IE46003B1 - 3-phenoxy-n-substituted morphinan derivatives, their manufacture and pharmaceutical preparations containing them - Google Patents
3-phenoxy-n-substituted morphinan derivatives, their manufacture and pharmaceutical preparations containing themInfo
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- IE46003B1 IE46003B1 IE2468/77A IE246877A IE46003B1 IE 46003 B1 IE46003 B1 IE 46003B1 IE 2468/77 A IE2468/77 A IE 2468/77A IE 246877 A IE246877 A IE 246877A IE 46003 B1 IE46003 B1 IE 46003B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
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- 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
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- 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
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Abstract
There are described levo-rotary 3-phenoxy morphinan derivatives of the general formula wherein R is halogen, nitro, lower alkyl, lower alkoxy, hydroxy or hydrogen; R1 is hydrogen, lower alkyl, lower alkenyl, -CH2(CH2)pR2 or -?-(CH2)p-R2; R2 is heteroaromatic, axomatic or cyclo-lower alkyl; p is an integer from 0 to 3; and n is an integer from 1 to 5 and pharmaceutically acceptable acid addition salts which are useful as analgesic and/or narcotic antagonists.
Description
The present invention relates to phenyl derivatives.
More particularly, the invention is concerned with levorotatory
3-phenoxy-N-substituted morphinan derivatives, a process for the manufacture thereof and pharmaceutical preparations containing same.
The levorotatory 3-phenoxy-N-substituted morphinan derivatives provided by the present invention are compounds of the general formula
, wherein n stands for 1, 2, 3, 4 or 5, R represents a hydrogen or halogen atom or a nitro, lower alkyl, lower alkoxy or hydroxy group and R^ represents a hydrogen atom or a lower alkyl or lower alkenyl group or a group of the formula -CH2(CHj) R2or —C(0)-(CH2)p—R2 in which R., represents a heteroaromatic, aromatic or cyclo-(lower alkyl) group and p stands for zero, 1, 2 or 3, and pharmaceutically acceptable salts thereof.
As used in this Specification, the term halogen includes bromine, chlorine, fluorine and iodine, with fluorine and bromine being preferred. The term lower alkyl includes both straight-chain and branched-chain saturated aliphatic hydro5 carbon groups containing from 1 to 7 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl etc). The methyl group is the preferred lower alkyl group. The term lower alkenyl designates both straight-chain and branched-chain aliphatic hydrocarbon groups containing from 2 to 7 carbon atoms which contain one olefinic double bond such as vinyl, allyl, prop-2-en-l-yl etc. The preferred lower alkenyl groups are the -CH2-CH=CH2, -CH2-CH=C(CH3)-CH3 and -CH2-C(CH3)=CH2 groups.
The term cyclo-(lower alkyl) designates saturated cyclic aliphatic hydrocarbon groups containing a ring having from 3 to
6 carbon atoms. Among the preferred cyclo-(lower alkyl) groups are the cyclopropyl, cyclobutyl and cyclohexyl groups. The term lower alkoxy designates lower alkoxy groups containing from 1 to 7 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy etc. The term heteroaromatic designates hydro20 carbon ring systems containing a hetero atom selected from oxygen, nitrogen and sulphur and having 5 or 6 members in the ring structure. Among the preferred heteroaromatic ring * structures are the thienyl, pyrolyl, furyl, pyridyl, pyranyl and like ring systems. The term aromatic designates a hydro25 carbon aromatic substituent such as phenyl and naphthyl, with phenyl being preferred.
According to the process provided by the present invention, the levorotatory 3-phenoxy-N-substituted morphinan derivatives
(XI) , wherein R^ has the significance given earlier, with a compound of the general formula
(XII) , wherein n and R have the significance given earlier and X represents a halogen atom, (b) for the manufacture of a compound of formula I in which R represents a hydroxy group, cleaving an ether of the general formula
(IA)
- 5 , wherein n and R^ have the significance given in claim 1 and R3 represents a lower alkyl group, or (c) for the manufacture of a compound of formula I in which R^ represents a group of the formula -C(0)—(CH2)p—R2, reacting a compound of the general formula
, wherein n and R have the significance given 10 earlier, with a compound of the general formula
X—CO-fCHgip Rg (IV) , wherein R2, g and X have the significance given earlier, or (d) for the manufacture of a compound of formula I in which R^ represents a group of the formula —CH2—(CH2)R^ reducing a compound' of the general formula
6003
D — , wherein R, R2 and £ have the significance given earlier, or (e) for the manufacture of a compound of formula I in 5 which R^ represents a hydrogen atom, treating a compound of the
, wherein n and R have the significance given earlier, with zinc in a lower alkanoic acid, or (f) for the manufacture of a compound of formula I in which R^ represents a group of the formula —CH.,— r2, reacting a compound of the general formula
, wherein n and R have the significance given earlier, with a compound of the general formula
X—CHg—(Ctyp-“^2 (X) , wherein R2, £ and X have the significance given earlier, or (g) for the manufacture of a compound of formula I in which R^ represents a hydrogen atom (i.e. a compound of formula VII), dealkylating a compound of formula IC, or (h) for the manufacture of a compound of formula I in which R^ represents a group of the formula —C(O)-CH2-(CH2)p—R2, reacting a compound of formula VII with a compound of formula IV, or (i) for the manufacture of a compound of formula I in which R^ represents a lower alkyl or lower alkenyl group, reacting a compound of formula VII with a compound of the general formula
X—R? , wherein X has the significance given earlier and R-, represents a lower alkyl or lower alkenyl group, or (j) cyclising a compound of the general formula
6 0 0 3
- 8 , wherein η, R and R. have the significance given earlier, and (k) if desired, converting a compound of formula I into 5 a pharmaceutically acceptable acid addition salt.
According to embodiment (a) of the process, a compound of formula I is manufactured from a compound of formula II by reaction with a compound of formula III.
The compounds of formulae II and III are reacted together 10 using a copper catalyst. The reaction is carried out in an organic solvent in the presence of an inorganic alkali metal base. Any conventional organic solvent can be used. Among the preferred solvents are nitrobenzene, collidine, diglyme and tertiary amines. Included among the tertiary amines are the cyclic tertiary amines such as pyridine and the tri(lower alkyl)amines such as trimethylamine, triethylamine etc. The reaction is also carried out in the presence of a base such as an alkali metal base. Included among the preferred bases are the alkali metal hydroxides such as potassium hydroxide and sodium hydroxide as well as the alkali metal carbonates and bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. The preferred inorganic base is a weak base such as potassium carbonate. The temperature and pressure are not critical and the reaction can be carried out at room temperature and atmospheric pressure. However, if desired, it can be carried out at an elevated temperature. Generally, it is preferred to carry out the
6 0 0 3 reaction at a temperature of from 100°C to 250°C. The reaction is carried out in the presence of a copper catalyst such ascupric chloride, cupric bromide, cupric sulphate, cuprous iodide, a mixture of copper-bronze and metallic copper, with granular copper being preferred.
Where a compound of formula I in which R represents a hydroxy group is desired, the aforementioned reaction of a compound of formula II with a compound of formula III in which R represents a hydroxy group yields a compound of formula I in which R represents a hydroxy group in poor yields. Therefore, it is preferred to manufacture such a compound of formula I according to embodiment (b) of the process. This involves using a compound of formula I in which R represents a lower alkoxy group as the starting material (i.e. a compound of formula IA), there being obtained a compound of the general formula
wherein n and Rj have the significance given earlier.
A compound of formula IA is converted into a compound of formula IB by ether cleavage. Any conventional ether cleavage method can be used. Preferred methods are the treatment of a ySteuuj
ΙΟ compound of formula IA with potassium hydroxide in diglyme or treatment of a compound of formula IA with pyridine hydrochloride or aqueous hydrogen bromide in acetic acid. Any of the conditions conventionally adopted in ether cleavage procedures can be used to convert a compound of formula IA into a compound of formula IB. It should be noted that the ether cleavage does not cleave the phenoxy group. Therefore, the phenoxy group cannot be cleaved from a compound of formula IA to give a material which would be an addictive narcotic.
The reaction of a compound of formula IC with a compound of formula IV according to embodiment (c) of the process is carried out at an elevated temperature, preferably at reflux in the presence of an inert organic solvent. Any conventional aromatic solvent can be used. Among the preferred aromatic solvents are the aromatic hydrocarbon solvents such as benzene or toluene.
The reduction of a compound of formula IE according to embodiment (d) of the process carried out using a strong metal hydride reducing agent such as an alkali metal aluminium hydride (e.g. lithium aluminium hydride) or a di(lower alkyl)aluminium hydride (e.g. diisobutyl aluminium hydride). Any of the conditions conventionally adopted when using these aluminium hydride reducing agents can be used to carry out the present reduction.
According to embodiment (e) of the process, a compound of formula VI is converted into a compound of formula I in which R^
- 11 4600 represents a hydrogen atom by treatment with zinc in a lower alkanoic acid.f i.e- one containing 2 to 7 carbon atoms). The lower alkanoic acid serves as the solvent medium in this embodiment. Any conventional lswer alkanoic acids such as acetic acid, propionic acid etc, can be used,
The temperature and pressure are not critical and the treatment can be carried out at room temperature and atmospheric pressure. On the other hand, the treatment can be carried out at a temperature as high as 100°C.
The compounds of formula vi can be prepared by treating a compound of formula 1C with trichloroethyl chloroformate. In carrying out this treatment, any inert organic solvent can be used as the organic solvent. Among the preferred solvents are the aromatic hydrocarbon solvents such as benzene and toluene. Generally, the treatment is carried out in the presence of a weak base. Any conventional weak inorganic bases can be used. Among the preferred weak bases are the alkali metal carbonates and bicarbonates such as potassium carbonate or sodium carbonate The temperature and pressure are not critical and the treatment can be carried out at room temperature or atmospheric pressure.
On the other hand, it can be carried out at an elevated temperature and pressure. Generally, it is preferred to carry out the treatment at the reflux temperature of the medium.
According to embodiment (f) of the process, a compound of formula VII is reacted with a compound of formula X in an organic solvent medium, preferably in a polar solvent, at room temperature to 300°C, preferably at 120°C to 300°C. Any polar
- xz solvent having a boiling point of from 120°C to 300°C can be used. Included among the preferred solvents are the high boiling polar solvents such as dimethylsulphoxide and dimethylformamide. The reaction is carried out in the presence of a base. Any conventional inorganic alkali metal base such as sodium bicarbonate, potassium carbonate or sodium carbonate can be used. Generally, it is preferred to use a weak organic base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate or potassium carbonate. Alternatively, a strong tertiary aliphatic amine such as triethylamine or diisopropylethylamine can be used. The temperature and pressure are not critical and the reaction can be carried out at room temperature or atmospheric pressure. Generally, it is preferred to carry out the reaction under reflux conditions.
According to embodiment (g) of the process, a compound of formula IC can be converted into a compound of formula I in which R^ represents a hydrogen atom using any dealkylation agent and procedure. Included among the dealkylation agents which can be used are cyanogen bromide followed by treatment with an inorganic mineral acid or ethyl chloroformate or phenyl chloroformate ester followed by treatment with an alkali metal hydroxide in a lower alkanol. Any of the conditions conventionally adopted in using these dealkylation agents can be used in this embodiment of the process.
According to embodiment (h) of the process, a compound of formula VII is reacted with a compound of formula IV. This reaction is carried out in an inert organic solvent, a polar solvent being preferred. Any conventional polar solvent can be used. Included among the preferred organic polar solvents are benzene, toluene and methylene chloride. The reaction is carried out in the presence of a base. Organic bases such as triethylamine, pyridine and the like are preferred. The temperature and pressure are not critical and the reaction can be carried out at room temperature or at an elevated temperature
Embodiment (i) of the process is carried out according to the same procedure as described earlier in connection with embodiment (f) of the process.
The cyclisation of a compound of formula XIII according to embodiment (j) of the process is carried out by treatment with a strong mineral acid. Any conventional strong mineral acid such as phosphoric acid, sulphuric acid or hydrochloric acid can be used, with phosphoric acid being preferred. The inorganic acid can be used as the solvent medium. The temperature and pressure are not critical and the treatment can be carried out at room temperature and atmospheric pressure. On the other hand, it can be carried out at a temperature as high as 250°C.
Generally, it is preferred to carry out the treatment at a temperature of from 100°C to 200°C.
The starting materials of formula XIII can be prepared from a compound of the general formula
6 Ο θ 3 (XI)
RgO
,Ν—R ) »Η , wherein R^ has the significance given earlier and Rg represents a lower alkyl group, via an intermediate of the general formula
HO
,N— R;
»H (XII) wherein R^ has the significance given earlier.
A compound of formula XI is converted into a compound of formula XII by ether cleavage. Any conventional ether cleavage method can be used. Among the preferred ether cleavage methods is the treatment of a compound of formula XI with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in an ether solvent such as diglyme. Generally, this ether cleavage is carried out at the reflux temperature of the medium. A compound of formula XII is converted into a compound of formula XIII by reaction with a compound of formula III. This reaction is carried out in the same manner as described earlier in connection with the reaction of a compound of formula II with a compound of formula III to give a compound of formula I.
The starting materials of formulae II, IV and X are known or can be prepared in an analogous manner to the known compounds.
The compounds of formula I form pharmaceutically acceptable acid addition salts with inorganic acids and organic acids.
Thus, they form pharmaceutically acceptable acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and with organic acids such as tartaric acid, oxalic acid, citric acid, camphorsulphonic acid, ethanesulphonic acid, toluenesulphonic acid, salicylic acid, ascorbic acid, maleic acid, succinic acid, formic acid, acetic acid and the like.
The compounds of formula I and their pharmaceutically acceptable acid addition salts are useful as analgesics and/or as narcotic antagonists. When administered orally or parenterally, they provide a relief from pain in the same manner as codeine. Furthermore, the compounds provided by this invention cannot be degraded chemically into compounds which have addiction liability such as Dromoran(trade mark).
The compounds of formula I and their pharmaceutically acceptable acid addition salts can be incorporated into standard pharmaceutical dosage forms. For example, they are useful for oral or parenteral administration together with the
- J.0 usual pharmaceutical adjuvant materials, examples of such materials being organic or inorganic inert carrier materials such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums and polyalkyleneglycols.
The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, suppositories or capsules) or in a liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations can contain adjuvant materials such as preservatives, stabilisers, wetting agents, emulsifying agents, salts for variation of the osmotic pressure or substances acting as buffers. The pharmaceutical preparations can also contain other therapeutically active substances.
It will thus be appreciated that the present invention also includes within its scope a pharmaceutical preparation containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof in association with a compatible pharmaceutical carrier.
The daily dosage in which a compound of this invention will be administered will, of course, vary with the particular compound in question (because of the very potency of the compounds), the chosen route of administration and the size of the recipient. The dosage administered is not subject to definite bounds, but it will usually be in effective amounts having regard to the pharmacological function of the compound of formula I. A typical route of administration for the present compounds of formula I is the oral route. By this route, a tablet containing a compound of formula I can be administered orally at the rate of 0.01 microgram to 0.15 microgram per day per kilogram of body weight.
The compounds of formula 1 and their pharmaceutically acceptable acid addition salts are used as analgesic pain killing agents. This analgesic activity can be demonstrated in the standard phenylguinone writhing test [_ Sigmund et al.,
Proc. Soc. Exp. Biol. Med. 95: 729 [1957]_7. The compounds provided by this invention significantly reduce pain and produce analgesic effects in mice exposed to intra-abdominally induced chemical pain, the ED50 being the dosage which reduces the total number of writhes by 50%. When the following levorotatory 3-phenoxy-N-substituted morphinan derivatives are tested, analgesic activity is observed as shown by the following ed3q levels when compared with the standard analgesic agent codeine which has an ΕΟ^θ of 3.9 mg/kg (p.c.).
(-)-3-Phenoxy-N-methylmorphinan tartrate; 2·° mg/kg (s.c.);
(-)-3-(p-methyl)phenoxy-N-methylmorphinan hydrochloride;
ED5q 23 mg/kg (s.c.);
(-)-3-(p-methoxy)phenoxy-N-methylmorphinan hydrochloride; EDi-θ 2.0 mg/kg (s.c.);
(-)-3-phenoxy-N-cyclobutylmethylmorphinan hydrochloride;
EDsq 13.0 mg/kg (s.c.);
(~}-3-phenoxy-N-phenethylraorphinan oxalate; ED^q °·9 mg/kg (s.c.);
(-)-3-phenoxy-N-[2-(2-furyl)ethyl]morphinan oxalate;
ED5q 1.0 mg/kg (s.c.);
43003
- 18 -,. (-)-3-phenoxy-N-[2-(2-thienyl)ethyl]morphinan sulphate;
ED^0 13.0 mg/kg (s.c.);
(-)-3-(m-fluoro)phenoxy-N-methylmorphinan d-tartrate;
ED5o 6.0 mg/kg (s.c.);
(-)-3-(o-methoxy)phenoxy-N-cyclopropyImethylmorphinan hydrochloride; Εϋ^θ 2.5 mg/kg (s^.c.);
(-)-3- (£-methoxy)phenoxy-N-cyclopropyImethylmorphinan hydrochloride; EDS0 I-3 mg/kg (s.c.);
(-)-3-(m-methoxy)phenoxy-N-methylmorphinan oxalate; ΕΟ^θ 10 2.5 mg/kg (s.c.);
(-)-3-(o-methoxy)phenoxy-N-methylmorphinan oxalate; ED5q 0.49 mg/kg (s.c.); .
(-)-3-(py-hydroxy)phenoxy-N-methylmorphinan hydrochloride; ED5q 1.3 mg/kg (s.c.);
(-)-3-(m-hydroxy)phenoxy-N-methylmorphinan d-tartrate;
ED5q 9.0 mg/kg (s.c.);
(-)-3-(σ-hydroxy)phenoxy-N-methylmorphinan d-tartrate; ED5o 1.8 mg/kg (s.c.);
(-)-3-(o-nitro)phenoxy-N-methylmorphinan hydrochloride;
ED5o 2.8 mg/kg (s.c.);
(-)-3-(£-fluoro)phenoxy-N-methylmorphinan hydrochloride; ED50 1.0 mg/kg (s.c.);
(-)-3-(o-fluoro)phenoxy-N-methylmorphinan oxalate; Εϋ^θ 3.0 mg/kg (s.c.);
(-)-3-pentafluorophenoxy-N-methylmorphinan oxalate; ED5o
9.2 mg/kg (s.c.); and (-)-3-phenoxy-N-cyclopropyImethylmorphinan hydrochloride; ED5o 1.7 mg/kg (s.c.).
The compounds of formula I effectively counteract morphine analgesia. This activity can be demonstrated in the mice tail flick test for morphine antagonism. This test is used to measure narcotic antagonism. Compounds are administered subcutaneously 10 minutes prior to the administration of morphine sulphate. The percentage evaluation in reaction time is determined during each test for 10 mg/kg s.c. of morphine sulphate and actual percentage increase is used in calculating the percentage antagonism of morphine analgesia. The percent antagonism is calculated according to the formula of Harris and Pierson (J. Pharmacol. Exp. Ther., 143: 141, 1964). When (-)-3-phenoxy-N-cyclopropylmethylmorphinan hydrochloride is used in this test, morphine antagonism activity is achieved as shown by an ED5Q of 40.28 mg/kg (s.c.).
4 6 0 0 3
s.. The following Examples illustrate the process provided by the present invention:
Example 1 (-)-3-Pentafluorophenoxy-N-methylmorphinan 5 A mixture of 6.0 g (0.023 mol) of (-)-3-hydroxy-N-methylmorphinan, 60 ml of freshly distilled pyridine, 4.8 g of potassium carbonate, 9.0 g of hexafluorobenzene and 6.0 g of granular copper was heated in a stainless steel container at 120°C for 7 days. After cooling, the container was opened and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between 700 ml of diethyl ether and 5-N aqueous sodium hydroxide. After removal of the diethyl ether, the residue was extracted with 200 ml of hexane. The residue obtained from the hexane extract (5.0 g) was chromatographed over 75 g of neutral alumina and eluted with methylene chloride, diethyl ether and ethyl acetate. After combination of the fractions, the solvents were removed under reduced pressure to give crude (-)-3-pentafluorophenoxy-N-methylmorphinan. For analysis, a sample was distilled?
boiling point 15O°-16O°C/O.1 mm Hg? [ct]^5 = -39.69° (c = 1.21 in methanol),
To the foregoing base, 3.6 g (0.01 mol), in 20 ml of diethyl ether was added a solution of 0.8 g of oxalic acid in 20 ml of diethyl ether. The crude oxalate was recrystallised from ethyl acetate to give (-)-3-pentafluorophenoxy-N-methylmorphinan oxalate hemihydrate of melting point 157°-16O°C?
[α]θ5 = -24.50° (c = 1.00 in methanol).
- 21 46003
Example 2 (-)- 3-Phenoxy-M-iriethy lmorphinan
A solution of 10.2 g (0.04 mol) of ¢-)-3-hydroxy-N-methylmorphinan in 240 ml of freshly distilled pyridine was refluxed while stirring under nitrogen with 18.5 g of bromobenzene, 13.8 g of potassium carbonate and 13.0 g of granular copper for 8 days. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between 500 ml of diethyl ether and 200 ml of 5-N aqueous sodium hydroxide. The diethyl ether solution was washed with water and dried. After removal of the diethyl ether, the residue was distilled, boiling point 18O°-185°C/O.l mm Hg, to give (-)-3-phenoxv-N-methylmorphinan. A sample was recrystallised from diethyl ether; melting point 87°-88°C; [a]25 = -60.10° (c = 1.01 in methanol).
To the foregoing base, 10.0 g (0.03 mol), in 50 ml of diethyl ether was added a solution of 3.2 g of oxalic acid in 100 ml of diethyl ether. The crude oxalate was recrystallised from ethanol to give (-)-3-phenoxy-N-methylmorphinan oxalate of melting point 184°-185°C (decomposition); [a]2^ = -35.47° (c = 1.00 in methanol).
To 7.0 g (0.02 mol) of the base obtained as described in the first paragraph of this Example in 25 ml of acetone was added with stirring a warm solution of 3.5 g of d-tartaric acid in 75 ml of acetone. The mixture was stirred at room temperature for 0.5 hour and then at 0°-5°C for 4 hours. The
- 22 4 6 0 0 3 tartrate salt was separated by filtration and recrystallised from 40 ml of ethanol to give (-)-3-phenoxy-N-methylmorphinan d-tartrate of melting point 131°-133°C; = “20.08° (c =
0.S9 in methanol).
Example 3 (-)-3-(ρ-Methyl)phenoxy-N-methylmorphinan A solution of 5.0 g (0.019 mol) of (-)-3-hydroxy-N-methylmorphinan in 20 ml of freshly distilled pyridine was refluxed while stirring under nitrogen with 6.4 g of £-bromotoluene,
4.0 g of potassium carbonate and 0.2 g of granular copper for days. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with 200 ml of diethyl ether and the diethyl ether solution was washed with 100 ml of 2-N sodium hydroxide and then with water and dried. After removal of the diethyl ether, the residue was distilled, boiling point 125°-140°C/0.15 mm Hg, to give (-)-3-(js-methyl)phenoxy-N-methylmorphinan. A sample was crystallised from diethyl ether; melting point 94°-96°C; [a]2^ = -55.98° (c = 1.00 in methanol).
Treatment of the foregoing base, 3.3 g (0.01 mol), with anhydrous hydrogen chloride in 5 ml of ethyl acetate gave 3.3 g of crude hydrochloride. Recrystallisation from ethyl acetate gave (-)-3-(p-methyl)phenoxy-N-methylmorphinan hydrochloride of melting point 223°-224°C; [a]2^ = -37.85° (c = 0.69 in methanol)
Example 4 (-)-3-(ρ-Methoxy)phenoxy-N-methylmorphinan
A solution of 5.1 g (0.02 mol) of (-)-3-hydroxy-N-methylmorphinan in 20 ml of freshly distilled pyridine was refluxed while stirring under nitrogen with 7.5 g of p-bromoanisole,
4.01 g of potassium carbonate and 0.2 g of granular copper for 7 days. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between 400 ml of diethyl ether and 100 ml of 10-N sodium hydroxide. The diethyl ether solution was washed with water and dried. After removal of the diethyl ether, the residue was distilled, boiling point 139°-155°C/0.15 mm Hg, to give ¢-)-3-(p-methoxy)phenoxy-N-methylmorphinan. Crystallisation from diethyl ether gave pure product of melting point 13O°-132°C;
[α]θ5 = -51.59° (c = 0.99 in methanol).
The foregoing base, 2.0 g (0.006 mol), was treated with anhydrous hydrogen chloride in ethyl acetate to give the crude hydrochloride salt. After crystallisation from ethyl acetate, there was obtained (-)-3-(p-methoxy)phenoxy-N-methylmorphinan hydrochloride of melting point 170°-172°C; [a]^® = -34.22° (c = 0.99 in methanol).
Example 5 (-) -3-(m-Methoxy)phenoxy-N-methylmorphinan
A solution of 5.1 g (0.02 mol) of (-)-3-hydroxy-N-methyl25 morphinan in 20 ml of freshly distilled pyridine was refluxed
- while stirring under nitrogen with 7.5 g of m-bromoanisole,
4.1 g of potassium carbonate and 0.2 g of granular copper for 10 days. Twice the volume of diethyl ether was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between diethyl ether and 5-N sodium hydroxide. The diethyl ether solution was washed with water and dried. After removal of the diethyl ether, the residue was distilled, boiling point 145°-160°C/0.1 mm Hg, to give (-)-3-(m-methoxy)phenoxy-N-methylmorphinan.
For analysis, a sample was crystallised from diethyl ether;
melting point 88°-90°C; [a]2^ = -61-31° (c = 1.00 in methanol).
To the foregoing base, 1.5 g (0.004 mol), in diethyl ether was added a solution of 0.4 g of oxalic acid in diethyl ether.
The crude oxalate salt was recrystallised from ethanol/diethyl ether, there being obtained (-)-3-(m-methoxy)phenoxy-N-methyl25 morphinan oxalate of melting point 148°-15O°C; [a)D = -39.60° (c = 1.00 in methanol).
Example 6 (-)-3-(p-Methoxy)phenoxy-N-methylmorphinan 20 A solution of 5.1 g (0.02 mol) of (-)-3-hydroxy-N-methylmorphinan in 20 ml of freshly distilled pyridine was refluxed while stirring under nitrogen with 7.5 g of o-bromoanisole,
4.1 g of potassium carbonate and 5.0 g of granular copper for 3 days. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between diethyl ether and 5-N sodium hydroxide.
The diethyl ether solution was washed with water and dried.
After removal of the solvent, the residue was distilled, boiling point 165°C/0.2 mm Hg, to give (-)-3-(o-methoxy)phenoxy-N-methylmorphinan. For analysis, a sample was crystallised from ethyl acetate; melting point 87°-89°C; = -59.32° (c =
1.16 in methanol).
To the foregoing base, 2.7 g (0.01 mol), in diethyl ether was added a solution of 0.7 g of oxalic acid in diethyl ether. The crude oxalate salt was recrystallised from ethanol/diethyl ether to give (-)-3-(o-methoxy)phenoxy-N-methylmorphinan oxalate of melting point 135°-187°C (decomposition); “
-37.19° (c = 0.99 in methanol).
Example 7 (-)-3- (p-Hydroxy)phenoxy-N-methylmorphinan
A mixture of 2.0 g (0.005 mol) of (-)-3-(p-methoxy)phenoxy-N-methylmorphinan and 20 g of pyridine hydrochloride was heated at 220°C while stirring under nitrogen for 25 minutes, cooled in an ice-bath and diluted with 50 ml of water. The mixture was made basic with concentrated ammonium hydroxide and extracted with 100 ml of chloroform. The chloroform solution was washed with 50 ml of water and dried. Removal of the solvent in vacuo gave a residue which was treated with diethyl ether and filtered to give (-)-3-(p-hydroxy)phenoxy-N-methylmorphinan. For analysis, a sample was crystallised from ethanol/diethyl ether; melting point 188°-190°C; [a]D=
-51.6° (c = 0.86 in methanol).
0 0 3
Treatment of the foregoing base, 1.4 g (0.004 mol), with anhydrous hydrogen chloride in 10 ml of ethyl acetate gave the crude hydrochloride. Crystallisation of this crude hydrochloride from ethanol/ethyl acetate gave (-)-3-(e-hydroxy)phenoxy-N-methylmorphinan hydrochloride of melting point 16O°-163°C (decomposition); [a]^ = ”34.55° (c = 0.99 in methanol).
Example 8 (-)-3-(m-Hydroxy)phenoxy-N-methylmorphinan
A mixture of 3.8 g (0.01 mol) of (-)-3-(m-methoxy)phenoxy-N-methylmorphinan and 30 g of pyridine hydrochloride was heated at 22O°C while stirring under nitrogen for 25 minutes, cooled in an ice-bath and diluted with water. The mixture was made basic with concentrated ammonium hydroxide and extracted with diethyl ether. The diethyl ether extracts were washed with water and dried. Removal of the solvent in vacuo gave (-)-3-(m-hydroxy) phenoxy-N-methylmorphinan. For analysis, a sample was recrystallised from ethanol; melting point 212°-214°C;
[α]θ5 = -53,13° (c = 1.00 in methanol).
To the foregoing base, 2.2 g (0.01 mol), in ethanol was added a solution of 1.0 g of d-tartaric acid in 20 ml of ethanol. The solution was diluted with diethyl ether and the crystals were collected. The crude salt was recrystallised from ethanol/ethyl acetate to give (-)-3-(m-hydroxy)phenoxy-N-methylmorphinan d-tartrate ethanolate of melting point 135°-138°C? [a]25 = -19.21° (c = 1.26 in methanol).
Abu 0 3
Example 9 (-)-3- (q-Hydroxy)phenoxy-N-methylmorphinan A mixture of 2.5 g (0.007 mol) of (-)-3-(o-methoxy)phenoxy-N-methylmorphinan and 25.0 g of pyridine hydrochloride was heated at 220°C while stirring under nitrogen for 25 minutes, cooled in an ice-bath and diluted with 50 ml of water. The mixture was made basic with concentrated aqueous ammonium hydroxide and extracted with 80 ml of chloroform. The chloroform solution was washed with water and dried. Removal of the solvent in vacuo gave the crude base. After crystallisation from ethyl acetate/hexane, there was obtained pure (-)-3-(o-hydroxy)phenoxy-N-metb.ylmorphinan of melting point 167°-168°C; [a]25 = -52.91° (c = 1.07 in methanol).
The foregoing base, 0.152 g (0.001 mol), and 0.07 g of d-tartaric acid were dissolved in 1 ml of hot ethanol and allowed to crystallise at room temperature. The crude salt was recrystallised from ethanol to give (-)-3-(o-hydroxy)phenoxy-N-methylmorphinan d-tartrate ethanolate of melting point 111°-112°C;. [c]p = -15.96° (c = 1.07 in methanol).
Example 10 (-)-3-(o-Nitro)phenoxy-N-methylmorphinan
A solution of 6.4 g (0.02 mol) of (-)-3-hydroxy-N-methylmorphinan in 30 ml of freshly distilled pyridine was refluxed while stirring under nitrogen with 10.0 g of l-bromo-2-nitrobenzene, 6.0 g of potassium carbonate and 0.3 g of granular
60.0 3 copper·for 3 days. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between diethyl ether and 5-N sodium hydroxide.
The diethyl ether solution was washed with water and dried.
The diethyl ether was removed and the residue was partitioned between chloroform and 5-N sodium hydroxide. After removal of the chloroform in vacuo, the residue was crystallised from diethyl ether to give (-)-3-(o-nitro)phenoxy-N-methylmorphinan of melting point 158°-16O°C; [a)D = -53.16° (c = 0.99 in methanol).
Treatment of the foregoing base, 2.0 g (0.005 mol), with anhydrous hydrogen chloride in ethyl acetate gave the crude hydrochloride. Crystallisation from ethyl acetate gave (-)-3-(o-nitro)phenoxy-N-methylmorphinan hydrochloride hemihydrate of melting point 155°-157°C (decomposition); [a]^® ~ -32.62° (c = 0.99 in methanol).
Example 11 (-)-3-(p-Pluoro)phenoxy-N-methylmorphinan
A solution of 5.1 g (0.02 mol) of (-)-3-hydroxy-N-methyl20 morphinan in 20 ml of freshly distilled pyridine was refluxed while stirring under nitrogen with 17,0 g of p-fluorobromobenzene, 4.1 g of potassium carbonate and 0.2 g of granular copper for 5 days. Twice the volume of diethyl ether was added and the mixture was filtered. The filtrate was concentrated in vacuo and the residue was suspended in 150 ml of hot hexane and filtered. The filtrate was washed with 5-N sodium
46093 hydroxide and then water and subsequently dried. After removal of the solvent, the residue was crystallised from hexane to give (-)-3-(p-fluoro)phenoxy-N-methylmorphinan of melting point 102°-104°C; [al2^ = -53.36° (c = 1.00 in methanol).
Treatment of the foregoing base, 4.0 g (0.01 mol), with anhydrous hydrogen chloride in ethyl acetate gave the crude hydrochloride. Recrystallisation from ethyl acetate gave (-)-3-(£>-fluoro)phenoxy-N-methylmorphinan hydrochloride hemihydrate of melting point 162°-164°C; [α]2^ = -34.83° (c = 0.98 in methanol).
Example 12 (-)-3-(p-Fluoro)phenoxy-N-methylmorphinan A solution of 2.0 g (0.007 mol) of (-)-3-hydroxy-N-methylmorphinan in 10 ml of freshly distilled pyridine was refluxed while stirring under nitrogen with 3.5 g of o-fluorobromobenzene, 2.0 g of potassium carbonate and 2.0 g of granular copper for 2 days. Twice the volume of diethyl ether was added and the mixture was filtered. The filtrate was concentrated in vacuo and the residue was taken up in 200 ml of diethyl ether and washed with 5-N sodium hydroxide. The diethyl ether solution was washed with water and dried.
Removal of the diethyl ether gave crude (-)-3-(o-fluoroJphenoxy-N-methylmorphinan. For analysis, a sample was crystallised from diethyl ether; melting point 113°-115°C; [a]2^ = -48.67° (c = 0.95 in methanol).
To the foregoing base, 2.5 g (0.007 mol), in diethyl ether was added a solution of 0.7 g of oxalic acid in 25 ml of diethyl ether. The crude oxalate salt was recrystallised from ethanol to give (-)-3-(o-fluoro)phenoxy-N-methylmorphinan oxalate of melting point 180°-;182°C; = -30.98° (c = 1.00 in methanol)
Example 13 (-)-3-Phenoxy-N-trichlorocarbethoxymorphinan
To a mixture of 2.3 g (0.007 mol) of (-)-3-phenoxy-N-methylmorphinan, 150 ml of benzene and 0.35 g of potassium carbonate were added dropwise 3.3 g of 2,2,2-trichloroethyl chloroformate. . The mixture was stirred at reflux for 6 days.
The mixture was diluted with diethyl ether and extracted with
4-N hydrochloric acid. The organic phase was washed with dilute ammonium hydroxide and water and then dried. Removal of the solvent gave (-)-3-phenoxy-N-trichlorocarbethoxymorphinan. For analysis, a sample was distilled; boiling point 230°-240°C/ 0.05 mm Hg; [a]2^ = “119.65° (c = 0.95 in methanol).
Example 14 (-)-3-Phenoxymorphinan
To a solution of 3.4 g (0.007 mol) of (-)-3-phenoxy-N-trichlorocarbethoxymorphinan in 40 ml of 90% acetic acid were added portionwise 2.0 g of zinc dust. The mixture was stirred at room temperature for 16 hours and filtered. The filtrate was concentrated in vacuo and the residue was partitioned between diethyl ether and dilute ammonium hydroxide. The
6 0 0 3 diethyl ether solution was extracted with 4-N hydrochloric acid. The acidic solution was extracted with chloroform. After removal of the chloroform, the crude hydrochloride was crystallised from ethanol to give (-)-3-phenoxymorphinan hydrochloride of melting point 322°-324°C; [a]23 = -33.88° (c = 1.00 in methanol).
Example 15 (-)-3-Phenoxy-N-cyclopropylcarbonylmorphinan
To a solution of 3.7 g (0.011 mol) of (-)-3-phenoxy-N-methylmorphinan in 50 ml of toluene were added dropwise at 5 °C
.8 g of cyclopropane carboxylic acid chloride in 25 ml of toluene. The mixture was allowed to warm to room temperature and was then refluxed for 15 hours. The solvent was removed in vacuo and the residue was partitioned between diethyl ether and dilute hydrochloric acid. The diethyl ether solution was washed with water and dried. Removal of the solvent in vacuo gave (-)-3-phenoxy-N-cyclopropylcarbonylmorphinan. For analysis, a sample was distilled; boiling point 230°-240°C/0.05 mm Hg; [a]25 = -173.45° (c = 0.99 in methanol).
Example 16 (-)-3-Phenoxy-N-cyclopropyImethylmorphinan
To a suspension of 0.4 g of lithium aluminium hydride in 20 ml of anhydrous tetrahydrofuran were added dropwise 4.6 g (0.011 mol) of (-)-3-phenoxy-N-cyclopropylcarbonylmorphinan in 30 ml of anhydrous tetrahydrofuran over a period of 15 minutes.
6 U v a
After refluxing the mixture under nitrogen for 16 hours, it was cooled to room temperature and water was added dropwise. The resulting suspension was filtered and the filtrate was concentrated. The residue was partitioned between diethyl ether and 4-N hydrochloric acid. The acidic phase was made basic with concentrated ammonium hydroxide and the aqueous suspension was extracted with diethyl ether. The diethyl ether solution was washed with water and dried. Removal of the diethyl ether under reduced pressure gave (-)-3-phenoxy-N-cyclopropylmethylmorphinan. For analysis, a sample was distilled; boiling point 190°-200°C/0.1 mm Hg; [a]25 = -89.07° (c = 0.99 in methanol).
Treatment of the foregoing base, 2.6 g (0.007 mol), with anhydrous hydrogen chloride in diethyl ether gave the crude hydrochloride. After crystallisation from ethyl acetate, there was obtained (-)-3-phenoxy-N-cyclopropylmethylmorphinan hydrochloride of melting point 186°-188°C; [a}^ = -67.16° (c = 1.00 in methanol).
Example 17 (-)-1-(p-Hydroxybenzyl)-2-methyl-l,2,3,4,5,6,7,8-octahydroisoquinoline
A mixture of 253.9 g (0.935 mol) of (-)-1-(p-methoxybenzyl)-2-methyl-l,2,3,4,5,6,7,8-octahydroisoquinoline and 1,2 litres of diethyleneglycol was warmed to 80°-100°C and 260 g of potassium hydroxide were added. The mixture was heated to 210°C and stirred at this temperature under a constant stream of nitrogen for 36 hours. From time-to-time during this period, the stop-cock was removed to allow the escape of water vapour since, if this had not been done, the desired internal temperature of 210°C would not have been attained. The dark brown solution was cooled to room temperature, diluted with 600 ml of water and extracted with 400 ml of diethyl ether.
The aqueous solution was made acidic with concentrated aqueous hydrochloric acid and then made basic with concentrated aqueous ammonium hydroxide. The aqueous suspension was extracted with four 250 ml portions of ethyl acetate. The ethyl acetate solution was washed with water and dried. Removal of the solvent gave crude (-)-1-(g-hydroxybenzyl)-2-methyl-l,2,3,4,5,6, 7,8-octahydroisoquinoline, For analysis, a sample was recrystallised from tetrahydrofuran/heptane; melting point
119°-12O°C; [α]£ = -36.01° (c = 0.98 in methanol).
Example 18 (-)-1-(p-phenoxybenzyl)-2-methyl-l,2,3,4,5,6,7,8-octahydroisoguinoline
A solution of 2.4 g (0.009 mol) of (-)-1-(g-hydroxybenzyl)20 -2-methyl-l,2,3,4,5,6,7,8-octahydroisoquinoline in 10 ml of freshly distilled pyridine was refluxed while stirring under nitrogen with 3.1 g of bromobenzene, 2.0 g of potassium carbonate and 0.1 g of granular copper for 9 days. The mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue were added 150 ml of diethyl ether and the material which was insoluble in the diethyl ether was removed by filtration. The filtrate was extracted with 2-N sodium hydroxide, washed with water and dried. Removal of the solvent gave {-)-(p-phenoxybenzyl)-2-methyl-l,2,3,4,5,6,7,8-octahydroisoquinoline. For analysis, a sample was distilled; boiling point 120°C/0.15 mm Hg; [a]2^ = -18.53° (c = 1.14 in methanol).
To the foregoing base, 1.0 g (0.003 mol), in 5 ml of diethyl ether was added a solution of 0.3 g of oxalic acid in diethyl ether. The crude oxalate was recrystallised from ethanol to give (-)-1- (p-phenoxybenzyl)-2-methyl-l,2,3,4,5,6,7,8-octahydroisoquinoline oxalate of melting point 16O°-1S2°C;
[a]25 = -37.17° (c = 1.00 in methanol).
Example 19
Acid catalysed cyclisation of (-)-1-(p-phenoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline
A mixture of 0.5 g (0.002 mol) of (-)-l-(g-phenoxybenzyl)-2-methyl-l,2,3,4,5,6,7,8-octahydroisoquinoline and 5 ml of 99% phosphoric acid was heated at 135°C while stirring under nitrogen for 3 days. The mixture was poured into ice-water and made basic with concentrated ammonium hydroxide. The aqueous suspension was extracted with chloroform. The combined chloroform extracts were washed with water, dried and the solvent removed to give crude (-)-3-phenoxy-N-methylmorphinan.
Example 20 (-)-3-Phenoxy-N-cyclobutylcarbonylmorphinan
To a solution of 3.9 g (0.01 mol) of (-)-3-phenoxy-N35
-methylmorphinan in 50 ml of toluene were added dropwise at room temperature 6.9 g of cyclobutane carboxylic acid chloride in ml of toluene. The mixture was stirred at room temperature for 1 hour and then heated at reflux for 12 days. The mixture was cooled to room temperature and washed successively with 4-N hydrochloric acid, water and 5-N sodium hydroxide. The organic phase was dried and filtered. Removal of the solvent in vacuo gave (-)-3-phenoxy-N-cyclobutylcarbonylmorphinan.
For analysis, a sample was distilled; boiling point 220°C/0.1 je mm Hg; [a]p = -163.25° (c = 0.98 in methanol).
Example 21 (-)-3-Phenoxy-N-cyclobutylmethylmorphinan To a suspension of 0.4 g of lithium aluminium hydride in 40 ml of anhydrous tetrahydrofuran were added dropwise 2.1 g (0.005 mol) of (-)-3-phenoxy-N-cyclobutylcarbonylmorphinan in 20 ml of anhydrous tetrahydrofuran. After refluxing the mixture under nitrogen for 3 hours, it was cooled to room temperature and water was added dropwise. The resulting suspension was filtered and the filtrate was concentrated.
The residue was dissolved in 50 ml of diethyl ether and extracted with 75 ml of 4-N hydrochloric acid. The aqueous solution was made basic with 10-N sodium hydroxide and extracted with 75 ml of diethyl ether. The diethyl ether solution was washed with water and dried. Removal of the solvent in vacuo gave crude (-)-3-phenoxy-N-cyclobutylmethylmorphinan. For analysis, a sample was distilled; boiling point 215°[a]^5 = -73.25° (c = 0.99 in methanol).
225°C/0.5 mm Hg;
Treatment of the foregoing base, 1.1 g (0.003 mol), with anhydrous hydrogen chloride in ethyl acetate gave the crude hydrochloride. After crystallisation from ethyl acetate, there was obtained pure (-)-3-phenoxy-N-cyclobutylmethylmorphinan hydrochloride of melting point 175°-177°C; [a]2^ = -66.59° (c = 1.03 in methanol).
Example 22 (-)-3-Phenoxy-N-phenylacetylmorphinan
To a mixture of 4.0 g (0.012 mol) of (-)-3-phenoxy10 morphinan, 2.5 g of triethylamine and 15 ml of methylene chloride was added dropwise a solution of 2.9 g of phenylacetyl chloride in 15 ml of methylene chloride. After refluxing the mixture for 14 hours, it was cooled to room temperature and washed successively with water, 4-N hydrochloric acid, 2-N sodium hydroxide and water. The organic solution was dried and the solvent was evaporated to give crude (-)-3-phenoxy-N-phenylacetylmorphinan. For analysis, a sample was distilled;
boiling point 24O°-25O°C/O.O5 mm Hg; [a]25 = -133,27° (c = 1.11 in methanol).
Example 23 (-)-3-Fhenoxy-N-phenethylmorphinan
To a suspension of' 0.8 g of lithium aluminium hydride in 40 ml of anhydrous tetrahydrofuran were added dropwise 4.2 g (0.01 mol) of (-)-3-phenoxy-N-phenylacetylmorphinan in 40 ml of anhydrous tetrahydrofuran over a period of 45 minutes. After refluxing the mixture under nitrogen for 3 hours, it was cooled to room temperature and water was added dropwise. The resulting suspension was filtered and the filtrate was concentrated. The residue was partitioned between diethyl ether and water. The diethyl ether solution was dried and the solvent was evaporated to give crude (-)-3-phenoxy-N-phenethylmorphinan. For analysis, a sample was distilled; boiling oc point 16O°-165°C/O.l mm Hg; [a]*3 = -100.27° (c = 0.55 in methanol).
To the foregoing base, 3.2 g (0.007 mol), in diethyl ether was added a solution of 0.8 g of oxalic acid in diethyl ether. The crude oxalate was recrystallised twice from ethanol to give pure (-)-3-phenoxy-N-phenethylmorphinan oxalate of melting point 217°-219°C; = “72.17° (c = 1.06 in methanol).
Example 24 (-)-3-Phenoxy-H-[ (2-furylmethyl)carbonyl]morphinan
To a mixture of 4.0 g (0.012 mol) of (-)-3-phenoxymorphinan, 2.5 g of triethylamine and 15 ml of methylene chloride was added dropwise a solution of 2.7 g of 2-furylaoetyl chloride.
After refluxing the mixture for 14 hours, it was cooled to room temperature and washed successively with water, 4-N hydrochloric acid, 5-N sodium hydroxide and water. The organic solution was dried and the solvent was evaporated to give crude (-)-3-phenoxy-N-[(2-furylmethyl)carbonyl]morphinan. For analysis, a sample was distilled; boiling point 215°-225°C/O.l mm Hg; [α]β = -135.36° (c = 1.06 in methanol).
Example 25 (-)-3-Phenoxy-N-[2-(2-furyl)ethyl3morphinan
To a suspension of 0.8 g of lithium aluminium hydride in ml of anhydrous tetrahydrofuran were added dropwise 5.1 g 5 (0.012 mol) of (-)-3-phenoxy-N-[(2-furylmethyl)carbonyl]morphinan in 40 ml of anhydrous tetrahydrofuran. After refluxing the mixture under nitrogen for 3 hours, it was cooled to room temperature and water was added dropwise. The resulting suspension was filtered and the filtrate was concentrated.
The residue was partitioned between diethyl ether and water.
The diethyl ether solution was washed with 5-N sodium hydroxide and dried. Removal of the solvent in vacuo gave an oily residue. This residue was purified by chromatography over 50 g of silica gel using diethyl ether for the elution to give (-)-3-phenoxy-N-[2-(2-furyl)ethyl]morphinan. For analysis, a sample was distilled; boiling point 145°-15O°C/O.1 mm Hg;
[a]2^ = -94.15° (c = 1.06 in methanol).
To the foregoing base, 1.2 g (0.003 mol), in diethyl ether was added a solution of 0.3 g of oxalic acid in diethyl ether.
The crude oxalate was recrystallised twice from ethanol to give (-)-3-phenoxy-N-[2-(2-furyl)ethyllmorphinan oxalate of melting point 195°-197°C (decomposition); = -64.52° (c = 1.03 in methanol).
Example 26 (-)-3-Phenoxy-N-[(2-thienylmethyl)carbonyllmorphinan
To a mixture of 4.0 g (0.012 mol) of (-)-3-phenoxy39 morphinan, 2.5 g of triethylamine and 15 ml of methylene chloride was added dropwise a solution of 3.3 g of 2-thienylacetyl chloride in 15 ml of methylene chloride. After refluxing the mixture for 15 hours, it was cooled to room temperature, diluted with methylene chloride and washed successively with water, 4-N hydrochloric acid, 5-N sodium hydroxide and water.
The organic phase was dried and the solvent was evaporated to give crude (-)-3-phenoxy-N-[(2-thienylmethyl)carbonyl]morphinan. For analysis, a sample was distilled; boiling point 235°-24O°C/
0.05 mm Hg; [a]^5 = -134.17° (c = 1.03 in methanol).
Example 27 (-)-3-Phenoxy-N-[2-(2-thienyl)ethyl]morphinan
To a suspension of 0.8 g of lithium aluminium hydride in ml of anhydrous tetrahydrofuran were added dropwise 6.2 g (0.014 mol) of (-)-3-phenoxy-N-[(2-thienylmethyl)carbonyl]morphinan in 40 ml of anhydrous tetrahydrofuran. After refluxing the mixture under nitrogen for 3 hours, it was cooled to room temperature and water was added dropwise. The resulting suspension was filtered and the filtrate was concentrated. The residue was dissolved in diethyl ether and the diethyl ether solution was extracted with 4-N hydrochloric acid. The aqueous phase was made basic with 10-N sodium hydroxide and extracted with diethyl ether. The organic phase was dried and the solvent was removed in vacuo to give crude (-)-3-phenoxy-N-[225 -(2-thienyl)ethyl]morphinan. For analysis, a sample was distilled; boiling point 15O°C/O.O5 mm Hg; [a]25 = -96.45° (c = 1.23 in methanol).
‘S'w'
The foregoing base, 3.0 g (0.007 mol, in diethyl ether was treated with sulphuric acid. The crude sulphate was recrystallised from methanol/diethyl ether to give pure (-)-3-phenoxy-N-[2-(2-thienyl)ethyl]morphinan sulphate of melting point
135°-138°C; [α]θ5 = -67.28° (c = 1.00 in methanol).
Example 28 (-)-3-(m-Fluoro)phenoxy-N-methylmorphinan
A mixture of 3.0 g (0.011 mol) of (-)-3-hydroxy-N-methylmorphinan, 50 ml of freshly distilled pyridine, 2.2 g of 310 -bromofluorobenzene, 2.4 g of potassium carbonate and 3.0 g of granular copper was heated in a stainless steel container at 120°C for 8 days. After cooling, the container was opened and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between diethyl ether and 10-N sodium hydroxide. The diethyl ether solution was washed with water and dried. Removal of the solvent in vacuo gave a dark residue which was distilled; boiling point
131°-140°C/0.15 mm Hg, to give (-)-3-(m-fluoro)phenoxy-N25
-methylmorphinan; [α]β = -56.79° (c = 1.04 in methanol).
To the foregoing base, 0.4 g (0.001 mol), in 2 ml of acetone.was added a solution of 0.2 g of d-tartaric acid in 10 ml of acetone. The crude tartrate was recrystallised from acetone to give (-)-3-(m-fluoro)phenoxy-N-methylmorphinan d-tartrate hemihydrate of melting point 121°-123°C; [a]25 =
-18.61° (c = 1.03 in methanol).
4-6003
Example 29 (-)-3-(o-Methoxy)phenoxy-N-cyclopropylmethylmorphinan
To a solution of 1.7 g (0.005 mol) of (-)-3-(o-methoxy)phenoxy-N-methylmorphinan in 25 ml of toluene were added dropwise under nitrogen at room temperature 2.5 g of cyclopropane carboxylic acid chloride in 15 ml of toluene. The mixture was refluxed for 13 days and the solvent was removed in vacuo.
The residue was partitioned between 500 ml of diethyl ether and 200 ml of 4-N hydrochloric acid. The diethyl ether solution was washed with dilute ammonium hydroxide and with water and subsequently dried. Removal of the solvent gave crude (-)-3-(o-methoxy)phenoxy-N-cyclopropylcarbonylmorphinan which was reduced without further purification.
To a suspension of 0.2 g of lithium aluminium hydride in 20 ml of anhydrous tetrahydrofuran was added dropwise 1.0 g (0.002 mol) of (-)-3-(o-methoxy)phenoxy-N-cyclopropylcarbonylmorphinan in 10 ml of anhydrous tetrahydrofuran. After refluxing the mixture under nitrogen for 15 hours, it was cooled to room temperature and water was added dropwise. The resulting suspension was filtered and the filtrate was concentrated. The residue was partitioned between diethyl ether and 4-N hydrochloric acid. The aqueous solution was made basic with 10-N sodium hydroxide and extracted with diethyl ether. The diethyl ether solution was washed with water and dried. Removal of the solvent in vacuo gave crude (-)-3-(o-methcxy)phenoxy-N-cyclopropylmethylmorphinan. For analysis, a sample was distilled; boiling point 21O°-22O°C/O.1 mm Hg;
[ct]25 = -57.34° (c = 0.52 in methanol).
V
Treatment of the foregoing base, 0.5 g (0.001 mol), with anhydrous hydrogen chloride in ethyl acetate gave the crude hydrochloride. After crystallisation from ethanol/diethyl ether, there was obtained (-)-3-(p-methoxy)phenoxy-N-cyclopropylmethylmorphinan hydrochloride of melting point 226°-227°C 25 (decomposition); [a]Q = -71-18° (c = 1.00 in methanol).
Example 30 (-)-3-(p-Methoxy)phenoxy-N-cyclopropylmethylmorphinan
To a solution of 1.9 g (0.005 mol) of (-)-3-(p-methoxy)phenoxy-N-methylmorphinan in 25 ml of toluene were added dropwise under nitrogen at room temperature 2.9 g of cyclopropane carboxylic acid chloride in 12 ml of toluene. The mixture was stirred at reflux for 13 days and the solvent was removed under reduced pressure. The residue was partitioned between diethyl ether and 4-N hydrochloric acid. The diethyl ether solution was washed with dilute ammonium hydroxide and with water and then dried. Removal of the solvent gave an oily residue which was distilled to give (-)-3-(p-methoxy)phenoxy-N-cyolopropylcarbonylmorphinan of boiling point 17O’C/O.O5 mm Hg. This compound was used for the reduction without further purification.
To a suspension of 0.4 g of lithium aluminium hydride in 20 ml of anhydrous tetrahydrofuran were added dropwise 2.2 g (0.005 mol) of (-)-3-(p-methoxy)phenoxy-N-cyclopropylcarbonylmorphinan in 10 ml of anhydrous tetrahydrofuran. After refluxing the mixture under nitrogen for 15 hours, it was cooled to room temperature and water was added dropwise. The
0 03 resulting suspension was filtered and the filtrate was concentrated. The residue was partitioned between diethyl ether and 4-N hydrochloric acid. The aqueous solution was made basic with 10-N sodium hydroxide and extracted with diethyl ether. The diethyl ether solution was washed with water and dried. Removal of the solvent in vacuo gave crude f—)—3—(jo— -methoxy)phenoxy-N-cyclopropylmethylmorphinan. For analysis, a sample was distilled; boiling point 215°-220°C/0.25 mm Hg;
[a]2® = -77.78° (c = 0.45 in methanol).
Treatment of the foregoing base, 1.5 g (0.004 mol), with anhydrous hydrogen chloride in ethyl acetate gave the crude hydrochloride. Recrystallisation from ethanol/diethyl ether gave (-)-3-(o-methoxy)phenoxy-N-cyclopropylmethylmorphinan hydrochloride of melting point 204°-206°C; [a]^® = -60.50° (c = 0.99 in methanol).
The following Examples illustrate pharmaceutical preparations provided by the present invention and the production thereof:
Example A
Tablets containing the following ingredients were produced:
v v v u>
Item Ingredient mg/tablet 1 (-)-3-Phenoxy-N-methylmorphinan 5.0 2 Lactose 99.0 3 Pregelatinised starch 10.0 5 4 Corn starch 15.0 5 Modified starch 10.0 6 Magnesium stearate 1.0 Weight of tablet 140 mg Items 1, 2, 3, 4 and 5 were mixed in a suitable mixer, 10 granulated with water and dried overnight in an oven. The mixture was then milled through a Fitzpatrick mill, mixed with item 6 and compressed to tablets on a suitable press. Example B Tablets containing the following ingredients were produced 15 Item Ingredient mg/tablet 1 (-)-3-Phenoxy-N-methylmorphinan 10.0 2 Lactose (anhydrous) 103.0 3 Avicel 45.0 4 Modified starch 10.0 20 5 Corn starch 30.0 6 Magnesium stearate 2.0 Weight of tablet 200 mg
Items 1, 2, 3, 4 and 5 were mixed in a suitable mixer for 10 to 15 minutes. The magnesium stearate (item 6) was added as
6003 a premix and the mixture obtained was mixed for 4 minutes. It was then compressed to tablets on a suitable press.
Example C
A capsule formulation containing the following ingredients 5 was produced:
Item
4
Ingredient mg/capsule (-)-3-Phenoxy-N-methylmorphinan 10.0
Lactose 218.0
Corn starch 50.0
Magnesium stearate 2.0
Talc 10.0
Fill weight of capsule 220 mg
Items 1, 2 and 3 were mixed in a suitable mixer and milled through a suitable mill. The resulting mixture was mixed with items 4 and 5 and filled into capsules on a capsule filling machine.
Example D
A capsule formulation containing the following ingredients was produced:
Item Ingredient mg/capsule 1 (-)-3-(p-Methoxy)phenoxy-N-methylmorphinan 25.0 2 Lactose 257.0 3 Corn starch 70.0 4 Magnesium stearate 3.0 5 Talc 15.0 Fill weight of capsule 370 mg Items 1, 2 and 3 were mixed in a suitable mixer and milled
through a suitable mill. The resulting mixture was mixed with 10 items 4 and 5 and filled into capsules on a capsule filling machine.
Example E
A capsule formulation was produced in the manner described in Example D using (-)-(p-methyl)phenoxy-N-methylmorphinan as the active ingredient.
Example F
Tablets containing the following ingredients were produced by a wet granulation procedure:
Item
Ingredient mg/tablet (-)-3-(g-Methoxy)phenoxy-N-methylmorphinan 0.5
Lactose 186.5
Modified starch 35
Pregelatinised starch
Distilled water q.s.
Magnesium stearate 4
Weight of tablet 250 mg
Items 1, 2, 3 and 4 were mixed in a suitable mixer and granulated with sufficient distilled water to proper consistency. The mixture was then milled, dried in a suitable oven, milled and mixed with magnesium stearate for 3 minutes. The mixture obtained was compressed to tablets on a suitable press equipped with appropriate punches.
Example G
Tablets containing the following ingredients were produced according to a wet granulation procedure:
Item Ingredient mg/tablet 1 (-)-3-Pentafluorophenoxy-N-methylmorphinan 2.0 2 Lactose 253.0 3 Modified starch 55 4 Pregelatinised starch 35 5 Distilled water g.s. 6 Magnesium stearate Weight of tablet 5 350 mg
Items 1, 2, 3 and 4 were mixed in a suitable mixer and granulated with sufficient distilled water to proper consistency The mixture was then milled, dried in a suitable oven, milled and mixed with magnesium stearate for 3 minutes. The mixture obtained was compressed to tablets on a suitable press equipped with appropriate punches.
Claims (83)
1. ) Compounds of the general formula , wherein n stands for 1, 2, 3, 4 or 5, R represents a hydrogen or halogen atom or a 5 nitro, lower alkyl, lower alkoxy or hydroxy group and R^ represents a hydrogen atom or a lower alkyl or lower alkenyl group or a group of the formula -CH 2 (CH 2 )pR 2 or -C(0)-(CH 2 ) —R 2 in which R 2 represents a 10 heteroaromatic, aromatic or cyclo-(lower alkyl) group and p stands for zero, 1, 2 or 3, and pharmaceutically acceptable salts thereof.
2. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 1, wherein R^ represents a lower alkyl group. 15
3. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 2, wherein R^ represents the methyl group.
4. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 1, wherein R^ represents a group of the formula —CH-—(CH_) —R o . 2 2 p 2
5. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 4, wherein g stands for zero.
6. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 5, wherein R 2 represents the cyclopropyl 5 group.
7. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 4, wherein g stands for 1.
8. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 7, wherein R 2 represents the phenyl group. 10
9. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 7, wherein R 2 represents the 2-furyl group.
10. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 1, wherein R^ represents a group of the formula -C(O)~(CH 2 )p-R 2 . 15
11. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 10, wherein g stands for zero.
12. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 11, wherein R 2 represents the cyclopropyl group. 20
13. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 1 wherein R represents a hydrogen atom.
14. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 1, wherein R represents a lower alkyl group.
15. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 14, wherein R represents the methyl group. 5
16. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 15, wherein n stands for 1.
17. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 1, wherein R represents a lower alkoxy group. 10
18. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 17, wherein R represents the methoxy group.
19. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 18, wherein n is 1.
20. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative 15 as claimed in claim 1, wherein R represents a hydroxy group.
21. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 20, wherein n stands for 1.
22. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 1, wherein R represents a nitro group. 20
23. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 22, wherein n stands for 1.
24. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 1, wherein R represents a halogen atom.
25. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 24, wherein R represents a fluorine atom.
26. ) A levorotatory 3-phenoxy-N-substituted morphinan derivative as claimed in claim 25, wherein n stands for 1 or 5.
27. ) (-)-3-Phenoxy-N-methylmorphinan.
28. ) (-)-3-(p-Methyl)phenoxy-N-methylmorphinan.
29. ) (-) -3-Phenoxy-N-phenethylmorphinan.
30. ) (-)-3-Phenoxy-N-[2-(2-furyl)ethyllmorphinan.
31. ) (-)-3-(o-Methoxy)phenoxy-N-cyclopropylmethylmorphinan.
32. ) (-)-3- (p-Methoxy)phenoxy-N-cyclopropylmethylmorphinan.
33. 3 3) (-,-3-(m-Methoxy)phenoxy-N-me thylmorphinan.
34. ) (-)-3-(o-Methoxy)phenoxy-N-methylmorphinan.
35. ) (-)-3-(p-Hydroxy)phenoxy-N-methylmorphinan.
36. ) (-)-3-(o-Hydroxy)phenoxy-N-methylmorphinan.
37. ) (-)-3-(o-Nitro)phenoxy-N-methylmorphinan,
38. 3 8) (-)-3-(p-Fluoro)phenoxy-N-methylmorphinan.
39. ) (-)-3-(o-Fluoro)phenoxy-N-methylmorphinan,
40. ) (-)-3-Pentafluorophenoxy-N-methylmorphinan.
41. ) (-)-3-Phenoxy-N-oyclopropylmethylmorphinan.
42. ) (-)-3-Phenoxy-N-cyclopropylcarbonylmorphinan.
43. ) A process for the manufacture of the levorotatory 3-phenoxy-N-substituted morphinan derivatives as set forth in claim 1, which process comprises (a) reacting a compound of the general formula (II) , wherein has the significance given in claim 1, with a compound of the general formula (III) ( R ), *| V v. ** μ , wherein n and R have the. significance given in claim 1 and X represents a halogen atom, or (bj for the manufacture of a compound of formula I in 5 which R represents a hydroxy group, cleaving an ether of the general formula ,- wherein n and R^ have the significance given in claim 1 and represents a lower 10 alkyl group, or (c) for the manufacture of a compound of formula I in which R^ represents a group of the formula -C¢0)-(CHjJp—Rj/ reacting a compound of the general formula , wherein n and R have the significance given in claim 1, with a compound of the general formula X—CO—(CH 2 )p—R 2 (IV) , wherein R 2 and £ have the significance given in claim 1 and X has the significance given earlier in this claim, or (d) for the manufacture of a compound of formula I in which represents a group of the formula -CH 2 —(CHj)^—R 2 , reducing a compound of the general formula , wherein R, R 2 and £ have the significance given in claim 1, or (e) for the manufacture of a compound of formula I in which Rj. represents a hydrogen atom, treating a compound of the general formula , wherein n and R have the significance given in claim 1, with zinc in a lower alkanoic acid, or 'U) V V (f) for the manufacture of a compound of formula I in which R^ represents a group of the formula -CH 2 —(CH 2 )p—R 2 , reacting a compound of the general formula , wherein n and R have the significance given in claim 1, with a compound of the general formula X_CH 2 -(CH 2 )p— R 2 A) , wherein R 2 and £ have the significance given in claim 1 and X has the significance given earlier in this claim, or (g) for the manufacture of a compound of formula I in which R^ represents a hydrogen atom, dealkylating a compound of formula IC, or (h) for the manufacture of a compound of formula I in which represents a group of the formula -C(O)-CH 2 ~(CH 2 )p—R 2 , reacting a compound of formula VII with a compound of formula IV, or (i) for the manufacture of a compound of formula I in which R^ represents a lower alkyl or lower alkenyl group, reacting a compound of formula VII with a compound of the general formula 4 6003 x—r 7 , wherein X has the significance given earlier in tnis claim and R_, represents a lower alkyl or lower alkenyl group, (j) cyclising a compound of the general formula , wherein n, R and R^ have the significance given in claim 1, and (k) if desired, converting a compound of formula I into a pharmaceutically acceptable acid addition salt.
44. ) A process as claimed in claim 43, wherein R^ represents a lower alkyl group.
45. ) A process as claimed in claim 44, wherein R^ represents the methyl group.
46. ) A process as claimed in claim 43, wherein R^ represents a group of the formula -CH 2 —(CH 2 )p-R 2 . * zero.
47. 48) A process as claimed in claim 47,. wherein R 2 represents the cyclopropyl group. 5
48. 49) A process as claimed in claim 46, wherein £ stands for I.
49. 50) A process as claimed in claim 49, wherein R 2 represents the phenyl group.
50. 51) A process as claimed in claim 49, wherein R 2 represents the 2-furyl group. 10
51. 52) A process as claimed in claim 43, wherein R^ represents a group of the formula —C(0)—(CH_) —R o . z P
52. 53) A process as claimed in claim 52, wherein £ stands for zero.
53. 54) A process as claimed in claim 53, wherein R 2 represents 15 the cyclopropyl group.
54. 55) A process as claimed in claim 43, wherein R represents a hydrogen atom.
55. 56) A process as claimed in claim 43, wherein R represents a lower alkyl group.
56. 57) A process as claimed in claim 56, the methyl group.
57. 58) A process as claimed in claim 57,
58. 59) A process as claimed in claim .43, lower alkoxy group.
59. 60) A process as claimed in claim 59, methoxy group.
60. 61) A process as claimed in claim 60,
61. 62) A process as claimed in claim 43, hydroxy group.
62. 63) A process as claimed in claim 62,
63. 64) A process as claimed in claim 43, nitro group.
64. 65) A process as claimed in claim 64,
65. 66) A process as claimed in claim 43, halogen atom.
66. 67) A process as claimed in claim 66, fluorine atom. wherein R represents wherein n stands for 1. wherein R represents a wherein R represents the wherein n stands for 1. wherein R represents a wherein n stands for 1. wherein R represents a wherein n stands for 1. wherein R represents a wherein R represents a
67. 68) A process as claimed in claim 67, wherein n stands for 1 or 5.
68. 69) A process as claimed in claim 43, wherein (-)-3-phenoxy-N-methylmorphinan is manufactured.
69. 70) A process as claimed in claim 43, wherein (-)-3-(g-methyl)phenoxy-N-methylmorphinan is manufactured.
70. 71) A process as claimed in claim 43, wherein (-)-3-phenoxy-N-phenethylmorphinan is manufactured.
71. 72) A process as claimed in claim 43, wherein (-)-3-phenoxy-N-[2-(2-furyl)ethyllmorphinan is manufactured.
72. 73) A process as claimed in claim 43, wherein (-)-3-(o-methoxy)phenoxy-N-cyclopropyImethylmorphinan is manufactured.
73. 74) A process as claimed in claim 43, wherein (—) —3—(£— -methoxy)phenoxy-N-cyclopropyImethylmorphinan is manufactured.
74. 75) A process as claimed in claim 43, wherein (-)-3-(m-methoxy)phenoxy-N-methylmorphinan is manufactured.
75. 76) A process as claimed in claim 43, wherein (-)-3-(0-methoxy)phenoxy-N-methylmorphinan is manufactured.
76. 77) A process as claimed in claim 43, wherein (-)-3-(£-hydroxy)phenoxy-N-methylmorphinan is manufactured. 61 46003
77. 78) A process as claimed in claim 43, wherein {—)—3—(o— -hydroxy)phenoxy-N-methylmorphinan is manufactured.
78. 79) A process as claimed in claim 43, wherein (-)-3-(0-nitro)phenoxy-N-methylmorphinan is manufactured. 5
79. 80) A process as claimed in claim 43, wherein (-)-3-(g-fluoro)phenoxy-N-methylmorphinan is manufactured.
80. 81) A process as claimed in claim 43, wherein (-)-3-(0-fluoro)phenoxy-N-methylmorphinan is manufactured.
81. 82) A process as claimed in claim 43, wherein (-)-3-penta~ fluorophenoxy-N-methylmorphinan is manufactured.
82. 83) A process as claimed in claim 43, wherein (-)-3-phenoxy- . -N-cyclopropyImethylmorphinan is manufactured.
83. 84) A process as claimed in claim 43, wherein (-)-3-phenoxy-17-cyclopropylcarbonylmorphinan is manufactured. 15 85) A process for the manufacture of the levorotatory 3-phenoxy-N-substituted morphinan derivatives as set forth in claim 1, substantially as hereinbefore described with reference to any one of the foregoing Examples. 36) A levorotatory 3-phenoxy-N-substituted morphinan derivative 20 as set forth in claim 1, when manufactured by the process claimed in any one of claims 43 to 85 inclusive or by an obvious chemical equivalent thereof. - 62 \ 87) A pharmaceutical preparation containing a levorotatory 3-phenoxy-N-substituted morphinan derivative as set forth in claim 1 in association with a compatible carrier material.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US74802276A | 1976-12-06 | 1976-12-06 | |
| US05/811,233 US4113729A (en) | 1976-12-06 | 1977-06-29 | 3-Phenoxymorphinans and derivatives thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE46003L IE46003L (en) | 1978-06-06 |
| IE46003B1 true IE46003B1 (en) | 1983-01-26 |
Family
ID=27114858
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2468/77A IE46003B1 (en) | 1976-12-06 | 1977-12-05 | 3-phenoxy-n-substituted morphinan derivatives, their manufacture and pharmaceutical preparations containing them |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS5392776A (en) |
| AR (1) | AR219510A1 (en) |
| AT (1) | AT364826B (en) |
| AU (1) | AU514827B2 (en) |
| CA (1) | CA1088935A (en) |
| DE (1) | DE2754062A1 (en) |
| DK (1) | DK540977A (en) |
| ES (3) | ES464751A1 (en) |
| FI (1) | FI773636A (en) |
| FR (1) | FR2372808A1 (en) |
| GB (1) | GB1589792A (en) |
| HU (1) | HU177640B (en) |
| IE (1) | IE46003B1 (en) |
| IL (1) | IL53532A (en) |
| IT (1) | IT1143727B (en) |
| LU (1) | LU78638A1 (en) |
| MC (1) | MC1172A1 (en) |
| NL (1) | NL7713432A (en) |
| NO (1) | NO774155L (en) |
| NZ (1) | NZ185860A (en) |
| PT (1) | PT67363B (en) |
| SE (1) | SE7713779L (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4247697A (en) * | 1979-09-10 | 1981-01-27 | Hoffmann-La Roche Inc. | 3-Phenoxy morphinans and their derivatives |
| TW264473B (en) * | 1993-01-06 | 1995-12-01 | Hoffmann La Roche |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH560194A5 (en) * | 1967-08-25 | 1975-03-27 | Hoffmann La Roche | |
| JPS493961B1 (en) * | 1969-06-24 | 1974-01-29 |
-
1977
- 1977-11-30 FI FI773636A patent/FI773636A/en not_active Application Discontinuation
- 1977-12-05 AT AT0869277A patent/AT364826B/en not_active IP Right Cessation
- 1977-12-05 CA CA292,433A patent/CA1088935A/en not_active Expired
- 1977-12-05 ES ES464751A patent/ES464751A1/en not_active Expired
- 1977-12-05 MC MC771272A patent/MC1172A1/en unknown
- 1977-12-05 DE DE19772754062 patent/DE2754062A1/en not_active Withdrawn
- 1977-12-05 PT PT67363A patent/PT67363B/en unknown
- 1977-12-05 LU LU7778638A patent/LU78638A1/xx unknown
- 1977-12-05 SE SE7713779A patent/SE7713779L/en not_active Application Discontinuation
- 1977-12-05 NL NL7713432A patent/NL7713432A/en not_active Application Discontinuation
- 1977-12-05 NO NO774155A patent/NO774155L/en unknown
- 1977-12-05 NZ NZ185860A patent/NZ185860A/en unknown
- 1977-12-05 IE IE2468/77A patent/IE46003B1/en unknown
- 1977-12-05 GB GB50495/77A patent/GB1589792A/en not_active Expired
- 1977-12-05 DK DK540977A patent/DK540977A/en unknown
- 1977-12-05 JP JP14520377A patent/JPS5392776A/en active Pending
- 1977-12-05 IL IL53532A patent/IL53532A/en unknown
- 1977-12-05 HU HU77HO2029A patent/HU177640B/en unknown
- 1977-12-06 AU AU31264/77A patent/AU514827B2/en not_active Expired
- 1977-12-06 IT IT30510/77A patent/IT1143727B/en active
- 1977-12-06 FR FR7736745A patent/FR2372808A1/en active Granted
- 1977-12-06 AR AR270265A patent/AR219510A1/en active
-
1978
- 1978-08-16 ES ES472573A patent/ES472573A1/en not_active Expired
- 1978-08-16 ES ES472572A patent/ES472572A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IL53532A0 (en) | 1978-03-10 |
| FI773636A (en) | 1978-06-07 |
| AR219510A1 (en) | 1980-08-29 |
| NL7713432A (en) | 1978-06-08 |
| IE46003L (en) | 1978-06-06 |
| SE7713779L (en) | 1978-06-07 |
| AU3126477A (en) | 1979-06-14 |
| ATA869277A (en) | 1981-04-15 |
| FR2372808B1 (en) | 1981-07-10 |
| AU514827B2 (en) | 1981-02-26 |
| ES472573A1 (en) | 1979-02-16 |
| ES472572A1 (en) | 1979-02-16 |
| IL53532A (en) | 1981-09-13 |
| FR2372808A1 (en) | 1978-06-30 |
| GB1589792A (en) | 1981-05-20 |
| MC1172A1 (en) | 1978-09-25 |
| NZ185860A (en) | 1980-10-24 |
| IT1143727B (en) | 1986-10-22 |
| LU78638A1 (en) | 1979-02-02 |
| PT67363B (en) | 1979-12-17 |
| JPS5392776A (en) | 1978-08-15 |
| PT67363A (en) | 1978-01-01 |
| DK540977A (en) | 1978-06-07 |
| DE2754062A1 (en) | 1978-06-08 |
| CA1088935A (en) | 1980-11-04 |
| ES464751A1 (en) | 1978-12-16 |
| AT364826B (en) | 1981-11-25 |
| NO774155L (en) | 1978-06-07 |
| HU177640B (en) | 1981-11-28 |
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