AU625559B2 - Pharmaceutical combination preparations and their use for the prophylaxis or treatment of bacterial infectious diseases - Google Patents

Description

Form COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

6255 59 Class Int. Class Application Number: Lodged: domplete Specification Lodged: o #s 6 w 6 o a *Related Art: ao Accepted: Published: a Q Name of Applicant: 4 0 "Adress of Applicant: Astual Inventor: a 4 4 e44 4 te Address for Service: HOECHST AKTIENGESELLSCHAFT 50 Bruningstrasse, D-6230 Frankfurt/Main 80, Federal Republic of Germany GERHARD SEIBERT, DIETER ISERT and NORBERT KLESEL -gg--QWSfta -:Watermark Patent Trademark Attorneys 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: PHARMACEUTICAL COMBINATION PREPARATIONS AND THEIR USE FOR THE PROPHYLAXIS OR TREATMENT OF BACTERIAL INFECTIOUS DISEASES The following statement is a full description of this invention, including the best method of performing it known to 1.

1IIr HOECHST AKTIENGESELLSCHAFT HOE 89/F 092 Dr.WN/rh Description Pharmaceutical combination preparations and their use for the prophylaxis or treatment of bacterial infectious diseases The present invention relates to pharmaceutical combination preparations and their use for the prophylaxis or treatment of bacterial infectious diseases.

It is known that antibiotics of the cephalosporin class, such as, for example, cefpirome, are outstandingly suitable for the therapy of bacterial infections, but that the antibacterial activity against certain gramwa eQ positive and gram-negative microorganisms, in particular So staphylococcus species, may not be sufficient. Infections with staphylococci, which show resistance to methicillin O, (MRSA, MRSE), usually do not come under the indication for cephalosporins. Antibiotics of the glycopeptide group, for example vancomycin, have an antibacterial activity which kills many staphylococci strains against which cephalosporins have little effect.

a 0 It has now been found that cephalosporin derivatives in I combination with the glycopeptide antibiotic decaplanin have a surprisingly clear synergistic effect against methicillin-resistant staphylococci. Synergistic effects of a-lactam antibiotics containing other glycopeptides, such as, for example, vancomycin, are described in H.

Portier et al., Infection 13/1 (1985) 123-128. Surprisingly, however, the synergistic effect of cephalosporin derivatives containing decaplanin against methicillinresistant staphylococci is very much stronger than can be found with vancomycin. It may additionally be found with all strains, whereas, for example, vancomycin and cefpirome only show this effect with some staphylococci strains.

2 The present invention therefore relates to a pharmaceutical combination preparation containing decaplanin, a compound of the formula A 4 44 tar o* 00 o o o 4 00 0 0 0 4 4 o aa 0 04 0 4' 0 0 0440 0440 0044

NHCH

Be

CH

1 2 CH(CH.i3) 2

V

0 41 0 I 4 or its physiologically tolerable salts and a cephalosporin derivative or its physiologically tolerable salts or esters.

Decaplanin is produced by culturing the microorganism Y 8636 910 (deposited in the German collection of microorganisms on the 5th August 1988, under the number DSM 4763), the decaplanin being isolated by known methods (European Patent Application 88 114 022.2).

The properties of decaplanin are described in European Patent Application 88 114 022.2. The production and the properties of cephalosporin derivatives are described, for example, in German Offenlegungsschriften 2,702,501, 3 2,713,272, 2,715,385, 2,810,922, 2,921,316, 2,922,036, in EP 0,064,740, in U.S. 4,278,793 or U.S. 4,501,739, in GB 2,105,334 or GB 2,105,335. The preferred physiologically tolerable salts and esters are also listed in the publications mentioned.

Preferred cephalosporin derivatives are those of the formula I H H

H

2 N--L C CONH S2N N-OR R 2 2o 2 So in which A denotes CH or N and aB** R 1 can have the meaning hydrogen, Cl-C 4 -alkyl, carboxy-

C

1

-C

4 -alkyl or a group of the formula

OH

COOH

and in which the group =N-OR 1 is in the syn-position,

R

2 can have the meaning hydrogen, methyl, methoxy, vinyl, acetoxymethyl, carbamoyloxymethyl, CH O CH N CH -N -CH(+l CONH 2 a or -CH 2

S-X,

2 or_ 2H -F I 7 -4 with X IN i H 3 CHl 3

-U

N- N Ii I I C"3 N-N Ocr CH -0 -N0e3 E 3C i:0 o o 00 0 0~* 00 00 0 0 *40 0 0 0 0 ~0~C 0 o 0'00 0000 0

WOO

Von

-C

Vn-H2 with Y hydrogen,

C

1

C

4 alkyithia,

C

1

-C

4 -alkoxy or

C

3

C

5 -cycloalkyl, 040~ 0 00 00 0 0 00 00 4 0 ~I 0£ i 0 O Von' where the fused rings may also be in the 3,4-position and may also be interrupted by oxygen,

-CH

2

S

-CH 2 J1

V

i T 5 5 thienopyridinio-methyl, furopyridinio-methyl or tetrazol-2-yl-methyl and R3 can stand for hydrogen, a physiologically tolerable cation, a physiologically tolerable ester radical or if the structure -CH 2 occurs in R2 for a negative charge.

In the formula I, A preferably denotes CH.

If R1 stands for Cl-C4-alkyl, suitable examples are methyl, ethyl or propyl, preferably methyl.

If R 1 stands for carboxy-C 1

-C

4 -alkyl, for example carboxymethyl, carboxyethyl or carboxypropyl, preferably the °o radical -CH 2 -COOH, but in particular the radical 0 o .e .C CH3 -C COOH 000 o oo CH 3 eoo are of interest.

Of the substituted pyridiniummethyl radicals listed oo above, 2,3-cyclopenteno- and methyl are preferred, as well as 4-methylthio-, 4-cyclopropyl- and 3-methoxy-pyridinium-methyl, and also 3,4cyclopenteno- and 3,4-cyclohexeno-pyridinium-methyl.

According to the invention, those compounds of the formula I are of very particular interest in which R1 stands for methyl and R2 for -CH 2

-OCOCH

3 (cefotaxime), *W C C (S COH (cefodizime),

H

3

C

N-N

-CH

2 S -N OH (ceftriaxone), if -6-

N-N

-CH SNc! C 3 (cefmenoxime) or _-CH (cefpirome), or -CH2-

R

1 stands for -CH 2 COOH and R2 for -CH=CH 2 (cefixime), cefodizime, cefpirome, cefotaxime, ceftriaxone again assuming a preferential position within this group.

If R2 stands for a -CH 2 -pyridinium compound, the carboxyl group is present in the general formula I as the anion of an internal salt 0

*R

3 can stand for hydrogen or a physiologically tolerable cation, such as, for example, ,an alkali metal cation, preferably potassium or sodium, in particular sodium, or else other physiologically tolerable cations known from the literature such as, for example, alkaline earth metal or organic ammonium ions for example, U.S.

4,278,793).

R

3 can furthermore stand for a physiologically tolerable ester radical, particularly interesting for enteral administration, such as, for example, for an acyloxymethyl or acyloxyethyl radical having 2 to 12, preferably 2 to 6 carbon atoms in the acyl moiety, preferably acetoxymethyl, l'-(acetoxy)ethyl or pivaloyloxymethyl, for 5-methyl-l,3-dioxalen-2-on-4-yl-methyl, or else for other, physiologically tolerable ester radicals, such as are described, for example, in EP-A 0,170,028.

9 it 7 -7- Particularly interesting cephalosporin derivatives which may be further mentioned under the aminothiazole cephalosporins which contain -H instead of are d cefotiam and, under the N-acyl-phenylglycine cephalosporins, cefoperazone for example, EP- 0,248,361).

Further examples for cephalosporin derivatives which are preferred according to the instant invention, are selected from the group of the following compounds: Cequinome, a compound of the formula H2 S 0 CCH2-N C .H2S04 t H5 oo c-c Cefuroxime, a compound of the formula

C

c c C C S C-CO--NH--C-C C N C-N C 0 0 C CH2-O-CO-NH2 CH3 COGHM Ceftizoxime, a compound of the formula N-OCH3 S HW-C-C-CNR-C-~C C MN S 0 C

COONA

T.1 T and Ceftazidime, a compound of the formula 0 S

C

C C N C-N C C=C e9 e H2N S 0 0 C CH2-N C I I *\I H3C-C-CH3 t-OOH C-C Further particularly preferred cephalosporin derivatives are selected from the group of the following compounds: 00 Cefepime, a compound of the formula 00 00 00 0 .0 0 N 0 H0 N H S 0000 0 0 NH S 7-(-aiothaol4y)-2hoymnoaetmd]--4 060 000. (oxazol- 5- yl) -pyrimidiniomethyl 1-8- oxo- 5- thia- 1azabicyclo- [4.2.Oloct-2-ene-2-carboxylate, a compound of Ce'the formula H H I I S HN N C CCONH H2 i 00 (6R,7R)-7-[(2-amino-thiazol-4-yl)-((Z)-(S)-m-carboxy-3,4dihydroxy-berizyloxyimino)-acetamido]-3- triazolo -pyrimidin- 7- yl )-thiomethyl 1-8oxo-5-thia-1-azabicyclo[4.2.O]oct-2-ene-2-carboxylic acid, 9a compound of the formula H2

COON

CH

3

COOH

00 .4 0 4 0044 and (6R,7R)-7-[(5-amino-l,2,4-thiadiazol-3-yl)-(Z)-methoxyimino-acetamido]-3- [4-carbamoyl-l-quinuclidiniomethyl]- 8-oxo-5-thia--l-azabicyclo[4.2.Ojoct-2-ene-2-carboxylate, a compound of the formula N ,,DH3 *0 0 t 09 R2N ONH 2 CO2 and their physiologically tolerable salts or esters.

A very particularly preferred cephalosporin derivative is cefpirome, a compound of the formula 0 7- J U. The production of the suitable components of the active compound combination according to the invention is described, for example, in the publications mentioned above.

The combination of cephalosporins and decaplanin according to the invention has a strong antibacterial effect and is therefore particularly well suited to the treatment of bacterial infections. The fact that the effect of the two components does not behave additively, but rather that an unexpected, strongly synergistic effect occurs, is important.

Even with microorganisms, against which a single component alone has no significant antibacterial effect, a 1 synergistic effect is to be observed in combination.

The preparations according to the invention thus register a spectrum of microorganisms at low minimum inhibitory concentrations which are not achieved by the individual components.

4,4 For the reasons mentioned, the combination preparation 4"1 according to the invention is superior to the individual components in the treatment of bacterial infections. It permits lower doses of the individual components to be given and a better outcome of treatment to be attained nonetheless.

Moreover, the combination preparation according to the invention is superior to other antibacterial combination preparations, such as, for example, the combination cefpirome/vancomycin (cf. Example 1).

The invention also relates to a process for the production of a pharmaceutical combination preparation, which comprises bringing

_V

a) a cephalosporin derivative or its physiologically tolerable salts or esters and b) decaplanin or its physiologically tolerable salts into a suitable form for administration, together with the acceptable excipients and, if appropriate, further auxiliaries and additives.

Thus, for example, injectable solutions, preferably isotonic aqueous solutions or suspensions which may be sterilized and auxiliaries, such as preservatives, stabilizers, wetting agents and/or emulsifiers, solubili- .0o zers, salts for regulating the osmotic pressure and/or buffer substances may be contained. The pharmaceutical combination preparations according to the invention S.which, if desired, may contain further chemotherapeutically useful substances, are prepared, for example, by ~means of conventional methods.

The combination preparations according to the invention are administered, for example, enterally or parenterally, parenteral administration being preferred.

For parenteral administration, the combination preparation according to the invention may be dissolved preferably immediately before use in sterile water or if necessary a buffer solution, such as, for example, a phosphate or carbonate buffer, as is customarily used for these purposes, and subsequently administered.

The doses of the cephalosporin derivative and of decaplanin in the preparations according to the invention are preferably selected so that the individual components would still not show a satisfactory or complete effect against methicillin-resistant staphylococci strains. The daily dose of the combination according to the invention (sum of the individual components) is between about 1 to 16 g, preferably about 4 to 8 g. The ratio of the in-

JI

16

,V

12 dividual components in the combination can be between about 1:9 and 9:1, preferably between about 1:5 and 5:1.

The dose in one administration unit can be selected, for example, between about 50 and 2000 mg.

However, it may be necessary to depart from the dosages mentioned depending on the type and the body weight of the human to be treated, the nature and the severity of v the disorder, the type of the preparation and the administration of the medicament and the period or interval within which administration takes place. Thus, in some cases it may be sufficient to manage with less than the abovementioned amount of active compound, whereas in other cases the abovementioned amount of active compound must be exceeded. The optimum dosage and manner of administration of the active compound required Sin each case may easily be determined by any person skilled in the art on the basis of his expert knowledge.

The following examples serve to illustrate the invention j without limiting it thereto.

Example 1 i jThe antibacterial activity of the combination preparai tions according to the invention was determined for the combination decaplanin cefpirome in the agar dilution I test using MUller-Hinton agar (inoculum size 5 x 104 microorganism-forming units/inoculation point).

i Combination experiments were carried out by the checkerboard method. The "fractional inhibitory concentrations" aA (FIC values) were determined by the method of Berenbaum Berenbaum, J. Infect. Dis. 137, (1978), 122 130).

Definition of Synergism: A combination of 2 substances is usually designated as synergistic if both components together inhibit the test strain at a concentration which is at most 1/4 of the MIC of the component alone (C.W.

A 13- Norden et al., J. Infect. Dis. 140 (1979), 624-633). When using this criterion in the "fractional inhibitory concentrations" (FIC) method, an FIC value of corresponds to synergism. Higher FIC values represent an additive effect.

As Table 1 shows, a combination of cefpirome with decaplanin surprisingly has a synergistic activity for all strains, whereas by means of the combination of cefpirome with vancomycin, 9 of the 19 strains are not synergistically influenced with an FIC value 0.5. The average FIC value for the combination cefpirome/o6 o decaplanin is also substantially lower than for cefpirome/vancomycin.

Table 1 cefpirome/decaplanin cefpirome/vancomycin 16 strains 4 strains 3 strains 6 strains >0.5-0.75 0 strains 8 strains a o o >0.75 0 strains 1 strain de 0 FIC 0.275 0.558 04 t Table 2 shows the FIC values of various cephalosporin derivatives in combination with decaplanin for certain Staphylococcus aureus strains. All preparations show synergistic action.

Table 2 Staphylococcus aureus Preparation 692 E 697 E 706 E 711a E Cefodizime 0.141 0.313 0.25 0.188 Cefquinome 0.25 0.375 0.141 0.375 Ceftazidime 0.156 0.313 0.313 0.156 Cefuroxime 0.188 0.375 0.313 0.141 1 14 H Cefotiam 0.188 0.281 0.25 0.141 Ceftriaxone 0.141 0.375 0.094 0.047 Ceftizoxime 0.25 0.25 0.047 0.062 Cefepime 0.188 0.25 0.188 0.281 E 1040 0.25 0.375 0.188 0.047 DQ 2556 0.25 0.25 0.375 0.313 Cefotaxime 0.188 0.313 0.25 0.125 Cefoperazone 0.188 0.266 0.188 0.078 j FIC (according to Berenbaum) (6R,7R)-7-[(5-amino-1,2,4-thiadiazol-3-yl)-(z)methoxy-imino-acetamido]-3-[4-carbamoyl-1-quinuclidiniomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate o 7-[(2-amino-thiazol-4-yl)-methoxyimino-acetamido]- 3-[4-(oxazol-5-yl)-1-pyridinio-methyl]-8-oxo-5-thioo° 1-azabicyclo[4.2.0]oct-ene-2-carboxylate 0 «4 a o Example 2 It was also possible to show the surprisingly found synergistic effect of a combination of decaplanin and cefpirome using 39 clinical isolates (methicillin- 0 resistant staphylococci), of which most showed a marked resistance to cefpirome (MIC >16 pg/ml). For this purpose, the minimum inhibitory concentration of cefpirome, decaplanin and a mixture of identical amounts of cefpirome and decaplanin was determined in the agar dilution test. As Fig. 1 shows, the antibacterial activity of the mixture is clearly higher than that of either individual components. It follows from Fig. 1 that the minimum inhibitory concentration, in which 90% of the strains are inhibited (MIC90%), customarily used as an assessment criterion, is at its lowest for the mixture of both components at 0.7 jg/ml. (MIC90% for decaplanin: pg/ml, MIC90% for cefpirome: 64 pg/ml).

4T Example 3 U Preparation of a parenteral preparation g of cefpirome and 0.5 g of decaplanin are dissolved in 10 ml of water for injection and subsequently administered.

Claims (5)

1. A pharmaceutical combination preparation containing decaplanin, a compound of the formula A HO OH CH 2 OH 0' r* 09 0040 0 *r 0 00 0 O *D 0 *040 044 HI' o *o 0 00 00 0 ooarr 0 HH CH 1 2 CH(CH 3 2 CH C0NH 2 HO 2 C 0 4 I 4 RO-HOO or its physiologically tolerable salts and a cephalosporin derivative or its physiologically tolerable salts or esters, said decaplanin and said cephalosporin derivative having a synergistic effect when administered sequentially or simultaneously.

2. A pharmaceutical combination preparation as claimed in claim 1, wherein the cephalosporin derivative is a compound of the formula I 0 00 0 0 0. 46; 4 4 4 :ii fC COKE HN;-R2 COOR 3 in which A denotes OH or N and R 1 stands for hydrogen, C-C 4 -alkyl, carboxyl-C 1 -C 4 -alkyl or a group of the formula L I *1 17 and the group =N-OR1 is in the syn-position, R2 can have the meaning hydrogen, methyl, methoxy, vinyl, acetoxymethyl, carbamoyloxymethyl, CH 3O /0 -CH 2-N 0 00 000 *0 0 0 0 0 0.00 0 00 2QH or -CH2S-X, with X COOh H 3 MI 3 T7 %C001i 0 ~k44 0 00 00 0 0 00 o o 0 0* 0 4~I I N-N N -N 0 11 I' X~N o NZ H)C\ 0 '0 with Y hydrogen, Cl- C4alkylthio, Cl-C4-alkoxy or C3- C5- cycloalkyJ. C=R~ V L -18- or -E- where the fused rings may also be in the 3,4-position and may be interrupted by oxygen, ior 2 2 4 t t at..thienopyridinio.-methyl, furopyridinio-methyl or tetrazol-2-yl-methyl and R3 can stand for hydrogen, a physiologically tolerable a .cation, a physiologi cally tolerable ester radical or if the structure -CH 2 occurs in R2- for a negative Ia charge.

3. A pharmaceutical combination preparation as claimed in claim 1 or 2, wherein the cephalosporin derivative is selected from the group comprising the following com- pounds: cefotaxime, cefixime, cefodizime, ceftriaxone, cefmenoxim, cefpirome, cefotiam, cefoperazone, cefepime, cefguinome, cefuroxime, ceftizoxime, ceftazidime, aminothiazol-4-yl)-nethoxyimino-acetamido--3- (oxazol-

5-yl)-l-pyridiniomethyl]-8-oxo-5-thia-l-azabicy- clo[4.2.O)oct-2-ene-2-carboxylate, (6R,7R)-7-[(2-amino-thiazol-4-yl)-((Z).-(S)-a-carboxy-3,4- dihydroxy-benzyloxyimino)-acetamidoj-3-[E(2-carboxy-5- methyl-S-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo- 5-thia-l-azabicyclot4.2.Ojoct-2-ene-2-carboxrlic acid and 3 Q t ;19- (6R,7R)-7-[(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-methoxyi- mino-acetamido]-3-[4-carbamoyl-1-quinuclidiniomethyl]-8- oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate and their physiologically tolerable salts and esters. 4. A pharmaceutical combination preparation as claimed in one of claims 1 3, wherein the cephalosporin deriva- tive is cefpirome, a compound of the formula SN-OCH3 CH 0 coo-. S• 5. A process for the production of a pharmaceutical combination preparation as claimed in one or more of claims 1 4, wherein decaplanin or its physiologically tolerable salts and a cephalosporin derivative or its physiologically tolerable salts or esters are brought into a suitable form for administration, together with physiologically tolerable excipients and, if appropriate, further auxiliaries and/or additives. as aimed in one or more of claims 1 4 for tne prophyl is or treatment of bacterial infectious dis- eases.

7. A pharmace ical combination preparation as claimed in one or more of c ims 1 4 as an agent for the prophylaxis or treatmen of bacterial infectious dis- eases. DATED this 24th day of August 19 HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT ATTORNEYS QUEEN STREET MFET,,'ITTRNE. VTC. 3000. {1 Y- -s i -~r 20 6. The use of a -harmaoutical combinatie- prepafatien- A method of prophylaxis or treatment of bacterial infectious diseases comprising administering to a patient suffering therefrom a pharmaceutical combination preparation as claimed in any one of claims 1 4. 7. A pharmaceutical combination preparation as claimed in one or more of claims 1 4 as an agent for the prophylaxis or treatment of bacterial infectious diseases. DATED this 13th day of March 1992. HOECHST AKTIENGESELLSCHAFT so 0 0 *0 00 0@ *000 *900 0000 b 04 o* 0 04 00 4 C t~ WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRAUA DBM/KJS/CH (DOC.10) AU4023889.WPC 8 j ;'i i