JPS6248669B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to phenanthrene derivatives, their preparation and pharmaceutical compositions containing them. The present invention is based on the formula In the formula, R ₁ is hydrogen, (C ₁ - ₁₀ ) alkyl, or (C ₃
~ ₇ ) is cycloalkyl, and _R2 is ( _C1 ~ ₅ )
alkyl, and the R ₃ substituents are the same and are hydroxy or acyloxy groups. R ₁ is preferably an alkyl group. When R ₁ is an alkyl group, it conveniently contains 1 to 6 carbon atoms and can mean, for example, methyl. _R2 has 1 to 4 carbon atoms, preferably 1 to 8
Conveniently, it is an alkyl group containing 5 carbon atoms. _{R 3} is the formula Ra-CO _- O-, where Ra(C _1-7 ) alkyl; (C _3-6 )
Cycloalkyl; _{unsubstituted} phenyl; mono- or di-substituted phenyl substituted with chlorine, fluorine, trifluoromethyl, _{( C1-4} ) alkyl or ( _C1-4 ) alkoxy; unsubstituted benzyl; or chlorine, fluorine or ( _C1-4 ) is an acyloxy group represented by the following, which is benzyl mono- or di-substituted with _alkoxy . A representative group of compounds has the formula ′ In the above formula, R ₂ is as described above, and a compound of the formula " In the above formula, _R2 is as described above, the R'a substituents are the same, and ( _{C1-7 )} alkyl;
( _C3-6 ) cycloalkyl; unsubstituted phenyl; mono- or di _- substituted phenyl substituted with chlorine _, fluorine, trifluoromethyl, ( _C1-4 ) alkyl or ( _C1-4 ) alkoxy; _or The compound is benzyl. _R2 is conveniently _{( C1-4} )alkyl.
R'a is conveniently (C _{1 -4} ) alkyl, (C ₃ -
₆ ) cycloalkyl, phenyl, phenyl monosubstituted with chlorine or methoxy, or benzyl. The compounds of the present invention can be produced by methods known per se. The present invention comprises a formula In the above formula, R ₁ and R ₂ are as described above,
Z is a cleavable ether group, by cleaving the ether group Z of the compound of formula a In the above formula, R ₁ and R ₂ are as described above, or by acylating a compound of formula b, In the above formula, R ₁ and R ₂ are as described above,
A method for preparing a compound of the formula is provided by preparing a compound in which the group R' ₃ is the same acyloxy group. The ether cleavage method of the present invention comprises a specific method a)
can be carried out by a conventional method of cleaving an ether group. For example, the reaction can be carried out with a strong mineral acid, such as hydrobromic acid or hydroiodic acid, at a temperature of at least 100°C, preferably at 100°C.
This can be carried out by treatment at a temperature of 130°C to the boiling point of the reaction mixture, particularly 130°C. The ether group(s), especially the group Z, is preferably 10
arylalkoxy or alkoxy containing up to 5 carbon atoms, especially benzyloxy, ethoxy or methoxy groups, more preferably methoxy groups. The acylation process according to the invention in particular process b) can be carried out by conventional methods for selective acylation of phenol groups in the presence of an amine function. for example,
As acylating agents it is possible to use functional derivatives of acids such as acid chlorides, acid bromides or acid anhydrides. Conveniently, the reaction is carried out by reacting the acid chloride in the presence of trifluoroacetic acid at a temperature of 20°C to the boiling point of the reaction mixture, or in the presence of pyridine at a temperature of 0°C to room temperature. 4,5,5a,6-tetrahydro- containing at least one ether group on one or both of the fused benzene rings, which are the starting materials in process a) and some of which are also the final products of the invention Dibenzo[cd,f]indole is the corresponding 4,5-dihydro-, correspondingly substituted or, if a compound unsubstituted at the 4-position is desired, oxo-substituted at the 4-position. It can be produced by method c), which consists of reducing the 5a,b-double bond of dibenzo[cd,f]indole. In particular, a compound of the formula In the above formula, R ₂ is the group Z as described above,
and X is hydrogen and Y is the same as R ₁ or X and Y together are oxo, and the 5a,6-double bond and, if present, - can be produced by reducing the group. The reduction is carried out by methods customary for the reduction of enamines or imines, for example in aqueous mineral acids, preferably hydrochloric acid, optionally with mercury () salts,
For example, it can be carried out with zinc in the presence of mercuric chloride (). The reaction is preferably carried out in an organic solvent,
For example, it can be carried out in a lower alkanol, such as ethanol, at a temperature of 50° C. to the boiling point of the reaction mixture. Under these conditions, the 4 present
-The oxo group is reduced at the same time. The resulting compounds of the invention can be isolated from the reaction mixture and purified by known methods. The free base form can be converted to the acid addition salt form and vice versa by conventional methods. Suitable acids for salt formation are hydrochloric acid, hydrobromic acid and methanesulfonic acid. The compounds of the invention have an asymmetric carbon atom in the 5a position and can be obtained as a racemate or as one of the optically active forms, ie as individual enantiomers. When the nucleus is substituted in the 4-position, especially when R ₁ in the formula is other than hydrogen, the compounds of the invention have two asymmetric carbon atoms in the 4 and 5a positions, Therefore 2
Different racemates can exist. Starting from optically active starting materials, optically active final products can be obtained. Racemic starting materials give racemic final products. The individual racemates can be prepared by known methods, e.g.
oisomeric salts), such as (+) or (-)tartaric acid or their salts with di-p-toluyl-1-acid or d-tartaric acid, can be separated into enantiomers. Resolution of the racemates can be carried out after the final stage of the synthesis or optionally at an earlier stage. Preferably the isomer separation is carried out before cleavage of the ether group. Starting materials of process c) which are monosubstituted in the 4-position, especially compounds of the formula when X is hydrogen and Y is other than hydrogen, have an asymmetric carbon atom in the 4-position. Upon reduction of these compounds, a second asymmetric carbon atom is formed at the 5a position. Formula a In the above formula, R ₂ and Z are as described above,
The compound can be produced, for example, according to the following reaction formula. In the above reaction _formula , the groups Z and _R2 are as described above, _R'2 is hydrogen or ( _C1-4 ) alkyl, Hal is iodine, bromine or chlorine,
Alk is lower alkyl. The reaction can be carried out by conventional methods. Compounds of formula V can be prepared according to a modification of the Curtius reaction, for example by reacting an acid of formula with sodium azide in the presence of trifluoroacetic acid and trifluoroacetic anhydride, followed by hydrolysis with a base. can be manufactured. Acylation of compounds of formula, for example, at acid acceptors, such as N-
This can _be carried out in the presence of ethyldiisopropylamine with a compound of the formula _R''2 --CO--Hal where Hal is as defined above and _R''2 is ( _C1-4 )alkyl. When R′ ₂ is hydrogen,
The reaction can be carried out by reacting a compound of formula with formic acid in the presence of N,N-carbonyldiimidazole. A compound of the formula can be reduced, for example with diborane. The preparation of a compound of the formula involves reacting a compound of the formula with a chloroformate in an organic solvent and in the presence of an acid acceptor, for example N-ethyldiisopropylamine. This can be carried out suitably. -110℃
Treatment of a compound of formula with, for example, an alkyllithium or aryllithium compound, preferably n-butyllithium or tert.-butyllithium, in tetrahydrofuran/hexane at a temperature in the range from -0°C gives compounds of formula a. The remaining 4-oxo-substituted starting materials in process c) can be prepared in a similar manner. formula b In the above formula, the group Z and R ₁ and R ₂ are as described above. For example, the compound represented by the following reaction formula, the group Z,
R ₁ , R ₂ and Hal are as described above, and An is aeon. The reaction can be carried out according to known methods. Acylation of a compound of the formula Hal―CO―R′ ₁
where R' ₁ is the same as R ₁ except that it may not mean hydrogen, and Hal is as previously described, is a compound of acid acceptor, such as N-ethyldiisopropylamine. This can be carried out by reacting in the presence of When R ₁ is hydrogen, the reaction can be carried out by reacting a compound of formula V with formic acid in the presence of N,N-carbonyldiimidazole. Compounds of the formula can be alkylated with alkyl iodides, preferably under the conditions of a phase transfer catalysis reaction, for example in the presence of tetrabutylammonium hydrogen sulfate. For example, treatment of compounds of formula X with n-butyllithium or tert.-butyllithium in tetrahydrofuran/hexane at temperatures ranging from -110°C to 0°C provides compounds of formula XI. formula
Dehydration of the compounds of XI can be carried out, for example, with mineral acids, such as hydrochloric acid in ethereal solution. The salt of formula XII can be reduced to b with sodium borohydride in tetrahydrofuran. _The starting material of formula When R ₁ is R′ ₁ as defined above, the compound of formula XI is
It can also be prepared in a conventional manner from a compound of formula a by reaction with a compound of formula R' ₁ --Li where R' ₁ is as described above. Compounds of formula XI in which R' is hydrogen can also be prepared in conventional manner from compounds of formula a by reduction with LiAlH ₄ . Compounds of formula b in which R ₁ is methyl can also be prepared according to the reaction scheme below. In the formula below,
The groups Z and R ₂ are as described above, Hal is a salt compound ion, bromide ion or iodide ion, and An is a chloride ion, bromide ion, iodide ion, CH ₃ -SO ₄ or C ₂ H ₅ SO ₄ and Rx is hydrogen and Ry is bromomethyl, or Rx and Ry together =
CH ₂ :-. Alkylation of a compound of formula is, for example, R ₂
is as described above, and by reaction with a compound of the formula An-R ₂ when An is chlorine, bromine or iodine, or by reaction with dimethyl sulfate or diethyl sulfate when R ₂ is methyl or ethyl. can be done. Ring opening of compounds of the formula may conveniently be carried out with an alkali metal alcoholate, preferably potassium tert.-butyrate, in dimethoxyethane, dioxane or tetrahydrofuran at a temperature of 0 DEG C. to 50 DEG C., preferably at room temperature. The preparation of compounds of the formula from compounds of the formula can be carried out under oxidizing conditions, for example with bromine or halogen releasing compounds, such as N-bromosuccinimide. Regioselective ring functionalization with bromine
The cyclofunctionalisation can be carried out at a temperature of 0 DEG C. to 50 DEG C., preferably at room temperature, conveniently in an inert organic solvent such as a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride, preferably chloroform. The reaction with N-bromosuccinimide may conveniently be carried out in the presence of water and optionally organic solvents such as dioxane, tetrahydrofuran, methylene chloride and chloroform at 0°C to 50°C, preferably at room temperature. The demethylation and subsequent rearrangement of the resulting quaternary compound of formula is conveniently carried out in an organic solvent, such as benzene, dimethylformamide or ethanolamine, preferably ethanolamine, at a temperature above 80°C, preferably between 80°C and
It is carried out at 110°C, particularly preferably at 100°C. The remaining starting materials of process c) which are unsubstituted or substituted in the 4-position by a substituent R ₁ other than hydrogen can be prepared in a manner analogous to that described above for compound b. The products of the above reactions can be isolated and purified by known methods. Unless the preparation of specific starting materials is specified, this can be carried out by conventional or analogous methods. It should be understood that some of the above compounds may exist in optically active forms. Certain of the above starting materials are novel and particularly useful intermediates for the preparation of pharmacologically active compounds and form part of the present invention. Therefore, the functional groups present, such as ether groups,
Due to the ketone group, the double bond in position 5a-6, the following compounds are valuable intermediates: a If more than one ether group is present, the groups are attached to the same fused benzene ring 4,5,5a,6-tetrahydro-dibenzo[cd,f]indoles having at least one ether group cleavable on one or both of the fused benzene rings under the conditions of b 4,5-dihydro-dibenzo [cd ，
f] indole. c 4,5-dihydro-4-oxo-dibenzo [cd, f] which has only one or two cleavable ether groups at any of the 7 to 10 positions and has no further oxy group Indole. In particular, the formula ′a In the above formula, R ₂ is as described above, ring B has only one or two cleavable ether groups, and there is no further oxy substituent in the nucleus, a compound of the formula 'b In the above formula, R ₁ and R ₂ are as described above,
Compounds of and formula ' in which rings A and/or B contain at least one cleavable ether group In the above formula, R ₁ , R ₂ and Hal are as described above, and ring A and/or B contains at least one cleavable ether group
b and are examples of such compounds) are valuable intermediates for the preparation of a wide variety of compounds due to the functional groups present, in particular ether and amino groups and halogen atoms. Conveniently, two ether groups are present in the intermediate, for example in the 9 and 10 positions. Conveniently the ether group(s) are (C ₁ -
₄ ) It is alkoxy. In the examples below all temperatures are given in degrees Celsius and are uncorrected. The absolute configuration of the optically active compound of the formula according to Example 7 when Z is methoxy and R ₁ and R ₂ are methyl is determined by X-ray analysis. The absolute configuration of other optically active compounds of the formula was determined by their optical rotation. It is assumed that compounds of the formula prepared from compounds of the corresponding formula have the same absolute configuration. Example 1 (5aRS)-4,5,5a6-tetrahydro-9,
10-dimethoxy-5-methyl-dibenzo[cd,f]indole (compound of formula) 3% aqueous solution of mercury chloride () 544 ml (0.06M)
272g (41.7M) while stirring under nitrogen atmosphere
of zinc dust and stir the mixture for 5 minutes at room temperature. 40 g of 4,5-dihydro-9,10-dimethoxy-5-methyl-4-oxo-dibenzo[cd,f]indole in 544 ml of ethanol
(0.316M) and also 3400ml of 2N hydrochloric acid. Raise the reaction temperature to 65° and hold at this temperature for 30 minutes. After addition of 272 ml of 37% hydrochloric acid, the reaction mixture is stirred at 65° C. for 16 hours. After cooling to 10°, filter the suspension. The filtered zinc dust was mixed with a 1:1 mixture of methylene chloride and ethanol at 1600 ml.
Wash with ml. Cool the liquid in an ice bath and concentrate.
Make alkaline with NH ₄ OH4 and make with methylene chloride.
Extract twice (2000 ml each time). The combined organic phases were dried, filtered and evaporated (5aRS) -
4,5,5a,6-tetrahydro-9,10-dimethoxy-5-methyl-dibenzo[cd,f]indole (melting point with decomposition after recrystallization from ether)
126-128°). NMR 100Mz (CDCl ₃ ): δ2.66ppm (3H, s,
N-CH ₃ ), 4.25 (1H, d, 11Hz, C-4α
H). The starting material can be prepared as follows: a A mixture of 860 ml (6.16 M) of trifluoroacetic anhydride and 860 ml (11.24 M) of trifluoroacetic acid is diluted with 8-bromo-3,4- under nitrogen at room temperature. Dimethoxy-phenanthrene-9-carboxylic acid
140.0 g (0.380 M) and stir the mixture for 10 minutes. The resulting brown transparent mixture -
Cool to 5° and add 30.4g of sodium azide.
(0.468M) is carefully added in solid form. 2
After stirring for 3 hours at °C, the reaction mixture is poured onto ice and the resulting suspension is filtered and washed with 1.4 parts of water. The white crude product is suspended in 2.5 ethanol and the reaction mixture is refluxed. After addition of 1680 ml of 2N sodium hydroxide, the resulting yellow clear solution is refluxed for 45 minutes. The solution is cooled to room temperature, extracted with methylene chloride, and the organic phase is dried and evaporated. The obtained 9-amino-8-bromo-3,4-dimethoxy-phenanthrene is
Melts at 107-108°. b 19.4 ml (0.346 M) of formic acid are added dropwise over 5 minutes to a suspension of 64.5 g (0.397 M) of N,N-carbonyl-diimidazole in 387 ml of anhydrous tetrahydrofuran and stirred for 30 minutes at room temperature. This solution was added to a solution of 100 g (0.301 M) of 9-amino-8-bromo-3,4-dimethoxy-phenanthrene in 1600 ml of tetrahydrofuran.
Add dropwise over 5 minutes at −3° and stir the reaction mixture for 16 hours. - After cooling at 10°,
The mixture is filtered, the crystals are washed with ether and dried in vacuo. The resulting 8-bromo-9-formylamino-3,4-dimethoxyphenanthrene melts at 191-193°. c 1000 ml of a 1 molar solution of diborane (1.0 M) in anhydrous tetrahydrofuran to 90 g of 8-bromo-9-formylamino-3,4-dimethoxy-phenanthrene in 900 ml of anhydrous tetrahydrofuran.
(0.249M) under a nitrogen atmosphere. The resulting solution is refluxed for 41/2 hours and then stirred at room temperature for 16 hours. After the mixture has been cooled to -5°, 1800 ml of 2N sodium hydroxide are added dropwise over 5 minutes. The reaction mixture is heated to reflux and tetrahydrofuran is removed by evaporation at normal pressure. 900 ml of ethanol is added to this hot aqueous solution and the ethanol is evaporated off at normal pressure. Add 900 ml of ethanol and evaporate on a rotary evaporator. The addition and evaporation of 900 ml of ethanol is repeated two more times. The solid yellow colored residue is added to 900 ml of methylene chloride and 900 ml of water and shaken with 900 ml of ice. The organic phase was separated and the aqueous phase was diluted with methylene chloride (900 ml each time).
Extract times. The combined organic phases are dried and evaporated. Pour the resulting oil into hot methanol approx.
Emulsify in 500ml and add methylene chloride to make about 1
form a solution of Methylene chloride is removed by heating in a rotary evaporator, ensuring that no two-phase formation occurs. The solution is cooled to -10° to obtain 8-bromo-9-methyl-amino-3,4-dimethoxy-phenanthrene. It melts by 75-77°. d 70 g (0.202 M) of 8-bromo-9-methylamino-3,4-dimethoxy-phenanthrene dissolved in 700 ml of anhydrous methylene chloride under nitrogen atmosphere and 139 ml of N-ethyldiisopropylamine
(0.808M) and ethyl chloroformate 38ml
Add (0.404M). The reaction mixture is stirred at room temperature for 16 hours and extracted with 500 ml of 2N hydrochloric acid. The organic phase is separated and shaken with 500 ml of saturated potassium bicarbonate solution. The aqueous phase is extracted three times (250 ml each time) with methylene chloride. The condensed organic phase is dried, evaporated and residual ethyl chloroformate is removed by heating at 70° in vacuo. Recrystallization from ether/petroleum ether gives 8-bromo-9-(N-ethoxycarbonyl-N-methyl)amino-3,4-dimethoxy-phenanthrene (melting point 100-110° C.). e 101.8 ml (0.167 M) of a 1.64 molar solution of n-butyllithium in hexane under a nitrogen atmosphere -
Tetrahydrofuran being stirred at 105°
Add over 10 minutes to a solution of 70 g (0.167 M) of 8-bromo-9-(N-ethoxycarbonyl-N-methyl)amino-3,4-dimethoxy-phenanthrene in 1890 ml and 630 ml of n-hexane. The reaction mixture is stirred at the same temperature for 25 minutes and then allowed to warm up to +10°. After careful addition of 200 ml of water, the reaction mixture was further diluted with 1500 ml of water and three times with methylene chloride (each time).
1500ml) Extract. The combined organic layers were dried, filtered and evaporated to give 4,5-dihydro-9,10-dimethoxy-5-methyl-4-oxo-dibenzo[cd,f]indole (from ether/petroleum ether). Melting point after recrystallization of 151
-152°). Example 2 From suitable compounds of formula a, the following compounds of formula can be obtained in a similar manner to Example 1. (5aRS)-5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-dibenzo[cd,f]indole (oil) NMR60MHz (CDCl ₃ ): δ4.40ppm (1H, dd, 10
Hz, and 1 Hz homoallylic coupling, C-4αH), 1.3
(3H, t, 7Hz, NCHzCH ₃ ). (5aRS)-4,5,5a,6-tetrahydro-
9,10-dimethoxy-5-n-propyl-dibenzo[cd,f]indole (oil) NMR60MHz (CDCl ₃ ): δ4.40ppm (1H, dd, 10
Hz, and 1 Hz homoarylic coupling, C-
4αH), 1.00 (3H, t, 7Hz,
_{NCH2CH2CH3 ) .} The starting material can be obtained as follows: a 110 ml of N-ethyldiisopropylamine
(0.638 M) is added to a solution of 100 g (0.302 M) of 9-amino-8-bromo-3,4-dimethoxy-phenanthrene in 500 ml of methylene chloride. 500ml of methylene chloride 41.6ml of acetyl chloride
(0.585M) solution is added dropwise to this mixture in 20 minutes. During this addition period, the temperature of the reaction mixture is maintained at 20° by cooling with an ice bath. After stirring at room temperature for 16 h, the mixture was
Pour onto 2N hydrochloric acid and extract with methylene chloride. The organic phase is washed with 2N sodium hydroxide solution, dried and evaporated to give 9-acetyl-amino-8-bromo-3,4-dimethoxy-phenanthrene (mp 200-202° after recrystallization of the ether). ). Similarly, 8-bromo-3,4-dimethoxy-9-propionylamino-phenanthrene (melting point 192-193°). b Analogously to Examples 1c) to 1e, the following compounds can be obtained: 5-ethyl-4,5-dihydro-9,10-dimethoxy-4-oxo-dibenzo [cd, f]
Indole (melting point, 125-126 with decomposition)
゜). 4,5-dihydro-9,10-dimethoxy-4
-Oxo-5-n-propyl-dibenzo[cd,f]indole (melting point, accompanied by decomposition)
103-105°). Example 3 5-ethyl-4,5,5a,6-tetrahydro-
9,10-dimethoxy-4-methyl-dibenzo[cd,f]indole (compound of formula) a 8-bromo-9-ethylamino-3,4-dimethoxy-phenanthrene 9-acetylamino-8-bromo-3, 4-dimethoxy-phenanthrene was reduced using diborane analogously to Example 1c) to give 8-dimethoxy-phenanthrene.
Bromo-9-ethylamino-3,4-dimethoxy-phenanthrene (melting point after recrystallization from ether, 103-105°) is produced. b 9-(N-acetyl-N-ethyl)amino-
8-Bromo-3,4-dimethoxy-phenanthrene 8-bromo-9-ethylamino-3,4-dimethoxy-phenanthrene was reacted with acetyl chloride in the same manner as in Example 2a) to form 9-(N-acetyl-N -ethyl)-amino-8-bromo-3,4-
Dimethoxy-phenanthrene (melting point 189° after recrystallization from ethyl acetate) c (4RS)-5-ethyl-4,5-dihydroxy-4-hydroxy-9,10-dimethoxy-4-
Methyl-dibenzo[cd,f]indole 2 of tert.-butyl-lithium in pentane
10 ml of a molar solution (20 mM) of 9-(N
-acetyl-N-ethyl)amino-8-bromo-3,4-dimethoxy-phenanthrene 4.04g
(10mM) at -105°. The temperature of the reaction mixture is allowed to reach room temperature and the mixture is poured onto ice. After extraction with methylene chloride, the organic phase is washed with water, dried and evaporated. Obtained crude product (4RS) in the form of yellowish brown foam -5-
Ethyl-4,5-dihydro-4-hydroxy-
The 9,10-dimethoxy-4-methyl-dibenzo[cd,f]indole is further reacted directly. 2.1ml of 5% ethereal methyllithium solution
(3.3mM) of 4,5-dihydro-9,10-dimethoxy-5- in 30ml of anhydrous tetrahydrofuran.
1 g of ethyl-4-oxo-dibenzo[cd,f]indole (prepared in Example 2)
Add dropwise to a solution of (3.3mM) at -60°. The reaction mixture is allowed to reach room temperature and is kept at this temperature for 30 minutes. The mixture is made alkaline with 2N sodium hydroxide solution and extracted with methylene chloride. The organic layer was dried and evaporated to (4RS)-5-ethyl-4,5-dihydro-4
-Hydroxy-9,10-dimethoxy-4-methyl-dibenzo[cd,f]indole is obtained as a dark green oil (JR spectrum CH ₂ Cl ₂ ):
3550cm _- ¹ (OH)]. The crude product is further processed directly. d 5-Ethyl-9,10-dimethoxy-4-methyl-dibenzo[cd,f]indolinium chloride 2 ml of saturated ethereal hydrogen chloride solution (10.5mM)
of crude (4RS)-5-ethyl-4,5-dihydro-4-hydroxy-9, dissolved in 30 ml of ether.
10-dimethoxy-4-methyl-dibenzo [cd,
f] Add 3.2 g (10 mM) of indole, which precipitates a red product. After stirring for 30 minutes, the product was filtered to give 5-ethyl-9,10-dimethoxy-4-methyl-dibenzo[cd,f]indolinium chloride, which was used directly in the next reaction. . e (4RS)-5-ethyl-4,5-dihydro-
9,10-dimethoxy-4-methyl-dibenzo[cd,f]indole 5-ethyl-9,10-dimethoxy-4-methyl-dibenzo[cd,f]indolinium chloride 100mg (0.33mM) was added to 3ml of anhydrous tetrahydrofuran and Add to a solution of 12.5 mg (0.33 mM) of sodium borohydride in 3 ml of ethanol. After a vigorous reaction, the mixture is stirred for 15 minutes. 3 ml of water are added and the mixture is extracted with methylene chloride. The organic phase was washed with water, dried and evaporated (4RS).
-5-Ethyl-4,5-dihydro-9,10-dimethoxy-4-methyl-dibenzo[cd,f]indole is obtained as a green oil. NMR60MHz (CDCl ₃ ): δ1.2ppm (3H, t, 7
Hz, NCH ₂ CH ₃ ), 1.49 (3H, d, 7Hz, C-
4-CH ₃ ), 3.5 (2H, q, 7Hz, NCN ₂ CH ₃ ),
4.88 (1H, q, 7Hz, C-4-H), 6.2
(1H, s, C-6-H), 8.98 (1H, d.8Hz, C
-1-H). IR (CH ₂ Cl ₂ ): 1635 cm ^-1

[Formula] f 5-ethyl-4,5,5a,6-tetrahydro-9,10-dimethoxy-4-methyl-dibenzo[cd,f]indole In the same manner as in Example 1, (4RS)-5-ethyl -4,5-dihydro-9,10-dimethoxy-4-
A mixture of two racemates (oil) by reducing methyl-dibenzo[cd,f]indole
The title compound is obtained as . Individual racemates can be separated by chromatography on silica gel. (±)-4R ^* , 5aS ^* ): NMR100MHz (CDCl ₃ ): δ1.42 (3H, d, 6
Hz, C-4α-CH ₃ ), (±)-(4R ^* , 5aR ^* ): NMR100MHz (CDCl ₃ ): δ1.18 (3H, d, 7
Hz, C-4β-CH ₃ ). Example 4 4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenzo [cd,
f] Indole [compound of formula] a (-)-(6aR)-5,6,6a,7-tetrahydro-10,11-dimethoxy-6-dimethyl-
4H-Dibenzo[de,g]quinolinium iodide Add 100ml (1.6M) of methyl iodide to methylene chloride.
(-)-(6aR)-5,6,6a,7- in 100ml
Tetrahydro-10,11-dimethoxy-6-methyl-4H-dibenzo[de,g]quinoline 100g
(0.34M) and the mixture is refluxed for 30 min. After cooling, ether was added to the reaction mixture and the precipitate was filtered and dried to give (-)-(6aR)-5,6,
6a,7-tetrahydro-10,11-dimethoxy-
6,6-dimethyl-4H-dibenzo[de,g]quinolinium iodide (decomposed at 173-176°) is obtained. b (9RS)-9,10-dihydro-3,4-dimethoxy-9-dimethylamino-8-vinyl-phenanthrene potassium tert.-butyrate 13.9g (124mM)
was dissolved in 560 ml of tetrahydrofuran under a nitrogen atmosphere to obtain (-)-(6aR)-5,6,6a,7-tetrahydro-10,11-dimethoxy-6,6-dimethyl-4H-dibenzo[de,g]. Add 47g (112mM) of quinolinium iodide. The mixture was stirred at room temperature for 1 h, poured onto ice, and diluted with 10% hydrochloric acid.
Add 560ml. Wash the mixture with ether.
The aqueous phase is neutralized with sodium bicarbonate, made alkaline at pH 9 with 50 ml of 20% sodium hydroxide solution and extracted three times (500 ml each time) with methylene chloride. The combined methylene chloride extracts are dried and evaporated. The residue was purified by chromatography on 1 Kg of silica gel using ether as eluent to give (9RS)-9,10-dihydro-3,
4-dimethoxy-9-dimethylamino-8-vinyl-phenanthrene (melting point: 109°) is obtained. c (4RS)-4,5-dihydro-9,10-dimethoxy-4,5-dimethyl-dibenzo [cd,
f] Indole (9RS)-9,10-dihydro-3,4-dimethoxy-9-dimethoxyamino-8-vinyl-phenanthrene (17.5 g (57 mM)) in 55 ml of water by stirring 10.2 g (57 mM) of N-bromosuccinimide. Add to the suspension. The reaction mixture is warmed and the product precipitates after a few minutes. After about 1 hour, the mixture was cooled in an ice bath and filtered to precipitate (5aRS)-4,5,5a,
6-tetrahydro-9,10-dimethoxy-5,5
-dimethyl-4-methylene-dibenzo [cd,
f] Obtain indolinium bromide (sintered at 135° and melted at 165°). The crude product is further processed directly. 19.7 g (50.7 mM) of the above obtained indolinium bromide in 100 ml of ethanolamine.
Stir at 100° for 1 hour. The reaction mixture is poured onto ice/water and extracted three times (300 ml each time) with methylene chloride. Dry the combined methylene chloride extracts,
Evaporate (4RS)-4,5-dihydro-9,10
-dimethoxy-4,5-dimethyl-dibenzo[cd,f]indole is obtained as an oil. This (4RS)-4,5-dihydro-9,10-dimethoxy-4,5-dimethyl-dibenzo [cd,
f] Indole can also be prepared as follows: 2.7 g of bromine in 15 ml of chloroform (0.86 ml;
(9RS) solution of 17mM) in 45ml of chloroform
-9,10-dihydro-3,4-dimethoxy-9-
Dimethyl-amino-3-vinyl-phenanthrene
Add dropwise to a solution of 4.8 g (15.5 mM) at room temperature. After the reaction, the mixture is cooled in an ice bath. Filter the resulting precipitate, add 10 ml of chloroform and ether
Wash with 100 ml of 4-bromomethyl-4,
5,5a,6-tetrahydro-9,10-dimethoxy-5,5-dimethyl-dibenzo[cd,f]indolinium bromide (sintered at 132° and 154-
melt at 158°). The product was directly converted to (4RS)-4,5-dihydro-9,10-dimethoxy-4,5-dimethyl-dibenzo [cd,
f] Converted to indole. d 4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenzo[cd,f]indole 400 ml of 3% aqueous solution of mercuric chloride ()
(44.2mM) to 200g (330mM) of zinc dust. Stir the mixture for 5 minutes and add 2N hydrochloric acid 2500
Add ml. (4RS) in 400ml of ethanol -
4,5-dihydro-9,10-dimethoxy-4,5
-dimethyl-dibenzo[cd,f]indole 15.7
(50mM) and stir the mixture at 50-60°.
Warm for an hour. After adding 200ml of 37% hydrochloric acid,
Stir the mixture at 90° for 14 hours. Cool the mixture, pass through the zinc dust, and rinse the liquid with ammonia solution.
Make alkaline at PH10. The mixture was extracted three times with methylene chloride (1000 ml each time), the combined methylene chloride extracts were dried over Na ₂ SO ₄ and evaporated to give 4,5,5a,6-tetrahydro-9,10-dimethoxy- 4,5-Dimethyldibenzo[cd,f]indole is obtained as a mixture of two racemates in the form of the free base. A mixture of two racemates was used as the eluent in methylene chloride/methanol (98.5:
1.5) Chromatograph on 1.8Kg of silica gel using 50ml fractions. Fraction 125−240 is (±)−(4R ^* ,5aS ^* )−
4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenzo [cd, f]
Contains indole. NMR spectrum of this base (CDCl ₃ 90MHz): δ1.44ppm (3H, d, 6
Hz, C-4a-CH ₃ ), melting point of the corresponding hydrochloride: 185
゜ or more (accompanied by decomposition). Fraction 250−330 is (±)−(4R ^* , 5aR ^* )−
4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenzo [cd, f]
Contains indole. NMR spectrum of this hydrochloric acid (CDCl ₃ , 90MHz): δ1.24ppm (3H, d,
7 Hz, C-4β-CH ₃ ), melting point of the corresponding hydrochloride: from 200° (with decomposition). Example 5 (±)-(4R ^* ,5aS ^* )-4,5, in the form of the base in 10 ml of ethyl acetate and 0.5 ml of methanol.
5a,6-tetrahydro-9,10-dimethoxy-
A solution of 5 g (18 mM) of 4,5-dimethyl-dibenzo[cd,f]indole was added to 3.8 g of (-)-tartaric acid in 22 ml of ethanol/ethyl acetate (1:1).
(22mM) and the mixture was stirred at room temperature for 1 h, then (-)-(4S,5aR)
-4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenzo [cd,
f] (−)-tartrate of indole crystallizes. Decomposition: 183-190°; [α] ²⁰ _D = 120.6° (H ₂ O, c = 0.5). The corresponding hydrochloride salt obtained by known methods decomposes between 210 and 255°;
[α] ²⁰ _D = -140° (H ₂ O, c = 0.5). The remaining mother liquor from crystallization of the tartrate salt is made alkaline with potassium carbonate and the mixture is extracted with methylene chloride. The combined organic extracts are washed neutral, dried and evaporated. Residue (approx.
2.5g; 9mM) in ethanol/ethyl acetate (1:
1) Mix with 1.65 g (11 ml) of (+) tartaric acid in 11 ml. After stirring at room temperature for 1 hour, (+)-(4R,
5aS)-4,5,5a,6-tetrahydro-9,10
-Dimethoxy-4,5-dimethyl-dibenzo[cd,f]indole (+)-tartrate crystallizes. Decomposition: 185-190°; [α] ²⁰ _D = +116° (H ₂ O, c = 0.5). Hydrochloride obtained by known methods is
Decompose at 215-230°: [α] ²⁰ _D = +140° (H ₂ O, c = 0.5). The following compound (±) - (4R ^* , 5aR ^* ) -4,
It can be obtained by a similar method from 5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenzo[cd,f]indole (in the form of the free base): (+)-(4S , 5aS) -4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenzo[cd,f]indole (-)-
Tartrate. Decomposition: 177-180°; [α] ²⁰ _D = +116° (H ₂ O, c = 0.5). Decomposition of the corresponding hydrochloride: 160-
164°; [α] ²⁰ _D = +160° (H ₂ O, c = 0.5).
(-)-(4R,5aR)-4,5,5a,6-tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenzo[cd,f]indole. Decomposition: 178-
182°; [α] ²⁰ _D = −114° (H ₂ O, c = 0.5). Corresponding salt division of hydrochloride: 158-162゜; [α] ²⁰ _D = -156
° (H ₂ O, c = 0.5). (±)-(4R ^* ,5aS ^* )-5-ethyl-4,
The following compound can also be obtained from 5,5a,6-tetrahydro-9,10-dimethoxy-4-methyl-dibenzo[cd,f]indole (in free base form) by a similar method: (+)-(4R ,5aS)-5-ethyl-4,5,
5a,6-tetrahydro-9,10-dimethoxy-4
-Methyl-dibenzo[cd,f]indole (-)-tartrate; [α] ²⁰ _D = +96° (H ₂ O, c=
0.5). The corresponding hydrochloride salt obtained by known methods is 185
- decomposes at 188°; [α] ²⁰ _D +121° (H ₂ O, c
=0.5). (-)(4S,5aR)-5-ethyl-4,5,
5a,6-tetrahydro-9,10-dimethoxy-4
-Methyl-dibenzo[cd,f]indole;
[α] ²⁰ _D = −102.4 (H ₂ O, c = 0.5). The corresponding hydrochloride salt obtained by known methods decomposes at 189-190°;
[α] ²⁰ _D = -122° (H ₂ O, c = 0.5). Example 6 (±) - (4R ^* , 5aS ^* ) - 4, 5, 5a, 6 -
Tetrahydro-9,10-dihydroxy-4,5
-dimethyl-dibenzo[cd,f]indole (compound of formula) (±)-(4R ^* ,5aS ^* )-4,5,5a,6-
Tetrahydro-9,10-dimethoxy-4,5-dimethyl-dibenzo[cd,f]indole 16.8g
(53.8mM) is dissolved in 400ml of a 47% aqueous solution of hydrobromic acid, and the solution is heated at 130° for 3 hours. After evaporation of the mixture, the residue is dissolved in ethanol and the solvent is evaporated. Crystallization of the residue from methanol/ether gives the hydrobromide salt of the title compound. The corresponding hydrochloride salt obtained by known methods decomposes at 185°; NMR 100MHz
(DMSO): δ1.81 (3H, d, 5Hz, C-4α-
_CH3 ). Example 7-37 By a method analogous to Example 6 and using the corresponding starting materials, compounds of formula a are obtained, where R ₁ and R ₂ are as indicated in the table below. be able to.

【table】

[Table] Example 38 (±)-(4R ^* ,5aS ^* )-9,10-dibenzoyloxy-4,5,5a,6-tetrahydro-
4,5-dimethyl-dibenzo[cd,f]indole [compound of formula] 4.7 ml (40.6 mM) of benzoyl chloride (±)-(4R ^* ,5aS ^* )-4 in 12 ml of trifluoroacetic acid
In addition to a solution of 1.3 g (4.31 mM) of 5,5a,6-tetrahydro-9,10-dihydroxy-4,5-dimethyl-dibenzo[cd,f]indole hydrochloride,
The mixture is refluxed for 1 hour. After evaporation of the reaction mixture,
The residue is extracted three times with methylene chloride (100 ml each time), the combined organic extracts are dried over sodium sulfate and evaporated. The residue was purified by chromatography through a column of 165 g of silica gel using methylene chloride/methanol (97:3) as eluent to give pure (±)-
(4R ^* ,5aS ^* )-9,10-dibenzoyloxy-4,5,5a,6-tetrahydro-4,5-dimethyl-dibenzo[cd,f]indole is obtained.
Hydrochloride after crystallization from ether/acetone215
Melts at ~225° (with decomposition);
NMR100MHz (DMSO): δ1.39ppm (3H, d,
6Hz, C-4α-CH ₃ ). Examples 39-103 By a method similar to Example 38 and using the corresponding starting materials, the formula In the above formula, R ₁ , R ₂ and R″ ₃ are as described in the table below. The following compound can be obtained.

【table】

【table】

【table】

【table】

【table】

TABLE The end products of the invention, particularly the compounds of formula, have pharmacological activity. In particular, the compound is tested in standard tests, such as U. Ungerstedt Acta Physiol
Contralateral rotation by microinjection of 6-hydroxydopamine in rats with substantia nigra lesions according to the principles of Scand.Suppl. (1971) 367 , 69-93. Central dopaminergic activity as demonstrated by induction of contralateral turning and dose-dependent stereotypic sniffing, licking and biting behavior in rats according to the test described below. Indicated for use as central dopaminergic stimulant agents: Rats, 180-222 g, are placed in a 30 cm diameter perspex cylinder on a wire rack. After 30 minutes of habituation to the cage, the rats are injected with the compound of the invention to be investigated. The behavior of the rats is observed for 2 minutes at 30 minute intervals for 2 hours and then every 60 minutes for the entire period up to 7 hours. Observed stereotypic behavior
Costall, Naylor and Olley [Euro J.Pharmac.
18 , 83-94 (1972)]. The scoring and criteria are as follows: 1. Intermittent sniffing. 2. Persistent sniffing, occasional licking. 3. Licking and occasional biting. 4. Strong and persistent bite. In these tests, the compound
0.03-30 mg per kg is administered intraperitoneally. The compounds are therefore indicated for use as central dopaminergic stimulants, for example for the treatment of Parkinson's disease (Morbus Parkinson). For this indication, the indicated daily dosage is from about 0.5 mg to about 100 mg, conveniently about 0.1 mg.
~2-4 times per day in unit dosage form containing about 50 mg
Administered in multiple divided doses or in sustained release form. Examples 48, 52-59, 62, 71, 72, 79, 80, 82,
Particular preference is given to the compounds 83, 84, 88, 89, 92, 93, 95, 96 and 103, especially the compounds of Examples 48, 55 and 62. The compounds of the invention can be administered in the form of pharmaceutically acceptable acid addition salts. These salt forms exhibit the same degree of activity as the free base forms. The compounds of the present invention have low toxicity, and when administered orally, approximately
It shows almost good non-toxicity at doses up to 350mg/Kg. For example, the compound of Example 48 has an LD ₅₀ of >300
mg/Kg (orally. Also provided are pharmaceutical compositions comprising in acid addition salt form. These compositions can be formulated in conventional manner, for example, into solutions, capsules or tablets. Example 104 (Anti-Parkinsonian activity) 1 U. Ungerschutetz test (U.
Ungerstedt Test) The antiparkinsonian activity of this compound was determined by measuring the central dopaminergic stimulating activity of this compound. Such activity was induced unilaterally in the nigrostriatal tracts by 6-hydroxydopamine, thereby inducing hypersensitivity of dopaminergic receptors. Demonstrated by induction of contralateral rotations in rats. This method is awesome. It is based on the method of Ungerschütt. Male OFA rats (140-160 g) were anesthetized with pentobarbital (NEMBUTAL) and placed in a David Kopf tube.
Kopf) stereotactic frame. A sagittal cut was made in the skin and the underlying tissue was scraped to expose the bregma. A 2 mm wide opening was made at +4.2 mm anteriorly and 1 mm laterally (right) from bregma, and a cannula [2R2 No. 3 cardiac needle] with an outer diameter of 0.3 mm was inserted 7.5 mm deep from the dura. I inserted it. Solution of 6-hydroxydopamine hydrochloride (2 mg/ml 6-OHDA in saline with 0.2 mg/ml ascorbic acid as antioxidant) 4-
μ was administered into the medial substantia nigra for 2 minutes using a Hamilton syringe driven by an “Agla” micrometer gauge.
ssubstantianigra). The cannula was then removed and the wound was closed with clips.
One week later, animals were challenged with 0.25 mg/Kg sc apomorphine and the total number of rotations was measured. Animals that responded by turning to the side opposite to the lesion were selected for further experiments. To facilitate comparisons between different compounds and between different groups of animals, the number of rotations for each animal was 0.25 mg/Kg ip apomorphine injected.
Corrected by a factor derived from the average of 560 total turns per animal obtained from 40 rats. Animals were used for the first 4 weeks after injury and once per week thereafter.
I received only one treatment. Recording of rotation was done by observation and manual counter. The direction of rotation was recorded in all cases. The total number of revolutions is the most important factor. The duration of effect is also important. Groups of at least 3 animals were used.

Table 2. Stereotypy in rats Dopaminergic activity was also determined by measuring the induction of stereotypy in rats.
In the Ungerschütztutt animal model, activity was determined against lesioned animals lacking dopamine, whereas stereotypic studies were performed on healthy animals. dopamine agonists
The majority of cases induce stereotypies in normal animals. Stereotypy testing was determined in rats according to the following standard method: Male OFA was placed in a 230 cm diameter perspex cylinder with a wire grid floor.
Rats (180-250g) were added. After 30 minutes to habituate to the cage, animals were injected subcutaneously with the compound at 30 mg/Kg ip and at 30 minute intervals for 2 hours.
Subsequently, observations were made at 60 minute intervals for a total of 7 hours. Regarding the degree of stereotypic behavior, Costalt et al. European. Journal. of. Pharmacology. (1972), No. 18
Volume, No. 83. (Costalt et al.EuroJ.Pharmacol.
(1972), 18 , 83.).
The scores and criteria are as follows. 1. Sniffing intermittently with moderate intensity; 2. Sniffing persistently and occasionally licking; 3. Licking noticeably and biting occasionally to moderately; 4. Biting strongly and persistently.

【table】

【table】

Claims (1)

[Claims] 1 formula where _{R 1} is hydrogen or (C _{1-10 ) alkyl, or (C 3-7 ) cycloalkyl, R 2 is (C 1-5 ) alkyl ,} and the two _{R 3} substituents are and hydroxy or _the following formula Ra-CO-O-, where Ra is (C _1-7 ) alkyl; (C _3-
6 ) Cycloalkyl; _{unsubstituted} phenyl; mono- or di-substituted phenyl substituted with chlorine, fluorine, _{trifluoromethyl} , ( _C1-4 ) alkyl or ( _C1-4 ) alkoxy; unsubstituted benzyl; or A compound represented by: which is benzyl mono- or di-substituted with chlorine, fluorine or ( _C1-4 )alkoxy, which is an acyloxy group represented by the _following , or an acid addition salt thereof. 2. The compound or acid addition salt thereof according to claim 1, wherein each R ₃ is hydroxy. 3. The compound or acid addition salt thereof according to claim 2, wherein R ₁ is methyl. 4. The compound or acid addition salt thereof according to claim 1, wherein each R ₃ is an acyloxy group. 5 Claim 2 which is 4,5,5a,6-tetrahydro-9,10-dihydroxy-4,5-dimethyl-dibenzo[cd,f]indole
Compounds or acid addition salts thereof. 6. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are methyl and ethyl, respectively. 7. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are methyl and n-propyl, respectively. 8. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are methyl and isopropyl, respectively. 9. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are methyl and n-butyl, respectively. 10. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are ethyl and methyl, respectively. 11. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are isopropyl and methyl, respectively. 12. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are n-propyl and methyl, respectively. 13. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are tert.-butyl and methyl, respectively. 14. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are sec-butyl and methyl, respectively. 15. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are n-butyl and methyl, respectively. 16. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are cyclopropyl and methyl, respectively. 17. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are hydrogen and methyl, respectively. 18. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are hydrogen and ethyl, respectively. 19. The compound or acid addition salt thereof according to claim 2, wherein R ₁ and R ₂ are hydrogen and n-propyl, respectively. 20 Claims 5 to 19 which are racemic
A compound or an acid addition salt thereof as described in any of the above. 21. The compound according to any one of claims 5 to 19 in an optically active form or an acid addition salt thereof. 22 Claims 5 to 1 which are in an optically active form and have a 4S, 5aR or 4R, 5aR configuration
A compound according to any of Item 6 or an acid addition salt thereof. 23 (+) - (4R, 5aS) - 4, 5, 5a, 6 -
Tetrahydro9,10-dihydroxy-4,5-
The compound according to claim 2, which is dimethyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 24 (-) - (4S, 5aR) - 4, 5, 5a, 6 -
Tetrahydro9,10-dihydroxy-4,5-
The compound according to claim 2, which is dimethyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 25 (+) - (4S, 5aS) - 4, 5, 5a, 6 -
Tetrahydro9,10-dihydroxy-4,5-
The compound according to claim 2, which is dimethyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 26 (-) - (4R, 5aR) - 4, 5, 5a, 6 -
Tetrahydro9,10-dihydroxy-4,5-
The compound according to claim 2, which is dimethyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 27 (-)-(4S, 5aR)-5-ethyl-4,
The compound according to claim 2, which is 5,5a,6-tetrahydro9,10-dihydroxy-4-methyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 28 9,10-dibenzoyloxy-4,5,
5. The compound according to claim 4, which is 5a,6-tetrahydro-4,5-dimethyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 29. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each H, methyl and p-chlorobenzoyloxy. 30. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each H, ethyl and phenylacetyloxy. 31. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each H, n-propyl and phenylacetyloxy. 32. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each H, n-propyl and propionyloxy. 33. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are respectively methyl, ethyl and p-trifluorobenzoyloxy. 34. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, ethyl and p-fluorobenzoyloxy. 35. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and p-bromobenzoyloxy, respectively. 36. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and phenylacetyloxy, respectively. 37. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, n-propyl and cyclohexylcarbonyloxy. 38. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, n-propyl and cyclopropylcarbonyloxy. 39. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, n-propyl and pentanoyloxy. 40. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, n-propyl and propionyloxy. 41. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and 3,4-dimethoxybenzoyloxy, respectively. 42. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, ethyl and p-chlorobenzoyloxy. 43. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, ethyl and o-chlorobenzoyloxy. 44. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are respectively methyl, ethyl and p-methoxybenzoyloxy. 45. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and m-methoxybenzoyloxy, respectively. 46. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and o-methoxybenzoyloxy, respectively. 47. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, methyl and phenylacetyloxy, respectively. 48. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are respectively methyl, methyl and cyclohexylcarbonyloxy. 49. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, methyl and cyclopropylcarbonyloxy, respectively. 50. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, methyl and butyryloxy, respectively. 51. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, methyl and acetyloxy, respectively. 52. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, n-propyl and isobutyryloxy. 53. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, n-propyl and benzoyloxy. 54. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, n-propyl and pivaloyloxy. 55. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and p-methylbenzoyloxy, respectively. 56. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are respectively methyl, ethyl and m-methylbenzoyloxy. 57. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and o-methylbenzoyloxy, respectively. 58 Claim 4 in which R ₁ , R ₂ and R ₃ are each methyl, methyl and pivaloyloxy
Compounds or acid addition salts thereof. 59. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, methyl and isobutyryloxy, respectively. 60 Claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, ethyl and benzoyloxy
Compounds or acid addition salts thereof. 61 Claim 4 in which R ₁ , R ₂ and R ₃ are each methyl, ethyl and pivaloyloxy
Compounds or acid addition salts thereof. 62. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, ethyl and isobutyryloxy. 63. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and p-methoxyphenylacetyloxy, respectively. 64. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and m-methoxyphenylacetyloxy, respectively. 65. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and o-methoxyphenylacetyloxy, respectively. 66. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and p-chlorophenylacetyloxy, respectively. 67. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and m-chlorophenylacetyloxy, respectively. 68. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and o-chlorophenylacetyloxy, respectively. 69. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and 2,6-dichlorophenylacetyloxy, respectively. 70 The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and 2,4-dichlorophenylacetyloxy, respectively. 71. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are methyl, ethyl and 3,4-dichlorophenylacetyloxy, respectively. 72 The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, ethyl and m-chlorobenzoyloxy. 73. The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, ethyl and m-fluorobenzoyloxy. 74 The compound or acid addition salt thereof according to claim 4, wherein R ₁ , R ₂ and R ₃ are each methyl, ethyl and o-fluorobenzoyloxy. 75 Claims 28 to 7 that are racemic
A compound according to any of Item 4 or an acid addition salt thereof. 76. The compound according to any one of claims 28 to 74 in an optically active form or an acid addition salt thereof. 77 Claim 28 which is in an optically active form and has a 4S, 5aR or 4R, 5aR configuration
and the compound according to any one of Items 33 to 74 or an acid addition salt thereof. 78 (-)-(4R,5aS)-9,10-di(p-
Chlorobenzoyloxy)-5-ethyl-4,
5. The compound according to claim 4, which is 5,5a,6-tetrahydro-4-methyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 79 (+)-(4S,5aR)-9,10-di(p-
Chlorobenzoyloxy)-5-ethyl-4,
5. The compound according to claim 4, which is 5,5a,6-tetrahydro-4-methyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 80 (+)-(4S, 5aR)-9,10-G-
(3,4-dimethoxybenzoyloxy)-5-
The compound according to claim 4, which is ethyl-4,5,5a,6-tetrahydro-4-methyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 81 (-)-(4S,5aR)-9,10-G-(o
-chlorobenzoyloxy)-5-ethyl-4,
5. The compound according to claim 4, which is 5,5a,6-tetrahydro-4-methyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 82 (+)-(4S,5aR)-9,10-di(p-
methoxybenzoyloxy)-5-ethyl-4,
5. The compound according to claim 4, which is 5,5a,6-tetrahydro-4-methyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 83 (+)-(4S,5aR)-9,10-di(p-
methylbenzoyloxy)-5-ethyl-4,
5. The compound according to claim 4, which is 5,5a,6-tetrahydro-4-methyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 84 (-)-(4S,5aR)-9,10-dibenzoyloxy-4,5,5a,6-tetrahydro-
The compound according to claim 4, which is 4,5-dimethyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 85 (-)-(4S,5aR)-9,10-diisobutyryloxy-4,5,5a,6-tetrahydro-
The compound according to claim 4, which is 4,5-dimethyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 86 (+)-(4S,5aR)-9,10-dibenzoyloxy-5-ethyl-4,5,5a,6-tetrahydro-4-methyl-dibenzo[cd,f]indole The compound according to item 4 or an acid addition salt thereof. 87 (-)-(4S, 5aR)-5-ethyl-4,
5,5a,6-tetrahydro-4-methyl-9,10
-dipivaloyloxy-dibenzo[cd,f]indole or an acid addition salt thereof according to claim 4. 88 (-)-(4S,5aR)-9,10-di(p-
methoxyphenylacetyloxy)-5-ethyl-4,5,5a,6-tetrahydro-4-methyl-
The compound according to claim 4, which is dibenzo[cd,f]indole, or an acid addition salt thereof. 89 (-)-(4S,5aR)-9,10-di(p-
Chlorophenylacetyloxy)-5-ethyl-
The compound according to claim 4, which is 4,5,5a,6-tetrahydro-4-methyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 90 (-)-(4S,5aR)-9,10-di(o-
Chlorophenylacetyloxy)-5-ethyl-
The compound according to claim 4, which is 4,5,5a,6-tetrahydro-4-methyl-dibenzo[cd,f]indole, or an acid addition salt thereof. 91 (-) - (4S, 5aR) - 4, 5, 5a, 6 -
Tetrahydro-4,5-dimethyl-9,10-di(phenylacetyloxy)-dibenzo [cd,
f] The compound according to claim 4, which is an indole or an acid addition salt thereof. 92 Claims 1 to 92 in free base form
A compound according to any of Item 91 or an acid addition salt thereof. 93 Claims 1-1 in the form of acid addition salts
A compound according to any of Item 91. 94 The following formula In the above formula, R ₁ is hydrogen or (C _1-10 ) alkyl or ( _{C 3-7} ) cycloalkyl, R ₂ is ( _{C 1-5} ) alkyl, and Z is a cleavable ether group _. The following formula a is characterized by cleaving the ether group Z of a compound of In the above formula, R ₁ and R ₂ are defined as above. A method for producing a compound represented by: 95 The following formula a In the above formula _, R ₁ is hydrogen or (C _{1-10 )} alkyl or (C _3-7 ) cycloalkyl, and R ₂
is ( _C1-5 ) _alkyl , and the following formula b is characterized by acylating the compound represented by In the above formula, the definitions of R ₁ and R ₂ are the same as above, and R′ ₃ is the same acyloxy group. 96 The following formula where R ₁ is hydrogen or (C _1-10 )alkyl or (C _3-7 )cycloalkyl, R ₂ is ( _{C 1-5} )alkyl, and the two _{R 3} substituents are _the same. and hydroxy or _the following formula Ra-CO-O-, where Ra is (C _1-7 ) alkyl; (C _3-
6 ) Cycloalkyl; _{unsubstituted} phenyl; mono- or di-substituted phenyl substituted with chlorine, fluorine, trifluoromethyl, ( _C1-4 ) alkyl or ( _C1-4 ) alkoxy; unsubstituted benzyl; or _chlorine , is mono- or di-substituted benzyl with fluorine or ( _{C 1-4} )alkoxy, is an acyloxy group represented by 1. A pharmaceutical composition for treating Parkinson's disease, comprising a carrier or diluent.