NO155729B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE CARBACYCLINES. - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE CARBACYCLINES. Download PDFInfo
- Publication number
- NO155729B NO155729B NO830399A NO830399A NO155729B NO 155729 B NO155729 B NO 155729B NO 830399 A NO830399 A NO 830399A NO 830399 A NO830399 A NO 830399A NO 155729 B NO155729 B NO 155729B
- Authority
- NO
- Norway
- Prior art keywords
- tetrahydropyran
- yloxy
- bicyclo
- methyl
- general formula
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 44
- RHLVCLIPMVJYKS-UHFFFAOYSA-N 3-octanone Chemical compound CCCCCC(=O)CC RHLVCLIPMVJYKS-UHFFFAOYSA-N 0.000 claims description 24
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 229960001123 epoprostenol Drugs 0.000 claims description 3
- 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 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 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 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 14
- 150000002576 ketones Chemical class 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- -1 hydroxy-methylene group Chemical class 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 description 7
- 239000012279 sodium borohydride Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000006567 deketalization reaction Methods 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000007127 saponification reaction Methods 0.000 description 6
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 150000002009 diols Chemical class 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- YNQURMQZAANBTO-QKPAOTATSA-N [(1'r,2'r,3'ar,6'as)-1'-formylspiro[1,3-dioxolane-2,5'-2,3,3a,4,6,6a-hexahydro-1h-pentalene]-2'-yl] benzoate Chemical compound C([C@H]1C[C@H]([C@@H]([C@H]1C1)C=O)OC(=O)C=2C=CC=CC=2)C21OCCO2 YNQURMQZAANBTO-QKPAOTATSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 101100310593 Candida albicans (strain SC5314 / ATCC MYA-2876) SOD4 gene Proteins 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- MYHXHCUNDDAEOZ-UHFFFAOYSA-N Prostaglandin A&2% Natural products CCCCCC(O)C=CC1C=CC(=O)C1CC=CCCCC(O)=O MYHXHCUNDDAEOZ-UHFFFAOYSA-N 0.000 description 3
- 101100190148 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) PGA2 gene Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 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
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 3
- 229960002986 dinoprostone Drugs 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 150000003815 prostacyclins Chemical class 0.000 description 3
- 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 3
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- ZBAQLJZFNFDEHP-PHGYJHJFSA-N (3aS,4R,5R,6aR)-4-[(3S)-2-bromo-4-methyl-3-(oxan-2-yloxy)oct-1-en-6-ynyl]-5-(oxan-2-yloxy)-3,3a,4,5,6,6a-hexahydro-1H-pentalen-2-one Chemical compound O1C(CCCC1)O[C@H]1[C@H]([C@H]2CC(C[C@H]2C1)=O)C=C([C@H](C(CC#CC)C)OC1OCCCC1)Br ZBAQLJZFNFDEHP-PHGYJHJFSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-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
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- 206010011091 Coronary artery thrombosis Diseases 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
- 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
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 2
- 208000030831 Peripheral arterial occlusive disease Diseases 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
- 208000006011 Stroke Diseases 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000003266 anti-allergic effect Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000007885 bronchoconstriction Effects 0.000 description 2
- 230000003727 cerebral blood flow Effects 0.000 description 2
- 238000006243 chemical reaction 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
- 238000000502 dialysis Methods 0.000 description 2
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 230000027119 gastric acid secretion 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
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 210000004347 intestinal mucosa Anatomy 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
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 230000036593 pulmonary vascular resistance Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000008359 toxicosis Effects 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- YXBSMYQLIPOMBZ-HADDFKIOSA-N (3aS,4R,5R,6aR)-4-[(3S)-2-bromo-4,4-dimethyl-3-(oxan-2-yloxy)oct-1-en-6-ynyl]-5-(oxan-2-yloxy)-3,3a,4,5,6,6a-hexahydro-1H-pentalen-2-one Chemical compound O1C(CCCC1)O[C@H]1[C@H]([C@H]2CC(C[C@H]2C1)=O)C=C([C@H](C(CC#CC)(C)C)OC1OCCCC1)Br YXBSMYQLIPOMBZ-HADDFKIOSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FQMVLQNNAODGQV-UHFFFAOYSA-N 1-dimethoxyphosphoryl-3,3-dimethylhept-5-yn-2-one Chemical compound COP(=O)(OC)CC(=O)C(C)(C)CC#CC FQMVLQNNAODGQV-UHFFFAOYSA-N 0.000 description 1
- QAQKMSOVMMCNSE-UHFFFAOYSA-N 1-dimethoxyphosphoryl-3-methylhept-5-yn-2-one Chemical compound COP(=O)(OC)CC(=O)C(C)CC#CC QAQKMSOVMMCNSE-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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- LWXOTBWEEWDTAE-UHFFFAOYSA-N CS(=O)C[K] Chemical compound CS(=O)C[K] LWXOTBWEEWDTAE-UHFFFAOYSA-N 0.000 description 1
- 101000862089 Clarkia lewisii Glucose-6-phosphate isomerase, cytosolic 1A Proteins 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 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
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 238000007295 Wittig olefination reaction Methods 0.000 description 1
- OMGJSHZOIXMBKM-QTDGGUCWSA-N [(1'R,2'R,3'aR,6'aS)-1'-(2-bromo-3-oxooct-1-en-6-ynyl)spiro[1,3-dioxolane-2,5'-2,3,3a,4,6,6a-hexahydro-1H-pentalene]-2'-yl] benzoate Chemical compound C1OC2(C[C@H]3C[C@H]([C@H]([C@H]3C2)C=C(C(CCC#CC)=O)Br)OC(C2=CC=CC=C2)=O)OC1 OMGJSHZOIXMBKM-QTDGGUCWSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229940006138 antiglaucoma drug and miotics prostaglandin analogues Drugs 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 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
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000003182 bronchodilatating effect Effects 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- UPQZOUHVTJNGFK-UHFFFAOYSA-N diethyl 2-methylpropanedioate Chemical compound CCOC(=O)C(C)C(=O)OCC UPQZOUHVTJNGFK-UHFFFAOYSA-N 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
- 239000003937 drug carrier Substances 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
- 238000006266 etherification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- BTDWSZJDLLLTMI-UHFFFAOYSA-N hex-2-yn-1-ol Chemical compound CCCC#CCO BTDWSZJDLLLTMI-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 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
- 210000004185 liver Anatomy 0.000 description 1
- SOHCYNFHNYKSTM-UHFFFAOYSA-N methylsulfinylmethane;oxolane Chemical compound CS(C)=O.C1CCOC1 SOHCYNFHNYKSTM-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000006772 olefination reaction Methods 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
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N ortho-diethylbenzene Natural products CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 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
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 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
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- CWXOAQXKPAENDI-UHFFFAOYSA-N sodium methylsulfinylmethylide Chemical compound [Na+].CS([CH2-])=O CWXOAQXKPAENDI-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003437 trachea Anatomy 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
Foreliggende oppfinnelse angår en analogifremgangsmåte for fremstilling av terapeutisk aktive (5E)-13,14,18,18,19,19-hexadehydro-6a-carba-prostaglandin-I2-derivater. The present invention relates to an analogue method for the production of therapeutically active (5E)-13,14,18,18,19,19-hexadehydro-6a-carba-prostaglandin-I2 derivatives.
I tysk offentliggjørelsesskrift 28 45 770 er det beskrevet carbacyclinderivater av generell formel: German publication publication 28 45 770 describes carbacycline derivatives of the general formula:
hvori R^ betegner hydrogen, alkyl, cycloalkyl, aryl eller en heterocyclisk rest, wherein R^ denotes hydrogen, alkyl, cycloalkyl, aryl or a heterocyclic residue,
A betegner en -CH2-CH2-, trans-CH=CH- eller -CHC-gruppe, A denotes a -CH2-CH2-, trans-CH=CH- or -CHC group,
W betegner en fri eller funksjonelt modifisert hydroxy-methylengruppe eller en fri eller funksjonelt modifisert W denotes a free or functionally modified hydroxy-methylene group or a free or functionally modified one
CH, CH,
-C- gruppe, hvori OH-gruppen star i a-stilling, -C- group, in which the OH group is in the a-position,
6h 6h
D og E betegner sammen en direkte binding eller D and E together denote a direct bond or
D betegner en rettkjedet eller forgrenet mettet eller umettet alkylengruppe med 1-10 C-atomer, som eventuelt kan være sub-stituert med fluoratom, D denotes a straight-chain or branched saturated or unsaturated alkylene group with 1-10 C atoms, which may optionally be substituted with a fluorine atom,
E betegner et oxygenatom eller en -C=C-binding eller en direkte binding, E denotes an oxygen atom or a -C=C bond or a direct bond,
1*2 betegner en alkyl-, cycloalkyl-, eller en eventuelt substi-tuert aryl- eller en heterocyclisk gruppe, 1*2 denotes an alkyl, cycloalkyl, or an optionally substituted aryl or a heterocyclic group,
R_ betegner en fri eller funksjonelt modifisert hydroxygruppe, og såfremt betegner et hydrogenatom, deres salter med fysiologisk akseptable baser. R_ denotes a free or functionally modified hydroxy group, and if it denotes a hydrogen atom, their salts with physiologically acceptable bases.
I IN
Forbindelsene utviser typiske egenskaper for prostacycliner, slik som f.ekb. senkning av den perifere artierielle og koronare vaskulære motstand/ inhibering av trombocyt- The compounds exhibit typical properties of prostacyclins, such as e.g. lowering of the peripheral arterial and coronary vascular resistance/inhibition of platelet
i in
aggregering og oppløsning av blodplatetromber, myocardial cytobeskyttelse og dermed senkning av det systemiske blodtrykk uten samtidig å senke minuttvolum og koronargjennom-blødning, de kan anvendes for behandling av slaganfall, profylakse og terapi av koronare hjertesykdommer, koronar trombose, hjerteinfarkt, perifere arteriesykdommer, arteriosklerose og trombose, behandling av sjokk, inhibering av bronchokonstriksjon, inhibering av magesyresekresjon, cytobeskyttelse av mage- og tarmslimhinne, de utviser antiallergiske egenskaper, senker den pulmonare vaskulære motstand og det pulmonare blodtrykk, øker nyregjennomblødningen, kan anvendes istedenfor! heparin eller som hjelpestoff ved hemofiltreringen ved dialysen, for konservering av blodplasma-konserver, spesielt av blodplatekonserver, inhibering av fødselssmerter, behandling av svangerskapstoksikose, økning av den cerebrale gjennomblødning etc. Ennvidere utviser de nye prostaglandinanaloger formeringshindrende egenskaper. aggregation and dissolution of platelet thrombi, myocardial cytoprotection and thereby lowering the systemic blood pressure without simultaneously lowering the minute volume and coronary blood flow, they can be used for the treatment of stroke, prophylaxis and therapy of coronary heart diseases, coronary thrombosis, heart attack, peripheral artery diseases, arteriosclerosis and thrombosis, treatment of shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion, cytoprotection of stomach and intestinal mucosa, they exhibit anti-allergic properties, lower pulmonary vascular resistance and pulmonary blood pressure, increase renal perfusion, can be used instead! heparin or as an auxiliary substance during hemofiltration during dialysis, for the preservation of blood plasma preserves, especially of platelet preserves, inhibition of labor pains, treatment of pregnancy toxicosis, increase of cerebral blood flow, etc. Furthermore, the new prostaglandin analogues exhibit proliferation-inhibiting properties.
Blant de i DE-OS |28 45 770 krevede forbindelser utviser (5E)-13,14,18,18,19,19-hexadehydro-6a-carba-prostaglandin-I2-forbindelsene som blodtrykksenkende middel og trombocyt-aggregeringshemmende middel fremragende egenskaper slik at doseringen kan ytterligere nedsettes og hvorved også uønskede bivirkninger enda sterkere tilbaketrenges. (5E)-13,14,18,18,19,19-hexadI ehydro-6a-carba-prostac~rlandin-I_-forbindelsene er ikke nevnt ved navn i DE-OS 28 45 770. Forbindelsene med A lik -C=C-gruppen er i forhold til de andre forbindelser hvori A betegner en -CI^-CH.,- eller trans-CH=CH-gruppe, ikke angitt. I Among the compounds claimed in DE-OS |28 45 770, the (5E)-13,14,18,18,19,19-hexadehydro-6a-carba-prostaglandin-I2 compounds exhibit outstanding properties as blood pressure-lowering agent and platelet-aggregation inhibitor so that the dosage can be further reduced and whereby unwanted side effects are also suppressed even more strongly. The (5E)-13,14,18,18,19,19-hexadI ehydro-6a-carba-prostac~rlandin-I_ compounds are not mentioned by name in DE-OS 28 45 770. The compounds with A equal to -C= The C group is not indicated in relation to the other compounds in which A denotes a -CI^-CH.,- or trans-CH=CH group. IN
Nomenklaturen av .forbindelsene er basert på et forslag av Morton und Brokaw (J. Org. Chem. A±, 2280 [1979]). (5E)-6a-carba-prostaglandin-l2 har derved følgende strukturformel: Oppfinnelsen angår således en analogifremgangsmåte ved fremstilling av terapeutisk aktive carbacyclinderivater av generell formel I The nomenclature of the compounds is based on a proposal by Morton und Brokaw (J. Org. Chem. A±, 2280 [1979]). (5E)-6a-carba-prostaglandin-12 thereby has the following structural formula: The invention thus relates to an analogous method for the production of therapeutically active carbacycline derivatives of general formula I
hvori R^, R^ r R^ og R^ betegner et hydrogenatom eller en alkylgruppe med 1-5 C-atomer, og in which R^, R^ r R^ and R^ denote a hydrogen atom or an alkyl group with 1-5 C atoms, and
Ri- betegner en alkylgruppe med 1-5 C-atomer, Ri- denotes an alkyl group with 1-5 C atoms,
såvel som deres salter med fysiologisk akseptable baser. as well as their salts with physiologically acceptable bases.
Som alkylgrupper , R2, R3, R^, R^ kommer rettkjedede og forgrenede alkylrester med 1-5 carbonatomer i betraktning, slik som f.eks. methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl. Foretrukne rester er methyl, ethyl, propyl og isopropyl, i særdeleshet methyl og ethyl. As alkyl groups, R2, R3, R^, R^, straight-chain and branched alkyl residues with 1-5 carbon atoms come into consideration, such as e.g. methyl, ethyl, propyl, butyl, isopropyl, isobutyl, pentyl. Preferred residues are methyl, ethyl, propyl and isopropyl, in particular methyl and ethyl.
For saltdannelsen er uorganiske og organiske baser For salt formation are inorganic and organic bases
i in
egnet, hvilke for fagmannen er kjent for dannelse av fysiologisk akseptable salter. Eksempelvis skal nevnes alkali-hydroxyder slik som natrium- og kaliumhydroxyd, jordalkali-hydroxyder slik som calciumhydroxyd, ammoniakk, aminer slik som ethanolamin, diethanolamin, triethanolamin, N-methyl-glucamin, morfolin, tris-(hydroxymethyl)-methylamin osv. suitable, which are known to the person skilled in the art for the formation of physiologically acceptable salts. Examples include alkali hydroxides such as sodium and potassium hydroxide, alkaline earth hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methyl-glucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.
Analogifremgangsmåten ifølge oppfinnelsen er kjenne-tegnet ved at en forbindelse av generell formel II The analog method according to the invention is characterized in that a compound of general formula II
hvori Rx, <R>2, <R>3, r4 og R5 har de ovenfor angitte betydninger og THP betegner tetrahydropyranylresten, omsettes med et Wittig-reagens av formel III 1 in which Rx, <R>2, <R>3, r4 and R5 have the meanings given above and THP denotes the tetrahydropyranyl residue, is reacted with a Wittig reagent of formula III 1
hvori Ph betegner én fenylgruppe, hvorpå isomerer separeres, beskyttelsesgrupper avspaltes og eventuelt at carboxylgruppen overføres med en fysiologisk akseptabel base til et salt. in which Ph denotes one phenyl group, after which isomers are separated, protective groups are split off and optionally that the carboxyl group is transferred with a physiologically acceptable base to a salt.
Omsetningen av forbindelsen av generell formel II med Wittig-reagenset av formel III, som fremstilles fra det tilsvarende fosfoniumsalt med methansulfinylmethylnatrium eller The reaction of the compound of general formula II with the Wittig reagent of formula III, which is prepared from the corresponding phosphonium salt with methanesulfinylmethylsodium or
j j
methansulfinylmethylkalium eller kalium-tert.-butylat i dimethylsulfoxyd eller dimethylsulfoxyd-tetrahydrofuranbland-inger, utføres ved temperaturer på fra 0 til 100°C, fortrinnsvis 20 til 60°C, i et aprotisk løsningsmiddel eller løsnings-middelblanding, fortrinnsvis dimethylsulfoxyd, dimethyl-formamid eller tetrahydrofuran. Separeringen av det derved erholdte Z- og E-konfigurerte olefin skjer på vanlig måte, eksempelvis ved søyle- eller skiktkromatografi. Ved den foregående beskrevne Wittig-olefinering skjer samtidig dannelse av 13,14-acetylenbindingen under avspaltning av hydrogen-bromid. methanesulfinylmethylpotassium or potassium tert.-butylate in dimethylsulfoxide or dimethylsulfoxide-tetrahydrofuran mixtures, is carried out at temperatures of from 0 to 100°C, preferably 20 to 60°C, in an aprotic solvent or solvent mixture, preferably dimethylsulfoxide, dimethylformamide or tetrahydrofuran. The separation of the Z- and E-configured olefin thus obtained takes place in the usual way, for example by column or layer chromatography. In the previously described Wittig olefination, simultaneous formation of the 13,14-acetylene bond takes place during splitting off of hydrogen bromide.
Avspaltning av beskyttelsesgruppene utføres i en vandig løsning av en organisk syre slik som f.eks. eddiksyre, propionsyre e.l. eller i en vandig løsning av en uorganisk syre, slik som f.eks. saltsyre. For å forbedre løseligheten tilsettes hensiktsmessig et vannblandbart inert organisk løsningsmiddel. Egnede organiske løsningsmidler er f.eks. alkoholer slik som methanol og ethanol, og ethere slik som dimethoxyethan, dioxan og tetrahydrofuran. Fortrinnsvis anvendes tetrahydrofuran. Avspaltningen utføres fortrinnsvis ved temperaturer på mellom 20 og 80°C. Removal of the protective groups is carried out in an aqueous solution of an organic acid such as e.g. acetic acid, propionic acid etc. or in an aqueous solution of an inorganic acid, such as e.g. hydrochloric acid. To improve the solubility, a water-miscible inert organic solvent is suitably added. Suitable organic solvents are e.g. alcohols such as methanol and ethanol, and ethers such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is preferably used. The separation is preferably carried out at temperatures of between 20 and 80°C.
Carboxylsyrene av generell formel I kan overføres med egnede mengder av de tilsvarende uorganiske baser til salter under nøytralisering. Eksempelvis erholdes ved oppløsning av de tilsvarende syrer i vann som inneholder den støkiometriske mengde base, det faste uorganiske salt etter avdampning av vann eller etter tilsetning av et vannblandbart løsnings-middel, f.eks. alkohol eller aceton. For fremstilling av et aminsalt oppløses PG-syren i et egnet løsningsmiddel, eksempelvis ethanol, aceton, diethylether eller benzen, og minst den støkiometriske mengde av aminet tilsettes til denne løs-ning. Derved utfelles saltet vanligvis i fast form, eller isoleres på vanlig måte eller fordampning av løsningsmidlet. The carboxylic acids of general formula I can be transferred with suitable amounts of the corresponding inorganic bases to salts during neutralization. For example, by dissolving the corresponding acids in water containing the stoichiometric amount of base, the solid inorganic salt is obtained after evaporation of water or after the addition of a water-miscible solvent, e.g. alcohol or acetone. To prepare an amine salt, the PG acid is dissolved in a suitable solvent, for example ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine is added to this solution. Thereby, the salt is usually precipitated in solid form, or isolated in the usual way or by evaporation of the solvent.
Forbindelsene av generell formel II som anvendes som utgangsmateriale, kan eksempelvis fremstilles ved at på i og for seg kjent måte et aldehyd av formel IV (DE-OS 28 45 770) omsettes med et fosfonat av generell formel V: The compounds of general formula II which are used as starting material can, for example, be prepared by reacting an aldehyde of formula IV (DE-OS 28 45 770) with a phosphonate of general formula V in a manner known per se:
i in
hvori R^, R2, R^, R^°i<9> R5 nar ^e ovenfor angitte betydninger, i nærvær av et deprotøniseringsmiddel, slik som f.eks. natriumhydrid eller kalium-tert.-butylat og et bromerings- in which R^, R2, R^, R^°i<9> R5 when ^e above stated meanings, in the presence of a deprotonating agent, such as e.g. sodium hydride or potassium tert-butylate and a bromination
i in
middel slik som f.eks. N-bromsuccinimid, under dannelse av et keton av generell formel VI: means such as e.g. N-bromosuccinimide, forming a ketone of general formula VI:
Etter reduksjon lav ketogruppen med natriumborhydrid og eventuelt epimerseparering, forsåpning av estergruppen, eksempelvis med kaliumcarbonat i methanol og ketalspaltning med vandig eddiksyre såvel som eventuell epimerseparering, erholdes ketonet av generell formel VII: After reduction of the keto group with sodium borohydride and possible epimer separation, saponification of the ester group, for example with potassium carbonate in methanol and ketal cleavage with aqueous acetic acid as well as possible epimer separation, the ketone of general formula VII is obtained:
Forethring av hydroxylgruppen med dihydropyran i nærvær av katalytiske mengder p-toluensulfonsyre gir forbindelsene av generell formel II. Etherification of the hydroxyl group with dihydropyran in the presence of catalytic amounts of p-toluenesulfonic acid gives the compounds of general formula II.
Fremstilling av fosfonatet av generell formel V skjer på i og for seg kjent måte ved omsetning av et alkylhalogenid (som lar seg fremstille fra den tilsvarende alkohol ved halogenering) av generell formel VIII: med det fra fosfonatet av generell formel IX tilvirkede dianion: Production of the phosphonate of general formula V takes place in a manner known per se by reacting an alkyl halide (which can be prepared from the corresponding alcohol by halogenation) of general formula VIII: with the dianion produced from the phosphonate of general formula IX:
hvori R1# R2, R^, R^ og R^ har de ovenfor angitte betydninger. wherein R1# R2, R^, R^ and R^ have the meanings given above.
En ytterligere tilgang til fosfonatet av generell formel V består i omsetning av anionet av methylfosfonsyre-dimethylester med en ester av generell formel X: A further approach to the phosphonate of general formula V consists in reacting the anion of methylphosphonic acid dimethyl ester with an ester of general formula X:
hvori R^, R2» R^« R4°9 har de ovenfor angitte betydninger og Ro, betegner en alkylgruppe med 1-5 carbonatomer, hvilken kan erholdes fra den tilsvarende malonsyreester ved alkylering med halogenidet av generell formel VIII og etter-følgende decarbalkoxylering. Esteren av generell formel X er også tilgjengelig fra carboxylsyren av generell formel XI: in which R , R 2 , R 4 , R 4 ° 9 have the meanings indicated above and Ro denotes an alkyl group with 1-5 carbon atoms, which can be obtained from the corresponding malonic acid ester by alkylation with the halide of general formula VIII and subsequent decarbalkoxylation. The ester of general formula X is also available from the carboxylic acid of general formula XI:
hvori R^ og R2 nar dejovenfor angitte betydninger, ved alkylering med halogenidet av generell formel VIII og etterfølg-ende forestring. wherein R 1 and R 2 have the meanings given above, by alkylation with the halide of general formula VIII and subsequent esterification.
Forbindelsene fremstilt ifølge oppfinnelsen, virker blodtrykkssenkende og!bronchodilaterende. De er videre egnet til inhibering av trombocyt-aggregering. Følgelig utgjør de nye prostacyclinderivater av formel I verdifulle farmasøytiske virkestoffer. Ennvidere utviser disse sammenlignet med de tilsvarende prostaglandiner ved lignende virkningsspekter en høyere spesifisitet og fremfor alt en vesentlig lengre aktivitet. Sammenlignet med PGI2 utviser de større stabilitet. Den høye vevsspesifisitet til de nye prostaglandiner vises ved undersøkelse av glattmuskulære organer slik som f.eks. marsvinileum eller på isolert kanin-trachea, hvor en vesentlig mindre stimulering observeres enn ved administrering av naturlige prostaglandiner av E-, A-eller F-type. The compounds produced according to the invention have a blood pressure-lowering and bronchodilating effect. They are also suitable for inhibiting platelet aggregation. Accordingly, the new prostacyclin derivatives of formula I constitute valuable pharmaceutical active substances. Furthermore, compared to the corresponding prostaglandins with a similar spectrum of action, these show a higher specificity and, above all, a significantly longer activity. Compared to PGI2, they exhibit greater stability. The high tissue specificity of the new prostaglandins is shown when examining smooth muscle organs such as e.g. marsvinileum or on isolated rabbit trachea, where a significantly smaller stimulation is observed than with the administration of natural prostaglandins of the E-, A- or F-type.
De nye carbacyclinderivater utviser egenskaper som er typiske for prostacycliner, slik som f.eks. senkning av den perifere arterielle og koronare vaskulære motstand, inhibering av trombocyt-aggregering og oppløsning av blodplatetromber, myocardial cytobeskyttelse og dermed senkning av det systemiske blodtrykk uten samtidig å senke minuttvolum og koronar gjennomblødning; de kan anvendes for behandling av slaganfall, for profylakse og behandling av koronare hjertesykdommer, koronar trombose, hjerteinfarkt, perifere arteriesykdommer, arteriosklerose og trombose, profylakse og behandling av ischaemiske angrep på ZNS-systemet, behandling av sjokk, inhibering av bronchokonstriksjon, inhibering av magesyresekresjon, cytobeskyttelse av mage- og tarmslim-hinnen, cytobeskyttelse i leveren og i pankreas; de utviser antiallergiske egenskaper, senker den pulmonare vaskulære motstand og det pulmonare blodtrykk, øker nyregjennomblød-ning, kan anvendes istedenfor heparin eller som hjelpestoff ved hemofiltreringen ved dialysen; de kan anvendes ved konservering av blodplasma, i særdeleshet blodplater, til inhibering av fødselssmerter, for behandling av svangerskapstoksikose, økning av den cerebrale gjennomblødning etc. Ennvidere utviser de nye carbacyclinderivater formeringshindrende egenskaper. Carbacyclinene fremstilt ifølge oppfinnelsen kan anvendes i kombinasjon med f.eks. 3-blokkere eller diuretika. The new carbacycline derivatives exhibit properties that are typical for prostacyclins, such as e.g. lowering of peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and dissolution of platelet thrombi, myocardial cytoprotection and thus lowering of systemic blood pressure without simultaneously lowering cardiac output and coronary blood flow; they can be used for the treatment of strokes, for the prophylaxis and treatment of coronary heart diseases, coronary thrombosis, myocardial infarction, peripheral artery diseases, arteriosclerosis and thrombosis, prophylaxis and treatment of ischemic attacks on the CNS system, treatment of shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion , cytoprotection of the stomach and intestinal mucosa, cytoprotection in the liver and in the pancreas; they exhibit anti-allergic properties, lower the pulmonary vascular resistance and the pulmonary blood pressure, increase renal perfusion, can be used instead of heparin or as an auxiliary substance in hemofiltration during dialysis; they can be used for preserving blood plasma, in particular platelets, for inhibiting labor pains, for treating pregnancy toxicosis, increasing cerebral blood flow, etc. Furthermore, the new carbacycline derivatives exhibit anti-proliferative properties. The carbacyclines produced according to the invention can be used in combination with e.g. 3-blockers or diuretics.
Dosen av forbindelsene er 1 - 150Cyug/kg/dag når de administreres til mennesker. Enhetsdosen for den farma-søytisk akseptable bærer utgjør 0,01 - 100 mg. The dose of the compounds is 1 - 150Cyug/kg/day when administered to humans. The unit dose for the pharmaceutically acceptable carrier is 0.01 - 100 mg.
Ved intravenøs injeksjon på våkne, hypertone rotter i doser på 5, 20 og lOO^ug/kg kroppsvekt utviser de nye forbindelser en sterkere blodtrykkssenkende og mer langvarig virkning enn PGE2 og PGA2 uten å utløse trykkfall slik som PGE2 eller kardiale arytmier slik som PGA2>When injected intravenously into awake, hypertensive rats at doses of 5, 20 and 100 µg/kg body weight, the new compounds exhibit a stronger blood pressure-lowering and longer-lasting effect than PGE2 and PGA2 without triggering pressure drops like PGE2 or cardiac arrhythmias like PGA2>
Ved intravenøs injeksjon på narkotiserte kaniner utviste de nye forbindelser i sammenligning med PGE2 og PGA2 en sterkere og betydelig lengre virkende blodtrykkssenkning uten å påvirke andre glattmuskulære organer eller organfunksjoner. When injected intravenously into anesthetized rabbits, the new compounds compared to PGE2 and PGA2 showed a stronger and significantly longer-acting lowering of blood pressure without affecting other smooth muscle organs or organ functions.
Søkeren har sammenlignet aktiviteten av (5E)-(16RS)-13,14-didehydro-16,20-dimethyl-18,18,19,19-tetra-dehydro-6a-carba-prostaglandin-I2 (forbindelse A) med forbindelsen ifølge eksempel 11 (forbindelse B) i norsk patentskrift 151 318 (relativ sammenligningsangivelse): The applicant has compared the activity of (5E)-(16RS)-13,14-didehydro-16,20-dimethyl-18,18,19,19-tetra-dehydro-6a-carba-prostaglandin-I2 (compound A) with the compound according to example 11 (compound B) in Norwegian patent specification 151 318 (relative comparison specification):
De ovenfor angitte data viser at forbindelsen fremstilt ifølge oppfinnelsen, utviser en meget fordelaktig terapeutisk aktivitet sammenlignet med den kjente forbindelse. The above data show that the compound produced according to the invention exhibits a very advantageous therapeutic activity compared to the known compound.
For parenteral administrering anvendes sterile, injiserbare, vandige løsninger eller oljeløsninger. For oral administrasjon er eksempelvis tabletter, dragéer eller kapsler egnet. For parenteral administration, sterile, injectable, aqueous solutions or oil solutions are used. For oral administration, for example, tablets, dragées or capsules are suitable.
De nye virkestoffer skal anvendes i forbindelse med de innen den galeniskej farmasi kjente hjelpestoffer til fremstilling av blodtrykkssenkende midler. The new active substances are to be used in connection with the excipients known within the field of galeniskej pharmacy for the production of blood pressure-lowering agents.
De etterfølgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
I IN
Eksempel 1 Example 1
(5E)-(16RS)-13,14-didehydro-16-methyl-18,18,19,19-tetra-dehydro-6a-carba-prostaglandin-l2(5E)-(16RS)-13,14-didehydro-16-methyl-18,18,19,19-tetra-dehydro-6a-carba-prostaglandin-12
Til en løsning av 9,4 g 4-carboxybutyltrifenylfosfoniumbromid i 20 ml dimethylsulfoxyd og 7,8 ml tetrahydrofuran ble ved 5°C og i løpet av 45 minutter tilsatt 4,75 g kalium-tert.-butylat, hvoretter blandingen ble omrørt i 45 minutter ved 5°C. Til den røde ylenløsning ble tilsatt en løsning av 1,83 g (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S, 4RS)-2-brom-4-methyl-3-(tetrahydropyran-2-yloxy)-oct-1-en-6-inyl]-bicyclo[3.3.0]octan-3-on i 3 ml tetrahydrofuran, og blandingen ble omrørt i 4 timer ved 40°C. Reaksjonsblandingen ble helt over1 i isvann, ble surgjort med 35%-ig sitron-syreløsning til pH 4-5 og ble ekstrahert tre ganger med methylenklorid. Den organiske fase ble ristet med saltvann, tørket over magnesiumsulfat og inndampet i vakuum. Residuet ble renset ved kromatografi på kiselgel. Med hexan/eddikester (3 + 2) ble det først erholdt 180 mg av det 5Z-konfigurerte olefin og som polar komponent 680 mg (5E)-(16RS)-13,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I2-ll,15-bis-(tetrahydro-pyranylether) som farve-løs olje. To a solution of 9.4 g of 4-carboxybutyltriphenylphosphonium bromide in 20 ml of dimethylsulfoxide and 7.8 ml of tetrahydrofuran, 4.75 g of potassium tert-butylate were added at 5°C over the course of 45 minutes, after which the mixture was stirred for 45 minutes at 5°C. To the red ylene solution was added a solution of 1.83 g of (IR,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 the mixture was stirred for 4 hours at 40°C. The reaction mixture was poured into ice water, acidified with 35% citric acid solution to pH 4-5 and extracted three times with methylene chloride. The organic phase was shaken with salt water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel. With hexane/acetic ester (3 + 2) 180 mg of the 5Z-configured olefin and 680 mg of (5E)-(16RS)-13,14-didehydro-16-methyl-18,18,19 were obtained as the polar component. ,19-tetrahydro-6α-carba-prostaglandin-12-11,15-bis-(tetrahydro-pyranyl ether) as a colorless oil.
IR (CHC13): 3500 (bredt), 2940, 2860, 2225, 1710, 1440/cm. IR (CHC13): 3500 (broad), 2940, 2860, 2225, 1710, 1440/cm.
For avspaltning av beskyttelsesgruppen ble 680 mg av For cleavage of the protecting group, 680 mg of
det ovenfor erholdte olefineringsprodukt omrørt med 25 ml av en blanding av eddiksyre/vann/tetrahydrofuran (65/35/10) the olefination product obtained above stirred with 25 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10)
i 20 timer ved 25°C. Deretter ble løsningen inndampet i vakuum, og residuet ble kromatografert på kiselgel. Med eddikester/eddiksyre (99,9 + 0,1) ble det erholdt 345 mg av tittelforbindelsen som farveløs olje. for 20 hours at 25°C. The solution was then evaporated in vacuo, and the residue was chromatographed on silica gel. With acetic ester/acetic acid (99.9 + 0.1) 345 mg of the title compound was obtained as a colorless oil.
IR: 3600, 3400 (bredt), 2930, 2225, 1710, 1603, 1020/cm. IR: 3600, 3400 (broad), 2930, 2225, 1710, 1603, 1020/cm.
Utgangsmaterialet for den ovenfor fremstilte tittelfor-bindelse fremstilles som følger: a) (1R,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-[(4RS)-2-brom-4-methyl-3-oxo-oct-l-en-6-inyl]-bicyclo[3.3.0]octan The starting material for the title compound prepared above is prepared as follows: a) (1R,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-[(4RS)-2-bromo-4-methyl-3 -oxo-oct-1-en-6-inyl]-bicyclo[3.3.0]octane
Til en suspensjon av 1,81 g natriumhydrid i 180 ml dimethoxyethan ble ved 0°C dråpevis tilsatt en løsning av 10,5 g 3-methyl-2-oxo-hept-5-in-fosfonsyredimethylester i 70 ml dimethoxyethan, blandingen ble omrørt i 1 time ved To a suspension of 1.81 g of sodium hydride in 180 ml of dimethoxyethane, a solution of 10.5 g of 3-methyl-2-oxo-hept-5-yne-phosphonic acid dimethyl ester in 70 ml of dimethoxyethane was added dropwise at 0°C, the mixture was stirred for 1 hour at
0°C, hvoretter 7,4 g finpulverisert N-bromsuccinimid ble tilsatt. Blandingen ble omrørt i 30 minutter ved 0°C, ble tilsatt en løsning av 11,4 g (IR,5S,6R,7S)-3,3-ethylen-dioxy-7-benzoyloxy-6-formyl-bicyclo[3.3.0]octan i 90 ml 0°C, after which 7.4 g of finely powdered N-bromosuccinimide was added. The mixture was stirred for 30 minutes at 0°C, a solution of 11.4 g of (IR,5S,6R,7S)-3,3-ethylene-dioxy-7-benzoyloxy-6-formyl-bicyclo[3.3. 0]octane in 90 ml
dimethoxyethan og b'le omrørt i 2 timer ved 0°C. Reaksjonsblandingen blé helt over i mettet ammoniumkloridløs-ning og ekstrahert |ined ether. Det organiske ekstrakt ble vasket nøytralt med vann, tørket over magnesiumsulfat og inndampet i vakuum.! Etter kromatograf! av residuet på kiselgel ble det med hexan/ether (3+2) erholdt 8,2 g av det umettede keton som farveløs olje. dimethoxyethane and stirred for 2 hours at 0°C. The reaction mixture was completely poured into saturated ammonium chloride solution and extracted with ether. The organic extract was washed neutrally with water, dried over magnesium sulfate and evaporated in vacuo. After chromatograph! of the residue on silica gel with hexane/ether (3+2), 8.2 g of the unsaturated ketone were obtained as a colorless oil.
IR: 2930, 2880, 1712, 1688, 1602, 1595, 1450, 1275, IR: 2930, 2880, 1712, 1688, 1602, 1595, 1450, 1275,
945/cm. 945/cm.
I IN
b) (lR,5S,6R,7R)-7-hydroxy-6-[(3S,4RS)-2-brom-3-hydroxy-4- b) (1R,5S,6R,7R)-7-hydroxy-6-[(3S,4RS)-2-bromo-3-hydroxy-4-
i in
methyl-oct-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on methyl-oct-1-en-6-inyl]-bicyclo[3.3.0]octan-3-one
Til en løsning av 5,9 g av det ifølge eksempel 1 a) fremstilte keton i |140 ml methanol ble ved -40°C porsjons-vis tilsatt 2,5 g natriumborhydrid, og blandingen ble om-rørt i 30 minutter 1 ved -40 oC. Deretter ble reaksjonsblandingen fortynnet med ether, ble vasket nøytral med vann, To a solution of 5.9 g of the ketone prepared according to example 1 a) in |140 ml of methanol, 2.5 g of sodium borohydride was added in portions at -40°C, and the mixture was stirred for 30 minutes at - 40 oC. Then the reaction mixture was diluted with ether, was washed neutral with water,
tørket over magnesiumsulfat og inndampet i vakuum. dried over magnesium sulfate and evaporated in vacuo.
Råproduktet (15-epimerblanding) ble løst i 200 ml methanol, 2,5 g kaiiumcarbonat ble tilsatt, og blandingen ble omrørt i 17 timer ved 23°C under argon. Deretter ble reaksjonsblandingen inndampet i vakuum, fortynnet med ether og vasket nøytral med saltvann. Reaksjonsblandingen ble tørket over magnesiumsulfat og inndampet i vakuum. The crude product (15-epimer mixture) was dissolved in 200 ml of methanol, 2.5 g of potassium carbonate was added, and the mixture was stirred for 17 hours at 23°C under argon. The reaction mixture was then evaporated in vacuo, diluted with ether and washed neutral with salt water. The reaction mixture was dried over magnesium sulfate and evaporated in vacuo.
Inndampningsresiien ble omrørt i 16 timer ved romtempera-tur med 300 ml av en blanding av eddiksyre/vann/tetrahydrofuran (65/35/10) og ble deretter inndampet i vakuum. Ved The evaporation residue was stirred for 16 hours at room temperature with 300 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10) and was then evaporated in vacuo. By
I IN
I IN
I IN
i in
i in
i in
søylekromatografi på kiselgel med ether/methylenklorid ble det først erholdt 1,6 g av den 15&-konfigurerte alkohol og som polar komponent 2,1 g av tittelforbindelsen (pG-nomenklatur 15a-hydroxy) som farveløs olje. column chromatography on silica gel with ether/methylene chloride, 1.6 g of the 15&-configured alcohol and, as polar component, 2.1 g of the title compound (pG nomenclature 15a-hydroxy) were first obtained as a colorless oil.
IR: 3600, 3430 (bredt), 2960, 2920, 2870, 1738, 1600, IR: 3600, 3430 (wide), 2960, 2920, 2870, 1738, 1600,
1400/cm. 1400/cm.
c) (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-2-brom-4-methyl-3-(tetrahydropyran-2-yloxy)-oct-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on c) (IR,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
En løsning av 1,6 g av den i eksempel 1 b) fremstilte a-alkohol, 16 mg p-toluensulfonsyre og 1,5 g dihydropyran i 50 ml methylenklorid ble omrørt i 35 minutter ved 0°C. Deretter ble reaksjonsblandingen fortynnet med ether, ristet med fortynnet natriumbicarbonat, vasket nøytralt med vann, tørket over magnesiumsulfat og inndampet i vakuum. Etter kromatografi av residuet på kiselgel ble det med hexan/ether (7+3) erholdt 2,17 g av tittelforbindelsen som farveløs olje. A solution of 1.6 g of the α-alcohol prepared in example 1 b), 16 mg of p-toluenesulfonic acid and 1.5 g of dihydropyran in 50 ml of methylene chloride was stirred for 35 minutes at 0°C. The reaction mixture was then diluted with ether, shaken with dilute sodium bicarbonate, washed neutrally with water, dried over magnesium sulfate and evaporated in vacuo. After chromatography of the residue on silica gel with hexane/ether (7+3), 2.17 g of the title compound was obtained as a colorless oil.
IR: 2940, 2870, 1735, 1450, 1120, 1018, 965/cm. IR: 2940, 2870, 1735, 1450, 1120, 1018, 965/cm.
Eksempel 2 Example 2
(5E)-(16RS)-13,14-didehydro-16,20-dimethyl-18,18,19,19-tetra-dehydro-6a-carba-prostaglandin-I^(5E)-(16RS)-13,14-didehydro-16,20-dimethyl-18,18,19,19-tetra-dehydro-6a-carba-prostaglandin-I^
Analogt med eksempel 1 ble det fra 1,6 g (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-2-brom-4-methyl-3-(tetrahydropyran-2-yloxy)-non-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on erholdt 640 mg (5E)-(16RS)-13,14-didehydro-16,20-dimethyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l2_ 11,15-bis-(tetrahydro-pyranylether) som farveløs olje. Analogous to example 1, from 1.6 g of (IR,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 obtained 640 mg of (5E)-(16RS)-13,14-didehydro-16,20 -dimethyl-18,18,19,19-tetrahydro-6a-carba-prostaglandin-12_ 11,15-bis-(tetrahydro-pyranyl ether) as a colorless oil.
IR: 3500 (bredt), 2942, 2860, 2224, 1710/cm. IR: 3500 (broad), 2942, 2860, 2224, 1710/cm.
■ Etter avspaltning av beskyttelsesgruppen som angitt i eksempel 1, ble det erholdt 0,3 g av tittelforbindelsen som farveløs olje. ■ After removal of the protecting group as indicated in Example 1, 0.3 g of the title compound was obtained as a colorless oil.
IR: 3600, 3350 (bredt), 2932, 2224, 1710, 1602/cm. IR: 3600, 3350 (broad), 2932, 2224, 1710, 1602/cm.
Utgangsmaterialet for den ovenfor erholdte tittelfor-bindelse ble fremstilt som følger: a) (lR,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-[(4RS)-2-brom-4-methyl-3-oxo-non-l-en-6-inyl]-bicyclo[3.3.0]octan The starting material for the title compound obtained above was prepared as follows: a) (1R,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-[(4RS)-2-bromo-4-methyl- 3-oxo-non-1-en-6-inyl]-bicyclo[3.3.0]octane
Analogt med eksempel 1 a) ble det fra 6 g 3-methyl-2-oxo-oct-5-inyl-fosfonsyre-dimethylester, 3,7 g N-bromsuccinimid og 5,6 gj (IR, 5S, 6R, 7R)-3, 3-ethylendioxy-7-benzoyloxy-6-formyl!-bicyclo [3 . 3 .0] octan erholdt 4,0 g av det umettede keton ;som farveløs olje. Analogous to example 1 a), from 6 g of 3-methyl-2-oxo-oct-5-inyl-phosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide and 5.6 g of (IR, 5S, 6R, 7R) -3, 3-ethylenedioxy-7-benzoyloxy-6-formyl!-bicyclo [3 . 3.0] octane obtained 4.0 g of the unsaturated ketone as a colorless oil.
IR: 2935, 2883, 1713, 1687, 1602, 1596, 1275, 947/cm. IR: 2935, 2883, 1713, 1687, 1602, 1596, 1275, 947/cm.
b) (1R,5S,6R,7R)-7-hydroxy-6-[(3S,4RS)-2-brom-3-hydroxy-4-methyl-non-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on b) (1R,5S,6R,7R)-7-hydroxy-6-[(3S,4RS)-2-bromo-3-hydroxy-4-methyl-non-1-en-6-inyl]-bicyclo[ 3.3.0]octan-3-one
Analogt med eksempel 1 b) ble det fra 3 g av det i eksempel 2 a) fremstilte keton etter reduksjon med 1,3 g natriumborhydrid, forsåpning med 1,2 g kaliumcarbonat og etterfølgende ketalspaltning med 150 ml av en blanding av eddiksyre/vann/tetrjahydrofuran erholdt 1,2 g av tittelforbindelsen (15ct-hydroxy) som f arveløs olje. Analogously to example 1 b), the ketone produced in example 2 a) was obtained from 3 g after reduction with 1.3 g of sodium borohydride, saponification with 1.2 g of potassium carbonate and subsequent ketal cleavage with 150 ml of a mixture of acetic acid/water/ tetrahydrofuran obtained 1.2 g of the title compound (15ct-hydroxy) as colorless oil.
IR: 3610, 3400 (brejdt) , 2960, 2870, 1739, 1600/cm. IR: 3610, 3400 (broad), 2960, 2870, 1739, 1600/cm.
c) (1R,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-2-brom-4-methyl-3-(tetrahydropyran-2-yloxy)-non-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on c) (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
Analogt med eksempel 1 c) ble det fra 0,78 g av den i eksempel 2 b) fremstilte diol og 0,7 g dihydropyran erholdt 1,1 g av tittelforbindelsen som farveløs olje. Analogous to example 1 c), 1.1 g of the title compound was obtained as a colorless oil from 0.78 g of the diol prepared in example 2 b) and 0.7 g of dihydropyran.
IR: 2940, 2872, 1736, 1450, 1120, 965/cm. IR: 2940, 2872, 1736, 1450, 1120, 965/cm.
Eksempel 3 Example 3
(5E) - (16RS) -20-ethyl-lj3,14-didehydro-16-methyl-18 ,18,19,19-tetradehydro-6a-carba-|i<p>rosta<g>landin-I„ (5E) - (16RS) -20-ethyl-lj3,14-didehydro-16-methyl-18,18,19,19-tetrahydro-6a-carba-|i<p>rosta<g>landin-I„
Analogt med eksempel 1 ble det fra 2 g (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-2-brom-4-methyl-3-(tetrahydropyran-2-yloxy)-dec-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on erholdt 900 mg (5E)-(16RS)-20-ethyl-l3,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I2-11,15-bis-(tetrahydropyranylether) som farveløs olje. Analogous to example 1, from 2 g of (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-2-bromo-4-methyl-3-(tetrahydropyran -2-yloxy)-dec-1-en-6-inyl]-bicyclo[3.3.0]octan-3-one obtained 900 mg of (5E)-(16RS)-20-ethyl-13,14-didehydro-16 -methyl-18,18,19,19-tetrahydro-6a-carba-prostaglandin-12-11,15-bis-(tetrahydropyranyl ether) as a colorless oil.
IR: 3500 (bredt), 2948, 2862, 2220, 1708/cm. IR: 3500 (broad), 2948, 2862, 2220, 1708/cm.
Etter avspaltning av beskyttelsesgruppen som beskrevet After cleavage of the protecting group as described
i eksempel 1, ble det erholdt 4 20 mg av tittelforbindelsen som farveløs olje. in Example 1, 4 20 mg of the title compound was obtained as a colorless oil.
IR: 3600, 3360 (bredt), 2930, 2858, 2220, 1708, 1601/cm. IR: 3600, 3360 (broad), 2930, 2858, 2220, 1708, 1601/cm.
Utgangsmaterialet for den ovenfor fremstilte tittelfor-bindelse ble fremstilt som følger: a) (IR,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-[(4RS)-2-brom-4-methyl-3-oxo-dec-l-en-6-inyl]-bicyclo[3.3.0]octan The starting material for the title compound prepared above was prepared as follows: a) (IR,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-[(4RS)-2-bromo-4-methyl- 3-oxo-dec-1-en-6-inyl]-bicyclo[3.3.0]octane
Analogt med eksempel 1 a) ble det fra 6,25 g 3-methyl-2-oxo-non-5-inyl-fosfonsyre-dimethylester, 3,7 g N-bromsuccinimid og 5,6 g (IR,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-formyl-bicyclo[3.3.0]octan erholdt 4,5 g av det umettede keton som farveløs olje. Analogous to example 1 a), from 6.25 g of 3-methyl-2-oxo-non-5-inyl-phosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide and 5.6 g of (IR,5S,6R, 7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo[3.3.0]octane obtained 4.5 g of the unsaturated ketone as a colorless oil.
IR: 2940, 2880, 1712, 1688, 1601, 1592, 1275, 948/cm. IR: 2940, 2880, 1712, 1688, 1601, 1592, 1275, 948/cm.
b) (IR,5S,6R,7R)-7-hydroxy-6-[(3S,4RS)-2-brom-3-hydroxy-4-methyl-dec-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on b) (IR,5S,6R,7R)-7-hydroxy-6-[(3S,4RS)-2-bromo-3-hydroxy-4-methyl-dec-1-en-6-inyl]-bicyclo[ 3.3.0]octan-3-one
Analogt med eksempel 1 b) ble det fra 4 g av det i eksempel 3 a) fremstilte keton etter reduksjon med natriumborhydrid, forsåpning med kaliumcarbonat og etterfølgende ketalspaltning med eddiksyre/vann/tetrahydrofuran (65/35/10) erholdt 1,5 g av tittelforbindelsen (15a-hydroxy) som farveløs olje. Analogous to example 1 b), 4 g of the ketone produced in example 3 a) after reduction with sodium borohydride, saponification with potassium carbonate and subsequent ketal cleavage with acetic acid/water/tetrahydrofuran (65/35/10) yielded 1.5 g of the title compound (15α-hydroxy) as a colorless oil.
IR: 3610, 3400 (bredt), 2955, 2868, 1738, 1601/cm. IR: 3610, 3400 (broad), 2955, 2868, 1738, 1601/cm.
c) (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-2-brom-4-methyl-3-(tetrahydropyran-2-yloxy)-dec-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on c) (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S,4RS)-2-bromo-4-methyl-3-(tetrahydropyran-2-yloxy)-dec -1-en-6-ynyl]-bicyclo[3.3.0]octan-3-one
Analogt med eksempel 1 c) ble det fra 1,2 g av den i eksempel 3 b) fremstilte diol erholdt 1,81 g av tittelforbindelsen som farveløs olje. Analogous to example 1 c), 1.81 g of the title compound was obtained as a colorless oil from 1.2 g of the diol prepared in example 3 b).
IR: 2942, 2868, 1738, 1450, 1125, 960/cm. IR: 2942, 2868, 1738, 1450, 1125, 960/cm.
d) 3-methyl-2-oxo-non-5-inyl-fosfonsyre-dimethylester d) 3-methyl-2-oxo-non-5-inyl-phosphonic acid dimethyl ester
Til en løsning av 15,8 g natrium i 340 ml ethylalkohol To a solution of 15.8 g of sodium in 340 ml of ethyl alcohol
ble ved 20°C dråpevis tilsatt 120 g methylmalonsyrediethylester. Etter 30 minutter ble dråpevis tilsatt 135 g l-brom-2-hexin (fremstilt fra hex-2-in-l-ol med fosfortribromid i pyridin), og 120 g of methylmalonic acid diethyl ester were added dropwise at 20°C. After 30 minutes, 135 g of l-bromo-2-hexine (prepared from hex-2-yn-l-ol with phosphorus tribromide in pyridine) was added dropwise, and
blandingen ble oppvarmet i 16 timer under tilbakeløpskjøling. Blandingen ble deretter filtrert, residuet ble vasket med methylenklorid og inndampet i vakuum. Residuet ble oppløst i the mixture was heated for 16 hours under reflux. The mixture was then filtered, the residue was washed with methylene chloride and evaporated in vacuo. The residue was dissolved in
i in
500 ml methylenklorid, ristet to ganger, hver gang med 50 ml 500 ml methylene chloride, shaken twice, each time with 50 ml
i in
vann, tørket over magnesiumsulfat og inndampet i vakuum. Residuet ble destillert i vakuum ved 14 torr og 148 - 152°C. Som destillat ble erholdt 155 g alkylert methylmalonsyreester som deretter ble oppvarmet under tilbakeløpskjøling i 1200 ml dimethyl-sulf oxyd og 12 ml vann sammen med 52 g lithiumklorid i 4,5 timer. Reaksjonsblandingen ble deretter helt over 15 1 isvann, ekstrahert<!>med ether, ekstraktet ble ristet med vann, tørket over magnesiumsulfat og inndampet i vakuum. water, dried over magnesium sulfate and evaporated in vacuo. The residue was distilled in vacuum at 14 torr and 148 - 152°C. 155 g of alkylated methylmalonic acid ester were obtained as distillate, which was then heated under reflux in 1200 ml of dimethyl sulfoxide and 12 ml of water together with 52 g of lithium chloride for 4.5 hours. The reaction mixture was then poured over 15 l of ice water, extracted<!>with ether, the extract was shaken with water, dried over magnesium sulfate and evaporated in vacuo.
Destillasjonen av residuet ga ved 94-96°C og 14 torr The distillation of the residue gave at 94-96°C and 14 torr
95 g 2-methyl-oct-4-insyreethylester som en farveløs væske. 95 g of 2-methyl-oct-4-inic acid ethyl ester as a colorless liquid.
Til en løsnini<g> av 176 g methanfosfonsyredimethylesteren To a solution of 176 g of the methanephosphonic acid dimethyl ester
i 2 1 tetrahydrofuran ble dråpevis tilsatt 640 ml av en 1,5 M butyllithiumløsning i hexan ved -70°C. Etter 15 minutter ble det langsomt tilsatt en løsning av 90 g 2-methyl-oct-4-insyre-ethylester i 300 ml tetrahydrofuran. Reaksjonsblandingen ble omrørt i 4 timer ved -70°C, nøytralisert med eddiksyre og inndampet i vakuum. Residuet ble tilsatt 200 ml vann, ekstrahert tre ganger, hver gang med 500 ml methylenklorid, ekstraktet ble ristet med 100i ml vann, tørket over magnesiumsulfat og inndampet i vakuum1. Destillasjonen av residuet ga ved 0,35 torr og 126-128°C 80 g av tittelforbindelsen som en farveløs væske. in 2 1 tetrahydrofuran, 640 ml of a 1.5 M butyllithium solution in hexane was added dropwise at -70°C. After 15 minutes, a solution of 90 g of 2-methyl-oct-4-acetic acid ethyl ester in 300 ml of tetrahydrofuran was slowly added. The reaction mixture was stirred for 4 hours at -70°C, neutralized with acetic acid and evaporated in vacuo. The residue was added to 200 ml of water, extracted three times, each time with 500 ml of methylene chloride, the extract was shaken with 100 ml of water, dried over magnesium sulfate and evaporated in vacuo1. The distillation of the residue gave at 0.35 torr and 126-128°C 80 g of the title compound as a colorless liquid.
i in
Eksempel 4 Example 4
(5E) -13,14-didehyd'ro-16 ,16-dimethyl-18 ,18,19,19-tetradehydro-6a-carba-prostaglandin-l2(5E)-13,14-didehydro-16,16-dimethyl-18,18,19,19-tetrahydro-6a-carba-prostaglandin-12
Analogt med eksempel 1 ble det fra 1,5 g (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-brom-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-oct-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on erholdt 610 mg (5E)-13,14-didehydro-16,16-dimethyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I2-ll,15-bis-(tetrahydropyran-2-ylether) som en farveløs olje. Analogous to example 1, from 1.5 g of (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-4,4-dimethyl-3- (tetrahydropyran-2-yloxy)-oct-1-en-6-inyl]-bicyclo[3.3.0]octan-3-one obtained 610 mg of (5E)-13,14-didehydro-16,16-dimethyl-18 ,18,19,19-tetrahydro-6α-carba-prostaglandin-12-11,15-bis-(tetrahydropyran-2-yl ether) as a colorless oil.
IR: 3500 (bredt), '2944, 2862, 2222, 1708/cm. IR: 3500 (broad), '2944, 2862, 2222, 1708/cm.
Etter avspaltning av beskyttelsesgruppen som beskrevet After cleavage of the protecting group as described
i eksempel 1, ble det erholdt 290 mg av tittelforbindelsen som farveløs olje. in Example 1, 290 mg of the title compound was obtained as a colorless oil.
IR: 3600, 3400 (bredt), 2930, 2862, 1708, 1600/cm. IR: 3600, 3400 (broad), 2930, 2862, 1708, 1600/cm.
Utgangsmaterialet ble fremstilt som følger: The starting material was prepared as follows:
a) (IR,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-(2-brom-4,4-dimethyl-3-oxo-oct-l-en-6-inyl)-bicyclo[3.3.0]octan a) (IR,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-(2-bromo-4,4-dimethyl-3-oxo-oct-1-en-6-inyl)- bicyclo[3.3.0]octane
Analogt med eksempel 1 a) ble det fra 6,25 g 3,3-dimethyl-2-oxo-hept-5-in-fosfonsyredimethylester, 3,7 g N-bromsuccinimid og 5,6 g (IR,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-formyl-bicyclo[3.3.0]octan erholdt 4,7 g av det umettede keton som farveløs olje. Analogously to example 1 a), 6.25 g of 3,3-dimethyl-2-oxo-hept-5-yne-phosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide and 5.6 g of (IR,5S,6R, 7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo[3.3.0]octane yielded 4.7 g of the unsaturated ketone as a colorless oil.
IR: 2940, 2878, 1710, 1688, 1602, 1594, 1448, 1270, 944/cm. IR: 2940, 2878, 1710, 1688, 1602, 1594, 1448, 1270, 944/cm.
b) (1R,5S,6R,7R)-7-hydroxy-6-[(3S)-2-brom-4,4-dimethyl-3-hydroxy-oct-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on b) (1R,5S,6R,7R)-7-hydroxy-6-[(3S)-2-bromo-4,4-dimethyl-3-hydroxy-oct-1-en-6-inyl]-bicyclo[ 3.3.0]octan-3-one
Analogt med eksempel 1 b) ble det fra 4 g av det i eksempel 4 a) fremstilte keton etter reduksjon med natriumborhydrid, forsåpning med kaliumcarbonat og etterfølgende ketalspaltning erholdt 1,40 g av tittelforbindelsen (15a-hydroxy) som farveløs olje. Analogous to example 1 b), 1.40 g of the title compound (15a-hydroxy) was obtained as a colorless oil from 4 g of the ketone produced in example 4 a) after reduction with sodium borohydride, saponification with potassium carbonate and subsequent ketal cleavage.
IR: 3600, 3410 (bredt), 2958, 2865, 1738, 1600/cm. IR: 3600, 3410 (broad), 2958, 2865, 1738, 1600/cm.
c) (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-brom-4,4-dimethyl-3-(tetrahydropyran —2-yloxy)-oct-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on c) (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-oct -1-en-6-ynyl]-bicyclo[3.3.0]octan-3-one
Analogt med eksempel 1 c) ble det fra 1,2 g av den i eksempel 4 b) fremstilte diol med dihydropyran erholdt 1,6 g av tittelforbindelsen som olje. Analogously to example 1 c), 1.6 g of the title compound was obtained as an oil from 1.2 g of the diol prepared in example 4 b) with dihydropyran.
IR: 2942, 2870, 1738, 1450, 1132, 960/cm. IR: 2942, 2870, 1738, 1450, 1132, 960/cm.
Eksempel 5 Example 5
(5E)-13,14-didehydro-18,18,19,19-tetradehydro-16,16,20-tri-methyl-6a-carba-prostaglandin-l2(5E)-13,14-didehydro-18,18,19,19-tetrahydro-16,16,20-tri-methyl-6a-carba-prostaglandin-12
Analogt med eksempel 1 ble det fra 1 g (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-brom-4,4-dimethyl-3-(tetrahydropyran-2-yloxy)-non-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on erholdt 400 mg (5E)-13,14-didehydro-18,18,19,19-tetra-dehydro-16,16,20-trimethyl-6å-carba-prostaglandin-I2-ll/15-bis-(tetrahydropyranylether) som farveløs olje. Analogous to example 1, from 1 g of (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-4,4-dimethyl-3-(tetrahydropyran -2-yloxy)-non-1-en-6-inyl]-bicyclo[3.3.0]octan-3-one obtained 400 mg of (5E)-13,14-didehydro-18,18,19,19-tetra -dehydro-16,16,20-trimethyl-6α-carba-prostaglandin-12-11/15-bis-(tetrahydropyranyl ether) as a colorless oil.
IR: 3510 (bredt), 2940, 2858, 2220, 1708/cm. IR: 3510 (broad), 2940, 2858, 2220, 1708/cm.
Etter avspaltning av beskyttelsesgruppen som beskrevet i eksempel 1, ble det erholdt 410 mg av tittelforbindelsen som farveløs olje. After removal of the protecting group as described in Example 1, 410 mg of the title compound were obtained as a colorless oil.
IR: 3600, 3340 (bredt), 2940, 2832, 2220, 1708, 1600/cm. IR: 3600, 3340 (broad), 2940, 2832, 2220, 1708, 1600/cm.
Utgangsmaterialet for den ovenfor erholdte tittelfor-bindelse ble fremstilt som følger: The starting material for the title compound obtained above was prepared as follows:
i in
a) (IR,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-(2-brom-4,4-dimethyl-3-oxo-rion-l-en-6-inyl)-bicyclo[3.3.0]octan a) (IR,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-(2-bromo-4,4-dimethyl-3-oxo-rion-1-en-6-ynyl)- bicyclo[3.3.0]octane
Analogt med eksempel 1 a) ble det fra 12,6 g 3,3-dimethyl-2-oxo-oct-r5-inyl-fosfonsyredimethylester, 7,4 g N-bromsuccinimid og 11,2 g (IR,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-formyl-bicyclo[3.3.0]octan erholdt 8,7 g av det umettede keton som farveløs olje. Analogously to example 1 a), 12.6 g of 3,3-dimethyl-2-oxo-oct-r5-inyl-phosphonic acid dimethyl ester, 7.4 g of N-bromosuccinimide and 11.2 g of (IR,5S,6R, 7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo[3.3.0]octane obtained 8.7 g of the unsaturated ketone as a colorless oil.
IR: 2946, 2880, 17l2, 1687, 1601, 1594, 1272, 948/cm. IR: 2946, 2880, 1712, 1687, 1601, 1594, 1272, 948/cm.
b) (IR,5S,6R,7R)-7+hydroxy-6-[(3S)-2-brom-4,4-dimethyl-3-hydroxy-non-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on b) (IR,5S,6R,7R)-7+hydroxy-6-[(3S)-2-bromo-4,4-dimethyl-3-hydroxy-non-1-en-6-inyl]-bicyclo[ 3.3.0]octan-3-one
Analogt med eksempel 1 b) ble det fra 5 g av det i eksempel 5 a) fremstilte keton etter reduksjon med natriumborhydrid, forsåpningimed kaliumcarbonat og etterfølgende ketalspaltning erholdt 1,80 g av tittelforbindelsen (15a-hydroxy) som farveløs olje.' Analogous to example 1 b), 1.80 g of the title compound (15a-hydroxy) was obtained as a colorless oil from 5 g of the ketone produced in example 5 a) after reduction with sodium borohydride, saponification with potassium carbonate and subsequent ketal cleavage.
IR: 3600, 3404 (bredt), 2958, 2864, 1738, 1601/cm. IR: 3600, 3404 (broad), 2958, 2864, 1738, 1601/cm.
c) (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-brom-4,4-dimethyl-3-!(tetrahydropyran-2-yloxy) -non-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on c) (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-4,4-dimethyl-3-!(tetrahydropyran-2-yloxy) - non-1-en-6-inyl]-bicyclo[3.3.0]octan-3-one
Analogt med eksempel 1 c) ble det fra 1,5 g av den i eksempel 5 b) fremstilte diol erholdt 2,20 g av tittelforbindelsen som farveløs olje.'<I>Analogously to example 1 c), 2.20 g of the title compound was obtained as a colorless oil from 1.5 g of the diol prepared in example 5 b).
IR: 2942, 2878, 1738, 1125, 968/cm. IR: 2942, 2878, 1738, 1125, 968/cm.
j j
i in
Eksempel 6 Example 6
(5E)-13,14-didehydro-18,18,19,19-tetradehydro-6a-carba-prostaglandin-^ (5E)-13,14-didehydro-18,18,19,19-tetrahydro-6a-carba-prostaglandin-^
Analogt med eksempel 1 ble det fra 400 mg (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-brom-3-(tetrahydropyran-2-yloxy)-oct-l-en-6-inyl]-bicyclo[3.3.3]octan-3-on erholdt 130 mg (5E)-13,14-didehydro-18,18,19,19-tetradehydro-6a-carba-prostaglandin-l^-ll,15-bis-(tetrahydropyranylether) Analogous to example 1, from 400 mg of (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-3-(tetrahydropyran-2-yloxy)- oct-1-en-6-inyl]-bicyclo[3.3.3]octan-3-one obtained 130 mg of (5E)-13,14-didehydro-18,18,19,19-tetrahydro-6a-carba-prostaglandin -1^-11,15-bis-(tetrahydropyranyl ether)
som farveløs olje. as colorless oil.
IR: 3500 (bredt), 2948, 2862, 2226, 1708/cm. IR: 3500 (broad), 2948, 2862, 2226, 1708/cm.
Etter avspaltning av beskyttelsesgruppen som beskrevet i eksempel 1, ble det erholdt 62 mg av tittelforbindelsen som farveløs olje. After removal of the protecting group as described in Example 1, 62 mg of the title compound were obtained as a colorless oil.
IR: 3610, 3350 (bredt), 2930, 2862, 2226, 1709, 1600/cm. IR: 3610, 3350 (broad), 2930, 2862, 2226, 1709, 1600/cm.
Utgangsmaterialet for den ovenfor fremstilte tittelfor-bindelse ble fremstilt som følger: a) (IR,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-(2-brom-3-oxo-oct-l-en-6-inyl)-bicyclo[3.3.0]octan The starting material for the title compound prepared above was prepared as follows: a) (IR,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-(2-bromo-3-oxo-oct-1- en-6-ynyl)-bicyclo[3.3.0]octane
Analogt med eksempel 1 a) ble det fra 5,8 g 2-oxo-hept-5-inyl-fosfonsyre-dimethylester, 3,7 g N-bromsuccinimid og 5,6 g (IR,5S,6R,7R)-3,3-ethylendioxy-7-benzoyloxy-6-formyl-bicyclo-[3.3.0]octan erholdt 4,7 g av det umettede keton som farveløs olje. Analogous to example 1 a), from 5.8 g of 2-oxo-hept-5-inyl-phosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide and 5.6 g of (IR,5S,6R,7R)-3 ,3-ethylenedioxy-7-benzoyloxy-6-formyl-bicyclo-[3.3.0]octane obtained 4.7 g of the unsaturated ketone as a colorless oil.
IR: 2932, 2880, 1712, 1688, 1600, 1592, 1272, 948/cm. IR: 2932, 2880, 1712, 1688, 1600, 1592, 1272, 948/cm.
b) (1R,5S,6R,7R)-7-hydroxy-6-[(3S)-2-brom-3-hydroxy-oct-l-en-6-inyl]-bicyclo[3.3.0]octan-3-on b) (1R,5S,6R,7R)-7-hydroxy-6-[(3S)-2-bromo-3-hydroxy-oct-1-en-6-inyl]-bicyclo[3.3.0]octane- 3-Mon
Analogt med eksempel 1 b) ble det fra 4 g av det i eksempel 6 a) fremstilte keton etter reduksjon med natriumborhydrid, forsåpning med kaliumcarbonat og etterfølgende ketalspaltning erholdt 1,35 g av tittelforbindelsen som farveløs olje. Analogous to example 1 b), 1.35 g of the title compound was obtained as a colorless oil from 4 g of the ketone produced in example 6 a) after reduction with sodium borohydride, saponification with potassium carbonate and subsequent ketal cleavage.
IR: 3600, 3410 (bredt), 2962, 2866, 1740, 1601/cm. IR: 3600, 3410 (broad), 2962, 2866, 1740, 1601/cm.
c) (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-brom-3-(tetrahydropyran-2-yloxy)-oct-l-en-6-inyl]-bicyclo- c) (IR,5S,6R,7R)-7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-3-(tetrahydropyran-2-yloxy)-oct-1-en-6 -inyl]-bicyclo-
[3.3.0]octan-3-on [3.3.0]octan-3-one
Analogt med eksempel 1 c) ble det fra 1,20 g av den i Analogously to example 1 c), 1.20 g of the i
eksempel 6 b) fremstilte diol med dihydropyran erholdt 1,61 g av tittelforbindelsen som farveløs olje. example 6 b) prepared diol with dihydropyran obtained 1.61 g of the title compound as a colorless oil.
IR: 2945, 2882, 1739, 1125, 968/cm. IR: 2945, 2882, 1739, 1125, 968/cm.
i in
Eksempel 7 I Example 7 I
(5E)-(16RS)-13,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I2-tris-(hydroxymethyl)-aminomethansalt (5E)-(16RS)-13,14-didehydro-16-methyl-18,18,19,19-tetrahydro-6a-carba-prostaglandin-12-tris-(hydroxymethyl)-aminomethane salt
Til en løsning av 358 mg (5E)-(16RS)-13,14-didehydro-16-methyl-18,18,19,19-tetradehydro-6a-carba-prostaglandin-I2To a solution of 358 mg of (5E)-(16RS)-13,14-didehydro-16-methyl-18,18,19,19-tetrahydro-6a-carba-prostaglandin-I2
i 60 ml acetonitril ble ved 65°C tilsatt en løsning av 121 mg tris- (hydroxymethyli) -aminomethan i 0,4 ml vann. Reaksjons- in 60 ml of acetonitrile at 65°C was added a solution of 121 mg of tris-(hydroxymethyl)-aminomethane in 0.4 ml of water. reaction
blandingen ble avkj'ølt under omrøring, og etter 16 timer ble løsningsmidlet dekantert fra og residuet ble tørket ved 25°C og 0,1 torr. Det ble erholdt 310 mg av tittelforbindelsen som en voksaktig masse. the mixture was cooled with stirring, and after 16 hours the solvent was decanted off and the residue was dried at 25°C and 0.1 torr. 310 mg of the title compound were obtained as a waxy mass.
Claims (3)
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 (3)
| Publication Number | Publication Date |
|---|---|
| NO830399L NO830399L (en) | 1983-08-09 |
| NO155729B true NO155729B (en) | 1987-02-09 |
| NO155729C NO155729C (en) | 1987-05-20 |
Family
ID=6155190
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO830399A NO155729C (en) | 1982-02-08 | 1983-02-07 | ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE CARBACYCLINES. |
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) | ES519627A0 (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 JP JP58017584A patent/JPH0611728B2/en not_active Expired - Lifetime
- 1983-02-07 CS CS83847A patent/CS235307B2/en unknown
- 1983-02-07 GR GR70438A patent/GR77967B/el unknown
- 1983-02-07 FI FI830414A patent/FI78064C/en not_active IP Right Cessation
- 1983-02-07 CA CA000421004A patent/CA1215362A/en not_active Expired
- 1983-02-07 AU AU11180/83A patent/AU567867B2/en not_active Ceased
- 1983-02-07 NO NO830399A patent/NO155729C/en unknown
- 1983-02-08 ZA ZA83851A patent/ZA83851B/en unknown
- 1983-02-08 DK DK052383A patent/DK156563C/en not_active IP Right Cessation
- 1983-02-08 ES ES519627A patent/ES519627A0/en active Granted
- 1983-02-08 IE IE246/83A patent/IE54554B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ATE24487T1 (en) | 1987-01-15 |
| NO155729C (en) | 1987-05-20 |
| ZA83851B (en) | 1983-10-26 |
| NZ203115A (en) | 1986-03-14 |
| DK52383D0 (en) | 1983-02-08 |
| FI78064C (en) | 1989-06-12 |
| FI78064B (en) | 1989-02-28 |
| EP0086404A1 (en) | 1983-08-24 |
| GR77967B (en) | 1984-09-25 |
| AU1118083A (en) | 1983-08-18 |
| DE3368609D1 (en) | 1987-02-05 |
| NO830399L (en) | 1983-08-09 |
| IL67839A0 (en) | 1983-06-15 |
| HU191197B (en) | 1987-01-28 |
| DK52383A (en) | 1983-08-09 |
| ES8400384A1 (en) | 1983-11-16 |
| ES519627A0 (en) | 1983-11-16 |
| FI830414A0 (en) | 1983-02-07 |
| DE3204443A1 (en) | 1983-08-18 |
| IE54554B1 (en) | 1989-11-22 |
| CA1215362A (en) | 1986-12-16 |
| DK156563C (en) | 1990-01-29 |
| JPS58146531A (en) | 1983-09-01 |
| FI830414L (en) | 1983-08-09 |
| CS235307B2 (en) | 1985-05-15 |
| SU1145926A3 (en) | 1985-03-15 |
| DD207901A5 (en) | 1984-03-21 |
| IE830246L (en) | 1983-08-08 |
| DK156563B (en) | 1989-09-11 |
| AU567867B2 (en) | 1987-12-10 |
| EP0086404B1 (en) | 1986-12-30 |
| JPH0611728B2 (en) | 1994-02-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK169815B1 (en) | Analogous Process for the Preparation of Carbacyclines | |
| US4692464A (en) | Novel prostacyclin derivatives and a process for the preparation thereof | |
| 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 | |
| NO156524B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE CARBACYCLINE DERIVATIVES. | |
| NO155729B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE CARBACYCLINES. | |
| HU191150B (en) | Process for producing new prostacycline derivatives | |
| JPH0446256B2 (en) | ||
| US4618626A (en) | Novel carbacyclin esters, process for the preparation thereof, and their use as medicinal agents | |
| IE58007B1 (en) | Novel carbacyclins,processes for their production and their use as medicinal agents | |
| JPH0510330B2 (en) | ||
| DK160759B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF CARBACYCLINE DERIVATIVES | |
| HU190901B (en) | Process for preparing new carbacycline derivatives and pharmaceutical preparations comprising these compounds | |
| NO170850B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 6-OXOPROSTAGLAND INGREDIATES |