MXPA97007113A - Morphinan hydroxamic acid compounds - Google Patents

Abstract

This invention provides a compound of the following formula:and the pharmaceutically acceptable salts thereof, wherein R is hydrogen, C1-C5 alkyl or an O-protecting group;B is a dircet bond, C1-C5 alkylene or C2-C5 alkenylene;R<1>is C1-C5 alkyl, C2-C5 alkenyl or C3-C7 cycloalkyl-C1-C3 alkyl;R<2>is hydroxy or C1-C5 alkoxy;R<3>is hydrogen, hydroxy or C1-C5 alkoxy;and R<4>is hydrogen, phenyl or heteroaryl selected from furyl, thienyl and pyrrolyl, the phenyl and heteroaryl being optionally substituted by one to five substitutents selected from halo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy and C2-C5 alkenyl. These compounds and pharmaceutical compositions containing such compounds are useful as analgesic, antiinflammatory, diuretic, anesthetic or neuroprotective agents, or an agent for stroke or treatment of functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject.

Description

COMPOUNDS OF MORPHINNY HYDROXYMIC ACID, COMPOSITIONS THAT CONTAIN AND USE THEMSELVES TECHNICAL C MPO This invention relates to novel compounds of rnorfinanhydroxyarnic acid and their pharmaceutically acceptable salts, and pharmaceutical compositions which contain the compounds. These compounds and compositions are useful as analgesic, antiinflanatope, diuretic, anesthetic or neuroprotective agents, or as an agent for the treatment of fulminating attack or functional diseases of the in + estino such as abdominal pain, for the treatment of their condition. + or mammal, especially a human subject.

BACKGROUND OF THE INVENTION Opioid analgesics such as mor * fine are therapeutically useful, but their use is strictly due to their side effects-such as pharmacological dependence. Therefore, analgesics with high utility and reduced tendency to cause pharmacological dependence are needed. Considerable pharmacological and biochemical studies have been carried out to discover opioid peptides and opioid receptors, and the discovery of opioid receptor subtypes such as mu, delta and kappa in peripheral and central nerves in a variety of species, including man. It has been a beginning towards the creation of new analgesics. Recently, a receptor similar to the opioid receptor (ORLi) Oean-Claude Meunier was identified and identified, and others, Nature, Vol. 377, 1995, p532-535). This receptor is a new receptor coupled to protein T, whose amino acid sequence is more closely related to opioid receptors. This receptor mediates the inhibition of cAMP accumulation induced by fors olma by the opiate agent in a stable OHO cell line (ORLi). This effect is not exerted either by the endogenous opioid peptides beta-endorphin, encephalmas and dmorphines, nor by selective mu-, delta- or kappa-opioid agonists. Thus, it is expected that compounds having an antagonistic activity towards the ORLi receptor as well as an agonist activity towards the u-, delta- and / or kappa-receptor receptors, especially the kappa receptor, exhibit good analgesic activities. International publications Nos. U093 / 15Q81 and UO95 / 01178 describe a variety of rnorfmanamide or analgesic, diuretic or antitumor compounds.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound of the following formula: (D) and pharmaceutically acceptable salts or solvates thereof, wherein R is hydrogen, Ci-C5 alkyl or a 0-protecting group, B is a direct bond, C 1 -C 5 alkylene or C 2 -C 5 alkenylene; Ci-C5 alkyl, C2 -Cs alkenyl or (C3-C7) -cycloalkyl-Ci-C3 alkyl, R2 is hydroxy or C1-C5 alkoxy, R3 is hydrogen, hydroxyl or Ci-C5 alkoxy; * is hydrogen, phenyl or heteroaryl selected from furyl, thienyl and pyrrolyl, the phenyl and heteroaryl are optionally substituted with one to five substi.tuyent.es selected from halogen, hydroxyl, Ci-C3 alkyl, Ci-03 alkoxy and alkenyl of C2-C5 The hydroxyarnic acid compounds of the present invention exhibit good binding affinity for the ORLi receptor, as well as significant agonist activity towards opioid receptors.Therefore, the compounds of the present invention are particularly useful as an agent analgesic in mammals, especially humans. They are also useful as antiinflammatory, diuretic, anesthetic or neuroprotective agents, or as an agent for the treatment of fulminating attack or functional diseases of the intestine such as abdominal pain, for the treatment of a mammalian subject, especially a human subject. Therefore, the present invention also provides a pharmaceutical composition useful as an analgesic, antiinflammatory, diuretic, anesthetic or neuroprotective agent, or an agent for the treatment of fulminating attack or functional diseases of the intestine such as abdominal pain., for the treatment of a mammalian subject, especially a human subject, comprising a therapeutically effective amount of a hydroxyamic acid compound of formula (I), or its pharmaceutically acceptable salt, together with a meat carrier vehicle acceptably. In addition, the present invention provides a method for the treatment of a medical condition for which an agonist activity toward opioid receptors and an antagonistic activity towards an ORLi receptor is required in a mammalian subject, especially a human subject, comprising administering said subject a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt.

DESCRIPTION OF THE INVENTION As used herein, the term "0-protecting group" means a hydroxyl protecting group to protect a hydroxyl group against undesirable reactions during synthetic procedures, including but not limited to, benzyl, tpfenilrnetol, tetrahydropylamyl, rnetox unethyl. and R ^ 'R' ^ i, wherein R ', R "and R'" are each Ci-C alkyl or femlo. Preferred compounds of this invention are those of formula (I) wherein R is hydrogen or C 1 -C 5 alkyl, B is a direct bond, C 1 -C alkylene, or C 2 -C 4 alkylene; R1 is C2-C5 alkenyl or (C3-C7) -cycloalkyl-Ci-C3 alkyl; R2 is hydroxyl or Ci-C3 alkoxy; R3 is hydrogen, hydroxyl or Ci-C3 alkoxy; and R * is phenyl or the hetero is optionally substituted with one to three substituents selected from halogen, hydroxyl and Ci-C3 alkyl. Preferred compounds of this invention are those of formula (I) wherein R is hydrogen or C1-C3 alkyl; B is a direct bond, C 1 -C 3 alkylene or C 2 -C 3 alkenylene; R1 is C2-C3 alkenyl or C3-C5 cycloalkylrnotyl; R2 and R3 are independently hydroxyl or Ci-C3 alkoxy; and R * is phenyl, fupyl, thienyl or pyrrolyl, optionally substituted with one to three substituents selected from halogen, hydroxyl and Ci-C3 alkyl.

The most preferred compounds of this invention are those of formula (I) wherein R is hydrogen, methyl or ethyl; B is methylene, ethylene, or ethenylene; R 1 is al.yl, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl; R2 and R3 are independently hydroxyl, methoxy or ethoxy; and R * is phenyl or furyl, optionally substituted with one to three substituents selected from fluorine and chlorine. Particularly preferred compounds of this invention are those of formula (I) wherein R is hydrogen or methyl; B is rnet i leño or ethenylene; Rl is al. i lo or cyclopropylmethyl; R2 is hydroxyl or methoxy; R3 is hydroxyl; Y R is 3,4-dichlorophenyl or furyl. The preferred individual compounds of this invention are: 17-Cyclo? Ropilmethyl-3,14β-dihydroxy-4,5α-epoxy-6α- (N-hydroxy-3,4-dichlorophenylacetamido) rnorfinano or its salts; 17-Cyclopropyl-phenyl-3,14-dihydroxy-4,5-epoxy-6β- (N-hydroxy-3,4-dichlorophenylacetarin) morphinan or its salts; 17-Ci-chloropylmethyl-3, 14 -3-dihydroxy-4, 5 < x-epox i -B - (N ~ -methoxy-3,4-dichlorophen.ylacet.arnido) morphinan or its salts; 17-Cyclopropylmethyl-3,14-dihydroxy-4,5a-epoxy-6β- (N-rnetoxy-3,4-dichlorophenylacetarnide) rnorfinano or its salts; 17-Cyclo? Ropilrnetyl-4,5a-e? Oxy-14a-hydroxy-3-methoxy-6a- (N-rnetoxy-3,4-dichlorophenylacetamido) morphinan or its salts; 17-A.li.l-3, 1 ß ~ dihi ro i ~ 4,5a-e ox.i.-6of .- (- et.oxi ~, 4- iclorofenilacet..ami o) morfin or o its salts; 1 - . 1-Cyclopropy lme -3,1 ß- di hydroxy-4, 5a-e? Ox i-6a- (-methoxy-3,4-dichlorobenzamido) rnorfinano or its salts; 1-Cyclo-pyrrolidinyl-3,14β-dihydroxy-, 5a-epoxy-6a- (N-rnetoxy-3 ^ -diclorocinarnide norf &nano or its salts; and 17-Allyl-3,14β-dihydroxy-4,5a- epoxy-6β- (N-rnetoxy: -3-furanacrylamido-morphinanfin or its salts) The individual compounds, particularly p re fe rites are 17-cyclopyriol et i 1 -3,14β-di hydrox i-4, 5a-e ? ox i -6a- (N-hydroxy-3, dichlorophenylacetamido) rnorfinano or its salts and 17-Cyclo? ropilmethyl-3,14β-dihydroxy-4,5a-epoxy-6a- (N-? -dichlorophenylacetamido) morphinan or its salts.

General Synthesis The compounds of formula (I) of this invention can be prepared as indicated in the following preparation methods. If we indicate otherwise, R, B, R, R2, R3 and R are as previously defined.

Method 0: (ED 0 «) (Ib) (wherein 5 is hydrogen, Ci-Cs alkyl or a 0-protecting group, such as t-butyldirne-diisyl (TBDMS)). In the preparation method 0, a mixture of the rnorfinanhydroxyarnic acid compounds of the formulas (la) and (Ib) of the present invention, can be obtained by the addition of * a compound of the formula (II) (particularly R5 is H) using normal acylation techniques known to those skilled in the art. For example, the compound of formula (II) can be reacted with a carboxylic acid compound of formula (III) (R4-B-C00H), in the presence of a coupling agent in an inert solvent of suitable reaction. Suitable coupling agents include dicyclohexylcarbodiirnide (DCC), water soluble carbodiirnide (CSO), 2-ethoxy? -N-ethoxy? Carbon? L-2, d? hydroquinoline, Bop Agent (henzotnazol-1-ilox? -tr? s (dinethylane not) -phosphonium hexafluorophosphate), diethyltrifephosphoxyphosphonate diethyl, diethyl cyanophosphonate, carbonyldiinidazole and diphenyl-foepholyl azide. Water-soluble carbodumide is preferred. Suitable inert reaction solvents include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, dioxane and tet rahydrofuran; halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane; amides such as N, N-dimet? asorrnarn? da; and nitplos such as acetonitrile. This reaction can be carried out at a temperature in the range from -30 ° C to 100 ° C, usually from 0 ° C to 30 ° C. The reaction takes place in about 30 minutes to 24 hours, usually 30 minutes to 3 hours, at room temperature. The resulting products can be isolated and purified by standard techniques. When the compound of formula (II) is used wherein -NR50R is -NHOMe; and R2 is OH, the compounds of the formulas (la) and (Ib) can be obtained, wherein R is methyl; and R2 is hydroxyl. When the compound of the formula (TI) wherein R2 is -0-TBDMS, and R and R5 are both TBDMS, the compounds of formulas (la) and (Ib) wherein R is TBDMS, and R2 is -O-TBDMS. These TBDMS groups can be removed by a conventional method such as treatment of the resulting compound (a) or (Ib) with tetrabutylammonium fluoride (TBAF), to give the compounds of formula (Ia) or (Ib) wherein R and R2 are OH. The above acylation can be carried out alternatively by a reaction of the compound of formula (II) with the other acylating agents, for example (1) acyl halide (eg, R4-B-C0C1); (2) anhydride (v. Gr., (R * -B-CO) 2?) Or an anhydride mixed in the presence of a base; or (3) carboxylic ester (eg, R4-B-C00R "" where R "" is lower alkyl) optionally in the presence of base. Experts can properly choose the conditions used for acylation methods. In addition, in the compounds of formula (I) wherein R2 is hydroxyl, they can be converted to alkoxy. by known 0-alkylation techniques known to the experts. The intermediates of formula (III) are known or can be prepared by known methods. Intermediate compounds of formula (lia) (compounds of formula (II) wherein -NR * 0R is -NHOMe; and R2 is OH) can be prepared as shown in the following preparation method B-I: Method B- I: (He has) As shown in the preparation method BI above, naltrexone hydrochloride (IV) is first reacted with 0-methylhydroxylanine hydrochloride (NH 2? Me ~ HCl) in a suitable solvent (for example ethanol) to obtain a compound of the formula (Goes). Naltrexone hydrochloride is a known compound and is available commercially. This reaction can be carried out at a temperature of 0 ° C to 150 ° C for 30 minutes to 24 hours Preferably, this reaction can take place at the reflux temperature of the solvent used for 1 to 5 hours.

Second, the compound (Va) can be subjected to reduction of hydride with a hydride agent such as sodium cyanoborohydride (NaBH3CN) in a suitable solvent such as methanol. The reaction can be carried out at a temperature of 0 ° C to 40 ° C for 30 minutes to 48 hours. Preferably, the reduction can be carried out at room temperature for 4 to 24 hours. Intermediate compounds of the formula (Ilb) (ie, the compounds of the formula (II) wherein R and R5 are t-butyldirnethylsilyl (TBDMS) and R2 is -0-TBDMS) can be prepared as shown in the following preparation method B-II.

Method B-II (wherein R6 is TBDMS) In the above preparation method B-II, a compound (Ilb) can be prepared by reacting naltrexone hydrochloride (TV) with hydroxylamino hydrochloride (NH2OH-HCI) in a suitable solvent (e.g. ethanol) ) to obtain a compound of the formula (Vb); and then subjecting the compound (Vb) to hydride reduction with a hydride agent (e.g., NaBH3CN) in a suitable solvent (eg, methanol), followed by reaction with t-butyl chloride. In a suitable solvent (eg DMF). The reaction conditions of these reactions are known to those skilled in the art (See E.D.Coreyand 0.Venkateswarlu, D.flrn.Chern. Soc., 1972.94, 6190; D.W.Hansen, Jr. and D.Pi lipauskas, 3.Org.Chem., 1985, 50, 945; Y D.F.Keana, G.?Heo, and G.T. Gaughan, 3. Org. Chem., 1985, 50, 346). The compounds of formula (I) of this invention are usually basic, and therefore form acid addition salts. All these salts are within the scope of this invention. However, it is necessary to use acid addition salts that are pharmaceutically acceptable for administration to a mammal. The acid addition salts can be prepared by standard methods, for example by contacting the basic compounds and acids in substantially equivalent proportions in water or in an organic solvent such as methanol or ethanol, or a mixture thereof. The salts can be isolated by evaporation of the solvent. Typical salts that can be formed are hydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, fluconate, saccharate, benzoate, rnetanosul fonate, p-toluensul fonate, oxalate and pamoate (1 , 1'-rnetylene-bis- (2-hydroxy-3-naphthoate)). The compounds of formula (I) of this invention wherein R is hydrogen, are acidic and form base salts. All these salts are within the scope of this invention. However, it is necessary to use a base salt that is pharmaceutically acceptable for administration to a mammal. The base salts can be prepared by standard methods, for example by contacting the acidic and basic compounds in substantially equivalent proportions in water or an organic solvent such as methanol or ethanol, or a mixture thereof. The salts can be isolated by evaporation of the solvent. Typical base salts that can be formed are sodium, potassium, calcium and magnesium salts, and also salts with ammonia and amines, such as ethyl acetate, diethylamine, triethylamine, cyclohexylamine, piperidine and morpholine. Bioprecursors (also called prodrugs) of the compounds of formula (I) are also included within the scope of this invention. A bioprecursor of a compound of formula (I) is a chemical derivative thereof which is easily converted back to the original compound of formula (I) in biological systems. In particular, a bioprecursor of a compound of formula (I) is converted back into the original compound of formula (I) after the bioprecursor has been administered to, and absorbed by, a mammalian subject, for example a human subject. For example, it is possible to make a bioprecursor of the compound of formula (I) in which R2 is hydroxyl group, making an ester of the hydroxyl group. Typical esters are simple alkanoate esters, such as acetate, propionate and butyrate. Further, when R 2 is a hydroxyl group, the bioprecursors can be made by converting the hydroxyl group to an acyloxy ethyl derivative (e.g., a pivaloyloxy derivative) by reaction with an acyloxirneyl halide (e.g., pivaloyloxymethyl chloride). When the compounds of the formula (I) of this invention can form solvates such as hydrates, these solvates are included within the scope of this invention. The compounds of this invention of formula (I) exhibit significant agonist activity towards opioid receptors and good antagonistic activity towards the ORLi receptor, and thus are useful as analgesic, antiinflammatory, diuretic, anesthetic and neuroprotective agents, or an agent for the treatment of fulminating attack or functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject. The activity of the compounds of formula (I) of the present invention is demonstrated by the activities of binding to the opioid receptor and the opioid-like receptor. This activity can be determined in homogenous preparations of intact guinea pig brain, as described by Regina, 0. and others in D. Receptor Res. 12: 171-180, 1992. In summary, the homogenous tissue preparation was incubated at 25 ° C for 30 minutes in the presence of labeled ligand and test compounds. The rnu sites are labeled with 1 nM of (3H) -i: D-Ala2, MePhe4, Gly-ol5] encephalitis (DAMGO), the delta sites with 1 nM of (3H) -CD-Pen2,5-equivalencein ( DPDPE), the kappa sites by (3H) -CI977 at 0.5nM and the ORLi sites by (3H) ~ nociceptin at 1.27nM. Non-specific binding is measured using CI977 (k) at 1 μM, DAMGO (m) at 1 μM, DPDPE (d) at IμM and noniceptin (ORLi) at lOOnM. The data are expressed as the IC 50 values obtained by a non-linear adjustment program using the Cheng and Prusoff equation. Some compounds prepared in the examples showed an IC50 value of rnenos of 50 nM. The analgesic activity of the compounds can also be demonstrated by the formalin test as described by Ulheeler-Aceto, H. et al. In Psychopharrnacology 104: 35-44,1991. In this test, male SD rats (80-100 g) are injected subcutaneously with a test compound dissolved in 0.1% rnethylcellulose saline or vehicle. After 30 minutes, 50 nrl of 2% forrnaline was injected into a hind paw. The number of licks of the injected paw per observation period is measured 15-30 minutes after injecting the formalin, and is expressed as percentage of inhibition comparatively with the respective vehicle group.

The sedation activity of the compounds can also be demonstrated by the rotating rod test as described by Hayes, A.G. and others in Br. 3. Pharrnacol. 79: 731-736, 1983. In this test, a group of 6 to 10 male SD rats (100-120 g) is selected for their ability to swing on a rotating bar (9 cm diameter, rotational speed of 5 rpm). The selected rats were then injected subcutaneously with a test compound dissolved in 0.1% methylcellulose saline. The animals are retested 30 minutes after treatment; it is considered that a rat falling from the bar more than twice within 150 seconds shows motor deterioration, and the performance of the animal is recorded (ie, the time on the rotating bar). The ED50 value, defined as the dose of the drug that halves the performance time, is observed in the control group. The compounds of the formula (I) of this invention can be administered through the oral, parenteral or topical routes to mammals. In general, these compounds are more conveniently administered to humans in doses ranging from 0.01 mg to 50 mg per day, although there will necessarily be variations depending on the weight and condition of the subject being treated, the condition of disease being treated. and the particular route of administration chosen. However, a dose level that is on the scale of about 0.01 mg to 1 mg per kg of body weight per day, in single or divided doses, is more conveniently used in humans to treat pain in a postoperative patient. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable vehicles or di.luyent.es by any of the previously indicated routes, and said administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, that is, they can be combined with several pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, solid candies, powders, sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such vehicles include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, oral pharmaceutical compositions can be conveniently sweetened and / or flavored. In general, the therapeutically effective compounds of this invention are presented in said dosage forms at concentration levels ranging from 5% to 70% by weight, preferably 10% to 50% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine can be used together with various disintegrators such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tablet manufacturing purposes. Solid compositions of a similar type can also be used as fillers in gelatin capsules; In this regard, preferred materials also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be combined with various sweetening or flavoring agents, coloring matter or colorants and, if desired, also emulsifying and / or suspending agents, together with diluyent.com such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof. For parenteral administration, solutions of a compound of the present invention in sesame or peanut oil or in aqueous propylene glycol can be used. Aqueous solutions should be conveniently regulated in their pH (preferably pH >; 8) if necessary, and the liquid diluent must first be made .isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin, and this can preferably be done by creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.

EXAMPLES AND PREPARATIONS The present invention is described by the following examples and preparations. However, it should be understood that the invention is not limited to the specific details of these examples and preparations. The melting points were determined with a Buchi icroaparate for melting point, and were not corrected. Infrared (IR) absorption spectra were measured by a Shimazu infrared spectrometer (IR-470). Unless otherwise indicated, the nuclear magnetic resonance (NMR) spectra of IH and 13C in CDCI3 were measured by a JEOL NMR spectrometer.

(JNM-GX270, 270MHz), and the peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. Peak forms are denoted as follows: s, individual band; d, doublet; t, triplet; multiple bands; br, broadband.

PREPARATION 1 Naltrexone oxime A suspension mixture of naltrexone hydrochloride (856 rng, 2265 mmol) and hydroxylamine hydrochloride (236 mg, 3.4 mmol) in ethanol (10 rnl) was stirred under stirring for 4 hours. After evaporating the ethanol, the remaining resulting white solid was dissolved in saturated aqueous solution of NaHC 3 and extracted with CH 2 Cl 2 (20ml x 3). The combined extract was dried (a2SO0), filtered and concentrated to give 832 g (88.1%) of amorphous white solid. This was almost pure, so it was used for the next reaction without purification. 1H NMR (270MHz, CDCI3) d 6.71 (HH, d, 3 = 8.1Hz), 6.58 (HH, d, J = 8.1Hz), 5.02 (HH, s), 3.20-3.00 (3H,, including HH, d , 3 = 18.7Hz to 3.04ppm), 2.72-2.64 (HH, m), 2.55 (HH, dd, 3 = 6.2, 8.7Hz), 2.48-2.15 (5H, m, including 2H, d, 3 = 6.2Hz ), 1.75-1.62 (ÍH, rn), 1.56 (ÍH, d, 3 = 11.4Hz), 1.40 (ÍH, td, 3 = 4.0, 13.6Hz), 0.92-0.80 (ÍH, m), 0.60-0.50 ( 2H,), 0.17-0.10 (2H, rn). 7 7 PREPARATION 2 17-Cyclopropylmethyl-4, 5o-epoxy-3, 14β-dihydroxy-6o-hydroxyamino-morphine and 17-cyclopropylmethyl-4, 5a-epoxy-3, 14β-dihydroxy-6β-hydroxyaminomorphine To a solution of naltrexone oxirane (832 mg, 2. 3 mrnol), sodium cyanoborohydride (289 mg, 4.6 nmol), and one piece of bromocresol green in methanol (20 ml), inert ethanol dissolved in gaseous HCl was added. until the reaction mixture continuously showed a yellow color. After stirring for 1.5 hours at room temperature, sodium cyanoborohydride (289 mg, 4.6 mrnols) was added to the reaction mixture followed by the addition of methanol dissolved in gaseous HCl until the reaction mixture continuously showed a yellow color. After stirring for 2.5 hours at room temperature, the methanol was evaporated. The resulting residue was basified with saturated aqueous NaHC 3 solution and extracted with CH 2 Cl 2 (20 ml x 3). The combined extract was dried (a2S02), filtered and concentrated to give 760 rng (92.2%) of amorphous white solid. This was stereoisomer mixture (a.pβ = 7: 3) with respect to an asymmetric center of C6. This mixture was used for the next reaction without purification. 1 H NMR (270MHz, CDC.I3) & 7.30-5.50 (3H, br.s almost flat), 6.70 (0.7H, d, 3 = 8.1Hz), 6.68 (0.3H, d, 3 = 8.1Hz), 6.55 (0.3H, d, J = 8.1Hz ), 6.52 (0.7H, d, 3 = 8.1Hz), 4.99 (0.7H, d, 3 = 3.3Hz), 4.76 (0.3H, d, 3 = 7.3Hz), 3.70-3.60 (0.7H, m) 3.15- 2.75 (2.3H, rn), 2.70-2.50 (2H, m), 2.45-1.35 (9H, n) 0.90-0.75 (2H, rn), O.'BO-O.SO (2H, rn), 0.20-0.10 (2H, rn). PRECAUTION 3 3-t-Butyldimethylsilyloxy-6o-N, 0-bis (t-butyldimethylsilyl) idroxylamino-17-cyclopropylmethyl-, 5'-epoxy-14β-hydroxymorphine and 3-t-butyl-dimethylsilyloxy-6β-N, 0- bis (t-butyldimethylsilyl) hydroxylamino-17-cyclopropyl-methyl-4,5a-epoxy-14β-hydroxymorphine To a solution of hydroxylamine derivative (0.59 g, 1.65 mmol) and imidazole (1.12 g, 16.5 mmol) in DMF (10 mL) was added t-butychlorodirne diisilane (1.24 g, 8.25 mmol) at room temperature. After stirring for 15 minutes, the reaction mixture was poured into water (30 nmol) and extracted with ether (20 rnl x 3). The combined extract was dried (a2S0 «), filtered and concentrated to give 1.74 g of colorless viscous oil. This was purified by column chromatography (silica gel: 200 g, CH2Cl2 / MeOH: 50/1 as eluent) to yield 165 mg of colorless viscous oil as isomer 6a (polar moieties) and 885 rng of isomer mixture of da, 6β . This mixture was used for the next reaction without separation. Isomer 6a: 1H NMR (270MHz, CDC.I3) 6 6.62 (HH, d, 3 = 8.1Hz), 6.47 (1H, d, 3 = 8.4Hz), 4.86 (HH, br.e), 3.45-3.30 UH ,? n), 3.20-3.00 (ÍH, rn), 3.03 (ÍH, d, J = 18.7Hz), 2.70-2.50 (2H, rn), 2.40-2.20 (4H, rn), 1.80-1.35 (5H, m), 0.99 (9H, s), 0.92 (9H, s), 0.92 (9H, s), 0.90-0.85 (1H, rn), 0.60-0.50 (2H, rn), 0.20 (3H, s), 0.17 (3H, s), 0.15-0.10 (2H, rn), 0.10 (12H, s).

PREPORTION 4 3-t-Butyldiroethylsilyloxy-6"- (N, t-butyldimethylsilyloxy-3,4-dichlorophenylacetamido) -17-cyclopropylmethyl-4,5-cethoxy-14β-hydroxyphthalene and 3-t-butyldyroxy-silyloxy-6β- (N , t-butyldimethylsilyloxy-3,4-dichlorophenylacetamido) -17-cyclopropyl-methyl-4, 5-octyloxy-14β-hydroxymorphine Or a stirred solution of mixture of isomer 6a, 6β of preparation 3 (885 mg, 1.26 mmol) and 3,4-dichlorophenylacetic acid (267 mg, 1.3 min) in CH2Cl2 (20 ml) was added USC (268 mg, 1.4 rnmoles) at room temperature. After stirring for 1 hour, 3,4-dichlorophenylacetic acid (103 mg, 0.5 mmol) and UISC (1.10 mg, 0.57 mmol) were added to the reaction mixture. The reaction mixture was stirred at rt for 2 hours. The reaction mixture was diluted with CH 2 Cl 2 (30 mL), washed with saturated aqueous NaHC 3 solution, dried (a 2 SO 3) and filtered. The filtrate was concentrated to give 1.48 g of colorless viscous oil. The oil was purified by column chromatography (silica gel: 200 g, hexane / ethyl acetate: 8/1 to 4/1 as eluent) to yield 0.30 g of 6β isomer, 0.11 g of isomer mixture 6a, 6β and 0.32 g of 6a isomer. 6tt Isomer: H-NMR (270MHz, CDCI3) 6 7.37 (H, d, 3 = 2.2Hz), 7.36 (1H, d, 3 = 8.1Hz), 7.13 (1H, dd, 3 = 2.2, 8.1Hz), 6.63 (1H, d, 3 = 8.1Hz), 6.48 (1H, d, 3 = 8.1Hz), 4.88 (1H, d, 3 = 2.9Hz), 4.45-4.35 (ÍH, rn), 3.79 (1H, d, 3 = 16.9Hz), 3.70 (1H, d, 3 = 16.5Hz), 3.08 (1H, d, 3 = 6.Hz), 3.02 (1H, d, 3 = 19.1Hz), 2.70-2.55 (2H, m ), 2.40-2.15 (4H,), 1.90-1.45 (5H, rn), 0.97 (9H, s), 0.95 (9H, s), 0.90-0.80 (ÍH,), 0.60-0.50 (2H, n), 0.25 (3H, s), 0.25 (3H, s), 0.20-0.10 (2H, m), 0.18 (3H, s), 0.12 (3H, s). IR (film): 3400, .1,670 crn ~. 6β Isomer: Its H NMR spectrum was very complicated due to the amide bond rotamers. Only the assignable peaks are shown below. 1H NMR (270MHz, CDC13), d 7.24 (HH, d, J = 8.1Hz), 6.93 (HH, br.s), 6.85 (HH, br.d, J = 8.1Hz), 6.75 (0.5H, d , 3 = 8.1Hz), 6.64 (0.5H, d, 3 = 8.1Hz), 6.62 (0.5H, d, 3 = 8.1Hz), 6.47 (0.5H, d, 3 = 8.1Hz), 4.86 (ÍH, d, 3 = 7.7Hz), 3.62 (2H, br.s), 1.02 (4.5H, s), 0.99 (4.5H, s), 0.98 (4.5H, s), 0.92 (4.5H, s), 0.60 -0.50 (2H, m), 0.30 (1.5H, s), 0.29 (1.5H, s), 0.21 (1.5H, s), 0.20 (1.5H, s), 0.17 (1.5H, s), 0.16 ( 1.5H, s), 0.10 (3H, s). IR (film): 3400, 1660 crn-i.

EXAMPLE 1 17-Cyclopropylmethyl-3, 14β-dihydroxy-, 5tt-epoxy-6a- (N-hydroxy-3, 4-chloro-enylacetamide) mor ina 0 a solution of 6or isomer. of preparation 4 (0.32 g, 0.41 rnmoles) in THF (1 mL) was added a solution of tetrabutylammonium fluoride at 1M in THF (1 mL, 1 mmol) at room temperature. After stirring for 0.5 hour, the reaction solution was poured into saturated aqueous NH4CL solution (20 nmol) and extracted with ethyl acetate (20 ml x 3).

After drying (a2S02) and filtering, the filtrate was concentrated to give 392 rng yellow solid. This was purified by preparative TLC (1 nrn thick plate, developed twice with CH2C1.2 / MeOH: 10 μl) to give 162 mg (72%) of yellow amorphous solid. 1H NMR (270MHz, CDC.I.3) 6 7.40-7.25 (2H, m), 7.12 (1H, br.d, J = 8.1Hz), 6.68 (HI, br.d, J = 7.7Hz), 6.58 -6.45 (1H, rn), 5.10-4.95 (ÍH, rn), 4.80-4.70 (ÍH, m), 3.91 (ÍH, br.d, 3 = 15.8Hz), 3.88-3.70 (ÍH, m), 3.25 -2.88 (2H, rn), 2.75-2.55 (2H, rn), 2.45-2.15 (3H,), 1.90-1.40 (7H,), 0.90-0.75 (1H, rn), 0. 60-0.50 (2H, m), 0.20-0.10 (2H, m). IR (film): 3500, 1640 cm ~ i. MS m / z: 544 (M +, 13), 527 (7), 340 (65), 161 (100). These 162 g of free amine were treated with MeOH (0.5 rnl) dissolved in gaseous HCl at room temperature. Then, the solvent was evaporated and the residue was solidified from ether by grating to yield 155 g of pale yellow powder. Analysis calculated for C 28 H 30 Cl 2 N 2 O 5 HCl H 2 O: C, 56.06; H, 5.54; N, 4.67. Found: C, 56.24; H, 5.63; N, 4.51. EXAMPLE 2 17-Cyclopropylmethyl-3,14-dihydroxy-, 5-octyloxy-6β- (N-hydroxy-3,4-dichlorophenylacetamido) morphine To a 6β isomer solution of preparation 4 (0.30 g, 0.39 mmol) in THF (1 ml) was added a solution of tetrabutylammonium fluoride at 1M in THF (1 ml, 1 ml) at room temperature. After stirring for 0.5 hour, the reaction solution was poured into saturated aqueous NH 4 Cl solution (20 rnl) and extracted with ethyl acetate (20 rnl x 3). After drying (Na 2 SO 3) and filtering, the filtrate was concentrated to give 279 g of yellow amorphous solid. This was purified by preparative TLC (1 rnm thick plate, developed with CH2C.12 / MeOH: 10/1) to give 170 rng (79.8%) of white amorphous solid. 1H NMR (270MHz, CDCI3) 6 7.36 (0.5H, br.d, 3 = 1.8Hz), 7. 28 (0.5H, d, 3 = 8.1Hz), 7.27 (0.5H, d, 3 = 8.1Hz), 7.02 (0.5H, d, 3 = 1.8Hz), 6.90 (0.5H, dd, 3 = 1.8, 7.3Hz), 6.87 (0.5H, d, 3 = 7.3Hz), 6.70 (0.5H, d, 3 = 8.1Hz), 6.69 (0.5H, d, 3 = 8.4Hz), 6.53 (0.5H, d, 3 = 8.1Hz), 4.98 (0.5H, d, 3 = 6.6Hz), 4.92 (0.5H, d, 3 = 7.7Hz), 4.25-4.10 (0.5H, rn), 3.93 (0.5H, d, 3 = 15.8Hz), 3. 79 (0.5H, d, 3 = 15.8Hz), 3.69 (0.5H, d, 3 = 15.8Hz), 3.67-3.55 (0.5H, rn), 3.48 (0.5H, d, 3 = 15.8Hz), 3.30 -2.90 (4H, rn), 2.75-2.20 (4H, rn), 1.80-1.05 (6H, n), 0.90-0.80 (ÍH, rn), 0.60-0.50 (2H, rn), 0.20-0.10 (2H, rn). IR (film): 3400, 3200, .1.640, 1630 crn "I. MS m / z: 544 (M +, 25.8), 528 (1.7), 367 (6.4), 327 (28), 161 (100). These 170 rng free amine were treated with MeOH (2 rnl.) Dissolved in gaseous HCl at room temperature. Then, the solvent was evaporated and the residue solidified from ether / methanol by grating to yield 119 rng of white powder. Analysis calculated for C 8H30Cl2N2OS HCl H2O: C, 56.06; H, 5.54; N, 4.67. Found: C, 56.41; H, 5.24; N, 4.66.

PREPARATION 5 6-Methoxyiminonaltrexone A suspension mixture of naltrexone hydrochloride (4.133 g, 10.9 rnmoles) and O-methylhydroxylannine hydrochloride (1.25 g, 15 rnmol.es) in ethanol (40 rnl) was shaken with stirring for 3 hours. After evaporating the ethanol, the remaining resulting white solid was dissolved in saturated aqueous solution of NaHC 3 and extracted with CH 2 Cl 1 (100 ml x 3). The combined extract was dried (Na 2 SO 3), filtered and concentrated to give 3,984 g (98.6%) of amorphous white solid. This was almost pure, so it was used for the next reaction without purification. H NMR (270MHz, CDC13) 6 6.73 (HH, d, 3 = 8.4Hz), 6.57 (1H, d, 3 = 8.1Hz), 5.30 (HH, s), 4.98 (HH, s), 3.89 (3H, s), 3.12 (HH, d, 3 = 6.2Hz), 3.05 (HH, d, 3 = 18.7Hz), 2.85-2.20 (9H, rn), 1.65-1.55 (2H, m), 1.40-1.25 (1H , n), 0.95-0.80 (ÍH, rn), 0.60-0.50 (2H, m), 0.20-0.10 (2H, m). IR (Nujol): 3200, 1640, 1615 crn ~ 1. MS m / z: 37KM + +1, '100), 370 (M +, 100), 339 (50), 329 (66), 315 (52), 273 (41), 243 (38), 110 (80).

PREPARATION 6 17-Cyclopropylmethyl-3,1 ß-dihydroxy-4,5α-epoxy-6-methoxyamino-morphine and 17-cyclopropylmethyl-3,14β-dihydroxy-4,5'-epoxy-6β-methoxyamine To a solution of 6-nitroxyninontrexone (3.97 g, 10.7 mmol), sodium cyanoborohydride (1.57 g, 25 mmol), and a piece of bromocresol green in methanol (40 nl), methanol dissolved in gaseous HCl was added until the Reaction mixture continuously showed a yellow color. After stirring for 0.5 hour at room temperature, sodium cyanoborohydride (1.40 g, 22 mmol) was added to the reaction mixture followed by the addition of methanol dissolved in gaseous HCl until the reaction mixture continuously showed a yellow color. After stirring for 8 hours at room temperature, the methanol was evaporated. The resulting residue was basified with saturated aqueous NaHC 3 solution and extracted with CH 2 Cl 2 (30 ml x 3). The combined extract was dried (N 2 SO), filtered and concentrated to give 3,962 g of amorphous white solid. This was purified by column chromatography (silica gel: 100 g, CH2Cl2 / MeOH: 30/1 as eluent) to give 1141 g of amorphous white solid as the main product polar moieties (6a isomer), 1.733 g of white solid amorphous as a mixture of isomers 6a, β, and 0.650 g of amorphous white solid as a more polar product (6β isomer). Again, 1733 g of the mixture of 6a, β isomers were purified by column chromatography (silica gel: 100 g, CH 2 Cl 2 / MeOH: 30 μl as eluent) to give 0.536 g of 6a isomer, 0.610 g of isomer mixture 6a, ß, and 0.739 g of 6β isomer. The total yield of 60c isomer was 42.1% and 6β isomer was 34.9%. Isomer 6or .: 1H NMR (270MHz, CDCI3) 6 6.70 (1H, d, 3 = 8.1Hz), 6.5.1 (ÍH, d, 3 = 8.1Hz), 4.85 (ÍH, d, 3 = 3.3Hz), 3.72-3.60 (HH, rn), 3.62 (3H, s), 3.10 (HH, d, 3 = 7.0Hz), 3.04 (HH, d, 3 = 18, Hz), 2.70-2.60 (HH, m), 2.57 (ÍH, dd, 3 = 6.6, 8.7Hz), 2.43-2.20 (4H, n), 1.80-1.35 (4H, m), 0.90-0.70 (2H, m), 0.60-0.50 (2H, rn), 0. 20-0.10 (2H, rn). IR (Nujol): 3350, 3250 crn ~ l. MS rn / z: 372 (M +, 100), 341 (100), 323 (37), 256 (54), 129 (52), 98 (52), 73 (95). 6β isomer: 1 H NMR (270 MHz, CDCl 3) d 6.68 (1 H, d, 3 = 8.4 Hz), 6.56 (1 H, d, 3 = 8.1 Hz), 4.69 (j, d, 3 = 7. Hz), 3.64 (3H, s), 3.07 (HH, d, 3 = 5.5Hz), 3.01 (HH, d, 3 = 18.3Hz), 2.75-2.60 (2H, rn), 2.58 (1H, dd, 3 = 5.9, 8.7 Hz), 2.37 (2H, d, 3 = 6.6Hz), 2.35-2.02 (3H, rn), 1.80-1.60 (2H, rn), 1.55-1.33 (2H, m), 0.90-0.80 (ÍH, n) , 0.60-0.50 (2H, m), 0.20-0.10 • (2H, rn). IR (Nujol): 3350, 3250 crn-. MS m / z: 372 μM +, 84), 357 (5), 34.1 (8), 327 (9), 323 (13), 226 (38), 84 (88), 55 (100).

EXAMPLE 3 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5'-epoxy-6ot- (N-methoxy-3,4-dichlorophenylacetamido) morphine To a stirred solution of 17-cyclo? Ro? Ilrnetii-4,5a-e? Oxy-3,14? -dihydroxy-6a-rnetoxiarninornorphine (240 mg, 0.64 mmol) and 3,4-dichlorophenylacetic acid (267 mg. 1.3 rnmoles) in CH 2 Cl 2 (5rnl) WSC (249 mg, 1.3 mmol) was added at room temperature. After stirring for 1 hour, the reaction solution was diluted with CH2Cl2 (20 nmol), washed with saturated aqueous NaHC 3 solution, dried (Na 2 SO 3), and filtered. The filtrate was concentrated to give 521 rng of amorphous white solid.

This was dissolved in mixed solvent (CH2Cl2 / MeOH: 1/4, 5 rnl).

To this solution was added K2CO3 (138 mg, 1 nrnol) at room temperature. After stirring for 1 hour, the MeOH was evaporated and the resulting residue was dissolved in water and extracted with CH2CI2 (20ml x2). After drying (Na 2 SO 3) and filtering, the filtrate was concentrated to give 521 mg of colorless viscous oil, which was purified by column chromatography (silica gel: 60 g, CH 2 Cl 2 / eOH: 20/1 as the unit) to produce 275 rng (76.8%) of amorphous white solid. 1H NMR (270MHz, CDCI3) d 7.44 (1H, d, 3 = 2.2Hz), 7.39 (1H, d, 3 = 8 Hz), 7.17 (HI, dd, 3 = 2.2, 8.1Hz), 6.70 (1H, d, 3 = 8.1Hz), 6.53 (1H, d, 3 = 8.1Hz), 4.85-4.75 (ÍH, rn), 4.77 (1H, d, 3 = 3.7Hz), 3.82 (ÍH, d, 3 = 15.4Hz), 3.78 (3H, s), 3.73 (ÍH, d, 3 = 15.4 Hz ), 3.10 (HH, d, 3 = 7.0 Hz), 3.03 (1H, d, 3 = 18.7Hz), 2.67-2.55 (2H, m), 2.42-2.17 (4H, rn), 1.85-1.30 (5H, rn), 0.90-0.77 (ÍH, m), 0.57-0.49 (2H, m), 0.15-0.08 (2H, m). IR (Nujol): 3350, 1630 crn ~ 1. This free amine, 275 rng, was treated with MeOH (2 ml) dissolved in CH1 gas at room temperature. Then the solvent was evaporated and the residue was solidified from ether-scraping to give 275 mg of white powder. Anal. Calculated for C29H32Cl2 2OS .HCl.H2O: c, 56.73; H, 5.75; N, 4.56 Found C, 56.51; H, 5.79; N, 4.47.

EXAMPLE 4 17-Cyclopropylmethyl-3, 14β-dihydroxy-, 5-epoxy-6β- (N-methoxy-3,4-dichlorophenylactamido) morphinan The title compound was prepared from 17-cyclopropyl-phenyl-4,5a-e-oxy-3,14-dihydroxy-6-β-methoxyamino-rnorphinan in a yield of 76.7% according to the procedure similar to that described in example 3 .1H NMR (260MHz, CDC13) d 7.41 (ÍH, br.s), 7.39 (1H, br.d, 3 = 9.5 Hz), 7.16 (1H, br.d, 3 = 7.7 Hz), 6.71 (1H, br.d, 3 = 7.3 Hz), 6.57 (ÍH, br.d, 3 = 8.1Hz), 4.90 (ÍH, d, 3 = 8.1 Hz), 4.20-4.05 (ÍH, n), 390-3.68 (5H , rn, including 3H, br.s. to 3.83 pprn), 3.15-3.06 (ÍH, rn), 3.03 (ÍH, d, 3 = 18.3Hz), 2.75-2.55 (2H, rn), 2.39 (2H, d , j = 6.2Hz), 2.38-2.10 (3H, rn), 1.70-1.25 (4H, rn), 0.90-0.80 (ÍH, rn), 0.60-0.50 (2H, rn), 0.20-0.20 (2H, rn ). IR (Nujol): 3300, 3250, 1660crn-l. MS m / z: 562 μM + +4.4), 560 (m ++ 2, 20), 558 (M +, 29), 543 (6), 527 (4), 412 (8), 326 (10), 256 (10), 210 (26), 156 (40), 55 (100). This free amine 115 mg was treated with MeOHl (rnl) dissolved in gaseous HCl at room temperature. Then the solvent was evaporated and the residue was solidified from ether-scraping and crystallized from MeOH / ether to give 107 mg of white powder, mp 238-243. Anal. Cale for C29 H32Cl2 2 OSHCIH2O: C, 56.73; H, 5.75; N, 4.56. Found. C, 56.36, H, 5.76; N, 4.54.

EXAMPLE 5 17-cyclopropylmethyl-, 5'-epoxy-15β-hydroxy-3-methoxy-6a- (N-methoxy-3,4-dichlorophenylacetamido) morphine or To this mixture of 17 ~ cycle? Ropilmetii-3, 14β-dihydroxy-4, 5a-epoxy-6a- (N-methoxy-3,4-dichlorophenylacetamido) morphinan (197 rng, 0.35 mmol), trimethylsilyldiazornetan (10% solution in CH2C.I2, 0.57 g, 0.5 rnmoles), diisopropylethylamine (65 mg, 0.5 mmol), ethanol (0.2 ml), and acetonitrile (2 ml) were stirred at room temperature for 13 hours. After evaporation of the solvent, the residual oil was purified by preparative thin layer crornate (plate 1 rnm thick CH2Cl2 / MeOH: 10/1) to give 47mg of amorphous solid. This was purified again by preparative thin layer chromatography (1 ml thick plate, CH 2 Cl 2 eOH: 10/1) to give 25 mg of amorphous solid as the desired product. 1H NMR (270MHz, CDC.l.3) d 7.41 (ÍH, d, 3 = 2.2Hz), 7.38 (1H, d, 3 = 8.1Hz), 7.16 (1H, dd, 3 = 1.8.8.1 Hz), 6.75 (1H, d, 3 = 8.Hz,) 6.59 (1H, d, 3 = 8.1Hz), 4.90 (H, td, 3 = 3.7, 13.2Hz9, 4.78 (H, d3 = 4Hz), 3.84 (3H , s), 3.83 (ÍH, d, 3 = 15.4Hz9, 3.82 (3H, s), 3.70 (1H, d, 3 = 1, 8Hz), 3.17 (ÍH, d, 3 = 6.6Hz), 3.06 (ÍH) , d, 3 = 18.7Hz), 2.75-2.20 (6H, rn), 1.88-1.25 (5H, rn), 0.95-0.80 (2H, rn), 0.60-0.50 (2H, rn), 0.20-0.10 (2H , rn) IR (film 3400, 1660 crn-i MS rn / z 576 (M ++ 4, 7), 574 (M ++ 2, 36), 572 (M +, 50), 545 (M ++ 4-OMe, 8), 543 (M ++ 2-0Me, 34), 541 (M * -OMe, 43).

PREPARATION 7 6-methoxyiminonaloxone The title compound was prepared from naloxone hydrochloride and O-methylhydroxylamine in a yield of 95.7% according to a procedure similar to that described in preparation 5"1 H NMR (270MHz, CDC1.3) d 6.83 (1H, d , 3 = 8.4 Hz), 6.59 (ÍH, d, 3 = 8.1Hz), 5.88-5.72 (ÍH, m), 5.27_5.14 (2, rn), 4.97 (1H, s), 3.89 (3H, s), 3.14 (ÍH, d, 3 = 3.7Hz), 3.10 (1H, d, 3 = 17.2Hz), 2.93 (ÍH, d, 3 = 6.2Hz), 2.84-2.74 (ÍH, m), 2.65-2.15 (5H, rn), 1.65-1.50 (2H, m), .1.40-1.23 (H, rn).

PREPARATION 8 17-AÜ1-3, 14β-dihydroxy-, 5tt-epoxy-6a-methoxyaminomorphonan and 17-allyl-3, 14β-dihydroxy-, 5-epoxy-6β-methoxyamomorphinan The title compounds were prepared from 6-r-methoxy-n-inninaloxane in 100% crude yield according to a procedure similar to that described in Preparation 6. Purification by gel column chromatography (CI-t2Cl-2 / MeOH: / 1 as eluant) gave 17-allyl-3,14-dihydroxy-4, 5a-e? Oxy-6a-methoxyamino-morphinan in a yield of 48.6% as less polar major isomer and 17-allyl-3,14β-dihydroxy-4 , 5cf.-epoxy-6β-rnetoxiarninornorfinano in a yield of 17.3% as smaller polar isomer and mixture of both isomers in a yield of 17.5%. Isomer 6a: 1H NMR (270MHz, CDC.l-3) d 6.70 (HH, d, 3 = 8.1Hz), 6.52 (1H, d, 3 = 8.1Hz), 5.81 (HH, tdd, 3 = 6.6, 10.3 16.9Hz), 5.25-5.13 (2H, rn9, 4.84 (HH, d, 3 = 3.7Hz), 3.65 (HH, td, 3 = 3.7, 13.2Hz), 3.62 (3H, s), 3.10 (HH, d , 3 = 5.9Hz), 3.08 (1H, d, 3 = 18, Hz, 2.92 (1H, d, 3 = 6.6Hz) 2.63-2.49 (2H, m), 2.34-2.15 (2H, m), 1.80- 1.35 (4H, m), 0.85-0.70 (HH, rn) .Systomer 6β: 1H NMR (270MHz, CDC13) d 6.67 (1H, d, 3 = 8.1Hz), 6.57 (HH, d, 3 = 8.1Hz) , 5.79 (1H, tdd, 3 = 5.2, 10.3, 17.2Hz), 5.25-5.13 (2H, rn), 4.70 (1H, d, 3 = 7.3Hz), 3.64 (3H, s), 3.12 (2H, d , 3 = 6.6Hz), 3.05 (ÍH, d, 3 = 18.3Hz), 2.89 (1H, d, 3 = 5.5Hz), 2.73-2.49 (3H, rn), 2.28-2.02 (3H,), 1.78- 1.57 (2H, rn), 1.49-1.25 (2H, rn).

EXAMPLE 6 17-Allyl-3,14β-dihydroxy-4,5-tx-epoxy-6a- (N-methoxy-3,4-dichlorophenylacetamido) mor inan The title compound was prepared from 6α-rnetoxyminonaloxane and 3,4-dichlorophenylacetic acid in a 67% yield according to a procedure similar to that described in Example 3. 1 H NMR (270MHz, CDC13) d 7.44 (1H, d, 3 = 2.2Hz), 7.39 (HH, d, 3 = 8.1Hz), 7.16 (1H, dd 3 = 2.2 8.1Hz), 6.71 (HH, d, 3 = 8.1Hz), 6.55 (HH, d, 3 = 8.1Hz), 5.79 (ÍH, tdd, 3 = 6.6, 10.6, 17.2 Hz), 5.25-5.15 (2H, rn), 4.85-4.75 (2H, m) 3.82 (1H, d, 3-15 .Hz ), 3.77 (3H, s), 3.73 (ÍH, d, 3 = 15.4Hz), 3.15-3.05 (3H, m), 2.92 (1H, d, 3 = 6.6Hz), 2.66-2.50 (2H, rn) , 2.30-2.15 (2H, rn), .1.85-1.35 (5H, rn). IR (Nujol): 3350, 1640crn- l.

MS m / z: 548 μM ++ 4, 5), 546 (M + +2, 23), 544 μM +, 33), 517 MM ++ 4-OMe, 6), 515 (M ++ 2 ~ OMe, 24) 513 ( M + -OMe, 30). The free amine, 110 rng, was treated with MeOH (2 rnl) dissolved in gaseous HCl at room temperature. Then the solvent was evaporated and the residue was solidified from ethanol / ether by scraping to give 100 rng of white powder. Anal. Cale. for C-28H30Cl2N2OSHCI .2.5H2O: C, 53.64; H, 5.79, N, 4.47. Found: C, 53.50; H, 5.58; N, 4.37.

EXAMPLE 7 17-Cyclopropylmethyl-3,14-dihydroxy-, 5a-epoxy- (N-methoxy-3, 4-dichlorobenzamido) mor inan A solution of 17-cyclopropyl-phenyl-3,14-dihydroxy-4, 5-o-epoxy-6-α-nanoxy-aminoanorphol (74 mg, 0.2 mole) and triethylamine (0.07 rnl, 0.5 mole) in CH2Cl2 (5rnl) was added 3,4-dichlorobenzoyl chloride (105 mg, 0.5 mmol) at room temperature. After being stirred for 0.5 hour, the solution was diluted with CH2Cl2 (lOml), washed with a saturated aqueous solution of NaHC3, dried (Na2SO4), filtered and concentrated to give 302 rng of white solid. To a solution of this solid in rnetanol / CH2Cl2 (4rnl / 4ml) was added K2CO3 (28 rng, 0. 2 rnrnoles) at room temperature. After stirring during 1 hour, the solvents evaporated. To this residue was added a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (10 L x2). The extract was dried (N 2S0 *), filtered and concentrated to give 201 mg of a pale yellow viscous oil, which was purified by preparative thin layer chromatography (plate 1 m thick x 2, CH 2 Cl 2 / methanol. / 1) to give 89 mg (81.7%) of a pale yellow viscous oil. 1H NMR (270MHz, CDC.I3) d 7.86 (1H, d, 3 = 1.8Hz), 7.60 (1H, dd, 3 = 1.8, 8.4Hz, 7.49 (HH, d, 3 = 8.4Hz), 6.72 (1H, d, 3 = 8.1Hz), 6.56 (HH, d, 3 = 8.4Hz), 5.00-4.88 (2H, m ), 3.51 (3H, s), 3.13 (HH, d, 3 = 6.6Hz), 3.06 (HH, d, 3 = 18.7Hz), 2.70-2.57 (2H, m), 2.44-2.20 (4H, rn) , 1.90-1.45 (5H, n), 0.95-0.80 (ÍH, rn), 0.60-0.50 (2H, m), 0.16-0.10 (2H, m); IR (film): 3350, 1630crn-l; MS m / z: 548 (M + +4.1), 546 (M + +2.6), 544 (M +, 8), 517MM + + 4-OMe, 1), 515 (M + + 2-OMe, 6), 513 (M + -OMe, 8), 346 (6), 303 (19), 173 (29), 55 (100).

EXAMPLE 8 17-Cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6a- (N-methoxy-3,4-dichlorocinamido) mor inana The title compound was prepared from 17-cyclopro? Ilmethyl-4,5a-e? Oxy-3,14β-dihydroxy-6a-methoxyarnino-morphinan in a yield of 21% according to the procedure similar to described in Example 3. 1H NMR (270MHz, CDCI3) d 7.65 (1H, d, 3 = 15.8Hz), 7.65 (ΔH, d, 3 = 2.2Hz), 7.46 (ΔH, d, 3 = 8Hz) , 7.38 (ÍH, dd, 3 = 1.8, 8.4Hz), 7.00 (ÍH, d, 3 = 15.8Hz), 6.74 (ÍH, d, 3 = 8.1Hz), 6.56 (ÍH, d, 3 = 8.4Hz) , 5.00-4.88 (2H,), 3.82 (3H, s), 3.25-3.15 (HH, m), 3.06 (1H, d, 3 = 18.3Hz), 2.80-2.20 (6H, rn), 1.90-1.40 ( 5H, rn), 0.95-0.82 (1H, rn), 0.60-0.52 (2H, rn), 0.20-0.14 (2H, rn); IR (Nujol): 3300, 3250, 164Qcrn-l; MS m / z: 574 (M + +4, 0.3), 572 (M + +2, 1.5), 570 (M + + 4-90Me, 0.6), 541 (M + + 2 ~ OMe, 2.4), 539 (M + + - OMe, 3.2), 339 (16), 310 (10), 256 (5), 199 (12), 55 (100).

EXAMPLE 17-AÜ1-3, 14β-dihydroxy-4, 5a-epoxy-6β- (N-methoxy-3-furanacrylamido) orphid The title compound was prepared from 6β-rnetoxiarninonaloxone and 3-furanacrylic acid in a yield of 10.5% according to a procedure similar to that described in example 3. 1H NMR (270) MHz, CDC13) d 7.67 (HH, br.s), 7.64 (1H, d, 3 = 1.5.0Hz), 7.44 (HH, br.s), 6.75 (-1H, d, 3 = 8.1Hz), 6.66-6.58 (3H, m, including 1H, d, 3 = 8.1Hz to 6.61pprn), 5.80-5.60 (ÍH, rn), 5.26-5.13 (2H,), 4.91 (ÍH, d, 3 = 8.1Hz), 4.40-4.20 (1H, m), 3.87 (3H, s), 3.14 (2H, d, 3 = 6.2Hz), 3.08 (ÍH, d, 3 = 1.8.3Hz), 2.91 (1H, d, 3 = 5.9Hz), 2.70-2.52 (2H, rn), 2.40-2.10 (3H, rn), 1.75-1.40 (4H, rn); IR (film): 3400, 3250, 1650, 1610crn-l; MS rn / z: 478 (M +, 5), 447 (M + -OMe, 18), 357 (3), 309 (3), 242 (6), 212 (15), 149 (8), 121 (100) . The chemical structures of the compounds prepared in Examples 1 to 9 are summarized in the following tables.

PICTURE (D Ex. # R Rl R2 R3 R4 1 H CH2 cyclopropylmethyl OH OH 3,4-dichlorophenyl 2 H CH2 cyclopropylmethyl OH OH 3, -di cio rofeni lo 3 Me CH2 cyclopropylmethyl OH OH 3,4-dichlorophenyl 4 Me CH2 cyclopropylmethyl OH OH 3, 4-dicorophenyl Me CH2 cyclopropylmethyl OMe OH 3,4-dichlorophenyl 6 I CH2 at i OH OH 3, 4-dicyorophenyl 7 I link cyclopropylmethyl OH OH 3,4-dichlorophenyl directly 8 Me CH = CH cyclopropylmethyl OH OH 3,4-dichlorophenyl 9 I CH = CH allyl OH OH furyl Note: The stereochemistry of the compounds of Examples # 1.3, 5-8 was 6S. The one in examples # 2,4 and 9 was 6R.

Claims (1)

1. 4. 1 NOVELTY OF THE INVENTION CLAIMS A compound of the following formula: (D and pharmaceutically acceptable salts thereof, wherein R is hydrogen, Ci-Cs alkyl or a 0-r-rotective group; B is a direct bond, Ci-Cs alkylene or C2-C5 alkenylene; R1 is Ci-C5 alkyl, C2-C5 alkenyl or C3-C7 cycloalkyl-Ci-C3 alkyl; R2 is hydroxyl or Ci-C5 alkoxy; R3 is hydrogen, hydroxyl or Ci-C5 alkoxy; and R * is hydrogen, phenyl, heteroaryl selected from furyl, thienyl and pyrrolyl, phenyl and heteroaryl being optionally substituted with one to five substituents selected from halogen, hydroxyl, Ci-C3 alkyl, Ci-C3 alkoxy and C2 alkenyl -C5 2. A compound according to claim 1, further characterized in that R is hydrogen or alkyl of Ci-Cs; B is a direct bond, Ci-C alkylene, or 2-C4 alkenylone; R 1 is alkenyl of O 2 -C 5 or cycloalkyl of C 3 -C 7 -alkyl of C 1 -C 3; R2 is hydroxyl or Ci-C3 alkoxy; R3 is hydrogen, hydroxyl or Ci-C3 alkoxy; and R 4 is phenyl or heteroaryl, optionally substituted with one to three subst 11 selected from halogen, hydroxyl and Ci-C 3 alkyl. 3. A compound in accordance with the claim 2, further characterized in that R is hydrogen or Ci-C3 alkyl, B is a direct bond, Ci-C3 alkylene or alkenylene of C2-C3; R is C2-C3 alkenyl or C3-C5 cycloalkyl ether; R2 and R3 are independently hydroxyl or Ci-C3 alkoxy and R4 is phenyl, furyl, tenyl or pyrrolyl, optionally substituted with one to three substituents selected from halogen, hydroxyl and Ci-C3 alkyl. 4. A compound in accordance with the claim 3, further characterized in that R is hydrogen, methyl or ethyl; B is rnetylene, ethylene or etemlene; R1 is aillo, cyclopropyl-nitrile, cyclobutyl-phenyl or cyclopentyl-phenyl; R2 and R3 are independently hydroxalo, methoxy or ethoxy; and R 4 is phenyl or fupl, optionally substituted by one to three eubst 1 receptors selected from fluorine and chlorine. 5. A compound in accordance with the claim 4, characterized adornas because R is hydrogen or methyl; B is rnetylene or ethylene; R1 is allyl or cyclopropylmethio; R2 is hydroxyl or rnetoxy; R3 is hydroxyl; and R * is 3,4-d? chlorophenone or furyl. 6. ~ A compound: in accordance with the claim 1 selected from 17-Cyclopropyl-trilel-3, 14β-dihydroxy-4,5a-epoxy-6a ~ (N-hydroxy-3,4-dichlorophenylacetarnide) rnorfinano or its salts; 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β- (N-hydroxy-3,4-dichlorophenylacetamido) morphinan or its salts; 17- Cyclo-pyrrolidone-3,14-dihydroxy-4,5-o-epoxy-6a- (N-methoxy-3,4-dic.lorophenylacetamido) morphinan or its salts; 17-Cyclopropyl-methyl-3,14-dihydroxy-4,5a-e? Oxi-6β- (N-rnetoxy-3,4-dichlorophene.l-acetamido) rnorfinano or its salts; 17-Cyclopropylphenyl-, 5a-epoxy-14β-hydroxy-3-methoxy-6a- (N-rnetoxy-3,4-dichloropheniollaceta-mido) rnorfinano or its salts; 17-Allyl-3, 1,4-dihydroxy-4,5a-epoxy-6a- (N-methoxy-3,4-dichlorophenylacetamido) rnorf inano or its salts; 17-Cyclo-pyrrolidone-3, 14β-dihydroxy-4, 5a-epoxy-6a- (N-methoxy-3,4-dichlorobenzamido) rnorf inano or its salts; 17- Cyclopropylmethyl-3,14β-dihydroxy-4,5a-epoxy-6a- (N-methoxy-3,4-dichlorocinarnido) rnorfinano or its salts; and 17-Allyl-3, 14β-dihi. drox i-4, 5a-e? ox i- 6β- (N-methoxy-3-furanacri lido) morphin or its salts. 7. A compound in accordance with the claim 6, selected from 17-cyclopropylrnetii-3, 14β-dihydroxy-4,5 a-epoxy-6a - (N-hydroxy-3,4-dichlorophenylacetamido) morphinan or its salts and 17-Cyclopropylmethyl-3, 14β -dihydroxy-4, 5a-e? oxi-6 - (N-rnetoxy-3,4-dichlorophenylacetamido) rnofinan or its salts. 8. A pharmaceutical composition useful as an analgesic, anti-inflammatory, diuretic, anesthetic or neuroprotective agent, or an agent for treatment of fulminating attack or diseases of the functioning of the intestine, comprising a compound according to claim 1, and a pharmaceutical carrier. inert. 9. The use of a therapeutically effective amount of a compound according to claim 1, in the preparation of compositions for the treatment of a medical condition for which an activity agonist towards opioid receptors and an antagonistic activity towards an receptor of ORLi, in a mammalian subject. SUMMARY OF THE INVENTION The invention provides a compound of the following formula: 15 (D And the pharmaceutically acceptable salts thereof, wherein R is hydrogen, C1-C5 alkyl or an O-protecting group; B is a direct bond, Ci-Cs alkylene or C2-C5 alkenylene; R1 is C1-C5alkyl, C2-C5alkenyl or C3-C7cycloalkyl-C1-C3alkyl; R2 is hydroxyl or C1-C5 alkoxy; R3 is Hydrogen, hydroxyl or Ci-C5 alkoxy; and R * is hydrogen, phenyl, heteroaryl selected from furyl, thienyl and pyrrolyl, phenyl and heteroaryl being optionally substituted with one to five substituents selected from halogen, hydroxyl, Ci-C3 alkyl, Ci-C3 alkoxy and C2-C5 alkenyl; pharmaceutical compositions and the use of said compounds in the preparation of said compositions to be used as analgesics, antiinflammatories, diuretics, anesthetics or neuroprotective agents, or an agent for fulminating attack or treatment of diseases of the intestine functioning such as abdominal pain, for treatment of a mammalian subject, especially a human being. 5 i « EA / MG / 33 / elt- * rnrnm * mvs * -l grn P97 / 992