EP0409894A1 - Sulfoxydes d'amine de platine en tant qu'agents anti-tumoraux - Google Patents

Sulfoxydes d'amine de platine en tant qu'agents anti-tumoraux

Info

Publication number
EP0409894A1
EP0409894A1 EP89904974A EP89904974A EP0409894A1 EP 0409894 A1 EP0409894 A1 EP 0409894A1 EP 89904974 A EP89904974 A EP 89904974A EP 89904974 A EP89904974 A EP 89904974A EP 0409894 A1 EP0409894 A1 EP 0409894A1
Authority
EP
European Patent Office
Prior art keywords
platinum complex
complex according
alkyl
platinum
dach
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP89904974A
Other languages
German (de)
English (en)
Other versions
EP0409894A4 (en
Inventor
Nicholas P. Farrell
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Vermont
Original Assignee
University of Vermont
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Vermont filed Critical University of Vermont
Publication of EP0409894A1 publication Critical patent/EP0409894A1/fr
Publication of EP0409894A4 publication Critical patent/EP0409894A4/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage

Definitions

  • Cisplatin cis-[PtCl 2 (NH3) 2 ]
  • Curable testicular cancer
  • sensitive ovarian
  • responsive head and neck, small cell lung
  • CBDCA 1,1'-cyclobutanedicarboxylate
  • a number of amines give complexes which are non-crossresistant with cisplatin.
  • the principal complexes studied by the prior art are those of 1,2-diaminocyclohexane (dach) and 1,1'-bis(aminomethyl) cyclohexane (damch).
  • dach 1,2-diaminocyclohexane
  • damch 1,1'-bis(aminomethyl) cyclohexane
  • 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:
  • Z(NH 2 ) 2 and 2 Z'NH 2 will be designated as (amine) 2 or am 2 in one-line structural formulas.
  • the present invention provides a general method for the solubilization of Pt(amine) 2 moieties which have been shown to have anti-tumor activity.
  • the method of the present invention involving the use of unsymmetrical sulfoxides, produces more water-soluble species than the parent [Pt(am) 2 Cl 2 ] compounds.
  • 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.
  • the sulfoxide moieties which are present in the platinum complexes of the present invention are 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.
  • R' is an aliphatic moiety
  • 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.
  • R' and R" are independently selected from the group consisting of C 1 -C 6 alkyl which is unsubstituted or substituted by phenyl, carboxy, C 1 -C 4 alkyl ester or C 2 -C 6 alkenyl; C 3 -C 7 cycloalkyl which is unsubstituted or substituted by phenyl, carboxy, C 1 -C 4 alkyl ester or C 2 -C 6 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 alkyl, C 1 -C 4 alkoxy (especially methoxy), halogen, hydroxy, C 2 -C 4 alkenyl, carboxy, C 1 -C 4 alkyl ester, amino, C 1 -C 4 alkyl amino and di(C 1 -C 4 alkyl) amino. It is essential that R' and R" be
  • Complexes of the general formula [Pt(am) 2 (R'R"SO)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 3 , weak nucleophiles such as HSO 4 , H 2 PO 4 , BF 4 , PF 6 , carboxylates such as formate, acetate, benzoate, and the like. Most preferred is NO-.
  • complexes of the general formula [Pt(am) 2 (R'R"SO)(SO 4 )] are neutral and are not associated with an external anion.
  • Bidentate amines which can be utilized in the platinum complexes of the present invention include 1,2-diaminocyclohexane (dach), 1-amino-2-aminomethylcyclohexane (amch), 1,1'-bis(aminomethyl) cyclohexane (damch), 1-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 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, C 2 -C 4 alkenyl, carboxy, C 1 -C 4 alkyl ester, amino, C 1 -C 4 alkylamino, and di(C 1 -C 4 alkyl) amino, ethylene diamine, 1,3-prop
  • Monodentate amines which can be utilized in the platinum complexes of the present invention include cyclopentylamine, cyclohexylamine, n-butylamine, iso-propylamine, and the like.
  • 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 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl and substituted phenyl, wherein the substituents on the phenyl ring are C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, C 2 -C 4 alkenyl, carboxy, amino, C 1 -C 4 alkyl amino, and di(C 1 -C 4 alkyl) amino.
  • the sulfate complexes are prepared from the known aminesulfate complexes (See for instance H.A. Menema et al.: Inorcr. Chem. Acta 114,127 (1986).
  • 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 water.
  • 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.
  • 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)Cl]NO 3 , showing particularly high activity.
  • the present results indicate that variation of the sulfoxide moiety results in potentiation of antitumor activity.
  • 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.
  • 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 mg/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.
  • the platinum complex 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.
  • 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.
  • these parameters can be readily determined by conventional screenin tests, such as, for instance, with L-1210 murine leukemia cell implanted in mice, and such complexes should naturally b avoided.
  • the tumors in patients which are to be treated with th platinum complexes of the present invention are those tumor which 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 known 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 cencers. 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 proceeding 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 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 BDF 1 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 IV illustrates the antitumoral activity of some optically active complexes (single enantiomers and single diasteroisomers) of the invention.
  • 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.
  • 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.
  • the Chloride salt was redissolved in MeOH. To this solution was added an equimolar weight of AgNO 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)Cl]NO 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
  • 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 AgNO 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
  • R' CH 3
  • R" Ph 1146 342 3020 - 3240
  • R ' CH 3
  • R CH 2 Ph 1132 355 3020 - 3280
  • R' CH 3
  • R" Ph 1144 334 3010 - 3250
  • R' CH 3
  • R" CH 2 Ph 1120 335 3010 - 3280 cha
  • R' CH 3
  • R'' CH 2 Ph 1128 340 3020 - 3280
  • This example relates to the use of complexes containing optically pure sulfoxide liganda (+)- and (-) -mathyl (p-tolyl) sulfoxide
  • optically pure complexes should have only one CH 3 resonance for the CH 3 group of the MTSO ligand, unlike diastereomers previously studied. This is confirmed in all cases.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Des complexes au platine ayant les formules [Pt(am)2ClR'R"SO]+X- et [Pt(am)2SO4R'R"SO], dans lesquelles (am)2 représente une amine bidentée, R' et R" sont des groupes organiques différents et X- représente un anion, présentent une acitivité anti-tumorale favorable in vivo contre des tumeurs susceptibles d'être traitées au platine.
EP19890904974 1988-04-13 1989-04-12 Platinum-amine-sulfoxides as anti-tumor agents Withdrawn EP0409894A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US18095688A 1988-04-13 1988-04-13
US180956 1994-01-13

Publications (2)

Publication Number Publication Date
EP0409894A1 true EP0409894A1 (fr) 1991-01-30
EP0409894A4 EP0409894A4 (en) 1992-12-02

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP19890904974 Withdrawn EP0409894A4 (en) 1988-04-13 1989-04-12 Platinum-amine-sulfoxides as anti-tumor agents

Country Status (7)

Country Link
EP (1) EP0409894A4 (fr)
KR (1) KR900700097A (fr)
AU (1) AU3447289A (fr)
ES (1) ES2013433A6 (fr)
GR (1) GR890100246A (fr)
WO (1) WO1989009598A1 (fr)
ZA (1) ZA892706B (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1238078B (it) * 1990-01-31 1993-07-05 Silvano Spinelli Cis-platino complessi con ammine e sulfinilcarbossilati chelanti
NL9001639A (nl) * 1990-07-19 1992-02-17 Amc Amsterdam Pt-houdende verbinding, werkwijze voor de bereiding ervan, alsmede toepassing van dergelijke verbindingen.
EP1394169B1 (fr) * 2002-08-29 2007-04-18 Jih-Ru Hwu Complexe organométallique
RU2721725C2 (ru) * 2015-12-22 2020-05-21 Ниппон Каяку Кабусики Каися Полимерный конъюгат координационного комплекса платины (ii) с производным сульфоксида

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS55144422A (en) * 1979-04-28 1980-11-11 Nippon Kayaku Co Ltd Purification of cis-dichlorodiammineplatinum(2)
US4808730A (en) * 1987-06-23 1989-02-28 American Cyanamid Company Synthesis of cisplatin analogs

Also Published As

Publication number Publication date
KR900700097A (ko) 1990-08-11
WO1989009598A1 (fr) 1989-10-19
EP0409894A4 (en) 1992-12-02
ES2013433A6 (es) 1990-05-01
ZA892706B (en) 1989-11-29
GR890100246A (el) 1990-01-31
AU3447289A (en) 1989-11-03

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