JPH03251564A - Dimethylcarbazole derivative - Google Patents

Abstract

NEW MATERIAL:A dimethylcarbazole derivative expressed by formula I [R<1> and R<2> are H, lower alkyl (substitutive with lower alkoxycarbonyl, di-lower alkylamino or morpholino), phenyl (substitutive with lower alkyl, halogen, lower alkoxy, NO2 or CF3) or R<2> and R<2>, together with the adjacent N, form pyrrolidino, piperidino or morpholino (the groups can be substituted with lower alkyl, phenyl, etc.)]. EXAMPLE:9-[(2-Diethylamino)ethylamino]carbonylmethyl-1,4-dimethylcarba zole. USE:Having inhibitory action on formation of peroxylipids and cerebral protective action and useful as a treating drug for cardiac infraction, hepatophaty, etc., PREPARATION:An alkyl alpha-halogenoacetate is reacted in the presence of a base and the resultant product is then hydrolyzed. The obtained product is subsequently reacted with amines expressed by formula II to afford 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.

Conventional technology Lipid peroxide causes denaturation of membranes and enzymes, resulting in impaired function and decreased function of the arteries, and is associated with arteriosclerotic diseases such as myocardial stiffness and cerebral stiffness, liver disease, pulmonary edema, and skin disease. It is known that it is associated with various diseases such as eye diseases and 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
Year> etc. 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.

Problems to be Solved by 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 novel dimethylcarbazole derivative having lipid peroxide suppressing action and brain protective action, and completed the present invention.

The present invention relates to formula I [wherein R' and R1 are the same or different and are a hydrogen atom, a lower alkyl group (the lower alkyl group is substituted with a lower alkoxycarbonyl group, a di-lower alkylamino group, or a morpholino group)] ) or phenyl group (
The phenyl group is one of a lower alkyl group, a halogen atom, a lower alkoxy group, a nitro group, or a trifluoromethyl group.
~2 elements may be substituted), or R'
and R1 together with the adjacent nitrogen atom represent a pyrrolidino group, piperidino group, piperazino group or morpholino group (the pyrrolidino group, piperidino group, piperazino group or morpholino group is a lower alkyl group, a phenyl group,
represents a group forming an oxo group, a carboxyl group, a lower alkoxycarbonyl group, or a benzyloxycarbonyl group (optionally substituted with 1 or 2 groups). ] It is a dimethylcarbazole derivative represented by.

In the present invention, the lower alkyl group refers to a linear or branched alkyl group having 1 to 4 radicals, and these include methyl group, propyl group, isopropyl group, butyl group, isobutyl group, and t-butyl group. It is the basis. A lower alkoxy group is a linear or branched alkoxy group having 1 to 4 atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an inbutyloxy group, etc. It is. A halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. The lower alkoxycarbonyl group is a group having an alkoxy group having a prime number of 1 to 3, and is, for example, a methoxycarbonyl group. A di-lower alkylamino group is an amino group substituted with a lower alkyl group, and includes, for example, a dimethylamino group, a diethylamino group, a dipropylamino group, and the like.

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

First, 1,4-dimethylcarbazoleobacterium Chemical Society (J.Chem.Soc.
).

1962, p. 3482. 9-alkoxycarbonylmethyl-1,4-dimethylcarbazole is obtained by reacting the compound with α-halogenoacetic acid alkyl ester in an organic solvent in the presence of a base. The bases used in this reaction are sodium hydride, potassium hydride, potassium t-butoxy, sodium carbonate,
Potassium carbonate, sodium hydroxide, potassium hydroxide, etc., and organic solvents include N. N-dimethylformamide,
These include dimethyl sulfoxide, tetrahydrofuran, acetone, dimethoxyfuran, and N-methylpyrrolidone.

Next, the 9-alkoxycarbonylmethyl-1,4-dimethylcarbazole sodium hydroxide obtained above,
9- by conventional hydrolysis using potassium hydroxide etc.
1,4-dimethylcarbazole.

Next, this and an amine represented by the following formula I (wherein R1 and R8 have the same meanings as above) are mixed in a reaction-inert solvent in the presence or absence of a condensing agent and a basic compound. The compound of the present invention can be obtained by the following reaction. In this reaction, solvents inert to the reaction include, for example, benzene,
Chloroform, methylene chloride, tetrahydrofuran, N
．． N-dimethylformamide, water, etc., or a mixture thereof, and the condensing agent is, for example, diethyl cyanphosphate, N. 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 subacid, and sodium 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.

Moreover, the compound of the present invention is 9-carboxymethyl-1.4
-It can also be obtained by converting dimethylcarbazole into an acid chloride using thionyl chloride or the like, and reacting the acid chloride with the above-mentioned amines.

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

The pharmacological effects of typical compounds of the present invention are shown below.

Test Example 1 Four times the amount of phosphate buffer (pH 7.4) was added to cerebral tissue collected from a male Wistar rat, homogenized, and then centrifuged at 2300 rpm for 10 minutes to obtain a supernatant. This was diluted 4 times with the above-mentioned phosphate buffer, and the test drug [the compound of the present invention (final concentration 300 μM) and vitamin E (final concentration 200 μM) as a comparison drug] was dissolved in 1 ml of this diluted solution in dimethyl sulfoxide 10-. Add 3
Incubated for 30 minutes at 7°C. The production amount of malondialdehyde, which is a decomposition product of the produced lipid peroxide, was determined by the thiobarbic acid method, and the inhibition rate was determined by setting the production amount of malondialdehyde in the dimethyl sulfoxide administration group as 100%.

The results are shown in Table 1.

ICR male mice (body weight 10-30 g) were used as test animals, and the study was conducted with 10 mice per group.

Pediatric Research (Pediat.Resea)
rch).

According to the method described in Vol. 8, pp. 238-243 (1974), 30 minutes after administration of each test drug shown in Table 2, the mice were decapitated, and the time until the end of gasping respiration (respiration duration) was measured. Each test drug was dissolved or suspended in physiological saline and administered intraperitoneally (50 ml/kg), and to the control group, only 5% gum arabic solution was administered in the same manner.

The results were as shown in Table 2 below.

The compound group of the present invention showed statistically significantly prolonged gasping respiration duration compared to the control group [Student
t-test (Student's t-test).

P < 0.　01.

Test Example 2 [Test for Measuring Cerebral Protective Effect by Gears Bing Method Cocontrol 11, 50±0.70 Example Next, the method for producing the compound of the present invention will be explained in more detail with reference to Examples.

Example (1) Under a nitrogen stream, 4.6 g of 60% sodium hydride and 47 ml of dimethyl sulfoxide were stirred at 60°C for 1 hour, and 20 g of 1,4-dimethylcarbazole and 100 ml of anhydrous tetrahydrofuran were added under water cooling, and the mixture was heated to room temperature. Stirred for 30 minutes. Next, a solution of 19 g of ethyl bromoacetate in 70 ml of anhydrous tetrahydrofuran was added under water cooling, and the mixture was stirred at room temperature for 11 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried, and recrystallized from methanol to obtain 9-ethoxycarbonylmethyl=1.4-dimethylcarbazole m. p. 133-135°C (2) Add 20 g of 9-ethoxycarbonylmethyl-1,4-dimethylcarbazole to a mixture of 200 ml of 10% aqueous sodium hydroxide solution and 200 ml of ethanol, and
The mixture was heated to reflux for an hour. After cooling, it is acidified with concentrated hydrochloric acid, and the precipitated crystals are collected by filtration, washed with water, and dried to give 9-carboxymethyl-1.
．． 4-dimethylcarbazole g was obtained.

m. p. 164-166℃ (3) 9-carboxymethyl-1 under a nitrogen stream.

5 g of 4-dimethylcarbazole and N. 1.51 g of N-diethylethylenediamine hydrochloride was added to N. Dissolve in 40ynll of N-dimethylformamide and add 3.0ml of diethyl cyanophosphate. 53. N. N-dimethylformamide 1
Add 5 ml solution followed by 4.5 ml of triethylamine. 19
g and stirred at room temperature for 14 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Next, the mixture was washed with an aqueous sodium hydrogen solution and a saturated saline solution in that order, and the solvent was concentrated. The crude product was recrystallized from chloroform-n-hexane to give 9-[
(2-Diethylamino)ethylaminococarbonylmethyl-1,4-dimethylcarbazole5. 53 g was obtained.

m. p. 172-173℃ Similarly, the following compounds were obtained.

9-[(3-diethylamino)propylaminococarbonylmethyl-1,4-dimethylcarbazole m. I),
160 to 162°C 9-[(3-dimethylamino>propylaminococarbonylmethyl- m.p. (N,N-dimethylcarbamoylmethyl)-1,4
-dimethylcarbazole m. I), 193-193. 5°C 9-(N-t-butylcarbamoylmethyl 1,4-dimethylcarbazole m.p. 231.5-232°C 9-[(N-ethoxycarbonylmethylylmethyl m.p. 205-206°C 9-[ N-(2-trifluoromethylphenyl)carbamoylmethylol m.p. 174-178°C 9-[N-(3-)'Jfluoromethylphenyl)carbamoylmethylco-1,4-dimethylcarbazole m.p. 174-178°C 9 [N-(2.5-dimethoxyphenyl)carbamoylmethyl m.p. 183-184°C 9-[N-(2-nitro-4-methoxyphenyl]carbamoylmethylsol m.p. 196- 198°C 9-[N-(4-chloro-2-methylphenyl)carbamoylmethylol m.p. 230°C (decomposition) 9-[N-(2-morpholinoethylmethyl 1'.I), 166°C 9 -pyrrolidinocarbonylmethyl-1,4-dimethylcarbazole m, p, 202-204°C 9-piperidinocarbonylmethyl-1,4-dimethylcarbazole m, p, 219-222°C 9-(4-methylpiperid nocarbonylmethyl)-1,
4-dimethylcarbazole m. p. 174-175°C 9-(4-methylpiperazinocarbonylmethyl)-1,
4-dimethylcarbazole m. p. 220-222°C 9-(4-phenylpiperazinocarbonylmethyl)-1
．． 4-dimethylcarbazole m. p. 238-285℃ 9-(2-oxopyrrolidinocarponylmethyl>1,4
-dimethylcarbazole m. p. 202-203°C 9-[(2-benzyloxycarbonyl)pyrrolidinocarbonylmethylsol m. p. 163-164°C 9-[(2-carboxypyrrolidino)carbonylmethyl m. p. 200-201°C 9-[(4-ethoxycarbonyl-2-oxopyrrolidino)carbonylmethylrubazole m.p. 163-164°C

Claims (1)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are the same or different and are a hydrogen atom, a lower alkyl group (the lower alkyl group is a lower alkoxycarbonyl group, a di-lower (which may be substituted with an alkylamino group or a morpholino group) or a phenyl group (the phenyl group may be substituted with one or two of a lower alkyl group, a halogen atom, a lower alkoxy group, a nitro group, or a trifluoromethyl group) or R^1 and R^2 together represent a pyrrolidino group, piperidino group, piperazino group or morpholino group (wherein the pyrrolidino group, piperidino group, piperazino group or morpholino group is 1 to 2 of lower alkyl group, phenyl group, oxo group, carboxyl group, lower alkoxycarbonyl group or benzyloxycarbonyl group
(optionally substituted). ] A dimethylcarbazole derivative represented by.