DK145859B - Analogifremgangsmaade til fremstilling af estre af 3-hydroxy-5beta-oestran-17-on - Google Patents
Analogifremgangsmaade til fremstilling af estre af 3-hydroxy-5beta-oestran-17-on Download PDFInfo
- Publication number
- DK145859B DK145859B DK437976AA DK437976A DK145859B DK 145859 B DK145859 B DK 145859B DK 437976A A DK437976A A DK 437976AA DK 437976 A DK437976 A DK 437976A DK 145859 B DK145859 B DK 145859B
- Authority
- DK
- Denmark
- Prior art keywords
- hydroxy
- acid
- steroid
- pentane
- oestran
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 10
- UOUIARGWRPHDBX-SAJNEQLASA-N (5r,8r,9r,10s,13s,14s)-3-hydroxy-13-methyl-2,3,4,5,6,7,8,9,10,11,12,14,15,16-tetradecahydro-1h-cyclopenta[a]phenanthren-17-one Chemical compound C1C(O)CC[C@@H]2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@@H]21 UOUIARGWRPHDBX-SAJNEQLASA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 10
- 150000003431 steroids Chemical class 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 4
- 230000001698 pyrogenic effect Effects 0.000 claims description 4
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 claims description 3
- 210000004185 liver Anatomy 0.000 claims description 3
- 150000004032 porphyrins Chemical class 0.000 claims description 3
- 229950003776 protoporphyrin Drugs 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 241000287828 Gallus gallus Species 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 2
- 230000006698 induction Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 8
- 239000011541 reaction mixture Substances 0.000 claims 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- FOYWCEUVVIHJKD-UHFFFAOYSA-N 2-methyl-5-(1h-pyrazol-5-yl)pyridine Chemical compound C1=NC(C)=CC=C1C1=CC=NN1 FOYWCEUVVIHJKD-UHFFFAOYSA-N 0.000 claims 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims 1
- IPIVAXLHTVNRBS-UHFFFAOYSA-N decanoyl chloride Chemical compound CCCCCCCCCC(Cl)=O IPIVAXLHTVNRBS-UHFFFAOYSA-N 0.000 claims 1
- 230000001605 fetal effect Effects 0.000 claims 1
- 229910052938 sodium sulfate Inorganic materials 0.000 claims 1
- 235000011152 sodium sulphate Nutrition 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 230000000913 erythropoietic effect Effects 0.000 description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- NPAGDVCDWIYMMC-IZPLOLCNSA-N nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 description 4
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 208000007502 anemia Diseases 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 230000010437 erythropoiesis Effects 0.000 description 3
- 229960004719 nandrolone Drugs 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 208000032467 Aplastic anaemia Diseases 0.000 description 2
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 230000001548 androgenic effect Effects 0.000 description 2
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
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- 235000019253 formic acid Nutrition 0.000 description 2
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- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 1
- UOUIARGWRPHDBX-DHMVHTBWSA-N 19-noretiocholanolone Chemical compound C1[C@H](O)CC[C@@H]2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@@H]21 UOUIARGWRPHDBX-DHMVHTBWSA-N 0.000 description 1
- DMUXSGAKEXSNGN-UHFFFAOYSA-N 2-ethyloctanoic acid Chemical compound CCCCCCC(CC)C(O)=O DMUXSGAKEXSNGN-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- UOUIARGWRPHDBX-UHFFFAOYSA-N 3alpha-Hydroxy-5beta-oestran-17-on Natural products C1C(O)CCC2C3CCC(C)(C(CC4)=O)C4C3CCC21 UOUIARGWRPHDBX-UHFFFAOYSA-N 0.000 description 1
- QGXBDMJGAMFCBF-BNSUEQOYSA-N 3alpha-hydroxy-5beta-androstan-17-one Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@@H]21 QGXBDMJGAMFCBF-BNSUEQOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
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- 206010065553 Bone marrow failure Diseases 0.000 description 1
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- 102000004190 Enzymes Human genes 0.000 description 1
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- QGXBDMJGAMFCBF-UHFFFAOYSA-N Etiocholanolone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 QGXBDMJGAMFCBF-UHFFFAOYSA-N 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
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- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
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- HJZLEGIHUQOJBA-UHFFFAOYSA-N cyclohexane propionic acid Chemical compound OC(=O)CCC1CCCCC1 HJZLEGIHUQOJBA-UHFFFAOYSA-N 0.000 description 1
- -1 decanoyloxy Chemical group 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
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- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
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- 229930182851 human metabolite Natural products 0.000 description 1
- 230000001096 hypoplastic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
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- 235000011056 potassium acetate Nutrition 0.000 description 1
- 150000003116 prednisolone derivatives Chemical class 0.000 description 1
- 230000001072 progestational effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002510 pyrogen Substances 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
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- 239000008117 stearic acid Substances 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 150000003515 testosterones Chemical class 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000002435 venom Substances 0.000 description 1
- 210000001048 venom Anatomy 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(W
(19) DANMARK
(12) FREMLÆGGELSESSKRIFT (11) 145859B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENET
(21) Ansøgning nr. 4379/76 (51) lnt.CI.3 C 07 J 1/00 (22) Indleveringsdag 29· S ep. 1976 (24) Løbedag 29. sep. 1976 (41) Aim. tilgængelig 31 . mar. 1977 (44) Fremlagt 21 . mar. 1983 (86) International ansøgning nr.
(86) International indieveringsdag (85) Videreførelsesdag -(62) Stamansøgning nr. -
(30) Prioritet 30. sep. 1975* 618176, US 4. jun. 1976, 693249, US
(71) Ansøger AKZO N.V., Arnhem, NL.
(72) Opfinder Henry A. Abrade, US.
(74) Fuldmægtig Firmaet Chas. Hude,_____ (54) Analogifremgangsmåde til fremstil* ling af estre af 3-hydroxy-5be= ta-østran-1 7-on.
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte ikke-pyrogene, erythro-poietisk virkende estre af 3-hydroxy-5p-østran-17-on af den i krav 1 angivne almene formel.
Erythropoiesi er dannelsesprocessen for røde blodlegemer.
QQ
^ Udtrykket anæmi indebærer et unormalt lavt antal cirkuleren- ;ø de røde blodlegemer eller en aftaget koncentration af hæmoglo- ^ bin i blodet. Forekomsten af anæmi afspejler enten marvsvigt
-J
v— eller for stort tab af røde blodlegemer eller begge dele.
^ Marvsvigt, d. v. s. nedsat erythropoiesi, kan optræde som re- Q sultat af mangelfuld ernæring, udsættelse for gift, tumorin- vasion eller andre og til tider ukendte årsager.
2 145859
Til behandling af anæmi, der skyldes svigt af benmarv (hypoplastiske og aplastiske anæmier), har det været foreslået at anvende stoffer, der kunne stimulere marven, såsom androgener eller corticosteroider. .Amerikansk patent nr. 3-383.282 beskriver forskellige 3,5-androsta= dien-3,17-diolderivater som havende erythropoietisk virkning. Amerikansk patent nr. 3.519.659 og 3.519.660 beskriver forskellige pred= nisolonderivater, som har antileukemivirkning.
Det er kendt, at erythropoietisk virkning udvises af metaboliter af visse androgene, anaboliske og progestationale steroider. Således beskriver levere m.fl. i rapporterne fra et symposium, der blev afholdt i forbindelse med the American Society of Hematology den 4. december 1971, kapitel 3, at etiocholanolon, en human metabolit af testosteron, har erythropoietisk virkning. Jepson, ibid., kapitel 2 beskriver, at nandrolon (19-nortestosteron, 17p-hydroxy-19-nor-4-androsten-3-on), et anabolisk steroid, har erythropoietisk virkning svarende til testosteron. Dette stof har imidlertid den ulempe at udvise androgene bivirkninger. Etiocholanolon har den væsentlige ulempe at være et pyrogen i mennesker.
Ifølge den foreliggende opfindelse har det vist sig, at visse estre af 3-hydroxy-5P-østran-17-on udviser erythropoietisk virkning, samtidig med at de ikke er pyrogene og udviser ingen eller ringe hormonale bivirkninger.
EorbindeIserne, der har vist sig at være ikke-pyrogene og aktive ved stimulering af erythropoiesi, har formlen f
B E
3 145859 hvor R·*· er acyloxy afledt af en organisk carboxylsyre med 1-18 kulstof atomer.
19-noretiocholanolon (3a-hydroxy-5P-østran-17-on) er en kendt forbindelse og er beskrevet af Engel m.fl., J. Biol. Chem. 231, 1, 159 (1958). Denne forbindelse er også beskrevet i en artikel af Oounsell i Tetrahedron, bind 15, 202-211 (1961). 19-noretiocholanolon kan også syntetiseres ved at hydrogenere nandrolon-17-acetat til det tilsvarende 5β-3-keto-Γ7β-acetat på den måde, der er beskrevet i J. Org. Chem. 31, 2394 (1966), og derefter reducere 3-ketogruppen til dannelse af 3α-hydroxygruppen under anvendelse af lithium-aluminium-triter t. -but oxyhydr id, beskytte 3a-hydroxygruppen, hydrolysere 176-ace= tatet, oxidere 17β-hydroxygruppen til 17-keto med CrO^-pyridin og til slut fjerne 3a-beskyttelsesgruppen.
Den 3β-βρϊιαβΓβ kan fås ved epimerisering af 19-norethicholanolon, f. eks. ved omdannelse af 3a-hydroxygruppen til dens 3-tosylat og forsæbning af tosylatet med kaliumacetat, eller endnu bedre efter fremgangsmåden, der er beskrevet i Tetrahedron Letters, bind 18, 1619 (1973), ved anvendelse af triphenylphosphin, diethylazodicarboxylat og myresyre.
3-esterne af de førnævnte forbindelser, som udviser erythropoietisk virkning, er hidtil ukendte forbindelser.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at 3r-hydroxy-5β-Østran-17-on bringes til at reagere med syren HR1 eller et anhy-drid eller halogenid deraf.
Som eksempler på organiske carboxylsyrer kan nævnes følgende: myre= syre, eddikesyre, propionsyre, smørsyre, valerianesyre, isocapron= syre, decansyre, undecylsyre, laurinsyre, tridecylsyre, myristinsyre, oliesyre, palmitinsyre, stearinsyre, trimethyleddikesyre, diethyl= eddikesyre, cyklohexancarboxylsyre, cyklopentylpropionsyre, cyklo= hexylsmørsyre, cyklohexylpropionsyre, undecylensyre, benzoesyre, phenyleddikesyre, phenylpropionsyre, phenylsmørsyre, malonsyre, rav= syre, glutarsyre, pimelinsyre og vinsyre.
4 145859
Ifølge opfindelsen er fortrinsvis acyloxy afledt af en organisk carboxylsyre med 3-12 kulstofatomer og især dekanoyloxy.
De førnævnte forbindelser fremstillet ifølge opfindelsen er egnede til administration deraf til mennesker eller andre varmblodede dyr i maaigder, der er effektive til at stimulere erythropoiesi, hvilke mængder i almindelighed er i intervallet fra ca. 5 til ca. 500 mg pr. enhedsdosis. Den sædvanlige metode til administration er parenteralt, til hvilket formål forbindelserne kan fremstilles i en form egnet til injektion som en opløsning eller suspension i 1 ml ampuller. Forbindelserne kan også administreres enteralt, herunder oromucosalt, i form af tabletter, piller, kapsler, suppositorier og lignende.
Det følgende forsøg illustrerer den erythropoietiske virkning af forbindelserne fremstillet ifølge opfindelsen.
• Primære fuglelevercellekulturer
Induktion af porphyrinsyntese og hæmdannelse i celler blev undersøgt i det primære fuglelevereellekultursystem, der er beskrevet af Granick og Kappas, J. Biol. Chem. 242, 4587-4593 (1967). Ifølge denne teknik bliver lever fra 16-17 dage gamle kyllingefostre hakket og cellerne 5 adskilt med trypsin. Suspensioner indeholdende 3 til 5 x 10 celler podes i små flasker, som indeholder en dækstrimmel og 1,0 ml Eagle's basalmedium suppleret med glutamin, oksefosterserum og antibiotika. Elaskerne inkuberes ved 57°C I 5$ 00^ og luft i 20 timer. Vækstmediet erstattes så med frisk medium, og der foretages tilsætning af steroidet efter behov. Efter reihkubation i yderligere 20 timer undersøges dækstrimlerne, der nu er overvokset med et monolag af hæpa-tiske parenchymalceller, under faseoptik og fluorescensoptik. Semi-kvantitative bestemmelser af cellulære porphyriner foretages på det grundlag, at værdier af fluorescensintensiteter, der ligger fra +1,0 til +4,0, er ækvivalente med ca. 5 til 50 x 10-^ mol protoporphyrin pr. mg protein på dækstrimmelen. Mængderne af protoporphyrin, som er dannet, afspejler niveauet af δ-aminolævulinat syntetase, som er det hastighedsbegrænsende enzym i hæmdannelsen.
Claims (2)
- 5 145859 De afprøvede forbindelser var 19-noretiocholanolon, 3-decanoat (A) og 38-hydroxy-5B-østran-17-on, decanoat (B). Begge forbindelserne viste sig at være ikke-pyrogene. Resultaterne er vist i følgende tabel: Tabel: Induktion af porphyrinsyntese med steroider i kultiverede kyllinge- fosterleverceller Protoporphyrin fundet (pmol/ Behandling Antal prøver og dosis mg protein, 20 timer)_ Steroid A 4-2 yg/ml 341,1 - 32,0 Steroid A 4-10 yg/ml 434,5 ί 45,9 Steroid B 4-2 yg/ml 323,8 - 43,6 Steroid B 4-10 yg/ml 375,7 - 51,7 Det følgende eksempel illustrerer fremgangsmåden ifølge opfindelsen. Eksempel lil en suspension af 10 g 3oc-hydroxy-5p-østran-17-on i 100 ml pentan og 10 ml pyridin sættes 10 ml decanoylchlorid ved 15°C i løbet af 1 time. Efter omrøring i 2 1/2 time sættes vand til reaktionsblandingen for at dekomponere overskuddet af syrechlorid. Reaktionsblandingen ekstraheres med pentan. Pentanekstrakten tørres på natriumsulfat og inddampes til tørhed. Remanensen krystalliseres af pentan. Udbyttet er 14,1 g 3oc-hydroxy-5P-østran-17-on-3a-decanoat, smeltepunkt 39”43°C, foj*0 = +90° (i CHClj).
- 1. Analogifremgangsmåde til fremstilling af estre af 3-hydroxy-53-østran-17-on med den almene formel
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61817675 | 1975-09-30 | ||
| US05/618,176 US4004005A (en) | 1975-09-30 | 1975-09-30 | Steroidal erythropoietic agents and therapeutic compositions and methods |
| US69324976 | 1976-06-04 | ||
| US05/693,249 US4049805A (en) | 1975-09-30 | 1976-06-04 | Steroidal erythropoietic agents and therapeutic compositions and methods |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK437976A DK437976A (da) | 1977-03-31 |
| DK145859B true DK145859B (da) | 1983-03-21 |
| DK145859C DK145859C (da) | 1983-10-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK437976A DK145859C (da) | 1975-09-30 | 1976-09-29 | Analogifremgangsmaade til fremstilling af estre af 3-hydroxy-5beta-oestran-17-on |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4049805A (da) |
| JP (1) | JPS5262263A (da) |
| CH (1) | CH625253A5 (da) |
| DE (1) | DE2643936A1 (da) |
| DK (1) | DK145859C (da) |
| FR (1) | FR2326198A1 (da) |
| GB (1) | GB1565229A (da) |
| IE (1) | IE43859B1 (da) |
| LU (1) | LU75901A1 (da) |
| NL (1) | NL7610812A (da) |
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| AU4093799A (en) | 1998-05-22 | 1999-12-13 | Board Of Trustees Of The Leland Stanford Junior University | Bifunctional molecules and therapies based thereon |
| US20050042679A1 (en) * | 1999-04-15 | 2005-02-24 | Monash University | Diagnostic indicator of thymic function |
| US20050020524A1 (en) * | 1999-04-15 | 2005-01-27 | Monash University | Hematopoietic stem cell gene therapy |
| US20040258672A1 (en) * | 1999-04-15 | 2004-12-23 | Monash University | Graft acceptance through manipulation of thymic regeneration |
| US20040265285A1 (en) * | 1999-04-15 | 2004-12-30 | Monash University | Normalization of defective T cell responsiveness through manipulation of thymic regeneration |
| AUPR074500A0 (en) * | 2000-10-13 | 2000-11-09 | Monash University | Treatment of t cell disorders |
| US20040241842A1 (en) * | 1999-04-15 | 2004-12-02 | Monash University | Stimulation of thymus for vaccination development |
| US20040259803A1 (en) * | 1999-04-15 | 2004-12-23 | Monash University | Disease prevention by reactivation of the thymus |
| US20060088512A1 (en) * | 2001-10-15 | 2006-04-27 | Monash University | Treatment of T cell disorders |
| AP2003002796A0 (en) * | 2000-10-13 | 2003-06-30 | Richard Boyd | Disease prevention by reactivation of the thymus |
| AU2002322720B2 (en) | 2001-07-25 | 2008-11-13 | Raptor Pharmaceutical Inc. | Compositions and methods for modulating blood-brain barrier transport |
| US20080279812A1 (en) * | 2003-12-05 | 2008-11-13 | Norwood Immunology, Ltd. | Disease Prevention and Vaccination Prior to Thymic Reactivation |
| CA2789262C (en) | 2005-04-28 | 2016-10-04 | Proteus Digital Health, Inc. | Pharma-informatics system |
| EP1945240B1 (en) | 2005-09-16 | 2016-12-28 | Raptor Pharmaceutical Inc | Compositions comprising receptor-associated protein (rap) variants specific for cr-containing proteins and uses thereof |
| TR201908314T4 (tr) | 2009-02-20 | 2019-06-21 | 2 Bbb Medicines B V | Glutatyon bazlı ilaç dağıtım sistemi. |
| KR101909711B1 (ko) | 2009-05-06 | 2018-12-19 | 라보라토리 스킨 케어, 인크. | 활성제-칼슘 포스페이트 입자 복합체를 포함하는 피부 전달 조성물 및 이들을 이용하는 방법 |
-
1976
- 1976-06-04 US US05/693,249 patent/US4049805A/en not_active Expired - Lifetime
- 1976-09-20 IE IE2077/76A patent/IE43859B1/en unknown
- 1976-09-22 GB GB39299/76A patent/GB1565229A/en not_active Expired
- 1976-09-28 LU LU75901A patent/LU75901A1/xx unknown
- 1976-09-29 JP JP51117876A patent/JPS5262263A/ja active Pending
- 1976-09-29 CH CH1231476A patent/CH625253A5/de not_active IP Right Cessation
- 1976-09-29 DK DK437976A patent/DK145859C/da not_active IP Right Cessation
- 1976-09-29 DE DE19762643936 patent/DE2643936A1/de not_active Withdrawn
- 1976-09-30 NL NL7610812A patent/NL7610812A/xx not_active Application Discontinuation
- 1976-09-30 FR FR7629388A patent/FR2326198A1/fr active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| US4049805A (en) | 1977-09-20 |
| NL7610812A (nl) | 1977-04-01 |
| FR2326198B1 (da) | 1980-10-10 |
| IE43859B1 (en) | 1981-06-17 |
| GB1565229A (en) | 1980-04-16 |
| DK437976A (da) | 1977-03-31 |
| DK145859C (da) | 1983-10-03 |
| LU75901A1 (da) | 1977-05-11 |
| JPS5262263A (en) | 1977-05-23 |
| IE43859L (en) | 1977-03-30 |
| DE2643936A1 (de) | 1977-03-31 |
| FR2326198A1 (fr) | 1977-04-29 |
| CH625253A5 (da) | 1981-09-15 |
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