Pharmaceutical Substances Syntheses, Patents, Applications - Part 119 docx

Lofexidine L 11 81 HCI, H3C-OH (1) 11 C 1 2.6-dichloro- 2-brorno- phenol propianitrile CI 2-(2,6-dichloro- phenoxy)propio- nitrile Op:q * HCI + (NH2 C,H,OH, A b 3 V NH CI NH2 ethyl 2-(2.6-dichloro- ethylene- phenoxy)propionirnidate diarnine (111) hydrochloride (11) dl-lacto- nitrile ethyl lactirnidate 2-(1 -hydroxy- hydrochloride ethyl)-2- jrnidozoline (N) sodium salt Reference(s): a US 3 966 757 (Nattermann GmbH; 29.6.1976; D-prior. 23.2.1967). DOS 1 695 555 (Nordmark-Werke; appl. 23.2.1967). GB 1 181 356 (Nordmark-Werke; valid from 23.2.1968; D-prior. 23.2.1967). b DE 1 935 479 (Nordmark-Werke; appl. 12.7.1967; D-prior. 12.7.1967). addition to DOS 1 695 555. synthesis of 2-(1 -chloroethyl)-2-imidazoline: Klarer, W.; Urech, E.: Helv. Chim. Acta (HCACAV) 27, 1762 (1944). use as insecticides: DE 2 818 367 (Ciba-Geigy; appl. 26.4.1978; CH-prior. 29.4.1977). Formulation(s): tabl. 0.2 mg (as hydrochloride) Trade Name(s): D: Lofetensin (Nattermann); GB: Britlofex (Britannia wfm Pharm.) BritLoflex (Britannia) 1182 L Lomefloxacin Lomefloxacin ATC: JOIMAO~; ~01~x17 (NY- 198) Use: quinolone antibacterial, gyrase inhibitor RN: 98079-5 1-7 MF: C,,H19F2N303 MW: 351.35 LD,,,: 246 mg/kg (M, i.v.); >4 g/kg (M, p.0.); 3800 mg/kg (R, p.0.) CN: (t)- l -ethyl-6,8-difluoro- 1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid monohydrochloride RN: 98079-52-8 MF: C,,HlyF2N3O3 . HCI MW: 387.81 LDS,,: 253 mg/kg (M, i.v.); 1608 mg/kg (M, p.0.); 328 mg/kg (R, i.v.); 1556 mgkg (R, p.0.) 2J.4-trifluoro- diethyl ethoxy- 3-ethoxycorbonyl- oniline rnethylenernalonote 4-hydroxy-6,7,8- trifluoroquinoline F (CH3 pyridine HCI F& + F F O-CH3 F CO~H 2-methyl- COOH Reference(s): EP 140 116 (Hokuriku; appl. 15.9.1984; ~-prior. 19.9.1983, 12.3.1984, 18.6.1984). DE 3 433 924 (Hokuriku; appl. 15.9.1984; J-prior. 19.9.1983, 12.3.1984, 18.6.1984). US 4 528 287 (Hokuriku; 9.7.1985; appl. 17.9.1984; J-prior. 19.9.1983, 12.3.1984, 18.6.1984). 0 0 0 piperazine 1 -ethyl-6.7.8-trifluoro- 1,4-dihydro-4-axo-3- isotonic solulion,for i.v. administration or as ophthalmic or nasal solution: US 4 780 465 (Hokuriku; 25.10.1988; appl. 20.5.1987; J-prior. 14.1.1987). DOS 3 715 918 (Hokuriku; appl. 13.5.1987; J-prior. 14.1.1987). 0 Lomefloxocin synthesis of 1-ethyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid: DE 3 031 767 (Kyorin; appl. 22.8.1980; J-prior. 22.8.1979). qu~nolinecarhoxylic acid lyophilizate: EP 322 892 (Kyorin; appl. 28.12.1988; J-prior. 28.12.1987). Fortnulation(.s): eye drops 0.3 %; tabl. 200 mg, 400 mg (as hydrochloride) Trade Name(s): F: Logiflox (Monsanto) Uniquin (Alfa USA: Maxaquin (Searle; I: Chimono (Lusofarmaco) Wassermann) Unimed) Maxaquin (Schiapparelli J: Bareon (Hokuriku; 1990) Searle) Lomefact (Shionogi; 1990) Lomifylline L 1 183 Lomifylline ATC: C04 Use: vasodilator (peripheral) RN: 10226-54-7 MF: C13H1XN403 MW: 278.31 EINECS: 233-547-0 CN: 3,7-dihydro-l,3-dimethyl-7-(5-oxohexyl)-lH-purine-2,6-dione Reference(s): US 3 422 107 (Chemische Werke Albert; 14.1.1969; D-prior. 5.9.1964, 2.7.1965, 10.7.1965, 24.7.1965). DE 1 233 405 (Chemische Werke Albert; appl. 5.9.1964). NO aCH3 4 Br CH3 theophylline 6-bromo-2-hexonone alternative syntheses: DOS 2 302 772 (Chemische Werke Albert; appl. 20.1.1973). DOS 2 330 741 (Chemische Werke Albert; appl. 16.6.1973). CH3 Lomifylline use as dissolving intermediary: DE 1 250 968 (Chemische Werke Albert; appl. 24.7.1965). oral pharmaceutica1,fortn: DOS 2 520 978 (Hoechst; appl. 10.5.1975). Formulation(s): tabl. 80 mg Trade Name(s): F: Cervilane (Cassenne)- comb. Lomustine (CCNU) ATC: LOlAD02 Use: antineoplastic RN: 13010-47-4 MF: C,HI,CIN30, MW: 233.70 EINECS: 235-859-2 LD,,: 38 mglkg (M, p.0.); 70 mgkg (R, p.o.1 CN: N-(2-chloroethy1)-N-cyclohexyl-N-nitrosourea cyclohexyl ethanolarnine isocyanate 1184 L Lonazolac 1 -(2-chlor0ethyl)-3 cyclohexylurea (I) Reference(s): Johnston, T.P. et al.: J. Med. Chem. (JMCMAR) 9, 892 (1966). starting material: Johnston, T.P. et al.: J. Med. Chem. (JMCMAR) 6, 669 (1963). Formulation(s): cps. 10 mg, 40 mg; tabl. 10 mg, 40 mg Trade Name(s): D: Cecenu (medac) I: Belustine (Rhbne-Poulenc USA: CeeNU (Bristol-Myers F: Btlustinc (Roger Bellon) Rorer) Squibb) Lonazolac ATC: MOlAB09 Use: non-steroidal anti-inflammatory KN: 53808-88-1 MF: C17H,3CIN202 MW: 312.76 EINECS: 258-791-5 CN: 3-(4-chloropheny1)- 1-phenyl- I H-pyrazole-4-acetic acid calcium salt RN: 75821-71-5 MF: C34H,CaCI,N,04 MW. 663.57 EINECS: 278-322-8 LD,,,: 670 mg/kg (M, p.0.); 845 mg/kg (R, p.0.); 790 mg/kg (g. p., p.0.); 650 mg/kg (rabbit, p.0.) 4'-chloraoceto- phenone OHC 3-(4-chlorophenyl)- 1 -phenyl-1 H-pyrazole- 4-corbaxoldehyde (I) NoBH, sodium boro- hydride ~~c% / CI 4'-chloroaceto- phenone phenylhydrazone 1. SOU2 2. NoCN 3. H+ b 2. sodium HO cyanide dimethylforrnornide. phosphorus oxychloride Lonazoloc (11) I Lonidamine L 1185 CaCI2 11 b calcium chlaride Reference(s): I Lonazolac calcium DE 1 946 370 (Byk Gulden; appl. 12.9.1969). US 4 325 962 (Byk Gulden; 20.4.1982; D-prior. 12.9.1969). US 4 146 721 (Byk Gulden; 27.3.1979; D-prior. 12.9.1968). Rainer, G. et al.: Arzneim Forsch. (ARZNAD) 31, 649 (1981). alternative synthesis of calcium salt: EP 299 504 (Spofa; appl. 15.7.1988; CS-prior. 17.7.1987). alternative synthesis of the free acid: GB 1 373 212 (Wyeth; appl. 7.12.1970). combination with analgesics: DE 2 605 243 (Byk Gulden; appl. 11.2.1976; LUX-prior. 14.2.1975). medical use for thrombocyte aggregation inhibition: . DE 3 444 633 (Byk Gulden; appl. 7.12.1984; CH-prior. 23.12.1983). Fonnulation(s): suppos. 400 mg; tabl. 200 mg, 300 mg Trade Name(s): D: Argun (Merckle) arthro akut (Ryk Gulden; Byk Tosse) Lonidamine ATC: LOlXXO7 Use: antineoplastic RN: 50264-69-2 MF: C,5H,oC12N202 MW: 321.16 EINECS: 256-510-0 LD,,: 435 mglkg (M, i.p.); 900 mglkg (M, p.0.); 525 mglkg (R, i.p.); 1700 mglkg (R, p.0.) CN: l-[(2,4-dichlorophenyl)methyl]-1H-indazole-3-carboxylic acid 1 H-indazale- 2.4-dichloro- 3-carbaxylic acid benzyl chloride Reference(s): DE 2 310 031 (Aziende chimiche Riunite; appl. 28.2.1973; I-prior. 29.2.1972). US 3 895 026 (Aziende chimiche Riunite; 15.7.1975; I-prior. 29.2.1972). Corsi, G.; Palazzo, G.: J. Med. Chem. (JMCMAR) 19,778 (1976). 1186 L Loperamide alternative synthesis: ES 545 644 (Lab. Ausonia; appl. 29.7.1985). medical use for treatment of cancer: BE 894 1 11 (Angelini Inst.; appl. 13.8.1982; I-prior. 17.8.1981). Forntulation(s): tabl. 150 mg Trade Name(s): I: Doridamina (Angelini; 1987) Loperamide ATC: A07DA03 Use: antidiarrheal RN: 53179-11-6 MF: C29H33CIN,02 MW: 477.05 EINECS: 258-416-5 LD,,: 105 mglkg (M, p.0.); 5.1 mglkg (R, i.v.); 98 mglkg (R, p.0.); 2.8 mgkg (dog, i.v.); 40 mgkg (dog, p.0.) CN: 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-a,a-diphenyl-1-piperidinebutanamide monohydrochloride RN: 34552-83-5 MF: C,,H,,CIN2O2~ HCl MW: 513.51 EINECS: 252-082-4 LD,,: 12.64mg/kg(M,i.v.); 105mgIkg(M,p.o.); 7.49 mglkg (R, i.v.); 185 mglkg (R, p.0.) ethylene ethyl diphenyl oxide ocetote 3.3-diphenyl- 4-bromo-2.2- 2-oxotetrahydro- diphenylbutyric furon acid (I) 4-bromo-2.2- diphenyl- butyryl chloride dimethyl-(3,3- diphenyltetro- hydro-2-furylidene)- ommonium bromide (11) I Loperomide Loprazolam L 1187 Reference(s): Stokbroehx, R.A. et al.: J. Med. Chem. (JMCMAR) 16,782 (1973). US 3 714 159 (Janssen; 30.1.1973; prior. 1.6.1970,30.3.1971). FR-appl. 2 100 711 (Janssen; appl. 28.5.1971; USA-prior. 1.6.1970, 30.3.1971). US 3 884 916 (Janssen; 20.5.1975; prior. 1.6.1970, 30.3.1971,7.12.1972). DOS 2 126 559 (Janssen; appl. 28.5.1971; USA-prior. 1.6.1970, 30.3.1971). Formulation(s): cps. 2 rng; sol. 0.2 rng; syrup 1 rngI5 ml; tabl. 2 mg (as hydrochloride) Trade Name(s): D: Imodiurn (Janssen-Cilag; 1976) Sanifug (Wolff) Santax (Asche) numerous generics F: Altocel (hex) Arestal (Janssen-Cilag) Diaretyl (RPR Cooper) Dyspagon (Pierre Fabre) Imodiurn (Janssen-Cilag; Loperyl (SmithKline 1976) Beecharn) GB: Irnodium (Janssen-Cilag; Tebloc (Lafare) 1975) J: Lopernin (Dainippon; Lopergan (Norgine) 1981) Novirnode (Tillomed) USA: Imodiurn (Janssen; 1977) I: Dissenten (SPA; 1979) Imodiurn (McNeil; 1977) Imodium (Janssen; 1979) Lopemid (Gentili) Loprazolam ATC: NOSCDll Use: tranquilizer, hypnotic RN: 61 197-73-7 MF: C2,H2,C1N,0, MW: 464.91 LD,,,: >I glkg (M, p.0.) CN: (Z)-6-(2-chloropheny1)-2,4-dihydro-2-[(4-rnethyl-l-piperazinyl)methyene]-8-nitro-lH-imidazo[l,2- a][l,4]benzodiazepin- 1-one mesylate RN: 61 197-93-1 MF: C2,H2,CIN,0,. xCH,O,S MW: unspecified 2. P2S5 pentosulfide 2-ornino-2'- glycine ethyl ester 1 -3-dihydro-5- chlorobenzo- hydrochloride (2-chloropheny1)- phenone 2H-1,4-benzo- diozepin-2-one 1. NoZCO, P.~N=c=N~ I1 02N 2. dicyclohexylcorbo- 02N diimide 0~1 ;::;::,ol (1) glycine 1188 L Loratadine N-methyl- Loprozolom piperozine Reference (s): DOS 2 605 652 (Roussel-Uclaf; appl. 12.2.1976; GB-prior. 4.1 1 .l975, 15.2.1975). US 4 044 142 (Roussel-Uclaf; 23.8.1977; GB-prior. 15.2.1975,4.9.1975). alternative synthesis: DOS 3 21 1 243 (Roussel-Uclaf; appl. 26.3.1982; F-prior. 27.3.1981). synthesis of 1,3-dihydro-7-nitro-5-(2-chlorophenyl)-2H- 1,4-benzodiazepin-2-thione: Sternbach, L.H. et al.: J. Med. Chem. (JMCMAR) 6, 261 (1963). Hester, J.B. et al.: J. Med. Chem. (JMCMAR) 14, 1078 (1971). DOS 2 164 777 (Upjohn; appl. 27.12.1971; USA-prior. 3.3.1971). US 3 402 171 (Roche; 17.9.1968; CH-prior. 2.12.1960). Formulation(s): tabl. 1 mg, 2 mg (as mesylate) Trade Name(s): D: Sonin (Lipha; 1987) GB: Dormonoct (Roussel; F: Havlane (Diamant; 1984) 1983); wfm generics Loratadine (Sch-2985 1) ATC: R06AX13 Use: antiallergic, non-sedating antihistaminic RN: 79794-75-5 MF: C22H,,ClN20p MW: 382.89 CN: 4-(8-chloro-5,6-dihydro-l1H-benzo[5,6]cyclohepta[l,2-b]pyridin-ll-ylidene)-l-piperidinecarboxylic acid ethyl ester @ H3Cx~~, 1.70 OC HN NC N, 2. conc. HZSO,. 75 OC + HoYh3 w H3C CH3 H3C . 2-cyono-3- methylpyridine 1. Bu-Li hexone, THF. -40 OC. NoBr 2. LCI . THF. -40 OC H3Cx~~3 CI POC13, reflux I 2. m-chlorobenzyl chloride CI Loratadine L 1189 FH3 a+Q THF. 40-50 OC CI CI Mg Cl (11) 1 -methyl- piperidin- 4-ylmognesium chloride (111) 8-chloro-5.6-dihydro- 11 H-benzo[5,6]cyclo- hepta[l ,2-blpyridin- 11 -one (VII) toluene V Lorotodine H benzene - Lorotadine 1190 L Loratadine 1 -(ethoxycarbonyl)- 4-piperidinone (WI) I. N~BH, 2. P(ocH~)~, 1 20°c 2. SOCI, 3. NOH. THF Vn- Lorotadine 1. sodium borohydride VI. TH F CF,SO,H toluene II + 111 + Iv Lorotadine trifluoromethone- sulfonic ocid Reference($): US 4 454 143 (Schering Corp.; 12.6.1984; prior. 16.3.1981). US 4 560 688 (Schering Corp.; 24.12.1985; prior. 16.3.1981). US 4 282 233 (Schering Corp.; 4.8.1981; prior. 19.6.1980). US 4 355 036 (Schering Corp.; 19.10.1982; prior. 19.6.1980, 16.3.1981). EP 42 544 (Schering; USA-prior. 19.6.1980). a R Schumacher, D.P. et al.: J Org. Chem. (JOCEAH) 54, 2242 (1989). US 4 731 447 (Schering Corp.; 15.3.1988; prior. 13.5.1985, 12.3.1986). b Villani, F.J. et al.: Arzneirn Forsch. (ARZNAD) 36, 131 1 (1986). Villani, F.J. et al.: J. Med. Chem. (JMCMAR) 15 (7), 750 (1972). c US 4 355 036 (Schering; 19.10.1982; appl. 16.3.198 1 ; USA-prior. 19.6.1980). d WO 9 840 376 (Cilag; appl. 6.3.1998; CH-prior. 1 1.3.1997). WO 9 838 166 (Jackson; appl. 26.2.1998). e WO 9 200 293 (Schering Corp.; appl. 21.6.1991; USA-prior. 22.6.1990). f WO 8 803 138 (Schering, appl. 29.10.1987; USA-prior. 31 .lO.l986). Formulation(s): eff. tabl. 10 mg; syrup 10 mglspoon; tabl. 10 rng Trade Name(s): D: Lisino (Essex Pharma; Clarityne (Schering- I: Clarityn (Schering-Plough) 1989) Plough) Fristamin (Li fepharma) F: Clarinase Repetabs GB: Clarityn (Schering-Plough; USA: Claritin (Schering) (Schering-Plough)-comb. 1989) . 19 7-7 3-7 MF: C2,H2,C1N,0, MW: 464.91 LD,,,: >I glkg (M, p.0.) CN: (Z )-6 -( 2-chloropheny1 )-2 ,4-dihydro- 2-[ (4-rnethyl-l-piperazinyl)methyene ]-8 -nitro-lH-imidazo[l, 2- a][l,4]benzodiazepin- 1-one. ocetote 3.3-diphenyl- 4-bromo-2. 2- 2-oxotetrahydro- diphenylbutyric furon acid (I) 4-bromo-2. 2- diphenyl- butyryl chloride dimethyl-(3, 3- diphenyltetro- hydro-2-furylidene )- ommonium. 3800 mg/kg (R, p.0.) CN: (t )- l -ethyl-6,8-difluoro- 1,4-dihydro- 7-( 3-methyl-1-piperazinyl )-4 -oxo-3-quinolinecarboxylic acid monohydrochloride RN: 9807 9-5 2-8 MF: C,,HlyF2N3O3 . HCI MW: