Isoxicam I 11 I1 C H + o&' -+ COOH (1) (Z)-0-formyl- lsotretinoin crotonic acid (cf. retinol synthesis) Reference(s): Garbers, C.F. et al.: J. Chern. Soc. C (JSOOAX) 1968, 1982. (Z)-P-formylcrotonic acid: Conradie, W.J. et al.: J. Chern. Soc. C (JSOOAX) 1964, 594. combination with taurine: US 4 545 977 (Searle; 8.10.1985; appl. 11.1.1985). medical use: DE 2 061 507 (Hoffrnann-La Roche; appl. 8.7.1971; prior. 14.12.1970). US 3 746 730 (Hoffmann-La Roche; 17.7.1973; appl. 17.12.1970; GB-prior. 13.12.1969). Formulatinn(s): cps. 2.5 mg, 5 mg, 10 rng, 20 mg; gel 0.05 % Trade Name(s): D: ISOTREX (Stiefel) Roaccutane (Roche; 1986) Roaccutane (Roche) Roaccutan (Roche; 1985) GB: Isotrex (Stiefel) I: Roaccutane (Rochc) F: Isotrex (Stiefel) Isotrexin (Stiefel) USA: Accutane (Roche; 1982) Isoxicam ATC: MOI Use: anti-inflammatory RN: 34552-84-6 MF: C,,H,,N,O,S MW: 335.34 EINECS: 252-084-5 LD,,: >5 g/kg (R, p.0.) CN: 4-hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-l,2-benzothiazine-3-carboxarnide I, I -d~ox~de 3-ethoxycarbonyl- 3-amino-5- 4-hydroxy-2-methyl- methyl- 2H-1,2-benzothiazine isoxozole 1 ,l -dioxide (cf. piroxicam synthesis) OH 0 lsoxicom '33 DOS 2 208 351 (Warner-Lambert; appl. 22.2.1972; USA-prior. 1.3.1971). Lornbardino, J.G.; Wiseman, E.H.: J. Med. Chem. (JMCMAR) 14,973 (1971). Zinnes, H. et al.: J. Med. Chern. (JMCMAR) 25, 12 (1982). Formulation(s): cps. 100 mg 11 12 1 Isoxsuprine Trade Name(s): D: Pacyl (Adenylchcmie); F: Vectren (Substantia); wfm Maxicam (Parke Davis); wiin 1: Floxicam (Menarini); wfm wfm Isoxsuprine ATC: CO4AAOl Use: vasodilator RN: 395-28-8 MF: C,,H,,NO, MW: 301.39 EINECS: 206-898-2 LD,,: 48 mglkg (M, i.v.); 200 mglkg (M, p.0.) CN: 4-hydroxy-cr-[1-[(1-methyl-2-phenoxyethyl)amino]ethyl]benzenemethanol hydrochloride RN: 579-56-6 MF: C,,H,,NO,. HCI MW: 337.85 EINECS: 209-443-6 LD,,: 6 1 mgkg (M, i.v.); 1.1 glkg (M, p.0.); 1.75 gfkg (R, p.0.); 57 mgikg (dog, i.v.); >I .2 glkg (dog, p.0.) phenoxypropone 4-hydroxy- 1 -phenoxy-2- 4'-benzyloxy- propiophenone lsaxsuprine Reference(s): US 3 056 836 (Philips; 2.10.1962; NL-prior. 28.3.1955). GB 832 286 (Philips; appl. 11.10.1957; NL-prior. 15.10.1956). GB 832 287 (Philips; appl. ll.lO.1957; NL-prior. 15.10.1956). norephedrine brornopropane Formulation(s): amp. 10 mg; cps. 40 mg; r. r. cps. 40 mg; tabl. 10 mg, 20 mg (as hydrochloride) Trade Name(s): D: Duvadilan (Thomael Duvadilan (Duphar): wfm Isokulin (Toho lyaku Duphar); wfm I: Duvadilan (UCM) Kenkyusho) Vasoplex (Lappe); wfm Fenam (UCM) Synzedrin (Teisan) F: Duvadilan (Solvay Pharma) Vasosuprina (Lusofarmaco) Vahodilan (Morita) GB: Defencin (Bristol); wfm J: Duvadilan (Daiichi) Vasoladin (Kanto) Isradipine 1 11 13 USA: Isolait (Elder); wfm Vasodilan (Mead Johnson); generic wfm Isradipine ATC: C02DE; COSCAOS (Isrodipine; PN 200- 1 10) Use: long acting calcium antagonist, antihypertensive, antianginal RN: 75695-93-1 MF: CI,H,,N,OS MW: 371.39 LD,,,: 1.2 mglkg (M, i.v.); 216 mg/kg (M, p.0.); 1.8 mglkg (R, i.v.); >3000 mg/kg (R, p.0.); 1.2 mglkg (rabbit, i.v.); 58 mglkg (rabbit, p.0.) CN: 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester H 1. H,C-L~ , H3CYNYCH3 CH3CH3 FH3 2. OHC-N, CH3 b 1. butyllithium, diisopropylomine 2.1 Jbenz- 2. dimethviformamide oxodiozole isopropyl 2-acetyl- 3-(2,1,3-benzodioxazol- 4-yl-2-propenoote (I) CHO H3Crn0yCH3 6" 0 0 CH, . .o N isopropyl ocetoocetote 2.1,3-benz- oxadiazale- 4-carboxaldehyde methyl 3-amino- 2-butenoate lsrodipine DE 2 949 491 (Sandoz; appl. 8.12.1979; CH-prior. 18.12.1978). GB 2 122 192 (Sandoz; appl. 13.6.1983; CH-prior. 15.6.1982). US 4 466 972 (Sandoz; 21.8.1984; appl. 19.3.1982; CH-prior. 18.12.1978). synrhesis of 2,1,3-benzoxadiazole-4-carboxaldehyde: CH 661 270 (Sandoz 15.1 1.1982; GB-prior. 18.11.1981). synthesis of enantiomers: DE 3 320 616 (Sandoz; appl. 8.6.1983; CH-prior. 15.6.1982). sustained release formulation: US 4 950 486 (Alza; 21.8.1990; prior. 7.1 1.1988,2.10.1987). US 4 946 687 (Alza; 7.8.1990; prior. 7.1 1.1988,2.10.1987). US 4 816 263 (Alza; 28.3.1989; prior. 7.1 1.1988,2.10.1987). hydrosol formulation: GB 2 200 048 (Sandoz; appl. 17.12.1987; D-prior. 19.12.1986, 15.12.1987). DE 3 742 473 (Sandoz; appl. 19.12.1986). combination with calcitonin: EP 202 282 (Sandoz; appl. 8.1 1.1985; GB-prior. 12.1 1.1984). 1 1 14 1 Itopride hydrvchloride nanoparticles: Leroueil-Le Verger, M. et al.: Eur. J. Pharm. Biopharm. (EJPBEL) 46, 137-143 (1998) Formulation(s): cps. 2.5 mg, 5 mg; s. r. tabl. 5 mg, 10 mg; tabl. 2.5 mg Trude Name(s): D: Lomir (Novartis Pharma) GB: Prescal (Novartis) Lomir (Sandoz) Vascal (Schwarz; 1991) I: Clivoten (Lifepharma) USA: Dyna Circ (Novartis) F: lcaz LP (Novartis) Esradin (Sigma-Tau) Itopride hydrochloride ATC: DOE (1 5 1235 (as hydrochloride); 149097 (as free base)) Use: peristaltic stimulant, gastric prokinetic agent RN: 122892-31-3 MF: C2,H1,N,04. HC1 MW: 394.90 LD5& 190.6 mglkg (M, i.v.) CN: N-[[4-[2-(dimethylamino)cthoxy]phenyl]methyl]-3,4-dimethoxybenzamide monohydrochloride base RN: 122898-67-3 MF: C,,,H2,N204 MW: 358.44 p-hydraxy- benzaldehyde NH,, H,C-OH, Roney-Ni I * 3.4-dimethoxy- ltopride hydrochloride benzoyl chloride 1. toluene H3codcl 2. tic, , I1 + H,C-0 preparation and formulation: EP 306 827 (Hokuriku Pharmaceutical Co.; appl. 15.3.1989; J-prior. 1.9.1988, 5.9.1987,22.9.1987, 29.9.1987, 5.10.1987). 0 H,C-0 H3C-0 synthesis of inrerntediure 11: US 2 879 293 (Hoffmann-La Roche; 1957). Formulation(s): tabl. 50 mg (hydrochloride) Itraconazole 1 11 15 Trade Name(s): J: Ganaton (Hokuriku) Itraconazole (R-51211) ATC: J02AC02 Use: antifungal (treatment of vaginal candidiasis pityriasis versicolor, dermatophytes and systemic mycoses) RN: 84625-61 -6 MF: C35H38Cl,N80, MW: 705.65 LD,,: 46.4 mglkg (M, i.v.); r320 mglkg (M, p.0.); 40 mglkg (R, i.v.); >320 mglkg (R, p.0.); >200 mglkg (dog, p.0.) CN: 4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol- 1-ylmethy1)-l,3-dioxolan-4-yl jmethoxy]phenyl]- I-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-l,2,4-triazol-3-one 2. Cl% . pyridine OH 1. bromine 2. benzoyl chloride 2'.4'-dichloro- glycerol acetophenone 1. NOH 2. seporotion by liquid chromotogrophy 3. H3C-SO2-CI . pyridine 0 cis-[Z-bromo- 1 H- 1.2.4- methyl-2-(2,4- triozole dichlorophenyl)- l,3-dioxolon-4- yimethyl] benzoate (I) cis-2-(2,4-dichloro- phenyl)-2-(1 H-1,2,4- triozol-1-ylmethy1)- 1,3-dioxolone-4- methonol methone- sulfanote (11) 11 16 1 Itraconazole 1. K,CO, 2. H2, Pd-C CI 3. phenyl chloroformote p-chloronitro- benzene 1. H2N-NH2 2. HNd% IV F 1. hydrozine 2. forrnomidine Reference(s): EP 1 18 138 (Janssen; appl. 24.1.1984; USA-prior. 28.2.1983). 2-brornobutone alternative synthesis: EP 6 71 1 (Janssen; appl. 13.6.1979; USA-prior. 23.6.1978, 14.3.1979). US 4 267 179 (Janssen; 12.5.1981; appl. 14.3.1979; prior. 23.6.1978). Meeres, J.; Backx, L.J.J.; Cutsem, J. van: J. Med. Chem. (JMCMAR) 27,894 (1984). ltraconozole synthesis of cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-tazol-l-ylmethyl)-l,3-dioxolane-4-methanol methanesulfonate: Meeres, J. et at.: J. Med. Chem. (JMCMAR) 22, 1003 (1979). Meeres, J.; Hendrickx, R.; Cutsem, J. van: J. Med. Chem. (JMCMAR) 26,611 (1983). topical liposomal formulation: WO 9 31 5 7 19 (Janssen; appl. 4.2.1993; EP-prior. 12.2.1992). pharmaceutical composition: WO 9 416 700 (Sepracor; appl. 27.1.1994; USA-prior. 27.1.1993). Formulation(s): cps. 100 mg, sol. 1 % Trade Name(s): D: Sempera (Glaxo Wellcome; F: Sporanox (Janssen-Cilag) Triasporin (Lifepharma) Janssen-Cilag) GB: Sporanox (Janssen-Cilag) J: Itrizole (Janssen-Kyowa) Siros (Janssen-Cilag) I: Sporanox (Janssen) USA: Sporanox (Janssen; 1999) Josamvcin J 11 17 Josam ych ATC: JOIFAO7 Use: antibiotic RN: 16846-24-5 MF: C42H69N0,5 MW: 828.01 EINECS: 240-871-6 CN: leucomycin V 3-acetate 4B-(3-methylbutanoate) propionate RN: 51016-68-3 MF: C4,H.,,NOI, MW: 884.07 CH3 Josamycin From fermentation solutions of Streptomyces narbonensis Val: josamyceticus (Am 17835). Reference(s): DOS 1 492 035 (Microbial Chem. Res.; appl. 3.6.1965; J-prior. 9.6.1964). US 3 636 197 (Yamanouchi; 18.1.1972; J-prior. 9.6.1964). alternative syntheses: from 10-acetyl- and 10,2'-diacetyljosamycin: JP-appl. 76/41 497 (Yamanouchi; appl. 2.10.1974). from 3-deacetyljosamycin: JP-appl. 77/41 294 (Microb. Res. Found.; appl. 26.9.1975). water soluble H2S0,-D-glucosamine addition compound. JP-appl. 77/71 489 (Yamanouchi; appl. 31.10.1975). solvent free crystals: JP-appl. 77/51 013 (Yamanouchi; appl. 16.10.1975). JP-appl. 761142 519 (Yamanouchi; appl. 3 1.5.1975). pllarmaceutical formulation: US 3 960 757 (Toyo Jozo; 1.6.1976; prior. 29.6.1973). Formulation(s): gran. 1 g; susp. 150 mg, 300 mg; tabl. 500 mg (as propionate) Trade Name(s): D: Wilprafen (Yamanouchi; I: Iosalide (Schering) J: Josamycin (Yamanouchi; 1984) Josaxin (UCB) 1970) F: Josacine (Bellon; 1980) Ill8 K Kanamycin (A) Kanamycin (A) ATC A07AA08; JOIGB04 Use: antibiotic RN: 59-01 -8 MF: C,nHy,N40,1 MW: 484.50 EINECS: 200-41 1-7 LD,,,: 115mg/kg(M,i.v.);20.7mg/kg(M,p.o.); 437 mglkg (R, 1.v.); >10 glkg (R, p 0.) CN: 0-3-amino-3-deoxy-a-D-glucopyranosyl-(1+6)-0-[6-am1no-6-deoxy-a-~-glucopyranosyl-(1+4)]-2- deoxy-D-streptamme sulfate (1:l) RN: 25389-94-0 MF: C,nH,,N4011 . H,SO, MW: 582.58 EINECS: 246-933-9 HOl From fcrmcntation solutions of Streptomyces kanamyceticus. Reference(s): US 2 93 1 798 (H. Umezawa, K. Maeda, M. Meda; 5.4.1960; J-prior. 5.9.1956). US 2 936 307 (Bristol-Myers; 1960; appl. 1957). US 2 967 177 (Bristol-Myers; 1961; appl. 1958). US 3 032 547 (Merck & Co.; 1962; appl. 1958). Formulation(s): amp. 1 g (as sulfate); cream 5 mglg; eye drops 5 mglml Trade Name(s): D: Kanamycin-POS (Ursapharm) Kanamy trex (Alcon) Kana-Ophthal (Winzer; as sulfate) F: Kamycine (Bristol-Myers Squibb) StCrimycine (CIBA Vision 0phthalmics)-comb. GB: Kannasyn (Sanofi Winthrop) 1: Dermaflogil (Nuovo Cons. Sanit. Naz.)-comb. Fluomicetina (Zoja)-comb. Kanaderm (Firma)-comb. Kanamicina Firma (Firma) Kanatrombina (Ba1dacci)- comb. Kanazone (SIT)-comb. Keimicina (Boehringer Mannh.) Roseomix (Farmigea)- comb. generic J: Kanacillin (Banyu; Meiji)- comb. Kanacyclin (Banyu; Meiji)- comb. Kanafuracin (Fujita)-comb. Kanamycin (Banyu; Meiji; Tanabe; Yamanouchl) generic USA: Kantrex (Bristol); wfm generic Kawain K 11 19 Kawain (Kavain; Cavain) ATC: C04 Use: anticonvulsant, psychotonic RN: 500-64-1 MF: C,,H,,O, MW: 230.26 EINECS: 207-907-2 LD,,,: 69 mgkg (M, i.v.); 1130 mglkg (M, p.0.) CN: [R-(E)]-5,6-dihydro-4-methoxy-6-(2-phenylethenyl)-2H-pyran-2-one 0 OvCHJ 2 LcHO H3c,7 1. N-brorno- 0 succinirnide 2. cinnamaldehyde 0 ethyl acetaacetate (1) dimethyl sulfote Kawain Referencefs): FR 1 526 596 (Spezialchemie; appl. 9.6.1967; D-prior. 29.7.1966). alternative svntheses: Fowler, E.M.; Henbest, H.B.: J. Chem. Soc. (JCSOA9) 1950,3642 (racemate). Kostermans, D.G.F.R.: Recl. Trav. Chim. Pays-Bas (RTCPA3) 70,79 (1951) (racemate). isolation of (+)-kawam: Borsche, W.; Peitzsch, W.: Ber. Dtsch. Chem. Ges. (BDCGAS) 63,2414 (1930). absolute configuration: Snatzke, G.; Hansel, R.: Tetrahedron Lett. (TELEAY) 1968, 1797. preparation of an endoanesthetic effective solution: GB 1 214 936 (Spezialchemie; valid from 5.6.1968; D-prior. 5.6.1967). review: Kretzschmer, R.; Teschendorf, H.J.: Chem Ztg. (CMKZAT) 98,24 (1974). Formulation(s): cps. 30 mg, 50 mg, 200 mg Trade Name(s): D: Ardeydystin Duront (Woelm)-comb.; Kavaform (Dr. Schwab)- (Ardeypham-comb.; wfm wfm comb. Neuronika (Klinge) 1120 K Kebuzone Kebuzone (Cetophenylbutazone; Ketophenylbutazon) ATC: MOlAAO6 Use: anti-inflammatory, antirheumatic RN: 853-34-9 MF: C,,H,,N,O, MW: 322.36 EINECS: 212-715-7 LD,,: 580 mgkg (M, i.v.); 750 mgkg (M, p.0.); 315 mglkg (R, i.v.); 720 mglkg (R, p.0.) CN: 4-(3-oxobutyl)-l,2-diphenyl-3,5-pyrazolidinedione CH3 No CH3 H3C7CH2 + 0G0JCH3 0J0JcH3 pb HO/'VO~ 1 0 0 - Po ethylene glycol methyl vinyl diethyl ketone rnolonote diethyl 2-(3-0x0- butyl)molonote diethyl 2-(3.3- hydrazobenzene ethylenedioxybutyl)- rnalonote (1) I Kebuzone 1 -2-diphenyl- pyrozolidine- 3.5-dione (form hydrozo- benzene and diethyl molonote) Refererzce(s): a Denss, R. et al.: Helv. Chim. Acta (HCACAV) 40,402 (1957). . CN: 4-[ 4-[ 4-[ 4-[ [ 2-( 2,4-dichlorophenyl )-2 -( lH-l,2,4-triazol- 1-ylmethy1)-l,3-dioxolan-4-yl jmethoxy]phenyl ]- I-piperazinyl]phenyl ]-2 ,4-dihydro- 2-( 1-methylpropyl )-3 H-l,2,4-triazol-3-one 2 Use: anti-inflammatory RN: 3455 2-8 4-6 MF: C,,H,,N,O,S MW: 335.34 EINECS: 25 2-0 8 4-5 LD,,: >5 g/kg (R, p.0.) CN: 4-hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl )-2 H-l,2-benzothiazine-3-carboxarnide. dichlorophenyl )- l,3-dioxolon- 4- yimethyl] benzoate (I) cis- 2-( 2,4-dichloro- phenyl )-2 -( 1 H-1,2, 4- triozol-1-ylmethy1 )- 1,3-dioxolone- 4- methonol methone- sulfanote (11) 11 16 1 Itraconazole