NO134984B - - Google Patents
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- NO134984B NO134984B NO456471A NO456471A NO134984B NO 134984 B NO134984 B NO 134984B NO 456471 A NO456471 A NO 456471A NO 456471 A NO456471 A NO 456471A NO 134984 B NO134984 B NO 134984B
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- alanine
- fluoro
- deutero
- fluorooxy
- antibacterial
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- UYTSRQMXRROFPU-UWTATZPHSA-N (2s)-2-amino-3-fluoropropanoic acid Chemical compound FC[C@@H](N)C(O)=O UYTSRQMXRROFPU-UWTATZPHSA-N 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 14
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims description 10
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000003999 initiator Substances 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- UYTSRQMXRROFPU-MIRRBZTDSA-N (2s)-2-amino-2,3,3-trideuterio-3-fluoropropanoic acid Chemical compound [2H]C([2H])(F)[C@@]([2H])(N)C(O)=O UYTSRQMXRROFPU-MIRRBZTDSA-N 0.000 claims description 4
- UYTSRQMXRROFPU-LIIDHCAMSA-N (2s)-2-amino-2-deuterio-3-fluoropropanoic acid Chemical compound FC[C@](N)([2H])C(O)=O UYTSRQMXRROFPU-LIIDHCAMSA-N 0.000 claims description 4
- 235000004279 alanine Nutrition 0.000 claims description 3
- SMBZJSVIKJMSFP-UHFFFAOYSA-N trifluoromethyl hypofluorite Chemical compound FOC(F)(F)F SMBZJSVIKJMSFP-UHFFFAOYSA-N 0.000 claims description 3
- QNAYBMKLOCPYGJ-LIIDHCAMSA-N (2r)-2-amino-2-deuteriopropanoic acid Chemical compound [2H][C@](C)(N)C(O)=O QNAYBMKLOCPYGJ-LIIDHCAMSA-N 0.000 claims description 2
- DGQBNDRZRZYTER-UHFFFAOYSA-N (pentafluoro-$l^{6}-sulfanyl) hypofluorite Chemical compound FOS(F)(F)(F)(F)F DGQBNDRZRZYTER-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 241001465754 Metazoa Species 0.000 description 9
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- UYTSRQMXRROFPU-REOHCLBHSA-N (2r)-2-amino-3-fluoropropanoic acid Chemical compound FC[C@H](N)C(O)=O UYTSRQMXRROFPU-REOHCLBHSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229960003767 alanine Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
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- 229940024606 amino acid Drugs 0.000 description 3
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- 102000004674 D-amino-acid oxidase Human genes 0.000 description 2
- 108010003989 D-amino-acid oxidase Proteins 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
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- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960005091 chloramphenicol Drugs 0.000 description 2
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 2
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- 229940079593 drug Drugs 0.000 description 2
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- 238000003682 fluorination reaction Methods 0.000 description 2
- -1 fluorooxy Chemical group 0.000 description 2
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- 229960002180 tetracycline Drugs 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
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- BXUGTBKNXOBNNP-HSHFZTNMSA-N (2s)-2-amino-3-fluoropropanoic acid;hydrochloride Chemical compound Cl.FC[C@@H](N)C(O)=O BXUGTBKNXOBNNP-HSHFZTNMSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- UYTSRQMXRROFPU-UHFFFAOYSA-N 2-azaniumyl-3-fluoropropanoate Chemical compound FCC(N)C(O)=O UYTSRQMXRROFPU-UHFFFAOYSA-N 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 108010041525 Alanine racemase Proteins 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- DYDCUQKUCUHJBH-UWTATZPHSA-N D-Cycloserine Chemical compound N[C@@H]1CONC1=O DYDCUQKUCUHJBH-UWTATZPHSA-N 0.000 description 1
- DYDCUQKUCUHJBH-UHFFFAOYSA-N D-Cycloserine Natural products NC1CONC1=O DYDCUQKUCUHJBH-UHFFFAOYSA-N 0.000 description 1
- 125000000030 D-alanine group Chemical group [H]N([H])[C@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 1
- 150000008541 D-alanines Chemical class 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 229920004459 Kel-F® PCTFE Polymers 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 241000606860 Pasteurella Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 241000607598 Vibrio Species 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
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- UUAGAQFQZIEFAH-UHFFFAOYSA-N chlorotrifluoroethylene Chemical compound FC(F)=C(F)Cl UUAGAQFQZIEFAH-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
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- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av de nye forbindelser 3-fluor-D-alanin, 2-deutero-3-fluor-D-alanin eller 2,3,3-trideutero-3-fluor-D-alanin, samt salter av disse forbindelser. The present invention relates to a process for the production of the new compounds 3-fluoro-D-alanine, 2-deutero-3-fluoro-D-alanine or 2,3,3-trideutero-3-fluoro-D-alanine, as well as salts of these compounds.
Den racemiske forbindelse 3-fluor-D,L-alanin er en kjent forbindelse beskrevet av Lettre et al., i Ann. Chem. 708, 75-85 The racemic compound 3-fluoro-D,L-alanine is a known compound described by Lettre et al., in Ann. Chem. 708, 75-85
(1967). De optiske isomerer har imidlertid ikke vært beskrevet, (1967). However, the optical isomers have not been described,
og heller ikke har den antibakterielle aktivitet av racematet vært undersokt. 3-fluor-D-alanin og dets optiske isomer fremstilles ikke ifolge oppfinnelsen- ved spaltning av det kjente racemat, men, som det vil fremgå senere, ved direkte fluorering av de kjente og kommersielt tilgjengelige D-alaniner. nor has the antibacterial activity of the racemate been investigated. 3-Fluoro-D-alanine and its optical isomer are not produced according to the invention - by cleavage of the known racemate, but, as will be seen later, by direct fluorination of the known and commercially available D-alanines.
Forbausende nok har det vist seg at bare under spesielle in vitro antibakterielle prøvemetoder gjorde den inhiberende aktivitet av 3-fluor-D-alanin seg gjeldende. Det var derfor mulig å vise at Surprisingly, it has been shown that only under special in vitro antibacterial test methods did the inhibitory activity of 3-fluoro-D-alanine manifest itself. It was therefore possible to show that
den in vitro antibakterielle aktivitet av de optiske isomerer er sammen-lignbare. Allikevel skiller isomerene seg markert in vivo. D-isomeren bibeholder sine antibakterielle egenskaper og tjener til å beskytte det infiserte dyr mens L-isomeren synes å mangle evnen til å beskytte bakterielt infiserte dyr og er enndog drepende for disse dyr i selv moderate dosemengder. the in vitro antibacterial activity of the optical isomers is comparable. Even so, the isomers differ markedly in vivo. The D-isomer retains its antibacterial properties and serves to protect the infected animal, while the L-isomer appears to lack the ability to protect bacterially infected animals and is nevertheless lethal to these animals in even moderate doses.
De nye forbindelser og deres salter er antibakterielle midler som er nyttige til å inhibere veksten av pato-gene bakterier av både gram-positive og gram-negative slekter som Streptoeoccus, Escherichia, Staphylocoecus, Salmonella, Pseudomonas, Diplococcus, Klebsiella, Proteus, Mycobacterium, Vibrio, Pasteurella og Serratia, såvel som antibiotisk resistente stammer derav. Illustrerende for slike patogener er Escherichia coli, Salmonella schott-muelleri, Proteus vulgaris, Proteus mirabilis, Pseudomonas aerugin-osa, Stephylococcus aureus og Streptoeoccus pyogenes. De nye forbindelser og deres salter kan således anvendes som antiseptiske midler for å fjerne påvirkelige organismer fra farma-søytisk, dentalt og medisinsk utstyr, og kan også anvendes på andre områder som er utsatt for infeksjon av slike organismer. The new compounds and their salts are antibacterial agents useful in inhibiting the growth of pathogenic bacteria of both gram-positive and gram-negative genera such as Streptoeoccus, Escherichia, Staphylocoecus, Salmonella, Pseudomonas, Diplococcus, Klebsiella, Proteus, Mycobacterium, Vibrio, Pasteurella and Serratia, as well as antibiotic-resistant strains thereof. Examples of such pathogens are Escherichia coli, Salmonella schott-muelleri, Proteus vulgaris, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus and Streptoeoccus pyogenes. The new compounds and their salts can thus be used as antiseptic agents to remove susceptible organisms from pharmaceutical, dental and medical equipment, and can also be used in other areas that are exposed to infection by such organisms.
D-isomeren av de nye forbindelser og deres salter er særlig verdifulle fordi de ikke bare har den ovennevnte anvendbarhet, men de er også nyttige ved behandling av sykdommer fremkalt av de oven-stående organismer i mennesker og dyr, og kan administreres i en lang rekke terapeutiske doseringer i konvensjonelle medier som f.eks. ved oral administrasjon i form av en kapsel eller tablett eller i en flytende opplosning eller suspensjon. Egnede formuler-inger kan innbefatte fortynningsmidler, granuleringsmidler, konser-veringsmidler, bindemidler, smaksstoffer og belegningsmidler som er vel kjent i faget, og dosene for produktene kan varieres over et vidt område med en ovre grense som bestemmes av den autoantagonistiske terskelverdi av den infiserende organisme med hensyn på 3-fluor-D-alanin i det umiddelbare område for ventet antibakterie11 virkning. Eksempelvis ville doser variere fra ca. 250 mg til ca. 500 mg 2 - k ganger daglig av aktiv bestanddel pr. 70 kg voksent menneske. Et voksende fordyr på veksttillatende terapi bor få ca. 100 g/tonn total-f(5r. Alternativt kan de administreres parenteralt ved injeksjon i et sterilt hjelpemedium. The D-isomer of the novel compounds and their salts are particularly valuable because they not only have the above utility, but are also useful in the treatment of diseases caused by the above organisms in humans and animals, and can be administered in a wide range therapeutic dosages in conventional media such as e.g. by oral administration in the form of a capsule or tablet or in a liquid solution or suspension. Suitable formulations may include diluents, granulating agents, preservatives, binders, flavorings and coating agents as are well known in the art, and the doses of the products may be varied over a wide range with an upper limit determined by the autoantagonistic threshold value of the infecting organism. with regard to 3-fluoro-D-alanine in the immediate area of expected antibacterial11 action. For example, doses would vary from approx. 250 mg to approx. 500 mg 2 - k times a day of active ingredient per 70 kg adult human. A growing pre-animal on growth-permitting therapy lives few approx. 100 g/tonne total-f(5r. Alternatively, they can be administered parenterally by injection in a sterile auxiliary medium.
Entydeligheten av den in vitro antibakterielle prove nevnt ovenfor skyldes den uvanlige egenskap hos 3-fluor-D-alanin at det er autoantagonistisk ved hoye konsentrasjoner. I standard antibakterielle utskillelsesforsbk som er beregnet på å plukke opp aktiviteter av meget lav størrelsesorden, og hvor folgelig relativt hoye konsentrasjoner av forsoksforbindelse anvendes, ville folgelig aktiviteten av 3-fluor-D-alanin bli oversett. The uniqueness of the in vitro antibacterial test mentioned above is due to the unusual property of 3-fluoro-D-alanine that it is autoantagonistic at high concentrations. In standard antibacterial secretion experiments which are intended to pick up activities of very low order of magnitude, and where therefore relatively high concentrations of test compound are used, the activity of 3-fluoro-D-alanine would therefore be overlooked.
Denne autoantagonistiske egenskap begrenser ikke dets anvendbarhet, da den bare opptrer f.eks. in vivo ved doser storre enn ca. This auto-antagonistic property does not limit its applicability, as it only acts e.g. in vivo at doses greater than approx.
10 ganger det gjennomsnittlige effektive helbredelsesnivå. 10 times the average effective healing level.
Mens 3-fluor-L-alanin metaboliseres hurtig og fullstendig med toksiske folger, er 3-fluor-D-alanin utsatt,for en meget langsommere nedbrytning in vivo. En mulig årsak er D-aminosyre-oxydaseenzymet som er tilstede i rikelige mengder i mennesker og rotter, men i meget lavere utstrekning i mus og visse planteetende husdyr. Hverken metabolisme-hastigheten, som- den kan påvirke blodinnholdet av den terapeutiske forbindelse, eller biproduktene fra denne metabolisme taler imidlertid mot anvendelsen av forbindelsen ved den dosemengde som er foreslått for mennesker eller dyr. While 3-fluoro-L-alanine is rapidly and completely metabolized with toxic consequences, 3-fluoro-D-alanine is subjected to a much slower breakdown in vivo. One possible cause is the D-amino acid oxidase enzyme, which is present in abundant amounts in humans and rats, but to a much lower extent in mice and certain herbivorous domestic animals. However, neither the rate of metabolism, which can affect the blood content of the therapeutic compound, nor the by-products of this metabolism speak against the use of the compound at the dose amount proposed for humans or animals.
Det har videre vist seg It has also been shown
at deuterering gir nye deutero-analoger som er betraktelig mindre utsatt for angrep av D-aminosyre-oxydase og allikevel bibeholder den antibakterielle styrke av opphavsforbindelsen. In vivo aktiviteten bkes og opprettholdes derved. that deuteration gives new deutero analogues which are considerably less susceptible to attack by D-amino acid oxidase and still retain the antibacterial potency of the parent compound. The in vivo activity is increased and maintained thereby.
Virksomheten av 3- fluor- D- alanin sammenlignet med andre antibiotika ved behandling av infiserte mus. CD. 1 hunmus av gjennomsnittsvekt 21,0 g ble injisert intraperitonealt med 0,5 ml av en passende fortynning av en 16 timers buljongkultur inneholdende de angitte patogener. The activity of 3-fluoro-D-alanine compared to other antibiotics in the treatment of infected mice. CD. 1 female mouse of average weight 21.0 g was injected intraperitoneally with 0.5 ml of an appropriate dilution of a 16 hour broth culture containing the indicated pathogens.
Infiseringsgraden er i hvert tilfelle angitt som det multippel av fortynningen av buljongkulturen som var dodelig for bare 50$ av den ubehandlede bestand, LD^Q-dosen.) Den terapeutiske forbindelse ble så straks administrert i et 0,5 ml volum ved en av de angitte veier, enten subcutant på ryggen (S.C.), intraperitonealt (I.P.) eller med sonde (oralt P.O.). I tilfelle av mus infisert med Streptoeoccus- eller Diplococcus-organismer ble dessuten en annen dose av terapeutisk middel administrert 6 timer efter infeksjon. Resultatene av disse forsok er uttrykt som den statistisk interpolerte dose som kreves for å beskytte ^ 0% av den infiserte bestand i et tidsrom av 7 dager efter smitte og behandling, (dodsfall blant dyr med mis-lykket behandling eller ubehandlede kontrolldyr inntrer i alle tilfelle i lopet av de forste 3 dager). Forkortelser hsr anvendt for forbindelsene som sammenlignes er: 3FDA - 3-fluor-D-alanin; In each case the degree of infection is given as the multiple of the dilution of the broth culture that was lethal to only 50$ of the untreated stock, the LD^Q dose.) The therapeutic compound was then immediately administered in a 0.5 ml volume at one of the indicated routes, either subcutaneously on the back (S.C.), intraperitoneally (I.P.) or by tube (oral P.O.). In addition, in the case of mice infected with Streptoeoccus or Diplococcus organisms, another dose of therapeutic agent was administered 6 hours after infection. The results of these experiments are expressed as the statistically interpolated dose required to protect ^0% of the infected population for a period of 7 days after infection and treatment, (deaths among animals with unsuccessful treatment or untreated control animals occur in all cases during the first 3 days). Abbreviations used for the compounds being compared are: 3FDA - 3-fluoro-D-alanine;
CYC = D-cycloserin*,' TET = tetracyclin; CLM'= kloramfenikol. CYC = D-cycloserine*,' TET = tetracycline; CLM'= chloramphenicol.
En markert overlegenhet 1 styrke for behandling av et bredt spektrum av bakterielle infeksjoner oppvises av 3-fluor-D-alanin. Særlig ved den praktiske orale administrasjon gir 3-fluor-D-alanin en grad av virksomhet som tilsvarer eller overgår den for de inn-arbeidede antibiotika kloramfenikol og tetracyclin. A marked superiority 1 strength for the treatment of a wide spectrum of bacterial infections is exhibited by 3-fluoro-D-alanine. Especially with practical oral administration, 3-fluoro-D-alanine gives a degree of activity that corresponds to or exceeds that of the incorporated antibiotics chloramphenicol and tetracycline.
Sammenligning av sikkerhet og helbredende virksomhet i mus av 3- fluor- L- alanin ( 3- FLA) og 3- f luor- D- alanin ( 3FDA). Comparison of safety and healing activity in mice of 3-fluoro-L-alanine (3-FLA) and 3-fluoro-D-alanine (3FDA).
Grupper på fem CD 1 hunmus av gjennomsnittsvekt 21 g tjente Groups of five CD 1 female mice of average weight 21 g served
enten som uinfiserte kontroller eller som objekter for antibakteri-ell terapi efter intraperitoneal injeksjon med 0,5 ml av en fortynnet buljongkultur av Escherichia coli 2017 som representerte 7 LD^q av bakterielle patogener. Terapeuticumet ble administrert i de angitte doser i et 0,5 ml volum ad oral vei i hvert tilfelle. either as uninfected controls or as subjects for antibacterial therapy after intraperitoneal injection with 0.5 ml of a diluted broth culture of Escherichia coli 2017 representing 7 LD^q of bacterial pathogens. The therapeutic agent was administered in the indicated doses in a volume of 0.5 ml orally in each case.
Toleransen hos mus overfor 3-FDA ovérstiger den overfor 3-FLA med en faktor på minst 10. Under den maksimalt tolererte dose er 3-FLA uten terapeutisk virkning. Mens moderate mengder av 3-FDA er fullstendig beskyttende, Oppviser hoyere mengder in vivo, som de gjor in vitro., tegn på auto ant ag on isme. The tolerance in mice to 3-FDA exceeds that to 3-FLA by a factor of at least 10. Below the maximum tolerated dose, 3-FLA has no therapeutic effect. While moderate amounts of 3-FDA are completely protective, higher amounts in vivo, as they do in vitro, show signs of auto ant ag on ism.
Innflytelse på bakterievekst av konseritrasjonsgradienter av Influence of concentration gradients on bacterial growth
3- FDA og 3- FLA, illustrerende autoantagonisme 3- FDA and 3- FLA, illustrating autoantagonism
Overflaten av et 2 mm tykt næringsagarskikt i en petriskål ble k p The surface of a 2 mm thick nutrient agar layer in a Petri dish was k p
belagt med 10 organisme/cm av en'"kultur av Escherichia coli 2017 og der ble så lagt på dem papirskiver, 7 mm i diameter, med de angitte mengder av 3-FDA eller 3-FLA. Efter inkubasjon ved 37°C i coated with 10 organisms/cm of a culture of Escherichia coli 2017 and paper discs, 7 mm in diameter, with the indicated amounts of 3-FDA or 3-FLA were then placed on them. After incubation at 37°C in
16 timer ble de sirkulære soner som var fri for bakterievekst rundt skivene målt. Enestående i tilfelle av 3-FDA, og der bare ved hoy- After 16 hours, the circular zones that were free of bacterial growth around the disks were measured. Unique in the case of 3-FDA, and there only at high-
ere drogeméngder, ble der iakttatt en ring av vekst som heftet til papirskiven så fulgt av en ring av bakteriefri agar. Den indre vekstsone, noyaktig i det hoye konsentrasjonsområde av konsentra-sjonsgradienten frembragt av diffunderende droger, er angitt som sonen for autoantagonisme. ere drug amounts, a ring of growth was observed which adhered to the paper disc then followed by a ring of bacteria-free agar. The inner growth zone, precisely in the high concentration range of the concentration gradient produced by diffusing drugs, is designated as the zone of autoantagonism.
De nye fluorerte aminosyrer fremstilles ifolge oppfinnelsen ved en fremgangsmåte som omfatter å behandle substratet med et fluoroxy-perfluoralkan eller fluoroxypentafluorsvovel under innflytelse av en fri radikal initiator som lys som innbefatter ultrafiolett lys, ioniserende bestråling som a-stråler eller mikrobolger, eller kjem-iske kjedeinitiatorer som azoforbindelser, f.eks. azo-bis-isobutyro-nitril eller kombinasjoner av slike fri radikalinitiatorer. Den fore-trukne arbeidsmåte er å opplose substratet i et passende opplosnings-middel som er inert overfor fluoreringsreaksjonen som flytende hydro-genfluorid, fluorsulfonsyre, trifluoreddiksyre eller svovelsyre, å eksponere opplesningen til den fri radikalinitiator, under kraftig roring og opprettholdelse av temperaturen, å tilsette den nodvendige mengde av fluoroxyreagenset langsomt til reaksjonsblandingen, og fortsette omroringen og bestrålingen inntil reaksjonen er fullstendig. The new fluorinated amino acids are produced according to the invention by a method which comprises treating the substrate with a fluorooxy-perfluoroalkane or fluorooxypentafluorosulphur under the influence of a free radical initiator such as light which includes ultraviolet light, ionizing radiation such as α-rays or microwaves, or chemical chain initiators as azo compounds, e.g. azo-bis-isobutyro-nitrile or combinations of such free radical initiators. The preferred method of working is to dissolve the substrate in a suitable solvent which is inert to the fluorination reaction such as liquid hydrogen fluoride, fluorosulphonic acid, trifluoroacetic acid or sulfuric acid, to expose the reading to the free radical initiator, with vigorous stirring and maintaining the temperature, to add the required amount of the fluorooxy reagent slowly to the reaction mixture, and continue stirring and irradiation until the reaction is complete.
På grunn av det lave kokepunkt av reagensene er det bekvemt å utfore reaksjonen ved temperaturer så lave som -80°C i hvilket tilfelle reaksjonen forloper ved atmosfæretrykk. Because of the low boiling point of the reagents, it is convenient to carry out the reaction at temperatures as low as -80°C in which case the reaction proceeds at atmospheric pressure.
Et passende reaksjonskar for atmosfæretrykkceaksjoner er et fremstilt av en "Kel-F" stav forsynt med et ultrafiolett gjennomslipp-bart vindu. Alternativt kan reaksjonen utfores i et trykkar som en "Hastelloy"-bombe eller en stålbombe med platinaforing, i hvilket tilfelle hoyere temperaturer, f.eks. opp til ca. 100°C kan anvendes. A suitable reaction vessel for atmospheric pressure reactions is one made from a "Kel-F" rod fitted with an ultraviolet transmissible window. Alternatively, the reaction can be carried out in a pressure vessel such as a "Hastelloy" bomb or a platinum-lined steel bomb, in which case higher temperatures, e.g. up to approx. 100°C can be used.
I slike tilfelle er anvendelsen av a-stråler eller røntgenstråler In such cases, the application of a-rays or X-rays
som fri radikalinitiator bekvem, da disse hoyenergistråler trenger as a free radical initiator convenient, as these high-energy rays need
'gjennom veggen av reaktoren. 'through the wall of the reactor.
Den ovenfor beskrevne fremgangsmåte kan utfores ved konvensjonelle satsmetoder, eller alternativt kan den kjores kontinuerlig i The method described above can be carried out by conventional batch methods, or alternatively it can be run continuously in
en rorformig reaktor enten med eller uten pakning som Ras.chig-ringer, sadler eller lignende, hvorigjennom substratet eller en opplosning av det og fluoreringsmidler pumpes, fortrinnsvis i motstrbm mens de ut-settes for radikalgenererende bestråling. a tubular reactor either with or without packing such as Ras.chig rings, saddles or the like, through which the substrate or a solution of it and fluorinating agents are pumped, preferably in counterflow while being exposed to radical-generating irradiation.
En bekvem kilde til bestråling for radikalgenerering har vist seg å være en "Hanovia"-kvikksblv-xenon-buelampe nr. 9778-I, drevet av en 1000 W krafttilførsel. Lampen var montert i enSchoeffel LH 15 1-N" projektor forsynt med en kvarts kondensorlinse og et varme-filter (vann). A convenient source of irradiation for radical generation has been found to be a "Hanovia" quick blue xenon arc lamp No. 9778-I, driven by a 1000 W power supply. The lamp was mounted in a Schoeffel LH 15 1-N" projector equipped with a quartz condenser lens and a heat filter (water).
Eksempel 1 Example 1
3- fluor- D- alanin 3-fluoro-D-alanine
I en oppløsning av 1,822 g D-(-)-alanin i V 5 ml flytende HF ble innfort 0,6 g fluoroxytrifluormethangass i lopet av en time under magnetisk omrbring, avkjblt i et tbrris-acetonbad og bestrålt med ultrafiolett lys. Efter 80 minutters ytterligere ultrafiolett bestråling ble ytterligere 2 g fluoroxytrifluormethangass innfort under ultrafiolett bestråling i lbpet av 1,5 timer, fulgt av ytterligere 1 times ultrafiolett bestråling. Into a solution of 1.822 g of D-(-)-alanine in V 5 ml of liquid HF, 0.6 g of fluorooxytrifluoromethane gas was introduced over the course of one hour under magnetic stirring, cooled in an ice-acetone bath and irradiated with ultraviolet light. After 80 minutes of additional ultraviolet irradiation, a further 2 g of fluorooxytrifluoromethane gas was introduced under ultraviolet irradiation for a period of 1.5 hours, followed by a further 1 hour of ultraviolet irradiation.
Opplbsningsmidlet ble fjernet ved å blåse gjennom det en strbm av nitrogengass. Residuet ble opplost i is^vann og en prove av det ble analysert i Spinco-Beckman-aminosyreanalyætoren som viste et <h>l%- ±g utbytte av 3-f luor-D-alanin, og 3, 2% ureagert utgangsmateriale. For isolasjon ble blandingen kromatografert på "Dowex 50 x 8" kation-bytteharpiks (H+<->formen). Til fortynning ble 2N saltsyre anvendt. Fra de passende fraksjoner fikk man ved inndampning i vakuum rent 3-fluor-D-alanin-hydroklorid. 3-fluor-D-alanin ble frigjort fra hydrokloridet i vann-pyridin-isopropanolblanding, smeltepunkt 166-168°C (spaltning), [a]^°, -9,3° (C = 2 i IN HC1). The solvent was removed by blowing through it a stream of nitrogen gas. The residue was dissolved in ice water and a sample of it was analyzed in the Spinco-Beckman amino acid analyzer which showed a <h>1%-±g yield of 3-fluoro-D-alanine, and 3.2% unreacted starting material. For isolation, the mixture was chromatographed on "Dowex 50 x 8" cation exchange resin (H+<-> form). For dilution, 2N hydrochloric acid was used. Pure 3-fluoro-D-alanine hydrochloride was obtained from the appropriate fractions by evaporation in vacuo. 3-Fluoro-D-alanine was liberated from the hydrochloride in water-pyridine-isopropanol mixture, mp 166-168°C (dec.), [α]^°, -9.3° (C = 2 in 1N HCl).
Eksempel 2 Example 2
2- deutero- 3- fluor- D- alanin 2- deutero- 3- fluoro- D- alanine
Deuterium ble innfort i a-stillingen på D-alanin ved å ut-sette L-alanin for påvirkning av alanin-racemase i <2>H^O, idet der til dette formål ble anvendt et rått enzympreparat fra Staphylo-coccus aureus [E. Ito og J. L. Strominger, J. Biol. Chem. £32) 2689 (1962)] som var blitt uttommende dialysert mot pufret H2O. Efter utvinnelse av det saltfrie alanin fra reaksjonsblandingen ved ionebyttemetoder, ble D-alaninet som var dannet, skilt'fra det opprinnelige L-alanin ved reaksjonsrekken: kjemisk N-acetyler-.ing og spesifikk enzymatisk deacetylering av L-isoraeren med svinenyre-acylase I som beskrevet av J. P. Greenstein og M. Winitz i <n>Chemistry of the Amino Acids", Vol. 3, s. 1831 (Wiley and Sons, New York 1961). 2/ 2H-D-alanin erholdt efter syrehydrolyse av det acylerte residuum var 95$ anriket på <2>H spesielt i 2-stillingen (bestemt ved NMR) og inneholdt mindre enn 1% L-alanin bestemt enzymatisk med L-alanin: oxoglutarat-trans-aminase. Deuterium was introduced into the a-position of D-alanine by exposing L-alanine to the action of alanine racemase in <2>H^O, using a crude enzyme preparation from Staphylococcus aureus [E . Ito and J.L. Strominger, J. Biol. Chem. £32) 2689 (1962)] which had been exhaustively dialyzed against buffered H 2 O. After recovery of the salt-free alanine from the reaction mixture by ion exchange methods, the D-alanine that was formed was separated from the original L-alanine by the reaction sequence: chemical N-acetylation and specific enzymatic deacetylation of the L-isomer with porcine kidney acylase I as described by J. P. Greenstein and M. Winitz in <n>Chemistry of the Amino Acids", Vol. 3, p. 1831 (Wiley and Sons, New York 1961). 2/ 2H-D-alanine obtained after acid hydrolysis of the acylated residuum was 95$ enriched in <2>H especially in the 2-position (determined by NMR) and contained less than 1% L-alanine determined enzymatically with L-alanine: oxoglutarate trans-aminase.
Ved å anvende fremgangsmåten i eksempel 1, men ved å erstatte D-alaninet anvendt der med en ekvivalent mengde 2-deutero-D-alanin, fremstilt som ovenfor, fikk man 2-deutero-3-fluor-D-alanin, smp. By applying the method in example 1, but by replacing the D-alanine used there with an equivalent amount of 2-deutero-D-alanine, prepared as above, 2-deutero-3-fluoro-D-alanine was obtained, m.p.
169°C, [a]p° -9,2 (C = 2, i IN HC1). ' 169°C, [α]p° -9.2 (C = 2, in 1N HCl). '
Eksempel '-4- Example '-4-
2, 3, 3- trideutero- 3- fluor- D- alanin 2, 3, 3- trideutero- 3- fluoro- D- alanine
2,3,3-trideutero D-alanin ble spaltet fra det kommersielt tilgjengelige perdeutero-alanin-racemat ved kjemisk N-acetylering fulgt av enzymatisk deacetylering av L-enheten som beskrevet i eksempel 2. 2,3,3-trideutero D-alanine was cleaved from the commercially available perdeutero-alanine racemate by chemical N-acetylation followed by enzymatic deacetylation of the L unit as described in Example 2.
Fotofluorering av perdeutero-D-alaninet ved fremgangsmåten beskrevet i eksempel 1, gir 2,3,3-trideutero-3-fluor-D-alanin. Photofluorination of the perdeutero-D-alanine by the method described in example 1 gives 2,3,3-trideutero-3-fluoro-D-alanine.
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DK153469B (en) * | 1979-07-26 | 1988-07-18 | Merrell Toraude & Co | METHOD OF PREPARING FLUORED ALKENYLAMINES |
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