EP0460153A1

EP0460153A1 - NEW-$g(b)-CARBOLINS, PROCESS FOR PREPARING THEM AND THEIR USE IN DRUGS

Info

Publication number: EP0460153A1
Application number: EP91900736A
Authority: EP
Inventors: Andreas Dr. Huth; Martin Dr. Krüger; Dieter Rahtz; Dieter Dr. Seidelmann; Ralph Dr. Schmiechen; Lechoslaw Dr. Turski; John Stewart Dr. Andrews; Herbert Hans Dr. Schneider
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 1989-12-23
Filing date: 1990-12-19
Publication date: 1991-12-11
Also published as: JPH04505928A; HUT59403A; WO1991009858A1; IE904704A1; HU912769D0; PT96351A; DE3943225A1; US5254563A; CA2050917A1

Abstract

On décrit des composés de la formule (I), où B est de l'azote ou CR4 et où R3 est CO-R ou -CHOH-R, et où R représente un résidu aryle ou hétaryle mono-ou bicyclique éventuellement substitué, ou bien un résidu C3-10 cycloalkyle ou bicycloalkyle. Les composés de la formule (I) se prêtent particulièrement au traitement de l'angoisse accompagnée de dépressions, d'épilepsie, de troubles du sommeil, de spasticités et de relaxation musculaire pendant l'anesthésie, et présentent aussi des propriétés amnestiques ou stimulant la mémoire.Compounds of formula (I) are described, where B is nitrogen or CR4 and where R3 is CO-R or -CHOH-R, and where R represents an optionally substituted mono- or bicyclic aryl or heteraryl residue, or a C3-10 cycloalkyl or bicycloalkyl residue. The compounds of formula (I) are particularly suitable for the treatment of anxiety accompanied by depression, epilepsy, sleep disturbances, spasticity and muscle relaxation during anesthesia, and also have amnestic or stimulating properties. memory.

Description

New ß-carbolines, processes for their production and their use in medicinal products

The invention relates to new ß-carbolines, their production and use in drugs.

From numerous publications such as EP-A-54507 it is known that β-carbolines influence the central nervous system and are suitable as psychotropic drugs. Surprisingly, it was found that the β-carbolines substituted in the 3-position according to the invention are bioavailable over a longer period of time and at the same time have a good affinity for the benzodiazepine receptors.

The compounds according to the invention have the general formula I.

wherein

R ^{A is} halogen, -CHR ¹ -R ² , phenyl or OR and can be one to two times and

Hydrogen or C _1-4 alkyl,

R ^{2 is} hydrogen, C _1-4 alkyl, -OC _1-4 alkyl or an optionally substituted phenyl, benzyl or phenoxy radical and

R ^{5 represents} hydrogen, tri-C _1-4 -alkylsilyl, C _{1 -4} -alkyl, C _3-7 -cycloalkyl or an optionally substituted phenyl, benzyl or hetaryl radical and

B nitrogen or CR ⁴ and R ^{4 is} hydrogen, C _1-4 alkyl or C _1-4 alkoxy-C _1-2 alkyl and

R ^{3 is} -CO-R or -CHOH-R and R represents an optionally substituted mono- or bicyclic aryl or hetaryl radical or a C _3-10 cycloalkyl or bicycloalkyl radical and their isomers and acid addition salts.

The substituent R ^A can be in the A ring in position 5-8, preferably in the 5-, β- or 7-position.

Alkyl contains both straight and branched chain residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl and tert. Butyl.

Halogen is to be understood as fluorine, chlorine, bromine and iodine.

Cycloalkyl can each represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and 2-methylcyclopropyl, 3-5 carbon atoms being preferred for the substituent R ⁵ .

If R ^{5 is} a hetaryl radical, this is 5- or 6-membered and contains 1-2 heteroatoms such as nitrogen, oxygen and / or sulfur. For example, the following 5- and 6-ring heteroaromatics may be mentioned: pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, thiazole, imidazole.

Preferred hetaryl radicals R ⁵ are nitrogen-containing heterocycles which are optionally substituted with halogen.

The substituent of the phenyl, benzyl and hetaryl radical R ⁵ can be one to three times in any position. Suitable substituents are halogens, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy, amino and C _1-4 alkoxy carbonyl, in particular fluorine, chlorine and bromine being preferred. Suitable substituents for the phenyl, benzyl and phenoxy radical R ² are the substituents for aromatics mentioned for R ⁵ , in particular halogen such as

Chlorine and bromine.

The aryl and hetaryl radical in R ³ can be present as a mono- or bicyclic and

5-12 ring atoms, preferably 5-9 ring atoms, contain, for example, phenyl, biphenylyl, naphthyl, indenyl as aryl radical and thienyl, furyl, pyranyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, iso-oxazolyl, thiazolyl, isothiazolyl, Quinolyl, isoquinolyl, benzo [1] thienyl, benzofuryl as a hetaryl radical with 1-2 heteroatoms such as sulfur, oxygen and / or nitrogen.

The substituent of the aryl and hetaryl radical R can be one to two times and can be halogen, C _1-4 alkyl, C _1-4 alkoxy, cyano, amino or nitro, where C _1-4 alkyl, C _1-4 Alkoxy and amino are preferred.

A bicycloalkyl radical R is understood to mean, for example, bicycloheptyl and bicylooctyl.

If a chiral center is present, the compounds of the formula I can be in the form of the diastereomers and mixtures thereof.

The physiologically compatible acid addition salts are derived from the known inorganic and organic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid and, for example, alkanesulfonic acids and, for example, alkanesulfonic acids and, for example, alkanesulfonic acids Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and others

The above-mentioned cycloalkyls having 3-5 carbon atoms and optionally substituted phenyl, biphenyl, naphthyl and thienyl are to be considered as particularly preferred embodiments for R. Because of their affinity for benzodiazepine receptors, the compounds of the formula I and their acid addition salts can be used as medicaments and exert antagonistic, inverse agonistic and agonistic effects on the properties known from benzodiazepines. At the same time, the compounds according to the invention have an extended duration of action.

Using the example of the 3-benzoyl derivative in comparison with the 3-carboxylic acid phenyl ester derivative, the table below shows that the compounds according to the invention not only have a higher stability towards liver enzymes, but also a better affinity for the benzodiazepine receptors, in particular better have vivo affinity. Affinity is determined by examining the displacement capacity of radioactively labeled flunitrazepam from the benzodiazepine receptors.

The ED ₅₀ value represents the dose of a test substance which brings about a reduction in the specific binding of the flunitrazepam to the benzodiazepine receptor in a living brain to 50% of the control value.

The in vivo test is listed as follows;

Groups of mice are injected with the test substance at different doses and usually intraperitoneally. After 15 minutes, the ³ H-flunitrazepam is administered intravenously to the mice. After a further 20 minutes, the mice are sacrificed, their forebrain removed and the radioactivity specifically bound to the brain membranes measured by scintillation payment. The ED ₅₀ value is determined from the dose / effect curves,

The metabolic stability is determined by incubating a homogenate of liver tissue in physiological saline with the test substance for 0 or 2 hours at 37 ° C. The incubation mixture is then extracted and the content of test substance in the extract is determined by HPLC / fluorimetry. The substance remaining after 2 hours compared to 0 hours is expressed in percent stability. Inhibition of H ³ -BD binding Metabolic stability in vivo Human liver homogenate

ED ₅₀ mg / kg 2 hours 37 ° C ---------------------------------------- -------------------------------------------------- --------------- A 5.0 72%

B> 90 ----------------------------------------------- -------------------------------------------------- ------------

A = 6-benzyloxy-4-methoxymethyl-3-benzoyl-ß-carboline

B = phenyl 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylate

The compounds according to the invention are further distinguished by anxiolytic and anticonvulsant activity.

To investigate the anxiolytic effect, the compounds are tested in a 4-plate test using the method of Boissier et al Eur. J. Pharmacol. 4, 145-150 (1968). Here, the minimum, lowest dose (MED) is given, which determines the locomotor activity of the punished mice after i.p. Treatment increased. A decrease in activity in the 4-plate test without punishment indicates sedative properties.

The compounds of the formula I are particularly suitable for the treatment of anxiety accompanied by depression, epilepsy, sleep disorders, spasticity and muscle relaxation during anesthesia and also show amnestic or memory-promoting properties.

For the use of the compounds according to the invention as pharmaceuticals, they are brought into the form of a pharmaceutical preparation which, in addition to the active ingredient for enteral or parenteral administration, has suitable pharmaceutical, organic or inorganic inert carrier materials, such as water, gelatin, gum arabic, milk sugar, starch, Contains magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.

Injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are particularly suitable for parenteral use.

Surfactant auxiliaries such as salts of bile acids or animal or vegetable phospholipids, but also mixtures thereof and liposomes or their components can also be used as carrier systems.

Tablets, coated tablets or capsules with talc and / or hydrocarbon carriers or binders, such as lactose, corn or potato starch, are particularly suitable for oral use. They can also be used in liquid form, for example as juice, to which a sweetener may be added.

The compounds according to the invention are introduced in a dose unit of 0.05 to 100 mg of active substance in a physiologically compatible carrier.

The compounds according to the invention are generally used in a dose of 0.1 to 300 mg / day, preferably 0.1 to 30 mg / day, particularly preferably 1-20 mg / day, for example as anxiolytics analogous to diazepam.

The compounds according to the invention can be prepared by methods known per se. For example, compounds of the formula I are obtained by Compounds of formula II

wherein R ^A and B have the above meaning and

R ^{9 is} hydrogen or a protective group and

Y cyano or -CO-Z and

Z is hydrogen, C _1-4 alkoxy or an acid derivative, with a metal-organic compound R-Me

and, if desired, then a trialkylsilyl group is split off to give the hydroxyl group or a hydroxy group etherified to R ^A = OR ⁵ or R ³ in the meaning of -CH-OH-R oxidized to the ketone or the protective groups are split off or the isomers are separated or the acid addition salts are formed.

For example, a Grignard compound such as R-Mg halogen or a lithium organic compound R-Li is suitable as the organic metal compound. Suitable for the reaction with the metal-organic compound

Acid derivatives are, for example, carboxamides -NR ⁷ R ⁸ , in which R ⁷

C _1-4 alkyl and R ^{8 represent} C _1-4 alkyl or C _1-4 alkoxy or R ⁷ and R ⁸ together with the nitrogen atom form an imidazole.

The reaction with the organometallic compound can be carried out at temperatures from -70 ° C. to room temperature in aprotic polar solvents such as cyclic and acyclic ethers or hydrocarbons. Examples of suitable solvents are diethyl ether, tetrahydrofuran, dioxane, toluene, hexane and others.

Suitable protective groups R ⁹ are all customarily used protective groups, such as, for example, alkyl, alkanoyl, aralkyl, arylsulfonyl,

Alkylsulfonyl or silyl radicals, where sulfonyl such as tosyl and mesyl and

Trialkylsilyl such as tert. Butyl-dimethylsilyl, trimethylsilyl and tert.

Butoxycarbonyl are preferred.

If a protective group R ⁹ or the tri-C _1-4 -alkylsilyloxy group R ^{A is present} in the compounds of the formula I, this can be carried out using the customary methods, such as by treatment with bases such as sodium or potassium hydroxide or alcoholate or Acids such as dilute mineral acid, trifluoroacetic acid or tetrabutylammonium fluoride, if necessary when the reaction mixture is worked up, are eliminated at room temperature or elevated temperature.

If the compounds according to the invention are etherified with R ^A in the meaning of OH, the methods described in EP-237467, EP-A-234173 and EP-A-130140 can be used, for example by using a reactive derivative R ⁵ X, in which X Halogen, tosylate, mesylate or triflate is reacted in the presence of a base in a polar solvent. Do the compounds of formula IR ^{3 have} the meaning of a -CHOH-R-

Group, this can be oxidized to a -CO-R group by optionally in the presence of an organic base such as pyridine, triethylamine with oxalyl chloride or with an oxidizing agent such as manganese dioxide,

Pyridine chlorochromate, chromium oxide, ferric chloride or oxidized according to the Oppenauer method or dehydrated in the presence of a copper catalyst.

Oxidation with azodicarboxylic acid esters, for example analogously to F.

Yoneda et al. J. Org. Chem. 32, 72 (1967) is possible.

The reaction can be carried out at room temperature or at an elevated temperature up to the boiling point of the reaction mixture in an inert solvent such as chlorinated hydrocarbons, hydrocarbons, acetone, alcohols such as tert. Butanol can be carried out.

The isomer mixtures can be separated into the diastereomers or enantiomers by customary methods such as, for example, crystallization, chromatography or salt formation.

To form the physiologically compatible acid addition salts, a compound of the formula I is dissolved, for example, in a little alcohol and a concentrated solution of the desired acid is added.

If the preparation of the starting compounds is not described, they are known or can be prepared analogously to known compounds or processes described here.

For example, the 3-formyl derivative of the formula II can be prepared analogously to the methods described in EP-A-218541 and EP-A-305322. The preparation of the 3-carboxylic acid esters and their reactive acid derivatives is described for example in EP-A-54507, EP-A-237467, EP-A-234173, EP-A-137390, EP-A-239667 and EP-A222693. The nitriles are prepared, for example, by the process described in EP-A-234137.

The following examples are intended to explain the process according to the invention. Preparation of the starting compounds:

A) 6-Benzyloxy-4-methoxymethyl-ß-carboline-3-carboxylic acid dimethylamide

Dimethylamine was introduced for 5 minutes into a solution of 1.0 g of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboximidazolide in 25 ml of dimethylformamide. The mixture was then diluted with ethyl acetate and washed with water, dried, filtered and concentrated. The residue was recrystallized from ethyl acetate and gave 680 mg of the title compound with a melting point of 174-176 ° C.

B) 6-Benzyloxy-4-methoxymethyl-ß-carboline-3-carboximidazolide

1.34 g of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid in 50 ml of absolute tetrahydrofuran were mixed with 45 ml of a freshly prepared 0.27 molar thionyldiimidazole solution in tetrahydrofuran at room temperature and stirred for 2 hours with the exclusion of moisture. After the solvent had been distilled off, the mixture was taken up in ethyl acetate / water, washed twice with water and once with saturated sodium chloride solution. The ethyl acetate phase was dried, concentrated and the crude product obtained was extracted with ethyl acetate. 1.31 g of the title compound with a melting point of 184-185 ° C. were obtained.

The following are produced analogously:

6- (2-pyrazinyloxy) -4-methoxymethyl-ß-carboline-3-carboximidazolide

5- (4-chlorophenoxy) -4-methoxymethyl-ß-carboline-3-carboximidazolide

5- (4-fluorobenzyloxy) -4-methoxymethyl-ß-carboline-3-carboximidazolide example 1

6-benzyloxy-3-cyclopropylcarbonyl-4-methoxymethyl-ß-carboline

To 618 mg of 6-benzyloxy-4-methoxymethyl-ß-carboline-3-carboximidazolide in 45 ml of absolute tetrahydrofuran were 18 ml of a 0.5 mol at - 6 to - 10 ° C in about 10 minutes. Solution of cyclopropylmagnesium bromide added dropwise in tetrahydrofuran and stirred for 1 hour while cooling with ice. After a reaction time of 16 hours at room temperature, the mixture was weakly acidified with dilute HCl solution, concentrated and extracted with methylene chloride. The organic phase was washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried and concentrated. Column chromatography on silica gel with methylene chloride / ethanol 12: 1 and recrystallization from ethyl acetate / petroleum ether gave 133 mg of the title compound with a melting point of 133 ° C.

The following are obtained analogously:

6-Benzyloxy-4-methoxymethyl-3- (1-naphthyl) carbonyl-ß-carboline melting point 223 - 224 ° C (ethyl acetate, ethanol, hexane).

6-benzyloxy-3- (2-methylcyclopropylcarbonyl) -4-methoxymethyl-ß-carboline

5- (4-chlorophenoxy) -3-cyclopropylcarbonyl-4-methoxymethyl-ß-carboline

6-benzyloxy-3- (cyclobutylcarbonyl) -4-methoxymethyl-ß-carboline melting point 153 - 154 ° C (ethyl acetate, hexane)

6- (2-pyrazinyloxy) -3-cyclopropylcarbonyl-4-methoxymethyl-ß-carboline melting point 167 - 169 ° C (ethyl acetate / hexane)

5- (4-fluorobenzyloxy-3-cyclopropylcarbonyl) -4-methxoymethyl-ß-carboline Example 2

6-benzyloxy-4-methoxymethyl-3-benzoyl-ß-carboline

A solution of 1.09 g of 6-benzyloxy-4-methoxymethyl-9-tosyl-ß-carboline-3-carboxylic acid isopropyl ester in 20 ml of absolute tetrahydrofuran was at 60 ° C. under argon with 2.1 ml of a 1.08 molar phenyl -Lithium solution in ether / hexane, stirred for 1 hour at - 60 ° C and then slowly warmed to room temperature. After a reaction time of 3 hours at room temperature, the mixture was acidified with nHCl and the solvent was distilled off. After taking up in ethyl acetate / water, the organic phase was separated off, washed with saturated sodium chloride solution, dried and concentrated. Crystallization from ethanol / petroleum ether gave 435 mg of the title compound, melting point 167-168 ° C.

The following are obtained analogously:

6-benzyloxy-4-methoxymethyl-3- (thiophen-2-yl -) - ß-carboline, melting point 165 ° C (ethyl acetate / petroleum ether)

6-benzyloxy-4-methoxymethyl-3- (2-methoxybenzoyl) -ß-carboline, melting point 145-146 ° C (ethyl acetate / petroleum ether)

3-benzoyl-6,7-dimethoxy-4-ethyl-ß-carboline, melting point 182-184 ° C (methylene chloride / ethanol) from 6,7-dimethoxy-4-ethyl-9-tosyl-ß-carboline-3- carboxylic acid ethyl ester, melting point 160-161 ° C (isopropanol).

3-benzoyl-5-benzyloxy-4-methoxymethyl-B-carboline, melting point 195-198 ° C (cyclohexane / ethyl acetate) from 5-benzyloxy-4-methoxymethyl-9-tosyl-ß-carboline-3-carboxylic acid ethyl ester, Melting point - 149-150 ° C (ethyl acetate).

3-Benzoyl-5-isopropoxy-4-methyl-ß-carboline, melting point 234-235 ° C (cyclohexane / ethyl acetate) from 5-isopropoxy-4-methyl-9-tosyl-ß-carboline-3-carboxylic acid methyl ester, melting point 197 -198 ° C (ethyl acetate). 3-Benzoyl-5- (4-fluorobenzyloxy) -4-methoxymethyl-ß-carboline melting point 213 - 214 ° C from 5- (4-fluorobenzyloxy) -4-methoxymethyl-9-tosyl-ßcarbolin-3-carboxylic acid ethyl ester 149 - 150 ° C

3 - [(2-methyl) -benzoyl] -6-benzyloxy-4-methoxymethyl-ß-carboline melting point 164 ° C (ethyl acetate, ethanol, hexane)

3- (4-phenylbenzoyl) -6-benzyloxy-4-methoxymethyl-ß-carboline melting point 108 - 109 ° C (ethyl acetate, ethanol, hexane)

3-Benzoyl-4-methoxymethyl-5- (4-chlorophenoxy) -ß-carboline melting point 238 - 240 ° C (methylene chloride, ethyl acetate, hexane) from 5- (4-chlorophenoxy) -4-methoxymethyl-9-tosyl-ß -carboline-3-carboxylic acid isopropyl ester with a melting point of 185-187 ° C.

Example 3

2-benzoyl-8-phenoxy-5H-pyrimido [5,4-b] indole

Analogously to Example 2, the title compound is obtained from 8-phenoxy-5-tosyl-5H-pyrimido [5,4-b] indole-2-carboxylic acid ethyl ester, melting point 251-253 ° C (ethyl acetate).

Production of the starting material:

2-Amino-5-phenoxy-benzonitrile is analogous to that of K. Clarke, W. Richard and R.M. Scrowston, J. Chem. Res. 1980 (2) 833-847 converted synthesis into 3-amino-4-phenoxy-1-tosylindol-2-carbonitrile, which analogously to the process described in EP-A-115248 in 8-phenoxy -5-tosyl-5H-pyrimido [5,4-b] indole-2-carboxylic acid ethyl ester with the melting point 136-139 ° C (ethanol) is transferred.

Example 4

3-benzoyl-5-ethoxymethyl-ß-carboline

Analogously to Example 2, the title compound is obtained from 5-ethoxymethyl-9-tosyl-ßcarbolin-3-carboxylic acid ethyl ester, melting point 195-197 ° C (ethyl acetate).

Production of the starting material:

By tosylation of the 5-ethoxymethyl-ß-carboline-3-carboxylic acid ethyl ester known from EP-110813, melting point 142-143 ° C. (ethanol).

Example 5

3-benzoyl-445-dimethyl-ß-carboline

Analogously to Example 2, the title compound is obtained from 4,5-dimethyl-9-tosyl-β-carboline-3-carboxylic acid ethyl ester, melting point 208-209 ° C. (ethyl acetate). The starting compounds are prepared by known esterification and tosylation of 4,5-dimethyl-β-carboline-3-carboxylic acid.

Example 6

3-benzoyl-5-ethoxymethyl-4-methoxymethyl-ß-carboline

Analogously to Example 2, the title compound is obtained from 5-ethoxymethyl-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid ethyl ester, melting point 180-182 ° C. (ethanol).

The starting material is prepared by tosylating the 5-ethoxymethyl-4-methoxymethyl-ß-carboline-3-carboxylic acid ethyl ester known from EP-A-161575, melting point 90-92 ° C. (ethanol).

Example 7

3-benzoyl-4-methoxymethyl-6-triisopropylsilyloxy-ß-carboline

A solution of 230 mg of 4-methoxymethyl-9-tosyl-6-triisopropylsilyloxy-ß-carboline-3-carboxylic acid isopropyl ester in 3.5 ml of absolute tetrahydrofuran was at - 60 ° C under argon with 0.38 ml of a 1.08 molar phenyllithi - um solution in ether / hexane, stirred for 1 hour at - 60 ° C and slowly warmed to room temperature. After standing at room temperature for 16 hours, 1N acetic acid / ethyl acetate was added to the reaction mixture, and the ethyl acetate phase was washed with water and saturated sodium chloride solution, dried and concentrated. After column chromatography on silica gel with cyclcohexane / ethyl acetate 1: 1 as the eluent, 69 mg of the title compound were obtained. Production of the starting material:

A) 4-methoxymethyl-6- (triisoprooylsilyloxy) -ß-carboline-3-carboxylic acid isopropyl ester

314 mg of 6-hydroxy-4-methoxymethyl-ß-carboline-3-carboxylic acid isopropyl ester were stirred in 20 ml of dichloromethane with 61 mg of 4-dimethylaminopyridine, 0.31 ml of triethylamine and 425 mg of chlorotriisopropylsilane for 7 hours at room temperature. The mixture was then washed with water and saturated sodium chloride solution, the organic phase was dried and concentrated. After purification of the crude product on a silica gel column with dichloromethane / ethanol 10: 1 as eluent and recrystallization from ether / petroleum ether, 392 mg of the desired compound were obtained, melting point 144-145 ° C.

B) 4-methoxymethyl-9-tosyl-6- (triisopropylsilyloxy) -ß-carboline-3-carboxylic acid isopropyl ester

1 g of 4-methoxymethyl-6- (triisopropylsilyloxy) -ß-carboline-3-carboxylic acid isopropyl ester, 132 mg of 4-dimethylaminopyridine and 0.45 ml of triethylamine were in 10 ml of dichloromethane at about 4 ° C with 615 mg of tosyl chloride added and then stirred at room temperature for 1 hour. After standing at room temperature for 16 hours, the mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. After chromatography on silica gel in the cyclohexane / ethyl acetate 1: 1 system, 1.32 g of the title compound was obtained from the isolated organic phase.

Example 8

3-benzoyl-6-hydroxy-4-methoxymethyl-ß-carboline

530 mg of 3-benzoyl-6-triisopropylsilyloxy-4-methoxymethyl-ß-carboline were dissolved in 7.5 ml of absolute tetrahydrofuran and after the addition of 1.1 ml of a 1.1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran for 0.5 hours under argon stirred at room temperature. After adding ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried and concentrated. After stirring with ethyl acetate / petroleum ether, 315 mg of the title compound were obtained, melting point 258 ° C.

Example 9

3-benzoyl-6- (5-bromopyridin-2-yloxy) -4-methoxymethyl-ß-carboline

332 mg of 3-benzoyl-6-hydroxy-4-methoxymethyl-ß-carboline and 130 mg of potassium hydroxide powder in 3 ml of dimethyl sulfoxide under argon were mixed with 285 mg of 2,5-dibromopyridine in 1 ml of dimethyl sulfoxide and 1 hour to 90 -95 ° C heated. The reaction mixture was poured onto ice water, acidified to pH 5 with 1N-acetic acid and shaken out with ethyl acetate. The ethyl acetate phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Chromatography on silica gel with dichloromethane / ethyl acetate 1: 1 as eluent and recrystallization of the main fraction from ethyl acetate / petroleum ether gave the title compound with a melting point of 193-194 ° C.

Example 10

6-benzyloxy-3- (1-hydroxy-1-dhenylmethyl) -4-methoxymethyl-ß-carboline

300 mg of 6-benzyloxy-3- (1-hydroxy-1-phenylmethyl) 4-methoxymethyl-9- (4-methylphenylsulfonyl) -ß-carboline were added to a sodium ethylate solution of 50 mg of 80% sodium hydride and 30 ml of absolute ethanol added and heated under reflux under argon for 2 hours. After distilling off the solution the residue was taken up in ethyl acetate and washed with saturated sodium chloride solution. 211 mg of the title compound were obtained after recrystallization from ethyl acetate / petroleum ether, melting point 190-191 ° C., from the ethyl acetate phase, which was dried over magnesium sulfate and concentrated, after column chromatography on silica gel in a dichloromethane / ethanol system.

The following are obtained analogously:

6-benzyloxy-3- (1-hydroxy-1-cyclopentylmethyl) -4-methoxymethyl-ß-carboline

Production of the starting material:

6-Benzyloxy-3- (1-hydroxy-1-phenylmethyl) -4-methoxymethyl-9- (4-methylphenylsulfonyl) -ß-carboline

A solution of 1.0 g of 6-benzyloxy-3-formyl-4-methoxymethyl-9- (4-methylphenylsulfonyl) -ß-carboline in 60 ml of absolute tetrahydrofuran was at -60 ° C under argon with 2.4 ml a 1.08 molar phenyllithium solution in ether / hexane, stirred for 1 hour at -60 ° C. and then slowly warmed to room temperature. After taking up in ethyl acetate / water, the organic phase was separated off, washed with saturated sodium chloride solution, dried and concentrated. After column chromatography on silica gel with the eluents dichloromethane / ethanol 15: 1 and cyclohexane / ethyl acetate 1: 1, 717 mg of the title compound with a melting point of 169-171 ° C. were obtained.

The following are obtained analogously:

With cyclopentyl magnesium bromide 6-benzyloxy-3- (1-hydroxy-1-cyclopentylmethyl) -4methoxymethyl-9- (4-methylphenylsulfonyl) -ß-carboline melting point 146 - 147 ° C (ethyl acetate, ethanol, hexane) Example 1 1

3-benzoyl-5- (2-chlorophenoxymethyl) -4-methoxymethyl-ß-carboline

Analogously to Example 2, the title compound is obtained from 5- (2-chlorophenoxymethyl) 4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid ethyl ester, melting point 149 ° -152 ° C. (ethanol).

Production of the starting material:

a) 4- (2-Chlorophenoxy) methyl indole

A solution of 4-hydroxymethylindole (1.0 g) in tetrahydrofuran is added to a solution of triphenylphosphine (2.92 g), 2-chlorophenol (1.43 g) and diethyl azodicarboxylate (1.49 g) in tetrahydrofuran (50 ml) (10 ml) added dropwise. After the reaction mixture has been stirred for three hours, the mixture is worked up in a customary manner and the crude product is chromatographed. Melting point 138 - 140 ° C (cyclohexane)

b) 5- (2-chlorophenoxy) methyl-4-methoxymethyl-ß-carboline-3-carboxylic acid ethyl ester

Representation analogous to F. Neef et al, 1983 Heterocycle 20, 1295 - 1313 (route a), melting point 167-168 ° C.

c) 5- (2-Chlorophenoxy) methyl-4-methoxymethyl-9-tosyl-ß-carboline-3-carboxylic acid ethyl ester

Representation analogous to Example 7B melting point 149 - 152 ° C (ethanol) Example 12

6-benzyloxy-3-cvclopentylcarbonyl-4-methoxymethyl-ß-carbolιn

50 mg of 6-benzyloxy-3- (1-hydroxy-1-phenylmethyl) -4-methoxymethyl-ß-carboline are stirred in 10 ml of methylene chloride with 300 mg of manganese dioxide for 1 hour at room temperature. After suction filtration over diatomaceous earth, the filtrate was evaporated and the residue was chromatographed over silica gel with methylene chloride: ethyl acetate = 2: 1. 20 mg of the title compound are obtained.

Claims

1.) Compounds of formula I.

wherein

R ^{A is} halogen, -CHR ¹ -R ² , phenyl or OR ⁵ and can be one to two times and

R ^{1 is} hydrogen or C _1-4 alkyl,

R ^{2 is} hydrogen, C _{1 -4} -alkyl, -OC _1-4 -alkyl or an optionally substituted phenyl, benzyl or phenoxy radical and

R ^{5 is} hydrogen, tri-C _1-4 -alkylsilyl, C _1-4 -alkyl, C _3-7 -cycloalkyl or an optionally substituted phenyl, benzyl or hetaryl radical and

B nitrogen or CR ⁴ and

R ^{4 is} hydrogen, C _1-4 alkyl or C _1-4 alkoxy-C _1-2 alkyl and

R ^{3 is} -CO-R or -CHOH-R and R represents an optionally substituted mono- or bicyclic aryl or hetaryl radical or a C _3-10 - cycloalkyl or bicycloalkyl radical and their isomers and acid addition salts.

2.) 6-Benzyloxy-4-methoxymethyl-3-benzoyl-ß-carboline

6- (5-bromopyridin-2-yloxy) -4-methoxymethyl-3-benzoyl-ß-carboline

6-benzyloxy-3-cyclopropylcarbonyl-4-methoxymethyl-ß-carboline

3.) Medicaments based on the compounds according to claims 1 and 2.

4.) Process for the preparation of the compounds according to claim 1, characterized in that

Compounds of formula II

wherein R ^A and B have the above meaning and

R ^{9 is} hydrogen or a protective group and

Y cyano or -CO-Z and

and, if desired, then a trialkylsilyl group is split off to the hydroxyl group or a hydroxyl group etherified to R ^A = OR ⁵ or R ³ in the meaning of -CH-OH-R oxidized to the ketone or cleaving off the protective groups or separating the isomers or forming the acid addition salts.