MXPA96005604A - New agonis compounds - Google Patents
New agonis compoundsInfo
- Publication number
- MXPA96005604A MXPA96005604A MXPA/A/1996/005604A MX9605604A MXPA96005604A MX PA96005604 A MXPA96005604 A MX PA96005604A MX 9605604 A MX9605604 A MX 9605604A MX PA96005604 A MXPA96005604 A MX PA96005604A
- Authority
- MX
- Mexico
- Prior art keywords
- carbon atoms
- alkyl
- aryl
- formula
- compounds
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 112
- 241001514645 Agonis Species 0.000 title 1
- 239000011780 sodium chloride Substances 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 7
- 238000002560 therapeutic procedure Methods 0.000 claims abstract 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 314
- 125000000217 alkyl group Chemical group 0.000 claims description 150
- 125000003118 aryl group Chemical group 0.000 claims description 100
- 125000003545 alkoxy group Chemical group 0.000 claims description 48
- -1 nitro, cyano, thiocyanato Chemical group 0.000 claims description 35
- 125000003342 alkenyl group Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 20
- 125000001589 carboacyl group Chemical group 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 14
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 14
- 150000002431 hydrogen Chemical group 0.000 claims description 13
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- HKOOXMFOFWEVGF-UHFFFAOYSA-N Phenylhydrazine Chemical class NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims description 11
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 11
- 230000000202 analgesic Effects 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000004423 acyloxy group Chemical group 0.000 claims description 10
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 201000002674 obstructive nephropathy Diseases 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 6
- 150000001350 alkyl halides Chemical class 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical class [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 claims description 6
- RFMQOHXWHFHOJF-UHFFFAOYSA-N cyano thiocyanate Chemical compound N#CSC#N RFMQOHXWHFHOJF-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- UOKZUTXLHRTLFH-UHFFFAOYSA-N O-phenylhydroxylamine Chemical class NOC1=CC=CC=C1 UOKZUTXLHRTLFH-UHFFFAOYSA-N 0.000 claims description 5
- 229910006069 SO3H Inorganic materials 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000005907 alkyl ester group Chemical group 0.000 claims description 5
- 125000004429 atoms Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 5
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 5
- 150000008050 dialkyl sulfates Chemical class 0.000 claims description 5
- 229940067157 phenylhydrazine Drugs 0.000 claims description 5
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 5
- FQXXSQDCDRQNQE-VMDGZTHMSA-N Thebaine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 FQXXSQDCDRQNQE-VMDGZTHMSA-N 0.000 claims description 4
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 238000003776 cleavage reaction Methods 0.000 claims description 4
- 230000000875 corresponding Effects 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- SCKXCAADGDQQCS-UHFFFAOYSA-N performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 229930003945 thebaine Natural products 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
- 230000036407 pain Effects 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000005977 3-phenylpropyloxy group Chemical group 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 2
- 125000005336 allyloxy group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M isothiocyanate Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 150000002989 phenols Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000004031 phenylhydrazines Chemical class 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 3
- ATDGTVJJHBUTRL-UHFFFAOYSA-N Cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 claims 1
- 125000004450 alkenylene group Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- JLYQVFASMVHLNJ-UHFFFAOYSA-N hexane;methane Chemical compound C.CCCCCC JLYQVFASMVHLNJ-UHFFFAOYSA-N 0.000 claims 1
- INAXVFBXDYWQFN-XHSDSOJGSA-N Morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 abstract description 3
- 229940051807 opiod analgesics Morphinan derivatives Drugs 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
- 239000000203 mixture Substances 0.000 description 18
- 229960000583 Acetic Acid Drugs 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 239000012362 glacial acetic acid Substances 0.000 description 16
- 238000002844 melting Methods 0.000 description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 13
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 10
- 239000000556 agonist Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000002194 synthesizing Effects 0.000 description 9
- BQJCRHHNABKAKU-KBQPJGBKSA-N Morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 102000003840 Opioid Receptors Human genes 0.000 description 8
- 108090000137 Opioid Receptors Proteins 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- 229960005181 morphine Drugs 0.000 description 8
- 229930014694 morphine Natural products 0.000 description 8
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 description 8
- 239000000730 antalgic agent Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000007832 Na2SO4 Substances 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 229940098779 methanesulfonic acid Drugs 0.000 description 6
- 230000003364 opioid Effects 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 229940035676 ANALGESICS Drugs 0.000 description 5
- 206010038678 Respiratory depression Diseases 0.000 description 5
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CDXSJGDDABYYJV-UHFFFAOYSA-N acetic acid;ethanol Chemical compound CCO.CC(O)=O CDXSJGDDABYYJV-UHFFFAOYSA-N 0.000 description 4
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000003389 potentiating Effects 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 125000000565 sulfonamide group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 231100000486 side effect Toxicity 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- YYCRAERBSFHMPL-XFKAJCMBSA-N (4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,4,7a,13-tetrahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical class O=C([C@@H]1O2)C=C[C@@]3(O)[C@]4([H])N(C)CC[C@]13C1=C2C(OC)=CC=C1C4 YYCRAERBSFHMPL-XFKAJCMBSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N Boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 210000003169 Central Nervous System Anatomy 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N Lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 208000003960 Microvillus inclusion disease Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241001274216 Naso Species 0.000 description 2
- 229940005483 OPIOID ANALGESICS Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000001184 potassium carbonate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 231100000197 serious side effect Toxicity 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- ZHUJMSMQIPIPTF-IBURTVSXSA-N (2R)-2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoic acid Chemical class C([C@@H](C(=O)N[C@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ZHUJMSMQIPIPTF-IBURTVSXSA-N 0.000 description 1
- NOBPDEYWFIONBA-WEZQJLTASA-N (4R,4aS,7aR,12bR)-4a-hydroxy-9-methoxy-3,7a-dimethyl-1,2,4,5,6,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one Chemical compound O=C([C@]1(C)O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C NOBPDEYWFIONBA-WEZQJLTASA-N 0.000 description 1
- MCMMCRYPQBNCPH-NEUULRRLSA-N (4R,7S,13R)-13-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-7-benzyl-3,3,14,14-tetramethyl-6,9,12-trioxo-1,2-dithia-5,8,11-triazacyclotetradecane-4-carboxylic acid Chemical compound C([C@H](N)C(=O)N[C@H]1C(C)(C)SSC([C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)CNC1=O)C(O)=O)(C)C)C1=CC=C(O)C=C1 MCMMCRYPQBNCPH-NEUULRRLSA-N 0.000 description 1
- YTGSYRVSBPFKMQ-UHFFFAOYSA-N 2,2,2-tribromoacetaldehyde Chemical compound BrC(Br)(Br)C=O YTGSYRVSBPFKMQ-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-Bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- LBLDMHBSVIVJPM-YZIHRLCOSA-N 4-[(R)-[(2S,5R)-2,5-dimethyl-4-prop-2-enylpiperazin-1-yl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1[C@H](C=1C=C(O)C=CC=1)N1[C@@H](C)CN(CC=C)[C@H](C)C1 LBLDMHBSVIVJPM-YZIHRLCOSA-N 0.000 description 1
- DHELIGKVOGTMGF-UHFFFAOYSA-N 5-chloro-1-phenyltetrazole Chemical compound ClC1=NN=NN1C1=CC=CC=C1 DHELIGKVOGTMGF-UHFFFAOYSA-N 0.000 description 1
- UEHGAHXMHNQDIT-UHFFFAOYSA-N 5-phenoxy-2H-tetrazole Chemical class C=1C=CC=CC=1OC=1N=NNN=1 UEHGAHXMHNQDIT-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N AI2O3 Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N Allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 229940064004 Antiseptic throat preparations Drugs 0.000 description 1
- 229960005261 Aspartic Acid Drugs 0.000 description 1
- LBLDMHBSVIVJPM-SWYRRKHMSA-N BW373U86 Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1[C@@H](C=1C=C(O)C=CC=1)N1[C@@H](C)CN(CC=C)[C@H](C)C1 LBLDMHBSVIVJPM-SWYRRKHMSA-N 0.000 description 1
- BMTQKHAPUBDXGH-WEZQJLTASA-N COc1ccc2C[C@H]3N(C)CC[C@]45c2c1O[C@@]4(C)C(=O)C=C[C@@]35O Chemical compound COc1ccc2C[C@H]3N(C)CC[C@]45c2c1O[C@@]4(C)C(=O)C=C[C@@]35O BMTQKHAPUBDXGH-WEZQJLTASA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N Carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- DEIVEMBVIDRUDW-NINZUIERSA-N Cl.C1C(=O)CC[C@H]2[C@]3([H])NCC[C@@]21C1=CC=CC(C)=C1C3 Chemical compound Cl.C1C(=O)CC[C@H]2[C@]3([H])NCC[C@@]21C1=CC=CC(C)=C1C3 DEIVEMBVIDRUDW-NINZUIERSA-N 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N Cyanogen Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- MCMMCRYPQBNCPH-WMIMKTLMSA-N DPDPE Chemical compound C([C@H](N)C(=O)N[C@@H]1C(C)(C)SSC([C@@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)CNC1=O)C(O)=O)(C)C)C1=CC=C(O)C=C1 MCMMCRYPQBNCPH-WMIMKTLMSA-N 0.000 description 1
- 206010013754 Drug withdrawal syndrome Diseases 0.000 description 1
- 108010045678 Enkephalin, D-Penicillamine (2,5)- Proteins 0.000 description 1
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- 239000008896 Opium Substances 0.000 description 1
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- LKCWTYWDYSYPCJ-UHFFFAOYSA-N [Br-](Br)Br.[Na+] Chemical compound [Br-](Br)Br.[Na+] LKCWTYWDYSYPCJ-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
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- ZZASRJYLQUPYFI-UHFFFAOYSA-N chloroform;N,N-dimethylformamide Chemical compound ClC(Cl)Cl.CN(C)C=O ZZASRJYLQUPYFI-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
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- 238000010520 demethylation reaction Methods 0.000 description 1
- MQYQOVYIJOLTNX-UHFFFAOYSA-N dichloromethane;N,N-dimethylformamide Chemical compound ClCCl.CN(C)C=O MQYQOVYIJOLTNX-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
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- 229940079593 drugs Drugs 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- CHDFNIZLAAFFPX-UHFFFAOYSA-N ethoxyethane;oxolane Chemical compound CCOCC.C1CCOC1 CHDFNIZLAAFFPX-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- KLGZELKXQMTEMM-UHFFFAOYSA-N hydride Chemical compound [H-] KLGZELKXQMTEMM-UHFFFAOYSA-N 0.000 description 1
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- 229910003480 inorganic solid Inorganic materials 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000000185 intracerebroventricular Methods 0.000 description 1
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- 239000007951 isotonicity adjuster Substances 0.000 description 1
- AHNJTQYTRPXLLG-UHFFFAOYSA-N lithium;diethylazanide Chemical compound [Li+].CC[N-]CC AHNJTQYTRPXLLG-UHFFFAOYSA-N 0.000 description 1
- 230000001926 lymphatic Effects 0.000 description 1
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- YGYAWVDWMABLBF-UHFFFAOYSA-N phosgene Chemical class ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OCFVSFVLVRNXFJ-UHFFFAOYSA-N potassium hydride Inorganic materials [H-].[K+] OCFVSFVLVRNXFJ-UHFFFAOYSA-N 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 125000002653 sulfanylmethyl group Chemical group [H]SC([H])([H])[*] 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
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- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
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Abstract
New morphinan derivatives of formula (I), their pharmaceutically acceptable salts, a process for their preparation and their use in therapy are described.
Description
NEW AGONISTS COMPOUNDS FIELD OF THE INVENTION The present invention relates to the new opioid receptor agonists, also as to their pharmaceutically acceptable salts, a process for their preparation and their use in the manufacture of pharmaceutical preparations.
BACKGROUND OF THE INVENTION Three major types of opioid receptors (compound term to refer to synthetic compounds having an effect similar to that of opium alkaloids, but not derived from it), μ, K and d are known and characterized. The identification of different opioid receptors has led to efforts to develop specific ligands for these receptors. It is known that these ligands are useful for at least two purposes: (a) to allow the more complete characterization of these different receptors and (b) to facilitate the identification of the new analgesic drugs. It has been shown that analgesic drugs that have specificity for a type of individual opioid receptor have less side effects (eg respiratory depression, constipation, dependence) and in case in which tolerance to a drug has developed, a second medication with Different specificity to the opioid receptor can be
REP: 23450 cash For example, the successful substitution of DADLE (intrathecal application), a partially d selective analgesic peptide, for morphine in a human patient with cancer, with tolerance to morphine has been demonstrated (ES Krames et al., Pain, Vol. 24 : 205-209, 1986). Evidence that a selective d-agonist could be a potent analgesic with less tolerance and susceptibility to dependence was presented by Frederickson et al. (Science, Vol. 211: 603-605, 1981). The peptide [D-Ala2, N-MeMet5] enkephalinamide or "methefamide" was one hundred times more potent than morphine in the hot plate test for analgesia after i.c.v. administration. (intracerebral ventricular). The precipitation of naloxone from withdrawal after chronic administration of methefamide and morphine in rats showed that animals treated with methefamide exhibited fewer withdrawal symptoms than those administered with morphine, with a score of only slightly above the saline reference group . Methefamide produced substantially less respiratory depression than morphine. Another selective d-peptide, [D-Pen2, D-Pen5] enkephalin (DPFPE) produces potent analgesic effects, while showing little, if any, respiratory depression (CN May, Br. J. Pharmacol., Vol. 98: 903-913, 1989). It was found that DPDPE does not produce gastrointestinal side effects (e.g., constipation) (T.F. Burks, Life Sci., Vol 43: 2177-2181, 1988). Since it is desirable that analgesics be stable against peptidases and be able to enter the CNS (central nervous system) easily, non-peptide analgesics are much more valuable.
Description of the prior art Recently a selective opioid d agonist, not peptide,
BW373U86 - a piperazine derivative, has been discovered. It is reported that BW 373U86 is a potent analgesic which does not produce physical dependence (P.H.K. Lee et al., J. Pharmacol. Exp. Ther., Vol. 267: 983-987, 1993). An undesired side effect of this compound is that it produces convulsions in animals. The seizures were antagonized by the naltrindol opioid selective agonist.
SUMMARY OF THE INVENTION The present invention provides novel analgesic compounds of the formula I
(I)
wherein Ri represents alkyl of 1 to 6 carbon atoms or hydrogen; R 2 represents hydrogen, hydroxy, alkoxy of 1 to 6 carbon atoms; alkenyloxy of 1 to 6 carbon atoms; arylalkyloxy of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyloxy is alkyloxy of 1 to 6 carbon atoms; 7 to 16 carbon atoms of arylcarbonyloxy wherein the aryl is 6 to 10 carbon atoms and the alkenyloxy is alkenyloxy of 1 to 6 carbon atoms; C 1 -C 6 -alkanoyloxy, C 1-6 -alkenoyloxy, arylalkanoyloxy with 7 to 16 carbon atoms wherein the C 1 is aryl of 6 to 10 carbon atoms and the alkanoyloxy is C 1-6 -alkanoyloxy carbon; R3 represents hydrogen, alkyl of 1 to 6 carbon atoms; alkenyl of 1 to 6 carbon atoms; arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; arylalkenyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkenyl is alkenyl of 1 to 6 carbon atoms, hydroxyalkyl (of 1 to 6 carbon atoms); alkoxyalkyl wherein the alkoxy is alkoxy of 1 to 6 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; CO2H; C02 (alkyl of 1 to 6 carbon atoms); R 4 is hydrogen, hydroxy; alkoxy of 1 to 6 carbon atoms; arylalkyloxy of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyloxy is alkyloxy of 1 to 6 carbon atoms; alkenyloxy of 1 to 6 carbon atoms; alkanoyloxy of 1 to 6 carbon atoms;
arylalkanoyloxy of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkanoyloxy is alkanoyloxy of 1 to 6 carbon atoms; alkyloxyalkoxy wherein the alkyloxy is alkyloxy of 1 to 4 carbon atoms and the alkoxy is alkoxy of 1 to 6 carbon atoms, R5 and Rβ each independently represent hydrogen;
OH, alkoxy of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms; hydroxyalkyl wherein the alkyl is alkyl of 1 to 6 carbon atoms; halo; nitro; cyano; thiocyanate; trifluoromethyl; C02H; C 2 (alkyl of 1 to 6 carbon atoms), CONH 2; CONH (alkyl of 1 to 6 carbon atoms); CON (alkyl of 1 to 6 carbon atoms); Not me; monoalkylamino of 1 to 6 carbon atoms; dialkyl amino of 1 to 6 carbon atoms; cycloalkylamino of 5 to 6 carbon atoms; SH; SO3H; SO 3 (alkyl of 1 to 6 carbon atoms); SO2 (alkyl of 1 to 6 carbon atoms); SO2NH2; SO2NH (alkyl of 1 to 6 carbon atoms); S02NH (depleted from 7 to 16 carbon atoms); SO (alkyl of 1 to 6 carbon atoms); or R5 and Rβ together form a phenyl ring which may be unsubstituted or substituted by halo, nitro, cyano, thiocyanate; alkyl of 1 to 6 carbon atoms; trifluoromethyl; alkoxy of 1 to 6 carbon atoms, CO2H; CO (alkyl of 1 to 6 carbon atoms), amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms, SH; SO3H; SO 3 (alkyl of 1 to 6 carbon atoms), SO 2 (alkyl of 1 to 6 carbon atoms), SO (alkyl of 1 to 6 carbon atoms) and X represents oxygen; sulfur; CH = CH; or NR9 wherein Rg is H, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms, arylalkenyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkenyl is alkenyl of 1 to 6 carbon atoms; C 1 -C 6 alkanoyl, and wherein the aryl is unsubstituted or is mono-, di- or trisubstituted independently with hydroxy, halo, nitro, cyano, thiocyanate, trifluoromethyl, alkyl of 1 to 3 carbon atoms alkoxy of 1 to 3 carbon atoms, C02H; CONH, C 2 2 (alkyl of 1 to 3 carbon atoms), CONH (alkyl of 1 to 3 carbon atoms), CON (alkyl of 1 to 3 carbon atoms), CO (alkyl of 1 to 3 carbon atoms) ); Not me; (monoalkyl of 1 to 3 carbon atoms) amino, (dialkyl of 1 to 3 carbon atoms) amino, cycloalkylamino of 5 to 6 carbon atoms, (alkanoyl of 1 to 3 carbon atoms) amido, SH, SO3H, SO3 (alkyl of 1 to 3 carbon atoms), SO 2 (alkyl of 1 to 3 carbon atoms), SO (alkyl of 1 to 3 carbon atoms), alkylthio of 1 to 3 carbon atoms or alkanoylthio of 1 to 3 atoms of carbon; with the proviso that when R2 is hydroxy, R3 can not be hydrogen; the compounds 6,7-dehydro-4,5-epoxy-3,14-dimethoxy-17-methyl-6,7-2 ', 3'-benzo [b] furanomorphinan; 6,7-dehydro-4,5a-epoxy-3-hydroxy-17-metii-6,7-2 ', 3, -benzo [b] furan-morphinan;
6,7-dehydro-4,5a-epoxy-3-hydroxy-17-methyl-6,7-2 ', 3'-indolomorphinan; 6,7-dehydro-4,5α-epoxy-3-hydroxy-17-methyl-7'-bromo-6,7-2 ', 3'-indolomorphinan; 3,14-diacetoxy-6,7-dehydro-4,5a-epoxy-17-methyl-6,7-2 \ 3'-indolomor-finano; 14-acetoxy-6,7-dehydro-4,5a-epoxy-3-hydroxy-17-methyl-6,7-2 ', 3'-indomorphinan; 6,7-dehydro-4, 5a-epoxy-3-hydroxy-14-methoxy-17-methyl-6,7-2 ', 3'-benzo [b] furanomorphinan; 14-benzyloxy-6,7-dehydro-4,5a-epoxy-3-hydroxy-17-methyl-6,7-2 ', 3'-benzo [b] furanomorphinan; and the pharmacologically acceptable salts of the compounds of formula (I). The aryl can be unsubstituted or mono-, di- or trisubstituted independently with hydroxy, halo, nitro, cyano, thiocyanate, trifluoromethyl, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, CO2H; CONH2, C02 (alkyl of 1 to 3 carbon atoms), CONH (alkyl of 1 to 3 carbon atoms), CON (alkyl of 1 to 3 carbon atoms) 2, CO (alkyl of 1 to 3) carbon atoms); Not me; (monoalkyl of 1 to 3 carbon atoms) amino, (dialkyl of 1 to 3 carbon atoms) amino, cycloalkylamino of 5 to 6 carbon atoms, (alkanoyl of 1 to 3 carbon atoms) amido, SH, SO3H, SO3 (alkyl of 1 to 3 carbon atoms), SO 2 (alkyl of 1 to 3 carbon atoms), SO (alkyl of 1 to 3 carbon atoms), alkylthio of 1 to 3 carbon atoms or alkanoylthio of 1 to 3 atoms of carbon. The definition given above for the aryl is valid for all substituents in the present application where the aryl is present. The pharmaceutically and pharmacologically acceptable salts of the compounds of the formula I include inorganic salts and suitable organic salts which can be used according to the invention. Examples of inorganic salts which may be used are the HCl salt, HBr salt, sulfuric acid salt and phosphoric acid salt. Examples of organic salts which can be used according to the invention are the salt of methanesulfonic acid, salt of salicylic acid, salt of fumaric acid, salt of maleic acid, salt of succinic acid, salt of aspartic acid, salt of citric acid , salt of oxalic acid and salt of orotic acid. However, these examples are not in any way limiting the salts which could be used according to the invention. The new selective morphinan d derivatives of formula I are useful as analgesics without being susceptible to dependence. They can be administered parenterally or non-parenterally. Specific routes of administration include oral, rectal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, intrathecal, transdermal, intraarterial, bronchial, lymphatic and intrauterine administration. Formulations suitable for parenteral and oral administration are preferred.
In a preferred embodiment Ri is selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; R2 is selected from methoxy, ethoxy, n-propyloxy, benzyloxy, benzyloxy substituted on the aromatic ring with F, Cl, N02, CN, CF3l OCH3, allyloxy, cinnamyloxy or 3-phenylpropyloxy; R3 is selected from hydrogen, methyl, ethyl, benzyl or allyl; R is selected from hydroxy, methoxy, methoxymethoxy or acetyloxy; Rs and Rβ are each independently selected from hydrogen, nitro, cyano, chloro, fluoro, bromo, trifluoromethyl, CO2H, CO2CH3, CONH2, CONH CH3, SH, SO2NH2, N (CH), SO2CH3 and X is selected from O , NH, NCH3, N-benzyl, N-allyl. In a particularly preferred embodiment R2 is selected from methoxy, ethoxy, n-propyloxy, benzyloxy or benzyloxy substituted on the aromatic ring with chlorine. R3 is selected from hydrogen or CH3; R4 is hydroxy; R5 and R6 are each independently selected from hydrogen, CO2H, CONH2, S02NH2 or SO2CH3; and X is selected from O or NH. The best mode known in the present is to use the compound according to example 1.
Preparation of the compounds The compounds represented by the formula (I) wherein R3 is alkyl of 1 to 6 carbon atoms, aralkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl it is alkyl of 1 to 6 carbon atoms; alkoxyalkyl wherein the alkoxy is alkoxy of 1 to 6 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; C02 (alkyl of 1 to 6 carbon atoms); alkanoyl of 1 to 6 carbon atoms; can be obtained by the following procedures: The thebaine of the formula
it is treated with dialkylsulfates, alkyl esters of fluorosulfonic acid, alkyl esters of alkylsulfonic acid, alkylesters of arylsulfopic acid, alkyl halides, alkenyl halides, aralkyl halides, aralkyl esters of alkylsulfonic acid, aralkyl esters of arylsulfonic acid, arylalkenyl halides or chloroformates, in solvents such as tetrahydrofuran or diethyl ether, a strong base such as n-butyl lithium, lithium diethylamide or lithium diisopropylamide is used at low temperatures (-20 to -80 ° C) (S. Boden et al., J. Org. Chem., Vol. 47: 1347-1349, 1982, Schmidhammer et al., Helv. Chim. Acta. Vol. 71: 642-647, 1988, Gates et al., J. Org, Chem. Vol.; 972-974, 1984), to give the compounds of formula (II),
wherein R is alkyl of 1 to 6 carbon atoms; alkenyl of 1 to 6 carbon atoms; arylalkyl of 7 to 16 carbon atoms, wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; arylalkenyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkenyl is alkenyl of 1 to 6 carbon atoms; alkoxylalkyl wherein the alkoxy is alkoxy of 1 to 6 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; C02 (alkyl of 1 to 6 carbon atoms); The thebaine 5-substituted derivatives (formula II) or thebaine are converted to the corresponding 14-hydroxycodeinones (compounds of formula III)
wherein R is as defined above or is hydrogen, by reaction with performic acid (H. Schmidhammer et al., Helv. Chim. Acta, Vol. 71: 1801-1804, 1988) or m-chloroperbenzoic acid, at a temperature between 0 and 60 ° C. The preferred procedure is the reaction with performic acid at 0-10 ° C (H. Schmidhammer et al., Helv. Chim. Acta. Vol. 71: 1801-1804, 1988). These 14-hydroxycodeinones are treated with dialkyl sulfates, alkyl halides, alkenyl halides, arylalkyl halides, arylalkenyl halides or chloroformates, in solvents such as N, N-dimethylformamide or tetrahydrofuran, a strong base such as hydride is used. sodium, potassium hydride or sodium amide to give compounds of formula (IV)
C wherein Ri is alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms, arylalkenyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkenyl is alkenyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, arylalkanoyl of 7 to 16 atoms of carbon wherein the aryl is aryl of 6 to 10 carbon atoms and the alkanoyl is alkanoyl of 1 to 6 carbon atoms, arylalkenoyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and alkenoyl is alkenoyl of 1 to 6 carbon atoms; R2 is hydrogen; alkyl of 1 to 6 carbon atoms; alkenyl of 1 to 6 carbon atoms, arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; arylalkenyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkenyl is alkeniium of 1 to 6 carbon atoms; alkoxylalkyl wherein the alkoxy is alkoxy of 1 to 6 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; C02 (alkyl of 1 to 6 carbon atoms); which compounds are in turn reduced by catalytic hydrogenation, a catalyst such as palladium on carbon and solvents such as methanol, ethanol or glacial acetic acid are used to give compounds of formula (V)
wherein Ri is alkyl of 1 to 6 carbon atoms, arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, arylalkanoyl having 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkanoyl is alkanoyl of 1 to 6 carbon atoms; R2 is hydrogen; alkyl of 1 to 6 carbon atoms, arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; alkoxyalkyl wherein the alkoxy is alkoxy of 1 to 6 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; CO2 (alkyl of 1 to 6 carbon atoms); Ether cleavage of these compounds by using boron tribromide (in a solvent such as dichloromethane or chloroform) at a temperature of about 0 ° C, 48% bromal acid (reflux) or other well-known reagents give the phenolic compounds of formula (SAW),
wherein Ri and R2 are as defined above in formula (V). Alkylation using alkyl halides, alkyl sulfates, sulfonic acid esters, aralkyl halides, arylalkenyl halides or acylation using carbonic acid chlorides, carbonic acid anhydrides or carbonic acid esters provides the compounds of formula (VII)
wherein Ri and R2 are as defined above in the formula (V), and R3 is alkyl of 1 to 6 carbon atoms, arylalkyo of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, arylalkanoyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkanoyl is alkanoyl of 1 to 6 carbon atoms, alkyloxyalkyl wherein the alkyloxy is alkyloxy of 1 to 4 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms, which after N-demethylation when using for example chloroformates or bromide of cyanogen, followed by cleavage of the corresponding carbamates or N-cyano compounds (compounds of formula Vlll)
wherein Ri, R2 and R3 are as defined in formula (V) and (VII), and Z is for example CO CH = CH2, CO2CHCICH3, CO2CHCH3, CO2Fen, CO2CH2, CCI3 or CN by treatment with the appropriate reagent such as aqueous acid, alkali, hydrazine, zinc, alcohol and the like derivatives No of formula (IX)
wherein Ri, R2 and R3 are as defined above in formulas (V) and (VII). The N-alkylation can be carried out with alkyl halide or dialkyl sulfate in solvents such as dichloromethane, chloroform or N, N-dimethylformamide in the presence of a base such as sodium hydrogen carbonate or potassium carbonate to produce derivatives of formula (X)
wherein R1, R2 and R3 are as defined above in formulas (V) and (VII) and Y is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, ter -butyl, 2-pentyl, 3-pentyl, 2-hexyl or 3-hexyl.
The cleavage of the ether can be carried out as described for the compounds of formula (V) to give derivatives of formula (XI)
wherein Ri and R2 are as defined above in formulas (V) and Y is as defined above in formula (X). The compounds according to formula (I), wherein wherein R2 is hydroxy can be obtained from the compounds of the formula (III), wherein R is as defined above. These compounds can be reduced by catalytic hydrogenation by using a catalyst such as palladium on carbon and solvents such as methanol, ethanol or glacial acetic acid to give the compounds of formula (V) wherein R 1 is hydrogen and R 2 is as defined above. The following reaction sequence and methods leading to the compounds of formulas (VI), (VII), (IX), (X) and (XI) wherein Ri is hydrogen and wherein R2 and R3 are as defined above in the formulas (V) and (VII), is analogous to the reaction sequence and procedures described above.
Further conversion to the compounds of formula (I) wherein R2 is hydroxy is described below. The compounds of formula (I) wherein R2 is hydrogen can be obtained from compounds of formula (II) wherein R is as defined above. Catalytic hydrogenation followed by acid hydrolysis (S. Boden, et al., J. Org. Chem. Vol. 47: 1347-1349, 1982) gives compounds of the formula (XII)
C
(XII a): R = (dihydrocodeinone) wherein R is as defined above in formula (II). The compounds of formula (XII) and (XII a) (Mannich and Lo enheim, Arch. Pharm., Vol. 258-295, 1920) can be converted to compounds of formula (V), (VI), (VII), Vlll), (IX), (X) and (XI) wherein the substituent at position 14 is hydrogen and R2 and R3 are as defined above in formula (V) and (VII), similarly as described above. Further conversion to compounds of formula (I) wherein R2 is hydrogen is described below.
The compounds of formula (I) wherein R 4 is hydrogen can be prepared from compounds of formulas (VI) or (XI) by alkylation with 5-chloro-1-phenyl-1H-tetrazole to give the phenyltetrazolyl ethers of formula ( XIV)
wherein Ri and R2 are as defined above, n is 0-5 and T is phenyltetrazolyl. Catalytic hydrogenation can provide (H. Schmidhammer et al., J. Med. Chem. Vol. 27: 1575-1579, 1984) compounds of formula (XV)
wherein R1 and R2 are as defined above and n is 0-5.
Compounds according to formula (I) wherein R 2 is as defined above and X represents NH are obtained by reaction of the compounds of formula (VI), (VII), (IX), (X), (XI) ) or (XV) with phenylhydrazine or substituted phenylhydrazine in solvents such as methanol, ethanol or glacial acetic acid in the presence of methanesulfonic acid, HCl or HBr. Phenylhydrazine substituted on the aromatic ring with halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, amino, nitro, cyano, thiocyanate, trifluoromethyl, CO H; C 2 (alkyl of 1 to 6 carbon atoms), CONH 2; CONH (alkyl of 1 to 6 carbon atoms); CON (alkyl of 1 to 6 carbon atoms); SO2NH2; S02 (alkyl of 1 to 6 carbon atoms) or the like can be used. The reaction can be carried out at a temperature between 20 and 160 ° C, preferably between 20 and 80 ° C. The compounds of formula (I) wherein R3 is as defined above and X represents oxygen are obtained by the reaction of the compounds of formula (VI), (VII), (IX), (X), (XI) or ( XV) with o-phenylhydroxylamine or substituted o-phenylhydroxylamine (in the aromatic ring) in solvents such as methanol, ethanol or glacial acetic acid in the presence of methanesulfonic acid, HCl or HBr. O-phenylhydroxylamine substituted on the aromatic ring with halogen, alkyl of 1 to 6 carbon atoms, amino, nitro, cyano, thiocyanate, trifluoromethyl, CO2H; C 2 (alkyl of 1 to 6 carbon atoms), CONH; CONH (alkyl of 1 to 6 carbon atoms); CON (alkyl of 1 to 6 carbon atoms); S? 2NH2; SO 2 (alkyl of 1 to 6 carbon atoms) or the like can be used.
The following examples describe in detail the preparation of the compounds according to the invention.
Example 1 Synthesis of 6,7-dehydro-4,5a-epoxy-14-ethoxy-3-hydroxy-5,17-dimethyl-6,7-2 ', 3'-indole-morphinan (compound 1). A mixture of 14-ethoxymethopon (H. Schmidhammer et al., Helv. Chim. Acta. Vol. 73: 1784-1787, 1990) (500 mg, 1.45 mmol), phenylhydrazine hydrochloride (340 mg, 2.35 mmol) and 10 ml of glacial acetic acid are refluxed for 48 hours. After cooling, the reaction mixture is poured on ice, made alkaline with NH 4 OH and extracted with CH 2 Cl 2 (3 x 10 ml). The combined organic layers are washed with H2O (3 x 15 ml), dried over Na2SO4 and evaporated. The resulting residue (546 mg orange brown foam) is crystallized with MeOH to yield 322 mg of the title compound which was further purified by column chromatography (grade IV basic alumina)., elution with (a) CH2Cl2, (b) CH2Cl2 / MeOH 99: 1). After evaporation of the corresponding fractions, 237 mg of slightly yellow crystals were obtained. Recrystallization from MeOH produced 116 mg (24%) of the title compound 1. Melting point 165-167 ° C. IR (KBr): 3285 (NH, OH) cm "1. CI-MS: m / z 417 (M" +1). NMR-1H (CDCl 3): d 8.15 (s, NH, OH), 7.35 (d, J = 8 Hz, 1 arom.H), 7.26 (d, J = 8 Hz, 1 arom.H), 7.13 (t , J = 8 Hz, 1 arom.H), 7.01 (t, J = 8 Hz, 1 arom.H), 6.64 (d, J = 8 Hz, 1 arom.H), 6.55 (d, J = 8 Hz , 1 arom.H), 2.40 (s, CH3N), 1.94 (s CH3-C (5)), 1.02 (t, J = 7 Hz, 3H, CH3CH2O). Analysis calculated for C26H2ßN2? 3. (480.60): C 69.98, H 7.55, N 5.83; found: C 70.23, H 7.40, N 5.87.
Example 2 Synthesis of 6,7-dehydro-4,5a-epoxy-3,4-dimethoxy-5,17-dimethyl-6,7-2 ', 3'-indole-morphinan (compound 2). A mixture of 5,14-o-dimethyloxycodone (H. Schmidhammer et al., Helv. Chim. Acta Vol. 73: 1784-1787, 1990) (300 mg, 0.87 mmol), phenylhydrazine hydrochloride (189 mg, 1.31 mmol) ), methanesulfonic acid (84 mg, 0.87 mmol) and 12 ml of glacial acetic acid is refluxed for 17 hours. After cooling, the reaction mixture was poured onto ice, made alkaline with concentrated NH 4 OH and extracted with CH 2 Cl 2 (3 x 10 ml). The resulting organic layers are washed with H2O (3 x 10 ml), dried over Na2SO4 and evaporated. The resulting residue (380 mg of yellowish crystals) is recrystallized from MeOH to yield 336 mg (93%) of the title compound 2 as light yellow crystals. Melting point 218-221 ° C. (KBr): 3800 (NH) cm "1. CI-MS: m / z 417 (M" +1). 1 H-NMR (CDCl 3): d 8.30 (s, NH), 7.48 (d, J = 8 Hz, 1 arom.H), 7.39 (d, J = 8 Hz, 1 arom.H), 7.12 (t, J = 8 Hz, 1 arom.H), 7.03 (t, J = 8 Hz, 1 arom.H), 6.58 (s, 2 arom.H), 3.73 (s, OCH3-C (3)), 3.28 (s) , OCH3-C (14)), 2.45 (s, NCH3), 1.87 (s, CH3-C (5)). Analysis calculated for C26H28N2? 3.2 eOH (480.60): C 69.98, H 7.55, N 5.83; found: C 70.19, H 7.41, N 5.95.
Example 3 Synthesis of ß-dehydro ^ .Sa-epoxy-S-hydroxy-methoxy-S. ^ -dimethyl-β-J '' S'-indolomorphinan (compound 3). A mixture of 14-methoxymethoponic hydrobromide (H. Schmidhammer et al., Helv. Chim. Acta Vol. 73: 1784-1787, 1900) (500 mg, 1.22 mmol), phenylhydrazine hydrochloride (211 mg, 1.46 mmol) and 10 ml of glacial acetic acid are refluxed for 24 hours. After cooling, the reaction mixture is poured onto ice, made alkaline with concentrated NH 4 OH and extracted with CH 2 Cl 2 (3 x 10 ml). The combined organic layers are washed with H O (3 x 15 ml), dried over NaSO SO and evaporated. The resulting residue (455 mg of slightly gray foam) is crystallized from MeOH to give 330 mg (67%) of the title compound 3, pure. Melting point 273-276 ° C (decomposes). IR (KBr): 3300 (NH, OH) cm "1. CI-MS: M / Z 403 (M" +1). NMR-1H (DMSO-dβ): d 11.10 and 8.78 (2s, NH, OH), 7.32 (dxd, J = 8 Hz, 2 arom.H), 7.07 (t, J = 8 Hz, 1 arom.H) 6.91 (t, J = 8 Hz, 1 arom.H), 6.44 (s, 2 arom.H), 3.32 (s, OCH3), 2.33 (s, NCH3), 1.81 (s, CH3-C (5) ). Analysis calculated for C26H26N2? 3.2MeOH (466.56): C 69.50, H 7.35, N 6.01; found: C 69.78, H 7.38, N 6.09.
Example 4 Synthesis of 6,7-dehydro-4,5a-epoxy-3,14-dihydroxy-5,17-dimethyl-6,7-2 ', 3'-indole-morphinan (compound 4). A mixture of 14-hydroxymethoxymethoponic hydrobromide (H. Schmidhammer et al., Helv. Chim. Acta Vol. 71: 1801-1804, 1988) (450 mg, 0.95 mmol), phenylhydrazine hydrochloride (280 mg, 1.93 mmol) and 15 ml of glacial acetic acid are refluxed for 20 hours. After cooling, the reaction mixture is poured onto ice, made alkaline with concentrated NH 4 OH and extracted with CH 2 Cl 2 (3 x 60 ml). The combined organic layers are washed with H O (3 x 60 ml) and brine, dried over NaSO SO and evaporated. The resulting residue (392 mg of a brown foam) is dissolved in glacial acetic acid and treated with 48% HBr. The crystals were collected and recrystallized from glacial acetic acid to yield 132 mg (25%) of the title compound 4 as colorless crystals. Melting point > 250 ° C (decomposes). IR (KBr): 3300 (NH, OH) cm "1. CI-MS: m / z 389 (M" +1). 1 H NMR (DMSO-dβ): d 11.28 (s, NH), 9.19 (s, OH-C (3)), 9.09 (broad s, "NH), 7.10 (m, 4 arom. H), 6.56 ( s, 2 arom. H), 6.12 (s, OH-C (14)), 2.88 (s, NCH3), 1.88 (s, CH3-C (5)). Analysis calculated for C2 H2 2? 3x HBr x 0.1 H2O (489.20): C 58.93, H 5.60, N 5.73, Br 16.33, Found: C 59.01, H 5.55, N 5.56, Br 16.17.
Eiemolo 5 Synthesis of 7,8-dehydro-4,5a-epoxy-14-hydroxy-3-methoxy-5,17-dimethyl-6,7-2 ', 3'-indolomorphinan bromide (compound 5). A mixture of 5-methyloxycodone (H. Schmidhammer et al., Helv. Chim. Acta Vol. 71: 1801-1804, 1988) (350 mg, 0.72 mmol), phenylhydrazine hydrochloride (260 mg, 0.79 mmol) and 15 ml of glacial acetic acid are refluxed for 18 hours. After cooling, the reaction mixture is poured onto ice, made alkaline with concentrated NH 4 OH and extracted with CH 2 Cl 2 (3 x 50 ml). The combined organic layers are washed with H20 (3 x 60 ml) and brine, dried over Na2SO4 and evaporated. The resulting residue (365 mg of a brown foam) was dissolved with glacial acetic acid and treated with 48% HBr. The crystals are collected and recrystallized from glacial acetic acid to give 130 mg (25%) of the title compound 5. HBr. Melting point >; 260 ° C (decomposes). IR (KBr): 3406, 3396, 3242 (NH, "NH, OH) cm" 1. CI-MS: m / z 403 (M "+1). RMN-1H (DMSO-dβ): d 11.34 (s, NH), 9.20 (broad s," NH), 7.05 (m, 4 arom.H) 6.76 (d, J = 8.3 Hz, 1 arom.H), 6.69 (d, J = 8.3 Hz, 1 arom.H), 6.17 (s, OH-C (14)), 3.65 (s, OCH3), 2.90 (s, NCH 3), 1 89 (s, CH 3 -C (5)). Analysis calculated for C 25 H 26 N 2 O 3 x HBr x 0.9 H O (499.63): C 60.10, H 5.81, N 5.61, Br 15.99; Found: C 60.11, H 5.97, N 5.55, Br 16.02.
Example 6 Synthesis of 6,7-dehydro-4,5a-epoxy-3-hydroxy-14-methoxy-5-methyl-6,7-2 ', 3'-indole-morphinan (compound 7). A solution of 4,5a-epoxy-3,14-dimethoxy-5-s methylmorphinan-6-one hydrochloride (H. Schmidhammer et al., Helv. Chim. Acta Vol. 77: 1585-1589, 1994) (1.0 g, 2.73 mmol) in 3.5 ml of 48% HBr is refluxed for 15 minutes. After cooling, the now brown solution is evaporated, the residue is treated with MeOH and evaporated again (this operation is repeated once). The oily residue is crystallized from MeOH to yield 713 mg (66%) of or 4,5-epoxy-3-hydroxy-14-methoxy-5-methylmorphinan-6-one hydrobromide (compound 6). Melting point > 230 ° C (decomposes). IR (KBr): 3545 and 3495 ("NH, OH) 1720 (CO) cm" 1. CI-MS: m / z 316 (M "+1). RMN-1H (DMSO-dβ): d 9.37 (s, OH), 8.65 (broad s, NH), 6.64 (dd, J = 8.2, 8.2 Hz , 2 arom.H), 3.36 (s, OCH3-C (14)), 1.48 (s, CH3-C (5)). Analysis calculated for C? 8H2? NO4.HBr.MeOH (428.33): C 5 53.28, H 6.12, N 3.27, Found: C 53.12, H 5.97, N 3.32, A mixture of 4,5-epoxy-3-hydroxy-14-methoxy-5-methylmorphinan-6-one hydrobromide (compound 6, 1.2 g, 3.03 mmol), phenylhydrazine hydrochloride (548 mg, 379 mmol) and 15 ml of glacial acetic acid are refluxed for 4 hours.After cooling, the reaction mixture is evaporated to a brown solid (2.14 g). ) which is refluxed in 10 ml of MeOH for 5 minutes and cooled.The solid is isolated (the mother liquor of this isolate is further processed, see below), dissolved in H20 and made alkaline with concentrated NH4OH. The precipitation is isolated to yield 569 mg (70%) of the title compound 7, pure, melting point> 270 ° C (decomposes). IR (KBr): 3395 and 3380 (NH, OH) cm "1. EI-MS: m / z 388 (M "+1) Analysis calculated for C24H24N2O3 x 0.3 H2O (393.87): C 73.19, H 6.30, N 7.11; Found: C 73.08, H 6.03, N 7.07. The upper residue is evaporated and the resulting residue (566 mg) is treated with 2 ml of hot MeOH to provide (after cooling) 201 mg (14%) of the title compound 7. HBr Melting point &230 ° C ( decomposes). RMN-1H of 7. HBr (DMSO-dβ): d 11.30 (s, NH), 9.13 and 8.50 (2s, "NH, OH), 7.33 (dd, J = 7.4, 7.4 Hz, 2 arom. H), 7.08 (t, J = 7.4 Hz, 1 arom.H), 6.93 (t, J = 7.4, 1 arom.H), 6.57 (s, 2 arom.H), 3.32 (s, CH3O-C ( 14)), 1.84 (s, CH3-C (5)).
Example 7 Synthesis of methane sulfonate of 6,7-dehydro-4,5a-epoxy-3-hydroxy-5,17-dimethyl-14-n-propyloxy-6,7-2 ', 3'-indolomorphinan (compuestol 1) . A solution of 14-hydroxy-5-methylcodeinone (H. Schmidhammer et al., Helv. Chim. Acta Vol. 71: 1801-1804, 1988) (5.0 g, 15.27 mmole) in 50 ml of N, N-dimethyl formamide Anhydrous is cooled to 0-5 ° C. Sodium hydride (1.47 g, 15.27 mmol, obtained from 2.7 g of 60% sodium hydride dispersion in oil by washing with petroleum ether) is added under a nitrogen atmosphere and the resulting mixture is stirred for 20 minutes. Allyl bromide (2.64 ml, 30.54 mmol) is then added in one portion and stirring is continued at 0-5 ° C for 30 minutes. The excess sodium hydride is carefully destroyed with small pieces of ice, then the mixture is poured onto 150 ml of ice / H2O. After extractions with CH 2 Cl 2 (3 x 50 ml) the combined organic layers are washed with H 2 O (3 x 100 ml) and brine, dried over Na 2 SO 4 and evaporated to yield 6.43 g of a slightly yellow crystalline residue. Treatment with boiling ethanol (6 ml) gave (after cooling) 3.01 g (54%) of 14-allyloxy-5-methylcodeinone (compound 8). Melting point 136-137 ° C. IR (KBr): 1664 (CO) cm "1. CI-MS: m / z 368 (M" +1). NMR-1H (DMSO-dβ): d 6.78 (d, J = 10.2 Hz, 1 olef H), 6.62 (d, J = 8.2 Hz, 1 arom.H), 6.54 (d, J = 8.2 Hz, 1 arom.H), 6.09 (d, J = 10.2 Hz, 1 olef.H), 5.87 (m, 1 olef.H), 5.15 (m, 2 olef.H), 3.79 (s, CH3O), 2.44 (s) , CH3N), 1.71 (s, CH3-C (5)). Analysis calculated for C22H25N04 (367.45): C 71.91, H 6.86, N 3.81; Found: C 71.69, H 7.03, N 3.75. A mixture of 14-allyloxy-5-methylcodeinone (compound 8; 3.2 g,
. 64 mmoles), 196 g of 10% Pd / C catalyst and 100 ml of ethanol is hydrogenated at 2.1 Kg / cm 2 (30 psi) and room temperature for 3 hours. The catalyst is filtered and the filtrate is evaporated. The residue (3.79 g of colorless oil) is crystallized from ethanol to yield 2.93 g (74%) of 7,8-dihydro-5-methyl-14-n-propyloxycodeicone (compound 9). Melting point 102-104 ° C. IR (KBr): 1718 (CO) cm "1. CI-MS: m / z 372 (M- + 1). RMN-1H (DMSO-dβ): d 6.50 (dd, J = 8.8 Hz, 2 arom. H), 4.76 (s, CH3O), 2.35 (s, CH3N), 1.61 (s, CH3.C (5)), 1.00 (t, J = 7 Hz, CH3). Analysis calculated for C22H29NO4.0.2 EtOH ( 380.69): C 70.67, H 8.00, N 3.68, Found: C 70.64, H 7.72, N 3.69 A 1 M solution of sodium tribromide in CH2Cl2 (54 ml) is added simultaneously to an ice-cooled solution of 7.8. -dihydro-5-methyl-14-n-propyloxycodeicone (compound 9; 2.7 g, 7.27 mmol) in 370 ml of CH2Cl2.After 2 hours of stirring at 0-5 ° C, a mixture of 90 g of ice is added. and 20 ml of concentrated NH OH The resulting mixture is stirred at room temperature for 30 minutes and then extracted with CH 2 Cl 2 (3 x 200 ml) The combined organic layers are washed with brine (300 ml), dried over Na 2 SO 4 and The residue (2.4 g of slightly brown foam) is crystallized from MeOH to give 1.48 g (57%) of 4,5a-epoxy-3-hydroxy-5,17-dimethyl-14-n-propyloximor finan-6-one (compound 10) as slightly brown crystals. An analytical sample was obtained by recrystallization of a small amount of MeOH. Melting point 193-195 ° C. IR (KBr): 3376 (OH), 1726 (CO) cm "1. El-MS: m / z 357 (M"). 1 H-NMR (CDCl 3): d 6.67 (d, J = 8.1 Hz, 1 arom.H), 6.52 (d, J = 8.1 Hz, 1 arom.H), 1.57 (s, CH3-C (5)), 0.96 (t, J = 7.2 Hz, CH3). Analysis calculated for C2? H27NO. (357.43): C 70.56, H 7.61, N 3.92; Found: C 70.50, H 7.88, N 3.92. A mixture of 4,5a-epoxy-3-hydroxy-5,17-dimethyl-14-n-propyloxymorfinan-6-one (compound 10, 350 mg g, 0.97 mmol), phenylhydrazine hydrochloride (212 mg, 1.47 mmol) and 20 ml of glacial acetic acid are refluxed for 24 hours. After cooling, the reaction mixture is poured onto ice and made alkaline with concentrated NH 4 OH and extracted with CH 2 Cl 2 (3 x 40 ml). The combined organic layers are washed with H2O (3 x 50 ml) and brine, dried over Na2SO4 and evaporated. The resulting residue (276 mg of brown foam) is dissolved in MeOH and treated with methanesulfonic acid to give 180 mg of the title compound. Recrystallization from MeOH yields 44 mg (9%) of pure compound 11. Melting point > 270 ° C. IR (KBr): 3203 (NH) cm "1 NMR-1H (DMSO-dβ): d 11.29 (s, NH), 9.13 (s, OH), 8.47 (s broad, 'NH), 7.15 (m, 4 arom.H), 6.58 (s, 2 arom.H), 2.97 (s, NCH3), 1.86 (s, CH3-C (5)), 0.57 (t, J = 7.3 Hz, CH3). C27H3oN2O3.CH3S? 3H.0.7H2O (539.27): C 62.36, H 6.62, N 5.19, S 5.95, Found: C 62.36, H 6.50, N 5.20, S 6.02.
Example 8 Synthesis of ßJ-dehydro ^ Sa-epoxy-M-ethoxy-S-methoxy-^ - m? Til-ß ^ '. S'-indolomorfinano (compound 12). A mixture of 14-o-ethyloxycidone hydrochloride (RJ Kobylecki et al., J. Med. Chem. Vol. 25: 116-120, 1982) (580 mg, 1.53 mmol), phenylhydrazine hydrochloride (265 mg, 1.83 mmol. ) and 8 ml of glacial acetic acid is stirred for 5 days at room temperature. The mixture is poured onto ice, made alkaline with concentrated NH 4 OH and extracted with CH 2 Cl 2 (3 x 10 ml). The combined organic layers are washed with H2O (3 x 15 ml), dried over Na2SO4 and evaporated. The resulting residue (590 mg of slightly orange foam) is crystallized from MeOH to yield 360 mg (56%) of compound 12. Melting point 143-145X (decomposes). IR (KBr): 3260 (NH) cm "1. CI-MS: m / z 417 (M" +1). 1 H-NMR (CDCl 3): d 8.22 (s, NH, OH), 7.39 (d, J = 8 Hz, 1 arom.H), 7.30 (d, J = 8 Hz, 1 arom.H), 7.15 (t , J = 8 Hz, 1 arom.H), 7.02 (t, J = 8 Hz, 1 arom.H), 6.58 (s, 2 arom.H), 5.66 (s, HC (5)), 3.74 (s) , CH3O), 2.39 (s, CH3N), 1.01 (t, J = 7 Hz, 3H, CH33CH2O). Analysis calculated for C26H28N2? 3.1.0MeOH (448.56): C 72.30, H 7.19, N 6.25; Found: C 72.50, H 6.93, N 6.58.
Example 9 Synthesis of 6,7-dehydro-4,5α-epoxy-14-ethoxy-17-isopropyl-3-methoxy-5-methyl-6,7-2 ', 3'-benzo [b] furanomorphinan (compound 14) ). A mixture of 14-ethoxy-7,8-dihydronorcodeinone hydrochloride (RJ Kobylecki et al., J. Med. Chem. Vol. 25: 116, 1982) (1.5 g, 4.1 mmol), potassium carbonate (3.2 g, 22.52 mmoles), isopropyl bromide (1.2 ml, 13.31 mmol) and anhydrous N, N-dimethylformamide (15 ml) is stirred at 50 ° C (bath temperature) for 7 days. The inorganic solid is filtered, the filtrate is evaporated, dissolved in 40 ml of CH 2 Cl 2 and washed with H 2 O (3 x 30 ml). The organic phase is dried over Na2SO4 and evaporated to give 1.79 (mg) of colorless crystals. Recrystallization from 1.7 ml of MeOH provides 1.15 g (76%) of compound 13 (= 14-ethoxy-17-isopropyl-7,8-dihydronorcodeinone). Melting point 188-190 ° C. IR (KBr): 1780 (CO) cm "1, NMR-1H (CDCl 3): d 6.65 (d, J = 8.3 Hz, 1 arom.H), 6.56 (d, J = 8.3 Hz, 1 arom.H) , 4.62 (s, HC (5)), 3.87 (s, CH3O), 1.23 (t, J = 6.8 Hz, 3H, CH3CH20) CI-MS (m / z 372 (M "+ 1). C22H2gNO x0.2 MeOH (337.89): C 70.56, H 7.95, N 3.71; Found: C 70.43, H 7.64, N 3.70 A mixture of compound 13 (250 mg, 0.67 mmole), o-phenylhydroxylamine hydrochloride (196) mg, 1.34 mmoles), methanesulfonic acid (0.1 ml) and anhydrous methanol (6 ml) are refluxed for 6 days.After cooling, the solution is basified with concentrated NH4OH and extracted with CH2Cl2 (3 x 50 ml). The combined organic layers are washed with H2O (3 x 50 ml) and brine (30 ml) and evaporated to give 217 mg of a brown foam which is crystallized from methanol to provide 102 mg of brown crystals which are recrystallized from methanol to produce 33 mg (11%) of pure compound 14. Melting point 199-201, 1 H-NMR (CDCl 3): d 7.10-6.42 (m, 6 arom. ), 4.90 (s, H-C (5)), 3.98 (s, 3 H, CH3O), 1.29 (t, J = 6.7 Hz, 3 H, CH3CH2O), 1.08 (dd, J = 6.1 Hz, 2 CH3). CI-MS: m / z 446 (M "+ 1) Analysis calculated for C28H3? NO4x1.8H2O (477.99): C 70.63, H 7.30, N 2.93; Found: C 70.33, H 7.00, N 2.84.
PHARMACEUTICAL PREPARATIONS For the preparation of a pharmaceutical formulation, the active ingredient can be formulated into an injection, capsule, tablet, suppository, solution or the like. The oral formulation and the injection are preferably used. The pharmaceutical formulation may comprise the selective agonist d alone or may also comprise carriers such as stabilizers, pH regulating agents, diluents, isotonic agents, antiseptics and the like. The pharmaceutical formulation may comprise the active ingredient described above in an amount of 1-95% by weight, preferably 10-60% by weight. The dose of the active ingredient can be appropriately selected depending on the administration objectives, route and conditions of administration of the patients. The active ingredient is administered in doses of between 10 mg and 5 g per day in the case of oral administration. The preferred dose for injection is 20-200 mg per day and the preferred amount for oral administration is 50-800 mg per day.
Biological studies Selective agonism was determined by using the preparations for longitudinal ileal muscle of electrically stimulated guinea pigs (GPI, containing myk opioid receptors) (PW Schiller et al., Biochem. Biophys. Res. Commun., Vol. 58 : 11-18, 1978; J. Di Maio et al., J. Med. Chem., Vol. 25: 1432-1438, 1982) and preparation of mouse vas deferens (MVD: containing opioid receptors μ, K and d) . The activities of the compounds to inhibit the contraction of the organs was measured. In the GPI, compounds 1 and 12 showed no contraction inhibition up to 5,000 nM and 10,000 nM, respectively. These findings suggest that there is no agonist effect on the m and k opioid receptors. In the MVD, the compounds tested showed selective d agonism.
The biological studies of the new morphinan derivatives of the formula (I) of the present invention, have shown that these compounds have selectivity for receptors or opioids and are effective as opioid agonists. Studies with selective opioid d agonists have shown that this class of compounds have no susceptibility to dependence and produce substantially less respiratory depression than morphine. Susceptibility to dependence and respiratory depression are the most serious side effects of opioid agonists used as analgesics (eg, morphine). Therefore, the compounds according to the present invention are useful as analgesics without showing the more serious side effects of opioid analgesics. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following
Claims (14)
1. A compound according to formula (I) 10 characterized in that Rt represents alkyl of 1 to 6 carbon atoms or hydrogen; R2 represents hydrogen, hydroxy, alkoxy of 1 to 6 atoms 15 carbon; alkenyloxy of 1 to 6 carbon atoms; arylalkyloxy of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyloxy is alkyloxy of 1 to 6 carbon atoms; arylalkenyloxy of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkenyloxy is alkenyloxy of 1 to 6 carbon atoms; alkanoyloxy of 1 to 6 carbon atoms, Alkenoyloxy of 1 to 6 carbon atoms, arylalcanoyloxy of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkanoyloxy is alkanoyloxy of 1 to 6 carbon atoms; R3 represents alkyl of 1 to 6 carbon atoms; alkenyl of 1 to 6 carbon atoms; arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; arylalkenyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkenyl is alkenylene of 1 to 6 carbon atoms, hydroxyalkyl (of 1 to 6 carbon atoms); alkoxyalkyl wherein the alkoxy is alkoxy of 1 to 6 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; CO2H; CO2 (alkyl of 1 to 6 carbon atoms); R 4 is hydrogen, hydroxy; alkoxy of 1 to 6 carbon atoms; arylalkyloxy of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyloxy is alkyloxy of 1 to 6 carbon atoms; alkenyloxy of 1 to 6 carbon atoms; alkanoyloxy of 1 to 6 carbon atoms; arylalkanoyloxy of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkanoyloxy is alkanoyloxy of 1 to 6 carbon atoms; alkyloxyalkoxy wherein the alkyloxy is alkyloxy of 1 to 4 carbon atoms and the alkoxy is alkoxy of 1 to 6 carbon atoms, Rs and Rβ each independently represent hydrogen; OH, alkoxy of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms; hydroxyalkyl wherein the alkyl is alkyl of 1 to 6 carbon atoms; halo; nitro; cyano; thiocyanate; trifluoromethyl; CO2H; C02 (alkyl of 1 to 6 carbon atoms), CONH2; CONH (alkyl of 1 to 6 carbon atoms); CON (C 1-6 alkyl) 2; amino; monoalkylamino of 1 to 6 carbon atoms; dialkyl amino of 1 to 6 carbon atoms; cycloalkylamino of 5 to 6 carbon atoms; SH; S03H; SO3 ( alkyl of 1 to 6 carbon atoms), SO2 (alkyl of 1 to 6 carbon atoms), SO2NH2, SO2NH (alkyl of 1 to 6 carbon atoms), SO2NH (arylalkyl of 7 to 16 carbon atoms), SO ( alkyl of 1 to 6 carbon atoms), or R5 and Re together form a phenyl ring which may be unsubstituted or substituted by halo, nitro, cyano, thiocyanato, alkyl of 1 to 6 carbon atoms, trifluoromethyl; 1 to 6 carbon atoms, C02H, CO (alkyl of 1 to 6 carbon atoms), amino, monoalkylamino of 1 to 6 carbon atoms, dialkylamino of 1 to 6 carbon atoms, SH; SO3H; H; SO3 (alkyl) from 1 to 6 carbon atoms), SO 2 (alkyl of 1 to 6 carbon atoms), SO (alkyl of 1 to 6 carbon atoms) and X represents oxygen, sulfur, CH = CH, or NR 9 where R 9 is H , alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 atoms of carbon, arylalkenyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkenyl is alkenyl of 1 to 6 carbon atoms; C 1 -C 6 alkanoyl, and wherein the aryl is unsubstituted or mono-, di- or tri-substituted independently with hydroxy, halo, nitro, cyano, thiocyanate, trifluoromethyl, alkyl of 1 to 3 carbon atoms , alkoxy of 1 to 3 carbon atoms, CO2H; CONH2CO2 (alkyl of 1 to 3 carbon atoms), CONH (alkyl of 1 to 3 carbon atoms), CON (alkyl of 1 to 3 carbon atoms) 2, CO (alkyl of 1 to 3 carbon atoms); Not me; (monoalkyl of 1 to 3 carbon atoms) amino, (dialkyl of 1 to 3 carbon atoms) amino, cycloalkylamino of 5 to 6 carbon atoms, (alkanoyl of 1 to 3 carbon atoms) amido, SH, S03H, S 3 3 (alkyl of 1 to 3 carbon atoms), SO 2 (alkyl of 1 to 3 carbon atoms), SO (alkyl of 1 to 3 carbon atoms), alkylthio of 1 to 3 carbon atoms or alkanoylthio of 1 to 3 carbon atoms; and the pharmacologically acceptable salts of the compounds of formula (I).
2. A compound according to claim 1, characterized in that Ri is selected from hydrogen, methyl, ethyl, n-propyl or isopropyl; R2 is selected from methoxy, ethoxy, n-propyloxy, benzyloxy, benzyloxy substituted on the aromatic ring with F, Cl, NO ?, CN, CF3, OCH3, allyloxy, cinnamyloxy or 3-phenylpropyloxy; R3 is selected from methyl, ethyl, benzyl or allyl; R 4 is selected from hydroxy, methoxy, methoxymethoxy or acetyloxy; Rs and Rβ are each independently selected from hydrogen, nitro, cyano, chloro, fluoro, bromo, trifluoromethyl, CO2H, CO2 CH3 CONH2 > CONH CH3 SH, SO2NH2, N (CH3) 2 > SO2CH3 and X is selected from O, NH, NCH3, N-benzyl, N-allyl.
3. A compound according to claim 1, characterized in that Ri is CH3; R 2 is selected from methoxy, ethoxy, n-propyloxy, benzyloxy or benzyloxy substituted on the aromatic ring with chlorine R 3 is CH 3; R4 is hydroxy; Rs and Rβ are each independently selected from hydrogen, CO2H, CONH2, SO2NH2 or S0 CH3; and X is selected from O or NH.
4. A compound according to claim 1, characterized in that it is 6,7-dehydro-4,5a-epoxy-14-ethoxy-3-hydroxy-5,17-dimethyl-6,7-2 ', 3'-indolomorphinan; 6,7-dehydro-4,5α-epoxy-3,14-dimethoxy-5,17-dimethyl-6,7-2 ', 3'-indolomorphinan; 6,7-dehydro-4,5a-epoxy-3-hydroxy-14-methoxy-5,17-dimethyl-6,7-2 ', 3'-indole-morphinan; 6,7-dehydro-4,5a-epoxy-3,14-dihydroxy-5,17-dimethyl-6,7-2 ', 3'-indolomorphinan x HBr; 7,8-dehydro-4,5a-epoxy-14-hydroxy-3-methoxy-5,17-dimethyl-6,7-2 ', 3'-indolomorphinan x HBr; 6,7-dehydro-4,5α-epoxy-3-hydroxy-14-methoxy-5-methyl-6,7-2 ', 3'-indolomorphinan; 6,7-dehydro-4,5a-epoxy-3-hydroxy-5,17-dimethyl-14-n-propyloxy-6,7,2 ', 3'-indolomorphinan hexane methane; 6,7-dehydro-4,5a-epoxy-14-ethoxy-17-isopropyl-3-methoxy-5-methyl-6,7-2 ', 3'-benzo [b] furanomorphinan.
5. A compound according to claim 1, characterized in that it is used in therapy.
6. A compound according to claim 1, characterized in that it is used as an analgesic.
7. A compound according to claim 1, characterized in that it is in the form of a pharmaceutically acceptable salt.
8. A compound according to claim 7, characterized in that the salt is an inorganic salt.
9. A compound according to claim 6, characterized in that the salt is an organic salt.
10. The use of a compound according to claim 1, characterized in that it is used for the manufacture of a medicament for the treatment of pain.
11. A pharmaceutical composition, characterized in that it comprises a compound or a pharmacologically acceptable salt thereof according to claims 1-9 as an active ingredient, together with a pharmaceutically acceptable carrier.
12. A method for the treatment of a subject suffering from pain, characterized in that an effective amount of a compound according to claims 1-9, is administered to a subject in need of such treatment.
13. A process for the preparation of a compound according to formula (I) according to claim 1, characterized in that (a. I) the thebaine of the formula it is treated with dialkylsulfates, fluorosulfonic acid alkyl esters, alkylsulfonic acid alkyl esters, arylsulfonic acid alkyl esters, alkyl halides, alkenyl halides, aralkyl halides, aralkyl esters of alkylsulfonic acid, aralkyl esters of arylsulfonic acid, arylalkenyl halides or chloroformates, to give compounds of the formula (II) e n d or n of R is alkyl of 1 to 6 carbon atoms; alkenyl of 1 to 6 carbon atoms; arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; arylalkenyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the aikenyl is alkenyl of 1 to 6 carbon atoms; alkoxylalkyl wherein the alkoxy is alkoxy of 1 to 6 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; CO2 (alkyl of 1 to 6 carbon atoms); (ii) the compound of formula (II) is reacted with performic acid or m-chloroperbenzoic acid at a temperature between 0 and 60 ° C, to give compounds of the formula (III) wherein R is as defined above (iii) the compounds of formula (III) are thereafter reacted with dialkylsulfates, alkyl halides, alkenyl halides, arylalkyl halides, arylalkenyl halides or chloroformates, in the presence of a base strong and a solvent, to give compounds of the formula (IV) wherein Ri is alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms. to 6 carbon atoms, arylalkenyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 14 carbon atoms and the alkenniium is alkenyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms, arylalkanoyl from 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms, arylalkenoyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkenoyl is alkenoyl having 1 to 6 carbon atoms; and R2 is alkyl of 1 to 6 carbon atoms; alkenyl of 1 to 6 carbon atoms, arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; arylalkenyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkenyl is alkenyl of 1 to 6 carbon atoms; alkoxylalkyl wherein the alkoxy is alkoxy of 1 to 6 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; C02 (alkyl of 1 to 6 carbon atoms); (iv) the compounds of formula (IV) are reduced to give the compounds of formula (V) l) wherein Ri is alkyl of 1 to 6 carbon atoms, arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms, alkanoyl from 1 to 6 carbon atoms, arylalkanoyl having 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkanoyl is alkanoyl of 1 to 6 carbon atoms; R2 is alkyl of 1 to 6 carbon atoms, arylalkyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; alkoxyalkyl wherein the alkoxy is alkoxy of 1 to 6 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; CO2 (alkyl of 1 to 6 carbon atoms); (v) the compounds of formula (V) in turn are confronted with reagents to achieve cleavage by ether, to give phenolic compounds according to formula (VI) wherein Ri and R2 are as defined above in formula (V); (vi) the compounds of formula (VI) are thereafter alkylated or acylated to give compounds of formula (VII) wherein Ri and R2 are as defined above in the formula (V), and R3 is alkyl of 1 to 6 carbon atoms, arylaikyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, arylalkanoyl of 7 to 16 carbon atoms wherein the aryl is aryl of 6 to 10 carbon atoms and the alkanoyl is alkanoyl of 1 to 6 carbon atoms. to 6 carbon atoms, alkyloxyalkyl wherein the alkyloxy is alkyloxy of 1 to 4 carbon atoms and the alkyl is alkyl of 1 to 6 carbon atoms; (vii) the compounds (VII) are thereafter N-demethylated, with the use of chloroformates or cyanogen bromide to give the corresponding carbamates or N-cyano compounds of the formula (Vlll) wherein Ri, R2 and R3 are as defined in formula (V) and (VII) and Z is CN, CO2CH = CH2, CO2CHCICH3. C02CH2CH3, C02Fen, C02CH2 CCI3; (viii) the compounds of formula (Vlll) are cleaved to give compounds according to formula (IX) wherein Ri, R2 and R3 are as defined above in formula (V) and (VII); (ix) the compounds (IX) are N-alkylated to produce compounds according to the formula (X) wherein Ri, R2 and R3 are as defined above in formula (V) and (VII) and Y is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, ter -butyl, 2-pentyl, 3-pentyl, 2-hexyl or 3-hexyl; (x) the cleavage of the ether gives compounds according to the formula (XI) wherein Ri and R2 are as defined above in formula (V) and Y is as defined above in formula (X) above; (b) the compounds of formulas (VI), (VII), (IX), (X), (XI) or (XV) are reacted with substituted phenylhydrazine or phenylhydrazine to give compounds according to formula (I) wherein R3 is as defined above and X represents NH; (c) the compounds of formulas (VI), (VII), (IX), (X), (XI) or (XV) are reacted with substituted o-phenylhydroxylamine or o-phenylhydroxylamine, to give compounds of formula ( I). wherein R3 is as defined above and X represents O.
14. A process according to claim 13, characterized in that the compound of the formula (II) of step (ii) is reacted with performic acid at a temperature of 0-10 ° C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9401727-4 | 1994-05-18 | ||
| PCT/SE1995/000504 WO1995031464A1 (en) | 1994-05-18 | 1995-05-09 | New agonist compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MXPA96005604A true MXPA96005604A (en) | 1998-02-01 |
| MX9605604A MX9605604A (en) | 1998-02-28 |
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ID=39165145
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX9605604A MX9605604A (en) | 1995-05-09 | 1995-05-09 | New agonist compounds. |
Country Status (1)
| Country | Link |
|---|---|
| MX (1) | MX9605604A (en) |
-
1995
- 1995-05-09 MX MX9605604A patent/MX9605604A/en unknown
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