CS235307B2 - Method of 6a-carbaprostaglandine -12 derivatives production - Google Patents
Method of 6a-carbaprostaglandine -12 derivatives production Download PDFInfo
- Publication number
- CS235307B2 CS235307B2 CS83847A CS84783A CS235307B2 CS 235307 B2 CS235307 B2 CS 235307B2 CS 83847 A CS83847 A CS 83847A CS 84783 A CS84783 A CS 84783A CS 235307 B2 CS235307 B2 CS 235307B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- formula
- bicyclo
- colorless oil
- title compound
- yloxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 3
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 40
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 241001417527 Pempheridae Species 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 4
- XZFRIPGNUQRGPI-WLPVIMDJSA-N Carbacyclin Chemical class C1\C(=C\CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 XZFRIPGNUQRGPI-WLPVIMDJSA-N 0.000 abstract 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 239000012230 colorless oil Substances 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- -1 ethanolamine Chemical compound 0.000 description 20
- 239000000243 solution Substances 0.000 description 17
- RHLVCLIPMVJYKS-UHFFFAOYSA-N 3-octanone Chemical compound CCCCCC(=O)CC RHLVCLIPMVJYKS-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 150000002576 ketones Chemical class 0.000 description 11
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 230000036772 blood pressure Effects 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 150000003180 prostaglandins Chemical class 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 5
- ZOUYMLXOFDNVRK-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydro-1h-pentalen-2-one Chemical compound C1CCC2CC(=O)CC21 ZOUYMLXOFDNVRK-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- 210000001772 blood platelet Anatomy 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical compound O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 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
- 150000001336 alkenes Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 2-octanone Chemical compound CCCCCCC(C)=O ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 206010011091 Coronary artery thrombosis Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 206010061216 Infarction Diseases 0.000 description 2
- 208000007914 Labor Pain Diseases 0.000 description 2
- 208000035945 Labour pain Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 208000002528 coronary thrombosis Diseases 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000006567 deketalization reaction Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000002615 hemofiltration Methods 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000007574 infarction Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000002633 shock therapy Methods 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 description 1
- UUSUFQUCLACDTA-UHFFFAOYSA-N 1,2-dihydropyrene Chemical compound C1=CC=C2C=CC3=CCCC4=CC=C1C2=C43 UUSUFQUCLACDTA-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QGNQUBKXAXDDAO-UHFFFAOYSA-N 1-dimethoxyphosphoryl-3-methyloct-5-yn-2-one Chemical compound CCC#CCC(C)C(=O)CP(=O)(OC)OC QGNQUBKXAXDDAO-UHFFFAOYSA-N 0.000 description 1
- MLOSJPZSZWUDSK-UHFFFAOYSA-N 4-carboxybutyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCC(=O)O)C1=CC=CC=C1 MLOSJPZSZWUDSK-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- KXUPLLNPRDDVGO-BESBDSHLSA-N CC#CCC(C)(C)C(=O)C(=C[C@@H]1[C@@H](C[C@H]2[C@@H]1CC3(C2)OCCO3)OC(=O)C4=CC=CC=C4)Br Chemical compound CC#CCC(C)(C)C(=O)C(=C[C@@H]1[C@@H](C[C@H]2[C@@H]1CC3(C2)OCCO3)OC(=O)C4=CC=CC=C4)Br KXUPLLNPRDDVGO-BESBDSHLSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 235000015854 Heliotropium curassavicum Nutrition 0.000 description 1
- 244000301682 Heliotropium curassavicum Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical class NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical class [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 101150095461 Tfrc gene Proteins 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000007885 bronchoconstriction Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000013110 gastrectomy Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000036593 pulmonary vascular resistance Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- YWFDDXXMOPZFFM-UHFFFAOYSA-H rhodium(3+);trisulfate Chemical compound [Rh+3].[Rh+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O YWFDDXXMOPZFFM-UHFFFAOYSA-H 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 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 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical compound OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
- C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
- C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
- C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
- C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
-
- 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
- C07F9/4015—Esters of acyclic unsaturated acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biochemistry (AREA)
- Molecular Biology (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)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Ink Jet Recording Methods And Recording Media Thereof (AREA)
- Lubricants (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Vynález se obecného vzorce I týká způsobu výroby derivátů bakerbeprosteglendinu-I2 COOHThe invention of the formula I relates to the preparation of derivatives I-bakerbeprosteglendinu 2 COOH
(I) ve kterém značí(I) in which denotes
Rp R2, Ry etom vodíku, methyl nebo ethylR p R 2 , R y is hydrogen, methyl or ethyl
Ri- methyl, ethyl nebo propyl, jakož i jejich isomerů a solí s fyziologicky nezávadnými bázemi.R 1 -methyl, ethyl or propyl, and their isomers and salts with physiologically acceptable bases.
Jako akylové skupiny Rp R2, Ry přicházejí v úvahu alkylové skupiny s 1 až atomy uhlíku s přímým nebo rozvětveným řetězcem, jako například methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl. Přednostními zbytky jsou methyl, ethyl, propyl a isopropyl, zejména methyl a ethyl.Suitable alkyl groups R p R 2 , R y are straight-chain or branched alkyl groups having 1 to carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl. Preferred radicals are methyl, ethyl, propyl and isopropyl, especially methyl and ethyl.
К tvorbě solí jsou vhodné anorganické a organické báze, které jsou odborníkům známé к tvorbě fyziologicky nezávadných solí. Příkladně je možno jmenovat hydroxidy alkalických kovů, jako hydroxid sodný a draselný, hydroxidy kovů alkalických zemin, jako hydroxid vápenatý, amoniak, aminy, jako ethanolamin, dlethenolamin, triethanolanln, N-methylglukamin, morfolln, trls-(hydroxymethyl)methylamin atd.Suitable inorganic and organic bases are known in the art for the formation of physiologically acceptable salts. Examples include alkali metal hydroxides such as sodium and potassium hydroxides, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, dlethenolamine, triethanolanine, N-methylglucamine, morpholine, trls- (hydroxymethyl) methylamine, and the like.
V DOSu č. 2 845 770 se nárokují deriváty karbacykllnu obecného vzorceNo. 2,845,770 claims carbacycline derivatives of the general formula
COOR«| (CH2)3 COOR «| (CH 2 ) 3
CHCH
«3 kde značí«3 where denotes
Rj vodík, alkyl, cykloalkyl, aryl nebo heterocyklický zbytek,R 1 is hydrogen, alkyl, cycloalkyl, aryl or a heterocyclic radical,
A skupinu -CH2-CH2-, trans CH=CH- nebo -CSC-,A is -CH 2 -CH 2 -, trans CH = CH- or -CSC-,
W volnou nebo funkčně obměněnou hydroxymethylenovou skupinu nebo volnou nebo funkčně obměněnou skupinuW is a free or functionally modified hydroxymethylene group or a free or functionally modified group
OH přičemž skupina OH je v poloze a,OH wherein the OH group is in the α,
D a E spolu přímou vazbu, neboD and E together are a direct bond, or
D alkylenovou skupinu в 1 až 10 atomy uhlíku, nasycenou nebo nenasycenou, s přímým nebo rozvětveným řetězcem, která je popřípadě substituována atomy fluoru,A C 1 to C 10 alkylene group, saturated or unsaturated, straight or branched, optionally substituted by fluorine atoms,
235 307235 307
E atom kyslíku nebo vazbu -C=C- nebo přímou vazbu,E is an oxygen atom or a -C = C- bond or a direct bond,
R skupinu alkylovou, cykloalkylovou, nebo popřípadě substituovanou skupinu arylovou nebo heterocyklickou,R is an alkyl, cycloalkyl, or optionally substituted aryl or heterocyclic group,
R volnou nebo funkčně obměněnou hydroxyskupinu a v případě, Že R má význam atomu vodíku její soli s fyziologicky nezávadnými bázemi.R is a free or functionally altered hydroxy group, and when R has the meaning of a hydrogen atom of a salt thereof with physiologically acceptable bases.
Sloučéníny mají vlastnosti typické pro prostaglandiny, jako jsou například snižování perigerního arteriálního a koronárního cévního odporu, Inhlblce agregace trombocytů a rozpouštění destičkových trombů, myokardlální cytoprotekce a tím snižování systemického krevního tlaku, aniž by se současně snižoval objem tepů a koronární prokrvení, léčení záchvatu mrtvice, profylaxe a terapie koronárních srdečních onemocnění, koronární trombózy, srdečního Infarktu, periferních cévních onemocnění, arterlosklerózy e trombózy, terapie šoku, inhlblce konstrlkce bronchů, inhlblce sekrece žaludečních kyselin, cytoprotekce žaludeční a střevní sliznice, antialerglcké vlastnosti, snižování pulmonérního cévního odporu a pulmonárního krevního tlaku, podpora prokrvování ledvin, použití místo heparlnu nebo jako adjuvans při dialýze hemoflltrace, konzervace konzerv krevní plazmy, zvláště konzerv krevních destiček, inhlblce porodních bolestí, léčení těhotenské toxlkózy, zvyšování cerebrálního prokrvení atd. Mimoto mají nové enalogy prostaglendinu antlprollferativní vlastnosti.Compounds have properties typical of prostaglandins such as lowering of perigeral arterial and coronary vascular resistance, platelet aggregation inhibition and platelet thrombus dissolution, myocardial cytoprotection and thereby lowering systemic blood pressure without simultaneously reducing pulse volume and coronary blood flow, treating seizures prophylaxis and therapy of coronary heart disease, coronary thrombosis, cardiac infarction, peripheral vascular disease, arterlosclerosis and thrombosis, shock therapy, bronchial constriction inhibition, gastric acid secretion inhibition, gastric and intestinal blood glucose cytoprotection, anti-pulmonary mucosal blood pressure, antialysis , support of renal blood supply, use in place of heparin or as adjuvant in dialysis of haemofiltration, preservation of canned blood plasma, especially canned blood platelets, inh lblce of labor pain, treatment of pregnancy toxosis, increased cerebral blood flow, etc. In addition, the new prostaglendin enalogs have anti-proliferative properties.
Mezi sloučeninami nárokovanými v DOS č. 2 845 770 ukazují sloučeniny (5E)-13,14,18,18,19,19-hexadehydro-6a-karba-prostaglandin-I2 jako prostředky snižující krevní tlak в jako prostředky potlačující agregaci trombocytů takové vynikající vlastnosti, že se u nich může nevíc snížit dávkování, čímž se ještě více může zabránit nežádoucím vedlejším účinkům.Among the compounds claimed in DOS No. 2 845 770, (5E) -13,14,18,18,19,19-hexadehydro-6α-carbba-prostaglandin-I 2 as blood pressure lowering agents v as platelet aggregation suppressing agents the excellent properties that the dosage can be reduced more and more so that undesirable side effects can be further prevented.
Sloučeniny (5E)-13,14,18,18,19,1^hexadehydro-óa-karbaprostaglandln-Ig nejsou v DOS č. 2 845 770 jmenovitě popsané. Sloučeniny s A jako skupina -CSC- nejsou oproti ostatním sloučeninám,ve kterých A značí skupinu -CR-CR- nebo skupinu trans -CH»CH zjevné.The compounds (5E) -13,14,18,18,19,14-hexadehydro-6α-carbaprostaglandin-Ig are not specifically disclosed in DOS No. 2,845,770. Compounds with A as a -CSC- group are not apparent compared to the other compounds in which A is -CR-CR- or trans -CH2CH.
Nomenklatura sloučenin se zakládá na návrhu Mortona a Brokawa (J. Org. Chem. 44.The nomenclature of the compounds is based on the design of Morton and Brokaw (J. Org. Chem. 44.
280 /1979/ ). (5E)-6a-Karba-prostaglandin-l2 podle toho následující strukturní vzorec:280 (1979). (5E) -6a-Carba-prostaglandin-12 accordingly, the following structural formula:
Způsob výroby derivátů ea-karbeprostaglandinů-R obecného vsorce I podle vynálezu spočívá v tom, že se C1R,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[\3S,4RS)-2-brom-3-(tetrahydropyran-2-yloxy)-alk-1-en-6-lnyl]-bicyklo [β,3,0]oktan-on obecného vzorce IIThe process for the preparation of the .alpha.-carbeprostaglandin-R derivatives of the general formula I according to the invention is characterized in that C1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- [1,3S, 4RS] -2-bromo -3- (Tetrahydropyran-2-yloxy) -alk-1-en-6-lnyl] -bicyclo [b, 3,0] octan-one of formula II
OO
CH « CBr -CH-^C--C— C«C- R <11)CH-CBr -CH- (C-C-C-R < 11 )
OTHP ÓTHPOTHP ÓTHP
kdewhere
R, R2, Rj, Rp Rg, mají význam uvedený u obecného vzorce I,R, R 2 , R 1, R p and R g are as defined in formula I,
THP značí tetoalydTopyranylový zbytek,. neché reagovat a enlontem 4-karp bjtyltrifenylfosnoulibboomidem, jakožto Wittigovým činidlem vzorce IIITHP stands for the tetoalyd -Topyranyl residue. and reacted with 4-carboxylic acid biphenylphosphinyllibboomide as the Wittig reagent of formula III
(III), kde(III), where
Ph značí OennOovou skupinu, a pak se dělí Isomery, ochranné skupiny se odštěpí a karboxylová skupina se popřípadě s fyziologicky nezávadnou bází převede v sůl.Ph is an OenO group, and then the isomers are separated, the protecting groups are cleaved, and the carboxyl group is optionally converted into a salt with a physiologically acceptable base.
Reakce sloučeniny obecného vzorce II s Wttigovým činidlem vzorce III, které se vyrobí z příslušné OosfonOové soli s oeeheanuSfinnOoethylnatrieo nebo oeetwneulOOeylofthnOkalfeo nebo kaliuo-tfrc.butyláfeo v dimeethysnlfoxidu nebo ve smOěích dioee^hn.8ulOfxidu a tetrahydrofuranu, se provádí při 'te^otách 0 až I00 °C, výhodns 20 ež 60 °C, v aprotlckém rozpouštědle nebo ve smmsi rozpouštědel, zvláště dimeethysulfoxidu,' dimethylfrm^a^midu nebo tetτahndrfOubanu. Dělení při tom získaných Z a E konfigurovaných olefinů se provádí obvyklým způsobem, například sloupcovou cte^t^o^matograioí nebo chboюStogbfOí ne vrstvě. Při shore popsené Wiitigově ol^ieMi nestává součesně ze odštěpení bromovodíku tvorbě 13,14-fCftnleefvé vazby.Reaction of a compound of formula II with Wttigovým agent of formula III which are prepared from the corresponding salt OosfonOové oeeheanuSfinnOoethylnatrieo or oeetwneulOOeylofthnOkalfeo or potassium tfrc.butyláfeo dimeethysnlfoxidu or in a hole-SMOE hn.8ulOfxidu and tetrahydro furan is carried out by P s' te ^ I Otach 0 to 00 ° C, preferably 20 to 60 ° C EŽ in AP rotlckém SMMS solvent or solvents, particularly dimeethysulfoxidu, '^ and ^ dimethylfrm bromide or tetτahndrfOubanu. The separation of the obtained Z and E configured olefins is carried out in a customary manner, for example by column readings or layers. At the same time as described by the Wiitig oliii, the cleavage of hydrogen bromide does not result in the formation of a 13,14-phenyl bond.
Oddtěpení ochranných skupin se provádí ve vodném roztoku organické kyseliny, například kyseliny octové, propionové a jiných, nebo ve vodném roztoku anorganické kyseliny» jako například kyseliny chlorovodíkové. Ke zlepšení rozpustnosti se účelně přidává inertní organické rozpouštědlo οίί^^ηύ s vodou· Vhodná organické rozpouštědle jsou například alkoholy, jako methanol, ethanol, ethery, jako dimethoxyethan, dioxan a tetrahydrofuran. Tetbahndboluban se používá přednostně, odštěpování se provádí zejména při teplotách 20 ež 80 °C.The deprotection is carried out in an aqueous solution of an organic acid such as acetic acid, propionic acid and others, or in an aqueous solution of an inorganic acid such as hydrochloric acid. Suitable organic solvents are, for example, alcohols such as methanol, ethanol, ethers such as dimethoxyethane, dioxane and tetrahydrofuran. Tetabahndboluban is preferably used, the cleavage being carried out in particular at temperatures of 20 to 80 ° C.
Karboxylová kyseliny obecného vzorce I se mohou vhodným mneostvím příslušných anorganických bází za neutralizace převést v soli. Například se při rozpouštění příslušných kyselin ve vodě, která obsahuje stechiometrické mneožtví báze, po odpaření vody nebo po přidání rozpouštědla mísitelného s vodou, například alkoholu nebo acetonu, může získat pevné anorganická sůl. K výrobě aminové soli se PGkkselina rozpastí ve vhodném rozpouštědle, například ethenolu, acetonu, difthnOethfbU nebo benzenu, a k tomuto roztoku se přidá alespoň stechiooetrické m^eožs^t^zí bOwu. Přitom se sůl obvykle vzniká v pevné formě nebo se po odpaření rozpouštědla izoluje obvyklým způsobem.The carboxylic acids of the formula I can be converted into the salt by neutralization with appropriate inorganic bases under neutralization. For example, a solid inorganic salt can be obtained by dissolving the appropriate acids in water containing the stoichiometric base of the base after evaporation of the water or after the addition of a water-miscible solvent such as an alcohol or acetone. To prepare the amine salt, the PG kieselguhr is dissolved in a suitable solvent such as ethanol, acetone, diphenyl ether or benzene and at least a stoichiometric mixture is added to this solution. In this case, the salt is usually formed in solid form or isolated after evaporation of the solvent in the usual manner.
Sloučeniny obecného vzorce II sloužící jako výchozí látka se mohou vyrábět například tím, že se známým způsobem aldehyd vzorce IV (DOS č. 2 845 770)The starting material compounds of the formula II can be prepared, for example, by the aldehyde of the formula IV (DOS No. 2,845,770) in a known manner.
CHOCHO
(IV) v přítomnosti deprotonisačního prostředku, 'například natriumhydridu nebo kalium-terc.butylátu a bromisadního prostředku, například N-bromsuukininimidu, nechá reagovat s fosfonáeem obecného vzorce V(IV) in the presence of a deprotonating agent, for example sodium hydride or potassium tert-butylate, and a bromisadium agent, for example N-bromosuccinimide, reacted with a phosphonate of formula V
«3 «4 ^C^--CsC-^R5 (V) kde « > ®3' ^4 a R5 mají dříve uvedený význam, na keton obecného vzorce VI? 3? 4? C? - CsC? 4 R 5 (V) wherein? 3? 4 and R 5 are as previously defined, to the ketone of formula VI
«А^2«3 «4 — C--C— C = C—Rg (VI)«А ^ 2« 3 «4 - C - C - C = C - Rg (VI)
Po redukci ketoskupiny natr*imiborhydridem a připadlém dělení epimerů, zityddlnění esterové skupiny, například uhliStanném draselným v ethanolu a ketalovém Štěpení vodnou kyselinou octovou, jakož i případlém dělení epimerů se dojde ke ketonu obecného vzorce VII ,Reduction of the keto group with sodium imiborhydride and subsequent separation of the epimers, deposition of an ester group such as potassium carbonate in ethanol and ketal digestion with aqueous acetic acid, as well as the possible separation of epimers, results in a ketone of formula VII,
O 'A RJ «2 «3^4(VII)O 'A R J' 2 '3 ^ 4 (VII)
CH=CBr -CH-C---C C=C-RgCH = CBr -CH-C-C = C-Rg
OHOH
Etherrfikad hydroxylových skupin dihydropyrenem v přítomnosti katalytického mnnoství kyseliny p-tolulosulf’onové dává sloučeniny obecného vzorce II.The hydroxyl ether ether of dihydropyrene in the presence of a catalytic amount of p-tolulosulfonic acid gives compounds of formula II.
Výroba fosfonátu obecného vzorce V se pro’^i^<^:í o sobě známým způsobem reakcí alkylhalogenidu (získatllod z příslušného alkoholu halogenací) obecného vzorce VIII ^^?4 Hal-C—C^C-RS s dianioněm vyrobeným z fosfonátu obecného vzorce IXPreparation of phosphonate of the formula V for '^ i ^ <^: I in known manner by reacting the alkylhalide (získatllod halogenation from the corresponding alcohol) of the formula VIII ^^? 4 Hal-C-C-Cr, with the dianion produced from a phosphonate of the formula IX
CH3O \ O O Ri Ro \|| II Ά /P-CH2-C--C — HCH 3 O \ OO Ri Ro | II Ά / P-CH 2 -C-C-H
CH3O (VIII) (IX) kde «1’ «2’ Rj’ «4 a Rj maaí dříve uvedený význam.CH3O (VIII) (IX) where '1' 2 'Rj' 4 and Rj have the previously mentioned meaning.
Daaší přístup k fosfonátům obecného vzorce V spočívá v reakci aniontu dimetthyesteru kyseliny meU^yfosforové s esterem obecného vzorce XAnother approach to the phosphonates of formula (V) is to react the anion of the dimethylethyl methosphoric acid anion with an ester of formula (X)
O R R2 R3 «4O R R2 R3-4
II < x < /II <x </
---C-----c---C-C-Rg (X) kde б--- C ----- c --- C-C-Rg (X) where б
z příslušného esteru kyseliny malonové elkylecí halogenidem obecného vzorce VIII e následnou dekerbalkoxylací.from the corresponding malonic ester by alkylation with a halide of formula VIIIe followed by deceralkoxylation.
Ester obecného vzorce X je také možno získat z karboxylová kyseliny obecného vzorce XIThe ester of formula (X) may also be obtained from a carboxylic acid of formula (XI)
(XI) kde a Rg mají dříve uvedený význam, alkylácí halogenidem obecného vzorce VIII a následnou esteriflkací.(XI) wherein and R 8 are as previously defined, alkylated with a halide of formula (VIII) followed by esterification.
Sloučeniny podle vynálezu působí snižování krevního tlaku a bronchodilatoricky. Jsou dále vhodné к potlačování agregace trombocytů. Proto nové deriváty prostaglandinu vzorce I představují cenné farmaceuticky účinné látky. Mimoto při podobném ppektru účinnosti, srovnáno s příslušnými prostaglendiny, vykazují vyšší specifičnost a podstatně delší účinnost. Ve srovnání s PGIg se vyznačují větší stabilitou. Vysoká tkáňová specifičnost nových prostaglandinů se ukazuje při pokusech ца orgánech s hladkým svalstvem, jako například na chenlleu morčat, nebo izolovaném tracheu králíků, kde je pozorovatelná podstatně menší stimulace než při aplikaci přírodních prostaglendinů typu E, A nebo F.The compounds of the invention act to lower blood pressure and bronchodilator. They are further suitable for suppressing platelet aggregation. Therefore, the novel prostaglandin derivatives of formula I are valuable pharmaceutically active substances. In addition, with a similar spectrum of activity, compared to the corresponding prostaglendins, they exhibit higher specificity and considerably longer potency. They are more stable than PGIg. The high tissue specificity of the new prostaglandins is shown in experiments on smooth muscle organs such as guinea pig chenlle or isolated rabbit trachea, where significantly less stimulation is observed than with natural prostaglendins type E, A or F.
Nové deriváty prostaglandinu mají vlastnosti typické pro prostacykllny, jako je například snižování periferního arteriálního a koronárního cévního odporu, lnhibice agregace trombocytů a rozpouštění destičkových trombů, myokardiélní cytoprotekce a tím snižování systemického krevního tlaku, aniž by se současně snižoval objem tepů a koronární prokrvení; léčení záchvatu mrtvice, profylaxe a terapie koronárních srdečních onemocnění, koronární trombózy, srdečního Infarktu, periferních onemocnění artérií, arteriosklerózy a trombózy, profylaxe a terapie ischemlckých ataků CNS-systému, terapie šoku, lnhibice bronchokonstrikce, lnhibice sekrece žaludečních kyselin, cytoprotekce žaludeční a.střevní silzníce, cytoprotekce v játrech a pankreatu; antialergické vlastnosti, snižování pulmonárního cévního odporu a pulmonárního krevního tlaku, posilování prokrvení ledvin, použití místo heparlnu nebo jako adjuvans při dialýze hemoflltrace, konzervace konzerv krevní plazmy, zvláště konzerv krevních destiček, lnhibice porodních bolestí, léčení těhotenské toxlkózy, zvyšování cerebrálního prokrvování atd. Mimo to mají nové deriváty prostaglandinu antlproliferatlvní vlastnosti. Prostaglandlny podle vynálezu se moho také používat v kombinaci s Λ-blokátory nebo diuretiky.The novel prostaglandin derivatives have properties typical of prostacyclins, such as lowering peripheral arterial and coronary vascular resistance, inhibiting platelet aggregation and platelet thrombus dissolution, myocardial cytoprotection, and thereby lowering systemic blood pressure without simultaneously reducing pulse volume and coronary blood flow; treatment of stroke, prophylaxis and therapy of coronary heart disease, coronary thrombosis, cardiac infarction, peripheral arterial disease, arteriosclerosis and thrombosis, prophylaxis and therapy of ischemic attacks of the CNS system, shock therapy, inhibition of bronchoconstriction and gastric acid gastrectomy magnesium, cytoprotection in liver and pancreas; antiallergic properties, reduction of pulmonary vascular resistance and pulmonary blood pressure, enhancement of renal blood flow, use instead of heparin or as adjuvant in dialysis of hemofiltration, preservation of canned blood plasma, especially canned blood platelets, inhibition of labor pains, treatment of pregnancy toxosis, the new prostaglandin derivatives have antlproliferative properties. The prostaglandins of the invention can also be used in combination with Λ-blockers or diuretics.
Dávka sloučenin je 1 ai 1 500 /Ug/kg/den, když se podávají lidským pacientům. Dávková jednotka pro farmaceuticky přijatelné nosiče činí 0,01 až 100 mg.The dose of the compounds is 1 to 1,500 [mu] g / kg / day when administered to human patients. The dosage unit for pharmaceutically acceptable carriers is 0.01 to 100 mg.
U intravenosní Injekce u bdělých, hypertonních krys v dávkách 5, 20 a 100 ^ug/kg tělesné hmotnosti ukazují sloučeniny podle vynálezu silnější účinek snižující krevní tlak a déle trvající účinek než POE^ a PGA2, aniž by vyvolávaly průjmy jako PGEg nebo kardlální arytmie jako PGA^.For intravenous injection in alert, hypertonic rats at doses of 5, 20 and 100 µg / kg body weight, the compounds of the invention show a stronger blood pressure lowering effect and a longer lasting effect than POE 2 and PGA 2 without causing diarrhea such as PGEg or cardiac arrhythmias. as PGA ^.
Při Intravenosní injekci u narkotizováných králíků ukazují sloučeniny podle vynálezu ve srovnání 8 PGEg a PGA^ silnější a podstatně déle trvající snížení krevního tlaku, aniž by se ovlivňovaly ostatní orgány 8 hladkým svalstvem nebo funkce orgánů. Pro parenterální aplikaci se používají sterilní, Injekční, vodné nebo olejové roztoky. Pro orální aplikaci jsou vhodné například tablety, dražé nebo kapsle.In an intravenous injection in anesthetized rabbits, the compounds of the invention show a stronger and substantially longer-lasting decrease in blood pressure compared to 8 PGE 8 and PGA 6 without affecting other organs 8 by smooth muscle or organ function. For parenteral administration, sterile, injectable, aqueous or oily solutions are used. For oral administration, for example, tablets, dragees or capsules are suitable.
35 30735 307
К přípravě léčiv se používají sloučeniny obecného vzorce I ve směsi s obvyklými pomocnými a nosnými látkami obvyklými v galenice.For the preparation of medicaments, the compounds of the formula I are used in admixture with conventional excipients and carriers customary in galenics.
P ř í к 1 e d I (5E)-(16RS)-13,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6a-karbB-prostaglandin-I2 Example I (5E) - (16RS) -13,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6α-carbB-prostaglandin-I 2
К roztoku 9,4 g 4-karboxybutyltrifenylfosfoniumbromidu ve 20 ml dlmethylsulfoxidu a 7,8 ml tetrahydrofuranu se při 5 °C během 45 minut přidá 4,75 g kalium terč.butylátu a míchá se 45 minut při 5 °C. К červenému roztoku ylenu se přidá roztok 1,83 g (1R,5S,6R,7R)-7 -(tetrahydropyran-2-yloxy)-6-£( 3S,4RS)-2-brom-4-methyl-3-(tetrahydropyran-2-yloxy)-okt-1-en-6-inyl]bicyklo [3,3,0]oktan-3-onu ve 3 ml tetrahydrofuranu a 4 hodiny se míchá při 40 °C. Reakční směs se vlije do ledové vody, 35% roztokem kyseliny citrónové se okyselí na pH 4 až 5 a 3x se extrahuje methylenchloridem. Organické fáze se třepe se solným roztokem, suší síranem hořečnatým a ve vakuu se odpaří. Zbytek se čistí chrcmatogrefií na silikagelu. Směsí hexan/acetát (3+2) se získá nejdříve 180 mg 5Z-konfigurovaného olefinu jakož i jako polární komponenty 680 mg (5E)-(l6RS)-13,l4-didehydro-l6-methyl-18,18,l9,19-tetradehydro-6a~karba-prostaglendin-I2-11,15-bis(tetrahydropyranylether) jako bezbarvý olej.To a solution of 9.4 g of 4-carboxybutyltriphenylphosphonium bromide in 20 ml of dimethylsulfoxide and 7.8 ml of tetrahydrofuran at 5 ° C is added 4.75 g of potassium tert-butyllate at 45 ° C over 45 minutes and stirred at 5 ° C for 45 minutes. To a red solution of ylene is added a solution of 1.83 g of (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- (3S, 4RS) -2-bromo-4-methyl-3- (tetrahydropyran-2-yloxy) -oct-1-en-6-ynyl] bicyclo [3.3.0] octan-3-one in 3 ml of tetrahydrofuran and stirred at 40 ° C for 4 hours. The reaction mixture was poured into ice water, acidified to pH 4-5 with 35% citric acid solution, and extracted three times with methylene chloride. The organic phases are shaken with brine, dried over magnesium sulphate and evaporated in vacuo. The residue was purified by silica gel chromatography. A mixture of hexane / acetate (3 + 2) initially yielded 180 mg of the 5Z-configured olefin and as a polar component 680 mg of (5E) - (16RS) -13,14-didehydro-16-methyl-18,18,19,19 -tetradehydro-6a-carba-prostaglandin-I2 -11,15-bis- (tetrahydropyranyl ether) as a colorless oil.
IC (CHC13): 3 500 (široký), 2 940, 2 860, 2 225, 1 710, 1 440/cm.IR (CHC1 3): 3500 (broad), 2940, 2860, 2225, 1710, 1440 / cm.
К odštěpení ochranných skupin se 680 mg získaného olefinačního produktu 20 hodin při 25 °C míchá s 25 ml směsi асеtát/voda/tetrahydrofuran (65/35/10). Potom se ve vakuu odpaří a zbytek se chromatografuje na silikagelu. Směsí ecetát/kyselina octová (99,9+0,1) se získá 345 mg titulní sloučeniny jako bezbarvý olej.For cleavage of the protecting groups, 680 mg of the obtained olefin product was stirred with 25 ml of an acetate / water / tetrahydrofuran (65/35/10) mixture at 25 ° C for 20 hours. It is then evaporated in vacuo and the residue is chromatographed on silica gel. The acetate / acetic acid mixture (99.9 + 0.1) afforded 345 mg of the title compound as a colorless oil.
IČ: 3 600, 3 400 (široký), 2 930, 2 225, 1 710, 1603, 1 020/cm.IR: 3600, 3400 (broad), 2930, 2225, 1710, 1603, 1020 / cm.
Výchozí látka pro shora uvedenou titulní sloučeninu se vyrobí následovně:The starting material for the above title compound is prepared as follows:
a) (1R,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-[2 (4RS)-2-brom-4-methyl-3-oxo-okt-1-en-6-lnyl] bicyklo [З,3,0] oktan. К suspenzi 1,81 g matrium hydridu ve 180 ml dlmethoxyethanu se při 0 °C přikape roztok 10,5 g methylesteru kyseliny 3-methyl-2-oxo-hept-5-in-fosfonové v 70 ml dímethoxyethanu, hodinu se míchá při 0 °C a pak se přidá 7,4 g jemně práškovaného N-bromsukctnimidu. Míchá se 30 minut při 0 °C, přidé se roztok 11,4 g (IR,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-formyl-bicyklo 3,3,0 oktanu v 90 ml dlmethoxyethanu a míchá se 2 hodiny při 0 °C. Reakční směs se vlije do nasyceného roztoku chloridu amonného a extrahuje se etherem. Organický extrakt se promyje vodou do neutrální reakce, suší síranem hořečnatým a ve vakuu se odpaří. Po chromatografii zbytku ne silikagelu se získá směsí hexan/ether (3+2) 8,2 g nenasyceného ketonu jeko bezbarvý olej.a) (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- [2- (4RS) -2-bromo-4-methyl-3-oxo-oct-1-ene-6- lnyl] bicyclo [З, 3.0] octane. A solution of 10.5 g of 3-methyl-2-oxo-hept-5-in-phosphonic acid methyl ester in 70 ml of dimethoxyethane is added dropwise at 0 [deg.] C. to a suspension of 1.81 g of sodium hydride in 180 ml of dimethoxyethane, stirred at 0 for 1 hour. ° C and then 7.4 g of finely powdered N-bromosuccinimide are added. Stir 30 min at 0 ° C, add a solution of 11.4 g (IR, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo 3,3,0 octane in 90 mL dimethoxyethane and stirred at 0 ° C for 2 hours. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ether. The organic extract was washed with water until neutral, dried over magnesium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel yielded 8.2 g of unsaturated ketone as a colorless oil with hexane / ether (3 + 2).
IČ: 2 930, 2 880, 1 712, 1688, 1 602, 1 595, 1 450, 1 275, 945/cm.IR: 2930, 2880, 1712, 1688, 1560, 1595, 1450, 1275, 945 / cm.
b) (1R,5S,6R,7R)-7-hydroxy-6-£(3S,4RS)-2-bronj-3-hydroxy-4-methyl-okt~1 -en-6-inyl] bicyklo [3,3,0]oktan-3-on. К roztoku 5,9 g ketonu vyrobeného podle příkladu la) ve 140 ml methanolu se při -40 °C po Částech přidá 2,5 g netriumborhydridu a 30 minut se míchá při -40 °C. Potom se zředí etherem, promyje vodou do neutrální reakce, suší se síranem hořečnatým a ve vakuu se odpaří. Surový produkt (15-epimerní směs) se rozpustí ve 200 ml methanolu, přidá se 2,5 g uhličitanu draselného a 17 hodin se míchá pod argonem při 23 °C. Potom se zahustí ve vakuu, zředí se etherem a solným roztokem promyje do neutrální reakce. Suší se síranem hořečnatým a ve vakuu odpaří. Zbytek se po odpaření míchá 16 hodin při teplotě místnosti s 300 ml směsi kyselina octová/voda/tetrahydrofuran (65/35/10) a pak se odpaří ve vakuu. Sloupcovou chromatograflí na silikagelu směsí ether/теthylenchlorid se získá nejdříve 1,6 g 15β konfigurovaného alkoholu, jakož i jako polární složku 2,1 g titulní sloučeniny (PG nomenklatura 15a-hydroxy) jako bezbarvý olej.b) (1R, 5S, 6R, 7R) -7-hydroxy-6- (3S, 4RS) -2-bromo-3-hydroxy-4-methyl-oct-1-en-6-ynyl] bicyclo [3] , 3,0] octan-3-one. To a solution of 5.9 g of the ketone prepared according to Example 1a) in 140 ml of methanol at -40 ° C was added portionwise 2.5 g of sodium borohydride and stirred at -40 ° C for 30 minutes. It is then diluted with ether, washed neutral with water, dried over magnesium sulphate and evaporated in vacuo. The crude product (15-epimeric mixture) was dissolved in 200 ml of methanol, 2.5 g of potassium carbonate was added and stirred under argon at 23 ° C for 17 hours. It is then concentrated in vacuo, diluted with ether and washed neutral with brine. It is dried over magnesium sulphate and evaporated in vacuo. The residue is stirred for 16 hours at room temperature with 300 ml of acetic acid / water / tetrahydrofuran (65/35/10) and then evaporated in vacuo. Column chromatography on silica gel with ether / methylene chloride yielded at first 1.6 g of the 15β configured alcohol, as well as as a polar component 2.1 g of the title compound (PG nomenclature 15a-hydroxy) as a colorless oil.
IČ: 3 600, 3 430 (široký), 2 960, 2 920, 2 870, 1 738, 1 600, 1 400/cm.IR: 3600, 3430 (broad), 2960, 2920, 2870, 1738, 1600, 1400 / cm.
235 307235 307
с) (1R,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-2-brom-4-methyl-3-(tetrahydropyran-2-yloxy)-okt-1-en-6-inylJ bicyklo [3, 3,θ] oktan-3-on. Roztok 1,6 g a alkoholu vyrobeného podle příkladu 1b), 16 mg kyseliny p-toluensulfonové a 1,5 g dihydropyranu v 50 ml methylenchlortdu se 35 minut míchá při 0 °C. Potom se zředí etherem, třepe se se zředěným roztokem hydrogenuhličitanu sodného, promyje vodou ďo neutrální reakce, suší síranem hořečnatým a ve vakuu se odpaří. Po chromatografii zbytku na silikagelu se získá směsí hexan/ether (7+3) 2,17 g titulní sloučeniny jako bezbarvý olej.(1R, 5S, 6R, 7R) -7- (Tetrahydropyran-2-yloxy) -6 - [(3S, 4RS) -2-bromo-4-methyl-3- (tetrahydropyran-2-yloxy) -oct 1-en-6-ynyl-bicyclo [3.3.0] octan-3-one. A solution of 1.6 g of the alcohol prepared according to Example 1b), 16 mg of p-toluenesulfonic acid and 1.5 g of dihydropyran in 50 ml of methylene chloride was stirred at 0 ° C for 35 minutes. It is then diluted with ether, shaken with dilute sodium bicarbonate solution, washed with water until neutral, dried over magnesium sulphate and evaporated in vacuo. After chromatography of the residue on silica gel, a mixture of hexane / ether (7 + 3) afforded 2.17 g of the title compound as a colorless oil.
IČ: 2 940, 2 870, 1 735, 1 450, 1 120, 1 018, 965/cm.IR: 2940, 2870, 1735, 1450, 1120, 018, 965 / cm.
Příklad 2 (5E)-( 16RS)-13,14-didehydro-16,20-dimethyl-IQ, 18,19,19-tetradehydro-6a-karba-prostaglandln-l2Example 2 (5E) - (16RS) -13,14-didehydro-16,20-dimethyl-10,18,19,19-tetradehydro-6α-carbamestaglandin-12
Analogicky příkladu 1 se z 1,6 g (1R,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[](3S,4RS)-2-brom-4-methyl-3-(tetrahydropyran-2-yloxy)-non-1-en-6-lnyl] bicyklo[3, 3,θ]oktan-3-onu získá 640 mg (5E)-(16RS)-13,l4-dldehydro-16,20-dimethyl-18,18,19,19-tetradehydro-6a-karba-prostaglendln-Ig-l1»15-bis-(tetrehydropyranylether) jako bezbarvý olej.Analogously to Example 1, from 1.6 g of (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6 - [] (3S, 4RS) -2-bromo-4-methyl-3- ( tetrahydropyran-2-yloxy) non-1-en-6-ynyl] bicyclo [3.3.0] octan-3-one gives 640 mg of (5E) - (16RS) -13,14-dihydro-16,20 -dimethyl-18,18,19,19-tetradehydro-6α-carboprostaglendin-Ig-11,15-bis (tetrehydropyranyl ether) as a colorless oil.
IČ: 3 500 (Široký), 2 942, 2 860, 2 224, 1 710/cm.IR: 3500 (Wide), 2942, 2860, 2224, 1710 / cm.
Po odětěpení ochranných skupin podle příkladu 1 se získá 0,3 g titulní sloučeniny jako bezbarvý olej.After deprotection according to Example 1, 0.3 g of the title compound is obtained as a colorless oil.
IČ: 3 600, 3 350 (Široký), 2 932, 2 224, 1 710, 1 602/cm.IR: 3,600, 3,350 (Wide), 2932, 2224, 1710, 1660 / cm.
Výchozí látka pro shora uvedenou titulní sloučeninu se vyrobí následovně:The starting material for the above title compound is prepared as follows:
a) (1R,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-β4RS)-2-brom-4-methyl-3-oxo-non-l-en-6-lnyl]bicyklo [3,3,oJoktana) (1R, 5S, 6R, 7R) -3,3-Ethylenedioxy-7-benzoyloxy-6-β4RS) -2-bromo-4-methyl-3-oxo-non-1-en-6-lnyl] bicyclo [3.3, octocan
Analogicky příkladu la) se z 6 g dimethýlesteru kyseliny 3-methyl-2-oxo-okt-5-inyl-fosfonové, 3,7 g N-bromsukeinimldu a 5,6 g (1R,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy- 6-formyl-bicyklo £3,3, oj oktanu získá 4,0 g nenasyceného ketonu jako bezbarvý olej.Analogously to Example 1a), from 6 g of 3-methyl-2-oxo-oct-5-ynylphosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide and 5.6 g of (1R, 5S, 6R, 7R) -3, 3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo [3.3.1] octane yields 4.0 g of unsaturated ketone as a colorless oil.
IČ: 2 935, 2 883, 1 713, 1 687, 1 602, 1 596, 1 275, 947/cm.IR: 2935, 2883, 1713, 1687, 1660, 1596, 1275, 947 / cm.
b) (1R,5S,6R,7R)-7-hydroxy-6-£(3S,4RS)-2-brom-3-hydroxy-4-methyl-non-1-en-6-inyl]bicyklo [3,3,0] oktan-3-onb) (1R, 5S, 6R, 7R) -7-hydroxy-6- (3S, 4RS) -2-bromo-3-hydroxy-4-methyl-non-1-en-6-ynyl] bicyclo [3] , 3,0] octan-3-one
Analogicky příkladu Ib) se z 3 g ketonu vyrobeného podle příkladu 2a) po redukci 1,3 g natriumborhydridem, zmýdelnění 1,2 g uhličitanu draselného a následném ketelovém Štěpení 150 ml směsi kyselina octové/voda/tetrahydrofuran, získá 1,2 g titulní sloučeniny (15a-hydroxy) jako bezbarvý olej.Analogously to Example Ib), 1.2 g of the title compound is obtained from 3 g of the ketone prepared according to Example 2a) after reduction with 1.3 g of sodium borohydride, saponification of 1.2 g of potassium carbonate and subsequent ketel digestion with 150 ml of acetic acid / water / tetrahydrofuran. (15α-hydroxy) as a colorless oil.
IČ: 3 610, 3 400 (Široký), 2 960, 2 870, 1 739, 1 600/cm.IR: 3,610, 3,400 (Wide), 2960, 2870, 1739, 1600 / cm.
c) (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-^(3S,4RS)-2-brom-4-tíiethyl-3-(tetrahydropyran-2-yloxy)-non-1-en-6-lnyl]bicyklo [3,3, Oj oktan-3-onc) (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- (3S, 4RS) -2-bromo-4-thiethyl-3- (tetrahydropyran-2-yloxy) -non -1-en-6-lnyl] bicyclo [3.3.0] octan-3-one
Analogicky příkladu 1c) se z 0,78 g dlolu vyrobeného podle příkladu 2b) a 0,7 g dlhydropyranu získá 1,1 g titulní sloučeniny jako bezbarvý olej.Analogously to Example 1c), from 0.78 g of the dlol prepared according to Example 2b) and 0.7 g of dlhydropyran, 1.1 g of the title compound is obtained as a colorless oil.
IČ: 2 940í 2 872, 1 736, 1 450, 1 120, 965/cm.IR: 2940, 2872, 1736, 1450, 1120, 965 / cm.
Příklad 3 (5E)-(l6RS)-20-ethyl-13,14-dldehydro-l6-methyl-18,18,19,19-tetradehydro-6e-karba-prostaglandin-IgExample 3 (5E) - (16RS) -20-ethyl-13,14-dihydro-16-methyl-18,18,19,19-tetradehydro-6e-carbamapaglandin-Ig
Analogicky příkladu 1 se ъ 2 g (1R,5S,6R,77)-77(tetr8hydropyrsn-2-yloxy)-6-f(3S,4RS)-2-brom-4-tnethyl-3- ^etoahitopp^an-^-ytoxi )-rek-1 -en-ó-lnljbi cyklp [3, 3,pJ oktan-3-onu získá 900 mg (5E)-(!6RS)-20oethyl-13,14-rirthy<riO-16-eeetyli11,18,19,19-tetradeyidro-6a-kerte-pOotaglandln-Ig-l 1 ,15-bls-hehOralycrOpiranyletheru) jako bezbarvý olej.Analogously to Example 1 ъ 2 g of (1R, 5S, 6R, 7 7) -77 (tetr8hydropyrsn-2-yloxy) -6-f (3S, 4RS) - 2-bromo-4-tnethyl-3-n-etoahitopp - ^ - yloxy) - r ek-1-en-O-C lnljbi YKL p [3, 3, PJ octan-3-one 900 mg of (5E) - (6RS) -20oethyl-13,14-rirthy < 10-1-16-ethyl-11,18,19,19-tetradeyidro-6a-kerte-pyotaglandin-Ig-1,1,15-bls-haloalypyranyl ether) as a colorless oil.
IČ: 3 500 (široký), 0 948, 0 860, '' 0 000, 1 708/cn.IR: 3500 (broad), 0 948, 0 860, 0 000, 1 708 / cm.
Po.odštěpení ochran-ých skupin podle příkladu 1 se získá 420 mg titulní sloučenin) jako bezbarvý olej.After deprotection according to Example 1, 420 mg of the title compound) was obtained as a colorless oil.
IČ: 3 600, 3 360 (široký), 0 930, 0 858, 2 000, 1 708, I 601/ce.IR: 3,600, 3,360 (broad), 0,930, 0,858, 2,000, 1,708, 1,601.
Výýhozi látka pro shora uvedenou titulní sloučeninu se získá následovně:The yield of the title compound is obtained as follows:
a) (1 R,5S,6R,7R3-ethilendioxi-7ebenzo^ox1-6-β4RS)-0-froe-^-eneetyL·3-oxo-dec-t(^-6-1-ι1] bliklo [3,3,0] oktona) (1 R, 5 S, 6 R, 7R3-e t h i il ethylenedioxy -7ebenzo ^ OX 1-6 -β4RS) - -from 0 - ^ - eneetyL · 3-oxo-dec-t (^ - 6- 1 -ι 1 ] flashed [3, 3,0 ] okton
Ap-logicki příkladu 1e) se z 6,05 g dimethyiesteru kyselini 3(eeeУy1-2-pχo-noo---lnyl-fosfo-ové, 3,7 g ^-bгPesukclnleidu 8 5,6 g (1R,5S, 6R,7R)-3,3(etУ1le-dlρχ1-7-benzP1lPX1-6-fpoeyl-bic1PlP [3,3,0] oktanu získá 4,5 g nenasiceného ketonu jako bezbarvý olej.In analogy to Example 1e), 5.6 g (1R, 5S, 6R) of 5.6 g (1R, 5S, 6R) were obtained from 6.05 g of dimethyl 3-ester (ethyl-2-phenoxy-phenylphosphonic acid), 3.7 g. , 7R) -3,3 (ethoxy-dl-β-7-benzP1PX1-6-fpoeyl-bip1P [3,3,0] octane yields 4.5 g of unsaturated ketone as a colorless oil.
IČ: 0 940, 0 880, 1 710, 1 688, 1 601, 1 590, 1 075, 948/cm.IR: 0 940, 0 880, 1 710, 1 688, 1 601, 1 590, 1 075, 948 cm @ -1.
b) (IR, 5S, 6), 7R)-7-hidroxy-6-([(3S, 4RS)--2-(brpιe-3-Уydrooy14-meetyl-dec-1 -en-6-inil] blciklo ]3, 3,0]pktan(3-on(b) (1R, 5S, 6), 7R) -7-Hydroxy-6 - ([(3S, 4RS) -2- (brpeye-3-Uydrooyl4-meetyl-dec-1-en-6-inyl) blciclo) 3,3,3] pktane (3-on
An-loglcki příkladu 1b) se z 4 g ketonu virobeného podle příkladu 3e), po redukci natrlm borhydrldem, z^eý^dě^l^í^i^ií uh^^lČStanem draselným a náslddnée ketalovée štěpení směsí kyselina octová/vora/teOrah1roofuran (65/ 35/10) získá 1,5 g titulní sloučenini (15a-hidroxi) jako bezbarvý olej.Analogously to Example 1b) from 4 g of the viret ketone according to Example 3e), after reduction with sodium borohydride, with potassium carbonate and subsequent ketal digestion with acetic acid (vor). tetralofuran (65/35/10) afforded 1.5 g of the title compound (15α-hydroxy) as a colorless oil.
IČ: 3 610, 3 400 (široký), 0 955, 0 868, 1 738, 1 601/ce.IR: 3,610, 3,400 (broad), 0,955, 1,868, 1,738, 1,601.
c) (1R ,5 S, 6R ,7R ))-7-(te trah^ro^ran-^^ox^^^ 3^S, 4RS j^broe--—meWy^Jjtotray1doppyraa^-yloxy jrec--(--n--6lnyl]bic1klP [3, ^^oktan-^-onc) (1R, 5S, 6R, 7R)) - 7- (te ^ ro ^ trahi healing - ^^^ ^^ OX 3 ^ S ^ j 4RS broe- - -meWy Jjtotra y ^ 1 ^ d oppyraa - yloxy j r ec-- (--n- -6 ynyl] bic1 to an lP [3, ^^ octane - ^ - one
Analogieki příkladu 1c) se z 1,0 g dlolu virobeného podle příkladu 3b) získá 1,81 g titulní sloučenini jako bezbarvý olej. IČ: 0 940, 0 868, 1 738, 1 450, 1 1.25, 960/cm.Analogously to Example 1c), 1.81 g of the title compound is obtained as a colorless oil from 1.0 g of the virol doloble of Example 3b). IR: 0 940, 0 868, 1738, 1450, 1125, 960 / cm.
d) Dimeethiester kyselini 3-eeehy1l2-oxo-n-n---inyl-foffpnpvé K roztoku 15,8 g sodíku ve 340 ml eto^a^otolu se při 00 °C pMtope 120 g toetoylesteru kyselini metlty)lmвlpnpvé. Po 30 minutách se přlkape 135 g l-brom-Č-yexinu (virobený z Уех-2-i-·^-olu s bromidem fosforitem v pyridinu) a zahřívá se 16 hodin pod zpětným chladičem. Potom se fliri^uje, zbytek se promyje meety/lencylori dem a ve vakuu se zehyusí. Zbytek se rozpistí v 500 ml meetyienchlpridu, dvetoét se vitřepe vždi s 50 ml vody, suší se síranem hořečnatým a ve vakuu se zhynut,!. Zbytek se ^stltoje ve vakuu při 1 862 pa a 148 až 152 °C. Získá se 155 g destilátu, elkilPVaného esteru kyselini metУylmalpnové, který se 4,5 hodlni pod zpětným chladičem zahřívá v 1 200 ml dimeetyisulfoxldu a 10 ml vodi s 52 g liyhumchloridu. Potom se vlije do 5 litrů ledové vody, extrahuje se etherem, extrakt se třepe s rodo^ s^í síranem lotočne^ým a ve vakuu se zahnut,!. Deetltoce zty^t-ku dává přl 94 až 96 °C a 1 862 Pa 95 g ethy^at-eru 2·(meehy1lpPph4-i--Pyseli-1 jako bezbarvou kapalinu»d) Dimeethiester eeehy1l2 3-oxo-NN --- foffpnpvé ynyl-1 To a solution of 5.8 g of d Cart in 340 ml of N, N-ethoxy Otol at 00 DEG C. 120 g pMtope toetoylesteru acid metlty) lmвlpnpvé. After 30 minutes, 135 g of 1-bromo-6-yexine (virobromo-2-i-4-ol with phosphorus tribromide in pyridine) was added dropwise and refluxed for 16 hours. It is then filtered, the residue is washed with methylene chloride and dried in vacuo. The residue is dissolved in 500 ml of meetylene chloride, the solution is shaken with 50 ml of water for 20 years, dried over magnesium sulphate and dried in vacuo. The residue was ^ stltoje vacuum at 1862 p aa 148-152 ° C. 155 g of distillate, the eluted methyl malponic acid ester, is obtained, which is refluxed in 1200 ml of dimethyl dimetisulfoxide and 10 ml of water with 52 g of lithium chloride for 4.5 hours under reflux. It is then poured into 5 liters of ice-water, extracted with ether, shaken with rhodium sulphate and bent under vacuum. Deetltoce of the title gives , at 94 DEG- 96 DEG C. and 18 mmHg, 95 g of ethylene-2-methylphosphine-i-Pyseli-1 as a colorless liquid.
К roztoku 176 g dimeetyriesteru kyselini methanfosfonové ve 0 1 hetrθУ1dopfuranu se p^lkape 640 ml 1,5 M roztoku v yexanu při -70 °C. Po 15 minutécy se pommlu přMá roztok 90 g sty^st^u 2-eeeth1lOPtt4-í--kyseli-1 ve 300 ml tetrsyidrofuranu. Míchá se 4 У^^!-1 přl -70 -eutoaHzuje se Pyseltoou octovou a ve vakuu se odpař·!. Ke zb^ku se přidá 200 ml vody, třikrát se extrahuje vždy 500 ml methylenchloridu, extrakt se vytřepe se 100 ml vody, suší síranem hořečnátým a zahustí se ve vakuu. Destilace zbytku dává při 46 Pa 8 126 až 128 °C 80 g titulní sloučeniny jako bezbarvou kapalinu.К dimeetyriesteru solution of 176 g of methanephosphonic acid at 0 to 1 hetrθУ1dopfuranu p ^ e o and p 6 1 40 m l of 5 M solution in y -7 Exan at 0 ° C. P 15 minutéc y pommlu přMá 90 g hundred ^ St ^ u 2 eeeth1lOPtt4 d - Acid-one in 300 ml tetrsyidrofuranu. Stir 4 У ^^! - 1 horizontal being -70 -eutoaHzuje Pyseltoou with acetic acid and evaporated in vacuo · !. The e-ZB is added to 200 ml of water, extracted three times with 500 ml methylene chloride, the extract is shaken with 100 ml of water, dried over magnesium sulfate and concentrated in vacuo. Distillation of the residue afforded 80 g of the title compound as a colorless liquid at 12 mbar (126-128 ° C).
Příklad 4 (5E)-13,14-didehydro-16,16-dimethyl-18,18,19,1 9-tetradehydro-óa-karba-prostaglandinAnalogicky příkladu 1 se z 1,5 g (1R,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-brom-4,4-dimethyl-3-(tetrahydropyren-2-yloxy)-okt-1-en-6-inyl] bicyklo цЗ,3,0] oktan-3-onu získá 610 mg (5E)-13,14-didehydro-l6,l6-dimethyl-18,18,19,19-tetrBdehydro-6a-karba-prostaglandin-^-l 1 ,15-bis-(tetrahydropyran-2-yletheru) jako bezbarvý olej.EXAMPLE 4 (5E) -13,14-Didehydro-16,16-dimethyl-18,18,19,1 9-Tetradehydro-6α-carbamaprostaglandin Analogously to Example 1, from 1.5 g of (1R, 5S, 6R, 7R) ) -7- (tetrahydropyran-2-yloxy) -6 - [(3S) -2-bromo-4,4-dimethyl-3- (tetrahydropyren-2-yloxy) -oct-1-en-6-ynyl] bicyclo цЗ, 3,0] octan-3-one yields 610 mg of (5E) -13,14-didehydro-16,16-dimethyl-18,18,19,19-tetrBdehydro-6α-carbab prostaglandin-4-yl 15-bis- (tetrahydropyran-2-yl ether) as a colorless oil.
IČ: 3 500 (široký), 2 944, 2 862, 2 222, 1 708/cm.IR: 3500 (broad), 2944, 2862, 2222, 1798 / cm.
Po odštěpení ochranných skupin podle příkladu 1 se získá 290 mg titulní sloučeniny jako bezbarvý olej.After deprotection of Example 1, 290 mg of the title compound is obtained as a colorless oil.
IČ: 3 600, 3 400 (široký), 2 930, 2 862, 1 708, 1 600/cm.IR: 3600, 3400 (broad), 2930, 2862, 1798, 1600 / cm.
a) (1R,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-(2-brom-4,4-dimethyl-3-oxo-okt-1-en-6-lnyl)bicyklo [3, 3,0] oktana) (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7-benzoyloxy-6- (2-bromo-4,4-dimethyl-3-oxo-oct-1-en-6-ynyl) bicyclo [3,3,0] octane
Analogicky příkladu la) se z 6,25 g dimethylesteru kyseliny 3,3-dlmethyl-2-oxo-hept-5-in-fosfonové, 3,7 g N-bromsukeinimIdu a 5,6 g (1R,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-formyl-bicyklo [3,3,0]oktanu získá 4,7 g nenasyceného ketonu jeko bezbarvý olej. IČ: 2 940, 2 878, 1 710, 1 688, 1 602, 1 594, 1 448, 1 270, 944/cm.Analogously to Example 1a), from 6.25 g of 3,3-dimethyl-2-oxo-hept-5-in-phosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide and 5.6 g (1R, 5S, 6R, 7R) ) -3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo [3.3.0] octane yields 4.7 g of unsaturated ketone as a colorless oil. IR: 2940, 2878, 1710, 1688, 1 602, 1594, 1448, 1270, 944 / cm.
b) (1R,5S,6R,7R)-7-hydroxy-6-£(3S)-2-brom-4,4-dimethyl-3-hydroxy-okt-1-en-6-inyl] bicyklo [3,3,0] oktan- 3-onb) (1R, 5S, 6R, 7R) -7-hydroxy-6- (3S) -2-bromo-4,4-dimethyl-3-hydroxy-oct-1-en-6-ynyl] bicyclo [3] , 3,0] octan-3-one
Analogicky příkladu 1b) se ze 4 g ketonu vyrobeného podle příkladu 4a) po redukci natriumborhydridem, zmýdelnění uhličitanem draselným a následném ketalovém štěpení získá 1,40 g titulní sloučeniny (15a-hydroxy) jako bezbarvý olej.Analogously to Example 1b), 1.40 g of the title compound (15α-hydroxy) is obtained as a colorless oil from 4 g of the ketone produced according to Example 4a) after reduction with sodium borohydride, saponification with potassium carbonate and subsequent ketal digestion.
IČ: 3 600, 3 410 (široký), 2 958, 2 865, 1 738, 1 600/cm.IR: 3600, 3410 (broad), 2958, 2865, 1738, 1600 / cm.
c) (1R,5S,6R,7R)-7-(tetrehydropyran-2-yloxy)-6-£( 3S)-2-hrom-4,4-dlmethyl-3-(tetrahydropyran-2-yloxy)-okt-1-en-6~lnyljbicyklo [3,3,0] oktan-3-onc) (1R, 5S, 6R, 7R) -7- (tetrahydro-pyran-2-yloxy) -6- (3S) -2-thromo-4,4-dimethyl-3- (tetrahydropyran-2-yloxy) -oct -1-en-6-ynyl] bicyclo [3.3.0] octan-3-one
Analogicky příkladu 1c) se z 1,2 g diolu vyrobeného podle příkladu 4b) s dlhydropyranem získá 1,6 g titulní sloučeniny jako olej.Analogously to Example 1c), 1.6 g of the title compound is obtained as an oil from 1.2 g of the diol prepared according to Example 4b) with dlhydropyran.
IČ: 2 942, 2 870, 1 738, 1 450, 1 132, 960/cm.IR: 2942, 2870, 1738, 1450, 1132, 960 / cm.
Příklad 5 (5E)-1 3,14-didehydro-18,18,19,19-tetradehydro-16,16,20-trimethyl-6a-karba-prostaglendln-I2 Example 5 (5E) -1,1,14-didehydro-18,18,19,19-tetradehydro-16,16,20-trimethyl-6α-carboprostaglendin- 12
Analogicky příkladu 1 se z 1 g (1R,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-£(3S)-2-brom-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-non-1-en-6-inyl] bicyklo [3,3,0]oktan-3-onu získá 400 mg (5E)-13,14-didehydro-18,18,19,19-tetradehydro-16,l6,20-trlmethyl-6a-karbaprostaglandin-Ig-l1,15-bl8-(tetrahydropyranyletheru) jako bezbarvý olej.Analogously to Example 1, from 1 g of (1R, 5S, 6R, 7R) -7- (tetrahydropyran-2-yloxy) -6- (3S) -2-bromo-4,4-dimethyl-3- (tetrahydropyran-2) -yloxy) -non-1-en-6-ynyl] bicyclo [3.3.0] octan-3-one gives 400 mg of (5E) -13,14-didehydro-18,18,19,19-tetradehydro- 16,16,20-trimethyl-6α-carbaprostaglandin-Ig-11,15-b18- (tetrahydropyranyl ether) as a colorless oil.
IČ: 3 510 (široký), 2 940, 2 858, 2 220, 1 708/cm.IR: 3,510 (broad), 2940, 2,858, 2,220, 1,708 / cm.
Po odštěpení ochranných skupin podle příkladu 1 se získá 410 mg titulní sloučeniny jako bezbarvý olej.After deprotection according to Example 1, 410 mg of the title compound is obtained as a colorless oil.
IČ: 3 600, 3 340 (široký), 2 940, 2 832, 2 220, 1 708, 1 600/cm.IR: 3600, 3340 (broad), 2940, 2832, 2220, 1718, 1600 / cm.
V^eidOízí. látka pro shora uvedenou titulní sloučeninu se vyrobí následovně:See all. the compound for the above title compound is prepared as follows:
a) (1R,5S,6R,77)-3,3-ethylendloxy-7-benzoyloxy-6-(2-trom-4,4-dimethyl-3-oxo-non-1-en-ó-i—yjtac^to [3,3,ÓJ otoan(a) (1R, 5S, 6R, 77) -3,3-ethylenedloxy-7-benzoyloxy-6- (2-thromo-4,4-dimethyl-3-oxo-non-1-en-6-i-yyacac) ^ it [ 3, 3, otoJ otoan
Annlogicky příkladu 1a) se z 12,6 g dimeethyesteru kyseliny 3,3-dimeethl.-23oxo-okt3 -5-inyl-fosoonové, 7,4 g N-bromsukkinimidu a 11,2 g (1R,5S,6R,7R)-3,3-ethylendioxy-7з 3benzoyloxy-6-formyy-bicyklo^3,3,o]oktanu získá 8,7 g nenasycená^ ketonu jako bezbarvý olej.In an analogous manner to Example 1a), 12.6 g of 3,3-dimethyl-23-oxo-oct-5-ynyl-5-ynylphosphonic acid dimeethylester, 7.4 g of N-bromosuccinimide and 11.2 g of (1R, 5S, 6R, 7R) -3,3-ethylenedioxy-7з 3benzoyloxy formyl-6- y - b bicyclo ^ 3, 3, o] of ZIS kt anu ka 8.7 g unsaturation e ^ t one of j and k b b ez arvý oil.
IČ: 2 946, 2 880, 1 712, 1 687, 1 601, 1 594, 1 272, 948/cm.IR: 2946, 2880, 1712, 1687, 1601, 1594, 1272, 948 / cm.
b) (1R,5S,6R,7R)-3-bhydOxxy3-3(33)-323boo-4,443lilmthhl-3--hydoxχ-nnn-1-enn3--nylÍbicyklo [3,3,0]okten3 3-^onb) (1R, 5S, 6R, 7R) -3- bh ydOx x y 3 - 3 ( 3 3) - 3 2 3 boo-4,44 3 µm h -3- y- dox χ -nnn-1- ENN 3 - - ny Li bicyclo [3.3.0] he ^ 3- okten3
Analogicky příkladu 1b) se z 5 g'ketonu vyrobeného podle příkladu 5a) po redukci natřiTmborhxdridem, zrnmddlnění uhličia-nem draselrým a následném ketalovém štěpení získá 1,80 g titulní sloučeniny (15ttзhχdroxχ- jako bezbarvý olej.Analogously to example 1b), from 5 g'ketonu produced according to example 5a) after reduction natřiTmborh x drid, carbonic zrnmddlnění draselrým-NEM and subsequent ketal cleavage, 1.80 g of the title compound (15ttзhχdrox χ - as a colorless oil.
IČ: 3 600, 3 404 (široký), 2 958, 2 864, 1 736, 1 601/cm.IR: 3,600, 3,440 (broad), 2,958, 2,864, 1,736, 1,601 / cm.
- c) (IR ,,S,67 ,,7) -3-(tetrahyddoχχУon-22χXloχl-3-[(3S)-2-b?om-3,4-diιneehhXl3“(tetoahyero^ran-^-ylox^-non-1 -en-6-inxl] bicyklo [3, 3,°j oktan-3-on- c) (R ,, S, 67 ,, 7) -3- (tetrahyddoχ Уon χ-χ 22 Xloχl- 3 - [(3S) -2-b? Om-3,4-diιneehhXl3 "(^ randomized tetoahyero ^ ^ yloxy -non- 1 -en-6-inxl] bicyclo [3, 3, j ° octan-3-one
Analogicky příkladu 1c) se z 1,5 g diolu vyrobeného podle příkladu 5b) získá 2,20 g titulní sloučeniny jeko bezbarvý olej.In analogy to Example 1c), 2.20 g of the title compound is obtained as a colorless oil from 1.5 g of the diol produced according to Example 5b).
IČ: 2 942, 2 878, 1 738, 1 125-, 968/cm.IR: 2942, 2878, 1738, 1125-, 968 / cm.
Příklade (5E)-1 3,14зeieehyďoχ18,18,19,19-tetredehχdrx— 6e-karlb-ppooSaglandin-I2EXAMPLE (5E) -1 3,14 e ie hy ď 18 ,1 ,1 ,1 ,1 ,1 ,1 red ,1 ,1 ,1 ,1--red ,1 ,1 ,1 red-red land land land land
An-logicty příkladu 1 se ze 400 mg (1R,5S,бR,7R)-3-(tetoehχ(e‘Ooχxon-22χχooχl-3-[(3S)з2зboxm-3-(tetoahldeo0pran---yloxy)-oχt-1-зn-3-3inχlЫcχklx[3,3,0]oktan-3-onu zísto 130 mg (5E-13,14зeidehydeoo11,18,19,1 9-tetrαeehχdro-3e-karbθ-ppoxttglanden-I2-11, ^-bls-detrahdrappiou-Xetheru) jako bezbarvý olej.An-logical p of manufacture to la d u 1, 400 mg of (1R, 5S, бR, 7R) - 3 - (te t oehχ (e 'O o χxon-22 χχ oo χl - 3 - [(3 S ) з2 зboxm- 3 - (l tetoah 0p randomized deo - yloxy) -o χ t-1 зn- 3-3 in χl Ыc χ klx [3, 3,0] octan-3-one detects (130 mg, 5E-13,14 (deidehydeo 11,18,19,1 9-tetramethyl- 3 ? -Carbopropoxyglandene-12-11,? -Bls-detraprappiouxether) as a colorless oil.
IČ: 3 500 (široký), 2 948, 2 862, 2 · 226, 1 708/cm.IR: 3500 (broad), 2,948, 2,862, 2,226, 1,708 / cm.
Po odštěpení ochranných skupin podle příkladu 1 se získá 62 mg titulní sloučeniny jako bezbarvý olej.After deprotection according to Example 1, 62 mg of the title compound is obtained as a colorless oil.
IČ: 3 610, 3 350 (široký), 2 930, 2 862, 2 226, 1 709, 1 600/cm.IR: 3,610, 3,350 (broad), 2930, 2862, 2226, 1779, 1600 / cm.
Výchozí látka pro shora uvedenou titulní sloučeninu se vyrobí následovně:The starting material for the above title compound is prepared as follows:
a) (1,,5,67,77)-3,7ззehyУen-eoxχl3-3bn-oylooy-3~(223box-Зз3зo-o3X-lзen-6-lI-X)bicykloС3^ oj oktana) (1,, 5,67,77) -3,7ззehyУen-eoxχ13-3bn-oylooy- 3 ~ (223box-Зз3зo-o3X-lзen-6-lI-X) bicy k loС 3 ^ o j octane
Annlogicky příkladu 1a) se z 5,8 g d^ceti^esteru k^eHny 2-xxo-hept-5-inχχзSosfonxvé7Annlogicky Example 1a), from 5,8 ceti GD ^ ^ k ^ eHny ester 2-Oxo-Phe-p t 5 in χχ зSosfonxvé7
3,7 g N-bromsutolnimIdu a 5,6 g (1R,7S,67,7R)-3,3-’etlllendioxy-7-benzoχloэχr-6-Sxrmyllbicyklx[3»3,0]oktanu zísto 4,7 g nenas^en^o totonu jato bezbarvý olej.3.7 g of N-bromsutolnimIdu and 5.6 g of (1R, 7S, 67,7R) -3,3-7-'etlllendioxy benzoχloэχr-6-Sxrmyllbicyklx [3 »3, 0] kt anus detects 4.7 nenas g ^ en ^ o totony Jato b ez b arvý oil.
IČ: 2 932, 2 880, 1 712, 1 688, 1 600, 1 592, 1 272, 948/cm.IR: 2932, 2880, 1712, 1688, 1600, 1592, 1272, 948 / cm.
35 30735 307
b) (1К,55,бН,77)-77Ьу(1гоху-6-[SS^-trom-ů-bydOxy-okt-1 -eň-6-inyl]bicyklo[3,3,0] oktan- 3-onb) (1К, 55, бН 7 7) -77Ьу (1гоху-6- [^ -trom SS-U-bydOxy oct-1-en-6-ynyl] bicyclo [3,3, 0] octan-3 -he
Analogicky příkladu 1b) se ze 4 g ketonu vyrobeného podle příkladu 6e) po redukci natru umborhydrideo, zmýddlnění uhličttmeo draselrým β následném ketalovém štěpení získá 1,35 g ti tulní sloučeniny jako bezbarvý olej.Analogously to Example 1b), 1.35 g of the title compound is obtained as a colorless oil from 4 g of the ketone produced according to Example 6e) after reduction of the sodium borohydride, saponification of potassium carbonate β followed by ketal cleavage.
IČ: 3 600, 3 410 (široký), 2 962, 2 866, 1 740, 1 $01/cm.IR: 3,600, 3,410 (broad), 2,962, 2,866, 1,740, $ 01 / cm.
c) (1R,55,бR,77)---(tltoahy(d?oppyonr2-y-oo:y)-6-[Ч3S)-2-to‘om-3-(tetrθhydoopyrθn-2-yloxy)-ott-1-lα-б-iαy-1 bic-klo L3,3,0] oktan-3-onc) (1R, 55, ÅR, 77) --- (trans-pyrrolidin-2-y-yyl) -6- [S3S) -2-thiom-3- (tetropyridopyrr-2-yloxy) - a t t-1 -lα б iαy -1-BIC - L clones 3, 3.0] octan-3 - one
Апг^с^^у příkladu 1c) se z. 1,20 g diolu vyrobeného podle příkladu 6b) s dihydropyoanem získá 1,61 g titulní sloučeniny jako bezbarvý olej.In Example 1c), 1.61 g of the diol produced according to Example 6b) with dihydropyoane gave 1.61 g of the title compound as a colorless oil.
IČ: 2 945, 2 882, 1 739, 1 125, 968/cm.IR: 2945, 2882, 1739, 1125, 968 / cm.
Příklad 7 (5E)-(16RS)-1 3,14-dldehyd?o-16-met1hrl -18,18,19,1 9-t^e^t^o^{^d^e^hyd^o^-6^-ki^rbÉ^-p]^c^í^^ba^^lenďin12-tois(hydooxymithyl)aminomethanová sůlExample 7 (5E) - (16RS) -1,114-dihydro-16-methyl-18,18,19,19-t-e-t-o-t-d-e-hydroxy 12-Tois (hyddooxymithyl) aminomethane salt
K roztoku 358 mg (5E)-(16RS)-13,14-iidehydro-16-methy--18,1θ,19,19-tetrθdehyiro-6αk^rb^-pi^(^o^ta/^^lan<^l.n^I2 v 60 ml aceto^trilu se dé při 65 °C roz.tok 121 mg tris-(yddroxymethyDeminomethanu ve 0,4 ml vody. Za míchání se nechá ochladit, po 16 hodinách se dekentuje od rozpouštěla a zbytek se suší při 25 °C a 13,3 Pa. Získá se 310 mg titulní sloučeniny jako voskovitá hmota.To a solution of 358 mg of (5E) - (16RS) -13,14-iidehydro-16-methyl - 18,1θ, 19.19-tetrθdehyiro-6αk ^ rb ^ -pi ^ (^ o ^ t and / ^^ LAN <ln ^ ^ I 2 in 60 ml of acetonitrile, de-three year at 65 ° C roz.to to 121 mg of tri s- (s DDR ox y methyDeminomethanu in 0.4 ml of water. Under stirring, allowed to cool, after 16 hours dekentuje is unnecessary to dissolve and the dried p s 25 ° C 1 3.3 mm Hg. ZIS ka 310 mg ti tu n e l compound as a waxy mass.
Claims (4)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823204443 DE3204443A1 (en) | 1982-02-08 | 1982-02-08 | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS235307B2 true CS235307B2 (en) | 1985-05-15 |
Family
ID=6155190
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS83847A CS235307B2 (en) | 1982-02-08 | 1983-02-07 | Method of 6a-carbaprostaglandine -12 derivatives production |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0086404B1 (en) |
| JP (1) | JPH0611728B2 (en) |
| AT (1) | ATE24487T1 (en) |
| AU (1) | AU567867B2 (en) |
| CA (1) | CA1215362A (en) |
| CS (1) | CS235307B2 (en) |
| DD (1) | DD207901A5 (en) |
| DE (2) | DE3204443A1 (en) |
| DK (1) | DK156563C (en) |
| ES (1) | ES8400384A1 (en) |
| FI (1) | FI78064C (en) |
| GR (1) | GR77967B (en) |
| HU (1) | HU191197B (en) |
| IE (1) | IE54554B1 (en) |
| IL (1) | IL67839A0 (en) |
| NO (1) | NO155729C (en) |
| NZ (1) | NZ203115A (en) |
| SU (1) | SU1145926A3 (en) |
| ZA (1) | ZA83851B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3225287A1 (en) * | 1982-07-02 | 1984-01-05 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW CARBACYCLINAMIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| DE3408699A1 (en) * | 1984-03-08 | 1985-09-12 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW CARBACYCLINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
| US4927963A (en) * | 1989-04-28 | 1990-05-22 | Syntex (U.S.A.) Inc. | Novel processes for the synthesis of certain bicyclo(4.2.0)octane derivatives with valuable therapeutic properties |
| DE4135193C1 (en) * | 1991-10-22 | 1993-03-11 | Schering Ag Berlin Und Bergkamen, 1000 Berlin, De |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2845770A1 (en) * | 1978-10-19 | 1980-04-30 | Schering Ag | NEW PROSTACYCLINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| CA1201712A (en) * | 1980-02-28 | 1986-03-11 | Paul A. Aristoff | Carbacyclin analogs |
| DE3104044A1 (en) * | 1981-02-02 | 1982-08-26 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW PROSTACYCLIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS |
-
1982
- 1982-02-08 DE DE19823204443 patent/DE3204443A1/en not_active Withdrawn
-
1983
- 1983-01-17 SU SU833534779A patent/SU1145926A3/en active
- 1983-01-28 NZ NZ203115A patent/NZ203115A/en unknown
- 1983-02-03 AT AT83101008T patent/ATE24487T1/en active
- 1983-02-03 DE DE8383101008T patent/DE3368609D1/en not_active Expired
- 1983-02-03 EP EP83101008A patent/EP0086404B1/en not_active Expired
- 1983-02-04 DD DD83247723A patent/DD207901A5/en not_active IP Right Cessation
- 1983-02-06 IL IL67839A patent/IL67839A0/en not_active IP Right Cessation
- 1983-02-07 HU HU83412A patent/HU191197B/en not_active IP Right Cessation
- 1983-02-07 AU AU11180/83A patent/AU567867B2/en not_active Ceased
- 1983-02-07 GR GR70438A patent/GR77967B/el unknown
- 1983-02-07 NO NO830399A patent/NO155729C/en unknown
- 1983-02-07 CA CA000421004A patent/CA1215362A/en not_active Expired
- 1983-02-07 JP JP58017584A patent/JPH0611728B2/en not_active Expired - Lifetime
- 1983-02-07 FI FI830414A patent/FI78064C/en not_active IP Right Cessation
- 1983-02-07 CS CS83847A patent/CS235307B2/en unknown
- 1983-02-08 IE IE246/83A patent/IE54554B1/en not_active IP Right Cessation
- 1983-02-08 DK DK052383A patent/DK156563C/en not_active IP Right Cessation
- 1983-02-08 ZA ZA83851A patent/ZA83851B/en unknown
- 1983-02-08 ES ES519627A patent/ES8400384A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES519627A0 (en) | 1983-11-16 |
| NZ203115A (en) | 1986-03-14 |
| FI78064B (en) | 1989-02-28 |
| EP0086404B1 (en) | 1986-12-30 |
| NO830399L (en) | 1983-08-09 |
| IE830246L (en) | 1983-08-08 |
| DE3368609D1 (en) | 1987-02-05 |
| ES8400384A1 (en) | 1983-11-16 |
| GR77967B (en) | 1984-09-25 |
| EP0086404A1 (en) | 1983-08-24 |
| FI830414A0 (en) | 1983-02-07 |
| JPS58146531A (en) | 1983-09-01 |
| ATE24487T1 (en) | 1987-01-15 |
| CA1215362A (en) | 1986-12-16 |
| FI830414L (en) | 1983-08-09 |
| DK156563C (en) | 1990-01-29 |
| JPH0611728B2 (en) | 1994-02-16 |
| AU1118083A (en) | 1983-08-18 |
| ZA83851B (en) | 1983-10-26 |
| FI78064C (en) | 1989-06-12 |
| DK52383D0 (en) | 1983-02-08 |
| SU1145926A3 (en) | 1985-03-15 |
| DK156563B (en) | 1989-09-11 |
| DD207901A5 (en) | 1984-03-21 |
| NO155729B (en) | 1987-02-09 |
| IL67839A0 (en) | 1983-06-15 |
| DE3204443A1 (en) | 1983-08-18 |
| DK52383A (en) | 1983-08-09 |
| AU567867B2 (en) | 1987-12-10 |
| NO155729C (en) | 1987-05-20 |
| IE54554B1 (en) | 1989-11-22 |
| HU191197B (en) | 1987-01-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0055208B1 (en) | Carbacyclins, process for their preparation and their utilization as pharmaceutical preparations | |
| CS219260B2 (en) | Method of making the prostacycline derivatives | |
| CS228916B2 (en) | Method of preparing new derivatives of 9 alpha,6-nitril | |
| US5013758A (en) | Novel carbacyclins, processes for their preparation and their use as medicinal agents | |
| IE831630L (en) | Carbacyclin derivatives | |
| US4497830A (en) | Carbacyclins, their preparation and pharmacological use | |
| CS235307B2 (en) | Method of 6a-carbaprostaglandine -12 derivatives production | |
| HU191150B (en) | Process for producing new prostacycline derivatives | |
| JPH0446256B2 (en) | ||
| PL148468B1 (en) | Method of obtaining novel derivatives of bicyclo /4.2.0/octane | |
| US4532236A (en) | Certain prostacyclins and their blood-pressure-lowering and thrombocyte-aggregation-inhibiting compositions and methods | |
| US4338316A (en) | 9-Aryloxy prostane derivatives | |
| CS226440B2 (en) | Method of preparing 7-oxoprostacycline derivatives | |
| FI77644C (en) | Process for the preparation of novel therapeutically useful 3-oxa-5-fluorocarbacycline derivatives. | |
| JPH0510330B2 (en) | ||
| HU190901B (en) | Process for preparing new carbacycline derivatives and pharmaceutical preparations comprising these compounds | |
| CS250247B2 (en) | Method of 2,3,4-trinol-1,5-inter-m-phenylen-6a-carba-prostaglandin-i2 new derivatives' production |