FI68227B - FREQUENCY REQUIREMENTS FOR ANALYTICAL OCH / ELLER MORFINANTAGONISTISKT AKTIVA 6,7-BENZOMORFANDERIVAT - Google Patents

Description

1 68227

Process for the preparation of analgesically and / or morphine antagonistically active 6,7-benzomorphane derivatives

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

It has been found that 6,7-benzomorphane derivatives having a kyaternary carbon atom at the 9-position and a substituent containing at least one acid atom at the 2-position have surprising pharmacological properties. In particular, they have an analgesic and / or morphine antagonistic effect. The novel compounds have the formula R 1 15 -CH 2 -A-C 2 -R 2 z 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 1-4 -alkoxy- C 1-6 alkyl or C 3-6 cycloalkyl, R 2 is hydrogen or C 1-3 alkyl, or R 1-6 and R 2 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group or a 4-6 membered heterocycloalkyl group having a single heteroatom one oxygen atom, R 3 is hydroxy, C 3-4 alkoxy, C 2-4 alkynyloxy or R 8 COO-, wherein R 8 is hydrogen, C 1-3 alkyl, phenyl or benzyl, R 4 is hydrogen, C 3-4 alkyl or phenyl and R 4 is hydrogen , hydroxy C 3-3 alkoxy or R 1-3 COO-, wherein R 1- is hydrogen, C 1-3 alkyl, phenyl, benzyl, phenethyl or 3-pyridyl.

Preferred compounds are generally those in which the oxygen atom of the nitrogen substituent is attached to a carbon which is in the./$ position relative to the nitrogen atom of the ring. A is thus preferably a direct bond.

A particularly preferred group of compounds of formula I are the compounds having the formula R'i s rpf «rCH2 ~ rR’2 Ia ηοΛΆΑ · 3 l.

CH 3 3 R 4 wherein R 6 is hydrogen, methyl, ethyl or ethynyl, R 6 is hydrogen, methyl or ethyl, R 4 is hydroxy, methoxy or ethoxy, and R 2 is hydrogen, methyl, ethyl, n-propyl or phenyl.

Of the compounds of formula Ia, those of formula 15 are particularly preferred

HO OH

20 'ch3 R, 4 where R' ^ has the same meaning as above.

A preferred group of compounds of formula I also comprises those compounds of formula I CH 1 -3 Ib R, wherein R "'and R' are as defined above and B is 35 q (-CH 2 -) n 'wherein n is 2, 3 or 4. Particularly preferred are compounds of formula Ib '_' "2 5 - ch2-c-ch2 L1 fJc-ch3 oh ib · R'l wherein R 'is as defined 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 -. The iminoethanosyl 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. Rase-20 ground can be divided into optical isomers. If the N-substituent has one or more asymmetric carbon atoms, there are more diastereoisomers.

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 acid addition salts can be prepared by alkylating a benzomorphane of formula R5 3 R4 4 68227 wherein R4 and R5 are as defined above with a compound of formula?

Z - CH2-A-- C-R2 V

K

Wherein A, R 1, R 2 and R 2 are as defined above and z is a leaving group of nucleophiles, preferably chlorine, bromine iodine, aryl, alkaryl or alkylsulfonyloxy, especially mesyloxy or tosyloxy, or Z is OH, the reaction being carried out by Raney in the presence of a nickel catalyst 15 when Z = OH, followed, if desired by a), a betzomorph of formula I in which at least one of the substituents R 1 and R 2 is hydroxy is alkylated to give a benzomorphane of formula I in which at least one of the substituents R 1 and R 2 is is alkoxy, and / or b) a benzomorphane of the formula I in which at least one of the substituents R 1 and R 2 is hydroxy is acylated to give a benzomorphan of the formula I in which R 3 is R 9 COO- and / or R 3 is R 1 COO-, and / or c) in a benzomorphane of the formula I in which at least one of the substituents and R 1 is alkoxy is cleaved by an ether bond to give a benzomorphane of the formula I in which at least one of the substituents R 1 and R 2 is hydroxy, and / ai d) a benzomorphan of the formula I in which R 1 is R 9 COO-30 and / or R 1 is R 1 COO- is hydrolysed to give a benzomorphan of the formula I in which at least one of the substituents R 3 and R- is hydroxy, and / or e) The free base according to I is converted into an acid addition salt.

When Z is a nucleophilic leaving group, the reaction is preferably performed using an equivalent amount or a small excess of an alkylating agent of formula V.

An acid scavenger which does not react with the alkylating agent is suitably used. Sterically hindered amines, e.g. dicyclohexylethylamine, are suitable for this purpose, but in general inorganic bases such as sodium or potassium carbonate or especially sodium or potassium bicarbonate are generally used.

The reaction is preferably carried out in an inert organic solvent, e.g. acetone, butanone, tetrahydrofuran, dimethylformamide, dimethylsulfoxy, dioxane or methylene chloride, or a mixture of such solvents. Tetrahydrofuran or dimethylformamide or mixtures thereof are preferred. In general, the reaction is carried out at a temperature in the range of 0 ° C to the boiling point of the solvent.

When less reactive alkylating agents are used, the reaction can be accelerated by the addition of catalyst 20 or an equivalent amount of sodium or potassium iodide.

When Z is OH, the reaction can be carried out in an inert water-immiscible solvent such as toluene using conventional reaction conditions. The reaction is preferably carried out in boiling toluene, at the same time removing the water formed. This method is preferably applied to compounds wherein R 3 is other than hydroxy.

If it is desired in the further reaction a) to convert two hydroxy groups (R 1 and R 2) into 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 sulfone ester, preferably a C 1-4 alkyl or C 1-4 alkenyl halide, with a different acidity of the hydroxy radicals R and R c. due to, can be selectively alkylated, e.g., by modifying the hydroxy radical Rj. with a base such as a dilute solution of an alkali metal hydroxide (e.g. NaOH) to an alkali metal salt and the resulting product is treated with e.g. a di-C 1-4 alkyl sulfate.

The 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 scavenger, in particular triethylamine or pyridine. Preferred 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-cleaving agents for further reaction c) are hydrogen halides, e.g. hydrobromic acid 15 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 at the R 1 position can be selectively hydrolyzed under mild conditions.

The starting materials of formula V are either known or can be prepared by known methods from known compounds.

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

Diastereoisomers can be separated in a known manner on the basis of their various physical and chemical properties, e.g. by fractional crystallization or column-3Q chromatography. Separation of the isomers can be performed after the last step of the synthesis or possibly at an earlier stage after the formation of the stereoisomer mixture. In the case of compounds of the formula I in which R1 is alkoxy or acyloxy, the diastereoisomers of the corresponding hydroxyl-35 compounds are preferably first separated by chromatography on 11,682,227. Each isomer is then alkylated or acylated separately.

The racemic mixtures can be divided into their isomeric 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 to a salt and vice versa to 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) Tail pull-15 test performed on male Wistar rats as described in Arzneim. Forsch.

13, 502 (1963), in which the measurement times were shortened from 15 seconds to 10 seconds. The results can be evaluated based on the following levels of analgesia: a) moderate analgesic activity (M.A.): tail withdrawal in 6-10 seconds, b) clear analgesia activity (P.A.): no tail withdrawal occurs within 10 seconds, but the rat moves the tail slightly in warm water.

c) Surgical analgesic activity (S.A.) with no tail 25 withdrawal in 10 seconds and no tail movement.

2) Nalorphine activity in the rat:

Male Wistar rats are given s.c. 0.63 mg / kg body weight of fentanyl, which causes respiratory arrest, lack of righting reflex, muscle stiffness, removal of surgical pain and loss of corneal and ear reflexes. The ability to act against these phenomena is measured by the nalorphine activity of the test compound, 30 minutes s.c. after injection, the animals are administered intravenously the test compound or the reference compound 35 nalorphine or pentazosin.

8 ...., v 68227 3) Rat instillation test:

Female Wistar rats (weight 150-190 g) are administered 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 control animals is defined as 100. Test and reference compounds are administered prior to acetic acid injection, with administration 30 minutes prior to s.c. 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 791239, 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 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-hydroxyethyl) -6,7-benzomorphane hydrochloride

To a mixture of 2.0 g (8.16 mmol) of 9,9-dimethyl-5-ethyl-21-hydroxy-6,7-benzomorphane and 2.4 g of potassium bicarbonate in 12 ml of dry tetrahydrofuran was added dropwise a solution of 1.12 g (9 mmol) of 2-bromoethanol in 5 ml of dry dimethylformamide. The reaction mixture was heated at 70 ° C until the reaction was complete.

II

68227, as determined by thin layer chromatography (ca.

20 hours).

The reaction mixture was poured into water and extracted 3 times with chloroform. The chloroform extracts were dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was applied to a silica gel column and eluted with toluene-ethyl acetate (grand elution). Fractions containing the desired compound were evaporated to dryness. The residue was converted to the HCl salt and crystallized from methanol-ether.

The title compound was obtained in 0.56 g, m.p. 227-231 ° C.

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

A mixture of 2.0 g (8.16 mmol) of 9,9-dimethyl-15,5-ethyl-21-hydroxy-6,7-benzomorphane, 0.62 g (8.16 mmol) of 2-ethoxyethanol and 1 .7 g of Raney nickel in 100 ml of dry toluene was refluxed for 48 hours under a nitrogen atmosphere. After the reaction mixture was cooled, Raney nickel was filtered off and the filtrate was evaporated to dryness. The residue was filtered through silica gel (50 g) using toluene / ethyl acetate (8: 2) as eluent. The fraction containing the desired compound was evaporated to dryness in vacuo and the residue (0.7 g) was converted into the HCl salt and crystallized from methanol / ethyl acetate to give 420 mg of the title compound, m.p. 222-226 ° C.

Examples 3-51

The following compounds were prepared as described in Examples 1 and 2: 68227

Eg Starting ς, n <> r

No>. Substance J N “Substituent Salt‘ p · ’

! I

--i-i-- 3 j A -CH2CH2OCH3 HCl 222-225 (dec.) 4 A -CH2CH2O2C2Cr3 HCl 220-230 (dec.) 5 A -CH2CH2OCH2_CH2CM3 HCl 205-2C5

6 A -CH 2 CH 2 OCH (CH 3) 2 MCI 187-1 SS

7 A -CH 2 CH 2 CH 2 OCH 3 HCl 205 (dec.) 8 B -CH 2 CH 2 OCH 3 HCl 197-2CO (dec.).

9 C -CM 2 CH 2 OCH 3 MCI 227-229 10 A -CH 2 CH 2 OC (CH 3) 3 HCl 196-198 11 A -CH 2 CF 2 CH 2 CH 2 CH 3 HCl 170-172 (dec.) 12 A -CH 2 CH (OCl 3) CH 3 HCl 235-233 and 13 Λ -CH 2 Cl! (OC2M (j) CH3 HCl 233 (dec.) 14 A -CH2C (Cl3) 20Cl3.3 HCl 195-193 15 A -CH2CH (OCl3) Cl2CH3 HCl 228-229 I _! ___ 11 68227

Ex. Starting Material N-Substituent Salt “No. No. No.” · I____ '16 B -CH2CH2OCH2CH3 HCl 202-204 (practice) 17 B -CH2CH (OCH3) CH3 HCl 224-226 18 C -CH2CH2OCH2CH3 HCl 208-211 19 C -CH2CH2CH2OCH3 HBr 210-212 2C c -CH2CH (0CM3) C113 HCl 244-248 21 D -CH2CH (OCH3) CH3 HCl 249-253 22 E -CH2CH2OCH3 MCI 244-252 23 E -CH2CH (OCH3) CH3 HCl 257 -266 * 24 A "CH27 \ HCl 246-249 24a A HCl 242-246 (+ isomer) 24b A HCl 243-247 (-isoisomer) 25 A -CH2CHGHCH3 MCI ^ 215-220 ^) 26 A -Cli2C (CH3) 20H HCl 230-234 Π f'8-lm ^ 27 A -CH2CHOCHCH2O3 | HCl | J 72-171 /) 12 68227

Eg Starting material N-Substituent Salt m.p. ° C

No____ 28 A -CH2CHOHCH2CH3 HCl 235-238 29 A -CH2_j / X HCl 259-268

OH

30 B -CH2C (CH3) 2OH HCl 222-224 31 B -CH2CHOHCH2OCH3 32 C -CH2C (CH) 2OH HCl 239-241 33 E -CH2C (CH3) 2OH HCl 196-201 34 E -CH2CHOHCH2OCH3 35 E -CH2CHOHCH3 (( COOK) jl57-1622) (HCl (261-2663) 36 E -CH2-HCl 243-253

OH

OF

37 E -CH 2 - / (COOH) 2 165-172

OH

38 B same HCl 250-254 39 C "HCl 247-251 40 D" HCl 216-219 41 F "HCl 203-205 42 B -CH2-HCl 265

OH

43 A -CH2- ^ HCl 248-252

OH

44 A -CH 2 / HCl 251-255 h-7

OH

13 68227

Eg Starting material N-Substituent Salt m.p. ° C

NO________________ 45 A -CH 2 CH 2 OH HCl 227-231

OH

46 A -CH2-6 (CH3) CH = CH2 HCl 230-236

OH

47 A -CH2-C (CH3) CH2CH3 HCl 233-235 (dec.)

OH

I f 2 48 A -CH 2 -C (CH 3) C = CH HCl (203-213 *) (208-2163)

OH

49 A -CH2-C (CH3) - <^ | (COOH) 2 182-186

OH

50 A -CH 2 -C (C-H -) - HCl 223-233

Z Z z> Z

51 G -CH 2 C (CH 3) 2 OH HCl 223-226

1) Isomer A + B

2) Isomer A

3) Isomer B

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-21-hydroxy-5-n-propyl-6,7-benzomorphane E: 9,9-dimethyl-5-phenyl-2'-hydroxy- 6,7-benzoforphane F: 9,9-dimethyl-5-ethyl-6,7-benzomorphan G: 9,9-dimethyl-5-n-propyl-2'-hydroxy-6,7-benzomorphan 14 68227

Example 52 9,9-Dimethyl-5-ethyl-21-methoxy-2- (2-methoxypropyl) -6,7-benzomorphan oxalate 1.7 ml (30 mmol) of methyl iodide and 0.93 g (20 mmol) of sodium hydride ( A 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- benzomorphan (e.g., 57) 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-base separation and evaporation of the organic phase to dryness under reduced pressure, the residue was converted into oxalate and crystallized from acetone and methanol-ethyl acetate to give 400 mg of the title compound, m.p., 157-162 ° C.

Example 53 9,9-Dimethyl-5-ethyl-2- (2-methyloxypropyl) -21-propionyloxy-6,7-benzomorphane oxalate 20 A mixture containing 1.5 g (4.7 mmol) of 9.9- dimethyl-5-ethyl-2'-hydroxy-2- (2-methoxypropyl) -6,7-benzomorphane (e.g. 57), 3.0 g of 100% metaphosphoric acid and 12.0 g of propionic anhydride, heated to 50 At -60 ° C with stirring for 30 minutes. 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 0.99 g of the title compound, m.p. 129-145 ° C.

Example 54 21-Benzoyloxy-9,9-dimethyl-5-ethyl-2- (2-hydroxy-2-methylpropyl) -6,7-benzomorphane hydrochloride 0.9 (6.4 mmol) benzoyl chloride in 10 mL of chloro- 68227 The form was added dropwise under a nitrogen atmosphere and with stirring to a solution of 1.54 g (4.85 mmol) of 9,9-dimethyl-5-ethyl-2 * -hydroxy-2- (2-hydroxy-2-methyl- propyl) -6,7-benzomorphane (e.g. 26) and 0.65 g of 5 (6.4 mmol) triethylamine in 20 mL of dry chloro Form. 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 55 9.9 Dimethyl-5-ethyl-2'-hydroxy-2- (3-hydroxy-prop-15-yl) -6,7-benzomorphane hydrochloride

A solution of 1.06 mL (9.33 mmol) of boron tribromide 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-2Q 2- (3-methoxypropyl) -6,7-benzomorphane hydrochloride e.g. in 28 ml of dry methylene dichloride. After stirring for 2.5 hours at room temperature, water was carefully added. Concentrated ammonia was added to the aqueous layer and the basic mixture was extracted three times with chloro-25 form. 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 56 9, 9. Dimethyl-2 1-hydroxy-2- (2-methoxy-2-methyl-35-propyl) -6,7-benzomorphane hydrochloride 16 68227 Using 9,9-dimethyl-2J-hydroxy-2- (2-hydroxy-2-methylpropyl) 9,9-Dimethyl-2H-methoxy-2- (2-methoxy-2-methylpropyl) -6,7-benzomorphane hydrochloride, m.p. 187-189 ° C, was prepared as starting material. (dec.J, as described in Example 53).

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 of dry dimethylformamide. 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 (dec.).

20 Examples 57-64

Methylation of the hydroxyl groups of the benzomorphans listed in the table below at the 2 'position and the N-substituent and conversion to the 2'-methoxy 2'-hydroxy group as described in Example 54 gave the corresponding final products. Examples corresponding to the starting materials are mentioned in the second column of the table 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.

Examples 65 and 66 3Q Analogously, the compound of Example 26 can be diethylated or dialyzed and the 2 * -ethoxy or allyloxy group converted to the 2'-hydroxy group to give the corresponding compounds as shown in the following table.

17 68227

Example Starting Salt Product m.p. (° C)

No._substance_ substituent_ 572) 252) -CH2CH (OCH3) CH3 HCl 115 (dec.) 573) 253) -CH2CH (OCH3) CH3 HCl 260 (dec.) 5 58 27 -CH2CH (OCH3) CH2OCH3 HCl 196-199 0CH3 59 24 -CH2 HCl 246-252 0CH3 ^ 60 29 -CH2- ^ y> HCl 253-260 10 61 311) -CH ^ CH (OCH_) CH2OCH, HCl 202-207 2) 2) 1 Δ 2 ό 61 ' 31 'same HCl 201-205 613) 313) "HCl 224-228 62 32 -CH2C (CH3) 2OCH3 HCl 195-198 63 34 -CH2CH (OCH3) CH2OCH3 HCl 202-207 15 0CH> \ 64 36 ^ HCl 262- 268 65 26 -CH.C (CH _) _ OC'Hc HCl 200-203

Δ Z> Δ Z D

20 66 26 -CH 2 C (CH 3) 2 OCH 2 CH = CH 2 HCl 195-198 _ 1) Mixture of A and B isomers 2) A isomer 3) B isomer

Example 67 2- (2-Acetoxy-2-methylpropyl) -9,9-dimethyl-5-ethyl-21-hydroxy-6,7-benzomorphane hydrochloride

A mixture of 1.25 g (4 mmol) of 9,9-dimethyl-5-ethyl-2 '- (2-hydroxy-2-methylpropyl) -6,7-benzomorphane (e.g. 26), 2, 5 g of metaphosphoric acid 30 (100%) and 12 ml of acetic acid hydride were heated at 60 ° C for 30 minutes. After cooling, water was carefully added and the solution was made alkaline and extracted with ethyl acetate, dried over magnesium sulfate 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.

13 68227

The compound was dissolved in isopropanol and acidified with isopropanol-HCl, heated to reflux for 3 hours to cleave the acetoxy group in the benzene ring. After evaporation to dryness, the mixture was crystallized from methanol-ethyl acetate to give 0.32 g of the title compound, m.p. 170-173 ° C.

Examples 68-74

Acylation of the hydroxyl groups of the Bent-somorphans mentioned in the following table at the 2 'position and the N-substituent and conversion of 21-acyloxy to the 2'-hydroxy group gave the corresponding final products as described in Example 67. The acylation was performed using the corresponding acid anhydride with the exception of benzoylation, which was performed with benzoyl chloride. In the second plas-15 of the table, the signs corresponding to the starting materials are shown here 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.

20 Example Starting Salt Product m.p. (° C)

No .__ substance__N substituent__ 68 251) -CH2CH (CH3) OOCCH3 HCl 204-208 692) 252) -CH2CH (CH3) OOCC2H5 HCl 200-204 693) 253) -CH2CH (CH3) OOCC2H5 HCl 198-201 25 702) 252 ) -CH „CH (CH.) OOCCcHc HCl 167-201 3) 3Ϊ * J bb 70 1 25 -CHOCH (CH) OOCC, -Hc HCl 200-203 η 3 \ 2 3 6 5 71 ^ 26 '-CH2C ( CH3) 2OOCC2H5 HCl 170-171 72; 26; -CH2C (CH3) 2OOCnC3H7 HCl 195-200 73 26 j -CH2C (CH3) 2OOCiC3H? HCl 182-185 30 74 32 -CH2 (CH3) 2OOCC2H5 HCl 201-204 ^ ^ A + B isomer 2) A + isomer 3) _.

B isoraeeri

I

Claims (2)

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, R 1, O 2 x 2 NC 1 -R 4 where A is a direct bond or -CH 2 ', is hydrogen, C 2 -alkyl, C 2 -C 3 alkenyl, C 2 , or and R 2 together with the carbon atom to which they are bonded form a C C₂ _ - alkenyloxy or R ^COO- wherein R R is hydrogen, C1-3 alkyl, phenyl or benzyl, R4 is hydrogen, C ^^ - alkyl alkyl or phenyl, and R ^ is hydrogen, hydroxy, C ^ ^3- alkoxy or R 2 COO- wherein R 7 is hydrogen, C 1-3 alkyl, phenyl, benzyl, phenethyl or 3-pyridyl, characterized in that a benzomorphan of the formula