WO1985003078A1 - Platinum and crown ether complexes with antineoplastic activity and drug containing them - Google Patents

Platinum and crown ether complexes with antineoplastic activity and drug containing them Download PDF

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Publication number
WO1985003078A1
WO1985003078A1 PCT/DE1985/000001 DE8500001W WO8503078A1 WO 1985003078 A1 WO1985003078 A1 WO 1985003078A1 DE 8500001 W DE8500001 W DE 8500001W WO 8503078 A1 WO8503078 A1 WO 8503078A1
Authority
WO
WIPO (PCT)
Prior art keywords
crown ether
platinum
mono
complexes
crown
Prior art date
Application number
PCT/DE1985/000001
Other languages
German (de)
English (en)
French (fr)
Inventor
Johanna Heimberger
Heimo Jürgen KELLER
Klaus Bernhard Keppler
Original Assignee
Medac Gesellschaft Für Klinische Spezialpräparate
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 Medac Gesellschaft Für Klinische Spezialpräparate filed Critical Medac Gesellschaft Für Klinische Spezialpräparate
Publication of WO1985003078A1 publication Critical patent/WO1985003078A1/de
Priority to DK405385A priority Critical patent/DK405385A/da
Priority to FI853426A priority patent/FI853426A0/fi

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
    • 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

  • the invention relates to platinum crown ether complexes having an antineoplastic action and medicaments containing them.
  • a drug containing the complex compound cis-diamminodichloroplatin (II) has been commercialized as a cancer chemotherapeutic agent.
  • This compound known under the International Nonproprietary Name (INN) cisplatin has proven to be an extremely potent antitumor agent, particularly in the treatment of testicular tumors, but also e.g. of ovarian tumors and small cell bronchial carcinomas.
  • a disadvantage of cisplatin is its relatively high toxicity. Its nephrotoxicity, myelotoxicity and its permanent hearing damage are particularly serious.
  • C is a mono- or bicyclic crown ether
  • X is halogen or the anion of mono- and di-carboxylic acids, an at least equivalent tumor-inhibiting activity to cisplatin with lower toxicity.
  • their water solubility is significantly greater than that of cisplatin, which makes their therapeutic use much easier.
  • the pH of a solution suitable for thermal therapy is almost neutral in contrast to the acidic cisplatin solution.
  • the invention therefore relates to the new platinum crown ether complexes of the above formula I, in which C, A and X have the meanings given above and medicaments containing them, in particular those for the treatment of cancer diseases.
  • a preferred subject of the invention are platinum-crown ether complexes of the general formula I, in which C is a mono- or bicyclic crown ether, A ammonia or amine functions contained in the crown ether and X is chlorine and carboxylic acid anion.
  • the platinum-crown ether complex [18] crown (6) cis-diammine dichloropiatin (II) is particularly preferred.
  • C1-C4-alkyl is understood to mean a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, with straight-chain alkyl radicals being preferred.
  • Halogen is understood to mean fluorine, chlorine, bromine, iodine and carboxylic acid anion, with fluorine, chlorine, bromine and carboxylic acid anion being preferred. Chlorine and carboxylic acid anion are particularly preferred.
  • Crown ether is understood not only to mean the monocyclic polymers of ethylene glycol (-OCH 2 CH 2 ) n , their benzo-substituted derivatives and thia analogues, but also those in which the length of the alkylene bridges varies and / or those in which the ether oxygen atoms are partially or are completely replaced by nitrogen atoms and / or those which are heteroaromatic systems, such as pyridine, furan or thiophene rings and / or those which are substituted by functional groups, such as -COOR, -OR, -NR-, wherein R denotes aromatic or aliphatic radicals or H, comprise.
  • Such crown ethers are referred to in English as "coronands" and the corresponding complexes as "coronates”.
  • crown ether is also understood to mean bicyclic diammines in which the two nitrogen atoms are connected by polyethylene bridges. Crown ethers of this type of structure are referred to as “cryptands” and their complexes as “cryptates”.
  • An overview of crown ethers and their representation can be found, for example, in DA Laidler and JF Stoddart, "Synthesis of crown ethers and analogues" in Supplement E., The chemistry of ethers, crown ethers, hydroxyl groups and their sulfur analogues, Part 1, publisher Saul Patai, John Wiley & Sons 1980, Chichester, New York, Brisbane, Toronto, pages 1 to 57.
  • the following are suitable as crown ethers:
  • Crown ethers are preferably considered, the tendency towards complex formation with platinum (II) being particularly pronounced due to the arrangement of the heteroatoms responsible for the formation of the coordinative bonds.
  • platinum-crown ether complexes according to the invention include particularly suitable are those crown ethers whose "inner cavity” has such a diameter that the heteroatoms can be carried out without too great a steric hindrance
  • Preferred platinum crown ether complexes according to the invention are therefore those in which the crown ether component has an inner diameter of 1.7 to 7 ⁇ , preferably 2.2 to 4 ⁇ and particularly preferably of 2.6 to 3.2 ⁇ .
  • the compounds according to the invention are prepared by reacting the corresponding cisdiammine platinum (II) dihalide or plartin dihalide with the corresponding crown ether. It is advantageous to carry out the reaction in a solvent under reflux. In many cases, it is more favorable to precipitate the reaction product from the reaction mixture by carefully adding suitable inert solvents, such as, for example, n-hexane or petroleum ether, than to isolate it by concentrating the reaction mixture.
  • suitable inert solvents such as, for example, n-hexane or petroleum ether
  • the invention also relates to a process for the preparation of the platinum crown ether complexes of the general formula I.
  • C is a mono- or bicyclic crown ether
  • the medicaments according to the invention are administered primarily intravenously, but also intraperitoneally, subcutaneously, rectally or orally. External application is also possible. Administration by intravenous injection or intravenous infusion is preferred.
  • the medicaments are produced by methods known per se, the complex compounds being used as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the new pharmaceutical preparations contain pharmaceutical carriers in addition to the active ingredient, the active ingredient content of these mixtures is 0.1 to 99.5, preferably 0.5 to 95 percent by weight of the total mixture.
  • the pharmaceutical preparations according to the invention when in unit doses and for application e.g. are intended for humans, contain about 0.1 to 500 mg, advantageously 10 to 200 mg and in particular 50 to 150 mg of active ingredient.
  • a single dose contains the active ingredient (s) in amounts of about 0.1 to about 5, preferably 1 to 3 mg / kg body weight. Similar doses can be used in oral treatment.
  • the treatment with the medicaments according to the invention can be combined with the administration of other cytostatics with different activity spectra. It can also be expedient to carry out the treatment on the principle of cyclic cytostatic therapy. A recovery phase is inserted after each treatment. It makes use of the experience that healthy tissue in most organs regenerates faster than malignant tissue.
  • the pharmaceutical preparations generally consist of the complex compounds and non-toxic, pharmaceutically acceptable pharmaceutical carriers, which are used as admixtures or diluents in solid, semi-solid or liquid form or as enveloping agents, for example in the form of a capsule, a tablet cover, a sachet or another container the therapeutically active ingredient are used.
  • a carrier can e.g. serve as a mediator for the absorption of medicinal products by the body, as a formulation aid, as a sweetener, as a taste corrector, as a colorant or as a preservative.
  • Aqueous suspensions may contain suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl cellulose, Natriumalkinat, polyvinyl pyrrolidone, gum tragacanth or gum acacia, dispersing and wetting agents, for example polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitan, such as polyoxyethylene sorbitan, and lecithin; conservee agents, for example methyl or propyl hydroxybenzoates; Flavoring agents; Contain sweeteners such as sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl cellulose, Natriumalkinat, polyvinyl pyrrolidone, gum tragacanth or gum acacia
  • dispersing and wetting agents for example polyoxyethylene stearate, heptadecaethyleneoxycetan
  • Emulsions can e.g. Olive, peanut or paraffin oil in addition to emulsifiers, such as e.g. Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavoring agents.
  • emulsifiers such as e.g. Acacia, tragacanth, phosphatides, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and sweeteners and flavoring agents.
  • the dispersing or wetting agents and / or pharmacologically acceptable diluents e.g. Propylene or butylene glycol
  • solubilizers e.g. Tweene, Cremophore or Polyvinylpyrrolidon
  • the active compounds can also be formulated in microencapsulated form with one or more of the stated carriers or additives.
  • BDF 1 mice are transferred approximately 10 6 P 388 leukemia cells in 0.2 ml of physiological saline intraperitoneally (ip). Leukemia is kept in passage on DBA / 2 mice. The leukemia cells are taken from freshly killed animals immediately before the transplant. At the
  • mice are used per dose.
  • the number of control groups (untreated animals) is chosen in more extensive experiments so that it corresponds approximately to the square root of the total number of groups.
  • the substances are in the form of aqueous solutions, if necessary with the aid of solubilizers, for example Cremohor EL R , in each case on day 1 to day 9 after
  • the transplant is carried out analogously to the P 388 leukemia model.
  • the substances are administered intraperitoneally on day 1 after the transplantation.
  • mice Approximately 4-week-old female BDF 1 mice weighing 18 to 25 g are transferred intramuscularly (im) with 0.2 ml of a tumor suspension in physiological saline (1 g tumor in 10 ml physiological saline). The carcinoma is kept in passage on C 57 Bl 6 mice.
  • the platinum crown ether compound according to the invention shows a higher median survival time at the same molar doses. While no cures were achieved with the doges used with cisplatin, cures were observed with the compounds according to the invention.
  • 5-FU was used as a standard therapeutic as an additional control.
  • Example 2 Single dose on day 1; 12 control animals; 6 animals per test group

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/DE1985/000001 1984-01-09 1985-01-08 Platinum and crown ether complexes with antineoplastic activity and drug containing them WO1985003078A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DK405385A DK405385A (da) 1984-01-09 1985-09-05 Antineoplastisk virkende platin-kroneether-komplekser og laegemiddel,der indeholder disse
FI853426A FI853426A0 (fi) 1984-01-09 1985-09-06 Kancermotverkande platina-kroneterkomplex och laekemedel innehaollande dessa.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19843400435 DE3400435A1 (de) 1984-01-09 1984-01-09 Antineoplastisch wirkende platin-kronenether-komplexe und diese enthaltende arzneimittel
DEP3400435.1 1984-01-09

Publications (1)

Publication Number Publication Date
WO1985003078A1 true WO1985003078A1 (en) 1985-07-18

Family

ID=6224506

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE1985/000001 WO1985003078A1 (en) 1984-01-09 1985-01-08 Platinum and crown ether complexes with antineoplastic activity and drug containing them

Country Status (7)

Country Link
EP (1) EP0171401A1 (fi)
JP (1) JPS61501029A (fi)
DE (2) DE3400435A1 (fi)
DK (1) DK405385A (fi)
FI (1) FI853426A0 (fi)
NO (1) NO853448L (fi)
WO (1) WO1985003078A1 (fi)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ306396B6 (cs) * 2014-12-16 2017-01-04 Vuab Pharma A.S. Rozpustný platnatý komplex s pyridinkarboxamidinovým ligandem a způsob jeho přípravy

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0051946A1 (en) * 1980-11-07 1982-05-19 Imperial Chemical Industries Plc Metal complexes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0051946A1 (en) * 1980-11-07 1982-05-19 Imperial Chemical Industries Plc Metal complexes

Also Published As

Publication number Publication date
DE3400435A1 (de) 1985-07-18
DE3524841A1 (de) 1987-01-15
NO853448L (no) 1985-09-02
JPS61501029A (ja) 1986-05-22
EP0171401A1 (de) 1986-02-19
DK405385D0 (da) 1985-09-05
FI853426L (fi) 1985-09-06
FI853426A0 (fi) 1985-09-06
DK405385A (da) 1985-09-05

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