DK144730B - ANALOGY PROCEDURE FOR PREPARING 2-DESCARBOXY-2-TETRAZOLYL (5) -PROSTAGLANDINE2 COMPOUNDS - Google Patents
ANALOGY PROCEDURE FOR PREPARING 2-DESCARBOXY-2-TETRAZOLYL (5) -PROSTAGLANDINE2 COMPOUNDS Download PDFInfo
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- DK144730B DK144730B DK430772AA DK430772A DK144730B DK 144730 B DK144730 B DK 144730B DK 430772A A DK430772A A DK 430772AA DK 430772 A DK430772 A DK 430772A DK 144730 B DK144730 B DK 144730B
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- Prior art keywords
- tetrazolyl
- pge2
- compounds
- descarboxy
- prostaglandins
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- 238000000034 method Methods 0.000 title description 9
- 229960002986 dinoprostone Drugs 0.000 description 17
- 150000003180 prostaglandins Chemical class 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 15
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 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 11
- 238000012360 testing method Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- -1 tetrazolyl prostaglandins Chemical class 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 125000003831 tetrazolyl group Chemical group 0.000 description 9
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- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
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- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
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- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 1
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 1
- SXXLKZCNJHJYFL-UHFFFAOYSA-N 4,5,6,7-tetrahydro-[1,2]oxazolo[4,5-c]pyridin-5-ium-3-olate Chemical compound C1CNCC2=C1ONC2=O SXXLKZCNJHJYFL-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 101000799461 Homo sapiens Thrombopoietin Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
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- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- URLCOJMZGZESAT-UHFFFAOYSA-N benzene formic acid oxolane Chemical compound OC=O.C1CCOC1.C1=CC=CC=C1 URLCOJMZGZESAT-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 150000003938 benzyl alcohols Chemical class 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
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- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
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- 239000012043 crude product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000138 effect on histamine Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- YMFBFFPJRABBPE-BTVCFUMJSA-N ethanol;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal Chemical compound CCO.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O YMFBFFPJRABBPE-BTVCFUMJSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 230000027119 gastric acid secretion Effects 0.000 description 1
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- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
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- 230000004130 lipolysis Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 208000015994 miscarriage Diseases 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- DZUXGQBLFALXCR-CDIPTNKSSA-N prostaglandin F1alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(O)=O DZUXGQBLFALXCR-CDIPTNKSSA-N 0.000 description 1
- 108700022737 rat Fat1 Proteins 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000003033 spasmogenic effect Effects 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 230000035884 vasodepression Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5407—Acyclic saturated phosphonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
(19) DANMARK(19) DENMARK
6 (12) FREMLÆGGELSESSKRIFT (11) 1W30B6 (12) PUBLICATION WRITING (11) 1W30B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENETDIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM
(21) Ansøgning nr. 4307/72 (51) |nt.ci.3 C 07 D 257/04 (22) Indleveringsdag 51 · &ug. 1972 (24) Løbedag 31- aug. 1972 (41) Aim. tilgængelig 2. mar. 1973 (44) Fremlagt 24. maj 1982 (86) International ansøgning nr.(21) Application No. 4307/72 (51) | nt.ci.3 C 07 D 257/04 (22) Filing Day 51 · & ug. 1972 (24) Running day 31- Aug. 1972 (41) Aim. available March 2 1973 (44) Submitted May 24, 1982 (86) International Application no.
(86) International indleveringsdag (85) Videreførelsesdag (62) Stamansøgning nr.(86) International filing day (85) Continuation day (62) Stock application no.
(30) Prioritet 1. S ep. 1971, 177102, US(30) Priority 1. S ep. 1971, 177102, US
(71) Ansøger PFIZER INC., New York, US.(71) Applicant PFIZER INC., New York, US.
(72) Opfinder Hans-Jurgen Ernst Hess, US: Thomas Ken Schaaf, US: Leonard Joseph Czuba, US.(72) Inventor Hans-Jurgen Ernst Hess, US: Thomas Ken Schaaf, US: Leonard Joseph Czuba, US.
(74) Fuldmægtig Ingeniørfirmaet Hofman-Bang & Boutard.(74) Associate Engineer Hofman-Bang & Boutard.
(54) Analogifremgangsmåde til frem* stilling af 2-descarboxy-2-tetrazolyl(5)-prostaglandin-E2-forbindelser.(54) Analogous process for preparing 2-descarboxy-2-tetrazolyl (5) -prostaglandin E2 compounds.
Opfindelsen angår en analogifremgangsmåde til fremstilling af visse hidtil ukendte analoge til de naturligt forekommende prostaglandiner, nemlig hidtil ukendte 2-descarboxy-2-tetrazolyl(5)-prostaglandin-E^-forbindelser med den i kravets indledning angivne almene formel I, hvilken fremgangsmåde er ejendommelig ved det i kravets kende-^ tegnende del anførte.The invention relates to an analogous process for the preparation of certain novel analogs to the naturally occurring prostaglandins, namely, novel 2-descarboxy-2-tetrazolyl (5) -prostaglandin-E 2 compounds of the general formula I as set forth in the preamble, which method is peculiar to that stated in the characterizing part of the claim.
D Prostaglandineme er umættede fedtsyrer med 20 carbonatomer, som [. udviser forskellige fysiologiske virkninger. F.eks. er prostaglan- f dineme af E- og A-rækkerne kraftige vasodilatorer (Bergstrom et al.,D The prostaglandins are unsaturated fatty acids with 20 carbon atoms, such as [. exhibits various physiological effects. Eg. the prostaglandins of the E and A rows are potent vasodilators (Bergstrom et al.,
Acta Physiol. Scand. 64,332-339, 1965 og Bergstrom et al., Life Scl.Acta Physiol. Scand. 64,332-339, 1965 and Bergstrom et al., Life Scl.
- 6,449-455, 1967). Denne relakserende virkning på små blodkar er sandsynligvis ansvarlig for det fald i systemisk arterieblodtryk (vasodepression) som iagttages ved intravenøs injection af PGE-^ og 144730 2 PGA-^ (Weeks and King, Federation Proc. 23,327» 1964; Bergstrom et al., I965, op. cit. Carlson et al., Acta Med. Scand. 193,423-430, 1968; og Carlson et al., Acta Physiol. Scand. 75,161-169» 1969).- 6,449-455, 1967). This relaxant effect on small blood vessels is probably responsible for the decrease in systemic arterial blood pressure (vasodepression) observed by intravenous injection of PGE-1 and PGA-2 (Weeks and King, Federation Proc. 23,327 »1964; Bergstrom et al. I965, op. Cit. Carlson et al., Acta Med. Scand. 193, 423-430, 1968; and Carlson et al., Acta Physiol. Scand. 75, 161-169 (1969).
En anden velkendt fysiologisk virkning for PGE^ og PGE2 er som bron-chodilator (Cuthbert, Brit. Med. J. 4,723-726, 1969).Another well-known physiological effect for PGE 2 and PGE 2 is as a bronchodilator (Cuthbert, Brit. Med. J. 4,723-726, 1969).
En anden vigtig fysiologisk rolle for de naturlige prostaglandiner er i forbindelse med formeringscyklus. PGE2 er kendt for at have evne til at fremkalde veer (Karim et al., J. Obstet Gynaec. Brit. Cwlth. 77,200t210, I97O) og også for at fremkalde terapeutisk abort (Karim et al., Brit. Med. J. i trykken). Der er blevet opnået patenter på flere prostaglandiner af E- og F-rækkerne, som fremkaldere af veer hos pattedyr (belgisk patsi tskrift nr. 754 158 og de patentskrift nr. 2 034 641) og på PGF1, F2 og F^ til kontrol af formeringscyklus (sydafrikansk patentskrift nr. 69/6089).Another important physiological role for the natural prostaglandins is in the propagation cycle. PGE2 is known to have the ability to induce labor (Karim et al., J. Obstet Gynaec. Brit. Cwlth. 77,200t210, I97O) and also to induce therapeutic abortion (Karim et al., Brit. Med. J. in print). Patents have been obtained on several prostaglandins of the E and F rows as mammalian carcinogens (Belgian Patent No. 754 158 and Patent Specification No. 2 034 641) and on PGF1, F2 and F propagation cycle (South African Patent Publication No. 69/6089).
Endnu andre kendte fysiologiske aktiviteter for PGE^ er til inhibe-ring af mavesyresekretion (Shaw og Ramwell, "Worcester Symp. on Prostaglandins" New York, Wiley, 1968, side 55-64) og også af blodpladeaggregation (Emmons et al., Brit. Med. J. 2,468-472, 1967).Still other known physiological activities for PGE1 are to inhibit gastric acid secretion (Shaw and Ramwell, "Worcester Symp. On Prostaglandins" New York, Wiley, 1968, pp. 55-64) and also platelet aggregation (Emmons et al., Brit. J. Med., 2,468-472, 1967).
Det er også kendt, at sådanne fysiologiske virkninger i vivo kun vil blive fremkaldt i et kort tidsrum efter indgivningen af et prostaglandin. En anseelig mængde vidnesbyrd angiver, at årsagen til det hurtige ophør af aktivitet er, at de naturlige prostaglandiner hurtigt og effektivt deaktiveres metabolisk vedp -oxidation af car-ooxylsyresidekæden og ved oxidation af 15o«, -hydroxylgruppen (Anggard et al., Acta. Physiol. Scand., 81, 396 (1971) og henvisninger deri).It is also known that such physiological effects in vivo will only be induced for a short time after the administration of a prostaglandin. A considerable amount of testimony indicates that the reason for the rapid cessation of activity is that the natural prostaglandins are rapidly and effectively deactivated metabolically by the oxidation of the carboxylic acid side chain and by the oxidation of the 15o Scand., 81, 396 (1971) and references therein).
Der var selvfølgelig et stærkt ønske om at frembringe analoge til prostaglandineme, som ville have fysiologiske aktiviteter svarende til de naturlige forbindelser, men hos hvilke selektiviteten af virkningen og varigheden af aktiviteten var forøget.Of course, there was a strong desire to produce analogues to the prostaglandins, which would have physiological activities similar to the natural compounds, but in which the selectivity of the action and duration of activity were increased.
Dette opnås medefe hidtil ukendte forbindelser, som fremstilles ved fremgangsmåden ifølge opfindelsen. Disse 2-descarboxy-2-tetrazolyl(5)-E2- prostaglandiner, hvori carboxylsyredelen er erstattet med tetra- 144730 3 zolringen, og hvori 15p-hydrogenet om ønsket kan være erstattet med en 15P-methylgruppe, tilfredstiller på enestående måde de ovennævnte krav, d.v.s. at de har Aktivitetsprofiler, som er sammenlignelige med de oprindelige prostaglandiners, og de udviser en længere virkningstid end de oprindelige prostaglandiner.This is also achieved with new compounds prepared by the process of the invention. These 2-descarboxy-2-tetrazolyl (5) -E2-prostaglandins, wherein the carboxylic acid moiety is replaced by the tetra-zole ring and wherein the 15β hydrogen may, if desired, be replaced by a 15β-methyl group, uniquely satisfies the above requirements , ie that they have Activity profiles comparable to those of the original prostaglandins and exhibit a longer duration of action than the original prostaglandins.
Fremgangsmåden ifølge opfindelsen og fremstillingen af mellemprodukter kan illustreres ved det følgepde reaktionsskema:The process of the invention and preparation of intermediates can be illustrated by the following reaction scheme:
ReaktionsskemaScheme
OHOH
i N"—Nin N "- N
. N *-N. N * -N
THPOTHPO
IIIIII
Jones’ reagens ΨJones' reagent Ψ
0 N —N0 N - N
N-NN-N
THPo' ^THPo '^
IVIV
Eddikesyre PGE2~tetrazolyl I (R1-#) 144730 4Acetic acid PGE2 ~ tetrazolyl I (R1- #) 4
Som vist i reaktionsskemaet behandles udgangsforbindelsen III, den tetrazolylanaloge til bis-THP-etheren af PGF2(X, først med Jones* reagens til dannelse af bis-THP-etheren af PGE2-tetrazolyl (IV), hvorefter dette mellemprodukt ved fremgangsmåden ifølge opfindelsen hydrolyseres med eddikesyre til dannelse af den ønskede PGE2-tetra-zolyl (I, R^=H), som koncentreres og renses ved søjlechromatografi.As shown in the reaction scheme, the starting compound III, the tetrazolyl analog of the bis-THP ether of PGF2 (X, first with Jones * reagent to form the bis-THP ether of PGE2-tetrazolyl (IV)), is then hydrolyzed by the process of the invention. with acetic acid to give the desired PGE 2 -tetrazolyl (I, R 2 = H), which is concentrated and purified by column chromatography.
Til fremstilling af 15β-methyl-derivater af den ovennævnte prostag-landin-E2-tetrazolyl-forbindelse anvendes blot udgarigsforbindelsen III med en methyl-gruppe i 15β-stillingen, og man går frem som angivet ovenfor til fremstilling af den ønskede forbindelse.For the preparation of 15β-methyl derivatives of the above-mentioned prostaglandin E2-tetrazolyl compound, only the base compound III with a methyl group in the 15β position is used, and proceed as indicated above to prepare the desired compound.
Talrige prøvninger in vivo har vist, at de ved fremgangsmåden i-følge opfindelsen fremstillede tetrazolyl-prostaglandin-analoge har lignende fysiologiske aktiviteter som de, der udvises af de naturlige prostaglandiner. Disse prøvninger omfatter bl.a. en prøvning for virkning på isoleret glat muskel fra kaninaorta og marsvinileum, en prøvning for inhibering af norepinephrin-induceret lipolyse hos isolerede rotte-fedtceller, en prøvning for virkning på histamininduceret bronchospasme hos marsvin, en prøvning for virkninger på hundeblodtryk og en prøvning for virkninger på rotteblodtryk.Numerous tests in vivo have shown that the tetrazolyl-prostaglandin analogs prepared by the process according to the invention have similar physiological activities as those exhibited by the natural prostaglandins. These tests include: a test for effect on isolated rabbit aortic and guinea pig smooth muscle, a test for inhibition of norepinephrine-induced lipolysis in isolated rat fat cells, a test for effect on histamine-induced bronchospasm in guinea pigs, a test for effects on canine blood pressure, and a test for effects on rat blood pressure.
Ved prøvningen på isoleret glat muskel fra kaninaorta fandtes tærskeldosen for spasmogen virkning at være 250 ng/ml for PGE2 og 500 ng/ml for PGE2-tetrazolyl. Ved den samme prøvning under anvendelse af marsvinileum blev der opnået værdier på 20 ng/ml og 100 ng/ml for de samme to forbindelser.When tested for isolated smooth muscle from the rabbit aorta, the threshold dose for spasmogenic effect was found to be 250 ng / ml for PGE2 and 500 ng / ml for PGE2 tetrazolyl. At the same test using guinea pigs, values of 20 ng / ml and 100 ng / ml were obtained for the same two compounds.
Ved prøvningen for beskyttelse af 100yug/ml af prøveforbindelsen over for histamin-indue er et bronchospasme hos marsvin blev der opnået værdier på 65-75 % håde for PGE2 og PGE2-tetrazolyl.In the test for protection of 100 µg / ml of the test compound against histamine-inducing guinea pig bronchospasm, values of 65-75% were obtained for PGE2 and PGE2-tetrazolyl.
Ved prøvningen for virkninger på hundeblodtryk fandtes både PGE2 og PGE2-tetrazolyl at være depressorer, og der blev opnået værdier på 0,l6^ug og 0,8yug/ml af de to forbindelser som tærskeldosis for denne virkning. I tilfælde af rotteblodtryk var forbindelserne også depressorer, og tærskeldosen for PGE2 og for PGE2-tetrazolyl var 10,0 /Ug/ml.In testing for effects on canine blood pressure, both PGE2 and PGE2 tetrazolyl were found to be depressants, and values of 0.16 µg and 0.8 µg / ml of the two compounds were obtained as the threshold dose for this effect. In the case of rat blood pressure, the compounds were also depressors and the threshold dose for PGE2 and for PGE2 tetrazolyl was 10.0 / ug / ml.
144730 5144730 5
At varigheden af virkningen af den 15 β-methyl-tetrazolyl-analoge er forøget i forhold til den oprindelige prostaglandin illustreres klart af de i den nedenstående Tabel 1 anførte data. Dette forsøg viser, at der blev opnået et sammenligneligt fald i blodtrykket hos anæsthetiserede hunde med en sammenlignelig intravenøst indgivet dosis af den naturlige prostaglandin PGE2 og af dens tetrazolyl-analoge. I tilfælde af den 15p-methyl-PGE2-tetrazolyl-analoge viste det sig, at selv om størrelsen af dosis må forøges for at opnå et lige så stort fald i blodtryk, så forøges det tidsrum, hvori dette reducerede tryk opretholdes, overordentlig stærkt.That the duration of action of the 15 β-methyl-tetrazolyl analog is increased over the original prostaglandin is clearly illustrated by the data set out in Table 1 below. This experiment shows that a comparable drop in blood pressure was achieved in anesthetized dogs with a comparable intravenously administered dose of the natural prostaglandin PGE2 and of its tetrazolyl analog. In the case of the 15β-methyl-PGE2-tetrazolyl analog, it was found that although the size of the dose must be increased to achieve an equally large drop in blood pressure, the time period during which this reduced pressure is maintained is greatly increased.
6 1Λ Λ 7 3 O6 1Λ Λ 7 3 O
TABEL· 1 1 2TABLE · 1 1 2
Hund Anvendt Dosis Præ Post mmHg Tilbage- nr. forbindelse mg/ml IV vendingstid min.Dog Applied Dose Pre Post mmHg Return No compound mg / ml IV turnaround min.
1 PffBg 4 158 110 28 25 PGE2-tetrazolyl 4 158 110 28 31 15-metbyl-PGE2- 50 155 108 27 57 tetrazolyl 2 PGE2 2 150 92 58 4 PGEg-tetrazolyl 2 125 95 50 6 15-me thyl-PGE 2 - 50 128 95 55 26 tetrazolyl 3 PGE2 2 115 92 23 6 PGE2-tetrazolyl 2 114 90 24 10 15-metbyl-PGE2- 50 114 90 24 120 tetrazolyl 4. PGE2 2 130 100 30 6 PGE2-tetrazolyl 2 132 110 22 6 15-methyl-PGE2- 50 136 103 55 50 tetrazolyl 5 PGE2 2 115 82 55 5 PGE2-tetrazolyl 2 110 90 30 8 15-methyl-PGE2- 50 120 92 28 40 tetrazolyl 1 Blodtryk før indgivning af midlet 2 Blodtryk efter indgivning af midlet 7 1U7301 PffBg 4 158 110 28 25 PGE2-tetrazolyl 4 158 110 28 31 15-methyl-PGE2 50 155 108 27 57 tetrazolyl 2 PGE2 2 150 92 58 4 PGEg-tetrazolyl 2 125 95 50 6 15-methyl-PGE 2 - 50 128 95 55 26 tetrazolyl 3 PGE2 2 115 92 23 6 PGE2-tetrazolyl 2 114 90 24 10 15-methyl-PGE2 50 114 90 24 120 tetrazolyl 4. PGE2 2 130 100 30 6 PGE2-tetrazolyl 2 132 110 22 6 15 -methyl-PGE2- 50 136 103 55 50 tetrazolyl 5 PGE2 2 115 82 55 5 PGE2-tetrazolyl 2 110 90 30 8 15-methyl-PGE2- 50 120 92 28 40 tetrazolyl 1 Blood pressure before administration of the agent 2 Blood pressure after administration of the agent 7 1U730
De hidtil ukendte forbindelser, som fremstilles ved fremgangsmåden ifølge opfindelsen, kan anvendes i en lang række farmaceutiske præparater, som indeholder forbindelsen eller et salt deraf, og de kan indgives ad en række forskellige veje, såsom intravenøst, oralt og topisk, herunder f.eks. aerosol, intravaginalt og intrana-salt.The novel compounds prepared by the process of the invention can be used in a wide variety of pharmaceutical compositions containing the compound or a salt thereof, and may be administered by a variety of routes, such as intravenously, orally and topically, including e.g. . aerosol, intravaginal and intranasal salt.
De naturlige prostaglandiner er velkendte midler til fremkaldelse af abort, og det kan med rimelighed forudsiges, at tetrazolyl-pros-taglandinerne vil dele denne evne. Til en sådan behandling kan en vandig suspension af PGE2~tetrazolyl passende indgives i en mængde på 0,2-5,0 mg/dosis med 1-7 orale doser pr. dag.The natural prostaglandins are well known means of inducing abortion, and it can reasonably be predicted that the tetrazolyl-pros-taglandins will share this ability. For such treatment, an aqueous suspension of PGE2-tetrazolyl may conveniently be administered in an amount of 0.2-5.0 mg / dose at 1-7 oral doses per day. day.
Hvis der ønskes en intravaginal abortbehandling kunne et egnet middel være en steril ethanolisk opløsning af denne tetrazolyl-prostag-landin eller lactosetabletter med denne forbindelse. Ved sådanne behandlinger kunne en egnet dosering være 15-200 mg/dosis méd 1 eller 2 doser daglig.If intravaginal abortion therapy is desired, a suitable agent could be a sterile ethanolic solution of this tetrazolyl-prostaglandin or lactose tablets with this compound. In such treatments, a suitable dosage could be 15-200 mg / dose with 1 or 2 doses daily.
I tilfælde hvor en abort midt i graviditeten er nødvendig kunne et effektivt middel være en ethanol-dextrose-oplø sning af PGE2-tetra-zolyl indgivet som en intravenøs infusion. En egnet dosering kunne være 5-500 yug/min. indgivet i et tidsrum fra omkring 1 til omkring 24 timer.In cases where a mid-pregnancy miscarriage is necessary, an effective agent could be an ethanol-dextrose solution of PGE 2 -tetrazolyl administered as an intravenous infusion. A suitable dosage could be 5-500 yug / min. administered for a period of from about 1 to about 24 hours.
En anden foreslået anvendelse for tetrazolyl-prostaglandineme er som vefremkalder. Til dette formål kunne en ethanol-saltvandsopløsning af PGE2-tetrazolyl anvendes som intravenøs infusion i en mængde på 3-100 ng/kg/min. i fra omkring 1 til omkring 10 timer.Another suggested use for the tetrazolyl prostaglandins is as a web remover. For this purpose, an ethanol saline solution of PGE 2 -tetrazolyl could be used as an intravenous infusion in an amount of 3-100 ng / kg / min. in from about 1 to about 10 hours.
Til fremstilling af enhver af ovennævnte doseringsformer eller enhver af de talrige andre mulige former kan anvendes forskellige reaktionsinerte fortyndingsmidler, excipienter eller bærere. Sådanne stoffer inkluderer f.eks. vand, ethanol, gelatiner, lactose, stivelser, magnesiumstearat, talcum, vegetabilske olier, benzylal-koholer, gummier, polyalkylenglycoler, petroleumvaseline, cholesterol og andre kendte bærere for medikamenter. Om ønsket kan disse 144730 8 farmaceutiske sammensætninger indeholde hjælpestoffer, såsom konserveringsmidler, befugtningsmidler, stabiliseringsmidler eller andre terapeutiske midler, såsom antibiotica.For the preparation of any of the above dosage forms, or any of the numerous other possible forms, various reaction-inert diluents, excipients or carriers may be used. Such substances include e.g. water, ethanol, gelatins, lactose, starches, magnesium stearate, talcum, vegetable oils, benzyl alcohols, rubbers, polyalkylene glycols, petroleum vaseline, cholesterol and other known carriers for medications. If desired, these pharmaceutical compositions may contain adjuvants such as preservatives, wetting agents, stabilizers or other therapeutic agents such as antibiotics.
De følgende eksempler tjener til yderligere at belyse fremgangsmåden ifølge opfindelsen.The following examples serve to further illustrate the process of the invention.
KKSEMPEL 1EXAMPLE 1
UdgangsforbindelseOutput Connector
Til en omrørt opløsning af 400 mg (0,731 millimol) 3β- [3a-(tetra-hydropyran-2-yloxy)-trans-1-octen-1-y 1J-2a-[6-(tetrazol-5-yl)-cis- 2-hexen- i-yi] -4a-(tetrahydropyran-2-yloxy)-ia-hydroxycyclopentan i 12.3 ml acetone ved -10 °C sattes dråbevis i løbet af fem minutter..0.,29 ml Jones-reagens, fremstillet i forvejen udfra 2,67 g chromtrioxid og 2.3 ml koncentreret svovlsyre fortyndet til 10 ml med vand. Den resulterende blanding blev lagret i 15 minutter ved -10° C og derpå behandlet med 0,46 ml isopropyl-alkohol. Blandingen blev omrørt i yderligere 5 minutter ved -10° C og opdelt mellem ethylacetat (30 ml) og vand (30 ml). Ethylacetatlaget blev skilt fra og kombineret med en ethylacetat-extrakt og det vandige lag. De kombinerede opløsninger blev vasket med tre 15 ml portioner vand, tørret over magnesiumsulfat og koncentreret (vandstrålepumpe, ca. 40-50° C), hvorved der blev opnået 358 mg 4a-(tetrahydropyran-2-yloxy)-3 β-[3α-(tetrahydropyran-2-yloxy)-trans-l-octen-l-yl)-2α-[6-(tetrazol- 5-yl)-cis-2-hexen-l-ylj-cyclopentanon som en viskøs olie.To a stirred solution of 400 mg (0.731 millimoles) of 3β- [3α- (tetrahydropyran-2-yloxy) -trans-1-octen-1-yl] -2- [6- (tetrazol-5-yl) - cis-2-Hexen-i-yi] -4a- (tetrahydropyran-2-yloxy) -ia-hydroxycyclopentane in 12.3 ml of acetone at -10 ° C was added dropwise over five minutes..0.29 Jones reagent , prepared in advance from 2.67 g of chromium trioxide and 2.3 ml of concentrated sulfuric acid diluted to 10 ml with water. The resulting mixture was stored for 15 minutes at -10 ° C and then treated with 0.46 ml of isopropyl alcohol. The mixture was stirred for a further 5 minutes at -10 ° C and partitioned between ethyl acetate (30 ml) and water (30 ml). The ethyl acetate layer was separated and combined with an ethyl acetate extract and the aqueous layer. The combined solutions were washed with three 15 ml portions of water, dried over magnesium sulfate and concentrated (water jet pump, about 40-50 ° C) to give 358 mg of 4α (tetrahydropyran-2-yloxy) -3β- [3α - (tetrahydropyran-2-yloxy) -trans-1-octen-1-yl) -2α- [6- (tetrazol-5-yl) -cis-2-hexen-1-yl] -cyclopentanone as a viscous oil.
2-Descarboxy-2-tetrazolyl(5)-PGEo2-decarboxy-2-tetrazolyl (5) -PGEo
Den ovenfor fremstillede olie blev omrørt med 10,7 ml eddikesyre og 5,8 ml vand under nitrogen ved 40-45° C i 3 timer. Den resulterende opløsning blev koncentreret (vandstrålepumpe, ca. 40-50°C) og remanensen (275 mg) blev kromatograferet på sur silicagel (25 g "Mallin-ckrodt Silicar CC-4", maskevidde 0,074-0,147 mm) under anvendelse af blandinger af chloroform og methanol som elueringsmidler til adskillelse af 130 mg af en uidentificeret blanding og 103 mg (udbytte 144730 9 37 %) af det ønskede produkt, 4a-hydroxy-3P-(3oc-hydroxy-trans-l-octen-l-yl)-2a- |]6-(tetrazol-5-yl)-cis-2-hexen-l-ylJ-cyclopentanon, som en klar, tyk, farveløs olie. Tyndtlagskromatografi af produktet på silicagel-glasplader under anvendelse af methylenchlorid-methanol (9:1) eller benzen-tetrahydrofuran-myresyre (15:5:2) som udviklingsmidler og synliggørelse af kromatogrammeme ved opvarmning med vanil-lin-phosphorsyre-reagens viste en enkelt plet ved Rf-værdier på henholdsvis 0,30 og 0,25 på de to systemer. Produktets IR-spektrumThe oil prepared above was stirred with 10.7 ml of acetic acid and 5.8 ml of water under nitrogen at 40-45 ° C for 3 hours. The resulting solution was concentrated (water jet pump, about 40-50 ° C) and the residue (275 mg) chromatographed on acidic silica gel (25 g of Mallin-capped Silicar CC-4, mesh size 0.074-0.147 mm) using mixtures of chloroform and methanol as eluents to separate 130 mg of an unidentified mixture and 103 mg (yield 14%) of the desired product, 4a-hydroxy-3β- (3oc-hydroxy-trans-1-octen-1-yl) ) -2- [6- (Tetrazol-5-yl) -cis-2-hexen-1-yl] -cyclopentanone, as a clear, thick, colorless oil. Thin layer chromatography of the product on silica gel glass plates using methylene chloride-methanol (9: 1) or benzene-tetrahydrofuran formic acid (15: 5: 2) as development agents and visualization of the chromatograms by heating with vanillin-phosphoric acid reagent showed a single stain at Rf values of 0.30 and 0.25 respectively on the two systems. The IR spectrum of the product
(CHCl*) udviste et stærkt absorptionsbånd ved 1730 cm“^ (C=0) og D(CHCl4) showed a strong absorption band at 1730 cm 2 (C = 0) and D
et moderat svagt bånd ved 3610 cm- (OH). Produktets UV-spektrum (95 % ethanol) viste kun slutabsorption. Dette produkt var 2-descar-boxy-2-tetrazolyl(5)-PGE2· Behandling af en lille prøve af produktet med 10 % vandigt natriumhydroxid og ethanol i 15 minutter ved stuetemperatur gav et enkelt produkt ved tyndtlagskromatografi (R^ 0,38; silicagel; benzen/tetrahydrofuran/myresyre, 15:5:2). Det sidstnævnte produkt UV-spektrum (95 % ethanol) udviste et absorptions-maximum ved 279 nm (19600).a moderately weak band at 3610 cm- (OH). The UV spectrum of the product (95% ethanol) showed only final absorption. This product was 2-descar-boxy-2-tetrazolyl (5) -PGE2 · Treatment of a small sample of the product with 10% aqueous sodium hydroxide and ethanol for 15 minutes at room temperature gave a single product by thin layer chromatography (R 3, 0.38; silica gel; benzene / tetrahydrofuran / formic acid, 15: 5: 2). The latter product UV spectrum (95% ethanol) exhibited an absorption maximum at 279 nm (19600).
EKSEMPEL 2EXAMPLE 2
UdgangsforbindelseOutput Connector
Til en opløsning, afkølet til -15° C, af 105 mg (0,187 millimol) chromatograferet la-hydroxy-4a-(tetrahydropyran-2-yloxy)-3 β- |3β-methyl-3a-(tetrahydropyran-2-yloxy)-trans-l-octen-l- yil -2a-[6-(te-trazol-5-yl)-ci s-2-hexen- 1-79 -cyclopentan i 2,0 ml acetone sattes dråbevis 0,1 ml af Jones' reagens. Blandingen blev omrørt i 30 minutter i kulden, og derpå tilsattes 0,5 ml 2-propanol. Opløsningen blev fortyndet med ethylacetat, vasket 2 gange med vand og 1 gang med mættet saltvand, tørret over vandfrit magnesiumsulfat og koncentreret, hvorved der blev opnået 82 mg (78 % udbytte) af en olieagtig keton. Den rå olie blev renset ved søjlechromatografi på silicagel ("Baker ' Analyzed'Reagent", maskevidde 0,074-0,250 mm) under anvendelse af 10 % ethylacetat i chloroform som elueringsmiddel, hvilket gav 56 mg (53,4 % udbytte) af den rensede olieagtige keton, 4a-(tetrahydropyran-2-yloxy)-3β-[3p-methyl-3a-(tetrahydropyran-2-yloxy)-trans-l-octen-l-y^ -2a-[6-(tetrazol-5-yl)-cis-2-hexen-l-yiJ cyclo- 144730 ίο pentanon. Tyndtlagschromatografi af det olieagtige produkt på sili-cagel-glasplader under anvendelse af 10 % methanol i methylenchlorld som elueringsmiddel viste en enkelt plet med en R^-værdi på 0,55·To a solution, cooled to -15 ° C, of 105 mg (0.187 millimoles) of chromatographed 1-hydroxy-4a- (tetrahydropyran-2-yloxy) -3β- | 3β-methyl-3a- (tetrahydropyran-2-yloxy) -trans-1-octen-1-yl-2- [6- (tetrazole-5-yl) -cis-2-hexene-1-79-cyclopentane in 2.0 ml of acetone was added dropwise 0.1 ml of Jones' reagent. The mixture was stirred for 30 minutes in the cold and then 0.5 ml of 2-propanol was added. The solution was diluted with ethyl acetate, washed 2 times with water and 1 time with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 82 mg (78% yield) of an oily ketone. The crude oil was purified by column chromatography on silica gel ("Baker 'Analyzed'Reagent", mesh size 0.074-0.250 mm) using 10% ethyl acetate in chloroform as eluent to give 56 mg (53.4% yield) of the purified oily ketone, 4α- (tetrahydropyran-2-yloxy) -3β- [3β-methyl-3α- (tetrahydropyran-2-yloxy) -trans-1-octenyl-2β- [6- (tetrazol-5-yl) -cis-2-hexen-1-yl Cyclo-pentanone. Thin layer chromatography of the oily product on silica gel glass plates using 10% methanol in methylene chloride as the eluent showed a single spot with an R
Strukturen blev bekræftet ved den fuldstændige identitet af dens IR-spektrum med spektret for 15-normethyl-forbindelsen se eksempel 1).The structure was confirmed by the complete identity of its IR spectrum with the spectrum of the 15-normethyl compound (see Example 1).
2-Desearboxy-2-tetrazolyl( 5)-15-methyl-PGEn2-Desearboxy-2-tetrazolyl (5) -15-methyl-PGEn
En opløsning af 57 mg (0,10 millimol) af den ovenfor fremstillede chromatograferede bis-THP ether i 0,88 ml af en 65:35 blanding a,f eddikesyre og vand blev omrørt ved 42° 0 i 4,0 timer og derpå koncentreret ved rotationsinddampning. Chromatografi af det rå produkt, som vejede 48 mg, på silicagel ("Mallinckrodt CC-4") under anvendelse af 2 % methanol i chloroform som elueringsmiddel gav 13 mg (33,4 % udbytte) af den olieagtige diol, 4(X-hydroxy-3P~[3a-hydroxy-3β-methyl-trans-l-octen-l-yij -2α-[6-(tetrazol-5-yl)cis-2-hexen-l-ylj-cyclopentanon. Denne forbindelse er 2-descarboxy-2-tetrazolyl- (5)-15methyl-PGE2.A solution of 57 mg (0.10 millimole) of the above-prepared chromatographed bis-THP ether in 0.88 ml of a 65:35 mixture of a, acetic acid and water was stirred at 42 ° for 4.0 hours and then concentrated by rotary evaporation. Chromatography of the crude product, which weighed 48 mg, on silica gel ("Mallinckrodt CC-4") using 2% methanol in chloroform as eluent gave 13 mg (33.4% yield) of the oily diol, 4 (X hydroxy-3β- [3α-hydroxy-3β-methyl-trans-1-octen-1-yl] -2α- [6- (tetrazol-5-yl) cis-2-hexen-1-yl] -cyclopentanone This compound is 2-descarboxy-2-tetrazolyl- (5) -15methyl-PGE 2.
Strukturen blev bekræftet ved den praktiske identitet af dens IR-spektrum med spektret for 15-normethyl-forbindelsen. Behandling af en methanolisk opløsning af det olieagtige produkt med 40 % vandigt kaliumhydroxid gav den forventede UV-absorption ved 278 nm (€ 20 000).The structure was confirmed by the practical identity of its IR spectrum with the spectrum of the 15-normethyl compound. Treatment of a methanolic solution of the oily product with 40% aqueous potassium hydroxide gave the expected UV absorption at 278 nm (€ 20,000).
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17710271A | 1971-09-01 | 1971-09-01 | |
US17710271 | 1971-09-01 |
Publications (2)
Publication Number | Publication Date |
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DK144730B true DK144730B (en) | 1982-05-24 |
DK144730C DK144730C (en) | 1982-10-18 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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DK430772A DK144730C (en) | 1971-09-01 | 1972-08-31 | ANALOGY PROCEDURE FOR PREPARING 2-DESCARBOXY-2-TETRAZOLYL (5) -PROSTAGLANDIN-E2 COMPOUNDS |
Country Status (12)
Country | Link |
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JP (1) | JPS5724348B2 (en) |
AR (4) | AR197304A1 (en) |
AT (3) | ATA51974A (en) |
CA (1) | CA978939A (en) |
DK (1) | DK144730C (en) |
ES (3) | ES406250A1 (en) |
FI (1) | FI55497C (en) |
FR (3) | FR2283147A1 (en) |
IL (3) | IL40183A (en) |
PH (3) | PH10023A (en) |
SE (4) | SE409032B (en) |
ZA (1) | ZA725827B (en) |
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1972
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- 1972-08-29 AT AT51974*A patent/ATA51974A/en not_active IP Right Cessation
- 1972-08-29 PH PH13850A patent/PH10023A/en unknown
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- 1972-08-30 FI FI2387/72A patent/FI55497C/en active
- 1972-08-30 SE SE7211233A patent/SE409032B/en unknown
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- 1972-08-31 CA CA150,669A patent/CA978939A/en not_active Expired
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1973
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1974
- 1974-06-03 PH PH15889A patent/PH10416A/en unknown
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1975
- 1975-11-26 FR FR7536205A patent/FR2283147A1/en active Granted
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- 1975-11-26 FR FR7536204A patent/FR2283134A1/en active Granted
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1976
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