DK155433B - 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
- Publication number
- DK155433B DK155433B DK182875AA DK182875A DK155433B DK 155433 B DK155433 B DK 155433B DK 182875A A DK182875A A DK 182875AA DK 182875 A DK182875 A DK 182875A DK 155433 B DK155433 B DK 155433B
- Authority
- DK
- Denmark
- Prior art keywords
- group
- carbon atoms
- water
- carbobenzyloxy
- benzyl
- Prior art date
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims 7
- 125000003545 alkoxy group Chemical group 0.000 claims 4
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 2
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Classifications
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- 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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- 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
DK 155433 BDK 155433 B
Den foreliggende opfindelse angår en analogifremgangsmåde 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 aminosyrederivater har den almene formel 5The amino acid derivatives prepared by the process of the invention have the general formula 5
NH--CH-COOHNH - CH-COOH
2 I2 I
Wn 1 CO-N-CH-(CH,),-B1 |l, 10 R R2 hvor B er en gruppe med formlen -SC^OH eller -ΟΡΟ(ΟΗ)2/ R er et hydrogenatom eller en alkylgruppe med 1-4 kulstof** 15 atomer, 2 R er et hydrogenatom eller en karboxylgruppe, n er 1 eller 2, og t er 1 eller 2, eller er fysiologisk acceptable salte eller optisk aktive antipoder deraf.Wn 1 CO-N-CH- (CH,), - B1, 10, R 2 where B is a group of the formula -SC 2 OH or -ΟΡΟ (ΟΗ) 2 / R is a hydrogen atom or an alkyl group of 1- 4 carbon ** 15 atoms, 2 R is a hydrogen atom or a carboxyl group, n is 1 or 2, and t is 1 or 2, or are physiologically acceptable salts or optically active antipodes thereof.
2020
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 skal på grund af dens biologiske virkning navnlig fremhæves v-L-25 glutamyltaurin, der svarer til formlen · h.n-ch-cooh 2 i CKpAmong the compounds of the invention, due to its biological effect, v-L-25 glutamyltaurine corresponding to the formula h.n-ch-cooh 2 in CKp
30 [ * XXIV30 [* XXIV
CH0 I 2 C0-NH-CH2-CH2-S020H og som har et bredt' terapeutisk og 35 præventivt virkningsspektrum over for sygelige forandringer der kan føres tilbage til beskadigelser af "AGAS" (det aerobiosfæri-ske genetiske adaptionssystem).CHO I 2 CO-NH-CH2-CH2-SO20H and which has a broad therapeutic and preventive spectrum of action against morbid changes that can be traced back to damage by "AGAS" (the aerobiospheric genetic adaptation system).
22
DK 155433 BDK 155433 B
Til belysning af begrebet "AGAS" opregnes i det følgende de vigtigste væv og organer der danner dette system.To illustrate the concept of "AGAS", the following are the main tissues and organs that form this system.
a) Alle biologiske grænseflader der står i berøring med den ydre luft som biosfæren(hud og huddannelser, øjets hornhinde 5 og Conjunlctiva, mund- og svælghulrum, luftveje og lunge); 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- 1 o nal); d) det tii findeling af næringen nødvendige tekodonte (i tandaveå)lerne med rødder fastgjorte) tandsæt; e) høre-, lugte-o g stemmeorganer.(a) all biological interfaces in contact with the external air such as the biosphere (skin and skin formation, eye cornea 5 and Conjunctiva, oral and pharyngeal cavities, respiratory tract and lung); 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 kidney channels); (d) the tooth decomposition of the nourishment required by the tooth (in tandave) clay with roots); e) hearing, smell and voice organs.
De omhandlede forbindelser udøver således en gunstig bi-15 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, begunsti-20 gelse af sårheling, almindelig aktiverende virkning på mesenkym, beskyttelse mod den stadigt voksende infektions- og tilsmudsningsfare hos hud og slimhinder (den fugtige slimhindes lyso-zymproduktion, aktivering af fimreepiteler i luftvejene osv.), forøget beskyttelse mod de af vira og svampe forårsagede infek-25 tioner.In addition, the compounds of the present invention act upon the following functions associated with the AGAS system: radiation protection, favoring wound healing, common activating effect on mesenchymal, protection against the ever-growing infection and contamination risk of skin and mucosa ( the lysozyme production of the moist mucosa, activation of the gut epithelium in the respiratory tract, etc.), increased protection against the infections caused by viruses and fungi.
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 30 nattemperatur, forhøjet fare for kvæstelser), idet de stabiliserer adaptionssyndromet og samtidigt afværger glukokortikoi-dernes perifere vævsskader (som fx skader i bindevævet, kvæstelser af knoglematrixbestanddele osv.). Udvikling af immun-homøostase (stigende erkendelsesevne hos legemet om hvilke cel-35 ler der er kropsegne og hvilke der ikke er)..The compounds of the present 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. adaptation syndrome and at the same time mitigates the peripheral tissue damage of the glucocorticoids (such as damage to the connective tissue, injury to bone matrix components, etc.). Development of immune homeostasis (increasing body recognition of which cells are capable and which are not).
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser udøver deres virkning dels umiddelbart, 3The compounds prepared by the process according to the invention exert their effect partly immediately, 3
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dels over reguleringen af vitamin A metabolismen, ved produktion af vitamin A metaboliter med stærkere polær karakter.partly through the regulation of vitamin A metabolism, by the production of vitamin A metabolites with a stronger polar character.
Denne virkning kan sammenlignes med parathormonets virkning på 25-hydroxycholecalciferol-1a-hydroxylase-enzymet i nyrekanalen. Virkningsretningerne af forbindelserne er følgende: 5 A) Virkninger med vitamin A-karakter: a) Farmakologiske og biokemiske virkningers forøgende virkning på kondroitinsulfatsyntese; gunstig virkning på sårhelingen eller på den ved indgift af kortison eksperimentelt 10 forringede sårheling hos rotter og hunde; potentierende virkning på vitamin A's virkning hos rotter og høns ved eksperimentelt fremkaldte hypo- eller hypervitaminoser; dæmpende virkninger på de ulcer ations-betingede stress-virkninger hos rotter; begunstigende virkning på degranulationen af mastocyter; forøgende virkning på 15 produktionen af lysozym; virkning på sporstofhusholdningen (silicium, zink, kobber, mangan, fluor); fremmende virkning på epiteldannelsen; fremmende virkning på den alkaliske fosfatasealctivitet; virkningen på den ved lokal indvirkning af vitamin A fremkaldte granulomposedannelse (Granulomsackbildung); det yderst flade for-20 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.This effect can be compared to the effect of the parathormone on the 25-hydroxycholecalciferol-1α-hydroxylase enzyme in the renal tract. The directions of action of the compounds are as follows: 5 A) Vitamin A grade effects: a) Increasing effect of pharmacological and biochemical effects on chondroitin sulfate synthesis; beneficial effect on the wound healing or on the experimentally reduced wound healing by cortisone in rats and dogs; potentiating effect on vitamin A's effect in rats and chickens in experimentally induced hypo- or hypervitaminosis; attenuating effects on the ulcer ation-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.
25 b) Klinislc-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 virkning; gunstig virkning på helingen ved operationssår og slimhindesår; erosio colli; pruritusagtige lidelser; nedsættelse af lugte- og smagssansen.B) 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; the susceptibility of skin and mucous membranes to viruses and fungi; cortisone antagonistic effect; beneficial effect on healing of operative and mucosal wounds; erosio colli; pruritus-like disorders; reducing the sense of smell and taste.
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4 B) Virkninger -uden vitamin A-karakter a) Farmakoligiske og biokemiske virkninger: virkning på blodsukkerniveauet med hensyn til en forbigående sænkning; forøgende virkning på fosfaturi, sænkende virkning på fosfatniveauet 5 i serum; strålingsbeskyttende virkning; formindskende virkning på den nødvendige tid der går med at nå målet ved labyrintforsøg hos inaktiverede dyr; formindskende virkning på eksperimentelt fremkaldte fluor- og kadmiumtoxikoser; forøgende virkning på den cykliske adenosinmonofosfat-udtømning af nyrerne; dæmpende virkning ^ ‘ på symptomerne ved· eksperimentelt fremkaldt lathyrismus; formindskelse af histaminfølsomheden; forøgende virkning på aktiviteten af leverenzymet tyrosinaminotransferase.4 B) Effects - other than Vitamin A grade a) Pharmacoligial and biochemical effects: effect on blood sugar levels with regard to a transient reduction; increasing effect on phosphaturia, lowering effect on phosphate level 5 in serum; radiation protective effect; reducing the time required to reach the goal of maze trials in inactivated animals; diminishing effect on experimentally induced fluorine and cadmium toxicosis; increasing effect on the cyclic adenosine monophosphate depletion of the kidneys; attenuating effect on the symptoms of experimentally induced lathyrism; decrease in histamine sensitivity; enhancing effect on liver enzyme tyrosine aminotransferase activity.
b) Terapeutiske virkninger: svage bestrålingsskader; 15 vitiligo; muskelhypotoni; psykoenergetiserende virkning; gunstig 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; 15 vitiligo; muscle hypotonia; psychoenergetic effect; beneficial effect on involutional and gerontological conditions as well as on the mnestic functions; keloid inclinations; spondylosis ankylo poetica; diseases of the movement organs due to wear and tear; scle-rotic fundus; amyloidosis; morphea; fibrocytic mastopathy.
2020
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser kan anvendes til tilsætning til lægemiddelblandinger. De forbedrer vitamin A metabolismen. Desuden forøges resorptionen af sporgrundstoffer ved hjælp af forbindelserne idet sporgrundstoffernes koncentration i blodet hæves.The compounds of the process according to the invention can be used for addition to drug mixtures. They improve vitamin A metabolism. In addition, the resorption of trace elements by the compounds is increased as the concentration of trace elements in the blood is increased.
25 I veterinærmedicinen har de ifølge opfindelsen fremstil 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 kravets kendetegnende del angivne.The process according to the invention is characterized by the characterizing part of the claim.
Fremgangsmåden ifølge opfindelsen belyses nærmere i det følgende ved hjælp af nogle eksempler.The process according to the invention is illustrated in the following by means of some examples.
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Eksempel 1 a) Karbobenzyloxy-γ-(g-benzyl)-L-glutamyltaurin 40,85 g (0,11 mol) karbobenzyloxy-L-glutaminsyre-a-ben- zylester (Liebigs Annalen 655, 200, 1962) opløses i 500 ml aceto- nitril. Opløsningen afkøledes til -15°C under udelukkelse af luft-5 fugtigheden. Til opløsningen sættes dråbevis under omrøring først 15,4 ml (0,11 mol) triætylamin og derpå 15,4 ml (o,11 mol) klormy-resyreisobutylester. Reaktionsblandingen omrøres ved -15°C i 40 minutter og derpå tilsættes 28 ml (0,2 mol) triætylamin efterfulgt af 11,26 g (0,05 mol) cystamin-hydroklorid og til sidst 250 ml ace- 10 tonitril. Blandingen efteromrøres ved -15 C i yderligere to timer og derpå i yderligere fire timer ved stuetemperatur.Example 1 a) Carbobenzyloxy-γ- (g-benzyl) -L-glutamyltaurine 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 11.26 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°CAfter the reaction time expires, the mixture is evaporated at 30 ° C
under vakuum. Remanensen optages under omrøring og afkøling i 200 ml isvand og blandingen inddampes påny ved 35°C under vakuum. Re-15 manensen indføres sammen med 250 ml vand og 500 ml ætylacetat 1 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% natriumkarbonatopløsning hver gang og derpå 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-oc-ben-zylester). Ætylacetatfasen tørres over vandfrit natriumsulfat og inddampes derpå under vakuum ved 30°C til tørhed. Der vindes en 25 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 N, N' -bis-/N-lcarbobenzyloxy-y- (α-benzyl )-L-glutamyl7-cystamin med smeltepunkt 91-92°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, together with 250 ml of water and 500 ml of ethyl acetate 1, is introduced into a separatory funnel and the organic phase is separated. In the said order, the organic phase is first shaken with 250 ml of water, then twice with 250 ml of 5% sodium carbonate solution each time and then 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 and benzyl ester can be recovered). The ethyl acetate phase is dried over anhydrous sodium sulfate and then evaporated under vacuum at 30 ° C to dryness. There is obtained a 25 thick, oily residue which quickly solidifies to a crystalline mass. This is torn 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. 29.3 g of N, N '-bis- / N-lcarbobenzyloxy-γ- (α-benzyl) -L-glutamyl7-cystamine are obtained, mp 91-92 ° C.
Beregnet for CMH.nN,0inSo (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% 35 6Calcd for CMH.NN, 0inSo (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% 35 6
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25,77 g (0,3 mol) af det ovenfor vundne N,N’- bis-^N-Icarbobenzyloxy-y-(a-benzyl)-L-glutamyl7-cystamin opløses i 75 ml iseddilcesyre. Den i is afkølede opløsning sættes i løbet af 15 minutter dråbevis til en frisk tilberedt blanding af 75 ml 30%s hydrogenperoxyd og 225 ml iseddikesyre. Efter tilsætningen 5 fjernes kølingen og reaktionsblandingen omrøres i fire timer ved stuetemperatur. Derpå inddampes der under vakuum ved 30°C. Det olieagtige produkt tørres i en elcssilckator først over fosforpent-oxyd og derpå over fast kaliumhydroxyd. Der vindes 28,5 g lcarbo-benzyloxy-y-(a-benzyl)-L-glutamyltaurin. Det rå produkt kan uden rensning anvendes til fremstilling af y-L-glutamyltaurin.25.77 g (0.3 mole) of the above-obtained N, N'-bis- N-Icarbobenzyloxy-γ- (α-benzyl) -L-glutamyl7-cystamine are dissolved in 75 ml of glacial acetic acid. The ice-cooled solution is added dropwise over 15 minutes to a freshly prepared mixture of 75 ml of 30% hydrogen peroxide and 225 ml of glacial acetic acid. After addition 5, 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 an electric silencer first over phosphorus pentoxide and then over solid potassium hydroxide. 28.5 g of lcarbo-benzyloxy-γ- (α-benzyl) -L-glutamyltaurine are obtained. The crude product can be used without purification to prepare γ-L-glutamyltaurine.
b) Ύ-L- QLutamyltaurin 5,79 g (12,1 mmol) af det ifølge eksempel 1 a) fremstillede 15 karbobenzyloxy-y-(a-benzyl)-L-glutamyltaurin opløses i en blanding af 100 ml ætanol og 25 ml vand og hydrogeneres under rystning i nærværelse af 0,5 g 10%s palladiumkulstof som katalysator. Efter at hydrogenforbruget er ophørt filtreres opløsningen hvorpå den inddampes ved 30°C under vakuum. Den olieagtige remanens tørres i 20 ekssikkator over fosforpentoxyd. Der vindes 3,1 g γ-L-glutamyltaurin der let opløses i vand men ikke i alkohol. Ved tilsætning af en lille smule vand og alkohol i små portioner kan produktet krystalliseres. Det krystallinske råprodukt smelter ved 202-204°C.b) Ύ-L-QLutamyltaurine 5.79 g (12.1 mmol) of the carbobenzyloxy-γ- (α-benzyl) -L-glutamyltaurine prepared in accordance with Example 1 a) are dissolved in a mixture of ethanol (100 ml) and 25 ml. water and hydrogenated with shaking in the presence of 0.5 g of 10% palladium carbon as a catalyst. After the hydrogen consumption has ceased, the solution is filtered and evaporated at 30 ° C under vacuum. The oily residue is dried in desiccator over phosphorus pentoxide. 3.1 g of γ-L-glutamyltaurine is obtained, which is easily dissolved in water but not in alcohol. By adding a small amount of water and alcohol in small portions, the product can be crystallized. The crystalline crude product melts at 202-204 ° C.
Råproduktet omkrystalliseres flere gange fra 80%s æta-25 nol. Der vindes 2,02 g rent slutprodukt som beregnet ud fra N,N'-bis-/N-karbobenzyloxy-y-(α-benzyl)-L-glutamyl7-cystamin svarer til et udbytte på 66%. Det rene produkt smelter ved 219-220°C. a^° = +14° (vand, c = 1,02). Den relative bevægelighed i forhold til cysteinsyre ved papirelelctroforese gennemført ved pH 6,5 ud-3 0 gør 0,73, ved pH 1,8 0,53.The crude product is recrystallized several times from 80% ethanol. 2.02 g of pure final product is obtained as calculated from N, N'-bis- / N-carbobenzyloxy-γ- (α-benzyl) -L-glutamyl7-cystamine corresponding to a yield of 66%. The pure product melts at 219-220 ° C. = + 14 ° (water, c = 1.02). The relative mobility to cysteic acid by paper electrophoresis carried out at pH 6.5 out-of-30 makes 0.73, at pH 1.8 0.53.
Rp (n-Butanol/pyridin/iseddike/vand 15:10:3:12) = 0,19.Rp (n-Butanol / pyridine / glacial acetic acid / water 15: 10: 3: 12) = 0.19.
Beregnet for CyHy^OgS (m = 254,27): C 33,07 H 5,55 N 11,02 0 37,75 S 12,61 fundet: C 33,15 H 5,76 N 10,94 0 37,53 S 12,17%.Calcd for CyHy 2 O 4 S (m = 254.27): C 33.07 H 5.55 N 11.02 0 37.75 S 12.61 Found: C 33.15 H 5.76 N 10.94 0 37, 53 S, 12.17%.
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Eksempel 2 a) Ύ-(a-Benzyl)-L-glutamyltaurin 26,32 g (55 mmol) af det ifølge eksempel 1 a) fremstillede lcarbobenzyloxy-y-(oc-benzyl)-L-glutamyltaurin opløses i 50 ml is-5 eddikesyre. Til opløsningen sættes 4 mol brombrinte opløst i 50 ml iseddike. Der iagttages en livlig kulstofdioxydudvikling. Reaktionsblandingen henstår ved stuetemperatur i to timer og inddampes derefter under vakuum ved 30°C. Den olieagtige remanens opløses i 170 ml vand og rystes fem gange med 70 ml æter hver gang.Example 2 a) )- (α-Benzyl) -L-glutamyltaurine 26.32 g (55 mmol) of the carbobenzyloxy-γ- (oc-benzyl) -L-glutamyltaurine prepared in Example 1 a) are dissolved in 50 ml of ice-cream. 5 acetic acid. To the solution is added 4 moles of hydrocarbon dissolved in 50 ml of glacial acetic acid. Lively carbon dioxide evolution is observed. The reaction mixture is left at room temperature for two hours and then evaporated under vacuum at 30 ° C. Dissolve the oily residue in 170 ml of water and shake five times with 70 ml of ether each time.
Den vandige fase inddampes ved 35°C under vakuum. Der vindes 20,42 g y-(a-benzyl)-L-glutamyltaurin som omkrystalliseres fra 90%s ætanol .The aqueous phase is evaporated at 35 ° C under vacuum. 20.42 g of γ- (α-benzyl) -L-glutamyltaurine are obtained, which is recrystallized from 90% ethanol.
Rp (n-Butanol/pyridin/iseddike/vand 15:10:3:12) = 0,53 Rp (n-butanol/iseddike/vand 4:l:l) = 0,39.Rp (n-Butanol / pyridine / glacial acetic acid / water 15: 10: 3: 12) = 0.53 Rp (n-butanol / glacial acetic acid / water 4: 1: 1) = 0.39.
15 b) γ-L-GlutamyltaurinB) γ-L-Glutamyltaurine
Det ifølge eksempel 2a) vundne y-(oc-benzyl)-L-glutamyltau-rin (20,42 g) opløses i 150 ml IN kaliumhydroxydopløsning. Opløsningen henstår i fire timer ved stuetemperatur og overføres derpå til en kolonne på 2 x 100 cm fyldt med "Dowex" 50 x 2 (Fluka, 100-200 mesh) der befinder sig i H -cyklus. Der elueres med vand. Beregnet fra begyndelsen af udvaskningen opsamles 300 ml eluat. Dette inddampes under vakuum ved 35°C. Den olieagtige remanens krystalliseres ved tilsætning af 8-10 ml vand og ca. 100 ml ætanol.The γ- (oc-benzyl) -L-glutamyl taurine (20.42 g) obtained in Example 2a) is dissolved in 150 ml of 1 N potassium hydroxide solution. The solution is left for four hours at room temperature and then transferred to a column of 2 x 100 cm filled with "Dowex" 50 x 2 (Fluka, 100-200 mesh) which is in the H cycle. Elute with water. From the beginning of the washout, 300 ml of eluate is collected. This is evaporated under vacuum at 35 ° C. The oily residue is crystallized by the addition of 8-10 ml of water and ca. 100 ml of ethanol.
25 Efter filtrering, vask med alkohol og tørring vindes 13,7 g y-L-glutamyltaurin. Det krystallinske produkt omkrystalliseres fra 80%s vandig ætanol. Der vindes 9,79 g rent produkt som regnet ud fra N,N'-bis-/N-lcarbobenzyloxy-y-(a-benzyl)-L-glutamyl7-cystamin svarer til et udbytte på 10%.After filtration, washing with alcohol and drying, 13.7 g of γ-L-glutamyltaurine are obtained. The crystalline product is recrystallized from 80% aqueous ethanol. 9.79 g of pure product are obtained as calculated from N, N'-bis- / N-lcarbobenzyloxy-γ- (a-benzyl) -L-glutamyl7-cystamine corresponding to a yield of 10%.
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Eksempel 3 ϊ-L-Glutamyltaurin 5,42 g (11 mmol) karbobenzyloxy-L-glutaminsyre-(a-ben-zyl)-y-p-nitrofenylester (Chem. Ber. 96, 204, 1963) opløses i 50 ml pyridin. Opløsningen afkøles til 0°C og inden for en halv time tildryppes der under intensiv omrøring en opløsning af 1,25 g (lo mmol) taurin i 20 ml vand. Derpå sættes der 3,08 ml (22 mmol) tri- 8 π i*' Ί Γ Γ / 7 Ο U ί\ ! ·. ι ϋ 'τ j C Ο ætylamin til blandingen, afkølingen og omrøringen afbrydes. Blandingen henstår ved stuetemperatur i 72 timer og inddampes derpå under vakuum. Remanensen opløses i 50 ml vand og der sættes IN saltsyre til den gule opløsning indtil den affarves. Por at fjerne p-nitrofenolen rystes opløsningen ti gange med 50 ml æter hver gang. Denne vandige fase '.nddampes under vakuum. Der vindes 6,9 g karbobenzyloxy-γ-(α-benzyl)-L-glutamyltaurin-triætylammoniumsalt.Example 3? -L-Glutamyltaurine 5.42 g (11 mmol) of carbobenzyloxy-L-glutamic acid (a-benzyl) -γ-p-nitrophenyl ester (Chem. Ber. 96, 204, 1963) are dissolved in 50 ml of pyridine. The solution is cooled to 0 ° C and within half an hour a solution of 1.25 g (100 mmol) of taurine in 20 ml of water is added dropwise. Then, 3.08 ml (22 mmol) of tri-8 π are added to * 'Ί Γ Γ / 7 Ο U ί \! ·. ι ϋ 'τ j C Ο ethylamine until the mixture, cooling and stirring are interrupted. The mixture is left at room temperature for 72 hours and then evaporated under vacuum. The residue is dissolved in 50 ml of water and IN hydrochloric acid is added to the yellow solution until it is decolorized. To remove the p-nitrophenol, shake the solution ten times with 50 ml of ether each time. This aqueous phase is evaporated under vacuum. 6.9 g of carbobenzyloxy-γ- (α-benzyl) -L-glutamyltaurine-triethylammonium salt are obtained.
Substansen hydrogeneres katalytisk på den i eksempel lb beskrevne måde og opløsningsmidlet fjernes ved inddampning under vakuum. For at fjerne triætylaminen opløses stoffet i en lille smule vand og overføres til en "Dowex" 50 x 2-lcolonne på 2 x 40 cm.The substance is catalytically hydrogenated in the manner described in Example 1b and the solvent is removed by evaporation under vacuum. To remove the triethylamine, the substance is dissolved in a small amount of water and transferred to a "Dowex" 50 x 2 column of 2 x 40 cm.
1010
Der elueres med vand." Der opsamles ca. 120 ml eluat og dette inddampes derpå under vakuum ved 35°C. Krystallisation og isolering af produktet sker på den måde der er beskrevet i eksempel lb. Der vindes 1,72 g γ-L-glutamyltaurin som i forhold til taurin svarer til et udbytte på 68%, smp. 219-220°C, = +14° (c = 1, i vand).Elute with water. "Approximately 120 ml of eluate are collected and then evaporated under vacuum at 35 ° C. Crystallization and isolation of the product are carried out in the manner described in Example 1b. 1.72 g of γ-L glutamyltaurine which corresponds to a yield of 68% relative to taurine, mp 219-220 ° C, = + 14 ° (c = 1, in water).
Eksempel 4 γ-D-GlutamyltaurinExample 4 γ-D-Glutamyltaurine
Karbobenzyloxy-γ- (α-benzyl) -D-g-lutamyltaurin-triætylammo-20 niumsalt fremstillet på den i eksempel 3 beskrevne måde hydrogeneres katalytisk på samme måde som i eksempel 3. Det vundne γ-D-glutamyl-taurin smelter ved 219-220°C, a^° = -13,9° (c = 1, i vand).Carbobenzyloxy-γ- (α-benzyl) -Dg-lutamyltaurine-triethyl-ammonium salt prepared in the manner described in Example 3 is catalytically hydrogenated in the same manner as Example 3. The obtained γ-D-glutamyl-taurine melts at 219-220 = -13.9 ° (c = 1, in water).
Eksempel 5 25 ---------- a) Karbobenzyloxy-Y-L-glutamyltaurin 529 mg (1,1 mmol) af det ifølge eksempel 1 a) fremstillede karbobenzyloxy-y-(a-benzyl)-L-glutamyltaurin opløses i 5 ml IN kaliumhydroxydopløsning og henstår i fire timer ved stuetempera-30 tur. Derpå udrystes opløsningen tre gange med 3 ml æter hver gang. Den vandige fase overføres på en med "Dowex" 50 x 2 fyldt kolonne på 1 x 20 cm og elueres med vand. ("Dowex" er et i Danmark indregistreret varemærke). Der opsamles 50 ml opløsning som inddampes til tørhed under vakuum ved 35°C. Der vindes råt karbobenzyloxy-35 γ-L-glutamyltaurin som renses ved papirelektroforese gennemført ved pH 6,5· Den relative bevægelighed i forhold til cysteinsyre udgør 1,05-Example 5 ---------- a) Carbobenzyloxy-YL-glutamyltaurine 529 mg (1.1 mmol) of the carbobenzyloxy-γ- (α-benzyl) -L-glutamyltaurine dissolved in Example 1a in 5 ml of 1N potassium hydroxide solution and leave for four hours at room temperature. Then the solution is shaken three times with 3 ml of ether each time. The aqueous phase is transferred to a 1 x 20 cm 1 x 20 cm column filled with "Dowex" and eluted with water. ("Dowex" is a trademark registered in Denmark). Collect 50 ml of solution which is evaporated to dryness under vacuum at 35 ° C. Crude carbobenzyloxy-35 γ-L-glutamyltaurine is obtained which is purified by paper electrophoresis carried out at pH 6.5. The relative motility to cysteic acid is 1.05%.
Rp (n-Butanol/pyridin/iseddike/vand 15:10:3:12) = 0,57.Rp (n-Butanol / pyridine / glacial acetic acid / water 15: 10: 3: 12) = 0.57.
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9 b) γ-L-GlutamyltaurinB) γ-L-Glutamyltaurine
Det ifølge eksempel 5a) vundne karbobenzyloxy-y-L-gluta-myltaurin opløses i 2 ml iseddike der indeholder 4 mol brombrinte. Blandingen henstår ved stuetemperatur i en halv time og inddampes derpå ved 35°C under vakuum. Remanensen rives fire gange med æter 5 og skilles derpå fra æteren ved dekantering. Det vundne γ-L-glu-tamyltaurin omkrystalliseres på den i eksempel 3 beskrevne måde.The carbobenzyloxy-γ-L-gluta-myltaurine obtained according to Example 5a) is dissolved in 2 ml glacial acetic acid containing 4 moles of hydrocarbon. The mixture is left at room temperature for half an hour and then evaporated at 35 ° C under vacuum. The residue is ripped four times with ether 5 and then separated from the ether by decanting. The obtained γ-L-glu-tamyltaurine is recrystallized in the manner described in Example 3.
Eksempel 6 γ-L-Glutamyltaurin,mononatriumsalt 10 ----- .Example 6 γ-L-Glutamyltaurine, monosodium salt 10 -----.
25,4 mg (0,1 mmol) γ-L-glutamyltaurm opløses i 2 ml vand og der sættes 10 ml 0,01 N natriumhydroxydopløsning til opløsningen. Blandingen inddampes ved 30°C under vakuum. Den hvide krystallinske remanens tørres i elcssikkator over fosforpen toxyd.Dissolve 25.4 mg (0.1 mmol) of γ-L-glutamyl taurine in 2 ml of water and add 10 ml of 0.01 N sodium hydroxide solution to the solution. The mixture is evaporated at 30 ° C under vacuum. The white crystalline residue is dried in elecsicator over phosphorous toxide.
15 Der vindes et mononatriumsalt af γ-L-glutamyltaurin. Produktet har intet skarpt smeltepunkt, begynder at skrumpe ved 200°C, dets farve bliver stadig mørkere, og ved ca. 250°C forkuller det. Produktet er lige dårligt opløseligt i metanol og ætanol.A monosodium salt of γ-L-glutamyltaurine is obtained. The product has no sharp melting point, begins to shrink at 200 ° C, its color becomes darker, and at approx. 250 ° C char it. The product is equally poorly soluble in methanol and ethanol.
Eksempel 7 20 ---------- a) Karbobenzyloxy-a-L-glutamyl-(γ-taurin)-glycin-ætylester_ 0,48 g (l mmol) karbobenzyloxy-a-L-glutamyl-(y-p-nitro- fenylester)-glycinætylester (Acta Chim. Acad. Sci. Hung. 65, 375, 2 5 1970) opløses i 6 ml ætylacetat. Opløsningen afkøles med isvand. Ved 0°C sættes der først 0,08 g (l mmol) cysteamin i 1 ml dimetyl-formamid til opløsningen hvorpå der tildryppes 0,14 ml (l mmol) triætylamin. Der begynder langsomt at udfælde sig et bundfald. Reaktionsblandingen henstår yderligere i nogen tid i isvand hvor-på den henstår endag ved stuetemperatur og til sidst fortyndes med en blanding i forholdet 1:1 af æter og ætylacetat. Bundfaldet fracentrifugeres og vaskes først med en blanding af æter og ætylacetat i forholdet 4:1 og derpå flere gange med æter. Efter tørring over svovlsyre vaskes bundfaldet tre gange med IN saltsyre, to gange med vand, to gange med mættet natriumhydrogenkarbonatopløsningExample 7 ---------- a) Carbobenzyloxy-αL-glutamyl (γ-taurine) glycine ethyl ester 0.48 g (1 mmol) carbobenzyloxy-αL-glutamyl (γ-nitrophenyl ester) ) -glycine ethyl ester (Acta Chim. Acad. Sci. Hung. 65, 375, 2.5 1970) is dissolved in 6 ml of ethyl acetate. The solution is cooled with ice water. At 0 ° C, 0.08 g (1 mmol) of cysteamine in 1 ml of dimethylformamide is first added to the solution, whereupon 0.14 ml (1 mmol) of triethylamine is added dropwise. A precipitate slowly begins to precipitate. The reaction mixture is left for some time in ice water, where it is left at room temperature for one day and finally diluted with a 1: 1 ratio of ether and ethyl acetate. The precipitate is centrifuged and washed first with a mixture of ether and ethyl acetate in a 4: 1 ratio and then several times with ether. After drying over sulfuric acid, the precipitate is washed three times with 1N hydrochloric acid, twice with water, twice with saturated sodium hydrogen carbonate solution.
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10 og til sidst atter to gange med vand hvorpå det tørres under vakuum over svovlsyre. Der vindes 0,35 g karbobenzyloxy-cc-L-glutamyl-(y-cysteamin)-glycinætylester svarende til et udbytte på 85%.10 and finally again twice with water and then dried under vacuum over sulfuric acid. 0.35 g of carbobenzyloxy-cc-L-glutamyl (γ-cysteamine) glycine ethyl ester is obtained, corresponding to a yield of 85%.
Beregnet for C]_8H25°6N3S = 411,4): C 52,6 H 6,1 S 7,8 5 fundet: C 53,4 H 6,5 S 7,7%Calc'd for C 18 H 25 ° 6 N 3 S = 411.4): C 52.6 H 6.1 S 7.8 Found: C 53.4 H 6.5 S 7.7%
Det infrarøde spektrum udviste følgende maksima for de karakteristiske grupper: NH 3310 cm”1, C=0 (C00C2H^) 1748 cm”1, 0=0 (Z) 1690 cm”1, 0=0 (amid) 1655 cm”1.The infrared spectrum exhibited the following maxima for the characteristic groups: NH 3310 cm ”1, C = 0 (C00C₂H ^) 1748 cm” 1, 0 = 0 (Z) 1690 cm ”1, 0 = 0 (amide) 1655 cm” 1 .
100 mg karbobenzyloxy-a-L-glutamyl-(y-cysteamin)-glycin-10 ætylester opløses i 2‘ ml iseddike og der sættes 0,5 ml 30%s hydro-genperoxyd til opløsningen. Reaktionsblandingen henstår i fire timer under isafkøling. Reaktionens fremadskriden følges med papir-elektroforese. Efter fortynding med vand lyofiliseres reaktionsblandingen. Slutproduktet vindes i form af et skum. Der vindes 15 0,11 g (95%) karbobenzyloxy-oc-L-glutamyl-(y-taurin)-glycinætyl- ester.Dissolve 100 mg of carbobenzyloxy-α-L-glutamyl (γ-cysteamine) glycine-10 ethyl ester in 2 ml of glacial acetic acid and add 0.5 ml of 30% hydrogen peroxide to the solution. The reaction mixture is left for four hours under ice-cooling. The progress of the reaction is followed by paper electrophoresis. After dilution with water, the reaction mixture is lyophilized. The final product is wound in the form of a foam. 0.11 g (95%) of carbobenzyloxy-α-L-glutamyl (γ-taurine) glycine ethyl ester is obtained.
b) a-L-Glutamyl-(γ-taurin)-glycin 2Q 100 mg af det ifølge eksempel ya) fremstillede karboben- zyloxy-a-L-glutamyl-(y-taurin)-glycinætylester opløses i en blanding af 1 ml trifluoreddilcesyre og 1 ml koncentreret saltsyre. Opløsningen holdes i tre timer ved 35°C i et lukket bomberør. Derefter inddampes opløsningen under vakuum, remanensen udludes flere gange med æter og n-hexan og inddampes påny. Der vindes et hvidt 2 5 amorft stof der ved elektroforetisk undersøgelse viser sig som en enhed og giver en positiv ninhydrinplet. Produktet er a-L-glutamyl-(γ-taurin)-glycin. Udbytte 0,06 g (88%).b) aL-Glutamyl (γ-taurine) glycine 2Q 100 mg of the carbobenzyloxy-αL-glutamyl (γ-taurine) glycine ethyl ester prepared in Example 1a is dissolved in a mixture of 1 ml of trifluoroacetic acid and 1 ml of concentrated hydrochloric acid. The solution is kept for three hours at 35 ° C in a closed bomb tube. The solution is then evaporated in vacuo, the residue is evaporated several times with ether and n-hexane and evaporated again. A white amorphous white substance is obtained which, by electrophoretic examination, appears as a unit and gives a positive ninhydrin spot. The product is α-L-glutamyl (γ-taurine) glycine. Yield 0.06 g (88%).
Beregnet for C^H^NgOyS (m = 311,3): 30 8 10·3 fundet: S 10,0%.Calculated for C CH ^NgO₂S (m = 311.3): δ 8 10 · 3 found: S 10.0%.
Det infrarøde spektrum udviste følgende maksima for de karakteristiske grupper: NH* 3100 cm"1 (bred); OH (C00H) 3200 cm 1 (bred); 0=0 (C00H) 1730 cm”1; 0=0 (amid-l) 1680 cm”1; 0=0 (amid-ll) 1560 ; S=0 (SOpOH) 1220 cm"1 (intensiv); S=0 (SOpO") 1045 cm”1The infrared spectrum showed the following maxima for the characteristic groups: NH * 3100 cm -1 (wide); OH (C00H) 3200 cm 1 (wide); 0 = 0 (C00H) 1730 cm -1, 0 = 0 (amide-1 1680 cm -1, 0 = 0 (amide-11) 1560; S = 0 (SOpOH) 1220 cm -1 (intensive); S = 0 (SOpO ") 1045 cm" 1
J JJ J
(intensiv).(intensive).
1111
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Hydrolyse: 20 mg af stoffet holdes i 1 ml 6N saltsyre i et tilsmeltet glasrør i 24 timer ved 105°C. Efter afkøling udtrækkes prøven af opløsningen ved elektroforese ved pH 1,8. Opløsningen indeholder glutaminsyre, glycin og taurin.Hydrolysis: 20 mg of the substance is kept in 1 ml of 6N hydrochloric acid in a molten glass tube for 24 hours at 105 ° C. After cooling, the sample is extracted by electrophoresis at pH 1.8. The solution contains glutamic acid, glycine and taurine.
5 c) Karbobenzyloxy-a-L-glutamyl-(γ-taurin)-glycin- metylester_ 0,47 g (1 mmol) karbobenzyloxy-a-L-glutamyl-^-p-nitro-fenylester)-glycinmetylester opløses i 6 ml pyridin. Under isafkøling sættes først 0,125 g (1 mmol) taurin i 2 ml vand og derpå 10 o,28 ml (2 mmol) triætylamin til opløsningen i så små portioner at opløsningen hele tiden forbliver klar. Reaktionsblandingen henstår ved stuetemperatur i tre dage. Efter inddampning under vakuum • vindes en olie som efter grundig udludning i æter og derpå i petroleumsæter tørres under vakuum over svovlsyre. Der vindes karboben-15 zyioxy-a-L-glutamyl-(y-taurin)-glycinmetylester.C) Carbobenzyloxy-α-L-glutamyl (γ-taurine) glycine methyl ester (0.47 g (1 mmol) carbobenzyloxy-α-L-glutamyl (β-nitro-phenyl ester) -glycine methyl ester is dissolved in 6 ml of pyridine. During ice-cooling, 0.125 g (1 mmol) of taurine is first added to 2 ml of water and then 10 o, 28 ml (2 mmol) of triethylamine to the solution in such small portions that the solution remains clear at all times. The reaction mixture is left at room temperature for three days. After evaporation under vacuum, an oil is obtained which, after thorough leaching in ether and then in petroleum ether, is dried under vacuum over sulfuric acid. Carbobenzyloxy-α-L-glutamyl (γ-taurine) glycine methyl ester is obtained.
d) a-L-Glutamyl-(γ-taurin)-glycin 100 mg af den ifølge eksempel 7c) fremstillede karboben-zyloxy-a-L-glutamyl-(y-taurin)-glycinmetylester omsættes med 4 ml 20 2N eddikesurt brombrinte ved stuetemperatur indtil den samlede mængde stof er gået i opløsning (ca. 30 minutter). Den vundne klare opløsning udfældes i 30 ml æter og henstår derpå på et koldt sted i en dag. Det fremkomne bundfald fracentrifugeres, vaskes flere gange med æter og tørres derpå under vakuum over kaliumhy-25 droxyd, svovlsyre og fosforpentoxyd. Det fremgår af den elektroforetiske undersøgelse at hydrogenbromidet af a-L-glutamyl-(γ-taurin) glycinmetylesteren vindes i praktisk talt ren form.d) αL-Glutamyl (γ-taurine) glycine 100 mg of the carbobenzylyloxy-αL-glutamyl (γ-taurine) glycine methyl ester prepared in Example 7c are reacted with 4 ml of 2N acetic acid hydrochloric acid at room temperature until combined amount of substance dissolved (about 30 minutes). The obtained clear solution is precipitated in 30 ml ether and then left in a cold place for a day. The resulting precipitate is centrifuged, washed several times with ether and then dried under vacuum over potassium hydroxide, sulfuric acid and phosphorus pentoxide. The electrophoretic study shows that the hydrogen bromide of the α-L-glutamyl- (γ-taurine) glycine methyl ester is recovered in practically pure form.
Det vundne salt omsættes under afkø- 30 ling med isvand i tre timer med 2 ml N natnumhydroxydopløsning. Hydrolysens fremadskriden følges elektroforetisk. Reaktionsblandingen underkastes ionbytning med 10 ml "Dowex" 50 i H+-form hvorefter den lyofiliseres. Da elektroforesen endnu viser forureninger omkrystalliseres produktet flere gange fra vandigt ætanol indtil der er opnået en tilsvarende renhed. Der vindes 40 mg (59%) a-L-glutamyl-(γ-taurin)-glycin.The obtained salt is reacted under cooling with ice water for three hours with 2 ml of N sodium hydroxide solution. The progress of hydrolysis is followed electrophoretically. The reaction mixture is subjected to ion exchange with 10 ml of "Dowex" 50 in H + form and then lyophilized. Since the electrophoresis still shows contaminants, the product is recrystallized several times from aqueous ethanol until a corresponding purity is obtained. 40 mg (59%) of α-L-glutamyl (γ-taurine) glycine is obtained.
1212
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Det infrarøde spektrum udviser følgende maksima for de karakteristiske grupper: NH 3310 cm""1; NH* 3100 cm 1 (bred; 0=0 (COOH) 1730 cm-1; C=0 (amid i) 1650 cm”1; C=0 (amid II) 1570 cm”1; S=0 1220 (intensiv), 1045 cm-1 (intensiv).The infrared spectrum exhibits the following maxima for the characteristic groups: NH 3310 cm "" 1; NH * 3100 cm 1 (wide; 0 = 0 (COOH) 1730 cm -1; C = 0 (amide i) 1650 cm -1) C = 0 (amide II) 1570 cm -1; S = 0 1220 (intensive) , 1045 cm -1 (intensive).
5 e) Y-L-Glutamyltaurin 100 mg af det under pkt. a+b eller c+d i nærværende eksempel fremstillede a-L-glutamyl-(γ-taurin)-glycin opløses i 25 ml af en 0,2 molær ammoniumhydrogenkarbonatpuffer med en pH-værdi på 8,5. Til opløsningen sættes 1 mg karboxypepti-10 dase A opløst i 0,5 ml vand. JFremstiller af enzymet: Serva,E) Y-L-Glutamyltaurine 100 mg of it under cl. α + b or c + d in this example, α-L-glutamyl (γ-taurine) glycine is dissolved in 25 ml of a 0.2 molar ammonium hydrogen carbonate buffer having a pH of 8.5. To the solution is added 1 mg of carboxypeptidase A dissolved in 0.5 ml of water. J Manufacturer of the enzyme: Serva,
Heidelberg). Blandingen holdes i 24 timer ved 37°C i termostat hvorpå den lyofiliseres. I det tørrede lyofilisat kan der eftervises Ύ-L-glutamyltaurin og glycin. Det rene γ-L-gluta-myltaurin kan vindes ved elektroforese eller kromatografi 15 på en "Dowex" 50-kolonne.Heidelberg). The mixture is kept for 24 hours at 37 ° C in thermostat and lyophilized. In the dried lyophilisate, Ύ-L-glutamyltaurine and glycine can be detected. The pure γ-L-gluta myltaurine can be obtained by electrophoresis or chromatography on a Dowex 50 column.
Eksempel 8 a) Karbobenzyloxy-γ-(α-benzyl)-L-glutamylhomotaurin 1,082 g (2,2 mmol) karbobenzyloxy-L-glutaminsyre-(a-ben- zyl)-y-p-nitrofenylester opløses i 6 ml af en blanding af pyridin og vand i forholdet 2:1. Til opløsningen sættes først 278 mg (2 mmol) homotaurin og derpå 0,59 ml (4,2 mmol) triætylamin. Den gule opløsning henstår ved stuetemperatur i 72 timer og inddampes derpå 25 under vakuum. Den olieagtige remanens opløses i vand, neutraliseres med saltsyre og ekstraheres derpå til fjernelse af p-nitrofenol i en kontinuerlig ekstraktør med æter i otte timer. Den vandige fase inddampes under vakuum. Der vindes 1,68 g karbobenzyloxy-γ-(a-ben-zyl)-L-glutamylhomotaurin.Example 8 a) Carbobenzyloxy-γ- (α-benzyl) -L-glutamylhomotaurine 1.082 g (2.2 mmol) of carbobenzyloxy-L-glutamic acid (α-benzyl) -yp-nitrophenyl ester is dissolved in a mixture of 6 ml. pyridine and water in a 2: 1 ratio. To the solution is first added 278 mg (2 mmol) of homotaurine and then 0.59 ml (4.2 mmol) of triethylamine. The yellow solution is left at room temperature for 72 hours and then evaporated under vacuum. The oily residue is dissolved in water, neutralized with hydrochloric acid and then extracted to remove p-nitrophenol in a continuous ether extractor for eight hours. The aqueous phase is evaporated under vacuum. 1.68 g of carbobenzyloxy-γ- (α-benzyl) -L-glutamyl homotaurine are obtained.
30 b) γ-L-GlutamylhomotaurinB) γ-L-Glutamylhomotaurine
Den samlede mængde af det ifølge eksempel 8a) fremstillede stof (1,68 g) opløses i 10 ml 50%s vandig ætanol hvorpå der tilsættes 0,3 g 10^s palladium-aktivkul og der ledes hydrogen gennem suspen-35 sionen i fire timer. Derpå filtreres opløsningen og inddampes under vakuum. Remanensen opløses i 1-2 ml vand og til fjernelse af tri-The total amount of the substance prepared according to Example 8a) (1.68 g) is dissolved in 10 ml of 50% aqueous ethanol, to which 0.3 g of 10 µl palladium activated carbon is added and hydrogen is passed through the suspension for four minutes. hours. The solution is then filtered and evaporated under vacuum. The residue is dissolved in 1-2 ml of water and to remove
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13 ætylamin .føres den til en kolonne på 1 x 35 cm med "Dowex" 50 x 2 på H+-form. Der elueres med vand. Der opsamles 50 ml eluat hvorel ter der inddampes under vakuum. Som remanens vindes 4Ί0 ml γ-L-glutamylhomotaurin hvilket svarer til et udbytte på 82%. Den ved pH 6,5 udførte elektroforese udviser en ringe mængde forurening 5 af dels neutrale, dels sure forbindelser (homotaurin eller gluta-minsyre). Produktet kan fx renses ved præparativ elektroforese.13 ethylamine is added to a 1 x 35 cm column with "Dowex" 50 x 2 in H + form. Elute with water. 50 ml of eluate are collected and evaporated under vacuum. As the residue, 4Ί ml of γ-L-glutamyl homotaurine is obtained, which corresponds to a yield of 82%. The electrophoresis carried out at pH 6.5 exhibits a small amount of contamination 5 of partly neutral and partly acidic compounds (homotaurin or glutamic acid). For example, the product may be purified by preparative electrophoresis.
Både ved elektroforese gennemført ved pli 6,5 og ved ele troforese gennemført ved pil 1,8 vandrer forbindelsen i retning <af katoden. Bevægeligheden i forhold til cysteinsyre udgør ved pH 6, 1q 0,68, ved pH 1,8 0,50.Both by electrophoresis carried out at pli 6.5 and by electrophoresis carried out by arrow 1.8, the compound migrates in the direction of the cathode. The mobility with respect to cysteic acid is at pH 6, 1q 0.68, at pH 1.8 0.50.
Rp (n-Butanol/pyridin/iseddike/vand 15:10:3:12) = 0,19-Eksempel 9 a) Karbobenzyloxy-Y-(α-benzyl)--L-glutamyl-N-metyltaurin 1,083 g (2,2 mmol) karbobenyzloxy-L-glutaminsyre-(a-ben- zyl)-y-p-nitrofenylester omsættes på den i eksempel 8a) beskrevne måde med 278 mg (2 mmol) N-metyltaurin. Der vindes 1,59 g karbo-benzyloxy-γ-(α-benzyl)-L-glutamyl-N-metyltaurin.Rp (n-Butanol / pyridine / glacial acetic acid / water 15: 10: 3: 12) = 0.19 Example 9 a) Carbobenzyloxy-Y- (α-benzyl) - L-glutamyl-N-methyltaurine 1.083 g (2 (2 mmol) carbobenyzloxy-L-glutamic acid (α-benzyl) -yp-nitrophenyl ester is reacted in the manner described in Example 8a) with 278 mg (2 mmol) of N-methyltaurine. 1.59 g of carbo-benzyloxy-γ- (α-benzyl) -L-glutamyl-N-methyltaurine are obtained.
20 b) Y-L-Glutamyl-N-metyltaurinB) Y-L-Glutamyl-N-methyltaurine
Den samlede mængde af det ifølge eksempel 9 a) fremstille stof (1,59 g) hydrogeneres katalytisk på den i eksempel 8 b) beskrev ne måde. Der vindes 423 mg γ-L-glutamyl-N-metyltaurin hvilket svarer til et udbytte på 79%. Både ved pH 6,5 og ved pH 1,8 vandrer 25 forbindelsen ved papirelektroforese i retning af katoden. Bevægeligheden i forhold til cysteinsyre: pH 6,5: 0,68; pH 1,8: 0,49.The total amount of the substance (1.59 g) prepared according to Example 9 (a) is catalytically hydrogenated in the manner described in Example 8 (b). 423 mg of γ-L-glutamyl-N-methyltaurine is obtained, which corresponds to a yield of 79%. Both at pH 6.5 and at pH 1.8, the compound migrates by paper electrophoresis in the direction of the cathode. Mobility to cysteic acid: pH 6.5: 0.68; pH 1.8: 0.49.
• (n-Butanol/pyridin/iseddike/vand 15:10:3:12) = 0,16.• (n-Butanol / pyridine / glacial acetic acid / water 15: 10: 3: 12) = 0.16.
Eksempel 10 30 ----------- a) Karbobenzyloxy-γ-(α-benzyl)-L-glutamyl-L-cysteinsyre 2,87 g (6,6 mmol) lcarbobenzyloxy-L-glutaminsyre-(a-ben-Zyi)-y-p-nitrofenylester opløses i 20 ml pyridin og der tilsættes en opløsning af 1,25 g (6 mmol) L-cysteinsyremonohydrat i en blan-35 ding af 17 ml vand og 17 ml pyridin. Efter tilsætning af 2,6 ml — ψExample 10 ----------- a) Carbobenzyloxy-γ- (α-benzyl) -L-glutamyl-L-cysteic acid 2.87 g (6.6 mmol) of carbobenzyloxy-L-glutamic acid ( The α-benzyl) -yp-nitrophenyl ester is dissolved in 20 ml of pyridine and a solution of 1.25 g (6 mmol) of L-cysteic acid monohydrate is added in a mixture of 17 ml of water and 17 ml of pyridine. After adding 2.6 ml - -
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14 (18,6 mmol) triætylamin henstår reaktionsblandingen ved stuetemperatur i 72 timer. Derpå inddampes opløsningen under vakuum ved 30°C. Remanensen opløses i 20 ml vand, syrnes med koncentreret saltsyre og rystes derpå 15 gange med 10 ml æter hver gang. Den vandige fase inddampes under vakuum ved 35°C. Der vindes karboben-5 zyloxy-γ- (α-benzyl)-L-glutamyl-L-cysteinsyre.14 (18.6 mmol) of triethylamine leaves the reaction mixture at room temperature for 72 hours. The solution is then evaporated under vacuum at 30 ° C. The residue is dissolved in 20 ml of water, acidified with concentrated hydrochloric acid and then shaken 15 times with 10 ml of ether each time. The aqueous phase is evaporated under vacuum at 35 ° C. Carbobenzyloxy-γ- (α-benzyl) -L-glutamyl-L-cysteic acid is obtained.
b) T-L-Glutarnyl-L-cysteinsyreb) T-L-Glutarnyl-L-cysteic acid
Det ifølge eksempel 10a) fremstillede produkt opløses i 20'ml vand, der tilsættes 0,3 g 10%s palladium-aktivt kul og der 10 ledes hydrogen gennem suspensionen i tre timer. Reaktionsblandingen oparbejdes på den i eksempel '8 b) beskrevne måde. Der vindes γ-L-glutamyl-L-cysteinsyre som smelter ved 187°C. I forhold til cy-steinsyre er bevægeligheden ved papirkromatografi: ved pH 6,5: 1,21; ved pH 1,8;: 0,54.The product prepared according to Example 10a) is dissolved in 20 ml of water, 0.3 g of 10% palladium-activated charcoal is added and hydrogen is passed through the suspension for three hours. The reaction mixture is worked up in the manner described in Example 8 (b). Γ-L-glutamyl-L-cysteic acid is obtained which melts at 187 ° C. Relative to cysteic acid, the mobility of paper chromatography is: at pH 6.5: 1.21; at pH 1.8; 0.54.
1515
Eksempel 11 a) Karbobenzyloxy-γ- (ct-benzyl) -L-glutamylkolaminf osf at 1,083 g (2,2 mmol) karbobenzyloxy-L-glutaminsyre-(a-ben- 20 zyl)-y-p-nitrofenylester opløses i 6 ml af en tilberedt blanding af pyridin og vand i forholdet 2:1. Til opløsningen sættes først 282 mg (2 mmol) kolaminfosfat (USA-patentskrift nr. 2.730.542) og derpå 0,87 ml (6,2 mmol) triætylamin. Reaktionsblandingen henstår ved stuetemperatur i 72 timer og inddampes derpå under vakuum. Den 25 videre oparbejdning foregår på den måde der er beskrevet i forbindelse med karbobenzyloxy-y-(a-benzyl)-L-glutamylhomotaurin (eksempel 8a). Der vindes 1,25 g karbobenzyloxy-y-(a-benzyl)-L-glutamyl-kolaminfosfatj.Example 11 a) Carbobenzyloxy-γ- (ct-benzyl) -L-glutamylcolamine phosphate is dissolved in 1.083 g (2.2 mmol) of carbobenzyloxy-L-glutamic acid (a-benzyl) -yp-nitrophenyl ester in 6 ml of a prepared mixture of pyridine and water in a 2: 1 ratio. To the solution is first added 282 mg (2 mmol) of colamine phosphate (U.S. Patent No. 2,730,542) and then 0.87 ml (6.2 mmol) of triethylamine. The reaction mixture is left at room temperature for 72 hours and then evaporated under vacuum. The further work-up is carried out in the manner described in connection with carbobenzyloxy-γ- (α-benzyl) -L-glutamylhomotaurine (Example 8a). 1.25 g of carbobenzyloxy-γ- (α-benzyl) -L-glutamyl-cholamine phosphate are obtained.
b) T-L-Glutamylkolaminfosfatb) T-L-Glutamylcolamine phosphate
Den samlede mængde af det i eksempel 11a) vundne produkt (1,25 g) hydrogeneres katalytisk for at fjerne beskyttelsesgrupperne. Hydrogeneringen såvel som rensningen ved ionbytning foretages på den måde der er beskrevet i eksempel 12b i forbindelse med fremstillingen af γ-L-glutamylhomotaurin. Der vindes 470 mg y-L-glutamylkolaminfosfat hvilket svarer til et udbytte på 91%. Det fremgår dog af papirelektroforese at produktet indeholder en foru-The total amount of the product obtained in Example 11a (1.25 g) is catalytically hydrogenated to remove the protecting groups. The hydrogenation as well as the purification by ion exchange is carried out in the manner described in Example 12b in connection with the preparation of γ-L-glutamyl homotaurine. 470 mg of γ-L-glutamylcolamine phosphate is obtained, which corresponds to a yield of 91%. However, it is evident from paper electrophoresis that the product contains a contaminant.
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15 rening på ca. 15-20% kolaminfosfat. Som rensningsmetode kommer bl.a. elektroforese på tale.15 purification of approx. 15-20% of colamine phosphate. As a cleaning method comes, among other things. electrophoresis on speech.
Ved papirelektroforese vandrer forbindelsen såvel ved pH 6,5 som ved pH 1,8 i retning af katoden. Bevægeligheden i forhold til cysteinsyre er: pH 6,5: 0,75; pH 1,8: 0,36.In paper electrophoresis, the compound migrates to the cathode at both pH 6.5 and pH 1.8. The motility relative to cysteic acid is: pH 6.5: 0.75; pH 1.8: 0.36.
5 Rp (n-Butanol/pyridin/iseddilce/vand 15:10:3:12) = 0,18.Rp (n-Butanol / pyridine / glacial acetic acid / water 15: 10: 3: 12) = 0.18.
Eksempel 12 a) Karbobenzyloxy-β-(a-benzyl)-L-aspartyltaurin 526 mg (1,1 mmol) lcarbobenzyloxy-L-asparaginsyre-(a-ben-zyl)-p-p-nitrofenylester (Chem.Ber. 97, 1789, 1964) opløses i 5 ml pyridin. Opløsningen afkøles til 0°C hvorpå der i små portioner tilsættes en opløsning af 125 mg (l mmol) taurin i 2 ml vand efterfulgt af 0,28 ml (2 mmol) triætylamin. Reaktionsblandingen hen-15 står ved stuetemperatur i 48 timer og inddampes derpå under vakuum. Remanensen opløses i 5 ml vand og til den i begyndelsen gule opløsning sættes en N saltsyre indtil opløsningen er affarvet. Til fjernelse af ρ-nitrofenol udrystes opløsningen ti gange med 5 ml æter hver gang. Den vandige fase inddampes under vakuum. Der vindes 20 478 g karbobenzyloxy-β-(a-benzyl)-L-aspartyltaurin.Example 12 a) Carbobenzyloxy-β- (a-benzyl) -L-aspartyl taurine 526 mg (1.1 mmol) of carbobenzyloxy-L-aspartic acid (a-benzyl) -p-nitrophenyl ester (Chem. Ber. 97, 1789 , 1964) is dissolved in 5 ml of pyridine. The solution is cooled to 0 ° C, and in small portions a solution of 125 mg (1 mmol) of taurine is added in 2 ml of water followed by 0.28 ml (2 mmol) of triethylamine. The reaction mixture is left at room temperature for 48 hours and then evaporated under vacuum. The residue is dissolved in 5 ml of water and to the initially yellow solution an N hydrochloric acid is added until the solution is decolorized. To remove ρ-nitrophenol, the solution is shaken ten times with 5 ml of ether each time. The aqueous phase is evaporated under vacuum. 20478 g of carbobenzyloxy-β- (a-benzyl) -L-aspartyl taurine are obtained.
b) β-L-Aspartyltaur inb) β-L-Aspartyl taurus
Den samlede mængde af det i eksempel 12a) vundne produkt opløses i 6 ml 50%s vandig ætanol. Til opløsningen sættes 100 mg 10%s palladium-aktivt kul hvorpå der hydrogeneres under indføring 25 af hydrogengas i fire timer. Efter filtrering og inddampning under vakuum fjernes triætylaminen fra produktet ved ionbytning på den måde der allerede er beskrevet i forbindelse med fremstillingen af γ-L-glutamylhomotaurin i eksempel 8 b). Der vindes 172 mg β-L-30 aspartyltaurin hvilket svarer til et udbytte på 91%. Produktet er forurenet med lille mængde taurin som bl.a. kan fjernes ved elektroforese.The total amount of the product obtained in Example 12a) is dissolved in 6 ml of 50% aqueous ethanol. To the solution is added 100 mg of 10% s of palladium-activated charcoal, which is hydrogenated during the introduction of hydrogen gas for four hours. After filtration and evaporation in vacuo, the triethylamine is removed from the product by ion exchange in the manner already described in connection with the preparation of γ-L-glutamylhomotaurine in Example 8 b). 172 mg of β-L-30 aspartyl taurine is obtained, which corresponds to a yield of 91%. The product is contaminated with a small amount of taurine. can be removed by electrophoresis.
Ved papirelelctroforese vandrer forbindelsen både ved pH 6,5 og ved pH 1,8 mod katoden. Bevægeligheden i forhold til cy~ 35 steinsyre: pH 6,5: 0,77; pH 1,8: 0,58.In paper electrophoresis, the compound migrates toward the cathode at both pH 6.5 and pH 1.8. Movement relative to cysteine stearic acid: pH 6.5: 0.77; pH 1.8: 0.58.
Rp (n-Butanol/pyridin/iseddilce/vand 15:10:3:12) = 0,16.Rp (n-Butanol / pyridine / glacial acetic acid / water 15: 10: 3: 12) = 0.16.
Eksempel 13Example 13
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16 a) Karbobenzyloxy-β-(a-benzyl)-L-aspartylhomotaurin 526 mg (1,1 mmol) karbobenzyloxy-L-asparaginsyre-(a-ben-zyl)-p-nitrofenylester og 139 g (l mmol) homotaurin omsættes på den 5 i eksempel 12 a) beskrevne måde. Der vindes karbobenzyloxy-β-(a-benzyl)-L-aspartylhomotaurin.16 a) Carbobenzyloxy-β- (α-benzyl) -L-aspartyl homotaurine 526 mg (1.1 mmol) of carbobenzyloxy-L-aspartic acid (α-benzyl) -p-nitrophenyl ester and 139 g (1 mmol) of homotaurine are reacted in the manner described in Example 12 (a). Carbobenzyloxy-β- (α-benzyl) -L-aspartylhomotaurine is obtained.
b) β-L-Aspartylhomotaurinb) β-L-Aspartyl homotaurin
Det ifølge eksempel 13a) vundne produkt hydrogeneres ka-10 talytisk på den i eksempel 8. b) beskrevne måde. Der vindes 203 mg (84/0 β-L-aspartylhomotaurin.The product obtained according to Example 13a) is catalytically hydrogenated in the manner described in Example 8. b). 203 mg (84/0 β-L-aspartylhomotaurine) is obtained.
Ved papirelektroforese vandrer forbindelsen både ved pHIn paper electrophoresis, the compound migrates at both pH
6,5 og ved pH 1,8 i retning af katoden. Bevægeligheden i forhold til cysteinsyre er: pH 6,5: 0,72; pH 1,8: 0,53.6.5 and at pH 1.8 in the direction of the cathode. The motility relative to cysteic acid is: pH 6.5: 0.72; pH 1.8: 0.53.
15 R^ (n-Butanol/pyridin/iseddike/vand 15:10:3:12) = 0,17.R R (n-Butanol / pyridine / glacial acetic acid / water 15: 10: 3: 12) = 0.17.
Eksempel 14 a) Karbobenzyloxy-β-(o-benzyl)-L-aspartylkolaminfosfat 2 Karbobenzyloxy-L-asparaginsyre-(α-benzyl)-β-ρ-ηΐtrofenyl- ester og kolaminfosfat omsættes med hinanden på den i eksempel Ha) beskrevne måde. Der vindes karbobenzyloxy-β-(α-benzyl)-L-aspartyl-kolaminfosfat.Example 14 a) Carbobenzyloxy-β- (o-benzyl) -L-aspartylcolamine phosphate 2 Carbobenzyloxy-L-aspartic acid (α-benzyl) -β-ρ-ηΐtrophenyl ester and colamine phosphate are reacted with each other in the manner described in Example Ha) . Carbobenzyloxy-β- (α-benzyl) -L-aspartyl-colamine phosphate is obtained.
b) β -L-Asparty lkolaminf osf at 25 —;—-b) β -L-Asparty cholesterol phosphate 25 -;
Det ifølge eksempel 14 a) vundne stof hydrogeneres katalytisk på den i eksempel 8b) beskrevne måde. Der vindes β-L-aspartyl-kolaminfosfat.The substance obtained in Example 14 a) is catalytically hydrogenated in the manner described in Example 8b). Β-L-aspartyl-colamine phosphate is obtained.
Ved papirelektroforese vandrer forbindelsen både ved pH 3Q 6,5 og ved pH 1,8 i retning af katoden. Bevægeligheden i forhold til cysteinsyre: pH 6,5: 0,81; pH 1,8: 0,40.In paper electrophoresis, the compound migrates at both pH 3Q 6.5 and pH 1.8 toward the cathode. Mobility relative to cysteic acid: pH 6.5: 0.81; pH 1.8: 0.40.
Rp (n-Butanol/pyridin/iseddike/vand 15:10:3:12) = 0,14.Rp (n-Butanol / pyridine / glacial acetic acid / water 15: 10: 3: 12) = 0.14.
3535
Eksempel 15Example 15
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17 T-L-Glutamylkolaminfosfat På den til fremstilling af glutaminsyre-y-amider egnede måde (Acta Chim. Acad. Sci. Hung. 64, 285, 1970) fremstilles lcarbc 5 benzyloxy-y-(a:-benzyl)-L-glutamyllcolamin. 4,14 g af dette produkt (10 mmol) opløses i 50 ml absolut pyridin og der tilsættes 9 g (33 mmol) difenylfosforsyrelclorid. Realctionsblandingen holdes i tolv timer ved 0°C og fortyndes derefter med 80 ml kloroform. Det udskilte produkt frafiltreres, vaskes med saltsyre og derpå med 10 vand og tørres til sidst i ekssiklcator over lcaliumhydroxyd. Det vundne karbobenzyloxy-γ-(a-benzyl)-L-glutamylkolaminfosfat opløse: i 15 ml iseddikesyre der indeholder 3,3 mol/1 brombrinte og opløsningen henstår i 15 minutter hvorefter den inddampes under vakuum ved 25°C. Remanensen opløses i 30 ml IN natriumhydroxyd og opløs-15 ningen henstår ved stuetemperatur i en time. Derpå indstilles pH= værdien på 4 med eddikesyre og til fjernelse af fenol og benzyl-alkohol ekstraheres opløsningen tre gange med 30 ml æter hver gang. Den vandige fase overføres til en kolonne med "Dowex" 50 på H+-form og elueres med vand. Eluatet inddampes under vakuum 20 og remanensen omkrystalliseres fra en blanding af acetone og vand i forholdet 2:1. Der vindes 0,8 g γ-L-glutamylkolaminfosfat„ t 25 30 3517 T-L-Glutamylcolamine Phosphate In the manner suitable for the preparation of glutamic acid γ-amides (Acta Chim. Acad. Sci. Hung. 64, 285, 1970), lcarbc 5 benzyloxy-γ- (α: -benzyl) -L-glutamylcolamine is prepared. Dissolve 4.14 g of this product (10 mmol) in 50 ml of absolute pyridine and add 9 g (33 mmol) of diphenylphosphoric acid chloride. The reaction mixture is kept at 0 ° C for twelve hours and then diluted with 80 ml of chloroform. The separated product is filtered off, washed with hydrochloric acid and then with 10 water and finally dried in desiccator over potassium hydroxide. Dissolve the obtained carbobenzyloxy-γ- (α-benzyl) -L-glutamylcolamine phosphate: in 15 ml glacial acetic acid containing 3.3 mol / l hydrochloric acid and leave the solution for 15 minutes, then evaporate in vacuo at 25 ° C. The residue is dissolved in 30 ml of 1N sodium hydroxide and the solution is left at room temperature for one hour. Then the pH = 4 is adjusted with acetic acid and to remove phenol and benzyl alcohol, the solution is extracted three times with 30 ml of ether each time. The aqueous phase is transferred to a column of "Dowex" 50 in H + form and eluted with water. The eluate is evaporated under vacuum 20 and the residue is recrystallized from a mixture of acetone and water in a 2: 1 ratio. 0.8 g of γ-L-glutamylcolamine phosphate is obtained
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1818
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 som 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 are shown as mean values + standard deviation with the number of brackets. Determination of whether there is a significant difference between control trials and trials in treated animals was done with Student's t-test.
1010
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 K 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 PK 0.001 xx P <0.01 20 Sprague Dawley rats (10 males and 10 females) weighing 25 180-200 g were treated orally with the daily indicated in Table 1 do see litoralon 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.
30 35 1930 35 19
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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 g mg μ g yg/dag I. Kontrol - - - 52+1,0(24} 1q II.Kontrol +Vitamin Ax litoralon granuloma local local oral g mg µg yg / day I. Control - - - 52 + 1.0 (24} 1q 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.
25 30 3525 30 35
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DK 155433 BDK 155433 B
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Tabel 5Table 5
DK 155433 BDK 155433 B
2222
Litoralons virkning på Rana dalmatina's metamorfoseThe effect of Litoralon on the metamorphosis of Rana dalmatina
Gruppe Kropslængde Halelængde _ mm_mm_ 5 Kontrol 45,9 + 0,2 31,4 + 0,2 (60)Group Body length Tail length _ mm_mm_ 5 Control 45.9 + 0.2 31.4 + 0.2 (60)
Behandlede dyr 40,2 + 0,2X 26,7 + 0,2X (60) x Signifikans: P < 0,001 1 q Forsøget udførtes med larver af Rana dalmatia med en 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 litoraion i to timer hver dag. Kontrolgruppen blev anbragt i 15 postevand uden tilsætning af litoraion. Haletudserne måltes på den 30. dag.Treated animals 40.2 + 0.2X 26.7 + 0.2X (60) x Significance: P <0.001 1 q The experiment was conducted with larvae of Rana dalmatia with a 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 litoraion for two hours each day. The control group was placed in 15 tap water without the addition of litoraion. The tails were measured on the 30th day.
Tabel 6Table 6
Litoralons virkning på blodsukkerniveauet 20Litoralone's effect on blood sugar levels 20
Gruppe I. Undersøgelse II. Undersøgelse _mg %_mg %_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) 25 Signifikans ved I. undersøgelse: P < 0,05 Signifikans ved II. undersøgelse: P < 0,01Treated animals 82.4 + 3.8 (10) 81 + 1.32 (10) 25 Significance at I. study: P <0.05 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. Blodsuk-30 kerbes teinmel serne udførtes efter metoden ifølge E. Hul tman. 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 sugar cane meal was carried out according to the method of E. Hulman. Litoralon was given orally at daily doses of 1 µg / kg.
3535
DK 155433 BDK 155433 B
2323
Biologisk forsøgsrapport B.Biological Test Report B.
Undersøgelse af syntetisk γ-aspartyltaurin og derivater deraf.Study of synthetic γ-aspartyl taurine and its derivatives.
5 1. β-aspartyl-N-metyltaurin a) Virkning på blodsukkerniveauet5 1. β-Aspartyl-N-methyltaurine a) Effect on blood sugar level
Kontrol 107 mg %Control 107 mg%
Behandlede dyr 93 mg %Treated animals 93 mg%
Signifikans: P < 0f05Significance: P <0f05
Til prøverne anvendtes 20-20 rotter. Målingerne gennemførtes 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. The measurements were carried out 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 serum 15 Oral dosis Fremkaldt vitamin A yg% yg/200 g legemsvægt 0 (kontrol) 8,5 5 11,0 1 11,5 20 0^3 12,5 0,1 16,1 0,05 14,8 0,01 12,5 0,005 10,5 25 Signifikans: P < 0,01b) Effect of increasing serum vitamin A level 15 Oral dose Induced vitamin A yg% yg / 200 g body weight 0 (control) 8.5 5 11.0 1 11.5 20 0 ^ 3 12.5 0.1 16.1 0.05 14.8 0.01 12.5 0.005 10.5 Significance: 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.
30 c) Virkning på blodets siliciumniveau:C) Effect on blood silicon level:
Silicium (mg/g blod) _ 0 timer_2® dage_40 dageSilicon (mg / g blood) _ 0 hours_2® days_40 days
Kontrolgruppe H0,0©4 0,120+0,©lø 0,154+0,015Control group H0.0 © 4 0.120 + 0, © Sat 0.154 + 0.015
Behandlingsgruppe 35 15 yg/dag 0,100+0,005 0,315+0,014** 0,345+0,015Treatment group 35 µg / day 0.100 + 0.005 0.315 + 0.014 ** 0.345 + 0.015
Behandlingsgruppe vy II 10 yg/dag 0,107+0,009 0,370+0,119** 0,360+0,017**Treatment Group View II 10 µg / day 0.107 + 0.009 0.370 + 0.119 ** 0.360 + 0.017 **
DK 155433 BDK 155433 B
2424
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.f Klin. Wschrft. 14, 1753, 1935) i 5 ml blodprøver, som blev taget fra dyrenes ørevene.Results are significant from the 13th day at the significance level P <0.001 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.f. 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 .jq granulomfremkaldende virkning forårsaget af implantation af vat;d) The effect of β-aspartyl-N-methyl-taurine and vitamin A on the .jq granulogenic effect caused by implantation of cotton wool;
Gruppe Dosis Vægt af tør-Group Dose Weight of dry
Vitamin Ax (3-aspartyl-N- rf 9ranulom metyltaurin lokal lokal oral mg jig jig/dag ^ Kontrol I. - - - 54+1,7Vitamin Ax (3-aspartyl-N- rf 9ranuloma methyltaurine local local oral mg gig / day ^ Control 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 Behandlingsgruppe V. - - 0,1 79 + 2,8Treatment Group IV. 2 0.1 - 67 + 2.6 Treatment 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 Ch.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 Ch.Ch., Spencer M.R. Tong T.G. and Poon R.J., Pharm.
3Q Sci., 62, 895, 1973). De dorsolateralt subkutant implanterede tamponer fjernedes efter 10 dage og måltes efter tørring ved 65°C til konstant vægt.3Q Sci., 62, 895, 1973). The dorsolaterally subcutaneously implanted tampons were removed after 10 days and measured after drying at 65 ° C to constant weight.
2. β-Asparfeyl-homotaurin.2. β-Asparfeyl homotaurin.
25 a) Virkning på blodsukkerniveauet25 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 155433 BDK 155433 B
25 b) Forøgende virkning på vitamin A-niveauet i serum25 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).
1 5 c) Virkning på blodets siliciumniveau;C) Effect on blood silicon level;
Silicium (mg/g blod) _0 timer_20 dage_40 dageSilicon (mg / g blood) _0 hours_20 days_40 days
Kontrolgruppe 0,104+0,009 0,134+0,015 0,157+0,020 on Behandlingsgruppe I. 5yg/dag 0,094+0,007 0,309+0,014 0,340+0,014 'Control group 0.104 + 0.009 0.134 + 0.015 0.157 + 0.020 on Treatment group I. 5yg / day 0.094 + 0.007 0.309 + 0.014 0.340 + 0.014 '
Behandlingsgruppe II. 10 yg/dag 0,109+0,010 0,372+0,120 0,363+0,0185^Treatment Group II. 10 µg / day 0.109 + 0.010 0.372 + 0.120 0.363 + 0.0185 ^
Signifikans, antal forsøgsdyr, arrangement og bestemmelsesmetode som angivet ovenfor under pkt. 1 c).Significance, number of test animals, arrangement and method of determination as indicated above under cl. 1 c).
25 d) Virkningen af β-aspartyl-homotaurin og vitamin A på den granu= lomfremkaldende virkning af implantation af vat:____25 d) The effect of β-aspartyl homotaurin and vitamin A on the granulomatous effect of cotton implantation: ____
Dosis Vægt af tørret 3Q Vitamin Ax β-aspartyl- granulom lokal homotaurin g mg lokal oral ______yg yg/dag_Dose Weight of dried 3Q Vitamin Ax β-aspartyl granuloma local homotaurin g mg local oral ______g / 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
DK 155433BDK 155433B
26 x Hoffmann la Roche26 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 3. γ-Glutamyl-kolaminfosfat.3. γ-Glutamyl-Colamine Phosphate.
a) Virkning på blodsukkerniveaueta) Effect on blood sugar level
Kontrolgruppe 104 mg%Control group 104 mg%
Behandlingsgruppe 93 mg%Treatment group 93 mg%
Signifikans, antal forsøgsdyr, arrangement og dosering var som angivet ovenfor under punkt la).Significance, number of test animals, arrangement and dosage were as indicated above under point 1a).
b) Forøgende virkning på vitamin A-niveauet i serumb) Increasing effect on serum vitamin A level
Oral dosis Vitamin A-virkning ^ yg/200 g legemsvægt yg% 0 (kontrol) 8,8 5 12,3 1 13,4 0,3 14,3 20 0/1 16,0 0,05 15,5 0,01 11,2 0,005_9j_2_Oral dose of Vitamin A action ^ yg / 200 g body weight yg% 0 (control) 8.8 5 12.3 1 13.4 0.3 14.3 20 0/1 16.0 0.05 15.5 0, 01 11.2 0.005_9j_2_
Signifikans, antal forsøgsdyr, arrangement og bestemmel-25 sesmetode var som angivet ovenfor under punkt 1 b).Significance, number of test animals, arrangement and method of determination were as indicated above under point 1 (b).
c) Virkning på blodets siliciumniveau;c) Effect on blood silicon level;
Silicium (mg/g blod) 0 timer 20 dage 40 dage 30 -2-2-Silicon (mg / g blood) 0 hours 20 days 40 days 30-2-2-
Kontrolgruppe 0,106+0,011 0,136+0,017 0,159+0,022Control group 0.106 + 0.011 0.136 + 0.017 0.159 + 0.022
Behandlingsgruppe I 5 yg/dag 0,096+0,009 0,311+0,016 0,340+0,017Treatment group I 5 µg / day 0.096 + 0.009 0.311 + 0.016 0.340 + 0.017
Behandlingsgruppe II 10 yg/dag 0,111+0,011 0,374+0,12lxx 0,365+0,019 55 Signifikans, antal forsøgsdyr, arrangement og bestemmel sesmetode var som angivet ovenfor under punkt 1 c).Treatment group II 10 µg / day 0.111 + 0.011 0.374 + 0.12lxx 0.365 + 0.019 55 Significance, number of test animals, arrangement and method of determination were as given above under item 1 (c).
DK 155433 BDK 155433 B
27 d) Virkningen af γ-glutamyl-kolaminfosfat og vitamin A på den granulomfremkaldende virkning af vatimplantation;_(D) the effect of γ-glutamyl-colamine phosphate and vitamin A on the granuloma-inducing effect of water implantation;
Dosis Vægt af tørret granulomDose Weight of dried granuloma
Vitamin Ax γ-glutamyl- mg 5 lokal kolaminfosfat mg lokal oral _μ g ug/dag_Vitamin Ax γ-glutamyl mg 5 Local Colamine Phosphate mg Local Oral _µg µg / day_
Kontrolgruppe I. - - - 49+1,2Control group I. - - - 49 + 1.2
Kontrolgruppe II. + opløsningsmiddel - - - 50+2,9 10 Behandlingsgruppe III. 2 - - 61+12,0Control group II. + solvent - - - 50 + 2.9 10 Treatment group III. 2 - - 61 + 12.0
Behandlingsgruppe IV. 2 0,1 - 62+2,1Treatment Group IV. 2 0.1 - 62 + 2.1
Behandlingsgruppe V. - - 0,1 74+2,3Treatment group V. - - 0.1 74 + 2.3
Behandlingsgruppe VI. 2 - 0,1 91+3,9 x Hoffmann la RocheTreatment Group VI. 2 - 0.1 91 + 3.9 x Hoffmann la Roche
Signifikans, antal forsøgsdyr, arrangement samt bestemmelsesmetode var som angivet under 1 d) ovenfor.Significance, number of test animals, arrangement and method of determination were as indicated under 1 d) above.
20 25 30 3520 25 30 35
Claims (4)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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HU74FE00000928A HU171576B (en) | 1974-04-29 | 1974-04-29 | Process for the isolation of gamma-l-glutamyl-taurine |
HUFE000928 | 1974-04-29 | ||
HU74CI1558A HU174114B (en) | 1975-03-26 | 1975-03-26 | Process for producing new aminoacid derivatives |
HUCI001558 | 1975-03-26 |
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DK182875A DK182875A (en) | 1975-10-30 |
DK155433B true DK155433B (en) | 1989-04-10 |
DK155433C DK155433C (en) | 1989-10-16 |
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DK182875A DK155433C (en) | 1974-04-29 | 1975-04-28 | METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF |
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 |
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. |
DK442477A DK155732C (en) | 1974-04-29 | 1977-10-06 | ANALOGY PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES |
DK442777A DK442777A (en) | 1974-04-29 | 1977-10-06 | PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES |
DK442677A DK159654C (en) | 1974-04-29 | 1977-10-06 | METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF |
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 |
DK442977A DK442977A (en) | 1974-04-29 | 1977-10-06 | GAMMA-L-GLUTAMYLTAURIN PROCEDURE |
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 |
Family Applications After (9)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
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 |
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. |
DK442477A DK155732C (en) | 1974-04-29 | 1977-10-06 | ANALOGY PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES |
DK442777A DK442777A (en) | 1974-04-29 | 1977-10-06 | PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES |
DK442677A DK159654C (en) | 1974-04-29 | 1977-10-06 | METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF |
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 |
DK442977A DK442977A (en) | 1974-04-29 | 1977-10-06 | GAMMA-L-GLUTAMYLTAURIN PROCEDURE |
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 |
Country Status (23)
Country | Link |
---|---|
JP (1) | JPS6012347B2 (en) |
AR (3) | AR218221A1 (en) |
AT (6) | AT361902B (en) |
AU (1) | AU499173B2 (en) |
BE (1) | BE828546A (en) |
BG (4) | BG26517A4 (en) |
CA (1) | CA1051802A (en) |
CH (4) | CH617183A5 (en) |
CS (4) | CS209855B2 (en) |
DD (2) | DD122377A5 (en) |
DE (2) | DE2518160A1 (en) |
DK (10) | DK155433C (en) |
EG (1) | EG11847A (en) |
ES (4) | ES436986A1 (en) |
FI (1) | FI65990C (en) |
FR (1) | FR2279388A1 (en) |
GB (1) | GB1504541A (en) |
IL (1) | IL47149A (en) |
NL (1) | NL183186C (en) |
NO (2) | NO146430C (en) |
PL (2) | PL111745B1 (en) |
SE (2) | SE430164B (en) |
SU (1) | SU747419A3 (en) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
US9662304B1 (en) * | 2013-06-13 | 2017-05-30 | Thermolife International, Llc | Substituted glutaurine compounds and substituted glutaurine derivatives |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU169462B (en) * | 1971-08-04 | 1976-11-28 |
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1975
- 1975-04-23 IL IL47149A patent/IL47149A/en unknown
- 1975-04-24 AT AT314075A patent/AT361902B/en not_active IP Right Cessation
- 1975-04-24 DE DE19752518160 patent/DE2518160A1/en active Granted
- 1975-04-24 DE DE2559989A patent/DE2559989C3/en not_active Expired
- 1975-04-25 SE SE7504828A patent/SE430164B/en not_active IP Right Cessation
- 1975-04-25 FI FI751256A patent/FI65990C/en not_active IP Right Cessation
- 1975-04-25 ES ES436986A patent/ES436986A1/en not_active Expired
- 1975-04-28 DD DD185727A patent/DD122377A5/xx unknown
- 1975-04-28 EG EG262/75A patent/EG11847A/en active
- 1975-04-28 CA CA225,659A patent/CA1051802A/en not_active Expired
- 1975-04-28 DD DD193288A patent/DD125070A5/xx unknown
- 1975-04-28 CH CH539075A patent/CH617183A5/de not_active IP Right Cessation
- 1975-04-28 GB GB17608/75A patent/GB1504541A/en not_active Expired
- 1975-04-28 SU SU752128794A patent/SU747419A3/en active
- 1975-04-28 DK DK182875A patent/DK155433C/en not_active IP Right Cessation
- 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 NO NO751504A patent/NO146430C/en unknown
- 1975-04-29 BE BE155914A patent/BE828546A/en not_active IP Right Cessation
- 1975-04-29 BG BG7530769A patent/BG26517A4/xx unknown
- 1975-04-29 BG BG7530768A patent/BG26369A4/xx unknown
- 1975-04-29 BG BG7529816A patent/BG26368A3/xx unknown
- 1975-04-29 BG BG7530770A patent/BG26370A4/xx unknown
- 1975-04-29 PL PL1975196801A patent/PL111745B1/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 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 AR262769A patent/AR217236A1/en active
- 1976-04-02 AR AR262770A patent/AR218222A1/en active
- 1976-11-13 ES ES453305A patent/ES453305A1/en not_active Expired
- 1976-11-13 ES ES453304A patent/ES453304A1/en not_active Expired
- 1976-11-13 ES ES453306A patent/ES453306A1/en not_active Expired
-
1977
- 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
- 1977-08-30 AT AT624777A patent/AT359084B/en not_active Expired
- 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 DK442877A patent/DK158676C/en active
- 1977-10-06 DK DK442477A patent/DK155732C/en not_active IP Right Cessation
- 1977-10-06 DK DK442777A patent/DK442777A/en not_active Application Discontinuation
- 1977-10-06 DK DK442677A patent/DK159654C/en not_active IP Right Cessation
- 1977-10-06 DK DK443077A patent/DK159267C/en not_active IP Right Cessation
- 1977-10-06 DK DK442977A patent/DK442977A/en unknown
-
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 AT0323079A patent/AT374484B/en not_active IP Right Cessation
- 1979-04-30 AT AT0323179A patent/AT370724B/en not_active IP Right Cessation
- 1979-10-19 CH CH943279A patent/CH621334A5/de not_active IP Right Cessation
- 1979-10-19 CH CH943379A patent/CH624098A5/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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Legal Events
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PBP | Patent lapsed |