WO1995031463A1

WO1995031463A1 - New antagonist compounds

Info

Publication number: WO1995031463A1
Application number: PCT/SE1995/000503
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: IL113631A0; DE69532580T2; EP0759922A1; JP4117801B2; DE69532580D1; ES2214501T3; SE9401728D0; AU690996B2; ATE259815T1; EP0759922B1; ZA953701B; US6136817A; AU2581795A; JPH10500131A

Abstract

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

Description

NEW ANTAGONIST COMPOUNDS

Field of the invention

The present invention is related to novel δ opioid receptor antagonists 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

Opiod antagonists have been indispensable as tools in opioid research. For example, the chief criterion for the classification of an agonist effect as being opioid receptor mediated is the ability of known opioid antagonists naloxone or naltrexone to reversibly antagonize this effect in a competitive fashion. The usefulness of naloxone and naltrexone for this purpose stems from the fact that they are universal opioid antagonists; that is, they are capable of antagonizing the agonist effects mediated by multiple opioid receptor types.

Since it is now firmly established that there are a minimum of three opioid receptor types (μ, K and δ), it has become increasingly evident that selective opioid antagonists are valuable pharmacological tools for identifying receptor types involved in the interaction with opioid agonists. One of the major advantages of selective opioid antagonists over selective agonists is their utility in probing the interaction of endogenous opioid peptides and new opioid agonists with opioid receptor types. Moreover, since it is sometimes not easy to distinguish among μ, K and δ opioid receptor mediated agonist effects if the pharmacological endpoints are identical (e.g. antinoάception or inhibition of a smooth muscle preparation by agonists), selective antagonists clearly have wider utility as tools than selective agonists. The general utility of selective antagonists as pharmacological tools depends upon the correlation of in vitro and in vivo acitivity. This can be accomplished more easily with non-peptide ligands because they generally can penetrate the blood- brain barrier and therefore can be administered peripherally in vivo. Also, they are less subject to metabolism than are peptides.

In addition to their uses as pharmacological tools, selective, non-peptide opioid antagonists have been described as having potential clinical applications in the treatment of a variety of disorders where endogenous opioids play a modulatory role. These include for instance disorders of food intake, shock, constipation, mental disorders, CNS injury, alcoholism, and immune function (immune stimulation or suppression) (P.S. Portoghese et al., J. Med. Chem., Vol 34: 1757- 1762, 1991).

Non-peptide, competitive, δ-selective opioid antagonists have been found recently. The prototypes are: cyprodime for μ (H. Schmidhammer et al., J. Med. Chem., Vol. 32:418-421, 1989; H. Schmidhammer et al., J. Med. Chem., Vol. 33: 1200-1206, 1990), norbinaltorphimine for (P. S. Portoghese et al., J. Med. Chem., Vol. 30:238-239, 1987), and naltrindole for δ opioid receptors (P.S. Portoghese et al., J. Med. Chem., Vol. 31:281-282, 1988).

These compounds (cyprodime, norbinaltorphinine and naltrindole) are being used as pharmacological tools. They have been tritium labelled and can be used as receptor selective ligands in opioid receptor binding studies to sort out the affinities of new ligands to different receptors and to determine whether a compound is selective to a special receptor.

An object of the present invention was to find new, highly selective δ opioid receptor antagonists with high potency. Another object was to find highly selective δ opioid receptor antagonists with high immunosuppressive potency. The high selectivity for δ opioid receptors would repress adverse side effects caused by the interaction with other receptors. Still another object was to find compounds which have a brain-cell protecting effect. The problem with the δ opiod receptor antagonists known from the prior art is that they are not highly selective.

Prior art

Certain opioid agonists represented by morphine, which act on μ receptors, are known to exhibit immunosuppressive effects. The agonist enkephalin, which acts on δ opioid receptors, exhibit immunostimulating effects (Plotnikoff, Enkephalins and Endorphins, Stress and Immune System, Plenum Press, 1986). Although a number of reports have been issued concerning the immunosuppressive effects of agonists of μ receptors, it is difficult to develop an immunosuppressive agent by employing an agonist of μ receptors, since such agonists show critical side effects such as addiction, respiratory depression, constipation etc.

Recently it has been reported that δ-selective opioid antagonists have immunosuppressive effects. See EP 456 833, EP 485 636 and EP 614 898.

Outline of the invention

The present invention provides novel compounds of the formula (I)

wherein R- represents C.-C-_g alkenyl; C₄-C₁₀ cycloalkylalkyl wherein the cycloalkyl is C₃-C₆

cycloalkyl and the alkyl is C--C₄ alkyl; C₄-C₁₀ cykloalkenylalkyl wherein the

cycloalkenyl is C₃-C₆ cykloalkenyl and the alkyl is C--C₄ alkyl; C₇-C₁₆ arylalkyl

wherein the aryl is C₆-C₁₀ aryl and the alkyl is C--C₆ alkyl; C₈-C₁₆ arylalkenyl

wherein the aryl is C₆-C₁₀ aryl and the alkenyl is C₂-C₆ alkenyl;

R-, represents hydrogen, hydroxy, C--C₆ alkoxy; C.-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.-C₆

alkenyloxy; C--C₆ alkanoyloxy; C₇-C₁₆ arylalkanoyloxy wherein the aryl is C₆-C₁₀

aryl and the alkylaroyloxy is C_α-C₆ alkylaroyloxy;

R₃ represents hydrogen, C--C₆ alkyl; C--C₆ alkenyl; C₇-C₁₆ arylalkyl wherein the

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

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

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

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

C₁₀ aryl and the alkyloxy is C--C₆ alkyloxy; C--C₆ alkenyloxy; C--C₆ alkanoyloxy;

C-,-C₁₆ arylalkanoyloxy wherein the aryl is C₆-C₁₀ aryl and the alkanoyloxy is C.-

C₆ alkanoyloxy; C₂-C₁₀ alkyloxyalkoxy wherein alkyloxy is C--C₄ alkyloxy and

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

C₆ alkyl)₂; amino; C--C₆ monoalkyl amino; C--C₆ dialkyl amino, C₅-C₆

cycloalkylamino; SH; S0₃H; S0₃(C--C₆ alkyl); S0₂(C--C₆ alkyl); S0₂NH₂;

S0₂NH(C--C₆ alkyl); S0₂NH (C₇-C-₆ 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; C--C₆ alkyl; trifluoromethyl; C--C₆ alkoxy, C0₂H,

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

S0₃(C.-C₆ alkyl), S0₂(C C₆ alkyl), SO(C--C₆ alkyl), and

X represents oxygen; sulfur; CH=CH or NR„ wherein R, is H, 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-C₁₀ aryl and the alkenyl is C.-C₆

alkenyl; C--C₆ alkanoyl,

with the proviso that when R_j is hydroxy R_g cannot be hydrogen, except when R₄

is hydrogen, OCH₂OCH₃, OCH₂OC₂H₅ or OCCPh)^

and pharmacologically acceptable salts thereof.

By aryl the following definitions are intended throughout the hole patent application.

Aryl may be unsubstituted or mono-, di- or trisubstituted independently with hydroxy, halo, nitro, cyano, thiocyanato, trifluoromethyl, C.-C₃ alkyl, C--C₃ alkoxy, C0₂H, C0₂ (C--C₃)alkyl, CONH₂, CONH(C_t-C₃ alkyl), CON(C--C₃ alkyl)₂,

CO(C--C₃ alkyl), amino, (C--C₃ monoalkyl)amino, (C.-C₃ dialkyl)amino, C₅-C₆

cycloalkylamino, (C--C₃ alkanoyDamino, SH, S0₃H, S0₃ (C--C₃ alkyl), S0₂ (C C₃

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

In a preferred embodiment

R- is selected from allyl, cinnamyl, cyclopropylmethyl or cyclobutylmethyl;

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

substituted in the aromatic ring with F, Cl, N0₂, CN, CF₃, CH₃ or 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; C0₂ CH₃, CONH₂; CONH CH₃,

CH₃, SH; S0₂NH₂; N(CH₃)₂, S0₂ CH₃; and

X is selected from O, NH, N CH₃, N-benzyl, N-allyl.

In an especially preferred embodiment R- is allyl or cyclopropylmethyl;

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

R_g is selected from hydrogen or CH-;

R₄ is hydroxy R₅ and R₆ are each 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 compounds of Examples 1, 6, 8, 18, 24, 41 and 42.

The novel compounds according to the invention are useful as immunsuppressive agents and/or as analgesics, and also after CNS-injuries by exerting a brain-cell protecting effect.

Earlier studies (cf. page 3) accomplished with δ-selective opioid antagonists have shown that this class of compounds exhibits immunosuppressive effects. Thus, the compounds of formula (I) of the present invention may be used for suppressing the rejection of transplants after organ transplantations and may be used in the treatment of rheumatic diseases, e.g. rheumatoid arthritis and/or as analgesics.

Pharmaceutically and pharmacologically acceptable salts of the compounds of formula I are also comprised in the invention. Suitable salts are inorganic salts such as HCl salt, HBr salt, sulfuric acid salt, phosphoric acid salt. Organic acid salts such as methanesulfonic acid salt, salicylic acid salt, fumaric acid salt, maleic acid salt, succinic acid salt, aspartic acid salt, citric acid salt, oxalic acid salt, orotic acid salt, although the salts are not restricted thereto, can also be used according to the invention. Preparation

The compounds represented by formula (I) 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, aralkyl halides, alkylsulfonic acid aralkyl esters, arylsulfonic acid aralkyl, arylalkenyl halides, 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), giving compounds of the formula II

wherein

R is C₁-C₆ alkyl; C--C₆ alkenyl; C₇-C₁₆ aralkyl 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; alkoxyalkyl wherein the alkoxy is C.-C₆ alkoxy and the

alkyl is C.-C₆ alkyl; C0₂ (C.-C₆ alkyl); The substituted thebaine derivatives

(formula (II)) or thebaine are converted into the corresponding 14- hydroxycodeinones according to formula III

wherein

R is as defined above or being hydrogen, by reaction with performic acid (s. 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 being treated with dialkyl sulfates, alkyl halides, alkenyl halides, aralkyl halides, arylalkenyl halides, 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--C₆ alkyl, C--C₆ alkenyl, C₇-C₁₆ arylalkyl wherein the aryl is C₆-C_l0 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, C₇-C₂₀ arylalkanoyl wherein the aryl

is C₆-C₁₄ aryl and the alkyl is C--C₆ alkyl, C₇-C₂₀ arylalkenoyl wherein the aryl is

C₆-C_]4 aryl and the alkyl is C--C₆ alkenoyl;

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

C₁₀ aryl and the alkyl is C.-C₆ alkyl; C₇-C_]6 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 C--C₆ alkyl; C0₂(C.-C₆ alkyl);

which in turn are reduced by catalytic hydrogenation using a catlayst 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--C₆ alkyl, C₇-C_]6 arylalkyl wherein the aryl is C₆-C_]0 aryl and the alkyl is

C₁-C₆ alkyl, C.-C₆ alkanoyl, C₇-C₁₆ arylalkanoyl wherein the aryl is C₆-C₁₀ aryl and

the alkanoyl is C-_^-C₈ alkanoyl; and

R-, is hydrogen; C--C₆ alkyl, C,-C₆ alkenyl C₇-C₁₆ arylalkyl wherein the aryl C₆-C₁₀

aryl and the alkyl is C--C₆ alkyl; C₇-C_]6 arylalkenyl wherein the aryl is C₆-C₁₀ aryl and alkenyl is C.-C₆ alkenyl; alkoxyalkyl wherein the alkoxy is C--C₆ alkyl;

C0₂(C--C₆ alkyl);

Thereafter N-demethylation can be carried out using chloroformates or cyanogen bromide to give intermediates of formula (VI)

wherein

R. and R_j are as defined above in formula (IV); and

R₃ is C0₂CHC1CH₃, C0₂CH=CH₂, C0₂CH₂CC1₃, C0₂CH₂CH₃, C0₂Ph, CN or the like.

The intermediate carbamates of formula (VI) can be cleaved by refluxing in alcohols (in the case of 1-chloroethyl carbamates), by addition of hydrogen halides or halogen and subsequent refluxing in alcohols (in the case of vinyl carbamates), or by reductive cleavage using zinc in glacial acetic acid or methanol (in the case of 2,2,2-trichloroethyl carbamates). Other carbonates may be cleaved using aqueous acid, alkali or hydrazine. The intermediate cyanamides of formula (VI) can be cleaved by acid hydrolysis. Alkylation of the corresponding N-nor derivatives of formula (VII)

wherein

R- and R_j are as defined above in formula (V), can be accomplished with alkenyl halides, cycloalkylalkyl halides, cycloalkenylalkyl halides, aralkyl halides, arylalkenyl halides, in solvents such as dichloromethane, 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 (VIII)

wherein

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

R_j represents C--C₆ alkenyl; C₇-C_]6 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; C₄-C₁₀ cycloalkylalkyl wherein the cycloalkyl is C₃-C₆

cycloalkyl and the alkyl is C.-C₄ alkyl; C₄-C₁₀ cycloalkylalkenyl wherein the

cycloalkenyl is C₃-C₆ cycloalkenyl and the alkyl is C--C₄ alkyl; Ether cleavage can be carried out using boron tribromide (in a solvent such as dichloromethane or chloroform at about 0 °C), 48 % hydrobromic acid (reflux), or other well known reagents for ether cleavage. The resulting phenols of formula (IX)

wherein

R-, R_j and R_j are as defined above, are being alkylated using alkyl halides, alkyl sulfates, sulfonic acid esters, aralkyl halides, arylalkenyl halides or acylated using carbonic acid chlorides, or carbonic acid esters to yield compounds of formula (X)

wherein

R-, R_j and R_g are as defined above; and

R₄ is hydrogen, C--C₆ alkyl, C₇-C₁₆ arylalkyl wherein the aryl is C₆-C₁₀ aryl and

the alkyl is C.-C₆ alkyl, C--C₆ alkenyl, C₇-C₁₆ arylalkenyl wherein the aryl is C₆-C₁₀

aryl and the alkenyl is C₁-C₆ alkenyl; C--C₆ alkanoyl, C₇-C₁₆ arylalkanoyl wherein

the aryl is C₆-C₁₀ aryl and the alkanoyl is C--C₆ alkanoyl, C₂-C₁₀ alkyloxyalkyl

wherein alkyloxy is C--C₄ alkyloxy and alkyl is C--C₆ alkyl, Compounds of the formula (I) wherein F^ is hydroxy may be obtained from compounds of formula (III) wherein R is defined as above. These compounds may 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 the formula (V) wherein R- is hydrogen and R_j is defined for R in formula (II).

The following reaction sequence and procedures leading to compounds of formulas (VI), (VII), (VIII), (IX) and (X) wherein the substituent in position 14 is hydroxy and the other substitutents are defined as above, is analogous to the reaction sequence and procedures described above. Further conversion to compounds of the formula (I) wherein 1^ is hydroxy is described below.

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

(XIa): R=H (dihydrocodeinone)

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

Compounds of the formula (XI) and (XIa) (Mannich and Lόwenheim, Arch.Pharm.Vol. 258:295, 1920) can be converted into compounds of formulas (V), (VI), (VII), (VIII), (IX), and (X) wherein the substituent in position 14 is hydrogen and R₂ and R₃ are as defined above, similarly as outlined 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 formula (IX) by alkylation with 5-chloro-l-phenyl- H-tetrazole to give the corresponding phenyltetrazolyl ethers of the formula XII)

wherein R-, 1^ and R_g are as defined above and R- also can be CH₃, and T is phenyl tetrazolyl.

Catalytic hydrogenation may afford (H. Schmidhammer et al., J. Med. Chem. Vol. 27:1575-1579, 1984) compounds of the formula (XIII)

wherein R R_j and R_g are as defined above and R- also can be CH^ In the case R. is CH₃, the N-methyl group has to be removed and the nitrogen alkylated as described above.

Alternatively, compounds of formula (I) wherein R- represents allyl or

cyclopropylmethyl and R_g represents H can be obtained by a shorter route starting either from naloxone (XlVa) or naltrexone (XlVa).

(XlVa): Naloxone - R is allyl (XlVb): Naltrexone - R is cyclopropylmethyl.

The 3-hydroxy group of compounds of formula (XIV) is being protected by alkylation with benzyl bromide, methoxymethyl bromide, ethoxymethyl bromide or trityl chloride (triphenylmethyl chloride) in a solvent such as N,N-dimethyl formamide or dichloromethane in the presence of a base to yield compounds of formula (XV)

wherein

R is allyl or cyclopropylmethyl and Y = CH₂Ph, CH₂OCH₃, CH₂OC₂H₅ or C(Ph)₃. These compounds are alkylated, alkenylated, cycloalkylalkylated, arylalkylated or arylalkenylated with dialkyl sulfates, alkyl halides, alkenyl halides, arylalkyl halides or arylalkenyl halides in solvents such as N,N-dimethyl formamide or tetrahydrofurane using a strong base such as sodium hydride, potassium hydride or sodium amide. The resulting 6-0,14-0-dialkylated compounds of formula (XVI)

wherein

R- is allyl or cyclopropylmethyl; and

R_j, is C--C₆ alkyl, C--C₆ alkenyl, C₇-C₁₆ arylalkyl wherein the aryl is C₆-C₁₀ aryl

and the alkyl is C--C₆ alkoxy, C₇-C₁₆ arylalkenyl wherein the aryl is C₆-C₁₀ aryl

and alkenyl is C--C₆ alkenyl; and Y as defined above;

can be hydrolized with diluted acids like hydrochloric acid or sulfuric acid to afford compounds or formula (XVII)

wherein

R_j is allyl or cyclopropylmehtyl; and R₂ is as defined above (formula XVI).

In the case R₂ is alkenyl or arylalkenyl the double bond may be reduced by catalytic hydrogenation to afford the corresponding saturated derivatives. Further conversion into compounds of formula (I) is described below.

Alternatively, compounds of formula (I) wherein R- represents allyl or

cyclopropylmethyl and R_g represents H can be prepared also via the following route: The carbonyl group in position 6 of naloxone (XVa) and naltrexone (XVb), respectively, is being protected by reaction with ethylene glycol in the presence of an acid (e.g. methanesulfonic acid) at temperatures between 20 and 200 °C to give ketals of formula (XVIII)

wherein R is allyl or cyclopropylmethyl.

The 3-hydroxy group of these ketals is being protected by alkylation with benzyl bromide, methoxymethyl bromide, ethoxymethyl bromide or trityl chloride in a solvent such as N,N-dimethyl formamide or dichloromethane in the presence of a base to yield compounds of formula (XIX)

wherein R is allyl or cyclopropylmethyl and Y is as defined above.

These compounds are alkylated, alkenylated, arylalkylated or arylalkenylated with dialkyl suflates, alkyl halides, alkenyl halides, arylalkyl halides or arylalkenyl halides in solvents such as N,N-dimethyl formamide or tetrahydrofurane using a strong base such as sodium hydride, potassium hydride or sodium amide. The resulting compounds of formula (XX)

wherein R- is allyl or cyclopropylmethyl, R_j is as defined above (formula (XVI)) and Y is as defined above

can be hydrolized in diluted acids like hydrochloride acid or sulfuric acid (a typical mixture for hydrolysis is: concentrated HCl: MeOH: H₂03/6/1 v/v/v) to

afford compounds of formula (XVII). Compounds of formula (I) wherein R- represents allyl or cyclopropyl-ethyl, R₃ represents H, and X represents NH or O can be prepared from compounds of formula (XVII) as described below.

Compounds of the formula (I) wherein R_g is as defined above and X represents NH are obtained by reaction of compounds of formula (Vffi), (X) or (XIII) 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 hydroxy, halogen, C.-C₆

alkyl, C--C₆ alkoxy, amino, nitro, cyano, thiocyanato, trifluoromethyl, C0₂H, C0₂

(C--C₆) alkyl, CONH₂, CONH (C.-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 O are obtained by reaction of compounds of formula (VIII), (IX), (X) or (XIII) with O- phenylhydroxyl amine or substituted (at the aromatic ring) O-phenylhydroxyl- amine 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 hydroxy, halogen, C--C₆ alkyl, C--C₆ alkoxy, amino, nitro,

cyano, thiocyanato, trifluoromethyl, C0₂H, C0₂ (C--C₆) alkyl, CONH₂, CONH

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

The invention will now be described in more detail by the following examples which are not to be construed as limiting the invention. Examples

Example 1

Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-14-ethoxy-3- hydroxy -5-methyl-6,7-2',3'-indolomorphinan hydrochloride (compound 1).

A mixture of 14-0-ethyl-5-methylnaltτexone (H. Schmidhammer et al, Helv. Chim. Acta, Vol. 76: 476-480, 1993) (580 mg, 1.51 mmol), phenylhydrazine hydrochloride (394 mg, 2.72 mmol), and 7 ml of glacial acetic acid was refluxed for 23 h. After cooling, the reaction mixture was poured on ice, alkalized with cone. NH₄OH and extracted with CH₂C1₂ (3x30 ml). The combined organic layers

were washed with H₂0 (3x80 ml), dried over Na₂S0₄ and evaporated. The remaining residue (615 mg brownish foam) was dissolved in little MeOH and Et₂0/HCl was added. Thus, 550 mg (95%) of the compound 1 were isolated. For analysis a small amount was recrystallized from MeOH. m.p. > 260°C (dec.) IR

(KBr): 3200 CNH, NH, OH)cm . CI-MS:m/z 457 (M^' +1). ⁷H-NMR ((d₆)DMSO): δ

11.34, 9.21. and 8.55 (3 s, ^*NH, NH, OH), 7.32 (m, 2 arom. H), 7.08 (t, J = 8.1 Hz, 1 arom. H), 6.94 (t, J = 8.1 Hz, 1 arom. H), 6.62 (d, J = 8.1 Hz, 1 arom. H); 6.55 (d. J = 8.1 Hz, 1 arom. H), 1.86 (s, CH₃-C(5)), 1.01 (t, J = 6.8 Hz, 3H, CH₃CH₂0). Analysis

calculated for C₂₉ H₃₂N₂0₃.HC1.H₂0 (511.06): C 68.16, H 6.90, N 5.48, Cl 6.94; found: C 67.87, H 6.88, N 5.30, Cl 7.28. Example 2

Synthesis of 17-Allyl-6,7-dihydro-4,5α-epoxy-14-ethoxy-3-hydroxy-5-methyl-6,7- 2',3'-indolomorphinan hydrochloride (compound 2).

A mixture of 14-0-ethyl-5-methylnaloxone (H. Schmidhammer et al., Helv. Chim. Acta Vol. 76:476-480, 1993) (1.2g, 2.66 mmol), phenylhydrazine hydrochloride (577 mg, 3.99 mmol), and 15 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 (3x80 ml), 1x30 ml). The combined organic layers were

washed with H₂0 (3x80 ml, 1x30 ml), dried over Na₂S0₄ and evaporated. The residue (1.3 g yellow-brown foam) was purified with column chromatography

(alumina basic grade IV, elution with CH₂C1₂). The corresponding fractions were combined and evaporated to give a colorless oil which was converted into the hydrochloride salt in the usual way and crystallized from MeOH/diethyl ether to yield 200 mg (17%) of the title compound 2. M.p. 168-170°C. IR

(CD₃OD): δ 7.39 (dd, J=7.8, 7.8 HZ, 2 arom. H), 7.14 (t, J=7.8 hz, 1 arom.H), 7.01

(t=7.8 HZ, 1 arom. H), 6.67 (s,2 arom. H), 6.02 (m, 1 olef. H), 5.72 (m, 2 olef. H), 1.99 (s, CH₃-C(5)), 1.09 (t, J=6.8 Hz, CH₃). Analysis calculated for C₂₈H₃₀N₂O₃.

HCl. 1.5 H₂0 (506.05): C 66.46, H 6.77 N 5.54, Cl 7.01; found: C 66.55, 6.68, N 5.39, Cl 6.98. Eaxmple 3

Synthesis of 6,7-Dehydro-4,5α-epoxy-14-ethoxy-3-hydroxy-5-methyl-17-(2- phenyl)ethyl-6,7-2',3'-indolomorphinan hydrochloride (compound 5).

A mixture of 4,5α-epoxy-14-ethoxy-3-methoxy-5-methylmorphinan-6-one hydrochloride (H. Schmidhammer et al., Helv. Chim. Acta Vol. 76, 476-480,1993) (3.0 g, 7.88 mmol), potassium carbonate (3.9 g, 28.2 mmol), 2-phenylethyl bromide (1.41 ml, 10.4 mmol), and of 20 ml anhydrous N,N-dimethyl formamide was stirred at 80°C (bath temperature) for 2h. After cooling and addition of 130 ml of

H₂0, the mixture was extracted with diethyl ether (3x60 ml). The combined

organic layers were washed with H₂0 (3x70 ml), dried over Na₂S0₄ and evaporated. The residue (3.6 yellow oil) was crystallized from MeOH to afford 2.1 g (70%) of 4,5α-epoxy-14-ethoxy-3-methoxy-5-methyl-17-(2- phenyl)ethylmorphinan-6-one (compound 3). M.p. 86-89°C. IR (KBr): 1725 (CO) cm^"1. CI-MS: m/z 448 (M⁺+l). ^-NMR (CDC1₃): δ 7.21 (m, 5 arom. H), 6.64

(d,J=8.2 Hz, 1 arom. H, 6.54 (d, J=8.2 Hz, 1 arom. H.), 3.85 (s, OCH₃), 1.60 (s, CH₃-

C(5)), 1.12 (t, J=6.8 Hz, CH₃). Analysis calculated for C^H^NO. (447.55): C 75.14,

H 7.43, N 3.13; found: C 75.04, H 7.69, N 3.26.

A solution of the compound 3 (1.5 g, 3.35 mmol) in 5 ml of 48% HBr was refluxed for 30 min and then evaporated. The residue was dissolved in MeOH and again evaporated (this procedure was repeated twice) to give a grey crystall ne residue (1.7 g) which was treated with hot MeOH to yield 950 mg (63%) of the compound 4. M.p.>270°C. IR (KBr): 1720 (CO) cm^'\ CI-MS: m/z 434 (M^*+l). ^!H-NMR

(DMSO-d₆): δ 9.38 and 8.48 (2 s, ^*NH, OH), 7.33 (m,5 arom. H), 6.68 (d, J=8.2 Hz, 1

arom. H), 6.64 (d, J=8.2 Hz, 1 arom. H), 1.51 (s, CH₃-C(5)), 1.34 (t, J=6.8 Hz, CH₃). Analysis calculated for C₂₇H_3]N0₄. HBr (514.45):C 63.04, H 6.27, N 2.72, Br 15.53; found: C 63.15, H 6.48, N 2.61, Br 15.37.

A mixture of the compound 4 (700 mg, 1.61 mmol), phenylhydrazine hydrochloride (513 mg), 3.54 mmol), and 15 ml of glacial acetic acid was refluxed for 6 h. The reaction mixture was poured on ice, alkalized with cone. NH₄OH and

extracted with CH₂C1₂ (3x80 ml, 1x30 ml). The combined organic layers were

washed with H₂0 (3x80 ml), dried over Na₂S0₄ and evaporated. The residue (600 mg slightly brown foam) was converted into the hydrochloride salt in the usual way and crystallized from MeOH/diethyl ether to yield 360 mg (51 %) of the title compound 5 as slightly pink crystals. M.p.>225°C. IR (KBr):3400 and 3200 CNH,

NH,OH). CI-MS:m/z 507 (M'+l). H-NMR (DMSO-d₆):δ 11.34, 9.19 and 8.97 CNH,

NH, OH), 7.34 (m, 7 arom. H), 7.08 (t, J=7.9 Hz, 1 arom.), 6.94 (t, J=7,9 Hz, 1 arom. H), 6.62 (d, J=8.4 Hz, 1 arom. H), 6.57 (d, J=8.4 Hz, 1 arom. H), 1.87 (s, CH3- C(5)),0.96 (t, J=6.9 Hz, CH₃). Analysis calculated for C^H^N- ,. HC1.2 H₂0

(579.14): C 68.44, H 6.79, N 4.84, Cl 6.12; found: C 68.81, H 6.55, N 4.72, Cl 6.40.

Example 4

Synthesis of 17-Allyl-6,7-dehydro-4,5α-epoxy-3-hydroxy-14-methoxy-5-methyl- 6,7-2'^'-indolomorphinan hydrochloride (compound 6).

A mixture of 14-0-methyl-5-methylnaloxone (H. Schmidhammer et al., Helv. Chim. Acta Vol. 77:1585-1589, 1994) (1.0 g, 2.8 mmol), phenylhydrazine hydrochloride (728 mg, 5.04 mmol), and 15 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 CK,^ (3x80 ml, 1x30 ml). The combined

organic layers were washed with F-^O (3x80 ml), dried over Na₂S0₄ and evaporated. The residue (1.1 g brownish foam) was converted in the usual way into the hydrochloride salt and crystallized from acetone to yield 190 mg (19%) of the tide compound 6 as slightly brown crystals. M.p. >280°C. IR (KBr): 3200 CNH,

NH,OH), ^]H-NMR: δ 7.32 (dd, J=7.9, 7.9 Hz, 2 arom. H), 7.06 (t, J=7.9 Hz, 1 arom. H), 6.93 (t, =7.9 Hz, 1 arom. H), 6,63 (d, J=8.2 Hz, 1 arom. H), 6.55 (d, J=8.2 Hz, 1 arom. H), 6.02 (m, lolef.H), 5.63 (m, 1 olef. H), 3.15 (s, OCH₃), 2.07 (s, CH₃-C(5)).

Analysis calculated for C₂₇H_2gN₂0₃. HCl. 1.7 H₂0. 0.9 MeOH (524.44): C64.41, H 7.09, N 5.22; found: C 64.44, H 6.87, N 4.94.

Example 5

Synthesis of 6,7-Dehydro-4,5α-epoxy-3-hydroxy-14-methoxy-5-methyl-17-(2- phenyl)ethyl-6,7-2',3'-indolomorphinan Hydrochloride (compound 9).

A mixture of 4,5α-epoxy-3,14-diιnethoxy-5-memylmorphinan-6-one hydrochloride (H. Schmidhammer et al., Helv. Chim. Acta Vol. 77:1585-1589, 1994) (2.24 g, 6.12 mmol), potassium carbonate (3.0 g, 21.9 mmol), 2-phenylethyl bromide (1.05 ml, 7.74 mmol), and 15 ml of anhydrous NJST-dimethyl formamide was stirred at 80°C (bath temperature) for 2 h. After cooling and addition of 110 ml of TrL D, the mixture was extracted with diethyl ether (3x60 ml). The combined

organic layers were washed with H₂0 (3x70 ml), dried over Na₂S0₄ and evaporated. The residue (2.9 yellow oil) was converted into the hydrobromide salt in the usual way and crystallized from MeOH to give 1.4 g (63%) of 4,5α-epoxy- 3,14-dimethoxy-5-methyl-17-(2-phenyl)ethylmorphinan-6-one hydrobromide (compound 7) as colorless crystals. A small portion of this material was recrystallized from MeOH for analyses. M.p. 94-96°C. IR (KBr): 3400 CNH), 1720

(CO) cm^'1. CI-MS: m/z 434 (M^*+l). ^-NMR (DMSO-d₆) δ 10.15 (s, ^*NH), 7.30 (m,

5 arom. H), 6.74 (d, J=8.2 Hz, 1 arom. H), 6.68 (d, J=8.2 Hz, 1 arom.), 3.87 (s, OCH₃-C(3)), 3.58 (s, OCH₃-C(14)), 1.60 (s, CH₃-C(5)). Analysis calculated for

C₂₇H₃₁N0₄. HBr (514.44): C 63.04, H 6.27, N 2.72; found: C 63.18, H 6.60, N 2.39.

A solution of the compound 7 (1.4 g, 3.32 mmol) in 5 ml of 48% HBr was refluxed for 30 min and then evaporated. The residue was dissolved in MeOH and again evaporated (this operation was repeated once) to afford a brownish crystalline residue (1.8 g) which was treated with hot MeOH to yield 590 mg (42%) of the compound 8.HBr. A small portion was recrystallized for analyses. M.p.>316°C. IR

(KBr):3400 CNH, OH), 1722 (CO)cm^'1. CI-MS: m/z 420 (M^*+l). ^-NMR (DMSO-

d₆) δ 8.95 and 8.45 (2s, ^"NH,OH), 6.90 (m, 5 arom. H), 6.23 (dd, J=8.2, 8.2 Hz, 2

arom. H), 2.97 s, OCH3), 1.08 (s, CH₃-C(5)). Analysis calculated for C₂₆H₂₉N0₄.

HBr. 0.2 MeoH (506.85): C 62.09, H 6.13, N 2.76, Br 16.77; found: C 61.79, H 6.18, N 2.63, Br 16.12.

A mixture of the compound 8. HBr (468 mg, 0.93 mmol), phenylhyrazine hydrochloride (343 mg, 2.36 mmol), and 15 ml of glacial acetic was refluxed for 7 h. After cooling, the reaction mixture was poured on ice, alkalized with con.

NH₄OH and extracted with CH₂C1₂ (3x70 ml, 1x30 ml). The combined organic

layers were washed with H₂0 (3x80 ml), dried over Na₂S0₄ and evaporated. The residue (410 mg slightly brown foam) was converted into the hydrochloride salt in the usual way and crystallized from MeOH/diethyl ether to give 390 mg (83%) of the title compound 9 as slightly pink crystals. An analytic sample was obtained by recrystallization of a small portion of this material from MeOH/diethyl ether.

M.p.257-260°C (dec). IR (KBr): 3460 CNH, NH, OH) cm^'1. CI-MS: m/z 493

(M^*+l). H-NMR (DMSO-d₆) δ 11.30, 9.20 and 9.05 (3 S, ^*NH, NH, OH), 7.25 (m, 7 arom. H), 7.10 (t, J=8.2 Hz, 1 arom. H), 6.96 (t, J=8.2 Hz, 1 arom. H), 6.59 (dd, J= 8.2, 8.2 Hz, 2 arom. H), 3.32 (s, OCH₃), 1.87 (s, CH₃-C(5)). Analysis calculated for C₃₂H₃₂N₂0₃. HCl. 3.7 MeOH (647.63): C 66.21, H 7.44, N 4.33; found: C 66.04, H 7.13, N 4.60.

Example 6

Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5c--epoxy-3-hydroxy-14- methoxy-5-methyl-6,7-2',3'indolomorphinan Hydrochloride (compound 10).

A mixture of 14-0-methyl-5-methylnaltrexone (H.Schmidhammer et al., Helv. Chim. Acta Vol. 77: 1585-1589, 1994) (620 mg, 1.68 mmol), phenylhydrazine hydrochloride (365 mg, 2.52 mmol), and 7 ml of glacial acetic acid was refluxed for 17.5 h. After cooling, the reaction mixture was poured on ice, alkalized with

NH₄OH and extracted with CH₂C1₂ (3x70 ml, 1x20 ml). The combined organic

layers were washed with H₂0 (3x80 ml), dried over Na₂S0₄ and evaporated. The residue (1.11 g brown foam) was purified by column chromatography (silica gel

230-400 mesh, mobile phase CH₂Cl₂/MeOH 90:9). The corresponding fractions were combined and evaporated to afford a slightly yellow foam which was dissolved in MeOH and treated with ethereal HCl to yield 520 mg (65%) of the compound 10 as colorless crystals. For analyses a small sample was recrystallized from MeOH. M.p. >250°C (dec). IR (KBr):3515 and 3220 CNH, NH, OH)cm^'\ CI-

MS: m/z 443 (M^*+l). ^-NMR (DMSO-d₆): δ 11.30, 9.12, 8.93 (3 s/NH, NH, OH), 7.34 (m, 2 arom. H), 7.09 (t, J=8.3 Hz, 1 arom. H), 6.95 (t, J=8.3 HZ, 1 arom. H), 6.63 (d, J=8.1 Hz, 1 arom. H), 6.56 (d, J=8.1 Hz, 1 arom. H), 3.24 (s, OCH₃), 1.87 (s, CH₃-

C(5)). Analysis calculated for C_2gH₃₀N₂O₃. HCl. 0.7 H₂0 (491.67):C 68.41, H 6.64, N 5.70, Cl 7.21; found: C 68.52, H 6.86, N 5.65, Cl 7.48. Example 7

Synthesis of 17-Allyl-6,7-dehydro-4,5α-epoxy-3-hydroxy-5-methyl-14-n- propyloxy-6,7-2',3'-indolomorphinan. CH₃S0₃H (compound 15).

A mixture of 7,8-dihydro-5-methyl-14-n-propyloxycodeinone described in our copending application with priority from May 18, 1994) (9; 2.67 g, 7.19 mmol),

KHC0₃ (3.6 g, 35.93 mmol), 1-chloroethyl chloroformate (4.73 ml, 43.12 mmol), and 35 ml of 1,2-dichloroethane was stirred under reflux for 3.5 h. After cooling, the inorganic material was filtered off and the filtrate evaporated. The residue (4.67 g of a yellowish oil of 17-(l-chloroethoxy)- carbonyl-4,5α-epoxy-3-methoxy- 5-methyl-14-n-propyloxymorphinan-6-one (compound 11); pure by TLC) was not further purified and characterized. A solution of the compound 11 in MeOH was refluxed for 1 h and then evaporated. The residue (3.54 g slightly brown foam) was crystallized from 2.5 ml MeOH/2 ml diethyl ether to give 1.68 g (66%) of

4,5α-epoxy-3-methoxy-5-methyl-14-n-propyloxy-morphinan-6-one hydrochloride

(compound 12). M.p. 186-188°C. IR (KBr): 3425 CNH₂), 1725 (CO)cm^'\ EI-MS: m/z

357 (Ml. ^!H-NMR (DMSO-d₆): σ 10.11 and 8.15 (2 broad s, ^*NH₂), 6.83 (d, J=8.2

Hz, 1 arom. H), 6.74 (d, J=8.2 Hz, 1 arom. H), 3.78 (s, CH₃0), 1.48 (s, CH₃-C(5)),

0.95 (t, J=7.4 Hz, CH_g). Analysis calculated for C₂₁H₂₇N0₄. HCl. 0.6 MeOH

(413.14): C 62.80, H 7.42, N 3.39, Cl 8.58; found: C 62.66, H 7.34, N 3.40, Cl 8.98. A mixture of the compound 12 (1.45 g, 3.68 mmol), allyl bromide (0.36 ml, 4.06 mmol), potassium carbonate (2.9 g, 20.8 mmol), and 10 ml of anhydrous N,N- dimethyl formamide was stirred at 80°C (bath temperature) for 1.5 h. The inorganic solid was filtered off and the filtrate evaporated to give 1.7 g of a yellowish oily residue. This residue was partitioned between CH₂C1₂ and H₂0.

The organic layer was washed with H_jO and brine, dried over Na₂S0₄ and evaporated. The residue (1.375 g of a slightly yellow oil) was crystallized from ethanol to yield 1.28 g (88%) of 17-allyl-4,5α-epoxy-3-methoxy-5-methyl-14-n- propyloxymorphinan-6-one (compound 13) as slightly yellow crystals. M.p. 122-

124°C. IR(KBr): 1720 (CO)cm^'\ EI-MS: m/z 397 (M^*). ^-NMR (CDC1₃): δ 6.63 (d,

J=8.3 Hz, 1 arom. H), 6.55 (d, J=8.3 Hz, 1 arom. H), 5.79 (m, 1 olef. H), 5.13 (m, 2 olef. H), 3.84 (s, OCH3), 1.60 (s, CH₃-C(5)), 1.00 (t, J=7.4 Hz, CH3). Analysis

calculated for C₂₄H_3]N0₄ (397.51): C 72.52, H 7.86, N 3.52; found: C 72.14, H 7.76,

N 3.44. A I M solution of boron tribromide in CH₂C1₂ (10.8 ml) was added to an

ice-cooled solution of the compound 13 (577 mg, 1.45 mmol) in 75 ml of CH₂C1₂ at

once. After stirring at 0-5°C for 2 h, a mixture of 20 g ice and 4 ml of cone NH₄OH was added. The resulting mixture was stirred at room temperature for 30 min and the extracted with CH-X.^ (3x50 ml). The combined organic layers were washed

with brine (70 ml), dried over Na₂S0₄ and evaporated. The residue (600 mg brownish foam) was converted into the hydrobromide salt in the usual way and crystallized from MeOH to afford 314 mg (47%) of 17-allyl-4,5α-epoxy-3-hydroxy- 5-memyl-14-n-propyloxymo hinan-6-one hydrobromide (compound 14). M.p. 244-247°C (dec). IR (KBr): 3441 and 3332 CNH, OH), 6.68 (d, J=8.2 Hz, 1 arom. H),

6.62 (d, J=8.2 Hz, 1 arom. H), 5.92 (m, 1 olef. H), 5.67 (m,2 olef. H), 1.49 (s, CH₃-

C(5)), 0.96 (t, J=7.2 Hz, CH₃).

A mixture of the compound 14 (300 mg, 0.65 mmol), phenylhydrazine hydrochloride (187 mg, 1.29 mmol), and 30 ml of glacial acetic acid was refluxed for 7.5 h. After cooling, the reaction mixture was poured on ice, alkalized with cone NH₄OH and extracted with C ^ l^ (3x60 ml). The combined organic layers

were washed with H₂0 (3x80 ml) and brine (50 ml), dried over Na₂S0₄ and evaporated. The residue (325 mg brownish foam) was converted into the methane sulfonate in the usual way and recrystallized from MeOH/diethyl ether to yield 264 mg (74%) of the title compound 15. Recrystallization of a small portion of this material from ethanol afforded an analytical sample. M.p. >256°C. FAB-MS: m/z

457 (M^*+l), ^-NMR (DMSO-d₆): δ 11.29, 9.17 and 8.45 (3 s, ^*NH, NH, OH), 7.32

(d, J=8.2 Hz, 2 arom. H), 7.10 (t, J=8.2 Hz, 1 arom. H), 6.94 (t, J=8.2 Hz, 1 arom. H),

I 6.59 (s, 2 arom. H), 5.90 (m, 1 olef. H), 5.68 (m, 2 olef. H), 1.88 (s, CH₃-C(5)), 0,55 (t,

J=7.3 Hz, CH₃). Analysis calculated for C₂₉H₃₂N₂0₃H. 0.5 H₂0 (561.70): C 64.15, H 66.4, N 4.99, S 5.72; found: C 64.08, H 6.87, N 5.09, S 5.87.

Example 8

Synthesis of 17-(Cy clopropylmethyl)-6,7-dehy dro-4,5α-epoxy-3-hydroxy-5- methyl-14-n-propyloxy-6,7-2,3'-indolomorphinan. CH₃S0₃H (compound 18).

A mixture of 4,5α-epoxy-3-methoxy-5-methyl-14-n-propyloxymorphinan-6-one hydrochloride (compound 12 of Example 7) (1.46 g, 3.71 mmol), potassium carbonate (2.24 g, 16.24 mmol), cyclopropylmethyl chloride (0.43 ml, 4.44 mmol), and 15 ml of anhydrous N,N-dimethyl formamide was stirred at 85°C (bath temperature) for 36 h. The inorganic solid was filtered off and the filtrate evaporated. A solution of the residue in 30 ml of CPL-C^ was washed with H_zO

(3x30 ml), dried over Na₂S0₄ and evaporated. The residue (1,69 g orange-yellow oil) was dissolved in diethyl ether and treated with ethereal HCl to give 920 mg (55%) of 17-(cyclopropylmethyl)-4,5α-epoxy-3-methoxy-5-methyl-14-n- propyloxymorphinan-6-one hydrochloride (compound 16) as colorless powder.

M.p. 156-158°C. IR (KBr): 3400 CNH), 1723 (CO) cm^'1. CI-MS: m/z 412 (M^*+l). ^αH-

NMR (DMSO-d₆): δ 8.57 (s, ^*NH), 6,85 (d, J=8.2 Hz, 1 arom. H), 6.75 (d, J=8.2 Hz, 1

arom. H), 3.79 (s, OCH₃), 1.51 (s, CH₃-C(5)), 0.97 (t, J=7.4 Hz, CH₃). Analysis calculated for C₂₅H₃₃N0₄. HCl. 0.6 H₂0 (458.81): C 65.45, H 7.73, N 3.05, Cl 7.73; found: C 65.45, H 7.85, N 3.08, Cl 7.84.

A I M solution of boron tribromide in CH₂C1₂ (7.3 ml) was added at once to an

ice-cooled solution of the compound 16 (480 mg, 0.97 mmol) in 50 ml of CH₂C1₂.

After 50 min stirring at 0-5°C, a mixture of 13 g ice and 3 ml cone NH₄OH was added. The resulting mixture was stirred at room temperature for 30 min and the extracted with CH₂C1₂ (3x30 ml). The combined organic layers were washed with

brine (45 ml), dried over Na₂S0₄ and evaporated. The residue (204 mg slightly brown foam) was treated with 0.5 ml hot MeOH to afford 302 mg (55 %) of 17- (cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-5-me yl-14-n-propyloxymorphinan-

6-one (compound 17). M.p. 184-186°C. IR (KBr): 3390 (OH), 1720 (CO)cm ^'\ CI-MS:

m/z 397 (M^*+l). ^JH-NMR (CDC1₃): δlθ.24 (broad s, OH), 6.73 (d, J=8.2 Hz, 1 arom.

H), 6.65 (d, J=8.2 Hz, 1 arom. H)1.62 (s, CH₃-C(5)), 1.00 (t,J=7.3 Hz, CH3). Analysis

calculated for C₂₄H₃₁N0₄. 0.6 MeOH (416.74): C 70.90, H 8.08, N 3.36; found: C 70.76, H 7.73, N 3.52.

A mixture of compound 17 (230 mg, 0.58 mmol), phenylhydrazine hydrochloride (142 mg, 0.98 mmol), and 23 ml of glacial acetic acid was refluxed for 3.5 h. After cooling, the reaction mixture was poured on ice, alkalized with con. NH₄OH and

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

H₂02x50 ml) and brine (50 ml), dried and evaporated. The residue (262 mg yellow-brown foam) was converted in the usual way into the methane sulfonate and crystallized from MeOH/diethyl ether to yield 204 mg (62%) of the compound 18. M.p. 295-298 (dec.) FAB-MS: m/z 471 (M^*+l). ^-NMR (DMSO-d₆) δ 11.27, 9.12 and 8.46 (3s, ^*NH, NH, OH), 7.14 (m, 4 arom. H), 6.59 (s, 2 arom. H), 1.90 (s, CH3-C(5)), 0.67 (t, J=7.3 Hz, CH₃) Analysis calculated for C₃Jti_MN₂O_y

CH₃S0₃H. 1.5 H₂0 (584.74): C 62.71, H 6.96, N 4.72, S 5.40; found: C 62.67, H 6.96, N 4.79, S 5.40.

Examples 9-24, and 28-30 illustrate further compounds, which can be prepared according to one of the methods described above.

Example 9

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-14-hydroxy-3-

(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 19).

M.p.l29-130°C. 1H-NMR (CDC1₃): δ 7.45 (d, J = 8.3 Hz, 1 arom. H), 7,37 (d, J = 8.3

Hz, 1 arom. H), 7.25 (m, 1 arom. H), 7.16 (m, 1 arom.), 6.86 (d, J = 8.3 Hz, 1 arom. H), 6.60 (d, J = 8.3 Hz, 1 arom. H), 5.63 (s, H-C(5)), 5.17 and 5.06 (2 d, J = 6.6, 6.6

Hz, 0CH₂0), 3.42 (s, CH₃0).

Example 10

17-Cyclopropylmethyl-6,7-dehydro-4^α-epoxy-14-hydroxy-3-(methoxymethoxy)- 6,7-2' ,3'-(N-methoxymethylindolo)morphinan (compound 20).

U NMR (CDC1₃): δ 7.44 (m, 2 arom. H), 7.20 (m, 1 arom. H), 7.07 (m, 1 arom. H), 6.82 (d,J = 8 Hz, 1 arom. H), 6.58 (J = 8 Hz), 5.81 (s, H-C(5)), 5.79 and 5.50 (2 d, J = 10.8, 10.8 Hz, NCH.O), 5.12 and 5.50 (2 d, J = 6.4, 6.4 Hz, OCK.O), 3,41 and 3.33 (2

s, 2 CH₃0). Example 11

17-(Cyclopropylmethyl)-6,7-dehydro-14-(2',6'-dichlorobenzyloxy)-4,5α-epoxy-14- 3-(methoxymethoxy)-6,7-2',3'-benzo[b]furanomorphinan (compound 21).

M.p. 180-182 °C. IH NMR (CDC1₃): δ 7.41 (d, J = 8.3 Hz, 1 arom. H), 7.33 (d, J = 8.3

Hz, 1 arom. H), 7.23 (m, 1 arom. H) 7.14 (m, 2 arom. H), 7.03 and 7.01 (2 d, J = 7.3, 7.3 Hz), 6.84 (d, J, 8.3 Hz, 1 arom. H) 6.59 (d, J = 8.3 Hz, 1 arom. H), 5.56 (s, H-

C(5)), 5.32 and 4.68 (2 d, J = 8.7, 8.7 Hz, OC^Ar), 5.16 and 5.05 (2 d, J = 6.6, 6.6

Hz, OCH₂0), 3.41 (s, CH₃0).

Example 12

17-(Cyclopropylmethyl)-6,7-dehydro-14-(2',6'-dichlorobenzyloxy)-4,5α-epoxy-3- hydroxy-6,7-2',3'-benzo[b]furanomorphinan (compound 22).

M.p. 193-195 °C (dec). IH NMR (CDC1₃): δ 7.42 (d, J = 8.3 Hz, 1 arom. H), 7.33 (d, J

= 8 Hz, 1 arom. H), 7.24 (m, 1 arom. H) 7.14 (m, 2 arom. H), 7.03 and 7.01 (2 d, J = 7.3 Hz, 1 arom. H), 6.64 (d, J, 8.1 Hz, 1 arom. H) 6.56 (d, J = 8.1 Hz, 1 arom. H), 5.58 (s, H-C(5)), 5.32 and 4.68 (2 d, J = 8.6 Hz, OCH₂ Ar).

Example 13

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-(methoxymethoxy)-14-(3'- nitrobenzyloxy)-6,7-2'^3'-benzo[b]furanomorphinan (compound 23).

'H NMR (CDC1₃): δ 8.25 (s, 1 arom. H), 7.28 (m, 4 arom. H), 7.15 (m, 1 arom. H) 6.87 (d, J = 8.3 Hz, 1 arom. H), 6.62 (d, J = 8.3 Hz, 1 arom. H), 5.66 (s, H-C(5)), 5.17 and 5.07 (2 d, J =6.6 Hz, OCH₂0) 4.92 and 4.44 (2 d, J = 11.5 Hz, OCH₂Ar), 3.42 (s,

CH₃0).

Example 14

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-14-(3'- nitrobenzyloxy)-6,7-2',3'-benzo[b]furanomorphinan hydrochloride (compound 24).

M.p. > 230 °C (dec). IH NMR (DMCO-d6): δ 9.40 (s, OH), 9.15 (broad s, ⁺NH), 7.84

(s, 1 arom. H) 7.60 (d, J = 8.8 Hz, 1 arom. H), 7.53 (d, J = 7.6 Hz, 1 arom. H), 7.45 (d, J = 8 Hz, 1 arom. H) 7.23 (d, J = 7.6 Hz, 1 arom. H), 7.19 (d, J = 7.6 Hz, 1 arom. H), 6.98 (m, 1 arom. H) 6.88 (d, J = 7.6 Hz, 1 arom. H) 6.69 (d, J =8.3 Hz, 1 arom. H), 6.66 (d, J = 8.3 Hz, 1 arom. H), 6.03 (s, H-C(5)), 4.98 and 4.87 (2 d, J = 14, 14 Hz, OCH₂Ph).

Example 15

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-(methoxymethoxy)-14-(2- naphtylmethoxy)-6,7-2'-3'-benzo[b]furanmorphinan (compound 25).

M.p. 198-201 °C. IH NMR (CDC1₃): δ 7.72-7.08 (m, 11 arom. H), 6.86 (d, J = 8.3 Hz, 1 arom. H), 6.62 (d, J = 8.3 Hz, 1 arom. H), 5.68 (s, H-C(5)), 5.17 and 5.07 (2 d, J = 6.6, 6.6 Hz, OCH₂0), 5.01 and 4.57 (2 d, J = 11.2, 11.2 Hz, OCH₂Ar), 3,42 (s, CH₃0). Example 16

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-14-(2'- naphtylmethoxy)-6,7-2',3'-benzo[b]furanomorphinan hydrochloride (compound 26).

M.p. > 215 °C. IH NMR (DMSO-d6): δ 9.42 (s, OH), 9.00 (broad s, ⁺NH), 7.68-6.85 (m, 11 arom. H), 6.71 (d, J = 8 Hz, 1 arom. H), 6.67 (d, J = 8 Hz, 1 arom. H), 6.04 (s, H-C(5)), 4.92 (s, OCH₂Ar).

Example 17

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-14-(2'-fluorobenzyloxy)-3- (methoxymethoxy)-6,7-2'-3'-benzo[b]furanmorphinan (compound 27).

^αH NMR (DMSO-d6): δ 7.56 (d, J = 8 FIz, 1 arom. H), 7.49 (d, J = 8 Hz, 1 arom. H), 7.31 (m, 1 arom. H), 7.21 (m, 1 arom . H), 6.81 (d, J = 8.4 Hz, 1 arom. H), 6.67 (d, J = 8.4 Hz), 5.72 (s, H-C(5)), 5.06 and 5.01 (2 d, J = 6.4, 6.4 Hz, OCH₂0), 4.89 and

4.57 (2 d, J = 11.6, 11.6 Hz, OCR, Ar), 3,33 (s, CH₃0).

Example 18

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-14-(2'-fluoro-benzyloxy)-3- hydroxy-6,7-2',3'-benzo[b]furanomorphinan Hydrochloride (compound 28).

M.p. > 215 °C. IH NMR (CDC1₃): δ 9.45 (s, OH), 9.04 (broad s, ⁺NH), 7.54 (d, J = 8.4 Hz, 1 arom. H) 7.31-6.73 (m, 7 arom. H), 6.71 (d, J = 8.2 Hz, 1 arom. H), 6.66 (d, J = 8.2 Hz, 1 arom. H), 5.98 (s, H-C(5)), 4.81 and 4.84 (2 d, J = 12 Hz, OCH₂ Ar). Example 19

14-Cinnamyloxy-17-(cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3- (methoxymethoxy)-6,7-2'-3'-benzo[b]furanomoφhinan (compound 29).

M.p. 156-159 °C. IH NMR (CDC1₃): δ 7.47 (d, J = 8 Hz, 1 arom. H), 7.33 (d, J = 8

Hz, 1 arom. H), 7.28-7.07 (m, 7 arom. H), 6.84 (d, J = 8.4 Hz, 1 arom. H), 6.59 (d, J = 8.4 Hz, 1 arom . H), 6.38 (d, J = 16 Hz, 1 olef. H), 6.13 (m, 1 olef. H), 5.68 (s, H-

C(5)), 5.16 and 5.06 (2 d, J = 6.4, 6.4 Hz, OCH₂0), 4.46 and 4.11 (2 m,OCH₂Ar), 3,42

(s, CH₃0).

Example 20

14-Cinnamyloxy-17-cyclopropylmethyl-6,7-dehydro-4,5α-epoxy-3-hydroxy-6,7-2'- 3'-benzo[b]furanomorphinan Salicylate (compound 30).

^l NMR (CDC1₃): δ 7.94 (d, J = 8 Hz, 1 arom. H), 7.35 (d, J = 8 Hz, 1 arom. H), 7.30-6.73 (m, 12 arom. H), 6.56 (d, J = 8 Hz, 1 arom. H), 5.96 (s, 2 olef. H), 5.55 (s, H-C(5)), 4.33-4.02 ( m, OCH,Ar).

Example 21

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-14-methoxy-3- (me oxymemoxy)-6,7-2'-3'-benzo[b]iαιranomoφhinan (compound 31).

'H NMR (DMSO-d6): δ 7.7.56 (d, J = 8 Hz, 1 arom. H), 7.52 (d, J = 8 Hz, 1 arom. H), 7.32 (dd, J = 8, 8 Hz, 1 arom. H), 5.64 (s, H-C(5)), 5.05 and 5.00 (2 d, J = 6.4, 6.4 Hz, OCH₂0), 3.32 (CH₃0). Example 22

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-14-methoxy-6,7-2'-3'- benzo[b]furanomorphinan hydrochloride (compound 32).

M.p. > 240 °C. 'H NMR (DMSO-d6): δ 9.47 (s, OH), 9.17 (broad s, ⁺NH), 7.61 (d, J

= 8 Hz, 1 arom. H), 7.53 (d, J = 8 Hz, 1 arom. H), 7.36 (dd, J = 8, 8 Hz, 1 arom. H), 7.27 (dd, J = 8, 8 Hz, 1 arom. H), 6.72 (d, J = 8.4 Hz, 1 arom. H), 6.65 (d, J = 8.4 Hz,

1 arom. H), 5.90 (s, H-C(5)), 3.35 (s, CH₃0).

Example 23

17-(Cyclopropylmethyl)-14-(2'-chlorobenzyloxy)-6,7-dehydro-4,5α-epoxy-3- (methoxymethoxy)-6,7-2'-3'-(N-methoxymethylindolo)morphinan (compound 33).

^:H NMR (CDCl_g): δ 7.56 (m, 1 arom. H), 7.44 (m, 1 arom. H), 7.37-7.17 (m, 3 arom .

H), 7.01 (m, 1 arom. H), 6.91 (m, 1 arom. H), 6.83 (d, J = 8.2 Hz, 1 arom. H), 6.59 (dd, J = 8.2, 8.2 Hz, 1 arom. H), 5.90 (s, H-C(5)), 5.82 and 5.55 (2 d, J = 11.2, 11.2

Hz, NCH₂0), 5.13 and 5.03 (2 d, J = 6.4, 6.4 Hz, OCH ), 4.98 and 4.56 (2 d, J = 13,

13 Hz, OCH₂Ar), 3.40 and 3.26 (2 s, 2 CH₃0).

Example 24

17-(Cyclopropylmethyl)-14-(2'-chlorobenzyloxy)-6,7-dehydro-4,5α-epoxy-3- hydroxy-6,7-2'-3'-indolomorphinan hydrochloride (compound 34).

M.p. > 250 °C (dec). IH NMR (DMSO-d6): δ 11.38 (s, NH), 9.38 (s, OH), 8.76 (broad s, ⁺NH), 7.34-6.85 (m, 8 arom. H), 6.72 (d, J = 8 Hz, 1 arom. H), 6.64 (d, J

8 Hz, 1 arom. H), 5.93 (s, H-C(5)), 4.80 and 4.67 (2 d, J = 13, 13 Hz, OCH₂ Ar).

Example 25

Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-3,14-dimethoxy-4,5α-epoxy-6,7- 2'-3'-benzo[b]furanomorphinan (compound 35).

Sodium hydride (144 mg, 6 mmol; obtained from 240 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of naltriben methanesulfonate (P.S. Portoguese et al., J. Med. Chem., Vol. 34: 1715-1720, 1991) 500 mg, 0.97 mmol) in 10 ml of anhydrous N,N-dimethyl-formamide at 0 °C. The resulting mixture was stirred at 0 °C for 15 min and then at room temperature for another 30 min. After cooling to 0 °C, dimethyl sulfate (380 μl, 4 mmol) was added and stirring was continued at first at 0 °C for 30 min and then at room temperature for 3 h. Excess sodium hydride was destroyed by addition of MeOH and H-,0. The resulting mixture was extracted with ethyl acetate (3 x 40 ml), the

combined organic layers were washed with H₂0 (2 x 30 ml) and brine (2 x 30 ml),

dried over Na₂S0₄ and evaporated to give a crystalline residue which was recrystallized from MeOH to afford 320 mg (74 %) of compound 35. M.p. 221-224 °C (dec). IH NMR (CDC1₃): δ 7.47-7.14 (m, 4 arom. H), 6.64 (d, J =8.4 Hz, 1 arom. H), 6.59 (d, J = 8.4 Hz, 1 arom . H), 5.62 (s, H-C(5)), 3.78 (s, CH₃0-C(3)), 3.31 (s,

CH₃0-C(14)).

Example 26

Synthesis of 17-Cyclopropylmethyl-6,7-dehydro-4,5α-epoxy-14-hydroxy-6,7-2',3'- benzo[b]furanomorphinan (compound 36).

A mixture of 3-deoxyonaltrexone (R. Krassnig and H. Schmidhammer, Heterocycles, Vol. 38: 877-881, 1994) (1,3 g, 3.99 mmol), O-phenylhydroxylamine hydrochloride (750 mg, 5.15 mmol), methanesulfonic acid (0.75 ml, 11.55 mmol), and ethanol (30 ml) was refluxed for 20 h. After cooling, the mixture was diluted with H₂0, alkalized with cone. NH₄OH and extracted with CH₂C1₂ (4 x 40 ml).

The combined organic layers were washed with Hβ (2 x 30 ml) and brine (30 ml),

dried over Na₂S0₄ and evaporated to give a brownish oil which was crystallized

form MeOH to yield 1.1 mg (69 %) of compound 36. M.p. > 260 °C. *H NMR

(CDC1₃): δ 7.45 (d, J = 8 Hz, 1 arom. H), 7.37 (d, J = 8 Hz, 1 arom. H), 7.26-7.13 (m,

2 arom. H), 7.01 (dd, J = 7.8, 7.8 Hz, 1 arom. H), 6.67 (d, J = 7.8 Hz, 1 arom. H), 6.59 (d, J = 7.8 Hz, 1 arom. H), 5.59 (s, H-C(5)), 5.00 (broad s, OH).

Example 27

Synthesis of 17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-14-hydroxy-6,7-2'- 3'-indolomorphinan hydrochloride (compound 37).

A mixture of 3-deoxyonaltτexone (R. Krassnig and H. Schmidhammer, Heterocycles, Vol. 38: 877-881, 1994) (1,5 g, 4.6 mmol), phenylhydrazine hydrochloride (1.0 mg, 6.9 mmol), 1M HCl in ether (5 ml), and methanol (20 ml) was stirred at room temperature for 3 days. After concentration to ca. half of the original volume in vacuo, the solution was refrigerated overnight. The colorless crystals formed were collcted to yield 1.54 g (77 %) of compound 37. M.p. > 240 °C

(dec). IH NMR (DMSO-d6): δ 11.37 (s, NH), 9.01 (broad s, ⁺NH), 7.36-6.94 (m, 5 arom. H), 6.78 (d, J = 7.8 Hz, 1 arom. H), 6.59 (d, J = 7.8 Hz, 1 arom. H), 6.55 (s, OH).

Example 28

17(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-14-(3'- chlorobenzyloxy)-6,7,2',3'-benzo[b]furanomoφhinan, hydrochloride (compound 39).

^]H NMR (DMSO-d6): δ 9.40 (s, OH), 8.59 (broad s, +NH), 7.53-6.90 (m, 8 arom. H),

6.65 (s, 2 arom. H), 6.03 (s, H-C(5)), 4.74 and 4.62 (2 d, J=13.6, 13.6 Hz, OCH₂(3'-

ClPh)). Analysis calculated for C₃₃H₃₀ClNO₄. HCl. 1.5 H₂0: C 65.67, H 5.68, N 2.32; found: C 65.31, H 5.37, N 2.33.

Example 29

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-14-(2'- chlorobenzyloxy)-6,7,2'^'-benzo [b]f ur anomorphinan Hydrochloride (compound 41).

M.p. > 220°C. *H NMR (DMSO-d6): δ 9.40 (s, OH), 8.59 (broad s, +NH), 7.56-6.90

(m, 8 arom. H), 6.66 (m, 2 arom. H), 6.03 (s, H-C(5)), 4.74 (s, OCH₂(2-ClPh)).

Analysis calculated for C₃₃H₃₀ClNO₄. Hcl. 1.5 JD: C 65.67, H 5.68, N, 2.32. Found: C 65.72, H 5.48, N 2.25. Example 30

14-Allyloxy-17-(cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy- -allyl- 6,7-2',3'-indolomorphinan hydrochloride (compound 42).

NMR of the free base (colorless oil) ^αH NMR (CDCl_g): δ 7.40 (d, J = 8.4 Hz, 1 arom. H), 7.24 (m, 1 arom. H), 7.15 (m, 1 arom. H), 7.03 (m, 1 arom. H), 6.57 (d, J = 8.4 Hz, 1 arom. H), 6.50 (d, J = 8.4 Hz, 1 arom. H), 6.08 (m, 1 olef. H), 5.76 (m, 1 olef. H), 5.72 (s, H-C(5)), 5.15-4.75 (m, 6 H, CH₂N,2 CH₂ = C), 4.24 and 3.92 (2 dd, J = 12.4, 4.8 Hz, CH₂0).

This free base was dissolved in ethyl ether and treated with HCl /ether solution HCl at 0°C. Isolation of the precipitate provided the title compound 42 as a solid.

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 antagonist 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 the amount of 1-95 % by weight, preferably 10-60 % by weight. The dose of the active ingredient may be appropriately selected depending on the objects of administration, administration route and conditions of the patients. The active ingredient may be administered in doses between 1 mg and 1 g 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 20-500 mg per day. Biological studies

δ- Antagonism was assessed using the electrical stimulated guinea-pig ileum longitudinal muscle preparation (GPI; containing μ and K opioid receptors) and mouse vas deferens preparation (MVD; containing μ, K and δ opioid receptors) (H. Schmidhammer et al., J. Med. Chem., Vol. 32: 418-421, 1989; H Schmidhammer et al., J. Med. Chem., Vol. 33: 1200-1206, 1990). The activity of the compound 1 of the Examples for inhibiting the suppression of contraction of the organs by three receptor selective agonists (DAMGO, μ; Cl 977, iς DPDPE, δ) was measured. The compound exhibited δ-selective opioid antagonism with very good μ/δ and κ/δ selectivity ratios.

Conclusion

The pharmacological studies of the novel morphinan derivatives of formula (I) of the present invention have shown that these compounds have selectivity for δ opioid receptors and are effective as opioid antagonists.

Claims

1. A compound according to the formula (I)

wherein

R- represents C--C₁₀ alkenyl; C₄-C₁₀ cycloalkylalkyl wherein the cycloalkyl is C₃-C₆

wherein the aryl is C₆-C₁₀ aryl and the alkenyl is C₂-C₆ alkenyl;

R-, represents hydrogen, hydroxy, C--C₆ alkoxy; C--C₆ alkenyloxy; C₇-C₁₆

arylalkyloxy wherein the aryl is C₆-C_]0 aryl and the alkyloxy is C_j-C₆ alkyloxy; C₇-

alkenyloxy; C_j-C₆ alkanoyloxy; C₇-C₁₆ arylalkanoyloxy wherein the aryl is C₆-C₁₀

aryl and the alkanoyloxy is C--C₆ alkanoyloxy;

R_g represents hydrogen, 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-C₁₀ aryl and the alkenyl is C--C₆ alkenyl; hydroxy(C.-C₆)alkyl; alkoxyalkyl wherein the alkoxy is C--C₆ alkoxy and the alkyl is C--C₆ alkyl; C0₂H; C0₂(C--C₆ alkyl);

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

C₁₀ aryl and the alkyloxy is C--C₆ akyloxy; C--C₆ alkenyloxy; C--C₆ alkanoyloxy;

,-C₁₆ arylalkanoyloxy wherein the aryl is C₆-C₁₀ aryl and the alkanoyloxy is C--

alkoxy is C--C₆ alkoxy;

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

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

C₆ alkyl)₂; amino; C.-C₆ monoalkyl amino; C,-C₆ dialkyl amino; C₅-C₆ cyhloalkyl

amino; SH; S0₃H; S0₃(C--C₆ alkyl); S0₂(C--C₆ alkyl); S0₂NH₂; S0₂NH(C_r

C₆alkyl); S0₂NH (C₇-C₂₀ 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; C--C₆ alkyl; trifluoromethyl; C--C₆ alkoxy, C0₂H, CO(C--C₆ alkyl),

amino, C--C₆ monoalkylamino, C--C₆ dialkylamino, SH; S0₃H; H; S0₃(C--C₆

alkyl), S0₂(C--C₆ alkyl), SO(C--C₆ alkyl), and

X represents oxygen; sulfur; CH = CH or NR_g wherein R₉ is H, C--C₆ alkyl, 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- or di- or trisubstituted independently with hydroxy, halo, nitro, cyano, thiocyanato, trifluoromethyl, C--C₃ alkyl, C--C₃

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

CO(C_λ-C₃ alkyl), amino, (C--C₃ monoalkyl)amino, (C.-C₃ dialkyl)amino, C₅-C₆

cyhloalkylamino (C--C₃ alkanoyDamino, SH, S0₃H, S0₃ (C--C₃ alkyl), S0₂ (C--C₃

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

with the proviso that when R_j is hydroxy, R₃ cannot be hydrogen, except when R₄

is hydrogen, OCH₂OCH₃, OCH₂OC₂H. or OC(Ph)₃ and pharmacologically acceptable salts thereof.

2. A compound according to claim 1, wherein

R- is selected from allyl, άnnamyl, cyclopropylmethyl or cyclobutylmethyl;

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

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; C0₂ CH₃; CONH₂; CONH CH_g;

SH; SO-JSTH^ N(CH₃)₂; S0₂CH₃; X is selected from oxygen; NH or N CH₃, N-benzyl, N-allyl.

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

4. A compound according to claim 1, wherein the salt is an inorganic salt.

5. A compound according to claim 1, wherein the salt is an organic salt.

6. A compound according to claim 1, which compound is

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-14-ethoxy-3-hydroxy-5-methyl- 6,7-2',3'-indolomorphinan hydrochloride;

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-14-methoxy-5- methyl-6,7-2',3'indolomorphinan hydrochloride;

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-5-methyl-14-n- propyloxy-6,7-2,3'-indolomorphinan CH₃S0₃H;

17-(Cyclopropylmethyl)-6,7-dehydro-14-(2',6'-dichlorobenzyloxy)-4,5α-epoxy-3- hydroxy-6,7-2',3'-benzo[b]furanomorphinan;

17-(Cydopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-14-(3'- nitrobenzyloxy)-6,7-2',3'-benzo[b]furanomorphinan hydrochloride;

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-14-(2'- naphtylmethoxy)-6,7-2',3'-benzo[b]furanomorphinan hydrochloride; 17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-14-(2'-fluoro benzyloxy )-3- hydroxy-6,7-2',3'-benzo[b]furanomorphinan hydrochloride;

14-Cinnamyloxy-17-(cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-6,7- 2'-3'-benzo[b]furanomorphinan salicylate;

17-(Cyclopropylmethyl)-14-(2'-chlorobenzyloxy)-6,7-dehydro-4,5α-epoxy-3- hydroxy-6,7-2'-3'-indolomorphinan hydrochloride;

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-14-methoxy-6,7-2'-3'- benzo[b]furanomorphinan hydrochloride;

17-(Cyclopropylmethyl)-6,7-dehydro-3,14-dimethoxy-4,5α-epoxy-6,7-2'-3'- benzo[b]furanomorphinan;

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

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-14-hydroxy-6,7-2'-3'- indolomorphinan hydrochloride;

17(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-14-(3'- chlorobenzyloxy)-6,7,2'^'-benzo[b]furanomorphinan hydrochloride;

17-(Cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy-14-(2'- chlorobenzyloxy )-6,7,2',3'-benzo [b]f uranomorphinan hydrochloride;

14-Allyloxy-17-(cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3-hydroxy- -allyl- 6,7-2',3'-mdolomorphinan hydrochloride; 7. A compound according to claim 1, for use in therapy.

8. A compound according to claim 1, for use as a medicament against rheumatic diseases.

9. A compound according to claim 8, wherein the rheumatic disease is rheumatoid arthritis.

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

11. Use of a compound according to claim 10, wherein the rheumatic disease is rheumatoid arthritis.

12. Use of a compound according to claim 1, for the manufacture of a medicament for suppressing the rejection of transplants after organ transplantations.

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

14. A method for the treatment of a subject suffering from a rheumatic disease, whereby an effective amount of a compound according to claim 1 is administered to a subject suffering from a rheumatic disease.

15. A method according to claim 14, wherein the rheumatic disease is rheumatoid arthritis.

16. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient together with a pharmaceutically acceptable carrier.

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

i) thebaine of the formula

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

wherein R is C--C₆ alkyl; C--C₆ alkenyl; C₇-C₁₆ aralkyl 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; alkoxyalkyl wherein the alkoxy is C_j-C₆ alkoxy

and the alkyl is C--C₆ alkyl; C0₂(C.-C₆ alkyl); ii) (II) is reacted with performic acid or m-chloroperbenzoic acid at a temperature in the range 0-60 °C yielding

C

iii) (III) is being treated with dialkyl sulfates, alkyl halides, alkenyl halides, aralkyl halides, arylalkenyl halides, chloroformates, using a strong base giving compounds according to formula (IV)

wherein

R, is C_t-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-C₁₀ aryl and

the alkenyl is Cl-C₆ alkenyl, C--C₆ alkanoyl, C₇-C₂₀ arylalkanoyl wherein the aryl

is C₆-C₁₄ aryl and the alkyl is C--C6 alkyl, C₇-C₂₀ arylalkenoyl wherein the aryl is

C₆-C₁₄ aryl and the alkyl is C.-C₆ alkenoyl;

R-, 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-C₁₀

alkoxy and the alkyl is C--C₆ alkyl; C0₂(C--C₆ alkyl); iv) catalytic hydrogenation of (IV) yields compounds according to formula (V)

wherein

R- and -^ are as defined above in formula (IV);

v) (V) is N-demethylated, giving compounds according to formula (VI)

wherein

R- and R_j are as defined above; and

R_g is C0₂CHC1CH₃, C0₂CH=CH₂, C0₂CH₂CC1₃, C0₂CH₂CH₃, C0₂Ph or CN;

vi) (VI) is cleaved giving compounds according to formula (VII)

wherein

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

vii) compounds (VII) are alkylated, yielding compounds according to formula (VIII)

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

R_g represents C--C₆ alkenyl; C₇-C₁₆ arylalkyl wherein the aryl is C₆-C₁₀ aryl and

alkenyl is C--C₆ alkenyl; C₄-C_]0 cycloalkylalkyl wherein the cycloalkyl is C₃-C₆

cycloalkyl and the alkyl is C--C₄ alkyl; alkyl; C₄-C₁₀ cycloalkylalkenyl wherein the

cycloalkenyl is C₃-C₆ cycloalkenyl and the alkyl is C,-C₄ alkyl;

viii) ether cleavage of (VIII) is performed, giving compounds according to formula (IX)

wherein

R-, R_j and R_g are as defined above;

ix) (IX) is alkylated or acetylated, giving compounds according to formula (X)

wherein R-, R., and R_g are as defined above; and

R₄ is hydrogen, C,-C₆ alkyl, C₇-C₁₆ aralkyl wherein the aryl is C₆-C₁₀ aryl and the

alkyl is C--C₆ alkyl, C₁-C₆ alkenyl, C₇-C₁₆ arylalkenyl wherein the aryl is C₆-C₁₀

aryl and the alkenyl is C_j-C₆ alkenyl; C.C₆ alkanoyl; C₇-C₁₆ arylalkanoyl wherein

the aryl is C₆-C₁₄ aryl and the alkanoyl is C--C₆ alkanoyl, C₂-C₁₀ alkyloxyalkyl

wherein alkyloxy is C--C₄ alkyloxy and alkyl is C.-C₆ alkyl,

x) (IX) or (X) is reacted with phenylhydrazine or substituted phenylhydrazine giving compoimds according to formula (I)

wherein R., R_j, R_g and R₄ are as defined above and X is NH;

R₅ and R₆ each independently represent hydrogen; OH; C--C₆ alkoxy; C--C₆ alkyl; hydroxyalkyl wherein the alkyl is C1-C6 alkyl; halo; nitro; cyano; thiocyanato; trifluoromethyl; C0₂H; C0₂(C--C₆ alkyl); CONH₂; CONH(C--C₆ alkyl); CON(C

C₆ alkyl)₂; amino; C--C₆ monoalkyl amino; C.-C₆ dialkyl amino; C₅-C₆

S0₂NH(C--C₆ alkyl); S0₂NH (C₇-C₂₀ 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; C--C₆ alkyl; trifluoromethyl; C--C₆ alkoxy, C0₂H,

CO(C.-C₆ alkyl), amino, C--C₆ monoalkylamino, C.-C₆ dialkylamino, SH; S0₃H;

S0₃(C--C₆ alkyl), S0₂(C--C₆ alkyl), SO(C--C₆ alkyl), and

X represents oxygen; sulfur; CH = CH, or NR_g wherein R₉ is H, C--C₆ alkyl, C.-C₆

alkenyl; C--C₆ alkanoyl, with the proviso that when R_j is hydroxy R₃ cannot be hydrogen, except when R₄

is hydrogen, OCH₂OCH₃, OC-H_jOC_jjH,. or OC (Ph),

xi) (IX) or (X) is reacted with O-phenylhydroxylamine or substituted O- phenylhydroxylamine, giving compounds according to formula (I)

wherein

R-, R-,, R_g, R₄ and R₅ are as defined above and X is O;

xii) thebaine is converted to 14-hydroxy codeinone formula

which in turn is converted to compounds according to formula (I)

(I)

wherein

R_g is H in essentially the same way as described for the 5-substituted series of compounds;

xiii) Compounds of the formula (II) wherein R is as defined above or hydrogen are reduced by catalytic hydrogenation followed by acid hydrolysis (s. Boden et al., J. Org. Chem., Vol. 47: 1347-1349, 1982) to give compounds of formula (XI)

wherein R is as defined above in formula (II) or hydrogen, which in turn is converted to compounds according to formula (I)

wherein

I^ is H, in essentially the same way as described for the 14-substituted series of compounds;

xiv) compounds of the formula (I) wherein R₄ is hydrogen are prepared from compounds of the formula (IX) by alkylation with 5-chloro-l-phenyl-lH-tetrazole, giving phenyltetrazolyl ethers of the formula (XII)

wherein R-, R_j and R_g are as defined above and R- also can be CH₃, and T is phenyltetrazolyl;

xv) catalytic hydrogenation of (XII) affords compounds of the formula (XIII)

wherein

R., R₂ and R_g are as defined above, or R_α can also be CH₃, with the proviso that

when R_g is CH₃ the N-methyl group is removed and the nitrogen alkylated as described above. xvi) (XIII) is converted to compounds according to formula (I)

wherein R₄ is hydrogen and R-, R_j, R₃, R₅ and R₆ are as defined above, in the same manner as described for 3-substituted derivatives above;

xvii) Compounds of formula (I) wherein R represents allyl or cyclopropylmethyl

and R_g represents H are obtained starting either from naloxone (XlVa) or naltrexone (XlVa).

(XlVa): Naloxone - R is allyl

(XlVb): Naltrexone - R is cyclopropylmethyl.

Whereby the 3-hydroxy group of compounds of formula (XIV) is being protected by alkylation with benzyl bromide, methoxymethyl bromide, ethoxymethyl bromide or trityl chloride (triphenylmethyl chloride) in a solvent such as N,N- dimethyl formamide or dichloromethane in the presence of a base to yield compounds of formula (XV)

wherein R is allyl or cyclopropylmethyl and Y = CH₂Ph, CH₂OCH₃, CH₂OC₂H₅ or C(Ph)₃.

When said compounds are alkylated, alkenylated, cycloalkylalkylated, arylalkylated or arylalkenylated with dialkyl sulfates, alkyl halides, alkenyl halides, arylalkyl halides or arylalkenyl halides in solvents using a strong base such as sodium hydride, potassium hydride or sodium amide are formed 6-0,14-0- dialkylated compounds of formula (XVI)

wherein

R- is allyl or cyclopropylmethyl; and

R₂ is C--C₆ alkyl, C--C₆ alkenyl, C₇-C₁₆ arylalkyl wherein the aryl is C₆-C₁₀ aryl

and alkenyl is C_j-C₆ alkenyl; and Y as defined above; Said compounds, can be hydrolized in diluted acids like hydrochloric acid or sulfuric acid to afford compounds or formula (XVII) 60

wherein

R- is allyl or cyclopropylmehtyl; and

R₂ is as defined above (formula XVI).

xviii) the carbonyl group in 6-position of naloxone of the formula (XlVa) and naltrexone of the formula (XlVb) respectively, is protected at a temperature between 20 and 200 °C, giving ketals of the formula (XVIII)

(XVIII)

wherein

R is allyl or cyclopropylmethyl;

xviii) the 3-hydroxy group in (XVIII) is protected by alkylation with benzyl bromide, methoxymethyl bromide, ethoxy methyl bromide or trityl chloride, giving compounds according to formula (XIX)

wherein

R is allyl or cyclopropylmethyl, and Y is as defined above;

xix) (XIX) is alkylated, alkenylated, arylalkylated or arylalkenylated, giving compounds according to formula (XX)

wherein

R. is allyl ι or cyclopropylmethyl, R-, i .s as defined above in formula (XVI) and Y is also as defined above;

xx) (XX) is hydrolized giving compounds according to formula (XVII), which in turn is converted to compounds according to formula (I) wherein R- is allyl or

cyclopropylmethyl, R_g is H and X is NH or O, exactly as described for the 5- substituted analogues.