HU196376B - Process for preparing morphinane derivatives and pharmaceutical compositions containing such compounds - Google Patents

Abstract

Compounds of formula I <IMAGE> wherein X and Y each denote hydrogen or together denote -O-, R1 denotes allyl optionally substituted by 1 to 3 alkyl groups, the substituent or substituents having in total a maximum of 3 C-atoms, cyclopropylalkyl with 7 to 12 C-atoms, R2 denotes hydrogen, C1-10 alkyl, C5-6 cycloalkyl, or optionally substituted pheny or phenyl-C7-12 alkyl, R3 denotes hydrogen, alkyl with 1 to 10 C-atoms or phenyl, R4 denotes hydrogen, OH, NR6R7, NHCOR, NHSO2R min or NHCOOR sec , R6 and R7, independently of one another, denote hydrogen or alkyl with 1 to 3 C-atoms, R denotes alkyl with 1 to 6 C-atoms, phenyl or -A-COOR sec , A denotes alkylene or alkenylene each with 2 to 4 C-atoms, R min denotes alkyl with 1 to 6 C-atoms or phenyl, R sec denotes methyl or ethyl and wherein either R3 is in the alpha -position and R4 is in the beta -position, or R3 is in the beta -position and R4 is in the alpha -position, or R3 and R4 together are =O, or =CH2, and R5 denotes hydrogen or methyl, with the provisos that when X and Y denotes -O-, R2 denotes hydrogen, R4 denotes a alpha -OH group and R3 and R5 denote hydrogen, R1 is other than cyclopropylmethyl or allyl, and that when R2,R3,R4 and R5 are each hydrogen, R1 is other than cyclopropylmethyl, in free base form or in acid addition salt form, as well as the physiologically hydrolysable, pharmaceutically acceptable esters of such compounds, which contain a free OH group, in free base form or in acid addition salt form. The compounds according to the invention are opiate agonists/antagonists and LH secretion stimulators. Intermediates of the formula III to XIV are claimed per se.

Description

The present invention relates to novel morphinan derivatives and to pharmaceutical compositions containing them.

17-Cyclopropylmethyl-14-methylmorphinan-3-ol is known from R. Belleau Special Publication, Royal Society of Chemistry London 1982, 200-221. literary space.

The novel morphine derivatives are represented by the general formula (I) wherein

- X and Y each independently represent a hydrogen atom or together form -O,

- R 1 is cyclopropylmethyl,

- R 2 is hydrogen, (C 1 -C 4) -alkyl, (C 5 -C 6) -cycloalkyl, or phenyl optionally substituted with HO;

- R3 is hydrogen,

- R 1 is hydrogen or hydroxy,

Ra is in the position of R and is in the position of R1, is in the position of Ra and is in the position of R1, or

- Ri and Ri together represent = Q and with the proviso that X and Y together cannot be -0- if

R2 is hydrogen, R1 is hydroxy at the α-position and Ra is hydrogen, respectively

R2, R5 and R1 may not be hydrogen at the same time.

The compounds of formula (I) may be prepared in the form of the free base or of an acid addition salt.

Thus, the compounds of the present invention may exist in free base form or in acid addition form and may be converted in the conventional manner. Examples of acid addition salts include hydrochlorides, hydrobromides, hydrogen maleate and hydrogen malonate

According to the present invention, the compounds of formula I can be prepared as follows:

to prepare a compound of formula (I) by subjecting a compound of formula (Ik) to ether cleavage.

In the above formula, in the description and in the examples, the configuration of the asymmetric carbon atoms in the intermediates and end products corresponds to the neutral (rotary) morphinan series, i.e., at position 9, R, position 13, and S. The invention also relates to the preparation of racemic mixtures of, for example, mixtures of compounds of formula I with their epimers.

In the above formula, it is preferred that

- R2 alkyl, especially methyl or ethyl, cycloalkyl, especially cyclohexyl, or phenyl or para-HO-phenyl

- Rs is hydrogen,

R 1 is hydroxy or hydrogen, especially hydroxy or

- Rs and Ri together -0-.

It is preferred that R5 and R1 together form oxygen, and preferably X and Y are hydrogen. Preferably, R 1 is hydroxy and is in the α-position.

The ether cleavage may be carried out using standard reagents such as hydrobromide, boron tribromide, or pyridine hydrochloride.

In the process, the starting materials (Formula (Ik)) can be prepared by following Scheme 1.

Compounds of formula (III) may be prepared by a process (a ') which is prepared by reacting a compound of formula (II)

II

Reaction with R2CH2-S-S-CH2R2 thiosulfinate (Diels-Adler reaction), the reagents are heated under reflux in an inert solvent such as toluene.

The opening of the furan ring may be accomplished by simultaneous position change of the S atom [process b ( ¹ )], for example by treatment with hydrogen bromide.

Ring S opening for the preparation of compounds of formula V (process le ') can be accomplished by reduction of compounds of formula IV and simultaneous saturation of the double bond and reduction of the oxo group, such as lithium in liquid ammonia.

Removal of the HS-bonded compound of formula (V) [(method d'i) can be carried out, for example, with Raney nickel in methanol.

In the compounds of formula (VI), the 6-hydroxy group can be converted to the oxo group in a known manner (process e ¹ ), for example by reaction with oxalyl dichloride and dimethylsulfoxide.

Compounds of formula (VII) wherein R2 is phenyl may be prepared directly from compounds of formula (III) by reaction with Raney nickel in methanol.

Compounds of formula (VII) are then brominated with, for example, bromine in glacial acetic acid, followed by HBr cleavage in an alkaline medium such as sodium hydroxide solution, and finally the bromine atoms that are still present and introduced, e.g.

The positions 1 and 7 are removed by reduction during the bromination in the first step. This reduction removal may be effected, for example, by hydrogenation in the presence of a palladium on carbon catalyst.

The starting materials containing X and Y are hydrogen and Ra and R1 are oxo can be prepared from compounds of formula VII according to Scheme 2.

Compounds of formula (VIII) may be prepared by known etherification of the 4-hydroxy group, for example, with halobenzene in the presence of a base and copper (f ').

The compounds of formula (VIII) thus obtained can be converted to the ketal group (method g ') using alcohol or glycol as is known in the art.

The resulting compound (IX) of the formula the 4-phenoxy group may be removed by reduction in [(h ¹⁾ of the method such as liquid sodium aid of ammonia.

Compounds of formula (X) wherein Z and Z * are C 1-3 alkyl or together form - (CH 2) 2 - or - (CH 2) 3 - are hydrolyzed to an oxo group in an acidic medium such as hydrochloric acid.

Compounds of formula (Ik) wherein one of Ib and Rt is a hydrogen atom and the other is a hydroxy group can be prepared by reacting a compound of formula (Ik) wherein Ib and R4 together form an oxo group and X and Y are hydrogen.

The reduction of the oxo group to the hydroxy group can be carried out in a known manner, for example with sodium borohydride as the reducing agent.

Compounds of formula (Ik) wherein R a and R 4 are hydrogen may be prepared by reduction of compounds of formula (XII) by reduction of the double bonds by conventional hydrogenation, such as palladium on charcoal.

The starting materials of formula (XII) can be obtained by dehydrating the compounds of formula (Ik), wherein one of Ra and R1 is hydroxy. The dehydrogenation is carried out in the usual manner, for example by heating in an acidic medium, for example in hydrochloric acid or in pyridine hydrochloride. In this way, a mixture of 5,6- and 6,7-didehydro compounds is obtained.

In the reactions listed above, when the compounds are obtained in which Re and R4 are different, the products are usually formed as mixtures of 6oc-Ra, 6/3-R4 and 6cc-R4, 63bib and are known in the art, e.g. may be selected separately by chromatography.

If the preparation of any of the starting materials is not described in detail, this method is known or can be carried out by analogy to the methods described in the examples.

The compounds of formula II are known. They can be prepared from Tebain in a known manner.

Further details of the invention are illustrated by the following examples.

Example 1

17-Cyclopropylmethyl-4,5cc-epoxy-3-methoxy-143-ethyl-morphinan-6-one (Compound Ik)

a) 6,14-Endo-etheno-6,7,8,14-tetrahydro-7-thia-8cc-methyl-N-cyclopropylmethyl-nortebain

N-Cyclopropylmethyl nortebaine (46.4 g, 0.132 mol) and S-ethyl ethanethiosulfinate (17.6 g, 0.128 mol) were heated under reflux for 1 hour in toluene (1000 ml) and washed twice with water after cooling. The organic layer was dried over sodium sulfate, concentrated and flash chromatographed on silica gel eluting with methylene chloride / methanol / concentrated ammonia 99.5: 5: 0.1. The title product is isolated as pale yellow crystals.

b) N-Cyclopropylmethyl-5,14-ethane-0-17oc-methyl-18-thianortebain-6-one

40.6 g (0.099 mole) of 1a) is stirred at room temperature with 150 ml of 48% hydrogen bromide to completely dissolve the starting material. As the product begins to crystallize, 60 ml of methanol is added and the mixture is stirred at 0 ° C for 1 hour. The hydrobromide of the title compound is filtered off and washed with a mixture of methanol and ether. M.p. 256-258 ° C.

c) N-Cyclopropylmethyl-4,6C-dihydroxy-14β- (1-mercaptoethyl) -3-methoxymorphinan

Lithium (4.3 g, 0.62 mol) was dissolved in 1.8 L of liquid ammonia at -45 ° C and compound (lb)

Dissolve 22.5 g (56.7 mmol) in 500 mL of tetrahydrofuran and add to the deep blue solution. After 20 minutes at -40 ° C, the solution was treated with solid ammonium chloride, the ammonia was distilled off and the residue was taken up in water and extracted three times with ether. After drying, concentration and flash chromatography with ethyl acetate / hexane (1: 4-1: 2), the organic phases are obtained as a colorless oil.

d) N-Cyclopropylmethyl-14-ethyl-4,6oc-dihydroxy-3-methoxymorphinan

130 g of Raney nickel are added to 1.5 liters of methanol and 13.4 g (33.3 mmol) of a compound prepared according to (le) are dissolved rapidly in 250 ml of methanol with vigorous stirring. After 15 minutes, the reaction mixture was filtered and concentrated. The residue was taken up in methylene chloride, dried over sodium sulfate and evaporated again to give the title compound as a pale red foam.

e) N-Cyclopropylmethyl-140-ethyl-4-hydroxy-3-methoxymorphinan-6-one

Oxalyl chloride (4.35 mL, 50.4 mmol) was added to methylene chloride (500 mL) at -60 ° C and mixed with a solution of dimethyl sulfoxide (7.2 mL, 100.7 mmol) in methylene chloride (85 mL). A solution of 17 g (45.8 mmol) of the compound of (1d) in methylene chloride (100 mL) was added rapidly at -78 ° C and then triethylamine (32 mL, 229 mmol) was added at -60 to -50 ° C and after 15 min. At 78 ° C. The reaction mixture is slowly warmed to room temperature, water is added and the mixture is extracted three times with methylene chloride. After drying, it was evaporated, flash chromatographed with ethyl acetate: hexane (1: 3-1: 1) to give the title compound as a colorless oil from the organic phases.

f) 17-Cyclopropylmethyl-4,5oeo-epoxy-3-methoxy-14f-ethyl-morphinan-6-one

14.6 g (39.6 mmol) of le) is added to 430 ml of glacial acetic acid and 19 g (119 mmol) of bromine is added dropwise in 200 ml of glacial acetic acid while stirring at room temperature for 30 minutes. After 90 minutes, the reaction mixture was concentrated, taken up in 1 L of methylene chloride and poured into 300 ml of 1 N sodium hydroxide solution with stirring. The methylene chloride phase was separated, washed with water, washed with a small amount of 10% pE = 7 tartaric acid, dried over sodium sulfate and evaporated. The residue was dissolved in glacial acetic acid (170 mL) and treated with water (130 mL) and 10% palladium on charcoal (3 g) and hydrogenated at room temperature and 1 atm for 15 hours. The palladium on carbon catalyst was filtered off, the glacial acetic acid was distilled off, the residue was taken up in ice in 2N sodium carbonate and extracted three times with methylene chloride. The organic layer was dried over sodium sulfate, concentrated, flash chromatographed with ethyl acetate: hexane (1: 5) to give the title compound as colorless crystals. Yield: 80-90%.

Example 2

17-Cyclopropylmethyl-4,5-c-epoxy-140-ethyl-3-hydroxymorphinan-6-one (Compound of Formula I)

3.25 g (8.9 mmol) of the compound of Example 1 and 10 g of pyridine hydrochloride are heated at 190 ° C for 3 hours, after being taken up in water and made basic with concentrated ammonia. Extract three times with methylene chloride. Flash chromatography of ethyl acetate: hexane (1: 5) gave the title compound as colorless crystals. Recrystallization from ether / pentane gave an analytically pure product. 157-158 ° C.

Example 3

140-Benzyl-17-cyclopropylmethyl-4,5c-epoxy-3-methoxy-morphinan-6-one (Compound Ik)

a) 6,14-Endo-etheno-6,7,8,14-tetrahydro-7-thia-8oc-phenyl-N-cyclopropylmethyl-nortebain

The procedure of Example 1a is followed. Mp 148-150 ° C.

b, N-Cyclopropylmethyl-3-methoxy-4-hydroxy-140-benzyl-morphinan-6-one g (42.3 mmol) of the compound from 3a and 200 g of Raney nickel in 1.3 L of methanol were heated for 4 hours. under reflux and add another 70 g Raney nickel and heat for 3 hours. The Raney nickel was filtered off and washed well with methanol. The combined methanol layers were evaporated and the residue was taken up in ether, dried over sodium sulfate, evaporated to give a colorless oil. Flash chromatography on silica gel (350 g) eluting with ethyl acetate / hexane (1: 8) gave the title compound as colorless crystals. 122-124 ° C.

c) 140-Benzyl-17-cyclopropylmethyl-4,5c-epoxy-3-methoxy-morphinan-6-one

2.2 g (5.1 mmol) of (3b) are added to 70 ml of glacial acetic acid, mixed with 2.45 g (15.3 mmol) of bromine in 30 ml of glacial acetic acid for 4 hours at room temperature and evaporated. The residue was taken up in methylene chloride, extracted with 100 ml of 1 N sodium 49 hydroxide while cooling with ice, and the organic phase was separated, extracted with water and 10% tartaric acid was added until pH 6 was reached. The organic layer was dried over sodium sulfate, evaporated and mixed with 200 ml of a 1: 1 mixture of water and glacial acetic acid, 4.2 g of sodium acetate and 0.75 g of 10% palladium on charcoal were added and the mixture hydrogenated at 3 atm. The mixture was filtered, evaporated, taken up in methylene chloride and washed with 2N sodium carbonate. The organic phase was dried, evaporated and flash chromatographed with ether / hexane (1: 3) to give the title compound as a colorless oil.

Example 4

14u-Benzyl-17-cyclopropylmethyl-4,5cc-epoxy-3-hydroxymorphinan-6-one hydrochloride (Compound of Formula I)

Prepared in analogy to Example 2, the title compound was converted to the hydrochloride with a mixture of ether, ethanol and hydrochloric acid. M.p. 260 ° C.

Example 5

N-cyclopropylmethyl-143-benzyl-3-methoxy-morphinan-6-one (Compound Ik)

a) N-Cyclopropylmethyl-140-benzyl-3-methoxy-4-phenoxy-rorphinan-6-one

8.9 g (19 mmol) of Example 3b), 5 ml (48 mmol) of bromobenzene and 8 g (58 mmol) of potassium carbonate are dissolved in 100 ml of pyridine, 2 g of Venus are added and the mixture is heated at 140 ° C for 16 hours. C. Ice water was added to the dark reaction mixture and the mixture was extracted three times with ether. The organic layers were dried over sodium sulfate, evaporated to give the title product as a dark oil which was further reacted without purification.

b) N-Cyclopropylmethyl-14-benzyl-3-methoxy-4-phenoxy-6,6-ethylenedioxymorphinan

9.2 g (18 mmol) of the compound from 5a), 30 mL (0.54 mol) of ethylene glycol and 9.4 g (50 mmol) of paratoluenesulfonic acid monohydrate are heated at reflux in 1 L of benzene for 4 hours. The reaction mixture was washed with 2N sodium carbonate, then once with water, dried over sodium sulfate, evaporated to give the title compound as a dark brown oil which was used without further purification in the following reaction.

c) N-Cyclopropylmethyl-14H-benzyl-3-methoxy-6,6-ethylenedioxymorphinan

9.7 g (17.6 mmol) of Example 5b) in toluene (250 mL) was added dropwise to 500 mL of liquid ammonia, prepared at -50 ° C, followed by the addition of 2.5 g (109 mmol) of sodium. After stirring for 4 hours at -55 to -35 ° C, the reaction was quenched with solid ammonium chloride and the ammonia was distilled off. The residue was taken up in water and extracted three times with ether. The ethereal phases were washed twice with 1N sodium hydroxide and once with water, dried over sodium sulfate, evaporated, and flash chromatographed to give the title compound as colorless crystals. ^ΙοΟο Μ = -28.8 ° (CHaOH).

d) N-Cyclopropylmethyl-14a-benzyl-3-methoxymorphinan-6-one

5.8 g (12.6 mmol) of Example 5c) is heated at reflux in 750 ml of 1N hydrochloric acid for 4 hours, then mixed with ice and concentrated ammonia after cooling and extracted three times with ether. After drying and evaporation of the organic phase, it is recrystallized from ether to give the title product, m.p. 165-167 ° C. Yield: 80-90%.

Example 6

N-Cyclopropylmethyl-14H-benzyl-3-hydroxymorphinan-6-one [Compound of Formula I]

The product of Example 5 (1.65 g, 4 mmol) and pyridine hydrochloride (8.6 g) were heated to 180 ° C, and after 1 hour, 8.6 g of pyridine hydrochloride was added and the temperature was further stirred at 180 ° C for 1 hour. on hold. Ice and concentrated ammonia were added to the reaction mixture and extracted three times with methylene chloride. After drying and concentration, it is subjected to flash chromatography (ethyl acetate: hexane = 1: 8) to give the hydrochloride of the title compound from the combined organic phases. M.p. 290 ° C. Hydrogen bromide, m.p. 280 ° C. (x) d ²⁰ (free base) = - 69.6 ° (CH 5 OH). Yield: 20-45%.

Example 7

14a-Benzyl-N-cyclopropylmethyl-6-hydroxy-3-methoxymorphinan and 14-benzyl-N-cyclopropylmethyl-6oc-hydroxy-3-methoxymorphinan (Compounds of formula (Ik))

2.7 mmol of N-cyclopropylmethyl-140-benzyl-3-methoxymorphinan-6-one of Example 5

Dissolve in -511 ml of ethanol and add 0.53 g of sodium borohydride (0.14 mol) and stir at room temperature for 3 hours. The reaction was quenched with water (20 mL) and stirred for a further 30 minutes. The ethanol was distilled off and the residue was extracted 3 times with methylene chloride. After drying and evaporation, the organic phase becomes a colorless oil which is purified by chromatography on a silica gel column. [methylene chloride (methanol) 100 concentrated ammonia 99: 1: 0.1]. The two compounds were isolated as a colorless oil.

Example 8

14u-Benzyl-N-cyclopropylmethyl-3,6u-dihydroxymorphinan [Compound of Formula I]

The preparation was carried out as in Example 2. M.p. 280 DEG C. (hydrochloride).

The following compounds of formula (I) were prepared from the appropriate starting materials as described above. In the table, malonate = hydrogen malonate.

Example number RZ Ra Ri X Y Op (° C) Salt form For example: s. by 9th C2H5 = 0 -SHE- > 280 HCI 1 and 2 10th H = 0 -0- 150-151 base 1 and 2 11th CH3 = 0 Η H > 280 HCI 5 and 6 12th -CHs H U-OH Η H 250 (dec.) HCI 13th CH3 H a-OH Η H 233-235 base 14th para HO-phenyl = 0 Η H > 230 HCI 2, 6 15th cyclohexyl = 0 Η H > 265 HCI 1 and 2

The compounds of formula (I) have a therapeutic effect and are therefore useful as active ingredients in medicine. In particular, the compounds exhibit morphine antagonist or mixed morphine agonist activity and morphine antagonist activity.

Due to the analgesic effect, the compounds can be used to treat pain of various origins.

Compounds of formula (I) that exhibit morphine antagonistic activity, particularly those wherein R 1 is hydrogen or hydroxy, or where R 3 and R 1 together form an oxygen atom, also enhance lutein hormone secretion (LH). Compounds of formula (I) wherein R2 is phenyl have a particularly strong LH-stimulating effect.

Therefore, the compounds can be used as opiate agonists and antagonists, especially those compounds wherein R 1 is hydrogen or hydroxy, or where R 3 and R 4 together form oxygen, as luteinizing hormone stimulators. Luteinizing hormone-stimulating compounds may be used, for example, to improve hypophthalmic LHRH function, such as anovulatory syndrome, amenorrhea, infertility, spontaneous hypogonatropic dysfunction, can be used. Compounds based on opiate antagonist activity may also be used against obesity, drug patients, alcohol intoxication, musculoskeletal disorders, cardiovascular and en65 totoxic shock, mental disorders such as Alzheimer's disease, and modulation of the immune system. The LH-stimulating effect is the most beneficial effect and therefore the compound of Example 6 is the preferred compound.

For opiate antagonists and agonists, analgesic and preferably LH-stimulating effects, the preferred daily dose is 10-100 mg / day, preferably in single doses up to 4 times daily, each dose containing 2-50 mg of active ingredient.

The active compounds of the invention may be administered in the form of the free base or of a pharmaceutically acceptable acid addition salt. The salts are prepared in a known manner and exhibit the same magnitude of activity as the free base form. Thus, the present invention also provides pharmaceutical compositions comprising the active ingredient in free base form or in the form of pharmaceutically acceptable acid addition salts together with a pharmaceutically acceptable carrier or diluent. The compositions are prepared in a known manner. The compositions are administered in a known manner, especially enterally, preferably orally, for example in the form of a tablet or capsule, or parenterally, for example in the form of an injectable solution or suspension.

Preferred compounds are those wherein R 2 is hydrogen, C 1 -C 4 alkyl or phenyl and R 3 and R 4 are as defined above, with the proviso that R 3 and R 1 together form an oxo group in the form of the free base or an acid addition salt.

Claims (7)

PATENT CLAIMS A process for the preparation of a compound of the formula I or an acid addition salt thereof, wherein - X and Y are each hydrogen or taken together to form -O, - R 1 is cyclopropylethyl, - R 1 is hydrogen, C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl, or phenyl optionally substituted with OH, - R3 is hydrogen, R 1 is hydrogen or hydroxy, R3 is in the cc position and R1 is in the β position or Ra is in the β position and Rí is in an oc position, or - Ra and R1 together represent = O and with the proviso that X and Y together cannot be -O- when R2 is hydrogen, R4 is hydroxy at the c position, and R3 is hydrogen or R2, R3 and R1 is not simultaneously hydrogen, characterized in that a compound of formula (Ik) is subjected to ether cleavage, wherein Rt-R1, X and Y are as defined above and optionally an acid addition salt is formed. A process for the preparation of N-30-cyclopropyl-β-ethyl-14β-benzyl-3-hydroxymorphinan-6-one according to claim 1, wherein the appropriate starting materials are reacted. 3. A process for the preparation of a pharmaceutical composition comprising mixing the compounds of formula (I) as claimed in claim 1, wherein the substituents are as defined in claim 1, with a conventional pharmaceutically acceptable carrier and converting it into a pharmaceutical composition. The process according to claim 3, wherein the active ingredient is 17-cyclopropylmethyl-4,5c-epoxy-14-ethyl-3-hydroxymorphinan-6-one in the form of the free base or in the form of an acid addition salt. 5. A process according to claim 3 wherein the active ingredient is 14-benzyl-17-cyclopropylmethyl-4,5-epoxy-3-hydroxymorphinan-6-one in free base form or in acid addition salt form. 6. The process according to claim 3, wherein the active ingredient is 17-cyclopropylmethyl-14-benzyl-3-hydroxymorphinone-6-one in the form of the free base or in the form of an acid addition salt. 7. The process according to claim 3, wherein the active ingredient is 14β-Ββηηζί1-17-cyclopropylmethyl-3,6o-dihydroxymorphine in the form of the free base or in the form of an acid addition salt.