JPH10168090A - Apoptotic inducer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare an apoptotic inducer useful for treatment, etc., of malignant tumor, leukemia, proliferative dermatosis, autoimmune diseases, HIV infection, hepatitis, renopathy, etc., by using a specific isopreniod derivative as an active ingredient. SOLUTION: This apoptotic inducer is prepared by using (6E,10E,14E,18E,22 E,26E)-3,7,11,15,19,23,17-heptamethyloctacosa-6,10,14,18,22,26-hexaenyl diammonium phosphate or (6E,10E14E,18E,22E,26E,30E,34E,38E)-3,7,11,15,19,23,27,31,35,39- decamethyltetraconta-6,10,14,18,22,30,34,38-nonaenyl diammonium phosphate as an isoprenoid derivative in the apoptotic inducer comprising the isoprenoid derivative represented by the formula [(n) is an integer of 5-10] as an active ingredient or its pharmacologically permissible salt. Thereby, the apoptotic inducer is useful for a therapeutic agent, an improving agent, etc., for various diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an apoptosis inducer,
More specifically, the present invention relates to a therapeutic / ameliorating agent for malignant tumor, leukemia, proliferative skin disease, rheumatoid arthritis, autoimmune disease, HIV infection, hepatitis, renal disease and the like.

[0002]

BACKGROUND OF THE INVENTION Apoptosis is a form of aggressive cell death, contrasted with necrosis. In apoptosis, a complex biochemical reaction occurs with the activation of cells, producing various proteins and DNA-degrading enzymes, which act on their own cells to cause cell death. Apoptosis is a physiological cell death that is indispensable for normal development / differentiation, and occurs in individual cells during normal biological tissue cell rotation and the like.
Therefore, excessive suppression of apoptosis causes many functional disorders.

[0003] Specifically, these disorders caused by suppression of apoptosis include malignant neoplasms, leukemias, proliferative skin diseases, rheumatoid arthritis, autoimmune diseases, HIV infection, hepatitis, renal diseases, and the like. At present, there is no effective therapeutic agent in any case, and a therapeutically / improving agent with high clinical utility has been demanded. Moreover, even if it is essential for normal biological functions, overexpression of apoptosis causes various diseases including neurodegenerative diseases.
Specifically, disorders caused by overexpression of these apoptosis include therapeutic agents for Alzheimer's disease, Parkinson's disease,
Diseases such as Down syndrome, diabetic neuropathy, neurodegenerative disease, diabetes, radiation exposure disorder, gastrointestinal tract disorder caused by anticancer drugs, etc., but the mechanism of apoptosis has not yet been elucidated, and all are still effective treatments At present, there is no drug, and there is no appropriate evaluation system that reflects the clinical situation.

[0004]

2. Description of the Related Art For example, WO-96 / 11686 discloses a novel heterocyclic compound having a acetylene side chain, which has a retinoid-like activity and also has an ability to induce apoptosis.
WO-96 / 17626 discloses an invention relating to a water-soluble ubiquinone preparation used for improving apoptosis.

[0005]

[Problems to be solved by the present invention] However, substances having a retinoid action generally have a problem of easily causing excessive disease, and the frequency of occurrence of side effects such as liver damage or kidney damage has been high. In addition, ubiquinone has not yet been confirmed to have a clinical apoptosis-inducing effect, and its usefulness was unknown.

[0006] Therefore, at present, there is no apoptosis inducing agent which has a useful effect for treating / improving various diseases and is also excellent in safety, and the development of new drugs is strongly desired. Was. In addition, overexpression of apoptosis is considered to be involved in its onset Alzheimer's disease therapeutic agent, Parkinson's disease, Down's syndrome, diabetic neuropathy, neurodegenerative disease, diabetes, radiation exposure disorders, gastrointestinal disorders caused by anticancer drugs, etc. At present, there is no appropriate model system that reflects a reaction occurring in a living body. Apoptosis caused by dolichol phosphate derived from living organisms may be involved in the establishment of these diseases, and substances that suppress apoptosis caused by dolichol phosphate or a substance that causes apoptosis by the same mechanism It can be a very effective treatment for the disease. However, since dolichol phosphate has low water solubility, it was extremely difficult to construct an apoptosis evaluation system.

[0007]

DISCLOSURE OF THE INVENTION The present inventors have long studied the mechanism of apoptosis, and have also searched for a clinically useful therapeutic / ameliorating drug based on apoptosis-inducing action. As a result, the isoprenoid derivative represented by the following general formula or a pharmacologically acceptable salt thereof, which is unexpectedly very similar to a natural product, has an extremely excellent apoptosis-inducing effect and has high water solubility. Thus, the present inventors have found that the intended purpose can be achieved as a main component of an evaluation system for various cell proliferative disease therapeutic agents or various cell degenerative disease therapeutic agents, and completed the present invention.

[0008]

Embedded image

(Wherein, n represents an integer of 5 to 10).

[0010] Accordingly, an object of the present invention is to provide an apoptosis-inducing agent which has no clinically effective drug, more specifically,
Apoptosis inducer, more specifically malignant tumor, leukemia,
Proliferative skin disease, rheumatoid arthritis, autoimmune disease, HI
It provides novel therapeutic and ameliorating agents with high clinical utility and excellent safety for V infection, hepatitis, renal disease, etc., as well as therapeutic agents for Alzheimer's disease, An object of the present invention is to construct an evaluation system that reflects the clinical treatment of a therapeutic agent for a disease such as Down syndrome, diabetic neuropathy, neurodegenerative disease, diabetes, radiation exposure disorder, and gastrointestinal tract disorder caused by an anticancer drug.

In addition, Biochemical and Biophysical Rese
arch Communications, 216 (3), 848-853, 1995. or 224 (1), 87-91, 1996. describe that the natural isoprenoid dolicholic acid has the ability to induce apoptosis. Have been. However, dolichol phosphate has an extremely high molecular weight and is not normally absorbed even when administered orally, and is likely to be ineffective clinically. Also, Jo
urnal of Biochemistry, 117 (1), 11-13, 1995. and Bi
ochemical and Biophysical Research Communications,
225 (3), 869-879, 1996.provides that similar isoprenoids such as geranylgeraniol having 20 carbon atoms and 4 double bonds have the ability to induce apoptosis, or
Biochemical and BiophysicalResearch Communication
s, 219 (1), 100-104, 1995. describe that 4,5-didehydrogeranylgeranilic acid, a didehydro form of a carboxylic acid derivative of geranylgeraniol, has apoptosis-inducing ability.

However, the present inventors have found that geranylgeraniol phosphate, a phosphate ester of geranylgeraniol or farnesol phosphate having a shorter chain length, has no apoptosis-inducing ability, and that α = n = 6 to 10 It has also been found that a saturated isoprenoid phosphate ester has an extremely excellent effect.

The isoprenoid derivative according to the present invention can be more specifically exemplified by the following compounds, but the present invention is not limited thereto. (1) Phosphoric acid (6E, 10E, 14E, 18E, 22E, 26E) -3,7,11,15,19,2
3,27-heptamethyloctacosa-6,10,14,18,22,26-hexaenyl diammonium (hereinafter HMOP) (2) Phosphoric acid (6E, 10E, 14E, 18E, 22E, 26E, 30E, 34E, 38E) -3,
7,11,15,19,23,27,31,35,39-Decamethyltetraconta
6,10,14,18,22,26,30,34,38-Nonaenyl diammonium (DMTP)

The isoprenoid derivative according to the present invention can be synthesized in a short step from a natural isoprenoid sold as a reagent, a pharmaceutical intermediate or an industrial raw material.

The isoprenoid derivative according to the present invention has a double bond in the molecule and has geometric isomers. However, the present invention is not limited to this, and any single geometric isomer may be used. Or a mixture of two or more. However, from the viewpoint of pharmacological activity, all trans
(E-form) is more preferable, but the present invention is not limited to this. It may be a hydrate. Further, the isoprenoid derivative according to the present invention may be in a free form (free form) or a pharmacologically acceptable salt thereof. When a salt is formed, specific examples thereof include an addition salt of an alkali metal, an addition salt of an alkaline earth metal, an ammonium salt, and an addition salt of an amine. An ammonium salt is more preferable.

The isoprenoid derivative according to the present invention has an extremely high LD50 value that cannot be measured experimentally and is extremely safe.

Next, the dosage form of the compound of the present invention includes, for example, oral preparations such as powders, fine granules, granules, tablets, coated tablets and capsules, external preparations such as ointments and patches, suppositories and injections Preparations and the like. At the time of formulation, it can be produced by a conventional method using a usual pharmaceutical carrier.

That is, in producing an oral preparation, an isoprenoid derivative and an excipient, and if necessary, an antioxidant, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent and the like are added. Powders, fine granules, granules, tablets, coated tablets, capsules and the like are prepared by a conventional method.

Examples of the excipient include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide, and the like.
For example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol polyoxyethylene block polymer, meglumine, etc. For example, starch, agar, gelatin powder,
Microcrystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethylcellulose / calcium, etc., as lubricants, for example, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc., as coloring agents for pharmaceuticals Those that are permitted to be added include cocoa powder, peppermint brain, aromasan, peppermint oil, dragon brain, cinnamon powder and the like as flavoring agents. Of course, these tablets and granules can be sugar-coated and optionally coated as needed.

In preparing an injectable preparation, a pH adjuster, a solubilizer, an isotonic agent and the like are added to the isoprenoid derivative.
If necessary, a solubilizing agent, a stabilizing agent, an antioxidant and the like are added, and the preparation is made by a conventional method.

The method for producing the external preparation is not limited.
It can be manufactured by an ordinary method. In other words, base materials used in the formulation include pharmaceuticals, quasi-drugs,
Various raw materials usually used for cosmetics and the like can be used.

Specific examples of the base material used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, alcohols, polyhydric alcohols, and the like. Examples include raw materials such as water-soluble polymers, clay minerals, and purified water, and further, if necessary, a pH adjuster, an antioxidant, a chelating agent, an antiseptic / antifungal agent,
Colorants and fragrances can be added, but the base material of the external preparation according to the present invention is not limited to these. If necessary, components such as a blood flow promoter, a bactericide, an anti-inflammatory agent, a cell activator, vitamins, amino acids, a humectant, a keratolytic agent, and the like can be added. The amount of the base material to be added is an amount that usually results in a concentration set in the production of an external preparation.

The clinical dose of the isoprenoid derivative in the present invention is not limited and varies depending on symptoms, severity, age, complications and the like, and also varies depending on the kind of salt, administration route, etc., but usually 10 mg per adult per day. 2000 mg, preferably 30 mg to 1500 mg, more preferably
50 mg to 1000 mg, administered orally, intravenously, intramuscularly, rectally or transdermally.

Next, with respect to typical examples of the isoprenoid derivatives according to the present invention, production examples thereof are shown below. However, it goes without saying that the isoprenoid derivative according to the present invention is not limited to these.

Production Example 1 Phosphoric acid (6E, 10E, 14E, 18E, 22E, 2
6E) -3,7,11,15,19,23,27-Heptamethyloctacosa-6,1
Synthesis of 0,14,18,22,26-hexaenyl diammonium (HMOP)

[0026]

Embedded image

4.7 ml of phosphorus oxychloride was dissolved in 50 ml of tetrahydrofuran. Here, at an internal temperature of -29 ° C to -31 ° C, (6
E, 10E, 14E, 18E, 22E, 26E) -3,7,11,15,19,23,27-Heptamethyloctacosa-6,10,14,18,22,26-hexen-1-ol 5g A solution of 13.9 ml of triethylamine and 50 ml of tetrahydrofuran was added dropwise over 30 minutes. The reaction solution was cooled to -40 ° C, 100 ml of a 3N-sodium acetate aqueous solution was added, and then the mixture was placed in a 40 ° C water bath for 25 minutes. Under ice cooling, diethyl ether and 1N-hydrochloric acid (150 ml) were added, and the mixture was separated. The aqueous layer was further extracted with diethyl ether. The ether layers were combined, washed with water, dried and concentrated under reduced pressure to obtain 5.9 g of an oily residue. This was purified using HPLC under the following conditions to obtain 3.5 g of the title compound as a colorless oil.

HPLC conditions: Stationary phase; YMC RI-355-30, I-30, 120A, AQ ODS Mobile phase; Methanol / water / ammonium acetate detector; UV

1H-NMR (400 MHz, CDCl3); δ (ppm) 0.90 (3
(H, d, J = 6.4Hz), 1.10-1.76 (5H, m), 1.59 (21H, s), 1.88-2.12
(22H, m), 3.80-3.95 (2H, m), 5.05-5.15 (6H, m), 7.41 (8H, br
-s). MASS (FAB); 577 (MH +).

Production Example 2 Phosphoric acid (6E, 10E, 14E, 18E, 22E, 2
6E, 30E, 34E, 38E) -3,7,11,15,19,23,27,31,35,39-Decamethyltetraconta-6,10,14,18,22,26,30,34, Synthesis of 38-nonaenyl diammonium (DMTP)

[0031]

Embedded image

A solution of 1.1 g (7.1 mmol) of phosphorus oxychloride in 10 ml of tetrahydrofuran was added at an external temperature of -30 to -40 ° C. (6E, 10E, 14
E, 18E, 22E, 26E, 30E, 34E, 38E) -3,7,11,15,19,23,27,31,3
5,39-decamethyltetraconta-6,10,14,18,22,26,30,3
4,38-nonaen-1-ol 1.0 g, triethylamine 1.4 g
A solution of (14.3 mM) in 10 ml of tetrahydrofuran was added dropwise. 1
Five minutes later, a 3N-sodium acetate aqueous solution was added, and the resultant was placed in a water bath at 40 ° C. Then, diethyl ether was added under ice cooling, and 1N
-Acidified with hydrochloric acid. The organic layer was washed with water, dried, concentrated under reduced pressure, and crystallized from methanol to obtain 860 mg of white crude crystals of the title compound. This crude crystal was prepared in the same manner as in Production Example 1.
Purification by HPLC and crystallization from methanol gave 490 mg of white crystals of the title compound.

1H-NMR (400 MHz, CDCl3); δ (ppm) 0.90 (3
(H, d, J = 6.59Hz), 1.16 (1H, m), 1.36 (1H, m), 1.41 (1H, m), 1.5
5 (1H, m), 1.59 (24H, s), 1.67 (3H, s), 1.70 (1H, m), 1.99-2.0
7 (34H, m), 3.89 (2H, m), 5.11 (9H, m). MASS (FAB-); 780 (MH-).

[0034]

Finally, in order to show the usefulness of the compound of the present invention as a therapeutic / ameliorating agent for leukemia, pharmacological experimental examples are given below as effect examples, but it goes without saying that the compound of the present invention or its use is not limited to these. No.

[0035]

[Example of pharmacological effect]

1. Method (1) Cells and culture conditions In the test, human monoblastic leukemia cell U937 was used. The medium is RPMI1640 containing 10% -fetal calf serum (hereinafter, 10% -FCS).
Was grown under the conditions of 37 ° C. and 5% CO 2. In the apoptosis experiment, the serum concentration was 0.5%.

(2) Addition conditions of test (evaluation target) compounds For the following compounds / solvents, 0.75, 1.5 and 3.
Solutions were prepared with RPMI1640 containing 0.5% -FCS so as to have a concentration of 0, 6.0, 12.0, or 24.0 μM. Control Solvent 1: ethanol Solvent 2: [ethanol: dodecane (98: 2, V / V)] Farnesyl phosphate / ethanol Geranylgeranyl phosp
hate) / ethanol HMOP / [ethanol: dodecane (98: 2, V / V)] DMTP / [ethanol: dodecane (98: 2, V / V)] dolicholic acid / [ethanol: dodecane (98: 2, V / V)] V /
V)] 5 × 10 5 cells suspended in 200 μl of RPMI1640 containing 0.5% -FCS were spread on a 24-well plate, and then 200 μl of a medium containing the above-described test compound solution was added. After gentle shaking, 37
It was allowed to act for a certain period of time at 5 ° C. and 5% CO 2.

(3) Confirmation of Apoptosis Apoptosis in cells follows the definition of apoptosis. This was confirmed by fragmentation of DNA extracted from the cells and chromatin condensation and nuclear fragmentation in the morphological observation of the cells.

(4) Isolation of DNA The cells were collected by centrifugation, and then 10 mM Tris-HCl buffer (pH
7.4), 100 μl of a cell lysis buffer containing 10 mM-EDTA and 0.5% -TritonX-100 was added, and the mixture was allowed to stand at 4 ° C. for 20 minutes. Then, 1
After centrifugation at 4,000 × G (4 ° C, 20 minutes), add 40 μg of RNaseA to the supernatant, and react at 37 ° C for 20 minutes.
0 μg was added, and the mixture was left at 37 ° C. for 30 minutes. Next, add 20 μl of 5M-NaCl and 120 μl of 2-propanol to this solution, and add
For overnight to precipitate the fragmented DNA. Centrifuge (14,0
(00 × G, 4 ° C., 15 minutes), the obtained DNA was dissolved in 10 μl of TE buffer, and used as a sample for agarose gel electrophoresis.

(5) Agarose electrophoresis The fragmented DNA was electrophoresed in a 1.7% Nusieve 3: 1 agarose gel. Stained with ethidium bromide, visualized under UV light and photographed.

(6) Morphological observation After fixation of cells with methanol, Giemsa staining or glutaraldehyde fixation, DAPI (4,6-diamidino-2-phenylindo) was used.
le) Staining was performed. Each was observed with an optical microscope or a fluorescence microscope. The percentage of apoptotic cells was expressed by counting apoptotic cells out of about 1000 cells after Giemsa staining, and is shown as an average of three experiments.

2. Results The fragmentation of DNA by HMOP and DMTP is described below. As described above, DNA fragmentation was observed on agarose gel when 6 μM dolichol phosphate was allowed to act on U937 cells for 4 hours, and it has been reported in the literature that dolichol phosphate induces apoptosis in U937 cells. Are known. Apoptosis induction by isoprenoids with different chain lengths and their derivatives (final concentration 6μM)
It was examined by fragmentation of DNA when it was allowed to act for a time (see FIG. 1).

DNA fragmentation similar to that of dolichol phosphate was observed by HMOP and DMTP. In contrast, HMOO and DMTO, in which the α-terminal of isoprenoid is alcohol,
No fragmentation was observed. On the other hand, DNA fragmentation was not observed with farnesol phosphate or geranylgeraniol phosphate, and the same applies to those alcohols. The effects of changes in the concentrations of dolichol phosphate and HMOP on DNA fragmentation are described below. Dolichol phosphate and HM
The concentration of OP was changed from 0.375 μM to 12 μM to act on U937 cells, and the effect on DNA fragmentation was examined (see FIG. 2).

When each of dolichol phosphate and HMOP was diluted by a factor of 2 from a final concentration of 12 μM and allowed to act for 4 hours, DNA fragmentation was observed at HMOP of 1.5 μM or more. On the other hand, DNA fragmentation was observed for dolichol phosphate at 3 μM or more, indicating that these compounds induce apoptosis in U937 cells in a dose-dependent manner.

The morphological changes of U937 cells treated with HMOP and DMTP are described below. The morphological changes of U937 cells that had undergone DNA fragmentation by HMOP were observed by Giemsa staining or DAPI staining for staining nuclei (see FIGS. 3, 4, 5, and 6).

According to Giemsa staining observation, cells treated with HMOP on untreated cells showed cell shrinkage, nucleus condensation, and nuclear fragmentation after 4 hours. Furthermore, in DAPI staining, chromatin condensation and nuclear fragmentation were similarly observed by HMOP. Similar results were obtained when DMTP was allowed to act on U937 cells. These are all typical apoptotic cells. In contrast, cells to which only the solvent ethanol: dodecane (98: 2) (0.8%) was added had the same morphology as untreated cells. The time course of the percentage of apoptotic cells in U937 cells and the dose dependence of the percentage of apoptotic cells in U937 cells are shown as mean ± standard deviation. In the table, the numerical value in parentheses means the standard deviation (SD).

(1) Time-dependent change in the percentage of apoptotic cells in U937 cells Solvent 1: ethanol, solvent 2: ethanol: todcan. ,,, And mean the same test compounds as described above.

(2) Dose dependence of the percentage of apoptotic cells in U937 cells

As is apparent from the above results, it is clear that HMOP and DMTP according to the present invention have an excellent apoptosis-inducing effect similarly to dolichol phosphate. On the other hand, farnesyl phosphate or geranylgeraniol phosphate, which has a short chain length, did not show an inducing effect.

From the results of the above pharmacological experiments, it is clear that the isoprenoid derivative according to the present invention has extremely excellent apoptosis-inducing ability and is effective for various diseases. Considering also the high safety of the isoprenoid derivative according to the present invention, the present invention can be expected to have extremely excellent clinical utility.

[Brief description of the drawings]

FIG. 1 is a diagram showing DNA fragmentation when the ability to induce apoptosis by isoprenoids and various derivatives thereof (final concentration: 6 μM) was applied to U937 cells for 4 hours.

FIG. 2 is a graph showing the effect on DNA fragmentation by changing the concentrations of dolichol phosphate and HMOP from 0.375 μM to 12 μM and acting on U937 cells.

FIG. 3 is a diagram in which the morphological changes of U937 cells that have undergone DNA fragmentation by HMOP are observed by Giemsa staining.

FIG. 4 is a diagram in which U937 cells are observed by Giemsa staining (control in FIG. 3).

FIG. 5 is a diagram in which morphological changes of U937 cells that have undergone DNA fragmentation by HMOP are observed by DAPI staining for staining nuclei.

FIG. 6 is a view in which U937 cells are observed by DAPI staining for staining nuclei (control in FIG. 5).

FIG. 7 is a graph showing a time-dependent change in the ratio of apoptotic cells in U937 cells. (Indicated by mean ± standard deviation)

FIG. 8 shows the dose dependence of the percentage of apoptotic cells in U937 cells. (Indicated by mean ± standard deviation)

────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] January 27, 1997

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Brief description of drawings

[Correction method] Change

[Correction contents]

[Brief description of the drawings]

FIG. 1. Apoptosis-inducing ability by isoprenoids and their various derivatives (final concentration: 6 μM) was measured by U937.
Drawing showing DNA fragmentation when allowed to act on cells for 4 hours
It is a photograph (electrophoresis pattern) which replaces .

FIG. 2 is a photograph (electrophoresis pattern) showing the effect on DNA fragmentation by changing the concentrations of dolichol phosphate and HMOP from 0.375 μM to 12 μM and acting on U937 cells.
) .

FIG. 3 is a drawing showing the morphological changes of U937 cells that have undergone DNA fragmentation by HMOP, as observed by Giemsa staining.
(Micrograph) .

FIG. 4 shows a drawing of U937 cells observed by Giemsa staining.
It is an alternative photograph (micrograph) (control of FIG. 3).

FIG. 5 is a diagram in which morphological changes of U937 cells that have undergone DNA fragmentation by HMOP are observed by DAPI staining for staining nuclei .
It is a photograph (microscope photograph) replacing a surface .

FIG. 6 is a photograph (micrograph) instead of a drawing observed by DAPI staining for staining nuclei of U937 cells (control in FIG. 5).

FIG. 7 is a graph showing a time-dependent change in the ratio of apoptotic cells in U937 cells. (Indicated by mean ± standard deviation)

FIG. 8 shows the dose dependence of the percentage of apoptotic cells in U937 cells. (Indicated by mean ± standard deviation)

Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 31/66 ADS A61K 31/66 ADS ADU ADU ADV ADV ADV DY DY DY AGZ AGZ

Claims (3)

[Claims] 1. An apoptosis-inducing agent or a pharmacologically acceptable salt thereof, comprising an isoprenoid derivative represented by the following general formula as an active ingredient. Embedded image (In the formula, n means an integer of 5 to 10.) 2. The method according to claim 1, wherein the isoprenoid derivative is phosphoric acid (6E, 10
E, 14E, 18E, 22E, 26E) -3,7,11,15,19,23,27-Heptamethyloctacosa-6,10,14,18,22,26-hexaenyl diammonium or phosphoric acid ( 6E, 10E, 14E, 18E, 22E, 26E, 30E, 34
E, 38E) -3,7,11,15,19,23,27,31,35,39-decamethyltetraconta-6,10,14,18,22,26,30,34,38-nonaenyl The apoptosis-inducing agent according to claim 1, which is diammonium. 3. The apoptosis-inducing agent according to claim 1, which is a therapeutic agent for malignant tumor, leukemia, proliferative skin disease, rheumatoid arthritis, autoimmune disease, HIV infection, hepatitis, and kidney disease.