NO136297B - - Google Patents

Description

The present invention relates to a new process for the production of 2-benzoylalkylbenzomorphan derivatives and their salts, which compounds are useful as non-addictive analgesics and pain relievers with a sedative effect.

2-benzoylalkylbenzomorphan derivatives produced according to the present invention have the general formula:

where R represents a hydrogen atom, a hydroxyl group or a C1-C3 oxy group; R 1 denotes hydrogen, C 1 -C 2 -alkyl, phenyl, halophenyl, C 2 -C 3 -alkylphenyl, C 2 -C 3 -alkylphenyl, hydroxyphenyl, trifluoromethylphenyl, aminophenyl, C 2 -C 3 -alkylthiophenyl , nitrophenyl or alkanoyloxyphenyl; R 1 - denotes hydrogen or C 1 -C 4 -alkyl; R 1 denotes hydrogen, halogen, C 1 -C 1 -alkyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkylthio, nitro, trifluoromethyl, amino or hydroxyl; R 4 denotes hydrogen, C 1 -C 4 -alkyloxy, halogen or C 1 -C 4 -alkyl; R^ denotes hydrogen or methyl, and n denotes a number from 2 to 4.

According to the present invention, compounds of formula I are prepared by reacting a 6,7-benzomorphane derivative with the formula:

where R, R-^, R2 and R5 have the meaning as indicated above, with a ketocarboxylic acid derivative or its functionally active derivative of the formula: where R^ and R^ have the meaning as above, and m denotes a number from 1-3, in preparation of a 2-acylbenzomorphane derivative of the formula no where R^f R£, R-jf R4 # R^ and m have the meaning as indicated above and Rg denotes a hydrogen atom, hydroxyl, C-^-C^-alkoxy or a group of general formula : (where R 3 , R 1 and m have the meaning as indicated above) and then reduces the prepared ,2-acylbenzomorphane derivative to a 2-alkylbenzomorphane derivative of the formula: where R, R 1 , R 1 , R 1 , R 4 , R 5 and n have the meaning as stated above, and further oxidises the 2-alkylbenzomorphane derivative produced to the desired 2-benzoylalkylbenzomorphane derivative, and optionally for the production of acid addition salts, this derivative is reacted with an organic or inorganic acid. 2-benzoylalkylbenzomorphan derivatives of formula I are, as mentioned, useful as non-narcotic analgesics without physical dependence upon oral or subcutaneous administration, according to animal experiments. 1 according to the invention, the oxidation of compounds of formula II is usually carried out with different oxidizing agents. Examples of oxidizing agents that can be used are chromic acid, chromates, nitric acid, manganese dioxide, oxygen, dimethyl sulfoxide, potassium permanganate, osmium oxide and the like. A neutral oxidation such as the Oppenauer oxidation or photo-oxidation can be used. The reaction is preferably carried out under mild conditions, e.g. by Oppenauer oxidation, using Jones's reagent, with chromic acid in pyridine or the like.

When other methods are used for this reaction, the intended 2-benzoylalkylbenzomorphan derivative is formed in very low yield or not at all.

When it comes to oxidation with Jones reagent (which is a mixture of chromic acid, concentrated sulfuric acid and water) one works within a temperature range of usually -5 to 30°C, preferably between approx. 0 and 10°C. Examples of organic solvents used during the oxidation are petroleum ether, ether, chloroform, carbon tetrachloride, benzene, acetic acid, acetone, pyridine, ethyl acetate and the like.

Compounds produced according to the invention all have a basic nitrogen atom in the basic structure and can thus form a large number of different acid addition salts. Acid addition is obtained with organic and inorganic acids such as e.g. formic acid, acetic acid, butyric acid, malic acid, fumaric acid, succinic acid, glutamic acid, tartaric acid, oxalic acid, citric acid, lactic acid, glycolic acid, gluconic acid, glucuronic acid, saccharinic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, glyceric acid, anthranilic acid, cholic acid, picolic acid, picric acid, tropic acid, indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid.

When there is an alkyl group in the 9-position (R 2 is a C 1 -C 2 alkyl group), compounds of formula I have two stereoisomers, the cis compound (R 2 is equal to the a position) and the trans compound (R 2 is . equal to the g position) . In addition, each of these isomers has asymmetric carbon atoms, and consequently four optically active isomers ((+)-cis, (-)-cis, (+)-trans, (-)-trans) are obtained by a common optical cleavage method.

According to the invention, the following 2-benzoylalkylbenzomorphan derivatives and their acid addition salts are advantageously prepared.

2<1->hydroxy-2-C3-p-fluorobenzoyl-1-propyl)-5,9-dimethyl-6,7-benzomorphan, m.p. 168-171<G>C,

2<1->hydroxy-2-(3-p-fluorobenzoyl-1-propyl)-5,9-diethyl-6,7-benzomorphan, m.p. 185-187°C,

2<1->hydroxy-2-(3-m-fluorobenzoyl-1-propyl)-5,9-dimethyl-6,7-benzomorphan, m.p. 167-170°C,

2<1->hydroxy-2-(4-p-fluorobenzoyl-1-butyl)-5,9-dimethyl-6,7-benzomorphan hydrochloride, m.p. 229-231°C,

2<1->hydroxy-2-(3-p-trifluoromethylbenzoyl-1-propyl)-5,9-dimethyl-6,7-benzomorphan, m.p. 116.5-120°C,

2'-hydroxy-2-(3-p-chlorobenzoyl-1-propyl)-5,9-dimethyl-6,7-benzomorphan, m.p. 179-181°C,

2-(3-p-fluorobenzoyl-1-propyl)-5,9-dimethyl-6,7-benzo-morph anhydrochloride, m.p. 164-166°C,

2<1->hydroxy-2-(3-p-methoxybenzoyl-1-propyl)-5,9-dimethyl-6,7-benzomorphan, m.p. 148-152.8°C,

2<1->hydroxy-2-(4-p-methoxybenzoyl-1-butyl)-5,9-dimethyl-6,7-benzomorphan, m.p. 181-182°C,

2<1->hydroxy-2-(3-o-methoxybenzoyl-1-propyl)-5-methyl-9-ethyl-6,7-benzomorphan, m.p. 148-151°C,

2'-hydroxy-2-(3-p-methylbenzoyl-1-propyl)-5,9-dimethyl-6,7-benzomorphan, m.p. 157.5-164.5°C,

2'-hydroxy-2-(3-(2,5-dimethylbenzoyl)-1-propyl)-5-methyl-9-ethyl-6,7-benzomorphan, m.p. 152-155°C,

2*-hydroxy-2-(3-benzoyl-1-propyl)-5,9-dimethyl-6,7-benzomorphan, m.p. 172-174°C, 2*-hydroxy-2-(3-p-methylthiobenzoyl-1-propyl)-5,9-dimethyl-6,7-benzomorphan, m.p. 154-156°C, 2'-hydroxy-2-(3-(3-fluoro-4-methylbenzoyl)-1-propyl)-5, 9-dimethyl-6,7-toenzomorphan, m.p. 131-134°C, 2'-methoxy-2-(3-p-fluorobenzoyl-1-propyl)-5,9-dimethyl-6,7-benzomorphan hydrochloride, m.p. 144-152°C, 2<1->hydroxy-2-(3-benzoyl-1-propyl)-5-methyl-9-ethyl-6,,7-benzomorph ane, m.p. 168-170°C, 2'-Hydroxy[2-(3-p-methoxybenzoyl-1-propyl)-5-methyl-9-ethyl-6,7-benzomorphan, m.p. 148.5-150°C, 2'-hydroxy-2-(4-(3,4-dimethoxybenzoyl)-1-butyl)-5,9-dimethyl-6,7-benzomorphan, m.p. 156-158°C, 2*-hydroxy-2-(3-p-fluorobenzoyl-1-propyl)-6,7-benzomorphan, m.p. 165.5 - 169°C, 2-(3-p-Fluorobenzoyl-1-propyl)-6,7-benzomorphane hydrochloride, m.p. 209-211°C, 2'-Hydroxy-2-(3-p-flubrobenzoyl-ethyl)-6,7-benzomorphan, m.p. 155-159°C, 2'-Hydroxy-2-(3-p-flubrobenzoyl-1-propyl)-5-methyl-f>,7-benzomorph ane, m.p. 169.5-171.5°C, 2'-hydroxy-2-(3-p-fluorobenzoyl-1-propyl)-5-phenyl-6,7-benzomorphan, m.p. 170-173°C, 2'-hydroxy-2-(4-p-[methoxybenzoyl-1-butyl)-3',5,9-trimethyl-6,7-benzomorphan, m.p. 128-130°C, 2*-hydroxy-2-(3-p-fluorobenzoyl-ethyl)-5,9-dimethyl-6,7-benzomorphan, m.p. 156.5-160°C, 2'-hydroxy-2-(3-p-fluorobehzyl-1-propyl)-31,5,9-trimethyl-6,7-benzomorphan hydrochloride, m.p. 214-217°C,

2-(3-p-fluorobenzoyl-1-propyl)-5-methyl-6,7-benzomorphan hydrochloride, m.p. 219-220°C,

2-(3-p-fluorobenzoyl-1-propyl)-5-phenyl-6,7-benzomorphine hydrochloride, m.p. 248-250°C.

In the following, the preparation of 2-alkyl-

benzomorphan compounds of formula II.

The above-mentioned compounds are prepared from suitable benzomorphane derivatives according to the previous reaction core, and the starting materials 6,7-benzomorphane derivatives are prepared from the corresponding known 2-methyl-6,7-benzomorphane derivatives in a known manner.

Benzomorphan derivatives of formula IV can be converted with high yield into corresponding 2-acylbenzomorphan derivatives of formula III.

During the execution of the above method, 6,7-benzomorphane derivatives of formula (IV) are acylated using a ketocarboxylic acid derivative of formula V or its functionally active derivative such as an acid chloride, acid bromide, benzyl ester, p-nitrophenyl ester, ethyl ester, acid anhydride, mixed anhydride and the like , to 2-acylbenzomorphane derivatives of formula III.

This reaction is preferably carried out in the presence of a basic reagent or a condensation agent such as pyridine, triethylamine, sodium carbonate, sodium hydroxide, dicyclohexyl carbodiimide and the like, in a suitable inert organic solvent such as tetrahydrofuran, ether, dioxane, benzene, toluene, chloroform, dichloromethane, acetone and dimethylformamide.

The mixed anhydrides mentioned above comprise compounds prepared by treatment with ethyl chloroformate, isobutyl chloroformate, benzyl chloroformate and the like.

When 2'-hydroxy-6,7-b*enzomorphan derivatives of formula IV (R is equal to a hydroxyl group) are acylated during this reaction, a 2<1->acyl-2-acylbenzomorphan derivative of formula III (Rg is a group with general formula:

or a 2-acylbenzomorphan derivative of formula III (Ro, is a hydroxyl group) depending on the reaction conditions.

The thus produced 2-acylbenzomorphan derivatives of formula III are transferred to corresponding 2-alkylbenzomorphan derivatives of formula II by reacting the substances III with a reducing agent.

A reducing agent such as an alkali metal in an alcohol

liquid solvent, hydrogen in the presence of a catalyst, metal hydride and the like, can be advantageously used.

It is advantageous to use a metal hydride such as lithium aluminum hydride, diisobutyl aluminum hydride, triisopropyl aluminum borohydride or the like, in an inert organic solvent.

part such as ether, tetrahydrofuran and dioxane.

The thus produced 2-alkylbenzomorphan derivatives of formula II or their salts are oxidized as described above and can easily be converted into 2-benzoylalkylbenzomorphan derivatives of formula I, which are the intended end products.

The invention is further illustrated by the following examples which constitute preferred embodiments.

Example 1 - 2'-hydroxy-2-(3-p-fluorobenzoyl-1-propyl)-5,9-dimethyl-6,7-benzomorphan (a) 2'-(g-p-fluorobenzoylpropionyloxy)-2-(g-p- fluorobenzoylpropionyl)-5,9-dlmethyl-6,7-benzomorphan

To a solution of 1.96 g of (3-p-fluorobenzoylpropionic acid and 1.01 g of triethylamine in 40 ml of chloroform is gradually added 1_.09 g of ethyl chloroformate while cooling to below 0°C. After stirring for 30 minutes at a temperature below At 0°C, 1.09 S 2'-hydroxy-5)9~dimethyl-6,7-benzomorphan is added to the mixture and stirred at 0 - 5°C for 1 hour. After stirring at room temperature overnight, 200 ml of chloroform is added to the reaction mixture. The mixture is washed with 10% ± g H 2 SO 3 , water, 5 µg NaHCO 3 and water, dried over anhydrous sodium sulfate. and filtered. The filtrate is concentrated to dryness to form the crude compound.

Recrystallization from ethyl acetate gives 2'-(p-p-fluoro-benzoylpropionyloxy)-2-(p-p-fluorobenzoylpropionyl)-5,9-dimethyl-6,7-benzomorphan, m.p.: 133 " 138 C.

kerosene: ^3, l680, 163O, 1590, 84O

Analysis calculated for C^<H>^<N>O^Fg;:

c 71.19, H 5.80, N 2.44 <%>

found: C 70.72, H 5.75, N 2.44 f°-

(b) 2'- hydroxyz- 2-( 4"- P- fluorophenyl- 4"- hydroxy- 1"-butyl)- 5, 9- dimethyl- 6, 7- benzomorphan 2 grams of lithium aluminum hydride are suspended in 50 ml of tetrahydrofuran and to to this suspension is added dropwise a solution of 6.6 g of 2'-(p-p-fluorobenzoylpropionyloxy)-2-(p-p-fluoro-benzoylpropionyl)-5j9~dimethyl-6,7-benzomorphan in 20 ml of tetrahydrofuran at below 10°G The mixture is heated under reflux for 6 hours with continuous stirring.

50 ml of tetrahydrofuran and 50 ml of water are gradually added to the ice-cooled reaction mixture, and the precipitate is filtered off. The filtrate is concentrated to remove the tetrahydrofuran and extracted with ether. The extract is washed with water and dried over anhydrous sodium sulfate and filtered. The solvent is evaporated to give the crude product. Recrystallization from ethyl acetate gives 2'-hydroxy-2-(4"-p-fluorophenyl-4M<->hydroxy-1M<->butyl)-5,9-dimethyl-6,7-benzomorphan, m.p.: 173 - 174°C.

IR ^ paraffin1 3200, 2550, 1603, 1501, 1211, IO52,

83O, 720

Analysis, calculated for C^H^qNO^:

C 75.16, H 7.89, N 3.65%

found: C 75.38, H 7.72, N 3.6l <<>f>.

(c) 2*-hydroxy-2-(3-P-fluorobenzoyl-1-propyl)-5,9-dimethyl-6,7-benzomorphan

A cold solution of 26.7 g of chromic acid in 23 ml of concentrated sulfuric acid and 4 ml of water is made up to 100 ml. This solution (Jones reagent) is 8N with respect to oxygen.

2'-hydroxy-2-(4,,-p-fluorophenyl-4"-hydroxy-1"-butyl)-5,9-dimethyl-6,7-benzomorphan (0.5 g) is dissolved in 20 ml of pure acetone (distilled over potassium permanganate), and the reagent described above is added dropwise from a microburette until a permanent orange-brown color indicates that the oxidation is complete, as the mixture is continuously stirred at below 5°C°

After 10 minutes, the mixture is poured into ice water with stirring and the solution is made alkaline with aqueous ammonia. The alkaline solution is extracted with ether. The extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness.

Recrystallization from acetone gives 2'-hydroxy-2-(3"P~ fluorobenzoyl-1-propyl)-5,9"dimethyl-6,7-benzomorphan, m.p.: 168 - 171°G. _x

IR ^ p<a>rafin12600, I69O, 1615, 1598, 1578, 1497,

1230, 845, 770.

Analysis, calculated for C2^H2gN02F:

c 75.56,' H 7.40, N 3.67%

found: C 75.58, H 7.33, N 3.62 fo.

This 6,7-benzomorphan is transferred to the hydrochloride, m.p.: 212 - 214°C.

IR S<>>paraffin1 258°' 2550, 1690, 1620, 1599, 1585,

1504, 1210, 1204, 1148, 831

Analysis, calculated for C2'^H2gN02ClF:

c 68.97, h 6.99, N 3.35, Cl 8.48% found: C 68.87, H 7.07, N 3.43, Cl 8.36%

In a similar way as indicated in example 1, the substances listed in table 1 were obtained.

Claims (1)

Vehicle whose sprung part can perform free movements in the vertical and lateral direction in relation to the unsprung vehicle part or the chassis, under which the sprung part of the vehicle is supported by air springs which are inclined in such a way that the axis lines of two and two springs which lie in one and the same, approximately across the longitudinal axis of the vehicle vertical plane, intersect each other, characterized by the fact that the air springs (1, 2, 3, 4) which are each inclined, are equipped with a separate regulating device (1', 2', 3 ', 4') which is affected by the vertical and lateral movements of the suspended vehicle part from its central position, thereby regulating the pressure in each air spring (1, 2, 3, 4) independently of the pressures in the other air springs in such a way that the height of the air springs remains the same or approximately the same.