WO1995031464A1

WO1995031464A1 - New agonist compounds

Info

Publication number: WO1995031464A1
Application number: PCT/SE1995/000504
Authority: WO
Inventors: Helmut Schmidhammer
Original assignee: Astra Aktiebolag
Priority date: 1994-05-18
Filing date: 1995-05-09
Publication date: 1995-11-23
Also published as: CA2189139A1; FI964576A; NO964871L; US5886001A; BR9507656A; SK139696A3; JPH10500132A; HU9603171D0; AU2581895A; EP0759923A1; PL317250A1; AU690281B2; IL113627A0; SE9401727D0; NZ287177A; ZA953699B; FI964576A0; IS4381A; CN1152314A; NO964871D0

Abstract

New morphinane derivatives of formula (I), their pharmaceutically acceptable salts, a process for their preparation and their use in therapy.

Description

NEW AGONIST COMPOUNDS

Field of the invention

The present invention is related to novel δ opioid receptor agonists as well as to their pharmaceutically acceptable salts, a process for their preparation and their use in the manufacture of pharmaceutical preparations.

Background of the invention

Three major types of opioid receptors, μ, K and δ, are known and characterized. The identification of different opioid receptors has lead to efforts to develop specific ligands for these receptors. These ligands are known to be useful for at least two purposes: a) to enable the more complete characterization of these different receptors, and b) to facilitate the identification of new analgesic drugs.

Analgesic drugs having specificity for an individual opioid receptor type have been demonstrated to have fewer side effects (e.g. respiratory depression, constipation, dependence), and in cases in which tolerance to one drug has developed, a second drug with different opioid receptor specificity may be effective. For example the successfull substitution of DADLE (intrathecal application), a partially δ-selective analgesic peptide, for morphine in a human cancer patient with morphine tolerance has been demonstrated (E.S. Krames et al., Pain, Vol. 24:205-209,1986). Evidence that a δ-selective agonist could be a potent analgesic with less tolerance and dependence liability was presented by Frederickson et al. (Science, Vol. 211:603-605,1981). The peptide, [D-Ala²,N- MeMet^s]enkephalin amide or "metkephamid", was hundred fold more potent than morphine in the hot-plate test for analgesia after i. c. v. (intracerebral ventricular) administration. Naloxone precipitation of withdrawal after chronic administration of metkephamid and morphine in rats showed that metkephamid-treated animals exhibited fewer withdrawal symptoms than those given morphine, scoring only a little above the saline control group. Metkephamid produced substantially less respiratory depression than morphine.

Another δ-selective peptide, [D-Pen², D-Pen⁵]enkephalin (DPDPE) produces potent analgesic effects while showing little if any respiratory depression (C.N. May, Br.J. Pharmacol., Vol.98:903-913,1989). DPDPE was found not to produce gastrointestinal side effects (e.g. constipation) (T.F.Burks, Life Sci., Vol.43:2177- 2181,1988). Since it is desireable that analgesics are stable against peptidases and are capable of entering the CNS easily, non-peptide analgesics are much more valuable.

Prior art

Recently a non-peptide, δ-selective opioid agonist, BW373U86 - a piperazine derivative, has been disclosed. BW 373U86 is reported to be a potent analgesic which does not produce physical dependence (P.H.K. Lee et al., JPharmacol.Exp.Ther., Vol. 267:983-987,1993).

An undesired side effect of this compound is that it produces convulsions in animals. The convulsions were antagonized by the δ-selective opioid antagonist naltrindole. Outline of the invention

The present invention provides novel analgesic compounds of the formula I

wherein

R, represents C_j-C₈ alkyl or hydrogen;

1*₂ represents hydrogen, hydroxy, 0,-C₈ alkoxy; C_j-C₆ alkenyloxy; C₇-C₁₆

arylalkyloxy wherein the aryl is C₆-C₁₀ aryl and the alkyloxy is C₁-C₆ alkyloxy; C₇-

C₁₆ arylalkenyloxy wherein the aryl is C₆-C₁₀ aryl and the alkenyloxy is C_α-C₆

alkenyloxy; C₁-C₆ alkanoyloxy, C₁-C₆ alkenoyloxy, C₇-C₁₆ arylalkanoyloxy

wherein the aryl is C₆-C₁₀ aryl, and the alkanoyloxy is C_]-C₆ alkanoyloxy;

R_g represents hydrogen, C.-C₆ alkyl; C₁-C₆ alkenyl; C₇-C₁₆ arylalkyl wherein the

aryl is C₆-C₁₀ aryl and the alkyl is C₁-C₆ alkyl; C₇-C₁₆ arylalkenyl wherein the aryl

is C₆-C₁₀ aryl and the alkenyl is C^-C₈ alkenyl; hydroxy(C₁-C₆)alkyl; alkoxyalkyl

wherein the alkoxy is C C₆ alkoxy and the alkyl is C₁-C₆ alkyl; C0₂H; C0₂(C C₆ alkyl);

R₄ is hydrogen, hydroxy; C_j-C₆ alkoxy; C₇-C₁₆ arylalkyloxy wherein the aryl is C₆-

C₁₀ aryl and the alkyloxy is C₁-C₆ akyloxy; C_]-C₆ alkenyloxy; C₁-C₆ alkanoyloxy; C₇-C₁₆ arylalkanoyloxy wherein the aryl is C₆-C₁₀ aryl and the alkanoyloxy is C,-

C₆ alkanoyloxy; alkyloxyalkoxy wherein alkyloxy is C₁-C₄ alkyloxy and alkoxy is

C.-C₆ alkoxy;

R₅ and R₆ each independently represent hydrogen; OH; C_j-C₈ alkoxy;

C_j-C₆ alkyl; hydroxyalkyl wherein the alkyl is C,-C₆ alkyl; halo; nitro; cyano;

thiocyanato; trifluoromethyl; C0₂H; C0₂(C.-C₆ alkyl); CONH₂; CONH (C₁-C₆

alkyl); CON(C_j-C₆ alkyl)₂; amino; C^C_g monoalkyl amino; C_j-C₆ dialkyl amino;

C₅-C₆ cycloalkylamino; SH; S0₃H; S0₃(C₁-C₆ alkyl); S0₂(C_j-C₆ alkyl); S0₂NH₂;

S0₂NH(C.- C₆ alkyl); S0₂NH(C₇-C₁₆ arylalkyl); SO(C₁-C₆ alkyl); or R₅ and R₆ together form a phenyl ring which may be unsubstituted or substituted by halo, nitro, cyano, thiocyanato; C₁-C₆ alkyl; trifluoromethyl; C_j-C₆ alkoxy, C0₂H,

CO(C_j-C₆ alkyl), amino, C_j-C₆ monoalkylamino, C₁-C₆ dialkylamino, SH; S0₃H;

S0₃(C₁-C₆ alkyl), S0₂(C_rC₆ alkyl), SO(C₁-C₆ alkyl), and

X represents oxygen; sulfur; CH=CH; or NR_Q wherein R_ς, is H, C_j-C₆ alkyl, C_j-C₆

alkenyl; C₇-C₁₆ arylalkyl wherein the aryl is C₆-C₁₀ aryl and the alkyl is C.-C₆

alkyl, C₇-C₁₆ arylalkenyl wherein the aryl is C₆-C₁₀ aryl and the alkenyl is C_]-C₆

alkenyl; C--C₆ alkanoyl, and

wherein aryl is unsubstituted or mono-, di- or trisubstituted independently with hydroxy, halo, nitro, cyano, thiocyanato, trifluoromethyl, C_J-C_J alkyl, C,-C₃

alkoxy, C0₂H, CONH₂ C0₂(C,-C₃ alkyl), CONH(C_]-C₃ alkyl), CON(C₁-C₃ alkyl)₂

CO^_j-C₈ alkyl); amino; (C_j^ monoalkyDamino, (C_j-C_j dialkyDamino, C₅-C₆ cycloalkylamino, (C^C_g alkanoyDamido, SH, S0₃H, S0₃(C,-C₃ alkyl), S0₂(C.-C₃

alkyl), SO(C,-C₃ alkyl), C.-C₃ alkylthio or C.-C₃ alkanoylthio;

with the proviso that when R_j is hydroxy, l cannot be hydrogen;

the compounds 6,7-Dehydro-4,5α-epoxy-3,14-dimethoxy-17-methyl-6,7-2',3'- benzo[b]furanomorphinan;

6,7-Dehydro-4,5α-epoxy-3-hydroxy-17-methyl-6,7-2',3'- benzo[b]furanomorphinan;

6,7-Dehydro-4,5α-epoxy-3-hydroxy-17-methyl-6,7-2',3'-indolomorphinan;

6,7-Dehydro-4,5α-epoxy-3-hydroxy-17-methyl-7'-bromo-6,7-2',3'- indolomorphinan;

3,14-Diacetocy-6,7-dehydro-4,5α-epoxy-17-methyl-6,7-2' '-indolomorphinan;

14-Acetoxy-6,7-dehydro-4,5α-epoxy-3-hydroxy-17-methyl-6,7-2',3'- indolomorphinan;

6,7-Dehydro-4,5α-epoxy-3-hydroxy-14-methoxy-17-methyl-6,7-2',3'- benzo [b]f uranomorphinan;

14-Benzyloxy-6,7-dehydro-4,5α-epoxy-3-hydroxy-17-methyl-6,7-2',3'- benzo [b]f uranomorphinan; being excluded,

and the pharmacologically acceptable salts of the compounds of the formula (I). Aryl may be unsubstituted or mono-, di- or trisubstituted independently with hydroxy, halo, nitro, cyano, thiocyanato, trifluoromethyl, C^C_g alkyl, C^C_g

alkoxy, C0₂H, CONH₂, C0₂(C₁-C₃ alkyl), CONH(C.-C₃ alkyl), CON(C C₃ alkyl)₂,

CO(C_t-C₃ alkyl); amino; (C₁-C₃ monoalkyDamino, (C_j-C₈ dialkyDamino, C₅-C₆

cycloalkylamino; (C,-C₃ alkanoyDamido, SH, S0₃H, 50₃(0,-0₃ alkyl), SO^C_j-^

alkyl), SO(C C₃ alkyl), C.-C₃ alkylthio or C,-C₃ alkanoylthio.

The above given definition for aryl is valid for all substituents in the present application where aryl is present.

Pharmaceutically and pharmacologically acceptable salts of the compounds of formula I include suitable inorganic salts and organic salts which can be used according to the invention. Examples of inorganic salts which can be used are HCl salt, HBr salt, sulfuric acid salt and phosphoric acid salt. Examples of organic salts which can be used according to the invention are methanesulfonic acid salt, salicylic acid salt, fumaric acid salt, maleic acid salt, succinic acid salt, aspartic acid salt, citric acid salt, oxalic acid salt and orotic acid salt. These examples are however not in any way limiting the salts which could be used according to the invention.

The novel δ-selective morphinane derivatives of the formula I are useful as analgesics without having dependence liability. They may be administered parenterally or non-parenterally. Specific routes of administration include oral, rectal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, intrathecal, transdermal, intraartherial, bronchial, lymphatic and intrauterine administration. Formulations suitable for parenteral and oral administration are preferred.

In a preferred embodiment R_j is selected from hydrogen, methyl, ethyl, n-propyl or isopropyl;

R₂ is selected from methoxy, ethoxy, n-propyloxy, benzyloxy, benzyloxy

substituted in the aromatic ring with F, Cl, N0₂, CN, CF₃, CH₃, OCH₃, allyloxy, cinnamyloxy or 3-phenylpropyloxy; R_g is selected from hydrogen, methyl, ethyl, benzyl or allyl;

R₄ is selected from hydroxy, methoxy, methoxymethoxy or acetyloxy;

R₅ and R₆ are each and independently selected from hydrogen, nitro, cyano,

chloro, fluoro, bromo, trifluoromethyl, C0₂H, C0₂CH₃, CONH₂, CONH CH₃, SH,

S0₂NH₂, N(CH₃)₂, S0₂ CH₃ and

X is selected from O, NH, NCH₃, N-benzyl, N-allyl.

In an especially preferred embodiment R, is CH₃;

R_j is selected from methoxy, ethoxy, n-propyloxy, benzyloxy or benzyloxy substituted in the aromatic ring with chlorine ₃ is selected from hydrogen or CH₃;

R₄ is hydroxy;

R₅ and R₆ are each and independently selected from hydrogen, C0₂H, CONH₂,

S0₂NH₂, or S0₂CH₃; and X is selected from O or NH.

The best mode known at present is to use the compound according to Example 1. Preparation of the compounds

The compounds represented by formula (I) wherein R, is C₁-C₆ alkyl, C₇-C₁₆

aralkyl wherein the aryl is C₆-C₁₀ aryl and the alkyl is C_j-C₆ alkyl; alkoxyalkyl

wherein the alkoxy is C_α-C₆ alkoxy and the alkyl is C,-C₆ alkyl; C0₂(C₁-C₆ alkyl);

C,-C₆ alkanoyl; may be obtained by the following methods:

Thebaine of the formula

is being treated with dialkylsulfates, fluorosulfonic acid alkyl esters, alkylsulfonic acid alkyl esters, arylsulfonic acid alkylesters, alkyl halides, alkenyl halides, aralkyl halides, alkylsulfonic acid aralkyl esters, arylsulfonic acid aralkyl esters, arylalkenyl halides or chloroformates, in solvents such as tetrahydrofurane or diethyl ether using a strong base such as n-butyl lithium, lithium diethyl amide or lithium diisopropyl amide at low temperatures (-20 to -80 °C) (s. Boden et al., J.Org.Chem., Vol.47:1347-1349, 1982, Schmidhammer et al., Helv.Chim. Acta. Vol.71:642-647,1988, Gates et al., J.Org. Chem. Vol. 54; 972-974, 1984), giving compounds of formula (II),

wherein R is C₁-C₆ alkyl; C₁-C₆ alkenyl; C₇-C₁₆ arylalkyl, wherein the aryl is C₆-

C_]0 aryl and the alkyl is C₁-C₆ alkyl; C₇-C₁₆ arylalkenyl wherein the aryl is C₆-C₁₀

aryl and the alkenyl is C_j-C₆ alkenyl; alkoxyalkyl wherein the alkoxy is C₁-C₆

alkoxy and the alkyl is C₁-C₆ alkyl; C0₂(C.-C₆ alkyl);

The 5-substituted thebaine derivatives (formula II) or thebaine are converted into the corresponding 14-hydroxycodeinones (compounds of formula III)

wherein R is as defined above or being hydrogen, by reaction with performic acid (H. Schmidhammer et al., Helv.Chim.Acta, Vol. 71:1801-1804, 1988) or m- chloroperbenzoic acid, at a temperature between 0 and 60 ° C. The preferred procedure is the reaction with performic acid at 0-10°C (H.Schmidhammer et.al., Helv. Chim. Acta. Vol. 71:1801-1804, 1988). These 14-hydroxycodeinones are being treated with dialkyl sulfates, alkyl halides, alkenyl halides, arylalkyl halides, arylalkenyl halides or chloroformates, in solvents such as N,N-dimethyl formamide or tetrahydrofurane using a strong base such as sodium hydride, potassium hydride or sodium amide giving compounds of formula (IV)

wherein

R, is C_j-C₈ alkyl, C₁-C₆ alkenyl, C₇-C₁₆ arylalkyl wherein the aryl is C₆-C₁₀ aryl

and the alkyl is C₁-C₆ alkyl, C₇-C_]6 arylalkenyl wherein the aryl is C₆-C₁₀ aryl and

the alkenyl is C₁-C₆ alkenyl, 0,-C₈ alkanoyl, C₇-C₁₆ arylalkanoyl wherein the aryl

is C₆-C₁₀ aryl and the alkanoyl is C₁-C₆ alkanoyl, C₇-C₁₆ arylalkenoyl wherein the

aryl is C₆-C₁₀ aryl and the alkenoyl is C_:-C₆ alkenoyl;

R₂ is hydrogen; C₁-C₆ alkyl; C₁-C₆ alkenyl C₇-C₁₆ arylalkyl wherein the aryl is C₆-

C₁₀ aryl and the alkyl is C_]-C₆ alkyl; C₇-C₁₆ arylalkenyl wherein the aryl is C₆-C₁₀

aryl and the alkenyl is C₁-C₆ alkenyl; alkoxyalkyl wherein the alkoxy is C,-C₆

alkoxy and the alkyl is C C₆ alkyl; C0₂(C_rC₆ alkyl);

which compounds in turn are reduced by catalytic hydrogenation using a catalyst such as palladium on charcoal and solvents such as methanol, ethanol, or glacial acetic acid to give compounds of formula (V)

wherein

R, is C_j-C₆ alkyl, C₇-C₁₆ arylalkyl wherein the aryl is C₆-C₁₀ aryl and the alkyl is

C₁-C₆ alkyl, C.-C₆ alkanoyl, C₇-C₁₆ arylalkanoyl wherein the aryl is C₆-C_]0 aryl and

the alkanoyl is C_j-C₆ alkanoyl;

R_j is hydrogen; C₁-C₆ alkyl, C₇-C_]6 arylalkyl wherein the aryl is C₆-C₁₀ aryl and the

alkyl is C_]-C₆ alkyl; alkoxyalkyl wherein the alkoxy is C_j-C₆ alkoxy and the alkyl

is C,-C₆ alkyl; C0₂(C₁-C₆ alkyl);

Ether cleavage of these compounds using boron tribromide (in a solvent such as dichloro methane or chloroform) at about 0°C, 48 % hydrobromic acid (reflux), or other well known reagents gives phenolic compounds of formula (VI),

wherein R₇ and R_j are as defined above in formula (V). Alkylation using alkyl halides, alkyl sulfates, sulfonic acid esters, aralkyl halides, arylalkenyl halides, or acylation using carbonic acid chlorides, carbonic acid anhydrides, or carbonic acid esters affords compounds of formula (VII)

wherein R_j and R_j are as definded above in formula (V), and

R₃ is C,-C₆ alkyl, C₇-C₁₆ arylalkyl wherein the aryl is C₆-C₁₀ aryl and the alkyl is

C_α-C₆ alkyl, C_j-C₈ alkenyl, C₇-C_]6 arylalkanoyl wherein the aryl is C₆-C₁₀ aryl and

the alkanoyl is C_α-C₆ alkanoyl, alkyloxyalkyl wherein alkyloxy is C_J- _J alkyloxy

and alkyl is C_j-C₆ alkyl,

which after N-demethylation using for instance chloroformates or cyanogen bromide followed by cleavage of the corresponding carbamates or N-cyano compounds (compounds of formula VIII)

wherein R.,

and R₃ are as defined above in formula (V) and (VII),

and Z is for instance C0₂CH=CH₂, C0₂CHC1CH₃, C0₂CH₂CH₃, C0₂Ph, C0₂CH₂

CC1₃ or CN by treatment with the adequate reagent such as aqueous acid, alkali, hydrazine, zinc, alcohol or the like N-nor derivatives of formula (IX)

wherein R_v R_j and R_g are as defined above in formula (V) and (VII).

N-alkylation can be accomplished with alkyl halide or dialkyl sulfate in solvents such as dichloro methane, chloroform or N,N-dimethyl formamide in the presence of a base such as sodium hydrogen carbonate or potassium carbonate to yield derivatives of formula (X)

wherein R., R₂ and R_g are as defined above in formula (V) and (VII), and Y is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, tert-butyl, 2-pentyl, 3-pentyl, 2-hexyl or 3-hexyl. Ether cleavage can be carried out as described for compounds of formula (V) giving derivatives of formula (XI)

wherein R and R_j are as defined above in formula (V), and Y is as defined above in formula (X).

Compounds according to formula (I) wherein R₂ is hydroxy may be obtained from compounds of the formula (III) wherein R is defined as above. These compounds can be reduced by catalytic hydrogenation using a catalyst such as palladium on charcoal and solvents such as methanol, ethanol, or glacial acetic acid to give compounds of formula (V) wherein R is hydrogen and R_j is as defined above.

The following reaction sequence and procedures leading to compounds of formula (VI),(VII),(VIII),(IX),(X), and (XI) wherein R. is hydrogen and wherein 1^

and R_g are as defined above in formula (V) and (VII), is analogous to the reaction sequence and procedures described above. Further conversion into compounds of the formula (I) wherein R_j is hydroxy is described below.

Compounds of the formula (I) wherein ^ is hydrogen may be obtained from compounds of the formula (II) wherein R is as defined above. Catalytic hydrogenation followed by acid hydrolysis (s. Boden et al., J. Org. Chem. Vol. 47: 1347-1349, 1982) gives compounds of the formula (XII)

(XII a): R= H (dihydrocodeinone)

wherein R is as defined above in formula (II).

Compounds of the formula (XII) and (XII a) (Mannich and Lδwenheim, Arch. Pharm., Vol. 258:295, 1920) can be converted into compounds of the formula (V), (VI), (VII), (VIII), (IX), (X) and (XI) wherein the substitutent in position 14 is hydrogen and P^ and R₃ are as defined above in formula (V) and (VII), similary as described above. Further conversion into compounds of the formula (I) wherein

R_j is hydrogen is described below.

Compounds of the formula (I) wherein R₄ is hydrogen may be prepared from compounds of the formulas (VI) or (XI) by alkylation with 5-chloro-l-phenyl-lH- tetrazole to give the corresponding phenyltetrazolyl ethers of the formula (XIV)

wherein R_j and R₂ are defined as above, n is 0-5 and T is phenyltetrazolyl. Catalytic hydrogenation may afford (H. Schmidhammer et al., J. Med. Chem. Vol. 27: 1575-1579, 1984), compounds of the formula (XV)

wherein R, and R_j are as defined above and n is 0-5.

Compounds according to the formula (I) wherein R_j is as defined above and X represents NH are obtained by reaction of compounds of formula (VI), (VII), (IX), (X), (XI) or (XV) with phenylhydrazine or substituted phenylhydrazine in solvents such as methanol, ethanol or glacial acetic acid in the presence of methanesulfonic acid, HCl or HBr. Phenylhydrazine substituted at the aromatic ring with halogen, hydroxy, C^C_g alkyl, C₁-C₆ alkoxy, amino, nitro, cyano, thiocyanato,

trifluoromethyl, C0₂H, C0₂(C₁-C₆ alkyl), CONH₂, CONH(C_j-C₆ alkyl), CON(C

C₆ alkyl)₂,S0₂NH₂,S0₂(C_]-C₆ alkyl) or the like may be employed. The reaction may be carried out at a temperature between 20 and 160 °C, preferably between 20 and 80 °C.

Compounds of formula (I) wherein R_g is as defined above and X represents oxygen are obtained by reaction of compounds of formula (VI), (VII), (IX), (X), (XI) or (XV) with O-phenylhydroxylamine or substituted (at the aromatic ring) O- phenylhydroxylamine in solvents such as methanol, ethanol, or glacial acetic acid in the presence of methanesulfonic acid, HCl or HBr. O-Phenylhydroxylamine substituted at the aromatic ring with halogen, C₁-C₆ alkyl, amino, nitro, cyano, thiocyanato, trifluoromethyl, C0₂H, C0₂(C₁-C₆ alkyl), CONH₂, CONH(C C₆

alkyl), CON(C C₆ alkyl)₂,S0₂NH₂,S0₂(C₁-C₆ alkyl) or the like may be employed.

The following examples describe in detail the preparation of the compounds according to the invention.

Example 1

Synthesis of 6,7-Dehydro-4,5α-epoxy-14-ethoxy-3-hydroxy-5,17-dimethyl-6,7-2'^'- indolomorphinan (compound 1).

A mixture of 14-ethoxymetopon (H. Schmidhammer et al. Helv. Chim Acta. Vol. 73: 1784-1787, 1990) (500 mg, 1.45 mmol), phenylhydrazaine hydrochloride (340 mg, 2.35 mmol) and 10 ml of glacial acetic acid was refluxed for 48 h. After cooling, the reaction mixture was poured on ice, alkalized with cone. NH₄OH and

extracted with CH₂C1₂ (3x10 ml). The combined organic layers were washed with

H₂0 (3x15 ml), dried over Na₂S0₄ and evaporated. The resulting residue (546 mg orange-brown foam) was crystallized with MeOH to yield 322 mg of the title compound which was further purified by column chromatography (alumina basic grade IV, elution with a) CH₂C1₂, b) CH₂Cl₂/MeOH 99:1). After evaporation of the corresponding fractions, 237 mg of slightly yellow crystals were obtained. Recrystallization from MeOH yielded 116 mg (24%) of pure title compound 1.

M.p. 165-167 °C. IR (KBr): 3285 (NH, OH)cm^"\ CI-MS:m/z 417 (M^* + 1). Η-

NMR(CDC1₃): δ 8.15 (s, NH, OH), 7.35 (d, J = 8 Hz, 1 arom. H), 7.26 (d, J = 8 Hz, 1 arom. H), 7.13 (t, J = 8 Hz, 1 arom. H), 7.01 (t, J = 8 Hz, 1 arom. H), 6.64 (d, J = 8 Hz, 1 arom. H), 6.55 (d. J = 8 Hz, 1 arom. H), 2.40 (s, CH₃N), 1.94 (s, CH₃-C(5)), 1.02 (t. J = 7 Hz, 3H, CH₃CH₂0). Analysis calculated for C₂₆H₂₈N₂0₃. (480.60): 69.98, H 7.55, N 5.83; found: C 70.23, H 7.40, N 5.87.

Example 2

Synthesis of 6,7-Dehydro-4,5α-epoxy-3,14-dimethoxy-5,17-dimethyl-6,7-2'^'- indolomorphinan (compound 2).

A mixture of 5,14-O-dimethyloxycodone (H. Schmidhammer et al., Helv. Chim. Acta Vol. 73: 1784-1787, 1990) (300 mg, 0.87 mmol), phenylhydrazine hydrochloride (189 mg, 1.31 mmol), methanesulfonic acid (84 mg, 0.87 mmol), and 12 ml of glacial acetic acid was refluxed for 17 h. After cooling, the reaction mixture was poured on ice, alkalized with cone. NH₄OH and extracted with

CH₂C1₂ (3x10 ml). The combined organic layers were washed with H₂0 (3x10 ml),

dried over Na₂S0₄ and evaporated. The resulting residue (380 mg yellowish crystals) was recrystallized from MeOH to yield 336 mg (93%) of pure title compound 2 as slightly yellow crystals. M.p. 218-221°C. (KBr): 3800 (NH) cm^"'. CI-

MS: m/z 417 (M^*+l). 'H-NMR (CDC1₃): δ 8.30 (s, NH), 7.48 (d, J= 8 Hz, 1 arom. H),

7.39 (d,J=8 Hz, 1 arom. H), 7.12 (t, J=8 Hz, 1 arom. H), 7.03 (t, J=8 Hz, 1 arom, H), 6.58 (s, 2 arom. H), 3.73 (s, OCH₃-C(3)), 3.28 (s, OCH₃-C(14)), 2.45 (s, NCH₃), 1.87

(s, CH₃-C(5)). Analysis calculated for C₂₆H₂₈N₂0₃. 2 MeOH (480.60): C 69.98, H 7.55, N5.83; found C 70.19, H 7.41, N 5.95.

Example 3

Synthesis of 6,7-Dehydro-4,5α-epoxy-3-hydroxy-14-methoxy-5,l 7-dimethyl-6,7- 2'3'-indolomorphinan (compound 3). A mixture of 14-methoxymetopon hydrobromide (H. Schmidhammer et al., Helv. Chim. Acta Vol. 73: 1784-1787, 1900) (500mg, 1.22 mmol) phenylhydrazine hydrochloride (211 mg, 1.46 mmol), and 10 ml of glacial acetic acid was refluxed for 24 h. After cooling, the reaction mixture was poured on ice, alkalized with cone. NH₄OH and extracted with CH₂C1₂ (3x10 ml). The combined organic layers

were washed with H₂0 (3 x 15 ml), dried over Na_jSO,, and evaporated. The resulting residue (455 mg slightly grey foam) was crystallized from MeOH to give 330 mg (67%) of pure title compound 3. M. p. 273-276°C (dec). IR (KBr): 3300

(NH, OH) cm-'. CI-MS: M/Z 403 (M^*+l). Η-NMR (DMSO-d₆): δ 11.10 and 8.78 (2 s, NH, OH), 7.32 (dxd, J= 8 HZ, 2 arom. H.) 7.07 (t, J=8 HZ, 1 arom. H), 6.91 (t, J=8

HZ, 1 arom. H), 6.44 (s, 2 arom. H), 3.32 (s. OCH₃), 2.33 (s, NCH₃), 1.81 (s, CH₃-

C(5)). Analysis calculated for C₂₅H₂₆N₂0₃. 2 MeOH (466.56):C 69.50, H 7.35, N 6.01; found: C 69.78, H 7.38, N 6.09.

Example 4

Synthesis of 6,7-Dehydro-4,5α-epoxy-3,14-dihydroxy-5,17-dimethyl-6,7-2'3'- indolomorphinan Hydrobromide (compound 4).

A mixture of 14-hydroxymetopon hydrobromide (H.Schmidhammer et al., Helv. Chim. Acta Vol. 71: 1801-1804, 1988) (450 mg, 0.95 mmol), phenylhydrazine hydrochloride (280 mg, 1.93 mmol), and 15 ml of glacial acetic acid was refluxed for 20 h. After cooling, the reaction mixture was poured on ice, alkalized with cone. NH₄OH and extracted with CH₂C1₂ (3x60 ml). The combined organic layers

were washed with H₂0 (3x60 ml) and brine, dried over Na₂S0₄ and evaporated.

The resulting residue (392 mg of a brownish foam) was dissolved in glacial acetic acid and treated with 48% HBr. The crystals were collected and recrystallized from glacial acetic acid to yield 132 mg (25%) of the title compound 4 as colorless crystals. M.p. >250°C (dec). IR (KBr)3300 CNH,OH)cm '. CI-MS:m/z 389(M^* +1). ^-NMR (DMSO-d₆): δ 11.28 (s, NH), 9.19 (s, OH-C(3)), 9.09 (broad s, ^*NH), 7.10

(m, 4 arom. H), 6.56 (s, 2 arom. H)6.12(s, OH-C(14)),2.88 (s, NCH₃), 1.88 (s, CH₃-

C(5)). Analysis calculated for C₂₄H₂₄N₂0₃ x HBr x 0.1 H₂0 (489.20); C 58.93, H 5.60, N 5.73, Br 16.33;

Found: C 59.01, H 5.55, N 5.56, Br 16.17.

Example 5

Synthesis of 7,8-Dehydro-4,5α-epoxy-14-hydroxy-3-methoxy-5,17-dimethyl-6,7- 2'3'-indolomorphinan Hydrobromide (compound 5).

A mixture of 5-methyloxycodon (H.Schmidhammer et al., Helv. Chim. Acta, Vol. 71: 1801-1804, 1988) (350 mg, 0.72 mmol), phenylhydrazine hydrochloride (260 mg, 1.79 mmol), and 15 ml of glacial acetic acid was refluxed for 18 h. After cooling, the reaction mixture was poured on ice, alkalized with cone NH₄OH and

extracted with CH₂C1₂ (3x50 ml). The combined organic layers were washed with

H₂0 (3x60 ml) and brine, dried over Na₂S0₄ and evaporated. The resulting residue (365 mg brownish foam) was dissolved in glacial acetic acid and treated with 48% HBr. The crystals were collected and recrystallized from glacial acetic acid to give 130 mg (25%) of pure title compound 5. HBr. M.p. >260°C (dec). IR (KBr): 3406, 3396, 3242 (NH, ^*NH, OH)cm^'\ CI-MS: m/z 403(M^*+1) Η-NMR

(DMSO-d₆): δ 11.34 (s, NH), 9.20 (broad s ^*NH), 7.05 (m, 4 arom. H), 6.76 (d, J=8,3

Hz, 1 arom. H). 6.69 (d, J=8.3 HZ, 1 arom. H), 6.17 (s,OH-C(14)), 3.65 (s,OCH₃),

2.90(s, NCH₃)1.89 (s,CH₃-C(5)). Analysis calculated for C₂₅H₂₆ N₂ O_s x HBr x

0.9H₂O (499.63): C 60.10, H 5.81, N 5.61, Br 15.99; Found: C 60.11, H 5.97, N 5.55, Br 16.02. Example 6

Synthesis of 6,7-Dehydro-4,5α-epoxy-3-hydroxy-14-methoxy-5-methyl-6,7-2',3'- indolomorphinan (compound 7).

A solution of 4,5α-epoxy-3,14-dimethoxy-5-memylmorphinan-6-one hydrochloride (H. Schmidhammer et al., Helv. Chim. Acta Vol. 77: 1585- 1589,1994) (1.0 g, 2.73 mmol) in 3.5 ml of 48% HBr was refluxed for 15 in. After cooling, the now brown solution was evaporated, the residue treated with MeOH and again evaporated (this operation was repeated once). The oily residue was crystallized from MeOH to yield 713 mg (66%) of colorless 4,5a-epoxy-3- hydroxy-14-methoxy-5-methylmorphinan-6-one hydrobromide (compound 6). M.p.>230°C (dec). IR (KBr): 3545 and 3495 CNH, OH), 1720 (CO)cm '.

CI-MS:m/z 316(M^*+1). Η-NMR(DMSO-d₆):δ 9.37 (s,OH), 8.65 (broad s, ^*NH₂),

6.64 (dd, J=8.2, 8.2 Hz, 2 arom. H), 3.36 (s, OCH₃-C(14)), 1.48 (s,CH₃-C(5)).

Analysis calculated for C_]8H₂₁N0₄. HBr. MeOH(428.33):C 53.28, H 6.12, N 3.27; found: C 53.12, H 5.97, N 3.32.

A mixture of 4,5α-epoxy-3-hydroxy-14-memoxy-5-methylmo hinan-6-one hydrobromide (compound 6, 1.2 g, 3.03 mmol), phenylhydrazine hydrochloride (548 mg, 3.79 mmol), and 15 ml of glacial acetic acid was refluxed for 4 h. After cooling, the reaction mixture was evaporated to give a brownish solid (2.14 g) which was refluxed in 10 ml of MeOH for 5 min and the refrigerated. The solid was isolated (the mother liquor of this isolation was further processed, see below), dissolved in H₂0 and alkalized with cone NH₄OH. The precipitation was isolated to yield 569 mg (70%) of pure title compound 7. M.p.>270°C (dec). IR (KBr): 3395 and 3380 (NH, OH)cm^"\ EI-MS: m/z 388 (Ml. Analysis calculated for C₂₄H₂₄N₂0₃

x 0.3 H₂0 (393.87): C 73.19, H 6.30, N 7.11; found: C 73.08, H 6.03, N 7.07. Above mother liquor was evaporated and the resulting residue (566 mg) treated with 2 ml of hot MeOH to afford (after refrigeration) 201 mg (14%) of the title compound 7.HBr. M.p.>230° (dec). *H-NMR of 7.HBr (DMSO-d₆):δ 11.30 (s, NH),

9.13 and 8.50 (2 s, ^*NH, OH), 7.33 (dd, J=7.4, 7.4 Hz, 2 arom. H), 7.08 (t, J=7.4 Hz, 1 arom. H) 6.93(t, J=7.4 Hz, 1 arom.H), 6.57 (s, 2 arom. H), 3.32 (s, CH₃0-C(14)), 1.84

(s, CH₃-C(5)).

Example 7

Synthesis of 6,7-Dehydro-4,5α-epoxy-3-hydroxy-5,17-dimethyl-14-n-propyloxy- 6,7-2',3'-indolomorphinan methane sulfonate (compound 11).

A solution of 14-hydroxy-5-methylcodeinone (H. Schmidhammer et al, Helv. Chim. Acta Vol. 71: 1801-1804, 1988) (5.0 g, 15.27 mmol) in 50 ml of anhydrous N,N-dimethyl formamide was cooled to 0-5°C. Sodium hydride (1.47 g, 15.27 mmol; obtained from 2,7 g of 60% sodium hydride dispersion in oil by washings with petroleum ether) was added under nitrogen atmosphere, and the resulting mixture stirred for 20 min. Then allyl bromide (2.64 ml, 30.54 mmol) was added in one portion, and stirring was continued at 0-5°C for 30 min. Excess sodium hydride was desroyed carefully with small pieces of ice, then the mixture was poured on 150 ml ice/H₂0. After extractions with CH₂C1₂ (3x50 ml), the combined

organic layers were washed with H₂0 (3x100 ml) and brine, dried over Na₂S0₄ and evaporated to yield 6.43 g of a slightly yellow crystalline residue. Treatment with boiling ethanol (6 ml) gave (after refrigeration) 3.01 g (54%) of 14-allyloxy-5- methylcodeinone (compound 8). M.p. 136-137°C. IR(KBr): 1664 (CO)cm ^"'. CI-

MS:m/z 368(M^*+1). Η-NMR (DMSO-d₆): δ 6.78 (d, J=10.2 Hz, 1 olef.H.), 6.62 (d,

J=8.2 Hz, larom.H), 6.54 (d, J=8.2 Hz, 1 arom. H), 6.09 (d, J=10.2 Hz, 1 olef.H),

5.87 (m, 1 olef. H), 5.15 (m, 2 olef.H), 3.79 (s, CH₃0), 2.44 (s, CH₃N), 1.71 (s, CH₃- C(5)). Analysis calculated for C₂₂H₂₅N0₄(367.45): C 71.91, H 6.86, N 3.81; found: C 71.69, H 7.03, N 3.75.

A mixture of 14-allyloxy-5-methylcodeinone (compound 8,3,2 g, 10.64 mmol), 196 mg of 10% Pd/C catalyst, and 100 ml of ethanol was hydrogenated at 30 psi and room temperature for 3 h. The catalyst was filtered off and the filtrate evaporated. The residue (3.79 g colorless oil) was crystallized from ethanol to yield 2.93 g (74%) of 7,8-dihydro-5-methyl-14-n-propyloxycodeinone (compound 9). M.p. 102-

104°C IR (KBr): 1718 (CO) cm-'. CI-MS:m/z 372 (M^*+l). Η-NMR (DMSO-d₆): δ

6.50 (dd, J=8,8 Hz, 2 arom. H), 4.76 (s, CH₃0), 2.35 (s, CH₃N), 1.61 (s, CH₃.C(5)),

1.00 (t, J=7 Hz, CH₃). Analysis calculated for C^H-^NO^ 0.2 EtOH (380.69): C 70.67, H 8.00, N 3.68; found: C 70.64, H 7.72, N 3.69.

A I M solution of boron tribomide in CH₂C1₂ (54 ml) was added at once to an ice- cooled solution of 7,8-dihydro-5-methyl-14-n-propyloxycodeinone (compound 9; 2.7 g, 7.27 mmol) in 370 ml of CH₂C1₂. After 2 h stirring at 0-5°C, a mixture of 90 g

of ice and 20 ml of cone NH₄OH was added. The resulting mixture was stirred at

room temperature for 30 min and then extracted with CH₂C1₂ (3x200 ml). The

combined organic layers were washed with brine (300 ml), dried over Na₂S0₄ and evaporated. The residue (2.4 g slightly brown foam) was crystallized from MeOH to give 1.48 g (57%) of 4,5α-epoxy-3-hydroxy-5,17-dimethyl-14-n- propyloxymoφhinan-6-one (compound 10) as slightly brown crystals. An analytical sample was obtained by recrystallization of a small amount from MeOH. M.p. 193-195°C. IR (KBr): 3376 (OH), 1726 (CO) cm^'1. EI-MS: m/z 357 (M^*). 'H-NMR (CDC1₃): δ 6.67 (d,J = 8.1 Hz, 1 arom. H), 6.52 (d,J = 8.1 Hz, 1 arom. H),

1.57 (s, CH₃-C(5)), 0.96 (t,J = 7.2 Hz, CH₃). Analysis calculated for C₂₁H₂₇N0₄ (357.43): C 70.56, H 7.61, N 3.92; found: C 70.50, H 7.88, N 3.92. A mixture of 4,5α-epoxy-3-hydroxy-5,17-dimethyl-14-n-propyloxymorphinan-6- one (compound 10; 350 mg, 0.97 mmol), phenylhydrazine hydrochloride 212 mg, 1.47 mmol), and 20 ml of glacial acetic acid was refluxed for 24 h. After cooling, the reaction mixture was poured on ice and alkalized with cone NH₄OH and

extracted with CH₂C1₂ (3x40 ml). The combined organic layers were washed with

H₂0 (3x50 ml) and brine, dried over Na₂S0₄ and evaporated. The resulting residue (276 mg brown foam) was dissolved in MeOH and treated with methanesulfonic acid to give 180 mg of the title compound. Recrystallization from MeOH yielded 44 mg (9%) of pure compound 11. M. p. > 270°C. IR (KBr): 3203 (NH) cm^'1. 'H-NMR (DMSO-d₆): δ 11.29 (s, NH), 9.13 (s, OH), 8.47 (broad s, ^*NH),

7.15 (m, 4 arom. H), 6.58 (s, 2 arom. H), 2.97 (s. NCH₃), 1.86 (s, CH₃-C(5)), 0.57 (t,J

= 7.3 Hz, CH₃). Analysis calculated for C₂₇H₃₀N₂O₃. CH₃S0₃H. 0,7 H₂0 (539.27): C 62.36, H 6.62, N 5.19, S 5.95; found: C 62.36, H 6.50, N 5.20, S 6.02.

Example 8

Synthesis of 6,7-Dehydro-4,5α-epoxy-14-ethoxy-3-methoxy-17-methyl-6,7-2',3'- indolomorphinan. (Compound 12).

A mixture of 14-O-ethyloxycydone hydrochloride (R.J. Kobylecki et al, J. Med. Chem. Vol.25: 116-120, 1982) (580 mg, 1.53 mmol), phenylhydrazine hydrochloride (265 mg, 1.83 mmol), and 8 ml of glacial acetic acid was stirred for five days at room temperature. The mixture was poured on ice, alkalized with cone NH₄OH and extractred with CH₂C1₂ (3x10 ml). The combined organic layers

were washed with H₂0 (3x15 ml), dried over Na₂S0₄ and evaporated. The resulting residue (590 mg slightly orange foam) was crystallized from MeOH to yield 360 mg (56%) of compound 12. M.p. 143-145°C (dec.) IR (Kbr): 3260 (NH)cm^' Cl-MS:m/z 417 (M^*+ 1). Η-NMRtCDCl_g): δ 8.22 (s, NH, OH), 7.39 (d, J = 8 Hz, 1 arom. H), 7.30 (d, J = 8 Hz, 1 arom. H), 7.15 (t, J = 8 Hz, 1 arom. H), 1 arom. H), 7.02 (t, J = 8 Hz, 1 arom. H), 6.58 (s, 2 arom. H), 5.66 (s, H-C(5)), 3.74 (s, CH₃0),

2.39 (s, CH₃N), 1.01 (t, J = 7 Hz, 3H, CH₃3CH₂0). Analysis calculated for

C₂₆H₂₈N₂0₃. 1.0 MeOH (448.56): C 72.30, H 7.19, N 6.25; found: C 72.50, H 6.93, N 6.58.

Example 9

Synthesis of 6,7-Dehydro-4,5α-epoxy-14-ethoxy-17-isopropyl-3-methoxy-5- methyl-6,7-2',3'-benzo[b]furanomorphinan (compound 14).

A mixture of 14-ethoxy-7,8-dihydronorcodeinone hydrochloride (R.J. Kobylecki et al., J. Med. Chem., Vol. 25: 116, 1982) (1.5g, 4.1 mmol), potassium carbonate (3.2 g, 22.52 mmol), isopropyl bromide (1.2 ml, 13.31 mmol), and anhydrous N,N- dimethylformamide (15 ml) was stirred at 50°C (bath temperature) for 7 days. The inorganic solid was filtered off, the filtrate evaporated, dissolved in 40 ml of CH₂

Cl₂ and washed with H₂0 (3x30 ml). The organic phase was dried over Na₂S0₄ and evaporated to give 1.79 colorless crystals. Recrystallization from 1.7 ml of MeOH afforded 1.15 g (76%) of compound 13 (=14-ethoxy-17-isopropyl-7,8- dihydronorcodeinone). M.p. 188-190°C. IR (Kbr): 1718 (CO) cm^'1. Η NMR

(CDC1₃): δ 6.65 (d, J = 8.3 Hz, 1 arom. H), 6.56 (d, J = 8.3 Hz, 1 arom H), 4.62 (s, H-

C(5)), 3.87 (s, CH₃0), 1.23 (t, J = 6.8 Hz, 3 H, CH₃CH₂0). Cl-MS (m7z 372 (M^*+l).

Analysis calculated for 0^,^0₄ x 0.2 MeOH (377.89): C 70.56, H 7.95, N 3.71; found: C 70.43, H 7.64, N 3.70.

A mixture of compound 13 (250 mg, 0.67 mmol), O-phenylhydroxylamine hydrochloride (196 mg, 1.34 mmol), methanesulfonic acid (0.1 ml) and anhydrous methanol (6 ml) was refluxed for 6 days. After cooling, the solution was alkalized with cone NH₄OH and extracted with CH₂C1₂ (3x 50 ml). The combined organic

layers were washed with H₂0 (3x50 ml) and brine (30 ml) and evaporated to give

217 mg of a brown foam which was crystallized from methanol to afford 102 mg of brownish crystal which were recrystallized from methanol to yield 33 mg

(11%) of pure compound 14. M.p. 199-201 °C. 'H NMR (CDC1₃): δ 7.10-6.42 (m, 6

arom. H), 4.90 (s, H-C(5)), 3.98 (s, 3 H, CH₃0), 1.29 (t, J = 6.7 Hz, 3 H, C Hp),

1.08 (dd, J = 6.1 Hz, 2 CH₃). CI-MS: m/z 446 (M^*+l). Analysis calculated for

C₂₈H₃₁N0₄ x 1.8 H₂0 (477.99): C 70.63, H 7.30, N 2.93; C 70.33, H 7.00, N 2.84.

Pharmaceutical preparations

For the preparation of a pharmaceutical formulation, the active ingredient may be formulated to an injection, capsule, tablet, suppository, solution or the like. Oral formulation and injection are preferably employed. The pharmaceutical formulation may comprise the δ-selective agonist alone or may also comprise expedients such as stabilizers, buffering agents, diluents, isotonic agents, antiseptics and the like. The pharmaceutical formulation may contain the above described active ingredient in an amount of 1-95 % by weight, preferably 10-60 % by weight. The dose of the active ingredient may appropriately be selected depending on the objects of administration, administration route and conditions of the patients. The active ingredient is administered in doses between 1 mg and 800 mg per day in case of administration by injection and in doses between 10 mg and 5 g per day in case of oral administration. The preferred dose for injection is 20-200 mg per day and the preferred amount for oral administration 50-800 mg per day. Biological studies

δ-Selective agonism was assessed using the electrical stimulated guinea-pig ileal longitudinal muscle preparations (GPI; containing m and k opioid receptors) (P.W. Schiller et al., Biochem. Biophys. Res. Commun., Vol. 58: 11-18, 1978; J. Di Maio et. al., J. Med. Chem., Vol. 25: 1432-1438, 1982) and mouse vas deferens preparation (MVD: containing μ, K and δ opioid receptors). The activities of the compounds to inhibit the contraction of the organs were measured. In the GPI, compounds 1 and 12 did not show inhibition of contraction up to 5.000 nM and 10.000 nM, respectively. These findings suggest that there is no agonist effect at m and k opioid receptors. In MVD, the tested compounds showed δ-selective agonism.

The biological studies of the novel morphinane derivatives of the formula (I) of the present invention have thus shown that these compounds have selectivity for δ opioid receptors and are effective as opioid agonists. Studies with δ-selective opioid agonists have shown that this class of compounds does not have dependence liability and produces substantially less respiratory depression than morphine. Dependence liability and respiratory depression are the most serious side effects of the opioid agonists used as analgesics (e.g. morphine). Accordingly, compounds according to the present invention useful as analgesics without showing the most serious side effects of opioid analgesics.

Claims

1. A compound according to the formula (I)

wherein

R, represents C₁-C₆ alkyl or hydrogen

R_j represents hydrogen, hydroxy ,C₁-C₆ alkoxy; C₁-C₆ alkenyloxy; C₇-C₁₆

arylalkyloxy wherein the aryl is C₆-C₁₀ aryl and the alkyloxy is C,-C₆ alkyloxy; C₇-

C₁₆ arylalkenyloxy wherein the aryl is C₆-C₁₀ aryl and the alkenyloxy is C_j-C₆

alkenyloxy; C_t-C₆ alkanoyloxy, C₁-C₆ alkenoyloxy, C₇-C_]6 arylalkanoyloxy

wherein the aryl is C₆-C₁₀ aryl and the alkanoyloxy is C_j-C₆ alkanoyloxy;

R_g represents hydrogen, C_j-C₆ alkyl; C_j-C₆ alkenyl; C₇-C₁₆ arylalkyl wherein the

aryl is C₆-C₁₀ aryl and the alkyl is C_j-C₆ alkyl; C₇-C_]6 arylalkenyl wherein the aryl

is C₆-C_l0 aryl and the alkenyl is C^-^ alkenyl; hydroxy(C_j-C₆)alkyl; alkoxyalkyl

wherein the alkoxy is C C₆ alkoxy and the alkyl is 0,-C₈ alkyl; C0₂H; C0₂(C.-C₆ alkyl);

R₄ is hydrogen, hydroxy; C₁-C₆ alkoxy; C₇-C₁₆ arylalkyloxy wherein the aryl is C₆-

C₁₀ aryl and the alkyloxy is ^-C₈ akyloxy; C_j-C₆ alkenyloxy; C,-C₆ alkanoyloxy; C₇-C₁₆ arylalkanoyloxy wherein the aryl is C₆-C₁₀ aryl and the alkanoyloxy is C_j-

C₆ alkanoyloxy; alkyloxyalkoxy wherein alkyloxy is C,-C₄ alkyloxy and alkoxy is

C-C, alkoxv;

R₅ and R₆ each and independently represent hydrogen; OH; C,-C₆ alkoxy; C,-C₆

alkyl; hydroxyalkyl wherein the alkyl is C_j-C₆ alkyl; halo; nitro; cyano;

thiocyanato; trifluoromethyl; C0₂H; C0₂(C C₆ alkyl); CONH^ CONH(C C₆

alkyl); CON(C_j-C₆ alkyl)₂; amino; C₁-C₆ monoalkyl amino; C₁-C₆ dialkyl amino;

C.-C₆ cycloalkylamino; SH; S0₃H; S0₃(C.-C₆ alkyl); S0₂(C,-C₆ alkyl); S0₂ NH2;

S0₂NH(C₁-C₆ alkyl); S0₂NH(C₇-C₁₆ arylalkyl); SO(C.-C₆ alkyl); or R₅ and R₆ together form a phenyl ring which may be unsubstituted or substituted by halo, nitro, cyano, thiocyanato; C₁-C₆ alkyl; trifluoromethyl; C,-C₆ alkoxy, C0₂H,

H; S0₃(C₁-C₆ alkyl), S0₂(C₁-C₆ alkyl), SO(C,-C₆ alkyl); and

X represents oxygen; sulfur; CH=CH; or NR₉ wherein R_g is H, C_j-C₈ alkyl, C₁-C₆

alkenyl; C₇-C₁₆ arylalkyl wherein the aryl is C₆-C₁₀ aryl and the alkyl is C_j-C₆

alkyl, C₇-C₁₆ arylalkenyl wherein the aryl is C₆-C₁₀ aryl and the alkenyl is C_j-C₆

alkenyl; C₁-C₆ alkanoyl, and

wherein aryl is unsubstituted or mono-, di- or trisubstituted independently with hydroxy, halo, nitro, cyano, thiocyanato, trifluoromethyl, C_J-C_J alkyl, C_j-^

alkoxy, C0₂H, CONH₂00₂(0^₃ alkyl), CONH(C₁-C₃ alkyl), CON(C_j-C₃ alkyl)₂

CO(C_α-C₃ alkyl); amino; (C_j-^ monoalkyDamino, ( -C₃ dialkyl)amino, C₅-C₆ cycloalkylamino, (C,-C₃ alkanoyDamido, SH, S0₃H, 50₃(0,-0₃ alkyl), 80₂(0,-0₃

alkyl), SO(C^-C₃ alkyl), C,-C₃ alkylthio or C,-C₃ alkanoylthio;

with the proviso that when R_j is hydroxy, R_j cannot be hydrogen;

t e compounds 6,7-Dehydro-4,5α-epoxy-3,14-dimethoxy-17-methyl-6,7-2',3'- benzo [b]f uranomorphinan;

6,7-Dehydro-4,5α-epoxy-3-hydroxy-17-methyl-6,7-2',3'-benzo[b]furano- morphinan;

6,7-Dehydro-4,5α-epoxy-3-hydroxy-17-met yl-6,7-2',3'-indolomorphinan;

3,14-Diacetocy-6,7-dehydro-4,5α-epoxy-17-methyl-6,7-2',3'-indolomorprύnan;

6,7-Dehydro-4,5α-epoxy-3-hydroxy-14-methoxy-17-methyl-6,7-2',3'- benzo[b]furanomorphinan;

and the pharmacologically acceptable salts of the compounds of the formula (I).

2. A compound according to claim 1, wherein

R. is selected from hydrogen, methyl, ethyl, n-propyl or isopropyl;

R_j is selected from methoxy, ethoxy, n-propyloxy, benzyloxy, benzyloxy

substituted in the aromatic ring with F, Cl, N0₂, CN, CF₃, CH₃,OCH₃, allyloxy, cinnamyloxy or 3-phenylpropyloxy;

R_g is selected from hydrogen, methyl, ethyl, benzyl or allyl;

R₄ is selected from hydroxy, methoxy, methoxymethoxy or acetyloxy;

R₅ and R₆ are each and independently selected from hydrogen, nitro, cyano,

chloro, fluoro, bromo, trifluoromethyl, 0O₂H, C0₂ CH₃ CONH₂, CONH CH₃ SH,

S0₂NH₂, N(CH₃)₂ S0₂ CH^ and

X is selected from O, NH, NCH₃, N-benzyl or N-allyl.

3. A compound according to claim 1, wherein

R, is CH₃;

R₂ is selected from methoxy, ethoxy, n-propyloxy, benzyloxy or benzyloxy substituted in the aromatic ring with chlorine;

1*₃ is selected from hydrogen or CH^

R₄ is hydroxy;

S0₂NH₂, or S0₂CH₃; and X is selected from O or NH.

4. A compound according to claim 1, being

6,7-Dehydro-4,5α-epoxy-14-ethoxy-3-hydroxy-5,17-dimethyl-6,7-2',3'- indolomorphinan;

6_/7-Dehydro-4,5α-epoxy-3,14-dimethoxy-5,17-dimethyl-6,7-2',3^,-indolomorphinan;

6,7-Dehydro-4,5α-epoxy-3-hydroxy-14-methoxy-5,17-dimethyl-6,7-2'3'- indolomorphinan;

6,7-Dehydro-4,5α-epoxy-3,14-dihydroxy-5,17-dimethyl-6,7-2'3'-indolomorphinan x HBr;

7,8-Dehydro-4,5α-epoxy-14-hydroxy-3-methoxy-5,17-dimethyl-6,7-2'3'- indolomorphinan x HBr;

6,7-Dehydro-4,5α-epoxy-3-hydroxy-14-methoxy-5-methyl-6,7-2',3'- indolomorphinan;

6,7-Dehydro-4,5α-epoxy-3-hydroxy-5,17-dimethyl-14-n-propyloxy-6,7-2' '- indolomorphinan methane sulfonate;

6,7-Dehydro-4,5α-epoxy-14-ethoxy-3-methoxy-17-methyl-6,7-2',3'- indolomorphinan;

6,7-Dehydro-4,5α-epoxy-14-ethoxy-17-isopropyl-3-methoxy-5-methyl-6,7-2',3'- benzo [b]fur anomorphinan.

5. A compound according to claim 1 for use in therapy.

6. A compound according to claim 1 for use as an analgesic.

7. A compound according to claim 1, in form of a pharmaceutically acceptable salt.

8. A compound according to claim 7, wherein the salt is an inorganic salt.

9. A compound according to claim 6, wherein the salt is an organic salt.

10. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of pain.

11. A pharmaceutical composition comprising a compound or a pharmacologically acceptable salt thereof according to claims 1-9 as an active ingredient, together with a pharmaceutically acceptable carrier.

12. A method for the treatment of a subject suffering from pain, whereby an effective amount of a compound according to claims 1-9 is administered to a subject in need of such treatment.

13. A process for the preparation of a compound according to formula (I) of claim 1, wherein

A. i) thebaine of the formula

is being treated with dialkylsulfates, fluorosulfonic acid alkyl esters, alkylsulfonic add alkyl esters, arylsulfonic acid alkylesters, alkyl halides, alkenyl halides, aralkyl halides, alkylsulfonic acid aralkyl esters, arylsulfonic add aralkyl esters, arylalkenyl halides or chloroformates, giving compounds of the formula (II)

wherein R is C_j-C₆ alkyl, C,-C₆ alkenyl, C₇-C,₆ arylalkyl wherein the aryl is C₆-C_]0

aryl and the alkyl is C.-C₆ alkyl; C₇-C₁₆ arylalkenyl wherein the aryl is C₆-C₁₀ aryl

and the alkenyl is C.-C₆ alkenyl; alkoxyalkyl wherein the alkoxy is C,-C₆ alkoxy

and the alkyl is C,-C₆ alkyl; C0₂ (Cι-C₆ alkyl);

ii) (II) is reacted with performic add or m-chloroperbenzoic add at a temperature between 0 and 60 °C, giving compounds of the formula (III)

wherein R is as defined above or being hydrogen;

iii) the compounds (III) are thereafter being treated with dialkylsulfates, alkyl halides, alkenyl halides, arylalkyl halides, arylalkenyl halides or chloroformates , in the presence of a strong base and a solvent, giving compounds of the formula (IV)

wherein R, is C,-C₆ alkyl, C,-C₆ alkenyl, C₇-C₁₆ arylalkyl wherein the aryl is C₆-C_]0

aryl and the alkyl is C,-C₆ alkyl, C₇-C₁₆ arylalkenyl wherein the aryl is C₆-C₁₄ aryl

and the alkenyl is C,-C₆ alkenyl, C₁-C₆ alkanoyl, C₇-C_]6 arylalkanoyl wherein the

aryl is C₆-C₁₀ aryl and the alkyl is C,-C₆ alkyl, C₇-C,₆ arylalkenoyl wherein the

aryl is C₆-C₁₀ aryl and the alkenoyl is C,-C₆ alkenoyl; and

₂ is hydrogen; C,-C₆ alkyl; C,-C₆ alkenyl C₇-C₁₆ arylalkyl wherein the aryl is C₆-

C₁₀ aryl and the alkyl is C,-C₆ alkyl; C₇-C₁₆ arylalkenyl wherein the aryl is C₆-C_]0 aryl and the alkenyl is C,-C₆ alkenyl; alkoxyalkyl wherein the alkoxy is C.-C₆

alkoxy and the alkyl is C₁-C₆ alkyl; C0₂(C₁-C₆ alkyl);

iv) the compounds (IV)

are reduced giving compounds of the formula (V)

C

wherein

R_j is C,-C₆ alkyl, C₇-C₁₆ arylalkyl wherein the aryl is C₆-C_]0 aryl and the alkyl is

C^C_g alkyl, C,-C₆ alkanoyl, C₇-C₁₆ arylalkanoyl wherein the aryl is C₆-C₁₀ aryl and

the alkanoyl is C.-C₆ alkanoyl;

R_j is hydrogen; C_j-C₆ alkyl, C₇-C₁₆ arylalkyl wherein the aryl is C₆-C₁₀ aryl and the

alkyl is C_j-C₆ alkyl; alkoxyalkyl wherein the alkoxy is C₁-C_ό alkoxy and the alkyl

is C C₆ alkyl; C0₂(C₁-C₆ alkyl);

v) the compounds (V) are in turn challenged with reagents to achieve ether deavage, giving phenolic compounds according to the formula (VI)

wherein R, and R_j are as defined above in formula (V);

vi) the compounds (VI) are thereafter alkylated or acylated giving compounds of the formula (VII)

wherein R and R₂ are as defined above in formula (V), and

C_t-C₆ alkyl, C_]-C₆ alkenyl, C₇-C₁₆ arylalkanoyl wherein the aryl is C₆-C_]0 aryl and

the alkanoyl is C_]-C₆ alkanoyl, alkyloxyalkyl wherein alkyloxy is C,-^ alkyloxy

and alkyl is C_]-C₆ alkyl, C C6 alkanoyl;

vii) the compounds (VII) are thereafter N-demethylated, employing chloroformates or cyanogen bromide giving the corresponding carbamates or N- cyano compounds of the formula (VIII)

wherein R., ^ and R₃ are as defined above in formula (V) and (VII), and Z is CN,

C0₂CH=CH₂, C0₂CHC1CH₃, CO₂CH₂CH3,CO2 Ph or C0₂CH₂CC1₃.

viii) the compounds (VIII) are cleaved giving compounds according to the formula (IX)

wherein R., ^ and R_g are as defined above in formula (V) and (VII);

ix) the compounds (IX) are N-alkylated yielding compounds according to the formula (X)

wherein R R_j and R₃ are as defined above in formula (V) and (VII), and Y is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, tert-butyl, 2-pentyl, 3-pentyl, 2-hexyl or 3-hexyl;

x) ether deavage gives compounds according to the formula (XI)

wherein R, and R^ are as defined above in formula (V), and Y is as defined in formula (X) above;

B) compounds of the formulas (VI), (VII), (IX), (X), (XI) or (XV) are reacted with phenylhydrazine or substituted phenylhydrazine giving compounds according to formula (I)

wherein R_g is as defined above and X represents NH;

C) compounds of the formulas (VI), (VII), (IX),(X), (XI) or (XV) are reacted with O-phenylhydroxylamine or substituted O-phenylhydroxylamine, giving compounds of the formula (I)

wherein R_g is as defined above and X represents O;

D) thebaine is converted to 14-hydroxycodeinone according to formula (XII)

which in turn is converted to compounds of the formula (I)

wherein R, and R-. are as defined above and ^ is hydrogen, with the proviso that

R₂ cannot be hydroxy when R₃ is hydrogen.

14. A process according to claim 13, whereby the compound of the formula (II) of step ii) is reacted with performic acid at a temperature of 0-10°C.