KR830000603B1 - Method for preparing isoquinoline derivative - Google Patents

Abstract

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Description

Method for preparing isoquinoline derivative

The present invention relates to a method for preparing a novel heterocyclic derivative having a wide range of pharmacological effects, and to a pharmaceutical composition comprising the derivative, which effectively treats or prevents diseases of the central nervous system of animals including humans.

Compounds mainly ergolin ring system such as the following have a surprisingly wide range of pharmaceutical activities.

Amides of Risergic acid, for example, are useful, have unique pharmacological properties, and naturally occurring peptide alkaloids; Ergokornin, ergocryptin, ergonobin, ergocristine, ergosine and ergotamine, and synthetic oxytocin alkaloids such as metergin and synthetic halucinogen-riseric acid diethylamide or LSD.

Ergotamine, 0-ergolene, which has a peptide side chain, has been used for the treatment of migraine headaches. Recently, ergokornin and 2-bromo-α-ergocryptin have been used in Proc. Soc. Exp'tl. Bio. Med. 135, 469 (1970) Nagasawa and Meites and Europ. According to Huson and his co-workers in J. Cancer, 353 (1970), it shows the inhibition of floractin and dimethylbenzanthracene-induced tumors in rats and can also refer to US Pat. Nos. 3,752,888 and 3,752,814. Non-peptide ergot derivatives, both naturally occurring and synthesized in whole or in part, have their complex pharmacological properties as peptidic derivatives. For example D-6-methyl-8-cyanomethyl ergoline is Coll. Czech. Chem. Manufactured by Simonmons and his collaborators in Commum., 33, 577 (1968), which is useful for preventing pregnancies as described in Nature, 221, 666 (1969), see US Pat. No. 3,732,231. It is useful for preventing the secretion of pituitary leuterotropin hormone and gonadotropin from the pituitary gland or inhibiting the secretion of prolactin (see Seda et al., Reprod. Fert., 24,263 (1971) and Mantle and Finn, id441). Able to know. Also see Coll. Czech. Chem. In Comm, 36, 220 (1971), Simonson and his co-workers produced C-6-methyl-8-ergolninyl acetamide, a compound with anti-hypertrophic and anti-lactic activity in rats. 2-halo derivatives of D-6-methyl-8-cyanomethyl ergoline and D-6-methyl-8-ergolinylacetamide were prepared and tested for their prolactin inhibitory activity (MJ Sweeney, JA Clemens). , EC Kornfeld and GA Poore, 64th Annual Meeting Amer.Assoc. Cancer Research, April, 1973). However, the preparation of 7- or 8-aza similar to 6-aza which naturally generates 6-aza with the above-mentioned ergot derivatives has not been attempted yet.

It is an object of the present invention to provide novel isoquinoline derivatives with useful pharmacological properties. Accordingly, the present invention provides isoquinoline or acid salts thereof of the following general formula (1).

[Wherein AB portion is represented by general formula -CH ₂ -NR ³ -or NR ³ -CH _2- ; Where R ³ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl, C _1-4 alkyl, optionally substituted benzyl, C _3-6 alkenyl or C _1-4 alka Noyl) and R is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl but optionally substituted benzyl; R ¹ and R ² are each hydrogen or have a chemical bond with each other; X is hydrogen or halogen.]

If AB is a group of the formula -CH ₂ -NR ^3- , the compound of the formula (1) can be represented by the formula (II).

If AB is a group of the formula -NR ³ -CH _2- , the compounds of the formula (I) can be represented by the formula (III).

These compounds are preferred when R ¹ and R ² are each hydrogen.

The term C _1-6 alkyl refers to branched and straight chain groups such as, for example, methyl, ethyl, n-propyl, isopropyl n-butyl, Sec-butyl, t-butyl, n-pentyl and n-hexyl, and C _3-6 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, C _3-6 cycloalkyl, C _1-4 alkyl is C bonded to an alkyl group as described above having 1-4 carbon atoms _3-6 cycloalkyl. Benzyl groups are preferably unsubstituted but include those substituted with 1-3 substituents such as halogen, alkyl such as methyl, alkoxy such as methoxy and nitro. C _3-6 alkenyl means, for example, allyl and 3,3-dimethyl propen-2-yl, and C _1-4 alkanoyl means, for example, acetyl and propanoyl, and halogen means fluorine, chlorine, Cancel, meaning oxo, most preferred with chlorine. In the above general formulas II and III, R and R ³ are preferably C _1-4 alkyl groups, especially methyl, X is preferably hydrogen, and more preferred is X is chlorine or cancellation.

New isoquinolines according to the invention are for example as follows:

1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

7-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

7,9-dimethyl-1,4,5,67,8-hexahydroindole [4,3-fg] isoquinoline;

7-n-propyl-9-methyl-1,4,5,7,8-hexahydroindole [4,3-fg] isoquinoline;

7-n-hexyl-9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

7-isopropyl-9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

7-isopropyl-9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

7-cyclpropyl-9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

7-cyclopropyl-9-methyl-9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

7-benzyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

7-allyl-9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

7- (3,3-dimethylproren-2-yl) -9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

7-acetyl-9methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

9-ethyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

9-ethyl-7-methyl1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

9-benzyl-7-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

9-methyl-1,4,5,6,7,8,9,10-octahydroindole [3'4-gh] isoquinoline;

8,9-dimethyl-1,4,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline;

8-n-propyl-9-methyl-1,4,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline;

8-n-hexyl-9-methyl-1,4,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline;

8-isopropyl-9-methyl-1,4,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline;

8-cyclopropyl-9-methyl-1,4,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline;

8-cyclopropylmethyl-propyl-9-methyl-1,4,5,6,7,8,9,10-octahydroindole 3,4-gh] isoquinoline;

8-benz-9-methyl-1,4,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline;

8-allyl-9-methyl-1,4,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline;

8- (3,3-dimethylpropen-2-yl) -9-methyl-1,4,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline;

8-acetyl-9-methyl-1,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline;

2-bromo-7,9-dimethyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

2-chloro-7-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

2-bromo-7-cyclopropylmethyl-9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline;

2-bromo-8,9-dimethyl-1,4,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline;

2-chloro-9-methyl-1,4,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline;

2-bromo-8-cyclopropylmethyl-9-methyl-1,4,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline;

The novel isoquinolines of the present invention are used in their free base and acid addition salt forms. Acid addition salts include, for example, inorganic or organic carboxylic acids such as hydrochloric acid, hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid, for example glycolic acid, maleic acid, hydroxy maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, salic acid, 0 Acetoxybenzoic acid, nicotinic acid, isonicotinic acid or organic sulfonic acids such as organic acids such as methane sulfonic acid, ethane sulfonic acid, 2-hydroxyethane sulfonic acid, toluene-p-sulfonic acid or naphthalene-2-sulfonic acid Preference is given to pharmaceutically acceptable non-toxic addition salts with suitable acids. In addition to pharmaceutically acceptable acid addition salts, other salts are included, for example, in the range of acid addition salts of picric acid or oxalic acid, which may be used as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable acid addition salts. Useful for identification, characterization or purification of bases.

Compounds of the present invention can be prepared from the ketones of the following general formula (IV), for example, as described by Cornfeld and his collaborators, for example, in US Chem.

Reaction (a) forms a corresponding enorate with lithium diisopropylamide in a suitable inert organic solvent such as tetrahydro futan at a temperature of -70 ° C to 0 ° C, followed by 2-nitroalkenes, for example 2-nitropro Alkylation with a suitable acetonylating agent, such as a pen, followed by hydrolysis with a strong acid, such as perchloric acid, effectively produces diketone.

The cyclization step (b) is a condensation which can be carried out by refluxing a diketone with a strong base such as potassium hydroxide in an alkanol solvent such as ethanol. In the cyclization step, the n-benzoyl protecting group is decomposed, and after the partial reaction, the joinin is reacted with acetic anhydride or similar acetylating agent to protect the 1-nitrogen atom of the system.

Reaction (c) involves aldol condensation similar to reaction (b) to provide an indorin cyclic structure, but at this stage 1-nitrogen atoms are not protected and active manganese dioxide using an organic solvent such as acetone in part instead of indole Or by aromatization with other suitable dehydrogenating agents.

Reactions (b), (e) and (P) can be accomplished by two methods, the first of which is a known Schmitt reaction in which ketones are reacted with hydrazoic acid in the presence of a suitable acid such as sulfuric acid. Switch to the corresponding oxime and then rearrange Bezoman.

Reactions (f), (i) and (q) are aromatized using the same conditions as mentioned in reaction (c) above and subsequently deprotected 1-nitrogen atoms using strong bases such as potassium hydroxide.

The N-alkylation reactions (g) and (r) can be effectively carried out by alkylating with a suitable alkylating agent and then generating cations at a strong base such as sodium hydride at 60-65 ° C. Reaction (1) is carried out at a slightly higher temperature, for example 70-75 ° C. for about 3 hours.

Reactions (h), (j) and (s) can be carried out, for example, in sodium dihydric bis (2-methoxy-) in an inert solvent such as benzene, toluene or tetrahydrofuran under a temperature of 0-50 ° C. Oxy) by using a reducing agent such as aluminate or lithium aluminum hydride.

Reaction (k) includes conventional alkylation or acylation reactions using hydrochlorides or anhydrides or reagents such as suitable alkyl halides or tosylates. The order of reaction (h) and (k) can also be changed.

Reaction (n) is to reduce ketone of general formula (II) by catalytic hydrogenation with hydrogen in the presence of an Adam catalyst, and reaction (m) is performed by the same process.

Reaction (o) is effected effectively by a suitable oxidation process using a reagent or pyridinium chlorochromate.

In order to obtain a compound of the general formula (1) wherein X is halogen, it is preferable to react the corresponding compound of the general formula (1) wherein X is hydrogen with a halogenating agent in an organic solvent. According to the method described in US Pat. No. 4,038,790, a suitable source of amphoteric chlorine is reacted with, for example, N-chlorosuccinimide, sulfuryl chloride or N-chloro velzotriazole. In the case of bromo compounds, suitable starting materials are reacted with a suitable source of, for example, bromine such as N-bromosuccinimide, pyridinium bromide perbromide, in particular wasteyl trimethyl ammonium tribromide.

Amides of formulas (VI) and (VIII) are novel and provide compounds of the general formula (VIII) according to the present invention.

를 나타내고, R, R¹, R², 및 R³는 상술한 바와 같다.The DE part in the formula is a general formula

And R, R ¹ , R ² , and R ³ are as described above.

The production process of the present invention comprises (a) reducing the compound of formula (iii), or (b) halogenating the compound of formula (I) wherein X is hydrogen when X is halogen, or (c) R Provided is a method for producing a compound represented by the general formula (I), wherein the compound of the general formula (I) wherein ³ is hydrogen is alkylated or acylated.

The compounds of the present invention have useful central nervous system activity and have low toxicity. This activity has been demonstrated by extensive testing in animal models using known methods such as the reversal of celiac-induced alfetamine-induced habitual behavior in rats and the impairment of conditional avoidance. In particular, the compounds of the general formula (I) and their pharmaceutically acceptable acid addition salts are strong compounds that act on the central nerve with neuroleptic, sedative, muscle relaxant or emetic. These properties, combined with high therapeutic effects, are useful for treating mild anxiety and for treating mental states such as schizophrenia and acute confusion.

The compounds of the present invention are effectively used in a wide range of dosages, and the actual dosage administered depends on factors such as the particular compound used, the condition to be treated and the condition to be treated and the type and size of the mammal to be treated. However, the dosage required is typically in the range of 0.05-10 mg / kg daily, for example 0.2-5 mg / kg is used for the treatment of adults.

The compounds and salts of the present invention are administered orally or by injection, for which the compounds and salts are usually used in the form of pharmaceutical compositions. Such compositions are prepared by methods known in the art of pharmacy and usually consist of at least one active compound or pharmaceutically acceptable salt of the present invention together with a pharmaceutically acceptable carrier.

In the preparation of the compositions of the present invention, the active ingredient is usually mixed with a carrier or diluted with a carrier or sealed with a carrier in the form of a capsule shakit, paper or other container. When the carrier acts as a diluent, it is a solid, semi-solid or liquid substance which acts as a base, excipient or medium with respect to the active ingredient. Suitable carriers are, for example, lactose, dextrose, sugar, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tracacanth gelatin, syrup, methyl cellulose, methyl- and propyl-hydroxybenzoate, talc , Magnesium stearate or mineral oil. The compositions of the present invention are made so that the active ingredient can be released rapidly or continuously after administration to a patient as is known in the art.

According to the method of administration, the compositions are made into oral tablets, capsules or suspensions and parenteral injection solutions. The composition is preferably made in unit dosage form containing 1-200 mg, especially 5-100 mg of active ingredient.

Non-limiting examples of the present invention will be described below.

Example 1

1-benzoyl-4-acetonyl-1,2,2, a, 3-tetrahydrobenz [cd] indole-5 (4H)-silver methyllithium (20 ml) in tetrahydrofuran (20 ml) distilled from lithium aluminum hydride 1.3M solution, 4ml, 0.0052mol) is cooled to -25 ° C, diisopropylamine (0.8ml, 0.006mol) is added and stirred until gas evolution stops. Cool the solution to −70 ° C. and add dropwise 1-benzoyl-1,2,2a, 3-tetrahydrobenz [cd] indol-5 (4H) -one (1.4 g, 0.004 mol) and heat to -20 ° C. Stir until a clear brown solution is formed (45 min). Cool down again to -70 ° C, add 2-nitropropene (0.5g, 0.006 mol) drop wise, heat to -30 ° C and stir for 2 hours. Perchloric acid (1 ml) is added and the reaction mixture is stirred for 18 hours. The reaction mixture is poured into moles (100 ml), extracted with ethyl acetate, washed with water, dried and evaporated to dryness. Chromatography on Solvail 30 silica gel (50% EtoAc / hexane) and crystallization from methanol yields the compound with a yield of 0.6 g (45%) and a melting point of 117-119 ° C.

Example 2

1-benzoyl-4- (2-oxobutyl) -1,2,2a, 3-tetrahydrobenz [cd] indole-5 (4H) -temperature amorphous oil as 1-benzoyl-1,2,2a, 3 -Prepared in a similar manner from tetrahydrobenz [cd] indole-5 (4H) -one and 2-nitrobutene. Yield 66%, boiling point 120 ° C./0.05 mm, cugellot.

Example 3

1-benzoyl-4- (2-oxopentyl) -1,2,2a, 3-tetrahydrobenz [cd] indole-5 (4H) -temperature Prepared in a similar manner as described in Example 2, which is an oil to be.

Example 4

1-Benzoyl-4-acetonyl in ethanol (100 ml) under 1-acetyl-2,3,4,5-tetrahydro-1H-indole [3,4-fg] indole-7 (6H) -one nitrogen gas -1,2,2a, 3-tetrahydrobenz [cd] indole-5 (4H) -one (1.3 g, 0.004 mol) is treated with potassium hydroxide (2.0 g) and refluxed for 2 hours. The reaction mixture is poured into ice / water, extracted with chloroform and dried (MgSO ₄ ) acetic anhydride (1 ml) is added to the dried extract and stirred for 1 hour. Evaporation to dryness and crystals of ethyl acetate / hexanes afford the product. Yield 0.6g (64%), Melting Point 180-182 ℃

Example 5

1-acetyl-8-methyl-2,3,4,5-tetrahydro-1H-indole [3,4-gf] indan-7 (6H) -one is 1-benzoyl-4- (2-oxobutyl) Similarly prepared from -1,2,2a, 3-tetrahydrobenz [cd] indol-5 (6H) -one.

Yield 57%, Melting Point 223-5 占 폚

Example 6

1-acetyl-6-ethyl-2,3,4,5-tetrahydro-1H-indole [3,4-fg] indan-7 (6H) -one is 1-benzoyl-4- (2-oxopentyl) Prepared in a similar manner from -1,2,2a, 3-tetrahydrobenz [cd] indol-5 (6H) -one. Yield 38%, melting point 168-9 degreeC.

Example 7

1-acetyl-2,3,4,5-tetrahydro-1H-indole [3,4-fg] -7 (6H)-is oxime.

1-acetyl-2,3,4,5-tetrahydro 1H-indole [3,4-fg] indan-7 (6H) -one (200 mg), hydroxylamine hydrochloride (100 mg) in methanol (10 ml) and Sodium acetate (50 mg) is cooled and filtered to recover the compound, and washed with water. The yield was 200 mg (95%), nuclear magnetic resonance (NMR) and mass spectrometric data confirmed the structure.

Example 8

1-acetyl-8-methyl-2,3,4,5-tetrahydro-1H-indole [3,4-fg] indan-7 (6H) -one oxime 1-acetyl-8-methyl-2,3 Similarly prepared from, 4,5-tetrahydro-1H-indole [3,4-fg] indan-7 (6H) -one. Yield 95%, Melting Point 320 ° C (Decomposition)

Example 9

1-acetyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one

Stir 1-acetyl-2,3,4,5-tetrahydro-1H-indole [3,4-fg] indan-7 (6H) -one oxime (200 mg) in polyphosphoric acid (2 ml) and give 60 hours for 2 hours. Heated to ° C. The reaction mixture is diluted with cold water, extracted with chloroform, washed with water, dried and evaporated to dryness with MgSO ₄ . Crystallization with methanol gives the product. Yield 160 mg (90%): melting point 300-5 ° C. (decomposition).

Example 10

1-acetyl-9-methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-8-methyl-2, Similarly prepared from 3,4,5-tetrahydro-1H-indole [3,4-fg] indan-7 (6H) -one oxime. Yield 180 mg (90%), melting point 214-6 ° C.

Example 11

1-acetyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one

Stir 1-acetyl-2,3,4,5-tetrahydro-1H-indole [3,4-fg] indan-7 (6H) -one (2.2 g, 0.0087 m) in glacial acetic acid (20 ml) and 60 ° C. Heated to. Sodium azide (0.6 g, 0.0087 mol) is added and concentrated sulfuric acid (2 ml) is added dropwise over 5 minutes. The reaction mixture is stirred at 60-65 [deg.] C. until gas evolution ceases, and two more additions of sodium azide and concentrated sulfuric acid are converted to all starting materials. The reaction mixture is poured into a mixture of ice / saturated sodium bicarbonate solution, extracted with chloroform, washed with water, dried and evaporated to dryness with MgSO ₄ . Determination with methanol will give this product. Yield 1.7 g (73%), melting point 300-5 degreeC.

Example 12

1-acetyl-9-methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one is converted to 1-acetyl-8-methyl-2, Similarly prepared from 3,4,5-tetrahydro-1H-indole [3,4-fg] indan-7 (6H) -one. Yield 75%, Melting Point 214-6 占 폚.

Example 13

1-acetyl-9-1,2,3,4,5,6-ethylhexahydroindole [4,3-fg] isoquinolin-8 (7H) -one to 1-acetyl-8-methyl-2,3 Similarly prepared from, 4,5-tetrahydro-1-indole [3,4-fg] indan-7 (6H) -one. Yield: 85%, Melting point 213-215 占 폚.

Example 14

1-acetyl-7-methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one

1-acetyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one (140 mg, 0.0005 moles) at 60 ° C. in dimethylformamide (10 ml Sodium hydride (50% dispersion, 30 mg, 0.0006 mol) is added to the stirred suspension and the reaction mixture is stirred for 30 minutes, then cooled to 10 ° C. and methyl iodide (100 mg, 0.0007 mol) is added. Continue stirring for 30 min, dilute the reaction mixture with water, extract with chloroform, wash, dry and evaporate to dryness with MgSO ₄ . Crystallin ethyl acetate afforded 60 mg (37%) of the product, the structure of which was confirmed by mass spectrometry.

Example 15

1-acetyl-7,9-dimethyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-9-methyl- Similarly prepared from 1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one. (75%), Melting Point: 210-212 ° C.

Example 16

1-acetyl-7-methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one

1-acetyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one (2.7 g, 0.01 mole) and cetyl trimethyl ammonium bromide (3.7 g , 0.01 mol) is suspended in tetrahydrofuran (50 ml) and stirred at room temperature.

Methyl iodide (3.0 g, 0.02 mol) and 50% sodium hydroxide (50 ml) are added and the mixture is vigorously stirred for 18 hours. The reaction mixture is poured into iced water, extracted with ethyl acetate, washed with water, dried (MgSO ₄ ) and evaporated to dryness. Elution with methanol in chloroform, chromatography on U30 silica gel and crystallization with ethyl acetate yield 1.3 g (48%) of the present compound having a melting point of 250-255 ° C.

Example 17

1-acetyl-7,9-dimethyl-1,2,3,4,5,6-dimethylhexahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-9-methyl Prepared from -1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 58%, Melting point: 210-212 ° C.

Example 18

1-acetyl-9-ethyl-7-1,2,3,4,5,6-methylhexahydro [4,3-fg] indoleisoquinolin-8 (7H) -one is 1-acetyl-9-ethyl Prepared from -1,2,3,4,5,6-hexahydro-indole [4,3-fg] isoquinolin-8 (7H) one. Yield: 61%, Melting point: 179-80 ° C.

Example 19

1-acetyl-9-methyl-7-n-propyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl- Similarly prepared from 9-methyl-1,2,3,4,5,6-hexahydro-indole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 91%, Melting point: 75-78 ° C.

Example 20

1-acetyl-7-n-hexyl-9-methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl- Prepared from 9-methyl-1,2,3,4,5,6-hexahydro indole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 81%, Melting point: 82-84 ° C.

Example 21

1-acetyl-7-allyl-9-methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-9- Prepared from methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 94%, Melting point: 135 ° C.

Example 22

1-acetyl-7- (3,3-dimethylpropen-2-yl) -9-methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinoline-8 (7H) -one is prepared from 1-acetyl-9-methyl-1,2,3,4,5,6-hexahydro indole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 71%, Melting point: 89-90 ° C.

Example 23

1-acetyl-7-cyclopropylmethyl-9-ethyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl- Prepared from 9-methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 42%, Melting point: 177-80 ° C.

Example 24

1-acetyl-7-benzyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-9-ethyl-1, Prepared from 2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 39%, Melting point: 215-218 ° C.

Example 25

1-Acetyl-7,9-dimethyl-1,2,3,4,9,10-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one was added to the reaction mixture at 75 ° C. for 3 hours. Aside from stirring, the preparation was carried out as in Example 14. Melting point: 233-235 ° C.

Example 26

In 1-acetyl-7,9-dimethyl-1,2,3,4,5,6,9,10-octahydroindole [4,3-fg] isoquinolin-8 (7H) -one ethanol (20 ml) Of 1-acetyl-7,9-dimethyl-1,2,3,4,9,10-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one (100 mg) under 60 p.si. Hydrogenate on platinum oxide (10 ml) for 4 hours. Filtration removes the catalyst, the solvent is removed in vacuo and crystallized with acetonitrile-diethyl ether to give the present compound having a melting point of 204-206 占 폚.

Example 27

7-methyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one

1-acetyl-7-methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one (100 mg) in ethanol (20 ml) was dissolved in 50 NaOH. Treat with solution (5 ml) and stir at 60 ° C. for 18 h. The reaction mixture is poured into ice-water, extracted with chloroform, washed with water, dried (MgSO ₄ ) and evaporated to dryness. Crude 7-methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one is dissolved in acetone and 18 hours with manganese dioxide on activated carbon (1 g) Stir it. Journal of Orgunic Chemistry, 35, 3971 (1970). The manganese dioxide was filtered off, the solution was evaporated to dryness and then crystallized with ethyl acetate to obtain the product as a crystalline product, the structure of which was confirmed by mass spectrometry.

Example 28

7,9-dimethyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-7,9-dimethyl-1,2,3, Prepared from 4,5,6-hexahydroindole- [4,3-fg] isoquinolin-8 (7H) -one. Melting point: 237-9 ° C.

Example 29

9-ethyl-7-methyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-9-ethyl-7-methyl-1, Prepared from 2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 53%, Melting point: 246-9 ° C.

Example 30

9-methyl-7-n-propyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-9-methyl-7-n- Prepared from propyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 36%, Melting point: 192-195 ° C.

Example 31

7-n-hexyl-9-methyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-7-n-hexyl-9- Prepared from methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 35%, Melting point: 139-141 ° C.

Example 32

7-allyl-9-methyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-7-allyl-9-methyl-1, Prepared from 2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Yield 55%.

Example 33

7- (3,3-dimethylpropen-2-yl) -9-methyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1- Acetyl-7- (3,3-dimethyl-propen-2-yl) -9-methyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinoline-8 ( Prepared from 7H) -one. Yield: 48%, Melting point: 225-30 ° C.

Example 34

7-cyclopropylmethyl-9-ethyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-7-cyclopropyl methyl-9- Prepared from ethyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Melting point: 213-215 ° C.

Example 35

7-benzyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-benzyl-1,2,3,4,5,6- Prepared from hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one.

Yield: 47%, Melting point: 207-208 ° C.

Example 36

7,9-dimethyl-1,4,5,6,9,10-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-7,9-dimethyl-1, Prepared from 2,3,4,5,6,9,10-octahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Melting point: 217-219 ° C.

Example 37

7-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline maleate

7-Methyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one (200 gm) is dissolved in dry benzene (10 ml) and stirred at room temperature. Sodium bis (2-methoxy-ethoxy) aluminum (Red-Al) (70% solution in benzene, 0.5 ml) is added and stirred for 2 hours, then the reaction mixture is diluted with cold water and extracted with ethyl acetate Washed and dried (MgSO ₄ ). Maleic acid (0.1 g) in ethyl acetate (5 ml) is added and the salt crystallizes.

Yield: 220 mg (79%), melting point: 200-202 ° C

Example 38

7,9-dimethyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline 7,9-dimethyl-1,4,5,6-tetrahydroindole [4, 3-fg] isoquinolin-8 (7H) -one is prepared in a similar manner and has similar properties. Melting point: 166-169 ° C.

Example 39

9-ethyl-7-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline maleate is 9-ethyl-7-methyl-1,4,5,6 Tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one is prepared in a similar manner. Yield: 80%, Melting point: 175-177 ° C.

Example 40

9-methyl-7-n-propyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline maleate is 9-ethyl-7-n-propyl-1,4 Prepared in a similar manner from, 5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 76%, Melting point: 130-132 ° C.

Example 41

7-n-hexyl-9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline maleate is 7-n-hexyl-9-methyl-1,4 Prepared in a similar manner from, 5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 75%, Melting point: 149-151 占 폚.

Example 42

7-allyl-9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline maleate is 7-allyl-9-methyl-1,4,5,6 Similarly prepared from tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one.

Yield: 80%, Melting point: 153-155 ° C.

Example 43

7- (3,3-dimethylpropylene-2-yl) -9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline maleate is 7- (3 Prepared similarly from, 3-dimethylpropen-2-yl) -9-methyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one. Yield: 80%, Melting point: 105-6 占 폚.

Example 44

7-cyclopropylmethyl-9-ethyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline maleate is 7-cyclopropylmethyl-9-ethyl-1,4 Similarly prepared from, 5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one.

Example 45

7-benzyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline maleate is 7-benzyl-1,4,5,6-tetrahydroindole [4,3 -fg] is analogously prepared from isoquinolin-8 (7H) -one.

Yield: 61%, Melting point: 206-208 ° C

Example 46

7,9-dimethyl-1,4,5,6,7,8,9,10-octahydroindole [4,3-fg] isoquinoline maleate is 7,9-dimethyl-1,4,5,6 Similarly prepared from, 9,10-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one.

Example 47

1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one

1-acetyl-1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8 (7H) -one (100 mg) in ethanol (5 ml) and dioxane (5 ml) Treat with 50% sodium hydroxide solution (5ml) and stir for 18 hours. The reaction mixture is poured into ice water, extracted with chloroform, washed with water, dried (MgSO ₄ ) and evaporated to dryness. Crude 1,2,3,4,5,6-hexahydroindole [4,3-fg] isoquinolin-8- (7H) -one is dissolved in acetone and stirred with manganese dioxide on activated carbon (1 g) for 18 hours. . Crystallization with ethyl acetate gives the compound having a melting point of 142-144 占 폚. The structure was confirmed by infrared and mass spectroscopy data.

Example 48

9-methyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one is 1-acetyl-9-methyl-1,2,3,4,5, Similarly prepared from 6-hexahydroindole [4,3fg] isoquinolin-8 (7H) -one.

Melting point: 198 ° C. (ethyl acetate).

Example 49

7-cyclopropylacetamido-9-methyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one

Triethylamine (5 drops) and cyclopropane in a 9-methyl-1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one solution dissolved in methylene chloride (10 ml) Carboxylic acid chromide (4 drops) is added, further diluted with methylene chloride, the reaction is stirred for 4 hours, washed with water, dried (MgSO ₄ ), evaporated to dryness and crystallized with ethyl acetate to obtain the present compound.

Example 50

1,4,5,6,7,8, -hexahydroindole [4,3-fg] isoquinoline

1,4,5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one (20 mg) is dissolved in dry benzene (10 ml) and stirred at room temperature. After adding Red-Al (70% solution dissolved in 0.1 ml of benzene) and stirring for 2 hours, the reaction mixture was diluted with water, extracted with chloroform, washed with water, dried (MgSO ₄ ) and evaporated to dryness. The crude amide is dissolved in ethyl acetate (5 ml) and maleic acid (10 mg) in ethyl acetate (1 ml) is added.

The crystals of the product are recovered by filtration.

Example 51

9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline maleate 9-methyl-1,4,5,6-tetrahydroindole [4,3- fg] is analogously prepared from isoquinolin-8 (7H) -one. Melting Point: 198-200 ℃

Example 52

7-cyclopropylmethyl-9-methyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline is 7-cyclopropylacetamido-9-methyl-1,4 Similarly prepared from, 5,6-tetrahydroindole [4,3-fg] isoquinolin-8 (7H) -one.

Example 53

4,5-dihydro-1H-indole [3,4-fg] indan-7 (6H) -one

1-benzoyl-4-acetonyl-1,2,3,4-tetrahydrobenz [cd] indole-5 (4H) -one (1.3 g, 0.004 mol) was dissolved in ethanol (100 ml) under nitrogen gas. 2.0 g) and reflux for 2 hours. The reaction mixture is poured onto ice / water, extracted with chloroform, dried (MgSO ₄ ) and evaporated to dryness. Crude 2,3,4,5, -tetrahydro-1H-indole [4,3-fg] indan-7 (6H) -one is dissolved in acetone (50 ml) and stirred for 36 hours with manganese idealized on activated carbon. . Manganese dioxide is filtered off, the solution is evaporated to dryness and then crystallized from chloroform / ethyl acetate to give the present product as a crystalline solid.

Example 54

8-methyl-4,5-dihydro-1H-indole [3,4-fg] indan-7 (6H) -one is 1-benzoyl-4- (2-oxobutyl) -1,2,2a, 3 Similarly prepared from tetrahydrobenz [cd] indole-5 (4H) -one.

Yield: 30%, Melting Point: 257-9 ° C

Example 55

4,5-Dihydro-1H-indole [3,4-fg] Indan-7 (6H) -one oxime

n-propane (10 ml) in 4,5-dihydro-1H-indole [3,4-fg] indan-7 (6H) -one (200 mg), hydroxylaminehydrochloride (100 mg) and sodium acetate ( 50 mg) was refluxed for 18 hours, the reaction mixture was diluted with chloroform, filtered through an alumina pad and evaporated to dryness. Crystallization to carbon tetrachloride yields the product in 150 mg (75%) yield.

Example 56

8-methyl-4,5-dihydro-1H-indole [3,4-fg] Indan-7 (6H) -one oxime is 8-methyl-4,5-dihydro-1H-indole [3,4- fg] similarly prepared from Indan-7 (6H) -one. Melting Point: 190-200 ℃

Example 57

1-acetyl-7-hydroxy-8-methyl-2,3,4,5,6,7,8,9-octahydro-1H-indole [3,4-fg] indane

Platinum oxide (10 mg) in 1-acetyl-8-methyl-2,3,4,5-tetrahydro-1H-indole [3,4-fg] indan-7 (6H) -one in ethanol (100 mg) 100 mg) is hydrogenated at 60 p.si until the absorption of hydrogen is complete, then filtered to remove the catalyst and the solution is evaporated to dryness. Crystallization with ethanol yields this product.

Yield: 80 mg (80%), melting point: 223-4 ° C

Example 58

1-acetyl-8-methyl-2,3,4,5,8,9-hexahydro-1H-indole [3,4-fg] indan-7 (6H) -one

1-acetyl-7-hydroxy-8-methyl-2,3,4,5,6,7,8,9-octahydro-1H-indole [3,4-fg] indane (50 mg) in acetone (10 ml) ) Is stirred, treated with zone reagent (1 ml), stirring is continued for 18 hours, and excess methanol is added to remove excess reagent. The reaction mixture is evaporated to dryness, separated between water and chloroform, the solvent is separated and washed with water, dried (MgSO ₄ ) and evaporated to dryness to afford the product. The product is crystallized with ethyl acetate. Yield: 68%, Melting point: 171-172 ° C

Example 59

1-acetyl-9-methyl-1,2,3,4,5,9,10-octahydroindole [3,4-gh] isoquinolin-7 (8H) -one

Dissolve 1-acetyl-8-methyl-2,3,4,5,8,9-hexahydro-1H-indole [3,4-fg] indan-7 (6H) -one (100 mg) in glacial acetic acid (5 ml). Stir and heat to 50 ° C. Sodium azide (40 mg) was added followed by concentrated sulfuric acid (0.1 ml), continued stirring at 50-55 ° C. until gas evolution ceased, and further addition of sodium azide and concentrated sulfuric acid to complete conversion of starting material. Let's do it. The reaction mixture is poured onto ice / saturated sodium bicarbonate solution, extracted with chloroform, dried (MgSO ₄ ) and evaporated to dryness. Crystallization with ethyl acetate gives the compound having a melting point of 224-226 占 폚.

Example 60

9-methyl-1,4,5,6,9,10-hexahydroindole [3,4-gh] isoquinolin-7 (8H) -one

1-acetyl-9-methyl-1,2,3,4,5,6,9,10-octahydroindole [3,4-gh] isoquinolin-7 (8H) -one (100 mg) in ethanol (10 ml) ) Is stirred at room temperature, and 50% sodium hydroxide solution (5 ml) is added and stirring is continued for 18 hours. The reaction mixture is poured onto ice water, extracted with chloroform, washed with water, dried (MgSO ₄ ) and evaporated to dryness to obtain the product. Its structure was confirmed by NMR and mass spectrometry data.

Example 61

1-acetyl-8,9-dimethyl-1,2,3,4,5,9,10-octahydroindole [3,4-gh] isoquinolin-7 (8H) -one

1-acetyl-9-methyl-1,2,3,4,5,9,10-octahydroindole [3,4-gh] isoquinolin-7 (8H) -one (100 mg) dissolved in dry dimethyl formamide The sodium hydride (20 mg) solution is stirred under nitrogen gas and heated at 60 ° C. for 30 minutes. The reaction mixture is cooled to 10 ° C. and methyl iodide (0.1 ml) is added. The reaction was stirred for 30 minutes, diluted with water, extracted with chloroform, washed with water, dried (MgSO ₄ ) and evaporated to dryness to obtain the present compound, which was crystallized with ethyl acetate. Melting Point: 184-186 ℃

Example 62

8,9-dimethyl-1,4,5,6,910-octahydroindole [3,4-gh] isoquinolin-7 (8H) -one

1-acetyl-8,9-dimethyl1,2,3,4,5,6,9,10-octahydroindole [3,4-gh] isoquinoline-7 in acetic acid (10 ml) and concentrated hydrochloric acid (10 ml) (8H) -one (0.3 g) was refluxed for 5 hours. The reaction mixture is poured into ice water, basified with sodium hydroxide, extracted with chloroform, washed, dried (MgSO ₄ ) and evaporated to dryness. The white solid is redissolved in acetone (20 ml) and MnO ₂ / C (3 g) is added. The mixture is stirred for 10 hours, then the catalyst is filtered off, the solvent is evaporated in vacuo and determined with ethyl acetate to afford the present compound having a melting point of 250-252 ° C.

Example 63

8,9-dimethyl-1,4,5,6,7,8,9,10-octahydroindole [3,4-gh] isoquinoline

8,9-dimethyl-1,1,5,6,9,10-hexahydroindole [3,4-fg] isoquinolin-7 (8H) -one (50 mg) dissolved in dry benzene (10 ml) was cooled to room temperature. Stir in and add "Red-Al" (0.1 ml). The solution was stirred for 2 hours, poured into cold water, extracted with chloroform, washed with water, dried (MgSO ₄ ) and evaporated to dryness to obtain the present compound. The structure thereof was confirmed by NMR and mass spectrometric data.

Example 64

7,9-dimethyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline (700 mg) was dissolved in THF (50 ml) and phenyl trimethylammonium tribromide (1.1 g) Add. The mixture is stirred at room temperature for 2 hours, diluted with water, basified with sodium hydroxide solution, extracted with ethyl acetate, washed, dried and evaporated to dryness. The crude product is chromatographed on basic alumina with chloroform and evaporated to give 500 mg of white solid. It is dissolved in ethanol and maleic acid (0.3 g) is added. The solution is terminated with ether until crystals appear and 2-bromo-7,9-dimethyl-1,4,5,6,7,8-hexahydroindole [4,3- with a melting point of 194-196 ° C.] fg] Isoquinoline (maleate salt) is filtered off.

The following examples illustrate pharmaceutical compositions containing the active compounds of the present invention. The active ingredient used is 7,9-dimethyl-1,4,5,6,7,8-hexahydroindole [4,3-fg] isoquinoline. However, such compounds may be replaced by other active solid compounds of the present invention.

Example 65

A tablet containing 10 mg of active ingredient is made as follows.

The active ingredient, starch and lactose are passed through No. 44 Mesh B. Sieve and mixed thoroughly. A solution of polyvinyl pyrrolidone was mixed with the resulting powder, which was then numbered 12, mesh ratio. s. Sieve passed through and the granules thus obtained were dried at 50-60 ° C. and then No. 16 mesh ratio. s. Pass the sieve. First, the No. 60 mesh ratio, S, sieve, sodium starch glycate, magnesium stearate and talc are added to the granules, mixed, and compressed into tablets to make tablets weighing 100 mg each.

Example 66

A capsule containing 20 mg of the drug is prepared as follows.

No. 44 mesh ratio of active ingredient, lactose, starch and magnesium stearate. s. Pass the sieve and fill 200 mg of the dose with light gelatine capsules.

Example 67

Suppositories containing 25 mg of active ingredient are prepared as follows.

No. 60 mesh ratio of active ingredient. s. After passing through a sieve and suspended in saturated fatty acid glycerides first dissolved using the lowest heat required, the mixture is poured into a 2 g suppository mold and cooled.

Example 68

A suspension containing 5 mg of drug per 5 ml unit dose is prepared as follows.

44 mesh b. s. Pass through a sieve and mix with sodium carboxymethylcellulose 50 and syrup to make a light paste. The benzoic acid solution, the fragrances and the pigments are diluted with some stirring of chloroform water with constant stirring and then sufficient chloroform water is added to make the desired dose.

Claims (1)

Isoquinoline represented by the following general formula (I) characterized by reducing the compound represented by the following general formula (i) and halogenating the compound of general formula (I) wherein X is hydrogen when the compound is X Process for the preparation of derivatives.

[Wherein the AB moiety is a general formula —CH ₂ —NR ³ — or NR ³ —CH ₂ —; Wherein R ³ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-4 alkyl, optionally substituted benzyl, C _3-6 alkenyl or C _1-4 alka Noyl), R is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl or optionally substituted benzyl, and R ¹ and R ² each represent hydrogen or mutually Represents a chemical bond and X represents hydrogen or halogen.

The DE part in the formula is a general formula

And R, R ¹ , R ² , and R ³ are the same as in the general formula (I).