JPH0569824B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Field This invention has a dopamine receptor stimulating effect,
The present invention relates to a 1,3,4,5-tetrahydrobenz[cd]indole derivative useful as a therapeutic agent for Parkinson's syndrome, a therapeutic agent for Huntington's chorea, a prolactin secretion regulator, and the like. Conventional technology Until now, the formula

Bromocriptine represented by [Formula]
It is well known that peptide-type ergot alkaloids, including ergot alkaloids, have dopamine receptor stimulating effects. The ergolene structure of these ergot alkaloids is essential for their activity.
Partially cleaved compounds were said to have no activity. Problems to be Solved by the Invention An object of the present invention is to provide a novel 1,3,4,5-tetrahydrobenz[cd]indole derivative that has a dopamine receptor stimulating effect and is useful as a therapeutic agent for Parkinson's syndrome. It is to be. Means for Solving the Problems The present inventors conducted research to find a compound that has a dopamine receptor stimulating effect using a 1,3,4,5-tetrahydrobenz [cd] indole derivative with a simple structure in which the ergolene skeleton is cleaved. As a result,
It was discovered that a compound having an alkylamino group at the 4-position and a 2-methyl-1-propenyl group at the 5-position can achieve the object, and the present invention was completed. That is, the present invention is based on the general formula

[Formula ^] 1,3,4 ^, 5-
Tetrahydrobenz[cd]indole derivatives and pharmacologically acceptable acid adducts thereof are provided. In the compound of formula () of the present invention, the carbons at the 4th and 5th positions are asymmetric carbons, and four stereoisomers exist depending on the arrangement of substituents on those carbons. These isomers are divided into two types of 4,5-cis isomers (4S,
5S; 4R, 5R) and 4,5-trans form (4S,
5R; 4R, 5S), but the compound of formula () of the present invention is not particularly limited to any of these isomers. The compound of formula () of the present invention is a new compound and has the formula

[Formula] (R ¹ in the formula has the same meaning as above) and the general formula R ³ -COOH () (R ³ in the formula is a lower alkyl group having 1 to 5 carbon atoms. ) with a reactive functional derivative of a carboxylic acid represented by the general formula

[C] (R ¹ and R ³ in the formula have the same meanings as above)
It can be produced by preparing a compound represented by and then reducing it with a suitable reducing agent, such as lithium aluminum hydride. The compound of general formula () used as a starting material in the method for producing a compound of general formula () of the present invention, in which R ¹ is a hydrogen atom, is a known compound and can be easily produced by the method described in the literature. [Japanese Patent Application No. 1985-85361]. In addition, compounds of general formula () in which R ¹ is a lower alkyl group can be produced by reacting a compound in which R ¹ is a hydrogen atom with an acylating agent to acylate it, and then reducing it with an appropriate reducing agent. can do. In the method for producing a compound of general formula () of the present invention,
The compound of general formula () used as the other starting material is a known compound and can be easily obtained as a commercial product or by manufacturing according to a known method. In order to suitably produce the compound of the present invention, the compound of the general formula () is dissolved in an inert solvent, such as methylene chloride, and the compound of the general formula ( ) and a base such as triethylamine are added and allowed to react at room temperature for 1 to 3 hours. A compound of general formula () is prepared by treatment and purification according to a conventional method, and then dissolved in an inert solvent such as tetrahydrofuran, lithium aluminum hydride is added, and the mixture is heated under reflux for 5 to 50 hours. After the reaction is completed, the desired product is obtained by treatment and purification according to conventional methods. The compound of general formula () thus obtained can be converted into an acid addition salt by a conventional method. Such acid addition salts include, for example, salts with inorganic acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates, acetates, oxalates, succinates, maleates, etc. Mention may be made of salts with organic acids such as acid salts, fumarates, malates, tartrates, etc. The dopamine receptor stimulating action of the compound of general formula () of the present invention was demonstrated in the striatum of mice.
- Dopa (L-DDPA) production measurement experiment [Journal of Pharmacological Methods, Vol. 14,
Pages 41-47, 1985; Naunyn-Schmiedberg's Archives
Pharmacology) Volume 296, pages 5-14, 1976]
and an experiment to observe the number of contralateral turning behaviors in mice with unilateral striatal destruction [Pharmacological Journal Vol. 98, No. 12, 1613-
1618 pages, 1978; Acta Physiologica
Scandinavica (Acta Physiologica)
Scandinavica) Suppl.367, pages 69-96,
1971; Neuropharmacology, Vol. 12, pp. 451-462, 1973]. Effects of the Invention The compound of formula () of the present invention exhibits a stimulating effect on dopamine receptors in mammals including humans, and is useful as a therapeutic agent for Parkinson's syndrome, a therapeutic agent for Huntington's chorea, a prolactin secretion inhibitor, and the like. EXAMPLES The contents of the present invention will be explained in more detail with reference to the following examples and reference examples. Note that all melting points of compounds in Examples are uncorrected. Example 1 4,5-trans-5-(2-methyl-1-propen-1-yl)-4-propylamino-1,
3,4,5-tetrahydrobenz[cd]indole 4,5-trans-4-amino-5-(2-methyl-1-propen-1-yl)-1,3,4,
5-tetrahydrobenz [cd] indole 2.1860
g was dissolved in 24.0 ml of methylene chloride. A solution prepared by dissolving 1.008 g of propionic acid chloride in 1.0 ml of methylene chloride was added to this while stirring at room temperature, and 2.0 ml of triethylamine was further added and stirred at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to separate the organic layer, and the aqueous layer was extracted with a mixed solution of methylene chloride-methanol (95:5, v/v). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystals were recrystallized from methylene chloride-n-hexane to yield 2.3408 g (85.8%) of 4,5-trans-5.
-(2-methyl-1-propen-1-yl)-4-
Propionylamino-1,3,4,5-tetrahydrobenz[cd]indole was obtained. Colorless needle crystals (methylene chloride-n-hexane) Melting point: 206-210℃ IR (KBr) ν _nax : 3200, 1654, 1516, cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 1.05 (3H, t, J = 7Hz), 1.72 (3H, d, J
= 1Hz), 1.89 (3H, d, J = 1Hz), 2.02 (2H,
q, J=7Hz), 2.78 (1H, dd, J=15.6and5.2
Hz), 3.24 (1H, dd, J=15.6and4.2Hz), 3.90
(1H, dd, J=9and5.5Hz), 4.22~4.52 (1H,
m), 5.04 (1H, br-d, J=9.5Hz), 5.36
(1H, br-d, J=9Hz), 6.70-6.94 (2H,
m), 7.00-7.18 (2H, m), 8.48 (1H, br-s) MS: m/z209 (M ⁺ -NHCOCH ₂ CH ₃ ) Elemental analysis value: (as C ₁₈ H ₂₂ N ₂ C) C% H% N% Calculated value 75.56 7.85 9.92 Actual value 76.58 7.95 9.96 4,5-trans-5-(2-methyl-1-propen-1-yl)-4-propionylamino-
1.102 g of 1,3,4,5-tetrahydrobenz [cd] indole and 20.0 g of anhydrous tetrahydrofuran
ml of lithium aluminum hydride dissolved in this
1.926 g was added and stirred under reflux for 7.5 hours. After the reaction was completed, methanol was added to the reaction solution to decompose the excess reagent, a 10% Rothschel salt aqueous solution was added, and the mixture was extracted with a mixed solvent of methylene chloride and methanol (95:5, v/v). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
The remaining crystals were recrystallized from methylene chloride-n-hexane to give 4,5-trans-5-(2-methyl-1
-propen-1-yl)-4-propylamino-
699.2 mg (66.8%) of 1,3,4,5-tetrahydrobenz[cd]indole was obtained. Colorless needle crystals (methylene chloride-n-hexane) Melting point: 138.5-140.0℃ IR (KBr) ν _nax : 3150, 3100, 1605, 1443, cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J=7Hz), 1.52(2H, sext,
J=7Hz), 1.74 (1H, br-s), 1.84 (3H, d,
J=1Hz), 1.88 (3H, d, J=1Hz), 2.36~
3.00 (3H, m), 2.74 (1H, br-d, J=11Hz),
3.28 (1H, br-d, J=11Hz), 3.84 (1H, t,
J=8.8Hz), 5.11 (1H, br-d, J9.5Hz), 6.64
~6.90 (2H, m), 7.00 ~ 7.20 (2H, m) 7.87
(1H, br-s) MS: m/z268 (M ⁺ ) Elemental analysis value: (as C ₁₈ H ₂₄ N ₄・1/2H ₂ O) C% H% N% Calculated value 77.93 9.08 10.10 Actual value 77.84 8.76 10.03 Example 2 4,5-cis-5-(2-methyl-1-propen-1-yl)-4-propylamino-1,3,
4,5-tetrahydrobenz[cd]indole 4,5-cis-4-amino-5-(2-methyl-1-propen-1-yl)-1,3,4,5-
37.0 mg of tetrahydrobenz[cd]indole was dissolved in 2.0 ml of methylene chloride, and 0.1 ml of propionic acid chloride and 2.0 ml of triethylamine were added thereto under ice cooling. After stirring at room temperature for about 1 hour, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with a methylene chloride-methanol (95:5, v/v) mixed solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel preparative thin layer chromatography (developing solvent: methylene chloride/methanol = 97/3,
41.7 ml (90.3%) of 4,5-
cis-5-(2-methyl-1-propen-1-yl)-4-propionylamino-1,3,4,5
-Tetrahydrobenz[cd]indole was obtained. Colorless prismatic crystal (methylene chloride-n-hexane) Melting point: 123.0-125.0℃ IR (KBr) ν _nax : 3360, 3270, 1631, 1520, cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 1.08 (3H, t , J=7.6Hz), 1.79(3H, d,
J=1.2Hz), 1.80 (3H, d, J=1.2Hz), 2.09
(2H, q, J = 7.6Hz), 2.86 (1H, ddd, J =
15.5, 7.0and1.0Hz), 3.10 (1H, ddd, J=
15.5, 4.5and1.0Hz), 4.05(1H, dd, J=
10.0and4.0Hz), 4.45-4.75 (1H, m), 5.19
(1H, br-d, J = 10.0Hz), 5.46 (1H, br-
d, J = 9.0Hz; NH), 6.83 (1H, dr-s),
6.67-6.80 (1H, m), 6.97-7.17 (2H, m),
8.04 (1H, br-s) MS: m/z282 (M ⁺ ) Elemental analysis value: (as C ₁₈ H ₂₂ N ₂ C) C% H% N% Calculated value 76.56 7.85 9.92 Actual value 76.27 7.94 9.98 4,5 -cis-5-(2-methyl-1-propen-1-yl)-4-propionylamino-1,
Dissolve 104.7 mg of 3,4,5-tetrahydrobenz[cd]indole in 14.0 ml of anhydrous tetrahydrofuran, and add lithium aluminum hydride to this solution.
441.4 mg was added, and the mixture was stirred under reflux for 43.5 hours under an argon atmosphere. Methanol was added under ice-cooling to decompose excess reagent, 10% Rothschel salt aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, 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: methylene chloride/methanol 95/5, v/v) to give 82.6 mg.
(83.0%) of 4,5-cis-5-(2-methyl-1
-propen-1-yl)-4-propylamino-
1,3,4,5-tetrahydrobenz[cd]indole was obtained. Colorless oil (hard candy-like) IR (film) ν _nax : 3410, 3150, 1602, 1441cm ^{-1 1} H−NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.5Hz), 1.49 (2H, sext ,
J=7.5Hz), 1.65 (1H, br-s, NH), 1.71
(3H, d, J=1.2Hz), 1.88 (3H, d, J=1.2
Hz), 2.53-3.35 (3H, m), 2.67 (2H, t, J
= 7.5Hz), 4.13 (1H, dd, J = 10.3and39Hz),
5.18 (1H, br-d, J=10.3Hz), 6.79 (1H, br
-d), 6.67-6.88 (1H, m), 6.91-7.15 (2H,
m) 7.95 (1H, br-s, NH) MS: m/z 268 (M ⁺ ) Example 3 4,5-trans-4-(N,N-dipropylamino)-5-(2-methyl-1 -Propene-1
-yl)-1,3,4,5-tetrahydrobenz[cd]indole 4,5-trans-5-(2-methyl-1-propen-1-yl)-4-propylamino-1,
125.0 mg of 3,4,5-tetrahydrobenz[cd]indole was dissolved in 4.0 ml of methylene chloride, 50.0 mg of propionic acid chloride and 2.0 ml of triethylamine were added thereto, and the mixture was stirred at room temperature for 2.0 hours. Methylene chloride-methanol (95:5, v/v) was added to the reaction solution.
The mixed solution was added, and the organic layer was washed successively with a saturated sodium chloride aqueous solution and water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent:
Chloroform/methanol/aqueous ammonia/n-
4,5-trans-5-(2-methyl-1-propen-1-yl)-4-(N-propionyl-N
79.8 mg (52.8%) of -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole was obtained. Colorless prism crystal (methanol-water) Melting point: 179.0-180.0℃ IR (KBr) ν _nax : 3263, 1616cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7Hz), 1.09and1. 16 (1:
1, total, 3H, each t, J=7Hz), 1.38~
1.88 (2H, m), 1.74 (3H, br-s), 1.82 (3H,
br-s), 2.32 (2H, q, J=7Hz), 2.68~
3.68 (4H, m), 3.92~4.60 (2H, m), 4.92~
5.20 (1H, m), 6.60~6.90 (2H, m), 6.96~
7.17 (2H, m), 7.92and8.05 (1:1total1H,
each br-s, NH) CIMS: m/z324 (M+1) Elemental analysis value: (as C ₂₁ H ₂₈ N ₂ O) C% H% N% Calculated value 77.73 8.70 8.63 Actual value 77.48 8.84 8.70 4,5-trans -5-(2-methyl-1-propen-1-yl)-4-(N-propionyl-N
601.2 mg of -propylamino)-1,3,4,5-tetrahydrobenz[cd]indole was dissolved in 15.0 ml of anhydrous tetrahydrofuran, and 1.4475 g of lithium aluminum hydride was added thereto, followed by stirring under reflux for 2.5 hours. Add methanol under ice cooling to decompose excess reagent, add 10% Rothsiel salt aqueous solution,
Extraction was performed with a mixed solvent of methylene chloride-methanol (95:5, v/v). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent: methylene chloride/
Methanol ammonia water/n-hexane 180/
10/1/64, v/v) to give 536.3 mg (93.2
%) of 4,5-trans-4-(N,N-dipropylamino)-5-(2-methyl-1-propene-
1-yl)-1,3,4,5-tetrahydrobenz[cd]indole was obtained. Colorless needle crystals (methanol-water) Melting point: 82-83℃ IR (KBr) ν _nax : 3370, 1600, 1443 cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 0.85 (6H, t, J = 7Hz), 1.39 (4H, sext,
J=7Hz), 1.74 (3H, d, J=1.2Hz), 1.84
(3H, d, J=1.2Hz), 2.48 (4H, t, J=7
Hz), 2.60-3.21 (3H, m), 3.92 (1H, t, J
= 9.5Hz), 5.14 (1H, br-d, J = 9.5Hz), 6.55
~6.81 (2H, m), 6.91 ~ 7.11 (2H, m), 7.71
(1H, br-s) MS: m/z310 (M ⁺ ) Elemental analysis value: (as C ₂₁ H ₃₀ N ₂ ) C% H% N% Calculated value 81.23 9.74 9.02 Actual value 80.90 10.01 9.05 Reference example 1 Mouse line Measurement of L-DOPA production in the striate body Using ddY male mice weighing 20 to 30 g, γ-
The effect on the increase in striatal L-DOPA production induced by butyrolactone (GBL) administration was investigated. Test compound 4,5-trans-5-(2-methyl-4-propen-1-yl)-4-propylamino-1,
3,4,5-tetrahydrobenz [cd] indole Group 3 to 5 male ddY mice weighing 20 to 30 g.
Mice were divided into three groups, and one group of mice was intraperitoneally administered with the test drug, and 30 minutes later, the test drug was administered at a concentration of 750 per kg of body weight.
mg of γ-butyrolactone (GBL) was administered intraperitoneally. Then, 5 minutes later, 100 mg of m-hydroxybenzylhydrazine dihydrochloride (NSD-1015, Sigma Chemicals) per 1 kg of body weight was intraperitoneally administered. After 30 minutes, the striatum was extracted, crushed in 1 ml of 0.4N perchloric acid, and then centrifuged to obtain 40μ of the supernatant.
The amount of L-DOPA in the sample [Sample] was separated and quantified using a high performance liquid chromatography equipped with an ODS-5 μm column and an electrochemical detector. Another group of mice received 750 mg/Kg of GBL intraperitoneally, and 5 minutes later,
NSD-1015 was administered intraperitoneally at 100 mg/Kg. The amount of L-DOPA produced [GBL] after 30 minutes was determined in the same manner. Another group of mice was given NSD-1015.
L-DOPA 30 minutes after intraperitoneal administration of 100 mg/Kg
The amount produced [NSD] was determined in the same manner. The dopamine receptor stimulation rate was determined by the following formula based on the amount of each product produced. DA receptor stimulation rate = (1-[Sample]-[NSD]/[GBL]-[NSD]) x 1
00 Results When 16 mg of the test drug per 1 kg of body weight was administered intraperitoneally, the stimulation rate was 85.3% (average of 3 cases). Reference Example 2 Measurement of contralateral turning behavior in mice with unilateral striatum destruction Test compound 4,5-trans-5-(2-methyl-1-propen-1-yl)-4-propylamino-1,
3,4,5-tetrahydrobenz[cd]indole 8μ of 6-hydroxydopamine (6-OHDA) in the unilateral striatum of ddY male mice weighing 20-30g
g/4μ was injected to destroy dopamine neurons.
After one week of normal breeding, apomorphine 0.1mg/
Kg was injected subcutaneously to induce 360° contralateral turning behavior.
Mice with a total number of turns of 200 to 300 times were selected. After 5 to 7 days, the test drug was administered intraperitoneally, and contralateral turning behavior was measured. Results After administration of test drug 20mg/Kg intraperitoneally
The total number of rotations in 150 minutes was 2546±985 (average of 5 cases).

Claims (1)

[Claims] 1 General formula [Formula] (R ¹ in the formula is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms, and R ² is a lower alkyl group having 2 to 6 carbon atoms) 1,3,4,5- represented
Tetrahydrobenz[cd]indole derivatives and pharmacologically acceptable acid addition salts thereof. ² 1,3,4,5-tetrahydrobenz [cd ] Indole derivatives and pharmacologically acceptable acid addition salts thereof. 3 1, 3, and 3 of claim 1 represented by the formula
4,5-tetrahydrobenz[cd]indole derivatives and pharmacologically acceptable acid addition salts thereof. 4 1, 3, and 3 according to claim 2 represented by the formula
4,5-tetrahydrobenz[cd]indole derivatives and pharmacologically acceptable acid addition salts thereof. 5 1, 3, and 3 of claim 2, represented by the formula
4,5-tetrahydrobenz[cd]indole derivatives and pharmacologically acceptable acid addition salts thereof.