Oleandomycin 0 1481 LiOH H N S + H2N>cH3 + @r NC lithium 2 hydroxide N02CN o-chloronitro- 2-omino-3-cyono- benzene 5-methylthiophene 2-(2-nitrooni1ino)- 5-methylthiophene- 3-corbonitrile (I) SnC12, HCI H EtOH/H20 W~CH, 1. _____, tin(@ N- 1. N-methyl- chloride NH2 piperozine CH3 Oionzopine Reference(s): EP 454 436 (Lilly; appl. 30.10.1991; GB-prior. 25.4.1990). EP 733 634 (Lilly; appl. 25.9.1996; USA-prior. 24.3.1995). US 5 229 382 (Lilly; 20.7.1993; GB-prior. 25.4.1990). EP 733 367 (Lilly & Co.; appl. 25.9.1996). Chakrabati, J.K. eta].: J. Med. Chem. (JMCMAR) 23, 878, 884 (1980). Hagopian, G.S.; Meyers, D.B.; Markham, J.K.: Teratology (TJADAB) 35(2), Abst. P65 (1987). intermediates and process for pr-eparing olanzapine: EP 831 098 (Eli Lilly; appl. 22.9.1997; USA-prior. 23.9.1996). pharmaceutical compositions: US 5 919 485 (Eli Lilly; 6.7.1999; appl. 20.9.1996; USA-prior. 24.3.1995). EP 830 864 (Eli Lilly; appl. 22.9.1997; USA-prior. 23.9.1996). crystalline olanzapine: EP 733 635 (Eli Lilly; appl. 22.3.1996; USA-prior. 24.3.1995). Formulation(s): f. c. tabl. 2.5 mg, 5 mg, 7.5 mg, 10 mg Trade Name(s): D: ZYPREXA (Lilly) I: Zyprexa (Lilly) GB: Zyprexa (Lilly; 1996) . USA: Zyprexa (Lilly) Oleandomycin (Troleandomycin) ATC: JOlFAOS Use: antibiotic RN: 3922-90-5 MF: C,,H,,NO,, MW: 687.87 EINECS: 223-495-7 LD,,,: 460 mglkg (M, i.v.); 8200 mglkg (M, p.0.); 440 mglkg (R, i.v.); 6700 mglkg (R, p.0.) CN: [3R-(3R*,5R*,6S*,7R*,gR*,l I R*,12R*,13R*,14S*,15S*)]-12-[(2,6-dideoxy-3-0-methyl-a-~-arabino- hexopyranosyl)oxy]-6-hydroxy-5,7,8,11,13,15-l~examethyl-14-[[3,4,6-trideoxy-3-(dimethylamino)-~-~- xylo-hexopyranosyl]oxy]- 1,9-dioxaspiro[2,13]hexadecane-4,lO-dione phosphate (1:l) RN: 7060-74-4 MF: C,,H,,NO,Z . H,PO, MW: 785.86 EINECS: 230-351 -7 LD,,,: 400 mglkg (M, i.v.); 4 glkg (M, p.0.); 480 mglkg (R, i.v.) 1 1482 0 Olprinone hydrochloride I Oleandomycin I From fermentation solutions of Streptornyces antibioticus. Reference(s): US 2 757 123 (Pfizer; 31.7.1956; prior. 1.6.1953, 29.6.1955). US 2 842 481 (Pfizer; 8.7.1958; prior. 12.3.1957). Formulation(s): cps. 250 mg; tabl. 100 mg; vial 500 mg (as phosphate) Trade Name(s): D: Oleandocyn (Pfizer); wfm I: Boramycina (Benvegna)- J: Matromycin (Taito Pfizer) F: Sigrnamycine (Rosa- comb.; wfm Sigmamycin (Pfizer)-comb. Phytopharma)-comb.; wfm Olmicina (Murgdn); wfm Taocin-O (Sankyo) generic; wfm Triolmicina (Ripari-Gero); USA: TAO (Pfizcr) wfm Olprinone hydrochloride (E-1020; Loprinone) ATC: COlD Use: cardiotonic, vasodilator, PDE III- inhibitor RN: 119615-63-3 MF: C,,H,,N40~ HCI MW: 286.72 LD,,,: 242 mglkg (M, i.v.); 210 glkg (M, p.0.); 176 mag (R, i.v.); 7804 mglkg (R, p.0.); >I00 mglkg (dog, i.v.) CN: 1,2-dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2-oxo-3-pyridinecarbonitrile monohydrochloride olprinone RN: 106730-54-5 MF: Cl4H,,N40 MW: 250.26 6-bromo-imidazo- 1 -chloro- [I ,2-olpyridine 2-methyl- propane Olsalazine sodium 0 1483 1. o,, HCI/H~O/C~H~OH 2. NaNO, b em3 0 6-(2-methyl-2- 1 -(imidazo[l.2-a]- pr0penyl)imidazo- [1,2-olpyridine (I) pyridine-6-yl)- 2-propanone (U) CH3 dimethylform- amide dimethyl acetol 1. DMF, 80-90 "C I cyonoocet- 1 Olprinone hydrochloride amide I Reference (s): preparation of intermediate II: JP 63 077 879 (Eisai; appl. 22.9.1986; J-prior. 22.9.1986). Yamanaka, M. et al.: ~hern. Pharrn. ~ull: (CPBTAL) 40 (6), 1486 (1992). preparation of olprinone from II: EP 199 127 (Eisai; appl. 25.3.1986; J-prior. 26.3.1985). Yamanaka, M. et al.: Chern. Pharrn. Bull. (CPBTAL) 39 (6), 1556 (1991). For~nularion(s): vial 5 mgl5 rnl Trade Narne(s): J: Coretec (Eisai) Olsalazine sodium (Di-5-ASA) ATC: A07EC03 Use: therapeutic (ulcerative colitis) RN: 6054-98-4 MF: C,,H,N2Na20, MW: 346.21 CN: 3.3'-azobis[6-hydroxybenzoic acid] disodiurn salt free acid RN: 15722-48-2 MF: C,4HloN,0, MW: 302.24 EINECS: 227-975-7 methyl 2-hydroxy- methone- 5-nitrobenzoote sulfonyl chloride methyl 2-methyl- methyl 5-omino- sulfonyloxy-5- Z-methylsulfonyl- nitrobenzoote oxybenzoote (I) 1484 0 Omapatrilat 1. NaNOZ, HCI 1. sodium nitrite 2. methyl solicylate T:::? "w"' HO qNQN 0 /H3 Reference(s): EP 36 636 (Pharmacia; appl. 19.3.1981; S-prior. 26.3.1980). US 4 528 367 (Pharmacia; 9.7.1985; S-prior. 26.3.1980). "kN p HO 0 ONa methyl 2-hydroxy-5-[(4- preparation of methyl 2-hydroxy-Snitrobenzoate: Kakigami, T.; Baba, K.; Usui, T.: Heterocycles (HTCYAM) 48 (12), 261 1 (1998). Baker et a].: J. Chem. Soc. (JCSOA9) 1950, 170. Barany; Pianka: J. Chem. Soc. (JCSOA9) 1946,965. Olsalazine sodium Formulation(s): cps. 250 mg; tabl. 500 mg methylsulfonyloxy-3-meth- oxycorbonylphenyl)azo]- benzoate Trade Narne(s): , . D: Dipentum (Pharmacia & GB: Dipentum (Pharmacia & . USA: Dipentum (Pharmacia & Upjohn; 1989) Upjohn; 1989) Upjohn) F: Dipentum (Pharmacia & I: Dipentum (Pharmacia & Upjohn) Upjohn; 1991) Omapatrilat (BMS- 1867 16) Use: antihypertensive, dual ACE and NEP (neutral endopeptidase) inhibitor RN: 167305-00-2 MF: C19H24N204S2 MW: 408.54 CN: (4S,7S,1OaS)-Octahydro-4-[[(2S)-2-mercapto-l-oxo-3-phenylpropyl]amino]-5-oxo-7H-pyrido[2,1- b][l,3lthiazepine-7-carboxylic acid sPNH~ 0 homocysteine thioloctone l.Z-0-Su. NaHC03. H20, acetone R Omapatrilat 0 1485 a CH30H. H~~-~ resolution il, (+I + b CH3 HOOC ? "JN/' cH3 H (S)-a-methyl- benzylamine n 1. EDCi, HOBt, HJC-N 0 iH 0- 2. Swern oxidatian.Cl%~~ , OMSO. CH2C12 (8)-I + 0 , rn 1. 4-methylmorpholine H3c/0*NH2 0 2. oxalyl chloride L-E-hydroxynorleucine methyl ester (11) [S-(R*,R*)]-2-[[4- (acetylthi0)- 1 -0xo-2- [[(phenylmethoxy)- carbonyl]amino]butyl]- amino]-6-oxohexonoic acid methyl ester (111) FH3 H3C-i4-I , CH2C12 N CH3 , iodotrimethylsilane [4S-(4a,7a,lOap)]-octa- hydro-4-[[(phenylmethoxy)- carbonyl]amino]-5-0x0- 7H-pyrido[Z.l -b][l.3]- thiazepine-7-carboxylic acid methyl ester (N) HOOC S CH3 1. BOP reagent, N(C~H&, CH~CI~ 2. NaO HzO, ChoH , HOO~ ti% (S)-2-acetylthio- benzenepropianic acid (VI) I Omapatrilat I BOP reagent: 1486 0 Omeprazole @ synthesis of L-r-hydroxynorleucine methyl ester (11) 1. NaH, OMF diethyl acetomidomalonote @ synthesis of (S)-2-(ocetylthio)benzenepropionic acid (Y1) HOOC,NH2 HOOC,Br H3C-COSH NaNOZ, KBr, HZS04 KOH, CH30H - vr sodium nitrite (R)-2-bromo- benzenepropionic acid reference(^): EP 629 627 (Brislol-Myers Squibb; appl. 13.6.1994; USA-prior. 15.6.1993). US 5 508 272 (Bristol-Myers Squibb; 16.4.1996; USA-prior. 15.6.1993). Robl, J.A. et al.: J. Med. Chem. (JMCMAR) 40, 1570-1577 (1997). WO 9 935 145 (Bristol-Myers Squibb; appl. 11.12.1998; USA-prior. 6.1.1998). Trade Narne(s): D: Vanlev (Bristol-Myers Squibb) Omeprazole (H-168168) ATC: A02BDO1 Use: H+/K+-ATPase-inhibitory ulcer therapeutic (Zollinger-Ell~son Syndrom, reflux oesophagit~s) RN: 73590-58-6 MF: Cl,HI9N3O3S MW: 345.42 LDs,,: 82.8 mglkg (M, i.v.); >4 g/kg (M, p.0.); >50 mglkg (R, i.v.); 2210 mglkg (R, po.) CN: 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole monosodium salt RN: 95510-70-6 MF: C,,Hl,N3Na03S MW: 367.41 LD,,: 278 mglkg (R, i.v.) 1. HNOZ. H2S04 0,CH3 H3cncH3 2. NoOH. H3C-OH _____, N' CH, 2. methonal 1 I pyridine N-oxide pyridine N-oxide (I) Omeprazole 0 1487 GH3 0 0 acetic anhydride 0 4-methoxy-3.5-dimethyl- 2-pyridinemethonol acetate (11) 0-CH3 0-CH3 NoOH thionyl chloride 2-(hydroxymethy1)-3.5- 2-(chloromethyl)-3.5- dimethyl-4-methoxy- dimethyl-4-methaxy- pyridine pyridine (IU) 4-methoxy-o- potassium ethyl- 5-methoxy-2-mercapta- phenylenediomine xonthogenote benzimidozole (IV) 1. NoOH I 1 Omeprazole I Referencc(s): EP 5 129 (Hassle; appl. 3.4.1979; S-prior. 14.4.1978). US 4 255 43 1 (Hassle; 10.3.1981; S-prior. 14.4.1978). alternative synthesis of 111: EP 103 553 (Hassle; appl. 30.6.1983; S-prior. 26.8.1982). alternative synthesis of omeprazole: WO 9 809 962 (Slovakofarma 13.3.1998; appl. 8.9.1997; SK-prior. 9.9.1996). WO 9 729 103 (PDI Res.; 14.8.1994; appl. 5.2.1997; CA-prior. 6.2.1996, 10.4.1996). WO 9 722 603 (Astra; 26.6.1997; appl. 5.12.1996; S-prior. 15.12.1995). US 5 374 730 (Torcan; 20.12.1994; appl. 4.11.1993). EP 533 264 (Merck & Co.; 24.3.1993; appl. 12.9.1992; USA-prior. 20.9.1991, 15.10.1991). WO 9 118 895 (Astra; 12.12.1991; appl. 5.6.1991; S-prior. 7.6.1990). EP 484 265 (Centro Gencsis para la Inv.; appl. 24.10.1991 ; E-prior. 3 1.10.1990). WO 9 850 361 (PDI Research; appl. 21.4.1998; CA-prior. 6.5.1997). WO 9 840 378 (Bristol-Myers Squibb; appl. 16.2.1998; DK-prior. 7.3.1997). WO 9 947 514 (Knoll AG; appl. 11.3.1999; GB-prior. 17.3.1998). EP 302 720 (Takeda Chem. Ind.; appl. 3.8.1988; I-prior. 4.8.1987). synthesis of intertnecliatest EP 226 558 (Hassle; appl. 8.9.1986; S-prior. 24.9.1985). ES 2 035 767 (Centro Genesis; 16.4.1993; appl. 5.4.1991) - -1 1488 0 Omoconazole nitrate alkaline salts: EP 124 495 (Hassle; appl. 28.2.1984; S-prior. 4.3.1983). ES 2 023 778 (Centro Genesis; 1.2.1992). WO 9 900 380 (Astra; appl. 11.6.1998; S-prior. 27.6.1997). cyclodextrin complexes: EP 190 239 (Byk Gulden Lomberg; appl. 24.7.1985; D-prior. 27.7.1984). oral composition: EP 247 983 (Yoshitomi; appl. 16.4.1987; GB-prior. 30.4.1986). WO 9 601 623 (Astra; 25.1.1996; appl. 7.6.1995; S-prior. 8.7.1994). US 5 232 706 (Esteve; 3.8.1993; E-prior. 3l.l2.l99O, 24.6.1991). WO 9 850 019 (Sage Pharm; appl. 8.5.1998; USA-prior. 9.5.1997; 15.10.1997). new crystalline form of omeprazole: WO 9 908 500 (Astra; appl. 10.1 1.1998). transdermal application: WO 9 000 054 (Upjohn; appl. 1.5.1989; USA-prior. 30.6.1988). treatment of osteoporosis: EP 338 066 (Hassle; appl. 27.10.1988; S-prior. 30.10.1987). Formulation(s): cps. I0 mg, 20 mg, 40 mg; vial 40 mg (as sodium salt) Trade Natne(s): D: Antra (Astra; 1989) I: Anthra (Astra J: Omepral (Fujisawa-Astra; Gastroloc (pharma-stern; Farmaceu tici) 1991) 1989) Losec (Plough; 1990) Omeprazon (Yoshitomi) F: Mopml (Astra; 1989) Mepral (Bracco; 1990) USA: Prilosec (Astra Merck) GB: Losec (Astra; 1989) Omeprazen (Malesci; 1990) Omoconazole nitrate ATC: DOIACl3;GOlAF16 Use: topical antifungal, antimycotic RN: 83621-06-1 MF: C20H,7C13N202 . HNO, MW: 486.74 CN: (Z)-1-[2-[2-(4-chlorophenoxy)ethoxy]-2-(2,4-dichlorophenyl)-1-methylethenyl]-1H-imidazole mononi trate omoconazole RN: 745 12- 12-2 MF: C,,H,7C1,N202 MW: 423.73 1.3-dichloro- 2-chloro- 2,2',4'-trichloro- benzene propionyl propiophenone chloride Ondansetron 0 1489 I. NOOH. (c,H,),N+ OH-, benzene C I Omoconazale nitrate Reference(s): US 4 210 657 (Siegfried AG; 1.7.1980; D-prior. 11.9.1978). US 4 554 356 (Siegfried AG; 19.1 1.1985; CH-prior. 23.1.1981). EP 8 804 (Siegfried AG; appl. 7.9.1979; D-prior. 1 1.9.1978). EP 69 754 (Siegfried AG; appl. 21 .l. 1982; CH-prior. 23.1.1981). Thiele, K. et al.: Helv. Chim. Acta (HCACAV) 70,441 (1987). preparation of 2,2',4'-trichloropropiopheno~le: Konosu, T. et al.: Chem. Pharm. Bull. (CPBTAL) 38 (5), 1258 (1990). Formulation(s): cream 10 mgll g Trade Name(s): D: Fungisan (Galderma) Fongarex (Besins- I: Afongan (Galderma) F: Fongamil (Biorga) Iscovesco) Ondansetron ATC: A04AAO1 Use: 5-HT,-antagonist, anti-emetic RN: 99614-02-5 MF: C,,H,,N,O MW: 293.37 CN: 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl- 1 H-imidazol-1 -yl)methyl]-4H-carbazol-4-one monohydrochloride RN: 99614-01-4 MF: C,,H,,N,O. HC1 MW: 329.83 LD,,: 20.2 mglkg (R, i.v.); 94.897 mag (R, p.0.); >15 mgfkg (dog, i.v.); >45 mglkg (dog, p.0.) monohydrochloride dihydrate RN: 103639-04-9 MF: C,,H,;N,O. HCI . 2H20 MW: 365.86 H 1. CH31 (I), NOH + OQ - a:~ 2. Pd(OAc),, PPh,. NaHCO, b I1 0 2. palladium ocetote. 0 triphenylphosphine 2-bromo- cyclohexane- 3-(2-bromoonilino)- 1490 0 Ondansetron corbozole-3-methan- aminium iodide (111) imidozole (N) 1 Ondansetron Reference(s): DOS 3 502 508 (Glaxo; appl. 25.1.1985; GB-prior. 25.1.1984, 15.10.1984). US 4 695 578 (Glaxo; 22.9.1987; appl. 17.11 .l986; prior. 22.1.1986; GB-prior. 25.1.1984). (R)-(+)-enantiomerr US 5 470 868 (Sepracor; 28.11.1995; prior. 26.6.1991; 27.8.1991) synthesis of intermediate II: Iida, H. et a].: J. Org. Chem. (JOCEAH) 45,2938 (1980). alternative syntheses: US 4 739 072 (Glaxo; appl. 23.7.1986; GB=prior. 24.7.1985). US 4 957 609 (Glaxo; 18.9.1990; GB-prior. 24.7.1985). US 4 725 615 (Glaxo; appl. 23.7.1986; GB-prior. 24.7.1985). Kim, M.Y. et al.: Heterocycles (HTCYAM) 45 (lo), 2041 (1997). antiemetic compositions: DOS 3 906 883 (Glaxo; appl. 3.3.1989; GB-prior. 4.3.1988). US 4 983 621 (Glaxo; 8.1.1991; appl. 6.7.1989; GB-prior. 7.7.1988). medical use for treating panic disorders: WO 9 012 569 (Sandoz; appl. 1.1 1.1990). medical use for treating dementia: EP 275 668 (Glaxo; appl. 16.12.1987; GB-prior. 17.12.1986). medical use fo'r treatment of withdrawal syndrome: WO 8 803 801 (Glaxo; appl. 20.1 1.1987; GB-prior. 21.1 1.1986). Formulation(s): amp. 4 mg/2 ml, 8 mg/4 rnl; f. c. tabl. 4 mg, 8 mg; sol. (inj.) 4 rngtml (as hydrochloride dihydrate) . R*,12R*,13R*,14S*,15S*) ]-1 2-[ (2,6-dideoxy- 3-0 -methyl-a-~-arabino- hexopyranosyl)oxy ]-6 -hydroxy-5,7,8,11,13,15-l~examethyl-1 4-[ [3,4,6-trideoxy- 3-( dimethylamino )-~ - ~- xylo-hexopyranosyl]oxy ]- 1,9-dioxaspiro[2,13]hexadecane-4,lO-dione. 0-CH3 0-CH3 NoOH thionyl chloride 2-( hydroxymethy1 )-3 . 5- 2-( chloromethyl )-3 . 5- dimethyl-4-methoxy- dimethyl-4-methaxy- pyridine pyridine (IU) 4-methoxy-o- potassium ethyl- 5-methoxy-2-mercapta-. 1,2-dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2-oxo-3-pyridinecarbonitrile monohydrochloride olprinone RN: 10673 0-5 4-5 MF: Cl4H,,N40 MW: 250.26 6-bromo-imidazo- 1 -chloro- [I ,2-olpyridine 2-methyl- propane