JP2651758B2 - Anthracene compounds that can be used as drugs - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to certain anthracene compounds for use in therapy and to medicaments containing said compounds.

[0002]

BACKGROUND OF THE INVENTION Problems to be Solved by the Invention
Winskia humboldtiana is a shrub belonging to the family Rhamnaceae, which is commonly found in northern and central Mexico and the semi-desert regions of the southwestern United States, such as Hagers Ha.
ndbuch der pharmazeutisch
en Praxis, 4th edition, Vol. 5, p. 397. The plant attracts attention due to the onset of paralysis when eating parts of the plant, but its symptoms are similar to those of Guillain-Barre syndrome, poliomyelitis and other peripheral polyneuropathies .

[0003] Extraneous neuronal damage has been widely reported in goats and sheep.

[0004] Research has hitherto been made especially on fruits. Dreyer et al. [J. Am. Chem. So
c. 97: 4986 (1975)] succeeded in isolating and analyzing four anthracene compounds in the form of dimers from the endocarp of the fruit. These compounds correspond to T-496, T-514, T-
516 and T-544.

Surprisingly, it has been found that the compounds according to the invention have a selective anticancer and cytotoxic effect and an antiviral effect. Particularly advantageous are effects on tumor cells.

[0006]

SUMMARY OF THE INVENTION The above-mentioned invention therefore has the formula (1):

Embedded image Wherein A represents C = O or C-OH, and B represents C
When A represents C—OH and B represents C—R ⁵ , the ring represented by groups A and B is an aromatic ring, and R ¹ and R ⁵ represent HR ⁵ or C—R ^{5. 2} is the same or different and is C
Acyl groups of ₁ -C _4, alkyl group of _{C 1} -C _4, C 1 -
Represents a C ₄ alkoxy group or R ¹ and R ² together with the carbon atoms to which they are attached, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a hydroxy group and a C ₁ -C least selected from acyloxy group having ₄ phenyl ring optionally substituted by 1 group represents a cyclohexanone ring each or tetrahydropyran ring, R ³
_Is, C 1 -C ₄ alkyl _group, an alkoxy group of C 1 -C _4, represents an acyloxy group or a hydroxy group of C 1 -C _4, radicals ^{R 4} and one is a hydrogen atom or a _{C 1} of the ^{R 5} -
A C ₄ alkoxy group , the other of the formula:

Embedded image (Wherein, R ⁶ , R ⁷ , R ⁸ and R ⁹ represent a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ acyloxy group or a hydroxy group) A compound represented by the formula or a tautomer or configuration isomer or optical isomer thereof as an active ingredient;
Or an antitumor pharmaceutical composition.

[0007] A particularly preferred embodiment is the formula:

Embedded image Wherein A, B and R ¹ to R ⁴ have the same meaning as described above.

In particular, the group R ⁴ is a group R ⁴ bonded to a phenyl ring.
It is preferably in the ortho position to ³ .

A further preferred embodiment is the formula (1.1),
(1.2) and (1.3),

Embedded image

Embedded image

Embedded image It is a compound shown by these.

In a further preferred embodiment, R ¹ is C ₁ -C
₄ represents an acyl group, particularly an acetyl group, wherein R ² is C ₁ -C ₄
Is a compound represented by the formula (1), which represents an alkyl group, particularly a methyl group.

In the above formula one of the radicals R ⁴ and R ⁵ , in particular the radical R ^5, is of the formula

Embedded image Represents a group represented by

Preferably, R ⁶ , R ⁹ and R ⁷ and R ⁸
One of them is a hydroxy group, and the other of R ⁷ and R ⁸ represents a C ₁ -C ₄ alkyl group, particularly a methyl group.

Particularly preferably, one of the radicals R ⁴ and R ⁵ has the formula:

Embedded image And especially bonded to the 2-position of the basic skeleton.

Preferably, in the above formula, the group R ³ represents a hydroxy group.

Particularly preferred compounds are

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image It is a compound shown by these.

Hereinafter, these compounds are indicated by abbreviations given according to the molecular weight.

In the process for producing the compounds of the present invention,
arwinskia plant (or other plant containing a compound of the present invention). For this purpose, the fruits are usually dried and ground. Subsequently, degreasing is performed with a non-polar organic solvent, for example, pentane, hexane, petroleum ether or the like. The defatted fruit is then extracted with a solvent of moderate polarity. Suitable solvents are chlorinated aliphatic hydrocarbons, for example, chloroform, dichloromethane, dichloromethane and the like. The extraction is usually performed 3 to 10 times (v /
This is performed by using the solvent of w). Depending on the purpose, 1/10 to 1/20 of the initial liquid volume for further processing
The extract is concentrated. Optionally, the solvent can be completely removed and the residue can be treated as described below.

From the concentrated extract, a precipitate containing the compound of the present invention is obtained by adding a non-polar organic solvent such as pentane, hexane, petroleum ether and the like. It is usually obtained by thin-layer chromatography, column chromatography or by fractional crystallization.

The compound of the present invention thus obtained can be converted to another compound of the present invention by a conventional chemical transformation such as esterification, etherification, ester or ether hydrolysis, substitution reaction of an aromatic ring, oxidation and reduction. Can be changed.

Compounds T-514, 496, 544 and 5
16 is itself Karwinski humbo
ldtiana fruit, for example, Am. So
c. , 97: 4986 (1975). A more extensive method for obtaining T-514 is described in Toxicon, 25 (5): 565-568 (19).
87).

Pharmacological studies have shown that the antitumor and cytotoxic effects of the compounds according to the invention are highly selective, especially for the liver, lungs and colon. The compounds of the present invention
Benign and malignant cells can be distinguished. They can therefore be used in particular for the treatment of liver, lung and colon cancer. Furthermore, the compounds according to the invention have an antiviral effect and are therefore, for example, herpes simplex type I, type II, III
It has been shown that it can be used for viral infections such as types.

The compounds of the present invention can be provided alone or in conjunction with other therapeutic drugs.
They can be provided as is, or generally, in the form of a drug, ie, as a mixture with a suitable pharmaceutical carrier and / or adjuvant. The compound or agent is provided in a form that can be administered orally or parenterally, preferably parenterally. To this end, the drug is added to a conventional pharmaceutical carrier and used, for example, in the form of an injectable solution.

The preparation of the medicament is carried out in the customary manner, in which the medicament is mixed with a pharmaceutical carrier and / or adjuvant.

For therapeutic use, the compounds of the present invention can be administered to mammals (humans and animals) in an amount of about 0.01 mg / kg body weight per day.
To about 2 mg, preferably about 0.01 mg to about 1 m
g, and particularly preferably from about 0.01 mg to about 0.5 m
g, or an amount of about 0.01 mg to about 0.1 mg. They can be administered together at once or in several divided doses. The above dosage ranges are exemplary only. Obviously, the optimal dose will be determined by a physician in view of age, weight, the disease being treated, the severity and site of the disease, and the like.

[0025]

The following examples illustrate the invention. Example 1 3,3 ′, 8,8 ′, 9,9′-hexahydroxy-3,3,4,4-tetrahydro- (7,1
0'-bisanthracene-1,1 '-(2H, 2H')
Preparation of dione (T-514):

Embedded image 500 g of dried and ground fruit of Karwinskia humboldtiana are sequentially extracted with 3 L of petroleum ether (boiling range about 60-70 ° C.) and 3 L of chloroform. The chloroform extract was concentrated to 100 ml,
The extract is precipitated by adding twice 0 ml of n-hexane. The obtained yellow powder was applied to silica gel G (layer thickness 0.5 m).
m) Fractionation is performed using benzene: acetone (2: 1) as a developing solution. The fraction with the lowest Rf value is Compound T-514
It is. The fraction is scraped off from the chromatography plate and eluted with acetone. The product is further purified on acetylated polyamide (layer thickness 0.5 mm) using methanol: water (2: 1) as a developing solution. After recrystallization from benzene-hexane, pure T-514 (50 mg) is obtained. Melting point: 178-180 ° C ¹ H-NMR and ¹³ C-NMR spectra are shown in Table 1 of Example 2. LD ₅₀ (intraperitoneal administration to mouse): 6.52 ± 0.86
mg / kg

Embodiment 2 T-514 '(T-514)
Preparation of Karwinskia par)
500 g of dried and ground fruit of vifolia was sequentially extracted with 3 L of petroleum ether, chloroform and methanol. The extractions were each performed at room temperature for 3 days. After evaporating the solvent of the chloroform extract, the mixture was developed on silica gel into three fractions with benzene: acetone (3: 1) containing 0.1% acetic acid. Each fraction was further purified by chromatography on silica gel and on acetylated polyamide. First
The compound named T-496 was obtained from the fraction, the T-514 from the third fraction, and the desired compound T-514 'from the second fraction. T- from benzene-hexane
514 ′ was recrystallized to obtain a yellow powder (450 mg) having a melting point of 169 to 171 ° C. UV (methanol) max: 220 (4.83), 2
66 (4.97), 408 (4.38) IR: 3360, 1625, 1350, 1250 EIMS: m / z (relative intensity): M ⁺ 514 (3
0), 478 (80), 240 (10), 43 (10
0)

The NMR spectra of T-514 and T-514 'are shown in Tables 1 and 2 below.

[Table 1]

[Table 2]

Example 3 Production of T-510:

Embedded image Karwinski affin humboldt
500 g of dried and ground fruits of Iana are sequentially extracted with 3 L of petroleum ether (boiling range 60-70 ° C.) and 3 L of chloroform. The chloroform extract is concentrated to 100 ml and the extract is precipitated by adding 300 ml of n-hexane. The resulting powder is converted to benzene on silica gel:
Purification by thin layer chromatography using acetone (3: 1) as solvent. The fraction having the maximum Rf value is purified on a silica gel column using benzene: acetone (40: 1) as a developing solvent. The fractions obtained are exposed for 24 hours, filtered and purified by chromatography on acetylated polyamide with chloroform: methanol (30: 1) and precipitated with a mixture of benzene: acetone. Yield 60 mg. Melting point: 136-138 ° C UV: λmax: 423 (4.28), 314 (4.
78), 204 (4.70), 226 (4.78) IR (cm ^-1 ): 3400, 1720, 1690, ¹
630, 1270, 750 ¹ H-NMR:

[Table 3]

Example 4 Production of T-496:

Embedded image 500 g of dried and ground fruit of Karwinskia humboldtiana are sequentially extracted with 3 L of petroleum ether (boiling range about 60-70 ° C.) and 3 L of chloroform. The chloroform extract was concentrated to 100 ml,
The extract is precipitated by adding twice ml of n-hexane. The obtained yellow powder was applied to silica gel G (layer thickness 0.5 m).
m) Fractionation is performed using benzene: acetone (2: 1) as a developing solution. The fraction having the maximum Rf value is subjected to chromatography on a silica gel column using benzene: acetone (40: 1) as a solvent. The purified product is precipitated with benzene-hexane. Yield: 50 mg of pure powder. Melting point: 230 ° C UV; λmax: 227 (4.66), 273 (4.
71), 397 (4.15) IR (cm ^-1 ): 3415, 1635, 1620, ¹
600

[Table 4]

Example 5 Production of T-ISO514:

Embedded image 500 g of dried and crushed fruits of Karwinskia umbelleta are mixed with 3 L of petroleum ether (boiling point 60 to 7).
0 ° C.) and 3 L of chloroform. The chloroform extract is concentrated to 100 ml and the extract is precipitated by adding 300 ml of n-hexane. The obtained powder is purified by thin layer chromatography on silica gel using benzene: acetone (2: 1) as a solvent. Minimum R
The fraction having the f-value is subjected to silica gel column chromatography. The product is eluted with benzene: acetone (1: 1) and then purified on a Sephadex column using methanol as solvent. Precipitation with n-hexane gives 30 mg of purified product. Melting point: 161-164 ° C UV; λmax: 422 (3.75), 270 (4.
64), 220 (4.1) IR (cm ^-1 ): 3400, 1630, 1600

[Table 5]

Example 6 Production of T-514:

Embedded image 500 g of dried and ground fruit of Karwinskia humboldtiana are sequentially extracted with 3 L of petroleum ether (boiling range about 60-70 ° C.) and 3 L of chloroform. The chloroform extract was concentrated to 100 ml,
The extract is precipitated by adding twice 0 ml of n-hexane. The obtained yellow powder was applied to silica gel G (layer thickness 0.5 m).
m) Fractionation is performed using benzene: acetone (2: 1) as a developing solution. The fraction having an intermediate Rf value is purified by column chromatography using silica gel using benzene: acetone (20: 1) as a developing solution. After re-chromatography, it was precipitated with n-hexane to give 200 m
g of purified product are obtained. Melting point: 166-168 ° C UV (methanol); λmax: 228 (4.6
7), 242 (4.77), 270 (4.63), 41
5 (4.00) IR (cm ^-1 ): 3390, 1625

[Table 6]

[Example 7] Cytotoxic effect of T-514: Human-derived cells were used for the test. As liver cells, benign Chang hepatocytes and three types of cell lines as neoplastic cells, namely Hepatom PLC / P
RF / 5, Hep with surface antigen of hepatitis B virus
3B and Hep2B without antigen were used.

As lung-derived cells, benign lung epithelial cells W
i1003 and four cell lines as neoplastic cells, namely squamous carcinoma, SK-mes-1, adenocarcinoma Calu, bronchial undifferentiated carcinoma Cha-Go-K-1 and small cell carcinoma NCI
-H69 was used.

As colon cells, benign colon epithelial cells CC
D-33Co and colon cancer cell line LoV as neoplastic cells
o was used.

The cell culture of each of the tested cell lines was a mixture of Eagle's basal medium and fetal sheep serum (9+
1) was used. Test substances (dissolved in ethanol or water) were added to cell cultures at the following concentrations (μg / ml). T-514: 2.5, 5, 10, 20, 40, 80,
160, 320 Doxorubicin: 0.025, 0.05, 0.1,
0.2, 0.4, 0.8, 1.6, 3.2, 6.4 4-Epidoxorubicin: 0.025, 0.05,
0.1, 0.2, 0.4, 0.8, 1.6, 3.2,
6.4 Vincristine: 0.002, 0.004, 0.00
8, 0.0156, 0.03125, 0.0625,
0.125, 0.25, 0.5, 1, 2, 4, 8, 16 5-fluorouracil: 6.25, 12.5, 25,
50, 100, 200, 400, 800, 1600, 3
200 Mitomycin: 0.25, 0.5, 1, 2, 4,
For the 8,16 control test, a solvent to which no test substance was added was used.

Evaluation after culturing for 72 hours was usually carried out by measuring the adhesion, morphology and proliferation of cells to a petri dish. Corrected therapeutic index LD _05% / ED _95%
Asked. Each value was extrapolated from the corresponding curve. The modified therapeutic index indicates the selectivity of the test substance. That is, a positive therapeutic index indicates that the tumor cells are more sensitive to the test substance than benign cells, whereas a negative modified therapeutic index indicates the opposite. The results are summarized in Table 3.

[Table 7]

[0037]

The results show that compound T-514 acts very selectively, ie, has a greater activity on malignant tumor cells than on benign tumor cells. The compounds of the present invention can therefore be used for the treatment of cancer and tumors with a wide safety margin.

Continuation of front page (56) References JP-A-62-207213 (JP, A) CHEM. PHARM. BULL. VOL. 38 NO. 5 (1990) p. 129-129 BULL. CHEM. SOC. ETH IOP. , VOL. 1NO. 1 (1987) p. 32-35

Claims (2)

(57) [Claims] (1) Formulas (I) to (VI): Embedded image Embedded image Embedded image Embedded image Embedded image Or an antitumor or antitumor pharmaceutical composition comprising an anthracene compound represented by any of the above or a tautomer, configurational isomer, or optical isomer thereof, and a pharmaceutical carrier. 2. The anticancer or antitumor pharmaceutical composition according to claim 1, comprising an anthracene compound represented by the formula (II) or a tautomer, configurational isomer or optical isomer thereof and a pharmaceutical carrier. Stuff.