DE1620407A1 - Process for the preparation of 3-hydroxy-6-oxo-N-phenaethylmorphinane compounds and their acid addition salts - Google Patents

Description

DR. I. M. MAAS DR. W. G. PFEIFFER PATENTA H WALTE

8 MÖNCHEN 23 UNGERERSTR. 25 - TEL. 333036

Shionogi & Co, Ltd · Osaka, Japan Process for the production of 3-hydroxy-6-oxo-N »phenethyl *

morphinan compounds and their acid addition salts

The invention relates to a method for the preparation of 3 ~ Hydroxy-6 ~ oxo-N-phenätbylmorphinanverbindungen and their Acid addition salts,

The method according to the invention is characterized in that a 3- * ethoxy'-6 ~ oxo ~ N ~ phenethylmorphihan compound the formula

N-CH ₂ CH ₂ -

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where J? a 3 ^J .nfaohbindung a ouev? -...- ρρο..biiiiur. ;; indicates, Ln at a known V / eiae of a hydro tyii.s cleavage with the formation of a · 5 hydroxy 6 ... v: o Γ; ph.3 lä'chy.'r .. phinane compound of the formula

HO ^ -ϊχ

GH ₉ GH ₂

where P is as defined above, subjecting t, uui d, base, optionally with an acid tohanieii

Examples of the starting compound (I) include p-iieihozy 6-cxr-N-phenethyl-T-dehydromorphinanCcis) and 5- "ethoxy 6 o;: o H-phenethylmorphinan (cis) ₃

The 3-methoxy-6-oxo-Ii-piienäthylmorphinan-Compound (I) used as the starting material can be prepared from 3-methoxy- »« 6-oxo-1Γ-methylmorphinane compounds (see USA ~ Pat ent very LfI; 5 08: * 09 'by reaction with cyanogen bromide, replacing the N-iääthylgrappe with a cyano group, treatment of the obtained IT-Üyanver connection with hydrochloric acid to eliminate the K "Cy ^; ir>, group and conversion of the obtained lf-unsubstituted Var ro .n ^ -. 'i \ g with V., α: -i

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BATH

Ethyl bromide are produced.

According to this, the 3 methoxy ö-oxo-N-phenethylniorphinan compounds (I) used as starting material are subjected to hydrolytic cleavage in a manner known per se, as is used for the cleavage of alkylphenyl ethers. j) treatment with a mineral acid (e.g. hydrobromic acid i hydroiodic acid) with heating; (2) treatment with a Kalogenverbindung of aluminum (s, B. "AIuminiumchloridj aluminum bromide _s aluminum). Iodide) or boron (ZOB Borrfluorid _f Borbromid.-boron chloride) ^ _n the presence or absence of an inert solvent (aB" benzene, toluene) with warming and subsequent treatment with water or an acid (3; treatment with an acid addition salt of a nbs.ö'3 iacB-pyriöinhydi-chloride, pyridinhjdrobi-oiaid; warmingf (4treatment with an alkali (srB-potassium) =

oxide .. ■ Nasriumhydroxyd) 3.η an inert solvent _;

, ^f Criäthy? -engj.ycol _5S leafhylene glycol; unäer -warm * vorzuga nvrai '^ an oxidationshemir _; end coat ⁽ a »B.

Alis 3-hydroxy- 6 - o> ro-li * phenitthylniorphinan - = - compound (II) is obtained one 3 = hydroxy - 6 "Oxo-K" -phenäthyl -? - dehydromorphinan (ice) or 3 = Hydroxy-6 - oxo li-phenäthylmorphinan (ice), which with organic

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Non-organic and inorganic acids form acid additions. Such acid addition salsas include, for example Hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, Hit Rate, Tartrate, Salicylate «Benzoate» Halate, Citrate and Acetates

The J-Hydroxy-ö-oxo-R-phenethylmorphinane compounds (II) and their acid addition asals obtainable according to the invention have remarkable analgesic activity · In of the following table are the analgesic activity and the Toxicity compared to levorphine tartrate (3-hydroxy-K-methylmorphine tartrate), a commercially available anaigetic Medium, stated

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Tabel link Analgesic activity

Haffner Heass "- Metnode

S 'Amour-Salth method

Toxicity

* »50 (mg / kg)

Levorphant atrate

3 * 9

189.8

ο ο to

3-Hydro: scy - 6-oxo-H-phenethyl ~ 7 ~ dehydromorphinan- (cie) - ■ alicylate

18.0

66.0

570.2

5-Hydroxj-6-oxo-N-

oi

68.0

150.0

> aoo, o

"lake

JESreiterungt The analgesic activity was after the Bitffne3MfothodefiReaee $ AvälE * earo * fat] i. do Pnaro. _f vol. 158 »ö 233 (19300 an Mäueen and according to the B * Amour» SBith- «ethode rD'Aa et al.t J. Pharmacol., vol. 1, ö 255 0946) 1 an Eatten and is as wökunge - -, the ratio of morphine indicated "that of" is ordered from 1 to "the tocytity was

> by subcutaneous administration of the test compound. Mouse checked "

PO

ο ο

As can be seen from the table above, 3 ~ hydroxy «> Oxo-N-phenylethylmorphinane compounds (II) and their acid addition salts are excellently suited as analgesic agents.

3-Hydroxy ~ 6 ~ oxo ~ N-phenethyl-7 = -dehydromorphinane (ice) and 3 ~ Hydroxy-6 ~ oxo ~ N-phenäthylmorphinan (ois) and their acid addition salts can be used alone or in combination with pharmaceutical Acceptable carriers are administered, the choice of which with regard to the preferred method of administration, the solubility of the Substance and standard pharmaceutical practice is done, Im In general, the dose of these substances is 1/20 to 1/3 of the dose of levorphant tartrate (3-hydroxy ~ H ~ fflethylaiorphinan}> The substances obtainable according to the invention are suitable for Be * treatment of the types of painful conditions often treated with the indicated known analgesic. The substances are particularly effective against pain, caused by rumore and surgical interventions are caused »Pharmaceutical preparations are, for example, tablets» capsules, pills, suspensions and solutions «in the manufacture of tablets For example, the substances can be filled with fillers (e.g. Lac » tose, potato starch, catfish starch) or binding agents (e.g. tragacanth gum, aoaoia gum, neck starch, gelatine) are combined. Furthermore, it is usually appropriate to use a dissolving Agents, e.g. shark starch, potato starch, alginic acid or the like to be used Example stearic acid, magnesium stearate or talc, together

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with sweeteners «e.g. saccharin, Erwünaoht« Furthermore, one can Flavor and aroma ©, e.g. * peppermint aroma, wintergreen oil, or use cherry flavor. Fillers can also be used in the manufacture of capsules «as described above for Tablets were listed. If the substances available according to the invention are used in the form of suspensions or solutions, they can be mixed with aqueous, sugar or substances VOB sorbitol-type containing carriers combine that one agent aur control of viscosity, ZoB. Magnesium aluminum silicate (Veegum) methyl cellulose or carboxymethyl cellulose and a suitable preservative, e.g. sodium benzoate or Parabens (methyl and propyl esters of p-hydroxybenzoic acid), included «In these liquid preparations can also coloring and flavoring substances as well as buffers may be included.

The compositions containing 3-hydroxy-6-oxo ~ N-phenethyl ~ 7-dehydroraorphinan (ice), 3-hydroxy ~ 6-> oxo <"- H ~ phenethylmorphinan (ice) or their acid addition salts can contain as dosage units in the form of a single daily dose or as smaller units, of which several together form a dose or be designed as larger units for division into individual doses. Compositions for parenteral Application can also be designed as individual dosage units or in larger amounts, of which in use Single doses are withdrawn «.

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The following examples explain the invention without it cu restrict" .

Parts by weight are in the same proportion to parts by volume like g su al

example 1

A solution of 8.4 parts by weight of aluminum bromide in 84 parts by volume of anhydrous benzene is mixed dropwise with stirring with a solution of 3 38 parts by weight of 3-methoxy-6-oxo-N-> phenethyl-7 "dehydromorphinane (ois) in 40 parts by volume of water-free benzene · the resulting mixture half an hour is heated under Rttokflutt and 3 hours cooled to 1O ⁰ C. the solution is decanted from the Benaolsohieht and the residue loss in 300 parts by volume of chloroform containing 5 5 * entnält ^ ethanol. the OhloroformluBung is sweimal with 100 Volume "parts 10 5 ^ aqueous latrium carbonate solution washed, dried over anhydrous potassium carbonate and concentrated to 50 parts by volume." After filtering off the precipitated crystals and recrystallizing from methanol, 1.42 parts by weight of 3-hydroxy-6 "Oxo-ff -phenäthyl-7-dehydromorphinane (ice) obtained as crystals from f. ^{183-184 0} C (decomp.).

-127.7 ° (C ₂ H ₅ -OH, c »1.012)

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The salicylate of these subetanes is recrystallized from methanol to crystals of P 217 to 218 ⁰ O (decomp.) «

Example 2 *

A solution of 1.58 parts by weight of 3-methoxy ~ 6 ~ oxo N ~ phen ~ ethylmorphinane (egg) in 15 parts by volume of 48 5% hydrobromic acid is refluxed for 15 minutes. The reaction mixture is concentrated under reduced pressure. The residue is mixed with water, made alkaline with aqueous ammonia and extracted with chloroform. The chloroform layer is washed with water and dried over anhydrous potassium carbonate. After the chloroform has been distilled off, 3-hydroxy-6-oxo-N-phenethylmorphinane (ois) is obtained as UI. By recrystallizing the substance from a Hi. A mixture of 0.62 parts by weight of salicylic acid and 20 parts by volume of Bethanoi gives 2.078 parts by weight of 3-hydroxy "6-oxo"> N-phenethylmorphinan (ice) salicylate, which after recrystallization from methanol gives crystals of F 28O ⁰ C (decomposition).

Example 3

50 g 3 * -Iiydro3cy-6-oxo "> Iir-phenäthal" -7-dehydromorphinan (cis) * 8a ' lycilat, 6.52 kg lactose, 3.00 kg shark starch and 210 g

0 0 9 8117 1 6 0 0 '- sad

- ίο -

Carbomethoxy cellulose are mixed together to form Lumps mixed together. The lumps will shrink and Passed through a 12 mesh sieve «Bas obtained granules mixed with 200 g talc and 20 g magnesium atearate and in usually processed into tablets, with 50,000 Ta- · tablets are obtained * Each tablet weighs 200 mg and contains 1.0 mg of the active ingredients.

Example 4

20 g of 3-hydroxy-6-oxo-H-phenylmorphinan (ice) salicylate , 14.00 kg of lactose and 4.90 kg of white starch are mixed, granulated with potato starch paste and dried. Bas "ranulat is sieved through a 16 meeh sieve and then mixed with 36Og talc and 40 g magnesium stearate. By tableting the mixture obtained in the usual way 100,000 tablets are obtained? Each tablet weighs 200 mg and contains 0.2 mg of the active ingredient,

Example 5

By dissolving 0.75 g of 3-hydroxy-6-oxo-H-phenethylmorphinan (cis) salioylate 10 liters of solution are prepared in physiological saline solution and filtered. the

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1t

They solution is atigefüllt under Stioketoff in 5000 ampoules and the ampoules are sterilized for 30 minutes at 115 ⁰ C. Each ampoule (2 ml) contains 0.15 mg of the active ingredient.

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Claims (1)

* ■ 12 - Claims , A process for the production 'of 3-hydroxy-6-oxo-N phenäthylmorphinan _p compounds characterized> reacting a 3-methoxy-6-oxo -N * phenäthylmorphinan compound of the formula -OH ₂ CH ₂ - where P is a single bond or a double bond, a hydrolytic cleavage with the formation of a 3 = hydroxy-6-oxo-N ~ phenethylmorphinane - compound of the formula 00 9 811/16 0 0 where F is as defined above »subject and optional the base obtained is treated with an acid. 009811/1600