RU2123000C1 - Morphinane o-aryl esters, pharmaceutical composition - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to morphinane O-aryl esters of the general formula (IA)

where R^2′ is free or substituted pyridyl, thiazolyl, thienyl, phenyl or a group of the formula

; R²⁰ is H, alkyl or a group R^1′ where one of Y and C(Y,Y¹)-CH₂OH is H and other alkyl, or both Y and Y¹ are alkyls at condition that when Y¹ is pyridyl or R^2′ phenyl then R^1′ can not be alkyl, or their pharmaceutical salts. Compounds of the formula (IA) decrease unwanted effect of neurotoxic damage and therefore they can be used for treatment of patients with convulsions and neuroinhereted sicknesess. EFFECT: improved method of synthesis, enhanced effectiveness of compounds.

Description

в которой R² представляет арил, гетероарил или группу формулы R²⁰

и R¹ представляет водород, алкил, группу формулы -C(Y, Y¹)CH₂OH или -CH₂W, где один из Y и Y¹ - водород, а другой - алкил или оба Y и Y¹ - алкил и W представляет циклоалкил, арил, алкил или аллил,
и их фармацевтически приемлемых солей для изготовления лекарственных средств, снижающих неблагоприятное воздействие на центральные нейроны токсического поражения, в частности поражения центральных нейронов, связанное с ишемией, гипоксией, гипогликемией, эпилепсией, болезнью Хантингтона или болезнью Альцгеймера, или для лечения конвульсий.The present invention relates to the use of compounds of the formula

in which R ² represents aryl, heteroaryl or a group of formula R ²⁰

and R ¹ represents hydrogen, alkyl, a group of the formula —C (Y, Y ¹ ) CH ₂ OH or —CH ₂ W, where one of Y and Y ¹ is hydrogen and the other is alkyl or both Y and Y ¹ are alkyl and W represents cycloalkyl, aryl, alkyl or allyl,
and their pharmaceutically acceptable salts for the manufacture of drugs that reduce the adverse effects on central neurons of toxic damage, in particular central neuron damage associated with ischemia, hypoxia, hypoglycemia, epilepsy, Huntington's disease or Alzheimer's disease, or for the treatment of convulsions.

в которой R^2' представляет замещенный или незамещенный пиридил, тиазолил, тиенил, фенил или группу формулы R²⁰ и R^1' представляет водород, алкил или группу формулы -C(Y, Y¹)CH₂OH, где один из Y и Y¹ - водород, а другой - алкил или оба Y и Y¹ - алкил, при условии, что когда R^2' представляет пиридил или фенил, тогда R^1' отличен от алкила.In another aspect, the invention relates to compounds of the formula:

in which R ^{2 '} represents a substituted or unsubstituted pyridyl, thiazolyl, thienyl, phenyl or a group of the formula R ²⁰ and R ^1' represents hydrogen, alkyl or a group of the formula -C (Y, Y ¹ ) CH ₂ OH, where one of Y and Y ¹ is hydrogen and the other is alkyl, or both Y and Y ¹ are alkyl, provided that when R ^{2 ′} is pyridyl or phenyl, then R ^{1 ′} is other than alkyl.

 The compounds of formula I, as described above, reduce the undesirable effects of neurotoxic lesions, and are therefore useful for the treatment of convulsions and non-degenerate diseases such as stroke, ischemia, hypoxia, hypoglycemia, epilepsy, Huntington’s disease, Alzheimer's disease, cortical paralysis, lung operations and stop heart disease, perinatal asphyxia, olivopontomuscular cerebral atrophy, oxygen deficiency, for example, as a result of drowning, spinal injury and poisoning by exogenous N-methyl-D-aspartate poisons (NMDA), for example , some forms of lyricism. The compounds of formula I are non-competitive antagonists of NMDA receptors. Accordingly, the compounds are particularly useful as a treatment for convulsions, neurodegenerate disease states, including neurological disorders such as epilepsy, stroke, and cerebral ischemia.

 The compounds of the invention relate to the non-opioid type of dextrorotatory morphinans having a cyclic system with absolute stereochemistry 9S, 14S, 13S, as illustrated by formula I.

 As used herein, the term “alkyl”, alone or in combination, refers to a straight or branched alkyl group containing 1-5 carbon atoms, preferably 1-4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl and the like . The term “aryl”, alone or in combination, means a group derived from an aromatic hydrocarbon, such as, for example, phenyl or naphthyl, which are unsubstituted or substituted by one or more substituents selected from alkyl, alkoxy, amino, nitro, halogen and hydroxy groups, preferably alkyl or halogen. The term “heteroaryl” means an aryl group according to the above definition, having 5 or 6 elements in a cyclic structure, and in which one or more ring carbon atoms are replaced by heteroatoms selected from N, S and O, and such a group is unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, nitro group, amino group, halogen, alkoxy group and hydroxy group. Suitable examples of heteroaryl include: pyridyl, thienyl, furyl, thiazolyl, pyrimidyl, pyrrole, quinolyl, and the like. The term "halogen" refers to chlorine, fluorine, iodine and bromine. The term "alkoxy group" alone or in combination refers to an alkyl group according to the above definition, attached via an oxygen atom; examples of alkoxy groups include: methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and the like.

 The invention also relates to pharmaceutical compositions containing a compound of formula IA or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions that reduce the adverse effects of neurotoxic damage and containing a compound of formula I or a pharmaceutically acceptable salt thereof.

In compounds of the formula, IR ^{2 is} preferably heteroaryl, in particular pyridyl or thiazolyl is recommended, and R ^{1 is} preferably hydrogen or alkyl, particularly methyl is recommended.

The compounds of formula I, the use of which is recommended in the method of the invention, include:
(+) - 3-phenoxy-N-methylmorphinan;
(+) - 3-thiazolyloxy simorphinan;
(+) - 3- [6-methyl-2- (pyridinyl) hydroxy] morphinan;
(+) - 17-methyl-3 - [(3-nitro-2-pyridinyl) oxy] morphinan;
(+) -β, β-dimethyl-3- (2-pyridynyloxy) morphinan-17-ethanol;
(9β, 13β, 14β) -3- (2-thienyloxy) -17-methylmorphinan;
(+) - 17-methyl-3- (3-pyridynyloxy) morphinan;
((9β, 13β, 14β)) -2 - [(17-methylmorphinan-3-yl) oxy] -3-pyridinamine;
(+) - 3- (2-pyrimidyloxy) -17-methylmorphinan and their pharmaceutically acceptable salts, in particular compounds selected from the group including:
(9β, 13β, 14β) -3 - [(6-bromo-2-pyridinyl) oxy] -17-methylmorphinan;
(9β, 13β, 14β) -17-methyl-3- (2-thiazolyloxy) morphinan;
(+) - 3-phenoxymorphinan;
(+) - 17-methyl-3- [6-methyl-2- (pyridinyl) oxy] morphinan;
(+) - 3- (2-pyridyloxy) morphinan;
(+) - 3 - [(3-nitro-2-pyridinyl) oxy] morphinan; and their pharmaceutically acceptable salts, especially the compound of formula I represented by (+) - 3- (2-pyridyloxy) -N-methylmorphinan.

The following compounds are especially recommended for use in the method of the invention:
(9β, 13β, 14β) -3 - [(6-bromo-2-pyridinyl) oxy] -17-methylmorphinan;
(9β, 13β, 14β) -17-methyl-3- (2-thiazolyloxy) morphinan;
(+) - 3-phenoxymorphinan;
(+) - 17-methyl-3- [6-methyl-2- (pyridinyl) oxy] morphinan;
(+) - 3- (2-pyridyloxy) morphinan;
(+) - 3 - [(3-nitro-2-pyridinyl) oxy] morphinan, especially (+) - 3- (2-pyridyl-oxy) -N-methylmorphinan and their pharmaceutically acceptable salts.

A recommended group of compounds of formula IA includes those compounds in which R ^{2 ′} is substituted or unsubstituted pyridyl, thiazolyl or phenyl, especially pyridyl and R ^{1 ′} is hydrogen or alkyl, alkyl is especially recommended. Examples of compounds of formula IA include:
(9β, 13β, 14β) -3- (2-thiazolyloxy) morphinan;
(+) -β, β-dimethyl-3- (2-pyridynyloxy) morphinan-17-ethanol;
(+) - 17-methyl-3- (3-pyridynyloxy) morphinan;
(9β, 13β, 14β) -2 - [(17-methylmorphinan-3-yl) oxy] -3-pyridinamine;
(+) - 17-methyl-3- (3-nitro-2-pyridinyl) morphinan and their pharmaceutically acceptable salts. The following compounds of formula IA are recommended:
(9β, 13β, 14β) -17-methyl-3- (2-thiazolyloxy) morphinan;
(+) - 3- (2-pyridyloxy) morphinan;
(+) - 17-methyl-3- [6-methyl-2- (pyridinyl) oxy] morphinan;
(+) - 3- [6-methyl-2- (pyridinyl) hydroxy] morphinan;
(9β, 13β, 14β) -3 - [(6-bromo-2-pyridinyl) oxy] -17-methylmorphinan;
(+) - 3- (3-nitro-2-pyridinyl) morphinan;
(+) - 3-phenoxymorphinan and their pharmaceutically acceptable salts.

 The compounds of formula I can be obtained according to the following reaction schemes 1-4.

In Scheme 1, R ² takes the above values, R ¹ represents hydrogen, alkyl or a group of the formula —CH ₂ W, where W takes the above values, X is halogen, n = 1 or 2, provided that n = 2 when R ² represents a group of formula R ²⁰ , and another condition that R ² is other than 3-nitro-2-pyridinyl when R ¹ is hydrogen.

Compounds of formulas II and III, which are known or can be prepared by known methods, are introduced in the presence of a copper catalyst into the Ullmann reaction (Ann. 350, 1906, 83) to form a compound of formula I. The reaction is carried out in an organic solvent in the presence of an alkali metal base. Any conventional organic solvents may be used, preferably nitrobenzene, collidine, diglyme or tertiary amines. Examples of tertiary amines include cyclic amines such as pyridine and tri (lower alkyl) amines such as trimethylamine, triethylamine and the like. The specified reaction is carried out in the presence of an inorganic base, such as an alkali metal base. Recommended bases include alkali metal hydroxides, such as potassium and sodium hydroxides, and alkali metal carbonates and bicarbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. As inorganic bases, weak bases such as potassium carbonate are recommended. Temperature and pressure do not play a decisive role: the reaction can be carried out at room temperature and atmospheric pressure. However, elevated temperatures may also be used. Typically, a reaction temperature in the range of 100-250 ^° C is preferred. Examples of copper catalysts include: copper (II) chloride, copper (II) bromide, copper (II) sulfate, copper (I) iodide, a mixture of copper bronze and metallic copper, but granular copper is especially recommended.

The compounds of formula I, in which R ² is pyridinyl, pyrimidyl or quinolinyl and R ¹ is methyl, can be obtained by the method of German patent N 2030981, and the compounds of formula I, in which R ² is phenyl and R ¹ is methyl, according to the method, cited in J. Med. Chem. 27, 1984, 1219.

 In Scheme 2, Z is phenyl or methyl.

According to Scheme 2, the compound of formula IIA is converted by the action of benzyl chloroformate or ethyl chloroformate into a compound of formula V. Any inert organic solvent, preferably an aromatic hydrocarbon solvent, for example benzene, toluene, methylene chloride, chloroform and the like, can be used. The reaction is usually carried out in the presence of a base, preferably an alkali metal carbonate, such as sodium or potassium carbonate, or an alkali metal hydroxide, such as sodium or potassium hydroxide. The reaction is recommended to be carried out while cooling in an ice bath. The compound of formula V is converted by action under the conditions of the above Ulman reaction with 2-chloro-3-nitropyridine to a compound of formula VI. Treatment with an inorganic acid such as hydrochloric acid, sulfuric acid and the like. a compound of formula VI is hydrolyzed to a compound of formula IB. As a solvent for this reaction, benzene and toluene are recommended. The reaction can be carried out at 30-100 ^o C and atmospheric pressure, preferably at room temperature.

может быть восстановлено в соединение формулы ID:

использованием железа в качестве восстановителя и в органическом растворителе, таком как этанол или метанол в присутствии неорганической кислоты, например соляной кислоты при 30-100^oC и атмосферном давлении.The compound of formula IC, which can be synthesized according to scheme I,

can be reduced to a compound of formula ID:

using iron as a reducing agent and in an organic solvent such as ethanol or methanol in the presence of an inorganic acid, for example hydrochloric acid at 30-100 ^o C and atmospheric pressure.

In Scheme 3, Hal is halogen, Y 'is alkyl, and R ² is as defined above.

As shown in Scheme 3, the compound of formula VII (known compound) is converted into the compound of formula XV by the action of the compound of formula VIII, which is known or can be obtained by known methods. When carrying out this reaction, any inert organic solvent may be used. Typically, the reaction is carried out in DMF and in the presence of a weak base, for example, an alkali metal carbonate or bicarbonate, such as sodium or potassium bicarbonate. In general, it is recommended that the reaction be carried out at about 100 ^° C. The compound of formula XV can be reduced to the compound of formula IX by the action of an alkali metal hydride, for example lithium aluminum hydride or di (lower alkyl) aluminum hydride, for example diisobutylaluminum hydride. A compound of formula IX can be converted to a compound of formula X by cleavage of an ether bond, for example, by treating a compound of formula IX with pyridine hydrochloride or aqueous hydrogen bromide. The compound of formula X under the conditions of the above Ulman reaction can be converted into a compound of formula IE.

In Scheme 4, R ² represents aryl or heteroaryl and R ¹ represents a group of the formula —C (CH ₃ ) ₂ CH ₂ OH. Compounds of formula IF in which R ¹ is a group of the formula —C (Y ¹ , Y) CH ₂ OH, Y and Y ¹ is alkyl other than methyl or Y is hydrogen and Y ¹ is alkyl can be prepared in a similar manner .

As shown in Scheme 4, the compound of formula VII is converted by the action of ethyl 2-bromopropionic acid into the compound of formula XI. When carrying out this reaction, any inert organic solvent may be used. Typically, the reaction is carried out in DMF and in the presence of a weak base, preferably an alkali metal carbonate or bicarbonate such as potassium or sodium bicarbonate. It is usually preferable to carry out the reaction at about 100 ^° C. The compound of formula XI is alkylated with methyl iodide to the compound of formula XII. In the reaction, any inert organic solvent can be used, preferably THF, ethyl ether or dioxane, and the reaction is carried out in the presence of a base, preferably lithium diisopropylamide, lithium N-cyclohexyl-N-isopropylamide or lithium diethylamide. It is generally preferable to carry out the reaction in a temperature range of from -70 to -40 ^° C. The compound of formula XII is reduced to the compound of formula XIII by the action of an alkali metal hydride, for example lithium aluminum hydride or di (lower alkyl) aluminum hydride, for example diisobutylaluminum hydride. The compound of formula XIII is converted to the compound of formula XIV by cleavage of an ether bond, preferably by the action of pyridine hydrochloride or aqueous hydrogen bromide. The compound of formula XIV under the conditions of the above Ulman reaction is converted to a compound of formula IF.

 As indicated above, the compounds of formula I exhibit activity as a non-competitive NMDA receptor, as a result of which they are applicable as neuroprotective agents, for example, for the treatment of central neuron lesions associated with ischemia, hypoxia, hypoglycemia, epilepsy, Huntington's disease or Alzheimer's disease. Such activity can be shown by the following tests.

1. NMDA-induced seizures in mice
Male mice aged 45-54 days and weighing 18-30 g were left without food for 24 hours, after which they were collected in groups of 10 animals for testing under various conditions. In general, the methodology of Lehmann et al., Described in J. Pharmacol.Exp. Ther. 240, 1987, 737-746. The test compound is administered intraperitoneally (m.p.) to the mice, and NMDA (175 mg / kg b.p.) is injected 30 minutes later. If any test compound is administered orally, then NMDA is injected after 60 minutes. NMDA dissolved in 0.9% saline. Test compounds are also dissolved in 0.9% saline or, if necessary, suspended in 5% acacia gum. All injections are carried out in a volume of 0.2 ml / 20 g body weight. Mice were observed for 30 minutes after the injection of NMDA, while noting four points: 1) the time before the first clonic convulsion; 2) the total number of mice prone to clonic seizures; 3) the total number of mice prone to tonic seizures; and 4) the total number of dead mice. The results are expressed as the number of mice protected at each dosage level of the test compound, which serves as an indication of the degree of protection at each dose and indicates the possible dosage level at which full protection occurs. A formula has been used that takes into account the number of “protected” mice in the control group, since NMDA at the applied dose causes seizures in less than 100% of the mice in the control group. Apply the following formula:
percent protection = 100 (EC) / (10-C),
Where
E is the number of mice protected at a given dose of the test compound, C is the number of mice not prone to seizure when the vehicle is introduced in the control group, and 10 is the number of mice in the group. This dosage level of the compound is considered active if, with this method of calculation, the percentage of protection is equal to or greater than 50 percent. The results are shown in table 1.

2. Acute glutamate neurotoxicity
A suspension of single cells is obtained from the cortex of rat embryos by treatment with a dispase (2.4 U / ml), followed by rinsing using Pasteur pipettes calcined on fire. Cells are applied onto poly-D-lysine-coated microtiter plates (96 cells / plate, 10 ⁵ cells / well) in full 100 μl of essential medium supplemented with 10% horse serum and penicillin / streptomycin. Five days later, non-neuronal cell division is stopped by the action of 10 ^-5 cytosine-arabinoside in combination with a 50% exchange of culture medium. Cultures are used in neurotoxicity assays starting from 8-12 days in vitro. An analysis of acute glutamate toxicity is carried out according to the method of J. Koh et al. (Neurosci. 8, 1988, 185-196) in 100 ml of control saline [DAC: 120 mM NaCl, 5.4 mM KCl, 0.8 mm MgCl ₂ , 1.8 mM CaCl ₂ , 25 mM Tris-HCl ( pH 7.4 at 25 ^° C) and 15 mM glucose] with 500 mM glutamate, aged 5-30 minutes at room temperature with or without added test substances. After washing, the cultures are kept for about a day at 37 ^° C. in 100 μl of DAC. To quantify neurodegeneration in the supernatant of cell culture according to the methodology of JGKlingman et al. (Neurosci. Meth. 31, 1990, 47-51) determine lactate dehydrogenase. The percentage of neuronal degeneration is calculated by taking the difference between unprotected and maximally protected cultures (with reference to the NMDA receptor antagonist) as 100%. According to the dose-response curves, IC ₅₀ values are calculated. The results are shown in table 2.

 The compounds of formula I form pharmaceutically acceptable salts with inorganic acids, for example: hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and with organic acids, for example tartaric acid, oxalic acid, citric acid, camphorosulfonic acid, ethanesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, ascorbic acid, maleic acid, succinic acid, formic acid, acetic acid, and the like.

 The compounds of formula I and their salts described above can be formulated in pharmaceutical dosage forms, for example, for oral or parenteral administration together with conventional pharmaceutical excipients such as water, gelatin, lactose, starch, magnesium stearate, talc , vegetable oils, gums, polyalkylene glycols, and the like. The pharmaceutical preparations can be used in the solid state, for example in the form of tablets, suppositories, capsules or in the liquid state, for example in the form of solutions, suspensions or emulsions. Pharmaceutical excipients may be added, including preservatives, stabilizers, wetting or emulsifying agents, salts for varying the osmotic pressure, or acting as buffer systems. Pharmaceutical preparations, in addition, may contain other pharmaceutical active substances.

 The daily dose of the compounds of formula I to be administered may vary depending on the particular compound selected, route of administration and recipient. A representative route of administration of a compound of formula I is the oral route of administration. In this way, an oral preparation of a compound of formula I is preferably administered in a dosage in the range of 0.01 μg to 0.15 μg per day per kilogram.

 The invention is further illustrated by the following examples.

Example 1
A solution of 5.1 g of (+) - 3-hydroxy-N-metallomorphinan in 120 ml of pyridine is boiled under nitrogen with 6.2 ml of bromobenzene, 6.9 g of potassium carbonate and 6.5 g of copper for four days. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ether and 2H sodium hydroxide. The ether solution was washed with water, then dried, and 4.3 g of (+) - 3-phenoxy-N-methylmorphine were obtained by removal of the solvent. A sample of the product is recrystallized from hexane, so pl. 89-91 ^o C; [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 60.39 ^o (c = 0.92, methanol).

To the obtained base (4.19 g in acetone), a solution of 1 g of oxalic acid in acetone is added. Recrystallization of the crude oxalate from isopropanol gave 2.5 g of (+) - 3-phenoxy-N-methylmorphinan oxalate, so pl. 179-180 ^o With, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 35.7 ^o (s = 1.00, methanol).

The fumarate is obtained by reaction in water with (+) - 3-phenoxy-N-methylmorphinan and fumaric acid. The product is isolated by filtration and after lyophilization, amorphous fumarate is obtained in the form of a hemihydrate, mp. 75-77 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D /}}$ + 33.53 ^o (s = 1.02, methanol).

Example 2
A solution of 3.35 g of the adduct of (+) - 3-hydroxy-N-methylmorphinan with benzene (crystallized from benzene) in 60 ml of pyridine is boiled until the temperature rises to 114 ^o C. The reaction mixture is then cooled and 20 ml of pyridine are added, 1 66 g of bromopyridine, 2 g of potassium carbonate and 0.26 g of copper. The mixture was boiled for 17 hours, then cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ether and 10% sodium hydroxide solution. The ethereal solution is washed with water, dried, and by removing the solvent, a product is obtained by crystallization from pet. ether receive 2.4 g of (+) - 3- (2-pyridyloxy) -N-methylmorphinan, so pl. 114-116 ^o With, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 53.58 ^o (c = 1.10, methanol).

A solution of 1.4 g of oxalic acid is added to 2.4 g of the obtained base in acetone. Recrystallization of the crude oxalate from isopropanol gave 2.9 g of (+) - 3- (2-pyridyloxy) -N-methylmorphinan oxalate, so pl. 188-190 ^o With, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 21.2 ^o (c = 1.00, methanol).

Fumarate recrystallized from acetone was also obtained, mp. 84-86 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 16.67 ^o (s = 0.696, methanol).

The base (6 g) in a mixture of 10 ml of methyl ethyl ketone and 2.8 ml of isopropanol is acidified with concentrated hydrochloric acid, then diluted with 15 ml of methyl ethyl ketone and allowed to crystallize for 48 hours. Filtration of the salt gives 1.5 g of (+) - 3- (2-pyridyloxy) -N-methylmorphinan hydrochloride as a hemihydrate, mp. 116-120 ^o With, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 23.11 ^o (c = 1.09, methanol).

Example 3
A solution of 3.35 g of the adduct of (+) - 3-hydroxy-N-methylmorphinan with benzene (crystallized from benzene) in 60 ml of pyridine is boiled until the temperature rises to 114 ^° C. Then the reaction mixture is cooled and 10 ml of pyridine are added, 2 g of potassium carbonate, 1.1 g of 2-chloro-6-methylpyridine and 0.26 g of copper. The mixture was boiled for 48 hours, then cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and a 2N potassium hydroxide solution. The ethyl acetate solution was washed with water, dried and the solvent was removed under reduced pressure. The residue was dissolved in chloroform and chromatographed on silica gel eluting with a mixture of chloroform-methanol (95: 5). Fractions 10-14 are combined and removal of the solvent gives 0.6 g of (+) - 17-methyl-3- [6-methyl-2- (pyridinyl) oxy] morphinan, b.p. 170-175 ^o With (0.05 mm), [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 66.34 ^o (c = 1.00, methanol).

The base (1.6 g) in acetone is treated with a solution of 0.8 g of fumaric acid in acetone. Recrystallization of the fumarate from acetone gives 1 g of the hydrate (E) -2-butenedioate (+) - 17-methyl-3- [6-methyl-2- (pyridinyl) oxy] morphinan, m.p. 128-130 ^o With, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 38.08 ^o (c = 1.00, methanol).

Example 4
A solution of 3.35 g of the adduct of (+) - 3-hydroxy-N-methylmorphinan with benzene (crystallized from benzene) in 60 ml of pyridine is boiled until the temperature rises to 114 ^o C. Then, 2 g of potassium carbonate are added to the solution, 1, 8 g of 2-chloro-3-nitropyridine and 0.3 g of copper. The resulting mixture was boiled for 30 hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The ethyl acetate solution was washed with 2N sodium hydroxide, then with brine and dried. Removal of the solvent gives, after crystallization from ethyl acetate, 2 g of (+) - 17-methyl-3 - [(3-nitro-2-pyridinyl) oxy] morphinan, m.p. 188-189 ^o With, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 51.38 ^o (c = 1.01, methanol).

0.553 g of fumaric acid was added to 1.7 g of the base in acetone and 1.8 g of (E) -2-butenedioate (+) - 17-methyl-3 - [(3-nitro-2-pyridinyl) oxy] was obtained by filtering the crystals. morphinan (2: 3), mp 107-108 ^o With, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 24.33 ^o (c = 1.01 methanol).

Example 5
A solution of 3.35 g of the adduct of (+) - 3-hydroxy-N-methylmorphinan with benzene (crystallized from benzene) in 60 ml of pyridine is boiled until the temperature rises to 114 ^° C. 1.66 g of 3-bromopyridine is added to the solution, 2.07 g of anhydrous potassium carbonate and 0.257 g of copper. The mixture is boiled for 24 hours, then cooled to room temperature and filtered. The filtrate was concentrated and the residue was extracted with ethyl acetate. The organic solution was washed with 2N potassium hydroxide solution, then with brine and dried. Removal of the solvent gives 1.4 g of (+) - 17-methyl-3- (3-pyridinyloxy) morphinan after crystallization from acetone, mp. 125-126 ^o With, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 64.40 ^o (c = 0.504, methanol).

0.668 g of base and 0.348 g of fumaric acid are mixed in 50 ml of water and heated until completely dissolved. The crystals are filtered off and, after freeze-drying, 1 g of (+) - 17-methyl-3- (3-pyridyloxy) morphinane (E) -2-butenedioate (2: 3) salt (4: 3) molar hydrate is obtained, m.p. 68-70 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 27.12 ^o (c = 1.006, methanol).

Example 6
A mixture of 3.35 g of (+) - 3-hydroxy-N-methylmorphinan, 2.07 g of potassium carbonate, 1.2 g of 2-chloropyrimidine, 0.25 g of copper in 60 ml of pyridine is boiled for 8 days, then cooled to room temperature and filtered. The filtrate was concentrated and the residue was extracted with ethyl acetate. The ethyl acetate solution was washed with 1N sodium hydroxide solution, then with brine and dried. Removal of the solvent affords 2 g of (+) - 3- (2-pyrimidinyloxy) -17-methylmorphinan. Recrystallization of the sample from ethyl acetate afforded a pure product with mp. 169-171 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 55.12 ^° (c = 0.923, methanol).

The base (1 g) in acetone is mixed with fumaric acid (0.4 g) and by filtering the crystals, 0.9 g of (E) -2-butenedioate (+) - 3- (2-pyrimidinyloxy) -17-methylmorphinan (2: 3), so pl. 115 - 117 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +20.56 ^o (c = 1.14, methanol).

Example 7
A mixture of 6.7 g of (+) - 3-hydroxy-N-methylmorphinan, 3.6 g of 2-chloro-5-nitropyridine, 0.6 g of copper, 4 g of anhydrous potassium carbonate (powder) in 120 ml of pyrimidine is boiled with stirring 30 hours The mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic solution was washed with 2N potassium hydroxide solution, then with brine and dried. The solvent was removed under reduced pressure and the residue was extracted with ether. Removal of the solvent afforded 4.7 g of (9β, 13β, 14β) -17-methyl-3 - [(5-nitro-2-pyridinyl) oxy] morphinan, m.p. 144 - 145 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +56.22 ^o (s = 1.03, methanol).

The base (1 g) in acetone is mixed with 0.45 g of fumaric acid and by filtration of the crystals, 1.2 g of (9β, 13β, 14β) -17-methyl-3 - [(5-nitro-2-pyridinyl) oxy] morphinan are obtained (E) -2-butenedioate (2: 3) salt, mp. 144 - 145 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 22.01 ^o (s = 1.00, methanol).

Example 8
A mixture of 2.6 g of (+) - 3-hydroxy-N-methylmorphinan, 2 g of potassium carbonate powder, 0.3 g of copper, 2.3 g of 2-bromothiazole in 60 ml of pyridine is boiled for 24 hours, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate solution was washed with a 2N potassium hydroxide solution, then with brine and the solvent was removed under reduced pressure. The residue (2.2 g) was chromatographed on silica gel, eluting with a mixture of chloroform-methanol-water-acetic acid (90:15: 10: 6, v / v). Fractions 6 to 18 were collected and, after removal of the solvent, 1.4 g of (9β, 13β, 14β) -17-methyl-3- (2-thiazolyloxy) morphinan were obtained. A sample of the product was recrystallized from ether-pet. Ether, mp. 116 - 117 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +67.38 ^o (s = 1.01, methanol).

0.45 g of fumaric acid was added to 1.3 g of the base in ethanol, and the resulting crystals were filtered off. Recrystallization of the salt from acetone afforded 0.7 g of (E) -2-butenedioate (9β, 13β, 14β) -17-methyl-3- (2-thiazolyloxy) morphinan, m.p. 127 - 128 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +35.85 ^o (s = 1.03, methanol).

Example 9
A solution of 3.35 g of the adduct of (+) - 3-hydroxy-N-methylmorphinan with benzene (recrystallized from benzene) in 50 ml of dry pyridine is boiled until the temperature rises to 114 ^o C. After cooling, add 2 g of potassium carbonate powder, 0 , 8 g of 2-bromothiophene and 0.26 g of copper and the mixture is boiled for 20 hours. After cooling, the mixture was filtered and the filtrate was concentrated under reduced pressure. The product is chromatographed on silica gel eluting with a mixture of chloroform-methanol-water-acetic acid (90: 15: 10: 6, v / v). From fractions 5 to 9, after removal of the solvent, 0.7 g of (9β, 13β, 14β) -3- (2-thienyloxy) -17-methylmorphinan is obtained, b.p. 205 - 210 ^o C (0.25 mm), [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +58.06 ^o (s = 0.261, methanol).

The base (0.8 g) in acetone is treated with 0.24 g of fumaric acid and the crystals are isolated to obtain 0.6 g of (E) -2-butenedioate (9β, 13β, 14β) -3- (2-thienyloxy) -17-methylmorphinan , mp 155 - 156 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +41.58 ^o (s = 1.02, methanol).

Example 10
A solution of 3.35 g of the adduct of (+) - 3-hydroxy-N-methylmorphinan with benzene (crystallized from benzene) in 60 ml of dry pyridine is boiled until the temperature rises to 114 ^o C. 2 g of potassium carbonate are added to the cooled solution, 1 , 8 g of 2-chloroquinoline and 0.3 g of copper and the mixture is boiled for 30 hours. The mixture was cooled, filtered and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic solution was washed with 2N potassium hydroxide solution, then with water and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with a mixture of chloroform-methanol-water-acetic acid (90: 15: 10: 6, v / v). From fractions 9 to 18, after removal of the solvent and recrystallization from acetone, 0.9 g of (9β, 13β, 14β) - -17-methyl-3- (2-quinolinyloxy) morphinan is obtained, m.p. 142 - 143 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +78.48 ^o (s = 0.81, methanol).

The base (0.8 g) in acetone is treated with 0.5 g of furmaric acid and, after isolation of the crystals, 1 g of (9β, 13β, 14β) -17-methyl-3- (2-quinolinyloxy) morphinan (E) -2-butenedioate is obtained (2: 3) salts, mp. 161 - 162 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +32.97 ^o (c = 0.98, methanol).

Example 11
A solution of 3.35 g of the adduct of (+) - 3-hydroxy-N-methylmorphinan with benzene (crystallized from benzene) in 60 ml of dry pyridine is boiled until the temperature rises to 113 ^o C. 2 g of potassium carbonate are added to the cooled solution, 0 3 g of copper and 2.8 g of 2,6-dibromopyridine. The mixture is boiled for 17 hours, then cooled and filtered. The filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate solution was washed with 2N potassium hydroxide solution, then with brine and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluting with a mixture of chloroform-methanol-water-acetic acid (90: 15: 10: 6 v / v). From fractions 8-19, after removal of the solvent and recrystallization of the residue, 1.2 g of (9β, 13β, 14β) -3 - [(6-bromo-2-pyridinyl) oxy] -17-methylmorphinan are obtained, so pl. 123 - 124 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +74.76 ^o (s = 1.03, methanol).

The base (0.8 g) in acetone is treated with 0.5 g of fumaric acid and 1.1 g of (9β, 13β, 14β) -3 - [(6-bromo-2-pyridyl) oxy] -17-methylmorphinan are obtained by isolation of crystals (E) -2-butenedioate (2: 3) salt, mp. 152 - 153 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +46.12 ^o (s = 1.02, methanol).

Example 12
A mixture of 2.6 g of (+) - 3-hydroxy-N-methylmorphinan, 2 g of 2-chloro-4-methyl-5-nitropyridine, 2 g of potassium carbonate powder, 0.3 g of copper and 60 ml of pyridine is boiled for 48 hours. After cooling, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between brine and ethyl acetate. The organic solution was washed with 2N potassium hydroxide solution, then with brine and dried. Removal of the solvent and recrystallization of the crude product from ether yields 2 g of (9β, 13β, 14β) -17-methyl-3 - [(4-methyl-5-nitro-2-pyridinyl) oxy [morphinan, m.p. 145 - 146 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D /}}$ +61.21 ^o (s = 1.04, methanol).

After treating 0.5 g of fumaric acid from 1.4 g of base in acetone, 1.7 g of (E) -2-butenedioate (9β, 13β, 14β) -17-methyl-3 - [(4-methyl-5-nitro 2-pyridinyl) oxy] morphinan, mp. 198 - 200 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +21.90 ^o (s = 1.08, methanol).

Example 13
A solution of 6.7 g of the adduct of (+) - 3-hydroxy-N-methylmorphinan with benzene (crystallized from benzene) in 120 ml of pyridine is boiled until the temperature rises to 113 ^° C. 4.5 g are added to the cooled solution in a nitrogen atmosphere potassium carbonate powder, 0.5 g of copper and 5.6 g of 2,6-dibromopyridine and the mixture is boiled for 20 hours. The mixture was cooled, filtered and concentrated under reduced pressure. The residue was extracted with ethyl acetate and the organic solution was washed with 2N potassium hydroxide solution. The solvent was removed and the residue was chromatographed on silica gel eluting with a mixture of chloroform-methanol-water-acetic acid (90: 15: 10: 6, v / v). From fractions 34 to 40, after removal of the solvent, 1 g of (9β, 13β, 14β) -2,6-pyridinylbis (hydroxy) -3,3'-bis (17-methyl-morphinan) is obtained, b.p. 280 - 285 ^o C (0.25 mm), [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +83.50 ^o (s = 0.94, methanol)
From 1 g of the base, after treatment with hydrogen chloride in acetone and recrystallization from ethanol-acetone, 0.7 g of dihydrochloride hemihydrate (9β, 13β, 14β) -2,6-pyridinylbis (hydroxy) -3,3'-bis (17- methyl morphinan), mp 257 - 258 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +72.68 ^o (s = 0.8, methanol).

Example 14
A mixture of 12.9 g of (+) - 3-hydroxymorphinan, 10 g of 2-bromopropionic acid ethyl ester, 8.4 g of anhydrous sodium carbonate and 100 ml of DMF is heated for 15 hours at 100 ^° C. The reaction mixture is concentrated to about 40 ml and distributed between water and ether. The aqueous solution was extracted with ether, the combined solutions were washed with water and dried. Removal of the solvent under reduced pressure yields 17.1 g of (+) - 3-methoxy-N- (2-ethoxycarbonyl-2-ethyl) morphinan. Sample product distilled, so pl. 180 ^o C, (0.07 mm), [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +70.78 ^o (s = 0.97, methanol).

Example 15
To a solution of 1.75 g of diisopropylamine in 20 ml of THF in a nitrogen atmosphere at -40 ^° C was added a hexane solution containing 10.9 ml of M n-butyl lithium. The resulting solution was stirred for 15 minutes at the same temperature and then cooled to -70 ^° C. A solution of 5.6 g of (+) - 3-methoxy-N- (2-ethoxycarbonyl-2-ethyl) was added dropwise to the obtained solution of lithium diisopropylamide. morphinan in 20 ml of dry THF. The resulting solution was allowed to warm to -40 ^° C, after which a solution of 2.5 g of methyl iodide in 10 ml of THF was added dropwise. Then the reaction mixture was stirred for 16 hours at room temperature. The resulting mixture was partitioned between water and ether. The ether solution is washed with water and dried. Removal of the solvent under reduced pressure gives 5.7 g of (+) - 3-methoxy-N- (2-ethoxycarbonyl-2-propyl) morphinan. Sample product distilled, so pl. 180 - 185 ^o C (0.08 mm), [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +82.5 ^o (s = 1.00, methanol).

Example 16
To a suspension of 1.2 g of LiAlH ₄ in 100 ml of THF was added dropwise a solution of 5.7 g of (+) - 3-methoxy-N- (2-ethoxycarbonyl-2-propyl) morphinan in 50 ml of THF. After boiling the mixture for 12 hours under nitrogen, it was cooled to room temperature and 20 ml of ethyl acetate and then 10 ml of water were added dropwise. The resulting suspension is filtered and the filtrate dried. Removal of the solvent under reduced pressure gave (+) - 3-methoxy-N- (2-hydroxymethyl-2-propyl) morphinan, mp 83 - 84 ^o C. a Sample of the product is distilled, so pl. 190 ^o C (0.08 mm), [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +74.5 ^o (s = 1.00, methanol).

A sample of the base (1.5 g) was treated with hydrogen chloride in ethyl acetate. Recrystallization from ethanol-ethyl acetate gave 1.53 g of (+) - 3-methoxy-N- (2-hydroxymethyl-2-propyl) morphinan hydrochloride, mp. 215 - 216 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +33.94 ^o (c = 1.00 methanol).

Example 17
A mixture of 1.2 g of (+) - 3-methoxy-N- (2-hydroxymethyl-2-propyl) morphinan and 11 ml of 62% hydrobromic acid is heated for 5 hours at 60 ^{° C.} under a nitrogen atmosphere. Excess reagent is removed under reduced pressure and by crystallization of the residue from a mixture of methanol-ethanol, 1.4 g of (+) - 3-hydroxy-N- (2-hydroxymethyl-2-propyl) morphinan hydrobromide are obtained, so pl. 165 - 167 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 38.29 ^o (c = 1.01, methanol).

The base (2 g) obtained from the above hydrobromide is treated with hydrogen chloride in acetone. After recrystallization from acetone, 1.9 g of (+) - 3-hydroxy-β, β-dimethylmorphinan-17-ethanol, mp. 254 - 255 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 41.75 ^o (c = 0.512, methanol).

Example 18
A solution of 2.9 g of (+) - 3-hydroxy-N- (2-hydroxymethyl-2-propyl) morphinan in 60 ml of dry pyridine is boiled until the temperature reaches 114 ^o C. 1.66 g of 2- are added to the cooled solution. bromopyridine, 0.3 g of copper and 1.4 g of potassium carbonate powder and the mixture is boiled for 20 hours. Then the mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ether and a 2N potassium hydroxide solution. The ether solution was washed with a 2N potassium hydroxide solution, then with brine and the solvent was removed under reduced pressure. The residue is chromatographed on silica gel eluting with methylene chloride. From fractions 11 to 15, after removal of the solvent, 2.3 g of (+) -β, β-dimethyl-3- (2-pyridinyloxy) morphinan-17-ethanol, [α] are obtained as an amorphous substance $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 61.09 ^o (c = 0.772, methanol).

1.5 g (54%) of dihydrochloride (+) -β, β-dimethyl-3- (2-pyridinyloxy) morphinan-17-ethanol dihydrochloride are obtained from 2.3 g of base in acetone when treated with hydrogen chloride, mp. 105 - 107 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 27.33 ^o (c = 1.19, methanol).

Example 19
A mixture of 1.9 g (+) - 17-methyl-1 - [(3-nitro-2-pyridyl) oxy] morphinan, 10 ml of ethanol, 3 ml of 6H hydrochloric acid and 3 g of iron is heated in a water bath for 30 minutes, after which add 3 ml of 6H hydrochloric acid. The mixture was cooled to room temperature, filtered, the filtrate was concentrated and made basic with a concentrated solution of ammonium hydroxide. The aqueous suspension was extracted with ethyl acetate, the organic solution was washed with brine and dried. The solvent was removed and the residue was chromatographed on silica gel eluting with a mixture of chloroform-methanol-water-acetic acid (90: 30: 10: 6, v / v). After removal of the solvent from fractions 3-14, 1.3 g of (9β, 13β, 14β) -2 - [(17-methylmorphinan-3-yl) oxy] -3-pyridinamine, i.e. bales, are obtained. 225 - 230 ^o C, (0.25 mm), [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +41.35 ^o (c = 0.906, methanol).

0.9 g of dihydrochloride (9β, 13β, 14β) -2 - [(17-methylmorphinan-3-yl) oxy] - 3-pyridinamine, so pl. 260 - 261 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +19.83 ^o (c = 0.98, methanol).

Example 20
A solution of 2.4 g of (+) - 3-hydroxymorphinan in 60 ml of pyridine is boiled until the temperature reaches 114 ^o C. To the cooled solution is added 20 ml of pyridine, 1.66 g of 2-bromopyridine, 2 g of potassium carbonate powder and 0, 26 g of copper. The mixture was boiled for 20 hours, then cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ether and a 2N potassium hydroxide solution. The ether solution was washed with brine, dried, and after removal of the solvent under reduced pressure, 3.1 g of (+) - 3- (2-pyridyloxy) morphinane were obtained. A sample of the product is crystallized from ether-petroleum ether, mp. 87 - 88 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +36.17 ^o (c = 0.976, methanol).

The base (3.4 g) in acetone is treated with maleic acid. Recrystallization of maleate from acetone gives 3 g of (Z) -butenedioate (+) - 3- (2-pyridyloxy) morphinane, mp 164 - 165 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +15.00 ^o (c = 0.833, methanol).

Example 21
A mixture of 2.4 g of (+) - 3-hydroxymorphinan, 1.7 g of bromobenzene, 600 mg of copper and 1.54 g of potassium carbonate powder in 60 ml of pyridine is boiled for 5 days in a nitrogen atmosphere. The mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ether and a 2N potassium hydroxide solution. The ether solution was washed with benzene, dried and the solvent was removed under reduced pressure. By treating the residue with hydrogen chloride in a mixture of ethanol-ethyl acetate, (+) - 3-phenoxy morphinane hydrochloride will be obtained, m.p. 320 - 321 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +15.00 ^o (c = 0.72, methanol).

The hydrochloride sample was converted into the free base by the action of a dilute solution of ammonium hydroxide and using ethyl acetate for extraction. A sample of the base crystallized from ether, so pl. 65 - 66 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +42.83 ^o (c = 0.68, methanol).

Example 22
A mixture of 2.4 g of (+) - 3-hydroxymorphinan, 1.4 g of 2-chloro-6-methylpyridine, 1.5 g of potassium carbonate powder and 300 mg of copper in 60 ml of pyridine is boiled for 3 days. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ether and a 2N potassium hydroxide solution. The ethyl ether solution was washed with brine, dried and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel, eluting with a methylene chloride-methanol mixture (90:30, v / v). Fractions 30 to 59 are combined and, after removal of the solvent, 0.6 g of (+) - 3- [6-methyl-2- (pyridinyl) oxy] morphinan, i.e. bales are obtained. 195 - 197 ^o C (0.05 mm), [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +48.54 ^o (c = 1.13, methanol).

Processing 0.6 g of the base in ethanol 600 mg of fumaric acid gives 0.6 g of (E) -2-butenedioate (+) - 3- [6-methyl-2- (pyridyl) oxy] morphinan. A salt sample was recrystallized from ethanol, so pl. 240 - 242 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ +36.43 ^o (c = 1.06, methanol).

Example 23
A mixture of 2.4 g of (+) - 3-hydroxymorphinan, 1.6 g of 2-bromothiazole, 1.4 g of potassium carbonate powder and 0.6 g of copper in 60 ml of pyridine is boiled with stirring for 24 hours in a nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase is washed with 2N potassium hydroxide solution, then with brine and dried. The solvent was removed and the residue was chromatographed on silica gel eluting with a mixture of chloroform-methanol-water-ethyl acetate (90: 15: 10: 6, v / v). From fractions 4 to 10, after removal of the solvent, 0.6 g of (+) - 3-thiazolyloxy simorphinan is obtained as an amorphous substance, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 51.82 ^o (c = 0.55, methanol).

The resulting free base (0.6 g) is treated with 0.2 g of maleic acid in acetone. Recrystallization from acetone gives 0.50 g of (+) - 3-thiazolyloxy simorphinan maleate, mp 179 - 180 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 32.51 ^o (c = 0.99, methanol).

Example 24
To a mixture of 2.4 g of (+) - 3-hydroxymorphinan, 10 ml of methylene chloride, while cooling in an ice bath, 2 g of benzyl chloroformate in 5 ml of methylene chloride and 4.4 ml of a 10% solution are added simultaneously over 5 minutes sodium hydroxide. The mixture was stirred for 1.5 hours at room temperature and the organic phase was separated. The aqueous layer was extracted with methylene chloride, then the combined organic solutions were washed with brine and dried. Removal of the solvent afforded 3.8 g of benzyl-3-hydroxymorphinan-N-carboxylate as an amorphous substance, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 138.6 ^o (c = 0.43, methanol).

Example 25
A mixture of 10.8 g of benzyl - (+) - 3-hydroxymorphinan-N-carboxylate, 4.6 g of 2-chloro-3-nitropyridine, 4 g of potassium carbonate powder and 0.8 g of copper in 100 ml of pyridine is boiled for 20 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was washed with heptane and then partitioned between ethyl acetate and a 2N potassium hydroxide solution. The organic solution was washed with brine, dried and filtered. The filtrate was treated with norite, filtered and the solvent was removed under reduced pressure. The residue is chromatographed on silica gel eluting with methylene chloride. From fractions 5 to 32, after removal of the solvent, 4.5 g of benzyl - (+) - 3 - [(3-nitro-2-pyridinyl) oxy] morphinan-N-carboxylate, [α] are obtained as an amorphous substance $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 123.9 ^o (c = 1.0, methanol).

Example 26
A mixture of 0.5 g of benzyl - (+) - 3 - [(3-nitro-2-pyridinyl) oxy] -morphinan-N-carboxylate, 8 ml of concentrated hydrochloric acid in 8 ml of benzene is stirred for 6 hours at room temperature, after which poured into ice water. The aqueous suspension is extracted with ether, then cooled and basified with a concentrated solution of ammonium hydroxide. The resulting aqueous suspension is extracted with ethyl acetate. The combined ethyl acetate solutions were dried and, after removal of the solvent, 0.3 g of (+) - 3 - [(3-nitro-2-pyridinyl) oxy] morphinan was obtained. A sample of the product was recrystallized from ethyl acetate-ether, mp. 161 - 162 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D /}}$ +60.62 ^o (c = 1.04, methanol).

The resulting base (0.3 g) is treated with hydrogen chloride. Recrystallization from 1H hydrochloric acid gives 0.3 g of (+) - 3 - [(3-nitro-2-pyridinyl) oxy] morphinan hydrochloride hydrate, mp. 149 - 150 ^o C, [α] $\genfrac{}{}{0ex}{}{\text{25}}{\text{D}}$ + 25.80 ^o (c = 1.15, methanol).

 The following pharmaceutical preparations are prepared by known methods.

Claims (4)

1. O-aryl esters of morphinanes of the general formula IA

where R ^{2 '} is a substituted or unsubstituted pyridyl, thiazolyl, thienyl, phenyl or a group of the formula R ²⁰ :

and R ^{1 ′} is hydrogen, alkyl or a group of the formula —C (Y, Y ′) is CH ₂ OH, where one of Y and Y ′ is hydrogen and the other is alkyl, or both Y and Y ′ are alkyl, provided that when R ^{2 '} is pyridyl or phenyl, then R ^1' cannot be alkyl, in particular compound IA, where R ^{2 '} is pyridyl or phenyl and R ^1' is hydrogen, or their pharmaceutically acceptable salts.  2. The compounds according to claim 1, characterized in that they are selected from the group consisting of: (9β, 13β, 14β) -17-methyl-3- (2-thiazolyloxy) morphinan, (9β, 13β, 14β) -3- (2-thiazolyloxy) morphinan, (+) - 3- (2-pyridyloxy) morphinan, (+) - 17-methyl-3- (3-pyridyloxy) morphinan, (+) - 17-methyl-3- [6- methyl-2 (pyridinyl) oxy] morphinan, (+) - 3- [6-methyl-2- (pyridinyl) oxy] morphinan, (9β, 13β, 14β) -3 - [(6-bromo-2-pyridinyl) oxy] -17-methylmorphinan, (9β, 13β, 14β) -2 - [(17-methylforfinan-3-yl) oxy] -3-pyridinamine, (+) - 17-methyl-3- (3-nitro-2 -pyridynyloxy) morphinan, (+) - 3- (3-nitro-2-pyridynyloxy) morphinan, (+) - 3-phenoxy morphinan, or their pharmaceutically acceptable salts, in astnosti (+) - β, β-dimethyl-3- (2-pyridinyloxy) morphinan-17-ethanol.  3. The compounds according to claim 1 or 2, having the ability to reduce the adverse effects of toxic damage to central neurons.  4. A pharmaceutical composition for reducing the effects of neurotoxic damage, characterized in that it contains a compound of general formula IA according to claim 1 or 2.

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