Nevirapine N 1421 1. H2S0,, pH 5 2. H,C CHO 3. NaBH CN (1 2. acetaldehyde 3. sodium cyano- FJH2 borohydride @ from 1-N-ethyl-a-deoxy-D-streptomin by fermentation with Micmmonospora inyoensis 1550F-1G Reference(s): DOS 2 462 485 (Scherico; appl. 1.8.1974; USA-prior. 6.8.1973, 19.3.1974). DOS 2 437 160 (Scherico; appl. 1.8.1974; USA-prior. 6.8.1973, 19.3.1974) - (also further methods). US 4 002 742 (Scherico; 11.1.1977; prior. 19.3.1974). Formulation(s): amp. 15 mgl1.5 ml, 50 mg /ml, 100 mglml, 150 mglml, 200 mg/2 ml (as sulfate) Trade Name(s): D: Certomycin (Essex GB: Netillin (Schering-Plough; J: Netilyn (Sankyo; 1985) Pharma; 1980) 1981) Vectacin (Essex) F: Netromicine (Schering- I: Nettacin (Schering-Plough; USA: Netromycin (Schering; Plough; 1983) 1982) 1983) Zetamicin (Menarini; 1982) Nevirapine (BI-RG-587) ATC: JOSAGO1 Use: antiviral, anti-AIDS therapeutic, reverse transcriptase inhibitor RN: 129618-40-2 MF: C,,H,,N,O MW: 266.30 CN: 11 -cyclopropyl-5,l l-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][l,4]diazepin-6-one Pa5, POCI, SnC14. CHSCOOH A CH3 CH3 CH3 2-hydroxy- 2-chloro-3- 3-omino-2- 3-nitro-4- nitro-4-me- chloro-4-me- methylpyridine thylpyridine thylpyridine (I) 1422 h' Nevirapine 2-chloro- nicotinoyl chloride (11) 2-chloro-N-(2- chloro-4-methyl- 3-pyridinyl)-3-pyri- dinecorboxornide N-(2-chloro-4-methyl- Neviropine 3-pyridy1)-2-cyclpro- pylornino-3-pyridine- corboxarnide (IV) y3 2-rnethoxy-3- di-tert-butyl 3-(tert-butoxy- ominopyridine dicorbonote corbonylornino)- 2-rnethoxy- pyridine (V) I. BuLi, E~~O 7H3 2. HCI. EtOAc v + H3C-I , H3C CH3 0 H CH, rnethoxy-4- rnethylpyridine rnethoxy-4-methyl- 3-pyridiny1)-3- pyridinecorbox- arnide (VI) Neviropine rr U ,.I I 0 0,CH3 1. KOH. CH30H 2. HCI 0yNH2 + oy -, NC CH3 NC C"3 CH3 cyono- ethyl ocetornide ocetoocetote 2.6-dichloro-4- methyl-3-pyridine- carbonitrile (VII) Nialamide N 14-23 2,6-dichloro-4- methyl-3-pyridine- carboxamide 3-amino-2,6- dichloro-4- methylpyridine v 1. NOH Nevirapine 0 0 CH3 2,6-dichloro-3- (2-chloronicotinoyl- amino)-4-methyl- pyridine (VIII) Referencefs): review: Pedersen, O.S.; Pedersen, E.B.: Synthesis (SYNTBF) ,(4), 479, (2000). a EP 429 987 (Boehringer Ing.; USA-prior. 19.10.1990). b US 5 532 358 (Boehringer Ing.; 2.7.1996; USA-prior. 12.10.1994). c EP 482 481 (Boehringer Ing.; appl. 16.10.1991; USA-prior. 19.10.1990). process for IV avoiding excess of cyclopropylamine: DE 4403 31 1 (Boehringer Ing.; D-prior. 3.2.1994). combination with HIV-protease inhibitors: WO 9 600 068 (Merck & Co.; appl. 23.6.1995; USA-prior. 27.6.1994). osmotic dosage forms: US 5 358 721 (Alza Corp.; appl. 4.12.1992; USA-prior. 4.12.1994). Formulation(s): tabl. 200 mg Trade Name(s): D: Viramune (Boehringer GB: Viramune (Boehringer USA: Viramune (Roxane; 1998) Ingel h.; 1998) Ingelh.; 1998) Nialamide ATC: N06AF02 Use: psychoanaleptic, antidepressant RN: 51-12-7 MF: C,,H,8N,02 MW: 298.35 EINECS: 200-079-3 LD,,,: 120 mgtkg (M, i.v.); 590 mag (M, p.0.); 1700 mag (R, p.0.) CN: 4-pyridinecarboxylic acid 2-[3-0x0-3-[(phenylmethyl)amino]propyl]hydrazide isoniazid methyl (4. v.) acrylate 1424 N Niaprazine benzylomine Niolomide Referencefs): US 2 894 972 (Pfizer; 14.7.1959; prior. 31.12.1958). US 3 040 061 (Pfizer; 19.6.1962; prior. 27.4.1959, 1.6.1961). Formulation(s): cps. 25 mg, 100 mg Trade Name(s): F: Niamide (Pfizer); wfm GB: Niamid (Pfizer); wfm J: Niamid (Taito Pfizcr) Niaprazine ATC: N05CM16 Use: antiallergic, bronchodilator, sedative RN: 27367-90-4 MF: CzOHz5FN40 MW: 356.45 EINECS: 248-431-5 LD,: 145 mglkg (M, i.v.); 890 mglkg (M, p.0.) CN: N-[3-[4-(4-fluoropheny1)- 1-piperazinyll- 1-methylpropyll-3-pyridinecarbpxamide I -(4-fluorophenyl)- piperozine dihydrochloride H2N-OH . HCI 0 LiAIH, I H~C-N J hydroxylomine DF hydrochloride N'OH nicotinoyl chloride DF 0 CH, Nioprozine I DOS 1 957 371 (Mauvernay; appl. 14.1 1.1969; F-prior. 14.1 1.1968). US 3 712 893 (Mauvernay; 23.1.1973; F-prior. 14.1 1.1968). Formulation(s): syrup 0.3 gI100 ml Trade Name(s): F: Nopron (SynthClabo) I: Nopron (Sanofi Winthrop) Nicardi pine ATC: C08C~04 Use: calcium antagonist RN: 55985-32-5 MF: C2,HZyN3O6 MW: 479.53 EINECS: 259-932-3 LD,,: 9.7 mglkg (M, i.v.); 480 mglkg (M, p.0.); 320 mglkg (R, p.0.) CN: 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2- [methyl(phenylmethyl)amino]ethyl ester monohydrochloride RN: 54527-84-3 MF: Cz6HzyN30,. HC1 MW: 515.99 EINECS: 259-198-4 LD,,: 19.9 mglkg (M, i.v.); 322 mgkg (M, p.0.); 15.5 mglkg (R, i.v.); 184 mglkg (R, p.0.); 5 mglkg (dog, i.v.) methyl 3-nitro- 3-amino- benzaldehyde crotonate 2-(methylbenvlamino)- ethyl ocetoocetate Nicordipine US 3 985 758 (Yamanouchi; 12.10.1976; J-prior. 20.2.1973). DOS 2 407 115 (Yamanouchi; appl. 15.2.1974; J-prior. 20.2.1973, 3.3.1973, 20.4.1973, 11.5.1973, 17.5.1 973, 24.7.1973,29.11.1973). Iwanami, M. et al.: Chem. Pharm. Bull. (CPBTAL) 27, 1426 (1979). (alternative syntheses are described). synthesis of enantiomers: Shibanuma, T. et al.: Chem. Pharm. Bull. (CPBTAL) 28,2809 (1980). Formulation(s): cps. 20 mg, 30 mg; s. r. cps. 30 mg, 45 mg, 60 mg (as hydrochloride) Trade Name(s): D: Antagonil (Novartis Pharma) F: Loxen (Novartis; 1986) GB: Cardene (Yamanouchi; 1986) I: Bionicard (Bioindustria) Cardioten (OFF) Cardip (Francia Farm.) Cardipinen (Farmaceutica Pr.) Lisanirc (Lisapharma) Neucor (CT) Nicapress (Benedetti) Nicardal (Italfarmaco) Nicarpin (Sancarlo) Nimicor (Formenti) Niven (Pulitzer) Perdipina (Novartis Farma) Ranvil (Gentili) Vasodin (Teofarma) Vasonorm (NCSN) J: Nicodel (Mitsui; 1981) Perdipine (Yamanouchi; 1981) 1426 N Nicergoline USA: Cardene (Roche; Wyeth- Ayerst) Nicergoline ATC: C04AE02 Use: vasodilator RN: 27848-84-6 MF: C,H,,BrN,O, MW: 484.39 EINECS: 248-694-6 LD,,,: 46 mglkg (M, i.v.); 633 mglkg (M, p.0.); 42 mgkg (R, i.v.); 1193 mglkg (R, p.0.); 20 mglkg (dog, i.v.); 790 mglkg (dog, p.0.) CN: (8P)-10-methoxy-l,6-dimethylergoline-8-methanol 5-bromo-3-pyridinecarboxylate (ester) tartrate RN: 32222-75-6 MF: C,H,,BrN303. xC4H,0, MW: unspecified EINECS: 250-964-3 methyl lysergote methyl 10-0- methyl-lumilysergote pyridine H&NH+.ryyL , 0/"" - Br$o/,,,r&NH N - I H y; CH3 CH3 lumilysergol 5-bromonico- lumilysergol 10-methyl 10-methyl ether (I) tinoyl chloride ether 8-0-(5-bromo- nicotinote) (11) methyl I Nicergoline iodide KNH, u + H3C-I potossium , omide Ho/",?p&N H2S0,. UV 2. 1. KOH. H,C-I DMSO - + H3C-OH -b I III N - I H CH3 H3C\ Brdf . ++ &N-cH3 - N N - I H CH3 lysergol [by extraction from Kolodono seeds (Colonyction-lpomoeo (Choisy) Hollier f. nova species)] Niceritrol h' 1427 Nicergoline CH3 1 -methyl- 1 Oa-meth- 5-bromonicotinic oxylumilysergol (111) acid Reference (s): US 3 879 554 (Soc. Farmaceutici Italia; 22.4.1975; I-prior. 20.3.1970). a US 3 228 943 (Soc. Farmaceutici Italia; 11.1.1966; I-prior. 11.6.1962). DOS 2 022 926 (Soc. Farmaceutici Italia; appl. 11.5.1970; I-prior. 13.5.1969). DOS 2 112 273 (Soc. Farmaceutici Italia; appl. 15.3.1 971; I-prior. 20.3.1970). Arcari, G. et al.: Experientia (EXPEAM) 28, 819 (1972). Bemardi, L.: Arzneim Forsch. (ARZNAD) 29 (11), 1204 (1979). alternative method for esterification with 5-bromonicotinic acid (imidazolide method): DOS 2 752 533 (LEK; appl. 24.1 1.1977; YU-prior. 22.12.1976). GB 1 557 506 (LEK; appl. 6.12.1977; YU-prior. 22.12.1976). b a) isolation of lysergol from kaladana seeds: Abou-Chaar, C.I.; Digenis, G.A.: Nature (London) (NATUAS) 212,6 I8 (1966). DOS 2 240 266 (Simes; appl. 16.8.1972; B-prior. 17.8.1971: 14.1.1972). DOS 2 834 703 (Simes; appl. 8.8.1978; CH-prior. 12.8.1977). b b) method: GB 2 018 245 (E. Corvi Mora; appl. 4.4.1979; I-prior. 5.4.1978). Formulation(s): cps. 5 mg, 10 mg, 15 mg, 30 mg; f. c. tabl. 5 mg, 10 mg, 20 mg, 30 mg; drg. 5 mg, 10 mg; tabl. 10 mg, 20 mg; vial 4 mgl4 rnl (as tartrate) Trade Name(s): D: Circo-Maren (Krewel F: Sermion (Specia; 1975) Sermion (Pharmacia & Meuselbach) I: Cebran (Garant) Upjohn) ergobel (Hormosan) Ergolin (Boniscontro & J: Sermion (Farmitalia- Memoq (Parke Davis) Gazzone) Tanabe) Nicerium (Neuro Hexal) Nicer (1st. Chim. Inter.) Sermion (Pharmacia & Sermidrina (Farmita1ia)- Upjohn; 1978) comb. Niceritrol ATC: CIOADO~ Use: cholesterol depressant, antiarteriosclerotic RN: 5868-05-3 MF: C2,H24N,0, MW: 556.53 EINECS: 227-519-7 CN: 3-pyridinecarboxylic acid 2,2-bis[[(3-pyridinylcarbonyl)oxy]methyl]-1,3-propanediyl ester pentoerythritol nicotinoyl I Niceritrol chloride 1428 N Niclosamide Referencefs): GB 1 022 880 (Bofors; appl. 18.1 1.1964; S-prior. 13.10.1964). Formulation(sJ: tabl. 500 mg Trade Name(s): 1: Perycit (Tosi); wfm J: Perycit (Sanwa Kagaku) Niclosamide ATC: P02DAOl Use: anthelmintic RN: 50-65-7 MF: C,,H,Cl,N20, MW: 327.12 EINECS: 200-056-8 LDs,]: 7500 pglkg (M, i.v.); 1 g/kg (M, p.0.); 2500 mgkg (R, p.0.) CN: 5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide CI phosphorus(lll) chloride 5-chlorosoli- 2-chloro-4- cylic acid nitroaniline Niclosornide Reference(s): US 3 079 297 (Bayer; 26.2.1963; prior. 26.9.1956, 21.10.1959; 31.5.1960). new formulations: GB 1 527 638 (Bayer; appl. 14.12.1976; D-prior. 20.12.1975). Formulation(sJ: tabl. 500 mg Trade Name(sJ: D: Yomesan (Bayer Vital) GB: Yomesan (Bayer) USA: Niclocide (Miles Pharm.); F. TrCdCmine (Roger Bellon) I: Yomesan (Bayer Italia) wfm Nicoclonate ATC: ClOAD Use: antiarteriosclerotic, hyperlipidemic RN: 10571-59-2 MF: Cl6H1,C1NO2 MW: 289.76 EINECS: -234-156-8 LD,,,: 2.27 gkg (M, i.p.) CN: 3-pyridinecarboxylic acid 1-(4-chloropheny1)-2-methylpropyl ester 4-chloro- isopropyl- 1 -(4-chlorophenyl)- Nicoclonote benzaldehyde magnesium 2-methyl-1 -propon01 bromide Nicofuranose N 1429 Referencefs): FR-M 3 454 (~tabl. Kuhlmann; appl. 10.4.1964). US 3 367 939 (~tabl. Kuhlmann; 6.2.1968; F-prior. 10.4.1964). Formularion(s): cps. 250 mg Trade Name(s): F: Lipidium-Sedaph I: Lipidium (Rorer) (Sedaph)-comb.; wfm Nicofuranose (Tetranicotinoylfructose) ATC: ClOAD03 Use: vasodilator RN: 15351-13-0 MF: C30H,4N40,0 MW: 600.54 EINECS: 239-385-7 CN: (3-D-fructofuranose 1,3,4,6-tetra-3-pyridinecarboxylate I. CHC13, pyridini, Qcl ' 0 iHOfloH 43E HOW^ 1. nicotinoyl chloride hydrochloride OH OH 8-D-fructo- 8-D-fructo- pyranose furonose N, 3 Nicofuronose Reference (s): CH 366 523 (Eprova; appl. 1958). Formulation(s); drg. 250 mg Trade Name(s): D: Bradilan (Mundipharma); GB: Bradilan (Napp); wfm wfm 1430 N Nicorandil Nicorandil RN: 65141-46-0 MF: C,HloN,O, MW: 166.18 LDSo: 626 mglkg (M, p.0.); 502 mg/kg (R, i.v.); 1220 mgkg (R, p.0.); 62.5 mglkg (dog, p.0.) CN: N-[2-(nitrooxy)ethyl]-3-pyridinecarboxamide ATC: COIDX16 Use: coronary vasodilator nicotinic acid methyl nicotinate Nicorondil Reference(s): Masayoshi, S.: Yakugaku Zasshi (YKKZAJ) 80, 1706 (1960). DE 2 7 14 713 (Chugai; prior. 1.4.1977). n~edical use: US 4 200 640 (Chugai; 29.4.1980; J-prior. 2.4.1976). JP-appl. 58/85 819 (Chugai; appl. 17.11.1981). transdermal application system: JP-appl. 59/10 513 (Nitto; appl. 12.7.1982). Formulation(s): tabl. 2.5 mg, 5 mg, 10 mg, 20 mg Trade Nnme(s): F: Adancor (Lipha SantC) GB: Ikorel (RhGne-Poulenc J: Perisalol (Mitsubishi; Ikorel (Bellon) Rorer) 1984) Sigmart (Chugai; 1984) Nicotafuryl (Thurfyl nicotinate) ATC: M01 Use: antirheumatic (extern), rubefacient RN: 70-19-9 MF: CllH13N03 MW: 207.23 EINECS: 200-727-5 CN: 3-pyridinecarboxylic acid (tetrahydro-2-furany1)methyl ester nicotinoyl tetrahydro- chloride furfuryl alcohol . 2-chloro- nicotinoyl chloride (11) 2-chloro-N-( 2- chloro-4-methyl- 3-pyridinyl )-3 -pyri- dinecorboxornide N-(2-chloro-4-methyl- Neviropine 3-pyridy1 )-2 -cyclpro- pylornino-3-pyridine-. l-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][l,4]diazepin-6-one Pa5, POCI, SnC14. CHSCOOH A CH3 CH3 CH3 2-hydroxy- 2-chloro- 3- 3-omino- 2- 3-nitro- 4- nitro-4-me- chloro-4-me- methylpyridine. cyono- ethyl ocetornide ocetoocetote 2.6-dichloro- 4- methyl-3-pyridine- carbonitrile (VII) Nialamide N 1 4-2 3 2,6-dichloro- 4- methyl-3-pyridine- carboxamide 3-amino-2, 6- dichloro- 4- methylpyridine