<div class="application article clearfix" id="description">
<p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number £71 615 <br><br>
New Zealand No. International No. <br><br>
271615 <br><br>
PCT/DE94/01009 <br><br>
Priority Date(s): 2>l\.S.la3. <br><br>
Complete Specification Filod: 2S.\?.\3.'3r..... Class: <br><br>
Publication <br><br>
P.O. Journal No: <br><br>
NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION <br><br>
Title of Invention: <br><br>
Alkoxy-substituted beta-carbolines acting on the ampa-receptor <br><br>
Name, address and nationality of applicant(s) as in international application form: <br><br>
SCHERING AKTIENGESELLSCHAFT, a German body corporate of Mullerstrasse 178, D-13353 Berlin, Federal Republic of Germany <br><br>
\ <br><br>
271615 <br><br>
Alkoxv-Subatltuted B-Carbolines The invention relates to alkoxy-B-carboline derivatives, <br><br>
their production and use in pharmaceutical agents as well as intermediate products to produce them. <br><br>
It is known from numerous publications that fl-carbolines have affinity to the benzodiazepine receptors and can be used as psychopharmaceutical agents on the basis of their affinity to the benzodiazepine receptors. <br><br>
It has now been found, surprisingly enough, that the compounds of formula I have an effect on the modulation point of the AMPA receptor or on AMPA receptor-dependent ion channels and correct the pathologically altered function of this receptor. The synaptic function of the excitatory amino acid L-glutamate is mediated mainly with AMPA receptors. Increased or reduced glutamatergic neurotransmission in the central nervous system leads to numerous neurological and psychiatric diseases. The compounds of formula I therefore are suitable for the production of pharmaceutical agents for symptomatic and preventive treatment of neurological and psychiatric diseases. <br><br>
The invention relates to the compounds of formula I <br><br>
in which <br><br>
2 <br><br>
271615 <br><br>
A means straight-chain or branched alkylene, which can be substituted with hydroxy, alkoxy or alkanoyloxy, or -(CH2)n-CO-(CH2)m, <br><br>
n,m is 1, 2 or 3, <br><br>
R1 and R2 are the same or different and mean hydrogen, C,_4 alkyl, cycloalkyl, C4.9 cycloalkylalkyl, phenyl, phenyl-C^g alkyl or R1 and R2 together with the nitrogen atom form a heterocyclic compound of formula (a) <br><br>
—N B , . <br><br>
\ / 0) <br><br>
in which <br><br>
B means a direct bond, oxygen, sulfur, >CH-R5, >COH-R5 or >N-R5 and <br><br>
R5 represents hydrogen, alkyl, .p or a phenyl, <br><br>
benzyl, benzoyl, a-hydroxy-benzyl, phenethyl, 2-oxo~2~ phenethyl, l-oxo-2-phenethyl or pyridine radical that is optionally substituted with C1.A alkyl, c,.4 alkoxy, halogen, hydroxy, -CF3 or -0-CF3 in one to three places, and <br><br>
Y means oxygen, sulfur or >NH, and <br><br>
R3 represents hydrogen, COOH, COO-C1.6 alkyl,. CO-R6 or a c6-i2 ary^ or hetaryl radical that is optionally substituted in one to three places with C,,_4 alkyl, Cj_7 <br><br>
2 <br><br>
271615 <br><br>
A means straight-chain or branched alkylene# which can be substituted with hydroxy, C1.6 alkoxy or alkanoyloxy, or -(CH2)n-CC • (CH2) <br><br>
n,ra is 1, 2 or 3, <br><br>
R1 and R2 are the same or different and mean hydrogen, C,_4 alkyl, cycloalkyl, C4.9 cycloalkylalkyl, phenyl, phenyl-C^j alkyl or R1 and R2 together with the nitrogen atom form a heterocyclic compound of formula (a) <br><br>
/ \ <br><br>
—N B <br><br>
\__/ <a> <br><br>
in which <br><br>
B means a direct bond, oxygen, sulfur, >CH-R5, >COH-R5 or >N-R5 and <br><br>
R5 represents hydrogen, CV4 alkyl, .p o-C7 or a phenyl, <br><br>
benzyl, benzoyl, a-hydroxy-benzyl, phenethyl, 2-oxo-2-phenethyl, l-oxo-2-phenethyl or pyridine radical that is optionally substituted with alkyl, Cv4 alkoxy, halogen, hydroxy, -CF3 or -0-CF3 in one to three places, and Y means oxygen, sulfur or >NH, and <br><br>
R3 represents hydrogen, COOH, COO-C^ alkyl,. CO-R6 or a C6-12 arY* or hetaryl radical that is optionally substituted in one to three places with CV4 alkyl, Cj_7 ;3 ;271615 ;cycloalkyl, halogen, alkoxy-C^ alkyl, alkoxy, phenyl or amino, ;R4 means hydrogen, alkyl, alkoxy-C^j alkyl and ;R6 means alkyl, C3.7 cycloalkyl, bicycloalkyl or a monocyclic or bicyclic C6.12 aryl radical that is optionally substituted with Cuu alkyl, alkoxy or amino, and ;R9 means hydrogen, Cj.6 alkyl, C1-6 alkanoyl, phenyi-C^ alkyl, optionally substituted benzenesulfonyl or C1-4 allkanesulfonyl, as well as their stereoisomers and salts. ;If the compounds of formula I have chiral centers, the invention encompasses all possible stereoisomers such as enantiomers and diastereomers as well as their mixtures and racemates. ;The substituent can be in the A-ring in 5- to 8-position, preferably in 5- or 6-position. ;Straight-chain or branched alkylene is, for example, methylene, ethylene, propylene, isopropylidene, 1-methylethylene 2-ethylpropylene, 2,2-dimethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, tetramethylene. The substituent of alkylene radical A is in any position, preferably in 2-, 3- or 4 position of the straight-chain alkylene radical. ;In each case, alkyl contains both straight-chain and branched-chain radicals, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, 2,2-dimethylpropyl and 2-methylbuty 1. ;4 ;271615 ;In each case, cycloalkyl can stand for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and 2-methyl-cyclopropyl. ;As cycloalkylalkyl radicals, for example, cyclopropylmethyl and cyclohexylmethyl can be mentioned. ;In each case, the phenyl-C,^ alkyl substituent can be straight-chained or branched in the alkyl radical, such as, for example, benzyl, phenethyl, a-methylbenzyl. ;As halogen, in each case fluorine, chlorine, bromine and iodine are suitable. ;Pyridine radical R5 is bound in 2-, 3- or 4-position. ;Aryl and hetaryl radical R3 can be present as a monocyclic or bicyclic compound and can contain 5-12 ring atoms, preferably 5-9 ring atoms, such as, for example, phenyl, biphenyl, naphthyl, indenyl as aryl radical and thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, l,3,4-oxadiazol-2-yl, l,2,4-oxadiazol-5-yl, l,2,4-oxadiazol-3-yl, quinolyl, ;isoquinolyl, benzo[l]thienyl, benzofuryl as hetaryl radical with 1-3 heteroatoms, such as sulfur, oxygen and/or nitrogen. ;As preferred heteroaryl radicals R3, isoxazol-3-yl, isoxazol-5-yl, l,2,4-oxadiazol-5-yl, l,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 optionally can be substituted, can be mentioned. Preferred aryl R3 is phenyl that is optionally substituted with halogen or C,_4 alkoxy. ;5 ;271615 ;Bicycloalkyl radical R6 is defined as bicycloheptyl and bicyclooctyl. As monocyclic or bicyclic aryl radical R6, for example, phenyl, biphenyl, naphthyl and indenyl can be mentioned. ;The alkanoyl radical is derived in each case from straight-chain or branched aliphatic carboxylic acids, such as, for example, formic acid, acetic acid, propionic acid, butyric acid, trimethylacetic acid or caproic acid. ;As sulfonic acid radicals R9, the known benzenesulfonic acids, which can be substituted with halogen or CV4 alkyl, as well as CV4 alkanesulfonic acids, such as, for example, methanesulfonic acid, p-toluenesulfonic acid, are suitable. ;The physiologically compatible salts are derived from inorganic and organic acids. Suitable are inorganic acids, such as, for example, hydrohalic acids, such as hydrochloric acid, hydrobroxnic acid, phosphoric acid, sulfuric acid or organic acids, such as, for example, aliphatic or aromatic mono- or dicarboxylic acids, such as formic acid, acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid or sulfonic acids, for example, alkanesulfonic acids, such as methanesulfonic acid or benzenesulfonic acids that are optionally substituted by halogen or CV4 alkyl, such as p-toluenesulfonic acid. ;Preferred are compounds of formula I, in which ;R1 and R2 together with the nitrogen atom form a heterocyclic compound of formula ;•N ;B ;(a) ;\ / ;6 ;271615 ;and ;R3 represents hydrogen, COOH, COOC^ alkyl or a C6"12 aryl or hetaryl radical that is optionally substituted in one to three places with C1-4 alkyl, Cj^ cycloalkyl, halogen, CV4 alkoxy, C1-4 alkoxy-C^j.gj^, phenyl or amino, and ;R4, R9 and A have the above meaning. ;Especially preferred are compounds of formula I in which A means straight-chain or branched C^j alkylene, which can be substituted with hydroxy or CV6 alkoxy, ;R1 and R2 together with the nitrogen atom form the heterocyclic compound ;N B ;Vv w ;R9 means hydrogen or Cv6 alkyl and ;R3 means hydrogen, COOH or COOC^ alkyl as well as their stereoisomers and salts. ;If R5 means a phenyl, benzyl, benzoyl, a-hydroxybenzy1, phenethyl, 2-oxo-2-phenethyl or l-oxo-2-phenethyl radical, which is substituted, halogen and C1.4 alkoxy can be viewed as preferred, especially the radical substituted with fluorine, whereby the substitution in 4-position is preferred. ;The production of the compounds of formula I is carried out in a way known in the art, by ;7 ;271615 ;a) a compound of formula II ;(ID ;in which ;R3, R4 and R9 have the above meaning, being reacted with an amine of formula III ;X_A-N^ (HO ;in which R1, R2 and A have the above meaning and X represents a leaving group, ;or fe) a compound of formula IV ;X-A-CT ;(IV) ;in which ;A, R3, R4 ;and R9 have the above meaning and X represents a ;8 ;271615 ;leaving group, being reacted with an amine of formula V ;R1 ;H —N v ;(V) ;R2 ;in which R1 and R2 have the above meaning, and optionally then substituent R9 being introduced or cleaved or the physiologically compatible salts being formed or the physiologically compatible salts being converted to the free compounds of formula X or racemates being separated. ;The nucleophilic substitution of leaving group X according to process variants a) and b) is performed under basic conditions according to commonly used methods in an organic solvent that is inert under the reaction conditions. ;As leaving groups X, halogens such as chlorine, bromine or iodine or organic sulfonic acid radicals such as the radical of an alkanesulfonic acid, for example, mesylate, triflate or the radical of an aromatic sulfonic acid, for example, ;toluenesulfonic acid or bromobenzenesulfonic acid, are suitable. ;As inert organic solvents, 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 of the above-mentioned solvents are suitable. ;As bases, inorganic and organic bases are suitable. ;Examples of inorganic bases are alkali or alkaline-earth hydroxide, -carbonate, -bicarbonate or -alcoholate. Examples of ;9 ;271615 ;organic bases are tertiary organic amines, such as tripropylamine, triethylamine, N-alkylmorpholine or N-alkylpiperidine. Excess amine of formula V can also be used as a base, however, or the reaction can be performed in the presence of phase transfer catalysts. ;The reaction temperature can be between 0°C and boiling temperature of the solvent. ;The introduction of substituent R9 can be carried out according to the commonly used alkylation, benzylation and sulfonylation processes, for example, by a reactive derivative such as the halide of substituent R9 being reacted in th;2 presence of bases with the carboline. ;The cleavage of substituent R9 is carried out in the usual way, basically or hydrogenolytically, according to the type of substituent. ;The compounds of formula I can be isolated from the reaction mixture in a way known in the art and purified. Acid addition salts can be converted in the usual way to the free bases and the latter optionally in the known way to physiologically compatible acid addition salts, for example by the solution being mixed with a concentrated solution of the desired acid. ;If the compounds of formula I contain a chiral center, the optically active compounds can be obtained from the racemates starting from optically active starting compounds or in a way known in the art. The enantiomer separation can be carried out, for example, by chromatography on optically active media, by ;10 ;271615 ;reaction with optically active acids and then fractionated crystallization. ;The invention also encompasses the compounds of formula IV ;in which A, R3, R4, R9 and X have the above meaning. The starting compounds of formula IV are valuable intermediate products for the production of pharmacologically effective compounds, for example, the compounds of formula I. ;The production of the compounds of formula IV is carried out according to processes known in the art, for example, by a) a compound of formula II ;in which R3, R4 and R9 have the above meaning, being ether if ied with a compound of formula VI ;in which A" and X' have the above meaning, and Y is a leaving gyoup, or ;(IV) ;(if) ;X—A—Y ;11 ;271615 ;b) a compound of formula II being ether if ied with an alcohol of formula VII Y—A—OH, and then leaving group X being introduced. ;As leaving group Y, the groups mentioned under X are suitable. The ether if ication is carried out in the usual way in the presence of bases. The introduction of leaving group X is performed with commonly used methods. ;In so far as the production of the starting compounds is not described, the latter are known or can be produced analogously to the known compounds or processes that are described here. ;For example, the production of the hydroxy derivatives of formula II can be carried out according to EP-A-130 140, EP 0161 574, EP 0305 322, WO 92/21679 and WO 92/22549. ;The compounds of formula I as well as their physiologically compatible salts can be used as pharmaceutical agents owing to their effect on the modulation point of the quisqualate receptor or of the quisqualate receptor-dependent ion channel. ;The pharmacological effectiveness of the compounds of formula 1 was determined by means of the tests described below: ;Hale NMRI mice weighing 18-22 g were kept under controlled conditions (0600-1800 hours light/dark cycle, with free access to food and water), and their assignment to groups was randomized. The groups consisted of 5-16 animals. The observation of the animals was performed between 0800 and 1300 hours. ;AMPA was sprayed into the left ventricles of mice that were able to move freely. The applicator consisted of a cannula with a stainless steel device, which limited the depth of injection to ;271615 ;3.2 mm. The applicator was connected to an injection pump. The injection needle was inserted perpendicular to the surface of the skull according to the coordinates of Montemurro and Dukelow. The animals were observed for up to 180 seconds until clonic or tonic seizures set in. Clonic movements that lasted longer than 5 seconds were counted as seizures. The beginning of the clonic seizures was used as an end point for the determination of the seizure threshold. The dose that was necessary to increase or reduce the seizure threshold by 50% (THRD50) was determined in 4-5 experiments. The THRD50 and the fiduciary limit were determined in a regression analysis. ;The results of these tests show that the compounds of formula I and their acid addition salts influence functional disorders of the AMPA receptor. They are therefore suitable for the production of pharmaceutical agents for symptomatic and preventive treatment of diseases that are triggered by alteration of the function of the AMPA receptor complex. ;The treatment with the compounds according to the invention prevents or delays cell damage and functional disorders that result because of disease and moderates the symptoms that thus result. ;The diseases that can be triggered by dysfunction of excitatory amino acids or altered glutamatergic neurotransmission fall into the category of, for example, neurodegenerative diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, multiple infarction dementia, amyotrophic lateral sclerosis, olivopontocerebellar ;13 ;271615 ;degeneration, epilepsy; cell damage by hypoglycemia, hypoxia, ischemia and disorders of energy metabolism; neuronal damage that is triggered by damage to the brain, such as stroke, brain trauma and asphyxia as well as psychoses, schizophrenia, anxiety conditions, attacks of pain, migraines and vomiting. Also, functional disorders such as memory disorders (amnesia), learning process disorders, vigilance symptoms and withdrawal symptoms after chronic intake of addictive agents- such as sedatives, hallucinogens, alcohols, cocaine and opiates are based on the dysfunction of glutamatergic neurotransmission. ;The indications can ba shown by commonly used pharmacological tests. ;The invention also encompasses pharmaceutical agents that contain the mentioned compounds, their production as well as the use of the compounds according to the invention for production of pharmaceutical agents that are used for treatment and prophylaxis of the above-mentioned diseases. The pharmaceutical agents are produced according to processes known in the art, by the active ingredient being put with suitable vehicles, adjuvants and/or additives into the form of a pharmaceutical preparation, which is suitable for enteral or parenteral administration. The 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 in the form of suppositories or in the form of injection solutions that can also be administered subcutaneously. As adjuvants for the desired pharmaceutical agent formulation, inert ;14 ;271615 ;organic and inorganic media that are known to one skilled in the art, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, etc., are suitable. Moreover, ;preservatives, stabilizers, wetting agents, emulsifiers, or salts can optionally be contained to alter the osmotic pressure or buffer. ;The pharmaceutical preparations can be present in solid form, for example, as tablets, coated tablets, suppositories, capsules, or in liquid form, for example, as solutions, suspensions or emulsions. ;As vehicle systems, near-interface adjuvants such as salts of bile acids or animal or plant phospholipids, but also mixtures of them, as well as liposomes or their components, can also be used. ;For oral administration, especially tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or binders, ;such as, for example, lactose, corn or potato starch, are suitable. Administration can also be done in liquid form, such as, for example, as juice, to which sweetener is optionally added. ;For the parenteral administration, especially injection solutions or suspensions, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are suitable. ;The dosage of the active ingredients can vary depending on the method of administration, the age and weight of the patient, ;15 ;271615 ;the type and severity of the disease to be treated, and similar factors. The daily dose can be given as a single dose to be administered one time or divided into 2 or more daily doses. The compounds are introduced in a dosage unit of 0.05 to 500 mg of active substance in a physiologically compatible vehicle. In general, 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 are to explain the production of the compounds of formula I: ;16 ;271615 ;Example 1 ;5—13—r 4—(4-Fluorobenzovl)-piperidin-l-vll-propoxv>-4-methoxvmethvl-B-carboline-3-carboxvlic acid isopropyl ester ;628 mg of 5-hydroxy-4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester is introduced in 100 ml of acetone, mixed with 600 mg of potassium carbonate and 760 mg of (4-fluorophenyl)-[1-(3-methylsulfonyloxypropyl)-4-piperidyl]-ketone and rrsfluxed for 3 hours under argon. After the organic phase is concentrated by evaporation, it is chromatographed on silica gel with hexane and acetone =1+1. The desired fractions are concentrated by evaporation and absorptively precipitated with ether. 630 mg of 5-{3-[4-(4-fluorobenzoyl)-piperidine]-propoxy}-4-methoxymethyl-B-carboliiie-3-carboxylic acid isopropyl ester of melting point 161-162°C is obtained. ;The (4-fluorophenyl)-l[l-(3-methylsulfonyloxy-propyl)-4-piperidyl]-ketone is obtained according to methods known in the literature by alkylation of 4-(4-fluorobenzoyl)-piperidine with 3-bromopropanol-l and potassium carbonate in dimethylformamide and subsequent reaction with methanesulfonic acid and triethylamine in methylene chloride. ;Produced analogously are: ;6-{3-[4-(4-Fluorobenzoyl)-piperidin-l-yl}-propoxy}-4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 153-155°C ;5-{ 3-[ 4-(4-f luorobenzoyl)-piperidin-l-yl-]-propoxy}-4-ethyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 178-180°C ;17 ;271615 ;5-{3-[4-(4-fluorobenzoyl)-piperidin-l-yl]-propoxy}-4-methyl-B-carboline-3-carboxylic acid-isopropyl ester, melting point ltS8-170°C ;5-{3-[4-(4-fluorobenzoyl)-piperidin-l-yl]-propoxy}-B-carboline-3-carboxylic acid isopropyl ester, melting point 182-184°C ;6-{3 [4-(4-f luorobenzoyl) -piperidin-l-yl]-propoxy}-4-methyl-B-carboline-3-carboxylie acid isopropyl ester ;5-{3[4-(4-fluorobenzoyl)-piperidin-l-yl]-propoxy}-4-methoxymethyl-B-carboline ;6-{3[4-(4-fluorobenzoyl)-piperidin-l-yl]-propoxy}-4-methoxymethyl-B-carboline ;5-{3 [4-(4-f luorobenzoyl) -piperidin-l-yl]-propoxy}-4-ethyl-B-carboline ;6-{3 [4-(4-f luorobenzoyl) -piperidin-l-yl] -propoxy}-4-methyl-B-carboline ;5-{3[4-(4-fluorobenzoyl)-piperidin-l-yl]-propoxy}-B-carboline ;5-{3[4-(4-fluorobenzoyl)-piperidin-l-yl]-propoxy}-4-methoxymethyl-9-methyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 115-117°C ;6-{3[4-(4-fluorobenzoyl)-piperidin-l-yl]-propoxy}-4-methoxymethyl-9-methyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 110-111°C ;5-{3 [4-(4-f luorobenzoyl) -piperidin-l-yl] -propoxy}-4-methoxymethyl-9-methyl-B-carboline ;18 ;271815 ;6-{3[4-(4-fluorobenzoyl)-piper id in-l-y1]-propoxy >-4-raethoxymethyl-9-methyl-B-carboline ;Example 2 ;5-f 3 r 4-Phenvl-pip,erazin-l-vn-propoxv'V-4-methoxvmet:hvl-B-carboline-3-carboxvlic acid isopropyl ester ;450 mg of fj-(3-chloropropoxy) -4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester is stirred in 20 ml of dimethy If onnamide with 245 mg of 4-phenylpiperazine and 0.21 ml of triethylamine at 100°C bath temperature for 18 hours under argon. After the solvent is distilled off, it is taken up in methylene chloride, and washed once each with water and saturated common salt solution. The organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate. 420 mg of 5-{3[4-phenyl-piper az in- 1-y 1 ] -propoxy } - 4 -methoxymethy 1-B-carbcl ine-3 -carboxy lie acid isopropyl ester of melting point 176-177°C is obtained. ;The 5-(3-chloropropoxy) -4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester required as starting material (melting point 178-180°C) is obtained by ether if ication of 5-hydroxy-4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester with l-bromo-3-chloropropane and potassium carbonate in dimethyIformamide. ;Example 3 ;According to the process indicated in Example 2, the following compounds are produced from 5-(3-chloropropoxy)-4- ;19 ;271615 ;methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester and a secondary amine: ;5-[3- (4-Benzyl-piperazin-l-yl) -propoxy] -4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 112-114°C ;5- [3-morpholin-l-yl) -propoxy ] -4-methoxymethyl-B-carboline-3 -carboxylic acid isopropyl ester, melting point 161-1S2°C ;5-{3- [4- (3,4,5-trimethoxyphenyl) - piperazin-l-yl] -prcpoxy^^-methoxymethy l-B-carboline-3 -carboxy lie acid isopropyl ester, melting point 135-136°C ;5-{3-[4-(4-fluorobenzy1)-piperidin-l-yl-]-propoxy > -4 -methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 126-128°C ;5-{3- [4— (4—f luoro—a-hydroxybenzyl) -piperidin-l-yl] -propoxy}-4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 110-115°C ;5-{3-[4-(4-chlorophenyl) -4-hydroxy-piperidin-l-yl] -propoxy}-4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester ;5-[3- (4-benzoyl-piperidin-l-yl) -propoxy] -4-methoxymethyl-B-carboline-3-carboxylic acid-isopropyl ester, melting point 133-135°C ;5-{3- [4- (4 -fluorophenethyl) -piper idin- 1-y 1 ] -propoxy} -4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester ;5-{ 3-[ 4-(2-oxo-2-(4-f luorophenethyl)-piper idin-l-yl ]-propoxy}-4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester ;20 ;271615 ;5—{3—[4—(l-oxo-2-(4-fluorophenethyl)-piperidin-l-yl]-propoxy}-4-methoxymethyl-6-carboline-3-carboxylic acid isopropyl ester ;Example 4 ;5—-f 4- i*4- (4-Fluorobenzovll -piperidin-l-vl-l-butoxv'l--4-iaethoxvmethvl-B-carboline-3-carboxvlic acid isopropyl ester <br><br>
235 mg of 5{4-[4-(4-fluorobenzoyl)-piperidin-l-yl]-butoxy}-4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester of melting point 103-105°C is obtained analogously to the process according to Example 2 from 520 mg of 5-(4-chlorobutoxy)4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 147-148°C, and 411 mg of 4-(4-fluorobenzoyl)-piperidine. <br><br>
Produced analogously are: <br><br>
6-{4-[4-(4-Fluorobenzoyl) -piperidin-l-yl-]-butoxy}-4-methoxymethyl-B-carboline-3-carboxylic acid isopropyi ester <br><br>
5-{4—[4—(4 -f luor o-a-hydroxybenzy 1) -p iper idin-l-y 1- } -butoxy } -4-methyl-B-carboline-3-carboxylic acid isopropyl ester <br><br>
5-{4-[4-(4-fluoro-a-hydroxybenzyl) -piperidin-l-yl-]-butoxy}- <br><br>
4-methoxymethy1-B-carbo1ine <br><br>
Example 5 <br><br>
5—-f2— T4- (4-Fluorobenzovl^ -pjperldin-l-vl-1 -ethoxvl-4-methoxvmethvl-B-carboline-3-carboxvlic acid isopropyl ester <br><br>
195 mg of 5-{2-[4-(4-fluorobenzoyl)-piperidin-l-yl]-ethoxy}-4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester of <br><br>
21 <br><br>
27181 <br><br>
melting point 161-163°C is obtained analogously to the process according to Example 2 from 510 mg of 5-(2-chloroethoxy)-4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester, melting point 194-195°C, and 311 mg of 4-(4-fluorobenzoyl)-piperidine. <br><br>
Produced analogously are: <br><br>
6-{2-[4-(4-Fluorobenzoyl)-piperidin-l-yl-]-ethoxy}-4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester <br><br>
5-{2-[4-(4-fluorobenzoyl)-piperidin-l-yl-]-ethoxy}-4-methoxymethyl-B-carboline <br><br>
5-{2-[4-(4-f luoro-a-hydroxybenzyl) -piperidin-l-yl-] -ethoxy}- <br><br>
4-methoxymethyl-9-methyl-B-carboline <br><br>
Example 6 <br><br>
5--T3-r4— f4—Fluorobenzovl^ -pjperidinol -2-hvdroxvpropoxv'V-4-methoxvmethvl-B-carboline-3-carboxylic acid isopropyl ester <br><br>
700 mg of 4-methoxymethyl-5-(2,3-epoxypropoxy) -B-carboline-3-carboxylic acid isopropyl ester is dissolved in 50 ml of propan-2-ol and mixed with 380 mg of 4-(4-f luorobenzoyl)-piperidine. After five hours of reflux under argon, the organic phase is concentrated by evaporation, and the residue is chromatocpraphed on silica gel with methylene chloride and ethanol = 1000 + 50. 655 mg of 5-{3-[4-(4-fluorobenzoyl) -piperidino]-2-hydroxypropoxy}-4-methoxymethyl-B-carboline-3-carboxylic acid isopropyl ester of melting point 143°C is obtained. <br><br>
4-Methoxymethy 1-5-(2,3-epoxypropoxy)-B-carboline-3-carboxylic acid isopropyl ester is obtained according to methods <br><br></p>
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