JP3097269B2 - Apovincamic acid amide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an apovincamic acid amide derivative useful as an anticancer effect enhancer.

[0002]

2. Description of the Related Art The anticancer effect enhancers reported so far are mainly calcium antagonists. Intracellular calcium ions are chemical mediators in cardiac muscle and smooth muscle cells, and play an important role in muscle excitation-contraction coupling. Calcium antagonists exert their main pharmacology by inhibiting the entry of calcium ions into cells.
Therefore, when anticancer effects are expected to be enhanced in cancer cells, calcium antagonists cause clinical adverse effects on the cardiovascular system due to their main pharmacological effects, and their development as anticancer effects enhancers. It is currently being hindered. on the other hand,
The compound of the present invention has a vincamine skeleton. Many derivatives having this skeleton have been developed, but none of them have an anticancer effect enhancing action.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a compound having a strong anticancer effect.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, have found that certain apovincamic acid amide derivatives have a strong anticancer agent effect-enhancing effect. completed. That is, the present invention uses the formula

[0005]

(Wherein, R ¹ and R ² each represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, or R ¹ and R ² together form a group having 2 to 6 carbon atoms. R ³ represents a hydrogen atom or a C 1-5 alkylene chain;
Alkyl groups. ) And an acid addition salt thereof.

In the present invention, an alkyl group means a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-
It refers to a linear or branched alkyl group such as a butyl group, an isobutyl group, and an n-pentyl group. An acid addition salt is
A salt to which an inorganic acid or an organic acid is added is shown. There are no particular restrictions on the inorganic or organic acid used in this case, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, glycolic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, Examples include salicylic acid, lactic acid, malic acid, methanesulfonic acid, and paratoluenesulfonic acid.

The compound of the present invention can be produced, for example, by the following method. [Method A]

[0009]

(In the reaction formula, R ¹ , R ² and R ³ are as defined above.) [Method B]

[0011]

(In the reaction formula, R ¹ , R ² and R ³ have the same meanings as described above.) According to the method A, 10-alkanoyl represented by the formula (II) known from JP-A-1-156977. It can be easily produced by amidating apovincamic acid. That is, first, a compound of the formula (II) is reacted with a halogenating agent (for example, thionyl chloride) in a benzene-based solvent (for example, benzene or toluene) in the presence of a catalytic amount of an amide-based solvent (for example, N, N-dimethylformamide). , Thionyl bromide, oxalyl chloride, etc.) at room temperature to 120 ° C. to give a carboxylic acid halide. The reaction time is 10 minutes to 8 hours. Then, a carboxylic acid halide is added to a compound of the formula R ¹ R ² N in a halogen-based solvent (eg, dichloromethane, chloroform, etc.) or a benzene-based solvent in the presence or absence of a tertiary amine (eg, triethylamine, diisopropylethylamine, etc.).
By reacting the compound represented by H (wherein R ¹ and R ² are as defined above) or a hydrochloride thereof at -10 ° C. to room temperature, a compound of the formula (I) is obtained. The reaction time is 10 minutes to 24 hours.

According to the method B, the apovincamic acid amide derivative represented by the formula (III) can be easily produced by acylation by a Friedel-Crafts reaction. That is, the compound of the formula (III) is reacted with an acylating agent in the presence of a Lewis acid (for example, a Lewis acid generally used for Friedel-Crafts reaction such as aluminum chloride, ferric chloride, tin tetrachloride, titanium tetrachloride, etc.). (Eg, acetyl chloride, acetic anhydride, propionyl chloride, etc.) and a solvent (eg, methylene chloride, ethylene chloride, carbon disulfide, carbon tetrachloride, nitromethane, nitroethane, nitrobenzene, and other solvents commonly used in Friedel-Crafts reactions) Single or mixed), 0 ° C ~
Reaction at 60 ° C. gives the compound of formula (I). The reaction time is 10 minutes to 24 hours.

The compound of the present invention exhibits the effects of the present invention when used in combination with an anticancer agent. No particular limitation is imposed on the anticancer agent used in combination. Includes anti-cancer substances such as antimetabolites such as arabinoside. As a method of administering the compound of the formula (I), it can be administered simultaneously with, before or after the anticancer drug, in combination with the anticancer drug, or separately. That is, the compound of the formula (I) can be used alone in various dosage forms and administered separately with various anticancer drugs. It can also be administered. As the dosage form of the formulation, depending on the type of anticancer drug, or according to the patient's symptoms, age and purpose of treatment, tablets, granules,
Oral administration agents such as powders, capsules, syrups and suspending agents, and parenteral administration agents such as injections and suppositories can be selected. These formulations use conventional excipients (eg, crystalline cellulose, starch, lactose, etc.), binders (eg, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), lubricants (eg, magnesium stearate, talc, etc.). Can be manufactured. Formula (I)
The dose of the compound is 50 to 15 when treating an adult.
The dose is divided into 1 to 3 times a day, and the dose can be appropriately increased or decreased depending on the age, weight, and symptoms of the patient.

[0015]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples. (Example 1) N, N-pentamethylene-10-acetylapobinkami
Acid amide 10-acetylapovincamic acid (3 g) was suspended in benzene (100 ml), and thionyl chloride (10 ml) was suspended in the suspension.
N, N-dimethylformamide (0.5 ml) was added and 3
Refluxed for 0 minutes. Benzene was concentrated under reduced pressure. Benzene (100 ml) was added again to the residue, and piperidine (5 m
l) was added and the mixture was stirred at room temperature for 1 hour. After washing the reaction solution with water,
It was dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ether. The eluate was concentrated and recrystallized from ethyl acetate to obtain colorless needle crystals (3 g). m. p. 185-195 ° C. NMR (DMSO-d ₆ , 200 MHz) δ (pp
m); 8.15 (1H, d, J = 1 Hz), 7.78
(1H, dd, J = 9 Hz, 1 Hz), 7.13 (1
H, d, J = 9 Hz), 5.32 (1H, s), 2.8
~ 4.0 (8H, m), 2.60 (3H, s), 1.2
0 to 2.10 (9H, m), 0.95 (3H, t, J =
7 Hz) The following compound was produced according to Example 1. Nn-hexyl-10-acetylapovincamic acid
Amide hydrochloride m. p. 190-195 ° C (decomposition) (recrystallized from methylene chloride-ethyl acetate; hereinafter, the solvent name in parentheses after the numerical value of the melting point indicates that the solvent was recrystallized from the solvent). NMR (DMSO-d ₆ , 200MHz) δ (pp
m); 11.67 (1H, brs), 8.80 (1H,
t, J = 6 Hz), 8.26 (1H, d, J = 1H)
z), 7.80 (1H, dd, J = 9 Hz, 1 Hz),
7.23 (1H, d, J = 9 Hz), 5.69 (1H,
s), 5.04 (1H, brs), 2.62 (3H,
s), 1.00 (3H, t, J = 7 Hz), 0.90
(3H, t, J = 7 Hz) (Example 2) N, N-dimethyl-10 -acetylapovincamic acid
Mido 10-acetylapovincamic acid (400 mg) was suspended in benzene (20 ml), and thionyl chloride (0.4 m
l), N, N-dimethylformamide (4 drops) was added and 2
Refluxed for 0 minutes. Benzene was concentrated under reduced pressure. Dichloromethane (20 ml) was added to the residue, cooled with ice, dimethylamine hydrochloride (320 mg), triethylamine (0.6 mg).
ml) and stirred at room temperature for 30 minutes. The reaction solution was washed with water, dried over magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography and eluted with chloroform. The eluate was concentrated and recrystallized from ethyl acetate to obtain colorless prism crystals (147 mg). m. p. 191 to 193 ° C NMR (CDCl ₃ , 200 MHz) δ (ppm);
8.13 (1H, d, J = 2 Hz), 7.79 (1H, d, J = 2 Hz)
dd, J = 9 Hz, 2 Hz), 7.09 (1 H, d, J
= 9 Hz), 5.37 (1H, s), 4.27 (1H,
brs), 3.18 (3H, s), 2.90 (3H, b
rs), 2.65 (3H, s), 1.01 (3H, t,
J = 8 Hz) The following compound was produced according to Example 2. N-ethyl-10-acetylapovincamic acid amide salt
Acid salt m. p. 270-273 ° C (ethanol) NMR (DMSO-d ₆ , 200 MHz) δ (pp
m); 11.52 (1H, brs), 8.82 (1H,
t, J = 7 Hz), 8.27 (1H, d, J = 2H)
z), 7.82 (1H, dd, J = 9 Hz, 2 Hz),
7.24 (1H, d, J = 9 Hz), 5.70 (1H, d, J = 9 Hz)
s), 5.05 (1H, brs), 3.70 (2H,
m), 2.92 to 3.35 (6H, m), 2.62 (3
H, s), 1.48 to 2.12 (6H, m), 1.19.
(3H, t, J = 7 Hz), 0.99 (3H, t, J =
7 Hz) (Example 3) Nn -butyl-10- acetylapovincaminate
To hydrochloride 10-acetylapovincamic acid (400 mg) was suspended in benzene (20 ml), and thionyl chloride (0.4 m
l), N, N-dimethylformamide (0.5 ml) was added, and the mixture was refluxed for 30 minutes. Benzene was concentrated under reduced pressure. Dichloromethane (20 ml) was added to the residue, ice-cooled, butylamine (0.4 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with water, dried over magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography and eluted with methanol-chloroform (1:50). The eluate was concentrated, and the residue was dissolved in ethanol.
A solution of N-hydrochloric acid in ethyl acetate (0.5 ml) was added. The deposited precipitate was collected by filtration and recrystallized from methanol-ethyl acetate to give colorless needle crystals (107 mg). m. p. 321 ° C. (decomposition) NMR (DMSO-d ₆ , 200 MHz) δ (pp
m); 11.80 (1H, brs), 8.80 (1H, brs)
t, J = 5 Hz), 8.25 (1H, d, J = 2H)
z), 7.81 (1H, dd, J = 9 Hz, 2 Hz),
7.23 (1H, d, J = 9 Hz), 5.69 (1H,
s), 5.03 (1H, brs), 2.62 (3H,
s), 0.99 (3H, t, J = 7 Hz), 0.95
(3H, t, J = 7 Hz) The following compound was produced according to Example 3. N, N-diethyl-10-acetylapovincamic acid
Amide hydrochloride m. p. 289-291 ° C (ethanol) NMR (DMSO-d ₆ ) δ (ppm); 11.75
(1H, brs), 8.26 (1H, d, J = 2H
z), 7.84 (1H, dd, J = 9 Hz, 2 Hz),
7.17 (1H, brd, J = 9 Hz), 5.40 (1
H, s), 5.17 (1H, brs), 3.45-3.
85 (4H, m), 2.91 to 3.29 (6H, m),
2.62 (3H, s), 2.12 (2H, m), 1.8
2 (2H, m), 1.62 (2H, m), 1.25 (3
H, t, J = 7 Hz), 1.01 (3H, t, J = 7H)
z), 0.99 (3H, t, J = 7 Hz) Nn -propyl-10 -acetylapovincamic acid
Mid m. p. 135-138 ° C (ethyl acetate) NMR (CDCl ₃ , 200 MHz) δ (ppm);
8.13 (1H, d, J = 2 Hz), 7.79 (1H, d, J = 2 Hz)
dd, J = 9 Hz, 2 Hz), 7.25 (1 H, d, J
= 9 Hz), 6.00 (1H, t, J = 7 Hz), 5.
72 (1H, s), 4.18 (1H, brs), 2.9
6 to 3.57 (6H, m), 2.64 (3H, s),
1.30 to 2.08 (10H, m), 1.02 (6H,
t, J = 7 Hz) Nn -pentyl-10 -acetylapovincamic acid
Amide hydrochloride m. p. 205-214 ° C. (decomposition) (methylene chloride-ethyl acetate) NMR (DMSO-d ₆ , 200 MHz) δ (pp
m); 11.67 (1H, brs), 8.80 (1H,
t, J = 6 Hz), 8.26 (1H, d, J = 1H)
z), 7.80 (1H, dd, J = 9 Hz, 1 Hz),
7.23 (1H, d, J = 9 Hz), 5.69 (1H,
s), 5.05 (1H, brs), 2.62 (3H,
s), 1.00 (3H, t, J = 7 Hz), 0.92
(3H, t, J = 7 Hz) N, N-hexamethylene-10 -acetylapobinkami
Acid amide m. p. 172 to 174 ° C (ethyl acetate) NMR (DMSO-d ₆ , 200 MHz) δ (pp
m); 8.12 (1H, d, J = 2 Hz), 7.74
(1H, dd, J = 8 Hz, 2 Hz), 7.20 (1
H, brd, J = 8 Hz), 5.29 (1H, s),
4.18 (1H, brs), 2.60 (3H, s),
0.93 (3H, t, J = 7 Hz) Nn -butyl-10-isobutyryl apovincamic acid
Amide hydrochloride m. p. 212-223 ° C. (decomposition) (methylene chloride-ethyl acetate) NMR (DMSO-d ₆ , 200 MHz) δ (pp
m); 11.72 (1H, brs), 8.80 (1H,
t, J = 6 Hz), 8.27 (1H, s), 7.83
(1H, dd, J = 9 Hz, 2 Hz), 7.24 (1
H, d, J = 9 Hz), 5.69 (1H, s), 5.0
4 (1H, brs), 3.77 (1H, septet,
J = 7 Hz), 1.23 (3H, d, J = 7 Hz),
1.22 (3H, d, J = 7 Hz), 0.99 (3H, d, J = 7 Hz)
t, J = 8 Hz), 0.95 (3H, t, J = 8 Hz) N-methyl-Nn-propyl-10-acetylapobi
Cinamic amide hydrochloride m. p. 200-202 ° C. (2-propanol) NMR (DMSO-d ₆ , 200 MHz) δ (pp
m); 11.75 (1H, brs), 8.28 (1H,
d, J = 2 Hz), 7.82 (1H, dd, J = 8H)
z, 2 Hz), 7.12 (1H, d, J = 8 Hz),
5.44 (1H, s), 5.14 (1H, brs),
3.30 to 3.88 (4H, m), 2.83 to 3.29
(8H, m), 2.61 (3H, s), 1.08-2.
27 (12H, m), 0.98 (3H, t, J = 7H
z) N, N-tetramethylene-10-acetylapobinkami
Acid amide m. p. 197 to 199 ° C (ethyl acetate) NMR (CDCl ₃ , 200 MHz) δ (ppm);
8.12 (1H, d, J = 2 Hz), 7.78 (1H, d, J = 2 Hz)
dd, J = 8 Hz, 2 Hz), 7.14 (1 H, d, J
= 8 Hz), 5.43 (1H, s), 4.22 (1H,
brs), 3.68 (2H, m), 2.87-3.32.
(8H, m), 2.65 (3H, s), 2.58 (2
H, m), 1.36 to 2.13 (10H, m), 1.0
1 (3H, t, J = 7 Hz) N, N-di-n-propyl-10 -acetylapobinka
Acid amide hydrochloride m. p. 192 to 194 ° C. (2-propanol) NMR (DMSO-d ₆ , 200 MHz) δ (pp
m); 11.67 (1H, brs), 8.27 (1H,
d, J = 2 Hz), 7.83 (1H, dd, J = 8H)
z, 2 Hz), 7.18 (1H, m), 5.40 (1
H, brs), 5.17 (1H, brs), 3.30
(4H, m), 2.97 to 3.99 (6H, m), 2.
62 (3H, s), 1.30 to 2.25 (10H,
m), 0.98 (6H, m), 0.72 (3H, t, J
= 7Hz)

The compound of the present invention significantly increases the antitumor effect of an anticancer drug. That is, the compound of the present invention not only increases the sensitivity of cancer cells that do not have resistance to the anticancer drug to the anticancer drug, but also enhances the drug sensitivity in cancer cells that have resistance, so that if this is used together with the anticancer drug, It is possible to cure a cancer that has become resistant to an anticancer drug and a cancer that is naturally resistant and difficult to treat. Conventionally, anticancer drugs are often administered in the highest possible dose in order to expect a therapeutic effect.However, the compound of the present invention reduces the amount of the anticancer drug used to enhance the anticancer sensitivity of cancer cells. It is also possible to obtain an antitumor effect at a low dose with low toxicity and low onset of toxicity. Hereinafter, the effects of the present invention will be described with reference to test examples. (Test Example) [Test for enhancing effect of incorporation of anticancer drug into anticancer drug-resistant cancer cells] The test for enhancing effect of incorporation of anticancer drug into anticancer drug-resistant cancer cells was conducted by Cancer Research.
rch), Vol. 41, pp. 1967-1972 (198
1 year). Human ovarian cancer cell A
The 2780 adriamycin resistant strain 2780AD [AM Rogan et al., Science
nce), Vol. 224, pp. 994-996 (19
1984)] with RPMI-1640 containing 5% fetal calf serum
1 × 10 ⁶ cells / ml were suspended in the culture solution. This cancer cell suspension was seeded at 1 ml per well in a 24-well multiwell culture plate, and cultured at 37 ° C. while passing 5% carbon dioxide gas through. Twenty-four hours later, the culture was treated with 20 nm of ³ H-vincristine (hereinafter abbreviated as ³ H-VCR) (1 ×).
10 ⁴ dpm / pmol), 5% fetal calf serum, 10 mM
RPMI-1640 culture medium containing Hepes buffer 0.5m
Replaced with l. Test compound (N, N-pentamethylene-
10-acetylapovincamic acid amide) was dissolved in dimethyl sulfoxide, and then diluted with phosphate buffered saline.
5 μl of this solution (the concentration of the test compound in the culture solution is 1.0 μg / ml and 10.0 μg / ml) was added to the culture solution, and the culture was continued at 37 ° C. for 2 hours while passing 5% carbon dioxide gas through. After that, the amount of ³ H-VCR incorporated into the cells was measured with a liquid scintillation counter. The effect was expressed as a ratio (%) to the amount of ³ H-VCR incorporated in the control group not treated with the drug. The results are shown in Table 1.

[0016]

[Table 1]

[0017]

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Shiro Nakaike 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 24-24 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Takashi Tsuruo 4828-15 Tsukahara, Minamiashigara-shi, Kanagawa Prefecture (58) Field surveyed (Int. Cl. ⁷ , DB name) STN)

Claims (1)

(57) [Claims] (1) Expression (Wherein, R ¹ and R ² each represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, or R ¹ and R ² together form an alkylene chain having 2 to 6 carbon atoms. And R ³ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.) And an acid addition salt thereof.