HU210679B - Process for producing new tetrahydro-pyrido/3,4-b/indol derivatives and pharmaceutical compositions containing the same - Google Patents

Abstract

Tetrahydro-pyrido-(3,4-b)-indole derivs. of formula (I) and their salts are new. In (I) R=H, 1-4C alkyl, aryl-(1-4C alkyl), or aryl; X=H or halogen; and n = 1-5. - (I) are prepd. from tetrahydro-pyrido-(3,4-b)-indole derivs. of formula (II), or from their salt adducts, (pref. liberated by a base), and an epoxy cpd. of formula (III), in an aprotic or dipolar aprotic solvent.

Description

The present invention relates to novel tetrahydropyrido [3,4-b] indole compounds of formula I wherein R is hydrogen, (C1-C4) -alkyl, fend or benzyl;

X is hydrogen or halogen; n is an integer from 1 to 5 and is pharmaceutically acceptable for the preparation of their acid addition salts by reacting a tetrahydropyrido [3,4] indole compound of formula II wherein R is as defined above; or an acid addition salt thereof, in the latter case, after liberating the base, reacting an epoxide compound of the formula (ahol) wherein X and n are as defined above in an organic aprotic or dipolar aprotic solvent and optionally a pharmaceutically acceptable acid addition to a salt.

The novel compounds of formula (I) exhibit significant pharmacological activity, in particular gastric acid secretion inhibitors and tissue protectors, and thus include processes for the preparation of pharmaceutical compositions containing the compounds (I) or salts thereof.

Structurally similar compounds of formula I are known in the art. For example, in the Indian Journal of Chemistry, Sect. B. 1989, 28B (4), 333-337] 2-acyl-3-carboxylic, 2,3,4-tetrahydropyrido [3,4-b] indole derivatives, among which they have anti-ulcer activity, are reported. Czechoslovakian Patent No. 262,100 also discloses biphasic 1,2,3,4-tetrahydropyrido [3,4-b] indole compounds with anti-ulcer activity.

The starting compounds of formula (Π) may be prepared as described in Berichte dér Deutschen Chemischen Gesellschaft 63, 2102-2111, 2245-2248 (1930) and 67, 2031-2035 (1934); Dutch Patent No. 6,512,087; Annus of Justus Liebigs, Chemie 520, 107-123 (1935). The epoxide compounds of formula (III) are partly commercially available and partly disclosed in British Patent No. 1,069,344.

The gastric acid secretion inhibitory activity of the compounds of formula I was investigated by the Shay method (Gastroenterology, 1945, 5, 43-61). The study consisted of starving 120-150 g female H-Wistar rats for 24 hours in a caged cage. The animals were given water. The pylorus of the animals was then ligated under mild ether narcosis. The test compounds were administered to the animals during surgery. Four hours later, the animals were anesthetized with ether narcosis. After removal of the stomach, the volume and pH of the stomach contents were measured. In some cases, the hydrochloric acid content was determined by titration.

One of the most potent representatives of the compound family is the preparation of (±) -2- [3- (pentafluorophenoxy) -2-hydroxypropyl] -1,2,3,4-tetrahydropyrido [3,4- b] indole has an ED ₅₀ of 24.1 mg / kg po in the above model. By way of comparison, cimetidine, one of the world's most widely traded ulcer inhibitors, is 1-cyano-2-methyl-3- {2 - [(< The ED ₅₀ of 5-methylimidazol-4-ylmethyl) thio] ethyl} guanidine was 50 mg / kg po

Compounds of formula (I) are prepared by reacting a tetrahydropyrido [3,4-b] indole compound of formula (II) in an aprotic organic solvent such as a chlorinated hydrocarbon, an aromatic hydrocarbon; or in a dipolar aprotic solvent, such as dimethylformamide, with an epoxide compound of formula (III). The addition reaction is carried out at the reflux temperature of the solvent used. The reaction is monitored by TLC and may be from 1 to 30 hours, depending on the solvent used.

After completion of the reaction, the resulting compounds of formula (I) may be purified, if desired, by recrystallization or column chromatography, or by conversion to a pharmaceutically acceptable acid addition salt in a known manner. The salt formation is carried out in a known manner in an inert organic solvent such as a C 1 -C 3 alcohol or acetone or a halogenated hydrocarbon such as chloroform or a mixture thereof by dissolving the compound of formula (I) in one of the above solvents, then add the appropriate acid to the solution until the pH of the mixture becomes slightly acidic (about pH 5-6). Salt formation may also be accomplished by adding to the solution a calculated amount of the desired acid in one of the solvents mentioned above. The precipitated acid addition salt is then isolated from the reaction mixture by any suitable means, such as filtration.

The compounds of formula (II) having a substituent other than R ₂ and the compounds of formula (III) exist in racemic or pure enantiomeric forms. Thus, since it is possible to form two centers of asymmetry in the reaction, the resulting compounds of formula (I) may be optically active compounds or diastereomeric mixtures, depending on the nature of the starting materials. Starting from compounds of formula II wherein R is hydrogen, they can be reacted with racemic or optically active (ΙΠ) epoxide compounds to give compounds of formula (I).

The active ingredient may be formulated in pharmaceutical compositions with non-toxic, inert, solid or liquid carriers and / or excipients used in the pharmaceutical industry for parenteral or enteral administration. Suitable carriers include, for example, water, gelatin, lactose, starch, pectin, magnesium stearate, stearic acid, talc, vegetable oils such as peanut oil, olive oil and the like. It can be used. The active ingredient may be in the form of standard pharmaceutical compositions, for example solid (round or square tablets, dragees, capsules, such as hard gelatin capsules, pills, suppositories, etc.) or liquid (e.g., oily or aqueous solution, suspension, emulsion, syrup, capsule, injectable oily or aqueous solution or suspension, etc.)

EN 210 679 Β. The amount of solid carrier can vary widely, preferably from about 25 mg to about 1 g. The compositions may optionally contain conventional pharmaceutical excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffers, flavoring agents, perfumes, and the like. may also be included. The compositions may also optionally contain other pharmaceutically acceptable compounds of known value without exhibiting synergistic effects. The composition is preferably formulated in dosage units appropriate to the desired route of administration. The pharmaceutical compositions may be prepared by conventional techniques, which include, for example, sifting, mixing, granulating, and pressing or dissolving the ingredients in the appropriate compositions. The compositions may be subjected to other conventional pharmaceutical operations (e.g., sterilization).

The following examples illustrate the process of the present invention without limiting its scope to these examples.

Example 1 (±) -2- [3- (Pentafluorophenoxy) -2-hydroxypropyl] -1,2,3,4-tetrahydropyrido [3,4-b] indole [(I) -R = H, X = fluorine, n = 5]

6.88 g (0.040 mol) of 1,2,3,4-tetrahydropyrido [3,4-b] indole and 8.2 ml (0.042 mol) of (±) -1,2-epoxy-3-pentafluorophenoxypropane. After refluxing for 22 hours, the precipitate formed after cooling was filtered, washed with chloroform and air-dried.

Yield: 5.62 g (34%)

Melting point: 185-186 ° C.

Example 2 (±) -2- [3-Phenoxy-2-hydroxypropyl] -1,2,3,4-tetrahydropyrido [3,4-b] indole 1 (1), X = H, R = H]

6.9 g (0.04 mol) of 1,2,3,4-tetrahydropyrido [3,4-b] indole and 8 ml (0.06 mol) of (±) -1,2-epoxy-3- phenoxypropane was boiled in 40 mL of dimethylformamide for 1 hour. The reaction mixture was concentrated in vacuo and the residual oil was recrystallized from ethyl acetate (80 mL).

Yield: 4.31 g (33.5%)

Melting point: 168-169 ° C (ethyl acetate).

Instead of 1,2,3,4-tetrahydropyrido [3,4-b] indole, (±) 1-methyl-1,2,3,4-tetrahydropyrido [3,4-b] indole is reacted with under conditions, 1-methyl-2- [3-phenoxy-2-hydroxypropyl] -1,2,3,4-tetrahydropyrido [3,4-b] indole is obtained as a diastereomeric mixture which is isolated as the hydrochloride salt.

Melting point: 150-152 ° C (acetonitrile).

Example 3 1-Benzyl-2- [3- (pentafluorophenoxy) -2-hydroxypropyl] -1,2,3,4-tetrahydropyrido [3,4-b] indole diastereomeric mixture [(I), X = fluorine, n = 5, R = benzyl]

2.62 g (0.010 mol) of (±) -1-benzyl-1,2,3,4-tetrahydropyrido [3,4-b] indole and 4 ml (0.024 mol) of (+) - 1,2-epoxy3- (pentafluorophenoxy) -propane is boiled in 50 ml of toluene for 30 hours. The reaction mixture was concentrated in vacuo, the residue was triturated with n-hexane, filtered, washed with n-hexane and air dried.

Yield: 4.82 g (96%)

M.p. 123-124 ° C.

Example 4 (±) -2- [3- (4-Chlorophenoxy) -2-hydroxypropyl] -1,2,3,4-tetrahydropyrido [3,4-b] indole [(1), X = chlorine atom, η -1, R = H]

3.44 g (0.020 mol) of 1,2,3,4-tetrahydropyrido [3,4-b] indole (3.4) (0.022 mol) (±) -1,2-epoxy-3- (4-chlorophenoxy) -propane is heated in 60 ml of toluene for 5 hours. The reaction mixture was concentrated in vacuo, the residue was triturated with diisopropyl ether, filtered, washed with diisopropyl ether and air dried. The crude product obtained (4.84 g) is chromatographed on a silica gel column in dichloromethane / methanol 9: 1.

Yield: 1.86 g (26%)

Melting point: 160-161 ° C.

Reaction of the corresponding 1-substituted 1,2,3,4-tetrahydropyrido [3,4] indole and 1,2-epoxy-3- (substituted-phenoxy) -propane with the above procedure gives the following compounds (in parentheses) the solvent used for the reaction and the solvent or mixture of solvents used for column chromatography):

(±) -2- [3- (4-bromophenoxy) -2-hydroxypropyl] -1,2,3,4-tetrahydropyrido [3,4-b] indole [(I), X = bromo, n =

1] (chloroform; chloroform / methanol = 9: 1)

Melting point: 177-178 ° C.

(±) -2- [3- (4-fluorophenoxy) -2-hydroxypropyl] -1,2,3,4-tetrahydropyrido [3,4-b] indole [(I), X = fluorine, n =

1] (chloroform; chloroform / methanol = 9: 1)

Melting point: 174-175 ° C. Diastereomeric mixture of 1-methyl-2- [3- (pentafluorophenoxy) -2-hydroxypropyl] -1,2.3,4-tetrahydropyrido [3,4-b] indole [(I), X = fluorine atom, n = 5 ] (chloroform; chloroform / methanol = 95: 5)

M.p. 133-134 ° C. Diastereomeric mixture of 1-propyl-2- [3- (pentafluorophenoxy) -2-hydroxypropyl] -1,2.3,4-tetrahydropyrido [3,4-b] indole [(I), X = fluorine, n = 5 ] (toluene; ethyl acetate)

Melting point 121-122 ° C. 1-Phenyl-2- [3- (pentafluorophenoxy) -2-hydroxypropyl] -1,2.3,4-tetrahydropyrido [3,4-b] indole diastereomeric mixture [(I), X = fluorine, n = 5] (toluene; ethyl acetate)

138-139 ° C.

Claims (3)

PATENT CLAIMS A process for the preparation of tetrahydropyrido [3,4-b] indole compounds of formula I wherein R is hydrogen, (C 1 -C 4) -alkyl, phenyl or benzyl; X is hydrogen or halogen, n is an integer of from 1 to 5 and is a pharmaceutically acceptable acid addition salt thereof. Characterized in that a tetrahydropyrido [3,4-b] indole derivative of the formula (Π) wherein R is as defined above - or an acid addition salt thereof, in the latter case after the release of a base of a compound of the formula (ΙΠ) with an epoxide compound wherein X and n are as defined above and optionally converting the resultant compound of formula (I) into a pharmaceutically acceptable acid addition salt. Process according to Claim 1, characterized in that the reaction of the compounds of formula (II) and (III) is carried out in an organic aprotic or dipolar-aprotic solvent at the reflux temperature of the solvent used. 3. A process for the preparation of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, wherein a compound of formula (I) according to claim 1 wherein R, X and n are as defined in claim 1. as defined herein - is mixed with a carrier and / or other excipients customary in the pharmaceutical industry to form a pharmaceutical composition.