JPS644519B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula () [In the formula, R is

【formula】

[Formula] (wherein R ₁ and R ₂ are a hydrogen atom or a lower alkyl group, and R ₃ is a hydrogen atom, an alkyl group, an aryl group, an alkoxy group, or a halogen) New derivatives of secalonic acid and their production method More specifically, novel compounds of formula () which are 4,4'-imidomethyl derivatives of secalonic acids represented by formula () useful as anti-cancer agents, and formula () Secalonic acids represented by the formula () R-CH ₂ OH () [wherein R is

【formula】

[Formula] (wherein R ₁ and R ₂ are a hydrogen atom or a lower alkyl group, and R ₃ is a hydrogen atom, an alkyl group, an aryl group, an alkoxy group, or a halogen). ] It relates to a method for producing a 4,4'-imidomethyl derivative of secalonic acids represented by the formula () by reacting the compound represented by the following. Until now, secalonic acid has seven stereoisomers, namely secalonic acid A, B, C, D, E, F, and G.
have been isolated from molds and lichens, and the literature is listed below. (1) Claviceps purpurea
Isolation of secalonic acids A, B, and C from (Literature: B.Frank and EMGottshalk,
Angew.Chem.Internat.Edn., 1964, 3, 441;
B.Franck, EMGottshalk, U.Ohnsorgo and
F. Hu¨per, Chem. Beri., 1966, 99, 3842; DJ
Abehart, YS Chen, P. de Mayo and J.B.
Stoteqrs, Tetrahedron, 1965, 21, 1417) (2) Secalonic acid A from Penicillium islandicum;
Isolation of B (References: JWApsimon, JACorran,
NGCreasey, W. Marlow, W. D. Whalley.
and KYSim, J.Chem.Soc., 1965, 4144) (3) Isolation of secalonic acid A from Parmelia entotheiochroa (References: I. Yoshioka, T. Nakanishi,
S. Izumi and I. Kitagawa, Chem.Pharm.
Bull., 1968, 16, 2090) (4) Penicillium oxalicum
Isolation of secalonic acid D from oxalicum) (Reference:
PWSteyn Tetrahedron, 1970, 26, 81) (5) Isolation of secalonic acid A from Aspergillus ochraceus (Experience: M. Yamazaki, Y. Maebayashi
and K. Miyaki, Chem.Pharm.Bull., 1971,
19, 199) (6) Cetraria ornata
Isolation of secalonic acid C (Experience: I. Yoshioka,
H. Yamauchi, K. Murata and I. Kitagawa,
Chem.Pharm.Bull., 1972, 20, 1082) (7) Isolation of secalonic acids A, E, and G from Pyrenochaeta terrestris (Reference: CO Howard, RA
W. Johnston, and ID Entwistle, J. Chem.
Soc.Comm., 1973, 464; CO Howard and
RAWJohnstone, J.Chem.Soc.Perkin
I.1973, 2440; I.Kurobane, LOVining and
AOMc Innes, Tetrahedron Letters, in
press) (8) Secalonic acid D from Aspergillus aculeatus,
Isolation of F (Reference: R, Anderson G.Bu¨chi, B.
Kobbe and ALDomain, J.Org.Chem.
1977, 42, 352) Compound (), secalonic acid, is an effective drug against ascites tumors in mice and rats, but on the other hand, it has the drawback of high toxicity. The present inventors have conducted extensive research to provide useful derivatives with reduced toxicity and further enhanced the anticancer effect of secalonic acids. As a result, the secalonic acid derivatives represented by formula () have low toxicity and strong control. They discovered that it has a cancer effect and completed the present invention. The compounds are also useful as intermediates in the manufacture of other pharmaceutical products. The novel secalonic acid derivatives represented by the formula () of the present invention are 4,4'-imidomethyl derivatives of secalonic acids such as secalonic acids A, B, C, D, E, F, and G represented by the formula (). , in which R
teeth

Aleic acid maleimide represented by the formula and

It is a phthalimide represented by the formula: R ₁ and R ₂ are hydrogen atoms or methyl, ethyl, n-propyl, sec-butyl, t
- Represents a lower alkyl group such as butyl, and specific examples of maleimides include maleimide, α-methylmaleimide, α-ethylmaleimide, α-n-
Propylmaleimide, α-t-butylmaleimide, -n-octylmaleimide, α,β-dimethylmaleimide, α,β-diethylmaleimide,
Examples include α,β-di-sec-butylmaleimide. R ₃ represents a hydrogen atom, an alkyl group such as methyl, ether, n-propyl, or t-butyl, an aryl group such as phenyl or tolyl, an alkoxy group such as methoxy or ethoxy, or a halogen such as chlorobrome; specific examples of phthalimides Examples include phthalimide, 3-methylphthalimide, 3,4-dimethylphthalimide, 3-t-butylphthalimide, 2- or 3-phenylphthalimide, 2-
or 3-methoxyphthalimide, 2- or 3
-chlorphthalimide, 2- or 3-cyanophthalimide, 2- or 3-monocarboxyphthalimide, 2,3-dicarboxyphthalimide,
2- or 3-sulfophthalimide, 2- or 3-di-n-propylaminocarbonylphthalimide, 2- or 3-dimethylaminocarbonylphthalimide, 2- or 3-aminosulfonylphthalimide, 2- or 3-dimethylaminosulfonylphthalimide etc. Next, a method for producing the novel secalonic acid derivative of the present invention will be explained. A novel secalonic acid derivative of formula () is obtained by a dehydration reaction (imide alkylation reaction) between a secalonic acid represented by formula () and an N-methylol derivative represented by formula (). This dehydration reaction involves concentrated sulfuric acid, fuming sulfuric acid, phosphoric acid,
Inorganic acids such as polyphosphoric acid, hydrogen fluoride, or organic acids such as methanesulfonic acid, ethanesulfonic acid, ethanolsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, acetic acid, formic acid, or subchloride, chloride Dehydrating agents or catalysts such as aluminum, phosphorus oxychloride, phosphorus pentoxide, boron trifluoride, and boron trifluoride etherate are used. Inorganic acids and organic acids simultaneously act as solvents. In particular, when a solvent is required, use an inert solvent for the reaction, such as alcohols such as methanol and ethanol, aromatic hydrocarbons such as monochlorobenzene, dichlorobenzene, trichlorobenzene, and nitrobenzene, dichloromethane, dibromomethane, and chloroform. , hydrocarbons such as 1,2-dichloroethane, carbon tetrachloride, and n-pentane; nitrogen-containing compounds such as pyridine, picoline, dimethylformamide, and dimethylacetamide;
Ethers such as tetrahydrofuran and dioxane, carbon disulfide, and liquid sulfite are used. The reaction temperature is usually -30℃ to 100℃, preferably 0
C to 80 C, and the reaction time generally ranges from 0.5 hours to 48 hours, preferably from 1 hour to 24 hours. The amount of the raw material secalonic acids used in the present invention and the N-methylol derivative represented by the formula () is based on the formula () per 1 mole of the raw material secalonic acids.
The amount of the N-methylol derivative represented by is in the range of 1 to 10 moles, preferably in the range of 2 to 4 moles. The reaction product obtained in the above reaction is separated and collected by conventional methods such as chromatography and recrystallization, and isolated as a novel secalonic acid derivative represented by the above formula (). For example, the reaction solution is poured into saturated saline or ice water at about -20 to -10°C, and the precipitated solid is removed. After washing the obtained solid, it can be purified by recrystallization, chromatography, etc., and the target substance can be isolated in a pure manner. Next, we will show the results of testing the antitumor effects of representative compounds of the present invention (), which show that they have remarkable antitumor effects against tumors in experimental animals, and that their toxicity is weaker than that of secalonic acids. It was confirmed that it can be a useful antitumor agent. That is, a group of 7 ICR mice were implanted with 1 x 10 ⁶ Ehrlichi tumor cells/mouse intraperitoneally, and 24 hours later, the following inventive compound containing 0.5% CMC was implanted. Dissolved or suspended in distilled water or physiological saline, 1
It was administered intraperitoneally to mice twice on day 3 and day 3. At this time, the ratio of the number of days of survival of the non-treated group to the number of days of survival of the drug-administered group expressed as a percentage (%) was expressed as the survival rate (T/C, %). The results were as shown in Table 1. Test compound (secalonic acid A, B, C, D,
E, F, G are SA, SB, SC, SD, SE, respectively.
(abbreviated as SF, SG) () 4,4'-bis(maleimidomethyl)-SA () 4,4'-bis(maleimidomethyl)-SD () 4,4'-bis(α-methylmaleimidomethyl) -SB () 4,4'-bis(α,β-dimethylmaleimidomethyl)-SE () 4,4'-bis(phthalimidomethyl)-SD () 4,4'-bis(phthalimidomethyl)-SF ( ) 4,4'-bis(3-methylphthalimidomethyl)-SD () 4,4'-bis(3-chlorophthalimidomethyl)-SD () 4,4'-bis(2-methoxyphthalimidomethyl)-SD

[Table] Next, examples will be given and explained. Example 1 1.3g (2mM) of secalonic acid A is dissolved in 80ml of methanesulfonic acid, 0.5g (4mM) of N-methylolmaleimide is added at 15°C, and the mixture is reacted by stirring at 20°C for 3 hours. The reaction solution was cooled to about -15°C and poured into 200 ml of saturated brine to precipitate a solid.
The precipitated solid was taken, washed with water, and then recrystallized in a chloroform-methanol system to obtain 0.9 g of 4,4'-bis(maleimidomethyl)-secalonic acid A (compound number) as yellow powder crystals. UV (CHCl ₃ ) λmax: 339 nm NMR (DMSO-d ₆ ) δppm: 1.10 (d, 6H), 2.2
~2.8 (m, 6H), 3.64 (s, 6H), 3.93 (d,
2H), 4.74 (s, 4H), 5.25 (d, 2H), 7.11 (s,
4H), 7.30 (s, 2H), 11.7 (s, 2H), 12.3~
14.0 (2H) The results were as shown in the antitumor test, and it showed high antitumor activity against Ehrlichi's ascites tumor.

[Table] Example 2 2.6g (4mM) of secalonic acid D was dissolved in 200ml of methanesulfonic acid, 1.2g (9.5mM) of N-methylolmaleimide was added at 15℃, and the solution was dissolved at 20℃.
Stir for some time to react. Pour the reaction solution into 400 ml of ice water to precipitate a solid. After removing the precipitated solid,
After washing with water and methanol, recrystallization was performed in a chloroform-methanol system to obtain 2.0 g of 4,4'-bis(maleimidomethyl)-secalonic acid D (compound number) as yellow powder crystals.
It showed strong antitumor effects. NMR (DMSO-d ₆ ) δppm: 1.08 (d, 6H), 2.2
~2.8 (m, 6H), 3.63 (s, 6H), 3.92 (d,
2H), 4.72 (s, 4H), 5.24 (d, 2H), 7.10 (s,
4H), 7.33 (s, 2H), 11.6 (s, 2H), 12.5~
14.5 (2H) UV (CDCl ₃ ) λmax: 338 nm Example 3 Using 1.3 g each of secalonic acids B, C, F, and G in place of secalonic acid A in Example 1, 0.6 g of N-methylol α-methylmaleimide and Example 1
The compounds shown in Table 2 were obtained by reacting under the same conditions as above. It showed strong antitumor effects.

【table】

[Table] Example 4 Secalonic acid instead of Secalonic acid D in Example 2
Using 2.6g (4mM) of E, dichloromethane
Dissolve the mixture in a mixture of 100 ml and methanesulfonic acid, add 1.2 g (9.5 mM) of N-methylol α,β-dimethylmaleimide at 15°C, and react by stirring at 20°C for 24 hours. After dichloromethane was distilled off from the reaction solution, it was poured into 400 ml of ice water to precipitate a solid. After removing the precipitated solid, it was washed with water and methanol, and then reconsolidated in a chloroform-methanol system to obtain 4,4'-bis(α,β-dimethylmailemidomethyl)-secalonic acid E ( Compound number) 1.8g was obtained. It showed strong antitumor activity. UV (dioxane) λmax: 338nm Example 5 1.9g (3mM) of secalonic acid D was dissolved in 100ml of methanesulfonic acid, 1.1g (6mM) of N-methylol phthalimide was added at 15℃, and the mixture was heated at 20℃ for 3 hours. Stir to react. The reaction solution was poured into 400 ml of saturated saline solution cooled to about -15°C to precipitate a solid. The precipitated solid was washed with water and methanol, and then dried to yield 2.3 g of a yellow solid.
By recrystallizing this product in a chloroform-methanol system, 1.8 g of 4,4'-bis(phthalimidomethyl)-secalonic acid D (compound number V) was obtained as yellow powdery crystals. It showed strong antitumor effects. NMR ( _CDCl3 ) δppm: 1.20 (d, 6H), 2.2-2.9
(m, 6H), 3.32 (s, 6H), 3.92 (d, 2H),
4.67 (d, 2H), 4.88 (s, 4H), 7.72 (s, 2H),
7.8-7.9 (m, 8H), 11.7 (s, 2H) UV (CHCl ₃ ) λmax: 338nm Example 6 Secalonic acid D 3.2g (5mM) and 2-methylol phthalimide 3.6g (20mM) were mixed with trifluoroacetic acid 50ml. Dissolve in a mixed solvent of 50 ml of dichloromethane under ice cooling, add 0.75 g of trifluoromethanesulfonic acid at 5°C, and react at 5°C for 48 hours. 80 ml of solvent was distilled off from the reaction solution, and the concentrated solution was -
Pour into 500 ml of saturated saline solution at 15°C to precipitate a solid. The precipitated solid was collected, washed with water and methanol, and dried to yield 3.3 g of a yellow solid.
By recrystallizing this product in a chloroform-methanol system, 2.7 g of 4,4'-bis(phthalimidomethyl)-secalonic acid D was obtained as yellow powdery crystals. The analytical values were consistent with Example 5. Example 7 A similar reaction was carried out using 1.9 g each of secalonic acids A, F, and G in place of secalonic acid D in Example 5 to obtain the products shown in Table 3. It showed strong antitumor effects.

[Table] Example 8 Except for using the following N-methylol derivative in place of N-methylol phthalimide in Example 5,
The same reaction as in Example 5 was carried out to obtain the corresponding secalonic acid D derivatives as shown in Table 4. It showed strong antitumor effects.

【table】

Claims (1)

[Claims] 1 Formula () [In the formula, R represents [Formula] [Formula] (In the formula, R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, and R ₃ represents a hydrogen atom, an alkyl group, an aryl group, an alkoxy group, or a halogen) . ] A novel secalonic acid derivative represented by. 2. The secalonic acid derivative according to claim 1, wherein R is [Formula]. 3. The secalonic acid derivative according to claim 1, wherein R is [Formula]. 4. The secalonic acid derivative according to claim 1, wherein the secalonic acid is secalonic acid A. 5. The secalonic acid derivative according to claim 1, wherein the secalonic acid is secalonic acid D. 6. The secalonic acid derivative according to claim 1, wherein the secalonic acid is secalonic acid E. 7. The secalonic acid derivative according to claim 1, wherein the secalonic acid is secalonic acid G. 8 formula () Secalonic acids represented by the formula () R-CH ₂ OH () [wherein R represents [formula] [formula] (wherein R ₁ and R ₂ are hydrogen atoms or lower alkyl groups, R ₃ represents a hydrogen atom, an alkyl group, an aryl group, an alkoxy group, or a halogen). ] By reacting with the compound (N-methylol derivative) represented by the formula () [In the formula, R represents [Formula] [Formula] (In the formula, R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, and R ₃ represents a hydrogen atom, an alkyl group, an aryl group, an alkoxy group, or a halogen) . ] A novel method for producing a secalonic acid derivative, characterized by producing a compound represented by the following.