FI68228C - FREQUENCY REPAIR OF ANALYTICAL OCH / ELLER MORFINANTAGONISTISKT AKTIVA 6,7-BENZOMORFANDERIVAT - Google Patents

Description

68228

Process for the preparation of 6,7-benzomorphane derivatives which are analgesically and / or morphine antagonist 5 Separated from application 791239

The invention relates to a process for the preparation of 6,7-benzomorphane derivatives and their acid addition salts.

It has been found that 6,7-benzomorphane derivatives having a quaternary carbon atom at the 9-position and a substituent containing at least one oxygen atom at the 2-position have surprising pharmacological properties. In particular, they have an analgesic and / or morphine-antagonistic effect. The formula of the new compounds is: R1-CH2-A - C - R2 1

20 II CH I

R 3 R

R 5 is CH 3 3 R 4 wherein A is a direct bond or -CH 2 -, R 1 is hydrogen, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy-C 1-2 alkyl or C 3-6 alkyl; C 1-6 alkyl, R 2 is hydrogen or C 1-2 alkyl, or R 1 and R 2 together with the carbon atom to which they are attached form a C 3-8 cycloalkyl group or a 4-6-30 membered heterocycloalkyl group having one oxygen atom as the sole heteroatom, R is hydroxy, C 1-4 alkoxy, C 2-4 alkenyloxy or R 1-4 COO-, wherein R 9 is hydrogen, C 1-3 alkyl, phenyl or benzyl, R 4 is hydrogen, C 1-4 alkyl or phenyl, and R 5 is hydrogen, hydroxy, C 1-4 alk-oxy or R 7 COO-, wherein R 7 is hydrogen, C 1-4 alkyl, phenyl, 2,6228 benzyl, phenethyl or 3-pyridyl.

Preferred compounds are generally those in which the oxygen atom of the nitrogen substituent is attached to a carbon in the ^ position relative to the nitrogen atom of the ring.

5 A is thus preferably a direct bond.

A particularly preferred group of compounds of formula I are those compounds of the formula: R "10, 1 / x /" "N_CH_ '/ X / 2 c-RA la

HO I

XCH 2 R "* R · 3 15 4 wherein R 1" is hydrogen, methyl, ethyl or ethynyl, 'is hydrogen, methyl or ethyl,' R 2 "'is hydroxy, methoxy or ethoxy, and is hydrogen, methyl, ethyl, n-propyl or phenyl.

Of the compounds of formula Ia, particularly preferred are those of the formula: CH, 25 1 (N /, /) -ch2-C_CH3 la ·

L · n f \ - ch3 J

HO \ J 0H

CH3 * 4 wherein R1 'is as defined above.

A preferred group of compounds of formula I also comprises compounds of formula:

II

68228 3 XVt:.: = -Τ '5 HC5 ^^^ Χ Η "1 CH3 3 R' 4 jg wherein" 1 and R4 'have the same meaning as above and Z is (-CH2-) / where n is 2, 3 or 4. Particularly preferred are compounds of the formula: CH_ 1 <15 - ° Η2 c - £ H2 Ib '

HO OH

I ch3 R '4 20 where' means the same as above.

The compounds of the formula I can be in the form of the free base or in the form of acid addition salts, for example salts with mineral acids, such as hydrochloric acid, hydrobromic acid or sulfuric acid, or with organic acids, such as maleic acid, oxalic acid or tartaric acid. The 6,7-benzomorphane structure has two asymmetric carbon atoms, and C 1-4. The 3Q iminoethanos bridge between C 1-4 and C 1-4 is always in the cis position (1,3-diaxial), and thus the compound exists as only one racemate, provided there are no asymmetric carbon atoms in the side chain. The racemate can be divided into optical isomers. If the N-substituent has one or more asymmetric carbon atoms, there are more diastereoisomers.

4 68228

The group of compounds of formula I comprises the free bases and acid addition salts, racemates, separated optical isomers and mixtures thereof.

The compounds of formula I and their salt addition salts can be prepared by 2-acyl-9,9-dimethyl-6,7-benzomorphane of the formula: 0 R, 11 I J -cac-r2 10 HlcH3 R 3 R 5 (III) R 4 wherein A, R 1, R 2, R 4 and are as defined above are reduced, followed by, if desired, (a) a benzomorphane of formula I wherein at least one of R 1 and R 1 - is hydroxy, alkylated - 2Q is obtained to obtain a benzomorphan of the formula I in which at least one of the substituents R 1 and R 2 is alkoxy, and / or (b) a benzomorphan of the formula I in which at least one of the substituents R 1 and R 2 is hydroxy is acylated to obtain a benzomorphan of formula I wherein R 1 is R 9 COO- and / or R 2 is R 7 COO-, and / or (c) in a benzomorphane of formula I wherein at least one of R 1 and R 2 is alkoxy, the ether bond is cleaved to give a benzomorphan of formula I 30 in which at least one of the substituents R 1 and R 2 is hydroxy, and / or (d) a compound of formula I an enzymorphan wherein R 1 is R 1 COO- and / or R 7 COO- is hydrolyzed to give a benzomorphan of formula I wherein at least one of the substituents R 1 and R 2 is hydroxy, and / or (e) a free base of formula I converted to an acid addition salt.

5 68228

The process is suitably carried out in a manner known per se, e.g. using diborane or a hydride complex such as lithium aluminum hydride. The hydride is added in an equivalent amount or in excess, preferably twice the equivalent amount. The reduction is preferably carried out in an inert solvent, in particular tetrahydrofuran, at a temperature between 0 ° C and the boiling point of the solvent. It should be noted that said reducing agents are also capable of reducing O-acyl groups. In compounds of formula III in which and are acyloxy groups, e.g. the groups are generally converted to hydroxy groups to give compounds of formula I wherein and R 1 are hydroxy groups.

For example, compounds of formula III may be prepared by acylation of a benzomorphane of formula: wherein R 1 and R 3 have the same meaning as defined above. with a compound of the formula: OR, »t 1 30 XCAC-R2 (IX) R3a wherein A, R1 and R2 have the same meaning as above, R1a

means the same as R, except for hydroxy and X is halo J

gene or 6 o * 6g228 H 1 -O-C-A-C-R-.

t ** R-.

2a The acylation of a benzomorphane of the formula IV is preferably carried out in the presence of an acid-binding agent, in particular triethylamine or pyridine. Suitable solvents are chloroform, pyridine or dimethylformamide. The reaction temperature is generally between 0 ° C and the boiling point of the reaction mixture.

Compounds of formula III in which R 3 is hydroxy may be prepared by hydrolysis of the corresponding compounds in which R 3 is acyloxy.

Compounds of formula III may also be prepared by reacting a benzomorph of formula IV with a carboxylic acid of formula: O R 1, HO-CACR, (X) 2 O wherein A, R 1, R 2 and R 2 are as defined above, dicyclohexylcarbodi in the presence of an imide. This acylation is carried out under normal reaction conditions, e.g. using chloroform as a solvent, after which the reaction product is isolated in a conventional manner.

If a benzomorphane of the formula IV in which R1 is hydroxy is used as starting material, the hydroxyl group can also be acylated to give a ferrous compound of formula III in which R1 is acyloxy, which, however, is again reduced to a hydroxy group in the next reaction step.

The preparation of benzomorphans of formula IV is described in NL patent applications 6,908,527, 6,908,528,35 and 7,601,924.

7 68228

If it is desired in the further reaction (a) to convert two hydroxy groups (R 1 and) to alkoxy groups, the hydroxy groups can first be converted into the corresponding alkali metal salts, e.g. with sodium hydride in an aprotic solvent. The salts are then treated with a C 1-4 alkyl or C 2-4 alkenyl halide or a C 1-4 alkyl or C 2-4 alkenyl sulfonic ester, preferably a C 1-4 alkyl or C 2-4 alkenyl halide. Due to hydroxy radicals and different acidity, R ,. alkyl-10 can be selectively reacted, e.g., by converting a hydroxy radical with an R 1 base, such as a dilute solution of an alkali hydroxide (e.g., NaOH), to an alkali metal salt, and the resulting product is treated, e.g., with di-C 1-4 alkyl sulfate.

Further reaction (b) is preferably carried out with an acid halide, e.g. an acid chloride or anhydride. The acylation is preferably carried out in the presence of an acid-binding agent, in particular triethylamine or pyridine. Suitable solvents include chloroform, pyridine and dimethylformamide. The reaction temperature is usually between 0 ° C and the boiling point of the reaction mixture. The 2'-OH group (R 2) can be selectively acylated by selecting the appropriate reaction conditions.

Suitable ether scavengers for further reaction (c) include hydrogen halides, e.g. hydrobromic acid and Lewis acids such as boron tribromide. Aromatic ether groups can be cleaved with sodium thioethoxide.

The hydrolysis according to the further reaction (d) can be carried out, for example, under acidic or temporal conditions, preferably in aqueous alkaline solution. The acyloxy group in the R 1-3 position can be selectively hydrolyzed under mild conditions.

The reaction products can be isolated from the reaction mixture and purified by conventional methods.

Diasteroisomers can be separated in a known manner on the basis of their various physical and chemical properties, e.g. by fractional crystallization or column chromatography. Separation of the isomers may be carried out after the last step of the synthesis or optionally at an earlier stage after the stereoisomer mixture has been formed. In the case of compounds of formula I having alkoxy or acyloxy, the diastereoisomers of the corresponding hydroxyl compounds are preferably first separated by chromatography.

Each isomer is then individually alkylated or acylated.

Racemic mixtures can be separated into their optical isomers, for example, by separating the salts of their optically active acids in a known manner.

The free base of formula I can be converted into a salt and vice versa a salt into the free base by conventional methods.

The compounds of formula I are pharmacologically active. In particular, they have analgesic and morphine antagonistic activity, and can thus be used as analgesics and morphine antagonists, as can be demonstrated by the following experiments: 1) A tail withdrawal test performed on male Wistar rats as described in Arzneim. Forsch. 13, 502 (1963), in which the measurement times were shortened from 25 seconds to 10 seconds. The results can be evaluated based on the following levels of analgesia: (a) moderate analgesic activity (MA): tail withdrawal in 6-10 seconds, (b) clear analgesic activity (PA): no tail withdrawal 30 occurs within 10 seconds, but the rat moves the tail slightly in warm water, ( c) surgical analgesic activity (SA) with no tail withdrawal in 10 seconds and no tail movement.

2) Nalorphine activity in rats: 35 Male Wistar rats are given s.c. 0.63 mg / kg body weight of fentanyl causing respiration

II

9 68228 blockade, absence of righting reflex, muscle stiffening, removal of surgical pain, and loss of corneal and earlobe reflexes. The ability to act against these phenomena measures the finin activity of the test compound nalor-5. 30 minutes s.c. after injection, the animals are administered intravenously the test compound or the reference compound nalorphine or pentazosin.

3) Rat torsion test:

Female Wistar rats (weight 150-190 g) are administered i-10 i.p. 1 ml of 1% acetic acid. Observations of the number of twists are made over the next 25 minutes. The average number of writhes in the control animals is defined as 100. Test and reference compounds are administered prior to acetic acid injection, with administration 30 minutes to 15 minutes before s.c. administration, and 45 minutes before in the case of oral administration.

The advantageous therapeutic properties of the 6,7-benzomorphane derivatives of the formula I are set out in more detail in strain application FI 791 239, in which the compounds of the formula I are compared with known compounds of close structure.

A suitable daily dose is 10-100 mg in 2-4 divided doses of 2.5-50 mg or administered in retard form.

The compounds may be administered as free bases or as pharmaceutically acceptable salts having the same activity as the free bases.

The compounds of formula I may be mixed with conventional pharmaceutically acceptable diluents and carriers and, if desired, other excipients and administered as tablets, capsules or solutions for injection. They may be co-administered with other Analgesics or other active agents such as sedatives, sedatives or hypnotics.

The following examples illustrate the invention.

Example 1 9,9-Dimethyl-5-ethyl-2'-hydroxy-2- (2-methoxyethyl) -6,7-benzomorphane hydrochloride 68228 10

To a solution of 3.0 g (12.3 mmol) of 9,9-dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphane in 45 ml of dry methylene dichloride and 26.8 ml of triethylate amine, a solution of 4.0 g (36.6 mmol) of methoxyacetyl chloride in 30 ml of dry methylene dichloride was added dropwise at room temperature.

The mixture was refluxed for 30 minutes. After cooling, water was added and the organic phase was separated from the aqueous phase, dried over magnesium sulphate and evaporated in vacuo. The mixture was filtered through a column of silica gel using a mixture of cyclohexane and acetone (3: 1) as eluent. The fraction containing 9,9-dimethyl-5-ethyl-2- (2-methoxyacetyl) -21- (2-ethoxyacetyloxy) -6,7-benzomorphane was evaporated to dryness to give a yellow oily residue (4.3 g).

The residue was dissolved in 80 ml of dry tetrahydrofuran. The solution was added dropwise under nitrogen at room temperature to a stirred suspension of 1.47 g (39 mmol) of lithium aluminum hydride in 30 ml of 20% tetrahydrofuran. After stirring for 30 minutes, 18 ml of ethyl acetate and then 150 ml of saturated ammonium chloride solution were carefully added dropwise. The resulting precipitate was filtered and washed with chloroform. The aqueous phase was separated from the chloroform phase and extracted three times with chloroform. The recovered chloroform layers were dried over magnesium sulfate and evaporated in vacuo. The resulting residue was converted to the HCl salt and crystallized from a mixture of methanol and ethyl acetate to give 2.4 g of the title compound 30 (m.p. 222-225 ° C, dec.).

Examples 2-7

As described above, the following N-substituted benzomorphane derivatives were obtained using the N-substituted benzomorphane derivatives 35 and the corresponding acid chlorides mentioned below.

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Eg Starting N-substituent Salt Melting point

No._Member ________ 2 A -CH ~ CH ~ OCH? CH_ HCl 222-230 -3 (decomposes) 5 3 A -CH2CH2OCH2CH2CH3 HCl 205-206 4 A -CH2CH2OCH (CH3) 2 HCl 187-188 5 A -CH2CH2CH2OCH3 HCl 205 (decomposes) ) 6 B -CH 2 CH 2 OCH, HCl 197-200 (decomposes) 1Q 7 C -CH 2 CH 2 OCH 3 HCl 227-229 Starting materials: A: 9,9-dimethyl-5-ethyl-21-hydroxy-6,7-benzomorphane, B: 9, 9-dimethyl-2'-hydroxy-6,7-benzomorphane, 15 ° C: 2'-hydroxy-5,9,9-trimethyl-6,7-benzomorphane Example 8 2- (2-t-butoxyethyl) -9, 9-Dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphane hydrochloride To a solution of 4.44 g (32.6 mmol) of t-but-20-oxyacetic acid in 25 ml of dry chloroform was added dropwise 15 a solution of 3.89 g (32.6 mmol) of thionyl chloride in 25 ml of dry chloroform under nitrogen and at room temperature. After stirring for 20 hours, a solution of 2.0 g (8.16 mmol) of 9,9-dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphane in 18 ml was added dropwise to the mixture: in triethylamine and 20 ml of dry chloroform. After refluxing for 30 minutes, the reaction mixture was cooled and water was added. The aqueous phase was extracted twice with chloroform, after which the combined chloroform layers were dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was filtered through a column of silica gel using a mixture of cyclohexane and acetone (3: 1) as eluent. The fraction containing 2- (2-t-butoxyacetyl) -2 '- (2-t-35-butoxyacetyloxy) -9,9-dimethyl-5-ethyl-6,7-benzomorphane was evaporated to dryness to give 12,68228. g of oily residue. This residue was dissolved in 25 ml of dry tetrahydrofuran, and the solution was added dropwise under a nitrogen atmosphere and at room temperature to a suspension of 0.69 g (18 mmol) of lithium aluminum hydride in 25 ml of dry tetrahydrofuran. After stirring for 30 minutes at room temperature, 15 ml of ethyl acetate and 150 ml of saturated ammonium chloride solution were carefully added dropwise, and the resulting precipitate was filtered and washed with chloro-10. The aqueous layer was separated from the chloroform layer and extracted three times with chloroform. The recovered chloroform layers were dried over magnesium sulfate, evaporated in vacuo, and the residue was converted to the HCl salt and crystallized from a mixture of methanol and ethyl acetate. The yield of the title compound was 1.7 g, m.p. 196-198 ° C. Examples 9-21 Using the N-substituted benzomorphane derivatives and the corresponding carboxylic acids mentioned below, the following N-substituted benzomorphane derivatives were obtained as described in Example 8.

Eg Starting N-substituent Salt Melting point

No._substances_________ 9 A -CH2CH2CH2OCH2CH3 HCl 170-172 (decomposes) 25 10 A -CH2CH (OCH3) CH3 HCl 235-238 11 A -CH2CH (OC2H5) CH3 HCl 233 (decomposes) 12 A -CH2C (CH3) 2OCH3 HCl 195-198 13 A -CH 2 CH (OCH 3) CH 2 CH 3 HCl 228-229 30 14 B -CH 9 CH 90 CH 9 CH 2 HCl 202-204 J (decomposes) 15 B -CH 2 CH (OCH 3) CH 3 HCl 224-226 16 C -CH 2 CH 2 OCH 2 CH 3 HCl 208-211 17 C -CH 9 CH -CH0OCH ^ HBr 210-212 35 Δ λ 6 18 C -CH2CH (OCH3) CH3 HCl 244-248 li 13 68228

Eg Starting N-substituent Salt Melting point

No. substance __________—-- 19 D -CH 2 CH (OCH 3) CH 3 HCl 249-253 20 E -CH 2 CH 2 OCH 3 HCl 244-252 5 21 E -CH 2 CH (OCH 3) CH 3 HCl 257-266 x x) Both diastereoisomers were separated by fractional crystallization. Isomer A m.p. 247-253 ° C and m.p. 262-267 ° C of isomer B.

^ Starting materials: A: 9,9-dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphane, B: 9,9-dimethyl-2'-hydroxy-6,7-benzomorphane, C: 2'- hydroxy-5,9,9-trimethyl-6,7-benzomorphane, D: 9,9-dimethyl-2'-hydroxy-5-n-propyl-6,7-benzo-15 morphane, E: 9.9- dimethyl-5-phenyl-2'-hydroxy-6,7-benzomorphan. Example. 22

As described in Example 1, but using pyridine as the solvent instead of methylene dichloride / triethylamine and refluxing for 1 hour instead of 30 minutes, the intermediate 9,9-dimethyl-2- (2-methoxyacetyl) -2 '- (2-methoxyacetyloxy) - was prepared. 6,7-benzomorphane using 0.9 g of 9,9-dimethyl-2'-hydroxy-6,7-benzomorphane in 15 ml of pyridine and 0.8 g of methoxyacetyl-25 chloride in 5 ml of pyridine. The yield of intermediate was 1.5 g (yellow oil). The benzomorphane of Example 6 was obtained by reduction as described in Example 1.

Examples 23-48 The following compounds were obtained as described in Examples 1-21: 14 68228

For example, the starting N substituent Suo

No. substance_______________ 23 A -CH2CH2OH HCl 227-231 24 A -CH2- / HCl 246-249 5

OH

24 A as HCl 242-246 (isomer) 24 A as HCl 243-247 (-isomer) 25 A -CH 9 CHOHCH 2 HCl 226-22925 3) 215-220 J 26 A -CH 2 C (CH 3) 2 OH HCl 230 -234 27 A -CH:) CHOHCH90CH2 HCl 168-17115] 5 Δ z J 2) 172-175 ^ 28 A -CH2CHOHCH2CH3 HCl 235-238 29 A -CH2-HCl 259-268

20 OH

30 B -CH2C (CH3) 2OH HCl 222-224 31 B -CH2CHOHCH2OCH3 32 C -CH ~ C (CH3) ..OH HCl 239-241 25 33 E -CH2C (CH3) 2OH HCl 196-201 34 E -CH2CHOHCH2OCH3 35 E -CH-CHOHCH (COOH). 157-16225 Δ J ^ 3) HCl 261-266J | 30 χ 36 E -CH 2 - <N HCl 243-25 3 2 Ny OH \ 37 E -CH 2 -N (COOH) 2 165-172 1 il

OH

68228

Eg Starting N-substituent Salt Melting point

No. substance ________ — __ 38 B as HCl 250-254 39 C as HCl 247-251 5 40 D as HCl 216-219 41 F as HCl 203-205 42 B -CH ~ / \ HCl 265 (decomposes) 10

OH

43 A -CH- / HCl 248-252 h

15 OH

44 A -CH 2 - \ HCl 251-255

OH

20 OH

45 A -CH 2 -C (CH 3) C 2 H 5 HCl 233-235

OH

46 A -CH2-C (CH3) - <^ | (COOH) 2 182-186 25 47 A -CH 2 -C (C 2 H b) 2 OH HCl 223-233 48 G -CH 2 -C (CH 3) 2 OH HCl 223-226 1) Isomers A + B; 2) Isomer A; 3) Isomer B 30 Starting materials; A: 9,9-dimethyl-5-ethyl-2'-hydroxy-6,7-benzomorphane, B: 9,9-dimethyl-21-hydroxy-6,7-benzomorphane, C: 2'-hydroxy-5, 9,9-trimethyl-6,7-benzomorphane, D: 9,9-dimethyl-2'-hydroxy-5-n-propyl-6,7-benzo-35 morphane.

16 68228 E: 9,9-dimethyl-5-phenyl-2'-hydroxy-6,7-benzomorphane, F: 9,9-dimethyl-5-ethyl-6,7-benzomorphane, G: 9, 9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzo-5 morphane.

Example 49 9.9-Dimethyl-5-ethyl-2 · -methoxy-2- (2-methoxypropyl) -6,7-benzomorphan oxalate 1.7 ml (30 mmol) of methyl iodide and 0.93 g of 1Q (20 mmol) of sodium hydride (55% suspension in oil)] was gradually added to a solution of 1.0 g (3.15 mmol) of 9,9-dimethyl-5-ethyl-2'-hydroxy-2- (2-methoxypropyl) -6,7-benzomorphane (e.g. 10) in 4.5 ml of dry tetrahydrofuran cooled to 0 ° C.

The reaction mixture was stirred for 3 hours at room temperature.

Excess sodium hydride is decomposed with water. After acid-po-base separation and evaporation of the organic phase to dryness under reduced pressure, the residue was converted into oxalate and crystallized from acetone and 20 ml of methanol-ethyl acetate to give 400 mg of the title compound, m.p. 157-162 ° C.

Example 50 9.9-Dimethyl-5-ethyl-2- (2-methyloxypropyl) -2'-propionyloxy-6,7-benzomorphanoxalate

A mixture of 1.5 g (4.7 mmol) of 9,9-dimethyl-5-ethyl-2'-hydroxy-2- (2-methoxypropyl) -6,7-benzomorphane (e.g. 10), 3.0 g of 100% metaphosphoric acid and 12.0 g of propionic anhydride were heated at SOSO 60 ° C for 30 minutes with stirring. The reaction mixture was cooled and poured into water. Concentrated ammonia was added to the aqueous layer, and the basic mixture was extracted with ethyl acetate. The resulting ethyl acetate layers were dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was converted to the oxalate and crystallized from methanol-ethyl acetate to give 17 68228 0.99 g of the title compound, m.p. 129-145 ° C.

Example 51 2'-Benzoyloxy-9,9-dimethyl-5-ethyl-2- (2-hydroxy-2-methylpropyl) -6,7-benzomorphane-5 hydrochloride 0.9 g (6.4 mmol) of benzoyl chloride in 10 ml chloroform was added dropwise under a nitrogen atmosphere with stirring to a solution of 1.54 g (4.85 mmol) of 9,9-dimethyl-5-ethyl-2'-hydroxy-2- (2-hydroxy-10-methylpropyl) - 6,7-benzomorphane (e.g. 26) and 0.65 g (6.4 mmol) of triethylamine in 20 ml of dry chloroform. After stirring overnight at room temperature, the solution was heated to reflux for 6 hours. After cooling, water was added and acid-base separation was performed. The base was converted to the HCl salt with isopropanol-HCl and crystallized from methanol-ethyl acetate to give 0.66 g of the title compound, m.p. 235-239 ° C.

Example 52 9,9-Dimethyl-5-ethyl-2'-hydroxy-2- (3-hydroxypropyl) -6,7-benzomorphane hydrochloride Solution containing 1.06 ml (9.33 mmol) of boron tribromide a in 15 ml of dry methylene dichloride, was added dropwise over 30 minutes to a solution of 1.0 g (2.82 mmol) of 9,9-dimethyl-5-ethyl-2'-hydroxy-2- (3- methoxypropyl) -6,7-benzomorphane hydrochloride (e.g. 5) in 28 ml of dry methylene dichloride.

After stirring for 2.5 hours at room temperature, water was carefully added. Concentrated ammonia 30 was added to the aqueous layer, and the basic mixture was extracted three times with chloroform. The obtained chloroform layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was filtered through silica gel using cyclohexane-acetone (3: 1) as eluent. Fractions containing the desired compound were evaporated to dryness under reduced pressure. The residue was converted to the HCl salt and crystallized from methanol-ethyl acetate to give 560 mg of the title compound, m.p. 235-239 ° C.

Example 53 9,9-Dimethyl-21-hydroxy-2- (2-methoxy-2-methylpropyl) -6,7-benzomorphane hydrochloride Using 9,9-dimethyl-2'-hydroxy-2- (2-hydroxy 2-Methylpropyl) -6,7-benzomorphane (e.g. 30) was prepared from 9,9-dimethyl-21-methoxy-2- (2-meth-10-oxy-2-methylpropyl) -6,7-benzomorphane hydrochloride as starting material. , sp. 187-189 ° C (decomposes), as described in Example 30.

To a stirred suspension of 24 mmol (1.2 g of a suspension in oil) of sodium hydride in 30 ml of dry dimethylformamide is added dropwise at room temperature 3 ml (50 mmol) of ethanediol. After stirring for 30 minutes, a solution of 532 mg (1.5 mmol) of 9,9-dimethyl-21-methoxy-2- (2-methoxy-2-methylpropyl) -6,7-benzomorphane hydrochloride in 45 ml was added dropwise. After heating under reflux for 3 hours, the solvent was evaporated under reduced pressure and the residue was subjected to acid-base separation. The free base was converted to the HCl salt and crystallized from methanol-isopropanol to give 210 mg of the title compound, m.p. 215-216 ° C (decomposes).

Examples 54-61

Methylation of the hydroxyl groups of the benzomorphans listed in the table below at the 2 'position and the N-substituent and conversion of the 2'-methoxy to the 2'-hydroxy group as described in Example 51 gave the corresponding final products. In the second column of the table, examples corresponding to the starting materials are mentioned and said N-substituents are related to the final product. The other substituents of the obtained compound are the same as in the starting material.

35 19 68228

Examples 62-63

Analogously, the compound of Example 26 can be diethylated or diallylated and the 2'-ethoxy or allyloxy group converted to the 2'-hydroxy group to give the corresponding compounds as shown in the following table.

Eg Starting N-bust support Salt Sp. ° C

No. substance 10 542) 25-2) I -CH2CH (OCH3) CH3 I HCl 115 (decomposes) 543) 2ζ 3) -CH2CH (OCH3) CH3 HCl 260 (decomposes) S5 £ * -CH2CH (OCH3) CH2OCH3 HCl 196- 199 och3 13 56 Λ4- "CH2 ~ ^ \! HCl 246-252 ° ch3 57 1¾ -CH2- ^ y> HCl 253-260 20 58 311) -CH2CH (OCH3) CH2OCH3 HCl 202-207 582) 312) as well as HCl 201-205 583) as well as HCl 224-228 25 59 ^ -CH2C (CH3) 20CH3 HCl 195-198 £ 0 34 -CH2CH (OCH3) CH2OCH3 HCl 202-207 och3 tl SC-HCl 262-268 & -CH2C (CH3) 20C2H5 HCl 200-203 63 -CH2C (CH3) 20CH2CH = CH2 HCl 195-198 1 1) Mixture of A and B isomers, 2) A isomer, 3) B isomer.

20 68228

Example 64 2- (2-Acetoxy-2-methylpropyl) -9,9-dimethyl-5-ethyl-21-hydroxy-6,7-benzomorphane hydrochloride A mixture containing 1.25 g (4 mmol) 9, 9-Dimethyl-5-ethyl-2 '- (2-hydroxy-2-methylpropyl) -6,7-benzomorphane (e.g. 26), 2.5 g of metaphosphoric acid (100%) and 12 ml of acetic acid hydride were heated to 60 ° C. ° C for 30 minutes. After cooling, water was carefully added and the solution was made alkaline and extracted with ethyl acetate, dried over magnesium sulphate and evaporated under reduced pressure. The compound was converted to the HCl salt and crystallized from methanol-ethyl acetate to give the diester, m.p. 180-185 ° C. The compound was dissolved in isopropanol and acidified with isopropanol-HCl, heated at reflux for 3 hours to cleave the acetoxy group in the benzene ring. After evaporation to dryness, the residue was crystallized from methanol-ethyl acetate to give 0.32 g of the title compound, m.p. 170-173 ° C.

Examples 65-71

Acylation of the hydroxyl groups of the benzomorphans listed in the following table at the 2 'position and the N-substituent and conversion to the 2'-acyloxy group to the 2'-hydroxy group gave the corresponding final products as described in Example 64. The acylation was performed using the corresponding acid anhydride with the exception of benzoylation, which was performed with benzoyl chloride. The second column of the table shows Examples 30 corresponding to the starting materials and said N-substituents are related to the final product. The other substituents in the final product are the same as in the starting material.

21 68228

Eg Starting N-substituent Salt Melting point

No. substance 65 * 2 $ 2 -CH2CH (tH3) OOCCH3 HCl 204-208 β62) X "CH, CH (CH3) 00CC.> Hc HCl 200-204 3 3 \ 2 and others 65) 2S '-CH2CH ( CH3) OXC2H5 HCl 198-201 en2) as2) -ch2ch (ch3) oocc6h5 hci 107-201 673) ^ 3) -CH2CH (CH3) OOCC6 <5 HCl 200-203 63 at -CH2C (CK3) 2OOCC2H5 HCl 170-171 69 at -CH2C (CH3) 2OOCnC3H7 HCl 193-200 * 0 at -CH2C (CH3) 2OOCiC3H? HCl 182-185 VI -CH2C (CH3) 2OXC2H5 HCl 201-204 1) A + B isomers; 2) the A isomer; 3) The B-isomer.

Claims (3)

A process for the preparation of analgesically and / or morphine antagonistically active, optically active and racemic 6,7-benzomorphan derivatives of Formula I and acid addition salts thereof, f1 io CU Wherein A is a direct bond or -CH 2 -, is hydrogen, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 1 -C 2 alkoxy-C 1 alkylf or R1 and R2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl group or a 4-6 membered heterocycloalkyl group containing an oxygen atom as a single heteroatom, R3 is hydroxy, C2-4 alkenyloxy or RgC00- where Rg is hydrogen, C1-4 alkyl, phenyl or benzyl, R4 is hydrogen, C1-4 alkyl or phenyl, and R4 is hydrogen, hydroxy, C1-3 alkoxy or R4 COO- where 25 R? is hydrogen, C 1-4 alkyl, phenyl, benzyl, phenethyl or 3-pyridyl, characterized in that a 2-acyl-9,9-dimethyl-6,7-benzomorphan of the formula R - Λ - C— R 0 III