JPS58203993A - Novel azepinoindole, manufacture and medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing azebino indinope and medicinal products containing the same.

European Patent Application No. 80106550.9 discloses a series of novel compounds useful as neuroleptics, antidepressants and antiallergic agents, viz. 2.3.4.5.6-Hexahide-6-phenylazepino[4,5-1]
) Indoles are disclosed and requested. This special. r'l
'The application describes 1.2.
3.4.5.6-hexahydro-6-phenyluazebino[4.5-b]indole is specifically exemplified.

According to the invention, 1-alkyl-1.2.3.4.5
．． As can be seen from the test results described below, 6-hexahydroazepino[4.5-b) indoles can be used, for example, as neuroleptics and/or especially as antidepressants.
It was found that it has particularly interesting pharmacological properties and is sufficiently durable.

Therefore, this invention provides 1-alkyl-1.2.3
．． 4. 5. 6-hexahydroazepino[4.5-
b] Indoles and acid addition salts thereof (hereinafter referred to as compounds of the present invention). The compound of this invention may be substituted at any position on the nucleus, for example, has an unsubstituted or substituted exocyclic phenyl group at the 6-position.

In particular, this invention provides a compound of the formula (I) [wherein R and k2 are each represented by Xr, water, halogen having an atomic number of 9 to 35, (C)1
-4 alkyl, (C)alkoxy, (C)
A1-41-4 Alkylthio, or trifluoromethyl, Rl and k
2 is each independently hydrogen, a halogen having an atomic number of 9 to 35, (C) alkyl, 1-4 3 or (c) alkoxy, R is hydrogen, (CI-
4) 1-4 alkyl, (C) cycloalkyl, (C)
3-64-9 cycloalkylalkyl, (C3-5) alkenyl (C
3-5) alkynyl, or formula (II) (wherein nl+
;! 1.2 or 3, means trifluoromethyl), k means (C)alkyl4
The present invention provides a compound represented by the following formula and an acid addition salt thereof.

In formula (T), R 1 and R 1 are preferably located at the 8th or 9th position of the nucleus. Preferably k2 and k2 are at the 3- or 4-position of the phenyl ring.

As the halogen, chlorine or fluorine, particularly chlorine, is preferred. Alkyl, alkylthio, and alkoxy are
Preference is given to one or two carbon atoms, especially one carbon atom.

The carbon atom at position 1 of the compounds of this invention is asymmetric.

However, the compounds of this invention may exist in a number of optically isomeric forms. Therefore, the compounds of this invention and the compounds of formula (I) include racemic forms as well as individual optically isomeric forms. The individual optical isomeric forms can be prepared according to a method such as 1'. i can do it. In addition,
It can also be obtained by using optically active starting materials from the beginning in the production method described below, and in this case, the corresponding optically active compound can be obtained as a final product as a pure product.

According to another Tokuso, this invention is based on the following methods: 1) A methyl group substituted with a leaving group at the 1st position is replaced with a 4-alkyl group whose nitrogen atom at the 2nd position is unsubstituted 1.2.3.4-
Tetrahydropyride [3.4-b) By treating indole or its acid addition salt with a /X hydride ion source, the nitrogen atom at the 3-position becomes unsubstituted 1-alkyl
．． 2. 3. 4. 5. 6-hexahydroazepino[4.5-b]indole or an acid addition salt thereof, or l1) 1-alkyl in which the nitrogen atom at position 3 is unsubstituted l.2
．． 3.4.5.6-hexahydroazebino (4.5-
b] 1-alkyl substituted at the 3-position by substituting an indole case or an acid addition salt thereof 1.2.3.
4.5.6-Hexahydroazebino[4.5-b]indole or an acid addition salt thereof, comprising the step of recovering the above-mentioned compound in free base form or acidified caro salt form. A method for producing the compound of this invention is proposed.

In particular, the compound of formula (I) or its acidification 1J1 as described above
1 salt is a compound represented by (wherein k?, R/1, R2, R''2 and R4 have the above meanings, and Y means a leaving group) or an acid addition salt thereof; By treatment with a hydride ion source, the formula (Ia) (wherein R i , R l , R 2 , d2 and R
4 has the meaning of 1) jl) or an acid addition salt thereof, or a compound of the above formula (Ia) or an acid addition salt thereof, a group R
3, the formula (Ib) (where R?,
R? , k2, k2 and R4 have the meanings given above, R3
means a group other than hydrogen in the group previously defined as k3) or an acid addition salt thereof, and recover the compound of formula (1) in the form of Yuya base or acid addition salt. It can be manufactured by a method consisting of:

Methods I) and a) are conveniently carried out according to conventional methods for analogous ring expansion reactions. This reaction is suitably carried out in an inert organic solvent, such as a cyclic or aliphatic solvent, preferably dioxane or tetrahydrofuran. A suitable temperature is from =1-J20°C to the boiling point of the solvent, preferably about 60°C. X is
For example, chlorine, bromine, hydroxy or tosyloxy, with chlorine being preferred.

As a hydride ion source, aluminum hydride,
Complex hydrides such as sodium borohydride or lithium aluminum hydride are preferred. Small << k? , R 1 , R 2 and R2 is chlorine, it is preferable to use aluminum hydride or aluminum borohydride. Formula (I
It is advisable to use acid addition salts of the compounds of II), such as the hydrochloride.

Method 11) or b) can be carried out according to conventional methods for substitution reactions of secondary amines.

Method b) is, for example, an alkylation reaction. The alkylation reaction can be carried out according to a similar conventional method for alkylating secondary cyclic amines. This method can be carried out using, for example, alkyl halides or alkyl sulfates. If desired, the compound of formula (Ia) can be treated with a suitable aldehyde and simultaneously reduced, for example by reduction in the presence of a catalytic ring element or a reducing agent such as formic acid.

Further, according to point 4, this method can be carried out in 2@L or less steps. For example, a compound of formula (Ia) is reacted with a halocarboxylic acid ester, in particular a chloro or bromocarboxylic acid ester, such as ethyl ester, and the resulting urethane is reduced in a conventional manner with, for example, lithium aluminum hydride. Alternatively, he-alkyl derivatives can also be obtained by derivation of the corresponding N-acyl derivatives obtained by conventional methods from compounds of formula (0).

Of course, the compounds of this invention can be prepared by other methods according to the invention.
It can be converted into a compound.

The starting material of formula (Il!) can be obtained, for example, as described below.

Z = ■, Br, c1 * k1●R l @ When R 2 and R'2 are not halogens Starting materials other than those represented by formula (nl), such as 4-alkyl-1.2,3.4-tetrahydro If the method for producing pyrido (3.4-bl indole is not specifically described), these compounds can be produced in a manner similar to the method for producing known compounds or the method described herein.

The free base form of the compounds of this invention can be converted to the acid addition salt form, and vice versa, according to conventional methods. Suitable acids include, for example, hydrochloric acid, hydrochloric acid, maleic acid, fumaric acid and succinic acid.

In the following examples, all temperatures are expressed in degrees Celsius and are uncorrected.

In the table, the following abbreviations were used.

l) Hydrochloride 2) Decomposition 3) Acidic fumarate 4) Free 14I base Example l 1.2.3.4.5.6-Hexahydride-1-methyl-
6-Phenylazepino (4.5-bl indole production [Method I) or a)) Sulfuric acid l-hydrate9. A solution prepared by dissolving 9 tttt in 100 liters of tetrahydrofuran was added dropwise to a suspension of 14.11 lithium aluminum hydride and 140 gt of tetrahydrofuran at O''C.The mixture was stirred at O℃ for 15 minutes. 1-chloromethyl-1.2.3.4-tetrahydride-4-methyl-9-phenylpyrido C3.4-b) Indole hydrochloride 21.4
Add ゜V little by little. The mixture is heated at 70'C for a further 2 hours, cooled to 0°C and to this is added dropwise a saturated sodium sulfate solution 5 (Jul. 30% sodium hydroxide).
Add 25 g of IJum solution and stir the whole at 35° C. for 1.5 hours. The mixture was filtered, the E solution was aarated, and the oily residue was filtered on silica gel with methylene chloride, ethanol, and
Chromatography with concentrated ammonia (95:4.5:0.5) gives the title compound, which is converted to the acid fumarate. mpl96-197"C
(Recrystallized from ethanol).

Starting material 1-chloromethyl-1. 2. 3. 4-
Tetrahydro-4-methyl-9-phenylpyride [3.
4-b] Indole can be obtained in a similar manner.

a) Preparation of 3-(1-nitro-2-probyl)-1-phenylindole 500 μl of a 5% ether solution of methyllithium,
Copper (Il7 6.2 1 and diethyl ether 2
Drop into 50 skin/t suspension solution at 0°C. The mixture was stirred for 1 hour and added with 3-(2-
Nitroethenyl)-1-phenylindole 42.3q
% tetrahydrofuran in 500 ztl was added dropwise at 0°C. The mixture is stirred for a further 1.5 hours, then poured onto ice and ammonium chloride and extracted with ethyl acetate. The organic layer is filtered using a supernatant such as earth, dried, and concentrated under reduced pressure. The residue is chromatographed on silica gel using toluene as eluent. The title compound is obtained as a pale yellow oil.

1)) Production value of 3-(1-amino-2-probyl)-1-phenylindole Acid l hydrate 7.7πt is converted into tetrahydrofuran 77ys
Lithium aluminum hydride is added to the cold solution dissolved in
2g and tetrahydrofuran 220 / 0 in the liquid
Drop at °C. The mixture was heated to reflux on an oil bath at 70°C, and 26.9 g of 3-(1-nitro-2-probyl)-1-phenylindole and 135 g of tetrahydrofuran were added to the mixture.
ml of solution dropwise. After 4.5 hours, the mixture was heated to 0°C.
8. 5
Add yptl. Furthermore, 30% lk sodium oxide} I
Jum solution 19IRl was added and the mixture was heated at 35°C for 30
Stir for a minute. Pass the mixture and concentrate the liquid. The oily residue is converted to the hydrochloride salt, giving mp 213-215°C (recrystallized from ethanol/ether).

()l-Yuguguchi methyl-1. 2. 3. 4-Tetrahydro-4-methyl-9-phenylpyrido [3.4-b
] Production of indole Chloroacetaldehyde (50% aqueous solution) 18yd,
Add to a mixture of 20.3 Da of 3-(1-amino-2-propyl)-1-phenylindole hydrochloride, 70 yttl of 2N4 acid and 200 g/water at 110°C. After 30 minutes, add chloroacetaldehyde to the mixture again.4. 5t
nt and heat for an additional 15 minutes, then cool the mixture to room temperature. The title compound is thus obtained, mp 225-228°C (+1} crystals from ethanol/ether).

Example 2 1.2.3.4,5.6-Hexahide-1.3-dizotyl-6-phenylazepino[4.5-b]indole production [Method 11) or b)) Sulfuric acid l-hydrate 2.56ml of tetrahydrofuran 25
．． A solution of 6 ml of lithium aluminum hydride and 3.65 ml of tetrahydrofuran was added. 5
Add it dropwise to the RL suspension at 0°C to 10°C.

Furthermore, 3-ethoxycarbonyl-1-2.3.4.5
．． 6-H-111:-1'-1-Methyl-6-phenylazepino[4.5-bl indole 5.58 g and tetrahydrofuran 2 (Jtl) solution is added dropwise. After 30 minutes, saturated sulfur solution is added. Add 13 ml of the solution and 6.4 txt of 30% sodium hydroxide solution to a refrigerator. The mixture is stirred at 35° C. for 15 minutes, filtered, and vacuumed.
Condensation I7 gives the title Ihi compound. m of acidic fumanoleate
p195-197°C (recrystallized from ethanol). Hydrochloride of IIIP 2 7 4-2 7 6° Co starting material 3-ethyne tricarbonyl-1.2.3.4.5.6-
Hexahydride-1-methyl-6-phenylzepino (4
．． 5-b3 indole can be obtained in a similar manner.

1.2.3. 4. 5. 6-hexahide-1-methyl-6-phenylazepinoC4.5-b] indole 4.5 g, ethyl chloroformate 3. 1 m/, a mixture of 45 ml of methylene chloride and 15 yttl of water is vigorously stirred for 10 minutes. Then, a solution of 1.3 q of sodium hydroxide dissolved in 26 yxl of water is added, and the mixture is stirred for an additional 10 minutes. Separate the organic layer and
Washing twice with % alcoholic acid solution, then water, drying, and concentration yields 3-ethoxycarbonyl-1. 2.
3. 4. 5. 6-hexahydro-1-methyl-
6-Phenylazepino [4'. 5-b] Obtain indole.

Example 3 1.2.3.4.5.6-Hexahide-1.3-dimethyl-6-phenylazepino[4.5-b) Production of indole [Method 11) or b)) 1.2.3 .4.5.6-hexahydro l-methyl-
6-phenylazepino [4.5-b) indole 55.
31 was heated and dissolved in 553 g/ethanol. 10g Raney nickel and 1 formaldehyde solution (35%)
8y is added and the mixture is hydrogenated at room temperature and atmospheric pressure for 2-4 hours. The catalyst is removed and the r liquid is concentrated to dryness. The residue is dissolved in diethyl ether, the solution is washed with saturated sodium chloride solution, the ether layer is separated, dried and concentrated to dryness. Dissolve the oily residue in 3 volumes of acetonitrile. The base is obtained by precipitation by inoculation and cooling in a water bath.

mp89-92°C0 base 142 da was dissolved in ethanol 750, w/ by heating,
Cool in a water bath and add 1. 8 0
Shake with ml. When inoculated and allowed to cool, hydrochloride precipitates. When this was washed with ether, dried, and recrystallized from 700 yttl of boiling ethanol, mp274-27
It becomes 6°C.

The starting material (Iij $1) is prepared as described in Example 1. In place of Wang Cheng 1a) and 1b), the following method is used.

a) Preparation of 3-(1-nitro-2-probyl)-1-phenylindole A Grignard compound is prepared from 36 g of magnesium pieces, 750 Ht of diethyl ether and 212.9 F of methyl iodide. After diluting with 1500 g of toluene and cooling to -60'C with dry ice 7/acetone, a solution of 132 g of 3-(2-bitroethenyl)-1-phenylindole dissolved in tetrahydrofuran 924y7 was stirred. , at a rate that maintains the temperature between -50'C and -60'C. Remove the dry ice/acetone bath and stir the mixture for 30 minutes.

The temperature rises to -40°C. The mixture was partitioned between 1 kg of ammonium chloride, 5 g of water and 3 e of ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off to give the title compound as an oil, which was diluted on silica gel with toluene/
Chromatographed as hexane (2:l) f'##1k.

b) Preparation of 3-(1-amino-2-probyl)-1-phenylindole 55 g of 3-(1-nitro-2-probyl)-1-phenylindole is dissolved by heating in 550 tons of ethanol.

Add 5.5y of Raney nickel and heat the mixture to 60°C.
Add hydrogen for 6-8 hours at 10 bar. The catalyst was removed, and the r solution was condensed to dryness. Dilute the oily residue with 10% ethanol.
0ii? and acidify with ethanolic hydrochloric acid (4N). Cool in a water bath for 90 minutes, add ether and inoculate with 9 crystals of the hydrochloride of the title compound to give a precipitate with a mp of 210-213°C.

Example 4 A compound of formula (II) in which R1 and k2 are hydrogen was prepared.

Example 5 (1)-1.2.3.4.5.6-hexahydride-1
．． 3-dimethyl-6-phenylazepino[4.5-b]
1.2.3.
．． 4.5.6-hexahydro-1.3-dimethyl-6-
Add to a solution of 7 enyl azepino (4.5-b) indole 55f and ethanol 400tgt. Stir the mixture at room temperature for 3 hours. The crystalline precipitate is collected and washed with diethyl ether. The salt is recrystallized by heating and dissolving the salt in a mixture of methanol and methylene chloride and distilling off the methylene chloride. This operation 1r is repeated 3 times to prepare 1 portion of the title compound (+)-1 dibenzoi tv-1) monotartrate. . pl50'c, [. ] Field angle 50°, C-1 (ethanol).

The methanol mother liquor is (+) − 1.2.3.4.5.
6-Hexahydride-1,3-dimethyl-6-phenylazebino [4,5-b] Used for the isolation of indole (Leprosy Example 6) For further purification, the salt is partitioned between ether and aqueous ammonia. It is converted into a base by

Dissolve 10 g of base and 5.17 f of monotartaric acid in 250 ml of ethanol. Leave the mixture for 24 hours and dissolve (
-1-)-L monotartrate is offshored. mp179-18
2・C, [α] 2”− 1 9.4°, C=1() t/−z,).

The salt is dissolved in pA(d) in methanol/methylene chloride, 60 times the volume of impropanol is added, and the methylene chloride is distilled off.This operation is repeated until the optical rotation becomes constant, and the title compound =+-L. Obtain monotartrate.

mpl85-186°C, [(!).

-24.1°, C=1 (methanol).

The salt is converted to the base by partitioning between ether and ammonia. The resulting base is treated with hydrochloric acid manufactured by Ethanol to obtain the hydrochloride salt of the title compound. mp20° 244°C, [α)D-45.8, C21 (ethanol).

Example 6 (+) - 1.2.3.4.5.6-Hexahide-
1.3-dimethyl-6-phenylazepino [4●5-b
) Preparation of Indole The methanol mother liquor of Example 5 is partitioned between diethyl ether and aqueous ammonia. The ether layer is dried over sodium sulfate and the solvent is distilled off. 30 g of the obtained base was mixed with (1) dibenzoyl, 38.87 y of monotartaric acid and 60 y of methanol.
Treat with a solution of 0++r/. The salt is recrystallized twice as described in Example 5 to give the title compound (1)-dibenzoyl-L monotartrate.

ml"150.5-151'C, [,) 20゜-
48.6・, Gz■] 1 (ethanol).

Further purification is carried out as in Example 5 using (-)-D monotartaric acid. By repeating the recrystallization until the optical rotation becomes constant, the (-)-D monotartrate 20° salt of the title compound is obtained. mp 1 8 5-1 8 6”C, [α
) o+24.0°, C-1 (methanol).

5 Execute the same method as before converting 30 to 1 hydrochloride 60 to 6.20c
O mp241 242”C,Cα)D+45.8,C
=1 (ethanol).

Example 7 A lower period compound belonging to formula (1) was produced.

The compounds of this invention exhibit pharmacological action and have many previous uses as medicines, such as therapeutic uses.

In particular, these compounds have been tested using standard test methods, such as inhibition of tetrabenazine-induced force and ptosis in rats [G. Steinore, Arzneimitzterhorschung, Vol. 14, No. 534 IIJ (
(1964) showed antidepressant activity. The test method is as follows.

Rats (Sprague-Dawley strain, female and /JIS,
120-1601, Juddeutsche Teilfarm, Tuttlingen, West Germany), the test compound was administered to groups of 6 animals approximately 5 to 20 times per day 30 minutes before intraperitoneal administration of tetrabenazine lQ 119 /kHz.
The dose of N was administered intraperitoneally. Tetrabenazine throw 440
After 1 minute, each rat was tested for catalepsy by placing its front paws on a 7 inch wooden block.The animal remained in this awkward position for up to 45 minutes.
Measured down to seconds. Immediately after measuring catalepsy, the degree of ptosis was recorded on a 4-point scale.

d + liH f: 1 indicates that the eyes are completely closed, and 4 indicates that the eyes are completely closed.

By combining the eye values recorded separately, it was determined that the maximum force could be ≦81. If catalepsy 5 is observed for 30 seconds or longer, it can be said that the tetrabenazine-induced force talepsy is antagonistic. Patients with ptosis of 3 or less can be said to be protected from the ptosis effect of tetrabenazine. This operation
The test was repeated 60 minutes after the administration of tetrabenazine.

These compounds therefore have use as antidepressants. In this application, the indicated amount of compound per day is approximately 25
from about 6 to about 250 q/d, preferably administered in 4 divided doses, twice daily, or as a sustained release drug.

Furthermore, these compounds exhibit neuroleptic effects in standard test methods. For example, compound 2-20q/Kg
'c When administered orally to rats, ■. Kleinlogel
Brain waves in medical e+ research,” Herrmann, Gustav Fischer-Ferlach, Stuttgart, New York.
75-88 (1982) during the sleep/wake cycle during a 48-hour recording period.
Paradoxical sleep decreased by 1k.

The compound of this invention has affinity for the in vivo 311-closapine binding site [D. Modification of Hausel et al., Life Sciences Vol. 23, No. 557CC (1978)]. The test method was as follows: 1 m of fresh 1f calf cortex was homogenized in 19 times the volume of Tris mild i'JJ solution and centrifuged. The pellet was suspended in 40 volumes of Tris buffer and the suspension was used for binding experiments. The composition of the test mixture (final volume 2 M/ ) was pll
7.4 Tris solution 50 mM, original tissue weight 4.
5 q 2 corresponding t Ti, 3 ■ 1-Clozapine 0.
65 nN1 and 1 μM of unlabeled clozapine for non-specific binding. 3 ■ Inhibition of I-Clozabine κ binding 11:. To determine the
Each was done twice.

After incubation for 40 minutes in a vacuum cleaner, the test mixture was rapidly passed through Whatman GF/Bp paper, the p solution was washed twice with water-cooled Tris buffer, and the sintering was measured.

These compounds therefore have use as neuroleptics. For this application, the daily instructional chew is approximately compound I
0 to about 600 ltg, preferably administered in unit doses containing about 2 to 300 ltg, given in 2 to 4 divided doses per day, or as a sustained release drug.

The compounds of this invention can be administered either in free base form or in the form of acid addition salts, which can be used as pharmaceutical agents. Such acid addition salt forms exhibit activity on the same order of magnitude as the free base form. This invention also provides pharmaceutical compositions comprising a compound of this invention in free base form or pharmaceutically acceptable acid addition salt form and a pharmaceutical carrier or diluent. Such compositions may be in the form of solutions or tablets, for example.

A preferred indication is use due to antidepressant activity. A preferred compound is the compound of Example 2.

One group of compounds of this invention comprises the formula (Il, where k
and k2 are each independently hydrogen, atomic vinegar 1 halogen No. 9 to 35, (C1 ,) alkyl Iu,
(C) alkoxy, (C) alkylthio, 1-41-4 or trifluoromethyl, k and k2 are water, R3 is hydrogen or (C1-4) alkyl, k is (
C) Alkyl and its acid addition 1-
4 It is salt.

Another group of compounds of this invention comprises formula (I) in which R
1 is hydrogen, halogen, (Cl,) alkyl, or (CI-4) alkoxy, Rl is hydrogen or halogen, R2 is hydrogen, halo'f7, (Cl,) alkyl, or (C1,) alkoxy, R2 is Hydrogen or (
C) alkoxy, R9 is hydrogen or l-4
or halogen, R3 is hydrogen or (C1-4) alkyl, k is (C1) alkyl, and 4 1-4 acid addition salts thereof.

Claims (1)

[Claims] +11 1) 4-alkyl group 122 with a methyl group substituted with a leaving group at the 1st position and an unsubstituted nitrogen atom at the 2nd position
．． 3. 4-Tetrahydropyrido [3.4-J By treating indole or its acid addition salt with a hydride ion source, the nitrogen atom at the 3-position is unsubstituted 1-alkyl-1.2.3.4.5 .6-hexahydroazepino C4.5-bl indole or its acid addition salt, or 11) l-alkyl-1.2 in which the nitrogen atom at position 3 is unsubstituted.
．． 3. 4. 5. 6-Hexapino
4.5-b] By subjecting indole or its acid addition salt to a substitution reaction, l-alkyl-substituted at the 3-position
1. 2. 3. 4. 5. 6-hexahydroazepi/(4.5-b)indole or its acid addition salt was obtained by multiplying the above ratio in free base form or acid addition salt form.
l-alkyl group consisting of 1. g. 2. 3
+4. 5. 6-hexahydroazepino [4.5-b
] A method for producing indole or its acid addition salt. i21 a) Formula Jllll) (wherein k?, 5 1g, R 2 , R 2 and k
4 has the meaning given below, and Y means a leaving group), or an acid addition salt thereof, is treated with a hydride ion source to form a compound of formula (Ia) (wherein R1
, R'1, R2, R'2 and k4 have the meanings given below) or an acid addition salt thereof; By introducing group k3 into 1-salt, formula (Ib) (wherein R?, d?, R2, R'2 and R4 have the meanings given below, and k3 is a group defined later as R3) can be obtained. (meaning a group other than hydrogen) or its i addition salt, the compound represented by
) in free base form or acid addition salt form, wherein R and R2 are each independently hydrogen, 1
Kyoko number 9 to 35/'% Rogen (Cl-4) alkyl, (C ) alkoxy, (C ) alkylthio, or trifluoromethyl, Rl and R2
are each independently hydrogen, atomic number 94I: 35
halogen, (C) alkyl, or (C1,
) alkoxy, R is hydrogen, (C1-4) alkyl, (
C) cycloalkyl, (C) 3-54-9 cycloalkylalkyl, (C) alkenyl, 3
-5 (C)alkynyl, or formula (U)3-5 (where m is l, 2 or 3, X is a bond, -CHOH-
or 1C01, R5 is hydrogen, halogen with atomic number 9 to 35, (C ) alkyl, (Cl ,)1-
4 means alkoxy or trifluoromethyl), k4 means (Cl ,)alkynole] or an acid addition salt thereof; Manufacturing method. (3) 1-alkyl-1.2.3.4.5.6-hexahydroazepino[4.5-b]indole or its acid described in the specification as one of the examples Method for producing addition salts. (4) 1-alkyl-1, 2, 3, 4, 5, 6 produced by the method described in claims 1, 2, or 3.
-hexahydroazepino[4.5-b]indole or an acid addition salt thereof. (5) 1-alkyl-1.2.3.4.5.6-hexahydroazepino[4.5-b]indole or an acid addition salt thereof. (6) A compound represented by the formula (11) according to claim 2 or an acid addition salt thereof. (7) A free base form of the compound according to any one of claims 4 to 6. or a pharmaceutical composition comprising an acceptable acid addition salt form of pharmaceutical L and a pharmaceutical carrier or diluent. (8) A methyl group substituted with a leaving group at the 1-position and a nitrogen atom at the 2-position Substituted 4-alkyl-1.2.3.4-tetrahydropyrido[3.4-b]indole or its acid f4 salt. (wherein k?, k?, k2, k2 and R4 are the claimed A compound or an acid addition salt thereof having the meaning given in Range 2, where Y means a leaving group. (10) Formula (wherein R?, R?, k2, R2 and k4 are A compound represented by the formula I "having the meaning given in claim 2" or an acid addition salt thereof. In the formula C, k?, k?, k2, R2 and R4 are
l' having the meaning given in claim 2) or an acid addition salt thereof.