JPH04247084A - New derivative of indole, process for producing same, use thereof as medicine and composition containing same - Google Patents

Abstract

PURPOSE: To obtain a new compound useful for prophylatic or curing treatment of cancers such as leukemia, tumor, or metabolic disease of normal genomes, autoimmune diseases such as multiple rheumatic arthritis and systemic lupur erythematosus.

CONSTITUTION: This compound denoted by the formula I, e.g. 2,9-dimethoxy-6,13- dioxo-pyradino [1,2-a:4,5-a'] diindole, etc., is obtained by allowing two molecules of 2-indole carboxylic acid, whose 5-position is optionally substituted or not substituted by group R and R', to condense in the presence of a condensing agent such as bicyclohexylcarbodiimide. In the formula I, R and R' are each H, hydroxy, 1-5C alkyl, halogen, 1-5C alkoxy, 1-3C acyloxy.

COPYRIGHT: (C)1992,JPO

Description

[Detailed description of the invention]

The present invention relates to new derivatives of indole, processes for their preparation, their use as pharmaceuticals and compositions containing them.

[0002] To control cell differentiation mechanisms, biologists can now use inducers (M. REISS, C. Gamba-Vital).
o, A. Sartorelli-Cancer Tr
eatment Reports 70-1, 20
1,86), no specific inhibitors of differentiation are available.

[0003]J. YOSHIMURA is ``Bulle
tin of Chemical Society
of Japan, vol. 46, 1973, pp.
2850-2853, 2,9-dibromo-6,13-dioxo-6H,13H-pyrazino[
1,2-a:4,5-a']diindole.

[0004]D. L. COFFEN is ``Journa
l of Organic Chemistry
”, vol. 42, 1977, pp948-952,
6H,13H-pyrazino[1,2-a:4,5-a']
-diindole-6,13-dione.

[0005] These documents make no mention of the therapeutic activity of the substances described.

The object of the present invention is to prepare compounds of the general formula I for use as medicaments in methods of therapeutic treatment of humans or animals.

00
07]

[Formula 3] [In the formula, R and R', which are the same or different, are a hydrogen atom, a hydroxy group, an alkyl group having 1 to 5 carbon atoms, a halogen atom, an alkoxy group having 1 to 5 carbon atoms, or 1 to 5 carbon atoms. An object of the present invention is to provide an indole derivative represented by the following formula (-3 acyloxy group) and a salt thereof to which a pharmaceutically acceptable acid has been added.

In the general formula I and the following description, the term alkyl having 1 to 5 carbon atoms refers to, for example, n-pentyl, n-butyl, n-propyl, isopropyl, preferably n-propyl. or ethyl group, particularly preferably methyl.

[0009] The halogen atom represents a chlorine atom, a fluorine atom or a bromine atom.

The term alkoxy having 1 to 5 carbon atoms means, for example, butoxy, propoxy or ethoxy, preferably methoxy.

Preferably, the acyloxy group contains 1 to 2 carbon atoms.

Examples of pharmaceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, and succinic acid. , tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkanesulfonic acids such as methanesulfonic acid or ethanesulfonic acid, arylsulfonic acids such as benzenesulfonic acid or para-toluenesulfonic acid, or salts formed with carboxylic acids. It is.

Among the above derivatives, formula I in which R and R' represent a hydrogen atom, a halogen atom, a hydroxy group, a C1-C3 alkoxy group, or a C1-C3 alkyl group
Of particular interest are derivatives thereof, and their salts with addition of pharmaceutically acceptable acids.

Further, a derivative in which R and R' represent a hydrogen atom, a hydroxy group, a chlorine atom, a fluorine atom, a methyl group, an ethyl group, a methoxy group or an ethoxy group, and a pharmaceutically acceptable acid is added. The salt is attracting even more attention.

A representative example of the product of the invention is 2,9-dimethoxy-6,13-dioxo-pyrazino[1,2-a:
4,5-a']diindole and 6,13-dioxo-
pyrazino[1,2-a:4,5-a']diindole,
and its salts to which a pharmaceutically acceptable acid has been added.

The derivatives of the invention have very important pharmacological properties. These derivatives are particularly suitable for leukemia cell K56
2 (Lozzio), exhibiting the property of significantly inhibiting erythroid differentiation, regardless of whether it is spontaneous differentiation or hemin-induced differentiation (J. Sutherland,
R. Turner, P. Mannoni-J. ofBi
Logical Response Modif
iers 5,250,86). The derivative of the present invention is
It suppresses the proliferation of cultured pathogenic cells and, as a result, has anti-cancer properties. These substances also serve as therapeutic agents for diseases associated with pathologies of cell differentiation.

The derivatives of the present invention are also very effective metabolic regulators, especially against aging.

The above characteristics will be discussed later in the experimental section. These properties confer pharmaceutical suitability to the indole derivatives and their salts with addition of pharmaceutically acceptable acids.

The medicament of the present invention can be used to treat leukemia or tumor (t
It is used in the prophylactic or therapeutic treatment of all types of cancer, such as umeur solide. It is also used to treat metabolic diseases of the normal genome and autoimmune diseases such as multiple rheumatoid arthritis and systemic lupus erythematosus.

The usual dosage is adjusted depending on the patient to be treated and the disease to be treated. For example, when the derivative of Example 1 is orally administered to humans for 7 to 70 days, the dosage is 1.
~100 mg/day.

[0021] It is also an object of the present invention to provide a pharmaceutical composition containing as an active ingredient at least one of the above-mentioned derivatives or a pharmaceutically acceptable acid-added salt thereof.

The derivative represented by the general formula I and the salt thereof to which a pharmaceutically acceptable acid has been added are mixed as medicinal ingredients into a pharmaceutical composition for oral or parenteral administration.

These pharmaceutical compositions may be solid or liquid, for example, and may be in the dosage forms customary in human medicine, such as uncoated tablets,
Sugar-coated tablets, capsules, granules, buccal preparations (cara
mel), has the form of suppositories, solutions, and injection preparations,
Prepared by conventional methods. In these pharmaceutical compositions, one or more active ingredients may be present in the presence of excipients customary in pharmaceutical compositions, such as talc, gum acacia, lactose, starch,
It is mixed with magnesium stearate, cocoa butter, an aqueous or non-aqueous vehicle, animal or vegetable lipids, paraffin derivatives, glycols, various wetting agents, dispersing agents or emulsifying agents, preservatives.

The object of the present invention is also that the 5th position contains groups R and R'.
A process for producing derivatives of general formula I and salts thereof, which comprises condensing two molecules of 2-indolecarboxylic acid, optionally substituted or unsubstituted by The goal is to provide the following.

Two molecules of 2-indolecarboxylic acid are condensed under conditions suitable for carrying out the process, preferably in the presence of a condensing agent such as dicyclohexylcarbodiimide.

Finally, it is an object of the invention that the general formula I

00
27]

[Formula 4] [In the formula, R and R', which are the same or different, are a hydrogen atom, a hydroxy group, an alkyl group having 1 to 5 carbon atoms, a halogen atom, an alkoxy group having 1 to 5 carbon atoms, or an alkyl group having 1 to 5 carbon atoms. (3) showing an acyloxy group (excluding derivatives showing R=R'=H and R=R'=Br), and a salt obtained by adding an inorganic or organic acid to the derivative. It is.

Among the above derivatives, R and R' represent a hydrogen atom, a halogen atom, a hydroxy group, a C1-C3 alkoxy group, or a C1-C3 alkyl group, and an inorganic or organic acid. Of particular interest is the added salt.

In particular, the above derivatives in which R and R' are a hydrogen atom, a hydroxy group, a chlorine atom, a fluorine atom, a methyl group, an ethyl group, a methoxy group or an ethoxy group, and the derivatives thereof to which an inorganic or organic acid has been added Salt attracted more attention,
2,9-dimethoxy-6,13-dioxo-pyrazino [
1,2-a:4,5-a'] diindoles and their salts with addition of inorganic or organic acids are most important.

Derivatives of general formula I generally have amphoteric nature. If necessary, it is advantageous to prepare salts of derivatives of general formula I by reacting the derivatives of general formula I with inorganic or organic acids in substantially stoichiometric proportions. In some cases, salts may be prepared without isolating the corresponding base.

The following examples illustrate the invention in a non-limiting manner.

Example 1 2,9-dimethoxy-6,13-dioxo-pyrazino [
1,2-a:4,5-a']diindole 1 g of 5-methoxy-2-indolecarboxylic acid and 2 g of dicyclohexylcarbodiimide are gently heated to reflux (115°C) in 8 ml of pyridine under an inert atmosphere. Heat to. 3
After a period of time, the precipitate formed is separated, returned to acetylacetone and ethanol sequentially at elevated temperature, washed with ether,
dry.

In the process mode described above, 180 mg of the desired product are obtained in the form of yellow crystals. The product has a melting point of 317~
318° C., is insoluble at low temperatures in common NMR solvents, and has a molecular weight (based on mass spectra) of 346.

A solution of the product of Example 1 in HMPA (hexamethylphosphoramide) was used to test the activity of this product against leukemia cell cultures of strain K562. After 3 days, the 5 x 10 mol/l solution inhibited cell proliferation;
No spontaneous differentiation of the erythroid lineage occurred. In contrast, 600,000 cells/ml and 20% erythroid differentiation were observed in control cultures. HMPA alone suppressed proliferation to about 600-400,000 cells/ml, but did not suppress differentiation (20%). The erythroid differentiation induced by hemin was 90% in control cultures, but only 17% in cultures containing 5 x 10-5 mol/l of the compound of Example 1. Furthermore, the presence of this substance decreased the cytotoxicity of HMPA in vitro. Also, in vivo, the daily dosage is 5 mg.
/kg, no adverse side effects were observed.

Example 2 6,13-dioxo-pyrazino[1,2-a:4,5-
a'] Diindole 2 g of 2-indolecarboxylic acid and 3 g of dicyclohexylcarbodiimide are gently heated to reflux temperature in 15 ml of pyridine for 1 hour. The cream-colored precipitate is separated by hot filtration, washed, recrystallized with acetylacetone, then washed with ethanol and dried.

0.925 g of the desired product was obtained in the form of pale yellow microcrystals. The melting point of the product was approximately 313°C.

Example 3 10 mg of 2,9-dimethoxy-6,13-dioxo-
Pyrazino[1,2-a:4,5-a'] diindole and excipients (excipients: lactose, starch, talc, magnesium stearate) in an amount that makes the finished tablet 100 mg are combined into tablets. was prepared.

Example 4 15 mg of 6,13-dioxo-pyrazino[1,2-a
:4,5-a'] diindole and finished tablet 100mg
Tablets were prepared by blending the following amounts of excipients (excipients: lactose, starch, talc, magnesium stearate).

Claims (12)

[Claims] Claims 1. A compound of general formula I for use in a method of therapeutic treatment of humans or animals, wherein R and R', which are the same or different, are a hydrogen atom, a hydroxy group, a carbon atom number of 1 to 5 alkyl group, halogen atom, alkoxy group having 1 to 5 carbon atoms, or acyloxy group having 1 to 3 carbon atoms], and a pharmaceutically acceptable acid. The salt added with. 2. A compound of formula I according to claim 1, characterized in that R and R' represent a hydrogen atom, a halogen atom, a hydroxy group, a C1-C3 alkoxy group, or a C1-C3 alkyl group. Derivatives and salts thereof with addition of pharmaceutically acceptable acids. 3. A compound of formula I according to claim 1, characterized in that R and R' represent a hydrogen atom, a hydroxy group, a chlorine atom, a fluorine atom, a methyl group, an ethyl group, a methoxy group or an ethoxy group. Derivatives and salts thereof with addition of pharmaceutically acceptable acids. 4. 2,9-dimethoxy-6,13-dioxo-pyrazino[1,2-a:4,5-a']diindole or 6,13-dioxo-pyrazino[1,2-a
:4,5-a']diindoles and their salts with addition of pharmaceutically acceptable acids. 5. A pharmaceutical composition comprising at least one medicament according to claim 1 as an active ingredient. 6. A pharmaceutical composition comprising at least one medicament according to claim 2 or 3 as an active ingredient. 7. A pharmaceutical composition comprising at least one medicament according to claim 4 as an active ingredient. 8. Two molecules of 2-indolecarboxylic acid, optionally substituted or unsubstituted in the 5-position by groups R and R', are condensed and the derivative of formula I is isolated and, if necessary, salified. A method for producing a derivative of general formula I and a salt thereof according to claim 1. [Claim 9] General formula I [Formula 2] [In the formula, the same or different R and R' are a hydrogen atom, a hydroxy group, an alkyl group having 1 to 5 carbon atoms, a halogen atom, and 1 to 5 carbon atoms; Derivatives represented by [representing an alkoxy group or an acyloxy group having 1 to 3 carbon atoms],
(However, other than R=R'=H and R=R'=Br), and salts thereof obtained by adding an inorganic or organic acid to a derivative of the above formula. 10. The compound of formula I according to claim 9, wherein R and R' represent a hydrogen atom, a halogen atom, a hydroxy group, a C1-C3 alkoxy group, or a C1-C3 alkyl group. Derivatives and their salts with addition of inorganic or organic acids. 11. The formula according to claim 9 or 10, wherein R and R' represent a hydrogen atom, a hydroxy group, a chlorine atom, a fluorine atom, a methyl group, an ethyl group, a methoxy group, or an ethoxy group. Derivatives of I and their salts with addition of inorganic or organic acids. 12. 2,9-dimethoxy-6,13-dioxo-pyrazino[1,2-a:4,5-a']diindole and its salts with addition of inorganic or organic acids.