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Indinavir sulfate 1 107 1 2, base XYI b r 1. L-tartaric acid (XVII) oleurn. H3C-CN, H20. -20 OC XVII Xvlll . XVI b 1 t3 dioxygenase OH H oio-conversion Reference(s): a WO 9 309 096 (Merck & Co.; appl. 3.11.1992; USA-prior. 8.1 1.1991, 15.5.1992). b WO 9 502 583 (Merck & Co.; appl. 11.7.1994; USA-prior. 16.7.1993). c Askin, D. et al.: Tetrahedron Lett. (TELEAY) 35 (4). 673 (1994). WO 9 502 584 (Merck & Co.; appl. 11.7.1994; USA-prior. 16.7.1993, 26.1.1994). d Maligres, P.E. et a].: Telrahedron Lett. (TELEAY) 36,2195 (1995). e WO 9 716 450 (Merck & Co.; appl. 25.10.1996; USA-prior. 30.10.1995,22.2.1996). f US 5 413 999 (Merck & Co.; appl. 7.5.1993; USA-prior. 8.11.1991). g WO 9 628 439 (Merck & Co.; appl. 11.3.1996; USA-prior. 15.3.1995). aa WO 9 636 629 (Merck & Co.; appl. 14.5.1996; USA-prior. 18.5.1995). WO 9 521 162 (Merck & Co.; appl. 30.1.1995; USA-prior. 4.2.1994). ab GB 2 302 690 (Merck & Co.; appl. 20.6.1996; GB-prior. 13.2.1996; USA-prior. 28.6.1995). ba WO 9 636 724 (Merck & Co.; appl. 15.5.1996; USA-prior. 19.5.1995). US 5 449 830 (Merck & Co., Procter/Gamble Co.; appl. 1 I .3.1994; USA-prior. 1 I .3.1994). bb WO 9 700 966 (Merck & Co.; appl. 14.6.1996, USA-prior. 13.2.1996, 20.6.1995). WO 9 612 818 (Merck & Co.; appl. 17.10.1995; USA-prior. 21.10.1994). reductive amination with pyridinecarboxaldehyde: US 5 508 404 (Merck & Co.; appl. 15.3.1995; USA-prior. 15.3.1995). prodrugs of indinavir: . WO 9 514 016 (Merck & Co.; appl. 14.1 1.1994; USA-prior. 18.1 1.1993). combination with AZT: WO 9 623 509 (Merck & Co.; appl. 29.1.1996; USA-prior. 1.2.1995). WO 9 604913 (Merck & Co.; appl. 7.8.1995; USA-prior. 20.7.1995, 11.8.1994, 14.1 1.1994). combination with e. g. neoarapine: WO 9 600 068 (Merck & Co.; appl. 23.6.1995; USA-prior. 27.6.1994). combination with quinoxalines: EP 728 481 (Bayer AG; appl. 14.2.1996; D-prior. 27.2.1995). cps. 200 mg, 400 mg (as sulfate) 1072 1 Indobufen Trade Narne(s): D: Crixivan (Merck Sharp & GB: Crixivan (Merck Sharp & USA: Crixivan (Merck & Co.) Do hme) Dohme) Indobufen ATC: BOl AClO Use: anti-inflammatory, antithrombocytic RN: 63610-08-2 MF: CI,H,,NO3 MW: 295.34 EINECS: 264-364-4 LD,,: 370 mglkg (M, i.v.); 697 mgfkg (M, p.0.); 333 mglkg (R, i.v.); 373 mgkg (R, p.0.) CN: (9-4-(1,3-dihydro- 1 -oxo-2H-isoindol-2-y1)-a-ethylbenzeneacetic acid sodium saIt RN: 94135-04-3 MF: C,,H,,NNaO, MW: 3 17.32 a-ethylbenzene- acetic acid phtholic anhydride Reference(s): US 4 118 504 (Carlo Erba; 3.10.1978; I-prior. 10.1 1.1970). DOS 2 154 525 (Carlo Erba; appl. 3.11.1971; I-prior. 5.1 1.1970). GB 1 344 663 (Carlo Erba; appl. 27.10.197 1; I-prior. 5.1 1.1970). Nannini, G. et a].: Arzneim Forsch. (ARZNAD) 23,1090 (1973). (alternative syntheses described) (11) synthesis of-ethyl p-amino-a-ethylphenylacetate: Wilds, A.L.; Biggerstaff, W.R.: J. Am. Chem. Soc. (JACSAT) 67, 789 (1945) Indabufen Forrnulation(s): amp. 200 mg (as sodium salt); tabl. I00 mg, 200 mg Trade Narne(s): I: Ibustrin (Pharmacia & Upjohn; 1984) Indometacin I 1073 Indometacin (Indomethacin) ATC: COlEB03; MOlABOl; M02AA23; SOlBCOl Use: anti-inflammatory, antipyretic, analgesic RN: 53-86-1 MF: C19H16C1N04 MW: 357.79 EINECS: 200-186-5 LDso: 30 mglkg (M, i.v.); 11.841 mglkg (M, p.0.); 21 mgkg (R, i.v.); 2.42 mgkg (R, p.0.); 100 mgkg (dog, i.v.); 160 mglkg (dog, p.0.) CN: l-(4-~hlorobenzoyl)-5-methoxy-2-methyl-lH-indole-3-acetic acid sodium salt hydrate RN: 74252-25-8 MF: C,,H,,C1Na04 . 3H20 MW: 419.81 @ Merck + Co. (4-methoxypheny1)- methyl hydrazine hydrochloride (I) levulinate (11) 0-CH, methyl J-methoxy- 2-methylindole-3- ocetate (111) H NoOH '0 COOH 5-methoxy-2-methylindole- 3-acetic acid 1. NOH. DMF 1. dicyclohexylcarbodiimide 2. tert-butyl alcohol r 1. sodium hydride 2. 4-chlorobenzoyl chloride (V) YOOH lndometocin 1074 1 Indometacin H V, pyridine I + OHC-CH, - H3C\ D~\N+-cH, V1l 0 acetoldehyde levulinic '0 acid @ Sumitorno H CH V , dioxane. 80-85 OC 0 Reference(s): a DE 1 232 150 (Merck & Co.; appl. 16.3.1962; USA-prior. 22.3.1961, 5.1.1962). DAS 1 620 014 (Merck & Co.; appl. 29.6.1966; USA-prior. 30.6.1965). DE 1 620 030 (Merck & Co.; appl. 16.3.1962; USA-prior. 22.3.1961, 5.1.1962). DE 1 620 031 (Merck & Co.; appl. 16.3.1962; USA-prior. 22.3.1961, 5.1.1962). DE 1 643 463 (Merck & Co.; appl. 12.10.1967; USA-prior. 13.10.1966, 14.8.1967). US 3 161 654 (Merck & Co.; 15.12.1964; appl. 11.6.1963; prior. 22.3.1961). b Yamamoto, H.: Chem. Pharm. Bull. (CPBTAL) 16,17 (1968). Yamamoto, H. et al.: Chem. Pharm. Bull. (CPBTAL) 16, 647 (1968). c DAS 1 795 674 (Sumitomo; appl. 8.4.1968; J-prior. 11.4.1967, 6.5.1967, 8.5.1967.23.5.1967, 27.5.1967, 29.5.1967, 8.11.1967, 12.12.1967, 14.12.1967). suspension for parenferal use: US 4 093 733 (Merck & Co.; 6.6.1978; appl. 9.9.1976). Forrnulation(s): cps. 25 mg, 50 mg; eye drops 1 %; gel 10 mg; sol. 8 mglml(1 %); s. r. cps. 75 mg; suppos. 50 mg, 100 mg; susp. 25 mg (as sodium salt hydrate) Trade Narnefs): D: Amuno (Merck Sharp & Confortid (Dumex; as Indo (ct-Arzneimittel) Dohme; 1965)-comb. sodium salt) lndometacin (Aliud Chibro-Amuno (Chibret) Elmetacin (Sankyo) Pharma) Indometacin farnesil 1 1075 lndometacin (Hey1)-comb. Indomisal (Brenner-Efeka) Indo-Top (ratiopharm) lnflam (Lichtenstein)- comb. Jenatacin (Jenapharm) various generics and combination preparations F: Ainscrid LP (Gerda SA) Chrono-lndocid 75 (Merck Sharp & Dohme) lndocid (Merck Sharp & Dohme; 1966) Indocollyre (Chauvin) GB: Artracin SR (Searle) Flexin Continus (Napp) lndocid (Morson) Indomod (Pharmacia & Upjohn) 1: Cidalgon (Ecobi) Difmetre (UCM)-comb. lmet (Firma) lndocid (Merck Sharp & Dohme) Indoxen (Sigma-Tau) Liometacen (Chiesi; as megluminate) Metacen (Chiesi) combination preparations J: Indacin (Merck-Banyu; 1966) lnderapollon (Kaigai) Indomethine (Kowa) lnmecin (Nippon Chemiphar) lnmetocin (Tobishi) Inteban (Sumitomo; 1967) lntedarl (Choseido) Lausit (Showa) Methazine (Sankyo) Mezolin (Meiji) Salinac (Nippon Kayaku) Taikosashin S (Taiho) Zalbico (Toyo Pharmar) USA: lndocin (Merck Sharp & Dohme; 1965) Indometacin farnesil (Indometacin farnesyl) ATC: MOlAB Use: non-steroidal anti-inflammatory, indometacin prodrug RN: 8580 1-02- 1 MF: C,,H,,ClNO, MW: 562.15 LD,,: >4 glkg (M, i.m.); 1305 mglkg (M, i.p.); 6800 mglkg (M, p.0.); 8gkg (M, s.c.); 2000 mglkg (R, i.m.); 3800 mglkg (R, i.p.); 1680 mgkg (R, p.0.); 2400 mglkg (R, s.c.); >3 glkg (dog, pa.) CN: 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid 3,7,11-trimethyl-2,6,1 O-dodecatrienyl ester SOCI, PCH, b 1 v\ \ 0 c I 3.7,l 1 -trimethyl-2.6.10- COOH dodecotrienol 0 indometocin I 0 CH, CH, CH, lndometocin farnesil (I) Reference(s): DE 3 226 687 (Eisai; appl. 16.7.1982; J-prior. 23.7.1981). US 4 455 316 (Eisai; 19.6.1984; appl. 8.7.1982; J-prior. 23.7.1981). US 4 576 963 (Eisai; 18.3.1986; appl. 14.5.1984; prior. 8.7.1982; J-prior. 23.7.1981). soft gelutine cupsdes: EP407 815 (Eisai; appl. 27.6.1990; J-prior. 10.7.1989). 1076 I Indoprofen - stabilisation with tocopherol: EP 387 655 (Eisai; appl. 5.3.1990; J-prior. 17.3.1989). Formula:ion(s): cps. 100 mg Trade Name(s): J: Infree (Eisai; 1991) Indoprofen ATC: MOlAElO Use: anti-inflammatory, analgesic RN: 31 842-01-0 MF: C,,H15N03 MW: 281.31 EINECS: 250-833-0 LD,,,: 700 mglkg (M, p.0.); 84 mgkg (R, p.0.) CN: 4-(1,3-dihydro- 1-0x0-2H-isoindol-2-y1)-a-methylbenzeneacetic acid phtholic ethyl 4-amino-a- anhydride rnethylphenylocetote (1) rCH, KOH 11 lndoprofen I phtholide ethyl 2-chloro- methylbenzoale DOS 2 154 525 (Carlo Erba; appl. 3.1 1.1971; I-prior. 5.1 1.1970, 10.1 1.1970). US 3 767 805 (Ciba-Geigy; 23.l0.1973; prior. 27.3.1968,3.9.1968, 13.1.1969, 18.3.1969, 18.7.1969, 8.9.1969, 3.2.1970). DOS 2 034 240 (Ciba-Geigy; appl. 10.7.1970; USA-prior. 18.7.1969,8.9.1969, l2.9.1969,3.2.1970, 25.5.1970). Nannini, G. et al.: Arzneim Forsch. (ARZNAD) 23, 1090 (1973). Formulation(s): tabl. 200 mg Indoramin 1 1077 Trade Name(s): J: Flosint (Carlo Erba) Indoramin ATC: C02CA02 Use: antihypertensive, a-adrenoceptor antagonist RN: 26844-12-2 MF: C22H,,N,0 MW: 347.46 EINECS: 248-041-5 LDS,,: 1800 rngkg (R, p.0.) CN: N-[l-[2-(1H-indol-3-yl)ethyl]-4-piperidinyl]benzamide monohydrochloride RN: 38821-52-2 MF: CZ2H2,N,O . HCl MW: 383.92 EINECS: 254-136-2 H,C-OH LiAIH, 8 +cl~c~-H3C"O~ 0 1 -1 aluminum indale oxalyl chloride phosphorus tribromide 3-(2-hydroxy- ethyl)indole (I) ethyl indole-3- hydride glyoxylate pyridine 3-(2-bromoethy1)- indole I Indoramin I HZ. Raney-Ni A ~eurne~er, J.L. et al.: J. Med. Chern. (JMCMAR) 12,450 (1969). DOS 1 770 460 (Wyeth; appl. 20.5.1968; GB-prior. 24.5.1967, 1.3.1968). H For~nulation(s): tabl. 20 rng, 25 mg, 50 mg (as hydrochloride) Trade Name(s): D: Wydora (Brenner-Efeka) GB: Baratol (Monmouth) I: Indorena (Lusofarmaco); F: Vidora (Wyeth) Doralese (Bencard) wfrn Inositol (Cyclohexitol; meso-Inositol; myo-Inositol) ATC: A05 Use: liver therapeutic RN: 87-89-8 MF: C,H,20, MW: 180.16 EINECS: 201-781-2 L&,: 10 gk (M, p.0.); >750 mglkg (R, i.v.) CN: myo-inositol 1078 I Inositol nicotinate I__:i Inositol Preparation by hydrolysis of phytin isolated from maize steep watcr [Ca- and Mg-salts of phytic acid (inositol hexa(dihydrogen phosphate))] with diluted sulfuric acid or with watcr under pressure. Reference(s): Bartow, E.B.; Walker, W.W.: Ind. Eng. Chem. (IECHAD) 30,300 (1938). US 2 112 553 (E. B. Bartow, W. W. Walker; 1938; appl. 1935). US 2 414 365 (American Cyanamid; 1947; appl. 1942). synthesis from hexahydroxybenzene: Wieland, H.; Wishart, R.S.: Ber. Dtsch. Chem. Ges. (BDCGAS) 47,2082 (1914). Anderson, R.C.; Wallis, E.S.: J. Am. Chem. Soc. (JACSAT) 70,2931 (1948). Formulation(s): drg. 5 mg, 50 mg Trude Name(s): D: Geriatric Pharmaton (P11armaton)-comb. Inosit-Zyma (Zyma); wfrn various generics and 50 more combination preparations I: Colamin (UCM-Difme) Enteroton (Panthox & Burck)-comb. Equipar (Lampugnani)- comb.; wfrn Inobetin (Boniscontro & Gazzone)-comb.; wfm Inosital (Biomedica Foscama); wfm Lisacol Metionina (Lisapharma)-comb.; wfrn Neoepa (Vis)-comb.; wfm Vitabil Composto (1BP)- comb.; wfm USA: Amino-Cerv (Milex)-comb. Mega-B (Arco)-comb. Megadose (Arco)-comb. Inositol nicotinate ATC: C04AC03 Use: vasodilator RN: 6556-11-2 MF: C42H30N60,, MW: 810.73 EINECS: 229-485-9 LD,,,: 345 mglkg (M, i.v.); >3O glkg (M, p.0.); . 268 mglkg (R, i.v.); >20 glkg (R, p.0.) CN: myo-inositol hexa-3-pyridinecarboxylate nicotinic ocid POCI, CI nicotinoyl chloride 4 HO OH pyridine ___* myo-inositol Inositol nicotinote Reference(s): Badgett; Woodward: J. Am. Chem. Soc. (JACSAT) 69,2907 (1947). GB 1 053 689 (Bofors: aool. 19.1 1.1965: S-orior. 21.1 1.1964). Iobenzamic acid 1 1079 Formulation(s): chewing tabl. 600 mg; tabl. 200 mg, 500 mg, 600 mg, 750 mg, 800 mg Trade Name(s): D: Hamovannad (Bastian- Werk) Hexanicit (Astra/Promed) Nicolip (Hennig) numerous combination prcparations F: Dilexpal (Winthrop); wfm Tensid (Bayer-Pharma)- comb.; wfrn GB: Hexopal (Sanof Winthrop) I: Angiokapsul (Schering)- comb.; wfrn Esantene (Ibis); wfrn Vascunicol (Boehringer Ing.); wfrn Vasonicit (Ibis); wfrn J: Clevamin (Kowa) Cycnate (Toyo Pharmar) Ebelin (Samva) Hexalmin (Maruishi) Hexainosineat (Hishiyama) Hexanate (Nippon Chemiphar) Hexanicit (Yoshitomi) Hexate (Mohan) Hexatin (Kobayashi) Hexit (Toho) Inochinate (Nichiiko) Inosinit (Kanto) Kotanicit (Kotani) Mesonex (Tokyo Tanabe) Mesosit (Toyo Jozo) Nasky (Nikken) Neonitin (Chugai) Nicosamin (Toyama) Nicosinate (Toyo S Ono) Nicosinit (Hokuriku) Nicotol (Maruko) Nicoxatin (Fuso) Romanit (Kowa) Salex (Iwaki) Sannecit (Sanko) Secotinen (Seiko) Shikicit (Shiki) Xatolone (Showa) Yonomol (Sawai) Iobenzamic acid (Acide iobenzamique) ATC: V08AC05 Use: X-ray contrast medium RN: 31 15-05-7 MF: ClhHll13N203 MW: 662.00 EINECS: 221-484- 1 LD,,: 530 mdkg (M, i.v.); 2870 mglkg (M, p.0.); 500 mglkg (K, I.v.); 2800 mgkg (R, p.0.) CN: N-(3-amino-2,4,6-triiodobenzoyl)-N-phenyl-~-alanine I 1. SOCI, H N 2. NaOH ____, I 1 1. lhionyl I methyl NH2 chloride NH2 3-anillnopropionate triiodobenzoic ocid Iobenzomic ocid L Reference(s): GB 870 321 (Oste~r. Stickstoffwerke; appl. 17.7.1959; A-prior. 23.7.1958, 2.8.1958). DE 1085 648 (Lentia; appl. 6.8.1958). US 3 051 745 (dsterr. Stickstoffwerke; 28.8.1962; A-prior. 23.7.1958). Formulation(s): tabl. 750 mg 1080 1 Iocarmic acid Trade Nnme(s): D: Bilibyk (Byk Gulden); wfm F: Osbil (Biodica); wfm I: Bilibyk (Byk Gulden); wfm Osbil (Byk Gulden); wfrn GB: Osbil (May & Baker); wfrn - - - Iocarmic acid ATC: VO~AAO~ Use: X-ray contrast medium RN: 10397-75-8 MF: C2,H2,I6N4Ou MW: 1253.87 EINECS: 233-86 1-8 LD,,,: 9.057g/kg(M,i.v.);>16glkg(M,p.o.); 13.3 glkg (R, i.v.); >16 glkg (R, p.0.) CN: 3,3'-[(I ,6-d1oxo-1,6-hexanediyl)di1mino]bis[2,4,6-triiodo-5-[(methylam1no)carbonyl]benzoic acid] meglumine salt (1:2) RN: 54605-45-7 MF: C24H201,N40u , 2C7H,,NOS MW: 1644.30 EINECS: 259-252-7 LD,,,: 10.9 mglkg (M, i.v.); >16 glkg (M, p.0.); 13.3 mglkg (R, i.v.); >I6 glkg (R, p.0.) COOH I COOH Reference(s): US 3 290 366 (Mallinckrodt; 6.12.1966; appl. 6.3.1963). GB 1 033 695 (Mallinckrodt; appl. 25.2.1964; USA-prior. 6.3.1963). 5-amino-N-methyl- adipoyl Formulation(s): amp. 3.02 g; inj. 60 % (as meglumine salt) lacarrnic acid Trade Nnme(s): D: Dimer-X (Byk Gulden); GB: Dimer X (May & Baker); wfm wfm F: Dimer-X (Guerbet); wfrn 1: Osbil (Byk Gulden); wfrn 2,4,6-triiodoisophthal- chloride arnic acid Iocetamic acid (Acide iocktamique) ATC: VO8ACO7 Use: X-ray contrast medium RN: 16034-77-8 MF: C,,H,,I,N20, MW: 613.96 EINECS: 240-173-1 LD,,,: ,410 mg/kg (M, i.v.); 700 mg/kg (R, i.v.); 7100 mg/kg (R, p.0.) CN: 3-[acetyl(3-amino-2,4,6-triiodophenyl)amino]-2-methylpropanoic acid 8 8 qNH2 + y3 + H3C 0 CH3 I H2C COOH '"02 acetic N02 anhydride 3-nitro- methacrylic aniline acid . pa.) CN: 1-( 4-chlorobenzoyl )-5 -methoxy-2-methyl-1H-indole-3-acetic acid 3,7,11-trimethyl-2,6,1 O-dodecatrienyl ester SOCI, PCH, b 1 v 0 c I 3.7,l 1 -trimethyl-2.6.1 0- COOH dodecotrienol. mgkg (R, p.0.) CN: ( 9-4 -( 1,3-dihydro- 1 -oxo-2H-isoindol-2-y1)-a-ethylbenzeneacetic acid sodium saIt RN: 9413 5-0 4-3 MF: C,,H,,NNaO, MW: 3 17.32 a-ethylbenzene- acetic acid phtholic. Use: anti-inflammatory, analgesic RN: 31 84 2-0 1-0 MF: C,,H15N03 MW: 281.31 EINECS: 25 0-8 3 3-0 LD,,,: 700 mglkg (M, p.0.); 84 mgkg (R, p.0.) CN: 4-( 1,3-dihydro- 1-0 x 0-2 H-isoindol-2-y1)-a-methylbenzeneacetic
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