NO165496B - Analogifremgangsmaate for fremstilling av nye epoksysteroider. - Google Patents
Analogifremgangsmaate for fremstilling av nye epoksysteroider. Download PDFInfo
- Publication number
- NO165496B NO165496B NO852501A NO852501A NO165496B NO 165496 B NO165496 B NO 165496B NO 852501 A NO852501 A NO 852501A NO 852501 A NO852501 A NO 852501A NO 165496 B NO165496 B NO 165496B
- Authority
- NO
- Norway
- Prior art keywords
- diphenyl
- salt
- cysteroids
- dioxopyrazolidine
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title description 2
- 239000004593 Epoxy Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- XDPKQGKEOCYMQC-UHFFFAOYSA-N 1,2-diphenylpyrazolidine-3,5-dione Chemical compound O=C1CC(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 XDPKQGKEOCYMQC-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- LGYTZKPVOAIUKX-UHFFFAOYSA-N kebuzone Chemical compound O=C1C(CCC(=O)C)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 LGYTZKPVOAIUKX-UHFFFAOYSA-N 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 abstract 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 abstract 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 abstract 1
- 239000005977 Ethylene Substances 0.000 abstract 1
- 206010020571 Hyperaldosteronism Diseases 0.000 abstract 1
- 229940122767 Potassium sparing diuretic Drugs 0.000 abstract 1
- 229960002478 aldosterone Drugs 0.000 abstract 1
- 230000003042 antagnostic effect Effects 0.000 abstract 1
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- 238000007796 conventional method Methods 0.000 abstract 1
- 125000004980 cyclopropylene group Chemical group 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 239000003286 potassium sparing diuretic agent Substances 0.000 abstract 1
- 229940097241 potassium-sparing diuretic Drugs 0.000 abstract 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 abstract 1
- 230000001568 sexual effect Effects 0.000 abstract 1
- 150000003431 steroids Chemical class 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 229960000194 kebuzone Drugs 0.000 description 5
- -1 1,2-diphenyl-3,5-dioxo-4 -(ethylenedi-oxybutyl )-pyrazolidine Chemical compound 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GVNNGJMKAFLSHZ-NSCUHMNNSA-N (e)-1,3-dichlorobut-1-ene Chemical compound CC(Cl)\C=C\Cl GVNNGJMKAFLSHZ-NSCUHMNNSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/002—Carbocyclic rings fused
- C07J53/004—3 membered carbocyclic rings
- C07J53/008—3 membered carbocyclic rings in position 15/16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
7a-acyltio-9alla-epoksy-20-spiroks-4-en-3,21-dioner med formel I. hvor R er en laverealkanoyl og -A-A- er en etylen-eller cyklopropylen-gruppe, oppviser en høy aldosteron-antagoniserende virkning uten nevneverdige seksual-spesifikke bivirkninger og er anvendbare. som kalium-sparende diuretikum i terapien for forskjellige former av hyperaldosteronisme. Forbindelsene kan oppnås ifølge konvensjonelle fremgangs-måter i steroid-kjemien.
Description
Fremgangsmåte ved fremstilling av 1,2-difenyl-3,5-dioxo-4-(3'-oxobutyl)-pyrazolidin.
Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av 1,2-difeny1-3,5-dioxo-4-(3 *-oxobutyl)-pyrazolidin, som også kalles ketofenylbutazon og som anvendes som legemiddel med betydelig antiinflammatorisk virkning.
De kjente fremgangsmåter for fremstilling av denne forbindelse starter tildels med 1,2-difenyl-3»5-dioxo-4-(3'-klorcroty1)-pyrazolidin, og tildels med 1,2-difenyl-3,5-dioxo-4-(ethylendi-oxybutyl )-pyrazolidin (Dense og medarb. Heiv. China. Acta kO, k02, En ytterligere metode går ut på å addere 1,2-difényl-3,5-dioxopyrazo'lidin eller et salt av dette til methylvinylketon eller å alkylere med den tilsvarende kvartære Mannich-base.
Det er kjent at man lett kan alkylere 1,2-difeny1-3,5-dioxo-pyazolidin med reaktive halogenforbindelser. Mens alltylerings-forsok med n-butylbromid ikke har fort frem (Chaleckij og medarb. Z.obsc.chim. 28, 2355» 1958), gir det reaktive 1,3-diklorbuten~2 godt utbytte av det tilsvarende 4-(3 '-klorcroty1)-derivat. Reak-sjonen forloper best i nærvær av en ekvivalent av et alkali. Eventuelt anvendes difenyldioxopyrazolidin i form av et salt, dvs» i en form hvor et aktivt hydrogenatom er erstattet med et kation. Overskudd av alkali forer til disubstituering og til andre uon~ skede reaksjoner.
Efter inngående studier av reaksjonsbetingelsene har det nu lykkes å finne frem til en fremgangsraåte for fremstilling av 1,2-dif eny1-3,5-dioxo-4-(31-oxobutyl)-pyrazolidin. Den nye fremgangsmåte utmerker seg ved at en forbindelse av den generelle formel:
CH3COCH2CH2X
hvor X betegner et halogenatom. fortrinsvis klor, kondenseres med 1,2-difeny1-3»5-dioxopyrazolidin eller et salt derav, i nærvær av et alkalisk kondenseringsmiddel, fortrinsvis et alkalime-tallalkoholat i en mengde storre enn 1 ekvivalent og ikke over 4 ekvivalenter, fortrinsvis i en mengde av 2 ekvivalenter, beregnet på den anvendte mengde av 1,2-difenyl-3,5-dioxopyrazolidinet eller av anionet av dets salt.
Denne kondensering forloper uten vanskeligheter i alkanoler med 1-4 carbonatomer, fortrinsvis methanol. Som 1,2-difenyl-3,5-dioxopyrazolidinsalt kan der anvendes et alkalimetallsalt, fortrinsvis natriumsaltet. Kondenseringen kan utfores ved tempe-raturer fra 30°C til reaksjonsblandingens koketemperatur.
Forsokene på å alkylere 1,2-difeny1-3,5-dioxopyrazolidinet med methyl-fi-halogenketoner, forst og fremst med methyl-(i-klor- , ethylketon, under de hittil benyttede betingelser, forte ikke frem, dvs. forte ikke til ketofenylbutazonet. Som reaksjonspro-dukt fikk, man en i alkalier bare delvis ppploselig blanding av forskjellige forbindelser. Forst efter den uventede erkjennelse at omsetningen, stikk i strid ved h<y>a man tidligere har ment, for-drer et overskudd av det alkaliske kondenseringsmidde!, fortrinsvis 2 ekvivalenter, har det lyktes å fremstille ketofenylbutazon uten vanskelighet og i hoyt utbytte. Som alkalisk kondenseringsmiddel kan man foruten alkaliraetallalkoholatene også anvende andre egnede, basisk reagerende uorganiske og organiske forbindelser.
Som ovenfor nevnt kan man ved fremgangsmåten ifolge oppfinnel-sen starte med 1,2-difeny1-3,5-dioxopyrazolidin eller med et salt av denne forbindelse. Forbindelsen kan lett fremstilles i hoyt utbytte ved kondensering av malonsyrediethylester med hydrazobenzen (Ruhkoph, Ber. 73, 820,1940).
Blant methyl-£-halogenethylketonene er raethyl-|i-klor-ethy 1-keton best egnet. Dette kan lett fremstilles ved omsetning av hydrogenklorid med paraformaldehyd og aceton. (Dermer, J. Am. Chem. Soc. 74,3417,1952).
Det erholdte urene ketofenylbutazon kan renses enten ved kry-stallisasjon eller ved overforing i natriumsaltet og påfblgende surgjoring av dette salt.
Eksempel
Til en ved opplosning av 4,6 g natrium i 120 ml methanol frem-stilt natriummethylatopplosning tilsettes 25,3 g 1,2-difenyl-3,5-dioxopyrazolidin. Efter oppvarmning til 6o°C tildryppes der ved denne temperatur i ldpet av 30 minutter under omroring 12 g methyl-(3-klorethylketon. Reaksjonsblandingen holdes under stadig omroring i 3 timer ved 6o°C, hvor den kokes i 3 timer med tilbake-lbpskjdling. Opplosningsmidlet avdestiUeres i vakuua, residuet opploses i 250 ml vann, og opplosningen filtreres efter tilset-ning av avfarvningskull. Efter avkjoling av filtratet til 0°C ut-felles produktet ved surgjoring med saltsyre. Utfelningen fra-filtreres, vaskes med 50 ml vann og tdrkes. Utbyttet av råpro-dukt er 27,5 g« Efter omkrystallisering, henholdsvis efter rens-ning over natriumsaltet, smelter det erholdte ketofenylbutazon ved 125 - 127°C.
Claims (1)
- Fremgangsmåte ved fremstilling av 1,2-difeny1-3,5-dioxo-4-(3'-oxobutyl)-pyrazolidin, karakterisert ved at en forbindelse av den generelle formel:CH3COCH2CH2X hvor X betegner et halogenatom, fortrinsvis klor, kondenseres med l,2«difenyl-3,5-dioxopyrazolidin ellec et salt derav, i nærvær av et alkalisk kondenseringsaiddel, fortrinsvis et alkalimetallalko-holat, i en mengde storre enn 1 ekvivalent og ikke over 4 ekviva lenter, fortri<n>svis i en mengde av 2 ekvivalenter, beregnet på den anvendte mengde av 1,2-difeny1-3,5-dioxopyrazolidinet eller av anionet av dets salt»
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH300984 | 1984-06-21 | ||
| CH464684 | 1984-09-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO852501L NO852501L (no) | 1985-12-23 |
| NO165496B true NO165496B (no) | 1990-11-12 |
| NO165496C NO165496C (no) | 1991-02-20 |
Family
ID=25691934
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO852501A NO165496C (no) | 1984-06-21 | 1985-06-20 | Analogifremgangsmaate for fremstilling av nye epoksysteroider. |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4670551A (no) |
| EP (1) | EP0165902B1 (no) |
| AR (2) | AR242036A1 (no) |
| AU (1) | AU582754B2 (no) |
| CA (1) | CA1239388A (no) |
| DE (1) | DE3569540D1 (no) |
| DK (1) | DK173854B1 (no) |
| ES (2) | ES8704967A1 (no) |
| FI (1) | FI83225C (no) |
| GR (1) | GR851499B (no) |
| HU (1) | HU192232B (no) |
| IE (1) | IE58050B1 (no) |
| IL (1) | IL75569A (no) |
| NO (1) | NO165496C (no) |
| NZ (1) | NZ212492A (no) |
| PT (1) | PT80663B (no) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69637140T2 (de) | 1995-12-11 | 2008-04-10 | G.D. Searle Llc, Chicago | Verfahren zur herstellung einer epoxy-verbindung |
| KR100523409B1 (ko) * | 1996-12-11 | 2005-10-24 | 지.디. 썰 엘엘씨 | 9,11-에폭시 스테로이드의 제조방법 및 이 제조방법에유용한 중간체 |
| EP1148061B1 (en) * | 1996-12-11 | 2007-10-17 | G.D. Searle LLC. | Epoxidation process |
| US6887991B1 (en) | 1996-12-11 | 2005-05-03 | G. D. Searle & Company | Processes for preparation of 9, 11-epoxy steroids and intermediates useful therein |
| WO1999061055A1 (en) | 1998-05-22 | 1999-12-02 | The Board Of Trustees Of The Leland Stanford Junior University | Bifunctional molecules and therapies based thereon |
| WO2003049745A1 (en) | 2001-12-12 | 2003-06-19 | Pharmacia Corporation | Method of treating ophthalmic disorders with epoxy-steroidal aldosterone receptor antagonists |
| US7235655B2 (en) | 2002-03-22 | 2007-06-26 | Pharmacia & Upjohn Company | Processes to prepare eplerenone |
| DK1889198T3 (da) | 2005-04-28 | 2015-02-09 | Proteus Digital Health Inc | Farma-informatiksystem |
| WO2007025780A2 (en) * | 2005-09-02 | 2007-03-08 | Recordati Ireland Limited | Aldosterone receptor antagonists |
| JP2009508494A (ja) | 2005-09-16 | 2009-03-05 | ラプトール ファーマシューティカル インコーポレイテッド | Ｃｒを含むタンパク質に対して特異的な受容体−結合タンパク質（ｒａｐ）変異体を含む組成物およびその使用 |
| WO2010095940A2 (en) | 2009-02-20 | 2010-08-26 | To-Bbb Holding B.V. | Glutathione-based drug delivery system |
| TWI556839B (zh) | 2009-05-06 | 2016-11-11 | 研究室護膚股份有限公司 | 包含活性劑－磷酸鈣粒子複合物之皮膚遞送組成物及其使用方法 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3013012A (en) * | 1960-12-22 | 1961-12-12 | Searle & Co | Alkanoylthio-17alpha-carboxyethyl-17beta-hydroxyandrosten-3-one lactones |
| US3095412A (en) * | 1961-12-19 | 1963-06-25 | Searle & Co | 9alpha, 11alpha-epoxy and 11beta-chloro-9alpha-hydroxy 17alpha-(2-carboxyethyl)-17beta-hydroxyandrost-4-en-3-one gamma-lactones and delta1 and delta6 analogs |
| GB1041534A (en) * | 1963-04-24 | 1966-09-07 | Merck & Co Inc | 20-spiroxane compounds |
| DE2652761C2 (de) * | 1976-11-16 | 1985-11-21 | Schering AG, 1000 Berlin und 4709 Bergkamen | 15,16-Methylen-Spirolactone, Verfahren zu deren Herstellung und diese enthaltende Arzneimittel |
| FI77669C (fi) * | 1983-04-13 | 1989-04-10 | Ciba Geigy Ag | 20-spiroxaner och analoger, som innehaoller en oeppen ring e, foerfarande foer deras framstaellning samt dessa innehaollande farmaceutiska preparat. |
| DE3481707D1 (de) * | 1983-08-17 | 1990-04-26 | Schering Ag | 7-alpha-substituierte 3-oxo-17alpha-pregn-4-en-21.17-carbolactone, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate. |
-
1985
- 1985-06-13 US US06/744,444 patent/US4670551A/en not_active Expired - Fee Related
- 1985-06-17 DE DE8585810277T patent/DE3569540D1/de not_active Expired
- 1985-06-17 EP EP85810277A patent/EP0165902B1/de not_active Expired
- 1985-06-19 FI FI852430A patent/FI83225C/fi not_active IP Right Cessation
- 1985-06-19 IL IL75569A patent/IL75569A/xx not_active IP Right Cessation
- 1985-06-19 CA CA000484418A patent/CA1239388A/en not_active Expired
- 1985-06-19 PT PT80663A patent/PT80663B/pt not_active IP Right Cessation
- 1985-06-19 GR GR851499A patent/GR851499B/el unknown
- 1985-06-20 NO NO852501A patent/NO165496C/no unknown
- 1985-06-20 NZ NZ212492A patent/NZ212492A/xx unknown
- 1985-06-20 ES ES544387A patent/ES8704967A1/es not_active Expired
- 1985-06-20 IE IE153585A patent/IE58050B1/en not_active IP Right Cessation
- 1985-06-20 HU HU852433A patent/HU192232B/hu not_active IP Right Cessation
- 1985-06-20 DK DK198502800A patent/DK173854B1/da not_active IP Right Cessation
- 1985-06-21 AR AR85300773A patent/AR242036A1/es active
- 1985-06-21 AU AU43971/85A patent/AU582754B2/en not_active Ceased
-
1986
- 1986-10-01 ES ES557112A patent/ES8707737A1/es not_active Expired
-
1989
- 1989-07-31 AR AR89314546A patent/AR245731A1/es active
Also Published As
| Publication number | Publication date |
|---|---|
| NO165496C (no) | 1991-02-20 |
| DK280085A (da) | 1985-12-22 |
| IE851535L (en) | 1985-12-21 |
| AU582754B2 (en) | 1989-04-13 |
| EP0165902B1 (de) | 1989-04-19 |
| GR851499B (no) | 1985-11-25 |
| US4670551A (en) | 1987-06-02 |
| DK173854B1 (da) | 2001-12-27 |
| NO852501L (no) | 1985-12-23 |
| ES557112A0 (es) | 1987-08-16 |
| ES544387A0 (es) | 1987-04-16 |
| PT80663A (en) | 1985-07-01 |
| PT80663B (en) | 1987-05-08 |
| IL75569A (en) | 1989-03-31 |
| FI852430A0 (fi) | 1985-06-19 |
| HUT38367A (en) | 1986-05-28 |
| FI852430L (fi) | 1985-12-22 |
| AU4397185A (en) | 1986-01-02 |
| HU192232B (en) | 1987-05-28 |
| FI83225C (fi) | 1991-06-10 |
| IL75569A0 (en) | 1985-10-31 |
| EP0165902A3 (en) | 1986-10-22 |
| AR242036A1 (es) | 1993-02-26 |
| ES8704967A1 (es) | 1987-04-16 |
| ES8707737A1 (es) | 1987-08-16 |
| IE58050B1 (en) | 1993-06-16 |
| CA1239388A (en) | 1988-07-19 |
| NZ212492A (en) | 1989-02-24 |
| DK280085D0 (da) | 1985-06-20 |
| DE3569540D1 (en) | 1989-05-24 |
| EP0165902A2 (de) | 1985-12-27 |
| FI83225B (fi) | 1991-02-28 |
| AR245731A1 (es) | 1994-02-28 |
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