IT8922055A1 - ESTERS OF CEFAMANDOL NAFATO, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS. - Google Patents
ESTERS OF CEFAMANDOL NAFATO, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS. Download PDFInfo
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- IT8922055A1 IT8922055A1 IT1989A22055A IT2205589A IT8922055A1 IT 8922055 A1 IT8922055 A1 IT 8922055A1 IT 1989A22055 A IT1989A22055 A IT 1989A22055A IT 2205589 A IT2205589 A IT 2205589A IT 8922055 A1 IT8922055 A1 IT 8922055A1
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- Prior art keywords
- esters
- pharmaceutical compositions
- formula
- nafato
- preparation
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 4
- ICZOIXFFVKYXOM-YCLOEFEOSA-M cefamandole nafate Chemical compound [Na+].CN1N=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)[C@H](OC=O)C=3C=CC=CC=3)[C@H]2SC1 ICZOIXFFVKYXOM-YCLOEFEOSA-M 0.000 title 1
- 150000002148 esters Chemical class 0.000 claims description 11
- -1 D-2-formyloxy -2-phenyl -acetamido Chemical group 0.000 claims description 9
- 230000000844 anti-bacterial effect Effects 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 claims 2
- JOLQKTGDSGKSKJ-UHFFFAOYSA-N 1-ethoxypropan-2-ol Chemical compound CCOCC(C)O JOLQKTGDSGKSKJ-UHFFFAOYSA-N 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 229960004592 isopropanol Drugs 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-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
- 241000220304 Prunus dulcis Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- Cephalosporin Compounds (AREA)
Description
Esteri del Cefamandolo Nafato, procedimento per la loro preparazione e relative composizioni farmaceutiche Esters of Cefamandolo Nafato, process for their preparation and related pharmaceutical compositions
Riassunto Summary
Vengono descritti gli esteri dell'acido 7?(D-2-formilossi -2-fenil -acetamido) -3-(1-metil-l-H-tetrazol -5"il)-tiometil-3" cefem-4-carbossilico con alcossi -2-propanolo in forma otticamente attiva o racema, che impiegati nella terapia delle affezioni batteriche, vengono assorbiti per via orale in quantit? nettamente superiori rispetto all'acido tal quale somministrato per la stessa via. Are the esters of 7? (D-2-formyloxy -2-phenyl -acetamido) -3- (1-methyl-1-H-tetrazol -5 "yl) -thiomethyl-3" cephem-4-carboxylic alkoxy acid described -2-propanol in optically active or racemic form, which used in the therapy of bacterial diseases, are absorbed orally in quantities? significantly higher than the acid as it is administered by the same route.
Descrizione dell' invenzione Description of the invention
La presente invenzione riguarda gli esteri dell'acido 7-(D-2-formilossi -2-fenil -acetamido)-3~(1-metil-l-H-tetrazol -5-il)-tiometil-3-cefem-4-carbossilico f la loro preparazione e loro composizioni farmaceutiche. The present invention relates to the esters of 7- (D-2-formyloxy -2-phenyl -acetamido) -3 ~ (1-methyl-1-H-tetrazol -5-yl) -thiomethyl-3-cephem-4-carboxylic acid f their preparation and their pharmaceutical compositions.
Il sale sodico dell' acido 7"(D-2-formilossi -2-fenil acetamido)-3~ (1-metil-l-H-tetrazol -5-il)-tiometil-3-cefem-4-carbossilico, ? noto con il nome di Cefamandolo Nafato. Questo sale avente attivit? antibatterica, presenta per? un inconveniente, ? possibile somministrare il suddetto principio attivo solo per via parenterale, in quanto solo per questa via il suddetto principio attivo esplica un azione antibatterica. The sodium salt of 7 "(D-2-formyloxy -2-phenyl acetamido) -3 ~ (1-methyl-1-H-tetrazol -5-yl) -thiomethyl-3-cephem-4-carboxylic acid, is known as the name of Cefamandolo Nafato.This salt having antibacterial activity, however, presents a drawback, it is possible to administer the aforementioned active principle only parenterally, as only in this way does the aforementioned active principle perform an antibacterial action.
Oggetto della presente invenzione sono gli esteri dell'acido 7-(D-2-formilossi -2-fenil -acetamido)3?{1-metil-l-H-tetrazol -5-il)-tiometil-3?cefem-4-carbossilico con alcossi -2-propanolo in forma otticamente attiva o racema, ed aventi formula (I) Object of the present invention are the esters of 7- (D-2-formyloxy -2-phenyl -acetamido) 3? {1-methyl-1-H-tetrazol -5-yl) -thiomethyl-3? Cephem-4-carboxylic acid with alkoxy -2-propanol in optically active or racemic form, and having formula (I)
E' stato infatti inaspettatamente trovato che gli esteri di formula (I), subiscono una idrolisi assai lenta nel tratt? gastro-intestinale , nell'ambito del quale esplicano una scarsa attivit? antibatterica , e sono invece in grado di passare nel sangue portale e di dare luogo ad alti livelli serici di antibiotico. In fact, it has been unexpectedly found that the esters of formula (I) undergo a very slow hydrolysis in the process. gastro-intestinal, in which they perform a poor activity? antibacterial, and are instead able to pass into the portal blood and give rise to high serum levels of the antibiotic.
In tal modo si realizza la possibilit? di somministrare il suddetto principio attivo per via orale. In this way the possibility is realized? to administer the aforementioned active ingredient orally.
Ulteriore oggetto della presente invenzione sono composizioni farmaceutiche ad attivit? antibatterica per somministrazione orale contenenti gli esteri di formula (I) secondo la presente invenzione come principio attivo in combinazione con diluenti o supporti farmaceuticamente accettabili. A further object of the present invention are active pharmaceutical compositions. antibacterial for oral administration containing the esters of formula (I) according to the present invention as active principle in combination with pharmaceutically acceptable diluents or carriers.
Le preparazioni farmaceutiche secondo la presente invenzione possono essere in forma solida come capsule, compresse, confetti e bustine, oppure in forma liquida, come sospensioni estemporanee. The pharmaceutical preparations according to the present invention can be in solid form such as capsules, tablets, sugared almonds and sachets, or in liquid form, as extemporaneous suspensions.
Nel trattamento delle infezioni batteriche umane i composti oggetto della presente invenzione possono essere somministrati per via orale in quantit? di circa 20-100 mg /Kg in dosi scaglionate 3 0 4 volte al giorno. In the treatment of human bacterial infections the compounds object of the present invention can be administered orally in quantities? of about 20-100 mg / kg in staggered doses 3 or 4 times a day.
Essi possono venire somministrati in unit? posologiche contenenti 500-750<- >1000-1500 o 2000 mg di principio attivo in combinazione con adatti supporti ed eccipienti fisiologicamente accettabili. Can they be administered in unit? dosages containing 500-750 <-> 1000-1500 or 2000 mg of active principle in combination with suitable supports and physiologically acceptable excipients.
I composti oggetto della presente invenzione possiedono una attivit? antibatterica straordinariamente marcata e nel contempo presentano una eccellente stabilit? ed un eccellente assorbimento se somministrati per via orale. The compounds object of the present invention possess an activity? extraordinarily marked antibacterial and at the same time have an excellent stability? and excellent absorption when administered orally.
In particolare si ? osservato che le somministrazioni orali forniscono picchi nel siero con livelli di circa il 20% inferiori del Cefamandolo Nafato somministrato in quantit? equivalenti, per via intramuscolare. In particular yes? observed that oral administrations provide peaks in serum with levels of about 20% lower than Cefamandal Nafato administered in quantities? equivalents, intramuscularly.
Per somministrazione orale i picchi ematici vengono raggiunti dopo circa 1 ora. For oral administration, blood peaks are reached after about 1 hour.
L'emivita ? di circa 40 minuti; somministrazioni ripetute non danno origine ad accumulo del farmaco. The half-life? about 40 minutes; repeated administrations do not give rise to accumulation of the drug.
Gli esteri secondo la presente invenzione vengono rapidamente idrolizzati nel plasma a Cefamandolo. The esters according to the present invention are rapidly hydrolyzed in the plasma at Cefamandol.
Costituisce un ulteriore oggetto della presente invenzione il processo per la preparazione degli esteri di formula (I) mediante reazione in solvente organico insolubile in acqua preferibilmente solvente clorurato ed in particolare cloroformio, l'acido 7-(D-2-formilossi -2-fenil -acetaroido)-3-(l-metil-l H-tetrazol -5-il)-tiometil-3-cefem-4-carbossilico di formula (II) A further object of the present invention is the process for the preparation of the esters of formula (I) by reaction in an organic solvent insoluble in water, preferably a chlorinated solvent and in particular chloroform, 7- (D-2-formyloxy-2-phenyl -acetaroid) -3- (1-methyl-1 H-tetrazol -5-yl) -thiomethyl-3-cefem-4-carboxylic of formula (II)
dove R' ? un alchile da 1 a 5 atomi di carbonio preferibilmente ? etile o metile; where R '? an alkyl of 1 to 5 carbon atoms preferably? ethyl or methyl;
in presenza di quantit? stechiometriche di dicilcloesilcarbodiimmide e di dimetilamminopiridina aggiunta in quantit? catalitica, preferibilmente a temperatura ambiente. in the presence of quantity? stoichiometric of dicylchlohexylcarbodiimide and of dimethylaminopyridine added in quantity? catalytic, preferably at room temperature.
Vengono riportati i seguenti esempi a scopo illustrativo, ma non limitativo della presente invenzione. The following examples are reported for illustrative but not limitative purposes of the present invention.
ESEMPIO 1 - 7"(D-2-formilossi -2-fenil -acetamido)3-(1-metil-l H-tetrazol -5-il)-tiometil-3_cefem-4-carbossilato 1 metossi-2-propile. EXAMPLE 1 - 7 "(D-2-formyloxy -2-phenyl -acetamido) 3- (1-methyl-1 H-tetrazol -5-yl) -thiomethyl-3_cefem-4-carboxylate 1 methoxy-2-propyl.
5.125 g di sale sodico di Cefamandolo Nafato vengono sciolti in 50 mi di acqua ; si trasferisce la soluzione in imbuto separatore da 200 mi unitamente a 100 mi di .cloroformio; si acidifica a pH3 con acido cloridrico concentrato e si agita energicamente. Lo strato di cloroformio si separa e si anidrifica con solfat? sodico anidro. 5.125 g of Cefamandolo Nafato sodium salt are dissolved in 50 ml of water; the solution is transferred into a 200 ml separating funnel together with 100 ml of chloroform; it is acidified to pH3 with concentrated hydrochloric acid and stirred vigorously. Does the chloroform layer separate and dry with sulfat? anhydrous sodium.
Alla soluzione cloroformica anidra si aggiungono, nell'ordine, 0.9012 g di l-metossi-2 propend o, 2.06 g di dicicloesilcarbodimmide e 0.02 g di 4-dimetilamminopiridina. To the anhydrous chloroform solution are added, in order, 0.9012 g of 1-methoxy-2 propend o, 2.06 g of dicyclohexylcarbodimide and 0.02 g of 4-dimethylaminopyridine.
51 lascia per 4 ore a temperatura ambiente al riparo dalla luce. Si filtra quindi la soluzione cloroformica , che viene lavata con 50 mi di una soluzione acquosa acidificata con acido cloridrico 0.1 N. 51 leaves for 4 hours at room temperature, protected from light. The chloroform solution is then filtered and washed with 50 ml of an aqueous solution acidified with 0.1 N hydrochloric acid.
La soluzione cloroformica si anidrifica con solfato di sodio anidro e si porta, con l'aiuto del vuoto, ad una temperatura non superiore a 30 ?C, ad un volume di circa 30 mi. The chloroform solution is dried with anhydrous sodium sulphate and brought, with the help of vacuum, to a temperature not exceeding 30 ° C, to a volume of about 30 ml.
Si aggiungono lentamente, sotto agitazione, 100 mi di ligroina. Il precipitato formato viene filtrato e lavato con acetone. 100 ml of ligroin are slowly added under stirring. The precipitate formed is filtered and washed with acetone.
Si ottengono circa 5?5 E di prodotto. You get about 5? 5 E of product.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02205589A IT1238210B (en) | 1989-10-18 | 1989-10-18 | Cefamandol naftate esters, preparation procedure and relative pharmaceutical compositions. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02205589A IT1238210B (en) | 1989-10-18 | 1989-10-18 | Cefamandol naftate esters, preparation procedure and relative pharmaceutical compositions. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| IT8922055A0 IT8922055A0 (en) | 1989-10-18 |
| IT8922055A1 true IT8922055A1 (en) | 1991-04-18 |
| IT1238210B IT1238210B (en) | 1993-07-12 |
Family
ID=11190804
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT02205589A IT1238210B (en) | 1989-10-18 | 1989-10-18 | Cefamandol naftate esters, preparation procedure and relative pharmaceutical compositions. |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1238210B (en) |
-
1989
- 1989-10-18 IT IT02205589A patent/IT1238210B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| IT1238210B (en) | 1993-07-12 |
| IT8922055A0 (en) | 1989-10-18 |
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