SK23896A3 - Alkoxy-substituted beta-carbolines, a method of their producing, their use and drugs containing these substances - Google Patents

Abstract

Compounds having the formula (I) are disclosed, as well as their preparation and use in medicaments acting on the AMPA-receptor.

Description

ALCOXYSUBSTITUTED β-CARBOLINS, METHOD OF MANUFACTURE, USE OF THERAPY AND ACTIVE SUBSTANCES CONTAINING THESE SUBSTANCES

Technical field

The invention relates to novel alkoxy-β-carboline derivatives, to a process for their preparation, to their use in pharmaceuticals, to pharmaceutical compositions containing them, and to intermediates for the preparation of these derivatives.

BACKGROUND OF THE INVENTION

It is known from many publications that β-carbolines have an affinity for benzodiazepine receptors and can be used as psychopharmaceuticals based on this affinity for benzodiazepine receptors.

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that the compounds of formula I below act on the MPA receptor modulation sites and / or AMPA receptor-dependent ion channels and correct pathologically altered function of this receptor. The sympathetic function of the excitatory amino acid L-glutamate is predominantly mediated via AMPA receptors. Increased or decreased glutamate neurotransmission in the central nervous system leads to many neurological and psychiatric diseases. The compounds of formula I below are therefore suitable for the manufacture of a medicament for the symptomatic and preventive treatment of neurological and psychiatric disorders.

Accordingly, the present invention provides alkoxy-substituted β-carboline derivatives of Formula I

in which

A is a straight or branched alkylene group having 1 to carbon atoms, which is optionally substituted by hydroxyl, alkoxy having 1 to 6 carbon atoms or alkanoyloxy of 1 to 6 carbon atoms, or - (CH ₂₎ -CO- (CH _2); where nam is 1, 2 or 3,

R ¹ and R ² are the same or different and represent a hydrogen atom, a C 1 -C 7 alkyl group, a C 4 -C 9 -C 4 alkyl group, a cycloalkyl carbon atom, a cycloalkylalkyl carbon atom, a phenyl group, a 1 to carbon phenylalkyl group alkyl atoms, or

R ² and R ² together with the nitrogen atom form a heterocycle of formula (a) (a) in which

B represents a direct bond, an oxygen atom, a sulfur atom or a group = CH-r5, = COH-R ^ or = N-R ^, wherein

R ⁵ represents hydrogen, alkyl having 1 to 4 carbon atoms, _cq <7, or optionally alkyl having 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, hydroxy, trifluoromethyl or -O- CF ₃ one to three times substituted phenyl, benzyl, benzoyl, α-hydroxybenzyl, phenethyl, 2-oxo2-phenethyl, 1-oxo-2-phenethyl or pyridine group and

Y represents an oxygen atom, a sulfur atom or a group = NH,

R ³ represents a hydrogen atom, a carboxyl group, a COO-alkyl group having 1 to 6 carbon atoms in an alkyl group, a CO-R ° group or, optionally, one to three times an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms , halogen, (C 1 -C 4) alkoxyalkyl of (C 1 -C 2) alkyl, (C 1 -C 4) alkoxy, phenyl or amino substituted (C 6 -C 12) aryl or heteroaryl group, wherein:

R ⁶ is C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 7 -C 9 bicycloalkyl or optionally C 1 -C 4 alkyl, C 1 -C 4 alkoxy or substituted amino a monocyclic or bicyclic aryl group having 6 to 12 carbon atoms,

R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyalkyl group having 1 to 4 carbon atoms in the alkoxy group and having 1 to 2 carbon atoms in the alkyl group, and

R ⁹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenylalkyl group having 1 to 2 carbon atoms in the alkyl, an optionally substituted benzenesulfonyl group or an alkanesulfonyl group having 1 to 4 carbon atoms such as as well as their stereoisomers and salts.

When the compounds of formula I have chiral centers, the present invention includes all possible stereoisomers as well as enantiomers and diastereomers as well as mixtures and racemates thereof.

The substituent in the A-ring may be in the 5 to 8 position, preferably 5 or 6.

A straight or branched alkylene group having 1 to 5 carbon atoms is, for example, a methylene group, an ethylene group, a propylene group, an isopropylidene group, a 1-methylethylene dimethylethylene dimethylethylene group, a group and an alkylene radical A is in

2-ethyl-propylene, 2,21,1-dimethylethylene, 1,2-tetramethylene. The substituent is at any position, preferably at position

A 2-, 3-, or 4- straight alkylene moiety.

Alkyl groups include both straight and branched groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, 2,2-dimethylpropyl and 2-methylbutyl.

Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 2-methylcyclopropyl.

Cycloalkylalkyl radicals include cyclopropylmethyl and cyclohexylmethyl.

The phenylalkyl substituent having 1 to 2 carbon atoms in the alkyl may be straight or branched in the alkyl moiety such as, for example, benzyl, phenethyl or α-methylbenzyl.

Suitable halogen is fluorine, chlorine, bromine or iodine.

The pyridine residue R ⁵ is bonded at the 2, 3 or 4 position.

The aryl or heteroaryl radical may exist as a monocycle or a bicyclic ring and contains 5 to 12 ring atoms, preferably 5 to 9 atoms. Examples include phenyl, biphenyl, naphthyl and indenyl such as aryl residues and thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, isoxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, oxazolyl, a thiazolyl group, an isothiazolyl group, a 1,3,4-oxadiazol-2-yl group, a 1,2,4-oxadiazol-5-yl group, a 1,2,4-oxadiazol-3-yl group, a quinolyl group, isoquinolyl, benzo [1] thienyl or benzofuryl as heteroaryl radicals having 1 to 3 heteroatoms such as sulfur, oxygen and / or nitrogen.

Preferred heteroaryl radicals R ³ include isoxazol-3-yl, isoxazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,2,4oxadiazol-3-yl, 1,3,4-oxadiazole 2-yl, thiazol-4-yl, thiazol-2-yl, pyrrol-2-yl, pyrrol-3-yl, 2-thienyl, 3-thienyl, pyridin-2-yl, pyridin-3-yl, pyridine -4-yl and oxazol-5-yl, which may optionally be substituted. Preferred aryl R ³ is a phenyl group optionally substituted by halogen or alkoxy of 1 to 4 carbon atoms.

The term bicycloalkyl radical refers to a bicycloheptyl group and a bicyclooctyl group. As the monocyclic or bicyclic aryl radical R ⁶ , for example, phenyl, biphenyl, naphthyl and indenyl can be mentioned.

The (C 1 -C 6) alkanoyl moiety is derived from straight or branched aliphatic carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, trimethylacetic acid or caproic acid.

Suitable sulfonic acid residues R @ ⁹ are the known benzenesulfonic acids which may be substituted by a halogen or an alkyl group having up to 4 carbon atoms, as well as alkanesulfonic acids having 1 to 4 carbon atoms, such as methanesulfonic acid and p-toluenesulfonic acid.

Physiologically acceptable salts are derived from inorganic and organic acids such as hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulfuric acid or phosphoric acid, or organic acids such as aliphatic or aromatic monocarboxylic or dicarboxylic acids such as formic, acetic, maleic acid, fumaric acid, glutaric acid, lactic acid, tartaric acid, citric acid, oxalic acid and glycoxylic acid, or sulfonic acids such as alkanesulfonic acids of 1 to 4 carbon atoms such as methanesulfonic acid or optionally halogenated or alkyl substituted benzenesulfonic acids such as p-toluenesulfonic acid.

Preferred are compounds of formula I wherein:

R ¹ and R ³ together with the nitrogen atom form a heterocycle of formula (a)

in which B is as defined above,

R ³ represents a hydrogen atom, a carboxyl group, a COO-alkyl group having 1 to 6 carbon atoms in the alkyl, or optionally one to three times an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, halogen, an alkoxy group having C 1 -C 4, C 1 -C 4 alkoxyalkyl, C 1 -C 2 alkyl, phenyl or amino substituted C 6 -C 12 aryl or heteroaryl, and R ⁴ , R ⁹ and A are as defined above.

Particularly preferred are compounds of formula I in which

A is a straight or branched alkylene group having 1 to 5 carbon atoms which may be substituted by a hydroxy or alkoxy group having 1 to 6 carbon atoms,

R ¹ and R ² together with the nitrogen atom form a heterocycle of formula (a)

(a) in which B is as defined above,

R ⁹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and

R ³ represents a hydrogen atom, a carboxyl group or a COO-alkyl group having 1 to 6 carbon atoms in the alkyl, and stereoisomers and salts thereof.

When it is phenyl, benzyl, benzoyl, α-hydroxybenzyl, phenethyl, 2-oxo-2-phenethyl or 1-oxo2-phenethyl which is substituted, halogen and C1-C4alkoxy are preferred. , especially a fluorine-substituted radical, substitution at the 4-position is preferred.

The present invention furthermore relates to a process for the preparation of alkoxysubstituted β-carbolines of the general formula I, which comprises:

a) a compound of formula II

wherein R ³ , R ⁴ and R ^{9 are} as defined above, are reacted with an amine of formula III

X —A — N

(H1) wherein R ¹ , R ² and A are as defined above and X is a leaving group, or

b) a compound of formula IV

in which A, R ³ , R ⁴ and R ^{9 are} as defined above and X is a leaving group, is reacted with an amine of formula V

wherein R ¹ and R ^{2 are} as hereinbefore defined, optionally optionally introducing or cleaving the substituent R ⁹ or forming a physiologically acceptable salt, or converting the physiologically acceptable salt into the free compounds of formula I, or separating the racemates.

The nucleophilic substitution of the leaving group X according to variants a) and b) is carried out by conventional methods in organic solvents inert under the reaction conditions under basic conditions.

Suitable leaving groups X are halogens such as chlorine, bromine or iodine, or organic sulfonic acid residues such as alkanesulfonic acid residues such as mesylate and triflate or aromatic sulfonic acid residues such as toluenesulfonic acid or bromobenzenesulfonic acid.

Suitable inert organic solvents are polar solvents such as dimethylformamide, dimethylacetamide, alcohols such as ethanol or methanol, cyclic ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons or aromatic hydrocarbons, as well as mixtures of the solvents mentioned.

Suitable bases are inorganic and organic bases. Examples of inorganic bases are alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates or alcoholates. Examples of organic bases include tertiary organic amines such as tripropylamine, triethylamine, N-alkylmorpholines or N-alkylpiperidines. However, an excess of the amine of formula (V) may be used as the base or the reaction may be carried out in the presence of phase transfer catalysts.

The reaction temperatures may range from 0 ° C to the boiling point of the solvent used.

The introduction of the R ⁹ substituent can be carried out by conventional alkylation, benzylation or sulfobenzylation procedures, for example by reacting a reactive derivative of the R ⁹ substituent in the presence of a base with carboline.

The cleavage of the substituent R ⁹ is carried out by conventional methods, depending on the type of substituent, basic or hydrogenolytic.

The compounds of formula I can be isolated and purified from the reaction mixture by known methods. Acid addition salts may be converted into the free base by conventional methods and converted into physiologically acceptable acid addition salts, as appropriate, by known methods, for example by mixing the solution with a concentrated solution of the desired acid.

If the compounds of formula I contain chiral centers, the optically active compounds can be obtained starting from optically active starting compounds or obtained from racemates by known methods. Separation of enantiomers may be carried out, for example, by chromatography on optically active carrier materials or by reaction with optically active acids followed by fractionated crystallization.

The present invention also relates to novel compounds of formula IV

in which they have

Starting intermediates of, for example, the compounds of formula I.

A, R ³ , compounds for production

R ⁴ , R ⁹ and X are as defined above.

IV are valuable pharmacologically active compounds of the above formula

The preparation of the compounds of the general formula (IV) is carried out by known methods, for example by:

a) a compound of formula II

(II) wherein R ³ , R ⁴ and R ^{9 are} as defined above, etherifies with a compound of formula VI

X - A - Y (VI) wherein A and X are as defined above and Y is a leaving group, or

b) etherifying the compound of formula II with an alcohol of formula VII

Y-A-OH (VII) wherein Y is as defined above, and then a leaving group X is introduced.

Suitable leaving groups are those mentioned for substituent X. Etherification is carried out in the usual manner in the presence of a base. The introduction of the leaving group X is carried out by conventional methods.

Unless the production of the starting compounds is described, they are known or can be produced analogously to known compounds or by the methods described herein.

For example, the preparation of hydroxy derivatives of the formula II according to EP-A 130 140, EP 0 161 574, EP 0 305 322, WO 92/21 697 and WO 92/22 549 can be carried out.

The compounds of the formula I as well as their physiologically acceptable salts are useful as medicaments because of their action on the quisqualate receptor modulator sites or the quisqualate receptor-dependent ion channel.

The pharmacological activity of the compounds of formula I is determined by the following test.

Male NMRI mice weighing 18-22 g are maintained under controlled conditions (6.00-18.00 hrs light / dark rhythm with free food and water availability) and divided into groups. Groups consist of 5 to 16 animals. Observation of the animals is performed between 8.00 and 13.00.

AMPA is injected into the left ventricle of the free-moving mouse. The applicator consists of a cannula with a stainless steel device that limits the injection depth to 3.2 mm. The applicator is connected to a syringe pump. The injection needle is inserted perendicular to the skull surface according to the Montemurry and Dukelow coordinates. The animals are observed until clinical or tonic seizures occur for up to 180 seconds. Clonic movements that last longer than 5 seconds are counted as convulsions. The onset of clonic seizures is used as the endpoint for determining the seizure threshold. The dose required to increase or decrease the seizure threshold by 50% (THRD ₅₀ ) is determined in 4-5 experiments. The THRD value and confidence limits are determined by regression analysis.

The results of these experiments show that the compounds of formula I and their acid addition salts affect functional disorders of the AMPA receptor. They are therefore suitable for the manufacture of a medicament for the symptomatic and preventive treatment of diseases that are caused by a change in the function of the AMPA-receptor complex.

Treatment with the compounds of the present invention suppresses or reduces cell damage and functional disorders occurring as a result of the disease, thereby reducing the symptoms induced.

Diseases that may be excitatory amino acids optionally induced by dysfunction altered by glutamate neurotransmission include, for example, neurodegenerative diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, multi-infarct dementia, amyotropic lateral sclerosis, epilepsy, olive sclerosis, olive sclerosis; cell damage by hypoglycemia, hypoxia, ischemia and energy metabolism disorders; neuronal damage caused by brain damage such as strokes, brain trauma and asphyxia, as well as psychoses, schizophrenia, fear states, pain states, migraine and emesis. Dysfunction of glutamate neurotransmission is also based on functional disorders such as memory disorders (amnesia), learning process disorders, manifestations of vigilance, and rejection manifestations after chronic intake of addictive substances such as sedative drugs, hallucinogens, alcohol, cocaine and opiates. Indications can be shown using conventional pharmacological tests.

The present invention also relates to pharmaceutical compositions comprising said compounds, their production and the use of the compounds of the present invention for the manufacture of medicaments which can be used for the treatment and prophylaxis of the aforementioned diseases. The medicaments are prepared by known methods by converting the active ingredient with suitable carriers, excipients and / or additives into a pharmaceutical preparation suitable for enteral or parenteral administration. Administration can be carried out orally or sublingually as a solid in the form of capsules or tablets, or as a liquid in the form of solutions, suspensions, elixirs or emulsions, or rectally as suppositories, or in the form of possibly also subcutaneous injectable solutions. Suitable excipients for the desired pharmaceutical formulations are those known to those skilled in the art, inert organic and inorganic carriers such as water, gelatin, acacia, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyethylene glycols and the like. Optionally, preservatives, stabilizers, wetting agents, emulsifiers or salts for varying the osmotic pressure or buffers may also be present.

The pharmaceutical preparations may be in solid form, for example, as tablets, dragees, suppositories and capsules, or in liquid form as solutions, suspensions or emulsions.

Surfactant adjuvants such as bile acid salts or animal or plant phospholipids, but also mixtures thereof, as well as liposomes or components thereof, can also be used as carrier systems.

For oral administration, tablets, coated tablets or capsules containing talc and / or hydrocarbon carriers or binders, such as lactose and corn or potato starch, are particularly suitable. The application can also be carried out in liquid form, for example as a juice to which a sweetener is optionally added.

For parenteral administration, particularly suitable are injectable solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil.

The dosage of the active compounds can be controlled according to the type of application, the age and weight of the patient, the type and severity of the disease to be treated and the like. The daily dose may be administered as a single dose per day, or divided into two or more daily doses. The active compounds are administered in an amount of 0.05 to 500 mg of active substance in a physiologically acceptable carrier. In general, the dose is 0.1 to 1000 mg / day (0.001 to 10 mg / kg), preferably 0.1 to 100 mg / day.

The following examples serve to illustrate the preparation of the compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

5- {3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy] -4-methoxymethyl-3-carboline- isopropyl ester-

3-carboxylic acid

628 mg of 5-hydroxy-4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester is placed in 100 ml of acetone, mixed with 600 mg of potassium carbonate and 760 mg of (4-fluorophenyl) - [1- (3-methylsulfonyloxypropyl) -4-piperidyl The ketone was added and the reaction mixture was heated to reflux for 3 hours under an argon atmosphere. After concentration, the organic phase is chromatographed on silica gel using 1: 1 acetone / hexane. The desired fractions are concentrated and triturated with diethyl ether. 630 mg of 5 {3- [4- (4-fluorobenzoyl) -piperidin-1-yl] -propoxy) -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester of melting point 161-162 ° C are obtained.

(4-Fluorophenyl) - [1- (3-methylsulfonyloxypropyl) -4-piperidyl] ketone is obtained by methods known from the literature by alkylation

Of 4- (4-fluorobenzoyl) -piperidine with 3-bromo-1-propanol and potassium carbonate in dimethylformamide followed by reaction with methanesulfonic acid and triethylamine in methylene chloride.

The following are produced in an analogous manner:

6- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy] -4-methoxymethyl-3-carboline-3-carboxylic acid isopropyl ester,

mp 153-155 ° C 5- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -4-ethyl-p-carboline-3-carboxylic acid isopropyl ester,

mp 178-180 ° C 5- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy] -4-methyl-β-carboline-3-carboxylic acid isopropyl ester,

mp 168-170 ° C 5- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -4-carboline-3-carboxylic acid isopropyl ester,

mp 182-184 C 6- {3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy} -p-carboline-3-carboxylic acid isopropyl ester,

5- (3- (4- (4-fluorobenzoyl) -piperidin-1-yl) -propoxy} -4-methoxymethyl-p-carboline,

6- (3- (4- (4-fluorobenzoyl) -piperidin-1-yl) -propoxy) -4-methoxymethyl-p-carboline,

5- (3- (4- (4-fluorobenzoyl) -piperidin-1-yl) -propoxy} -4-ethyl-β-carboline,

6- (3- (4- (4-fluorobenzoyl) -piperidin-1-yl) -propoxy} -4-methyl-β-carboline,

5- {3- (4- (4-fluorobenzoyl) piperidin-l-yl] -propoxy) -

-β-carboline, 5- {3- [4- (4-fluorobenzoyl) -piperidin-1-yl] -propoxy} -4-methoxymethyl-9-ethyl-3-carboline-3-carboxylic acid isopropyl ester,

mp 115 to 117 ° C 6- (3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -4-methoxymethyl-9-methyl-3-carboline-3-carboxylic acid isopropyl ester,

mp 110 to 111 ’C

5- (3- (4- (4-fluorobenzoyl) -piperidin-1-yl) -propoxy) -4-methoxymethyl-9-methyl-p-carboline,

6- (3- (4- (4-fluorobenzoyl) -piperidin-1-yl) -propoxy} -4-methoxymethyl-9-methyl-p-carboline.

Example 2

5- {3- [4-Phenyl-piperazin-1-yl] -propoxy] -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester

450 mg of 5- (3-chloropropoxy) -4-18-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester are mixed with 245 mg of 4-phenylpiperazine and 0.21 ml of triethylamine at a bath temperature of 100 ° C in 20 ml of dimethylformamide for 20 hours. 18 hours under argon. After distilling off the solvent, the residue is taken up in methylene chloride and washed once with water and once with saturated sodium chloride solution. The organic phase is dried, filtered and concentrated. The residue is chromatographed on silica gel with ethyl acetate. 420 mg of 5- (3- [4-phenyl-piperazin-1-yl] -propoxy} -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester, m.p. 176-177 ° C, is obtained.

5- (3-Chloropropoxy) -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester (melting point 178 DEG-180 DEG C.) is required as a starting material by etherification of 5-hydroxy-4-methoxymethyl-p-carboline isopropyl ester -3-carboxylic acid 1-bromo-3-chloropropane and potassium carbonate in dimethylformamide.

Example 3

Following the procedure of Example 2, the following compounds were prepared from 5- (3-chloropropoxy) -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester and the secondary amine:

5- {3- [4-Benzyl-piperazin-1-yl] -propoxy) -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester,

mp 112-114 ´C 5- {3- [Morpholin-1-yl] -propoxy) isopropyl ester -

4-methoxymethyl-.beta.-carboline-3-carboxylic acid,

mp 112 to 114 ´C 5- {3- [4- (3,4,5-Trimethoxyphenyl) piperazin-1-yl] propoxy} -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester,

mp 135-136 ´C 5- {3- [4- (4-Fluorobenzyl) -piperidin-1-yl] -propoxy) -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester,

mp 126 to 128 ´C 5- {3- [4- (4-Fluoro-α-hydroxybenzyl) piperidin-1-yl] -propoxy) -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester,

mp 110-115 ° C 5- {3- [4- (4-Chloro-phenyl) -4-hydroxypiperidin-1-yl] -propoxy} -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester, 5- {3- 3- Isopropyl ester [4-benzoyl-piperidin-1-yl] -propoxy] -4-methoxymethyl-β-carboline-3-carboxylic acid,

mp 133-135 ° C 5- {3- [4- (4-Fluoro-phenethyl) -piperidin-1-yl] -propoxy) -4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, 5- {3- [4- 5- {3- [4- (1-Oxo-2- (2-oxo-2- (4-fluorophenethyl) piperidin-1-yl) propoxy} -4-methoxymethyl-p-carboline-3-carboxylic acid (2-oxo-2- (4-fluorophenethyl) piperidin-1-yl)) 4-fluorophenethyl) piperidin-l-yl] propoxy) -4-methoxymethyl-.beta.-carboline-3-carboxylate.

Example 4

5- {4- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -butoxy} -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester

Starting from 520 mg of 5- (4-chlorobutoxy) -420-fluoroethoxymethyl-p-carboline-3-carboxylic acid isopropyl ester (m.p. 147-148 ° C) and 411 mg of 4- (4-fluorobenzoyl) -piperidine were obtained in an analogous manner to Example 2 235 mg of 5- (4- [4- (4-fluorobenzoyl) -piperidin-1-yl] -butoxy) -4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, m.p. 103-105 ° C.

The following are produced in an analogous manner:

6- {4- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -butoxy} -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester, 5- {4- [4- (4-Fluoro) isopropyl ester alpha-hydroxy-benzyl) -piperidin-l-yl] -butoxy} -4-methyl-3-carboline-3-carboxylic acid,

5- {4- [4- (4-fluoro-a-hydroxy-benzyl) -piperidin-l-yl] -butoxy} -

4-metoxymety1-β-karbo1ín.

Example 5

5- {2- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -ethoxy} -4-methoxymethyl-4-carboline-3-carboxylic acid isopropyl ester

From 510 mg of 5- (4-chloroethoxy) -4-methoxymethyl-4-carboline-3-carboxylic acid isopropyl ester (m.p. 194-195 ° C) and 311 mg of 4- (4-fluorobenzoyl) -piperidine were obtained in analogy to Example 2 195 mg of 5- {2- [4- (4-fluorobenzoyl) -piperidin-1-yl] -ethoxy} -4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, m.p. 161-163 ° C.

The following are produced in an analogous manner:

6- {2- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -ethoxy} -4-methoxymethyl-4-carboline-3-carboxylic acid isopropyl ester,

5- {2- [4- (4-fluorobenzoyl) piperidin-l-yl] -ethoxy} -4-metoxymetylβ-carboline,

5- {2- [4- (4-fluoro-a-hydroxy-benzyl) -piperidin-l-yl] -ethoxy} -

4-methoxymethyl-beta-carboline.

Example 6

5- {3- [4- (4-Fluorobenzoyl) piperidino] -2-hydroxypropoxy} -4-methoxymethyl-p-carboline-

3-carboxylic acid

700 mg of 4-methoxymethyl-5- (2,3-epoxypropoxy) -β-carboline-3-carboxylic acid isopropyl ester is dissolved in 50 ml of 2-propanol and treated with 380 mg of 4- (4-fluorobenzoyl) -piperidine. After refluxing under argon for a few hours, the organic phase is concentrated and the residue is chromatographed on silica gel with methylene chloride / ethyl alcohol 100:50 to give 655 mg of 5- {3- [4- (4- (4-) - 4- isopropyl ester). fluorobenzoyl) -piperidino] -2-hydroxypropoxy} -4-methoxymethyl-p-carboline-3-carboxylic acid, m.p. 143 C.

4-Methoxymethyl-5- (2,3-epoxypropoxy) p-carboline-3-carboxylic acid isopropyl ester is obtained according to methods known in the literature by etherification of 5-hydroxy-4-methoxymethyl-3-carboline-3-carboxylic acid isopropyl ester with epichlorohydrin and potassium carbonate in dimethylformamide.

In an analogous manner there are obtained:

5- {3- [4- (4-Fluorobenzoyl) -piperidino] 2-hydroxypropoxy) -4-ethyl-p-carboline-3-carboxylic acid isopropyl ester,

mp 119 to 129 ´C 5- (3- [4- (2-Fluoro-1-piperazinyl) -2-hydroxy-propoxy) -4-methoxymethyl-4-carboline-3-carboxylic acid isopropyl ester,

mp 198-200 ° C.

Example 7

5- {3- [4- (4-Fluorobenzoyl) piperidino] -2-methoxypropoxy} -4-methoxymethyl-p-carboline-

3-carboxylic acid

435 mg of 5- {3- [4- (4-fluorobenzoyl) piperidino] -2-hydroxypropoxy) -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester is dissolved in 40 ml of ethylene glycol dimethyl ether, mixed with 20 mg of sodium hydride (90%) and cooled in an ice bath to 0 ° C. To this reaction mixture was added dropwise 0.05 ml of methyl iodide, and the reaction mixture was stirred for 4 hours. After warming to room temperature, stirring was continued for 2 hours. After evaporation of the solvent, the residue obtained is chromatographed on silica gel using methylene chloride / ethyl alcohol 100:50.

175 mg of 5- {3- [4- (4-fluorobenzoyl) -piperidino] -2-methoxypropoxy} -4-methoxymethyl-p-carboline-3-carboxylic acid isopropyl ester, m.p. 137-139 ° C.

Claims (7)

PATENT CLAIMS 1. Alkoxy-substituted β-carboline derivatives of the general formula I * in which A represents a straight or branched alkylene group having from 1 to 5 carbon atoms; 5 C atoms, which is optionally substituted by hydroxy, C -C 6 carbon atoms or alkanoyloxy of 1 to 6 carbon atoms, or - (CH _{2) n} ^- CO (CH _{2) m} -, wherein us is 1, 2 or 3, Z 2 z,, R and R are the same or different and represent a hydrogen atom, a C 1 -C 7 alkyl group, a C 4 -C 9 -C 4 alkyl group, a cycloalkyl carbon atom, a cycloalkylalkyl carbon atom, a phenyl group, a C 1 -C 2 phenylalkyl group in alkyl, or 1 2 R and R together with the nitrogen atom form a heterocycle of formula (a) (a) wherein B represents a direct bond, an oxygen atom, a sulfur atom or a group = CH-R ⁵ , = COH-R ⁵ or = NR ⁵ , wherein R ⁵ represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 47 group. or optionally C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxy, trifluoromethyl, or -O-CF 3, optionally substituted by phenyl, benzyl, benzoyl, α-hydroxybenzyl, phenethyl, 2-to-3-methyl, -oxo2-phenethyl, 1-oxo-2-phenethyl or pyridine and a Y represents an oxygen atom, a sulfur atom or a group = NH, R represents a hydrogen atom, a carboxyl group, a COO-alkyl group having 1 to 6 carbon atoms in the alkyl group, a CO-R6 group or, optionally, one to three times an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, (C1 -C4) alkoxyalkyl having 1 to 2 carbon atoms in alkyl, (C1 -C4) alkoxy, phenyl or amino substituted (C6 -C12) aryl or heteroaryl, wherein: R ⁶ represents a C 1 -C 4 alkyl group, a C 3 -C 7 cycloalkyl group, a C 7 -C 9 bicycloalkyl group, or optionally a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or an amino substituted group a monocyclic or bicyclic aryl group having 6 to 12 carbon atoms, R ⁴ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyalkyl group having 1 to 4 carbon atoms in the alkoxy group and having 1 to 2 carbon atoms in the alkyl group, and R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenylalkyl group having 1 to 2 carbon atoms in the alkyl, an optionally substituted benzenesulfonyl group or an alkanesulfonyl group having 1 to 4 carbon atoms, their stereoisomers and salts. 2. The compound according to claim 1, wherein R @ ² and R @ ² together with the nitrogen atom form a heterocycle of formula (a). 3. A compound according to claim 1, which is 5- {3- [4- (4-Fluorobenzoyl) -piperidinol] -propoxy] -4-methoxymethyl-4-carboline-3-carboxylic acid isopropyl ester. A medicament based on alkoxy-substituted β-carboline derivatives according to claims 1 and 2. ,, Use of alkoxy-substituted β-carboline derivatives according to claims 1 and 2 for the manufacture of medicaments. 6. A process for the preparation of alkoxy-substituted β-carboline derivatives according to claim 1, characterized in that a) reacting a compound of formula II (II) wherein R ³ , R ⁴ and R ^{9 are} as defined above with an amine of formula III r. in which they have R ¹ X —A - R ² a R1 And the aforementioned (III) meaning is a leaving group, or b) reacting a compound of formula IV (IV) wherein A, R ³ , R ⁴ and R ^{9 are} as defined above and X is a leaving group, with an amine of formula V wherein R ¹ and R ^{2 are} as defined above, and optionally optionally introducing or cleaving the substituent R ^9, or forming a physiologically acceptable salt, or converting the physiologically acceptable salt into the free compounds of formula I, or separating the racemates. Compounds of formula IV wherein R ³ , R ⁴ , R ⁹ , A and X are as defined above.