DE936687C - Process for the production of poorly soluble penicillin compounds - Google Patents
Process for the production of poorly soluble penicillin compoundsInfo
- Publication number
- DE936687C DE936687C DEC6273A DEC0006273A DE936687C DE 936687 C DE936687 C DE 936687C DE C6273 A DEC6273 A DE C6273A DE C0006273 A DEC0006273 A DE C0006273A DE 936687 C DE936687 C DE 936687C
- Authority
- DE
- Germany
- Prior art keywords
- compounds
- penicillin
- production
- poorly soluble
- organic bases
- 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
- 238000000034 method Methods 0.000 title claims description 6
- 238000004519 manufacturing process Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 5
- 150000007513 acids Chemical class 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 2
- 125000001302 tertiary amino group Chemical group 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229930182555 Penicillin Natural products 0.000 description 10
- 229940049954 penicillin Drugs 0.000 description 7
- 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 6
- -1 alkyl radical Chemical group 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 230000001387 anti-histamine Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 230000036765 blood level Effects 0.000 description 2
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- BECAAKAVMYEKLN-UHFFFAOYSA-N 4-amino-2-iodobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C(I)=C1 BECAAKAVMYEKLN-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000000721 bacterilogical effect Effects 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000723 toxicological property Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung von schwer löslichen Penicillinverbindungen Es ist bereits bekannt, schwer lösliche Pen.icillinverbindungen, nämlich Verbindungen: des Penicillins mit den Dialkylaminoalkylestern der o-Oxy-p-aminoben(zoesäure oder o-Jod-p-aminobenzoesäure durch Umsetzung dieser mit den Additionsverbindungen der Penicillinsäuren mit Diisopropy läthern in Gegenwart. geeigneter Lösungsmittel herzustellen.Process for the production of poorly soluble penicillin compounds It is already known poorly soluble penicillin compounds, namely compounds: of penicillin with the dialkylaminoalkyl esters of o-oxy-p-aminobes (zoesäure or o-Iodo-p-aminobenzoic acid by reacting this with the addition compounds of the Ethereal penicillic acids with diisopropyl in the presence. to prepare suitable solvents.
Aus der deutschen Patentschrift 817 912 ist ein Verfahren bekannt zur Herstellung schwer löslicher Salize aus Penicillin: und organischen Basen durch Umsetzen der Addliti.onsverbindung aus Pen4cillinsäuren und. Diisop.ropyläther mit organischen Basen. in einem geeigneten Lösungsmittel.A method is known from German patent specification 817 912 for the production of sparingly soluble salizates from penicillin: and organic bases Implementation of the additive compound from pen4cillic acids and. Diisop.ropyl ether with organic bases. in a suitable solvent.
Von den zahlreichen Antihistamin-Präparaten, diie zur Zeit therapeutisch angewandt werden, bilden nur sehr wenige mit Additionsverbindungen der Penicililinsäuren mit Diisopropyläther krist,alli@ne Verbindungen. Überwiegend werden nichtkristalline Produkte gebildet.Of the numerous antihistamine preparations currently therapeutic are used, form only very few with addition compounds of penicillinic acids with diisopropyl ether, alli @ ne compounds. They are predominantly non-crystalline Products made.
Es. wurde nun .gefunden, daß auch andere schwer lösliche Penici.llinverbindtuigen über die Additionsverbindungen der Penicillinsäuren mit Diisopropyläther hergestellt werden können. Gemäß der Erfindung werden diese Additionsverbindungen mit Benzimidazdlverbindungen der allgemeinen Formel I in der X einen Alkylrest, der gegebenenfalls substituiert sein kann, und Y einen aliphatischen Rest, der wenigstens eine sekundäre oder tertiäre Aminogruppe enthält, bedeuten, in Gegenwart geeigneter Lösungsmittel, umgesetzt. Mit besonderem Erfolg verwendet man als Benzimidazolverbindung das i - p - Chlorbenzyl - 2 - N - pyrrollidyl - methylbenzimidazol: Die Produkte dies erfindungsgemäßen; Verfahrens snndi in: Wasser außerordentlich schwer löslich. Beispielsweise beträgt bei 24° die Löslichkeit der Penicillinverbindung des i-p-Ohlorben@zyl-2-N-pyrroLidyl-methyl-benzimidazols in Wasser .nur 0,03'/o (i cm3 der gesättigten wäßrigen Lösung enthält maximal 300 i. E. Penicillin). Die Löslichkeit in Wasser ist beispielsweise sehr viel geringer als bei den entsprechenden schwer löslichen: Verbindungen der Penicilline mit den Dialkylaminoalkylestern der p-Arninobenzoesäure.It. it has now been found that other sparingly soluble penicillin compounds can also be produced via the addition compounds of penicillic acids with diisopropyl ether. According to the invention, these addition compounds with benzimidazdl compounds of the general formula I in which X is an alkyl radical, which may optionally be substituted, and Y is an aliphatic radical which contains at least one secondary or tertiary amino group, in the presence of suitable solvents. The benzimidazole compound used with particular success is i - p - chlorobenzyl - 2 - N - pyrrollidyl - methylbenzimidazole: The products according to the invention; Process snndi in: Water extremely poorly soluble. For example, at 24 ° the solubility of the penicillin compound of ip-chlorobenzyl-2-N-pyrrolidyl-methyl-benzimidazole in water is only 0.03% (1 cm3 of the saturated aqueous solution contains a maximum of 300 iU penicillin ). The solubility in water is, for example, very much lower than in the case of the corresponding sparingly soluble: Compounds of penicillins with the dialkylaminoalkyl esters of p-aminobenzoic acid.
Mit der Schwerlöslichkeit der Pemicillinsalze -in Wasser sind wichtige therapeutische Eigenschaften eng verbunden., die man als Depoteffekt bezeichnet. Dieser Depoteffekt, für den die Dauer des Fortbestehens des .im Tierexperiment oder am Menschen nach parenteraler Applikation des jeweiligen Penicillinsalzes auftretenden Penicillin-Blutspiegels als Meßzahl dient, ist eine direkte Funktion der Schwerlöslichkeit. Untersuchungen am Tier und am Menschen habem gezeigt, daß nun Einklang mit der Schwerlöslichkeit der therapeutisch wirksame Blutspiegel nach Anwendung der Verbindungen gemäß der Erfindung wesentlich länger bestechen bleibt als bei den bekannten Depot Penicillinen.With the poor solubility of the pemicillin salts in water are important therapeutic properties closely related., which is called the depot effect. This depot effect, for which the duration of the .im animal experiment or occurring in humans after parenteral application of the respective penicillin salt Penicillin blood level is used as a measure, is a direct function of the poor solubility. Studies on animals and humans have shown that there is now consistency with the poor solubility the therapeutically effective blood level after application of the compounds according to The invention remains bribing much longer than the well-known depot penicillins.
Auch hinsichtlich ihrer günstigen toxikologischen Eigenschaften erwiesen sich die Produkte gemäß der Erfindung in einer eingehenden tierexperimentellen Verglenthsprüfung nicht nur den wenigen bekannten Antihistamin-Penicillinsalzen überlegen, sondern sogar dem heute in der Therapie allgemein verwendeten Salz aus p-Amnnob7enzoesäureäthylaminoäthylester und Penicillin. Diese überlegen, heit ist überraschend und war in keiner Weise vorauszusehen.Also proven with regard to their favorable toxicological properties the products according to the invention in a detailed animal experiment comparison test not only superior to the few known antihistamine penicillin salts, but even the salt of p-Amnnob7enzoesäureäthylaminoäthylester commonly used in therapy today and penicillin. This superiority is surprising and could not be foreseen in any way.
Bei einem bakteriologischen Vergleich hat sich gezeigt, daß- die erfindungsgemäß hergestellten Verbindungengegenüber Staphyloikökkens.tämmen eine teilweise sogar bemerkenswert höhere Wirksamkeit besitzen als die üblichen. Standardpenicilline. Angesichts der steigenden Resistenzentwicklung der Staphylokokken gegen die üblichen Penicillinsalze besitzt daher das erfindungsgemäß hergestellte Produkt eine erhöhte Bedeutung. Wird als zweite Komponente beim Verfahren eine der angeführten Benzimidazolverbindungen angewandt, die antihistaminische Wirkung haben, so werden bei der Anwendung dieser Verbindungen allergische Erscheinungen bei dien behandelten@ Personen beseitigt, die bei Anwendung von Penicillin allein häufig auftreten. Beispiel Man löst 4,36 g Penicil.lin-Dü@sopropyläthex-Komplexverbindun@g in 30 ccm Tetrachloräthan und fügt dazu eine Lösung von 3,26 g 1-(p-Chlorbenzyl) -2-N-pyrrolidyl-methyl-bemimidazol in 40 ccm Chloroform. Bei gutem Rühren fällt das neue Penicillinsalz zunächst in schmieriger, bald aber erstarrender Form in guter Ausbeute aus. Es schmilzt bei 144 bis. 145 ° unter Zersetzung und hat eine Aktivität von etwa goo IE/mg.A bacteriological comparison has shown that the compounds prepared according to the invention are sometimes even remarkably more effective than the usual ones against Staphyloikökkens.tämmen. Standard penicillins. In view of the increasing development of resistance of the staphylococci to the usual penicillin salts, the product produced according to the invention is therefore of increased importance. If one of the listed benzimidazole compounds, which have an antihistaminic effect, is used as the second component in the process, allergic phenomena are eliminated in the treated persons when these compounds are used, which often occur when using penicillin alone. EXAMPLE 4.36 g of Penicil.lin-Dü @ sopropyläthex -komplexverbindungen are dissolved in 30 ccm of tetrachloroethane and a solution of 3.26 g of 1- (p-chlorobenzyl) -2-N-pyrrolidyl-methyl-bemimidazole in is added 40 cc of chloroform. With thorough stirring, the new penicillin salt initially precipitates in a greasy, but soon solidifying form in good yield. It melts at 144 to. 145 ° with decomposition and has an activity of about goo IU / mg.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEC6273A DE936687C (en) | 1952-08-17 | 1952-08-17 | Process for the production of poorly soluble penicillin compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEC6273A DE936687C (en) | 1952-08-17 | 1952-08-17 | Process for the production of poorly soluble penicillin compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE936687C true DE936687C (en) | 1955-12-22 |
Family
ID=7013860
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEC6273A Expired DE936687C (en) | 1952-08-17 | 1952-08-17 | Process for the production of poorly soluble penicillin compounds |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE936687C (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE817912C (en) * | 1949-06-20 | 1951-10-22 | Leo Pharm Prod Ltd | Process for the production of poorly soluble salts from benzylpenicillin with organic bases, in particular procaine |
| GB673558A (en) * | 1949-06-20 | 1952-06-11 | Knud Abildgaard Elling | Production of a difficultly soluble salt of benzylpenicillin with an organic base |
-
1952
- 1952-08-17 DE DEC6273A patent/DE936687C/en not_active Expired
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE817912C (en) * | 1949-06-20 | 1951-10-22 | Leo Pharm Prod Ltd | Process for the production of poorly soluble salts from benzylpenicillin with organic bases, in particular procaine |
| GB673558A (en) * | 1949-06-20 | 1952-06-11 | Knud Abildgaard Elling | Production of a difficultly soluble salt of benzylpenicillin with an organic base |
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