FI68224B - 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

! 68224

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

Separated from FI Application No. 803237

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

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-di-acetoxy 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. .

In particular, the invention relates to compounds of formula I: X 1 R 2 (I) R 4 CH 3 or 3 optionally substituted by hydroxy and / or alkoxy-2,68224 alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl, alkenyloxyalkyl, aralkyl, arylhydroxyalkyl, aralkenyl tetrahydrofurylalkyl or optionally alkyl-substituted furylalkyl-5-yl or isoxazolylalkyl; is hydrogen or methyl; R 3 is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl or alkoxyalkyl and R 4 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 hydroxy and / or. alkoxy-substituted alkyl, alkenyl, alkynyl or cycloalkylalkyl, aralkyl, arylhydroxyalkyl or tetrahydrofurylalkyl or optionally alkyl-15-substituted furylalkyl. R 3 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 nucleus by at least two carbon atoms. Cycloalkyl groups preferably contain up to six carbon atoms. Aryl is preferably phenyl.

Alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkylalkyl groups, such as R 1, may be substituted, preferably mono- or di-substituted, more preferably mono-substituted, by hydroxy and / or alkoxy. The hydroxy and alkoxy substituents are separated from the benzomorphan nucleus by at least two carbon atoms. The acyl residues in R 1, R 3 and R 4 are preferably physiologically hydrolyzable ester residues.

The aliphatic R 1 groups preferably contain up to six carbon atoms in total. The aliphatic R3 and R4 groups preferably contain six carbon atoms, more preferably four carbon atoms in total. The aliphatic moieties of the R 1 and R 3 groups terminating in an aryl, cycloalkyl or heterocyclic group preferably contain up to four, more preferably two, carbon atoms.

3,68224

In the thigh, when the end group is a cycloalkyl or heterocycle, the aliphatic moiety is most preferably methylene. In the R 1 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 isoxazolylalkyl 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 1-8 hydroxyalkyl, C 2-8 (alkoxyalkyl), wherein the alkyl moiety is optionally mono-substituted with hydroxy or nitro, C 1-6 alkenyl, J - C 3-6 alkynyl, C 1-6 (cycloalkylmethyl), (1-hydroxycycloalkyl) methyl-C 1-6 -N- (1-methoxy-cycloalkyl) -20-methyl-C phenylalkyl), C 1-4 (phenylhydroxyalkyl), tetrahydrofurylmethyl or furylmethyl optionally ring-substituted with methyl, R 2 is hydrogen or methyl, R 3 is hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-4 alkyl; alkenyl, C 3-6 alkynyl or C 1-6 (phenylalkyl) and R 1-4 is hydrogen, hydroxy, C 1-4 alkoxy or C 3-6 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 hydroxy and alkoxy substituents on the aliphatic residue R 1 are preferably in the 2-position. Preferred alkoxy substituents are methoxy and ethoxy, with methoxy being 4,68224 most preferred. The above hydroxy substituents may be acylated, preferred acyl groups are acetyl, propionyl and benzoyl, acetyl being most preferred.

Preferred hydroxy- and / or alkoxy-substituted R 1-5 alkyl groups are 2-hydroxypropyl, 2-hydroxybutyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-2-methylbutyl, 2-hydroxy-3-methoxypropyl, 2-methoxyethyl , 2-methoxypropyl, 2,3-dimethoxypropyl, 2-methoxybutyl, 2-methoxy-2-methylpropyl, 2-methoxy-2-methylbutyl, 2-ethoxyethyl-10-yl and 2-isopropoxyethyl, especially 2-hydroxy-2 -methylpropyl, 2-methoxyethyl, 2-methoxypropyl and 2-methoxy-2-methylpropyl, especially 2-hydroxy- and 2-methoxy-2-methylpropyl. Preferred R 1 acyloxyalkyl groups are 2-acetoxy and 2-propionyloxy-2-methylpropyl, the former being most preferred.

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

may be e.g. (1-hydroxycycloalkyl) methyl, in which case the 1-hydroxy group may be optionally acylated, the acyl group being preferably acetyl, propionyl and benzoyl and especially acetyl. As (1-hydroxycycloalkyl) -25 methyl, R 1 is preferably (1-hydroxycyclopropyl), (1-hydroxycyclobutyl) or (1-hydroxycyclopentyl) methyl, most preferably (1-hydroxycyclopropyl) or (1-hydroxycyclobutyl) -. methyl. When R 1 is (1-acyloxycycloalkyl) methyl, it is preferably (1-acetoxycyclopropyl) -30 methyl, (1-acetoxycyclobutyl) methyl or (1-acetoxycyclopentyl) methyl, the first two being most preferred.

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

il 5 68224

When R 1 is phenylalkyl, it is preferably benzyl or phenethyl. When phenylhydroxyalkyl is present, it is preferably β-hydroxyphenethyl. When tetrahydrofurylmethyl or furylmethyl is 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-furylfuryl. -methylfurfuryl 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 hydroxyalkyl is present, 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 benzo-20, 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, ethoxy or n-propyloxy, more preferably methoxy. When R 4 is alkenyloxy, it is preferably allyloxy.

Compounds of formula I wherein R 4 is other than hydrogen are preferred.

Particularly interesting compounds of the formula I are those in which independently: 1) R 1 is a) monohydroxy or alkoxy-substituted alkyl, i.e. hydroxyalkyl or alkoxyalkyl, in particular 2-hydroxy or 2-methoxyalkyl, ) alkenyl or alkynyl, in particular alkynyl, in particular 3-butynyl, and / or 68224 c) (1-hydroxy) - or (1-methoxycycloalkyl) -methyl, in particular (1-hydroxycyclopropyl) -methyl and (1-hydroxy-cyclobutyl) -methyl, in addition the hydroxyl groups in R 1 may optionally be acylated, preferably with acetyl or propionyl, more preferably with acetyl.

2) R 2 n is methyl.

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

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

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

II

7 68224 m) is (1-hydroxycyclopentyl) methyl and is hydrogen or methyl, especially methyl, n) is tetrahydrofurfuryl and R 1 is methyl or ethyl, especially methyl or 5 o) is 3-butynyl and R 1 is hydrogen or methyl .

The compounds of the formula I can be in the form of free bases or their acid addition salts, for example salts with mineral acids, such as hydrochloric, hydrobromic or sulfuric acid, or 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 1 and, when R e is hydrogen, a third asymmetric carbon atom C 15. Because iminoethane bridges atoms and C ,. between is fixed in the cis configuration (1,3-diaxial), so and when the Cj atoms are the only asymmetric centers, there will be only one racemate. This racemate can be resolved into optical isomers. If 20 and Cg are the only asymmetric carbon atoms, then 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 proposed by May / E.L. May, J.

Org. Chem. 26, 18S, 1621 (1961) / if the C8 methyl group 25 is in the trans position with respect to its iminoethane bridge and thus in the cis position with respect to the substituent OR2, then the isomer is considered to be the ^ isomer. If the C8 methyl group is in the cis position relative to the iminoethane bridge and thus in the trans position with respect to the OR4, the isomer is considered to be the β-isomer. The c * and β-iso-30 isers can each be in two optically active forms, i.e., as levorotatory and dextrorotatory enantiomers. 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 I according to the invention comprise the free base and acid addition salt forms, as well as their racemates and their separate optically active isomers, e.g. diastereomeric mixtures, separate diastereomers, D, L-racemates and separate D- and L-isomers, however, 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) a compound of formula I having hydrogen and R 2 to R 4 are the same as above is reacted with a compound of formula IV -Y wherein R 11 is the same when R 1 and Y 2 are a nucleophilic leaving group and then, if desired, one or more of the following steps are performed: B) alkylating a compound of formula I wherein R 1, R 2 and / or R 2 is a hydroxy group or contains a hydroxy group; and / or C) hydrogenating a compound of formula I wherein R 1 O or R 2 is alkenyloxy; and / or D) hydrogenating a compound of formula I wherein R 1 is alkenyl; and / or E) ether cleavage is performed on a compound of formula I wherein R 1, R 30 and / or R 4 is alkoxy or contains alkoxy; and / or F) acylating a compound of formula I wherein R 1, R 2 and / or R 2 is a hydroxyl group or contains a hydroxyl group; and / or G) a compound of formula I in which R 1, R 2 O and / or R 2 is an acyloxy group or contains an acyloxy group is hydrolysed or subjected to reductive cleavage; and / or H) dehydroxylating a compound of formula I wherein R 1 is hydroxyl 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.

35 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 · I! 9,68224

In process A, the compound of formula IV is preferably halogen, in particular chlorine, bromine or iodine, or an aryl, aralkyl or alkylsulphonyloxide group, in particular methoxy or tosyloxy. The reaction is preferably carried out using equimolar amounts or a small excess of a compound of formula IV. The reaction is conveniently carried out in the presence of an acid scavenger which does not react with the compound of formula IV, for example sterically hindered amines such as di-, cyclohexylethylamine and in particular inorganic bases such as calcium, sodium or potassium carbonate and especially sodium or potassium bicarbonate. The reaction is preferably carried out in an inert organic solvent, with tetrahydrofuran or dimethylformamide or mixtures thereof being preferable, the reaction temperature being between 0 ° C and the boiling point of the solvent. With less active compounds IV, the reaction can be accelerated by the addition of catalytic or equivalent amounts of sodium or potassium iodide.

Processes BH can be carried out using as starting material a compound of formula I obtained according to the ring-forming reaction described in FI patent application 833269 or using as starting material a compound of formula I obtained by the methods described in FI patent applications 803237, 833269 and 833268.

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 reacting an alkali metal alkoxide 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.

10 68224

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.

5 The reaction rate slows down as the molecular weight of the alkylating agent increases. Therefore, compounds of formula I in which R 1 is n-propyl or a higher alkyl group are preferably prepared by catalytic hydrogenation of the corresponding compound in which R 1 is 2-alkenyl (method C), since the latter is obtained more rapidly in a larger range of 2-alkenyl halides. due to reactivity.

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 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 wherein R 3 is alkyl, alkenyl, alkynyl, aralkyl or hydroxyalkyl and / or R 1 is alkoxy can be selectively converted by ether cleavage to give the corresponding compounds wherein R 4 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 10 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 cleavage 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 starting materials in which R 2 O is hydroxylated

II

11 6 8224 li, even more powerful methods can be used, e.g. using 47% hydrobromic acid for decomposition.

Compounds of formula I wherein R 10 and R are the same and both are alkoxy or acyloxy may be prepared from the corresponding compounds wherein R 30 and R 4 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 2 O and R 2 both are alkenyloxy can be reduced according to Method C. The reduction is preferably performed using a palladium or palladium / 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 a 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 20 ° C and the boiling point of the reaction mixture. However, the acylation using a carboxylic 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 selectively hydrolyzed, e.g. in aqueous solution, to give the corresponding 21-hydroxy-5-acyloxy compound of formula I (Method G). Due to the phenolic nature of the 21-hydroxy group, it can be directly selectively alkylated or acylated according to Methods B and F.

Compounds of formula I having a hydroxyl-containing oral support R 1 may be alkylated to give the corresponding compounds in which the hydroxyl has been replaced by alkoxy. The alkylation is conveniently performed according to Method 35B, as described above. When the starting material contains more than one hydroxyl group, e.g. when it is hydroxyl, these groups are generally converted simultaneously to alkoxy groups. Due to the different reactivity of the hydroxyl groups at positions 2 ', 5 and N-substituents, hydroxyl groups such as R 1 or both such as R 1 and R 2 may be selectively alkylated if desired. For example, the hydroxyl group R 1 can be selectively alkylated by reacting it in a dilute alkali metal hydroxide solution in the presence of an alkali metal salt and then reacting the resulting compound with a dialkyl sulfate. The hydroxyl groups R 1 and the hydroxyl groups in R 1 can also be selectively alkylated by taking into account the steric hindrances of the hydroxyl groups R 10 and the groups R 1, e.g. by carefully alkylating the hydroxyl group using a calculated amount of alkylating agent.

Compounds of formula I having an acyloxy group in the substituent R 1 may also be prepared from the corresponding hydroxy compounds by acylation, e.g. according to method F, as described above. Hydroxyl groups, e.g. R30 and R3, are also generally acylated. Selective acylation, such as alkylation, is also possible in view of the varying reactivities of the hydroxyl groups.

Compounds of formula I in which R 1 contains a hydroxyl group may be prepared from the corresponding compounds in which R 1 contains an alkoxy substituent by cleavage of the ether according to Method E. Suitable ether cleavage agents include hydrobromic acid and Lewis acids such as boron tribromide. Depending on the choice of reagent, alkoxy-30 groups such as R 30 and R 4 may also be converted to hydroxyl. Selective cleavage of aromatic ether groups can be performed using, for example, alkali metal thioalkoxides such as sodium thioethoxide.

Compounds of formula X in which R 1 contains a hydroxyl group may also be prepared by hydrolysis of compounds in which R 1 contains an acyloxy group according to Method G, e.g. by acid or base hydrolysis, preferably with water, alcohol or aqueous-alcoholic solution. Such acyloxy groups can also be removed from the δ-intermediate by cleavage. When R 2 O and R 2 are acyloxy, they generally simultaneously convert to hydroxyl. Acyloxy groups, such as R 4, are selectively hydrolyzed, e.g., using a dilute solution of hydrochloric acid in methanol or ethanol, taking advantage of the fact that these are less stable compounds when hydrolyzed than the acyloxy groups in R 1.

Compounds of formula I containing hydrogen may also be prepared by dehydroxylation of the corresponding compounds wherein R 1 is hydroxyl (Method H), e.g. by reacting them with 1-phenyl-5-chlorotetrazole or dicyclohexylcarbodiimide and catalytically hydrating. The reaction products obtained by W. J. Musliner 3a J. W. Gates, J. Amer. Chem. Soc. 88, 4271 (1966), H. C. Beyerman et al., Rec. Trav. chim. 95, (1976) and E. Vowinkel 20 and C. Wolff, Chem. Ber. 107, 907 (1974) J.

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 known techniques 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 Joppu-30 product or at an earlier stage during the synthesis. Racemic mixtures can be separated into optical isomers, e.g., by separation of their salts with suitable optically active acids, e.g. camphorsulfonic acid.

It will be 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.

14 68224

The compounds of the formula I are pharmacologically active, in particular as analgesics, narcotic antagonists and inhibitors of luteinizing hormone secretion, as shown by the following 5 animal experiments:

Analgesic activity 1. Tail retraction ability in the rat. A method using a male Wistar rat is described in Arzneim. Forsch. 13, 502 (1963), the 15 second measurement time 10 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 si-15 retraction in 10 seconds, but light tail movement in hot water , C) Surgical analgesic activity (SA): no tail retraction for 10 seconds and no movement in hot water.

20 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 weighing 150-190 g and writhing over the next 25 ml to 25 minutes. recorded. 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 treatment desired. The indicated daily dose is about 0.001 to 10 mg / kg of animal body weight, administered in conveniently divided doses 2 to 4 times a day or in a sustained release form. The total daily dose indicated is about 1 to 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. mg, more preferably about 2.5 to 50 mg of a compound of formula I.

Narcotic Interaction Activity 5 Fentanyl interaction test in rats. 0.63 mg / kg fentanyl is administered subcutaneously to male Wistar rats to induce 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, test animals are injected intravenously with test compound and pentazocine or nalorphine as a reference.

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 active at all or have very little narcotic activity. The indicated dosage and unit dosage forms for narcotic-antagonistic use are the same as described above for analgesic use.

Inhibitory activity on luteinizing hormone secretion 25]. Prevention of ovulation in rats. 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% 7 and are allowed access to food and water at will. Animals that have been shown to have a regular 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 35 eggs in both tubes is counted under a two-section microscope. Oocyte detachment is considered to be inhibited only when no ova are found. Five rats are used for one assay.

16 68224 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. Female rats of the Ivanova 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 radioimmulological 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.

Thus, the compounds of formula I have been shown to be useful in the treatment of high levels of 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 prostate 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 in the form of unit doses administered 2-4 times a day or in 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 10, preferably about 2 mg of a compound of formula I.

17 68224

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 may be administered in combination with other analgesics or with other active ingredients such as palliative agents, sedatives and hypnotics.

Example 1 a) 2-Allyl-9,9-dimethyl-2'-hydroxy-5-methoxy-6,7-benzomorphane hydrochloride

A mixture of 1.4 g (5 mmol) of 9,9-dimethyl-2'-20 hydroxy-5-methoxy-6,7-benzomorphane hydrochloride, 1.04 g (7.5 mmol) of calcium carbonate and 0.75 g of g (6.25 mmol) of allyl bromide in 250 ml of dimethylformamide, is heated at 70 [deg.] C. for 3.5 hours and then concentrated under reduced pressure. The residue is added to a mixture of 50 ml of water and 50 ml of chloroform and the aqueous phase is extracted twice with chloroform / butanol (9: 1). The combined organic phases are concentrated under reduced pressure. The residue is converted into the hydrochloride and crystallized from methanol / ethyl acetate to give 1.38 g of the title compound, m.p. 218-220 ° C (decomposes).

The following compounds were obtained by alkylation of the indicated starting material with RX, respectively: 18 68224 Starting materials; A: 2 ', 5-dihydroxy-9,9-dimethyl-6,7-benzomorphan B: 2', 5-dimethoxy-9,9-dimethyl-6,7-benzomorphan C: 9,9-dimethyl-2 ' -hydroxy-5-methoxy-6,7-benzomorphan 5D: 9,9-dimethyl-5-ethoxy-2'-hydroxy-6,7-benzomorphane E: 5-allyloxy-9,9-dimethyl-2 * - methoxy-6,7-benzomorphane F: 5-allyloxy-9,9-dimethyl-21-hydroxy-6,7-benzomorphan 10 G: 9,9-dimethyl-21-hydroxy-5-propoxy-6,7-benzo - morphane H: 5-butyloxy-9,9-dimethyl-2'-hydroxy-6,7-benzomorphane

15 No. Starting material N-substituent X from KX group Salt M.p.

(R from RX) b A CH 2 CH 2 Cl 2 SO 2 C 6 H 5 CH 2 HCl 235-237 c B CH 2 CH = € (CH 3) 2 Br oxalate-196-198 ti 20 d C CH 2 C 3 CH Br HCl 216-218 d 'C CH 2 CH 2 Cl 2 CH 2 SO 2 C 6 H 5 CH 3 Ha 193-197 e C CH - 1 J Br Ha 201-203

25 * O

f D CJ ^ CHC (CH3) 2 Br Ha 204-206 g D OL> -1 ^ J Br Ha 230-234

O

30

Examples 2-7

In analogy to the process described in Examples 1a) to 1g), the following compounds are also prepared: 35 11 19 68224

No. Starting N-Substance Salt Sp. ° C

substance support (= R1) 2 A CH3 base 161 3 B CH3 HCl 212-214 (decomposes) 4 E CH3 HCl 207-209 5a) C CH3 base 183-185 5b) G CH3 HCl 243-246 5c) F CH3 HCl 227-232 (decomposes) 6a) A CH2- <C ^ HCl 260-262 6b) A CK2CH2OCH2CH3 HCl 245-250 6c) A CH2CH (OCH3) CH3 HCl 235-238 6d A CH2C (CH3) 2OCH3 HCl 234-238 e B Base Oil f C CH2CH2CH IIC1 22 0-222 gc CH2CH2CH2CH3 HCl 212-214 hc Cl12 ~ \] HCl 238-240 ic CH2CH (OCH3) CH3 HCl 219-224 * ^ c CH2CH2C6H5 HCl 224-229 k C CH2 '\ \ HCl 197-200 0 CH _ — __ i 31 1 c CH0-A) Oxalate 188-190

"O

/ X

m D CU2 HCl 2 2 9-2 31 n D CH2CH (OCK3) CH3 HCl 210-213 20 6 8 2 2 4

No. Starting material N-substituent Salt Melting point

o D CH2CH OCH2CH3 HCl 214-216 p D CH2CII20Cl (CH3) 2 HCl 198-202 q D CII CH (OCl3) CH CH3 HCl 210-213 r E CH2 - ^^ Base oil s F CH2CH (OCH3) CH3 HCl 214- 216 t G CH 2 Cl 2 (OCH 3) CH 3 HCl 219-222 and H CH 2 CH 2 OCH 3 HCl 164-167 7a) CH 3 C (OII) (CH 2), HCl 235-239 (dec.) OH 3 2

b A I

CH 2 - J HCl 2 41-2-18

OH

c HCl 245 (d)

OH

d Λ CH 2 -V "HCl 227-230

OH

e b CH2 ~ ^ C KCl 201-206 f c CH2C (OH) (CH3) 9 HCl 207-210 g c CH2CH (OH) C6H5 Base 170-175

OH

h c CH2 ~ ^ \ HCl 160-169

OH

i c HCl 231-234 li 21 68224

No. Starting material Product N-sub- Salt Sp ° C _____tuenttl_

OM

j c CH2-V ^ HCl 218-221 * D CH2C (OH) (CH3) 2 MCI 197-200

OH

1 d CH 2 Cl 2 225-22 S

OH

m D HCl 22 8-2 34 n D CH2CII (OH) CH2OCH3 Base oil ° F CH2C (OH) C (CH2) 2 HCl 201-203 P G CH2C (OH) (CH3) 2 MCI 208-212

OH

q H CH2 ~ <\ HCl 209-212 1 1 CH2C (OH) (CH3) 2 JIC1 193-195 OH ^ g I pu un2 ^ \ J HCl 188-191 t J CH2C (OH} (CH3) 2 HCl 203- 205

OH

U J Ch2 ^ \ i HCl 203-205

v A CH2C (OH) CH2OCH3 ΜΛ) Base oilXX

w CH 2 (OH) CH 2 OCH 3 * (3) Base 148-151 ° C

22 6 8 2 2 4 m)

Diastereomers A and B have been separated using thin layer chromatography. Isomer X m.p. (HCl salt) is 226-227 ° C, and the melting point of isomer Y (methanesulfonic acid salt) is 183-186 ° C.

5, νχ)

The crude product is reacted directly according to Example 9.

Starting materials: Starting materials A-H are saunas as given in Example 1. Starting material I is 5- (2-butenyloxy) -9,9-dimethyl-2'-hydroxy-6,7-benzomorphane. The starting material J is 5-benzyloxy-9,9-dimethyl-2'-hydroxy-6,7-benzomorphane. Examples 8-10

In analogy to the procedure of Examples 1-7, the following compounds were prepared:

No. Starting material N-substituent_Salt_Sp ° C

8a) C ch2 "V ^ HCl 225-227 b) C CH2CH = C (CH3) 2 oxalate 206-207 c) F CH2 ~ 0 HCl 223-228 20 9a) C CH2C (OCH3) (CH3) 2 HCl 180- 185 b) D Ct 12 C (OCH 3) (CH 3) 2 HCl 184-133 c) D CH 2 CH (OCH 3) CK:) OCH 3 HCl 188-192 25 CH 3 ° d) D εΗ2 "^ ζ ^] HCl 2 26-230 CH..0 \ / \ e) D CH _- <> 1IC1 211-220

30 2 XX

CH ^ O

fx) A CH2 \ ^ HCl 2 39-251 9 A CH_CH (OCH,) CH ,, OCH ** HCl 190-193 35 2 3 2 3 10 D CH2C (CH3) OCOC3H7 base 160-163

If 68224

Example 11 5-Hydroxy-2'-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 (see Example 2) in 1500 ml of water, after which 135 g (1.07 mol) of dimethyl sulphate are added dropwise to the solution over 45 minutes at 80- 85 ° C, After heating for 5 hours at a temperature of about 80 ° C, 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 (decomposes).

Example 12 2 ', 5-Dihydroxy-2,9,9-trimethyl-6,7-benzomorphane A solution of 31.1 g (10.1 mol) of 2', 5-dimethoxy-2,9,9- trimethyl-6,7-benzomorphane hydrochloride (cf. Example 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 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 13 21,5-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-21-methoxy-2,9,9-trimethyl-benzomorphan dissolved in 500 ml of peroxide-free tetrahydrofuran, followed by dropwise addition of more than 45 142 g (1.0 mol) of methyl iodide and the mixture are stirred for 4 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-6,7-15 benzomorphane (cf. Example 2) and proceeding according to Example 8a using twice the amount of sodium hydride and methyl iodide, 2', 5-dimethoxy- 2,9,9-trimethyl-6,7-benzomorphane hydrochloride.

c) Repeating Example 13b) using ethyl iodide instead of 20 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) By proceeding according to Example 13c) using allyl bromide instead of ethyl iodide and a reaction time of 6 hours, 21,5-diallyloxy-2,9,9-trimethyl-6,7-benzomorphane in the form of a non-crystalline base is obtained.

E) Proceeding according to Example 13c) using 5-hydroxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane (cf. Example 1a of FI patent application 833269) gives 5-ethoxy-2 ' -methoxy-2,9,9-trimethyl-6,7-benzomorphane in the form of a non-crystalline base.

35 f) The procedure according to Example 13d) using 25 6 8 2 2 4 5-hydroxy-21-methoxy-2,9,9-trimethyl-6,7-benzomorphane gives 5- (allyloxy) -2'-methoxy-2 , 9,9-trimethyl-6,7-benzomorphane hydrochloride, m.p. 207-209 ° C.

g) Following the procedure of Example 13f) using 5-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.

h) Following the procedure of Example 13f) 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 14 2 ', 5-Di-n-propoxy-2,9,9-trimethyl-6,7-benzomorphane. hydrochloride 15 a) 2.98 g (9.1 mmol) of 2,5,5-diallyloxy-2,9,9-trimethyl-6,7-benzomorphane (cf. Example 13d) 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). 2.9 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 '-. <5Ubst. 5-n. Salt mp

obtained product __starting __________________ b 8f OCH ^ OCbH ^ (n) residual oil c 8g (XH3 OC3H9 (n) HCl 213-216 30

Example 15 2'-Hydroxy-5- (3-hydroxypropoxy) -2,9,9-trimethyl-6,7-benzomorphane hydrochloride a) 24 ml of a 1M solution of diborane in tecrahydrofuran 35 are added dropwise over two Runs at 26 6 8 2 2 to -10 ° C in a solution of 2.02 g (6 mmol) of 5-allyloxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride (cf. Example 13f) dissolved To 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 one hour 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 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 12 g), 5- (2-hydroxybutoxy-2'- 20 methoxy-2,9,9-trimethyl-6,7-benzoinorphan in the form of the free base, which can lead to the reaction without purification.

Example 16 9,9-Dimethyl-21-hydroxy-5-methoxy-6,7-benzomor-25-voice hydrochloride (R f = H, starting material)

Method 1

A solution of 285 ml of ethanethiol (3.86 mol) in 570 ml of dimethylformamide (DMF) is added dropwise to a suspension of 124.4 g (2.85 mol) of sodium hydride 30 (55% suspension in 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. At reflux for six hours,

II

After 27 68224, the reaction mixture is concentrated under reduced pressure 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 once with 500 ml of chloroform / butanol (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 ml of dichloromethane are added dropwise over 45 ml 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 1 of FI patent application 833269 15) 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 833269) are added portionwise to a mixture of 14.4 g (115.5 mmol) of aluminum trichloride-30 dia, 14.5 ml of nitrobenzene and 250 ml of benzene. After refluxing for 8 hours and cooling to 1 ° C, the aluminum chloride complex obtained is extracted with 250 ml of ice-cold 2N hydrochloric acid, the temperature being kept below 40 ° 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 28 6 822 4 is extracted three times with 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 5 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 in which 10 1 * 2 is methyl and is hydroxy are prepared according to methods 1 and 2, respectively (for compound j, the 2'-methoxy group of the product originally obtained is removed by treatment with 47% hydrobromic acid in analogy to Example 12 = method 4) 15

No. Start- R, R ^ Go-- Salt Mp ° C

Substance Obtained Product __ a 13b CH3 CH3 2 base 183-185 b 13c CH ~ C-Hc 2 oxa- 216-218 20 ^ c 14a CH3 n_C3H7 2 HCl 243-246 d 13f CH3 allyl 1 HCl 227-232 (d) e 15a CH 3 3-hydroxy-1 HCl 170 (d) propyl f 13g OI. 2-butenyl 1 HCl 238-241 g 14c CH3 n-C4H9 1 HCl 255-257 h 15b CH3 2-hydroxy-HCl 243-246 sibutyl i 13h CH3 benzyl 1 HCl 237-2 40 j sdb HH 4 HBr 280-283 (d) 30 k xf H 2 base 208-210 1 5 * g H allyl 1 base 228-230 m s4i H nC-JI-, 1 HCl 232-236 n sti H 2-bute- 1 base oil os «j H 26103 oil 35 p sdc H benzyl 1 base oil (compounds 16j-16p starting materials).

Il 29 68224 9C) The compound according to Example 11 of FI patent application 333269,

Example 17 a) Using 2-cyclobutylmethyl-5 ', 5-dimethoxy-9,9-dimethyl-6,7-benzomorphane (Example 6c) as starting material and proceeding according to Example 16, Method 1, 2-cyclobutylmethyl- 9,9-dimethyl-2 1-hydroxy-5-methoxy-6,7-benzomorphine hydrochloride, m.p. 225-227 ° C.

B) Using 2 ', 5-dimethoxy-9,9-dimethyl-2- (3-methyl-2-butenyl) -6,7-benzomorphane hydrochloride (Example 1e) as starting material and following the procedure of Example 16, Method 2, to give 9,9-dimethyl-21-hydroxy-2- (3-methyl-2-butenyl) -5-methoxy-15,6,7-benzomorphane oxalate, m.p. 206-207 ° C (decomposes).

c) Using 5-allyloxy-2-cyclobutylmethyl-9,9-dimethyl-2 "-methoxy-6,7-benzomorphane (Example 6r) as starting material and following the procedure of Example 16.1, the result is 5- allyloxy-2-20 cyclobutylmethyl-9,9-dimethyl-21-hydroxy-6,7-benzomorphane hydrochloride, mp 223-228 ° C.

Example 18 2-Cyclobutylmethyl-9,9-dimethyl-2'-hydroxy-5-propoxy-6,7-benzomorphane hydrochloride Using 5-allyloxy-2-cyclobutylmethyl-9,9-dimethyl-21-hydroxy Treatment of 6,7-benzomorphane hydrochloride (Example 17c) according to Example 9a gives the title compound, m.p. 221-225 ° C.

Example 19 Following the procedure described in Example 13b and Example 16, Method 1, the following compounds of formula I are obtained: 30 6 8 2 2 4

For example, the starting material N-substituent of the product Salt Sp. (° C) support a 7 f CH2C (OCH3) (CH3) 2 HCl 180-185 b 7 k CH2C (OCH3) (CH3) 2 hc1 184-188 ^ C 7 n CH2CH (OCH3) CH, CCH, uq 188- 192 CH3 ° d 71 CH2 ~ ^ \ j HCl 228-230

CH O

e V \ e 7 m CH 2 — y 11 Cl 211-220 ch 7 o f 7 b CH 2 ~ ^ \] HCl 2 39-251 9 7 v CrUCH (OCH,) CH.OCH **! HCl i 190-193 “3 4 3 | | 10 Note. In the process of Example 19f, the amounts of sodium hydride and methyl iodide are reduced to two equivalents to leave the 5-hydroxy group intact.

XX

Isomer A.

Example 20 a) 2'-Hydroxy-5-propionyloxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride 3.0 g (12 mmol) of 2 ', 5-dihydroxy-2,9,9-trimeryl The -6,7-benzomorphane hydrochloride (cf. Example 2) is heated for three hours in a mixture of 45 ml of oropionic acid-20 hydride 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

II

31 68224 The 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 21,5-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.

10 Evaporate the solvent 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-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 16j) as starting material and proceeding according to Example 16j, 2', 5-diacetoxy-9, 9-dimethyl-6,7-benzomorphane (starting material).

This is further allowed to react without purification.

d) Using 9,9-dimethyl-21-hydroxy-2- (2-hydroxy-2-methylpropyl) -5-methoxy-6,7-benzomorphane hydrochloride as starting material (cf. Example 7f) and proceeding according to Example 20a gives 9,9-dimethyl-5-methoxy-2'-propionyloxy-2- (2-methyl-2-propionyloxypropyl) -6,7-benzomorphane hydrochloride, m.p. 96-102 ° C.

After hydrolysis of the 2'-propionyloxy group, 9,9-dimethyl-21-hydroxy-5-methoxy-2- (2-methyl-2-propionyloxypropyl) -6,7-benzomorphane is obtained, m.p. 178-180 ° C.

e) Using 5-ethoxy-9,9-dimethyl-2'-hydroxy-2- (2-hydroxy-2-methylpropyl) -6,7-benzomorphane hydrochloride as starting material (cf. Example 7k) and proceeding according to Example 20a 9,9-dimethyl-5-ethoxy-2'-hydroxy-2- (2-methyl-2-propionyloxypropyl) -6,7-benzomorphane is obtained, m.p. 160-163 ° C.

68224 32

Example 21 a) 5-Hydroxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride

A mixture of 3.7 g (15 mmol) of 21,5-dihydroxy-5,9,9-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 are heated at 100 ° C for five hours. After cooling, the salt is filtered off 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 21- (1-phenyl-5-tetrazolyloxy-5-hydroxy-2,9,9-trimethyl-6,7-benzomorphane, mp 158-164 ° 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 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 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 21-hydroxy-5-methoxy-2,9,9-trimethyl-6,7-benzomorphane (cf. Example 5a) as starting material and proceeding accordingly, 5-methoxy-2,9,9-trimethyl -6,7-benzomorphane hydrochloride, m.p.

308-223 ° C.

c) Using 9,9-dimethyl-5-ethoxy-21-hydroxy-6,7-benzomorphane (cf. Example 16k) as starting material and proceeding accordingly, 9,9-dimethyl-5-ethoxy-6 is obtained. 7-Benzomorphan as a non-crystalline substance (starting material).

35 Example 22 5-Acetoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride Using 5-hydroxy-2,9,9-trimethyl-33 6 8 2 2 4 6,7-benzomorphane hydrochloride as starting material (cf. Example 21a) and proceeding according to Example 20b, the title compound is obtained, m.p. 225-227 ° C.

Example 23 5 a) 21-Acetoxy-5-hydroxy-2- (1-acetoxy-cyclopropylmethyl) -9,9-dimethyl-6,7-benzomorphane 60 g (19.8 mmol) of 21.5- dihydroxy-2- (1-hydroxy-cyclopropylmethyl) -9,9-dimethyl-6,7-benzomorphane 10 (cf. Example 7b) is refluxed for one hour in 60 ml of acetic anhydride in the presence of a few drops of pyridine. 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 sponges using toluene / ethyl acetate (1: 1) as eluent to give the title compound as an oil.

b) The diacetate obtained in 21,5-dihydroxy-2- (1-acetoxy-cyclopropylmethyl) -9,9-dimethyl-6,7-benzomorphan oxalate a) is dissolved in 50 ml of methanol and neutralized with IN 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 careful basification with concentrated 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 resulting base is converted to the oxalate and the product is recrystallized from methanol / ethyl acetate to give the title compound, m.p. 196-198 ° C.

34 68224

Example 24 (+) and (-) - 5-hydroxy-2'-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride 13.0 g (50 mmol) of (+) - 5-hydroxy 2'-Methoxy-2,9,9-5 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 = + 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 results in the formation of the (+) - salt 15 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 α (J = 5 = + 90, 5 °.

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

Example 25 (+) - 2'-hydroxy-5-methoxy-2,9,9-trimethyl-6,7-25 benzomorphane hydrochloride Using (+) - 5-hydroxy-21-methoxy-2,9,9- trimethyl-6,7-benzomorphane (cf. Example 24) and proceeding according to the procedure set forth in Example 13a and Example 16, Method 1, to give the title compound, m.p. 220-223 ° C and - + 84.7 °.

Example 26 (-) - 2, -Hydroxy-5-methoxy-2,9,9-trimethyl-6,7-benzomorphane hydrochloride Using as starting material (-) - 5-hydroxy-2'-methoxy-35 2,9,9 -trimethyl-6,7-benzomorphane (cf. Example 24) and following the procedure of Example 25 gives the title compound, m.p. 219-222 ° C and α (λ = -83.1 °.

Claims (9)

68224 A process for the preparation of 6,7-benzomorphane derivatives of the formula I which are useful as analgesics, narcotic antagonists and inhibitors of luteinizing hormone secretion: in the formula wherein R 1 is optionally hydroxy / or alkoxy-C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 2-8 -cycloalkyl or C 3-8 -cycloalkyl- (C 1-8) -alkyl; C 2-8 alkenyloxy- (C 1-8) alkyl, aryl- (C 1-8) alkyl, arylhydroxy- (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; is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl- (C 1-8) alkyl, hydroxy- (C 1-8) alkyl or (C 1-8) alkoxy- (C 1-8) alkyl; ) alkyl and R 1 is hydrogen, hydroxyl, C 1-8 alkoxy or C 2-8 alkenyloxy, wherein in said compounds the hydroxyl groups may be acylated; and for the preparation of their acid addition salts, characterized in that A) a compound of formula I in which R 1 is hydrogen and R 2 -R. 1 III 4 are the same as above, reacted with a compound of formula R 1 -Y III ^ (IV) having the same as R 1 and Y is a nucleophilic leaving group; and then, if desired, one or more of the following steps are performed: B) alkylating a compound of formula I wherein R 30 and / or R 6 is a hydroxy group or contains a hydroxy group; C) a compound of formula I wherein R 1 O or R 4 is alkenyloxy is hydrogenated; D) a compound of formula I wherein R 1 is alkenyl, Hydrogen; E) performing ether cleavage on a compound of formula I wherein R 1, R 2 and / or R 2 are alkoxy or contain alkoxy; F) acylation of a compound of formula I wherein R 1, R 2 and / or R 2 is a hydroxyl group or contains a hydroxyl group; G) a compound of formula I in which R 1, R 2 O and / or R 4 is an acyloxy group or contains an acyloxy group is hydrolyzed or subjected to reductive cleavage; H) dehydroxylating a compound of formula I wherein R 4 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. 68224 37 For the preparation of 6,7-benzomorphan derivatives of formula I, which is an analogue of 5 analogues, antagonists for narcotic drugs and inhibitors for secretion of luteinising hormones: f I f / R II »A A 2 10. A 4. XCH3 oe3 is a valentyl-C1-6-alkyl, C2-8-alkenyl, C2-8-alkynyl, optionally hydroxy- or alkoxy-substituted alkoxy, C 3-8 cycloalkyl or C 3-8 cycloalkyl- (C 1-6) alkyl, C 2-8 alkenyloxy- (C 1-6) alkyl, aryl- (C 1-6) alkyl, arylhydroxy- (C 1-6) alkyl, aryl- (C 1-6) alkyl ~,) alkenyl or tetrahydrofuryl-C 1-6 alkyl; or optionally C 1-8 alkyl substituted with furyl- (C 1-8) alkyl or isoxazolyl- (C 1-8) alkyl; R2 is hydrogen or methyl; R3 is hydrogen, C1-8-alkyl, C2-8-alkenyl, C2-8-alkynyl, aryl- (C1-8g) alkyl, hydroxy- (C1-8) alkyl or C1-8-alkoxy- (C1-8) -alkyl a mixture of hydroxyl, C 1-6 alkoxy or C 2-6 alkenyloxy, 25 colors of hydroxyl groups and such compounds as acylate, as well as a radical addition; känne-t e c k n a t därav, att A) en förening med formuleln I, color är väte och R2-R4 är samma som ovan, omsätts med en förening med formuleln 30 R ^ I'tI-Y (IV), color R ^ 111 is samma som R ^ och Y Y en nucleophilic group, and dehydrated, ifali self-contained, utilized or otherwise derived from Stegen; B) in the case of formula I, the color R 1, R 30 and / or R 4 is a hydroxyl group or a hydroxyl group, alky-35;