WO2004046153A1

WO2004046153A1 - Prodrug esters of ceftriaxone

Info

Publication number: WO2004046153A1
Application number: PCT/IB2003/005327
Authority: WO
Inventors: Vandana RAINA; Yatendra Kumar; Ram Chander Aryan
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2002-11-21
Filing date: 2003-11-21
Publication date: 2004-06-03
Also published as: AU2003302109A1

Abstract

The invention relates to prodrug esters of ceftriaxone. The invention also relates to processes for preparing prodrug esters of ceftriaxone, pharmaceutical compositions that include the prodrug esters and to methods for using the prodrug esters. The prodrug esters of ceftriaxone are useful as antimicrobial agents and are suitable for oral administration.

Description

PRODRUG ESTERS OF CEFTRIAXONE

Field of the Invention

The field of the invention relates to prodrug esters of ceftriaxone. The invention also relates to processes for preparing prodrug esters of ceftriaxone, pharmaceutical compositions that include the prodrug esters and to methods for using the prodrug esters.

Background of the Invention

Research and development efforts have continued with the cephalosporin antibiotics focusing on the structural modification to circumvent mechanisms of resistance as well as to enhance oral bioavailability and bio-disposition profiles. Among the newer cephalosporin generation, these goals have been realized with some success by modification of the substi uents at positions 2, 3, 4 and 7 of the cephalosporin rings. Perhaps the most significant modifications have involved incorporation of an aminothiazole ring and an alkoxyimino group at the 7-position. These substituents present in the third generation cephalosporins improve antibacterial spectrum by enhancing affinity for target transpeptidase enzyme and by imparting resistance to mactivation by a variety of beta lactamases.

Some of the newer cephalosporins also contain chemically and metabolically stable substituents at the 3-position of the β-lactam ring, allowing for oral activity.

In several new cephalosporins, the 4-carboxyl group has been converted to a lipophilic ester prodrug moiety. This modification enhances oral absorption.

In general, third generation cephalosporin compounds exhibit excellent antibacterial activity but are poor in absorption from digestive tract, and therefore are usually administered by injection. However, the preferred route of administration is oral for obvious reasons except where large doses of an antibiotic are to be administered quickly. Unfortunately, of many cephalosporin derivatives discovered, very few possess a combination of superior antibacterial activity, broad antibacterial spectrum against both gram positive and gram negative bacteria (especially against Staphylococcus aureus) and the ability to be absorbed efficiently through the digestive tract thus rendering parenteral administration inevitable. In recent years, many efforts have been made to improve the absorption of cephalosporin derivatives through the digestive tract by introducing a lipophilic ester residue into the 4-position carboxylic acid of cephalosporin compound. These include cefteram pivoxil and cepodoxime proxetil as disclosed in U.S. Patent Nos. 4,489,072 and 4,486,425, respectively which have been developed as orally active prodrugs, in which the carboxyl group is esterified to increase lipophilicity.

U.S. Patent No. 5,389,625 discloses an increase in the oral absorption of cephalosporin compounds by introducing an amino acid as a basic moiety onto the weakly basic, amino group on the thiazole ring, thereby increasing the water solubility (bifunctional compounds).

Although various attempts to improve absorption from the digestive tract by chemically modifying cephalosporin compounds either by preparing mono-functional or bi-functional prodrugs have been made, yet not many drugs are known which meet all the requirements of good absorption, high antibacterial activity and a broad antibacterial spectrum.

In an already overcrowded cephalosporin field, where the introduction of a particular substituent in the cephalosporin nucleus does not ensure the improvement of one property and may adversely affect other properties in an unpredictable manner and even where a particular chemical modification which is known to improve the properties of one particular compound and is in no way any indication that a similar modification will likewise improve the properties of another compound, we reasoned that a modification in ceftriaxone molecule at carboxyl group, would have an even better water solubility and therefore set out to prepare, hitherto unknown prodrugs of ceftriaxone.

Summary of the Invention

The present invention provides certain prodrug esters of ceftriaxone and are useful as antimicrobial agents. The prodrug esters have good solubility in water, easily absorbable from digestive tract and are suitable for oral administration.

The invention also includes the enantiomers, stereoisomers, diastereomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these prodrug esters having the same type of activity. In one general aspect there are provided certain prodrug esters of ceftriaxone of Formula I, wherein R is an "esterified carboxyl group" and may include an alkyl, 1- alkanoyloxyalkyl, 1-alkoxycarbonyloxyalkyl, cycloalkyl, cycloalkyloxy or alkoxy having from one to ten carbon atoms. Compounds of Formula la, lb and Ic, wherein R is as shown below are certain specific examples of the invention.

FORMULA I

In another general aspect there is provided a process for the preparation of prodrug esters of ceftriaxone of Formula I.

In another general aspect there is provided a pharmaceutical composition and dosage forms containing a therapeutically effective amount of the prodrug esters of ceftriaxone of Formula I and which may also contain phaπnaceutically acceptable carriers, excipient or diluents which are useful for the treatment of bacterial infections.

In another general aspect there is provided a method of treating bacterial infections comprising administering to a mammal in need thereof, a therapeutically effective amount of prodrug esters of ceftriaxone of Formula I as described above. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Detailed Description of the Invention

The inventors have found certain new prodrugs of ceftriaxone of Formula I, wherein R is an "esterified carboxyl group" and includes an alkyl, 1-alkanoyloxyalkyl, 1- alkoxycarbonyloxyalkyl, cycloalkyl, cycloalkyloxy or alkoxy having from one to ten carbon atoms, for example, ceftriaxone cilexetil of formula la, ceftriaxone proxetil of formula lb, and ceftriaxone pivoxil of formula Ic. The new prodrug esters are characterized by the spectral data as given in the examples described herein after.

FORMULA I

o la R = CH— 0— C— 0 — (^

CH₃

The inventors have also developed a process for the preparation of the prodrugs of ceftriaxone of Formula I, wherein R is an "esterified carboxyl group" and includes an alkyl, 1-alkanoyloxyalkyl, 1-alkoxycarbonyloxyalkyl, cycloalkyl, cycloalkyloxy or alkoxy having from one to ten carbon atoms or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula II,

FORMULA H

with a compound of Formula III,

FORMULA HI

wherein R] is an alkyl, 1-alkanoyloxyalkyl, 1-alkoxycarbonyloxyalkyl, cycloalkyl, cycloalkyloxy or alkoxy having from one to ten carbon atoms.

In general, the reaction is carried out in the presence of a suitable organic solvent and a base to avoid the formation of a by product, Δ²-isomer.

The term "esterified carboxyl group" refers to compounds of Formula I, wherein

R includes an alkyl, 1-alkanoyloxyalkyl, 1-alkoxycarbonyloxyalkyl, cycloalkyl, cycloalkyloxy or alkoxy group.

The alkanoyloxy has from two to ten carbon atoms. In particular, the alkanoyloxy has from two to seven carbon atoms and the alkyl moiety has from one to six carbon atoms. Examples include acetoxymethyl, propionyloxymethyl n-butyryloxymethyl, iso- valeryloxymethyl, pivaloxylmethyl, 1-acetoxyethyl, n-valeroxymethyl, 2- methylbutyryloxy- methyl, isovaleroxymethyl, n-hexanoyloxymethyl, 3- methylvaleroxymethyl, neohexanoyloxy-methyl, 2-methylhexanoyloxymethyl, 2,2- dimethylbutyryloxymethyl, 2,2-dimethylpropionyloxy-methyl, diethylacetoxymethyl, dipropylacetoxymethyl, 1-propionyloxyethyl, 1-isobutyryloxyethyl, 1-n-valoryloxyethyl, 1-pivaloxyloxyethyl, 1-pivaloxyloxymethyl, 1-isovaloryloxyethyl, and 1- cyclohexanoyloxyethyl.

The alkoxy moiety of alkoxycarbonyloxyalkyl has from one to ten carbon atoms. In particular, it has from one to seven carbon atoms and the alkyl moiety has from one to six carbon atoms. Examples include 1-methylethoxycarbonyloxyethyl, 1- methoxycarbonylethoxyethyl, 1-ethoxycarbonyloxyethyl, 1-n-propoxycarbonyloxy ethyl, 1-tertbutoxycarbonyloxy ethyl, 1-tertbutoxycarbonyloxymethyl, 1- pentyloxycarbonyloxyethyl, and 1-cyclohexyloxycarbonyloxy- ethyl.

Examples of carboxyl protecting groups include 1-cyclohexyloxycarbonyloxyethyl (cilexetil), 2,2,-dimethylpropionyloxymethyl (pivoxil), and 1- methylethoxycarbonyloxyethyl (proxetil) .

The suitable organic solvent includes tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, dioxane, dimethoxyethane, methylene chloride, acetone, ethyl acetate, and mixtures thereof.

The base includes any compound having at least one nitrogen as a heteroatom, including, for example, diisopropylethylamine, diphenylamine, N-tert- butylcyclohexylamine, hexamethyldisilazide, l,5-diazabicyclo[4.3.0]non-5-ene, 1,8- diazabicyclo[5.4.0]undec-7-ene, and mixtures thereof.

The reaction is carried out at a temperature ranging from about 40°C to about - 20°C.

The resulting prodrug esters of ceftriaxone may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.

The compositions include dosage forms suitable for oral and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration. The oral dosage forms may include solid dosage forms, like powder, tablets, capsules, as well as liquid suspensions. Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and are not intended to limit the scope of the invention. Although the examples are directed to certain prodrug esters of ceftriaxone, the principles described in these examples can be applied to other prodrug esters of ceftriaxone.

EXAMPLE 1

Preparation of l-[l-(cyclohexyloxy)carbonyloxy)ethyl] (6R-7R)-7-[2-[2-aminothiazol-4- yl)-2-((Z)-methoxyimino)acetamido]-[(2,5-dihydro-2-methyl-5-oxo-6-hydroxy] 1 ,2,4- triazin-3-yl] thio]methyl]-8-oxo-5-thia-azabicyclo[4.2.0]Oct-2-ene-carboxylate (ceftriaxone cilexetil of Formula la).

To N, N-dimethylacetamide (60 ml) at 0-5°, was added 1,8-diazabicyclo [5.4.0]undec-7- ene (DBU) (7.8 g, 0.0513 mol) drop wise followed by the addition of acetic acid (3.24 g, 0.054 moles). The reaction mixture was stirred for 30 minutes to obtain DBU - acetate salt. Ceftriaxone acid (30 g, 0.0541 moles) was dissolved in N, N-dimethylacetamide (140 ml) at 20-22°C and solution was cooled to -10°. To this ceftriaxone solution, DBU - acetate salt solution was added at -10 to -5° in 15 minutes and the reaction mixture was stirred at -5°C for 1 hour. Iodo ethylcyclohexyl carbonate (15.28 g, 0.0513 moles) was added slowly at -10° and the reaction mass was stirred at -10°C for 2.5 hour. Then, the reaction mixture was added to chilled ethyl acetate (400 ml, 0°C) and stirred for 20 minutes. Water (300 ml) was added to it and further stirred for 15 minutes. The layers were separated and the organic layer was washed successively with 0.5% hydrochloric acid (300 ml), water (100 ml), 1% sodium thiosulfate solution (200 ml), and finally with 10% brine (200 ml). The organic layer was concentrated to 60 ml and was added drop wise to hexane (280 ml). The solid so obtained was filtered, washed with hexane (280 ml) and finally concentrated to obtain the solid product (19.0 g). This solid was dissolved in acetone (340 ml) at 0-5°C. A solution of sodium-2-ethylhexanoate (4.14 g, 0.025 moles) was added till pH 7.5. It was stirred for 20 minutes at 0-5°C, filtered and washed with acetone (20 ml x 2). The solid was dried and then suspended in a mixture of ethyl acetate (50 ml) and water (200 ml) and pH was adjusted to 2.8 with dilute hydrochloric acid. The organic layer was concentrated to 20 ml and to it hexane (160 ml) was added at room temperature. It was stirred for 20 minutes. The product was filtered, washed with hexane (20 ml) and finally dried to obtain the product (la) (7.5 g).

Mass Spectrum: Iv +1 = 725

Η-NMR in DMSO-D₆ (δ, ppm): 1.24-1.98 (m,10H), 1.45 (d, 3H), 3.59 (s, 3H), 3.60-3.80 (m, 2H), 3.82 (s, 3H) 3.99-4.04 (m, IH), 4.35 - 4.50 (m, IH), 4.50-4.70 (m, IH), 5.15-5.19 (m, IH), 5.84 (m, IH), 6.71 (s, IH), 6.8-7.0 (m, IH), 7.2 (s, 2H), 9.5-9.61 (dd, IH).

IR ( Br) cm^-1: 3324, 2937, 1787, 1757, 1654, 1533, 1377.

The following two examples were prepared analogously and spectral data is provided as below.

EXAMPLE 2

Methylene-[6R,7R]-7-[2-(2-aminothiazol-4-yl)-2-[(Z)-methoxyimino)acetamido]-3-[(2,5- dihydro-2-methyl-5-oxo-6-hydroxy] 1 ,2,4-triazin-3-yl]-thio]-methyl]-8-oxo-5-thia- 1 - azabicyclo-[4.2.0]oct-2-ene-2-carboxylate-pivalate, (ceftriaxone pivoxil of Formula lb)

Mass Spectrum: M^"1" +1 = 669

Η-NMR in DMSO-D₆ (δ, ppm): 1.17(s, 9H), 3.6 (s, 3H), 3.6-3.8 (m, 2H), 3.83 (s, 3H), 4.02( d, IH), 4.55 (d, IH), 5.16-5.18 (d, IH), 5.81-5.83 (m, 2H), 6.02-6.04 (d, IH), 6.74 (s, IH), 7.27 (bs , 2H), 9.6-9.63 (d , IH).

IR (KBr) cm^-1: 3325, 2927, 1786, 1751, 1654, 1533, 1369.

EXAMPLE 3

[ 1 -[ 1 -(methylethoxy)carbonyl)oxy)ethyl] (6R,7R),7-[2-(2-aminothiazol-4yl)-2-[(Z)- methoxy imino)acetamido]-3-[(2,5-dihydro-2-methyl-5-oxo-6-hydroxy) 1 ,2,4-triazin-3- yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, (ceftriaxone proxetil of Formula Ic)

M^"1" +1: 685 Η-NMR in DMSO-D₆ (δ, ppm): 1.23 (d, 6H), 152 (d, 3H), 3.59 (s, 3H), 3.6-3.8 (q, 2H), 3.82 (s, 3H), 3.99-4.06 (dd, IH) 4.37-4.52 (dd, IH), 4.76-4.82 (m, IH), 5.15-5.20 (m, IH), 5.82-5.86 (m, IH), 6.72 (s, IH), 6.84-6.92 (m, IH), 7.2 (s, 2H), 9.58-9.63 (dd, IH).

IR (KBr) cm-¹: 3324, 1780, 1760, 1653, 1533, 1375.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

We Claim:

Compounds having the structure of Formula I:

FORMULA I

and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, enantiomers, stereoisomers, or diastereomers, wherein R is an alkyl, 1- alkanoyloxyalkyl, 1-alkoxycarbonyloxyalkyl, cycloalkyl, cycloalkyloxy or alkoxy having from one to ten carbon atoms.

The compound according to claim 1, wherein R is selected from the group consisting of acetoxymethyl, propionyloxymethyl n-buryryloxymethyl, iso- valvylbxymethyl, pivaloxyloxymethyl, 1-acetoxyethyl, n-valeroxymethyl, 2-methyl butyryloxymethyl, isovaleroxymethyl, n-hexanoyloxymethyl, 3- methylvaleroxymethyl, neohexanoyloxy-methyl, 2-methylhexanoyloxymethyl, 2,2- dimethylbutyryloxymethyl, 2,2-dimethylpropionyloxymethyl, diethylacetoxymethyl, dipropylacetoxymethyl, 1-propionyl oxyethyl, 1- isobutyryloxyethyl, 1-n-valoryloxyethyl, 1-pivaloxyloxyethyl, 1- pivaloxyloxymethyl, 1-isovaloryloxyethyl, 1-cyclohexanoyloxyethyl, 1- methoxycarbonyl ethoxyethyl, 1-ethoxycarbonyloxyethyl, 1-n-ρropoxycarbonyloxy ethyl, 1-tertbutoxy carbonyloxyethyl, 1-tertbutoxycarbonyloxymethyl, 1- methylethoxycarbonyloxyethyl, 1-pentyloxycarbonyloxy ethyl and 1- cyclohexyloxycarbonyloxyethyl .

3. A compound having the structure of Formula I:

FORMULA I

or a pharmaceutically acceptable salt thereof, wherein R is 1-[1- (cyclohexyloxy)carbonyloxy)ethyl].

4. A compound having the structure of Formula I:

FORMULA I

or a pharmaceutically acceptable salt thereof, wherein R is 2,2,- dimethylpropionyloxymethyl.

A compound having the structure of Formula I:

FORMULA I or a pharmaceutically acceptable salt thereof, wherein R is [1-[1- (methylethoxy)carbonyl)oxy)ethyl].

A process of preparing a compound having the structure of Formula I:

FORMULA I

or a pharmaceutically acceptable salt thereof, wherein R is an alkyl, cycloalkyl, 1- alkanoyloxyalkyl, 1-alkoxycarbonyloxyalkyl, cycloalkyloxy or alkoxy having from one to ten carbon atoms, comprising reacting a compound of Formula II,

FORMULA π

with a compound of Formula III,

0

II

I— CH— O— C— Ri

FORMULA HI

wherein Ri is an alkyl, 1-alkanoyloxyalkyl, 1-alkoxycarbonyloxyalkyl, cycloalkyl, cycloalkyloxy or alkoxy having from one to ten carbon atoms.

7. The process according to claim 6, wherein Rj is selected from the group consisting of acetoxymethyl, propionyloxymethyl n-butyryloxymethyl, iso-valvyloxymethyl, pivaloxylmethyl, 1-acetoxyethyl, n-valeroxymethyl, 2-methyl butyryloxymethyl, isovaleroxymethyl, n-hexanoyloxymethyl, 3-methylvaleroxymethyl, neohexanoyloxy-methyl, 2-methylhexanoyloxymethyl, 2,2- dimethylbutyryloxymethyl, 2,2-dimethylpropionyloxymethyl, diethylacetoxymethyl, dipropylacetoxymethyl, 1-propionyl oxyethyl, 1- isobutyryl oxyethyl, 1-n-valoryloxyethyl, 1-pivaloxyloxyethyl, 1- pivaloxyloxymethyl, 1-isovaloryloxyethyl, 1-cyclohexanoyloxyethyl, 1- methoxycarbonyl ethoxyethyl, 1-ethoxycarbonyloxyethyl, 1-n- propoxycarbonyloxy ethyl, 1-tertbutoxy carbonyloxyethyl, 1- tertbutoxycarbonyloxymethyl, 1-methylethoxycarbonyloxyethyl, 1- pentyloxycarbonyloxy ethyl and 1-cyclohexyloxycarbonyloxyethyl.

8. The process according to claim 6, wherein the compound of Formula II reacts with a compound of Formula III in the presence of an organic solvent.

9. The process according to claim 8, wherein the organic solvent is selected from the group consisting of tetrahydrofuran, N,N-dimethylacetamide, N,N- dimethylfoπnamide, dioxane, dimethoxyethane, methylene chloride, acetone, ethyl acetate, or mixtures thereof.

10. The process according to claim 6, wherein the reaction is caπied out in the presence of a base.

11. The process according to claim 10, wherein the base is selected from the group consisting of diisopropylethylamine, diphenylamine, N-tert-butylcyclohexylamine, hexamethyldisilazide, l,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo [5.4.0]undec-7-ene, or mixtures thereof.

2. A process of preparing a compound having the structure of Formula I:

FORMULA I

or a pharmaceutically acceptable salt thereof, wherein R is 1-[1- (cyclohexyloxy)carbonyloxy)ethyl], comprising reacting a compound of formula II,

FORMULA IE

with a compound of Formula III,

0 I— CH— O— C— Rj

FORMULA III

wherein Ri is l-[l-(cyclohexyloxy)carbonyloxy)ethyl].

3. A process of preparing a compound having the structure of Formula I:

FORMULA I

or a pharmaceutically acceptable salt thereof, wherein R is 2,2,- dimethylpropionyloxymethyl, comprising reacting a compound of fonmύa II,

FORMULA II

with a compound of Formula III,

O

II I— CH— O— C— R_j

ORMULA rπ

wherein Ri is 2,2,-dimethylpropionyloxymethyl.

14. A process of preparing a compound having the structure of Formula I:

FORMULA I

or a pharmaceutically acceptable salt thereof, wherein R is [1-[1- (methylethoxy)carbonyl)oxy)ethyl], comprising reacting a compound of formula II,

FORMULA H

with a compound of Foπnula III,

O

II I— CH— O— C— R₂

FORMULA m

wherein Ri is [ 1 - [ 1 -(methylethoxy)carbonyl)oxy)ethyl] .

15. A phamiaceutical composition comprising the compound of claim 1, 3, 4 or 5 optionally together with pharmaceutically acceptable carriers, excipients or diluents.

16. A pharmaceutically acceptable composition comprising a pharmaceutically acceptable effective amount of a compound according to claim 1 , 3, 4 or 5, or a phaπnaceutically acceptable salt thereof with a pharmaceutically acceptable caixier for treating bacterial infections.

17. A method of treating bacterial infections in a mammal comprising administering to said mammal, a therapeutically effective amount of a compound of Fonnula I

FORMULA I

wherein R is selected from an alkyl, 1-alkanoyloxyalkyl, 1- alkoxycarbonyloxyalkyl, cycloalkyl, cycloalkyloxy or alkoxy having from one to ten carbon atoms or a pharmaceutically acceptable salt thereof.