Pharmaceutical Substances Syntheses, Patents, Applications - Part 76 pps

Epinastine hydrochloride E 75 1 Formulation(s): tabl. 5 mg Trade Name(s): D: Stimovul (Organon); wfm I: Stimovul (Organon Italia) J: Stimovul (Ravasm) ! ,t Epinastine hydrochloride VAL-801CL) ATC: R06AX24 Use: antihistaminic RN: 108929-04-0 MF: CI,H1,N, . HCl MW: 285.78 , LD,,,: 17 mgkg (R, I.v.); 192 mglkg (R, p.0.) CN: 9,13b-dihydro-1 H-d1benz[c~imidazo[1,5-a]azep1n-3-amine monohydrochlor~de epinastine RN: 80012-43-7 MF: C,,H,SN, MW: 249.32 1. ethanol. THF 2. NaOH 3. HCI + Br-CN -b 6-ominomethyl- cyonogen Epinostine hydrochloride 6,ll-dihydro-5H- bromide dibenz[b,e]azepine (11) 3. GOOH 2. N-methyl- benzylamine OMF . HCI - I Epina3tine hydrochloride I Epinostine 752 E Epinephrine Reference (s): a DE 3 008 944 (Bochringer Ing.; appl. 5.3.1981; D-prior. 8.3.1980). starting material: Hunziker, E. et al.: Helv. Chim. Acta (HCACAV) 49/11, 1433 (1966); 5011, 245 (1967). b EP 496 306 (Boehringer Ing.; appl. 18.1 .l992; D-prior. 2.5.1.1991). composition with PAF-antagonists: WO 8 910 143 (Schering Corp.; appl. 24.4.1989; USA-prior. 27.4.1988). Formulation(sJ: tabl. 10 mg, 20 mg Trade Name(s): J: Alesion (Nippon Boehringer Ing./Sakyo) Epinephrine (Adrenaline) ATC: AOIADO 1; B02BC09; C01CA24; R03AAO1; SOlEAOl Use: sympathomimetic, vasoconstrictor RN: 51-43-4 MF: C,H,,NO, MW: 183.21 EINECS: 200-098-7 LD,,,: 217 pgkg (M, i.v.); I50 pgfkg (R, i.v.); 100 @kg (dog, i.v.) CN: (R)-4-[I-hydroxy-2-(methylamino)ethyl]-1,2-benzenedi0l hydrochloride RN: 55-3 1-2 MF: C,H,,NO, . HCl MW: 219.67 EINECS: 200-230-3 LD,,,: 140 wg/kg (M, i.v.); 24 mgkg (R, p.0.) tartrate (1:l) RN: 51-42-3 MF: C,HI,NO,. C,H,O, MW: 333.29 EINECS: 200-097-1 LD,o: 1780 pglkg (M, i.v.); 4 mgkg (M, p.0.); 82 pg/kg (R, i.v.) 2-chloro-3',4'- methylamine 7.4'-dihydroxy- DL-epinephrine (I) dihydroxy- 2-methylomino- acetaphenone acetophenone (+)-tartaric acid I_____, H CH3 Epirizole E 753 Reference(s): DRP 152 814 (Hoechst; 1903). DRP 157 300 (Hoechst; 1903). DRP 222 451 (Hoechst; 1908). lbllar, B.F.: J. Am. Chem. Soc. (JACSAT) 70, 2067 (1948) Formulation(s): amp. 0.05 md10 ml, 1 mgfml, 2.05 md2.05 ml (as hydrochloride); eye drops 2 mglml, 5 mg/ ml; eye ointment 1 mglg (as tartrate) Trade Name(s): D: Adrenalin 1:1000 JENAPHARMA (Jenapharm) Adrenalin Medihalcr (Kettelhack-Riker) Anaphylaxie-Besteck Losung Z.J. (SmithKline Beecham) Fastjekt (Allergopharma) Suprarenin (Hoechst) numerous combination preparations F: Anahelp (Stallergknes) Anakit (Dome-Hollister- S tier) DyspnC-Inhal (Augot) Eppy 1 % (Allergan France) Glaucadrine (Merck Sharp & Dohme-Chibret)-comb. numerous combination preparations and generics GB: Accusite (Matrix)-comb. Epipen (ALK) Eppy (Chauvin) Simplene (Chauvin) combination preparations I: Adrenal (Lifepharma) Adrenalina Ism (Nuovo ISM) Eppy (Merck Sharp & Dohme) Rinantipiol (Antipio1)- comb. Xylocaina (Astra-Simes) Xylonor (0gna)-comb. J: Vaponefrin (Tokyo M.I.) USA: Epi E-Z Pen (Dey) EpiPen (Dey) Sensorcaine with Epinephrine (Astra)-comb. Sus-Phrine (Forest) Xylocaine with Epinephrine (Astra)-comb. Epirizole (Mepirizole) ATC: MO1 A; N02B; SOlB Use: analgesic, anti-inflammatory RN: 18694-40-1 MF: ClIH,4N402 MW: 234.26 EINECS: 242-507-1 LD,,: 550 mgkg (M, i.v.); 740 mgkg (M, p.0.); 214 mglkg (R, i.v.); 445 mglkg (R, p.0.) CN: 4-methoxy-2-(5-methoxy-3-methyl-lH-pyrazol-l-yl)-6-methylpyrimidine , I hydmzine OH CI 0, CH3 hydrote 6-methyl- 2,4-dichloro- 2-chloro-4- uracil 6-methyl- methoxy-6- pyrimidine rnethylpyrim~dine dimethyl sulfote 2-hydrazina-4- diketene Epirizole methoxy-2-me- thylpyrimidine (I) Referencels): FR-M 6 793 (Daiichi Seiyaku; appl. 31.8.1967). DAS 2237 632 (Daiichi Seiyaku; appl. 31.7.1972; J-prior. 31.7.1971, 5.8.1971). 754 E Epirubicin intermediates: Vanderhaeghe, H.; Claesen, M.: Bull. Soc. Chim. Belg. (BSCBAG) 68, 30 (1959). Formulation(s): tabl. 50 mg, 100 mg Trade Nam(s): I: Diacon (IBI); wfm J: Analock (Taito Pfizer) Mebron (Daiichi) Epirubicin (Pidorubicin; 4'-epi-Adriamycin) ATC: LOlDB03 Use: antineoplastic RN: 56420-45-2 MF: C2,H2,N0,, MW: 543.53 LD,,,: 16.07 mglkg (M, i.v.); 14.27 mglkg (R, i.v.); 2 mgkg (dog, iv.) CN: (8S-cis)-l0-[(3-amino-2,3,6-trideo~y-a-~-alnbino-hexopyranosyl)oxy]-7,8,9,1O-tetrahydro-6,8,11- trihydroxy-8-(hydroxyacety1)- I methoxy-5,12-naphthacenedione hydrochloride RN: 56390-09-1 MF: C2,H,,N0,, . HCI MW: 579.99 F C 0 CF3 + 3KK + HO 0 0 NH~ HN 'f CF3 periodote, HN CF3 0 rutheniurn(N) K 0 methyl 2,3,6-tri- trilluoroocetic oxide (11) deoxy-3-amino- onhydride (I) pyranoside NoBH4 CH,COOH I1 sodium borohydride I - I HN CF3 K HN CF3 0 K 0 2.3,6-trideoxy-3-trifluoro- acetamida-4-0-trifluoro- acetyl-a-L-arabino- hexopyranosyl chloride (N) p Epitiostanol E 755 odriomycinone 2,Z-dimethoxy- propane I Epirubicin 1. HgO. HgBr2 2. NaOH V + IV -b Reference(s): Arcamone, F. et al.: J. Med. Chem. (JMCMAR) 18,703 (1 975). DOS 2 510 866 (Farmitalia; appl. 20.3.1975; GB-prior. 22.3.1974). HO CH3 US 4 058 519 (Farmitalia; 15.1-1.1977; appl. 19.3.1975; GB-prior. 22.3.1974). alternative synthesis: DOS 2 618 822 (Farmitalia; appl. 29.4.1976; GB-prior. 30.4.1975). purijication: GB 2 133 005 (Farmitalia; appl. 16.12.1983). Formulation(s): vial 10 mg, 20 mg, 50 mg (as hydrochloride) Trade Name(s): D: Farmo~blcin (Pharmacia GB: Pharmarubicin (Pharmacia J: Farmorubicin (Farmitalia) & Upjohn; 1984) & Upjohn; 1985) F: Farmorublcine (Pharmacia I: Farmorubicina (Farmitalia; & Upjohn; 1986) 1984) Epitiostanol (Epithioandrostanol; Epithiostanol) ATC: G03B; L02BA Use: antiestrogen, antineoplastic RN: 2363-58-8 MF: C19H,oOS MW: 306.51 LD,,: 1160 mgkg (M, i.p.) CN: (2a,3a,5a,l7P)-2,3-epithioandrostan-17-01 R H3C-S-CI , 0 + HSCN HO 0 methanesulfo- chloride H 178-ocetoxy-2.3-epoxy- thiocyonic Sa-ondrostone acid 756 E Epitizide Reference(s): GB 977 599 (Shionogi; valid from 19.12.1962; J-prior. l9.12.I96l). NL 6 400 226 (Shionogi; appl. 15.1.1 964). Takeda, K. et al.: Tetrahedron (TETRAB) 21,329 (I 965). Formulation(s): vial 10 mg Trade Namefs): J: Thiodrol (Shionogi) Epitizide (Epithiazide) ATC: C021, Use: antihypertensive, diuretic RN: 1764-85-8 MF: C,oH,,CIF,N,O,S, MW: 425.86 EINECS: 217- 18 1-9 CN: 6-chloro-3,4-dihydro-3-[[(2,2,2-trifluoroethyl)thio]methyl]-2H-l,2,4-benzothiadiazinc-7-sulfonamide mercaptoocet- 2,2,2-tri- oldehyde fluoroethyl dirnethyl iodide ocetol 1.2-dimethoxyethone, HCI I + _______* CI 5-chloro-2.4-di- ominosulfonyl- aniline (cf. chlorothiozide synthesis) (2.2.2-trifluoroethyl- thio)ocetoldehyde dirnethyl ocetol (I) Epitizide US 3 009 911 (Pfizer; 21.11.1961; prior. 3.6.1960, 14.9.1960,4.1.1961). Trade Name(s): GB: Thiavcr (Riker); wfm Epoprostenol E 757 Epoprostenol (PGI,; Prostacyclin) ATC: BOlAC09 Use: anticoagulant, platelet aggregation inhibitor RN: 35121-78-9 MF: C,H,,Os MW: 352.47 CN: (5Z,9a,l la,13E,15S)-6,9-epoxy-11,15-dihydroxy-prosta-5,13-dien-l-oic acid monosodium salt RN: 61849-14-7 MF: C,H,,NaO, MW: 374.45 EINECS: 263-273-7 prostoglandin F2,, 11.1 5-bis- (tetrahydropyran-2-yI) ether (cf. dinoprost synthesis) 1. CH3COOH 2. KOC(CH,), I + 2. potassium tert-butylote 1 Epoprostenol GCH3 1 iodine. I ,,7' OH 2. sodium ethylate I - prostaglandin F2, methyl ester Epoprostenal sodium Reference(s): Corey, E.J. et al.: J. Am. Chem. Soc. (JACSAT) 99, 2006 (1976). Nicolaou, K.C. et al.: Lancet (LANCAO) 1977, 1058. review: The Merck Index, 12th Ed., 1352 (Rahway 1996). Formulation(s): vial (lyo.) 0.5 mg (as sodium salt) Trade Narne(s): GB: Flolan (Glaxo Wellcome) USA: Flolan (Glaxo Wellcome; as sodium salt) 758 E Eprazinone Eprazinone ATC: R05CB04 Use: antitussive RN: 10402-90-1 MF: C2,H3,N20, MW: 380.53 EINECS: 233-873-3 LD,,,: 1 l 1 mglkg (M, i.p.); 246 mglkg (M, s.c.) CN: 3-[4-(2-ethoxy-2-phenylethyl)-1-piperazinyl]-2-methyl-I-phenyl-l-propanone dihydrochloride RN: 10402-53-6 MF: C,,H3,N202 . 2HCl MW: 453.45 EINECS: 233-872-8 LD,,,: 20 mgikg (M, i.v.); 286 mglkg (M, p.0.); 763 mglkg (R, p.0.) Br-O-C(CH,)3 ____+ tert-butyl piperozine styrene hypobromite (1) 1 + (CH,O), + dcH, poroform- propiophenone Eprazinone aldehyde Reference(s): DAS 1 695 43 1 (Mauvernay; appl. 9.6.1967; GB-prior. 27.6.1966). JP-appl. 540 22-379 (Asahi; appl. 21.7.1977). JP-appl. 540 22-380 (Asahi; appl. 21.7.1977). JP-appl. 540 22-381 (Asahi; appl. 21.7.1977). JP-appl. 540 22-382 (Asahi; appl. 21.7.1977). Formulation(s): tabl. 5 mg, 20 mg, 50 mg; cps. 100 mg; suppos. 50 mg, 100 mg (as dihydrochloride) Trade Namefs): D: Eftapan (Merckle) I: Mucitux (Recordati); wfm F: Mucitux (Riom) J: Resplen (Chugai) Eprosartan (SKB 108566; SKF 108566) ATC: C09CA02 Use: antihypertensive, angiotensin 11 antagonist RN: 133040-01-4 MF: C,3H,4N,0,S MW: 424.52 CN: (E)-a-[[2-Butyl-1-[(4-carboxyphe11yl)methyl]-1H-imidazol-5-yl]methylene]-2-thiophenepropanoic acid rnesylate RN: 144143-96-4 MF: C,3H,4N,04S . CH40,S MW: 520.63 Eprosartan E 759 imidazole triethyl orthoformate 1 -diethaxymethyl imidozole (I) 1. 12. No2C03. dioxone, H20 BuLi. THF. 2. H C1,OB. K2C03. OMF I + I-CH, b I1 2. benzyl chloromethyl ether butyl iodide 2-butyl- imidozole N-methyl- ~-(~-p~rid~l)- forrnomide 1. HCI (deprotection) O CH 2. K2C03. DMF 111 + do/ r methyl (4-bromo- rnethy1)benzoote (N) methyl 4-[(2-butyl-5- formyl-4-iodoimidozol- 1 -yl)methyl]benzoote (V) "c\$ 1. , LOA, THF Hz, Pd-C. CH,OH " - VIlI I 1. methyl 3-(2-thienyl)propionate (VII) methyl 4-[(2-butyl- 5-formyl-lH-imidozol- 1-yl)methyl]benzoote (VI) dOIcH3 1. DBU. toluene 0 2. NoOH. ethanol, H,O (~1) 1 Eprosorton 760 E Eprosartan 2-butyl-4-chloro imidozole-5- corboxoldehyde methyl 4-[(Z-butyl-4- chloro-5-formylimidozol- 1 -yl)methyl]benzoote (M) Hz, Pd-C. piperidine/pyridine. CH,OH toluene VI ______, monomethyl 2-(24hienylmethyl)- molonote (X) KOH, ethonol ____, 1. liq. NH3 Eprosorton I 1.3-dihydroxy- acetone pentonomidine 5-(ocetoxymethyl)- 1 -ocetyl-2-butyl- imidazole (XII) (CH3 HC N CH 3YY 3 (CF,CO),O. CH3CH3 XI1 + HO trifluoroocetic anhydride, DlPEA methyl 4-(hydroxy- methyl 4-[[5-acetoxymethy1)- methy1)benzoate Z-butylimidazol-1 -yl]methyl]- benzoate (XI11) . p.0.) CN: 4-methoxy- 2-( 5-methoxy-3-methyl-lH-pyrazol-l-yl )-6 -methylpyrimidine , I hydmzine OH CI 0, CH3 hydrote 6-methyl- 2,4-dichloro- 2-chloro- 4- uracil 6-methyl- methoxy- 6- pyrimidine. (8S-cis)-l 0-[ (3-amino-2,3,6-trideo~y-a-~-alnbino-hexopyranosyl)oxy ]-7 ,8,9,1O-tetrahydro-6,8,1 1- trihydroxy- 8-( hydroxyacety1 )- I methoxy-5,12-naphthacenedione hydrochloride RN: 5639 0-0 9-1 MF:. RN: 176 4-8 5-8 MF: C,oH,,CIF,N,O,S, MW: 425.86 EINECS: 21 7- 18 1-9 CN: 6-chloro-3,4-dihydro- 3-[ [(2,2,2-trifluoroethyl)thio]methyl ]-2 H-l,2,4-benzothiadiazinc-7-sulfonamide mercaptoocet- 2,2,2-tri-