DK155143B - Antioestrogent laegemiddel til behandling af benigne og canceroese tilstande i brystet - Google Patents
Antioestrogent laegemiddel til behandling af benigne og canceroese tilstande i brystet Download PDFInfo
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- DK155143B DK155143B DK420385A DK420385A DK155143B DK 155143 B DK155143 B DK 155143B DK 420385 A DK420385 A DK 420385A DK 420385 A DK420385 A DK 420385A DK 155143 B DK155143 B DK 155143B
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- UHKJKVIZTFFFSB-UHFFFAOYSA-N 1,2-diphenylbutan-1-one Chemical compound C=1C=CC=CC=1C(CC)C(=O)C1=CC=CC=C1 UHKJKVIZTFFFSB-UHFFFAOYSA-N 0.000 description 1
- YOUWVLSTAZVPHM-UHFFFAOYSA-N 1-(4-hydroxyphenyl)-2-phenylbutan-1-one Chemical compound C=1C=CC=CC=1C(CC)C(=O)C1=CC=C(O)C=C1 YOUWVLSTAZVPHM-UHFFFAOYSA-N 0.000 description 1
- OBBFYFBJWYPOQQ-UHFFFAOYSA-N 1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbutan-1-one Chemical compound C=1C=CC=CC=1C(CC)C(=O)C1=CC=C(OCCN(C)C)C=C1 OBBFYFBJWYPOQQ-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
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- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
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- 238000011835 investigation Methods 0.000 description 1
- JNWNAQZSBRFGPC-UHFFFAOYSA-M magnesium;2-(phenoxy)oxane;bromide Chemical compound [Mg+2].[Br-].O1CCCCC1OC1=CC=[C-]C=C1 JNWNAQZSBRFGPC-UHFFFAOYSA-M 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
DK 155143 B
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Den foreliggende opfindelse angår et antiøstrogent lægemiddel af den i patentkravets indledning angivne art til behanlding af benigne og cancerøse tilstande i brystet, altså af visse former for svulster i brystkirtlen 5 i deres hormonafhængige former.
Der kendes allerede nu et antiøstrogen som kan indgives oralt, benævnt tamoxifen, som består af 1-[ρ-(β-dimetylaminoætoxy)-fenyl]-trans-l,2-difenylbut-l-en, der forhandles under specialitetsnavnet "Nolvadex". For 10 at opnå en antiøstrogenisk aktivitet på de østrogene receptorers niveau navnlig -i brystkirtlen, er det nødvendigt oralt at indgive fra 10 til 30 ml om dagen af denne forbindelse, og det bevirker skadelige bivirkninger, navnlig en paradoksisk stimulering af ovarierne.. Disse 15 sidstnævnte virkninger begrænser i høj grad udnyttelsen af tamoxifen.
Det er desuden påvist at tamoxifen efter oral indgift omdannes under passagen gennem leveren til talrige me-tabolitter, herunder 1—[p—(β-dimetylaminoætoxy)-fenyl]-20 trans-l-(p -hydroxyfenyl)-2-fenylbut-l-en eller 4-hydroxytamoxi- fen, der er den aktive form af produktet på molekylært niveau. På den anden side synes dette 4-hydroxyderivat indgivet direkte ad den orale vej at blive nedbrudt hurtigere end tamoxifen, og af denne grund er det unyttigt 25 at indgive det ad denne vej. Desuden er det også kendt at 4-hydroxyderivatet er fra tyve til hundrede gange mere aktivt end tamoxifen som antiøstrogen på de østrogene receptorers niveau. Imidlertid følger indgiften oralt eller parenteralt ad anden vej end den perkutane 30 til en diffusion af dette produkt gennem organismen, hvilket blandt andet bevirker en skadelig paradoksisk stimulering af ovarierne.
Man har iøvrigt beskrevet 4-hydroxytamoxifenderi-vatet som et antiøstrogent middel med henblik på at ind-35 give det oralt eller muligvis parenteralt, idet administrationen selv er begrænset til en injektion. Som nævnt ovenfor synes oral.indgift at være af begrænset 2
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effektivitet på grund af ødelæggelsen af selve forbindelsen ved indgreb af leveren, mens en injektion, der fører til indførelse af forbindelsen i blodkredsløbet, kan fremkalde de forannævnte skadelige virkninger på ovarierne 5 i kraft af en systemisk effekt.
Skriftet Chemical Abstracts, bind 96, nr. 9, 1.
Marts 1982, side 29, abstrakt 62664k, Columbus, Ohio, (fJSA) & Eur. J. Cancer Clin.. Oncol. 1981, 17(9), 1063-1065, M. Sluyser et al., "Effect of monihydroxytamoxi-10 fen om mouse mammary tumors", beskriver egenskaberne af monohydroxytamoxifen uden af specificere cis- eller trans-formen, og i sammenhæng med en pellet under huden og følgelig ikke perkutant.
Nærværende opfinderes arbejde gennem 15 år over 15 metabolismen af steroide hormoner som indgives i alkoholisk opløsning ad den perkutane vej har gjort det muligt at påvise (Journal of Clinical Investigation(USA) 1970, 4£:31) at den perkutane indgiftsvej for steroider med kort halveringstid tillader direkte adgang til 20 målorganet, mens oral eller selv intravenøs indgift af det samme steroid begunstiger metabolisme deraf i leveren på bekostning af den effektive koncentration i receptorvævene. De således fremkaldte lever-bypasses påvistes for første gang for testosteron (Journal of 25 Clinical Endocrinology and Metabolism (USA) 1969, 29;437) og derefter senere for progesteron (Journal of Clinical Endocrinology (USA) 1969, 2^:1590 og 1974, ,38:142 og Fransk patent nr. 2515041). I tilfælde af progesteron var det muligt at påvise at indgiften af dette steroid 30 i alkoholisk opløsning eller i en 60%s vandig alkoholisk gel tillod lokal retention i 48 timer af forbindelsen som var passeret gennem den kutane barriere (10%). I modsætning hertil ødelægges ved oral indgift 90% af den indgivne dosis ved den første passage gennem leveren.
35 Nærværende opfindere forsøgte derfor i deres un dersøgelser at administrere 4-hydroxytamoxifenderivatet perkutant for at undgå alle systemiske virkninger, og 3
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det viste sig overraskende at denne forbindelse i 60%s alkoholisk opløsning, påført på hud der lå over cancerøse brystsvulster,viste sig at have evne til at passere gennem den kutane barriere og blive optaget på receptor-5 molekylerne i disse svulster. Nærværende ansøgere har i modsætning hertil iagttaget at tamoxifen ikke kan aktiveres til sit 4-hydroxyderivat ad den perkutane vej eftersom brystet ikke til sin disposition ligesom leveren har de enzymer der behøves til omdannelsen.
10 Det anti-østrogene lægemiddel afledt af tamoxifen, hvis· aktive bestanddel består af 1-[p-(3-dimetylaminoætoxy)-feny1]-trans-1-(p-hydroxy-fenyl)-2-fenylbut-l-en, benævnt 4-hydroxytamoxifen, foreligger ifølge opfindelsen som en vandig alkoholisk gel der 15 kan administreres perkutant, og om ønsket indeholder det kendte excipienter.
4-Hydroxytamoxifens overskriden af den kutane barriere blev påvist ved hjælp af spordoser af tritieret 4-hydroxytamoxifen påført i alkoholisk opløsning i 24 timer 20 før fjernelse af cancerøse bryster. Undersøgelser udført i laboratorium viste at 4-hydroxytamoxifen viste sig i sin oprindelige form på niveauet for de proteinstrukturer som svarer til hormonale receptorer. Det har derfor evne til at have antiøstrogen virkning på dette niveau.
25 En lille portion af radioaktiviteten metaboliseres til uidentificerede produkter (3%). I parallelforsøg på-førtes dette samme produkt i radioaktiv form på huden af et rask individ og der fortoges beregning af den radioaktivitet som viste sig i urinen i løbet af 15 dage ' 30 efter indgiften af produktet. Hastigheden af elimina tionen med urinen viser at der sker en svag og gradvis nedbrydning af produktet. I det cirkulerende blod kan der kun opdages spor af produktet - der finder følgelig ingen akkumulering sted. Det er kun som sekundær effekt 35 at stoffet når leveren, hvor det inaktiveres.
Den kendsgerning at 4-hydroxytamoxifen er opløseligt i alkohol og kan absorberes af huden 4
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gør det muligt at oparbejde denne forbindelse som en alkoholisk gel der egner sig til perkutan administration, og nærværende ansøgeres undersøgelser har vist en koefficient for kutan absorption nær ved 1% for 4-hydroxytamoxi-5 fen. På i og for sig kendt måde indeholder den alkoholiske gel foruden 4-hydroxytamoxifen forskellige excipienter der behøves til konditionering og for at gøre det muligt, at perkutan penetration finder sted, navnlig "Carbopol"^ ætylalkohol og vand. De daglige doser af produktet til ad-10 ministration kan let beregnes ved hjælp af absorptionskoefficienter af lægemidlerne og de doser som det ønskes at opnå for 4-hydroxytamoxifen på niveauet for dets receptormolekyler .
Et præparat af en gel ifølge opfindelsen til perku-15 tan administration angives nedenfor som eksempel der ikke på nogen måde er begrænsende: 4-hydroxytamoxifen 0,15 g 20 "Carbopol"® 934 1 g
Triætanolamin 1,5 g 95%s ætylalkohol 50 ml
Vand, indtil 100 g © 25 ("Carbopol" 934 er en karboxyvmylpolymer med ak tive karboxylgrupper, der bidrager til at danne stabile emulsioner med aminer).
30 Ved perkutan administration på brystet koncentrerer disse produkter sig selektivt i brystkirtlen og elimineres derefter med forsvindende hastigheder i biologiske væsker. Den opnåede effekt er den modsatte af den der iagttages i tilfælde af oral indgift, hvor der må opnås 35 en høj plasmakoncentration for at få en lav lokal koncentration. I tilfælde af perkutan indgift er hastig- 5
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hederne maksimale nær ved indgiftsstedet og minimale i blodkredsløbet og leveren. Denne teknik tilfredsstiller derfor den opstillede fordring: topisk antiøstro-gen medicinbehandling med mulig sigte på behandling (syg-5 dom i brystet) og uden skadelige bivirkninger.
Teknikken med topisk 4-hydroxytamoxifen-administra-tion er derfor tilpasset på en sådan måde at der frembringes optimering af virkningerne af et antiøstrogen på et specifikt målorgan. Ingen anden medicinbehandling til-10 fredsstiller disse standarder.
Fremstilling af 4-hydroxytamoxifen er i og for sig kendt og kan fx udføres i henhold til en modifikation af den syntese som er beskrevet af Robertson og Katzenel-lenbogen (J. Org. Chem. 1982, 47, 2387, og J. Steroid, 15 Biochem. 1982, 16, 1), der finder sted i flere trin: 1) Reaktion mellem 4-(β-dimetylaminoætoxy)-a-ætyl-deoxybenzoin og p-(2-tetrahydropyranyloxy)-fenylmagne-siumbromid; 20 2) særskilt herfra dannelse af l-(4-hydroxyfenyl)-2- fenyl-l-butanon ved hydroxylering af 1,2-difenyl-l-bu-tanon; 3) omsætning mellem produkterne (1) og (2) fører til dannelse af l-[p-(6-dimetylaminoætoxy)-fenyl]-l-[p-(2- 25 tetrahydropyranyloxy)-fenyl]-2-fenylbutan-l-ol; 4) dehydratisering med metanol/saltsyre frembringer.
1-[p-(β-dimetylaminoætoxy)-fenyl]-trans-1-(p-hydroxy-fenyl)-2-fenylbut-l-en = 4-OH-tamoxifan, en blanding af cis- og trans-isomerer; 30 5) adskillelse af cis- og trans-isomeren ved kroma- tografering og krystallisation til konstant specifik aktivitet.
35
Claims (1)
- DK 155143 B Antiøstrogent lægemiddel til behandling af benigne og cancerøse tilstande i brystet og i hvilket det virk-5 somme materiale består af 1-[p-(/3-dimetylaminoætoxy)-fenyl]-trans-1-(p-hydroxyfenylj-2-fenylbut-1-en, kendetegnet ved at det foreligger som en gel af vandig alkoholisk type, der kan administreres ad den perkutane vej, og om ønsket indeholder i og for sig kendte excipienter. 10 15 20 25 • - f 30 35
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8400927A FR2558373B1 (fr) | 1984-01-20 | 1984-01-20 | Medicament antioestrogene a base de 4-hydroxytamoxifene pour administration percutanee |
| FR8400927 | 1984-01-20 | ||
| PCT/EP1984/000436 WO1985003228A1 (fr) | 1984-01-20 | 1984-12-21 | Medicament antioestrogene pour administration percutanee |
| EP8400436 | 1984-12-21 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK420385A DK420385A (da) | 1985-09-17 |
| DK420385D0 DK420385D0 (da) | 1985-09-17 |
| DK155143B true DK155143B (da) | 1989-02-20 |
| DK155143C DK155143C (da) | 1989-07-03 |
Family
ID=9300348
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK420385A DK155143C (da) | 1984-01-20 | 1985-09-17 | Antioestrogent laegemiddel til behandling af benigne og canceroese tilstande i brystet |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US4919937A (da) |
| EP (2) | EP0151326B1 (da) |
| JP (1) | JPH0667826B2 (da) |
| AT (1) | ATE73334T1 (da) |
| DE (1) | DE3485581D1 (da) |
| DK (1) | DK155143C (da) |
| FR (1) | FR2558373B1 (da) |
| WO (1) | WO1985003228A1 (da) |
Families Citing this family (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8604528D0 (en) * | 1986-02-24 | 1986-04-03 | Ici Plc | Therapeutic agents |
| EP0462189B1 (en) * | 1989-03-10 | 1995-09-27 | Endorecherche Inc. | Combination therapy for treatment of estrogen sensitive diseases |
| US5119827A (en) * | 1990-09-05 | 1992-06-09 | Board Of Regents, The University Of Texas System | Mechanisms of antiestrogen resistance in breast cancer |
| US5518734A (en) * | 1991-09-25 | 1996-05-21 | Beta Pharmaceuticals Co. | Transdermal delivery system for estradiol and process for manufacturing said device |
| US5705185A (en) * | 1991-09-25 | 1998-01-06 | Beta Pharmaceuticals Co. | Transdermal delivery of estradiol and process for manufacturing said device |
| GB9207437D0 (en) * | 1992-04-03 | 1992-05-20 | Orion Yhtymae Oy | Topical administration of toremifene and its metabolites |
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| DE4407742C1 (de) * | 1994-03-08 | 1995-06-22 | Hexal Pharma Gmbh | Transdermales System in Form eines Pflasters mit einem Tamoxifen-Derivat |
| WO1997036570A1 (de) * | 1996-03-29 | 1997-10-09 | S.W. Patentverwertungs Ges. M.B.H. Edelsbacher U. Partner | Kosmetikum bzw. kosmetikzusammensetzung zur glättung und straffung der haut bei gestörtem unterhaut-binde-fettgewebe, insbesondere bei der 'cellulite' |
| RU2123838C1 (ru) * | 1996-07-31 | 1998-12-27 | Акционерное общество открытого типа "Нижфарм" | Состав для лечения гирсутизма |
| EP0943333A1 (de) * | 1998-03-18 | 1999-09-22 | S.W. Patentverwertungs GmbH | Medikament zur Prophylaxe und/oder Behandlung des Mammakarzinoms enthaltend einen Hemmer der Bildung von Oestrogenen |
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| FI982733L (fi) * | 1998-12-17 | 2000-06-18 | Orion Yhtymae Oyj | Trifenyylietyleeniantiestrogeenien liukoisia koostumuksia |
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| DE10054294A1 (de) * | 2000-11-02 | 2002-05-16 | Heinrich Wieland | Topische Behandlung bei der Mastalgie |
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| US9173836B2 (en) | 2003-01-02 | 2015-11-03 | FemmeParma Holding Company, Inc. | Pharmaceutical preparations for treatments of diseases and disorders of the breast |
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| US7968532B2 (en) * | 2003-12-15 | 2011-06-28 | Besins Healthcare Luxembourg | Treatment of gynecomastia with 4-hydroxy tamoxifen |
| JP5069469B2 (ja) * | 2003-12-15 | 2012-11-07 | ラボラトワール ブザン アンテルナスィヨナル | 女性化乳房治療用の薬剤を製造する際の４−ヒドロキシタモキシフェンの使用 |
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| US7507769B2 (en) * | 2004-03-22 | 2009-03-24 | Laboratoires Besins International | Treatment and prevention of benign breast disease with 4-hydroxy tamoxifen |
| EP1579856A1 (en) * | 2004-03-22 | 2005-09-28 | Laboratoires Besins International | Treatment and prevention of benign breast disease with 4-hydroxy tamoxifen |
| EP1748770B1 (en) * | 2004-03-22 | 2008-04-09 | Laboratoires Besins International | Treatment and prevention of benign breast disease with 4-hydroxy tamoxifen |
| DK1799201T3 (da) * | 2004-10-14 | 2009-03-30 | Besins Int Lab | 4-Hydroxy-tamoxifen gelformuleringer |
| EP1647271A1 (en) * | 2004-10-14 | 2006-04-19 | Laboratoires Besins International | 4-Hydroxy tamoxifen gel formulations |
| US20070088012A1 (en) * | 2005-04-08 | 2007-04-19 | Woun Seo | Method of treating or preventing type-2 diabetes |
| SI1937276T1 (sl) | 2005-10-12 | 2013-04-30 | Unimed Pharmaceuticals, Llc C/O Abbott Laboratoires 100 Abbott Park Road | Izboljšani testosteronski gel in postopek uporabe |
| KR100850910B1 (ko) * | 2006-12-22 | 2008-08-07 | 삼성전자주식회사 | 블루투스 디바이스를 연결하기 위한 장치 및 방법 |
| US20080153789A1 (en) * | 2006-12-26 | 2008-06-26 | Femmepharma Holding Company, Inc. | Topical administration of danazol |
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0002097B1 (en) * | 1977-08-22 | 1981-08-05 | Imperial Chemical Industries Plc | Triphenylalkene derivatives, process for their preparation and pharmaceutical compositions containing them |
| DE3046719C2 (de) * | 1980-12-11 | 1983-02-17 | Klinge Pharma GmbH, 8000 München | 1,1,2-Triphenyl-but-1-en-Derivate, Verfahren zu ihrer Herstellung und Arzneimittel |
| FR2515041A1 (fr) * | 1981-10-26 | 1983-04-29 | Besins Jean | Medicament a base de progesterone pour le traitement des affections mammaires |
-
1984
- 1984-01-20 FR FR8400927A patent/FR2558373B1/fr not_active Expired
- 1984-12-19 EP EP84201920A patent/EP0151326B1/fr not_active Expired
- 1984-12-21 AT AT85900469T patent/ATE73334T1/de not_active IP Right Cessation
- 1984-12-21 DE DE8585900469T patent/DE3485581D1/de not_active Expired - Lifetime
- 1984-12-21 JP JP60500495A patent/JPH0667826B2/ja not_active Expired - Fee Related
- 1984-12-21 EP EP85900469A patent/EP0169214B1/fr not_active Expired - Lifetime
- 1984-12-21 WO PCT/EP1984/000436 patent/WO1985003228A1/fr not_active Ceased
- 1984-12-21 US US06/777,786 patent/US4919937A/en not_active Expired - Lifetime
-
1985
- 1985-09-17 DK DK420385A patent/DK155143C/da active
Also Published As
| Publication number | Publication date |
|---|---|
| EP0151326B1 (fr) | 1989-07-12 |
| EP0169214B1 (fr) | 1992-03-11 |
| US4919937A (en) | 1990-04-24 |
| FR2558373A1 (fr) | 1985-07-26 |
| EP0151326A1 (fr) | 1985-08-14 |
| JPH0667826B2 (ja) | 1994-08-31 |
| FR2558373B1 (fr) | 1987-07-03 |
| ATE73334T1 (de) | 1992-03-15 |
| DE3485581D1 (de) | 1992-04-16 |
| DK155143C (da) | 1989-07-03 |
| DK420385A (da) | 1985-09-17 |
| JPS61500914A (ja) | 1986-05-08 |
| EP0169214A1 (fr) | 1986-01-29 |
| WO1985003228A1 (fr) | 1985-08-01 |
| DK420385D0 (da) | 1985-09-17 |
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