WO1993010074A1 - Derives d'arylethanolamines et leur utilisation comme agonistes beta-3-adrenergiques - Google Patents
Derives d'arylethanolamines et leur utilisation comme agonistes beta-3-adrenergiques Download PDFInfo
- Publication number
- WO1993010074A1 WO1993010074A1 PCT/GB1992/002135 GB9202135W WO9310074A1 WO 1993010074 A1 WO1993010074 A1 WO 1993010074A1 GB 9202135 W GB9202135 W GB 9202135W WO 9310074 A1 WO9310074 A1 WO 9310074A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- pharmaceutically acceptable
- compound
- ester
- amide
- Prior art date
Links
- 239000000556 agonist Substances 0.000 title description 6
- 102000012367 Beta 3 adrenoceptor Human genes 0.000 title description 2
- 108040005346 beta3-adrenergic receptor activity proteins Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 125
- 238000000034 method Methods 0.000 claims abstract description 76
- 150000002148 esters Chemical class 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 150000001408 amides Chemical class 0.000 claims abstract description 40
- 239000012453 solvate Substances 0.000 claims abstract description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 230000008569 process Effects 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical group 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 125000006239 protecting group Chemical group 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 244000144972 livestock Species 0.000 claims description 8
- 201000001320 Atherosclerosis Diseases 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 201000001421 hyperglycemia Diseases 0.000 claims description 6
- 238000011321 prophylaxis Methods 0.000 claims description 6
- 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
- 230000003247 decreasing effect Effects 0.000 claims description 5
- 230000035879 hyperinsulinaemia Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 231100000252 nontoxic Toxicity 0.000 claims description 4
- 230000003000 nontoxic effect Effects 0.000 claims description 4
- 230000004083 survival effect Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 230000004584 weight gain Effects 0.000 claims description 3
- 235000019786 weight gain Nutrition 0.000 claims description 3
- UTKKKUHJKQKXIC-SFHVURJKSA-N methyl 2-[4-[2-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]acetate Chemical compound C1=CC(OCC(=O)OC)=CC=C1CCNC[C@H](O)C1=CC=CC(Cl)=C1 UTKKKUHJKQKXIC-SFHVURJKSA-N 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
- 239000000126 substance Substances 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 239000002253 acid Substances 0.000 abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- -1 C1-6 alkyl carboxylic acids Chemical class 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- DZGWFCGJZKJUFP-UHFFFAOYSA-N tyramine Chemical compound NCCC1=CC=C(O)C=C1 DZGWFCGJZKJUFP-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- 229960003732 tyramine Drugs 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 210000002837 heart atrium Anatomy 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000007822 coupling agent Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000000969 carrier 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
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000004130 lipolysis Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N monoethanolamine hydrochloride Natural products NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
- IXQGCWUGDFDQMF-UHFFFAOYSA-N o-Hydroxyethylbenzene Natural products CCC1=CC=CC=C1O IXQGCWUGDFDQMF-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- YRWKKFQSHIMQDJ-OAHLLOKOSA-N (2r)-2-(3-chlorophenyl)-2-hydroxy-n-[2-(4-hydroxyphenyl)ethyl]acetamide Chemical compound O=C([C@H](O)C=1C=C(Cl)C=CC=1)NCCC1=CC=C(O)C=C1 YRWKKFQSHIMQDJ-OAHLLOKOSA-N 0.000 description 2
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 2
- 0 C[C@@](CN*CCc(cc1)ccc1O)c1cc(C(F)(F)F)ccc1 Chemical compound C[C@@](CN*CCc(cc1)ccc1O)c1cc(C(F)(F)F)ccc1 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102000015779 HDL Lipoproteins Human genes 0.000 description 2
- 108010010234 HDL Lipoproteins Proteins 0.000 description 2
- YZWBKTBBZQCRCB-OAHLLOKOSA-N O=C([C@H](O)C=1C=CC=CC=1)NCCC1=CC=C(O)C=C1 Chemical compound O=C([C@H](O)C=1C=CC=CC=1)NCCC1=CC=C(O)C=C1 YZWBKTBBZQCRCB-OAHLLOKOSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 2
- 230000003579 anti-obesity Effects 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000001746 atrial effect Effects 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 2
- 229940125388 beta agonist Drugs 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000003345 hyperglycaemic effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000000284 resting effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- CBEMVOYIUQADIA-SSDOTTSWSA-N (2r)-2-(3-bromophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC(Br)=C1 CBEMVOYIUQADIA-SSDOTTSWSA-N 0.000 description 1
- SAMVPMGKGGLIPF-SSDOTTSWSA-N (2r)-2-(3-chlorophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC(Cl)=C1 SAMVPMGKGGLIPF-SSDOTTSWSA-N 0.000 description 1
- WECBNRQPNXNRSJ-SSDOTTSWSA-N (2r)-2-hydroxy-2-[3-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC(C(F)(F)F)=C1 WECBNRQPNXNRSJ-SSDOTTSWSA-N 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000004747 1,1-dimethylethoxycarbonyl group Chemical group CC(C)(OC(=O)*)C 0.000 description 1
- SHCFCJUJGBRSPO-UHFFFAOYSA-N 1-cyclohexylcyclohexan-1-amine Chemical compound C1CCCCC1C1(N)CCCCC1 SHCFCJUJGBRSPO-UHFFFAOYSA-N 0.000 description 1
- RIRGCFBBHQEQQH-UHFFFAOYSA-N 2-(hydroxymethyl)-5-[6-(1-phenylpropan-2-ylamino)purin-9-yl]oxolane-3,4-diol Chemical compound N=1C=NC=2N(C3C(C(O)C(CO)O3)O)C=NC=2C=1NC(C)CC1=CC=CC=C1 RIRGCFBBHQEQQH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- IYTJRMRETHPZAC-UHFFFAOYSA-N 4,4-dibenzylpiperidine Chemical compound C1CNCCC1(CC=1C=CC=CC=1)CC1=CC=CC=C1 IYTJRMRETHPZAC-UHFFFAOYSA-N 0.000 description 1
- AZANSEGKOHVXJD-NTISSMGPSA-N 4-[2-[[(2r)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenol;hydrochloride Chemical compound Cl.C([C@H](O)C=1C=C(Cl)C=CC=1)NCCC1=CC=C(O)C=C1 AZANSEGKOHVXJD-NTISSMGPSA-N 0.000 description 1
- ALCPGHOSMXVEGW-INIZCTEOSA-N 4-[2-[[(2r)-2-hydroxy-2-phenylethyl]amino]ethyl]phenol Chemical compound C([C@H](O)C=1C=CC=CC=1)NCCC1=CC=C(O)C=C1 ALCPGHOSMXVEGW-INIZCTEOSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 229940123031 Beta adrenoreceptor agonist Drugs 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- YFRFIBYRGUMUFI-INIZCTEOSA-N C([C@H](O)C=1C=C(Br)C=CC=1)NCCC1=CC=C(O)C=C1 Chemical compound C([C@H](O)C=1C=C(Br)C=CC=1)NCCC1=CC=C(O)C=C1 YFRFIBYRGUMUFI-INIZCTEOSA-N 0.000 description 1
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 1
- VKHMBEXKDRFEHO-GFCCVEGCSA-N C[C@@H](C(NCCc(cc1)ccc1O)=O)c1cc(C(F)(F)F)ccc1 Chemical compound C[C@@H](C(NCCc(cc1)ccc1O)=O)c1cc(C(F)(F)F)ccc1 VKHMBEXKDRFEHO-GFCCVEGCSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- IWDCLRJOBJJRNH-UHFFFAOYSA-N Cc(cc1)ccc1O Chemical compound Cc(cc1)ccc1O IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 206010046763 Uterine atony Diseases 0.000 description 1
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 1
- YSVZGWAJIHWNQK-UHFFFAOYSA-N [3-(hydroxymethyl)-2-bicyclo[2.2.1]heptanyl]methanol Chemical compound C1CC2C(CO)C(CO)C1C2 YSVZGWAJIHWNQK-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- WGNZRLMOMHJUSP-UHFFFAOYSA-N benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium Chemical compound C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 WGNZRLMOMHJUSP-UHFFFAOYSA-N 0.000 description 1
- 102000015005 beta-adrenergic receptor activity proteins Human genes 0.000 description 1
- 108040006818 beta-adrenergic receptor activity proteins Proteins 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- HDRXZJPWHTXQRI-BHDTVMLSSA-N diltiazem hydrochloride Chemical compound [Cl-].C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CC[NH+](C)C)C2=CC=CC=C2S1 HDRXZJPWHTXQRI-BHDTVMLSSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007952 growth promoter Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- CEHJSGDRKABQIE-FERBBOLQSA-N methyl 2-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenoxy]acetate hydrochloride Chemical compound COC(=O)COC1=CC=C(C=C1)CCNC[C@@H](C2=CC=CC=C2)O.Cl CEHJSGDRKABQIE-FERBBOLQSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 235000013594 poultry meat Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 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
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000003512 tremorgenic effect Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229960004319 trichloroacetic acid Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000000636 white adipocyte Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
Definitions
- This invention relates to novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine and agriculture.
- European Patent Number 0023385 discloses certain compounds which are described as having activity as an anti-obesity and/or anti-hyperglycaemic agents.
- HDL high-density-lipoprotein
- R represents hydrogen, halogen or CF 3 .
- R is substituted in the 3-position on the phenyl ring.
- R represents halogen, especially chlorine or bromine, or CF 3 .
- R represents chlorine, especially 3-chloro.
- the compounds of formula (I) have an asymmetric carbon atom, marked with an asterisk in the formula. These compounds may, therefore, exist in one of two stereoisomeric forms.
- the present invention encompasses all stereoisomers of the compounds of the general formula (I), whether free from other isomers or admixed with other isomers in any proportion, and thus includes for instance, racemic mixtures of enantiomers.
- the assymmetric carbon is in the R-configuration.
- 'alkyl' when used alone or when forming part of other groups (such as the 'alkoxy' group) includes straight- or
- halogen refers to fluorine, chlorine, bromine and iodine, preferably chlorine.
- Suitable esters are in-vivo hydrolysable esters.
- in-vivo hydrolysable ester relates to a pharmaceutically acceptable ester which readily breaks down in the human or non-human animal body to leave the free hydroxy group.
- Suitable in-vivo hydrolysable ester groups are those used conventionally in the art, for example those provided by C 1-6 alkyl carboxylic acids.
- esters of compounds of formula (I) are esters of the carboxyl group of formula (I).
- the hydroxy group present in the moiety -CH(OH)CH 2 NH ('the ethanolamine hydroxyl group') or any hydroxyl group present in the compound of formula (I) may be derivatised as an ester.
- Suitable esters of the carboxyl group of formula (I) include alkyl esters, especially C 1-6 alkyl esters such as methyl.
- Suitable esters of hydroxyl groups are those provided by an aryl carboxylic acid, an arylalkyl carboxylic acid or a C 1-6 alkyl carboxylic acid.
- the ethanolamine hydroxyl group is present as a free hydroxyl group.
- Suitable pharmaceutically acceptable amides are those of formula NR s R t wherein R s and R t each independently represent hydrogen, alkyl or alkoxy alkyl.
- Suitable pharmaceutically acceptable salts of the compounds of formula (I) include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium, alkahne earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with C 1-6 alkylamines such as triethylamine, hydroxy- C 1-6 alkylamines such as 2-hydroxyethylamine, bis-(2- hydroxyethyl)- amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as
- bicyclohexylamine or with procaine, dibenzylpiperidine, N-benzyl-b-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline.
- Compounds of formula (I) also form acid addition salts.
- Pharmaceutically acceptable acid addition salts may be, for example, salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulophonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid or acetylsalicylic acid.
- Suitable pharmaceutically acceptable solvates are conventional solvates, preferably hydrates.
- the invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, which process comprises reacting an activated form of a compound of formula (II):
- R is as defined in relation to formula (I), R x represents hydrogen or a hydroxy protecting group and R y represents hydrogen or a nitrogen protecting group; with a compound of formula (III): L-CH 2 COOR z (III) wherein R z is hydrogen or a protecting group and L represents a leaving group; and thereafter if necessary carrying out one or more of the
- a suitable leaving group L is a halogen atom, preferably a bromine atom.
- a suitable activated form of a compound of formula (II) is an anionic form.
- reaction between an activated form of a compound of formula (II) and a compound of formula (III) may be carried out in any suitable solvent, generally an aprotic solvent such as acetone, tetrahydrofuran or
- dimethylformamdde at any temperature providing a suitable rate of formation of the required product at an ambient temperature or at an elevated temperature, such as in the range of from 20°C to 150°C, for example 60°C; conveniently when acetone is the solvent a suitable temperature is the reflux temperature.
- An activated form of a compound of formula (II) may be prepared by the appropriate conventional procedure.
- an anionic form may be prepared by treating a compound of formula (II) with a base such as sodium carbonate.
- the activated form of compound (II) is prepared in situ.
- R is as defined in relation to formula (I)
- R x and R y are as defined in relation to formula (II)
- R z is as defined in relation to formula (II), providing that at least one of R x , R y or R z represents a protecting group; and thereafter if necessary carrying out one or more of the following optional steps:
- Suitable protecting groups R x include trialkyl silyl groups.
- R x is hydrogen.
- R y is a nitrogen protecting group, for example a tert-butyloxy carbonyl group
- Suitable protecting groups R z include conventional carboxyl protecting groups, such as C 1-6 alkyl groups.
- R z is hydrogen
- the deprotection of the compound of formula (IA) may be carried out using any suitable, conventional procedure appropriate to the particular protecting group chosen.
- R y is a tert-butyloxycarbonyl group
- the compound of formula (IA) is deprotected using mild acidic hydrolysis, using for example trifluoroacetic acid in an inert, solvent such as dichloromethane, preferably under an inert atmosphere such as nitrogen and preferably under anhydrous conditions.
- R x represents a trialkyl silyl group it may be removed by mild acid hydrolysis.
- R z represents a C 1-6 alkyl group then it may be removed by mild basic hydrolysis.
- the compounds of formula (IA) may be prepared as described above by reaction between the compounds of formulae (II) and (III).
- the compounds of formula (II) may be prepared by reacting a compound of formula (IV):
- R and R x are as defined in relation to formula (II) with tyramine, and subsequently reducing the resulting amide; and thereafter, if
- reaction between a compound of formula (IV) and tyramine may be carried out under conventional amidation conditions, for example in an inert solvent, such as dry dichloromethane, in the presence of a coupling agent, at any temperature which provides a suitable rate of formation of the required product, conveniently at low to ambient temperature, for example 0°C or ambient temperature; and preferably in an inert
- atmosphere such as nitrogen.
- Suitable coupling agents are conventional coupling agents such as N,N'- dicylohexylcarbodiimide, benzotriazol-1-yloxy tris(dimethylamino)- phosphoniumhexafluorophosphate and benzotriazol-1-yloxy tripyrrolidinophosphoniumhexafluorophosphate.
- the reduction of the resulting amide may be effected by use of any appropriate, conventional reducing method, for example by using a borane such as boranedimethylsulphide in refluxing tetrahydrofuran, preferably under nitrogen.
- a borane such as boranedimethylsulphide in refluxing tetrahydrofuran, preferably under nitrogen.
- Suitable protecting groups include those used conventionally in the art for the particular group or atom being protected, for example those mentioned hereinbefore.
- Protecting groups may be prepared and removed using the appropriate conventional procedure: For example, tert-butyloxycarbonyl protecting groups may be prepared by treating the appropriate compound of formula (II) with di-tert-butyl dicarbonate in the presence of a base such as triethylamine.
- a base such as triethylamine.
- tert-butyloxycarbonyl protecting groups may be removed by mild acidic hydrolysis, such as by treatment with trifluoroacetic acid.
- R z is a C 1-6 alkyl group, it may be removed using mild, basic hydrolysis.
- a leaving group is any group that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups are halogen atoms, mesyloxy groups and tosyloxy groups.
- Compounds of formula (IA) and (II) are considered to be novel and thus form a further aspect of the invention.
- Compounds of formulae (III) and (IV) are either known compounds or can be prepared from known compounds by known processes or processes analogous to known processes for example those disclosed in Organic Synthesis, Collective Vol. 3 p. 381 (for compounds of formula (III) and p. 538 (for compounds of formula (IV)).
- Tyramine is a known compound.
- a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof may also be prepared according to methods disclosed in EP 0023385, such methods are incorporated herein by reference.
- the salts, esters, amides and solvates of compounds of formula (I) may be produced by methods conventional in the art:
- acid addition salts may be prepared by treating a compound of formula (I) with the appropriate acid.
- Esters of compounds of formula (I) maybe prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required compound of formula (I) with the appropriate alkanol under acidic conditions.
- One convenient process for preparing C 1-6 alkyl esters of compounds of formula (I), and especially a methyl ester is provided by treating a compound of formula (II) with a compound of formula (III) wherein R z represents C 1-6 alkyl, especially methyl.
- Amides of compounds of formula (I) may be prepared using conventional amidation procedures, for example amides of formula CONR s R t of a compound of formula (I) may be prepared by treating a compound of formula (I) with an amine of formula HNR s R t wherein R s and R t are as defined above.
- a C 1-6 alkyl ester such as a methyl ester, of a compound of formula (I) may be treated with an amine of the
- optically active acid as a resolving agent.
- Suitable optically active acids which maybe used as resolving agents are described in 'Topics in
- any enantiomer of a compound of the invention may be obtained by stereospecific synthesis using optically pure starting
- an enantiomer of the compound of formula (I) may be prepared by reaction of an enantiomer of the compound of formula (II) with a compound of formula (III), for example the R-enantiomer of compound (I) would be prepared from the R- enantiomer of compound (II).
- the relevant enantiomeric substrates are conveniently prepared using methods discussed above, for example the R- enantiomer of compound of formula (II) may be prepared from the R- enantiomer of the compound of formula (IV).
- the absolute configuration of any compound of the general formula (I) may be determined by conventional X-ray crystallographic techniques.
- the compounds of the present invention have valuable pharmacological properties:
- the present invention accordingly provides a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a
- the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a
- Suitable non-human animals include non-human mammals especially pets such as dogs and cats.
- the present invention further provides a compound of formula (I), or pharmaceutically acceptable salt, ester or amide thereof; or a
- the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, for tile manufacture of a medicament for the treatment of hyperglycaemia in human or non-human animals.
- the present invention also provides the use a compound of formula (I), or pharmaceutically acceptable salt, ester or amide thereof; or a
- hyperinsulinaemia in human or non-human animals is hyperinsulinaemia in human or non-human animals.
- a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor.
- pharmaceutically acceptable embraces compounds, compositions and ingredients for both human and veterinary use: for example the term “pharmaceutically acceptable salt” embraces a veterinarily acceptable salt.
- composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
- compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection, are also envisaged.
- Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules.
- Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
- the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
- Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.
- composition will be formulated in unit dose form.
- unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually from 2 to 100 mg or from 0.1 to 500 mg, and more especially from 0.1 to 250 mg.
- the present invention further provides a method for treating
- hyperglycaemia in a human or non-human animal which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, to a hyperglycaemic human or non-human animal in need thereof.
- the present invention further provides a method for treating obesity or for the treatment and/or prophylaxis of atherosclerosis in a human or non-human animal, which comprises administering an effective,
- the active ingredient may be administered as a
- the compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg that is a total daily dosage in the range of from 1.4. 10 -3 mg/kg to 86 mg/kg , more usually in the range of from 0.014 mg/kg to 21.4 mg/kg.
- the treatment regimens for atherosclerosis are generally as described for hyperglycaemia.
- the active ingredient may be adminstered by mouth, usually once or twice a day and in an amount in the range of from about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg.
- the present invention also provides a method for increasing weight gain and/or improving the feed utilisation efficiency and/or increasing lean body mass and/or decreasing birth mortality rate and increasing post/natal survival rate; of livestock, which method comprises the administration to livestock of an effective non-toxic amount of a compound of formula (I) or a veterinarily acceptable salt, ester or amide thereof; or a veterinarily acceptable solvate thereof.
- the compounds of formula (I) and the veterinarily acceptable salts, ester or amide thereof may be administered to any livestock in the abovementioned method, they are particularly suitable for increasing weight gain and/or feed utilisation efficiency and/or lean body mass and/or decreasing birth mortality rate and increasing post-natal survival rate; in poultry, especially turkeys and chickens, cattle, pigs and sheep.
- the compounds of formula (I) or veterinarily acceptable salts, ester or amide thereof will normally be administered orally although non-oral modes of administration, for example injection or implantation, are also envisaged.
- the compounds are also envisaged.
- the present invention also provides a veterinarily acceptable premix formulation comprising a compound of formula (I), or a
- Suitable carriers are inert conventional agents such as powdered starch. Other conventional feed-stuff premix carriers may also be employed.
- Lipolysis Rat white adipocytes were prepared by collagenase digestion as described by Rodbell (1964) with the modification of Honnor et al. (1985), in that adenosine (200nM) was included in the preparation to inhibit basal lipolysis.
- lipolysis stimulated by ⁇ -agonists was measured over 30 minutes in medium where the adenosine concentration was controlled; the medium included (-)-N 6 -(2-phenylisopropyl)adenosine (100nM) + deaminase as decribed by Honnor et al. (1985).
- the incubation was stopped by addition of trichloracetic acid (0.2ml of 10% w/v) to 1ml of cells.
- Glycerol was measured by the fluorimetric method of Boobis and Maugham (1983).
- Rat uterine horns were removed and bisected longitudinally. Each tissue was tied to a glass tissue holder and placed in Krebs-Henseleit solution in a 30 ml organ bath as before. Tissues were placed under a resting tension of lg and allowed to equilibrate. Each uterine strip was pre-contracted by the addition of 40mM K + to the bath to produced a steady tonic
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
L'invention concerne un composé de la formule (I) ou un sel acide pharmaceutiquement acceptable, un ester ou amide de celui-ci, ou un solvate de celui-ci pharmaceutiquement acceptable, dans laquelle R représente hydrogène, halogène ou CF3; l'invention concerne également un procédé de préparation de ce composé, une composition pharmaceutiquement le contenant et l'utilisation de ce composé ou composition en médécine et en agriculture.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB919124512A GB9124512D0 (en) | 1991-11-19 | 1991-11-19 | Novel compounds |
GB9124512.6 | 1991-11-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993010074A1 true WO1993010074A1 (fr) | 1993-05-27 |
Family
ID=10704842
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1992/002135 WO1993010074A1 (fr) | 1991-11-19 | 1992-11-19 | Derives d'arylethanolamines et leur utilisation comme agonistes beta-3-adrenergiques |
Country Status (8)
Country | Link |
---|---|
AU (1) | AU2949192A (fr) |
GB (1) | GB9124512D0 (fr) |
MX (1) | MX9206614A (fr) |
NZ (1) | NZ245157A (fr) |
PT (1) | PT101066A (fr) |
TW (1) | TW222619B (fr) |
WO (1) | WO1993010074A1 (fr) |
ZA (1) | ZA928859B (fr) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5541197A (en) * | 1994-04-26 | 1996-07-30 | Merck & Co., Inc. | Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity |
US5561142A (en) * | 1994-04-26 | 1996-10-01 | Merck & Co., Inc. | Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity |
EP0659737A3 (fr) * | 1993-12-21 | 1997-03-05 | Bristol Myers Squibb Co | Substituts pour Catécholamines utiles comme agonistes B3. |
WO2007011065A3 (fr) * | 2005-07-22 | 2007-08-16 | Mitsubishi Pharma Corp | Compose intermediaire utilise pour la synthese d'un agent pharmaceutique, procede de production de ce dernier |
WO2008015558A3 (fr) * | 2006-08-04 | 2008-07-10 | Univ Bari | Ligands du récepteur bêta-3 et leurs utilisation thérapeutique |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0023385A1 (fr) * | 1979-06-16 | 1981-02-04 | Beecham Group Plc | Dérivés d'éthanamines, leur préparation et leur utilisation dans des compositions pharmaceutiques |
EP0099707A1 (fr) * | 1982-07-16 | 1984-02-01 | Beecham Group Plc | Dérivés d'éther 2-aminoéthyles, leurs procédés de préparation et compositions pharmaceutiques les contenant |
WO1984004091A1 (fr) * | 1983-04-19 | 1984-10-25 | Beecham Group Plc | Derives de 2-phenylethylamine pharmaceutiquement actifs |
EP0386603A2 (fr) * | 1989-03-07 | 1990-09-12 | F. Hoffmann-La Roche Ag | Bisphénéthanolamine |
-
1991
- 1991-11-19 GB GB919124512A patent/GB9124512D0/en active Pending
-
1992
- 1992-11-17 MX MX9206614A patent/MX9206614A/es unknown
- 1992-11-17 ZA ZA928859A patent/ZA928859B/xx unknown
- 1992-11-17 PT PT101066A patent/PT101066A/pt not_active Application Discontinuation
- 1992-11-17 NZ NZ245157A patent/NZ245157A/en not_active IP Right Cessation
- 1992-11-19 WO PCT/GB1992/002135 patent/WO1993010074A1/fr active Application Filing
- 1992-11-19 AU AU29491/92A patent/AU2949192A/en not_active Abandoned
- 1992-11-20 TW TW081109301A patent/TW222619B/zh not_active IP Right Cessation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0023385A1 (fr) * | 1979-06-16 | 1981-02-04 | Beecham Group Plc | Dérivés d'éthanamines, leur préparation et leur utilisation dans des compositions pharmaceutiques |
EP0099707A1 (fr) * | 1982-07-16 | 1984-02-01 | Beecham Group Plc | Dérivés d'éther 2-aminoéthyles, leurs procédés de préparation et compositions pharmaceutiques les contenant |
WO1984004091A1 (fr) * | 1983-04-19 | 1984-10-25 | Beecham Group Plc | Derives de 2-phenylethylamine pharmaceutiquement actifs |
EP0386603A2 (fr) * | 1989-03-07 | 1990-09-12 | F. Hoffmann-La Roche Ag | Bisphénéthanolamine |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0659737A3 (fr) * | 1993-12-21 | 1997-03-05 | Bristol Myers Squibb Co | Substituts pour Catécholamines utiles comme agonistes B3. |
US5541197A (en) * | 1994-04-26 | 1996-07-30 | Merck & Co., Inc. | Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity |
US5561142A (en) * | 1994-04-26 | 1996-10-01 | Merck & Co., Inc. | Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity |
WO2007011065A3 (fr) * | 2005-07-22 | 2007-08-16 | Mitsubishi Pharma Corp | Compose intermediaire utilise pour la synthese d'un agent pharmaceutique, procede de production de ce dernier |
US7994315B2 (en) | 2005-07-22 | 2011-08-09 | Mitsubishi Tanabe Pharma Corporation | Intermediate compound for synthesizing pharmaceutical agent and production method thereof |
WO2008015558A3 (fr) * | 2006-08-04 | 2008-07-10 | Univ Bari | Ligands du récepteur bêta-3 et leurs utilisation thérapeutique |
US8017613B2 (en) | 2006-08-04 | 2011-09-13 | Universita' Degli Studi Di Bari | Beta-3 receptor ligands and their use in therapy |
US8354412B2 (en) | 2006-08-04 | 2013-01-15 | Universita' Degli Studi Di Bari | Beta-3 receptor ligands and their use in therapy |
CN101516826B (zh) * | 2006-08-04 | 2015-03-04 | 巴里学习大学 | β-3受体配体 |
Also Published As
Publication number | Publication date |
---|---|
GB9124512D0 (en) | 1992-01-08 |
ZA928859B (en) | 1994-05-05 |
AU2949192A (en) | 1993-06-15 |
TW222619B (fr) | 1994-04-21 |
MX9206614A (es) | 1994-02-28 |
NZ245157A (en) | 1995-03-28 |
PT101066A (pt) | 1994-02-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5750701A (en) | Heterocyclic ethanolamine derivatives with β-adrenoreceptor agonistic activity | |
EP0236624B1 (fr) | Phényl-éthanolamines substituées, procédés pour leur préparation et compositions pharmaceutiques les contenant | |
CA1287060C (fr) | Hydrochlorure de paroxetine cristallin | |
EP0652884B1 (fr) | Composes d'arylethanolamine phosphonates presentant une activite anti-hyperglycemique et/ou anti-obesite | |
WO1998022480A1 (fr) | Derives de propanolamine aryloxy ou arylthio contenant du phosphore | |
WO1993010074A1 (fr) | Derives d'arylethanolamines et leur utilisation comme agonistes beta-3-adrenergiques | |
EP0170121B1 (fr) | Hydroxy-2-aryloxy-3-propyl ou hydroxy-2-benzofuranyl-2-éthyl amines tertiaires douées d'une activité antihyperglycémique et/ou anti-obèse | |
EP0140359A1 (fr) | Dérivés de morpholine | |
US6136852A (en) | 3,4-disubstituted phenylethanolaminotetralincarboxylic acid derivatives | |
WO1995004047A1 (fr) | Derives de 2-benzoheterocyclyloxy ou de thiopropanolamine a activite d'agoniste du recepteur adrenergique | |
JPH02306947A (ja) | キラルβ―アミノ酸の製造方法 | |
EP0164700A2 (fr) | Bis-(bêta-hydroxyphényléthyl)amines | |
EP0142102B1 (fr) | Amines tertiaires | |
US5326762A (en) | Inhibitors of acyl-coenzyme A: cholesterol acyl transferase | |
EP0717746B1 (fr) | Derives d'acide phosphinique ayant une action contre l'hyperglycemie et/ou contre l'obesite | |
EP0139921B1 (fr) | Dérivés de 2-phényléthylamine | |
WO1994024090A1 (fr) | Derives d'arylethanolamine et utilisation de ces derniers dans le traitement de l'obesite de l'hyperglycemie | |
CZ20067A3 (cs) | Zpusob výroby hydrochloridu (S)-N-methyl-3-(1-naftyloxy)-3-(2-thienyl)propylaminu (duloxetinu) | |
JPH05117236A (ja) | ジクロロアニリン化合物 | |
OA11683A (en) | Use of thiahzolidinediones for the treatment of hyperglycaemia. | |
FR2616149A1 (fr) | Nouveau derive de l'acide benzo (b) thiophene - 7 carboxylique, son procede de preparation et les compositions pharmaceutiques qui le contiennent | |
WO1984004091A1 (fr) | Derives de 2-phenylethylamine pharmaceutiquement actifs | |
EP0171760A2 (fr) | Phénoxypropylaminoéthoxyphénoxyacétamides substitués | |
US7259263B2 (en) | Method of synthesis of azole-containing amino acids | |
FR2706897A1 (fr) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA JP KR US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL SE |
|
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: CA |