NO770085L - METAMPICILLIN LYSINATE WITH IMPROVED WATER SOLUBILITY AND PROCEDURE FOR ITS PREPARATION - Google Patents
METAMPICILLIN LYSINATE WITH IMPROVED WATER SOLUBILITY AND PROCEDURE FOR ITS PREPARATIONInfo
- Publication number
- NO770085L NO770085L NO770085A NO770085A NO770085L NO 770085 L NO770085 L NO 770085L NO 770085 A NO770085 A NO 770085A NO 770085 A NO770085 A NO 770085A NO 770085 L NO770085 L NO 770085L
- Authority
- NO
- Norway
- Prior art keywords
- metampicillin
- lysinate
- ampicillin
- water solubility
- procedure
- Prior art date
Links
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims description 10
- FZECHKJQHUVANE-MCYUEQNJSA-N metampicillin Chemical compound C1([C@@H](N=C)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 FZECHKJQHUVANE-MCYUEQNJSA-N 0.000 title claims description 9
- 229960003806 metampicillin Drugs 0.000 title claims description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-M lysinate Chemical compound NCCCCC(N)C([O-])=O KDXKERNSBIXSRK-UHFFFAOYSA-M 0.000 title claims description 8
- 238000000034 method Methods 0.000 title claims description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 16
- 229960000723 ampicillin Drugs 0.000 claims description 15
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 14
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 description 3
- 235000019766 L-Lysine Nutrition 0.000 claims description 3
- 239000004472 Lysine Substances 0.000 claims description 3
- -1 methyl ampicillin Chemical compound 0.000 claims description 3
- 239000011734 sodium Chemical group 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 2
- 229910052782 aluminium Chemical group 0.000 claims 2
- 239000004411 aluminium Chemical group 0.000 claims 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical group [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 2
- 239000011575 calcium Chemical group 0.000 claims 2
- 229910052791 calcium Inorganic materials 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 239000011591 potassium Chemical group 0.000 claims 2
- 229910052700 potassium Inorganic materials 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 239000003929 acidic solution Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 1
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 125000001176 L-lysyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C([H])([H])C([H])([H])C(N([H])[H])([H])[H] 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960003311 ampicillin trihydrate Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-M ampicillin(1-) Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Den foreliggende oppfinnelse vedrører en ny type ampicillin som har forbedret vannoppløselighet og større anvendelse som antibiotikum, samt fremgangsmåte til fremstilling av denne forbindelse som vil bli betegnet som metampicillin-lysinat. The present invention relates to a new type of ampicillin which has improved water solubility and greater use as an antibiotic, as well as a method for the production of this compound which will be designated as metampicillin lysinate.
Penicillin-G, slik det forelå da det først ble oppdaget, hadde den ulempe at det var kjemisk ustabilt, noe som innvirket på dets aktivitet og videre at dets bruk som et antibiotikum var begrenset til grampositive bakterier. Den senere oppdagelse av ampicillin som kunne fås fra\6jjjaminopenicillanj3yre^ (penicil-lanic acid), skaffet et antibiotikum som også var effektivt mot i3Ef^?5-~™- bakterier. Penicillin-G, as it existed when it was first discovered, had the disadvantage that it was chemically unstable, which affected its activity and further that its use as an antibiotic was limited to Gram-positive bacteria. The later discovery of ampicillin which could be obtained from \6jjjjaminopenicillanj3yre^ (penicil-lanic acid), provided an antibiotic which was also effective against i3Ef^?5-~™- bacteria.
Uheldigvis oppviser begge disse typer penicillin fortsatt noen av de samme skadelige bivirkninger som naturlig penicillin, Unfortunately, both of these types of penicillin still exhibit some of the same harmful side effects as natural penicillin,
og de har dessuten lav oppløsélighet i vann. Således er oppløse-ligheten av ampicillin eller metampicillin relativt lav, og denne lave oppløsélighet har en ugunstig innvirkning på anti-biotikumets absorpsjon i mage- og tarmsystemet. and they also have low solubility in water. Thus, the solubility of ampicillin or metampicillin is relatively low, and this low solubility has an unfavorable effect on the antibiotic's absorption in the stomach and intestinal system.
Det er derfor en hensikt med den foreliggende oppfinnelse,It is therefore an object of the present invention,
å skaffe en ny type ampicillin med en vesentlig større vannopp-løselighet og stabilitet enn noen av de tidligere kjente ampi-cilliner og metampicilliner. to obtain a new type of ampicillin with a significantly greater water solubility and stability than some of the previously known ampicillins and meta-ampicillins.
Ifølge den foreliggende oppfinnelse er det funnet at enAccording to the present invention, it has been found that a
ny type metampicillin som nu skal beskrives og som kan betegnes som metampicillin-<ly>f<in>^<t>], har en vannoppløselighet som er 2,1 ganger høyere enn vannoppløseligheten av ampicillin-trihydrat. Forbindelsen ifølge oppfinnelsen har således den fordel at den new type of metampicillin which is now to be described and which can be designated as metampicillin-<ly>f<in>^<t>], has a water solubility which is 2.1 times higher than the water solubility of ampicillin trihydrate. The compound according to the invention thus has the advantage that it
kan foreligge lett tilgjengelig i flytende form og dessuten absorberes i mage- og tarmsystemet. can be readily available in liquid form and is also absorbed in the stomach and intestinal system.
Forbindelsen er et derivat av metylen ampicillin hvor 5 ' amino-5'karboksylPentyl-aminometyl radikalet er substituert i The compound is a derivative of methylene ampicillin where the 5' amino-5'carboxylPentyl-aminomethyl radical is substituted in
aminostillingen på 6-amino-penicillansyrens L-aminobenzyl-radikal. Dens kjemiske struktur og formel er som følger: the amino position of the L-aminobenzyl radical of 6-amino-penicillanic acid. Its chemical structure and formula are as follows:
Trihydratet er et hvitt, nålformet krystallinsk pulver med formelen C„-.H_ nO^NcS • 3H„0. Det kjemiske navn på denne The trihydrate is a white, needle-shaped crystalline powder with the formula C„-.H_ nO^NcS • 3H„0. The chemical name of this
23 296b 2 r 23 296b 2 yrs
forbindelse er D- (-) -6- FlO-.(N-5 1 amino-5 'karboksyl^pentylramino-metyl)-aminofenyl-acetamid -3,3-dimetyl-7-okso-4-tio-l-azabicykloheptan-2 karboksylsyre-trihydrat, men den er gitt navnet ampicillin-metylenlysinat eller metampicillin-lysinat fordi L-lysin er bundet til metylenaminoLenzylrpenicillansyre. compound is D-(-)-6- FlO-.(N-5 1 amino-5 'carboxyl^pentylramino-methyl)-aminophenyl-acetamide -3,3-dimethyl-7-oxo-4-thio-1-azabicycloheptane -2 carboxylic acid trihydrate, but it is given the name ampicillin methylene lysinate or metampicillin lysinate because L-lysine is bound to methyleneaminoLenzylperpenicillanic acid.
Metampicillin-lysinat fremstilles syntetisk ved en fremgangsmåte som består av flere trinn. I det første trinn omsettes1 formaldehyd med ampicillin, hvilket gir metylolampi-.; ' Metampicillin lysinate is produced synthetically by a process consisting of several steps. In the first step, 1 formaldehyde is reacted with ampicillin, which gives methyllampi-.; '
cillin som raskt går over til metylenampiclllin wV f ' I som er beskrevet nedenfor. For å gjøre ampicillinet, som bafe~er svakt oppløselig, vannoppløsélig, blir det: i det cillin which rapidly converts to methyleneampiclllin wV f ' I which is described below. To make the ampicillin, which is slightly soluble in water, it becomes: in the
første trinn omdannet til natriumampicillinat ved tilsetningfirst step converted to sodium ampicillinate by addition
av natriumkarbonat eller natriumbikarbonat ved en temperatur på 7-10°C og en pH-verdi på 7,0 - 8,0, idet en ampicillin-konsentrasjon på 0,01 mol og en natriumbikarbonat-konsentrasjon på 0,01 mol benyttes. Etter at ampicillinet er blitt gjort vannoppløsélig, lar man en 37-40 prosents formaldehyd-oppløs-ning reagere med ampicillinet i en ca. 2-10 N formalinoppløs-ning, da konsentrasjonen påvirker utbyttet. of sodium carbonate or sodium bicarbonate at a temperature of 7-10°C and a pH value of 7.0 - 8.0, using an ampicillin concentration of 0.01 mol and a sodium bicarbonate concentration of 0.01 mol. After the ampicillin has been made water-soluble, a 37-40 percent formaldehyde solution is allowed to react with the ampicillin for approx. 2-10 N formalin solution, as the concentration affects the yield.
Det neste trinn i fremgangsmåten består i å omsette L-lysin som er en aminosyre, med det mellomprodukt som frem-kommer i det første trinn, og resultatet er metampicillin-lysinat, som er sluttproduktet av syntesen. The next step in the method consists of reacting L-lysine, which is an amino acid, with the intermediate product that appears in the first step, and the result is metampicillin lysinate, which is the final product of the synthesis.
Nedenfor er de kjemiske formler og fremgangsmåter som inngår i reaksjonen vist. Below are the chemical formulas and methods involved in the reaction shown.
EKSEMPEL A EXAMPLE A
En suspensjon av ampicillin (19,5 0 g) i vann (10 00 ml) ble avkjølt til 5°C, langsomt omrørt i 30 minutter for å gi en homogen oppslemning og en pH-verdi på 7-8 frembragt ved tilsetning av en 10% ■ s natriumbikarbona.t-oppløsning (51 ml) . A suspension of ampicillin (19.50 g) in water (1000 ml) was cooled to 5°C, slowly stirred for 30 minutes to give a homogeneous slurry and a pH of 7-8 produced by the addition of a 10% sodium bicarbonate solution (51 ml).
En blanding av denne oppløsning og formalin.(5,8 ml) inneholdende mer enn 37 prosent formaldehyd ble omrørt i 1 time. Deretter ble L-lysin (8,05 g) tilsatt under omrøring som pågikk i 1 time og oppløsningen gjort sur ved tilsetning av saltsyre (7,0 ml) for å gi en pH-verdi på 2,5 - 3,0. En hvit krystallinsk utfelling av metampicillin-L-lysinat fremkom. Etter at blandingen hadde fått stå ved 0°C i 24 timer, ble utfellingen filtrert fra, vasket med tørt aceton og så tørket ved en temperatur på under 40°C. Dette ga et utbytte på 54,9% av et hvitt pulver med et smeltepunkt på 197°-198°C (nedbrytes). A mixture of this solution and formalin (5.8 ml) containing more than 37 percent formaldehyde was stirred for 1 hour. Then L-lysine (8.05 g) was added with stirring for 1 hour and the solution acidified by the addition of hydrochloric acid (7.0 ml) to give a pH value of 2.5 - 3.0. A white crystalline precipitate of metampicillin-L-lysinate appeared. After the mixture had been allowed to stand at 0°C for 24 hours, the precipitate was filtered off, washed with dry acetone and then dried at a temperature below 40°C. This gave a yield of 54.9% of a white powder with a melting point of 197°-198°C (decomposes).
Metampicillin-L-lysinatet produsert ved den foreliggende oppfinnelse er oppløselig i vann, men uoppløselig i etanol ogv! kloroform. Oppløseligheten i eddiksyre er 25 mg/ml og i dimetylformamid 8 mg/ml. The metampicillin-L-lysinate produced by the present invention is soluble in water, but insoluble in ethanol etc! chloroform. The solubility in acetic acid is 25 mg/ml and in dimethylformamide 8 mg/ml.
Den spesifikke optiske rotasjon erifoOl<2>^0= 240(C=0,25) og K^.er 0,765 ved tynnsjiktskromatografi på silikagel med 5% eddiksyre og 95% aceton som oppløsningsmiddel under bruk av vanlige fremgangsmåter. The specific optical rotation erifoOl<2>^0= 240(C=0.25) and K^ is 0.765 by thin layer chromatography on silica gel with 5% acetic acid and 95% acetone as solvent using standard procedures.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO770085A NO770085L (en) | 1977-01-11 | 1977-01-11 | METAMPICILLIN LYSINATE WITH IMPROVED WATER SOLUBILITY AND PROCEDURE FOR ITS PREPARATION |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO770085A NO770085L (en) | 1977-01-11 | 1977-01-11 | METAMPICILLIN LYSINATE WITH IMPROVED WATER SOLUBILITY AND PROCEDURE FOR ITS PREPARATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO770085L true NO770085L (en) | 1978-07-12 |
Family
ID=19883288
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO770085A NO770085L (en) | 1977-01-11 | 1977-01-11 | METAMPICILLIN LYSINATE WITH IMPROVED WATER SOLUBILITY AND PROCEDURE FOR ITS PREPARATION |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO770085L (en) |
-
1977
- 1977-01-11 NO NO770085A patent/NO770085L/en unknown
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