Oxytetracycline 0 1541 Formulafion(s): vaginal jelly 0.025 % (as sulfate) Trade Name(s): D: Antimycoticum Stulln (Stu1ln)-comb.; wfrn Aperisan Gel (Dentinox)- comb.; wfm Brand-u. Wundgel Herit (Engelhard)-comb.; wfrn Chinomint Plus (Chinoso1fabrik)-comb.; wfm Chinosol (Chinoso1fabrik)- comb.; wfm Fungiderm (Terra-Bio)- comb.; wfrn Nasalgon (Labophama)- comb.; wfrn Onychofissan (Fink)- comb.; wfrn Ovis (Warner)-comb.; wfrn Robumycon (Robugen)- comb.; wfrn Semori (Luitpold); wfrn Trachi form-V (Starke)- comb.; wfrn F: Chromargon (Richard)- comb. Dermacide (Labs. CS)- comb. Quinocarbine (GNR- pharma)-comb. UvCline (Crinex) GB: Aci-jel (Ortho-Cilag)- comb.; wfrn I: Anticolitico Roberts (Manetti Roberts); wfrn Cortanol (Schiapparelli Farm.)-comb.; wfrn Foille (1snardi)-comb.; wfrn Leucorsan (Zil1iken)-comb. Viderm (Gerassini)-comb. USA: Aci-jel (Ortho-McNei1)- comb. Oxytetracydine ATC: D06AA03; G01AA07; J01AA06; SO 1 AA04 Use: antibiotic RN: 79-57-2 MF: C,,H,N,O, MW: 460.44 EJNECS: 201-212-8 LDo,: 140 mglkg (M, i.v.); 2240 mglkg (M, p.0.); 260 mglkg (R, i.v.); 4800 mglkg (R, p.0.) CN: [4S-(4a,4aa,5a,5aa,6(3,12aa)]-4-(dimethylamino)- l,4,4a7S,5a,6,1 1,12a-octahydro-3,5,6,10,12,12a- hexahydroxy-6-methyl- 1,11 -dioxo-2-naphthacenecarboxamide monohydrochIoride RN: 2058-46-0 MF: C2,H2,N209 . HC1 MW: 496.90 EINECS: 218-161-2 LD,,,: 100mg/kg(M,i.v.);6696mglkg(M,p.o.); 302 mglkg (R, i.v.) Oxytetracycline From fermentation solutions of Streptomyces rimosus. Reference(s): US 2 51 h 080 (Pfizer; 1950; prior. 1949). Finlay, A.C. et al.: Science (Washington, D.C.) (SCIEAS) 111,85 (1950). stabilized formulations: US 3 017 323 (Pfizer; 16.1.1962; prior. 1952). US 3 026 248 (Pfizer; 20.3.1962; prior. 11.9.1959). BE 861 855 (Philips; appl. 14.12.1977; GB-prior. 16.12.1976). Formulation(s): cps. 250 mg, 500 mg; eye ointment 10 mglg; ointment 10 mglg; vial 5 ml (as hydrochloride) 1542 0 Oxytocin Trade Narne(s): D: Bisolvomycin (Boehringer 1ng.)-comb. with bromhexine Corti Biciron (S & K Pharma)-comb. with tramazoline Corti Biciron Augensalbe (S & K Pharma)-comb. with dexamethasone 21- isonicotinate Dura Tetracyclin (durachemie) Macocyn (Mack) F: Oxytetracyclin Augensalbe Jenapharm (Alcon; Jenapharm) Oxytetracyclinsalbe (Leyh) Terracortil (Pfizer)-comb. with hydrocortisone Terramycin (Pfizer)-comb. TerramycinIDepot (Pfizer) Terravenos (Pfizer) Tetracycletten (Voigt) GB : Tetra-Gelomyrtol (Poh1)- comb. Tetra-Tablinen (Beiersdorf- Tablinen) Tetra-Tablinen (Sanorania) I: Vendarcin (Schering) numerous combination J: preparations Auricularum (SCro1am)- comb. USA: Posicycline (Alcon) Primyxine (Thera France)- comb. Ster-Dex (CIBA Vision 0phthalmics)-comb. Terramycine (Pfizer) Tetranase (Rottapharm) comb. Stecsolin (Squibb) Terra-cortril (Pfizer)-comb. Terramycin (Pfizer)-comb. Trimovate (Glaxo Wellcome)-comb. Cosmiciclina (Alfa 1ntes)- comb. Geomycin (Otsuka) Oxeten (Mochida) Terramycin (Taito F'fizer) Terra-Cortril (Pfizer) Terramycin (Pfizer) Urobiotic-250 (Pfizer) Oxytocin ATC: HOIBBO2 Use: posterior lobe of pituitary gland hormone RN: 50-56-6 MF: C,,H,,N,2012S2 MW: 1007.21 EINECS: 200-048:4 LD,,: 5800 pglkg (M, i.v.); >514 mglkg (M, p.0.); 2275 pgkg (R, i.v.); >20.52 mglkg (R, p.0.) CN: L-~ysteinyl-~-tyrosyl-~-isoleucyl-~-glutaminyl-~-asparaginyl-~-cystein~l-~-prolyl-~-leuc~l~l~cinamide cycllc (136)-disulfide oxidation ____, L-C 6 L Tyr L Ilo-L-Glu-L-Asp-L-Cys-L-Pro-L-Leu-Gly-NH2 f (only schematic) In each case by use of S- and N-trityl groups Ozagrel 0 1543 Reference(s): US 2 938 891 (Roussel-Uclaf; 31.5. 1960; F-prior. 30.3.1956). US 3 076 797 (Roussel-Uclaf; 5.2.1963; F-prior. 22.7.1957). Formulation(s): amp. 3 iulml, 5 iulml, 10 iu/ml; spray 40 iulml Trade Name(s): D: Orasthin (Hoechst) F: Oxytocin Hexal (Hexal) GB: Oxytocin-Noury (Nourypharma) Syntocinon (Novartis I: Pharma) Syntometrin (Novartis J: Pharma)-comb. Synthocinon (Novartis) Pitocin (Sankyo) Syntocinon (Novartis) Pituitan (Nippon Zoki) Syntometrine (Novartis)- Syntocinon (Sandoz- comb. Sankyo) Syntocinon (Novartis USA: Pitocin (Parke Davis) Farma) Atonin-0 (Teikoku Zoki) Orasthin (Hoechst) Ozagrel (OKY-046) ATC: BOlAC Use: thromboxane synthetase inhibitor, platelet aggregation inhibitor RN: 82571-53-7 MF: C,,H,2N202 MW: 228.25 LD,,: 1940 mgikg (Mm, i.v.); 1580 mgikg (Mf, i.v.); 3800 mgikg (M, p.0.); 1150 mgikg (Rm, i.v.); 1300 mglkg (Rf, i.v.); 5900 mglkg (R, p.0.) CN: (E)-3-[4-(1H-imidazol-l-ylmethyl)phenyl]-2-propenoic acid monohydrochloride monohydrate RN: 83993-01-5 MF: C13H,2N202. HCI . H20 MW: 282.73 monohydrochloride RN: 7871 2-43-3 MF: C,,H12N202 . HCI MW: 264.71 2. benzayl peroxide fl0^CH3 - , H,C 1. N-bromo- succinimide ethyl 4-methylcinnamote imidazole ethyl 4-(1 -imidozolylmethyl)- cinnamote ethyl 4-(bromomethy1)- cinnamate (1) NoOH 4 P-cOO" Ozagrel Reference(s): US 4 226 878 (Kissei, Ono; 7.10.1980; J-prior. 13.6.1978). DOS 2 923 815 (Ono; appl. 12.6.1979; J-prior. 13.6.1978). Iizuka, K. et al.: J. Med. Chem. (JMCMAR) 24, 1139 (1981). 1544 0 Ozagrcl synthesis of ethyl 4-(bromomethy1)cinnamate: DOS 2 755 759 (Merck & Co.; appl. 14.12.1977; USA-prior. 17.12.1976). Fomulution(s): amp. 20 mg Trade Name(s): J: Cataclot (Ono; 1988) Xanbon (Kissei; 1988) Paclitaxel P 1545 Paclitaxel (BMS-181339; NSC- 125973) ATC: LOlCDOl Use: antineoplastic RN: 33069-62-4 MF: C47H51N014 MW: 853.92 CN: [2aR-[2aa,4P,4aP,6fl,9a(aR*,@S*), 1 la, 12a, l2aa,l2ba]]-P-(benzoy1amino)-a- hydroxybenzenepropanoic acid 6,12b-bis(acetyloxy)-12-(ben~~lo~y)-2a,3,4,4a,5,6,9,10,11,12,12a,l2b- dodecahydro-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,1 l -methano- 1 H-cyclodeca[3,4]benz[1.2- cloxet-9-yl ester 0 pyridine. 23 OC + Tes-CI + Hp$ 10-deocetylboccotin In (I) triethyl- (isolated from the leaves sily l of Taxus boccota L.) chloride pyridine, 0 OC __* ocetyl chloride 7-0-triethylsilyl- baccatin I11 (UI) 1. BuLi, hexone, THF. -45 OC 2. separation of epimers by chromatography ond recrystallization cis- 1 -benzoyl- 2',7-bis(triethylsily1)- 3-(triethylsilyl- paclitaxel (V) oxy)-4-phenyl- 2-azetidinone (N) 1546 P Paclitaxel 0 aq. HF, acetonitrile. pyridine. 0 OC v. I Paclitaxel @ synthesis of IV: ethyl glycolate triethyl- silyl chloride (VI) '? Tes 1. BuLi, ether H C N CH, ' xH$H3 THF, -50 OC - 78 OC "I1 + p""' . + N lithium diiso- 2. benzoyl propylomide chloride (VIII) N-(trimethyl- cis-3-(triethyl- aldehyde imine benzaldehyde p-methoxy- aniline 2. ceric ammonium nitrate. H CH3CN, -10 OC b 0 2-ocetoxyacetyl chloride (X) cis-3-ocetyloxy- 4-phenyl-2- azstidinane (XI) Paclitaxel P 1547 KOH. HZO. THF 1. VI , pyridine 0 "C 2. BuLi. VlII (3R.45)-3- hydroxy-4- phenyl-2- ozetidinone (XU) 1. KOH 2. KOtBu. 1. THF, H+ H 3 C 'f 0,CH3 F) 2. BuLi, ether, VIII , -78 OC py, H3C-8-CI 0 XI + H,C+O~CH, * 02,m ethyl vinyl ether (XlU) " 6 nyi chloride 1. BuLi, THF, -45 OC 2. HCI. C,H,OH, 0 OC NOON 1. us CY toluene, 73 OC COOH 2. HCI. C2H50H. H20 0 CH3 Y 1. di(2-pyridyl) corbonote 0,CH3 4-dimethylomino- pyridine (2R.3S)-N-benzoyl- 0-0 -ethoxyethyl)- 3-phenylisoserine (XV) @ synthesis of intermediote XV (or unprotected onologues) (for more 3-phenylisoserine syntheses see Docetoxel) 1. NoN3. C2H50H 0 2. HCI, C2H50H 3. Hz. Pd-C. CzH50H OH threo-ethyl 2-hydroxy-3- amino-3-phenyl- propionote (XVI) - - - - 1548 P Paclitaxel 2. XllI 3. LIOH, C2H50H XVI , xv u tert-butanol. K20s02(0H)4, OH 0 DHQ-PHAL 0 , * AH3 CH3 N-methyl- morpholine oxide trons-methyl cinnamote XVIl - 2. acetyl bromide 1. NoN,, DMF. 50 OC 2. HZ, Pd-C 3. 10% oq. HCI 4. VIII, 2N NaOH XVIII + / OH rCooH (2R.3S)-N-benzoyl- 3-phenylisoserine (XIX) THF. CH2CI,. -35 OC H,C//'M@ ._____* dN - N-benzoyl-L- vinylmagnesium phenylglycinal bromide Tos-OH. CH,CN 2. RuCI,. NolO,, CH,CN. NaHCO, 3. (+)-ephedrine, acetone xx -xv (-)-(lS.2S)-N-(2- hydroxy-1 -phenyl- 3-butenyl)benz- omide (XX) cis-methyl cinnamale N-oxide (XXI) Paclitaxel P 1549 1. KOH, THF 2. HCI, CH OH 3.qo3fl 3. benzoic onhydride b methyl (2R,3S)-benzoylomino~ 2- hydroxy-3-phenylpropionate microbial reduction ______* O/"CH, (?)-ethyl 2-oxo-3- benzoylamino-3- phenylpropionate (2R,3S)-N-benzoyl- 3-phenylisoserine ethyl ester Lipase PS-30 (from Pseudomonos cepacia) 0 29 "C, pH 7.0 0' 1550 P Paclitaxel Reference(s): a Denis, J.N. et al.: J. Am. Chem. Soc. (JACSAT) 110, 5917-5919 (1988). WO 9 306 094 (Florida State Univ.; appl. 22.9.1992; USA-prior. 3.4.1992, 23.9.1991). George, G.I. et al.: J. Med. Chem. (JMCMAR) 35,4230-4237 (1992). aa US 5 01 5 744 (Florida State Univ.; appl. 14.11.1989). Georg, G.I. et al.: Bioorg. Med. Chem. Lett. (BMCLEB) 3,2467-2470 (1993). ab WO 9 418 164 ( Univ. New York State; appl. 28.1.1994; USA-prior. 1.2.1993). Ojima, I. et al.: J. Org. Chem. (JOCEAH) 56, 1681-1683 (1991). Holton, R.A. et al.: Bioorg. Med. Chem. Lett. (BMCLEE) 3, 2475 (1993). b US 5 254 703 (Florida State Univ.; appl. 6.4.1992; USA-prior. 6.4.1992). EP 428 376 (Florida State Univ.; appl. 13.1 1.1990; USA-prior. 14.1 1.1989). c Denis, J.N. et al.: J. Am. Chem. Soc. (JACSAT) 110,5917-5919 (1988). ca Denis, J.N. et al.: J. Org. Chem. (JOCEAH) 51,46-50 (1986). cb Sharpless, B. et al.: J. Org. Chem. (JOCEAH) 59,5104 (1994). cc Denis, J.N. et al.: J. Org. Chem. (JOCEAH) 56,6939 (1991). EP 528 729 (RhGne-Poulenc Rorer; appl. 17.8.1992; F-prior. 19.8.1991). cd Deng, L. et al.: J. Org. Chem. (JOCEAH) 57,4320-4323 (1992). Denis, J.N. et al.: J. Org. Chem. (JOCEAH) 55, 1957 (1990). ce WO 9 3 17 997 (RhGne-Poulenc Rorer; appl. 16.9.1993; F-prior. 10.3.1992). WO 9 422 813 (RhGne-Poulenc Rorer; appl. 25.3.1994; F-prior. 29.3.1993). cf Pabel, R.N. et al.: Tetrahedron: Asymmetry (TASYE3) 33, 5185-5188 (1993). cg Pabel, R.N. et al.: Biotechnol. Appl. Biochem. (BABIBC) 20,23-33 (1994). further chemoenzymalic resolutions: Hoenig, H. el al.: Tetrahedron (TETRAB) 46,3841-50 (1990). Gonet, D M. et al.: J. Org. Chem. (JOCEAH) 58, 1287-1289 (1993). Brieva, R. et al.: J. Org. Chem. (JOCEAH) 58, 1068 (1993). ester~fication: Commercon, A. et al.: Tetrahedron Lett. (TELCAY) 33,5185 (1992). reviews: Hepperle, M.; Georg, G.1.: Drugs Future (DRFUD4) 19,573-584 (1994). Georg, G.I. et al.: Expert Opin. Ther. Pat. (EOTPEG) 4, 109-120 (1994). Nicolaou, K.C. et al.: Angew. Chem. (ANCEAD) 107,2247-2259 (1995). total synthesis of faxanes: Holton, R.A. et al.: J. Am. Chcm. Soc. (JACSAT) 116, 1599-1600 (1994). Masters, J.J. et al.: Angew. Chcm. (ANCEAD) 107, 1883 (1995). Nicolaou, K.C. et al.: Nature (London) (NATUAS) 367,630-634 (1994). US 5 274 137 (K. C. Nicolaou et a].; appl. 23.6.1992; USA-prior. 23.6.1992) Wessjohann, L.: Angew. Chem. (ANCEAD) 106, 1011 (1994). purijcation of 10-deacetylbaccatin 111: WO 9 421 622 (RhGne-Poulenc Rorer; appl. 18.3.1994; F-prior. 22.3.1993). production of taxanesfrom explant tissue: EP 568 821 (Squibb; appl. 6.4.1993; USA-prior. 7.4.1992) liposome formulation: US 5 415 869 (Univ. New York State; appl. 12.1 1.1993; USA-prior. 12.1 1.1993). cyclodextrine complexes: WO 9 426 728 (Chinoin; appl. 9.5.1994; HU-prior. 12.5.1993). use ugainst protozoa: WO 9 41 2 172 (Th. Jefferson Univ.; appl. 2.12.1993; USA-prior. 2.12.1992, 26.1.1993). Formulation(s): vial 30 mgI5 ml . L-~ysteinyl-~-tyrosyl-~-isoleucyl-~-glutaminyl-~-asparaginyl-~-cystein~l-~-prolyl-~-leuc~l~l~cinamide cycllc (136)-disulfide oxidation ____, L-C 6 L Tyr L Ilo-L-Glu-L-Asp-L-Cys-L-Pro-L-Leu-Gly-NH2 f. 6,12b-bis(acetyloxy )-1 2-( ben~~lo~y )-2 a,3,4,4a,5,6,9,10,11,12,12a,l2b- dodecahydro-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,1 l -methano- 1 H-cyclodeca[3,4]benz[1. 2- cloxet-9-yl ester 0 pyridine. 23 OC + Tes-CI + Hp$ 10-deocetylboccotin. RuCI,. NolO,, CH,CN. NaHCO, 3. (+)-ephedrine, acetone xx -xv (-) -( lS.2S)-N-( 2- hydroxy-1 -phenyl- 3-butenyl)benz- omide (XX) cis-methyl cinnamale N-oxide (XXI) Paclitaxel P 1549