JPH0739431B2 - Platinum urea complex - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] The present invention relates to a novel platinum cyclic urea complex having an antitumor effect.

It has been conventionally known that various platinum compounds have an antitumor effect, and for example, cisplatin (B. Rosenberg
et al, Nature 222, 385,1965) or malonate (1,2-
Diaminocyclohexane) platinum (II) (Japanese Patent Laid-Open No. 53-3164)
8) etc. have been reported. However, many of these platinum complexes have strong nephrotoxicity and low solubility in water, and are difficult to formulate.

The present inventors have found that the platinum complex formed by the reaction of a diammine or diamine platinum (II) derivative with a cyclic alkylene urea has remarkably low side effects such as renal toxicity and myelosuppression.
The inventors have found that the antitumor agent has extremely high solubility in water and completed the present invention.

[Structure of Invention]

 The present invention has the formula[In the formula, A is a linear or branched alkyl group having 2 to 5 carbon atoms.
Len, the dotted line between C and O or between C and N
It is a heavy bond, and X Is an anion, and n is
1 or 2, B and D are the same or different and are 2-
Represents minomethylpyridine, or B and D together,
Ethylenediamine, propylenediamine, 2-aminometh
Cylpyrrolidine, 1-amino-2-aminomethylhexa
1,2-diaminopentane or 1-amino-2-a
Indicates minomethylpentane. ] Bi-coordinated white with
It is a gold cyclic urea complex.

In the above formula, the linear or branched alkylene having 2 to 5 carbon atoms of A is, for example, — (CH ₂ ) ₂ —, —CH (CH ₃ ) CH _{2
-, - CH (CH 3)} CH (CH 3) -, - (CH 2) 3 -, - CH
_{(CH 3) CH 2 CH 2} -, - CH 2 CH (CH 3) CH 2 -, - CH
_{(CH 3) CH (CH 3} ) CH 2 -, - CH (CH 3) CH 2 CH (C
_{H 3) -, - (CH} 2) 4 -, or -CH (CH ₃₎ CH ₂ CH
₂ CH ₂ - and the like. Suitable - (CH _{2) 2} - or - (CH _{2) 3} - it is.

In the above formula, the anion of X is, for example, nitrate ion, perchlorate ion, sulfate ion or carbonate ion, preferably nitric acid or sulfate ion.

When X is a monovalent anion, n is 2. When X is a divalent anion, n is 1.

The aromatic amines of B and D are Can be given.

Suitable B and D are And B and D together Is.

The complex of the present invention is synthesized according to the following formula.

In the formula (2), Y and Y ′ are the same or different, and are H ₂ O, nitrate ion, hydroxide ion, perchlorate ion, or Y and Y ′ together are a sulfate ion or a carbonate ion, and Is H ₂ O, nitrate ion, hydroxide ion or Y and Y ′ together is a sulfate ion.

B, D, X in equation (2) And n are the same as above.
It is significant.

In formula (3), A has the same meaning as described above.

The compound of the present invention is synthesized, for example, by the following method.

Method (A) cis-dichloro-diamineplatinum (II) is reacted with 2 equivalents of silver nitrate or 1 equivalent of silver sulfate to prepare an aqueous solution of cis-diaco-diamineplatinum (II) nitrate or sulfate (2). Add 1 equivalent to 1/2 equivalent of cyclic alkylene urea, and adjust to pH 7 by adding 1N caustic soda as needed. The solution is stirred at 0 ° to 100 ° C for 1 hour to 40 days, preferably at room temperature to 60 ° C for 10 hours to 40 days. The target compound (1) is obtained by concentrating the reaction solution as needed, adding an organic solvent such as methanol, ethanol, isopropanol or ether, and collecting the deposited precipitate.
Is obtained. The precipitate obtained here can be purified using Diaion CHP-20P, Sephadex or an ion exchange resin or the like, if necessary.

(B) Method cis-diaco-diamine platinum (I obtained by the method (A)
When water is distilled off under reduced pressure from the aqueous solution of nitrate or sulfate of (I) (2), cis-dinitrate (diamine) platinum (I
I) or cis-sulfate (diamine) platinum (II) is obtained. Cyclic alkylene urea in a water suspension of this product.
Add 5 to 1 equivalent and 1 equivalent of caustic soda,
When the reaction treatment is carried out in the same manner as in the method (A), the target compound is obtained.

(C) method cis-diaco-diamine platinum (I obtained by the method (A)
1 equivalent of caustic soda was added to the nitrate or sulfate (2) aqueous solution of I), and the mixture was stirred at room temperature for 1 hour to 14 hours, and then water was distilled off under reduced pressure to remove bis (hydroxo-cis-
A nitrate or sulfate of (diamine) platinum (II) is obtained. Cyclic alkylene urea (0.5 to 1 equivalent) is added to an aqueous solution of this product, and the mixture is stirred at room temperature to 50 ° C. for 1 to 40 days and then treated in the same manner as in the method (A) to obtain the target compound.

〔The invention's effect〕

The compound obtained by the present invention is mouse leukemia L1210.
, Has an antitumor effect equal to or higher than that of cisplatin,
Moreover, it is also sufficiently effective against cisplatin-resistant mouse leukemia L1210. Moreover, side effects such as renal toxicity and bone marrow suppression are weak, and the drug is easy to administer due to its extremely high water solubility.

When the platinum complex according to the present invention is administered as a carcinostatic agent, it is usually administered parenterally, for example, as an injection. Although the dose varies depending on the age, medical condition, etc., the usual adult daily dose is 10 mg to several g in divided doses.

Next, the present invention will be described more specifically with reference to examples.
The present invention is not limited to this.

Example 1 Hydroxo (ethyleneurea-N, O) -bis (ethylenediamine) platinum (II) nitrate Ethylenediamine platinum (II) dinitrate (379mg)
1N-sodium hydroxide aqueous solution 1ml was added to the water suspension of 1.
Stir at room temperature for hours.

Add ethyleneurea (60 mg) and stir at 28 ° C for 10 days.
The insoluble matter in the reaction solution is removed, and water is distilled off under reduced pressure. Dissolve the residue in a small amount of water and use Diaion CHP20-P (approx. 100 m
l) The product was applied to a column and eluted with water. The fraction containing the target substance was freeze-dried to obtain 120 mg of the target substance as a colorless powder.

NMR spectrum (270 MHz, D ₂ O) δ _ppm : 2.2-2.7 (8H, m), 3.20 (2H, t, J = 7.7Hz), 3.77 (2H, t,
J = 7.7Hz). Example 2 Hydroxo (ethyleneurea-N, O) bis (2-aminomethylpyrrolidine) platinum (II) nitrate To a water suspension (15 ml) of 2-aminomethylpyrrolidine platinum (II) dinitrate (700 mg) was added 1N-sodium hydroxide aqueous solution (1.67 ml), and the mixture was stirred at room temperature for 4 days. Insoluble matter in the reaction solution was removed, and ethylene urea (100 mg) was added to the solution.
Add and leave at 28 ° C for 1 month. The insoluble matter in the reaction solution is removed and the solution is concentrated under reduced pressure. Diaion CHP with residue
It was applied to a -20P column, eluted with water, and the fraction containing the target substance was freeze-dried to obtain 91 mg of the target product as a colorless powder.

NMR (270 MHz, D ₂ O) δ _ppm : 1.3 to 2.2 (8H, m), 2.2 to 3.5 (10H, m), 3.7 to 3.85 (2H,
m), 3.9 to 4.15 (2H, m). Example 3 Hydroxo (ethyleneurea-N, O) -bis (2-aminomethylpyridine) platinum (II) nitrate Aqueous suspension of 2-aminomethylpyridine platinum (II) dinitrate (300 mg) in a 1N-sodium hydroxide aqueous solution 0.7
Add ml and stir overnight at 28 ° C. Add ethyleneurea (42mg) to the reaction mixture and leave at 28 ° C for 1 month. The insoluble matter in the reaction solution is removed, and the solution is concentrated under reduced pressure. The residue was applied to a Diaion CHP-20P column, eluted with water, and the fraction containing the target substance was freeze-dried to obtain 33 mg of the target product as a colorless powder.

NMR (270MHz, D ₂ O) δ _ppm : 3.27 (2H, t, J = 7.2Hz), 3.89 (2H, t, J = 7.2Hz), 4.00
(2H, d, J = 18Hz), 4.10 (2H, d, J = 18Hz), 7.33 (2H, t, J
= 6Hz), 7.43 (2H, d, J = 7.2Hz), 7.92 (2H, d, t, J = 6,7.
2Hz), 8.01 (2H, d, J = 6Hz). Example 4 Hydroxo (ethyleneurea-N, O) -bis (dianmine) platinum (II) nitrate When the reaction and treatment were carried out in the same manner as in Example 1 from diammine platinum (II) dinitrate, the target compound was obtained.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Tomio Kobayashi 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Shigeki Muramatsu 1-258 Hiromachi, Shinagawa-ku, Tokyo No. Sankyo Stock Company (56) References Japanese Patent Publication 6-55752 (JP, B2)

Claims (1)

[Claims] 1. A formula [In the formula, A represents a straight chain or branched chain alkylene having 2 to 5 carbon atoms, a dotted line represents that one of C—O or C—N is a double bond, and X ⁻ is an anion. And n is 1
Or 2 and B and D are the same or different and represent 2-aminomethylpyridine, or B and D together are ethylenediamine, propylenediamine, 2-aminomethylpyrrolidine, 1-amino-2-amino Indicates methylhexane, 1,2-diaminopentane or 1-amino-2-aminomethylpentane. ] The tetracoordinate divalent platinum cyclic | annular urea complex which has these.