NO129522B - - Google Patents
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- Publication number
- NO129522B NO129522B NO02226/68A NO222668A NO129522B NO 129522 B NO129522 B NO 129522B NO 02226/68 A NO02226/68 A NO 02226/68A NO 222668 A NO222668 A NO 222668A NO 129522 B NO129522 B NO 129522B
- Authority
- NO
- Norway
- Prior art keywords
- dione
- chloro
- acetate
- dichloro
- pregnadien
- Prior art date
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 150000003431 steroids Chemical class 0.000 claims description 2
- 150000003128 pregnanes Chemical class 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000016087 ovulation Effects 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- 206010001928 Amenorrhoea Diseases 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000003152 gestagenic effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000000757 progestagenic effect Effects 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QDFXRVAOBHEBGJ-UHFFFAOYSA-N 3-(cyclononen-1-yl)-4,5,6,7,8,9-hexahydro-1h-diazonine Chemical compound C1CCCCCCC=C1C1=NNCCCCCC1 QDFXRVAOBHEBGJ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010063146 Uterine hypoplasia Diseases 0.000 description 1
- ZALMZWWJQXBYQA-UHFFFAOYSA-N [N].[Cl] Chemical compound [N].[Cl] ZALMZWWJQXBYQA-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 210000004246 corpus luteum Anatomy 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical class Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000546 inhibition of ovulation Toxicity 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- HSPSCWZIJWKZKD-UHFFFAOYSA-N n-chloroacetamide Chemical compound CC(=O)NCl HSPSCWZIJWKZKD-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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
- A61K31/57—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
- A61K31/573—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 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K31/567—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 substituted in position 17 alpha, e.g. mestranol, norethandrolone
-
- 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
- A61K31/568—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 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
- 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
- A61K31/568—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 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/569—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 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
hvor R1 og R2 hver for seg betegner hydrogen eller sammen betegner en methylengruppe og hvor A-B betegner gruppene:
hvor R^ betegner hydrogen eller lavere alkanoyl,
R^ betegner hydrogen eller fluor,
R,- betegner methyl, eller hydrogen hvis
R^ og R^ danner en methylengruppe.
Fremgangsmåten utmerker seg ved at et tilsvarende S-klor-A^'^-steroid av generell formel
hvor R^, R^ og A-B har de tidligere angitte betydninger, omsettes med et positivt eller.negativt klordannende reagens, hvoretter det dannede reaksjonsprodukt behandles med en base.
Positivt og negativt klor frigjores under reaksjonen fra
egnede klorholdige forbindelser. Positivt klor dannes f.eks. fra N-klor-acylaminer ■ eller acylimider, fortrinnsvis -acetamid og
-succinimid, men også fra hypokloritter såsom tert.butylhypokloritt.
Som forbindelser som danner negativt klor, er klorider aktuelle,
fortrinnsvis lithiumklorid. Dessuten kan også elementært klor spaltes i positivt og negativt klor.
Fremgangsmåten ifolge oppfinnelsen utfores f.eks..ved. at. man
omsetter steroidet opplost i eddiksyre med lithiumklorid og N-klor-
succinimid ved lave temperaturer i nærvær av en sterk vannfri syre,
såsom hydrogenklorid i dioxan eller tetrahydrofuran. Ved klorering av A^-dobbeltbinding dannes en k-, 6, 7-. eller 6,6,7-triklorforbindelse,
som behandles med en fortrinnsvis organisk base til det er oppnådd fullstendig hydrogenklorid av spaltning og -binding. Egnede organiske baser er pyridin, kinolin, lutidin, anilin, diazabicyclononen, dimethylformamid osv.
For 6,6,7-triklorforbindelæn avledet fra 6-klorforbindelsen forloper hydrogenkloridavspaltningen allerede ved temperaturer opp mot romtemperatur. Denne fremgangsmåte foretrekkes på grunn av det glatte reaksjonsforlop og det hoyere utbytte av den onskede ^,6-diklorforbindelse.
Den partielle klorering av A^-dobbeltbindingen og den avsluttende avspaltning av hydrogenklorid under vanciing av et kloratom har hittil ikke vært undersokt for 6-klorerte forbindelser. Reaks j.onsf orlopet var heller ikke å forutse og er overraskende.
Således har f.eks. forsok på å utfore den analoge reaksjon med N-brom-succinimid ikke lykkedes.
De nye ^-,6-diklor-A<14>"'^-steroider har verdifulle farmasøytiske egenskaper eller finner anvendelse som utgangsmaterialer ved fremstilling av legemidler. Den sterke gestagene virkning av de nye diklorforbindelser ifolge oppfinnelsen overtreffer den sterke virkning av 6-klor-A^'^-pregnadien. Den okede virkning som folge av ^--klor-substituenten er overraskende, da eksempelvis ^--klor-progesteron har vesentlig svakere virkning enn progesteron (Chemistry and Industry, Bd. lU-, side 5^8 (1963).
Den gestagene virkning av diklorforbindelsene ifolge fremgangsmåten overstiger også virkningen av nylig offentliggjorte ^-,6-diklor-A h- ' 6-pregnadiener. Dessuten utviser de nye forbindelser en betydelig overlegenhet med hensyn til den ovulasjonshemmende virkning såvel i forhold til de kjente 6-klor- samt de nå kjente ^,6-diklor-A^'^-pregnadiener.
Den nedenstående tabell viser overlegenheten av de nye frem-gangsmåteprodukter sammenlignet med de kjente, sterkt gestagent virk-somme forbindelser III, IV og V ved peroral adminstering på dyr.
Den gestagene virkning ble fastslått ved den vanlige Clauberg-test.
Den ovulasjonshemmende virkning ble testet på hunrotter. Tabellen angir den dose ved hvilken ovulasjonen uteble for 50$ av dyrene. (WD^q).
Ved ovulasjonshemningstesten viste forbindelse I seg å være særlig virksom. Denne forbindelse utmerket seg dessuten ved at den i motsetning til de ovrige forbindelser som er oppfort i tabellen,
også er fri for antiandrogene virkninger i hoye doser.
De nye forbindelser kan med godt resultat anvendes for behandling blant annet av de folgende gynekologiske forstyrrelser: primær og sekundær amenorrhoea, endometriose, hypoplasia uteri, funksjonelle blødninger (glandulær-zystisk hyperplasia, sterilitet ved utilstrekkelig gul-legemefunksjon og syklussvingninger. Ytterligere indikasjoner oppnåes ved fremskreden endometrium-carcinoma og også ved prostatahypertrophia. Likeledes kan de nye forbindelser anvendes for å forhindre befruktning.
Doseringen vil avhenge av strengheten av sykdomstilfellet. Vanligvis anvendes mellom 5 og 100 mg aktivt stoff pr. dag. Eksempelvis lar sterke menstruasjonssvingninger seg regulere ved cyklustilpasset behandling med daglige doser a 10 mg.
Ved fremstilling av legemidlene går man frem på vanlig måte, idet de aktive stoffer anvendes sammen med de i den galeniske farmasi vanlige bærerstoffer, fortynning smidler og smaksstoffer for fremstilling av de onskede anvendelsesformer, såsom tabletter, drageer, kapsler, oppløsninger, osv. Konsentrasjonen av aktivt stoff i legemidlet er avhengig av anvendelsesformen. Således inneholder en tablett fortrinnsvis 0,1-10 mg, mens oppløsninger for parenteral anvendelse inneholder 1-20 mg/ml opplosning.
De folgende eksempler illustrerer oppfinnelsen.
Eksempel 1
5,0 g 6-klor-l,2a-methylen-A h ' 6-pregnadien-17a-ol-3,20-dion-17-acetat omsettes i 2^5 ml eddiksyre med 2^,5 g lithiumklorid og 5,0 g N-klorsuccinimid. Etter tilsetning av 10 ml dioxan mettet med hydrogenkloridgass omrores blandingen i 1 time ved romtemperatur. Den omrores deretter med isvann, og utfelningen som dannes, frafiltreres og opploses i methylenklorid. Methylenkloridfasen vaskes deretter med natriumhydrogencarbonåtopplosning og vann,
torres over natriumsulfat og inndampes til tbrrhet i vakuum. Residuet opploses I 30 ml pyridin og tillates å stå i 16 timer ved romtemperatur. Etter fortynning med ether vaskes opplosningen med fortynnet saltsyre og vann, hvoretter den torres over natriumsulfat og inndampes til torrhet I vakuum. Det tilbakeblivende residuum kromatograferes på kiselsyregel. Ved omkrystallisering fra isopropylehter fåes 1,6 g 6-diklor-l,2a-methylen-A ' -pregnadien-17a-ol-3,20-dion-17-acetat med smeltepunkt 256-257°C.
UV:£218=5700; ^=1^100.
Eksempel 2
3,0 g 6-klor-l,2a; l6,17a-bismethylen-A ' -pregnadien-3,20-dion omsettes i 150 ml eddiksyre med 15 g lithiumklorid og 13,0 g N-kloracetamid. Etter tilsetning av 6 ml dioxan, mettet med klor-nydrogengass, omrores blandingen i 1 time ved romtemperatur. Opp-arbeidingen utfores som beskrevet i eksempel 1. Etter kromatografering på kiselsyregel og omkrystallisering.fra ethylacetat fåes 1,62 g 6-diklor-l,2a; 16,17a-bismethylen-A^'^-pregnadien-3,20-dion med smeltepunkt 266,5-269°C.
UV:£ = 1^-000
297
Eksempel
800 mg 6-klor-l,2a-methylen-l6a-methyl-A h ' 6-pregnadien-17a-ol-3,20-dion-17_acetat omsettes og opparbeides som beskrevet i eksempel 1. Etter kromatografering på kiselsyregel og omkrystallisering fra isopropylether fåes <*>+20 mg <1>+,6-diklor-l,2a-methylen-l6a-methyl-A '^-pregna-dien-17a-ol-3,20-dion-17-acetat med smeltepunkt 2<1>+5-2<1>+7°C.
uV:£.219=5650;t 296= 13200.
Claims (1)
- Eksempel h 1,98 g 21-f]»uor-6-klor-l,2a-methylen-A h ' 6-pregnadien-17a~ol-3,20-dion-17-acetat omsettes og opparbeides som beskrevet i eksempel 1. Etter kromatografering på kiselsyregel og omkrystallisering fra isopropylether fåes ^70 mg 21-fluor-<1>+,6-diklor-l,2a-methylen-A<1+>,^-pregnadien-l7a-ol-3,20-dion-17-acetat med smeltepunkt 267,5-268,5°C. UV:£2l8= 58^0; f,295=1^100. Eksempel 5 5,0 g 6-klor-l6a-methylA k ' 6-pregnadien-17a-ol-3,20-dion-17-acetat omsettes og opparbeides som beskrevet i eksempel 1. Etter kromatografering på kiselsyregel og omkrystallisering fra isopropylether fåes 1,66 g 4-, 6-diklor-l6ct-methyl-A ' -pregnadien-l7a-ol-3,20-dion-17-acetat med smeltepunkt 176-176,5°C. UV:e299= ^30°.Analogifremgangsmåte ved fremstilling av terapeutisk aktive 4-,6-diklor-A li ' £.-steroider av pregnanrekken av generell formel: hvor R-^ og R2 hver for seg betegner hydrogen eller sammen betegner en methylengruppe og hvor A-B betegner gruppene:hvor R betegner hydrogen eller lavere alkanoyl, R^ betegner hydrogen eller fluor,Rj-. betegner methyl, eller hydrogen hvis R-^ og R^ danner en methylengruppe, karakterisert ved at et tilsvarende 6-klor-A^'^-steroid av generell formelhvor R-p R^ og A-B har de tidligere angitte betydninger, omsettes med et positivt eller negativt klordannende reagens, hvoretter det dannede reaksjonsprodukt behandles med en base.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1967SC040852 DE1643027B2 (de) | 1967-06-09 | 1967-06-09 | 4,6-dichlor-delta hoch 4,6- steroide der pregnanreihe |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO129522B true NO129522B (no) | 1974-04-22 |
Family
ID=7435899
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO02226/68A NO129522B (no) | 1967-06-09 | 1968-06-07 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US3789087A (no) |
| AT (1) | AT280499B (no) |
| BE (1) | BE716258A (no) |
| BR (1) | BR6899582D0 (no) |
| CH (1) | CH560230A5 (no) |
| CS (1) | CS163723B2 (no) |
| DE (1) | DE1643027B2 (no) |
| DK (2) | DK124610B (no) |
| ES (1) | ES354795A1 (no) |
| FI (1) | FI45176C (no) |
| FR (2) | FR1588812A (no) |
| GB (1) | GB1240339A (no) |
| NL (1) | NL161768C (no) |
| NO (1) | NO129522B (no) |
| PL (1) | PL73566B1 (no) |
| SE (1) | SE341396B (no) |
| YU (1) | YU33977B (no) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0792152B1 (en) | 1994-11-22 | 2004-04-14 | Balance Pharmaceuticals, Inc. | Methods of contraception |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB838773A (en) * | 1955-07-20 | 1960-06-22 | Farmaceutici Italia | 4-substituted steroid compounds and preparation thereof |
| US3452058A (en) * | 1958-11-13 | 1969-06-24 | Syntex Corp | 6-substituted-6-dehydro androstanes and pregnanes |
| GB1050218A (no) * | 1964-10-13 | |||
| DE1593516C3 (de) * | 1966-08-25 | 1975-05-15 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | 4-Halogen-1,2 alpha; 6,7 betabismethylen-delta hoch 4-3-ketosteroide, Verfahren zu ihrer Herstellung sowie diese Steroide enthaltende Mittel |
| US3707537A (en) * | 1969-01-08 | 1972-12-26 | Hoffmann La Roche | 4-chloro-4,6-diene-6-halo or lower alkyl steroids |
-
1967
- 1967-06-09 DE DE1967SC040852 patent/DE1643027B2/de active Granted
-
1968
- 1968-05-21 DK DK234568AA patent/DK124610B/da unknown
- 1968-05-29 AT AT516368A patent/AT280499B/de not_active IP Right Cessation
- 1968-05-31 FI FI681532A patent/FI45176C/fi active
- 1968-06-03 YU YU1278/68A patent/YU33977B/xx unknown
- 1968-06-04 CH CH828768A patent/CH560230A5/xx not_active IP Right Cessation
- 1968-06-05 SE SE07534/68A patent/SE341396B/xx unknown
- 1968-06-05 BR BR199582/68A patent/BR6899582D0/pt unknown
- 1968-06-05 US US00734513A patent/US3789087A/en not_active Expired - Lifetime
- 1968-06-06 CS CS4207A patent/CS163723B2/cs unknown
- 1968-06-07 NO NO02226/68A patent/NO129522B/no unknown
- 1968-06-07 BE BE716258D patent/BE716258A/xx unknown
- 1968-06-07 FR FR1588812D patent/FR1588812A/fr not_active Expired
- 1968-06-07 ES ES354795A patent/ES354795A1/es not_active Expired
- 1968-06-08 NL NL6808107.A patent/NL161768C/xx not_active IP Right Cessation
- 1968-06-08 PL PL12743668A patent/PL73566B1/xx unknown
- 1968-06-10 GB GB27559/68A patent/GB1240339A/en not_active Expired
- 1968-09-05 FR FR165163A patent/FR8342M/fr not_active Expired
-
1971
- 1971-07-08 DK DK336171AA patent/DK128189B/da unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL161768B (nl) | 1979-10-15 |
| FR1588812A (no) | 1970-03-16 |
| AT280499B (de) | 1970-04-10 |
| BR6899582D0 (pt) | 1973-05-10 |
| CH560230A5 (no) | 1975-03-27 |
| YU127868A (en) | 1978-02-28 |
| DE1643027B2 (de) | 1977-12-08 |
| NL6808107A (no) | 1968-12-10 |
| DE1643027C3 (no) | 1978-08-17 |
| FR8342M (no) | 1970-12-21 |
| BE716258A (no) | 1968-12-09 |
| NL161768C (nl) | 1980-03-17 |
| DE1643027A1 (de) | 1971-04-15 |
| ES354795A1 (es) | 1969-11-01 |
| CS163723B2 (no) | 1975-11-07 |
| YU33977B (en) | 1978-09-08 |
| SE341396B (no) | 1971-12-27 |
| US3789087A (en) | 1974-01-29 |
| FI45176C (fi) | 1972-04-10 |
| DK124610B (da) | 1972-11-06 |
| DK128189B (da) | 1974-03-18 |
| PL73566B1 (no) | 1974-10-31 |
| GB1240339A (en) | 1971-07-21 |
| FI45176B (no) | 1971-12-31 |
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