JPH0447673B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD OF THE INVENTION The present invention relates to pyrroloindole derivatives, methods for their production, and pharmaceutical compositions containing them. Structure and purpose The present invention is based on the formula (): (In the formula, R is hydrogen or a straight chain or branched chain
A pyrrolo[3,2,1-hi]indole derivative represented by a C _1-4 alkyl group, R ₁ and R ₂ are the same or different and represent hydrogen, halogen, or a C _1-4 alkyl group, and is a pyrrolo[3,2,1-hi]indole derivative represented by and optically active isomers, as well as pharmaceutically acceptable salts thereof, particularly acid addition salts. The compound group () of the present invention can be produced according to the following reaction formula. In the above reaction formula, R' = alkyl (preferably ethyl), X = halogen (preferably iodine)
It is. Formulas () in which R′ is an alkyl group, especially ethyl
The starting ester represented by N-aminoindole (this compound was described by ANKost et al .
(1964)) and according to the method of H. Rapoport et al. (JACS [1958], 80 , 5574-5). According to the process of the invention, the starting ester () is hydrogenated with chlorine in the presence of tin at ambient temperature to give the compound (). Next, this compound () was reacted with ethylenediamine in the presence of trimethyaluminium to form R
is hydrogen or alkyl halide RX in a solvent, for example in the presence of diisopropylamine and butyllithium.
(In the formula, R is C _1-4 alkyl, X is halogen,
The resulting alkyl compound () is reacted with ethylenediamine in the presence of trimethylaluminum to form a compound of the formula () in which R is a C _1-4 alkyl group.
The compound is obtained. The compound () thus obtained can be converted into an acid addition salt by a well-known method. The present invention will be explained in more detail with reference to Examples below. The structure of the obtained compound was confirmed based on elemental analysis and IR and NMR spectra. Example 1 2-(4,5-dihydro- 1H -imidazol-2-yl)-1,2,3,4,5-tetrahydropyrrolo[3,2,1-hi]indole and its fumarate salt ( 1) Add ethyl 4, 5-dihydropyrrolo[3,
2,1-hi]indole-2-carboxylate
Add 15.8g (0.073mol) together with 150ml of ethanol. The mixture is cooled to -20 DEG C. and hydrogen chloride gas is bubbled through at this temperature until a solution is obtained. Then 26.1 g (0.22 g atomic weight) of granulated tin are added all at once, the cold bath is removed and stirring is continued for 20 hours at room temperature. A yellow suspension is obtained which is concentrated on a water bath and taken up in 550 ml of absolute ethanol. The mixture is cooled and ammonia is blown in until the pH is 9-10 to precipitate the tin salt.
The tin salt is washed with cold ethanol, the washing liquid is thoroughly drained, and the obtained liquid is evaporated to dryness.
The residue is subjected to silica gel column chromatography, eluting with methylene chloride. Finally, 11.65 g of yellow oil are obtained. (2) 16 ml of toluene and 25.2% strength under argon in a 100 ml Keller flask equipped with a magnetic stirrer, reflux condenser with calcium chloride tube, thermometer, argon inlet, dropping funnel and Dean-Stark apparatus. 10.3ml of trimethylaluminum hexane solution
(0.025 mol) in this order, and then, while cooling, add 1.6 ml (equivalent to 1.43 g or 0.024 mol) of ethylenediamine dissolved in 4.5 ml of toluene. After stirring this mixture for 5 minutes, it was heated to 50 °C and at this temperature 3.3 g (0.015 g) of the product obtained above were obtained.
mol) dissolved in 15 ml of toluene. The mixture is then heated under reflux for 6 hours and then cooled. After the mixture has been cooled to between -10 DEG and -15 DEG C., it is hydrolyzed with 10.2 ml of water under stirring and then extracted with ethyl acetate. The organic fractions are combined and washed with sodium chloride solution, dried and filtered and the solvent is evaporated. Approximately 3 g of a fat-like solid material remains, from which the fumarate salt is prepared directly. To do this, take up this solid substance in 50 ml of ethanol and add to the solution obtained by filtering 1.5 g (0.013 mol) of fumaric acid in 100 ml of ethanol.
The resulting solution is stirred, concentrated to dryness and the residue is taken up in acetone, filtered, dried under vacuum and recrystallized from ethanol. The yield of the fumarate salt obtained is 1.65 g, and the melting point is 184.5-186°C. Example 2 2-methyl-2-(4,5-dihydro-1 H −
imidazol-2-yl)-1,2,4,5-
Tetradropyrrolo[3,2,1-hi]indole and its fumarate salt 2.1. Ethyl-2-methyl-1,2,4,5,-
Tetrahydropyrrolo[3,2,1-hi]indole-2-carboxylate was placed in a 250 ml Keller flask equipped with a magnetic stirrer, thermometer, argon inlet and addition funnel placed in a cold bath under an argon atmosphere. , 5.6 ml (0.04 mol) of diisopropylalumine and 35 ml of tetrahydrofuran (THF). After cooling the reaction mixture between −70° and −75°C,
1.6M hexane solution of butyllithium in 25 minutes
Add ml (0.04 mol). Keep in the temperature range of -70° to -75°C for 1 hour,
7 g (0.0322 mol) of ethyl 1,2,4,5-tetrahydropyrrolo[3,2,1-hi]indole-2-carboxylate in 25 ml of THF
Add solution. While maintaining the temperature between −70° and −75°C,
12.4 ml (0.2 mol) of methyl iodide in 20 minutes
Add 20ml THF solution. The reaction mixture is kept in the range of -70 DEG to -75 DEG C. for 1 hour and then left at room temperature for 3 hours and 30 minutes.
The reaction mixture is then poured into ice water. Make a saturated solution of sodium chloride and extract with diethyl ether. The extract is washed with water and dried over Na ₂ SO ₄ 2.
Separate the organic layer. This is evaporated to dryness under reduced pressure on a water bath. The residual oil is purified through a silica column using methylene chloride as eluent. 2.2. 2-Methyl-2-(4,5-dihydro-1H
-imidazol-2-yl)-1,2,4,5
-Tetrahydropyrrolo[3,2,1-hi]indole and its fumarate salt In a 50 ml Keller flask equipped with a magnetic stirrer, reflux condenser, thermometer, argon inlet, dropping funnel and Dean-Stark apparatus, add argon. Under atmosphere, add 10 ml of toluene and 5.4 ml (0.013 mol) of a 25.2% strength trimethylaluminum hexane solution, and then heat to 0°C.
Cool and add 0.9 ml (equivalent to 0.013 mol) of ethylenediamine dissolved in 3 ml of toluene. The mixture was stirred for 10 minutes and then heated to 50°C and at the same temperature 1.9 g (0.0082
Add a 10 ml solution of mol) in toluene. Then,
The mixture is heated to reflux for 6 hours and then allowed to cool. After cooling this mixture to −10° to −15°C,
Hydrolyze with 5.4 ml of water while stirring and then extract with ethyl acetate. The combined organic fractions are washed with sodium chloride solution, dried, filtered and the solvent is evaporated. The fumarate salt is prepared directly from the residual yellow solid material. To do this, mix this solid with 25 ml of ethanol.
filter this solution and add fumaric acid to it.
Add 0.7 g (0.006 mol) to 50 ml of ethanol and add the filtered solution. The resulting solution is stirred and concentrated to dryness, and the residue is taken up in an accent, filtered, dried in vacuo, and recrystallized from ethanol. The melting point of the fumarate obtained is 192−194
It is ℃. Example 3 2-n-propyl-2-(4,5,-dihydro-
1H -imidazol-2-yl)-7-methyl-1,2,4,5-tetrahydropyrrolo[3,
2,1-hi]indole and its fumarate salt 3.1. 5-Methyl-1-nitroso-2,3-dihydro-1H-indole 5-Methyl-2-indoline in a 500 ml three-necked flask equipped with a magnetic stirrer. [GWGribble
and JHHoffman (Synthesis, 1977, 859−
860) from indole according to the method of J.
E. Nordlander et al. (J.Org.Chem. 46 , 778-782,
18 g (0.14 mol), 20
Add 300ml of % sulfuric acid. Cool the solution to 0°C and add sodium nitrite to
A solution of 9.7 g (0.14 mol) in 30 ml of water is added.
The reaction mixture is kept at 0° C. throughout this addition. After stirring at 0°C for 30 minutes, the aqueous layer was diluted with ether.
Extract with 500ml. The ether layer is washed with water and then with saturated sodium chloride solution and dried over magnesium sulfate. Distill the solvent under reduced pressure. The obtained product is used as it is in the next step. 3.2. 5-Methyl-2,3-dihydro-1H-indol-1-amine Lithium aluminum hydride 6.08 g under argon atmosphere in 2 three-necked flasks equipped with a mechanical stirrer, a condenser, a dropping funnel and a thermometer. g
(0.16 mol) and 300 ml of tetrahydrofuran (THF). To this suspension is added 22 g (0.14 mol) of the compound obtained above dissolved in 300 ml of THF. Maintain temperature at 35°C. After stirring the reaction mixture at 20°C for 4 hours,
Hydrolyze (water, 10 ml). Then 1N NaOH
Add 10ml and then 20ml of water. After stirring the suspension at 20° C. for 30 minutes, it is filtered and the residue is washed with ether. Dry the organic layer with sodium sulfate. Distill the solvent under reduced pressure. The obtained compound is used as it is in the next step. 3.3. Ethyl 2-([5-methyl-2,3-dihydro-1H-indol-1-yl]imino)propanoate In a 500 ml flask (one-shot) equipped with a magnetic stirrer and condenser, add the above under an argon atmosphere. 20g (0.13 mol) of the compound ethylpyruvate
Add 16.24 g (0.14 mol), 200 ml of ethanol, and 0.5 ml of acetic acid. The reaction mixture is stirred at 80°C for 5 hours. Ethanol is distilled off under reduced pressure, and the residue is purified by column chromatography (Sio ₂ ; eluent=cyclohexane/ether (2:1)).
The obtained compound is used as it is in the next step. 3.4. Ethyl-7-methyl-4,5-dihydropyrrolo[3,2,1-hi]indole-2-carboxylate 25 ml of 3-carboxylate with magnetic stirrer and cooling tube
7 g (0.028 mol) of the compound obtained above and 8 ml of acetic acid were placed in a necked flask under an argon atmosphere.
Add 3.42 ml (0.028 mol) of BF ₃ etherate. The reaction mixture is stirred at 90°C for 50 minutes.
This is cooled and hydrolyzed (water, 40 ml). Ether extract the aqueous layer (3X200ml). The organic layer is washed with sodium bicarbonate solution and then with saturated sodium chloride solution and dried over sodium sulfate. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography (SiO ₂ ; eluent=cyclohexane/ether (2:1)).
The obtained ester () is subjected to the next step. 3.5. Ethyl-7-methyl-1,2,4,5-tetrahydropyrrolo[3,2,1-hi]indole-2-carboxylate 21 ml of ethanol in a 50 ml three-necked flask equipped with a magnetic stirrer and condenser. Put in. The ethanol is saturated with hydrochloric acid at -10°C. 2.4 g (0.011 mol) of the ester obtained above, then tin
Add 3.8g (0.032g atomic weight). The reaction mixture is stirred at +20° C. for 8 hours. The solvent is distilled off under reduced pressure and the residue is dissolved in 50 ml of ethanol.
This mixture is saturated with ammonia to a pH of 9. The suspension is filtered and the ethanol is distilled off under reduced pressure. The residue is dissolved in water and the aqueous layer is extracted with ether (300 ml); this ether layer is washed with a saturated solution of sodium chloride and then dried over sodium sulfate. Thus we obtain ester (). 3.6. Ethyl-2-n-propyl-7-methyl-
1,2,4,5-tetrahydropyrrolo[3,
2,1-hi]indole-2-carboxylate diisopropylamine under argon in a 500 ml three-necked flask equipped with a magnetic stirrer.
Add 0.600g (0.006mol) and 5ml of THF.
The solution is cooled to -78°C and 3.75 ml (0.006 mol) of n-butyllithium in hexane is added. This solution was stirred at -78℃ for 30 minutes, and 1.15g (0.005mol) of the ester obtained above was added to 10ml of THF.
and add. The reaction mixture was heated to −78°C for 1
Stir for hours (brown color). Add 1.02 g (0.006 mol) of 1-iodopropane to 5 ml of THF. The reaction mixture is stirred at -78°C for 1 hour and then at 20°C for 1 hour. This mixture is hydrolyzed (water, 10 ml). Extract the aqueous layer with ether. The ether layer is washed with water, then with a saturated solution of sodium chloride, and then dried over sodium sulfate. The obtained ester () is used in the next step. 3.7. 2-n-propyl-2-(4,5-dihydro-1H-imidazol-2-yl)-7-methyl-1,2,4,5-tetrahydropyrrolo[3,2,1-hi]indole and its fumarate salt a Toluene was added to a 50 ml three-necked flask equipped with a magnetic stirrer and a condenser under an argon atmosphere.
10 ml and 4.5 ml (0.011 mol) of a 25% strength trimethylaluminum hexane solution. The solution is cooled to -10 DEG C. and then 0.640 g (0.011 mol) of ethylenediamine is added in 5 ml of toluene. Add this reaction mixture to 20
After returning to °C, the ester obtained in 3.6.
Add 1.22 g (0.0044 mol) to 10 ml of toluene. The reaction mixture is stirred at 110°C for 4 hours. After cooling to -10°C, it is hydrolyzed (water, 5 ml) and 50 ml of ethyl acetate is added. After stirring this mixture at 0°C for 30 minutes,
pass Dry the solution with Na ₂ SO ₄ . The solvent is removed under reduced pressure. Prepare the fumarate salt directly from the product. b. In a 250 ml flask (one sip) equipped with a magnetic stirrer, add 20 ml of ethanol to the compound obtained in a.
Introduce the contents inside and add 0.500g of fumaric acid.
(0.0042 mol) in 30 ml of ethanol. After stirring the solution for 30 minutes, the ethanol is distilled off under reduced pressure. Take up the residue in ether. After filtration and vacuum drying, it is recrystallized from ethanol. Thus melting point 178−180
Obtain the fumarate salt at °C. The following Table 1 shows a group of compounds of the present invention obtained in the same manner as in the above examples.

[Table] When the compounds of the present invention were subjected to pharmacological experiments,
It was found to be useful as an α ₂ -antagonist. The in vitro potency and selectivity of the compounds of the present invention as antagonists to α ₂ -receptors was investigated. _GMDrew (European
Journal of Pharmacology, 42 (1977) 123−
130), 30nm prazosin and 1μ
The inhibitory effect of clonidine, a well-known α ₂ -agonist, was determined on the vas deferens stimulated at a frequency of 0.1 Hz in the presence of m-cocaine. The pA ₂ values of the compounds of the invention were within the range of 7 to 9.5. For each representative compound of formula (),
The _pA2 values are shown in Table 2 below. Table 2 Compound number _pA Binary value 1 9.40 2 8.88 3 8.14 4 8.54 5 7.85 7 8.93 8 7.73 10 7.70 12 7.86 13 7.18 14 7.62 15 7.14 17 7.86 19 9.50 20 8.81 2 1 8.33 22 7.45 23 7.63 24 8.43 25 7.85 Also, Eq. The acute toxicity of the compounds of the present invention was evaluated by measuring the LD ₅₀ value when the compound () was administered intraperitoneally or orally to mice, and it was revealed that these compounds are suitable as pharmaceutical preparations. The LD ₅₀ values (mg/Kg) of representative compounds of formula () in this experiment are listed below: Compound number LD ₅₀ (mg/Kg) Intraperitoneal administration Oral administration 1 61 200 4 40 95 18 60 95 bottles Since the compounds of the invention have strong α ₂ -antagonistic effects, they can be used to treat depression (alone or in combination with other products that inhibit the uptake mechanism of nerve cells), hypotension, and post-surgery symptoms. It can be used to treat ileal paralysis, asthma and obesity. Such pharmaceutical compositions may be in dosage forms suitable for oral, rectal or parenteral administration, such as capsules, tablets, etc.
They can be formulated into pellets, gelatin capsules or solutions, or syrups or suspensions suitable for oral administration. If necessary, suitable excipients may be included. The daily dose can be 0.1 to 10 mg/Kg orally. Formulation Example Tablets are manufactured according to the following formulation by a conventional method: 2-(4,5-dihydro- 1H -imidazol-2-yl)-1,2,3,4,5-tetrahydropyrrolo[3,2, 1,-hi] 100 mg of indole fumarate (compound of Example 1), 150 mg of cornstarch, 100 mg of lactose and 25 mg of dicalcium phosphate are mixed uniformly. cornstarch 25
A 10% aqueous corn starch paste prepared from 10 mg is mixed into this mixture, and 2 mg of calcium stearate is mixed in and then compressed to form tablets.

Claims (1)

[Claims] 1 Formula (): (In the formula, R is hydrogen or a straight chain or branched chain
_{pyrrolo [ 3,2 ,} 1-hi] Indole derivatives and salts thereof. 2 Formula (a): (In the formula, R ^a is hydrogen, and R ₁ and R ₂ are the same or different and represent hydrogen, halogen, or C _1-4 alkyl group.) 3,2,1-hi] A method for producing an indole derivative or a salt thereof, comprising the formula (): (wherein R ₁ and R ₂ are as defined above and R' represents an alkyl group) is hydrogenated with hydrochloric acid at ambient temperature in the presence of tin to obtain the formula (): (wherein R ₁ , R ₂ and R′ follow the above definitions) A compound of the formula () is obtained, and then the compound of the formula () is reacted with ethylenediamine in the presence of trimethylaluminum to form the formula (
A method comprising obtaining a compound of a) and further optionally converting the obtained compound (a) into a pharmaceutically acceptable salt. 3 Formula (b): (In the formula, R ^b is a linear or branched C _1-4 alkyl group, and R ₁ and R ₂ are the same or different and represent hydrogen, halogen, or a C _1-4 alkyl group.) A method for producing a pyrrolo[3,2,1-hi]indole derivative or a salt thereof including optically active isomers, the method comprising the formula (): (wherein R ₁ and R ₂ are as defined above and R' represents an alkyl group) is hydrogenated with hydrochloric acid at ambient temperature in the presence of tin to obtain the formula (): (wherein R ₁ , R and R' are according to the above definitions), and then the compound of formula () is converted to alkyl halide R ^b
Alkylated by reacting with X (in the formula, R ^b represents C _1-4 alkyl and X represents a halogen), resulting in the formula (): (wherein R ₁ , R ₂ , R ^b and R' are according to the above definitions) is reacted with ethylenediamine in the presence of trimethylaluminum to obtain a compound of formula (b), further comprising the desired A method comprising converting the compound (b) obtained by the method into a pharmaceutically acceptable salt. 4 Formula (): (In the formula, R is hydrogen or a straight chain or branched chain
_{pyrrolo [ 3,2 ,} 1-hi] A therapeutic agent for depression comprising an indole derivative or a salt thereof as an active ingredient and a pharmaceutically acceptable excipient.