WO1980000566A1 - N-substituted-6-oxamorphinans - Google Patents

N-substituted-6-oxamorphinans Download PDF

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Publication number
WO1980000566A1
WO1980000566A1 PCT/US1978/000079 US7800079W WO8000566A1 WO 1980000566 A1 WO1980000566 A1 WO 1980000566A1 US 7800079 W US7800079 W US 7800079W WO 8000566 A1 WO8000566 A1 WO 8000566A1
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WO
WIPO (PCT)
Prior art keywords
compound
hydrogen
formula
alkyl
pharmaceutically acceptable
Prior art date
Application number
PCT/US1978/000079
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English (en)
French (fr)
Inventor
T Montzka
R Partyka
J Matiskella
Original Assignee
Bristol Myers Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol Myers Co filed Critical Bristol Myers Co
Priority to DE782857122T priority Critical patent/DE2857122T1/de
Priority to PCT/US1978/000079 priority patent/WO1980000566A1/en
Publication of WO1980000566A1 publication Critical patent/WO1980000566A1/en
Priority to SE8003442A priority patent/SE441750B/sv
Priority to SG740/84A priority patent/SG74084G/en
Priority to KE3478A priority patent/KE3478A/xx

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/26—Benzomorphans

Definitions

  • R 1 is hydrogen, (lower)alkyl, cyclopropylmethyl, cyclobutylmethyl, allyl, -CH 2 C ⁇ C-R 3 ,
  • R 3 is hydrogen or methyl, and R 2 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.
  • R 1 is H, (lower) alkyl, (lower) alkenyl.
  • n which R 6 is H or CH 3 ;
  • R 2 is H, (lower) alkyl, (lower) alkanoyl, cinnamoyl,
  • R 3 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.
  • R 1 is H, (lower)alkyl, (lower) alkenyl,
  • R 6 is H or CH 3 ;
  • R 2 is H, (lower) alkyl, (lower)- alkanoyl, cinnamoyl,
  • R 3 is H or (lower) alkyl; and R 4 and R 5 are alike or different and each is H, (lower) alkyl or trifluoromethyl, or when taken together R 4 and R 5 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.
  • R 1 is hydrogen, (lower) alkyl, cyclopropylmethyl, cyclobutylmethyl, allyl, -CH 2 ChC-R 3 ,
  • R 3 is hydrogen or methyl, and R 2 is hydrogen
  • 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.
  • the compounds have the structure of Formula XXXV in which R 1 is hydrogen,
  • R 2 is hydrogen or (lower) alkyl, or a pharmaceutically acceptable salt thereof.
  • the compounds have the structure of Formula XXXV in which R 1 is hydrogen, methyl, cyclopropylmethyl or cyclobutylmethyl, and R 2 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
  • the compounds have the structure of Formula XXXV in which R 1 is cyclopropylmethyl and R 2 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
  • the compounds have the structure of Formula XXXV inwhich R 1 is cyclobutylmethyl and R 2 is hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
  • a most preferred embodiment is the compound of Formula XXXV in which R 1 is cyclopropylmethyl and R 2 is hydrogen
  • the compounds of the present invention have the 6-oxamorphinan nucleus which is numbered and represented by the following plane formula.
  • 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:
  • 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.
  • (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.
  • 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.
  • this invention relates to a process for the preparation of a 6-oxamorphinan of the formula
  • R 1 is (lower) alkyl, cyclopropylmethyl, cyclobutylmethyl, allyl, -CH 2 C ⁇ C-R 3 ,
  • R 3 is hydrogen or methyl
  • R 2 is hydrogen, (lower) alkyl, (lower) alkanoyl or nicotinoyl, or a pharmaceutically acceptable salt thereof, which process comprises the con secutive steps of
  • R 4 is (lower) alkyl with an alkylating or acylatiing agent of the formula in which W is hydrogen, (lower)alkyl, cyclopropyl, cyclobutyl,
  • R 3 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
  • R 4 , Z and W are as defined above; and when Z is a carbonyl moiety
  • R 4 may be (lower) alkyl.
  • 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 R 4 is methyl) , for use as the starting material in the above process.
  • Compounds of Formula XXI in which R 4 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.
  • products of Formula XXXV in which R 2 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 R 1 is cyclopropylmethyl and R 2 is ethoxy.
  • inert organic solvent means an organic solvent that does not participate in the reaction of the extent that it emerges unchanged from the reaction.
  • 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.
  • the inert solvent used may also include (lower) alkanols such as methanol, ethanol, n-propanol, isopropanol and the like.
  • appropriate base includes inorganic salts such as NaOH, KOH, K 2 CO 3 , Na 2 CO 3 , NaHCO 3 , KHCO 3 , 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.
  • 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 (ED 50 ) .
  • 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.
  • (-)-XI is a potent antitussive agent in the unanesthetiz ⁇ d dog following subcutaneous administrtion. Its ED 50 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.
  • mice Buprenorphine and (-) XI were tested for physical dependence liability in mice.
  • mice treated for two days with repeated subcutaneous injections of either (-)-XI or buprenorphine did not exhibit withdrawal jumping (abstinence) when challenged with naloxone.
  • 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.
  • it is predicted that the physical dependence liability of (-)-XI in man will be nil or of a low order.
  • the animal data indicate that buprenorphine will be morphine-like in man.
  • Example 1 The following examples are intended to illustrate the invention without limiting it in any way.
  • Example 1 The following examples are intended to illustrate the invention without limiting it in any way.
  • 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 (MgSO 4 ) , 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) 11 ⁇ -Carbethoxymethyl-6-carbomethoxy-8-methoxy-3-methyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (III)
  • step (a) 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.
  • step (d) 0.002 m
  • sodium thioethoxide (0.03 m) prepared from sodium hydride and ethyl mercaptan
  • 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 (Na 2 SO 4 ) , filtered, and concentrated.
  • step (a) 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°
  • step (b) 17-Cyclobutylmethyl-3-hydroxy-6-oxamorphinan
  • step (a) 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.
  • step (a) 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.
  • 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).
  • step (b) 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,
  • step (c) (c 1.15, chloroform) .
  • Anal. calc'd for C 17 H 25 NO 3 C, 70.07; H, 8.65; N, 4.81. Found: C, 70.20; H, 8.86; N, 4.63.
  • step (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) .
  • Example 3 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),
  • step (a) 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 C 20 H 27 NO 2 ⁇ C 4 H 6 O 6 ⁇ 1/2 (CH 4 O) : C, 61.36;
  • step (a) The product [ (-) -X] of step (a) was demethylated by the general procedure of Example 2 to produce the title product.
  • step (a) 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)
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/US1978/000079 1978-09-12 1978-09-12 N-substituted-6-oxamorphinans WO1980000566A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
DE782857122T DE2857122T1 (de) 1978-09-12 1978-09-12 N-substituted-6-oxamorphinans
PCT/US1978/000079 WO1980000566A1 (en) 1978-09-12 1978-09-12 N-substituted-6-oxamorphinans
SE8003442A SE441750B (sv) 1978-09-12 1980-05-07 N-substituerade 6-oxamorfinaner
SG740/84A SG74084G (en) 1978-09-12 1984-10-22 N-substituted-6-oxamorphinans
KE3478A KE3478A (en) 1978-09-12 1984-10-24 N-substituted-6-oxamorphinans

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/US1978/000079 WO1980000566A1 (en) 1978-09-12 1978-09-12 N-substituted-6-oxamorphinans
WOUS78/00079 1978-09-12

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KE (1) KE3478A (enrdf_load_html_response)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114292889A (zh) * 2022-03-14 2022-04-08 河南省医药科学研究院 一种紫穗槐花多糖的制备方法及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3853889A (en) * 1973-07-18 1974-12-10 Bristol Myers Co 3,14-substituted-8-oxamorphinans
US4016167A (en) * 1975-10-28 1977-04-05 Bristol-Myers Company N-Substituted-6,8-dioxamorphinans

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3853889A (en) * 1973-07-18 1974-12-10 Bristol Myers Co 3,14-substituted-8-oxamorphinans
US4016167A (en) * 1975-10-28 1977-04-05 Bristol-Myers Company N-Substituted-6,8-dioxamorphinans

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114292889A (zh) * 2022-03-14 2022-04-08 河南省医药科学研究院 一种紫穗槐花多糖的制备方法及其应用
CN114292889B (zh) * 2022-03-14 2023-11-21 河南省医药科学研究院 一种紫穗槐花多糖的制备方法及其应用

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Publication number Publication date
SE441750B (sv) 1985-11-04
SG74084G (en) 1985-04-26
SE8003442L (sv) 1980-05-07
DE2857122C2 (enrdf_load_html_response) 1991-05-08
DE2857122T1 (de) 1980-12-04
KE3478A (en) 1984-11-16

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