FI74961C - FOERFARANDE FOER FRAMSTAELLNING AV SAOSOM PSYKOFARMAKA ANVAENDBARA 4-METOXIMETYLSUBSTITUERADE -KARBOLIN-3-KARBOXYLSYRADERIVAT. - Google Patents

Description

74961

Process for the preparation of 4-methoxymethyl-substituted 6-carboline-3-carboxylic acid derivatives 4 useful as psychopharmaceuticals - For the preparation of 4-methoxymethyl-substituted 6-carboline-3-carboxylic acid derivatives

The invention relates to a process for the preparation of novel 6-carboline-3-carboxylic acid derivatives. These new compounds have valuable pharmacological properties. They particularly affect the central nervous system and are suitable for use in psychopharmaceuticals.

The compounds according to the invention are 4-methoxymethyl-substituted 6-carboline-3-carboxylic acid derivatives of the general formula (I): ch2och3 r04a Ab c (,)

A H

in which formula represents an alkyl group or a benzyl group having 1 to 4 carbon atoms; and R * - is an alkyl group having 1 to 4 carbon atoms.

The substituent on the A ring may be in the 5-, 6-, 7- or 8-position. The A ring may be mono- or di-substituted with the substituent Ra. Stations 5 and 6 are considered the best.

Canadian Patent No. 786,351 discloses 8-carboline-3-carboxylic acid amides substituted in the 1-position by an alkyl group containing up to 5 carbon atoms, a trifluoromethyl, phenyl or benzyl group, and two compounds having a 7-position in the 1-position. there are no substituents, namely 6-carboline-3-carbohydrazine and 6-carboline-3-carboxylic acid amide.

Danish Patent No. 98,436 describes a process for the preparation of β-carboline-3-carboxylic acid methyl ester.

PI Patent 68829 discloses closely related β-carboline-3-carboxylic acid derivatives having various substituents at the 4-position and some of which have good affinity for benzodiazepine receptors. However, compared to these compounds, the compounds of the invention surprisingly have a good anticonvulsant effect in addition to a good benzodiazepine receptor affinity.

The test report

It is known (Squires R.E. and Braestrup C., Nature (London) 266 (1977) 734) that there are certain sites in the central nervous system of vertebrates that have a very specific tendency to bind 1,4- and 1,5-benzodiazepines. These sites are called benzodiazepine receptors.

The pharmacological properties of the compounds of the invention were studied by determining their ability to displace radiolabeled flunitrazepam from such benzodiazepine receptors.

The displacement activity of the compounds of the invention was determined by IC50 and ED50 values.

The IC50 value refers to the concentration that displaces 50% of the specific binding of lunitrazepam in vitro, and the ED50 value refers to the dose of test substance (mg / kg) that reduces the specific binding of flunitrazepam to benzodiazepine receptors in living brain by 50% from control 3,74961 liars. The procedure for performing these experiments is described in FI publication 68829.

The anticonvulsant effect was studied by determining the inhibition of seizures induced by Penty-lenetetrazole (pentazole) in mice. Pentazole is administered to mice subcutaneously at 150 mg / kg hydrochloric acid (pH 2-3) 15-30 minutes after intraperitoneal administration of the test compound. This amount causes clonic and tonic seizures that result in death in untreated animals. Count the number of mice that experience seizures and the number of mice that die 30 minutes after pentazole administration (PTZ seizure antagonism).

The ED50 values mentioned in the following table were determined according to the method of Litchfield and Wilxocon (J.Pharmacol. Exp.Ther. 9j> (1949) 99-103) in an amount of antagonistically active substance which protects 50% of the animals from convulsions and death.

4,74961

Table CHjOCHj 2

PTZ

R * R20 in vitro in vivo in vivo IC50 ED50 ED50 _nq / kq_mg / kg_mg / kg_ C2H5 6-OCH2 “C6H5 3.2 4.5> 50 7-OCH3 CH3 S-OCH2 ~ C6H5 0.6 7 30 n-C3 -H7 5-0 "CH2-C8H5 0.8 0.8 5 C2H5 5-0-C2H5 Ö72 274> 30 C2H5 5-0-n-C3H7 Ö7i ITÖ 30 EN 68829 6-methoxy-4-methyl-6-mentioned values did not reproduce carboline-3-carboxyl-> 100 acid ethyl ester via_ 5-ethyl-4-methyl-8-carboline-3-carboxylic acid ethyl ester_1 ^ 9_3_> 100_

The process according to the invention for the preparation of said 3-carboline-3-carboxylic acid derivatives is characterized in that the indole derivative of the general formula II, 5 74961 CH2OCH3 '0 -. 00

B

2 wherein R1 is as defined above, the ring is cyclized / and the compound thus formed is dehydrated to form the corresponding unsaturated compound / and, if desired, the compound of formula I obtained is re-esterified in the 3-position.

A preferred embodiment of the process comprises cyclizing the compound of formula (II) with formaldehyde to give the corresponding 1 / 2,3 / 4-tetrahydrocarboline and then dehydrating the compound. The starting material can be dissolved *, either in water in the presence of an acid or a base and heated with formaldehyde, or it can be dissolved in an inert, water-immiscible solvent such as benzene, toluene, keyylene, chlorobenzene, anise, mesitylene and heated together with paraformaldehyde. . This gives a 1,2,3,4-tetrahydro-9H-pyrido [3,4-t] indole derivative which is dehydrated without further steps.

According to another preferred embodiment of the process, the compound of formula (II) is treated with formic acid to give the corresponding formyl compound and this compound is cyclized with phosphorus oxychloride or polyphosphoric acid to give the corresponding dihydrocarboline, which is then dehydrated.

The dehydration of the compound obtained by cyclization can be carried out according to a method known per se. One such method comprises dissolving or suspending the starting material in an inert solvent. Suitable solvents are all aprotic solvents having a boiling point above 100 ° C and which are inert to the starting material. Examples which may be mentioned are xylene, mesitylene, anisole, toluene, chlorobenzene and diphenyl ether. Next, elemental sulfur is added to such an extent that about 1 molar equivalent of sulfur is used per double bond. A small excess is not only harmless, but appropriate. The reaction mixture is refluxed for several hours, during which time the reaction is monitored by thin layer chromatography.

Another method is dehydration with DDQ (dichlorodicyanobenzoquinone) or chloroaniline in benzene, toluene, xylene, dioxane, tetrahydrofuran, methylene chloride or dimethoxyethane at a temperature of 0-60 ° C and using a reaction time of 0.5-4 hours. .

Yet another process is dehydration using noble metal catalysts such as platinum in finely divided form, fine palladium or palladium on carbon in xylene, mesitylene or cumene at 120-180 ° C for a reaction time of 2 hours to 16 hours.

Any desired re-esterification of the 3-position ester group can take place in a manner known per se. Thus, the starting material can be reacted with an alcohol of formula ROH using a catalytic amount of ROHa for 3-6 hours at a temperature of 80-120 ° C. The esterification may optionally be carried out with an alcohol ROH in the presence of an acid catalyst such as paratoluenesulfonic acid, HCl or CuCl2.

The further treatment of the compounds thus formed is carried out by methods known per se, such as, for example, extraction, crystallization, chromatography, etc.

The compounds of this invention may be used in the preparation of pharmaceutical preparations, e.g., for oral and parenteral administration to mammals, including humans, according to known galenic methods.

Suitable excipients for the preparation of pharmaceutical preparations are physiologically acceptable organic or inorganic carriers for enteral and parenteral administration which are inert to the compounds according to the invention.

Examples of such carriers are water, saline solutions, alcohols, polyethylene glycol, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol acid wax, pentaerythritol fatty acid

The pharmaceutical preparations can be sterilized and / or may be admixed with excipients such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, buffers and colorants.

Particularly suitable for parenteral use are injectable solutions or suspensions, in particular aqueous solutions in which the active ingredient is dissolved in polyhydroxyethoxylated castor oil.

Tablets, granules or capsules containing talc and / or a carbohydrate carrier or binder, such as, for example, lactose, corn or potato starch, are particularly suitable for oral use. Dosage can also take place in liquid form, such as, for example, juice, to which a sweetener may be added.

The compounds of this invention are administered in dosage units of 0.05 mg to 10 mg of active ingredient in a physiologically acceptable carrier.

74961 The compounds of this invention are used in a dose of 0.1 to 300 mg / day, preferably 1 to 30 mg / day.

Example 1 18 g of 4-ethoxy-6-methoxymethyltryptophanethyl ester was dissolved in 350 ml of toluene, mixed with 2.48 g of paraformaldehyde and heated for 3.5 hours using a water separator. After cooling, 4.5 g of 10% palladium-on-carbon was added and heated under reflux for 20 hours. The cooled solution was filtered and concentrated. The residue obtained was chromatographed on silica gel, eluting with hexane / acetic acid ester. The main fraction was crystallized from acetic acid ester / diisopropyl ether to give 6.4 g of 5-ethoxy-4-methoxymethyl-E-carboline-3-carboxylic acid ethyl ester, m.p. 148-149 ° C.

Preparation of starting material: a) 191.0 ml of isopropylamine were added dropwise over 2 hours to 165.3 g of methoxyacetaldehyde, while cooling with ice so that the temperature in the mixture did not rise above 10 ° C. After stirring for a further 30 minutes at 5 ° C, solid potassium hydroxide was added portionwise until 2 phases formed, after which the upper phase was separated and mixed again with potassium hydroxide solution and allowed to stand for 12 hours at 5 ° C. The solution was then filtered and the filtrate was distilled over about 2 g of barium oxide in a water jet vacuum. 110.9 g of isopropylimine of methoxyacetaldehyde were obtained, boiling point 35-39 ° C (40-30 mmHg).

b) To a solution of 32 g of 4-ethoxyindole in 134 ml of glacial acetic acid was added dropwise, under ice-cooling, 30 g of the imine obtained above in 50 ml of toluene so that the temperature in the mixture did not rise above 10 ° C. The mixture was then stirred for 12 hours at 5 [deg.] C., after which the reaction mixture was slowly stirred in about 1.7 liters of ice water, the organic phase was separated and the aqueous phase was extracted twice with 180 ml of toluene each time. The pH of the aqueous phase was then adjusted by dropwise addition of 6N sodium hydroxide solution under ice-cooling, and the mixture was extracted with benzene and ether. The alkaline phase extracts were dried over sodium sulfate and concentrated. 20 g of a pale yellow oil were obtained, which was used in the next step without further purification.

c) A solution of 20 g of the product obtained above in 500 ml of toluene was mixed with 21 g of nitroacetic acid ethyl ester and stirred under argon for 16 hours at 80 ° C. After cooling, the mixture was washed twice, each time with 400 ml of 1N hydrochloric acid, then with saturated brine, dried over sodium sulfate and then concentrated. 35 g of adduct were obtained as an oily mixture of isomers, which were used in the next reaction without further purification.

d) 24.9 g of the product obtained above were dissolved in 600 ml of ethanol and hydrogenated after the addition of about 32 g of Raney nickel at room temperature under normal pressure. After 4800 ml of hydrogen was consumed, the catalyst was filtered off and the filtrate was concentrated. 18 g of 4-ethoxy-6-methoxymethyltryptophanethyl ester were obtained as an oily mixture of isomers.

The following 3-carbolines were prepared as described above: 5-Methoxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, melting point 168-170 ° C, 6-methoxy-4-methoxymethyl-6-carboline-3- carboxylic acid ethyl ester, melting point 175-177 ° C, 10 74961 7-methoxy-4-methoxymethyl-3-carboline-3-carboxylic acid ethyl ester, melting point 161-163 ° C, 5-benzyloxy-4-methoxymethyl-3-carboline- 3-carboxylic acid ethyl ester, melting point 185-188 ° C, and 6.7-dimethoxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, melting point 163-164 ° C, 6-benzyloxy-4-methoxymethyl-8-carboline -3-carboxylic acid ethyl ester, m.p. 165-166 ° C.

Example 2: 30 mg of sodium was dissolved in 15 ml of absolute methanol. Then, 300 mg of 6,7-dimethoxy-4-methoxymethyl-3-carboline-3-carboxylic acid ethyl ester was added, and the reaction mixture was heated under reflux for 2 hours. The cooled solution was poured into sodium hydrogen phosphate solution and extracted with acetic acid ester. Crystallization from hexane / methylene chloride gave 270 mg of 6,7-dimethoxy-4-methoxymethyl-3-carboline-3-carboxylic acid methyl ester, m.p. 163-164 ° C.

In the same manner as above, the following compounds were prepared from the above 3-carboline-3-carboxylic acid ethyl ester and the corresponding alcohol: 6.7-dimethoxy-4-methoxymethyl-3-carboline-3-carboxylic acid n-propyl ester, melting point 172-174 ° C, 6,7-dimethoxy-4-methoxymethyl-3-carboline-3-carboxylic acid isopropyl ester, melting point 166-168 ° C, and 4-methoxymethyl-3-carboline-3-carboxylic acid n-propyl ester, melting point 154-157 ° C.

Claims (2)

1. Menetelmä psychofarmakoina käyttökel poisten, kaavan I mukaist CH2OCH3 A H 4-methoxymethyl-substituoitujen 8-carboliini-3-carboxyyl-happojohdannaisten valmistamiseksi, jossa kaavassa tarkoittaa 1-4 hiiliatomia sisäääää yes R ^ - on 1-4 hiiliatomia sisältävä alkyyliryhmä, tunnettu siitä, että yleisen kaavan II mukainen indoli johvandainen, CH2OCH3 - H jossa kaavassa R ^ ja R ^ · tarkoittavat samea kuin yllä, saatetaan reagoimaan formaldehydon tai , yes no muodostunut yhdiste dehydrataan vastaavan tyydyttymät-tömän yhdisteen muodostamiseksi ja haluttaessa saatu kaavan I mukainen yhdiste uudelleenesteröidään 3-asemassa. 1 Patent Tivaatimuksen 1 mucainen menetelmä, tunnettu siitä, one valmistetanylhististe 5-bentsyloxy-4-methoxymethyl-carboliin-3-carboxyylhappoethyl ester. 12 7 4 9 61 A process for preparing as psychopharmaceutical 4-methoxymethyl-substituted B-carboline-3-carboxylic acid derivatives of formula I CR2OCH3 \ COOR1 m R 0 A ΓΓί C Γ AH which represents an alkyl group of 1-4 carbon atoms or a benzyl group ; and R 1 represents an alkyl group of 1-4 carbon atoms, characterized in that an indole derivative of the general formula II CM 2 OCR 3 a -Ocpyr "-"> A in which R 1 and R 2 - are the same as above, is reacted with formaldehyde or formic acid and, if required, the formyl intermediate formed is cyclized, and the resulting compound is dehydrated to form the corresponding unsaturated compound and, if desired, the obtained compound is re-esterified at the 3-position. A process according to claim 1, characterized in that the compound 5-benzyloxy-4-methoxy-methyl-carboline-3-carboxylic acid ethyl ester is prepared.