bicyclo[3.2.l]octane dihydrochloride (2.15 g) is obtained in the form of white 20 crystals which melt with decomposition at 296-8"C. Exo-3-acetylamino-3-acetylaminomethyl-bicyclo[3.2.l]octane can be obtained in the following way: The procedure is as in Example 1, but starting from exo-3-acetylamino-3-cyano-bicyclo[3.2.1]octane (4 g) in 25 acetic acid (60 cc) and acetic anhydride (3.8 cc) in the presence of Adams platinum oxide (0.5 g); concentrating to dryness, chromatographing on a column 5.5 cm in diameter T 9 0 K 0 O C -j' h v \j %jf - 25 - containing silica gel (300 g), eluting with a mixture of ethyl acetate and ethanol (85/15 by volume) and collecting fractions of 100 cc. The fractions between 1200 and 1800 cc are concentrated to dryness; exo-3-acetylamino-3-5 acetylaminomethyl-bicyclo[3.2.1]octane (4.1 g) is thus obtained in the form of a colourless oil. NMR spectrum (2 00 MHz, DMSO, <5 in ppm) 8.00 (t, -CH2-NH-CO-CH3) 7.40 (s, -NH-CO-CH3) 10 3.30 (d, -CH2-NH-CO-CH3) 1.65 and 1.82 (2s, -CO-CH3 and -CO-CH3) 1.25 to 1.60 and 1.90 to 2.15 (complex, 12 H of the cycle) Exo-3-acetylamino-3-cyano-bicyclo[3.2.l]octane can be 15 obtained in the following way: The procedure is as in Example 1, but starting from exo-3-amino-3-cyano-bicyclo[3.2.1]octane (10 g) in diethyl ether (100 cc) and acetic anhydride (10 cc); concentrating to dryness, chromatographing the residue on a column 8 cm in 20 diameter containing silica gel (500 g), eluting with a mixture of dichloromethane and ethyl acetate (90/10 by volume) and collecting fractions of 100 cc. The fractions between 1400 and 3000 cc are concentrated to dryness; exo-3-acetylamino-3-cyano-bicyclo[3.2.1]octane (8.69 g) is obtained 25 in the form of a viscous colourless oil. 2329 5 9 NMR spectrum (2 00 MHz, DMSO, 6 in ppm) 8.35 (s, -NH-CO-CH3) 1.90 (s, -CO-CH3) 1.40 to 2.05 and 2.35 to 2.45 (complex, 12 H of the 5 cycle) Exo-3-amino-3-cyano-bicyclo[3.2.1]octane can be obtained under the conditions described by H. CHRISTENSEN et al., J. Med. Chem., 26, 1374-8 (1983). EXAMPLE 7 10 The procedure is as in Example 1, starting from 2- amino-2-aminomethyl-bicyclo[2.2.2]octane dihydrochloride (2.27 g) in methanol (15 cc) and a 1 N solution (20 cc) of sodium hydroxide in water, and potassium tetrachloroplatinate (4.15 g) in solution in water (42 cc). 15 Cis-(2-amino-2-aminomethyl- bicyclo[2.2.2]octane)dichloroplatinum (1.93 g) is thus obtained in the form of a yellow-beige powder which melts with decomposition at 317°C. 2-Amino-2-aminomethyl-bicyclo[2.2.2]octane 20 dihydrochloride can be obtained in the following way: The procedure is as in Example 1, but starting from 2-acetylamino 2-acetylaminomethyl-bicyclo[2.2.2]octane (4.6 g) in a 6 N solution (100 cc) of hydrochloric acid in water for 48 hours under reflux; taking up the residue from 25 the evaporation in ethanol (25 cc) and diethyl ether (75 cc) , 2-amino-2-aminomethyl-bicyclo[2.2.2]octane dihydrochloride y*>\ 13 'L 9 5 9 - 27 - (3 g) is obtained in the form of white crystals which melt at 302-303 *C. 2-Acetylamino-2-acetylaminomethyl-bicyclo[2.2.2]octane can be obtained in the following way: 5 The procedure is as in Example 1, but starting from 2-acetylamino-2-cyano-bicyclo[2.2.2]octane (5.8 g) in acetic acid (100 cc) and acetic anhydride (5.6 cc) in the presence of Adams platinum oxide (0.6 g) ; chromatographing the residue from the evaporation on a column 5.5 cm in diameter 10 containing silica gel (200 g), eluting with a mixture of ethyl acetate and ethanol (75/25 by volume) and collecting fractions of 50 cc. The fractions between 800 and 1750 cc are concentrated to dryness; 2-acetylamino-2-acetylaminomethyl-bicyclo[2.2.2]octane (5.45 g) is thus obtained in the form of 15 a pale yellow viscous oil. NMR spectrum (2 00 MHz, DMSO, 6 in ppm) 7.35 (t, -CH2-NH-CO-CH3) 6.30 (s, -NH-CO-CH3) 3.45 (d, -CH2-NH-CO-CH3) 20 1.82 and 1.98 (2s, -CO-CH3 and -CO-CH3) 1.35 to 2.25 (complex, 12 H of the cycle) 2-Acetylamino-2-cyano-bicyclo[2.2.2]octane can be obtained in the following way: Bicyclo[2.2.2]octanone (9.92 g) is dissolved in 25 diethyl ether (100 cc) and zinc iodide (0.5 g) is added and a solution of trimethylsilyl cyanide (10 g) in diethyl ether (20 cc) is then added to the suspension obtained. Stirring is continued for 30 minutes at between 20 and 25 *c, a solution (120 cc), saturated at O'C, of ammonia in methanol is then added and the suspension obtained is refluxed for 4 hours. 5 The solvents are evaporated under reduced pressure (5.2 kPa), the residue is taken up in diethyl ether (150 cc), acetic anhydride (12 cc) is added and the mixture is stirred for 16 hours at 20*C. After concentrating the solvents, the residue is chromatographed on a column 10 cm in diameter containing 10 silica gel (1500 g) , eluting with a mixture of dichloromethane and ethyl acetate (90/10 for 5000 cc then 50/50 by volume) and collecting fractions of 50 cc. The fractions between 6050 and 64 50 cc are concentrated to dryness; 2-acetylamino-2-cyano-bicyclo[2.2.2]octane (5.9 g) 15 is thus obtained in the form of a pale yellow viscous oil. NMR spectrum (300 MHz, CDCI3, <5 in ppm) 5.9 (s, -NH-CO-CH3) 2.05 (s, -CO-CH3) 1.6 to 2.5 (complex, 12 H of the cycle) 20 Bicyclo[2.2.2]octanone can be prepared under the conditions described by B. ROCHE et al.f J. Org. Chem., 49(21), 3881-7 (1984). EXAMPLE 8 The procedure is as in Example 1, starting from 8-25 amino-8-aminomethyl-tricyclo[5. 2.1. 0/2, 6]decane dihydrochloride (0.37 g), in the form of the endo racemate, '23 2 S 5 9 - 29 - in methanol (5 cc) and a 1 N solution (3 cc) of sodium hydroxide in water, and potassium tetrachloroplatinate (0.61 g) in solution in water (6 cc). Cis-(8-amino-8-aminomethyl-5 tricyclo[5.2.1.0/2,6]decane)dichloroplatinum (0.42 g) is thus obtained, as the endo racemate, in the form of a yellow-beige powder which melts with decomposition at 314"C. 8-Amino-8-aminomethyl-tricyclo[5.2.1.0/2,6]decane, in the form of the endo racemate, can be obtained in the 10 following way: 8-Amino-tricyclo[5.2.1.0/2,6]decyl-8-carboxamide (0.40 g), in the form of the endo racemate, is suspended in anhydrous tetrahydrofuran (30 cc) and a 2 N solution (5 cc) of "dimethyl borane-sulphide" complex in tetrahydrofuran is 15 added dropwise. The solution obtained is refluxed for 20 hours; after cooling, a 2 N solution (10 cc) of hydrochloric acid in diethyl ether is added. After concentrating to dryness, the powder obtained is dissolved in water (5 cc) and the pH is adjusted to 10 by the addition of sodium hydroxide 20 as a 4 N solution in water, in the presence of dichloromethane (10 cc). After decanting, the aqueous phase is reextracted with dichloromethane (2x5 cc) and the combined organic phases are washed with water (5 cc), dried over sodium sulphate and concentrated to dryness under 25 reduced pressure (5.2 kPa). The colourless oil obtained is dissolved in ethanol (5 cc) and a 2 N solution (5 cc) of hydrochloric acid in diethyl ether is added. The precipitate formed is drained and washed with diethyl ether (2x2 cc) . 8-Amino-8-aminomethyl-tricyclo[5.2.1.0/2,6]decane dihydrochloride (0.44 g) is 5 obtained, as the endo racemate, in the form of white crystals which melt with decomposition at 282-285*C. 8-Amino-tricyclo[5.2.1.0/2,6]decyl-8-carboxamide, in the form of the endo racemate, can be obtained in the following way: 10 The procedure is as in Example 11, but starting from a suspension of 8-benzyloxycarbonylamino- tricyclo[5.2.1.0/2,6]decyl-8-carboxamide (3.12 g), in the form of the endo racemate, in ethanol (300 cc) and a 1 N solution (12 cc) of hydrochloric acid in water, in the 15 presence of 10 % palladium-on-charcoal (0.5 g) and under a hydrogen pressure of 140 kPa for 4 hours at 50°C. After filtering off the catalyst and concentrating the filtrate to dryness, taking up the residue in water (100 cc), rendering alkaline to pH 10 and extracting with dichloromethane, 8-20 amino-tricyclo[5.2.1.0/2,6]decyl-8-carboxamide (1.62 g) is thus obtained in the form of bright white platelets which melt at 131°C. 8-Benzyloxycarbonylamino-tricyclo[5.2.1.0/2,6]decyl-8-carboxamide, in the form of the endo racemate, is prepared 25 in the following way: The procedure is as in Example 11, but starting from 1 232953 - 31 - 8-benzyloxycarbonylamino-tricyclo[5.2.1.0/2,6]decyl-8-carboxylic acid (4.8 g) , in the form of the endo racemate, in anhydrous tetrahydrofuran (150 cc) and anhydrous triethylamine (2.05 cc); and isobutyl chloroformate (2.1 cc), 5 followed by bubbling of ammonia. The precipitate formed is poured into water (200 cc), drained, washed with water (3 x 50 cc) and dried in an oven at QO'C. 8-Benzyloxycarbonylamino-tricyclof 5.2.1.0/2,6]decyl-8-carboxamide (3.11 g) is thus obtained in the form of a white 10 powder which melts at 148'C. 8-Benzyloxycarbonylamino-tricyclo[5.2.1.0/2,6]decyl-8-carboxylic acid, in the form of the endo racemate, can be obtained in the following way: The procedure is as in Example 11, but starting from 15 8-amino-tricyclo[5.2.1.0/2,6]decyl-8-carboxylic acid (5.3 g), in the form of a mixture of the endo and exo racemates in a ratio of (6/1) , in a 1 N solution (60 cc) of sodium hydroxide in water and benzyl chloroformate (3.85 cc). Extracting the excess benzyl chloroformate with diethyl ether, then 20 acidifying the aqueous phase to pH 1 and extracting the oil, which then decants, with dichloromethane and recrystallizing the oily residue, after concentration, in a mixture of water and ethanol (30/70 by volume) (250 cc), 8-benzyloxycarbonylamino-tricyclo[5.2.1.0/2,6]decyl-8-25 carboxylic acid (4.98 g) is then obtained, as the endo racemate, in the form of a white powder which melts at 122°C. - 32 23 2 9b9 8-Amino-tricyclo[5.2.1.0/2,6]decyl-8-carboxylic acid, in the form of a mixture of the endo and exo racemates in a ratio of (6/1), can be obtained under the conditions described by J.R. SUFRIN et al., Mol. Pharmacol., 15, 661-677 5 (1979). EXAMPLE 9 The procedure is as in Example 1, starting from 8-amino-8-aminomethyl-tricyclo[5.2.1.0/2,6]decane dihydrochloride (0.80 g), in the form of the exo racemate, in 10 methanol (5 cc) and a 1 N solution (6 cc) of sodium hydroxide in water, and potassium tetrachloroplatinate (1.24 g) in solution in water (12 cc). A cis-(8-amino-8-aminomethyl-tricyclo[5.2.1.0/2,6]decane)dichloroplatinum (0.85 g) is thus 15 obtained, as the exo racemate, in the form of a yellow-beige powder which melts with decomposition at 318°C. 8-Amino-8-aminomethyl-tricyclo[5.2.1.0/2,6]decane, in the form of the exo racemate, can be obtained in the following way: 20 The procedure is as in Example 1, but starting from 8-acetylamino-8-acetylaminomethyl-tricyclo[5.2.1.0/2,6]decane (1.97 g), in the form of the exo racemate, in a 6 N solution (50 cc) of hydrochloric acid in water for 24 hours under reflux. Taking up the residue from the evaporation in ethanol 25 (20 cc) and diethyl ether (80 cc), 6-amino-8-aminomethyl-tricyclo[5.2.1.0/2,6]decane dihydrochloride (1.26 g), is - 33 - 232959 obtained, as the exo racemate, in the form of white crystals which melt at 273-5"C. 8-Acetylamino-8-acetylaminomethy1-tricyclo[5.2.1.0/2,6]decane, in the form of the exo racemate, 5 can be obtained in the following way: The procedure is as in Example 1, but starting from 8-acetylamino-8-cyano-tricyclo[5.2.1.0/2 , 6]decane (5.8 g), in the form of the exo racemate, in acetic acid (100 cc) and acetic anhydride (5.6 cc), in the presence of Adams platinum 10 oxide (0.6 g)? recrystallizing the residue from the evaporation in a mixture of ethanol and water (25/75 by volume) (200 cc), 8-acetylamino-8-cyano- tricyclo[5.2.1.0/2,6]decane (4.33 g) is obtained, as the exo racemate, in the form of bright white crystals which melt at 15 2 04'C. 8-Acetylamino-8-cyano-tricyclo[5.2.1.0/2,6]decane, in the form of the exo racemate, can be obtained in the following way: The procedure is as in Example 1, but starting from 20 8-amino-8-cyano-tricyclo[5.2.1.0/2,6]decane (4 g), in the form of the exo racemate, in diethyl ether (100 cc) and acetic anhydride (3.85 cc); 8-acetylamino-8-cyano-tricyclo[5.2.1.0/2,6]decane (4.35 g) is obtained, as the exo racemate, in the form of fine white crystals which melt at 25 141° C. 8-Amino-8-cyano-tricyclo[5.2.1.0/2,6]decane, in the 23? 9 h Q v ^ - 34 - form of the exo racemate, is obtained quantitatively from its hydrochloride, which can be obtained, in the form of the pure exo racemate, under the conditions described by J.R. SUFRIN et al., Mol. Pharmacol., 15, 661-677 (1979). 5 EXAMPLE 10 A solution of potassium tetrachloroplatinate (2.07 g) and potassium iodide (3.32 g) in water (20 cc) is brought to 80"C for 15 minutes. The solution of potassium tetraiodoplatinate thus obtained is then added to a solution 10 of 2-amino-2-aminomethy1-bicyclo[2.2.1]heptane dihydrochloride (1.06 g), in the form of the exo (1R, 2R, 4S) and (IS, 2S, 4R) racemate, in methanol (5 cc) and a 1 N solution (10 cc) of sodium hydroxide in water. After stirring for 3 hours at 25°C in the absence of light, the precipitate 15 formed is drained on a glass frit, washed with water (3x5 cc) and then with acetone (5 cc); the diiodo complex (2.67 g) is thus obtained. All of this complex is suspended in methanol (10 cc) and water (90 cc); silver nitrate (1.55 g) is added and the 20 mixture is then stirred for 4 hours in the absence of light. After draining the silver iodide formed, the solution is clarified on a cartridge having a pore size of 3 n. Potassium chloride (1.01 g) is added to the solution of diaqua platinum dinitrate thus obtained and the mixture is 25 stirred for 4 hours in the absence of light. The precipitate formed is drained and washed with water (3 x 10 cc). Cis-(2- 232959 - 35 - amino-2-aminomethyl-bicyclo[2.2.1]heptane)dichloroplatinum (1.34 g) is thus obtained, as the exo racemate monohydrate, in the form of a yellow-beige powder which melts with decomposition at 333°C. 5 2-Amino-2-aminomethyl-bicyclo[2.2.1]heptane dihydrochloride, in the form of the exo racemate, can be obtained in the following way: The procedure is as in Example 3, but starting from 2-acetylamino-2-acetylaminomethyl-bicyclo[2.2.l]heptane 10 (7.85 g), in the form of the exo racemate, in a 6 N solution (250 cc) of hydrochloric acid in water for 8 hours under reflux; taking up the residue from the evaporation in ethanol (100 cc) and diethyl ether (300 cc), 2-amino-2-aminomethyl-bicyclo[2.2.l]heptane dihydrochloride (6.87 g) is obtained in 15 the form of white crystals which melt at 271'C. 2-Acetylamino-2-acetylaminomethy1-bicyclo[2.2.l]heptane, in the form of the exo racemate, can be obtained in the following way: The procedure is as in Example 3, but starting from 20 2-acetylamino-2-cyano-bicyclo[2.2.1]heptane (7.14 g), in the form of the exo racemate in acetic acid (250 cc) and acetic anhydride (7.5 cc), in the presence of Adams platinum oxide (0.7 g); taking up the residue from the evaporation in water and ethanol (80/20 by volume) (100 cc), 2-acetylamino-2-25 acetylaminomethyl-bicyclo[2.2.l]heptane (8.7 g) is thus obtained in the form of fine white crystals which melt at 232 9 5 - 36 - 2 08 * C. 2-Acetylamino-2-cyano-bicyclo[2.2.1]heptane, in the form of the exo racemate, can be obtained in the following way: 5 The procedure is as in Example 3, but starting from 2-amino-2-cyano-bicyclo[2.2.1]heptane (6.33 g), in the form of the mixture of the exo and endo racemates in a ratio of (8/1), in diethyl ether (100 cc) and acetic anhydride (4.7 cc); after recrystallization from a mixture of ethanol 10 and water (15/85 by volume) (300 cc), 2-acetylamino-2-cyano-bicyclo[2.2.1]heptane (7.14g) is obtained in the form of fine white crystals which melt at 164"C. Using the conditions described by H.S. TAGER et al., J. Amer. Chem. Soc., £4(3), 968-972 (1972), 2-amino-2-cyano-15 bicyclo[2.2.ljheptane melting at 232-233°C is obtained after two successive recrystallizations from the minimum of aqueous 1 N solution of hydrochloric acid. 2-Amino-2-cyano-bicyclo[2.2.1]heptane can be obtained quantitatively, in the form of a colourless oil which 20 crystallizes at about 20"C and corresponds to the mixture of the exo and endo racemates in a ratio of (8/1), by neutralization of its hydrochloride. EXAMPLE 11 2-Amino-2-aminomethyl-bicyclo[2. 2.1]heptane 25 (0.098g), in the form of the endo racemate, is dissolved, in the absence of light, in methanol (10 cc) and water (15 cc). - 37 - 2 3 2 9 5 9 A solution of potassium trichloro(ethylene)platinate (Zeise salt) (0.258 g) in methanol (5 cc) is added. The mixture is heated at 35*C for 3 hours and stirring is then continued for 20 hours at 20*C. The precipitate formed is drained, washed 5 with a mixture of methanol and water (50/50 by volume) (2 x 2.5 cc) and then with methanol (2.5 cc). Cis-(2-amino-2-aminomethyl- bicyclo[2.2.1]heptane)dichloroplatinum (0.150 g) is thus obtained, as the endo (1R, 2S, 4S) and (IS, 2R, 4R) racemate 10 dihydrate, in the form of a yellow-beige powder which melts with decomposition at 322*C. 2-Amino-2-aminomethyl-bicyclo[2.2.l]heptane, in the form of the endo racemate, can be obtained in the following way: 15 2-Amino-bicyclo[2.2.1]heptyl-2-carboxamide (0.308 g), in the form of the endo racemate, is dissolved, under nitrogen, in anhydrous tetrahydrofuran (25 cc) and a 1 N solution (10 cc) of diborane in anhydrous tetrahydrofuran is added. The mixture is refluxed for 20 hours; after cooling to 20 0°C, ethanol (20 cc) is added, followed, with care, by a 2 N solution (5 cc) of hydrochloric acid in diethyl ether. The solvents are concentrated to dryness under reduced pressure (5.2 kPa), the residue is taken up in water (20 cc) and the mixture is rendered alkaline to pH 10 by the addition of a 25 IN solution of sodium hydroxide in water and then extracted with dichloromethane (3 x 20 cc). 2-Amino-2-aminomethyl- - 38 - 232959 bicyclo[2.2.1]heptane (0.195 g) is thus obtained, in the form of a pale yellow oil; this diamine can be characterized by its hydrochloride, a white powder which melts at 291*C. 2-Amino-bicyclo[2.2 .1]heptyl-2-carboxamide, in the 5 form of the endo racemate, can be obtained in the following way: 2-Benzyloxycarbonylamino-bicyclo[2.2.l]heptyl-2-carboxamide (4.32 g), in the form of the endo racemate, is suspended in ethanol (150 cc) and a 1 N solution (15 cc) of 10 hydrochloric acid in water and 10 % palladium-on-charcoal (0.5 g) is then added. The mixture is subjected to a hydrogen pressure of 140 kPa for 4 hours at 50*C. After cooling, filtering off the catalyst and concentrating the filtrate to dryness under reduced pressure (5.2 kPa), the residue is 15 taken up in water (100 cc) and the mixture is rendered alkaline to pH 10 by the addition of a 2 N solution of sodium hydroxide in water and extracted with dichloromethane (4 x 100 cc). 2-Amino-bicyclo[2.2.l]heptyl-2-carboxamide (1.66 g) is thus obtained in the form of bright white 20 platelets which melt at 178*C. 2-Benzyloxycarbonylamino-bicyclo[2.2.1]heptyl-2-carboxamide, in the form of the endo racemate, is prepared in the following way: 2-Benzyloxycarbonylamino-bicyclo[2.2.1]heptyl-2-25 carboxylic acid (11.6 g), in the form of the endo racemate, is dissolved in anhydrous tetrahydrofuran (200 cc) and _ 39 „ 2 3 2 9 u i anhydrous triethylamine (6.2 cc). After cooling to -20'C, isobutyl chloroformate (5.7 cc) is added and the white suspension obtained is stirred for 1 hour at between -20 and 0*C and ammonia is then bubbled through, with stirring, at 5 O'C until the mixture is saturated. Stirring is then continued for 16 hours at 20*C and the precipitate formed is poured into water (700 cc), drained, washed with water (3 x 50 cc) and dried in an oven at 80"C. 2-Benzyloxycarbonylamino-bicyclo[ 2 . 2 .1 ]heptyl-2-carboxan\ide 10 (9.5 g) is thus obtained in the form of a white powder which melts at 188*C. 2-Benzyloxycarbonylamino-bicyclo[2.2.1]heptyl-2-carboxylic acid, in the form of the endo racemate is prepared in the following way: 15 2-Amino-bicyclo[2.2.1]heptyl-2-carboxylic acid (12.4 g), in the form of a mixture of the endo and exo racemates in a ratio of (12/1), is dissolved in a 1 N solution (220 cc) of sodium hydroxide in water. After cooling to -10 ° C, benzyl chloroformate (18.3 cc) is added, the 20 mixture is then stirred for 5 hours and the temperature is allowed to return from -10 to +20*C. The excess benzyl chloroformate is then extracted with diethyl ether (2 x 100 cc), the aqueous phase is then acidified to pH 1 by the addition of concentrated hydrochloric acid and the oil, 25 which then decants, is extracted with dichloromethane (3 x 100 cc). After reconcentration of the dichloromethane £, w ad 13 under reduced pressure (5.2 kPa) , the oily residue is recrystallized from a mixture of water and ethanol (65/35 by volume) (300 cc). 2-Benzyloxycarbonylamino-bicyclo[2.2.l]heptyl-2-carboxylic acid (13.5 g) is thus -5 obtained in the form of a white powder which melts at 129*C. 2-Amino-bicyclo[2.2.1]heptyl-2-carboxylic acid, in the form of a mixture of the endo and exo racemates in a ratio of (12/1), can be obtained under the conditions described by H.N. CHRISTENSEN et al., J. Biol. Chem., 244(6). 10 1510-20 (1969). The present invention also provides pharmaceutical compositions which contain, as active ingredient, at least one platinum complex of formula (I) (in the free form or in the form of a salt) in combination with one or more 15 compatible and pharmaceutically acceptable diluents or adjuvants. These compositions can be used parenterally, The compositions for parenteral administration can be sterile, aqueous or non-aqueous solutions, suspensions or emulsions. The solvent or vehicle used can be, for example, 20 propylene glycol, a polyethylene glycol, a vegetable oil, e.g. olive oil, or an injectable organic ester, e.g. ethyl oleate. These compositions can also contain adjuvants, in particular wetting agents, emulsifiers or dispersing agents. The sterilization can be effected in various ways, for 25 example with the aid of a bacteriological filter, by incorporating a sterilizing agent in the composition, by - 41 - 23 2 § 5 9 irradiation or by heating. They can also be prepared in the form of solid sterile compositions which will be dissolved at the time of use in sterile water or any other sterile injectable medium. 5 In human therapy, the medicaments according to the present invention are particularly useful for the treatment of cancers of the digestive system, lung cancers, cancers of the testicles or of the ovaries and also for the treatment of cancers of the head and the neck. 10 In a general manner, the physician will determine the dosage which he considers the most appropriate as a function of the age, the weight and all the other factors inherent to the subject to be treated. The preferred mode of administration is intravenous. 15 As an illustration, the medicaments according to the invention can be administered to man intravenously in an amount of 250 to 1000 mg/m2 of body surface per treatment. The following example illustrates a composition according to the present invention: 20 Example A 50 cc bottle is filled under sterile conditions with cis-(1-amino-l-aminomethyl- bicyclo[3.2.1]octane)dichloroplatinum hydrate (835.3 mg) and an ampoule is provided containing sterile isotonic glucose 25 solution (50 cc), to be added to the bottle at the time of use. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 42 - 232 9 5 The solution thus prepared, which contains 800 mg of cis-(1-amino-l-aminomethyl- bicyclo[3.2.l]octane)dichloroplatinum, is ready for incorporation in a perfusion liquid. r q - 43 - WHAT WE/^ CLAIM IS:

1. A platinum complex of formula: B1 *2 X \ / Pt / \ ^ NH2 ' *2 in which: R^ and R2 together with the carbon atom to which 5 they are attached form a saturated or unsaturated polycyclic carbocyclic radical containing 7 to 12 carbon atoms, or a saturated or partially saturated mono-, bi- or tricyclic heterocyclic radical containing 5 to 11 ring atoms and a single hetero-atom chosen from oxygen, sulphur and nitrogen, the said nitrogen being unsubstituted or substituted by an alkoxycarbony 1 radical, the said mono-, bi- or tricyclic heterocyclic radical being otherwise unsubstituted, and X. and X2 represent chlorine or together form y E n - either a radical of formula: o 2 NAY 1992 -J - 0 — C - (CR6R7)n - C — 0 - o '/ 0 0 15 in which n is 0, 1 or 2 and, when n is 1, R6 and R7 are identical or different and are hydrogen atoms or alkyl radicals or form, together with the carbon atom to which they are attached, a cyclobutyl radical, or when n is 2, Rg and R7 are hydrogen atoms - or a radical of the formula: OH I - 0 - C —(CR6R7)n - P - 0 - II II 0 0 in which n( Rg and R7 are as defined above, the aforesaid alkyl radicals and alkyl portions containing 1 to 4 carbon atoms each in a straight or branched chain, and its hydrates and its salts where such exist.

2- A platinum complex according to claim 1, in which R-l and R2 together with the carbon atom to which they are attached form a divalent radical derived from bicyclo £2.2.1] heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[3.2.2}nonane, bicyclo[3.3.1]nonane, adamantane, decahydronaphthalene, 1,2,3,4-tetrahydronaphthal ene, spiro[5.5]undecane, tricyclo[5.2.1.0/2,6]decane or indane, or Ri and R2 together with the carbon atom to which they are attached form a 4-chromanyl, 3-coumaryl, 4-homopiperidinyl, 4-piperidinyl, 3-pyrrolidinyl,

3-quinuclidinyl, 4-tetrahydropyranyl, 3-tetrahydrofuryl,

4-tetrahydrothiopyranyl, 3-tetrahydrothiofuryl or 1,2,3,4-tetrahydroquinol -4-yl radical, and its hydrates and its salts. 3. A platinum complex according to claim 1, in which R^ and R2 together with the carbon atom to which they are cttached form a divalent radical derived fran bicyclo [2.2.1] heptane', adamantane, bicyclo£3.2.ljoctane, bicyclo[2.2.2joctane or tricyclo 5.2.1.0/2,6 decane and X-^ and X2 represent /« ■ - f/y ji« ( \"2 JUNI99: r 45 chlorine or together form a radical of formula: oh — 0 — c - (CR6R7)n - P - 0 II II 0 0 in which n is 1 and R6 and R7 are hydrogen atoms or methyl radicals or together form a cyclobutyl radical, and its hydrates and its salts. 4. A platinum complex according to claim 1 which is cis -(2-amino-2-aminomethyl-bicyclo[2.2.l]heptane)-dichloroplatinum and its hydrates.

5. A platinum complex according to claim 1 which is cis-(2-amino-2- aminomethyl-bicyclo[3 . 2 .1] octane) - dichloroplatinum and its hydrates. 6. A platinum complex according to claim 1 which is cis-(2-amino-2-aminomethyl-adamantane)dichloroplatinum and its hydrates. 7. A platinum complex according to claim 1 which is cis-(3-amino-3-aminomethyl-bicyclo[3.2.1]octane) -dichloroplatinum and its hydrates. 8. A platinum complex according to claim 1 which is cis-(2-amino-2-aminomethyl- bicyclo[2.2.2]octane)dichloroplatinum and its hydrates. 9. A process for the preparation of a platinum complex according to claim 1, which comprises reacting /v /• O ■ V \ 18 MAR 1992 ♦»*\ r / r, "? - 4

6 - potassium tetrachloroplatinate with a diamine of formula: r2 NH2 R, _|^ \ nh2 in which R;l and R2 are as defined in claim 1, then, when it is desired to obtain a complex according to claim 1 in which X^ and X2 are other than chlorine, converting the chlorinated complex obtained into a dicarboxylated or phosphonocarboxylated complex according to claim 1 and, if desired, converting a phosphonocarboxylated complex obtained into a salt. 10. A process according to claim 9, in which the potassium tetrachloroplatinate is treated with the diamine in the presence of an excess of potassium iodide, and the diiodo complex obtained as an intermediate is treated with silver nitrate and then with an excess of alkali metal chloride to produce the complex according to claim 1 in which Xj and X2 are chlorine. 11. A process for the preparation of a platinum complex according to claim 1, which comprises reacting potassium trichloro(ethylene)platinate with a diamine as defined in claim 9, then, when it is desired to obtain a complex according to claim 1 in which X]_ and X2 are other -^j'g^^than chlorine, converting the dichlorinated complex gained into a dicarboxylated or phosphonocarboxylated * C: ■, \J - 4

7 - complex according to claim 1 and, if desired, converting a phosphonocarboxylated complex obtained into a salt. 12. A process according to any one of claims 9 .to 11, wherein the chlorinated complex obtained is converted into a dicarboxylated or phosphonocarboxylated complex by first converting the said chlorinated complex into a diaqua dinitrate complex of formula: *2 N»2 0H2 1 ^Pt2* ^ , 2N03" / \ NH2 0H2 in which and R2 are as defined in any one of claims 1 to 3, and then reacting the said dinitrate complex with a salt of an acid of formula: OH I HOC - (CR6R7 )n — COH Hoc — (CR5R7 )n — POH II II or || |l 00 00 in which Rg, R7 and n are as defined in any one of claims 1 to 3, and then, if necessary, the phosphonocarboxylated complex is liberated from its salt and, if appropriate, converted into another salt. 13. A process according to any one of claims 9 to 11, wherein the chlorinated complex obtained is converted : r: q S - 4

8 - into a dicarboxylated or phosphonocarboxylated complex by first converting the said chlorinated complex into a diaqua dinitrate complex of formula: *2 r, / Is'H? 0h2 \ / pt2* NH2' ^ OH2 , 2N03" in which R;j_ and R2 are as defined in any one of claims 1 to 3, the said dinitrate complex is then passed over an anion exchange resin (OH form) followed by the addition of an acid of formula: oh hoc - (cr5r7)n - coh h0c _ (cr5r7)n - pok I "II II 0 c 0 0 in which R6, R7 and n are as defined in any one of claims 1 to 3, and then, if appropriate, the complex obtained is converted into a salt. 14. A process for the preparation of a platinum complex according to claim 1 substantially as described in any one of Examples 1 to 11. 15. A platinum complex according to claim 1 when produced by a process as claimed in any one of claims 9 to 14 . 16. a pharmaceutical composition, which contains at y £■ least one platinum complex according to any one of claims 1 ' ,?s'^/sv7 - 4

9 - to 8 or 15, optionally in the form of a salt or hydrate, in combination with one or more compatible and pharmaceutically acceptable diluent or adjuvant. A#Mw]P&. Byj^/Tholr Authorlsod Agents, A. J. PARK & SON </div>