HU199901B - Process for production of derivatives of hydrazon with morfinane carcass - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to novel, morphonanic hydrazone derivatives of the general formula (III) and their acid addition salts, wherein Y-NH 2; Z- (CH2) 2; Rlt R3 -CH3; R2 H; or A-NH-phenyl; Z- (CH2) 2; R3 H; Rj -CH * R2 OH or H; or Y-NHCNH2 or -NHCSNH2; Z- (CH2) 2- or-CH «CH-; Rj -CH3 or allyl; R3Hvagy-CH3; R 2 is H or OH, but when R j and R 3 are -CH 3 and R 2 H, then Y can only be -NHCSNH 2; or Y is -NH-dinitrophenyl ·, Z - (CH2) 2 - or -CH - CH-; R-CH3; R 3 -CH 3 and R 2 -OH, or R 3 H and R 2 -OH and azines of formula IV wherein R 2 is OH or H. EN 199901 B Scope of the specification: 6 pages, Figure 1 -1-

Description

The present invention relates to a novel morphine-based hydrazone derivative of the formula (III) and its acid addition salts

Y-NH ₂ ;

Z- (CH ₂ ) ₂ ;

R _h R ₃ -CH ₃ ; R ₂ H; obsession

A is -NH-phenyl;

Z- (CH ₂ ) ₂ ;

R ₃ H; Ru is -CH ₃ , R ₂ OH, or H; obsession

Y is -NHCONH ₂ or -NHCSNH ₂ ;

Z (CH ₂ ) ₂ - cut; ' -CH 2 CH-;

R _{x is} -CH ₃ or allyl;

R _{3 is} H or -CH ₃ ;

R _{2 is} H or OH, but when R ₃ and R _{3 are} -CH ₃ and R ₂ H, then Y can only be -NHCSNH ₂ ; obsession

Y is -NH-dinitrophenyl;

Z- (CH ₂ ) ₂ -or-CH = CH-;

R 1 is -CH ₃ ;

R _{3 is} -CH ₃ and

R _{2 is} -OH, or R _{3 is} H and R _{2 is} -OH - and the azines of formula IV wherein R ₂ is -H or H are morphinan ketones of formula (1) - wherein Z, R _{1 (} R ₂ and R ₃ are the reaction of the above - and the hydrazines of the formula (II) or salts thereof in which Y is the above - or reacting the ketones of the formula (I) with the corresponding hydrazones for the preparation of the azines.

Certain morphinan derivatives, e.g. the reaction of 14-hydroxydihydromorphinone, Naloxone and Naltrexon with hydrazine was first reported in 1980 by G. W. Pastern and E. F. Hahn [J. Med. Chem., 23, 674 (1980)], and pharmacological examination of the resulting condensation products, hydrazones, revealed that the parent molecule's original activity (analgesic or morphine antagonist) was retained, but the duration of action was significantly increased. Further studies have shown that the effect of hydrazone derivatives can be explained by the formation of ketazines [E.F. Hahn, M. Carroll-Buatti; G. Pasternak, J. Neuroscience 2 (5) 572 (1982); E. F. Hahn, G. Pasternak: Life Sci. 31, 1385 (1982); S. Galetta, G. S. F. Ling. L. Wolfin, G. W. Pasternak, Life Sci. 31, 1389 (1982)]. Indeed, in vitro, authentic ketazines were selectively bound to μ szel receptors in vitro by 20 to 40 times more than the corresponding hydrazone analogs. US researchers naloxone phenylhydrazone was produced in pharmacological testing [Szucs, M. Toth G. S .: MTA Benyhe Biol. Share. Inter. 25,655 (1982)], whereas in 1983 Chinese authors described the hydrazones and Ν, Ν-dimethyl hydrazones of 14-hydroxymorphinone and 14-hydroxycodeinone [M. Liu, C. Chi, Y. Gvo, C. Zhu, Yaoxue Xuebao 18,475 (1983); 100 (15) 121411b (1984)].

A review of the literature reveals that the hydrazone derivatives of several morphine backbone ketones have been previously described, but mainly for analytical analysis, since semicarbazones, phenyl hydrazones, 2,4-dinitrophenyl hydrazones are well-crystallizable compounds.

In addition to these hydrazones, the production of the hydrazone of 14-hydroxydihydrocodeinone was reported as early as 1924 [E. Speyer, K. Sarre: Wages. 57, 1422 (1924)].

Two of the ketones mentioned as starting compounds are the semicarbazone, codeine [L. Knorr, H. Hörlein: Wages. 40, 2032 (1907)] and dihydrocodeinone [A. Stein, Pharmazie 10 180 (1955)] is known in the literature.

As stated above, the hydrazone derivatives are of great pharmacological interest, therefore, our own studies on other compounds of formula III wherein Ϊ, Rx, R ₂ , R ₃ and Y are as defined above (e.g., dihydrocodeinone, dihydromorphinone, codeinone, 14-hydroxycodeinone, 14-hydroxydihydrocodeinone). In addition to the hydrazones, substituted hydrazones (semicarbazone, thiosemicarbazone, phenylhydrazone, 2,4-dinitrophenylhydrazone) were also prepared, in which case no ketazines were formed, but these derivatives provided opportunities for the formation of new compounds.

The hydrazone derivatives obtained in our own studies, which were confirmed by modern structural methods (IR, PMR, MS), differed significantly from the literature in terms of physical constants. It has been found that the above reactions, using alcohol (methanol, ethanol) or dimethylformamide as solvent, produce a small amount (10-20%) of ketazine. In addition to the instrumental studies, the structure of the corresponding ketazine was confirmed by the preparation of the corresponding hydrazone and ketone.

Biological Measurement:

1) Specific binding:

The effect of the compounds on the binding of tritiated Naloxone at concentrations of 10 ' ⁷ moles and 10' ⁵ moles was investigated in rat brain preparations. The results provide insight into the extent to which these compounds compete for the specific binding sites of the labeled Naloxone. The table shows the degree of specific binding of the remaining tritiated Naloxone.

Where there is a high degree of inhibition - that is, the specific labeled Naloxon binding value is low - these are compounds with high affinity for opiate receptors. Compounds that only slightly reduced specific binding, even at KP ⁵ molar concentrations, are not significant opiate receptor binding. For comparison, 1 nanomolar tritiated-Naloxone binding (100%) was added without the additives.

-2Compound Ligand Concentration

IO ' ⁷ moles IO ³ moles

HU 199901Β

Table 1

Specific binding of tritiated Naloxone (%}

Oxycodone hydrazone (known compound) 92 ± 25 13 ± 7 Dihydromorphinone semicarbazone 69 ± 13 6 ± 4 Dihydromorphinone-phenylhydrazone 5 ± 4 10 ± 14 Dihydromorphinone-dinitrophenylhydrazone 17 ± 2 0.5 ± 0.7 Oxymorphone dinitrophenylhydrazone 33 ± 1 l ± 0.3 Dihydromorphinone thiosemicarbazone 16 ± 5 19 ± 4 Oxymorphone thiosemicarbazone 37 ± 9 0 Naloxone semicarbazone L5 ± 40 22 ± 11

For the tests the membrane preparation

G. W. Pasternak, H. A. Wilson, S. H. Snyder [Molecular Pharmacol. 11: 340-51 (1975)]. The labeled Naloxone had a specific radioactivity of 72.4 ci / mmol / G. 20

Tóth, M. Kramer, F. Sirokmán, A Borsodi, A Rónai: J. Label. Comp. Radiopharm. 19, 1021 (1976)).

2) Analgesic effect:

The analgesic efficacy of the compounds was tested in rats by the hot plate and tail flick method.

The test compounds were converted into salts with pharmaceutically acceptable acids (hydrochloric acid, tartaric acid, phosphoric acid).

Table 2

Analgesic efficacy of some compounds

Compound Hot Plate ED _S0 mg / kg. neither. Tail Flick ^ED 50 mg / kg. neither. Dihydromorphinone semicarbazone 0,085 0.13 Oxycodone semicarbazone 0.58 0.45 Dihydrocodeinone thiosemicarbazone 1.7 0.6 Oxycodone phenylhydrazone (out of scope) 0.8 1.2 Oxymorphone dinitrophenylhydrazone 0.37 0.27 Dihydromorphinone-dinitrophenylhydrazone 0.27 0.18 Oxymorphone semicarbazone 0.9 0.9 Morphine (Comparative Compound) 3.6 5.0

According to the present invention, new morphinane backbone hydrazone derivatives of formula III are prepared by reacting ketones of formula I wherein Z, R _b R ₂ and R ₃ are as defined in the introduction with hydrazone of formula II or a hydrazone derivative in which Y is as defined above or a salt thereof in an aqueous or alcoholic solution at a temperature of 20-100 ° C such that when Y is -NH ₂ , the molar ratio of the compounds of formula I and 50 is : 10 when Y is other than -NH ₂ and above is 1: 1.5.

The invention is further illustrated by the following examples, which are not limited to the examples.

Melting points were determined on a Koffler or capillary and data were not corrected. 60

Merck 5554 silica gel 60 µm films were used for thin layer chromatography.

Running agents: chloroform-acetone-diethylamine

5: 4: 1 (A); chloroform-methanol-c.ammonium hydroxide 90: 10: 5 (B); chloroform-methanol 9: 1 (C); benzene-methanol 8: 2 (D).

The spots were detected under UV light and with Dregendorff reagent. PMR images were recorded on a Bruker W200SY MHz instrument, chemical shifts are reported in 6 (ppm) units. When characterizing geometric isomers, the trans (E) and cis (z) isomers are designated relative to the 50 proton.

Mass spectra were performed on a VG-7035 (GC-MS-DS) using electron collision ionization. Relative intensities are given in brackets after the mass numbers.

Examples

1. 14-OH-Dihydrocodeinone Hydrazone (Intermediate for the Preparation of the Azine of Example 2) is dissolved in 5 ml of 100% hydrazine hydrate in dimethylformamide and added to the above solution.

HU 199901Β, in portions, was mixed with 2.0 g of 14-OH-dihydrocodeinone. After heating for two hours on a water bath, cool, and pour into 100 ml of ice water. The precipitated crystalline material is filtered off, washed with cold water to give 1.5 g of crude product. Chromatography on silica gel (chloroform: methanol 9: 1, v / v) crystallizes the pure fractions (TLC B) from methanol.

Melting point: 192 - 94 'C.

PMR (CDCl ₃ ): 6.6; 6.7dd (H-1.2; 2H); 5.33s (-NH ₂ ; 2H deuterated), 4.93s (H-50; 1H), 3.8s (OCH ₃ ; 3H), 2.35s (N-CH ₃ ; 3H).

MS (C ₁₈ H ₂₃ N ₃ O ₃ ; 329.38): 329 (92), 313 (10).

2.14-OH-Dihydrocodeinone Azine

0.6 g of 14-OH-dihydrocodeinone hydrazone and 0.7 g of 14-OH-dihydrocodeinone in 30 ml of abs. dissolved in benzene and refluxed for 4 hours. After evaporation of the benzene, the residue is recrystallized twice from ethanol to give 0.25 g of azine, m.p. 199-202 ° C.

PMR (CDCl ₃ ): 6.65dd (H-1.2; 2H), 4.95s (H-50; 1H), 3.75s (-OCH ₃ ; 3H), 2.35s (N-Mc; 3H). ).

MS (C ₃₆ H 4 N ₄ O _{6 2;} 626.73): 626 (8), 611 (7), 313 (43).

3. Dihydrocodeinone hydrazone ml abs. in methanol 4 mL abs. hydrazine was dissolved and 1.0 g of dihydrocodeinone was added in portions with stirring. After stirring for two hours, methanol was evaporated in vacuo, to the residue was added sodium tetraborate (50 mL) and extracted with chloroform (3 x 25 mL). The chloroform portion was washed with sodium chloride water and dried over magnesium sulfate. Evaporation gave 1.0 g of an oily hydrazone containing minimal azine by thin layer chromatography (system B).

Pure hydrazone can be obtained by preparative thin layer chromatography, but it is also a mixture of geometric isomers.

PMR (CDCl ₃ ): 6.7dd (H-1.2; 2H), 6.3s (-NH ₂ ); 1H trans), 5.25 s (H-5 and -NH ₂ ; 2H cis), 4.9s (H-50; 1H, trans), 3.8d (-OCH ₃ ), 2.35 s (N-CH _3). 3H), cis / trans ratio 67/33.

MS (C ₁₈ H ₂₃ N ₃ O ₂ - 313.38): 313 (40),

298 (11).

4.14-OH-Dihydrocodeinone Semicarbazone

In the same manner as in the preparation of dihydrocodeinone semicarbazone (Pharmazil 10 180-6 (1955)), 3.2 g of 14-OH-dihydrocodeinone are obtained as a crude product, which is a two-layer, thin-film mixture of color and anti-isomers.

Crystallization (chloroform-ethanol) affords pure semicarbazone, m.p. 236-28 ° C.

PMR (DMSO-d 6): 9.25s (NH; 1H), 6.8dd (H-1.2; 2H), 6.4s (-NH ₂ ; 2H), 4.8s (H-50; 1H) .

3.75 _(OCH3, 3H), 2,3s (N-Me, 3H).

The crude product has two 5-O-H values: 4.85 (trans) and 5.17 ppm (cis) (CDCl ₃ ); the ratio of isomers is 1: 1.

MS (C ₁₉ H _M N ₄ O ₄ - 372.41): 372 (25), 355 (58), 313 (70).

5.14-OH-Codeinone Semicarbazone

As described for the preparation of dihydrocodeinone semicarbazone, 3.0 g of 14-OH-codeinone is formed as 2.8 g of a crystalline crude product consisting of a thin layer (system A and B) of two component colorant isomers.

Crystallization from methanol gave a single product, m.p. 260-63 ° C.

PMR (CDCl ₃ ): 8.72s (NH; 1H), 6.7dd 10 (H -1.2; 2H), 6.3d (H-8; 1H), 5.85d (H-7; 1H) , 6,19s (H-50; H, trans), 5,0s ₍₂ · ΝΗ; 2H) 3,8s _(-OCH3; 3H), 2,4s _(N-CH3, 3H).

MS (C ₁₉ H ₂₂ N ₄ O ₄ - 370.40): 370 (35),

353 (22), 313 (29).

6.14-OH-dihydromorphinone semicarbazone

The preparation is similar to that described for dihydrocodeinone semicarbazone, with a reaction time of only two hours. 3.0 g of 14-OH-dihydromorphinone gives 2.5 g of semicarbazone which is homogeneous on a thin layer. Crystallized from ethanol, m.p. 217-20'C.

PMR (CDCl ₃ ): 8.35s (NH; 1H), 6.6dd (H-1.2; 2H), 6.0s (-NH ₂ ; 2H), 4.93s (H-50; 14; trans )

2.3s (N-Me; 3H).

MS (C ₈ H ₂₂ N ₄ O ₄ - 358.39): 358 (5), 327 (49).

7. Dihydromorphinone semicarbazone

From 2.85 g of dihydromorphinone 3.2 g of dihydromorphinone semicarbazone can be obtained as described for 14-OH-dihydro30 morphinone semicarbazone. The material also contains a minor impurity component on the thin layer, but is recrystallized from methanol to give a homogeneous product.

195 - 98 'C.

PMR (DMSO-d 6) 6.6dd (H-1.2; 2H), 6.4s (-NH ₂ ; 2H), 4.9s (H-50; 1H), 2.3s (N-Me; 3H) ). In the crude product, the 50-protons have zero values:

4.9 (trans) and 5.34 (cis) ppm; isomer ratio

71:29.

MS (C ₁₈ H ₂₂ N ₄ O ₃ - 342.39): 342 (58),

325 (85), 283 (86).

8. Naloxone Semicarbazone

From 0.65 g of Naloxone and 0.25 g of semicarbazide chlorohydrate, 0.5 g of Naloxone semicarbazone is formed as described for the preparation of 14-hydroxy-dihydromorphinone semicarbazone, which is homogeneous by thin layer chromatography.

M.p. 239-42 ° C (dec.).

PMR (DMSO-d 6): 9.15s (NH; 1H), 6.45dd (H-1.2; 2H), 5.8m (allyl proton; 1H), 5.0-5.2m (allyl proton; 2H), 4.75 s (H-50; 1H).

MS (C ₂₀ H ₂₄ N ₄ O ₄ - 384.42): 384 (6), 298 (12).

9. Naloxone methyl ether semicarbazone Dissolve 0.25 g semicarbazide chlorohydrate in ml water and add 0.68 g Naloxone methyl ether and heat on a water bath for 2 hours. After cooling, it is made basic (pH ~ 9; concentrated soda solution) and the crystalline material is filtered off and washed with water. 0.6 g of crude product is obtained which gives two spots on a thin layer (mixture of color-anti geometric isomers).

HU 199901 Β

PMR (DMSO-date): The -OCH ₃ group gives two signals (3.75 ppm) and two 5? Protons with a chemical shift of 4.70 (trans and 4.82 (cis) ppm). Isomer ratio: 21 / 79th

MS (C 21 H 26 N 4 O 4 398.45): expected.

10. Dihydrocodeinone thiosemicarbazone

3.0 g of dihydrocodeinone are suspended in 15 ml of water and dissolved in 10 ml of normal hydrochloric acid while heating. Add 1.0 g of thiosemicarbazide and heat on a water bath for 2 hours. After warm filtration, the dihydrocodeinone thiosemicarbazone chlorohydrate (4.0 g) precipitated rapidly after cooling. Recrystallize from water. Melting point (capillary): yellow at 210 ° C and decomposes at 250-55 ° C. The chlorohydrate is dissolved in water (1.0 / 100 mL water) and the base is precipitated with concentrated soda solution (pH ~ 9). Filter, wash with water.

PMR spectrum is a mixture of geometric isomers.

PMR _(DMSO-d6): 10,32s (NH, 2H cis and trans), 8,32s _(-NH2; 2H cis and trans), 7,75s _(NH2, H cis), 7,45s ( -NH ₂ ; 1H trans), 6.6-6.75m (H-1,2), 5.45s (H-5H, 1HC); 4.87s (H-5β, 1H), isomer ratio 63:37 = trans: cis.

MS (C ₁₉ H ₂₄ N ₄ O ₂ S - 372.47): 372 (29), 355 (17), 297 (20), 242 (48).

11. 14-OH-Dihydrocodeinone thiosemicarbazone

3.1 g of 14-OH-dihydrocodeinone according to the method described for dihydrocodeinone thiosemicarbazone

4.2 g of 14-OH-dihydrocodeinone thiosemicarbazone hydrochloride are formed. The chlorohydrate crystallizes well from water and has a melting point (capillary). 230-35 ° C (dec.).

The separated base has a melting point of 150-54 ° C (dec.).

PMR (CDCl 3): 8.63s (NH; 1H), 7.48s (-NH ₂ ; 1H), 6.65dd (H-1,2, 2H), 6.4s (NH ₂ ; 1H), 4, 92s (H-5, 1H), 3.8s (-OCH3; 3H), 2.35s (N-Me; 3H), 2.35s (N-Me; 3H), Pure trans isomer.

MS (C ₁₉ H ₂₄ N ₄ O ₃ S - 388.47): 388 (72), 371 (100), 313 (42).

14.12-OH .kodeinon thiosemicarbazone

From 3.1 g of 14-OH-codeinone, the same procedure as for dihydrocodeinone thiosemicarbazone gives 3.7 g of 14-OH-codeinone-1-iosemicarbazone chlorohydrate. Recrystallized from water, m.p. 290-95 ° C (dec.).

PMR _(DMSO-d6): 10,15s (NH, IH), 8,48s; 7.95s (-NH ₂ , 2H), 6.6dd (H-1.2; 2H), 6.25d (H-7; 1H), 6.05s (H-8; 1H), 5.87 ( H-5 / ?; IH), 3,7s (OCH3, 3H), 2,35s _(N-CH3, 3H), pure cis isomer.

MS (C ₁₉ H ₂₂ N ₄ O ₃ S - 386.46): 386 (100), 269 (50), 311 (43).

13. Dihydromorphinone-thioserocarbazone

From 2.8 g of dihydromorphinone, 2.5 g of dihydromorphinone thiosemicarbazone chlorohydrate is formed as described for dihydrocodeinone thiosemicarbazone. The latter, although crystallized well in water, has no definite melting point.

After repeated recrystallization of the chlorohydrate, the separated base is bi-component by thin layer chromatography (eluent A ν. B).

PMR _(DMSO-d6): 10,41s (NH; cis 1Η) 10,32s (NH, H trans), 9, l0s (C3-OH), 8.25 s (NH _2, 2H cis and trans ), 7,67s _(NH2, H cis), 7.52 s (NH _2, H trans), 6,55s (H = 1.2, 2H), 5,45s (H-6 / ?; 1H cis), 4.85s (H-5 [beta]; 1H trans) 2.3s (N-Me; 3H); · isomer. 69:31 (trans * .: cis).

MS C ₁₈ H ₂₂ N ₄ O ₂ S - 358.45): expected.

14. 14-OH-Dihydromorphinone thiosemicarbazone

In the same manner as for dihydrocodeinone thiosemicarbazone, 2.8 g of 14-OH-dihydromorphinone thiosemicarbazone hydrochloride are obtained from 3.0 g of 14-OH-dihydromorphinone. The chlorohydrate has no definite melting point, even after repeated recrystallization from water. The separated base is two-component based on TLC. The base crystallizes well from ethanol or methanol, but is not homogeneous by TLC.

PMR (DMSO-d <s): 10,18s (NH -I 2H cis + trans) 8,32s _(-NH2; 2H, cis + trans) 7.65 _(NH2, H cis), 7 , 55s (-NH _2; H trans) 5,33s (H-5 / H ?; cis), 4,76s (H-5 / H ?; trans), 2,3s (N-Me, 3H); isomer ratio: cis / trans 21/79.

MS (C ₁₈ H ₂₂ N ₄ O ₃ S - 374.45): expected.

15. Dihydromorphinone phenyl hydrazone, 1.4 g dihydromorphinone and 1.3 ml freshly distilled phenyl hydrazine in 30 / ml abs. dissolved in ethanol and the resulting red oil triturated with ether. The resulting crystalline material is filtered off, washed with ether and a little cold ethanol to give 1.0 g of dihydromorphinone-phenyl-hydrazone, which is two-component by thin layer chromatography (A ν B system). PMR analysis showed a mixture of color and anti isomers (trans / cis = 28/72).

PMR _(DMSO-d6): 9,67s (NH H Cis), 8,82s (NH, IH trans) 7,3- 7, Orn (C ^ Hs, 5H), 6,6- 6,7m (H-1,2), 5.4s (H-5H, 1H; cis) 5.12s (H-5) 9; H; trans), 2.4s (N-Me; 3H).

MS (C ₂₃ H ₂₅ N ₃ O ₂ - 375.45): 375 (100),

283 (19), 212 (20).

16:14-OH-dihydromorphinone phenylhydrazone

From 1.5 g of 14-OH-dihydromorphinone according to the procedure described for dihydromorphinone-phenyl-hydrazone, 1.2 g of 14-O-H-dihydromorphinone-phenyl-hydrazone are obtained. The material showed two spots by thin layer chromatography, consisting of color and anti isomers.

PMR (CDCl 3): 9.3s (NH; 1H), 7.2-7, Om (C ₆ H ₅ ), 6.7-6.5m (H-1.2; 2H), 5.3s (H -5; 1H; cis), 5.05s (H-5?, 1H; trans), 2.3s (N-Me; 3H).

MS (C ₂₃ H ₂₅ N ₃ O ₃ - 391.45): 391 (100).

17. 14-OH-Dihydrocodeinone-2,4-dinitrophenylhydrazone

The method described for the preparation of dihydrocodeinone-2,4-dinitrophenylhydrazone (see the literature cited in Example 4) was followed by 1.55 g of 14-OH-di-51.

HU 199901 Β 2.1 g of 14-OH-dihydrocodeinone-2,4-dinitrophenylhydrazone chlorohydrate are formed.

The base can be crystallized from a mixture of chloroform-ethanol, m.p. 232-35 'C.

PMR (CDCl ₃ ): 12.8s (NH; 1H), 9.15d (Ar-H; 1H), 8.33dd (Ar-H; 1H), 7.9d (Ar-H; 1H), 6, 75dd (H-1.2; 2H), 5.33s (H-5H; 1H-cis), 3.8s (-OCH3; 3H), 2.4s (N-Me; 3H).

MS (C 24 H 25 N 5 O 7 - 495.48): 495 (40),

478 (M-17; 16).

18. 14-OH-Codeinone-1,4-Dinitrophenylhydrazone

From 1.55 g of 14-OH-codeinone, 2.2 g of 14-OH-codeinone-2,4-dinitrophenylhydrazone chlorohydrate are obtained in the same manner as for the preparation of dihydrocodeinone-2,4-dinitrophenylhydrazone. The base separated from the chlorohydrate crystallizes from ethyl acetate, m.p. 157-60 ° C.

PMR (CDCl 3): 12.15s (NH; 1H), 9.2d (Ar-H; 1H), 8.44dd (Ar-H; 1H), 7.95d (Ar-H; 1H), 6.7dd (H-1,2; 2H), 6.5d (H-8; 1H), 6.1d (H-7; 1H), 5.43s (H-5β, 1H cis), 3.8s ( _-OCH3; 3H), 2,4s (N-Me, 3H).

MS (C ₂₄ H ₂₃ N ₅ O ₇ - 493.46): 493 (27), 476 (M-17; 10).

19. Dihydromorphinone-2,4-dinitrophenylhydrazone

1.4 g of dihydromorphinone, 2.0 g of dihydromorphinone-2,4-dinitrophenylhydrazone chlorohydrate are obtained by the same procedure as described for dihydrocodeinone-2,4-dinitrophenylhydrazone. The base obtained from the salt by thin layer chromatography (systems A and B) is a mixture of two components, color and anti isomers. Separation cannot be achieved by crystallization (ethanol or methanol) or chromatography (column chromatography or preparative TLC).

Neither does aqueous recrystallization of the chlorohydrate result.

PMR (CDCl ₃ ): 13.17s (NH; 12H; cis), 11.10s (NH; 1H, trans), 9.15dd (Ar-H; 1H), 8.25dd (Ar-H; 1H) , 6.7m (H-1.2; 2H), 5.35s (H-5H, 1H trans), 2.4s (N-Me; 3H); cis-trans ratio: 27:: 73.

MS (C ₂₃ H ₂₃ N ₅ O ₆ - 465.35): 465 (63),

448 (M -17; 12), 431 (M-34; 34).

20. 14-OH-Dihydromorphinone-2,4-dinitrophenylhydrazone

From 1.5 g of 14-OH-dihydromorphinone, 1.5 g of 14-OH-dihydromorphinone-2,4-dinitrophenylhydrazone chlorohydrate are obtained in a similar manner to that described for dihydrocodeinone-2,4-dinitrophenylhydrazone. The detached base is a two-component TLC. The two isomers (syn and anti) cannot be separated by crystallization or preparative thin layer chromatography.

PMR (CDCl ₃ ): 13, Is (NH; 1H trans), 11,15s (NH; 1H cis), 9.2m (Ar-H), 8.3m (Ar-H), 8.1d and 7, 9d (Ar-H), 6.7m (H-1,2), 5.38s (H-5H, cis).

PMR (C ₆ D ₆ ) 12.95s (NH; trans) 10.60s (NH; cis) 8.8d; 8.6d (Ar-H), 7.8m (Ar-H), 7.65d; 7.4d (Ar-H), 6.8m (H-1,2), 5.03s (H-5β, cis), 4.73s (H-5β, cis), 4.73 ( H-5 (trans), isomer ratio trans / cis = 60/40.

MS (C ₂₃ H ₂₃ N ₅ O ₇ - 481.45): 481 (62),

464 (M-17; 18), 447 (M-34; 32).

Claims (1)

Process for Morphinan Hydrazone Derivatives of the Formula III and Acid Addition Salts thereof Y-NH ₂ ; Z- (CH ₂ ) ₂ ; R 1, R ₃ -CH ₃ ; R _{2 is} H or A is -NH-phenyl; Z- (CH ₂ ) ₂ ; R ₃ H; R 1 is -CH ₃ , R _{2 is} OH or H; obsession Y is -NHCONH ₂ or -NHCSNH ₂ ; Z- (CH ₂ ) ₂ - or -CH = CH-; R 1 is -CH ₃ or allyl; R _{3 is} H or -CH ₃ ; R _{2 is} H or OH, but if R 1 and R _{3 are} -CH ₃ and R ₂ H, then Y can only be -NHCSNH ₂ ; obsession Y is -NH-dinitrophenyl; Z- (CH ₂ ) ₂ - or -CH = CH-; R 1 is -CH ₃ ; R _{3 is} -CH ₃ and R ₂ -OH or R ₃ H and R ₂ -OH - and azines of formula IV wherein R ₂ is -OH or H, wherein a) for the preparation of compounds of formula III, a ketone of formula I wherein Z, R 1, R ₂ and R ₃ are as defined above, with a hydrazine or hydrazine derivative of formula II, wherein Y is as defined above, or with a salt thereof in an aqueous or alcoholic solution at a temperature of 2 ° C to 100 ° C such that the molar ratio of the compounds of formulas I and II when Y is -NH _{2 is} 1:10 if Y is other than NH ₂ and the above base, 1: 1.5, optionally forming an acid addition salt of the resulting base of formula (III), or liberating the base from a resulting salt, or b) for the preparation of azines of formula IV, a hydrazone of formula III wherein Y is -NH ₂ , Z (CH ₂ ) ₂ , R 1 and R ₃ -CH _3, and R _{2 is} hydrogen; The OH group is reacted with a ketone of formula (I): wherein Z, R 1, R ₂ and R ₃ are as defined above.