| JPS55144422A | 1980-11-11 |
Chem.-Biol. Interactions Volume 11, 1975 pages 145-161 (see page 160)
See also references of EP 0409894A4
| 1. | A platinum complex of the formula or NH wherein z' is a bidentate amine, Z'NH is a monodentate NH, amine, R' and R" are different organic groups and X~ is a pharmaceutically acceptable anion. |
| 2. | A platinum complex according to claim 1 wherein R' and R" are independently selected from the group consisting of C^ Cfi alkyl optionally substituted by phenyl, carboxy, C,C. alkyl ester or C2C8 alkenyl; C3~C_, cycloalkyl optionally substituted by phenyl, carboxy, C.C. alkyl ester or C2C8 alkenyl; and phenyl optionally substituted by a substituent selected from the group consisting of C^C, alkyl, C^C. alkoxy, halogen, hydroxy, C C . alkenyl, carboxy C C. alkyl ester, amino, C C. alkyl amino, and di(C1~C4 alkyl)amino. |
| 3. | A platinum complex according to claim 4, wherein Z' is C^C8 cycloalkyl or C3C,0 alkyl, each alkyl being optionally substituted with a substituent selected from the group consisting of C Cg alkyl, C2~C6 alkenyl, phenyl and substituted phenyl. |
| 4. | A platinum complex according to claim 5, wherein Z' is cycloalkyl. |
| 5. | A platinum complex according to claim 6, wherein Z1 is cyclopentyl or cyclohexyl. |
| 6. | A platinum complex according to claim 4, wherein Z is an alkylene group of 3 to 10 carbon atoms, a cycloalkylene group of 3 to 10 carbon atoms, phenylene or pyridyl. |
| 7. | A platinum complex according to claim 8, wherein Z is cyclohexylidene. |
| 8. | A platinum complex according to claim 4, wherein R' is methyl and R" is phenyl, tolyl or benzyl. |
| 9. | A platinum complex according to claim 1, wherein X is Cl, Br or NO . |
| 10. | A platinum complex according to claim 11, wherein X is NO. |
| 11. | A platinum complex according to claim 1 which is optically active. |
| 12. | An antitumor composition comprising an antitumor effective amount of a platinum complex according to claim 1 in combination with a pharmaceutically acceptable carrier. |
| 13. | An antitumor composition according to claim 14 containing 1500 g of the platinum complex. |
| 14. | A method of treating an animal having a tumor susceptible to therapy with platinum which comprises administering to said animal an antitumor effective amount of a platinum complex according to claim 1. |
| 15. | A pharmaceutical composition comprising a compound as claimed in claim 1 for use in a method of treating an animal having a tumor susceptible to therapy with platinum which comprises administering to said animal an antitumor effective amount of a platinum complex according to claim 1. |
Background of the Invention
The clinical use of platinum complexes in cancer chemotherapy is now well established. The clinical utility of Cisplatin (cis-[PtCl2 (NH3) 2 ]) may be classified principally as curable (testicular cancer) , sensitive (ovarian) and responsive (head and neck, small cell lung) and this spectrum of activity is matched by the "second-generation" analog Carboplatin ([Pt(NH 3 ) 2 (CBDCA) ] , CBDCA = 1,1'-cyclobutanedicarboxylate) . The principal advantage of the latter complex is considered to be the reduction in the severe nephrotoxicity of the parent complex, the spectrum of activity being very similar, although this may eventually change.
Current areas for further development of platinum complexes (and indeed metal complexes in general) have been described as disease-oriented and drug-oriented. In the former, combination with other drugs or radiation is necessary to expand the clinical role. In drug-oriented terms increase in allowable dosage by limitation of * toxic side effects or changes in route of administration can be achieved. Besides bettering the clinical spectrum of cisplatin itself, some of these desired improvements could be incorporated into analogs and the selection of potentially useful drugs involves the search for complexes which satisfy one, or all, of three basic criteria:
1. Development of new selectivity, including a broader spectrum of activity than cisplatin, and especially activity in cisplatin-resistant lines
2. Modification of the therapeutic index, either through greater clinical effectiveness or reduced toxicity, in the latter case with activity at least equal to cisplatin.
3. Modification of phar acokinetic properties such as solubility which would allow other routes of administration. The structure-activity relationships developed for platinum complexes has led to the development of a large number of complexes with antitumor activity. The basic adaptation of the parent molecule involved use of other amines besides NH 3 and modification of the leaving group by substitution of the chloride
with groups such as carboxylate, dicarboxylate or sulfate.
A number of " amines give complexes whic are non-cross- resistant with cisplatin. The principal complexes studied by the prior art are those of 1,2-diaminocyclohexane (dach) and 1,1'- bis(aminomethyl) cyclohexane (damch) . Despite considerable interest in a full clinical trial of a dach or damch complex, no one compound with suitable properties of aqueous solubility, stability * and ease of formulation and synthesis has as yet been found, and early results on Phase 1 trials of such complexes have been disappointing. A clinical trial of a compound non-cross- resistant with cisplatin is a high priority of the art.
A limiting factor in development of dach and damch platinum complexes has been both aqueous solubility and chemical stability. Thus, whereas complexes of NH 3 containing dicarboxylate ligands are stable for days in aqueous solution, the corresponding complexes of dach hydrolyse more readily.
The potential for use of sulfur-bound dimethylsulfoxide as leaving group in complexes of type c_is_-[Pt(am) 2 (DMSO) 2 ] 2+ nas been recently, outlined; see N. Farrell "Platinum, Gold and Other Metal Chemotherapeutic Agents" ACS Symposium 209 f 279 (1983) and N.. Farrell: J. Chem. Soc. fChe . Co m.) 1014 (1980). The rationale for these complexes is that despite the high trans influence of DMSO, which would be expected to labilize the- group trans to it, the mutual labilization of the two DMSO ligands results in initial loss of DMSO to give aquo species, maintaining the cis-Pt(am) 2 moiety intact. Kinetic studies confirmed these observations; see S. Lanza, D. Minnitti, R. Romeo, and M.L. Tobe: Inorcr. Chem. 22 r 2006 (1983) . Further hydrolysis would give the active diaquo species:
[Pt (am) 2 (DMSO) 2 ] 2+ —*. [Pt (am) 2. (DMS0) (H 2 0) ] 2+ → [Pt(am) 2 (H 2 0) 2 ] 2+
The series of bis(DMSO) complexes were not, however, active in vivo, due perhaps to the 2+ charge and lack of penetration into the cell. A further problem may be the rate at which the second sulfoxide ligand reacts, either to give the active diaquo species
or in a direct reaction with DNA, the purported intracellular target of Pt complexes; see A.L. Pinto and S.J. Lippard: Bioche . Biophvs. Acta 780, ' 167 (1985) . The series [Pt(am) 2 (DMSO) Cl] has been studied for their kinetic parameters and it is stated that this series is not antitumor active; (see A.R. Khokhar and M.L. Tobe: J. Clin. Hematol. Oncol. 7(1) , 114 (1977) .
Summary of the Invention The present invention provides platinum complexes which exhibit good water-solubility and favorable antitumor activity, both in vitro and in vivo. Those complexes have the following structures:
or
wherein is a bidentate amine, Z'NH 2 is a monodentate amine, R' and R" are different organic groups and X~ is a pharmaceutically acceptable anion. Since S0 4 is divalent, there is no anion X~ in those complexes wherein the Cl attached to the central platinum atom is replaced by sulfate.
For convenience, Z(NH 2 ) 2 and 2 Z'NH- will be designated as (amine) 2 or am, in one-line structural formulas.
In general the present invention provides a general method for the solubilization of Pt(amine)- moieties which have been shown to have anti-tumor activity. In all instances, the method of the present invention, involving the use of unsymmetrical sulfoxides, produces more water-soluble species than the parent [Pt(am) 2 C1-] compounds. Thus any platinum complexes utilizing bidentate amines or monodentate amines developed in the future can be solubilized by the unsymmetrical sulfoxide method of the present invention.
Detailed Description of the Invention
As indicated above, the sulfoxide moieties which are present in the platinum complexes of the present invention are unsymmetrical sulfoxide moieties. In these unsymmetrical sulfoxide moieties, one or both of R' and R" may be aliphatic, such as alkyl or the like, or one or both of R' and R" may be aromatic, such as aryl, alkaryl, aralkyl, or the like. Preferably, however, R' is an aliphatic moiety and R" is an aromatic moiety (that is, R" is aryl or is a group having an aryl substituent thereon) . The aryl groups are preferably phenyl, and the alkyl groups are preferably lower alkyl.
More specifically, R' and R" are independently selected from the group consisting of C,-C- alkyl which is unsubstituted or substituted by phenyl, carboxy, c η ~ c 4 alkyl ester or C 2 ~Cg alkenyl; C 3 -C 7 cycloalkyl which is unsubstituted or substituted by phenyl, carboxy, c - ~ c _ \ alkyl ester or C 2 -C 8 alkenyl; or phenyl; wherein each phenyl is unsubstituted or substituted by at least one substituent selected from the group consisting of C 1 _C 4 a lkγl/ c ι -c 4 alkoxy (especially methoxy) , halogen, hydroxy, C_.-C 4 alkenyl, carboxy, C,-C 4 alkyl ester, amino, - - ~ -- Λ alkyl amino and di(C,-C 4 alkyl) amino. It is essential that R' and R" be different so that the S atom in the sulfoxide, when complexed with the Pt(amine) 2 ~containing compound, is chiral.
Complexes of the general formula [Pt(am) 2 (R'R"S0) Cl] are cationic (the sulfoxide group is neutral) and an anion X~ is
required to balance the charge on the complex. Any pharmaceutically acceptable anion is suitable for this purpose. Particularly suitable are Cl, * Br, NO-, weak nucleophiles such as HS0 4 , H 2 P0 4 , BF 4 , PFg, carboxylates such as formate, acetate, benzoate, and the like. Most preferred is NO-. As indicated above, complexes of the general formula [P (am) - (R'R"SO) (S0 4 ) ] are neutral and are not associated with an external anion.
Abbreviations are used in this specification for the sulfoxides R'R"SO as listed below:
Dimethyl Sulfoxide DMSO
Methyl Benzyl Sulfoxide MBSO
Dibenzyl Sulfoxide DBSO
Methyl Phenyl Sulfoxide MPSO
Diphenyl Sulfoxide DPSO
Methyl Tolyl Sulfoxide MTSO
Bidentate amines which can be utilized in the platinum complexes of the present invention include 1,2-diaminocyclohexane (dach) , l-amino-2-aminomethylcyclohexane (amch) , 1,1'- bis(aminomethyl) cyclohexane (damch) , l-amino-2-aminomethyl-3,3,5- trimethylcyclohexane, 2-aminopyridine, 2-aminomethylpyridine, 2-aminopiperidine, 2-methylaminopiperidine, 1,2-diaminobenzene (wherein the benzene ring is unsubstituted or substituted by C 1~ C 6 a lky ' c ι~ C 4 alkoxy, halogen, hydroxy, C 2 ~C 4 alkenyl, carboxy, C--C. alkyl ester, amino, C--C 4 alkylamino,
and di(C--C 4 alkyl)amino, ethylene diamine, 1,3-propane diamine, 2, 2-diethyl-l, 3-propanediamine and 1,2-diaminocycloheptane. Thus the bidentate amine moieties will preferably be of the general formula:
Z-[(CH 2 ) n -NH 2 ] 2 wherein Z is a divalent moiety selected from the group comprising (a) cycloalkyl of 3 to 8 carbon atoms, (b) alkyl of 3 to 10 carbon atoms, (c) pyridine, (d) piperidine, and (e) phenyl; said moieties being further unsubstituted or substituted by at least one further substituent selected from the group comprising c - ~ c alkyl, C 2 ~ β alkenyl, phenyl and substituted phenyl, wherein the substituents on the phenyl ring are C,-C 4 alkyl, C,-C 4 alkoxy, halogen, hydroxy, C 2 -C. alkenyl, carboxy, amino, C,-C 4 alkyl amino, and di(C,-C 4 alkyl)amino, and n is 0 or an integer of 1 to 6.
Monodentate amines which can be utilized in the platinum complexes of the present invention include cyclopentylamine, cyclohexylamine, n-butylamine, iso-propylamine, and the like.
Thus the monodentate amine moieties will preferably be of the general formula
Z '-NH 2 wherein Z ' is a moiety selected from the group comprising (a) cycloalkyl of 3 to 8 carbon atoms (b) alkyl of 3 to 10 carbon atoms, said cycloalkyl and alkyl moieties being unsubstituted or
substituted by at least one substituent selected from the group comprising C^Cg alkyl, C -C 6 alkenyl, phenyl and substituted phenyl, wherein the substituents on the phenyl ring are C- ^ -C^ alkyl, alkoxy, halogen, hydroxy, C 2 -C 4 alkenyl, carboxy, amino, C 1 -C 4 alkyl amino, and di(C j _-C 4 alkyl)amino.
There are two general synthetic schemes for preparing the complexes of the present invention. In one, displacement of sulfoxide from known [PtCl 2 (R'R"SO) 2 ] , prepared by standard methods, see J.H. Price, A.N. Williamson, R.F. Schramm, and B.B. Wayland: Inorcr. Chem. 11, 1280 (1972) , by a chelating diamine results in the desired cation, as described for DMSO complexes; see R.Romeo, D. Minnitti, S. Lanza, and M.L. Tobe: Inorq. Chem. Acta 22, 87 (1977) :
1) K 2 PtCl 4 + R'R"SO ■ [PtCl 2 (R R"SO) 2 ] + 2KC1
2) [PtCl 2 (R / R"SO) 2 ] + 2am -—* [PtCl(R'R"SO) (am) 2 ]C1 + R'R"SO
3) CPtCl(R'R"Sb) (am) 2 ]Cl + AgN0 3 ■ [Pt(am) 2 (R'R"SO)C1]N0 3 +
AgCl
In the second scheme, displacement of chloride from the known [PtCl 2 (am)23 gives the desired complex:
4) K 2 -?tCl 4 + 2 am — → CPtCl 2 (am) 2 ] rPt C l, ( am )2 l + E.'R"RSO + Λ [Pt(am) l- «.
.-, gN0 3 > [Pt(am) 2 (R R S O)C l ]
5) L " ^ • ++ AAgσCCll
The sulfate complexes are prepared from the known amine- sul ate complexes (See for instance H.A. Menema et al.: Inorcr. Chem. Acta 114,127 (1986).
6) [Pt(am) 2 S0 4 l + R'R"S0 --→- [Pt(am) 2 ( ^'^O)S0 4 ]
Reaction 1 is normally conducted at a temperature of 24 to 35°C, in water. Reaction 2 is generally conducted at a temperature of 24 to 35°C, in methanol. Reaction 3 is generally conducted at a temperature of 24 to 35°C, in methanol. Reaction
4 is generally conducted at a temperature of 24 to 35°C, in v/ater. Reaction 5 is generally conducted at a temperature of 24 to 35°C, in methanol. Reaction 6 is generally conducted at a temperature of 24 to 35°C, in methanol.
In the case of 1, 2-diaminocyclohexane (dach) the differential activity of the optical and geometric isomers has been recognized (see M. Noji, K. Oktamoto, Y. Kidani and T. Tashiro: J. Med. Chem. 24, 508 (1981). The present inventors have used both a racemic mixture (denoted dach) and the optically pure isomers (denoted R,R-dach and S,S-dach), and noted differences in activity but noted further that sulfoxides such as. methylphenyl and methylbenzyl are also optically active. Their complexes with optically active amines therefore lead to diastereomers, as evidenced by two peaks for the -CH 3 protons of MPSO in the 1 HNMR spectrum of [Pt(dach) (MPSO)C1]N0 3 . The 1 HNMR spectrum of the -CH 3 protons of [Pt(R,R-dach) (MPSO)Cl]N0 3 also show splitting, indicating a pair of diastereomers. The chirality of the sulfoxide is a dictating factor in the activity. This is a novel feature of this invention, as the unsymmetrical sulfoxides represent the first examples of chiral ligands as leaving groups in platinum complexes which exhibit antitumor activity.
The compounds of the present invention are water-soluble, stable complexes which exhibit antitumor activity with some of the compounds, such as [Pt(damch) (MPSO) C1]N0 3 , showing particularly high activity. The present results indicate that variation of the sulfoxide moiety results in potentiation of antitumor activity.
These platinum complexes of the present invention may be administered to patients, including humans or animals, having tumors susceptible to platinum therapy, especially cisplatin and carboplatin therapy. Furthermore, since the compounds of the present invention are non-crossresistant with cisplatin, the tumors which can be treated include tumors which are resistant to cisplatin (and carboplatin) therapy. The compounds may be administered in the form of sterile aqueous solutions, which are
preferably administered intravaneously or interarterially, although other forms of administration may be indicated in given cases.
Solutions for" intravaneous injections will normally be sterile physiological solutions. Suitable dosage forms can also include oily or aqueous injectable preparations, for intramuscular or intraperitoneal injection, syrups or the like liquid preparations, and solid dosage forms such as capsules, tablets and the like.
The effective amount of the complex of the present invention which should be administered to a patient can be determined by conventional methods which will be apparent to the skilled clinician. Normally, the activity of the platinum complex of the present invention will be evaluated in the screen along with the known complex such as cis-platin or carboplatin. The relative potency and the therapeutic index, i.e., the ratio of therapeutic effectiveness to toxicity, compared to that of the known analog will normally determine the relative dosage compared to the conventional doses of the analog for the type of malignancy being treated. Normally, however, from 1 to 500 g/kg of the platinum complex will be administered to the patient in a given dose, with the dosage regime varying depending upon various factors which are well known to the skilled clinician.
At times it may be advantageous to administer the platinum complex of the present invention in combination with one or more agents that potentiate the tumor activity or mitigate any undesired side-effects of the platinum complex. For instance, the platinum complexes of the present invention may be administered together with reduced glutathione, as taught by U.S. patent application serial number 105,169, filed 7 October 1987, the disclosure of which is hereby incorporated by reference.
It is recognized that certain of the platinum complexes having the formula shown above may have sufficiently high toxicity, or sufficiently low therapeutic indices, so as to be unsuitable for antitumor therapy in patients. However, these
11
r_,i.ra__5ters can be readily determined by conventional screenin -t.-e. 5 ts, such as, for instance, with L-1210 murine leukemia cell i.rplanted in mice, and such complexes should naturally b a oided.
The tumors in patients which are to be treated with th platinum complexes of the present invention are those tumor w' ich are known to be susceptible to platinum therapy, such a tumors which are known to be treatable with cis-platin and carbo platin, as is well knov/n to those in the art. It is known tha cisplatin and carboplatin have been clinically used at th present to treat testicular, ovarian, bladder and head and nec c ncers. It is also known that these agents have shown at leas limited activity against non-small-cell lung cancer, osteogeni sarcoma, Hodgkins lymphoma, melanoma and breast cancer. Cisplati has been found to be active against ' squamous cell carcinoma o the head and neck, squamous cell carcinoma of the cervix, oa cell or small cell anaplastic lung cancer, non-small-cell lun cancer (in combination with VP-16 or vinca alkaloids) , adenocarcinoma of the stomach, carcinoma of the esophagus, adenocarcinoma of the prostate, osteogenic sarcoma, soft tissu and bone sarcomas, non-Hodgkins lymphoma, adenocarcinoma of th breast, brain tumors, thyroid cancer and endometrial cancer . All of the proceding tumors should respond to treatment with the platinum complexes of the present invention. The complexes of the present invention should also be active against certain tumors which are resistant to cisplatin, as is shown by animal studies conducted on the present complexes.
The in vitro and in vivo" evaluation procedures utilized have been outlined, (see M.P. Hacker et al.: Cancer Res. 45, 4748 (1985) . In tissue culture, L-1210 murine leukemia cells are grown using McCoy's 5A modified medium supplemented with glutamine, antibiotics, and 10% horse serum. The population doubling time is of the order of 12h. Cells are seeded at a concentration of 1-2 x 10 cells/ml and complex concentrations added and tested in triplicate. Percent inhibition is calculated in standard fashion
using a computer program based on the Litchfield and Wilcoxon procedure. An arbitrary concentration of 15 uM is considered a reasonable cut off point.
The principal in vivo screen is also L-1210 murine leukemia. The cells are grown as an ascites by weekly intraperitoneal inoculation of 10 6 cells to BDFτ_ mice (from NIH) . Treatment is routinely by i.p. administration 24h after inoculation. Primary treatment schedules are day 1, days 1, 5, 9 or days 1 through 9. Usually the second scheme is employed but final doses may be adapted depending on toxicity response. The efficacy is determined as %T/C by calculation of MST (Mean S.urvival Time) of treated versus control x 100. Survivors to 30d are not included.
TABLE I
IN VITRO ACTIVTY OF TP fa ) 2 (R'- -R"-SO CΠNO 3 in L1210 LEUK1SMIA
AMINE R'R"SO ID 50 (ug/ml) dach. • DMSO 4.3
(R,R)dach MBSO 0.52
(R,R)dach DBSO 3.5 dach MPSO 0.9 dach DTSO 2.7 damch DMSO 3.3 damch MBSO 2.9 damch MPSO 0.61 damch DPSO 0.39 cha* MBSO 3.5 cha* DBSO 2.7 cpa* MPSO 2.5
L for [Pt(am) 2( R ' r R"SO) (S0 4 ) ] : dach MBSO 5.0 dach DBSO 3.1
*cha — cyclohexylamine cpa = cyclopentylamine
It will be noted that all of the platinum complexes which produced low I 5 0 values in Table I wore unsymmetrical complexes except for the ninth complex, wherein the sulfoxide moioty was DPSO. However, that complex was toxic, 3 reflected by Table II. While a comparison of the last two compounds of Table I indicate that the DBSO moiety produced better (or lower) values of ID 50 , Table III indicates that in vivo the MBSO moiety produced significantly higher antitumor results than the DBSO moiety.
_ι___________j_l r TN VIVO...AHT.TTU OR ACTIVITY fPt(am) 2 < K I -R.-".SO C11 HO 3
7.L3LQ
A am R Λ SO Doisas • -T/C
(mg/kg)
R,R-daσh DMSO 3 x 100 131
R,R-d_ι«h MPSO 3 X 50 211 (1/6)
3 x 25 176
K,R-daσh MBSO 3 y. 100 292 (3/6)
3. X 50 165
Rf -d ch DBSO 3 X..100 142 dainαh. DMSO 3 x 100 152 dawoh 1-ΪPSO dαtoσh DPSO 1 X 100 OXIC
ξ Complexes dlcGolvαtl in o.lM Salino solution. SOday survivor parentheses.
*all sulfoxides as raeemic mixtures
TABLE III
IN VIVO ΛHTITUMOR ACTIVITY
1,1210 am R'R"SO Doεe* T/C (rag/kg)
dach MBSO 3 x 100 222 ( 1/ 6 ) dach DBSO 3 X 50 120
TABLE IV
Biological c fata for Ooticallv Pure Coπrolexes. I_L210 DATA FOR [Pfc (grains) (R^SOj Clj ^ MENE Rj 2 S0 ' * DOSE %T/C# (mgΛg) damch (-)i-nso 50 X 3 205 (1/6)
2 .5* 100 X 3 146 (2/6) daincii (+}I_ESO 50 X 3 229 (2/6)
50 X 1 176 (1/6)
100 X 1 208 (3/5) 321* (2/5)
R,R-daciι (-)MISO 50 X 3 244 (2/6) 100 x 3 281 (2/6)
R,R-dac (+)mso 50 X 3 129
' 100 X 1 103
S,S-dax_h (-)KESO 50 X 3 190 (1/6) 251* 100 X 3 290 (3/6) 315* (2/6)
S f S-dach (+)MISO 50 X 3 139
MTSO = ethyltolylsulfoxide, dach - 1, 2-diaminocyclohexane. damch - 1, 1-diaminomethylcyclohexane.
_ injections on a l,5,9d schedule. All complexes dissolved in 0.9% saline. 30d. Survivors in parentheses.
# T/C values calcd. at 30d, exclusive of survivors.
* T/C values calcd. at 60d, exclusive of survivors.
Table IV illustrates the antitumoral activity of some optically active complexes (single enantiomers and single diasteroisomers) of the invention. For each of the compounds reported in table IV, the sign (+) or (-) refers to the optical rotation of the optically active chiral sulfoxide produced when the unsymmetrical sulfoxide is complexed with the platinum compound.
It will be noted from the results reported in Table IV that, independent of the chirality of the amine ligand (in compounds 1, 2 damch is an achiral ligand; in compounds 3, 4, 5 and 6 R,R- dach and S,S-dach are chiral ligands) , significantly better results are observed with one of the two possible enantiomers of the chiral sulfoxide. Based on these results, it appears that using unsymmetrical sulfoxides as leaving groups in platinum complexes, the absolute configuration S and/or R of the chiral sulfoxide ligand affects the overall antitumor activity of the complexes.
In general, the chiral sulfoxides of the present invention do not exhibit cross-resistance to cisplatin, which is a significant advantage. The chiral sulfoxides have a broad therapeutic range and high activity, and no disadvantages have been noted, compared to other platinum-containing chemotherapeutic agents.
Examples of the Invention COMPARATIVE EXAMPLE A
PREPARATION OF [Pt(dach) (DMSO) C1]N0 3 FROM [PtCl 2 (DMSO) 2 ] The neutral Platinum Dimethylsulfoxide complex, [Pt(DMSO) 2 C1 2 ] , was prepared according to Price, supra. The complex (2.35 g. , 0.0056 mol) was added to a solution of 1,2- Diaminocyclohexane (Dach) (0.69 ml. 0.0056 mol) in HPLC grade methanol. The slurry was stirred for 10 minutes, during which time the light yellow-Platinum complex dissolved. The mixture was stirred for an additional hour to ensure completion of the
reaction. The methanol was rotoevaporated giving [Pt(Dach) (DMSO)C1]C1, a white solid, which was filtered and washed with acetone.
The Chloride salt was redissolved in MeOH. To this solution was added an equimolar weight of AgNθ 3 dissolved in hot MeOH. The mixture was stirred in the dark overnight. After filtering insoluble AgCl the methanol was rotoevaporated giving the nitrate salt [Pt(dach) (DMSO)C1]N0 3 . The product was recrystallized from MeOH/Ether by dissolving in MeOH, reducing the volume to 2 ml., diluting with ether and freezing overnight. The white crystals which formed were washed with ether and dried in a pistol over p 2°5-
EXAMPLE 1
PREPARATION OF [Pt(dach) (MPSO)Cl]N0 3 FROM [Pt(Dach)Cl 2 ] The [Pt(l,2-diaminocyclohexane)Cl 2 ] was prepared by standard procedures.
The Platinum (dach)-methylphenyl sulfoxide (MPSO) complexes were prepared by adding an equimolar amount of MPSO (0.0151 g., 0.0065 mol) to a slurry of Pt(dach)Cl 2 (2.4843 g. , 0.0065 mol) in HPLC grade methanol. To this was added 1 equivalent of AgN0 3 dissolved in hot methanol. The reaction mixture was stirred overnight in. the dark. The insoluble AgCl precipitate was filtered and the filtrate rotoevaporated until the volume of methanol was approximately 2 ml. The concentrated solution was diluted with ether until a white solid just began forming. It was placed in the freezer overnight and the resultant white crystals were filtered and washed with ether. A second recrystallization was done in the same manner. The complex was dried in vacuum over
?2°5-
EDSKEHT i ANALYSES f Calculated. fFoundU
[Pt am)-(R , R"SO) C1]K0 3
(am) R'R"SQ _____ . %N
(dach) R'-R ,, ' H 3 19.82 (20.14) 4.13 (4.25) 8.67 ( 8.58)
R«=CH 3 , R"=H. 28.55 (28.52) 4.03 (3.90) 7.69 ( 7.57)
R« =R"=H_-αi 3 37.71 (35.24) 4.40 (4.67) 6.60 ( 6.46)
(tolyl)
R'-=αi 3/ R' I -Cil2H 29.71 (29.97) 4.09 (4.20) 7. OB (7.49) R'- R"«<2_2_-- 38.95 (37.71) 4.15 (4.40) 6.68 (6.60)
(damch) ΛR'_-R " --CI. 3 23.41 (22.34) 4.68 (4.20) 8.19 ( 7.50)
R»=CH 3 , R"=Hl 31.32 (31.21) 4.52 (4.34) 7.31 ( 7.30)
R'=R π -=I_l 37.69 (37.54) 4.40 (4.20) 6.60 ( 6.72)
R'=CH 3 , R"= H2-.l 32.22 (32.62) 4.27(4.75) 7.81 (7.14)
cpa f H 3/ R'HE-i 35.27(33.86) 5.09(4.98) 6.51(6.97)
Cha R , '«-C__3- " " <ll2-Si 36.87(37.23) 5.79(5.59) 6.52(6.28) and for [Pt(dac ) (R»R"SO)S0 3 :
30.05(29.91) 4.27(4.29) 4.96(5.00) 40.96(41.57) 5.64(5.35) 5.15(4.41)
MAJOR IR WAYS [Pt (cm) (R , R M S0)Cl]lK) 3
(am) R'R"SO v(SO) cm-^ vfPt-Cl) αn-^ v(NH 2 ϊ αn-^
(dach)
(damch) *R'- "- 2Ϊ3 1103 334 2910 3250
R'=CH 3 , R^Ri 1144 334 3010 3250 R«"=R"«-_-l 1100 320 3010 3250 R» __. 3/ R"«=€H 2 Fh 1120 335 3010 3280 cha '-Ofc, R' ,* =CH 2 Ph 1128 340 3020 3280 R' « "-<H2lh 1115 342 3020 3250
and for [Pfc(R-R-dach) (RR S0)S0 4 ] '- HT, R"-α_2--l V(SO) 1175 (sharp), 1120(br)
(MBSO V,
R'- R» « H2Hα (DBSO) V(S0) = 1140 (V. br.) sh - shoulder, br * - broad, v. br. -» very broad.
NMR PEAKS [Pt (am R , R ,l SO)Cl]H0 3
(am) 2 R'R"SO αi 3 -RSO H--RSO Di£ le Ugg
(Dad) R'=R"=CH 3 3.49 (d)6II 2.58 (m)2H <=CH3, R"=___ 3.52 (d)3H 7.75 (d)3H 2.05 (m)2H 8.15 (d)2H 1.60 (m)2H 1.10-1.40 (m)
(Damch) *R I =R".=CH 3 3.49 " (s)6H 1.30-1.50 (m) R'=CH 3 , R"=I-_ 3.73 (ε)3H 7.75 (d)3H 2.50-2.65 (m) 8.15 (d)2H s * - ***• singlet d = ** doublet m = multiplet EXAMPLE 2
Preparation of [Pt(am) 2 (HTSθ)cl]N0 3 ϊhis cacαmple relates to the use of ccπplexes containing cptie^lly pure Eulfcodda Uganda (+)- and (-) - atliyl (p-tolyl) sulf oxida
(K (B-_H3C^. 4 )SO / KI O . Ihe ligand was prepared by the general pixxDedura of Drab vicz et al. J. 0r_τ. Qem. 47, 3325 (1982) . The free ligands were ciharac_teriεed by their optical rotation as given in the above quoted paper:
(+ ' ) I_ES0 [*] D - 144.3° (lit. value 150.1, optical purity 86%)
(-) KESO [_;] D = -145° (optical purity 86 %)
__ha cάπplexes wars prepared in the standard manner by addition of one equivalent of the ligand to a suspension of the appropriate
[Pt (diamine) Cl 2 ] in MeOH in the presence of one equivalent of
A ND3. To cfctain optically pure enanticmars of the 1, 2- iε_-αI__nocy- clohexane (dach) ligand the p ra ^ forms (R,R and S,S) were vised.
These were obtained commercially and used without furthe purification. Work up was as per previous examples. The complexe were characterised by IR, NMR, CD and elemental analyses. Th
sign of, the optically pure sulfoxide changes upon co plexation to Platinum. The signs quoted and used hereinbelow refer to the sign of the complexed ligand, incorporated into the specific complex.
Elemsntal Λnαlyee3 for [Pt <a_4_".} (Rι 2 S )Cl] 0 3
(1) damch (-)l_ISO 32.34(32.57) 4.59(4.52) 6.97(7.31)
(2) dαmch (+)MTSO 31.60(32.57) 4.47(4.52) 7.08(7.31)
(3) R,R-dach (-)KISO 29.67(20.55) 4.06(4.03) 7.20(7.69)
(4) R,R-dach (+)MISO 30.12(28.55) 4.04(4.03) 7.22(7.69)
(5) S,S-dad (-)MISO 28.84(20.55) 3.94(4.03) 7.33(7.69)
(6) S,S-dach (+)MCSO 30.03(28.55) 3.97(4.03) 7.29(7.69)
Spectroscopic Data
The optically pure complexes should have only one CII 3 resonance for ' the CH 3 group of the MTSO ligand, unlike diastereomers previously studied. This is confirmed in all cases.
Major NMR data for [Pt(am) 2 (R R s o)Cl]N0 3
(ea_) 2 B,'R"SO Chemical Shift of S-CH 3
(Pt-H coupling for ££-S-C-B in Hz)
damch (-)MESO 3.67 (17.93) damch . (+)MTSO 3.65
R,R-dach (-)MISO 3.69 (15.80)
R,R-dach (+)MTSO 3.67 (22.2)
S,S-dach (-)MISO 3.68 (14.5)
S,S-dach (+)MISO 3.67 (17.1)
All complexes run in D 2 0. The rest of the spectra show peaks typical of the amine and p-tolyl (CH 3 and -C5II4-) residues. The Circular Dichroism Spectra of one set of complexes (those of the damch ligand) are shown in Fig.l. These confirm the optical purity of the complexes and also the sign inversion.