JPH0533954B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to indole derivatives useful as pharmaceuticals or intermediates thereof.

BACKGROUND ART Indole derivatives have various pharmacological actions, and many compounds useful as pharmaceuticals are known.

For example, the expression Pindolol, represented by , has a β-blocking effect and is used as an antiarrhythmic agent and a vasodilator. In addition, various compounds in which the side chains of this compound are changed and compounds in which nuclear substituents are introduced are also being studied. For example, the general formula [R ¹¹ in the formula is a hydrogen atom, an aralkyl group, or a formula (In the formula, B is a reactive functional group or a group that forms a covalent bond with R ¹⁵ , and R ¹⁵ is a hydrogen atom, aliphatic or aromatic acyl group), R ¹² is a hydrogen atom or lower alkyl group, R ¹³
is a hydrogen atom, a methyl group, or a group represented by the formula -CH ₂ -O-R ¹⁵ (R ¹⁵ in the formula has the same meaning as above), R ¹⁴ is an aminocarbonyl group, a cyano group, an oximinomethyl group , a formyl group, a hydroxymethyl group, or a lower alkoxycarboimidoyl group, where R ¹⁴ is a formyl group and R ¹¹ is not an aralkyl group] have been reported. [European Patent Application Publication No.
No. 45910].

Problems to be Solved by the Invention In order to find a β-blocker even stronger than pindolol, various modifications of side chains, introduction of nuclear substituents, etc. have been carried out, and several preferred compounds have been discovered. Many of these compounds have two indole skeletons.
It has a change at the position, and those having a substituent at the 3-position are not well known. In particular, few compounds having an aminoalkyl chain at the 3-position have been reported.

An object of the present invention is to provide a novel indole derivative useful as an intermediate for producing pindolol-like compounds having an aminoalkyl chain at the 3-position of the indole ring.

Means for Solving the Problems The present invention provides formulas useful as pharmaceuticals or intermediates for their production. The present invention provides an indole derivative represented by:

The compound of formula () of the present invention is a new compound and can be produced as follows. That is, the expression It can be produced by reacting the compound represented by with nitromethane.

The compound of formula () used as a starting material in the production method of the present invention is a new compound, and can be produced as follows. That is, the expression It can be obtained by reacting the indole derivative represented by with epichlorohydrin in the presence of a base such as potassium carbonate.

In addition, by reacting the compound of this formula () with an amine derivative represented by the general formula R ³ −NH ₂ () (R ³ in the formula is a lower alkyl group), the compound of the general formula A compound represented by (R ³ in the formula has the same meaning as above) can be obtained.

The compound of formula () used as a starting material in this production method can be produced by reacting 4-hydroxy-3-indolecarbaldehyde with allyl bromide in the presence of a base, such as potassium carbonate.

To suitably carry out the production method of the present invention, the compound of formula () is dissolved in nitromethane, ammonium acetate is added thereto, and the mixture is heated and stirred at 80 to 100°C for 1 to 5 hours. After the reaction is completed, the desired product is obtained by treatment and purification according to conventional methods.

Effects of the Invention The compound of formula () of the present invention is useful as a pharmaceutical or as an intermediate in the production of pharmaceuticals. For example, a compound derived from a compound of formula (b) that can be produced from a compound of formula () or a compound obtained by reducing this is β as well as pindolol.
- Expected as a blocking agent. Furthermore, compounds derived from the compound of formula () can be derived into various pindole-like compounds by reacting with amines. For example, 1-allyl-4-[(2-hydroxy-3-isopropylamino)propoxy]tryptamine obtained by reacting the corresponding tryptamine derivative derived from the compound of formula () with isopropylamine is β-blocking. It is a very useful compound as a drug.

EXAMPLES The contents of the present invention will be explained in more detail with reference to the following reference examples and examples. Note that the melting points of the compounds in each Reference Example and Examples are all uncorrected.

In each reference example and example, mp is melting point, IR is infrared absorption spectrum, ¹ H-NMR is proton nuclear magnetic resonance spectrum, MS is mass spectrum,
Anal. represents the elemental analysis value.

Reference example 1 1-allyl-4-hydroxy-3-indolecarbaldehyde 2.8732g of 4-hydroxy-3-indolecarbaldehyde was mixed with 50.0g of N,N-dimethylformamide.
ml, to which 3.238 g of allyl bromide, 230.5 mg of tetra-n-butylammonium bromide,
3.220 g of potassium carbonate was added, and the mixture was stirred at room temperature for 24 hours. After neutralizing the reaction mixture by adding 2N hydrochloric acid, the solvent was distilled off under reduced pressure. Saturated brine was added to the residue, and methylene chloride-methanol (95:5,
The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methyl chloride) to obtain 2.6507 g (74%) of 1-allyl-4-hydroxy-3-indolecarbaldehyde.

Colorless prismatic crystal (methylene chloride-n-hexane) mp78.0-79.0℃ IR (KBr) νmax: 3420, 1620, 1535 cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 4.61 (2H, brd, J = 5.6Hz ), 4.91~5.40 (2H,
m), 5.57-6.24 (1H, m), 6.50-6.80 (2H,
m), 6.93-7.17 (1H, m), 7.48 (1H, s),
9.33 (1H, s), 10.30 (1H, s, OH) MS m/z: 201 (M ⁺ ), [C ₁₂ H ₁₁ NO ₂ : 201] Reference example 2 1-allyl-4- [(2,3 -Epoxy)propoxy]-3-indolecarbaldehyde (Compound C) 296.7mg of 1-allyl-4-hydroxy-3-indolecarbaldehyde was dissolved in 6.0ml of N,N-dimethylformamide, and 421.8mg of epichlorohydrin and carbonic acid were dissolved in 6.0ml of N,N-dimethylformamide. Potassium 199.7mg, Tetra-n
- Add 32.5 mg of butylammonium bromide to 85
Stirred at ℃ for 18 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with a mixed solvent of methylene chloride and methanol (95:5, v/v). The organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (developing solvent: methyl chloride/methanol = 98:2, v/v), and 102.8 mg (27%) of 1-allyl was extracted from the band of Rf0.64-0.50. -4-[(2,3-epoxy)propoxy]-3-indolecarbaldehyde (compound C)
I got it.

Colorless needle crystals (methylene chloride-n-hexane) mp101.0-102.0℃ IR (KBr) νmax: 1655, 1579, 1517 cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 2.70-3.06 (2H, m), 3.26-3.56 (1H, m),
4.15 (1H, dd, J=11and4.4Hz), 4.40 (1H,
dd, J=11and3.6Hz), 4.73(2H, brd, J=
5.0Hz) 4.96-5.46 (2H, m), 5.70-6.36 (1H,
m), 6.69 (1H, dd, J=7.2and1.2Hz), 6.97
(1H, dd, J=8.4and1.2Hz), 7.21 (1H, dd,
J=8.4and7.2Hz), 7.84 (1H, s), 10.50 (1H,
s) MS m/z: 257 (M ⁺ ), [C ₁₅ H ₁₅ NO ₃ = 257] Reference example 3 1-allyl-4-[(2,3-epoxy)propoxy]-3-indolecarbaldehyde 1- Dissolve 49.3 mg of allyl-4-hydroxy-3-indolecarbaldehyde in 1.0 ml of N,N-dimethylformamide, add 81.5 mg of epichlorohydrin, 7.7 mg of potassium iodide, and potassium carbonate.
80.3 mg was added, and the mixture was heated and stirred at 80 to 85°C for about 13 hours. The solvent was distilled off under reduced pressure, water was added to the residue,
Extraction was performed with a mixed solvent of methylene chloride-methanol (95:5, v/v). After washing the organic layer with water and drying over inorganic sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to preparative thin layer chromatography on silica gel (developing solvent: methylene chloride/methanol =
95/5, v/v) to yield 52.7 mg (83.7%) of 1-allyl-4-[(2,3-epoxy)propoxy]-3-indolecarbaldehyde.

The physical constants of this product were the same as those of Compound C obtained in Reference Example 2.

Reference example 4 1-allyl-4-[(3-tert-butylamino-
2-Hydroxy)propoxy]-3-indolecarbaldehyde 500.2mg of 1-allyl-4-[(2,3-epoxy)propoxy]-3-indolecarbaldehyde was dissolved in 50.0ml of isopropanol, and tert-
440.4 mg of butylamine was added and the mixture was refluxed with stirring for about 8 hours. After distilling off the solvent under reduced pressure, water was added to the miscellaneous residue, and methylene chloride-methanol (95:5, v/
v) Extracted with mixed solvent. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol/aqueous ammonia = 200/10/1, v/v) to obtain 548.5 mg (85%) of 1-allyl-4-
[(3-tert-butylamino-2-hydroxy)propoxy]-3-indolecarbaldehyde was obtained.

Pale yellow oil IR (film) νmax: 3400, 1655, 1514 cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 2.64 (2H, brs, NH, OH),
2.70~2.93 (2H, m), 3.83~4.40 (1H, brm),
4.13 (2H, brs), 4.69 (2H, brd, J=5.2Hz),
4.90~5.43 (2H, m), 5.60~6.33 (1H, m),
6.65 (1H, dd, J=7and1.5Hz), 6.88 (1H, dd,
J=8and1.5Hz), 7.17(1H, dd, J=8and7
Hz), 7.69 (1H, s), 10.14 (1H, s) MS m/z: 330 (M ⁺ ), [C ₁₉ H ₂₆ N ₂ O ₃ = 330] Example 1 1-allyl-4- [( Dissolve 28.5 mg of 2,3-epoxy)propoxy]-3-nitrovinylindole 1-allyl-[4-(2,3-epoxy)propoxy]-3-indole carbaldehyde in 8.0 ml of nitromethane, and add ammonium acetate to this. 44.3 mg was added, and the mixture was heated and stirred at 80°C for 1 hour. After cooling, an appropriate amount of water was added and 30 ml of methylene chloride was added for extraction. The water bath was further extracted with methylene chloride-methanol (95:5, v/v), and the organic layers were combined, washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: methylene chloride/methanol = 98/2, v/v).
31.9 mg (95.9%) of 1-allyl-4-[(2,3-
Epoxy)propoxy]-3-nitrovinylindole was obtained.

Yellow prism crystal (methylene chloride-n-hexane) mp 98.5-99.5℃ IR (KBr) νmax: 3430, 1620, 1608cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 2.65-3.11 (2H, m), 3.34- 3.57 (1H, m),
4.20 (2H, d, J = 4.8Hz), 4.63 (2H, brd, J
=5Hz), 4.86~5.43 (2H, m), 5.43~6.00
(1H, m), 6.55 (1H, m), 6.55 (1H, dd, J
=7.4and1.5Hz), 6.83(1H, dd, J=8and7.2
Hz), 7.10 (1H, dd, J=8 and 7.4Hz), 7.32
(1H, s), 7.74 (1H, d, J=15Hz), 8.36
(1H, d, J = 15Hz) MS m/z: 300 (M ⁺ ), [C ₁₆ H ₁₆ N ₂ O ₄ = 300] Reference example 5 1-allyl-4-[(2-hydroxy-3-isopropyl Amino)propoxy]tryptamine 1-allyl-4-[(2,3-epoxy)propoxy]-3-nitrovinylindole (150 mg) was dissolved in anhydrous tetrahydrofuran (10 ml), and lithium aluminum hydride (380 mg) was added.
The mixture was stirred and refluxed for 30 minutes. Methanol was added to the reaction mixture under ice-cooling, then Rothsiel salt aqueous solution was added, and then methylene chloride-methanol (95:5, v/
v) Extracted with mixed solvent. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was dissolved in 10 ml of tetrahydrofuran, 275 mg of isopropylamine was added, and the mixture was heated under reflux at 90° for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to preparative thin layer chromatography using an alumina carrier and a chloroform-methanol-ammonia water (45:5:0.5, v/v) mixed solvent as a developing solvent. Purification yielded 43.5 mg (26%) of 1-allyl-4-[(2hydroxy-3-isopropynylamino)propoxy]tryptamine.

Colorless oil IR (film): ν _nax : 3300, 2950, 1510 cm ^{-1 1} H-NMR (CD ₃ OD) δ: 1.09 (6H, d, J = 7Hz), 2.60-3.04 (3H,
m), 2.98 (4H, brs), 3.92-4.28 (3H, m),
4.69 (2H, brd, J=5.2Hz), 4.90~5.43 (2H,
m), 5.60-6.33 (1H, m), 6.50 (1H, dd, J
=7.5and1.8Hz), 6.84-7.32 (3H, m) MS m/z: 331 (M ⁺ ) [C ₁₉ H ₂₉ N ₃ O ₂ : 331]

Claims (1)

[Claims] 1 formula An indole derivative represented by