CH622017A5 - Process for the preparation of novel 2-tetrahydrofurfuryl-6,7-benzomorphans - Google Patents

Abstract

Novel 2-tetrahydrofurfuryl-6,7-benzomorphans of the formula I, in which R<1> denotes methyl, ethyl or propyl; R<2> denotes hydrogen, methyl or ethyl; R<3> denotes hydrogen or methyl; and R<4> denotes alkyl having 1 to 4 carbon atoms are prepared by O-alkylating an appropriate 2'-hydroxy compound. The resulting bases of the formula I can then be converted into their acid addition salts. The compounds of the formula I and their acid addition salts are distinguished by a therapeutically utilisable action on the central nervous system. Particularly to be emphasised is their analgesic action, which frequently excels that of morphine, without exhibiting the undesired side effects of morphine, e.g. the addictive action. <IMAGE>

Description

The invention relates to a process for the preparation of new 2-tetrahydrofurfuryl-6,7-benzomorphans of the formula I.

designation

Form of II

configuration

(±) -H

racemic

-

(-) - n turning left

1R, 5R, 9R

(+) - n turning right

1 p, 5 p, 9 p

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622017

With the N-tetrahydrofurfuryl substitution, an additional asymmetry center occurs in the molecule (at the C-2 "in the tetrahydrofuran ring). It is therefore to be expected that two rows (1,1) and (I , 2) of racemic diastereomers and the associated optical antipodes, which owe their existence to the following possible combinations:

designation

configuration

Benzomorphan

N-tetrahydro-furfuryl residue

1.1

1.2

1 R, 5 R, 9 R - (-) 1 S, 5 S, 9 S - (+)

1R, 5 R, 9 R - (-) IS, 5S, 9S - (+)

D - (-) \ L - (+) /

L - (+) \ D - (-) /

racemic diastereomer 1 racemic diastereomer 2

Which of the optical antipodes belonging to (1,1) or (1,2) is the left-handed and which is the right-handed shape cannot be specified on the basis of the configuration, but only results from the measurement in the polarimeter.

For some of the 2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphans (formula I, R1 = R2 = CH3 and R3 = H) obtainable according to the invention, it has been shown that the direction of rotation of the base body of formula II is not changed by introducing the D - (-) - or L - (+) - tetrahy-drofurfuryl residue. It is likely, but by no means certain, to predict that this connection also applies to compounds of the formula I with other combinations of R1 to R4.

With regard to the nomenclature of the compounds of the formula I, there is no difficulty with the optically active representatives, as can be seen from the table above. If the 1R, 5R, 9R or IS, 5S, 9S label is used, the configuration on the C-9 is clearly defined and the «a» in the chemical name can be omitted. With the racemic compounds, however, one cannot predict which of the two possible diastereomers is present. In the description, both racemic diastereomers are identified by (±) and distinguished from one another by the addition of “diastereomer 1” or “diastereomer 2”, where 1 and 2 mean the sequence of the isolation.

The compounds are prepared according to the invention by using a compound of the formula III

N CH

correspondingly O-alkylated and the process products optionally converted into their physiologically acceptable acid addition salts.

The O-alkylation can be carried out by various methods. Preferred alkylating agents and methods that enable selective O-alkylation are

without the nitrogen being quaternized. Corresponding diazoalkanes and phenyltrialkylammonium hydroxides are particularly suitable alkylating agents for this purpose. If diazoalkanes are used, it works in diethyl ether or tetrahydrofuran, preferably at room temperature. When using phenyltrialkylammonium hydroxides, the starting compound is expediently heated together with the alkylating agent in a suitable inert solvent, preferably in dimethylformamide.

The reaction products obtained can be isolated from the batches using customary methods. If necessary, the raw products obtained can be applied using special methods, e.g. column chromatography, before being crystallized in the form of the bases or suitable acid addition compounds.

Depending on the choice of reaction conditions and reactants, the reaction products obtained are either sterically uniform compounds or mixtures of racemic or optically active diastereomers.

Depending on the choice of reaction conditions and reactants, the reaction products obtained are either sterically uniform compounds or mixtures of racemic or optically active diastereomers.

Because of their different chemical and physical properties, diastereomers can be prepared by known methods, e.g. by fractional crystallization. Racemic compounds can be separated into the corresponding antipodes using conventional racemate resolution methods.

The starting compounds of formula III can be prepared by using a norbenzomorphan of formula IV

H

with a compound of formula V

wherein X denotes a nucleophilically removable group, preferably a halogen atom, in particular chlorine, bromine or iodine, or an arylsulfonyloxy, aralkylsulfonyloxy or an alkylsulfonyloxy group.

The optically active tetrahydrofurfuryl halides of formula III can be obtained from the known optically active alcohols (F.C. Hartmann and R. Barker, J. Org. Chem. 29 [1964] 873-877) by halogenation, e.g. with phosphorus pentachloride s

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4th

or phosphorus pentabromide (Org. Synth. 23, 88).

L - (+) - tetrahydrofurfuryl alcohol: [a] ^ s = + 15.3 ° (c = 5,

Nitromethane) Kp76 ° / 16mmHg D - (-) - tetrahydrofurfury alcohol: [a]], 5 = —15.7 ° (c = 5,

Nitromethane) bp 76 ° / 16mmHg L - (+) - tetrahydrofurfuryl bromide: [o.] ^ 5 = + 3.9 ° (c = 5,

Nitromethane)

Bp 66-67 ° / 16 mm Hg D - (-) - tetrahydrofurfuryl bromide: [a] ^ ä = -3.8 ° (c = 5,

Nitromethane)

Kp 67 ° / 16 mm Hg.

Corresponding sulfonic acid esters can be prepared by reacting the tetrahydrofurfuryl alcohols with sulfonic acid halides.

The compounds of the formula I which can be prepared according to the invention are bases and can be converted into their physiologically tolerated acid addition salts in the customary manner. Acids suitable for salt formation are, for example, mineral acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, or organic acids, such as acetic acid, propionic acid, butyric acid, valeric acid, pivalic acid, caproic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid Lactic acid, pyruvic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-hydroxybenzoic acid, salicylic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, ascorbic acid, 8-chlorothheophylline, methanesulfonic acid and ethanephosphoric acid.

The compounds of the formula I which can be prepared according to the invention and their acid addition salts have a therapeutically useful effect on the central nervous system. The analgesic effect, which e.g. can be demonstrated on the mouse in the writhing test, hot plate test and Haffner test. The most effective representatives for subcutaneous injection, depending on the test, reach ten to thirty times the strength of morphine. Despite this high effectiveness, the typical side effects of morphine, e.g. the Straub tail phenomenon and the mane gear. The absence of these side effects, which are typical in particular for compounds with activity in the Haffner test, suggests the absence of other undesirable properties of the morphine, in particular the lack of addiction. The relationship between the tail and addiction potential is documented in the literature; see. I. She-mano and H. Wendel: A Rapid Screening Test for Potential Addiction Liability of New Analgesie Agents, Toxicol. Appi. Pharmacol. 6 (1964) 334-339. The new compounds are further distinguished by a greater therapeutic breadth in comparison to morphine. The compounds also show no morphine-like effect on the morphine-addicted rat.

The compounds of the formula I which can be prepared according to the invention and their acid addition salts can be used enterally or else parenterally. The dosage for enteral and parenteral use is about 0.5 to 100 mg, preferably between 1 and 20 mg. The compounds of formula I or their acid addition salts can with other painkillers or with other active ingredients, eg. B. sedatives, tranquillizers, hypnotics can be combined. Suitable pharmaceutical dosage forms are, for example, tablets, capsules, suppositories, solutions, suspensions, powders or emulsions; the galenical auxiliaries commonly used can

Carriers, explosives or lubricants or substances are used to achieve a depot effect. The preparations can be produced using the methods customary in galenics.

The tablets can consist of several layers. Correspondingly, dragées can be produced by coating cores produced in the same way as the tablets with agents usually used in dragee coatings.

The core can also consist of several layers to achieve a depot effect or to avoid incompatibilities. Likewise, the dragéehille can be constructed from several layers in order to achieve a depot effect.

Juices containing the compounds of formula I and optionally other active ingredients can additionally contain sweeteners, taste-improving agents, e.g. Flavorings. They can also contain suspending agents, thickeners, wetting agents and / or protective substances.

Injection solutions can be prepared in the usual way, e.g. prepared with the addition of preservatives or stabilizers and filled into injection bottles or ampoules.

Suitable suppositories can be produced, for example, by mixing with conventional carriers, such as neutral fats or polyethylene glycol or its derivatives.

The following example illustrates the invention in a non-restrictive manner.

example

(±) -2-tetrahydrofurfuryl-2 / -methoxy-5,9a-dimethyl-6,7-benzomorphan (O-methyl derivative of diastereomer I)

3.37 g (0.01 mol) (±) -2-tetrahydrofurfuryl-2'-hydroxy-5,9a-dimethyl-6,7-benzomorphan hydrochloride (Diastereomer I) and 1.9 g (0.011 mol) phenyl trimethyl-ammonium chloride are dissolved together in 100 ml of methanol, and 1.08 g (0.02 mol) of sodium methylate are added to the solution while stirring. Sodium chloride precipitates, which is suctioned off after 2 hours of stirring. The filtrate is evaporated, the residue is dissolved with dimethylformamide and the solution is evaporated again. Fresh dimethylformamide (30 ml) is then added and the reaction mixture is refluxed for 2 hours. After cooling, the mixture is evaporated and the residue is shaken in a separating funnel with 50 ml of 2N NaOH and 50 ml of chloroform. After separation of the phases, the aqueous solution is extracted twice with 50 ml of chloroform. The combined extracts are washed with water, dried with sodium sulfate and i.V. evaporated. The residue is purified by chromatography on 200 g of silica gel using the eluent chloroform / methanol / conc. Ammonia in the volume ratio 90: 10: 0.5 cleaned. For this purpose, the evaporation residue is dissolved in 20 ml of the flow agent and the solution is applied to a silica gel column, which was prepared using the flow agent mentioned, for chromatography. The eluate is eluted and collected in fractions of 25 ml. After testing by thin-layer chromatography, the fractions are combined with the pure substance and evaporated i.V. a. The residue is dissolved with a little ethanol and the solution acidified with ethanolic HCl and mixed with ether until the cloudiness begins. The hydrochloride crystallizes, which, after standing overnight, is filtered off with suction at 2 ° C. and washed with ethanol / ether 1: 1, then ether and dried at 80 ° C. 1.5 g of the title compound are obtained with a melting point of 207 to 208 ° C., which does not change after recrystallization from ethanol / ether.

The starting compound is made as follows:

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21.7 g (0.1 mol) (±) -2-hydroxy-5,9a-dimethyl-6,7-benzomorphan, 13.7 g sodium hydrogen carbonate, 19.9 g (0.12 mol) (± ) -Tetrahydrofurfuryl bromide and 2 g of potassium iodide are heated to 100 ° C. in 200 ml of dimethylformamide with vigorous stirring for 18 hours. The mixture is then cooled and 400 ml of water are added within 2 hours, the product is filtered off with suction and the residue is washed several times with water. After the last sharp suction and drying at 80 ° C., 25.4 g of a crystallizate is obtained, which consists of the two racemic diastereomers I and II of (±) -2-tetrahydrofurfuryl-2-hydroxy-5,9a-dimethyl-6 , 7-benzomorphans exists. The mother liquor is discarded.

The racemic diastereomers I and II are separated in the form of their hydrochlorides. The procedure is as follows: The diastereomer mixture is concentrated with the addition of 7.3 ml. Hydrochloric acid dissolved in 100 ml of ethanol. Crystallization occurs immediately. After standing overnight, the product is filtered off with suction, washed with ethanol / ether 1: 1 then with ether and dried in air and finally at 80 ° C. 13.5 g of not quite pure hydrochloride of diastereomer I and the mother liquor 1 are obtained. Recrystallization from 350 ml of ethanol gives 8.1 g of pure substance with a melting point of 294 ° C. and the mother liquor 2. Evaporation of the mother liquor 2 leads to 100 ml to 2.6 g of post-crystallizate with a melting point of 287 to 288 ° C. and the mother liquor 3. The latter is mixed with the mother liquor 1 IV evaporated and the residue crystallized from 50 ml of ethanol, a further 1.5 g of substance from the melting point of 287 to 288 ° C. and the mother liquor 4 being obtained. The crystals from melting point 287 to 288 ° C are combined (4.1 g) and recrystallized from 40 ml of ethanol. This gives again 2.9 g of pure hydrochloride of diastereomer I with a melting point of 294 ° C. and is mother liquor 5. The total yield of pure substance from the melting point of 294 ° C. is thus 11.0 g.

Diastereomer II can be isolated from mother liquors 3, 4 and 5.

B

Claims (6)

622017 2nd PATENT CLAIMS 1. Process for the preparation of new 2-tetrahydrofurfuryl-6,7-benzomorphans of the formula I (I), wherein R1 methyl, ethyl or propyl; R2 is hydrogen, methyl or ethyl; R3 is hydrogen or methyl; and R4 is alkyl with 1 to 4 carbon atoms, and of their acid addition salts, characterized in that a norbenzomorphan of the formula III N CH " i / 2 (III) correspondingly O-alkylated and the process products optionally converted into their physiologically acceptable acid addition salts. 2. The method according to claim 1, characterized in that the compounds of the formula are used in the form of the racemates. 3. The method according to claim 1, characterized in that the compounds of the formula Ol are used in the form of the optically active compounds. 4. The method according to claim 1, characterized in that one starts from a compound of formula III with race-mix tetrahydrofurfuryl. 5. The method according to claim 1, characterized in that one starts from a compound of formula III with an optically active tetrahydrofurfuryl radical. 6. The method according to claim 1, characterized in that one carries out the reaction in the presence of an organic solvent or solvent mixture. (I) 5 wherein R1 methyl, ethyl or propyl; R2 is hydrogen, methyl or ethyl; 20 R3 is hydrogen or methyl; and R4 is alkyl with 1 to 4 carbon atoms, and their acid addition salts. In the compounds of the formula I obtainable according to the invention, the radicals R1 and R2 are arranged in the cis position with respect to the carbocy-2s clic ring. It follows from this that, provided that R1 and R2 are the alkyl groups mentioned and R2 is different from R3, only compounds of the a series with cis-containing alkyl radicals R1 and R2 are obtained. Compounds of the formula I in which R1 30 and R2 denote methyl (2-tetrahydrofurfuryl-2'-hydroxy-5,9-dimethyl-6,7-benzomorphane) are preferably prepared. With the definition of the compounds of the formula I given above, the following situation arises with regard to the stereochemistry: the norben-3s zomorphan of the formula II on which the compounds are based (II), has 2 asymmetry centers if R2 = R3 or 3 asymmetry centers if R2 is not identical to R3. Because of the rigid installation of the asymmetry centers Cl and C-5 in a bridged ring system and because of the definition of the asymmetry center C-9 (restriction to the a series), the Nor-60 compounds of formula II on which formula I are based only exist in a single one race-mix shape and the associated optical antipodes. 65