ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Volume 32, Number 2, issued February 1988, DOERN et al., "National Collaborative Study of the Prevalence of Antimicrobial Resistance Among Clinical Isolates of Haemophilus Influenzae", pages 180-185.
THE JOURNAL OF INFECTIOUS DISEASES, Volume 170, Number 1, issued 1994, HUGHES et al., "Relative Potency of 10 Drugs With Anti-Pneumocyctis Carinii Activity in an Animal Model", pages 906-911.
M. WINDHOLZ et al., "The Merck Index, an Encyclopedia of Chemicals, Drugs and Biologicals, Tenth Edition", Published 1983, by MERCK & CO., INC. (N.J.), page 16, Number 104.
| 1. | A pharmaceutical composition of an er thromycin derivative combined with acetylsulfisoxazole according to the structural formulas: where R is hydrogen; CICIO alkylcarbonyl, or substituted CICIO alkyl wherein said substituent is amino or cyano; RI and R. |
| 2. | are independently hydrogen, hydroxyl or amino; and the pharmaceutical salts and esters thereof. |
| 3. | 2 A pharmaceutical composition of a erythromycin derivative combined with acetylsulfisoxazole according to the structural formula: x / *•• and the pharmaceutically acceptable salts, esters and metal complexes thereof, wherein Rl is hydrogen, CICIO alkylcarbonyl or unsubstituted or substituted Cl C 10 alkyl [where] wherein said substituent is amino or cyano; R2 and RJ are hydrogen; R2 and R3 together are oxo; R4 is hydrogen or CICIO alkylcarbonyl; R' and R* are independently hydrogen, hydroxy or amino; R1 and R* together are oxo or oximino; R' and R1 are independently hydrogen, CICIO alkyl or phenylsulfonyl; R* is hydrogen, or CICIO alkylcarbony, R10 is hydrogen, and R" is hydrogen or acetyl. |
| 4. | The composition as claimed in claim 1 , wherein the erythromycin derivative has the structural formula: wherein R is methyl, R1 is H and R2 is OH. |
| 5. | The composition as claimed in claim 1 , wherein the erythromycin derivative has the structural formula: wherein R is amino alkyl carbonyi, R1 is H and Rz is OH. |
| 6. | The composition as claimed in claim 1 , wherein the erythromycin derivative has the structural formula: wherein R is cyano, R1 is an amino group, and R2 is H. AMENDED CLAIMS [received by the International Bureau on 12 August 1997 ( 12.08.97) ; original claims 1 5 replaced by amended claims 1 5 (3 pages) ] 1 A pharmaceutical composition of an erythromycin derivative combined with acetylsulfisoxazole according to the structural formulas: where R is hydrogen; C|Cιo alkylcarbonyl, or substituted dCio alkyl wherein said substituent is amino or cyano; R1 and R2 are independently hydrogen, hydroxyl or amino; and the pharmaceutical salts and esters thereof. |
| 7. | 2 A pharmaceutical composition of a erythromycin derivative combined with acetylsulfisoxazole according to the structural formula: and the pharmaceutically acceptable salts, esters and metal complexes thereof, wherein R1 is hydrogen, CiCio alkylcarbonyl or unsubstituted or substituted. CιC)0 alkyl [where] wherein said substituent is amino or cyano; R2 and R3 are hydrogen; R2 and R3 together are oxo; R4 is hydrogen or C Cιo alkylcarbonyl; R5 and R6 are independently hydrogen, hydroxy or amino; R5 and R6 together are oxo or oximino: R7 and R8 are independently hydrogen. CpCio alkyl or phenylsulfonyl; R9 is hydrogen, or CιCι0alkylcarbonyl, R10 is hydrogen, and Ru is hydrogen or acetyl. |
| 8. | 3 The composition as claimed in claim 1, wherein the erythromycin derivative has the structural formula: wherein R is methyl, R1 is H and R2 is OH. |
| 9. | 4 The composition as claimed in claim 1, wherein the erythromycin derivative has the structural formula: wherein R is amino alkyl carbonyi, R is H and R is OH 5 The composition as claimed in claim 1, wherein the er thromycin derivative has the structural formula: wherein R is cyano, R is an amino group, and R is H. |
Of
CHRIS PLATT
For
UNITED STATES LETTERS PATENT
On
-Aza-9-Dcoxo-l 1-Deσxy-Eιythromycin A and Derivβtives Combined with Suifisoxazole
TITLE: lO-Aza-9-Dcoxo-l 1-Deoxy-Erythromycin A and Derivatives Combined with Suifisoxazole
BACKGROUND OF THE INVENTION
Field Of The Invention
The present invention relates to a novel group of chemical compounds providing antibacterial activity, and which are useful in the therapy of bacterial infections in mammals. More specifically, the invention relates to compositions including the derivatives of the welUknown antibiotic, erythromycin A.
Description of Related Art
The related art includes:
Tarpay et at, Antimicrobial Agents and Chemotherapy, Vol.22, No. I, pages 145*147 (1982). Hughes et al., J. of Infectious Diseases, Vol. 170, No. 1 , pages 906-911, (1 94). Doem et al., Antimicrobial Agents and Chemotherapy, Vol.32, No.2, pages 180-185 (1 88). U. S. Patents:
4,328,334 to Korbrehel et al 4,464,527 to Bright et al
4,465,674 to Bright et al 4,492,688 to Bright et al
4,512,982 to Hanske et al 4,517,359 to Kobrehel et al
4,526,889 to Bright et al 4,518,590 to Hanske et at
4,886,792 to Djokie 4,957,905 to Hunt et al
SUMMARY OF THE INVENTION
The erythromycin derivatives act by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfere with microbial protein synthesis. Nucleic acid synthesis is not afrected. The suifisoxazole inhibits bacterial synthesis of dihydrofolic acid by preventing the
97/
condensation of the ptcndine with para-aminobenzoic acid through competitive inhibition of the enzyme dihydopteroate synthetase. After absorption the erythromycin derivative is largely bound to plasma proteins and readily diffuses into most body fluids. Rapid distribution of erythromycin derivative into tissues and high concentration within cells results in higher concentrations in tissues than in serum or plasma. Erythromycin derivative seems to concentrate in fibroblasts and phagocytes as demonstrated by in vivo incubation techniques. Such derivatives are modifications of the well-known antibiotic, erythromycin A, having the following structure:
The erythromycin derivatives of the present invention relate to the compounds of the following structure and derivatives thereof, which form a novel class of 14-mcmbcred azalides characterized in that the heterocyclic nitrogen atom is situated at the 10 position. The inventive step in the present invention is that these compounds are combined with suifisoxazole for enhanced antibacterial activity. The present invention provides for novel pharmaceutical compositions and methods for their use as antibacterial agents.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
An important challenge in regards to antibiotics, is how to avoid the problem of pathological resistance to these medications. By combining two different antibiotics, each having different mechanisms of action, but which work synergistically together this problem can be overcome. The present invention stems from the discovery that certain erythromycin derivatives are easily
tolerated by patients without causing gastrointestinal disturbances. Additionally when combined with suifisoxazole, resistance to Entcrococcus Faecalis, mcthacillin-resistant stapylococci, and erythromycin resistant gram-positive strains is achieved. The inventive combination provides protection from a greater antibacterial spectrum then either erythromycin or suifisoxazole alone. Thus, this new invention not only saves lives by providing a combination that overcomes medication resistance but is more easily tolerated without stomach upset and vomiting; side effects experienced by many people taking erythromycin alone.
Specifically the basis for the present invention is the pharmaceutical composition of an erythromycin derivative combined with acetylsulfisoxazole according to the structural formulas shown in Claim 1 below, where R is hydrogen; CI-CIO alkylcarbonyl, or substituted CT-C10 alkyl wherein said substituent is amino or cyano; and Rt and R2 are independently hydrogen, hydroxyl or amino; and including the pharmaceutical salts and esters thereof. Chemically acetylsulfisoxazole is N-(3,4,-Dimetly-5-isoxazole)-N-sulfanylactamide. Suifisoxazole, where the acetyl group is replaced by H is an alternative substitution in the invention. Alternative possibilities for the erythromycin derivative include, but are not limited to, the structural formulas as shown in either Claim 3 where R is methyl, R' is H and R\ in Claim 5 where R is ammino alkyl carbonyi, R 1 is H and R* is OH, and in Claim 6 where R is cyano, R' is an ammino group, and R 1 is H.
In an alternate embodiment, the composition of the present invention may be formulated wherein the erythromycin derivative has the general structural formula as shown below in Claim 2, including the pharmaceutically acceptable salts, esters and metal complexes thereof, wherein R' is hydrogen, Cl -Cl 0 alkyl carbonyi or unsubstituted or substituted Cl -CIO alkyl wherein the substituent is amino or cyano; R* and R 3 are hydrogen; R 1 and R 1 together are oxo; R* is hydrogen or Cl -CIO alkylcarbonyl; R 5 and R' arc independently hydrogen, hydroxy or amino; R 5 and R' together are oxo or oximino; R 7 and R* are independently hydrogen, CI-CIO alkyl or phenylsulfonyl; R* Is hydrogen, or C1-C10 alkylcαrbony, and R" is hydrogen. Examples of operable substitutions for the nine variables include the following:
E El El Bl El Bl Bl Bl Bl
CH3 H H H M OH H H H
In formulating the combination of the present invention it has been found that the mixture ratio by weight, of erythromycin to suifisoxazole, may range from 100:1 to as much as 1 :1, and even trace amounts of suifisoxazole may be operative. The preferred ratio is 100:38. The erythromycin and suifisoxazole are prepared following standard laboratory procedures and processes that all competent workers in the field of the present invention will know.
The various alternative formulations of the present invention may take the form of a compressed pill, a powder in an easy to swatlow caplet, or even as a fluid dissolved in a liquid such as water. In all cases, the formulation is to be taken orally.