Fluvastatin sodium F 921 nortropine N-(8-fluoroethyl)- nortropine N-(p-fluorocthyl)nar- tropine benzilate (V) V+N b Flutropium bromide Reference(s): DE 2 540 633 (Boehringer Ing.; appl. 12.9.1976). Banholzer, R. et al.: Arzneim Forsch. (ARZNAD) 36, 1161 (1986). synthesis of nortropine benzilate: Bertholdt, H. et al.: Arzneim Forsch. (ARZNAD) 17, 719 (1967) Trade Name(s): I: Flubron (S. S. Pharm.) Fluvastatin sodium (SRI-62320; XU-62-320; XU-620) ATC: B04AB04 Use: hyperlipidemic, HMG-CoA- reduclase inhibitor RN: 93957-55-2 MF: C,H2,FNNa04 MW: 433.46 CN: [R*.S*-(E)]-(~)-7-[3-(4-fluorophenyl)-I-(l-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid monosodium salt free acid RN: 93957-54- 1 MF: C2,HZ6FNO4 MW: 41 1.47 1. HAI[CH2CH(CH3)2]2 toluene. THF, -78 'C 2. MnD2, Et20 b 1. diisobutylalurninum hydride ethyl 3-(4-fluoro- phenyl)-1 -isopropyl- indale-2-corboxylate 3-(4-fluor0phenyl)- 1 -isopropylindole- 2-carboxoldehyde (I) 922 F Fluvastatin sodium 2-(tributylstannyl)vinyl ethyl ether H3Cy~~3 THF, -78 OC ___, (E)-3-[3-(4-fluoro- phenyl)-1 -isopropyl- indol-2-yl]- propenal (11) methyl ocetoacetate methyl (f)-(E)-7-[3-(4-fluoro- phenyl)-1 -isopropylindol- 2-yl]-5-hydroxy-3-oxohept- 6-enoate (ID) I. (H,c),c-NH, . BH,. C2H50H H3Cy~~3 2. separation of the diastereorners I11 / \ - w0 F 0-CH3 methyl (+)-erythro-(~)-3.5-dih~drax~- 7-[3-(4-fluorophenyl)- 1 -isopropyl- indol-Z-yllhept-6-enoate (IV) *O - ONa F Fluvastatin sodium Fluvastatin sodium F 92 NoH. BuLi. THF " + - aOH, H3C 0 CH- I tert-butyl acetometote tert-butyl (2)-(E)-7-[3-(4-lluoro- phenyl). 1 -isopropylind0l-2-~l]- 5-hydroxy-3-oxohept-6-enoate (VI) 1. CH,OB(C,H,), NaF3H4. THF, CH30H (stereoselective reduction) 2. H202. ethyl acetate H3Ck~~3 (hydrolysis of the cyclic boronate) VI 1, diethylmethoxybarane - '%O F 0RH3 CH3 tert-butyl (?)-erythro-(E)-7- [3-(4-fluoraphenyl)-1 -isopropyl- indal-2-yl]-3,s-dihydroxy- hept-6-enoote (VIl) NaOH, THF, 10 OC VII _____* @ synthesis of 3-(4-fluorophenyl)-1 -isopropylindole -2-carboxaldehyde (1): a-chloro-p- N-isopropyl- fluoraoceto- aniline phenone DMF, 100aC + Referencefs): a WO 8 402 131 (Sandoz; appl. 18.1 1.1983; USA-prior. 22.1 1.1982, 4.1 l.l983,4.3.1985). aa Walkup, R.E. et al.: Tetrahedron Lett. (TELEAY) 26 (la), 2155-2158 (1985). b EP 363 934 (Sandoz; appl. 11.10.1989; USA-prior. 13.10.1983, 22.5.1989). composition with improved storage stability: US 5 356 896 (Sandoz; 18.10.1994; appl. 22.12.1992; USA-prior. 12.12.1991). oral pharmaceutical composition: EP 547 000 (Sandoz; appl. 8.12.1992; USA-prior. 12.12.1991). combination with sqr~alene synthase inhibitors: EP 482 498 (Squibb; appl. 16.10.1991; USA-prior. 19.10.1990). EP401 705 (Squibb; appl. 1.6.1990; USA-prior. 5.6.1989). 924 F Fluvoxamine combination with ACE inhibitors: EP 461 548 (Squibb; appl. 6.6.1991; USA-prior. 11.6.1990). EP 457 514 (Squibb; appl. 10.5.1991; USA-prior. 15.5.1990). combination with niacin or probucol: EP 373 507 (Squibb; appl. 7.12.1982; USA-prior. 12.12.1988). composition containing coenzyme Q10: US 4 933 165 (Merck & Co.; 12.6.1990; appl. 18.1.1989; USA-prior. 18.1.1989). US 4 929 437 (Merck & Co.; 29.5.1990; appl. 2.2.1989; USA-prior. 2.2.1989). Formulation(s): cps. 21 .O6 rng, 42.12 mg Trade Name(s): D: Cranoc (AstraPromed) F: Fractal (Sinbio) GB: Lescol (Novartis) Loco1 (Novartis Pharma) Lescol (Novartis) USA: Lescol (Novartis) Fluvoxamine ATC: N06AB08 Use: antidepressant RN: 54739- 18-3 MF: C,,HzIF3N,0z MW: 3 18.34 CN: (0-5-methoxy- 1 -[4-(trifluorornethyl)phenyl]- 1-pentanone 0-(2-arninoethy1)oxime hydrogen maleate RN: 6171 8-82-9 MF: C,,Hz,F3N202 . C4H404 MW: 434.41 4'-trifluorornethyl-5- 0-(2-amifloethyl)- rnethoxyvalerophenone (1) hydroxylarnine H~N-O'~ H3C'~~Cr, Fluvoxarnine H~N-'' 1 + HO-NH2 p 2-chloro- hydroxyl- ethylarnine arnine Reference(s): DE 2 610 886 (Philips Gloeilampenfabrieken; appl. 7.10.1976; prior. 16.3.1976). US 4 085 225 (Philips Corp.; 18.4.1978; appl. 13.3.1976; NL-prior. 20.3.1975). NL 7 503 310 (Philips Gloeilampenfabrieken; appl. 20.3.1975). Formulation(s): f. c. tabl. 50 rng, 100 mg; tabl. 25 rng, 50 mg, 100 mg (as hydrogen rnaleate) Trade Name(s): D: Fevarin (Solvay GB: Faverin (Solvay; 1987) USA: Luvox (Solvay) Arzneirnittel; 1984) I: Durnirox (Upjohn) F: Floxyfral (Solvay Pharma; Fevarin (UCM) 1986) Maveral (Fannades) 6 Folescutol F 925 Folescutol ATC: C05C Use: capillary therapeutic, capillary protectant RN: 15687-22-6 MF: C14HI,N0, MW: 277.28 EINECS: 239-783-0 CN: 6,7-dihydroxy-4-(4-morpholinylmethyl)-2H-l-benzopyran-2-one hydrochloride RN: 36002- 19-4 MF: C14H,,NOs . HCI MW: 3 13.74 EINECS: 252-83 1-5 HJCYO Ox~Of~3 + H2S04 b ::y mzO bFi B morphollne H,C 0 1,2,4-tnacetoxybenzene ethyl 4-chloro- 4 chloramethyl- Folescutol acetoacetate 6.7-d~hydroxy- chrornen-2-one Reference(s): FR-M 2 035 (Lab. Dausse; appl. 29.6.1962). Formulation(s): drg. 20 mg in comb. Trade Name(s): D: Detensitral (Kar1spharma)- F: Covalan (Dausse); wfm Tensitral (Dausse)-comb.; comb.; wfm wfm Folic acid (Pteroylglutamic acid) ATC: B03BBOl Use: antianemic, growth factor RN: 59-30-3 MF: C,,lH,,N706 MW: 441.40 EINECS: 200-419-0 LD,& 282 mglkg (M, i. v.); 10 glkg (M, p.0.) CN: N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-~-glutamic acid monosodium salt RN: 6484-89-5 MF: C,,H,,N,NaO, MW: 463.39 EINECS: 229-348-3 LD,,: 631 mglkg (M, i.v.); 526 mglkg (R, i.v.) u OH guonidine ethyl 2,4-diarnino-6- cyonoacetote hydroxypyrirnidine 926 F Folic acid H2NQk,, COOH NaHS03, pH 4-5 OH 0 LOOH 6-hydroxy-2.4.5- 1.1,3-tri- N-(4-aminobenzoyl)- triaminopyrimidine (I) chlaroacetone L-glutamic acid (11) Folic acid CHO NaHS03, pH 4-5 I + Brk~r + 11 r 2,3-dibromo- propianaldehyde NaHSO,, pH 4-5 I + yo + 11 0 CH, pyruvaldehyde Reference(s): Wailer, C.W. et al.: J. Am. Chem. Soc. (JACSAT) 70, 19 (1948). Hultquist, M.E. et al.: J. Am. Chem. Soc. (JACSAT) 70, 23 (1948). Angier, R.B. et al.: J. Am. Chem. Soc. (JACSAT) 70, 25 (1948). Boothe, J.H. et al.: J. Am. Chem. Soc. (JACSAT) 70, 27 (1948). US 2 436 073 (American Cyanamid; 1948; appl. 1945). US 2 442 836 (American Cyanamid; 1948; appl. 1945). US 2 443 078 (American Cyanamid; 1948; appl. 1945). US 2 443 165 (American Cyanamid; 1948; appl. 1946). US 2 444 002 (American Cyanamid; 1948; appl. 1946). US 2 472 482 (American Cyanamid; -1949; appl. 1947). US 2 477 426 (American Cyanamid; 1949; appl. 1948). US 2 547 501 (American Cyanamid; 1951; appl. 1946). US 2 599 526 (American Cyanamid; 1952; appl. 195 1). US 2 719 157 (Shionogi; 1955; appl. 1951). US 2 956 057 (Kongo Kagaku Kabushiki Kaisha; 1960; J-prior. 1955). use oj'propargyl aldehyde: US 2 766 240 (Aries Labs.; 1956; appl. 1953). condensation with a-bromoacroleine: US 2 476 360 (Parke Davis; 1949; appl. 1946). alternative synthesis (via 2-amino-6-formyl-4-hydroxy-pteridine): US 2 786 056 (Merck & Co.; 1957; appl. 1954). US 2 816 109 (Merck & Co.; 1957; appl. 1954). US 2 821 527 (Merck & Co.; 1958; appl. 1954). US 2 821 528 (Merck & Co.; 1958; appl. 1954). US 3 067 200 (Merck & Co.; 4.12.1962; prior. 3.5.1954,20.2.1957). Bieri, J.H.; Viscontini, M.: Helv. Chim. Acta (HCACAV) 56, 2905 (1973). Fulinic acid F 927 synthesis via 2-amino-4-hydroxy-6-halogenoin~thylpteridine: US 2 547 519 (American Cyanamid; 1951; appl. 1946). US 2 547 520 (Amcrican Cyanamid; 195 1 ; appl. 1946). US 2 584 538 (American Cyanamid; 1952; appl. 1948). improved method for synthesis of 2-amino-4-hydroxy-6-methylptcridine: GB 1 503 476 (Lonza; appl. 6.1 .lY77; CH-prior. 13.1 .I 976). US 4 094 874 (Lonza; 13.6.1978; CH-prior. 13.1.1976). Formulation(s): amp. 5 mg15 ml; tabl. 5 mg Trade Name(s): D: Folarell (Sanorell) Fol-ASmedic (Dyckerhoff) Folsan (Solvay Arzneimittel) GB : Folsaure Injektionslosung (Hevert) Folverlan (Verla) Lafol (Brenner-Efcka; LAW) numerous combination preparations F: Alvityl (Solvay Pharma)- comb. Azedavit (Whitehall)- comb. Azinc complexe (Arkopharma)-comb. I: Carencyl (Riom)-comb. ~16vit Vitamine B9 (Nicholas)-comb. Forvital (Whitehall)-comb. Lofenalac (Bristol-Myers Squibb)-comb. Plenyl (0berlin)-comb. Speciafoldine (Specia) Vivamyne (Whitehall). comb. Ferfolic SV (Sinc1air)- comb. Ferrograd Folic (4bbott)- comb. Folex-350 (Shire)-comb. Galfer F.A. (Galen)-comb. Lexpec (Rosemont) . Meterfolic (Sinclair)-comb. Pregaday (Evans)-comb. Slow-Fe folic (Novartis)- comb. numerous combination preparations Combetasi (ISI; as calcium salt)-comb. Efargen (Teofarma)-comb. Epargriseovit (Farrnita1ia)- comb. Eparmefolin (Bracco; as calcium salt)-comb. Ferrofolin (Farmades; as calcium salt)-comb. . Ferrograd Folic (Abbott)- comb. Ferrotre (Mediolanum) comb. Folina (Astra-Simes) Folinemic (Firma; as calcium salt)-comb. Lederfolin (Cyanamid; as calcium salt) Oro B 12 (Ripari-Gero)- comb. Tonofolin (Zyma; as calcium salt) J: Foliamin (Takeda) Folical (Shionogi) USA: Bevitamcl (Westlake) Cefol (Abbott) Folic (Lederle) Materna (Lederle) various generic preparations Folinic acid (Citrovorum factor) ATC: A04A; V03AB Use: antianemic, growth factor, antidote (as calcium salt, at overdose of folic acid antagonists) RN: 58-05-9 MF: C20H23N707 MW. 473.45 EINECS: 200-361-6 CN: N-[4-[[(2-amino-5-formyl-l,4,5,6,7,8-hexahydra-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-~-glutamic acid calcium salt (1:l) (leucovorin calcium) RN: 1492-1 8-8 MF: C,,,H,,CaN,O, MW. 5 1 1.5 1 EINECS: 21 6-082-8 LD,,: 732 mglkg (M, i.v.); >7 glkg (M, pa.); >8 gkg (R, PA.) dcium salt (1:l) pentahydrate RN: 6035-45-6 MF: C,,H,ICaN,07 . SH,O MW: 601 .58 928 F Fomepizole HN N N 0 0 ZJNUQ H + HCOOH H3c~oJLH3 40 OC OH / N,,,cCOOH I folk ocid (q. v.) Reference(s): US 2 741 608 (Research Corp.; 1956; prior. 1950). DOS 2 836 599 (US Department of Commerce; appl. 22.8.1978; USA-prior. 22.8.1977). Temple, C. et al.: J. Med. Chem. (JMCMAR) 22,731 (1979). 10-farrnylfolic acid (I) Formulution(s): amp. 3 mg, 5 mg, 6 mg, 10 mg, 15 mg, 30 mg, 50 mg; cps. 5 mg; tabl. 15 mg, 25 mg (as calcium salt); amp. 1.5 mg, 3 mg, 15 mg, 30 mg, 350 mg; cps. 15 mg; powder 50 mg, 100mg, 200 mg, 300 mg; tabl. 15 mg; vial 100 mg, 200 mg, 300 mg (as calcium salt pentahydrate) Folinic acid Trade Nume(s): D: Calciurnfolinat (Rh6ne- Poulenc); wfm Leucovorin (Lederle); wfm Rescuvolin (medac); wfrn F: Elvorine (Wyeth-Lederle) Folinate de calcium (Aguettant) Folinoral (Therabel Lucien Pharma) Lederfoline (Wyeth- Lederle) Osfolate (ASTA Medica) Perfolate (ASTA Medica) GB: Calcium Leucovorin (Lederle); wlm Refolinon (Pharrnacia & Upjohn) Rescufolin (Nordic); wfin I: Adinepar (Leben1s)-comb. Hepafactor (S~gma-Tau)- comb. Rekord B 12 complex (Sigma-Tau)-comb. J: Leucovorin (Lederle) USA: Calcium Leucovorin (Lederle); wfm Fomepizole Use: antidote for ethlene glycol, competitive inhibitor of alcohol dehydrogenase RN: 7554-65-6 MF: C4H6N2 MW: 82.11 EINECS: 231-445-0 CN: 4-Methyl-1H-pyrazole Pd-Mg0. AI2O3, 25'C or N2H4 -H20 I,, Nal, H20. H2S04 hydrate CH3 2-methyl-2- 4.5-dihydro- Fomepizole propenal 4-methyl- pyrozole Fominoben F 929 Reference(s): Pechrnann, H.; Burkard, E.: Ber. Dtsch. Chem. Ges. (BDCGAS) 33, 3590 (1900). Hoyce, D.S. eta].: J. Org. Chem. (JOCEAH) 20, 1681 (1955). Momose, T. et a].: Heterocycles (HTCYAM) 30, 789 (1990). DE4 328 228 (BASF; prior. 23.8.1993). US 5 569 769 (BASF; 29.10.1996; D-prior. 23.8.1993). DE 3 918 979 (BASF; prior. 10.6.1989). EP366 328 (Nissan Chem. Ind.; appl. 17.10.1989; J-prior. 26.10.1988). Formulation(s): vials, 1 glml; 1.5 ml Tmde Name(s): USA: Antizol (Orphan Medical; 1998) Fominoben ATC: ~06 Use: antitussive, respiratory analeptic RN: 18053-31-1 MF: C2,H24ClN30, MW: 401.89 EINECS: 241-964-4 CN: N-[3-chloro-2-[[methy1[2-(4-morpholinyl)-2-oxoethyl]amino]methyl]phenyl]benzamide monohydrochloride RN: 24600-36-0 MF: C2,H24CIN,03 . HCI MW: 438.36 EINECS: 246-344-7 benzoyl 3-chloro- chloride 2-methylaniline 0 0-Br 0 N-bromo- succinimide Reference(s): DE 1 795 259 (Thomae; appl. 13.7.1966). sorcosine Kriiger, G. et al.: Arzneim Forsch. (ARZNAD) 23,290 (1973) Fominoben Formulation(s): amp. 40 mgl5 ml; drg 160 mg (as hydrochloride) morpholide Trade Namels): D: Broncho-Noleptan Noleptan (Thomae); wfm Tussirama (Serpero); wfm (Thomae); wfm I: Terion (Lusafarmaco); wfm 930 F Fomocaine Fomocaine ATC: R02AD Use: local anesthetic RN: 17692-39-6 MF: C20H25N02 MW: 3 11.43 CN: 4-[3-[4-(phenoxymethyl)phenyl]propyl]morpholine 3-phenyl-1- proponol 3-phenylpropyl chloride 0';"" 0- 3-(4-phenoxymethyl- line (n) phenyl)propyl chloride Fomocoine H,C,MqBr bromide 4-bromomethyl- 4-phenoxymethyl- benzonitrile benzonitrile Roney-Ni 4'-phenoxymethyl- propiophenone (In) Reference(s): a Oelschlager, H.: Arzneirn Forsch. (ARZNAD) 9, 313 (1959). GB 786 128 (Prornonta; appl. 15.1 1.1955; D-prior. 15.1 1.1954). b Oelschlager, H. et al.: Arzneim Forsch. (ARZNAD) 27, 1625 (1 977). pharmacology: Nieschulz, 0. et al.: Arzneim Forsch. (ARZNAD) 8,539 (1958). Formularion(s): cream 4 gI100 g (4 %); ointment 4 g1100 g (4 %) Trade Name(s): D: Brand- und Wund-Gel Erbocain (Heilit); wfrn Herit (Engelhard)-comb.; Erboproct (Hei1it)-comb.; wfrn wfrn . THF, -7 8 OC ___, (E )-3 -[ 3-( 4-fluoro- phenyl )-1 -isopropyl- indol-2-yl ]- propenal (11) methyl ocetoacetate methyl (f )-( E )-7 -[ 3-( 4-fluoro- phenyl )-1 -isopropylindol- 2-yl ]-5 -hydroxy-3-oxohept-. (SRI-62320; XU-6 2-3 20; XU-620) ATC: B04AB04 Use: hyperlipidemic, HMG-CoA- reduclase inhibitor RN: 939 5 7-5 5-2 MF: C,H2,FNNa04 MW: 433.46 CN: [R*.S *-( E) ]-( ~ )-7 -[ 3-( 4-fluorophenyl)-I-(l-methylethyl )-1 H-indol-2-yl ]-3 ,5-dihydroxy-6-heptenoic. boronate) VI 1, diethylmethoxybarane - '%O F 0RH3 CH3 tert-butyl (?)-erythro-(E )-7 - [ 3-( 4-fluoraphenyl )-1 -isopropyl- indal-2-yl ]-3 ,s-dihydroxy- hept-6-enoote (VIl) NaOH, THF, 10 OC