DK155732B - ANALOGY PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES - Google Patents

ANALOGY PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES Download PDF

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DK155732B
DK155732B DK442477AA DK442477A DK155732B DK 155732 B DK155732 B DK 155732B DK 442477A A DK442477A A DK 442477AA DK 442477 A DK442477 A DK 442477A DK 155732 B DK155732 B DK 155732B
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effect
compound
general formula
optically active
vitamin
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DK442477AA
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DK442477A (en
DK155732C (en
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Laszlo Feuer
Arpad Furka
Ferenc Sebestyen
Jolan Hercsel
Erzsebet Bendefy
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Chinoin Gyogyszer Es Vegyeszet
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Priority claimed from HU74CI1558A external-priority patent/HU174114B/en
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    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/08Carboxylic 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
    • AHUMAN NECESSITIES
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
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Description

DK 155732BDK 155732B

Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte aminosyre-derivater med den almene formel R1-NH-CH-CO-A1The present invention relates to an analogous process for the preparation of novel amino acid derivatives of the general formula R1-NH-CH-CO-A1

5 I5 I

(CHo) I(CHo) I

I 2 η 1I 2 η 1

CO-N-CH-(CH0 ) -BCO-N-CH- (CHO) -B

I '2 2 tI '2 2 t

R RR R

11 12 hvor A , B , R, R , R , n og t har de i krav 1 1 s indled-10 ning angivne betydninger, eller fysiologisk acceptable salte eller optisk aktive antipoder deraf.11, wherein A, B, R, R, R, n and t have the meanings specified in the preamble of claim 1, or physiologically acceptable salts or optically active antipodes thereof.

Disse forbindelser har værdifulde biologiske eller farmakologiske virkninger.These compounds have valuable biological or pharmacological effects.

Blandt de ifølge opfindelsen fremstillede forbin-15 delser skal på grund af dens biologiske virkning navnlig fremhæves γ-L-glutamyltaurin, der har formlen H„N-CH-COOH Å I CH„ I ÅAmong the compounds of the invention, due to its biological action, it is particularly noted that γ-L-glutamyltaurine having the formula H₂N-CH-COOH

CH2 XXIVCH2 XXIV

20 C0-NH-CH2-CH2-S020HC0-NH-CH2-CH2-SO20H

og som har et bredt terapeutisk og præventivt virkningsspektrum over for sygelige forandringer der kan føres tilbage til beskadigelser af "AGAS" (det aerobiosfæri-25 ske genetiske adaptionssystem).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).

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 berø-30 ring med den ydre luft som biosfæren (hud og huddannelser, øjets hornhinde og Conjunktiva, mund- og svælghulrum, luftveje og lunge); b) skelet og led (rørknogler og svampeagtige knogler, kugleled, synoviale membraner, skeletmuskulatur); 35 c) de til reguleringen af ionhusholdningen delta gende organer (transepiteliske transporsystem: tarmtrævler og nyrekanal); 2(a) All biological interfaces that are in contact with the external air such as the biosphere (skin and skin formation, corneal and conjunctival eyes, oral and pharyngeal cavities, respiratory tract and lung); b) skeleton and joints (tubular and spongy bones, ball joints, synovial membranes, skeletal muscle); C) the organs involved in the regulation of the ionic household (transepithelial transport system: intestinal tracts and renal duct); 2

DK 155732BDK 155732B

d) det til findeling af næringen nødvendige teko-donte (i tandaveolerne med rødder fastgjorte) tandsæt; e) høre-, lugte- og stemmeorganer.d) the tooth kit needed for comminuting the food (rooted in tandaveolans); (e) hearing, smell and voice organs.

De omhandlede forbindelser udøver således en gun-5 stig biologisk 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: strålingsbe-10 skyttelse, begunstigelse af sårheling, almindelig aktiverende virkning på mesenkym, beskyttelse mod den stadigt voksende infektions- og tilsmudsningsfare hos hud og slimhinder (den fugtige slimhindes lysozymproduktion, aktivering af fimreepiteler i luftvejene), forøget beskyt-15 telse mod de af vira og svampe forårsagede infektioner.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 mesenchyme, 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), 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 20 forskelle mellem dag- og nattemperatur, forhøjet fare for kvæstelser), idet de stabiliserer adaptionssyndromet og samtidigt afværger glukokortikoidernes perifere vævsskader (som fx skader i bindevævet, kvæstelser af knoglema-trix-bestanddele). Udvikling af immunhomøostase (stigende 25 erkendelsesevne hos legemet om hvilke celler 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 in day and night temperature, increased risk of injury) as they stabilize. adaptation syndrome and at the same time mitigates the peripheral tissue damage of glucocorticoids (such as damage to the connective tissue, injury to bone-trix constituents). Development of immuno-homeostasis (increasing body recognition of which cells are suitable and which are not).

De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser udøver deres virkning dels umiddelbart, dels over reguleringen af vitamin A metabolismen, 30 ved produktion af vitamin A metaboliter med stærkere polær karakter. Denne virkning kan sammenlignes med parathormonets virkning på 25-hydroxycholecalciferol-1oclhy-droxylase-enzymet i nyrekanalen. Virkningsretningerne af forbindelserne er følgende: 35 3The compounds prepared by the process of the invention exert their effect, both immediately and partly through the regulation of vitamin A metabolism, in the production of vitamin A metabolites of a stronger polar nature. This effect is comparable to the effect of the parathormone on the 25-hydroxycholecalciferol-1oclhydroxylase enzyme in the renal tract. The directions of action of the compounds are as follows:

DK 155732BDK 155732B

Δ) Virkninger med vitamin A-karakterer: a) Farmakologiske og biokemiske virkninger:Δ) Vitamin A grade effects: a) Pharmacological and biochemical effects:

Forøgende virkning på kondroitinsulfatsyntese; gunstig virkning på sårhelingen eller på den ved indgift af kortison eksperi- 5 mentelt forringede sårheling hos rotter og hunde; potenserende virkning på vitamin A's virkning hos rotter og høns ved eksperimentelt fremkaldte hypo- eller hypervitaminoser; dæmpende virkning på de ulcerations-betingede stress-virkninger hos rotter; begunstigende virkning på degranulationen af mastocyter; forøgende virkning på 10 produktionen af lysozym; virkning på sporstofhusholdningen (silicium, zink, kobber, mangan, fluor); fremmende virkning på epiteldannelsen; fremmende virkning på den alkaliske fosfataseaktivi-tet; virkning på den ved lokal indvirkning af vitamin A fremkaldte granulomposedannelse (Granulomsackbildung); det yderst flade for-15 løb af dosis-virkningskurven eller ændringen af virkningens fortegn ved store doser; aktiverende virkning på Golgi-apparatet; begunstigende virkning på dannelsen af slim- eller bægerceller; forøgende virkning på koncentrationen af vitamin A.Increasing effect on chondroitin sulfate synthesis; beneficial effect on the wound healing or on the experimentally impaired wound healing in rats and dogs by cortisone administration; potentiating effect on the effect of vitamin A in rats and chickens in experimentally induced hypo- or hypervitaminoses; attenuating effect on the ulceration-related stress effects in rats; beneficial effect on the degranulation of mastocytes; increasing effect on the production of lysozyme; effect on household traceability (silicon, zinc, copper, manganese, fluorine); promoting effect on epithelial formation; promoting effect on the alkaline phosphatase activity; effect on the granuloma bag formation (Granulomsackbildung) induced by local action of vitamin A; the extremely flat course of the dose-effect curve or the change of effect sign at large doses; activating effect on the Golgi apparatus; beneficial effect on the formation of mucus or goblet cells; increasing effect on the concentration of vitamin A.

20 b) Klinisk-terapeutiske indikationer: keratokonjunktivis sicca; Sjogrens syndrom; rhino-laryngo-pharingitis sicca; ozæna; kronisk bronchitis; sinobronchitis; mucoviscidose; konstitutionelle lungesygdomme hos småbørn; paradentose; hudens og slimhindernes smittetilbøjelighed for vira og svampe; kortison-antagonistisk 25 virkning; gunstig virkning på helingen ved operationssår og slimhindesår; erosio colli; pruritusagtige lidelser; nedsættelse af lugte- og smagssansen.B) Clinical-therapeutic indications: keratoconjunctivis sicca; Sjogren's syndrome; rhino-laryngo-pharingitis sicca; ozæna; chronic bronchitis; sinobronchitis; mucoviscidosis; constitutional lung disease in young children; periodontal disease; skin and mucosal susceptibility to viruses and fungi; cortisone antagonistic action; beneficial effect on healing of operative and mucosal wounds; erosio colli; pruritus-like disorders; reducing the sense of smell and taste.

30 B) Virkninger uden vitamin A-karakter a) Farmakologiske og biokemiske virkninger: virkning på blodsukkerniveauet med hensyn til en forbigående sænkning; forøgende virkning på fosfaturi, sænkende virkning på fosfatniveauet t 35 i serum; strålingsbeskyttende virkning; formindskende virkning på 430 B) Vitamin A-grade effects (a) Pharmacological and biochemical effects: effects on blood glucose levels with a transient decrease; increasing effect on phosphaturia, lowering effect on phosphate level t 35 in serum; radiation protective effect; diminishing effect on 4

DK 155732BDK 155732B

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 5 på symptomerne ved eksperimentelt fremkaldt lathyrismus; formindskelse af histaminfølsomheden; forøgende virkning på aktiviteten af leverenzymet tyrosinaminotransferase.the time needed 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 5 on the symptoms of experimentally induced lathyrism; decrease in histamine sensitivity; enhancing effect on liver enzyme tyrosine aminotransferase activity.

b) Terapeutiske indikationer: svage bestrålingsskader; vitiligo; muskelhypotoni; psykoenergetiserende virkning; gunstig 10 virkning på involutionelle og gerontologiske tilstande samt på de mnestiske funktioner; keloide tilbøjeligheder; spondylosis ankylo-poetica; sygdomme hos bevægelsesorganerne på grund af slid; scle-rotisk fundus; amyloidose; morphæa; fibrocytisk mastopati.b) Therapeutic indications: weak radiation damage; vitiligo; muscle hypotonia; psychoenergetic effect; beneficial effect on involutional and gerontological conditions as well as on the mnestic functions; keloid inclinations; spondylosis ankylo-poetics; diseases of the movement organs due to wear and tear; scle-rotic fundus; amyloidosis; morphea; fibrocytic mastopathy.

I veterinærmedicinen har de ifølge opfindelsen fremstil-15 lede forbindelser lignende anvendelsesområder som i humanmedicinen, dvs. fx hudskader (afskalning), sårheling og knoglebrud.In the veterinary medicine, the compounds prepared according to the invention have similar fields of application as in human medicine, ie. eg skin damage (peeling), wound healing and bone fractures.

Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav 1's kendetegnende del angivne. - ·The process according to the invention is characterized by the characterizing part of claim 1. - ·

Ved fremgangsmåden ifølge opfindelsen fremstilles forbin-20 delserne med den almene formel I ved dannelse af en syreamidbinding. Herved sammenkobles et ved aminogruppen eller ved amino- og a-karboxyl-gruppen med en eller flere beskyttelsesgrupper eventuelt substitueret derivat af en α-aminodikarbonsyre over sin ω-karboxyl-gruppe med fx 2-aminoætansulfonsyre, 3-aminopropansulfonsyre eller 25 2-fosfonætanolamin. Ved dannelsen af syreamidbindingen kan der anvendes forskellige beskyttelsesgrupper. Koblingsmåden er aktivester-metoden (monografi vedrørende opbygning og selektiv fjernelse af beskyttelsesgrupper og koblingsmetoder: E. Schroder, K. Liibke: The peptides, bind 1: Methods of peptide 30 synthesis, Academic Press, 1965).In the process of the invention, the compounds of general formula I are prepared by forming an acid amide bond. Hereby, at the amino group or at the amino and α-carboxyl group, one or more protecting groups optionally substituted derivative of an α-aminodicarboxylic acid over its ω-carboxylic group is linked with, for example, 2-aminoethanesulfonic acid, 3-aminopropanesulfonic acid or 2-phosphonethanolamine. Various protecting groups can be used in the formation of the acid amide bond. The mode of coupling is the active ester method (monograph on structure and selective removal of protecting groups and coupling methods: E. Schroder, K. Liibke: The peptides, Volume 1: Methods of peptide synthesis, Academic Press, 1965).

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 5,42 g (li mmol) karbobenzyloxy-L-glutaminsyre-(a-ben-zyl)-y-p-nitrofenylester (Chem, Der. 96, 204» 1963) opløses i 50 5 ml pyridin. Opløsningen afkøles til 0°C og inden for en halv time tildryppes der under intensiv omrøring en opløsning af 1,25 g (10 mmol) taurin i 20 ml vand. Derpå sættes der 3»08 ml (22 mmol) tri-ætylamin til blandingen og afkøling og omrøring afbrydes. Blandingen henstår ved stuetemperatur i 72 timer og inddampes derpå 10 under vakuum. Remanensen opløses i 50 ml vand og der sættes IN saltsyre til den gule opløsning indtil den affarves. For at fjerne p-nitrofenolen rystes opløsningen ti gange med 50 ml æter hver gang. Den vandige fase inddampes under vakuum. Der vindes 6,9 g kar bobenzyloxy-γ- (α-benzyl )-L-glut amyltaurin-triætylammoniumsalt.Example 1 5.42 g (1 mmol) of carbobenzyloxy-L-glutamic acid (a-benzyl) -γ-p-nitrophenyl ester (Chem. Der. 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 (10 mmol) of taurine in 20 ml of water is added dropwise. Then 3 »08 ml (22 mmol) of triethylamine is added to the mixture and 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 ether each time. The aqueous phase is evaporated under vacuum. 6.9 g of carbene benzyloxy-γ- (α-benzyl) -L-glut amyltaurine-triethylammonium salt are obtained.

15 Relativ mobilitet i forhold til cysteinsyre ved papirelektroforese ved pH 6,5 er 0,5.Relative mobility to cysteic acid by paper electrophoresis at pH 6.5 is 0.5.

20 Eksempel 2 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 . 25 mmol) homotaurin og derpå 0,59 ml (4,2 mmol) triætylamin. Den gule opløsning henstår ved stuetemperatur i 72 timer og inddampes derpå 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 30 inddampes under vakuum. Der vindes 1,68 g karbobenzyloxy-y-(a-ben-zyl)-L-glutamylhomotaurin. Relativ mobilitet i forhold til cysteinsyre ved papirelektroforese ved pH 6,5 er 0,49.Example 2 1.082 g (2.2 mmol) of carbobenzyloxy-L-glutamic acid (α-benzyl) -γ-p-nitrophenyl ester are dissolved in 6 ml of a mixture of pyridine and water in a 2: 1 ratio. To the solution is first added 278 mg (2.25 mmol) of homotaurin 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 30 is evaporated under vacuum. 1.68 g of carbobenzyloxy-γ- (α-benzyl) -L-glutamyl homotaurine are obtained. Relative mobility to cysteic acid by paper electrophoresis at pH 6.5 is 0.49.

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Eksempel 3 1.083 g (2,2 mmol) karbobenzyloxy-L-glutaminsyre-(a-ben-zyl)—y—p—nitrofenylester omsættes på den i eksempel 2 beskrevne 5 måde med 278 mg (2 mmol) N-metyltaurin. Der vindes 1,59 g karbo-benzyloxy-y-(α-benzyl)-L-glutamyl-N-metyltaurin. Dets relative mobilitet i forhold til cysteinsyre ved papirelektroforese ved pH 6,5 er 0,49.Example 3 1.083 g (2.2 mmol) of carbobenzyloxy-L-glutamic acid (α-benzyl) γ-p-nitrophenyl ester is reacted in the manner described in Example 2 with 278 mg (2 mmol) of N-methyltaurine. 1.59 g of carbo-benzyloxy-γ- (α-benzyl) -L-glutamyl-N-methyltaurine are obtained. Its relative mobility to cysteic acid by paper electrophoresis at pH 6.5 is 0.49.

1q Eksempel 4 2,87 g (6,6 mmol) karbobenzyloxy-L-glutaminsyre-(a-ben-zyl)-y-p-nitrofenylester opløses i 20 ml pyridin og der tilsættes en opløsning af 1,25 9 (6 mmol) L-cysteinsyremonohydrat i en blan-15 ding af 17 ml vand og 17 ml pyridin. Efter tilsætning af 2,6 ml' (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 20 vandige fase inddampes under vakuum ved 35°C. Der vindes karboben-zyloxy-y-(a-benzyl)-L-glutamyl-L-cysteinsyre. Forbindelsens relative mobilitet 1 forhold til cysteinsyre ved papirelektroforese ved pH 2,0 er 1,03.Example 4 2.87 g (6.6 mmol) of carbobenzyloxy-L-glutamic acid (α-benzyl) -yp-nitrophenyl ester are dissolved in 20 ml of pyridine and a solution of 1.25 g (6 mmol) of L is added. -cysteic acid monohydrate in a mixture of 17 ml of water and 17 ml of pyridine. After the addition of 2.6 ml of (18.6 mmol) of triethylamine, the reaction mixture is left 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. The relative mobility of the compound in relation to cysteic acid by paper electrophoresis at pH 2.0 is 1.03.

2b Eksempel 5 1.083 g (2,2 mmol) karbobenzyloxy-L-glutaminsyre-(a-ben-zyi)—y—p—nitrofenylester opløses i 6 ml af en tilberedt blanding af pyridin og vand i forholdet 2:1. Til opløsningen sættes først 30 282 mg (2 mmol) kolaminfosfat (US 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 videre oparbejdning foregår på den måde der er beskrevet i forbindelse med karbobenzyloxy-y-(a-benzyl)-L-glutamylhomotaurin (eksem-35 pel 2). Der vindes 1,25 g karbobenzyloxy-y-(a-benzyl)-L-glutamyl-kolaminfosfat. Produktets relative mobilitet i forhold til cysteinsyre ved papirelektroforese ved pH 2,0 er 0,9,2b Example 5 1.083 g (2.2 mmol) of carbobenzyloxy-L-glutamic acid (a-benzyl) -γ-p-nitrophenyl ester are dissolved in 6 ml of a prepared mixture of pyridine and water in a 2: 1 ratio. To the solution is first added 30 282 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. Further work-up is carried out in the manner described in connection with carbobenzyloxy-γ- (α-benzyl) -L-glutamylhomotaurine (Example 2). 1.25 g of carbobenzyloxy-γ- (α-benzyl) -L-glutamyl-cholamine phosphate are obtained. The relative mobility of the product to cysteic acid by paper electrophoresis at pH 2.0 is 0.9,

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Eksempel 6 526 mg (1,1 mmol) karbobenzyloxy-L-asparaginsyre-(oc-benzyl)-|3-p-nitrofenylester (Chem.Ber. 97, 1789, 1964) opløses i 5 ml pyridin. Opløsningen afkøles til 0°C hvorpå der 5 i små portioner tilsættes en opløsning af 125 mg (1 mmol) taurin i 2 ml vand efterfulgt af 0,28 ml (2 mmol) triætyl-amin. Reaktionsblandingen henstår ved stuetemperatur i 48 timer og inddampes derpå under vakuum. Remanensen opløses i 5 ml vand og til den i begyndelsen gule opløsning sættes 1N 10 saltsyre indtil opløsningen er affarvet. Til fjernelse af p-nitrofenol udrystes opløsningen ti gange med 5 ml æter hver gang. Den vandige fase inddampes under vakuum. Der vindes 478 mg karbobenzyloxy-ø-(a-benzyl)-L-aspartyltaurin. Denne forbindelses relative mobilitet i forhold til cysteinsyre 15 ved papirelektroforese ved pH 6,5 er 0,51.Example 6 526 mg (1.1 mmol) of carbobenzyloxy-L-aspartic acid (oc-benzyl) - 3-p-nitrophenyl ester (Chem. Ber. 97, 1789, 1964) is dissolved in 5 ml of pyridine. The solution is cooled to 0 ° C, then a solution of 125 mg (1 mmol) of taurine in 2 ml of water is added in small portions 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 is added 1N 10 hydrochloric acid until the solution is decolorized. To remove p-nitrophenol, the solution is shaken ten times with 5 ml of ether each time. The aqueous phase is evaporated under vacuum. 478 mg of carbobenzyloxy-α- (α-benzyl) -L-aspartyl taurine are obtained. The relative mobility of this compound relative to cysteic acid 15 by paper electrophoresis at pH 6.5 is 0.51.

Eksempel 7 526 mg (1,1 mmol) karbobenzyloxy-L-asparaginsyre-(a-2Q benzyl)-β-p-nitrofenylester og 139 mg (1 mmol) homotaurin omsættes på den i eksempel 6 beskrevne måde. Der vindes kar-bobenzyloxy-|3-(a-benzyl)-If-aspartylhomotaurin. Dets relative mobilitet i forhold til cysteinsyre ved papirelektroforese ved pH 6,5 er 0,5.Example 7 526 mg (1.1 mmol) of carbobenzyloxy-L-aspartic acid (α-2Q benzyl) -β-p-nitrophenyl ester and 139 mg (1 mmol) of homotaurine are reacted in the manner described in Example 6. Carbobenzyloxy-3- (a-benzyl) -If-aspartyl homotaurine is obtained. Its relative mobility to cysteic acid by paper electrophoresis at pH 6.5 is 0.5.

2525

Eksempel 8Example 8

Karbobenzyloxy-L-asparaginsyre-(α-benzyl)-β-p-nitro-fenylester og kolaminfosfat omsættes med hinanden på den i 2Q eksempel 5 beskrevne måde. Der vindes karbobenzyloxy-/3-(cx-benzyl)-L-aspartylkolaminfosfat. Dets relative mobilitet i forhold til cysteinsyre ved papirelektroforese ved pH 2,0 er 0,9.Carbobenzyloxy-L-aspartic acid (α-benzyl) -β-p-nitrophenyl ester and colamine phosphate are reacted with one another in the manner described in Example 5. Carbobenzyloxy- [3- (cx-benzyl) -L-aspartylcolamine phosphate is obtained. Its relative mobility to cysteic acid by paper electrophoresis at pH 2.0 is 0.9.

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De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelsers biologiske virkning skal i det følgende belyses i to biologiske forsøgsrapporter, A og B. I disse forsøgsrapporter vises den biologiske virkning for fire forskellige typer af 5 forbindelser med den almene formel I. De undersøgte forbindelser har alle ubeskyttede N-terminale og C-terminale grupper, 1 1 dvs. R er hydrogen og A er hydroxy. Forbindelser med den al- mene formel I, hvor R er forskellig fra hydrogen og/eller hvor 1 A er forskellig fra hydroxy har den samme biologiske virkning 10 som de tilsvarende ubeskyttede aminosyrederivater, idet man må forvente at beskyttelsesgrupperne fraspaltes i organismen.The biological effect of the compounds of the invention according to the invention will be elucidated in two biological test reports, A and B. In these test reports, the biological effect of four different types of 5 compounds of general formula I. The compounds tested have all unprotected N -terminal and C-terminal groups, 1 1 ie. R is hydrogen and A is hydroxy. Compounds of general formula I wherein R is different from hydrogen and / or where 1A is different from hydroxy have the same biological effect 10 as the corresponding unprotected amino acid derivatives, one having to expect the protecting groups to be cleaved in the organism.

Biologisk forsøgsrapport A.Biological Test Report A.

1515

Undersøgelse af γ-L-glutamyltaurin som i nærværende .rapport betegnes litoralon.Examination of γ-L-glutamyltaurine as in this report is called litoralon.

I de efterfølgende tabeller 1-6 er forsøgsresultaterne vist som middelværdier + standardafvigelse med antallet af bestem-2Q melser i parentes. Bestemmelse af om der er signifikant forskel mellem kontrolforsøg og forsøg med behandlede dyr blev foretaget med Students t-test.In the following Tables 1-6, the experimental results are shown as mean values + standard deviation with the number of determinations in parentheses. Determination of whether there is a significant difference between control trials and trials in treated animals was done with Student's t-test.

Tabel 1 25 Litoraions virkning på vitamin A-koncentrationen i serum.Table 1 25 Effect of Litoraion on vitamin A concentration in serum.

Gruppe litoralon vitamin A-koncentration i serum _ug/dag_mg %_ I. Kontrol - 28,3+0,7 (20) 30 II. 0,1 41,9 + 1,0X (20) III. 0,3 32,9 + 1,1XX (20) IV. 1,0 27,4 + 0,6 (20) x P < 0,001 25 xx P < 0,01Group of litoralone vitamin A concentration in serum _ug / day_mg% _ I. Control - 28.3 + 0.7 (20) 30 II. 0.1 41.9 + 1.0X (20) III. 0.3 32.9 + 1.1XX (20) IV. 1.0 27.4 + 0.6 (20) x P <0.001 25 xx P <0.01

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9 20 Sprague Dawley rotter (10 hanner og 10 hunner) vejende 180-200 g behandledes oralt med de i tabel 1 angivne daglige doser litoralon i form af en vandig opløsning i en periode på 8 dage. På den 9. forsøgsdag aflivedes dyrene ved dekapitering og 5 blodet opsamledes. Vitamin A-koncentrationen i serumet bestemtes ved Neeld og Pearsons metode.9 20 Sprague Dawley rats (10 males and 10 females) weighing 180-200 g were orally treated with the daily doses of litoralone in Table 1 in the form of an aqueous solution for a period of 8 days. On the 9th test day, the animals were sacrificed by decapitation and the blood was collected. The vitamin A concentration in the serum was determined by Neeld and Pearson's method.

Tabel 2Table 2

Virkning af litoralon og vitamin A på granulomdannelse frem- 10 kaldt af implanterede vatkuqler_Effect of Litoralon and Vitamin A on Granule Formation Caused by Implanted Cotton Balls

Gruppe Dosis Tør vægt af . x .,, Ί granulomGroup Dose Dry weight off. x. ,, Ί granuloma

Vitamin A litoralon lokal lokal oral y 15 mg ug yg/dag_ I. Kontrol - - - 52 + 1,0 (24) II. Kontrol +Vitamin A litoralon local local oral y 15 mg ug yg / day_ I. Control - - - 52 + 1.0 (24) II. Control +

Opløsningsmiddel - - - 54+3,1(8) III. 2 - - 64 + 2,5 (8) 20 “ IV. 2 0,1 - 65 + 2,7 (8) V. - - 0,1 73 + 2,9 (8) VI. 2 - 0,1 90 + 4,1 (8) x Hoffmann La Roche 25Solvent - - - 54 + 3.1 (8) III. 2 - - 64 + 2.5 (8) 20 “IV. 2 0.1 - 65 + 2.7 (8) V. - - 0.1 73 + 2.9 (8) VI. 2 - 0.1 90 + 4.1 (8) x Hoffmann La Roche 25

Forskellen er signifikant: mellem gruppe II og III ved 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 P <0.05, between II and V at P <0.001, and between V and VI at P <0.01. The granule formation was determined according to Lee et al with male Sprague-Dawley rats weighing 110-120 g. The tampons were removed from the dorsolateral subcutaneous implants after 10 days and weighed after drying to constant weight at 65 ° C.

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DK 155732BDK 155732B

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Tabel 5Table 5

Litoralons virkning på Rana dalmatina's metamorfoseThe effect of Litoralon on the metamorphosis of Rana dalmatina

Gruppe Kropslængde Halelængde 5 _mm_mm_Group Body length Tail length 5 _mm_mm_

Kontrol 45,9 +0/2 31,4+0,2 (60)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 i ηTreated animals 40.2 + 0.2X 26.7 + 0.2X (60) x Significance: P <0.001 in η

Forsøget udførtes med larver af Rana dalmatina 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 litoralon i to timer hver dag. Kontrolgruppen blev anbragt i 15 postevand uden tilsætning af litoralon. Haletudserne måltes på den 30. dag.The experiment was conducted with larvae of Rana dalmatina 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 litoralon for two hours each day. The control group was placed in 15 tap water without the addition of litoralone. The tails were measured on the 30th day.

Tabel 6 2Q Litoralons virkning på blodsukkerniveauetTable 6 2Q Litoralone's effect on blood sugar levels

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) 25Treated animals 82.4 + 3.8 (10) 81 + 1.32 (10) 25

Signifikans ved I. undersøgelse: P < 0,05 Signifikans ved II. undersøgelse: P < 0,01Significance 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 2Q blodprøver på den 5. forsøgsdag efter 18 timers faste. Blodsukkerbestemmelserne udførtes efter metoden ifølge E. Hultman.Male CGY white body rats 160-180 g were used for the experiment. The animals were kept on a standard diet. 2Q blood samples were taken on the 5th day of trial after 18 hours of fasting. The blood glucose assays were performed according to the method of E. Hultman.

Litoralon blev indgivet oralt i daglige doser på 1 yg/kg.Litoralon was given orally at daily doses of 1 µg / kg.

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Biologisk forsøgsrapport B.Biological Test Report B.

Undersøgelse af diverse forbindelser med formel I.Investigation of various compounds of formula I.

1. β-aspartyl-N-metyltaurin 5 a) Virkning på blodsukkerniveauet Kontrol 107 mg %1. β-Aspartyl-N-methyltaurine 5 a) Effect on blood sugar level Control 107 mg%

Behandlede dyr 93 mg %Treated animals 93 mg%

Signifikans: P < 0,05Significance: P <0.05

Til prøverne anvendtes 20-20 rotter. Målingerne gennem-10 førtes efter 18 timers faste. Den anvendte dosis var 1 yg/kg legemsvægt i 4 dage i form af en opløsning ved oral indgift.20-20 rats were used for the samples. Measurements were carried out -10 after 18 hours of fasting. The dose used was 1 µg / kg body weight for 4 days in the form of a solution by oral administration.

b) Forøgende virkning på vitamin A-niveauet i serumb) Increasing effect on serum vitamin A level

Oral dosis Kone., vitamin A, mg% 15 yg/200 g legemsvægt 0 (kontrol) 8,5 5 11,0 1 11,5 0,3 12,5 20 0,1 16,1 0,05 14,8 0,01 12,5 0,005 10,5 2,. Signifikans: P < 0,01Oral dose Conical vitamin A, mg% 15 µg / 200 g body weight 0 (control) 8.5 5 11.0 1 11.5 0.3 12.5 20 0.1 16.1 0.05 14.8 0.01 12.5 0.005 10.5 2 ,. 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.

c) Virkning på blodets siliciumniveau:c) Effect on blood silicon level:

Silicium (mg/g blod) 0 timer 20 dage_40 dage_Silicon (mg / g blood) 0 hours 20 days_40 days_

Kontrolgruppe 0,110+0,004 0,120+0,010 0,154+0,015Control group 0.110 + 0.004 0.120 + 0.010 0.154 + 0.015

Behandlingsgruppe 15 yg/dag 0,100+0,005 0,315+0,014 0,345+0,015Treatment group 15 µg / day 0.100 + 0.005 0.315 + 0.014 0.345 + 0.015

Behandlingsgruppe II 10 yg/dag 0,107+0,009 0,370+0,119 0,360+0,017 xx Signifikans: P < 0,001 14Treatment Group II 10 µg / day 0.107 + 0.009 0.370 + 0.119 0.360 + 0.017 xx Significance: P <0.001 14

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Resultaterne er signifikante fra 20. dag ved niveau 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 daglige doser. Bestemmelsen af silicium udførtes i-5 følge Gaubatz's metode (Gaubatz E., Klin. Wschrft. 14, 1753, 1935) i 5 ml blodprøver, som blev taget fra dyrenes ørevene.Results are significant from day 20 at 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 daily doses shown in the table. The determination of silicon was carried out i-5 according to Gaubatz's method (Gaubatz E., Clin. Wschrft. 14, 1753, 1935) in 5 ml blood samples taken from the animals' ears.

Hver gruppe bestod af fem dyr.Each group consisted of five animals.

d) Virkning af j3-aspartyl-N-metyl-taurin og vitamin A på den 10 granulomfremkaldende virkning forårsaget af implantation af vat:_d) Effect of β-aspartyl-N-methyl-taurine and vitamin A on the 10 granulogenic effect caused by the implantation of cotton wool:

Gruppe Dosis Vægt af tør-Group Dose Weight of dry

Vitamin Ax 3-aspartyl-N- ret 9ranulomVitamin Ax 3-aspartyl-N- ret 9ranuloma

t . IRCTt. IRCT

metyltaurm lokal lokal oral 15 _mg_yg yg/dag____methyl taurus local local oral 15 mg / day / day ____

Kontrol I. - - - 54+1,7Control I. - - - 54 + 1.7

Kontrol II. + opløsningsmiddel - - - 55+3,4Control II. + solvent - - - 55 + 3.4

Behandlingsgruppe III. 2 - - 66+12,5 2g Behandlingsgruppe IV. 2 0,1 - 67 + 2,6Treatment Group III. 2 - - 66 + 12.5 2g Treatment Group IV. 2 0.1 - 67 + 2.6

Behandlingsgruppe V. - - 0,1 79+2,8Treatment group V. - - 0.1 79 + 2.8

Behandlingsgruppe VI. 2 - 0,1 96+4,4 x Hoffmann la Roche 25 Forskellene er signifikante som følger:Treatment Group VI. 2 - 0.1 96 + 4.4 x Hoffmann la Roche 25 The differences are significant as follows:

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.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 grupper på hver fem Sprague-Dawley hanrotter med legemsvægt 110-120 g ved me-30 toden ifølge Lee et al (Lee K.H., Fu Ch.Ch., Spencer M.R.The determination of granuloma was performed on groups of five 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. og Poon R.J., Pharm. Sci., 62, 895, 1973). De dor-solateralt subkutant implanterede tamponer fjernedes efter 10 dage og måltes efter tørring ved 65°C til konstant vægt.Tong T.G. and Poon R.J., Pharm. Sci., 62, 895, 1973). The dor- solaterally subcutaneously implanted tampons were removed after 10 days and measured after drying at 65 ° C to constant weight.

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2. β-Aspartyl-homotaurin, a) Virkning på blodsukkerniveauet2. β-Aspartyl homotaurine, a) Effect on blood sugar level

Kontrolgruppe 105 mg%Control group 105 mg%

Behandlet gruppe 94 mg% 5 Signifikans, antal forsøgsdyr og forsøgsmetode var som angivet under pkt. 1 a) ovenfor.Treated group 94 mg% 5 Significance, number of test animals and test method were as given in section. 1 a) above.

b) Forøgende virkning på vitamin A-niveauet i serumb) Increasing effect on serum vitamin A level

Oral dosis Koncentration vitamin AOral dose Vitamin A concentration

10 pg/200 g legemsvægt mg% 0 (kontrol) 8,6 5 12,0 1 13,5 0,3 14,0 15 0,1 15,8 0,05 15,0 0,01 12,0 0,005_10,0_10 pg / 200 g body weight mg% 0 (control) 8.6 5 12.0 1 13.5 0.3 14.0 15 0.1 15.8 0.05 15.0 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).

c) Virkning på blodets siliciumniveau:c) Effect on blood silicon level:

Silicium (mg/g blod) 25 _0 timer _20 dage_40 dage__Silicon (mg / g blood) 25 _0 hours _20 days_40 days__

Kontrolgruppe 0,104+0,009 0,134+0,015 0,157+0,020Control group 0.104 + 0.009 0.134 + 0.015 0.157 + 0.020

Behandlingsgruppe I. 5yg/dag 0,094+0,007 0,309+0,014 0,340+0,014Treatment group I. 5yg / day 0.094 + 0.007 0.309 + 0.014 0.340 + 0.014

Behandlingsgruppe II. 10 pg/dag 0,109+0,010 0,372+0,120 0,363+0,018ΛΛ 30 Signifikans, antal forsøgsdyr, arrangement og bestemmel sesmetode som angivet ovenfor under pkt. 1 c).Treatment Group II. 10 pg / day 0.109 + 0.010 0.372 + 0.120 0.363 + 0.018ΛΛ 30 Significance, number of test animals, arrangement and method of determination as indicated above under section. 1 c).

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d) Virkning af β-aspartyl-homotaurin og vitamin A på den granu-lomfremkaldende virkning af implantation af vat;_(d) Effect of β-aspartyl homotaurin and vitamin A on the granulomatous effect of cotton implantation;

Dosis Vægt af tørretDose Weight of dried

Vitamin Ax β-aspartyl- granulom 5 lokal homotaurin g mg lokal oral _μg yg/dag_Vitamin Ax β-aspartyl granuloma 5 local homotaurin g mg local oral _µg yg / day_

Kontrolgruppe I - - - 52+1,5Control group I - - - 52 + 1.5

Kontrolgruppe II - - - 53+3,2 + opløsningsmiddel 10 Behandlingsgruppe III. 2 - - 64+12,3Control group II - - - 53 + 3.2 + solvent 10 Treatment 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

Behandlingsgruppe VI._2_ 0,1_94 + 4,2__ x Hoffmann la Roche 15Treatment group VI._2_ 0.1_94 + 4.2__ x Hoffmann la Roche 15

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).

3. γ-Glutamyl-kolaminfosfat.3. γ-Glutamyl-Colamine Phosphate.

a) Virkning på blodsukkerniveauet 20(a) Effect on blood sugar levels 20

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).

25 b) Forøgende virkning på vitamin A-niveauet i serum25 b) Increasing effect on serum vitamin A level

Oral dosis Vitamin A-koncentration yg/200 g legemsvægt_mg%_________ 0 (kontrol) 8,8 30 5 12'3 1 13,4 0,3 14,3 0,1 16,0 0,05 15,5 0,01 11,2 35 0,005_9j2_ 17Oral dose of Vitamin A concentration yg / 200 g body weight_mg% _________ 0 (control) 8.8 30 5 12'3 1 13.4 0.3 14.3 0.1 16.0 0.05 15.5 0.01 11.2 35 0.005_9j2_ 17

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Signifikans, antal forsøgsdyr, arrangement og bestemmelsesmetode 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: 5 Silicium (mg/g blod) _0 timer_20 dage_40 dage_c) Effect on blood silicon level: 5 Silicon (mg / g blood) _0 hours_20 days_40 days_

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 xx I 5 yg/dag 0,096+0,009 0,311+0,016 0,340+0,017 .. Behandlingsgruppe vv xx 10 II 10 yg/dag 0,111+0,011 0,374+0,121xx 0,365+0,019Treatment group xx I 5 µg / day 0.096 + 0.009 0.311 + 0.016 0.340 + 0.017 .. Treatment group vv xx 10 II 10 µg / day 0.111 + 0.011 0.374 + 0.121xx 0.365 + 0.019

Signifikans, antal forsøgsdyr, arrangement og bestemmelsesmetode var som angivet ovenfor under punkt 1 c).Significance, number of test animals, arrangement and method of determination were as indicated above under point 1 (c).

d) Virkning af γ-glutamyl-kolaminfosfat og vitamin A på den 1 s granulomfremkaldende virkning af vatimplantation;_(d) Effect of γ-glutamyl-cholamine phosphate and vitamin A on the 1 s granuloma-inducing effect of water implantation;

Dosis Vægt af tør ret granulomDose Weight of dry straight granuloma

Vitamin Ax γ-glutamyl- mg lokal kolaminfosfat mg lokal oral 2Q _yg yg/dag_Vitamin Ax γ-glutamyl mg local colamine phosphate mg local oral 2Qg / day / day

Kontrolgruppe I. - - - 49+1,2Control group I. - - - 49 + 1.2

Kontrolgruppe II. + opløsningsmiddel - - - 50+2,9Control group II. + solvent - - - 50 + 2.9

Behandlingsgruppe III. 2 - 61 + 12,0Treatment Group III. 2 - 61 + 12.0

Behandlingsgruppe IV. 2 .0,1 - 62+2,1 25 Behandlingsgruppe V. - - 0,1 74+2,3Treatment Group IV. 2 .0.1 - 62 + 2.1. Treatment 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, ntal forsøgsdyr, arrangement samt bestem:-melsesmetode var som angivet under ' 1 d) ovenfor.Significance, number of test animals, arrangement and determination: - method of measurement was as indicated under '1 d) above.

3535

Claims (2)

1. Analogifremgangsmåde til fremstilling af amino-syrederivater med formlen1. Analogous process for preparing amino acid derivatives of the formula 5 R1-NH-CH-CO-A1 ( CEL· ) I I 2 n -i CO-N-CH-(CH9 ) -B I 2 * ^ R R hvor 10. er hydroxy, C^_^alkoxy eller fenyl-C^^alkoxy; B1 er en gruppe med formlen -S020H eller-OPO(OH)2; R er hydrogen eller alkyl med 1-4 kulstofatomer; R er hydrogen, _^alkoxykarbonyl eller fenyl-C^^alkoxy-karbonyl; 2 15. er hydrogen eller karboxyl, n er 1 eller 2 og t er 1 eller 2, eller fysiologisk acceptable salte eller optisk aktive antipoder deraf, kendetegnet ved at man omsæt-20 ter en optisk aktiv eller racemisk forbindelse med den almene formel r'-nh-ch-coa (CH2)n II5 R1-NH-CH-CO-A1 (CEL ·) II 2 n -i CO-N-CH- (CH9) -BI 2 * RR where 10. is hydroxy, C, _ ^ alkoxy or phenyl-C ^ ^ alkoxy; B1 is a group of the formula -SO20H or -OPO (OH) 2; R is hydrogen or alkyl of 1-4 carbon atoms; R is hydrogen, alkoxycarbonyl or phenyl-C 1-4 alkoxycarbonyl; 2 is hydrogen or carboxyl, n is 1 or 2 and t is 1 or 2, or physiologically acceptable salts or optically active antipodes thereof, characterized by reacting an optically active or racemic compound of the general formula r ' -nh-ch-coa (CH2) n II 25 COA2 1 1 hvor R , A og n har de ovenfor angivne betydninger, og 2 A er p-nitrofenoxy, pentaklorfenoxy eller alkoxykarbo-nyloxy med 2-4 kulstofatomer i alkoxydelen, med en op-30 tisk aktiv eller racemisk forbindelse med den almene formel NH- CH -(CEL·).-B1 III R Å2 2 * 35 2 1 hvor R, R , B og t har de ovenfor angivne betydninger, _ DK 155732B hvorefter man om ønsket omdanner den således vundne forbindelse til et fysiologisk acceptabelt salt deraf eller frigør den fra et salt og/eller fremstiller den vundne forbindelse i optisk aktiv form ved opspaltning af et vun-5 det racemisk produkt.Wherein R, A and n are as defined above and 2A is p-nitrophenoxy, pentachlorophenoxy or alkoxycarboxyloxy having 2-4 carbon atoms in the alkoxy moiety, with an optically active or racemic compound with the general Formula NH-CH - (CEL ·). - B1 III R Å2 2 * 35 2 1 wherein R, R, B and t have the meanings given above, and if desired, the compound thus obtained is converted into a physiologically acceptable salt thereof or release it from a salt and / or prepare the obtained compound in optically active form by digestion of a obtained racemic product. 2. Fremgangsmåde ifølge krav 1, kendetegnet ved at en forbindelse med den almene formel II, fortrinsvis en N-karbobenzyloxyaminodikarboxylsyre-oc-benzyl-ω-ρ-nitrofenylester, omsættes med en forbindelse med den almene 10 formel III, fortrinsvis med taurin, N-metyltaurin, homo-taurin, kolaminfosfat eller cysteinsyre, i nærværelse af vandig pyridin. 15 20 25 30 35Process according to claim 1, characterized in that a compound of the general formula II, preferably a N-carbobenzyloxyaminodicarboxylic acid oc-benzyl-ω-ρ-nitrophenyl ester, is reacted with a compound of the general formula III, preferably with taurine, N -methyltaurine, homo-taurine, colamine phosphate or cysteic acid, in the presence of aqueous pyridine. 15 20 25 30 35
DK442477A 1974-04-29 1977-10-06 ANALOGY PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES DK155732C (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
HUFE000928 1974-04-29
HU74FE00000928A HU171576B (en) 1974-04-29 1974-04-29 Process for the isolation of gamma-l-glutamyl-taurine
HUCI001558 1975-03-26
HU74CI1558A HU174114B (en) 1975-03-26 1975-03-26 Process for producing new aminoacid derivatives

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DK442477A DK442477A (en) 1977-10-06
DK155732B true DK155732B (en) 1989-05-08
DK155732C DK155732C (en) 1989-10-02

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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
DK442877A DK158676C (en) 1974-04-29 1977-10-06 METHOD OF ANALOGUE FOR THE PREPARATION OF POLYMERS OR OLIGOMER AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS.
DK442977A DK442977A (en) 1974-04-29 1977-10-06 GAMMA-L-GLUTAMYLTAURIN PROCEDURE
DK442577A DK442577A (en) 1974-04-29 1977-10-06 PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES
DK442377A DK155520C (en) 1974-04-29 1977-10-06 METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF
DK442777A DK442777A (en) 1974-04-29 1977-10-06 PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES
DK443077A DK159267C (en) 1974-04-29 1977-10-06 METHOD OF ANALOGUE FOR THE PREPARATION OF TAURIN DERIVATIVES OR HOMOTAURIN DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF
DK442677A DK159654C (en) 1974-04-29 1977-10-06 METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF
DK442477A DK155732C (en) 1974-04-29 1977-10-06 ANALOGY PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES
DK245783A DK155672C (en) 1974-04-29 1983-05-31 METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS OR OPTICALLY ACTIVE ISOMER THEREOF

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DK182875A DK155433C (en) 1974-04-29 1975-04-28 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.
DK442977A DK442977A (en) 1974-04-29 1977-10-06 GAMMA-L-GLUTAMYLTAURIN PROCEDURE
DK442577A DK442577A (en) 1974-04-29 1977-10-06 PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES
DK442377A DK155520C (en) 1974-04-29 1977-10-06 METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF
DK442777A DK442777A (en) 1974-04-29 1977-10-06 PROCEDURE FOR THE PREPARATION OF AMINO ACID DERIVATIVES
DK443077A DK159267C (en) 1974-04-29 1977-10-06 METHOD OF ANALOGUE FOR THE PREPARATION OF TAURIN DERIVATIVES OR HOMOTAURIN DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF
DK442677A DK159654C (en) 1974-04-29 1977-10-06 METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS THEREOF

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HU178199B (en) * 1976-05-06 1982-03-28 Chinoin Gyogyszer Es Vegyeszet New process for producing amides of omega-amino-carboxylic acids
HU180443B (en) * 1979-04-02 1983-03-28 Chinoin Gyogyszer Es Vegyeszet Process for preparing a pharmaceutical preparation with synergetic action against radiation
HU185632B (en) * 1981-03-27 1985-03-28 Chinoin Gyogyszer Es Vegyeszet New process for preparing gamma-glutamyl-taurine
CH665645A5 (en) * 1981-07-09 1988-05-31 Michel Flork DIPEPTIDE DERIVATIVES AND THEIR PREPARATION PROCESS.
HU208072B (en) * 1990-02-28 1993-08-30 Chinoin Gyogyszer Es Vegyeszet Process for producing pharmaceutical composition suitable for preventing and curing autoimmune diseases and skin affections caused by heat and light radiacion
JPH0680964A (en) * 1991-12-27 1994-03-22 Sogo Yatsukou Kk Active-oxygen scavenger
JPH11180846A (en) * 1997-12-15 1999-07-06 Sogo Pharmaceut Co Ltd Cosmetic
DE10133197A1 (en) * 2001-07-07 2003-01-23 Beiersdorf Ag Use of topical compositions containing beta-amino acids, guanidinoethanesulfonate, homotaurine and their precursors and derivatives e.g. to improve skin condition and to treat or prevent skin disorders
DK2089417T3 (en) 2006-10-12 2015-03-23 Bhi Ltd Partnership Methods, Compounds, Compositions and Vehicles for Delivery of 3-Amion-1-Propanesulfonic Acid
US9662304B1 (en) * 2013-06-13 2017-05-30 Thermolife International, Llc Substituted glutaurine compounds and substituted glutaurine derivatives

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DK159267C (en) 1991-02-18
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SE7504828L (en) 1975-10-30
IL47149A (en) 1979-05-31
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FR2279388B1 (en) 1978-07-28
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DK442777A (en) 1977-10-06
SE7812884L (en) 1978-12-14
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NO149036C (en) 1984-02-01
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DK442977A (en) 1977-10-06
AT370724B (en) 1983-04-25
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