DE2233088A1 - BENZOMORPHAN DERIVATIVES - Google Patents

Description

where E-, and

are the same or different and are hydrogen

Atoms or lower alkyl radicals and R ₇ and R ^ are identical or different and mean lower alkyl radicals, and their salts with physiologically acceptable acids.

The compounds of general formula I can be used both in the form of the racemates and in the form of the optically active antipodes
are present.

Physiologically compatible inorganic and organic acids are suitable for salt formation. Such acids are for example Hydrochloric and hydrobromic acid, sulfuric acid, phosphoric acid, '

309883/1464

SCHERiNGAG

- 2 -. Patent department

Acetic acid, propionic acid, lactic acid, malonic acid, succinic acid, tartaric acid, citric acid, maleic acid, malic acid, Heptagluconic acid, etc.

It has been found that the new compounds of general formula I ^y have a valuable effect pharmakologisch.es profile by uniting a good analgesic and antitussive activity with a morphinantagonistischen effect component and with sedative, muscle relaxant, and antidepressant properties in itself. The compounds are largely free from the undesirable side effects of morphine and its analgesic derivatives used in therapy and have a lower potential for physical dependence. The compounds according to the invention differ advantageously from the previously known analgesic partial antagonists of the morphine, morphinan and benzomorphan types, some of which have found their way into therapy, in that they are free from morphine-like stimulating properties. The compounds have practically no potential for abuse and appear particularly suitable for the outpatient treatment of painful conditions. The active ingredients according to the invention are intended to be used in conjunction with the auxiliaries known and customary in galenic pharmacy for the production of drugs with analgesic activity.

309883/1464

SCHERINGAG

"~ O ~~ Patent Department

Oral use includes tablets, coated tablets, capsules, Pills, granules, suspensions and solutions are all considered.

Each tablet should contain 0.1-50 g of active ingredient, for example.

Solutions for parenteral administration include, for example 0.01 - 1% active ingredient in aqueous solution.

The invention also relates to a process for the preparation of the bensomorphan derivatives of the general formula I, thereby characterized in that a benzomorphane of the general formula II

where IU and E ^ have the same meaning as in formula I, in a manner known per se with an epoxide of the general formula III

R.-

■ CIL

(III),

4 -

309883 / U6A

SCHERING AG

- 4 - Patent Department

wherein R-, and R2 ^ ^{e have the} same meaning as in formula I, or a halohydrin of the general formula IV

CH ₂ -X (IV)

where E- and Ro have the same meaning as in formula I " and X and Y are different and represent a hydroxyl group or stands for a halogen atom, converts.

The reaction is expediently carried out in an alcohol such as methanol, ethanol, n- or i-propanol, a butyl or amyl alcohol carried out, with the addition of water can be beneficial. The response time varies widely and depends on the Reaction components and the reaction temperature. At reaction temperatures between 0 and 200 C the reaction time is 2 hours to 14 days. Temperatures between 70 and 120 C, at which times of a few hours can be expected is.

When reacting with a halohydrin of the general formula IV, it is advantageous to use the hydrohalic acid which is liberated to be caught by adding an acid-binding agent. As acid-binding agents, for example, sodium or Potassium bicarbonate or magnesium oxide are possible.

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-5- SCHERINGAG

Patent department

The following examples serve to illustrate the invention Procedure.

The compounds are in each case 5j9-cis-dialkyl-6,7 - b enz omorphander ivate.

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309883/146 4

SCHERING AG

Patent department

example 1

2 g (i) -2 ^l- hydroxy-5> 9-dimethyl-6,7-t ^> önzomorplian and 1 g isobutene oxide were dissolved in 9 ml methanol. ^{The reaction mixture was heated to 100 °} C. for 6 hours in a sealed tube. The methanol was then distilled off and the residue was distilled in vacuo. At a pressure of 0.001 mm of mercury, 2.37 g of a colorless oil passed over between 178 and 198 ° C. and crystallized on treatment with acetone. After recrystallization from the same solvent it was 1.3 g (*) - 2'-hydroxy-2- (2-hydroxy-2-methylpropyl) -5,9-d.imethyl-6,7-benzomorphane with a melting point of 154- 156 C.

The compound dissolved in 1 η hydrochloric acid. The solid hydrochloride was obtained from the solution by evaporation.

Analogously to example 1, for example, the following can also be produced:

(ί) -2 · -Hydroxy-2- (2-hydroxypentyl) -5,9-Ä.imethyl-6,7-benzomorphane.

(_) _ 5_lthyl-2 ^l -hydroxy-2 ~ (2-hydroxy ~ 3-methyl-butyl) ~ 9-methyl ~ 6,7 ~ benzomorphane.

(t) ~ 5,9-Diethyl-2'-hydroxy-2- (2-hydroxy-2-methyl-propyl) -6,7-benzonorphane.

(_) _ 2 "-Hydroxy-2-hydroxypropyl) ~ 9-methyl-5-propyl-6,7-benzomorphane.

(-) - 2'-Hydroxy-2- (2-hydroxylT) ropyl) -5-methyl-9-propyl-6,7-benzomorphane.

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309883/1464

SCHERiNG AG

". Patent department

Example 2 ,

2 S (R) -2'-hydroxy-5j9 ~ cLimetliyl-6 _t 7-benzomorphan were reacted in analogy with Example Isobutenoxyd. 1 On cooling, 1.6 g of (-) - 2'-hydroxy-2- (2-hydroxy-2-methylpropyl) -5 ^ 9-dimethyl-6,7-benzomorphane crystallized out from the reaction solution. Melting point: 182-184 ° C.

Example 3

1.24 g (~) -5-ethyl ~ 2'-hydroxy ~ 9 ~ methyl-6,7-'benzomorphan were reacted analogously to Example 1 with 0.88 g of isobutene oxide in 80 ml of methanol. After cooling, the reaction mixture was with 48% aqueous hydrobromic acid acidified and evaporated. The residue, a brown oil, was taken up in a little isopropanol. 1.3 g crystallized from the solution on standing (±) -5-ethyl-2'-hydroxy-2- (2-hydroxy-2-methylpropyl) -9-methyl-6,7- ^ enzomorphan hydrobromide in the form of colorless crystals with a melting point of 157-168 ° C.

Example 4-

Analog -Example 3 vrurde (-) - 5-lthyl-2 ^{l-hydroxy-9-methyl-6,7-benzomorphan} with Isobutenoxyd for (-) - 5 ~ ~ 2 lthyl ^l-hydroxy ~ 2- (2-hydroxy-2 ~ met] iylpropyl) -9-methyl-6,7-benzomorphane implemented. Tendon point of the llydrobromide: 208-210 ° C, yield: 72%.

309883 / U64

_ ₈ _ ■ SCHERING AG

Patent department

Example 5 '

The (i) -9 ~ ethyl ~ 2'-hydroxy-2- (2-hydroxy ~ 2-methylpropyl) -5-methyl-6,7-benzomorphane hydrobromide was prepared analogously to Example 3. Melting point: 205-21O ⁰ C.

Example 6

• 1 »5 g (-) - 9-ethyl-2'-hydroxy-5-Kethyl-6,7-benzomorphane were reacted analogously to Example 3 with 0.72 g of isobutene oxide and converted into the hydrobromide. 2.4 g of (-) ~ 9 ~ ethyl-2'-hydroxy-2- (2-hydroxy-2-methylpropyl) -5-methyl-6,7-benzomorphane hydrobromide are isolated.
Melting point: 210-211 ⁰ C.
(-) - prepared 9-ethyl-2'-hydroxy-5-methyl ~ 6,7 ~ benzomorphan vrurde _w i _e follows:

40.0 g (i) -9-ethyl-2-benzyl-2'-hydroxy-5-methyl-6,7-benzomorphane were dissolved in 52 ml of ethanol. A solution of 44.6 g of (-) - 0,0-dibenzoyl-L-tartaric acid in 100 ml was added to this solution hot ethanol added. The mixture was left in the refrigerator at -f3 ° C. overnight. Then became the failed Sucked off precipitate. It weighed 20.4 g dry. Melting point: 197 ° C. "

The crystals were suspended in water and the suspension Made alkaline with 0.5 normal sodium hydroxide solution. The base released in this way was extracted with ether, the ether with water washed, dried over potassium carbonate and evaporated. It

"9 309883/1464

SCHERINGAG

~ * ^ · "~ Patent Department

13,0g (+) - 9-ethyl-2-benzyl-2'-hydroxy-5-methyl-6,7-benzom'orphan remained in the form of an oil. It was converted into the hydrobromide, which melts after recrystallization from isopropanol at 260-263 ⁰ C.

The mother liquor, from which the right-handed enantiomer had been isolated as dibenzoyl tartrate, was made alkaline with 0.5 normal sodium hydroxide solution. The base was isolated as described above. 29 »4 g of a brown, viscous oil were obtained. This substance was taken up in 37 ^ l ethanol and mixed with a hot solution of 32.6 g Ο, Ο-dibenzoyl-D-vartic acid in 75 ^ l ethanol. After standing overnight at +3 ⁰ C and the precipitated crystals were sucked off and 3>'£ iit little ice-cold ethanol washed. It was 20.6 g dry. Melting point: 200 ⁰ C.

From the dibenzoyl tartrate of the levorotatory antipode thus obtained, the base was released in the same way as the dextrorotatory form. 13.5 g were isolated, q / ^ (dextrorotatory form) + 81.2 ° ) in 2% acetic acid (levorotatory form) -82.4 °

The hydrobromide of the linoleum-related form melted after recrystallization from isopropanol at 260-263 C.

16.2 g (-) - 9-ethyl-2-benzyl-2 '~ hydroxy-5-2iethyl-6,7-' benzomorphane hydrobromide were dissolved in 200 ml of dimethylformamide and with the addition of 0.87 g of 10% palladium carbon at one temperature

- 10 309883/1464

_ ₁₀ _. SCHERINGAG

Patent department

hydrogenated from 55 ° C i under a hydrogen pressure of 60 atm. After shaking for 5 hours in the autoclave, the reaction had ended. The catalyst was filtered off with suction and the solvent was evaporated off in vacuo. The residue was taken up in ethanol and made alkaline with aqueous ammonia. The solution was cooled with ice water. The base which had crystallized out was filtered off with suction, washed with water and dried. The crude product was treated with 4-0 ml of isopropanol to give 7.2 g of (-) - 9-ethyl-2 ^I-hydroxy-5 ™ methyl-6,7-benzomorphan of melting point 260-264 ⁰ C.
/ a / jj - 33 »3 in 2% acetic acid, c = 1

Example 7

Analogously to Example 3, 1.85 g of (+) - 5-ethyl-2'-hydroxy-9-ethyl 6,7-b enz omorphan reacted with 0 / 4-9 ml 1,2-epoxypropane. The resulting (-f-) -5-Ethyl-2 -hydroxy-2-(2-hydroxypropyl) -9-methylbenzomorphane hydrobromide melted at 206-207 G.

Example 8

Ii60 S (-) - 2 ^l C heated. 12 ml of 0.66 normal hydrobromic acid were added to the cooled solution. The mixture was evaporated in vacuo and the residue taken up in water. The solution was treated with charcoal and brought to a ρττ value of approximately 8 with sodium bicarbonate solution,

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309883/1464

SCHERINGAG

- 11 - Patent pending

An oily precipitate separated out. It was extracted with ether, the ether was dried and evaporated. The residue, a pale, viscous oil, crystallized on trituration. Recrystallization from very \ Fenig benzene were added 0.7 g of pure (~) -2 '~ hydroxy ~ 2- (2-hydroxypropyl) -5) 9-d.iniethyl-6 _r 7-benzomorphan of melting point 133-135 C obtained .

Example 9 "

Following the procedure of Example 3, 2 g of (-) - 2'-hydroxy-5,9-diiaethyl-6,7-benzomopropane and 0.49 ml of ethylene oxide were reacted with one another and converted into the hydrobromide. 0.9 g of (-) - 2 '~ hydroxy-2- (2-hydroxy-ethyl) -5,9- * dimethyl-6,7-benzomorphane hydrobromide crystallized from acetone. The compound thus obtained Contains, 4% crystal \ tfasser, their melting point dragging on of 80-110 ⁰ C.

Example 10

1 S (-f) -2 ^f -hydroxy-5.9 "<iimethyl-6,7-benzomorphane and 350 mg of 1,2-epoxybutane were dissolved in 10 ml of methanol and heated to 100 ° C. for 6 hours in a sealed tube After cooling, the reaction solution was acidified with aqueous 48% hydrobromic acid, treated with activated charcoal and evaporated. Benzene was added 3 times to the evaporation residue and the benzene was distilled off again of 0.1 mm

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309883/1464

SCHERING AG

1 P -

^Χί - Patent Department

Mercury column and 70 ° C first above, phosphorus pentoxide, then dried over potassium hydroxide. It crystallized during digestion with isopropanol. After recrystallization from isopropanol

melted the (±) ~ 2'-hydroxy-2 (2 ~ hydroxybutyl) -5> 9 ~ dimethyl ~

6,7-benzomorphan ~ hydrobiOmid at 125 ° C.

Example11

1.85 @ ^ 5 - ethyl ~ 2 '~ 9 ~ hydroÄy-methyl ~ 6,7-benzomorphan were dissolved in 25 ml of methanol "and heated with 0.415 ml of ethylene oxide in Bombenröhr 6 hours at 100 ⁰ C JJach addition of 12th , 2 ml of 0.66 normal aqueous hydrobromic acid to the cooled solution, it was evaporated in vacuo. The residue was dissolved in water -ge. "!" The solution is treated with charcoal and neutralized with sodium bicarbonate. The precipitated base is absorbed into ether, the ether

Sulphst extract was washed with water and dried over sodium.

The oil remaining after evaporation of the ether slowly crystallized. Recrystallization from benzene gave 1 g (-f) -5-Ethyl-2-hydroxy-2- (2-hydroxyethyl) ~ 9 ~ methyl ~ 6,7-1) enzomorphan obtained in the form of colorless crystals with a melting point of 160 ~ 161 ° C.

Example 12

Following the procedure of Example 3, 1.85 g of (~) -5-ethyl-2'- ■ hydroxy ~ 9 ~ ethyl-6,7 ~ benzomorphane with 0.49 ^ l 1,2-Epo: x7> ^T piOpan implemented. The reaction product was converted into the hydrobromide. The resulting (-) ~ 5 ~ Ethy.l-2 '-hydroxy-2 ~ (2' hydroxypropyl) -9 ~

309883 / U64

SCHERiNGAG

Patent ineligible

methyl ~ 6,7-benzomorph8Ji hydrobromide having the melting point of 205-206 ⁰ C. Yield 1.4 g.

example

Following the procedure of Example 11, (-) ~ 5 ~ ethyl ~ 2 ^l -hydroxy 2- (2-hydroxyethyl) -9-methyl-6,7-benzomorphane was prepared.

Melting point: 162-163 ° C.

Example IA

1? 55 E (• f -) - 5-ethyl-2'-hydroxy-9-methyl-6,7-benzomorphan were dissolved in 50 ml of ethanol and eight with the addition of 0.625 S 2-bromoethanol and 0.7 g of sodium bicarbonate Boiled under reflux for hours. After cooling, the undissolved material was filtered off and the filtrate was evaporated in vacuo. The evaporation residue was dissolved in dilute hydrochloric acid, treated with activated charcoal and neutralized with sodium bicarbonate solution. The solution was then extracted with ether, the combined ether extracts were dried and evaporated. The residue was recrystallized from benzene and gave 0.9 g of (f) ~ 5 ~ ethyl-2 ^l -hydroxy ~ 2- (2 ~ hydroxyethyl) -9-methyl-6,7-benzomorphane with a melting point of 161-162 ° C.

Example 1 ^>

1 ? 85 g of (-f) -5 ~ ethyl-2'-hydroxy-9- »ethyl ~ 6,7 ~ benzomorphane resulted with 0.73 ml of '1,2-epoxybutane following the procedure of Example J

3Öd883 / U64

SCHERINGAG

Patent department

2.5 S (• {•) -5-ethyl-2 ^l -liydro; ^ - 2-t2- ~ hydroxyl3utyl) ~ 9-methyl-6,7-benzomorphan-hydrobroinide. The substance crystallized with 3 % water of crystallization. Their melting point remained indistinct even after recrystallization from isopropanol.

Example 16

1> 85 S (-) - 5-ethyl-2 ^l -hydroxy-9-methyl-6,7-benzomorphane with 0.73 ml of 1,2-epoxybutane by the method of Example 3 gave this only by using acetone was modified instead of isopropanol for recrystallization, 1.0 g of (-) ~ 5-ethyl-2'-hydro:>: y-2- (2-hydroxybutyl) -6,7-benaomorphane hydrobromide of melting point 158-162 ^O C.

309883 / U6A

Claims (1)

Pat ent claims SCHERING AG Patent department 1.) Benzomorphane derivatives of the general formula I (D, wherein R-, and R- are the same or different, and hydrogen atoms or lower alkyl radicals and E, and E ^ equal or are different and mean lower alkyl radicals ", and their salts with physiologically compatible bases. 2.) (-) -2 '-Hydroxy-2- (2-hydroxy-2-methylpropyl) ~ 5 ₅ 9-dimethyl-6 _} 7- "β-benzoilox * phane and its hydrochloride. 3.) (~) -2 '-Hydroxy-2- (2-hydroxy ~ 2-ethylpropyl) -5? 9-diiaethyl ~ 6.7 ~ "benzomorphane. 4.) {-) ~ 5-Ethyl-2'-hydroxy-2- (2 ~ hydro: xy-2 ~ methylpiOpyl) -3- methyl-6,7-keiizo! N 309883 / U6A ■ - IG ■ - SCHERiNGAG Patent department 5 ') (~) ~ 5-Ätliyl-2' -hydroxy-2 • - ^(2-oxy-2-f hYdi mGtliylpropyl) 9-iiietliyl ~ 6.7 6.) (i) -9 ~ Ethyl ™ 2 '-hydroxy-2- (2-hydroxy-2-methylpropyl) - ^ 6.7-t> enzomorph8Ji-] iydro "bromide. 7.) C -) -9-ethyl-2 ~ hydroxy-2- (2-hydroxy-2-methylpropyl) -5- methyl-6,7 ~ "bensonorpftan-hydro" broiriid. 8.) (+) -5-Ethyl-2 ^l -hydroxy "2- (2-hydr'oxypropyl) -9-methyl-6,7 benzornorphane hydrobromide. 9) (~) -2 '-hydroxy ~ 2 ~ (2-2iydroxypropyl) ~ 5? 9-Ä.imethyl-G, 10.) (-) - 2 '-IIydroxy-2- (2-hydroxyethyl) -5i9-cLiiaothyl-6,7- "benzo morpliari-hydrol ·)! "omid. 11.) (t) - "2 ^l -Hyd phan hydrobromide. 12.) (-f) -3 "Ä
morplian " 13.) (-) "5-Ät) iyl-2'-hydroxy ~ 2 ~ (2 ~ hydiOxypropyl) -9 ~ methyl-6,7-beiis: o morphan hydrobroinid. 17th 309883 / U64 _ ₁₇ ._ SCHERING AG Patent department ) (-) ~ 5 ~ ethyl ~ 2'-hydroxy ~ 2 ~ (2- ~ hydroxyä.thyl) ~ 9-methyl-6,7 ~ b enz omorphan. ) (• J-) ~ 5-ethyl ~ 2 «-hydroxy-2 - (2 ~ hydroxybutyl) -9-methyl ~ 6,7-" b enz omorphan-hydr obr omid. 16.) (-) - 5 ~ ethyl-2 '-hydroxy-2- (2 ~ hydro: *: ybutyl) -6 _} 7 hydrobroniid. 17 ·) C -) - 2 * -Hydroxy ~ 2- (2-bydroxypentyl) -5,9-dimethyl ~ 6,7-benzomorphane. 18.) (~) -5-Ethyl ~ 2'-hydroxy-2- (2-hydroxy-3-methyl "butyi) -9-methyl-6,7-benzomorphane. 19.) (i) -5,9 ™ diethyl-2 '~ hydroxy-2- (2-hydro ^ -2-methylpropyl) -6,7-t) enz omorplian. 20.) (~) -2'-Hydro5cy ~ 2 "(2-hydroxyi ' ⁾ i ^> opyl) -9-" ^me " ^tn y ¹ " 5-propyl-6,7-benzomorphane. 21.) (~) ~ 2 · -Hydroxy-2- (2-hydroxypropyl) -5-me-bh.yl-9-propyl-6,7-benzomorphane. 22.) Process for the division of the benzomorphane derivatives general Porrael I, characterized in that one - 18 - 30S883 / U64 SCHERiNG AG Patent department Bensomorphan of the general F in ei II H t wherein E-, and R ₁ . have the same meaning as in formula I, in a manner known per se with'einem epoxy of the general formula III E-, CK ■ 0- (IH), r; wherein R-. and R ₂ <ü ^{e have the} same meaning as in formula I, or a halohydrin of the general formula IV CH ₂ -X (IV) - - 19th 309883 / U64 SCHERINGAG ~ * ■ * -? ~ Patent Department R- and Ro have the same meaning as in formula I. "and X. and X are different and represent a hydroxyl group or a halogen atom, converts »23«) Medicines, characterized by the content of one Compound of the general formula I "or * a salt thereof. y 309883/1464 BATH ORIGINAL