JPS63154660A - 1,3,4,5-tetrahydrobenz(cd)indole derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is 1-5C alkyl; R<2> is H or 1-6C alkyl). EXAMPLE:4, 5-Trans-5-(2-methyl-1-propene-1-yl)-4-propionylamino-1,3,4,5-tetra hydrobenz[cd]indole. USE:An intermediate for production of medicine. PREPARATION:A compound expressed by formula II is dissolved in methylene chloride or the like and a reactive functional derivative of carboxylic acid expressed by formula III and triethylamine are added to the solution and the mixture is stirred at the room temperature to provide the compound expressed by formula I.

Description

[Detailed description of the invention] Industrial application field This invention is a novel L useful as an intermediate in the production of pharmaceuticals.
3.4.5-f Concerning trahydrobenz[:cd:]indole derivatives.

BACKGROUND OF THE INVENTION Ergot alkaloids have been used in various pharmaceutical products. For example, a migraine treatment agent, a peripheral vascular disorder treatment agent, a senile brain dysfunction treatment agent, a uterine contractile agent, a uterine hemostatic agent,
These include antihypertensive agents and hyperprolactinism treatment agents.

All of these ergot alkaloids have an ergolene structure as a basic skeleton, and most of them are peptide-type compounds having a peptide chain in the side chain. In recent years, active clavine-type compounds with relatively simple side chains have been discovered and used, but these still have an ergolene structure as their basic skeleton. Until now, this ergolene structure was essential for the expression of activity of ergot alkaloids.
Compounds with this skeleton cleaved were thought 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 useful as an intermediate in the production of pharmaceuticals.

Means for Solving the Problems The present inventors have developed a simple structure in which the ergolene skeleton is cleaved.
．． 3.4.5-Tetrahydrobenz[cd]indole derivatives, which have an alkylamino group at the 4-position and a 2-methyl- It has been found that a compound having a 1-propenyl group has a dopamine receptor stimulating effect 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.

The present invention provides compounds useful as intermediates for the production of these compounds, which have the general formula (wherein R1 is a lower alkyl group having 1 to 5 carbon atoms,
R2 is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms.

The compound of general formula (I) of the present invention is a new compound and can be produced by the following method.

For example, a compound represented by the general formula (R2 in the formula has the same meaning as above) and a carboxylic acid represented by the general formula (% formula %) (R+ in the formula has the same meaning as above). It can be produced by reacting with a reactive functional derivative.

The compound of general formula (II) used as a starting material in the method for producing the compound of general formula (■) of the present invention, in which R2 is a hydrogen atom, is a known compound and can be produced by the method described in the literature. [Japanese patent application, 1939
1-85361].

In addition, a compound of general formula (II) in which R2 is a lower alkyl group can be prepared by reacting a compound of general formula (II) in which R2 is a hydrogen atom with an appropriate acylating agent.
It can be produced by reducing the acyl derivative using an appropriate reducing agent such as lithium aluminum hydride.

The compound of general formula (I) used as the other starting material in the method for producing a compound of general formula (I) of the present invention is a known compound, and can be easily obtained as a commercially available product or by manufacturing according to a known method. can be obtained.

In the compound of general formula (1) of the present invention, carbons at the 4th and 5th positions are asymmetric carbons, and four stereoisomers exist depending on the arrangement of substituents on these carbons.

Furthermore, these isomers consist of two types of 4,5-cis forms (4S, 5S;
4R, 5R) and 4.5-) lance form (4S, 5R; 4
R, 5S), but the compound of general formula (I) of the present invention is not particularly limited to any of them.

Effects of the Invention The compound represented by the general formula (1) of the present invention can be made useful as a pharmaceutical by reducing it with a suitable reducing agent. is an alkyl group
R2 has the same meaning as above).

These compounds have a dopamine receptor stimulating effect and are useful as therapeutic agents for Parkinson's syndrome, therapeutic agents for Huntington's chorea, prolactin secretion inhibitors, and the like.

EXAMPLES The content of the present invention will be explained in more detail with reference to the following examples. Note that all melting points of compounds in each example are uncorrected.

Example 1 l)-4-propionylamino-1,3,4,5-tetrahydro4.5-)lan-4-amino-5-(2-methyl-1-propen-1-yl)-1,3 ,4,5-tetrahydrobenz[:cd:1indole2.1860
g was dissolved in 24.0 mg of methylene chloride. Add 1.008 g of propionic acid chloride to this and 1.0 g of methylene chloride.
A solution dissolved in - was added to the solution under stirring at room temperature, and further triethylamine 2. On+1 was 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 mixed with methylene chloride-methanol (95:5.
v/v) Extracted with a mixed solvent. The organic layers were combined, washed with saturated brine, and dried over anhydrous sulfuric acid. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from methylene chloride-〇-hexane to give 2J408 g (85,8
%) of 4.5-) lance-5-(2-methyl-1-propen-1-yl)-4-propionylamino-1,3,
4,5-tetrahydrobenz[cd]indole was obtained.

Colorless needle-like crystals (methylene chloride-n-hexane) Melting point: 206-210°C IR (KBr) v: 3200. 1654.1516 c
m-''H-NMR (CDC13) δ: 1.05 (3H, t, J=7Hz),
1.72(3)1. d, J=IHz), 1
．． 89(3)1. d, J=IHz), 2.
02 (2ft.

Q, J=7Hz), 2.78(1)1. d
d, J=15.6 and5.2Hz>, 3.2
4 (IH, dd, J45.6 and4.2t(z)
, 3.90 (IH, dd, J=9 and5
．． 511z), 4.22-4.52 (IH, m),
5.04 (LH.

br-d, J=9゜5flz), 5.36 (I
H,br-d, J=9)1z), 6.70~6
．． 94 (2H, m), 7.00-7.18 (2H,
m), 8.48 (LH,br-s)MS:
m/z 209 (M”-NHCOCH2C
)+3) Elemental analysis value: (as C+al122N20) 0% N% N% Calculated value 76.56 7.85 9.92 Actual value 76.58 7.95 9.96 Example 2 4-propionylamino-1,3 ,4,5-tetrahydrobe4,5-cis-4-amino-5-(2-methyl-1
37.0 μm of -propen-1-yl)-1,3,4,5-tetrahydrobenz[cd]indole was dissolved in 2.0 μm of methylene chloride, and 0.1 μm of propionic acid chloride was dissolved in the solution.
mj2,) ethylamine 0.2ai! was added under ice cooling. After stirring at room temperature for about 1 hour, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and methylene chloride-methanol (9
5:5. v/v) Extracted with a mixed solvent. 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).
97/3. v/v) to produce 41.7 mg (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 prism crystal (methylene chloride-n-hexane) Melting point: 123.0 ~ 125.0℃ 1R (K
Br) ν□, : 3360. 3270. 1631.
1520 cm-''+1-NMR (CDCI3) δ: 1.08 (3H, t, J=7.6Hz),
C79 (3fl, d, J-1, 2Hz),
1.80(311,d, J=1.21(z),
2.09 (2H, Q, J=7.6Hz),
2.86 (IH, ddd, J=15.5. 7.0
and 1.0)1z), 3.10(LH,d
dd.

J=15.5. 4.5 and 1.0Hz),
4゜05(ill, dd.

J40. Oand 4゜OHz>, 4.45~4.
75(1)1゜m), 5.19(IN, br-
d, J=10.011z), 5.46(LH,
br-d, J=9.0Hz; NH), 6.
83(it(.

br-s), 6.67-6.80(ill, m
>, 6.97-7.17 (2t (, mL 8.0
4. ('LH,br-s)MS: m/z
282 (M”) Elemental analysis value + (CI8822N
20) 0% 8% N% Calculated value 76.56 7.85 9.92 Actual value 76.27 7.94 9.981
Example 3 4.5-) lance-5-(2-methyl-1-propene-
1-yl)-4-propionylamino-1,3,4,5
-Tetrahydrobenz (cd) indole 1.102g
was dissolved in 20°Od of anhydrous tetrahydrofuran, and 1.926g of lithium aluminum hydride was added thereto to give a solution of 7.5
Stir at reflux for an hour. After the reaction, methanol was added to the reaction solution to decompose excess reagent, 10% Rochelle salt aqueous solution was added, and methylene chloride-methanol (95:5.v/
v) Extracted with mixed solvent. 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-) lance-5-(2-methyl-1=propen-1-yl)-4-propylamino-1,3,4,5
-tetrahydrobenz[cd]indole at 699.
2 mg (66, 8%) was obtained.

Colorless needle-like crystals (methylene chloride-Kohexane) 1 and melting point + 138.5 ~ 140.0℃ IR (K
Br) v,,: 3150,3100. 1605. 1
443 cm-''H-NMR (CDCI,) δ: 0.92 (38, t, J=7Hz), 1.
52 (2H, sex, J=7Hz), 1.74 (I
H, br-s), 1.84 (3ft, d,
J-1Hz), 1.88 (3H, d, , J=I
Hz), 2.36-3.00 (3H, m>, 2
．． 74 (ltl, br-d, J=11)1z)
.

3.28 (IH, br-d, J=11Hz), 3.
84 (01, t.

J=8.8Hz), 5.11(LH,br-d,
J=9.5tlz).

6.64~6.90 (2N, m), 7.00~
7.20 (2tl, m).

7,87 (it(,br-s) MS': m/z 268 (M") Elemental analysis value: (C111H24N4・1/2+420
)0% 8% N% Calculated value? 7.93 9.08 10.10 Actual value 77.84 8.76 10.034.
5-) Lance-5-(2-methyl-1-propene-1-
yl)-4-propylamino-1,3,4,5-tetrahydrobenz[:cd:]indole 125.0mg
was dissolved in 4.0 ml of methylene chloride, and 50.0 mg of propionic acid chloride and 0.2 ml of triethylamine were dissolved therein.
A fart was added and the mixture was stirred at room temperature for 2.5 hours. A mixed solvent of methylene chloride and methanol (95:5. v/v) was added to the reaction solution, and the organic layer was washed successively with a saturated aqueous sodium bicarbonate 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-hexane-180/10/1/64.v
/v) purified with Lte4.5-) lance-5-(2-methyl-1-propen-1-yl)-4-IN-propionyl-N-propylamino)-1,3,4,5- Tetrahydrobenz (cd) indole 79.8 mg (52,
8%).

Colorless prismatic crystal (methanol-water) Melting point +
179.0 ~ 180.0℃ IR (KBr) Sea, l' 3263.1616 cm-''H-N
MR (CDCl2) δ: 0.91 (3ft, t, J=7Hz>, 1
．． 09 and 1.16 (1:l, total 3
)1. each t, J=7Hz), 1.38~
1.88(2)1. m), 1.74(3t(,b
r-s), 1.82 (3ft, br-s), 2
．． 32 (2H, Q, J=7tlz), 2.68~3
．． 68 (4)1. m), 3.92-4.60
(28, m).

4.92-5.20 (IH, m>, 6.60-6.9
0 (2H.

m), 6.96-7.17 (2tl, m), 7.
92 and 8, o5 (1:l total IIL
each br-s, NH) CIMS:
m/z 324 (M+1) Elemental analysis value'
(C2+t12eN*0 トL TE)6% N
%N%

Claims (5)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. A 1,3,4,5-tetrahydrobenz[cd]indole derivative represented by (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1 in the formula is a lower alkyl group having 1 to 5 carbon atoms) 1, 3, 4,
5-tetrahydrobenz[cd]indole derivative. (3) 1, 3, 4, 5 described in claim 1 expressed by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
-Tetrahydrobenz[cd]indole derivative. (4) 1, 3, 4, 5 described in claim 2 expressed by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
-Tetrahydrobenz[cd]indole derivative. (5) 1, 3, 4, 5 described in claim 2 expressed by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
-Tetrahydrobenz[cd]indole derivative.