Novel glycopeptide derivatives

SUMMARY OF THE INVENTION
This invention relates to new glycopeptide derivatives of formula (I) which have useful anti-bacterial activity and to methods for preparing these compounds from the glycopeptide antibiotics vancomycin, A51568A, A51568B, M43A and M43D.
This invention also relates to pharmaceutical formulations containing the formula (I) compounds and to methods of using these compounds as antibacterial agents.
DETAILED DESCRIPTION OF THE INVENTION
New, improved antibiotics are continually in demand, particularly for the treatment of human diseases. Increased potency, expanded spectrum of bacterial inhibition, increased in vivo efficacy, and improved pharmaceutical properties (such as greater oral absorption, higher blood or tissue concentrations, longer in vivo half life, and more advantageous rate or route of excretion and rate or pattern of metabolism) are some of the goals for improved antibiotics.
In the search for new antibiotics, structural modification of known antibiotics is attempted whenever possible Many antibiotics, including the glycopeptides, however, have such complex structures that even small changes are difficult to make. Furthermore, it is difficult to predict the effect these changes will make in the desired activity. Processes for modifying known antibiotics and the new active derivatives made by such processes continue, therefore, to be of great importance.
The compounds of the invention are new members of the glycopeptide group of antibiotics. The compounds can be prepared from the known glycopeptides vancomycin (see, for example, U.S. Pat. No. 3,067,099), antibiotic A51568 factor A (see U.S. Pat. No. 4,495,179) and A51568 factor B (see U.S. Pat. No. 4,558,008); antibiotic M43A (see U.S. Pat. No. 4,548,925) and antibiotic M43D (see U.S. Pat. No. 4,547,488).
The compounds of this invention have general formula (I): ##STR1## wherein R is hydrogen or methyl;
n is 1 or 2; and
(i) R.sub.1 is hydrogen or methyl;
R.sub.2 and R.sub.3, independently, are hydrogen or a group of the formula: R.sub.6 R.sub.7 CH--;
R.sub.6 and R.sub.7 are independently R.sub.5, R.sub.5 --(C.sub.1 -C.sub.5 -alkyl) or R.sub.5 --(C.sub.2 -C.sub.5 -alkenyl);
R.sub.5 is hydrogen, C.sub.1 -C.sub.10 -alkyl, C.sub.2 -C.sub.10 -alkenyl, C.sub.1 -C.sub.4 alkoxy, C.sub.3 -C.sub.10 -cycloalkyl, C.sub.5 -C.sub.12 -cycloalkenyl, phenyl, napththyl, indenyl, tetralinyl, decalinyl, adamantyl, a monocyclic heterocyclic ring system comprising 3 to 8 atoms in the ring or a bicyclic heterocyclic ring system comprising 6 to 11 atoms, provided that at least one atom of the ring system is carbon and at least one atom of the ring system is a heteroatom selected from O, N and S, and R.sub.5 may be substituted with one or more hydroxy, nitro, C.sub.1 -C.sub.10 -alkoxy, C.sub.1 -C.sub.10 -alkyl, phenyl, C.sub.1 -C.sub.6 -alkylthio, nitrile, halo, C.sub.2 -C.sub.4 -acylamino, amino, C.sub.1 -C.sub.4 -dialkylamino groups; and R.sub.4 is hydrogen; or
(ii) R.sub.1 and R.sub.2 and/or R.sub.3 and R.sub.4 together form a group of the formula ##STR2## provided that: (1) at least one of R.sub.2 and R.sub.3 must be other than hydrogen; (2) when n is 2, R must be hydrogen; (3) when R is methyl and R.sub.3 is hydrogen, R.sub.2 cannot be methyl and (4) when R and R.sub.1 are both methyl, then R.sub.2 is hydrogen or methyl and n is 1;
and salts of these compounds.
One group of compounds of this invention have formula 1: ##STR3## wherein R is hydrogen or methyl;
R.sub.1 is hydrogen;
R.sub.2 and R.sub.3, independently, are hydrogen, R.sub.5 --(C.sub.1 -C.sub.6)-alkyl or R.sub.5 --(C.sub.2 -C.sub.6 -alkenyl); and R.sub.4 is hydrogen; or
R.sub.1 and R.sub.2 or R.sub.3 and R.sub.4 together form an R.sub.5 --(C.sub.1 -C.sub.6 alkylidenyl) or R.sub.5 --(C.sub.2 -C.sub.6 -alkenylidenyl) group;
R.sub.5 is C.sub.1 -C.sub.10 -alkyl, C.sub.2 -C.sub.10 -alkenyl, C.sub.3 -C.sub.10 -cycloalkyl, C.sub.5 -C.sub.12 -cycloalkenyl, phenyl, napththyl, indenyl, tetralinyl, decalinyl, adamantyl, a monocyclic heterocyclic ring system comprising 3 to 8 atoms in the ring or a bicyclic heterocyclic ring system comprising 6 to 11 atoms, provided that at least one atom of the ring system is carbon and at least one atom of the ring system is a heteroatom selected from O, N and S, and wherein R.sub.5 may be substituted with one or more hydroxy, C.sub.1 -C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkylthio, halo or amino groups; and
n=1 or 2;
provided that: (1) at least one of R.sub.2 and R.sub.3 must be other than hydrogen; and (2) when n is 2, R must be hydrogen;
and the salts of these compounds.
Formula (I) compounds in which R.sub.2 is an R.sub.6 R.sub.7 CH-- group and R.sub.3 is hydrogen are preferred.
A second group of compounds of this invention have formula 2: ##STR4## wherein R.sub.2a is hydrogen or methyl;
R.sub.3a is R.sub.5 --(C.sub.1 -C.sub.6 -alkyl) or R.sub.5 --(C.sub.2 -C.sub.6 -alkenyl); and
R.sub.4a is hydrogen; or
R.sub.3a and R.sub.4a together form an R.sub.5 --(C.sub.1 -C.sub.6 -alkylidenyl) or R.sub.5 --(C.sub.2 -C.sub.6 -alkenylidenyl) group and salts of these compounds.
The compounds of the invention can be prepared by reacting vancomycin, antibiotic A51568 factor A, A51568 factor B, M43A or M43D, which have the following structural formulas
__________________________________________________________________________ ##STR5## ##STR6## ##STR7##Compound R.sub.b R.sub.1b R.sub.2b n__________________________________________________________________________Vancomycin CH.sub.3 H H 1M43A CH.sub.3 CH.sub.3 CH.sub.3 1M43D CH.sub.3 CH.sub.3 H 1A51568A H H H 1A51568B H H H 2__________________________________________________________________________
with a ketone or aldehyde of formula: ##STR8## so as to form alkylidene or alkenylidene derivatives of the invention, optionally followed by reduction so as to form alkyl or alkenyl derivatives.
The reaction with the R.sup.6 R.sup.7 CO compound is preferably carried out at temperatures between 25.degree. and 100.degree. C., preferably from 25.degree. to 70.degree. C., utilizing a polar aprotic solvent such as dimethylformamide.
The reduction of the Schiff's base thus formed can be effected using a chemical reducing agent such as a metal borohydride, for example sodium cyanoborohydride. Once again an aprotic solvent such as dimethylformamide is preferred and the reduction can be effected using temperatures in the range from 25.degree. to 100.degree. C., preferably about 70.degree. C.
It will be appreciated that the sugar groups in the above formulae have the same configuration as do those in vancomycin, i.e., .alpha.-O-vancosaminyl-.beta.-O-glucosyl.
Each R.sub.6 and R.sub.7 group may have from 1 to 15 carbon atoms, and preferably the sum of the carbon atoms in R.sub.6 and R.sub.7 is no greater than 15. Those compounds wherein either R.sub.1 and R.sub.2 or R.sub.3 and R.sub.4 together form an R.sub.5 --(C.sub.1 -C.sub.6 -alkylidenyl) or R.sub.5 --(C.sub.2 -C.sub.6 -alkenylidenyl) group are known as Schiff bases.
The terms "C.sub.1 -C.sub.5 -alkyl", "C.sub.1 -C.sub.6 -alkyl" and "C.sub.1 -C.sub.10 -alkyl" refer to a saturated, straght- or branched-chain alkyl group containing the specified number of carbon atoms. The terms "C.sub.2 -C.sub.5 -alkenyl", "C.sub.2 -C.sub.6 -alkenyl" and "C.sub.2 -C.sub.10 -alkenyl" refer to an unsaturated straight or branched-chain alkenyl group containing the specified number of carbon atoms. Those compounds wherein R.sub.2 or R.sub.3 is R.sub.5 --(C.sub.1 -C.sub.6 -alkyl) or R.sub.5 --(C.sub.2 -C.sub.6 -alkenyl), referred to herein as "reduced Schiff bases", are prepared by reduction of the corresponding compounds wherein either R.sub.1 and R.sub.2 or R.sub.3 and R.sub.4 represent an R.sub.5 --(C.sub.1 -C.sub.6 -alkylidenyl) or R.sub.5 -(C.sub.2 -C.sub.6 -alkenylidenyl) group.
Methoxy, ethoxy and tert-butoxy are typical C.sub.1 -C.sub.6 -alkoxy groups. Methylthio, n-propylthio and isopentylthio are typical C.sub.1 -C.sub.6 -alkylthio groups. Halo substituents are selected from the group consisting of chloro, bromo, fluoro and iodo. Cyclopropyl, cycloheptyl and cyclohexadienyl are examples of C.sub.3 -C.sub.10 -cycloalkyl and C.sub.5 -C.sub.12 -cycloalkenyl groups.
The formula 1 compounds can be prepared from the antibiotics vancomycin, A51568A and A51568B. The formula 2 compounds can be prepared from the antibiotics M43A and M43D.
The compounds of the invention are shown as zwitterions. Those in the art will recognize, however, that each has a carboxyl group, one or two amino groups and three phenolic groups which can react to form various salts. All such forms of the compounds are part of this invention. The salts are useful, for example, for separating and purifying the antiobiotics. In addition, the salts have an improved solubility in water.
The salts are prepared using standard procedures for salt preparation. For example, the zwitterion can be neutralized with an appropriate acid to form an acid addition salt.
The acid addition salts are particularly useful. Representative suitable salts include those salts formed by standard reactions with both organic and inorganic acids such as, for example, sulfuric, hydrochloric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, cholic, pamoic, mucic, D-glutamic, d-camphoric, glutaric, glycolic, phthalic, tartaric, formic, lauric, stearic, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic and like acids.
Pharmaceutically acceptable acid addition salts are an especially preferred group of salts of this invention.
This invention further relates to processes for preparing the compounds of the invention from the glycopeptide antibiotics vancomycin, A51568A, A51568B, M43A and M43D. For convenience in discussing the processes of this invention, the following subgroups are designated:
______________________________________Com-pounds Definition______________________________________1a 1 compounds wherein R.sub.1 and R.sub.2 or R.sub.3 and R.sub.4 together form an R.sub.5 --(C.sub.1 --C.sub.6 --alkylidenyl) or R.sub.5 --(C.sub.2 --C.sub.6 --alkenylidenyl) group1b 1 compounds wherein R.sub.2 or R.sub.3 is R.sub.5 --(C.sub.1 --C.sub.6 --alkyl) or R.sub.5 --(C.sub.2 --C.sub.6 --alkenyl)2a 2 compounds wherein R.sub.3a and R.sub.4a together form an R.sub.5 --(C.sub.1 --C.sub.6 --alkylidenyl) or R.sub.5 --(C.sub.2 --C.sub.6 --alkenyli- denyl) group2b 2 compounds wherein R.sub.3a is R.sub.5 --(C.sub.1 --C.sub.6 --alkyl) or R.sub.5 --(C.sub.2 --C.sub.6 --alkenyl)______________________________________
In one aspect, this invention provides a process for preparing a formula 1a compound which comprises reacting vancomycin, A51568A or A51568B with the corresponding ##STR9## aldehyde or ketone wherein R.sub.6 and R.sub.7 are as defined, supra, preferably, in a polar aprotic solvent until the 1a compound is formed. A preferred temperature range for this process is from about 25.degree. to about 70.degree. C., and a preferred time is from about 3 to about 18 hours.
In a second aspect, this invention provides a process for preparing a formula 1b compound which comprises reacting the corresponding formula 1a compound with a reducing agent to reduce the R.sub.6 R.sub.7 C.dbd.N-- double bond(s) in the 1a compound. A preferred reducing agent for this process is a borohydride such as, for example, sodium cyanoborohydride.
In another aspect, this invention provides a process for preparing a formula 2a compound which comprises reacting M43A or M43D with the corresponding ##STR10## aldehyde or ketone in a polar aprotic solvent unit the 2a compound is formed. A preferred temperature range for this process is from about 25.degree. to about 70.degree. C., and a preferred time is from about 2 to about 18 hours.
In yet another aspect, this invention provides a process for preparing a formula 2b compound which comprises reacting the corresponding formula 2a compound with a reducing agent to reduce the R.sub.6 R.sub.7 C.dbd.N--double bond in the formula 2a compound. A preferred reducing agent for this process is a borohydride such as, for example, sodium cyanoborohydride.
When preparing those formula 1b and 2b compounds wherein the R.sub.2, R.sub.3, or R.sub.3a group contains a --C.dbd.C-- group, the reducing agent used should be one which selectively reduces the R.sub.6 R.sub.7 C.dbd.N-- group only. Sodium borohydride is an example of such a selective reducing agent.
The compounds of this invention are useful antibacterial agents. The formula 1b and 2b compounds are preferred for this purpose.
The formula 1b compounds wherein R.sub.2 is hydrogen and R.sub.3 is an R.sub.5 --(C.sub.1 -C.sub.6 -alkyl) or R.sub.5 --(C.sub.2 -C.sub.6 -alkenyl) group are especially useful. Within this group, those compounds wherein the R.sub.3 moiety contains from eight to twelve carbon atoms are particularly beneficial.
The formula 1b compounds wherein R is methyl, R.sub.2 is hydrogen and R.sub.3 is an R.sub.5 --(C.sub.1 -C.sub.6 -alkyl or R.sub.5 --(C.sub.2 -C.sub.6 -alkenyl) group are more readily and inexpensively prepared since the starting material, vancomycin, is a commercial product.
Another useful group of formula 1b compounds are those wherein R.sub.3 is hydrogen and R.sub.2 is an R.sub.5 --(C.sub.1 -C.sub.6 -alkyl) or R.sub.5 --(C.sub.2 -C.sub.6 -alkenyl) group. Preferred compounds within this group are those wherein the R.sub.2 moiety contains from five to fourteen carbon atoms. Economically preferably compounds within this group are those wherein R is methyl (the compounds prepared from vancomycin).
Yet another group of formula 1b compounds are those wherein R.sub.2 and R.sub.3 are both R.sub.5 --(C.sub.1 -C.sub.6 -alkyl) or R.sub.5 --(C.sub.2 -C.sub.6 -alkenyl) groups. Again, the most preferred compounds of this subgroup are those wherein R is methyl.
Illustrative compounds of this invention are listed in Tables I-IV.
TABLE I______________________________________Illustrative Formula 1b Compounds.sup.aCompoundNo. R R.sub.2 R.sub.3______________________________________ 1 Me H n-dodecyl 2 Me H n-decyl 3 Me n-decyl H 4 Me n-decyl n-decyl 5 Me H n-nonyl 6 Me n-nonyl n-nonyl 7 Me H n-octyl 8 Me n-octyl H 9 Me n-octyl n-octyl10 Me H n-heptyl11 Me n-heptyl H12 Me n-heptyl n-heptyl13 Me H n-hexyl14 Me n-hexyl H15 Me H n-pentyl16 Me n-pentyl H17 Me H n-butyl18 Me n-butyl H19 Me n-butyl n-butyl20 Me H n-propyl21 Me n-propyl H22 Me n-propyl n-propyl23 Me Et H24 Me Et Et25 H n-decyl H26 H H n-decyl27 H isooctyl H28 Me Me Me29 Me isopropyl isopropyl30 Me H isopropyl31 Me H 5-hydroxy-n-pentyl32 Me 5-hydroxy-n-pentyl H33 Me " 5-hydroxy-n-pentyl34 Me H 6-bromo-n-hexyl35 Me 6-bromo-n-hexyl H36 Me H 3-ethoxy-n-propyl37 Me 3-ethoxy-n-propyl H38 Me 3-ethoxy-n-propyl 3-ethoxy-n-propyl39 Me H benzyl40 Me benzyl H41 Me benzyl benzyl42 H H benzyl43 Me H 3-phenyl-n-(prop-2-enyl)44 Me 3-phenyl-n- H (prop-2-enyl)45 Me H 3-phenyl-n-propyl46 Me H (pyrid-3-yl)methyl47 Me (pyrid-2-yl)methyl H48 Me H (2-amino-thiazol- 4-yl)ethyl49 H H phenethyl50 Me H (indol-3-yl)methyl51 Me H (adamant-1-yl)methyl52 Me H n-undecyl53 Me H 3-(methylthio)-n-propyl54 Me 3-(methylthio)- H n-propyl______________________________________ .sup.a In these compounds, n = 1 and R.sub.4 = H
TABLE II______________________________________Illustrative Formula 1a Compounds whereinR.sub.1 --R.sub.2 = Alkylidenyl or Alkenylidenyl.sup.aCompoundNo. R R.sub.1 --R.sub.2 Group______________________________________55 Me n-decylidenyl56 Me n-nonylidenyl57 Me n-octylidenyl58 Me n-heptylidenyl59 Me n-hexylidenyl60 Me n-pentylidenyl61 Me n-butylidenyl62 Me n-propylidenyl63 Me ethylidenyl64 H n-decylidenyl65 Me isopropylidenyl66 Me 5-hydroxy-n-pentylidenyl67 Me 6-bromo-n-hexylidenyl68 Me 3-ethoxy-n-propylidenyl69 Me benzylidenyl70 Me 3-phenyl-n-(prop-2-enylidenyl)71 Me 3-phenyl-n-propylidenyl72 Me (pyrid-4-yl)methylidenyl73 Me (2-amino-thiazol-4-yl)ethylidenyl74 Me phenethylidenyl75 Me (indol-3-yl)methylidenyl76 Me (adamant-1-yl)methylidenyl77 Me 3-(methylthio)-n-propylidenyl78 Me n-undecylidenyl______________________________________ .sup.a In these compounds, n = 1 and R.sub.3 and R.sub.4 = H
TABLE III______________________________________Illustrative Formula 1a Compounds wherein R.sub.1 --R.sub.2and R.sub.3 --R.sub.4 = Alkylidenyl or Alkenylidenyl.sup.aCmpd.No. R R.sub.1 --R.sub.2 Group R.sub.3 --R.sub.4 Group______________________________________79 Me n-decylidenyl n-decylidenyl80 Me n-nonylidenyl n-nonylidenyl81 Me n-octylidenyl n-octylidenyl82 Me n-heptylidenyl n-heptylidenyl83 Me n-butylidenyl n-butylidenyl84 Me n-propylidenyl n-propylidenyl85 Me ethylidenyl ethylidenyl86 H n-decylidenyl n-decylidenyl87 Me isopropylidenyl isopropylidenyl88 Me 5-hydroxy-n- 5-hydroxy-n- pentylidenyl pentylidenyl89 Me 6-bromo-n- 6-bromo-n- hexylidenyl hexylidenyl90 Me 3-ethoxy-n- 3-ethoxy-n- propylidenyl propylidenyl91 Me benzylidenyl benzylidenyl92 Me 3-phenyl-n-(prop- 3-phenyl-n-(prop- 2-enylidenyl) 2-enylidenyl)93 Me 3-phenyl-n- 3-phenyl-n- propylidenyl propylidenyl94 Me (pyrid-4-yl)- (pyrid-4-yl)- methylidenyl methylidenyl95 Me (2-aminothiazol-4- (2-aminothiazol-4- yl)ethylidenyl yl)ethylidenyl96 Me phenethylidenyl phenethylidenyl97 Me (indol-3-yl)- (indol-3-yl)- methylidenyl methylidenyl98 Me (adamant-1-yl)- (adamant-1-yl)- methylidenyl methylidenyl______________________________________ .sup.a In these compounds, n = 1
TABLE IV______________________________________Illustrative Formula 1a Compounds whereinR.sub.3 and R.sub.4 = Alkylidenyl or Alkenylidenyl.sup.aCompoundNo. R R.sub.3 --R.sub.4 Group______________________________________ 99 Me n-dodecylidenyl100 Me n-decylidenyl101 Me n-nonylidenyl102 Me n-octylidenyl103 Me n-heptylidenyl104 Me n-hexylidenyl105 Me n-pentylidenyl106 Me n-butylidenyl107 Me n-propylidenyl108 Me ethylidenyl109 H n-decylidenyl110 Me isopentylidenyl111 Me 5-hydroxy-n-pentylidenyl112 Me 6-bromo-n-hexylidenyl113 Me 3-ethoxy-n-propylidenyl114 Me benzylidenyl115 Me 3-phenyl-n-(prop-2-enylidenyl)116 Me 3-phenyl-n-propylidenyl117 Me (pyrid-4-yl)methylidenyl118 Me (2-amino-thiazol-4-yl)ethylidenyl119 Me phenethylidenyl120 Me (indol-3-yl)methylidenyl121 Me (adamant-1-yl)methylidenyl122 Me n-undecylidenyl123 Me 3-(methylthio)-n-propylidenyl______________________________________ .sup.a In these compounds, n = 1 and R.sub.2 = H
Illustrative formula 2 compounds of this invention are listed in Tables V and VI.
TABLE V______________________________________Illustrative Formula 2b CompoundsCompoundNo. R.sub.2a R.sub.3a______________________________________124 Me n-decyl125 H n-decyl126 Me n-hexadecyl127 Me isooctyl128 Me n-butyl129 Me benzyl130 Me 5-hydroxypentyl131 Me 3-(methylthio)-n-propyl132 Me 3-phenyl-n-(prop-2-enyl)133 H (pyrid-3-yl)methyl134 Me benzyl______________________________________
TABLE VI______________________________________Illustrative Formula 2a CompoundsCompoundNo. R R.sub.3a --R.sub.4a Group______________________________________135 Me n-decylidenyl136 H n-decylidenyl137 Me n-hexadecylidenyl138 Me isooctylidenyl139 Me n-butylidenyl140 Me benzylidenyl141 Me 5-hydroxy-n-pentylidenyl142 Me 3-(methylthio)-n-propylidenyl143 Me 3-phenyl-n-(prop-2-enylidenyl)144 H (pyrid-3-yl)methylidenyl145 Me benzylidenyl______________________________________
The formula (I) compounds inhibit the growth of a broad spectrum of pathogenic bacteria, especially Gram-positive bacteria. Tables VII and VIII summarize the minimal inhibitory concentrations (MIC's) at which the compounds inhibit certain organisms, as determined by standard agar-dilution assays.
TABLE VII In Vitro Activity of Formula (I) Compounds MIC (mcg/ml) Organism Compound Number.sup.a 1 2 3 4 5 6 7 8 9 10 Staphylococcus aureus NRRL B313 0.25 0.125 0.5 2 0.25 1 0.25 0.5 1 0.25 Staphylococcus aureus V41 0.25 0.25 0.5 4 0.25 1 0.25 0.5 1 0.5 Staphylococcus aureus X400 0.25 0.25 0.5 4 0.25 1 0.25 1 1 0.5 Staphyloco ccus aureus S13E 0.25 0.25 0.5 4 0.25 2 0.25 1 1 0.5 Staphylococcus epidermidis EPI1 0.5 0.25 2 16 0.5 4 1 2 4 2 Staphylococcus epidermidis 222 0.125 0.25 1 4 0.25 2 0.5 1 2 1 Streptococcus pyogenes C203 0.125 0.06 0.5 2 0.125 1 0.125 0.5 0.5 0.5 Streptococcus pneumoniae Park 1 0.25 0.125 0.5 4 0.25 2 0.125 1 1 0.125 Streptococcus faecium ATCC 9790 0.25 0.25 0.5 4 0.25 1 0.25 1 1 0.5 Streptococcus sp. group D 2041 0.125 0.25 1 4 0.5 2 0.5 2 2 1 Haemophilus influenzae C.L. >128 128 128 >128 64 >128 32 128 >128 128 Haemophilus influenzae 76 >128 128 >128 >128 64 >128 32 128 >128 128 Escherichia coli N10 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 Escherichia coli EC14 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 Escherichia coli TEM >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 Klebsiella pneumoniae X26 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 Klebsiella pneumoniae X68 >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 Klebsiella pneumoniae KAE >128 >128 >128 >128 >128 >128 >128 >128 >128 >128 12 13 15 17 19 20 22 24 26 124 Staphylococcus aureus NRRL B313 0.5 0.5 0.5 1 0.5 1 2 1 0.25 0.5 Staphylococcus aureus V41 1 1 1 1 1 1 2 1 0.25 0.5 Staphylococcus aureus X 400 1 1 1 1 1 1 2 2 0.25 0.5 Staphylococcus aureus S13E 1 0.5 1 1 1 1 2 1 0.25 0.5 Staphylococcus epidermidis EPI1 2 2 2 4 2 4 4 2 0.5 1 Staphylococcus epidermidis 222 1 1 1 2 1 1 4 2 0.25 0.5 Staphylococcus pyogenes C203 0.5 0.5 0.5 1 0.5 0.5 2 1 0.25 0.25 Streptococcus pneumonia e Park 1 0.5 0.125 0.125 0.5 0.5 0.5 1 1 0.25 0.5 Streptococcus faecium ATCC 9790 1 1 1 2 1 1 2 2 0.5 0.5 Streptococcus sp. group D 2041 1 1 2 4 2 1 8 4 0.5 0.5 Haemophilus influenzae C.L. >128 128 128 128 >128 128 >128 <128 128 >64 Haemophilus influenzae 76 128 128 128 128 128 128 128 128 128 >64 Escherichia coli N10 >128 >128 >128 >128 >128 >128 >128 >128 >128 >64 Escherichia coli EC14 >128 >128 >128 >128 >128 >128 >128 >128 >128 64 Escherichia coli TEM >128 >128 >128 >128 >128 >128 >128 >128 >128 >64 Klebsiella pneumoniae X26 >128 >128 >128 >128 >128 > 128 >128 >128 >128 >64 Klebsiella pneumoniae X68 >128 >128 >128 >128 >128 >128 >128 >128 >128 >64 Klebsiella pneumoniae KAE >128 >128 >128 >128 >128 >128 >128 >128 >128 >64 .sup.a Compound Numbers from Tables I-V
TABLE VIII__________________________________________________________________________In Vitro Activity of Formula (I) Compounds MIC (mcg/ml) Compound Number.sup.aOrganism 77 80 81 84 93 94 105__________________________________________________________________________Staphylococcus aureus NRRL B313 0.25 0.25 0.06 0.125 0.5 0.25 0.5Staphylococcus aureus V41 0.5 0.5 0.125 0.125 1 0.5 0.5Staphylococcus aureus X400 0.5 0.25 0.125 0.125 1 0.5 0.5Staphylococcus aureus S13E 0.5 0.25 0.06 0.125 0.5 0.5 0.5Staphylococcus epidermidis EPI1 1 1 0.25 0.25 2 1 1Staphylococcus epidermidis 222 0.5 0.5 0.125 0.25 1 0.5 0.5Streptococcus pyogenes C203 0.25 0.25 0.06 0.06 0.25 0.25 0.5Streptococcus pneumoniae Park 1 0.125 0.03 0.06 0.03 0.25 0.25 0.06Streptococcus faecium ATCC 9790 0.5 0.25 0.06 0.125 0.25 0.25 0.5Streptococcus sp. group D 2041 1 1 0.25 0.25 0.5 0.25 2Haemophilus influenzae C.L. 128 64 32 32 >128 >128 64Haemophilus influenzae 76 128 64 32 64 >128 >128 64Escherichia coli N10 >128 >128 >128 >128 >128 >128 >128Escherichia coli EC14 >128 >128 >128 >128 >128 >128 >128Escherichia coli TEM >128 >128 >128 >128 >128 >128 >128Klebsiella pneumoniae X26 >128 >128 >128 >128 >128 >128 >128Klebsiella pneumoniae X68 >128 >128 >128 >128 >128 >128 >128Klebsiella pneumoniae KAE >128 >128 >128 >128 >128 >128 >128__________________________________________________________________________ .sup.a Compound Numbers = Example Numbers
The compounds of this invention have also shown in vivo antimicrobial activity against experimental bacterial infections. When two doses of test compound were administered to mice in experimental infections, the activity observed was measured as an ED.sub.50 value [effective dose in mg/kg to protect 50% of the test animals: see Warren Wick, et al., J. Bacteriol. 81, 233-235 (1961)]. ED.sub.50 values observed are given in Tables IX and X.
TABLE IX______________________________________ED.sub.50 Values for Formula 1 Compounds.sup.a ED.sub.50 (mg/kg/2) Compound Numbers.sup.bOrganism 1 2 3 5 7 8______________________________________Staphylococcus >5 1.8 >5 2.9 3.4 >5aureusStreptococcus 0.31 1.6 4.6 0.56 0.98 3.7pyogenesStreptococcus 0.42 0.51 3.6 0.81 0.44 3.1pneumoniae______________________________________ .sup.a Administered subcutaneously .sup.b Compound numbers from Table I
TABLE X______________________________________ED.sub.50 Values for Formula (I) Compounds.sup.a ED.sub.50 (mg/kg/2) Compound Numbers.sup.bOrganism 77 80 81 84 93 94 105______________________________________Staphylococcus 1.1 1.34 0.74 0.65 0.19 >0.12 0.98aureusStreptococcus 0.8 0.78 1.16 0.69 0.62 0.66 1.18pyogenesStreptococcus 1.2 0.41 1.26 1.14 0.23 0.2 1.25pneumoniae______________________________________ .sup.a Administered subcutaneously .sup.b Compound numbers = Example Numbers
Pharmaceutical formulations of formula (I) and their pharmaceutically acceptable salts are also part of this invention. Thus, a formula (I) compound, preferably as a pharmaceutically acceptable salt, can be formulated for oral or parenteral administration for the therapeutic or prophylactic treatment of bacterial infections. For example, the compound can be admixed with conventional pharmaceutical carriers and excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers and the like. The compositions comprising a formula (I) compound will contain from about 0.1 to about 90% by weight of the active compound, and more generally from about 10 to about 30%. The compositions may contain common carriers and excipients, such as corn starch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid. Disintegrators commonly used in the formulations of this invention include croscarmellose sodium, microcrystalline cellulose, corn starch, sodium starch glycolate and alginic acid. Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose. Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica. Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used. It may be desirable to add a coloring agent to make the dosage form more esthetic in appearance or to help identify the product.
For intravenous (IV) use, a water soluble form of the antibiotic can be dissolved in one of the commonly used intravenous fluids and administered by infusion. Such fluids as, for example, physiological saline, Ringer's solution or 5% dextrose solution can be used.
For intramuscular preparations, a sterile formulation of a suitable soluble salt form of the compound, for example the hydrochloride salt, can be dissolved and administered in a pharmaceutical diluent such as Water-for-Injection, physiological saline or 5% glucose solution. A suitable insoluble form of the compound may be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, e.g. an ester of a long chain fatty acid such as ethyl oleate.
For oral use, a sterile formulation of a suitable salt form of the antibiotic, for example, the hydrochloride salt, formulated in a diluent such as distilled or deionized water, is particularly useful.
Alternatively, the unit dosage form of the antibiotic can be a solution of the antibiotic or preferably a salt thereof in a suitable diluent in sterile, hermetically sealed ampoules. The concentration of the antibiotic in the unit dosage may vary, e.g. from about 1 percent to about 50 percent depending on the particular form of the antibiotic and its solubility and the dose desired by the physician.
In a further aspect, this invention provides a method for treating infectious diseases, especially those caused by Gram-positive microorganisms, in animals. The animal may be either susceptible to, or infected with, the microorganism. The method comprises administering to the animal an amount of a formula (I) compound or its pharmaceutically acceptable salt which is effective for this purpose. In general an effective amount of a formula (I) compound is a dose between about 0.5 and about 100 mg/kg. A preferred dose is from about 10 to about 60 mg/kg of active compound. A typical daily dose for an adult human is from about 250 mg to about 1.0 g.
In practicing this method, the antibiotic can be administered in a single daily dose or in multiple doses per day. The treatment regime may require administration over extended periods of time, e.g., for several days or for from two to three weeks. The amount per administered dose or the total amount administered will depend on such factors as the nature and severity of the infection, the age and general health of the patient, the tolerance of the patient to the antibiotic and the microorganism or microorganisms involved in the infection.
A convenient method of practicing the treatment method is to administer the antibiotic via IV infusion. In this procedure a sterile formulation of a suitable soluble salt of the antibiotic is incorporated in a physiological fluid, such as 5% dextrose solution, and the resulting solution is infused slowly IV. Alternatively, the piggy-back method of IV infusion can also be used.
In another embodiment, this invention relates to methods of increasing feed-utilization efficiency in poultry, swine, sheep and cattle, of promoting growth rates in cattle raised for meat production and of enhancing milk production in lactating ruminants. For increasing feed-utilization efficiency and promoting growth, a formula (I) compound is administered orally in a suitable feed in an amount of from about 2 to about 200 grams per ton of total feed. For beef cattle, for example, a range of about 12 to 3000 mg/head/day is suitable. For enhancing milk production in lactating ruminants, oral administration of a daily amount of from about 0.04 to about 16 mg/kg of body weight (or about 25 to about 5000 mg/ruminant/day) is suggested.

The following examples are provided to illustrate this invention. To simplify discussion, "N.sup.van " is used to indicate the nitrogen on vancosamine and "N.sup.leu " is used to indicate the nitrogen in the leucine group. Reactions were followed by analytical high performance liquid chromatography (HPLC) using a Water's Bondapak C.sub.18 column with a gradient solvent system of CH.sub.3 CN and 0.5% triethylamine (pH 3) buffer and detecting with UV at 254 nm.
EXAMPLES 1-2
Preparation of N.sup.van -(n-Decylidenyl)vancomycin (Compound 100) and N.sup.van -(n-Decyl)vancomycin (Compound 2)
Vancomycin free base (5 g, 3.58 mmoles) was dissolved in dimethylformamide (DMF, 75 ml). n-Decyl aldehyde (0.7 ml, 3.72 mmoles) was added. The reaction mixture was stirred for 2 hours in a 70.degree. C. oil bath to give N.sup.van -(n-decylidenyl)vancomycin (Compound 100).
Sodium cyanoborohydride (275 mg, 4.4 mmoles) was added to the solution containing Compound 100. The reaction mixture was stirred for another 2 hours in the oil bath and then was cooled to room temperature and transferred to a Virtis jar. Celite was added until a thick paste formed. The paste was evaporated under vacuum overnight. The powdery residue obtained was stirred with methanol and filtered three times. The methanol filtrates were combined and evaporated to dryness under vacuum. The residue obtained was triturated with diethyl ether. The insoluble residue was dissolved in methanol and filtered, and the filtrate was evaporated to dryness under vacuum.
This product was purified by reversed-phase high performance liquid chromatography (HPLC), using a Water's Prep Pak/500 column, eluting with an acetonitrile-water gradient system and detecting with UV at 280 nm, to give 793.5 mg of N.sup.van -(n-decyl)vancomycin (Compound 2). The identity of the product was confirmed by fast-atom-bombardment mass spectrometry (FABMS).
EXAMPLES 3-73
The procedure described Examples 1-2 (with the appropriate starting aldehyde) was used to prepare mono-N.sup.van -, mono-N.sup.leu - and di-N.sup.van, N.sup.leu derivatives. In general, the smaller the group to be added, the more complex the crude product and the more difficult the isolation. Generally, the major product is the N.sup.van derivative. When A51568A is the starting antibiotic, however, the major product is the N.sup.leu derivative. Once again the identity of the product was confirmed by fast-atom-bombardment mass spectrometry. The intermediate Schiff's bases were not isolated (ni) but a molecular ion is given in all cases for the reduced alkyl product.
The following compounds were thus prepared:
______________________________________Com-pound Name______________________________________99 N.sup.van --(n-dodecylidenyl)vancomycin (ni) 1 N.sup.van --(n-dodecyl)vancomycin, M.sup.+ = 161579 N.sup.van, N.sup.leu --di(n-decylidenyl)vancomycin (ni) 4 N.sup.van, N.sup.leu --di(n-decyl)vancomycin, M.sup.+ = 172755 N.sup.leu --(n-decylidenyl)vancomycin (ni) 3 N.sup.leu --(n-decyl)vancomycin, M.sup.+ + 1 = 1588101 N.sup.van --(n-nonylidenyl)vancomycin (ni) 5 N.sup.van --(n-nonyl)vancomycin, M.sup.+ = 157380 N.sup.van, N.sup.leu --di(n-nonylidenyl)vancomycin (ni) 6 N.sup.van, N.sup.leu --di(n-nonyl)vancomycin, M.sup.+ = 1700102 N.sup.van --(n-octylidenyl)vancomycin (ni) 7 N.sup.van --(n-octyl)vancomycin, M.sup.+ + 1 = 156081 N.sup.van, N.sup.leu --di(n-octylidenyl)vancomycin (ni) 9 N.sup.van, N.sup.leu --di(n-octyl)vancomycin, M.sup.+ = 167157 N.sup.leu --(n-octylidenyl)vancomycin (ni) 8 N.sup.leu --(n-octyl)vancomycin, M.sup.+ + 1 = 1560103 N.sup.van --(n-heptylidenyl)vancomycin (ni)10 N.sup.van --(n-heptyl)vancomycin, M.sup.+ = 154582 N.sup.van, N.sup.leu --di(n-heptylidenyl)vancomycin (ni)12 N.sup.van, N.sup.leu --di(n-heptyl)vancomycin, M.sup.+ + 1 = 164358 N.sup.leu --(n-heptylidenyl)vancomycin (ni)11 N.sup.leu --(n-heptyl)vancomycin, M.sup.+ = 1545104 N.sup.van --(n-hexylidenyl)vancomycin (ni)13 N.sup.van --(n-hexyl)vancomycin, M.sup.+ = 153159 N.sup.leu --(n-hexylidenyl)vancomycin (ni)14 N.sup.leu --(n-hexyl)vancomycin, M.sup.+ = 1531105 N.sup.van --(n-pentylidenyl)vancomycin (ni)15 N.sup.van --(n-pentyl)vancomycin, M.sup.+ 1 = 151860 N.sup.leu --(n-pentylidenyl)vancomycin (ni)16 N.sup.leu --(n-pentyl)vancomycin, M.sup.+ + 1 = 1727106 N.sup.van --(n-butylidenyl)vancomycin (ni)17 N.sup.van --(n-butyl)vancomycin, M.sup.+ = 150383 N.sup.van, N.sup.leu --di(n-butylidenyl)vancomycin (ni)19 N.sup.van, N.sup.leu --di(n-butyl)vancomycin, M.sup.+ + 1 = 156061 N.sup.leu --(n-butylidenyl)vancomycin (ni)18 N.sup.leu --(n-butyl)vancomycin, M.sup.+ = 1503107 N.sup.van --(n-propylidenyl)vancomycin (ni)20 N.sup.van --(n-propyl)vancomycin, M.sup.+ + 1 = 149084 N.sup.van, N.sup.leu --di(n-propylidenyl)vancomycin (ni)22 N.sup.van, N.sup.leu --di(n-propyl)vancomycin, M.sup.+ + 1 = 153262 N.sup.leu --(n-propylidenyl)vancomycin (ni)21 N.sup.leu --(n-propyl)vancomycin, M.sup.+ + 1 = 149085 N.sup.van, N.sup.leu --di(ethylidenyl)vancomycin (ni)24 N.sup.van, N.sup.leu --diethylvancomycin, M.sup.+ = 150363 N.sup.leu --ethylidenylvancomycin (ni)23 N.sup.leu --ethylvancomycin, M.sup.+ = 147528 N.sup.van, N.sup.leu --dimethylvancomycin (64% pure), M.sup.+ = 147664 N.sup.leu --(n-decylidenyl)-A51568A (ni)25 N.sup.leu --(n-decyl)-A51568A, M.sup.+ = 1573109 N.sup.van --(n-decylidenyl)-A51568A (ni)26 N.sup.van --(n-decyl)-A51568A, M.sup.+ = 1573135 N.sup.van --(n-decylidenyl)-M43A (ni)124 N.sup.van --(n-decyl)-M43A, M.sup.+ + 1 = 1616122 N.sup.van --(n-undecylidenyl)vancomycin (ni)52 N.sup.van --(n-undecyl)vancomycin, M.sup.+ + 1 = 1602113 N.sup.van --(3-ethoxy-n-propylidenyl)vancomycin (ni)36 N.sup.van --(3-ethoxy-n-propyl)vancomycin, M.sup.+ + 1 =153468 N.sup.leu --(3-ethoxy-n-propylidenyl)vancomycin (ni)37 N.sup.leu --(3-ethoxy-n-propyl)vancomycin, M.sup.+ + 1 =153490 N.sup.van,N.sup.leu --di(3-ethoxy-n-propylidenyl)- vancomycin (ni)38 N.sup.van,N.sup.leu --di(3-ethoxy-n-propyl)- vancomycin, M.sup.+ + 1 = 1619111 N.sup.van --(5-hydroxy-n-pentylidenyl)- vancomycin (ni)31 N.sup.van --(5-hydroxy-n-pentyl)vancomycin, M.sup.+ = 153366 N.sup.leu --(5-hydroxy-n-pentylidenyl)- vancomycin (ni)32 N.sup.leu --(5-hydroxy-n-pentyl)vancomycin, M.sup.+ = 153388 N.sup.van,N.sup.leu --di(5-hydroxy-n-pentylidenyl)- vancomycin (ni)33 N.sup.van,N.sup.leu --di(5-hydroxy-n-pentyl)- vancomycin, M.sup.+ = 1619123 N.sup.van --(3-methylthio-n-propylidenyl)- vancomycin (ni)53 N.sup.van --(3-methylthio-n-propyl)vancomycin, M.sup.+ = 153677 N.sup.leu --(3-methylthio-n-propylidenyl)- vancomycin (ni)54 N.sup.leu --(3-methylthio-n-propyl)vancomycin, M.sup.+ = 1536______________________________________
EXAMPLES 74-109
Similarly prepared were the following reduced compounds. Once again, the intemediate Schiff's bases were not isolated.
______________________________________Exam-ple No.______________________________________74 N.sup.van --(cyclohexylmethyl)vancomycin, M.sup.+ = 154375 N.sup.leu --(cyclohexylmethyl)vancomycin, M.sup.+ = 154376 N.sup.van,N.sup.leu --di(cyclohexylmethyl)vancomycin, M.sup.+ = 163977 N.sup.van ( -p-diethylaminobenzyl)vancomycin, M.sup.+ + 1 = 160978 N.sup.van ( -p-isopropylbenzyl)vancomycin, M.sup.+ = 157979 N.sup.van --(benzyl)vancomycin, M.sup.+ = 153880 N.sup.van --( -p-bromobenzyl)vancomycin, M.sup.+ = 161781 N.sup.van --( -p-butylbenzyl)vancomycin, M.sup.+ + 1 = 159482 N.sup.van,N.sup.leu --( -p-butylbenzyl)vancomycin, M.sup.+ + 1 = 174083 N.sup.van,N.sup.leu --( -p-butoxybenzyl)vancomycin, M.sup.+ = 177184 N.sup.van --( -p-butoxybenzyl)vancomycin, M.sup.+ = 160985 N.sup.van --(4-pentylbenzyl)vancomycin, M.sup.+ + 1 = 160886 N.sup.van --(4-pentyloxybenzyl)vancomycin, M.sup.+ + 1 = 162487 N.sup.van --(pyrrol-2-ylmethyl)vancomycin, M.sup.+ + 1 = 152688 N.sup.van --(pyridin-2-ylmethyl)vancomycin, M.sup.+ = 153889 N.sup.van --(furan-2-ylmethyl)vancomycin, (poor spectrum)90 N.sup.van,N.sup.leu --( -p-isopropylbenzyl)vancomycin, M.sup.+ = 171191 N.sup.van --( -p-methylthiobenzyl)vancomycin, M.sup.+ = 158392 N.sup.van,N.sup.leu --( -p-methylthiobenzyl)vancomycin, M.sup.+ = 158393 N.sup.van --( -p-octylbenzyl)vancomycin M.sup.+ + 1 = 165094 N.sup.van --( -p-octyloxybenzyl)vancomycin, M.sup.+ + 1 = 166595 N.sup.van --( -p-methoxybenzyl)vancomycin, M.sup.+ + 1 = 156896 N.sup.van --(6-nitro-3,4-dimethoxybenzyl)vancomycin, M.sup.+ + 1 = 164297 N.sup.leu --(6-nitro-3,4-dimethoxybenzyl)vancomycin, M.sup.+ + 1 = 164298 N.sup.leu --( -p-methoxybenzyl)vancomycin (65% pure), M.sup. + + 1 = 156899 N.sup.van,N.sup.leu --( -p-methoxybenzyl)vancomycin, M.sup.+ + 1 = 1668100 N.sup.van --( .sub.--m-bromobenzyl)vancomycin, M.sup.+ = 1617101 N.sup.van --( -o-bromobenzyl)vancomycin, M.sup.+ = 1617102 N.sup.van --( -p-chlorobenzyl)vancomycin, M.sup.+ = 1572103 N.sup.van --(2,6-dichlorobenzyl)vancomycin, M.sup.+ = 1606104 N.sup.van --( -p-acetamidobenzyl)vancomycin, M.sup.+ = 1595105 N.sup.van --( -p-hydroxybenzyl)vancomycin, M.sup.+ = 1553106 N.sup.leu --( -p-hydroxybenzyl)vancomycin, M.sup.+ = 1553107 N.sup.van,N.sup.leu --( -p-hydroxybenzyl)vancomycin, M.sup.+ = 1659108 N.sup.van --( -p-dimethylaminobenzyl)vancomycin, M.sup.30 + 1 = 1581109 N.sup.van --( -p-cyanobenzyl)vancomycin, M.sup.+ + 1______________________________________ = 1563
EXAMPLES 110-133
Using the procedure described in Examples 1-2 (with the appropriate starting aldehyde or ketone), the following compounds can be prepared:
N.sup.van -(isopropylidenyl)vancomycin
N.sup.van -(isopropyl)vancomycin
N.sup.leu -(isopropylidenyl)vancomycin
N.sup.leu -(isopropyl)vancomycin
N.sup.van,N.sup.leu -di(isopopylidenyl)vancomycin
N.sup.van,N.sup.leu -di(isopropyl)vancomycin
N.sup.van,N.sup.leu -di(n-decylidenyl)-A51568A
N.sup.van,N.sup.leu -di(n-decyl)-A51568A
N.sup.van -(isooctylidenyl)-A51568A
N.sup.van -(isooctyl)-A51568A
N.sup.van -(n-decylidenyl)-A51568B
N.sup.van -(n-decyl)-A51568B
N.sup.leu -(n-decylidenyl)-A51568B
N.sup.leu -(n-decyl)-A51568B
N.sup.van -(n-decylidenyl)-M43D
N.sup.van -(n-decyl)-M43D
N.sup.van -(benzylidenyl)vancomycin
N.sup.van -[3-phenyl-n-(prop-2-enylidenyl)]vancomycin
N.sup.van -[(adamant-1-yl)methylidenyl]vancomycin
N.sup.leu -(phenethylidenyl)vancomycin
N.sup.van -(benzyl)vancomycin
N.sup.van -(3-phenyl-n-prop-2-enyl)vancomycin
N.sup.van -[(adamant-1-yl)methyl]vancomycin
N.sup.leu -phenethylvancomycin

Number	Name	Date
3067099	McCormick et al.	Dec 1962
4495179	Hoehn et al.	Jan 1985
4547488	Merkel	Oct 1985
4548925	Higgins, Jr. et al.	Oct 1985
4558008	Boeck et al.	Dec 1985

Novel glycopeptide derivatives

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Harris et al., "Structure of the Glycopeptide Antibiotic Vancomycin, Evidence for an Asparagine Residue in the Piptide," J. Am. Chem. Soc., 104, 4293-4295 (1982).
Pfeiffer, "Structural Features of Vancomycin," Reviews of Infectious Diseases, vol. 3, Suppl., S205-S209 (Nov.-Dec. 1981).