CZ2001399A3 - Novel 2,3,3a,4,9,9a -hexahydro-8-hydroxy-1H-benz(f)indoles, process of their preparation and their use as medicaments - Google Patents

Abstract

The present application relates to substituted derivatives 2,3,3a, 4,9,9a-hexahydro-8-hydroxy-1H-benz [f] indoles, a method for their manufacture and use as a medicament. Indole derivatives correspond to general formula I.

Description

···

SUMMARY OF THE INVENTION

The present invention relates to novel substituted 2,3,3a, 4,9,9a-hexahydro-8-hydroxy-1H-benz [f] indole derivatives, to a process for their preparation and to their use as a medicament. The indole derivatives of the invention correspond to the general formula V

1 where they can mean

X a single bond, -O-, C 1 -C ₄ -alkyl, C 1 -C ₃ -alkoxy, -O-CH ₂ -CH 2 -O- or -O-CH ₂ -CH 2 -NH-;

R ^{1 is} hydrogen, methyl, ethyl or phenyl;

R ^{2 is} hydrogen or methyl;

R ^{3 is} hydrogen, F, Cl, Br, hydroxy or methoxy;

R ^{4 is} hydrogen, methyl or ethyl;

R ^{5 is} hydrogen, methyl or ethyl;

R ^{6 is} hydrogen, methyl or ethyl;

R ⁷ t-butyl, cyclohexyl;

n is an integer of 0 or 1;

Y N or CH;

Z is O, NH or S;

R ^{8 is} hydrogen, methyl, F, Cl, Br or methoxy;

R ^{9 is} hydrogen, methyl, F, Cl, Br or methoxy;

The present invention provides individual stereoisomers, mixtures thereof, and physiologically acceptable addition salts with inorganic or organic acids - such as HCl or HBr.

Pure enantiomeric compounds and the corresponding racemates are claimed. The respective trans-derivatives are preferred.

The disclosed compounds are novel. 1- (C 1 -C ₈ ) -alkyl-, (C 1 -C ₈ ) -alkenyl- or (C ₁ -C ₈ ) -alkynyl-2,3,3a,

4,9,9a-hexahydro-1H-benz [f] indoles [WO-91/00856, C.-H.Lin et.al.J.

Med.Chem.1993, 36, 1069-1083]. These compounds have been characterized as D ₂ and 5-HT 1A agonists and are known in the treatment of a number of psychiatric and metabolic diseases. In contrast, the aralkyl-, aryloxyalkyl-, alkoxy-, cycloalkylalkyl- and t-butylalkyl compounds claimed herein are not yet disclosed in the prior art.

Biological properties

It is known that hypoglycemia, hypoxia, anoxia, trauma and ischemia resulting in cell damage and functional disruptions are partly based on increased synaptic activity. In a number of experiments such hypoglycemic and hypoxic conditions have been shown to lead to massive depolarization of the affected cells.

This depolarization causes pathogenic growth of intracellular calcium and increased release of exitatorial amino acids in neuronal tissue. The voltage-dependent sodium channel plays a key role in this cascade. By blocking it, it is possible to prevent cell depolarization, thereby reducing calcium flow through voltage-dependent cation channels as well as receptor-NMDA channels in neuronal tissue. Further, the reduced influx of sodium ions into the cell is prevented by the calcium / sodium ion exchanger working in opposition and drawing calcium into the cell. In addition, the reduced influx of sodium ions into the cell prevents the glutamate transporter from working in opposition and releasing glutamate [C.P. Taylor and B.S.Meidrum, Trends Pharmacol.

Sci., 16, 309-316 (1995); J.Urenjak and T.P.Obrenovitch Am.Soc. Pharmacol. Rev. 48, 21-67 (1996)].

The claimed compounds are blockers of voltage-dependent sodium channels. These are compounds that displace batrachotoxin (BTX) with high affinity (K, <1000 nM) competitively or uncompetently at the sodium channel binding site. In blocking sodium channels, such substances exhibit a use-dependency, i.e., the sodium channels must first be activated in order to bind the substance to the sodium channel. Maximum sodium channel blockage is achieved only after repeated stimulation. As a result, the substance binds to sodium channels, which are activated several times. Thus, the substances are able to be effective preferably in parts of the body that are pathologically overstimulated.

BTX binding on the sodium channel serves as a test system to demonstrate the sodium channel blocking effect [S.W.Postma & W.A.

Catterall, Mol. Pharmacol 25, 219-227 (1984)] and patch-camb experiments to show that the compounds of the invention block the electrically stimulated sodium channel in a "use-dependent" manner [W.A.Catterall, Trends Pharmacol. Sci., 8, pp. 57-65 (1987),

Furthermore, the neuroprotective effect of the compounds of the invention has been shown to block veratridine-induced glutamate release [S.Villauneva, P.Frenc, Y.Dragnic, F.Orrego, Brain Res.461, 377-380 (1988)].

Veratridine is a toxin that permanently opens the sodium channel. This leads to an increased influx of sodium ions into the cell. Despite the above cascade, this sodium flux in neuronal tissue leads to an increased release of glutamate. The glutamate release can be antagonized by the compounds of the invention.

The anticonvulsant properties of the compounds of the invention have been exemplified by the protective effect against convulsions induced by maximal electroshock in mice [M.A. Rodawski & R.J.Porter, Pharmacol.Rev.42,

223-286 (1990)], neuroprotective properties have been demonstrated by a protective effect on the MCAO model of rats [U.Pschorn &

J. Stroke Cerebrocascular Diseases, 6, 93-99 (1996)].

It has further been described that a sodium channel blocker can be used to treat cyclophrenia (manic depressive disease) [J.R.Calabrese, C. Bowden, M. J. Watshville; in Psychopharmacology:

The Fourth Generation of Progress (Eds.:D.E.BIoom and D.J.Kupfer)

1099-1111, New York: Raven Press Ltd.].

Thus, it has been shown that the 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-oles of the general formula (1) can be used in diseases whose cause is based on impaired function due to irritation. This results in diseases such as arrhythmias, convulsions, cardiac and cerebral ischemia and neurodegenerative diseases of various origins; this means, for example: status epilepticus, hypoglycemia, hypoxia, anoxia, brain trauma, brain swelling, including stroke, perinatal asphyxia, amyotropic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotonia, cardiac infarction , angina pectoris, pain of various forms, resp. etiology-such as: nociceptor pain with irritation of pain receptors and transmission of impulses to the CNS or neuropathic pain due to damage to the peripheral or central nervous system (eg amputation, paralysis, esophagus or diabetic polyneuropathy), pain due to functional disorders- such as migraine caused by faulty vascular regulation, back pain caused by improper posture - including psychsomatic processes such as activation of sympathetic fear, muscle tension during emotional stress. Particular mention may be made in this context of use as a local anesthetic.

Formulation examples

1. Tablets

Ingredients:

Active ingredient according to the invention: Stearic acid Grape sugar wt. wt. parts

474 wt. parts

The components are usually processed to 500 mg tablets. If necessary, the active substance content may be increased or decreased and the amount of grape sugar reduced or increased accordingly.

2.

Cípky

Ingredients:

Active substance according to the invention Lactose, powdered

Cocoa butter

100 wt. wt. parts

1555 wt. parts

The parts are usually processed into suppositories weighing 1.7 g.

Solution for infusion

The active ingredient of the invention is dissolved in a pharmaceutically effective amount, e.g., in a physiologically acceptable starting solution - e.g. a 5% xylit- or mannitol solution known in the art and suitable for infusion - in a manner known in the art.

5. Inhalation powder

The micronized powder of the active substance (compound of formula I; particle size ca. 0.5 to 7 µmη) is filled into gelatin capsules in an amount of 5 mg, optionally with the addition of micronized lactose. The powder is inhaled from a conventional inhalation device, for example according to DE-A 3345722, the contents of which are hereby referred to.

Method of production

The key compounds in the synthesis are nor-hexahydro-1H-benz [indole 2a, which are depicted herein as the corresponding (-) - enantiomers,

3a and 3b.

Scheme 1:

Compound 2a was obtained as described in Scheme 2.

Scheme 2:

Synthesis 3a and 3b can be carried out analogously to the method described in WO-A-91/00856. The synthesis is shown in Scheme 3.

The introduction of N-substituents takes place by reacting the key compounds 2a, 3a, 25 and 3b with acylating agents to intermediates 11 and their subsequent

- 11 by reduction or direct alkylation of the key compounds 2a, respectively. 3a or 3b with alkylating agents or by reaction with aldehydes to 12 and subsequent reduction. In Scheme 4, these pathways are illustrated, for example, for the key compounds (-) - 2a.

Scheme 4:

The compounds of the invention may subsequently be spatially selectively substituted in the partial structure of benzindole. Scheme 5 shows an example for compound (-) - 2b.

(-) - 2k

Various embodiments are apparent to those skilled in the art from the present disclosure. It is to be emphasized that these examples and descriptions serve only to illustrate and not to limit the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1:

Trans-1-formyl-8-methoxy-3α, 4,4-trimethyl-2,3,3α, 4,9,9α-hexahydro-1H-benz [f] indole (5) 9 ··· • 9

99 ·· ·

- 13 To a suspension of 88.0 g (0.66 mol) of aluminum chloride in 420 ml of absolute dichloromethane at 0-5 ° C is added dropwise a solution of 60.1 g (0.22 mol) of N-formyl-2- (2'-Methoxyphenyl) -methyl-3,3-dimethyl-4-methylene-5-piperidine (4) in 200 mL of dichloromethane. Allow to react for 3 hours at 5 ° C and place on 800 ml of ice. The organic phase is separated and the aqueous phase is extracted twice more with 250 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The residue was chromatographed on silica gel 10 (500 g silica gel, solvent: ethyl acetate). It is obtained

36.0 g (60%) trans-1-formyl-8-methoxy-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1H-benz [f] indole (5) as oil.

Example 2:

Trans-8-methoxy-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1H-benz [f] indole (6)

9.6 g (35 mmol) of trans-1-formyl-8-methoxy-3a, 4,4-trimethyl-2,3,3a,

4,9,9a-hexahydro-1H-benz [f] indole (5) is dissolved in 75 ml of n-propanol and 25 ml of conc. hydrochloric acid and 15 ml of water. Heat at reflux for 12 h, remove the alcohol in vacuo and dilute with 800 ml of water. Extract with 150 ml ethyl acetate (waste), basify the aqueous phase with sodium hydroxide and extract three times with 200 ml ethyl acetate.

φ φ

The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. 8.6 g (100%) of trans-8-methoxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole (6) were obtained as oil.

Example 3:

(-) - 1R-trans-8-methoxy-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1 H -benz [f] indole malate ((-) 6MA) and (+) - 1S-trans-methoxy-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1H-benz [f] indole malate ((+) 6MA)

8.6 g (35 mmol) of trans-8-methoxy-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1H-benz [f] indole (6) are dissolved in 89 ml of methanol and a solution of 8.5 g (63 mmol) of L - (-) - malic acid in 85 ml of methanol are added. The mixture is stirred at room temperature for 1 hour, the crystals formed are filtered off with suction and recrystallized from 200 ml of methanol. 4.8 g (35%) of (-) - 1 R-trans-8-methoxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benzo were obtained. f] indole malate ((-) 6MA).

Melting point: 214 DEG C., [.alpha.] D @ ²⁵ = -42.1 DEG (C = 1, methanol).

The mother liquor was concentrated, basified with ammonia and extracted twice with 200 ml ethyl acetate. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo.

····

Subsequently, (+) - 1S-trans-methoxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benzo is isolated using D - (+) - malic acid. [f] malate ((+) 6 MA).

Yield: 3.5 g (25%).

Melting point: 214 ° C, [α] _D ²⁵ = + 46.1 ° (C = 1, methanol)

Example 4:

io (-) - 1R-trans-8-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole hydrobromide ((-) 2aBr)

4.8 g (12.8 mmol) of (-) - 1 R-trans-8-methoxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] The indole malate ((-) 6MA) is first converted with ammonia to the free base. Subsequently, 8 ml of water and 25 ml of 62% hydrobromic acid are added and heated under reflux for 3 hours. It is then concentrated in vacuo and the residue is crystallized from 30 ml of acetone.

Yield: 3.9 g (98%),

Melting point: > 250 DEG C., [.alpha.] _D @ ²⁵ = -68.4 DEG (C = 1, methanol).

···· ί

Analogous to Example 4, the following are produced:

(+) - 1R-trans-8-hydroxy-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1H-benz [f] indole hydrobromide ((+) 2aBr )

19.3 g (51 mmol) of (+) - 1R-trans-8-methoxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] were added. ] indole malate ((+) 6MA).

Yield: 14.4 g (91%),

Melting point: > 250 DEG C. [.alpha.] _D @ ²⁵ = + 70.0 DEG (C = 1; methanol).

Example 5:

Trans- (±) -1-benzyl-8-methoxy-2,3,3a, 4,9,9a-hexahydro-1H-benzo [f] indol-2-one ((8a) and cis - (+) -1-Benzyl-8-methoxy-2,3,3a

4,9,9a-Hexahydro-1H-benz [f] indol-2-one (8b)

3.6 g (14.5 mmol) of (±) -1,2,3,4-tetrahydro-5-methoxy-3-oxo-2-naphthaleneacetic acid methyl ester (7) and 7,8 g (73 mmol) of benzylamine Dissolve in 50 mL of THF and 50 mL of methanol. Cool to 0 ° C, acidify to pH 4.5 with glacial acetic acid and stir for 30 min.

Subsequently, 1.8 g (29 mmol) of sodium cyanoborohydride was added and stirred at room temperature for 3 days. The reaction mixture was quenched with a 20% sodium hydroxide solution and an organic solvent.

-17- .......... · ^; · Ί

!

is removed in vacuo. Subsequently, it is extracted three times with 150 ml of dichloromethane each, the combined organic phases are washed once with saturated sodium chloride solution, dried over magnesium sulphate and the solvent is removed in vacuo. The residue is chromatographed on silica gel (ca.1000g silica gel, ethyl acetate / cyclohexane 1: 1).

0.5 g (10%) of 8a and 1.1 g (25%) of 8b are obtained as an oil.

Example 6:

io Cis- (±) -1-benzyl-8-methoxy-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole (9b)

0.51 g (13.4 mmol) of LiAlH ₄ is dissolved in 5 ml of THF, cooled to 0 ° C and a solution of 1.0 g (3.3 mmol) of cis- (±) -1-benzyl-8- is added dropwise. methoxy-2,3,

3a, 4,9,9a-Hexahydro-1 H -benzo [f] indol-2-one (8b) in 20 mL THF.

Subsequently, it is heated at reflux for 5 hours, cooled to room temperature and 100 ml of saturated sodium sulphate solution are added. It is extracted three times with 100 ml of ethyl acetate each, the combined organic phases are dried over magnesium sulphate and the solvent is removed in vacuo. The residue is suspended in 15 ml of methanol, filtered off with suction from the insoluble matter and the solvent is removed in vacuo.

0.5 g (52%) of 9b is obtained as an oil.

Analogous to Example 6, the following are produced:

Trans-tert -benzyl-S-methoxy-2'-SaAa-α-hexahydro-1H-benz [f] indole (9a)

Charge 0.21 g (5.5 mmol) of LiAlH 4 and 0.5 g (1.6 mmol) of trans- (±) -1-benzyl-8-methoxy-2,3,3a, 4,9,9a- hexahydro-1 H -benzo [f] indol-2-one (8a). Yield: 0.4 g (85%).

io Example 7:

Cis- (±) -8-methoxy-2,3,3a, 4,9,9a-hexahydro-1 H -benzo [f] indole (10b)

Dissolve 1.7 g (5.8 mmol) of cis- (±) -1-benzyl-8-methoxy-2,3,3a, 4,9,9a-hexahydro15-1H-benz [f] indole (9b) in 35 ml of methanol and hydrogenated at 20 [deg.] C. under a hydrogen pressure of 5 bar (0.5 Mpa) to 0.2 g Pd / C (10%).

After 5 h, filter through silica gel and remove the solvent in vacuo. 1.2 g (100%) of 10b is obtained as an oil.

Analogous to Example 7, the following are produced:

Trans- (±) -8-methoxy-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole (10a)

Charge 0.47 g (1.6 mmol) of trans- (±) -1-benzyl-8-methoxy-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole (9a). .

·· «·

0.32 g (100%) of 10a is obtained as an oil.

Example 8:

Cis- (±) -8-hydroxy-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole hydrobromide (3bBr)

0.55 g (2.7 mmol) of cis- (±) -8-methoxy-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole (10b) was added to 6 mL water and 12 ml conc. of hydrobromic acid and heated at reflux for 20 h. Subsequently, it is concentrated under vacuum, the residue is redissolved in ethanol and the solvent is again removed under vacuum. 0.69 g (95%) of the desired product is obtained as the hydrobromide.

Analogous to Example 8, the following are produced:

Trans- (±) -8-hydroxy-2,3,3a, 4,9,9a-hexahydro-1 H -benzo [f] indole hydrobromide (3aBr)

0.32 g (1.6 mmol) of trans - (+) - 8-methoxy-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole (10a) was charged.

Yield: 0.41 g (95%) f

- 20 · · 20 20 20

Example 9:

(-) - (1R, 2'R) -trans-1- (2'-benzyloxy) -propyl-8-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a- Hexahydro-1H-benz [f] indole hydrochloride ((- (2bHCI))

4.65 g (-) - 1 R-trans-hydroxy-3α, 4,4-trimethyl-2,3,3a, 4,9,9-hexahydro-1H-benz [f] indole hydrobromide (( - (2aHBr) and 5.0 g (39 mmol) of triethylamine are dissolved in 35 ml of dichloromethane and after 30 min. A solution of 3.6 g (18 mmol) of (+) - R-2-benzyloxypropionic acid chloride in 10 ml of dichloromethane is added dropwise. Stir for 2 h at room temperature, add 20 ml of 2 N hydrochloric acid and separate the organic phase. The organic phase is dried over magnesium sulphate, the solvent is removed in vacuo and the residue is dissolved in 60 ml of tetrahydrofuran.

1.9 g (50 mmol) of LiAlH ₄ are added to the solution, the temperature rising to 35 ° C. After 1 h, 20 ml of a 40% ammonium tartrate solution are added, the organic phase is separated and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo.

The residue was dissolved in 50 ml of acetone and precipitated as hydrochloride with ethereal hydrochloric acid. The crystals were collected and washed with acetone.

Yield: 2.8 g (45%)

Melting point: 236 DEG C. [.alpha.] _D @ ²⁵ = (-) 124.3 DEG (C = 1 in methanol).

Analogous to Example 9, the following are produced:

(-) - (1R, 2'S) -trans-1- (2'-benzyloxy) -propyl-8-hydroxy-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1H -benz [f] indole hydrochloride ((-) 2cCI)

5.9 g (19 mmol) of (-) 1 R-trans-hydroxy-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1H-benz [f] indole- ((-) 2aHBr) hydrobromide and (-) - S-2-benzyloxypropionic acid 3.8 g (19 mmol).

Yield: 3.2 g (40%) 10 Melting point:> 250 ° C [α] _D ²⁵ = (-) 11.9 ° (C = 1 in methanol) (+) - (1S, 2'S) -trans- 1- (2'-Benzyloxy) -propyl-8-hydroxy-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1H-benz [f] indole hydrochloride ((+) 2bHCl )

1.6 g (5 mmol) of (+) - 1R-trans-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole- ((+) 2aBr) hydrobromide and (-) - S-2-benzyloxypropionic acid 1.0 g (5.0 mmol).

Yield: 1.3 g (63%)

Mp: 236 ° C [α] D ²⁵ = (+) 124.8 ° (C = 1 in methanol) (+) - (1S, 2'R) -trans-1- (2'-benzyloxy) -propyl -8-hydroxy-3α, 4,4-trimethyl-2,3,3α, 4,9,9α-hexahydro-1H-benz [f] indole hydrochloride ((+) 2cHCl)

- 22 ··· 3 · 3 ·· · «· · · · · · · · ·« ·

1.6 g (5 mmol) of (+) - 1R-trans-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] were added. indole hydrochloride ((+) 2aBr) and 1.0 g (5 mmol) of (+) - R-2-benzyloxypropionic acid chloride. Yield: 1.0 g (48%)

Melting point:> 250 ° C [α] _D ²⁵ = (+) 12.7 ° (C = 1 in methanol) (+) - (1S, 2'S) -trans-8-hydroxy-1- (2'-methoxy -2-phenyl) -ethyl-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1H-benz [f] indole hydrochloride 10 ((+) 2dHCl)

1.6 g (5 mmol) of (+) - 1R-trans-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole are added. ((+) 2aBr) hydrobromide and 0.9 g (5 mmol) of (+) - S-2-methoxyphenylacetic acid chloride.

Yield: 0.9 g (45%)

Melting point:> 250 ° C [α] _D ²⁵ = (+) 174.2 ° (C = 1 in methanol) (_) - (1 R) -trans-8-hydroxy-1- (2'-phenoxy) - ethyl-3a, 4,4-trimethyl-2,3,3a,

4,9,9a-Hexahydro-1H-benz [f] indole hydrochloride ((-) 2eHCI)

1.6 g (5 mmol) of (-) - 1 R-trans-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole are added. ((-) 2aHBr) hydrobromide and 0.8 g (6 mmol) of 2-phenoxyacetic acid chloride.

- 23 Yield: 0.9 g (46%)

Melting point: 248 DEG C. [ _.alpha. ] _{D @} ²⁵ = (-) 69.3 DEG (C = 1 in methanol) (+) - (1S) -trans-8-hydroxy-1- (2'-phenoxy) ethyl -3a, 4,4-trimethyl-2,3,3a,

4,9,9a-Hexahydro-1H-benz [f] indole hydrochloride ((+) 2eHCI)

1.6 g (5 mmol) of (+) - 1S-trans-hydroxy-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1H-benz [f] indole hydrobromide are added. ((+) 2aHBr) 10 and 0.8 g (6 mmol) of 2 phenoxyacetic acid chloride.

Yield: 1.2 g (62%)

Melting point: 254 ° C [α] _D ²⁵ = (+) 71.5 ° (C = 1 in methanol)

Trans- (±) -8-hydroxy-1- (2 '- (2-phenoxy) -ethoxy) -ethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole oxalate (3eOX)

0.2 g (0.74 mmol) of trans- (±) -8-hydroxy-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole hydrobromide (3aBr) are added and 0.2 g (0.93 mmol) of 2- (2'-phenoxy) -ethoxyacetic acid chloride. The base was converted with ethereal oxalic acid to oxalate.

Yield: 0.16 g (55%)

Melting point: 181 ° C

Cis- (±) -8-hydroxy-1- (2 '- (2-phenoxy) -ethoxy) -ethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole- oxalate (3fOX)

- 24 Charge 0.63 g (2.3 mmol) of cis- (±) -8-hydroxy-2,3,3a, 4,9,9a-hexahydro5 1H-benz [f] indole hydrobromide (3dHBr), and 0.5 g (2.6 mmol) of 2- (2'-phenoxy) -ethoxyacetic acid chloride. The base was converted with ethereal oxalic acid to oxalate.

Yield: 0.3 g (33% (

Melting point: 176 ° C

Example 10:

(+) - (1S, 2'S) -trans-1- (2 '- (2,6-difluorobenzyloxy) -propyl-8-3a, 4,415-trimethyl-2,3,3a, 4,9,9a-hexahydro- 1H-benz [f] indole had hydrochloride ((+) 2fHCl)

1.46 g (4.7 mmol) of (+) - 1R-trans-hydroxy-3a, 4,4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [ f] Indole hydrobromide ((+) 2aHBr) and 1.0 g (4.6 mmol) of (-) - S-2- (2 ', 6'-difluorobenzyloxy) -propionic acid are dissolved in a mixture of 50 ml of tetrahydrofuran and 50 ml of dichloromethane and 0.8 g of benzotriazole and 4 ml of ethyldiisopropylamine are added.

Then 0.9 g TBTU was added and stirred for 2 h at room temperature. The solvent is then removed, dissolved in 100 ml of ethyl acetate

- 25 and extracted once with 100 ml of saturated potassium hydrogen carbonate solution and once with 100 ml of 1N hydrochloric acid solution. The organic phase is dried over magnesium sulphate and the solvent is removed in vacuo. The residue was dissolved in 20 mL of THF and 0.5 g (13 mmol) of LiAlH _{4 was added} . The mixture is left to react for 1 hour at 50 DEG C., 50 ml of a 40% ammonium tartrate solution are added, the organic phase is separated and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo.

The residue was dissolved in acetone (50 ml) and precipitated with ethereal hydrochloric acid as the hydrochloride. The crystals were collected and washed in acetone.

Yield: 1.3 g (63%)

Melting point: 242 DEG C. [.alpha.] D @ ²⁵ = (+) 116.4; (C = 1 in methanol)

In analogy to Example 10, the following are produced:

(-) - (1R, 2'S) -trans-1- (2 '- (2,6-difluorobenzyloxy) -propyl-8-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9, 9α-Hexahydro-1H-benz [f] indole hydrochloride ((+) 2flCl7HCl)

1.5 g (4.7 mmol) of (-) - 1R-trans-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] are added. (-) 2aBr indole hydrobromide and (-) - S-2- (2 ', 6'-difluorobenzyloxy) -propionic acid (1.0 g, 4.6 mmol).

Yield: 1.3 g (63%)

Melting point: 260 ° C

- 26 [α] ²⁵ = (-) 33.8 ° (C = 1 in methanol) (1RS, 2'S) -trans-1- (2'-benzyloxy) -propyl-8-hydroxy-2,3,3a , 4,9,9ahexahydro-1H-benz [f] indole oxalate (3cOX)

0.2 g (0.74 mmol) of trans- (±) -8-hydroxy-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole hydrobromide (3aBr) and 0 13 g (0.74 mmol) of (-) - S- (2- (benzyloxy) -propionic acid) were converted into the oxalate with ethereal oxalic acid.

Yield: 0.13 g (46%)

Melting point: 193 ° C (1RS, 2'S) -cis-1- (2'-benzyloxy) -propyl-8-hydroxy-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] Indole oxalate (3dOX)

0.46 g (1.7 mmol) of cis- (±) -8-hydroxy-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole hydrobromide (3bHBr) and 0 are added. 31 g (1.7 mmol) of (-) - S- (2- (benzyloxy) -propionic acid) were converted into the oxalate with ethereal oxalic acid.

Yield: 0.25 g (38%)

Example 11:

- 27 (-) - (1R) -trans-8-hydroxy-1- (2 '- (2-phenoxy) -ethoxy) -ethyl-3a, 4,4-trimethyl-5,3,3a, 4,9, 9α-Hexahydro-1H-benz [f] indole hydrochloride ((-) 2hHCI)

3.1 g (10 mmol) of (-) - 1R-trans-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9ahexahydro-1H-benz [f] indole hydrobromide (Y 2- (2Br) and 2.2 g (11 mmol) of 2- (2-phenoxy) -ethoxy-ethyl chloride are dissolved in 50 ml of DMF (dimethylformamide), a catalysed amount of K1 and 3 g of sodium carbonate are added.

The mixture was heated to reflux for 57 h. Subsequently, it is aspirated with inorganic salts and the solvent is removed in vacuo. The residue was dissolved in 100 ml of water, extracted three times with 100 ml of ethyl acetate and the combined organic extracts were washed once more with 50 ml of water, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was filtered through a short silica gel column (25 g silica gel, 300 ml ethyl acetate), dissolved in acetone and precipitated as hydrochloride with ethereal hydrochloric acid.

Yield: 3.3 g (76%)

Melting point: 186 ° C [α] _D ²⁵ = (-) 72.1 ° (C = 1 in methanol)

Analogous to Example 11, the following were produced:

(+) - (1S) -trans-8-hydroxy-1- (2 '- (2-phenoxy) -ethoxy) -ethyl-3α, 4,4-trimethyl-28-

-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole hydrochloride (( ⁺ ) 2hHCI)

3.1 g (10 mmol) of (+) - 1R-trans-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexyhydro-1H-benz [f] indole- ((+) 2aHBr) hydrobromide and 2.2 g (11 mmol) of 2- (2-phenoxy) -ethoxy-ethyl chloride.

Yield: 3.2 g (74%)

Melting point: 186 DEG C. [ _.alpha. ] _{D @} ²⁵ = (+) 71.4 DEG (C = 1 in methanol) .alpha. (+) - (1S) -trans-8-hydroxy-1- (2 ' - (2-)) (8'-quinolinoxy) -ethoxy) -ethyl-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1H-benz [f] indole hydrochloride ((+) 2iHCI)

1.25 g (4 mmol) of (+) - 1 R-trans-hydroxy-3a, 4,4-trimethyl-2,3,3a,

4,9,9a-hexahydro-1H-benz [f] indole hydrobromide ((+) 2aHBr) and 1.2 g (4 mmol) of 2- (2 '- (8-quinolinoxy) -ethoxy) -ethyl chloride.

Yield: 0.8 g (40%)

Melting point: 167 DEG C. [ _.alpha. ] _{D @} ²⁵ = (+) 44.2 DEG (C = 1 in methanol) (-) - (1 R) -trans-8-hydroxy-1- (2 '- (2- ( 8'-quinolinoxy) -ethoxy) -ethyl-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole ((-) 21)

1.25 g (4 mmol) of (-) - 1 R-trans-hydroxy-3α, 4,4-trimethyl-2,3,3a, 25 4,9,9α-hexahydro-1H-benz [f] were added. of indole hydrobromide ((-) 2aBr) and 1.2 g

29 (4 mmol) of 2- (2 '- (8'-quinolinoxy) -ethoxy) -ethyl chloride. The free base crystallized from ethyl acetate / cyclohexane.

Yield: 0.7 g (39%)

Melting point: 163 ° C with [α] D ²⁵ = (-) 84.8 ° (C = 1 in methanol)

Example 12:

io (+) - (1S) -trans-1- (3-furanyl) -methyl-8-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benzo [f] indole hydrochloride ((+) 2iHCI)

0.93 g (4 mmol) of (+) - 1 R-trans-hydroxy-3α, 4,4-trimethyl-2,3,3a, 4,9,9α-hexahydro-1H-benz [f] indole ( (+) 2a) and 0.6 ml (7.2 mmol) of 3-fural15 aldehyde are dissolved in 10 ml of methanol, the molecular sieve is added and stirred at room temperature for two hours. It is then filtered off the molecular sieve and the filtrate is added to 0.31 g (5 mmol) of sodium cyanoborohydride and 1.2 ml of glacial acetic acid. Allow to stand overnight, add 20 mL of 4N hydrochloric acid and concentrate in vacuo. The residue was dissolved in acetone and precipitated as the hydrochloride with ethereal hydrochloric acid.

Yield: 0.7 g (50%)

Melting point:> 250 ° C [α] D ²⁵ = (+) 99.8 ° (C = 1 in methanol)

Analogous to Example 12, the following are produced:

(-) - (1R) -trans-1- (3-furanyl) -methyl-8-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H- benz [f] indole hydrochloride ((-) 2jHCI)

0.93 g (4 mmol) of (-) - 1R-trans-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole are added. ((-) 2a) and 0.6 mL (7.2 mmol) of 3-furanylaldehyde.

Yield: 0.7 g (50%) 10 Melting point:> 250 ° C [α] _D ²⁵ = (-) 102.3 ° (C = 1 in methanol)

Example 13:

(-) - (1R, 2'S) -trans-1- (2'-benzyloxy) -propyl-7-chloro-8-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9, 9a-Hexahydro-1H-benz [f] indole hydrochloride ((-) 2'HCl) and (-) - (1R, 2'S) -trans-1- (2'-benzyloxy) -propyl-5-chloro-8- hydroxy-3α, 4,4-trimethyl-2,3,3α, 4,9,9α-hexahydro-1H-benz [f] indole hydrochloride ((-) 2kHCl)

1.0 g (2.4 mmol) of (-) - (1R, 2'S) -trans-1- (2'-benzyloxy) -propyl-8-hydroxy-3a, 4,4-trimethyl-2,3,3a (4,9,9a-hexahydro-1H-benz [f] indole-hydro-25 ((-) 2cHCl) chloride) and 0.3 g (2.5 mmol) of N-chlorosuccinimide were suspended in the

The reaction mixture was stirred in 20 ml of glacial acetic acid and stirred at room temperature for 24 h, the suspension becoming a solution. Subsequently, the solution is concentrated in vacuo, and 100 ml of ice is added to the residue

2N sodium hydroxide and shake three times with 100 ml of ethyl acetate.

The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. Subsequently, the residue is chromatographed on alumina (dichloromethane / methanol 19: 1). Appropriate fractions are concentrated and the residue is dissolved in 15 ml of acetone and precipitated with ethereal hydrochloric acid to give the hydrochloride.

io = 0.4 g (37%) of ((-) - 21HCl), m.p. 218 DEG C., [.alpha.] D @ ²⁵ = (-) 12.3 DEG (C = 1 in methanol) and 0.44. g (41%) ((-) - 2kHCl), melting point:> 250 ° C, [α] _D ²⁵ = (-) 14.4 ° (C = 1 in methanol).

Analogous to Example 13, the following are produced:

(-) - (1R, 2'R) -trans-1- (2'-Benzyloxy) -propyl-7-chloro-8-hydroxy-3a, 4,4-trimethyl-2,3,3a, 4,9 9a-hexahydro-1H-benz [f] indole hydrochloride ((-) 2IHCl) and (-) - (1R, 2'R) -trans-1- (2'-benzyloxy) -propyl-5-chloro- 8-hydroxy-20a, 4,4-trimethyl-2,3,3a, 4,9,9a-hexahydro-1H-benz [f] indole hydrochloride ((-) 2mHCl)

0.42 g (1.0 mmol) of (-) - (1R, 2'S) -trans-1- (2'-benzyloxy) -propyl-8-hydroxy-3α, 4,4-trimethyl-2,3 is added. 3a, 4,9,9a-hexahydro-1H 25 benz [f] indole hydrochloride ((-) 2 [ΗΟ) and 0.13 g (1.1 mmol) of N-chlorosuccinimide. There was obtained 0.1 g (22%) of ((-) - 2 [HCl]), melting point: 252 DEG C., [.alpha.] _D @ ²⁵ = (-) 117.5 DEG (C = 1 in methanol) and 0, 17 g (38%) of ((-) - 2mHCl), mp: 252 ° C, [α] ²⁵ _D = (-) 126.7 ° (C = 1 in methanol).

The authors hereby refer to the complete content of German Patent Application Publication No. 198 34 714.6, the priority of which the present application claims.

Claims (5)

ZOO-W * Claims 1. Derivatives 2,3,3a ₎ 4 ₁ 9,9a-hexahydro-8-hydroxy-1H-benz [f] indole 5 of the general formula 1: where they can mean X a single bond, -O-, C 1 -C 4 -alkyl, C 1 -C 3 -alkoxy, -O-CH ₂ -CH ₂ -O- or -O-CH ₂ -CH ₂ -NH-; R ^{1 is} hydrogen, methyl, ethyl or phenyl; R ^{2 is} hydrogen or methyl; R ^{3 is} hydrogen, F, Cl, Br, hydroxy or methoxy; R ^{4 is} hydrogen, methyl or ethyl; R ^{5 is} hydrogen, methyl or ethyl; - 34 R ^{6 is} hydrogen, methyl or ethyl; R ⁷ tert-butyl, cyclohexyl, 10 n an integer of 0 or 1; Y N or CH; Z is O, NH or S; R ^{8 is} hydrogen, methyl, F, Cl, Br or methoxy; R ^{9 is} hydrogen, methyl, F, Cl, Br or methoxy. Compounds according to claim 1 in the form of a trans isomer. 2 BC 3 And isolating the reaction product of formula (II); 10. A process for the preparation of a compound of formula (I), wherein the nitrogen of the compound of formula (2) or (3) is reacted with a alkylating agent in a manner known per se. Wherein Z is a nitrogen-substituted leaving group, and the reaction product is isolated. - 37 11. A process for the preparation of compounds of formula (1), characterized in that the nitrogen of the compound of formula (2) or (3) is reacted with an aldehyde to form an intermediate of formula (12), and Pharmaceutical composition, characterized in that, in addition to the usual excipients and carriers, it also contains the compounds according to claim 1 and their acid addition salts. - 34 • · Use of a compound according to claim 1 as a medicament. Use of a compound according to claim 1 for the manufacture of a medicament for suppressing glutamate release. Use according to claim 5 for the manufacture of a medicament for the treatment of arrhythmias, convulsions, cardiac and cerebral ischemia and neurodegenerative diseases. Use according to claim 5 for the manufacture of a medicament for the treatment of diseases of the group: status epilepticus, hypoglycaemia, hypoxia, anoxia, brain trauma, brain swelling, stroke, perinatal asphyxia, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophilia, hypotonia, heart attack, heart rhythm disorders, angina pectoris, pain of various origins, particularly for the treatment of neuropathies. Use according to claim 4 for the manufacture of a local anesthetic. 9. A process for the preparation of a compound of formula (1), wherein the nitrogen of the compound of formula (2) or (3) is reacted in a manner known in the art with an acylating agent wherein Y is a nitrogen-displaceable leaving group. 25 to the corresponding intermediate of formula (11) and this is then reduced, in a manner known in the art, to the corresponding indole derivative of formula (1). 5 is reduced to the final product of formula (1) and isolated.