DE2315339A1 - N- (HETEROARYLMETHYL) -2'-HYDROXY-5.9. 9-TRIMETHYL BENZOMORPHANES, THEIR ACID ADDITION SALTS, THE MEDICINAL PRODUCTS CONTAINING THESE AND THE METHOD FOR THEIR MANUFACTURING - Google Patents

Description

Case 1/489
Dr.Cr/Ha

CH. Boehringer Sohn, Ingelheim am fihein 1

N-CHeteroarylmethyl) -2'-hydroxy-5.9.9-trimethylbenzo ~

morphans, whose acid addition salts, these *

holding drugs as well as procedures too

their manufacture

The invention relates to new N- (heteroarylmethyl) -2 ^f hydroxy-5.9.9-trimethylbenzomorphanes of the general formula I and their acid addition salts with valuable therapeutic properties. In formula I, R is a hydrogen atom or a methyl group and X is an oxygen or sulfur atom.

The invention includes both optically inactive racemates or racemic mixtures as well as the pure optical antipodes.

The preparation of the benzomorphans according to the invention of the general

/ 2 409842/1072

say. Formula I is made through

1. Implementation of a norbenzomorphans of the formula II with a Furylmethyl or. Thienylmethyl derivative of the formula IH wherein R and X have the meanings given above and Y is a halogen atom, preferably chlorine or bromine or an alkylsulfonyloxy or Means arylsulfonyloxy group; or

2. Reduction of an amide of the formula IY, wherein R and X are as above Have the meaning mentioned and R-, a hydrogen atom or denotes an acyl radical, with complex metal hydrides, preferably with lithium aluminum hydride.

The reaction of the Morbenzomorphans of formula II is carried out with the calculated quantity or a slight excess of the alkylating agent of the formula ¹ III in the presence of acid-binding substances useful. Acid-binding agents which can be used are amines such as triethylamine, dicyclohexylethylamine or metal carbonates such as sodium carbonate or potassium carbonate or metal hydrogen carbonates, preferably sodium hydrogen carbonate or metal hydroxides or oxides. The reaction is advantageously carried out in an inert solvent or solvent mixture, for example tetrahydrofuran, dioxane, methylene chloride, dimethylformamide, dimethyl sulfoxide. Mixtures of tetrahydrofuran and dimethylformamide are preferably used. The reaction temperature can be varied within wide limits; temperatures between ⁰ ° C. and the boiling point of the solvent or solvent mixture are preferred. After the reaction, the reaction products are isolated, purified and crystallized with the aid of known methods.

When reducing compounds of the. Formula IT will be either

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the calculated amount or, advantageously, an excess of the complex hydride, preferably up to twice the calculated amount. It is expedient to work in suitable inert solvents or solvent mixtures, for example ethers, preferably in tetrahydrofuran. The reaction temperature is variable within wide limits. ^{Temperatures between 0} ° C. and the boiling point of the solvent or solvent mixture are preferred. In the reduction of O-acyl-benzomorphanamides, compounds of formula IV, in which R, denotes an acyl radical, with complex metal hydrides, in addition to the reduction of the carbonyl group, the O-acyl radical is also split off at the same time, resulting in compounds of formula I. Reaction products are isolated and crystallized using known methods.

The 5.9.9-Tfcimethyl-norbenzomorphan used for method I " is known from the German Offenlegungssehrift 2 027 077. Starting compounds of formula III are obtained, e.g. starting from corresponding known purane or thiophene carboxylic acid esters by reduction to hydroxymethylfurans or hydroxymethylthiophenes, which are converted into corresponding halomethylfurans or halomethylthiophenes by means of acid halides can. On the other hand, one can use hydroxymethylfurans or hydroxymethylthiophenes esterify with sulfonic acids to produce compounds of formula III, wherein Y is an alkylsulfonyloxy or arylsulfonyloxy radical.

Starting compounds of Pormel IV are obtained by reacting 5.9.9-trimethyl-norbenzomorphane of Pormel II with purancarboxylic acid chlorides or thiophenecarboxylic acid chlorides of the formula V, in which X and R are as defined above, prepared.

/ 4

Acid chlorides of the formula V are obtained by reacting the appropriate Carboxylic acids with inorganic acid halides, e.g. phosphorus pentachloride, phosphorus oxychloride or thionyl chloride.

The compounds of the formula I according to the invention are bases and can be converted into their physiologically compatible acid addition salts in the usual way, e.g. by dissolving them in alcohols or ketones and adding essential acid solutions. Acids suitable for salt formation are, for example, mineral acids, such as Hydrochloric acid, hydrobromic acid, hydriodic 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, capric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, Lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, parahydroxybenzoic acid, phthalic acid, cinnamic acid, salicylic acid, Ascorbic acid, e-chlorotheophyllim methanesulfonic acid or the like.

The N- (heteroarylmethyl) -2'-hydroxy-5.9.9-trimethylbenzomorphanes of the formula I and their acid addition salts have a therapeutically useful effect on the central nervous system. They are compounds with morphine-antagonistic and / or analgesic properties. The morphine antagonism can be demonstrated in mice and rats in the Haffner test (German medical weekly publication Volume 55, page 731 (1929)). In the more sensitive pharmacological analgesic tests e.g. hot plate test (J. pharmacol. Erp, therap. Volume 80, page 300 (1944)) or the writhing test ( ^J. pharmacol. Exp. Therap. Volume 154, page 319 (1966)) ) analgesic efficacy can be demonstrated.

^{/ 5}

The compounds of general formula I according to the invention and their acid addition salts can be enterally or parenterally can be applied. The dosage for oral use is approximately 10 to 300 mg, preferably between 50 and 150 mg. The compounds of the formula I or their acid addition salts can also be used with other analgesic agents or with other types Active ingredients e.g. sedatives, tranquilizers, hypnotics are combined. Combinations can also be made with making addictive analgesics. Suitable pharmaceutical dosage forms are. or tablets, capsules, suppositories, solutions, Suspensions or powders; in this case, the galenic auxiliary, carrier, Disintegrants or lubricants or substances to achieve a depot effect are used. The production of such galenic Dosage forms are carried out in the usual way according to known manufacturing methods.

The following examples illustrate the invention without restricting it.

Example 1 (method 1)

2- (5-thienylmethyl) -2 '-hydro3cy-5. 9.9-trimethyl-6,7-benzomorphane hydrochloride

2.31 g (0.01 mol) of 2-hydroxy-5,9,9-trimethyl ^{t-benzomorphan,} 1.26 g (0.015 mol) of NaHCO ₃ and 1.95 g of 3-bromomethylthiophene (Ο, Οΐί-mol) are heated under reflux for 5 hours with stirring in 35 ml of tetrahydrofuran / diaethylformamide (2: 1 v / v). It is then concentrated in vacuo and the residue with methylene chloride and water

/ 6 409842/107?

shaken vigorously. The organic phase is separated, twice Washed vigorously with water, dried with sodium sulfate and evaporated. The remaining oily base is in 20 ml of absolute ethanol dissolved with 5 ml of 2.η ethereal hydrochloric acid acidified and carefully mixed with ether. 2.62 g of hydrochloride are obtained in a yield of 72% theory a melting point of 206-209 ° C

Example 2 (method 2) . .- ~

2- (furfuryl) -2'-hydroxy-5,9,9-tritaethyl-6,7-henzomorphane hydrochloride

2.31 g (0.01 mol) 2 ^{I-hydroxy-5,9,9-trimethyl-benzomorphan} is dissolved in 30 ml of absolute methylene chloride and mixed with 4 ml of M-ethylamine. 1.44 g (0.011 mol) of 2-furancarboxylic acid chloride are added dropwise to this solution at room temperature over the course of 15 minutes. Then it is heated for 1 hour in the reflux. The solution is then diluted with methylene chloride and shaken vigorously several times with water.

After drying and concentration, the residue is dissolved in 35 ml of absolute tetrahydrofuran and added to 0.76 g of LiAlH. (0.02 mol) in 35 ml of absolute tetrahydrofuran. Eb is refluxed for a further 2 hours. The cooled mixture is carefully decomposed with 76 ml of saturated "diammonium tartrate solution. After standing for a long time it is separated off, the aqueous phase is shaken twice with 100 ml of methylene chloride and the organic phase is combined with the tetrahydrofuran residue. After vigorous washing with water, the organic phase is washed over Na ₂ The residue, which remains as an oily base, is dissolved in 20 ml of absolute ethanol, 5 ml of ethereal hydrochloric acid are added and the hydrochloride is obtained in crystalline form by careful addition of ether.

77 40 9 842/107 '/

Yield: 2.8 g = 80,65ε of theory Melting point: 180-184 ⁰ C.

The ^f olgenden compounds of formula analogous to the above examples

getting produced

example
No.

Yield in terms of theory

M.p.

ro

procedure

-CH ₂ -

I I

77.2 220-4

-CH,

255-8

83.2

21-6

/8th

409842/107?

Example R Yield MP. Process

No. $ of (C)

theory

. 6 -CH ₂ -IL H 55.4 201-4

B. __lOrmul ijsrungs b_e i, s £ ie ^ l, e
Example 9: tablets

2- (Fu * furyl) -2 · -hydroxy-5,9., 9-

trimethyl-6,7-benzomorphane

hydrochloride 50.0 mg

Milk sugar '95.0 mg

4 0S8 4. ? / 1 0 7>

Corn starch colloidal silica loaiche starch magnesium stearate

45 » 0 mg 2 , 0 mg 5 , 0 mg 3 , 0 mg

total 200.0 mg

Manufacturing:

The active ingredient is intimately mixed with some of the excipients and granulated with a solution of the soluble starch in water. After the granules have dried, the rest of the excipients are mixed in and the mixture is made into tablets of 200 mg each compressed, each tablet containing 50 mg of active ingredient.

Example 10: Dragees

2- (3-Thienylme thy 1) -2'-hydroxy-5,9,9-trimethyl-ojT -benzomorphane hydrochloride 75.0 mg

Milk sugar 100.0 mg

Corn starch 65.0 mg

colloidal silica 2.0 mg

soluble starch 5.0 mg

Magnesium stearate 3.0 mg

a total of 250.0 mg

Manufacturing:

The active ingredient and the excipients are described as in Example 9, pressed into tablet cores which are coated with sugar, talc and gum arabic in the usual way.

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- ίο -

Example 11: Suppositories

2- (furfuryl) ^-2-hydroxy-r 5.9 »9-trimethyl-6,7-ben2omörphan hydrochloride 50.0 mg

Milk sugar 250.0 mg

suppository mass q.s. ad. 1.7 g

Manufacturing:

The active ingredient and the milk powder are intimately mixed with one another and uniformly suspending the mixture in the molten suppository mass. The suspension is cooled in Molds poured into suppositories weighing 1.7 g each, each suppository containing 50 mg of active ingredient.

Example 11: ampoules ^r

2 <3-Ihieny! Methyl) -2-hydroxy-5,9,9-trimethyl-6 ^ -benzomorphane hydrochloride 50.0 mg

Sodium chloride 5.0 mg

double distilled water q.s. ad 5.0 ml

Manufacturing:

The active ingredient and the sodium chloride are distilled in double Dissolve water, filter the solution free of particles and fill it in sterile ampoules with 5 ml content each.

/ 11 409842/1072

Claims (10)

-IL- PATENT CLAIMS 1 ^; . N- (Heteroarylmethyl) -2'-hydroxy-5 »9,9-trimethyl-benzomorphanes of the general formula I, in which R is a hydrogen atom or a methyl group and X is an oxygen or sulfur atom, and acid addition salts thereof. 2. Raeemates or racemic mixtures and optically active forms of the compounds of the formula I according to Claim 1 and their acid addition salts. 3. Process for the preparation of K- (heteroaryl ^ ethyl) -2'-hydroxy -5,9,9-trimethyl-beneomorphanes of the general formula I and their acid addition salts, characterized in that a) a benzomorphan of the formula II with a heteroarylmethyl derivative of the formula III, in which R and X have the meanings given above and Y is a halogen atom, preferably a Bromine or chlorine atom or an alkylsulfonyloxy or arylsulfonyloxy group means, converts; or b) an amide of the formula IV, in which X and R are as mentioned above Have meanings and R, a hydrogen atom or a Acyl radical, with a, preferably complex, metal hydride reduced and optionally the compounds of the general formula I in their physiology harmless Acid addition salts transferred. 4. The method according to claim 3, characterized in that one carries out the reactions in the presence of an organic solvent or reading medium mixture. / 12 40984? / 107V 5. The method according to claim 3 and / or 4, characterized in that the reactions are carried out at a temperature of -10 ⁰ C to the boiling point of the solvent or solvent • carries out misehea. 6. The method according to any one of the preceding claims 3 to 5, da-. characterized in that the U-alkylation is in the presence of an acid-binding agent. 7. The method according to claim 6, characterized in that the acid-binding agent amines, metal carbonates, hydrogen carbonates » Hydroxides or oxides used. 8. The method according to claim 7, characterized in that one as amines triethylamine, dicyclohexylethylaminials metal carbonates Sodium carbonate or potassium carbonate and as metal hydrogen carbonates Hatriumhydrogenearbonet used. 9. Pharmaceutical preparations, characterized in that they use one or more compounds of the general formula I or their physiologically acceptable acid addition salts as the active ingredient contain. 10. Process for the preparation of medicaments according to claim 9, characterized in that one or more compounds of the formula I or their acid addition salts with customary galenic auxiliaries, carriers, disintegrants or lubricants or substances to achieve a deptovirxung to tablets, Formulated capsules, suppositories, coated tablets, powders, solutions or emulsions. / 13