FI68225C - FOERFARANDE FOER FRAMSTAELLNING AV 6,7-BENZOMORFANDERIVAT VILKA AER ANVAENDBARA SOM ANALGETISKA MEDEL ANTAGONISTER FOER NAKOTISKA MEDEL OCH INHIBITORER FOER SEKRETION AV LUTEINISE RIGSHORMON - Google Patents

Description

68225

Process for the preparation of 6,7-benzomorphane derivatives useful as analgesics, narcotic antagonists and inhibitors of luthenizing hormone secretion 5

Separated from FI Application No. 803237

The present invention relates to novel derivatives of 6,7-benzomorphane.

5-Hydroxy and 2 ', 5-dihydroxy-2-methyl-6,7-benzomorphane as well as the 5-acetoxy and 5-propionyloxy derivatives of the former and the 2', 5-diacetoxy derivatives of the latter are known, e.g. J. Med . Chem. 13, 1223 (1970) and J. Med. Chem. 20, 11, 1413-1419 (1988).

Four of these compounds are said to have poor analgesic activity, which is lower than that of the corresponding 5-H derivatives. The fifth compound is reported to have no analgesic activity.

In accordance with the present invention, it has now surprisingly been found that certain 5-oxy-substituted benzomorphans having a tertiary or quaternary carbon atom in the 9-position have valuable pharmacological activity, in particular analgesic and narcotic activity as well as inhibition of luteinizing hormone secretion. .

The invention relates in particular to compounds of the formula I,> V? <R · Ri, o AA. \ "CH ..

0 * 3 35 optionally having alkoxy-substituted alkyl, alkenyl, alkynyl, cycloalkylalkyl, alkenyloxyalkyl, aralkyl, aralkenyl or tetrahydrofurylalkyl 68225 or optionally alkyl-substituted furylalkyl or isoxynylalkyl, alkyl, hydrogen, alkyl, R 2 is hydrogen, alkyl, alkyl, or aralkyl, hydroxyalkyl or alkoxyalkyl and R 1 is hydrogen, hydroxy, alkoxy or alkenyloxy, in addition, in the compounds of formula I, each hydroxyl group may be optionally acylated.

R 1 as defined above is preferably optionally alkoxy-substituted alkyl, alkenyl, alkynyl or cycloalkylalkyl, aralkyl, or tetrahydrofurylalkyl or optionally alkyl-substituted furylalkyl. R 1 is preferably hydrogen, alkyl, alkenyl, hydroxyalkyl, aralkyl or alkoxyalkyl.

In the compounds of the formula I, the saturated or unsaturated hydrocarbon chains may be branched or straight-chain and preferably contain up to six carbon atoms. The double bonds are separated from the benzomorphan core by at least two carbon atoms. Cycloalkyl-20 groups preferably contain up to six carbon atoms. Aryl is preferably phenyl.

Alkyl, alkenyl, alkynyl, and cycloalkylalkyl groups, such as R 1, may be substituted, preferably mono- or di-substituted, more preferably mono-substituted, with alkoxy. The alkoxy substituents are separated from the Bent-somorphan core by at least two carbon atoms. The acyl residues and R 1 are preferably physiologically hydrolyzable ester residues.

The aliphatic R 1 groups preferably contain up to six carbon atoms in total. The aliphatic R 1 and R 2 groups preferably contain six carbon atoms, more preferably four carbon atoms in total. The aliphatic moieties of the R 1 and R 2 groups terminating in an aryl, cycloalkyl or heterocyclic group preferably contain up to four, more preferably two, carbon atoms.

11 3 68225

When the end group in the slurry is cycloalkyl or a heterocycle aliphatic moiety, it is most preferably methylene. In the R1 group, the alkoxy substituents preferably contain up to three, more preferably two, carbon atoms, with the methoxy group being most preferred. The alkyl substituents on the furylalkyl or isooxazolylalkyl group R 1 are preferably methyl and said groups are preferably mono-substituted. In the group R 1, the alkoxy substituents methoxy and ethoxy, especially methoxy, are preferred. Preferred acyl residues are phenylalkanoyl having up to four carbon atoms in the alkanoyl moiety, alkanoyl having up to four carbon atoms and nicotinoyl, especially benzoyl, acetyl and propionyl.

Preferred compounds of formula I are those wherein R 1 is C 1-6 alkyl, C 2-8 alkoxyalkyl, wherein the alkyl moiety is optionally monosubstituted with nitro, C 1-8 alkenyl, C 1-8 alkynyl, C 4-7 cycloalkylmethyl, C 4-7 ("(1-hydroxycycloalkyl) methyl), (1-methoxycycloalkyl) methyl], C 7-8- (phenylalkyl), C 7-8-20 (phenylhydroxyalkyl), tetrahydrofurylmethyl or furylmethyl optionally ring-substituted with methyl , R 2 is hydrogen or methyl,

R 9 is hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkenyl, C 1-4 alkynyl or C 7-8 (phenylalkyl) and R 8 is hydrogen, hydroxy, C 1-4 alkoxy or C 1-4 alkenyloxy, in addition, in the compounds of formula I, each hydroxyl group may be optionally acylated.

When R 1 in the compounds of formula I is alkyl, it is preferably methyl, ethyl, n-propyl, n-butyl, isobutyl, sec-butyl or n-hexyl, more preferably methyl, ethyl or n-butyl and most preferably methyl .

The alkoxy substituents in the aliphatic residue R 1 are preferably in the 2-position. Preferred alkoxy substituents are methoxy and ethoxy, with methoxy being most preferred.

4,68225

Preferred alkoxy-substituted alkyl groups include 2-methoxyethyl, 2-methoxypropyl, 2,3-dimethoxypropyl, 2-methoxybutyl, 2-methoxy-2-methylpropyl, 2-methoxy-2-methylbutyl, 2-ethoxyethyl and 2-isopropyl. -5-oxyethyl, especially 2-methoxyethyl, 2-methoxypropyl and 2-methoxy-2-methylpropyl, especially 2-methoxy-2-methylpropyl.

When alkenyl or alkynyl is preferably allyl, 3-methyl-2-butenyl, propargyl or 3-butynyl, most preferably 3-butynyl. When R 1 is cycloalkylmethyl, it is preferably cyclopropylmethyl or cyclobutylmethyl.

When R 1 is (1-methoxycycloalkyl) methyl, it is preferably (1-methoxycyclopropyl), (1-methoxycyclo-butyl) or (1-methoxycyclopentyl) methyl, (1-methoxycyclopropyl) and ( 1-methoxycyclobutyl) methyl are most preferred.

When R 1 is phenylalkyl, it is preferably benzyl or phenyl. When R 1 is tetrahydrofurylmethyl or furylmethyl optionally ring-substituted with methyl, it is preferably tetrahydrofurfuryl, furfuryl, 3-furylmethyl, 3-methylfuryl or 2-methyl-3-furylmethyl, more preferably tetrahydrofurfuryl, furfuryl and 3-methylfuryl. and most preferably tetrahydrofurfuryl.

R 2 may be hydrogen or methyl. Preferably R 2 is methyl.

R 2 may be hydrogen. When R 1 is alkyl, it is preferably methyl, ethyl, n-propyl or n-butyl, more preferably methyl or ethyl. When R 1 is hydroxyalkyl, it is preferably 3-hydroxypropyl or 2-hydroxybutyl. When R 1 is alkenyl, it is preferably allyl or 2-butenyl. When R 1 is phenylalkyl, it is preferably benzyl. When R 2 O is hydroxy, it can be acylated. R 1 is then preferably acetyl, propionyl or benzoyl, more preferably acetyl.

li 5 68225 R4 may be hydrogen or hydroxy. When hydroxy is present, it can be acylated. R 1 is then preferably acetoxy, propionyloxy or benzoyloxy, more preferably acetoxy. When R 1 is alkoxy, it is preferably methoxy, ethoxy or n-propyloxy, more preferably methoxy. When R 1 is alkenyloxy, it is preferably allyloxy.

Compounds of formula I in which R 1 is other than hydrogen are preferred.

Particularly interesting compounds of formula I are those in which independently: 1) R 1 is a) monoalkoxy-substituted alkyl, in particular 2-hydroxy- or 2-methoxyalkyl, b) alkenyl or alkynyl, in particular alkynyl, in particular 3-butynyl , and / or c) (1-methoxycycloalkyl) methyl, 2) R 2 is methyl.

3) R 1 is hydrogen or alkyl, especially hydrogen, methyl or ethyl.

4) R 1 is hydroxy or alkoxy, especially hydroxy or methoxy.

Further preferred are compounds of formula I wherein R 2 is methyl and R 1 is hydroxy and wherein: a) R 1 is methyl and R 1 is hydrogen, methyl, ethyl, n-propyl, allyl or 2-butenyl; is allyl and R 1 is methyl, c) R 1 is 3-methyl-2-butenyl and R 1 is methyl or ethyl, d) R 1 is cyclopropylmethyl and R 2 is methyl, e) R 1 is cyclobutylmethyl and R 1 is hydrogen, methyl, ethyl, n-propyl or allyl, f) R 1 is 2-methoxypropyl and R 1 is hydrogen, methyl, ethyl or allyl, g) R 1 is 2-methoxy-2-methylpropyl and R 1 is hydrogen, methyl or ethyl, h) R 1 is (1-methoxycyclopropyl) methyl and R 1 is hydrogen or ethyl, 68225 i) R 1 is (1-methoxycyclobutyl) methyl and R 1 is ethyl, j) R 2 is tetrahydrofurfuryl and is methyl or ethyl, especially methyl or 5 k) R 1 is 3-butynyl and R 1 is hydrogen or methyl.

The compounds of formula I may be in the form of free bases or their acid addition salts, for example as salts with mineral acids such as hydrogen chloride, hydrogen bromide or sulfuric acid, or as salts with organic acids such as maleic, oxalic or tartaric acid.

The ring system of the 6,7-benzomorphane in question contains two asymmetric carbon atoms and, when R 1 is hydrogen, the third asymmetric carbon atom C 8. Since the iminoethane bridge between the atoms C. and Cc is solidly in the cis-15 configuration (1,3-diaxial), with C 1-4 and the atoms being the only asymmetric centers, there will be only one racemate. This racemate can be resolved into optical isomers. If C 1, C 1 and C 8 are the only asymmetric carbon atoms, then the compounds are in two diastereoisomers with a different configuration at the C 8 position. According to the nomenclature of 5,9-dialkyl-6,7-benzomorphans proposed by May / E.L. May, J. Org. Chem. 26, 188, 1621 (1961) J, if the C8 methyl group is in the trans position relative to the iminoethane bridge and thus in the cis position with respect to the substituent OR1, then the isomer is considered to be the <X isomer. If the C8 methyl group is in the cis position with respect to the iminoethane bridge and thus in the trans position with respect to OR1, the isomer is considered to be the β-isomer. The ε and β isomers may each be in two optically active forms, i.e., left and right circulating enan-30 thiomers. These can also be resolved into individual isomers. The number of possible stereomeric forms naturally increases if other asymmetric centers are present in the side chains, i.e. in the N-substituent.

It is to be understood that the compounds of formula 35a I according to the invention comprise the free base and acid addition salt forms, as well as their racemates and the individual optically active isomers, e.g. diastereomeric mixtures 7,68225, the individual diastereomers, D, L-racemates. and separate D and L isomers. However, for pharmacological activity, levorotatory isomers are generally more active.

The present invention also relates to a process for the preparation of compounds of formula I, in which A) a compound of formula III is reduced, N-CO-R * 1 ^ R2 (III) 15R3, wherein R ^ 11 has the meaning that - CH 2 -R * 11 is a group R 1 as defined above and R 2 "R 4 are as defined above / and then, if desired, one or more of the following steps are carried out: B) a compound of formula I in which R 10 and / or R 2 is a hydroxy group or contains a hydroxy group, alkylated; C) hydrogenating a compound of formula I wherein R 10 or R 2 is alkenvy-25; D) the compound of formula I having alkenyl is hydrated; E) performing ether cleavage on a compound of formula I wherein R 1, R 2 and / or R 2 is alkoxy or contains alkoxy; F) a compound of formula I in which R 1 O and / or R 2 is a hydroxyl group or contains a hydroxyl group is acylated; G) a compound of formula I wherein r n is - or R is a 3 '' 4 acyloxy group or contains an acyloxy group, is hydrolysed or subjected to reductive cleavage; and / or 8 68225 H) a compound of formula I wherein R 1 is hydroxyl is dehydroxylated to give a compound of formula I containing hydrogen and, if necessary, the compound of formula I thus obtained is converted into its acid addition salt.

It is to be understood that the above reactions and intermediates may be performed in any suitable order. The procedures for reactions (B) to (H) are described in more detail below.

In Method A, the reduction is conveniently performed using diborane or a high reduction capacity complex hydride such as lithium aluminum hydride. The hydride can be used equimolarly or in excess. The reduction is preferably carried out in an inert solvent, in particular tetrahydrofuran, at a temperature between 0 ° C and the boiling point of the solvent.

The starting materials of formula III used in this process can be prepared by reacting a compound of formula I wherein R is hydrogen with the compound of formula VIII.

^ II

with an acyl halide according to R. -CO-Hal (VIII), wherein II 1 R 1 is the same as above and Hal is halogen, preferably chlorine, or a corresponding carboxylic anhydride. The acylation is preferably carried out in the presence of an acid scavenger, in particular trimethylamine or pyridine. Suitable solvents are, for example, chloroform, pyridine or dimethylformamide. The reaction temperature is generally between 0 ° C and the boiling point of the reaction mixture. If the acylation is performed using a carboxylic acid anhydride in the presence of ortho-phosphoric acid, the hydroxyl groups present, such as and R 2 O, are acylated without acylation at the 2-position.

Compounds of formula III may also be prepared by reacting a compound of formula I wherein R 1 is hydrogen with a compound of formula R 1 -CQ-OH (IX) wherein R 1 is the same as above, e.g. in the presence of dicyclohexyl carbonimide using preferably 35 chloroform as the solvent.

It is clear that method A is not suitable for all substituents, R 1 and R 4. Thus R * 1 in starting materials, e.g.

Il 68225 9 of formula IX used for the preparation of compounds of formula III should not contain hydroxyl groups. However, the compounds containing the hydroxyl groups of the formula III can be prepared by using the corresponding starting materials in which the hydroxyl group has been covalent with acyloxy and hydrolyzing them in the product obtained. If compounds of the formula III in which R 1 is an acyloxy 4 and / or R 1 contains an acyloxy group are reduced, these will usually be converted into a hydroxyl group.

Processes BH can be carried out using as starting material a compound of formula I obtained according to the ring-forming reaction described in F1 Patent Application No. 803237 or using as starting material a compound of formula I obtained using the method described in FI patent applications No. 803237, 833267 and 833269.

Compounds of formula I wherein R 1 is hydrogen and R 1 is hydrogen or alkoxy prepared by Method A may also be converted to the corresponding compounds wherein R 1 is alkyl, alkenyl, alkynyl or aralkyl by first converting them to alkali metal alkoxides, for example with sodium hydride and giving the alkali metal alkoxide. react with an alkyl, alkenyl, alkynyl or aralkyl halide (Method B). Particularly suitable solvents for both reaction steps are aprotic organic solvents, e.g. tetrahydrofuran, dimethylformamide or toluene. The reaction conditions depend on the reactivity of the reactants. Generally, the temperature is between 15 ° C and the boiling point of the solvent, and the reaction time is generally between 2 and 48 hours. The rate of the reaction slows down as the molecular weight of the alkylating agent increases. Therefore, compounds of formula I in which R 1 is an n-propyl or higher alkyl group are preferably prepared from catalytic hydrogenation of the corresponding compound in which R 1 is 2-alkenyl (Method C), since the latter is obtained more rapidly due to the higher reactivity of 2-alkenyl halides. .

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The resulting compounds of formula I having alkenyl can be advantageously converted to the corresponding compounds having hydroxyalkyl by hydration, e.g. by reaction first with diborane, then with hydrogen peroxide / sodium hydroxide (method D). In this way, for example, 5-allyloxybenzomorphane derivatives can be converted into the corresponding 5- (3-hydroxypropoxy) derivatives.

The resulting compounds of formula I in which R 1 is alkyl, alkenyl, alkynyl, aralkyl or hydroxyalkyl and / or is alkoxy can be selectively converted by cleavage of the ether into the corresponding compounds in which R 1 is hydroxyl (method E). Cleavage of the ether can be enhanced by the use of, e.g., an alkali metal thioalkoxide, e.g., sodium thioethoxide, in an aprotic solvent such as dimethylformamide at a temperature between 100 ° C and the boiling point of the reaction mixture. Provided that the R 2 O group of the starting material is resistant to aluminum trichloride or boron tribromide, e.g. as in the case of alkoxy, these reagents can also be used for selective ether cleavage at the 2 'position. The reaction is preferably carried out using boron tribromide with dichloromethane as the solvent at a temperature between -10 ° C and the boiling point of the reaction mixture. When using starting materials where R 3 <3 is hydroxyl, even more potent methods can be used, e.g. using 47% hydrobromic acid for cleavage.

Compounds of formula I wherein R 1 O and R 2 are the same and both are alkoxy or acyloxy may be prepared from the corresponding compounds wherein R 1 O and R 2 are hydroxyl. Such dialkoxy compounds can be prepared as described above according to Method B. Instead of an alkyl halide, an alkenyl halide can be used and the obtained compound in which R 1 O and R 4 are both alkenyloxy can be reduced according to Method C. The reduction is preferably carried out using palladium or

II

68225 dium / charcoal catalyst. If desired, the alkoxy group R 1 in the obtained product can be converted to hydroxyl according to Method E. The R 10 O and acylation of the hydroxyl groups (Method F) can be carried out e.g. using carboxylic acid anhydride or acid chloride in the presence of an acid scavenger, preferably triethylamine or pyridine. Suitable solvents for the reaction are, for example, chloroform, pyridine or dimethylformamide. The reaction temperature is between 0 ° C and the boiling point of the reaction mixture. However, the acylation using 10 carboxylic anhydrides is preferably carried out using the anhydride itself as a solvent and adding orthophosphoric acid. In this case, the reaction temperature is preferably about 60 ° C.

Acyloxy groups, such as R 1, can be selectively hydrolyzed directly, e.g. in aqueous solution, to give the corresponding 2'-hydroxy-5-acyloxy compound of formula I (Method G). Due to the phenolic nature of the 2'-hydroxy group, it can be directly selectively alkylated or acylated according to Methods B and F.

Compounds of formula I in which R 4 is hydrogen may also be prepared by dehydroxylation of the corresponding compounds in which R 4 is hydroxyl (method H), e.g. by reacting them with 1-phenyl-5-chlorotetrazole or dicyclohexylcarbodiimide and catalytically hydrogenating reaction products obtained ^ cf. W.J. Musliner and J. W. Gates, J. Amer. Chera. Soc. 88, 4271 (1966), H.C. Beyerman et al., Rec. trav. chim. 95, (1976) and E. Vowinkel and C. Wolff, Chem. Ber. 107, 907 (1974) 7.

The products obtained from methods A-H can be isolated and purified in a known manner, e.g. by column chromatography before crystallization, in the form of an addition salt or the free base.

Diastereomers can be separated according to the prior art based on their varying chemical and physical properties, e.g. using fractional crystallization or column chromatography.

Separation of the isomers can be performed on the final product or at an earlier stage during the synthesis. Racemic mixtures can be divided into optical isomers, e.g., by separating their salts with suitable optically active acids, e.g. camphorsulfonic acid.

It is apparent from the foregoing description that, in addition to their pharmacological activity, which will be described below, many of the compounds of formula I are also useful intermediates in the synthesis of other derivatives of formula I.

The compounds of the formula I are pharmacologically active, in particular as analgesics and narcotic antagonists, as well as inhibitors of luteinizing hormone secretion, as shown in the following animal experiments.

Analgesic activity 1. Tail retraction ability in the rat. A method using male Wistar rats is described in Arzneim.

Forsch. 13, 502 (1963), the 15-second measurement time has been shortened to 10 seconds. The results are classified according to the following scale: A) Moderate analgesic activity (MA): tail retraction time 6-10 seconds, B) Apparent analgesia activity (PA): no tail retraction in 10 seconds, but slight tail movement in hot water, C ) Surgical analgesic activity (SA): no tail retraction in 10 seconds and no movement in hot water.

2. Twist test in rat. The test substance is administered subcutaneously 30 minutes before or orally 45 minutes before intraperitoneally injecting 1 ml of 1% acetic acid into female Wistar rats weighing 150-190 g and recording twists over the next 25 minutes. The results are compared with those obtained by intraperitoneal injection of 1% acid into untreated control animals.

Thus, the compounds of formula I can be used as analgesic agents. For this purpose, the dosage will, of course, depend on the compound employed, the mode of administration and the 68225 treatment desired. The indicated daily dose is about 0.001-10 mg / kg body weight of the animal, administered in conveniently divided doses 2-4 times a day or in sustained release form. The total daily dose indicated is about 1 to 5,250 mg, preferably about 10 mg, more preferably about 10 to 100 mg, conveniently administered orally in unit dosage form containing about 0.25 to 100 mg, preferably about 2.5 mg, more preferably about 2 , 5-50 mg of a compound of formula I.

Narcotic Interaction Activity 10 Fentanyl interaction test in rats. 0.63 mg / kg fentanyl is administered subcutaneously to male Wistar rats to provide respiratory depression, loss of righting reflex, muscle stiffness, surgical analgesia, and inhibition of corneal and ear reflexes. The ability of the test compound to counteract said phenomena is considered to be a measure of the narcotic activity of the test compound. Thirty minutes after fentanyl administration, the test animals are injected intravenously with the test compound and pentazonin or nalorphine as a reference substance.

According to the above test, the compounds of formula I prove to be useful in the treatment of an overdose of a narcotic agent, e.g. morphine. In addition, the test shows that the compounds themselves are not or only very little narcotically active. The indicated dosage and unit dosage forms for narcotic antagonistic use are the same as described above for the use of analgesia.

Anti-luteinizing hormone secretion activity 30 1. Prevention of oocyte shedding in the rat. Adult female rats of the Ivanova strain, each weighing 200-250 g, are kept under standard conditions, / * 14 hours light (04.00-18.00), 24 ° C and a relative humidity of 55-60% J, and are allowed to reach access to food and water. Animals that have been shown to have a regular four-day heat cycle are shown to be administered either subcutaneously or orally prior to heat, at doses of 13.00 and again at 16.00.

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At 20 hours after the first dose, the rats are sacrificed, the fallopian tubes are removed, and the total number of eggs in both tubes is counted twice with a scissor microscope. Oocyte shedding is now considered to be inhibited-5 only when no ovum is found. Five rats are used for one assay.

2. Prevention of ovulation in a hamster. The above procedure is repeated using adult female golden hamsters (Mesocricetus auratus, Fiillingsdorf), weighing about 100 g, and the test compound is administered subcutaneously in three doses before heat at 11.00, 13.00 and 16.00. Animals are sacrificed 22 hours after the first injection.

3. Luteinizing hormone serum study in rats. Oaa-15 pregnant Ivanova Wistar rats are ovariectomized under Evipan anesthesia. 20 days after healing, the test compound is administered subcutaneously in varying doses. One hour after administration, rats are sacrificed and serum luteinizing hormone levels are determined using standard radioimmunoassay techniques. Five rats are used per dose and the mean amount of luteal hormone found in the animals is expressed as a percentage of the mean found in the solvent-treated control animals.

The compounds of formula I have thus been shown to be useful in the treatment of interfering high luteinizing hormone secretion, in particular in the treatment of disorders caused by or associated with excessive luteinizing hormone secretion, e.g. in the treatment of menopausal syndrome or prostatic hyperplasia.

The dosage amount of a compound according to this aspect of the invention will again vary depending on, for example, the particular compound used, the route of administration, the treatment conditions and the treatment desired.

The daily dose indicated for this purpose is about 35 0.001-1.0 mg / kg, depending on the route of administration, e.g. subcutaneously or orally, conveniently presented in unit dosage form administered 2-4 times a day or in a sustained release form. The indicated total daily oral dose is about 0.1 to preferably about 0.5 to 20 mg, preferably about 4.0 mg, conveniently administered in unit dosage form containing about 0.025, preferably about 0.125 to 5, preferably about 2 mg, a compound of formula I.

The compounds of formula I may be administered as the free base or as a pharmaceutically acceptable acid addition salt, which salt forms generally have the same class of activity as the free bases.

The compounds of formula I may also be administered in optically active or racemic form.

The compounds of formula I may also be mixed with conventional pharmaceutically acceptable diluents or carriers and, optionally, other excipients and administered, for example, in the form of tablets, capsules, powders and injectable solutions. They can be administered in combination with other analgesics or with other active ingredients such as palliatives, sedatives and hypnotics.

Example 1 2-Cyclobutylmethyl-2 ', 5-dihydroxy-9,9-dimethyl-6,7-benzomorphane hydrochloride 3 g (25 mmol) of cyclobutylcarbonyl chloride dissolved in 15 ml of dichloromethane are added dropwise over 10 minutes to a solution of 2.33 g (10 mmol) of 2 ', 5-dihydroxy-9,9-dimethyl-6,7-benzomorphane in 70 ml of dichloromethane and 8 ml of triethylamine. After refluxing for 4 hours under reflux, the reaction mixture is allowed to cool and washed three times with 25 ml of water and once with 25 ml of 1N hydrochloric acid. The organic phase is concentrated under reduced pressure and the residue is dissolved in 20 ml of dry tetrahydrofuran. The solution is added dropwise to a suspension of 1.5 g (44.1 mmol) of lithium alanine hydride in 25 ml of tetrahydrofuran. After refluxing for 5 hours, the solution is cooled and 7.5 g of sodium sulphate are carefully added. The precipitate obtained is filtered off, washed with tetrahydrofuran and the filtrate is concentrated under reduced pressure.

After converting the residue to the hydrochloride and crystallizing from methanol / ethyl acetate, 2.5 g of the title compound are obtained, m.p. 260-262 ° C.

The following compounds are prepared using the appropriate carboxylic acid chlorides (substituents R2, and the product compounds are the same as in the starting compounds), respectively:

10 No. Starting material N-substituent Salt Melting point

R1 b A CH2CH2OCH2CH3 HCl 245-250 c A CH2CH (OCH3) CH3 HCl 235-238 d A CHOC (CH3), OCH, HCl 234-238 15 l 3 i 3 17 68225

No. Starting material N-substituent Salt Sp. (° C) _ (R1) _e B Base Oil \ / f C CHOCHOCH HCl 220-222 g C CH2CH2CH2CH3 HCl 212-214 5 h. C HCl 238-240 i C CH2CH (OCH3) CH3 HCl 219-224 * j C CH „CH_C, H, HCl 224-229 l 2 6 8 k C CH, - \} HCl 197-200

O

CH - 3! 1 C CH.A 7 Oxalate 186-190

- V

10 m D CH2 - ^^ HCl 229-231 n D CH2CH (OCK3) CH3 HCl 210-213 OD CH2CH2OCH2CH3 HCl 214-216 p D 'CH2CH2OCH {CU3) 2 HCl 198-202 q D Cl2CH (OCH3) CH2CH3 HCl 210-213 15 r E CH2 - <^^ Base oil s F CH2CH (OCH3) CH3 HCl 214-216 t G CH2CH (OCH3) CH3 HCl 219-222 u 1H CH2CH2OCH3 HCl 164-167 18 68225 x The diastereoisomeric mixture is separated by fractional crystallization X -isoisomer (HCl salt) m.p. 226-227 ° C, Y-isomer (methanesulfonic acid salt) m.p. 183-186 ° C.

Starting materials: A: 2 ', 5-dihydroxy-9,9-dimethyl-6,7-benzomorphane B: 2', 5-dimethoxy-9,9-dimethyl-6,7-benzomorphane 10 C: 9,9-dimethyl-2'-hydroxy-5-methoxy-6,7-benzomorphane D: 9,9-dimethyl-5-ethoxy-2'-hydroxy-6,7-benzomorphane E: 5-allyloxy -9,9-dimethyl-2'-methoxy-6,7-15 benzomorphane F: 5-allyloxy-9,9-dimethyl-2'-hydroxy-6,7-benzomorphane G: 9,9-dimethyl-2'-hydroxy -5-propoxy-6,7-benzomorphane 20H: 5-butyloxy-9,9-dimethyl-21-hydroxy-6.7-benzomorphane Examples 2-8

In analogy to the method described in Examples 1a) to 1g), the following compounds are also prepared: 25 19 68225

No. Starting material N-substituent Salt Melting point

_ ^ _ 2 A CH 2 base 161 3 B CH 3 HCl 212-214 (decomposes) 4 E CH 3 HCl 207-209 5a) C CH 3 base 183-185 b) G CH 3 HCl 243-246 c) F CH 3 HCl 227-232 (decomposes) 6a) C CH2 "O HCl 225-227 b) F CH2" 0 HCl 223-228 7a) C CH2C (OCH3) (CH3) 2 HCl 180-185 b) D CH2C (OCH3) (CH3) 2 HCl 184-188 c) D CH2CH (OCH3) CH2OCH3 HCl 188-192 CH3 ° d) D CH2 -X <I HCl 226-230 CH3 ° e) D CH2 \ ^ / HCl 211-220 CH3 ° f * A CH2- ^ <^ HCl 239-251 g) A CH2CH (OCH3) CH2OCH3X HCl 190-193 8 D CH2C (CH3) OCOC3H7 base 160-163 20 68225

Example 9 5-Hydroxy-21-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride 316 g of sodium hydroxide are added to a solution of 5 to 49.4 g (0.2 mol) of 2 ', 5- dihydroxy-2,9,9-trimethyl-6,7-benzomorphane in 1500 ml of water, followed by the dropwise addition of 135 g (1.07 mol) of dimethyl sulfate over 80 minutes at 80-85 ° C. After heating at about 80 ° C for 5 hours, the reaction mixture is cooled and extracted twice with 500 ml of chloroform. The collected chloroform phases are dried over sodium sulfate and evaporated under reduced pressure. The residue is converted into the hydrochloride and crystallized from a mixture of methyl and ethyl acetates to give 46.4 g of the title compound. The product has a melting point of 233-236 ° C (dec).

Example 10 2 ', 5-Dihydroxy-2,9,9-trimethyl-6,7-benzomorphane

A solution of 31.1 g (0.1 mol) of 2 ', 5-dimethoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride (cf.

Example 2 2) in 150 ml of 47% hydrobromic acid, refluxed for half an hour. After cooling, the solution is diluted with 150 ml of water and poured into 450 g of ice and 150 ml of 25% ammonia. The resulting crystals are filtered, washed with water and dried in vacuo. 24.4 g of the title compound are thus obtained, m.p. 174-177 ° C. The crystals contain one mole of water of crystallization.

Example 11 2 ', 5-Dimethoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride a) 21.8 g (0.5 mol) of a 55% dispersion of sodium hydride in oil are added to 52.2 g: (0.2 mol) of 5-hydroxy-2'-methoxy-2,9,9-trimethyl-benzomorphane (cf. Example 5 of FI Patent Application No. 803237) dissolved in 500 ml of peroxide-free tetrahydrofuran, followed by 142 g (1.0 mol) of methyl iodide are added dropwise over 45 minutes and the mixture is stirred for four hours at room temperature. To the resulting reaction mixture is carefully added 9 ml of water and the tetrahydrofuran is evaporated off under reduced pressure. After adding 250 ml of water to the residue, it is extracted three times with 250 ml of chloroform. The combined chloroform phases are dried over sodium sulfate and concentrated under reduced pressure. The residue is converted into the hydrochloride, washed with toluene to remove paraffin oil and crystallized from methanol / ethyl acetate. 53.5 g of the title compound are obtained, m.p. 212-214 ° C (decomposes).

b) Starting from 2 ', 5-dihydroxy-2,9,9-trimethyl-6,7-benzomorphane (cf. Example 2) and proceeding according to Example 11a using twice the amount of sodium hydride and methyl iodide, 2', 5-dimethoxy-2 , 9,9-trimethyl-6,7-benzomorphane hydrochloride.

c) Repeating Example 11b using ethyl iodide instead of methyl iodide and carrying out the reaction at boiling temperature instead of room temperature gives, after recrystallization from acetone / methanol (9: 1), 25-diethoxy-2,9,9-trimethyl-6,7- benzomorphane hydrochloride, m.p. 2Q6-208 ° C.

d) Following the procedure of Example 11c using allyl bromide instead of ethyl iodide and a reaction time of six tannins, 2 ', 5-diallyloxy-2,9,9-trimethyl-6,7-benzomorphane in the form of a non-crystalline base is obtained.

e) By proceeding according to Example 11c using 5-hydroxy-21-methoxy-2,9,9-trimethyl-6,7-benzomorphane (cf. FI Patent Application No. 833,269 e.g. la), 30 2'-Methoxy-2,9,9-trimethyl-6,7-benzomorphane in the form of a non-crystalline base.

f) By proceeding according to Example IId using 5-hydroxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane (cf. Example 5 of FI Patent Application No. 803237), 35 gives 5- (allyloxy) -2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride, m.p. 207-209 ° C.

22 682 2 5 g) Following the procedure of Example IIf using 2-butenyl bromide instead of allyl bromide, 5- (2-butenyloxy) -2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride, m.p. . 210-212 ° C.

5 h) Following the procedure of Example IIf using benzyl bromide instead of allyl bromide, 5-benzyloxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride is obtained, m.p. 185-189 ° C.

Example 12 21,5-Di-n-propoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride a) 2.98 g (9.1 mmol) of 2 ', 5-diallyloxy-2.9 1,9-Trimethyl-6,7-benzomorphane (cf. Example IId) dissolved in 70 ml of absolute ethanol is hydrogenated at room temperature under normal pressure using 300 mg of Pd / C (5%) as catalyst. After uptake of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is converted into the hydrochloride and crystallized from methanol / acetone (1: 9). 2.1 g of the title compound are obtained, m.p. 190-193 ° C (decomposes).

The 2,9,9-trimethyl-6,7-benzomorphane derivatives shown in the following table are obtained, respectively:

No. The 2'-subst. 5-n. Salt mp

obtained product according to 2 5__startz__ b bll 0CH3 OC ^ H ^ (n) base oil c llg OCH3 OC3H9 (n) HCl 213-216

Example 13 30 - 2'-Hydroxy-5- (3-hydroxypropoxy) -2,9,9-trimethyl-6,7-benzomorphane hydrochloride a) 24 ml of a 1M solution of diborane in tetrahydrofuran are added dropwise over a period of more than two hours at a temperature of 35- 10 ° C to a solution of 2.02 g (6 mmol) of 5-allyloxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride (see Example IIf) dissolved in 25 ml to tetrahydrofuran. After stirring for 4 hours at room temperature, 16 ml of 1N sodium hydroxide solution and 2 ml of 30% hydrogen peroxide are carefully added dropwise.

After 5 hours of reaction at room temperature, 30 ml of 1N hydrochloric acid are added and the mixture is boiled for a further hour under reflux. Tetrahydrofuran is distilled off under reduced pressure, the acidic aqueous phase is basified with 25 ammonia itself and extracted three times with 25 ml of 10 chloroform. The combined chloroform phases are dried over magnesium sulfate and concentrated under reduced pressure. After converting the residue to the hydrochloride and crystallizing from methanol / ethyl acetate, 1.15 g of the title compound are obtained, m.p. 187-193 ° C.

B) Starting from 5- (2-butenyloxy) -2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride (cf. Example 11g), 5- (2-hydroxybutoxy-2'-methoxy) is obtained. -2,9,9-trimethyl-6,7-benzomorphane in the form of the free base, which can lead to the reaction without purification.

Example 14 9,9-Dimethyl-2'-hydroxy-5-methoxy-6,7-benzomorphane hydrochloride (starting material III starting material = H) Method 1 25 A solution of 285 ml of ethanethiol (3.86 mol) in 57 ml. dimethylformamide (DMF) is added dropwise to a suspension of 124.4 g (2.85 mol) of sodium hydride (55% in suspension oil) in 1900 ml of dry DMF. The resulting suspension is stirred for 45 minutes and 49.6 g (190 mmol) of 2 ', 5-dimethoxy-9,9-dimethyl-6,7-benzomorphane in 190 ml of dry DMF are added dropwise over 20 minutes. The originally formed volatile components are distilled off and the reaction mixture is heated until the DMF boils. After refluxing for 6 hours, the reaction mixture is concentrated under reduced pressure (24,68225) and the residue is dissolved in 500 ml of toluene and 2000 ml of 2N hydrochloric acid. The acidic aqueous phase is basified with 500 ml of 25% ammonia and extracted three times with 500 ml of chloroform / hutanol (8: 2). After evaporation of the organic phase, the residue is converted into the hydrochloride and crystallized from isopropanol to give 29.0 g of the title compound (a), m.p. 249-251 ° C (decomposes).

Method 2 40 ml (352 mmol) of boron tribromide dissolved in 250 10 ml of dichloromethane are added dropwise over 45 minutes at room temperature to a suspension of 59.5 g (200 mmol) of 2 ', 5-dimethoxy-9,9-dimethyl- 6,7-Benzomorphane hydrochloride (cf. Example Ia of FI patent application 833 269) in 1000 ml of dry dichloromethane. After stirring for 3 hours at room temperature, the reaction mixture is poured into 500 ml of ether. After the addition of one liter of water, the mixture is basified by adding about 150 ml of 25% ammonia and extracted five times with chloroform / butanol (8: 2). The combined organic phases are concentrated under reduced pressure, the residue is converted into the hydrochloride and crystallized from methanol / ethyl acetate to give 48.8 g of the same title compound as before, m.p. 249-252 ° C (decomposes).

Method 3 11.4 g (38.3 mmol) of 2 ', 5-dimethoxy-9,9-dimethyl-6,7-benzomorphane hydrochloride (cf. Example 1a of FI patent application S3j 269) are added portionwise to a mixture of 14, 4 g (115.3 mmol) of aluminum trichloride, 14.5 ml of nitrobenzene and 250 ml of benzene. After boiling at reflux for 8 hours and cooling to 10 [deg.] C., the aluraline chloride complex obtained is extracted with 250 ml of ice-cold 2N hydrochloric acid, the temperature being kept below 40 [deg.] C. After stirring for 30 minutes, the aqueous phase is separated and basified by adding 25% ammonia. On standing, a precipitate forms which is filtered, washed with chloroform / butanol (8: 2). The filtrate is extracted three times with 68225 chloroform / butanol (8: 2) and concentrated under reduced pressure. The residue is chromatographed using 300 g of basic alumina and chloroform / methanol (19: 1) as eluent. The fractions containing the desired product are concentrated under reduced pressure, the residue is converted into the hydrochloride and crystallized from methanol / ethyl acetate to give 2.7 g of the title compound, m.p. 246-249 ° C (decomposes).

The following compounds of formula I wherein R 2 is methyl and is hydroxy are prepared according to methods 1 and 2, respectively (for compound K, the 2'-methoxy group of the product originally obtained is removed by treatment with 47% hydrobromic acid according to Example 10 r method 4) Starting material R1 * 3 ”e" e: Su ° la SP · <° C)

Obtained Product_content_ a Ub CH3 CH3 2 base 183-185 b 11c CH3 C2H5 2 oxalate 216-218 c 12a CH3 n-C3H7 2 HG1 243-246 20 d llf CH3 allyl 1 HCl 227-232 (d) e 13a CH3 3-hydroxy - 1 HCl 170 (d) propyl 11 g CH3 2-butenyl 1 HCl 238-241 25 g 12c CH3 n-C4Hg 1 HCl 255-257 h 13b CH3 2-hydroxy- | HCl 243-246 butyl 11 l CH 3 benzyl 1 HCl 237-240 j bx H H 4 HBr 280-2S3 (d) k fx H C-H,. 2 base 208-210

30 Δ D

1 gx H allyl 1 base 228-230 m hx H n-C3H? 1 HCl 232-236 n ix H 2-butenyl 1 base oil o jx H n “C4H9 2 base oil n kx H. benzyl 1 base oil 35 y x) Compound according to Example 11 of FI claim 833 269. (Examples 14j-p illustrate the preparation of the starting material III starting material, R 2 H) 26 68225

Example 15 a) Using 2-cyclobutylmethyl-2 ', 5-dimethoxy-9,9-dimethyl-6,7-benzomorphane (Example 1e) as starting material and proceeding according to Example 14, Method 1, 2-cyclobutylmethyl is obtained. -9,9-di-, methyl-2'-hydroxy-5-methoxy-6,7-benzomorphane hydroclone, m.p. 225-227 ° C.

b) Using 2 ', 5-dimethoxy-9,9-dimethyl-2- (3-methyl-2-butenyl) -6,7-benzomorphane hydrochloride as starting material and proceeding according to Example 14, Method 2, to give 9,9-dimethyl-2'-hydroxy-2- (3-methyl-2-butenyl) -5-methoxy-6,7-benzomorphane oxalate, m.p. 206-207 ° C (decomposes).

c) Using 5-allyloxy-2-cyclobut-15-methylmethyl-9,9-dimethyl-2'-methoxy-6,7-benzomorphane (Example 1r) as starting material and proceeding according to Method 1 of Example 14, 5-allyloxy- 2-cyclobutylmethyl-9,9-dimethyl-2'-hydroxy-6,7-benzomorphane hydrochloride, m.p. 223-228 ° C.

Example 16 2-Cyclobutylmethyl-9,9-dimethyl-2'-hydroxy-5-propoxy-6,7-benzomorphane hydrochloride Using 5-allyloxy-2-cyclobutylmethyl-9,9-dimethyl-2'- Hydroxy-6,7-benzomorphane hydrochloride (Example 17c) according to Example 9a gives the title compound, m.p. 221-225 ° C.

Example 17

Following the procedure of Example 11b and Example 14, Method 1, the following compounds of formula I are obtained: 27,68225

No. Starting Product Product N-Substance- Salt Sd. (° c) xxx) '____tuenttl_ 5 Λ 7 f CH 2 c (OCH 2) (CH 3) 2 HCl 180-185 b 7 k CH 2 C (OCH 3) (CH 3) 2 HCl 184-183 c 7 n CH 2 CH (OCH 3) CH 2 OCH 3 HCl 188 -192 CH3 ° 10 S d 71 CH2 ~ ^ \ j HCl j 228-230 I i I ch3o I 6 7 m CH2 - ^ / ^> HCl 211-22 0 15 CH, 0 f 7 b CH2 - ^ ^ HCl 239 -251.97 v cH2CH (OCH3) CH2OCH3 ** HCl 190-193 20 x ^ Note. In the process of Example 17f, the amounts of sodium hydride and methyl iodide are reduced to two equivalents to leave the 5-hydroxy group intact.

25 l

XK'Isomer A

** x) Reference is made to the examples of FI patent application 833 267. Example 18 a) 2'-Hydroxy-5-propionyloxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride 3.0 g (12 mmol) of 21,5-dihydroxy-2,9,9-trimethyl- 6,7-Benzomorphane hydrochloride (cf. Example 2) is heated for three hours in a mixture of 45 ml of propionic anhydride and 6 g of orthophosphoric acid. After cooling, the reaction mixture is poured into 100 g of ice water and the pH is adjusted to 8 by adding dilute sodium hydroxide. The aqueous phase is extracted three times with 25 ml of chloroform, the combined chloroform extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in dry ether and carefully acidified by adding isopropanol / HCl. The resulting precipitate is filtered and washed with ether to give 3.6 g of 2 ', 5-dipropionyloxy-2,9,9-trimethyl-6,7-benzoic acid hydrochloride, m.p. 213-217 ° C.

3.6 g (9.1 mmol) of this diester are dissolved in 25 ml of isopropanol, 5 ml of 5N isopropanol / HCl are added and the resulting solution is refluxed for 4 hours. The solvent is evaporated off under reduced pressure. The residue is treated with acetone and the resulting crystals are filtered to give 2.8 g of the title compound, m.p. 227-230 ° C.

b) By proceeding similarly, but using acetic anhydride instead of propionic anhydride and without isolating the intermediate, 5-acetoxy-2'-hydroxy-2,9,9-trimethyl-6,7-benzomorphane is obtained, m.p. 158-160 ° C.

c) Using 21,5-dihydroxy-9,9-dimethyl-6,7-benzomorphane (cf. Example 14k) as starting material and proceeding according to Example 13b), 2 ', 5-diacetoxy-9 is obtained. 9-dimethyl-6,7-benzomorphan (lähtcyhdiste). This is further allowed to react without purification.

d) Using 9,9-dimethyl-2'-hydroxy-2- (2-hydroxy.-2-methylpropyl) -5-methoxy-6,7-benzomorphane hydrochloride as starting material (cf. Example 7 of FI patent application 833 267 f) If you proceed according to Example 18a, 9,9-dimethyl-5-methoxy-2'-propionyloxy-2- (2-methyl-2-propionyloxypropyl) -6,7-benzomorphane hydrochloride is obtained, m.p. 96-102 ° C.

After hydrolysis of the 2'-propionyloxy group, 9,9-diruethyl-2'-hydroxy-5-netoxy-2- (2-methyl-2-propionyloxypropyl) -6,7-benzomofran is obtained, m.p. 178-180 ° C.

e) Using 5-ethoxy-9,9-dimethyl-2 '- 35 hydroxy-2- (2-hydroxy-2-methylpropyl) -6,7-benzomorphane hydrochloride as starting material (cf. Example 7k) ) and following the procedure of Example 18a gives 9,9-dimethyl-5-ethoxy-2'-hydroxy-2- (2-methyl-2-propionyloxy-propyl) -6,7-benzomorphane, m.p. 160-163 ° C.

* Example 19 a) 5-Hydroxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride

A mixture of 3.7 g (15 mmol) of 21,5-dihydroxy-2,9,9-trimethyl-6,7-benzomorphane (cf. Example 2), 3 g (16.5 mmol) of 5-chloro-1- phenyl] itetrazole and 5 g of calcium carbonate in 100 ml of dry dimethylformamide are heated at 100 ° C for five hours. After cooling, the salt is filtered and the filtrate is concentrated under reduced pressure. The residue is extracted with 25 ml of acetone 15 and 25 ml of ether. The resulting crystals are filtered off and dried, yielding 3.3 g of 2 '- (1-phenyl-5-tetrazolyloxy-5-hydroxy-2,9,9-trimethyl-6,7-benzomorphane, m.p. 164 ° C.

3.12 g (8 mmol) of this product dissolved in 250 ml of ethanol are hydrogenated using 500 ml of palladium on activated carbon (5%) as catalyst. After the theoretical amount of hydrogen has been bound, the catalyst is filtered off and the solvent is concentrated under reduced pressure. The residue is dissolved in 25 ml of toluene and extracted twice with 25 ml of 2 5 N hydrochloric acid. The acidic aqueous phase is basified with 25% ammonia and extracted twice with 25 ml of chloroform. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is taken up in hydrochloride and crystallized from acetone to give 1.0 g of the title compound, m.p. 250-252 ° C.

b) Using 2'-hydroxy-5-methoxy-2,9,9-trimethyl-6,7-benzomophan as starting material (cf. Example 5a) and proceeding accordingly, 5-methoxy-2,9,9-trimethyl-6 is obtained, 7-benzomorphane hydrochloride, m.p.

35 218-223 ° C.

30 68225 c) Using 9,9-dimethyl-5-ethoxy-2'-hydroxy-6,7-benzomorphane as starting material (cf. Example 5 1 of FI patent application No. 833 267) and proceeding accordingly, 9,9-dimethyl -5-ethoxy-5,6,7-benzomorphane as a non-crystalline substance.

Example 20 5-Acetoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride Using 5-hydroxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride as starting material (cf. Example 19a) and following the procedure of Example 18b, the title compound is obtained, m.p. 225-227 ° C.

Example 21 a) 2'-Acetoxy-5-hydroxy-2- (1-acetoxy-cyclopropylmethyl) -9,9-dimethyl-6,7-benzomorphane 60 g (19.8 mmol) of 2 ', 5- dihydroxy-2- (1-hydroxycyclopropylmethyl) -9,9-dimethyl-6,7-benzomorphane (cf. Example 7b of FI Patent Application No. 833 267) is refluxed for one hour in 60 ml of acetic acid-20 hydride in the presence of a few pyridine drops. The solution is evaporated to dryness, the residue is dissolved in water, the aqueous solution is basified with ammonium hydroxide and extracted with ethyl acetate. The combined organic phases are washed with water, dried and evaporated under reduced pressure. The residue is chromatographed on SiO 2 using toluene / ethyl acetate (1: 1) as eluent to give the title compound as an oil.

b) 21,5-Dihydro-2- (1-acetoxy-cyclopropylmethyl) -9,9-dimethyl-6,7-benzomorphan oxalate The diacetate obtained in 30 a) is dissolved in 50 ml of methanol and neutralized with 1N hydrochloric acid. A catalytic amount (19 mg) of p-toluenesulfonic acid is added and the solution is refluxed for 1.5 hours. The solution is evaporated to dryness under reduced pressure and the residue is dissolved in water. After carefully basification with ammonium hydroxide, the solution is extracted with ethyl acetate and the collected organic phases are washed with water, dried over magnesium sulphate and evaporated under reduced pressure. After chromatography on SiO 2, eluent toluene / ethyl acetate (1: 1), the base obtained is converted into the oxalate and the product is recrystallized from methanol / ethyl acetate to give the title compound, m.p. 196-198 ° C.

Example 22 (+) and (-) - 5-hydroxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride 13.0 g (50 mmol) of (+) - 5-hydroxy- 2'-Methoxy-2,9,9-trimethyl-6,7-benzomorphane in 125 ml of ethanol is added to a solution of 11.6 g (50 mmol) of d-camphorsulfonic acid in 125 ml of water. The mixture is evaporated to dryness under reduced pressure. 125 ml of methanol, 250 ml of ethyl acetate and 250 ml of ether are added to the residue to give a crystalline (++) salt. The salt is crystallized twice from methanol / ethyl acetate until a constant melting point of 225-229 ° C and a constant rotation = + 76 ° are reached.

Yield 4.2 g. In addition, 3 g of the mother liquor are obtained after light evaporation. Further evaporation of the mother liquor gives a (+) salt which, after double recrystallization, has a m.p. 218-222 ° C and rotation ^ = 25 -36. The (+) - base is obtained from the (++) - salt by treatment with concentrated ammonia and conversion to the hydrochloride, m.p. 248-252 ° C and / c <7q5 = + 90.5 °.

The (+) - salt is treated with concentrated ammonia accordingly and the resulting (-) base is converted into the hydrochloride, 30 m.p. 250-253 ° C, C ^ J2 ^ = “91 °.

Example 23 (+) - 2'-hydroxy-5-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride Using (+) - 5-hydroxy-2'-methoxy-35 2,9,9 as starting material -trimethyl-6,7-benzomorphane (cf. Example 22) 32 682 25 by the procedure of Example 11a and Example 14, Method A, gives the title compound, m.p. 220-223 ° C and - + 84.7 °.

Example 24 5 (-) - 2'-hydroxy-5-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride Using as starting material (-) - 5-hydroxy-21-methoxy-2,9, 9-trimethyl-6,7-benzomorphane (cf. Example 22) and following the procedure of Example 23 gives the title compound, m.p. 219-222 ° C and = -83.1 °.

Claims (6)

A process for the preparation of 6,7-benzomorphan derivatives of the formula I which are useful as analgesics, narcotic antagonists and inhibitors of luteinizing hormone secretion, in which R is optionally alkoxy-substituted. C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl- (C 1-8) alkyl; C 2-6 alkenyloxy- (C 1-8) alkyl, aryl- (C 1-8) alkyl, aryl- (C 2-8) alkenyl or tetrahydrofuryl- (C 1-8) alkyl; or optionally C 1-6 alkyl-substituted furyl- (C 1-8) alkyl or isoxazolyl- (C 1-8) alkyl; R 2 is hydrogen or methyl, R 3 is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl- (C 1-6) alkyl, hydroxy- (C 1-8) alkyl or C 1-8 alkoxy- (C 1-8) ) alkyl and R 4 is hydrogen, hydroxyl, C 1-8 alkoxy or C 1-6 alkenyloxy, said hydroxyl groups in said compounds being acylated, and for the preparation of their acid addition salts, characterized in that 30 (A) reduction according to formula III 'Thdistö / X II 1 jL I (III) | or3 34 68225 wherein Rasila is such that -C1-4 -R * 1 is a group as defined above and R2-R4 are as defined above; and then, if desired, performing one or more of the following steps: B) a compound of formula I in which R 1 O and / or R 2 is a hydroxy group or contains a hydroxy group is alkylated; C) a compound of formula I wherein R 1 O or R 2 is alkenyloxy is hydrogenated; D) a compound of formula I wherein R 1 is alkenyl is hydrated; E) performing ether cleavage on a compound of formula I wherein R 1, R 10 and / or R 2 are alkoxy or contains alkoxy; F) acylation of a compound of formula I in which R 1 O and / or R 2 is a hydroxyl group or contains a hydroxyl group; G) a compound of the formula I in which R 1 O and / or R 4 is an acyloxy group or contains an acyloxy group is hydrolysed or subjected to reductive cleavage; H) a compound of formula I wherein R 1 is hydroxyl is dehydroxylated to give a compound of formula I wherein R 1 is hydrogen; and, if necessary, converting the compound of formula I thus obtained into its acid addition salt. Patent 35: 6 8225 For the preparation of a 6,7-benzomorph derivative of formula I, preferably an analogue of 5 analogues, an antagonist for narcotic drugs and an inhibitor for secretion of luteinising hormones, ΦΛφ CH-, 0R3 15 C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 cycloalkyl- (C 1-8) alkyl optionally substituted with alkoxy; C 2-8 alkenyloxy- (C 1-8) alkyl, aryl- (C 1-8) alkyl, aryl- (C 2-8) alkenyl or tetrahydrofuryl- (C 1-8) alkyl; or optionally C 1-6 alkyl-substituted furyl- (C 1-6) alkyl or 20 isoxazolyl (C 1-6) alkyl; R 2 is methyl or C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl- (C 1-8) alkyl, hydroxyl- (C 1-8) alkyl or C 1-8 alkoxy- (C 1-8) alkyl ) -alkyl and 25 R 1 is a compound, hydroxyl, C 1-6 alkoxy or C 2-8 alkenyloxy, a color hydroxyl group in the above-mentioned acyl ester, the same as a hydrogenation salt, which is converted to a mixture, Fig. A) in the form of a reduction of formula III, 30 / \ N-CO-R * 1 JL f 7 J <r2 (iii) O 3