JPS61286396A - Novel platinum complex and use thereof - Google Patents

Abstract

NEW MATERIAL:A cis-diaminocyclohexanolplatinum comples expressed by formula I, II, III or IV (R<1>-R<8> are H or OH, provided that one carbon atom is not substituted by two OH groups in the carbon atoms constituting the cyclohexane ring). EXAMPLE:Dichloro(2-deoxystreptamine)platinum (II). USE:An antitumor agent having improved antitumor activity equal to or better than that of cisplatin and readily administrable due to high solubility thereof. PREPARATION:An aqueous solution of diaminocyclohexanol hydrochloride or hydrobromide which is a starting material is added to an aqueous solution of potassium chloroplatinate (II) which a starting material to carry out reaction and soldium hydrogencarbonate is added thereto. the resultant mixture is allowed to stand in a refrigerator to deposit crystals of the aimed compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new water-soluble cis-diaminocyclohexanol platinum complex and an antitumor agent containing the compound as an active ingredient.

Conventional technology Ever since cisplatin (cis-dichlorodiamine platinum (■)) was discovered to have excellent antitumor properties (Nature (
Nature) +Volume 222, Page 385, 1969
See year. ), its use as an antitumor agent has been extensively studied, and it is now being used clinically in the United States, Britain, and France. However, because cisplatin has strong side effects such as nephrotoxicity, nausea, vomiting, and hearing loss, researchers in various countries are trying to synthesize and develop a second-generation platinum complex that has stronger antitumor properties and fewer side effects than cisplatin. It is progressing. Among them, cis-dichloro-1,2-diaminocyclohexane platinum (■) (Chemical Biological Interactions (Chsm, Blol, Intera
ctions), Vol. 5, p. 415, 1972. ) is said to be effective, but there are problems with water solubility. Focusing on this point, we have developed a method using JP-A-53-3164
See specification No. 8. ), 4-cal is xyphthalate (1,
2-diaminocyclohexane) platinum (■) (Unexamined Japanese Patent Publication No. 1983
See specification No.-46752. ) and other compounds with excellent water solubility have been developed.

It is desired to develop water-soluble cisplatin analogues with low toxicity and strong antitumor activity that can be used as excellent antitumor agents.

As a result of intensive research to achieve the above object, the present inventors succeeded in synthesizing a new platinum complex by using diaminocyclohexanols as the amine component, and furthermore, the complex with -1210
, 8-180, and found that it can be used as an excellent antitumor agent, leading to the completion of the present invention. That is, the platinum complex compound of the present invention is a cis-diaminocyclohexanol platinum complex represented by any of the following general formulas (%) and an antitumor agent containing this as an active ingredient. In the formula, R-R represents a hydrogen atom or a hydroxyl group,
However, in order to prevent two hydroxyl groups from substituting one carbon atom at the same time in the carbon atoms constituting the cyclohexane ring,
Represent each.

The platinum (II) complex compound of the present invention is produced by adding diaminocyclohexanol hydrochloride or bromate aqueous solution to an aqueous solution of potassium chloroplatinate (If), adding sodium bicarbonate to the solution, and collecting the precipitated crystals by adding sodium bicarbonate and leaving the mixture in a refrigerator. , can be easily manufactured by washing. In addition, the aforementioned diaminocyclohexanols were prepared by the method previously reported by Invention J [Poutet.

Chemical Society Japan (Bull, Che
m.

Soc, Jpn,) Volume 37, Page 733, 1964
Year; Vol. 38, p. 758, 1965 - Vol. 38, p. 2026, 1965; Vol. 39, p. 170, 1966; Vol. 40, p. 1295, 1967
See year. ] or the method described in the literature [Journal American Chemical Society (J, Amer, Che
m, Soc,) Volume 80.

See page 752, 1958. ] can be synthesized.

The compound of the present invention has antitumor properties equivalent to or better than cisplatin, and is highly water-soluble and therefore easy to administer. The compound of the present invention can be dissolved in a suitable injection solvent and administered by intravenous, intramuscular, subcutaneous injection, or infusion.

Example The present invention will be specifically explained with reference to Examples.

Example 1 Potassium chloroplatinate (II) 1711%' (0,41
mmol) in 1.4 ml of water, and add DL-2 to this.
, 3-noamino-(1,2/3)-cyclohexanol dinohydrochloride (Bull, Chem.
Soc, Jpn, ), Volume 37, Page 733, 196
See Year 4. ) IoolW (0,49 mmol) k water 0.
Add the solution dissolved in 6 tires, then wash with 689 liters of sodium bicarbonate, dry under reduced pressure, and dichloro[DL
-2,3-diamino-(1,273)-cyclohexanol]platinum (ID 118) (yield 72%) was obtained.

Melting point: 301-302°C Elemental analysis value: C16H44N2Ct2PtO Example 2 DL-myo-inosadiamine-1,2-dihydrochloride 441'l & (0.17 mmol) was reacted in the same manner as in Example 1 to give yellow crystals of dichloro(DL- myo-inosadiamine-162) platinum(II) 45■ (yield 70
%) was obtained.

Melting point 240-242°C Elemental analysis value C6H44N2Ct204Pt [Example 3 2-Deoxystrezotamine dihydrochloranide (Jar American Chemical Society)
J, Aynsr, Chem, Soc, ), No. 8
Volume 0, page 752.

See 1958. ) 80m? (0.19 mmol)
was reacted in the same manner as in Example 1 to give yellow crystals of dichloro(2-
Deoxystreptamine) platinum(II) 57cm (yield: 69cm) was obtained.

Melting point 219-221°C Elemental analysis value C6H14N2C620, calculated value as Pt C: 16.83, H: 3.30, N:
6.54 measured value C: 16.85. H: 3.4
9. N: 6.25cm Example 4 Antitumor Test 1 (1) Using donor animals IC1%/CRJC1c/CRJ, 7 animals per group (7
Weekly) was used.

(2) Test method Inject Sarcoma-180°I x 1 into the abdominal cavity of the above mouse.
The survival rate was examined with the day when 0' cells were transplanted as day 0. The various Pt(n) complex compounds prepared in Examples 1 to 3 were
It was administered intraperitoneally to the eye. Physiological saline was used as the injection solvent, and physiological saline was used as a control.

As shown in Table 1, the results showed that the pt(II) complex of the present invention exhibited excellent antitumor activity.

Table 1 Example 5 Antitumor Test 2 (1) Donor Animals Br) F1 mice (female) were used in a group of 5 mice (7 weeks old).

(2) Test method The survival rate was determined from the day 01 when 1×10 5 murine leukemia L1210 lung tumor cells were intraperitoneally transplanted into the mouse. The various PL(II) complex compounds prepared in Examples 1 to 3 were intraperitoneally administered on the first day of the month. Physiological saline was used as the injection solvent, and physiological saline was used as a control.

As shown in Table 2, the results showed that the Pt(II) complex of the present invention exhibited excellent antitumor activity.

Table 2 Effects of the Invention As is clear from the above, the novel platinum complex of the present invention exhibits excellent antitumor activity and can be expected to be used as an anti-)jΦ tumor agent. Therefore, the present invention is extremely useful in the pharmaceutical industry.

Procedural amendment document July 1985 201 Official of the Office of Corrections! 1, Indication of 1985 Patent Application No. 127551, 2, Name of the invention, 11 new platinum bodies, J: Purpose of use, 3, Person making the amendment, A'1, Relationship, Patent applicant, I 1st place Kyobashi, Chuo-ku, Tokyo-1, 5-8, 5, supplementary j
[Number of inventions increased due to n/a 7. The statement of contents of the amendment is amended as follows.

(1) On page 8, line 2, [melting point 301-302°C] is corrected to [melting point 301-302°C (decomposition)].

(2) On page 8, line 13, [melting point 240-242°C] is corrected to [melting point 240-242°C (decomposition)].

(3) On page 9, line 5, "melting point 219-221°C" is corrected to "melting point 219-221°C (decomposition)".

(4) Page 9, line 8, rN: 6.25% The following statement is inserted between “Example 4” on line 1 and 9.

[Example 4 Myo-inosadiamine-1,3-dihydrochloride (J, OrL Chem, 33.2831 (1
968)) 152 mg (0.60 mmol) in Example 1
By recrystallizing the crystals reacted in the same manner as above from 1,N hydrochloric acid, 93 mg of dichloro(myo-inosadiamine-1,3)platinum (IT) (yield: 3
4%).

Melting point 253-260℃ (decomposition) Elemental analysis value Cs l-114N2 CI 20a P
Calculated value as t C: 16,22, l-1:
3.18, N: 6,31 Measured value C: 16.1
5, H: 3.19, N: 6,05 +(
5) On page 9, line 9, "Example 4" is corrected to "Example 5."

(6) On page 11, line 1, "Example 5" is corrected to "Example 6."

Below

Claims (2)

[Claims] (1) The following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) ▲ Mathematical formulas, chemical formulas, There are tables, etc. ▼ (IV) Cis-diaminocyclohexanol platinum complexes shown in any of the following. In the formula, R^1 to R^8 each represent a hydrogen atom or a hydroxyl group, but so as not to substitute two hydroxyl groups on one carbon atom in the carbon atoms constituting the cyclohexane ring. (2) The following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) ▲ Mathematical formulas, chemical formulas, An antitumor agent containing a cis-diaminocyclohexanol platinum complex as an active ingredient, shown in any of the following tables. In the formula, R^1 to R^8 each represent a hydrogen atom or a hydroxyl group, but so as not to substitute two hydroxyl groups on one carbon atom in the carbon atoms constituting the cyclohexane ring.