FI56838C - ANALOGIFICATION OF THERAPEUTIC ACTIVATION OF THERAPEUTIC ACTIVE 6-DESOXY-6-AZIDO-7,8-DIHYDROISOMORFINDER - Google Patents

Description

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Patent- och ragicterstyrelMn Amitkin utltgd och utl.ikrHtm publicirid 31 * 12.79 '(32) (33) (31) Privilege requested —Begird priority 04.09 * 73

Hungary-Hungary (HU) AA-750 (71) Alkaloid Vegyeszeti Gyar, Tiszavasvari, Hungary-Hungary (HU) (72) Rezsö 'Bognär, Debrecen, Sandor Makleit, Debrecen, Geza Kiss, Debrecen, Sändor Ber ^ nyi, Debrecen, Terez Mile, Debrecen, Jözsef Knoll, Budapest,

Sandor Elek, Tiszavasvari, Istvan Gyöker, Tiszavasvari, Attila Zoltai, Tiszavasväri, György Toth, Tiszavasvari, Laszlo Litkei, Tiszavasvari,

Hungary-Hungary (HUj (74) Oy Kolster Ab (54) Analog method for the preparation of therapeutically active 6-deoxy-6-azido-7,8-dihydroisomorphine derivatives - Analogiförfarande för framställning av therapeutiskt aktiva 6-deoxy-6-azido ~ 7,8- dihydroisomor-finderivat

The invention relates to an analogous process for the preparation of therapeutically active 6-deoxy-6-azido-7,8-dihydroisomorphine derivatives of the formula wherein R 'is hydrogen or hydroxy and R "is hydrogen or ethyl, provided that when R * is hydrogen R "is ethyl, and for the preparation of their acid addition salts.

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The invention is characterized in that a) for the preparation of a compound of formula I in which R 'is hydroxy and R "is hydrogen or ethyl, the 3-hydroxy group of 7,8-dihydro-1H-hydroxyisomorphine is protected and the 6-hydroxy group is converted into a group , which is capable of being replaced by azide ions, after which the compound thus obtained is subjected to azidolysis, and that the 3-O-protecting group is removed if desired, or b) for the preparation of a compound of formula I in which R 'is hydrogen and R "is ethyl, The 6-hydroxy group of - (O-ethyl) -7,8-dihydroisomorphine is converted to a group capable of being replaced by azide ions, after which the compound thus obtained is azidolyzed and, if necessary, the free base is converted into the corresponding acid addition salt or the acid addition salt into the corresponding base.

The compounds of the invention may be used alone, in combination with other morphine derivatives or other compounds in human medicine, primarily because of their analgesic efficacy.

The starting materials for the process according to the invention, 7,8-dihydromorphine and 1H-hydroxy-7,8-dihydromorphine, are known compounds. The hydroxy groups in the 3- and / or 6-position of the compounds can be protected before azidolysis by various methods. The hydroxy group in the 3-position is preferably protected with a tetrahydropyranyl or methylene methoxy group. These groups can be removed during or after azidolysis.

In the preparation of 3-substituted derivatives, the 3-hydroxy group of 7,8-dihydromorphine and 1β-hydroxy-7,8-dihydromorphine is protected by an acyl, ethyl, aralkyl or aryl group and, when ethyl is protected, is not removed during azolysis. and not after that.

According to a preferred embodiment of the process according to the invention, the hydroxy group in the 3-position of the starting materials is protected by partial acylation, preferably by acetylation, formylation or benzoylation, it being expedient to use anhydrides in the esterification. However, other known reagents can also be used.

Acyl groups can also be used to protect the hydroxy group in the 6-position. Using more intense reaction conditions, both the 3- and 6-hydroxy groups are acylated to give 3,6-diacyl derivatives.

Highly advantageous intermediates for acidolysis are obtained when the hydroxy group in the 6-position is esterified with arylsulfonic acid or alkylsulfonyl acid groups. In this case, it is expedient to use a p-toluenesulfonyl or methanesulfonyl group.

3,66838

The acidolysis can be carried out in excellent yields, for example, by partially esterifying the hydroxy group in the 3-position by reaction with acetic anhydride and then esterifying the hydroxy group in the 6-position with p-toluenesulfonic acid.

Acidolysis is the most important step in the reaction sequence of the invention. During acidolysis, the 6-position, saccharified hydroxy group is replaced with an azido group. This occurs by reaction with a metal azide. In the first place, sodium, lithium or potassium azide or a compound which, on decomposition during the reaction, gives off azido groups is used.

During azidolysis, the most labile protecting groups in the 3-position are easily cleaved, so that simultaneously with the introduction of the azido group, the hydroxy group in the 3-position is released again. In this way, for example, the 3-O-acyl derivative can be easily converted into the corresponding 3-hydroxy derivative.

The compounds of the invention may be isolated from the reaction mixture as their salts or as free bases.

The salts obtained in the reaction can be converted into more physiologically tolerable salts, or salts with better physicochemical properties. Thus, tartrates, acetates, salicylates, benzoates, hydrochlorides and formates of the compounds can be prepared.

The compounds according to the invention can be formulated into pharmaceutical preparations for immediate parenteral, oral or rectal administration in a manner known per se, using known excipients and auxiliaries.

Of the compounds according to the invention, in particular 6-deoxy-6-azido-1H-hydroxy-7,8-dihydroisomorphine has particularly advantageous therapeutic properties. In comparison with the main known narcotic and analgesic compounds, it can be stated that the therapeutic index of 6-deoxy-6-azido-1H-hydroxy-7,8-dihydroisomorphine is more advantageous than any compound known so far, for example more advantageous than the previously proposed 6 -deoxy-6-azido-7,8-dihydroisomorphine / Acta Chim. Acad. Sci. Hung. 58, 203 (1968); Orvostydomany 22, 265 (1971) 7 · In addition, the new compounds are superior in that the risk of dependence is lower, which is a significant advantage when it comes to morphine derivatives.

The invention is illustrated by the following examples.

Example 1 10 g of 1β-hydroxy-7,8-dihydromorphine are suspended in 1 liter of water and 100 g of sodium carbonate are added to the suspension. With vigorous stirring, add a total of 50 ml of acetic anhydride in three portions. After bubbling, the reaction mixture is stirred a little more and then extracted with 5 x 200 ml of chloroform. The combined chloroform phases are washed first with 2 x 50 ml of sodium hydroxide solution, then with 200 ml of water, dried over sodium sulphate and then evaporated to dryness. The yield is almost quantitative to give 3- (O-acetyl) -1U-hydroxy-7,8-dihydromorphine, which can be used in the following reactions.

Example 2 10 g of 3- (O-acetyl) -1H-hydroxy-7,8-dihydromorphine are dissolved in 1 + 0 ml of anhydrous pyridine and 7 g of p-toluenesulfonic acid chloride 1 + 0 are added dropwise to the stirred solution at 0-5 ° C. per ml of anhydrous pyridine. The reaction mixture is further stirred, allowed to stand overnight and then poured into 1 liter of saturated aqueous sodium bicarbonate solution. The mixture is extracted with 3 x 200 ml of chloroform. The combined chloroform solutions are washed with 2 x 100 ml of water and dried over magnesium sulfate. It is then evaporated to dryness. The residue is crystallized from anhydrous ether. The resulting 3- (O-acetyl-11 + -hydroxy-6- (O-p-toluenesulfonyl) -7,8-dihydromorphine melts at 193-19 ° C.

Example 3 10 g of 3 '(O-acetyl) -11 + -hydroxy-6- (O-p-toluenesulfonyl) -7,8-dihydromorphine are dissolved in 310 ml of dimethylformamide and 20 g of sodium azide 1 + 6 ml are added to the solution: in water. The reaction mixture is kept at 100 ° C for 2 hours, then poured into 1 liter of water and extracted with 3 x 250 ml of chloroform. The combined chloroform solutions are washed with 2 x 100 ml of saturated aqueous sodium chloride solution, then dried over magnesium sulphate and evaporated to dryness at 60 ° C. The residue is crystallized from acetone. 6-Deoxy-6-azido-11 + -hydroxy-7,8-dihydroisomorphine, melting at 222-223 ° C, is obtained in good yield.

Example U

Work as described in Example 2 using the reagents mentioned therein, except that methanesulfonic acid chloride is used in the same molar ratio instead of toluenesulfonic acid chloride. The obtained crystalline 3- (O-acetyl) -1k-hydroxy-6- (O-methanesulfonyl) -7,8-dihydromorphine melts at 179-118 ° C.

Example 5 10 g of the 6- (O-p-toluenesulfonyl) derivative obtained according to Example 2 and Example U, respectively, are dissolved in 300 ml of n-methylpyrrolidone and subjected to azidolysis as described in Example 3. 6-Deoxy-6-azido-11 + -hydroxy-7,8-dihydroisomorphine, melting at 222-223 ° C, is well obtained. The reaction shown can also be carried out in hexamethylphosphoric triamide.

Example 6 0.072 g (3.12 nmol) of metallic sodium is dissolved in 10 ml of ethyl alcohol and 0.9 g (3.12 mmol) of 7,8-dihydromorphine is added to this solution and then 0.1 + 8 g (3.12 mmol) of ) ethyl iodide. The reaction mixture is heated for 1 hour in a water bath. The reaction mixture is allowed to cool and the sodium iodide is filtered off.

5 S3ö3i2

The filtrate is adjusted to pH 5 with dilute hydrochloric acid and evaporated to dryness in vacuo. The residue is dissolved in 20 ml of water, the pH of the solution is adjusted to 9 with aqueous sodium hydroxide solution. The solution is extracted 3 times with 30 ml of chloroform each time. The combined chloroform extracts are washed twice with 15 ml of water each time, dried over magnesium sulphate and evaporated to dryness. The residue is recrystallized from n-hexane. Yield 0.92 g (9%) of 3- (O-ethyl) -7,8-dihydromorphine, mp 9-95 ° C. IpQ-q ~ 131 ° (c = 1.0 abs-ethyl alcohol).

Example 7

Step 1 IU, 85 g of 3-O-ethyl-7,8-dihydromorphine are dissolved in 60 ml of anhydrous pyridine and 6.0 lU g / U, 06 ml is added dropwise to the solution cooled to 0-5 ° C over a period of about 20 minutes with stirring. / methanesulphonic acid chloride dissolved in 60 ml of anhydrous pyridine. The reaction mixture is stirred for a further two hours, left to stand for 2 hours at room temperature and then poured into 1.5 liters of saturated aqueous sodium bicarbonate solution. The reaction mixture is further treated as described in the above examples. The solvent and pyridine are distilled off. The resinous residue obtained is taken up in warm absolute ether. Crystallization will begin soon. 11.86 g of [6] [6- (O-methanesulfonyl) dihydroisomorphine are obtained, melting at 135-136 [deg.] C. [.alpha.] D @ 20 -96.1 DEG [.

Step 2 11.0 g of 6- (O-methanesulfonyl) dihydroisamorphine are dissolved in 330 ml of dimethylformamide and 18.19 g of sodium azide in 51.2 ml of water are stirred in the solution. The homogeneous reaction mixture is kept at 100 ° C for 2 hours and then cooled. The reaction mixture is then poured into 1.65 liters of water, the aqueous solution is extracted with k x 200 ml of chloroform. The combined chloroform phases are washed with 2 x 110 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and the solvent is evaporated off below 50 ° C. The resinous residue is taken up in absolute ether. The separating flaky precipitate is removed by filtration. The filtrate is evaporated to dryness to leave 6.8 g of purified resinous mass. This is dissolved in 102 ml of anhydrous ethyl alcohol and a hot solution of 3 g of D-tartaric acid in 30 ml of ethyl alcohol is mixed with the solution. The tartrate stands out as yellow, plate-like crystals. Recrystallize from water twice. The resulting 3- (O-ethyl) -6-deoxy-6-azido-7,8-dihydroismorpholine bitartrate melts at 55-56 ° C. Δ7D = -192 ° C = 0.5 chloroform /. An aqueous base can be obtained from an aqueous solution of bitartrate by basifying the solution with sodium carbonate.

The activity of the product prepared in Example 3 (Compound I) is compared below with that of azidomorphine and a few other known analgesics (95% safety margins given in parentheses).

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Table I

Hot plate test + /

Compound LDS0 mg / kf, s.c. MD ^ s.c. mg / kg (rats) (rats) 310 M, 7

Morphine / 267, 2-349.6 / / 2.9-7.8 / 28 1.9

Methadone (24.5-31.9) / 1.4-2.5 / 280 4.9

Pethidine / 194, 4-403.2 / / 4.1-5.5 / 280 9.1

Pentazocine / 241.3-328, 8/4, 78-17, 29/13 0.016

Athetoorphin (11.7-19.0) / 0.0067-0.088 / 200 0.012

Compound I / 161.2-248.6 / 70.0071-0.020 / __ + / Woolfe G · 3a Mchonaldt A.P.J.Phanarac. exp. Ther. 80, 300 (1944)

Table II

Compound Therapeutic index Tail f $ iok test ++ / (10,. / 0) ,,.] Rat. «Djo-e / kg ..o. (Rotin.)

Morphine 66 1.8 / 1.08-3.15 /

Methadone 14.7 1.6 / 1.1-2.3 /

Pethidine 57.1 / 2.7-6.6 /

Pentazocine 30.8 12.2 / 8.1-18.3 /

Acidonorphine 812.5 0.012 / 0.0089-0.016 / τν, Λ, .χ. r 16666.6 0.029

Compound I / 0.022-0.037 / _______ ++ / D'Aaour, DiK. and Saith, D.L.J. Pharaac. exp.Ther. 72, 74 (1941) 7 06838

Table III

Compound Therapeutic Vrithing Test +++ Prepared ++++ index ED_Qmg / kg e.o. muscle fibers “* /» *> «* U1» (in mice) ^. * /. 1

Morphine 17 2.2 0.69 · * 6 »0 / 0.65-0.76 /

Methadone 17.5 0.71 / 0, M 8-1.05 /

Pethidine 6 5.1 3.3 / 1.59-6.93 /

Pentazocine 23, 0 8.1 * / 5, 46-12 ', 3 /

Azldomorphine 1083.3 0.013 ° * 63 / 0.009-0.018 /

Ytadiete I 6896.5 0.051 O, / / 0.036-0.070 /

In parentheses: $ 95 safety margin +++ Va »der Vends, C. and Margolin, S. 7ed. Proc. 15 494 (1956) ++++ Paton, W.D.M. If All, E.g., Br. J. Pharnao. 35 10 (1969)

Table IV compares Compound I to morphine and azidomorphine by measuring physical propensity to depend (2-day jump test in mice).

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Comparing the antitussive activity of 3- (O-ethyl) -6-deoxy-6-azido-7β-dihydroisomorphine (azidoethylmorphine) prepared according to the invention with codeine and 3- (O-methyl) -6-azido-7β-8- the corresponding values for dihydroisomorphine (azidocodeine) were obtained as follows:

Compound At ° 50 orally administered codeine 100 azidocodeine 2.5 azidoethylmorphine 1.67

The results show that the antitussive effect of az'ethidoethylmorphine is better than that of codeine and azidocodeine. In addition, with long-term "oral administration of the drug to rats over a period of more than 2 weeks, the rats tolerated the azidoethylmorphine prepared according to the invention better than codeine and azidocodeine. This is shown in the following figure The experiments were performed on groups of 20 rats that received a dose of AtD 2+ (100-cough drug effect) for 2 weeks once a week.

Codeine% 1+ 8 12 16 20 2k Weeks 20 ....... ·· ** 60, · ...... * • * · · # 100 _ 20 • · m »9 ψ

Acidocodeine 60 .... t * * * "* ..... * * * '* 100 * · ·«

Azidoethyl 20 morphine 60 «·· · r · 100j ................................

The percentage of surviving rats had dropped to practically 0 after 2 weeks of codeine administration, while the corresponding percentage had fallen just below 100% m after 20 weeks of azidoethylmorphine administration. Thus, the therapeutic index of azidoethylmorphine in long-term treatment is substantially better than that of codeine and azidocodeine.

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The following Tables V-VIII show the antitussive effect and effect on respiratory parameters of compounds A and B and intermediate C prepared according to the invention.

Table V

Cough drug effect in rats (Gossvald's method, each dose was studied using a group of 10 animals)

Compound ED, _n Activity in codeine? compared to codeine 19.00 1.00 compound C 3 ^, ^ 0.55 compound B 0.03 * + 558.82 compound A 3.5 5, ^ 2

Compound ED _ ms / kg Activity on codeine? compared to codeine 100.0 1.00 compound B 9.0 11.11 compound C 103.2 0.87 compound A 1.67 59.88

Table VI

Cough medicine effect in cats (Domenjoz method. AtD - dose that works as a cough medicine)

Compound AtD 50 mg / kg iv. AtD 100 mg / kg iv. The activity encodes as compared to codeine 1.55 5.07 1.03 compound B 0.006 0.018 201.66 compound C 2.58 8.32 0.6l compound A 0.5 * + 0.8U 6.03

Table VII

Effect on respiratory parameters in cats anesthetized with pentobarbital

Compound freq. AtDloo resp. AtDlOO perctf AtDlOO_ freq. control resp, control perctf control codeine 0.82 0.83 0.70 compound B 0.9 ^ 0.97 0.93 compound C 0.85 0.72 0.65 compound A 0.95 0.91 0.88 circuits.

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Table VII shows that the effective dose does not affect the respiratory

Code freq. = respiratory rate resp = inhaled air parctf = respiratory volume per minute compound A = 3- (O-ethyl) -6-deoxy-6-azido-7,8-dihydroisomorphine compound B = 6-deoxy-6-azido-7.8- dihydro-1H-hydroxyisomorphine compound C = 3- (O-ethyl) -6- (Op-toluenesulfonyl) -7,8-dihydroisomorphine; ·. '· »·

Claims (1)

12, 58838 Patents: Analogous process for the preparation of therapeutically active 6-deoxy-6-azido-7,8-dihydroisomorphine derivatives of the formula R "- ° - R "is hydrogen or ethyl, provided that when R 'is hydrogen R" is ethyl, and for the preparation of their acid addition salts, characterized in that a) for the preparation of a compound of formula I in which R' is hydroxy and R "is hydrogen or ethyl, the 3-hydroxy group of 7,8-dihydro-1-hydroxy-isomorphine is protected and the 6-hydroxy group is converted to a group capable of being replaced by azide ions, after which the compound thus obtained is subjected to azidolysis and the 3-O-protecting group is removed if desired, or b) to prepare a compound of formula I wherein R 'is hydrogen and R "is ethyl, the 6-hydroxy group of 3- (O-ethyl) -7,8-dihydroisomorphine is converted to a group capable of being replaced by azide ions, followed by the resulting compound is azidolyzed, j a that, if necessary, the free base is converted into the corresponding acid addition salt or the acid addition salt is converted into the corresponding base.