Claims for Patent: 9,447,108

Summary for Patent: 9,447,108

Title:	Deuterated morphine derivatives
Abstract:	The invention relates to new morphine derivatives deuterated at the 7,8-position of the morphine ring, furthermore to a process for the preparation thereof, and to pharmaceutical compositions comprising them. The new deuterated morphine derivatives show high and selective .mu.-opioid receptor binding activity leading to the benefit of higher analgesic activity at lower dosages inducing thereby reduced adverse effects compared to the hydrogenated derivatives. The compounds of the invention are useful for example in the treatment of pain or can be used as antitussive agents with a reduced risk of the possibility of drug abuse.
Inventor(s):	Fulop; Ferenc (Szeged, HU), Mandity; Istvan (Szeged, HU)
Assignee:	Szegedi Tudomanyegyetem (Szeged, HU)
Application Number:	14/781,116
Patent Claims:	1. A compound of general formula (I) ##STR00003## wherein R.sub.1 is --OH, --OR.sub.4, --O-2,4-dinitrophenyl, --OC(.dbd.O)C.sub.1-6 alkyl, --OC(.dbd.O)phenyl, --OC(.dbd.O)pyridyl; R.sub.2 is hydrogen, --OH, --OR.sub.4, --Cl, --N.sub.3, bis(2-chloroethyl)amino-, --OC(.dbd.O)--C.sub.1-16 alkyl, --OC(.dbd.O)phenyl, --OC(.dbd.O)pyridyl, --(N-methyl-N--C(.dbd.O)--CH.dbd.CH-fur-3-yl), and the dotted line is absent or R.sub.2 is --O, --CH.sub.2, --N--NH.sub.2, --NOH, --N--O--C.sub.1-6alkyl wherein the alkyl is optionally substituted with a caboxyl group, and the dotted line represents a chemical bond, R.sub.3 is hydrogen, --O, --C.sub.1-6 alkyl optionally substituted by phenyl, (C.sub.3-7 cycloalkyl)-(C.sub.1-6 alkyl)-, --(C.sub.1-6alkyl)-O--(C.sub.1-6alkyl), --C.sub.2-7 alkenyl; R.sub.4 is --C.sub.1-6 alkyl optionally substituted by a phenyl or by a 6 membered saturated heterocycle attached by a nitrogen and containing at least one more heteroatom selected from O, S and N; R.sub.5 is absent or is --C.sub.1-6 alkyl and the ring nitrogen bears a positive charge, with the proviso that R.sub.5 is not absent when R.sub.2 is .dbd.O; R.sub.6 is hydrogen, --C.sub.1-6 alkyl; X is hydrogen, --OH, --OR.sub.4, --O-cinnamoyl, --NH(C.sub.1-6 alkyl); D is deuterium and stereoisomers including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof, as well as tautomers and salts thereof. 2. The compound of claim 1 wherein R.sub.1 is --OH, --O-methyl, --O-ethyl-, --O-benzyl, --O-(2,4-dinitro)phenyl, --O-acetyl, --O-propionyl, --O-benzoyl, --O--(C.dbd.O)nicotinyl, --O-(2-morpholino)-ethyl; R.sub.2 is --H, --OH, --Cl, bis(2-chloroethyl)amino-, --O-methyl, --O-propionyl, --O-acetyl, --O-benzoyl, --O--(C.dbd.O)nicotinyl, --O--(C.dbd.O)myristyl, --(N-methyl-N--C(.dbd.O)-- --CH.dbd.CH-fur-3-yl) and the dotted line is absent, or R.sub.2 is --CH.sub.2, --O, --N--O--CH.sub.2COOH, --N--NH.sub.2, and the dotted line represents a chemical bond; R.sub.3 is --H, --O, -methyl, cyclopropylmethyl-, phenylethyl-, -pentyl, methoxyethyl-, cyclobutylmethyl-, -allyl; R.sub.4 is --H, -methyl, -ethyl, benzyl; R.sub.5 is -methyl and the ring nitrogen bears a positive charge; R.sub.6 is --H, -methyl; X is hydrogen, --OH, --O-cinnamoyl, --NHpentyl, --O-methyl, --O-ethyl, --O--(CH.sub.2).sub.3-Ph; D is deuterium and stereoisomers including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof, as well as tautomers and salts thereof. 3. The compound of claim 1 selected form the group consisting of (5.alpha.,6.alpha.,7.beta.,8.beta.)-3,6-dihydroxy-4,5-epoxy-17-methyl-(7,- 8-.sup.2H2)-morphinan, (5.alpha.,6.alpha.,7.beta.,8.beta.)-4,5-epoxy-6-hydroxy-3-methoxy-17-meth- yl-(7,8-.sup.2H2)-morphinan, (5.alpha.,6.alpha.,7.beta.,8.beta.)-4,5-epoxy-3-ethoxy-6-hydroxy-17-methy- l-(7,8-.sup.2H2)-morphinan, (5.alpha.,6.alpha.,7.beta.,8.beta.)-3,6-diacetoxy-4,5-epoxy-17-methyl-(7,- 8-2H.sub.2)-morphinan and stereoisomers, enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof, as well as tautomers and salts thereof. 4. A pharmaceutical composition comprising a compound of general formula (I) of claim 1 or stereoisomers including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof, as well as tautomers and salts thereof and one or more pharmaceutically acceptable carriers and/or excipients. 5. A pharmaceutical comprising the compound of general formula (I) according to claim 2. 6. The pharmaceutical composition of claim 4 in the form of capsules, sachets, tablets, powders, granules, drops, syrups, suspensions, emulsions, oral therapeutic systems, soft gelatin capsules, lozenges, bolus, fine granule, powder, couplet, pill, dry syrup, coated preparations including sugarcoated tablets, couplets, film-coated tablets and coated granulated powder, elixir, limonade, extract, drinkable preparation and soft and hard capsule agents filling liquid or semi-solid substance, multi-layer granules, multi-layer tablets or dry coated tablet, tablets by separating granules, microcapsules, foaming pharmaceutical preparation, chewable preparation, dissolving preparation in the mouth, matrix preparation, solid solutions, lozenges, suppositories, rectal solutions, ready-to-use injectable solution, sterile injectable aqueous or oleaginous suspension, sterile powders, granules, tablets, suppositories, adhesive therapeutic systems, nasal aerosol or inhalation system, ointment, cream, enema formulation, iontophoretic application, coating an implantable medical device. 7. A pharmaceutical composition comprising a compound of general formula (I) of claim 1 or stereoisomers including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof, as well as tautomers and salts thereof in a combination with one or more active agents. 8. The pharmaceutical composition of claim 7 wherein the one or more active agents are selected from the group consisting of antihistamines, calcium channel blockers, sedatives, antiepileptics, anticonvulsant, other opioid agonists and antagonists, NMDA receptor antagonist, benzodiazepines, antiaddictives, phenotiazines, antidepressants, non-steroidal anti-inflammatory drugs, local anesthetics, psychostimulants, psychedelics, anticoagulants, antitussives, glucocorticoids, muscle relaxants, parasympathomimetics, antiemetics, imidazoline receptor agonist, sympathomimetics, .alpha..sub.2-adrenergic receptor agonists, GABA receptor agonists, 5-HT1A agonist, proton pump inhibitors, histamine-2 receptor antagonist, intravenous anesthetics, cannabinoids, antibiotics, inhalational anaesthetics, antihypertensives, centrally acting non-opioid analgesics, stimulants, norepinephrine reuptake inhibitors, estrogen receptor agonists, antipsychotics, TNF inhibitors, expectorants, serotonin-norepinephrine reuptake inhibitors, serotonine receptor antagonists, antitumor agents, nasal decongestants, antihistamines, vitamines antitussives or the pharmaceutical compositions comprising a compound of formula (I) may be co-administered with such agents. 9. The pharmaceutical composition of claim 7 wherein the one or more additional active agents are selected from the group consisting of cyclizine, naltrexone, ethorphine, paracetamol, metamizol sodium, coffein, ephedrine, naloxone, acetylsalicylic acid, ibuprofen, phenacetin, naproxen, indomethacin, diclofenac, promethazine, scopolamine, d,l-methylephedrine, chlorpheniramine, phenyltoloxamine citrate, lyzozime, romifidine, gabapentin, oxycodone, tramadol, ketamine, midazolam, mitragynine, ibogaine, pregabalin, escitalopram, citalopram, pentazocine, nalbuphine, dezocine, butorphanol, buprenorphine, ketorolac, ziconotide, cocaine, heparin, fentanyl, sufentanil, alfentanyl, remifentanil, dextromethorphan, bupivacaine, meperidine, tizanidine, alprazolam, neostigmine, norketamine, droperidol, clonidine, baclofen, lorazepam, nortriptyline, noradrenaline, carbachol, maprotiline, dexmedetomidine, omeprazole, phencyclidine, propofol, .DELTA..sup.9-tetrahydrocannabinol, butamben, lidocaine, nifedipine, prednisone, amitriptyline, chlordiazepoxide, cefazolin, desipramine, serotonin, hydroxyzine, clonazepam, amphetamine, alcohol, acetaminophen, dipyrone, LSD, levomepromazine, diphenhydramine, minocycline, nitrous oxide, methadone, zolpidem, ethylketazocine, lisinopril, captopril, losartan, MDMA, flupirtin, caffeine, methoxetamine, phenobarbital, amfonelic acid, nisoxetine, tamoxifen, cyclazocine, chlorpromazine, cetirizine, ranitidine, trazodone, haloperidol, bupropion, prednisone, etanercept, levobupivacaine, ropivacaine, butalbital, guaifenesin, duloxetine, ondansetron, angiostatin K1-3, DL-.alpha.-difluoromethyl-ornithine, endostatin, fumagillin, genistein, minocycline, staurosporine, (.+-.)-thalidomide, bleomycim, carboplatin, carmustine, chlorambucil, cyclophosphamide, cis-diammineplatinum(II) dichloride (cisplatin), melphalan, mitoxantrone, oxaliplatin (.+-.)-amethopterin (methotrexate), 3-amino-1,2,4-benzotriazine-1,4-dioxide, aminopterin, cytosine .beta.-D-arabinofuranoside, 5-fluoro-5'-deoxyuridine, 5-fluorouracil, ganciclovir, hydroxyurea, mitomycin C, actinomycin D, daunorubicin, doxorubicin, homoharringtonine, idarubicin, S(+)-camptothecin, curcumin, (-)-deguelin, etoposide, formestane, fostriecin, hispidin, 2-imino-1-imidazoli-dineacetic acid (cyclocreatine), mevinolin, trichostatin A, tyrphostin AG 34, tyrphostin AG 879, 5-aza-2'-deoxycytidine, 5-azacytidine, cholecalciferol (Vitamin D3), hydroxytamoxifen, melatonin, mifepristone, raloxifene, all trans-retinal (Vitamin A aldehyde), retinoic acid, all trans (Vitamin A acid), 9-cis-retinoic acid, 13-cis-retinoic acid, retinol (Vitamin A), tamoxifen, troglitazone, colchicine, dolastatin 15, nocodazole, paclitaxel, podophyllotoxin, rhizoxin, vinblastine, vincristine, vindesine, vinorelbine (Navelbine), 17-(allylamino)-17-demethoxygeldanamycin, 4-amino-1,8-naphthalimide, apigenin, brefeldin A, cimetidine, dichloromethylene-diphosphonic acid, leuprolide (Leuprorelin), luteinizing hormone-releasing hormone, pifithrin-.alpha., rapamycin, sex hormone-binding globulin, thapsigargin, urinary trypsin inhibitor fragment (Bikunin), levo-methamphetamine, naphazoline, oxymetazoline, phenylephrine, phenylpropanolamine, propylhexedrine, synephrine, tetrahydrozoline, xylometazoline azelastine, hydroxyzine, desloratadine, cyproheptadine, emadastine, levocabastine, azelastine, carbinoxamine, levocetirizine, fexofenadine, diphenhydramine, brompheniramine, loratadine, clemastine, certirizine, Vitamin A (retinol), Vitamin B1 (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine), Vitamin B7 (biotin), Vitamin B9 (folate), Vitamin B12 (cobalamin), Vitamin C (ascorbic acid), Vitamin D (calciferol), Vitamin E, Vitamin K, alloclamide, chloperastine, tipepidine, sodium dibunate, tipepidine, cloperastine fendizoate, codeine, dihydrocodeine, pentoxyverine, noscapine, carbetapentane, dimemorfan, benproperine, isoaminile, oxeladin, eprazinone, clobutinol, clofedanol, fominoben, I-methylephedrine, trimetoquinol, pseudoephedrine, phenylpropanolamine, methoxyphenamine, ambroxol, bromhexine, isopropamide and salts thereof. 10. The pharmaceutical composition according to claim 7 wherein the one or more active agents are selected from the group consisting of cyclizine, naltrexone, buprenorphine, ethorphine, paracetamol, metamizol, coffein, ephedrine, naloxone, acetylsalicylic acid, ibuprofen, phenacetin, naproxen, indomethacin, diclofenac, promethazine, scopolamine, d,l-methylephedrine, chlorpheniramine, phenyltoloxamine, lyzozime and pharmacologically acceptable salts thereof. 11. The pharmaceutical composition according to claim 7 wherein the additional active agent is administered to a patient simultaneously, separately or sequentially with a compound of the general formula (I). 12. A process for the preparation of compounds of general formula (I) of claim 1 and the salts thereof said process comprising reacting a 7,8-didehydro-morphine derivative of general formula (II) ##STR00004## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and X are defined in claim 1, with deuterium gas in the presence of a catalyst or with organic and inorganic deuteride ion or deuterium radical or deuterium gas sources and optionally transforming the compound obtained into a salt. 13. The process of claim 12 wherein the reaction proceeds in a reactor at a pressure between 2-500 bars, with deuterium gas in the presence of Pd/BaSO.sub.4 catalyst at a temperature range of 20-100.degree. C. in an aprotic solvent. 14. A method for the treatment of pain or cough, said method comprising administering to a patient in need thereof a compound of general formula (I) or stereoisomers including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof, as well as tautomers and salts thereof according to claim 1. 15. The method of claim 14 wherein the compound of general formula (I) or stereoisomers including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof, as well as tautomers and salts thereof is administered orally together with one or more pharmaceutically acceptable carriers and/or excipients. 16. The compound of claim 1 wherein R.sub.2 is hydrogen, --OH, --OR.sub.4, --Cl, --N.sub.3, bis(2-chloroethyl)amino-, --OC(.dbd.O)--C.sub.1-6alkyl, --OC(.dbd.O)phenyl, --OC(.dbd.O)pyridyl, --(N-methyl-N--C(.dbd.O)--CH.dbd.CH-fur-3-yl), and the dotted line is absent or R.sub.2 is --CH.sub.2, --N--NH.sub.2, --NOH, --N--O--C.sub.1-6alkyl wherein the alkyl is optionally substituted with a caboxyl group, and the dotted line represents a chemical bond. 17. The method of claim 14 wherein R.sub.1 is --OH, --O-methyl, --O-ethyl-, --O-benzyl, --O-(2,4-dinitro)phenyl, --O-acetyl, --O-propionyl, --O-benzoyl, --O--(C.dbd.O)nicotinyl, --O-(2-morpholino)-ethyl; R.sub.2 is --H, --OH, --Cl, bis(2-chloroethyl)amino-, --O-methyl, --O-propionyl, --O-acetyl, --O-benzoyl, --O--(C.dbd.O)nicotinyl, --O--(C.dbd.O)myristyl, --(N-methyl-N--C(.dbd.O)-- --CH.dbd.CH-fur-3-yl) and the dotted line is absent, or R.sub.2 is --CH.sub.2, --O, --N--O--CH.sub.2COOH, --N--NH.sub.2, and the dotted line represents a chemical bond; R.sub.3 is --H, --O, -methyl, cyclopropylmethyl-, phenylethyl-, -pentyl, methoxyethyl-, cyclobutylmethyl-, -allyl; R.sub.4 is --H, -methyl, -ethyl, benzyl; R.sub.5 is -methyl and the ring nitrogen bears a positive charge; R.sub.6 is --H, -methyl; X is hydrogen, --OH, --O-cinnamoyl, --NHpentyl, --O-methyl, --O-ethyl, --O--(CH.sub.2).sub.3-Ph; D is deuterium. 18. The method of claim 14 wherein the compound is selected from the group consisting of (5.alpha.,6.alpha.,7.beta.,8.beta.)-3,6-dihydroxy-4,5-epoxy-17-methyl-(7,- 8-.sup.2H2)-morphinan, (5.alpha.,6.alpha.,7.beta.,8.beta.)-4,5-epoxy-6-hydroxy-3-methoxy-17-meth- yl-(7,8-.sup.2H2)-morphinan, (5.alpha.,6.alpha.,7.beta.,8.beta.)-4,5-epoxy-3-ethoxy-6-hydroxy-17-methy- l-(7,8-.sup.2H2)-morphinan, (5.alpha.,6.alpha.,7.beta.,8.beta.)-3,6-diacetoxy-4,5-epoxy-17-methyl-(7,- 8-.sup.2H2)-morphinan and stereoisomers, enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof, as well as tautomers and salts thereof. 19. The method of claim 14 wherein the compound of general formula (I) or stereoisomers, enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof, as well as tautomers and salts thereof is in the form of a pharmaceutical composition in combination with one or more active agents.

Details for Patent 9,447,108

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Immunex Corporation	ENBREL	etanercept	For Injection	103795	11/02/1998		2033-04-15
Immunex Corporation	ENBREL	etanercept	For Injection	103795	05/27/1999		2033-04-15
Immunex Corporation	ENBREL	etanercept	Injection	103795	09/27/2004		2033-04-15
Immunex Corporation	ENBREL	etanercept	Injection	103795	02/01/2007		2033-04-15