DE931169C - Process for the production of antibiotically active, water-soluble complex compounds of the penicillin series or their aqueous solutions - Google Patents
Process for the production of antibiotically active, water-soluble complex compounds of the penicillin series or their aqueous solutionsInfo
- Publication number
- DE931169C DE931169C DEC7244A DEC0007244A DE931169C DE 931169 C DE931169 C DE 931169C DE C7244 A DEC7244 A DE C7244A DE C0007244 A DEC0007244 A DE C0007244A DE 931169 C DE931169 C DE 931169C
- Authority
- DE
- Germany
- Prior art keywords
- water
- salt
- penicillin
- soluble
- complex compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000002960 penicillins Chemical class 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 title claims description 9
- 238000000034 method Methods 0.000 title claims description 7
- 239000007864 aqueous solution Substances 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 150000003839 salts Chemical class 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 claims description 6
- 239000012429 reaction media Substances 0.000 claims description 4
- 230000003115 biocidal effect Effects 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- ASXBYYWOLISCLQ-HZYVHMACSA-N dihydrostreptomycin Chemical class CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](CO)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O ASXBYYWOLISCLQ-HZYVHMACSA-N 0.000 claims description 3
- -1 oxy groups Benzene series carboxylic acid Chemical class 0.000 claims description 3
- 229960005322 streptomycin Drugs 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims 1
- 230000000536 complexating effect Effects 0.000 claims 1
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 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 8
- 239000000243 solution Substances 0.000 description 7
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- 229940049954 penicillin Drugs 0.000 description 4
- CZWJCQXZZJHHRH-YCRXJPFRSA-N 2-[(1r,2r,3s,4r,5r,6s)-3-(diaminomethylideneamino)-4-[(2r,3r,4r,5s)-3-[(2s,3s,4s,5r,6s)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy-4-hydroxy-4-(hydroxymethyl)-5-methyloxolan-2-yl]oxy-2,5,6-trihydroxycyclohexyl]guanidine;sulfuric acid Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](CO)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](CO)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O CZWJCQXZZJHHRH-YCRXJPFRSA-N 0.000 description 3
- 229960001162 dihydrostreptomycin sulfate Drugs 0.000 description 3
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 229960005219 gentisic acid Drugs 0.000 description 2
- 229940056360 penicillin g Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- TUDXHDSCPJSDIO-UHFFFAOYSA-N 4-amino-2-hydroxybenzoic acid;sodium Chemical compound [Na].NC1=CC=C(C(O)=O)C(O)=C1 TUDXHDSCPJSDIO-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- ASXBYYWOLISCLQ-UHFFFAOYSA-N Dihydrostreptomycin Natural products O1C(CO)C(O)C(O)C(NC)C1OC1C(CO)(O)C(C)OC1OC1C(N=C(N)N)C(O)C(N=C(N)N)C(O)C1O ASXBYYWOLISCLQ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 1
- FNAZKAPRBSUSHL-UHFFFAOYSA-N O.O.[Na].Nc1ccc(C(O)=O)c(O)c1 Chemical compound O.O.[Na].Nc1ccc(C(O)=O)c(O)c1 FNAZKAPRBSUSHL-UHFFFAOYSA-N 0.000 description 1
- 239000004105 Penicillin G potassium Substances 0.000 description 1
- 239000004107 Penicillin G sodium Substances 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 229960002222 dihydrostreptomycin Drugs 0.000 description 1
- 239000011872 intimate mixture Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 235000019368 penicillin G potassium Nutrition 0.000 description 1
- 235000019369 penicillin G sodium Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
Classifications
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung antibiotisch wirksamer, wasserlöslicher Komplexverbindungen der Penicillinreihe bzw. von deren wäßrigen Lösungen Die bisher bekanntgewordenen, therapeutisch verwerteten Depotpräparate der Penicillinreihe enthalten meist ein in Wasser mehr oder minder schwerlösliches Salz aus einem Penicillin und einer organischen Base, wie dem Diäthylamino-äthyl-Ester der p-Aminobenzoesäure, dem I-(p-Chlorbenzyl)-2-pyrrolidylmethylbenzimidazol oder einer ähnlichen Verbindung. Man kann diese Penicillinsalze entweder als solche oder als Gemisch mit einem wasserlöslichen Penicillinsalz, wie dem Penicillin-G-Natrium oder dem Penicillin-G-Kalium, oder auch als Gemische mit einem anderen Antibioticum, wie Streptomycin oder Dihydrostreptomycin, verwenden. Alle diese Präparate bilden jedoch mit Wasser keine echten Lösungen, sondern milchige Suspensionen.Process for the production of antibiotically effective, water-soluble Complex compounds of the penicillin series or their aqueous solutions So far known, therapeutically used depot preparations of the penicillin series usually contain a salt from a penicillin that is more or less sparingly soluble in water and an organic base, such as the diethylamino-ethyl ester of p-aminobenzoic acid, the I- (p-chlorobenzyl) -2-pyrrolidylmethylbenzimidazole or a similar compound. One can use these penicillin salts either as such or as a mixture with a water-soluble one Penicillin salt, such as penicillin G sodium or penicillin G potassium, or also as mixtures with another antibiotic, such as streptomycin or dihydrostreptomycin, use. However, all of these preparations do not form real solutions with water, but milky suspensions.
Es wurde nun gefunden, daß antibiotisch wirksame, wasserlösliche Komplexverbindungen der Penicillinreihe erhalten werden, wenn man ein Salz oder ein Gemisch der vorerwähnten Art mit einem wasserlöslichen Salz einer pharmakologisch verträglichen, d. h. nicht toxischen Carbonsäure der Benzolreihe in einem geeigneten Reaktionsmedium, vorzugsweise in Wasser, zur Reaktion bringt. Vorzugsweise werden gemäß der Erfindung solche pharmakologisch verträglichen Carbonsäuren der Benzolreihe verwendet, die eine oder mehrere Oxygruppen enthalten oder durch einen cyclischen Substituenten substituiert sind. Beispielsweise lassen sich vorteilhaft die wasserlöslichen Salze, z. B. die Natriumsalze, der Salizylsäure, der p-Aminosalizylsäure oder der Gentisinsäure verwenden. It has now been found that antibiotically effective, water-soluble Complex compounds of the penicillin series can be obtained when using a salt or a mixture of the aforementioned kind with a water-soluble salt of a pharmacologically compatible, d. H. non-toxic carboxylic acid of the benzene series in a suitable Reaction medium, preferably in water, to react. Preferably be according to the invention, such pharmacologically acceptable carboxylic acids of the benzene series used that contain one or more oxy groups or by a cyclic Substituents are substituted. For example, the water-soluble Salts, e.g. B. the sodium salts, salicylic acid, p-aminosalicylic acid or the Use gentisic acid.
Die Bildung der neuen wasserlöslichen Komplexverbindungen erfolgt zweckmäßig durch Umsetzung des in Wasser schwerlöslichen Penicillinsalzes bzw. eines Gemisches eines solchen Penicillinsalzes mit einem anderen antibiotisch wirksamen Salz, wie einem Streptomycin- oder D ihydrostreptomycinsalz, mit einem Überschuß des wasserlöslichen Salzes der Carbonsäure der Benzotreihe, wobei zweckmäßig Wasser als Reaktionsmedium verwendet wird. Die so erhaltenen Lösungen können als solche verwendet werden. Man kann die Komplexverbindungen aber auch durch schonendes Verdampfen des Reaktionsmediums, wie durch Gefriertrocknung, isolieren. Die derart isolierten Stoffe lassen sich gewünschtenfalls wiederum ohne Schwierigkeiten in wäßrige Lösungen überführen. The new water-soluble complex compounds are formed expediently by reacting the sparingly water-soluble penicillin salt or a Mixture of such a penicillin salt with another antibiotic active Salt, such as a streptomycin or dihydrostreptomycin salt, with an excess of the water-soluble salt of the carboxylic acid of the benzot series, advantageously water is used as the reaction medium. The solutions thus obtained can be used as such be used. The complex compounds can also be removed by gentle evaporation of the reaction medium, such as by freeze drying, isolate. The so isolated If desired, substances can again be converted into aqueous solutions without difficulty convict.
Durch das vorliegende Verfahren wird eine erhebliche Bereicherung der Technik erzielt, da die Anwendung der so erhaltenen Komplexverbindungen in Form von wäßrigen Lösungen technisch vorteilhafter ist als die in Form von Suspensionen. The present procedure will be a considerable enrichment the technology achieved, since the application of the complex compounds thus obtained in the form of aqueous solutions is technically more advantageous than that in the form of suspensions.
Der Erfolg des Verfahrens ist überraschend und konnte nicht vorausgesehen werden.The success of the procedure is surprising and could not be foreseen will.
Beispiel I Eine innige Mischung von 500 mag des Doppelsalzes aus p-Aminobenzoesäurediäthylaminoäthylester und Penicillin und der Menge Dihydrostreptomycinsulfat, die 500 mg der Base äquivalent ist, wird mit einer Lösung von 2 g Natriumsalicylat in 10 ccm Wasser übergossen. Nach kurzem Schütteln tritt völlig klare Lösung ein. Example I An intimate mixture of 500 mag of the double salt p-aminobenzoic acid diethylaminoethyl ester and penicillin and the amount of dihydrostreptomycin sulfate, which is equivalent to 500 mg of the base is treated with a solution of 2 g of sodium salicylate Poured over 10 cc of water. After brief shaking, a completely clear solution appears.
Beispiel 2 500 mg des Doppelsalzes aus 4-Amino-2-oxybenzoesäurediäthylaminoäthylester und Penicillin werden in einer Lösung von I,3 g Dihydrostreptomycinsulfat in 10 ccm H20 aufgeschlämmt. Nach Zufügen von 2 g p-aminosalicylsaurem Natrium-Dihydrat tritt in wenigen Augenblicken klare Lösung ein. Durch Verdampfen des Wassers kann eine therapeutisch hochwirksame, in Wasser gut lösliche Substanz erhalten werden. Example 2 500 mg of the double salt of 4-amino-2-oxybenzoic acid diethylaminoethyl ester and penicillin are in a solution of 1.3 g of dihydrostreptomycin sulfate in 10 ccm H20 slurried. After adding 2 g of p-aminosalicylic acid sodium dihydrate a clear solution occurs in a few moments. By evaporation of the water can a therapeutically highly effective substance which is readily soluble in water can be obtained.
Beispiel 3 Man bringt eine Mischung von 500 mg des Doppelsalzes aus 4 - Amino - 2 - oxybenzoesäurediäthylaminoäthylester und Penicillin und I,3 g Dihydrostreptomycinsulfat wie im Beispiel 2 in Lösung. Durch Gefriertrocknung erhält man das wasserlösliche Produkt in fester Form. Example 3 A mixture of 500 mg of the double salt is applied 4 - amino - 2 - oxybenzoic acid diethylaminoethyl ester and penicillin and 1.3 g of dihydrostreptomycin sulfate as in Example 2 in solution. The water-soluble one is obtained by freeze-drying Solid form product.
Beispiel 4 Man verfährt wie im Beispiel 2. An Stelle des p-aminosalicylsauren Natriums verwendet man nun 2 g gentisinsaures Natrium. Example 4 The procedure is as in Example 2. Instead of p-aminosalicylic acid Sodium one now uses 2 g of gentisic acid sodium.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEC7244A DE931169C (en) | 1953-03-07 | 1953-03-07 | Process for the production of antibiotically active, water-soluble complex compounds of the penicillin series or their aqueous solutions |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEC7244A DE931169C (en) | 1953-03-07 | 1953-03-07 | Process for the production of antibiotically active, water-soluble complex compounds of the penicillin series or their aqueous solutions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE931169C true DE931169C (en) | 1955-08-01 |
Family
ID=7014081
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEC7244A Expired DE931169C (en) | 1953-03-07 | 1953-03-07 | Process for the production of antibiotically active, water-soluble complex compounds of the penicillin series or their aqueous solutions |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE931169C (en) |
-
1953
- 1953-03-07 DE DEC7244A patent/DE931169C/en not_active Expired
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