IL43589A - 16-phenoxy-15-hydroxy derivatives of 17,18,19,20-tetranorprostaglandins and their preparation - Google Patents
16-phenoxy-15-hydroxy derivatives of 17,18,19,20-tetranorprostaglandins and their preparationInfo
- Publication number
- IL43589A IL43589A IL43589A IL4358973A IL43589A IL 43589 A IL43589 A IL 43589A IL 43589 A IL43589 A IL 43589A IL 4358973 A IL4358973 A IL 4358973A IL 43589 A IL43589 A IL 43589A
- Authority
- IL
- Israel
- Prior art keywords
- compound
- double bond
- phenoxy
- phenyl
- cis
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 92
- -1 mono-substituted phenyl Chemical group 0.000 claims description 49
- 150000003180 prostaglandins Chemical class 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 239000002253 acid Substances 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 9
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 9
- 229930194542 Keto Natural products 0.000 claims description 8
- 125000001589 carboacyl group Chemical group 0.000 claims description 8
- 125000000468 ketone group Chemical group 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 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 claims description 3
- 125000003435 aroyl group Chemical group 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000012024 dehydrating agents Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 230000002862 amidating effect Effects 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 40
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 239000000203 mixture Substances 0.000 description 28
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 22
- 229940093499 ethyl acetate Drugs 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 229960000583 acetic acid Drugs 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 150000003857 carboxamides Chemical group 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 239000010779 crude oil Substances 0.000 description 8
- 229960002986 dinoprostone Drugs 0.000 description 8
- 238000010828 elution Methods 0.000 description 8
- 210000002460 smooth muscle Anatomy 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- 239000012535 impurity Substances 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 206010000210 abortion Diseases 0.000 description 6
- 231100000176 abortion Toxicity 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 150000002431 hydrogen Chemical group 0.000 description 6
- 230000006698 induction Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 230000001766 physiological effect Effects 0.000 description 5
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 5
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000003810 Jones reagent Substances 0.000 description 3
- 125000003047 N-acetyl group Chemical group 0.000 description 3
- 208000008469 Peptic Ulcer Diseases 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 230000035558 fertility Effects 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- POKRQUNDSGAZIA-OALUTQOASA-N 7-[(1r,2s)-2-octylcyclopentyl]hepta-2,4-dienoic acid Chemical compound CCCCCCCC[C@H]1CCC[C@@H]1CCC=CC=CC(O)=O POKRQUNDSGAZIA-OALUTQOASA-N 0.000 description 2
- 208000009079 Bronchial Spasm Diseases 0.000 description 2
- 101100310593 Candida albicans (strain SC5314 / ATCC MYA-2876) SOD4 gene Proteins 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- 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 2
- MYHXHCUNDDAEOZ-UHFFFAOYSA-N Prostaglandin A&2% Natural products CCCCCC(O)C=CC1C=CC(=O)C1CC=CCCCC(O)=O MYHXHCUNDDAEOZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 101100190148 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) PGA2 gene Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 239000004015 abortifacient agent Substances 0.000 description 2
- 231100000641 abortifacient agent Toxicity 0.000 description 2
- 230000001262 anti-secretory effect Effects 0.000 description 2
- 230000000767 anti-ulcer Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- YXVFYQXJAXKLAK-UHFFFAOYSA-N biphenyl-4-ol Chemical compound C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 229940124630 bronchodilator Drugs 0.000 description 2
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- SKCNIGRBPJIUBQ-UHFFFAOYSA-N chloroform;ethyl acetate Chemical compound ClC(Cl)Cl.CCOC(C)=O SKCNIGRBPJIUBQ-UHFFFAOYSA-N 0.000 description 2
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000027119 gastric acid secretion Effects 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000003529 luteolytic effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- LGRLWUINFJPLSH-UHFFFAOYSA-N methanide Chemical compound [CH3-] LGRLWUINFJPLSH-UHFFFAOYSA-N 0.000 description 2
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 230000027758 ovulation cycle Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000001850 reproductive effect Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- DPOINJQWXDTOSF-DODZYUBVSA-N 13,14-Dihydro PGE1 Chemical compound CCCCC[C@H](O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O DPOINJQWXDTOSF-DODZYUBVSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 239000005046 Chlorosilane Substances 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 240000005578 Rivina humilis Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003509 anti-fertility effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000002965 anti-thrombogenic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- LURYMYITPCOQAU-UHFFFAOYSA-N benzoyl isocyanate Chemical compound O=C=NC(=O)C1=CC=CC=C1 LURYMYITPCOQAU-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- YCXVDEMHEKQQCI-UHFFFAOYSA-N chloro-dimethyl-propan-2-ylsilane Chemical compound CC(C)[Si](C)(C)Cl YCXVDEMHEKQQCI-UHFFFAOYSA-N 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 210000004211 gastric acid Anatomy 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
- 150000002373 hemiacetals Chemical class 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004460 liquid liquid chromatography Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- WPHGSKGZRAQSGP-UHFFFAOYSA-N methylenecyclohexane Natural products C1CCCC2CC21 WPHGSKGZRAQSGP-UHFFFAOYSA-N 0.000 description 1
- OUPLTJDZPQZRBW-UHFFFAOYSA-N n-(oxomethylidene)methanesulfonamide Chemical compound CS(=O)(=O)N=C=O OUPLTJDZPQZRBW-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- HVFSJXUIRWUHRG-UHFFFAOYSA-N oic acid Natural products C1CC2C3CC=C4CC(OC5C(C(O)C(O)C(CO)O5)O)CC(O)C4(C)C3CCC2(C)C1C(C)C(O)CC(C)=C(C)C(=O)OC1OC(COC(C)=O)C(O)C(O)C1OC(C(C1O)O)OC(COC(C)=O)C1OC1OC(CO)C(O)C(O)C1O HVFSJXUIRWUHRG-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- MYHXHCUNDDAEOZ-FOSBLDSVSA-N prostaglandin A2 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1C=CC(=O)[C@@H]1C\C=C/CCCC(O)=O MYHXHCUNDDAEOZ-FOSBLDSVSA-N 0.000 description 1
- 150000003155 prostaglandin A2 derivatives Chemical class 0.000 description 1
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical compound CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 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
- 239000007858 starting material Substances 0.000 description 1
- 239000002731 stomach secretion inhibitor Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- GJVUAUBGMGCLEB-UHFFFAOYSA-M triphenyl-[4-(2h-tetrazol-5-yl)butyl]phosphanium;bromide Chemical compound [Br-].N=1N=NNC=1CCCC[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 GJVUAUBGMGCLEB-UHFFFAOYSA-M 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 230000035884 vasodepression Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5407—Acyclic saturated phosphonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Furan Compounds (AREA)
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
,17 »opi m»n-15-»opiK3B-16 nnVm Bnaani o'l i iBo sniimBB^O ,19 16-Phenoxy-15-hydroxy derivatives of 17» 1! 19» 20-tetranorprostaglandins and their preparation PFIZER INC. 0. 41693 P.C. 5445/5445A This invention relates to certain novel analogs of the naturally occurring prostaglandins and to various novel intermediates useful in their preparation. In particular it relates to novel &J-pentanorprostaglandins .
The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. For instance, the prostaglandins of the E and A series are potent vasodilators (Bergstrom, et al. , Acta Physiol. Scand. 64:332-33, 1965 and Bergstrom, et al. > Life Sci. 6:449-455, 19671? and lower systemic arterial blood pressure (vasodepression) on intravenous administra tion (Weeks and King, Federation Proc . 23:327, 1964; Bergstrom, et al. , 1965, op. cit. ; Carlson, et al. , Acta Med. Scand. 183:423-1968; and Carlson, et al. , Acta Physiol. Scand. 75:161-169, 1969) . Another well known physiological action for PGE^ and PGE2 is as a bronchodilator (Cuthbert, Brit. Med. J. 4:723-726, 1969).
Still another important physiological role for the natural prostaglandins is in connection with the reproductive cycle GE2 is known to possess the ability to induce labor (Karim, et al. , J. Obstet Gynaec. Brit. Cwlth. 77:200-210, 1970) , induce therapeutic abortion (Bygdeman, et al. , Contraception , _4, 293, 1971) and to be useful for control of fertility (Karim, Contraception , 3, 173 (1971)). Patents have been obtained for several prostaglandins of the E and F series as inducers of labor in mammals (Belgian Patent 754,158 and West German Patent 2,034,641), and on PGF^, F2 and F3 for control of the reproductive cycle (South Africa Patent 69/6089).
Still other known physiological activities for PGE^ are in the inhibition of gastric acid secretion (Shaw and Ramwell, In: Worcester Symp. on Prostaglandins , New York, Wiley, It Is now known that such physiological effects will be produced in vivo for only a short period, following the administration of a prostaglandin. A substantial body of evidence indicates that the reason for this rapid cessation of activity is that the natural prostaglandins are quickly and efficiently metabolically deactivated by β-oxidation of the carboxylic acid side-chain and t!y oxidation cf the l¾,\-hydroxyl group (Anggard, et al., Acta.
Physiol. Scand. , 8l, 396 (1971) and references cited therein). * It was, of course, considered desirable to create analogs of the prostaglandins which would have physiological activities equivalent to the natural compounds, but in which the selectivity of action and the duration of the activity would be increased.
Increased selectivity of action would be expected to alleviate the' severe side effects, particularly gastrointestinal side effects, frequently observed following systemic administration of the natural prostaglandins (see Lancet, 536, 1971).' According to the invention there is provided a compound of the formula: wherein Ar is phenyl, or mono-substituted phenyl wherein said. substituent is halo, trifluoromethyl , phenyl, lower alkoxy or lower alkyl;- is a single bond or ci_s double bond; Z is a single bond or trans double bond; M is keto, N and L when taken together form a single" bond, or N is c<.-0R3 when L is hydrogen;.
R3 is hydrogen or 2-tetrahydropyran 1; X is p_-phenylphenoxycarbonyl ; . tetrazolyl; ' -C-OR' wherein R' is hydrogen, alkyl of from 1-10 carbon atoms , cycloalkyl, aralkyl of from 7-9 carbon atoms, phenyl or mono- (lower alkyl ) henyl ; or 0 -CNHR" wherein R" is alkanoyl having from 2-10 carbon atoms, aroyl, arylsul dnyl , a Ikylsulfonyl of from .1 to 7 carbon atoms and wherein L, M and N are so selected as to complete the structure of a prostaglandin of the A, E or F series, the lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups at the C9- , C]_]_- and C ^~ positions, and the pharmaceutically acceptable salts of the compounds wherein X is COOH.
The compound of formula I above may be prepared by a a) when N Is -hydroxy1 and L is hydrogen, and Ar, n, m, M, W, X and Z are as defined above, said compound is prepared by treating the 11- and 15-tetrahydropyranyl ethers of a compound of Formula I above, with a suitable acid; b) when N and L, when taken together form a single bond, M is keto and Ar, n, m, R, W, X and Z are as defined above, said compound is prepared by reacting a compound of Formula I, above, wherein N is" -hydroxy and L is hydrogen, M is keto and Ar, n, m, R, W, X and Z are as defined above, with a suitable dehydrating agent; c) when and Ar, n, R, W and Z are as defined above, said compound is prepared by reacting a compound of the Formula I, above, wherein N is^-hydroxy and L is hydrogen, M is keto, Ar, n, m, R, W, X and Z are as defined above, with a suitable reducing agent, and if desired, separating the 9;- and 9?-isomers; d) when N is < -hydroxy , L is hydrogen, Ar , R, n, m, M and X are as defined above, and W and Z are single bonds, said compound is prepared by catalytic reduction of a compound of Formula I, above, wherein Ar, R, n, m, M and X are as defined above, W is a single bond or cis double bond when Z is a trans double bond and Z is a single bond when W is a cis double bond; e) when N is -hydroxy , L is hydrogen, Ar, R, n, m, X and double bond, said compound is prepared by selective reduction of a compound of Formula I, or the trialkylsilyl ester of a compound of Formula I, wherein X is COOH, above, wherein Ar, R, n, m, X and M are as defined above and W and Z are double bonds, and when required, converting those compounds of Formula I wherein X is COOR' wherein R' is hydrogen to their esters and substituted amides, as defined above, by reaction with suitable ester^ ifying and a idating reagents, respectively. and, if desired, preparing the 9Λ-, l - and I A- lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups by reacting said compounds with the appropriate acylating agents and, if desired, preparing the pharmaceutically acceptable salts of these compounds wherein X is COOH.
Within the ambit of the invention is a process for preparing a compound of the structure: OH and the epimer thereof; wherein Ar, Z, W and X are as defined above and THP is 2-tetrahydropyranyl ; characterized by reacting a compound of Formula II: wherein Ar and Z are as defined above with an ylide of the formula: (CgH5) 3P=CH-CH2-CH2-CH2-X wherein X is as defined above with the proviso that when X = CC^R' the compound of Formula II is first reacted with an ylide of the Formula (CgH5) 3-P=CH-CH2CH2CH2C02H and the resulting product esterified if desired, to afford a compound of Formula IIA wherein Ar, X and Z are as defined above and is a cis double bond, and, when required, subsequently reducing the compound thus formed to afford a compound of Formula IIA wherein Ar, X and Z are as defined above and W is a single bond; by reducing a compound of Formula IIA above, wherein Ar and X are as defined above, W is a cis double bond, and Z is a trans double bond to form a compound of Formula IIA above wherein Ar and X are as defined above and W and Z are single bonds; by selectively reducing a compound of Formula IIA above, wherein Ar and X are as defined above, W is a cis double bond and Z is a trans double bond, to form a compound of Formula IIA wherein Ar and X are as defined above, W is a single bond and Z is a trans double bond.
Further, an aspect of the invention is concerned with a process for preparing a compound of the structure: ...IIB wherein Ar, THP, Z, W and X are as defined above; characterized by reacting a compound of Formula OH wherein Ar, THP, X, W and Z are as defined above with chromic acid in aqueous sulfuric acid and acetone.
In general, the present invention comprises a compound of the structure: and its epimer; wherein Ar, Z, L, N, M, W and X are as defined above.
More specifically, the present invention comprises compounds of the Formulas OH and its Cg and epimers, IB and its (^5 epimer and its epimer, wherein Ar, X, Y and Z are as defined above.
Additionally, the present invention comprises pound of the formula: and the Cg and epimers thereof; wherein Ar, THP, Z, and X are . as defined above; and a compound of the formula and the C15 epimer thereof; wherein Ar, THP, Z, and X are as defined above.
Preferred compounds are those of Formula I wherein ^OH M is ¾ ; L is a single bond, and N is ot-hydroxyl , and its C]_5 epimer; wherein Ar is phenyl and said prostaglandin is PGE2 wherein Ar is phenyl and said prostaglandin is PGF2C*- ; wherein J phenyl and said prostaglandin is PGA2.
Additional preferred compounds are those of Formula I wherein M is ~^-0H, X is tetrazolyl, W is a cis double bond, Z is a trans double bond and Ar is phenyl; wherein X is 0 -C-NHR" wherein R" is methylsulfonyl , W is a cis double bond, Z is a trans double bond and Ar is phenyl; and wherein X is 0 -C-NHR" wherein R" is methylsulfonyl , is a cis double bond, Z is a trans double bond and Ar is m-methoxyphenyl .
Further preferred compounds are those of Formula I 0 wherein M is oxo and; wherein X is -C-NHR" wherein R" is acetyl, W is a cis double bond, Z is a trans double bond, Ar is phenyl; 0 wherein X is -C-NHR" wherein R" is acetyl, W is a cis double bond, Z is a trans double bond, and Ar is m-methoxyphenyl; wherein X is tetrazolyl, W is a cis double bond, Z is a trans double bond, O and wherein X is -C-NHR" wherein R" is methylsulfonyl , W is a cis double bond, Z is a trans double bond, and Ar is phenyl.
More specifically, preferred compounds are 16-Phenoxy PGE2 p-biphenylyl ester, 16-Phenoxy PGF2i- p_-biphenylyl ester, and 16-Phenoxy PGF2 r p_-biphenylyl ester.
Also preferred are the Cg epimers of the compounds of Formula IIA.
Other preferred prostaglandins are as follows: A compound of Formula I wherein Ar is phenyl and said prostaglandin is PGE2.
A compound of Formula I wherein Ar is phenyl, and said prostaglandin is PGFj^C A compound of Formula I wherein Ar is phenyl and said prostaglandin is PGF2^.
Especially preferred prostaglandins are the following: A compound according to Formula IA wherein X is CONHOCCH3, is a cis double bond, Z is a trans double bond and Ar is phenyl.
A compound according to Formula IA wherein X is tet-razolyl, W is a cis double bond, Z is a trans double bond and Ar is phenyl.
A compound according to Formula IA wherein X is CONHSO2CH3, W is a cis double bond, Z is a trans double bond and Ar is phenyl.
A compound according to Formula IA wherein X is CO HSO2CH3, W is a cis double bond, Z is a trans double bond, and Ar is m-methoxyphenyl.
A compound according to Formula IB wherein X is CONHCOCH3, W is a cis double bond, Z is a trans double bond, and Ar is phenyl.
A compound according to Formula IB wherein X is CONHCOCH3 wherein W is a cis double bond, Z is a trans double bond and Ar is m-methoxyphenyl.
A compound according to Formula IB wherein X is tetrazolyl, W is a cis double bond, Z is a trans double bond and Ar is phenyl.
A compound according to Formula IB wherein X is CO HSO2CH3, is a cis double bond, Z is a trans double bond and Ar is phenyl.
Novel intermediates of the formulae below are also a feature of this invention. arid the Cg and (^5 epimers thereof; wherein Ar, Z, W and X are as defined above and THP is 2-tetrahydropyranyl.
As shown in scheme A 8.—¾>9, is a Wittig condensation in which hemiacetal 8 is reacted with (4-carbohydroxy-n-butyl ) triphenylphosphoniuin bromide in dimethyl sulfoxide, in the presence of sodium methylsulfinyl methide. 9_ is purified by column chromatography.
The conversion 9 -^12 ^s an acidic hydrolysis of the tetrahydropyranyl groups. Any acid may be used which does not cause destruction of the molecule in the course of the removal of the protecting group; however, this is accomplished most often by use of 65% aqueous acetic acid. The product is purified as above. _9 —^IOI is an oxidation of the secondary alcohol 9_ to the ketone l). This may be accomplished using any oxidizing agent which does not attack double bonds; however, the Jones reagent is usually preferred. The product is purified as above.
— — The product is purified as above. 11'—^ 15 is an acid-catalyzed dehydration. Any acid may fee used for the process which does not cause extensive decomposition of the product, but the most usual procedure consists of dissolving 11 in an excess of 97% formic acid followed by dilution with ice water and extraction of the product after the starting material has been consumed. The product is purified as above.
As is illustrated in scheme B, _5 may be substituted for in scheme A to provide prostaglandin derivatives II1, 12' and 15' Scheme C, illustrates the preparation of the various reduced prostaglandin precursors: 1 —^22 is carried out as illustrated on scheme A for —^ . 22^ can be used as both a precursor to a 13 , 14-dihydro-IS-subs ituted-lj -pentanorprostaglandin of the "2-series" or as an intermediate to _23, a precursor to a 13 , 14-dihydro-15-substituted-'U -pentanorprostaglandin of the "1-series". 22—- 23 is carried out by catalytic hydrogenation. Intermediates of the type 21 are prepared by selective reduction of the 5, 6-cis double bond at low temperature. Especially preferred for this reduction is the use of palladium on carbon as a catalyst and a reaction temperature of-20°. Intermediates of the type 21. are not only precursors to 15-substituted- '.' -pentanorprostaglandins of the "l-series" through the route 9_ —~15 of scheme A, but also as a precursor to compounds of the type _23 through the route already discussed for 22 —>>23.
Scheme A Scheme C Furthermore, the 15-substituted-(xJ-pentanorprostaglandins of the F-L and FjcX, series may be obtained directly from the corresponding prostaglandin analog of the "2-series" by first protecting the hydroxyl by introducing dimethyl isopropyl silyl groups, reducing selectively the cis double bond, and removing the protecting group.
The introduction of the protecting group is usually accomplished by treatment of the prostaglandin analog with dimethyl isopropyl chlorosilane and triethylamine, the reduction is accomplished as discussed above for 9^ —721 and removal of the protecting group is accomplished by contacting the reduced protected compound with 3:1 acetic acid:water .for 10 minutes or until reaction is substantially complete.
The C]_5 epimers of _21, 22 and 2_3 can be used as precursors to the 15-epi series of prostaglandin derivatives described above.
In the foregoing procedures, where purification by chromatography is desired, appropriate chromatographic supports include neutral alumina and silica gel and 6O-200 mesh silica gel is generally preferred. The chromatography is suitably conducted in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane and n-hexane, as further illustrated in the appended examples .
It' will be se.en that the foregoing formulae depict' optically active compounds. It will be clear, however, that jj the corresponding racemates will exhibit valuable biological activity by virtue, of their content of the above-mentioned biologically active optical isomer, and it is intended that such racemates also be embraced by "the foregoing formulae herein and in the appended claims. The racemic mixtures are readily jj prepared by the same methods employed herein to synthesize the optically 'active species, by mere substitution of correspond! racemic precursors in place of optically active starting materialsj.
In numerous in vivo and in vitro tests we have demonstrated that the new prostaglandin analogs possess physio-j| logical activities comparable to those exhibited by the natural prostaglandins. These tests include, among others, a test for effect on isolated smooth muscle from guinea pig uterus, guinea pig ileum and rat uterus, inhibition of histamine-induced bronchospasm in the. guinea pig, and effect on dog blood pressure, j| inhibition of stress-induced ulceration in the rat, inhibition jo gastric acid and pepsin secretion in rat and dog, inhibitic of collagen or ADP-induced blood platelet aggregation and abortifacient activity in rats and guinea pigs by luteolytic and The physiological responses observed in these tests are useful in determining the utility of the test substance for the treatment of various natural and pathological conditions. Such determined utilities include: antihypertensive activity, bronchodilator activity, antithrombogenic activity, antiulcer activity, smooth muscle activity useful as an anti-fertility agent, for the induction of labor, and as an abortifacient7, and anti-fertility activity through a mechanism not affecting smooth muscle, for example, luteolytic mechanisms, and the synchronization of the estrous cycle in farm animals.
The novel compounds of this invention possess more selective activity profiles than the corresponding naturally occurring prostaglandins, and in many cases, exhibit a longer duration of action. For example, l6-phenoxy-(*'-tetranor-prostaglandin E^ which exhibits smooth muscle stimulating activity comparable to PGEg, is inactive in inhibition of histamine-induced bronchospasms in guinea pigs. Furthermore, although the threshold dose of hypotensive response of lS-phenoxy-'-tetranor PGE2 in dogs is higher than that of PGE2, the duration of action is markedly prolonged relative to PGE2. The 15-substituted-t*-'-pentanor-prostaglandins of the PGE0, PGF2£ exhibit similar smooth muscle stimulant activity, whereas the corresponding derivatives of the AQ, A^, A2 and 13, I -dihydro PGA2 series have gastric antisecretory/antiulcer activity.
Particularly useful for fertility control, abortion and Induction of labor are the Ιβ-phenoxy -tetranorprostaglandins of the and Fg^ series based on especially outstanding smooth muscle stimulating activity, and at the same time reduced blood pressure effects. Similarly, the substituted ^/-pentanor-prostaglandins of the PGE-j_, PGF0a, PGFla> Άηά 13, l -dihydro P F2a series are useful for fertility control including abortion and induction of labor on the basis of their smooth muscle stimulant activity. The novel 15-substituted w/-pentanorprostaglandin-13, 14-dihydro-E analogs can be employed in the treatment of peptic ulcers. The novel prostaglandins with a β-ΟΗ at the 15-position are in general less potent, although frequently more selective than the corresponding α-hydroxyl epimers. Additionally, the prostaglandins having a β-hydroxyl at C-15 are valuable intermediat to prostaglandins having a a-hydroxyl at C-15 through a j recycling process involving an oxidation and reduction at C-15. 43589/3 The new compounds of this invention can be used in a variety of pharmaceutical formulations which contain the compound, and they may be administered in the same manner as natural prostaglandins by a variety of routes, such as intra-venous, oral, intravaginal , intra- and extra-araniotic , among others .
I For induction of abortion, tablets or an aqueous ; suspension or alcoholic solution of 16-phenoxy-uAtetranor-: prostaglandin would appropriately be administered at oral doses of about 0.1-20 mg., with 1-7 doses per day being employed.
For intravaginal administration a suitable formulation would be lactose tablets or an impregnated tampon of the same agent. For such treatments suitable doses would be from about 0.1-20 mg/dose with 1-7 doses being employed. For intra-amniotic administration a : suitable formulation would be an aqueous solution containing 0.05-10 mg/dose with 1-7 doses being employed. For extra-; amniotic administration a suitable formulation would be an I aqueous solution containing 0.005-1 mg/dose with 1-5 doses being employed. ,· Alternatively, the l6-phenoxy-/-tetranor- prostaglandins of this invention can be infused intravenously for induction of abortion at doses of 0.05-50 μg/ in te for ' period I of from about 1-24 hours. For synchronization of the estrous cycle i 'in pigs, sheep, cows or horses, a solution or suspension .containing 0.03-30 mg/day of Ιβ-phenoxy- -tetranorprostaglandin is ■administered subcutaneously from 1-4 days. « 15-substituted-tii.pentanorprostaglandins of the A series 'are useful gastric antisecretory and antiulcer agents, as are the 15-substituted- -pentanorprostaglandins of the E series. For treatment of peptic ulcers these compounds are administered preferably orally in the form of capsules or tablets at doses cf 0.001 to 0.1 mg/kg/day.
To prepare any of the above dosage forms or any of the numerous other forms possible, various reaction-inert diluents, excipients or carriers may be employed. Such substances include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly, cholesterol, and other. known carriers for medicaments. If desired, these pharmaceutical compositions may contain auxiliary substances such as preserving agents, wetting agents, stabilizing agents, or other therapeutic agents such as antibiotics.
Various modifications are possible on the upper side chain of the prostaglandins of this invention; such modifications do not, as a rule, alter the basic biological activity of the prostaglandin, although they may increase selectivity and duration of action further and reduce toxicity. For example, a tetrazoyl moiety may be placed at the C-^ position as described in Israel a lication Number 40183 filed August 22, 1972 and in the appended ^xamples . For example, 16-phenoxy-PGE2~tetrazoyl has the same utility as 16-phenoxy PGE2 esters; namely, for induction of labor or abortion, and for the inhibition of gastric acid secretion and treatment of peptic ulcers.
Another upper side chain modification which may be made in the prostaglandins of this invention is substitution of the carboxylate moiety at the position by a carboxamide moiety. The method for preparing these compounds are disclosed in Israel Specification Number 4 2385 filed May 29 , 19 73 and in the appended examples. Alternatively, the novel compounds of this invention representee by structures IA and IB (where X 0 is CNHR" and wherein . R" is as defined previously), can be prepared from compound 9 of scheme A (or the corresponding 15-epimers of 9 ) by reaction with appropriate isocyanates, followed by hydrolysis with dilute acid. The utility of N-methylsulfonyl- 16-phenoxy PGE carboxamide, for example, is the same as that of 16-phenoxy ^G^ 2 es ters - One particularly beneficial ester is the p_-biphenyly 1 ester. Such esters are prepared in the appended examples by simply adding p_-phenylphenol to the prostaglandin analogue in methylene chloride in the presence of a dehydrating agent, for example, dicyclohexylcarbodiimide, and stirring overnight. Although not more potent in in vitro smooth muscle tests,- abortifacient evaluation of 16-phenoxy- i-tetranor PGE2 and p-biphenylyl esters demonstrated that these p-biphenylyl esters possess physiological activities markedly greater than those of the free acids.
The following examples are merely illustrative, and in no way limit the scope of the appended claims. In these examples it will be appreciated that all temperatures are expressed in Centigrade, all melting and boiling points are uncorrected. 9-0xo-ll^, 15 - is- (tetrahydropyran-2-yloxy) -l6-phenoxy-cis-5 trans-13-ω-tetranor-prostadienoic acid: To a solution cooled to -10° under nitrogen of 7 ^ (1.3 mmole) 9<-hydroxy-ll^-, 154,-bis- (tetrahydropyran-2-yloxy)-l6-phenoxy-cis-5-trans-13-k-tetranor-prostadienoic * acid in 13 ml reagent grade acetone was added drcpwise to Ο.56 nil (l ll mmole) of Jones' reagent. After 20 minutes at -10°, 0.2β0 ml. 2-propanol as added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 75 ml ethyl acetate, washed with water (3 x 10 ml.), dried (MgSO^) and concentrated to give 75 mg. of S-oxo-lldj 15^-bis-(tetrahydropyran~2--yloxy-l6-phenoxy-cis-5-trar.s-13-^1-tetranor-prostadienoic acid, which was chromatographed on silica gel using ethyl acetate as eluent to afford 50 rag. of pure 10. 9-0xo-ll , 15^-dihydroxy-l6-phenoxy-cis-5-trans-13^^etranor prostadienoic acid; , A solution of 505 (0.9 mmole) 9-oxo-ll^, 15<*- bis-(betrahydropyran-2-yloxy)-l6-phenoxy-cis-5"trans~13~^-tetranor-prostadienoic acid in 6.3 ml. of a 65:35 mixture of glacial acetic acidrwater was stirred under nitrogen at 25° for l8 hours then was concentrated by rotary evaporation. The resultant crude oil was purified "by column chromatography on silica gel (Mallinckrodt CC-4 100-200 mesh) using ethyl acetate as eluent.-After elution of less" polar impurities the oily -oxo-ll^, 15^-dihydroxy-l6--phenoxy-cis-5-trans-13-fe'-tetranor-prostadier-oic acid weighing 210 mg. was collected. -1 Ir (CHCI3J displayed a broad band at 1725 cm for carbonyl absorptions, and a band at 70 cm" for the 13, 14-trans-double bond. 9it,ll<2>, 15-d-trihydroxy-l6-phenoxy-cis-5-trans 13- --tetranor-prostadienoic ac,ld: A mixture of 375 mg (0.65 mmole) 9-i-hydroxy-ll^, 1 ^-bis~(tetrahydropyran-2-yloxy)-l6-phenoxy-ci-s-5-trans-13-'>'-tetranor-prostadienoic acid, acetic acid (6.5 ml) and water (3.5 ml) was stirred under nitrogen at room temperature for 20 hours. The resulting clear solution was concentrated under reduced pressure and the residue (380 ng) was dissolved in ethyl acetate. The ethyl acetate solution was washed with brine (20 ml), dried (NaSOZj.) and concentrated to a clear oil. Chromatography on- silica gel (Mallinckrodt CC-7) using chloroform and then ethyl acetate as eluent afforded the desired product, ll^ 15^-trihydroxy-l6-phenoxy~cjLs--5-trans--13-«{-tetranor-prostadienoic acid as a colorless oil weighing 8 mg.
EXAMPLE V 9^-Hydroxy-ll# (tetrahydropyran-2-yloxy) -16-phenoxy - - .tetranor-prostrinolc acid; A mixture of 1 0 mg (0.33 mmole) 9^-hydroxy-ll^, 15^-ols-(tetra ydropyran-2-yloxy)-l6-phenoxy-cis-5-tra-s--13-'^-tetranor-prostadienoic acid, 5 palladium on carbon (150 mg)in methanol (10 ml) is stirred under an atmosphere of hydrogen for 60 hours at room temperature. The mixture is filtered and concentrated to give i^-hy ro y-ll^ 154- "bis- ( etrahydropyran-2-yloxy) -I6-phenoxy-£A-tetranor-prostanoic acid. 9*1,11 , 15^-Trihydroxy-l6-phenoxy^-tetranor-prostanoi'c acid: Hydrolysis of 20 mg ^-hydro y-lid., lyi.-bis- (tetrahydro-pyran-2-yloxy)-l6-phenoxy-A-tetranor-prostanoic acid is carried out with acetic acid (0.5 nl) and water (0.3 ml) under nitrogen at room temperature for 20 hours. Purification as described' n Example iv affords pure ei» ll^, 152.-trihydroxy-10-phenoxy- -te ranor prostanoic acid. 9-Oxo-l-W, 15<4-dihydroxy-l6-phenoxy-
Isolation of the product and hydrolysis with acetic acid and water at room temperature as described in Example III gives pure 9-oxo-ll<2, 15^-dihydroxy-l6-phenoxy-&A-tetranor-prostanoic acid. - · ^ 9~Oxo-1¾ > -iydroxyl6 phenoxy-cis-5, 10. trans-13-fe/~tetranor-prostatrienoic ■ acid ; A mixture of 52 mg (0.1 mmole) 9-oxo-ll^, l^-dihydroxy^ l6-phenoxy cI ^"trans-13-&/-tetranor-prostadicnoic acid with 0,2 ml 7?S formic acid is stirred at 25° for 2.5 hours. About 5 m iee«-water is added to the reaction mixture which is then extracted with ethyl acetate, dried ( a2S0i) and concentrated to give a crude oil. Chromatography of the crude product ©n silica gel (Mallinckrodt CC-7) using methylene chloride-§thyl acetate as eluent gives the desired 9-oxo-15^-hydroxy- 10, rans-13-V-tetrancr-prostatrienoic acid.
EXAMPLE IX 9-Oxo-15^-hydroxy-l6-phGncxy-tct-te ranor-prost-10--eroic acid ; 9-oxo-ll^ 15^dihydroxy-l6-phenoxy-^-tetranor~pro£tanoic acid is treated with 7 formic acid as described in Example VIII and converted to colorless oily 9-oxo~15^-hydroxy-l6-phenoxy-W-tetranor-prost-10-enoic acid.
EXAMPLE 9l4-Hyd oxy-lLf , 15^- is- (tetrahydropyran-2-yloxy) -16-phenoxy-13-trans-/^-tetranorprostenoic acid: A heterogeneous mixture" of 800 mg of 9^-hydroxy-ll^, l^-bis- (tetraaydropyran-2-yloxy)-l6-phenoxy- is-5-trans-13-^-tetranor-prostadienoic acid and 80 mg of 5^ palladium on charcoal in 10 ml of absolute methanol is stirred under 1 atmosphere of hydrogen at -22° for 5 hours. The mixture is then filtered and the filtrate is concentrated to afford ^-hydroxy-ll^, l^-bis-(tetrahyGropyran-2-yioxy)-l6-phenoxy-13-trans-¾.'-tetranorprostenoic acid.
Hydrolysis with acetic acid and- water in the usual manner affords 16-phenoxy PGF^. acid: — , / A .'solution of 72 mg 9-oxo-lldf 154-dihydroxy-l6-phenoxy-cis-5-trans-13-'¾-tetranor-prostadienoic acid in 5 ml of anhydrous ether is treated with 450 rag dime hylisopropyl chlorosilane and 36 m of triethylamine at room temperature under nitgoren for 8 hours. The reaction mixture is cooled to 0°, methanol is added, and the resulting solution is washed with water, dried and is concentrated. The residue is dissolved in methanol (6 ml) and 30 mg of 5^ palladium on charcoal is added. The- resulting mixture is stirred at -22° under 1 atmosphere of hydrogen for - hours. After filtration and concentration of the filtrate, the residue is stirred with a 65:35 mixture cff acetic acid:water for 10 minutes at room temperature. The mixture is diluted with water, extracted with ethyl acetate, dried ( a'gSO^) and concentrated to afford, after purification by silica gel chromatography, 9-oxo-ll
EXAMPLE XIII £-Biphenylyl 9-οχο-13£{,, 15A-dihydroxy-16-phenoxy-cis-5-trans-13-(,^-tetranor-prostadienoate : To a solution of 50 mg (0.13 mmole) of 9-oxo-ll°< , 15 - dihydroxy-16-phenoxy-cis- S-trans-lS-^ tetranor-prostadienoic acid and 63 mg (0.4 mmole) of p_-phenylphenol in 10 ml of dry methylene chloride was added 825 mg (0.4 mmole) of dicyclohexylcarbodiimide and the solution stirred overnight at room temperature. After concentration, the crude product was purified by silica gel chromatography to give the desired p-biphenylyl ester, m.p. 100- 102°.
Anal. ; Calc'd for C36H3606: C, 75.53; H, 6.71 Found: C, 75.65; H, 6.83.
EXAMPLE XIV p_-Biphenylyl lls^-, 15>A-trihydroxy-16-phenoxy-cis-5-trans-13-tjj-tetranor-prostadienoate: To a solution of 106 mg of 9A, 11 ~ , 15 ·: -trihydroxy-16- phenoxy-cis-5-trans-13-t'J-tetranor-prostadienoic acid and 189 mg of £-phenylphenol in 30 ml dry methylene chloride was added 600 mg of dicyclohexylcarbodiimide and the solution stirred overnight at room temperature. After concentration, the crude product was purified by silica gel chromatography to give 80 mg pure p_- biphenylyl ester, m.p. 101-103°.
Anal . : Calc'd for C34H3806: C, 75.25; H, 7.06 Found: C, 75.38; H, 7.30. 9ft, 11α, 15a-Trihydroxy-l6-phenoxy~cis-5-tran3-13- -tctranor-prostadier.oic acid tris-hydroxymethylamino methane salt: To a solution of 0.70 mmole of 9/3, li*-, 15^-trihydroxy-l6-phenoxy-cis-5-trans-13 acid in 35 nil of dry acetonitrile, heated at 80° is added a solution of So rag (0.68 mmole) of t is-hydroxymethylaminomethane in 0.15 ml of \-istzer with vigorous stirring. The mixture is allowed to cool to room . . temperature and 9 3 lla, 1 a -trihydroxy-l6-phenoxy-cis-5-trans-13-t--tetranor-prostadienoic. acid tris-hydroxymethylamino methane salt -is collected.
~^ EXAMPLE- XVIII 9-Oxo-l!l , 1 ^ -"bisformyloxy-l6-phenoxy- is--5-^rar.s-13-L^-tetranor~ prostadienoic acid To a solution of 0.1 mmole ! 9-oxo-13cc , Ιζα -dihydroxy- t l6-phenoxy-cis-5-trans-13- ,-tetranor-prostadienoic acid in 0.5 ml of dry tetrahydrofuran is added 29 "nig (0.33 mmole) of formic aceti anhydride and 35 mg (0.33 mmole) of 2, 6-lutidine. The solution is stirred for 1 hour under nitrogen at room temperature then 36 mg of water is added. The mixture is stirred at room temperature for additional one hour and diluted with ethyl acetate. The diluted solution is washed with 0.1N KC1, water and brine, then dried (Na2S0^) . Chromatography of the crude product on silica gel affords the desired bis ormyloxy compound.
EXAMPLE XIX β, 11α, 15a-Trlspivaloyloxy-l6-phenoxy-cis-5-trans--13-^-tetranor--pros adienoic acid " To a solution of 0.2 mmole of $β, 11a, 15a-trihydroxy~l6-phenoxy-cis-5-trans-13-'J-tetranor-prostadienoic acid in 1 ml of pyridine is added 120 nig (1.0 cimole) of pivaloyl chloride. The solution is stirred 4 hours at 45° under nitrogen then is cooled 'tci room temperature. Water (40 mg) is added and the mixture stirred 2 hours at room temperature and diluted with ethylacetate. The diluted solution is washed with dilute HC1, water and then brine. Concentration and purification "by chromatography on silica gel gave the desired trispivaloyloxy acid. i ... ;j ; :j · EXAMPLE _ XX ■■' l-(Tetrazol-5-yl)-9a-hydroxy-lla, 15a-bis- (tetrahydropyran-2-yloxy) -■ 3.6-phenoxy-cis-5-trans-13->-tetranorprostadiene To a solution of 4- (tetrazol-5-yl)butyltriphenyl phosphonium bromide (1.49 g.) in a dry nitrogen atmosphere in 6.0 ml. dry DMSO was added 3.24 ml. of a 2.0M solution of sodium . methylsulf nylmethide in DMSO. To this solution was added dropwise a solution of 615 mg. 2-^5a-hydroxy-3 - (tetrahydropyran-2- yloxy) -2jS- (3a- (tetrahydropyran-2-yloxy) - -phenoxy-trans-l- buten-l-yl)cyclopent-la-yl7ace dehyde, γ-hemiacetal in 5.0 ml, dry DMSO over a period of 20 minutes. After an additional 2 hour stirring at room temperature, the reaction mixture was poured onto ice water. 'The basic aqueous solution was acidified with 0.1K HCl and extracted with ethyl acetate. The residue obtained after evaporation of the solvent was chromatographed to give 680 mg. pure colorless oily 1- (tetrazol-5-yl)-9a-hydroxy-lla, 15a- ¾is-(tetraliydropyran-2-yloxy)-l6-phenoxy-cis-5-trans-13- r,-tetranor- prostadiene.
EXAMPLE XXI l~(Tetrazol-5-yl ) -9 , Hot, 15o.-trihydroxy-l6-phenoxy-cis-5-tr ns-- 13-UA-tetranor-r>rostadiene A solution of 300 mg. 1- (tetrazol-5-yl)-9ct-hydroxy- 11a, 15a-bis (tetrahydropyran-2-yloxy)-l6-phenoxy-cis-5-trans-13- /-tetranor-prostadiene in 6 ml. of 65:35 mixture of glacial 'acetic acid:water was stirred under nitrogen at 25° for 18 hours and then was concentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7, 100-200 mesh) using mixtures of chloroform: ethyl acetate as eluant. After elution of less polar impurities the colorless, oily 1- (tetrazol-5-yl)-9°t, 11a, 15a-trihydroxy-l6- phenoxy-cis- -trans-lS-'-tetranorprostadiene weighing 220 mg. (8C$ yield) was collected.
. %- ' ■ EXAMPLE II 1- (Tetrazol-5-yl ) -9-oxo-lla, 15a-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-5- raJis-l3-L/-tetranor-prostadiene To a solution cooled to -15° under nitrogen, of 600 mg. 1- (tetrazol-5-yl)-9a-hydroxy-lla, 15a-bis- (tetrahydropyran-2-yloxy) l6-phenoxy-cis-5-trans-13-t.t/-tetranor-prostadiene in 12 ml. reagent grade acetone was added dropwise 0.6 ml. of Jones' reagent.
After 30 minutes at -10°, 0.6 ml. 2-propanol was added and the reaction mixture was allowed to stir an additi onal 5 minutes at which time it was combined with 75 nil. ethyl acetate, washed with water (3 x 10 ml.), dried (NagSOjj.) and concentrated to give 5 0 mg of the colorless^ oily l-(tetrazol-5~yl) -9-oxo-lla, 15a-bis-(tetrahydropyran-2-yloxy) -l6-phenoxy-cis-5-trans-13-v-tetranor-prostadiene. · EXAMPLE XXIII 1-(Tetrazol-5-yl)-9-oxo-lla, 15a-dihydroxy-l6-phenoxy-cis-5-trans- 13-/-tetranor-prostadiene A solution of 508 mg. 1- (tetrazol-5-yl)-9-oxo-lla, 15a-bis- (tetrahydropyran-2-yloxy)-16-pheno y-cis-5-trans-13-U-tetranor-prostadiene in 10 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 20 hours. and then was concentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel (Mallinckrodt CC-7 100-200 mesh) using mixtures of chloroform: ethyl acetate as eluants. After elution of less polar impurities the colorless oily 1- (tetrazol-5-yl)-9-oxo-lla, 15a-d_hydroxy-l6- f phenoxy-cis-5-trans-13- -tetranor-prostadiene weighing 2h0 mg. was obtained.
: ' ' ' |; EXAMPLE xxiv ■ N-Methanesulfonyl-9a-hydroxy-ll , 15a-bis - (tetrahydropyran-2-yloxy) l6-phenoxy-cis-5-trans~13-t-tetranor-prostadienaniide To a solution of 1.7 g.
EXAMPLE XXV N-Methanesulfonyl-¾ rlXyj, 15p(.-trihydroxy-l6-phenoxy-cis- 5-trans- 13-U-tetranor-prostadienamide A solution of 250 mg . of N-methanesulfonyl-9 -hydroxy- 15dv- is- ( tetrahydropyran-2-yloxy) -16-phenoxy-cis- 5-trans-13- (j-tetranor-prostadienamide in 5 ml. of 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25° for 18 hours and then was concentrated to a crude oil, which was purified by column chromatography on silica gel (Mallinckrodt CC-7, 100-200 mesh) using mixtures of chloroform: ethyl acetate as eluants.
After elution of less polar impurities the colorless oily N- methanesulfony1-9¾, 1lc-, 15 .-1rihydroxy- 16-phenoxy-cis- 5-trans-13- tetranor-prostadienamide weighing 180 mg. was collected. The product was shown to be homogeneous by liquid-liquid chromatography EXAMPLE XXVI N~Methanesulfonyl~9-oxo-l_ <. , 15^-bis- (tetrahydropyran-2-yloxy) -16- phenoxy-cis- 5-trans-13-(^)-tetranor-prostadienamide To a solution cooled to - 10 ° under nitrogen, of 400 mg. of methanesulfonyl-9 -hydroxy-13 c , 15x.-bis- (tetrahydropyran- 2-yloxy) - 16-phenoxy-cis 5-trans- 13-(Aj-tetranor-prostadienamide in 8 ml. reagent grad^ acetone was added dropwise 0.4 ml. of Jones reagent. After 30 minutes at - 10° , 0.4 ml. 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 60 ml. ethyl acetate, washed with water ( 3 X 10 ml.), dried ( a2SC>4) and concentrated to afford 380 mg. of the colorless oily N-methanesulfonyl-9-oxo- 11"°^, 15^-bis- ( tetrahydropyran- 2-yloxy ) - 16-phenoxy-cis- 5-trans- 13-lO-tetranor-prostadienamide .
EXAMPLE XXVII N-Methanesulfonyl-9-οχο-ΙΙΎ, 15^-bis-dihydroxy-l 6-phenoxy-cis- 5-traris-13-!J-1-¾tranor-prostadienamide A solution of 260 mg. of N-methanesulfonyl-9-oxo-ll-l , 15¾-bis- (tetrahydropyran-2-yloxy) -16-phenoxy-cis- 5-trans-l3- j-tetra-nor-prostadienamide in 6 ml. of a 65:35 mixture of glacial acetic acidtwater was stirred under nitrogen at 25° for 20 hours and then was concentrated to a crude oil which was purified by column chromatography on silica gel (Mallinckrodt CC-7, 100-200 mesh) using mixtures of chloroform: ethyl acetate as eluants . After elution of less polar impurities the colorless N-methanesulfonyl-9-oxo-lloyL5 bis-dihydroxy-16-phenoxy-cis- 5-trans-13-¾-tetranor-prostadienamide weighing 130 mg. was obtained. The product crystallized from ether as colorless crystals, m.p. 76°.
EXAMPLE XXVIII 9β, 11α, 15a-Trihydroxy-l6-phenoxy-cis-5-trans-13-(<-tetranor-prostadienoic acid To a stirred solution of 0.l8 g. (0.47 mmole) 9-oxo-lla, 15a-dihydroxy-l6-phenoxy-cis-5-trans-13-^-tetranor-prostadienoic a id in MeOH (20 ml.) at 0° was added a cold solution of 0.06 g. a3¾ in MeOH (10 ml) . After 1 hour at 0°, the reaction was quenched by addition of water (4 ml.) and concentrated under reduced pressure. The residue was acidified with 10 HC1 to pH 3, extracted with ethyl acetate, dried (NagSO^) and concentrated. Chromatography on 20 g. silica gel (CC-7) and elution with methanol-benzene afforded pure 9£, 11ο-, 15a-trihydroxy-l6-phenoxy-cis-5-trans-l3-tv-tetranor-prostadienoic acid, as a colorless oil, homogenous on t.l.c, rf Ο.25 (C^Hg-dioxan-HCOgH, 15:5:2).
:I; EXAMPLE X—IX ΐ' N-Benzoyl 9-OXO-HQJ 15a-dihydroxy-5-cis-13-trans-l6-phenoxy-,½-. tetranorprostadienamide : To 1.0 m mole of 9-oxo-lla, 15 -bis_-(tetrahydropyran-2-yl oxy) l6-phenoxy-cis- -trans-13-W-tetranorprostadienoic acid (Example VII •in h0 ml. THF is added 2 ml. triethylamine. After 15 minutes of stirring at room temperature 10.0 ml of 0.1 molar benzoylisocyanate : in THF is added. After a further hour of stirring, the reaction mixture is neutralized with acetic acid and the solvent removed by evaporation (in vacuo) . The resultant residue is taken up in . methylene chlorine and washed successively with water and sodium bicarbonate to yield, after drying and solvent evaporation, - benzoyl 9-oxo-llAJ 15a-bis- (tetrahydropyran-2-yl oxy)-l6-phenoxy- cis-5-trans-13- -tetranorprostadienamide . This intermediate is the hydrolized overnight with acetic "acid/water (as in Example IX) and purified by column chromatography to give the desired N-benzoyl-9-oxo-llct^l5Q-dihydroxy-5-cis-13-trans-l6-phenoxy- r- tetranorprostadienamide . ;i EXAMPLE ' XXX N-Methanesulfonyl 9-oxo-lla, 15a-dihydroxy-5-cis-13-trans-l6-phenoxy- A-tetranornrostadienamide: To 1,0 m mole of 9-oxo-lla,15a-bis- (tetrahydropyran-2-yl oxy) l6-phenoxy-cis-3-trans-13-^-tetranorprostadienoic acid (Example VIII in 0 ml, THF is added 2 ml triethylamine . After 15 minutes ' of stirring at room temperature 10.0 ml of 0.1 molar methane-sulfonylisocyanate in THF is added. After a further hour of stirring, the reaction mixture is neutralized with acetic acid and the solvent removed "by evaporation (in vacuo) . The resultant residue is taken up in methylene chlorine and washed successively with water and sodium bicarbonate to yield, after drying and solvent evaporation, N-methanesulfonyl 9-oxo-ll , 15 - s (tetrahydropyran-2-yl oxy)-l6-rphenoxy-cis-5-tran5-l3-/-tetranor-prostadienamide. This intermediate is then hydrolized overnight with acetic acid/water (as in Example -K£-) and purified by column chromatography to give the desired N-methanesulfonyl 9-oxo-lla, 15a-dihydroxy-5-cis-.13-trans-l6-phenoxy- -tetranorprostadienamide . · , _ ·- ■ ' ! . ' , ' EXAMPLE XXXI !j N-Acetyl-9a-hydroxy-llot, 15a-bis- (tetrahydropyran-2-yloxy) -16- ;l phenoxy-cis-5-trans -13-t -tetranor-prostadienamide i; To a solution of 5 .32 g ^T-(acetamido carbonyl)butyl7- triphenyl phosphonium bromide in a dry nitrogen atmosphere in 10 ml dry DMSO was added 17.7 ml of a 2.0 M solution of sodium methyl- sulfinyl methide in DMSO. To this red ylid solution was added dropwise a solution of 0. 24 g (1 .1 mmoles) 2-/5a-hydroxy-3a- (tetrahydropyran-2-yloxy) -2 - (3a- (tetrahydropyran-2-yloxy) -4- phenoxy-trans-l-buten-l-yl) cyclopen-la-yl7acetaldehyde, γ-hemiaceta in 10 ml dry DMSO over a period of 20 minutes. After an additional 2 hours stirring^ at room temperature, the reaction mixture was poured onto ice water. The basic aqueous solution was washed twice with ethyl acetate (3 x 25 ml) and combined organic extracts washed once with water (10 ml), dried (Na SO.,) and evaporated to 2 ^ ■ an oil. Chromatography on silica gel afforded 0.66 gm pure oily ; N-acetyl-9a-hydroxy-lla, 15a-bis_-(tetrahydropyran-2-yloxy) -l6- phenoxy-cis-5-trans-13-u/-tetranor-prostadienamide .
EXAMPLE XXXII N-Acetyl-9a, 11α, 15.-trihydroxy-l6«-phenoxy-cis-5-trans-13-i^'-tetranor-prostadie.nanide A solution of 0.39 6 of N-acetyl-9cc-hydroxy-lla, 15a-"bis-(tetrahydropyran-2-yloxy) -l6-phenoxy-cis-5-trans-13- u^-tetranor-prostadienamide in 5 ml of 65 : 35 mixture of glacial acetic acid: water was stirred und¾r nitrogen at 25 ° for l8 hours and then was concentrated to a crude oil, which was purified "by column chromatography on silica gel (CC-7 ) , using mixtures of chloroform ethyl acetate as eluant. After elution of less polar impurities the colorless oil-' N-acetyl-9a, 11a, 15a-trihydroxy-l6-phenoxy-cis-5-trans-13-LJ-tetranor-prostadienamide weighing 95 mg. was collect EXAMPLE XXIII N-Acetyl-9-oxo-ll , 15a-"bis- (tetrahydropy an-2-yloxy) -l6-phenoxy-cis-5-trans-13-U.'-1etranor-prostadienamide : To a solution cooled to -10° under nitrogen, of 39^ raS N-acetyl-9a-hydroxy-ll , 15a- is- (tetrahydropyran-2-yloxy) -16-phenoxy-cis-^-trajs-lS-t'-tetranor-prostadienamide in 10 ml reagent-grade acetone v/as added drop ise 0.27 ml of Jones reagent. After 30 minutes at -10°, 0.4 ml 2-propanol was added and the reaction mixture v/as allowed to stir an additional 5 minutes at which time it v/as combined with 60 ml ethyl acetate, washed with water (3 x 10 ml), drie"d (Na2S0ij.) and concentrated to afford 3 0 mg of colorless oily N-acetyl 9-oxo-ll , 15a-tis- (tetrahydropyran-2-yloxy) l6-phenoxy-cis-5-trajis-13-i^'-tetranor-prostadienamide.
EXAMPLE XXXIV N-Acetyl-9-oxo-llQ, i a-bjjs-dihydroxy-l6-^henox -cis-5-trans-13-tetranor- rostadienamide A solution of 390 mg of N-acetyl-9-oxo-llct, 15a-bis-(tetrahydropyran-2-yloxy)-l6-phenoxy-cis-5-trans-13- ^-tetranor-prostadienainide in 8 ml of a 65:35 mixture of glacial acetic ac water was stirred under nitrogen at 25° for 20 hours and then w concentrated to a crude oil which was purified by column chromatography on silica gel using mixtures of chloroform ethyl acetate as eluants. After elution of less polar impurities the colorless oily N-acetyl-9-oxo-lla, 15a-bis-dihydroxy-l6--phenoxy-cis-5-tr ans-13-V-tetranor-prostadienamide weighing 76 mg.
Name Spe N-Acetyl 16-phenoxy-6?-tetranor PGF2a . IR i carboxamide 1675 955 16-Phenoxy-i-^-tetranor PGF2p p-biphenylyl IR i 176 965 N-Methanesulfonyl 16-phenoxy i?-tetranor carboxamide N-Methc'.nesulfonyl 16- (m-chlorophenoxy) IR tetranor PGEi carboxamide 5.8 10.
N-Methanesulfonyl tetranor PGE carb N-tnethanesulfonyl carboxamide 5. 3.2 Name S 2-Descarboxy-2- (tetrazol-5-yl) - 6- (m-trifluoromethylphenoxy) -£?-tetranor PGF£a N- ethanesulfonyl 16- (m-trifluoromethylphenoxy) - N t*)-tetranor PGE carboxamide 7. 5. 5 2 N-methanesulfonyl 16- (p-methoxyphenoxy) I tetranor PGF0 carboxamide 1 9 2-Descarboxy-2- (tetrazol-5-yl) tetranor PGF20 N-Acetyl 16-phenoxy-U-tetranor PGE2 carboxamide -methanesulfonyl 16-phenoxy- -tetranor PGF, I arboxaraide 1 9 N-Benzoyl 16-phenoxy- -tetranor carboxamide 9 Name Spe 2-Descarboxy-2- (tetrazol-5-yl) 16-phenoxy-iJ-tetranor PGF9 N-methanesuIfonyl 16- (m-chlorophenoxy) tetranor PGE0 carboxamide N-Ethanesulfonyl 16-phenoxy-t^-tetranor IR PGF _ carboxamide 171 965 N-Phenylsulfonyl 16-phenoxy- -tetranor IR PGE carboxamide 173 965 N-Ethanesulfonliy 16-phenoxy-l3-tetranor IR PGE2 carboxamide 173 970 N-inethanesulfonyl 16-phenoxy- ?-tetranor IR PGA2 carboxamide 17 97
Claims (22)
1. A compound of the formula: November 8, 3.972 except for oonpoiu-ids of claim 2 and its C15 epimer; wherein Ar is phenyl, or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl , phenyl, lower alkoxy or lower alkyl; is a single bond or cis double bond; Z is a single bond or trans double bond; keto, N and L when taken together form a single bond, or N is 0I-OR3 when L is hydrogen; R3 is hydrogen or 2-tetrahydropyrany1; X is £-phenylphenoxycarbonyl ; tetrazolyl; -C-OR' wherein R' is hydrogen, alkyl of from 1-10 carbon atoms , cycloalkyl, aralkyl of from 7-9 carbon atoras , phenyl or mono- (lower alkyl) phenyl ; "or O -CNHR" wherein R" is alkanoyl having from 2-10 carbon atoms, aroyl, arylsulfonyl , alkylsulfonyl of from 1 to 7 carbon atoms and wherein L, M and N are so selected as to complete the structure of a prostaglandin of the A, E or F series the lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups at the C9- , C_ - and C15- positions, and the pharmaceutically acceptable salts of the compounds wherein X is COOH.
2. A compound of Formula I wherein Ar, Z, N, L, M, R3 '413589-2 o and W are as defined in Claim 1, and X is tetrazolyl or -C-NHR" wherei R" is alkanoyl having from 2-10 carbon atoms, aroyl, arylsulfonyl , alkylsulfonyl of from 1 to 7 carbon atoms; and wherein L, M and N are so selected as to complete November 7, the structure of a prostaglandin of the A, E or F series, the 1973 lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups at the Cg-, Cii~ and C15- positions, and the pharmaceutically acceptable salts of the compounds wherein X is COOH.
3. A compound according to Claim 1 of the structure: OH wherein Ar, X, and Z are as defined in Claim 1, and its epimer.
4. The comp Doouunndd ooff CCllaaiimm 11 wwhheerreeiinn MM iiss H hydrogen, and N is ^-hydroxyl, and its C15 epimer.
5. A compound according to Claim 1 of the structure: wherein Ar, X, W and Z are as defined in Claim 1, and its C15 epimer.
6. A compound according to Claim 1 of the structure: .v. * 43589/3 wherein Ar, X, W and Z are as defined in Claim 1, and its C^5 epimer.
7. A compound of the structure: wherein Ar, X, W and Z are as defined in Claim 1 and THP 2-tetrahy.dropyranyl , and the Cg and C-j^ epimers thereof .
8. A compound of the structure: wherein Ar, X, W and Z are as defined in Claim 1 and THP is 2-tetrahydropyranyl . and the C15 epimer thereof.
9. The compound of Claim 1, wherein Ar is phenyl and said prostaglandin is the analogue of PGE^.
10. The compound of Claim 1, wherein Ar is phenyl and said prostaglandin is the analogue of PGF .
11. - The compound of Claim 1, wherein Ar is phenyl and said prostaglandin is the analogue of P^tF^^.
12. The compound of Claim 1, wherein Ar is phenyl and said rosta landin is the analo ue of PG 43589/3 o
13. November 13. A compound according to Claim 3, wherein X is -C-NHR" 7, 1973 wherein R" is acetyl, is a cis double bond, Z is a trans double bond, and Ar is phenyl.
14. A compound according to Claim 3, wherein X is tetrazolyl W is a cis double bond, Z 'is a trans double bond, and Ar is phenyl. n
15. A compound according to Claim 3, wherein X is -C-NHR" wherein R" is methylsulfonyl , is a cis double bond, Z is a trans double bond, and Ar is phenyl. 0 ·
16. A compound according to Claim 5, wherein X is -C-NHR" wherein R" is acetyl, W is a cis double bond, Z is a trans double bond, and Ar is phenyl.
17. A compound according to Claim 5, wherein X is tetrazolyl, W is a cis double bond, Z is a trans double bond, and Ar is phenyl.
18. A compound according to Claim 5, wherein X is 0 -C-NHR" wherein R" is methylsulfonyl , W is a cis double bond, Z is a trans double bond, and Ar is phenyl.
19. 16-Phenoxy -tetranor pGE2 p_-biphenylyl ester.
20. 16-Phenoxy ~W -tetranor PGF2
21.. 16-Phenoxy - ω -tetranor PGF2^ P-biphenylyl ester.
22. A process for preparing a compound according to Claim 1 of the structure: wherein Ar, L, M, N, W, X and Z are as defined in Claim 1, and its C^5 epimer; and wherein L, M and N are so selected as to complete the structure of a prostaglandin of the A, E ' 43589-2 any free hydroxy1 groups at the Cg-, C^- and Cx5~positions, and the pharmaceutically acceptable bases of the compounds wherein X is COOH, characterized by the fact that a) when N is ^-hydroxy and L is hydrogen, and Ar, M, W, X and Z are as defined above, said compound is prepared by treating the 11- and 15-tetrahydropyranyl ethers of a compound of Formula I1 above, with a suitable acid; b) when N and L, when taken together form a single bond, is keto and Ar, W, X and Z are as defined above, said compound is prepared by reacting a compound of Formula I' above, wherein N is c-hydroxy and L is hydrogen, M is keto and Ar , W, X and Z are as defined above, with a suitable dehydrating agent; c) when & .OH N is oi-hydroxy and L is hydrogen, M is or '-0H ' H and Ar, W and Z are as defined above, said compound is prepared by reacting a compound of the Formula I1 above, wherein N is -hydroxy and L is hydrogen, is keto, Ar , W, X and Z are as defined above, with a suitable reducing agent, and, if desired, separating the 9°<- and 9^5- isomers; d) when N is °<-hydroxy, L is hydrogen, Ar, M and X are as defined above, and W and Z are single bonds, said compound is prepared by catalytic reduction of a compound of Formula I' above, wherein Ar , and X are as defined above, W is a single bond or cis double bond when Z is a trans double bond and Z is a single bond when W is a cis double bond; e) when N is d -hydroxy, L is hydrogen, Ar, X and M are as defined above, W is a single bond and Z is a trans double bond, said compound is prepared by selective reduction of a compound of Formula I' above or the trialkysilyl ester of a compound of Formula I' above, wherein X is COOH, Ar, X and M are as defined above and W and Z are double bonds , and when required, converting those compounds Formula I* above wherein X is COOH to their esters and substituted amides, as defined above, by reaction with suitable esterifying and amidating reagents, respectively, and, if desired, preparing the 9.-, 11°<- and lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups by reacting said compounds with the appropriate acyl-ating agents and, if desired, preparing the pharmaceutically acceptable salts of these compounds wherein X is COOH.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL50307A IL50307A (en) | 1972-11-08 | 1973-11-07 | Dimethyl 2-oxo-3-phenoxypropyl phosphonates |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30481372A | 1972-11-08 | 1972-11-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL43589A0 IL43589A0 (en) | 1974-03-14 |
| IL43589A true IL43589A (en) | 1980-01-31 |
Family
ID=23178133
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL43589A IL43589A (en) | 1972-11-08 | 1973-11-07 | 16-phenoxy-15-hydroxy derivatives of 17,18,19,20-tetranorprostaglandins and their preparation |
Country Status (29)
| Country | Link |
|---|---|
| JP (3) | JPS5416491B2 (en) |
| AR (3) | AR200585A1 (en) |
| AT (3) | AT367034B (en) |
| AU (1) | AU470375B2 (en) |
| BE (1) | BE806995A (en) |
| CA (3) | CA1085831A (en) |
| CH (1) | CH597176A5 (en) |
| CS (3) | CS182791B2 (en) |
| DD (4) | DD118856A5 (en) |
| DE (1) | DE2355540C2 (en) |
| DK (1) | DK144247C (en) |
| ES (3) | ES420325A1 (en) |
| FI (1) | FI60389C (en) |
| FR (3) | FR2205335B1 (en) |
| GB (3) | GB1456512A (en) |
| HK (3) | HK27979A (en) |
| HU (3) | HU171819B (en) |
| IE (1) | IE39537B1 (en) |
| IL (1) | IL43589A (en) |
| IN (1) | IN139384B (en) |
| KE (3) | KE2932A (en) |
| MY (3) | MY7900243A (en) |
| NL (1) | NL164273C (en) |
| NO (3) | NO147836C (en) |
| PH (3) | PH13272A (en) |
| SE (4) | SE448992B (en) |
| SU (4) | SU584766A3 (en) |
| YU (3) | YU39715B (en) |
| ZA (1) | ZA738554B (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3929862A (en) * | 1974-01-08 | 1975-12-30 | Upjohn Co | Substituted tolylesters of PGF{HD 2{B {60 |
| GB1506816A (en) * | 1975-03-31 | 1978-04-12 | Upjohn Co | Prostaglandins |
| US3986764A (en) * | 1975-03-31 | 1976-10-19 | Gte Automatic Electric Laboratories Incorporated | Panel for supporting a pair of elongated mating connectors and selectively locking them together |
| ES449162A1 (en) * | 1975-06-23 | 1977-12-16 | Syntex Inc | 16-Phenoxy and 16-substituted phenoxy-prostatrienoic acid derivatives |
| GB1516414A (en) * | 1975-08-22 | 1978-07-05 | Ici Ltd | Prostane derivatives |
| SE7809008L (en) * | 1977-12-12 | 1979-06-13 | Upjohn Co | USE OF PROSTAGLAND TYPE AMIDES TO CONTROL OR REGULATE THE REPRODUCTION CYCLE IN INDIVIDUALS OF MAMMALS |
| DK523378A (en) * | 1978-01-16 | 1979-07-17 | Pfizer | PROCEDURE FOR THE PREPARATION OF N- (TETRAZOL-5-YL) PROSTAGLANDIN CARBOXAMIDES OR SALTS THEREOF |
| SK3382000A3 (en) * | 1997-09-09 | 2000-10-09 | Procter & Gamble | A compound having structure of aromatic substituted prostaglandins and its use for the treatment of bone disorders |
| JP4834224B2 (en) | 1999-03-05 | 2011-12-14 | デューク ユニバーシティ | C16 unsaturated FP-selective prostaglandin 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 |
| US20020037914A1 (en) | 2000-03-31 | 2002-03-28 | Delong Mitchell Anthony | Compositions and methods for treating hair loss using C16-C20 aromatic tetrahydro prostaglandins |
| US20020172693A1 (en) * | 2000-03-31 | 2002-11-21 | Delong Michell Anthony | 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 |
| JP2002329615A (en) * | 2001-05-02 | 2002-11-15 | Ohira Denshi Kk | Toroidal coil |
| US6476064B1 (en) * | 2001-06-13 | 2002-11-05 | Allergan, Inc. | Cyclopentane heptan(ene) acyl sulfonamide, 2-alkyl or 2-arylalkyl, or 2-heteroarylalkenyl derivatives as therapeutic agents |
| EP1812017A2 (en) | 2004-10-21 | 2007-08-01 | Duke University | Ophthamological drugs |
| 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1324737A (en) * | 1970-11-02 | 1973-07-25 | Upjohn Co | Prostaglandins and the preparation thereof |
| IE37602B1 (en) * | 1971-05-11 | 1977-08-31 | Ici Ltd | Cyclopentane derivatives |
-
1972
- 1972-11-07 DD DD182498*A patent/DD118856A5/xx unknown
-
1973
- 1973-10-29 SE SE7314686A patent/SE448992B/en unknown
- 1973-11-07 AR AR250885A patent/AR200585A1/en active
- 1973-11-07 ZA ZA738554A patent/ZA738554B/en unknown
- 1973-11-07 YU YU2880/73A patent/YU39715B/en unknown
- 1973-11-07 DD DD182499*A patent/DD119411A5/xx unknown
- 1973-11-07 FI FI3443/73A patent/FI60389C/en active
- 1973-11-07 AU AU62247/73A patent/AU470375B2/en not_active Expired
- 1973-11-07 IE IE2002/73A patent/IE39537B1/en unknown
- 1973-11-07 AT AT0936973A patent/AT367034B/en not_active IP Right Cessation
- 1973-11-07 DK DK601073A patent/DK144247C/en not_active IP Right Cessation
- 1973-11-07 DD DD174504A patent/DD109212A5/xx unknown
- 1973-11-07 CH CH1563973A patent/CH597176A5/xx not_active IP Right Cessation
- 1973-11-07 DE DE2355540A patent/DE2355540C2/en not_active Expired
- 1973-11-07 NL NL7315263.A patent/NL164273C/en not_active IP Right Cessation
- 1973-11-07 PH PH15191A patent/PH13272A/en unknown
- 1973-11-07 IL IL43589A patent/IL43589A/en unknown
- 1973-11-07 IN IN2448/CAL/73A patent/IN139384B/en unknown
- 1973-11-07 GB GB5175873A patent/GB1456512A/en not_active Expired
- 1973-11-07 FR FR7339544A patent/FR2205335B1/fr not_active Expired
- 1973-11-07 JP JP12527273A patent/JPS5416491B2/ja not_active Expired
- 1973-11-07 DD DD182497*A patent/DD117233A5/xx unknown
- 1973-11-07 ES ES420325A patent/ES420325A1/en not_active Expired
- 1973-11-07 GB GB2285876A patent/GB1456514A/en not_active Expired
- 1973-11-07 GB GB2395076A patent/GB1456513A/en not_active Expired
- 1973-11-07 CA CA185,274A patent/CA1085831A/en not_active Expired
- 1973-11-07 NO NO4288/73A patent/NO147836C/en unknown
- 1973-11-07 BE BE1005485A patent/BE806995A/en not_active IP Right Cessation
- 1973-11-08 CS CS7300007669A patent/CS182791B2/en unknown
- 1973-11-08 HU HU73PI00000452A patent/HU171819B/en unknown
- 1973-11-08 HU HU73PI451A patent/HU173507B/en unknown
- 1973-11-08 CS CS7500006065A patent/CS182793B2/en unknown
- 1973-11-08 HU HU72PI00000399A patent/HU172703B/en unknown
- 1973-11-08 CS CS7500006066A patent/CS182794B2/en unknown
- 1973-11-11 SU SU7301971722A patent/SU584766A3/en active
-
1974
- 1974-06-06 AR AR254090A patent/AR202931A1/en active
- 1974-06-06 AR AR254091A patent/AR199966A1/en active
- 1974-09-26 NO NO743493A patent/NO148998C/en unknown
- 1974-12-18 ES ES433047A patent/ES433047A1/en not_active Expired
- 1974-12-18 ES ES433046A patent/ES433046A1/en not_active Expired
-
1975
- 1975-02-18 SU SU752106791A patent/SU667141A3/en active
- 1975-02-18 NO NO750535A patent/NO149139C/en unknown
- 1975-02-19 SU SU752106125A patent/SU893130A3/en active
- 1975-07-24 PH PH17410A patent/PH13110A/en unknown
- 1975-07-24 PH PH17409A patent/PH13325A/en unknown
- 1975-08-22 FR FR7526059A patent/FR2279729A1/en active Granted
- 1975-08-22 FR FR7526060A patent/FR2283146A1/en active Granted
-
1976
- 1976-07-23 AT AT544676A patent/AT353285B/en active
- 1976-07-23 AT AT544576A patent/AT360672B/en not_active IP Right Cessation
- 1976-10-15 JP JP51123738A patent/JPS5257147A/en active Pending
- 1976-10-15 JP JP51123737A patent/JPS5253841A/en active Pending
-
1977
- 1977-01-24 SE SE7700716A patent/SE445111B/en not_active IP Right Cessation
- 1977-01-24 SE SE7700717A patent/SE436278B/en not_active IP Right Cessation
- 1977-01-24 SE SE7700718A patent/SE431756B/en not_active IP Right Cessation
- 1977-07-11 CA CA341,898A patent/CA1088931A/en not_active Expired
- 1977-07-11 CA CA341,897A patent/CA1088930A/en not_active Expired
-
1978
- 1978-07-27 SU SU782629453A patent/SU745362A3/en active
-
1979
- 1979-03-15 KE KE2932A patent/KE2932A/en unknown
- 1979-03-15 KE KE2930A patent/KE2930A/en unknown
- 1979-03-15 KE KE2931A patent/KE2931A/en unknown
- 1979-05-03 HK HK279/79A patent/HK27979A/en unknown
- 1979-05-03 HK HK280/79A patent/HK28079A/en unknown
- 1979-05-03 HK HK281/79A patent/HK28179A/en unknown
- 1979-12-30 MY MY243/79A patent/MY7900243A/en unknown
- 1979-12-30 MY MY245/79A patent/MY7900245A/en unknown
- 1979-12-30 MY MY246/79A patent/MY7900246A/en unknown
-
1980
- 1980-10-23 YU YU2707/80A patent/YU36975B/en unknown
- 1980-10-23 YU YU2706/80A patent/YU37316B/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4087604A (en) | Substituted ω-pentanorprostaglandins | |
| US4304907A (en) | Bicyclo lactone intermediates for prostaglandin analogs | |
| IL43589A (en) | 16-phenoxy-15-hydroxy derivatives of 17,18,19,20-tetranorprostaglandins and their preparation | |
| US4073934A (en) | Novel acetylenic prostaglandin analogs | |
| DE2659215A1 (en) | PROSTAGLANDIN ANALOGA | |
| EP0299914A1 (en) | 9-Halogen (Z) prostaglandin derivatives, process for their production and their use as medicines | |
| US4011262A (en) | 13,14-Dihydro-15-substituted-ω-pentanorprostaglandins of the two series | |
| CH628028A5 (en) | METHOD FOR PRODUCING NEW PROSTAGLANDIN ANALOGS WITH TRIPLE BINDING BETWEEN C-13 AND C-14. | |
| US4699920A (en) | 9-halo-2-prostaglandin derivatives, processes for the preparation thereof and use thereof as medicinal agents | |
| US4033989A (en) | 9-Deoxy-PGF2 Analogs | |
| US4013695A (en) | 4,4,5,5-Tetradehydro-PGE1 analogs | |
| US4169895A (en) | Antisecretory 16,16-dimethyl-17-oxaprostaglandins | |
| US4060534A (en) | 9-Deoxy-9-methylene-PGF compounds | |
| IE44016B1 (en) | 11-deoxy-16-aryl-17,18,19,20-tetranorprostaglandins | |
| CA1092102A (en) | 11-oxo-prostaglandin derivatives and processes for their manufacture | |
| IE47549B1 (en) | Acetyleneprostaglandins and process for their production | |
| US4035415A (en) | Omega-nor-cycloalkyl-13,14-dehydro-prostaglandins | |
| CH642063A5 (en) | METHOD FOR PRODUCING PROSTAGLANDIN ANALOGS IN WHICH THE CARBONYL GROUP ON THE C-9 IS REPLACED BY A METHYLENE GROUP. | |
| US4229585A (en) | Fluoro-prostaglandins | |
| US4404372A (en) | 15-Substituted-ω-pentanorprostaglandin derivatives | |
| DE2606051A1 (en) | 2,2-DIFLUORO-PROSTAGLANDIN-E, -F LOW ALPHA, -F LOW BETA, -A AND -B ANALOGA AND METHOD FOR THEIR PRODUCTION | |
| JPS6126970B2 (en) | ||
| US4078021A (en) | Dimethyl 2-oxo-6-cyanohexyl-phosphonate | |
| JPS6049632B2 (en) | 16-phenoxy prostaglandin analogue | |
| US4244887A (en) | Substituted ω-pentanorprostaglandins |