DE1668685C3 - 17-Hydroxy- and 17-acyloxy-6 beta, 7 beta-epoxy-1 alpha, 2 alpha-methylene-4-pregnen-3,20-diones, processes for their preparation and agents containing them - Google Patents
17-Hydroxy- and 17-acyloxy-6 beta, 7 beta-epoxy-1 alpha, 2 alpha-methylene-4-pregnen-3,20-diones, processes for their preparation and agents containing themInfo
- Publication number
- DE1668685C3 DE1668685C3 DE19681668685 DE1668685A DE1668685C3 DE 1668685 C3 DE1668685 C3 DE 1668685C3 DE 19681668685 DE19681668685 DE 19681668685 DE 1668685 A DE1668685 A DE 1668685A DE 1668685 C3 DE1668685 C3 DE 1668685C3
- Authority
- DE
- Germany
- Prior art keywords
- pregnen
- methylene
- dione
- epoxy
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title description 3
- 239000004593 Epoxy Substances 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000005711 Benzoic acid Substances 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 235000010233 benzoic acid Nutrition 0.000 description 4
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000002280 anti-androgenic effect Effects 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- -1 preparation Chemical compound 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 201000000736 Amenorrhea Diseases 0.000 description 2
- 206010001928 Amenorrhoea Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 231100000540 amenorrhea Toxicity 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 230000003152 gestagenic effect Effects 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 231100000546 inhibition of ovulation Toxicity 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010063146 Uterine hypoplasia Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 208000030270 breast disease Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000004246 corpus luteum Anatomy 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- SMPAPEKFGLKOIC-UHFFFAOYSA-N oxolane;hydrochloride Chemical class Cl.C1CCOC1 SMPAPEKFGLKOIC-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 238000007127 saponification reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000001625 seminal vesicle Anatomy 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
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 201000010653 vesiculitis Diseases 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
CH3
I
C = OCH 3
I.
C = O
J^ OAc as J ^ OAc as
OROR
worin R Wasserstoff oder eine Acylgruppe, X Chlor oder Brom und Ac eine Acylgruppe bedeutet, in einem gegen die Reaktionspartner inerten Lösungsmittel mit Basen umsetzt und gegebenenfalls eine freie 17-Hydroxygruppe verestert.where R is hydrogen or an acyl group, X is chlorine or bromine and Ac is an acyl group, in reacts a solvent inert to the reactants with bases and optionally a free 17-hydroxy group esterified.
40 Die Erfindung betrifft neue 17-Hydroxy- und 17 - Acyloxy - 6ß,7ß - epoxy -1«>2* - metbylen - 4 - pregnen-3,20-dione, in denen die Acyloxygruppe bis zu 15 Kohlenstoffatome enthält oder sich von einer anorganischen Säure ableitet. 40 The invention relates to new 17-hydroxy- and 17-acyloxy- 6ß, 7ß -epoxy -1 «> 2 * - metbylen - 4 - pregnen-3,20-diones, in which the acyloxy group contains up to 15 carbon atoms or differs from derived from an inorganic acid.
Die Säurereste leiten sich von Säuren mit bis zu 15 Kohlenstoffatomen, die in der StercH-hemie üblicherweise für Veresterungen angewandt rden, ab Diese Carbonsäuren können auch ungesättigt, verzweigt, mehrbasisch oder in üblicher Weise: z. B. durch Hydroxyl-, Amino-, Oxogruppen oder Halogenatome substituiert sein. Geeignet sind auch cycloaliphatische, aromatische, gemischt aromatisch-aliphatische oder heterocyclische Säuren, die ebenfalls in üblicher Weise substituiert sein können. Als bevorzugte Säuren zur Ausbildung des Acylrestes seien beispielsweise genannt: Essigsäure, Propionsäure, Capronsäure, Önanthsäure, Undecylsäure, ölsäure, Tnmethylessigsäure, Halogenessigsäure, Dichloressigsäure, Cyclopentylpropionsäure, Phenylpropionsäure, Phenylessigsäure, Phenoxyessigsäure, Dialkylammoessigsäure, Piperidinoessigsäure, Bernsteinsäure, Benzoesäure u.a. Für die Herstellung wasserlöslicher Präparate kommen insbesondere Ester anorganischer Säuren in Betracht, wie die der Schwefel- und der Phosphorsäure.The acid residues are derived from acids with up to 15 carbon atoms, which are usually used for esterification in steric chemistry. These carboxylic acids can also be unsaturated, branched, polybasic or in the usual way : e.g. B. substituted by hydroxyl, amino, oxo groups or halogen atoms. Cycloaliphatic, aromatic, mixed aromatic-aliphatic or heterocyclic acids, which can likewise be substituted in the usual way, are also suitable. Preferred acids for the formation of the acyl radical are, for example: acetic acid, propionic acid, caproic acid, enanthic acid, undecylic acid, oleic acid, methyl acetic acid, haloacetic acid, dichloroacetic acid, cyclopentylpropionic acid, phenylpropionic acid, phenylacetic acid, phenoxyacetic acid, preparation, benzoic acid, succinic acid, etc., for the preparation of water-soluble benzoic acid, succinic acid, benzoic acid, benzoic acid, dialkylammoacetic acid, oleic acid, enanthic acid, dialkylammoacetic acid, and others In particular, esters of inorganic acids come into consideration, such as those of sulfuric and phosphoric acid.
Die neuen 6/3,7/?-Epoxy-la,2A-melhyIensteroide besitzen wertvolle pharmakologische Eigenschaften. Sie zeigen eine überraschend gestagene Wirksamkeit, besonders nach oraler Verabfolgung. Ein besonderer Vorteil der erfindungsgemäßen Verbindungen liegt darin, daß diese praktisch keine antiandrogene Nebenwirkung besitzen. Überraschenderweise entfalten die neuen Gestagene auch in hohen Dosen keine zentrale Hemmwirkung (Ovulationshemmung).The new 6 / 3.7 /? - Epoxy-la, 2A-melhyIensteroide possess valuable pharmacological properties. They show surprisingly gestagenic effectiveness, especially after oral administration. A particular advantage of the compounds according to the invention lies in that they have practically no anti-androgenic side effects. Surprisingly, the New gestagens do not have a central inhibitory effect even in high doses (inhibition of ovulation).
Die folgende Tabelle zeigt die Überlegenheit der erfindungsgemäßen Verbindungen am Beispiel des 17 - Acetoxy - dßjß - epoxy - 1λ,2λ - methylen - 4 - pregnen-3,20-dions (1). Als Vergleichssubstanz dient das bekannte Gestagen o-Chlor-n-aceloxy^.o-pregnadien-3,20-dion (II).The following table shows the superiority of the compounds according to the invention using the example of 17-acetoxy- dßjß -epoxy-1λ, 2λ-methylene-4-pregnen-3,20-dione (1). The known gestagen o-chloro-n-aceloxy ^ .o-pregnadiene-3,20-dione (II) serves as a comparison substance.
η c Claubcrg-Tcsl
η c
D O Ovulationh
DO
HemmungAnti-androgen test
inhibition
Schwellenwert I '~ ·
Threshold
Dosis V ' "·
dose
Die gestagene Wirkung wurde im üblichen Clauberg-Test geprüft.The gestagenic effect was tested in the usual Clauberg test.
Als Schwellenwert wurde die Gesamtdosis bestimmt, die bei mindestens zwei von drei Kaninchen eine transformatorische Umwandlung des Endomelriums bewirkt.The total dose was determined as the threshold value, which is one in at least two out of three rabbits causes transformational transformation of the endomelrium.
Die Ovulationshemmung wurde durch Tubeninspektion überprüft.The ovulation inhibition was checked by tube inspection.
Zur Bestimmung der antiandrogenen Nebenwirkung erhielten kastrierte männliche Ratten über 7 Tage täglich die Testsubstanz per os (p. o.) verabreicht. Über den gleichen Zeitraum erhielten die Tiere täglich 0,1 mg Testostcronpropionat subcutan. Am 8. Tag wurden die Tiere getötet und die Gewichte der Geschlechtsdrüsen bestimmt. Es wurde die durch die Testsubstanz bewirkte prozentuale Hemmung des Wachstums der Samenblasen (SbI.) und der Prostata (Pr.) ermittelt.To determine the antiandrogenic side effect, castrated male rats were given for 7 days the test substance administered orally (p. o.) daily. The animals received daily for the same period 0.1 mg testostcron propionate subcutaneously. On the 8th day the animals were sacrificed and the weights of the sex glands certainly. The percentage inhibition of the growth of the seminal vesicles (SbI.) And the prostate caused by the test substance was determined (Pr.) Determined.
Das Hauptanwendungsgebiet der erfindungsgemäßen Wirkstoffe iit die Behandlung folgenderThe main field of application of the active ingredients according to the invention is the treatment of the following
i 668 685 Oi 668 685 O
3 43 4
gynäkologischer Störungen: Primäre Amenorrhoe und zweckmäßigerweise mit einem reaktionsfähigen Säure-gynecological disorders: primary amenorrhea and expediently with a reactive acidic
tekundäre Amenorrhoe von längerer Dauer, Zyklus- derivat in Gegenwart basisch« Reagenzien durchge-secondary amenorrhea of longer duration, cycle derivative in the presence of basic «reagents passed through
«törungen bei unzureichender Gelbkörperfunktion, führt Speziell genannt seien der Umsatz mit Säure-«Disorders with inadequate corpus luteum function leads to special mentioning the turnover with acid
Endometriose, .Uterushypoplasie, prämenstruelle Be- anhydrid bzw. -halogenid in Gegenwart von PyridinEndometriosis, uterine hypoplasia, premenstrual anhydride or halide in the presence of pyridine
achwerden und Mastopathie. S in der Hitze.sickness and mastopathy. S in the heat.
Die Dosierung erfolgt entsprechend der Schwere des Die als Ausgangsstoffe des erfindungsgemäßen VerKrankheitsfalles.
Im allgemeinen wird man zwischen fahrens dienenden, in der Literatur bisher nicht be-5
und 100 mg täglich verabfolgen. Die Herstellung der schriebenen 6/3-Hydroxy- bzw. o/i-Acyloxy^a-halogen-Axzneimittelspezialitäten
erfolgt in üblicher Weise, steroide können aus den entsprechenden <de-ungeindem
man die Wirkstoffe mit geeigneten Zusätzen, to sättigten Steroiden hergestellt werden.
Trägersubstanzen und Geschmackskorrigentien zu den So erhält man beispielsweise aus 17-Acyloxyfeandelsüblichen
Applikationsformen verarbeitei. Für la^a-methylen^.o-pregnadien-S^O-dionmitN-Bromdie
orale Applikation kommen insbesondere Tabletten, bzw. N-Chlor-succinimid und Wasser in Gegenwart
Dragees, Kapseln, Pillen, Suspensionen oder Lösungen von Perchlorsäure in Dioxan folgende 60-Hydroxyin
Frage. »5 7«-halogensteroide:The dosage is carried out according to the severity of the die as starting materials of the disease case according to the invention. In general, 5 and 100 mg will be administered daily between those used for driving, which has not yet been found in the literature. The 6/3-hydroxy or o / i-acyloxy ^ a-halogen specialty drugs are produced in the usual way, steroids can be produced from the corresponding <d e -un by using the active ingredients with suitable additives, to saturated steroids .
Carrier substances and taste corrections for the processing, for example, from 17-acyloxyfeandels. For oral administration of la ^ a-methylen ^ .o-pregnadiene-S ^ O-dione with N-bromine, especially tablets or N-chloro-succinimide and water in the presence of coated tablets, capsules, pills, suspensions or solutions of perchloric acid in dioxane are the following 60-hydroxyin question. »5 7« -halogen steroids:
Die Erfindung betrifft außerdem ein Verfahren zur 1χ . Brom. eß .h d _ n _ a(e . χ 2Ä_me_The invention also relates to a method for 1χ . Bromine . eat . hd _ n _ a (e . χ 2Ä _ me _
Herstellung von 17-Hydnwy-und H-Acyloxy-^-ep- thylen-4-pregnen-3,2iWion, F. 185 bis 185,5°C.Production of 17-Hydnwy- and H-acyloxy- ^ - epthylen-4-pregnen-3,2iWion, m.p. 185 to 185.5 ° C.
oxy-l«,2*-methylen-4-pregnen-3 20-dionen, dadurch Ίχ . ßrom . 6ß _ hd _ χη . hexan loxy.oxy-1 «, 2 * -methylene-4-pregnen-3 20-dione, thereby Ίχ . ßrom . 6ß _ hd _ χη . hexane loxy .
gekennze.chnet( daß man 60-Hydroxy- bzw. 6^-Acyl- l«,2«.meÜiylen-4-piegnen-3,2iMion als öl. G ekennze.chnet ( that 60-hydroxy- or 6 ^ -acyl- 1 ", 2" .meÜiylen-4-piegnen-3,2iMion is used as an oil.
oxy-7«-halogenstero.de der allgemeinen Formel ao y^-Chlor-o/J-hydroxy-n-acetoxy-la^-me-oxy-7 «-halogenstero.de of the general formula ao y ^ -Chlor-o / J-hydroxy-n-acetoxy-la ^ -me-
„TJ thyien-4-pregnen-3,20-dion, F. 239 bis 239,5 0C." TJ thyien-4-pregnen-3,20-dione, F. 239 to 239.5 0 C.
CH3 CH 3
j Aus n-Acetoxy-lix^A-methylen^.o-pregnadien-j From n-acetoxy-lix ^ A-methylene ^ .o-pregnadiene-
C-Ci 3,20-dion mit N-Brom- bzw. N-Chlorsuccinimid und C-Ci 3,20-dione with N-bromo- or N-chlorosuccinimide and
as der entsprechenden Carbonsäure in chlorwasserstoffgesättigtem Tetrahydrofuran entstehen beispielsweiseas the corresponding carboxylic acid in saturated hydrogen chloride Tetrahydrofuran is formed, for example
mit Essigsäure:with acetic acid:
7« - Brom - 60,17 - diacetoxy - 1λ,2λ - methylen-30 4-pregnen-3,20-dion, F. 194 bis 195°C.7 "- bromine - 60.17 - diacetoxy - 1λ, 2λ - methylene-30 4-pregnen-3,20-dione, m.p. 194 to 195 ° C.
7« - Chlor - 6/3,17 - diacetoxy - 1«,2λ - methylen-",20-dion, F. 237 bis 238"C.7 "- chlorine - 6 / 3.17 - diacetoxy - 1", 2λ - methylene - ", 20-dione, F. 237 to 238 "C.
OR mit Ameisensäure:OR with formic acid:
35 7«-Brom-6/2-formyloxy-17-acetoxy-l<x,2«-methy-35 7 "-Bromo-6/2-formyloxy-17-acetoxy-1 <x, 2" -methy-
worin R Wasserstoff oder eine Acylgruppe, X Chlor len-4-pregnen-3,20-dion, F. 217 bis 218,5°C.wherein R is hydrogen or an acyl group, X is chlorine-4-pregnen-3,20-dione, mp 217 to 218.5 ° C.
oder Brom und Ac eine Acylgruppe bedeutet, in einem 7*-Chlor-6/?-formyloxy-17-acetoxy-l«,2*-methy-or bromine and Ac is an acyl group, in a 7 * -chloro-6 /? - formyloxy-17-acetoxy-l «, 2 * -methy-
gegen die Reaktionspartner inerten Lösungsmittel mit len-4-pregnen-3,20-dion, F. 247 bis 248 C.Solvent inert to the reactants with len-4-pregnen-3,20-dione, F. 247 to 248 C.
Basen umsetzt und gegebenenfalls eine freie 17-Hy- . 11Reacts bases and optionally a free 17-Hy-. 11th
droxygruppe verestert. 4° e 1 s ρ ι eesterified droxy group. 4 ° e 1 s ρ ι e
Als inerte Lösungsmittel dienen vorzugsweise mit 10,0 g 7»-Brom-6/?-hydroxy-17-acetoxy-la,2a-me-The inert solvents used are preferably 10.0 g of 7 »-Bromo-6 /? - hydroxy-17-acetoxy-la, 2a-me-
Wasser mischbare Lösungsmittel, wie Methanol, thylen-4-pregnen-3,20-dion werden in 200 ml ÄthanolWater-miscible solvents such as methanol, ethylene-4-pregnen-3,20-dione are dissolved in 200 ml of ethanol
Äthanol, Aceton, Tetrahydrofuran, Dimethylsulfoxid und 100 ml Aceton gelöst, mit einer Lösung von 10 gEthanol, acetone, tetrahydrofuran, dimethyl sulfoxide and 100 ml of acetone dissolved with a solution of 10 g
oder Gemische von diesen Lösungsmitteln, wie Kaliumcarbonat und 25 ml Wasser versetzt undor mixtures of these solvents, such as potassium carbonate and 25 ml of water, and
Äthanol mit Aceton. 45 48 Stunden bei 250C gerührt. Danach wird in WasserEthanol with acetone. 45 stirred at 25 ° C. for 48 hours. After that, in water
Als Basen für den erfindungsgemäßen Oxiranring- eingegossen, der Niederschlag abgesaugt, gewaschen,Poured in as bases for the oxirane ring according to the invention, the precipitate is filtered off with suction, washed,
Schluß kommen beispielsweise Alkalimetallcarbonate getrocknet und aus Aceton/Hexan umkristallisiert,Finally, for example, alkali metal carbonates are dried and recrystallized from acetone / hexane,
und -hydrogencarbonate, wie Kaliumcarbonat und Man erhält 7,15 g 17-Acetoxy-6/?,7/5-epoxy-l«,2ft-me-and hydrogen carbonates, such as potassium carbonate and 7.15 g of 17-acetoxy-6 / ?, 7/5-epoxy-1 «, 2ft-me-
Natriumhydrogencarbonat, Alkalimetallhydroxide, wie thyIen-4-pregnen-3,20-dion vom Schmelzpunkt 244 bisSodium hydrogen carbonate, alkali metal hydroxides, such as thyIen-4-pregnen-3,20-dione from melting point 244 to
Kalium- und Natriumhydroxid, Alkalimetallalkoho- 50 245°C. UV: eM0 = 15 800.Potassium and sodium hydroxide, alkali metal alcohol - 50 245 ° C. UV: e M0 = 15,800.
late, wie Kalium-tert.-butylat, u. a. in Frage. Das gleiche 6/?,7|9-Epoxid entsteht analog auslate, such as potassium tert-butoxide, inter alia. in question. The same 6 / ?, 7 | 9 epoxy is produced analogously
Je nach der Stärke der eingesetzten Base und der 7λ-Brom-6/9,17-diacetoxy-l«,2«-methylen-4-pre-Depending on the strength of the base used and the 7λ-bromo-6 / 9,17-diacetoxy-1 «, 2« -methylene-4-pre-
Höhe der Reaktionslemperatur erhält man mehr oder gnen - 3,20 - dion und aus 7« - Brom - 6ß - formyloxy-At the level of the reaction temperature one obtains more or less - 3.20 - dione and from 7 "- bromine - 6ß - formyloxy-
minder große Anteile an Verseifungsprodukt. Durch 17-acetoxy-l«,2*-methylen-4-pregnen-3,20-dion.less large proportions of saponification product. By 17-acetoxy-1 «, 2 * -methylene-4-pregnen-3,20-dione.
geeignete Wahl der Reaktionsbedingungen kann man 55 . . . .a suitable choice of reaction conditions can be found 55. . . .
zu freien oder zu veresterten 17a-Hydroxyverbindun- b e 1 s ρ 1 e lto free or to esterified 17a-hydroxy compounds b e 1 s ρ 1 e l
gen gelangen. So entsteht mit Kaliumcarbonat in Eine Lösung von 1,2 g 7«-Chlor-6/9-hydroxy-17-acet-get gen. So with potassium carbonate in a solution of 1.2 g of 7 "-Chlor-6/9-hydroxy-17-acet-
Äthanol und Aceton bei Raumtemperatur das oxy-l«,2«-methylen-4-pregnen-3,20-dion in 241 Me-Ethanol and acetone at room temperature the oxy-1,2 "-methylene-4-pregnen-3,20-dione in 241 Me-
6/?,7/?-Epoxid mit der unveränderten Acyloxygruppe thanol wird mit 600mg Kaliumcarbonat in 3 ml Wasser6 / ?, 7 /? - epoxy with the unchanged acyloxy group is ethanol with 600mg potassium carbonate in 3 ml water
in 17«-Stcllung. Mit den gleichen Reaktionsmitteln 60 versetzt und 3 Stunden zum Sieden erhitzt. Danachin 17 "position. The same reactants 60 are added and the mixture is heated to the boil for 3 hours. Thereafter
entsteht in der Hitze nach einer Reaktionszeit von etwa wird in Wasser gegossen, der ausgefallene Nieder-arises in the heat after a reaction time of about is poured into water, the precipitated low-
20 Stunden ein Epoxid, dessen 17-Acyloxygruppe schlag abgesaugt, in Methylenchlorid aufgenommen,20 hours an epoxide, the 17-acyloxy group of which is sucked off with suction, taken up in methylene chloride,
weitgehend verseift ist. Mit Kaliumhydroxid als Base mit Wasser gewaschen, getrocknet und im Vakuumis largely saponified. Using potassium hydroxide as the base, washed with water, dried and in vacuo
bildet sich bereits nach kurzer Reaktionszeit bei eingeengt. Nach Chromatographie an Kieselgel wer-forms after a short reaction time when concentrated. After chromatography on silica gel
Raumtemperatur das 6/?,7/?-Epoxid mit der freien 65 den, umkristallisiert aus Isopropyläther, 650 mgRoom temperature the 6 / ?, 7 /? - epoxide with the free 65 den, recrystallized from isopropyl ether, 650 mg
17ix-Hydroxygruppe. 17 - Acetoxy - 6/3,7/8 - epoxy - 1λ,2λ - methylen - 4 - pre-17ix-hydroxy group. 17 - acetoxy - 6 / 3.7 / 8 - epoxy - 1λ, 2λ - methylene - 4 - pre-
Die gewünschtenfalls nachträgliche Veresterung gnen-3,20-dion vom Schmelzpunkt 240 bis 2420C er-If desired, subsequent esterification raising campaigns-3,20-dione of melting point 240-242 0 C ER-
bzw. Reacylierung der 17«-Hydroxygruppe wird halten. UV: ε£40 = 15 000.or reacylation of the 17'-hydroxy group will hold. UV: ε £ 40 = 15,000.
Das gleiche 6/?,7/?-Epoxid entsteht analog aus 7a-Chlor-6/?,17-diacetoxy-la,2a-methylen-4-pregnen-3,20-dion und aus 7«-Chlor-6/?-formylo>;y-17-acetoxyl«,2«-methylen-4-pregnen-3,20-dion The same 6 / ?, 7 /? - epoxy is produced analogously 7a-chloro-6 / ?, 17-diacetoxy-la, 2a-methylene-4-pregnen-3,20-dione and from 7 "-chloro-6 /? - formylo>; y-17-acetoxyl", 2 "-methylene-4-pregnen-3,20-dione
3,0 g Ta-Brom-o^-hydroxy-lT-acetoxy-la.lt-methylen-4-pregnen-3,20-dion werden in 60 ml Äthanol gelöst, mit einer Lösung von 1,5 g Kaliumcarbonat in 7,5 ml Wasser versetzt und 24 Stunden zum Sieden erhitzt. Danach wird in Wasser gegossen, der Niederschlag abgesaugt, gewaschen, getrocknet und aus Aceton/Hexan umkristallisiert. Man erhält l^og 17 - Hydroxy - ββ,Ίβ - epoxy -1«,2« - methylen - 4 - pregnen-3,20-dion vom Schmelzpunkt 280 bis 2830C. UV: ε«, = 15100.3.0 g of Ta-bromo-o ^ -hydroxy-lT-acetoxy-la.lt-methylene-4-pregnen-3,20-dione are dissolved in 60 ml of ethanol, with a solution of 1.5 g of potassium carbonate in 7 , 5 ml of water are added and the mixture is heated to boiling for 24 hours. It is then poured into water, the precipitate is filtered off with suction, washed, dried and recrystallized from acetone / hexane. Obtained l ^ og 17 - hydroxy - ββ, Ίβ - epoxy -1 ', 2' - methylene - 4 - pregnene-3,20-dione of melting point 280-283 0 C. UV: ε "= 15100th
Eine Lösung von 500 mg 7«-Brom-6/?-hydroxy-17-acetoxy-l«,2«-methylen-4-pregnen-3,20-dion in 10 ml Äthanol und 5 ml Aceton versetzt man mit 2,5 ml einer 20%igen wäßrigen Kalilauge und rührt 30 Minuten bei Raumtemperatur. Das Gemisch wird in Wasser eingegossen, die ausgefällte Substanz abgesaugt, mit Wasser gewaschen, im Vakuum getrocknet und aus Aceton/Hexan umkristallisiert. Man erhält 297 mg 17 - Hydroxy - 6ßjß - epoxy -1«,2« - methylen-4-pregnen-3,20-dion vom Schmelzpunkt 279 bis 2810C.A solution of 500 mg of 7 "-Brom-6 /? - hydroxy-17-acetoxy-1", 2 "-methylene-4-pregnen-3,20-dione in 10 ml of ethanol and 5 ml of acetone is mixed with 2, 5 ml of a 20% strength aqueous potassium hydroxide solution and stir for 30 minutes at room temperature. The mixture is poured into water, the precipitated substance is filtered off with suction, washed with water, dried in vacuo and recrystallized from acetone / hexane. This gives 297 mg of 17 - hydroxy - 6ßjß - epoxy -1 ', 2' - methylene-4-pregnene-3,20-dione of melting point 279-281 0 C.
»o Beispiels»O example
1,0 g 7« - Brom - 6ß - hydroxy - 17 - hexanoyloxyl«,2«-methylen-4-pregnen-3,20-dion werden unter den in Beispiel 1 beschriebenen Bedingungen umgesetzt.1.0 g of 7 "- bromine - 6β - hydroxy - 17 - hexanoyloxyl", 2 "-methylene-4-pregnen-3,20-dione are reacted under the conditions described in Example 1.
Das Rohprodukt wird an Kieselgel chromatographiert. Mit 9 bis 11% Aceton/Pentan eluiert man 550 mg 17 - Hexanoyloxy - 6ß,lß - epoxy - 1λ,2α - methylen-4-pregnen-3,20-dion als zähes öl. UV: ε^ = 15 400. Das öl erstarrt nach einiger Zeit zu einer kristallinenThe crude product is chromatographed on silica gel. With 9 to 11% acetone / pentane, 550 mg of 17-hexanoyloxy- 6ß, lß- epoxy-1λ, 2α -methylene-4-pregnen-3,20-dione are eluted as a viscous oil. UV: ε ^ = 15 400. The oil solidifies after some time to a crystalline one
ao Masse, die bei 129 bis 13O0C schmilzt.ao mass, which melts at 129 to 13O 0 C.
Claims (6)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL31038A IL31038A (en) | 1968-01-11 | 1968-11-08 | 17-hydroxy-and 17-acyloxy-6beta,7beta-epoxy-1alpha,2alpha-methylene-4-pregnene-3,20-diones and process for their manufacture |
| FI339668A FI45177C (en) | 1968-01-11 | 1968-11-28 | Process for the preparation of 17-hydroxy- and 17-acyloxy-6beta, 7beta -epoxy-1alpha, 2alpha-methylene-4pregnene-3,20-diones. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1967SC040469 DE1643017B2 (en) | 1967-03-31 | 1967-03-31 | PROCESS FOR THE PRODUCTION OF 6-CHLORO-1,2ALPHA-METHYLENE DELTA HIGH 4,6-PREGNADIENES |
| DESC041823 | 1968-01-11 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1668685A1 DE1668685A1 (en) | 1971-10-07 |
| DE1668685B2 DE1668685B2 (en) | 1974-08-29 |
| DE1668685C3 true DE1668685C3 (en) | 1975-04-24 |
Family
ID=25993457
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1967SC040469 Granted DE1643017B2 (en) | 1967-03-23 | 1967-03-31 | PROCESS FOR THE PRODUCTION OF 6-CHLORO-1,2ALPHA-METHYLENE DELTA HIGH 4,6-PREGNADIENES |
| DE19681668685 Expired DE1668685C3 (en) | 1967-03-31 | 1968-01-11 | 17-Hydroxy- and 17-acyloxy-6 beta, 7 beta-epoxy-1 alpha, 2 alpha-methylene-4-pregnen-3,20-diones, processes for their preparation and agents containing them |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1967SC040469 Granted DE1643017B2 (en) | 1967-03-23 | 1967-03-31 | PROCESS FOR THE PRODUCTION OF 6-CHLORO-1,2ALPHA-METHYLENE DELTA HIGH 4,6-PREGNADIENES |
Country Status (10)
| Country | Link |
|---|---|
| AT (2) | AT279818B (en) |
| BE (1) | BE712938A (en) |
| CH (2) | CH564039A5 (en) |
| DE (2) | DE1643017B2 (en) |
| DK (2) | DK116941B (en) |
| FR (2) | FR1579547A (en) |
| GB (1) | GB1229428A (en) |
| NL (2) | NL156706B (en) |
| NO (1) | NO127535B (en) |
| SE (2) | SE343056B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH545777A (en) * | 1971-02-05 | 1974-02-15 |
-
1967
- 1967-03-31 DE DE1967SC040469 patent/DE1643017B2/en active Granted
-
1968
- 1968-01-11 DE DE19681668685 patent/DE1668685C3/en not_active Expired
- 1968-02-26 DK DK75068A patent/DK116941B/en not_active IP Right Cessation
- 1968-03-06 AT AT220568A patent/AT279818B/en not_active IP Right Cessation
- 1968-03-12 AT AT244668A patent/AT301038B/en not_active IP Right Cessation
- 1968-03-22 DK DK126368A patent/DK116208B/en unknown
- 1968-03-26 CH CH450768A patent/CH564039A5/xx not_active IP Right Cessation
- 1968-03-27 CH CH451568A patent/CH548382A/en not_active IP Right Cessation
- 1968-03-28 NL NL6804394A patent/NL156706B/en not_active IP Right Cessation
- 1968-03-28 NL NL686804395A patent/NL155020B/en unknown
- 1968-03-29 SE SE422068A patent/SE343056B/xx unknown
- 1968-03-29 SE SE422168A patent/SE331839B/xx unknown
- 1968-03-29 FR FR1579547D patent/FR1579547A/fr not_active Expired
- 1968-03-29 BE BE712938D patent/BE712938A/xx unknown
- 1968-04-01 GB GB1229428D patent/GB1229428A/en not_active Expired
- 1968-06-27 FR FR156884A patent/FR7900M/fr not_active Expired
-
1969
- 1969-01-10 NO NO101/69A patent/NO127535B/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BE712938A (en) | 1968-09-30 |
| FR1579547A (en) | 1969-08-29 |
| DE1668685A1 (en) | 1971-10-07 |
| DE1643017B2 (en) | 1976-09-09 |
| AT301038B (en) | 1972-08-25 |
| DK116208B (en) | 1969-12-22 |
| SE331839B (en) | 1971-01-18 |
| DE1668685B2 (en) | 1974-08-29 |
| GB1229428A (en) | 1971-04-21 |
| NL6804395A (en) | 1968-10-01 |
| FR7900M (en) | 1970-05-11 |
| DE1643017A1 (en) | 1971-04-15 |
| CH548382A (en) | 1974-04-30 |
| SE343056B (en) | 1972-02-28 |
| NL156706B (en) | 1978-05-16 |
| NL155020B (en) | 1977-11-15 |
| CH564039A5 (en) | 1975-07-15 |
| DK116941B (en) | 1970-03-02 |
| NL6804394A (en) | 1968-10-01 |
| AT279818B (en) | 1970-03-25 |
| NO127535B (en) | 1973-07-09 |
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| Date | Code | Title | Description |
|---|---|---|---|
| C3 | Grant after two publication steps (3rd publication) | ||
| E77 | Valid patent as to the heymanns-index 1977 |