EP0729472A1 - Piperidinylcamphorsulfonyl oxytocin antagonists - Google Patents
Piperidinylcamphorsulfonyl oxytocin antagonistsInfo
- Publication number
- EP0729472A1 EP0729472A1 EP95902668A EP95902668A EP0729472A1 EP 0729472 A1 EP0729472 A1 EP 0729472A1 EP 95902668 A EP95902668 A EP 95902668A EP 95902668 A EP95902668 A EP 95902668A EP 0729472 A1 EP0729472 A1 EP 0729472A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- substituted
- alkyl
- compound
- mammal
- unsubstituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000003336 oxytocin antagonist Substances 0.000 title abstract description 18
- 229940121361 oxytocin antagonists Drugs 0.000 title description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 197
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 claims abstract description 64
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 claims abstract description 62
- 238000000034 method Methods 0.000 claims abstract description 60
- 229960001723 oxytocin Drugs 0.000 claims abstract description 58
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 55
- 208000006399 Premature Obstetric Labor Diseases 0.000 claims abstract description 28
- 208000005171 Dysmenorrhea Diseases 0.000 claims abstract description 25
- 206010013935 Dysmenorrhoea Diseases 0.000 claims abstract description 24
- 238000012384 transportation and delivery Methods 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 206010020772 Hypertension Diseases 0.000 claims abstract description 4
- -1 Chemical group 0.000 claims description 88
- 101800000989 Oxytocin Proteins 0.000 claims description 61
- 102100031951 Oxytocin-neurophysin 1 Human genes 0.000 claims description 61
- 125000001424 substituent group Chemical group 0.000 claims description 60
- 241000124008 Mammalia Species 0.000 claims description 49
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 46
- 229910052757 nitrogen Inorganic materials 0.000 claims description 37
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 34
- 125000005842 heteroatom Chemical group 0.000 claims description 30
- 238000009739 binding Methods 0.000 claims description 29
- 230000027455 binding Effects 0.000 claims description 28
- 102000005962 receptors Human genes 0.000 claims description 26
- 108020003175 receptors Proteins 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 claims description 20
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical group 0.000 claims description 17
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 16
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 230000003042 antagnostic effect Effects 0.000 claims description 13
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 10
- 150000002431 hydrogen Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 8
- 125000002393 azetidinyl group Chemical group 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 101000986765 Homo sapiens Oxytocin receptor Proteins 0.000 claims description 7
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 claims description 7
- 108010004977 Vasopressins Proteins 0.000 claims description 7
- 102000002852 Vasopressins Human genes 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 102000052321 human OXTR Human genes 0.000 claims description 7
- 230000001939 inductive effect Effects 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 229960003726 vasopressin Drugs 0.000 claims description 7
- 125000005248 alkyl aryloxy group Chemical group 0.000 claims description 6
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 150000002923 oximes Chemical class 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000005910 alkyl carbonate group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 4
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical class [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 208000004880 Polyuria Diseases 0.000 claims description 3
- 230000004520 agglutination Effects 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 230000035619 diuresis Effects 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 230000024883 vasodilation Effects 0.000 claims description 3
- 125000006647 (C3-C15) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006564 (C4-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 2
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims 18
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 claims 2
- NFGODEMQGQNUKK-UHFFFAOYSA-M [6-(diethylamino)-9-(2-octadecoxycarbonylphenyl)xanthen-3-ylidene]-diethylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCCOC(=O)C1=CC=CC=C1C1=C2C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C21 NFGODEMQGQNUKK-UHFFFAOYSA-M 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 20
- 230000032696 parturition Effects 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 5
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 abstract description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 abstract description 2
- 206010019280 Heart failures Diseases 0.000 abstract description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 abstract description 2
- 201000009273 Endometriosis Diseases 0.000 abstract 1
- 206010021036 Hyponatraemia Diseases 0.000 abstract 1
- 208000010877 cognitive disease Diseases 0.000 abstract 1
- 208000013403 hyperactivity Diseases 0.000 abstract 1
- 239000002536 vasopressin receptor antagonist Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 259
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 181
- 239000000243 solution Substances 0.000 description 140
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 136
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 119
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 115
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 98
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 95
- 235000019439 ethyl acetate Nutrition 0.000 description 92
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 90
- 125000003003 spiro group Chemical group 0.000 description 77
- 229940093499 ethyl acetate Drugs 0.000 description 75
- 238000004128 high performance liquid chromatography Methods 0.000 description 75
- 239000000047 product Substances 0.000 description 72
- 238000004458 analytical method Methods 0.000 description 70
- 239000000203 mixture Substances 0.000 description 70
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 66
- 239000007787 solid Substances 0.000 description 66
- 239000002904 solvent Substances 0.000 description 65
- 238000005481 NMR spectroscopy Methods 0.000 description 64
- 239000011541 reaction mixture Substances 0.000 description 63
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 59
- 229940073584 methylene chloride Drugs 0.000 description 59
- 230000002829 reductive effect Effects 0.000 description 58
- 239000003921 oil Substances 0.000 description 54
- 235000019198 oils Nutrition 0.000 description 54
- 239000000741 silica gel Substances 0.000 description 54
- 229910002027 silica gel Inorganic materials 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- 238000010265 fast atom bombardment Methods 0.000 description 47
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 39
- 229910052938 sodium sulfate Inorganic materials 0.000 description 38
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 34
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 33
- 235000011152 sodium sulphate Nutrition 0.000 description 33
- 239000012267 brine Substances 0.000 description 32
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
- 239000006260 foam Substances 0.000 description 29
- 239000000377 silicon dioxide Substances 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- 238000003756 stirring Methods 0.000 description 26
- 238000010828 elution Methods 0.000 description 25
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- 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 23
- 238000004809 thin layer chromatography Methods 0.000 description 23
- 238000001819 mass spectrum Methods 0.000 description 22
- 241001465754 Metazoa Species 0.000 description 21
- 238000004587 chromatography analysis Methods 0.000 description 21
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 21
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 description 20
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 20
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 description 18
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 17
- 235000011114 ammonium hydroxide Nutrition 0.000 description 17
- 239000000908 ammonium hydroxide Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 15
- 230000000694 effects Effects 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- QXNXVWNYCKUANQ-UHFFFAOYSA-N spiro[indene-1,4'-piperidine] Chemical compound C1CNCCC21C1=CC=CC=C1C=C2 QXNXVWNYCKUANQ-UHFFFAOYSA-N 0.000 description 14
- 101800001144 Arg-vasopressin Proteins 0.000 description 13
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 11
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 11
- 239000000463 material Substances 0.000 description 11
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- 230000035935 pregnancy Effects 0.000 description 11
- 210000004291 uterus Anatomy 0.000 description 11
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
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- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 230000001965 increasing effect Effects 0.000 description 9
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 8
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 8
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- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
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- 125000004432 carbon atom Chemical group C* 0.000 description 7
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
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- 239000000843 powder Substances 0.000 description 6
- 150000003180 prostaglandins Chemical class 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- NJAKCIUOTIPYED-UHFFFAOYSA-N 4-iodobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(I)C=C1 NJAKCIUOTIPYED-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 5
- 102000004279 Oxytocin receptors Human genes 0.000 description 5
- 108090000876 Oxytocin receptors Proteins 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 229940116211 Vasopressin antagonist Drugs 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- HRTHPQOIDCOMHE-UHFFFAOYSA-N tert-butyl spiro[indene-1,4'-piperidine]-1'-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC21C1=CC=CC=C1C=C2 HRTHPQOIDCOMHE-UHFFFAOYSA-N 0.000 description 5
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
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- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
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- WCJYTPVNMWIZCG-UHFFFAOYSA-N xylylcarb Chemical compound CNC(=O)OC1=CC=C(C)C(C)=C1 WCJYTPVNMWIZCG-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/5765—Six-membered rings condensed with carbocyclic rings or carbocyclic ring systems
Definitions
- the present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, such compounds generally pharmacologically useful as agents in obstetric and gynecologic therapy.
- the aforementioned pharmacologic activities are useful in the treatment of mammals. More specifically, the compounds of the present invention can be used in the treatment of preterm labor, stopping labor preparatory to Caesarean delivery, and in the treatment of dysmenorrhea. At the present time, there is a need in the area of obstetric and gynecologic therapy for such agents.
- Tocolytic (uterine-relaxing) agents that are currently in use include ⁇ 2-adrenergic agonists, magnesium sulfate and ethanol.
- Ritodrine the leading ⁇ 2-adrenergic agonist, causes a number of cardiovascular and metabolic side effects in the mother, including tachycardia, increased renin secretion, hyperglycemia (and reactive hypoglycemia in the infant).
- Other ⁇ 2-adrenergic agonists, including terbutaline and albuterol have side effects similar to those of ritodrine.
- Magnesium sulfate at plasma concentrations above the therapeutic range of 4 to 8 mg/dL can cause inhibition of cardiac conduction and neuromuscular transmission, respiratory depression and cardiac arrest, thus making this agent unsuitable when renal function is impaired.
- Ethanol is as effective as ritodrine in preventing premature labor, but it does not produce a corresponding reduction in the incidence of fetal respiratory distress that administration of ritodrine does.
- oxytocin may be a physiological initiator of labor in several mammalian species including humans. Oxytocin is believed to exert this effect in part by directly contracting the uterine myometrium and in part by enhancing the synthesis and release of contractile prostaglandins from the uterine endometrium/decidua. These prostaglandins may, in addition, be important in the cervical ripening process.
- the compounds of the present invention are also useful in the treatment of dysmenorrhea. This condition is characterized by cyclic pain associated with menses during ovulatory cycles. The pain is thought to result from uterine contractions and ischemia, probably mediated by the effect of prostaglandins produced in the secretory endometrium. By blocking both the direct and indirect effects of oxytocin on the uterus, a selective oxytocin antagonist can be more efficacious for treating dysmenorrhea than current regimens.
- An additional use for the present invention is for the stoppage of labor preparatory to Caesarean delivery.
- compounds of the present invention are antagonists of oxytocin and bind to the oxytocin receptor.
- oxytocin receptor When the oxytocin receptor is bound by the compounds of the present invention, oxytocin is antagonized by being blocked from its receptor and thus being unable to exert its biologic or pharmacologic effects.
- These compounds are useful in the treatment and prevention of oxytocin-related disorders of animals, preferably mammals and especially humans. These disorders are primarily preterm labor and dysmenorrhea. The compounds would also find usefulness for stoppage of labor preparatory to Caesarean delivery.
- oxytocin antagonists have now been shown to inhibit the release of oxytocin-stimulated luteinizing hormone (LH) by anterior pituitary cells.
- Compounds of the present invention are also inhibitors of vasopressin and can bind to the vasopressin receptor. These compounds are useful in inducing vasodilation, treating hypertension, inducing diuresis and inhibiting platelet agglutination.
- the compounds of the present invention are balanced oxytocin and vasopressin antagonists useful for treating preterm labor and dysmenorrhea.
- Y is absent or is
- m is an integer of from zero to one
- n is an integer of from zero to five;
- p is an integer of from zero to five;
- q is an integer of from zero to five;
- R 1 and R 2 are each independently
- R 5 and R 6 are independently
- R 7 and R 8 are independently
- R 7 and R 8 are, together with the carbons to which they are attached, joined to form a 5-membered hetercyclic ring containing 2 hetero atoms where said hetero atoms are N and O;
- R 12 is
- R 13 is
- R 15 is
- R 18 is unsubstituted or substituted heterocyclic rings selected from azetidinyl,
- halogen unsubstituted or substituted heterocyclic rings selected from azetidinyl,
- R 1 and R 2 are each independently
- R 5 and R 6 are independently
- R 7 and R 8 are, together with the carbons to which they are attached, joined to form a 5-membered heterocyclic ring containing 2 hetero atoms where said hetero atoms are N and O;
- R 12 is
- Illustrative of the invention is a pharmaceutical composition, comprising a compound of formula I in a
- Illustrations of the present invention include methods of antagonizing the binding of oxytocin to its receptor site, preventing preterm labor, treating dysmenorrhea, and stopping labor preparatory to cesarean deliv ery, in a mammal in need thereof, comprising the step of administering to the mammal a pharmacologically effective amount of a compound of formula I.
- Exemplifying the invention are methods of antagonizing vasopressin from binding to its receptor site, inducing vasodilation, treating hypertension, inducing diuresis, and inhibiting platelet agglutination, in a mammal in need thereof comprising the step of administering to the mammal a pharmacologically effective amount of a compound of formula I.
- An example of the invention is a method of increasing fertility and embryonic survival in a farm animal comprising
- improving survival of a farm animal neonate comprising controlling timing of parturition to effect delivery of the neonate during daylight hours by administering to a farm animal which is expected to deliver the neonate within 24 hours a pharmacologically effective amount of a compound of the present invention.
- Another illustration of the invention is a method of controlling the timing of estrus in a farm animal, comprising
- An embodiment of the invention is a pharmaceutical composition, comprising the compound of formula II in a pharmacologically effective amount for antagonizing the binding of oxytocin to its receptor site, and a pharmaceutically acceptable carrier.
- Illustrative of the invention are methods of antagonizing the binding of oxytocin to its receptor site, preventing preterm labor, treating dysmenorrhea, and stopping labor preparatory to cesarean delivery, in a mammal in need thereof, comprising the step of
- Also encompassed in the instant invention are methods of treating preterm labor and dysmenorrhea in a mammal in need thereof, comprising administering to the mammal a pharmacologically effective amount of a compound which binds to a human oxytocin receptor with a binding affinity which is no more than ten-fold higher or ten-fold lower than the binding affinity with which the compound binds to a human arginine-vasopressin-V 1 a (AVP-V 1 a ) receptor.
- AVP-V 1 a human arginine-vasopressin-V 1 a
- More particularly illustrating the the invention are the methods of treating preterm labor and dysmenorrhea, wherein the compound binds to the human oxytocin receptor with a binding affinity which is no more than five-fold higher or five-fold lower than the binding affinity with which the compound binds to the human AVP-V 1 a receptor.
- Exemplifying the invention are the methods of treating preterm labor and dysmenorrhea, wherein the compound is selected from
- pharmaceutically acceptable salts and esters refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
- Representative salts and esters include the following:
- Hydrobromide Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate , Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,
- pharmaceutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
- alkyl shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range.
- lower alkyl shall mean straight or branched chain alkanes of one to five total carbon atoms, or any number within this range.
- alkenyl shall mean straight or branched chain alkenes with one or more degrees of unsaturation at any position on the chain, of two to ten total carbon atoms, or any number within this range.
- alkynyl shall mean straight or branched chain alkynes with one or more degrees of unsaturation at any position on the chain, of two to ten total carbon atoms, or any number within this range.
- aryl shall mean phenyl, naphthyl or fluorenyl.
- cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms.
- trihaloalkylsulfonyloxo shall mean the substituent .
- alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g. aralkoxyaryloxy), it shall be interpreted as including those limitations given above for "alkyl” or "aryl.”
- Designated numbers of carbon atoms e.g. C 1 - 10 ) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
- halogen shall include iodine, bromine, chlorine and fluorine.
- preterm labor shall mean expulsion from the uterus of a viable infant before the normal end of gestation, or more particularly, onset of labor with effacement and dilation of the cervix before the 37th week of gestation. It may or may not be associated with vaginal bleeding or rupture of the membranes.
- dismenorrhea shall mean painful menstruation.
- Caesarean delivery shall mean incision through the abdominal and uterine walls for delivery of a fetus.
- substituted shall be deemed to include multiple degrees of substitution by a named substitutent.
- substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
- the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers. Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention.
- Oxytocin (OT) and arginine vasopressin (AVP) are structurally related peptide hormones of the pituitary gland having distinct biological functions. OT is released from the pituitary in response to stimuli related to parturition (e.g., labor, suckling of the neonate). Circulating OT then stimulates uterine activity to promote labor and delivery and contracts mammary gland myoepithelium to elicit milk-letdown postpartum. AVP, on the other hand, is secreted into the bloodstream by disturbances in hemostasis such as reduced blood pressure or blood volume and/or increased plasma osmolality. AVP acts to correct these imbalances by enhancing peripheral vascular resistance and by promoting water reabsorption by the kidney.
- AVP arginine vasopressin
- AVP-V 1 a receptors vascular smooth muscle
- AVP-V 2 receptors kidney receptors
- AVP-V 1 a receptors are also located in uterine smooth muscle to cause contraction and on platelets to mediate aggregation.
- the contractile responses of the uterus and mammary glands to OT appear to be transduced by a separate, single receptor subtype.
- a third, relatively obscure vasopressin receptor subtype, AVP-V 1b has been identified in the pituitary gland where it mediates the stimulatory effects of AVP on adrenocorticotrophic hormone (ACTH) release.
- ACTH adrenocorticotrophic hormone
- the ability of the compounds of the present invention to antagonize oxytocin makes these compounds useful as pharmacologic agents for mammals, especially for humans, for the treatment and prevention of disorders wherein oxytocin may be involved. Examples of such disorders include preterm labor and dysmenorrhea. These compounds may also find usefulness for stoppage of labor preparatory to Cesarean delivery.
- the oxytocin antagonist compounds of the present invention are also useful for improving reproductive efficiency in farm animals.
- farm animals e.g., sheep, cattle, swine and goats
- the beginning of the estrous cycle is typically marked by behavioral estrus when the female animal accepts the male for mating.
- Ovulation of the ovarian follicle occurs shortly after onset of estrus and cells in the follicle give rise to the corpus luteum.
- the cells that form the corpus luteum produce progesterone and they also produce oxytocin.
- the secretion of oxytocin from the corpus luteum and/or pituitary acts on the uterine endometrium to stimulate the secretion of prostaglandins (in particular PGF) which, in turn, causes the regression of the corpus luteum of the ovary.
- PGF prostaglandins
- PGF is, therefore, the luteolytic hormone.
- destruction of the corpus luteum removes the source of progesterone which is key to the preparation of the uterus for pregnancy.
- the presence of a viable conceptus i.e., the embryo and its associated membranes) is necessary to prevent the luteolytic process.
- the first key signal that the conceptus must produce is the one to prevent regression of the corpus luteum (i.e., the maternal recognition of pregnancy signal).
- the conceptus secretes a factor that antagonizes the action of oxytocin to induce luteolysis. This results in maintenance of a functioning corpus luteum and the continued secretion of progesterone which is obligatory to the initiation of pregnancy.
- an oxytocin antagonist of the present invention at this critical period after fertilization (i.e., just prior to or during the period of maternal recognition of pregnancy) supplements the natural signal from the conceptus (i.e., maternal recognition of pregnancy) to prolong corpus luteal function.
- the result is to increase pregnancy rates by enhancing the chances of impregnation through a reduction in embryonic loss.
- a mated animal for example, a mated ewe, is treated with an oxytocin antagonist compound beginning on between day 10 to day 15 after onset of estrus.
- the oxytocin antagonist compound is administered to the mated animal for a period of one day to three weeks, preferably one week to three weeks, most preferably one week to two weeks.
- the compounds of the present invention are also useful in farm animals for controlling the timing of parturition so that delivery of neonates occurs during the daytime. Approximately 80% of livestock are delivered at night and up to 5 to 10% of newborns die because the deliveries are not monitored properly. An oxytocin antagonist compound of the present invention administered to the mother on the evening before expected delivery delays parturition so that the delivery occurs during the daylight hours. By delaying the timing of parturition, proper monitoring of the delivery and the neonates is ensured, resulting in increased survival rates of the
- the oxytocin antagonists of the instant invention can also be used to control the timing of estrus in a cycling farm animal by preventing luteal regression.
- An oxytocin antagonist compound of the instant invention is administered to a cycling farm animal prior to expected estrus to prevent regression of the corpus luteum.
- Daily administration of the compound retards estrus until administration of the compound ceases.
- the oxytocin antagonist compound is administered at least 1 day prior to expected estrus.
- the compounds of the present invention also bind to the vasopressin receptors and are therefore useful as vasopressin
- Vasopressin antagonists are useful in the treatment or prevention of disease states involving vasopressin disorders, including their use as diuretics and their use in congestive heart failure.
- balanced oxytocin and vasopressin antagonists useful for treating preterm labor and dysmenorrhea.
- the terms "balanced oxytocin and vasopressin antagonist(s),” “balanced oxytocin/vasopressin compound(s),” and “balanced oxytocin/arginine-vasopressin (AVP)-V 1 a compound(s),” as used herein, are defined as a compound which has a ten-fold or less separation between the binding affinity of the compound for a human oxytocin receptor and the binding affinity of the compound for a human AVP-V 1 a receptor.
- a balanced oxytocin/vasopressin compound will provide a more effective treatment for preterm labor and dysmenorrhea.
- oxytocin receptors are up-regulated in the uterine myometrium during labor and before and during menstruation (AVP-V 1 a receptors are also present but are not up-regulated), the observation that the uterus responds to both oxytocin and AVP and that the sensitivity of the uterus to the contractile effects of oxytocin is highest during labor and menstruation, and the fact that oxytocin/AVP-stimulated synthesis of contractile prostaglandins occurs during labor and menstruation indicates that a balanced
- oxytocin/vasopressin antagonist compound would provide effective treatment for both preterm labor and dysmenorrhea.
- vasoconstrictor activity of AVP contributes to uterine ischemia and pain.
- balanced oxytocin/vasopressin compounds such as the balanced
- oxytocin/vasopressin compounds disclosed herein provide a novel approach for the treatment of preterm labor and dysmenorrhea.
- the compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as a tocolytic agent.
- the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
- Oral dosages of the present invention when used for the indicated effects, will range between about 0.3-6.0 gm/day orally.
- the most preferred doses will range from 0.1 to about 10 mg/minute during a constant rate infusion.
- compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
- preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
- the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.
- the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
- carrier suitable pharmaceutical diluents, excipients or carriers
- the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
- suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
- suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, zanthan gum and the like.
- the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
- Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
- the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
- Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol,
- the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, poly lactic acid, polepsilon caprolactone, polyhydroxy butyric acid,
- polyorthoesters polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- the present invention is also directed to combinations of the compounds of formula I with one or more agents useful in the treatment of oxytocin related disorders such as preterm labor, dysmenorrhea and stopping labor prior to cesarean delivery.
- the compounds of the instant invention may be effectively administered in combination with effective amounts of other agents used in the treatment of preterm labor, such as antenatal steroids
- Preferred combinations are simultaneous or alternating treatments of an oxytocin receptor antagonist of the present invention and an antenatal steroid. These combinations have beneficial effects on the neonate by both decreasing uterine activity to prolong gestation and increasing fetal maturation.
- the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be
- the compounds of the instant invention can be prepared readily according to the following reaction schemes and Examples or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
- the most preferred compounds of the invention are any or all of those specifically set forth in these Examples. These compounds are not, however, to be construed as forming the only genus that is considered as the invention, and any combination of the compounds or their moieties may itself form a genus.
- the following examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless noted otherwise.
- BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
- EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
- FAB MS fast atom bombardment mass spectroscopy
- Hydroxylamine hydrochloride (30 g) was added in three portions over ca. 20 minutes. After 2 hours, an additional 10 g of hydroxylamine hydrochloride was added (over 10 minutes). At 30, 40, and 50 minutes additional elapsed time, further 3 g lots of hydroxyl-amine
- reaction mixture was concentrated to oil and chromatographed using a silica "flash" column with 40% ethyl acetate in hexane as eluent.
- Fractions 12-20 contained the product.
- Fractions 11-18 contained the desired product and these were concentrated to an oil.
- Ether-hexane was added and removed to yield 27 mg of the title compound as a white amorphous powder.
- Step 2 Endo-(1S)-1 '-(((2-(noradamantyl-1 -carbonylamino)-7,
- Diisopropyl-ethylamine (50 ml) was added to make the solution basic. After tlc(silica-methylene chloride(9)-methanol(l)) showed a new spot, the reaction was concentrated to an oil. The oil was dissolved in methylene chloride-ether(l :3) and the solution was washed with water, sodium bicarbonate (sat., aqueous), water, 10% potassium bisulfate, and brine. After drying with sodium sulfate, the solution was filtered and concentrated to an oil. Ether-hexane was added and removed under reduced pressure to give the title compound as a white solid.
- endo-1S-1'-(((2-amino-7,7-dimethylbicyclo(2.2.1.)-hept-1 -yl)-methyl)-sulfonyl)spiro(1H-indan-1 ,4'-piperidine) 50 mg, 0.000125 M
- S-3-((tert.-butoxycarbonyl)amino)-2-oxo-1-pyrrolidine acetic acid 32.2 mg, 0.000125 M
- benzotriazol-1-yloxytris (dimethylamino)- phosphoniumhexafluoro-phosphate (Sequalog) (55 mg, 0.000125 M) in acetonitrile (3 ml).
- Endo-1S-1'-(((2-(S-3-(tert.-butoxycarbonyl)amino)-2-oxo-1-pyrrolidineacetylamino-)-7,7-dimethyl-bicyclo(2.2.1.)hept-1-yl)-methyl)-sulfonyl)spiro(1H-indan-1 ,4'-piperidine) was dissolved in ethyl acetate (5 ml) and cooled to -5°C. This was placed under a nitrogen atmosphere and hydrogen chloride gas was bubbled in for 10 minutes. The solvent was removed under reduced pressure. Ether was added and removed under reduced pressure to give 23.7 mg of the title compound as a white solid.
- Step 1 Endo-(1S)-1 '-(((2-(L-N-tertbutoxycarbonyl-histidinoylamino)-7,7-dimethylbicyclo(2.2.1)-hept-1 -yl)-methyl- sulfonyl)spiro(1 H-indan- 1 ,4-piperidine)
- endo-1S-1 '-(((2-amino-7,7-dimethylbicyclo(2.2.1.)hept-1-yl)-methyl)-sulfonyl)spiro(1H-indan-1 ,4'-piperidine) 50 mg, 0.000125 M
- L-N-tert, butoxycarbonyl histidine 29.9 mg, 0.000125 M
- benzotriazol-1-yloxytris(dimethylamino)phosphonium-hexafluorophosphate (Sequalog)
- Step 2 Endo-(1S)-1'-(((2-(L-N-histidinoylamino)-7,7-dimethylbicyclo(2.2.1)-hept-1 -yl)-methyl-sulfonyl)spiro(1H- indan-1 ,4-piperidine)
- endo-1S-1'-(((2-amino-7,7-dimethylbicyclo(2.2.1.)-hept-1-yl)-methyl)-sulfonyl)spiro(1H-indan-1 ,4'-piperidine) 50 mg, 0.000125 M
- D-N-tert. butoxycarbonylim-benzyl-histidine 43 mg, 0.000125 M
- benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (Sequalog) 55 mg, 0.000125 M) in acetonitrile (3 ml).
- Endo-(1 S)-1 '-(((2-(D-N-(tert.butoxycarbonyl)-im- benzylhistidinoylamino)-7,7-dimethylbicyclo(2.2.1.)-hept-1-yl)-methyl)-sulfonyl)spiro(1H-indan-1 ,4'-piperidine' was dissolved in ethyl acetate (5 ml) and cooled to -5°C. This was placed under a nitrogen atmosphere and hydrogen chloride gas was bubbled in for 10 minutes. The solvent was removed under reduced pressure. Ether was added and removed under reduced pressure to give the title compound as a white solid.
- Endo(1 S)-1 '-(((2-(S-3-tert-butoxycarbonyl-amino-2-oxo-1 -azepine acetylamino)-7,7-dimethylbicylo-(2.2.1.)-hept-1 -yl)-methyl)-sulfonyl)spiro(1H-indan-1 ,4'-piperidine) was dissolved in ethyl acetate (5 ml) and cooled to 5°C. This was placed under a nitrogen atmosphere and hydrogen chloride gas was bubbled in for 10 minutes. The solvent was removed under reduced pressure. Ether was added and removed under reduced pressure to give the title compound as a white solid.
- triethylamine (ca. 5-6 mL) was added to adjust the pH of the mixture (as determined by spotting a sample on E. Merck pH 5-10 colorpHast sticks, moistened with water) to 9-9.5. The mixture was stirred for 1 hour at ambient temperature, then filtered. The filtrate was divided in half, and each half (ca. 300 mL) was flash chromatographed on a separate 15", 2"diameter silica column packed with 3:2 (v:v) methylene
- triethylamine was added as needed to adjust the pH of the mixture to 9- 9.5 (moistened E. Merck colorpHast sticks).
- the mixture was stirred at ambient temperature for 1 hour, then poured onto a silica gel column (10", 2" id) packed with CH 2 CL2 and eluted with 1 :1 Et 2 O:CH 2 CI 2 .
- the product fractions were combined and evaporated to dryness in vacuo to provide the title compound as a solid which was recrystallized from petrolium ether and dried 6 hours in vacuo at ambient
- Hydroxylamine hydrochloride (30 g) was added in three portions over ca. 20 minutes. After 2 hours, an additional 10 g of hydroxylamine hydrochloride was added (over 10 minutes). At 30, 40 and 50 minutes additional elapsed time, further 3 g lots of hydroxylamine hydrochloride were added. After another 30 minutes, the mixture was poured into water (2 L) and extracted 3X with ethyl acetate (300 mL portions). The organic layers were combined, washed with 1N HCl (600 mL total), dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. EtOH (abs; ca. 250 mL) was added to the resulting thick syrup and the solution allowed to stand at ambient temperature overnight.
- Example 23 To a solution of the product of Example 23 (107 mg, 0.300 mmol) in glacial acetic acid (10 mL) was added zinc dust (24 mg, 0.367 mmol). The temperature was then increased to reflux. After 30 minutes, the mixture was cooled to room temperature, filtered, then concentrated under reduced pressure. Purification by flash
- Example 29 The product of Example 29 (60 mg) was dissolved in 3 ml of methanol and treated with 50 ml (1.59 mmole) of 95% hydrazine at 23°C. After 24 hours the solvent was removed under vacuum and the residue was suspended in toluene. Rotoevaporation of this suspension gave the crude product, which was chromatographed on four 0.5 mm procoated silica gel plates (chloroform-methanol-ammonium hydroxide, 92:8:0.8 v/v elution). The title compound was obtained as an
- Ethanolamine (6.66 mL, 0.1103 mmol) was placed in a 3-neck round bottom flask and heated to reflux. Once at relux, styrene oxide (6.28 mL, 0.0557 mmol) was added dropwise to the reaction mixture over 15 minutes. The reaction mixture was refluxed an additional 2 hours and then allowed to cool. The product, N-(2-hydroxyethyl)-N-(2-hydroxy-2-phenylethyl)amine, was obtained as a clear oil by vacuum distillation.
- N-(2-hydroxyethyl)-N-(2-hydroxy-2-phenylethyl)amine (1.30 g, 7.16 mmol) was dissolved in chloroform and then while under a nitrogen blanket, thionyl chloride (1.05 mL, 14.32 mmol) was added dropwise over 10 minutes.
- the reaction mixture was then refluxed for 1 hour and allowed to cool to room temperature. Water was then added to the mixture and allowed to stir 1 hour.
- the reaction mixture was separated and the organic layer was washed three times with 3N HCl.
- the aqueous layers were combined and then basified with 40% sodium hydroxide.
- the aqueous layer was extracted 3 times with ether, the organics were combined, and dried over sodium sulfate.
- the organic layer was filtered and the filtrate concentrated to a yellow oil.
- reaction mixture was concentrated to dryness and treated with 5% citric acid solution.
- the water layer was then basified with saturated sodium bicarbonate and extracted 3 times with ethyl acetate.
- Example 42 The procedure of Example 42 was carried out using 49.6 mg, 0.115 mmol of (1S)-(((7,7-dimethyl-(2-endo-aminomethyl-2-exo-hydroxy)-bicicylo-(2.2.1)-hept-1-yl)-methyl)sulfonyl)spiro(1H-indene-1 ,4'-piperidine),26.5 mg, 0.138 mmol of EDC, 18.7 mg, 0.138 mmol of HBT, 48 mL, 0.345 mmol of triethylamine, and substituting 4-benzoylbenzoic acid (31.3 mg, 0.138 mmol) for 2,2-bis-(hydroxymethyl)-propionic acid. Chromatographic elution was with 2% methanol in CH 2 CI 2 . The title compound was obtained and dried in vacuo, overnight. m.p.: 110-135°C
- Example 42 The procedure of Example 42 was carried out using 94.5 mg, 0.22 mmol of (1S)-(((7,7-dimethyl-(2-endo-amino-methyl-2-exo-hydroxy)-bicicylo-(2.2.1)-hept-1-yl)-methyl)-sulfonyl)spiro(1H-indene-1,4'-piperidine), 49.8 mg, 0.26 mmol of EDC, 35.2 mg, 0.26 mmol of HBT, 90 mL, 0.66 mmol of triethylamine, and substituting t-boc-L-serine(bzl) (76.8 mg, 0.26 mmol) for 2,2-bis-(hydroxymethyl)-propionic acid. Chromatographic elution was with 98/2 of
- Example 44 The product of Example 44 (120 mg, 0.17 mmol) was dissolved in 4% formic acid in methanol. Palladium hydroxide catalyst (25 mg) was added to the solution and it was placed on a PARR apparatus under 50 p.s.i. of hydrogen, overnight. The reaction mixture was filtered over solka floe and the filtrate was concentrated to a clear oil. This clear oil was dissolved in 2 mL of ethyl acetate and chilled to 0°C. At this point, 5 mL of prechilled sat'd HCl/ethyl acetate solution was added dropwise. The reaction mixture was allowed to stir for 1 hour and then concentrated to dryness.
- Lithium bis(trimethylsilyl)amide (21.3 ml of a 1.0M THF solution, 21.3 mmol) was cooled to -78°C under N 2 , treated with acetonitrile (1.07 ml, 20.4 mmol) and stirred 15 minutes.
- a THF solution (30 mL) of (1S)-1'-(((7,7-dimethyl-2-oxobicyclo(2.2.1 )-hept-1 -yl)methyl)sulfonyl)spiro(1H-indene-1 ,4'-piperidine) (40 gm, 10 mmol) was added dropwise and stirred 10 minutes after addition was complete. 6N HCl (2.8 ml) was added to the cold reaction all at once and the mixture was allowed to warm to 25°C.
- Lithium Aluminum Hydride (8.0 ml, 8.0 mmol, of a 1.0 M THF solution) was cooled to 0°C, treated dropwise with a THF solution (37 ml) of (1S)-1'-(((2-endo-cyano-methyl-7,7-dimethyl-2-hydroxybicyclo-(2.2.1)-hept-1-yl)methyl)sulfonyl)spiro(1H-indene-1,4'-piperidine) (4.4 gm, 10.0 mmol) and the reaction stirred 10 minutes.
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Application Number | Priority Date | Filing Date | Title |
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US15352193A | 1993-11-16 | 1993-11-16 | |
US153521 | 1993-11-16 | ||
PCT/US1994/013483 WO1995014025A1 (en) | 1993-11-16 | 1994-11-16 | Piperidinylcamphorsulfonyl oxytocin antagonists |
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EP0729472A1 true EP0729472A1 (en) | 1996-09-04 |
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EP95902668A Withdrawn EP0729472A4 (en) | 1993-11-16 | 1994-11-16 | Piperidinylcamphorsulfonyl oxytocin antagonists |
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JP (1) | JPH09505310A (en) |
AU (1) | AU687953B2 (en) |
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WO (1) | WO1995014025A1 (en) |
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US5599809A (en) * | 1994-09-29 | 1997-02-04 | Merck & Co., Inc. | Method for improving reproductive efficiency in farm animals |
CA2432825A1 (en) * | 2000-12-15 | 2002-06-20 | Emory University | Nonpeptide agonists and antagonists of vasopressin receptors |
SE0100902D0 (en) | 2001-03-15 | 2001-03-15 | Astrazeneca Ab | Compounds |
SE0103710D0 (en) | 2001-11-07 | 2001-11-07 | Astrazeneca Ab | Compounds |
SE0202539D0 (en) | 2002-08-27 | 2002-08-27 | Astrazeneca Ab | Compounds |
SE0401762D0 (en) | 2004-07-05 | 2004-07-05 | Astrazeneca Ab | Novel compounds |
US7648992B2 (en) | 2004-07-05 | 2010-01-19 | Astrazeneca Ab | Hydantoin derivatives for the treatment of obstructive airway diseases |
US7786141B2 (en) | 2004-08-19 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Dihydrospiroindene modulators of muscarinic receptors |
EP2374455A3 (en) * | 2004-08-19 | 2012-03-28 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
RU2007124373A (en) | 2004-11-29 | 2009-01-10 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | MUSCARINE RECEPTION MODULATORS |
SE0403086D0 (en) | 2004-12-17 | 2004-12-17 | Astrazeneca Ab | Compounds |
SE0403085D0 (en) | 2004-12-17 | 2004-12-17 | Astrazeneca Ab | Novel componds |
RU2008130094A (en) | 2005-12-22 | 2010-01-27 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | MUSCARINE RECEPTOR MODULATORS |
WO2007100670A1 (en) | 2006-02-22 | 2007-09-07 | Vertex Pharmaceuticals Incorporated | Spiro condensed piperidnes as modulators of muscarinic receptors |
CN101426499A (en) | 2006-02-22 | 2009-05-06 | 弗特克斯药品有限公司 | Modulators of muscarinic receptors |
EP2040706A2 (en) | 2006-06-29 | 2009-04-01 | Vertex Pharmceuticals Incorporated | Modulators of muscarinic receptors |
JP2010500412A (en) | 2006-08-15 | 2010-01-07 | バーテックス ファーマシューティカルズ インコーポレイテッド | Modulator of muscarinic receptor |
CN101573121A (en) | 2006-08-18 | 2009-11-04 | 弗特克斯药品有限公司 | Modulators of muscarinic receptors |
US8927715B2 (en) | 2006-08-25 | 2015-01-06 | Vitae Pharmaceuticals, Inc. | Inhibitors of 11β-hydroxysteroid dehydrogenase type 1 |
TW200831488A (en) | 2006-11-29 | 2008-08-01 | Astrazeneca Ab | Novel compounds |
WO2009045519A1 (en) | 2007-10-03 | 2009-04-09 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
JP2016513112A (en) * | 2013-02-18 | 2016-05-12 | ザ スクリプス リサーチ インスティテュート | Vasopressin receptor modulators with therapeutic potential |
CN117050198A (en) * | 2023-08-07 | 2023-11-14 | 张琦 | High-stability cellulose acetate and preparation method thereof |
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US5091387A (en) * | 1990-03-02 | 1992-02-25 | Merck & Co., Inc. | Spirocyclic oxytocin antagonists |
IL99957A0 (en) * | 1990-11-13 | 1992-08-18 | Merck & Co Inc | Piperidinylcamphorsulfonyl oxytocin antagonists and pharmaceutical compositions containing them |
EP0533243B1 (en) * | 1991-09-16 | 1997-12-17 | Merck & Co. Inc. | Hydantoin and succinimide-substituted spiroindanylcamphorsulfonyl derivatives |
US5204349A (en) * | 1991-09-16 | 1993-04-20 | Merck & Co., Inc. | Amide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists |
-
1994
- 1994-11-16 JP JP7514668A patent/JPH09505310A/en active Pending
- 1994-11-16 WO PCT/US1994/013483 patent/WO1995014025A1/en not_active Application Discontinuation
- 1994-11-16 CA CA002174650A patent/CA2174650A1/en not_active Abandoned
- 1994-11-16 EP EP95902668A patent/EP0729472A4/en not_active Withdrawn
- 1994-11-16 AU AU11852/95A patent/AU687953B2/en not_active Ceased
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WO1995014025A1 (en) | 1995-05-26 |
AU1185295A (en) | 1995-06-06 |
JPH09505310A (en) | 1997-05-27 |
CA2174650A1 (en) | 1995-05-26 |
AU687953B2 (en) | 1998-03-05 |
EP0729472A4 (en) | 1997-03-19 |
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