NO853063L - PROCEDURE FOR THE PREPARATION OF SUBSTITUTED GUANIDINBENZOIC ACID PHENYL ESTERS. - Google Patents
PROCEDURE FOR THE PREPARATION OF SUBSTITUTED GUANIDINBENZOIC ACID PHENYL ESTERS.Info
- Publication number
- NO853063L NO853063L NO853063A NO853063A NO853063L NO 853063 L NO853063 L NO 853063L NO 853063 A NO853063 A NO 853063A NO 853063 A NO853063 A NO 853063A NO 853063 L NO853063 L NO 853063L
- Authority
- NO
- Norway
- Prior art keywords
- acid
- guanidinebenzoic
- ester
- hydrochloride
- acrosin
- Prior art date
Links
- -1 PHENYL ESTERS Chemical class 0.000 title claims description 14
- 239000002253 acid Substances 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- DNOSZYUZVCJLMM-UHFFFAOYSA-N carbamimidoylazanium;benzoate Chemical class NC(N)=[NH2+].[O-]C(=O)C1=CC=CC=C1 DNOSZYUZVCJLMM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims 5
- 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 1
- JEVCWSUVFOYBFI-UHFFFAOYSA-N cyanyl Chemical compound N#[C] JEVCWSUVFOYBFI-UHFFFAOYSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 108090000107 Acrosin Proteins 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- YKUCHDXIBAQWSF-UHFFFAOYSA-N methyl 3-hydroxybenzoate Chemical compound COC(=O)C1=CC=CC(O)=C1 YKUCHDXIBAQWSF-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 102100026041 Acrosin Human genes 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 230000004720 fertilization Effects 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229940122863 Acrosin inhibitor Drugs 0.000 description 4
- 101000998633 Drosophila funebris Male accessory gland serine protease inhibitor Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 210000000287 oocyte Anatomy 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 206010042573 Superovulation Diseases 0.000 description 3
- 230000003509 anti-fertility effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 210000000582 semen Anatomy 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QSZCGGBDNYTQHH-UHFFFAOYSA-N 2,3-dimethoxyphenol Chemical compound COC1=CC=CC(O)=C1OC QSZCGGBDNYTQHH-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229940124558 contraceptive agent Drugs 0.000 description 2
- 239000003433 contraceptive agent Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004899 motility Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical compound OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 description 1
- JJDMDNNJDGIVCG-UHFFFAOYSA-N 3-hydroxy-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(O)=C1 JJDMDNNJDGIVCG-UHFFFAOYSA-N 0.000 description 1
- NGMMGKYJUWYIIG-UHFFFAOYSA-N 3-hydroxybenzamide Chemical compound NC(=O)C1=CC=CC(O)=C1 NGMMGKYJUWYIIG-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 1
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000720330 Homo sapiens Acrosin Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229940008309 acetone / ethanol Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 238000000376 autoradiography Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- YQDHCCVUYCIGSW-LBPRGKRZSA-N ethyl (2s)-2-benzamido-5-(diaminomethylideneamino)pentanoate Chemical compound NC(=N)NCCC[C@@H](C(=O)OCC)NC(=O)C1=CC=CC=C1 YQDHCCVUYCIGSW-LBPRGKRZSA-N 0.000 description 1
- MWSMNBYIEBRXAL-UHFFFAOYSA-N ethyl 3-hydroxybenzoate Chemical compound CCOC(=O)C1=CC=CC(O)=C1 MWSMNBYIEBRXAL-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000009027 insemination Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 210000004340 zona pellucida Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
Description
Oppfinnelsen angår nye, substituerte guanidinbenzo-syrefenylestere, deres anvendelse såvel som fremgangsmåter til fremstilling av dem og av farmasøytiske preparater inne-holdende disse i henhold til patentkravene. The invention relates to new, substituted guanidine benzoic acid phenyl esters, their use as well as methods for producing them and pharmaceutical preparations containing them according to the patent claims.
Arylestere av 4-guanidinbenzosyrer er egnet for en vaginal befruktningshindring (US patent 4 4 23 069)• Aryl esters of 4-guanidinebenzoic acids are suitable for a vaginal fertilization barrier (US patent 4 4 23 069)•
De virker som inhibitor for det for en befruktning essen-sielle enzym akrosin, en innen akrosomet i spermatozoer lokalisert serin-proteinase. Akrosin er avgjørende viktig for den del av befruktningen ved hvilken spermatozoene trenger igjennom Zona pellucida (Oolemma) , de innerste tre skikt som omgir eggcellen. They act as an inhibitor of the essential enzyme acrosin for fertilization, a serine proteinase located within the acrosome in spermatozoa. Acrosin is crucially important for the part of fertilization in which the spermatozoa penetrate through the Zona pellucida (Oolemma), the innermost three layers that surround the egg cell.
Det har nu vist seg at de nye guanidinbenzosyreestere med den generelle formel I It has now been shown that the new guanidine benzoic acid esters of the general formula I
hvor X er hydrogen, en cyanogruppe eller en alkoxygruppe med 1-4 carbonatomer, som f.eks. methoxy-, ethoxy- eller propoxygruppen, og Y er et hydrogenatom, en alkoxy- eller alkoxycarbonylgruppe med 1-4 carbonatomer, som f.eks. methoxy-, ethoxy-, propoxy- eller methoxycarbonyl-, ethoxy-carbonyl-, propoxycarbonylgruppen, eller en -C-NRR'-gruppe where X is hydrogen, a cyano group or an alkoxy group with 1-4 carbon atoms, such as e.g. the methoxy, ethoxy or propoxy group, and Y is a hydrogen atom, an alkoxy or alkoxycarbonyl group with 1-4 carbon atoms, such as e.g. the methoxy, ethoxy, propoxy or methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl group, or a -C-NRR' group
0 0
hvor R og R<1>er et hydrogenatom eller en lavere mettet alkylgruppe med 1-4 carbonatomer som eksempelvis methyl-, ethyl-, propyl- eller i-propylgruppen, idet X og Y ikke samtidig skal være hydrogen, såvel som deres fysiologisk akseptable salter med uorganiske eller organiske syrer, where R and R<1> are a hydrogen atom or a lower saturated alkyl group with 1-4 carbon atoms such as, for example, the methyl, ethyl, propyl or i-propyl group, as X and Y must not simultaneously be hydrogen, as well as their physiologically acceptable salts with inorganic or organic acids,
som f.eks. saltsyre, sitronsyre eller p-toluensulfonsyre, overraskende oppviser en betraktelig sterkere virksomhet overfor de kjente aryl-guanidinbenzoater såvel som like for example. hydrochloric acid, citric acid or p-toluenesulfonic acid, surprisingly exhibit considerably stronger activity against the known aryl-guanidine benzoates as well as
(human)-akrosininhibitor og også som antikonsepsjonsmidler (human)-acrosine inhibitor and also as contraceptives
i dyreforsøk. in animal experiments.
Farmakologiske iakttagelser Pharmacological observations
1. ) Akrosin (- human)- bestemmelse 1. ) Acrosin (- human)- determination
Dette forsøk utgjør den egentlige primærsikting. Den gir et holdepunkt for den inhibitoriske effekt av en forbindelse på enzym (humanakrosin) selv, men tillater ennå ikke noen avgjørelse over den biologiske effektivitet (dvs. hemning av akrosin i det intakte spermium såvel som befruktningshindrende virksomhet) av de undersøkte forbindelser. This attempt constitutes the actual primary screening. It provides a starting point for the inhibitory effect of a compound on the enzyme (human acrosin) itself, but does not yet allow any decision on the biological effectiveness (ie inhibition of acrosin in the intact sperm as well as anti-fertilization activity) of the investigated compounds.
Det ved en sur ekstraksjon av humanspermier utvundne enzym akrosin inkuberes med forskjellige konsentrasjoner av den potensielle inhibitor, og den konsentrasjon bestemmes som fører til en 50%-ig hemning av akrosinaktivitet. Serum-proteinase-akrosinet spalter på fysiologisk vis fortrinnsvis arginin- og lysin-gruppene. Derfor anvendes for in vitro-undersøkelsen for aktivitetsbestemmelse av akrosin en benzoyl-arginin-ethylester som substrat. The enzyme acrosin obtained by acid extraction of human spermatozoa is incubated with different concentrations of the potential inhibitor, and the concentration that leads to a 50% inhibition of acrosin activity is determined. The serum proteinase acrosin physiologically cleaves preferentially the arginine and lysine groups. Therefore, a benzoyl-arginine ethyl ester is used as substrate for the in vitro investigation for activity determination of acrosin.
De målte data (tabell 1) underbygger ikke bare en inhiberende virkning av forbindelsene ifølge oppfinnelsen (nr. 2 til 6) på enzymet akrosin, men underbygger også at deres effektivitet er større enn den tidligere kjente forbindelse nr. 1 som må anses som ledende forbindelse. The measured data (table 1) not only substantiate an inhibitory effect of the compounds according to the invention (no. 2 to 6) on the enzyme acrosin, but also substantiate that their effectiveness is greater than the previously known compound no. 1 which must be considered as a leading compound .
2. ) Gelatinolyse 2. ) Gelatinolysis
Denne prøve er likeledes å anse som en bestanddel av primærundersøkelsen. For den ønskede befruktningshindrende virkning av en akrosininhibitor er det, foruten den egentlige akrosinhemning på det isolerte enzym, av essensiell betydning at en slik inhibitor er i stand til å trenge igjennom plasmaet og den ytre akrosomale membran av et intakt spermium, da akrosin er lokalisert i den indre akrosomale membran. This test is also to be considered a component of the primary examination. For the desired fertility-preventing effect of an acrosin inhibitor, it is, in addition to the actual acrosin inhibition of the isolated enzyme, of essential importance that such an inhibitor is able to penetrate the plasma and the outer acrosomal membrane of an intact sperm, as acrosin is located in the inner acrosomal membrane.
Som særlig egnet for undersøkelsen av denne spesielle problemstilling har gelatinolysemodellen ifølge P. Gaddum og R. Z. Blandau (Science 170: 749 - 751), modifisert ifølge W. B. Schill (Int. J. Andrology 4: 25 - 38) og efter egen utarbeidelse, vist seg. Ved denne metode anvendes det ikke belyste, fikserte og med methylenblått farvede film- plater for autoradiografi, hvis gelatinskikt blir oppløst ved den lytiske aktivitet av akrosin. Som følge derav danner det seg om spermiehodene godt synlige, hvite ringer (såkalt halogendannelse/lysisring). Ved en hemning av akrosin bortfaller dannelsen av disse ringer. The gelatinolysis model according to P. Gaddum and R. Z. Blandau (Science 170: 749 - 751), modified according to W. B. Schill (Int. J. Andrology 4: 25 - 38) and according to their own preparation, has proven to be particularly suitable for the investigation of this particular problem . In this method, non-illuminated, fixed film plates stained with methylene blue are used for autoradiography, the gelatin layer of which is dissolved by the lytic activity of acrosin. As a result, clearly visible white rings form around the sperm heads (so-called halo formation/lysis ring). When acrosin is inhibited, the formation of these rings ceases.
For å undersøke gjennomtrengbarheten av en påvist akrosininhibitor og dermed hemningen av akrosin i det intakte spermium blir humanspermier forinkubert med flere konsentrasjoner av inhibitoren.Derpå blir en aliquot anbragt på To investigate the permeability of a proven acrosin inhibitor and thus the inhibition of acrosin in the intact sperm, human sperm are pre-incubated with several concentrations of the inhibitor. An aliquot is then placed on
de tilsvarende bearbeidede (se ovenfor) gelatinplater anbragt på objektglasset og inkubert i dyrkeskranken i fuktig atmos-fære. Derpå blir under fasekontrastmikroskopet graden av halogendannelse bestemt semikvantitativt. the similarly processed (see above) gelatin plates placed on the slide and incubated in the culture counter in a moist atmosphere. The degree of halogen formation is then determined semi-quantitatively under the phase contrast microscope.
De i tabell 2 angitte farmakologiske resultater av denne prøve underbygger The pharmacological results of this sample given in Table 2 support this
effektiviteten hhv. overlegenheten av anførte forbindelser over den tidligere kjente ledende forbindelse (nr. 1). the efficiency or the superiority of said compounds over the previously known conductive compound (No. 1).
3.) In vitro- befruktning ( mus) 3.) In vitro fertilization (mouse)
Denne prøve tillater en første kontroll av den befruktningshindrende effektivitet såvel som en kontroll av virkeprinsippet i og for seg: I en mediumdråpe ifølge Brinster, Whitten og Whittingham som inneholder inhibitoren, blir så de ved super-ovulering vundne oocytter overført. Derpå blir en aliquot av det ubehandlede musespermium pipettert. Konsentrasjonen av inhibitoren velges slik at ingen hemning av motiliteten foreligger. 24 timer senere blir antallet av de delte og ikke-delte oocytter og dermed befruktningshastigheten bestemt. This test allows a first check of the anti-fertilization effectiveness as well as a check of the working principle in and of itself: In a drop of medium according to Brinster, Whitten and Whittingham containing the inhibitor, the oocytes obtained by super-ovulation are then transferred. An aliquot of the untreated mouse sperm is then pipetted. The concentration of the inhibitor is chosen so that there is no inhibition of motility. 24 hours later, the number of divided and undivided oocytes and thus the fertilization rate are determined.
Det blir også prøvet om akrosininhibitoren som skal undersøkes, anvendt i et system i hvilket det umiddelbart kommer i kontakt med oocytter og sæd, kan hemme befruktning - uten at en hemning av motiliteten av sæden foreligger. It is also tested whether the acrosin inhibitor to be investigated, used in a system in which it immediately comes into contact with oocytes and sperm, can inhibit fertilization - without inhibiting the motility of the sperm.
I tabell 3 er oppført den på grunnlag av denne prøve bestemte befruktningshemmende virkning av forbindelsene ifølge oppfinnelsen, eksempelvis av 2-cyano- hhv. 3-methoxycarbonyl-forbindelsen (nr. 2 hhv. 3) sammenlignet med den tidligere kjente, ledende forbindelse (nr. 1): verdiene viser en tydelig overlegenhet av de nye forbindelser. Table 3 lists the antifertility effect determined on the basis of this test of the compounds according to the invention, for example of 2-cyano- or The 3-methoxycarbonyl compound (no. 2 and 3) compared to the previously known leading compound (no. 1): the values show a clear superiority of the new compounds.
4.) In vivo-befruktning (kaniner) etter kunstig insemin-asjon med preinkubert sæd 4.) In vivo fertilization (rabbits) after artificial insemination with pre-incubated semen
Denne prøve muliggjør angivelse av den befruktningshindrende effektivitet under in vivo-betingelser: Kaninsæd, som utvinnes ved hjelp av en kunstig vagina, preinkuberes med akrosininhibitoren som skal undersøkes. Derpå blir induksjon av en superovulasjon med PMS (pregnant mare serum) forbehandlede hunn-kaniner inseminert kunstig med forbehandlet sæd. Til utløsning av superovulasjon fåes til slutt HCG (human chorionic gonado-tropin). 36 timer senere avlives dyrene, eggledere og uteri taes ut og spyles for å få de tidlige embryoer, hhv. udelte oocytter, og på grunnlag av deres antall bestemmes befruktningshastigheten. This test enables the indication of the anti-fertilization efficiency under in vivo conditions: Rabbit semen, which is extracted by means of an artificial vagina, is preincubated with the acrosin inhibitor to be investigated. Then induction of a superovulation with PMS (pregnant mare serum) is pretreated female rabbits artificially inseminated with pre-treated semen. HCG (human chorionic gonadotropin) is finally obtained to trigger superovulation. 36 hours later, the animals are euthanized, the fallopian tubes and uteri are removed and flushed to obtain the early embryos, respectively. undivided oocytes, and on the basis of their number the fertilization rate is determined.
Også resultatene (se tabell 4) av dette in vivo-forsøk underbygger for forbindelsene ifølge oppfinnelsen anvendt i eksempel på forbindelsene nr. 2 og 3, i sammen-ligning med den ledende forbindelse (nr. 1) en overraskende høy økning av den befruktningshemmende virkning (befrukt-ningsgraden synker fra 51 til 4 hhv. 1%). Also, the results (see table 4) of this in vivo experiment substantiate for the compounds according to the invention used in the example of compounds no. 2 and 3, in comparison with the leading compound (no. 1), a surprisingly high increase of the antifertility effect (the fertilization rate drops from 51 to 4 or 1%).
Bortsett fra det egentlige virkningsprinsipp blir den befruktningshindrende virkning av foreliggende forbindelser som skal patenteres, avgjort avhengig av den egnede formuler-ing . Apart from the actual principle of action, the antifertility effect of the present compounds to be patented is decided depending on the suitable formulation.
For den praktiske anvendelse som legemiddel blir forbindelsene ifølge oppfinnelsen ved i og for seg kjente metoder i galenikken formulert til vaginal-befruktningshindrende midler. For practical use as medicine, the compounds according to the invention are formulated into vaginal contraceptives by methods known per se in galenics.
Som anvendelsesform er geler, kremer, skum, små tapper eller oppløselige filmer, egnet. Foretrukket er anvendelsen av et "langsomt frigjørende" system for å få en vedvarende befruktningshindrende virkning over lengre tid (inntil 24 timer). As a form of application, gels, creams, foams, small drops or soluble films are suitable. The use of a "slow-release" system is preferred in order to obtain a sustained contraceptive effect over a longer period of time (up to 24 hours).
Som hensiktsmessige bærermaterialer som kan benyttes alene eller sammen med egnede oppløsningsmidler som vann og som må gi en lett fordeling av virkestoffet, men som selv ikke må være for flytende, kommer bl.a. polyethylenglycol-derivater som methylcellulose-forbindelser på tale. Suitable carrier materials which can be used alone or together with suitable solvents such as water and which must give an easy distribution of the active ingredient, but which must not be too liquid themselves, include, among other things polyethylene glycol derivatives such as methylcellulose compounds in question.
Konsentrasjonen av virkestoffet ligger i området på 0,1 - 10,0 vekt%. The concentration of the active ingredient is in the range of 0.1 - 10.0% by weight.
For anvendelse på mennesker utgjør doseenheten pr. anvendelse 1-10 mg. For use on humans, the dose unit is per application 1-10 mg.
Frems till ingen... av de ifølge oppfinnelsen anvendte guanidinbenzosyreestere med den generelle formel I skjer ifølge krav 8 etter i og for seg kjente metoder for for-estring av carboxylsyrer. Foretrukket er den ved 0°C - 30°C gjennomførte, ved dicyclohexylcarbodiimid-bevirkede og en sur, som f.eks. p-toluensulfonsyre, og en basisk, som f.eks. pyridin, katalysator påskyndet kondensasjon av fenoler med den generelle formel II None of the guanidine benzoic acid esters of the general formula I used according to the invention are produced according to claim 8 according to methods known per se for the esterification of carboxylic acids. Preferred is the one carried out at 0°C - 30°C, by dicyclohexylcarbodiimide-effected and an acid, such as e.g. p-toluenesulfonic acid, and a basic, such as e.g. pyridine, catalyst accelerated condensation of phenols of the general formula II
hvor X og Y er som angitt i krav 1, med et salt av 4-guani-dinbenzosyre (fortrinnsvis hydrokloridet) i et egnet inert, aprotisk, polart oppløsningsmiddel som eksempelvis dimethylformamid, dimethylacetamid, dimethylsulfoxyd, tetra-hydrofuran, diethylether, methylenklorid, acetonitril eller pyridin. Efter egnet opparbeidelse og rensning (som viktigste biprodukt må N,N'-dicyclohexylurea fjernes) ved konvensjonelle metoder som filtrering, ekstrahering med egnede oppløsningsmidler, såvel som fremfor alt kromato-grafiske skillemetoder blir den ønskede guanidinbenzosyre-ester med den generelle formel I, alt efter reaksjonsfør-ingen, erholdt som frie baser eller som uorganiske eller organiske salter, som f.eks. hydroklorid, citrat eller p-toluensulfonat. Ved for fagmannen kjente metoder og måter kan saltene overføres til de frie baser, hhv. kan de frie baser overføres til salter. where X and Y are as stated in claim 1, with a salt of 4-guanidinebenzoic acid (preferably the hydrochloride) in a suitable inert, aprotic, polar solvent such as, for example, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, diethylether, methylene chloride, acetonitrile or pyridine. After suitable processing and purification (as the most important by-product, N,N'-dicyclohexylurea must be removed) by conventional methods such as filtration, extraction with suitable solvents, as well as above all chromatographic separation methods, the desired guanidine benzoic acid ester with the general formula I becomes, all after the reaction, obtained as free bases or as inorganic or organic salts, such as e.g. hydrochloride, citrate or p-toluenesulfonate. By methods and ways known to the person skilled in the art, the salts can be transferred to the free bases, resp. can the free bases be transferred to salts.
Eksempel 1 Example 1
En blanding av 1,0 g (4,64 mmol) 4-guanidinbenzosyre-hydroklorid, 2,12 g (13,92 mmol) 3-hydroxybenzosyre-methyl-ester og 100 mg (0,58 mmol) vannfri p-toluensulfonsyre om-røres under argon ved 0°C i 4 ml pyridin i 15 timer. Efter tilsetning av 2,87 g (13,92 mmol) dicyclohexylcarbodiimid omrøres i ytterligere 3 dager ved værelsetemperatur, og derpå tilsettes 1 ml iseddik ved 0°C. Efter en røretid på 2 timer ved 0°C frafiltreres faststoff, filtratet tilsettes ca. 25 g is og syres med-5 N saltsyre til pH = 1. Efter underskiktning med 25 ml methylenklorid omrøres i nok 1 time under is-avkjøling og derpå inndampes ved 50°C. Den erholdte olje-krystall-blanding (9,93 g) kromatograferes på silicagel med methylenklorid/methanol/iseddik (80:20:0,1). Derpå omkrystalliseres fra kloroform, hvilket gir 270 mg 4-guanidin-benzosyre-(3-methoxycarbonylfenyl)-ester-hydroklorid med smeltepunkt 194 - 195°C. A mixture of 1.0 g (4.64 mmol) 4-guanidinebenzoic acid hydrochloride, 2.12 g (13.92 mmol) 3-hydroxybenzoic acid methyl ester and 100 mg (0.58 mmol) anhydrous p-toluenesulfonic acid about -stir under argon at 0°C in 4 ml of pyridine for 15 hours. After adding 2.87 g (13.92 mmol) of dicyclohexylcarbodiimide, the mixture is stirred for a further 3 days at room temperature, and then 1 ml of glacial acetic acid is added at 0°C. After a stirring time of 2 hours at 0°C, solids are filtered off, the filtrate is added approx. 25 g of ice and acidify with 5 N hydrochloric acid to pH = 1. After undercoating with 25 ml of methylene chloride, stir for another 1 hour under ice-cooling and then evaporate at 50°C. The resulting oil-crystal mixture (9.93 g) is chromatographed on silica gel with methylene chloride/methanol/glacial acetic acid (80:20:0.1). It is then recrystallized from chloroform, which gives 270 mg of 4-guanidine-benzoic acid-(3-methoxycarbonylphenyl)-ester hydrochloride with a melting point of 194 - 195°C.
Eksempel 2 Example 2
Gjennomføring og anvendte mengder svarende til de i eksempel 1. Det blir imidlertid istedenfor 3-hydroxybenzo-syre-methylesteren anvendt 2,31 g (13,9 2 mmol) 3-hydroxy-benzosyre-ethylester. Den efter inndampning erholdte olje-krystallblanding (12,4 g) kromatograferes på silicagel med methylenklorid/methanol/iseddik (80:10:0,1), og den tilsvarende fraksjon (960 mg) omkrystalliseres fra aceton/ethanol. Man får 330 mg 4-guanidinbenzosyre-(3-ethoxycarbonylfenyl)-ester-hydroklorid med smeltepunkt 137°C. Implementation and amounts used corresponding to those in example 1. However, instead of the 3-hydroxybenzoic acid methyl ester, 2.31 g (13.92 mmol) of 3-hydroxybenzoic acid ethyl ester are used. The oil-crystal mixture obtained after evaporation (12.4 g) is chromatographed on silica gel with methylene chloride/methanol/glacial acetic acid (80:10:0.1), and the corresponding fraction (960 mg) is recrystallized from acetone/ethanol. 330 mg of 4-guanidinebenzoic acid-(3-ethoxycarbonylphenyl)-ester hydrochloride with a melting point of 137°C is obtained.
Eksempel 3 Example 3
Gjennomføring og anvendte mengder svarende til de i eksempel 1. Imidlertid blir det istedenfor 3-hydroxy-benzosyre-methylesteren anvendt 1,66 g (13,92 mmol) 2-hydroxybenzonitril. Den efter inndampning erholdte olje-krystallblanding (12,55 g) kromatograferes på silicagel med methylenklorid/methanol/iseddik (90:10:0,1), og den tilsvarende fraksjon omkrystalliseres fra 15 ml kloroform. Man får 960 mg 4-guanidinbenzosyre-(2-cyanfenyl)-ester-hydroklorid med smeltepunkt 178°C. Implementation and quantities used correspond to those in example 1. However, instead of the 3-hydroxybenzoic acid methyl ester, 1.66 g (13.92 mmol) of 2-hydroxybenzonitrile is used. The oil-crystal mixture obtained after evaporation (12.55 g) is chromatographed on silica gel with methylene chloride/methanol/glacial acetic acid (90:10:0.1), and the corresponding fraction is recrystallized from 15 ml of chloroform. 960 mg of 4-guanidinebenzoic acid (2-cyanophenyl) ester hydrochloride with a melting point of 178°C is obtained.
Eksempel 4 Example 4
Gjennomføring og anvendte mengder svarer til dem i eksempel 1. Imidlertid anvendes istedenfor 3-hydroxybenzo-syre-methylester 2,15 g (13,92 mmol) 2,3-dimethoxyfenol. Den efter inndampning erholdte olje (4,46 g) kromatograferes på silicagel med methylenklorid/methanol/isedik (8:2:1), og den tilsvarende fraksjon på 750 mg digreres efter hverandre med 70 ml ethanol/methylenklorid (1:1) og 10 ml methylenklorid ved værelsetemperatur. Efter avsugning fåes 24 5 mg 4-guanidinbenzosyre-(2,3-dimethoxyfenyl)-ester-hydroklorid med smeltepunkt 197 - 201°C (spaltning). Implementation and amounts used correspond to those in example 1. However, instead of 3-hydroxybenzoic acid methyl ester, 2.15 g (13.92 mmol) of 2,3-dimethoxyphenol are used. The oil obtained after evaporation (4.46 g) is chromatographed on silica gel with methylene chloride/methanol/glacial acetic acid (8:2:1), and the corresponding fraction of 750 mg is successively digested with 70 ml ethanol/methylene chloride (1:1) and 10 ml methylene chloride at room temperature. After extraction, 24 5 mg of 4-guanidinebenzoic acid-(2,3-dimethoxyphenyl)-ester hydrochloride with melting point 197 - 201°C (decomposition) is obtained.
Eksempel 5 Example 5
Gjennomføring og anvendte mengder svarer til dem i eksempel 1. Imidlertid anvendes istedenfor 3-hydroxybenzo-syre-methylesteren 1,91 g (13,92 mmol) 3-hydroxybenzamid. Efter behandling med 5 N saltsyre og underskiktning med methylenklorid blir det utfelte faststoff (820 mg) avsuget og utkokt med 17 ml kloroform. Ved filtrering fåes 530 mg 4-guanidinbenzosyre-(3-carbamoylfenyl)-ester-hydroklorid med smeltepunkt 104 - 105°C. Implementation and amounts used correspond to those in example 1. However, instead of the 3-hydroxybenzoic acid methyl ester, 1.91 g (13.92 mmol) of 3-hydroxybenzamide is used. After treatment with 5 N hydrochloric acid and undercoating with methylene chloride, the precipitated solid (820 mg) is filtered off with suction and boiled with 17 ml of chloroform. By filtration, 530 mg of 4-guanidinebenzoic acid-(3-carbamoylphenyl)-ester hydrochloride with a melting point of 104 - 105°C is obtained.
Eksempel 6 Example 6
Gjennomføring og anvendte mengder svarer til dem i eksempel 1. Imidlertid anvendes istedenfor 3-hydroxybenzo-syre-methylesteren 1,81 g (12,00 mmol) 3-hydroxy-N-methyl-benzamid. Efter behandling med 5 N saltsyre ekstraheres med methylenklorid. Vannfasen blir efter nøytralisasjon med natriumhydrogencarbonat inndampet, og det gjenblivende, faste residuum utrøres efter hverandre med 300 ml ethanol og 150 ml isopropanol. Implementation and amounts used correspond to those in example 1. However, instead of the 3-hydroxybenzoic acid methyl ester, 1.81 g (12.00 mmol) of 3-hydroxy-N-methyl-benzamide is used. After treatment with 5 N hydrochloric acid, extract with methylene chloride. After neutralization with sodium bicarbonate, the water phase is evaporated, and the remaining solid residue is stirred successively with 300 ml of ethanol and 150 ml of isopropanol.
De forenede filtrater inndampes, det oljeaktige residuum (2,40 g) kromatograferes på silicagel med methylenklorid/ethanol (1:1), og den tilsvarende fraksjon om krystalliseres fra 30 ml isopropanol. Man får 330 mg 4-guanidinbenzosyre-(3-methylcarbamoylfenyl)-ester-hydroklorid med smeltepunkt 194,5 - 195,6°C (spaltning). The combined filtrates are evaporated, the oily residue (2.40 g) is chromatographed on silica gel with methylene chloride/ethanol (1:1), and the corresponding fraction is crystallized from 30 ml of isopropanol. 330 mg of 4-guanidinebenzoic acid (3-methylcarbamoylphenyl) ester hydrochloride with a melting point of 194.5 - 195.6°C (decomposition) is obtained.
Claims (10)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843429114 DE3429114A1 (en) | 1984-08-03 | 1984-08-03 | SUBSTITUTED GUANIDINOBENZOESAEUREPHENYLESTER, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO853063L true NO853063L (en) | 1986-02-04 |
Family
ID=6242556
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO853063A NO853063L (en) | 1984-08-03 | 1985-08-02 | PROCEDURE FOR THE PREPARATION OF SUBSTITUTED GUANIDINBENZOIC ACID PHENYL ESTERS. |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0170180A1 (en) |
| JP (1) | JPS6143151A (en) |
| CN (1) | CN85104997A (en) |
| DE (1) | DE3429114A1 (en) |
| DK (1) | DK341685A (en) |
| ES (1) | ES8604121A1 (en) |
| FI (1) | FI852676L (en) |
| GR (1) | GR851900B (en) |
| NO (1) | NO853063L (en) |
| PT (1) | PT80906A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4843094A (en) * | 1985-11-12 | 1989-06-27 | Ono Pharmaceutical Co., Ltd. | Derivatives of p-guantidinobenzoic acid and pharmaceutical agents containing them as active ingredient |
| JPH0764801B2 (en) * | 1985-11-12 | 1995-07-12 | 小野薬品工業株式会社 | p-guanidinobenzoic acid phenyl ester derivative |
| DE3681408D1 (en) * | 1985-11-12 | 1991-10-17 | Ono Pharmaceutical Co. Ltd., Osaka, Jp | |
| US5247084A (en) * | 1985-11-12 | 1993-09-21 | Ono Pharmaceutical Co., Ltd. | Derivatives of p-guanidinobenzoic acid |
| JP5010713B2 (en) * | 2010-05-19 | 2012-08-29 | 住友化学株式会社 | Method for producing camostat hydrochloride |
| CN114805141A (en) * | 2021-01-27 | 2022-07-29 | 中国科学院上海药物研究所 | 4-guanidinobenzoic acid aryl ester compound and application thereof in resisting SARS-CoV-2 virus |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2044760B (en) * | 1979-03-01 | 1983-03-23 | Ono Pharmaceutical Co | Guanidinobenzoic acid derivatives |
| JPS5634662A (en) * | 1979-08-31 | 1981-04-06 | Ono Pharmaceut Co Ltd | Guanidinobenzoic acid derivative and its preparation |
| US4423069A (en) * | 1982-01-20 | 1983-12-27 | University Of Illinois Foundation | Contraceptive method |
-
1984
- 1984-08-03 DE DE19843429114 patent/DE3429114A1/en not_active Withdrawn
-
1985
- 1985-07-01 CN CN198585104997A patent/CN85104997A/en active Pending
- 1985-07-05 FI FI852676A patent/FI852676L/en not_active Application Discontinuation
- 1985-07-20 EP EP85109112A patent/EP0170180A1/en not_active Withdrawn
- 1985-07-26 DK DK341685A patent/DK341685A/en not_active Application Discontinuation
- 1985-08-01 ES ES545805A patent/ES8604121A1/en not_active Expired
- 1985-08-02 NO NO853063A patent/NO853063L/en unknown
- 1985-08-02 GR GR851900A patent/GR851900B/el unknown
- 1985-08-02 PT PT80906A patent/PT80906A/en unknown
- 1985-08-02 JP JP60169943A patent/JPS6143151A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DK341685A (en) | 1986-02-04 |
| JPS6143151A (en) | 1986-03-01 |
| CN85104997A (en) | 1986-12-31 |
| ES8604121A1 (en) | 1986-02-01 |
| FI852676L (en) | 1986-02-04 |
| ES545805A0 (en) | 1986-02-01 |
| EP0170180A1 (en) | 1986-02-05 |
| DE3429114A1 (en) | 1986-02-13 |
| DK341685D0 (en) | 1985-07-26 |
| PT80906A (en) | 1985-09-01 |
| FI852676A0 (en) | 1985-07-05 |
| GR851900B (en) | 1985-12-02 |
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