F Etymemazine E 821 1. P0Cl3 "3C\ 2. H20 CH3 CHO H3cx; ' I + N-CHO ~HC 4 AHC H &' \O CH3 acetone '0 CH3 '3'3 4-rnethoxy-2,3,6- trirnethylbenz- aldehyde CH3 H3C C$CH CzH5-MgBr, THF CH3 H3C Hz, Pd-C n + HCFCH + ethyl- \O WH CH3 -HC \O pH2 CH3 rnognesium CH3 CH3 triphenyl- phosphine 1. DMF, NOH I IV 0-CH, 2. ethyl 3-formyl- I crotonote ., CH, I (cf. retinol synthesis) Etretinote Reference(s): Mayer, H. et al.: Experientia (EXPEAM) 34, 1105 (1978). US 4 105 681 (Roche; 8.8.1978; prior. 22.3.1974; 1.8.1975; 13.8.1976). DOS 2 414 619 (Roche; appl. 26.3.1974; CH-prior. 30.3.1973). US 4 215 215 (Hoffmann-La Roche; 29.7.1980; prior. 6.7.1979). medical use: US 4 200 647 (Hoffmann-La Roche; 29.4.1980; appl. 12.12.1978; CH-prior. 21.12.1977). Formulation(s): cps. 10 mg, 25 mg Trade Name(s): D: Tigason (Roche; 1982); GB: Tigason (Roche); wfm USA: Tegison (Roche; 1986) wfm I: Tigason (Roche) F: Tigason (Roche); wfm J: Tigason (Roche) Etymemazine ATC: RO~AD (~th~lisobutrazin; Ethotrimeprazine; Ethylisobutrazine) Use: antihistaminic, tranquilizer, hypnotic RN: 523-54-6 MF: C2,,HZ6N2S MW: 326.51 CN: 2-ethyl-N,N,P-trimethyl-lOH-phenothiazine-lO-propanamine 822 E Etynodiol acetate monohydrochloride KN: 3737-33-5 MF: C,,,H,,N,S . HCI MW: 362.97 EINECS: 223-1 11-8 LD,,,: 70 mg/kg (M, i.v.) 2. 3-dirnethylornino-2- 2-ethyl- rnethylpropyl chloride phenothiozine Etyrnsrnorine L Reference(s): DE 1 034 638 (RhBne-Poulenc; appl. 1955; F-prior. 1954) Trade Name(s): F: Nuital (Vaillant-Defresnc); wfm Etynodiol acetate ATC: G03AA . (~th~nodioldiacetat; Ethynodiol diacetate; Etynodiol Use: progestogen (in with diacetate) estrogen as oral contraceptive) RN: 297-76-7 MF: C2dH,204 MW: 384.52 EINECS: 206-044-9 CN: (3P,17a)- 19-norpregn-4-en-20-yne-3,17-diol diacetate norethisterone ocetote (4. v) etynodiol (I) pyridine, I? ocetic anhydride (Il) Etynodiol ocetote NCPA. 6 I + 11 -+ triethylornine, 4-dimethylomino- pyridine Exalamide E 823 Reference(s): s US 3 176 013 (Searle; 30.3.1965; appl. 25.7.1963). DE 1 668 604 (Gedeon Richter; appl. 7.9.1967; H-prior. 7.9.1969). DE 2 137 557 (Gedeon Richter; appl. 27.7.1971; H-prior. 29.7.1970). b DE 2 137 856 (Searle; appl. 29.7.1971 ; USA-prior. 30.6.1970). alternative synthesis: DD 91 649 (G. Teichmiiller et a].; appl. 2.3.1971). Formulation(s): tabl. 1 mg Trade Name(s): D: Alfames E (Kade)-comb.; wfm Ovulen (Boehringer Mannh.)-comb.; wfrn Ovulen (Searle)-comb.; wfm F: Luto-mCtrodiol (Monsanto; as diacetate) GB: Femulen (Searle) Ovaras (Serono)-comb.; I: Luteolas (Serono)-comb.; wfm wfrn J: Ovulen (Dainippon)-comb. Luteonorrn (Serono); wfrn USA: Demulen 21/28 (Sear1e)- Metrulen (SPA)-comb.; comb. wfm Miniluteolas (Serono)- comb.; wfrn Exalamide ATC: DO~AE Use: topical antifungal RN: 53370-90-4 MF: C,,H,,NO, MW: 221.30 EINECS: 258-504-3 LD,,,: 13.21 g/kg (M, p.0.); >5 dkg (R, pa.) CN: 2-(hexy1oxy)benzarnide Reference(s): GB 726 786 (Herts Pharrn.; appl. 1952). NaOCZH, OH .+ Br-CH, solicylomide n-hexyl bromide pharmaceutical formulation: GB 872 891 (Smith & Nephew; appl. 1957). Bevin, E.M. et al.: J. Pharrn. Pharrnacol. (JPPMAB) 4, 872 (1952). Exolomide Formulation(s): ointment 5 %; sol. 5 % Trade Name(s): J: Hyperan (S. S. Pharrn.) Exifone ATC: N07X Use: cognition enhancer, nootropic RN: 52479-85-3 MF: C13H,,,07 MW: 278.22 EINECS: 257-945-9 LD,,,: 355 mdkg (R, i.p.); 1425 rnglkg (R, p.0.) CN: (2,3,4-trihydroxyphenyl)(3,4,5-trihydroxyphenyl)methanone 824 E Exifone 3.4.5-trihydroxy- pyrogollol Exifone benzoic acid I "p'~~~ + &OH POCI,, ZnC12 OH phosphorus OH oxychloride Reference(s): DE 2 501 443 (Lab. Pharmascience; appl. 15.1.1975; F-prior. 15.1.1974). GB 1 495 331 (Lab. Pharmascience; appl. 15.1.1975; F-prior. 15.1.1974). 0 OH Hornn HO OH OH Formulation(s): tabl. 200 mg 7kade Name(s): F: Adlone (Pharmascience; 1988); wfm Fadrozole F 825 Fadrozole ATC: LOI (CGS- 16949A) Use: antineoplastic, non-steroidal arornatase inhibitor RN: 131833-76-6 MF: Cl4HI3N7 MW: 223.28 CN: (~)-4-(5,6,7,8-tetrahydroimidazo[l,5-a]pyridin-5-yl)benzon~t~le I monohydrochloride RN: 102676-96-0 MF: C,4H13N3 . HCI MW: 259.74 @)-form RN: 102676-86-8 MF: C14H13N3 MW: 223.28 HO N-CH3 trimethylchloro- / 3 H3C done (I) H ,c' 4-(3-hydroxy- dimethylcorb- pmpyl)-1 H- amoyl chloride imidazole 4-cyano- benzyl bromide ( Fadrozole 1.1 , NOH y3 ti3C,,Ofl~~ , 0HCm4N-Bi-CH3 0 2. diisobutyl- CH, " 4-[3-(ethoxy- - aluminum 4-(3-formylpropyl)- carbonyl)propyl]- hydride 1 -(trimethylsilyl)- 1H-imidazale imidozole (111) 4-(tert-butyl- 4-[4-[4-(tert-butyl- carbamoy1)-1 - carbomoyl)-phenyll-4- bromobenzene hydroxybutyl]-1 -(trimethyl- silyl)imidazole 826 F Famciclovir Reference(s): EP 165 904 (Ciba-Geigy AG; appl. 17.6.1985; USA-prior. 20.6.1 984; 20.6.1985). administration of (-)-fadrozole: WO 9 528 156 (Sepracor Inc.; appl. 1 1.4.1995; USA-prior. 14.4.1994) preparation of starting materials: Ganellin, C.R. eta].: J. Med. Chem. (JMCMAR) 39 (19), 3806 (1996). Pasini, C.: Gazz. Chim. Ital. (GCITA9) 87, 1464, 1473 (1957) Akabori: Ber. Dtsch. Chem. Ges. B (BDCBAD) 66 151, 156 (1933). Formulation(s): tabl. 1 mg (as hydrochloride) Trade Name(s): J: Afema (Ciba-Geigy) USA: Arensin (Ciba-Geigy) Famciclovir (BRL-42810) ATC: J05AB09; SOlAD07 Use: antiviral RN: 104227-87-4 MF: C14H19NS04 MW: 321.34 CN: 2-[2-(2-amino-9H-purin-9-yl)ethyl]- 1,3-propanediol diacetate (ester) 0 CH, 9' K2C03 DMF k + B&OyCH3 ___* H2N N 0 Z-omino-6- chloropurine EP 182 024 (Beecham Group; appl. 9.9.1985; GB-prior. 16.8.1985) alternative preparation of intermediate I: WO 9 528 402 (SmithKline Beecham; appl. 19.4.1995; GB-prior. 19.4.1994) Fnrmulation(s): f. c. tabl. 125 mg, 250 mg, 500 mg Trade Name(s): D: Famvir (SmithKline GB: Famvir (SmithKline USA: Famvir (SmithKline Beecham) Beecham) Beecham) Famotidine F 827 Farnotidine ATC: AO~BAO~ Use: ulcer therapeutic, Hz-receptor antagonist RN: 76824-35-6 MF: CRHlSN,O,S3 MW: 337.45 LD,: 244.4 mglkg (M, i.v.) CN: 3-[[[2-[(aminoiminomethyl)amino]-4-thiazolyl]methyl]thio]-N-(aminosulfonyl)propanimidamide propionitrile thiourea 1,3-dichloro- S-(2-ornino-4- (1) acetone thiazolylrnethyl)- isothioureo benzoyl isothiocyonate iodide N\S "CN 2. sulfornide I lNH I Fornotidine Referencefs): DOS 2 951 675 (Yamanouchi; appl. 21.12.1979; J-prior. 2.8.1979). DOS 3 008 056 (Yamanouchi; appl. 3.3.1980; J-prior. 6.3.1979, 23.6.1979). GB 2052 478 (Yamanouchi; appl. 6.3.1980; J-prior. 6.3.1979, 23.6.1979). GB 2 055 800 (Yamanouchi; appl. 20.12.1979; J-prior. 2.8.1979). US 4283 408 (Yamanouchi; 11.8.1981; J-prior. 2.8.1979). synthesis of S-[2-aminothiazol-4-ylmethyl]isothiourea: !$rape, JM.; Lund, A.H.; ziegler, C.: J. Am. Chem. Soc. (JACSAT) 68, 2155 (1946). preparation of 4-chloromethylthiazol-2-ylamine hydrochloride: Passarotti, C.M.; Valenti, M.; Marini, M.: Boll. Chim. Farm. (BCFAAI) 134 (1 I), 639-643 (1995). Formulation(s): f. c. tabl. 10 mg, 20 mg, 40 mg; oral susp. 40 mgl5 ml; vial (lyo.) 20 mg Trade Name(s): D: Ganor (Boehringer Ing.) GB: Pepcid (Morson; 1987) USA: Mylanta (Johnson & Pepdul (MSD 1: Famodil (Sigma-Tau) Johnson-Merck) Chibropharm; 1986) Gastridin (Merck Sharp & Pepcid (Merck; 1986) F: Pepcidac (Labs. Jean-Paul Dohme) Pepcid (Johnson & Martin) Motiax (Neopharmed) Johnson-Merck) Pepdine (Merck Sharp & J: Gaster (Yamanouchi; 1985) Dohme-Chibret) 828 F Faropenem sodium Faropenem sodium Use: penem antibiotic (Furopenem; SUN 5555) RN: 122547-49-3 MF: C,,H,,NNaO,S MW: 307.30 CN: [5R-[3(R*),5a,6a(R*)]]-6-(l-tlydroxyethyl)-7-oxo-3-(tetrahydro-2-furmyl)-4-thia-l-azabicyclo[3.2.O]- hept-2-ene-2-carboxylic acid sodium salt hydrate RN: 158365-5 1-6 MF: C,,HI4NNaO5S . 5/2H,O MW: 704.68 acid RN: 106560-14-9 MF: Cl,H,SNO,S MW: 285.32 1. brucine dihydrote 3. HCI, H,O, 1 H3C 0-c~~ In HOOC 0 (+).tetrahydro- 2. seporotion of diostereomeric solts (R)-(+)-tetrohydro- furon-2-corboxylic furon-2-corboxylic ocid acid (I) 1. SOCI, ~bs/O 2. NoHS NoOH. THF 1. thionyl 0 [3R(1 'R).4R]-(+)-4-ocetoxy- chloride R-(+)-tetrahydro- 3-[1 -(tert-butyldimethyl- 2. sodium silyloxy)ethyl]-2-ozetidinone (11) (HI) furon-2-thio- hydrogen- corboxylic ocid sulfide CH2 OHC O ,+CH benzene + K 0 2 -+ OII~I glyoxylote (W 1. SOCI, 2.0J3 2. triphenylphosphine (V) Faropenem sodium F 829 - v 1, tetrabutylommonium fluoride 2. sodium 2-ethylhexanaate / Faropenem sodium I preparation of intermediate 11: 1. [Ru,CI, (+)-BINAP], H, 2. HCI COOH H3C OH methyl 2-(benzyl- ominomethyl)-3- oxabutonoote (2S.3R)-2-(aminomethyl)- 3-hydroxybutanoic .acid hydrochloride (VI) w H~C& 11 triphenylphasphine, 2. TBDMS-chloride di-2-pyridyl disulfide 0 H Reference(s): EP 199 446 (Suntory; appl. 7.3.1986; I-prior. 9.3.1985). WO 9 203 443 (Suntory; appl. 16.8.1991; J-prior. 20.8.1990). preparation of intermediate II: . EP 369 691 (Takasago Int. Corp.; appl. 10.1 1.1989; J-prior. 15.1 1.1988). EP 371 875 (Takasago Int. Corp.; appl. 28.1 1.1989; J-prior. 29.1 1.1988). EP488 611 (Takasago Int. Corp.; appl. 25.11.1991; J-prior. 30.1 1.1990). Murahashi, S. et al.: Tetrahedron Lett. (TELEAY) 32 (19), 2145 (1991). alternative preparation of (3S, 1'R)-3-(1'-hydroxyethy1)azetidin-2-one: Fuganti, C. et a].: J. Chem. Soc. Perkin Trans. 1 (JCPRB4) 1 (1 9), 2247 (1993). Fuganti, C. et al.: Bioorg. Med. Chem. Lett. (BMCLE8) 2 (7), 723 (1994). preparation of racemic tetrahydrofuran-2-carboxylic acid: Wienhaus; Sorge: Ber. Dtsch. Chem. Ges. (BDCGAS) 46, 1929 (1913). Kaufmann; Adams: J. Am. Chem. Soc. (JACSAT) 45,3041 (1923). Wilson: J. Chem. Soc. (JCSOA9) 1945, 58, 59. preparation of (R)-(+)-tetrahydrofuran-2-carboxylic acid: Rarnh, A. et al.: J. Med. Chem. (JMCMAR) 38, 2830 (1995). Belanger, PC., Williams, H.W.R.: Can. J. Chem. (CJCHAG) 61, 873 (1 983). Formulation(s): tabl. 150 mg, 200 mg 830 F Fasudil Trade Natne(s): J: Farom (Suntory; 1999) Fasudil (AT-877; HA- 1077) RN: 103745-39-7 MF: CI4H,,N,O2S MW: 291.38 CN: hexahydro- 1-(5-isoquinolinylsu1fonyl)- 1 H- 1,4-diazepine monohydrochloride RN: 105628-07-7 MF: C14Hl,N,02S . HCI MW: 327.84 S0Cl2, DMF ;pJJ H S03H O=S.O piperazine I CI isoquinoline isoquinoline ATC: JOlCAl2 Use: vasodilator, calcium channel blocker Fosudil chloride Reference(s): EP 187 371 (Asahi Chem.; appl. 23.12.1985; J-prior. 27.12.1984). Formulation(s): amp. 30 mgl2 ml (as hydrochloride) Trade Name(s): J: Eril (Asahi Kasei; as , hydrochloride) Fasdil (Asahi Chem.) Febuprol ATC: AOSAB Use: choleretic RN: 3 102-00-9 MF: C,1H2,,0, MW: 224.30 EINECS: 221-454-8 LD,,,: 436 mglkg (M, i.p.); 3050 mglkg (M, p.0.); 400 mglkg (R, i.p.); 2370 mglkg (R, p.0.) CN: I-butoxy-3-phenoxy-2-propanol phenol (I) epichloro- glycidyl phenyl Febuprol hydrin ether . [5R-[3(R*),5a,6a(R*)] ]-6 -( l-tlydroxyethyl )-7 -oxo- 3-( tetrahydro-2-furmyl )-4 -thia-l-azabicyclo[3.2.O ]- hept-2-ene-2-carboxylic acid sodium salt hydrate RN: 1 5836 5-5 1-6 MF: C,,HI4NNaO5S . 5/2H,O MW: 704.68 acid RN: 10656 0-1 4-9 . 0HCm4N-Bi-CH3 0 2. diisobutyl- CH, " 4-[ 3-( ethoxy- - aluminum 4-( 3-formylpropyl )- carbonyl)propyl ]- hydride 1 -( trimethylsilyl )- 1H-imidazale imidozole (111) 4-( tert-butyl- 4-[ 4-[ 4-( tert-butyl-. [3R(1 'R).4R ]-( + )-4 -ocetoxy- chloride R-(+)-tetrahydro- 3-[ 1 -( tert-butyldimethyl- 2. sodium silyloxy)ethyl ]-2 -ozetidinone (11) (HI) furon-2-thio- hydrogen- corboxylic ocid sulfide