DK153784B - ANALOGY PROCEDURE FOR THE PREPARATION OF 2-N- (METHIONINOMETHYL) DOXYCYCLIN OR SALTS THEREOF - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF 2-N- (METHIONINOMETHYL) DOXYCYCLIN OR SALTS THEREOF Download PDFInfo
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- DK153784B DK153784B DK501674AA DK501674A DK153784B DK 153784 B DK153784 B DK 153784B DK 501674A A DK501674A A DK 501674AA DK 501674 A DK501674 A DK 501674A DK 153784 B DK153784 B DK 153784B
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- doxycycline
- methioninomethyl
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- salts
- doxycyclin
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- 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
- A61K31/65—Tetracyclines
-
- 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
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- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
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- Chemical & Material Sciences (AREA)
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- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Denne opfindelse angår en analogifremgangsmåde til fremstilling af et hidtil ukendt, antibiotisk aktivt, vandopløseligt derivat af doxycyclin, nemlig 2-N-(methioninomethyl)doxycyclin med den i kravets indledning angivne almene formel (I) eller et terapeutisk acceptabelt vandopløseligt salt deraf med en organisk eller uorganisk syre eller et fysiologisk acceptabelt mono- eller polyvalent metalsalt deraf.This invention relates to an analogous process for the preparation of a novel, antibiotically active, water-soluble derivative of doxycycline, namely 2-N- (methioninomethyl) doxycycline of the general formula (I) of claim 1 or a therapeutically acceptable water-soluble salt thereof with an organic or inorganic acid or a physiologically acceptable mono- or polyvalent metal salt thereof.
De omhandlede forbindelser udmærker sig ved høj opløselighed i vand ved neutral pH-værdi og kan derfor indgives såvel pr. os som intramuskulært eller intravenøst, og de bevarer endvidere doxycyclinets antibiotiske aktivitet uforandret.The compounds of the invention are characterized by high solubility in water at neutral pH and can therefore be administered as us as intramuscular or intravenous, and they also retain the antibiotic activity of the doxycycline unchanged.
Det ved fremgangsmåden ifølge opfindelsen fremstillede methioninomethylderivat af doxycyclin (6-deoxy-5-hydroxy-tetracyclin) bevarer i det væsentlige basisforbindelsens antibiotiske aktivitet samtidig med at man undgår basis-forbindelsens ulemper. Mere specielt har det ifølge opfindelsen fremstillede derivat i forhold til doxycyclin uventet vist sig at have en stærkt forbedret opløselighed i vand ved neutral pH-værdi med deraf følgende manglende tendens til udfældning, forbedret patient-tolerance, forbedret stabilitet, forbedrede blodspejlsværdier, samt en hurtig og total absorption fra tarmen. Endvidere er dets toxicitet lavere. Alle de førnævnte særlige fordele fremgår af de i eksemplet anførte data.The methioninomethyl derivative of doxycycline (6-deoxy-5-hydroxy-tetracycline) produced by the process of the invention essentially retains the antibiotic activity of the basic compound while avoiding the disadvantages of the basic compound. More particularly, the derivative of the invention produced in relation to doxycycline has unexpectedly been found to have a greatly improved solubility in water at neutral pH with consequent lack of precipitation, improved patient tolerance, improved stability, improved blood levels, and a rapid and total absorption from the gut. Furthermore, its toxicity is lower. All of the aforementioned particular advantages are apparent from the data set forth in the example.
Ud over de ovennævnte fordele har det som det måske mest overraskende aspekt af opfindelsen vist sig, at ip vivo aktiviteten af methioninomethylderivatet er væsentligt bedre end af basisforbindelsen doxycyclin.In addition to the above advantages, it has been found, as perhaps the most surprising aspect of the invention, that the in vivo activity of the methioninomethyl derivative is substantially better than that of the basic compound doxycycline.
Blandt andet udviser derivatet i dyr med staphylococcus-infektion i nyren en bedre aktivitet end hydrochloridet af doxycyclin enten med hensyn til reduktion åf morta- litetsindexet eller med hensyn til reduktion af sta-phylococcus-koncentrationer i det renale parenkym. I dette tilfælde er de bedste resultater blevet opnået ved intravenøs injektion selv på et senere tidspunkt efter infektionernes opståen end det, der er sædvanligt ved denne type undersøgelser. Det fremgår også af de i eksemplet, afsnit D), anførte resultater for den kemo-terapeutiske aktivitet, at det ifølge opfindelsen fremstillede methioninomethyl-derivat ved intravenøs injektion giver aktivitetsværdier, som er 70-80 % bedre end de, som opnås med basisforbindelsen (jfr. de anførte PD^g-værdier).Among other things, the derivative in animals with staphylococcus infection of the kidney exhibits better activity than the hydrochloride of doxycycline either in terms of reduction in mortality index or in reducing staphylococcus concentrations in the renal parenchyma. In this case, the best results have been obtained by intravenous injection even at a later stage after the onset of infections than is usual in this type of study. It is also apparent from the results of the chemotherapeutic activity set forth in the example, section D), that the methioninomethyl derivative of the invention produced by intravenous injection yields activity values 70-80% better than those obtained with the base compound ( cf. the stated PD ^ g values).
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at doxycyclin bringes i kontakt med en ækvimolær mængde methionin i nærvær af formaldehyd i et polært opløsningsmiddel ved sådanne temperaturer og i sådanne tidsrum, som er nødvendige til opnåelse af fuldstændig reaktion, fortrinsvis ved en temperatur på 10-80 °C, hvorpå den dannede forbindelse om ønsket overføres i et terapeutisk acceptabelt vandopløseligt salt med en organisk eller uorganisk syre eller et fysiologisk acceptabelt monoeller polyvalent metalsalt.The process of the invention is characterized in that doxycycline is contacted with an equimolar amount of methionine in the presence of formaldehyde in a polar solvent at such temperatures and for such periods as are necessary to achieve complete reaction, preferably at a temperature of 10-80 ° C, where desired, the compound formed, if desired, is transferred into a therapeutically acceptable water-soluble salt with an organic or inorganic acid or a physiologically acceptable mono or polyvalent metal salt.
Formaldehydet tilsættes fortrinsvis i en mængde på 1 mol pr. mol doxycyclin og kan anvendes i form af en vandig opløsning, som en gas eller endog på fast form. Egnede opløsningsmidler er mono- eller polyvalente alkoholer med 1-4 carbonatomer, vand, dioxan, tetrahydro-furan, methylisobutylketon og N,N-dimethylformamid.The formaldehyde is preferably added in an amount of 1 mole per ml. mole of doxycycline and may be used in the form of an aqueous solution, such as a gas or even in solid form. Suitable solvents are mono- or polyhydric alcohols having 1-4 carbon atoms, water, dioxane, tetrahydrofuran, methyl isobutyl ketone and N, N-dimethylformamide.
Reaktionstemperaturerne ligger som nævnt fortrinsvis mellem 10 og 80 °C, og det mest foretrukne interval er 30-40 °C.The reaction temperatures are, as mentioned, preferably between 10 and 80 ° C, and the most preferred range is 30-40 ° C.
Reaktionstiderne kan variere fra 20 minutter til 240 minutter.Reaction times can range from 20 minutes to 240 minutes.
Produktet kan isoleres ved udfældning fra det opløsningsmiddel, hvori dannelsen finder sted, eller det kan udfældes med et andet opløsningsmiddel, hvori det er uopløseligt, eller det kan opnås ved frysetørring.The product can be isolated by precipitation from the solvent in which the formation takes place, or it can be precipitated with another solvent in which it is insoluble, or it can be obtained by freeze-drying.
Produktet kan anvendes, som det er, eller i form af terapeutisk acceptable, opløselige salte med uorganiske eller organiske syrer, og det kan endvidere anvendes som dets mono- eller polyvalente metalsalte.The product can be used as is, or in the form of therapeutically acceptable soluble salts with inorganic or organic acids, and it can also be used as its mono- or polyvalent metal salts.
Fremgangsmåden ifølge opfindelsen belyses nærmere i det følgende eksempel.The process of the invention is illustrated in more detail in the following example.
EksempelExample
Ved 65 °C opløstes 4,44 g vandfri doxycyclin-base under omrøring i 140 ml absolut ethanol.At 65 ° C, 4.44 g of anhydrous doxycycline base was dissolved with stirring in 140 ml of absolute ethanol.
Ved 35 °C tilsattes 1,5 g methionin opløst med 1,2 ml 30 % NaOH og 1,1 ml 35 % formaldehyd.At 35 ° C, 1.5 g of methionine dissolved with 1.2 ml of 30% NaOH and 1.1 ml of 35% formaldehyde were added.
Omrøringen fortsattes i 30 minutter ved 35 °C og i yderligere 30 minutter ved 30 °C, hvorefter det opnåede produkt blev frafiltreret og udvasket med ethanol.Stirring was continued for 30 minutes at 35 ° C and for another 30 minutes at 30 ° C, after which the product obtained was filtered off and washed with ethanol.
Efter vakuumtørring ved 40 °C blev der opnået 4,85 g produkt i form af et lysegult pulver, smeltepunkt 208 °C.After vacuum drying at 40 ° C, 4.85 g of product was obtained in the form of a light yellow powder, mp 208 ° C.
pH-værdien af en 5 % vandig opløsning var 7,1.The pH of a 5% aqueous solution was 7.1.
Produktets opløselighed var mere end 1 g pr. ml.The solubility of the product was more than 1 g / ml. ml.
Sammensætning: C28H35N3°10S (molvægt 605,6).Composition: C28H35N3 ° 10S (molecular weight 605.6).
Beregnede værdier: C: 55,5 %; H: 5,8 %; 0: 26,4 %; S: 5,3 % N: 7,0 Si.Calculated values: C: 55.5%; H: 5.8%; 0: 26.4%; S: 5.3% N: 7.0 Si.
Fundne værdier: C: 54,6 %; H: 5,9 %; 0: 27,1 %; S: 5,4 %; N: 6,5 K.Values found: C: 54.6%; H: 5.9%; 0: 27.1%; S: 5.4%; N: 6.5 K.
I det følgende anføres resultaterne af nogle farmakologiske, kemiske og kemoterapeutiske undersøgelser, som skal belyse de vigtigste egenskaber hos den i henhold til eksemplet fremstillede forbindelse.The following are the results of some pharmacological, chemical and chemotherapeutic studies which will illustrate the main properties of the compound prepared according to the example.
A) Forbindelsen er opløselig i vand ved pH-værdier i nærheden af det neutrale; 1 g derivat opløses i 0,7 ml vand.A) The compound is soluble in water at pH values near the neutral; Dissolve 1 g of derivative in 0.7 ml of water.
B) Stabiliteten af forbindelsen i vandig opløsning er den samme eller bedre end af doxycyclin under analoge betingelser. Dette er bekræftet ved spektro-fotometriske undersøgelser.B) The stability of the compound in aqueous solution is the same or better than that of doxycycline under analogous conditions. This is confirmed by spectrophotometric studies.
C) Den minimale inhiberende koncentration (MIC) af forbindelsen fremstillet ifølge eksemplet sammenlignet med doxycyclin for en række standardbakteriestammer som anført nedenfor viser, at derivatets aktivitet for samme indhold af doxycyclin er praktisk taget den samme som af doxycyclin.C) The minimum inhibitory concentration (MIC) of the compound prepared according to the example compared to doxycycline for a number of standard bacterial strains as set forth below shows that the activity of the derivative for the same content of doxycycline is practically the same as that of doxycycline.
_M.I.C. - værdi_M.I.C. - value
Forbindelse frem-Doxycyclin stillet ifølge eks.Compound forward Doxycycline provided according to Ex.
S. aureus 209P 0,2 0,25 S. aureus 171G 0,05 0,07 S. pyrogenes ATCC 8663 0,05 0,07 S. faecalis ATCC 8043 0,25 0,35 B. arculans ATCC 9961 0,05 0,04 B. subtilis ATCC 6633 0,05 0,04 S. lutea ATCC 10054 0,05 0,07 D. pneumoniae 0,01 0,02 E. coli 113-3 1,3 2,0 E. coli 266 0,75 1,0 E. coli ATCC 8739 2,0 2,75 E. coli ATCC 10530 1,25 1,75 K. pneumoniae 132 1,5 2,25 P. vulgaris ATCC 9920 >50 50 P. rettgerii ATCC 9250 1,75 2,5 P. mirabilis ATCC 9921 >100 100 D) Nedenfor er anført resultater med hensyn til den kemoterapeutiske aktivitet af forbindelsen fremstillet ifølge eksemplet udtrykt som PD^g-værdien i mus inficeret med forskellige bakteriestammer.S. aureus 209P 0.2 0.25 S. aureus 171G 0.05 0.07 S. pyrogenes ATCC 8663 0.05 0.07 S. faecalis ATCC 8043 0.25 0.35 B. arculans ATCC 9961 0.05 0.04 B. subtilis ATCC 6633 0.05 0.04 S. lutea ATCC 10054 0.05 0.07 D. pneumoniae 0.01 0.02 E. coli 113-3 1.3 2.0 E. coli 266 0.75 1.0 E. coli ATCC 8739 2.0 2.75 E. coli ATCC 10530 1.25 1.75 K. pneumoniae 132 1.5 2.25 P. vulgaris ATCC 9920> 50 50 P. rettgerii ATCC 9250 1.75 2.5 P. mirabilis ATCC 9921> 100 100 D) The following are results of the chemotherapeutic activity of the compound prepared according to the example expressed as the PD µg value in mice infected with different bacterial strains.
ForbindelseConnection
Indgiv- fremstillet Doxycyclin ningsvej Dosis ifølge eks. PD^q infektion vej (a) (b) PD<.g * % mg/kg _mq/kq__ S. aureus (d) oral S. 9,04 - 7,48 intravenøs S. 7,11 78,6 (c) subkutan M. 1,67 18,5 (c) 2,21 S. pyrogenes 8668 oral S. 7,55 - 5,74 intravenøs S. 5,41 71,6 (c) S. pyrogenes (d) oral S. 0,64 - 0,51 intravenøs S. 0,47 73,3 (c) E. coli 266 oral S. 52,1 - 38,0 intravenøs S. 36,7 70,4 (c) E. coli (d) oral S. 20,4 - 16,2 intravenøs . S. 14,6 71,5 (c) K. pneumoniae subkutan S. 1,32 intravenøs S. 1,03 78,0 (e) a) = Indgivningsvej: oral, intravenøs, subkutan b) = Dosis: enkelt (S) eller multipel (M).Administration of Doxycycline route Dose according to ex. PD ^ q infection pathway (a) (b) PD <.g *% mg / kg _mq / kq__ S. aureus (d) oral S. 9.04 - 7.48 intravenous S. 7.11 78.6 (c) subcutaneous M. 1.67 18.5 (c) 2.21 S. pyrogenes 8668 oral S. 7.55 - 5.74 intravenous S. 5.41 71.6 (c) S. pyrogenes (d) oral S. 0.64 - 0.51 intravenous S. 0.47 73.3 (c) E. coli 266 oral S. 52.1 - 38.0 intravenous S. 36.7 70 , 4 (c) E. coli (d) oral S. 20.4 - 16.2 intravenously. S. 14.6 71.5 (c) K. pneumoniae subcutaneous S. 1.32 intravenous S. 1.03 78.0 (e) a) = Route of administration: oral, intravenous, subcutaneous b) = Dose: single (S ) or multiple (M).
c) = Procent af oral PD^g-værdi d) = Stammer af klinisk oprindelse.c) = Percent of oral PD ^ g value d) = Strains of clinical origin.
e) = Procent af subkutan PD^g-værdi.e) = Percent of subcutaneous PD ^ g value.
E) Blodspejlsværdien for forbindelsen fremstillet ifølge eksemplet i mus, rotter og kaniner efter en enkelt oral dosis på 12,5 mg/kg er til forskellige tidspunkter lig med eller højere end blodspejlsværdien for doxycyclin under samme betingelser.E) The blood level of the compound prepared according to the example in mice, rats and rabbits after a single oral dose of 12.5 mg / kg is at different times equal to or higher than the blood level of doxycycline under the same conditions.
F) Akut toxicitet (LD^g) for forbindelsen fremstillet ifølge eksemplet over for mus og rotter.F) Acute toxicity (LD LDg) of the compound prepared according to the example for mice and rats.
Data sammenlignet med data for doxycyclin (i parenteser).Data compared to data for doxycycline (in parentheses).
Dyreart Indqivninqsve.j LD,-g mq/kqAnimal species Indqivninqsve.j LD, -g mq / kq
Mus oral >2000X (>2000)x intravenøs 394 (257) 670 (425)Mice oral> 2000X (> 2000) x intravenous 394 (257) 670 (425)
Rotte oral >3000x (>3000)x 582 (370) x) Forsøgene begrænset til en maksimal dosis på 2,0 g/kg eller 3,0 g/kg og derefter indstillet, eftersom de ikke har større betydning.Rat oral> 3000x (> 3000) x 582 (370) x) The trials limited to a maximum dose of 2.0 g / kg or 3.0 g / kg and then adjusted as they are of no greater importance.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2948673 | 1973-09-28 | ||
| IT2948673 | 1973-09-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK501674A DK501674A (en) | 1975-05-26 |
| DK153784B true DK153784B (en) | 1988-09-05 |
| DK153784C DK153784C (en) | 1989-01-23 |
Family
ID=11227072
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK501674A DK153784C (en) | 1973-09-28 | 1974-09-24 | ANALOGY PROCEDURE FOR THE PREPARATION OF 2-N- (METHIONINOMETHYL) DOXYCYCLIN OR SALTS THEREOF |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS6044293B2 (en) |
| AT (1) | AT337359B (en) |
| BE (1) | BE820474A (en) |
| CA (1) | CA1031774A (en) |
| CH (1) | CH614190A5 (en) |
| DE (1) | DE2446586A1 (en) |
| DK (1) | DK153784C (en) |
| ES (1) | ES430512A1 (en) |
| FR (1) | FR2246275B1 (en) |
| GB (1) | GB1484345A (en) |
| IL (1) | IL45741A (en) |
| NL (1) | NL7412764A (en) |
| NO (1) | NO140345C (en) |
| SE (1) | SE398875B (en) |
| ZA (1) | ZA746147B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6442586U (en) * | 1987-09-07 | 1989-03-14 | ||
| CN102688492A (en) * | 2007-03-23 | 2012-09-26 | 分子研究中心公司 | Compositions and methods for anti-inflammatory treatments |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1863M (en) * | 1961-03-24 | 1963-06-17 | Erba Carlo Spa | Salts of novel derivatives of antibiotics of the tetracycline type. |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES262241A1 (en) * | 1959-11-23 | 1961-02-01 | Erba Carlo Spa | Procedure for preparing new derivatives of tetracycline antibiotics (Machine-translation by Google Translate, not legally binding) |
-
1974
- 1974-09-24 DK DK501674A patent/DK153784C/en active
- 1974-09-25 CA CA210,080A patent/CA1031774A/en not_active Expired
- 1974-09-25 IL IL45741A patent/IL45741A/en unknown
- 1974-09-26 NO NO743489A patent/NO140345C/en unknown
- 1974-09-26 GB GB41918/74A patent/GB1484345A/en not_active Expired
- 1974-09-26 AT AT776274A patent/AT337359B/en not_active IP Right Cessation
- 1974-09-27 ZA ZA00746147A patent/ZA746147B/en unknown
- 1974-09-27 SE SE7412215A patent/SE398875B/en not_active IP Right Cessation
- 1974-09-27 CH CH1305774A patent/CH614190A5/en not_active IP Right Cessation
- 1974-09-27 BE BE149013A patent/BE820474A/en not_active IP Right Cessation
- 1974-09-27 NL NL7412764A patent/NL7412764A/en not_active Application Discontinuation
- 1974-09-28 JP JP49112212A patent/JPS6044293B2/en not_active Expired
- 1974-09-28 ES ES430512A patent/ES430512A1/en not_active Expired
- 1974-09-30 DE DE19742446586 patent/DE2446586A1/en not_active Withdrawn
- 1974-09-30 FR FR7432896A patent/FR2246275B1/fr not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1863M (en) * | 1961-03-24 | 1963-06-17 | Erba Carlo Spa | Salts of novel derivatives of antibiotics of the tetracycline type. |
Also Published As
| Publication number | Publication date |
|---|---|
| SE7412215L (en) | 1975-03-29 |
| NO140345B (en) | 1979-05-07 |
| AU7381274A (en) | 1976-04-01 |
| IL45741A0 (en) | 1974-11-29 |
| NL7412764A (en) | 1975-04-02 |
| DE2446586A1 (en) | 1975-04-03 |
| IL45741A (en) | 1977-12-30 |
| FR2246275A1 (en) | 1975-05-02 |
| NO140345C (en) | 1979-08-15 |
| JPS6044293B2 (en) | 1985-10-02 |
| AT337359B (en) | 1977-06-27 |
| GB1484345A (en) | 1977-09-01 |
| JPS5062970A (en) | 1975-05-29 |
| NO743489L (en) | 1975-04-28 |
| DK153784C (en) | 1989-01-23 |
| DK501674A (en) | 1975-05-26 |
| SE398875B (en) | 1978-01-23 |
| CA1031774A (en) | 1978-05-23 |
| CH614190A5 (en) | 1979-11-15 |
| BE820474A (en) | 1975-01-16 |
| FR2246275B1 (en) | 1978-07-21 |
| ES430512A1 (en) | 1977-01-16 |
| ATA776274A (en) | 1976-10-15 |
| ZA746147B (en) | 1975-11-26 |
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