JPH072744B2 - Indolo [6,5,4-cd] indole derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to an indolo [6,5,4-cd] indole derivative useful as a drug or an intermediate for producing a drug.

More specifically, the present invention has a prolactin secretion inhibitory activity, useful as a therapeutic agent for hyperprolactinosis, a milk secretion inhibitor, etc., and also useful as an intermediate for the production of a drug having an indole skeleton. The present invention provides an indole [6,5,4-cd] indole derivative represented by the formula (wherein R is a hydrogen atom, a hydroxyl group or an acetoxy group).

[Conventional technology]

Compounds having an indole skeleton, especially ergot alkaloids, have various pharmacological activities, and are useful for treating migraine, treating peripheral vascular disorders, treating senile cerebral dysfunction, uterine constrictor, uterine hemostatic agent, antihypertensive agent, Many compounds are used as pharmaceuticals such as prolactinosis therapeutic agents.

Most of such ergot alkaloids are peptide-type compounds having an ergolen structure as a basic skeleton and having a peptide chain in the side chain. In recent years, clavin-type compounds having relatively simple side chains have been found to be active and have been used as pharmaceuticals, but these also have an ergolen structure as a basic skeleton.

Conventionally, this ergolen structure has been essential for the activity expression of ergot alkaloids, but benzindole derivatives in which the ergolen structure is cleaved or modified, azepinoindole derivatives, compounds such as indoloindole derivatives have been studied, Some active compounds have been found and reported.

Heretofore, as the indolo [6,5,4-cd] indole derivative of the present invention, The compound represented by [Journal of
American Chemical Society (J. Am. Chem.
Soc.) 78, 3087 (1956)].

However, this compound was produced from the consideration of chemical reactivity or synthetic interest, and nothing is described about its action.

[Problems to be solved by the invention]

An object of the present invention is to provide a novel indole having a prolactin secretion inhibitory effect, useful as a therapeutic agent for hyperprolactinosis, a milk secretion inhibitor, or as an intermediate for the production of a drug having another indole skeleton (6,5,4- cd] indole derivatives.

[Means for solving problems]

The present invention was investigated to find a novel indolo [6,5,4-cd] indole derivative useful as a drug or an intermediate for producing a drug, and as a result, a certain 1,3,4,5-tetrahydrobenz [cd The present invention has been completed by finding that it can be produced extremely easily from an indole derivative.

Indolo represented by the general formula (I) of the present invention [6,5,4-cd]
The indole derivative is a novel compound and can be produced as follows.

That is, the formula A compound represented by the formula (I) wherein R is a hydroxyl group by reduction and ring closure using a suitable reducing agent such as zinc amalgam. A compound represented by can be obtained. Further, by treating the compound represented by the formula (Ia) with titanium trichloride, the compound of the formula (I) wherein R is a hydrogen atom, The compound of formula (Ia) can be obtained by acetylating the compound of formula (Ia) by a conventional method.
And R is an acetoxy group in the formula A compound represented by can be produced.

Further, the compound of formula (Ib) is obtained by reducing the compound of formula (III) with an excess of a reducing agent. It can also be produced by ring-closing the compound represented by

The compound of formula (III) used as a starting material in the present production method is a known compound and can be easily produced by a method described in the literature or a method similar thereto [Heterocycles, vol. 20, p. 1983]. , (19
1983); Progress in pharmaceutical research, Research report volume 1, p. 45, (1985)].

The compound of the general formula (I) of the present invention has a 4,5-cis form (4S, 5S- or 4R, 5R-) depending on the arrangement of substituents at the 4- and 5-positions.
And 4,5-trans isomers (4R, 5S- or 4S, 5R-) exist, but the present invention is not particularly limited to them.

〔The invention's effect〕

The compound of the general formula (I) of the present invention has a prolactin secretion inhibitory action and is useful as a therapeutic agent for hyperprolactinosis, a milk secretion inhibitor, etc., and also useful as an intermediate for the production of a drug having another indole skeleton. It is a compound.

〔Example〕

The contents of the present invention will be described in more detail with reference to examples and examples. The melting points of the compounds in Reference Examples and Examples are all uncorrected.

Reference Example 1 Methyl 2- (4,5-trans-4-amino-1,3,4,5-tetrahydrobenz [cd] indol-5-yl) acetate Zinc powder 317.4 mg mixed with mercuric chloride 51.2 mg Then, 2.0 ml of 2N-hydrochloric acid was added, and the mixture was stirred at 23 ° C for 5 minutes. The supernatant was decanted and 2.0 ml of 2N hydrochloric acid was newly added. Methyl 2- (4,5-trans-4-nitro-1,3,4,5-tetrahydrobenz [cd] indol-5-yl) acetate 28.7mg
Was dissolved in 6.0 ml of methanol, and the mixture was refluxed for 13 hours. After cooling, the reaction solution was filtered to remove solids, and the solvent was distilled off under reduced pressure. The residue was made alkaline by adding saturated aqueous sodium hydrogen carbonate solution, and then extracted with a methylene chloride-methanol (95: 5) mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (developing solvent: methylene chloride / methanol = 95/5) to give 19.7 mg (77.0%) of methyl 2- (4,5-trans-4-amino-1). There was obtained 3,3,4,5-tetrahydrobenz [cd] indol-5-yl) acetate.

Colorless oil IR (film): 3370, 1723 cm ^-1 NMR (CDCl ₃ ) δ: 1.90 (2H, br-2), 2.39 to 3.73 (4H, m) 2.53 (2H, d,
J = 6.5Hz), 3.61 (3H, s), 6.51 to 7.18 (4H, m), 8.19 (1
H, br-s) High MS: m / z (as C ₁₄ H ₁₆ N ₂ O ₂ ) Calculated value 244.1211 Measured value 244.1211 Reference Example 2 Methyl 2- (4,5-cis-4-amino-1,3, 4,5-Tetrahydrobenz [cd] indol-5-yl) acetate Zinc powder 1134.0 mg and mercuric chloride 189.8 mg were mixed, 2N-hydrochloric acid 15.0 ml was added, and the mixture was stirred at 21 ° C. for 5 minutes. The supernatant was decanted and 7.5 ml of 2N hydrochloric acid was newly added. To this solution, a solution of 106.8 mg of methyl 2- (4,5-cis-4-nitro-1,3,4,5-tetrahydrobenz [cd] indol-5-yl) acetate in 22.0 ml of methanol was added, Refluxed for 4 hours.
After cooling, the reaction solution was filtered to remove solids, and the solvent was distilled off under reduced pressure. The residue was made alkaline with saturated aqueous sodium hydrogen carbonate solution and then extracted with a methylene chloride-methanol (95: 5) mixed solvent. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 83.0 mg.
(87%) methyl 2- (4,5-cis-4-amino-1,3,4,5-
Tetrahydrobenz [cd] indol-5-yl) acetate was obtained.

Colorless oil IR (film): 3350, 1715 cm ^-1 NMR (CDCl ₃ ) δ: 2.25 (2H, br-s), 2.42 to 3.80 (6H, m) 3.63 (3H,
s), 6.57 to 7.13 (4H, m), 8.12 (1H, br-s) MS m / z: 244 (M ⁺ ) Example 1 6a, 9a-trans-6,6a, 7,8,9,9a -Hexahydro-4H-indolo [6,5,4-cd] indole-8-one Methyl 2- (4,5-trans-4-amino-1,3,4,5-tetrahydrobenz [cd] indole-5 -Yl) acetate 21.8
mg was dissolved in 4.5 ml of methanol, 0.5 ml of saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred at 23 ° C. for 27 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with a methylene chloride-methanol (95: 5) mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Recrystallize the residual crystals from methanol,
14.4 mg of 6a, 9a-trans-6,6a, 7,8,9,9a-hexahydro-4H-indolo [6,5,4-cd] indol-8-one were obtained.
The mother liquor was concentrated and purified by silica gel preparative thin layer chromatography (developing solvent: methylene chloride / methanol = 95/5) to obtain 2.1 mg of the desired product. Total yield 16.5 mg (87.0
%) Colorless prism (methanol) Melting point:> 300 ° C IR (KBr): 3270, 3170, 1674cm ^-1 NMR (DMSO-d ₆ ) δ: 1.92 ~ 3.87 (6H, m), 6.36 ~ 7.25 (4H, m), 7.87 (1
H, br-s), 10.51 (1H, br-s) MS m / z: 212 (M ⁺ ) Example 2 6a, 9a-cis-6,6a, 7,8,9,9a-hexahydro-7- Hydroxy-4H-indolo [6,5,4-cd] indole-8-one 154.1 mg of zinc powder and 25.2 mg of mercuric chloride were mixed, 2.0 ml of 2N-hydrochloric acid was added, and the mixture was stirred for 5 minutes. The supernatant was decanted off and 2.0 ml of 2N-HCl was newly added. Methyl 2-in this liquid
A solution prepared by dissolving 28.1 mg of (4,5-cis-4-nitro-1,3,4,5-tetrahydrobenz [cd] indol-5-yl) acetate in 6.0 ml of methanol was added, and the mixture was refluxed for 4 hours. After cooling, the reaction solution was filtered to remove solids, and the solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with a methylene chloride-methanol (5: 1) mixed solvent, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and 6
a, 9a-cis-6,6a, 7,8,9,9a-Hexahydro-7-hydroxy-4H-indolo [6,5,4-cd] indol-8-one 8.8mg
(38.0%) was obtained.

Colorless needle crystals (methanol) Melting point:> 300 ℃ IR (KBr): 3340,1675,1635cm ^-1 NMR (pyridine-d ₅ ) δ: 2.65 (1H, dd, J = 15.5and5.8Hz), 2.97 ( 1H, dd, J ＝
15.5and7.2Hz), 3.36 (2H, br-d, J = 5.0Hz), 3.73 (1H, b
rq, J = 6.4Hz), 4.31 (1H, q, J = 5.0Hz), 5.67 (1H, br-
s), 6.76 ~ 7.54 (4H, m), 8.38 ~ 8.70 (1H, br-s) MS m / z: 228 (M ⁺ ) On the other hand, the aqueous layer and the washing solution were combined and saturated aqueous sodium hydrogen carbonate solution was added. After making alkaline, methylene chloride-
Extract with a mixed solvent of methanol (95: 5), wash with water, dry over anhydrous sodium sulfate and evaporate the solvent under reduced pressure to remove methyl 2-
(4,5-cis-4-amino-1,3,4,5-tetrahydrobenz [cd] indol-5-yl) acetate 14.2 mg (57.0
%) Was obtained.

The physical constant of this compound was exactly the same as that of the compound obtained in Reference Example 2.

Example 3 6a, 9a-cis-6,6a, 7,8,9,9a-hexahydro-4H-indolo [6,5,4-cd] indol-8-one methyl 2- (4,5-cis- Dissolve 83.0 mg of 4-amino-1,3,4,5-tetrahydrobenz [cd] indol-5-yl) acetate in 9.0 ml of methanol, add 1.0 ml of saturated aqueous sodium hydrogen carbonate solution, and stir at 23 ° C for 16 hours. did. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with a methylene chloride-methanol (95: 5) mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residual crystals were washed with methylene chloride to give 6a, 9a-
Cis-6,6a, 7,8,9,9a-hexahydro-4H-indolo (6,
5,0.0 mg of 5,4-cd] indole-8-one was obtained. The washings were concentrated and purified by silica gel preparative thin layer chromatography (developing solvent: methylene chloride / methanol = 97/3) to obtain 7.5 mg of the desired product. Total yield 57.5 mg (80.0%) colorless needles (methanol) Melting point: 263 to 266 ° C (dec.) IR (KBr): 3210,1667 cm ^-1 NMR (pyridine-d ₅ ) δ: 2.61 (1H, dd , J = 16and6.8Hz), 2.74 to 3,23 (1H,
m), 3.09 (2H, br-d, J = 5.6Hz), 3.78 (1H, br-q, J = 6.4H
z), 4.20 (1H, q, J = 5.6Hz), 4.60 to 5.00 (1H, m), 6.80
~ 7.53 (4H, m), 8.50 (1H, br-s) MS m / z: 212 (M ⁺ ) Example 4 6a, 9a-cis-6,6a, 7,8,9,9a-hexahydro-4H -Indolo [6,5,4-cd] indole-8-one 6a, 9a-cis-6,6a, 7,8,9,9a-hexahydro-7-hydroxy-4H-indolo [6,5,4- cd] Indore-8-on 20.1m
g dissolved in 5.0 ml methanol, ammonium acetate 165.2m
g was added, and 0.34 ml (6 molar equivalents) of a 16% titanium trichloride aqueous solution was added all at once with vigorous stirring, and the mixture was stirred at 23 ° C. for 30 minutes. Methylene chloride and water were added to the reaction solution, the organic layer was separated, and the aqueous layer was further methylene chloride-methanol (95: 5).
It was extracted with a mixed solvent. The organic layer was combined with the extract, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (developing solvent: methylene chloride / methanol = 97/3) to give 6a, 9a-cis-6,
6a, 7,8,9,9a-hexahydro-4H-indolo (6,5,4-cd)
3.2 mg (17.0%) of indole-8-one was obtained.

The physical constants of this compound were all the same as those of the compound obtained in Reference Example 3.

Example 5 6a, 9a-cis-7-acetoxy-6a, 7,8,9,9a-hexahydro-4H-indolo [6,5,4-cd] indole-8-one 6a, 9a-cis-6, 6a, 7,8,9,9a-Hexahydro-7-hydroxy-4H-indolo [6,5,4-cd] indole-8-one 34.4m
g was dissolved in 2.0 ml of pyridine, 1.0 ml of acetic anhydride was added, and
The mixture was stirred at ° C for 15 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel preparative thin layer chromatography (developing solvent: methylene chloride / methanol = 97/3) to give 6a, 9a-cis-7-acetoxy-6,6a. , 7,8,9,9a-Hexahydro-4H-
Indolo [6,5,4-cd] indole-8-one 35.2 mg (87.0
%) Was obtained.

Colorless needle crystals (methanol) Melting point: 182 ~ 184 ℃ IR (KBr): 3400,1788,1701cm ^-1 NMR (20% CD ₃ OD in CDCl ₃ ) δ: 2.18 (3H, s), 2.54 (1H, dd, J = 16.4and6.4Hz), 2.
69 to 3,48 (3H, m), 3.87 (1H, br-q, J = 6.8Hz), 4.38 (1
H, q, J = 5.4Hz), 6.63 to 7.26 (4H, m) MS m / z: 270 (M ⁺ )

Claims (1)

[Claims] 1. A general formula An indolo [6,5,4-cd] indole derivative represented by the formula (wherein R is a hydrogen atom, a hydroxyl group or an acetoxy group).