GB2210039A

GB2210039A - 3,4-diamino-tetrahydropyran-pt (II)

Info

Publication number: GB2210039A
Application number: GB8722534A
Authority: GB
Inventors: R Stephen Hanessian
Original assignee: Individual
Current assignee: Individual
Priority date: 1987-09-24
Filing date: 1987-09-24
Publication date: 1989-06-01
Anticipated expiration: 2007-09-24
Also published as: GB2210039B; GB8722534D0

Abstract

This invention relates to novel substituted (3, 4-diaminotetrahydropyran) dihaloplatinum - (II) complexes and processes of preparation therefor. These compounds may be used at catalysts and, as well have, anticancer properties.

Description

Cis-Platinum Derivatives This invention relates in one aspect to new platinum diamine compounds; in a further aspect, this invention relates to processes of preparing such compounds. Still further, this invention also provides a method of using such diamine compounds for medical purposes; the invention also provides compositions containing, as the active ingredient, platinum diamine derivatives as defined hereinafter.

Known platinum diamine compounds are described by Rosenberg (B. Rosenberg et al, tyre Z22 38 (1969).

Specifically, cis-dichlorodiamineplatinum(II), also known as cisplatin, as described, discloses both cisand trans-isomers and are disclosed to exist in an aqueous solution in the 2+ oxidation state. In addition, octahedral 4+ analogs are also known.

Cisplatin compounds of the formula

wherein R1 is a cyclic ring containing between 3 to 8 carbon atoms, are disclosed in Braddock et al, Chem. Biol. Interact., 1975, 11(13), 145-161. These compounds have relatively little activity for medicinal purposes (as discussed hereinafter).

Japanese Patent: Application No. Sho 60-127551, Dated: June 12, 1985 discloses compounds of the following formulae

In the above compounds, groups R1 through R8 are designated as hydrogen or hydroxy, with the proviso that one carbon atom in the cyclohexane ring cannot be substituted by two OH groups. Such compounds are stated to have certain medicinal activity.

Another publication is J. Chem. Soc., 1986, page 459 which discloses two diamino sugars, namely, the platinum complexes of methyl 2,3-diamino-2,3-dideoxy D-mannopyranoside, and 2,3-diamino-2,3-dideoxy-Dglucose. European application 167,071 of January 8, 1986 discloses compounds of the formula

US Patent No. 4,587,331 patented May 6, 1986 by J.J. Hlavka et al discloses other platinum complexes of a linear and cyclic nature, in which the platinum may have dihydroxy substituents.

The present invention provides new derivatives of cis-platinum compounds having the formula

or the corresponding positional isomer of the formula

wherein X is a protective group, (to be described hereinafter) R1 is H, alkyl,or O-alkyl, R2 is H, OH, alkyl, or O-alkyl and R3 is H, alkyl or alkyl-alkoxy.

Each of the isomers (II) and (III) exist as cis and trans stereo-isomers. For convenience, these isomers will be generally called "cis-platinum compounds and their corresponding positional isomers." Protective group X may be any suitable group such as, a halogen, e.g., chlorine, bromine, or iodine, a nitrate, sulfate and the anion of a monobasic organic acid such as glucuronic acid; or still further, X can be a monodentate ligand or a di-anionic chelate group, e.g.

oxalates (C2042-), malonates, [(02C)2CR'R"] (wherein R' and R" are H, alkyl, OH, or taken together represent alkylene units of 2-3 carbons in length) which are typical examples of 0,0-bonded chelates or 1,1cyclobutane dicarboxylates.

Thus, in one aspect, the present invention provides a compound selected from the group consisting of

wherein X is a protective group, selected from the group consisting of halides and di-anionic chelating agents, R1 is H, alkyl or O-alkyl, R2 is H, OH, alkyl or Oalkyl, and R3 is H, alkyl, or alkylalkoxy.

The novel compounds of the present invention may find application as chiral catalysts and as intermediates for chemical catalysts useful for asymmetric synthesis of different compounds. In addition, such compounds can have anti-microbial activity. Still further, such compounds find use as anti-cancer compounds, as described herein in greater detail.

This invention also relates to a process of preparing such compounds, which process is selected from one of the following: (a) a compound of the formula

which comprises: (i) reacting a compound of formula

with K2PtX4, or ii) first catalytically reducing a compound of formula

to form a compound of formula

and then reacting that compound with K2PtX4; or (b) a compound of the formula

which comprises (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to provide a compound of formula

and then reacting that compound with K2PtX4; or (c) a compound of the formula

which comprises: (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to provide a compound of formula

and then reacting that compound with K2PtX4; or (d) a parent compound of the formula

which comprises: (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to a compound of formula

and then reacting that compound with K2PtX4; or (e) an analog compound of the formula

which comprises: (i) reacting a compound of formula

with K2PtX4 to provide a compound of formula

then reacting that compound with the acid (H2X') or salt (Na2X') form of anion, X'; or (ii) first catalytically reducing a compound of formula

to form a compound of formula

then reacting that compound with K2PtX4 to provide a compound of formula R2# R3 # NH2 X O NH2 X R1 and then reacting that compound with the acid (H2X') or salt (Na2X') form of anion, X'; or f) a compound of the for

which comprises: (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to form a compound of formula

and then reacting that compound with K2PtX4; or (g) a compound of the formula

which comprises: (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to provide a compound of formula

and then reacting that compound with K2PtX4; or (h) a compound of the formula

which comprises: : (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to provide a compound of formula

and then reacting that compound with K2PtX4; or (i) a parent compound of the formula

which comprises: (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to a compound of formula

and then reacting that compound with K2PtX4; or (j) an analog compound of the formula

which comprises: (i) reacting a compound of formula

with K2PtX4 to provide a compound of formula

and then reacting that compound with the acid (H2X') or salt (Na2X') form of anion, X'; or (ii) first catalytically reducing a compound of formula

to form a compound of formula

then reacting that compound with K2PtX4 to provide a compound of formula

and then reacting that compound with the acid (H2X') or salt (Na2X') form of anion, X'; wherein X is a protective group, R1 is H, X' is the anion of said di-anionic chelating agent, R1, H, alkyl or O-alkyl, R2 is H, OH, alkyl or O-alkyl, and R3 is H, alkyl, or alkylalkoxy selected from the group consisting of a halogen, e.g., chlorine, bromine, or iodine, a nitrate, sulfate, a monobasic organic acid, e.g. glucuronic acid; a monodentate ligand or a di-anionic chelate group, e.g. oxalates (C2042-), malonates, [(02C)2CR'R"] (wherein R' and R" are H, alkyl, OH, or taken together represent alkylene units of 2-3 carbons in length) or l,l-cyclobutane dicarboxylates.

In accordance with a further aspect, a pharmaceutical composition is provided comprising as the essential active ingredient, a compound selected from those described above, together with a pharmaceutically acceptable carrier therefor.

In accordance with still further aspect of this invention a method is provided for the treatment of tumors comprising: selecting a mammal having such tumor; and treating the mammal with a pharmaceutical composition comprising as the essential active ingredient, a compound as described above, together with a pharmaceutically acceptable carrier therefore.

In the above processes, catalytic reduction may be carried out using conventional techniques and catalysts for that purpose. Such catalysts, temperature conditions and general reaction parameters are known to those skilled in the art.

In addition to the other properties of the compounds of the present invention and as noted above, certain compounds, particularly those in which R1 is H, or lower alkoxy, R2 is H, hydroxy or lower alkoxy, and R3 is hydrogen, have been found to exhibit anti-cancer activity, namely against L1210 leukemia implanted in CDF, mice. The compounds of the present invention have been found to be similar in lab screening profile to the known compound, cisplatin, which places the compounds of this invention in the class of coordination compounds that have therapeutic activity against a wide spectrum of human tumours, either alone or in combination with other agents, e.g. adriamycin, 5-fluorouracil, etc. In 1979, the FDA approved cisplatin for use in humans.

Although the mode of action is still unknown, it has been found that cisplatin and its analogs bind to the DNA and disturb the normal functions of the cell. In another hypothesis, the drug is believed to enhance antigenicity so that tumors become more susceptible to destruction by the host's immune system. Moreover, the compounds of the present invention have additional unexpected properties, namely they are more soluble than cisplatin in physiological saline, and they are believed to be effective against tumors which have a resistance to cisplatin.

Regardless of the precise mode of action, the efficacy and potential of cisplatin as an antitumor agent are of some significance. Although cisplatin exerts its preferential toxicity to tumor cells when compared to normal cells at a therapeutic index which allows its clinical use, the situation is still far from perfect and there are also serious side effects to overcome. An improvement is still sought in therapeutic index. Among the major drawbacks are nephrotoxicity, neurotoxicity, gastro-intestinal problems (emesis) and depression of the function of the bone marrow thus producing fewer than normal white blood cells and platelets. These have obviously limited the size of the dose and continue to be a major impediment to the broader use of cisplatin in humans.

At present, patients using cisplatin are induced to increase their flow of urine by intravenous administration of 1-2 liters of fluid. The drug is then administered intravenously together with a diuretic. A most recent development is the administration of Dmannitol which is believed to "flush out" residual cisplatin from the body. These are nonetheless relatively harsh treatments even in the face of lifethreatening situations.

There is a renewed interest in the treatment of a variety of tumors with platinum coordination compounds. (B. Rosenberg, Cancer Treatment Reports 63, 1943 (1979); and Science, 192, 774 (1976); Chem. Eng.

News, Jan. 21, 1980, p.35). Reports on the clinical status of cisplatin in cancer chemotherapy, generally on extremely advanced cases, indicate promising anticancer activity. (J.A. Gottlieb and B. Drewinko, Cancer Chemother. Rep., 59, 621 (1975). Cisplatin, as noted above, has had success in the treatment of testicular carcinoma (H.J. Wallace and D. 3. Higby, Recent Results Cancer Res. 48, 167 (1974), hand and neck cancer (I.H.

Krakoff and A. J. Lippman, Recent Results Cancer Res., 48, 183 (1974) squamous cell carcinoma, malignant lymphoma and endometrial carcinoma (J. M. Hill et al, Cancer Chemother. Rep., 48, 145 (1974) and J. M. Hill et al, Cancer Chemother. Rep. 59 647 (1975), and ovarian adenocarcinoma (E. Wittshaw and B. Care, Cancer Res., 48, 178 (1974). Researchers at Georgetown University in Washington have reported remarkable success in treating brain tumors with this drug (Chem. Eng. News, Oct. 6, 1980, p. 27). The patients in this case were 10 children whose tumors had resisted many forms of chemotherapy. Even more recent clinical studies are reported as follows: 1. Cisplatin - Current Status and New Developments.

AW Preslayko, S.T. Crooke, S.K. Carter (eds), Academic Press, 1980.

2. Platinum Coordination Complexes in Cancer Chemotherapy. M.D. Hacker, E.B. Douple, I.H.

Krokoff (eds).

Developments in Oncology Senes, Martinus Nijhoff, 1984.

3. Platinum Cancer Chemotherapy, Proceedings.

(M. Nicolini and G. Bandok, (eds), 1987.

As previously mentioned, Cisplatin treatment has certain disadvantages. For example, it is not very soluble in water which renders its intravenous administration questionable. Some derivatives are known to maintain the desired levels of activity (T.A. Connors, M.J. Cleare and K. R. Harrap, Cancer Treatment Reports 63,1499 (1979), but the solubility characteristics were not noticeably improved; thus, e.g. malonato (1,2 diaminocyclohexane) platinum (II) has been found to be effective against a number of animal tumors in addition to L1210 Leukemia (J.H. Burchenal et al, Cancer Treatment Reports, 63, 1493 (1979). Nephro-toxicity and other forms of toxicity remain as the most serious drawback of cisplatin and the limited number of analogs tested so far.The synthesis of different platinum coordination compounds with greater water solubility, less renal toxicity and greater antitumor activity is a goal that is still actively sought by investigators (see Roberts and Thomson below).

The primary mode of action (J. J. Roberts and A. J. Thomson, Prog. Nucl. Acid Res., Mol. Biol., 22, 71 (1979) and A. D. Kelman and H. J. Persesie, Cancer Treatment Reports, 63, 1445 (1979) of cisplatin and its derivatives is localized at the intracellular DNA level.

While the sites within the various bases to which cisplatin binds are known, their relative importance to antitumor activity have not been conclusively discerned.

The bound cisplatin drug would result in template inactivation of DNA and the accumulation of potentially lethal damage.

With respect to their transport, again, little is known except that the drug must be able to penetrate the cell membrane prior to exerting intra-cellular tumoridical action. The active form must be electrically neutral in the plasma prior to transport. Otherwise a carrier-mediated mechanism has to be involved for which there is no evidence (L.A. Zwelling and K. W. Kohn, Cancer Treatment Reports, 63, 1439 (1979).

In the above-defined compounds, the compounds of the present invention exist in one of two positional isomeric forms, as disclosed above. Such compounds also individually exist as stereo-isomers, as will be evident from the Examples hereinafter referred to. Accordingly, the present invention embraces both the positional isomers and stereo-isomers of the compounds described herein.

Preferred compounds of the present invention are those compounds where R1, in addition to being H, is lower alkyl, namely alkyl having from 1 to 4 carbon atoms. This likewise applies to the O-alkyl R1 substituents which preferably have 1 to 4 carbon atoms.

Another series of preferred compounds of the present invention is where R2, in addition to being H or OH, are compounds where alkyl is lower alkyl, namely alkyl containing from 1 to 4 carbon atoms and as such, this includes O-alkyl as containing 1 to 4 carbon atoms.

A particularly preferred group of R2 substituents is H, OH and lower alkoxy such as methoxy.

Another series of preferred compounds of the present invention comprises those compounds in which R3 is H, or lower alkyl, wherein alkyl contains from 1 to 4 carbon atoms; thus, C1-C4 alkyl and C1-C4 alkyl-O-Cl-C4 alkyl are preferred groups, with R3 being most advantageously H.

A most preferred group of compounds of formula II and formula III is where R1 is H or lower alkoxy, such as methoxy, ethoxy or the like; R2 is H, OH or lower alkoxy such as methoxy or ethoxy; and R3 is H or lower alkyl such as methyl or ethyl.

As described before, the protective group X may be any suitable group such as, a halogen, e.g., chlorine, bromine, or iodine, a nitrate, sulfate and a monobasic organic acid such as glucuronic acid; or still further, X can be a monodentate ligand or a di-anionic chelate group, e.g. oxalates (C2042-), malonates, [(02C)2CR'R"] (wherein R' and R" are H, alkyl, OH, or taken together represent alkylene units of 2-3 carbons in length) which are typical examples of 0,0-bonded chelates or l,l-cyclobutane dicarboxylates.

Complexes in which the nature of the X group, in the following formula

is varied, are prepared according to the following reaction schemes la, lb, and 2a, 2b using the complexes in which X in the starting diamine is I,C1. The diamine is abbreviated

Complexes in which the nature of the X group, in the following formula

SCHEME

Compound 5 Compound 6 As noted above, one aspect of the invention includes novel compositions of matter and a method of treating certain cancers in mammals using the novel compounds of this invention.The inter-relationship of dosages for animals of various sizes and species and humans is described by Freiereich, E.J., et al., Quantitative Comparison of Toxicity of Anticancer Agents in Mouse, Rat, Hamster, Dog, Monkey and Man. Cancer Chemother. Rep., 50, No. 4, 219-244, May 1966. A preferred dosage regimen is about 5 mg/day to about 200mg/day, per kg of body weight. This dosage may be adjusted to provide the optimum therapeutic response, and may be administered daily or be proportionally reduced as indicated by the exigencies of the therapeutic situation. The active compound may be administered by the intravenous, intramuscular or subcutaneous routes.

The active compounds may be administered parenterally. Solutions or dispersions of the active compound can be prepared in water, suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.

In all cases the form must be sterile and must be fluid; it must also be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol, liquid polyethylene glycol), suitable mixtures thereof and vegetable oils.

The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

As used herein "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.

The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subject to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The requisite for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.

The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore disclosed.

A unit dosage form can, for example, contain the principal active compound in amounts ranging from about 2 mg to over 200 mg with from about 5 to 180 mg being preferred. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.

Regression and palliation of cancers are attained, for example, using intraperitoneal administration. A single intravenous dosage or repeated daily dosages can be administered. Daily dosages up to about 5 to 10 days are often sufficient. It is also possible to dispense one daily dosage or one dose on alternate of less frequent days. As can be seen from the dosage regimens, the amount of principal active ingredient administered is a sufficient amount to aid regression and palliation of the cancer or the like.

Having thus generally described the invention, reference will now be made to the following Examples, describing preferred embodiments.

EXAMPLES In the following tables and discussion, seven especially preferred compounds of this invention are referred to: compound (1), [SP-4-2(3a,4ss,5a,6ss)]-dichloro- [4,5-diamino tetrahydro-6-methoxy-2H-pyran-3-ol-N,N'] platinum; compound (2), [SP-4-2-(2ss,3a,4ss,5a)]-dichloro [tetrahydro-2,5-dimethoxy-2H-pyran-3,4-diamine-N,N'] platinum; compound (3), [SP-4-2-(3a,4ss,5a)]-dichloro[4f5- diaminotetrahydro-2H-pyran-3-ol-N,N] platinum; compound (4), [SP-4-2-(3a,4,5) ]-dichloro[tetrahydro-5-methoxy-2H- pyran-3,4-diamine-N,N'] platinum; compound (5), [SP-42(trans)]-dichloro(tetrahydro-2H-pyran-3,4-diamine-N,N') platinum; compound (6), [SP-4-2-(trans)]-(ethanedioato(2-)- 0,0')-(tetrahydro-2H-pyran-3,4-diamine-N,N') platinum; and compound (7) [SP-4-2-(trans)]-(1,1-cyclobutanedi-carboxylato (2-)0,01)(tetrahydro-2H-pyran-3,4-diamine-N,N') platinum.

(1) 128691 [SP-4-2(3α,4ss,5α, 6ss)]- Dichloro-[4,5-diamino tetrahydro-6-methoxy-2H pyran-3-ol-N,N'] platinum (2) 128693 [SP-4-2-(2ss,3α,4ss, 5α)]- Dflchloro [tetrahydro-2, 5- dimethoxy-2H-pyran-3,4 diamine-N,N'] platinum (3) - [SP-4-2-(3α,4ss,5α)]- Dichloro[4,5-diaminotetra hydro-2H-pyran-3-ol-N,N'] platinum (4) - [SP-4-2-(3α,4ss,5α;)] Dichloro[tetrahydro-5- methoxy-2H-pyran-3,4 diamine-N,N'] platinum (5) 130349 [SP-4-2(trans)] Dichloro(tetrahydro-2H- pyran-3,4-Diamine-N,N') platinum (6) 130350 [SP-4-2(trans)](Ethane dioato(2-)-0,0')-(tetra hydro-2H-pyran-3,4 Diamine-N,N') platinum (7) 22124x124 [SP-4-2-(trans)]-(1,1 Cyclobutanedi-carboxylato (2-)-0,0")(tetrahydro-2H- pyran-3,4-diamine-N,N') platinum (8) 1090050 is cisplatin (Diaminedichloro platinum (II)) (9) 118996 is [SP-4-2]-Dichloro-[lR,2R Diaminocyclohexane] platinum (10) 55263 is chlorambucil Compounds 109050, 118996 and 55263 are included for purposes of comparison.

The results of in vitro tests against various strains of cells L1210 and P388 on separate dates are shown below in Table I.

TABLE 1 ID 50 ( g/ml) COMPOUND Strain 109050 118996 128691 128693 130349 22124x124 55263 L1210 S 0.283 0.078 4.51 12 1.96 6.6 1.32 L1210 S# 0.258 0.098 3.99 8.92 L1210 PTR4 2.21 0.09 4.52 5.12 10 45 3.76 L1210 PTR4# 3.43 0.107 4.51 28.4 DDP5 5.61 0.133 28.2 62.8 12.3 47 3.84 DDP5# 4.19 0.121 17.9 32.2 L1210/DACH 0.221 1.4 5.69 8.29 11.9 26 1.14 L1210/DACH# 0.534 2.54 13.4 19.5 P388 S 0.09 0.066 0.973 7 2.01 6.3 0.378 P388 S# < 0.78 0.064 0.995 > 3.12 P388 PTR4 2.68 < 1.25 19 64.7 > 38 89 1.09 P388 PTR4# 5.05 0.747 15.1 52.1 Note: # indicates the second set of tests, in both sets of tests 128691, and 128693 were dissolved in saline, while 55263 was dissolved in ethanol.

In vivo testing against intraperitoneol L1210 implants (the results or which are shown in Table II) showed that 128691 was highly active while 128693 although less active also showed marked activity.

ANTITUMOR DATA (in vivo)a TABLE II LAD, Animal Weight T/C Activity (Activity Compound Dose Toxicity Change,g. (%) Rating Rating) (mg/ (&num;dead/ kg) group) 128691 50 0/6 -2.7 323 +±t+ 25(++++) LDT 128693 50 1/6 -2.5 218 +++ 25(-) Cisplatin 10 1/6 -4.8 323 ++++ (Control) 5.8 0/6 -0.4 262 ++++ a Dose Schedule: compounds administered (i.p) on Days 3, 7, 11 Tumor: implanted i.p.

LAD: lowest active dose LDT: lowest dose tested These tests demonstrate the anti-cancer properties of the compounds 128691 and 128693.

EXAMPLE 1 (1)

To a solution of dimethoxypropane (3 mMol), p-toluenesulfonic acid monohydrate (0.02 mMol) and acetone (2ml) was added methyl ss-L-arabinopyranoside (1) (1 mMol).

The mixture was stirred for 1 hour at room temperature.

After cooling, the mixture was neutralized with triethylamine, then evaporated below 30 C. The residue was extracted with CH2C12. The extract was washed with cold water and saturated sodium chloride, dried (Na2SO4), evaporated to give a syrup which contained more than 95% of compound (2) methyl 3,4-0-isopropylidene-8-L-arabino- pyranoside [a]D + 192.4 (C 1.81, CHC13).

lit: a) [α]D + 199.1 (C 3.3, CHC13) (Honeyman) b) [a]D + 175.7 (C 5.2, CHCl3) (Mukherjee) NMR, IR spectra confirmed the proposed structure EXAMPLE 2

A solution of the above compound (6) methyl 2,3-anhydro-8-L-lyxopyranoside obtained from compound (2) methyl-3,4-0isopropylidene-ss-L-arabinopyranoside via the sequence a) tosylation b) aquacetic acid c) sodium methoxide (0.923 g, 6.32 mMol) and dihydropyran (3 ml, 32.9 mMol) in dry methylene chloride (50 ml) containing pyridinium p-toluenesulfonate (PPTS) (0.18 g, 0.72 mMol) was stirred for 1.5 h at room temperature.

The solution was diluted with 50 ml ether, then washed with half-saturated NaCl (2 x 25 ml), dried with anhydrous Na2SO4, and evaporated to give a syrup. The syrup was applied to a silica gel column. Elution with ethyl acetate/hexane (1:1) then concentration gave the THP epoxide compound (7) methyl 2,3-anhydro-4-0-tetrahydro pyranyl-ss-L-lyxopyranoside (1.32 g, 91%) as a syrup.

[alD + 65.8 (C 1.23, CHC13) NMR, IR spectra confirmed the proposed structure.

EXAMPLE 3

To a solution of the epoxide (7) methyl 2,3anhydro-4-0-tetrahydropyranyl-ss-L-lyxopyranoside of Example 2 (26.4 g, 115 mMol) in 2-methoxyethanol-water (14:1, 1350 ml) was added sodium azide (30 g, 153 mMol) and ammonium chloride (12.3 g, 230 mMol). The mixture was heated at 1100C for 20 hours, and evaporated to give a residue which was extracted with dichloromethane. The extract was washed with water, dried, and evaporated to give a syrup which was applied to a silica gel column.

Elution with hexane/ethyl acetate (1:1) gave the THP ether isomers of the above 2-azide derivative (8) methyl 2-azido-2-dioxy-4-0-tetrahydropyranyl-ss-L-xylopyranoside- side (7.5 g, 24%).

[α]D + 11.9 (C 0.78, CHCl3); m.p. 66-68 C, and the THP ether isomers of 3-azide derivative (9) methyl 3-azido 3-dioxy-4-0-tetrahydropyranyl-ss-L-arabinopyranoside (14.8 g, 47.2%).

[a]D + 189.7 (C 1.3, CHC13) NMR, IR spectra confirmed the proposed structure.

EXAMPLE 4

To a cold solution of the compound (8) methyl 2-azido-2-dioxy-4-0-tetrahydropoyranyl-ss-L-xylopyrano- side, Example 3 (7.4 g, 27.1 mMol), pyridine (40 ml) and DMAP (cat.) was 'added drop-wise a pre-cooled (OOC) solution of methanesulphonyl chloride (6.5 ml, 84 mMol) in 40 ml pyridine. The mixture was left at room temperature for 1 day. After hydrolysis of the excess of methanesulphonyl chloride, the solution was poured into ice-water and extracted with chloroform. The extract was washed with cold hydrochloric acid (2%) and cold water and then dried (Na2SO4) and evaporated to give a syrup.Flash column chromatography with ethyl acetate/ hexane (1:3, then 2:3, then 1:1) gave the THP isomer 10a (4.09 g, 43%), [a]D -26.9 (C 0.85, CHC13) m.p. 89-910C, and the THP isomer 10b (3.6 g, 38%) [a]D +82.7 (C 1.8, CHC13) NMR, IR spectra confirmed the proposed structure.

EXAMPLE 5

The compound (10a) methyl 2-azido-2-dioxy-3-0 methanesulfonyl-4-0-tetrahydropyranyl-ss-L-xylopyrano- side (3 g, 8.55 mMol) in methanol (100 ml) was treated with hydrazine mono-hydrate (99-100%) (4.6 ml, 82.5 mMol). Raney nickel (0.4 g) was added and the mixture boiled under reflux until decomposition of the hydrazine was complete (monitored by TLC, -5h). The mixture was filtered, evaporated to a syrup, then applied to a silica gel column. Elution with AcOEt, then AcOEt-MeOH (10:1) gave compound (11) methyl 2,3-epimino-2,3 dideoxy-4-0-tetrahydropyranyl-ss-L-ribopyranoside (1.9 g, 97%) as a syrup.

[a]D -80.5 (C 1.11, CHC13) IR, MS spectra confirmed the proposed structure.

EXAMPLE 6

A suspension of the above aziridine compound (11) methyl 2,3-epimino-2,3-dideoxy-4-0-tetrahydro pyranyl-ss-L-ribopyranoside (1.8 g, 7.86 mMol), sodium azide (2.0 g, 30.77 mMol), and ammonium chloride (0.85 g, 15.89 mMol) in 2-methoxyethanol (112 ml) -water (8 ml) was heated for 11 h at 110 C. The mixture was evaporated directly and the residue extracted with dichloromethane (3 x 100 ml). The extract was washed with half-saturated NaHC03 (3 x 50 ml), dried (Na2SO4) and evaporated to give a yellow syrup which was applied to a silica gel column. Elution with CH2C12 - MeOH (20:1) gave the compound (12) methyl 2-amino-3-azido 2,3-dideoxy-4-0-tetrahydropyranyl-ss-L-xylopyranoside (1.7 g, 80%) as a syrup.

[a]D ]D -67.9 (C 0.99, CHC13) IR, MS, NMR spectra confirmed the proposed structure.

EXAMPLE 7

To a solution of THP ether compound (12) methyl 2-amino-3-azido-2,3-dideoxy-4-0-tetrahydropyranyl-ss-L- xylopyranoside (32 mg, 0.118 mMol) in ethanol (1.5 ml) was added pyridinium p-toluenesulfonate (PPTS) (59 mg, 0.24 mMol). The solution was strirred for l day at then evaporated. The residue was applied to a silica gel column. Elution with CH2C12 - MeOH - triethylamine (100:10:1) followed by concentration, gave compound (13) methyl 2-amino-3-azido-2, 3-dideoxy-i3 -L-xylopyranoside (18 mg, 80%) as crystals.

[a]D +20.0 (C 0.24, CH3CH2OH) m.p. 141-143 0C IR, MS, NMR spectra confirmed the proposed structure.

EXAMPLE 8

To a solution of the azide (13) methyl 2-amino 3-azido-2,3-dideoxy-8-L-xylopyranoside (395 mg, 2.1 mMol) in methanol-distilled water (1:1, 18 ml) was added palladium-on-activated-charcoal (10% pd, 230 mg) suspended in methanol (3.8 ml). The mixture was hydrogenated under atmospheric pressure at room temperature for 24 hours.

The catalyst was then removed by filtration through celite. Evaporation and co-evaporation with ethanol to dryness gave the compound (14) methyl 2,3-diamino-2,3 dideoxy-ss-L-xylopyranoside (290 mg, 85%) as white crystals.

[1D +84.5 (C 0.33, CH3OH) m.p. 200-202 0C (decomposition) NMR, IR spectra confirmed the proposed structure. EXAMPLE 9

The diamine compound (14) methyl 2,3-diamino 2,3-dideoxy-B-L-xylopyranoside (28i mg, 1 mMol) was transferred, using distilled water (0.9 ml) into a solution containing K2PtCl4 (430 mg, 1.03 mMol) in distilled water (3.9 ml). The mixture was stirred manually until homogeneous, and was left standing in darkness. After 2 hours the slow crystallization process began in the form of bright yellow plates. When'the original red colour of the solution became yellow or orange-yellow, the crystals were filtered, washed with cold water (3 times) and dried under a stream of air, in the absence of light, for several hours, to afford bright yellow crystals of the compound (15) [SP-4-2-(3a,4ss,5a)]- Dichloro[4,5-diaminotetrahydro-2H-pyran-3-ol-N,N']platinum (325 mg, 43.7%).

m.p. 2700 C -(darkening), 305-310 (decomposition) [a]D +144 (C 0.06, H20) MS spectrum confirmed the proposed structure.

EXAMPLE 10

To a solution of THP ether (10a) methyl 2 azido-2-dioxy-3-0-methanesulfonyl-4-0-tetrahydropyranyl- ss-L-xylopyranoside (0.96 g, 2.74 mMol) in ethanol (35 ml) was added pyridinium p-toluenesulfonate (PPTS) (0.1 g, 0.4 mMol). The solution was stirred for 7 hours at 55 C, and then evaporated. the residue was applied to a silica gel column. Elution with hexane/ethyl acetate (4:5, then 1:2) and then concentration gave the compound (16) methyl 2-azido-2-dioxy-3-0-methanesulfonyl-ss-L-xylo- pyranoside (0.73 g. quantitative) as white crystals.

m.p. llloC-111.50C [a]D +27.0 (C 1.05, CHC13) NMR, IR, MS spectra confirmed the proposed structure. EXAMPLE 11

To a solution of THP ether (10b) which is a diasteromer of (10a) methyl 2-azido-2-dioxy-3-0methanesulfonyl-4-0-tetrahydroxypyranyl-ss-L-xylopyranoside (3.6 g,. 10.3 mMol) in ethanol (120 ml) was added pyridinium p-toluenesulfonate (PPTS) (0.5 g, 2 mMol). The solution was stirred for 7 hours at 550 C, and then evaporated. The residue was applied to a silica gel column. Elution with hexane/ethyl acetate (2:3, then 1:3) followed by concentration gave the compound (16) methyl 2-azido-2-dioxy-3-0-methane sulfonyl-ss-L-xylopyranoside (2.74 g quantitative) as white crystals.

m.p. 110-110 0C [α]D + 27.3 (C 1.03, CHC13).

EXAMPLE 12

To a solution of compound (16) methyl 2-azido 2-dioxy-3-0-methanesulfonyl-ss-L-xylopyranoside (2.48 g., 9.3 mMol) in dry ether (300 ml) was added iodomethane (2.3 ml, 37 mMol),' and then dry, finely divided silver oxide (4.3 g, 18.5 mMol) is added in portions. The suspension was heated under reflux for 4 days. After cooling, the mixture was filtered, and evaporated to a syrup which was applied to a silica gel column.

Elution with hexane/ethyl acetate (1:1) followed by concentration gave compound (17) methyl 2-azido-dioxy 3,4-di-0-methanesulfonyl-ss-L-arabinopyranoside (2.34 g, 89.6%) as a colorless syrup.

[a]D +34.4 (C 1.51, CHC13) NMR and IR spectra confirmed the proposed structure. EXAMPLE 13

The compound (17) methyl 2-azido-2-dioxy-3,4-0 di-0-methansulfonyl-ss-L-arabinopyranoside (2.29 g, 8.15 mMol) in methanol (100 ml) was treated with hydrazine monohydrate (99-100%) (5.5 ml) and Raney nickel (0.3 g).

The mixture was boiled under reflux until decomposition of the hydrazine was complete (monitored by TLC, approximately 5 hours), and then was filtered and evaporated to a syrup which was applied to a silica gel column.

Elution with CH2C12 - MeOH (20:1), followed by concentration gave the aziridine (18) methyl 2,3-epimino-2-3 dideoxy-4-0-methyl-ss-L-ribopyranoside (0.9 g, 70%) as a syrup.

[a]D -19.9 (C 1.18, CHC13) MS, IR spectra confirm the proposed structure.

EXAMPLE 14

A mixture of the aziridine compound (18) methyl 2,3-epimino-2-3,dideoxy-4-0-methyl-ss-L-ribopyranoside (0.84 g, 5.28 mMol), sodium azide (1.4 g, 21.4 mMol) and ammonium chloride (0.58 g, 10.8 mMol) in 2-methoxyethanol (75 ml) - water (5.5 ml) was heated for 17 hours at 1100C, and then evaporated directly. The residue was extracted with dichloromethane (4 x 25 ml) and the resulting solution was washed with half-saturated NaHCO3 (2 x 2.5 ml), dried (Na2S04), and evaporated to give a syrup which was applied to a silica gel column. Elution with CH2Cl2 - MeOH (20:1) followed by concentration gave the azide (19) methyl 2-amino-3-azido-2,3-dideoxy-4-0-methyl-ss-L-xylopyranoside (0.85 g, 80%) as a syrup.

D -5.2 (C 1.02, CHCl3) NMR, MS spectra confirmed the proposed structure.

EXAMPLE 15

To a solution of the azide (19) methyl 2-amino-3 azido-2,3-dideoxy-4-0-methyl-ss-L-xylopyranoside (0.77 g, 3.18 mMol) in methanol-distilled water (1:1, 30 ml) was added palladium-on-activated-charcoal (10% Pd, 400 mg) suspended in methanol (8 ml). The mixture was hydrogenated under atmospheric pressure at room temperature for 24 hours. The catalyst was then removed by filtration through celite*. Evaporation of the resulting solution, followed by co-evaporation with ethanol to dryness gave compound (20) methyl 2,3-diamino-2,3 dideoxy-4-0-methyl-ss-L-xylopyranoside (0.63 g, 94%) as white crystals.

D +101.2 (C 0.60, CH3OH) m.p. 60-620C NMR, MS spectra confirmed the proposed structure.

* = Trade Mark EXAMPLE 16

The diamine (20) methylo2,3-diamino-2,3- dideoxy-4-0-methyl- 8-L-xylopyranoside (0.59 g, 3.35 mMol) was transferred, using distilled water (2.4 ml), into a solution containing K2PtC14 (1.4 g, 3.37 mMol) in distilled water (15 ml). The mixture was stirred manually until homogeneous, and was left standing in darkness. After 4 hours the slow crystallization process began in the form of bright yellow plates.When the original red colour of the solution became yellow or orange-yellow, the crystals were filtered, washed with cold water (5 x 4 ml) and dried under a stream of air in the absence of light, for several hours, to afford bright yellow crystals of (21) [SP-4-2-(3α, 4ss, 5α)]- Dichloro[tetrahydro-5-methoxy-2H-pyran-3,4-diamine- N,N']platinum (0.89 g, 60%).

m.p. 2950C (darkening): 325-3300C (decomposition) +120.9 (C 0.11, H2).

EXAMPLE 17

To 0.6g of(22)96.06 mmol) in 26 ml of EtOH and 8 ml H20 was added 1.58g of NaN3 (24 mmol) and 1.30g of NH Cl(24mmol). The resulting mixture was ref fluxed for 1 4 hour, cooled, and concentrated. The residue was dissolved in H20 and then extracted continuously with Eft20 for 24 hours. The Et20 layer was dried and concentrated to yield 1 g of (23). Compound (23) was dissolved in EtOH and hydrogenated at atmospheric pressure (0.15g 10% Pd/C). The resulting solution was filtered through celite and filtrate was acidified with EtOH/HCl to give, after cooling, 0.62g of (24) (54%). Analyses (C,H,N,C1) were within 0.4% of the theoretical values.

Mass spectroscopic (FAB) and IR analyses confirmed the proposed structure.

EXAMPLE 18

K2PtI4 was prepared in situ by adding solid KI (9.4g; 56.6 mmoles) to 95 ml of a solution of K2PtC14 (3.91 g; 9.42 mmoles). To this solution was added, as a solid, the dihydrochloride of compound (24) (A.2HC1) followed by the slow addition of 18.8ml of l.ON NaOH.

The resulting complex (25) was filtered and washed with O.OIN KI and H2O(0 C). To a 50ml slurry of (25) was added, with stirring, a 50ml solution of AgN03(3.20g; 18.84 mmoles) to prepare a solution of the corresponding diaquo species, [PtA(H20)2j , 2N03. After removal of excess Ag ion using NaCl, 20 ml of 2M NaCl solution was added to the solution of [PtA(H20)2] 2+ with warming ,2N03 in preparing compound (26), [Pt(3,4-diaminopyran)C12], as a fine yellow powder.

NMR(13c, 1H) and IR confirmed the proposed structure.

EXAMPLE 19

A solution of Ag2S04 (0.697g; 0.312 mmol) was added to a lOml(H20) slurry of (25), the mixture was warmed (500C) for 15 minutes, and then allowed to react overnight with agitation. After filtering of AgI(s), the filtrate was treated successively with (1) 15ml of a solution of H2C2 0 (0.297g; 2.35 mmol) and (2) 10.25ml of 0.459N Ba(0H)2 solution which was added drop-wise with stirring. After stirring the reaction mixture overnight, the solution (pH = 4.4) was warmed to 55-60 C for 15 minutes, concentrated using a rotoevaporator, and then cooled to 0 C to initiate crystallization. The crystals were collected by filtration, washed thoroughly with H2O(0 C), 95%Et0H(0 C), and then dried in air and high vacuum.The crude product was re-crystallized from H20 (0.52g/15mlH20 &commat;850C) to yield 0.31g (33%) of (27).

NMR('H,13C), Mass spectroscopy (FAB), IR confirmed the proposed structure.

EXAMPLE 20

A solution of AgN03 (1.019g; 6.00 mmole) was added to a stirred slurry of (26) in H20. The mixture was warmed for 20 minutes at 50-550C, and then allowed to react overniaht with aaitation. After filterina the AgCl(s) formed a solution of

(2NaOH +

was added to the filtrate and the solution was warmed at 50 C for 15 minutes. Cooling to 0 C initiated crystallization. The mixture was placed in a refrigerator, (0 C) overnight. The white crystalline product (28) was filtered, washed (3X) with H20(0 C) and absolute Et0H(0 C) and dried in vacuo to constant weight to yield 0.80g(59%) of (28).

NMR(13C, 195pt), mass (FAB) and IR spectroscopic analysis confirmed the proposed structure.

Claims

.CLAIMS

1. A process of preparing: (a) a compound of the formula

which comprises: (i) reacting a compound of formula

with K2PtX4, or ii) first catalytically reducing a compound of formula

to form a compound of formula

and then reacting that compound with K2PtX4; or (b) a compound of the formula

which comprises (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to provide a compound of formul

and then reacting that compound with K2PtX4; or (c) a compound of the formula

which comprises: (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to provide a compound of formula

which comprises:: (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to a compound of formula

which comprises: (i) reacting a compound of formula

with K2PtX4 to provide a compound of formula

to form a compound of formula

then reacting that compound with K2PtX4 to provide a compound of formula

and then reacting that compound with the acid (H2X') or salt (Na2X') form of anion, X'; or f) a compound of the formula

which comprises: (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to form a compound of formula

and then reacting that compound with K2PtX4; or (g) a compound of the formula

which comprises: (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to provide a compound of formula

and tijen reacting that compound with K2PtX4; or (h) a compound of the formula

which comprises: (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to provide a compound of formula

which comprises: (i) reacting a compound of formula

with K2PtX4, or (ii) first catalytically reducing a compound of formula

to a compound of formula

which comprises: (i) reacting a compound of formula

with K2PtX4 to provide a compound of formula

to form a compound of formula

then reacting that compound with K2PtX4 to provide a compound of formula

and then reacting that compound with the acid (H2X') or salt (Na2X') form of anion, X'; wherein X is a protective group, R1 is H, X' is the anion of said di-anionic chelating agent, R1, H, alkyl or O-alkyl, R2 is H, OH, alkyl or O-alkyl, and R3 is H, alkyl, or alkylalkoxy selected from the group consisting of a halogen, e.g., chlorine, bromine, or iodine, a nitrate, sulfate, a monobasic organic acid, e.g.

glucuronic acid; a monodentate ligand or a di-anionic chelate group, e.g. oxalates (C2042), malonates, [(02C)2CR'R"] (wherein R' and R" are H, alkyl, OH, or taken together represent alkylene units of 2-3 carbons in length) or 1,1-cyclobutane dicarboxylates.

2. A process as defined in Claim 1 of preparing a compound of the formula

which comprises reacting a compound of formula

with K2PtC14.

3. A process as defined in Claim 1 of preparing a compound of the formula

which comprises first catalytically reducinq a compound of formula to form a compound of form

and then reacting that compound with K2PtC14,

4. A process as defined in Claim 1 of preparing a compound of the formula

which comprises reacting a compound of formula

with K2PtC14.

5. A process as defined in Claim 1 of preparing a compound of the formula

which comprises first catalytically reducing a compound of formula to provide a compound of formul

and then reacting that compound with K2PtC14.

6. A process as defined in Claim 1 of preparing a compound of the formula

which comprises (i) reacting a compound of formula

with K2PtC14.

7. A process as defined in Claim 1 of preparing a compound of the formula

which comprises first catalytically reducing a compound of formula

to provide a compound of formula

and then reacting that compound with K2PtC14.

8. A process as defined in Claim 1 for preparing a parent compound of the formula

which comprises reacting a compound of formula

with K2PtC14.

9. A process as defined in Claim 1 for preparing a parent compound of the formula

which comprises first catalytically reducing a compound of formula

to a compound of formula

and then reacting that compound with K2PtC14.

10. A process as defined in Claim 1 for preparing an analog compound of the formula

which comprises reacting a compound of formula

with K2PtC14 to provide a compound of formula

and then reacting that compound with the acid (H2X') or salt (Na2X) form of anion X', wherein X' is an oxalate, malonate or l,l-cyclobutanedicarboxylate ion.

11. A process as defined in Claim 1 for preparing an analog compound of the formula

which comprises first catalytically reducing a compound of formula

to form a compound of formula

then reacting that compound with K2PtX4 to provide a compound of formula

and then reacting that compound with the acid(H2X)or salt(Na2X)form of anion X, wherein is an oxalate, malonate or l,l-cyclobutanedicarboxylate ion.

12. A process as defined in Claim 1 of preparing a compound of the formula

which comprises reacting a compound of formula

with K2PtC14.

13. A process as defined in Claim 1 of preparing a compound of the formula

which comprises first catalytically reducing a compound of formula

to form a compound of formula

and then reacting that compound with K2PtC14.

14. A process as defined in Claim 1 of preparing a compound of the formula

which comprises reacting a compound of formula

with K2PtC14.

15. A process as defined in Claim 1 of preparing a compound of the formula

which comprises first catalytically reducing a compound of formula

to provide a compound of formula

and then reacting that compound with K2PtC14.

16. A process as defined in Claim 1 of preparing a compound of the formula

which comprises reacting a compound of formula

with K2PtC14.

17. A process as defined in Claim 1 of preparing a compound of the formula

which comprises first catalytically reducing a compound of formula

to provide a compound of formula

and then reacting that compound with K2PtC14.

18. A process as defined in Claim 1 for preparing a parent compound of the formula

which comprises: reacting a compound of formula

with K2PtC14.

19. A process as defined in Claim 1 for preparing a parent compound of the formula

which comprises first catalytically reducing a compound of formula

to provide a compound of formula

and then reacting that compound with K2PtCl4.

20. A process as defined in Claim l for preparing an analog compound of the for mula

which comprises reacting a compound of formula

with K2PtX4 to provide a compound of formula

and then reacting that compound with the acid (H2X) or salt (Na2X) form of anion X, wherein X is an oxalate, malonate or l,l-cyclobutanedicarboxylate ion.

21. A process as defined in Claim 1 for preparing an analog compound of the formula

which comprir.? first catalytically reducing a compound of formula

to provide a compound of formula

then reacting that compound with K2PtX4 to provide a compound of formula

and then reacting that compound with the acid (H2X') or salt (Na2X') form of anion, X'; or, wherein X' is an oxalate, malonate or l,l-cyclobutanedicarboxylate ion.

22. A process of preparing a compound of the formula

by reacting a compound of the formula

with K2PtC14.

23. A process of preparing a compound of the formula

by reacting a compound of formula

with K2PtC14.

24. A process as defined in Claim 1 of preparing a compound of the formula

which comprises reacting a compound of formula

with K2PtC14.

25. A process of preparing a compound of the formula

which comprises reacting a compound of formula

with K2PtC14.

26. A process as defined in Claim 1 which comprises selecting the starting diamine compound whereby to produce a novel substituted (3,4-diaminotetrahydropyran dihaloplatinum-(II) complex selected from the group consisting of: (l) [SP-4-2(3α, 4ss, 5α, 6ss)]- dichloro-[4,5-diamino tetrahydro-6-methoxy-2H pyran-3-ol-N,N'] platinum; (2) [SP-4-2-(2ss, 3α, 4ss, 5α)]- dichloro[tetrahydro-2,5 dimethoxy-2H-pyran-3,4 diamine-N,N'] platinum; [SP-4-2-3α,4ss,5α)]- (3) dichloro[4,5-diaminotetra hydro-2H-pyran-3-ol-N,N'] platinum; (4) [SP-4-2-(3α, 4ss, 5α)]- dichloro[tetrahydro-5- methoxy-2H-pyran-3,4 diamine-N,N'] platinum;; (5) [SP-4-2(trans)] dichloro(tetrahydro-2H pyran-3 , 4-diamine-N,N') platinum; (6) [SP-4-2(trans)](ethane dioato(2-)-0,0')-(tetra hydro-2H-pyran-3,4 diamine-N,N') platinum; and (7) [SP-4-2-(trans)]-(1,1 cyclobutonedi-carboxylato (2-)-0,0')(tetrahydro-2H pyran-3,4-diamine-N,N') platinum.

27. A process for the preparation of [SP-4-2(3a, 4ss,5a)]- dichloro-[4,5-diaminotetrahydro-2H-pyran-3-ol- N,N'] platinum which comprises reacting methyl 2,3 diamino-2,3-dideoxy-8-L-xylopyranoside with K2PtC14.

28. A process for the preparation of [SP-4-2-(3a, 4ss,5α)]-dichloro[tetrahydro-5-methoxy-2H-pyran-3,4- diamine-N,N'] platinum which comprises reacting methyl 2,3-dideoxy-4-0-methyl-ss-L-xylopyranoside with K2PtCl4.

29. A process for the preparation of

which comprises reacting

with a solution of silver nitrate, followed by removal of excess silver ions and reaction with a sodium chloride solution.

30. A process for preparing

which comprises reacting

with a solution of silver sulphate, followed by reaction of the intermediate

with a solution of oxalic acid and barium hydroxide.

31. A process for preparing

which comprises reacting

with a solution of silver nitrate, followed by the reaction of the intermediate

with a solution of sodium malonate.

32. A compound selected from the group consisting of

wherein X is a protective group, selected from the group consisting of halides and di-anionic chelating agents, R1 is H, alkyl or O-alkyl, R2 is H, OH, alkyl or 0alkyl, and R3 is H, alkyl, or alkylalkoxy.

33. A compound as defined in Claim 32 of the formula

34. A compound as defined in Claim 32 of the formula

35. A compound as defined in Claim 32 of the formula

36. A compound as defined in Claim 32 of the formula

37. A compound as defined in Claim 32 of the formula

38. A compound as defined in Claim 32 of the formula

39. A compound as defined in Claim 32 of the formula

40. A compound as defined in Claim 32 of the formula

41. A compound as defined in Claim 32 of the formula

42. A compound as defined in Claim 32 of the formula

43. A compound of the formula

44. A compound of the formula

45. A compound of the formula

46. A compound of the formula

47.A compound of the formula

48. A. compound of the formula

49. A compound of the formula

50. A novel substituted (3,4-diaminotetrahydropyran) dihaloplatinum-(II) complex selected from the group consisting of: (1) [SP-4-2(3α,4ss,5α,6ss)]- dichloro-[4,5-diamino tetrahydro-6-methoxy-2H pyran-3-ol-N,N'] platinum; (2) [SP-4-2-(2ss,3α, 4ss, 5α,)]- dichloro[tetrahydro-2r5- dimethoxy-2H-pyran-3,4 diamine-N,N'] platinum; (3) [SP-4-2-(3α,4ss,5α,)]- dichloro[4,5-diaminotetra hydro-2H-pyran-3-ol-N,N'] platinum; (4) [SP-4-2-(3α,4ss,5α,)]- dichloro[tetrahydro-5 methoxy-2H-pyran-3,4 diamine-N,N'] platinum; ; (5) [SP-4-2(trans)]- dichloro(tetrahydro-2H pyran-3,4-diamine-N,N') platinum; (6) [SP-4-2(trans)](ethane dioato(2-)-0,0')-(tetra hydro-2H-pyran-3,4- diamine-N,N') platinum; and (7) [SP-4-2-(trans) ]-(1,1- cyclobutonedi-carboxylato (2-)-0,0' ) (tetrahydro-2H- pyran-3,4-diamine-N,N') platinum.

51. A pharmaceutical composition comprising as the essential active ingredient, a compound according to Claim 32, together with a pharmaceutically acceptable carrier therefore.

52. A pharmaceutical composition comprising as the essential active ingredient, a compound according to Claim 50, together with a pharmaceutically acceptable carrier therefore.

53. A method for the treatment of tumors which comprises: selecting a mammal having such tumor; and treating said mammal with a pharmaceutical composition comprising as the essential active ingredient, a compound according to Claim 32, together with a pharmaceutically acceptable carrier therefore.

54. A method for the treatment of tumors which comprises: selecting a mammal having such tumor; and treating said mammal with a pharmaceutical composition comprising as the essential active ingredient, a compound according to Claim 50, together with a pharmaceutically acceptable carrier therefore.