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United States Patent (19) (11) 4,029,882 Wright (45) June 14, 1977

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United States Patent (19) (11) 4,029,882 Wright (45) June 14, 1977 United States Patent (19) (11) 4,029,882 Wright (45) June 14, 1977 54 SELECTIVE ACYLATION OF THE C-1 3,780,018 12/1973 Konishi et al. .............. 260/210 AB AMNO GROUP OF AMNOGLYCOSDE 3,781,268 12/1973 Kawaguchi et al. ......... 260/210 AB ANTIBOTCS 3,792,037 2/1974 Kawaguchi et al. ......... 260/210 AB 3,796,698 3/1974 Naito et al. ................. 260/210 AB (75) Inventor: John J. Wright, Orange, N.J. 3,796,699 3/1974 Naito et al. ...... ... 260/210 AB O 3,828,021 8/1974 Beattie et al. .... ... 260/210 AB 73) Assignee: Shering Corporation, Kenilworth, 3,868,360 2/1975 Daniels et al. .............. 260/210 AB 22 Filed: Mar. 19, 1974 O R PUBLICATIONS (21) Appl. No.: 452,586 Julian et al., “Chem. Abst.' vol. 75, 1971, p. 316592. vVs. Yavary 52)52l U.S. Cl. ................................. s 36/17fis s: Attorney,Primary Examiner-Johnnie Agent, or Firm-Carver R. Brown Joyner; Stephen I51) Int. C.’........................................ cost Coan; Raymond McDonald 58) Fieldield of Search ................ 260/210 AB, 33; 57 ABSTRACT A novel process for preparing novel 1-N-acyl-4,6-di 56) References Cited (aminoglycosyl)aminocyclitols is disclosed. The com UNITED STATES PATENTS pounds are useful as antibacterial agents. 3,244,590 4/1966 Schaffner et al. ........... 260/210 AB 3,753,973 8/1973 Umezawa et al. ........... 260/210 AB 18 Claims, No Drawings 4,029,882 2 and/or an amino substituent and separating the acyl SELECTIVE ACYLATION OF THE C-1 AMNO ated antibiotic from the reaction medium. GROUP OF AMNOGLYCOSDE ANTBIOTICS SUMMARY OF THE INVENTION This invention relates to semisynthetic antibacterial In one of its process aspects, this invention may be set agents. More particularly, this invention relates to forth as follows: A process for 1-N-acylating 4,6-di semisynthetic aminoglycoside aminocyclitol an (amino-glycosyl)aminocyclitol antibiotics which com tibacaterial agents prepared from antibiotics elabo prises reacting a partially neutralized acid addition salt rated principally but not exclusively by species of mi of such antibiotic with an acylating agent derived from croorganisms from Micromonospora and Streptomy O a carboxylic acid having 1 to 8 carbon atoms, said cetes genera. In particular, this invention relates to acylating agent being unsubstituted or mono substi semisynthetic aminoglycoside aminocyclitol antibacte tuted by a substituent selected from the group consist rial agents wherein the C-1 amino group of the ing of hydroxy and amino. aminocyclitol moiety bears an acyl group and to the In another of its process aspects, this invention may non-toxic acid addition salts of such agents. This inven 15 be set forth as follows: In the process for preparing tion also relates to methods for acylating aminoglyco 1-N-hydroxyaminoacyl derivatives of 4,6-di-(amino side aminocyclitol antibiotics at the C-1 amino position glycosyl)aminocyclitol antibiotics by acylating such to produce acyl derivatives wherein the acyl function antibiotics with an acylating agent derived from a car optionally bears an amino and/or a hydroxy substitu boxylic acid having 3 to 8 carbon atoms, said acylating 20 agent bearing a hydroxy and an amino substituent on ent. different carbon atoms, the improvement which com Prior Art prises acylating a partially neutralized acid addition salt of said antibiotic. U.S. Pat. No. 3,541,078, issued Nov. 15, 1970, de In its product aspect, this invention may be described scribes an antibiotic complex which is elaborated by 25 as a 1-N-Z-4,6-di-(aminoglycosyl)aminocyclitol anti strains of Bacillus circulans. The complex consists of bacterial agent selected from the group consisting of two members designated ambutyrosin A and am 1-N-Z-gentamicin A, 1-N-Z-gentamicin B, 1-N-Z-gen butyrosin B (butyrosin A and B). The antibiotics are of tamicin B, 1-N-Z-gentamicin C, 1-N-Z-gentamicin the aminoglycoside-aminocyclitol class but are unique C, 1-N-Z-gentamicin C, 1-N-Z-gentamicin C, 1-N- in that the aminocyclitol moiety, 2-deoxystreptamine, 30 Z-gentamicin X2, 1-N-Z3', 4'-dideoxykanamycin B, is acylated at the C-1 amino position by a hydrox 1-N-Z-sisomicin, 1-N-Z-verdamicin, 1-N-Z-tobramy yaminoacyl group, the group being derived from a cin, 1-N-Z-antibiotic G-418, 1-N-Z-antibiotic 66-40B, hydroxy-y-aminobutyric acid (HABA). 1-N-Z-antibiotic 66-40D, 1-N-Z-antibiotic JI-20A, 1 In a publication by Akita et al. in the Journal of Anti N-Z-antibiotic J-20B, 1-N-Z-antibiotic G-52, 1-N-Z- biotics (Japan) 23, 173-183 (1970) is set forth the 35 mutamicin 1, 1-N-Z-mutamicin 2, 1-N-Z-mutamicin 4, chemical structure of an antibiotic designated SF-755 1-N-Z-mutamicin 5, 1-N-Z-mutamicin 6, and the non which antibiotic was subsequently named, ribostamy toxic acid addition salts thereof wherein Z is an acyl cin. Ribostamycin is structurally related to butyrosin B group derived from a hydrocarbon carboxylic acid but does not have a HABA group on the 2-deoxystrep having 1 to 5 carbon atoms, said acyl group being un tamine moiety. However, Kawaguchi et al. The Jour 40 substituted or mono substituted by either hydroxy or nal of Antibiotics (Japan) 25, No. 12, 741-2)success amino, said acyl group being straight chain, branched fully acylated ribostamycin at the C-1 amino position of chain or cyclic, said acyl group also being saturated or the 2-deoxystreptamine moiety with L(-)-a-hydroxy-y- unsaturated with the proviso that when Z is formyl or is aminobutyric acid and obtained an improved antibiotic unsaturated it must also be unsubstituted. Exemplary of having activity against some ribostamycin resistant 45 the acyl groups embraced by the product aspect of this organisms. By applying an acylation technique to kana invention are formyl, acetyl, propionyl, propenoyl, mycin A, Kawaguchi and his coworkers produced an butyryl, isobutyryl, cyclopropylcarbonyl, hydroxya antibiotic having substantially enhanced applied use cetyl, aminoacetyl, 4-hydroxybutyryl, 4-aminobutyryl characteristics when compared with kanamycin. The and the like. antibiotic has been designated BB-K8, (see the Journal 50 Blocking groups and methods for employing the of Antibiotics (Japan), 25, No. 12, 695-731). same are well known in the art. For example, such More recently, U.S. Pat. No. 3,780,018, issued De groups and methods are described in the patents and cember 18, 1973, describes a process whereby 1-L- publications referred to hereinabove under, “Prior (-)-y-amino-a-hydroxybutyryllgentamicin C are 2'- Art.” In those instances wherein the desired acyl deriv L-(-)-y-amino-a-hydroxybutyrylligentamicin C are 55 ative bears a hydroxy substituent, such substituent may prepared by reacting gentamicin C with a blocked be protected (blocked) by acylating the same. active ester of L-(-)-y-amino-a-hydroxybutyric acid As used herein, the terms “blocking group' or "pro (HABA) followed by deblocking via methods known to tecting group' refers to groups which render the the art and separation of the reaction mixture by chro blocked or protected amino and/or hydroxy groups matographic means. All of the above-noted prior art 60 inert to subsequent desired chemical manipulation, but processes are effected by reacting the antibiotic free which can easily be removed at the end of the synthetic nitrogen base with a blocking group or by acylating the sequence without cleaving the desired N-aminoacyl or unblocked free nitrogen base with an acylating agent. N-aminohydroxyacyl or N-hydroxyacyl group. I have discovered a process for preparing novel 1-N- As used herein, the term "partially neutralized acid acyl derivatives of 4,6-di-(aminoglycosyl)aminocyclitol 65 addition salt' means that each mole or antibiotic has antibiotics which comprises reacting a partially neutral less than a stoichiometric number of moles of acid ized acid addition salt of such antibiotic with an acylat associated therewith, i.e., less than the "per' acid addi ing agent which agent may optionally bear a hydroxy tion salt. For example, one equivalent or gentamicin C 4,029,882 3 4 having five amino groups would require five equiva grams to develop for about 16 hours then dry the pa lents of acid to form the “per' acid addition salt. The pers. Plate one paper on an agar plate seeded with process of this invention is effected on an acid addition Staphylococcus aureus (A.T.C.C. 6538P), spray the salt of gentamicin C, having less than five equivalents duplicate with the conventional ninhydrin solution and of acid; four for example. Further, the term "acid addi heat to develop. Incubate the agar plate at 37°C over tion salt” embraces such salts as may be formed be night and combine the solution from tubes containing tween the basic antibiotic and an acid without regard to the material that migrates like gentamicin C (i.e., whether the acid may be termed inorganic or organic. tubes 290-360). Exemplary of acids embraced by the term are sulfuric, Replace tubes 290–360 with fresh tubes containing hydrochloric, phosphoric, nitric, acetic, propionic, 10 40 ml. of upper phase and 40 ml. lower phase. Re-set succinic, oxalic, cyclopropylcarboxylic, trimethylace the apparatus for an additional 2800 transfers and re tic, maleic, benzoic, phenylacetic, trifluoroacetic or the peat the chromatographic procedure performed above. like. Combine tubes 1-16 and concentrate in vacuo to ob Aminoglycoside antibiotics and amines in general are tain 1.3 gms. of Antibiotic C. usually more readily manipulated as acid addition salts 15 Antibiotics 66-40B and 66-40D are disclosed and than as free nitrogen bases.
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