WO1985003078A1

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

Info

Publication number: WO1985003078A1
Application number: PCT/DE1985/000001
Authority: WO
Inventors: Johanna Heimberger; Heimo Jürgen KELLER; Klaus Bernhard Keppler
Original assignee: Medac Gesellschaft Für Klinische Spezialpräparate
Priority date: 1984-01-09
Filing date: 1985-01-08
Publication date: 1985-07-18
Also published as: JPS61501029A; DE3524841A1; DK405385A; EP0171401A1; DE3400435A1; NO853448L; FI853426L; DK405385D0; FI853426A0

Abstract

Platinum and crown ether complexes having the general formula (I), wherein C is a mono- or bicyclic crown ether, A is ammonia or a mono- or di-Cl-C4-alkylamine or an amine function contained in the crown ether and X is halogen or the anion of mono- and dicarbonic acids. Said complexes have an interesting cytostatic activity and are therefore appropriate for the treatment of cancers.

Description

Platinum crown ether complexes with antineoplastic action and medicaments containing them

Technical field

The invention relates to platinum crown ether complexes having an antineoplastic action and medicaments containing them.

State of the art

Recently, 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.

Numerous other platinum complexes (DE-OS 24 45 418, DE-OS 28 37 237, DE-OS 26 26 559, DE-OS 25 39 179) and complex compounds of other transition metals have recently been proposed as agents having a cytostatic effect. It is known that certain crown ethers show bacteriostatic and virustatic activity, for which their ability to form complexes with metals is held responsible. In addition, considerations were made to exploit the specificity of some crown ethers for alkali and alkaline earth ions for influencing the mineral metabolism of the human and animal body. Description of the invention

Surprisingly, it has now been found that platinum crown ether complexes of the general formula I

[C _1-2 Pt A _1-2 ] X _1-2 (I),

where C is a mono- or bicyclic crown ether, A ammonia or a mono- or di-Cl-C4-alkylamine or amine functions contained in the crown ether and X is halogen or the anion of mono- and di-carboxylic acids, an at least equivalent tumor-inhibiting activity to cisplatin with lower toxicity. At the same time, 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. These platinum crown ether complexes are therefore very suitable for the treatment of cancer.

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".

Furthermore, in the context of this invention, 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. In the context of the present invention, the following are suitable as crown ethers:

[18] Krone (6) (IUPAC nomenclature: 1,4,7,10,13,16-hexaoxacyclooctade c a n);

N-phenyl-13-aza-1,4,7,10-tetraoxacyclopentdecane; 1,4,7,14,23-pentaoxa (7.2) orthocyclo (2,6) pyridinophane; 1,4,7,10,13,16-hexaoxacyclooctadecane-2,3,11,12-tetracarboxylic acid; Hexaoxadiazabicyclo [8,8,8] hexacosan (Kryptofix 222);

4,7,13,16-tetraoxa-1,10-diazacycloocta decane (κryptofix 221); Heptaoxadiazabicyclo [8.8.1 '.] Octacosan (Kryptofix 322) octaoxadiazabicyclo [8.11.11.] Dotriacontan (Kryptofix 332); Nonaoxadiazabicyclo [11/11/11] pentatriacontan (Kryptofix 333); 2,3,11,12-dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11diene;

2,3,11,12-dicyclohexy1-1,4,7,10,13,16-hexaoxacyclooctadecane; 2,3,14,15-dibenzo-1,4,7,10,13,16,19,22-octaoxacyclotetracosane-2,14-diene;

2,3,14,15-dicyclohexyl-1,4,7,10,13,16,19,22-octacyclotetra cosan;

1,4,10,13-tetraoxa-7,16-dithiacyclooσtadecan0 ¹ , 0 ⁴ , 0 ¹⁰ , 0 ¹³ , S ⁷ , S ¹⁶ ;

1,4,7,10,13,16-hexathiacyclooctadecane;

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. To form 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

Can coordinate platinum (II). 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 Å, preferably 2.2 to 4 Å and particularly preferably of 2.6 to 3.2 Å.

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.

The invention also relates to a process for the preparation of the platinum crown ether complexes of the general formula I.

[C _1-2 Pt A _1-2 ] X _1-2 (I),

in which C is a mono- or bicyclic crown ether, A ammonia or a mono- or di-C1-C4-alkylamine or amine function contained in the crown ether and X is halogen or the anion of mono and di-carboxylic acids, characterized in that the crown ether C is reacted with a PtX ₂ A _0-2 compound.

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.

In general, it has proven to be advantageous in human medicine to administer the active ingredient (s) when administered parenterally in a daily dose of about 0.1 to 5, preferably 1 to 3, single doses in order to achieve the desired results. 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. As is customary in internal tumor therapy, to reduce the risk of side effects, 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 determination of the respectively required optimal dosage and type of application of the active substances can easily be done by any expert on the basis of his specialist knowledge.

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; Conserve agents, for example methyl or propyl hydroxybenzoates; Flavoring agents; Contain sweeteners such as sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.

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.

Sterile injectable aqueous suspensions, liposomes, isotonic saline solutions or other solutions, the dispersing or wetting agents and / or pharmacologically acceptable diluents, e.g. Propylene or butylene glycol, and / or solubilizers, e.g. Tweene, Cremophore or Polyvinylpyrrolidon, contain.

If appropriate, the active compounds can also be formulated in microencapsulated form with one or more of the stated carriers or additives.

The following example explains the invention in more detail without restricting it.

H e r s t e l l u n g s b e i s p i e l

1.) 1,4,7,10,13,16-hexaoxacyclooctadecane-diammine dichloroplatinum (II)

2.09 g (7 mmol) of cisdiammine dichloroplatinum (II) and 1.85 g (7 mmol) [18] crown (6) are refluxed for 10 hours in acetone or chloroform. The slightly yellow-colored reaction solution is concentrated. Then hexane is added and then boiled under reflux. When cooling, the title compound fails. Yellow crystals of melting point 235 ° C are obtained. Yield: 47%. Analysis: C ₁₂ H ₃₀ O ₆ N ₂ Cl ₂ Pt

Calculated: 25.54% C; 5.36% H; 4.96% N; 34.57% Pt Found: 25.82% C; 5.59% H; 4.75% N; 34.10% Pt. 1H NMR spectra in d ⁶ -acetone [18] crown (6) protons: at 3.6 ppm (singlet); Amine protons at 2.8 ppm (singlet).

2.) 1,10-diaza-4,7,13,16-tetraoxacyclooctadecane-dichloroplatin (II)

Platinum (II) chloride is suspended in a solution of 1,10-diaza4,7,13,16-tetraoxacyclooctadecane in methylene chloride, which contains equimolar amounts of the diaza crown ether, and stirred at room temperature with the exclusion of light. A yellow solution is formed after 8-10 hours. The solvent is distilled off in a rotary evaporator. The resulting precipitate is filtered off and dried in a high vacuum with slight heating (60 ° C). The light yellow, amorphous solid has a melting point of 165 ° C. Yield: 56.8%.

Analysis: C ₁₂ H ₂₆ Cl ₂ N ₂ O ₄ Pt; M _r : 528.34

Calculated: 27.28% C; 4.96% H; 5.30% N; Found: 27.50% C; 5.05% H.

P h a r m a k o l o g i e

P 388 leukemia model

Approximately 4 week old female weighing 18 to 25 g

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

Oberimpfen the animals are randomized. 3 to 6 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

Transplantation administered intraperitoneally daily, or using other therapy regimens on day 1,5 and 9.

Results from the described P 388 leukemia model are summarized in Table I below. The factor T / C given in percent means the percentage

Extension of the median survival time of the untreated control animals.

The experiment is stopped as soon as the median survival time T / C of the treated animals has reached 300% of the median survival time of the untreated animals. To calculate the median survival time, the animals still alive at the end of the trial are considered to have died at the end of the trial. L 1210 leukemia model

Approximately 4 week old 18 to 25 g female BDF ₁ mice become approximately 10 ⁵ L 1210 leukemia cells in 0.2 ml physiological

Transfer saline intraperitoneally. Leukemia is kept in passage on DBA / 2 mice.

The transplant is carried out analogously to the P 388 leukemia model. The substances are administered intraperitoneally on day 1 after the transplantation.

Results from the described L 1210 leukemia model are summarized in Table II below.

Lewis Lunq Carcinoma

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 substances are administered intraperitoneally from day 1 to day 11 after the transplant. Results from the described Lewis lung carcinoma are summarized in Table III below.

Table 1 Example 1: Therapy on day 1

T / C [%]

dose

[m mol / kg] Pt (NH ₃ ) ₂ C! ₂ [18] crown (6) Pt (NH ₃ ) ₂

0.0167 134 (0/3) 179 (0/3)

0.033 130 (0/3) 232 (2/3)

0.0667 60 (0/3) 145 (1/3)

Compared to cisplatin, 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.

Example 2: Therapy Day 1 - Day 9;

12 control animals, 6 animals per test group compound dosage T / C mg / kg m mol / kg

18 C 6 platinum 0.94 0.0016 143

Cisplatin 0.5 0.0016 114

Table II Example 1: Single administration on day 1; 9 control animals; 3 animals per test group

Compound dosage T / C (%) mg / kg mmol / kg

18 C 6 platinum 9 0.017 180

28 0.049 247

Cisplatin 5 0.017 153

15 0.049 153

5-fluorouracil 00 1.54 135

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

Compound dosage T / C (%) mg / kg mmol / kg

18 C 6 platinum 19 0.033 240

Cisplatin 10 0.033 196

5-fluorouracil 200 1.54 130

5-FU was used as a standard therapeutic as an additional control. Table III

Therapy day 1 - day 1 1;

18 control animals, 6 animals per test group

Compound dosage T / C (%) mg / kg mmol / kg

18 C 6 platinum 0.94 0.0016 105

1.87 0.0033 111

2.82 0.005 120

Cisplatin 0.5 0.0016 97

1 0.0033 108

1.5 00.005 105

Claims

Patent claims:

1. platinum crown ether complexes of the general formula,

[C _{_1-2} Pt A _1-2] X _1-2 (I),

wherein

C is a mono- or bicyclic crown ether,

A is ammonia or a mono- or di-C1-C4-alkylamine or amine functions contained in the crown ether and X is halogen or the anion of mono- and di-carboxylic acids.

2. platinum crown ether complexes according to claim 1, characterized in that in the general formula I

C is a mono- or bicyclic crown ether,

A is ammonia and amine functions contained in the crown ether and X is chlorine and carboxylic acid anion.

3. platinum crown ether complexes according to claim 1 or 2, characterized in that in the general formula I

A and X have the meanings given and C denotes a mono- or bicyclic crown ether, the interior of which has an inner diameter of 1.7 to 7 Å, preferably 2.2 to 4 Å and particularly preferably from 2.6 to 3.2 Å.

4. 1,4,7,10,13,16-hexaoxacyclooctadecane-diammine dichloroplatinum (II) and

1,10-diaza-4,7,13,16-tetraoxacyclooσtadecane dichloroplatin (II).

5. Process for the preparation of the platinum crown ether complexes of the general formula I

[C _{1 -2} Pt A _{1 -2} ] X _{1 -2} (i),

wherein

C is a mono- or bicyclic crown ether,

A ammonia or a mono- or di-C1-C4-alkylamine or amine functions contained in the crown ether and

X is halogen or the anion of mono- and di-carboxylic acids, characterized in that the crown ether C is reacted with a compound PtX ₂ A _0-2 .

6. Medicament containing one or more platinum crown ether complexes according to one of claims 1 to 4.

7. Use of the platinum crown ether complexes specified in claims 1 to 4 for the treatment of cancer.