DK143128B - ANALOGY PROCESSING & TASTING FOR PREPARATION OF 1-ARYLOXY-2-HYDROXY-3-ALKYLAMINOPROPANES OR THEIR PHYSIALLY ACCEPTABLE ACID ADDITION SALTS - Google Patents
ANALOGY PROCESSING & TASTING FOR PREPARATION OF 1-ARYLOXY-2-HYDROXY-3-ALKYLAMINOPROPANES OR THEIR PHYSIALLY ACCEPTABLE ACID ADDITION SALTS Download PDFInfo
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Description
1 A31281 A3128
Den foreliggende opfindelse angår en analogi-fremgangsmåde til fremstilling af hidtil ukendte race-miske eller optisk aktive l-aryloxy-2-hydroxy-3-alkynyl-aminopropaner eller deres fysiologisk acceptable syre-5 additionssalte.The present invention relates to an analogous process for the preparation of novel racemic or optically active 1-aryloxy-2-hydroxy-3-alkynylaminopropanes or their physiologically acceptable acid addition salts.
De omhandlede forbindelser har den i krav 1 14 5 angivne almene formel I, hvori symbolerne R , R og R har de i kravet angivne betydninger.The compounds of the invention have the general formula I as claimed in claim 14, wherein the symbols R, R and R have the meanings specified in the claim.
De omhandlede forbindelser fremstilles ifølge 10 opfindelsen ved en af de i krav 1 angivne fremgangsmåder a)-c) : a) Omsætning af en forbindelse med den i krav 1 angivne almene formel II, hvori R^ har den for formel I angivne betydning, og z betegner gruppen -CH-CEL eller x σ 15 -CHOH-C^-Hal (Hal = halogen), med en amin med den i krav 1 angivne almene formel III, hvori R^ og R^ har de for formel I angivne betydninger.The present compounds are prepared according to the invention by one of the processes a) -c) as defined in claim 1: a) Reaction of a compound of the general formula II according to claim 1, wherein R 1 is as defined for formula I, and z represents the group -CH-CEL or x σ 15 -CHOH-C 2 -Hal (Hal = halogen), with an amine of the general formula III set forth in claim 1 wherein R 1 and R 2 have the meanings given for formula .
b) Hydrolyse af et oxazolidinderivat med den i krav 14 5 1 angivne formel VI, hvori R , R og R har den for 20 formel I angivne betydning, og X betegner en -CO-, -C^- eller -CH- lavere alkyl-gruppe, f.eks. med natrium- eller kaliumhydroxidopløsning i vand eller i en alkohol-vand-blanding.b) Hydrolysis of an oxazolidine derivative of the formula VI as claimed in claim 14, wherein R, R and R are as defined for formula I and X is a -CO-, -C 2 - or -CH- lower alkyl group, e.g. with sodium or potassium hydroxide solution in water or in an alcohol-water mixture.
c) Til fremstilling af sådanne forbindelser med den 2 5 almene formel I, hvori R^ betegner en CN-gruppe:c) For the preparation of such compounds of the general formula I wherein R 1 represents a CN group:
Indføring af en CN-gruppe i forbindelser med den i krav 4 5 1 angivne almene formel IX, hvori R og R har den for formel I angivne betydning, og Y betegner en aminogrup-pe eller halogen. Dette kan i det tilfælde, at Y beteg-30 ner en aminogruppe, ske ved diazotering og kogning i nærværelse af cyanider, såsom KCN, og i det tilfælde, at Y betegner halogen, ved omsætning med Cu(I)CN, fortrinsvis i et højt kogende opløsningsmiddel.Introduction of a CN group into compounds of the general formula IX as claimed in claim 4, wherein R and R are as defined for formula I and Y is an amino group or halogen. This may occur in the case that Y represents an amino group by diazotization and boiling in the presence of cyanides, such as KCN, and in the case that Y represents halogen, by reaction with Cu (I) CN, preferably in a high boiling solvent.
De til udførelse af fremgangsmåderne a) til c) 3 nødvendige udgangsmaterialer er til dels kendte, dels kan de fremstilles på i og for sig kendt måde. Således kan epoxiderne med formlen II let fremstilles ved omsætning med en passende phenol eller et passende pheno- 143128 2 lat med formlen R1The starting materials necessary for carrying out processes a) to c) are partly known and partly can be prepared in a manner known per se. Thus, the epoxides of formula II can be readily prepared by reaction with a suitable phenol or a suitable phenol of formula R1
^V_OKt X^ V_OKt X
' 5 hvori R^ har den ovenfor angivne betydning, og Kt betyder hydrogen eller en kation (f.eks. en alkalimetal-kation). Epoxiderne kan på deres side benyttes til fremstilling af yderligere udgangsmaterialer, f.eks.Wherein R 1 is as defined above and K 1 is hydrogen or a cation (e.g., an alkali metal cation). The epoxides, in turn, can be used to prepare additional starting materials, e.g.
10 kan halogenhydrinerne med formel II fremstilles ved omsætning af epoxiderne med den pågældende halogenbrin-tesyre.10, the halohydrins of formula II can be prepared by reacting the epoxides with the appropriate hydrochloric acid.
Aminer med formel III er kendte og udgør for størstedelen handelsprodukter.Amines of formula III are known and constitute for the most part commercial products.
15 Oxazolidinonerne med formlen VI (dvs. forbindel ser, hvori X = CO) kan f.eks. fremstilles ud fra epoxiderne med formlen II, idet man omsætter disse med en (udfra chlormyresyreethylester og en amin med formlen II fremstillelig) urethan med formlen 4The oxazolidinones of formula VI (i.e., compounds in which X = CO) can e.g. are prepared from the epoxides of formula II, reacting them with a (from chloroformic acid ethyl ester and an amine of formula II) urethane of formula 4
20 R20 R
iin
HCeC-HN-C-OC-H,- XIIIHCeC-HN-C-OC-H, - XIII
I II 2 5 R_ OI II 2 5 R_ O
4 5 hvori R og R har den ovenfor angivne betydning.Wherein R and R are as defined above.
Forbindelserne med formlen IX indeholder alle-25 rede det færdige l-phenoxy-2-hydroxy-3-alkynylaminopro-pan-skelet og kan derfor, idet man går ud fra den tilsvarende phenol, fremstilles analogt med den ovenfor beskrevne fremgangsmåde a) over den tilsvarende 1-phe-noxy-2,3-epoxypropan (der kan fremstilles ud fra den 30 nævnte phenol ved reaktion med epichlorhydrin) ved omsætning med en alkynylamin med formlen III.The compounds of formula IX already contain the final 1-phenoxy-2-hydroxy-3-alkynylaminopropane backbone and can therefore, starting from the corresponding phenol, be prepared analogously to the process described above a) above the corresponding 1-pheoxy-2,3-epoxypropane (which can be prepared from the said phenol by reaction with epichlorohydrin) by reaction with an alkynylamine of formula III.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser har et asymmetrisk C-atom i CHOH-gruppen og forekommer derfor som racemat såvel som i 35 form af de optiske antipoder. Disse kan, foruden ved racematspaltning med sædvanlige hjælpesyrer, såsom dibenzoyl- (eller di-p-toluyl-) D-vinsyre eller D-3-bromkamfer-8-sulfonsyre, også opnås ved at man går ud 143128 3 fra et optisk aktivt udgangsmateriale.The compounds prepared by the process of the invention have an asymmetric C atom in the CHOH group and therefore appear as racemates as well as in the form of the optical antipodes. These, in addition to racemate cleavage with conventional auxiliary acids such as dibenzoyl (or di-p-toluyl) D-tartaric acid or D-3-bromo-camphor-8-sulfonic acid, can also be obtained by starting from an optically active starting material .
De omhandlede l-phenoxy-2-hydroxy-3-alkynylami-nopropaner med formlen I kan på sædvanlig måde overføres i deres fysiologisk acceptable syreadditions-5 salte. Egnede syrer er f.eks. saltsyre, brombrinte- syre, svovlsyre, methansulfonsyre, maleinsyre, eddikesyre, oxalsyre, mælkesyre, vinsyre eller 8-chlortheo-phyllin.The present 1-phenoxy-2-hydroxy-3-alkynylaminopropanes of Formula I can be transferred in their usual manner in their physiologically acceptable acid addition salts. Suitable acids are e.g. hydrochloric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, acetic acid, oxalic acid, lactic acid, tartaric acid or 8-chlorotheophylline.
Forbindelserne med den almene formel I og deres 10 fysiologisk acceptable syreadditionssalte har ved dyreforsøg med marsvin vist værdifulde terapeutiske egenskaber, især β-adrenolytiske egenskaber, og kan derfor anvendes i medicinen f.eks. til behandling eller prophylaxis af sygdomme i hjertekransårerne og 15 til behandling af hjertearrhytmier, især af tachycar-dier. Også forbindelsernes blodtryksænkende egenskaber er terapeutisk interessante. Forbindelserne har i forhold til kendte β-receptor-blokerere, f.eks. handelsproduktet 1-(1-naphthyloxy)-2-hydroxy-3-iso-20 propylaminopropan (Propranolol) den fordel, at de er betydeligt mindre toksiske og har en overlegen virkning.The compounds of general formula I and their physiologically acceptable acid addition salts have shown valuable therapeutic properties in animal experiments with guinea pigs, especially β-adrenolytic properties, and can therefore be used in the medicine e.g. for the treatment or prophylaxis of coronary artery disease and for the treatment of cardiac arrhythmias, especially of tachycardia. The compounds' blood pressure lowering properties are also therapeutically interesting. The compounds have, relative to known β-receptor blockers, e.g. the commercial product 1- (1-naphthyloxy) -2-hydroxy-3-iso-propylaminopropane (Propranolol) has the advantage of being significantly less toxic and having a superior effect.
Især sådanne forbindelser med den almene formel 4 5 I, hvori både R og R betegner en methylgruppe (sub-25 stituerede l-phenoxy-3-(l,l-dimethyl-2-propynyl- amino-1)-2-propanoler), har herved vist sig værdifulde.Especially such compounds of general formula I, wherein both R and R represent a methyl group (substituted 1-phenoxy-3- (1,1-dimethyl-2-propynylamino-1) -2-propanols) , has proved valuable in this.
Blandt de foretrukne betydninger for R^ skal især alkenyl (f.eks. allyl) og alkynyl (f.eks. ethy-30 nyl og propynyl) og cyan fremhæves, især når de står i 2-stilling til propanolamin-sidekæden. Vigtige enkelte forbindelser er især 1-(2-cyano-phenoxy)-3-(1,1-dimethyl-2-propynylamino-l)-2-propanol og l-(2-ethy-nylphenoxy)-3-(1,l-dimethyl-2-propynylamino-l)-2-pro-35 panol, 1-(2-allyl-phenoxy)-3-(1,l-dimethyl-2-propynyl-anino-1)-2-propanol og 1-(3-chlorphenoxy)-3-(1,1-di-methyl-2-propynylamino-l)-2-propanol og deres fysiologisk acceptable syreadditionssalte.In particular, among the preferred meanings for R 1, alkenyl (e.g., allyl) and alkynyl (e.g., ethynyl and propynyl) and cyan should be highlighted, especially when in the 2-position to the propanolamine side chain. Most important single compounds are in particular 1- (2-cyano-phenoxy) -3- (1,1-dimethyl-2-propynylamino-1) -2-propanol and 1- (2-ethynylphenoxy) -3- (1, 1-dimethyl-2-propynylamino-1) -2-propanol, 1- (2-allyl-phenoxy) -3- (1,1-dimethyl-2-propynylamino-1) -2-propanol and 1- (3-Chlorophenoxy) -3- (1,1-dimethyl-2-propynylamino-1) -2-propanol and their physiologically acceptable acid addition salts.
4 U31284 U3128
Enkeltdosis for de omhandlede forbindelser ligger ved 1-300 mg, fortrinsvis 5-100 mg (oralt) og 1-20 mg (parenteralt).The single dose of the subject compounds is at 1-300 mg, preferably 5-100 mg (orally) and 1-20 mg (parenterally).
Fremgangsmåden ifølge opfindelsen belyses nærme-5 re gennem de følgende eksempler.The process of the invention is further elucidated by the following examples.
Eksempel 1 1- (2-Allylphenoxy)-3-(1,l-dimethyl-2-propynylamino-l)- 2- propanoloxalat (efter fremgangsmåde a)).Example 1 1- (2-Allylphenoxy) -3- (1,1-dimethyl-2-propynylamino-1) -2-propanol oxalate (according to process a)).
9.5 g (0,05 mol 1-(2-allylphenoxy)-2,3-epoxy-10 propan opløses i 60 ml methanol, der tilsættes 8,3 g (0,1 mol) l,l-dimethyl-2-propyn-amin-l og opvarmes i 3 timer til kogning under tilbagesvaling. Efter af-destillation af opløsningsmidlet opløses den basiske remanens i acetone, og der tilsættes en opløsning af 6 g 15 oxalsyre i acetone. Det krystallinske oxalat, der udskilles, omkrystalliseres endnu en gang af acetone.Dissolve 9.5 g (0.05 mole of 1- (2-allylphenoxy) -2,3-epoxy-propane in 60 ml of methanol, adding 8.3 g (0.1 mole) of 1,1-dimethyl-2-propyne -amine-1 and heated for 3 hours to reflux. After distillation of the solvent, the basic residue is dissolved in acetone and a solution of 6 g of oxalic acid in acetone is added. of acetone.
Udbytte: 4,7 g, Smp.:114-146°C.Yield: 4.7 g, mp: 114-146°C.
Eksempel 2 1-(2-Cyanophenoxy)-3-(l,l-dimethyl-2-propynylamino-l)-20 2-propanol · HC1 (efter fremgangsmåde a)).Example 2 1- (2-Cyanophenoxy) -3- (1,1-dimethyl-2-propynylamino-1) -20 2-propanol · HCl (according to process a)).
17.5 g (0,1 mol) 1-(2-cyanophenoxy)-2,3-epoxy-propan opløses i 130 ml ethanol og efter tilsætning af 16,6 g (0,2 mol) l,l-dimethyl-2-propyn-amin-l opvarmes i 2 timer til kogning under tilbagesvaling. Opløsnings- 25 midlet afdestilleres, den tilbageværende remanens syr-nes med HC1 og udrystes. Efter frasugning af uopløseligt stof gøres filtratet alkalisk med NaOH, den udfældende base opløses i chloroform og den organiske fase tørres efter fraskillelse over Na2SO^. Efter filtrering af-30 destilleres chloroformen og remanensen omkrystalliseres af eddikeester under tilsætning af petroleumsether.17.5 g (0.1 mole) of 1- (2-cyanophenoxy) -2,3-epoxy-propane are dissolved in 130 ml of ethanol and after addition of 16.6 g (0.2 mole) of 1,1-dimethyl-2 propynamine-1 is heated for 2 hours to reflux. The solvent is distilled off, the residue is acidified with HCl and shaken. After suction of insoluble matter, the filtrate is made alkaline with NaOH, the precipitated base is dissolved in chloroform and the organic phase is dried after separation over Na 2 SO 4. After filtration, the chloroform is distilled off and the residue is recrystallized from vinegar ester with the addition of petroleum ether.
Basen opløses i acetonitril og syrnes med alkoholisk HC1. Hydrochloridet udkrystalliserer farveløst.The base is dissolved in acetonitrile and acidified with alcoholic HCl. The hydrochloride crystallizes colorlessly.
Udbytte: 13,9 g (rent stof ifølge tyndtlagschromato-35 gram). Smp.: 169-171°C.Yield: 13.9 g (pure material according to thin layer chromatograms). Mp: 169-171 ° C.
143128 5 I analogi med eksemplerne 1 og 2 blev følgende forbindelser med formlen I fremstillet ved fremgangsmåde a), dvs. ved reaktion med den på passende måde substituerede l-phenoxy-2,3-epoxypropan med formel II 5 med den ønskede amin med formlen III i ethanol:By analogy to Examples 1 and 2, the following compounds of formula I were prepared by process a), i. by reaction with the appropriately substituted 1-phenoxy-2,3-epoxypropane of formula II 5 with the desired amine of formula III in ethanol:
Tabel 1 4 5 R R R Smp. af HCl-sal- tet, såfremt andet ikke er _angivet_Table 1 4 5 R R R Mp. of the HCl salt, unless otherwise stated
10 2-CN C2H5 C2H5 170-171°C2-CN C2H5 C2H5 170-171 ° C
2-CH2-CH=CH2 C2H5 C2H5 128-129°C2-CH2-CH = CH2 C2H5 C2H5 128-129 ° C
2- Br CH3 CH3 138-139°C2- Br CH3 CH3 138-139 ° C
4-CN CH3 CH3 194-196°C4-CN CH3 CH3 194-196 ° C
2-C5CH CH3 CH3 165-167°C2-C5CH CH3 CH3 165-167 ° C
15 2-C1 CH3 CH3 170-171°C2-C1 CH3 CH3 170-171 ° C
3- C1 CH3 CH3 142-144°C3- C1 CH3 CH3 142-144 ° C
2- CN CH3 CH3 176-177°C2- CN CH3 CH3 176-177 ° C
3- Br CH, CH, 183-185°C3- Br CH, CH, 183-185 ° C
(dihydrochlorid)(Dihydrochloride)
2Q 2-CSC-CH3 CH3 CH3 164-166°C2Q 2-CSC-CH3 CH3 CH3 164-166 ° C
2-C1 CH3 CH3 150-151°C2-C1 CH3 CH3 150-151 ° C
2-CN CH3 CH3 56-59°C (base)2-CN CH3 CH3 56-59 ° C (base)
Eksempel 3 1-(2-Cyanophenoxy)-3-(1,l-dimethyl-2-propynylamino-l)-25 2-propanol · HC1 (ifølge fremgangsmåde b).Example 3 1- (2-Cyanophenoxy) -3- (1,1-dimethyl-2-propynylamino-1) -25 2-propanol · HCl (according to process b).
2,84 g (0,01 mol) 3-(l,l-dimethyl-2-propynyl-l)- 5-(2-cyanophenoxymethyl)-oxazolidin-2-on opvarmes i 3 timer til kogning under tilbagesvaling i 20 ml ethanol efter tilsætning af 3 g KOH i 6 ml H20. Efter af-30 destillation af opløsningsmidlet digereres remanensen med Η2<0 og ekstraheres med chloroform. Chloroformopløsningen udrystes derpå med fortyndet HC1 og den fraskilte vandige fase gøres alkalisk med NaOH. Den udfældede base optages i chloroform og den organiske fase 35 vaskes med H20 og tørres over Na2SO^. Efter filtrering afdestilleres chloroform, og remanensen krystalliseres 143128 6 af eddikeester under tilsætning af petroleumsether.2.84 g (0.01 mole) of 3- (1,1-dimethyl-2-propynyl-1) - 5- (2-cyanophenoxymethyl) oxazolidin-2-one is heated for 3 hours to reflux in 20 ml ethanol after adding 3 g of KOH in 6 ml of H2 O. After distilling off the solvent, the residue is digested with Η2 <0 and extracted with chloroform. The chloroform solution is then shaken with dilute HCl and the separated aqueous phase is made alkaline with NaOH. The precipitated base is taken up in chloroform and the organic phase 35 is washed with H 2 O and dried over Na 2 SO 4. After filtration, chloroform is distilled off and the residue is crystallized by vinegar ester with the addition of petroleum ether.
Udbytte: 1,3 g. Snip.: 84-86°C (base). Blandings smeltepunkt med autentisk stof: 83-85°C.Yield: 1.3 g. Snip: 84-86 ° C (base). Melting point with authentic substance: 83-85 ° C.
Eksempel 4 5 1-(2-Cyanophenoxy)-3-(l,l-dimethyl-2-propynylamino-l)- 2-propanol · HC1 (ifølge fremgangsmåde c).Example 4 1- (2-Cyanophenoxy) -3- (1,1-dimethyl-2-propynylamino-1) -2-propanol · HCl (according to process c).
0,697 g (0,002 mol) 1-(2-bromphenoxy)-3-(1,1-dimethyl-2-propynyl-amino-l)-2-propanol-hydrochlorid blandes med 0,376 g (0,0042 mol) Cu(I)CN og 0,4 g 10 dimethylformamid og opvarmes i 2 timer til 190°C. Efter afkøling digereres med ^0 og gøres alkalisk med NaOH.0.697 g (0.002 mol) of 1- (2-bromophenoxy) -3- (1,1-dimethyl-2-propynylamino-1) -2-propanol hydrochloride are mixed with 0.376 g (0.0042 mol) of Cu (I). CN and 0.4 g of dimethylformamide and heated for 2 hours to 190 ° C. After cooling, digest with ^ 0 and make alkaline with NaOH.
De basiske dele optages i chloroform og vaskes med vand. Chloroformen afdestilleres, og remanensen renses over en kiselgelsøjle. Den således vundne rene base opløses 15 i acetonitril og syrnes med alkoholisk HC1. Hydrochlo-ridet udkrystalliserer farveløst. Smp.: 168-171°C.The basic parts are taken up in chloroform and washed with water. The chloroform is distilled off and the residue is purified over a silica gel column. The pure base thus obtained is dissolved in acetonitrile and acidified with alcoholic HCl. The hydrochloride crystallizes colorlessly. Mp: 168-171 ° C.
Claims (5)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2309887 | 1973-02-28 | ||
| DE2309887A DE2309887C2 (en) | 1973-02-28 | 1973-02-28 | 1-aryloxy-2-hydroxy-3-alkynylaminopropane derivatives and their physiologically acceptable acid addition salts, pharmaceutical preparations and manufacturing processes for the compounds |
| DE19742403809 DE2403809C2 (en) | 1974-01-26 | 1974-01-26 | 1-Aryloxy-2-hydroxy-3-alkynylaminopropanes and processes for their manufacture and pharmaceutical preparations |
| DE2403809 | 1974-01-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK143128B true DK143128B (en) | 1981-06-29 |
| DK143128C DK143128C (en) | 1981-11-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK105174A DK143128C (en) | 1973-02-28 | 1974-02-27 | METHOD OF ANALOGUE FOR THE PREPARATION OF 1-ARYLOXY-2-HYDROXY-3-ALKYNYLAMINOPROPANES OR THEIR PHYSIALLY ACCEPTABLE ACID ADDITION SALTS |
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|---|---|
| US (1) | US3925446A (en) |
| JP (1) | JPS594417B2 (en) |
| AT (1) | AT330150B (en) |
| BG (7) | BG21394A3 (en) |
| CA (1) | CA1062717A (en) |
| CH (7) | CH605689A5 (en) |
| CS (1) | CS186263B2 (en) |
| DD (1) | DD110652A5 (en) |
| DK (1) | DK143128C (en) |
| ES (7) | ES423466A1 (en) |
| FI (1) | FI62054C (en) |
| FR (1) | FR2218900B1 (en) |
| GB (1) | GB1450287A (en) |
| HU (1) | HU168598B (en) |
| IE (1) | IE39482B1 (en) |
| IL (1) | IL44301A (en) |
| MX (2) | MX4588E (en) |
| NL (1) | NL169733C (en) |
| NO (1) | NO138062C (en) |
| PH (1) | PH9722A (en) |
| PL (2) | PL91560B1 (en) |
| SE (1) | SE411897B (en) |
| SU (1) | SU793381A3 (en) |
| YU (2) | YU50074A (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4038313A (en) * | 1970-01-08 | 1977-07-26 | Ciba-Geigy Corporation | Cycloalkylureido phenoxy propanolamines |
| US4078146A (en) * | 1972-07-06 | 1978-03-07 | Aktiebolaget Hassle | Phenoxy propanolamines |
| US4035420A (en) * | 1972-07-06 | 1977-07-12 | Aktiebolaget Hassle | Substituted ureido alkylene phenoxy propanolamines |
| GB1374366A (en) * | 1972-07-21 | 1974-11-20 | Science Union & Cie | Propanol derivatives and a process for their preparation |
| AT334385B (en) * | 1973-12-20 | 1976-01-10 | Chemie Linz Ag | PROCESS FOR THE PREPARATION OF NEW PHENOXYPROPYLAMINE DERIVATIVES AND THEIR SALTS |
| US4243681A (en) * | 1977-10-11 | 1981-01-06 | Mead Johnson & Company | Alkylthiophenoxypropanolamines and pharmaceutical compositions and uses thereof |
| DE2805404A1 (en) * | 1978-02-09 | 1979-08-16 | Merck Patent Gmbh | 1-ARYLOXY-3-NITRATOALKYLAMINO-2-PROPANOLS AND METHOD FOR THE PRODUCTION THEREOF |
| DE3009036A1 (en) * | 1980-03-08 | 1981-09-24 | C.H. Boehringer Sohn, 6507 Ingelheim | NEW L- (ACYLAMINO-ARYLOXY-) 2-HYDROXY-3-ALKINYLAMINOPROPANES AND METHOD FOR THEIR PRODUCTION |
| DE3009047A1 (en) * | 1980-03-08 | 1981-09-24 | C.H. Boehringer Sohn, 6507 Ingelheim | NEW L- (ACYLAMINO-ARYLOXY-) 2-HYDROXY-3-ALKINYLAMINOPROPANES AND METHOD FOR THEIR PRODUCTION |
| US4387103A (en) * | 1980-11-28 | 1983-06-07 | American Hospital Supply Corporation | Method for treatment or prophylaxis of cardiac disorders |
| US4454154A (en) * | 1981-06-23 | 1984-06-12 | American Hospital Supply Corporation | Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents |
| US4559359A (en) * | 1981-06-23 | 1985-12-17 | American Hospital Supply Corporation | Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents |
| DE3248835A1 (en) * | 1981-06-23 | 1983-06-30 | American Hospital Supply Corp | COMPOSITIONS FOR TREATING GLAUCOMA |
| US4455317A (en) * | 1981-06-23 | 1984-06-19 | American Hospital Supply Corporation | Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents |
| US4578403A (en) * | 1981-06-23 | 1986-03-25 | American Hospital Supply Corporation | Method for treating glaucoma by the topical administration of selectively metabolized beta-blocking agents |
| DE3133719A1 (en) * | 1981-08-26 | 1983-03-10 | Boehringer Ingelheim KG, 6507 Ingelheim | NEW 1-ARYLOXY-3-ALKINYLAMINO-2-PROPANOLS AND METHOD FOR THE PRODUCTION THEREOF |
| JPH02130007U (en) * | 1989-03-31 | 1990-10-26 | ||
| CA2554696C (en) * | 2004-02-13 | 2009-06-30 | Warner-Lambert Company Llc | Androgen receptor modulators |
| JP5838114B2 (en) | 2012-04-02 | 2015-12-24 | 株式会社リガク | X-ray topography equipment |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3459782A (en) * | 1963-08-26 | 1969-08-05 | Boehringer Sohn Ingelheim | 1-substituted phenoxy-2-hydroxy-3-isopropylamino-propanes |
| GB1199037A (en) * | 1967-09-27 | 1970-07-15 | Ici Ltd | Alkanolamine Derivatives |
| US3541130A (en) * | 1967-02-06 | 1970-11-17 | Boehringer Sohn Ingelheim | 1-(cyanophenoxy)-2-hydroxy-3-tert.-butylamine propanes |
-
1974
- 1974-02-11 AT AT104774A patent/AT330150B/en not_active IP Right Cessation
- 1974-02-21 ES ES423466A patent/ES423466A1/en not_active Expired
- 1974-02-22 US US444713A patent/US3925446A/en not_active Expired - Lifetime
- 1974-02-25 CS CS7400001369A patent/CS186263B2/en unknown
- 1974-02-25 FI FI544/74A patent/FI62054C/en active
- 1974-02-26 BG BG26940A patent/BG21394A3/xx unknown
- 1974-02-26 BG BG25901A patent/BG20564A3/xx unknown
- 1974-02-26 BG BG26939A patent/BG21208A3/xx unknown
- 1974-02-26 BG BG26941A patent/BG20335A3/xx unknown
- 1974-02-26 BG BG26943A patent/BG20566A3/xx unknown
- 1974-02-26 HU HUBO1487A patent/HU168598B/hu unknown
- 1974-02-26 DD DD176809A patent/DD110652A5/en unknown
- 1974-02-26 BG BG26938A patent/BG20334A3/xx unknown
- 1974-02-26 BG BG26942A patent/BG20565A3/xx unknown
- 1974-02-27 MX MX745489U patent/MX4588E/en unknown
- 1974-02-27 CH CH1485677A patent/CH605689A5/xx not_active IP Right Cessation
- 1974-02-27 NO NO740670A patent/NO138062C/en unknown
- 1974-02-27 IL IL44301A patent/IL44301A/en unknown
- 1974-02-27 DK DK105174A patent/DK143128C/en not_active IP Right Cessation
- 1974-02-27 JP JP49023221A patent/JPS594417B2/en not_active Expired
- 1974-02-27 PH PH15555*UA patent/PH9722A/en unknown
- 1974-02-27 PL PL1974169115A patent/PL91560B1/pl unknown
- 1974-02-27 GB GB894974A patent/GB1450287A/en not_active Expired
- 1974-02-27 CH CH278074A patent/CH605636A5/xx not_active IP Right Cessation
- 1974-02-27 YU YU00500/74A patent/YU50074A/en unknown
- 1974-02-27 SE SE7402622A patent/SE411897B/en not_active IP Right Cessation
- 1974-02-27 CH CH1485577A patent/CH605638A5/xx not_active IP Right Cessation
- 1974-02-27 PL PL1974183356A patent/PL93591B1/pl unknown
- 1974-02-27 MX MX745493U patent/MX4592E/en unknown
- 1974-02-27 CH CH1485977A patent/CH605690A5/xx not_active IP Right Cessation
- 1974-02-27 CH CH1486077A patent/CH605691A5/xx not_active IP Right Cessation
- 1974-02-27 CH CH1485477A patent/CH605637A5/xx not_active IP Right Cessation
- 1974-02-27 CA CA193,683A patent/CA1062717A/en not_active Expired
- 1974-02-28 NL NLAANVRAGE7402704,A patent/NL169733C/en not_active IP Right Cessation
- 1974-02-28 FR FR7406835A patent/FR2218900B1/fr not_active Expired
- 1974-02-28 IE IE428/74A patent/IE39482B1/en unknown
- 1974-08-27 CH CH1485877A patent/CH605639A5/xx not_active IP Right Cessation
-
1975
- 1975-01-29 SU SU752100046A patent/SU793381A3/en active
- 1975-04-04 ES ES436316A patent/ES436316A1/en not_active Expired
- 1975-04-04 ES ES436314A patent/ES436314A1/en not_active Expired
- 1975-04-04 ES ES436315A patent/ES436315A1/en not_active Expired
- 1975-04-04 ES ES436313A patent/ES436313A1/en not_active Expired
- 1975-04-04 ES ES436312A patent/ES436312A1/en not_active Expired
- 1975-04-04 ES ES436311A patent/ES436311A1/en not_active Expired
-
1980
- 1980-04-22 YU YU01095/80A patent/YU109580A/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |