23-C-SUBSTITUTED MYCAMINOSYL TYLONOLIDE

Abstract: Novel 23-C-substituted mycaminosyl tylonolide of the general formula (I) wherein R¹ represents a lower alkyl group, an aryl group, a lower alkenyl group or a lower alkinyl group, R² represents a hydrogen atom or a hydroxyl group. These compounds have excellent antibacterial activities.

Description: 23-C-SUBSTITUTED MYCAMINOSYL TYLONOLIDE This invention relates to atibacterial compounds which show antibacterial against various pathogens including gram-positive and -negative bacteria, the production of these compounds, and medical cornsosi- -tions containing them. The compounds of this invention are those of the general formula-(I) EMI1.1 wherein RÚ represents a lower alkyl group, an aryl group, a lower alkenyl groun or a lower alkinyl group, R rep- resents a hydrogen atom or a hydroxyl group Symbols herein have the same significances throughout unless otherwise indicated. The term "Lower alkyl" in the foregoing definitions means a straight or branched carbon chain alkyl having 1 to 5 carbon atoms. Thus, examples of the "lower alkyl" are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. Examples of the "aryl" in the foregoing definitions are phenyl, naphthyl, etc The tern lower alkenyl" in the foreso-- ing definitions means a straight cr branched carbon chain alkenyl having 2 to 6 carbon atoms and having one or two double bonds Thus examples of the "lower alkenyl" are vinyl (CH2=CH-1), 1-propenyl (CH3-CH=H-), 2-propenyl (CH2=CH-CH2-), iso-propenyl (CH2=C-), 2-butenyl CH3 CH3-CH=CH-CH2-), 2-pentenyl (CH3-CH2-CH=CH-CH2-), etc. The term "lower alkinyl'1 in the foregoing definitions means a straight or branched carbon chain alkinyl having 2 to 6 carbon atoms and having triple bond(s) Thus es- amples of the "lower alkinyl" are ethinyl (CH=-C-), 2propargyl ( CH=C-CH2-), 2-butinyl ( CH3-C¯C-CH2-), 2penten-4-inyl (CH#C-CH=CH-CH2), etc. The compounds of this invention have an asymmetric carbon atom at the 23-position, and so there are optical isomers. Thus this invention includes all of the isomers, individually and in any combination, e.g. racemic compound(s), optically active isomer(s), etc. British Patent Publication 2,081,711 and European Patent Publication 70,170 disclose tylosin compounds having only mycaminose or desosamine as sugar component. These publications disclose tylosin compounds wherein the 23-position carbon atom has a substituent such as a halogen atom, a hydroxyl group, an alkanyloxy group, EMI2.1 (wherein R6 represents a hydrogen atom or a lower alkyl group which may be substituted by a -3hydroxyl group, R7 represents a hydrogen atom, an alkyl group which may be substituted by a hydroxyl group, an aryl group, an aralkyl group, etc.), etc. The compounds of tis invention of the formula (I) are novel compounds having excellent antibacterial activity, and have the characteristic that the 23position carbon atom has a substituent selected from lower alkyl, aryl, lower alkenyl, and lower alkinyl groups. The compounds of this invention have shown antibacterial activity against various pathogens including gram-positive and -negative bacteria, and in partitular the compounds have shown activity against several important gram-negative bacteria. Thus, the compounds are useful for medicaments (especially anti biotics) for the prevention or treatment of diseases caused by such bacteria. Antibacterial medicaments containing the compounds according to this invention can be prepared by conventional methods using conventional carriers or excipients; such carriers or excipients may be organic or inorganic, solid or liquid materials which are pharmaceutically acceptable and suitable for oral or paren- teral administration or for external application. They may for example be administered as capsules, tablets (such as sugar-coated tablets), ointments, suppositories, solutions, suspensions, emulsions, etc. The appropriate dose is deterrined in each case considering factors -ucn as the symptom, age and sex of the patient, but for an adult 10 -1000 mg per single dose is usally administered one to four times per day. Concerning the antimicrobial activity of the compounds or this invention or the formula (I), minimum efective inhibitory concentrations (MIC) of the com¯ pounds are shown in the following Table. EMI4.1 tylcnolir'- <tb> <SEP> Table <SEP> (MIC <SEP> t/m1) <SEP> MT: <SEP> = <SEP> osvl <SEP> tvlcnolid <SEP> 4d620.YV <SEP> nVU-aVUrO-I,/ <tb> <SEP> Cc <SEP> .----- <SEP> No. <tb> <SEP> I <SEP> 1IT <SEP> DT <SEP> to(3) <SEP> 8t <SEP> 4(2) <SEP> t7 <SEP> 6 <SEP> a <SEP> ;1: <SEP> lOlt*;l(l <SEP> i0'' <SEP> j% <tb> <SEP> B. <SEP> Subtilis <SEP> 58!3n <SEP> <SEP> 78 <SEP> 0 <SEP> 7e <SEP> 0-39 <SEP> 0-39 <SEP> Q-:9 <SEP> ¯0-3 <SEP> 0.s9 <SEP> 3 <SEP> 12 <tb> <SEP> E;mRL <SEP> ¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯¯ <tb> <SEP> M. <SEP> luteus <SEP> !s0.2 <SEP> < 0.2 <SEP> s0.: <SEP> \'0.2 <SEP> 0.2 <SEP> 0.2 <SEP> < 0.2 <SEP> 40. <SEP> 40. <SEP> 0.2 <SEP> 0. <tb> <SEP> PC <SEP> 1001 <tb> <SEP> c <SEP> = <SEP> ^ <SEP> < <SEP> ' <SEP> t <tb> <SEP> Smith <SEP> 1.56 <SEP> 0.33 <SEP> 1.56 <SEP> 1.56 <SEP> 0.78 <SEP> 0.39 <SEP> 0.39 <SEP> < 0.2 <SEP> 0.78 <SEP> 1.5- <SEP> 0.78 <tb> <SEP> KI. <SEP> - <SEP> ¯¯ <tb> <SEP> K <SEP> ¯nl2e <SEP> i <tb> <SEP> ECI-s02 <SEP> 3.12 <SEP> 1.56 <SEP> '6i3 <SEP> 1 <SEP> 3.12 <SEP> 6.25 <SEP> 1.56 <SEP> 3.1) <SEP> 3.12 <SEP> 3.12 <SEP> 3.12 <SEP> ' <tb> <SEP> Salanrnr¯+idiS <tb> <SEP> 1891 <SEP> 1 <SEP> 3.12 <SEP> 1.56 <SEP> 3.12 <SEP> 3.12 <SEP> 3.12 <SEP> 3.12 <SEP> 3.12 <SEP> 3.12 <SEP> 3.12 <SEP> 3.12 <SEP> 3.12 <tb> <SEP> Pseud.- <SEP> aeruginosa <SEP> <tb> <SEP> A3 <SEP> X <SEP> 25 <SEP> 12.512.512.56.25 <SEP> 25 <SEP> 12.5 <SEP> 6.25 <SEP> - <SEP> 6.25 <SEP> 3..??.. <tb> The compounds or this invention can be produced in the following manner: : EMI4.2 compound of formula (I) In the above formula Rê' represents a hydrogen atom or a proteced hydroxyl group, R represents a protective group for a hydroxyl group R4 represents a protected aldehyde group, R5 represents a protective group for a hydroxyl group. The compounds (I) can thus be produced by reacting 23-deoxy-23-oxo-mycaminosyl tylonolide derivatives of formula (II) with Grignard reagent of the formula: RÚMgX (wherein R1 is as defined above, and X represents a halogen atom) or with organic lithium compound of the formula: RÚ-Li (wherein RÚ is as defined above) [step 1], and then releasing the hydroxyl- and aldehyde-protective groups[step 2]. Practical examples of protective groups are as follows: Protective group for a hydroxy group in the case of Rê and R5: a lower acyl group such as an acetyl group, a propionyl group, a butyryl group, etc. Protective group or a hydroxyl group in the case of R3: a tert-butyldimethylsilyl group, a 2-pvranyl group, a 2-fuxanyl group, etc. Protected aldehyde in the case of R4: acetal or thioacetal; practically, dimethylacetal, diethylacetal, diethylthioacetal, ethyleneacetal, ethylenethio acetal, propyleneacetal, etc. Examples of Grignard reagent of the formula: are are lower alkyl magnesium halide (such as methyl magnesium bromide, ethyl magnesium bromide, butyl magnesium bromide etc.), acryl magnesium halide (such as phenyl magnesium bromide, naphthyl magnesium bromide, etc.) lower alkenyl magnesium halide (such as vinyl magnesium bromide, 2-propenyl magnesium bromide, etc.) and lower alkinyl magnesium halide (such as ethinyl magnesium bromide, 2-propinyl magnesium bromide), etc. Examples of the organic lithium compoud of the formula Rl-Li are methyl lithium (CH3Li), butyl lithium (CH3 - CH2-CH2-CH2Li), ethylene lithium (CH2=CHLi), 2-propene lithium, 2-propine lithium, 2-phenyl lithium, etc. The reaction of the starting material (II) with the Grignard reagent or the organic lithium compound [step 11 is usually performed in an organic solvent (such as dry ether, tetrahydrofuran, etc.) at low temperature (for example, -50 to -80 C). The reaction can be completed within 1 to 3 hours. The compounds thus formed are usually racemic compounds. If optical active isomers are desired, the formed products can be subjected to conventional prodedures suc as sIlica gel column chromatography to isolate optical isomers. The compounds (I) can be obtained after releasing the protective groups [step 2]. The removal of Rê' and R5 (protective groups for 2#- and 4'-hydroxyl groups of mycaminose) is easily performed in conventional manner for example, by heating in a suitable solvent such as methanol, a water-containing alcohol, or aprotic solvent containing water. The removal of R (protective group for hydroxyl group) and the aldehyde protective group can be performed in a conventIonal manner, for example, by treatment with mineral acid such as. hydrochloric acid, sulfuric acid, etc. or organic acid such as triluoroacetic acid, trichloroacetic acid, etc. The invention is illustrated by the following Examples. The production methods for some of the start- ing materials for this invention are shown by the following Reference Examples. In these Examples NMR means a nuclear magnetic resonance spectrum, and Me means a methyl group; the auoted chromatography eluant ratios are by volume. Reference Example 1 EMI8.1 673 mg of 2',4'-di-O-acetyl-3-O-tert-butyldimethyl- silyl mycaminosyl tylonolide diethylacetal was dissolved in 6-.6 ml of dry benzene and 6.6 ml of dry dimethyl sulfoxide. After adding thereto 150 mq of pyridinium trifluoroacotate and 624 mg of N,N'-dicvclohexyl carbo- diimide, the mixture was stirred at room temperature for 5 hours. The reaction mixture was added to a solution of 255 mg of oxalic acid dihydrate in 6.6 ml of dioxane, and the mixture was stirred for 1 hour at room temperature; The precipitates thus formed were removed by filtration and the reaction solution was concentrated under reduced pressure to give a syrupy material. The syrupy material was dissolved in 100 ml of benzene. The solution was washed with saturated aqueous sodium hydrogencarbonate and then with saturated aqueous sodium sulfate, and dried over anhydrous sodium sulfate. The solution was concent-ated under reduced pressure to provide 70() mg of a solid material of 2',4'-di-O-acetyl-3-O-tert butyldimethylsilyl-23-deoxy-23-oxo-mycaminosyl tylonolids diethylacetal. This product was used for the next reaction step, without purification. Reference Example 2 EMI9.1 900 mg of 2'-0-acetyl-3-O-tert-butyLdimethylsilyl- 4'-dcoxvìiycaminosyl tylonolide diethvl acetal was dissolved in 9 ml of dry benzene and 9 ml of dry dimethyl sulfoxide, and after adding thereto 215 mg of pyridinium trifluoroacetate and 914 mg of N,N'-dicyclohexyl carbo diimide, the mIxture was stirred at room temperature for 4 hours. The reaction mixture was poured into 9 ml of a solution of 372 mg of oxalic acid dihydrate in 9 mL of dioxane, and the mixture was stirred for 1 hour. Insoluble materials were removeci by filtration, and the filtrate was concentrated under recsced pressure - A syrupy material obtained was dissolved in 100 ml of benzene, and the solution was washed with saturated aqueous sodium hydrogencarbonate and then with saturated aqueous sodium sulfate, dried over anhydrous sodium sulfate, and cencentrated under reduced pressure to give 1 g of a solid material of 2'-O-acetyl-3-O-tert-butyldimethylsilyl- 23,4'-dideoxy-23-oxo-mycaminosyl tylonolids diethylacetal. This product was used for the next reaction step, without purification. Example 1 (1) EMI10.1 To a cold solution (-780C) of 0.67 g of 2',4'-O-acetyl-3-O-tert-butyldimethylsilyl- 23-deoxy-23-oxo-mycaminosyl tylonolids diethylacetal was in 7 ml of dry tetrahyrofuran was added 1 ml of 1 M tetrahyrofuran solution of methyl magnesium bromide I as kept for 3 hours at that temperature. The reaction mixture was poured into saturated aqueous ammonium chloride, and extract ed with 35 ml of chloroform The extract was washed with saturated aqueous sodium sulfate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed (Kiesel gel-60: 70 g ; toluene:ethyl acet ate: 5:2 - 1:1) to give 230 mg of one optical isomer (A) and 180 mg of another optical isomer (B) of 2',4' di-O-acetyl-3-O-tert-butyldimethylsilyl-23-C-methyl mycaminosyl tylonolide diethylacetal (these optical isomers are those caused by the 23-position asymetric carbon atom) NMR (CDC13) (A) #(ppm) t 0.83 9H @ EMI12.1 <tb> <SEP> 1.12 <SEP> 3 <SEP> a <SEP> 23 <SEP> - <SEP> C <SEP> --"Jle <tb> <SEP> 2.0 <SEP> 6E <SEP> 2', <SEP> t"0C0C'¯3 <tb> <SEP> 2.3 <SEP> w <SEP> 6 <SEP> E <SEP> N <SEP> Me, <tb> <SEP> 4.10 <SEP> lE <SEP> 23 <SEP> - <SEP> r--e <tb> <SEP> e <tb> (B) <SEP> 8 <SEP> a(30m) <tb> <SEP> 3-0-Si <SEP> --00-5i <SEP> (Me <SEP> ) <SEP> tBu <tb> <SEP> 1. <SEP> 1 <SEP> 3 <SEP> 23 <SEP> - <SEP> C--Xe <tb> <SEP> 2.08 <SEP> 6E <SEP> 2', <SEP> 4'- <SEP> Q <SEP> C3 <SEP> C-3 <tb> <SEP> 2.3 <SEP> 6 <SEP> 6 <SEP> E <SEP> N <SEP> - <SEP> Mez <tb> <SEP> Q <SEP> a <SEP> a <SEP> I <SEP> E <SEP> 23 <SEP> - <SEP> OE <tb> <SEP> : :ve <tb> EMI12.2 A solution of /230 mg of the optical isomer (A) of 2',4'-di-O-Acetyl-3-O-tert-butyldimethylsilyl 23-C-methylmycaminosyl tylonolide diethylacetal in S ml o methanol was kept at 500C overnight. The reaction mixture was concentrated under reduced pressure to give 200 mg of 3-O-tert-butyldimethylsilyl-23-C-methylmycaminosyl tylonolide diethylacetal. NMR (CDCL3) #(ppm) 0.88 9H 3-O-Si(Me)z tBu 6 w*) 6. N - Mez 4.7 0 I E E - 23 6.07 1H H-13 EMI13.1 A solution of /200 mg of 3-O-tert-butyldimethylsilyl-23-C-methyl mycaminosyl tylonolide diethylacetal (obtained at (2) above) in 1.2 ml of acetonitrile and 1.2 ml of IN hydrochloric acid was kept at rcom temperature overnight To the reaction mixture was added saturated aqueous sodium hydrogencarbonate (pH 9), and the mixture was extract- ed with 3 ml of chloroform and the solution washed with 3 ml of a saturated aqueous sodium sulfate solution, diied over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed(Kiesel gel-60: 18 g; chloroform:methanol:28% aaueous ammonia : 10:1: 0.1) to give 121 m of 23-C-methylmycaminosyl tylono- lide. NMR (CDCL3) #(ppm) 1.15 3H 23-C-Me 1.81 3H 22-Me 2.51 6H N-Mez 4.08 1H H-23 4.26 1H H-11 5.20 1H H-15 6.07 1H H-13 9.69 1H H-20 Example 2 EMI15.1 A solution of 114 mg of the optical isomer (B) obtained by Example 1 (1) of 2',4'-di-O-acetyl-3-0-tert-butyldimethylsilyl- 23-C-methylmycaminosyl tylonolide diethylacetal in 2.2 ml of methanol was kept at 50 C overnicht. It was concentrated under reduced pressure, and the residue was chromotographed (Kiesel gel-60:22 g; chloroform:methanol: 12:1-5:1) to give 70 mg of 3-O-tert-butyldimethylsilyl-23-Cmethylmycaminosyl tylonolide diethylacetal. NMR (CDCl3) # (ppm) 0.88 9H 3-O-Si(Me)1tBu 2.5 5 6 E N - Me1 4.0 1 1 E E - 23 5.30 lE H- 13 EMI16.1 A solution of A solution of 53 mg of 3-O-tert-butyldimethylsilyl-23-C-methylmycaminosyl tylonolide diethylacetal (obtained at (1) above) in 0.27 ml of acetonitrile and 0.27 ml of 1N hydroxychloric acid was kept at room temperature overnight. Usual work-up (cf. Ex.1(3)) gave a solid, which was chromatographed(Kiesel gel-60 chloroform:methanol:28% aqueous ammonia solution: 10:1: 0.1) to give 22 mg of 23-C-methylmycaminosyl tylonolide diethylacetal. NMR (CDCl3) #(ppm) 1.23 3H 23-C-Me 1.83 3H 22-Me 2.50 6H N-Me1 3.98 1H H-23 4.23 1 E E - 1' 4.91 1H H-15 5.76 1H H-13 9.70 1H H-20 Example 3 (1) EMI18.1 To a solution of /1.01 g of 2',4'-di-O-acetyl-3-O-tert-butyldimethyl silyl-23-deoxy-23-oxo-mycaminosyl tylonolide diethylacetal in 10.5 ml of dry tetrahydrofuran, was added 0.89 ml of 3M diethyl ether solution of ethyl magnesium bromide at -78 C. After 1 hour, the reaction mixture was poured into a saturated aqueous ammonium chloride solution. Usual workup (cf. Ex.1(1)) gave a solid, which was chromatographed (Kiesel gel-60: 50 g; toluene: ethyl acetate: 3:1) to give 397.7 mg of one optical isomer (A) and 312.5 mg of another optical isomer (B) of 2',4'-di-O-acetyl-3-O- tert-butyldimethylsilyl-23-C-ethylmycaminosyl tylonolide diethylacetal (these optical isomers are those caused by the 23-ositior asymmetric carbon atom). (2) EMI19.1 A solution of /397.7 mg of the optical isomer (A) obtained at (1) above of 2',4'-di-O-acetyl-3-O-tert-butyldimethylsilyl23-C-ethylmycaminosyl tylonolide diethylacetal in 12 ml of methanol was kept at 50 C overnight. Usual work-up gave a solid, which was chromatographed (Kiesel gel-60: 50 g; chloroform:methanol 28 % aqueous ammonia solution: 15:1:0.1) to give 271.3 mg of 3-O-tert-butyldimethylsilyl-23-C-ethylmycaminosyl tylonolide diethylacetal. NMR (CDCl3) # (ppm) 0.87 9H 3-O-Si (Me)2 tBu 2.56 6H NMe2 4.0 6 1 E E - 23 6.00 1H H - 13 EMI20.1 A solution of /60 mg of 3-O-tert-butyldimethylsilyl-2- 3-C-eLhyl mycaminosyl tylonolide diethylacetal (obtained at (2) above) in 0.3 ml of acetonitrile and 0.3 ml of 1N hydrochloric acid was et . at 370C overniaht. Usual work-up (of. Ex. 1(3)) gave a solid which was chromatographed (Kiesel gel-60: 6 g, chloroform:methanol:28% aqueous ammonia solution: 20:1:0.1-15:1:0.1) to give 33.7 mg of 23-C ethylmycaminosyl tylonolide. NMR (CDCl3) # (ppm) 0.90 3H 23-CH2CH3 1.42 2H 23-CH2CH3 1.81 3H 22-Me 2.52 6H NMe2 4.27 1H H-1' 5.24 1H H-15 6.0 6 1 H tE-13 9.68 1H H-20 Example 4 (I) EMI22.1 A solution of / 312.5 mg of the optical isomer (B) obtained bv Example 3 (1) of 2',4'-di-O-acetyl-3-O-tert-butyldiemethylsilyl-23-C-ethylmycaminosyl tylonolide diethylacetal in 6.3 ml of methanol was kept at 50 C avernight. Usual work-up gave a solid, which was chromatographed (Kiesel gel-60: 30 g; chloroform:methanol:28% aqueous ammonia solution: 18:1:0.1) to give 73.2 mg of 3-O-tert-butyldimethylsilyl-23-C-ethylmycaminosyl tylonolide diethylacetal. NMR (CDCl3) # (ppm) 0.87 9H 3-O-Si (Me)=tBu 2.56 6H NMe 4.10 1H H-23 5.75 1H H-13 EMI23.1 A solution of 46.4 mg of 3-O-tert-butyldimethylsilyl-23-C-ethylmycaminosyl tylonolide diethylacetal obtained at (1) above in 0.2 ml of acetonitrile and 0.2 ml of 1N hydrochloric acid was kept at room temperature for two days. Usual work-up (cf. Ex.2(2)) gave a solid, which was chromatographed (Kiesel gel-60: 6 g; chloroform:methanol:28% aquesous ammonia :20;1:0.1-15:1:0.1) to provide 8.8 m of 23-Cethylmycaminosyl tylonolide. NMR (CDCl3) # (ppm) 0.99 3H 23-C 1.60 2H 23-C 1.81 3H 22-Me 2.51 6H NMe2 4.2 7 1 E E - 1' 4.9 5 1 E E -15 5.76 1H H - 13 9.70 1 1H E - 20 Example 5 (1) EMI24.1 To a cold (-78 C) solution of / 1 g of 2'-O-tert-butyldimethylsilyl 23-,4'-dideoxy-23-oxo-mycaminosyltylonolide diethyl acetal in dry tetrahydrofuran, was added 1.6 ml of 1M tetrahydrofuran solution of methyl magnesium bromide. After 1 hour, the reaction mixture was poured into saturated aqueous ammonium chloride. Usual work-up (cf. Ex.l(1)) gave a solid, which was chromatographed (Kiesel gel-60: 90 g; toluene:acetone: 4:1-1:1) to give 380 mg of one optical isomer (A) and 160 mg of another optical isomer (B) of 2'-O-acetyl-3-O-tert-butyldimethylsilyl-4'-deoxy 23-C-methylmycaminosyl tylonoloide dietylacetal (these isomers are those caused by the 23-position asymmetric carbon). NMR (CDCl3) (A) # (ppm) 0.86 9H 3-O-Si(Me)=tBu 1.12 3H 23-C-Me 2.10 3 K 2'-OCOCH3 9 .? z 6 K NMez 4.10 1H H - 23 5.97 1H H - 13 (E) # (ppm) 0.85 9H 3-O-Si(Me)=tBu 1.1 9 3 E 23 -C-Me 2.09 3H 2'-OCOCH3 2.27 6H NMe2 3.98 1H H-23 5.75 1H H-13 EMI26.1 380 mg or the optical isomer (A) obtained at (1) above of 2'-O-acetyl-3-O-tert-butyldimethylsilyl-4'deoxy-23-C-methylmycaminosyl tylonolide diethylacetal was subjected to methanqlysis and hydrolysis as described before to give a solid, which was chromatographed (Kiesel gel-60: 10 g; chloroform:methanol:28% aaueous ammonia : 15:1: 0.1) to provide 130 mg of 4'-deoxy-23-C-methylmycaminosyl tylonolide. NMR (CDCl3) a (pom) 1.83 3H 22-Me 2.27 6H NMe2 4.2 2 1 E E - 1' 9 1H CHO Example 6 EMI28.1 72 mg of the optical isomer (B) obtained by Example 5 (1) of 2'-O-acetyl-3-O-tert-butyldimethylsilyl-4' deoxy-23-C-methylmycaminosyl tylonolide diethylacetal was treated as described for Example 5(2) to give a solid, which was chromatographed (Kiesel gel-60: 14 g; chloroform:methanol:20% aqueous ammonia : 15:1: 0.1) to provide 26 mg of 4'-deoxy-23-C-methymycaminosyl tylonolide. NMR (CDCl3) # (ppm) 1.24 3H 23-C-Me 1.83 3H 22-Me 2.28 6H NMe2 3.99 1H E-23 4.22 1H E-1' 4.89 1H E-15 5.80 1H E-13 9.71 1H E-20 Example 7 EMI29.1 To a cold (-78 C) solution of / 1 g of 2', 4'-di-O-acetyl-3-O-tert-butyldimethyl silyl-23-deoxy-23-oxo-mycaminosyl tylonolide diethyl acetal in 10 ml of tetrahydrofuran, was added 1.2 ml of 2 M. tetrahydrofuran solution or phenol 1 magnesium bromide and it was kept at that temperature for 30 minutes. Usual work-up as described in Ex. 1 (1) gave a solid, which was chromatographed (Kiesel gel-60: 50 g; toluene: ethyl acetate 4:1) to give 587 mg of 2',4'-di-O-acetyl-3-O-tert- butyldimethylsilyl-23-C-phenylmycaminosyl tylonolide diethylacetal. EMI30.1 <tb> <SEP> NMR <SEP> (CDCl3) <tb> Ï <SEP> (pom <SEP> ) <tb> <SEP> 0.9 <SEP> 9E <SEP> 3 <SEP> - <SEP> O <SEP> ¯ <SEP> Si( <SEP> Me) <SEP> t3u <tb> <SEP> 2.1 <SEP> 6E <SEP> 2', <SEP> 4' <SEP> - <SEP> O <SEP> C <SEP> 0 <SEP> This <tb> <SEP> 2.35 <SEP> 6E <SEP> NMez <tb> <SEP> 7.25 <SEP> --SE <SEP> -So) <tb> EMI31.1 A solution of j 432 mg of 2 or, 4'-di-O-acetyl-3-O-tert-butyldimethyl. silyl-23-C-phenylmycaminosyl tylonolide diethylacetal in 8.65 ml of methanol was kept at 500 C overnight. Usual work-up gave 137 mg of 3-O-tert-butyl- dimethylsilyl-23-C-phenylmycaminosyl tylonolide diethylacetal. NMR (CDC13) # (ppm) 0.93 9H 3-O-Si(Me)2tBu 2.50 6H NMe2 EMI32.1 <tb> <SEP> t <SEP> ^ <SEP> { <SEP> 1 <SEP> 7 <SEP> E <SEP> - <SEP> 1 <tb> 7.25 <tb> EMI32.2 A solution of /1.37 mg of 3-O-tert-butyldimethylsilyl-23-C-phenylmycaminosyl tylonolide diethylacetal in 0.69 ml of acetonitrile and 0.69 ml of 1N hydrochloric acid was kept at room temperature overnight. Usual work-up as described in Ex. 1(3) gave, after chromatography (Kiesel gel-60: 13 g; chloroform:methanol:28% aqueous ammonia :15:1:0.1-12:1:0.1), 65.5 mg of 23-C-phenylmycaminosyl tylonolide. NMR (CDCl3) # (ppm) 2.50 6H NMe2 4.32 1H H-1' 5.47 1H H-13 7.25 5H -# 9.74 1H CHO Example 8 EMI33.1 To a cold (-780C) solution of To a cold (-10 C) solution of 782 mg of 2', 4'-di-O-acetyl-3-O-tert-butyl-dimethyl silyl-23-deoxy-23-oxomycaminosyl tylonolide diethylacetal in 10 ml of tetrahydrofuran, was added 2.5 ml. of 1 M ether solution of allyl magnesium bromide. Usual work-up as described in Ex.1(1) gave, after chromatography (toluene:ethyl acetate: 2:1 as eluant). 201 m of one optical isomer (A) and 119 mg of another optical isomer (B) of 2',4'-di-O-acetyl-3-O- tert-butyldimethylsilyl-23-C-(2-propenyl)mycaminosyl tylonolide diethylacetal. NMR (CDCl3) (A) #(ppm) 0.90 9H Si-tBu 2.10 6H 2'4'-OCOMe 2.40 6H NMe2 4.41 1H H-1' (B) #(ppm) 0.90 9H Si-tBu 2.10 6H 2'4'-OCOMe 2.40 6H NMe2 6.32 1H H-10 EMI35.1 201 mg of the optical isomer (A) and 119 mg of the optical isomer (B) obtained at (1) above of 2',4'-di-O-acetyl- 3-O-tert-butyl-dimethylsilyl-23-C-(2-propenyl)mycaminosyl tylonolide diethylacetal were subjected to methanolysis to give, after chromatography (chloroform: methanol: 28% aqueous ammonia: 30:1:0.1), respectively 66 mg of one optical isomer (C) and 60 mg of another optical isomer (D) of 3-O-tert-butyldimethylsilyl-23 C-(2-propenyl)mycaminosyl tylonolide diethyl acetal as solid material. NMR (CDCl3) (C) # (ppm) 0.90 9H Si-tBu 1.86 3H 22-Me 2.55 6H NMe2 4.33 1H H-1' 6.27 1H H-10 (D) # (ppm) 0.90 9H Si-tBu 1.83 3H 22-Me 2.57 6H NMe2 4.33 1H H-1' 6.10 1H H-13 EMI37.1 66 me of the optical isomer (C) and 60 mg of the optical isomer (D) of 3-O-tert-butyldimethylsilyl-23 C-(2-propenyl)mycaminosyl tylonolida diethylacetal were hydrolysed. Usual work-up gave, after chromatography (chloroform:methanol:28% aqueous ammonia 20:1:0.1), respectively 40 mg of one optical isomer (E) and 39 mg of another optical isomer (F) of 23-C-(2 propenyl)mycaminosyl tylonolide as solid meterial. NMR (CDCl3) (E) # (ppm) 1.79 3H 22-Me 2.50 6H NMe2 4.27 1H H-1' 5.04 - 5.18 2H H-26 a. b. 5.65 - 5.82 1H H-25 6.11 1H H-13 6.30 1H H-10 7.40 1H H-11 9.59 1H H-20 (F) # (ppm) 1.83 3H 22-Me 2.51 6H NMe2 4.29 1H H-1' 4.98 1H H-15 5.13 - 5.23 2H H-26 a. b. 5.65 - 5.37 2H H-13 # H-25 6.25 1H H-10 7.26 1H H-11 9.70 1H H-20 Example 9 EMI39.1 To a cold (-78 C) solution of 903 mg of 2', 4'-di-O-acatyl-3-O-tert-butyl-dimethylsilyl-23-deoxy-23-oxo-mycaminosyl tylonolide diethylacetal, was added vinyl magnesium bromide (2M tetrahydrofuran solution), and usual work-up gave, after chromatography, 422 mg of one optical isomer (A) and 166 mg of another optical isomer (B) of 2', 4'-di-O acetyl-3-O-tert-butyldimethylsilyl-23-C-vinylmycaminosyl tylonolide diethylacetal as solid material. NMR (CDCl3) (A) # (ppm) 0.91 9H Si-tBu 2.11 6H 2'.4'-OCOMe 2.40 6H NMe2 4.42 1H H-1' 6.30 1H H-10 (B) # (ppm) 0.90 9H Si-tBu 2.10 6H 2'.4'-OCOMe 2.40 6H NMe2 6.31 1H H-10 EMI40.1 422 mg of the isomer (A) and 166 mg of the isomer (B) of 2,4-di-O-aocty]-3-O-tert-butyl diemethylsilyl-23-C-vinylmycaminosyl tylonolide diethylacetal were treated as in Example 8 (2) to give respect ively 350 mg of one isomere (C) and 73 mg of another isomer (D) of 3-O-tert-butyldimethylsilyl-23-C-vinylmycaminosyl tylonolide diethylacetal as solid meterial. NMR (CDCl3) (C) # (ppm) 0.87 9H Si-tBu 2.55 6H NMe2 4.30 1H H-1' 6.28 1H H-10 (D) # (ppm) 0.90 9H Si-tBu 2.55 6H NMe2 6.30 1H H-10 7.25 1H H-11 EMI42.1 350 mg of the isomer (C) and 73 mg of the isomer (D) of 3-O-tert-butyldimethylsilyl-23-C-vinylmycaminosyl tylonolide diethylacetal were treated as in Example 8 (3) to give respectively 186 mg of one isomer (E) and 45 mg of another isomer (F) of 23-C-vinylmycaminosyl tylonolide cS solid material. NMR (CDC13) (E) # (ppm) 1.78 3H 22-Me 2.3 2 -ri 4.28 1H NMe2 4.39 1H H-23 5.14 1H H-25a 5.2 - 5.3 2H H-15 # H-25 b 5.77 1H H-24 6.05 1H H-13 6.27 1H H-10 7.35 1H H-11 9.69 1H H-20 (F) # (ppm) 1.84 3H 22-Me 2.51 6H NMe2 4.25 - 4.34 2H H-1' # H-23 4.92 1H H-15 5.27 - 5.36 2H H-25 a, b 5.76 1H H-13 5.92 1H H-24 6.27 1H H-10 7.29 1H H-11 9.70 1H H-20 Example 10 EMI44.1 703 mg of 2'-O-acetyl-3-O-tert-butyldimethylsilyl4'-deoxymycaminosyl tylonolide diethylacetal was treated as in Example 9 (1) to give 300 mg of one isomer (A) and 105 mg of another isomer (R) of 2'-O-acetyl- 3-O-tert-butyldimethylsilyl-4'-deoxy-23-C-vinylmycaminosyl tylonolide diethylacetal as solid material. NMR (CDCl3) (A) # (ppm) 0.88 9H Si-tBu 2.11 3H 2'-OCOMe 2.30 6H NMe2 6.00 1H H-13 6.29 1H H-10 (E) # (ppm) 0.88 9H Si-tBu 2.10 3H 2'-OCOMe 2.29 6H NMe2 5.71 1H H-13 6.27 1H H-10 EMI45.1 300 mg of the isomer (A) and 105 mg of the isomer (B) of 2'-O-acetyl-3-O-tert-butyldimethylsilyl-4'-deoxy-23 C-vinylmycaminosyl tylonolide diethylacetal were treated as in Example 8 (2) to give respectively 175 mg of one optical isomer (C) and 65 mg of another optical isomer (D) of 3-O-tert-butyldimethylsilyl-4'-deoxy-23-C-vinylmycaminosyl tylonolide diethylacetal as solid material. NMR (CDCl3) (C) # (ppm) 0.90 9H Si-tBu 2.33 6H NMe2 4.77 1H H-20 6.30 1H H-10 (D) # (ppm) 0.91 9H Si-tBu 2.32 6H NMe2 6.31 1H H-10 7.27 1H H-11 EMI47.1 175 mg of the isomer (C) and 65 mg of the isomer (D) of 3-O-tert-butyldimethylsilyl-4'-deoxy-23-C-vinylmycaminosyl tylonolide diethylacetal were treated as in Example 8 (3) to give respectively 86 mg of one isomer (E) and 41 mg of another isomer (F) or 4'-deoxy-23-C-vinylmycaminosyl tylonolide as solid material. NMR (CDCl3) (D) # (ppm) 1.76 3H 22-Me 2.27 6H NMe2 4.22 1H H-1' 4.41 1H H-23 5.1 - 5.3 3H H-25 a.b, H-16 5.77 1H H-24 6.09 1H H-13 6.30 1H H-10 9.70 1H H-20 (F) # (ppm) 1.82 3H 22-Me 2.27 6H NMe2 4.23 1H H-1' 4.34 1H H-23 4.91 1H H-15 5.28 - 5.38 2H H-25 a, b 5.79 1H H-13 5.94 1H H-24 6.31 1H H-10 7.31 1H H-11 9.71 1H H-20 Example 11 EMI49.1 832 m of 2',4'-di-O-acetyl-3-O-tert-butyldimethylsilyl 23-deoxy-23-oxo-mycaninosyl tylonolide diethylacetal was treated with ethinyl magnesium bromide (tetrahydro furan solution) to give 160 mg of one isomer (A) and 177 mg of another isomer (B) of 2',4'-di-O-acetyl-3-O- tert-butyldimethylsilyl-23-C-ethinylmycaminosyl tylonolide diethylacetal as solid material. NMR (CDCl3) (A) # (ppm) 0.90 9H Si-tBu 2.10 6H 2',4'-OCOMe 2.41 6H NMe2 6.08 1H H-13 6.33 1H H-10 (B) # (ppm) 0.90 9H Si-tBu 2.10 6H 2',4'-OCOMe 2.40 6H NMe2 6.10 1H H-13 6.30 1H H-10 EMI50.1 160 mg of the isomer (A) and 177 mg of the isomer (B) of 2',4'-di-O-acetyl-3-O-tert- butyldimethylsilyl23-C-ethylmycaminosyl tylonolide diethylacetal were treated as in Example 8 (2) to give respectively 109 mg of one isomer (C) and 129 mg another isomer (D) of 3-O-tert-butyldimethylsilyl-23-C-ethinylmycaminosyl tylonolida diethylacetal as solid material. NMR (CDCl3) (C) # (ppm) 0.88 9H Si-tSu 2.53 6H NMe2 4.30 1H H-1' 6.05 1H H-13 6.32 1H H-10 7.30 1H H-11 (D) # (ppm) 0.88 9H Si-tBu 2.55 6H NMe2 4.33 1H H-1' 5.10 1H H-15 6.15 1H H-13 6.30 1H H-10 EMI52.1 109 mg of the isomer (C) and 129 mg of the isomer (D)# of 3-O-tert-butyldimethylsilyl-23-C-ethinylmycaminosyl tylonolide diethylacetal were treated as in Example 8 (3) to give respectively 75.5 mg of one isomer (E) or 101 mg of another isomer (F) of 23-Cethinylmycaminosyl tylonolide as solid material. NMR (CDCl3) (E) # (ppm) 1.84 3H 22-Me 2.51 6H NMe2 4.28 1H H-1' 4.63 1H H-23 5.23 1H H-15 6.12 1H H-13 6.34 1H H-10 7.39 1H H-11 9.70 1H H-20 (F) # (ppm) 1.85 3H 22-Me 2.51 6H NMe2 2.74 1H H-25 4.27 1H H-1' 4.58 1H H-23 5.10 1H H-15 6.12 1H H-13 6.30 1H H-10 7.43 1H H-11 9.69 2H H-20 Example 12 EMI53.1 814 mg of 2'-O-Cetyl-3-O-tert-butyldimethylsilyl4'-deoxymycaminosyl tylonolide diethylacetal was treated as in Example 11 (1) to give 103 mg of one isomer (A) and 118 mg of another isomer (B) of 2' O-acetyl-3-O-tert-butyldimethyl-4'-deoxy-23-C-ethinylmycaminosyl tylonolide diethylacetal as solid material. NMR (CDCl3) (A) # (ppm) 0.90 9H Si-tBu 2.12 3H 2'-OCOMe 2.30 6H NMe2 6.07 1H H-13 6.33 1H H-10 (B) # (ppm) 0.89 9H Si-tBu 2.10 3H 2'-OCOMe 2.30 6H NMe2 6.03 1H H-13 6.30 1H H-10 EMI55.1 103 mg of the isomer (A)and 118 m of te isomer (B) of 2'-O-acetyl-3-O-tert-butyldimethylsilyl-4'-deoxy23-C-ethinylmycaminosyl tylonolide diethylacetal were treated as in Example 8 (2) to give respectively 62 mg of one iscmer (C) or 70 mg of another isomer (D) of 3-O-tert-butyldiemthylsilyl-4'-deoxy-23-C-ethinylmycaminosyl tylonolide diethylacetal as solid material. NMR (CDCl3) (C) # (ppm) 0.88 9H Si-tBu 2.31 6H NMe2 5.28 1H H-15 6.07 1H H-13 6.33 1H - 1 O (D) # (ppm) 0.87 9H Si-tBu 2.30 6H NMe2 5.03 1H H-15 6.07 1H H-13 6.30 1H H-10 EMI56.1 62 mg of the isomer (C) and 70 mg of the isomer (D) of 3-O-tert-butyldimethylsilyl-4'-deoxy-23-C-ethinylmycaminosyl tylonolide diethylacetal were treated as in Example 8 (3) to give respectively 38 mg of one isomer (E) and 40 mg of another isomer (F) of 4'-deoxy23-C-ethinylmycaminosyl tylenoclide as solid material NMR (CDCl3) (E) # (ppm) 1.82 3H 22-Me 2.27 6H NMe2 2.50 1H H-25 4.23 1H H-1' 4.64 1H H-23 5.23 1H H-15 6.13 1H H-13 6.34 1H H-10 7.42 1H H-11 9.72 1H H-20 (F) # (ppm) 1.84 3H 22-Me2 2.28 6H NMe2 2.70 1H H-2S 4.22 1H H-1' 4.57 1H H-23 5.08 1H H-15 6.11 1H H-13 6.35 1H H-10 7.43 1H H-11 9.72 1H H-20

Claims: CLAIMS: 1. A 23-C-substituted mycaminosyl tylonolien compound of the following general formula (I): EMI58.1 wherein RÚ represents a C1 to C5 alkyl group, an aryl group, a C2 to C6 alkenyl group or a C2 to C6 alkinyl group, and Rê represents a hydrogen atom or hydroxyl group. 2. A compound according to claim 1 wherein RÚ represents a C1 to C5 alkyl group, a C2 to C6 alkyl group, or a C2 to C6 alkinyl group. 3. A process for producing a compound according to claim 1 which is characterizes by reacting a compound of the formula: EMI58.2 with Grignard reagent of the formula RÚMgX or with organic lithium com 1 pound of the and then raleasin the hydroxyl- and aldehyde-protective groups wherein Rê' represents a hydrogen atom or a protected hydroxyl group, R3 represents a protective group for a hydroxyl group, R represents a protected aldehyde group, R5 represents a protective group for a hydroxyl group RÚ and R2 are as defined in claim. 1 and X represents a halogen atom. 4. An antibacterial composition containing as an effective component at least one compound according to claim 1

Inventors: SAKAMOTO, SHUICHI, TAKEUCHI, TOMIO, TANAKA, AKIHIRO, TSUCHIYA, TSUTOMU, UMEZAWA, HAMAO, UMEZAWA, SUMIO
Applicants: MICROBIAL CHEM RES FOUND
Application year: 1985
Main classification: C07H17
IPC codes: C07H17