JPS62190143A - Novel tropolone derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> is alkyl, hydroxyl, amino, amide, carboxy, alkoxycarbonyl, benzyloxy, alkoxycarbonylmethyloxy, phenyl; R<2> is H or incorporates with R<1> to form formula IV). EXAMPLE:4-Benzyloxy-alpha,alpha-bis(2-hydroxyl-6-isoproyltropolon-3-yl )-toluene. USE:Anticancer agent. It has excellent anticancer action and other pharmaceutical activity in some cases. The dose is 0.5-1mg/kg body weight based on the active ingredient. PREPARATION:The compound of formula II with hinokitiol of formula III is reacted under heating in a solvent or without solvent, in the presence of or absence of a catalyst at 150-180 deg.C for 1-10hr to give a compound of formula I where R<1> is alkyl, amide, alkoxycarbonyl, alkoxycarbonylmethyloxy, benzyloxy or phenyl.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to novel trobolone derivatives.

More specifically, the present invention relates to a novel troborone derivative having excellent pharmacological effects as an anticancer drug.

(Prior Art) The applicant previously filed an application for a compound having one troborone ring in the molecule, which is produced by the reaction of an acetal of an aromatic aldehyde such as benzaldehyde diethyl acecure with a troborone derivative such as hinokitiol. (Patent Application No. 58-181087).

In addition, the applicant has discovered that a trobolone derivative having two tropolone rings in the molecule can be obtained by changing the molar ratio of the reactants in the above reaction and increasing the reaction conditions, and has filed a patent application. (Sho 58-181088).

Furthermore, the applicant of the present invention has created a troborone ring in the molecule by reacting 3-(α-ethoxybenzyl)-6-ituprobil troborone with various phenolic compounds or heterocyclic compounds as described in Japanese Patent Application No. 181087/1987. He discovered that a different type of compound from that of the patent application No. 58-181087 could be obtained and filed an application.
0-56565).

Additionally, the applicant has applied for a compound having two tropolone rings in the molecule produced by the reaction of an acetal of an aldehyde having a heterocyclic group such as furyl, chenyl, or pyridyl with a trobolone derivative such as hinokitiol ( (Special Application Shozutsu No. 60-266555).

(Problems to be Solved by the Invention) An object of the present invention is to provide a novel trobolone derivative having an excellent anticancer effect, which has a different structure from the conventional trobolone derivatives described above. .

(Means for Solving the Problems) The present invention is based on the general formula (wherein R1 is alkyl, hydroxy, amino, amido, carboxy, alkoxycarbonyl, hensyloxy, alkoxycarbonylmethyloxy, or phenyl, and R2 is hydrogen or together with R1 to form 10-C] (to form □-0-).

As used herein, the term alkyl refers to an alkyl group having from 1 to about 5 carbon atoms, such as methyl, ethyl, j
Examples include so- or n-propyl, n-butyl, n-pentyl, and the like.

The term alkoxycarbonyl also includes 2 to about 6 carbon atoms.
It represents an alkoxycarbonyl having carbonyl, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like.

The term amide also refers to an amide of the formula -NHCOR3, where R3 is alkyl as defined above.

In the above compound, the troboryl group has a resonance structure as shown by the following formula.

Therefore, it should be understood that the present invention includes compounds having these resonance structures or mixtures thereof.

The troborone derivative of formula (1) of the present invention can be produced, for example, as shown in the reaction formula below.

(It) That is, the derivative of formula (+) can be produced by heating and reacting hinokitiol (III) with a compound of formula (n) in a solvent or without a solvent in the presence or absence of a catalyst.

The above reaction is usually carried out at about 150 to 180° C. for about 1 to 10 hours, depending on the type of reactants, whether or not a catalyst is used, etc.

As the catalyst, potassium tert-butoxide, triethylamine, sodium hydride, sodium amide, etc. can be used, and potassium tert-butoxide is particularly preferred. When using a catalyst, the amount used is usually determined by the formula (
About 0.01 to 1 mole of hinokitiol in III)
A molar range is preferred.

Further, as the solvent, xylene, cymene, tetralin, pyridine, a mixed solvent thereof, etc. can be used.

In the above reaction, the compound of formula (It) is usually used in an amount of about 0.5 to 1 mole per mole of hinokitiol (■).

Examples of the compound of formula (II) include substituted benzaldehyde diethyl acetal and biperonal diethyl acetal having a substituent such as alkyl, acetamide, alkoxycarbonyl, benzyloxy, phenyl or methoxycarbonylmethyloxy.

In the present invention, the compound in which R' is hydroxyl can be produced by further catalytic reduction of the compound in which R1 is benzyloxy produced as described above.

Catalytic reduction can be carried out, for example, by reducing the above compound with hydrogen in a suitable solvent in the presence of palladium supported on carbon.

Further, in the present invention, compounds in which R1 is amino, carboxy, or carboxymethyloxy can be produced by hydrolyzing compounds in which R1 is amide, alkoxycarbonyl, or alkoxycarbonylmethyloxy, respectively. The detailed conditions for these catalytic reduction and hydrolysis will become clearer from the Examples described below.

The compound of formula (1) thus obtained can be isolated and characterized by conventional methods. For example, it can be purified by recrystallization from a suitable solvent or mixed solvent such as methanol, ether, ethyl acetate, ethyl acetate and chloroform, etc. Alternatively, it can be eluted by silica gel column chromatography using a suitable eluent and then recrystallized from the solvent as described above.

Compounds of the invention have been found to have anticancer effects and, in some cases, other pharmaceutical activities. This anticancer activity has been demonstrated in animal studies at dosages typically between 0.5 and 5 B/kHz. For human treatment, the dosage administered may be e.g.
5-1 mg/kg, but of course dosages outside this range can be used at the discretion of the patient's medical treatment. The anticancer active compounds of formula (I) can be administered by enteral or parenteral routes, and for this purpose are usually in the form of at least one pharmaceutically acceptable salt, or a pharmaceutical preparation consisting of the active ingredient in combination with a carrier. formulated into a composition.

The compounds of the invention and compositions thereof are, of course, compatible with particular routes of administration. Thus, tablets, pills, capsules, solutions, or suspensions can be used for oral administration. For parenteral administration, sterile injection solutions or suspensions can be used. For rectal administration, suppositories can be used. Creams, lotions, or ointments can be used for topical administration. Of course, the above compounds can be formulated into delayed or connected play-resistant forms.

(Effects of the Invention) The compound (2) of the present invention clearly has an excellent anticancer effect from the Examples described below, and is therefore extremely useful as an anticancer drug.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 Synthesis of 4-benzyloxy-α,α-bis(2-hydroxy-6-ituprobyltroboron-3-yl)toluene 4-benzyloxybenzaldehyde diethyl acecool (3.5 g -12 mmol) and hinokitiol (1
, 4 g, 24N1110+) were heated to 180° C. for 3 hours in an argon stream, and the reaction mixture was separated by silica gel chromatography. Hexane-ethyl acetate (4:1
), 4-hensyloxy-α,α-bis(2
-Hydroxy-6-isoprobyltropolon-3-yl)toluene was obtained (hereinafter referred to as compound A). Yield ff12.7g (yield 42%). Melting point 203-204℃
.

Elemental analysis: C, 77,91; 11,6.52 NMR
δ: 1.26 (121, d), 2.50 to 3.20
(2+1.m), 5.09 (211,s), 6.68
(III, s), 6.70-7.70 (1511, m)
, 9.61 (2+I, s) Example 2 α,α-bis(2-hydroxy-6-isoprobyltroborone-3-
Synthesis of -334-methylenedioxytoluene biveronal diethyl acetal (3.4 g).

15mlol), potassium tert-butoxide (
0.25 g% 2.5 mmo+) and 0.5 g of N,N-hexamethylphosphoramide (HMPA) were dissolved in 20 ml of xylene and heated under reflux for 12 hours. The reaction mixture was acidified with 10% Hα, the precipitated crystals were collected by filtration, and recrystallized from dichloromethane to give α,α-bis(2-
Hydroxy-6-isopropyltroben-3-yl)3
, 4-methylenedioxytoluene was obtained. (below,
(referred to as compound B). Yield ff12.9g (yield 41%)
. Melting point: 214-215°C.

Elemental analysis: C, 72,98; I+, 6.02NMR
δ: 1.32 (121!, d), 2.50-3.20
(211, m), 6.76 (111, s), 6.80~
7.90 (1511, m), 9.61 (211, s) Examples 3 to 6 The following compounds were synthesized in the same manner as in the above examples. The results obtained are shown in Table 1.

Real Jill+7 α,α-bis(2-hydroxy-6
Synthesis of 4-hydroxytoluene Compound A (Ig, 2 mmol) obtained in Example 1 was dissolved in a mixed solvent of dioxane-ethanol with 10% Pd-
Catalytic reduction in the presence of C (0.1 g) yields α.

α-bis(2-hydroxy-6-itupropyltropon-3-yl)4-hydroxytoluene was obtained (hereinafter referred to as compound G). .

Yield ff10.76g (yield 91%).

Melting point: 219-220°C.

Elemental analysis: C, 74,72; II, 6.69HMR
δ: 1.2B (12+1.d), 2.50-3.30
(2+1.Meng), 6.6H111,s), 6.75-7
．． 60 (10 fl, m), 8.50-9.50 (311
, b) Example 8 4-amino-α,α-bis(2-hydroxy-
Synthesis of 6-itubrobiltropon=3-yl)toluene Compound C obtained in Example 3 (2.2 g, 5 mmol
) was dissolved in 30 ml of acetic acid, 10% MCI' was added thereto, and the mixture was heated under reflux for 10 hours. The reaction mixture was poured into water, made alkaline with saturated potassium bicarbonate solution, and then extracted with methylene dichloride. The methylene dichloride layer was washed with water, dried, and concentrated to precipitate crystals. This was recrystallized from a methanol-methylene dichloride mixed solvent to obtain the title compound. (Hereinafter referred to as compound H). Yield 1.3
g (yield 66%).

Melting point 244-245°C Elemental analysis: C, 74, 80, 11, 6, 64; N,
2.92HMRδ: 1.07 (12+1.d), 2.
50-3.10 (211, +a), 6.43 (2) 1.
b), 6.52(1)1. s), 6.50-7.50
(1011,+m) Example 9 Synthesis of 4-carboxy-α,α-bis(2-hydroxy-6-isoprobyltrobon-3-yl)toluene Compound D obtained in Example 4 (0.8g, 2+++mo
l) in a mixed solvent of methanol-water (2:1) Loom
10g of NaOII was added to this, and 2
The mixture was heated to reflux for 0 minutes. After acidifying with 5% Hα, methanol was distilled off and the precipitate was extracted with methylene dichloride.

The methylene dichloride layer was washed with water, dried, and then concentrated. The residue was recrystallized from a mixed solvent of ether and methylene dichloride to obtain the title compound (hereinafter referred to as Compound I). Yield 0.6g (82%).

Melting point 256-257°C.

Elemental analysis: C, 72, 79, 1+, 6.12HMRδ
: 1.26 (12H, d), 2.60-3.30 (2
! l, m), 6.70-7.60 (9H, m), 8.0
0-8.50 (2H4), 10.16 (3H, s) Example 10 4-Carboxymethyloxy-α.

Synthesis of α-bis(2-hydroxy-6T isopropyltrobon-3-yl)toluene In the same manner as in Example 9, the title compound (hereinafter referred to as compound J) was obtained from compound E obtained in Example 5. Ta.

Yield 73%. Melting point 242-243°C.

Elemental analysis: C, 71,01, II, 6.19HMRδ
: 1.30(12+1.d), 2.50~3.30(
21Lm), 4.66 (21,s), 6.65 (111
，! l), 6.70-7.70 (10) 1. a+), 1
0.30(3)1. s) Compound K in equimolar amounts of CJ6ON
After dissolving a in ethanol containing a, the ethanol was distilled off under reduced pressure to obtain the sodium salt in quantitative yield. Melting point>300℃.

Example 11 Anti-tumor test KB-Cell growth inhibition test KB-cells in Eagles minimal esse
ntial medium (MEM)-10%Ca1f
5erva medium and 37°C in a 5% carbon dioxide solvent vessel.
The experiments were carried out using those cultured in On the first day, KB cells were diluted to contain 2XlO'/mf cells, and 3 m
Plant l in 60 crane clocks. On the second day, the test drugs were added at 100, 30, and 1013.1 pg/ml, respectively, and cultured in the same manner. Cells that survived on the fourth day were removed from the watch glass using trypsin, and the number of cells was counted. At this time, the concentration of the drug required to show a substantial 50% growth inhibition in the number of cells compared to the control without the addition of the drug (EDS) is determined, and the drug's inhibition of cancer cell growth is determined. Expressed as an effect. The results are shown in Table 2.

Life extension effect test on cancer-bearing mice: 6 CDF mice as 1 group P2S5)11
After transplanting 101' cells into each mouse, the 10th
On the fifth day, the test drug was administered intraperitoneally to the mice. The survival effect was evaluated as the ratio (T/C%) of the survival days of the treated group to the survival days of the untreated group. The results are shown in Table-2.

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 is alkyl, hydroxy, amino, amido, carboxy, alkoxycarbonyl, benzyloxy, alkoxycarbonylmethyloxy, or phenyl. and R^2 is hydrogen or together with R^1 forms -O-CH_2-O-).