USRE43372E1 - C16 unsaturated FP-selective prostaglandins analogs - Google Patents
C16 unsaturated FP-selective prostaglandins analogs Download PDFInfo
- Publication number
- USRE43372E1 USRE43372E1 US12/479,532 US47953209A USRE43372E US RE43372 E1 USRE43372 E1 US RE43372E1 US 47953209 A US47953209 A US 47953209A US RE43372 E USRE43372 E US RE43372E
- Authority
- US
- United States
- Prior art keywords
- ring
- compound
- monocyclic
- substituted
- alkyl
- 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.)
- Expired - Lifetime
Links
- 150000003180 prostaglandins Chemical class 0.000 title description 24
- 229940094443 oxytocics prostaglandins Drugs 0.000 title description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 90
- 208000020084 Bone disease Diseases 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- 125000003118 aryl group Chemical group 0.000 claims description 52
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 42
- 125000001424 substituent group Chemical group 0.000 claims description 38
- 125000002950 monocyclic group Chemical group 0.000 claims description 36
- -1 thianaphthyl Chemical group 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 22
- 125000001188 haloalkyl group Chemical group 0.000 claims description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- 125000004429 atom Chemical group 0.000 claims description 18
- 125000005605 benzo group Chemical group 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 230000003287 optical effect Effects 0.000 claims description 14
- 150000001408 amides Chemical class 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 150000003949 imides Chemical class 0.000 claims description 13
- 125000001544 thienyl group Chemical group 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 11
- 150000003536 tetrazoles Chemical class 0.000 claims description 10
- 208000010412 Glaucoma Diseases 0.000 claims description 9
- 208000001132 Osteoporosis Diseases 0.000 claims description 9
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 241001465754 Metazoa Species 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 5
- 208000010392 Bone Fractures Diseases 0.000 claims description 3
- 208000029725 Metabolic bone disease Diseases 0.000 claims description 3
- 206010049088 Osteopenia Diseases 0.000 claims description 3
- 230000000699 topical effect Effects 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000003246 corticosteroid Substances 0.000 claims 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 62
- DZUXGQBLFALXCR-CDIPTNKSSA-N prostaglandin F1alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(O)=O DZUXGQBLFALXCR-CDIPTNKSSA-N 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 28
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- DZUXGQBLFALXCR-UHFFFAOYSA-N (+)-(9alpha,11alpha,13E,15S)-9,11,15-trihydroxyprost-13-en-1-oic acid Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CCCCCCC(O)=O DZUXGQBLFALXCR-UHFFFAOYSA-N 0.000 description 20
- 0 [1*]CCCCCC[C@@H]1C(CCC(CC)O[2*])C(O)C[C@@H]1O Chemical compound [1*]CCCCCC[C@@H]1C(CCC(CC)O[2*])C(O)C[C@@H]1O 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 17
- 239000012267 brine Substances 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 210000000988 bone and bone Anatomy 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000005842 heteroatom Chemical group 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 239000007832 Na2SO4 Substances 0.000 description 10
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 238000012986 modification Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 7
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 238000000935 solvent evaporation Methods 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001336 alkenes Chemical class 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 230000004410 intraocular pressure Effects 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000007910 systemic administration Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000006386 Bone Resorption Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102000015433 Prostaglandin Receptors Human genes 0.000 description 3
- 108010050183 Prostaglandin Receptors Proteins 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000024279 bone resorption Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- YFHHIZGZVLHBQZ-KDACTHKWSA-N 17-phenyl-trinor-prostaglandin F2alpha Chemical class C([C@H](O)\C=C\[C@@H]1[C@H]([C@@H](O)C[C@H]1O)C\C=C/CCCC(O)=O)CC1=CC=CC=C1 YFHHIZGZVLHBQZ-KDACTHKWSA-N 0.000 description 2
- DMAYBPBPEUFIHJ-UHFFFAOYSA-N 4-bromobut-1-ene Chemical compound BrCCC=C DMAYBPBPEUFIHJ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- AVJGUYWNXQWZKN-OSKLNTDESA-N COC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC=C(C2=CC=CC=C2)C=C1 Chemical compound COC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC=C(C2=CC=CC=C2)C=C1 AVJGUYWNXQWZKN-OSKLNTDESA-N 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SJOMUDYNXLVITH-GECPZMRISA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC2=C(C=C(F)C=C2)S1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC2=C(C=C(F)C=C2)S1 SJOMUDYNXLVITH-GECPZMRISA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 2
- 239000000030 antiglaucoma agent Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000008416 bone turnover Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- JMVOCSLPMGHXPG-UHFFFAOYSA-N dipotassium;dioxido(dioxo)osmium Chemical compound [K+].[K+].[O-][Os]([O-])(=O)=O JMVOCSLPMGHXPG-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000010603 microCT Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910052762 osmium Inorganic materials 0.000 description 2
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 2
- 230000011164 ossification Effects 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 150000003168 prostaglandin F1α derivatives Chemical class 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 229910052682 stishovite Inorganic materials 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- HXLKPGIKMOTKCC-UHFFFAOYSA-N 1-bromo-3-methylidenepentane Chemical compound CCC(=C)CCBr HXLKPGIKMOTKCC-UHFFFAOYSA-N 0.000 description 1
- IUXHPSPHPKXTPA-UHFFFAOYSA-N 1-bromobut-1-ene Chemical compound CCC=CBr IUXHPSPHPKXTPA-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FZWBNHMXJMCXLU-UHFFFAOYSA-N 2,3,4,5-tetrahydroxy-6-[3,4,5-trihydroxy-6-[[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxyhexanal Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OCC(O)C(O)C(O)C(O)C=O)O1 FZWBNHMXJMCXLU-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- IZMWJUPSQXIVDN-UHFFFAOYSA-N 4-bromo-2-methylbut-1-ene Chemical compound CC(=C)CCBr IZMWJUPSQXIVDN-UHFFFAOYSA-N 0.000 description 1
- XLYOGWXIKVUXCL-UHFFFAOYSA-N 4-bromobut-1-yne Chemical compound BrCCC#C XLYOGWXIKVUXCL-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- ZFLIKZJFUHVQIW-SQMYNBDPSA-N BrC1=CC=CC=C1.COC(=O)CCCCCC[C@H]1C(O[Si](C)(C)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCC(O)C1=CC=CC=C1.COC(=O)CCCCCC[C@H]1C(O[Si](C)(C)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCC=O.O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC=CC=C1 Chemical compound BrC1=CC=CC=C1.COC(=O)CCCCCC[C@H]1C(O[Si](C)(C)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCC(O)C1=CC=CC=C1.COC(=O)CCCCCC[C@H]1C(O[Si](C)(C)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCC=O.O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC=CC=C1 ZFLIKZJFUHVQIW-SQMYNBDPSA-N 0.000 description 1
- KFWDGVNDQPZPJO-OMLMIFPSSA-N C.C=CCCBr[MgH].C=CCC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]1CCCCCCC(=O)OC.C=CCC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCCCCCC(=O)OC.COC(=O)CCCCCCC1=C[C@H](O)CC1=O.COC(=O)CCCCCCC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O.COC(=O)CCCCCC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCC(O)C1=CC2=C(C=CC=C2)S1.COC(=O)CCCCCC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCC=O.ClCCl.ClCCl.O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC2=C(C=CC=C2)S1.O=[Os](=O)(=O)(=O)([K])[K].[Li]C1=CC2=C(C=CC=C2)S1 Chemical compound C.C=CCCBr[MgH].C=CCC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]1CCCCCCC(=O)OC.C=CCC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCCCCCC(=O)OC.COC(=O)CCCCCCC1=C[C@H](O)CC1=O.COC(=O)CCCCCCC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O.COC(=O)CCCCCC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCC(O)C1=CC2=C(C=CC=C2)S1.COC(=O)CCCCCC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCC=O.ClCCl.ClCCl.O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC2=C(C=CC=C2)S1.O=[Os](=O)(=O)(=O)([K])[K].[Li]C1=CC2=C(C=CC=C2)S1 KFWDGVNDQPZPJO-OMLMIFPSSA-N 0.000 description 1
- ZFVHTXYBZANYOG-ZDFDFPNYSA-N C/O=C(\CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)/C1=C/C2=C(C=CC=C2F)S1)NO Chemical compound C/O=C(\CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)/C1=C/C2=C(C=CC=C2F)S1)NO ZFVHTXYBZANYOG-ZDFDFPNYSA-N 0.000 description 1
- NJKMLFPFODVQHG-PCYYLRNMSA-N CC(C)OC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)/C1=N/C2=C(C=CC(F)=C2)S1 Chemical compound CC(C)OC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)/C1=N/C2=C(C=CC(F)=C2)S1 NJKMLFPFODVQHG-PCYYLRNMSA-N 0.000 description 1
- PEENDXIERAOKOK-OFQYZJKJSA-N CC(C)OC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=CC=CC=C1 Chemical compound CC(C)OC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=CC=CC=C1 PEENDXIERAOKOK-OFQYZJKJSA-N 0.000 description 1
- KFZWHYMWTUKKNP-SBJLQEHUSA-N CC(C)OC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=C(F)C=NC=C1 Chemical compound CC(C)OC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=C(F)C=NC=C1 KFZWHYMWTUKKNP-SBJLQEHUSA-N 0.000 description 1
- HEFMWNUEVOPGSP-OCQIDRNCSA-N CC1=CC(F)=C(C#CC(O)CC[C@H]2[C@H](O)C[C@H](O)[C@@H]2CCCCCCC(=O)O)C=C1 Chemical compound CC1=CC(F)=C(C#CC(O)CC[C@H]2[C@H](O)C[C@H](O)[C@@H]2CCCCCCC(=O)O)C=C1 HEFMWNUEVOPGSP-OCQIDRNCSA-N 0.000 description 1
- LJXJWIFYDMXWDI-CIALLKDMSA-N CC1=CC(F)=C(Cl)C=C1C(O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(=O)O Chemical compound CC1=CC(F)=C(Cl)C=C1C(O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(=O)O LJXJWIFYDMXWDI-CIALLKDMSA-N 0.000 description 1
- JAXJBTWJXULYAX-VZEIPUFQSA-N CC1=CC2=C(C=C1)C=C(Br)C=C2.CC1=CC2=CC=C(C(O)CC[C@H]3[C@H](O)C[C@H](O)[C@@H]3CCCCCCC(=O)O)C=C2C=C1.COC(=O)CCCCCC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCC(O)C1=CC=C2C=C(C)C=CC2=C1.COC(=O)CCCCCC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCC=O Chemical compound CC1=CC2=C(C=C1)C=C(Br)C=C2.CC1=CC2=CC=C(C(O)CC[C@H]3[C@H](O)C[C@H](O)[C@@H]3CCCCCCC(=O)O)C=C2C=C1.COC(=O)CCCCCC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCC(O)C1=CC=C2C=C(C)C=CC2=C1.COC(=O)CCCCCC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CCC=O JAXJBTWJXULYAX-VZEIPUFQSA-N 0.000 description 1
- GBXDPSBJLYREOJ-VZLBGKQBSA-N CC1=CC=C(C#CC(O)CC[C@H]2[C@H](O)C[C@H](O)[C@@H]2CCCCCCC(=O)O)C=C1 Chemical compound CC1=CC=C(C#CC(O)CC[C@H]2[C@H](O)C[C@H](O)[C@@H]2CCCCCCC(=O)O)C=C1 GBXDPSBJLYREOJ-VZLBGKQBSA-N 0.000 description 1
- ALYZNZDSFLHORX-MEYGQTPLSA-N CC1=CC=C(C(O)CC[C@H]2[C@H](O)C[C@H](O)[C@@H]2CCCCCCC(=O)O)C=C1 Chemical compound CC1=CC=C(C(O)CC[C@H]2[C@H](O)C[C@H](O)[C@@H]2CCCCCCC(=O)O)C=C1 ALYZNZDSFLHORX-MEYGQTPLSA-N 0.000 description 1
- WZVIERNYMNVUSI-RTMFQXSFSA-N CC1=CC=CC2=C1C(F)=C(C(O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(=O)OC(C)C)C=C2 Chemical compound CC1=CC=CC2=C1C(F)=C(C(O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(=O)OC(C)C)C=C2 WZVIERNYMNVUSI-RTMFQXSFSA-N 0.000 description 1
- ZQSVCPACLMDCON-ROQLGUTQSA-N CC1=CC=CC2=C1C=C(C(O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(=O)O)C=C2 Chemical compound CC1=CC=CC2=C1C=C(C(O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(=O)O)C=C2 ZQSVCPACLMDCON-ROQLGUTQSA-N 0.000 description 1
- PXGPLTODNUVGFL-YNNPMVKQSA-N CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O Chemical compound CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)C[C@H](O)[C@@H]1C/C=C\CCCC(=O)O PXGPLTODNUVGFL-YNNPMVKQSA-N 0.000 description 1
- GYYBZANIXKTXOK-NTHVSDAKSA-N CCOC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=CC=C(F)C=C1 Chemical compound CCOC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=CC=C(F)C=C1 GYYBZANIXKTXOK-NTHVSDAKSA-N 0.000 description 1
- UZWHLKIDNBTEIK-NUIBLQIESA-N CCOC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC(F)=CC(F)=C1 Chemical compound CCOC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC(F)=CC(F)=C1 UZWHLKIDNBTEIK-NUIBLQIESA-N 0.000 description 1
- JAQWSGFNEJJFEJ-OCQIDRNCSA-N COC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(F)C=CC=C1 Chemical compound COC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(F)C=CC=C1 JAQWSGFNEJJFEJ-OCQIDRNCSA-N 0.000 description 1
- WSBJIHGXKIHLBT-AZLLUMCGSA-N COC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(F)C=CC=C1.NO.O=C(CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(F)C=CC=C1)NO Chemical compound COC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(F)C=CC=C1.NO.O=C(CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(F)C=CC=C1)NO WSBJIHGXKIHLBT-AZLLUMCGSA-N 0.000 description 1
- IBLODKJVBDMTJV-VZLBGKQBSA-N COC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=CC(F)=CC=C1 Chemical compound COC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=CC(F)=CC=C1 IBLODKJVBDMTJV-VZLBGKQBSA-N 0.000 description 1
- KHUCPHRWVBQFKW-NUIBLQIESA-N COC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC2=C(C=C1)OC=C2 Chemical compound COC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC2=C(C=C1)OC=C2 KHUCPHRWVBQFKW-NUIBLQIESA-N 0.000 description 1
- YAWVQNMVIBIOLC-MEYGQTPLSA-N CS(=O)(=O)NC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)/C1=C/C2=C(C=CC=C2)S1 Chemical compound CS(=O)(=O)NC(=O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)/C1=C/C2=C(C=CC=C2)S1 YAWVQNMVIBIOLC-MEYGQTPLSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 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
- 206010061218 Inflammation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000282341 Mustela putorius furo Species 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 206010028735 Nasal congestion Diseases 0.000 description 1
- 208000000693 Neurogenic Urinary Bladder Diseases 0.000 description 1
- WMSPXQJUXIBGKJ-KWQQHVHJSA-N O=C(CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)/C1=N/C2=C(C=CC=C2)S1)NO Chemical compound O=C(CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)/C1=N/C2=C(C=CC=C2)S1)NO WMSPXQJUXIBGKJ-KWQQHVHJSA-N 0.000 description 1
- XQBFNRBVKVOQND-RVQSCQQMSA-N O=C(O)CCCCCCC1C(CCC(O)C#CC2=CC=C(C3=CC=CC=C3)C=C2)C(O)C[C@@H]1O Chemical compound O=C(O)CCCCCCC1C(CCC(O)C#CC2=CC=C(C3=CC=CC=C3)C=C2)C(O)C[C@@H]1O XQBFNRBVKVOQND-RVQSCQQMSA-N 0.000 description 1
- DPNJJGWKLZQJNF-TVIJTFOQSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(Cl)C=CC=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(Cl)C=CC=C1 DPNJJGWKLZQJNF-TVIJTFOQSA-N 0.000 description 1
- YGJUBZDNZVTIMO-IQRXXKDYSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(F)C(F)=CC=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(F)C(F)=CC=C1 YGJUBZDNZVTIMO-IQRXXKDYSA-N 0.000 description 1
- SLKMIQQTZRTFQX-TVIJTFOQSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(F)C=CC(F)=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(F)C=CC(F)=C1 SLKMIQQTZRTFQX-TVIJTFOQSA-N 0.000 description 1
- QLOSEJCBGSTJNX-TVIJTFOQSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(F)C=CC=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=C(F)C=CC=C1 QLOSEJCBGSTJNX-TVIJTFOQSA-N 0.000 description 1
- NSZNFNIBBNLOCX-ZILNPUCOSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=CC(F)=C(F)C=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=CC(F)=C(F)C=C1 NSZNFNIBBNLOCX-ZILNPUCOSA-N 0.000 description 1
- YVUOAAGJVGMKJE-XNDCSVHZSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=CC(F)=CC(F)=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=CC(F)=CC(F)=C1 YVUOAAGJVGMKJE-XNDCSVHZSA-N 0.000 description 1
- CMIALVOQIGUPHK-XNDCSVHZSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=CC=C(Cl)C=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CC1=CC=C(Cl)C=C1 CMIALVOQIGUPHK-XNDCSVHZSA-N 0.000 description 1
- IVKYUAKBIIDXSH-VZLBGKQBSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CCC1=CC=CC=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CCC1=CC=CC=C1 IVKYUAKBIIDXSH-VZLBGKQBSA-N 0.000 description 1
- IDOPSIAVCDKURK-OCQIDRNCSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CCC1=CC=CC=C1F Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C#CCC1=CC=CC=C1F IDOPSIAVCDKURK-OCQIDRNCSA-N 0.000 description 1
- ROJYBSXGGGOJGC-YZZCSLRSSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=C(Cl)C=CC=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=C(Cl)C=CC=C1 ROJYBSXGGGOJGC-YZZCSLRSSA-N 0.000 description 1
- DEEKBLUDVGZTLE-YZZCSLRSSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=C(F)C=CC=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=C(F)C=CC=C1 DEEKBLUDVGZTLE-YZZCSLRSSA-N 0.000 description 1
- FVMVMMTXALYEBU-YRROVBCYSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=C2=CC=CC(F)=C2=CC=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=C2=CC=CC(F)=C2=CC=C1 FVMVMMTXALYEBU-YRROVBCYSA-N 0.000 description 1
- RCVRUUIWIIGAST-GECPZMRISA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC(C(F)(F)F)=CC=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC(C(F)(F)F)=CC=C1 RCVRUUIWIIGAST-GECPZMRISA-N 0.000 description 1
- YQOMPXDELSHSPV-MEYGQTPLSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC2=C(C=C1)SC=C2 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC2=C(C=C1)SC=C2 YQOMPXDELSHSPV-MEYGQTPLSA-N 0.000 description 1
- MLKZJHLPWQSGHM-JYIDZMCVSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC2=C(C=C1)SC=N2 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC2=C(C=C1)SC=N2 MLKZJHLPWQSGHM-JYIDZMCVSA-N 0.000 description 1
- IZQJDEVUOHLUBO-GKASCSKRSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC2=C(C=CC=C2F)C=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC2=C(C=CC=C2F)C=C1 IZQJDEVUOHLUBO-GKASCSKRSA-N 0.000 description 1
- UYQKCFQKUYBPCN-GECPZMRISA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC=C(C(F)(F)F)C=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CC=C(C(F)(F)F)C=C1 UYQKCFQKUYBPCN-GECPZMRISA-N 0.000 description 1
- NPHQIGDXRHBCPL-QNSJUHLCSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CN=CC=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=CN=CC=C1 NPHQIGDXRHBCPL-QNSJUHLCSA-N 0.000 description 1
- FUUQYYSQBLWYLA-KWQQHVHJSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=NC2=C(C=CC=C2)S1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=NC2=C(C=CC=C2)S1 FUUQYYSQBLWYLA-KWQQHVHJSA-N 0.000 description 1
- RLCCRPCXZSVRCH-PDVXFVOMSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=NC2=C(S1)C(F)=CC=C2 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C1=NC2=C(S1)C(F)=CC=C2 RLCCRPCXZSVRCH-PDVXFVOMSA-N 0.000 description 1
- LUSUEWLCBVFMPQ-TVIJTFOQSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C=CC1=C(F)C=C(F)C=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CCC(O)C=CC1=C(F)C=C(F)C=C1 LUSUEWLCBVFMPQ-TVIJTFOQSA-N 0.000 description 1
- SQGUTRPRKHMHCP-VBRDFVIOSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@H](O)C1=C(F)C2=C(C=CC=C2)C=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@H](O)C1=C(F)C2=C(C=CC=C2)C=C1 SQGUTRPRKHMHCP-VBRDFVIOSA-N 0.000 description 1
- DEEKBLUDVGZTLE-PYIJOLGTSA-N O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@H](O)C1=C(F)C=CC=C1 Chemical compound O=C(O)CCCCCC[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@H](O)C1=C(F)C=CC=C1 DEEKBLUDVGZTLE-PYIJOLGTSA-N 0.000 description 1
- WMSPXQJUXIBGKJ-HOBFEBRJSA-N OC(CC[C@H](C(CCCCCCC(NO)=O)[C@H](C1)O)[C@@H]1O)c1nc(cccc2)c2[s]1 Chemical compound OC(CC[C@H](C(CCCCCCC(NO)=O)[C@H](C1)O)[C@@H]1O)c1nc(cccc2)c2[s]1 WMSPXQJUXIBGKJ-HOBFEBRJSA-N 0.000 description 1
- SQGUTRPRKHMHCP-UKZVQBFXSA-N O[C@@H](CCC([C@@H](CCCCCCC(O)=O)[C@H](C1)O)[C@@H]1O)c(ccc1c2cccc1)c2F Chemical compound O[C@@H](CCC([C@@H](CCCCCCC(O)=O)[C@H](C1)O)[C@@H]1O)c(ccc1c2cccc1)c2F SQGUTRPRKHMHCP-UKZVQBFXSA-N 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 1
- 239000011609 ammonium molybdate Substances 0.000 description 1
- 235000018660 ammonium molybdate Nutrition 0.000 description 1
- 229940010552 ammonium molybdate Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000037118 bone strength Effects 0.000 description 1
- 230000007883 bronchodilation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940119743 dextran 70 Drugs 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- 230000004821 effect on bone Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical class O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000003529 luteolytic effect Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 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
- 230000003278 mimic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011809 primate model Methods 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- KJIOQYGWTQBHNH-UHFFFAOYSA-N undecanol Chemical compound CCCCCCCCCCCO KJIOQYGWTQBHNH-UHFFFAOYSA-N 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0016—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing only hydroxy, etherified or esterified hydroxy groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Physical Education & Sports Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
This is a reissue of U.S. Pat. No. 6,586,463 and also a continuation reissue application of Reissue application Ser. No. 11/174,420. More than one reissue application has been filed for the reissue of U.S. Pat. No. 6,586,463. The reissue applications are application Ser. Nos. 12/479,532 (which is the present application) and 11/174,420 (which is abandoned), both of which are reissues of U.S. Pat. No. 6,586,463. Re. application Ser. No. 11/174,420, filed Jul. 1, 2005 now abandoned, is a reissue application of application Ser. No. 09/946,021, filed Sep. 4, 2001, now U.S. Pat. No. 6,586,463, which is a continuation under 35 U.S.C. §120 of PCT International Application Ser. No. PCT/US00/05301, filed Feb. 29, 2000; which claims priority to Provisional Application Ser. No. 60/122,924, filed Mar. 5, 1999.
The subject invention relates to certain novel analogs of the naturally occurring prostaglandins. Specifically, the subject invention relates to novel Prostaglandin F analogs. The subject invention further relates to methods of using said novel Prostaglandin F analogs. Preferred uses include methods of treating bone disorders and glaucoma.
Naturally occurring prostaglandins (PGA, PGB, PGE, PGF, and PGI) are C-20 unsaturated fatty acids. PGF2, the naturally occurring Prostaglandin F in humans, is characterized by hydroxyl groups at the C9 and C11 positions on the alicyclic ring, a cis-double bond between C5 and C6, and a trans-double bond between C13 and C14. Thus PGF2 has the following formula:
Analogs of naturally occurring Prostaglandin F have been disclosed in the art. For example, see U.S. Pat. No. 4,024,179 issued to Bindra and Johnson on May 17, 1977; German Patent No. DT-002,460,990 issued to Beck, Lerch, Seeger, and Teufel published on Jul. 1, 1976; U.S. Pat. No. 4,128,720 issued to Hayashi, Kori, and Miyake on Dec. 5, 1978; U.S. Pat. No. 4,011,262 issued to Hess, Johnson, Bindra, and Schaaf on Mar. 8, 1977; U.S. Pat. No. 3,776,938 issued to Bergstrom and Sjovall on Dec. 4, 1973; P. W. Collins and S. W. Djuric, “Synthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogs”, Chem. Rev. Vol. 93 (1993), pp. 1533-1564; G. L. Bundy and F. H. Lincoln, “Synthesis of 17-Phenyl-18,19,20-Trinorprostaglandins: I. The PG1 Series”, Prostaglandins, Vol. 9 No. 1 (1975), pp. 1-4; W. Bartman, G. Beck, U. Lerch, H. Teufel, and B. Scholkens, “Luteolytic Prostaglandins: Synthesis and Biological Activity”, Prostaglandins, Vol. 17 No. 2 (1979), pp. 301-311; C. liljebris, G. Selen, B. Resul, J. Stemschantz, and U. Hacksell, “Derivatives of 17-Phenyl-18,19,20-trinorprostaglandin F2α Isopropyl Ester: Potential Antiglaucoma Agents”, Journal of Medicinal Chemistry, Vol. 38 No. 2 (1995), pp. 289-304.
Naturally occurring prostaglandins are known to possess a wide range of pharmacological properties. For example, prostaglandins have been shown to: relax smooth muscle, which results in vasodilatation and bronchodilatation, to inhibit gastric acid secretion, to inhibit platelet aggregation, to reduce intraocular pressure, and to induce labor. Although naturally occurring prostaglandins are characterized by their activity against a particular prostaglandin receptor, they generally are not specific for any one prostaglandin receptor. Therefore, naturally-occurring prostaglandins are known to cause side effects such as inflammation, as well as surface irritation when administered systemically. It is generally believed that the rapid metabolism of the naturally occurring prostaglandins following their release in the body limits the effects of the prostaglandin to a local area. This effectively prevents the prostaglandin from stimulating prostaglandin receptors throughout the body and causing the effects seen with the systemic administration of naturally occurring prostaglandins.
Prostaglandins, especially prostaglandins of the E series (PGE), are known to be potent stimulators of bone resorption. PGF2 has also been shown to be a stimulator of bone resorption but not as potent as PGE2. Also, it has been demonstrated the PGF2 has little effect on bone formation as compared to PGE2. It has been suggested that some of the effects of PGF2 on bone resorption, formation and cell replication may be mediated by an increase in endogenous PGE2 production.
In view of both the wide range of pharmacological properties of naturally occurring prostaglandins and of the side effects seen with the systemic administration of these naturally occurring prostaglandins, attempts have been made to prepare analogs to the naturally occurring prostaglandins that are selective for a specific receptor or receptors. A number of such analogs have been disclosed in the art. Though a variety of prostaglandin analogs have been disclosed, there is a continuing need for potent, selective prostaglandin analogs for the treatment of a variety diseases and conditions.
The invention provides novel PGF analogs. In particular, the present invention relates to compounds having a structure according to the following formula:
This invention also includes optical isomers, diastereomers and enantiomers of the formula above, and pharmaceutically-acceptable salts, biohydrolyzable amides, esters, and imides thereof.
The compounds of the present invention are useful for the treatment of a variety of diseases and conditions, such as bone disorders and glaucoma. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for bone disorders and glaucoma using theses compounds or the compositions containing them.
“Alkyl” is a saturated or unsaturated hydrocarbon chain having 1 to 18 carbon atoms, preferably 1 to 12, more preferably 1 to 6, more preferably still 1 to 4 carbon atoms. Alkyl chains may be straight or branched. Preferred branched alkyl have one or two branches, preferably one branch. Preferred alkyl are saturated. Unsaturated alkyl have one or more double bonds and/or one or more triple bonds. Preferred unsaturated alkyl have one or two double bonds or one triple bond, more preferably one double bond. Alkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted alkyl are mono-, di-, or trisubstituted. The substituents may be lower alkyl, halo, hydroxy, aryloxy (e.g., phenoxy), acyloxy (e.g., acetoxy), carboxy, monocyclic aromatic ring (e.g., phenyl), monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, and amino.
“Lower alkyl” is an alkyl chain comprised of 1 to 6, preferably 1 to 3 carbon atoms.
“Aromatic ring” is an aromatic hydrocarbon ring. Aromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic aromatic rings contain from about 5 to about 10 carbon atoms, preferably from 5 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Bicyclic aromatic rings contain from 8 to 12 carbon atoms, preferably 9 or 10 carbon atoms in the ring system. Bicyclic aromatic rings include ring systems wherein one ring in the system is aromatic. Preferred bicyclic aromatic rings are ring systems wherein both rings in the system are aromatic. Aromatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo and haloalkyl. Preferred aromatic rings include naphthyl and phenyl. The most preferred aromatic ring is phenyl.
“Carbocyclic aliphatic ring” is a saturated or unsaturated hydrocarbon ring. Carbocyclic aliphatic rings are not aromatic. Carbocyclic aliphatic rings are monocyclic. Carbocyclic aliphatic rings contain from about 4 to about 10 carbon atoms, preferably from 4 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Carbocyclic aliphatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo and haloalkyl. Preferred carbocyclic aliphatic rings include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. More preferred carbocyclic aliphatic rings include cyclohexyl, cycloheptyl, and cyclooctyl.
“Halo” is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred are chloro and fluoro, especially fluoro.
“Haloalkyl” is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents. Preferred haloalkyl are C1-C12; more preferred are C1-C6; more preferred still are C1-C3. Preferred halo substituents are fluoro and chloro. The most preferred haloalkyl is trifluoromethyl.
“Heteroalkyl” is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 1 to 18 member atoms (carbon and heteroatoms) in the chain, preferably 1 to 12, more preferably 1 to 6, more preferably still 1 to 4. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more double bonds and/or one or more triple bonds. Preferred unsaturated heteroalkyl have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di-, or trisubstituted. The substituents may be lower alkyl, halo, hydroxy, aryloxy (e.g., phenoxy), acyloxy (e.g., acetoxy), carboxy, monocyclic aromatic ring (e.g., phenyl), monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, and amino.
“Lower heteroalkyl” is a heteroalkyl chain comprised of 1 to 6, preferably 1 to 3 member atoms.
“Heteroaromatic ring” is an aromatic ring containing carbon and from 1 to about 4 heteroatoms in the ring. Heteroaromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaromatic rings contain from about 5 to about 10 member atoms (carbon and heteroatoms), preferably from 5 to 7, and most preferably from 5 to 6 in the ring. Bicyclic heteroaromatic rings include ring systems wherein only one ring in the system is aromatic. Preferred bicyclic heteroaromatic rings are ring systems wherein both rings in the system are aromatic. Bicyclic heteroaromatic rings contain from 8 to 12 member atoms, preferably 9 or 10 in the ring. Heteroaromatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo, haloalkyl, and phenyl. Preferred monocyclic heteroaromatic rings include thienyl, thiazolo, purinyl, pyrimidyl, pyridyl, and furanyl. More preferred monocyclic heteroaromatic rings include thienyl, furanyl, and pyridyl. The most preferred monocyclic heteroaromatic ring is thienyl. Preferred bicyclic heteroaromatic rings include benzo[β]thiazolyl, benzo[β]thiophenyl, quinolinyl, quinoxalinyl, benzo[β]furanyl, benzimidizolyl, benzoxazolyl, indolyl, and anthranilyl. More preferred bicyclic heteroaromatic rings include benzo [β]thiazolyl, benzo [β]thiophenyl, and benzoxazolyl.
“Heteroatom” is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.
“Heterocyclic aliphatic ring” is a saturated or unsaturated ring containing carbon and from 1 to about 4 heteroatoms in the ring, wherein no two heteroatoms are adjacent in the ring and no carbon in the ring that has a heteroatom attached to it also has a hydroxyl, amino, or thiol group attached to it. Heterocyclic aliphatic rings are not aromatic. Heterocyclic aliphatic rings are monocyclic. Heterocyclic aliphatic rings contain from about 4 to about 10 member atoms (carbon and heteroatoms), preferably from 4 to 7 member atoms, and most preferably from 5 to 6 member atoms in the ring. Heterocyclic aliphatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo and haloalkyl. Preferred heterocyclic aliphatic rings include piperzyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and piperdyl.
“Phenyl” is a monocyclic aromatic ring which may or may not be substituted with from about 1 to about 4 substituents. The substituents may be fused but not bridged and may be substituted at the ortho, meta or para position on the phenyl ring, or any combination thereof. The substituents may be halo, acyl, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents on the phenyl ring include halo and haloalkyl. The most preferred substituent is halo. The preferred substitution pattern on the phenyl ring is ortho or meta. The most preferred substitution pattern on the phenyl ring is meta.
The subject invention involves compounds having the following structure:
In the above structure, R1 is CO2H, C(O)NHOH, CO2R3, CH2OH, S(O)2R3, C(O)NHR3, C(O)NHS(O)2R4, or tetrazole; wherein R3 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; and R4 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring. Preferred R3 is methyl, ethyl, and isopropyl. Preferred R, is CO2H, C(O)NHOH, CO2R3, C(O)NHS(O)2R4, and tetrazole. Most preferred R, is CO2H and CO2R3.
In the above structure, R2 is H or lower alkyl. The most preferred R2 is H.
In the above structure, X is C≡C or a covalent bond.
In the above structure, Z is an aromatic ring or a heteroaromatic ring provided that when Z is a heteroaromatic ring and X is a covalent bond, Z is attached to C15 via a Carbon member atom. When X is C≡C, preferred Z is monocyclic aromatic ring. When X is C≡C, more preferred Z is furanyl, thienyl, and phenyl. When X is a covalent bond, preferred Z is a bicyclic heteroaromatic ring.
The invention also includes optical isomers, diastereomers and enantiomers of the above structure. Thus, at all stereocenters where stereochemistry is not defined (C11, C12, and C15), both epimers are envisioned. Preferred stereochemistry at all such stereocenters of the compounds of the invention mimic that of naturally occurring PGF2.
As can be readily seen from the description above, the invention can be placed into two subgenuses based upon the functional group “X.” Formula A1 (X is C≡C) and Formula A2 (X is a covalent bond) below depict these two subgenuses:
It has been discovered that the novel PGF analogs of the subject invention are useful for treating bone disorders, especially those that require a significant increase in bone mass, bone volume, or bone strength. Surprisingly, the compounds of the subject invention have been found to provide the following advantages over known bone disorder therapies: (1) An increase trabecular number through formation of new trabeculae; (2) An increase in bone mass and bone volume while maintaining a more normal bone turn-over rate; and/or (3) An increase in bone formation at the endosteal surface without increasing cortical porosity.
In order to determine and assess pharmacological activity, testing of the subject compounds in animals is carried out using various assays known to those skilled in the art. For example, the bone activity of the subject compounds can be conveniently demonstrated using an assay designed to test the ability of the subject compounds to increase bone volume, mass, or density. An example of such assays is the ovariectomized rat assay.
In the ovariectomized rat assay, six-month old rats are ovariectomized, aged 2 months, and then dosed once a day subcutaneously with a test compound. Upon completion of the study, bone mass and/or density can be measured by dual energy x-ray absorptometry (DXA) or peripheral quantitative computed tomography (pQCT), or micro computed tomography (mCT). Alternatively, static and dynamic histomorphometry can be used to measure the increase in bone volume or formation.
Pharmacological activity for glaucoma can be demonstrated using assays designed to test the ability of the subject compounds to decrease intraocular pressure. Examples of such assays are described in the following reference, incorporated herein: C. liljebris, G. Selen, B. Resul, J. Sternschantz, and U. >Hacksell, “Derivatives of 17-Phenyl-18,19,20-trinorprostaglandin F2α Isopropyl Ester: Potential Antiglaucoma Agents”, Journal of Medicinal Chemistry, Vol. 38 No. 2 (1995), pp. 289-304.
Compounds useful in the subject invention can be made using conventional organic syntheses. A particularly preferred synthesis is the following general reaction scheme:
In Scheme 1, R1, R2, X, and Z are as defined above. The methyl 7[3-(R)-hydroxy-5-oxo-1-cyclopent-1-yl] heptanoate (S1a) depicted as starting material for Scheme 1 is commercially available (such as from Sumitomo Chemical or Cayman Chemical).
The C11 alcohol of methyl 7-[3-(R)-hydroxy-5-oxo-1-cyclopent-1-yl] protecting group is a silyl group. In the above Scheme 1, methyl 7-[3-(R)-hydroxy-5-oxo-1-cyclopent-1-yl] heptanoate (S1a) is reacted with a silylating agent and base in a solvent that will allow the silylation to proceed. Preferred silylating agents include tert-butyldimethylsilyl chloride and tert-butyldimethylsilyl trifluoromethanesulphonate. The most preferred silylating agent is tert-butyldimethylsilyl trifluoromethanesulphonate. Preferred bases include triethylamine, trimethylamine, and 2,6-lutidine. More preferred bases include triethylamine and 2,6-lutidine. The most preferred base is 2,6-lutidine. Preferred solvents include halocarbon solvents with dichloromethane being the most preferred solvent. The reaction is allowed to proceed at a temperature preferably between −100° C. and 100° C., more preferably between −80° C. and 80° C., and most preferably between −70° C. and 23° C.
The resulting silylated compound is isolated by methods known to those of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, the silyl ether is purified after isolation by distillation under vacuum.
The silylated compound is then reacted with the cuprate generated via Grignard formation of the appropriate alkenyl bromide as disclosed, for example, in the following references: H. O. House et. al., “The Chemistry of Carbanions: A Convenient Precursor for the Generation of Lithium Organocuprates”, J. Org. Chem. Vol. 40 (1975) pp. 1460-69; and P. Knochel et. al., “Zinc and Copper Carbenoids as Efficient and Selective a'/d' Multicoupling Reagents”, J. Amer. Chem. Soc. Vol. 111 (1989) p. 6474-76. Preferred alkenyl bromides include 4-bromo-1-butene, 4-bromo-1-butyne, 4-bromo-2-methyl-1-butene, and 4-bromo-2-ethyl-1-butene. The most preferred alkenyl bromide is 4-bromo-1-butene. Preferred solvents include ethereal solvents, of which diethyl ether and tetrahydrofuran are preferred. The most preferred solvent is tetrahydrofuaran. The Grignard reagent is allowed to form at a temperature between 100° C. and 23° C., more preferably between 85° C. and 30° C., and most preferably between 75° C. and 65° C. The reaction time is preferably between 1 hour and 6 hours, with a more preferred reaction time being between 2 hours and 5 hours, and the most preferred reaction time being between 3 hours and 4 hours.
Once the Grignard reagent is formed, the cuprate is generated from the alkenyl magnesium species. The temperature range for cuprate formation is between −100° C. and 0° C. The preferred temperature range is between −80° C. and −20° C. The more preferred temperature range is between −75° C. and −50° C. The preferred reaction time is between 30 minutes and 6 hours. The more preferred reaction time is between 45 minutes and 3 hours. The most preferred reaction time is between 1 hours and 1.5 hours.
The alkene thus formed is isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, the alkene is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 10% EtOAc/hexanes as the eluent. The alkene is then reacted with a hydride reducing agent and a polar, protic solvent to give the C-9 alcohol. Preferred reducing agents include lithium aluminum hydride, sodium borohydride, and L-selectride. More preferred reducing agents include sodium borohydride, and L-selectride. The most preferred reducing agent is sodium borohydride. Preferred solvents include methanol, ethanol, and butanol. The most preferred solvent is methanol. The reduction is carried out at a temperature between −100° C. and 23° C. The preferred temperature range is between −60° C. and 0° C. The most preferred temperature range is between −45° C. and −20° C.
The resulting alcohol is isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, the alcohol is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent.
The resultant alcohol can be protected as described previously herein. Preferred silylating agents in this case also include tert-butyldimethylsilyl chloride and tert-butyldimethylsilyl trifluoromethanesulphonate. The most preferred silylating agent is tert-butyldimethylsilyl trifluoromethanesulphonate. Preferred bases include triethylamine, trimethylamine, and 2,6-lutidine. More preferred bases include triethylamine and 2,6-lutidine. The most preferred base is 2,6-lutidine. Preferred solvents include halocarbon solvents with dichloromethane being the most preferred solvent. The reaction is allowed to proceed at a temperature preferably between −100° C. and 100° C., more preferably between −80° C. and 80° C., and most preferably between −70° C. and 23° C.
The resulting silylated compound is isolated by methods known to those of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, the silyl ether is purified after isolation by distillation under vacuum.
The protected or alcohol is then treated with a form of osmium, and sodium periodate in a solvent where they are both soluble. Preferred forms of osmium include osmium tetraoxide and potassium osmate. Preferred solvent systems include 1:1 mixtures of acetic acid and water and 1:1:2 mixtures of water, acetic acid and THF. The result of this treatment is the aldehyde, S1b.
The compound S1b is isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, S1b is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent.
The key intermediate aldehyde depicted as S1b can be reacted with a variety unsaturated carbon nucleophiles to provide the C-9 and C-11-protected 13,14-dihydro-16-tetranor prostaglandin F1α derivatives depicted as S1c.
With alkyne nucleophiles, the reaction is carried out preferably at between −80° C. and 0° C., more preferably between −80° C. and −20° C., and most preferably between −80° C. and −40° C. Preferred bases for the reaction include n-butyl lithium, s-butyl lithium, t-butyl lithium, and lithium diisopropyl amide (LDA). Preferred solvents for the reaction are ether solvents. Preferred solvents include diethyl ether, and tetrahydrofuran. The most preferred solvent is tetrahydrofaran. With heterocyclic nucleophiles, preferred solvents include ethereal solvents. More preferred ethereal solvents include diethyl ether, dibutyl ether and tetrahydrofuran. The most preferred ethereal solvent is tetrahydrofuran.
The resulting compounds depicted as S1c can then be deprotected using techniques known to one of ordinary skill in the art, and isolated yielding the 13,14-dihydro-15-substituted-15-pentanor prostaglandin Flot derivatives depicted by Formula I. Compounds depicted by Formula I are exemplified in Examples 1-43.
Compounds depicted by Formula II can be made directly from the C-9 and C-11-protected 13,14-dihydro-16-tetranor prostaglandin F1α derivatives depicted as S1c by methods known to one of ordinary skill in the art. For example, the condensation of methyl esters of S1c with amines or hydroxylamine provides compounds depicted by Formula II. Compounds depicted by Formula II are exemplified in Examples 44-47. These compounds are isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization.
The following non-limiting examples illustrate the compounds, compositions, and uses of the present invention.
Compounds are analyzed using 1H and 13C NMR, Elemental analysis, mass spectra, high resolution mass spectra and/or IR spectra as appropriate.
Typically, inert solvents are used, preferably in dried form. For example, tetrahydrofuran (THF) is distilled from sodium and benzophenone, diisopropylamine is distilled from calcium hydride and all other solvents are purchased as the appropriate grade. Chromatography is performed on silica gel (70-230 mesh; Aldrich) or (230-400 mesh; Merck) as appropriate. Thin layer chromatography analysis is performed on glass mounted silica gel plates (200-300 mesh; J. T. Baker) and visualized using uv light, 5% phosphomolybdic acid in EtOH, or ammonium molybdate/cerric sulfate in 10% aqueous H2SO4.
To a solution of Methyl-7-[3-(R)-hydroxy-5-oxo-1-cyclopenten-1-yl] heptanoate S2a (1 equiv.) in CH2Cl2 at −78° C. is added 2,6 Lutidine (1.3 equiv.) dropwise over 15 minutes. The solution is kept at −78° C., and TBDMS Triflate (1.2 equiv.) in CH2Cl2 is added dropwise over 15 minutes. The reaction is warmed gradually to room temperature and stirred at room temperature for 15 hours. Aqueous 10% HCl is added and the layers are separated. The water layer is extracted with CH2Cl2 and the organic layers are combined. The organic layer is washed with brine, dried (Na2SO4) and concentrated. The residue is distilled under vacuum (10 mm Hg) to provide the silyl ether S2b.
To a slurry of Mgo powder (2 equiv.) in THF at room temperature is added one crystal of iodine (catalytic 12)and 1-bromobutene (2 equiv.) dropwise over 10 minutes. The reaction proceeds to exotherm as the addition continues. After the addition is complete, the reaction is refluxed for 3 hours and cooled to room temperature. The Grignard is diluted with THF and added via cannula to a 3-necked flask equipped with mechanical stirring and charged with CuBr.DMS (2 equiv.) in a 1:1 solution of THF/DMS at −78° C. After the addition of the Grignard (20 min), the reaction is stirred for 1 hour at −78° C. The color of the reaction is dark red at this point. A solution of the ketone S2b (1 equiv.) in THF is then added dropwise over 25 minutes. The reaction is stirred at −78° C. for 15 minutes, then allowed to warm slowly to room temperature over 2 hours. The reaction is quenched with aqueous NH4Cl and the excess DMS is allowed to evaporate overnight. The reaction is partitioned between brine/CH2Cl2and the layers are separated. The aqueous layer is back-extracted with CH2Cl2 and the organic layers are combined and dried (Na2SO4). The solvent is removed in vacuo and the residue is chromatographed on SiO2 (10% hexane/EtOAc) to give the ketone precursor to S2c.
The ketone precursor to S2c (1 equiv.) is dissolved in MeOH and cooled to −40° C. Sodium borohydride (0.9 equiv.) is added portionwise over 10 minutes. After the addition is complete, the reaction is stirred for 13 hours at −40° C. and then for 12 hours at −78° C. The reaction is quenched with water, partitioned between brine and CH2Cl2, and the layers separated. The aqueous layer is back-extracted with CH2Cl2 and the organic layers are combined and dried (Na2SO4). The solvent is removed in vacuo and the residue chromatographed on SiO2 (30% EtOAc/hexanes) to give the alcohol S2c.
The alcohol S2c (1 equiv.) is dissolved in CH2Cl2 and cooled to 0° C. and added is 2,6 lutidine (1.3 equiv.) dropwise over 15 minutes. The solution is kept at −78° C., and TBDMS Triflate (1.2 equiv.) in CH2Cl2 is added dropwise over 15 minutes. The reaction is warmed gradually to room temperature and stirred at room temperature for 15 hours. Aqueous 10% HCl is added and the layers are separated. The water layer is extracted with CH2Cl2 and the organic layers are combined. The organic layer is washed with brine, dried (Na2SO4) and concentrated. The residue is chromatographed (10% EtOAc in hexanes) to provide the silyl ether S2d.
In a 50 mL round-bottomed flask, Sodium periodate (2 equiv.) and 10 mL of water are added. This is stirred until the periodate has completely dissolved. Then an equal portion of glacial acetic acid is added, followed by two portions of tetrahydrofuran. Finally, a few mole percent of potassium osmate are added, followed by the alkene S2d (1 equiv.). The reaction is stirred at room temperature under nitrogen with TLC being used to monitor the reaction. When no starting material is evident by TLC, The reaction is quenched with brine and is extracted with ethyl acetate and hexanes in a 4:1 ratio. The organic layer is washed with brine to neutral pH, dried over sodium sulfate, and concentrated. After column chromatography, (7:3, Hexane: Ethyl Acetate) S2e is obtained.
The aldehyde S2e is dissolved in a few mL of dry THF and is added dropwise to a −78° C. THF solution of the lithium anion of thianapthylene (prepared by combining n-butyl lithium and thianaphthylene at −78° C.) a 50 mL round-bottomed flask. This is stirred until the reaction has ceased to progress as evidenced by TLC. Then the reaction is quenched at −78° C. with a saturated solution of ammonium chloride and is extracted with ethyl acetate and hexanes in a 4:1 ratio. The organic layer is washed with brine to neutral pH, dried over sodium sulfate, and concentrated. After column chromatography, (7:3, Hexane: Ethyl Acetate) S2f is obtained.
To a small round-bottomed flask, is added methyl ester S2f and 3 mL of CH3CN and 0.1 mL of HF/Pyridine (0.1 mmol, 1 equiv.) are added while the flask is warmed from 0° C. to room temperature. After 3 hours at 21° C., the reaction is quenched with saturated aqueous NaCl. The aqueous layer is extracted three times with CH2Cl2. The organic layers are combined and washed three time with 1N HCl, brine, and dried (Na2SO4). After column chromatography, (7:3, Hexane: Ethyl Acetate) a clear oil is obtained. This oil is added to a few mL of a 3:1 THF: water solution, and the flask is cooled to 0° C. An excess amount (2.5 equiv.) of lithium hydroxide is added, the ice bath is removed, and the reaction is stirred at room temperature overnight. Methylene chloride and saturated citric acid are added to the reaction mixture, the aqueous layer is washed 3 times with methylene chloride, the organic layers are combined and washed with brine, dried (Na2SO4), concentrated in vacuo, and the residue is chromatographed (methylene chloride, methanol, acetic acid, 9.6, 0.4, 0.015), to provide S2g.
Examples 2-22 are prepared using substantially the same procedures as those described in Example 1, substituting the appropriate starting materials. The skilled artisan may change temperature, pressure, atmosphere, solvents or the order of reactions as appropriate. Additionally, the skilled artisan may use protecting groups to block side reactions or increase yields as appropriate. All such modifications can readily be carried out by the skilled artisan in the art of organic chemistry, and thus are within the scope of the invention.
10
The aldehyde S2e from Example 1 is dissolved in a few mL of dry THF and is added dropwise to a −78° C. THF solution of the Grignard species (prepared by combining Magnesium and bromobenzene at 0° C.) a 50 mL round-bottomed flask. This is stirred until the reaction has ceased to progress as evidenced by TLC. Then the reaction is quenched at −78° C. with a saturated solution of ammonium chloride and is extracted with ethyl acetate and hexanes in a 4:1 ratio. The organic layer is washed with brine to neutral pH, dried over sodium sulfate, and concentrated. After column chromatography, (7:3, Hexane: Ethyl Acetate) S3a is obtained.
To a small round-bottomed flask, is added methyl ester S3a and 3 mL of CH3CN and 0.1 mL of HF/Pyridine (0.1 mmol, 1 equiv.) are added while the flask is warmed from 0° C. to room temperature. After 3 hours at 21° C., the reaction is quenched with saturated aqueous NaCl. The aqueous layer is extracted three times with CH2Cl2. The organic layers are combined and washed three time with 1N HCl, brine, and dried (Na2SO4). After column chromatography, (97:3, dichloromethane:methanol) a clear oil is obtained. This oil is added to a few mL of a 3:1 THF: water solution, and the flask is cooled to 0° C. An excess amount (2.5 equiv.) of lithium hydroxide is added, the ice bath is removed, and the reaction is stirred at room temperature overnight. Methylene chloride and saturated citric acid are added to the reaction mixture, the aqueous layer is washed 3 times with methylene chloride, the organic layers are combined and washed with brine, dried (Na2SO4), concentrated in vacuo, and the residue is chromatographed (methylene chloride, methanol, acetic acid, 9.6, 0.4, 0.015), to provide S3b.
Examples 24-35 are prepared using substantially the same procedures as those described in Example 23, substituting the appropriate starting materials. The skilled artisan may change temperature, pressure, atmosphere, solvents or the order of reactions as appropriate. Additionally, the skilled artisan may use protecting groups to block side reactions or increase yields as appropriate. All such modifications can readily be carried out by the skilled artisan in the art of organic chemistry, and thus are within the scope of the invention.
The aldehyde S2e from Example 1 is dissolved in a few mL of dry THF and is added dropwise to a −78° C. THF solution of naphthyl anion (prepared by t-butyl Lithium and the naphthyl bromide at −78° C.) a 50 mL round-bottomed flask. This is stirred until the reaction has ceased to progress as evidenced by TLC. Then the reaction is quenched at −78° C. with a saturated solution of ammonium chloride and is extracted with ethyl acetate and hexanes in a 4:1 ratio. The organic layer is washed with brine to neutral pH, dried over sodium sulfate, and concentrated. After column chromatography, (7:3, Hexane: Ethyl Acetate) S4a is obtained.
To a small round-bottomed flask, is added methyl ester S4a and 3 mL of CH3CN and 0.1 mL of HF/Pyridine (0.1 mmol, 1 equiv.) are added while the flask is warmed from 0° C. to room temperature. After 3 hours at 21° C., the reaction is quenched with saturated aqueous NaCl. The aqueous layer is extracted three times with CH2Cl2. The organic layers are combined and washed three time with 1N HCl, brine, and dried (Na2SO4). After column chromatography, (97:3, dichlormethane:methanol) a clear oil is obtained. This oil is added to a few mL of a 3:1 THF: water solution, and the flask is cooled to 0° C. An excess amount (2.5 equiv.) of lithium hydroxide is added, the ice bath is removed, and the reaction is stirred at room temperature overnight. Methylene chloride and saturated citric acid are added to the reaction mixture, the aqueous layer is washed 3 times with methylene chloride, the organic layers are combined and washed with brine, dried (Na2SO4), concentrated in vacuo, and the residue is chromatographed (methylene chloride, methanol, acetic acid, 9.6, 0.4, 0.015), to provide S4b.
Examples 37-42 are prepared using substantially the same procedures as those described in Example 36, substituting the appropriate starting materials. The skilled artisan may change temperature, pressure, atmosphere, solvents or the order of reactions as appropriate. Additionally, the skilled artisan may use protecting groups to block side reactions or increase yields as appropriate. All such modifications can readily be carried out by the skilled artisan in the art of organic chemistry, and thus are within the scope of the invention.
In a flame-dried 25 mL round-bottomed flask equipped with a magnetic stir bar is placed 13,14-dihydro-16,17-didehydro-17-o-fluorophenyl trinor Prostaglandin F1α methyl ester (Example 17) (1.0 equiv.) in methanol. To this solution is added hydroxylamine in methanol (1.25 equiv.). The solution stirred for a few minutes. The solution is then treated with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue is purified by chromatography to give 13,14-dihydro-16,17-didehydro-17-o-fluorophenyl trinor Prostaglandin F1α 1-hydroxamic acid.
Examples 45-47 are prepared using substantially the same procedures as those described in Example 44, substituting the appropriate starting materials. The skilled artisan may change temperature, pressure, atmosphere, solvents or the order of reactions as appropriate. Additionally, the skilled artisan may use protecting groups to block side reactions or increase yields as appropriate. All such modifications can readily be carried out by the skilled artisan in the art of organic chemistry, and thus are within the scope of the invention.
Compositions of the subject invention comprise a safe and effective amount of the subject compounds, and a pharmaceutically-acceptable carrier. As used herein, “safe and effective amount” means an amount of a compound sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
In addition to the compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier. The term “pharmaceutically-acceptable carrier”, as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a subject. The term “compatible”, as used herein, means that the components of the composition are capable of being commingled with the compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the subject being treated.
Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens®; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents, excipients; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
The choice of a pharmaceutically-acceptable carrier to be used in conjunction with a compound is basically determined by the way the compound is to be administered. The compounds of the present invention may be administered systemically. Routes of administration include transdermal; oral; parenterally, including subcutaneous or intravenous injection; topical; and/or intranasal.
The appropriate amount of the compound to be used may be determined by routine experimentation with animal models. Such models include, but are not limited to the intact and ovariectomized rat models, the ferret, canine, and non human primate models as well as disuse models.
Preferred unit dosage forms for injection include sterile solutions of water, physiological saline, or mixtures thereof. The pH of said solutions should be adjusted to about 7.4. Suitable carriers for injection or surgical implants include hydrogels, controlled- or sustained release devises, polylactic acid, and collagen matrices.
Suitable pharmaceutically-acceptable carriers for topical application include those suited for use in lotions, creams, gels and the like. If the compound is to be administered perorally, the preferred unit dosage form is tablets, capsules and the like. The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well-known in the art. Their selection will depend on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be made without difficulty by those skilled in the art.
The compounds of the present invention are useful in treating many medical disorders, including for example, ocular disorders, hypertension, fertility control, nasal congestion, neurogenic bladder disorder, gastrointestinal disorders, dermatological disorders, and osteoporosis, post-menopausal osteoporosis, osteopenia, and bone fracture.
The compounds of the present invention are useful in increasing bone volume and trabecular number through formation of new trabeculae, bone mass while maintaining a normalized bone turnover rate, and formation at the endosteal surface without removing bone from the existing cortex. Thus, these compounds are useful in the treatment and prevention of bone disorders.
The preferred routes of administration for treating bone disorders are transdermal and intranasal. Other preferred routes of administration include rectal, sublingual, and oral.
The dosage range of the compound for systemic administration is from about 0.01 to about 1000 μg/kg body weight, preferably from about 0.1 to about 100 μg/kg per body weight, most preferably form about 1 to about 50 μg/kg body weight per day. The transdermal dosages will be designed to attain similar serum or plasma levels, based upon techniques known to those skilled in the art of pharmacokinetics and transdermal formulations. Plasma levels for systemic administration are expected to be in the range of 0.01 to 100 nanograms/ml, more preferably from 0.05 to 50 ng/ml, and most preferably from 0.1 to 10 ng/ml. While these dosages are based upon a daily administration rate, weekly or monthly accumulated dosages may also be used to calculate the clinical requirements.
Dosages may be varied based on the patient being treated, the condition being treated, the severity of the condition being treated, the route of administration, etc. to achieve the desired effect.
The compounds of the present invention are also useful in decreasing intraocular pressure. Thus, these compounds are useful in the treatment of glaucoma. The preferred route of administration for treating glaucoma is topically.
The following non-limiting examples illustrate the subject invention. The following composition and method examples do not limit the invention, but provide guidance to the skilled artisan to prepare and use the compounds, compositions and methods of the invention. In each case other compounds within the invention may be substituted for the example compound shown below with similar results. The skilled practitioner will appreciate that the examples provide guidance and may be varied based on the condition being treated and the patient.
Pharmaceutical compositions in the form of tablets are prepared by conventional methods, such as mixing and direct compaction, formulated as follows:
Ingredient | Quantity (mg per tablet) | ||
Compound of Example 1 | 5 | ||
Microcrystalline Cellulose | 100 | ||
Sodium Starch Glycollate | 30 | ||
Magnesium Stearate | 3 | ||
When administered orally once daily, the above composition substantially increases bone volume in a patient suffering from osteoporosis.
Pharmaceutical compositions in liquid form are prepared by conventional methods, formulated as follows:
Ingredient | Quantity | ||
Compound of Example 32 | 1 | mg | ||
Phosphate buffered physiological saline | 10 | ml | ||
Methyl Paraben | 0.05 | ml | ||
When 1.0 ml of the above composition is administered subcutaneously once daily, the above composition substantially increases bone volume in a patient suffering from osteoporosis.
Topical pharmaceutical compositions for lowering intraocular pressure are prepared by conventional methods and formulated as follows:
Ingredient | Amount (wt %) | ||
Compound of Example 1 | 0.004 | ||
Dextran 70 | 0.1 | ||
Hydroxypropyl methylcellulose | 0.3 | ||
Sodium Chloride | 0.77 | ||
Potassium chloride | 0.12 | ||
Disodium EDTA (Edetate disodium) | 0.05 | ||
Benzalkonium chloride | 0.01 | ||
HCL and/or NaOH | pH 7.2-7.5 | ||
Purified water | q.s. to 100% | ||
While particular embodiments of the subject invention have been described, it would be obvious to those skilled in the art that various changes and modifications to the compositions disclosed herein can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.
Claims (69)
1. A compound having the structure:
wherein
a) R1 is selected from the group consisting of CO2H, C(O)NHOH, C2R3,CH2OH, S(O)2R3, C(O)NHR3. C(O)NHS(O)2R4, and tetrazole, wherein R3 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic alphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; and
R4 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring;
(b) R2 is H or lower alkyl;
(c) X is a covalent bond;
(d) Z is an aromatic ring or a heteroaromatic ring provided that when Z is a heteroaromatic ring and X is a covalent bond, Z is attached to C15 via a Carbon member atom; and
(e) any optical isomer, diastereomer enantiomer of the above structure or a pharmaceutically-acceptable salt, or bio-hydrolyzable amide, ester, or imide thereof.
2. The compound of claim 1 4 wherein R1 is selected from the group consisting of CO2H, C(O)NHOH, CO2R3, C(O))NHS(O)2R4, or tetrazole R3 is heteroalkyl, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring.
3. The compound of claim 2 wherein Z is a bicyclic heteroaromatic ring.
4. The A compound of claim 3 wherein having the structure:
wherein
(a) R1 is selected from the group consisting of CO2H, CO2R3, S(O)2R3, and C(O)NHR3, wherein R3 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring;
(b) R2 is H;
(c) X is a covalent bond;
(d) Z is selected from the group consisting of: benzo[β](β)thiazolyl, benzo[β](β)thiophenyl, thianaphthyl, and benzoxazolyl; and
(e) any optical isomer, diastereomer, enantiomer of the above structure or a pharmaceutically-acceptable salt, or bio-hydrolyzable amide, ester, or imide thereof.
5. The compound of claim 4 wherein Z is substituted with one a substituent, said one substitutent being selected from the group consisting of: lower alkyl, halo, and haloalkyl.
6. The compound of claim 4 wherein R2 is H.
7. The compound of claim 6 4 wherein R1 is CO2H or CO2R3.
8. A method of treating a human or other animal subject having a bone disorder, said method comprising administering to said subject a compound according to the structure:
wherein
(a) R1 is selected from the group consisting of CO2H, C(O)NHOH, CO2R3, CH2OH, S(O)2R3, and C(O)NHR3, C(O)NHS(O)3R4, and tetrazole;
wherein R1 R3 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; and
R4 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring;
(b) R3 R2 is H or lower alkyl;
(c) X is a covalent bond;
(d) Z is an aromatic ring or a heteroaromatic ring provided that when Z is a heteroaromatic ring and X is a covalent bond, Z is attached to C15 via a Carbon member atom selected from the group consisting of benzo(β)thiazolyl, benzo(β)thiophenyl, thianaphthyl, and benzoxazolyl; and
(e) any optical isomer, diastereomer, enantiomer of the above structure or a pharmaceutically-acceptable salt, or bio-hydrolyzable, amide, ester, or imide thereof.
9. The method of claim 8 wherein said bone disorder is osteoporosis.
10. The method of claim 9 wherein in osteoporosis is post-menopausal.
11. The method of claim 9 wherein in osteoporosis is cortico-steroid induced.
12. The method of claim 8 wherein said bone disorder is osteopenia.
13. The method of claim 8 wherein said bone disorder is a bone fracture.
14. The method of claim 8 wherein said compound is administered orally.
15. The method of claim 8 wherein said compound is administered transdermally.
16. The method of claim 8 wherein said compound is administered intranasally.
17. A method of treating glaucoma, said method comprising administering to human or other animal a safe and effective amount of a compound according to the structure:
wherein
(a) R1 is selected from the group consisting of CO3H CO2H, C(O)NHOH, CO2R3, CH2OH, S(O)2R3, and C(O)NHR3, C(O)NHS(O)2R4, and tetrazole;
wherein R1 R3 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; and R4 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring;
(b) R2 is H or lower alkyl;
(c) X is a covalent bond;
(d) Z is an aromatic ring or a heteroaromatic ring provided that when Z is a heteroaromatic ring and X is a covalent bond, Z is attached to C15 via a Carbon member atom selected from the group consisting of benzo(β)thiazolyl, benzo(β)thiophenyl, thianaphthyl, and benzoxazolyl; and
(e) any optical isomer, diastereomer, enantiomer of the above structure or a pharmaceutically-acceptable salt, or bio-hydrolyzable, amide, ester, or imide thereof.
18. The method of claim 17 , wherein said compound is administered topiclally topically.
19. The compound of claim 4, wherein Z is benzo(β)thiophenyl.
20. The compound of claim 4, wherein R3 is methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, or phenyl.
21. The compound of claim 4, wherein R1 is CO2R3 and wherein R3 is a substituted alkyl.
22. The compound of claim 4, wherein Z is thianaphthyl, R1 is CO2R3, and R3 is an alkyl substituted with from 1 to 4 OH groups.
23. A pharmaceutical composition comprising a compound having the structure:
wherein
(a) R1 is selected from the group consisting of CO2H, CO2R3, S(O)2R3, and C(O)NHR3, wherein R3 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring;
(b) R2 is H;
(c) X is a covalent bond;
(d) Z is selected from the group consisting of benzo(β)thiazolyl, benzo(β)thiophenyl, thianaphthyl, and benzoxazolyl; and
(e) any optical isomer, diastereomer, enantiomer of the above structure or a pharmaceutically-acceptable salt, or bio-hydrolyzable amide, ester, or imide thereof; and
(f) said composition comprising a pharmaceutically acceptable carrier.
24. A compound having the structure:
wherein
(a) R1 is selected from the group consisting of C(O)NHOH, CO2R3, S(O)2R3, C(O)NHR3, C(O)NHS(O)2R4, and tetrazole, wherein R3 is substituted alkyl, heteroalkyl, substituted carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; and
R4 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring;
(b) R2 is H or lower alkyl;
(c) X is a covalent bond;
(d) Z is a bicyclic heteroaromatic ring, where Z is attached to C15 via a Carbon member atom, and wherein Z is selected from the group consisting of benzo (β)thiazolyl, benzo (β)thiophenyl, thianaphthyl, and benzoxazolyl; and
(e) any optical isomer, diastereomer, enantiomer of the above structure or a pharmaceutically-acceptable salt, or bio-hydrolyzable amide, ester, or imide thereof.
25. The compound of claim 24 wherein R3 is heteroalkyl, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring.
26. The compound of claim 24 wherein Z is substituted with a substituent, said substituent being selected from the group consisting of lower alkyl, halo, and haloalkyl.
27. The compound of claim 24 wherein R2 is H.
28. The compound of claim 27 wherein R1 is CO2R3.
29. The compound of claim 24, wherein R1 is CO2R3, and wherein R3 is a substituted alkyl.
30. The compound of claim 29, wherein R3 is substituted with an OH.
31. The compound of claim 29, wherein R3 is substituted with a substituent selected from the group consisting of halo, aryloxy, acyloxy, carboxy, monocyclic aromatic ring, monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, lower alkyl, and amino.
32. The compound of claim 29, wherein R3 is substituted with from 1 to 4 substituents.
33. The compound of claim 29, wherein R3 is substituted with from 1 to 4 OH groups.
34. The compound of claim 24, wherein Z is thianaphthyl, R1 is CO2R3 and R3 is an alkyl substituted with from 1 to 4 OH groups.
35. The compound of claim 34, wherein Z is substituted with a substituent, said substituent being selected from the group consisting of lower alkyl, halo, and haloalkyl.
36. The compound of claim 35, wherein Z is substituted with a substituent, said substituent being selected from the group consisting of lower alkyl, halo, and haloalkyl.
37. A method of treating a human or other animal subject having a bone disorder, said method comprising administering to said subject a compound according to the structure:
wherein
(a) R1 is selected from the group consisting of CO2H, C(O)NHOH, CO2R3, CH2OH, S(O)2R3, C(O)NHR3, C(O)NHS(O)2R4 and tetrazole;
wherein R3 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; and
R4 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring;
(b) R2 is H or lower alkyl;
(c) X is a covalent bond;
(d) Z is an aromatic ring or a heteroaromatic ring provided that when Z is a heteroaromatic ring and X is a covalent bond, Z is attached to C15 via a Carbon member atom; and
(e) any optical isomer, diastereomer, enantiomer of the above structure or a pharmaceutically-acceptable salt, or bio-hydrolyzable amide, ester, or imide thereof.
38. The method of claim 37 wherein said bone disorder is osteoporosis.
39. The method of claim 38 wherein osteoporosis is post-menopausal.
40. The method of claim 38 wherein osteoporosis is cortico-steroid induced.
41. The method of claim 37 wherein said bone disorder is osteopenia.
42. The method of claim 37 wherein said bone disorder is a bone fracture.
43. The method of claim 37 wherein said compound is administered orally.
44. The method of claim 37 wherein said compound is administered transdermally.
45. The method of claim 37 wherein said compound is administered intranasally.
46. The method of claim 37, wherein Z is thianaphthyl, R1 is CO2R3, and R3 is an alkyl substituted with from 1 to 4 OH groups.
47. A method of treating glaucoma, said method comprising administering to human or other animal a safe and effective amount of a compound according to the structure:
wherein
(a) R1 is selected from the group consisting of C(O)NHOH, CO2R3, S(O)2R3, C(O)NHR3, C(O)NHS(O)2R4, and tetrazole,
wherein R3 is substituted alkyl, heteroalkyl, substituted carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; and R4 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring;
(b) R2 is H or lower alkyl;
(c) X is a covalent bond;
(d) Z is a bicyclic heteroaromatic ring, provided that Z is attached to C15 via a Carbon member atom; and
(e) any optical isomer, diastereomer, enantiomer of the above structure or a pharmaceutically-acceptable salt, or bio-hydrolyzable amide, ester, or imide thereof.
48. The method of claim 47, wherein said compound is administered topically.
49. The method of claim 47, wherein R3 is heteroalkyl, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring.
50. The method of claim 47, wherein R1 is CO2R3, and wherein R3 is a substituted alkyl.
51. The method of claim 50, wherein said substituted alkyl is substituted with an OH.
52. The method of claim 47, wherein R3 is an alkyl or carbocyclic aliphatic ring substituted with a substituent selected from the group consisting of hydroxyl, halo, aryloxy, acyloxy, carboxy, monocyclic aromatic ring, monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, lower alkyl, and amino.
53. The method of claim 52, wherein R3 is substituted with from 1 to 4 substituents.
54. The method of claim 47, wherein R3 is substituted with from 1 to 4 OH groups.
55. The method of claim 47, wherein Z is thianaphthyl, R1 is CO2R3, and R3 is an alkyl substituted with from 1 to 4 OH groups.
56. The method of claim 55, wherein Z is substituted with a substituent, said substituent being selected from the group consisting of lower alkyl, halo, and haloalkyl.
57. A pharmaceutical composition comprising a compound having the structure:
wherein
(a) R1 is selected from the group consisting of C(O)NHOH, CO2R3, S(O)2R3, C(O)NHR3, C(O)NHS(O)2R4, and tetrazole, wherein R3 is substituted alkyl, heteroalkyl, substituted carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; and
R4 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring;
(b) R2 is H or lower alkyl;
(c) X is a covalent bond;
(d) Z is a bicyclic heteroaromatic ring, provided that Z is attached to C15 via a Carbon member atom, wherein Z is selected from the group consisting of benzo(β)thiazolyl, benzo(β)thiophenyl, thianaphthyl, and benzoxazolyl;
(e) any optical isomer, diastereomer, enantiomer of the above structure or bio-hydrolyzable amide, ester, or imide thereof; and
(f) said composition comprising a pharmaceutically acceptable carrier.
58. The pharmaceutical composition of claim 57, wherein R3 is heteroalkyl, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring.
59. The pharmaceutical composition of claim 57, wherein Z is substituted with a substituent, said substituent being selected from the group consisting of lower alkyl, halo, and haloalkyl.
60. The pharmaceutical composition of claim 57, wherein R2 is H.
61. The pharmaceutical composition of claim 57, wherein R3 is substituted with a substituent selected from the group consisting of hydroxyl, halo, aryloxy, acyloxy, carboxy, monocyclic aromatic ring, monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, lower alkyl, and amino.
62. The pharmaceutical composition of claim 57, wherein the pharmaceutically acceptable carrier is suitable for topical application of the composition.
63. The pharmaceutical composition of claim 57, wherein Z is thianaphthyl, R1 is CO2R3 and R3 is an alkyl substituted with from 1 to 4 OH groups.
64. A pharmaceutical composition comprising a compound having the structure:
wherein
(a) R1 is CO2R3, wherein R3 is a substituted alkyl;
(b) R2 is H or lower alkyl;
(c) X is a covalent bond;
(d) Z is a bicyclic heteroaromatic ring, provided that Z is attached to C15 via a Carbon member atom;
(e) any optical isomer, diastereomer, enantiomer of the above structure or bio-hydrolyzable amide, ester, or imide thereof; and
(f) said composition comprising a pharmaceutically acceptable carrier.
65. The pharmaceutical composition of claim 64, wherein R3 is substituted with an OH.
66. The pharmaceutical composition of claim 64, wherein R3 is substituted with from 1 to 4 substituents.
67. The pharmaceutical composition of claim 64, wherein R3 is substituted with from 1 to 4 OH groups.
68. A compound having the structure:
wherein
(a) R1 is selected from the group consisting of C(O)NHOH, CO2R3, S(O)2R3, C(O)NHR3, and C(O)NHS(O)2R4, wherein R3 is substituted alkyl, heteroalkyl, substituted carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; and
R4 is heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, or monocyclic heteroaromatic ring;
(b) R2 is H or lower alkyl;
(c) X is a covalent bond;
(d) Z is a bicyclic heteroaromatic ring where Z is attached to C15 via a Carbon member atom; and
(e) any optical isomer, diastereomer, enantiomer of the above structure or a pharmaceutically-acceptable salt, or bio-hydrolyzable amide, ester, or imide thereof.
69. A method of treating glaucoma, said method comprising administering to human or other animal a safe and effective amount of a compound according to the structure:
wherein
(a) R1 is selected from the group consisting of C(O)NHOH, CO2R3, S(O)2R3, C(O)NHR3, and C(O)NHS(O)2R4, wherein R3 is substituted alkyl, heteroalkyl, substituted carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring; and
R4 is heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, or monocyclic heteroaromatic ring;
(b) R2 is H or lower alkyl;
(c) X is a covalent bond;
(d) Z is a bicyclic heteroaromatic ring where Z is attached to C15 via a Carbon member atom; and
(e) any optical isomer, diastereomer, enantiomer of the above structure or a pharmaceutically-acceptable salt, or bio-hydrolyzable amide, ester, or imide thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/479,532 USRE43372E1 (en) | 1999-03-05 | 2009-06-05 | C16 unsaturated FP-selective prostaglandins analogs |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12292499P | 1999-03-05 | 1999-03-05 | |
PCT/US2000/005301 WO2000051980A1 (en) | 1999-03-05 | 2000-02-29 | C16 unsaturated fp-selective prostaglandins analogs |
US09/946,021 US6586463B2 (en) | 1999-03-05 | 2001-09-04 | C16 unsaturated FP-selective prostaglandins analogs |
US17442005A | 2005-07-01 | 2005-07-01 | |
US12/479,532 USRE43372E1 (en) | 1999-03-05 | 2009-06-05 | C16 unsaturated FP-selective prostaglandins analogs |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/946,021 Reissue US6586463B2 (en) | 1999-03-05 | 2001-09-04 | C16 unsaturated FP-selective prostaglandins analogs |
Publications (1)
Publication Number | Publication Date |
---|---|
USRE43372E1 true USRE43372E1 (en) | 2012-05-08 |
Family
ID=22405663
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/946,021 Ceased US6586463B2 (en) | 1999-03-05 | 2001-09-04 | C16 unsaturated FP-selective prostaglandins analogs |
US12/479,532 Expired - Lifetime USRE43372E1 (en) | 1999-03-05 | 2009-06-05 | C16 unsaturated FP-selective prostaglandins analogs |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/946,021 Ceased US6586463B2 (en) | 1999-03-05 | 2001-09-04 | C16 unsaturated FP-selective prostaglandins analogs |
Country Status (20)
Country | Link |
---|---|
US (2) | US6586463B2 (en) |
EP (1) | EP1159266B1 (en) |
JP (2) | JP4834224B2 (en) |
KR (1) | KR20010108316A (en) |
CN (1) | CN1350521A (en) |
AT (1) | ATE281432T1 (en) |
AU (1) | AU766163B2 (en) |
BR (1) | BR0008776A (en) |
CA (1) | CA2364948C (en) |
CO (1) | CO5160251A1 (en) |
CZ (1) | CZ20013174A3 (en) |
DE (1) | DE60015508T2 (en) |
ES (1) | ES2232434T3 (en) |
HU (1) | HUP0200258A2 (en) |
IL (1) | IL145122A0 (en) |
MX (1) | MXPA01008955A (en) |
NO (1) | NO20014241L (en) |
NZ (1) | NZ513825A (en) |
PL (1) | PL350917A1 (en) |
WO (1) | WO2000051980A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9579270B2 (en) | 2000-03-31 | 2017-02-28 | Duke University | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL350917A1 (en) * | 1999-03-05 | 2003-02-10 | Procter & Gamble | C16 unsaturated fp-selective prostaglandins analogs |
US20020013294A1 (en) | 2000-03-31 | 2002-01-31 | Delong Mitchell Anthony | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
US20020037914A1 (en) * | 2000-03-31 | 2002-03-28 | Delong Mitchell Anthony | Compositions and methods for treating hair loss using C16-C20 aromatic tetrahydro prostaglandins |
US6531504B2 (en) * | 2001-05-17 | 2003-03-11 | Allergan, Inc. | Prostanoic acid derivatives as agents for lowering intraocular pressure |
EP1395263B1 (en) * | 2001-06-14 | 2009-12-30 | Allergan, Inc. | 3, 7 or 3 and 7 thia or oxa prostanoic acid derivatives as agents for lowering intraocular pressure |
US7169807B2 (en) * | 2004-04-09 | 2007-01-30 | Allergan, Inc. | 10-Hydroxy-11-dihydroprostaglandin analogs as selective EP4 agonists |
US20060135609A1 (en) * | 2004-10-21 | 2006-06-22 | Duke University | Ophthamological drugs |
US20070254920A1 (en) * | 2006-04-26 | 2007-11-01 | Aerie Pharmaceuticals, Inc. | Prodrug derivatives of acids using alcohols with homotopic hydroxy groups and methods for their preparation and use |
ES2358558T3 (en) * | 2007-02-01 | 2011-05-11 | Allergan, Inc. | THIOPHENE DERIVATIVES AS MEDICINES FOR THE TREATMENT OF EYE HYPERTENSION. |
US7964595B2 (en) * | 2008-01-18 | 2011-06-21 | Allergan, Inc. | Thiophenyl prostaglandin derivatives for treating glaucoma and ocular hypertension |
US8623918B2 (en) * | 2008-10-29 | 2014-01-07 | Novaer Holdings, Inc. | Amino acid salts of prostaglandins |
US8722739B2 (en) | 2008-10-29 | 2014-05-13 | Novaer Holdings, Inc. | Amino acid salts of prostaglandins |
US20110293549A1 (en) | 2009-02-03 | 2011-12-01 | Athena Cosmetics, Inc. | Composition, method and kit for enhancing hair |
CN108084074B (en) * | 2017-12-25 | 2018-11-20 | 厦门欧瑞捷生物科技有限公司 | A kind of method of simple and effective synthesis dinoprost |
Citations (282)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US13294A (en) | 1855-07-17 | Improved apparatus for cooling repeating fire-arms | ||
US37914A (en) | 1863-03-17 | Improved automatic nose-bag | ||
US37913A (en) | 1863-03-17 | Improvement in sewing-machines | ||
US146439A (en) | 1874-01-13 | Improvement in pruning-shears | ||
DE1617477U (en) | 1950-09-27 | 1950-12-14 | Heinrich Dressel | WHEEL HOLDER FOR BIKES, FOR EXAMPLE FOR BABY CARRIAGES AND SMALL VEHICLES. |
US3382247A (en) | 1965-11-01 | 1968-05-07 | Upjohn Co | 6-amino-1, 2-dihydro-1-hydroxy-2-imino-4-phenoxypyrimidines |
US3435053A (en) | 1966-06-06 | 1969-03-25 | Upjohn Co | Cyclopenta(b)pyrans |
BE746615A (en) | 1969-03-01 | 1970-07-31 | Herten Kurt | MEANS OF PREVENTING HAIR LOSS |
US3524867A (en) | 1966-06-06 | 1970-08-18 | Upjohn Co | Process for producing cyclopenta (b)pyrans |
GB1236227A (en) | 1967-05-22 | 1971-06-23 | Ciba Geigy Ag | Cyclopentyl-alkanoic acid derivatives |
US3598858A (en) | 1958-05-28 | 1971-08-10 | Sune Bergstrom | Pge2 and pge3 |
GB1251750A (en) | 1968-11-12 | 1971-10-27 | ||
US3636120A (en) | 1967-10-09 | 1972-01-18 | Upjohn Co | Prostaglandin e primary alcohols |
US3644363A (en) | 1969-09-02 | 1972-02-22 | Richardson Merrell Inc | 1 4-dioxidoquinoxalinyl nitrones |
GB1285371A (en) | 1968-08-29 | 1972-08-16 | Upjohn Co | Improvements in or relating to therapeutic methods using prostaglandins |
US3723427A (en) | 1971-11-16 | 1973-03-27 | American Cyanamid Co | Hindered tris(meta-hydroxybenzyl)cyanurate antioxidants |
US3776939A (en) | 1958-05-28 | 1973-12-04 | S Bergstrom | Dihydro-pgf1a |
US3776938A (en) | 1958-05-28 | 1973-12-04 | S Bergstrom | Dihydro-pge1 |
FR2182928A1 (en) | 1972-04-05 | 1973-12-14 | Ciba Geigy Ag | |
FR2108027B1 (en) | 1970-09-28 | 1974-03-29 | Curt Georgi Imes Spa | |
JPS4969636U (en) | 1972-09-29 | 1974-06-18 | ||
JPS4993342U (en) | 1972-12-05 | 1974-08-13 | ||
DE2409460A1 (en) | 1973-02-28 | 1974-08-29 | Ono Pharmaceutical Co | PROSTAGLAND COMPOUNDS AND METHOD OF MANUFACTURING THEREOF |
JPS49101356U (en) | 1972-12-20 | 1974-08-31 | ||
JPS49102647U (en) | 1972-12-23 | 1974-09-04 | ||
US3839409A (en) | 1958-05-28 | 1974-10-01 | Kemiska Inst Karolinska I | Pge3 esters and alkanoates |
US3882241A (en) | 1969-12-01 | 1975-05-06 | Upjohn Co | Use of prostaglandins E and F for prevention of pregnancy in humans |
US3882245A (en) | 1972-11-01 | 1975-05-06 | Upjohn Co | Use of prostaglandins in combating shock |
DE2365101A1 (en) | 1973-12-21 | 1975-07-10 | Schering Ag | NEW PROSTANIC ACID DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
US3896156A (en) | 1970-06-30 | 1975-07-22 | Upjohn Co | Dihydroprostaglandin e, analogs |
US3928588A (en) | 1974-02-22 | 1975-12-23 | Upjohn Co | Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors |
US3934013A (en) | 1975-02-21 | 1976-01-20 | Syntex (U.S.A.) Inc. | Pharmaceutical composition |
DE2460990A1 (en) | 1974-12-21 | 1976-07-01 | Hoechst Ag | NEW PROSTAGLANDIN ANALOGS AND PROCEDURES FOR THEIR PRODUCTION |
JPS5186449U (en) | 1974-12-30 | 1976-07-10 | ||
FR2239458B3 (en) | 1973-07-31 | 1976-07-16 | Aries Robert | |
US3974213A (en) | 1972-07-13 | 1976-08-10 | Pfizer Inc. | 13,14-Dihydro-15-substituted-ω-pentanorprostaglandins |
DE2605584A1 (en) | 1975-02-14 | 1976-08-26 | Ono Pharmaceutical Co | PROSTAGLANDIN ANALOGS |
US3984455A (en) | 1973-07-16 | 1976-10-05 | The Upjohn Company | Prostaglandin E1 analogs |
US3984424A (en) | 1972-11-08 | 1976-10-05 | Pfizer Inc. | P-biphenyl esters of 15-substituted-ω-pentanorprostaglandins |
DE2517771A1 (en) | 1975-04-18 | 1976-10-28 | Schering Ag | NEW PROSTAGLANDIN ACETYLENE ANALOGS AND METHOD FOR THEIR PRODUCTION |
GB1456513A (en) | 1972-11-08 | 1976-11-24 | Pfizer | Derivatives of cyclopentaneacetic acid |
GB1456838A (en) | 1972-11-08 | 1976-11-24 | Pfizer | 16,17,18,19,20-pentanorprostaglandins |
US4011262A (en) | 1972-07-13 | 1977-03-08 | Pfizer Inc. | 13,14-Dihydro-15-substituted-ω-pentanorprostaglandins of the two series |
US4018812A (en) | 1975-06-16 | 1977-04-19 | Ono Pharmaceutical Co., Ltd. | 16-methylene-prostaglandin compounds |
US4024179A (en) | 1972-11-08 | 1977-05-17 | Pfizer Inc. | Substituted ω-pentanorprostaglandins |
US4051238A (en) | 1976-06-03 | 1977-09-27 | The Upjohn Company | Treatment of genital tract diseases of domestic animals with prostaglandins |
US4061671A (en) | 1974-04-03 | 1977-12-06 | Hoechst Aktiengesellschaft | Analogues of prostaglandins |
JPS5253841Y2 (en) | 1972-12-12 | 1977-12-07 | ||
DE2737808A1 (en) | 1976-08-27 | 1978-03-16 | Pfizer | 2-SUBSTITUTED ARYL HETEROCYCLIC OMEGA PENTANOR PROSTAGLANDIN |
US4089885A (en) | 1976-11-05 | 1978-05-16 | American Home Products Corporation | Prostaglandin derivatives |
JPS5328160Y2 (en) | 1975-05-16 | 1978-07-15 | ||
US4105854A (en) | 1974-04-22 | 1978-08-08 | Imperial Chemical Industries Limited | Prostanoic acid derivatives |
US4123441A (en) | 1976-09-22 | 1978-10-31 | The Upjohn Company | Enlarged-hetero-ring prostacyclin analogs |
US4128577A (en) | 1975-12-29 | 1978-12-05 | The Upjohn Company | 15-Methyl- and 16-phenoxy-PGF2 α, amides |
US4139619A (en) | 1976-05-24 | 1979-02-13 | The Upjohn Company | 6-Amino-4-(substituted amino)-1,2-dihydro-1-hydroxy-2-iminopyrimidine, topical compositions and process for hair growth |
US4152527A (en) | 1972-11-08 | 1979-05-01 | Pfizer Inc. | 15-Substituted-ω-pentanorprostaglandins |
GB1545411A (en) | 1976-08-27 | 1979-05-10 | Pfizer | P-biphenylyl esters of 15-peteroaryl-16,17,18,19,20-pentanorprostaglandins |
US4154950A (en) | 1975-03-31 | 1979-05-15 | The Upjohn Company | 15-Epi-15-methyl-16-phenoxy-PGE compounds |
US4158667A (en) | 1976-02-04 | 1979-06-19 | The Upjohn Company | 6-Keto PGF analogs |
US4171331A (en) | 1978-06-05 | 1979-10-16 | Miles Laboratories, Inc. | 1 And 2-substituted analogues of certain prostaglandins |
US4206151A (en) | 1978-12-21 | 1980-06-03 | American Cyanamid Company | 15-Deoxy-16-hydroxy-16-vinyl or cyclopropyl prostan-1-ols of the E, A and F series |
US4217360A (en) | 1975-02-27 | 1980-08-12 | Schering Aktiengesellschaft | Novel 1,3-benzodioxaneprostanoic acid derivatives and process for the preparation thereof |
US4225507A (en) | 1979-07-05 | 1980-09-30 | The Upjohn Company | 19-Hydroxy-19-methyl-PGI2 compounds |
US4225508A (en) | 1979-07-05 | 1980-09-30 | The Upjohn Company | 19-Hydroxy-PGI2 compounds |
US4268522A (en) | 1976-06-14 | 1981-05-19 | Pfizer Inc. | 13,14-Dihydro-15-alkenyl- and 13,14-dihydro-15-alkynyl prostaglandins and analogs thereof |
US4284646A (en) | 1976-08-06 | 1981-08-18 | Schering Aktiengesellschaft | Prostanoic acid derivatives and their preparation |
US4296504A (en) | 1980-07-07 | 1981-10-27 | Lawson Daniel C | Toilet seat lock |
US4311707A (en) | 1979-02-12 | 1982-01-19 | American Cyanamid Company | Process for topically producing cutaneous vasodilation for the treatment of vasospastic or ischemic conditions |
GB2048254B (en) | 1979-04-02 | 1983-05-25 | Upjohn Co | 19,20 -didehydro-19-hydroxy and 19-oxo-prostaglandin derivatives |
JPS5829710Y2 (en) | 1979-05-25 | 1983-06-29 | スガツネ工業株式会社 | lock |
US4499293A (en) | 1976-09-22 | 1985-02-12 | The Upjohn Company | PGI2 Salts |
US4543353A (en) | 1981-11-27 | 1985-09-24 | Farmitalia Carlo Erba S.P.A. | Ester and amide derivatives of 13,14-didehydro prostaglandins |
WO1986000616A1 (en) | 1984-07-13 | 1986-01-30 | Gail Sansone Bazzano | Substituted pyrimidine oxides useful for hair growth promotion |
US4596812A (en) | 1976-05-24 | 1986-06-24 | The Upjohn Company | Methods and solutions for treating male pattern alopecia |
US4599353A (en) | 1982-05-03 | 1986-07-08 | The Trustees Of Columbia University In The City Of New York | Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma |
JPS61218510A (en) | 1985-03-22 | 1986-09-29 | Dai Ichi Seiyaku Co Ltd | Agent for hair |
US4621100A (en) | 1981-09-25 | 1986-11-04 | The Upjohn Company | Treatment of osteoporosis with prostaglandins |
US4704386A (en) | 1985-08-29 | 1987-11-03 | G. D. Searle & Co. | 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(phenylsulfinyl-, and phenylsulfonyl)alkanoyl]hydrazides |
EP0249194A3 (en) | 1986-06-09 | 1988-02-10 | American Cyanamid Company | Topical prostaglandin formulations |
US4757089A (en) | 1985-06-14 | 1988-07-12 | Massachusetts Eye And Ear Infirmary | Increasing aqueous humor outflow |
US4812457A (en) | 1984-11-21 | 1989-03-14 | Research Development Corporation | Prostaglandin derivatives |
WO1989003384A1 (en) | 1987-10-07 | 1989-04-20 | Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US4883819A (en) | 1986-07-31 | 1989-11-28 | The Trustees Of Columbia University In The City Of New York | Use of A, B and C prostaglandins and derivatives thereof to treat ocular hypertension and glaucoma |
US4889845A (en) | 1986-06-09 | 1989-12-26 | American Cyanamid Company | Vehicle for topical application of pharmaceuticals |
EP0170258B1 (en) | 1984-07-31 | 1989-12-27 | Syntex (U.S.A.) Inc. | 11-substituted-16-phenoxy and 16-substituted phenoxy-prostatrienoic acid derivatives |
WO1990002553A1 (en) | 1988-09-06 | 1990-03-22 | Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
JPH0222226Y2 (en) | 1981-02-04 | 1990-06-14 | ||
US4952581A (en) | 1987-04-03 | 1990-08-28 | The Trustees Of Columbia University In The City Of New York | Use of a prostaglandin in combination with an adrenergic blocking agent for reduction of intraocular pressure |
US4968812A (en) | 1989-06-23 | 1990-11-06 | Shell Oil Company | Spirolactonelactams |
US5001153A (en) | 1987-09-18 | 1991-03-19 | K.K. Ueno Seiyaku Oyo Kenkyujo | Ocular hypotensive agents |
JPH0383926A (en) | 1989-08-29 | 1991-04-09 | Hisamitsu Pharmaceut Co Inc | Ointment composition |
JPH0334934Y2 (en) | 1984-07-31 | 1991-07-24 | ||
US5041439A (en) | 1986-06-13 | 1991-08-20 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions |
JPH0383925U (en) | 1989-12-14 | 1991-08-26 | ||
US5063057A (en) | 1990-09-26 | 1991-11-05 | Elizabeth Arden Co., Division Of Conopco, Inc. | Cosmetic capsules |
WO1992002495A1 (en) | 1990-07-27 | 1992-02-20 | Schering Aktiengesellschaft Berlin/Bergkamen | Cyclopentane derivatives, process for producing them and their pharmaceutical use |
EP0295092B1 (en) | 1987-06-12 | 1992-09-23 | Unilever Plc | Skin treatment composition |
JPH04300833A (en) | 1991-03-29 | 1992-10-23 | Green Cross Corp:The | Prostaglandin e1-containing fat emulsion-loaded aerosol |
US5166178A (en) | 1987-09-18 | 1992-11-24 | K.K. Ueno Seiyaku Oyo Kenkyujo | Ocular hypotensive agents |
US5194429A (en) | 1988-10-01 | 1993-03-16 | K.K. Ueno Seiyaku Oyo Kenkyujo | Ocular hypotensive agents |
US5212324A (en) | 1990-04-04 | 1993-05-18 | R.-Tech Ueno Ltd. | Treatment of cataract with 15-keto-prostaglandin compounds |
US5219885A (en) | 1987-02-16 | 1993-06-15 | Froelich Juergen | Prostaglandin E1 derivatives as pharmaceutically active agents, and pharmaceutical compositions containing these compounds, especially for transcutaneous administration |
JPH05331025A (en) | 1992-05-29 | 1993-12-14 | Toray Ind Inc | Hair tonic and growing agent |
US5288754A (en) | 1992-02-04 | 1994-02-22 | Allergan, Inc. | Polar C-1 esters of prostaglandins |
US5296504A (en) | 1988-09-06 | 1994-03-22 | Kabi Pharmacia | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5302617A (en) | 1990-04-27 | 1994-04-12 | Kabushikikaisha Ueno Seiyaku Oyo Kenkyuio | Biochemical treatment with 15-dehydroxy-16-oxoprostaglandin compounds |
WO1994008585A1 (en) | 1992-10-13 | 1994-04-28 | Alcon Laboratories, Inc. | Combinations of prostaglandins and clonidine derivatives for the treatment of glaucoma |
US5312832A (en) | 1991-05-17 | 1994-05-17 | Allergan, Inc. | Ocular hypotensive 2-decarboxyl-2-acylthioalkyl prostaglandin derivatives |
US5321128A (en) | 1988-09-06 | 1994-06-14 | Kabi Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5332730A (en) | 1992-10-16 | 1994-07-26 | Allergan, Inc. | Azido derivatives of cyclopentane heptanoic or heptenoic acid |
US5340813A (en) | 1992-11-09 | 1994-08-23 | Cell Therapeutics, Inc. | Substituted aminoalkyl xanthine compounds |
US5352708A (en) | 1992-09-21 | 1994-10-04 | Allergan, Inc. | Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
WO1995000552B1 (en) | 1994-06-09 | 1995-02-02 | Prostaglandin receptor ep3 and dna encoding it | |
US5409911A (en) | 1992-09-11 | 1995-04-25 | Merck & Co., Inc. | Prostaglandin analog for treating osteoporosis |
WO1995011003A1 (en) | 1993-10-20 | 1995-04-27 | Pharmacia Ab | New use of prostaglandins |
WO1995011033A1 (en) | 1993-10-22 | 1995-04-27 | Commonwealth Scientific And Industrial Research Organisation | Polyoxometallates in the treatment of flavivirus infections |
US5422371A (en) | 1992-05-27 | 1995-06-06 | Arch Development Corp. | Methods and compositions for inhibiting 5α-reductase activity |
US5426115A (en) | 1989-11-22 | 1995-06-20 | Kabushikikaisha Ueno Seiyaku Oyo Kenkyujo | Use of 15-keto-prostaglandin compound for improvement of encephalic function |
WO1995018102A1 (en) | 1993-12-28 | 1995-07-06 | Allergan | Cyclopentane(ene) heptenoic or heptanoic acids and derivatives thereof useful as therapeutic agents |
US5431881A (en) | 1993-12-10 | 1995-07-11 | Palacios; Henry J. | Treatment of hair loss and dermatological problems |
WO1995019165A1 (en) | 1994-01-12 | 1995-07-20 | Duke University | Method of treating disorders of the eye |
WO1995019964A1 (en) | 1994-01-19 | 1995-07-27 | Allergan | Ep2-receptor agonists as agents for lowering intraocular pressure |
US5500230A (en) | 1987-01-23 | 1996-03-19 | The General Hospital Corporation | Method for treatment of glaucoma with nitrogen containing guanylate cyclase activators |
WO1996010407A1 (en) | 1994-09-30 | 1996-04-11 | Alcon Laboratories, Inc. | Use of 9-deoxy prostaglandin derivatives to treat glaucoma |
US5510383A (en) | 1993-08-03 | 1996-04-23 | Alcon Laboratories, Inc. | Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension |
US5516652A (en) | 1993-10-06 | 1996-05-14 | Merck Frosst Canada Inc. | DNA encoding prostaglandin receptor IP |
US5567079A (en) | 1992-11-17 | 1996-10-22 | Felder; Anton | Method for the hydraulic branching of an open stream and hydraulically working channel branch |
US5576315A (en) | 1991-05-03 | 1996-11-19 | G.D. Searle & Co. | Substituted dibenzoxazepine compounds and methods for treating osteoporosis and ischemia |
WO1996036599A1 (en) | 1995-05-18 | 1996-11-21 | Allergan | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents for the treatment of ocular hypertension |
US5578640A (en) | 1992-05-20 | 1996-11-26 | Loyola University Of Chicago | Protective prostaglandins for use in conjunction with chemotherapeutic agents |
WO1997003973A1 (en) | 1995-07-21 | 1997-02-06 | Fujisawa Pharmaceutical Co., Ltd. | 4,5-diaryl oxazole derivatives |
US5605814A (en) | 1993-08-31 | 1997-02-25 | Merck Frosst Canada Inc. | DNA encoding human prostaglandin receptor EP2 |
FR2730811B1 (en) | 1995-02-17 | 1997-03-21 | Oreal | METHOD FOR DIAGNOSING AND / OR MONITORING THE EVOLUTION OF A HAIR DISORDER AND / OR MEASURING THE EFFECTIVENESS OF A TREATMENT APPLIED TO COMBAT A HAIR DISORDER |
WO1997015319A1 (en) | 1995-10-23 | 1997-05-01 | Queen's University At Kingston | Method and pharmaceutical composition for chondrostimulation with a prostaglandin (e.g. misoprostol) and tgf-beta, optionally in combination with igf-1 |
US5641494A (en) | 1992-03-20 | 1997-06-24 | Janssen Pharmaceutica N.V. | Agent for regulating the greasiness of the skin |
WO1997023225A1 (en) | 1995-12-22 | 1997-07-03 | Alcon Laboratories, Inc. | Combinations of dp and fp type prostaglandins for lowering iop |
WO1997023223A1 (en) | 1995-12-22 | 1997-07-03 | Alcon Laboratories, Inc. | Substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
WO1997023226A1 (en) | 1995-12-22 | 1997-07-03 | Alcon Laboratories, Inc. | Combinations of prostaglandins and miotics for lowering intraocular pressure |
WO1997009049A3 (en) | 1995-09-01 | 1997-07-10 | Allergan Inc | Method for effecting vasodilation with (1,5-inter)aryl prostaglandin derivatives |
CA1339132C (en) | 1989-09-12 | 1997-07-29 | Johan W. Stjernschantz | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5658897A (en) | 1996-04-08 | 1997-08-19 | Allergan | Cyclopentane(ene) heptanoic or cyclopentane(ene) heptenoic acid, 2-hydrocarbyl phosphinyloxyalkyl or phosphonamidoalkyl as therapeutic agents |
WO1997029735A1 (en) | 1996-02-19 | 1997-08-21 | Monash University | Dermal penetration enhancers and drug delivery systems involving same |
US5663203A (en) | 1986-09-11 | 1997-09-02 | Schering Aktiengesellschaft | Agents containing prostacyclin derivatives for topical application |
US5670506A (en) | 1993-04-05 | 1997-09-23 | Cell Therapeutics, Inc. | Halogen, isothiocyanate or azide substituted xanthines |
WO1997039754A1 (en) | 1996-04-18 | 1997-10-30 | Alberta Cancer Board | Use of prostaglandins to treat ataxia telangiectasia |
US5688819A (en) | 1992-09-21 | 1997-11-18 | Allergan | Cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
JPH09295921A (en) | 1996-05-01 | 1997-11-18 | Bimeeku:Kk | Hair growing and tonic agent |
WO1997031895A3 (en) | 1996-02-29 | 1997-12-18 | Allergan Inc | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
US5703108A (en) | 1996-02-28 | 1997-12-30 | Pfizer Inc. | Bone deposition by certain prostaglandin agonists |
WO1998000100A1 (en) | 1996-07-03 | 1998-01-08 | The Board Of Regents Of The University Of Oklahoma | Enhancement of skin pigmentation by prostaglandins |
US5716609A (en) | 1995-07-25 | 1998-02-10 | Panacea Biotec Limited | Therapeutic anti-inflammatory and analgesic composition containing nimesulide for use transdermally and a process for the manufacture thereof |
US5719140A (en) | 1993-04-30 | 1998-02-17 | G.D. Searle & Co. | 2, 3-, 4-, 5-, 6-, 7-, 8-, 9- and /or 10-substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use |
WO1998012175A1 (en) | 1996-09-17 | 1998-03-26 | Asahi Glass Company Ltd. | Fluorinated prostaglandin derivatives and medicines |
WO1998013016A1 (en) | 1996-09-27 | 1998-04-02 | The Procter & Gamble Company | Stable photoprotective compositions |
WO1998019680A1 (en) | 1996-11-01 | 1998-05-14 | Alcon Laboratories, Inc. | Use of a combination of carbonic anhydrase inhibitors and prostaglandins for treating glaucoma |
WO1998021180A1 (en) | 1995-06-07 | 1998-05-22 | Alcon Laboratories, Inc. | Conformationally rigid aryl- or heteroaryl prostaglandins for use in glaucoma therapy |
WO1998020881A1 (en) | 1996-11-12 | 1998-05-22 | Alcon Laboratories, Inc | 15-ketal prostaglandins for the treatment of glaucoma or ocular hypertension |
US5770759A (en) | 1987-04-30 | 1998-06-23 | R-Tech Ueno, Ltd. | Prostaglandins of the F series |
WO1998021182A3 (en) | 1996-11-12 | 1998-06-25 | Alcon Lab Inc | Use of cis-δ4 analogs of prostaglandins as ocular hypotensives |
US5773472A (en) | 1993-11-03 | 1998-06-30 | Pharmacia Ab | Method and means for prevention of cataract |
WO1998028264A1 (en) | 1996-12-20 | 1998-07-02 | Pfizer Inc. | Prevention of loss and restoration of bone mass by certain prostaglandin agonists |
WO1998027976A1 (en) | 1996-12-20 | 1998-07-02 | Pfizer Inc. | Prevention and treatment of skeletal disorder with ep2 receptor subtype selective prostaglandin e2 agonists |
WO1998021181A3 (en) | 1996-11-12 | 1998-07-16 | Alcon Lab Inc | 15-fluoro prostaglandins as ocular hypotensives |
WO1998033497A1 (en) | 1997-02-04 | 1998-08-06 | Johnstone Murray A | Method of enhancing hair growth |
US5792851A (en) | 1996-09-03 | 1998-08-11 | Albert Einstin College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Human prostaglandin transporter |
WO1998020880A3 (en) | 1996-11-12 | 1998-08-20 | Alcon Lab Inc | 11-Halo prostaglandins for the treatment of glaucoma or ocular hypertension |
JPH10251225A (en) | 1996-09-17 | 1998-09-22 | Santen Pharmaceut Co Ltd | Fluorine-containing prostaglandin derivative and medicine |
JPH10287532A (en) | 1997-04-17 | 1998-10-27 | R Tec Ueno:Kk | Hair-growing agent |
WO1998047515A1 (en) | 1997-04-22 | 1998-10-29 | Pharmacia & Upjohn Ab | THE USE OF α-METHYL-P-TYROSINE TO INHIBIT MELANIN PRODUCTION IN IRIS MELANOCYTES |
WO1998039293A3 (en) | 1997-03-07 | 1998-11-05 | Alcon Lab Inc | 13-thia prostaglandins for use in glaucoma therapy |
US5834498A (en) | 1992-09-21 | 1998-11-10 | Allergan | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
WO1998050024A1 (en) | 1997-05-09 | 1998-11-12 | The Mount Sinai School Of Medicine Of The City University Of New York | 8-iso-prostaglandins for glaucoma therapy |
US5840847A (en) | 1993-06-25 | 1998-11-24 | Merck Frosst Canada, Inc. | Purified prostaglandin receptor FP |
WO1998053809A1 (en) | 1997-05-30 | 1998-12-03 | Merck & Co., Inc. | Ophthalmic compositions for treating ocular hypertension |
WO1998057930A1 (en) | 1997-06-18 | 1998-12-23 | Alcon Laboratories, Inc. | Keto-substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
WO1998057942A1 (en) | 1997-06-18 | 1998-12-23 | Alcon Laboratories, Inc. | 9-oxa prostaglandin analogs as ocular hypotensives |
WO1999002165A1 (en) | 1997-07-11 | 1999-01-21 | Pharmacia & Upjohn Ab | Prostaglandin derivatives devoid of side-effects for the treatment of glaucoma |
US5863948A (en) | 1985-06-14 | 1999-01-26 | Massachusetts Eye And Ear Infirmary | Increasing aqueous humor outflow |
US5877211A (en) | 1997-11-21 | 1999-03-02 | Allergan | EP2 receptor agonists as neuroprotective agents for the eye |
WO1999012554A1 (en) | 1997-09-09 | 1999-03-18 | The University Of Western Australia | Chemical supplementation of bone |
WO1999012556A1 (en) | 1997-09-08 | 1999-03-18 | The Public Health Research Institute Of The City Of New York, Inc. | HIV-1 gp120 V1/V2 DOMAIN EPITOPES CAPABLE OF GENERATING NEUTRALIZING ANTIBODIES |
WO1998058911A3 (en) | 1997-06-23 | 1999-03-18 | Pfizer | Prostaglandin agonists |
WO1999012552A1 (en) | 1997-09-10 | 1999-03-18 | Merck & Co., Inc. | 9a-AZALIDES AS VETERINARY ANTIMICROBIAL AGENTS |
WO1999012560A1 (en) | 1997-09-09 | 1999-03-18 | Creative Biomolecules, Inc. | Synergistic effects of op/bmp morphogens and gdnf/ngf neurotrophic factors |
WO1999012557A1 (en) | 1997-09-12 | 1999-03-18 | Smithkline Beecham Corporation | Novel prokaryotic polynucleotides, polypeptides and their uses |
WO1999012550A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | Method of increasing bone volume |
WO1999012896A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | Aromatic c16-c20-substituted tetrahydro prostaglandins useful as fp agonists |
WO1999012555A1 (en) | 1997-09-11 | 1999-03-18 | Purdue Research Foundation | Galactosidase modified submucosal tissue |
WO1999012559A1 (en) | 1997-09-09 | 1999-03-18 | The Regents Of The University Of California | Inhibition of apoptotis using prosaposin receptor agonists |
WO1999012899A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | A process for making prostaglandin f analogs |
WO1999012558A1 (en) | 1997-09-10 | 1999-03-18 | Allegheny University Of The Health Sciences | Inhibitors of collagen assembly |
WO1999012553A1 (en) | 1997-09-08 | 1999-03-18 | Idec Pharmaceuticals Corporation | Methods for producing human antibodies in scid mice using dendritic cells |
WO1999012897A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | A process for making epoxide intermediates |
WO1999012895A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | Aromatic c16-c20-substituted tetrahydro prostaglandins useful as fp agonists |
WO1999012551A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | Method of increasing bone volume using non-naturally-occurring fp selective agonists |
WO1999012898A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | Aromatic c16-c20-substituted tetrahydro prostaglandins useful as fp agonists |
US5885974A (en) | 1994-12-06 | 1999-03-23 | Michael M. Danielov | Therapeutic methods utilizing naturally derived bio-active complexes and delivery systems therefor |
US5885766A (en) | 1995-02-17 | 1999-03-23 | Societe L'oreal S.A. | Method of screening of substances for their effect on the expression of mediators of inflammation in a hair follicle |
US5892099A (en) | 1997-01-27 | 1999-04-06 | Ono Pharmaceutical Co., Ltd. | 3,7-dithiaprostanoic acid derivative |
GB2330307A (en) | 1998-02-07 | 1999-04-21 | Glaxo Group Ltd | EP4 Receptor antagonists as bone resorption inhibitors |
WO1999019300A1 (en) | 1997-10-10 | 1999-04-22 | Pfizer Inc. | Prostaglandin agonists and their use to treat bone disorders |
WO1999021562A1 (en) | 1997-10-28 | 1999-05-06 | Asivi, Llc | Treatment of female sexual dysfunction |
WO1999022731A1 (en) | 1997-10-30 | 1999-05-14 | Vaysman, Pyotr | Method and composition for treatment of sexual dysfunction |
WO1999012563A3 (en) | 1997-09-11 | 1999-05-27 | Us Health | Mucosal cytotoxic t lymphocyte responses |
WO1999025358A1 (en) | 1997-11-19 | 1999-05-27 | Allergan Sales, Inc. | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
WO1999025357A1 (en) | 1997-11-14 | 1999-05-27 | United Therapeutics Corporation | USE OF 9-DEOXY-2', 9-α-METHANO-3- OXA-4,5,6- TRINOR-3, 7-(1',3'-INTERPHENYLENE) -13,14-DIHYDRO- PROSTAGLANDIN F1 TO TREAT PERIPHERAL VASCULAR DISEASE |
WO1999030675A1 (en) | 1997-12-18 | 1999-06-24 | Johnson & Johnson Consumer Companies, Inc. | Methods for improving the health of hair and scalp |
WO1999032640A1 (en) | 1997-12-22 | 1999-07-01 | Hopital Sainte-Justine | Antagonists of g-protein-coupled receptor |
WO1999032641A1 (en) | 1997-12-22 | 1999-07-01 | Unilever N.V. | A process for site-directed integration of multiple copies of a gene in a mould |
WO1999032441A1 (en) | 1997-12-22 | 1999-07-01 | Alcon Laboratories, Inc. | 13-oxa prostaglandins for the treatment of glaucoma and ocular hypertension |
WO1999033794A1 (en) | 1997-12-25 | 1999-07-08 | Ono Pharmaceutical Co., Ltd. | φ-CYCLOALKYL-PROSTAGLANDIN E2 DERIVATIVES |
WO1999030718A3 (en) | 1997-12-18 | 1999-09-10 | Nathan Earl Scott | PROSTAGLANDIN E2/F2α COMBINATION FOR TREATING IMPOTENCE AND ENHANCING SEXUAL AROUSAL |
US5958723A (en) | 1995-01-26 | 1999-09-28 | Merck Frosst Canada & Co. | DNA encoding prostaglandin receptor DP |
WO1999050242A1 (en) | 1998-03-31 | 1999-10-07 | The Procter & Gamble Company | C11 oxymyl and hydroxylamino prostaglandins useful as fp agonists |
WO1999050241A1 (en) | 1998-03-31 | 1999-10-07 | The Procter & Gamble Company | C11 oxymyl and hydroxylamino prostaglandins useful as medicaments |
WO1999047497A3 (en) | 1998-03-13 | 1999-10-28 | Merck Frosst Canada Inc | Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment |
US5985597A (en) | 1993-05-26 | 1999-11-16 | Merck Frosst Canada, Inc. | DNA encoding prostaglandin receptor EP1 |
US5990346A (en) | 1995-06-26 | 1999-11-23 | Teijin Limited | Prostaglandins and processes for production thereof |
EP0925787A4 (en) | 1997-02-27 | 1999-12-01 | Toray Industries | Drugs for ameliorating pulmonary circulation |
WO1999061029A1 (en) | 1998-05-25 | 1999-12-02 | Taisho Pharmaceutical Co., Ltd. | Sleep inducing agent |
WO1999064621A1 (en) | 1998-06-11 | 1999-12-16 | Winthrop-University Hospital | Methods of diagnosing renal salt wasting syndrome and alzheimer's disease and methods of treating the same |
WO1999065527A1 (en) | 1998-06-17 | 1999-12-23 | Pharmacia & Upjohn Company | Solution comprising prostaglandins and benzyl alcohol |
WO1999065303A1 (en) | 1998-06-15 | 1999-12-23 | Macrochem Corporation | Composition and method for treating penile erectile dysfunction |
US6013823A (en) | 1992-06-08 | 2000-01-11 | New Pharma International Corp. | Trans-pentavalent 2-15-deoxy-16-hydroxy-16-methyl-PGE1 methyl ester (B-407) |
WO2000002450A1 (en) | 1998-07-08 | 2000-01-20 | Fibrogen, Inc. | Method for treatment of fibrosis related diseases by the administration of prostacyclin derivatives |
WO2000003980A1 (en) | 1998-07-15 | 2000-01-27 | Ono Pharmaceutical Co., Ltd. | 5-THIA-φ-SUBSTITUTED PHENYL-PROSTAGLANDIN E DERIVATIVES, PROCESS FOR PRODUCING THE SAME AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT |
WO2000003736A1 (en) | 1998-07-14 | 2000-01-27 | Alcon Laboratories, Inc. | Prostaglandin product |
WO2000004899A1 (en) | 1998-07-21 | 2000-02-03 | Merck & Co., Inc. | Ophthalmic compositions for treating ocular hypertension |
WO2000004898A1 (en) | 1998-07-21 | 2000-02-03 | Merck & Co., Inc. | Ophthalmic compositions for treating ocular hypertension |
US6025375A (en) | 1993-12-20 | 2000-02-15 | Fujisawa Pharmaceutical Co., Ltd. | 4,5-diaryloxazole derivatives |
WO2000009557A1 (en) | 1998-08-12 | 2000-02-24 | Kazusa Dna Research Institute Foundation | Novel gene and protein pgth encoded thereby |
US6030959A (en) | 1997-04-04 | 2000-02-29 | Monsanto Company | Gastro-specific prodrugs |
US6031001A (en) | 1994-09-21 | 2000-02-29 | Synphra Ab | Use of prostaglandins |
US6037364A (en) | 1992-09-21 | 2000-03-14 | Allergan Sales, Inc. | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
WO2000013664A1 (en) | 1998-09-08 | 2000-03-16 | L.A.M. Pharmaceutical Corp | Drug preparations for treating sexual dysfunction |
WO1999012561A9 (en) | 1997-09-09 | 2000-03-16 | Hoffmann La Roche | FRACTURE HEALING USING PTHrP ANALOGS |
WO2000015608A1 (en) | 1998-09-14 | 2000-03-23 | Ono Pharmaceutical Co., Ltd. | φ-SUBSTITUTED PHENYL-PROSTAGLANDIN E DERIVATIVES AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT |
US6043264A (en) | 1995-01-06 | 2000-03-28 | Toray Industries, Inc. | Benzene-condensed heterocyclic derivatives and their uses |
WO2000016760A3 (en) | 1998-09-23 | 2000-06-08 | Fujisawa Pharmaceutical Co | New use of prostaglandin e2 antagonists |
US6110969A (en) | 1997-02-04 | 2000-08-29 | Ono Pharmaceutical Co. Ltd. | Cycloalkyl-prostaglandin E2 derivatives |
WO2000051980A1 (en) | 1999-03-05 | 2000-09-08 | The Procter & Gamble Company | C16 unsaturated fp-selective prostaglandins analogs |
WO2000051979A1 (en) | 1999-03-05 | 2000-09-08 | The Procter & Gamble Company | C16 unsaturated fp-selective prostaglandins analogs |
WO2000051971A1 (en) | 1999-03-01 | 2000-09-08 | Pfizer Products Inc. | Oxamic acids and derivatives as thyroid receptor ligands |
US6121253A (en) | 1998-11-20 | 2000-09-19 | Merck Frosst Canada & Co. | Prostaglandin conjugates for treating or preventing bone disease |
WO2000054810A1 (en) | 1999-03-12 | 2000-09-21 | Alcon Laboratories, Inc | Combination therapy for treating glaucoma |
EP0648488B1 (en) | 1993-10-13 | 2000-11-29 | L'oreal | Method to alter hairgrowth and compositions therefor |
EP0911321A3 (en) | 1997-10-10 | 2001-01-31 | Pfizer Inc. | Compounds for the treatment of osteoporosis |
WO2000007627A8 (en) | 1998-08-04 | 2001-02-08 | Johnson & Johnson Consumer | Topical delivery systems for active agents |
WO2001010873A1 (en) | 1999-08-04 | 2001-02-15 | The Procter & Gamble Company | Novel 2-decarboxy-2-phosphinico prostaglandin f analogs |
EP0970697A4 (en) | 1997-09-17 | 2001-02-21 | Toray Industries | Cervical maturing agent |
US20010047025A1 (en) | 2000-01-18 | 2001-11-29 | Garcia Maria L. | Method for treating ocular hypertension |
US20020013294A1 (en) | 2000-03-31 | 2002-01-31 | Delong Mitchell Anthony | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
WO2001074315A3 (en) | 2000-03-31 | 2002-02-21 | Procter & Gamble | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
WO2001074313A3 (en) | 2000-03-31 | 2002-02-21 | Procter & Gamble | Compositions and methods for treating hair loss using c16 - c20 aromatic tetrahydro prostaglandins |
WO2001074307A3 (en) | 2000-03-31 | 2002-04-11 | Procter & Gamble | Compositions and methods for treating hair loss using oximyl- and hydroxylamino- prostaglandins |
US20020044953A1 (en) | 2000-07-28 | 2002-04-18 | Michelet Jean Francois | Use of non-prostanoic agonists of prostaglandin EP-2 and/or EP-4 receptors as cosmetic agents for attenuating, reducing or stopping the loss of head hair and other hairs |
EP0857718B1 (en) | 1996-06-10 | 2002-08-14 | Sucampo AG | Endothelin antagonist |
US6444840B1 (en) | 1998-03-31 | 2002-09-03 | The Procter & Gamble Co. | C11 oxymyl and hydroxylamino prostaglandins useful as FP agonists |
WO2002067901A1 (en) | 2001-02-22 | 2002-09-06 | Skyepharma Canada Inc. | Fibrate-statin combinations with reduced fed-fasted effects |
EP1008588B1 (en) | 1997-02-10 | 2003-04-16 | Ono Pharmaceutical Co., Ltd. | 11,15-o-dialkylprostaglandin e derivatives, process for producing the same, and drugs containing the same as the active ingredient |
US20030083381A1 (en) | 2000-03-31 | 2003-05-01 | Hiroki Kumagai | Hair growth or hair formation controlling agents |
WO2003051822A1 (en) | 2001-12-19 | 2003-06-26 | Astrazeneca Ab | Substituted phenylpropionic acid derivatives as agonists to human peroxisome proliferator-activated receptor alpha (ppar) |
JP2003180399A (en) | 2001-09-28 | 2003-07-02 | Pfizer Prod Inc | Method related to a-c repeat z-sequence upstream from aldose reductase gene |
US20030147823A1 (en) | 2002-02-04 | 2003-08-07 | Allergan, Inc. | Method of enhancing hair growth |
WO2003077910A1 (en) | 2002-03-18 | 2003-09-25 | Pfizer Products Inc. | Methods of treatment with selective ep4 receptor agonists |
US20030199590A1 (en) | 2002-07-25 | 2003-10-23 | Cagle Gerald D | Prostaglandin analogues for promotion of hair growth |
EP1016660B1 (en) | 1997-09-19 | 2003-10-29 | Shionogi & Co., Ltd. | Compounds having 2.2.1]bicyclo skeleton |
US20040157912A1 (en) | 2002-05-14 | 2004-08-12 | Old David W. | 8-Azaprostaglandin analogs as agents for lowering intraocular pressure |
US20040167190A1 (en) | 1988-09-06 | 2004-08-26 | Pharmacia Aktiebolag | Prostagladin derivatives for the treatment of glaucoma or ocular hypertension |
US20040171596A1 (en) | 2002-04-01 | 2004-09-02 | Laszlo Prokai | Prodrugs for use as ophthalmic agents |
US20050058614A1 (en) | 2003-09-15 | 2005-03-17 | Allergan, Inc. | Methods for the treatment of gray hair using cyclopentane(ene) heptan(en)oic acid amides |
US6894175B1 (en) | 1999-08-04 | 2005-05-17 | The Procter & Gamble Company | 2-Decarboxy-2-phosphinico prostaglandin derivatives and methods for their preparation and use |
US20060135609A1 (en) | 2004-10-21 | 2006-06-22 | Duke University | Ophthamological drugs |
US7070768B2 (en) | 2003-09-25 | 2006-07-04 | Allergan, Inc. | Method for imparting artificial tan to human skin |
US20070161699A1 (en) | 2003-11-26 | 2007-07-12 | Duke University | Method of preventing or treating glaucoma |
US7288029B1 (en) | 2005-01-19 | 2007-10-30 | Gkn Driveline North America, Inc. | Propshaft with crash-worthiness |
US20070254920A1 (en) | 2006-04-26 | 2007-11-01 | Aerie Pharmaceuticals, Inc. | Prodrug derivatives of acids using alcohols with homotopic hydroxy groups and methods for their preparation and use |
WO2007125818A1 (en) | 2006-04-24 | 2007-11-08 | Jsr Corporation | Polymer and photosensitive resin composition comprising the same |
US20090018204A1 (en) | 2007-07-13 | 2009-01-15 | Brinkenhoff Michael C | Composition and method for enhancing hair growth |
US20100105771A1 (en) | 2008-10-29 | 2010-04-29 | Delong Mitchell A | Amino acid salts of prostaglandins |
US20100105775A1 (en) | 2008-10-29 | 2010-04-29 | Delong Mitchell A | Amino acid salts of prostaglandins |
EP0947500B1 (en) | 1996-12-18 | 2011-02-23 | Ono Pharmaceutical Co., Ltd. | Sulfonamide derivatives and drugs containing the same as the active ingredient |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1386146A (en) * | 1972-05-03 | 1975-03-05 | Ici Ltd | Cyclopentane derivatives |
GB1428137A (en) * | 1972-09-27 | 1976-03-17 | Ici Ltd | Prostanoic acid derivatives |
JPS50157344A (en) * | 1974-03-20 | 1975-12-19 | ||
GB1517562A (en) * | 1975-06-13 | 1978-07-12 | Ici Ltd | Prostane derivatives |
EP0705277B1 (en) | 1993-06-25 | 1998-10-21 | Merck Frosst Canada Inc. | Prostaglandin receptor ep3 and dna encoding it |
-
2000
- 2000-02-29 PL PL00350917A patent/PL350917A1/en unknown
- 2000-02-29 CN CN00807185A patent/CN1350521A/en active Pending
- 2000-02-29 EP EP00917686A patent/EP1159266B1/en not_active Expired - Lifetime
- 2000-02-29 IL IL14512200A patent/IL145122A0/en unknown
- 2000-02-29 CA CA2364948A patent/CA2364948C/en not_active Expired - Lifetime
- 2000-02-29 MX MXPA01008955A patent/MXPA01008955A/en not_active Application Discontinuation
- 2000-02-29 BR BR0008776-9A patent/BR0008776A/en not_active Application Discontinuation
- 2000-02-29 NZ NZ513825A patent/NZ513825A/en unknown
- 2000-02-29 HU HU0200258A patent/HUP0200258A2/en unknown
- 2000-02-29 ES ES00917686T patent/ES2232434T3/en not_active Expired - Lifetime
- 2000-02-29 AT AT00917686T patent/ATE281432T1/en not_active IP Right Cessation
- 2000-02-29 CZ CZ20013174A patent/CZ20013174A3/en unknown
- 2000-02-29 WO PCT/US2000/005301 patent/WO2000051980A1/en not_active Application Discontinuation
- 2000-02-29 JP JP2000602208A patent/JP4834224B2/en not_active Expired - Fee Related
- 2000-02-29 AU AU38620/00A patent/AU766163B2/en not_active Expired
- 2000-02-29 DE DE60015508T patent/DE60015508T2/en not_active Expired - Lifetime
- 2000-02-29 KR KR1020017011293A patent/KR20010108316A/en not_active Application Discontinuation
- 2000-03-06 CO CO00016012A patent/CO5160251A1/en unknown
-
2001
- 2001-08-31 NO NO20014241A patent/NO20014241L/en not_active Application Discontinuation
- 2001-09-04 US US09/946,021 patent/US6586463B2/en not_active Ceased
-
2009
- 2009-06-05 US US12/479,532 patent/USRE43372E1/en not_active Expired - Lifetime
-
2010
- 2010-09-16 JP JP2010208198A patent/JP2011037861A/en active Pending
Patent Citations (373)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US37914A (en) | 1863-03-17 | Improved automatic nose-bag | ||
US37913A (en) | 1863-03-17 | Improvement in sewing-machines | ||
US146439A (en) | 1874-01-13 | Improvement in pruning-shears | ||
US13294A (en) | 1855-07-17 | Improved apparatus for cooling repeating fire-arms | ||
DE1617477U (en) | 1950-09-27 | 1950-12-14 | Heinrich Dressel | WHEEL HOLDER FOR BIKES, FOR EXAMPLE FOR BABY CARRIAGES AND SMALL VEHICLES. |
US3839409A (en) | 1958-05-28 | 1974-10-01 | Kemiska Inst Karolinska I | Pge3 esters and alkanoates |
US3776938A (en) | 1958-05-28 | 1973-12-04 | S Bergstrom | Dihydro-pge1 |
US3852337A (en) | 1958-05-28 | 1974-12-03 | Kemiska Institutionen Karolins | Pgf tetraols and alkanoyl esters |
US3776939A (en) | 1958-05-28 | 1973-12-04 | S Bergstrom | Dihydro-pgf1a |
US3706789A (en) | 1958-05-28 | 1972-12-19 | Sune Bergstrom | Pgf{11 {60 |
US3598858A (en) | 1958-05-28 | 1971-08-10 | Sune Bergstrom | Pge2 and pge3 |
US3691216A (en) | 1958-05-28 | 1972-09-12 | Sune Bergstrom | Pge2 methyl ester and pge2 methyl ester diacetate |
US3382247A (en) | 1965-11-01 | 1968-05-07 | Upjohn Co | 6-amino-1, 2-dihydro-1-hydroxy-2-imino-4-phenoxypyrimidines |
US3524867A (en) | 1966-06-06 | 1970-08-18 | Upjohn Co | Process for producing cyclopenta (b)pyrans |
US3435053A (en) | 1966-06-06 | 1969-03-25 | Upjohn Co | Cyclopenta(b)pyrans |
GB1236227A (en) | 1967-05-22 | 1971-06-23 | Ciba Geigy Ag | Cyclopentyl-alkanoic acid derivatives |
US3636120A (en) | 1967-10-09 | 1972-01-18 | Upjohn Co | Prostaglandin e primary alcohols |
DE1801750C3 (en) | 1967-10-09 | 1981-02-12 | The Upjohn Co., Kalamazoo, Mich. (V.St.A.) | Prostaglandin E carbinols and their tricarboxylic acid esters |
GB1285371A (en) | 1968-08-29 | 1972-08-16 | Upjohn Co | Improvements in or relating to therapeutic methods using prostaglandins |
GB1285372A (en) | 1968-08-29 | 1972-08-16 | Upjohn Co | Improvements in or relating to prostaglandins and the preparation thereof |
GB1251750A (en) | 1968-11-12 | 1971-10-27 | ||
BE746615A (en) | 1969-03-01 | 1970-07-31 | Herten Kurt | MEANS OF PREVENTING HAIR LOSS |
US3644363A (en) | 1969-09-02 | 1972-02-22 | Richardson Merrell Inc | 1 4-dioxidoquinoxalinyl nitrones |
US3882241A (en) | 1969-12-01 | 1975-05-06 | Upjohn Co | Use of prostaglandins E and F for prevention of pregnancy in humans |
US3896156A (en) | 1970-06-30 | 1975-07-22 | Upjohn Co | Dihydroprostaglandin e, analogs |
FR2108027B1 (en) | 1970-09-28 | 1974-03-29 | Curt Georgi Imes Spa | |
DE2255731C2 (en) | 1971-11-16 | 1982-04-01 | American Cyanamid Co., Wayne, N.J. | 1,3,5-Tris- (4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl) -s-triazine-2,4,6- (1H, 3H, 5H) -trione and its use as Antioxidants |
US3723427A (en) | 1971-11-16 | 1973-03-27 | American Cyanamid Co | Hindered tris(meta-hydroxybenzyl)cyanurate antioxidants |
US3798275A (en) | 1972-04-05 | 1974-03-19 | Ciba Geigy Corp | Etherified mercapto-methoxyamines |
FR2182928A1 (en) | 1972-04-05 | 1973-12-14 | Ciba Geigy Ag | |
US3974213A (en) | 1972-07-13 | 1976-08-10 | Pfizer Inc. | 13,14-Dihydro-15-substituted-ω-pentanorprostaglandins |
US4011262A (en) | 1972-07-13 | 1977-03-08 | Pfizer Inc. | 13,14-Dihydro-15-substituted-ω-pentanorprostaglandins of the two series |
JPS4969636U (en) | 1972-09-29 | 1974-06-18 | ||
US3882245A (en) | 1972-11-01 | 1975-05-06 | Upjohn Co | Use of prostaglandins in combating shock |
GB1456512A (en) | 1972-11-08 | 1976-11-24 | Pfizer | Substituted 16,17,18,19,20-pentanorprostaglandins |
GB1456514A (en) | 1972-11-08 | 1976-11-24 | Pfizer | Substituted dialkyl 2-oxopropylphosphonates |
US4024179A (en) | 1972-11-08 | 1977-05-17 | Pfizer Inc. | Substituted ω-pentanorprostaglandins |
US4152527A (en) | 1972-11-08 | 1979-05-01 | Pfizer Inc. | 15-Substituted-ω-pentanorprostaglandins |
GB1456838A (en) | 1972-11-08 | 1976-11-24 | Pfizer | 16,17,18,19,20-pentanorprostaglandins |
GB1456513A (en) | 1972-11-08 | 1976-11-24 | Pfizer | Derivatives of cyclopentaneacetic acid |
US3984424A (en) | 1972-11-08 | 1976-10-05 | Pfizer Inc. | P-biphenyl esters of 15-substituted-ω-pentanorprostaglandins |
DE2355731C3 (en) | 1972-11-08 | 1981-01-15 | Pfizer Inc., New York, N.Y. (V.St.A.) | Derivatives of w -nor-prostaglandins- E2IUId -F2 a, processes for their preparation and pharmaceutical compositions containing them Pfizer Ine, New York, N.Y. (YStA.) |
JPS4993342U (en) | 1972-12-05 | 1974-08-13 | ||
JPS5253841Y2 (en) | 1972-12-12 | 1977-12-07 | ||
JPS49101356U (en) | 1972-12-20 | 1974-08-31 | ||
JPS49102647U (en) | 1972-12-23 | 1974-09-04 | ||
DE2409460A1 (en) | 1973-02-28 | 1974-08-29 | Ono Pharmaceutical Co | PROSTAGLAND COMPOUNDS AND METHOD OF MANUFACTURING THEREOF |
US3966792A (en) | 1973-02-28 | 1976-06-29 | Ono Pharmaceutical Co., Ltd. | Prostaglandin compounds |
US3984455A (en) | 1973-07-16 | 1976-10-05 | The Upjohn Company | Prostaglandin E1 analogs |
FR2239458B3 (en) | 1973-07-31 | 1976-07-16 | Aries Robert | |
US4004020A (en) | 1973-12-21 | 1977-01-18 | Schering Aktiengesellschaft | Novel prostanoic acid derivatives and process for the preparation thereof |
DE2365101A1 (en) | 1973-12-21 | 1975-07-10 | Schering Ag | NEW PROSTANIC ACID DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
US3928588A (en) | 1974-02-22 | 1975-12-23 | Upjohn Co | Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors |
US4061671A (en) | 1974-04-03 | 1977-12-06 | Hoechst Aktiengesellschaft | Analogues of prostaglandins |
US4105854A (en) | 1974-04-22 | 1978-08-08 | Imperial Chemical Industries Limited | Prostanoic acid derivatives |
DE2460990A1 (en) | 1974-12-21 | 1976-07-01 | Hoechst Ag | NEW PROSTAGLANDIN ANALOGS AND PROCEDURES FOR THEIR PRODUCTION |
JPS5186449U (en) | 1974-12-30 | 1976-07-10 | ||
DE2605584A1 (en) | 1975-02-14 | 1976-08-26 | Ono Pharmaceutical Co | PROSTAGLANDIN ANALOGS |
US4128720A (en) | 1975-02-14 | 1978-12-05 | Ono Pharmaceutical Company | Prostaglandin analogues |
US3934013A (en) | 1975-02-21 | 1976-01-20 | Syntex (U.S.A.) Inc. | Pharmaceutical composition |
DE2605242A1 (en) | 1975-02-21 | 1976-09-02 | Syntex Inc | ANTI-INFLAMMATORY MEDICINAL FOR LOCAL USE |
US4217360A (en) | 1975-02-27 | 1980-08-12 | Schering Aktiengesellschaft | Novel 1,3-benzodioxaneprostanoic acid derivatives and process for the preparation thereof |
US4154950A (en) | 1975-03-31 | 1979-05-15 | The Upjohn Company | 15-Epi-15-methyl-16-phenoxy-PGE compounds |
DE2517771A1 (en) | 1975-04-18 | 1976-10-28 | Schering Ag | NEW PROSTAGLANDIN ACETYLENE ANALOGS AND METHOD FOR THEIR PRODUCTION |
US4073934A (en) | 1975-04-18 | 1978-02-14 | Schering Aktiengesellschaft | Novel acetylenic prostaglandin analogs |
JPS5328160Y2 (en) | 1975-05-16 | 1978-07-15 | ||
FR2314712B2 (en) | 1975-06-16 | 1978-12-08 | Ono Pharmaceutical Co | |
US4018812A (en) | 1975-06-16 | 1977-04-19 | Ono Pharmaceutical Co., Ltd. | 16-methylene-prostaglandin compounds |
US4128577A (en) | 1975-12-29 | 1978-12-05 | The Upjohn Company | 15-Methyl- and 16-phenoxy-PGF2 α, amides |
US4158667A (en) | 1976-02-04 | 1979-06-19 | The Upjohn Company | 6-Keto PGF analogs |
US4139619A (en) | 1976-05-24 | 1979-02-13 | The Upjohn Company | 6-Amino-4-(substituted amino)-1,2-dihydro-1-hydroxy-2-iminopyrimidine, topical compositions and process for hair growth |
US4596812A (en) | 1976-05-24 | 1986-06-24 | The Upjohn Company | Methods and solutions for treating male pattern alopecia |
US4051238A (en) | 1976-06-03 | 1977-09-27 | The Upjohn Company | Treatment of genital tract diseases of domestic animals with prostaglandins |
US4268522A (en) | 1976-06-14 | 1981-05-19 | Pfizer Inc. | 13,14-Dihydro-15-alkenyl- and 13,14-dihydro-15-alkynyl prostaglandins and analogs thereof |
US4489092A (en) | 1976-08-06 | 1984-12-18 | Schering Aktiengesellschaft | Prostanoic acid derivatives and their preparation |
US4284646A (en) | 1976-08-06 | 1981-08-18 | Schering Aktiengesellschaft | Prostanoic acid derivatives and their preparation |
DE2737808A1 (en) | 1976-08-27 | 1978-03-16 | Pfizer | 2-SUBSTITUTED ARYL HETEROCYCLIC OMEGA PENTANOR PROSTAGLANDIN |
GB1545411A (en) | 1976-08-27 | 1979-05-10 | Pfizer | P-biphenylyl esters of 15-peteroaryl-16,17,18,19,20-pentanorprostaglandins |
GB1542569A (en) | 1976-08-27 | 1979-03-21 | Pfizer | 2-substituted-15-heteroaryl-16,17,18,19,20-pentanor-prostaglandins |
US4123441A (en) | 1976-09-22 | 1978-10-31 | The Upjohn Company | Enlarged-hetero-ring prostacyclin analogs |
US4499293A (en) | 1976-09-22 | 1985-02-12 | The Upjohn Company | PGI2 Salts |
US4089885A (en) | 1976-11-05 | 1978-05-16 | American Home Products Corporation | Prostaglandin derivatives |
US4171331A (en) | 1978-06-05 | 1979-10-16 | Miles Laboratories, Inc. | 1 And 2-substituted analogues of certain prostaglandins |
US4206151A (en) | 1978-12-21 | 1980-06-03 | American Cyanamid Company | 15-Deoxy-16-hydroxy-16-vinyl or cyclopropyl prostan-1-ols of the E, A and F series |
US4311707A (en) | 1979-02-12 | 1982-01-19 | American Cyanamid Company | Process for topically producing cutaneous vasodilation for the treatment of vasospastic or ischemic conditions |
GB2048254B (en) | 1979-04-02 | 1983-05-25 | Upjohn Co | 19,20 -didehydro-19-hydroxy and 19-oxo-prostaglandin derivatives |
JPS5829710Y2 (en) | 1979-05-25 | 1983-06-29 | スガツネ工業株式会社 | lock |
US4225508A (en) | 1979-07-05 | 1980-09-30 | The Upjohn Company | 19-Hydroxy-PGI2 compounds |
US4225507A (en) | 1979-07-05 | 1980-09-30 | The Upjohn Company | 19-Hydroxy-19-methyl-PGI2 compounds |
US4296504A (en) | 1980-07-07 | 1981-10-27 | Lawson Daniel C | Toilet seat lock |
JPH0222226Y2 (en) | 1981-02-04 | 1990-06-14 | ||
US4621100A (en) | 1981-09-25 | 1986-11-04 | The Upjohn Company | Treatment of osteoporosis with prostaglandins |
US4543353A (en) | 1981-11-27 | 1985-09-24 | Farmitalia Carlo Erba S.P.A. | Ester and amide derivatives of 13,14-didehydro prostaglandins |
US4599353A (en) | 1982-05-03 | 1986-07-08 | The Trustees Of Columbia University In The City Of New York | Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma |
WO1986000616A1 (en) | 1984-07-13 | 1986-01-30 | Gail Sansone Bazzano | Substituted pyrimidine oxides useful for hair growth promotion |
EP0170258B1 (en) | 1984-07-31 | 1989-12-27 | Syntex (U.S.A.) Inc. | 11-substituted-16-phenoxy and 16-substituted phenoxy-prostatrienoic acid derivatives |
JPH0334934Y2 (en) | 1984-07-31 | 1991-07-24 | ||
US4812457A (en) | 1984-11-21 | 1989-03-14 | Research Development Corporation | Prostaglandin derivatives |
JPS61218510A (en) | 1985-03-22 | 1986-09-29 | Dai Ichi Seiyaku Co Ltd | Agent for hair |
US4757089A (en) | 1985-06-14 | 1988-07-12 | Massachusetts Eye And Ear Infirmary | Increasing aqueous humor outflow |
US5863948A (en) | 1985-06-14 | 1999-01-26 | Massachusetts Eye And Ear Infirmary | Increasing aqueous humor outflow |
US4704386A (en) | 1985-08-29 | 1987-11-03 | G. D. Searle & Co. | 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(phenylsulfinyl-, and phenylsulfonyl)alkanoyl]hydrazides |
US4889845A (en) | 1986-06-09 | 1989-12-26 | American Cyanamid Company | Vehicle for topical application of pharmaceuticals |
US5280018A (en) | 1986-06-09 | 1994-01-18 | American Cyanamid Company | Vehicle for optical application of pharmaceuticals |
EP0249194A3 (en) | 1986-06-09 | 1988-02-10 | American Cyanamid Company | Topical prostaglandin formulations |
US5041439A (en) | 1986-06-13 | 1991-08-20 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions |
US4883819A (en) | 1986-07-31 | 1989-11-28 | The Trustees Of Columbia University In The City Of New York | Use of A, B and C prostaglandins and derivatives thereof to treat ocular hypertension and glaucoma |
US5663203A (en) | 1986-09-11 | 1997-09-02 | Schering Aktiengesellschaft | Agents containing prostacyclin derivatives for topical application |
US5500230A (en) | 1987-01-23 | 1996-03-19 | The General Hospital Corporation | Method for treatment of glaucoma with nitrogen containing guanylate cyclase activators |
US5681850A (en) | 1987-02-16 | 1997-10-28 | Froelich; Juergen C. | Method of treatment of impotence with prostaglandin E1 derivatives |
US5973002A (en) | 1987-02-16 | 1999-10-26 | Froelich; Juergen C. | Prostaglandin E1 derivatives as pharmacologically active agents, especially for transcutaneous administration |
US5464868A (en) | 1987-02-16 | 1995-11-07 | Froelich; Juergen C. | Prostaglandin E1 derivatives for transdermal administration and methods of treatment therewith |
US5219885A (en) | 1987-02-16 | 1993-06-15 | Froelich Juergen | Prostaglandin E1 derivatives as pharmaceutically active agents, and pharmaceutical compositions containing these compounds, especially for transcutaneous administration |
US4952581A (en) | 1987-04-03 | 1990-08-28 | The Trustees Of Columbia University In The City Of New York | Use of a prostaglandin in combination with an adrenergic blocking agent for reduction of intraocular pressure |
US5770759A (en) | 1987-04-30 | 1998-06-23 | R-Tech Ueno, Ltd. | Prostaglandins of the F series |
EP0295092B1 (en) | 1987-06-12 | 1992-09-23 | Unilever Plc | Skin treatment composition |
US5001153A (en) | 1987-09-18 | 1991-03-19 | K.K. Ueno Seiyaku Oyo Kenkyujo | Ocular hypotensive agents |
EP0308135B1 (en) | 1987-09-18 | 1992-11-19 | R-Tech Ueno Ltd. | Ocular hypotensive agents |
US5166178A (en) | 1987-09-18 | 1992-11-24 | K.K. Ueno Seiyaku Oyo Kenkyujo | Ocular hypotensive agents |
US5166178B1 (en) | 1987-09-18 | 1998-07-21 | R Tech Ueno Ltd | Ocular hypotensive agents |
WO1989003384A1 (en) | 1987-10-07 | 1989-04-20 | Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5321128A (en) | 1988-09-06 | 1994-06-14 | Kabi Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US20040167190A1 (en) | 1988-09-06 | 2004-08-26 | Pharmacia Aktiebolag | Prostagladin derivatives for the treatment of glaucoma or ocular hypertension |
US6030999A (en) | 1988-09-06 | 2000-02-29 | Pharmacia & Upjohn Aktiebolag | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5296504A (en) | 1988-09-06 | 1994-03-22 | Kabi Pharmacia | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5422369A (en) | 1988-09-06 | 1995-06-06 | Kabi Pharmacia Ab | Prostaglanddin derivatives for the treatment of glaucoma or ocular hypertension |
US5627208A (en) | 1988-09-06 | 1997-05-06 | Pharmacia Aktiebolag | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5422368A (en) | 1988-09-06 | 1995-06-06 | Kabi Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
WO1990002553A1 (en) | 1988-09-06 | 1990-03-22 | Pharmacia Ab | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5578618A (en) | 1988-09-06 | 1996-11-26 | Pharmacia Aktiebolag | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5849791A (en) | 1988-09-06 | 1998-12-15 | Pharmacia Aktiebolag | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5194429A (en) | 1988-10-01 | 1993-03-16 | K.K. Ueno Seiyaku Oyo Kenkyujo | Ocular hypotensive agents |
US4968812A (en) | 1989-06-23 | 1990-11-06 | Shell Oil Company | Spirolactonelactams |
JPH0383926A (en) | 1989-08-29 | 1991-04-09 | Hisamitsu Pharmaceut Co Inc | Ointment composition |
CA1339132C (en) | 1989-09-12 | 1997-07-29 | Johan W. Stjernschantz | Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension |
US5426115A (en) | 1989-11-22 | 1995-06-20 | Kabushikikaisha Ueno Seiyaku Oyo Kenkyujo | Use of 15-keto-prostaglandin compound for improvement of encephalic function |
JPH0383925U (en) | 1989-12-14 | 1991-08-26 | ||
US5212324A (en) | 1990-04-04 | 1993-05-18 | R.-Tech Ueno Ltd. | Treatment of cataract with 15-keto-prostaglandin compounds |
US5302617A (en) | 1990-04-27 | 1994-04-12 | Kabushikikaisha Ueno Seiyaku Oyo Kenkyuio | Biochemical treatment with 15-dehydroxy-16-oxoprostaglandin compounds |
WO1992002495A1 (en) | 1990-07-27 | 1992-02-20 | Schering Aktiengesellschaft Berlin/Bergkamen | Cyclopentane derivatives, process for producing them and their pharmaceutical use |
US5063057A (en) | 1990-09-26 | 1991-11-05 | Elizabeth Arden Co., Division Of Conopco, Inc. | Cosmetic capsules |
JPH04300833A (en) | 1991-03-29 | 1992-10-23 | Green Cross Corp:The | Prostaglandin e1-containing fat emulsion-loaded aerosol |
US5576315A (en) | 1991-05-03 | 1996-11-19 | G.D. Searle & Co. | Substituted dibenzoxazepine compounds and methods for treating osteoporosis and ischemia |
US5312832A (en) | 1991-05-17 | 1994-05-17 | Allergan, Inc. | Ocular hypotensive 2-decarboxyl-2-acylthioalkyl prostaglandin derivatives |
US5288754A (en) | 1992-02-04 | 1994-02-22 | Allergan, Inc. | Polar C-1 esters of prostaglandins |
US5641494A (en) | 1992-03-20 | 1997-06-24 | Janssen Pharmaceutica N.V. | Agent for regulating the greasiness of the skin |
US5578640A (en) | 1992-05-20 | 1996-11-26 | Loyola University Of Chicago | Protective prostaglandins for use in conjunction with chemotherapeutic agents |
US5605931A (en) | 1992-05-20 | 1997-02-25 | Loyola University Of Chicago | Protective prostaglandins for use in conjunction with chemotherapeutic agents |
US5578643A (en) | 1992-05-20 | 1996-11-26 | Loyola University Of Chicago | Protective prostaglandins for use in conjunction with chemotherapeutic agents |
US5422371A (en) | 1992-05-27 | 1995-06-06 | Arch Development Corp. | Methods and compositions for inhibiting 5α-reductase activity |
JPH05331025A (en) | 1992-05-29 | 1993-12-14 | Toray Ind Inc | Hair tonic and growing agent |
US5508303A (en) | 1992-05-29 | 1996-04-16 | Toray Industries, Inc. | Hair-growing composition |
EP0572014B1 (en) | 1992-05-29 | 1996-10-16 | Toray Industries, Inc. | Hair-growing composition containing prostaglandin I 2 derivatives |
US6013823A (en) | 1992-06-08 | 2000-01-11 | New Pharma International Corp. | Trans-pentavalent 2-15-deoxy-16-hydroxy-16-methyl-PGE1 methyl ester (B-407) |
US5409911A (en) | 1992-09-11 | 1995-04-25 | Merck & Co., Inc. | Prostaglandin analog for treating osteoporosis |
US5834498A (en) | 1992-09-21 | 1998-11-10 | Allergan | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
US5352708A (en) | 1992-09-21 | 1994-10-04 | Allergan, Inc. | Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
US5688819A (en) | 1992-09-21 | 1997-11-18 | Allergan | Cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
US5607978A (en) | 1992-09-21 | 1997-03-04 | Allergan | Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
US6403649B1 (en) | 1992-09-21 | 2002-06-11 | Allergan Sales, Inc. | Non-acidic cyclopentane heptanoic acid,2-cycloalkyl or arylalkyl derivatives as therapeutic agents |
US6037364A (en) | 1992-09-21 | 2000-03-14 | Allergan Sales, Inc. | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
WO1994008585A1 (en) | 1992-10-13 | 1994-04-28 | Alcon Laboratories, Inc. | Combinations of prostaglandins and clonidine derivatives for the treatment of glaucoma |
US5480900A (en) | 1992-10-13 | 1996-01-02 | Alcon Laboratories, Inc. | Combinations of prostaglandins and clonidine derivatives for the treatment of glaucoma |
US5332730A (en) | 1992-10-16 | 1994-07-26 | Allergan, Inc. | Azido derivatives of cyclopentane heptanoic or heptenoic acid |
US5340813A (en) | 1992-11-09 | 1994-08-23 | Cell Therapeutics, Inc. | Substituted aminoalkyl xanthine compounds |
US5567079A (en) | 1992-11-17 | 1996-10-22 | Felder; Anton | Method for the hydraulic branching of an open stream and hydraulically working channel branch |
US5670506A (en) | 1993-04-05 | 1997-09-23 | Cell Therapeutics, Inc. | Halogen, isothiocyanate or azide substituted xanthines |
US5719140A (en) | 1993-04-30 | 1998-02-17 | G.D. Searle & Co. | 2, 3-, 4-, 5-, 6-, 7-, 8-, 9- and /or 10-substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use |
US6031079A (en) | 1993-05-26 | 2000-02-29 | Merck Frosst Canada, Inc. | Purified prostaglandin receptor EP1 |
US5985597A (en) | 1993-05-26 | 1999-11-16 | Merck Frosst Canada, Inc. | DNA encoding prostaglandin receptor EP1 |
US5869281A (en) | 1993-06-25 | 1999-02-09 | Merck Frosst Canada Inc. | DNA encoding prostaglandin receptor FP |
US5840847A (en) | 1993-06-25 | 1998-11-24 | Merck Frosst Canada, Inc. | Purified prostaglandin receptor FP |
US5510383A (en) | 1993-08-03 | 1996-04-23 | Alcon Laboratories, Inc. | Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension |
US5889052A (en) | 1993-08-03 | 1999-03-30 | Alcon Laboraties, Inc. | Use of cloprostenol and fluprostenol analogues to treat glaucoma and ocular hypertension |
US5665773A (en) | 1993-08-03 | 1997-09-09 | Alcon Laboratories, Inc. | Cloprostenol and fluprostenol analogues and their use to treat glaucoma and ocular hypertension |
EP0639563B1 (en) | 1993-08-03 | 2005-01-12 | Alcon Laboratories, Inc. | Use of fluprostenol isopropyl ester for the manufacture of a medicament for the treatment of glaucoma and ocular hypertension |
US5759789A (en) | 1993-08-31 | 1998-06-02 | Merck Frosst Canada, Inc. | Prostaglandin receptor EP2 |
US5605814A (en) | 1993-08-31 | 1997-02-25 | Merck Frosst Canada Inc. | DNA encoding human prostaglandin receptor EP2 |
US5516652A (en) | 1993-10-06 | 1996-05-14 | Merck Frosst Canada Inc. | DNA encoding prostaglandin receptor IP |
EP0648488B1 (en) | 1993-10-13 | 2000-11-29 | L'oreal | Method to alter hairgrowth and compositions therefor |
WO1995011003A1 (en) | 1993-10-20 | 1995-04-27 | Pharmacia Ab | New use of prostaglandins |
WO1995011033A1 (en) | 1993-10-22 | 1995-04-27 | Commonwealth Scientific And Industrial Research Organisation | Polyoxometallates in the treatment of flavivirus infections |
US5773472A (en) | 1993-11-03 | 1998-06-30 | Pharmacia Ab | Method and means for prevention of cataract |
US5431881A (en) | 1993-12-10 | 1995-07-11 | Palacios; Henry J. | Treatment of hair loss and dermatological problems |
US6025375A (en) | 1993-12-20 | 2000-02-15 | Fujisawa Pharmaceutical Co., Ltd. | 4,5-diaryloxazole derivatives |
WO1995018102A1 (en) | 1993-12-28 | 1995-07-06 | Allergan | Cyclopentane(ene) heptenoic or heptanoic acids and derivatives thereof useful as therapeutic agents |
US6124344A (en) | 1993-12-28 | 2000-09-26 | Allergan Sales, Inc. | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
US5587391A (en) | 1993-12-28 | 1996-12-24 | Allergan | Cyclopentane(ene) heptenoic or heptanoic acids and derivatives thereof useful as therapeutic agents |
US6716876B2 (en) | 1993-12-28 | 2004-04-06 | Allergan, Inc. | Cyclopentane(ENE)heptenoic or heptanoic acids and derivatives thereof useful as therapeutic agents |
US6160129A (en) | 1993-12-28 | 2000-12-12 | Allergan Sales, Inc. | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
US6126957A (en) | 1994-01-12 | 2000-10-03 | Duke University | Method of treating disorders of the eye |
US5458883A (en) | 1994-01-12 | 1995-10-17 | Duke University | Method of treating disorders of the eye |
WO1995019165A1 (en) | 1994-01-12 | 1995-07-20 | Duke University | Method of treating disorders of the eye |
US6534082B1 (en) | 1994-01-12 | 2003-03-18 | Duke University | Method of treating disorders of the eye |
WO1995019964A1 (en) | 1994-01-19 | 1995-07-27 | Allergan | Ep2-receptor agonists as agents for lowering intraocular pressure |
WO1995000552B1 (en) | 1994-06-09 | 1995-02-02 | Prostaglandin receptor ep3 and dna encoding it | |
US6031001A (en) | 1994-09-21 | 2000-02-29 | Synphra Ab | Use of prostaglandins |
WO1996010407A1 (en) | 1994-09-30 | 1996-04-11 | Alcon Laboratories, Inc. | Use of 9-deoxy prostaglandin derivatives to treat glaucoma |
US5698733A (en) | 1994-09-30 | 1997-12-16 | Alcon Laboratories, Inc. | Use of 9-deoxy prostaglandin derivatives to treat glaucoma |
US5885974A (en) | 1994-12-06 | 1999-03-23 | Michael M. Danielov | Therapeutic methods utilizing naturally derived bio-active complexes and delivery systems therefor |
US6043264A (en) | 1995-01-06 | 2000-03-28 | Toray Industries, Inc. | Benzene-condensed heterocyclic derivatives and their uses |
US5958723A (en) | 1995-01-26 | 1999-09-28 | Merck Frosst Canada & Co. | DNA encoding prostaglandin receptor DP |
US5885766A (en) | 1995-02-17 | 1999-03-23 | Societe L'oreal S.A. | Method of screening of substances for their effect on the expression of mediators of inflammation in a hair follicle |
FR2730811B1 (en) | 1995-02-17 | 1997-03-21 | Oreal | METHOD FOR DIAGNOSING AND / OR MONITORING THE EVOLUTION OF A HAIR DISORDER AND / OR MEASURING THE EFFECTIVENESS OF A TREATMENT APPLIED TO COMBAT A HAIR DISORDER |
WO1996036599A1 (en) | 1995-05-18 | 1996-11-21 | Allergan | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents for the treatment of ocular hypertension |
WO1998021180A1 (en) | 1995-06-07 | 1998-05-22 | Alcon Laboratories, Inc. | Conformationally rigid aryl- or heteroaryl prostaglandins for use in glaucoma therapy |
US6169111B1 (en) | 1995-06-07 | 2001-01-02 | Alcon Laboratories, Inc. | Conformationally rigid aryl prostaglandins for use in glaucoma therapy |
US5990346A (en) | 1995-06-26 | 1999-11-23 | Teijin Limited | Prostaglandins and processes for production thereof |
US5972965A (en) | 1995-07-21 | 1999-10-26 | Fujisawa Pharmaceutical Co., Ltd. | 4,5-diaryl oxazole derivatives |
WO1997003973A1 (en) | 1995-07-21 | 1997-02-06 | Fujisawa Pharmaceutical Co., Ltd. | 4,5-diaryl oxazole derivatives |
US5716609A (en) | 1995-07-25 | 1998-02-10 | Panacea Biotec Limited | Therapeutic anti-inflammatory and analgesic composition containing nimesulide for use transdermally and a process for the manufacture thereof |
WO1997009049A3 (en) | 1995-09-01 | 1997-07-10 | Allergan Inc | Method for effecting vasodilation with (1,5-inter)aryl prostaglandin derivatives |
WO1997015319A1 (en) | 1995-10-23 | 1997-05-01 | Queen's University At Kingston | Method and pharmaceutical composition for chondrostimulation with a prostaglandin (e.g. misoprostol) and tgf-beta, optionally in combination with igf-1 |
US5994397A (en) | 1995-12-22 | 1999-11-30 | Alcon Laboratories, Inc. | Substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
US6025392A (en) | 1995-12-22 | 2000-02-15 | Alcon Laboratories, Inc. | substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
WO1997023225A1 (en) | 1995-12-22 | 1997-07-03 | Alcon Laboratories, Inc. | Combinations of dp and fp type prostaglandins for lowering iop |
WO1997023226A1 (en) | 1995-12-22 | 1997-07-03 | Alcon Laboratories, Inc. | Combinations of prostaglandins and miotics for lowering intraocular pressure |
WO1997023223A1 (en) | 1995-12-22 | 1997-07-03 | Alcon Laboratories, Inc. | Substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
WO1997029735A1 (en) | 1996-02-19 | 1997-08-21 | Monash University | Dermal penetration enhancers and drug delivery systems involving same |
US5703108A (en) | 1996-02-28 | 1997-12-30 | Pfizer Inc. | Bone deposition by certain prostaglandin agonists |
US5741810A (en) | 1996-02-29 | 1998-04-21 | Allergan | Cyclopentane heptan(ene)oic acid, 2- heteroarylalkenyl derivatives as therapeutic agents |
WO1997031895A3 (en) | 1996-02-29 | 1997-12-18 | Allergan Inc | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
US5658897A (en) | 1996-04-08 | 1997-08-19 | Allergan | Cyclopentane(ene) heptanoic or cyclopentane(ene) heptenoic acid, 2-hydrocarbyl phosphinyloxyalkyl or phosphonamidoalkyl as therapeutic agents |
WO1997039754A1 (en) | 1996-04-18 | 1997-10-30 | Alberta Cancer Board | Use of prostaglandins to treat ataxia telangiectasia |
JPH09295921A (en) | 1996-05-01 | 1997-11-18 | Bimeeku:Kk | Hair growing and tonic agent |
EP0857718B1 (en) | 1996-06-10 | 2002-08-14 | Sucampo AG | Endothelin antagonist |
WO1998000100A1 (en) | 1996-07-03 | 1998-01-08 | The Board Of Regents Of The University Of Oklahoma | Enhancement of skin pigmentation by prostaglandins |
US5792851A (en) | 1996-09-03 | 1998-08-11 | Albert Einstin College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Human prostaglandin transporter |
JPH10251225A (en) | 1996-09-17 | 1998-09-22 | Santen Pharmaceut Co Ltd | Fluorine-containing prostaglandin derivative and medicine |
WO1998012175A1 (en) | 1996-09-17 | 1998-03-26 | Asahi Glass Company Ltd. | Fluorinated prostaglandin derivatives and medicines |
WO1998013016A1 (en) | 1996-09-27 | 1998-04-02 | The Procter & Gamble Company | Stable photoprotective compositions |
WO1998019680A1 (en) | 1996-11-01 | 1998-05-14 | Alcon Laboratories, Inc. | Use of a combination of carbonic anhydrase inhibitors and prostaglandins for treating glaucoma |
WO1998020880A3 (en) | 1996-11-12 | 1998-08-20 | Alcon Lab Inc | 11-Halo prostaglandins for the treatment of glaucoma or ocular hypertension |
WO1998020881A1 (en) | 1996-11-12 | 1998-05-22 | Alcon Laboratories, Inc | 15-ketal prostaglandins for the treatment of glaucoma or ocular hypertension |
WO1998021182A3 (en) | 1996-11-12 | 1998-06-25 | Alcon Lab Inc | Use of cis-δ4 analogs of prostaglandins as ocular hypotensives |
WO1998021181A3 (en) | 1996-11-12 | 1998-07-16 | Alcon Lab Inc | 15-fluoro prostaglandins as ocular hypotensives |
EP0947500B1 (en) | 1996-12-18 | 2011-02-23 | Ono Pharmaceutical Co., Ltd. | Sulfonamide derivatives and drugs containing the same as the active ingredient |
WO1998027976A1 (en) | 1996-12-20 | 1998-07-02 | Pfizer Inc. | Prevention and treatment of skeletal disorder with ep2 receptor subtype selective prostaglandin e2 agonists |
WO1998028264A1 (en) | 1996-12-20 | 1998-07-02 | Pfizer Inc. | Prevention of loss and restoration of bone mass by certain prostaglandin agonists |
US5892099A (en) | 1997-01-27 | 1999-04-06 | Ono Pharmaceutical Co., Ltd. | 3,7-dithiaprostanoic acid derivative |
US6262105B1 (en) | 1997-02-04 | 2001-07-17 | Murray A. Johnstone | Method of enhancing hair growth |
US6110969A (en) | 1997-02-04 | 2000-08-29 | Ono Pharmaceutical Co. Ltd. | Cycloalkyl-prostaglandin E2 derivatives |
WO1998033497A1 (en) | 1997-02-04 | 1998-08-06 | Johnstone Murray A | Method of enhancing hair growth |
EP1008588B1 (en) | 1997-02-10 | 2003-04-16 | Ono Pharmaceutical Co., Ltd. | 11,15-o-dialkylprostaglandin e derivatives, process for producing the same, and drugs containing the same as the active ingredient |
EP0925787A4 (en) | 1997-02-27 | 1999-12-01 | Toray Industries | Drugs for ameliorating pulmonary circulation |
WO1998039293A3 (en) | 1997-03-07 | 1998-11-05 | Alcon Lab Inc | 13-thia prostaglandins for use in glaucoma therapy |
US6030959A (en) | 1997-04-04 | 2000-02-29 | Monsanto Company | Gastro-specific prodrugs |
JPH10287532A (en) | 1997-04-17 | 1998-10-27 | R Tec Ueno:Kk | Hair-growing agent |
WO1998047515A1 (en) | 1997-04-22 | 1998-10-29 | Pharmacia & Upjohn Ab | THE USE OF α-METHYL-P-TYROSINE TO INHIBIT MELANIN PRODUCTION IN IRIS MELANOCYTES |
WO1998050024A1 (en) | 1997-05-09 | 1998-11-12 | The Mount Sinai School Of Medicine Of The City University Of New York | 8-iso-prostaglandins for glaucoma therapy |
US6037368A (en) | 1997-05-09 | 2000-03-14 | Mount Sinai School Of Medicine | 8-iso- prostaglandins for glaucoma therapy |
WO1998053809A1 (en) | 1997-05-30 | 1998-12-03 | Merck & Co., Inc. | Ophthalmic compositions for treating ocular hypertension |
WO1998057930A1 (en) | 1997-06-18 | 1998-12-23 | Alcon Laboratories, Inc. | Keto-substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
WO1998057942A1 (en) | 1997-06-18 | 1998-12-23 | Alcon Laboratories, Inc. | 9-oxa prostaglandin analogs as ocular hypotensives |
WO1998058911A3 (en) | 1997-06-23 | 1999-03-18 | Pfizer | Prostaglandin agonists |
WO1999002165A1 (en) | 1997-07-11 | 1999-01-21 | Pharmacia & Upjohn Ab | Prostaglandin derivatives devoid of side-effects for the treatment of glaucoma |
WO1999012556A1 (en) | 1997-09-08 | 1999-03-18 | The Public Health Research Institute Of The City Of New York, Inc. | HIV-1 gp120 V1/V2 DOMAIN EPITOPES CAPABLE OF GENERATING NEUTRALIZING ANTIBODIES |
WO1999012553A1 (en) | 1997-09-08 | 1999-03-18 | Idec Pharmaceuticals Corporation | Methods for producing human antibodies in scid mice using dendritic cells |
WO1999012551A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | Method of increasing bone volume using non-naturally-occurring fp selective agonists |
WO1999012897A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | A process for making epoxide intermediates |
US5977173A (en) | 1997-09-09 | 1999-11-02 | Wos; John August | Aromatic C16 -C20 -substituted tetrahydro prostaglandins useful as FP agonists |
WO1999012550A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | Method of increasing bone volume |
WO1999012559A1 (en) | 1997-09-09 | 1999-03-18 | The Regents Of The University Of California | Inhibition of apoptotis using prosaposin receptor agonists |
US6107338A (en) | 1997-09-09 | 2000-08-22 | The Procter & Gamble Company | Aromatic C16 -C20 -substituted tetrahydro prostaglandins useful as FP agonists |
WO1999012899A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | A process for making prostaglandin f analogs |
US6048895A (en) | 1997-09-09 | 2000-04-11 | The Procter & Gamble Company | Aromatic C16-C20 substituted tetrahydro prostaglandins useful as FP agonists |
WO1999012554A1 (en) | 1997-09-09 | 1999-03-18 | The University Of Western Australia | Chemical supplementation of bone |
WO1999012896A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | Aromatic c16-c20-substituted tetrahydro prostaglandins useful as fp agonists |
WO1999012560A1 (en) | 1997-09-09 | 1999-03-18 | Creative Biomolecules, Inc. | Synergistic effects of op/bmp morphogens and gdnf/ngf neurotrophic factors |
WO1999012561A9 (en) | 1997-09-09 | 2000-03-16 | Hoffmann La Roche | FRACTURE HEALING USING PTHrP ANALOGS |
WO1999012895A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | Aromatic c16-c20-substituted tetrahydro prostaglandins useful as fp agonists |
WO1999012898A1 (en) | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | Aromatic c16-c20-substituted tetrahydro prostaglandins useful as fp agonists |
WO1999012558A1 (en) | 1997-09-10 | 1999-03-18 | Allegheny University Of The Health Sciences | Inhibitors of collagen assembly |
WO1999012552A1 (en) | 1997-09-10 | 1999-03-18 | Merck & Co., Inc. | 9a-AZALIDES AS VETERINARY ANTIMICROBIAL AGENTS |
WO1999012555A1 (en) | 1997-09-11 | 1999-03-18 | Purdue Research Foundation | Galactosidase modified submucosal tissue |
WO1999012563A3 (en) | 1997-09-11 | 1999-05-27 | Us Health | Mucosal cytotoxic t lymphocyte responses |
WO1999012557A1 (en) | 1997-09-12 | 1999-03-18 | Smithkline Beecham Corporation | Novel prokaryotic polynucleotides, polypeptides and their uses |
EP0970697A4 (en) | 1997-09-17 | 2001-02-21 | Toray Industries | Cervical maturing agent |
EP1016660B1 (en) | 1997-09-19 | 2003-10-29 | Shionogi & Co., Ltd. | Compounds having 2.2.1]bicyclo skeleton |
WO1999019300A1 (en) | 1997-10-10 | 1999-04-22 | Pfizer Inc. | Prostaglandin agonists and their use to treat bone disorders |
EP0911321A3 (en) | 1997-10-10 | 2001-01-31 | Pfizer Inc. | Compounds for the treatment of osteoporosis |
WO1999021562A1 (en) | 1997-10-28 | 1999-05-06 | Asivi, Llc | Treatment of female sexual dysfunction |
WO1999022731A1 (en) | 1997-10-30 | 1999-05-14 | Vaysman, Pyotr | Method and composition for treatment of sexual dysfunction |
WO1999025357A1 (en) | 1997-11-14 | 1999-05-27 | United Therapeutics Corporation | USE OF 9-DEOXY-2', 9-α-METHANO-3- OXA-4,5,6- TRINOR-3, 7-(1',3'-INTERPHENYLENE) -13,14-DIHYDRO- PROSTAGLANDIN F1 TO TREAT PERIPHERAL VASCULAR DISEASE |
WO1999025358A1 (en) | 1997-11-19 | 1999-05-27 | Allergan Sales, Inc. | Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents |
US5877211A (en) | 1997-11-21 | 1999-03-02 | Allergan | EP2 receptor agonists as neuroprotective agents for the eye |
WO1999030718A3 (en) | 1997-12-18 | 1999-09-10 | Nathan Earl Scott | PROSTAGLANDIN E2/F2α COMBINATION FOR TREATING IMPOTENCE AND ENHANCING SEXUAL AROUSAL |
WO1999030675A1 (en) | 1997-12-18 | 1999-06-24 | Johnson & Johnson Consumer Companies, Inc. | Methods for improving the health of hair and scalp |
WO1999032441A1 (en) | 1997-12-22 | 1999-07-01 | Alcon Laboratories, Inc. | 13-oxa prostaglandins for the treatment of glaucoma and ocular hypertension |
WO1999032640A1 (en) | 1997-12-22 | 1999-07-01 | Hopital Sainte-Justine | Antagonists of g-protein-coupled receptor |
WO1999032641A1 (en) | 1997-12-22 | 1999-07-01 | Unilever N.V. | A process for site-directed integration of multiple copies of a gene in a mould |
US6232344B1 (en) | 1997-12-22 | 2001-05-15 | Alcon Laboratories, Inc. | 13-Oxa prostaglandins for the treatment of glaucoma and ocular hypertension |
WO1999033794A1 (en) | 1997-12-25 | 1999-07-08 | Ono Pharmaceutical Co., Ltd. | φ-CYCLOALKYL-PROSTAGLANDIN E2 DERIVATIVES |
GB2330307A (en) | 1998-02-07 | 1999-04-21 | Glaxo Group Ltd | EP4 Receptor antagonists as bone resorption inhibitors |
WO1999047497A3 (en) | 1998-03-13 | 1999-10-28 | Merck Frosst Canada Inc | Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment |
US6444840B1 (en) | 1998-03-31 | 2002-09-03 | The Procter & Gamble Co. | C11 oxymyl and hydroxylamino prostaglandins useful as FP agonists |
US6410780B1 (en) | 1998-03-31 | 2002-06-25 | The Procter & Gamble Co. | C11 oxymyl and hydroxylamino prostaglandins useful as medicaments |
WO1999050242A1 (en) | 1998-03-31 | 1999-10-07 | The Procter & Gamble Company | C11 oxymyl and hydroxylamino prostaglandins useful as fp agonists |
WO1999050241A1 (en) | 1998-03-31 | 1999-10-07 | The Procter & Gamble Company | C11 oxymyl and hydroxylamino prostaglandins useful as medicaments |
WO1999061029A1 (en) | 1998-05-25 | 1999-12-02 | Taisho Pharmaceutical Co., Ltd. | Sleep inducing agent |
WO1999064621A1 (en) | 1998-06-11 | 1999-12-16 | Winthrop-University Hospital | Methods of diagnosing renal salt wasting syndrome and alzheimer's disease and methods of treating the same |
WO1999065303A1 (en) | 1998-06-15 | 1999-12-23 | Macrochem Corporation | Composition and method for treating penile erectile dysfunction |
WO1999065527A1 (en) | 1998-06-17 | 1999-12-23 | Pharmacia & Upjohn Company | Solution comprising prostaglandins and benzyl alcohol |
WO2000002450A1 (en) | 1998-07-08 | 2000-01-20 | Fibrogen, Inc. | Method for treatment of fibrosis related diseases by the administration of prostacyclin derivatives |
WO2000003736A1 (en) | 1998-07-14 | 2000-01-27 | Alcon Laboratories, Inc. | Prostaglandin product |
WO2000003980A1 (en) | 1998-07-15 | 2000-01-27 | Ono Pharmaceutical Co., Ltd. | 5-THIA-φ-SUBSTITUTED PHENYL-PROSTAGLANDIN E DERIVATIVES, PROCESS FOR PRODUCING THE SAME AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT |
WO2000004898A1 (en) | 1998-07-21 | 2000-02-03 | Merck & Co., Inc. | Ophthalmic compositions for treating ocular hypertension |
WO2000004899A1 (en) | 1998-07-21 | 2000-02-03 | Merck & Co., Inc. | Ophthalmic compositions for treating ocular hypertension |
WO2000007627A8 (en) | 1998-08-04 | 2001-02-08 | Johnson & Johnson Consumer | Topical delivery systems for active agents |
WO2000009557A1 (en) | 1998-08-12 | 2000-02-24 | Kazusa Dna Research Institute Foundation | Novel gene and protein pgth encoded thereby |
WO2000013664A1 (en) | 1998-09-08 | 2000-03-16 | L.A.M. Pharmaceutical Corp | Drug preparations for treating sexual dysfunction |
WO2000015608A1 (en) | 1998-09-14 | 2000-03-23 | Ono Pharmaceutical Co., Ltd. | φ-SUBSTITUTED PHENYL-PROSTAGLANDIN E DERIVATIVES AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT |
WO2000016760A3 (en) | 1998-09-23 | 2000-06-08 | Fujisawa Pharmaceutical Co | New use of prostaglandin e2 antagonists |
US6121253A (en) | 1998-11-20 | 2000-09-19 | Merck Frosst Canada & Co. | Prostaglandin conjugates for treating or preventing bone disease |
WO2000051971A1 (en) | 1999-03-01 | 2000-09-08 | Pfizer Products Inc. | Oxamic acids and derivatives as thyroid receptor ligands |
AU766163B2 (en) | 1999-03-05 | 2003-10-09 | Duke University | C16 unsaturated fp-selective prostaglandins analogs |
CA2364948C (en) | 1999-03-05 | 2011-04-26 | The Procter & Gamble Company | C16 unsaturated fp-selective prostaglandins analogs |
EP1159266B1 (en) | 1999-03-05 | 2004-11-03 | Duke University | C-16 unsaturated fp-selective prostaglandins analogs |
US6586463B2 (en) | 1999-03-05 | 2003-07-01 | The Procter & Gamble Company | C16 unsaturated FP-selective prostaglandins analogs |
WO2000051979A1 (en) | 1999-03-05 | 2000-09-08 | The Procter & Gamble Company | C16 unsaturated fp-selective prostaglandins analogs |
WO2000051980A1 (en) | 1999-03-05 | 2000-09-08 | The Procter & Gamble Company | C16 unsaturated fp-selective prostaglandins analogs |
US6451859B1 (en) | 1999-03-05 | 2002-09-17 | The Procter & Gamble Company | C16 unsaturated FP-selective prostaglandins analogs |
WO2000054810A1 (en) | 1999-03-12 | 2000-09-21 | Alcon Laboratories, Inc | Combination therapy for treating glaucoma |
US7115659B2 (en) | 1999-08-04 | 2006-10-03 | The Procter & Gamble Company | Method of treating a condition by administering a prostaglandin derivative |
WO2001010873A1 (en) | 1999-08-04 | 2001-02-15 | The Procter & Gamble Company | Novel 2-decarboxy-2-phosphinico prostaglandin f analogs |
US6372730B1 (en) | 1999-08-04 | 2002-04-16 | The Procter & Gamble Company | 2-decarboxy-2-phosphinico Prostaglandin F analogs |
US6894175B1 (en) | 1999-08-04 | 2005-05-17 | The Procter & Gamble Company | 2-Decarboxy-2-phosphinico prostaglandin derivatives and methods for their preparation and use |
US7074942B2 (en) | 1999-08-04 | 2006-07-11 | The Procter & Gamble Company | 2-decarboxy-2-phosphinico prostaglandin derivatives and methods for their preparation and use |
US6548535B2 (en) | 2000-01-18 | 2003-04-15 | Merck & Co., Inc. | Method for treating ocular hypertension |
US20030191173A1 (en) | 2000-01-18 | 2003-10-09 | Garcia Maria L. | Method for treating ocular hypertension |
US20010047025A1 (en) | 2000-01-18 | 2001-11-29 | Garcia Maria L. | Method for treating ocular hypertension |
US20020146439A1 (en) | 2000-03-31 | 2002-10-10 | Delong Mitchell Anthony | Compositions and methods for treating hair loss using oximyl and hydroxylamino prostaglandins |
US7388029B2 (en) | 2000-03-31 | 2008-06-17 | Duke University | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
US20020013294A1 (en) | 2000-03-31 | 2002-01-31 | Delong Mitchell Anthony | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
WO2001074314A3 (en) | 2000-03-31 | 2002-02-21 | Procter & Gamble | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
US20090286769A1 (en) | 2000-03-31 | 2009-11-19 | Duke University | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
US20080241078A1 (en) | 2000-03-31 | 2008-10-02 | Duke University | Compositions and methods for treating hair loss using c16-c20 aromatic tetrahydro prostaglandins |
US7407987B2 (en) | 2000-03-31 | 2008-08-05 | Duke University | Compositions and methods for treating hair loss using C16-C20 aromatic tetrahydro prostaglandins |
US20030083381A1 (en) | 2000-03-31 | 2003-05-01 | Hiroki Kumagai | Hair growth or hair formation controlling agents |
US20020172693A1 (en) | 2000-03-31 | 2002-11-21 | Delong Michell Anthony | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
US20080103184A1 (en) | 2000-03-31 | 2008-05-01 | Duke University | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
US20060247214A1 (en) | 2000-03-31 | 2006-11-02 | Duke University | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
WO2001074315A3 (en) | 2000-03-31 | 2002-02-21 | Procter & Gamble | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
WO2001074313A3 (en) | 2000-03-31 | 2002-02-21 | Procter & Gamble | Compositions and methods for treating hair loss using c16 - c20 aromatic tetrahydro prostaglandins |
WO2001074307A3 (en) | 2000-03-31 | 2002-04-11 | Procter & Gamble | Compositions and methods for treating hair loss using oximyl- and hydroxylamino- prostaglandins |
US20060121069A1 (en) | 2000-03-31 | 2006-06-08 | Duke University | Compositions and methods for treating hair loss using oximyl and hydroxylamino prostaglandins |
US20020037914A1 (en) | 2000-03-31 | 2002-03-28 | Delong Mitchell Anthony | Compositions and methods for treating hair loss using C16-C20 aromatic tetrahydro prostaglandins |
US20020044953A1 (en) | 2000-07-28 | 2002-04-18 | Michelet Jean Francois | Use of non-prostanoic agonists of prostaglandin EP-2 and/or EP-4 receptors as cosmetic agents for attenuating, reducing or stopping the loss of head hair and other hairs |
WO2002067901A1 (en) | 2001-02-22 | 2002-09-06 | Skyepharma Canada Inc. | Fibrate-statin combinations with reduced fed-fasted effects |
JP2003180399A (en) | 2001-09-28 | 2003-07-02 | Pfizer Prod Inc | Method related to a-c repeat z-sequence upstream from aldose reductase gene |
WO2003051822A1 (en) | 2001-12-19 | 2003-06-26 | Astrazeneca Ab | Substituted phenylpropionic acid derivatives as agonists to human peroxisome proliferator-activated receptor alpha (ppar) |
US20080070988A1 (en) | 2002-02-04 | 2008-03-20 | Allergan, Inc. | Method of Enhancing Hair Growth |
US20090203659A1 (en) | 2002-02-04 | 2009-08-13 | Allergan, Inc. | Method of enhancing hair growth |
WO2003066008A1 (en) | 2002-02-04 | 2003-08-14 | Allergan, Inc. | Method of enhancing hair growth |
US20030147823A1 (en) | 2002-02-04 | 2003-08-07 | Allergan, Inc. | Method of enhancing hair growth |
US20070282006A1 (en) | 2002-02-04 | 2007-12-06 | Woodward David F | Method of enhancing hair growth |
WO2003077910A1 (en) | 2002-03-18 | 2003-09-25 | Pfizer Products Inc. | Methods of treatment with selective ep4 receptor agonists |
US20040171596A1 (en) | 2002-04-01 | 2004-09-02 | Laszlo Prokai | Prodrugs for use as ophthalmic agents |
US20040157912A1 (en) | 2002-05-14 | 2004-08-12 | Old David W. | 8-Azaprostaglandin analogs as agents for lowering intraocular pressure |
US20030199590A1 (en) | 2002-07-25 | 2003-10-23 | Cagle Gerald D | Prostaglandin analogues for promotion of hair growth |
US20050058614A1 (en) | 2003-09-15 | 2005-03-17 | Allergan, Inc. | Methods for the treatment of gray hair using cyclopentane(ene) heptan(en)oic acid amides |
US7070768B2 (en) | 2003-09-25 | 2006-07-04 | Allergan, Inc. | Method for imparting artificial tan to human skin |
US20070161699A1 (en) | 2003-11-26 | 2007-07-12 | Duke University | Method of preventing or treating glaucoma |
US20060135609A1 (en) | 2004-10-21 | 2006-06-22 | Duke University | Ophthamological drugs |
WO2006047466A3 (en) | 2004-10-21 | 2006-09-21 | Univ Duke | Ophthamological drugs |
US7288029B1 (en) | 2005-01-19 | 2007-10-30 | Gkn Driveline North America, Inc. | Propshaft with crash-worthiness |
WO2007125818A1 (en) | 2006-04-24 | 2007-11-08 | Jsr Corporation | Polymer and photosensitive resin composition comprising the same |
WO2007127639A3 (en) | 2006-04-26 | 2008-06-12 | Aerie Pharmaceuticals Inc | Prodrug derivatives of acids using alcohols with homotopic hydroxy groups and methods for their preparation and use |
US20070254920A1 (en) | 2006-04-26 | 2007-11-01 | Aerie Pharmaceuticals, Inc. | Prodrug derivatives of acids using alcohols with homotopic hydroxy groups and methods for their preparation and use |
US20090018204A1 (en) | 2007-07-13 | 2009-01-15 | Brinkenhoff Michael C | Composition and method for enhancing hair growth |
WO2009011744A2 (en) | 2007-07-13 | 2009-01-22 | Athena Cosmetics Corporation | Composition and method for enhancing hair growth |
US20100105771A1 (en) | 2008-10-29 | 2010-04-29 | Delong Mitchell A | Amino acid salts of prostaglandins |
US20100105775A1 (en) | 2008-10-29 | 2010-04-29 | Delong Mitchell A | Amino acid salts of prostaglandins |
Non-Patent Citations (293)
Title |
---|
"Agents for Glaucoma," Journal of the American Pharmaceutical Association, New Drugs of 2001, http://www.edscape.com/viewarticle/436631—22 (2007) 4 pages. |
"Bimatoprost (ophthalmic)" Medlineplus, Health information online (Jul. 24, 2001) 4 pages, www.nlm.nih.gov/medlineplus/druginfor/uspdi/500295. |
Abramovitz, M. et al., "Cloning and expression of a cDNA for the human prostanoid FP receptor," J. Biol. Chem. (1994) 269:2632-2636. |
Abramovitz, M. et al., "The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs," Biochimica et Biophysica Acta (2000) 1483(2):285-293. |
Adis, Adisinsight: ZD-6416, AstraZeneca (United Kingdom) Mar. 27, 2000, 1 page. |
AGN-192024, Pharmaprojects, HB4 S1G (2006). |
Allergan Press Release, "Phase III Lumigan? (AGN 192024) data presented at American Academy of Ophthalmology," Mar. 1, 2000, 5 pages. |
Alm et al., "Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning," Ophthalmology (1995) 102(12):1743-1752. |
Alm, A. et al., "Phase III latanoprost studies in Scandanavia, the United Kingdom and the United States," Surv. Ophthalmol. (1997) 41(Suppl 2):S105-S110. |
Alm, A. et al., "Uveoscleral outflow—a review," Exp. Eye Res. (2009) 88(4):760-768, Epub Jan. 3, 2009. |
Alm, A., "The potential of prostaglandin derivates in glaucoma therapy; prostaglandins and derivates," Curr. Opin. Opthalmol (1993) 4(11):44-50. |
Al-Sereiti, M.R., et al., "Pharmacology of Rosemary (Rosmarinus Officinalis Linn.) and Its Therapeutic Potentials," Indian Journal of Experimental Biology, vol. 37, Feb. 1999, pp. 124-130. |
Anonymous, "Alprostadil (nexmed):Alprox-TD, Befar, Femprox, Prostaglandin E1 (nexmed)," Drugs R&D (1999) 2(6):413-414. |
Audoly, L.P. et al., "Identification of specific EP receptors responsible for the hemodynamic effects of PGE2," Am. J. Physiol. (1999) 46(3):H924-930. |
Australian Patent Office Action dated Jul. 3, 2002 (2 pages) for Australian Patent No. 766163 (also cited separately on the enclosed 1449A), claiming priority to International Application No. PCT/US00/05301 (WO 00/51980) filed Feb. 29, 2000 and U.S. Appl. No. 60/122,924, filed Mar. 5, 1999. |
Australian Patent Office Action dated Jul. 8, 2003 (2 pages) for Australian Patent No. 766163 (also cited separately on the enclosed 1449A), claiming priority to International Application No. PCT/US00/05301 (WO 00/51980) filed Feb. 29, 2000 and U.S. Appl. No. 60/122,924, filed Mar. 5, 1999. |
Bartman et al., "Synthesis and Biological Activity", Prostaglandins, 1979, pp. 301-311, vol. 17, No. 2. |
Bartman, W., et al., "Leutolytic Prostaglandins Synthesis and Biological Activity", Prostaglandins, vol. 17, No. 2, pp. 301-311, 1979. |
Bean, G.W., "Commercially available prostaglandin analogs for the reduction of intraocular pressure: similarities and differences," Survey of Ophthalmology (2008) 53(1):S69-84. |
Berglund, B.A. et al., "Investigation of structural analogs of prostaglandin amides for binding to and activation of CB1 and CB2 cannabinoid receptors in rat brain and human tonsils," Adv. Exp. Med. Biol. (1999) 469:527-533. |
Bito, L., "A new approach to the medical management of glaucoma, from the bench to the clinic, and beyond," The Proctor Lecture (2001) 42(6):1126-1133. |
Bito, L.Z. et al., "Long-term maintenance of reduced intraocular pressure by daily or twice daily topical application of psotaglandins to cat or rhesus monkey eyes," Invest. Ophthalmol. Vis. Sci. (1983) 24(3):312-319. |
Brandt, J.D. et al., "Comparison of once-or twice-daily bimatoprost with twice-daily timolol in pateints with elevated IPO. A three month clinical tril," Ophthalmology (2001) 108(6):1023-1031. |
Bundy et al., "Synthesis of 17-Phenyl-18,19,20-trinorprostaglandins I. The Pg, Series", Prostaglandins, 1975, pp. 1-4, vol. 9, No. 1. |
Bundy, G. L., and Lincoln, F. H., "Synthesis of 17-Phenyl-18, 19, 20-Trinoprostaglandins 1. The PG, Series," Prostaglandins, vol. 9, No. 1, (Jan. 1975), pp. 1-4. |
Cadet, P. et al., "Molecular identification and functional expression of mu3, a novel alternatively apliced variant of the human mu opiate receptor gene," J. Immunol. (2003) 170(10):5118-5123. |
Camras, C.B. et al. "Bimatoprost, the prodrug of a prostaglandin analogue," Br. J. Ophthalmol. (2008) 92:862-863. |
Camras, C.B. et al., "Latanoprost, a prostaglandin analog, for glaucoma therapy," Ophthalmology (1996) 103(11):1916-1924. |
Camras, C.B. et al., "Multiple dosing of prostaglandin F2alpha or epinephrine on cynomolgus monkey eyes," Invest. Ophthalmol. Vis. Sci. (1987) 28(3):463-469. |
Camras, C.B. et al., "Multiple dosing of prostaglandin F2alpha or epinephrine on cynomolgus monkey eyes," Invest. Ophthalmol. Vis. Sci. (1987) 28(6):921-926. |
Camras, C.B. et al., "Multiple dosing of prostaglandin F2alpha or epinephrine on cynomolgus monkey eyes," Invest. Ophthalmol. Vis. Sci. (1988) 29(9):1428-1436. |
Camras, C.B. et al., "Reduction of intraocular pressure in normal and glaucomatous primate (Aotus trivirgatus) eyes by topically applied prostaglandin F2alpha," Curr. Eye Res. (1981) 1(4):205-209. |
Camras, C.B., "Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma," Ophthalmology (1996) 103(1):138-147. |
Camras, C.B., "Detection of the free acid of bimatoprost in aqueous humor samples from human eyes treated with bimatoprost before cataract surgery," American Academy of Ophthalmology (2004) 2193-2198. |
Canadian Patent Office Action dated Aug. 6, 2009 (2 pages) for Canadian Patent No. 2364948 (also cited separately on the enclosed 1449A), claiming priority to International Application No. PCT/US00/05301 (WO 00/51980) filed Feb. 29, 2000 and U.S. Appl. No. 60/122,924, filed Mar. 5, 1999. |
Canadian Patent Office Action dated Jul. 27, 2004 (2 pages) for Canadian Patent No. 2364948 (also cited separately on the enclosed 1449A), claiming priority to International Application No. PCT/US00/05301 (WO 00/51980) filed Feb. 29, 2000 and U.S. Appl. No. 60/122,924, filed Mar. 5, 1999. |
Canadian Patent Office Action dated May 31, 2010 (1 page) for Canadian Patent No. 2364948, claiming priority to International Application No. PCT/US00/05301 (WO 00/51980) filed Feb. 29, 2000 and U.S. Appl. No. 60/122,924, filed Mar. 5, 1999. |
Canadian Patent Office Action dated Nov. 1, 2006 (2 pages) for Canadian Patent No. 2364948 (also cited separately on the enclosed 1449A), claiming priority to International Application No. PCT/US00/05301 (WO 00/51980) filed Feb. 29, 2000 and U.S. Appl. No. 60/122,924, filed Mar. 5, 1999. |
Canadian Patent Office Action dated Oct. 30, 2007 (3 pages) for Canadian Patent No. 2364948 (also cited separately on the enclosed 1449A), claiming priority to International Application No. PCT/US00/05301 (WO 00/51980) filed Feb. 29, 2000 and U.S. Appl. No. 60/122,924, filed Mar. 5, 1999. |
Canadian Patent Office Action dated Sep. 4, 2008 (2 pages) for Canadian Patent No. 2364948 (also cited separately on the enclosed 1449A), claiming priority to International Application No. PCT/US00/05301 (WO 00/51980) filed Feb. 29, 2000 and U.S. Appl. No. 60/122,924, filed Mar. 5, 1999. |
Cantor, L.B. et al., "Levels of bimatoprost acid in the aqueous humour after bimatoprost treatment of patients with cataract," Br. J. Ophthalmol. (2007) 91:629-632. |
Cantor, L.B., "Reply—bimatoprost, the prodrug of a prostaglandin analogue," Br. J. Ophthalmol. (2008) 92:863-864. |
CAS RN 155206-00-1 (May 20, 1994). |
Cayatte, A.J. et al., "The thromboxane A2 receptor antagonist S18886 decreases atheroschlerotic lesions and serum intracellular adhesion molecule-1 in the Apo E knockout mouse," Circulation (1998) 96:115. |
Center for Drug Evaluation and Research, "Medical Officer's Review of NDA, Application No. 21-275," Mar. 14, 2001; 120-day safety update Jan. 23, 2001; Mar. 2, 2001; Sep. 18, 2000, 63 pages. |
Chen, J. et al., "AGN 191129: a neutral prostaglandin F-2 alpha (PGF2a) analog that lacks the mitogenic and uterotonic effects typical of FP receptor agonists," IOVS (1999) 40:3562-B420, p. S675. |
Chyun, Y.S. et al., "Stimulation of bone formation by prostaglandin E2," Prostaglandins (1984) 27:97-103. |
Clissold, D., "The potential for prostaglandin pharmaceuticals," Spec. Publ.-R. Soc. Chem. (1999) 244:115-129. |
Coleman, R.A. et al., "Prostanoids and their receptors," Comprehensive Med. Chem., Membranes and Receptors (1990) 3:643-714. |
Coleman, R.A. et al., "VIII. International Union of Pharmacology. Classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes," Pharmacol. Rev. (1994) 46(2):205-229. |
Collins, P.W. et al., "Synthesis of therapeutically useful prostaglandin and prostacyclin analogs," Chem. Rev. (1993) 93:1533-1564. |
Corsini, A. et al., "(5Z)-Carbacyclin discriminates between prostacyclin receptors coupled to adenylate cyclase in vascular smooth muscle and platelets," Br. J. Pharmacol. (1987) 90:255-261. |
Crowston, J.G. et al., "Effect of bimatoprost on intraocular pressure in prostaglandin FP receptor knockout mice," Invest. Ophthal. Vis. Sci. (2005) 46:4571-4577. |
Darnell, J. et al., "Cell-to-cell signaling: hormones and receptors," Mol. Cell. Biol. (1990) 738-743. |
Davies, S.S., "Hydrolysis of bimatoprost (lumigan) to its free acid by ocular tissue in vitro," J. Ocular Pharm. Thera. (2003) 19(1):45-54. |
Dean, T.R. et al., "Improvement of optic nerve head blood flow after one-week topical treatment with travoprost (AL-06221) in the rabbit," IOVS (1999) 40(4):2688-B563, p. S509. |
Del Toro, F. et al., "Characterization of prostaglandin E2 receptors and their role in 24,25-(OH)2D2-mediated effects on resting zone chondrocytes," J. Cell Physiol. (2000) 182(2):196-208. |
Delong, M.A., "Prostaglandin receptor ligands: recent patent activity," Drugs (2000) 3(9):1039-1052. |
Depperman, W.J., Jr., "Up-to-date scalp tonic," New Eng. J. Med. (1970) 283(2):1115. |
DuBiner, H. et al., "Efficacy and safety of bimatoprost in patients with elevated intraocular pressure: a 30-day comparison with latanoprost," Survey of Ophthal. (2001) 45(S4):S353-S360. |
Eisenberg, D.L. et al., "A preliminary risk-benefit assessment of latanoprost and unoprostone in open-angle glaucoma and ocular hypertension," Drug Safety (1999) 20(6):505-514. |
Ellis, C. K., et al., "Metabolism of Prostaglandin D2 in the Monkey," J. of Biological Chem., vol. 254, No. 10, pp. 4152-4163 (1979). |
European Patent Office Action dated May 30, 2003 (2 pages) for European Patent No. 1159266 (also cited separately on the enclosed 1449A), claiming priority to International Application No. PCT/US00/05301 (WO 00/51980) filed Feb. 29, 2000 and U.S. Appl. No. 60/122,924, filed Mar. 5, 1999. |
Fagot, D. et al., "Mitogenic signaling by prostaglandins in chemically transformed mouse fibroblasts: comparison with phorbol esters and insulin," Endocrinology (1993) 132(4):1729-1734. |
Fall, P. M., et al "Inhibition of Collagen Synthesis by Prostaglandins in the Immortalized Rat Osteoblastic Cell Line Pyla: Structure-Activity Relations and Signal Transduction Mechanisms," J. Bone Miner. Res. (1994) 9:1935-1943 (abstract). |
Faulkner, R., "Aqueous humor concentrations of bimatoprost free acid, bimatoprost and travoprost free acid in cataract surgical patients administered multiple topical ocular doses of LUMIGAN® or TRAVATAN®," J. Ocular Pharm. Thera. (2010) 26(2):147-156. |
FDA Label for Approved NDA 22-184—Lumigan 0.01% and Lumigan 0.03% (Aug. 31, 2010) 5 pages. |
FDA Press Release, "FDA News" of Mar. 16, 2001 entitled "FDA approves two new intraocular pressure lowering drugs for the management of glaucoma," 2 pages. |
Fiscella, R.G., "Peek into the drug pipeline," Review of Optometery Online, Jan. 15, 2001, pp. 1-5. |
Fitzpatrick, F. A., "Separation of Prostaglandins and Thromboxanes by Gas Chromatography with Glass Capillary Columns," Analytical Chemistry, vol. 50, No. 1, pp. 47-52, 1978. |
Flisiak, R. et al., "Effect of misoprostol on the course of viral hepatitis B," Hepato-Gastroenterology (1997) 44(17):1419-1425. |
Frenkel, R.E. et al., "Evaluation of circadian control of intraocular pressure after a single drop of bimatoprost 0.03% or travoprost 0.004%," Curr. Med. Res. Opin. (2008) 24(4):919-923, epub Feb. 8, 2008. |
Funk, C.D. et al., "Cloning and expression of a cDNA for the human prostaglandin E receptor EP1 subtype," J. Biol. Chem. (1993) 268:26767-26772. |
Gandolfini, S. et al., "Three-month comparison of bimatoprost and latanoprost in patients with glaucoma and ocular hypertension," Adv. In Therapy (2001) 18(3):110-121. |
Garadi, R. et al., "Travoprost: a new once-daily dosed prostaglandin for the reduction of elevated intraocular pressure," IOVS (1999) 40(4):4378-B181, p. S831. |
Geng, L. et al., "Topical or systemic 16,16 dm-prostaglandin E2 or WR-2721 (WR-1065) protects mice and alopecia after fractionated irradiation," Int. J. Radiat. Biol. (1992) 61(4):533-537. |
Geng, L., Malkinson, F.D., Hanson, W.R., "Misoprostol, A PGE1 Analog that is Radioprotective for Murine Intestine and Hair, Induces Widely Different Cytokinetic Changes in these Tissues," Journal of Investigative Dermatology, 1996, vol. 106, No. 4, p. 858. |
Gerth, J. et al., "Drug makers reap profits on tax-backed research," New York Times, Apr. 23, 2000, 10 pages. |
Giuffre, G., "The effects of prostaglandin F2alpha in the human eye," Graefe's Arch. Clin. Exp. Ophthalmol. (1985) 222:139-141. |
Griffin, B.W. et al., "AL-8810: a novel prostaglandin F2a analog with selective antagonist effects at the prostaglandin F2a (FP) receptor," J. Pharmacol. Exp. Ther. (1999) 290(3);1278-1284. |
Hall, A., Smith, W. H. T., "Clinprost Teijin," Current Opinion in Cardiovascular, Pulmonary & Renal Investigation Drugs, 1999, 1(5), pp. 605-610. |
Hallinan, E.A. et al., "Aminoacetyl moiety as a potential surrogate for diacylhydrazine group of SC-51089, a potent PGE2 antagonist, and its analogs," J. Med. Chem. (1996) 39:609-613. |
Hanson, W.R. et al., "16,16 dm prostaglandin 2 protects from acute radiation-induced alopecia in mice," Clin. Res. (1988) 36(6):906a. |
Hanson, W.R. et al., "Misoprostol, A PGE1 Analog that is Radioprotective for Murine Intestine and Hair, Induces Widely Different Cytokinetic Changes in these Tissues," J. Invest. Dermatol. (1996) 106(4):858. |
Hanson, W.R. et al., "Subcutaneous or topical administration of 16,16 dimethyl prostaglandin E2 protects from radiation-induced alopecia in mice," Int. J. Radiat. Oncol. Biol. Phys. (1992) 23(2):333-337. |
Hartke, J.R. et al., "Prostanoid FP agonists build bone in the ovariectomized rat," J. Bone Min. Res. (1999) 14(T326): S207. |
Hayashi, M. et al., "Prostaglandin Analogues Possessing Antinidatory Effects. 1. Modification of the omega Chain," J. Med. Chem. (1980) 23(5):519-524. |
Hayashi, M. et al., "Prostaglandin Analogues Possessing Antinidatory Effects. 1. Modification of the ω Chain," J. Med. Chem. (1980) 23(5):519-524. |
Hecker, M. et al., "Studies on the interaction of minoxidil with prostacyclin synthase in-vitro," Biochem. Pharmacol. (1988) 37(17):3363-3365. |
Hellberg, M.R. et al., "The hydrolysis of the prostaglandin analog prodrug bimatoprost to 17-phenyltrinor PGF2a by human and rabbit ocular tissue," J. Ocular Pharmacol. Ther. (2003) 19:97-103. |
Higginbotham, E.J. et al., "One-year randomized study comparing bimatoprost and timololin in glaucoma and ocular hypertension," Arch. Ophthal. (2002) 120(10):1286-1293. |
Houssay, A.B. et al., "Effects of prostaglandins upon hair growth in mice," Acta Physiol. Let. Am. (1976) 266(3):186-191. |
Huang, A. et al., "Different modes of inhibition of increase in cytosolic calcium and aggregation of rabbit platelets by two thromboxane A2 antagonists," Asia Pacific Journal of Pharmacology (1994) 9:163-171. |
Hulan, H.W. et al., "The development of dermal lesions and alopecia in male rats fed grapeseed oil," Can. J. Physiol. Pharmacol. (1976) 54(1):1-6. |
Hulan, H.W. et al., "The effect of long-chain monoenes on prostaglandin E2 synthesis by rat skin," Lipids (1977) 12(7):604-609. |
Ichikawa, E.A. et al., "Molecular aspects of the structures and functions of the prostaglandin E receptors," J. Lipid Mediators Cell Signaling (1996) 14:83-87. |
International Preliminary Examination Report for Application No. PCT/IB99/00478 (WO 99/50241) dated Jun. 23, 2000 (5 pages). |
International Preliminary Examination Report for Application No. PCT/US00/05299 (WO 99/51979) dated Mar. 16, 2001 (7 pages). |
International Preliminary Examination Report for Application No. PCT/US00/05301 (WO 00/51980) dated Mar. 16, 2001 (6 pages). |
International Preliminary Examination Report for Application No. PCT/US00/20851 (WO 01/10873) dated Oct. 12, 2001 (8 pages). |
International Preliminary Examination Report for Application No. PCT/US01/10368 (WO 01/74313) dated Jun. 14, 2002 (2 pages). |
International Preliminary Examination Report for Application No. PCT/US01/10369 (WO 01/74314) dated Jun. 14, 2001 (3 pages). |
International Preliminary Examination Report for Application No. PCT/US01/10370 (WO 01/74315) dated Jun. 14, 2002 (2 pages). |
International Preliminary Examination Report for Application No. PCT/US01/10547 (WO 01/74307) dated Jun. 14, 2002 (2 pages). |
International Preliminary Examination Report for Application No. PCT/US98/18339 (WO 99/12895) dated Jun. 28, 1999 (4 pages). |
International Preliminary Examination Report for Application No. PCT/US98/18340 (WO 99/12896) dated Dec. 6, 1999 (7 pages). |
International Preliminary Examination Report for Application No. PCT/US98/18594 (WO 99/12898) dated Sep. 7, 1999 (5 pages). |
International Search Report for Application No. PCT/IB99/00478 (WO 99/50241) dated Jul. 12, 1999 (3 pages). |
International Search Report for Application No. PCT/IB99/00480 (WO 99/50242) dated Jun. 25, 1999 (3 pages). |
International Search Report for Application No. PCT/US00/05299 (WO 99/51979) dated Jul. 28, 2000 (3 pages). |
International Search Report for Application No. PCT/US00/05301 (WO 00/51980) dated Jul. 21, 2000 (3 pages). |
International Search Report for Application No. PCT/US00/20851 (WO 01/10873) dated Nov. 7, 2000 (4 pages). |
International Search Report for Application No. PCT/US01/10368 (WO 01/74313) dated Nov. 7, 2001 (3 pages). |
International Search Report for Application No. PCT/US01/10369 (WO 01/74314) dated Nov. 7, 2001 (3 pages). |
International Search Report for Application No. PCT/US01/10370 (WO 01/74315) dated Nov. 7, 2001 (3 pages). |
International Search Report for Application No. PCT/US01/10547 (WO 01/74307) dated Jan. 2, 2002 (2 pages). |
International Search Report for Application No. PCT/US98/18339 (WO 99/12895) dated Dec. 3, 1998 (2 pages). |
International Search Report for Application No. PCT/US98/18340 (WO 99/12896) dated Dec. 8, 1998 (3 pages). |
International Search Report for Application No. PCT/US98/18594 (WO 99/12898) dated Dec. 3, 1998 (3 pages). |
Jakobsson, P.J. et al., "Membrane-associated proteins in elcosanoid and glutathione metabolism (MAPEG)-a widespread protein superfamily," Am J. Resp. Crit. Care Med. (2000) 161:S20-S24. |
Japanese Patent Office Action dated Apr. 16, 2010 (7 pages) for Japanese Patent No. 2000-602208, claiming priority to International Application No. PCT/US00/05301 (WO 00/51980) filed Feb. 29, 2000 and U.S. Appl. No. 60/122,924, filed Mar. 5, 1999. |
Japanese Patent Office Action dated Dec. 3, 2010 (6 pages) for Japanese Patent No. 2000-602208, claiming priority to International App. No. PCT/US00/05301 (WO 00/51980) filed Feb. 29, 2000 and U.S. Appl. No. 60/122,924, filed Mar. 5, 1999. |
Jimenez de Asua, L. et al., "The stimulation of the initiation of DNA synthesis and cell division in Swiss mouse 3T3 cells by prostaglandin F2alpha requires specific functional groups in the molecule," J. Biol. Chem. (1983) 256(14): 8774-8780. |
Jimenez, J.J. et al., "Stimulated monocyte-conditioned media protect for cytosine arabinoside-induced alopecia in rat," Clin. Res. (1990) 38(4):973a. |
Johnstone, M.A., "Hypertrichosis and increased pigmentation of eyelashes and adjacent hair in the region of the ipsilateral eyelids of patients treated with unilateral topical latanoprost," Amer. J. Ophthal (1997) 544-547. |
Johnstone, M.A., Brief latanoprost Rx induces hypertrichosis, IOVS (1998) 39(4):1180-B61. |
Jordan, B.A. et al., "G-protein coupled receptor heterodimerization modulates receptor function," Nature (1999) 399(6737):697-700. |
Karim, S.M.M. et al., "Prostaglandins and human respiratory tract smooth muscle: structure activity relationship," Adv. Prostaglandin Thromboxane Res. (1980) 7:969-980. |
Kaufman, P.L., "Effects of intracamerally infused prostaglandins on outflow facility in cynomolgus monkey eyes with intact or retrodisplaced ciliary muscle," Exp. Eye Res. (1986) 43:819-827. |
Kende, et, al., "Prostaglandin Phosphonic Acids Through Homolytic Halodecarboxylation of Prostaglandins F1alpha and F2alpha," Tetrahedron Letters, vol. 40, pp. 8189-8192 (1999). |
Kende, et, al., "Prostaglandin Phosphonic Acids Through Homolytic Halodecarboxylation of Prostaglandins F1α and F2α," Tetrahedron Letters, vol. 40, pp. 8189-8192 (1999). |
Kerstetter, J.R. et al., "Prostaglandin F2 alpha-l-isopropylester lowers intraocular pressure without decreasing aqueous humor flow," Am. J. Ophthalmology (1988) 105:30-34. |
Kiriyama, M. et al., "Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells," Br. J. Pharm. (1997) 122:217-224. |
Kluender, H.C. et al., "The Synthesis of Diethylphosphonoprostaglandin Analogs" Prostaglandins and Medicine (1979) 2(6):441-444. |
Krauss, A.H.P. et al., "Evidence for human thromboxane receptor heterogeneity using a novel series of 9,11-cyclic carbonate derivatives of prostaglandin-F2-alpha," Br. J. Pharmacol. (1996) 117(6):1171-1180. |
Kvedar, J.C. et al., "Topical minoxidil in the treatment of male pattern alopecia," Pharmacotherapy (1987) 7(6):191-197. |
Lachgar, S. et al., "Effect of VEGF and minoxidil on the production of arachidonic acid metabolites by cultured hair, dermal papilla cells," Eur. J. Dermatol. (1996) 6(5):365-368. |
Lachgar, S. et al., "Hair dermal papilla cell metabolism is influenced by minoxidil," Fundam Clin. Pharmacol. (1997) 11(2):178. |
Lachgar, S. et al., "Modulation by minoxidil and VEGF of the production of inflammatory mediators by hair follicle dermal papilla cells," J. Invest. Derm. (1995) 104(1):161. |
Lardy, C. et al., "Antiaggregant and antivasospastic properties of the new thromboxane A2 receptor antagonist sodium 4-[[1-[[[(4-chlorophenyl) sulfonyl]amino] methyl] cyclopentyl] methyl] benzeneacetate," Arzneim.-Forsch./Drug Res. (1994) 44(11):1196-1202. |
Lee, P.-Y. et al., "The effect of prostaglandin F2alpha on intraocular pressure in mormotensive human subjects," Invest. Ophthalmol. Vis. Sci. (1988) 29(10):1474-1477. |
Letter from Bernice Tao at Apotex, Inc. to the General Counsels at Allergan, Inc. and Duke University regarding "Apotex Bimatoprost Topical Solution 0.03% Paragraph IV Certification—U.S. Patent Nos. 7,351,404 and 7,388,029" (Jul. 26, 2010) 49 pages. |
Liang, Y. et all., "Identification and pharmacological characterization of the prostaglandin FP receptor and FP receptor varian complexes," Br. J. Pharmacol. (2008) 154:1079-1093. |
Liljebris et al., "Derivatives of 17-Phenyl-18,19,20-trinor-prostaglandin F2αIsopropyl Ester: Potential Antigalucoma Agents", J. Med. Chem., 1995, pp. 289-304, vol. 38, No. 2. |
Liljebris, C., Selen, G., Resul, B. Stjernschantz, J., and Hacksell, U., "Derivatives of 17-Phenyl-18, 19, 20 Trinorprostaglan F2alpha Isopropyl Ester: Potential Antiglaucoma Agents," Journal of Medicinal Chemistry, vol. 38, No. 2, (1995), pp. 289-304. |
Liljebris, C., Selen, G., Resul, B. Stjernschantz, J., and Hacksell, U., "Derivatives of 17-Phenyl-18, 19, 20 Trinorprostaglan F2α Isopropyl Ester: Potential Antiglaucoma Agents," Journal of Medicinal Chemistry, vol. 38, No. 2, (1995), pp. 289-304. |
Ling, G. et al., "16,16 dm prostaglandin E2 protects mice from fractionated radiation-induced alopecia," Clin. Res. (1990) 38(3):858a. |
Lumigan 6-month phase 3 data presented at American Glaucoma Society Meeting, Mar. 2, 2001, Business Wire, 3 pages. |
Lundy, M.W. et al., "Restoration of cancellous architecture and increased bone strength in aged osteopenic rats treated with fluprostenol, "J. Bone Min. Res. (1999) 1(4)SA368:S401. |
Malkinson, F.D. et al., "Prostaglandins protect against murine hair injury produced by ionizing radiation or doxorubicin," J. Invest. Dermatol. (1993) 101(1, Suppl):135S-137S. |
Maruyama, T. et al., "EP1 receptor antagonists suppress tactile allodynia in rats," Prostaglandins Lipid Mediat. (1999) 59:217. |
Matsumura, H., "Prostaglandins and Sleep," Saishin No to Shinkai Kagaku Shiritzu 10, 1998, pp. 79-89 (no English translation available). |
Maw, G.N., "Pharmacological therapy for the treatment of erectile dysfunction," Annu. Rep. Med. Chem. (1999) 34:71-80. |
Maxey, K.M., "The hydrolysis of bimatoprost in corneal tissue generates a potent prostanoid FP receptor agonist," Survey of Ophthalmology (2002) 47(1):S34-40. |
McCullough, P.A., "Ridogrel,"Current Opinion in Anti-inflammatory & Immunomodulatory Investigation Drugs (1999) 1(3):265-276. |
Michelet, J.F. et al., "Activation of cytoprotective prostaglandin synthase-1 by minoxidil as a possible explanation for its hair growth-stimulation effect," J. Invest. Dermatol. (1997) 108(2):205-209. |
Millikan, L.E., "Treatment of alopecia," J. Clin. Pharmacol. (1987) 27(9):715. |
Millikan, L.E., "Treatment of male pattern baldness," Drug Therapy (1989) 19(3):62-73. |
Mishima, H.K. et al., "A comparison of latanoprost and timolol in primary open-angle glaucoma and ocular hypertension," Arch. Ophthalmol. (1996) 114:929-932. |
Miyamoto, T., et al., "A comparison in the Efficacy and Safety between Ramatroban (BAY u 3405) and Ozargrel HCl for Bronchial Asthma: A Phase III, Multi-Center, Randomized, Double-Blind, Group Comparative Study," 13, 1997, pp. 599-639 Abstract (in English). |
Mori, S. et al., "Effects of prostaglandin E2 on production of new cancellous bone in the axial skeleton of overlectomized rats," Bone (1990) 11:103-113. |
Murakami, T. et al., "Effect of isocarbacyclin methyl ester incorporated in lipid microspheres on experimental models of peripheral obstructive disease," Arzheim.-Forsh/Drug Res. (1995) 45(II)(9):991-994. |
Narumiya, S., "Roles of prostanoids in health and disease, lessons from receptor-knockout mice," Int. Congr. Ser. (1999) 1181:261-269. |
Negishi, M. et al., "Molecular mechanisms of diverse actions of prostanoid receptors," Biochimica et Biophysica Acta (1995) 1259:109-120. |
Norridin, R.W. et al., "The role of prostaglandins in bone in vivo," Prostaglandins, Leukotrienes and Essential Fatty Acids (1990) 41:139-149. |
Olsen, E.A. et al., "Transdermal viprostol in the treatment of male pattern baldness," J. Amer. Acad. Dermatol. (1990) 23(3 Part 1):470-472. |
Orlicky, D.J., "Negative regulatory activity of a prostaglandin F2a receptor associated protein (FPRP)," Prostaglandins, Leukotrienes and Essential Fatty Acids (1996) 54(4):247-259. |
Ortonne, J-P. et al., "Hair melanin's and hair color: ultrastructural and biochemical aspects," J. Soc. Inv. Derm. (1993) 82S-89S. |
Pfeiffer, N., "New developments in glaucoma drug therapy," Ophthalmologist (1992) 89:W1-W13. |
Phamaprojects, No. 6321, Merck & Co. (2006) 1 page. |
Poyer, J.F. et al., "Prostaglandin F2 alpha effects on isolated rhesus monkey ciliary muscle," Invest. Ophthalmol. Vis. Sci. (1995) 36(12):2461-2465. |
Rampton, D.S., Carty, E., Van Nueten, L., Anti-Inflammatory Profile in Vitro of Ridogrel, a Putative New Treatment for Inflammatory Bowel Disease, Gastroenterology, 1999, (116) G3477, p. 801. |
Response from the Food and Drug Administration to Pfizer's Citizen Petition and a Supplement (Aug. 31, 2010) at 23 (Exhibit 5), 26 pages. |
Resul, B. et al., "Phenyl-substituted prostaglandins: potent and selective antiglaucoma agents," J. Med. Chem. (1993) 36(2):243-248. |
Roenigk, H.H.,"New topical agents for hair growth," Clinics in Dermatology (1988) 6(4):119-121. |
Romano, M.R., "Evidence for the involvement of cannabinoid CB1 receptors in the bimatoprost-induced contractions on the human isolated ciliary muscle," Invest. Opthal. Vis. Sci. (2007) 48(8):3677-3682. |
Roof, S.L. et al., "mRNA expression of prostaglandin receptors EP1, EP2, EP3 and EP4 in human osteoblast-like cells and 23 human tissues," J. Bone Min. Res. (1996) 11:S337. |
Ruel, R. et al., "New class of biphenylene dibenzazocinones as potent ligands for the human EP1 prostanoid receptor," Bioorg. Med. Chem. Lett. (1999) 9:2699-2704. |
Sakuma, Y. et al., "Crucial involvement of the PE4 subtype of prostaglandin E receptor in osteoclast formation by proinflammatory cytokines and lipopolysaccharide," J. Bone Min. Res. (2000) 15(2):218-227. |
Sauk, J.J. et al., "Influence of prostaglandin E-1 prostaglandin E-2 and arachidonate on melanosomes in melanocytes and keratinocytes of anagen bulbs in-vitro," J. Invest. Dermatol. (1975) 64(5):332-337. |
Sharif, N. A. et al., "Bimatoprost and its free acid are prostaglandin FP receptor agonists," Eur. J. Pharmacol. (2001) 432(2-3):211-213. |
Sharif, N.A. et al., "3H AL-5848 ([3H]9 beta-(+)-fluprostenol). Carboxylic acid of travoprost (AL-6221), a novel FP prostaglandin to study the pharmacology and autoradiographic localization of the FP receptor," J. Phar. Pharmacol. (1999) 51(6):685-694. |
Sharif, N.A. et al., "Cat iris sphincter smooth-muscle contraction: comparison of FP—class prostaglandin analog agonist activities," J. Ocul. Pharmacol. Ther. (2008) 24(2):152-163. |
Sharif, N.A. et al., "Human ciliary muscle cell responses to FP—class prostaglandin analogs: phosphoinositide hydrolysis, intracellular Ca2+ mobilization and MAP kinase activation," J. Ocul. Pharmacol. Ther. (2003) 19:437-455. |
Sharif, N.A. et al., "Human trabecular meshwork cell responses induced by bimatoprost, travoprost, unoprostone, and other FP prostaglandin receptor agonist analogues," Invest. Ophthalmol. Vis. Sci. (2003) 44:715-721. |
Sharif, N.A., "Ocular hypotensive FP prostaglandin (PG) analogs: PG receptor subtype binding affinities and selectivities, and agonist potencies at FP and other PG receptors in cultured cells," J. Ocular Pharm. Thera. (2003) 19(6):501-515. |
Sharif, N.A., "Update and commentary on the pro-drug bimatoprost and a putative 'prostamide receptor'," Expert Rev. Ophthalmol. (2009) 4(5):477-489. |
Sherwood, M. et al., "Six-month comparison of bimatoprost once-daily and twice-daily with timomol twice-daily in patients with elevated intraocular pressure," Surv. Ophthal. (2001) 45(4):S361-S368. |
Shih, M.S. et al., "PGE2 induces regional remodeling changes in Haversian envelope: a histomorphometric study of fractured ribs in beagles," Bone and Mineral (1986) 1:227-234. |
Shimazaki, A., et al. "New Ethacrynic Acid Derivatives as Potent Cytoskeletal Modulators in Trabecular Meshwork Cells," Biol. Pharm. Bull. vol. 27, No. 6, 2004, pp. 846-850. |
Shimazaki, A., et al., "Effects of the New Ethacrynic Acid Derivative SA9000 on Intraocular Pressure in Cats and Monkeys," Biol Pharm. Bull. vol. 27, No. 7, 2004, pp. 1019-1024. |
Sjoquist, B. et al., "Ocular and systemic pharmacokinetics of latanoprost in humans," Surv. Ophthalmol. (2002) 47(Supp 1):S6-12. |
Sjoquist, B. et al., "Pharmacokinetics of latanoprost in the cynomolgus monkey. 3rd communication: tissue distribution after topical administration on the eye studied by whole body autoradiography, Glacoma research laboratories," Arzneimittelforschung (1999) 49:240-249. |
Souillac, P. et al., "Characterization of delivery systems, differential scanning calorimetry," Encyclopedia of Controlled Drug Delivery, John Wiley & Sons (1999) 212-227. |
Spada, C.S. et al., "Bimatoprost and prostaglandin F(2 alpha) selectively stimulate intracellular calcium signaling in different cat iris sphincter cells," Exp. Eye Res. (2005) 80(1):135-145. |
Sredni, B. et al., "The protective role of the immunomodulator AS101 against chemotherapy-induced alopecia studies on human and animal models," Int. J. Cancer (1996) 65(1):97-103. |
Stamer, W.D. et al., "Cellular basis for bimatoprost effects on human conventional outflow," Invest. Ophthalmol. Vis. Sci. (2010) 51(10):5176-5181, Epub Apr. 30, 2010. |
Stjernschantz, J. et al., "Phenyl substituted prostaglandin analogs for glaucoma treatment," Drugs of the Future (1992) 17(8):691-704. |
Stjernschantz, J., "Studies on ocular inflammation and development of a prostaglandin analogue for glaucoma treatment," Exp. Eye Res. (2004) 78(4):759-766. |
Stjernschantz, J.W., "From PGF2alpha-isopropyl ester to latanoprost: a review of the development of Xalatan: the Proctor lecture," Invest. Ophthalmol. Vis. Sci. (2001) 42(6):1134-1145. |
Tereda, N. et al., "Effect of a thromboxane A2 receptor antagonist, ramatroban (BAY U3405), on inflammatory cells, chemical mediators and non-specific nasal hyperactivity after allergen challenge in patients with perennial allergic rhinitis," Allergology Int. (1998) 47(1):59-67. |
The Newsletter of the Glaucoma Foundation, Fall 2000, vol. 11, No. 2, 11 pages. |
Tomita, Y. et al., "Melanocyte-stimulating properties of arachidonic acid metabolites: possible role in postinflammatory pigmentation," Pigm. Cell Res. (1992) 5(5, Pt. 2):357-361. |
U.S. Appl. No. 90/009,430, filed Mar. 15, 2009, Woodward. |
U.S. Appl. No. 90/009,431, filed Mar. 10, 2009, Johnstone. |
Ueda, K. et al., "Brief clinical and laboratory observations: coritical hyperostosis following long-term administration of prostaglandin E1 in infants with cyanotic congenital heart disease," J. Pediatrics (1980) 97:834-836. |
United States Office Action for U.S. Appl. No. 09/148,006 dated Jan. 29, 1999 (3 pages). |
United States Office Action for U.S. Appl. No. 09/148,374 dated Feb. 11, 1999 (4 pages). |
United States Office Action for U.S. Appl. No. 09/148,374 dated Jan. 11, 2000 (4 pages). |
United States Office Action for U.S. Appl. No. 09/148,374 dated May 28, 1999 (3 pages). |
United States Office Action for U.S. Appl. No. 09/148,374 dated Oct. 1, 1999 (3 pages). |
United States Office Action for U.S. Appl. No. 09/148,538 dated Apr. 8, 1999 (6 pages). |
United States Office Action for U.S. Appl. No. 09/647,380 dated Sep. 18, 2001 (8 pages). |
United States Office Action for U.S. Appl. No. 09/647,381 dated Sep. 20, 2001 (8 pages). |
United States Office Action for U.S. Appl. No. 09/774,555 dated Aug. 31, 2006 (9 pages). |
United States Office Action for U.S. Appl. No. 09/774,555 dated Jan. 6, 2006 (6 pages). |
United States Office Action for U.S. Appl. No. 09/774,555 dated Jul. 9, 2002 (8 pages). |
United States Office Action for U.S. Appl. No. 09/774,555 dated May 23, 2005 (7 pages). |
United States Office Action for U.S. Appl. No. 09/774,556 dated Dec. 14, 2004 (5 pages). |
United States Office Action for U.S. Appl. No. 09/774,556 dated Jul. 18, 2005 (6 pages). |
United States Office Action for U.S. Appl. No. 09/774,556 dated Mar. 19, 2002 (11 pages). |
United States Office Action for U.S. Appl. No. 09/774,556 dated Mar. 23, 2004 (10 pages). |
United States Office Action for U.S. Appl. No. 09/774,556 dated May 14, 2003 (2 pages). |
United States Office Action for U.S. Appl. No. 09/774,557 dated Mar. 5, 2003 (9 pages). |
United States Office Action for U.S. Appl. No. 09/774,557 dated Nov. 26, 2004 (10 pages). |
United States Office Action for U.S. Appl. No. 09/774,558 dated Apr. 15, 2003 (11 pages). |
United States Office Action for U.S. Appl. No. 09/774,558 dated Apr. 25, 2002 (13 pages). |
United States Office Action for U.S. Appl. No. 09/774,558 dated Dec. 4, 2003 (11 pages). |
United States Office Action for U.S. Appl. No. 09/774,558 dated Mar. 28, 2006 (8 pages). |
United States Office Action for U.S. Appl. No. 09/774,558 dated Nov. 5, 2004 (6 pages). |
United States Office Action for U.S. Appl. No. 09/914,531 dated Dec. 7, 2001 (5 pages). |
United States Office Action for U.S. Appl. No. 09/946,021 dated Jan. 15, 2002 (5 pages). |
United States Office Action for U.S. Appl. No. 09/946,021 dated May 24, 2002 (4 pages). |
United States Office Action for U.S. Appl. No. 09/946,021 dated Oct. 15, 2002 (4 pages). |
United States Office Action for U.S. Appl. No. 11/138,097 dated Jul. 16, 2007 (1 page). |
United States Office Action for U.S. Appl. No. 11/174,420 dated Aug. 20, 2007 (8 pages). |
United States Office Action for U.S. Appl. No. 11/174,420 dated Dec. 5, 2008 (6 pages). |
United States Office Action for U.S. Appl. No. 11/174,420 dated Feb. 3, 2010 (6 pages). |
United States Office Action for U.S. Appl. No. 11/174,420 dated Jul. 22, 2009 (5 pages). |
United States Office Action for U.S. Appl. No. 11/334,689 dated Aug. 25, 2009 (11 pages). |
United States Office Action for U.S. Appl. No. 11/476,246 dated Jul. 22, 2009 (9 pages). |
United States Office Action for U.S. Appl. No. 11/565,297 dated Jul. 12, 2007 (5 pages). |
United States Office Action for U.S. Appl. No. 11/565,297 dated Jul. 31, 2007 (5 pages). |
United States Office Action for U.S. Appl. No. 11/967,423 dated Feb. 4, 2009 (10 pages). |
United States Patent Office Action for U.S. Appl. No. 11/174,420 dated Feb. 3, 2010 (6 pages). |
United States Patent Office Action for U.S. Appl. No. 11/334,689 dated Apr. 30, 2010 (11 pages). |
United States Patent Office Action for U.S. Appl. No. 11/476,246 dated Apr. 19, 2010 (7 pages). |
United States Patent Office Action for U.S. Appl. No. 12/138,733 dated Feb. 23, 2011 (8 pages). |
United States Patent Office Action for U.S. Appl. No. 12/138,733 dated Nov. 24, 2009 (10 pages). |
United States Patent Office Action for U.S. Appl. No. 12/260,522 dated May 25, 2011 (14 pages). |
United States Patent Office Action for U.S. Appl. No. 12/260,534 dated Nov. 18, 2011 (8 pages). |
United States Patent Office Action for U.S. Appl. No. 12/479,532 dated Oct. 6, 2009 (5 pages). |
United States Patent Office Action for U.S. Appl. No. 12/535,513 dated Dec. 18, 2009 (10 pages). |
United States Patent Office Action for U.S. Appl. No. 12/535,513 dated Mar. 3, 2011 (8 pages). |
United States Patent Office Notice of Allowance for U.S. Appl. No. 11/174,420 dated Jan. 12, 2011 (5 pages). |
United States Patent Office Notice of Allowance for U.S. Appl. No. 12/138,733 dated Jun. 3, 2010 (5 pages). |
United States Patent Office Notice of Allowance for U.S. Appl. No. 12/535,513 dated Jun. 3, 2010 (5 pages). |
Van Alphen, G.W.H.M. et al., "The effect of prostaglandins on the isolated internal muscles of the mammalian eye, including man," Documenta Ophthalmologica (1977) 42(2):397-415. |
Vandenburgh, A.M. et al., "A one-month dose-response study of AGN 192024, a novel antiglaucoma agent, in patients with elevated intraocular pressure," IOVS (1999) 40(4):4373-B176, p. S830. |
Vayssairat, M., Preventive Effect of an Oral Prostacyclin Analog, Beraprost Sodium, on Digital Necrosis in Systemic Scierosis, J. of Rheumatol., 1999, 26(10), pp. 2173-2178. |
Vengerovsky, A.I. et al., "Hepatoprotective action of prostaglandins," Eksp. Klin Farmakof. (1997) 60(5):78-82. |
Verbeuren, T., et al., "The TP-Receptor Antagonist S 18886 Unmasks Vascular Relaxation and Potentiates the Anti-Platelet Action of PGD2," Journal of the International Society Thrombosis and Haemostasis, Jun. 6-12, 1997, p. 693. |
Vielhauer, G.A. et al., "Cloning and localization of hFP(S): a six-transmembrane mRNA splice variant of the human FP prostanoid receptor," Arch. Biochem. Biophys. (2004) 421(2):175-185. |
Villumsen, J. et al., "Prostaglandin F2alpha-isopropylester eye drops: effect on intraocular pressure in open-angle glaucoma," Br. J. Ophthalmol. (1989) 73:975-979. |
Vincent, J.E., "Prostaglandin synthesis and selenium deficiency a hypothesis," Prostaglandins (1974) 8(4):339-340. |
Vippagunta, "Crystalline solids," Adv. Drug Del. Rev. (2001) 48:3-26. |
Voss, N.G. et al., "Induction of anagen hair growth in telogen mouse skin by topical latanoprost application," IOVS (1999) 40:3570-B428, p. S676. |
Waddell, K. A., et al., "Combined Capillary Column Gas Chromatography Negative Ion Chemical Ionization Mass Spectrometry of Prostanoids," Biomed. Mass Spectrom., vol. 10, No. 2, pp. 83-88 (1983). |
Wand, M., "Latanoprost and hyperpigmentation of eyelashes," Archives of Ophthalmology (1997) 115(9):1206-1208. |
Wang, Y. et al., "The design and synthesis of 13, 14-dihydro prostaglandin F1a analogs as potent and selective ligands for the human FP receptor," J. Med. Chem. (2000) 43(5):945-952. |
Watson et al., "A six-month, randomized, double-masked study in comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension," Ophthalmology (1996) 103:126-137. |
White, J.H. et al., "Heterodimerization is required for the formation of a functional GABA(B) receptor," Nature (1998) 396(6712):679-682. |
Wilson, S.J. et al., "Dimerization of the human receptors for prostacyclin and thromboxane facilitates thromboxane receptor-mediated cAMP generation," J. Biol. Chem. (2004) 279(51):53036-53047. |
Woodward, D., "Replacement of carboxylic acid group of prostaglandin F2a with a hydroxyl or methoxy substituent provides biologically unique compounds," Br. J. Pharma. (2000) 130(8):1933-1943. |
Woodward, D.F. et al., "Bimatoprost effects on aqueous humor dynamics in monkeys," J. Ophthalmol. (2010) Article ID 926192, 5 pages. |
Woodward, D.F. et al., "Bimatoprost: a novel antiglaucoma agent," Cardiovasc. Drug Rev. (2004) 22(2):103-120. |
Woodward, D.F. et al., "Emerging evidence for additional prostanoid receptor subtypes," Curr. Top. Pharmacol. (1998) 4:153-163. |
Woodward, D.F. et al., "Identification of an antagonist that selectively blocks the activity of prostamides (prostaglandin-ethanolamides) in the feline iris," Br. J. Pharmacol. (2007) 150:342-352. |
Woodward, D.F. et al., "Molecular characterization and ocular hypotensive properties of the prostanoid EP2 receptor," J. Oc. Pharm. Therap. (1995) 11(3):447-454. |
Woodward, D.F. et al., "Pharmacological characterization of a novel anti-glaucoma agent," J. Pharmacol. Exp. Ther. (2003) 305:772-785. |
Woodward, D.F. et al., "Studies on the ocular effects of a pharmacologically novel agent prostaglandin F2 alpha 1-OCH3 (AGN 191129) N-S," Arch. Pharmacol. (1998) 358(1):P1713. |
Woodward, D.F. et al., "The pharmacology of bimatoprost (Lumigan)," Surv. Ophthalmol. (2001) 45(Suppl 4):S337-45. |
Written Opinion for Application No. PCT/IB99/00478 (WO 99/50241) dated Feb. 21, 2004 (4 pages). |
Written Opinion for Application No. PCT/IB99/00480 (WO 99/50242) dated Jan. 18, 2000 (6 pages). |
Written Opinion for Application No. PCT/US00/05299 (WO 99/51979) dated Oct. 20, 2000 (7 pages). |
Written Opinion for Application No. PCT/US00/05301 (WO 00/51980) dated Oct. 20, 2000 (7 pages). |
Written Opinion for Application No. PCT/US00/20851 (WO 01/10873) dated Jul. 10, 2001 (9 pages). |
Written Opinion for Application No. PCT/US98/18340 (WO 99/12896) dated Aug. 2, 1999 (7 pages). |
Written Opinion for Application No. PCT/US98/18594 (WO 99/12898) dated May 25, 1999 (5 pages). |
Yamaji, K. et al., "Prostaglandins E1 and E2, but not F2alpha or latanoprost, inhibit monkey ciliary muscle contraction," Curr. Eye Res. (2005) 30(8):661-665. |
Yoshida, K. et al., "Synthesis and pharmacological activities of the new TXA2 receptor antagonist Z-335 and related compounds," AFMC (1995) 95:53. |
Zeigler, T., "Old drug, new use: new research shows common cholesterol-lowering drug reduces multiple sclerosis symptoms in mice," Natl. Institute of Neurological Disorders and Stroke (2003) 2 pages. |
Zimbric, M.L. et al., "Effects of latanoprost of hair growth in the bald scalp of stumptailed macaques," IOVS (1999) 40:3569-B427, p. S676. |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9579270B2 (en) | 2000-03-31 | 2017-02-28 | Duke University | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
Also Published As
Publication number | Publication date |
---|---|
PL350917A1 (en) | 2003-02-10 |
EP1159266B1 (en) | 2004-11-03 |
US20020037913A1 (en) | 2002-03-28 |
CO5160251A1 (en) | 2002-05-30 |
BR0008776A (en) | 2001-12-18 |
NO20014241D0 (en) | 2001-08-31 |
DE60015508D1 (en) | 2004-12-09 |
DE60015508T2 (en) | 2005-04-21 |
EP1159266A1 (en) | 2001-12-05 |
JP2011037861A (en) | 2011-02-24 |
NO20014241L (en) | 2001-11-05 |
NZ513825A (en) | 2001-09-28 |
AU766163B2 (en) | 2003-10-09 |
IL145122A0 (en) | 2002-06-30 |
AU3862000A (en) | 2000-09-21 |
HUP0200258A2 (en) | 2002-05-29 |
CA2364948A1 (en) | 2000-09-08 |
ATE281432T1 (en) | 2004-11-15 |
JP4834224B2 (en) | 2011-12-14 |
JP2002538139A (en) | 2002-11-12 |
CN1350521A (en) | 2002-05-22 |
US6586463B2 (en) | 2003-07-01 |
CA2364948C (en) | 2011-04-26 |
WO2000051980A1 (en) | 2000-09-08 |
MXPA01008955A (en) | 2002-04-24 |
CZ20013174A3 (en) | 2002-02-13 |
ES2232434T3 (en) | 2005-06-01 |
KR20010108316A (en) | 2001-12-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
USRE43372E1 (en) | C16 unsaturated FP-selective prostaglandins analogs | |
US5977173A (en) | Aromatic C16 -C20 -substituted tetrahydro prostaglandins useful as FP agonists | |
US6107338A (en) | Aromatic C16 -C20 -substituted tetrahydro prostaglandins useful as FP agonists | |
EP1012137B1 (en) | Aromatic c16-c20-substituted tetrahydro prostaglandins useful as fp agonists | |
US6451859B1 (en) | C16 unsaturated FP-selective prostaglandins analogs | |
US6410780B1 (en) | C11 oxymyl and hydroxylamino prostaglandins useful as medicaments | |
US6444840B1 (en) | C11 oxymyl and hydroxylamino prostaglandins useful as FP agonists | |
US6359181B1 (en) | Cyclopentane 1-hydroxy alkyl or alkenyl-2-one or 2-hydroxy derivatives as therapeutic agents | |
CA2324590C (en) | C11 oxymyl and hydroxylamino prostaglandins useful as fp agonists |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FPAY | Fee payment |
Year of fee payment: 12 |
|
AS | Assignment |
Owner name: AERIE DISTRIBUTION, INC., NORTH CAROLINA Free format text: RELEASE BY SECURED PARTY;ASSIGNORS:DEERFIELD PARTNERS, L.P.;DEERFIELD PRIVATE DESIGN FUND III, L.P.;DEERFIELD SPECIAL SITUATIONS FUND, L.P.;AND OTHERS;REEL/FRAME:046431/0500 Effective date: 20180723 |