JPS5879994A - Novel adamantane platinum complex - Google Patents

Abstract

NEW MATERIAL:An adamantane platinum complex of formulaI{X and Y are halogen, nitrato, OH, sulfonato, lactic acid residue or group of formula II[(m) is an integer 1-6], or X and Y form a group of formula III (R is H, OH or lower alkyl), etc.}. EXAMPLE:Dichloro(1,2-diaminoadamantane)platinum (II). USE:Parenterally administered as an antitumor agent due to improved antitumor action with low toxicity thereof. PROCESS:1,2-Diaminoadamantane hydrochloride is reacted with an alkali metallic tetrahalogenoplatinate (II) having the halogen to be introduced in water to give the compound of formulaI(X and Y are halogen). The X and Y groups are then converted into the desired groups. For example, a compound of formulaI(X and Y are the same and halogen) is reacted with silver nitrate in water to give the compound of formulaI(X and Y are the same and nitrato).

Description

[Detailed Description of the Invention] Conventional. Cisplatin (BrisLol & Co.)
Regarding platinum complexes including . It is expected to enhance antitumor effects and reduce toxicity. A lot of research has been done. For example, various platinum compounds such as malonato(12-diaminocyclohexane)platinum (■) [in JP-A-53-37-37] and sulfato(12-diaminocyclohexane)platinum (formerly [Special Sho 511-Gugu Otsu θ]) 4C are used. The present inventors have reported that exo, eis-2,3-diaminohycyclo(,2,,2,/) into which a bicyclo ring diamine was introduced as a carrier ligand. We have discovered that a methane platinum complex has an excellent antitumor effect against L/2/θ. In order to find a platinum compound with low strain, several highly strained ring diamine platinum (F) hulls were researched and the present invention was completed.

The compound of the present invention can be represented by the general formula (I').

(However, X and Y represent the same group, halogen, nitra I--hydroxyl group, s11/hona I-,
Lactic acid residue, -0CO(C,,J-1,2nρm-/
)'OH, -0CO (CnH, 2n-20n, ), -O
H, or bar0CO(C1, H21, oI,)-CI
(O wo suka.

X and Y together represent a hydroxyl group or a hydroxycarboxylic acid residue when X represents nidorado;

When X represents sulfato, Y represents aco, and when X represents a hydroxyl group, Y represents a hydroxycarboxylic acid, a lower aliphatic carboxylic acid, or a residue of a water-soluble vitamin having a carboxyl group, respectively. . Another 1m
is/~B integer.

n is an integer of 5, p is an integer of 2 to 5, and R
represents hydrogen, hydroxyl group, or lower alkyl. ) To describe the definitions of the above symbols in more detail, ``Halogen'' means chloro, bromo, and iodo, with chloro being preferred.

Sulfonate means lower alkylsulfonates such as methanesulfonate and arylsulfonates such as benzenesulfonate. Hydroxycarboxylic acids include, for example, glycolic acid.

Examples include glyceric acid, lactic acid, gluconic acid, gulonic acid, glucoheptonic acid, galacturonoic acid, and curcuronic acid, but other natural or synthetic lr hydroxycarboxylic acids that conform to the above formula are also within the scope of the present invention.

Examples of lower aliphatic carboxylic acids include acetic acid and propionic acid. Examples of water-soluble vitamins having a carboxyl group include pan I, thenic acid 9, folic acid, and biotin. Lower alkyl includes methyl, ethyl, and butyl.

The compounds of the present invention can be prepared by known methods (J,
Pl+arm, Sc i, Otsu! ;, 373-32g
(/97 Otsu)] can be synthesized. That is, Z2-diaminoadamantane hydrochloride CJ, which is a known compound J),
Org, Cll0IIL3, /li2/(/97/
)'J and an alkali metal salt of a tetrahalogenoplatinic (jll) acid having a halogen to be introduced are reacted in water to obtain a compound (1) in which X and Y are halogens. As the alkali metal salt of tetrahalogenoplatinic (If) acid, potassium tetrachloroplatinic acid (I) is particularly preferred. The reaction proceeds under weak basic conditions, particularly preferably in the presence of sodium bicarbonate. Reaction is usually /~3
Completed in days.

Compound (1) in which X and Y are halogen obtained above
) and silver nitrate in water.

A compound (1) is obtained in which X and Y are nidorado.

This reaction is carried out under light shielding and is usually completed in 1 to 3 days. X
By treating compound (1) in which Y is nidorado with a weak base, compound (I) in which either X or Y is a hydroxyl group can be obtained, and ammonium hydroxide is particularly preferred as the weak base. [U, S, Patent Ku/
/ 3. 'AI! (Method described in /97g)]X
Compound (1), in which X and Y are sulfonato, can be obtained by reacting compound (I) in which Y is a halogen with a silver salt of a sulfonic acid having a desired sulfonate group, such as silver methanesulfonate. Two equivalents of silver salt of sulfonic acid may be applied to the raw material.

When compound (f) in which X and Y are halogens is reacted with silver sulfate, compound (1) in which X is sulfato and Y is aco is obtained. This reaction was carried out at room temperature.

It is best to do this under light-shielding conditions and can be completed in <3 days.

Compound (1) in which X and Y are carboxylado is obtained by reacting compound (1) in which X and Y are nidorado with a monocarboxylic acid or an alkali metal salt thereof in water. When an alkali metal salt of carboxylic acid is applied to the raw material, 10,000 of X or Y becomes carboxylad.

When 2 equivalents are applied, both X and Y are replaced by carboxylad.

Compound (I), in which X and Y are dicarboxylad, is reacted with a dicarboxylic acid or an alkali metal salt thereof in water to obtain compound (I), in which X and Y together are dicarboxylad. This reaction is carried out under cooling to heating and is usually completed in several tens of minutes to several days, although this may vary depending on the type of carboxylic acid and the type and number of substituents.

X and Y are Nidorado solution anopalite (AI + erliLe) IRA-
%θθ, Tawny Termouse (Dowex) I, Tireion SA-10
By treatment with an anion exchange resin (OH-type) such as A. A compound (1) is obtained in which both X and Y are hydroxy. Since the compound (I) in which both X and Y are hydroxy is unstable in a solid state, it is usually preferable to use it in the next reaction as a solution.

By adding a monocarboxylic acid to an aqueous solution of compound (1) in which X and Y are hydroxy and causing a reaction. Compounds (1) are obtained in which X and/or Y are carboxylads. to carboxylate to the raw material. When two equivalents are applied, both X and Y are substituted with carboxylad. This reaction is carried out at room temperature to elevated temperature and is usually completed in several tens of minutes to several days.

Compound (1) of the present invention exhibits a strong inhibitory effect on various tumor cells. For example, the activity of representative compounds against murine leukemia L/2/θ is shown below.

Test method 106 ascites cells of murine leukemia L/210 were treated with BDF,
Transplanted into the abdominal cavity of a mouse. A prescribed amount of each drug is intraperitoneally administered at 1:1 the day after transplantation.

Judgment of effectiveness The survival rate (ILS) is calculated from the average survival days of each administration group and the average survival days of the untreated control group according to the following formula.

Average survival days of untreated control group x 10θ Test drug (1) Acosulfate (12-cyaminoadamantane)
Platinum(II) (2) Digluconato(i2-cyaminoadamantane)platinum(n) (3) Dichloro(cis-diammine)platinum(It)
(Cisblatin) -and- Administer to the mouth for results.

For example, compound (I) can be used in suitable injection preparations (eg, distilled water for injection, physiological saline, 3% aqueous butosucrose solution).

The drug may be dissolved or suspended in ethanol water, glycerin water, propylene glycol water, olive oil, peanut oil, etc.) and administered by intravenous injection, intramuscular injection, or subcutaneous injection. Compound (1) can be sealed in an ampoule as a solution or suspension; It is preferable to store the amplifier in a container and prepare it before use. A stabilizer may also be added. When compound (1) is used for tumor treatment in adults.

Usually administered parenterally at a daily dose of /[1/~3 times/θθN. Examples are shown below to clarify aspects of the present invention.

Example / /, 2-diaminoadamantane dihydrochloride / 73゜πV (
3,0,! ;'i lmol) and 7270 mmol of potassium platinum chloride (3θS mmol) dissolved in θml of water were added with 30ml of sodium bicarbonate. +++, & (
0θE IJ mol) was added as a solid and stirred at room temperature for 3 days. The produced solid was filtered, washed successively with water, acetonate, and ether, and then dried under reduced pressure to obtain the pale yellow-green title compound 2/23θ■ (yield 93%). 〉3θθ
°C Elemental analysis calculation value (%) (as C,, H7, N, PtC1,)C
,2779;H,lA/9 ,N, ,4.4#iC1,
#, 410°PL, G S/G actual measurement value (%) C, 271,0; H, 'AO/, N, t, 1.7. C
1,/A, 20rPt, 1I-1A and 7 IR: v”j0' 3223.3//3(ME,)c
m'Example Nizinidorado(12-diaminoadamantane)platinum(It
) Compound 27fθda (7729 mol) was suspended in water jθ1Ili, silver nitrate/θN (36 mmol) was added, and the mixture was stirred for 2 days in the dark. Remove the white precipitate of silver chloride,
% potassium chloride aqueous solution to remove excess silver nitrate.

After confirming that the mother liquor did not become cloudy due to the addition of the aqueous potassium chloride solution, it was concentrated to dryness using a rotary evaporator, and the resulting residue was dried under reduced pressure at 33"C to produce the title compound 3jSθ■ (yield: 2) as a pale yellow solid. %).

mp2.4tj~233”C (decomposition) Elemental analysis calculation value (%) (as C,,H,,N4IO,Pt)
C, 2'1.7'l-, H, 3,7g; N, /13'1
Actual value (%) C, 2'A79iH, 3, 73:N, 1133-/2- Nujo I IR, v 3.27'l, 3:1.3 Otsu, -?
/ ri'i'("I(J)c771' Example
3 Acosulfate (12-diaminoadamantane) cap (
n) Compound 2qθθ~ (093 mmol) was suspended in 25 ml of water, 290 N (093 mmol) of silver sulfate was added, and 9
The reaction vessel was protected from light and stirred at room temperature for 2 days.

When treated in the same manner as in Example 2, the yellow title compound G377 was obtained.
WW (yield f, 5%) is obtained. “P, decomposes above 23%°C.

Elemental analysis calculation value (%) (as C,, H,2, N, O, SPc) for C,2, 21. -, H, Senkou iNJzawo;Pv,
G lθ7 actual measurement value (%) C,,2, θ3;H, lAθ3;N, Otsu, θOtsu
;Pt, 3JnZ7Nujol IR, ν ~3gθθ (wide, OR), 322θ
, 3/θθ (NI(,) , / //7. /θ2g(so) ml'Example Gudihydroxy(12-diaminoadamanotane)platinum (old compound 3/3j~(02g mmol) ml of water by heating, and concentrated using a rotary evaporator to a concentration of 21 R/ml.This solution was passed through a column packed with anion exchange resin, Tire Iono 5AJA (011 difference), and the resulting aqueous solution was Concentrate to dryness under reduced pressure at room temperature. J is obtained as a light brown solid, but it is unstable and gradually becomes colored at room temperature. Yield of 5/θ9 ~ (99% yield). − decomposes.

Elemental analysis calculation value (%) (as C, oH, oN, 20.Pv)
-1gu- c, 3θ3f, H, bu/θ; N, 7θ? Actual value (%) C, 30/θ; H,, ff, 2/iN, 70g Example j Ethylmalonato (12-diaminoadamanotane) platinum (
n) Containing ethylmalonic acid 7# (θθ33i mol) in 1 ml of aqueous solution containing mol of Compound 30033'i')/
Add ml of aqueous solution and leave for 3 hours. The contents are concentrated to /sl using a rotary evaporator at about jθ°C and cooled with water. Count the number of white crystalline solids that precipitate, and
Dry under reduced pressure for 2θ minutes to obtain 2# (yield: 6%).

Decomposes above the desired temperature of θ°C.

Elemental analysis calculation value (%) (as C,,H,N,0□Pt)c,
3 Otsu Otsu Otsu, H, 449, 2, N, 3.7θ1PLjn7
θ Actual value (%) c, 3 Otsu 2 Otsu; H, lA7 GuiNJ Otsu? HPt, 3wa 3otsugo Rniji':,',' 3.2/2. ．． 3//! ;
(N11.), /6 Otsu 3. /! ;7 Otsu (C-(), N also) ゛Example Otsu diglucona l-(/:2-diaminoadamanotane) platinum(II) R= -(CHOH) 4t-CH,20H-/Otsu- Compound 3270 ~ (0377i remol) in water bath tsl
Dissolve it under heating, add 2 parts of sodium gluconoate to this, and add 9 parts of sodium gluconoate.
119 (71,729 mol) was added and left at room temperature for 3 days. This solution was heated at θ° using a rotary evaporator.
Concentrate below C. The residue was washed with anhydrous ethanol and then recrystallized from a water-methanol-ethanol mixed solvent to obtain 1 ng (yield: 5%) of the title compound 737θ.

g! i Humidity. Desired // θ°C or higher (in a sealed tube) Elemental analysis calculated value (%) (as C, 2, 2H1loN, 207□PL) C, 3, 1. ! ;;H, left 3A ;N, 3
．． 73 HPt, Yu595 actual measurement value (%) C133θZiH, 3,27iN, 3.9! ； ；
P t , 275gujol IR, ν 3333 , 3233 , 3 / /,
! (Ill wide, OH1 group).

/Otsu 10(C-θ)α-' Example 7 To an aqueous solution of Otsu mt containing 30/2 mmol of compound, an aqueous solution of mug shavings containing gluconic acid and 23 IIg (0/26 mmol) was added, and the mixture was heated to room temperature. So / 11. ' Leave it still for a while.

The water is removed under reduced pressure and the residue is reprecipitated from alcohol-ether. Dry under reduced pressure at Otsu θ°C to obtain the title compound and 6OtsuQ (97% yield). Decomposes at temperatures above 93°C.

Elemental analysis calculation value (%) (as C, H3oN, 0.PL)
”C,33,,!;/,H,3,27〼N,44
Actual measurement value (%) C, 33, 3θ; H, 3, 22: N, 3. θ3 toad P1.
, 33. /3I R, vNil Jo l 3 Otsu θθ~
3θθθ(11" wide, OII, MIr)l/Otsuθhiro(C-θmeter JI(,2)z Example niR--(C)I2), -NH-Co-CHOH-C(C
H3) 6 ml of aqueous solution containing 300 f'i mol of 2-CH,OH compound contains 2 mol of pantothenic acid θOIE.
Add ml of aqueous solution and let stand at room temperature for 7 hours. The water is removed under reduced pressure and the residue is reprecipitated from alcohol-ether. A slightly brownish powdery solid was heated at θ°C for 70°C.
Dry under reduced pressure for a minute. The title compound 9'l-'l- (%) is obtained. decomposes above 22θ°C.

Elemental analysis calculation value (%) (as C, H3 voice 30, Pt) c,
3 and 2.3; H, 3,9/; N, 7θg; pt, 3s, 7θ actual value (%) −,,7,0=C,37! ;2;H,37;N,7. I2:PL,
3th, 9th IR Niji Nu, j, o l 3th 0th 3θ0
θ (wide, OII, NT-1,), /Otoguyu.

/Otsu2J, /3Otsuθ (NH2, coo, CONII)
tm, 'Patent applicant: Shionogi & Co., Ltd.

Claims (1)

[Claims] General formula: (However, X and Y represent the same group, halogen, nidrado, hydroxyl group, sulfonate, lactic acid residue, -oco (c, □8□) -OH
1-OCO(CnHjn-20n,)-OH, or
When Lt-OCO(CpH, 2,0,2p)-CHO is represented by X and Y together and X represents nidorado, Y represents a hydroxyl group or a hydroxycarphonic acid residue. When X represents sulfato, Y represents aco, and when X represents a hydroxyl group, Y represents a hydroxycarboxylic acid, a lower aliphatic carbonic acid, or a residue of a water-soluble vitamin having a carboxyl group. Further, 1m represents an integer from 1 to O, nl represents an integer from t to j, and p represents an integer from 2 to g. R represents hydrogen, hydroxyl group, or lower alkyl).