JPS6197292A - Novel gallium complex compound and its use - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula Mm[Gan(L)pFq(H2O)r]Fs(H2 O) t). (With the proviso that, m is 0-3; n is 1, or 2; p is 1-3; q is 0, 2, 3, or 4; r is 0, or 2; s is 0, 1, or 3; t is 0, or 2; M is monofunctional cation; L is ligand such as 1,1-dithiolite, 1,2-dithiolite, or dialkylcarbamic acid anion, 2,2-dipyridine, 2,2',2'-terpyridine, 5-oxy-2-oxymethyl-gamma-pyrrone, etc., compound containing S, N, or O, or its residue). EXAMPLE:A complex compound. USE:A carcinostatic agent. PREPARATION:For example, an inorganic salt such as gallium sulfate, gallium fluoride, etc., or its complex in an aqueous solutiohn is blended with an aqueous solution of a ditiol, an alkali metal salt of dithiocarbamic acid, or an amine, etc., to become a ligand by stirring.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel gallium complex compound and an anticancer agent containing the same as an active ingredient.

A large number of drugs have been known as anticancer agents, but all of them have their pros and cons. In recent years, the anticancer effects of metal-containing complexes have been attracting attention, and platinum complexes have become well known as a representative example. However, the 1-1 platinum complex has side effects such as nephrotoxicity, which is a major obstacle.

Conventionally, organic germanium compounds have attracted much attention in terms of pharmacological activity (for example, Japanese Patent Publication No. 46-2, 498).
No., Special Publication No. 1982-21,855, Special Publication No. 1971-160
, No. 319, Japanese Patent Publication No. 54-160.742, and Japanese Patent Publication No. 118,015/1983. ).

On the other hand, regarding the antitumor activity of lithium compounds, it has been reported that inorganic salts such as gallium nitrate, gallium sulfate, and gallium chloride exhibit a slight suppressive effect on certain tumors (Journal of the Nat.
ional Cancer In5titudinal,,
47 r 1121 (1971)).

The present inventors have discovered that trivalent 〃Ga(I[I), which is in a physicochemically more stable state, forms stable complexes with organic compounds containing sulfur, nitrogen, or oxygen, and these The present inventors have discovered that this compound has excellent antitumor activity, and have completed the present invention.

That is, the gallium complex compound of the present invention is represented by the general formula (%), and a drug containing at least one of these as an active ingredient has excellent antitumor activity.

In the formula, m=0, 1,2,3, n=1.2, p=1,2°3, q=ot2t3,4, r=0,2, s=0.1,3
, t=0,2, M is a monovalent cation, L is a ligand, 1,1-dithiolite, 1,2-dithiolite, mono- or dialkyl carbamate anion, Ethylxanthate anion, 2゜2-dipyridine, 2
．． 2',2''-thylpyridine, 5-oxy-2-oxymethyl-γ-pyrone, 3-oxy-2-methyl-γ-pyrone, catechol, 2-hydroxy-1,4-benzoquinone, salicylic acid, salicylaldehyde, Each represents any one type of sulfur-containing, nitrogen-containing, or oxygen-containing compound selected from various ions of glutathione, or a residue thereof.

The ligand represented by 1.1-dithiolite is 2
, 2-dicyanoethylene-1,1-dithiolite, 2,
2,2-bis(carboxyalkyl)ethylene-1,1- such as 2-bis(carboxyethyl)ethylene-1,1-dithiolite), 2,2-bis(carboxypropyl)ethylene-1,1-dithiolite, etc. ;/Thiolite, 2
-nitroethylene-1,1-dithiolite and the like.

In addition, examples of the ligand represented by 1,2-dithiolite include toluene-3,4-dithiolite, 1-ethylbenzene-3,4-dithiolite, 1゜3-dithio-2-thione-4,5 -dithiolite, 1,2-dicyanoethylene-1,2-dithiolite, 1,2-bis(carboxyethyl)ethylene-1,2-thiolyte), 1,2-bis(carboxypropyl)ethylene-1, Examples include 1,2-bis(carboquinalkyl)ethylene-1,2-dithiolite such as 2-dithiolite.

The Ga(III) complex compound represented by the above general formula has a strong growth-inhibiting effect particularly on Ehrlich ascites cancer cells and S-180 ascites cancer cells, and can be used as a therapeutic agent for cancer.

To produce the Ga(II[) complex compound of the present invention, an inorganic salt such as gallium sulfate or gallium heptafluoride or a gallium complex is added to an aqueous solution of the above phthiols, an alkali metal salt of dithiocarbamic acid, or a ligand. This can be easily achieved by adding and stirring amines that can be used as a precipitate, and high purity can be obtained by filtering, washing, and drying the resulting precipitate.

The anticancer agent containing the Ga(In) lead compound of the present invention as an active ingredient is useful as a drug for treating humans and mammals, and can be administered orally in preparations such as tablets, capsules, or elixirs. Alternatively, it can be used to suppress tumors in living organisms by formulating it as a sterile solution or suspension for parenteral administration.

The active ingredient used in the present invention is generally 0.2 to 5 per patient (animals and humans) in need of treatment.
A dose range of 00 mg can generally be divided into several doses, thus giving a total daily dose of 1-2000+ ng per day. Dosage will vary depending on the severity of the disease, the weight of the patient, and other factors recognized by those skilled in the art.

The materials used in the present invention may be incorporated with physiologically acceptable vehicles, carriers, excipients, binders, preservatives, stabilizers, flavoring agents, etc. in unit dosage forms required for generally accepted pharmaceutical practice. Ru.

The amount of active substance in these compositions or preparations is such that a suitable dosage within the indicated range will be obtained.

Specific agents that can be incorporated into the tablets, capsules, etc. are: binders such as tragantuan, gum arabic, corn starch or gelatin; excipients such as fine cellulose; Leavening agents such as cornstarch, pregelatinized starch, alginic acid, etc.; Lubricants such as magnesium stearate; Sweetening agents such as sucrose, lactose or saccharin; Flavoring agents such as peppermint, 7 duck/oil or cherry, When the dosage unit form is a capsule, materials of the above type can additionally contain a liquid carrier such as an oil or fat.

Various other materials can be present as coatings or to otherwise alter the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. A chimitube or elixir can contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

Sterile compositions for injection include the active substance dissolved or suspended in a vehicle such as water for injection, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil and the like or a synthetic fatty vehicle such as ethyl oleate and the like. It can be formulated according to normal formulation practices. Buffers, antioxidants, etc. can be combined as necessary.

Next, the present invention will be specifically explained using examples.

Ga2 (SO2), 18H201,88g (2,5m
An aqueous solution of 1.64 g (7.5 ml) of mol) dissolved in 40 ml of water is added and stirred at room temperature, immediately forming a precipitate.

30 minutes later G4. ? Collect by suction filtration using a lath filter,
The mixture was dried under reduced pressure in a calcium chloride desiccator overnight at room temperature to obtain 0.89 g of yellow powder (yield: 32%).

Elemental analysis: [Calculated value as Ga2(C4N2S2)sl C, 25.7%; N, 15.0%; S, 3
4.4% actual value C, 26.9%: N, 14.4%;
S, 36.8% infrared absorption spectrum: 1'! ! x(am-'): 460,530,900
,1110,1300,1520,1B30Gaz(S
o4)z・18H200,94g(1,2511+a+
ol) in 20 ml of water, a solution of 2,2-bis(carboxyethyl)ethylene-1,1-dithiolnicalium in 20 mN of water was added, and upon stirring at room temperature, a white precipitate was immediately formed. 30 minutes later G4. Collect by suction filtration using a lysed filter and place in a calcium chloride desiccator.
Dry in vacuum overnight in a vacuum chamber to obtain 0.28 g of white powder (yield 13%)
)was gotten.

Elemental analysis: [Calculated values as Gaz(CaHsOzSz)il; C, 34,22%; H, 3,59%;
S, 22.84% actual value; C, 33,69%; H
, 3,35%; S, 23.56% Infrared absorption spectrum: Br νll1ax(ca+-'): 650, 1150
, 1260 , 1605Gaz (So<): +・18
H200,94g (1,25n+mol) in water 20ml
1.40 g of 1,2-dicyanoethylene (7,
A solution of 5 mmol) dissolved in 20 mN of water is added and stirred at room temperature to form a yellowish white precipitate.

This was collected by suction filtration through a 64 glass filter, dried overnight under reduced pressure in a calcium chloride desiccator, and a yellow powder of 0.9
1 g (65% yield) was obtained.

Elemental analysis: Calculated values as Na, Ga (C4N2S2)3: C, 25.8%; N, 15.0%; S, 35.4%
Actual value: C, 25.7%; N, 15.1%; S, 36
．． 6% infrared absorption spectrum: ・≦Spoon (・・−・): 510,870,1150,1
460,2200Gaz(So-)s・18Hz0 0
．． 94g (1.25mmol) in 5mj of water! dissolved in
1,3-dithio-2-thousand 2.06 g (7,5 mmo
A solution prepared by dissolving 1) in water and oil is added and stirred at room temperature to form a precipitate. This was filtered through a G4ff glass filter and dried under reduced pressure in a calcium chloride desiccator overnight to obtain 0.87 g (yield: 45%) of brown powder.

Elemental analysis: Calculated value as Kz[Ga(C3Ss)s]:
C, 13.9%; S, 61.9% actual value: C,
14.4%; S, 59.8% Infrared absorption spectrum: Br νmax (cm-'): 460,525,910,1
030.1450Ga2(S0,)=”18HzOO
, 94 g (1,25 mmol) was dissolved in 20 rIIl of water, and 80 g (3,75 mmol) of 2-nitroethylene-1°0 was dissolved in 20 rIIl of water.
A solution of 20 mmol) of water is added and stirred at room temperature to form a brown-yellow precipitate. This is G4. Iy
It was collected by suction filtration using a glass filter, and dried under reduced pressure in a calcium chloride desiccator overnight to obtain 0.66 g of brown powder (yield: 44
%)was gotten.

Elemental analysis: Calculated values as [Ga2(C2HO2N S2)3]: C, 13,2%; H, 0,6%; N,
7.7%; S, 35.3% Actual value: C, 12.5%; H, 0.8%; N, 6.7
%; S, 33.8% Ga2(So4)z"18Hz0 1.88g (2,5
mmol) in 40 ha of water, 2.57 g (15.0 ma+ol) of sodium quethyldithiocarbamate
When an aqueous solution prepared by dissolving this in 40 ml of water is added and stirred at room temperature, the mixture begins to become cloudy. After stirring for 30 minutes, the mixture was collected by suction filtration using a G4 glass filter and washed with water. Dry under reduced pressure in a calcium chloride desiccator overnight at room temperature to give a white powder of 1.9
4 g (yield 75%) was obtained.

Elemental analysis: Calculated values as [Ga(CsHIOr'J S 2) 3]: C, 25, 1%; H, 4, 2%; N, 9
．． 8%; S, 44.7% Actual value: C, 25.1%; H, 4.2%; N, 9.7%
;S, 44.8% Infrared absorption spectrum Br νwax(am-'): 570,610,1110,
1260,1600Ga2(So<)s”18H201
, 88 g (2; 5 mnol) in 40 ml of water. dissolved in
Potassium xanthodate 2.40g (15, Ommol
) to 40m of water, i! Add an aqueous solution dissolved in and continue stirring at room temperature to form a white precipitate. G4. It was collected by suction filtration using a filtration filter, and dried under reduced pressure in a calcium chloride desiccator overnight at room temperature to give 1.17 g of white powder (yield 5.
4%) was obtained.

Elemental analysis: Ga (CzHsO32): + Calculated value: C, 24,9%; H, 3,5%; S, 44.4% Actual value: C, 24,0%; H, 3,3 %; S, 41.5%
Infrared absorption spectrum: ・H″-(...-): 805,1110,1260
, 1440, 1605 Example 8 NaK[Ga(Et
2dtc)F4]GaF3”3H201,808g(
10, Ommol) was dissolved in 50 mjj of 46% 7-hydrofluoric acid by heating and dissolving it in water. Add KF O, 581 to this solution.
g (10, Ommol) in 10 m of water, [! A solution dissolved in was added thereto, stirred at room temperature, and heated to dryness on a water bath to precipitate crystals.

After washing this with cold water, place it in a CaC1□ desiccator.
dried at room temperature and normal pressure in a
] 1.69 g (yield 77%) of white powder crystals were obtained.

K[GaF, (HzO)21 1,104g (5,Om
mol) in 100a+ffi of water by heating on a water bath, and add sodium diethyldithiocarbamate Et2dtcNa.3Hzo dissolved in 50ml of water.
When 1,127 g (5, OaIarol) was added, a white precipitate instantly formed. The residue was collected by suction filtration using a G3ff glass filter and dried under reduced pressure in a CaCl2 desiccator to obtain 0.93 g (yield: 56%) of white powdery crystals.

Elemental analysis: NaK (Ga(CsH+oN S 2)F 4)
Calculated value as C, 16,9%; H, 2,13%; N
, 3.9%; S, 18.0%; F, 21.3% Actual value C, 18.0%; H, 3.2%; N 4.2%;
S, 20.0%; F, 19.9% Infrared spectrum G a F 3.3H20 to K in the same manner as in Example 3
[GaF 4 (Hzo ) 2] was obtained. K[GaF
210.442 g (2,0 mmol) of 4(H2O) was dissolved in 80 mN of water by heating on a water bath, and 200,901 g of sodium diethyldithiocarbamate EtzdtcNa.3H (4, Oa
+mol), a white precipitate instantly occurs. G4
．． The residue was collected by suction filtration using a f7' Las filter and dried under reduced pressure in a calcium chloride tensor for about two weeks to obtain 0.79 g of white powdery crystals (yield: 89%).

Elemental analysis: Calculated values as K[Ga(CsH+oN32)2F2]: C, 27,1%; H, 4,6%; N,
6.3%; S, 28.9%; F, 8.6% Actual value; C, 28.9%; H, 4.4%; N, 8.3
%; S, 31.4%; F, 8.1% Infrared absorption spectrum: ・Shoji (...): 500,570,990,12
05,1270,1430.1500 K[GaF4(Hz/'tX14 Q
J-/l: ＾---1)? -1011-(Iy-k
The mixture was dissolved by heating on a l-prebath, toluene-3,4-dithi was added thereto, and the mixture was stirred at room temperature for 24 hours. The liquid turned from yellow to milky color and further changed to yellowish white. After cooling with water, G
4. The residue was collected by suction filtration using a lath filter and dried under reduced pressure in a CaCl2 desiccator to obtain 0.75 g (yield: 45%) of pale green powdery crystals.

Elemental analysis K[Ga(CtH+oOzSz) Calculated value as F21: C, 24,9%; H, 3,0%; S, 19
．． 0%F, 11.3% Actual value: C, 25.8%; H, 2.6%; S', 1
9.9% F, 11.0% infrared spectrum! /max(am-'): 480,740,10
30.1450 Example 11 ['”(CHO)2F2 IF ・(H20)2 K synthesized in the same manner as in Example 3 [G a F = (Hz
O)2]0.552g (2.5mmol) in 100mj
! of water by heating on a water bath. Add 2,
2'-noviridyl ()-()0, 781 g (5, O
A solution prepared by heating and dissolving 100 ml of water (100 ml of water) was added, and the mixture was stirred at room temperature for 7 hours. When this mixed solution is concentrated under reduced pressure using a rotary evaporator, the liquid turns pink.

After cooling in the refrigerator overnight, the formed crystals were filtered through a G4F lath filter and dried under reduced pressure in a CaCl2 desiccator for 8 days to obtain 0.73 g of pale pink powder crystals (yield 62%).
)was gotten.

Elemental analysis C2oH2o O2N -F -Ga Calculated values as a: c, s0, s%; H, 4,3%; N; 11
, 8%F, 12.0% Actual value: C, 49.2%; H, 3.9%; N, 1
1.0%F, 11.8% Infrared spectrum *(.・-・); 4'40,470,530,730
, 750, 1030, 1440 in 20 ml of water,
G 112(SO-)-・18H203,76g(5
mmol) and stir to completely dissolve.

While stirring, add 15 m2 (3 m2) of 2N NaOH aqueous solution.
When 0 mmol) is gradually added dropwise, the pH becomes approximately 7. ? If left overnight in a fr storage, the white crystals will discolor. G3: Collected by suction filtration using a lath filter and dried under reduced pressure in a calcium chloride desiccator overnight, yielding 2.76 g of white powder.
(yield 56%) was obtained.

Elemental analysis: [Calculated value as Ga(C=HsO<)il: C, 43.9%; H, 3.1% Actual value: C, 4
3,2%; H,3,4% Example 13 Antitumor activity test (1) Test animals ICR/CRJ mice (female) were used, 5 to 8 mice per group (
6 weeks old) was used.

(2) Test method (in vitro) The survival rate was examined using the day when 1 xio' Ehrlich ascites cancer cells were intraperitoneally transplanted into the mouse as day 0. Various Ga(II[) complex compounds prepared in Examples 1 to 11 were administered, and physiological saline was used as a control.

As shown in R1, the results show that Ga(III) of the present invention
The complex compound was found to exhibit excellent antitumor activity.

Table 1 1) The lysate was prepared with physiological saline. 2) The administration port was set as day 0 when the cancer was inoculated, and (-7 to -3
, +1 to +5) were administered from day -73 to day 13 and from day +1 to day 0 of +5.

Published 18th Edition (As is clear from the above examples, Ga(III) of the present invention
) The complex compound can be easily prepared and exhibits excellent activity as an anticancer agent.

Claims (1)

[Claims] 1) General formula Mm[Gan(L)pFq(H_2O)r]Fs(H_
A gallium complex compound represented by 2O)t. In the formula, m=0, 1, 2, 3, n=1, 2, p=1, 2,
3, q=0, 2, 3, 4, r=0, 2, S=0, 1, 3
, t=0, 2, M is a monovalent cation, L is a ligand, 1,1-dithiolite, 1,2-dithiolite, mono- or dialkyl carbamate anion, ethyl xanthate anion, 2,2-dipyridine, 2,
2',2''-terpyridine, 5-oxy-2-oxymethyl-γ-pyrone, 3-oxy-2-methyl-γ-pyrone, catechol, 2-hydroxy-1,4-benzoquinone, salicylic acid, salicylaldehyde, Represents any one of sulfur-containing, nitrogen-containing or oxygen-containing compounds selected from various glutathione ions, or their residues. 2) 1,1-dithiolite has ▲mathematical formulas, chemical formulas, tables, etc.▼, ▲Mathematical formulas, chemical formulas,
There are tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The gallium complex compound according to claim 1, which is a ligand selected from the group consisting of. 3) 1,2-dithiolite has ▲mathematical formula, chemical formula, table, etc.▼, ▲mathematical formula, chemical formula,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, in the formula, each R represents a lower alkyl group having 1 to 5 carbon atoms) The gallium complex compound according to claim 1, which is a ligand selected from the group consisting of: 4) General formula Mm[Gan(L)pFq(H_2O)r]Fs(H_
An anticancer agent containing at least one complex compound represented by 2O)t as an active ingredient. In the formula, m=0, 1, 2, 3, n=1, 2, p=1, 2,
3, q=0, 2, 3, 4, r=0, 2, S=0, 1, 3
, t=0, 2, M is a monovalent cation, L is a ligand, 1,1-dithiolite, 1,2-dithiolite, mono- or dialkyl carbamate anion, ethyl xantodecyate anion, 2,2-dipyridine, 2,
2',2''-terpyridine, 5-oxy-2-oxymethyl-γ-pyrone, 3-oxy-2-methyl-γ-pyrone, catechol, 2-hydroxy-1,4-benzoquinone, salicylic acid, salicyl Each represents any one type of sulfur-containing, nitrogen-containing or oxygen-containing compound selected from various ions such as aldehyde and glutathione, or a residue thereof.