JPH03251565A - Carbazole derivative - Google Patents

Abstract

NEW MATERIAL:A carbazole derivative expressed by the formula I (R is 1- piperidino, 1-piperazino, 1-morpholino or trifluoromethylanilino substituted with 1-pyrrolidino, 1-piperidino or lower alkyl). EXAMPLE:9-Pyrrolidinocarbonylmethylcarbazole. USE:Having inhibitory action on formation of peroxylipids and cerebral protective action and useful as a remedy for cardiac infarction, hepatopathy and aging- related diseases. PREPARATION:Carbazole is reacted with an alkyl alpha-halogenoacetate in the presence of a base to provide a 9-alkoxycarbonylmethylcarbazole, which is then hydrolyzed with sodium hydroxide, etc., to afford 9-carboxymethylcarbazole. The resultant compound is subsequently reacted with amines expressed by formula II (R is an above-mentioned group) to provide the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to carbazole derivatives having lipid peroxide production inhibiting activity and brain protective activity.

Lipid peroxides cause denaturation of membranes and enzymes, leading to cell damage and functional decline, leading to arteriosclerotic diseases such as myocardial stiffness and cerebral stiffness, liver disease, pulmonary edema, It is known to be associated with various diseases such as skin diseases and eye diseases, and with aging. Also,
Lipid peroxide inhibitors increase blood flow through cerebral vasodilation when brain cells are in an ischemic state due to cerebral vascular disorder, supplying oxygen to the brain and improving the oxygen deficient state in the brain. Furthermore, it prevents cell death by promoting the effective use of intracellular adenosine triphosphate.

Examples of drugs that suppress lipid peroxide, improve cerebral circulation, and promote cerebral metabolism include vinpocetine (Neuropsychopharmacology, Vol. 7, p. 113, 1985), idebenone (Pharmacology and Treatment, Vol. 13, No. 673, 1985
) are known. On the other hand, a compound having a structure similar to that of the compound of the present invention is 9-(N.

Although N-dimethylaminocarbonylmethylzole is known, the above effects have not been fully reported.

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a compound that suppresses lipid peroxide and protects the brain.

Means for Solving the Problems As a result of intensive studies on compounds having a carbazole skeleton, the present inventors discovered a new carbazole derivative having lipid peroxide suppressing action and brain protective action, and completed the present invention.

The present invention relates to the formula I [wherein R is a 1-pyrrolidino group, a 1-piperidino group,
It is a carbazole derivative represented by ], which represents a 1-piperidino group, a 1-piperazino group, a 1-morpholino group, or a trifluoromethylanilino group substituted with a lower alkyl group.

In the present invention, a lower alkyl group is a linear or branched alkyl group having an R prime number of 1 to 4, and these include a methyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a t-butyl group. It is the basis.

The compound of formula I can be produced by various methods, for example, by the following method.

First, carbazole and α-halogen acetic acid alkyl ester are reacted in an organic solvent in the presence of a base to produce 9-alkoxycarbonylmethylcarbazole.

The bases used in this reaction include sodium hydride, potassium hydride, t-butoxypotassium, secondary sodium, potassium rehydrate, sodium hydroxide, potassium hydroxide, etc., and the organic solvents include N,N-dimethylformamide, dimethyl These include sulfoxide, tetrahydrofuran, acetone, dimethoxyfuran, and N-methylpyrrolidone.

In the next step, the 9-alkoxycarbonylmethylcarbazole obtained above is subjected to conventional hydrolysis using sodium hydroxide, potassium hydroxide, etc. to give 9-carboxymethylcarbazole and the formula R-H (in the formula, The compound of the present invention can be obtained by reacting amines represented by (R has the same meaning as above) in a solvent inert to the reaction in the presence or absence of a condensing agent and a basic compound. I can do it.

In this reaction, solvents inert to the reaction include, for example, benzene, chloroform, methylene chloride, tetrahydrofuran, N.I. N-dimethylformamide, water, etc., or a mixture thereof, and the condensing agent is, for example, diethyl cyanophosphate, N-dimethylformamide, water, etc. These include N-dicyclohexylcarbondiimide, diphenylphosphoryl azide, phosphorous acid trialkyl ester, phosphorus trichloride, and oxaline chloride. Examples of the basic compound include pyridine, triethylamine, sodium hydroxide, potassium hydroxide, sodium rehydrate, potassium hydroxide, and thorium hydride. After the reaction is completed, crystals are usually precipitated by adding water, and the desired product can be obtained by filtration. In addition, when crystals do not precipitate, the compound of the present invention can be obtained by extraction with a suitable solvent (eg, benzene, chloroform, ethyl acetate, etc.) and subsequent treatment by a conventional method.

The compound of the present invention can also be obtained by converting 9-rupoxymethyl-rubazole into an acid chloride using thionyl chloride or the like, and allowing the above-mentioned amines to react with the acid chloride.

Effects of the Invention According to the present invention, a compound having lipid peroxide suppressing action and brain protective action has been provided.

Next, the method for producing the compound of the present invention will be explained in more detail with reference to Examples.

Example (1) 60% sodium hydride under nitrogen flow2. 63
After cooling with water, 10 g of carbazole and 80 ml of anhydrous tetrahydrofuran were added, and the mixture was stirred at room temperature for 30 minutes.

Then ethyl bromoacetate 10. A solution of 5 g of anhydrous tetrahydrofuran (40 ml) was added under water cooling, and the mixture was stirred at room temperature for 11 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
After washing with water and drying, it was recrystallized from tutanol to obtain 9-ethoxycarbonylmethylcarbazole.

m. p. 94-95. 5°C (2) The mixture was added to a mixture of 100 ml of 9-ethoxycarbonylmethylcarbazoletanol and heated under reflux for 2 hours.

After cooling, acidify with concentrated hydrochloric acid, collect the precipitated crystals by filtration, wash with water,
After drying, it was recrystallized from chloroform to obtain 9-carboxymethylcarbazole.

11, 1), 190-191°C (3) Under a nitrogen stream, 5 g of 9-carboxymethylcarbazole and 1.74 g of pyrodine were mixed with dimethylformamide 4
Dissolve in 0 ml and add 3, 5 diethyl cyanophosphate to this.
3 g of N. Add 15 ml of N-dimethylformamide solution, then add 4. triethylamine. Add 19 g,
Stirred at room temperature for 14 hours. Water was added to the mixture and extracted with ethyl acetate. The mixture was washed successively with a 5% hydrochloric acid solution, an aqueous sodium hydrogen solution, and a saturated saline solution, and the solvent was concentrated. The composition was recrystallized from benzene to obtain 9-pyrrolidinocarbonylmethylcarbazole.

m. p.　207~209℃ The following compounds were obtained in the same manner as above.

9-piperidinocanocarbonylmethylcarbazole m. p
．． 166-168°C 9-(4-methylpiperidino)carbonylmethylcarbazole m. p. 183-186°C 9-morpholinocarbonylmethylcarbazole m. p.
256-258°C 9-(2-trifluoromethinophenol)carbamoylmethylcarbazole m. p. 234-236℃

Claims (1)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is 1-pyrrolidino group, 1-piperidino group,
Indicates a 1-piperidino group, 1-piperazino group, 1-morpholino group or trifluoromethylanilino group substituted with a lower alkyl group. ] A carbazole derivative represented by.