FI68226C - FOERFARANDE FOER FRAMSTAELLNING AV 6,7-BENZOMORFANDERIVAT VILKA AER ANVAENDBARA SOM ANALGETISKA AEMNEN ANTAGONISTER FOER NARKOTISKA MEDEL OCH INHIBITORER FOER SEKRETION AV LUTEINISERINGSHORMON - Google Patents

Description

1 68226

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 21,5-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 at the 9-position have valuable pharmacological activity, in particular analgesic and narcotic activity as well as the secretion of luteinizing hormone. .

The invention relates in particular to compounds of the formula I, -N ---

30 XXuX

(I) CH-,

OR J

Wherein R 1 is hydrogen, alkyl, or aralkyl, 68226 1 * 2 is hydrogen or methyl, is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl or alkoxyalkyl, and R 4 is hydrogen, hydroxy, alkoxy or alkenyloxy, in addition to formula I In the compounds of the invention, each hydroxyl group may be optionally acylated.

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 nucleus by at least two carbon atoms. Aryl is preferably phenyl.

The acyl residues in R 1 and R 2 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 groups terminating in an aryl, cycloalkyl or heterocyclic group preferably contain up to four, more preferably two, carbon atoms. 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 hydrogen, C 1-6 alkyl or C 1-6 alkyl- (phenylalkyl), R 2 is hydrogen or methyl, R 1 is hydrogen, C 1-6 alkyl, C 1-6 alkyl; -hydroxyalkyl, C3-4 alkenyl, C3-4 alkynyl or C 1-4 (phenylalkyl) and R 4 is hydrogen, hydroxy, C 1-4 alkoxy or C 1-4 alkenyloxy, in addition, in the compounds of the formula I, each hydroxyl group can be optionally acylate.

3 68226

The compounds of formula I may contain hydrogen. When it 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.

When R 1 is phenylalkyl, it is preferably benzyl or phenethyl.

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

R 10 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.

is then preferably acetyl, propionyl or benzoyl, more preferably acetyl.

R 1 may be hydrogen or hydroxy. When R 1 is hydroxy, 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, toxin 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 2 is methyl.

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

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

Further preferred are compounds of formula I wherein R 2 is methyl and R 2 is hydroxy and wherein: 4 68226 a) R 1 is methyl and is hydrogen, methyl, ethyl, n-propyl, allyl or 2-butenyl.

The compounds of the formula I can be in the form of the free bases or of their acid addition salts, for example as salts with mineral acids, such as hydrogen chloride, hydrobromic acid 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 C and Ce and, when R1 is hydrogen, a third asymmetric carbon atom C8.

Since the iminoethane bridge between atoms C. and Cc is

λ O

in the ti cis configuration (1,3-diachal), so and when the atoms are the only asymmetric centers, there will be only one racemate in the -15 country. This racemate can be resolved into optical isomers. If C ^, Cj. and Cg are the only asymmetric carbon atoms, so the compounds are in two diastereoisomers with a different configuration at the Cg position. According to the nomenclature of 5,9-dialkyl-6,7-benzomorphans 20 proposed by May / E.L. May, J. Org. Chem. 26, 1621 (1961L // if the C8 methyl group is in the trans position with respect to the imonoethane bridge and thus in the cis position with respect to the substituent OR4, then the isomer is considered to be the os isomer. If the C8 methyl group is in the cis position with respect to the imincetane bridge and isomer is considered to be the β-isomer.

and / or 3 isomers of voivar. each in two optically active forms, i.e. as levorotatory and dextrorotatory enantiomers. These can also be decomposed into separate 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 will be appreciated that the compounds of formula 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, separate diastereomers, D, L-racemates. and the separate D and L isomers, however, the levorotatory isomers for pharmacological activity are generally more active.

The present invention also relates to a process for the preparation of compounds of formula I, wherein A) the compound of formula II is converted to ring structures, (Ii)

X X

Wherein R * is hydrogen, alkyl or aralkyl, each X is alkoxy or both are oxygen and R 2 and R 4 are as defined above, optionally cleaving the ether at position 2 'to give a compound of formula I wherein R 1 is the same as R R 1, R 2 is hydrogen or alkyl, and if desired the compound obtained is converted into another compound of the formula I by substituting or modifying the group R 1, R 3 and / or R 4.

Conversion of a first compound of formula I to another compound of formula I by substitution or modification of existing substituents R 1, R 2 and / or R 2 can be carried out by methods well known in benzomorphan chemistry, e.g. according to the following methods (final steps only) ); and then, if desired, performing one or more of the following steps: B) dealkylating or dearalkylating a compound of formula I wherein R 1 is alkyl or aralkyl to give a compound of formula I wherein R 1 is hydrogen; and / or C) alkylating a compound of the formula I in which R 10 is and / or contains a hydroxy group or contains a hydroxy group; and / or 68226 D) hydrogenating a compound of formula I wherein R 10 or R 2 is alkynyloxy; and / or E) a compound of formula I wherein R 1 is alkenyl is hydrated; and / or F) performing ether cleavage on a compound of formula I wherein R 30 and / or R 6 is alkoxy or contains alkoxy; and / or G) a compound of the formula I in which R 1 O and / or R 2 is a hydroxyl group or contains a hydroxyl group is acylated; and / or H) a compound of the formula I in which R 1, O 0 and / or R 4 is an acyloxy group or contains an acyloxy group is hydrolysed or subjected to reductive cleavage; and / or I) de-hydroxylating a compound of formula I wherein R 1 is hydroxyl to give a compound of formula I wherein R 4 is hydrogen; and, if necessary, converting the compound of formula I thus obtained into its acid addition salt.

It is to be understood that the above reactions and intermediate transformations may be performed in any suitable order. The procedures for carrying out reactions (B) to (I) or for preparing the desired starting materials from the compounds of formula I obtained by the ring-forming reaction (A) are described in more detail below.

According to the invention, it has surprisingly been found that the basic ring-forming reaction (A) can be carried out selectively to obtain specific end products using a suitable Lewis acid, for example aluminum trichloride or boron trifluoride. In this case, R 4 in the compound of formula II is preferably not acyloxy, as this leads to undesired side reactions. In the starting material R 4 is preferably alkoxy, in particular methoxy and R 1 is preferably alkyl or aralkyl, in particular methyl or benzyl, in particular methyl. Depending on the reaction conditions, the final products obtained may have different substituents at the 2 'and 5' positions.

Reaction of a compound of formula II having alkoxy and both X together with oxygen with boron trifluoride, optionally complexed with an alcohol, ether or other suitable oxygen donating molecule gives 2'-hydroxy and 2'-alkoxy. A 1: 1 molar mixture of 5-hydroxy-benzomorphan derivatives. This reaction takes place in two steps. The first step is suitably carried out in an alkanol, preferably methanol, which acts as a solvent. After removal of the solvent, the resulting complex is boiled in an aprotic solvent such as benzene and the resulting benzomorphane derivative is isolated. Alternatively, it is possible to convert the resulting boron trifluoro-15 ride complex with an alkanol to a dialkyl ketone acetal of formula II, wherein each X is alkoxy, by carrying out the reaction in an aqueous base. The di-alkyl ketone acetal can then be reacted in an aprotic solvent such as dichloromethane in the presence of boron trifluoride optionally complexed with an alkanol such as methanol to give the corresponding 21,5-dialkoxy, preferably 2 ', 5-dimethoxy-benzomorphan derivatives. Reaction of a compound of formula II wherein both X is together oxygen and is alkoxy, preferably methoxy, under mild conditions and using aluminum trichlorides gives the corresponding 21-alkoxy-5-hydroxy-benzomorphane derivative. This reaction is conveniently carried out with benzene or nitrobenzene or a mixture thereof and using 2 equivalents of aluminum trichloride.

If the latter reaction is carried out under stronger conditions, for example using more than two equivalents, preferably three equivalents, of aluminum trichloride, a longer reaction time and an elevated reaction temperature, the formation of a 2 *, 5-hydroxybenzomorphane derivative is preferred. The reaction temperature is preferably 15 to 15 ° C, depending on whether a 2'-alkoxy or 2'-hydroxy-5-hydroxy-benzomorphan derivative is desired.

When ring formation is performed using compounds of formula 5 II wherein R 1 is hydrogen, the corresponding 2'-unsubstituted-5-hydroxy or 5-alkoxybenzomorphane derivatives are obtained.

The ring-forming reaction can also be carried out using strong inorganic acids, especially 48% hydrobromic acid, J. Med. Chem. 13, 1323 (1970), although ring formation with Lewis acid is generally preferred. For ring formation with strong acids, temperatures between room temperature and the boiling point of the reaction mixture are preferred. In the benzomorphane derivatives thus obtained, R 2 O has a hydroxyl group. Upon ring formation, alkoxy or acyloxy substituents such as R 1 become hydroxyls.

For the ring formation reactions described above, it is generally preferred to use compounds of formula II wherein R 1 is hydrogen or lower alkoxy. R * is preferably alkyl or aralkyl, especially methyl or benzyl, because the reaction proceeds more rapidly and results in better yields. In the latter case, the resulting compounds can be dealkylated or debenzylated as described below (Method B).

Method B can be carried out, for example, using cyanogen bromide according to Brown's method / yrt.

H. A. Hageman, Org. React. 7, 198 (1953) and K.W. Bentley, 30 Techniques of Organic Chemistry 11, 773 (1963) or chloroformic acid ester or catalytic debenzylation. The first two methods are only suitable when there is no hydroxyl group at the 2 'position.

The reaction is preferably carried out using an alkyl or phenol ester of chloro-formic acid, generally ethyl ester and the resulting product is saponified and decarboxylated. The saponification and decarboxylation can be carried out, for example, in an alcoholic base solution, preferably calcium hydroxide in n-butanol.

Processes C-I can be carried out using as starting material a compound of formula I obtained according to the ring-forming reaction A used as starting material, or using as starting material a compound of formula I obtained, for example, according to method B.

The compounds of formula I prepared by Method A wherein R 1 is hydrogen and is hydrogen or alkoxy 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 sodium hydride and reacting an alkali metal alkoxide with an alkyl, alkenyl, alkynyl or aralkyl halide (Method C). 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 reaction rate slows as the alkylating agent Mole-25 has an increase in the basis weight. Therefore, compounds of formula I having an n-propyl or higher alkyl group are preferably prepared by catalytic hydrogenation of the corresponding compound in which R 1 is 2-alkenyl (Method D), since the latter is obtained more rapidly due to the higher reactivity of 2-alkenyl halides.

The resulting compounds of formula I in which R 1 is alkenyl can be advantageously converted to the corresponding compounds in which R 1 is hydroxyalkyl by hydration, e.g. by reaction with diborane first, then with hydrogen peroxide / sodium hydroxide (method E). In this way, e.g., 5-allyloxybenzmorphane derivatives can be converted to 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 decomposed into the corresponding compounds in which R 1 is hydroxyl (method f). The decomposition of the ether can be enhanced by using 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 the selective decomposition of the ether 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 10 is hydroxyl, even more potent methods can be used, e.g., using 47% bronive-20 blank acid for decomposition.

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 2 O and R 2 are hydroxyl. Such dialkoxy compounds can be prepared as described above according to the method. Instead of an alkyl halide, an alkenyl halide can be used and the obtained compound in which R 1 O and both are alkynyloxy can be reduced according to the method. The reduction is preferably performed using palladium or palladium / charcoal catalyst. If desired, the alkoxy group R 1 in the obtained product can be converted to hydroxyl according to method f. The acylation of the hydroxy groups R 10 and R 2 (method g) can be carried out e.g. using a carboxylic acid anhydride or an acid chloride in the presence of an acid-binding agent, preferably triethylamine or pyridine. Suitable solvents

II

11 68226 reactions 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 a carboxylic acid anhydride 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 directly selectively hydrolyzed, e.g. in aqueous solution, to give the corresponding 2'-hydroxy-5-acyloxy compound of formula I (Method H). Due to the phenolic nature of the 2'-hydroxy group, it can be directly selectively alkylated or acylated according to Methods C and H.

When compounds of formula I wherein R 1 is hydroxyl are desired, the synthetic steps are preferably as follows; ring formation (Method A), resulting in compounds of formula I wherein R 1 is alkyl or aralkyl and R 1 is alkoxy, dealkylation (Method B), resulting in corresponding compounds wherein R 1 is hydrogen, decomposition of ether (Method F) To convert R 1 to hydroxyl.

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

30 Chem. Ber. 107, 907 (1974 \ J

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

12 68226

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. The racemic mixtures can be divided into optical isomers, e.g. by separating their salts with suitable optically active acids, e.g. camphorsulphonic acid.

10 It follows 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 starting materials of formula II in which R 2 is hydrogen are known from Japanese Patent Application No. 75 58072 / Chemical Abstracts 87, 53468 (177) //. Compounds of the formula II in which R 1 is methyl are known, for example, from Dutch Patents Nos. 69,085,227 and 20,69,08528 and the corresponding GB Patent No. 1,299,669.

Other starting materials of formula II can be prepared accordingly.

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

Analgesic activity 1. Tail retraction ability in the rat. A method using 30 male Wistar rats is disclosed in the publication

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, li 13 682 2 6 B) Apparent analgesia activity (PA): no tail retraction within 10 seconds, but slight tail movement in hot in water, C) Surgical analgesic activity (SA): no tail retraction within 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 intraperitoneal injection of 1 ml of 1% acetic acid into female Wistar rats 10 with a mean weight of 150-1SO 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 depend on the particular compound used, the mode of administration and the treatment desired. The indicated daily-20 torsion is about 0.001 to 10 mg / kg of animal body weight, administered in conveniently divided batches 2-4 times a day or in sustained release form. The total daily dose indicated is about 1 to 250 mg, preferably about 10 mg, most 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 to 50 mg of a compound of formula I.

Narcotic counteracting activity

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 earlobe reflexes. The ability of a test compound to have a narcotic anti-35 activity is considered to be the ability to counteract said phenomena. Thirty minutes after administration of phenanyl, experimental animals are injected intravenously with test compound and pentazosin or nalorphine as a reference.

According to the above test, the compounds of formula I proved 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.

10 The indicated dosage and unit dosage forms for narcotic drug use are the same as described above for analgesic use.

Anti-luteinizing hormone secretion activity 1. Prevention of ovulation in rats. Adult female rats of the Ivanova-15 strain, each weighing 200-250 g, are kept under standard conditions / 14 hours light (04.00-18.00), 24 ° C and 55-60% relative humidity / and are allowed access to food and water at will. Animals that have been shown to have a regular 20 to four-day heat cycle are administered the test compound either subcutaneously or orally before heat, at doses at 13.00 and again at 16.00. At 20 hours after the first dose, the rats are sacrificed, the fallopian tubes are removed, and the total number of oocytes in both tubes is counted with a two-section microscope. Oocyte detachment is considered to be inhibited only when no ova are 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, Fttllings-Dorf) 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 35 after the first injection.

Il 15 68226 3. Luteinizing hormone serum study in rats. Female rats of the Ivanona Wistar strain 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 radioimmunological techniques. Five rats are used per dose and the mean amount of luteinizing 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, e.g., the particular compound used, the route of administration, the treatment conditions and the treatment desired.

The daily dose indicated for this purpose is about 0.001 to 1.0 mg / kg, depending on the route of administration, e.g. subcutaneously or orally, conveniently divided into 25 unit doses to be administered 2-4 times a day or in sustained release form. The indicated total daily oral dose is about 0.1 - 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 10, 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.

16 68226

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

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

Example 1 a) 5-Hydroxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride A mixture of 59.5 g (0.2 moles) of 2- (4-methoxybenzyl ) -1,3,3,3-trimethyl-4-piperidinone hydrochloride and 53.8 g (0.4 mol) of aluminum trichloride in 54 g of nitrobenzene and 1500 ml of dry benzene are refluxed for one hour. After cooling, the reaction mixture 20 is extracted with 750 ml of 4N sodium hydroxide solution, keeping the temperature below 35 ° C. The organic phase is separated and extracted with 750 ml of 1N hydrochloric acid. The acidic aqueous phase is basified by adding 100 ml of 25% ammonia and extracted three times with chloroform. The collected chloroform phases are dried over sodium sulfate and evaporated under reduced pressure. The residue 46.7 g is converted into the hydrochloride by reaction with isopropanol / HCl and crystallized from a mixture of methanol and ethyl acetate. The yield of the title compound is 44.6 g, m.p. 233-236 ° C 30 (decomposes).

b) Using 3,3-dimethyl-2- (4-methoxy-benzyl) -4-piperidino as starting material, 9,9-dimethyl-5-hydroxy-2'-methoxy-6,7-benzomorphane hydrochloride, respectively, is obtained. mp. 215-218 ° C (decomposes).

li 68226 c) By proceeding accordingly and using 2- (4-methoxybenzyl) -1,3-dimethyl-4-piperidone as starting material and separating the two isomers obtained by crystallization, the following is obtained:

1) 2,9or-dimethyl-5-hydroxy-2'-methoxy-6,7-benzo-5-morphane hydrochloride, m.p. 252-253 ° C

2) 2,9 / 3-dimethyl-5-hydroxy-2'-methoxy-6,7-benzomorphane hydrochloride, m.p. 288-289 ° C.

Example 2 2 ', 5-Dihydroxy-2,9,9-trimethyl-6,7-benzomorphane A mixture of 59.5 g (0.2 mol) of 2- (4-methoxybenzyl) -1,3, 3-Trimethyl-4-piperidone hydrochloride and 80.1 g (0.6 mol) of aluminum trichloride in 80 g of nitrobenzene and 1,500 ml of dried benzene are stirred for 30 minutes at room temperature and then boiled for 5 hours under reflux. The resulting benzomorphane / aluminum trichloride complex crystallizes. After cooling to 15 ° C, 1,500 ml of ice-cold 2N hydrochloric acid solution are added. After filtration, the acidic aqueous phase is separated from the organic phase and basified by adding 750 ml of 25% ammonia-20. The solution obtained is extracted three times with 500 ml of a mixture of chloroform and n-butanol (8: 2). The combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. The crystalline product, 51.4 g, is recrystallized from ethyl acetate. 35.1 g of the title compound are obtained, m.p. 161 ° C (decomposes).

(Note: The substance contains 0.5 moles of ethyl acetate.)

Example 3 5-Hydroxy / methoxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride 66 ml of boron trifluoride / methanol complex are added with stirring over 30 minutes to a solution of 52.2 g (0 , 2 mol) of 2- (4-methoxybenzyl) -1,3,3-trimethyl-4-piperidone in 220 ml of methanol, the temperature being kept below 35 ° C.

After stirring the reaction mixture for 16 hours at room temperature, the reaction mixture is evaporated under reduced pressure. Evaporation is repeated after the addition of toluene to remove any methanol present.

18 68226 The residue, 130 g, is dissolved in 500 ml of dry benzene and refluxed with stirring for nine hours. During the reaction, 250 ml of benzene and all volatile components are removed by distillation. The volume of the reaction mixture 5 is kept constant by the regular addition of 250 ml of benzene. After cooling, the reaction mixture obtained is extracted by adding 66 g of powdered sodium hydroxide and, after 30 minutes, 300 ml of water. The benzene and aqueous phases are separated. The aqueous phase is extracted twice with 250 ml of chloroform. The combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. The residue containing 55.0 g ± 1: 1 of a mixture of the title compound is converted into the HCl salt and crystallized from a mixture of methanol and ethyl acetate, m.p. 183-190 ° C (decomposes).

Half of the resulting mixture is converted to the corresponding 2 ', 5-dihydroxy-6,7-benzomorphane derivative according to the procedure described in Example 7. One half of the mixture is converted to the corresponding 21,5-dimethoxy-6,7-benzomorphane derivative according to the procedure described in Example 8a.

Example 4 2 ', 5-Dimethoxy-2,9,9,9-trimethyl-6,7-benzomorphane hydrochloride 40 ml of ethereal boron trifluoride are added dropwise over 20 minutes with stirring to a solution of 52.2 g of 25 ( 0.2 mol) of 2- (4-methoxybenzyl) -1,3,3-trimethyl-4-piperidone in 500 ml of methanol, the temperature being kept below 35 ° C.

After stirring for 16 hours at room temperature, 40 g of powdered sodium hydroxide are added. After further stirring for 30 minutes, the sodium salts obtained are filtered off and washed with methanol. The filtrate is evaporated under reduced pressure and, after adding 500 ml of water, extracted three times with 150 ml of chloroform. The chloroform phases are dried over sodium sulfate and evaporated under reduced pressure. After crystallization from 200 ml of petroleum ether (b.p. 60-80 ° C) and further recrystallization, 25.4 g of 4,4-dimethoxy-2- (4-methoxybenzyl) -1,3,3- trimethylpiperidine, m.p. 91-92.5 ° C.

I! 19 68226 18.0 g (0.056 mol) of the obtained 4,4-dimethoxy compound dissolved in 90 ml of dry benzene are added dropwise at room temperature over 4.5 hours to a mixture of 60 ml of benzene and 2.4 ml of boron trifluoride-saturated solution. 5 working methanol. After refluxing for 6 hours, 20 g of powdered sodium hydroxide are added. After stirring for a further 30 minutes, the sodium salts are filtered off, the filtrate is evaporated off under reduced pressure, 200 ml of water are added and the resulting mixture is shaken three times with 100 ml of chloroform. The collected chloroform extracts are dried over sodium sulfate and evaporated under reduced pressure. The residue, 22.3 g, is chromatographed on 500 g of SiO 2 using toluene / methanol (3: 1) as eluent. The fractions containing the desired product are collected, evaporated under reduced pressure and converted into the corresponding hydrochloride. After crystallization from 25 ml of a methanol / acetone mixture (1: 9), 4.64 g of the title compound are obtained, m.p. 210-212 ° C (decomposes).

Example 5 2 ', 5-Dihydroxy-2,9,9, -trimethyl-6,7-benzomorphane A mixture of 59.5 g (0.2 mol) of 2- (4-methoxybenzyl) -1, 3,3-Trimethyl-4-piperidone hydrochloride in 600 ml of 47% hydrobromic acid is refluxed for 16 hours, the originally obtained volatile components are distilled off until a boiling point of 124 ° C is reached. After cooling, the reaction mixture is diluted with 600 ml of water, filtered if necessary and poured into 500 ml of 25% ammonia and 250 g of ice. After extraction three times with 200 ml of a chloroform / butanol mixture (8: 2), followed by evaporation under reduced pressure, 48.3.3 g of crude product are obtained. The crude product is chromatographed on 750 g of alumina using chloroform / methanol (95: 5) as eluent. 14.8 g of the title compound are obtained, m.p. 184-188 ° C.

20 6 8 2 2 6

Example 6 5-Hydroxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride 316 g of sodium urea hydroxide are added to a solution of 49.4 g (0.2 mol) of 2 ', 5 -dihydroxy-2,9,9-trimethyl-6,7-benzomorphane in 1500 ml of water, after which 135 g (1.07 mol) of dimethyl sulphate are added dropwise to the solution over a period of 45 minutes at a temperature of 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 is identical to the compound obtained according to Example 1a).

Example 7 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 4 4) 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 crystals obtained are filtered off, 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 8 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 52.2 g to (0.2 mol) of 5-hydroxy-2'-methoxy-2,9,9-trimethyl-benzomorphan (cf. Example 1a) dissolved in 500 ml of peroxide-free tetrahydrofuran, followed by dropwise addition of more than For 45 minutes, 142 g (1.0 mol) of methyl iodide and and the mixture are 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. Residue 5 is converted to 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 21,5-dihydroxy-2,9,9-trimethyl-6,7-10 benzomorphane (cf. Example 2) and proceeding according to Example 8a using twice the amount of sodium hydride and methyl iodide, 2 ', 5-dimethoxy is again obtained. - 2.9.9-trimethyl-6,7-benzomorphane hydrochloride.

c) Repeating Example 8b using ethyl iodide instead of methyl iodide and carrying out the reaction at reflux instead of room temperature gives, after recrystallization from acetone / methanol (9: 1), 2 ', 5-diethoxy-2,9,9-trimethyl-6, 7-benzomorphane hydrochloride, m.p. 206-208 ° C.

D) Following the procedure of Example 8c using allyl bromide instead of ethyl iodide and a reaction time of 6 hours, 2 ', 5-diallyloxy-2,9,9-trimethyl-6,7-benzomorphane in the form of a non-crystalline base is obtained.

e) Following the procedure of Example 8c using 5-hydroxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane (cf. Example 1a), 5-ethoxy-2'-methoxy-2.9. 9-trimethyl-6,7-benzomorphane in the form of a non-crystalline base.

f) Following the procedure of Example 8d using 5-hydroxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane (cf. Example 1a), 5- (allyloxy) -2'-methoxy- 2,9,9-trimethyl-6,7-benzomorphane hydrochloride, m.p. 207-209 ° C.

g) Following the procedure of Example 8g using 2-butenyl bromide instead of allyl bromide, 5- (2-butenyloxy) -2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride is obtained, m.p. 210-212 ° C.

22 68226 h) Following the procedure of Example 8f 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 9 2 ', 5-Di-n-propoxy-2,9,9-trimethyl-6,7-benzomorphonic hydrochloride a) 2.98 g (9.1 mmol) of 2', 5-diallyloxy 2,9,9-Trimethyl-6,7-benzomorphane (cf. Example 8d) dissolved in 10 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. Example 2'-subst. 5-n. Suola Sp. (° C) 2q ca. starting material substance __ b 8f 0CH 3 OC 3 H 2 (n) base oil c 8g OCH 3 OC 3 H 9 (n) HCl 213-216

Example 10 2'-Hydroxy-5- (3-hydroxypropoxy) -2,9,9-trimethyl-6,7-benzomorphane hydrochloride a) 24 ml of a 1M solution of diborane in tetranydrofuran are added dropwise over two hours at -10 ° C to a solution of 2.02 g (6 mmol) of 5-allyloxy-2'-30-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride (cf. Example 8f) dissolved in 25 ml of 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 35 hours of reaction at room temperature, 30 ml of 1N hydrochloric acid are added and the mixture is refluxed for a further hour. Tetra-hydrofuran is distilled off under reduced pressure, acidic

II

23 6 8 2 2 6 The basic phase is made basic with 25% ammonia and extracted three times with 25 ml of 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 8 g), 5- (2-hydroxybutoxy-2'- 10 methoxy-2,9,9-trimethyl-6,7-benzomorphan in the form of the free base, which can lead to the reaction without purification.

The following compounds of formula I containing hydrogen and methyl are prepared according to the methods described in Examples 1-5: No. Salt Sp. (° C) R. R-.

11 q J __Aproduct Product_ 11.1 HCl 220-222 (d) OCH3 CH3

11.2 HCl 217-220 (d) OCH 3 H

20 11.3 base oil OC2H3 C2Hj- 11.4 146-148 OCH3 11.5 HCl 203-205 OCH3 allyl 11.6 base oil 0CH3 C3H4 (n) 11.7 base oil 0CH3 2-butenyl 25 11.8 base oil OCK3 (n) 11.9 base oil 0CH3 benzyl 11.10 HCl 243-246 (d) OH CH3

The following compounds of formula I wherein R 1 is methyl and R 2 is hydroxy are also prepared according to the methods described in Examples 1-5: 24 6822 6

No. R ^ R ^ Suola Sp. (° C) _Product_Product_ 11.11 CH3 CH3 base 183-185 11.12 CH3 C2H5 oxalate 216-218 5 11.13 CH3 n_C3H7 HCl 243-246 11.14 CH3 allyl HCl 227-232 (d) 11.15 CH3 3-hydroxy-KCl 170 (d) propyl 11.16 CH3 2-butenyl HCl 238-241 10 11.17 CH3 n "C4H9 HCl 255-257 11.18 CH3 2-hydroxy-HCl 243-246 butyl 11.19 CH3 benzyl HCl 237-240 11.20 HH Hbr 280-283 (d) 15 11.21 H C2H5 base 208-210 11.22 H allyl base 228-230 11.23 H n_C3H7 HCl 232-236 11.24 H 2-butenyl base oil 11.25 H n-C4Hg base oil 20 11.26 H benzyl base oil 11.27 n-C3H7 CH3 hc1 220-222 11.28 n-C4H9 CH3 HCl 212-214 11.29 -CH2CH2-C6H5 CH3 HCl 224-229 1 2 3 4 5 6 7 8 9 10 11

Example 12 2 a) 2 · Hydroxy-5-propionyloxy-2,9,9-trimethyl-3,6,7-benzomorphane hydrochloride 4 3.0 g (12 mmol) of 2 ', 5-dihydroxy-2,9,9 -trimethyl-6,7-benzorophenane hydrochloride (cf. Example 2) is heated for three hours in a mixture of 45 ml of propionic anhydride and 6 g of orthophosphoric acid. Cooling 8

then the reaction mixture is poured into 100 g of ice water and pH

9 is adjusted to 8 by the addition of dilute sodium hydroxide.

10

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. Residue 68226 is dissolved in dry ether and carefully acidified by the addition of 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-benzomorphane 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 isolation of the intermediate, 5-acetoxy-21-hydroxy-2,9,9-trimethyl-6,7-benzomorphane is obtained, m.p. 158-160 ° C.

c) Using 2 ', 5-dihydroxy-9,9-dimethyl-6,7-benzomorphane (cf. Example 11-20) as starting material and proceeding according to Example 11.11, 2', 5-diacetoxy- 9,9-dimethyl-6,7-benzomorphan. This is further allowed to react without purification.

Example 13 a) 5-Hydroxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride

A mixture of 3.7 g (15 mmol) of 2 ', 5-dihydroxy-2,9,9-trimethyl-6,7-benzomorphane (cf. Example 2), 3 g (16.5 mmol) of 5-chloro -1-phenyltetrazole and 5 g of calcium carbonate in 100 ml of dry dimethylformamide, 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 and 25 ml of ether. The resulting crystals are filtered off and dried, yielding 3.3 g of 2 '- (1-phenyl-5-tetrazol-35-yloxy-5-hydroxy-2,9,9-trimethyl-6,7-benzomorphane, mp 158-164 ° C.

26 6 8 2 2 6 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 5 is concentrated under reduced pressure. The residue is dissolved in 25 ml of toluene and extracted twice with 25 ml of 1N 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 10 and concentrated under reduced pressure. The residue is converted into the 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-benzomorphane (cf. Example 11.11) as starting material 15 and proceeding accordingly, 5-methoxy-2,9,9 -trimethyl-6,7-benzomorphane hydrochloride, m.p. 218-223 ° C.

c) Using 9,9-dimethyl-5-ethoxy-2'-hydroxy-6,7-benzomorphane (cf. Example 11.21) as starting material and proceeding accordingly, 9,9-dimethyl-5-ethoxy -6,7-benzomorphan as a non-crystalline substance.

Example 14 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 13a) and proceeding according to Example 12b , the title compound is obtained, m.p. 225-227 ° C.

Example 15 9,9-Dimethyl-5-methoxy-6,7-benzomorphane Using 5-methoxy-2,9,9-trimethyl-6,7-benzomorphane (cf. Example 14b) as starting material and proceeding according to the procedures described in Examples 1-5 , the title compound is obtained. This is further allowed to react without purification.

68226 27

Example 16 9,9-Dimethyl-2'-hydroxy-5-propionyloxy-6,7-benzomorphane hydrochloride Using 2-benzyl-2'-benzyloxy-5,9,9-dimethyl-5-hydroxy-6,7-benzomorphane as starting material it is reacted with propionic anhydride according to the procedure described in Example 13 to give 2-benzyl-2'-benzyloxy-9,9-dimethyl-5-propionyloxy-6,7-benzomorphane. After hydrolysis of the benzyl groups, 9,9-dimethyl-2'-hydroxy-5-propionyloxy-6,7-benzomorphane is obtained.

Example 17 (+) 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. To the residue are added 125 ml of methanol, 250 ml of ethyl acetate and 250 ml of ether 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 of +7 6 ° 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 melting point of 218-222 ° C and a rotation = -36. The (+) base is obtained from the {++) salt by treatment with concentrated ammonia and conversion to the hydrochloride, m.p. 248-252 ° C and Zc <7q ^ = + 90.5 °.

The (-) salt is treated accordingly with concentrated ammonia and the resulting (-) base is converted into the hydrochloride, m.p. 250-253 ° C, ε <7β5 = -91 °.

The following compounds are prepared analogously: a) (+) - 2'-hydroxy-5-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride, m.p. 220-223 ° C, and b) (-) - 2'-hydroxy-5-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride, m.p. 219-222 ° C.

Claims (1)

30. I) vi j CT3 XX wherein hydrogen, alkyl, aralkyl, each X is alkoxy 35 or both together represent oxygen and R 2 and R 4 are 29 6 8 2 2 6 are the same as above, wherein the ether is optionally cleaved at position 2 ' ; and then, if desired, performing one or more of the following steps: B) dealkylating or dearalkylating a compound of formula I wherein R 1 is alkyl or aralkyl to give a compound of formula I wherein R 1 is hydrogen; C) alkylating a compound of formula I in which R 1 O and / or R 2 is a hydroxy group or contains a hydroxy group; D) hydrogenating a compound of formula I wherein R 1 O or R 2 is alkynyloxy; E) a compound of formula I wherein R 1 is alkenyl is hydrated; F) ether cleavage of a compound of formula I wherein R 10 and / or R 2 is alkoxy or contains alkoxy; G) acylation of a compound of formula I wherein R 10 and / or R 4 is a hydroxyl group or contains a hydroxyl group; H) a compound of the formula I in which R 1 and / or R 2 is an acyloxy group or contains an acyloxy group is hydrolysed or subjected to reductive cleavage; I) a compound of formula I wherein R 1 is hydroxyl is dehydroxylated to give a compound of formula X wherein R 1 is hydrogen; and, if necessary, converting the compound of formula I thus obtained into its acid addition salt. 68226 30 For the preparation of a 6,7-benzomorphan derivative of formula I, which is an analogue of an analgesic 5, an antagonist for a narcotic drug and an inhibitor for the secretion of luteinising hormones, -R1 1 ° I, A .A At (I) ' YV OR3 15. light formula, C 1-6 alkyl, or aryl- (C 1-6) alkyl; R 2 is hydrogen or C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl- (C 1-8) alkyl, hydroxy- (C 1-8) alkyl or C 1-6 alkoxy- C 1-6 alkyl and C 1-4 alkyl, C 1-6 alkoxy or C 2-6 alkenyloxy, a variety of hydroxyl groups and such compounds as the acyl ester, as well as a preferred addition salt, which can be converted to Figure 25 A) with Formula II cycles, X x color R * is a residue, alkyl or aralkyl, shade X is alkoxy or a mixture of tamsammers betyder syre och Rj and R ^ är samma 35 som ovan, varvid etern valfritt har spaltats i ställning