DK153486B - Analogifremgangsmaade til fremstilling af krystallinsk n-formimidoyl-thienamycin-monohydrat - Google Patents
Analogifremgangsmaade til fremstilling af krystallinsk n-formimidoyl-thienamycin-monohydrat Download PDFInfo
- Publication number
- DK153486B DK153486B DK278879AA DK278879A DK153486B DK 153486 B DK153486 B DK 153486B DK 278879A A DK278879A A DK 278879AA DK 278879 A DK278879 A DK 278879A DK 153486 B DK153486 B DK 153486B
- Authority
- DK
- Denmark
- Prior art keywords
- formimidoyl
- thienamycin
- monohydrate
- preparation
- thienamycine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 150000004682 monohydrates Chemical class 0.000 title description 2
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 claims abstract description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- -1 N-formimidoyl-thienamycin monohydrate Chemical class 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 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 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052708 sodium Chemical group 0.000 description 2
- 239000011734 sodium Chemical group 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- WIESNNVNXBYTFK-FLIBITNWSA-N (z)-2-[(2,2-dimethylcyclopropanecarbonyl)amino]oct-2-enoic acid Chemical compound CCCCC\C=C(C(O)=O)/NC(=O)C1CC1(C)C WIESNNVNXBYTFK-FLIBITNWSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 229940090955 Dipeptidase inhibitor Drugs 0.000 description 1
- 102000004860 Dipeptidases Human genes 0.000 description 1
- 108090001081 Dipeptidases Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af den hidtil ukendte forbindelse krystallinsk N-formimidoyl-thienamycin-monohydrat.
Antibiotiket N-formimidoyl-thienamycin med den i det følgende angivne formel i er kendt, se f.eks. belgisk patentskrift nr. 848 545.
Den krystallinske form for N-formimidoyl-thienamycin, som er omhandlet i den foreliggende opfindelse, fremstilles ud fra en lyofiliseret prøve af I og har vist sig at have en uventet stabilitet på fast form i forhold til den lyofiliserede form.
Den lyofiliserede (amorfe) form er let hygroskopisk og umedgørlig, idet den bliver statisk elektrisk ladet. Som følge deraf vil den tiltrækkes af instrumenter og udstyr og klumpe og således være vanskelig at arbejde med. I modsætning hertil er den krystallinske form fast, stabil og let at have med at gøre.
N-formimidoyl-thienamycin eksisterer som et monohydrat og identificeres utvetydigt ved hjælp af følgende parametre for krystallen, som opnås ved røntgendiffraktion.
Spids- Spids- position Intensitet position Intensitet 2- Q d-afstand 2- 0 d-afstand fCuKoc) (A) 1/1 . (CuKa) (A) l/l.
9,75 9,07 100 26,9 5,31 75 11.35 7,80 40 28,7 3,11 37 13,85 6,39 11 29,9 2,99 17 14.5 6,11 4 30,8 2,90 7 15.75 5,63 14 31,85 2,81 12 17.5 5,06 30 32,6 2,75 10 18.9 4,69 27 32,9 2,72 10 19.6 4,53 12 33,4 2,68 5 20,0 4,44 14 33,9 2,64 10 21,45 4,14 30 34,8 2,58 26 21.75 4,08 36 35,6 2,52 14 22.3 3,98 45 37,0 2,43 5 22.9 3,88 30 38,3 2,35 9 23.3 3,82 28 39,3 2,29 6 24.3 3,66 33 40,0 2,25 9 25.35 3,52 24 42,0 2,20 14 25,8 3,45 20 42,4 2,14 18
Krystallinsk N-formimidoyl-thienamycin-monohydrat fremstilles ifølge opfindelsen ud fra en vand/ethanol-opløsning af N-formimidoyl-thienamycin. Følgende eksempel forklarer fremgangsmåden nærmere.
EKSEMPEL
Krystallinsk N-formimidoyl-thienamycin
En lyofiliseret prøve af N-formimidoyl-thienamycin (62 mg) opløses i 1,0 ml vand og fortyndes med 5,5 ml 95%'s ethanol. Den resulterende opløsning neddykkes i et isbad, der omrøres med en magnetisk omrører, og der podes med N-for-mimidoyl-thienamycin-monohydrat-krystaller opnået ved en procedure, der beskrives i det følgende. Efter 1 1/2 times omrøring udvindes krystallerne med 1 ml ethanol og tørres under vacuum ved 50°C i 1 time, hvorved der opnås 56 mg krystallinsk N-formimidoyl-thienamycin-monohydrat. Podekrystallerne, der anvendes ved krystallisationen, fremstilles på følgende måde:
En lyofiliseret prøve af N-formimidoyl-thienamycin (24,5 mg) opløses i 0,5 ml vand, fortyndes til 3,0 ml med ethylalko-hol og opbevares i en fryser (-5°C). Efter to ugers forløb observeres der krystaller på væggen af reagensglasset.
N-formimidoyl-thienamycin anvendes som antibiotikum, hvilket fremgår af ovennævnte belgiske patentskrift nr. 848 545.
Ved behandlingen af bakterieinfektioner hos mennesket administreres den omhandlede forbindelse oralt eller parente-ralt efter konventionelle procedurer for antibiotisk administrering i en mængde på fra ca. 2 til ca. 600 mg pr. kg pr. dag og foretrukkent ca. 15 - 150 mg/kg/dag foretrukkent i opdelte doser, f.eks. 3-4 gange om dagen. Der kan administreres dosisenhedsformer indeholdende f.eks. 25, 250, 500 eller 1000 mg aktiv bestanddel med hensigtsmæssige fysiologisk acceptable bærere eller excipienser. Dosisenhederne forefindes i form af væskepræparater, såsom opløsninger eller suspensioner, eller som faste stoffer i tabletter eller kapsler. Det vil selvsagt forstås, at den optimale dosis i et givent tilfælde afhænger af den type og grad af infektion, der skal behandles, og de mindre doser vil blive anvendt til pædiatrisk anvendelse. Det vil ikke være svært for fagmanden at foretage sådanne justeringer .
Foruden anvendelse alene er det særlig foretrukkent at anvende N-formimidoyl-thienamycin i kombination med en dipep-tidase (E.C. 3.4.13.11) inhibitor.
Rækken af dipeptidase-inhibitorforbindelser har den almene formel:
2 "5 hvori R og R-' er carbonhydridgrupper med henholdsvis 3-10 og 1-15 carbonatomer. I hver af disse carbonhydridgmpper kan et hydrogenatom være erstattet med halogen, eller en ikke-terminal methylengruppe kan være erstattet med oxygen eller svovl, herunder oxiderede former af sidstnævnte. Et hydrogen-atom i R kan også være erstattet med en carboxy-, alkoxy- carbonyl-, amido-, amidino-, cyano-, mercapto- og phosphono- 2 eller aminogruppe. R er foretrukkent en forgrenet eller cylisk alkylgruppe med 3-10 carbonatomer, med den begrænsning, at nabocarbonatomet til carbonylgruppen ikke kan være tertiært. R·1 er hydrogen, alkyl med 1-6 carbonatomer eller dialkylamino-alkyl (f.eks. -CH2CH2N(C2H5)2, -CH2CH(CH5)N(CH^)2).
En særlig foretrukken undergruppe af inhibitorforbindelser 2 3 er en, hvori R er 2,2-dimethylcyclopropyl, og R er alkyl 3 med 1-15 carbonatomer, idet R foretrukkent er alkyl med 1-5 carbonatomer.
3
Den mest foretrukne inhibitor er den, hvori R er alkyl med 2 1 5 carbonatomer, R er 2,2-dimethylcyclopropyl, og R er hydrogen eller natrium. Denne forbindelse er Z-2-(2,2-dimethyl-cyclopropancarboxamido)-2-octansyre eller natriumsaltet deraf.
Den mest foretrukne administreringsvej er parenteral, og den mest foretrukne dosisform for natrium-Z-2-(2,2-dimethylcyclo-propancarboxamido)-2-octenoatet med krystallinsk N-formimidoyl-thienamycin er 75 eller 150 mg af førstnævnte forbindelse og 150 mg af sidstnævnte, administreret sammen, ved injektion af en steril vandig opløsning 3 eller 4 gange daglig for et menneske.
Claims (1)
1. Analogifremgangsmåde til fremstilling af krystallinsk N-formimidoyl-thienamycin-monohydrat, kendetegnet ved, at man opløser N-formimidoyl-thienamycin i vand, fortyndet med et overskud af ethanol, hvorpå man neddykker blandingen i et isbad og omrører sammen med podekrystaller af N-formimidoyl-thienamycin, indtil der er opnået krystaller, hvorpå man udvinder krystallerne.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US92137978A | 1978-07-03 | 1978-07-03 | |
| US92137978 | 1978-07-03 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK278879A DK278879A (da) | 1980-01-04 |
| DK153486B true DK153486B (da) | 1988-07-18 |
| DK153486C DK153486C (da) | 1988-11-28 |
Family
ID=25445341
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK278879A DK153486C (da) | 1978-07-03 | 1979-07-02 | Analogifremgangsmaade til fremstilling af krystallinsk n-formimidoyl-thienamycin-monohydrat |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0006639B1 (da) |
| JP (1) | JPS559090A (da) |
| AT (1) | ATE1676T1 (da) |
| DE (1) | DE2963882D1 (da) |
| DK (1) | DK153486C (da) |
| IE (1) | IE48356B1 (da) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE50333B1 (en) * | 1979-11-02 | 1986-04-02 | Merck & Co Inc | Antibacterial compositions comprising a beta-lactam-type compound and a 3-substituted propenoate |
| US4374772A (en) * | 1981-03-19 | 1983-02-22 | Merck & Co., Inc. | Process for the preparation of N-formimidoyl thienamycin and reagents therefor |
| US4713451A (en) * | 1984-04-09 | 1987-12-15 | Merck & Co., Inc. | Crystalline dimethyliminothienamycin |
| JPS61207617A (ja) * | 1985-03-05 | 1986-09-16 | Toyobo Co Ltd | ポリエステル繊維の製造方法 |
| IE60588B1 (en) * | 1986-07-30 | 1994-07-27 | Sumitomo Pharma | Carbapenem compound in crystalline form, and its production and use |
| DK168047B1 (da) * | 1987-12-07 | 1994-01-24 | Lederle Japan Ltd | (1r,5s,6s)-2-substitueret thio-6-oe(r)-1-hydroxyethylaa-1-methyl-carbapenem-3-carboxylsyrederivater, fremgangsmaade til remstilling deraf, midler og praeparater indeholdende den krystallinske forbindelse samt dens anvendelse. |
| US5317016A (en) * | 1991-08-20 | 1994-05-31 | Shionogi Seiyaku Kabushiki Kaisha | Pyrrolidylthiocarbapenem derivative |
| MXPA04004604A (es) * | 2001-11-16 | 2004-09-10 | Ranbaxy Lab Ltd | Proceso para la preparacion de imipenem cristalino. |
| CN100497338C (zh) * | 2006-01-05 | 2009-06-10 | 上海医药工业研究院 | 4－甲基－7－氧－1－氮杂双环[3.2.0]庚－2－烯－2－羧酸类衍生物的制备方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK523576A (da) * | 1975-11-21 | 1977-05-22 | Merck & Co Inc | Fremgangsmade til fremstilling af substituerede n-methylen-derivater af thienamycin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS226166B2 (cs) * | 1975-11-21 | 1984-03-19 | Merck & Co Inc | Způsob přípravy derivátů thienamycinu |
-
1979
- 1979-07-02 DK DK278879A patent/DK153486C/da active
- 1979-07-03 EP EP79102240A patent/EP0006639B1/en not_active Expired
- 1979-07-03 AT AT79102240T patent/ATE1676T1/de active
- 1979-07-03 DE DE7979102240T patent/DE2963882D1/de not_active Expired
- 1979-07-03 JP JP8357379A patent/JPS559090A/ja active Granted
- 1979-08-08 IE IE1191/79A patent/IE48356B1/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK523576A (da) * | 1975-11-21 | 1977-05-22 | Merck & Co Inc | Fremgangsmade til fremstilling af substituerede n-methylen-derivater af thienamycin |
Also Published As
| Publication number | Publication date |
|---|---|
| IE791191L (en) | 1980-01-03 |
| DE2963882D1 (en) | 1982-11-25 |
| EP0006639B1 (en) | 1982-10-20 |
| DK153486C (da) | 1988-11-28 |
| IE48356B1 (en) | 1984-12-26 |
| DK278879A (da) | 1980-01-04 |
| ATE1676T1 (de) | 1982-11-15 |
| EP0006639A1 (en) | 1980-01-09 |
| JPH0248557B2 (da) | 1990-10-25 |
| JPS559090A (en) | 1980-01-22 |
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