MXPA00002430A - Aromatic c16 - Google Patents
Aromatic c16Info
- Publication number
- MXPA00002430A MXPA00002430A MXPA/A/2000/002430A MXPA00002430A MXPA00002430A MX PA00002430 A MXPA00002430 A MX PA00002430A MX PA00002430 A MXPA00002430 A MX PA00002430A MX PA00002430 A MXPA00002430 A MX PA00002430A
- Authority
- MX
- Mexico
- Prior art keywords
- ring
- preferred
- dihydro
- tetranor
- alkyl
- Prior art date
Links
- 125000003118 aryl group Chemical group 0.000 title claims description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 208000003432 Bone Disease Diseases 0.000 claims abstract description 10
- 239000011780 sodium chloride Substances 0.000 claims abstract description 7
- 150000001408 amides Chemical class 0.000 claims abstract description 4
- 150000002148 esters Chemical class 0.000 claims abstract description 4
- 230000003287 optical Effects 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 125000001188 haloalkyl group Chemical group 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 101710006116 IL31RA Proteins 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 101700014033 nhr-5 Proteins 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims 1
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 23
- 208000010412 Glaucoma Diseases 0.000 abstract description 8
- 201000010099 disease Diseases 0.000 abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 4
- 150000003949 imides Chemical class 0.000 abstract description 2
- -1 or are fused Chemical group 0.000 description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 150000003180 prostaglandins Chemical class 0.000 description 29
- 239000002904 solvent Substances 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 125000004429 atoms Chemical group 0.000 description 17
- 150000004702 methyl esters Chemical class 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 210000000988 Bone and Bones Anatomy 0.000 description 15
- 239000010410 layer Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 229940082622 Prostaglandin cardiac therapy preparations Drugs 0.000 description 13
- 229940077717 Prostaglandin drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD) Drugs 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 125000004432 carbon atoms Chemical group C* 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 229940094443 oxytocics Prostaglandins Drugs 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000012267 brine Substances 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000012038 nucleophile Substances 0.000 description 9
- DZUXGQBLFALXCR-CDIPTNKSSA-N prostaglandin F1alpha Chemical class 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 9
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 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 7
- 239000002253 acid Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 150000002118 epoxides Chemical class 0.000 description 7
- 239000008079 hexane Substances 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 230000002194 synthesizing Effects 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000006011 modification reaction Methods 0.000 description 6
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- SKRDXYBATCVEMS-UHFFFAOYSA-N Isopropyl nitrite Chemical compound CC(C)ON=O SKRDXYBATCVEMS-UHFFFAOYSA-N 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N Pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- RMVRSNDYEFQCLF-UHFFFAOYSA-N Thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 4
- 150000001728 carbonyl compounds Chemical class 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229910052681 coesite Inorganic materials 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 229910052906 cristobalite Inorganic materials 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000005712 crystallization Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 150000004795 grignard reagents Chemical class 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 230000004410 intraocular pressure Effects 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- 239000003586 protic polar solvent Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910052904 quartz Inorganic materials 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000003638 reducing agent Substances 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 235000012239 silicon dioxide Nutrition 0.000 description 4
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 4
- 238000000935 solvent evaporation Methods 0.000 description 4
- 229910052682 stishovite Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229910052905 tridymite Inorganic materials 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- VYLVYHXQOHJDJL-UHFFFAOYSA-K Cerium(III) chloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 3
- YEESKJGWJFYOOK-LDDGIIIKSA-N Leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SCC(N)C(=O)NCC(O)=O YEESKJGWJFYOOK-LDDGIIIKSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- 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 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 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 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 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
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- 150000002617 leukotrienes Chemical class 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 238000007910 systemic administration Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- JIRRJTAAVDYFBH-ZWBIQZHISA-J tetrasodium;(7Z)-7-[[4-[4-[(2Z)-2-(6-anilino-1-oxo-3-sulfonatonaphthalen-2-ylidene)hydrazinyl]-3-hydroxyphenyl]-2-hydroxyphenyl]hydrazinylidene]-8-oxonaphthalene-1,3,6-trisulfonate;copper Chemical compound [Na+].[Na+].[Na+].[Na+].[Cu].[Cu].OC1=CC(C=2C=C(O)C(N\N=C\3C(=CC4=C(C(=CC(=C4)S([O-])(=O)=O)S([O-])(=O)=O)C/3=O)S([O-])(=O)=O)=CC=2)=CC=C1N\N=C(C(=CC1=C2)S([O-])(=O)=O)\C(=O)C1=CC=C2NC1=CC=CC=C1 JIRRJTAAVDYFBH-ZWBIQZHISA-J 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- 238000006257 total synthesis reaction Methods 0.000 description 3
- HWBIQJOWCBKZJW-UHFFFAOYSA-N $l^{1}-silanyloxysilicon Chemical compound [Si]O[Si] HWBIQJOWCBKZJW-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- DMAYBPBPEUFIHJ-UHFFFAOYSA-N 4-bromobut-1-ene Chemical compound BrCCC=C DMAYBPBPEUFIHJ-UHFFFAOYSA-N 0.000 description 2
- 208000006386 Bone Resorption Diseases 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
- 229910052684 Cerium Inorganic materials 0.000 description 2
- 238000010485 C−C bond formation reaction Methods 0.000 description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N Diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- MPCRDALPQLDDFX-UHFFFAOYSA-L Magnesium perchlorate Chemical compound [Mg+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O MPCRDALPQLDDFX-UHFFFAOYSA-L 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M Perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 2
- 230000036823 Plasma Levels Effects 0.000 description 2
- 102000015433 Prostaglandin Receptors Human genes 0.000 description 2
- 108010050183 Prostaglandin Receptors Proteins 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N Trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 239000000030 antiglaucoma agent Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000024279 bone resorption Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229910052802 copper Inorganic materials 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
- ZGTMUACCHSMWAC-UHFFFAOYSA-L disodium;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000001404 mediated Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 238000010603 microCT Methods 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 150000002829 nitrogen Chemical group 0.000 description 2
- 230000011164 ossification Effects 0.000 description 2
- 125000004430 oxygen atoms Chemical group O* 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000000707 stereoselective Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- DPFYBZWSVVKNPZ-AQWIXGDGSA-N (3S,4S,6R)-2-[[(2R,4R,5R)-3,5-dihydroxy-4-methoxy-6-(methoxymethyl)oxan-2-yl]methoxymethyl]-6-ethyloxane-3,4,5-triol Chemical compound O[C@H]1[C@@H](O)C(O)[C@@H](CC)OC1COC[C@@H]1C(O)[C@H](OC)[C@H](O)C(COC)O1 DPFYBZWSVVKNPZ-AQWIXGDGSA-N 0.000 description 1
- HXLKPGIKMOTKCC-UHFFFAOYSA-N 1-bromo-3-methylidenepentane Chemical compound CCC(=C)CCBr HXLKPGIKMOTKCC-UHFFFAOYSA-N 0.000 description 1
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- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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 Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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
Abstract
The invention provides novel PGF analogs. In particular, the present invention relates to compounds having a structure according to formula (A), wherein R1, R2, R3, R4, X, Y and Z are defined below. This invention also includes optical isomers, diastereomers and enantiomers of said formula, 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 these compounds or the compositions containing them.
Description
TETRAHYDRO AROMATIC PROSTAGLANDINES SUBSTITUTED WITH 16 TO 20 ATTOMS OF CARBON, USEFUL AS PROSTAGLANDIN AGONISTS F
TECHNICAL FIELD
The present invention relates to certain novel analogues of prostaglandins as they occur in nature. Specifically, the present invention relates to novel analogs of Prostaglandin F, as well as to methods for employing such novel analogues of Prostaglandin F. Prred uses include methods of treating glaucoma and bone disorders.
BACKGROUND OF THE INVENTION
The prostaglandins as they occur in nature (PGA, PGB, PGE, PGF and PGI) are unsaturated fatty acids of C-20. PGF2a, the prostaglandin F that occurs naturally in humans, is characterized by hydroxyl groups at the Cg and Cu positions in the alicyclic ring, a cis double bond between C5 and C6 and a double trans bond between C-? 3 and C-? Four. Therefore, PGF2a has the following formula:
Prostaglandin F analogues have been described in the art as they occur in nature. For example, see patent E.U.A. 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 July 1, 1976; patent of E.U.A. No. 4,128,720 issued to Hayashi, Kori and Miyake on December 5, 1978; patent of E.U.A. No. 4,011, 262, issued to Hess, Johnson, Bindra and Schaaf on March 8, 1977; patent of E.U.A. No. 3,776,938 issued to Bergstrom and Sjovall on December 4, 1973; P.W. Collins and S. W. Djuric, "Synthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogs", Chem. Rev. Vol. 93 (1993), p. 1533-1564; G. L. Bundy and F. H. Lincoln, "Synthesis of 17-Phenyl-18,19,20-Trinorprostaglandins: I. The PG-i Series", Prostaqlandins. Vol. 9 No. 1 (1975), pp. 1-4; W. Bartman, G. Beck, U. Lerch, H. Teufel and B. Scholkens, "Luteoltytic Prostaglandins: Synthesis and Biological Activity", Prostaqlandins, Vol. 17 No. 2 (1979), pp. 301-311; C. liljebris, G. Selen, B. Resul, J. Sternschantz and U. Hacksell, "Derivatives of 17-Phenyl-18,19,20-trinorprostaglandin F2a Isopropyl Ester: Potential Antiglaucoma Agents", Journal of Medical Chemistry, Vol. 38 No. 2 (1995), pp, 289-304. It is known that prostaglandins as they occur in nature possess a wide variety of pharmacological properties. For example, prostaglandins have been shown to relax smooth muscle, which causes vasodilation and bronchodilation, inhibit the secretion of gastric acids, inhibit platelet aggregation, reduce intraocular pressure and induce labor. Although prostaglandins as they occur in nature are characterized by their activity against a receptor of
The particular prostaglandin, in general, is not specific for any prostaglandin receptor. Therefore, it is known that prostaglandins as they occur in nature cause side effects, such as inflammation, as well as irritation of the surface when administered systemically. In general, it is believed that the rapid metabolism of prostaglandins as such
occur in nature after their release in the body limits some of the effects of prostaglandin to a local area. This effectively prevents the prostaglandin from stimulating the prostaglandin receptors in the body and causing the effects observed with the systemic administration of prostaglandins as they occur in nature. It is known that prostaglandins, especially E-series prostaglandins (PGE), are potent stimulators of bone resorption. It has also been shown that PGF2a is a resorption stimulator
^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^ gjj ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ It has also been shown that PGF2a has little effect on bone formation. It has been suggested that some of the effects of PGF2a on bone resorption, the formation and retraction of cells can be mediated through an increase in the production of endogenous PGF2. In view of the wide variety of pharmacological properties of prostaglandins as they occur in nature and the side effects seen with the systemic administration of these prostaglandins as they occur in nature, an attempt has been made to prepare analogues to protaglandins as they occur in nature, which are selective for a specific recipient or receptors. A variety of such analogs have been described in the art. Although a variety of prostaglandin analogs have been described, there is a continuing need for selective and potent prostaglandin analogues for the treatment of a variety of diseases and disorders.
BRIEF DESCRIPTION OF THE INVENTION
The invention provides novel analogs of PGF: In particular, the present invention relates to compounds having a structure according to the following formula:
^^^^^^^^^^^^^^ gg ^ j¡ ^^^^^^^^ á ^^^^ - -j ^ fe ^ aaSteiS HO
wherein R-i, R2, R3, R4, X, Y and Z are defined below. This invention also includes isomers, diastereomers and optical enantiomers of the above formula, and pharmaceutically acceptable salts, briohydrolyzable 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 glaucoma and bone disorders. Therefore, the invention also provides pharmaceutical compositions comprising these compounds. Even the invention provides methods of treatment for bone and glaucoma disorders by the use of these compounds or the compositions containing them.
DETAILED DESCRIPTION OF THE INVENTION
Terms and definitions "Acyl" is a group suitable for acylating a nitrogen atom to form an amide or carbamate or an oxygen atom to form an ester group. Preferred acyl groups include benzoyl, acetyl, tert-butylacetyl, para-phenylbenzoyl and trifluoroacetyl. The acyl groups of greater
«Fta» iia - áfe »- ^ preference include acetyl and benzoyl. The most preferred acyl group is still acetyl. "Alkyl" is a saturated or unsaturated hydrocarbon chain having 1 to 18 carbon atoms, preferably 1 to 12, most preferably 1 to 6, most preferably still 1 to 4 carbon atoms. The alkyl chains can be straight or branched. Preferred branched alkyl chains have one or two branches, preferably one branch. The preferred alkyl chains are saturated. The unsaturated alkyl chains have one or more double bonds and / or one or more triple bonds. Preferred unsaturated alkyl chains have one or two double bonds and a triple bond, most preferably a double bond. The alkyl chains can be unsubstituted or substituted with 1 to 4 substituents. The preferred alkyl chains are unsubstituted. The alkyl chains substituted are preferably mono-, di-, or tri-substituted. Preferred alkyl substituents include halogen, hydroxy, aryl (eg, phenyl, tolyl, alkyloxyphenyl, alkyloxycarbonylphenyl, halogenphenyl, heterocyclyl, and heteroaryl. "Aromatic ring" is an aromatic hydrocarbon ring system.Aromatic rings are monocyclic ring systems or Fused bicyclics The monocyclic aromatic rings contain from about 5 to about 10 carbon atoms, preferably from 5 to 7 carbon atoms and most preferably still from 5 to 6 carbon atoms in the ring.The bicyclic aromatic rings contain from 8 to 12 carbon atoms, preferably 9 or 10 carbon atoms in the ring The aromatic rings can be unsubstituted or substituted with 1 to 4 substituents on the ring The preferred aromatic ring substituents include: halogen, cyano, alkyl, heteroalkyl, halogenalkyl, phenyl, phenoxy or any combination thereof. preferred include halogen and halogenoalkyl. Preferred aromatic rings include naphthyl and phenyl. The most preferred aromatic ring is phenyl. "Carbocyclic aliphatic ring" is a saturated or unsaturated hydrocarbon ring. The carbocyclic aliphatic rings are not aromatic. The carbocyclic aliphatic rings are monocyclic, or are fused, spiro or bridged bicyclic ring systems. The monocyclic carbocyclic aliphatic rings contain from about 4 to about 10 carbon atoms, preferably from 4 to 7 carbon atoms and most preferably still from 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic aliphatic rings contain 8 to 12 carbon atoms, preferably from 9 to 10 carbon atoms in the ring. The carbocyclic aliphatic rings may be unsubstituted or substituted with 1 to 4 substituents on the ring. Preferred carbocyclic aliphatic ring substituents include: halogen, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. The most preferred substituents include halogen and halogenoalkyl. Preferred carbocyclic aliphatic rings include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl. The most preferred carbocyclic aliphatic rings include cyclohexyl, cycloheptyl and cyclooctyl. The most preferred carbocyclic aliphatic ring is still cycloheptyl. "Halogen" is fluorine, chlorine, bromine or iodine. The preferred halogen is fluorine, chlorine and bromine; chlorine and fluorine are preferred, especially fluorine. "Halogenoalkyl" is a straight, branched or cyclic hydrocarbon substituted with one or more halogen substituents. Preferred halogenoalkyls are C -? - C? 2; more preferably they are Ci-Cß; even more preferably they are C1-C3. The preferred halogen substituents are fluorine and chlorine. The most preferred halogenoalkyl is trifluoromethyl. "Heteroalkyl" is a saturated or unsaturated chain containing carbon and at least one heterogeneous atom, where none of the two heterogeneous atoms is adjacent. The heteroalkyl chains contain from 1 to 18 atoms (carbon and heterogeneous atoms) in the chain, preferably 1 to 12, most preferably 1 to 6, most preferably still 1 to 4. The heteroalkyl chains can be straight or branched. The branched heteroalkyl chains preferably have one or two branches, preferably one branch. The preferred heteroalkyl chains are saturated. The unsaturated heteroalkyl chains have one or more double bonds and / or one or more triple bonds. The unsaturated heteroalkyl chains preferably have one or two double bonds and one triple bond, most preferably one double bond. The heteroalkyl chains can be unsubstituted or substituted with 1 to 4
&substituents The preferred heteroalkyl chains are unsubstituted. Preferred heteroalkyl substituents include halogen, hydroxy, aryl (e.g., phenyl, tolyl, alkyloxyphenyl, alkyloxycarbonylphenyl, halogenphenyl), heterocyclyl and heteroaryl. For example, alkyl chains substituted with the following 5 substituents are heteroalkyl, alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, pentoxy), aryloxy (eg, phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy, acyloxyphenoxy), acyloxy (eg, propionyloxy, benzoyloxy, acetoxy), carbamoyloxy, carboxy, mercapto, alkylthio, acylthio, arylthio (eg, phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, alkyloxycarbonylphenylthio),
amino (e.g., amino, C1-C3 mono- and di-alkylamino, methylphenylamino, methylbenzylamino, C1-C3 alkylamido, carbamamide, ureido, guanidino). "Heterogeneous atom" is a nitrogen, sulfur or oxygen atom. Groups that contain more than one heterogeneous atom may contain different heterogeneous atoms. 15"Heterocyclic aliphatic ring" is a saturated or unsaturated ring containing carbon and from 1 to about 4 heterogeneous atoms in the ring, where none of the two heterogeneous atoms is adjacent to the ring, and no carbon in the ring that have a heterogeneous atom attached to it also have a hydroxyl, amino or thiol group attached to it. The Rings
heterocyclic aliphatics are not aromatic. The heterocyclic aliphatic rings are monocyclic or are fused or bridged bicyclic ring systems. Monocyclic heterocyclic aliphatic rings contain from about 4 to about 10 atoms (carbon and atoms)
MttaM £ - > *? t4? * && amp; heterogeneous), preferably from 4 to 7, and most preferably from 5 to 6 in the ring. The bicyclic heterocyclic aliphatic rings contain from 8 to 12 atoms, preferably 9 or 10 in the ring. The heterocyclic aliphatic rings can be unsubstituted or substituted with 1 to 4 substituents on the ring. Heterocyclic aliphatic ring substituents include: halogen, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. The most preferred substituents include halogen and halogenoalkyl. Preferred heterocyclic aliphatic rings include pipercyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and piperdyl. "Heteroaromatic ring" is an aromatic ring system containing carbon and from 1 to about 4 heterogeneous atoms in the ring. Heteroaromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaromatic rings contain from about 5 to about 10 atoms (carbon and heterogeneous atoms) preferably from 5 to 7, and most preferably from 5 to 6 in the ring. The bicyclic heteroaromatic rings contain from 8 to 12 atoms, preferably 9 or 10 in the ring. The heteroaromatic rings may be unsubstituted or substituted with 1 to 4 substituents on the ring. Preferred heteroaromatic ring substituents include: halogen, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. The most preferred substituents include halogen, haloalkyl and phenyl. Preferred heteroaromatic rings include thienyl, thiazolo, purinyl, pyrimidyl, pyridyl and furanyl. The Rings
most preferred heteroaromatics include thienyl, furanyl and pyridyl. The most preferred heteroaromatic ring is thienyl. "Lower alkyl" is an alkyl chain radical that includes
from 1 to 6, preferably 1 to 4 carbon atoms. "Phenyl" is a monocyclic aromatic ring that can be
substituted or not with about 1 to about 4 substituents. The substituents can be substituted at the ortho, meta or para position on the phenyl ring, or any combination thereof. Preferred phenyl substituents include: halogen, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. The most preferred substituents on the phenyl ring include halogen and halogenalkyl. The most preferred substituent is halogen. The preferred substitution pattern in the phenyl ring is ortho or meta. The most preferred substitution pattern in the phenyl ring is ortho.
Compounds The present invention encompasses compounds having the following structure: HO
In the above structure, ^ is CO2H, C (O) NHOH, CO2R5, CH2OH, S (0) 2R5, C (O) NHR5) C (O) NHS (O) 2R5, or tetrazole; wherein R5 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring or heteroaromatic ring. Preferred R5 is CH3, C2H5, C3H7. Ri preferred is CO2H, C (0) NHOH, CO2CH3, CO2C2H5, C02C3H7, CO2C4H9, CO2C3H702 and C (O) NHS (O) 2R5. Ri of greater preference is CO2H, C (0) NHOH, CO2CH3 and C02C3H5. Ri of even greater preference is still CO2H and C02CH3. In the above structure, R2 is H or lower alkyl. Preferred R2 is H and CH3. Most preferred R2 is H. In the above structure, X is NR6R7, OR8, SR9, S (O) R9, S (O) 2Rg or F; wherein R6, R7 and Re are independently selected from the group consisting of H, acyl, alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring or heteroaromatic ring; and wherein Rg is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring or heteroaromatic ring. Preferred R6 and R are H, CH3 and C2H5. Preferred R8 is H, CH3, C2H5 and C3H7. Preferred R9 is CH3 and C2H5. Preferred X is NR6R7 and OR8. X most preferred is OH. In the above structure R3 and R4 are independently selected from the group consisting of H, CH3 and C2H5. R3 and R4 are preferably H.
In the above structure, Y is NR10, S, S (O) or S (O) 2; wherein R-io is H, acyl, alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring or heteroaromatic ring. R-io preferably is H and CH3. And preferably it is NH and S. In the above structure, Z is carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring or heteroaromatic ring. Preferred Z is monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, monocyclic aromatic ring and monocyclic heteroaromatic ring. Z most preferably is monocyclic aromatic ring or monocyclic heteroaromatic ring. Z most preferably is thienyl or phenyl. The invention also includes isomers, diastereomers and optical enantiomers of the above structure. Therefore, in all stereocenters where the stereochemistry is not defined (Cu, C-? 2, C15, and Cie), both epimers are visualized. The preferred stereochemistry in all mentioned stereocenters of the compounds of the invention simulate that of PGF2a as it occurs in nature. It has been discovered that the novel PGF analogs of the present invention are useful for the treatment of bone disorders, especially those that require a significant increase in bone mass, bone volume or bone strength. Surprisingly, it has been found that the compounds of the present invention provide the following advantages over known therapies for bone disorders: 1) an increase in the trabecular number through the formation of new trabeculae; 2) an increase in
^ Oá t ^ i i ^^ í ^^^ m.
bone mass and bone volume while maintaining a more normal rate of bone conversion rate; and 3) an increase in bone formation on the endosteal surface without increasing the cortical porosity. To determine and assess the pharmacological activity, tests of the present compounds are carried out on animals, using various tests known to those skilled in the art. For example, the bone activity of the present compounds can be conveniently demonstrated using a test designed to examine the ability of the present compounds to increase bone volume, mass or density. An example of such tests is the test in ovariectomized rats. In the test in ovariectomized rats, ovriectomy is practiced in rats of six months of age, they are allowed to grow 2 more months, and then they are dosed once a day subcutaneously with a compound test. At the end of the study, the mass and / or bone density can be measured by absorptiometry by dual x-ray energy (DXA) or peripheral quantitative computed tomography (pQCT), or microcomputed tomography (mCT). Alternatively, static and dynamic histomorphometry can be used to measure the increase in bone volume or formation. The pharmacological activity for glaucoma can be demonstrated using tests designed to examine the ability of the present compounds to lower intraocular pressure. Examples of such tests are described in the following reference incorporated herein: C. Liljebris, G. Selen, B. Resul, J. Stemschantz, and U. Hacksell, "Derivatives of 17- Phenil-18,19,20- trinorprostaglandin F2a Isopropyl Ester: Potential Antiglaucoma Agents ", Journal of Medicinal Chemistry, Vol. 38 No. 2 (1995), pp. 289-304. The compounds useful in the present invention can be made using conventional organic synthesis. The preferred synthesis in particular is the following general reaction scheme.
SCHEME 1
Formula V when X = SR9, NaD4 X = ORa, SR9
Formula VI X = S (0) n n = 1 2 In scheme 1, R-i, R2, R3, 4, X, Y and Z are as defined above. The methyl 7 [3- (R) -hydroxy-5-oxo-1-cyclopent-1-yl] (S1a) heptanoate described as starting material for scheme 1 is commercially available (eg, from Sumitomo Chemical or Cayman Chemical). In Scheme 1 above, methyl 7 [3- (R) -hydroxy-5-oxo-1-cyclopent-1-yl] (S1a) heptanoate is reacted with a silylating agent and base in a solvent that will allow continue the silylation. Preferred silylating agents include tert-butyldimethylsilyl chloride and tert-butyldimethylsilyl trifluoromethanesulfonate. The most preferred silylating agent is tert-butyldimethylsilyl trifluoromethanesulfonate. Preferred bases include triethylamine, trimethylamine and 2,6-lutidine. The most preferred bases include triethylamine and 2,6-lutidine. The most preferred base is 2,6 lutidine. Preferred solvents include halogencarbon solvents with dichloromethane being the most preferred solvent. The reaction is allowed to continue at a temperature preferably between -100 ° C and 100 ° C, most preferably between -80 ° C and 80 ° C, and most preferably still between -70 ° C and 23 ° C. The resulting silylated compound is isolated by methods known to those skilled 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.
Subsequently, the silylated compound is reacted with the cuprate generated through Grignard formation of the appropriate alkenyl bromide, as described 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 to '/ 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 ether solvents, of which diethyl ether and tetrahydrofuran are preferred. The most preferred solvent is tetrahydrofuran. The Grignard reagent is allowed to form at a temperature between 100 ° C and 23 ° C, most preferably between 85 ° C and 30 ° C, and most preferably still between 75 ° C and 65 ° C. The reaction time is preferably between 1 hour and 6 hours, with a reaction time of greater preference between 2 hours and 5 hours, and the reaction time of even greater preference between 3 hours and 4 hours. Once the Grignard reagent is formed, the cuprate is generated from the alkenyl magnesium species. The temperature scale for cuprate formation is between -100 ° C and 0 ° C. The preferred temperature scale is between -80 ° C and -20 ° C. The most preferred temperature scale is between -75 ° C and -50 ° C. The preferred reaction time is between 30 minutes and 6 hours. The most preferred reaction time is between 45 minutes and 3 hours. The most preferred reaction time is still between 1 hour and 1.5 hours. The compound described as S1 b is isolated by methods known to those skilled 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 10% EtOAc / hexanes as the eluent. S1 b is then reacted with a hydride reducing agent and a polar protic solvent to produce the Cg alcohol. Preferred reducing agents include lithium aluminum hydride, sodium borohydride and L-selectruro. 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 still between -45 ° C and -20 ° C. The resulting alcohol of S1 b is isolated by methods known to one skilled 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. Alcohol can be protected as described hereinabove. The protected or unprotected alcohol is then treated with meta-chloroperbenzoic acid in a halogencarbon solvent to provide the novel epoxide intermediate, described as S1c. Preferred halogenocarbon solvents include dichloromethane, dichloroethane and chloroform. The most preferred halogenocarbon solvents are dichloromethane and dichloroethane. The most preferred halogenocarbon solvent is still dichloromethane. The compound described as S1c is isolated by methods known to one skilled 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 intermediate epoxide described as S1c can be reacted with a variety of oxygen, sulfur and nitrogen containing nucleophiles, as described for example in J. G. Smith, "Synthetically Useful Reactants of Epoxides", Synthesis (1984) p. 629-656 to provide the 13,14-dihydro-15-substituted-16-tetranor Prostaglandin F1a derivatives protected with Cu of the formula I.
With the sulfur nucleophiles, the reaction is preferably carried out between 150 ° C and 0 ° C, most preferably between 120 ° C and 20 ° C, and most preferably still between 80 ° C and 50 ° C. Preferred bases for the reaction include triethylamine, N, N diisopropylethylamine and trimethylamine. The most preferred base 5 is triethylamine. The solvents for the reaction are aromatic hydrocarbon solvents. Preferred solvents include xylenes, toluene and benzene. The most preferred solvent is benzene. With nitrogen and oxygen nucleophiles, preferred solvents include ether solvents and polar protic solvents. The ethereal solvents of higher
Preference includes diethyl ether, dibutyl ether and tetrahydrofuran. The most preferred ether solvent is tetrahydrofuran. The most preferred polar protic solvents include ethyl alcohol, methyl alcohol and tert-buityl alcohol. The most preferred polar protic solvent is still ethyl alcohol. The process of ring opening with nitrogen and oxygen nucleophiles can be catalyzed with Lewis acids. The Lewis acids include magnesium perchlorate, trimethylsilyltrifluoromethanesulfonate and trimethylaluminum. The most preferred Lewis acid is still magensium perchlorate. The reaction is carried out at a temperature between
150 ° C and 23 ° C, preferably between 125 ° C and 40 ° C, and most preferably between 100 ° C and 75 ° C. The resulting compounds can be isolated, but are generally deprotected using techniques known to one skilled in the art.
»Ja« .afr-, a ^ - -. ^ .M: .-- ^. , - ^^^^ technique, and are isolated as the final 13,14-dihydro-15-substituted-16-tetranor Prostaglandin F1a derivative. The compounds described by formula I appear in examples 2-28. The compounds described by formula II can be made directly from those described in formula I by methods known to one skilled in the art. For example, the condensation of methyl esters of formula I with amines or hydroxylamine provides compounds described by formula II. The compounds described by formula II appear in examples 29-32. The compounds described by formula II can be made directly from those described in formula I by methods known to one skilled in the art. The appropriately protected derivative of the formula I is oxidized to the ketone following the procedure described in the following references. A. McKillop and D.W. Young, "Organic Synthesis Using Supported Reagents - Part 1", Svnthesis (1979) p. 401-22; G. Piancatelli, et.al, "Pyridium Chlorochromate: A Versatile Oxidation Organic Synthesis", Svnthesis (1982) p.245-58; E.J. Corey and J.W. Suggs, "Pyridinium Chlorochromate: An Efficient Reagent for Oxidation of Primary and Secondary Alcohole to Carbonyl Compounds", Tetrahedron Lett. Vol. 31 (1975) p. 2647-50; and references cited there. Subsequently, the ketone is condensed with N-methylamine to produce the mine. The addition of the methylceride nucleophile (-1.5 equivalent), as described for example in T. Imamoto, et.al, "Carbon-Carbon Bond Forming Reactions Using Cerium Metal or Organcerium (III) Reagents", J. Orq. Chem. Vol. 49 (1984) p. 3904-12; T. Imamoto, et.al, "Reactions of Carbonyl Compounds with Grignard Reagents in the Presence of Cerium Chloride," J. Am. Chem. Soc. Vol. 111 (1989) p. 4392-98; and references cited therein) yields the aminomethyl derivative of formula III. The compounds described by formula III appear in examples 39-42. The compounds described by formula IV and formula V can be made from the compounds described in formula I by activation and subsequent nucleophilic displacement of the properly functioning hydroxyl group. Transformations of this type are described in the following references: E.J. Corey et.al, "Simple Stereospecific Routes to 9-epi-prostaglandin F2a", J.C.S. Chem. Comm. (1975) p. 658-9; E.J. Corey et al, "Superoxide ion as a Synthetically Useful Oxygen Nucleophile" Tetrahedron Lett. (1975) p. 3183-6; E.J. Corey et.al, "Total Synthesis of 5-desoxy Leukotriene D. A New and Useful Equivalent of the 4-Formvl-Trans, Trans-1, 3-Butadienvl Anion", Tetrahedron Lett. Vol. 23 (1982) p. 3463-66 and references cited therein. The compounds described by the formula V appear in examples 33-36. The compounds described by formula VI can be prepared from those described in formula V (where X is SRg) by selective oxidation methods, as described for example in the following references: E.J. Corey et.al, "Pathways for Migration and Cleavage of the S-Peptide Unit of the Leukotrienes", Tetrahedron Lett. Vol. 23 (1982) p. 3467-70; Prostaqlandins Vol. 24 (1982) p. 801; Y. Girard et.al, "Synthesis of
^ ^^^^^ A ^^^^^^^^^ the Sulfones of Leukotrienes C4, D4 and E4", Tetrahedron Lett, Vol. 23 (1982) p.1023-26, and references cited therein. by formula VI they appear in Examples 37-38 The following non-limiting examples illustrate the compounds, compositions and uses of the present invention.
EXAMPLES
Compounds are analyzed using 1 H and 13 C NMR, elemental analysis, mass spectra, high resolution mass spectra and / or IR spectra, as appropriate. Inert solvents are almost always used, preferably in anhydrous form. For example, tetrahydrofuran (THF) is distilled from sodium and benzophenone, diisopropylamine is distilled from calcium hydride and the rest of the solvents are purchased, according to the appropriate degree. Chromatography is performed on silica gel (70-230 mesh, Aldrich) or (230-400 mesh, Merck), as appropriate. The thin-layer chromatography analysis is performed on silica gel plates mounted on glass (200-300 mesh, Baker) and visualized using UV, 5% phosphomolybdic acid in EtOH or ammonium molybdate / ceric sulfate in 10% H2SO4 aqueous.
EXAMPLE 1 Preparation of 13,14-dihydro-16- (3-fluorophenylthio) tretanor prostablandin
F1a (1¡) and 13,14-dihydro-15-methyl-16- (3-fluorophenitol) tetranor prostaqlandin Fia di):
or O, .C02Me) CuBrDMS & TBDMSOTf í 1 1b BrMg- 2) NaBH,
1c R = H 1e R = H 1d, R = CH 3 1f, R = CH 3
1g, R = H 1l R = H 1h, R = CH 3 1), R = CH 3
a) Heptanoate 1 b of methyl 7- (2-oxo-4- (1,1,1,2-tetramethyl-1-silapropoxy) cyclopent-1-enyl): To a solution of heptanoate 1a of methyl-7- [ 3- (R) -hydroxy-5-oxo-1-cyclopent-1-yl] (1 equivalent) in CH 2 Cl 2 at -78 ° C is added 2,6 lutidine (1.3 equivalent) dropwise over 15 minutes. The solution is maintained at -78 ° C, and TBDMS triflate (1.2 equivalent) in CH2Cl2 is added dropwise over 15 minutes. The reaction is gradually warmed to room temperature and stirred at room temperature for 15 hours. 10% aqueous HCl is added and the layers separated. The water layer is extracted with CH2Cl2 and the organic layers are combined. The organic layer is washed with brine, dried (Na 2 SO 4) and concentrated. The residue is distilled under vacuum (10 mm Hg) to produce silyl ether 1 b as a yellow liquid. b) Heptanoate 1c, 1d of methyl 7- (5-but-3-enyl-2-hydroxy-4- (1,1,1,2-tetramethyl-1-silapropoxy) cyclopentyl): To a suspension of Mg powder ° (2 equivalent) in THF at room temperature add a crystal of l2 and 1-bromobutene (2 equivalent) 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 by cannula to a three-necked flask equipped with mechanical stirring and charged with CuBr DMS (2 equivalent) in a 1: 1 solution of THF / DMS at -78 ° C. After the addition of the Grignard (-20 minutes), 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 1 b (1 equivalent) in THF is then added dropwise over 25 minutes. The reaction is stirred at -78 ° C for 15 minutes, then allowed to slowly warm to room temperature for 2 hours. The reaction is quenched with aqueous NH 4 Cl and the excess DMS is allowed to evaporate overnight. The reaction is partitioned between brine / CH2Cl2 and the layers are separated. The aqueous layer is extracted with CH2Cl2 and the organic layers are combined and dried with (Na2SO). The solvent is removed in vacuo, and the residue is passed through SiO2 chromatography (10% hexane / EtOAc) to give the ketone precursor to 1c as a clear oil. The 1d ketone precursor is prepared in substantially the same manner. The ketone precursor at 1c is dissolved in MeOH and cooled to -40 ° C. Sodium borohydride (0.9 equivalent) is added in portions for 10 minutes. After completing the addition, the reaction is stirred for 13 hours at -40 ° C and then for 12 hours at -78 ° C. The reaction is quenched with water, divided between brine and CH2Cl2 and the layers separated. The aqueous layer is extracted with CH2Cl2 and the organic layers are combined and dried with (Na2SO). The solvent is removed in vacuo and the residue is chromatographed on SiO2 (30% EtOAc / hexanes) to produce alcohol 1c as a colorless oil. The alcohol 1d is prepared substantially in the same manner. c) Heptanoate 1e, 1f of methyl 7- (2-hydroxy-5- (2- (2-oxiranyl) ethyl) -4- (1,1,1,2-tetramethyl-1-silapropoxy) cyclopentyl: Alcohol 1c (1 equivalent) is dissolved in CH2CI2 and cooled to 0 ° C. Sodium bicarbonate is added, followed by m-CPBA (57% -85% purity) (3 equivalent) in portions for 15 minutes. the reaction is stirred for 20 hours at room temperature, the reaction is poured into water, partitioned between brine and CH2Cl2, and the layers are separated.The aqueous layer is extracted with CH2Cl2 and the organic layers are combined and dried with (Na2S0) The solvent is removed in vacuo and the residue is chromatographed on SiO2 (20%).
& *? T ** m.
EtOAc / hexanes) to produce diastereomers of epoxide 1e as a colorless oil. Compound 1f is synthesized in substantially the same manner. d) Methyl esters of 13,14-dihydro-16- (3-fluorophenylthio) tetranor prostaglandin F1a (1g), and 13,14-dihydro-15-methyl-16- (3-fluorophenylthio) tetranor prostaglandin F-? a ( 1 h): In a 5 ml beaker, epoxide 1e (1 equivalent) and 100 ml of dry benzene are added. The flask is cooled to 0 ° C and then treated with 60 ml of 3-fluorothiophenol (1.2 equivalent) and 78 ml of triethylamine (1.2 equivalent) as described in JG Smith, "Synthetically Useful Reactants of Epoxides", Svnthesis (1984). ) p. 629-656, and references cited therein. The ice bath is removed and the reaction is stirred at room temperature under nitrogen overnight. TLC is used to monitor the reaction. Excess thiophenol is added, if necessary. The reaction is quenched with brine and extracted with methylene chloride. The organic layer is washed three times with 1 N HCl, brine, dried over sodium sulfate and concentrated. Without further purification, 3 ml of CH3CN and 0.1 ml of HF / Pyridine (0.1 mmol) are added to this crude reaction mixture while the flask is kept at 0 ° C. After three hours, at 0 ° C, the reaction is quenched with saturated NaCl. The aqueous layer is extracted three times with CH2Cl2, the organic layers are combined and washed three times with 1 N HCl, brine and dried over (Na2SO). After column chromatography (7: 3, Hexane: Ethyl Acetate), the clear oil 1 g is obtained. The ester 1 h is prepared in substantially the same manner.
e) 13,14-dihydro-16- (3-fluorophenylthio) tetranor prostaglandin F1a (1 i), and 13,14-dihydro-15-methyl-16- (3-fluorophenylthio) tetranor prostaglandin F-ta (1j): To a 5 ml beaker is added 50 mg (0.12 mmol) of methyl ester 1 g of 13,14-dihydro-16- (3-fluorophenylthio) tetranor prostaglandin F1a methyl ester of 13,14-dihydro-16,16 -dimethyl-16- (2-fluorophenoxy) -16-tetranor prostaglandin Fia and 4 ml of aqueous THF solution (3: 1, THF: H2O), and the flask is cooled to 0 ° C. An excess amount (2.5 equivalent) 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 three times with methylene chloride, the organic layers are combined and washed with brine, dried over concentrated (Na2SO) in vacuo and the residue is passed through chromatography (methylene chloride, methanol, acetic acid, 9.6. 0.4, 0.015) to produce 30 mg of clear oil 1i. The acid 1j is prepared in substantially the same manner. By substantial use of the method of Example 1 (and using the appropriate thiophenol), the following compounds of Examples 2-23 are obtained.
^^? ^^^^^^ ^^^ EXAMPLE 2 Methyl ester of 13,14-dihydro-16- (phenylthio) tetranor Prostaqlandin Fia
EXAMPLE 3 Methyl ester of 13.14-dihydro-16- (3-methylphenylthio) tetranor Prostaglandin Fia
EXAMPLE 4 Methyl ester of 13.14-dihydro-16- (3-trifluoromethylphenylthio) tetranor Prostaqlandin Fia
EXAMPLE 5 Methyl ester of 13,14-dihydro-16- (2,3,5,6-tetrafluorophenylthio) tetranor Prostaqlandin Fia
EXAMPLE 6 Methyl ester of 13,14-dihydro-16- (2-methylphenylthio) tetranor Prostaqlandin Fia
EXAMPLE 7 Methyl ester of 13,14-dihydro-16- (4-methylphenylthio) tetranor Prostaqlandin Fia
EXAMPLE 8 Methyl ester of 13,14-dihydro-16- (2-fluorophenylthio) tetranor Prostaqlandin Fia
EXAMPLE 9 Methyl ester of 13.14-dihydro-15-methyl-16- (phenylthio) tetranor Prostaqlandin Fia
EXAMPLE 10 Methyl ester of 13.14-dihydro-15-methyl-16- (2-methylphenylthio) tetranor Prostaqlandin Fia
^^^^^^^ «? ^^ jtóßfc¡i ^ __ ^ _ ^ ^^^^^^ ijSgi? Ii? EXAMPLE 11 13.14-Dihydro-16- (2-thienophenylthio) tetranor methyl ester Prostaqlandin
EXAMPLE 12 13,14-dihydro-16- (phenylthio) tetranor Prostaqlandin Fia
EXAMPLE 13 13,14-dihydro-16- (3-methylphenylthio) tetranor Prostaqlandin Fia
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ EXAMPLE 14 13,14 -dihydro-16- (3-trifluoromethylphenylthio) tetranor Prostaqlandine Fia
EXAMPLE 15 13,14-dihydro-16- (2,3,5,6-tetrafluorophenylthio) tetranor Prostaqlandin Fia
EXAMPLE 16 13,14-dihydro-15-methyl-16- (2-methylphenylthio) tetranor Prostaqlandin Fia
jg! ^ - ^^^^^ jg ^ i |! t¡fe * jfe 3g EXAMPLE 17, 14-dihydro-16- (4-methylphenylthio) tetranor Prostaqlandine Fia
EXAMPLE 18 13,14-dihydro-16- (1-naphthylthio) tetranor Prostaqlandin Fia
EXAMPLE 19, 14-dihydro-16- (cyclohexylthio) tetranor Prostaqlandin Fia
EXAMPLE 20 13,14-dihydro-16-? 2-fluorophenylthio) tetranor Prostaqlandin F a
EXAMPLE 21 13,14-dihydro-15-methyl-16- (phenylthio) tetranor Prostaqlandin Fia
EXAMPLE 22, 14-dihydro-15-methyl-16- (3-methylphenolithium) tetranor Prostaqlandin Fia
EXAMPLE 23 13,14-dihydro-16- (3-fluorophenylsulfonyl) tetranor Prostaqlandin Fia To a solution of 13,14-dihydro-16- (3-flurophenylthio) tetranor prostaglandin F1a (1 equivalent) in CHCl3 at -78 ° C add peracetic acid (2 equivalent) drop by drop. The solution is stored at -78 ° C for 1 hour, then allowed to warm to 0 ° C and stored at 0 ° C for 1 hour. NaCl is added and the layers separated. The aqueous layer is extracted with CH2Cl2 and the organic layers are combined. The organic layer is washed with brine, dried (Na 2 SO 4) and concentrated. The residue is passed through
Chromatography on SiO2 (96 CH2Cl2, 4 MeOH, 0.1 acetic acid) to produce 13,14-dihydro-16- (3-flurophenylsulfonyl) tetranor prostaglandin F1a as a clear oil.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ & EXAMPLE 24 Preparation of 13,14-dihydro-16- (3-methylphenylamino) tetranor methyl ester Prostaqlandin Fia
To a 10 ml beaker is added epoxide 1e (1.26 mmol), m-Toludin (1.5 equivalent), 10 mg of magnesium perchlorate and 2 ml of THF, after which the reaction is refluxed under nitrogen overnight. The flask is cooled to room temperature and the solvent removed in vacuo. Without further purification of this crude reaction mixture, 3 ml of CH3CN and 0.5 ml of HF / Pyridine (0.5 mmol, 0.6 equivalent) are added while the flask is kept at 0 ° C. After 5 hours at 0 ° C, the reaction is quenched with saturated NaCl. The aqueous layer is extracted three times with CH2Cl2. The organic layers are combined and washed three times with saturated NaHC 3, brine and dried over (Na 2 SO 4). After column chromatography (95% CH2Cl2, 5% MeOH), 13,14-dihydro-16- (3-methylphenolimino) tetranor prostaglandin F1a methyl ester is obtained as a clear oil.
^^^^^^ ^^^^^ ^^^ ^ ^ ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ tetranor Prostaglandin Fia
To a 5 ml beaker are added 13,14-dihydro-16- (3-methylphenylamino) tetranor prostaglandin F1a methyl ester (0.15 mmol) and 4 ml of THF aqueous solution (3: 1, THF: H2O). ). The flask is cooled to 0 ° C, and an excess amount of lithium hydroxide (2.5 equivalent) is added. The ice bath is removed and the reaction is stirred at room temperature during the
night Methylene chloride and saturated citric acid are added to the reaction mixture, and the aqueous layer is washed three times with methylene chloride. The organic layers are combined and washed with brine, dried (Na 2 SO 4), concentrated and passed through chromatography (methylene chloride, methanol, acetic acid, 9.6, 0.4, 0.015) to yield 13,14-dihydro-16- (3-15 methylphenylamino) tetranor prostaglandin F1 a as a clear oil. By the substantial use of the method of Examples 24 and 25 (and by using the appropriate aniline), the following compounds of Examples 26-28 are obtained.
^^^^^^^ f ^^^^^^^ g ^^ t ^^ a ^^^^^^^ # j ^ fe ^^^^ ig ^^ EXAMPLE 26 Methyl ester of 13.14-dihydro- 16- (Phenylamino) tetranor Prostaqlandin
EXAMPLE 27 13,14-dihydro-16- (2-methylphenylamino) tetranor Prostaqlandin Fia
EXAMPLE 28 13,14-dihydro-16- (phenylamino) tetranor Prostaqlandin Fia
S ^ AtaUtimmiÜm.
EJEÉJÉO 29 Preparation of 1-hydroxamic acid 13,14-dihydro-16- (3-trifluoromethylphenylthio) tetranor Prostaqlandine Fia
A 13.14-dihydro-16- (3-trifluoromethylphenyltho) tetranor prostaglandin F1a methyl ester (Example 4) (1.0 equivalent) is placed in a 25 ml flacon-dried flask equipped with a magnetic stir bar. in methanol. Hydroxylamine in methanol (1.25 equivalent) is added to this solution. The solution is stirred for 18 hours. Then, the solution is treated with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with brine, dried over anhydrous MgSO, filtered and concentrated under reduced pressure. The residue is purified by chromatography to give 1-hydroxamic acid of 13,14-dihydro-16- (3-trifluoromethylphenylthio) tetranor prostaglandin F1a. By substantial use of the method of Example 29 (and by using the appropriate hydroxylamine or sulfonamide), the following compounds of Examples 30-32 are obtained.
EXAMPLE 30 1-Hydroxamic acid of 13.14-dihydro-16- (2-fluorophenylthio) tetranor Prostaqlandin Fia
EXAMPLE 31 1-Hydroxamic acid of 13,14-dihydro-16- (3-chlorophenylamino) tetranor Prostaqlandin Fia
EXAMPLE 32 1-N-methanesulfonamide of 13,14-dihydro-15-methyl-16- (2-methylphenylthio) tetranor Prostaqlandin Fia
EXAMPLE 33 Preparation of 13,14-dihydro-15-methylthio-15-dehydroxy-16- (N-methylphenylamino) tetranor Prostaqlandin Fia
NaSCH3
The suitable bis-silylated compound synthesized in Example 1 is treated with methanesulfonyl chloride (1.2 equivalent) and base (1.2 equivalent) as described in the following references E.J. Corey et.al, "Simple Stereospecific Routes to 9-epi-prostaglandin F2a", J.C.S. Chem. Comm. (1975) p. 658-9; E.J. Corey et al, "Superoxide ion as a Synthetically Useful Oxygen Nucleophile" Tetrahedron Lett. (1975) p. 3183-6; and references cited therein) to generate the intermediate mesylate, which is then treated immediately with nucleophiles (sodium thiomethoxide) as described in E.J. Corey et al, "Total Synthesis of 5-desoxy Leukotriene D. A New and Useful Equivalent of the 4-Formyl-Trans. Trans-1.3-Butadienvl Anion", Tetrahedron Lett. Vol. 23 (1982) p. 3463-66 and the references cited therein to produce 13, ^? idro-15-methylthio-15-dehydroxy-16- (N-methylphenylamino) tetranor prostaglandin F1a after deprotection as described in example 1. Examples 34-36 are prepared using substantially the same procedure as described in the example 33 (using the appropriate derivative of formula IV). The person skilled in the art can change temperature, pressure, atmosphere, solvents or the order of the reactions, as appropriate. In addition, one skilled in the art can employ protection groups to block side reactions or increase yields, as appropriate. All these modifications can be easily carried out by the expert in the field of organic chemistry, and are therefore within the scope of the invention.
EXAMPLE 34 1-Hydroxamic acid of 13,14-dihydro-15-methylthio-15-dehydroxy-16- (N-methyl-phenylamino) tetranor Prostaqlandin Fia
EXAMPLE 35 13.14-Dihydro-15-methoxy-15-dehydroxy-16- (2-fluorophenylthio) tetranor Prostaqlandin Fia
EXAMPLE 36 13.14-Dihydro-15-butoxy-15-dehydroxy-16- (phenylthio) tetranor methyl ester Prostaqlandin Fia
EXAMPLE 37 Preparation of 13,14-dihydro-15-sulfonylmethyl-15-dehydroxy-16- (N-methyl-phenylamino) tetranor methyl ester Prostaqlandin Fia
1 * ~ ** f- The methyl ester is treated with the appropriate oxidation agent as described in the following references: E.J. Corey et.al, "Total Synthesis of 5-desoxy Leukotriene D. A New and Useful Equivalent of the 4-Formvl-Trans. Trans-1, 3-Butadienvl Anion", Tetrahedron Lett. Vol. 23 (1982) p. 3463-66; Prostaqlandins Vol. 24 (1982) p.801; Y. Girard et.al, "Synthesis of the Sulfones of Leukotrienes C4, D4 and E4", Tetrahedron Lett. Vol. 23 (1982) p.1023-26; and references cited therein, or as described in example 23. Example 38 is prepared using substantially the same procedure as that described in example 37 (using the appropriate derivative of formula V). The person skilled in the art can change temperature, pressure, atmosphere, solvents or the order of the reactions, as appropriate. In addition, one skilled in the art can employ protection groups to block side reactions or increase yields, as appropriate. All these modifications can be easily carried out by the expert in the field of organic chemistry, and are therefore within the scope of the invention.
EXAMPLE 38 13,14-Dihydro-15-sulfoxylmethyl-15-dehydroxy-16- (N-methyl-phenylamino) tetranor methyl ester Prostaglandin Fia
EXAMPLE 39 Preparation of 13,14-dihydro-15-methyl-15-aminomethyl-16- (2-fluorophenylthio) tetranor Prostaqlandin Fia
1) CH3NH2 2) CeCI3, MeLi acid
The appropriately protected derivative of Example 8 is oxidized to the ketone as described in the following references: A. McKillop and D.W.
Young, "Organic Synthesis Using Supm $ lied Reagents - Part 1", Svnthesis (1979) p. 401-22; E.J. Corey and J.W. Suggs, "Pyridinium Chlorochromate: An Efficient Reagent for Oxidation of Primary and Secondary Alcohols to Carbonyl Compounds", Tetrahedron Lett. Vol. 31 (1975) p. 2647-50; and references therein cited, and then condensed with N-methylamine to produce the mine. The addition of the methylceride nucleophile (-1.5 equivalent) (for examples of nucleophilic addition mediated with cerium chloride see: T. Imamoto, et.al, "Carbon-Carbon Bond Forming Reactions Using Cerium Metal or Organcerium (III) Reagents", J. Orq Chem. Vol. 49 (1984) p.3904-12; T. Imamoto, et al., 10"Reactions of Carbonyl Compounds with Grignard Reagents in the Presence of Cerium Chloride", J. Am. Chem. Soc. Vol. 111 (1989) pp. 4392-98; and references cited therein) yields the aminomethyl derivative, which is then transformed as described in Example 1 to produce 13,14-dihydro-15-methyl-15-aminomethyl -16- (2-fluorophenylthio) tetranor Prostaglandin Fia. Examples 40-42 are prepared using substantially the same procedure as that described in example 39 (using the appropriate derivative of formula I). The person skilled in the art can change temperature, pressure, atmosphere, solvents or the order of the reactions, as appropriate. In addition, one skilled in the art can employ protection groups 20 to block side reactions or increase yields, as appropriate. All these modifications can be easily carried out by the expert in the field of organic chemistry, and are therefore within the scope of the invention.
- anei-a »-» ^^^ gjgg¡égj9 «^ g = S l ^? s EXAMPLE 40 1-N-methanesulfonamide of 13.14-dihydro-15-methyl-15-aminomethyl-16- (2-fluorophenylthio) tetranor Prostaqlandina Fia
EXAMPLE 41 13,14-Dihydro-15-ethyl-15-aminomethyl-16- (phenylthio) tetranor isopropyl ester Prostaqlandin Fia
EXAMPLE 42 13.14-Dihydro-15-ethynyl-15-aminomethyl-16- (4-methylphenylthio) tetranor isopropyl ester Prostaqlandin Fia
• > * tr r. ^^ A * »** - * ** ** --.--! Compositions The compositions of the present invention comprise a safe and effective amount of the compounds, and a pharmaceutically acceptable carrier. As used herein, "safe and effective amount" means an amount of compound sufficient to induce significantly a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit / risk), under good medical judgment. A safe and effective amount of a compound will vary with the particular condition treated,
the age and physical condition of the patient under treatment, the severity of the condition, the duration of the treatment, the nature of the concurrent therapy, the particular pharmaceutically acceptable vehicle used, and similar factors within the knowledge and experience of the responsible physician. In addition to the compound, the compositions of the present
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 that are suitable for administration to a subject. The term "compatible", as used herein, means that
The components of the composition are capable of combining with the compound, each other, such that there is no interaction that can substantially reduce the pharmaceutical efficacy of the composition under commonly used situations. Pharmaceutically acceptable vehicles
a.a ^ .'- A ,,. However, they must, of course, have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to the subject under treatment. Some examples of substances that can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose, and sucrose; starches such as corn starch 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, stearate
magnesium; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol, alginic acid, emulsifiers such as Tweens® wetting agents, such as sodium lauryl sulfate, coloring agents,
sweetening agents, excipients, tableting agents, stabilizers, antioxidants, preservatives; pyrogen-free water, isotonic saline solution and pH-regulating phosphate solutions. The choice of a pharmaceutically acceptable vehicle to be used in conjunction with a compound is basically determined by the manner in which the
compound will be administered. The compounds of the present invention can be administered systemically. Routes of administration include transdermal, oral, parenteral, including subcutaneous or intravenous, topical and / or intranasal.
^^^! ^^ The adequate amount of compound to be used will be determined by routine experimentation with animal models. Such models include, but are not limited to ovariectomized and intact rat models, ferret, canine and non-human primate models, as well as models that are no longer used. Dosage forms per unit that are preferred for injection include sterile solutions of water, saline physiological solutions or mixtures thereof. The pH of these solutions should be adjusted to approximately 7.4. Suitable vehicles for injection or surgical implants include hydrogels, sustained or controlled release devices, polylactic acid and collagen matrices. Pharmaceutically acceptable carriers for topical application include those suitable for use in lotions, creams, gels, and the like. If the compound will be administered perorally, the preferred dosage form per unit are tablets, capsules and the like. Pharmaceutically acceptable carriers suitable for the preparation of dosage forms per unit for oral administration are already known in the art. Their selection will depend on secondary considerations such as flavor, cost and shelf stability, which are not important for the purposes of the present invention. And they can be performed without difficulty by those skilled in the art.
Methods of use The compounds of the present invention are useful for the treatment of many medical disorders, including for example, eye disorders, hypertension, fertility control, nasal congestion, neurogenic bladder disorders, gastrointestinal disorders, dermatological disorders and osteosporosis. The compounds of the present invention are useful for increasing bone volume and trabecular number by forming new trabeculae, increasing bone mass while maintaining a normalized bone conversion rate, and bone formation on the endosteal surface without removing bone. of the existing bark. In this way, these compounds are useful in the treatment and prevention of bone disorders. The administration routes that are preferred to treat bone disorders are transdermal and intranasal. Other preferred routes of administration include rectal, sublingual and oral. The dosage scale of the compound for routine 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 from about 1 about 50 μg / kg in body weight per day. Transdermal dosages will be designed to obtain similar serum or plasma levels, based on techniques recognized by those skilled in the art of pharmacokinetics and transdermal formulations. Plasma levels for systemic administration are
J ^^ j ^^ ^ g u ^ | Expect them to be on a scale of 0.01 to 100 nanograms / ml. Most preferably 0.05 to 50 ng / ml, and most preferably 0.1 to 10 ng / ml. While such dosages are based on cumulative dosages of daily, weekly or monthly administration, they can also be used to calculate the clinical requirements. Dosages may vary based on the patient being treated, the condition treated, the severity of the condition treated, the route of administration, etc. to achieve the desired effect. The compounds of the present invention are also useful for lowering intraocular pressure. In this way, these compounds are useful in the treatment of glaucoma. The preferred route for administration for the treatment of glaucoma is topical.
Composition Examples and Method 15 The following non-limiting examples illustrate the present invention. The following examples of composition and methods do not limit the invention, but provide guidance to the person skilled in the art so that he can prepare and use the compounds, compositions and methods of the invention. In each case, other compounds within the invention can be replaced by the
composite of the example shown below with similar results. The trained physician will appreciate that the examples provide guidance and may vary based on the condition being treated and the patient.
EXAMPLE A
The pharmaceutical compositions in tablet form are prepared by conventional methods, such as mixing and direct compaction, formulated as follows:
Ingredient Amount (mq per tablet) Compound of example 20 5 Microcrystalline cellulose 100 Sodium starch glycolate 30 Magnesium stearate 3
When orally administered once a day the above composition substantially increases bone volume in patients suffering from osteoporosis.
EXAMPLE B
The pharmaceutical compositions in liquid form are prepared by conventional methods, formulated as follows:
'& amp; & ** m ^ **** ***. "_. ^ A ^. ^. ^ A > . ^^^ ».. ^. . .WftÍÉ.8É.rir ^^ Ingredient Quantity Compound of example 20 5 mg Phosphate physiological saline pH regulator 10 ml Methylparbeno 0.05 ml
When 1.0 ml of the above composition is administered subcutaneously once a day, the above composition substantially increases bone volume in a patient suffering from osteoporosis.
EXAMPLE C
Topical pharmaceutical compositions for decreasing intraocular pressure are prepared by conventional methods and are formulated as follows:
Inqredient Quantity (% by weight) Compound of the example of 42 0.004 Dextran 70 0.1 Hydroxypropylmethylcellulose 0.3 Sodium chloride 0.77 Potassium chloride 0.12 Disodium EDTA (disodium edetate) 0.05
Benzalkonium Chloride 0.01 HCl and / or NaOH pH 7.2-7.5 Purified water c.s to 100%
While the particular embodiments of the present invention have been described, it will be obvious to those skilled in the art that various changes and modifications can be made to the compositions described herein without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all modifications that are within the scope of this invention.
^^ g ^ Ü ^ ¡^ ¡ßl ^ a¿ ís ^ íié é ^ s ^? s ¿??? á jit ^^^^ t i? i? ? ^ Sea.m
Claims (9)
1. - A compound that has the structure: HO characterized in that a) RT is C02H, C (0) NHOH, C02R5, CH2OH, S (0) 2R5, C (0) NHR5, C (0) NHS (0) 2R5, or tretazole; characterized in that R5 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring, or heteroaromatic ring; b) R2 is H or a lower alkyl; c) X is NR6R7, 0R8, SRg, S (0) Rg, S (0) 2Rg, characterized in that R6, R7 and R8 are independently chosen from the group consisting of H, acyl, alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring or heteroaromatic ring; and characterized in that Rg is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring or heteroaromatic ring; d) R3 and R4 are independently selected from the group consisting of H, CH3 and C2H5; e) Y is NR10, S, S (O) or S (0) 2, characterized in that R10 is H, acyl, alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring or heteroaromatic ring; f) Z is a carbocyclic aliphatic ring, aliphatic ring
The heterocyclic ring, aromatic ring or heteroaromatic ring; and any isomer, diastereomer, optical enantiomer of the above structure, or a pharmaceutically acceptable salt, or a biohydrolysable amide, ester or me thereof thereof. 2. The compound according to claim 1, further characterized in that R1 is selected from the group consisting of C02H, C (0) NHOH, C02CH3, and C02C3H7.
3. The compound according to claim 2, further characterized in that R2 is H or CH3.
4. The compound according to claim 3, further characterized in that X is OH and Y is S or NH.
5. The compound according to claim 4, further characterized in that Z is thienyl or phenyl.
6. The compound according to any of the preceding claims further characterized in that Z is substituted, said substituents being independently chosen from the group consisting of halogen, alkyl, haloalkyl, cyano, nitro, alkoxy, phenyl and phenoxy.
7. The compound according to any of the preceding claims further characterized in that Z is substituted, said substituents being halogen or alkyl. • iffmftr-r- ^ fim rf MrttMftímti yj ^^ jj ^ g ^
8. The use of a compound as claimed in any of the preceding claims in the preparation of a medicament for treating a bone disorder in a human or other mammal.
9. The use of the compound as claimed in claim 8, wherein said bone disorder is osteoporosis. - A- tWiíinirtifpliiii? IMtt ^
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US60/058,217 | 1997-09-09 |
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MXPA00002430A true MXPA00002430A (en) | 2001-11-21 |
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