DK155520B - METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF - Google Patents
METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF Download PDFInfo
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- DK155520B DK155520B DK442377AA DK442377A DK155520B DK 155520 B DK155520 B DK 155520B DK 442377A A DK442377A A DK 442377AA DK 442377 A DK442377 A DK 442377A DK 155520 B DK155520 B DK 155520B
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- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
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- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
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- A61K8/00—Cosmetics or similar toiletry preparations
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- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
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- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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Description
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Den foreliggende opfindelse angår en analogifremgangsmå-de til fremstilling af hidtil ukendte aminosyrederivater med værdifulde biologiske og farmaceutiske virkninger.The present invention relates to an analogous process for the preparation of novel amino acid derivatives having valuable biological and pharmaceutical effects.
De ved fremgangsmåden ifølge opfindelsen fremstillede amino-5 syrederivater har den almene formel R^-NH-CH-COA1The amino acid derivatives prepared by the process of the invention have the general formula R 1 -NH-CH-COA 1
«rVn I«RVn I
io co-n-(ch2) t“ so2ohio co-n- (ch2) t “so2oh
RR
1 1 hvor A , R, R , n og t har de i krav 1's indledning angivne betydninger, eller er et fysiologisk acceptabelt salt deraf eller ^ en optisk aktiv isomer deraf.1, wherein A, R, R, n and t have the meanings given in the preamble of claim 1, or are a physiologically acceptable salt thereof or an optically active isomer thereof.
Disse forbindelser har værdifulde biologiske eller farmakologiske virkninger. Alle de ifølge opfindelsen fremstillede forbindelser er hidtil ukendte.These compounds have valuable biological or pharmacological effects. All the compounds of the invention are novel.
Blandt de ifølge opfindelsen fremstillede forbindelser 2o skal på grund af dens biologiske virkning navnlig fremhæves γ-L-glutamyltaurin, der svarer til formlen H-N-CH-COOH 2 !Of the compounds 20 according to the invention, due to its biological action, in particular, γ-L-glutamyltaurine corresponding to the formula H-N-CH-COOH 2 is to be highlighted.
ch9 XXIVch9 XXIV
25 f225 f2
C0-NH-CH2-CH2-S020HC0-NH-CH2-CH2-S020H
og som har et bredt terapeutisk og præventivt virkningsspektrum over for sygelige forandringer der kan føres tilbage til beska-2o digelser af "AGAS" (det aerobiosfæriske genetiske adaptionssystem) .and which has a broad therapeutic and preventive spectrum of action against morbid changes that can be traced back to the claims of "AGAS" (the aerobiospheric genetic adaptation system).
Til belysning af begrebet "AGAS" opregnes i det følgende de vigtigste væv og organer der danner dette system. 1 a) Alle biologiske grænseflader der står i berøring med den ydre luft som biosfæren (hud og huddannelser, øjets hornhinde og Conjunktiva, mund- og svælghulrum, luftveje og lunge);To illustrate the concept of "AGAS", the following are the main tissues and organs that form this system. 1 (a) All biological interfaces in contact with the external air such as the biosphere (skin and skin formation, eye cornea and conjunctiva, oral and pharyngeal cavities, respiratory tract and lung);
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2 b) skelet og led (rørknogler og svampeagtige knogler, kugleled, synoviale membraner, skeletmuskulatur); c) de til reguleringen af ionhusholdningen deltagende organer (transepiteliske transportsystem: tarmtrævler og nyreka- 5 nal); d) det til findeling af næringen nødvendige tekodonte (i tandaveolerne med rødder fastgjorte) tandsæt; e) høre-, lugte-o g stemmeor ganer.2 (b) skeleton and joints (tubular and spongy bones, joints, synovial membranes, skeletal muscle); (c) the organs involved in the regulation of the ion household (transepithelial transport system: intestinal tracts and renal duct); (d) the toothpaste (rooted in the tooth anaolobes with roots) needed to decompose the food; e) hearing, smell and voice organs.
De omhandlede forbindelser udøver således en gunstig bi-10 ologisk eller terapeutisk virkning på de her opregnede organer eller væv af AGAS-systemet.Thus, the compounds of this invention exert a favorable biological or therapeutic effect on the organs or tissues of the AGAS system enumerated herein.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser virker desuden på følgende funktioner der står i sammenhæng med AGAS-systemet: strålingsbeskyttelse, begunstigelse af 15 sårheling, almindelig aktiverende virkning på mesenkym, beskyttelse mod den stadigt voksende infektions- og tilsmudsningsfare hos hud og slimhinder (den fugtige slimhindes lysozymproduktion, aktivering af fimreepiteler i luftvejene osv.)/ forøget beskyttelse mod de af vira og svampe forårsagede infektioner.The compounds of the process according to the invention additionally act on the following functions which are related to the AGAS system: radiation protection, favoring wound healing, general activating effect on mesenchymal, protection against the ever growing infection and soiling danger of skin and mucosa (the moist mucosal lysozyme production, activation of gut epithelium in the respiratory tract, etc.) / increased protection against infections caused by viruses and fungi.
2020
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser er virksomme mod de stadigt og i høj grad stigende stress-virkninger der er knyttet til livet på fastlandet (fx meteorologisk indflydelse, store forskelle mellem dag- og nattemperatur, forhøjet fare for kvæstelser), idet de stabiliserer adaptions-25 syndromet og samtidigt afværger glukokortikoidernes perifere vævsskader (som fx skader i bindevævet, kvæstelser af knoglematrix-bestanddele osv.). Udvikling af immunhomøostase (stigende erkendelsesevne hos legemet om hvilke celler der er kropsegne og hvilke der ikke er).The compounds prepared by the process of the invention are effective against the ever-increasing stress effects associated with mainland life (e.g., meteorological influence, large differences between day and night temperature, increased risk of injury) as they stabilize adaptations. -25 syndrome and at the same time avert the peripheral tissue damage of the glucocorticoids (such as damage to the connective tissue, injuries to bone matrix components, etc.). Development of immune homeostasis (increasing body recognition of which cells are suitable and which are not).
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser udøver deres virkning dels umiddelbart, dels over reguleringen af vitamin A metabolismen, ved produktion af vitamin A me-taboliter med stærkere polær karakter. Denne virkning kan sammenlignes med parathormonets virkning på 25-hydroxycholecalciferol-Ια-hydroxylase-enzymet i nyrekanalen. Virkningsretningerne af forbindelserne er følgende:The compounds prepared by the process according to the invention exert their effect, both directly and partly through the regulation of vitamin A metabolism, in the production of vitamin A metabolites of a stronger polar nature. This effect is comparable to the effect of the parathormone on the 25-hydroxycholecalciferol-Ια-hydroxylase enzyme in the renal tract. The directions of action of the compounds are as follows:
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3 A) Virkninger med vitamin A-karakter: a) Farmakologiske og biokemiske virkninger: forøgende virkning på kondroitinsulfatsyntese; gunstig virkning på sårhelingen eller på den ved indgift af kortison eksperi- 5 mentelt forringede sårheling hos rotter og hunde; potentierende virkning på vitamin A's virkning hos rotter og høns ved eksperimentelt fremkaldte hypo- eller hypervitaminoser; dæmpende virkning på de ulcerations-betingede stress-virkninger hos rotter; begunstigende virkning på degranulationen af mastocyter; forøgende virkning på 10 produktionen af lysozym; virkning på sporstofhusholdningen (silicium, zink, kobber, mangan, fluor); fremmende virkning på epiteldannelsen; fremmende virkning på den alkaliske fosfataseaktivitet; virkningen på den ved lokal indvirkning af vitamin A fremkaldte granulomposedannelse (Granulomsackbildung); det yderst flade for-15 løb af dosis-virkningskurven eller ændringen af virkningens fortegn ved store doser; aktiverende virkning på Golgi-apparatet; begunstigende virkning på dannelsen af slim- eller bægerceller; forøgende virkning på koncentrationen af vitamin A.3 A) Vitamin A grade effects: a) Pharmacological and biochemical effects: increasing effect on chondroitin sulfate synthesis; beneficial effect on the wound healing or on the experimentally impaired wound healing in rats and dogs by cortisone administration; potentiating effect on vitamin A's effect in rats and chickens in experimentally induced hypo- or hypervitaminosis; attenuating effect on the ulceration-related stress effects in rats; beneficial effect on the degranulation of mastocytes; increasing effect on the production of lysozyme; effect on household traceability (silicon, zinc, copper, manganese, fluorine); promoting effect on epithelial formation; promoting effect on the alkaline phosphatase activity; the effect on the granuloma bag formation (Granulomsackbildung) caused by local action of vitamin A; the extremely flat course of the dose-effect curve or the change of effect sign at large doses; activating effect on the Golgi apparatus; beneficial effect on the formation of mucus or goblet cells; increasing effect on the concentration of vitamin A.
20 b) Klinisk-terapeutiske virkninger: keratokonjunktivis sicca; Sjogrens syndrom; rhino-laryngo-pharingitis sicca; ozæna; kronisk bronchitis; sinobronchitis; mucoviscidose; konstitutionelle lungesygdomme hos småbørn; paradentose; hudens og slimhindernes smittetilbøjelighed for vira og svampe; kortison-antagonistisk 25 virkning; gunstig virkning på helingen ved operationssår og slimhindesår; erosio colli; pruritusagtige lidelser; nedsættelse af lugte- og smagssansen. 1 B) Virkninger uden vitamin A-karakter a) Farmakologiske og biokemiske virkninger: virkning på blodsukkerniveauet med hensyn til en forbigående sænkning; forøgende virkning på fosfaturi, sænkende virkning på fosfatniveauet 35 i serum; strålingsbeskyttende virkning; formindskende virkning påB) Clinical-therapeutic effects: keratoconjunctivis sicca; Sjogren's syndrome; rhino-laryngo-pharingitis sicca; ozæna; chronic bronchitis; sinobronchitis; mucoviscidosis; constitutional lung disease in young children; periodontal disease; skin and mucosal susceptibility to viruses and fungi; cortisone antagonistic action; beneficial effect on healing of operative and mucosal wounds; erosio colli; pruritus-like disorders; reducing the sense of smell and taste. 1 B) Vitamin A-grade effects (a) Pharmacological and biochemical effects: effects on blood glucose levels with a transient decrease; increasing effect on phosphaturia, lowering effect on phosphate level 35 in serum; radiation protective effect; diminishing effect on
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4 den nødvendige tid der gå?med at nå målet ved labyrintforsøg hos inaktiverede dyr; formindskende virkning på eksperimentelt fremkaldte fluor- og kadmiumto xiko s er; forøgende virkning på den cykliske adenosinmonofosfat-udtømning af nyrerne; dæmpende virkning 5 på symptomerne ved eksperimentelt fremkaldt lathyrismus; formindskelse af histaminfølsomheden; forøgende virkning på aktiviteten af leverenzymet tyrosinaminotransferase.4 the time needed to reach the goal of maze trials in inactivated animals; decreasing effect on experimentally induced fluorine and cadmium toxico s is; increasing effect on the cyclic adenosine monophosphate depletion of the kidneys; attenuating effect 5 on the symptoms of experimentally induced lathyrism; decrease in histamine sensitivity; enhancing effect on liver enzyme tyrosine aminotransferase activity.
b) Terapeutiske virkninger: svage bestrålingsskader; vitiligo; muskelhypotoni; psykoenergetiserende virkning; gunstig 10 virkning på involutionelle og gerontologiske tilstande samt på de mnestiske funktioner; keloide tilbøjeligheder; spondylosis ankylo-poetica; sygdomme hos bevægelsesorganerne på grund af slid; scle-rotisk fundus; amyloidose; morphæa; fibrocytisk mastopati.b) Therapeutic effects: weak radiation damage; vitiligo; muscle hypotonia; psychoenergetic effect; beneficial effect on involutional and gerontological conditions as well as on the mnestic functions; keloid inclinations; spondylosis ankylo-poetics; diseases of the movement organs due to wear and tear; scle-rotic fundus; amyloidosis; morphea; fibrocytic mastopathy.
I veterinærmedicinen har de ifølge opfindelsen fremstil-15 lede forbindelser lignende anvendelsesområder som i humanmedicinen, dvs. fx hudskader (afskalning), sårheling og knoglebrud.In the veterinary medicine, the compounds prepared according to the invention have similar fields of application as in human medicine, ie. eg skin damage (peeling), wound healing and bone fractures.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav 1's kendetegnende del angivne.The process according to the invention is characterized by the characterizing part of claim 1.
Acyleret cystamin eller et derivat deraf substitueret 20 ved aminogruppen med et α-aminodikarbonsyrederivat kan således omsættes med hydrogenperoxyd eller med persyre hvorved disulfid-bindingen spaltes oxydativt og der opstår en forbindelse med den almene formel I.Thus, acylated cystamine or a derivative thereof substituted at the amino group by an α-aminodicarboxylic acid derivative can be reacted with hydrogen peroxide or with peracid, whereby the disulfide bond is oxidatively cleaved and a compound of the general formula I.
Hvis den funktionelle gruppe i udgangsmaterialet er en 25 p-toluensulfonylgruppe (J. Chem. Soc. 824, 1964) vindes der ved substitutionen med alkalimetalsulfit eller alkalimetalhydrogen-sulfit forbindelser med den almene formel I. Hvis udgangsforbindelsen indeholder en sulfonsyreestergruppe vindes forbindelserne med den almene formel I ved skånsom partiel hydrolyse.If the functional group of the starting material is a 25-p-toluenesulfonyl group (J. Chem. Soc. 824, 1964), the substitution with alkali metal sulfite or alkali metal hydrogen sulfite is obtained by compounds of the general formula I. If the starting compound contains a sulfonic acid ester group, the compounds of the general formula are obtained. Formula I by gentle partial hydrolysis.
30 Fremgangsmåden ifølge opfindelsen belyses nærmere i det følgende ved hjælp af nogle eksempler.The process according to the invention is elucidated in the following by means of some examples.
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Eksempel 1 a) Fremstilling af udgangsmateriale 40,85 g (0,11 mol) lcarbobenzyloxy-L-glutaminsyre-a-ben-zylester (Liebigs Annalen 655, 200, 1962) opløses i 500 ml aceto-5 nitril. Opløsningen afkøledes til -15°C under udelukkelse af luftfugtigheden. Til opløsningen sættes dråbevis under omrøring først 15,4 ml (0,11 mol) triætylamin og derpå 15,4 ml (0,11 mol) klormy-resyreisobutylester. Realetionsblandingen omrøres ved -15°C i 40 minutter og derpå tilsættes 28 ml (0,2 mol) triætylamin efterfulgt 10 af 11,26 g (0,05 mol) cystamin-hydroklorid og til sidst 250 ml ace-tonitril. Blandingen efteromrøres ved -15°C i yderligere to timer og derpå i yderligere fire timer ved stuetemperatur.Example 1 a) Preparation of Starting Material 40.85 g (0.11 mol) of carbobenzyloxy-L-glutamic acid α-benzyl ester (Liebigs Annalen 655, 200, 1962) are dissolved in 500 ml of acetonitrile. The solution was cooled to -15 ° C to exclude the humidity. To the solution is added dropwise, with stirring, first 15.4 ml (0.11 mole) of triethylamine and then 15.4 ml (0.11 mole) of chloromyric acid isobutyl ester. The reaction mixture is stirred at -15 ° C for 40 minutes and then 28 ml (0.2 mole) of triethylamine is added followed by 10.26 g (0.05 mole) of cystamine hydrochloride and finally 250 ml of acetonitrile. The mixture is stirred at -15 ° C for a further two hours and then for another four hours at room temperature.
. Efter reaktionstidens udløb inddampes blandingen ved 30°C under vakuum. Remanensen optages under omrøring og afkøling i 200 15 ml isvand og blandingen inddampes påny ved 35°C under vakuum. Remanensen indføres sammen med 250 ml vand og 500 ml ætylacetat i en skilletragt og den organiske fase skilles fra. Den organiske fase udrystes i. den nævnte rækkefølge først med 250 ml vand, derpå to gange med 250 ml 5%s natriumkarbonatopløsning hver gang og derpå 20 to gange med 250 ml IN saltsyre og til sidst med 250 ml vand. (Ud fra den ved udrystningen med natriumkarbonatopløsning vundne vandige fase kan der ved syrning med saltsyre og udrystning med æter genvindes ca. 5 g ikke omsat karbobenzyloxy-L-glutaminsyre-ct-ben-zylester). Ætylacetatfasen tørres over vandfrit natriumsulfat og 25 inddampes derpå under vakuum ved 30°C til tørhed."Der vindes en tyk, olieagtig remanens som hurtigt stivner til en krystallinsk masse. Denne rives med 250 ml absolut æter hvorpå krystallerne frafiltreres. Det rå produkt (40-42 g) omkrystalliseres fra en blanding af 100 ml ætylacetat og 170 ml æter. Der vindes 29,3 g 30 N,N'-bis-^N-karbobenzyloxy-y-(a-benzyl)-L-glutamyl7-cystamin med . smeltepunkt 9l-92°C.. After the reaction time expires, the mixture is evaporated at 30 ° C under vacuum. The residue is taken up with stirring and cooling in 200 ml of ice water and the mixture is evaporated again at 35 ° C under vacuum. The residue is introduced with 250 ml of water and 500 ml of ethyl acetate into a separatory funnel and the organic phase is separated. The organic phase is shaken in the above order first with 250 ml of water, then twice with 250 ml of 5% sodium carbonate solution each time and then 20 twice with 250 ml of 1N hydrochloric acid and finally with 250 ml of water. (From the aqueous phase obtained by shaking with sodium carbonate solution, by acidification with hydrochloric acid and shaking with ether, about 5 g of unreacted carbobenzyloxy-L-glutamic acid ct-benzyl ester can be recovered). The ethyl acetate phase is dried over anhydrous sodium sulfate and then evaporated in vacuo at 30 ° C to dryness. "A thick, oily residue is obtained which quickly solidifies to a crystalline mass. It is grated with 250 ml of absolute ether and the crystals are filtered off. The crude product (40 -42 g) is recrystallized from a mixture of 100 ml of ethyl acetate and 170 ml of ether to give 29.3 g of 30 N, N'-bis- ^ N-carbobenzyloxy-y- (a-benzyl) -L-glutamyl7-cystamine with m.p. 91-192 ° C.
Beregnet for C44H50N4010S2 (M = 859,05): C 61,52 H 5,89 N 6,52 S 7,46 fundet: C 60,85 H 5,91 N 6,61 S 7,72.%.Calcd. For C44H50N4010S2 (M = 859.05): C 61.52 H 5.89 N 6.52 S 7.46 found: C 60.85 H 5.91 N 6.61 S 7.72%.
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6 b) Fremgangsmåden ifølge opfindelsen 25,77 g (0,3 mol) af det ifølge eksempel la) vundne N,N'-bis-/N-karbobenzyloxy-y-(a-benzyl)-L-glutamyl7-cystamin opløses i 75 ml iseddikesyre. Den i is afkølede opløsning sættes i løbet 5 af 15 minutter dråbevis til en frisk tilberedt blanding af 75 ml 30%s hydrogenperoxyd og 225 ml iseddikesyre. Efter tilsætningen fjernes kølingen og reaktionsblandingen omrøres i fire timer ved stuetemperatur. Derpå inddampes der under vakuum ved 30°C. Det olieagtige produkt tørres i en ekssikkator først over fosforpent-10 oxyd og derpå over fast kaliumhydroxyd. Der vindes 28,5 g karbo- benzyloxy-y-(a-benzyl)-L-glutamyltaurin.Den relative motilitét af dette produkt i forhold til cysteinsyre ved papirelektrofo-rese er 0,5 ved pH 6,5.6 b) The process of the invention 25.77 g (0.3 mol) of the N, N'-bis- / N-carbobenzyloxy-y- (a-benzyl) -L-glutamyl7-cystamine obtained in Example 1a 75 ml glacial acetic acid. The ice-cooled solution is added dropwise over 5 to 15 minutes to a freshly prepared mixture of 75 ml of 30% hydrogen peroxide and 225 ml of glacial acetic acid. After the addition, the cooling is removed and the reaction mixture is stirred for four hours at room temperature. Then it is evaporated under vacuum at 30 ° C. The oily product is dried in a desiccator first over phosphorus pentoxide and then over solid potassium hydroxide. 28.5 g of carbenzyloxy-γ- (α-benzyl) -L-glutamyltaurine are obtained. The relative motility of this product to cysteic acid by paper electrophoresis is 0.5 at pH 6.5.
15 Eksempel 2 4,14 g (10 mmol) karbobenzyloxy-y-(oc-benzyl)-L-glutamyl-kolamin opløses i 40 ml pyridin og opløsningen afkøles til -10°C.Example 2 4.14 g (10 mmol) of carbobenzyloxy-γ- (oc-benzyl) -L-glutamyl-colamine are dissolved in 40 ml of pyridine and the solution is cooled to -10 ° C.
I små portioner tilsættes under intensiv omrøring 2,1 g (li mmol) 20 p-toluensulfonylklorid. Reaktionsblandingen omrøres ved 0°C i tre timer og ud'hældes derefter på 40 g smeltende is. Det udskilte bundfald frafiltreres, vaskes med vand og omkrystalliseres til sidst fra en blanding af ætanol og petroleumsæter. Produktet underkastes katalytisk hydrogenering med 10%s palladiumkulstof som katalysator. Det __ efter hydrogeneringen vundne og tørrede stof opløses i 30 ml vand, og der sættes 10,1 g (40 mmol) natriumsulfit-heptahydrat til opløsningen. Opløsningen omrøres ved 40°C i 24 timer og inddampes derefter under vakuum. Remanensen opløses med en lille mængde vand og bringes over på en kolonne med "Dowex" 50 hvorfra der elueres med 3Q vand. Eluatet inddampes under vakuum og remanensen tørres over kaliumhydroxyd. Efter omkrystallisation fra 80%s ætanol vindes 1,6 g y-L-glutamyltaurin med smp. 219-220°C.In small portions, under intensive stirring, 2.1 g (1 mmol) of 20 p-toluenesulfonyl chloride is added. The reaction mixture is stirred at 0 ° C for three hours and then poured onto 40 g of melting ice. The precipitated precipitate is filtered off, washed with water and finally recrystallized from a mixture of ethanol and petroleum ether. The product is subjected to catalytic hydrogenation with 10% palladium carbon as the catalyst. The hydrogen recovered and dried substance is dissolved in 30 ml of water, and 10.1 g (40 mmol) of sodium sulfite heptahydrate is added to the solution. The solution is stirred at 40 ° C for 24 hours and then evaporated under vacuum. The residue is dissolved with a small amount of water and transferred to a column of "Dowex" 50, eluting with 3Q of water. The eluate is evaporated under vacuum and the residue is dried over potassium hydroxide. After recrystallization from 80% ethanol, 1.6 g of γ-L-glutamyltaurine is obtained with m.p. 219-220 ° C.
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Eksempel 3 a) Karbobenzoxy-L-glutaminsyre-a-benzyl-y-cysteamid (Udgangsforbindelse) I 5 ml absolut ætylacetat opløses 0,49 g (1 mmol) karbo-5 benzoxy-L-glutaminsyre-a-benzyl-y-p-nitrofenylester. Under afkøling i isvand tildryppes der 0,08 g (1 mmol) cysteamin i 1 ml dimetylformamid. Efter tilsætning af 0,14 ml (2 mmol) triætyl-amin holdes reaktionsblandingen i nogle timer på 0°C, hvorefter den henstår ved stuetemperatur i 2 dage. Reaktionsblandin-10 gen inddampes under vakuum og remanensen optages i 20 ml ætylacetat. Ætylacetatopløsningen vaskes tre gange med N saltsyre, to gange med vand og derpå med en 5%s natriumkarbonatopløsning flere gange indtil den gule farve forsvinder. Efter vask gentagne gange med vand tørres opløsningen over natriumsulfat og 15 inddampes under vakuum. Det tilbageværende råprodukt (0,35 g) optages med æter og tørres.Example 3 a) Carbobenzoxy-L-glutamic acid α-benzyl-γ-cysteamide (Starting Compound) In 5 ml of absolute ethyl acetate, dissolve 0.49 g (1 mmol) of carbo-benzoxy-L-glutamic acid α-benzyl-γ-nitrophenyl ester . While cooling in ice water, 0.08 g (1 mmol) of cysteamine is dropped into 1 ml of dimethylformamide. After the addition of 0.14 ml (2 mmol) of triethylamine, the reaction mixture is kept at 0 ° C for a few hours, after which it is left at room temperature for 2 days. The reaction mixture is evaporated in vacuo and the residue is taken up in 20 ml of ethyl acetate. The ethyl acetate solution is washed three times with N hydrochloric acid, twice with water and then with a 5% sodium carbonate solution several times until the yellow color disappears. After washing repeatedly with water, the solution is dried over sodium sulfate and evaporated under vacuum. The remaining crude product (0.35 g) is taken up with ether and dried.
Beregnet for C22H27°5N2S (M = 431,5): C 61,3 H 6,3 S 7,4 Fundet: C 62,0 H 6,3 S 8,0%.Calculated for C 22 H 27 ° 5 N 2 S (M = 431.5): C 61.3 H 6.3 S 7.4 Found: C 62.0 H 6.3 S 8.0%.
20 Infrarødt spektrum: NH: 3320, C=0 (COObenzyl): 1740, C=0 (Z) 1695, C=0 (amid-I): 1650, C=0 (amid-II): 1560 cm"1.Infrared spectrum: NH: 3320, C = O (COObenzyl): 1740, C = 0 (Z) 1695, C = 0 (amide-I): 1650, C = 0 (amide-II): 1560 cm -1.
Tyndtlagskromatografi: i et system af n-butanol/eddikesyre/py-ridin/vand (30:60:20:24) efterlades en samlet klorpositiv plet.Thin layer chromatography: in a system of n-butanol / acetic acid / pyridine / water (30: 60: 20: 24) leaves a total chlorine positive stain.
25 b) Karbobenzyloxy-γ-(α-benzyl)-L-glutamyltaurin I 2 ml iseddike opløses 10 cg karbobenzoxy-L-glutamin-syre-a-benzyl-y-cysteamid og der tilsættes 0,5 ml 30%s hydro-genperoxyd. Reaktionsblandingen henstilles i 4 timer under af-30 køling med isvand. Der udtages prøver hver time fra reaktionsblandingen og reaktionens fremadskriden kontrolleres ved elek-troforese. Efter opløsning af reaktionsblandingen i vand frysetørres reaktionsblandingen.B) Carbobenzyloxy-γ- (α-benzyl) -L-glutamyltaurine In 2 ml glacial acetic acid dissolve 10 cg of carbobenzoxy-L-glutamic acid α-benzyl-γ-cysteamide and 0.5 ml of 30% genperoxyd. The reaction mixture is allowed to stand for 4 hours under cooling with ice water. Samples are taken every hour from the reaction mixture and the progress of the reaction is checked by electrophoresis. After dissolving the reaction mixture in water, the reaction mixture is freeze-dried.
De ved fremgangsmåden ifølge opfindelsen fremstillede 35 forbindelsers biologiske virkning skal i det følgende belyses i to biologiske forsøgsrapporter, A og B. I disse forsøgsrapporter vises den biologiske virkning for forskellige typer afThe biological effect of the compounds of the present invention produced in the following is elucidated in two biological test reports, A and B. In these test reports, the biological effect of different types of
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8 forbindelser med den almene formel I. De undersøgte forbindelser har alle ubeskyttede N-terminale og C-terminale grupper, 1 1 dvs. R er hydrogen og A er hydroxy. Forbindelser med den al-mene formel I, hvor R er forskellig fra hydrogen og/eller8 compounds of the general formula I. The compounds studied have all unprotected N-terminal and C-terminal groups, 1 1 ie. R is hydrogen and A is hydroxy. Compounds of general formula I wherein R is different from hydrogen and / or
-I-IN
5 hvor A er forskellig fra hydroxy har den samme biologiske virkning som de tilsvarende ubeskyttede aminosyrederivater, idet man må forvente at beskyttelsesgrupperne fraspaltes i organismen.5 where A is different from hydroxy has the same biological effect as the corresponding unprotected amino acid derivatives, one having to expect the protecting groups to be cleaved in the organism.
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Biologisk forsøgsrapport A.Biological Test Report A.
Undersøgelse af γ-L-glutamyltaurin som i nærværende rapport betegnes litoralon.Study of γ-L-glutamyltaurine as in this report is called litoralon.
5 I de efterfølgende tabeller 1-6 er forsøgsresultaterne vist soro middelværdier + standardafvigelse med antallet af bestemmelser i parantes. Bestemmelse af om der er signifikant forskel mellem kontrolforsøg og forsøg med behandlede dyr blev foretaget med Students t-test.5 In the following Tables 1-6, the test results show soro mean values + standard deviation with the number of determinations in parentheses. Determination of whether there is a significant difference between control trials and trials in treated animals was done with Student's t-test.
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Tabel 1Table 1
Litoralons virkning på vitamin A-koncentrationen i serum.Effect of Litoralon on vitamin A concentration in serum.
Gruppe litoralon vitamin A-koncentration i serum 15 _yg/dag____ I. Kontrol - 28,3 + 0,7 (20) II. 0,1 41,9 + 1,0X (20) III. 0,3 32,9 + 1,1XX (20) IV. 1,0 27,4 + 0,6 (20) 20 x P <; 0,001 xx P < 0,01 20 Sprague Dawley rotter (10 hanner og 10 hunner) vejende 25 180-200 g behandledes oralt med de i tabel 1 angivne daglige do ser litoralon i form af en vandig opløsning i en periode på 8 dage. På den 9. forsøgsdag aflivedes dyrene ved dekapitering og blodet opsamledes. Vitamin A-koncentrationen i serumet bestemtes ved Neeld og Pearsons metode.Group of Litoralone Vitamin A concentration in serum 15 µg / day ____ I. Control - 28.3 + 0.7 (20) II. 0.1 41.9 + 1.0X (20) III. 0.3 32.9 + 1.1XX (20) IV. 1.0 27.4 + 0.6 (20) 20 x P <; 0.001 xx P <0.01 20 Sprague Dawley rats (10 males and 10 females) weighing 25 180-200 g were orally treated with the daily doses of litoralone in Table 1 in the form of an aqueous solution for a period of 8 days. On the 9th test day, the animals were sacrificed by decapitation and the blood was collected. The vitamin A concentration in the serum was determined by Neeld and Pearson's method.
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Tabel 2Table 2
Virkningen af litoralon og vitamin A på granulomdannelse frem-kaldt af implanterede vatkugler_ 5 Gruppe Dosis Tør vægt afEffect of Litoralone and Vitamin A on Granule Conversion Caused by Implanted Cotton Balls_ 5 Group Dose Dry Weight of
Vitamin Ax litoralon granulom lokal lokal oral mg yg yg/dag I. Kontrol - - - 52 + 1,0 (24) 10 II.Kontrol +Vitamin Ax litoralon granuloma local local oral mg yg yg / day I. Control - - - 52 + 1.0 (24) 10 II.Control +
Opløsningsmiddel - - - 54 + 3,1 (8) III. 2 - - 64+2,5 (8) IV. 2 0,1 - 65 + 2,7 (8) V. - 0,1 73 + 2,9 (8) 15 VI. 2 - 0,1 90 + 4,1 (8) x Hoffmann La RocheSolvent - - - 54 + 3.1 (8) III. 2 - - 64 + 2.5 (8) IV. 2 0.1 - 65 + 2.7 (8) V. - 0.1 73 + 2.9 (8) 15 VI. 2 - 0.1 90 + 4.1 (8) x Hoffmann La Roche
Forskellen er signifikant: mellem gruppe II og III ved 20 P < 0,05, mellem II og V ved P < 0,001, og mellem V og VI ved P < 0,01. Granulomdannelsen bestemtes ifølge Lee et al med Sprague-Dawley hanrotter vejende 110-120 g. Tamponerne fjernedes fra de dorsolaterale subkutane implantationer efter 10 dage og vejedes efter tørring til konstant vægt ved 65°C.The difference is significant: between groups II and III at 20 P <0.05, between II and V at P <0.001, and between V and VI at P <0.01. Granule formation was determined according to Lee et al with male Sprague-Dawley rats weighing 110-120 g. The tampons were removed from the dorsolateral subcutaneous implants after 10 days and weighed after drying to constant weight at 65 ° C.
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Tabel 5Table 5
DK 155520BDK 155520B
1313
Litoralons virkning på Rana dalmatina's metamorfoseThe effect of Litoralon on the metamorphosis of Rana dalmatina
Gruppe Kropslængde Halelængde mm_ran_ ^ Kontrol 45,9 + 0,2 31,4 + 0,2 (60)Group Body length Tail length mm_ran_ ^ Control 45.9 + 0.2 31.4 + 0.2 (60)
Behandlede dyr 40,2 + 0,2X 26,7 + 0,2X (60) x Signifikans: P < 0,001Treated animals 40.2 + 0.2X 26.7 + 0.2X (60) x Significance: P <0.001
Forsøget udførtes med larver af Rana dalmatia med en 10 alder på 30 dage, en kropslængde på 20-25 mm, og med allerede synlige fremspirende bagben. I løbet af en periode på 30 dage blev forsøgsdyrene anbragt i postevand indeholdende 0,5 yg/ml litoralon i to timer hver dag. Kontrolgruppen blev anbragt i postevand uden tilsætning af litoralon. Haletudserne måltes på...The experiment was performed with larvae of Rana dalmatia with a 10 age of 30 days, a body length of 20-25 mm, and with already visible projecting hind legs. Over a period of 30 days, the test animals were placed in tap water containing 0.5 µg / ml litoralon for two hours each day. The control group was placed in tap water without the addition of litoralone. The tits were measured on ...
15 den 30. dag.15 on the 30th day.
Tabel 6Table 6
Litoralons virkning på blodsukkerniveauet 2g Gruppe I. Undersøgelse II. Undersøgelse _mg %_mg %_Effect of Litoralone on Blood Sugar Level 2g Group I. Study II. Survey _mg% _mg% _
Kontrol 94 + 3,6 (10) 94 + 4,09 (10)Control 94 + 3.6 (10) 94 + 4.09 (10)
Behandlede dyr 82,4 + 3,8 (10) 81 + 1,32 (10)Treated Animals 82.4 + 3.8 (10) 81 + 1.32 (10)
Signifikans ved I. undersøgelse: P < 0,05 25 Signifikans ved II. undersøgelse: P < 0,01Significance at I. study: P <0.05 25 Significance at II. study: P <0.01
Hvide CGY-hanrotter med legemsvægt 160-180 g anvendtes til forsøget. Dyrene holdtes på en standard diæt. Der blev taget blodprøver på den 5. forsøgsdag efter 18 timers faste. Blodsukkerbestemmelserne udførtes efter metoden ifølge E. Hultman. Litoralon blev indgivet oralt i daglige doser på 1 yg/kg.Male CGY white body rats 160-180 g were used for the experiment. The animals were kept on a standard diet. Blood samples were taken on the 5th day of testing after 18 hours of fasting. The blood glucose assays were performed according to the method of E. Hultman. Litoralon was given orally at daily doses of 1 µg / kg.
35 1435 14
DK 15S520BDK 15S520B
Biologisk forsøgsrapport B.Biological Test Report B.
Undersøgelse af syntetisk γ-aspartyltaurin og derivater deraf.Study of synthetic γ-aspartyl taurine and its derivatives.
1. β-aspartyl-N-metyltaurin 5 a) Virkning på blodsukkerniveauet Kontrol 107 mg %1. β-Aspartyl-N-methyltaurine 5 a) Effect on blood sugar level Control 107 mg%
Behandlede dyr 93 mg %Treated animals 93 mg%
Signifikans: P < 0,05Significance: P <0.05
Til prøverne anvendtes 20-20 rotter. Målingerne gennem-10 førtes efter 18 timers faste. Den anvendte dosis var 1 yg/kg legemsvægt i 4 dage i form af en opløsning ved oral indgift.20-20 rats were used for the samples. Measurements were carried out -10 after 18 hours of fasting. The dose used was 1 µg / kg body weight for 4 days in the form of a solution by oral administration.
b) Virkning til forøgelse af vitamin A-niveauet i serumb) Effect to increase serum vitamin A level
Oral dosis Fremkaldt vitamin A yg% 15 yg/200 g legemsvægt 0 (kontrol) 8,5 5 11,0 1 11,5 0,3 12,5 20 0,1 16,1 0,05 14,8 0,01 12,5 0,005 10,5Oral dose Evoked vitamin A yg% 15 yg / 200 g body weight 0 (control) 8.5 5 11.0 1 11.5 0.3 12.5 20 0.1 16.1 0.05 14.8 0.01 12.5 0.005 10.5
Signifikans: P < 0,01Significance: P <0.01
Til forsøgene anvendtes 20-20 Wistar hanrotter med legemsvægt 200-220 g.For the experiments, 20-20 Wistar male rats weighing 200-220 g were used.
Forsøgsperiode: 6 dage.Trial period: 6 days.
c) Virkning på blodets'siliciumniveau:c) Effect on blood silicon level:
Silicium (mg/g blod) __0 timer_20 dage_40 dage_Silicon (mg / g blood) __0 hours_20 days_40 days_
Kontrolgruppe 0,110+0,004 0,120+0,010 0,154+0,015Control group 0.110 + 0.004 0.120 + 0.010 0.154 + 0.015
Behandlingsgruppetreatment Group
15 yg/dag 0,100+0,005 0,315+0,014XX 0,345+0,015XX15 µg / day 0.100 + 0.005 0.315 + 0.014XX 0.345 + 0.015XX
35 “35 "
Behandlingsgruppetreatment Group
II 10 yg/dag 0,107+0,009 0,370+0,119XX 0,360+0,017XXII 10 µg / day 0.107 + 0.009 0.370 + 0.119XX 0.360 + 0.017XX
xx Signifikans: P < 0,001xx Significance: P <0.001
DK 155520BDK 155520B
1515
Resultaterne er signifikante fra den 13. dag ved signifikansniveauet P < 0,01 og fra den 20. dag ved niveauet P < 0,001. Forsøgene udførtes på indavlede hankaniner med legemsvægt 2,5-3 kg. Den aktive bestanddel blev indgivet oralt i de i tabellen viste 5 daglige doser. Bestemmelsen af silicium udførtes ifølge Gaubatz's metode (Gaubatz E., Klin. Wschrft. 14, 1753, 1935) i 5 ml blodprøver, som blev taget fra dyrenes ørevene.The results are significant from the 13th day at the significance level P <0.01 and from the 20th day at the level P <0.001. The experiments were performed on inbred male rabbits of body weight 2.5-3 kg. The active ingredient was administered orally in the 5 daily doses shown in the table. The determination of silicon was performed according to Gaubatz's method (Gaubatz E., Clin. Wschrft. 14, 1753, 1935) in 5 ml of blood samples taken from the animals' ears.
d) Virkningen af β-aspartyl-N-metyl-taurin og vitamin A på den 10 granulomfremkaldende virkning forårsaget af implantation af vat:d) The effect of β-aspartyl-N-methyl-taurine and vitamin A on the 10 granulomatous effects caused by the implantation of cotton wool:
Gruppe Dosis Vægt af tør-Group Dose Weight of dry
Vitamin Ax B-aspartyl-N- ret 9railulom metyltaurin lokal lokal oral mg Ug ug/dag 15 —----------------Vitamin Ax B-aspartyl-N-ret 9railulom methyltaurine local local oral mg ug / day 15 —----------------
Kontrol I. - - 54+1,7Control I. - - 54 + 1.7
Kontrol II. + opløsningsmiddel - - - 55+3,4Control II. + solvent - - - 55 + 3.4
Behandlingsgruppe III. 2 - - 66+12,5Treatment Group III. 2 - - 66 + 12.5
Behandlingsgruppe IV. 2 0,1 - 67+2,6 20 ~Treatment Group IV. 2 0.1 - 67 + 2.6 ~ 20
Behandlingsgruppe V. - - 0,1 79+2,8Treatment group V. - - 0.1 79 + 2.8
Behandlingsgruppe VI. 2 - 0,1 96+4,4 x Hoffmann la RocheTreatment Group VI. 2 - 0.1 96 + 4.4 x Hoffmann la Roche
Forskellene er signifikante som følger: 25 Mellem gruppe II og III P < 0,05, mellem gruppe II og V P < 0,001 og mellem gruppe V og VI P < 0,01.The differences are significant as follows: 25 Between groups II and III P <0.05, between groups II and V P <0.001 and between groups V and VI P <0.01.
Bestemmelsen af granulom udførtes på Sprague-Dawley hanrotter med legemsvægt 110-120 g ved metoden ifølge Lee et al (Lee K.H., Fu Cb.Ch., Spencer M.R. Tong T.G. og Poon R.J., Pharm.The determination of granuloma was performed on male Sprague-Dawley body weights 110-120 g by the method of Lee et al (Lee K.H., Fu Cb.Ch., Spencer M.R. Tong T.G. and Poon R.J., Pharm.
30 Sci., 62, 895, 1973). De dorsolateralt subkutant implanterede tamponer fjernedes efter 10 dage og måltes efter tørring ved 65°C til konstant vægt. 1 β-Aspar tyl-homotaurin; 35 a) Virkning på blodsukkerniveauet30 Sci., 62, 895, 1973). The dorsolaterally subcutaneously implanted tampons were removed after 10 days and measured after drying at 65 ° C to constant weight. 1 β-Aspar tyl-homotaurin; 35 a) Effect on blood sugar level
Kontrolgruppe 105 mg%Control group 105 mg%
Behandlet gruppe 94 mg%Treated group 94 mg%
Signifikans, antal forsøgsdyr og forsøgsmetode var som angivetSignificance, number of test animals and test method were as indicated
DK 155520BDK 155520B
16 b) Forøgende virkning på vitamin A-niveauet i serum16 b) Increasing effect on serum vitamin A level
Oral dosis Fremkaldt vitamin AOral dose Induced vitamin A
yg/200 g legemsvægt _yg%_ 0 (kontrol) 8,6 5 5 12,0 1 13,5 0,3 14,0 0,1 15,8 0,05 15,0 10 0,01 12,0 _0,005_10,0_yg / 200 g body weight _yg% _ 0 (control) 8.6 5 5 12.0 1 13.5 0.3 14.0 0.1 15.8 0.05 15.0 10 0.01 12.0 _0 , 005_10,0_
Signifikans, antal forsøgsdyr og forsøgsmetode var som angivet ovenfor under pkt. Ib).Significance, number of test animals and test method were as indicated above under section. Ib).
15 c) Virkning på blodets siliciumniveau;C) Effect on blood silicon level;
Silicium (mg/g blod) _0 timer_20 dage_40 dage_Silicon (mg / g blood) _0 hours_20 days_40 days_
Kontrolgruppe 0,104+0,009 0,134+0,015 0,157+0,020 20 BehandlingsgruppeControl group 0.104 + 0.009 0.134 + 0.015 0.157 + 0.020 Treatment group
I. Spg/dag 0,094+0,007 0,309+0,014xx 0,340+0,014XXI. Spg / day 0.094 + 0.007 0.309 + 0.014xx 0.340 + 0.014XX
Behandlingsgruppetreatment Group
II. 10 ug/dag 0,109+0,010 0,372+0,120 0,363+0,018XXII. 10 µg / day 0.109 + 0.010 0.372 + 0.120 0.363 + 0.018XX
Signifikans, antal forsøgsdyr, arrangement og bestemmel-25 sesmetode som angivet ovenfor under pkt. 1 c).Significance, number of test animals, arrangement and method of determination as set out above under cl. 1 c).
d) Virkningen af β-aspartyl-homotaurin og vitamin A på den granu- lomfremkaldende virkning af implantation af vat:_(d) The effect of β-aspartyl homotaurin and vitamin A on the granulomatous effect of cotton implantation:
Dosis Vægt af tørret 30 Vitamin Ax β-aspartyl- Jfanulom lokal homotaurin ^ mg lokal oral _μg yg/dag_Dose Weight of dried 30 Vitamin Ax β-aspartyl-Jfanuloma local homotaurin ^ mg local oral _µg yg / day_
Kontrolgruppe I - - - 52+1,5Control group I - - - 52 + 1.5
Kontrolgruppe II - - - 53+3,2 35 + opløsningsmiddelControl group II - - - 53 + 3.2 + 35 + solvent
Behandlingsgruppe III. 2 - - 64+12,3Treatment Group III. 2 - - 64 + 12.3
Behandlingsgruppe IV. 2 0,1 - 65+2,4Treatment Group IV. 2 0.1 - 65 + 2.4
Behandlingsgruppe V. - - 0,1 77+2,6Treatment group V. - - 0.1 77 + 2.6
Rphandlinasarnnnp VT_ 2 — Π.1Rphandlinasarnnnp VT_ 2 - Π.1
DK 155520BDK 155520B
17 x Hoffmann la Roche17 x Hoffmann la Roche
Signifikans, antal forsøgsdyr, arrangement og bestemmelsesmetode var som angivet ovenfor under punkt ld).Significance, number of test animals, arrangement and method of determination were as indicated above under point (ld).
5 10 15 20 25 30 355 10 15 20 25 30 35
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HU74FE00000928A HU171576B (en) | 1974-04-29 | 1974-04-29 | Process for the isolation of gamma-l-glutamyl-taurine |
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DK442877A DK158676C (en) | 1974-04-29 | 1977-10-06 | METHOD OF ANALOGUE FOR THE PREPARATION OF POLYMERS OR OLIGOMER AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS. |
DK442977A DK442977A (en) | 1974-04-29 | 1977-10-06 | GAMMA-L-GLUTAMYLTAURIN PROCEDURE |
DK442577A DK442577A (en) | 1974-04-29 | 1977-10-06 | PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES |
DK442377A DK155520C (en) | 1974-04-29 | 1977-10-06 | METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF |
DK442777A DK442777A (en) | 1974-04-29 | 1977-10-06 | PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES |
DK443077A DK159267C (en) | 1974-04-29 | 1977-10-06 | METHOD OF ANALOGUE FOR THE PREPARATION OF TAURIN DERIVATIVES OR HOMOTAURIN DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF |
DK442677A DK159654C (en) | 1974-04-29 | 1977-10-06 | METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF |
DK442477A DK155732C (en) | 1974-04-29 | 1977-10-06 | ANALOGY PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES |
DK245783A DK155672C (en) | 1974-04-29 | 1983-05-31 | METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS OR OPTICALLY ACTIVE ISOMER THEREOF |
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DK442877A DK158676C (en) | 1974-04-29 | 1977-10-06 | METHOD OF ANALOGUE FOR THE PREPARATION OF POLYMERS OR OLIGOMER AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS. |
DK442977A DK442977A (en) | 1974-04-29 | 1977-10-06 | GAMMA-L-GLUTAMYLTAURIN PROCEDURE |
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DK442677A DK159654C (en) | 1974-04-29 | 1977-10-06 | METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF |
DK442477A DK155732C (en) | 1974-04-29 | 1977-10-06 | ANALOGY PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES |
DK245783A DK155672C (en) | 1974-04-29 | 1983-05-31 | METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS OR OPTICALLY ACTIVE ISOMER THEREOF |
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HU178199B (en) * | 1976-05-06 | 1982-03-28 | Chinoin Gyogyszer Es Vegyeszet | New process for producing amides of omega-amino-carboxylic acids |
HU180443B (en) * | 1979-04-02 | 1983-03-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing a pharmaceutical preparation with synergetic action against radiation |
HU185632B (en) * | 1981-03-27 | 1985-03-28 | Chinoin Gyogyszer Es Vegyeszet | New process for preparing gamma-glutamyl-taurine |
CH665645A5 (en) * | 1981-07-09 | 1988-05-31 | Michel Flork | DIPEPTIDE DERIVATIVES AND THEIR PREPARATION PROCESS. |
HU208072B (en) * | 1990-02-28 | 1993-08-30 | Chinoin Gyogyszer Es Vegyeszet | Process for producing pharmaceutical composition suitable for preventing and curing autoimmune diseases and skin affections caused by heat and light radiacion |
JPH0680964A (en) * | 1991-12-27 | 1994-03-22 | Sogo Yatsukou Kk | Active-oxygen scavenger |
JPH11180846A (en) * | 1997-12-15 | 1999-07-06 | Sogo Pharmaceut Co Ltd | Cosmetic |
DE10133197A1 (en) * | 2001-07-07 | 2003-01-23 | Beiersdorf Ag | Use of topical compositions containing beta-amino acids, guanidinoethanesulfonate, homotaurine and their precursors and derivatives e.g. to improve skin condition and to treat or prevent skin disorders |
DK2089417T3 (en) | 2006-10-12 | 2015-03-23 | Bhi Ltd Partnership | Methods, Compounds, Compositions and Vehicles for Delivery of 3-Amion-1-Propanesulfonic Acid |
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- 1975-04-25 ES ES436986A patent/ES436986A1/en not_active Expired
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- 1975-04-25 SE SE7504828A patent/SE430164B/en not_active IP Right Cessation
- 1975-04-28 CH CH539075A patent/CH617183A5/de not_active IP Right Cessation
- 1975-04-28 NO NO751504A patent/NO146430C/en unknown
- 1975-04-28 CA CA225,659A patent/CA1051802A/en not_active Expired
- 1975-04-28 SU SU752128794A patent/SU747419A3/en active
- 1975-04-28 EG EG262/75A patent/EG11847A/en active
- 1975-04-28 FR FR7513230A patent/FR2279388A1/en active Granted
- 1975-04-28 AU AU80564/75A patent/AU499173B2/en not_active Expired
- 1975-04-28 DD DD193288A patent/DD125070A5/xx unknown
- 1975-04-28 DD DD185727A patent/DD122377A5/xx unknown
- 1975-04-28 DK DK182875A patent/DK155433C/en not_active IP Right Cessation
- 1975-04-28 GB GB17608/75A patent/GB1504541A/en not_active Expired
- 1975-04-29 BG BG030770A patent/BG26370A4/en unknown
- 1975-04-29 BG BG030768A patent/BG26369A4/en unknown
- 1975-04-29 PL PL1975196801A patent/PL111745B1/en unknown
- 1975-04-29 BG BG030769A patent/BG26517A4/en unknown
- 1975-04-29 NL NLAANVRAGE7505075,A patent/NL183186C/en not_active IP Right Cessation
- 1975-04-29 CS CS752987A patent/CS209855B2/en unknown
- 1975-04-29 BE BE155914A patent/BE828546A/en not_active IP Right Cessation
- 1975-04-29 BG BG029816A patent/BG26368A3/en unknown
- 1975-04-29 PL PL1975196798A patent/PL111746B1/en unknown
- 1975-04-30 JP JP50051612A patent/JPS6012347B2/en not_active Expired
-
1976
- 1976-04-02 AR AR262768A patent/AR218221A1/en active
- 1976-04-02 AR AR262770A patent/AR218222A1/en active
- 1976-04-02 AR AR262769A patent/AR217236A1/en active
- 1976-11-13 ES ES453304A patent/ES453304A1/en not_active Expired
- 1976-11-13 ES ES453306A patent/ES453306A1/en not_active Expired
- 1976-11-13 ES ES453305A patent/ES453305A1/en not_active Expired
-
1977
- 1977-08-30 AT AT624777A patent/AT359084B/en not_active Expired
- 1977-08-30 AT AT624977A patent/AT351007B/en not_active IP Right Cessation
- 1977-08-30 AT AT624877A patent/AT359085B/en not_active IP Right Cessation
- 1977-10-06 DK DK442877A patent/DK158676C/en active
- 1977-10-06 DK DK442977A patent/DK442977A/en unknown
- 1977-10-06 DK DK442577A patent/DK442577A/en not_active Application Discontinuation
- 1977-10-06 DK DK442377A patent/DK155520C/en not_active IP Right Cessation
- 1977-10-06 DK DK442777A patent/DK442777A/en not_active Application Discontinuation
- 1977-10-06 DK DK443077A patent/DK159267C/en not_active IP Right Cessation
- 1977-10-06 DK DK442677A patent/DK159654C/en not_active IP Right Cessation
- 1977-10-06 DK DK442477A patent/DK155732C/en not_active IP Right Cessation
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1978
- 1978-09-22 CS CS786128A patent/CS209856B2/en unknown
- 1978-09-22 CS CS786130A patent/CS209858B2/en unknown
- 1978-09-22 CS CS786129A patent/CS209857B2/en unknown
- 1978-12-14 SE SE7812884A patent/SE441356B/en not_active IP Right Cessation
-
1979
- 1979-04-30 AT AT0323179A patent/AT370724B/en not_active IP Right Cessation
- 1979-04-30 AT AT0323079A patent/AT374484B/en not_active IP Right Cessation
- 1979-10-19 CH CH943379A patent/CH624098A5/de not_active IP Right Cessation
- 1979-10-19 CH CH943279A patent/CH621334A5/de not_active IP Right Cessation
- 1979-10-19 CH CH943179A patent/CH621333A5/de not_active IP Right Cessation
-
1981
- 1981-03-10 NO NO810816A patent/NO149036C/en unknown
-
1983
- 1983-05-31 DK DK245783A patent/DK155672C/en not_active IP Right Cessation
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PBP | Patent lapsed |