Pharmaceutical Substances Syntheses, Patents, Applications - Part 19 pptx

Batroxobin B 181 1. DIC/HOEt 2. separation of diastereorners by crystollizotion VtI b Referencefs): a DE 2904 552 (Yamanouchi Pharm.; appl. 7.2.1979; J-prior. 14.2.1978). b CN 85 107 590 (Faming Zhuanli Sheqing Gonhai S.; appl. 11.10.1985; J-prior. 24.1.1985). alternative syntheses: Hirose, Y.; Kariya, K.; Sasaki, I.; Kuronom Y; Achiwa, K.: Tetrahedron Lett. ('TELEAY) 34 (37), 5915 (1993). JP 6 279 409 (Mercian Corp.; J-prior. 26.3.1993). JP 7 070 066 (Amano Pharma Co.; prior. 3.9.1993). alternative synthesis of optically active I-benzyl-3-hydroxypyrrolidine: JP 9 263 578 (Koei Chemical Co.; appl. 29.3.1996). X-ray structure and synthesis of all enantiomers: Tamazawa, K ct al.: J. Med. Chem. (JMCMAR) 29 (12), 2504 (1986) Formulation(s): tabl. 5 mg, 10 mg, 15 mg (as hydrochloride) Trade Name(s): J: Hypoca R (Yamanouchi; 1992) Batroxobin ATC: B02BX03 Use: anticoagulant, fibrinolytic RN: 9039-61-6 MF: unspecified MW: unspecified EINECS: 232-918-4 LD,,: 384 @kg (M, i.v.); 210 pglkg (R, i.v.); 380 pglkg (dog, i.v.) CN: bothrops atrox serine protcinase Fibrinolytic effecting protcasc cnzyme from the poison secretion (venom) of Bothrops atrox with glycoprotein structure. It has thrombin similarly endopeptidase activity. hrification by chromatographic methods. Reference(s): US 3 849 252 (Pentapharm; 19.11.1974; CH-prior. 18.1.1971). DOS 2 201 993 (Pentapharm; appl. 17.1.1972; CH-prior. 18.1.1971). Formulation(s): amp. 20 iu. Trade Name(s): I: Botropase (Ravizza) J: Defibrase (Tobishi- Reptilase (Lepetit) Fujisawa) 182 B Beclamide Beclamide ATC: N03AX30 Use: antiepileptic, anticonvulsant RN: 501-68-8 MF: C,,HI,C1NO MW: 197.67 EINECS: 207-927-1 LD,,,: 1 g/kg (M, p.0.); 770 rndkg (R, i.v.); 3200 rndkg (R, p.0.) CN: 3-chloro-N-(phenylrnethy1)propanarnide benzylomine 3-chloropropionyl I Beclomde chloride Referencefs): US 2 569 288 (American Cyanamid; 1951; prior. 1949). Formularion(s): drg. 330 rng, 500 mg Trade Name ( s): D: Neuracen (Promonta); wfm F: PosCdrine (Aron); wfm Posedrin (Promonta); wfm GB: Nydrane (Rona); wfm I: Posedrine (Aron); wfm Beclobrate ATC: B04AC Use: hyperlipidemic RN: 55937-99-0 MF: C2,,H2,C10, MW: 346.85 EINECS: 259-912-4 CN: (+)-2-[4-[(4-chlorophenyl)rnethyl]phenoxy]-2-rnethylbutanoic acid ethyl ester 4-chlorobenzyl phenol 4-chloro-4'-hydroxy- chloride diphenymethone (I) 2. ethanol 2-methyl- ethyl 2-rnethyl- butyric acid butonoote ethyl 2- rnethyl-2- Beclobrote bromobutyrote (Il) Beclometasone B 183 CHCIJ, KOH I + H3C~~~3 - 0 ethyl methyl ketone Reference(s): DOS 2 461 069 (Siegfried; appl. 23.12.1974; CH-prior. 27.1 2.1973, 28.3.1 974,3.10.1974, 18.11.1974). BE 823 904 (Siegfried; appl. 18.1 1.1974; CH-prior. 27.12.1973). US 4 153 803 (Siegfried; 8.5.1979; CH-prior. 27.12.1973, 28.3.1974, 18.1 1.1974). Thiele, K. et al.: Arzneim Forsch. (ARZNAD) 29,711 (1979). synthesis of 1: Klarmann, E. et al.: J. Am. Chem. Soc. (JACSAT) 54, 3315 (1932). Huston, R.C. et al.: J. Am. Chem. Soc. (JACSAT) 55,4639 (1933). synlhpsis of ethyl 2-methylbutanoate: Gardner, R.: 3. Chem. Soc. (JCSOA9) 1938, 53. Fonnulation(s): tabl. 100 mg Trade Narne(s): CH: Beclipur (Siegfried; 1988) Beclosclerin (Siegfried; Turec (Zyma; 1988) 1988) Beclometasone (Beclomethasone) ATC: A07EA07; D07AC15; ROl ADO1 ; R03BAOI Use: glucocorticoid RN: 4419-39-0 MF: C22H2,C10T MW: 408.92 EINECS: 224-585-9 CN: (1 1P, 16P)-9-chloro-11,17,21 -trihydroxy-l6-methylpregna-l,4-diene-3,20-dione dipropionate RN: 5534-09-8 MF: C28H3,C10, MW: -521.05 EINECS: 226-886-0 LD,,,: >5 g/kg (M, p.0.); >3.75 gikg (R, p.0.) 21 -acetoxy-17-hydroxy-16p methylpregna- 1.4.9(11)-triene- 3,20-dione (intermediate in syntheses of betarnethasone, q.v.) beclometosone 21 -acetate (I) 184 B Beclometasone F) + ~3~7Op3 pyridine. O°C H,O. HCIO, 1 propionic onhydride Re ference(s): d3 / CI H 0 Beclometosone Beclomethosone dipropionote a GB 912 378 (Merck & Co.; appl. 3.6.1959; USA-prior. 19.6.1958). GB 912 379 (Merck & Co.; appl. 3.6.1959; USA-prior. 19.6.1958). alternative synthesis: GB 901 093 (Scherico; appl. 22.7.1958; USA-prior. 22.7.1957). US 4 041 055 (Upjohn; 9.8.1977, appl. 17.1 1.1975). b BE 649 170 (Glaxo; appl. 11.6.1964; GB-prior. 11.6.1963). FR 2 274 309 (Plurichemie; appl. 27.3.1975; P-prior. 27.3.1974, 10.3.1975). medical use: DOS 2 320 11 1 (Allen & Hanburys; appl. 19.4.1973; GB-prior. 20.4.1972). Formulation(s): cream 0.025 %; dose aerosol (0.05 pg, 0.25 pglpuff); nasal spray (0.05pgIpuff); powder inhaler Trade Name(s): D: AeroBec Autohaler (3M MedicaIASTA Medica AWD) Beclorhinol (Lindopharm) Becloturmant (Desitin) Beconase (Glaxo) Beconase Aquosum (Glaxo) Beconase Dosier-Spray (Glaxo) Sanasthmax (Glaxo) Sanasthmyl (Glaxo) Sanasthmyl Dosier-Aerosol Rotadish (Glaxo) Viarox (By k Essex) Viarox (Byk Gulden) Viarox Dosier-Aerosol (Byk Essex) F: Beclojet (Promedica) BCconase (Glaxo Wellcome) BCcotide (Glaxo Wellcome) Prolair Autohaler (3M SantC) Rhinirex (Irex) Spir (Inava) GB: Aerobec (3M) Asmabec (Evans) Beclazone (Baker Norton) Becloforte (Allen & Hanburys) Becodisks (Allen & Hanbury s) Beconase (Allen & Hanbury s) Becotide (Allen & Hanburys) Filair (3M) Propaderm (Glaxo Wellcome) 1: Becotide (Glaxo) Bronco-Turbinal (Valeas) Cleniderm (Chiesi) Clenigen (Chiesi)-comb. Clenil (Chiesi) Clenil spray (Chiesi) Inalone (Lampugnani) Menaderm (Menarini) Proctisone (Chiesi)-comb. Propaderm (Demcan) Rino-Clenil (Chiesi) Turbinal (Valeas) J: Aldecin (Schering-Plough) Becloderm (Kobayashi) Beconase (Glaxo) Becotide (Nippon Glaxo) Becotide (Glaxo) Belg (Kowa) Betozon (Ohta) Betozon (Ohta Seiyaku) Entyderma (Taiyo) Hibisterin (Nippon Zoki) Korbutone (Nippon Glaxo) Mulunet (Tatsumi) Befunolol B 185 Propaderm (Shin Nihon; USA: Beclovent (Glaxo Vancenase (Schering- Jitsugyo-Glaxo Fuji; as Wellcome) Plough; as dipropionate) dipropionate) Beconase (Glaxo Vanceril (Schering; as Rhinocort (Fujisawa) Wellcome) dipropionate) Salcoat (Fujisawa) Beconase (Glaxo Soluroid (Nikken) Wellcome; as dipropionate) Befunolol ATC: C07AA; SOlED06 Use: P-adrenoceplor blockcr RN: 39552-01-7 MF: C,,H2,N04 MW: 291.35 LD,,: 100-105 mglkg (M, i.v.) CN: (+)-1-[7-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]-2-benzofuranyl]ethanone hydrochloride RN: 39543-79-8 MF: C16H21N04 . HCI MW: 327.81 LD,,: 65 mgkg (M, i.v.); 950 mglkg (M, p.0.); 922 mglkg (R, p.0.) H C H C '0 1.HBr '0 2. <CI , CH, KOH b 1 CHO 0 1. hydrobrornic acid 2-hydroxy-3- chloro- 2-acetyl-7- 2. epichlorohydrin, piperidine rnethoxy- ocetone methoxybenzo- benraldehyde furon Reference(s): DOS 2 223 184 (Kakenyaku Kako; appl. 12.5:1972; J-prior. 13.5.1971, 14.7.1971, 28.10.1971,6.1.1972). US 3 853 923 (Kakenyaku Kako; 10.12.1974; J-prior. 13.5.1971, 14.7.1971, 28.10.1971,6.1.1972). US 4056 626 (Kakenyaku Kako; 1.1 1.1977; J-prior. 6.1.1972; 13.5.1971). (f)-2-ocetyl-7-glycidyl- isopropyl- synthesis of 2-acetyl-7-methoxybenzofuran: Bergel et al.: J. Chem. Suc. (JCSOA9), 1944,261 Befunolol Formulution(s): eye drops 2.5 mglml, 5 mghl axybenzoiuron (I) arnine Trude Name(s): D: Glauconex (Alcon; 1984) 1: Betaclan (Angelini) F: Bentos (CIBA Vision J: Bentos (Kaken; as Ophthalmics; 1987) hydrochloride; 1983) 186 B Bekanamycin Bekanamycin (Kanamycin B) ATC: A07AA; JOIKD; SO1 AA Use: aminoglycoside antibiotic RN: 4696-76-8 MF: C,8H,7N,01, MW: 483.52 EINECS: 225-170-5 LD,,: 136 rnglkg (M, i.v.) CN: 0-3-amino-3-deoxy-cx-~-glucopyranosyl-(l+6)-0-[2,6-diamino-2,6-dideoxy-a-~-glucopyranosyl- (I +4)]-2-deoxy-D-streptamine sulfate (1:l) RN: 29701-07-3 MF: C,8H,7N,0,0. H2S04 MW: 581.60 LD,,: 112 mglkg (M, i.v.); 141 mglkg (R, i.v.); >10 g/kg (R, p.0.) Fermentation of Streptornyces kanamyceticus (ATCC 12853) and precipitation with sodium dodecylphenylsulfonate. Reference(s): DAS 1 115 413 (H. Urnezawa; appl. 1958; USA-prior. 1957). US 2 967 177 (Bristol-Myers; 1961; prior. 1958). US 3 032 547 (Merck & Co., 15.1.1962; prior. 12.9.1958). alternative synthesis: US 2 931 798 (H. Umezawa et al.; 1960; J-prior. 1956). US 2 936 307 (Bristol-Myers; 1960; prior. 1957). total synthesis: Umezawa, S. et al.: Bull. Chem. Soc. Jpn. (BCSJAR) 42, 537 (1969). structure: Ito, T.: J. Antibiot., Ser. A (JAJAAA) 17, 189 (1964). review: Wakazawa, T. et al.: J. Antibiot., Ser. A (JAJAAA) 14A, 180, 187 (1961). Formulation(s): cps. 250 rng; gran. 250 mg; powder; susp. 200 mg Trade Name(s): I: Kanendos (Crinos; as Visumicina (Merck Sharp sulfate) & Dohme)-comb. Micomplex (Schiapparelli J: Kanendomycin (Meiji Seark-comb. Seika; as sulfate) Bemegride B 187 8 Bemegride ATC: R07AB05 Use: antidote for barbiturate poisoning, analeptic RN: 64-65-3 MF: C,H,,N02 MW: 155.20 EINECS: 200-588-0 LD,,: 16 mglkg (M, i.v.); 41 mglkg (M, p.0.); 16 mgikg (R, i.v.) CN: 4-ethyl-4-methyl-2,6-piperidinedione HOOC COOH 0 0 Q H3C LcH3 + ~~d~~~~~ CH3 methyl ethyl ethyl cyanaacetate 2.4-dicyano-3- ketone ethyl-3-methyl- glutarimide (CH,-C0),0 I acetic y " . anhydride H3C CH3 Y H3C CH3 3-ethyl-3-methyl- glutaric acid (I) 3-ethyl-3-methyl- / Bernegride glutoric anhydride Benica, W.S.; Wilson, C.H.O.: J. Am. Pharm. Assoc. (JPHAA3) 39,451,454 (1950). Formulation(s): amp. 5 mglml (5 %, 10 %) Trade Narnefs): D: Eukraton (Nordmark); wfm F: MCgimide (Aspros- GB: Megimide (Nicholas); wfm Nicholas); wfm J: Antibarbi (Tanabe) Bemetizide ATC: C03E Use: diuretic RN: 1824-52-8 MF: C15H,6CIN304S2 MW: 401.90 EINECS: 217-357-5 LD,,: 345 mglkg (M, i.v.); >5 glkg (M, p.0.); >5 glkg (R, p.0.) CN: 6-chloro-3,4-dihydro-3-(1 -phenylethyl)-2H-l,2,4-benzothiadiazine-7-sulfonamide 1 ,l -dioxide 5-chlora-2,4-bis- hydratropic Bernetizide (aminosulfonyl)oniline aldehyde (cf. chlorothiazide synthesis) 188 B Benactyzine Reference(s): AT 230 382 (Dr. H. Voigt; appl. 8.3.1961; D-prior. 23.2.1961). Topliss, J.G. et al.: J. Org. Chem. (JOCEAH) 26, 3842 (1961). Jacobi, H.; Fontaine, R.: Arzneim Forsch. (ARZNAD) 16, 1186, 1332 (1966). Formulation(s): drg. 10 mg, 20 mg Trade Name(s): D: Dehydro sanol (Sano1)- Diucomb (Me1usin)-comb. F: Tensigradyl (Oberva1)- comb. comb.; wfm Benactyzine ATC: N04A Use: ataractic, neuroleptic, anticholinergic RN: 302-40-9 MF: C2nH2sN03 MW: 327.42 EINECS: 206- 123-8 LD,,,: 100 mglkg (M, i.p.); 159 mg/kg (M, s.c.); 135 mg/kg (R, i.m.) CN: a-hydroxy-a-phenylbenzeneacetic acid 2-(diethy1amino)ethyI ester hydrochloride RN: 57-37-4 MF: C20H2sN03 . HC1 MW: 363.89 EINECS: 200-324-4 LD,,: 14.3 mgkg (M, i.v.); 160mg/kg(M, p.0.); 184 mgkg (R, p.0.) ethyl benzilote 2-diethylomino- ethanol I Benoctyzine Referencefs): US 2 394 770 (American Cyanamid; 1946; prior. 1942). Formulation(s): amp. 2 mglml, 0.3 %; tabl. 1 mg Trade Name(s): D: Brondiletten (Albert- I: Pre Ciclo (Ibis)-comb.; .I: Rousse1)-comb.; wfm wfm Perasthman (Polypharm)- Sirenitas (Benvegna)- comb. comb.; wfm Morcain (Tatsumi); wfrn Parpon (Santen); wfrn Benaprizine (Benapry zine) ATC: NO4 Use: antiparkinsonian RN: 22487-42-9 MF: C2,H27N03 MW: 341.45 CN: a-hydroxy-a-phenylbenzeneacetic acid 2-(ethylpropy1amino)ethyl ester hydrochloride RN: 3202-55-9 MF: C2,HZ7NO3. HC1 MW: 377.91 LD,,,: 500 mglkg (M, p.0.) I Benazepril B 189 NaOCH3 HO-~~CH~ methyl benzilote 2-(ethylpropylomin0)- Benoprizine ethonol I I Reference{s): US 3 746 743 (Beecham; 17.7.1973; GB-prior. 22.8.1963). Formulation{s): tabl. 10 mg (as hydrochloride), 50 mg Trade Name(s): GB: Brizin (Beecham); wfm I: Zinadril (Smith Kline Beecham) Benazepril (Benzapril) ATC: C09AA07 Use: antihypertensive (ACE inhibitor) RN: 86541-75-5 MF: C,H2,N20, MW: 424.50 CN: [S-(R*,R*)]-3-[[l-(ethoxycarbonyl)-3-phenylpropy~]amino]-2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepine- 1-acetic acid monohydrochloride RN: 86541-74-4 MF: C,H,,N,O, . HC1 MW: 460.96 ti 0 H,. Pd-C, PCI5. xylene. 90 OC CH3COOH, CH3COONa I 2,3.4,5-tetrohydro- 3.3-dichloro-2.3.4.5- 1H-l -benz- letrohydro- 1H-l- azepin-2-one benzozepin-2-one B,/hO-CH3 H 0 H 0 0 NaN , DMSO. 80 OC KOH. THF 1 + ethyl 11 3-chloro-2.3.4.5-te- trohydro-1H-1 -benz- ozepin-2-one (I) 3-ozido-2.3.4.5-te- bromoacetote trohydro-1 H-l-benz- ozepin-2-one 0 1. Hz. Pd-C ($-cH3 2. resolution with L-tortoric acid in CH,OH NoOH. CH30H ethyl 3-ozido- 2.3.4.5-telrahydro- 2-oxo-1H-1 -benz- azepin-1 -ocetate (11) ethyl (3s)-3-amino- 2.3.4.5-tetrohydro- 2-oxo-1H-1 -benz- azepin-1 -ocetote I 1190 B Bencyclane 1. NaBH4 2. recrystallization (35)-3-amino- ethyl 2-0x0- I -(corboxymethyl)- 4-phenylbutyrote Benozepril reference(^): Watthey, J.W.H. et a].: J. Med. Chem. (JMCMAR) 28, 1511 (1985). US 4 410 520 (Ciba-Geigy; 18.10.1983; prior. ll.8.l98l,9.ll.I98l, 19.7.1982). EP 72 352 (Ciba-Geigy; appl. 5.8.1982; USA-prior. 11.8.1981,9.11.1981). EP 206 993 (Ciba-Geigy; appl. 9.6.1986; CH-prior. 13.6.1985) 1 Formulation(s): f. c. tabl. 5 mg, 10 mg, 20 mg (as hydrochloride) Trade Natnefs): D: Cibacen (Novartis Pharma) Cibadrex (Novartis)-comb. J: Cibacen (Novartis; as Cibadrex (Novartis 1: Cibadrex (Ciba-Geigy)- hydrochloride) Pharrnal-comb. comb. USA: Lotensin (Ciba) F: Briazide (Pierre Fabre)- Tensanil (Zyma) Lotensin (Ciba)-comb. with comb. Zinadur (Smith Kline Hydrochlorothiazide Briem (Pierre Fabre) Beecham)-comb. . Lotrel (Ciba)-comb. with Cibactre (Novartis) Amlodipine Bencyclane ATC: ~04~x1 I (Benciclano) Use: antispasmodic, vasodilator RN: 2179-37-5 MF: C,,H,,NO MW: 289.46 EINECS: 218-547-0 CN: N,N-dimethyl-3-[[l-(phenylmethyl)cycloheptyl]oxy]-l-propanamine fumarate (I: 1) RN: 14286-84-1 MF: C,9H31N0. C4H404 MW. 405.54 EINECS: 238-204-9 LD,,: 45 mgkg (M, i.v.); 446 mglkg (M, p.0.); 41 mgkg (R, i.v.); 414 mglkg (R, p.0.) benzylmog- cyclo- nesium chloride heptanone + l-benzyl- cycloheptonol 1. NaNH2 2. 7% C'-NCH, b 1. sodium omide 2. 3-dimethylomino- propyl chloride Reference(s): HU 151 865 (Egyesiilt Gyogyszer; appl. 18.8.1963). Bencyclone J 1 Formulation(sj: drg. 75 mg, 100 mg . NoOH. CH30H ethyl 3-ozido- 2.3.4.5-telrahydro- 2-oxo-1H-1 -benz- azepin-1 -ocetate (11) ethyl (3s )-3 -amino- 2.3.4.5-tetrohydro- 2-oxo-1H-1 -benz- azepin-1 -ocetote I 1190 B Bencyclane. ethyl 11 3-chloro-2.3.4.5-te- trohydro-1H-1 -benz- ozepin-2-one (I) 3-ozido-2.3.4.5-te- bromoacetote trohydro-1 H-l-benz- ozepin-2-one 0 1. Hz. Pd-C ($-cH3 2. resolution with L-tortoric. 469 6-7 6-8 MF: C,8H,7N,01, MW: 483.52 EINECS: 22 5-1 7 0-5 LD,,: 136 rnglkg (M, i.v.) CN: 0-3 -amino-3-deoxy-cx-~-glucopyranosyl-(l+6 )-0 -[ 2,6-diamino-2,6-dideoxy-a-~-glucopyranosyl- (I +4) ]-2 -deoxy-D-streptamine