DE1445854A1 - New benzomorphans and processes for their production - Google Patents

Description

Dr R. Kcervigsbarger -. ~~~ -—— -__,

Patent Attorneys -

MOwchon 2, BrHuhaueetraße 4 / llt

J. R. GEIGY A. G. BASEL 21

19O5 / .GC 127/2 * '

New benzomorphans and processes for their production

The present invention relates to new benzomorphane derivatives «RiBääaa ^ MsBSBttskstaMOHiBB with valuable pharmacologisehen Properties, as well as a method for their production.

It has surprisingly been found that compounds of the general formula I,>

ο I!

- C - OR ₄

in which R-, hydrogen, the hydroxyl group »one lower

Alkoxy »or Alkanoyjoxyrest,

R _{2 is} hydrogen, a lower alkyl or β-methoxyethyl radical or a phenyl radical which is optionally substituted by a halogen atom, a hydroxyl group or a lower alkyl, alkoxy or alkanoyl group,. R _{3 is} hydrogen or a lower alkyl radical, and

Usually a lower alkyl or a phenyl radical

mean,

valuable pharmacological properties, in particular have analgesic effectiveness »

ORIGINAL INSPECTED

809811/1096

In contrast to morphine and an- " their known benzomorphans, surprisingly free from , addictive properties »Also show the new Benzomorphans have antitussive effects and some of them are antagonists of morphine » The compounds can be administered parenterally or orally in one

usual pharmaceutical form of administration are used, i.e. in the form of, tablets, capsules, powders, suspensions,

Solutions, syrups, etc. Of particular advantage are sustained-release forms that follow any. ..

known processes that can be produced ». . , ·

In the compounds of the general formula. I is E, besides hydrogen, the Hydro.scyl group, a methpxy-, ethoxyT ^ i ■ ,. _; , n-propoxy, isopropoxy or n-butoxy radical, the ethoxy, propionoxy or butyroxy radical, R ₂ is a lower alkyl radical, in addition to hydrogen, such as in particular methyl, ethyl, n-propyl, isopropyl, η-butyl , isobutyl, sec-butyl, tert "butyl, n-pentyl, the ß-methoxy-ethyl radical, the phenyl, chlorophenyl, bromophenyl, hydroxyphenyl, methylphenyl", ethyl-phenyl- ^, propyiphenyl, methoxyphehyl -, 'ethoxyphenyl,' propoxyphenyl, acetoxyphenyl, propiohoxypnenyl or butyroxy- ¹ phenyl radical. In _{addition to hydrogen, R 3} is a lower alkyl radical, such as, in particular, the methyl radical, and also the ethyl, n-propyl or isopropyl radical;

Besides the phenyl radical, R- is a lower alkyl radical such as the methyl, ethyl «, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, tert-butyl or n-amyl radical.

The production of compounds of the general formula I takes place in this way _? that a compound of the general formula II,

in which "■

R ₅ denotes hydrogen or a lower alkyl radical, and R ₁ , Rp, Ro have the meanings given under formula I, with a carbonic acid derivative of the general formula III,

Shark - C - OR _{4 (III)}

in which Hal denotes a halogen atom and R. has the meanings given under formula I «converts and, if desired, a compound of the general formula I in which R denotes the hydroxyl group, alkylates or alkanoylates in a manner known per se, or, SLIs R, an alkoxy or alkanoyl group, hydrolyzed in a manner known per se _#

Compounds of the general formula II are obtained e.g. by cyclizing a compound of the general formula

, ■ "· 'ORIGINAL INSPECTED

809811/1095

(IV)

in which . .

R ₅ ^{1 has} the meaning of Εκ with the exception of hydrogen, and B-jRp5B _{3 have} the meanings given under formula I, in Gegenwatt a Lewis acid .zu a compound of the general formula Hai.

(Ha)

These connections are desired by the cyanogen bromide ab ' building reaction according to von Braun in compounds of the general formula Hb, '

- ^H ; '. (lib)

in which B-,, Bp and Rg have the meanings given under formula I, transferable.

Ils are carbonic acid derivatives of the general formula III For example, the following are suitable * chlorocarbonic acid methyl, -äthyl-, -propyl-, -butyl-, -ämyl- ^ and -phenyl-ester, as well as the corresponding bromine derivatives.

As an alloying agent, ie for the conversion of the 2 ^l -hydroyl group into a lower one. Alkoiy group, come in particular

809811 / 1OSf

• Diazoalkanes. Like £ .B. Diazomethane, in question.

As an alkanoylating agent, i.e. for (you converting the 2'-hydroxyl group into a lower alkanoyloxy group are suitable especially reactive functional derivatives of lower alkanecarboxylic acids, such as anhydrides and Halides, such as acetic anhydrides, propionic anhydrides, Acetyl chloride, acetyl bromide, propionyl chloride as well Propionyl bromide. ll

If R _{1 is} a lower alkoxy or alkanoyloxy group, it can be hydrolyzed in a manner known per se, for example by the action of an aqueous mineral acid or an alkali.

It is advantageous to carry out the reaction according to the invention in a suitable, inert organic solvent, such as, in particular, toluene or anhydrous benzene, the reaction usually being carried out at an elevated temperature, for example at the boiling point of the reaction mixture. The Uaset? IUNG be "k & m also in einör inert atmosphere, for example under nitrogen, performed *

As can be seen from formula 1, the compounds according to the invention can exigti eten in optically isomeric forms * So; The presence of asymmetrical carbon materials in the form of morphine leads to the formation of 4 and 1 forms. R ^ in formula \ I a Alkyirest so stereo isomeric gind possible may be the Alkylgrupp © ice or tranf Laum 5-position R ₅ bound '''~ - "'. _'; --.-. ,. - ^ ....- ■

ftncjflii / 1096

6 - , - ■■■ '■. . ■ · ■ -.- -

The geometrical or sterolomeric forms can be _:

if necessary, be separated in a "known manner," e.g. by fractional crystallization or by distillation.

If one wants to separate enantiomorphic forms, in

usual way under. Use of an optically active acid to form the diastereoisomeric salts. All of these isomeric forms are also a subject of the invention. _: -,.

-I · en Se hydrobromic acid, sulfuric acid, phosphorus sulphonic acid, ethanedisulphonic acid _f β-Hydro ^^ fainansulfοητ -. ' _: acid, acetic acid, propionic acid, fumaric acid, fumaric acid, .-. Lactic Acid 5 Malic Acid ^^ Sinsic Acid, Gitric Acid »Benzoic _{Acid 1} SalieyisäjHe'li ^ Phenylacetic acid and mandelic acid form the versions of the general formula I salts, which are partly- '' aB PQglö Bi!

The following examples explain: the implementation of the method according to the invention, however, by no means the only embodiments of the same are "The. Temperatures are given in degrees Celsius,; '·'

80 081 t /

14458S4

example 1

a) 4- (8-methoxyethyl) pyridine methyl iodide

Methyl odide (313 g, 137 ml, 2.20 mol). Is stirred into a solution of 274 g (2.00 mol) 4- (ß-Methoxyätnylpyridin) in ml of acetone and 200 ml of benzene are dropped in at such a rate that that reflux is maintained. Then 3 hours .treiter is stirred, the reaction mixture ons to room temperature is allowed to cool. The mixture is cooled overnight, the product is separated off, recrystallized from acetone and dried, melting point 75-78 °.

b) 1-methyl-4- (B-methoxyethyl) -1 * 2 .5.S-tetrahydropyridine

A solution of 223 g (0.80 mol) 4- (ß-methoxyethyl) -pyridinmethylj odid in 32ο ml of water and 32ο ml of methanol is under Stirring at such a rate in a solution of 50 g (1.2 mol) of sodium borohydride in 240 ml of water added dropwise that the temperature is kept at 50-6o ° - Then another solid sodium borohydride (44 g) was added and the mixture was stirred overnight at room temperature «. The solution will be sent ■ filtered, concentrated in vacuo to about a third of its volume and extracted several times with ether. The essential extracts are washed over with saturated aqueous sodium sulfate

Dried sodium sulfate and evaporated. The residue results after distillation the product has a boiling point of 90-92 ° / 12 Torr,

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- 8 -. ■■■ -.- ■■■:

c) 1-Benzyl-1 * -methvl "4> * (B-methoxyethvl ^ l" 2.5 _f 6-tetrahydropyridinium chloride _ ■

By adding a 10 molar excess Benzyl chloride to a solution of 7.8 g of l-methyl-4- (ß-methoxyethyl) -l, 2,5,6-tetrahydropyridine the quaternary salt is prepared in 30 ml of acetone. The reaction mixture is at room temperature left to stand, the crystallized product is separated off And recrystallized from acetone, melting point 134.5-137.5 °.

d) 2- ^ benzyl -4- (β-metho3tyethyl) -l-methyl-1 ^ 2 _> 5 ^ 6-tetrahydro-pyridln

A solution of 2.0 mol of phenyllithium in ether (71.5 ml, 0.143 mol) is stirred into a suspension of dry 1-benzyl-1-methyl-4- (ß-methoxyethyl) -1,2.5, 6-tetrahydropyridinium chloride (35.8 g, 0.127 mol) is added dropwise to 225 ml of anhydrous ether at such a rate that a slight reflux is maintained. The mixture is refluxed for a further 2 hours, cooled and with 100 ml of 2-n. Hydrochloric acid acidified. The aqueous phase is separated off and again made alkaline with concentrated ammonium hydroxide while cooling with ice. The product is extracted with ether, the extract is dried over sodium sulfate and evaporated. The product is then distilled. Boiling Point 12S-135 ° / 0.5 Torr * Since "picrate obtained by addition of a solution of 20.8 g (0.091 mol) in 200 Hcrlnsäure $ ii methanol su a solution of 27 g _f 2 {0.111 Fioi) of the" _f A raw tea in 30 ml of ethanol. You can form an oil. Acstone is added to maintain the solution

Let it stand in the refrigerator for a few days, then it will • Product isolated and recrystallized from ethanol-acetone, Melting point 100.5-102.5 ° (after drying for three hours at 60 ° / 0.1 Torr).

2-Benzyl-4- (p-methoxyethyl) -l-methyl-1,2,5,6- * tetrahydropyridine can also be produced using the following process: A solution of 30.0 ml of benzyl chloride in 100 ml of ether is kept stirring and refluxing for one hour Suspension of 8.0 g of magnesium shavings and 8.0 g of magnesium powder in 250 ml of ether are added. The mixture is taking another 2 hours Stirring was kept at reflux and the solution then passed through glass wool filtered into an addition funnel and added over 10 minutes a suspension of 56.0 g kept under stirring and reflux 4- (ß-methoxy-ethyl) - pyridine-methyl iodide in 100 ml of ether added. This mixture is stirred and refluxed for a further 2 hours heated, whereupon 150 ml of a cold saturated solution of Add ammonium chloride containing 20 ml of concentrated aqueous ammonia.

The ethereal solution is separated off and extracted with a cold aqueous solution of 20 ml of concentrated hydrochloric acid. The aqueous extracts are made alkaline with ammonia and extracted with ether. The ether solution is dried over sodium sulfate and evaporated, Mari receives crude 2-benzyl-4- {| -methoxyethyl) · «1-methyll, 2-dihydropyridine in the form of an oil * The oil is dissolved TQ ml of methanol, and with cooling and stirring becomes 6 _? O g of sodium hydroxide added. The solution is refluxed for 1 1/4 hours

809811/1096

· ■ ■ '■■■ ..-' '-ίο -'; ■■ '-. ; ■■: '".- ■' ■ - ■ V. ■■■ · '-"' .. ■■■ '· ■ ".

heated and left to stand at room temperature overnight. The methanol is removed in vacuo, the residue with water • and ether shaken, the ethereal solution dried over sodium sulfate, evaporated and the residue distilled in vacuo, and a second boiling point of 150 ° / 4 Torr * The first fraction becomes A first fraction with a boiling point of 125 ° / 1 Torr / er

■ redistilled and the distillate for the one described below Cyclization reaction used,

) 2 -Methv1-5 - ( 8-methoxväthvl) - »6.7 -b enzomor uhan-hy dr ο chi or 1 d

A solution of the soluble portion of 12.0 g of aluminum tribromide in 20 ml of carbon disulfide is made in the course of 10 minutes with stirring and cooling with; Ice added to a solution of 3.0 g of freshly distilled 2-benzyl-4 - (- ß-methyl) -1, 2 ₃ 5,6-tetrahydropyridine in 20 ml of carbon disulfide. ■ After 5 minutes, the cold bath is removed, the mixture is heated to reflux temperature and refluxed for 30 minutes. The mixture is then cooled, the solution is decanted and the residue is washed with carbon disulfide. After the viscous residue is over

ml
When ice has been poured, 2% concentrated aqueous ammonia is added. Then chloroform is added and the mixture is heated with stirring to melt the ice and the

- ■. Warm mixture. The solids are filtered off and well washed with chloroform, the chloroform layer is separated, • dried over anhydrous sodium sulfate and evaporated. The oil obtained as a residue is distilled at 130 ° / 0.05 Torr and the distillate is converted into the hydrochloride with ether-acetone

y converts. This salt is recrystallized twice from acetone and gives 2-methyl-5- (ß-methoxyethyi) -6,7-benzomorphan-hydrochlor ± d, / melting point 163-165 °. '. . ^ ^;

809811/1096 I '

f) 2-Carbethoxv-5- (B-methoxväthyl) -6 «7-benzomorphane

A solution of 5 ml of ethyl chloroformate in 35 ml of toluene ·. is stirred under nitrogen into a solution of 10.35 g of 2-methyl-5- •, (ß-methoxy ~ ethyl) -6,7-benzomorphan in 35 ml of toluene. The solution is refluxed for 6 hours, cooled, filtered and the filtrate is evaporated. * The residue is dissolved in Dlehlomethah, washed with 1N hydrochloric acid, dried over sodium sulfate and evaporated. 2-Carbethoxy-5- ^: (ß-methoxyethyl) -6,7-benzomorphane, melting point 84.5-86 ° (after recrystallization of the oil from aqueous ethanol) is obtained.

Example 2 ^:

2 '-Acetoxy ^ -carbethoxy-S-phenyl-S ^ -benzomorphane

A solution of 1.5 g of 2 ^l -acetoxy-2-methyl-5-phenyl-6,7-benzomorphane in 50 ml of anhydrous benzene is a solution of 1.5 g of ethyl chloroformate in 25; ml of anhydrous benzene added. The mixture becomes two ■! Maintained at reflux for hours and stirred for 15 hours. The solution is then filtered, washed with 1N hydrochloric acid, dried over magnesium * · ■; sulfate dried and evaporated. This gives 2 ^l -acetoxy-2-car- > bathoxy-S-phenyi-eiT-benziomorphan, melting point Io5 * -lo7 °. ₄ I.

In analogous catfish, "2'-acetoxy-2-carbätoxy- -5-methyl * 0β-ethy1-6,7-benzomorphan is produced from Z ^% * acetoxy-2 _s 5-dimethyl-9ß-ethyl ^"? "BenÄomorphan , melting point 122-124 °, /

809-1 1/1096

''. ■ ".'- ■ ', ■ - 12 - _: .- ■■■.: ■■■■■ ....' · - ■■ '

Example 3

2- '~ Hydroxy-2-C! Arbäthoxv-5-phenvl ~ 6 .T-benzottorphan A mixture of 0.8 g of 2'-acetoxy-2-carbethoxy-5'-phenyT-

6,7-benzomorphan and 40 ml 2-n
Heated to reflux, cooled and extracted with chloroform. The extracts are evaporated in vacuo and the residue is recrystallized from benzene-petroleum ether # 2'-Hydroxy-Z-carbethoxy-S-phenyl-e ^ -benzomorphane, melting point 207-208 °, is obtained.

Example 4 ■. ...

2 '-Hydroxy ^ -carbophenoxy-S-phenyl-e ^ -benzomoTPhan-hemihydr'at

5.0 g of 2 ^l -hydroxy-5-phenyl-6,7-benzomorphane and 75 ml of benzene are placed in a 200 ml three-necked flask equipped with a 4nagnetischeffi stirrer, cooler, thermometer and dropping funnel. While the 'resulting' slurry is being stirred, 8.9 g of phenyl chloroformate in 50 ml of benzene are added dropwise over a period of 30 minutes. The slurry is refluxed for 4 hours, then cooled and filtered. The benzene solution is dried over sodium sulfate and concentrated to dryness, the white residue is dissolved in 150 ml of ethyl acetate, concentrated to about 100 ml and cooled. 2 ^l -hydroxy-2-carbo.phehoxy-5-phenyl-6,7-benzomorphane hemihydrate are obtained. Melting point .219-22O ⁰ . The product is recrystallized from n-butanol. Melting point 223-225 °. ·. ,; ■■■ ■■ .. '" ., _'. /

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Claims (1)

* ■ PATENT CLAIM Process for the preparation of new substituted 6,7-benzomorphanes of the general formula I _? Il - OR ₄ ■■ '-. "■■■■■ - ■■ (I) in which R-, hydrogen, the hydroxyl group, a lower one Alkoxy or alkanoyloxy radical, Rp hydrogen, a lower alkyl or ß-Methoxyäthylrest or an optionally by a halogen atom, a hydroxyl group or a lower alkyl, alkanoyloxy or Alkoxy group-substituted phenyl radical, Ro is hydrogen or a lower alkyl radical, and R ^ mean a lower alkyl or a phenyl radical · characterized in that'man a connection of the general Formula II,. (II) in which R, - is hydrogen or a lower alkyl radical indicates and R ^, R ₂ , Ro have the meanings given under formula I, with a carbonic acid derivative of the general formula III, 80 9811/1806 \ O it Hal - C - OR, (III) in which Hal means a halogen atom and R. the under. Formula I ■ has given meanings, and, if desired, a compound of the general Formula I, in which R-r denotes the hydroxyl group, alkylated in a manner known per se or, alkanoyl-tert, or if Rn is an alkoxy or alkanoyloxy group, in hydrolyzed in a known manner «-? Sa / lw / 11/23/64 ORIGINAL INSPEGTED 809811/109 6