JPH0558894A - Antitumor agent - Google Patents

Abstract

PURPOSE:A new antitumor agent containing a diisopropylbenzylidene heterocyclic compound exhibiting a thyroxinase activity as an active ingredient, and having low toxicity and strong safety. CONSTITUTION:An antitumor agent containing a 3,5-diisopropylbenzylidene heterocyclic compound of formula I [R<1> is H, benzyl; R<2> is H, acyl of formula COR<3> (R<3> is H, 1-3C alkyl), etc.; X<1> is group of formula II or III, etc.; Y<1> is CH2, group of formula II, etc.; i-Pr is isopropyl] or its salt as an active ingredient. 2--(3,5-Diisopropyl-4-hydroxybenzylidene)-1,4-benzothiazine-3-(4-hydro gen)- one-1,1-dioxide and 3-(3,5-diisopropyl-4-hydroxybenzylidene)-2-oxyindole are preferable as the compounds of formula I. The active ingredient of the formula I is preferably administered at a dose of 10-1000mg/kg several times a day, i.e., totally at a dose of 20-4000mg/kg a day.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel antitumor agent having low toxicity.

[0002]

The compounds used in the antitumor agent of the present invention are disclosed in JP-A-62-29570, JP-A-62-29579, JP-A-62-39522, JP-A-62-39523 and JP-A-62-39558. , JP 62-39564, JP
62-42923, JP 62-42925, JP 62-111962, JP
No. 63-141955, which is described in JP-A No. 63-222153 and is known.
However, these compounds are only known to have excellent antiallergic action and tyrosine kinase inhibitory action for their pharmacological actions.

[0003]

Many of the antitumor agents currently in use attack cancer cells and exert a tentative antitumor effect. However, they also show toxicity to normal cells and increase the patient's physical strength. Due to the problem of exhaustion, it is difficult to use for a long period of time, and often cannot completely cure the tumor. Therefore, today, development of a new antitumor agent that exhibits an antitumor effect without showing toxicity to normal cells is awaited.

[0004]

[Means for Solving the Problems] The present inventors have been interested in the physiology of cancer cells and the function of tyrosine kinases, and have synthesized various tyrosine kinase inhibitors, and have studied their physiological activity. The following general formulas (I) and (I
I), (III), (IV), (V), (VI), (VII), (VII
The compounds of I), (IX), (X), and (XI) that exhibit tyrosine kinase inhibitory activity strongly suppress the growth of cancer cells, while exhibiting a tyrosine kinase inhibitory activity despite their structural similarity. We found that none of the compounds suppressed the growth of cancer cells. Based on this knowledge, further research was conducted, and the following general formulas (I), (II), (III),
(IV), (V), (VI), (VII), (VIII), (IX),
The present invention was completed by finding that the compounds represented by (X) and (XI) have antitumor activity and extremely low toxicity.

That is, the present invention has the general formula (I):

[0006]

[Chemical 29]

Wherein R ¹ is a hydrogen atom or a benzyl group, R ² is a hydrogen atom, and COR ³ (R ³ is a hydrogen atom or a C ₁ -C ₃ alkyl group) or an phenyl group. , X ¹ is

[0008]

[Chemical 30]

(R ⁴ represents a hydrogen atom or a C ₁ -C ₃ alkyl group) or

[0010]

[Chemical 31]

(R ⁵ represents a hydrogen atom or a C ₁ -C ₃ alkyl group), --NHCO--, an oxygen atom or a sulfur atom, or X ¹ -Y ¹ is

[0012]

[Chemical 32]

(R ⁶ represents a hydrogen atom, a C ₁ -C ₃ alkyl group, a morpholino group or a phenyl group),

[0014]

[Chemical 33]

I-Pr represents an isopropyl group) 3,5-diisopropylbenzylidene heterocyclic compound represented by the general formula (II):

[0016]

[Chemical 34]

(In the formula, R ⁷ is a hydrogen atom, a C ₁ -C ₃ alkyl group, or

[0018]

[Chemical 35]

(M 1 represents an integer of ¹ to 3), R ⁸ is

[0020]

[Chemical 36]

(N ¹ is an integer of ¹ to 4, R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom or a C _{1 to} C ₃ alkyl group), or R ⁷ and R ⁸ are bonded to each other.

[0022]

[Chemical 37]

(O and p are the same or different and each represents an integer of 1 to 4, X ² represents an oxygen atom or NR ¹¹ (R ¹¹ represents a hydrogen atom or a C _{1 to} C ₃ alkyl group)) ,
i-Pr represents an isopropyl group), a 4-thiazolinone derivative represented by the general formula (III):

[0024]

[Chemical 38]

(In the formula, R ¹² is a hydrogen atom, a cyano group or amide, R ¹³ is an amide or CONHCONH ₂ , i-
3,5-diisopropyl-4-hydroxystyrene derivative represented by the general formula (I
V):

[0026]

[Chemical Formula 39]

Wherein R ¹⁴ is a carboxyl group or a carbamoyl group, R ¹⁵ is a C ₁ -C ₄ alkyl group, a cyano group or a hydroxyethyl group, and t-Bu is a tertiary butyl group. , 5-ditertiary butyl-4
-Hydroxystyrene derivative, general formula (V):

[0028]

[Chemical 40]

(Where R ¹⁶ is the formula:

[0030]

[Chemical 41]

(R ¹⁷ and R ¹⁸ are both OH or R
^At least one of R ¹⁷ and R ¹⁸ represents a phenoxy group) or a substituted phenyl group or a ferrocenyl group), an α-cyanoacrylic acid amide derivative represented by the general formula (VI):

[0032]

[Chemical 42]

(Where Ar is

[0034]

[Chemical 43]

(R ¹⁹ and R ²⁰ are the same or different, and C ₁
~C represents an alkyl group having ₄₎ or

[0036]

[Chemical 44]

The substituted phenyl group represented by: X ³ is-(C
H ₂ ) ₂ -or

[0038]

[Chemical formula 45]

Y ² represents an oxygen atom or NH) α-benzylidene-γ-butyrolactone or γ
-Butyrolactam derivative, general formula (VII):

[0040]

[Chemical formula 46]

(Wherein R ²¹ and R ²² are the same or different and each is a hydrogen atom, a hydroxyl group or a C ₁ -C ₄ alkoxy group, or R ²¹ is a phenoxy group and R ²² is a hydrogen atom; ²³ is a nitro group, R ²⁴ is a hydrogen atom, or R
²³ and R ²⁴ are combined to form -COOCH ₂ CH ₂ -or -C.
ONHCONH-), a styrene derivative represented by the general formula (VIII):

[0042]

[Chemical 47]

(In the formula, R ²⁵ is a C ₁ -C ₄ alkyl group,
R ²⁶ is a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group, and R ²⁷ is

[0044]

[Chemical 48]

An arylcarbamoyl group represented by R ²⁸
Is a hydrogen atom, or R ²⁷ and R ²⁸ are bonded to each other to -CO
X ⁴ CH ₂ CH ₂ — (X ⁴ is NH or

[0046]

[Chemical 49]

(R ²⁵ and R ²⁶ are the same as above))), a 4-alkoxystyrene derivative represented by the general formula (IX):

[0048]

[Chemical 50]

(In the formula, X ⁵ is a hydrogen atom, an alkoxy group represented by R ³³ O (R ³³ represents a C _{1 to} C ₃ alkyl group), a C _{1 to} C ₅ alkyl group, a nitro group, and an amino group. Base,
Hydroxyl group, halogen or COOR ³⁴ (R ³⁴ is C _{1 to} C ₃
Represents an alkyl group), R ²⁹ represents a hydrogen atom, a C ₁ -C ₃ alkyl group or R ³⁵ CO (R ³⁵ represents a phenyl group or a C ₁ -C ₃ alkyl group). The acyl group shown, R ³⁰ is a hydrogen atom or a C ₁ -C ₅ alkyl group, R ³¹ is COOR ³⁶ (R ³⁶
Represents a hydrogen atom or a C _{1 to} C ₄ alkyl group) or amide, R ³² represents a cyano group or an alkylsulfonyl group represented by R ³⁷ SO ₂ (R ³⁷ represents a C _{1 to} C ₄ alkyl group), Or R ³¹ and R ³² are bonded to each other

[0050]

[Chemical 51]

(R ³⁸ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, Y ³ represents an oxygen atom or NH) or

[0052]

[Chemical 52]

N ² is an integer of 1 to 5 when X ⁵ is halogen, 0 or 1 in other cases, and m ² is an integer of 0 to 3), a 3-phenylthiomethylstyrene derivative, General formula (X):

[0054]

[Chemical 53]

(In the formula, R ³⁹ and R ⁴⁰ are the same or different and are a hydrogen atom or a C _{1 to} C ₃ alkyl group, R ⁴¹ and R ^40.
42 are the same or different,

[0056]

[Chemical 54]

, Ph represents a phenyl group) and a general formula (XI):

[0058]

[Chemical 55]

(In the formula, R ⁴³ is a hydrogen atom or C _{1 to} C ₃
The alkyl group of R ⁴⁴ is

[0060]

[Chemical 56]

(R ⁴⁵ represents a hydrogen atom, a C ₁ -C ₃ alkyl group, a phenyl group or a benzyl group, and R ⁴⁶ represents a phenyl group or a benzyl group) or a phenoxy group. The present invention relates to an antitumor agent containing a salt of an α-cyanocinnamic acid amide derivative or a salt-forming compound thereof.

[0062]

EXAMPLES In the 3,5-diisopropylbenzylidene heterocyclic compound represented by the general formula (I) of the present invention, R ¹
Is a hydrogen atom or a benzyl group, R ² is a hydrogen atom or C
An acyl group represented by OR ³ (R ³ is the same as above), X ¹
But

[0063]

[Chemical 57]

(R ⁴ is the same as above) or

[0065]

[Chemical 58]

, --NHCO--, an oxygen atom or a sulfur atom, or X ¹ --Y ¹ is

[0067]

[Chemical 59]

The following are preferred.

Among the compounds included in the general formula (I), a particularly preferable compound is 2- (3,5-diisopropyl-4-hydroxybenzylidene) -1,4-benzothiazine-3- (4 -Hydrogen) -one-1,1-dioxide (Compound A):

[0070]

[Chemical 60]

3- (3,5-diisopropyl-4-hydroxybenzylidene) -2-oxindole (Compound B):

[0072]

[Chemical formula 61]

And the like.

In the 4-thiazolinone derivative represented by the general formula (II) of the present invention,

[0075]

[Chemical formula 62]

Is preferred.

Among the compounds included in the general formula (II), a particularly preferable compound is 5- (3,5-diisopropyl-4-hydroxybenzylidene) -2- (N ', N'-
Dimethylethyl) amino-1,3-thiazol-4-one (Compound C):

[0078]

[Chemical formula 63]

5- (3,5-diisopropyl-4-hydroxybenzylidene) -2- (4-methylpiperazinyl) -1,3-thiazol-4-one (Compound D):

[0080]

[Chemical 64]

And the like.

In the 3,5-diisopropyl-4-hydroxystyrene derivative represented by the general formula (III) of the present invention, R is
¹² is a hydrogen atom or a cyano group, R ¹³ is an amide or -C
Those which are ONHCONH ₂ are preferred.

Among the compounds included in the above general formula (III), a particularly preferable compound is α-cyano-3,5-
Diisopropyl-4-hydroxycinnamic acid amide (Compound E):

[0084]

[Chemical 65]

And the like.

In the 3,5-ditertiary-butyl-4-hydroxystyrene derivative represented by the general formula (IV) of the present invention, it is preferable that R ¹⁴ is a carbamoyl group and R ¹⁵ is a cyano group or a hydroxyethyl group. .

Among the compounds included in the above general formula (IV), a particularly preferable compound is α-cyano-3,5-
Ditert-butyl-4-hydroxycinnamic acid amide (Compound F):

[0088]

[Chemical formula 66]

And the like.

In the α-cyanoacrylic acid amide derivative represented by the general formula (V) of the present invention,

[0091]

[Chemical formula 67]

Is preferred.

Among the compounds included in the general formula (V), a particularly preferable compound is α-cyano-3-phenoxycinnamic acid amide (Compound G):

[0094]

[Chemical 68]

And the like.

In the α-benzylidene-2-butyrolactone or γ-butyrolactam derivative represented by the general formula (VI) of the present invention,

[0097]

[Chemical 69]

Is preferred.

Among the compounds included in the general formula (VI), a particularly preferable compound is 3- (3,5-dimethylthiomethyl-4-hydroxybenzylidene) -2-oxindole (Compound H):

[0100]

[Chemical 70]

3- (3,5-diphenylmethyl-4-hydroxybenzylidene) -2-oxindole (Compound I):

[0102]

[Chemical 71]

Examples thereof include 3- (3,5-dimethylthiomethyl-4-hydroxybenzylidene) -2-pyrrolidinone.

In the styrene derivative represented by the general formula (VII) of the present invention, R ²¹ and R ²² are the same or different hydroxyl groups or C ₁ -C ₂ alkoxy groups, R ²³ is a nitro group,
R ²⁴ is a hydrogen atom or R ²³ and R ²⁴ are bonded to -COOC
H ₂ CH ₂ - or a is is preferable -CONHCONH-.

Among the compounds included in the general formula (VII), a particularly preferable compound is α- (2,5-dihydroxybenzylidene) -γ-butyrolactone (Compound J):

[0106]

[Chemical 72]

And the like.

In the 4-alkoxystyrene derivative represented by the general formula (VIII) of the present invention, R ²⁵ is a C ₁ -C ₃ alkyl group, and R ²⁶ is a C ₁ -C ₃ alkyl group or C ₁ -C _3.
C ₃ alkoxy group, R ²⁷ is

[0109]

[Chemical formula 73]

An allylcarbamoyl group represented by: R ²⁸ is a hydrogen atom, or R ²⁷ and R ²⁸ are bonded to each other to form —COX ⁴ CH.
₂ CH ₂ — (X ⁴ is the same as above) is preferred.

Among the compounds included in the above general formula (VIII), 3,4-dimethoxy-2 is particularly preferable.
-Hydroxycinnamic acid anilide (Compound K):

[0112]

[Chemical 74]

And the like.

In the 3-phenylthiomethylstyrene derivative represented by the general formula (IX) of the present invention, X ⁵ is a hydrogen atom, halogen, R ³³ O (R ³³ is the same as the above) or C ₁
To C ₅ alkyl group, R ²⁹ is hydrogen atom, R ³⁰ is hydrogen atom or C _{1 to} C ₅ alkyl group, and R ³¹ is COOR ³⁶ (R
³⁶ is the same as above) or amide, R ³² is a cyano group or R ³⁷ SO ₂ (R ³⁷ is the same as above), or R ³¹ and R ³² are bonded to each other.

[0115]

[Chemical 75]

The following are preferred, and specifically,

[0117]

[Chemical 76]

[0118]

[Chemical 77]

[0119]

[Chemical 78]

[0120]

[Chemical 79]

Is preferred.

Of the compounds included in the above general formula (IX), a particularly preferable compound is α-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamic acid amide (Compound L):

[0123]

[Chemical 80]

4- (3-ethoxy-4-hydroxy-5-phenylthiomethylbenzylidene) -1-phenylpyrazolidine
-3,5-dione (Compound M):

[0125]

[Chemical 81]

3- (3-Ethoxy-4-hydroxy-5-phenylthiomethylbenzylidene) -2-pyrrolidinone (Compound N):

[0127]

[Chemical formula 82]

And the like.

In the tribenzylamine derivative represented by the general formula (X) of the present invention, R ³⁹ and R ⁴⁰ are both ethyl groups, and R ⁴¹ and R ⁴² are both

[0130]

[Chemical 83]

The following are preferred, and specifically,

[0132]

[Chemical 84]

[0133]

[Chemical 85]

[0134]

[Chemical 86]

Is preferred.

Among the compounds included in the above general formula (X), a particularly preferable compound is N, N-bis [5- (2 '
-Carbamoyl-2'-cyanoethenyl) -3-ethoxy
-2-Hydroxybenzyl] benzylamine (Compound O):

[0137]

[Chemical 87]

N, N-bis [5- (2'-benzylamino-4'-
Oxo-1 ′, 3′-thiazolideenemethyl) -3-ethoxy-2-hydroxybenzyl] benzylamine (Compound P):

[0139]

[Chemical 88]

And the like.

In the α-cyanocinnamic acid amide derivative represented by the general formula (XI) of the present invention, R ⁴³ is a hydrogen atom or a C ₁ -C ₃ alkyl group, and R ⁴⁴ is

[0142]

[Chemical 89]

A group represented by (R ⁴⁵ and R ⁴⁶ are the same as above) is preferable.

Among the compounds included in the above general formula (XI), a particularly preferable compound is α-cyano-3-diphenylamino-5-ethoxy-4-hydroxycinnamic acid amide (compound Q):

[0145]

[Chemical 90]

And the like.

The above general formulas (I), (II), (III) and (I
V), (V), (VI), (VII), (VIII), (IX),
The methods for producing the derivatives represented by (X) and (XI) are described in JP-A-62-29570, JP-A-62-29579, and JP-A-62-3952, respectively.
2, JP-A-62-39523, JP-A-62-39558, JP-A-62-3956
4, JP-A-62-42923, JP-A-62-42925, JP-A-62-111962
, JP-A-63-141955 and JP-A-63-222153.

The above-mentioned active ingredient used in the present invention may be administered in any dose as long as it shows no toxicity to patients (animals and humans) in need of treatment. It can be administered in a dose range of 1000 mg / kg, generally in several divided doses, and thus a total daily dose of 20 to 4000 mg / kg per day. The dose can vary depending on the severity of the illness, the weight of the patient and other factors recognized by those of skill in the art.

The antitumor agent of the present invention is prepared as a solid preparation or a liquid preparation and administered orally or parenterally.
Solid formulations for oral administration include powders, granules, tablets, pills,
Liquid formulations for parenteral and oral administration, such as capsules,
It can be used in the form of elixirs, suspensions, emulsions, syrups, alcohol solutions, oily solutions and the like.

Examples of solid carriers for pharmaceutical use include lactose, starch, sucrose, mannitol, sorbit, dextrin, cellulose, calcium carbonate, etc., and if necessary, suitable auxiliary agents such as lubricants and binders are added. can do. As the liquid carrier for medicine, there are water, ethanol, glycerin, propylene glycol, vegetable oil, a common solvent such as oily ester, and if necessary, a suitable wetting agent, suspending agent, emulsifier, sweetener, flavoring agent, preservative, etc. Auxiliaries can be added.

The antitumor agent of the present invention exhibits an excellent antiproliferative effect on various tumor cells, as well as toxicity, as is clear from the test results for human tumors transplanted into nude mice and human tumor-derived cells described later. Kai 62-29570, JP 62-29579, JP 62-39522, JP 62-39523, JP 62
62-39558, JP-A-62-39564, JP-A-62-42923, JP-A-62
-42925, JP 62-111962, JP 63-141955, JP
Both are extremely low as described in 63-222153. Therefore, the compounds of the present invention are useful as safe and potent antitumor agents.

Hereinafter, the pharmacological action and effect of the antitumor agent of the present invention will be described in detail with reference to experimental examples, but the present invention is not limited to such examples.

Cancer Cell Proliferation Inhibitory Example 1 Alpha Minimal Essential Medium (hereinafter abbreviated as Alpha MEM) containing 10% (volume%) fetal calf serum (hereinafter abbreviated as FCS). Gibco BRL ( Human oral cancer-derived cancer cell line MH- grown in a semi-confluent manner in GIBCO BRL)
After trypsinization of 85, alpha ME containing 10% FCS
The cells were suspended at a cell concentration of 1 × 10 ⁵ cells / ml using M, and the suspension was placed in a 96-well multiwell dish at 100 μ / well.
It was dispensed in liters. Then, after culturing at 37 ° C. under 5% CO ₂ for 24 hours, the medium was removed and 100 μl of serum-free alpha-MEM containing the serially diluted test compound was added. The solvent in which the test compound was dissolved was added to the control wells. As the test compound, the compound L and the compound L
Α-Cyano-4-hydroxycinnamic acid amide (Compound R) which does not exhibit tyrosine kinase activity in the structural analogue of (Compound R) (Cancer Research, Vol. 49, 2374-
2378, (1989)) was used. Cultured for 24 hours after addition of the test compound, then [methyl - ³ H] thymidine ^{([methyl - 3 H] Tymidine} ) ( Amersham (Amersham
18.5 KBq) was added to each well, and the cells were cultured for 4 hours to incorporate [ ³ H] thymidine into the proliferating cells. After washing the cells with Ca ⁺⁺ and Mg ⁺⁺ free phosphate buffer (hereinafter abbreviated as CMF-PBS), 100 μl of 0.25% trypsin / 0.02 was added per well.
% Ethylenediaminetetraacetic acid disodium (hereinafter EDTA
The cells are recovered as a suspension by adding a liquid and incubating at 37 ° C. for 10 minutes.
It was placed in a vial containing ml of liquid scintillator ACS-II, and the radioactivity taken up by the cells was measured by a liquid scintillation counter. Table 1 shows the average radioactivity and the standard deviation (SD) of the results examined with n = 6. Compound L, which exhibits tyrosine kinase inhibitory activity, is MH-85 [ ³
H] thymidine uptake was strongly inhibited, but Compound R, which does not show tyrosine kinase inhibitory activity, did not inhibit at all.

[0154]

[Table 1]

Example 2 A human oral cancer cell line HSC-2, a human tongue cancer cell line HSC-3, was added to each well of a 24-well multi-well dish.
Human breast cancer-derived cell lines ZR-75-1 and MCF-7, human colon cancer-derived cell lines LOVO and DLD-1, human lung cancer-derived cell line PC-9, human gastric cancer-derived cell line KATOII
I, human endometrial cancer-derived cell line HEC-1, human cervical cancer-derived cell line HeLaS ₃ , human bladder cancer-derived cell line E
1 ml of a cell suspension in which J-1 was suspended at a concentration of 10 ⁵ cells / ml was added, and the cells were cultured at 37 ° C. under 5% CO ₂ for 4 hours to adhere the cells to the dish, and then the cells were plated on each well. Diluted test compound was added. The solvent in which the test compound was dissolved was added to the control wells. After that, [Methyl-
³ H] thymidine ([methyl- ³ H] Tymidine) (manufactured by Amersham) was added to each well at 37 Bq, and the culture was continued. After 16 hours, the cells were washed 3 times with 1 ml of phosphate-buffered saline (hereinafter abbreviated as PBS) per well, then 500 μl of 10% trichloroacetic acid solvent was added and allowed to stand for 10 minutes. 400 μl of 0.5 N-N
Dissolve with aOH solution, neutralize with glacial acetic acid, put 30 μl of the solution into a vial, and liquid scintillator ACSII
2 ml was added and the radioactivity was measured using a liquid scintillation counter. Measurement was carried out at n = 2, and based on the obtained results, the concentration of each compound at which cancer cell growth was inhibited by 50% was determined and shown in Table 2.

[0156]

[Table 2]

Example 3 BALB / C-nu / JCL mice were subcutaneously transplanted 50
Human oral cancer MH-85 grown daily was removed into sterile drops, and about 5-6 mm square (about 100 mg) was taken from one group of 5 BALB / C.
-Nu / JCL mice (6 weeks old, male) were transplanted subcutaneously into the flank. 24 hours after transplantation, compound L was added to 200 μ / mouse
g Intraperitoneal administration once a day for 21 days continuously, 15 days, 30 days
On days 49, 59, the major and minor diameters of the tumor were measured, the tumor size (mm ³ ) was calculated, and the tumor growth inhibition rate of the compound L-administered group relative to the control group was calculated using the following formula and compared. did.

[0158]

[Equation 1]

The results are shown in Table 3.

[0160]

[Table 3]

[0161]

INDUSTRIAL APPLICABILITY The present invention provides a safe and potent antitumor agent with low toxicity.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 31/12 8413-4C 31/16 8413-4C 31/165 8413-4C 31/22 8413-4C 31/27 8413-4C 31/275 8413-4C 31/34 7252-4C 31/365 7252-4C 31/40 7252-4C 31/415 7252-4C 31/505 7252-4C 31/535 7252-4C C07D 209 / 34 9283-4C 231/20 6701-4C 307/33 // C07D 207/38 7019-4C 233/32 7252-4C 277/54 7019-4C 279/16 8314-4C

Claims (11)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ is a hydrogen atom or a benzyl group, R ² is a hydrogen atom, COR ³ (R ³ represents a hydrogen atom or a C _{1 to} C ₃ alkyl group), an acyl group or a phenyl group, X ¹ Is (R ⁴ represents a hydrogen atom or a C ₁ -C ₃ alkyl group) or (R ⁵ represents a hydrogen atom or a C ₁ -C ₃ alkyl group), —NHCO—, an oxygen atom or a sulfur atom, or X ¹ —Y ¹ is (R ⁶ represents a hydrogen atom, a C ₁ -C ₃ alkyl group, a morpholino group or a phenyl group), And i-Pr represents an isopropyl group), an antitumor agent containing, as an active ingredient, a 3,5-diisopropylbenzylidene heterocyclic compound or a salt of a salt-forming compound thereof. 2. General formula (II): (In the formula, R ⁷ is a hydrogen atom, a C ₁ -C ₃ alkyl group, or (M 1 represents an integer of ¹ to 3), R ⁸ is (N ¹ is an integer of ¹ to 4, R ⁹ and R ¹⁰ are the same or different and represent a hydrogen atom or a C _{1 to} C ₃ alkyl group), or R ⁷ and R ⁸ are bonded to each other. ] (O and p are the same or different and are integers of 1 to 4, X ² is an oxygen atom or N—R ¹¹ (R ¹¹ is a hydrogen atom or C _{1 to} C)
₃ represents an alkyl group of ₃ ), i-Pr represents an isopropyl group) or an antitumor agent containing a salt of a 4-thiazolinone derivative or a salt-forming salt thereof as an active ingredient. 3. General formula (III): (In the formula, R ¹² represents a hydrogen atom, a cyano group or an amide, and R ¹³
Is an amide or CONHCONH ₂ , and i-Pr represents an isopropyl group) 3,5-diisopropyl-4-
An antitumor agent containing a salt of a hydroxystyrene derivative or a salt-forming salt thereof as an active ingredient. 4. General formula (IV): (In the formula, R ¹⁴ is a carboxyl group or a carbamoyl group,
R ¹⁵ is a C ₁ -C ₄ alkyl group, a cyano group or a hydroxyethyl group, and t-Bu is a tertiary butyl group) 3,5-ditertiarybutyl-4-hydroxystyrene derivative or a salt thereof. An antitumor agent containing a salt of possible substances as an active ingredient. 5. A compound represented by the general formula (V): (In the formula, R ¹⁶ is the formula: (Wherein R ¹⁷ and R ¹⁸ are both OH or at least one of R ¹⁷ and R ¹⁸ represents a phenoxy group) represents a substituted phenyl group or a ferrocenyl group) or an α-cyanoacrylic acid amide derivative An antitumor agent containing a salt of a salt-forming substance as an active ingredient. 6. General formula (VI): (In the formula, Ar is (R ¹⁹ and R ²⁰ are the same or different and represent a C _{1 to} C ₄ alkyl group) or A substituted phenyl group represented by and X ³ is-(CH ₂ ) ₂ -or Y ² represents an oxygen atom or NH), and is an antitumor agent containing an α-benzylidene-γ-butyrolactone or γ-butyrolactam derivative or a salt of a salt-forming compound thereof as an active ingredient. 7. A compound represented by the general formula (VII): (In the formula, R ²¹ and R ²² are the same or different and are a hydrogen atom,
A hydroxyl group or a C ₁ -C ₄ alkoxy group, R ²¹ represents a phenoxy group, R ²² represents a hydrogen atom, and R ²³
Is a nitro group, R ²⁴ is a hydrogen atom, or R ²³ and R ²⁴ are combined to form —COOCH ₂ CH ₂ — or —CONHCONH.
An antitumor agent containing a styrene derivative represented by-) or a salt of a salt-forming compound thereof as an active ingredient. 8. A compound represented by the general formula (VIII): (In the formula, R ²⁵ is a C ₁ -C ₄ alkyl group, and R ²⁶ is a C ₁ -C ₄ alkyl group.
C ₄ alkyl group or C ₁ -C ₄ alkoxy group, R
²⁷ is [Chemical 20] An arylcarbamoyl group represented by, R ²⁸ is a hydrogen atom,
Or R ²⁷ and R ²⁸ are bonded to each other to form —COX ⁴ CH ₂ C
H ₂ — (X ⁴ is NH or (R ²⁵ and R ²⁶ are the same as the above))), and an antitumor agent containing a salt of a 4-alkoxystyrene derivative or a salt-forming salt thereof as an active ingredient. 9. General formula (IX): (In the formula, X ⁵ is a hydrogen atom, an alkoxy group represented by R ³³ O (R ³³ represents a C _{1 to} C ₃ alkyl group), C ₁ to
C ₅ alkyl group, nitro group, amino group, hydroxyl group, halogen or alkoxycarbonyl group represented by COOR ³⁴ (R ³⁴ represents a C _{1 to} C ₃ alkyl group), R ²⁹ is hydrogen atom, C _{1 to} C ₃ alkyl group or R ³⁵ CO (R
³⁵ represents a phenyl group or a C _{1 to} C ₃ alkyl group), and R ³⁰ represents a hydrogen atom or C ₁ to C ₃ .
C ₅ alkyl group, R ³¹ is COOR ³⁶ (R ³⁶ represents a hydrogen atom or a C ₁ -C ₄ alkyl group) or amide, R ³² is a cyano group or R ³⁷ SO ₂ (R ³⁷ is C ₁ -C
₄ represents an alkyl group of ₄ ), or R ³¹ and R ³² are bonded to each other. (R ³⁸ is a hydrogen atom or a C ₁ -C ₄ alkyl group, Y ³
Represents an oxygen atom or NH) or And n ² is an integer of 1 to 5 when X ⁵ is halogen,
In other cases, an antitumor agent containing a 3-phenylthiomethylstyrene derivative represented by 0 or 1, and m ² represents an integer of 0 to 3) or a salt of a salt-forming salt thereof as an active ingredient. 10. General formula (X): (Wherein R ³⁹ and R ⁴⁰ are the same or different, a hydrogen atom or a C _{1 to} C ₃ alkyl group, R ⁴¹ and R ⁴² are the same or different, and , Ph represents a phenyl group), or an antitumor agent containing as an active ingredient a salt of a tribenzylamine derivative or a salt-forming salt thereof. 11. A compound represented by the general formula (XI): (In the formula, R ⁴³ is a hydrogen atom or a C ₁ -C ₃ alkyl group, and R ⁴⁴ is (R ⁴⁵ represents a hydrogen atom, a C ₁ -C ₃ alkyl group, a phenyl group or a benzyl group, and R ⁴⁶ represents a phenyl group or a benzyl group) or an phenoxy group. An antitumor agent containing, as an active ingredient, a cinnamic acid amide derivative or a salt thereof capable of forming a salt.