Brinzolamide B 261 ethyl vinyl ether CrO,/H,SO,. acetone VI + Tos-OH, THF WE ~~c-0~~ ____* + v 0 0,CH3 sodium Y CH3 methylate (?)-2-(3-bromopropy1)- 4-(1 -ethoxyethoxy)- 3.4-dihydro-2H-thieno- [3.2-el- 1,2-thiazine 1 ,l -dioxide 1. BuLi, THF 2. SOz 3. HOSA - 2. sulfur dioxide O A 0,CH3 Y CH3 (VI) I. (+)-I~C~BCI,THF 2. Tos-CI. THF 3. H,N-CH, VII + 1. (+)-8-chlorodiisopropyl- compheylborone 2. tosyl chloride 3. ethylamine (VIII) " 0 3,4-dihydro-2-(3-methoxypropy1)- 4-0~0-2H-thieno[3,2-e]-1,2-thiozine- 6-sulfonornide 1 .l-dioxide (VII) Brinzolornide I 1H.SH-pyrrolo[l.2-c]- 1. HCI. THF 0 \\S/NH2 1,3,2-oxazaborole, 2. pyridiniurn perbrornide Q BH3 - THF * p M B r 0 ~7o/~~~ NaH, THF * M 3-bromo-l -methoxy- propone (X) Brinzolamide 262 B Brinzolamide ethonol, H20 thioureo 0 3-acetyl-2.5- benzyl dichlorothiophene chloride 3-acetyl-5-chloro- 2-(benzylthio)- thiophene (XII) 1. CIZ, ethyl acetate 2. NH, pyridinium perbrornide. 3. H202 ethyl ocetate. O°C XI1 - XI11 3-(brornoocetyl)- 5-chloro-2- thiophenesulfonomide (XlIl) K2C03, DMSO XN + X b 4-hydroxy-2-(3-rnethoxy- propy1)-2H- thieno[3.2-el- 1,2-thiozine 1.1-dioxide (XV) XVI 1. trimethyl orthoocetote 3. ethylornine Reference(s): a US 5 378 703 (Alcon; 3.1.1995; USA-prior. 9.4.1990). b US 5 470 973 (Alcon; 28.1 1.1995; USA-prior. 3.10.1994). c Conrow, R.E. et al.: Org. Process Res. Dev. (OPRDFK) 3 114-120 (1999). Brodimoprim B 263 ophthalmic compositions with prostaglandins: WO 9 853 809 (Merck + Co.; 3.12.1998; appl. 26.5.1998; USA-prior. 30.5.1997). WO 9 819 680 (Alcon; appl. 5.9.1997: USA-prior. 1.1 1.1996). process for manrifacturing ophthalmic suspensions: W09 825 620 (Alcon; appl. 5.9.1997; USA-prior. 11.12.1996). pharmaceutical compositions: WO 9 702 825 (Alcon; appl. 12.7.1995). W09 115 486 (Alcon; appl. 3.4.1991; USA-prior. 9.4.1990). Formulation(s): ophth. susp. 1% in dispensers (2.5,5, 10 and 15 ml) Trade Name(s): USA: Azopt (Alcon; 1998) Brodimoprim (Ro- 10-5970) ATC: JOIEA02 Use: . antibacterial RN: 56518-41-3 MF: C,,H1,BrN,O, MW: 339.19 EINECS: 260-238-8 CN: 5-[(4-Bromo-3,5-dimethoxyphenyl)methyl]-2,4-pyrimidinediamine hydrochloride RN: 56518-40-2 MF: C13HlsBrN402, HCI MW: 375.65 0 I? 1. NoOH, H20 6H 2. H3c >,0J~3 0 HO OH 1. bromine HC = '0 2. dirnethyl sulfate Br 3.5-dihydroxy- methyl 4-bromo-3,5- benzoic acid dimethoxybenzoate ti2, P~/BOSO,, H3C/0-~~ xylene 4. HC NoOCH3. CH30H , I11 H3G0 0/CH3 '0 3-rnethoxypropionitrile Br Br 4-brorno-3.5-dimethoxy- benzoldehyde (11) 4-bromo-3.5-dimethoxy- guonidine a-(methoxymethyl)- carbonate (1V) cinnamonitrile (111) I Brodimoprirn 264 B Brodimoprim U'U - H dimethyl 2,6-dimethoxy- terephthalote 1.0n- 2. S0Clp 3. H,. Pd/BaSO, methyl 4-amino-3.5-di- methoxybenzoote (V) a-(rnorpholinornethylene)- hydrocinnornonitrile H N, NaOCH3, CH30H _L____, Brodirnoprirn Br 4-bromo-3.5-dimethoxy- a-(onilinomethylene)- hydrocinnornonitrile (VII) Reference(s): a CA 1 017 743 (Hoffmann-La Roche; CH-prior. 8.1 1.1973). DE 2 452 889 (Hoffmann-La Roche; appl. 7.1 1.1974; CH-prior. 8.11.1973). b Kompis, I., Wick. A.: Helv. Chim. Acta (HCACAV) 60 (8), 3025 (1977). alternative preparation of 4-bromo-3,s-dimethoxybenzaldehyde: Barknecht, C.F.; Nichols, D.E.: J. Med. Chem. (JMCMAR) 14,370 (1971). Formulation(s): gran. 200 mg; susp. 1 %, 50 mg; tabl. 200 mg Trade Name(s): I: Hyprim (Fisons) Unitrim (Fisons; 1993) Bromazepam B 265 Bromazepam ? ATC: N05BA08 Use: tranquilizer RN: 1812-30-2 MF: C,,HloBrN,O MW 3 16.16 EINECS: 217-322-4 LD,: 879 mg/kg (M, p.0.); 1950 mgkg (R, p.0.) CN: 7-bromo-l,3-dihydro-5-(2-pyridinyl)-2H-1,4-benzodiazepine-2-one P,OI0. pyridine, A , 3 H20 1. phenyllithiurn 0 2. 2-pyridyllithiurn anthrenilamide and 2-brornopyridine) anthranilonitr~le (from phenyllithiurn 2-(2-orninobenzay1)- pyridine (I) 0 0 acetic anhydr~de 2-(2-acetarnida- 2-(2-acetamido-5-brorno- benzoy1)pyridine benzoyl)pyndine (11) H~N>~"~~~ 0 oHCI pyridine b glycine ethyl ester hydrochloride I Brornazeparn I u ? 2. H3C''OQVc~3 0% H202, CH3COOH 0 ' pH3 I. sodium hydride ' 2. diethyl oxolate Z-picaline 2-picoline ethyl 2-pyridyl- 1 -axide pyruvate 1'-oxide (In) 4-brornophenyl- hydrozine hydrochloride ethyl 5-brorno-3- (2-pyridy1)indole- 2-carboxylate 1'-oxide (N) 266 B Bromazine 1. KOH H 5-bromo-3-(2-pyridyl). indole-2-carbonitrile (V) 1. LiAIH4 2. HCI v + 2-ominomethyl-5-bromo- 3-(2-pyridyl)indole dihydrochloride US 3 100 770 (Roche; 13.8.1963; appl. 11.8.1961). US 3 182 065 (Roche; 4.5.1965; appl. 9.4.1964; prior. 19.4.1963). US 3 182 066 (Roche; 4.5.1965; appl. 9.4.1964; prior. 19.4.1963). US 3 182 067 (Roche; 4.5.1965; appl. 9.4.1964). Fryer, R.I. et al.: J. Pharm. Sci. (JPMSAE) 53, 264 (1964). modijed methods: DAS 2 233 483 (Roche; appl. 7.7.1972; GB-prior. 8.7.1971,7.10.1971). DOS 2 252 378 (Roche; appl. 25.10.1972; CH-prior. l8.ll.1971). alternative synthesis of 2-(2-amino-5-bromobenzoy1)pyridine: DAS 2 256 614 (Roche; appl. 17.1 1.1972). DAS 1 813 241 (Roche; appl. 6.12.1968; J-prior. 8.12.1967, 9.12.1967, 12.12.1967, 25.4.1968). combination with sulpiride: DAS 2 342 214 (Roche; appl. 21.8.1973; CH-prior. 21.9.1972). Formulation(s): tabl. 3 mg, 6 mg Trade Name(s): D: Bromazenil (Neuro Hexal) neo OPT (Optimed) I: Compendium (Polifarma) Bromazepam (Heumann) Normoc (Merckle) Lexotan (Roche) Durazanil (durachemie) F: Anxyrex (Irex) J: Lexotan (Nippon Roche) Gityl (Krewel Meuselbach) Lexomil Roche (Roche) USA: Lectopam (Roche); wfm Lexotanil (Roche) GB: Lexotan (Roche) Bromazine (Bromdiphenhydramine) ATC: R06AAOl Use: antihistaminic RN: 118-23-0 MF: C,,H,,BrNO MW: 334.26 EINECS: 204-238-8 CN: 2-[(4-bromophenyl)phenylmethoxy]-N,N-dimethylethanamine hydrochloride RN: 1808-12-4 MF: C,,H,,BrNO . HCl MW: 370.72 EINECS: 217-310-9 LD,,: 63 mgkg (M, i.v.); 366 mglkg (M, p.0.); 55 mglkg (R, i.v.); 602 mglkg (R, p.0.); 21 mglkg (dog, i.v.) !P Bromelain B 267 FH3 xoH CCI,, 2 H~-~~cH~ , Br 2-dimethylomino- \ Br Br ethanol 4-bmmo- 4-bromobenz- bsnzhydrol hydryl bromide Reference (s): GB 670 622 (Parke Davis; appl. 1948; CH-prior. 1947). Formulation(s): cps. 25 mg Trade Name(s): D: Ambodryl (Parke Davis); I: Ambodryl (Parke Davis); wfm wfm F: Ambodryl (Parke Davis); USA: Ambodryl (Parke Davis); wfm wfm . Bromelain (Bromelin) ATC: B06AA11; JOl AA Use: anti-inflammatory, antineoplastic RN: 9001-00-7 MF: unspecified MW: unspecified EINECS: 232-572-4 LD,,,: 30 mgkg (M, i.v.); >10 gkg (M, p.0.); >I0 gkg (R, p.0.) CN: bromelain, juice A concentrate of proteolytic enzymes derived from Ananas comosus Merr. proteolytic enzyme (glycoprotein) relative molecular mass = 33000 By extraction from pineapple stems with water and precipitation with acetone or ammonium sulfate. Reference(s): Heinicke, R.M.: Science (Washington, D.C.) (SCIEAS) 118,753 (1953). US 3 002 891 (Pineapple Research Inst. Hawai; 3.10.1961; appl. 12.12.1958). purification: US 2 950 227 (Schering AG: 1960; prior. 1956,1959). Formulation(s): drg. 4.5 mg, 8 mg, 20 mg, 40 mg, 45 mg, 90 mg; tabl. 500 F.1.P E. Trade Name(s): D: Bromelain 200 Phlogenzym (Mucos) Tetranase (Rottapharm). (Ursapharm) Proteozym (Wiedemann) comb. Enzym-Wied Traumanase (Nattermann) 1: Ananase (Rottapharm) (Wiedemann)-comb. Wobenzym (Mucos)-comb. J: Kimotab (Mochida) Floradix (Sa1ushaus)-comb. F: Extranase (Rottapharm) USA: Ananase (Rorer); wfm Mulsal (Mucos)-comb. 268 B Bromfenac sodium Bromfenac sodium (AHR-10282) ATC: NO2 Use: anti-inflammatory RN: 91714-93-1 MF: C1,Hl,BrNNaO, MW: 356.15 CN: 2-amino-3-(4-bromobenzoy1)benzeneacetic acid monosodium salt sesquihydrate RN: 120638-55-3 MF: Cl5Hl1BrNNaO3. 3/2H20 MW: 766.35 free acid RN: 91714-94-2 MF: C15H12BrN0, MW: 334.17 tert-butyl hypo- chlorite ethyl ?-(methyl thio)acetate 7-(4-bromabenzoy1)- 3-(rnethylthb-2.3- dihydro-1 H- indol-2-one (I) 1. Raney-Ni. THF 2. NaOH _____* Bromfenac sadium I US 4 126 635 (Robins Co.; appl. 15.4.1977; USA-prior. 17.5.1972, 25.4.1973). US 4 568 695 (Robins Co.; USA-prior. 7.12.1983). Welsh, D.A. et al.: J. Med. Chem. (JMCMAR) 27, 1379-1388 (1984). Formulation(s): cps. 25 mg (as sodium salt) Trade Name(s): USA: Duract (Wyeth-Ayerst) Bromhexine (Bromexina) ATC: R05CB02 Use: expectorant RN: 3572-43-8 MF: C,,H2,Br2N2 MW: 376.14 EINECS: 222-684-1 CN: 2-amino-3,5-dibromo-N-cyclohexyl-N-methyIbenzenemethanmine monohydrochloride RN: 61 1-75-6 MF: Cl,H2,Br2N2 . HC1 MW: 412.60 EINECS: 210-280-8 LD,,: 44 mg/kg(M,i.v.); 3 glkg(M, p.0.); 6 g/kg (R, p.0.) Bromindione B 269 2-nitrobsnzyl cyclohexyl- (2 -nitrobenzyl) - N-(2-0rninobenzyl)- Lmmlds methylamine (cyclohexyl)-methylomine N-cyclohexyl-methylamine (1) I Bromhexine I Reference(s): DE 1 169 939 (Thomae; appl. 20.11.1961). US 3 336 308 (Boehringer Ing.; 15.8.1967; D-prior. 14.10.1963). Keck, J.: Justus Liebigs Ann. Chem. (JLACBF) 662, 17 1 (1963). Engelhom, R.; Piischmann, S.: Arzneim Forsch. (ARZNAD) 13,464 (1963). Arch, F.: Arzneh-Forsch. (ARZNAD) 13,480 (1963). alternative syntheses: DAS 2 31 1 637 (Thomae; appl. 9.3.1973). DAS 2 365 624 (Thomae; appl. 27.3.1973; J-prior. 30.3.1972,4.7.1972). DAS 2 315 310 (Thomae; appl. 27.3.1973; J-prior. 30.3.l972,4.7.1972). DAS 2 443 712 (Thomae; appl. 12.9.1974). DOS 2633 518 (Egyt; appl. 26.7.1976; H-prior. 28.10.1975). DOS 2412 119 (Huhtam&i; appl. 13.3.1974; SF-prior. 15.3.1973, 2.7.1973,9.1.1974, 8.2.1974) use as mucous membrane local anesthetic: DOS 2 729 786 (Thomae; appl. 1.7.1977). Fomulation(s): amp. 8 mgl4 ml; drg. 8 mg, 12 mg; drops 8 mg/4 ml; syrup 4 mg (as hydrochloridc); tabl. 4 mg, 8 mg, 10 mg, 20 mg Trade Namers): D: Aparsonin (Merckle) Berotec solvens (Boehringer 1ng.)-comb. . Bisolvomycin (Boehringer 1ng.)-comb. Bisolvon (Roehringer Ing.) Bisolvonat (Boehringer 1ng.)-comb. Customed (Chefaro) I: Bertabronc (Rerta-Mi)- Lubrirhin (Alcon) comb. Omniapharm (Merckle) Bisolvon (Boehringer Ing.) Synergomycin (Abbott) Broncokin (Geymonat) F: Bisolvon (Boehringer Ing.) Tauglicolo (SIT)-comb. GB: Alupent (Boehnnger 1ng.)- combination preparations comb. J: Bisolvon (Tanabe; as hydrochloride) Bromindione (Bromophenindione; Brophenadione) RN: 1146-98-1 MF: C,,H,BrO, MW: 301.14 LD5< 200 mglkg (M, p.0.) CN: 2-(4-bromopheny1)- 1 H-indene- l,3(2H)-dione ATC: M04 Use: anticoagulant 270 B Bromisoval phtholide 4-bromo- 1 Brornindione / benzoldehyde Reference(s): US 2 847 474 (USV; 1958; appl. 1954). cf. also anisindione Formdation(s): amp. 8 mg14 ml Trade Name(s): F: Fluidane (Metadier-Tours); wfrn Bromisoval ATC: N05CM03 Use: sedative, slightly hypnotic RN: 496-67-3 MF: C,H, ,BrN20, MW: 223.07 EINECS: 207-825-7 ' LD50: 2 g/kg (M, p.0.); 1 glkg (R, p.0.) CN: N-(aminocarbony1)-2-bromo-3-mcthylbutananlide isovaleric acid a-brornoiso- vaieryl bromide Bromisovol L Reference(s): DRP 185 962 (Knoll; 1906). Formulation(s): drg. 20 mg, 50 mg Trade Name(s): D: Brom-Nervacit (Herbert)- Sekundal (Woelm)-comb.; comb.; wfm wfm Ventrivcrt Tabletten (Do1orgiet)-comb.; wfrn Bromural (Knoll)-comb.; Steno-Valocordin F: Beneural (Chantereau); w tin (Promonta)-comb.; wfm wfm Diffucord, -N (Do1orgiet)- Tempidorm N (Roland)- J: Brovarin (Nippon comb.; wfm comb.; wfm Shinyaku) Rebuso Tabletten Valocordin (Promonta)- USA: Bromural (Knoll); wfm (Ravensberg)-comb.; wfm comb.; wfm . 0 3,4-dihydro- 2-( 3-methoxypropy1 )- 4-0 ~ 0-2 H-thieno[3,2-e ]-1 ,2-thiozine- 6-sulfonornide 1 .l-dioxide (VII) Brinzolornide I 1H.SH-pyrrolo[l.2-c ]- 1. HCI. THF 0 \S/NH2 1,3,2-oxazaborole,. VI + Tos-OH, THF WE ~~c-0~~ ____* + v 0 0,CH3 sodium Y CH3 methylate (? )-2 -( 3-bromopropy1 )- 4-( 1 -ethoxyethoxy )- 3.4-dihydro-2H-thieno- [3.2-el- 1,2-thiazine 1 ,l -dioxide. RN: 181 2-3 0-2 MF: C,,HloBrN,O MW 3 16.16 EINECS: 21 7-3 2 2-4 LD,: 879 mg/kg (M, p.0.); 1950 mgkg (R, p.0.) CN: 7-bromo-l,3-dihydro- 5-( 2-pyridinyl )-2 H-1,4-benzodiazepine-2-one P,OI0.