JPH04312596A - Chartreusin derivative salt and anti-cancer agent containing the same - Google Patents

Abstract

PURPOSE:To provide the subject novel stable compound (including the quaternary ammonium salt thereof) having a high anti-cancer activity without depending on cancer-inoculated sites and administered sites, and useful as an anti-cancer agent, etc., by reacting an exo type chartreusin derivative with an alkyl halide. CONSTITUTION:N,N-Dimethylglycine hydrochloride is reacted with exo type 3', 4'-O-benzylidene chartreusin in the presence of triethylamine and dicyclohexylcarbodiimide in anhydrous pyridine. The resultant exo type chartreusin derivative of formula I [Q' is a group of formula II (R is 1-11C alkane diyl, etc.; Z1, Z2 are 1-6C alkyl, etc.,), etc.,][e.g. type 6-O-(N,N- dimethylglycyl)-3', 4'-O-benzylidene chartreusin]is reacted with an alkyl halide (e.g. methyl iodide) to provide an exo type chartreusin derivative quaternary ammonium salt of formula III [Q is a group of formula IV (Z3 is 1-3C alkyl; X is halogen), etc.,].

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD The present invention relates to novel quaternary ammonium salts of exo-type chartrusin derivatives, anticancer agents containing them as active ingredients, and methods for producing them.

0002

[Prior Art and Problems] It is already known that chartrusin has anticancer activity; for example, in Cancer Research No. 37,
1666-1672 (1977), P-388,
It has been reported that it was effective against L-1210 leukemia and B-16 melanoma. However, this effect was obtained in a system in which the cancer was implanted into the peritoneal cavity and the drug was administered intraperitoneally; no effect could be obtained if the cancer inoculation site and the drug administration site were changed. It is also reported that there was no such thing. Due to this situation, chartresin has not yet been developed.

0003

[Background for solving the problem] The present inventors focused on the excellent anticancer activity of chartrusin, and conducted extensive studies to eliminate the difference in effect expression due to the difference between the cancer inoculation site and the drug administration site. , a system in which the cancer is transplanted intraperitoneally and the drug is administered intravenously, a system in which the cancer is transplanted subcutaneously and the drug is administered intravenously, etc. Even if the site of cancer inoculation and the drug administration site are changed, excellent anti-inflammatory effects can be achieved. A novel chartrusin derivative exhibiting cancer activity was discovered, and the present applicant previously filed an application as JP-A-62-99391. On the other hand, among these derivatives of chartrusin, water-soluble derivatives using amino acids are salts such as hydrochloride of amino groups. Since the molecules of this type of derivatives are weakly basic, the aminoacyl moiety in the phenolic hydroxyl group becomes unstable, and formulations must be devised for clinical use. However, the aminoacyl moiety converted into a quaternary ammonium salt has increased stability and is clinically useful. Furthermore, the present inventors have discovered that this quaternary ammonium salt of exo-type chartrusin also exhibits excellent anticancer activity even when the cancer inoculation site and the drug administration site are different, thereby completing the present invention.

0004

DISCLOSURE OF THE INVENTION That is, the present invention relates to general formula (I);

0
005]

[Chemical formula 1]

[In the formula, Q is

[0007]

[Case 2]

(wherein R, R' and R'' are an optionally substituted alkane (C1-11) diyl group or an optionally substituted cycloalkane (C3-10) diyl group, and Z
1' and Z1'' are a hydrogen atom or an optionally substituted alkyl (C1-6) group, Z1 and Z2 are an optionally substituted alkyl (C1-6) group, and Z3 is an alkyl (C1-6) group that may be substituted.
(C1-3) group, which may form a heterocycle (C2-10) having a nitrogen atom which may be substituted with Z1 and Z2), X is a halogen atom, and the hydrogen of this Q The total number of atoms excluding atoms is 30 or less] A quaternary ammonium salt of an exo-type chartrusin derivative,
The present invention relates to anticancer agents containing these as active ingredients and methods for producing them.

In the general formula (I), "optionally substituted alkanes (C1-11)" represented by R, R' and R"
Diyl group or optionally substituted cycloalkane (C3-
10) Examples of the substituents of "diyl group" include hydroxyl group, alkoxy (C1-6) group, aminocarbonyl group, etc., and "optionally substituted alkyl (C1 Examples of the substituent of the group "~6)" include a hydroxyl group and an alkoxy (C1-3) group.

Alkanes represented by R, R' and R'' (
C1-11) diyl group, Z1, Z1', Z1'' and Z2
an alkyl group or alkyl moiety represented by R,
The alkyl moieties as substituents represented by R', R'', Z1, Z1', Z1'' and Z2 may be either linear or branched.

The "heterocycle (C2-10) having a nitrogen atom" formed by Z1 and Z2 is aziridine (C2-10).
2), pyrrolidine (C4), morpholine (C4), piperidine (C5), heptaethyleneimine (C7), etc., and substitution of "heterocycle (C2-10) having a nitrogen atom that may be substituted" Examples of the group include a hydroxyl group, an alkyl (C1-4) group, and an alkoxy (C1-3) group. The alkyl group or alkyl moiety herein may be either linear or branched, as described above.

The compound of the present invention can be produced, for example, by the following method. First step

[0013]

[C5]

[0014] Second step

[0015]

[C6]

Q' in the above general formulas (II) and (IV)
teeth

[0017]

[C4]

(wherein R, R', R'', Z1', Z1''
, Z1 and Z2 are as described above), examples of neutral solvents include chloroform, ethyl acetate, dimethylformamide, etc., examples of basic solvents include pyridine, and examples of bases include triethylamine. Examples of the condensing agent include carbodiimides such as dicyclohexylcarbodiimide.

[0019]

EXAMPLES Next, specific synthesis examples of the compounds of the present invention will be described.

Synthesis Example Exo-type 6-o-(N,N-dimethylglycyl)-3',4'-o-benzylidene-chartruscin methyl iodide salt (quaternary ammonium salt) (Compound No. 1 ) synthesis

(1) After adding 767 mg of N,N-dimethylglycine hydrochloride to 20 ml of anhydrous pyridine under stirring,
556 mg of anhydrous triethylamine was added to form a solution. A solution of 3.64 g of exo-type 3',4'-o-benzylidenechartruscin dissolved in 40 ml of anhydrous chloroform was added thereto, followed by 1.36 g of dicyclohexylcarbodiimide, and the mixture was stirred at room temperature for 3 hours and 30 minutes.

After the reaction was completed, a small amount of methanol was added and the mixture was stirred at room temperature for 30 minutes, then ethyl acetate was added, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was recrystallized from a mixed solvent of chloroform and ethyl acetate, and 2.7 g of crude crystals were obtained.
Obtained.

The crude crystals were dissolved in 300 ml of chloroform, washed successively with water, diluted hydrochloric acid, water, and brine, concentrated under reduced pressure, and dissolved in diluted hydrochloric acid.

After washing this aqueous solution with ethyl acetate,
Extracted with chloroform while adding aqueous sodium bicarbonate. The extracted chloroform layer was washed with water and brine in that order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized with a mixed solvent of chloroform and ethyl acetate to obtain the exo form 6-o-(N,
2.3 g of N-dimethylglycyl)-3',4'-o-benzylidenechartruscin was obtained.

(2) Exo-type 6-o-(N,N-dimethylglycyl)-3',4'- obtained in step (1) above
After 280 mg of o-benzylidene chartrecin was dissolved in 3.4 ml of chloroform and 10.3 ml of ethyl acetate, 520 mg of methyl iodide was added, and the mixture was stirred at room temperature for 6 hours.

After the reaction is completed, it is concentrated under reduced pressure and recrystallized from a mixed solvent of chloroform and ethyl acetate to give a melting point of 194-198.
284 mg of the target product was obtained.

Next, examples of specific compounds included in the present invention are shown below. General formula (I);

[0028]

[Chemical formula 1]

[0029]

[Table 1]

As shown in the test examples below, the compound of the present invention has the following properties:
Shows excellent effects on p-388 leukemia cells.

The anticancer activity, dosage and method of administration, and acute toxicity of the compounds of the present invention will be described below.

(1) Anticancer activity BDF1 mice were given p-
388 leukemia cells were intraperitoneally transplanted at a rate of 1×10 6 cells/mouse, and the test drug was intravenously administered three times on the 1st, 5th, and 9th days after transplantation. The survival rate (%) of each treatment group was determined by observing the survival of the mice for 35 days and setting the number of survival days of mice in the control group administered with physiological saline as 100.
The results are shown in Table 2. The drug was prepared by adding physiological saline to the test compound to form a solution.

[0033]

[Table 2]

(2) Dosage and administration method The dose of the anticancer agent of the present invention cannot be absolutely defined due to differences in administration conditions, but it is usually about 5 to 60 mg of the active ingredient per kg of body weight per day, preferably about 10 to 60 mg per kg of body weight. It is 40 mg.

When administering the drug, the above-mentioned dosage may be administered all at once or in divided doses, and may be increased or decreased depending on the exigencies of the therapeutic condition.

[0036] Furthermore, the anticancer agent of the present invention can be formulated in the same manner as ordinary pharmaceuticals, for example, it can be formulated from an active ingredient and various pharmacologically acceptable carriers, such as an inert diluent.
These can be administered intravenously.

(3) Using acutely toxic ddY mice, compound No. 1 of the present invention formulated according to the formulation example described below. In intravenous administration of No. 1, not a single mouse died even after administering 60 mg/kg, indicating acute toxicity (LD50
) was confirmed to be 60 mg/kg or more.

Next, examples of formulations of the anticancer agent of the present invention will be described.

Formulation Example Exo-type 6-o-(N,N-dimethylglycyl)-3',4'-o-benzylidenechartruscin methyl iodide salt (quaternary ammonium salt)9.
0mg to Tween-80 (Tween-80) 0.20
ml and then add 2.8 ml of physiological saline little by little to form a solution.

[0040]

The present invention provides a clinically useful anticancer agent that exhibits excellent anticancer activity even when the site of cancer inoculation and the site of drug administration are changed, and has enhanced stability in formulation.

Claims (3)

[Claims] Claim 1: General formula (I) [Formula 1] [In the formula, Q is [Formula 2] (In the formula, R, R' and R'' are an optionally substituted alkane (C1-11) diyl group or It is an optionally substituted cycloalkane (C3-10) diyl group, and Z1' and Z1
" is a hydrogen atom or an optionally substituted alkyl (C1-6
) group, Z1 and Z2 are optionally substituted alkyl (C1-6) groups, Z3 is an alkyl (C1-3) group, and has a nitrogen atom that may be substituted with Z1 and Z2 may form a heterocycle (C2-10)),
X is a halogen atom, and the total number of atoms in Q excluding hydrogen atoms is 30 or less]. Claim 2: General formula (I) [Formula 1] [In the formula, Q is [Formula 2] (In the formula, R, R' and R'' are an optionally substituted alkane (C1-11) diyl group or It is an optionally substituted cycloalkane (C3-10) diyl group, and Z1' and Z1
" is a hydrogen atom or an optionally substituted alkyl (C1-6
) group, Z1 and Z2 are optionally substituted alkyl (C1-6) groups, Z3 is an alkyl (C1-3) group, and has a nitrogen atom that may be substituted with Z1 and Z2 may form a heterocycle (C2-10)),
X is a halogen atom, and the total number of atoms excluding hydrogen atoms in Q is 30 or less]. Characteristic anticancer agent. [Claim 3] General formula (II) [In the formula, Q' is [Formula 4] (In the formula, R, R' and R'' are an optionally substituted alkane (C1-11) diyl group or an optionally substituted cycloalkane (C3-10) diyl group, and Z1' and Z1
" is a hydrogen atom or an optionally substituted alkyl (C1-6
) group, Z1 and Z2 are optionally substituted alkyl (C1-6) groups, and Z1 and Z2 may form a heterocycle (C2-10) having a nitrogen atom that may be substituted. general formula (I), characterized by reacting an exo-type chartrusin derivative represented by 2] (wherein R, R', R'', Z1', Z1'', Z1 and Z
2 is as described above, Z3 is an alkyl (C1-3) group), and the total number of atoms excluding hydrogen atoms in Q is 30 or less]. A method for producing class ammonium salt.