148016-81-3 Usage
Description
Doripenem monohydrate is an ultra-broad-spectrum injectable β-lactam antibiotic, belonging to the subgroup of carbapenems. It is a 1β-methyl carbapenem derivative, which enhances metabolic stability to renal dehydropeptidase-1 (DHP-1) and leads to improved antibacterial potency. Doripenem is a white to somewhat yellowish crystalline powder, moderately soluble in water, slightly soluble in methanol, and virtually insoluble in ethanol. It is also soluble in N,N-dimethylformamide and can form a monohydrate when mixed with water. Doripenem was introduced by Shionogi Co. of Japan under the brand name Finibax in 2005 and is being marketed outside Japan by Johnson & Johnson.
Uses
Used in Pharmaceutical Industry:
Doripenem is used as an antibiotic for the treatment of bacterial respiratory and urinary tract infections. It acts by decreasing the process of cell wall growth, which eventually leads to the elimination of the infectious cell bacteria.
Used in Complicated Urinary Infections:
Doripenem hydrate is used to treat complicated urinary infections, including Pyelonephritis caused by E.coli. It is promoted in the United States under the brand name DORIBAX(R).
Used in Metabolic Stability Enhancement:
The introduction of a 1β-methyl group to the carbapenem skeleton of Doripenem enhances its metabolic stability to renal dehydropeptidase-1 (DHP-1), resulting in improved antibacterial potency.
Brand Names:
Doripenem is marketed under the brand names Doribax and Finibax.
Antimicrobial activity
Doripenem have a broad spectrum of bacterial activity including both gram-positive and gram-negative bacteria but it is not active against MRSA. It is stable against β-lactamases including those with extended spectrum, but it is susceptible to the action of carbapenemases (Mandell, 2009). Thus it can be used in the treatment of infections such as: complex abdominal infections, pneumonia within the setting of a hospital, and complicated infections of the urinary tract including kidney infections with septicemia. Doripenem is also more active against Pseudomonas aeruginosa then other carbapenems.
Pharmacokinetics
Cmax 500 mg intravenous infusion (1 h): c. 23 mg/L after 1 h500 mg intravenous infusion (4 h): c. 8 mg/LPlasma half-life: 1 hVolume of distribution: 16.8 L (steady state)Plasma protein binding: 8.1%Absorption and distributionDoripenem is not absorbed after oral administration. It penetrates well into most tissues and fluid, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria at the site of infection for the approved indications.Metabolism and excretionMetabolism of doripenem to the microbiologically inactive ring-opened metabolite occurs primarily by renal dehydropeptidase. Based on area under the concentration–time curve (AUC) values in plasma following a single 500 mg dose in healthy volunteers, 18% appears as metabolite and the rest as unchanged drug.Excretion is primarily by the renal route. Within 24 h after dosing, 78.7% and 18.5% of the dose was recovered in urine as unchanged drug and the ring-opened metabolite, respectively. After administration of radiolabeled doripenem, 0.7% of the total radioactivity was recovered in feces after 1 week.
Clinical Use
Doripenem is indicated for use for the treatment of intra-abdominal infections, and complicated urinary tract infections.Complicated urinary tract infections, including pyelonephritisNosocomial pneumonia, including ventilator-associated pneumonia (Europe)
Side effects
The most commonly reported adverse effects of doripenem include pain or swelling at the injection site, nausea, headache, and diarrhea.Seizure and central nervous system (CNS) side effects are observed rarely (<1%), though headache is reported by 2.3% of patients. Other common drug-related adverse reactions are diarrhea (2.0%), nausea (1.9%), anemia (1.4%) and phlebitis (1.4%). Hypersensitivity reactions related to intravenous administration of the study drug and Clostridium difficile colitis occurred at a rate of less than 1%. However, patients with a history of hypersensitivity reactions to other β-lactam agents should be treated cautiously.
Synthesis
the hydroxyl proline is protected as the PNZ ester 32 first in
95% yield. The protected proline acid 32 was converted to
the methyl ester with refluxing sulfuric acid in methanol
followed by conversion of the alcohol to the mesylate 34 in
91% overall yield from 30. The mesylate ester was reduced
with sodium borohydride to provide alcohol 35, which was
converted without purification to thiol ester 36 by reacting
with potassium thioacetate. Mitsunobu reaction
of alcohol 36 with BOC-sulfonyl urea 38, which was prepared
from chlorosulfonyl isocyanate with ammonia in tbutanol
in 90% yield, provided the key thioacetate intermediate
39. Finally, protected doripenem 42 was prepared by
coupling thiol 40, obtained by hyrolysis of thioacetate 39,
with enolphosphate 41 in 88% yield. Deprotection
of intermediate ester and carbamate protecting groups
via hydrogenation gave the desired carbapenem VI, which
was isolated after crystallization. Final form of the drug
doripenem was prepared by sterilization, crystallization and
granulation.
Dosage
Doripenem was initially developed in Japan and has received approval there in 2005 as Finibax. Finibax is indicated for multiple bacterial infections, the majority of which are respiratory indications.The usual dose, according to the Japanese label, is 250 mg intravenously (i.v.) infused over 30 to 60 minutes 2 or 3 times a day; the maximum dose is 500 mg per administration up to a total dose of 1,500 mg/day.
Mode of action
Doripenem's bactericidal function is due to its inhibition of the third stage of bacterial cell wall synthesis. Binding to penicillin-binding proteins weakens the cell wall and leads to cell death due to lysis of the cell wall.Doripenem is effective against both grampositive and gramnegative aerobic bacteria.It may be more potent in vitro against Pseudomonas aeruginosa than meropenem.
Check Digit Verification of cas no
The CAS Registry Mumber 148016-81-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,8,0,1 and 6 respectively; the second part has 2 digits, 8 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 148016-81:
(8*1)+(7*4)+(6*8)+(5*0)+(4*1)+(3*6)+(2*8)+(1*1)=123
123 % 10 = 3
So 148016-81-3 is a valid CAS Registry Number.
InChI:InChI=1/C15H24N4O6S2/c1-6-11-10(7(2)20)14(21)19(11)12(15(22)23)13(6)26-9-3-8(17-5-9)4-18-27(16,24)25/h6-11,17-18,20H,3-5H2,1-2H3,(H,22,23)(H2,16,24,25)/t6-,7-,8-,9-,10-,11-/m0/s1
148016-81-3Relevant articles and documents
Practical Large-Scale Synthesis of Doripenem: A Novel 1β- Methylcarbapenem Antibiotic
Nishino, Yutaka,Kobayashi, Makoto,Shinno, Taneyoshi,Izumi, Kenji,Yonezawa, Hiroshi,Masui, Yoshiyuki,Takahira, Masayuki
, p. 846 - 850 (2003)
A practical large-scale process for the synthesis of doripenem hydrate (1), a novel parenteral 1β-methylcarbapenem antibiotic, from p-nitrobenzyl-protected enolphosphate 2b and N-(p-nitrobenzyloxycarbonyl)- protected aminomethylpyrrolidine 3c is described. We found effective extraction conditions to remove p-toluidine and most other organic impurities using a THF/ water system containing an inorganic salt. Significant improvements have been made to the previous synthesis using a medicinal chemical procedure. The new process requires no chromatographic purification and affords the target compound 1 as a sterile crystalline powder. Several kilograms of compound 1 were successfully prepared by this process.
A method for preparing Doripenem
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Paragraph 0028; 0033; 0034, (2017/12/27)
The invention belongs to the field of medicine synthesis and particularly relates to a doripenem preparation method. The method includes the steps that a compound 5 reacts with concentrated sulfuric acid in methanol to obtain a compound 4; the compound 4 and p-Nitrobenzyl-6-(1-hydroxyethyl)-1-azabicyclo(3.2.0)heptane-3,7-dione-2-carboxylate (a compound 3) are subjected to a condensation reaction under the condition that N,N-diisopropylethylamine exists, water and ethyl acetate are added and stirred after the reaction, an ethyl acetate layer is collected, alcohol is added in ethyl acetate collection liquid, crystallization is carried out, and a compound 2 is obtained; the product is dissolved through ethyl acetate; after a monopotassium phosphate solution and a phase transfer reagent of triethylbenzylammonium chloride are added, zinc powder is added into the ethyl acetate/monopotassium phosphate solution in batches to react and obtain doripenem. According to the method, reaction conditions are moderate, the technology is simple, and the conversion rate and the yield are high. Two-phase reaction is used in deprotection reaction, and the after-treatment process is simplified. The zinc powder which is cheap is used, so that the method is economical, and a new concept and a new method are provided for doripenem preparation.
Method for preparing high purity doripenem
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Paragraph 0029; 0032, (2016/11/14)
The invention discloses a method for preparing high purity doripenem. The method comprises the following steps: (1) conducting a contact reaction on carbapenem bicyclic nucleus and (2S,4S)-1-p-nitrocarbobenzoxy-4-sulfenyl-2-(N-sulfamoyl amino)methylpyrrolidine in a water and 1,4-dioxane mixed solvent in the presence of copper salt and triethylamine; adding water and ethyl acetate, stirring, standing for layering, concentrating the ethyl acetate layer; recrystallizing a dichloromethane and petroleum ether mixed solvent to obtain (1R,5S,6S)-2-[(3S,5S)-1-nitrophenyl formate-5-sulfamoyl amino methylpyrrolidine-3-sulfenyl]-6-[(1R)-1-ethoxyl]-1-methyl-1-carba-2-penem-3-p-nitrobenzyl carboxylate; and (2) adding the product obtained in the step (1), tetrabutyl ammonium chloride and 0.2M of phosphate buffered solution having a pH value of 8 into a reaction kettle which is filled with water, replacing three times with hydrogen, adding hydrogen to react, filtering, concentrating the filtrate, and recrystallizing in methanol to obtain doripenem.
