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6-(AMINO ACID)-MORPHINAN DERIVATIVES IN COMBINATION WITH PERMEATION ENHANCERS FOR USE AS AN ORALLY, RECTALLY, TRANSDERMALLY OR NASALLY ADMINISTERED MEDICAMENT

20170217976 · 2017-08-03

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to a composition for use in an orally, or rectally, transdermally or nasally administered medicament, characterized in that it includes: (b) at least one compound of Formula (I) and (b) at least one permeation enhancer, selected from the group consisting of saturated and/or unsaturated organic fatty acids, or pharmaceutically and pharmacologically acceptable salts thereof, and thiomers. It further relates to a pharmaceutical formulation comprising said composition. It furthermore relates to bioreversible esters of compounds of Formula (I).

    ##STR00001##

    Claims

    1. Composition for use in an orally, rectally, transdermally or nasally administered medicament, the composition comprising: (a) at least one compound of Formula (I) ##STR00010## wherein the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 have the following meaning: R.sub.1 is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; R.sub.2 is selected from hydrogen, C.sub.1-C.sub.6-alkyl; C.sub.1-C.sub.6-monohydroxyalkyl; C.sub.2-C.sub.6-dihydroxyalkyl; C.sub.3-C.sub.6-trihydroxyalkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; R.sub.3 is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl, C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.6-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; R.sub.4 is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; R.sub.5 and R.sub.6, which can be the same or different, provided that not both are hydrogen, and are selected from hydrogen, C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; CH(A)CO.sub.2B, wherein A is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.3-C.sub.10-cycloalkyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; and wherein B is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; phenyl; substituted phenyl; (C.sub.1-C.sub.6-alkyl)CONH.sub.2; CH(A)SO.sub.3B, wherein A and B are defined as above; CH(A)COB1, wherein A is defined as above, and B1 is NH.sub.2; preferably wherein R.sub.5 is as defined above and R.sub.6 is CH(A)CO.sub.2H, wherein A is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.3-C.sub.10-cycloalkyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl. and/or a pharmaceutically acceptable acid addition or base addition salt thereof, wherein the composition further comprises (b) at least one permeation enhancer, selected from the group consisting of saturated and/or unsaturated organic fatty acids, or pharmaceutically and pharmacologically acceptable salts or esters thereof; thiomers; and further organic compounds, selected from acetone; alcohols, glycols and glycerides such as ethanol, caprylic alcohol, propylene glycol; essential oils such as niaouli oil, eucalyptus oil, Alpinia oxyphylla oil, turpentine oil, sweet basil oil, tulsi oil, cardamom oil, peppermint oil, fennel oil, black cumin oil; terpenes such as geraniol, nerol, linalool, limonene, α-terpineol, β-terpineol, γ-terpineol, menthol, carveol, menthone, pulegone, iso-pulegone, piperitone, carvomenthone, carvone, 1,8-cineole, α-thujene, car-3-ene, α-pinene, β-pinene, verbenol, verbenone, verbanone, camphor, fenchone, farnesol, nerolidol, (−)-guaiol, (+)-cedrol, (−)-α-bisabolol, bisabolene, azulenes, (+)-longifolene, (−)-isolongifolol, β-caryphyllene, (+)-aromadendrene, (+)-β-cedrene, phytol, squalene, (+)-limonene, (+)-carvone, (+)-neomenthol, β-caryophyllene oxide, (+)-cedryl acetate; pyrrolidones such as 2-pyrrolidone, 1-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 1-butyl-2-pyrrolidone, 1-hexyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, 1-(2-hydroxyethyl)-2-pyrrolidone; oxazolidinones such as 4-decyloxazolidin-2-one; substituted amino acetates such as dodecyl-N,N-dimethylaminoacetate, dodecyl-2-methyl-2-(N,N-dimethylaminoacetate); azone; surfactants such as sodium lauryl sulphate, cetryltrimethyl ammonium bromide, nonoxynol surfactants, dodecyl betaine, sorbitan monolaureate, polysorbates (e.g. 20, 40, 60, 65, 80), dodecyldimethyl ammoniumpropane sulfate; N,N-dimethyformamide; dimethylsulfoxide, decylmethylsulfoxide; phospholipids such as phosphatidyl glycerol derivatives; cyclodextrin and cyclodextrin complexes; amino acid derivatives such as esters; glucosamine; urea and derivatives; polysaccharides, capsaicin; α-tocopherol; liposomes; invasomes, cyclodextrins such as α-, β- and γ-cyclodextrin, methycyclodextrin, hydroxypropyl β-cyclodextrin, dimethyl-β-cyclodextrin; fusidic acid derivatives such as sodium taurodihydrofusidate, sodium glycodihydrofusidate, sodium phosphate-dihydrofusidate; phosphatidylcholine, didecanoyl-L-α-phosphatidylcholine; bile salts such as sodium cholate, sodium deoxycholate, sodium glycholate, sodium taurocholate, sodium taurodeoxycholate, sodium glycodeoxycholate; starch, degradable starch, soluble starch; dextrane; cellulose; hyaluronic acid esters, as well as mixtures thereof.

    2. Composition according to claim 1, wherein it comprises compound (a) in an amount of 0.001 to 98% by weight, based on the total volume of the composition.

    3. Composition according to claim 1, wherein the at least one permeation enhancer (b) is selected from the group consisting of saturated and/or unsaturated organic fatty acids, or pharmaceutically and pharmacologically acceptable salts or esters thereof, and thiomers.

    4. Composition according to claim 1, wherein the at least one permeation enhancer (b) is selected from the group consisting of capric acid, or a pharmaceutically and pharmacologically acceptable salt thereof, lauric acid, or a pharmaceutically and pharmacologically acceptable salt thereof, Cremophor® EL, PAA.sub.450 and PAA.sub.450-Cys.

    5. Composition according to claim 1, wherein it comprises the at least one permeation enhancer (b) in an amount of 0.01 to 60% by weight, based on the total volume of the composition.

    6. Composition according to claim 1, wherein it comprises at least one pharmaceutically acceptable excipient.

    7. Composition according to claim 1, for the treatment of pain.

    8. Composition according to claim 1, for the treatment of gastric diseases (inflammation of the stomach, gastric ulcers), intestinal diseases, particularly chronic inflammation of the small and large intestines (irritable colon syndrome—colon irritabile, colitis ulcerosa, Morbus Crohn), diarrhea, constipation and ileus; rheumatic diseases such as rheumatoid arthritis, osteoarthritis, arthrosis, spondylosis, lumbago, lupus erythematosus and spondylarthropathy; tumors and cancer; obesity and overweight; hepatic disorders, and liver inflammatory disorders.

    9. Composition according to claim 1, for the withdrawal of drug addiction, such as to opiates, cocaine, alcohol, for the withdrawal of food, buying, Internet, computer, phone and gambling addiction, for the treatment of psychic diseases, psychosis, schizophrenia, stress-related conditions (such as depression and anxiety), eating disorders and for the reduction of food intake in humans.

    10. Pharmaceutical formulation wherein it comprises the composition of claim 1.

    11. Pharmaceutical formulation according to claim 10, wherein it is in the dosage form of an oral strip, a solution, a softgel, a suspension, an emulsion, a syrup, an elixir, a hydrogel, an adhesive gel, a suppository, an enema, a sublingual tablet, a sublingual film, a sublingual spray, a buccal tablet, a buccal patch, a buccal film, a buccal liquid, a buccal semisolid, a buccal spray, a lollipop.

    12. Pharmaceutical formulation according to claim 11, wherein it is in the dosage form of a tablet, a pill, a dragée, a capsule, a softgel capsule.

    13. Pharmaceutical formulation according to claim 12, wherein it further comprises an enteric coating.

    14. Compound of Formula (II) for use in an orally, rectally, transdermally or nasally administered medicament, ##STR00011## wherein the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 have the following meaning: R.sub.1 is selected from hydrogen; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-monohydroxyalkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-dihydroxyalkyl; C3-C30, preferably C3-C12, more preferably C.sub.3-C.sub.6-trihydroxyalkyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.15-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; R.sub.2 is selected from hydrogen; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-monohydroxyalkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-dihydroxyalkyl; C3-C30, preferably C3-C12, more preferably C.sub.3-C.sub.6-trihydroxyalkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is O.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkanoyl; C3-C30, preferably C3-C12, more preferably C.sub.3-C.sub.6-alkenoyl; C3-C30, preferably C3-C12, more preferably C.sub.3-C.sub.6-alkinoyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkanoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkanoyl preferably is C.sub.1-C.sub.6-alkanoyl; C9-C30, preferably C.sub.9-C.sub.16-arylalkenoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenoyl preferably is C.sub.3-C.sub.6-alkenoyl; C9-C30, preferably C.sub.9-C.sub.16-arylalkinoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkinoyl preferably is C.sub.3-C.sub.6-alkinoyl; R.sub.3 is selected from hydrogen; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; alkoxyalkyl, wherein alkoxy is C.sub.1-C.sub.6-alkoxy and alkyl is C.sub.1-C.sub.6-alkyl; CO.sub.2(C.sub.1-C.sub.6-alkyl); CO.sub.2H; CH.sub.2OH; R.sub.4 is selected from hydrogen; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C12, preferably C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkanoyl; C3-C30, preferably C3-C12, more preferably C.sub.3-C.sub.6-alkenoyl; C3-C30, preferably C3-C12, more preferably C.sub.3-C.sub.6-alkinoyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkanoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkanoyl preferably is C.sub.1-C.sub.6-alkanoyl; C9-C30, preferably C.sub.9-C.sub.16-arylalkenoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenoyl preferably is C.sub.3-C.sub.6-alkenoyl; C9-C30, preferably C.sub.9-C.sub.16-arylalkinoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkinoyl preferably is C.sub.3-C.sub.6-alkinoyl; iminomethyl, formamidinyl, C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6—N-alkyl- and N,N′-dialkylformamidinyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6—N-alkenyl- and N,N′-dialkenylformamidinyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6—N-alkynyl- and N,N′-dialkynylformamidinyl; C4-C30, preferably C.sub.4-C.sub.16—N-cycloalkylalkyl- and N,N′-dicycloalkylalkylformamidinyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16—N-cylcoalkylalkenyl- and N,N′-dicycloalkylalkenylformamidinyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16—N-cycloalkylalkynyl- and N,N″-dicycloalkylalkynylformamidinyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.5-alkynyl; C7-C30, preferably C.sub.7-C.sub.16—N-arylalkyl- and N,N′-diarylalkylformamidinyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; R.sub.5 is selected from hydrogen, C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.5-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; CH(A)CO.sub.2B, wherein A is selected from hydrogen; hydroxyl; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; amino; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkylamino; guanidino; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl-CO.sub.2B; C.sub.1-C.sub.6-monohydroxyalkyl; C.sub.2-C.sub.6-dihydroxyalkyl; C.sub.3-C.sub.6-trihydroxyalkyl; C.sub.1-C.sub.6-monoaminoalkyl; C.sub.2-C.sub.6-diaminoalkyl; C.sub.3-C.sub.6-triaminoalkyl; C.sub.1-C.sub.6-alkylguanidino; C.sub.1-C.sub.6-alkylcarboxamide; C.sub.1-C.sub.6-alkylhydroxycarbonyl; C.sub.1-C.sub.6-sulfhydrylalkyl; C.sub.2-C.sub.12-alkylthioalkyl, wherein alkylthio is preferably C.sub.1-C.sub.6 and alkyl is preferably C.sub.1-C.sub.6; and wherein B is selected from hydrogen; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.5-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; phenyl; substituted phenyl; (C.sub.1-C.sub.6-alkyl) CONH.sub.2; (C.sub.1-C.sub.6-alkyl)CONH(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CONH(C.sub.1-C.sub.6-alkyl-CONH.sub.2); (C.sub.1-C.sub.6-alkyl)CONHC(C.sub.1-C.sub.6-alkylOH).sub.3; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl) (heterocyclic ring); (C.sub.1-C.sub.6-alkyl)CONH-heterocyclic ring; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH—C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl) (C.sub.1-C.sub.6-alkyl-CONH.sub.2); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH—C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CONHCO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)CO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)COO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl)CO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)OCO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)OO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)COO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl) CO.sub.2H; (C.sub.1-C.sub.6-alkyl)OCOO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)S(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)SO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)SO.sub.2(C.sub.1-C.sub.6-alkyl); phthalidyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl; CH(A)SO.sub.3B, wherein A and B are defined as above; CH(A)COB1, wherein A is defined as above, and B1 is NH.sub.2; NH—C1-C12, more preferably NH—C.sub.1-C.sub.6-alkyl; N—(C1-C12).sub.2, more preferably N—(C.sub.1-C.sub.6).sub.2-alkyl; R.sub.6 is selected from CH(A)CO.sub.2B, wherein A is defined as above, and wherein B is selected from C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.5-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; phenyl; substituted phenyl; (C.sub.1-C.sub.6-alkyl)CONH.sub.2; (C.sub.1-C.sub.6-alkyl)CONH(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CONH(C.sub.1-C.sub.6-alkyl-CONH.sub.2); (C.sub.1-C.sub.6-alkyl)CONHC(C.sub.1-C.sub.6-alkylOH).sub.3; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl) (heterocyclic ring); (C.sub.1-C.sub.6-alkyl) CONH-heterocyclic ring; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH—C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl) (C.sub.1-C.sub.6-alkyl-CONH.sub.2); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH—C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CONHCO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)CO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl)CO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)OCO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)OO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)COO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl) CO.sub.2H; (C.sub.1-C.sub.6-alkyl)OCOO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)S(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)SO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)SO.sub.2(C.sub.1-C.sub.6-alkyl); phthalidyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl; CH(A)SO.sub.3B, wherein A and B are defined as above; and CH(A)COB1, wherein A is defined as above, and B1 is NH.sub.2; NH—C1-C12, more preferably NH—C.sub.1-C.sub.6-alkyl; N—(C1-C12).sub.2, more preferably N—(C.sub.1-C.sub.6).sub.2-alkyl.

    15. Compound according to claim 14 for the treatment of pain.

    16. Compound according to claim 14, for the treatment of gastric diseases (inflammation of the stomach, gastric ulcers), intestinal diseases, particularly chronic inflammation of the small and large intestines (irritable colon syndrome—colon irritabile, colitis ulcerosa, Morbus Crohn), diarrhea, constipation and ileus; rheumatic diseases such as rheumatoid arthritis, osteoarthritis, arthrosis, spondylosis, lumbago, lupus erythematosus and spondylarthropathy; tumors and cancer; obesity and overweight; hepatic disorders, and liver inflammatory disorders.

    17. Compound according to claim 14, for the withdrawal of drug addiction, such as to opiates, cocaine, alcohol, for the withdrawal of food, buying, Internet, computer, phone and gambling addiction, for the treatment of psychic diseases, psychosis, schizophrenia, stress-related conditions (such as depression and anxiety), eating disorders and for the reduction of food intake in humans.

    Description

    EXAMPLE 1-1: PERMEATION STUDIES OF 2-[(4,5α-EPOXY-3-HYDROXY-14β-METHOXY-17-METHYLMORPHINAN-6β-YL)AMINO]ACETIC ACID DIHYDROCHLORIDE HYDRATE ETHANOLATE (“HS731”) IN THE ABSENCE OF A PERMEATION ENHANCER

    [0140] Ussing type diffusion chambers with a surface area of 0.64 cm.sup.2 were utilized. Rat small intestine was excised immediately after sacrificing the animal and mounted in the chamber. The donor and acceptor compartments of the chamber were filled with 1.0 ml of the freshly prepared incubation medium containing either 40 mM HEPES buffer (HEPES=2-(4-(2-hydroxyethyl)-1-piperazinyl)-ethane sulfonic acid) adjusted to pH 7.5 or 6.5 or 50 mM sodium acetate buffer adjusted to pH 5.5. Permeation studies were performed in an atmosphere of 95% O.sub.2 and 5% CO.sub.2 at 37° C. and were started 15 minutes after the mounting of the tissue. For the determination of the permeability of HS731 (synthesized in accordance with to the procedure described for compound 70 in EP-A1-1762569) the solution in the donor chamber, apical side, was replaced by 1.0 ml incubation medium containing 2 mg of HS731. Over three hours incubation period 100 μl samples were withdrawn from the acceptor chamber at the basolateral side every 30 minutes, and the volume was replaced by the same medium (without HS731) equilibrated to 37° C. The samples were centrifuged at 7,200 g for 5 minutes and the supernatant was analyzed via HPLC. Cumulative corrections were performed for the previously removed samples to determine the total amount permeated. Results of the permeation studies from apical to basolateral side through rat intestinal mucosa displayed a greater permeation of HS731 at pH 7.5 followed by pH 6.5 and pH 5.5. At pH 7.5 HS731 showed the highest permeation (11%) through rat intestinal mucosa. Therefore the permeation studies in the presence of permeation enhancers were performed at pH 7.5.

    EXAMPLE 1-2: PERMEATION STUDIES WITH HS731 AFTER ADDITION OF A PERMEATION ENHANCER

    [0141] The permeation of HS731 was performed using 40 mM HEPES buffer adjusted to pH 7.5 as described in Example 1 in the presence of different permeation enhancers (Table 1-2).

    [0142] The middle chain fatty acid capric acid, the sodium salt of lauric acid and the surfactant Cremophor® EL was added to the donor chamber in a concentration of 1% (m/v) (Table 1-2, entries 1 to 3). Additional results were gathered for the use of the polymer poly(acrylic acid) (PAA.sub.450) as well as its thiol group bearing conjugate poly(acrylic acid)-cysteine (PAA.sub.450-Cys) in a concentration of 0.5% (m/v) (Table 1-2, entries 4 and 5). Finally, capric acid was added in a concentration of 0.25% (m/v) (Table 1-2, entry 6).

    TABLE-US-00002 TABLE 1-2 Exemplary compositions of HS731 and different permeation enhancers. Concentration Active Permeation Entry Composition Compound Permeation Enhancer Enhancer 1 A HS731 Capric Acid   1% (m/v) [Sigma, Austria] 2 B HS731 Cremophor ® EL   1% (m/v) [Fluka, Austria] 3 C HS731 Sodium laureate   1% (m/v) [Fluka, Austria] 4 D HS731 PAA.sub.450 0.5% (m/v) [Sigma, Austria] 5 E HS731 PAA.sub.450-Cys 0.5% (m/v) [ThioMatrix, Austria] 6 F HS731 Capric acid 0.25% (m/v)  [Sigma, Austria]

    [0143] Enhanced permeation was achieved with all permeation enhancers used (Table 1-3). The results show in general a permeation enhancing effect with an enhancement ratio (ER) range from 1.2 to 2.4. Capric acid and Cremophor® EL in a concentration of 1% (m/v) led to a greater permeation of HS731 compared to the other enhancers (Table 1-3, entries 1 and 2). No significant differences between the permeation of HS731 in addition of 0.5% (m/v) PAA.sub.450, 0.5% (m/v) PAA.sub.450-Cys and 0.25% (m/v) capric acid were observed (Table 1-3, entries 3 to 5).

    TABLE-US-00003 TABLE 1-3 Enhancement ratios (ER) for the permeation of HS731 in the presence of different permeation enhancers. Entry Composition Enhancement Ratio (ER) 1 A 2.4 2 B 1.9 3 D 1.8 4 F 1.7 5 E 1.6 6 C 1.2

    EXAMPLE 1-3: FURTHER OPIOID RECEPTOR AGONISTS

    [0144] The c log P and log D values were calculated with MarvinSketch software [http://www.chemaxon.com/products/marvin/marvinsketch/].

    [0145] [.sup.35S]GTPγS binding was performed as described in: M. Spetea et al., J. Med. Chem. 2011, 54, 980-988. Opioid receptor binding was performed as described in: M. Spetea et al., Eur. J. Pharmacol. 2004, 483, 301-308

    TABLE-US-00004 TABLE 1-4 Physiochemical properties and opioid receptor activities of agonists [00003]embedded image [.sup.35S]GTPγS binding, MOR.sup.c R.sub.1 6-NH clog D.sup.a Binding K.sub.i (nM).sup.b EC.sub.50 % Compound (AA) α/β R.sub.2 clog P.sup.a (pH 7.4) MOR DOR KOR (nM) stim..sup.d Morphine OH H 6.55 217 113 36    106 OMO O H 0.85 0.01 0.97 80.5 61.6 4.40  98 14-OMO O Me 1.53 0.56 0.10 4.80 10.2 1.17 127 HS730 Gly α Me −1.68 −2.70 0.89 15.4 43.2 — — HS731 Gly β Me −1.68 −2.70 0.83 7.86 44.8 3.88 107  1 L-Ala α Me −1.12 −2.13 0.77 26.9 142 — —  2 L-Ala β Me −1.12 −2.13 1.90 7.71 63.7 — —  3 L-Phe α Me 0.54 −0.48 0.95 3.67 28.5 0.03 116  4 L-Phe β Me 0.54 −0.48 2.58 1.03 151 — —  5 Gly α Et −1.33 −2.31 0.57 10.3 45.2 — —  6 Gly β Et −1.33 −2.31 0.95 5.31 102 — —  7 Gly α PP 0.77 −0.17 0.19 0.22 0.73 — —  8 Gly β PP 0.77 −0.17 0.16 0.19 0.81 — —  9 L-Tyr α Me 0.24 −0.78 0.83 2.18 39.5 — — 10 L-Tyr β Me 0.24 −0.78 3.20 3.89 186 — — 11 L-Phe α H −0.10 −1.46 2.30 19.0 344 — — 12 L-Phe β H −0.10 −1.46 6.91 8.29 634 — — 13 L-Ala α H −1.76 −3.12 3.00 170 710 — — 14 L-Ala β H −1.76 −3.12 11.0 78.7 542 — — 15 GABA α Me −1.26 −2.29 0.77 12.5 45.6 1.90 113 16 GABA β Me −1.26 −2.29 1.41 6.61 147 — — 17 L-Gln α Me −2.28 −3.29 3.24 5.13 351 — — 18 L-Gln β Me −2.28 −3.29 2.48 4.87 290 — — 19 L-Glu α Me −1.47 −4.37 1.45 9.03 87.2 1.61 105 20 L-Glu β Me −1.47 −4.37 11.6 7.64 1252 — — 21 L-β-Ala α Me −1.44 −2.48 1.30 60.0 182 — — 22 L-β-Ala β Me −1.44 −2.48 1.04 13.9 71.4 — — 23 L-Met α Me −0.46 −1.48 0.93 4.03 109 — — 24 L-Met β Me −0.46 −1.48 3.88 2.40 468 — — 25 Gly-Gly β Me −3.10 −4.14 4.62 7.52 203 — — 26 L-Asn α Me −2.56 −3.56 1.17 3.37 74.0 0.64 109 27 L-Asn β Me −2.56 −3.56 1.26 2.25 103 — — 28 L-Val α Me −0.23 −1.24 3.16 3.91 325 — — 29 L-Val β Me −0.23 −1.24 3.04 3.52 305 — — 30 D-Val α Me −0.23 −1.24 1.70 1.93 202 — — 31 D-Val β Me −0.23 −1.24 1.02 1.68 159 — — 32 L-Val-L-Tyr α Me 0.28 −0.75 0.82 1.19 69.0 — — 33 L-Val-L-Tyr β Me 0.28 −0.75 0.44 1.38 390 — — 34 L-Thr α Me −1.75 −2.76 1.03 4.13 120 — — 35 L-Thr β Me −1.75 −2.76 0.79 5.16 58.6 — — 36 L-Ser α Me −2.16 −3.18 2.21 5.32 196 1.21  96 37 L-Ser β Me −2.16 −3.18 2.14 5.29 152 3.24 101 38 L-Lys α Me −1.25 −4.85 0.19 1.27 12.6 — — 39 L-Lys β Me −1.25 −4.85 0.53 3.34 33.7 — — 40 L-Leu α Me 0.14 −0.88 0.68 2.34 141 — — 41 L-Leu β Me 0.14 −0.88 1.32 1.01 297 — — 42 L-Ile α Me 0.22 −0.80 0.84 3.20 131 — — 43 L-Ile β Me 0.22 −0.80 1.46 1.30 163 — — 44 L-Asp α Me −1.76 −4.65 1.36 14.6 50.2 — — 45 L-Asp β Me −1.76 −4.65 3.42 22.6 351 — — 46 L-Trp β Me 0.64 −0.38 0.65 1.19 8.66 0.61 112 47 L-Abu α Me −0.59 −1.61 0.76 37.5 144 — — 48 L-Abu β Me −0.59 −1.61 1.83 1.30 201 — — 49 L-Chg α Me 0.64 −0.37 1.23 14.3 177 — — 50 L-Chg β Me 0.64 −0.37 1.66 1.30 118 — — 51 D-Phe α Me 0.54 −0.48 0.61 3.69 76.4 — — 52 D-Phe β Me 0.54 −0.48 1.28 1.19 139 — — 53 D-Ala α Me −1.12 −2.13 0.69 10.4 71.5 — — 54 D-Ala β Me −1.12 −2.13 1.48 11.3 142 — — .sup.aCalculated with MarvinSketch software; .sup.bDetermined in in vitro binding assays in rat brain (MOR and DOR) or guinea pig brain (KOR) membranes; .sup.cStimulation of [.sup.35S]GTPγS binding to human MOP expressed in CHO cells; .sup.dMeasured against DAMGO; AA: amino acid residue; OMO: oxymorphone; 14-OMO: 14-O-methyloxymorphone; PP: phenylpropyl; —: not tested; morphine, OMO and 14-OMO are reference compounds;

    [0146] Most of the 6-(amino acid)-morphinans (compounds 1-54, HS730 and HS731) show high binding affinities to the MOR (K.sub.i values in the nanomolar and subnanomolar range), while DOR binding is mostly somewhat lower, and KOR binding in most cases considerably lower. A number of compounds were evaluated for agonist potency and efficacy at the MOR using the [.sup.35S]GTPγS functional assay in CHO cells expressing human MOR receptors. These compounds show high agonist potency and efficacy. According to the calculated log D value, the listed compounds (1-54) have a lipophilicity similar to HS731 and thus addition of a permeation enhancer produces a superior bioavailability after oral, rectal, transdermal and/or nasal administration. In the prior art, satisfactory oral bioavailability has been attributed only to compounds with a c log D value of above 1. (Tetko I. V. and Poda G I, J. Med. Chem. 2004, 47, 5601-5604) Accordingly, the compounds according to embodiment 1 are to be considered as compounds of low bioavailability, which, together with their high hydrophilicity, severely impairs their therapeutic use, as the prior art does not disclose a concept for reaching satisfactory bioavailability for this type of compounds.

    TABLE-US-00005 TABLE 1-5 Ionization constants and octanol-water partition (logP) and distribution (logD) coefficients of selected opioid morphinans logD Compound pK.sub.a logP (pH = 7.4) Morphine.sup.a) 8.15 0.88 0.06 Oxymorphone.sup.a) 8.33 0.67 −0.32 14-O-Methyloxymorphone.sup.a) 8.18 0.60 −0.25 14-Methoxymetopon.sup.a) 8.36 1.12 0.11 HS731 2.4 −0.78 −2.06 35 ND −1.38 ND 15 ND −0.36 ND 38 ND −0.66 ND 45 ND −2.20 ND ND = not determined .sup.a)Data of these compounds have been published: Riba P. et al. Brain Res. Bull. 2010, 81, 178-184

    [0147] Lipophilicity of opioid morphinans was evaluated at 25° C. by determination of partition coefficient (log P) and distribution coefficient (log D) in an immiscible (biphasic) octanol/water medium using the PCA200/Cheqsol instrument (Sirius Analytical Instruments, Sussex, UK). All titrations were performed in 0.15M KCl solution under argon gas. The pKa was determined by the shape of the titration curve and partition coefficients were determined by the shift in titration curve of pK.sub.a in the presence of octanol. The analysis of pH-metric data was performed by RefinementPro software (version 2.0, Sirius, Sussex, UK).

    [0148] The experimentally obtained log P values of 6-amino acid substituted morphinans with a zwitterionic amino acid moiety (such as HS731), which makes them extremely hydrophilic, are considerably lower than for morphine, oxymorphone, 14-O-methyloxymorphone and 14-methoxymetopon. For HS731 an experimentally pKa value of 2.4 and a log D value of −2.06 was found.

    [0149] Morphine has an oral bioavailability of about 40% and is used typically without penetration entrances. Calculated values of hydromorphone, which is structurally closely related to morphine, oxymorphone, 14-O-methyloxymorphone and 14-methoxymetopon, are: c log P 1.62 and pk.sub.a 8.59 (Marvin Sketch). These calculated values of hydromorphone are somewhat higher compared to the experimentally obtained values of the other structurally related compounds, morphine, oxymorphone, 14-O-methyloxymorphone and 14-methoxymetopon.

    [0150] In any case, these values do show that the compounds to be used according to the invention differ vastly with respect to relevant properties from well known compounds used as reference herein.

    EXAMPLE 1-4: OPIOID RECEPTOR ANTAGONISTS

    [0151] The c log P and log D values were calculated with MarvinSketch software [http://www.chemaxon.com/products/marvin/marvinsketch/].

    [0152] [.sup.35S]GTPγS binding was performed as described: M. Spetea et al. Life Sci. 2001, 69, 1775-1782. Opioid receptor binding was performed as described in: M. Spetea et al., Eur. J. Pharmacol. 2004, 483, 301-308

    TABLE-US-00006 TABLE 1-6 Physiochemical properties and opioid receptor activities of antagonists [00004]embedded image [.sup.35S]GTPγS binding, MOR.sup.c R.sub.1 6-NH clog D.sup.a Binding K.sub.i (nM).sup.b EC.sub.50 K.sub.e Compound (AA) α/β R.sub.2 clog P.sup.a (pH 7.4) MOR DOR KOR (nM) (nM).sup.d NTX O — H 1.67 0.13 0.54 14.8 0.81 >10,000 0.59 14-OMe-NTX O — Me 2.31 0.68 0.46 7.88 1.17 >10,000 0.49 14-OEt-NTX O — Et 2.67 0.98 0.35 4.13 0.93 >10,000 0.31 59 L-Phe α H 0.68 −1.36 1.41 3.53 2.65 >10,000 0.25 60 L-Phe β H 0.68 −1.36 1.83 2.79 8.99 >10,000 0.24 61 Gly α Me −0.90 −1.57 0.68 5.15 4.65 >10,000 0.63 62 Gly β Me −0.90 −1.57 1.31 4.76 9.31 >10,000 0.19 63 L-β-Ala α Me −0.66 −1.34 1.35 6.25 7.81 >10,000 0.27 64 L-β-Ala β Me −0.66 −1.34 1.51 8.12 11.7 >10,000 0.96 65 GABA α Me −0.48 −1.16 1.21 10.7 5.31 >10,000 0.94 66 GABA β Me −0.48 −1.16 3.36 10.2 16.8 >10,000 1.06 67 Gly α H −1.55 −3.58 0.88 13.1 2.81 — — 68 L-Val α Me 0.55 −0.11 0.44 0.53 3.34 — — 69 L-Val β Me 0.55 −0.11 0.66 1.35 3.00 — — 70 D-Val α Me 0.55 −0.11 0.62 0.71 3.54 — — 71 D-Val β Me 0.55 −0.11 1.52 0.35 23.0 — — 72 L-Ala β Me −0.33 −1.00 2.13 5.80 11.5 — — 73 L-Asp β Me −0.98 −3.91 2.24 0.64 11.7 — — 74 L-Glu α Me −0.69 −3.63 1.93 3.61 6.66 — — 75 L-Glu β Me −0.69 −3.63 3.35 2.77 12.9 — — 79 L-Abu β Me 0.19 −0.48 3.39 6.20 19.1 — — .sup.aCalculated with MarvinSketch software; .sup.bDetermined in in vitro binding assays in rat brain (MOR and DOR) or guinea pig brain (KOR) membranes; .sup.cStimulation of [.sup.35S]GTPγS binding to human MOP expressed in CHO cells; .sup.dMeasured against DAMGO; AA: amino acid residue; NTX: Naltrexone; 14-OMe-NTX: 14-O-Methylnaltrexone; 14-OEt-NTX: 14-O-Ethylnaltrexone; —: not tested; NTX, 14-OMe-NTX und 14-OEt-NTX are reference compounds.

    [0153] All 6-(amino acid)-morphinans (compounds 55-79) show high binding affinities to the MOR (K.sub.i values in the nanomolar and subnanomolar range), while DOR binding is mostly somewhat lower and KOR binding lower. In the functional assay, [.sup.35S]GTPγS binding at MOR, the 6-(amino acid)-morphinans (compounds 59-66) exhibit antagonist K.sub.e values in the subnanomolar or low nanomolar range, thus proving high antagonism mediated via the MORs.

    Embodiment 2

    [0154] Optimizing the bioavailability of a candidate molecule is a key objective in drug discovery programs. Clearly, compounds exhibiting low oral bioavailability are likely to require high doses to achieve the desired effects, since systematic exposure to the active compound will be limited. Optimal physicochemical properties to allow high transcellular absorption are well established and include a limit on molecular size, hydrogen bonding potential and adequate lipophilicity. Hydrogen bonding groups of an active compound can be masked by addition of another moiety, most commonly an ester in order to increase lipophilicity. Such bioreversible derivatives have considerable higher bioavailability and usually undergo enzymatic cleavage by enzymes to regenerate the parent drug after absorption [K. Beaumont, R. Webster, I. Gardner, K. Dack. Curr. Drug Metab. 2003, 4, 461-485].

    [0155] The above defined object is thus also solved by a compound of Formula (II) for use in an orally, rectally, transdermally or nasally administered medicament,

    ##STR00005##

    [0156] wherein the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 have the following meaning:

    [0157] R.sub.1 is selected from hydrogen; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-monohydroxyalkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-dihydroxyalkyl; C3-C30, preferably C3-C12, more preferably C.sub.3-C.sub.6-trihydroxyalkyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl;

    [0158] R.sub.2 is selected from hydrogen; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-monohydroxyalkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-dihydroxyalkyl; C3-C30, preferably C3-C12, more preferably C.sub.3-C.sub.6-trihydroxyalkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkanoyl; C3-C30, preferably C3-C12, more preferably C.sub.3-C.sub.6-alkenoyl; C3-C30, preferably C3-C12, more preferably C.sub.3-C.sub.6-alkinoyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkanoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkanoyl preferably is C.sub.1-C.sub.6-alkanoyl; C9-C30, preferably C.sub.9-C.sub.16-arylalkenoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenoyl preferably is C.sub.3-C.sub.6-alkenoyl; C9-C30, preferably C.sub.9-C.sub.16-arylalkinoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkinoyl preferably is C.sub.3-C.sub.6-alkinoyl;

    [0159] R.sub.3 is selected from hydrogen; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; alkoxyalkyl, wherein alkoxy is C.sub.1-C.sub.6-alkoxy and alkyl is C.sub.1-C.sub.6-alkyl; CO.sub.2(C.sub.1-C.sub.6-alkyl); CO.sub.2H; CH.sub.2OH;

    [0160] R.sub.4 is selected from hydrogen; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C12, preferably C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkanoyl; C3-C30, preferably C3-C12, more preferably C.sub.3-C.sub.6-alkenoyl; C3-C30, preferably C3-C12, more preferably C.sub.3-C.sub.6-alkinoyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkanoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkanoyl preferably is C.sub.1-C.sub.6-alkanoyl; C9-C30, preferably C.sub.9-C.sub.16-arylalkenoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenoyl preferably is C.sub.3-C.sub.6-alkenoyl; C9-C30, preferably C.sub.9-C.sub.16-arylalkinoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkinoyl preferably is C.sub.3-C.sub.6-alkinoyl; iminomethyl, formamidinyl, C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6—N-alkyl- and N,N′-dialkylformamidinyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6—N-alkenyl- and N,N′-dialkenylformamidinyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6—N-alkynyl- and N,N′-dialkynylformamidinyl; C4-C30, preferably C.sub.4-C.sub.16—N-cycloalkylalkyl- and N,N′-dicycloalkylalkylformamidinyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16—N-cylcoalkylalkenyl- and N,N′-dicycloalkylalkenylformamidinyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16—N-cycloalkylalkynyl- and N,N′-dicycloalkylalkynylformamidinyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16—N-arylalkyl- and N,N′-diarylalkylformamidinyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl;

    [0161] R.sub.5 is selected from hydrogen, C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.5-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl;

    [0162] CH(A)CO.sub.2B, wherein A is selected from hydrogen; hydroxyl; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; amino; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkylamino; guanidino; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl-CO.sub.2B; C.sub.1-C.sub.6-monohydroxyalkyl; C.sub.2-C.sub.6-dihydroxyalkyl; C.sub.3-C.sub.6-trihydroxyalkyl; C.sub.1-C.sub.6-monoaminoalkyl; C.sub.2-C.sub.6-diaminoalkyl; C.sub.3-C.sub.6-triaminoalkyl; C.sub.1-C.sub.6-alkylguanidino; C.sub.1-C.sub.6-alkylcarboxamide; C.sub.1-C.sub.6-alkylhydroxycarbonyl; C.sub.1-C.sub.6-sulfhydrylalkyl; C.sub.2-C.sub.12-alkylthioalkyl, wherein alkylthio is preferably C.sub.1-C.sub.6 and alkyl is preferably C.sub.1-C.sub.6; and wherein B is selected from hydrogen; C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.5-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; phenyl; substituted phenyl; (C.sub.1-C.sub.6-alkyl)CONH.sub.2; (C.sub.1-C.sub.6-alkyl)CONH(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CONH(C.sub.1-C.sub.6-alkyl-CONH.sub.2); (C.sub.1-C.sub.6-alkyl)CONHC(C.sub.1-C.sub.6-alkylOH).sub.3; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)(heterocyclic ring); (C.sub.1-C.sub.6-alkyl)CONH-heterocyclic ring; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH—C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)(C.sub.1-C.sub.6-alkyl-CONH.sub.2); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH—C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CONHCO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)CO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl)CO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)OCO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)OO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)COO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CO.sub.2H; (C.sub.1-C.sub.6-alkyl)OCOO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)S(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)SO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)SO.sub.2(C.sub.1-C.sub.6-alkyl); phthalidyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl;-

    [0163] CH(A)SO.sub.3B, wherein A and B are defined as above;

    [0164] CH(A)COB1, wherein A is defined as above, and B1 is NH.sub.2; NH—C1-C12, more preferably NH—C.sub.1-C.sub.6-alkyl; N—(C1-C12).sub.2, more preferably N—(C.sub.1-C.sub.6).sub.2-alkyl;

    [0165] R.sub.6 is selected from CH(A)CO.sub.2B, wherein A is defined as above, and wherein B is selected from C1-C30, preferably C1-C12, more preferably C.sub.1-C.sub.6-alkyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkenyl; C2-C30, preferably C2-C12, more preferably C.sub.2-C.sub.6-alkynyl; C4-C30, preferably C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C5-C30, preferably C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C7-C30, preferably C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.5-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C8-C30, preferably C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; phenyl; substituted phenyl; (C.sub.1-C.sub.6-alkyl)CONH.sub.2; (C.sub.1-C.sub.6-alkyl)CONH(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CONH(C.sub.1-C.sub.6-alkyl-CONH.sub.2); (C.sub.1-C.sub.6-alkyl)CONHC(C.sub.1-C.sub.6-alkylOH).sub.3; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)(heterocyclic ring); (C.sub.1-C.sub.6-alkyl)CONH-heterocyclic ring; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH—C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)(C.sub.1-C.sub.6-alkyl-CONH.sub.2); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH—C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CONHCO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)CO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)N(C.sub.1-C.sub.6-alkyl)CO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)OCO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)OO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)COO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CO.sub.2H; (C.sub.1-C.sub.6-alkyl)OCOO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)S(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)SO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)SO.sub.2(C.sub.1-C.sub.6-alkyl); phthalidyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl;

    [0166] CH(A)SO.sub.3B, wherein A and B are defined as above; and

    [0167] CH(A)COB1, wherein A is defined as above, and B1 is NH.sub.2; NH—C1-C12, more preferably NH—C.sub.1-C.sub.6-alkyl; N—(C1-C12).sub.2, more preferably N—(C.sub.1-C.sub.6).sub.2-alkyl.

    [0168] Said compounds of Formula (II) may also be designated as “bioreversible esters” of compounds of Formula (I).

    [0169] Bioreversible alkyl esters of 6-(amino acid)-morphinans may be synthesized according to established procedures in the art which may be derived from the experimental part of EP-A1-1762569. Diesters, acyloxyalkyl esters, aryl esters, glycolamide esters, glycolic esters, glycolate esters, aminoethyl esters may be prepared according to established procedures in the art [H. Bundgaard. In: Design of Prodrugs 1985; H. Bundgaard, N. M. Nielsen. Int. J. Pharmaceutics 1988, 43, 101-110; N. M. Nielsen, H. Bundgaard. J. Pharm. Sciences 1988, 77, 285-298; N. M. Nielsen, H. Bundgaard. J. Med. Chem. 1989, 32, 727-734].

    [0170] The nitrogen of Formula (II), to which R.sub.1 is attached, may also be substituted by two substituents R.sub.1, which may be the same or different and which are defined as above, and wherein the second, quarternised substituent R.sub.1 may additionally be hydroxyl, oxyl (N-oxide) and alkoxyl.

    [0171] The term “bioavailability” as used herein has the same meaning as defined for Embodiment 1.

    [0172] The term “absorption” as used herein has the same meaning as defined for Embodiment 1.

    [0173] The terms “oral administration”, “rectal administration”, “transdermal administration” and “nasal administration” as used herein have the same meaning as defined for Embodiment 1.

    [0174] It was surprisingly found herein that compounds according to Formula (II) have an increased bioavailability which allows a reduced administration frequency and/or a reduced dosage of the drug upon administration which significantly contributes to patient compliance and patient satisfaction.

    [0175] In a preferred embodiment, which may be combined with any of the embodiments described herein, the compound of Formula (II) according to Embodiment 2 is used in an orally, rectally or nasally administered medicament. In a more preferred embodiment, the compound of Formula (II) according to Embodiment 2 is used in an orally or rectally administered medicament.

    [0176] The dotted line between carbon atoms 7 and 8 of Formula (II) designates that these carbon atoms may be unsaturated (olefinic C—C double bond between C7 and C8) or saturated (C—C single bond between C7 and C8).

    [0177] Some compounds according to Formula (II) may exist in different stereochemical configurations and/or may show more than one crystalline structure, in particular the compounds possessing one or more chiral carbon atom. Embodiment 2 comprises all those specific embodiments, such as diastereomers, enantiomers, in any given or desired mixture or in isolated form. Furthermore, compounds according to Formula (II) also comprise PEGylated derivatives, poly-L-glutamic acid (PGA) conjugates, N-(2-hydroxypropyl)methacrylamide (HMPA) copolymers, and other polymer conjugates or derivatives thereof as well as polymorphic forms.

    [0178] The terms “alkyl”, “alkenyl” and “alkynyl” as used herein include both branched and unbranched alkyl, alkenyl and alkynyl groups as well as mono-, di- and trihydroxy-substituted branched and unbranched alkyl, alkenyl and alkynyl groups. These groups furthermore may be substituted once, twice or three times with substituents selected independently from hydroxy, halogen, nitro, cyano, thiocyanato, trifluoromethyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, CO.sub.2H, CONH.sub.2, CO.sub.2(C.sub.1-C.sub.3-alkyl), CONH(C.sub.1-C.sub.3-alkyl), CON(C.sub.1-C.sub.3-alkyl).sub.2, CO(C.sub.1-C.sub.3-alkyl); amino; (C.sub.1-C.sub.3-monoalkyl)amino, (C.sub.1-C.sub.3-dialkyl)amino, C.sub.5-C.sub.6-cycloalkylamino; (C.sub.1-C.sub.3-alkanoyl)amido, SH, SO.sub.3H, SO.sub.3(C.sub.1-C.sub.3-alkyl), SO.sub.2(C.sub.1-C.sub.3-alkyl), SO(C.sub.1-C.sub.3-alkyl), C.sub.1-C.sub.3-alkylthio or C.sub.1-C.sub.3-alkanoylthio. Further suitable substituents are cyclic groups, including carbocycles and heterocycles which may be saturated, unsaturated or aromatic. Preferred examples comprise from 3 to 8 ring atoms, selected from C, N, O, and S. Aryl can be unsubstituted or mono-, di- or tri-substituted, wherein the substituents can be chosen independently from hydroxy, halogen, nitro, cyano, thiocyanato, trifluoromethyl, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy, CO.sub.2H, CONH.sub.2, CO.sub.2(C.sub.1-C.sub.3-alkyl), CONH(C.sub.1-C.sub.3-alkyl), CON(C.sub.1-C.sub.3-alkyl).sub.2, CO(C.sub.1-C.sub.3-alkyl); amino; (C.sub.1-C.sub.3-monoalkyl)amino, (C.sub.1-C.sub.3-dialkyl)amino, C.sub.5-C.sub.6-cycloalkylamino; (C.sub.1-C.sub.3-alkanoyl)amido, SH, SO.sub.3H, SO.sub.3(C.sub.1-C.sub.3-alkyl), SO.sub.2(C.sub.1-C.sub.3-alkyl), SO(C.sub.1-C.sub.3-alkyl), C.sub.1-C.sub.3-alkylthio or C.sub.1-C.sub.3-alkanoylthio. Further suitable substituents are cyclic groups, including carbocycles and heterocycles which may be saturated unsaturated or aromatic. Preferred examples comprise from 3 to 8 ring atoms, selected from C, N, O, and S.

    [0179] The term “aryl” as used herein defines aromatic rings comprising preferably from 5 to 14 ring atoms and the term aryl comprises furthermore carboxylic aryl groups as well as heterocyclic aryl groups, comprising preferably from 1 to 3 heteroatoms, selected from N, O and S. The aryl groups as defined herein may furthermore be fused ring systems such as naphthyl or anthracenyl or the corresponding heterocyclic groups comprising from 1 to 3 heteroatoms selected from N, O, and S.

    [0180] The above definitions for “alkyl”, “alkenyl”, “alkynyl” and “aryl” are valid for all embodiments of Embodiment 2.

    [0181] In a preferred embodiment of the compound according to Embodiment 2, which may be combined with any of the preceding and following embodiments, the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 of the compound of Formula (II) have the following meaning:

    [0182] R.sub.1 is selected from hydrogen; C.sub.1-C.sub.12-alkyl; C.sub.2-C.sub.12-alkenyl; C.sub.2-C.sub.12-alkynyl; C.sub.1-C.sub.12-monohydroxyalkyl; C.sub.2-C.sub.12-dihydroxyalkyl; C.sub.3-C.sub.12-trihydroxyalkyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl;

    [0183] R.sub.2 is selected from hydrogen; C.sub.1-C.sub.12-alkyl; C.sub.1-C.sub.12-monohydroxyalkyl; C.sub.2-C.sub.12-dihydroxyalkyl; C.sub.3-C.sub.12-trihydroxyalkyl; C.sub.2-C.sub.12-alkenyl; C.sub.2-C.sub.12-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl;

    [0184] R.sub.3 is selected from hydrogen; C.sub.1-C.sub.12-alkyl; C.sub.2-C.sub.12-alkenyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; alkoxyalkyl, wherein alkoxy is C.sub.1-C.sub.6-alkoxy and alkyl is C.sub.1-C.sub.6-alkyl;

    [0185] R.sub.4 is selected from hydrogen; C.sub.1-C.sub.12-alkyl; C.sub.2-C.sub.12-alkenyl; C.sub.2-C.sub.12-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.2-C.sub.12-alkanoyl; C.sub.3-C.sub.12-alkenoyl; C.sub.3-C.sub.12-alkinoyl; C.sub.7-C.sub.16-arylalkanoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkanoyl preferably is C.sub.1-C.sub.6-alkanoyl; C.sub.9-C.sub.16-arylalkenoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenoyl preferably is C.sub.3-C.sub.6-alkenoyl; C.sub.9-C.sub.16-arylalkinoyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkinoyl preferably is C.sub.3-C.sub.6-alkinoyl;

    [0186] R.sub.5 is selected from hydrogen, C.sub.1-C.sub.12-alkyl; C.sub.2-C.sub.12-alkenyl; C.sub.2-C.sub.12-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl;

    [0187] CH(A)CO.sub.2B, wherein A is selected from hydrogen; hydroxyl; C.sub.1-C.sub.12-alkyl; C.sub.2-C.sub.12-alkenyl; C.sub.2-C.sub.12-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; amino; C.sub.1-C.sub.6-alkylamino; guanidino; C.sub.1-C.sub.6-alkyl-CO.sub.2B; C.sub.1-C.sub.6-monohydroxyalkyl; C.sub.2-C.sub.6-dihydroxyalkyl; C.sub.3-C.sub.6-trihydroxyalkyl; C.sub.1-C.sub.6-monoaminoalkyl; C.sub.2-C.sub.6-diaminoalkyl; C.sub.3-C.sub.6-triaminoalkyl; C.sub.1-C.sub.6-alkylguanidino; C.sub.1-C.sub.6-alkylcarboxamide; C.sub.1-C.sub.6-alkylhydroxycarbonyl; C.sub.1-C.sub.6-sulfhydrylalkyl; C.sub.2-C.sub.12-alkylthioalkyl, wherein alkylthio is preferably C.sub.1-C.sub.6 and alkyl is preferably C.sub.1-C.sub.6; and wherein B is selected from hydrogen; C.sub.1-C.sub.12-alkyl; C.sub.2-C.sub.12-alkenyl; C.sub.2-C.sub.12-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; phenyl; substituted phenyl; (C.sub.1-C.sub.6-alkyl)CONH.sub.2; (C.sub.1-C.sub.6-alkyl)CONH(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CONH(C.sub.1-C.sub.6-alkyl-CONH.sub.2); (C.sub.1-C.sub.6-alkyl)CONHC(C.sub.1-C.sub.6-alkylOH).sub.3; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl)(heterocyclic ring); (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH).sub.2; (C.sub.1-C.sub.6-alkyl)CON(C.sub.1-C.sub.6-alkyl-OH—C.sub.1-C.sub.6-alkyl).sub.2; (C.sub.1-C.sub.6-alkyl)COO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)CO.sub.2H; (C.sub.1-C.sub.6-alkyl)OCOO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)S(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)SO(C.sub.1-C.sub.6-alkyl); (C.sub.1-C.sub.6-alkyl)SO.sub.2(C.sub.1-C.sub.6-alkyl); phthalidyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl;

    [0188] CH(A)SO.sub.3B, wherein A and B are defined as above;

    [0189] CH(A)COB1, wherein A is defined as above, and B1 is NH.sub.2; NH—C1-C12, more preferably NH—C.sub.1-C.sub.6-alkyl; N—(C1-C12).sub.2, more preferably N—(C.sub.1-C.sub.6).sub.2-alkyl;

    [0190] R.sub.6 is CH(A)CO.sub.2B, wherein A is selected from hydrogen; hydroxyl; C.sub.1-C.sub.12-alkyl; C.sub.2-C.sub.12-alkenyl; C.sub.2-C.sub.12-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.3-C.sub.10-cycloalkyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.1-C.sub.6-monohydroxyalkyl; C.sub.2-C.sub.6-dihydroxyalkyl; C.sub.3-C.sub.6-trihydroxyalkyl; C.sub.1-C.sub.6-monoaminoalkyl; C.sub.2-C.sub.6-diaminoalkyl; C.sub.3-C.sub.6-triaminoalkyl; C.sub.1-C.sub.6-alkylguanidino; C.sub.1-C.sub.6-alkylcarboxamide; C.sub.1-C.sub.6-alkylhydroxycarbonyl; C.sub.1-C.sub.6-sulfhydrylalkyl; C.sub.2-C.sub.12-alkylthioalkyl, wherein alkylthio is preferably C.sub.1-C.sub.6 and alkyl is preferably C.sub.1-C.sub.6; and wherein B is selected from C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; phenyl; substituted phenyl; CH.sub.2CH.sub.2N—(C.sub.1-C.sub.6-alkyl).sub.2; CH.sub.2CON—(C.sub.1-C.sub.6-alkyl).sub.2.

    [0191] In an alternative preferred embodiment of the compound according to Embodiment 2, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are defined as above, with the difference that R.sub.2 is not hydrogen.

    [0192] In a more preferred embodiment of Embodiment 2, the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 of compound of Formula (II) have the following meaning:

    [0193] R.sub.1 is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl;

    [0194] R.sub.2 is selected from hydrogen, C.sub.1-C.sub.6-alkyl; C.sub.1-C.sub.6-monohydroxyalkyl; C.sub.2-C.sub.6-dihydroxyalkyl; C.sub.3-C.sub.6-trihydroxyalkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl;

    [0195] R.sub.3 is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl, C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl;

    [0196] R.sub.4 is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl;

    [0197] R.sub.5 is selected from hydrogen, C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; CH(A)CO.sub.2B, wherein A is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.3-C.sub.10-cycloalkyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; and wherein B is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl;

    [0198] CH(A)SO.sub.3B, wherein A and B are defined as above;

    [0199] CH(A)COB1, wherein A is defined as above, and B1 is NH.sub.2;

    [0200] R.sub.6 is CH(A)CO.sub.2B, wherein A is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.3-C.sub.10-cycloalkyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; and wherein B is selected from C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; phenyl; substituted phenyl; CH.sub.2CH.sub.2N—(C.sub.1-C.sub.6-alkyl).sub.2; CH.sub.2CON—(C.sub.1-C.sub.6-alkyl).sub.2.

    [0201] In an alternative more preferred embodiment of the compound according to Embodiment 2,

    [0202] R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are defined as above, with the difference that R.sub.2 is not hydrogen.

    [0203] In an even more preferred embodiment of Embodiment 2, the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 of compound of Formula (II) have the following meaning:

    [0204] R.sub.1 is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl;

    [0205] R.sub.2 is selected from hydrogen, C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl;

    [0206] R.sub.3 is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl;

    [0207] R.sub.4 is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C2-C6-alkynyl;

    [0208] R.sub.5 is selected from hydrogen, C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.5-C.sub.16-cycloalkylalkenyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.5-C.sub.16-cycloalkylalkynyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl;

    [0209] CH(A)CO.sub.2B, wherein A is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; and wherein B is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.8-C.sub.16-arylalkenyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkenyl preferably is C.sub.2-C.sub.6-alkenyl; C.sub.8-C.sub.16-arylalkynyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkynyl preferably is C.sub.2-C.sub.6-alkynyl; phenyl; substituted phenyl;

    [0210] R.sub.6 is CH(A)CO.sub.2B, wherein A is selected from hydrogen; C.sub.1-C.sub.6-alkyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; C.sub.4-C.sub.16-cycloalkylalkyl, wherein cycloalkyl preferably is C.sub.3-C.sub.10-cycloalkyl and alkyl preferably is C.sub.1-C.sub.6-alkyl; and wherein B is selected from and wherein B is selected from C.sub.1-C.sub.6-alkyl; C.sub.2-C.sub.6-alkenyl; C.sub.2-C.sub.6-alkynyl; C.sub.7-C.sub.16-arylalkyl, wherein aryl preferably is C.sub.6-C.sub.10-aryl and alkyl preferably is C.sub.1-C.sub.6-alkyl; phenyl substituted phenyl; CH.sub.2CH.sub.2N—(C.sub.1-C.sub.6-alkyl).sub.2; CH.sub.2CON—(C.sub.1-C.sub.6-alkyl).sub.2.

    [0211] In an alternative even more preferred embodiment of the compound according to Embodiment 2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are defined as above, with the difference that R.sup.2 is not hydrogen.

    [0212] Further preferred embodiments of the compound of Embodiment 2 are shown in Table 2-1.

    TABLE-US-00007 TABLE 2-1 Further preferred embodiments of compounds according to Formula (II) Further preferred Particularly preferred Most preferred R.sub.1 C1-C6-alkyl, methyl, ethyl, 2- methyl, C1-C6-alkenyl, C.sub.4-C.sub.16- phenylethyl, cyclopropylmethyl, or cycloalkylalkyl, or C.sub.7- cyclopropylmethyl or allyl C.sub.16-arylalkyl allyl R.sub.2 as defined above for C1-C6-alkyl, particularly Methyl, ethyl, benzyl the even more methyl, ethyl and or preferred embodiment (substituted) propyl; 3-phenylpropyl or the alternative even arylalkyl as defined more preferred above for the even embodiment, with the more preferred preference that R.sub.2 is embodiment not a group which forms an ester with O R.sub.3 hydrogen, hydrogen, methyl, and hydrogen C1-C6-alkyl or C7- benzyl C16-arylalkyl R.sub.4 hydrogen, hydrogen, methyl or hydrogen C1-C6-alkyl or C2-C6- propargyl alkynyl R.sub.5 as defined above for hydrogen, C1-C6 alkyl, hydrogen the even more C.sub.7-C.sub.16-arylalkyl, C.sub.4-C.sub.16- preferred embodiment cycloalkylalkyl R.sub.6 as defined above for CH(A)CO.sub.2B, wherein A CH(A)CO.sub.2B, wherein the even more is hydrogen; C1-C6- A is hydrogen and preferred embodiment alkyl; C4-C16- C1-C6-alkyl, and B is cycloalkylalkyl, C.sub.7-C.sub.16- C1-C6-alkyl, arylalkyl; and B is C1- CH.sub.2CH.sub.2N(CH.sub.3).sub.2, or C6-alkyl, phenyl, CH.sub.2CON—(C.sub.2H.sub.5).sub.2 substituted phenyl, CH.sub.2CH.sub.2N—(C.sub.1-C.sub.6-alkyl).sub.2 or CH.sub.2CON—(C.sub.1-C.sub.6-alkyl).sub.2 Configuration α, β α, β α, β C6 Connectivity C—C single bond, C—C single bond C—C single bond C7-C8 C—C double bond

    [0213] All preferred embodiments for compounds according to Formula (II) as described above and in Table 2-1 may be combined with one another as well as with all the preceding and following embodiments of Embodiment 2. Also all alternative embodiments for compounds according to Formula (II) may be combined with one another as well as with all the preceding and following embodiments of Embodiment 2.

    [0214] In a particularly preferred embodiment, R.sub.1 and R.sub.2 of compounds according to Formula (II) represent alkyl at the same time, in particular methyl. In an alternative particularly preferred embodiment, R.sub.1 represents cycloalkylalkyl, in particular cyclopropylmethyl, and R.sub.2 represents alkyl or arylalkyl, in particular methyl, benzyl or 3-phenylpropyl. Compounds of Formula (II) with this substitution pattern have been found to be particularly suitable for the enhancement of the oral, rectal, transdermal and nasal bioavailability.

    [0215] The compounds of Formula (II) according to Embodiment 2 may be used for the treatment of pain.

    [0216] Specifically, the pain which may be treated by the compound of Formula (II) according to Embodiment 2 comprises acute and chronic pain; pain on the locomotor system such as pain in the neck, back, hip, knee, shoulder; arthritic pain, osteoarthritic pain, or myofacial pain; treatment of complex regional pain syndromes, phantom pain, facial neuralgia, postherpetic neuralgia, rheumatalgia, rheumatic pain, sciatic pain, spinal pain, cancer pain, tumor pain, pain from burns, pain after accidents, pain due to acute and chronic inflammation, visceralgia, headaches such as for example tension headaches, cervically related headache or migraine, pain after central lesions such as for example with paraplegia or thalamic lesions, neuralgic pain such as zoster neuralgia, postzoster neuralgia, ischaemic pain such as angina pectoris or peripheral occlusive arterial disease, postoperative pain, neuropathic pain such as pain with diabetic neuropathy, pain after virus infections or pain after nerve lesions, hyperalgesia, allodynia, idiopathic pain, visceral pain, abdominal pain, and toothache.

    [0217] In particular, the compound of Formula (II) according to Embodiment 2 may be used for the treatment of acute and chronic pain, pain of the locomotor system, arthritic and osteoarthritic pain, cancer and tumor pain, postoperative pain, neuropathic pain, migraine, and inflammatory pain.

    [0218] The compound of Formula (II) according to Embodiment 2 is further suitable for the treatment of gastric diseases (inflammation of the stomach, gastric ulcers), intestinal diseases, particularly chronic inflammation of the small and large intestines (irritable colon syndrome—colon irritabile, colitis ulcerosa, Morbus Crohn), diarrhea, constipation, ileus, post-operative ileus, opioid-induced bowel dysfunction and other gastrointestinal motility disorders; rheumatic diseases such as rheumatoid arthritis, osteoarthritis, arthrosis, spondylosis, lumbago, lupus erythematosus and spondylarthropathy; tumors and cancer; obesity and overweight; hepatic disorders, liver inflammatory disorders, obesity and overweight.

    [0219] Moreover, the compound of Formula (II) according to Embodiment 2 is suitable for the withdrawal of drug addiction, such as to opiates, cocaine or alcohol, for the withdrawal of food, buying, internet, computer, phone and gambling addiction, for the treatment of psychic diseases, psychosis, schizophrenia, stress-related conditions (e.g. depression and anxiety), eating disorders and to reduce food intake in humans.

    [0220] Embodiment 2 also relates to a composition for use in an orally, rectally, transdermally or nasally administered medicament, the composition comprising the compound of Formula (II) and at least one permeation enhancer, which is selected from the group consisting of saturated and/or unsaturated organic fatty acids, or pharmaceutically and pharmacologically acceptable salts or esters thereof; thiomers; and further organic compounds, selected from acetone; alcohols, glycols and glycerides such as ethanol, caprylic alcohol, propylene glycol; essential oils such as niaouli oil, eucalyptus oil, Alpinia oxyphylla oil, turpentine oil, sweet basil oil, tulsi oil, cardamom oil, peppermint oil, fennel oil, black cumin oil; terpenes such as geraniol, nerol, linalool, limonene, α-terpineol, β-terpineol, γ-terpineol, menthol, carveol, menthone, pulegone, iso-pulegone, piperitone, carvomenthone, carvone, 1,8-cineole, α-thujene, car-3-ene, α-pinene, β-pinene, verbenol, verbenone, verbanone, camphor, fenchone, farnesol, nerolidol, (−)-guaiol, (+)-cedrol, (−)-α-bisabolol, bisabolene, azulenes, (+)-longifolene, (−)-isolongifolol, β-caryphyllene, (+)-aromadendrene, (+)-β-cedrene, phytol, squalene, (+)-limonene, (+)-carvone, (+)-neomenthol, β-caryophyllene oxide, (+)-cedryl acetate; pyrrolidones such as 2-pyrrolidone, 1-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 1-butyl-2-pyrrolidone, 1-hexyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, 1-(2-hydroxyethyl)-2-pyrrolidone; oxazolidinones such as 4-decyloxazolidin-2-one; substituted amino acetates such as dodecyl-N,N-dimethylaminoacetate, dodecyl-2-methyl-2-(N,N-dimethylaminoacetate); azone and derivatives thereof; surfactants such as sodium lauryl sulphate, cetryltrimethyl ammonium bromide, nonoxynol surfactants, dodecyl betaine, sorbitan monolaureate, polysorbates (e.g. 20, 40, 60, 65, 80), dodecyldimethyl ammoniumpropane sulfate; N,N-dimethyformamide; dimethylsulfoxide, decylmethylsulfoxide; phospholipids such as phosphatidyl glycerol derivatives; cyclodextrin and cyclodextrin complexes; amino acid derivatives such as esters; glucosamine; urea and derivatives; polysaccharides, capsaicin; α-tocopherol; liposomes; invasomes, cyclodextrins such as α-, β- and γ-cyclodextrin, methycyclodextrin, hydroxypropyl β-cyclodextrin, dimethyl-β-cyclodextrin; fusidic acid derivatives such as sodium taurodihydrofusidate, sodium glycodihydrofusidate, sodium phosphate-dihydrofusidate; phosphatidylcholine and homologs, didecanoyl-L-α-phosphatidylcholine; bile salts such as sodium cholate, sodium deoxycholate, sodium glycholate, sodium taurocholate, sodium taurodeoxycholate, sodium glycodeoxycholate; starch, degradable starch, soluble starch; dextrane; cellulose; hyaluronic acid esters.

    [0221] In a preferred embodiment, which may be combined with any of the preceding or following embodiment, the eat least one permeation enhancer is selected from the group consisting of saturated and/or unsaturated organic fatty acids, or pharmaceutically and pharmacologically acceptable salts thereof, and thiomers.

    [0222] The term “saturated and/or unsaturated organic fatty acid” as used herein has the same meaning as defined in connection with embodiment 1.

    [0223] Examples for saturated organic fatty acids bearing a terminal carboxylic group and a saturated, linear alkyl chain include behenic acid (C22), arachidic acid (C20), stearic acid (C18), palmitic acid (C16), myristic acid (C14), lauric acid (C12), capric acid (C10), and caprylic acid (C8). Examples for unsaturated organic fatty acids with one terminal carboxylic group and a linear alkyl at least one olefinic bond include erucic acid (C22, cis-Δ.sup.13), eicosapentaenoic acid (C20, cis,cis,cis,cis,cis-Δ.sup.5,Δ.sup.8,Δ.sup.11,Δ.sup.14,Δ.sup.17), arachidonic acid (C20, cis,cis,cis,cis-Δ.sup.5,Δ.sup.8,Δ.sup.11,Δ.sup.14), α-linolenic acid (C18, cis,cis,cis-Δ.sup.9,Δ.sup.12,Δ.sup.15), linoelaidic acid (C18, trans,trans-Δ.sup.9,Δ.sup.12), linoleic acid (C18, cis,cis-Δ.sup.9,Δ.sup.12), vaccenic acid (C18, trans-Δ.sup.11), elaidic acid (C18, trans-Δ.sup.9), oleic acid (C18, cis-Δ.sup.9), sapienic acid (C16, cis-Δ.sup.6), palmitoleic acid (C16, cis-Δ.sup.9) myristoleic acid (C14, cis-Δ.sup.9).

    [0224] The aliphatic tail chain of the organic fatty acid may be further substituted such as by alkyl groups, hydroxyl groups and/or carboxyl groups. Examples for saturated and unsaturated fatty acids wherein the aliphatic tail chain bears at least one further substituent are ricinoleic acid and phytanic acid.

    [0225] The substituents of the aliphatic tail chain of the organic fatty acid may also be further substituted. In particular, hydroxyl groups may be polyalkoxylated, for example by reaction with ethylene oxide to form polyethylene glycol ethers resulting in polyalkoxylated saturated and/or unsaturated organic fatty acids. In a preferred embodiment of the composition of Embodiment 2, which may be combined with any of the preceding and following embodiments, the at least one permeation enhancer (component (b)) is a polyalkoxylated saturated and/or unsaturated organic fatty acid. Particularly preferred in this regard is Cremophor® EL Castor Oil by BASF, wherein the major component is polyethoxylated castor oil, which is derived by reacting castor oil with ethylene oxide in a molar ratio of 1:35.

    [0226] A pharmaceutically and pharmacologically acceptable salt of the saturated and/or unsaturated organic fatty acid may be derived from acid or base addition to the fatty acid. In a preferred embodiment of the composition of Embodiment 2, which may be combined with any of the preceding or following embodiments, the pharmaceutically and pharmacologically acceptable salt of the saturated and/or unsaturated organic fatty acid is a metal base addition salt, such as a lithium salt, sodium salt, potassium salt, beryllium salt, magnesium salt, and calcium salt. Particularly preferred is a sodium or potassium salt.

    [0227] The term “thiomer” as used herein has the same meaning as defined in connection with Embodiment 1. Herein, the thiomer is preferably selected from the group consisting of PAA.sub.450 and PAA.sub.450-Cys.

    [0228] It is particularly preferred to provide the compound of Formula (II) in a composition for use in a orally, rectally, transdermally or nasally administered medicament together with at least one permeation enhancer selected from the group consisting of capric acid, or a pharmaceutically and pharmacologically acceptable salt thereof, lauric acid, or a pharmaceutically and pharmacologically acceptable salt thereof, Cremophor® EL, PAA.sub.450 and PAA.sub.450-Cys. Preferably, said composition is used as in orally, rectally or nasally administered medicament, and particularly preferably, said composition is used in an orally or rectally administered medicament.

    [0229] Permeation enhancers, which are particularly suitable for transdermal administration of the composition of Embodiment 2 are selected from acetone; alcohols, glycols and glycerides such as ethanol, caprylic alcohol, propylene glycol; essential oils such as niaouli oil, eucalyptus oil, Alpinia oxyphylla oil, turpentine oil, sweet basil oil, tulsi oil, cardamom oil, peppermint oil, fennel oil, black cumin oil; terpenes such as geraniol, nerol, linalool, limonene, α-terpineol, β-terpineol, γ-terpineol, menthol, carveol, menthone, pulegone, iso-pulegone, piperitone, carvomenthone, carvone, 1,8-cineole, α-thujene, car-3-ene, α-pinene, β-pinene, verbenol, verbenone, verbanone, camphor, fenchone, farnesol, nerolidol, (−)-guaiol, (+)-cedrol, (−)-α-bisabolol, bisabolene, azulenes, (+)-longifolene, (−)-isolongifolol, caryphyllene, (+)-aromadendrene, (+)-β-cedrene, phytol, squalene, (+)-limonene, (+)-carvone, (+)-neomenthol, β-caryophyllene oxide, (+)-cedryl acetate; pyrrolidones such as 2-pyrrolidone, 1-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 1-butyl-2-pyrrolidone, 1-hexyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, 1-(2-hydroxyethyl)-2-pyrrolidone; oxazolidinones such as 4-decyloxazolidin-2-one; substituted amino acetates such as dodecyl-N,N-dimethylaminoacetate, dodecyl-2-methyl-2-(N,N-dimethylaminoacetate); azone and derivatives thereof; surfactants such as sodium lauryl sulphate, cetryltrimethyl ammonium bromide, nonoxynol surfactants, dodecyl betaine, sorbitan monolaureate, polysorbates (e.g. 20, 40, 60, 65, 80), dodecyldimethyl ammoniumpropane sulfate; N,N-dimethyformamide; dimethylsulfoxide, decylmethylsulfoxide; phospholipids such as phosphatidyl glycerol derivatives; cyclodextrin and cyclodextrin complexes; amino acid derivatives such as esters; glucosamine; urea and derivatives; polysaccharides, capsaicin; α-tocopherol; liposomes; invasomes.

    [0230] Permeation enhancers, which are particularly suitable for transdermal administration of the composition of Embodiment 2 are selected from cyclodextrins such as α-, β- and γ-cyclodextrin, methycyclodextrin, hydroxypropyl 3-cyclodextrin, dimethyl-β-cyclodextrin; fusidic acid derivatives such as sodium taurodihydrofusidate, sodium glycodihydrofusidate, sodium phosphate-dihydrofusidate; phosphatidylcholine and homologs, didecanoyl-L-α-phosphatidylcholine; bile salts such as sodium cholate, sodium deoxycholate, sodium glycholate, sodium taurocholate, sodium taurodeoxycholate, sodium glycodeoxycholate; starch, degradable starch, soluble starch; dextrane; cellulose; hyaluronic acid esters; mucoadhesive drug delivery systems.

    [0231] As regards the amounts of the at least one compound of Formula (II) and the at least one permeation enhancer in the composition according to Embodiment 2, the at least one compound of Formula (II) is preferably comprised in an amount of 0.001 to 98% by weight, based on the total volume of the composition (m/v). More preferably, the amount in the composition of Embodiment 2 is 0.01 to 95% by weight, 0.02 to 90% by weight, 0.05 to 80% by weight, 0.06 to 70% by weight, 0.07 to 50% by weight, and 0.09 to 30% by weight, based on the total volume of the composition (m/v). Particularly preferred is an amount of component the compound of Formula (II) of 0.1 to 20% by weight, based on the total volume of the composition (m/v). These preferred embodiments are combinable with any of the preceding and following embodiments.

    [0232] The amount of the at least one permeation enhancer in the composition according to Embodiment 2 is preferably, and in combination with any of the preceding and following embodiments, 0.01 to 60% by weight, based on the total volume of the composition (m/v). More preferred is an amount of 0.05 to 40% by weight, and 0.1 to 30% by weight, based on the total volume of the composition (m/v). Particularly preferred is an amount of 0.2 to 20% by weight of the at least one permeation enhancer, based on the total volume of the composition (m/v).

    [0233] The composition according to Embodiment 2 comprises in a preferred embodiment, which may be combined with any of the preceding and following embodiments, at least one further pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are additional materials used in pharmaceutical compositions in order to bind the pharmaceutically active ingredients into a form suitable for administration. These pharmaceutically acceptable excipients may be selected from the same group as described for embodiment 1 of the present invention.

    [0234] Embodiment 2 also relates to a pharmaceutical formulation comprising compound of Formula (II) according to Embodiment 2 or the composition of Embodiment 2 as described above.

    [0235] For the rectal administration of the compound of Formula (II) or the composition according to Embodiment 2, the pharmaceutical formulation according to Embodiment 2 is preferably in the dosage form of a suppository or an enema.

    [0236] For the sublingual administration of the compound of Formula (II) or the composition according to Embodiment 2, the pharmaceutical formulation according to Embodiment 2 is preferably in the dosage form of a sublingual tablet, a sublingual film, or a sublingual spray.

    [0237] For the buccal administration of the compound of Formula (II) or the composition according to Embodiment 2, the pharmaceutical formulation according to Embodiment 2 is preferably in the dosage form of a buccal tablet, a buccal patch, a buccal film, a buccal liquid, a buccal semisolid, a buccal spray, or a lollipop.

    [0238] For the peroral administration of the compound of Formula (II) or the composition according to Embodiment 2, the pharmaceutical formulation according to Embodiment 2 is preferably in the dosage form of a tablet, a pill, a dragée, a capsule, a softgel capsule.

    [0239] For the transdermal administration of the compound of Formula (II) or the composition according to Embodiment 2, the pharmaceutical formulation according to Embodiment 2 is preferably in the form of a transdermal patch (such as reservoir-type and matrix-type patches), microneedles, sonophoresis, electroporation, electro-osmosis, iontophoresis, iontophoresis patch, short-duration shock waves, photomechanical waves.

    [0240] For the nasal administration of the compound of Formula (II) or the composition according to Embodiment 2, the pharmaceutical formulation according to Embodiment 2 is preferably in the dosage form of a spray (such as liquid spray, powder spray), squirt system or drops.

    [0241] In a particularly preferred embodiment, which may be combined with any of the preceding or following embodiments, the aforementioned tablet, pill, dragée, capsule, or softgel capsule has an enteric coating allowing a controlled release of the compound of Formula (II) by targeting target later segments of the gastrointestinal tract by using an enteric coating known in the art that dissolves at higher pH values.

    [0242] For the transdermal administration of the compound of Formula (II) according to Embodiment 2, the pharmaceutical formulation according to Embodiment 2 is preferably in the dosage form of a transdermal patch (e.g. reservoir-type, matrix-type patches), microneedles, sonophoresis, electroporation, electro-osmosis, iontophoresis, iontophoresis patch, short-duration shock waves, photomechanical waves.

    [0243] For the nasal administration of the compound of Formula (II) or the composition according to Embodiment 2, the pharmaceutical formulation according to Embodiment 2 is preferably in the dosage form of a spray (e.g. liquid, powder), squirt system or drops.

    [0244] The pharmaceutical formulation comprising the compound of Formula (II) or the composition according to Embodiment 2 comprises in a preferred embodiment, which may be combined with any of the preceding or following embodiments, 0.1 to 3,000 mg of compound of Formula (II). In a more preferred embodiment, it comprises 1 to 500 mg of compound of Formula (II), in an even more preferred embodiment 1.5 to 300 mg, and in a particularly preferred embodiment, which may be combined with any of the preceding and following embodiments, 2 to 200 mg of compound of Formula (II).

    [0245] The pharmaceutical formulation comprising the compound according to Formula (II) may be produced in accordance with established procedures known by the person skilled in the art.

    [0246] Embodiment 2 of the present invention shall be further illustrated be the following examples.

    EXAMPLE 2-1: 6-(AMINO ACID)-MORPHINAN OPIOID RECEPTOR AGONISTS AND THEIR ESTER DERIVATIVES (ESTERIFICATION OF THE AMINO ACID CARBOXYL GROUP)

    [0247] The c log P and log D values were calculated with MarvinSketch software [http://www.chemaxon.com/products/marvin/marvinsketch/].

    [0248] Opioid receptor binding was performed as described in: M. Spetea et al., Eur. J. Pharmacol. 2004, 483, 301-308

    TABLE-US-00008 TABLE 2-2 Opioid receptor activities of agonists and their esters [00006]embedded image R.sub.1 6-NH Binding K.sub.i (nM).sup.b Compound (AA) α/β R.sub.2 MOR DOR KOR Morphine OH — H 6.55 217 113 OMO O — H 0.97 80.5 61.6 14-OMO O — Me 0.10 4.80 10.2 HS730 Gly α Me 0.89 15.4 43.2 HS730-Et ester Gly-ester α Me 0.28 0.96 8.57 HS730-t-Bu ester Gly-ester α Me 0.48 0.54 12.1 HS730-nOc ester Gly-ester α Me 1.29 3.23 2.97 HS730-benzyl ester Gly-ester α Me 0.19 0.91 0.47 HS731 Gly β Me 0.83 7.86 44.8 HS731-Et ester Gly-ester β Me 0.74 0.81 21.9 HS731-t-Bu ester Gly-ester β Me 1.30 0.68 56.2 HS731-nOc ester Gly-ester β Me 2.56 2.71 3.87 HS731-benzyl ester Gly-ester β Me 0.29 0.74 2.86  1 L-Ala α Me 0.77 26.9 142  1-t-Bu ester L-Ala-ester α Me 0.29 0.41 11.3  2 L-Ala β Me 1.90 7.71 63.7  2-t-Bu ester L-Ala-ester β Me 1.13 1.36 93.6  3 L-Phe α Me 0.95 3.67 28.5  3-t-Bu ester L-Phe-ester α Me 0.50 0.93 32.5  4 L-Phe β Me 2.58 1.03 151  4-t-Bu ester L-Phe-ester β Me 2.56 2.66 151  5 Gly α Et 0.57 10.3 45.2  5-t-Bu ester Gly-ester α Et 0.20 0.31 15.0  6 Gly β Et 0.95 5.31 102  6-t-Bu ester Gly-ester β Et 0.81 0.57 34.1  7 Gly α PP 0.19 0.22 0.73  7-t-Bu ester Gly-ester α PP 1.40 1.01 1.26  7-Et ester Gly-ester α PP 0.43 0.25 0.44  8 Gly β PP 0.16 0.19 0.81  8-t-Bu ester Gly-ester β PP 1.03 0.92 2.02  8-Et ester Gly-ester β PP 0.37 0.21 0.41  9 L-Tyr α Me 0.83 2.18 39.5  9-t-Bu ester L-Tyr-ester α Me 0.59 0.42 12.3 10 L-Tyr β Me 3.20 3.89 186 10-t-Bu ester L-Tyr-ester β Me 1.53 1.88 184 15 GABA α Me 0.77 12.5 45.6 15-t-Bu ester GABA-ester α Me 0.22 7.99 8.82 16 GABA β Me 1.41 6.61 147 16-t-Bu ester GABA-ester β Me 0.54 1.63 8.79 17 L-Gln α Me 3.24 5.13 351 17-t-Bu ester L-Gln-ester α Me 0.18 0.18 8.97 18 L-Gln β Me 2.48 4.87 290 18-t-Bu ester L-Gln-ester β Me 1.65 1.35 163 19 L-Glu α Me 1.45 9.03 87.2 19-t-Bu ester L-Glu-ester α Me 0.27 0.32 18.3 20 L-Glu β Me 11.6 7.64 1252 20-t-Bu ester L-Glu-ester β Me 1.53 0.19 81.5 21 L-β-Ala α Me 1.30 60.0 182 21-t-Bu ester L-β-Ala-ester α Me 0.31 0.83 13.5 22 L-β-Ala β Me 1.04 13.9 71.4 22-t-Bu ester L-β-Ala-ester β Me 0.35 0.23 7.54 23 L-Met α Me 0.93 4.03 109 23-t-Bu ester L-Met-ester α Me 0.32 0.12 10.5 24 L-Met β Me 3.88 2.40 468 24-t-Bu ester L-Met-ester β Me 1.83 0.81 166 26 L-Asn α Me 1.17 3.37 74.0 26-t-Bu ester L-Asn-ester α Me 0.45 0.33 5.33 27 L-Asn β Me 1.26 2.25 103 27-t-Bu ester L-Asn-ester β Me 0.60 0.66 75.8 28 L-Val α Me 3.16 3.91 325 28-t-Bu ester L-Val-ester α Me 0.25 0.18 10.5 29 L-Val β Me 3.04 3.52 305 29-t-Bu ester L-Val-ester β Me 1.03 0.86 214 30 D-Val α Me 1.70 1.93 202 30-t-Bu ester D-Val-ester α Me 0.11 0.093 22.7 31 D-Val β Me 1.02 1.68 159 31-t-Bu ester D-Val β Me 1.98 0.21 206 32 L-Val-L-Tyr α Me 0.82 1.19 69.0 32-t-Bu ester L-Val-L-Tyr- α Me 0.11 0.17 3.50 ester 33 L-Val-L-Tyr β Me 0.44 1.38 390 33-t-Bu ester L-Val-L-Tyr- β Me 0.14 0.27 24.1 ester 34 L-Thr α Me 1.03 4.13 120 34-t-Bu ester L-Thr-ester α Me 0.20 0.37 9.24 35 L-Thr β Me 0.79 5.16 58.6 35-t-Bu ester L-Thr-ester β Me 0.51 0.65 102 36 L-Ser α Me 2.21 5.32 196 36-t-Bu ester L-Ser-ester α Me 0.20 0.17 6.20 37 L-Ser β Me 2.14 5.29 152 37-t-Bu ester L-Ser-ester β Me 0.60 0.64 83.3 38 L-Lys α Me 0.19 1.27 12.6 38-t-Bu ester L-Lys-ester α Me 0.17 0.092 0.89 39 L-Lys β Me 0.53 3.34 33.7 39-t-Bu ester L-Lys-ester β Me 0.58 0.88 21.4 40 L-Leu α Me 0.68 2.34 141 40-t-Bu ester L-Leu-ester α Me 0.087 0.13 8.07 41 L-Leu β Me 1.32 1.01 297 41-t-Bu ester L-Leu-ester β Me 0.57 0.42 240 42 L-Ile α Me 0.84 3.20 131 42-t-Bu ester L-Ile-ester α Me 1.04 1.00 29.2 43 L-Ile β Me 1.46 1.30 163 43-t-Bu ester L-Ile-ester β Me 2.87 2.12 208 44 L-Asp α Me 1.36 14.6 50.2 44-t-Bu ester L-Asp-ester α Me 0.40 0.20 12.6 45 L-Asp β Me 3.42 22.6 351 45-t-Bu ester L-Asp-ester β Me 2.14 0.40 172 46 L-Trp β Me 0.65 1.19 8.66 46-t-Bu ester L-Trp-ester β Me 0.26 0.36 9.89 .sup.aDetermined in in vitro binding assays in rat brain (MOR and DOR) or guinea pig brain (KOR) membranes; AA: amino acid residue; OMO: oxymorphone; 14-OMO: 14-O-methyloxymorphone; PP: phenylpropyl; morphine, OMO and 14-OMO are reference compounds.

    [0249] All 6-(amino acid)-morphinan esters of compounds 1-10, 15-24, 24-46 and HS730 and HS731 show high binding affinities to the MOR (K.sub.i values in the low nanomolar and subnanomolar range). Some of the esters display comparable binding affinities to both DOR and MOR while for others the DOR binding is somewhat lower. All esters show lower KOR binding compared to binding to the MOR and DOR.

    EXAMPLE 2-2: AGONIST POTENCIES OF HS731 IN THE MOUSE VAS DEFERENS PREPARATION IN COMPARISON TO ITS ETHYL ESTER (HS731-ET ESTER)

    [0250] The mouse vas deferens bioassay was performed as described in: M. Spetea et al., Eur. J. Pharmacol. 2004, 483, 301-308

    TABLE-US-00009 TABLE 2-3 Agonist potencies of HS731 in the mouse vas deferens preparation in comparison to its ethyl ester (HS731-Et ester) Compound IC.sub.50 (nM) DAMGO 76.6 14-OMO 7.76 HS731 7.00 HS731-Et ester 23.8 14-OMO: 14-O-methyloxymorphone; DAMGO and 14-OMO are reference compounds.

    [0251] In mouse vas deferens bioassay, HS731 exhibits a similar high agonist potency compared to its parent compound 14-O-methyloxymorphone, while the ethyl ester of HS731 (HS731-Et ester) is about 3.5 times less potent than HS731.

    EXAMPLE 2-3: ANTINOCICEPTIVE POTENCIES OF HS731 AND ITS ETHYL ESTER (HS731-ET ESTER) IN THE TAIL-FLICK TEST IN RATS AFTER ORAL ADMINISTRATION

    [0252] The rat tail-flick test was performed as described in: S. Furst et. al. J. Pharmacol. Exp. Ther. 2005, 312, 609-618

    TABLE-US-00010 TABLE 2-4 Antinociceptive potencies of HS731 and its ethyl ester (HS731- Et ester) in the tail-flick test in rats after oral administration ED.sub.50 (p.o., mg/kg) Compound 30 min 1 h 2 h 3 h 4 h HS731 21.0 5.52 6.78 6.33 HS731-Et ester >2.5 2.34 0.85 0.71 0.82

    [0253] Surprisingly, the antinociceptive potency of the bioreversible ethyl ester of HS731 (HS731-Et ester) was considerably higher than the parent compound HS731 after oral administration—after 1 h ca. 2-fold, after 2 h ca. 8-fold and after 3 h ca. 9-fold higher. Thus, the oral bioavailability of the bioreversible ethyl ester derivative HS731-Et ester is significantly better than of the parent compound HS731. Despite the fact that in the in vitro mouse vas deferens bioassay, the HS731-Et ester is much less potent than HS731 as an agonist, in vivo it is surprisingly a highly potent agonist in producing an analgesic effect in rats after oral administration.

    EXAMPLE 2-4: PHYSIOCHEMICAL PROPERTIES OF BIOREVERSIBLE ESTERS OF OPIOID AGONISTS

    [0254] The c log P and log D values were calculated with MarvinSketch software [http://www.chemaxon.com/products/marvin/marvinsketch/].

    TABLE-US-00011 TABLE 2-5 Physiochemical properties of bioreversible esters of opioid agonists [00007]embedded image R clogP clogD C.sub.2H.sub.5 1.43 0.36 C(CH.sub.3).sub.3 2.12 1.06 (CH.sub.2).sub.7CH.sub.3 4.17 3.11 Ph 2.73 1.66 CH.sub.2Ph 2.79 1.73 CH.sub.2CON(C.sub.2H.sub.5).sub.2 0.90 −0.15 CH.sub.2N(CH.sub.3).sub.2 1.20 0.13 CH.sub.2OCOOC.sub.2H.sub.5 1.91 0.84 CH.sub.2OCO—C(CH.sub.3).sub.3 2.73 1.66

    [0255] Surprisingly, it was found that all bioreversible esters listed in Table 2-5 exhibit c log P and c log P values which are well suitable for high bioavailability after oral, rectal, transdermal and/or nasal administration.

    EXAMPLE 2-5: 6-(AMINO ACID)-MORPHINAN OPIOID RECEPTOR ANTAGONISTS AND THEIR T-BUTYL ESTER DERIVATIVES (ESTERIFICATION OF THE AMINO ACID CARBOXYL GROUP)

    [0256] The c log P and log D values were calculated with MarvinSketch software [http://www.chemaxon.com/products/marvin/marvinsketch/].

    [0257] Opioid receptor binding was performed as described in: M. Spetea et al., Eur. J. PharmacoL 2004, 483, 301-308

    TABLE-US-00012 TABLE 2-6 Opioid receptor activities of antagonists and their t-butyl esters [00008]embedded image R.sub.1 Binding K.sub.i (nM).sup.b Compound (AA) 6-NH α/β R.sub.2 MOR DOR KOR NTX O — H 0.54 14.8 0.81 14-OMe-NTX O — Me 0.46 7.88 1.17 14-OEt-NTX O — Et 0.35 4.13 0.93 55 L-Phe α Et 0.35 0.70 2.60 55-tBu ester L-Phe-ester α Et 0.63 2.38 4.12 56 L-Phe β Et 1.04 1.76 11.6 56-tBu ester L-Phe-ester β Et 2.00 6.33 17.9 57 L-Phe α Me 0.51 1.17 4.21 57-tBu ester L-Phe-ester α Me 0.68 0.58 1.78 58 L-Phe β Me 1.23 2.02 8.42 58-tBu ester L-Phe-ester β Me 2.41 4.56 13.1 59 L-Phe α H 1.41 3.53 2.65 59-tBu ester L-Phe-ester α H 1.00 2.15 5.00 60 L-Phe β H 1.83 2.79 8.99 60-tBu ester L-Phe-ester β H 5.49 1.12 17.6 61 Gly α Me 0.68 5.15 4.65 61-tBu ester Gly-ester α Me 0.43 0.50 1.41 62 Gly β Me 1.31 4.76 9.31 62-Bu ester Gly-ester β Me 2.66 0.96 8.36 63 L-β-Ala α Me 1.35 6.25 7.81 63-tBu ester L-β-Ala α Me 0.81 2.10 1.41 64 L-β-Ala β Me 1.51 8.12 11.7 64-tBu ester L-β-Ala β Me 1.52 0.91 2.13 65 GABA α Me 1.21 10.7 5.31 65-tBu ester GABA-ester α Me 0.46 2.69 0.60 66 GABA β Me 3.36 10.2 16.8 66-tBu ester GABA-ester β Me 2.13 3.78 2.81 68 L-Val α Me 0.44 0.53 3.34 68-tBu ester L-Val-ester α Me 1.81 0.85 3.13 69 L-Val β Me 0.66 1.35 3.00 69-tBu ester L-Val-ester β Me 1.23 0.70 4.32 70 D-Val α Me 0.62 0.71 3.54 70-tBu ester D-Val-ester α Me 0.63 0.51 18.8 71 D-Val β Me 1.52 0.35 23.0 71-tBu ester D-Val-ester β Me 1.94 0.24 15.2 72 L-Ala β Me 2.13 5.80 11.5 72-tBu ester L-Ala-ester β Me 0.89 0.32 9.68 73 L-Asp β Me 2.24 0.64 11.7 73-tBu ester L-Asp β Me 4.41 1.20 18.2 74 L-Glu α Me 1.93 3.61 6.66 74-tBu ester L-Glu-ester α Me 1.93 0.49 10.4 75 L-Glu β Me 3.35 2.77 12.9 75-tBu ester L-Glu-ester β Me 3.34 1.50 11.6 76 L-Leu α Me 0.72 2.20 7.87 76-tBu ester L-Leu α Me 0.13 0.092 0.80 77 L-Leu β Me 1.96 1.13 11.0 77-tBu ester L-Leu β Me 0.13 0.094 0.68 78 L-Ile β Me 1.62 1.44 9.49 78-tBu ester L-Ile β Me 0.98 0.52 5.67 .sup.aCalculated with MarvinSketch software; .sup.bDetermined in in vitro binding assays in rat brain (MOR and DOR) or guinea pig brain (KOR) membranes; AA: amino acid residue; NTX: Naltrexone; 14-OMe-NTX: 14-O-Methylnaltrexone; 14-OEt-NTX: 14-O-Ethylnaltrexone; NTX, 14-OMe-NTX und 14-OEt-NTX are reference compounds.

    [0258] All 6-(amino acid)-morphinan t-butyl esters of compounds 55-66 and 68-78 show high binding affinities to the MOR (K.sub.i values in the low nanomolar and subnanomolar range). Some of the esters display comparable binding affinities to both DOR and MOR while for others the DOR binding is somewhat lower. All esters show lower KOR binding compared to binding to the MOR and DOR.

    EXAMPLE 2-6: PHYSIOCHEMICAL PROPERTIES OF BIOREVERSIBLE ESTERS OF OPIOID ANTAGONISTS

    [0259] The c log P and log D values were calculated with MarvinSketch software [http://www.chemaxon.com/products/marvin/marvinsketch/].

    TABLE-US-00013 TABLE 2-7 Physiochemical properties of bioreversible esters of opioid antagonists [00009]embedded image R clogP clogD C.sub.2H.sub.5 2.21 1.50 C(CH.sub.3).sub.3 2.90 2.19 (CH.sub.2).sub.7CH.sub.3 4.95 4.24 Ph 3.51 2.80 CH.sub.2Ph 3.58 2.86 CH.sub.2CON(C.sub.2H.sub.5).sub.2 1.68 0.98 CH.sub.2N(CH.sub.3).sub.2 1.98 1.27 CH.sub.2OCOOC.sub.2H.sub.5 2.69 1.98 CH.sub.2OCO—C(CH.sub.3).sub.3 3.51 2.80

    [0260] Surprisingly, it was found that all bioreversible esters listed in Table 2-7 exhibit c log P and c log D values which are well suitable for high bioavailability after oral, rectal, transdermal and/or nasal administration.