HUT73845A - Alkoxy-substituted beta-carbolines acting on the ampa-receptor, process for producing them and pharmaceutical compositions - Google Patents

Description

The present invention relates to β-carbolines of formula (I) wherein

A is an alkylene group which may be substituted by a hydroxy, alkoxy or alkanoyloxy group, or

- (CH ₂ ) _n -CO- (CH ₂ ) _m - wherein n, m is 1, 2 or 3;

R ¹ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl, or

R-L and together with the nitrogen atom form a group of formula (a) in which

B is a direct bond, oxygen, sulfur,> CH-R ⁵ ,> COH-R 4 or> NR 4 where

R ⁵ is hydrogen, alkyl or b, or optionally substituted phenyl, benzyl, benzoyl, o-hydroxybenzyl, phenethyl, 2-oxo-2-phenethyl, 1-oxo-2 a phenethyl or pyridine group;

Y is oxygen, sulfur or > NH, < 3 > is hydrogen, carboxyl, alkyloxycarbonyl, -CO-R, or optionally substituted aryl or heteroaryl, is alkyl, cycloalkyl, bicycloalkyl. or an optionally substituted mono or bicyclic aryl group,

R ⁴ is hydrogen, alkyl, alkoxyalkyl, and

R ⁹ is hydrogen, alkyl, alkanoyl, phenylalkyl, optionally substituted benzenesulfonyl or alkanesulfonyl, and their use in the preparation of a medicament.

61 955 / PA

S.B.G. & K

International

Patent Office H-1062 Budapest, Andrássy út 113. Phone: 34-24-950, Fax: 34-24-323. ' '• ····· ··· · ······· · ··· · «· · ···

/ substituted β-carbolines

BACKGROUND OF THE INVENTION The present invention relates to alkoxy substituted β-carboline derivatives, to their preparation and their use as medicaments, and to intermediates useful for their preparation.

The activity of β-carbolines against benzodiazepine receptors is known from several publications and based on this activity the compounds can be used as psychopharmacones.

Surprisingly, it has been found that compounds of formula I act on the modulation site of AMPA receptors and AMPA receptor-dependent inocytes, and can correct pathologically altered function of these receptors. The excitatory amino acid exerts its L-glutamate synaptic function mainly through the AMPA receptor. Increased or decreased glutamate neurotransmission in the central nervous system leads to a number of neurological and psychiatric disorders. The compounds of formula (I) are therefore useful in the manufacture of a medicament for the symptomatic and prophylactic treatment of neurological and psychiatric disorders.

The present invention relates to a compound of formula (I): wherein:? · ···

A is a linear or branched C 1 -C 5 alkylene group which may be substituted by hydroxy, C 1 -C 6 alkoxy or C 1 -C 6 alkanoyloxy, or - (CH ₂ ) _n -CO - (CH ₂ ) _m -. wherein n, m is 1, 2 or 3;

R ^{1 is the} same or different and is hydrogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 9 cycloalkylalkyl, phenyl, phenyl (C 1 -C 2) alkyl, or

R ¹ and R 4 together with the nitrogen atom form a group of formula (a) in which

B is a direct bond, oxygen, sulfur,> CH-R ^,> COH-R ^ or> NR ^ wherein

^R5 is hydrogen, C1-4 alkyl, (b) a group of formula or optionally with C 1-4 alkyl,

Phenyl, benzyl, benzoyl, α-hydroxybenzyl, phenethyl, 2-oxo, tri-substituted with C1-C4 alkoxy, halogen, hydroxy, trifluoromethyl or trifluoromethoxy;

2-phenethyl, 1-oxo-2-phenethyl or pyridine;

Y is O, S or NH;

R ³ is hydrogen, carboxyl, (C 1 -C 6) powder or optionally C 1 -C 4 alkyl,

C 6 -C 12 aryl or heteroaryl monosubstituted with C 3 -C 7 cycloalkyl, halogen, C 1 -C 4 alkoxy-C 1 -C 2 alkyl, C 1 -C 4 alkoxy, phenyl or amino, C 4 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 7 -C 9 bicycloalkyl, or C 6 -C 12 mono- or bicyclic aryl optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or amino,

R ⁴ is hydrogen, C 1-4 alkoxy) - (1-2)

R ⁹ is hydrogen,

C 1-6 -alkyl, C 1-6 -alkanoyl, phenyl-C 1-2 -alkyl, optionally substituted benzenesulfonyl or C 1-4 -alkanesulfonyl, as well as the stereoisomeric forms and salts thereof.

Where the compounds of formula (I) contain an asymmetric center, the invention encompasses all possible stereoisomers, including enantiomers and diastereomers, and mixtures thereof, and racemates.

Ring A is substituted with 5-8, preferably 5- or

They are in position 6.

C 1-5 straight or branched chain alkylene groups include, for example, methylene, ethylene, propylene, isopropylidene, 1-methylethylene, 2-ethylpropylene, 2,2-dimethylethylene, -dimethylethylene, 1,2-dimethylethylene or tetramethylene. The substituents on the alkylene group A are attached at any position, preferably at the 2-, 3- or 4-position of the linear alkylene group.

Alkyl is a straight and branched chain group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, 2 2-dimethylpropyl and 2-methylbutyl.

Cycloalkyl may mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 2-methylcyclopropyl.

Examples of cycloalkylalkyl include cyclopropylmethyl and cyclohexylmethyl.

The substituent alkyl chain of the phenyl (C 1-2 alkyl) group may be straight or branched, such as benzyl, phenethyl and θ'-methylbenzyl.

Suitable halogens include fluorine, chlorine, bromine and iodine.

The pyridine ^R5 is 2-, 3- or 4-position is attached.

In R ^3, the aryl and heteroaryl moieties may be mono- or bicyclic and may have from 5 to 12, preferably from 5 to 9 ring atoms, such as phenyl, biphenyl, naphthyl or indenyl and such heteroaryl as heteroaromatic

Thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,3-sulfur, oxygen and / or nitrogen atoms, 4-oxadiazol-2-yl,

1.2.4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, quinolyl, isoquinolyl, benzo [1] thienyl, and benzofuryl.

Preferred heteroaryl groups represented by R.3 include isoxazol-3-yl, isoxazol-5-yl, 1,2,4-oxadiazol-5-yl,

1.2.4-Oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, thiazol-4-yl, thiazol-2-yl, pyrrol-2-yl, pyrrol-3-yl -, 2-thienyl, 3-thienyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl and oxazol-5-yl, which may be optionally substituted. Preferred aryl is phenyl optionally substituted with R 1, optionally substituted with halogen or C 1-4 alkoxy.

Bicycloalkyl at R ⁶ is understood to mean bicycloheptyl and bicyclooctyl. Examples of the mono- or bicyclic aryl radicals R 1 include phenyl, biphenyl, naphthyl and indenyl.

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

As the sulfonic acid group, the known benzenesulfonic acids which may be substituted by halogen or (C 1 -C 4) alkyl and the (C 1 -C 4) alkanesulfonic acids, such as methanesulfonic acid and p-toluenesulfonic acid are suitable.

The physiologically tolerable salts can be derived from inorganic and organic acids. Suitable inorganic acids are, for example, halogenated hydrogens such as hydrochloric, hydrobromic, phosphoric, sulfuric or organic acids such as aliphatic or aromatic mono- or dicarboxylic acids such as formic, acetic, maleic, fumaric, succinic acid, lactic acid, boric acid, citric acid, oxalic acid, glyoxylic acid, or sulfonic acids such as C1-C4 alkanesulfonic acids such as methanesulfonic acid or benzenesulfonic acids optionally substituted with halogen or C1-C4 alkyl groups such as p-toluenesulfonic acid.

Preferred compounds of formula (I) wherein R a and R ² together form a heterocyclic group of formula (a) · nitrogen, and

R ³ is hydrogen, carboxyl, (C 1 -C 6) alkoxy-carbonyl or optionally substituted with (C 1 -C 4) -alkyl, (C 3 -C 7) -cycloalkyl, halo, (C 1 -C 4) -alkoxy, (C 1 -C 4) -alkoxy - C 6 -C 12 aryl or heteroaryl monosubstituted or tri-substituted with (C 1-2 alkyl), phenyl or amino; and

R ⁴ and A are as defined above.

Particularly preferred are compounds of formula I wherein:

A is a linear or branched C 1 -C 5 alkylene group which may be substituted by a hydroxy group or a C 1 -C 6 alkoxy group,

R ¹ and R ² together with the nitrogen atom form a heterocyclic group of formula (a),

R ⁹ is hydrogen or C 1-6 alkyl and

R ³ is hydrogen, carboxyl or (C 1 -C 6) alkoxy-carbonyl, and stereoisomeric forms and salts thereof.

When ^R5 is phenyl, benzyl, benzoyl, α-hydroxybenzyl, phenethyl, 2-oxo-2-phenethyl or 1-oxo-2-phenethyl means and substituted, then preferred substituents include a halogen atom and a C 1-4 alkoxy group, in particular a fluorine substituent, is preferred, wherein the substituent is preferably attached at the 4-position.

The compounds of formula (I) are prepared in a manner known per se, characterized in that:

a) reacting a compound of formula II wherein R ³ , R ⁴ and R ⁹ are as defined above, an amine of formula III wherein R ⁴ , R ² and A are as defined above and X is a leaving group , obsession

b) reacting a compound of formula 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 introducing or cleaving the R ⁹ substituent or forming a physiologically tolerable salt or converting the physiologically tolerable salt to the free compound of formula (I) or separating the racemate.

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In processes a) and b), the nucleophilic substitution of the leaving group X is carried out in the usual manner in the presence of a base in an inert organic solvent.

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

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

Suitable bases are inorganic and organic bases. Examples of inorganic bases include alkali or alkaline earth metal hydroxide, carbonate, bicarbonate or alcohol. Organic bases include tertiary amines such as tripropylamine, triethylamine, N-alkylmorpholine or N-alkylpiperidine. However, an excess of the amine of formula (V) as the base may also be used as a solvent or the reaction may be carried out in the presence of a phase transfer catalyst.

The reaction temperature ranges from 0 ° C to the reflux temperature of the solvent used.

The R ⁹ group may be introduced by standard alkylation, benzylation and sulfonation procedures, for example by reacting a reactive derivative of the R ⁹ group, e.g.

Its halide is reacted with carboline in the presence of a base.

Cleavage of the group can also be carried out in known manner under basic conditions or by hydrogenolysis.

The isolation and purification of the compounds of formula (I) from the reaction mixture is carried out in a manner known per se. The acid addition salt may be converted into the free base in a conventional manner and, if desired, converted into a physiologically acceptable acid addition salt in a known manner, for example by reaction with a concentrated solution of the desired acid.

Where the compound of formula (I) contains a chiral center, the optically active compounds may be prepared from optically active starting materials or racemates known per se. Enantiomers may be separated, for example, by chromatography on an optically active support, reaction with an optically active acid and subsequent fractional crystallization.

The invention also relates to compounds of formula IV wherein A, R ⁴ , R 4 and X are as defined above.

The starting compound of formula (IV) is a valuable intermediate which is pharmaceutically active, for example in the preparation of compounds of formula (I).

The compounds of formula (IV) are prepared in a manner known per se, for example by:

a) a compound of formula II wherein:

R ⁴ and R 4 are etherified with a compound of formula XAY (VI) above, wherein A and X are as defined above, and Y is a leaving group, or

b) etherifying a compound of formula II with an alcohol of formula Y-A-OH (VII) and then introducing the leaving group X.

Suitable leaving groups for Y are those designated as X. The etherification is carried out in the usual manner in the presence of a base. Exit group X is introduced by standard methods.

The preparation of a starting compound which is not described is known or can be prepared by known methods or by the method described herein.

For example, the hydroxy derivatives of formula II can be obtained as described in EP-A-130 140, EP 0161 574, EP 0305 322, WO 92/21679 and WO 92/22549.

The compounds of formula (I) and their physiologically tolerable salts can be used as medicaments because of their action on the modulation site of the quaternary receptor or quaternary receptor dependent ion channels.

The pharmacological activity of the compounds of formula I was determined by the following assays.

Male NMRI mice weighing 18-22 g were housed under controlled conditions (6 to 18 hours light / dark cycle, free access to food and water) and randomized. The groups consisted of 5-16 mice. The animals were observed between 8 am and 1 pm.

AMPA was injected into the left ventricle of free-moving mice. The dispenser consisted of a spoon with a stainless steel structure that injected a depth of 3.2 mm into the vial. restricted. The dispenser is connected to an injection pump. The needle was guided perpendicular to the surface of the head according to Montemurro and Dukelow coordinates. The animals were observed for 180 seconds until the onset of clonic or tonic seizure. Clonic motion that lasted for more than 5 seconds was considered a cramp. The onset of clonic seizure was taken as the end point in the seizure threshold determination. The dose required to increase or decrease the seizure threshold by 50% (THRD ^ q) was determined in 4-5 experiments. The THRD ^ q and the tolerance limit were calculated by regression analysis.

The results of this experiment show that the compounds of formula I and their acid addition salts influence the functional dysfunction of AMPA receptors. They are therefore suitable for the manufacture of a medicament for the symptomatic and prophylactic treatment of diseases caused by altered function of the AMPA receptor complexes.

Treatment with the compounds of the present invention prevents or delays the resulting cellular damage and dysfunction and alleviates the resulting symptoms.

Diseases that can be triggered by dysfunction of excitatory amino acids or altered glutamate neurotransmission, such as neurodegenerative diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease, Aging dementia, muscle wasting lateral sclerosis, olivopontocerebellum; cell damage in hypoglycemia, hypoxia, ischemia, and disorders of energy metabolism; nerve damage triggered by brain damage such as wind chills, brain trauma and suffocation, as well as psychosis, schizophrenia, anxiety states, pain, migraine and vomiting. Functional disorders such as memory disorders (amnesia), learning disabilities, chronic withdrawal use of drugs such as sedative drugs, hallucinogens, alcohol, cocaine and opiates are also based on glutamate neurotransmitter dysfunction. Usual pharmacological tests can be used to detect indications.

The invention also encompasses medicaments containing said compounds, and the use of the compounds of the invention for the preparation of medicaments for the treatment and prevention of the diseases listed above. The medicaments are prepared by methods known per se, wherein the active ingredient is formulated into a pharmaceutical composition for enteral or parenteral administration with suitable carriers, excipients and / or additives. The administration can be effected orally or sublingually in the form of a solid capsule or tablet, or in the form of a solution, suspension, elixir or emulsion, or rectally in the form of a suppository or, optionally, subcutaneous injection. Suitable excipients for the desired dosage form are the organic and inorganic carriers known in the art, such as water, gelatin, acacia, milk sugar, starch, magnesium13.

stearate, talc, vegetable oils, polyalkylene glycols and the like are suitable. In addition, the compositions may also contain preserving, stabilizing, wetting, emulsifying agents or salts or buffers to modify the osmotic pressure.

The pharmaceutical compositions may be in the form of a solid, for example a tablet, dragee, suppository, capsule or liquid, such as a solution, suspension or emulsion.

Surfactants such ^as gallic acid salts or animal or plant phospholipids, as well as mixtures thereof, and liposomes or their constituents may be used as carrier systems.

Tablets, dragees or capsules containing talc and / or hydrocarbon carriers or excipients such as lactose, corn or potato starch are particularly suitable for oral administration. The administration can also be effected in liquid form, for example in the form of a lecithin, to which a sweetener is added.

For parenteral administration, in particular solutions or suspensions for injection, in particular aqueous solutions of the active ingredient in polyhydroxyethoxylated castor oil, are suitable.

The dosage of the active ingredient will vary depending on the route of administration, the age and weight of the patient, the type and severity of the disease being treated, and the like. The daily dose may be administered as a single dose or as a daily dose in two or more divided doses. The compound is administered in dosage units containing 0.05 to 500 mg of the active ingredient in physiologically tolerated carrier.

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Generally, a dose of 0.1 to 1000 mg / day (0.001 to 10 mg / kg), preferably 0.1 to 100 mg / day, is used.

The following examples illustrate the preparation of compounds of formula (I).

Example 1

- {3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy} -4-

- (Methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester

To 628 mg of 5-hydroxy-4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester and 100 ml of acetone were added 600 mg of potassium carbonate and 760 mg of (4-fluorophenyl) - [1- (3) Methylsulfonyloxypropyl -4-piperidyl] ketone is added and the mixture is refluxed under argon for 3 hours, after evaporation of the organic phase, the residue is chromatographed on silica gel, eluting with a 1: 1 mixture of hexane and acetone. The desired fractions were evaporated and mixed with diethyl ether to give 630 mg of 5- {3- [4- (4-fluorobenzoyl) piperidin-1-yl] propoxy} -4- (methoxymethyl) -β-. m.p. 161-162 [deg.] C. is obtained as the carboline-3-carboxylic acid isopropyl ester.

(4-Fluoro-phenyl) - {1- [3- (methylsulfonyloxy) -propyl] -4-piperidyl} -ketone is known in the art from 4- (4-fluoro-benzoyl) -piperidine; It is prepared by reacting 3-bromopropanol-1 potassium carbonate in dimethylformamide and then in methylene chloride with methanesulfonic acid and triethylamine.

In a similar manner, the following compounds were obtained:

- {3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy} -4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester, m.p.

153-155 ° C;

5- (3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy} -4-ethyl-

-B-carboline-3-carboxylic acid isopropyl ester, m.p. 178-180 ° C;

- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -4-methyl-β-carboline-3-carboxylic acid isopropyl ester, m.p. 168-170 ° C;

- {3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy} -β-carboline-3-carboxylic acid isopropyl ester, m.p. 182-184 ° C;

- {3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy} -4-methyl-

-β-carboline-3-carboxylic acid isopropyl ester;

- (3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy} -4-

- (methoxy-methyl) -β-carboline;

6- (3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy} -4-

- (methoxy-methyl) -β-carboline;

5- (3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy} -4-ethyl-β-carboline;

- {3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy} -4-

methyl-β-carboline;

- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -β-carboline;

- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -4-

- (methoxymethyl) -9-methyl-β-carboline-3-carboxylic acid isopropyl ester, m.p. 115-117 ° C;

- {3- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -4-

- (methoxymethyl) -9-methyl-β-carboline-3-carboxylic acid isopropyl ester, m.p. 110-III ° C ·

5- (3- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -propoxy} -4- (methoxymethyl) -9-methyl-B-carboline;

- {3 - [4- (4-Fluorobenzoyl) -piperidin-1-yl] -propoxy} -4 16 • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· * • · · · · ···

- (methoxymethyl) -9-methyl-β-carboline in.

Example 2

5- [3- (4-Phenyl-piperazin-1-yl) -propoxy] -4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester

450 mg of isopropyl 5- (3-chloropropoxy) -4-methoxymethyl-β-carbonyl-3-carboxylic acid in 20 ml of dimethylformamide with 245 mg of 4-phenylpiperazine and 0.21 ml of triethyl amine in a 100 ° C bath for 18 hours under argon. After distilling off the solvent, the residue was taken up in dichloromethane and washed once with water and brine. The organic phase is dried, filtered and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate. This gives 420 mg of 5- [3- (4-phenylpiperazin-1-yl) propoxy] -4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester, m.p. 176-177 ° C. They are C's.

The starting material was 5- (3-chloropropoxy) -4- (methoxymethyl) -β-carbonyl-3-carboxylic acid isopropyl ester (m.p. 178-180 ° C) 5-hydroxy-4- (methoxy) isopropyl ester is prepared by etherification of isopropyl ester of β-carboline-3-carboxylic acid with 1-bromo-3-chloropropane in the presence of potassium carbonate and dimethylformamide.

Example 3

In the same manner as in Example 2, the following compound is prepared from 5- (3-chloropropoxy) -4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester and a secondary amine.

new platforms:

5- [3- (4-Benzyl-piperazin-1-yl) -propoxy] -4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester, m.p. 112-114 ° C;

5- [3- (Morpholin-1-yl) -propoxy] -4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester, m.p. 161-162 ° C;

5- {3- [4- (3,4,5-Trimethoxyphenyl) piperazin-1-yl] propoxy} -4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, op. 135-136 ° C;

- (3- [4- (4-Fluoro-benzyl) -piperidin-1-yl] -propoxy} -4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester, m.p. 126-128) C;

- {3- [4- (4-Fluoro-hydroxy-benzyl) -piperidin-1-yl] -propoxy} -4- (methoxymethyl) -E-carboline-3-carboxylic acid isopropyl ester, op. 110-115 ° C;

- {3- [4- (4-Chloro-phenyl) -4-hydroxy-piperidin-1-yl] -propoxy} -4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester;

5- [3- (4-Benzoyl-piperazin-1-yl) -propoxy] -4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester, m.p. 133-135 ° C;

- (3- [4- (4-Fluorophenethyl) piperidin-1-yl] propoxy} -4-methoxymethyl) -E-carboline-3-carboxylic acid isopropyl ester;

5- (3- (4- [2-Oxo-2- (4-fluorophenyl) ethyl] piperidin-1-yl} propoxy} -4- (methoxymethyl) -β-carboline-3- carboxylic acid isopropyl ester;

5- (3- (4- [1-Oxo-2- (4-fluorophenyl) ethyl] piperidin-1-yl} propoxy} -4- (methoxymethyl) -β-carboline-3- carboxylic acid isopropyl ester.

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Example 4

5- (4- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -butoxy} -4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester

520 mg of 5- (4-chlorobutoxy) -4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester (m.p. 147-148 ° C) and 411 mg

- (4-Fluorobenzoyl) piperidine Following the procedure of Example 2, 235 mg of 5- {4- [4- (4-fluorobenzoyl) piperazin-1-yl] butoxy} -4-methoxymethyl ) -β-carboline-3-carboxylic acid isopropyl ester melting at 103-105 ° C.

Similarly, the following compounds were prepared:

- {4- [4- (4-Fluorobenzoyl) -piperidin-1-yl] -butoxy} -4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester;

- {4- [4- (4-Fluoro-α-hydroxybenzyl) piperidin-1-yl] butoxy} -4-methyl-β-carboline-3-carboxylic acid isopropyl ester;

5- (4- [4- (4-Fluoro-α-hydroxybenzyl) piperidin-1-yl] butoxy} -4- (methoxymethyl) -β-carboline.

Example 5

5- (2- (4- (4-Fluorobenzoyl) piperidin-1-yl] ethoxy} -4- (methoxymethyl) β-carboline -3-carboxylic acid isonropyl ester)

510 mg of 5- (2-chloroethoxy) -4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester (m.p. 194-195 ° C) and 311 mg

From 4- (4-fluorobenzoyl) piperidine as in Example 2, 195 mg of 5- {2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethoxy} -4- (methoxy) methyl isocarboline-3-carboxylic acid isopropyl ester, m.p. 161-163 ° C.

In a similar manner, the following compounds were obtained:

6- (2- [4- (4-Fluoro-benzoyl) -piperidin-1-yl] -ethoxy} -4- (methoxy)

methyl) -β-carboline-3-carboxylic acid isopropyl ester;

- {2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethoxy} -4-methoxymethyl-β-carboline;

- {2- [4- (4-Fluoro-α-hydroxybenzyl) piperidin-1-yl] ethoxy} -4- (methoxymethyl) -β-carboline.

Example 6

- {3- [4- (4-Fluoro-benzoyl) -piperidino] -2-hydroxy-propoxy} -4- (methoxymethyl) -E-carboline-3-carboxylic acid isopropyl ester

700 mg of 4-methoxymethyl-5- (2,3-epoxypropoxy) -β-carboline-3-carboxylic acid isopropyl ester are dissolved in 50 ml of propan-2-ol and 380 mg of 4- ( 4-Fluorobenzoyl) piperidine is added. After refluxing for 5 hours under argon, the organic phase is evaporated and the residue is chromatographed on silica gel, eluting with methylene chloride / ethanol (1000/50 by volume). There was thus obtained 655 mg of isopropyl ester of 5- {3- [4- (4-fluorobenzoyl) piperidino] -2-hydroxypropoxy} -4- (methoxymethyl) -β-carboline-3-carboxylic acid. 143 ° C.

Isopropyl 4- (methoxymethyl) -5- (2,3-epoxypropoxy) -β-carboline-3 carboxylic acid is prepared according to methods known in the art, 5-hydroxy-4- (methoxymethyl) -β-. from isopropyl ester of carboline-3-carboxylic acid by etherification with epichlorohydrin in the presence of potassium carbonate in dimethylformamide.

In a similar manner, the following compounds were prepared:

5- {3- [4- (4-Fluorobenzene-1) -piperidino] -2-hydroxy-propoxy} -4-ethyl-B-carboline-3-carboxylic acid isopropyl ester, m.p. 119-129 ° C; 5- {3- [4- (2-Fluoro) -1-piperazinyl] -2-hydroxypropoxy} -4-

isopropyl ester of (methoxymethyl) -β-carboline-3-carboxylic acid, m.p. 198-200 ° C.

Example 7

- {3- [4- (4-Fluorobenzoyl) -piperidinol-2-methoxy-propoxy} -4- (methoxymethyl) -β-carboline-3-carboxylic acid isopropyl ester

435 mg of isopropyl ester of 5- {3- [4- (4-fluorobenzoyl) piperidino] -2-hydroxypropoxy} -4-methoxymethyl-β-carboline-3-carboxylic acid Sodium hydride (20 mg, 90%) in glycol dimethyl ether was added, the mixture was cooled to 0 ° C, and methyl iodide (0.05 ml) was added dropwise and stirred for 4 hours. After warming to room temperature, stirring was continued for 2 hours. The solvent was evaporated and the residue was chromatographed on silica gel, eluting with methylene chloride / ethanol (1000/50 by volume). 175 mg of 5- {3- [4- (4-fluorobenzoyl) piperidino] -2-methoxypropoxy} -4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester are thus obtained. mp 137-139 ° C.

• · * V · · · «·« · • 4 ·> «9 * · • 4 · 4 4 · β 9

PATENT CLAIMS

Claims (6)

PATENT CLAIMS CLAIMS 1. Compounds of formula (I): wherein: A is a straight or branched C 1 -C 5 alkylene group which may be substituted by hydroxy, C 1 -C 6 alkoxy or C 1 -C 6 alkanoyloxy, or - (CH ₂ ) _n -CO- (CH ₂ ) _m - wherein n, m is 1, 2 or 3; R ¹ and R ^{2 are the} same or different and are hydrogen, C 1-4 alkyl, C 3-7 cycloalkyl, C 4-9 cycloalkylalkyl, phenyl, phenyl (C 1-2 alkyl), or R ¹ and R ^{2 taken} together with the nitrogen atom · form a group of formula (a) in which B is a direct bond, oxygen, sulfur,> CH-R ³ ,> COH-R ³ or> NR ⁵ , wherein R ³ is hydrogen, (C 1 -C 4) -alkyl, (b) or optionally triple substituted with (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, halo, hydroxy, trifluoromethyl or trifluoromethoxy phenyl, benzyl, benzoyl, α-hydroxybenzyl, phenethyl, 2-oxo-2-phenethyl, 1-oxo-2-phenethyl or pyridine; Y is O, S or NH; R ³ is hydrogen, carboxyl, (C 1 -C 6) alkoxy-carbonyl, -CO-R ⁶ or optionally C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, halo, (C 1 -C 4) alkoxy; (C 1 -C 12 alkyl), (C 1 -C 4 alkyl), (C 1 -C 4) alkoxy, phenyl or amino, C 6 -C 12 aryl or heteroaryl, C 1-4 alkyl, C 3-7 cycloalkyl, 7-9; C 6 -C 12 mono- or bicyclic aryl, optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or amino, R ⁴ is hydrogen, (C1-C6) alkyl, (C1-C4) alkoxy (C1-C2) alkyl, and R ⁹ is hydrogen, C 1-6 alkyl, C 1-6 alkanoyl, phenyl (C 1-2 alkyl), optionally substituted benzenesulfonyl or C 1-4 alkanesulfonyl, and stereoisomeric forms and salts thereof. 2. A compound according to claim 1 of formula (I) Ί 9 compounds in which R and R a. with a nitrogen atom to form a heteroaryl group of formula (a). The compound of claim 1 which is 5- {3- [4- (4-fluorobenzoyl) piperidino] propoxy} -4- (methoxymethyl) -β- carboline-3-carboxylic acid isopropyl ester. A pharmaceutical composition comprising the compounds of claims 1 and 2. Use of compounds according to claims 1 and 2 for the preparation of a pharmaceutical composition. 6. A process for the preparation of compounds according to claim 1, characterized in that a) reacting a compound of formula II wherein R ³ , R ⁴ and R ⁹ are as defined above, an amine of formula III wherein R ⁴ , R ² and A are as defined above and X is a leaving group , obsession b) reacting a compound of formula 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 ⁴ and R ^{6 2 *} are the above and, if desired, the substituent R ^{9 is} introduced or cleaved, or a physiologically tolerable salt is formed, or the physiologically tolerable salt is converted to the free compound of formula (I) or the racemate is separated.