Zipeprol Z 2201 Zimeldine 2 134 379 (AB HBssle; appl. 12.4.1972; S-prior. 28.4.1971). alternative syntheses: BE 835 802 (Astra; appl. 21.1 1.1975; S-prior. 21.1 1.1974). SU 650 501 (Pharmastra; appl. 21.5.1976). Formulation(s): 100 mg, 200 mg (as dihydrochloride) Trade Name(s): D: Normud (Astra); wfm GB: Zelmid (Astra); wfm Zipeprol ATC: R05DB15 Use: antitussive RN: 34758-83-3 MF: CZ3H3,N,O3 MW: 384.52 .EINECS: 252-191-7 CN: 4-(2-methoxy-2-phenylethyl)-a-(methoxyphenylmethyl)-1-piperazineethanol dihydrochloride RN: 34758-84-4 MF: C2,H3,NzO3 . 2HCl MW: 457.44 EINECS: 252-192-2 LD,,: 44.3 mglkg (M, i.v.); 300 mglkg (M, p.0.); 32.7 mglkg (R, i.v.); 435 mglkg (R, p.0.); 228 mglkg (dog, p.0.) tert-butyl hypobromite styrene (1) 2-methoxy-2- 1 -(2-methoxy-2- phenylethyl phenylethy1)- bromide piperozine (n) (H3C),C-0-Br tert-butyl cinnamyl alcohol hypobromite 1,2-epoxy-3- methoxy-3-phenyl- propane (UI) 2202 Z Ziprasidone hydrochloride I Zipeprol I Rejerence(s): US 3 7 18 650 (Mauvernay; 27.2.1973; F-prior. 2.3.1970). DE 2 109 366 (CERM; appl. 30.9.1971; prior. 27.2.1971). Formulation(s): drg. 75 mg; syrup 0.5 % (as dihydrochloride) Trade Name(s): F: Respilhe (Winthrop; 1973) I: Zitoxil (Italfarmaco; 1979) Ziprasidone hydrochloride (CP-88059-1) Use: antipsychotic, dopamine D2- antagonist, 5-HT2-antagonist RN: 138982-67-9 MF: C21H2,ClN40S . HCl . H20 MW: 467.42 CN: ~-[2-[4-(l,2-Benzisothiazol-3-yl)-l-piperazinyl]ethyl]-6-chloro-l,3-dihydro-2H-indol-2-one hydrochloride hydrate base RN: 146939-27-7 MF: CzIH2,ClN4OS MW: 412.95 hydrochloride RN: 122883-93-6 MF: C,IH21ClN40S~ HCl MW: 449.41 mesyIate RN: 18.5021-64-1 MF: C21H21ClN40S . CH403S MW: 509.05 H H2N-NHZ, 0 CI C,H,OH, NoOCH, H c1,,kCI , AICI,. CH2C12 chloroocetyl chloride 0 H,c,;~,cH, ' H CF,COOH c I triethylsilane, ,. u trifluoroacetic (1) acid 6-chloro-5- (2-chloroethy1)- oxindole (n) Ziprasidone hydrochloride Z 2203 I-(1,2-benziso- thiazol-3-yl)- piperozine (111) 1. POCI, (\NH 2.~~3 -, 111 2. piperazine 2.5-dichloro- taluene Ziprasidone hydrochloride I H3c-C~CH, H3C-N, CH, CH3 THF ______, tert-butoxybis- rnethone Xo2 H3C CH3COOH PN CI CH,COOH. CI/'V~' IV + Ill - S,N, N,) + V d sod~urn triacetoxy- borohydride 1. 3N HCI 2. SOCI2, CYOH 3. No2Sp04, THF. H20 VI - 3. sodium hyposulfite Ziprasidone hydrochloride u 2204 Zolimidine Reference(s): a Howard, H.R. et al.: J. Labelled Compd. Radiopharm. (JLCRD4), 1994, 51. US 5 206 366 (Pfizer; 27.4.1993; USA-prior. 26.8.1992). EP 281 309 (Pfizer; appl. 24.2.1988; WO-prior. 2.3.1987). b Urban, F.J. et al: Synth. Commun. (SYNCAV) 26 (a), 1629-1638 (1996). IJS 5 359 068 (Pfizer; 25.10.1994; USA-prior. 28.6.1993). monohydrate: EP 586 191 (Pfizer; appl. 25.8.1993; USA-prior. 1.9.1992). mesylate dihydrate salts: WO 9 742 191 (Pfizer; appl. 10.4.1997; USA-prior. 7.5.1996). cyclodextrin inclusion complexes: EP 81 1 386 (Pfizer; appl. 24.4.1997; USA-prior. 7.5.1996). Formulation(s): cps. 20 mg, 40 mg, 60 mg, 80 mg Trade Name(s): USA: Zeldox (Pfizer) Zolimidine ATC: A02BX10 Use: ulcer therapeutic RN: 1222-57-7 MF: C,4H,2N202S MW: 272.33 EINECS: 214-947-4 LD,,,: >4 glkg (M, p.0.); 3710 mglkg (R, p.0.) CN: 2-[4-(methylsulfonyl)phenyl]imidazo[1,2-a]pyridine 2-ornino- 2-brorno-4'-methyl- pyridine sulfonylacetophenone I Zolirnidine I 1 Refererzce(s): GB 991 589 (Lab. Bioterapico Milanese Selvi; valid from 23.7.1963; I-prior. 30.4.1963). Almirante, L. et al.: J. Med. Chem. (JMCMAR) 8, 305 (1965). Formula~ion(s): cps. 200 mg Trade Narne(s): 1: Solimidin (Selvi); wfm USA: Mutil (Lakeside); wfm Zolmitriptan (31 1C90; BW-311C90) ATC: N02CC03 Use: antimigraine agent, 5-HT,D-agonist RN: 139264-17-8 MF: C,,H2,N302 MW: 287.36 CN: (S)-4-[[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl]-2-oxazolidinone monohydrochloride RN: 139264-19-0 MF: C,6H2,N302. HCl MW: 323.82 racemic monohydrochloride RN: 139346-15-9 MF: C,,H2,N302~ HCl MW: 323.82 Zolmitriptan Z 2205 synthesis of intermediote 111: 1. S0CI2. CH,OH HOOC 2. sodium borohydride 4-nitro-L-phenyl- olonine (I) 1. KOH or NoOH 2. H2, Pd-C 3. NaN02. HCI 0 4. SnCI2 0 H n + ,ll, /CCI3 - CI 0 2. hydrogen. pollodium 3. sodium nitrite di~hosgene 4. tin(1l) chloride (S)-4-(4-hydrozinobenzy1)- 2-oxozolidinone hydrochloride (Ill) or: 1. KOH or NoOH 2. H2. Pd-C 3. NoNO,, HCI 4. SnClp , 111 2. hydrogen. pollod~um 3. sodium nitrite phosgene 4. tin(l1) chloride synthesis of intermediote V: 1. H20, KOH 0 2. Hz, Pd-C 2. hydrogen. pallodium benzyl isocyanote 1. NoN02. HCI 0 2. SnCI, H N , 1. sodium nitrite 2. tin@) chloride ' (5)-5-(4-hydrozinobenzy1)- 2.4-imidozolidinedione hydrochloride (V) butonol diethyl ocetal (VI) I 2206 Z Zolmitriptan 1. C2H50H, H20, A 2. H2C=0. H20. CH30H 3. NoCNBH3 4. FH3 111 + 2. formaldehyde 3. sodium cyonoborohydride 4-chlorabutanol 4. dimethylomine (WI) diethyl ocetal (VII) 3-cyonoproponol diethyl ocetal 1. PPE, CHC13, A 2. Hz. Pd-C. C2H50H. VIIl D( 1. polyphosphote ester 2. hydrogen, pollodium, ethanol 1. C2H50H. H20. A 2. Bo(OH),. H20 v+ VI - 2. borium hydroxide HOOC N-CH3 H3C 3-[3-(2-dimethylominoethyl)- 1H-indol-5-yl]-L-alanine (X) 1. thionyl chloride, methonol I I 2. sodium barahydride 3. diethyl carbonate, potassium carbonote alternative synthesis of X: 1. C2H50H. H20. A 2. HzC=O. H20. CH,OH 3. NoCNBH3 4. VIII 5. BO(OH)~, H20 v + vn b x 3. sodium cyonoborohydride 5. borium hydroxide Reference(s): WO 9 1 18 897 (The Wellcome Foundation; appl. 12.12.1991; GB-prior. 7.6.1990, 1.2.1991). Glenn, R.C. et al.: J. Med. Chem. (JMCMAR) 38,3566 (1995). Zolpidem Z 2207 synthesis of 4-dimethylaminobutanal diethyl acetal: Desaty, K.: Croat. Chem. Acta (CCACAA) 36, 103, 107 (1964). Somin, I.N. et al.: J. Org. Chem. (JOCEAH) 1,201 1 (1965). Bhattacharyya, S.: Tetrahedron Lett. (TELEAY) 35 (IS), 2401 (1994). Harries et al.: Justus Liebigs Ann. Chem. (JLACBF) 410,65 (1915). synthesis of 4-chlorobutanal diethyl acetal: Loftfield: J. Am. Chem. Soc. (JACSAT) 73, 1365 (1951). Anet et a].: Aust. J. Sci. Res. Ser. A (AJSRA2) 3, 336 (1950). Winterfeld et al.: Arch. Pharm. Ber. Dtsch. Pharm. Ges. (APBDAJ) 293, 325 (1960). Tamelen, Van et al.: Bioorg. Chem. (BOCMBM) 5,283 (1976). Formulation(s): f. c. tabl. 2.5 mg; tabl. 2.5 mg Trade Narne(s): D: Asco Top (Zeneca) GB: Zomig (Zeneca) Zolpidem (SL-80-0750-23N) ATC: N05CF02 Use: hypnotic with affinity to benzodiazepine receptor RN: 82626-48-0 MF: C,9H21N,0 MW: 307.40 CN: N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide tartrate (2:l) RN: 99294-93-6 MF: C,,H2,N30 1/2C4H60, MW: 764.88 LD,,: 695 mg/kg (M, p.0.); 2700 mgkg (R, p.0.) tartrate (1:l) RN: 103188-50-7 MF: C,,H2,N,0. C4H,06 MW: 457.48 2-amino-5- bromomethyl 2-(4-methylpheny1)-6- rnethylpyridine 4-methylphenyl methylimidozo[l -2-01- ketone pyridine (I) 1. CH31 "3C 2 NoCN r H3C 1. methyl iodide NC' 2. sodium cyonide 1. HCI, CH3COOH 2. P0Cl3 3. n 111 -b 2. phosphoryl chloride Zolpidem 2208 Z Zomepirac 2.2-dimethoxy- N.N-dimethyl- ocetomide Reference(s): a EP 50 563 (Synthelabo; appl. 15.10.1981; F-prior. 22.10.1980). DE 3 163 524 (Synthelabo; appl. 15.10.198 1; F-prior. 22.10.1980). b EP 251 859 (Synthelabo; appl. 17.6.1987; F-prior. 27.6.1986). 2,2-dimethoxy-N,N-dimethylacetamide: US 3 361 757 (Du Pont; 15.1 1.1965). Formulation(s): f. c. tabl. 10 mg; tabl. 5 mg, 10 mg (as tartrate) Trade Name(s): D: Bikalm (Byk Gulden) Stilnox (SynthClabo; 1988) Stilnox (Synthelabo; 1990) Stilnox (Synthelabo) GB: Stilnoct (Lorex) J: Myslee (Fujisawa) F: Ivadal (Cipharm) I: Niotal (Synthelabo) USA: Ambien (Searle) Zomepirac ATC: MOlABM Use: analgesic, anti-inflammatory RN: 33369-31-2 MF: C,,H,,C1NO3 MW: 291.73 EINECS: 251-474-2 CN: 5-(4-chlorobenzoyl)- 1,4-dimethyl-1 H-pyrrole-Zacetic acid sodium salt dihydrate RN: 64092-49-5 MF: C,,H,,ClNNaO, . 2H20 . MW: 349.75 diethyl acetone- methyl- chloro- ethyl 1,4-dimethyl- dicorboxylote omine acetone 3-ethoxycorbonyl- pyrrole-2-ocetote (I) 4-chlorobenzoyl chloride Zonisamide Z 2209 11 quinoline. copper chrornite ' I 00 m4 Zomepirac Reference(s): DE 2 102 746 (McNeil; appl. 21.1.197 1 ; USA-prior. 26.1.1970). US 3 952 012 (McNeil; 20.4.1976; prior. 16.2.1973, 26.1.1970, 1.7.1968, 26.7.1967). Carson, J.R.; Wong, S.: J. Med. Chem. (JMCMAR) 16, 172 (1973). alternative syntheses: BE 762 060 (McNeil; appl. 26.1.1971; USA-prior. 26.1.1970). DOS 2 339 140 (McNeil; appl. 2.8.1973; USA-piior. 3.8.1972). US 3 865 840 (McNeil; 11.2.1975; prior. 16.2.1973, 26.7.1967, 1.7.1968, 26.1.1970). Formulation(s): tabl. 100 mg (as sodium salt dihydrate) Trade Name(s): D: Zornax (Cilag); wfm F: Zomax (Cilag); wfm USA: Zomax (McNeil); wfm Zonisamide ATC: NO~AA (AD-810) Use: anticonvulsant, antiepileptic RN: 68291-97-4 MF: CuH,N203S MW: 212.23 LD,: 699 rnglkg (M, i.p.); 816 mglkg (M, i.v.); 1829 mglkg (M, p.0.); 1009 mglkg (M, s.c.); 733 rnglkg (R, i.p.); 672 mglkg (R, i.v.); 1992 mglkg (R, p.0.); 925 mglkg (R, s.c.); 1 glkg (dog, p.0.) CN: 1,2-benzisoxazole-3-methanesulfonamide monosodium salt . RN: 68291-98-5 MF: CuH,N2Na0,S MW: 234.21 4-hydroxy- 1 -2-benzisoxazole- cournarin 3-acetic acid 1. P0Cl3 "GO* 2. NH3 sodium II - -No "Br sulfite ->-u II 3-bromomethyl- sodium 1.2-benz- 1,2-benzisoxozole (I) isoxazole-3-methane- sulfonote Reference(s): DE 2 825 410 (Dainippon; appl. 9.6.1978). US 4 172 896 (Dainippon; 30.10.1979; appl. 5.6.1978). Uno, H. et al.: J. Med. Chem. (JMCMAR) 22, 180 (1979). 2210 Z Zopiclone synthesis of3-bromomethyl-1,2-benzisoxazole: Uno, H. et a].: Chem. Pharm. Bull. (CPBTAL) 24,632 (1976). Giannella, M. et al.: Chim. Ther. (CHTPBA) 7, 127 (1972). oral formulation: JP 63 150 220 (Dainippon; appl. 15.12.1986). alternative synthesis: Mohareb, R.M. et a].: Z. Naturforsch., B: Chem. Sci. (ZNBSEN) 45, 1067 (1990). Formulation(s): powder 200 mglg; tabl. 100 mg Trade Narne(s): J: Excegran (Dainippon; 1990) Zopiclone (RP-27267) ATC: NOSBX; NOSCFO1 Use: anxiolytic, hypnotic RN: 43200-80-2 MF: C,,H,,CIN601 MW: 388.82 EINECS: 256-138-9 . LD5,,: 580 mglkg (M, i.p.); 321 mg/kg (M, i.v.); 2174 mglkg (M, p.0.); 280 mglkg (R, i.v.); 827 mglkg (R, p.0.); 400 mglkg (dog, i.v.); 2500 mglkg (dog, p.0.) CN: 4-methyl-1 -piperazinecarboxylic acid 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-py~olo[3,4- blpyrazin-5-yl ester pyrozine-2,3- 2-amino-5- 3-(5-chloropyrtd-2-yl- 6-(5-chloropyrld-2-yI)- d~corboxylic chloropyr~d~ne corbarnoyl)pyrilz~ne-2- 5,7-dioxo-6,7-dihydro- onhydride corboxyltc ocld 5H-pyrrolo[3.4-blpyrozlne (I) 4->1 - 1 -chlorocorbonyl-4- methylpiperazine 0 Zopiclone Referencefs): DOS 2 300 491 (RhBne-Poulenc; appl. 5.1.1973; F-prior. 7.1.1972,9.9.1972). US 3 862 149 (RhBne-Poulenc; 21.1.1975; F-prior. 7.1.1972,9.9.1972). Formulation(s): f. c. tabl. 7.5 mg Trade Name(s): D: Ximovan (RhBne-Poulenc GB: Zimovane (RhBne-Poulenc J: Amoban (RhBne-Poulenc- Rorer; 1991) Rorer) Chugai) F: Imovane (Specia Groupe I: Imovane (RhBne-Poulenc RhBne-Poulenc Rorer) Rorer; 1989) . 4-methyl-1 -piperazinecarboxylic acid 6-( 5-chloro-2-pyridinyl )-6 ,7-dihydro-7-oxo-5H-py~olo[3, 4- blpyrazin-5-yl ester pyrozine-2, 3- 2-amino- 5- 3-( 5-chloropyrtd-2-yl- 6-( 5-chloropyrld-2-yI )-. (31 1C90; BW-311C90) ATC: N02CC03 Use: antimigraine agent, 5-HT,D-agonist RN: 13926 4-1 7-8 MF: C,,H2,N302 MW: 287.36 CN: (S )-4 -[ [ 3-[ 2-( dimethylamino)ethyl ]-1 H-indol-5-yl]methyl ]-2 -oxazolidinone. hydrochloride (CP-8805 9-1 ) Use: antipsychotic, dopamine D 2- antagonist, 5-HT2-antagonist RN: 13898 2-6 7-9 MF: C21H2,ClN40S . HCl . H20 MW: 467.42 CN: ~-[ 2-[ 4-( l,2-Benzisothiazol-3-yl)-l-piperazinyl]ethyl ]-6 -chloro-l,3-dihydro-2H-indol-2-one