US3819635A - 14-hydroxymorphinan derivatives - Google Patents

14-hydroxymorphinan derivatives Download PDF

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US3819635A
US3819635A US00217633A US21763372A US3819635A US 3819635 A US3819635 A US 3819635A US 00217633 A US00217633 A US 00217633A US 21763372 A US21763372 A US 21763372A US 3819635 A US3819635 A US 3819635A
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compound
ether
compounds
formula
solution
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I Pachter
B Belleau
I Monkovic
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Bristol Myers Co
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Bristol Myers Co
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Priority to BE788478D priority Critical patent/BE788478A/xx
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Priority to US00217633A priority patent/US3819635A/en
Priority to PH21191A priority patent/PH14440A/en
Priority to CA150,036A priority patent/CA999578A/en
Priority to AU46228/72A priority patent/AU470102B2/en
Priority to SE7211522A priority patent/SE398877B/xx
Priority to DK440172AA priority patent/DK141624B/da
Priority to IE1213/72A priority patent/IE36687B1/xx
Priority to IE103/76A priority patent/IE36688B1/xx
Priority to DE2243961A priority patent/DE2243961A1/de
Priority to CH1315472A priority patent/CH590845A5/xx
Priority to DE2265255A priority patent/DE2265255C2/de
Priority to NL7212176.A priority patent/NL162072C/xx
Priority to GB4161972A priority patent/GB1412129A/en
Priority to JP8916172A priority patent/JPS5310596B2/ja
Priority to YU227772A priority patent/YU45099B/sh
Priority to CY980A priority patent/CY980A/xx
Priority to GB1057175A priority patent/GB1412130A/en
Priority to DE2265256A priority patent/DE2265256C2/de
Priority to FR7231816A priority patent/FR2154481B1/fr
Priority to DD165557A priority patent/DD100255A5/xx
Priority to PH13920A priority patent/PH14344A/en
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Priority to SE7506292A priority patent/SE403286B/xx
Priority to DK329977A priority patent/DK142620B/da
Priority to KE2911A priority patent/KE2911A/xx
Priority to HK26/79A priority patent/HK2679A/xx
Priority to MY27/79A priority patent/MY7900027A/xx
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • 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
    • C07D221/28—Morphinans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

Definitions

  • R represents a hydrogen atom or a (lower)alkyl group (e.g., methyl, ethyl, propyl)
  • R represents a hydrogen atom, an aryloXy group (e.g., phenyloxy, naphthyloxy) or a substituted phenyloxy, substituted naphthyloxy wherein the substituent is (lower)alkyl (e.g., methyl, ethyl, propyl), (lower)alkoxy, (e.g., methoxy, ethoxy, propoxy), nitro or amino
  • X represents a hydrogen atom or a hydroxyl group and, in Formula I, one or two double bond(s) exist(s) in the C ring.
  • British Pat. No. 1,028,407 discloses compounds having the generic formula wherein R represents an alkyl group having not more than five carbon atoms (e.g., methyl, ethyl, propyl), R represents a hydrogen atom or an aryloxy group (e.g., phenyloxy or naphthyloxy), R" represents a methylene group, a carbonyl group or a ketalated carbonyl .group (e.g., ethylenedioxymethylene or diethoxymethylene), X represents a hydrogen atom or hydroxyl group and Y represents an alkyl group having not more than five carbon atoms (e.g., methyl, ethyl or propyl), an aryl group (e.g., phenyl or naphthyl) or an aralkyl group in which the alkyl moiety has not more than five carbon atoms (e.g.,
  • R is H, (lower)acyl, trichloroacetyl or cinnamoyl; or a pharmaceutically acceptable acid addition salt thereof are analgetic agents, narcoatic antagonists or intermediates in the preparation of such agents.
  • narcotic analgetics such as codiene, 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 nareoatic antagonists.
  • the compounds of the instant invention have the basic morphinan nucleus which is numbered and represented by the following plane formula:
  • the isomorphinans disclosed and claimed herein are primarily useful as intermediates in the preparation of the biologically potent analgetic and/or narcotic antagonist agent of the present invention.
  • isomorphinan and morphinan compounds of the present invention can exist as two optical isomers, the levorotatory and dextrorotatory isomers.
  • the optical isomers can be graphically illustrated as:
  • the present invention embodies all of the isomorphinan and morphinan isomers including the optical isomers in their resolved form. Those isomers which do not possess the desired biological activity can be transformed chemically into the desired product.
  • optical isomers can be separated and isolated by fractional crystallization of the diastereoisomeric salts formed, for instance, with dor l-tartaric acid or D-(+)- u-bromocamphor sulfonic acid.
  • the levorotatory isomers of the compounds of the present invention are the most preferred embodiments.
  • (lower) alkyl is defined as an alkyl radical containing 1 to 6 carbon atoms.
  • (Lower)alkenyl is defined as a hydrocarbon radical of 3 to 7 carbons containing one double bond.
  • (lower)acyl is an acyl radical of 2 to 6 carbon atoms, e.g., acetyl, propionyl, isobutyryl, etc.
  • pharmaceutically acceptable acid addition salt is defined to include all those inorganic and organic acid salts of the compounds of the instant invention, which salts 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 I with hydrochloric, sulfuric, nitric, phosphoric, phosphorous, hydrobromic, maleic, malic, ascorbic, citric or tartaric, pamoic, lauric, stearic, palmitic, Oleic, myristic, lauryl sulfuric, naphthalinesulfonic, linoleic or linolenic acid, and the like.
  • the compounds of the instant invention are prepared by a total synthesis comprising at least 12 steps. Surprisingly, the synthesis is eificient and appears commercially feasible. The process is outlined in charts I, II, III and IV.
  • CHART I CH CE 0 3 1e 3 ii I II k can g E 1 3 110 xam e .6 H0 N P. v 2
  • a preferred embodiment of the present invention is the compounds having the formula XXXVI! and C3' 7 alkenyl in which R is H or CH R is selected from the group comprising II N onto-c111 -omo-, and l! 0,
  • R is selected from the group comprising H, (lower)acyl, trichloroacetyl and cinnamoyl; or a pharmaceutically acceptable acid addition salt thereof.
  • R is selected from the group comprising H, (lower) acyl, trichloroacetyl and cinnamoyl; or a pharmaceutically acceptable acid addition salt thereof.
  • R is H or CH R is and R is H, (lower)acyl, trichloroacetyl or cinnamoyl; or a pharmaceutically acceptable acid addition salt thereof.
  • Another more preferred embodiment is the compounds of formula XXXXI where R is R is 0 l H, CH3. or CH;
  • R is H; or a pharmaceutically acceptable acid addition salt thereof.
  • a preferred embodiment of the present invention is the compounds having the formula 9 wherein R is H or (lower)alkyl, R is H,
  • a more preferred embodiment is the compound of formula XXXXIV wherein R' is (3H or the oxalate salt thereof.
  • step (A) R' is methyl, the inert organic solvent is methylene chloride, dichloroethane or a (lower)alkanol, the organic tertiary amine is pyridine or triethylamine and the reaction is conducted at about 15 C. to about reflux temperature.
  • step (A) the organic solvent is methanol, ethanol, n-propanol or isopropanol, the tertiary amine is triethylamine and the reaction is conducted at about reflux temperature for about 5 to about 20 hours.
  • Another preferred embodiment of the present invention is the process for the preparation of compounds having the formula in which R is (lower)alkyl, which process comprises the consecutive steps of (A) Dehydrating the compound having the formula 10 N-CO R VIIIa in which R and R are (lower)alkyl, with a dehydrating agent to produce a compound having the formula n-co a in which R and R are as above; and
  • a more preferred embodiment is the process for the preparation of compounds of formula XXXXIIa wherein in step (A) the dehydrating agent is selected from the group comprising POCl P 0 thionyl chloride or KHSO in a tertiary amine selected from the group comprising pyridine, n-methylpiperidine, triethylamine and N,N-di-methylaniline, in the temperature range of about 15 C. to about 40 C., R is CH and in step (B) the hydroxide is sodium or potassium hydroxide.
  • the dehydrating agent is selected from the group comprising POCl P 0 thionyl chloride or KHSO in a tertiary amine selected from the group comprising pyridine, n-methylpiperidine, triethylamine and N,N-di-methylaniline, in the temperature range of about 15 C. to about 40 C.
  • R is CH
  • step (B) the hydroxide is sodium or potassium hydroxide.
  • a most preferred embodiment is the process for the preparation of compound of formula XXXXIIa wherein in step (A) R is methyl, the dehydrating agent is P001 the tertairy amine is pyridine, the temperature is about 20-25 C.; and in step (B) the hydroxide is potassium hydroxide.
  • Another preferred embodiment of the present invention is the process for the preparation of compounds having the formula XXXXIIIa which process comprises the consecutive steps of (A) Treating the compound having the formula N' COCF in which R is as above;
  • R is (lower)alkyl
  • a more preferred embodiment is the process of preparing compounds of formula XXXXIIIa wherein in step (A) the acylating agent is trifluoroacetic anhydride, the inert organic solvent is ether, dioxane or tetrahydrofuran; in step (B) the perbenzoic acid is m-chloroperbenzoic acid which is employed in about a 10% molar excess, in methylene chloride or dichloroethane at about room temperature; in step (C) the (lower)alkanol is methanol, ethanol, n-propanol or isopropanol at about reflux temperature for about 3 to 10 minutes; in step (0) the organic solvent is ether, dioxane or tetrahydrofuran, at about reflux temperatures for 10 to 60 minutes; and in step (E) at about 170200 C. for about 1 hour.
  • the acylating agent is trifluoroacetic anhydride
  • the inert organic solvent is ether,
  • a most preferred embodiment is the process of preparing compounds of formula XXXXIIIa wherein in step (A) the acylating agent is trifluoroacetic anhydride, the solvent is dry ether; in step (B) m-chloroperbenzoic acid is employed in 10% excess in methylene chloride at about room temperature; in step (C) the alkanol is absolute ethanol at reflux tempenature for 5 minutes; in step (D) the solvent is tetrahydrofuran at about reflux temperature for about 15 minutes, and in step (E) the temperature is about 185-195 C. for about 1 hour.
  • Another preferred embodiment is the process for the preparation of compounds having the formula XXIIIa.
  • R is (lower)alkyl
  • step (C) the acylating agent is trifiuoroacetic anhydride, the inert organic solvent is ether, dioxane or tetrahydrofuran; in step (D) the perbenzoic acid is m-chloroperbenzoie acid which is employed in about a 10% molar excess, in methylene chloride or dichloroethane, at about room temperature; in step (E) the (lower)alkanol is methanol, ethanol, n-propanol or isopropanol at about reflux temperature for about 3 to 10 minutes; in step (F) the organic solvent is ether, dioxane or tetrahydrofuran, at about reflux tem- 15 peratures, for 10 to 60 minutes; and in step (G) the temperature is about l70-200 C. for about 1 hour.
  • a most preferred embodiment of the present invention is the process for preparing compounds of formula XXIIIa wherein in step (A) R is methyl, the dehydrating agent is PCl the tertiary amine is pyridine and the temperature is about 20-25 C.; in step (B) the hydroxide is potassium hydroxide; in step (C) the acylating agent is trifluoroacetic anhydride, the solvent is dry ether; in step (D) rn-chloroperbenzoic acid is employed in excess in methylene chloride at about room temperature; in step (E) the alkanol is absolute ethanol at reflux temperature for 5 minutes; in step (F) the solvent is tetrahydrofuran at about reflux temperature for about minutes; and in step (G) the temperature is about 185-195 C. for about 1 hour.
  • All of the compounds of the preferred embodiments herein are novel and valuable for this properties as analgesic and/or narcotic antagonist agents, or as intermediates in the preparation of compounds having these biological activities.
  • the compounds having the formula XXXXI are those which possess the most desirable properties; i.e., analgesic and/or narcotic antagonist properties.
  • Some of the isomorphinan compounds of formula XXXX also have some biological activity, i.e., antitussive, mild analgetic, etc., activity, but their primary usefulness is in the preparation of compounds having the formula XXXXI
  • 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.
  • haloperidol 4- [4- (p-chlorophenyl -4-hydroxypiperidino] 4-fluorobutyrophenone (Merck Index, 8th edition, p. 515) has found some experimental use in the alleviation of narcotic addiction withdrawal symptoms. It is therefore a preferred embodiment of the present invention to combine haloperidol with the narcotic antagonists of the instant invention, particularly l-3,14-dihydroxy-6-cyclopropylmethylmorphinan, to produce a product not only preventing narcotic abuse, but at the same time providing supportive therapy in the absence of opiates.
  • Haloperidol is commonly administered orally in 0.5 to 5.0 mg. two or three times daily depending upon the severity of the illness. A dose of haloperidol in this range would be administered contemporaneously with an effective dose of the narcotic antagonist to produce the desired result.
  • narcotic antagonists in. combination with anti-anxiety agents such as chlorodiazepoxide and diazeparn, or phenathiazines like chlorpromazine, primazine or methotrimeprazine.
  • the most potent narcotic antagonist is l-3,14 dihydroxy 6 cyclopropylmethylmorphinan (XIXa).
  • the compound is active both orally and parenterally.
  • the normal parenteral dosage range in HO l 1-hydroxy-7-methoxy-1,2,3,4 tetrahydro 2,2 tetramethylene-1-naphthaleneacetonitrile (III).
  • III HO l 1-hydroxy-7-methoxy-1,2,3,4 tetrahydro 2,2 tetramethylene-1-naphthaleneacetonitrile
  • THF anhydrous tetrahydrofuran
  • Example 3 CH3 0 q 1 (2 aminoethyl)-7-methoxy-1,2,3,4-tetrahydro-2,2- tetramethylene-l-naphthol (IV).T0 a stirred suspension of 0.57 g. (0.015 mole) of lithium aluminum hydride in 20 ml. anhydrous tetrahydrofuran (THF) under N was added a solution of 2.71 g. (0.01 mole) of III in 20 ml. tetrahydrofuran. The reaction mixture was stirred for 4 hours at room temperature (r.t.). It was then cooled and treated with 0.6 ml. of water, followed by 0.6 ml.
  • THF anhydrous tetrahydrofuran
  • Example 4 (2 aminoethyl) l,2,3,4,4a,9-hexahydro-6-methoxyphenanthrene (V).Method A: Compound IV [1.50 g. (000548)] free base liberated from 2 g. of oxalate salt) in 5 ml. of ether was treated with 1.5 ml. of concentrated HCl under N at 55 -60 C. for 5 hours. To the cooled mixture were added in succession 10 ml. of ether and 10 ml. of water. After shaking, the two layers were separated. The acidic layer was made alkaline with aqueous ammonia and extracted with ether. The ether layer was dried (K CO and concentrated to yield 1.30 g. of pale yellow oil V. It was converted to an oxalate salt in acetone. The crystals were filtered and washed with a small amount of methylene chloride. The IR and NMR spectra were consistent with the structure.
  • Method B 120 g. of the oxalate salt of IV was slurried in 700 ml. of water, and to it was added 400 ml. of benzene and 60 ml. of concentrated ammonia. The mixture was stirred until all the solid had disappeared (ca. 15 minutes) and then layers were separated. The water layer was extracted with another 100 ml. of benzene, and the combined benzene layers were shaken with 200 ml. of satuated NaCl solution, filtered over K CO and concentrated in vacuo. The residual oil (ca. g.) was dissolved in 300 ml. of ether in a one 1.
  • N ethoxycarbonyl 14 hydroxy 3 methoxyisomorphinan (VIII).-The following reaction was carried out under a nitrogen atmosphere. To a stirred and refluxing suspension of 1.76 g. (73.34 mmole) of sodium hydride in 200 ml. of dry benzene was added a solution of 5.87 g. (66.67 mmole) of dry t-amyl alcohol in 50 ml. of dry benzene. When the hydrogen evolution had subsided (ca. 15 minutes) a solution of 23.0 g. (66.67 mmole) of the epoxide VII in 500 ml. of dry benzene was added dropwise during 4 hours.
  • Example 10 21 yield 5.64 g. of a mixture of u and (XII) epoxides.
  • the IR and NMR spectra were consistent with the structure.
  • a sample distilled at 145 C./0.05 mm. was analysed.
  • Example 11 N-ethoxycarbonyl-14-hydroxy 3 methoxymorphinan (XIII).-To a solution of 2.5 g. (0.00728 mole) of the mixture of XI and XII epoxides in 100 ml. of anhydrous ethanol was added 0.76 g. (0.02 mole) of sodium borohydride. The mixture was refluxed during 3 hours after which time additional portions (0.38 g.) of sodium borohydride were added every hour during 7 hours. The reaction mixture was cooled, acidified with dilute hydrochloric acid and extracted with methylene chloride. The dried solution (MgSO was evaporated yielding 2.3 g. of an oil.
  • TLC Thin layer chromatography
  • A1 0 CHCl revealed four components which the following Rf values 0.2, 0.3, 0.5 and 0.6.
  • the first spot was identified as the isomorphinan VIII, while the third spot is some unreacted starting material.
  • the crude oil in chloroform was chromatographed through an alumina column (200 g.). After concentration of the eluate, the remaining oil was recrystallized from an ether-petroleum ether mixture. There was thus obtained 1.27 g. of a white solid (mainly second fraction on TLC) which after two recrystalliza tions from isopropanol melted at l39-40 C.
  • the IR and NMR spectra were consistent with the structure.
  • Example 12 14 hydroxy-3-methoxy-N-rnethylmorphinan (XIV).- To a stirred suspension of 0.17 g. (0.0045 mole) of lithium aluminum hydride in ml. anhydrous tetrahydrofuran was added, under N a solution of 0.518 g. (0.0015 mole) of XIII in 10 ml. tetrahydrofuran. The reaction mixture was heated under reflux for 18 hours. Work-up in the usual manner atforded 330 mg. of an oil which was crystallized from petroleum ether. Recrystallization from methanol afforded an analytical sample melting at 113- 15 C. The IR and NMR spectra were consistent with the structure.
  • Example 13 3,14-dihydoxy-N-methylmorphinan (XV).700 mg. of XIV and 7 ml. of 48% HBr were refluxed under N for 15 minutes. The reaction mixture was cooled, diluted with a small amount of ice Water, made basic with aqueous ammonia and extracted with CHC13. The CHCl extracts were dried (MgSO and evaporated to dryness. The residue was taken up in ether and filtered through Celite-charcoal. The filtrate crystallized. It was filtered to 22 give 400 mg. of a solid which was recrystallized from MeOH to give a white solid, 330 mg., mp. 206-8 C. The IR and NMR spectra were consistent with the structure. Anal.-Calcd. for C H NO C, 74.69; H, 8.48; N, 5.12. Found: C, 74.82; H, 8.58; N, 4.97.
  • Example 14 3-methoxy-A -morphinan (XI).--A mixture of 32.7 g. (0.1 mole) of crude X, ml. of n-octanol and 28.0 g. KOH pellets was refluxed under nitrogen for 45 minutes. After cooling, the mixture was treated with water and ether (600 ml.). The water layer was discarded, and the organic layer was extracted with 300 ml. of 2 N HCl and 2X 300 ml. of water. The combined aqueous extracts were basified with aqueous ammonia and the free base was taken up in ether, to yield 20 g. of the crude product after drying over K CO and evaporation.
  • XI 3-methoxy-A -morphinan
  • the product was converted to an oxalate salt in anhydrous ether.
  • the resulting salt was recrystallized from an acetone-methanol mixture to yield 12 g. (34.8%), m.p. 82 C. Recrystallization from a methanolacetone mixture afforded a sample melting at 187189 C.
  • the IR and NMR spectra were consistent with the structure.
  • Example 15 N-cyclopropylcarbonyl 3 methoxy-A -morphinan (XVI).-The acid chloride of cyclopropylcarboxylic acid (3.0 g., 28.7 mmole) was added to a cooled and stirred solution of 6.4 (25 mmole) of XI and 2.5 g. (31.3 mmole) of pyridine in 30 ml. of methylene chloride over a period of 10 minutes. After stirring for another 10 minutes, the solution was washed successively with water, 15 ml. of 0.2 .N NaOH, 10 ml. of 1 N HCl, and again with water. After drying over Na SO the solvent was evaporated, and the residue crystallized from 15 ml.
  • Example 16 N-cyclo pro pylcarbonyl-S 14-ep oxy- 3 -methoxymorphinan (XVII).To a solution of 3.33 g. (10.3 mmole) of XVI in 35 ml. CH CI at 0 C. was added 2.31 g. of 85% m-chloroperbenzoic acid (11.3 mmole). The mixture was stirred at 0-5 C. until all the peracid was dissolved. The mixture was left at room temperature for 6 hours. Work up in usual manner afforded an oil which was dissolved in 10 ml. of ether and left for 24 hours at 5 C. The
  • Example 17 C130 OH N cyclopropylmethyl 14 hydroxy 3 methoxymorphinan (XVIII).T stirred suspension of 1.8 g. of LiAlH in 50 ml. of anhydrous THF was added dropwise during 5 minutes a solution of 6.0 g. (17 mmole) of XVII in ml. THF. The mixture was refluxed during one hour and then worked up in the usual manner. The product was dissolved in petroleum ether (b.p. 40-60 C.) and filtered through Celite-charcoal to give 5.73 g. of an oil. Treatment with anhydrous HCl in ether afforded 6.15 g. (95.5%) of the hydrochloride salt, m.p. 223-25 C. Recrystallization from methanol-ether increased the m.p. to 259-60 C. The IR and NMR spectra were consistent with the structure.
  • Example 18 3,14 dihydroxy N cyclopropylmethylmorphinan (XIX).-Method A: A mixture of 4.1 g. (11.7 mmole) of the hydrochloride salt of XVIII and 13.4 g. of anhydrous pyridine hydrochloride was heated under nitrogen at 187-95 C. for 1 hour. The cooled mixture was dissolved in 40 ml. of water, basified with aqueous ammonia and extracted with 2x 40 ml. of ether. Drying and evaporation of the solvent yielded 3.0 g. of semi-solid product, which was dissolved in ether. After treatment with charcoal, the product crystallized to yield 2.54 g. (69.4%) of free base, m.p.
  • reaction mixture was stirred in the cold for one hour, and then at room temperature for three hours.
  • the reaction mixture was cooled (ice-bath) and carefully decomposed with 350 ml. of cold water.
  • It was transferred into a four I. Erlenmeyer flask and treated carefully with 200 ml. of concentrated ammonium hydroxide with cooling and stirring. The layers were separated and the aqueous layer extracted with 200 ml. of methylene chloride. The combined organic extracts were dried (MgSO and evaporated, in vacuo, to give an oil in quantitative yield.
  • Example 19 CHO 3-methoxy-N-trifiuoroacetyl-A morphinan (XX).
  • XX 3-methoxy-N-trifiuoroacetyl-A morphinan
  • Example 20 8,14-ep0xy-3-methoxy N trifluoroacetylmorphinan (XXI).-The procedure is the same as that described for the preparation of compound VII in Example 6 using the following materials 23.85 (10.96 mmole) of compound XX; 2.07 g. (12 mmole) of m-chloroperbenzoic acid; and 30 ml. of methylene chloride. Reaction time, 6 hours.
  • Example 21 Example 22 l4-hydroxy-3-methoxymorphinan (XXIII).A solution of 800 mg. of the amine-epoxide (XXII) in ml. of tetrahydrofuran was added dropwise at room temperature, to a suspension of 500 mg. of lithium aluminum hydride in 5 ml. of dry tetrahydrofuran. After the addition had been completed the reaction mixture was stirred and refluxed during fifteen minutes. Work-up as usual yielded 700 mg. of an oil which was dissolved in ether and the resulting solution was filtered through a Celite-charcoal mixture. The filtrate was treated with a saturated solution of hydrochloric acid in ether to yield 720 mg. of a white hydrochloride salt which after recrystallization from methanol melted at 243-44 C. (dec.). The IR and NMR were consistent with the structure.
  • Example 23 3,14-dihydroxy-morphinan (XXIV).-A mixture of 140 mg. (0.5 mmole) of XXIII and 0.55 g. of pyridine hydrochloride was heated under N, at 185-95 C. for 1 hour. The mixture was cooled, treated with water and NH OI-I and extracted with CHCl The CHCI extracts were dried and evaporated to give a solid 53.6 mg. This was treated wtih ether and filtered. The solid was recrystallized from MeOH to give mg./m.p. 264- 66 C. (d.). The IR and NMR spectra were consistent with the structure.
  • Example 24 N-cyclobutylcarbonyl l4 hydroxy 3 methoxymorphinan (XXV).T0 a stirred and cooled solution of 400 mg. (0.00146 mole) of the amino alcohol XXIII in 0.16 g. (0.002 mole) of dry pyridine and 5 ml. of methylene chloride, there was added, dropwise, a solution of 0.19 g. (0.0016 mole) of the acid chloride of cyclobutyl carboxylic acid in 5 ml. of methylene chloride.
  • Example 25 N cyclobutylmethyl 14 hydroxy 3 methoxymorphinan (XXVI).T0 a suspension of 1.0 g. of lithium aluminum hydride in 5 ml. of dry tetrahydrofuran was added at room temperature, under an atmosphere of nitrogen, a solution of 2.14 g. (6 mmole) of the amide XXV in 25 ml. of tetrahydrofuran. The reaction mixture was then refluxed during thirty minutes and worked up as usual to yield 2.0 g. of an oil which was dissolved in ether and the resulting solution filtered through a Celitecharcoal mixture.
  • Example 26 N cyclobutylmethyl 3,14 dihydroxymorphinan (XXVII).A mixture of 1.0 g. (2.58 mmole) of XXVI and 10 ml. of 48% HBr was refluxed, under a nitrogen atmosphere, during five minutes. After cooling, the reaction mixture was diluted with water and made basic with aqueous ammonium hydroxide. The aqueous basic mixture was extracted with chloroform and the combined chloroform extracts were dried over anhydrous sodium sulfate. After evaporation of the solvent, the residual oil (730 mg.) was taken up in dry ether and the resulting solution filtered through Celite-charcoal. The filtrate was treated with a saturated solution of hydrogen chloride in dry ether.
  • the hydrochloride salt thus obtained was collected by filtration and recrystallized from a methanolacetone mixture to yield 565 mg. (56.5 %')of crystals melting at 272-74 C. (dec.).
  • the IR and NMR spectra were consistent with the structure.
  • Example 27 N-allyl-l4-hydroxy-3-methoxymorphinan (XXVIII). To a stirred mixture of 900 mg. (3.3 mmole) of the aminoalcohol XXIII and 1.7 g. (16.5 mmole) of triethylamine in 12 ml. of absolute ethanol was added, at room temperature and under nitrogen, a solution of 0.605 g. mmole) of allyl bromide. After the addition had been completed the reaction mixture was refluxed for eighteen hours and then evaporated to dryness. The residue was mixed 'with a aqueous sodium carbonate solution and the resulting mixture extracted with several portions of ether.
  • Example 28 N-allyl-3,l4-dihydroxymorphinan (XXIX).--To a solution of 3.814 g. (12.135 mmole) of XXVIII in 90 ml. of dry CH Cl at -80 C. was added under N dropwise a solution of 9.4252 g. (37.42 mmole) of BBr of 20 ml. of dry CH Cl The resulting reaction mixture was allowed to Warm up to room temperature slowly for 18 hours. It was decomposed with ice-water and the layers separated, the CH CI solution washed with water and saturated NaCl solution. It was dried and evaporated to give 3.76 g. of an oil. This was converted to its HCl salt in acetone.
  • the HCl salt obtained was recrystallized from water-acetone to give 1.15 g. of a white solid.
  • the mother liquor was concentrated and converted to its free base.
  • the free base was chromatographed on A1 0 (Act. 4) and eluted with CHCI to give a fraction (1.35 g.) which was converted to its HCl salt.
  • the HCl salt was recrystallized from H O-acetone to give 950 mg.
  • the IR and NMR were consistent with the structure.
  • Example 29 N-dimethylallyl 14 hydroxy 3 methoxymorphinan (XXX).Substitution in the procedure of Example 27 for the allyl bromide used therein of an equimolar quantity of dimethylallyl bromide produces the title compound.
  • Example 30 -CH N CH C N-dimethylallyl-3,l4-dihydroxym0rphinan (XXXI) Substitution in the procedure of Example 28 for the compound XXVIII used therein of an equimolar quantity of compound XXX produces the title compound.
  • Example 31 N-2'-methylallyl 14 hydroxy 3 methoxymorphinan (XXXIIyfiSubstitution in the procedure of 'Example 27 for the allyl bromide used therein of an equimolar quantity of Z-methylallyl bromide produces the title com- (XXXIII).-Substitution in the procedure of Example 28 for the compound XXVIII used therein of an equimolar quantity of compound XXXII produces the title compound.
  • Example 33 N cyclopropylmethyl-3-acetoxy-l4-hydroxymorphinan (XXXIV).-Equimolar quantities of acetyl chloride, compound XIX and pyridine are mixed together in dry methylene chloride and the resultant mixture is heated to 60 C. for several hours under a nitrogen atmosphere to produce the title compound.
  • Example 34 o wa 1 II on N 0,-0 "N N-cyclopropylmethyl 3 nicotinoyloxy-14-hydroxymorphinan (XXXV).Equimolar quantities of nicotinoyl chloride hydrochloride, compound XIX and pyridine are mixed together in dry methylene chloride and the mixture is heated to 50 C. for 3 hours to produce the title compound.
  • Example 36 ..cg o o-ti-cn N cyclobutylmethyl 3,14 diacetoxymorphinan (XXXVII).-Two moles each of acetic anhydride and pyridine are mixed with one mole of compound XXVII in dry methylene chloride. The solution is heated to reflux for 24 hours under nitrogen to produce the title compound.
  • Example 37 Example 38 Resolution of dl-3,14-dihydroxy-N-cyclopropylmethylmorphinan into its d and 1 optical isomers.
  • l-3,14- dihydroxy-N-cyclopropylmethylmorphinan (XIXa) dl- 3,14 dihydroxy-N-cyclopropylmethylmorphinan (7.835 g., 25 mmole) as the free base was dissolved in 15 ml. of hot methanol. To this was added a solution of 3.75 g. (25 mmole) of l-tartaric acid in 15 ml. of hot methanol. The resulting solution was diluted with 30 ml. of acetone and let stand at 5 C. for 60 hours to crystallize. It was filtered to yield 3.2 g. of a crystalline solid (A). The mother liquor was evaporated to dryness and was made basic with aqueous ammonia to give approximately 5.0 g. of free base (B).
  • Example 39 Resolution of the compounds of the instant invention into their respective optical isomers-Substitution into the general procedure of Example 38 for the dl-3,14-dihydroxy-N-cyclopropylmethylmorphinan used therein of an equimolar quantity of a dl-3,l4-dihydroxy-N-substituted-morphinan will produce the resolved d and l isomers.
  • Example 40 1 3,14 dihydroxy N-cyclopropylmethyhnorphinan pamoate.1 3,14 dihydroxy-N-cyclopropylmethylmorphinan (0.1 mole) is dissolved in hot methanol. A solution of 0.1 mole of pamoic acid dissolved in hot nitrobenzene is added to the first solution with vigorous agitation. The product that crystallizes is the pamoate salt of XIXa.
  • Example 41 Salt preparation of the compounds of the instant invention.-Substitution in the procedure of example 40 for the pamoic acid used therein of an equimolar quantity of sulfuric, nitric, phosphoric, phosphorous, hydrobromic, maleic, malic, ascorbic, citric, tartaric, lauric, stearic, palmitic, oleic, myristic, lauryl, sulfuric, naphthabenzenesulfonic, linoleic or linolenic acid produces the corresponding acid addition salt of 1-3,l4-dihydroxy-N-cyclopropylmethylmorphinan.
  • R is selected from the group consisting of in which R is H or CH R is selected from the group consisting of H, (lower)alkyl or 1 to 6 carbon atoms (lower)alkanoyl of 2 to 6 carbon atoms and and R is selected from the group consisting of H and (lower)alkanoyl of 2 to 6 carbon atoms; or a pharmaceutically acceptable acid addition salt thereof.
  • a compound of claim 1 having the formula in which R is H or CH R is and R is H or acetyl; or a pharmaceutically acceptable acid addition salt thereof.
  • a compound of claim 2 wherein R is is CH: -cmfl -cmor -orn-oH o R is and R is H; or a pharmaceutically acceptable acid addition salt thereof.
  • DONALD G. DAUS Primary Examiner US. Cl; X.R.

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US00217633A 1971-09-08 1972-01-13 14-hydroxymorphinan derivatives Expired - Lifetime US3819635A (en)

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Application Number Priority Date Filing Date Title
BE788478D BE788478A (fr) 1971-09-08 Procede de preparation de composes analgesiques
US00217633A US3819635A (en) 1971-09-08 1972-01-13 14-hydroxymorphinan derivatives
PH21191A PH14440A (en) 1972-01-13 1972-05-25 Intermediates in the preparation of 14-hydroxy morphinan derivatives
CA150,036A CA999578A (en) 1971-09-08 1972-08-23 14-hydroxymorphinan derivatives
AU46228/72A AU470102B2 (en) 1971-09-08 1972-09-01 Isomorphinan and morphinan derivatives and process for their preparation
DK440172AA DK141624B (da) 1971-09-08 1972-09-06 Analogifremgangsmåde til fremstilling af morphinanderivater.
IE1213/72A IE36687B1 (en) 1971-09-08 1972-09-06 N-substituted-14-hydroxy-3-substituted morphinan derivatives
IE103/76A IE36688B1 (en) 1971-09-08 1972-09-06 3-substituted-morphinan derivatives
SE7211522A SE398877B (sv) 1971-09-08 1972-09-06 Forfarande for framstellning av 14-hydroxi-morfinanderivat
JP8916172A JPS5310596B2 (en, 2012) 1971-09-08 1972-09-07
CH1315472A CH590845A5 (en, 2012) 1971-09-08 1972-09-07
DE2265255A DE2265255C2 (de) 1971-09-08 1972-09-07 2-Aminoäthylhexahydrophenanthren-Derivate und deren Säureadditionssalze
NL7212176.A NL162072C (nl) 1971-09-08 1972-09-07 Werkwijze voor het bereiden van pijnstillende, anti- -narcotische geneesmiddelen, aldus verkregen gevormde geneesmiddelen,alsmede werkwijze voor het bereiden van daarvoor geschikte actieve stoffen.
GB4161972A GB1412129A (en) 1971-09-08 1972-09-07 N-substituted-14-hydroxy-3-substituted morphinane derivatives
DE2243961A DE2243961A1 (de) 1971-09-08 1972-09-07 Verfahren zur herstellung von analgetischen verbindungen
YU227772A YU45099B (sh) 1971-09-08 1972-09-07 Postupak za proizvodnju n-supstituisanih morfinana
CY980A CY980A (en) 1971-09-08 1972-09-07 3-substituted-morphinan derivatives
GB1057175A GB1412130A (en) 1971-09-08 1972-09-07 3-substituted-morphinan derivatives
DE2265256A DE2265256C2 (de) 1971-09-08 1972-09-07 Morphinanderivate und Verfahren zu deren Herstellung
FR7231816A FR2154481B1 (en, 2012) 1971-09-08 1972-09-07
DD165557A DD100255A5 (en, 2012) 1971-09-08 1972-09-08
PH13920A PH14344A (en) 1972-01-13 1972-09-19 14-hydroxymor hinan derivatives
SE7506292A SE403286B (sv) 1971-09-08 1975-06-02 Mellanprodukter for framstellning av 1,4-hydroximorfinanderivat
DK329977A DK142620B (da) 1971-09-08 1977-07-20 Fremgangsmåde til fremstilling af morphinanderivater.
KE2911A KE2911A (en) 1971-09-08 1978-12-24 3-substituted-horphinan derivatives
HK26/79A HK2679A (en) 1971-09-08 1979-01-11 3-substituted-morphinan derivatives
MY27/79A MY7900027A (en) 1971-09-08 1979-12-30 3-substituted-morphinan derivatives

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DE (3) DE2243961A1 (en, 2012)
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GB (2) GB1412130A (en, 2012)
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Cited By (24)

* Cited by examiner, † Cited by third party
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US3910920A (en) * 1973-11-07 1975-10-07 Bristol Myers Co 3,14,17-Substituted-6,7-tetramethylenemorphinans
US3980641A (en) * 1975-07-31 1976-09-14 Bristol-Myers Company Process for the preparation of 14-hydroxymorphinans
US4017497A (en) * 1975-11-18 1977-04-12 Bristol-Myers Company Process for the preparation of 14-hydroxymorphinan derivatives
US4052389A (en) * 1976-03-23 1977-10-04 Bristol-Myers Company Derivatives of 9,10-dihydroxy-1-(p-alkoxybenzyl)-perhydroisoquinoline oxazine-3-one
US4115389A (en) * 1977-05-02 1978-09-19 Bristol-Myers Company Process of N-demethylating (-)-1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline
US4139534A (en) * 1977-02-17 1979-02-13 Bristol-Myers Company Process for the preparation of 14-hydroxymorphinan derivatives
US4228285A (en) * 1979-02-28 1980-10-14 Bristol-Myers Company 14-Hydroxy-6-oxamorphinans and 14-hydroxy-6-oxaisomorphinans
US4241066A (en) * 1977-03-23 1980-12-23 Reckitt & Colman Products Limited 14-Amino derivatives of morphine, methods of making them and analgesic compositions containing them
US4241067A (en) * 1977-03-23 1980-12-23 Reckitt & Colman Products Limited 14-Amino derivatives of morphine, methods of making them and analgesic compositions containing them
US4272540A (en) * 1979-04-24 1981-06-09 Sisa, Incorporated 14-Methoxymorphinan-6-one compounds and therapeutic methods of treating pain and drug dependence with them
US4322427A (en) * 1981-04-16 1982-03-30 Bristol-Myers Company Analgetic compositions and methods of use
US4338320A (en) * 1978-11-15 1982-07-06 The Board Of Regents Of The University Of Nebraska Esters of 6'-hydroxycinchonine, and a method of treating arrythmia with them
DK155322B (da) * 1976-03-23 1989-03-28 Bristol Myers Co Fremgangsmaade til fremstilling af 14-hydroxymorphinan-derivater og farmaceutisk acceptable syreadditionssalte deraf samt mellemprodukt til anvendelse ved fremgangsmaaden
US5504208A (en) * 1993-08-13 1996-04-02 Galena A.S. Process for the preparation of 3, 14β-dihydroxy-17-normorphinan
US5972953A (en) * 1993-07-19 1999-10-26 Toray Industries, Ltd. Brain cell protective agent
US6177438B1 (en) * 1993-07-23 2001-01-23 Toray Industries, Inc. Morphinan derivatives and pharmaceutical use thereof
US6197344B1 (en) 1998-02-25 2001-03-06 Abbott Laboratories Butorphanol sustained release formulations
WO2003097608A2 (en) 2002-05-17 2003-11-27 Jenken Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
US20040167164A1 (en) * 1998-05-05 2004-08-26 Jose Pozuelo Compositions and methods for treating particular chemical addictions and mental illnesses
US20050261329A1 (en) * 2002-05-17 2005-11-24 Jenken Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
US20090169508A1 (en) * 2003-05-16 2009-07-02 Jenkin Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
US7923454B2 (en) 2002-05-17 2011-04-12 Jenken Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
CN103073496A (zh) * 2013-02-18 2013-05-01 苏州立新制药有限公司 右美沙芬的制备方法
KR20170071508A (ko) 2014-10-14 2017-06-23 히사미쓰 세이야꾸 가부시키가이샤 첩부제

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4058531A (en) * 1976-03-23 1977-11-15 Bristol-Myers Company Process for the preparation of 14-hydroxymorphinan derivatives

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3166559A (en) * 1965-01-19 J-lower alkoxy-x-phenyloxy-ix-hydroxy-
GB1028407A (en) * 1962-04-06 1966-05-04 Shionogi & Co Improvements in or relating to morphinan derivatives and their preparation
FR1362540A (fr) * 1963-04-05 1964-06-05 Shionogi & Co Dérivés n substitués du morphinane et leur production

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3910920A (en) * 1973-11-07 1975-10-07 Bristol Myers Co 3,14,17-Substituted-6,7-tetramethylenemorphinans
US3980641A (en) * 1975-07-31 1976-09-14 Bristol-Myers Company Process for the preparation of 14-hydroxymorphinans
US4017497A (en) * 1975-11-18 1977-04-12 Bristol-Myers Company Process for the preparation of 14-hydroxymorphinan derivatives
US4052389A (en) * 1976-03-23 1977-10-04 Bristol-Myers Company Derivatives of 9,10-dihydroxy-1-(p-alkoxybenzyl)-perhydroisoquinoline oxazine-3-one
DK155322B (da) * 1976-03-23 1989-03-28 Bristol Myers Co Fremgangsmaade til fremstilling af 14-hydroxymorphinan-derivater og farmaceutisk acceptable syreadditionssalte deraf samt mellemprodukt til anvendelse ved fremgangsmaaden
US4139534A (en) * 1977-02-17 1979-02-13 Bristol-Myers Company Process for the preparation of 14-hydroxymorphinan derivatives
US4241066A (en) * 1977-03-23 1980-12-23 Reckitt & Colman Products Limited 14-Amino derivatives of morphine, methods of making them and analgesic compositions containing them
US4241067A (en) * 1977-03-23 1980-12-23 Reckitt & Colman Products Limited 14-Amino derivatives of morphine, methods of making them and analgesic compositions containing them
US4115389A (en) * 1977-05-02 1978-09-19 Bristol-Myers Company Process of N-demethylating (-)-1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline
US4338320A (en) * 1978-11-15 1982-07-06 The Board Of Regents Of The University Of Nebraska Esters of 6'-hydroxycinchonine, and a method of treating arrythmia with them
US4228285A (en) * 1979-02-28 1980-10-14 Bristol-Myers Company 14-Hydroxy-6-oxamorphinans and 14-hydroxy-6-oxaisomorphinans
US4272540A (en) * 1979-04-24 1981-06-09 Sisa, Incorporated 14-Methoxymorphinan-6-one compounds and therapeutic methods of treating pain and drug dependence with them
US4322427A (en) * 1981-04-16 1982-03-30 Bristol-Myers Company Analgetic compositions and methods of use
US5972953A (en) * 1993-07-19 1999-10-26 Toray Industries, Ltd. Brain cell protective agent
US6147084A (en) * 1993-07-19 2000-11-14 Toray Industries, Inc. Brain cell protective agent
US6177438B1 (en) * 1993-07-23 2001-01-23 Toray Industries, Inc. Morphinan derivatives and pharmaceutical use thereof
US5504208A (en) * 1993-08-13 1996-04-02 Galena A.S. Process for the preparation of 3, 14β-dihydroxy-17-normorphinan
US6197344B1 (en) 1998-02-25 2001-03-06 Abbott Laboratories Butorphanol sustained release formulations
US20040167164A1 (en) * 1998-05-05 2004-08-26 Jose Pozuelo Compositions and methods for treating particular chemical addictions and mental illnesses
EP2987788A1 (en) 2002-05-17 2016-02-24 Taiwanj Pharmaceuticals Co., Ltd. Opioid and opioid-like compounds and uses thereof
WO2003097608A2 (en) 2002-05-17 2003-11-27 Jenken Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
US20050261329A1 (en) * 2002-05-17 2005-11-24 Jenken Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
US7501433B2 (en) 2002-05-17 2009-03-10 Jenken Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
US7923454B2 (en) 2002-05-17 2011-04-12 Jenken Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
US20090169508A1 (en) * 2003-05-16 2009-07-02 Jenkin Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
US8017622B2 (en) 2003-05-16 2011-09-13 Jenken Biosciences, Inc. Opioid and opioid-like compounds and uses thereof
US9776971B2 (en) 2003-05-16 2017-10-03 Taiwanj Pharmaceuticals Co., Ltd. Opioid and opioid-like compounds and uses thereof
CN103073496A (zh) * 2013-02-18 2013-05-01 苏州立新制药有限公司 右美沙芬的制备方法
CN103073496B (zh) * 2013-02-18 2015-08-26 苏州立新制药有限公司 右美沙芬的制备方法
KR20170071508A (ko) 2014-10-14 2017-06-23 히사미쓰 세이야꾸 가부시키가이샤 첩부제
US10307381B2 (en) 2014-10-14 2019-06-04 Hisamitsu Pharmaceutical Co., Inc. Patch

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GB1412130A (en) 1975-10-29
NL162072C (nl) 1980-04-15
IE36688B1 (en) 1977-02-02
DE2265256C2 (de) 1985-10-24
SE7506292L (sv) 1975-06-02
SE398877B (sv) 1978-01-23
AU470102B2 (en) 1976-03-04
KE2911A (en) 1979-01-26
DE2265255C2 (de) 1986-06-05
FR2154481B1 (en, 2012) 1976-04-23
BE788478A (fr) 1973-03-06
JPS5310596B2 (en, 2012) 1978-04-14
YU45099B (sh) 1992-07-20
DD100255A5 (en, 2012) 1973-09-12
IE36687B1 (en) 1977-02-02
CY980A (en) 1979-03-23
IE36687L (en) 1973-03-08
CH590845A5 (en, 2012) 1977-08-31
DE2243961C2 (en, 2012) 1988-07-21
HK2679A (en) 1979-01-19
DK141624C (en, 2012) 1980-10-13
DK141624B (da) 1980-05-12
SE403286B (sv) 1978-08-07
YU227772A (en) 1982-02-28
JPS4834864A (en, 2012) 1973-05-22
GB1412129A (en) 1975-10-29
DE2265255A1 (de) 1977-01-27
FR2154481A1 (en, 2012) 1973-05-11
DE2243961A1 (de) 1973-04-05
NL7212176A (en, 2012) 1973-03-12
AU4622872A (en) 1974-03-07
DE2265256A1 (de) 1977-01-27
CA999578A (en) 1976-11-09
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