WO1980000566A1

WO1980000566A1 - N-substituted-6-oxamorphinans

Info

Publication number: WO1980000566A1
Application number: PCT/US1978/000079
Authority: WO
Inventors: T Montzka; R Partyka; J Matiskella
Original assignee: Bristol Myers Co
Priority date: 1978-09-12
Filing date: 1978-09-12
Publication date: 1980-04-03
Also published as: DE2857122T1; SG74084G; SE441750B; DE2857122C2; KE3478A; SE8003442L

Abstract

Non-addictive N-substituted 6-oxamorphinans of the formula (FORMULA) having analgetic, narcotic antagonist, antitussive and ADH inhibiting properties and prepared by synthetic chemical procedures.

Description

N-Substituted-6-Oxamorphinans I . Descriptions

TECHNICAL FIELD This invention relates to 6-Oxamorphinans of the formula

wherein R¹ is hydrogen, (lower)alkyl, cyclopropylmethyl, cyclobutylmethyl, allyl, -CH₂C≡C-R³ ,

in which R ³ is hydrogen or methyl, and R² is hydrogen,

(lower) -alkyl, (lower) alkanoyl or nicotinoyl, and pharmaceutically acceptable salts thereof, which possess analgetic, narcotic antagonist, antitussive and/or ADH inhibitory activity, or are useful intermediates in the preparation of such compounds.

BACKGROUND ART U.S. Patent 3,853,889 discloses substituted 8-oxanorphinsns having the formula

wherein R¹ is H, (lower) alkyl, (lower) alkenyl.

n which R⁶ is H or CH₃; R² is H, (lower) alkyl, (lower) alkanoyl, cinnamoyl,

and R³ is H or (lower) alkyl; and pharmaceutically acceptable acid addition salts thereof. The compounds are stated to be analgetic agents, narcotic antagonists or intermediates in the preparation of such agents. U.S. Patent 3,959,290, a continuation-in-part of the above-identified patent, has a substantially identical disclosure.

U.S. Patent 4,016,167 discloses substituted 6,8-dioxamorphinans having the formula

wherein R¹ is H, (lower)alkyl, (lower) alkenyl,

in which R⁶ is H or CH₃; R² is H, (lower) alkyl, (lower)- alkanoyl, cinnamoyl,

R ³ is H or (lower) alkyl; and R⁴ and R⁵ are alike or different and each is H, (lower) alkyl or trifluoromethyl, or when taken together R ⁴ and R⁵ are a carbonyl function or a spiroalkyl group of 3 to 7 carbon atoms; and pharmaceutically acceptable acid addition salts thereof. The compounds are stated to possess analgetic agonist/antagonist activity or to be useful intermediates.

BRIEF SUMMARY OF INVENTION This invention relates to 6-oxamorphinans of the formula

wherein R¹ is hydrogen, (lower) alkyl, cyclopropylmethyl, cyclobutylmethyl, allyl, -CH₂ChC-R³,

in which R ³ is hydrogen or methyl, and R² is hydrogen,

(lower) alkyl, (lower) alkanoyl or nicotinoyl, and pharmaceutically acceptable salts thereof, and to their total synthesis from the known compound, 6-carbomethoxy-8-methoxy-3-methyl-11-oxo-1,2,3,4,5, 6-hexahydro-2, 6-methano-3-benzazocine [5-carbomethoxy-2'-methoxy-2-methyl-9-oxo-6,7-benzomorphan] . Drug abuse by thrill-seeking youth or by people looking for an escape from the realities of everyday life has become more and more commonplace in our present society. One class of widely abused drugs are the narcotic analgetics such as codeine, morphine, meperidine, etc. It is because of the high addictive potential of these agents that much time and money are being expended by the pharmaceutical industry and by governments to try and discover and develop new non-addicting analgetics and/or narcotic antago nists. it was therefore an object of the present invention to find novel low abuse analgetics and/or narcotic antagonists It was a further object of the present invention to develop a method of synthesis that would not be dependent upon opium alkaloids as starting materials. The objects of the present invention have been achieved by the provision of the compounds of Formula XXXV and their total synthesis from 6-carbomethoxy-8-methoxy-3-methyl-11-oxo-1, 2 , 3, 4, 5, 6-hexahydro-2,6-methano-3-benzazocine. In a preferred embodiment of this invention the compoundshave the structure of Formula XXXV in which R¹ is hydrogen,

(lower) alleyl, cyclopropylmethyl or cyclobutylmethyl, and R² is hydrogen or (lower) alkyl, or a pharmaceutically acceptable salt thereof.

In a more preferred embodiment of this invention the compounds have the structure of Formula XXXV in which R¹ is hydrogen, methyl, cyclopropylmethyl or cyclobutylmethyl, and R² is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.

In a still more preferred embodiment of this invention the compounds have the structure of Formula XXXV in which R¹ is cyclopropylmethyl and R² is hydrogen or methyl, or a pharmaceutically acceptable salt thereof. In another still more preferred embodiment of this invention the compounds have the structure of Formula XXXV inwhich R ¹ is cyclobutylmethyl and R² is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.

A most preferred embodiment is the compound of Formula XXXV in which R¹ is cyclopropylmethyl and R² is hydrogen

(and most preferably the (-)-isomer of said compound), or a pharmaceutically acceptable salt thereof.

Another most preferred emodiment is the compound of Formula

XXXV in which R ¹ is cyclobutylmethyl and R² is hydrogen (and most preferably the (-)-isomer of said compound), or a pharmaceutically acceptable salt thereof.

Another most preferred embodiment is the compound of

Formula XXXV in which R ¹ is cyclopropylmethy and R² is methyl (and most preferably the (-)-isomer of said compound) , or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF INVENTION

The compounds of the present invention have the 6-oxamorphinan nucleus which is numbered and represented by the following plane formula.

Although the preceding nucleus and the structure of Formula XXXV above have been drawn in planar form, the 6-oxamorphinans are optically active compounds and may exist as the racemic (±) mixture or as the individual (+) and (-)isomers. The optical isomers of the compounds of Formula XXXV can be graphically illustrated as follows:

For convenience, planar formulae will normally be used throughout the specification and claims. It is to be understood, however, that such planar formulae or the use of the designation "6-oxamorphinan" is meant to include the racemic mixture and the individual (+) and (-) isomers unless the specific text indicates otherwise.

For the purpose of this disclosure and the appended claims, the term (lower) alkyl is defined as a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, e.g. methyl, propyl, isobutyl, etc. The term (lower) alkanoyl is defined as a straight or branched chain alkanoyl radical containing from 2 to 6 carbon atoms, e.g. acetyl, propionyl, isobutyryl, etc. The term pharmaceutically acceptable salt is defined as a salt of a compound of this invention with any of the inorganic or organic acids which are commonly used to produce nontoxic salts of medicinal agents containing amine functions. Illustrative examples would be those salts formed by mixing the compounds of Formula XXX with hydrochloric, sulfuric, nitric, phosphoric, phos phorous, hydrobromic, maleic, malic, ascorbic, citric, tartaric, pamoic, lauric, stearic, palmitic, oleic, myris tic, lauryl sulfuric, naphthalenesulfonic, linoleic or linolenic acid, or the like.

The compounds of this invention are prepared by a total synthesis comprising multiple steps, as outlined in the following chart.

In another aspect, this invention relates to a process for the preparation of a 6-oxamorphinan of the formula

wherein R¹ is (lower) alkyl, cyclopropylmethyl, cyclobutylmethyl, allyl, -CH₂C≡C-R³,

in which R ³ is hydrogen or methyl, R² is hydrogen, (lower) alkyl, (lower) alkanoyl or nicotinoyl, or a pharmaceutically acceptable salt thereof, which process comprises the con secutive steps of

(A) treating a compound of the formula

in which R⁴ is (lower) alkyl with an alkylating or acylatiing agent of the formula

in which W is hydrogen, (lower)alkyl, cyclopropyl, cyclobutyl,

in which R³ is hydrogen or methyl, Z is

and X is chloro, bromo or iodo, in an inert organic solvent in the presence of an appropriate base, to produce a compound having the formula

in which R⁴, Z and W are as defined above; and when Z is a carbonyl moiety

(B) treating compound XXII with a reducing agent selected from lithium aluminum hydride, aluminum hydride, diborane and sodium bis (2-methoxyethoxy) aluminum hydride, in an inert organic solvent, to produce a compound having the formula

in which R⁴ and W are as defined above; and when desired

(C) cleaving the ether function of compound XXII or XXIII with sodium thioethoxide, hydrobromic acid, boron trifluoride or pyridine hydrochloride, in an inert organic solvent, to produce a compound having the formula

in which Z and W are as defined above; and if desired

(D) acylating compound XXIV with an acylating derivative of an acid of the formula

in which R⁵ is (lower) alkyl or nicotinoyl, in an inert organic solvent, to produce a compound of the formula

in which R⁵ , Z and W are as defined above. In starting material XXI for the above process, R⁴ may be (lower) alkyl. In Chart I above the initial starting material (I) contains a methoxy group in the corresponding position and thus produces the compound of Formula VIII, which also contains a methoxy group in the corresponding position (i.e. a compound of Formula XXI in which R⁴ is methyl) , for use as the starting material in the above process. Compounds of Formula XXI in which R⁴ is (lower) alkyl other than methyl may be prepared from Compound VI of Chart I by the following reaction scheme which illustrates the preparation of the corresponding ethoxy compound. The corresponding propoxy, butoxy, etc. compounds may be prepared in a similar manner by utilizing the appropriate allyl halide, e.g. propyl iodide or butyl iodide.

Alternatively, products of Formula XXXV in which R² is (lower) alkoxy other than methoxy may be prepared from the compound of Formula VIII by the following reaction scheme which illustrates the preparation of the compound of Formula XXXV in which R¹ is cyclopropylmethyl and R² is ethoxy.

For the purpose of this disclosure the term "inert organic solvent" means an organic solvent that does not participate in the reaction of the extent that it emerges unchanged from the reaction. Such solvents are methylene chloride, chloroform, dichloroethane, tetrachloromethane, benzene, toluene, ether, ethyl acetate, xylene, tetrahydrofuran, dioxane, dimethylacetamide, dimethylformamide, and the like when an acid halide is employed. When an alkylation reaction is being performed, the inert solvent used may also include (lower) alkanols such as methanol, ethanol, n-propanol, isopropanol and the like.

The term "appropriate base" includes inorganic salts such as NaOH, KOH, K₂CO₃, Na₂CO₃ , NaHCO₃, KHCO₃, and the like and those tertiary amines commonly employed as a proton acceptor in acylation reactions. Such amines are tri (lower) alkylamines, e.g. trimethylamine, triethylamine, and the like, pyridine, dimethylaniline, N-methylpiperidine, and the like. Acceptable inert organic solvents for use in the reduction step (B) in the above process include among others, diethyl ether, dioxane, tetrahydrofuran, benzene, xylene, toluene and the like.

All of the compounds of this invention are novel and valuable for their properties as analgetic and/or narcotic antagonist agents, or as intermediates in the preparation of compounds having these biological properties. Some of these compounds also possess potent antitussive or ADH (anti diuretic hormone) inhibitory activity. It is well known in the narcotic analgesic prior art that it is possible for some compounds to possess both agonist and antagonist properties. An agonist is a compound that imitates a narcotic analgesic and possesses analgetic qualities. An antagonist is a compound that counteracts the analgetic and euphoric properties of a narcotic analgetic. It is possible for a compound to have both properties. A good example of such a compound is cyclazocine.

In vivo testing was conducted on many of the compounds of the present invention. Table 1 reports the number of mgs per kg of body weight which were required to produce an agonist or antagonist effect in 50% of the mice tested (ED₅₀) .

(1) A 50% reduction in number of phenylquinone induced writhings [Siegmund, E. A. et al. , Proc. Soc. Biol. & Med., 95, 729 (1957)].

(2) Antagonism of Straub Tail induced by oxymorphone (2 mg/kg, s.c.) in 50% of the mice. In more detailed tests, a preferred compound of this invention, (-) -17-cyclopropylmethyl-3-hydroxy-6-oxamorphinan [(-)- XI] , was compared with buprenorphine, butorphanol an morphine sulfate for analgetic and antitussive activity, and with buprenorphine, butorphanol and naloxone for antagonist activity.

Table 2 shows that the analgetic potencies of all three antagonist analgetics were approximately equal by the subcutaneous route of administration, whereas the oral potency of (-)-XI was markedly better than butorphanol and equivalent to buprenorphine. The oral/parenteral analgetic potency ratio for (-)-XI was comparable to buprenorphine and approximately ten times better than butorphanol. The parenteral/intraventricular potency ratios indicate that (-)-XI and butorphanol penetrate the blood-brain barrier more readily than either morphine or buprenorphine and to about the same degree as each other.

Table 3 shows that (-)-XI is about twice as potent as butorphanol in blocking the effects of the opioids, oxymorphone and morphine. A comparison of the oral/parenteral potency ratios relative to antagonist activity also shows that the oral/parenterial ratio of (-) -XI is superior to butorphanol and about equal to that of buprenorphine. The very poor oral/parenteral potency ratios for naloxone agree with its relative lack of oral activity in man except at exceptionally high doses.

j

Table 4 shows that (-)-XI is a potent antitussive agent in the unanesthetizεd dog following subcutaneous administrtion. Its ED₅₀ indicates that it is 1.7 times as potent as butorphanol and approximately 7 times as potent as morphine sulfate by the subcutaneous route. Further, the compound appears to have a significantly longer duration of activity than either butorphanol or morphine sulfate.

The oral antitussive ED_50's in the unanesthetized dog for the above three compounds have been determined to be as follows : h

These values indicate that (-)-XI is 8 times as potent as butorphanol and 16 times as potent as morphine sulfate by the oral route.

Buprenorphine and (-) XI were tested for physical dependence liability in mice. In primary physical dependence tests, mice treated for two days with repeated subcutaneous injections of either (-)-XI or buprenorphine did not exhibit withdrawal jumping (abstinence) when challenged with naloxone. Thus, neither compound showed any physical dependence liability in this test model. The compounds were then tested as substitutes for morphine in withdrawn morphine- dependent mice. Compound (-)-XI showed no evidence of substitution for morphine at doses of from 3 to 54 mg/kg sc. However, complete substitutuion for morphine was shown by buprenorphine at doses of 1 mg/kg sc, or less. On the basis of this test model, it is predicted that the physical dependence liability of (-)-XI in man will be nil or of a low order. However, the animal data indicate that buprenorphine will be morphine-like in man.

The following examples are intended to illustrate the invention without limiting it in any way. Example 1

(a) 11-Carbethoxymethylidine-6-carbomethoxy-8-methoxy- 3-methyl-1,2,3,4,5,6-hexahvdro-2 ,6-methano-3-benzazocine (II)

A solution of triethyl phosphonoacetate (9 g; 0.04 m) in benzene (50 ml.) was slowly added to a suspension of NaH (1.92 g of a 50% dispersion in mineral oil; 0.04 m) in benzene (50 ml.) and the mixture was stirred for 45 minutes. A solution of 6-carbomethoxy-8-methoxy-3-methyl-11-oxo-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine [(I), prepared by the procedure of Example 5 of U.S. Patent 4,016,167] (11.6 g; 0.04 m) in benzene (50 ml.) was added and the mixture was stirred in an oil bath at 45°C for 3 hours. The mixture was allowed to cool overnight (18 hours) and then diluted with water (100 ml.). The benezene layer was separated, washed with saturated NaCl solution, dried (MgSO₄) , filtered, and concentrated. The residue was taken up in acetonitrile, washed with n-pentane and concentrated to give an oil (14 g) . GLC analysis indicated th is material to contain about 88% of a mixture of isomers of the title compound. (b) 11α-Carbethoxymethyl-6-carbomethoxy-8-methoxy-3-methyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (III)

The crude material (II) prepared in step (a) (14 g) was taken up in 200 ml. ethanol and hydrogenated at 45 psi using 3.5 g 10% palladium on carbon as catalyst until the theoretical hydrogen uptake was observed (~40 hours). The catalyst was removed by filtration and the filtrate was concentrated to leave crystalline material. This material was recrystallised from ethanol-water to give the pure title compound (8 g) ; GLC analysis indicates > 98% purity; mp 117-118°C.

Anal. Calc'd for C₂₀H₂₇NO₅: C, 66.46; H, 7.53; N, 3.88.

Found: C, 66.17; H, 7.38; N, 3.98.

(c) 11α- (2 ' -Hydroxyethyl)-6-hydroxymethyl-8-methoxy-3-methyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (IV) A solution of the product (III) of step (b) (4.1 g; 0.0114 m) in tetrahydrofuran was added to a suspension of LiAlH₄ (1.7 g) in tetrahydrofuran (100 ml.). This mixture was heated at reflux for 19 hours. After cooling, this mixture was cautiously treated with 5 ml. saturated aqueous Na₂SO₄ solution and warmed with stirring until the solids were white. The solids were removed by filtration and the filtrate was concentrated. The crystalline residue was recrystallized from acetone-methanol (10:1) to give the title compound, mp 161-162°C. Anal. Calc'd for C₁₇H₂₅NO₃ : C, 70.07; H, 8.65; N, 4.81.

Found: C, 70.43; H, 8.76; N, 4.64. (d) 3-Methoxy-17-methyl-6-oxamorphinan (V) Material (IV) prepared in step (c) (11.6 g; 0.04 m) was treated with 100 ml. 10N sulfuric acid and heated 4 hours on a steam bath. This solution was cooled in an ice bath, basified with concentrated ammonium hydroxide and extracted with methylene chloride. The extracts were dried (MgSO₄)_, filtered, and concentrated. GLC on the resulting oil indicated incomplete reaction. The above procedure was repeated to give an oil (9.8 g) which GLC indicated ~ 99% pure. This oil was converted to a hydrochloride salt in 2-propanol, mp 255-260°C (decomp) .

Anal. Calc'd for C₁₇H₂₃NO₂HCl: C, 65.91; H, 7.80; N, 4.53. Found: C, 65.57; H, 7.83; N, 4.39. Example 2

A mixture of the product (V) of Example 1, step (d) (0.002 m) and sodium thioethoxide (0.03 m) (prepared from sodium hydride and ethyl mercaptan) in 30 ml. dimethylformamide was heated at reflux under nitrogen for 3 hours The solvent was removed at reduced pressure. The cooled residue was treated with water, acidified with acetic acid, then basified with potassium carbonate and extracted with methylene chloride. The extracts were dried (Na₂SO₄) , filtered, and concentrated. The residue was crystallized from acetonitrile then converted to a fumarate salt in 1-propanol (3/4 fumaric acid per mole of base as indicated by nmr and analysis) , mp 213-223°C (decomp) . Anal. Calc ' d for C₁₆H₂₁NO₂ · 3/4 (C₄H₄O₄) : C, 65.87; H, 6.99;

N, 4.05.

Found: C, 65.36 ; H, 7.22 ; N, 3.84; H₂O, 0.76. Example 3

A refluxing mixture of the product (V) of Example 1, step (d) (0.029 m obtained from 8.9 g of the hydrochloride salt)and 10g potassium carbonate in toluene (100 ml.) wastreated with a solution of phenyl chloroformate (13.5 g;0.086 m) in toluene (50 ml.). This mixture was heated at reflux for 40 hours. The reaction mixture was cooled and

treated with water. The layers were separated and the organic extract washed with saturated NaCl, dried (MgSO₄) , filtered, and concentrated to give crude 17-carbophenoxy-3-methoxy-6-oxamorphinan (VII) . This material was treated with a mixture of 400 ml. 2-propanol, 100 ml. water and 48g potassium hydroxide and heated at reflux for 40 hours. The 2-propanol was removed at reduced pressure. The residue was diluted with water and extracted with methylene chloride. The extracts were dried (MgSO₄) , filtered, and concentrated to give crude title product which was purified as a hydrogen fumarate salt from 1-propanol (9.8g), mp 231- 233°C.

Anal. Calc'd for C₁₆H₂₁NO₂·C₄H₄O₄: C, 63.98; H, 6.71; N,3.73.

Found: C, 64.19; H, 6.94; N,3.71. Example 4

(a) 17-Cyclopropylmethyl-3-methoxy-6-oxamorphinan (X)

A solution of the free base of the product (VIII) of Example 3 (0.005 m obtained from 1.9 g of the hydrogen fumarate salt) in methylene chloride (30 ml.) and tri ethylamine (1.5 ml.) was treated with a solution of cyclopropylcarbonyl chloride (0.58 g; 0.0055 m) in methylene chloride (5 ml.). After stirring for 2 hours this mixture was treated with dilute hydrochloric acid. The layers were separated and the methylene chloride layer was washed with water. The aqueous layers were extracted with two more portions of methylene chloride. The extracts were combined, dried (MgSO₄) , filtered, and concentrated to give 17-cyclopropylcarbonyl-3-methoxy-6-oxamorphinan (IX) as an oil. This oil dissolved in tetrahydrofuran (20 ml.) was added to a suspension of lithium aluminum hydride (0.57 g) in tetrahydrofuran (20 ml.). This mixture was heated at reflux for 18 hours. To this cooled mixture was cautiously added saturated aqueous sodium sulfate solution (1.8 ml.) and a few drops of dilute sodium hydroxide. The reaction mixture was warmed until the solids were completely white. Solid sodium sulfate was added and the solids were removed by filtration and washed well with ethyl acetate. Concentration of the filtrates gave the title product (1.5 g) which was converted to a hydrochloride salt in ethanol (1.5g), mp 259-264°C.

Anal. Calc'd for C₂₀H₂₇NO₂ HCl: C, 68.66; H, 8.08; N, 4.01.

Found: C, 68.38; H, 8.02; N, 4.02. (b) 17-Cyclopropylmethyl-3-hydroxy-6-oxamorphinan (XI)

The product (X) of step (a) was demethylated to produce the title product using sodium thioethoxide in dimethylform-amide by the general procedure described in Example 2. The resulting title product was converted to a hydrochloride salt in 2-propanol containing a few drops of water, mp 140°

(decomposition of hydrate).

Anal. Calc'd for C₁₉H₂₅NO₂ HCl 1/2 (H₂O) : c, 66.17; H, 7.89;

N, 4.06; H₂O, 2.55.

Found: C, 66.00; H, 7.78; N, 4.01; H₂O, 2.83. Example 5

(a) 17-Cyclobutylmethyl-3-methoxy-6-oxamorphinan (XIII) The general procedure of Example 4, step (a) was repeated, except that the cyclopropylcarbonyl chloride utilized therein was replaced by an equivalent amount of cyclobutylcarbonyl chloride. The title product was purified as the hydrochloride salt from ethanol, with mp 202-206°C.

Anal. Calc'd for C₂₁H₂₉NO₂.HCl: C, 69.31; H, 8.31; N, 3.85.

Found: C, 69.38; H, 8.56; N, 4.02.

(b) 17-Cyclobutylmethyl-3-hydroxy-6-oxamorphinan (XIV) The product (XIII) of step (a) was demethylated to produce the title product using sodium thioethoxide in dimethyl formamide by the general procedure described in Example 2. The title product was purified as a crystalline base from 95% ethanol; mp 197-198°C.

Anal. Calc'd for C₂₀H₂₇NO₂: C, 76.64; H, 8.68; N, 4.47.

Found: C, 76.60; H, 8.51; N, 4.51 Example 6 (-)-3-Methoxy-17-methyl-6-oxamorphinan [(-)-v]

(a) 11-Carbethoxymethylidine-6-carbomethoxy-8-methoxy-3-methyl-1,2,3,4,5, 6-hexahydro-2 ,6-methano-3-benzazocine [II, (-) -isomer series]

The general procedure of Example 1, step (a) was repeated, except that the racemic 6-carbomethoxy-8-methoxy-3-methyl-11-oxo-1,2,3,4,5,6-hexahydro-2, 6-methano-3-benzazozine (I) utilized therein was replaced by an equivalent amount of the corresponding (-) -isomer (prepared according to the procedure of Example 40 of U. S. Patent 4,016,167). The title product was obtained in 82% yield as an oil (~ 93%purity) of a double bond (cis/trans) isomeric mixture which was used directly in the next step without determining rotation.

(b) (-) -11α-Carbethoxymethyl-6-carbomethoxy-8-methoxy-3-methyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine [ (-)- III]

The product of step (a) was treated according to the procedure of Example 1, step (b), to obtain the title compound,mp 107-108ºc,

(c 1.0, methanol). Anal, calc'd for C₂₀H₂₇NO₅: C, 66.46; H, 7.53; N, 3.88.

Found: C, 65.94; H, 7.42; N, 3.71; H₂O, 0.53. (c) (-) -11α- (2 ' -Hydroxvethyl) -6-hydroxymethyl-8-methoxy- 3-methyl-1,2 ,3,4,5,6-hexahydro-2 , 6-methano-3-benzazocine

[(-) -IV]

The product [(-)-lll] of step (b) was treated according to the procedure of Example 1, step (c) , to obtain the title product in 87% yield, mp 185-188°C,

(c 1.15, chloroform) . Anal. calc'd for C₁₇H₂₅NO₃: C, 70.07; H, 8.65; N, 4.81. Found: C, 70.20; H, 8.86; N, 4.63. (d) (-) -3-Methoxy-17-methyl-6-oxamorphinan [ (-) -v] The product [(-)-IV]of step (c) was treated according to the procedure of Example 1, step (d) , [only four hours of heating was required] to give the title product in 89% yield. It was isolated as a hydrogen maleate salt from ethyl acetate-acetone, mp 156-159°C,

102.3° (c 1.04, methanol) .

Anal. Calc'd for C₁₇H₂₃NO₂·C₄H₄O₄: C, 64.76; H, 6.99; N,3.60.

Found: C, 64.39; H, 6.91; N,3.46. Example 7

The general procedure of Example 3 was repeated except that the 3-methoxy-17-methyl-6-oxamorphinan (V) utilized herein was replaced by an equimolar amount of the corresponding (-) -isomer [prepared in Example 6, above], to produce the title compound. It was isolated as (+) -hydrogen tartrate from methanol mp 252-262°C (decomp),

Anal, calc'd for C₁₆H₂₁NO₂·C₄H₆O₆ ^: C, 64.65; H, 7.23; N,4.19.

Found: C, 63.69; H, 6.96; N,4.03; H₂O, 1.07. Example 8

(a) (-)-17-Cyclopropylmethyl-3-methoxy-6-oxamorphinan [(-)- X]

The general procedure of Example 4, step (a) was repeated except that the 3-methoxy-6-oxamorphinan (VIII) utilized therein was replaced by an equimolar amount of the corresponding (-) isomer [prepared in Example 7 above] , to produce the title compound. It was isolated as a crystalline (-)- hydrogen tartrate hemimethanolate from methanol, mp 190- 192°C, (c 1.02, water).

Anal. Calc'd for C₂₀H₂₇NO₂·C₄H₆O₆·1/2 (CH₄O) : C, 61.36;

H, 7.36; N,2.92. Found: C, 61.03;

H, 7.39;

N, 2.77.

(b) (-)-17-Cyclopropylmethyl-3-hydroxy-6-oxamorphinan [(-)- XI]

The product [ (-) -X] of step (a) was demethylated by the general procedure of Example 2 to produce the title product.

It was purified as a crystalline (-) -tartrate hemihydrate from methanol water, mp 243-249°C (decomp), (c 1.13, water).

Anal, calc d for (C₁₉H₂₅NO₂)₂·C₄H₆O₆·1/2 (H₂O): C, 66.55; H, 7.58; N, 3.70; H₂O, 1.17.

Found :C, 66.47, H, 7.55; N, 3.64; H₂O, 1.26. Example 9

Equimolar quantities of 17-cyclopropylmethyl-3-hydroxy-6- oxamorphinan (XI) , acetyl chloride and pyridine are mixed together in dry methylene chloride and the resultant mixture is heated at reflux for several hours to produce the title compound Example 10

Equimolar amounts of 17-cyclopropylmethyl-3-hydroxy-6- oxamorphinan (XI) , nicotinoyl chloride hydrochloride and pyridine are mixed together in dry methylene chloride and the mixture is heated at reflux for 3 hours to produce the title compound. Example 11

(a) 17-Allyl-3-methoxy-6-oxamorphinan (XVII)

A mixture of 3-methoxy-6-oxamorphinan (VIII) (0.005m), allyl bromide (0.006 m) and potassium carbonate (2 g) in 20 ml acetonitrile is heated at reflux for 18 hours. The mixture is filtered and the filtrate concentrated. The residue is treated with water and extracted with ethyl acetate. The extracts are dried (Na₂SO₄) and concentrated to give the title compound.

(b) 17-Allyl-3-hydroxy-6-oxamorphinan (XVIII)

The product (XVII) of step (a) is demethylated by the general procedure of Example 2 to produce the title product. Example 12 17-(3' ,3'-Dimethylallyl)-3-hydroxy-6-oxamorphinan (XX)

The general procedure of Example 11, Steps (a) and (b) , is repeated, except that the allyl bromide utilized therein is replaced by an equimolar amount of 3,3-dimethylallyl bromide, and the title compound is thereby produced. Example 13 3-Ethoxy-6-oxamorphinan (XXX)

(a) 3-Acetoxy-17-methyl-6-oxamorphinan (XXVI)

A mixture of the product (VI) of Example 3 (free base) (0.01 m) and 20 ml acetic anhydride is heated at 100°C for 2 hours. The excess acetic anhydride is removed at reduced pressure. The residue is treated with dilute sodium carbonate and extracted with methylene chloride to produce the title compound.

(b) 3-Acetoxy-17-carbophenoxy-6-oxamorphinan (XXVII) A mixture of XXVI (0.01 m) from Step (a) above, 4 g potassium carbonate and phenylchloroformate (0.03 m) in 50 ml toluene is heated at reflux for 24 hours. The cooled reaction mixture is treated with water. The toluene layer is separated, dried (MgSO₄) , filtered and concentrated to give the title product as a crude oil used directly in the next reaction.

(c) 17-Carbophenoxy-3-hydroxy-6-oxamorphinan (XXVIII) A cooled solution of XXVII from Step (b) above (0.01 m) in 25 ml 2-propanol (~10° C) is treated with a solution of potassium hydroxide (3 g) in 25 ml water and is stirred under nitrogen at 10°C for 2 hours. The reaction mixture is acidified with phosphoric acid and the 2-propanol removed at reduced pressure. The aqueous mixture is extracted with methylene chloride. The extracts are dried (MgSO₄) and concentrated to produce the title compound.

(d) 17-Carbophenoxy-3-ethoxy-6-oxamorphinan (XXIX)

A mixture of XXVIII (0.005 m) from Step (c) above, ethyl iodide (0.01 m) and potassium carbonate (2 g) in 20 ml acetonitrile is heated at reflux for 18 hours. The mixture is filtered and the filtrate concentrated. The residue is treated with water and extracted with methylene chloride. The extracts are dried (MgSO₄) , filtered and concentrated to give the title compound. (e) 3-Ethoxy-6-oxamorphinan (XXX)

A mixture of XXIX (0.005 m) from Step (d) above, 6 g potassium hydroxide, 75 ml 2-propanol and 20 ml water is heated at reflux for 40 hours. The 2-propanol is removed at reduced pressure. The resultant mixture is extracted with methylene chloride. The extracts are dried (Na₂SO₄)_, filtered and concentrated to produce the title compound.

Example 14 17-Cyclopropylmethyl-3-ethoxy-6-oxamorphinan (XXXIV)

(a) 3-Hydroxy-6-oxamorphinan (XXXI) 3-Methoxy-6-oxamorphinan (VIII) is demethylated using sodium thioethoxide in dimethylformamide by the general procedure of Example 2 to produce the title product.

(b) 17-Cyclopropylcarbonyl-3-hydroxy-6-oxamorphinan (XXXII) The product XXXI of Step (a) (0.005 m) and triethylamine (1.5 ml) in methylene chloride (30 ml) is treated with a solution of cyclopropylcarbonyl chloride (0.0055 m) in methylene chloride (5 ml) . After stirring for 2 hours the mixture is treated with dilute hydrochloric acid. The layers are separated, the methylene chloride layer is washed with water, and the aqueous layers are extracted with two more portions of methylene chloride. The combined methylene chloride layers are dried (MgSO₄) , filtered and concentrated to give the title product.

(c) 17-Cyclopropylcarbonyl-3-ethoxy-6-oxamorphinan (XXXIII) A mixture of the product of Step (b) (XXXII) (0.005 m) , ethyl iodide (0.006 m) and potassium carbonate (2 g) in 20 ml of acetonitrile is heated at reflux for 18 hours. The mixture is then filtered and the filtrate is concentra ted. The residue is treated with water and extracted with ethyl acetate. The extracts are dried (Na₂SO₄) and concentrated to give the title product. (d) 17-Cvclopropylmethyl-3-ethoxy-6-oxamorphinan (XXXIV) The product of Step (c) (XXXIII) (0.005 m) in tetrahydrofuran (20 ml) is added to a suspension of lithium aluminum hydride (0.57 g) in tetrahydrofuran (20 ml), and the mixture is heated at reflux for 18 hours. The mixture is then cooled and saturated sodium sulfate solution (1.8 ml) and a few drops of dilute sodium hydroxide are cautiously added. The mixture is warmed until the solids are completely white. Solid sodium sulfate is added, the solids are removed by filtration and washed well with ethyl acetate. Concentration of the combined filtrate and washes gives the title product.

STATEMENT OF INDUSTRIAL APPLICATION The N-substituted 6-oxamorphinan compounds of the present invention are low abuse analgetics and narcotic analgetics. They are prepared by total synthesis from 6-carbomethoxy-8-methoxy-3-methyl-11-oxo-1,2, 3,4, 5-hexahydro-2 , 6-methano-3- benzazocine and are not derived from opium alkaloids.

Claims

II . Claims

1. A 6-oxamorphinan of the formula

wherein R¹ is hydrogen, (lower) alkyl, cyclopropylmethyl, cyclobutylmethyl, allyl, -CH₂CΞC-R³ ,

in which R³ is hydrogen or methyl, and R² is hydrogen,

(lower) alkyl, (lower) alkanoyl or nicWtinoyl, or a pharmaceutically acceptable salt thereof.

2. A 6-oxamorphinan of Claim 1 in which R¹ is hydrogen,

(lower) alkyl, cyclopropylmethyl or cyclobutylmethyl, and R² is hydrogen or (lower) alkyl, or a pharmaceutically acceptable salt thereof.

3. A 6-oxamorphinan according to any of Claims 1 and 2, in which R¹ is hydrogen, methyl, cyclopropylmethyl or cyclobutylmethyl, and R² is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.

4. The compound of any of Claims 1-3, in which R¹ is cyclobutylmethyl and R² is hydrogen, or a pharmaceutically acceptable salt thereof.

5. The (-) -isomer of the compound of Claim 4, or a pharmaceutically acceptable salt thereof.

6. The compound of any of Claims 1 -3, in which R¹ is cyclopropylmethyl and R² is methyl, or a pharmaceutically acceptable salt thereof.

7. The (-) -isomer of the compound of Claim 6, or a pharmaceutically acceptable salt thereof.

8. A process for the preparation of a 6-oxamorphinan according to any of Claim 1-7, which process comprises the consecutive steps of

(A) treating a compound of the formula

in which R⁴ is (lower) alkyl with an alkylating or acylating agent of the formula

X - (z) - w in which W is hydrogen, (lower) alkyl, cyclopropyl, cyclobutyl,

in which R³ is hydrogen or methyl, Z is

in which R⁴, Z and W are as defined above; and when Z is a carbonyl moiety

in which R⁴ and W are as defined above; and when desired (C) cleaving the ether function of compound XXII or XXIII with sodium thioethoxide, hydrobromic acid, boron trifluoride or pyridine hydrochloride, in an inert organic solvent, to produce a compound having the formula

in which Z and W are as defined above; and if desired

in which R⁵, Z and W are as defined above, and, if desired, converting by methods known per se the product into a pharmaceutically acceptable salt.