Pharmaceutical Substances Syntheses, Patents, Applications - Part 71 pot

P Dolasetron mesilate D 701 1. sodium borohydride 2. dihydropyron 1. tBu-OK, toluene. 100°C 2. HCI. reflux VIP HO (VII) I, q (VIII) , CH,CI,, OMAP 0 BCF3 2. H3C-S03H M - H3C-S03H I Dolasetron rnesilote I synthesis of intermediate VIlI + CH2CIZ 88 F,C 0 CF, COOH indole-3- trifluoroocetic carboxylic acid onhydride altemotive preporotion via 0-methoxycorbonylglutoroldehyde dimethyl molonote diostereomeric mixture of l-methoxycorbonyl- 3-cyclopentene oxide (trans:cis N 3:l) (X) 1. LiH, OMF 2. NoOH, MeOH . @LCH3 methyl J-cyclopentene- 1-corboxylote (M) VIII OEH , CH2Clz CI, X rn-chloroperbenzoic ocid p-methoxycorbonyl- glutoroldehyde (XI) 702 D Domiodol 1. 03, MeOH, H20, -5 to O°C 2. H3C-S-CH3 M XI A b Dolasetron rnesilate 1. ozone 2. dirnethyl sulfide Referencefs): EP 339 669 (Merrell Dow Pharm. Inc.; appl. 28.4.1989; USA-prior. 29.4.1988). EP 266 730 (Merrell Dow Pharm. Inc.; appl. 2.1 1.1987; USA-prior. 3.1 1.1986). Formulation(s): amp. 12.5 mgl0.625 ml, 100 mg/5 ml; f. c. tabl. 50 mg, 200 mg Trade Name(s): D: Anemet (Hoechst Marion USA: Anzemet (Hoechst Marion Roussel; 1997) Roussel; 1997) Domiodol ATC: R05CB08 Use: mucoly tic agent RN: LD50: CN: 61869-07-6 MF: C5H,I03 MW: 244.03 79-89 mgikg (M, i.v.); 140-145 mgkg (M, p.0.) 2-(iodomethy1)- l,3-dioxolane-4-methanol COOH H~CVO~~~ H0,S H3C-0 - acid glycerol 1 -benzyl brornoacetaldehyde (1) ether diethyl acetal HZ, Pd-C I + HO iodide Dorniodol Reference (s): DOS 2 610 704 (Maggioni; appl. 13.3.1976; I-prior. 2.4.1975) Formulation(s): sachet 60 mg; sugar coated tabl. 60 mg; syrup 0.6 % Trade Natne(s): I: Mucolitico (Maggioni- Winthrop) Domiphen bromide (Phenododecinium bromide) ATC: AOlAB06 Use: disinfectant RN: 538-71-6 MF: C,,H,oBrNO MW: 414.47 EINECS: 208-702-0 LD,,,: 31 mglkg (M, i.v.); 18 mgikg (R, i.v.) CN: N,N-dimethyl-N-(2-phenoxyethy1)-1-dodecanaminium bromide Domperidone D 703 2-phsnoxyethyl d~methyl- bromide (I) amme dodecyl bromide I Domiphen bromide I + H2N-CH3 b O/'*W- / CH3 dodecylamine dodecyl(2-phenoxyethy1)omlne (111) methyl brom~de Reference(s). 1 US 2 581 336 (Ciba; 1952; CH-prior. 1944). Formulation(s): tabl. 0.5 mg L 1 Tmde Name(s): GB: Bradosol Plus (Novartis Iodosan Nasale Oradol (Novart~s-Takeda) Consumer)-comb. (SmithKline Beecham)- USA: Bradosol Bromide (Ciba- 3 Bradoral (Zyma) comb. Ge~gy); wfm J: Brado (Novartis-Takeda)- comb. Domperidone ATC: A03FA03 Use: anti-emetic RN: 57808-66-9 MF: C22H24CIN502 MW: 425.92 EINECS: 260-968-7 LD,,: 46500 pglkg (M, i.v.); >8 glkg (M, p.0.); 41700 pglkg (R, I.v.); 5243 mglkg (R, p.0.); 42700 pglkg (dog, i.v.); >I60 mglkg (dog, p.0.) CN: 5-chloro-1-[1-[3-(2,3-dihydro-2-oxo-1H-benzimidazo-l-yl)propyl]-4-piperidinyl]-1,3-dihydro-2H- benzirnidazol-2-one 704 D Domvcridone r + KOCN 4 potassium cyonote (11) ethyl 4-amino- piperidine-1 - corbaxylate 48% aq. HBr H b Hs. Roney-Ni + v Darnperidone US 4 066 772 (Janssen; 3.1.1978; prior. 21.7.1975, 17.5.1976). DE 2 632 870 (Janssen; appl. 21.7.1976; USA-prior. 21.7.1975). Formulation(s): eff. gran. 10 mg; f. c. tabl. 10 mg; suppos. 30 mg; susp.10 mglml; tabl. 10 mg Trade Name(s): D: Motilium (Byk Gulden; Motilium (Sanofi Peridon (Fisons; 1979) Winthrop; 1982) Italchimici) F: Motilium (Janssen-Cilag; I: Fobidon (Biomedica J: Nauzelin (Kyowa Hakko; 1983) Foscama) 1982) PCridys (Robapharm) Gastronorm (Janssen) GB: Domperamol (Servier)- Mod (Irbi) comb. Motilium (Janssen; 1982) Donepezil hydrochloride D 705 Donepezil hydrochloride ('-2020) ATC: N06DA02 Use: cognition disorders, acetylcholinesterase inhibitor RN: 12001 1-70-3 MF: CZ4H2,NO3 . HCl MW: 415.96 CN: 2,3-dihydro-5,6-dimethoxy-2-[[l-(phenylmethyl)-4-piperidinylmethyl]-1 H-inden-I-one hydrochloride base RN: 120014-06-4 MF: C24H,9N03 MW: 379.50 BuLi, iPr2NH. THF OHC ethyl acetate H~C-O@= e HCI H3C-0 ' 1 -benzyl-4-(5.6-dimethoxy- 1-oxoindan-2-ylidenemethy1)- pipendine (I) I Donepezil hydrochloride I Reference(s): EP 296 560 (Eisai Co.; appl. 22.6.1988; J-prior. 22.6.1987). Imura, J. et al.: J. Labelled Compd. Radiopharm. (JLCRD4) 27, 835-839 (1989). Fomulation(s): tabl. 5 mg, 10 mg Trade Name(s): D: Aricept (EisaiIPfizer) GB: Aricept (EisaiPfizer) USA: Aricept (EisaiPfizer) Dopamine ATC: COlCA04 Use: sympathomimetic RN: 51-61-6 MF: C8HIlNOz MW: 153.18 EINECS: 200-110-0 LD,,: 59 mgkg (M, i.v.) CN: 4-(2-aminoethy1)-l,2-benzenediol hydrochloride RN: 62-31-7 MF: C8H1,NOz.HCl MW: 189.64 EINECS: 200-527-8 LD,,: 156 mgkg (M, i.v.); 4361 mglkg (M, p.0.); 4800 pgkg (R, i.v.); 2859 mglkg (R, p.0.); 79 mgkg (dog, i.v.) 706 D Dopexamine hornoveratryl- arnine (cf. popaverine synthesis) Doparnine I Reference(s): Schopf; Bayerle: Justus Liebigs Ann. Chem. (JLACBF) 513, 196 (1934). alternative with HCI: DE 247 906 (K. W. Rosenmund et al.; 1909). Hahn, G.; Stiehl, K.: Ber. Dtsch. Chem. Ges. (BDCGAS) 69. 2640 (1936) FR-appl. 2 332 748 (P. Fabre; appl. 28.1 1.1975). combination with "nitro"-preparations (for treulmerrt of cardiogenic shock): DOS 2 649 162 (Natlermann; appl. 28.10.1976). Formulation(s): vial 50 mg, 200 mg, 250 mg, 500 mg (for inf. sol.) Trade Name(s): D: Dopamin AWD (ASTA Dopamin Solvay (Solvay Mcdica AWD) Arzneimittel) Dopamin Fresenius F: Dopamine 200 Lucien GB : (Fresenius-Klinik) (Lucien) Dopamin ratiopharm Dopamine Nativelle I: (ratiopharm) (Procter & Gamble) J: USA: Dopamine Pierre Fabre (Pierre Fabre) Intropin (Arnar-Stone); wfm Revivan (Astra-Simes) Inovan (Kyowa Hakko) generics Dopexamine ATC: COICA14 Use: cardiotonic RN: 86197-47-9 MF: C22H,,N202 MW: 356.51 CN: 4-[2-[[6-[(2-phenylethyl)amino]hexyl]amino]ethyl]-1,2-benzenediol dihydrochloride RN: 86484-9 1-5 MF: C,,H,,N,O, .2HCI MW: 429.43 0 Ad HOOC 0 hornoveratrylarnine chlaride monoethyl adipate ethyl 6-0x0-6-[2-(3,4-dimethoxy- 6-0x0-6-[2-(3.4-dimethoxy- phenyl)ethylarnino]hexanoote (I) phenyl)ethylarnino]hexonoic acid (n) Dornase alfa D 707 C Dopexomme i i' Referencels): 1 EPX! O6l (Fisons, appl. 22.7.1982; GB-prior. 5.8.1981,9.10.1981, 17.1 1.1981). k 1 synthesis of 11: / Kametani, T. eta].: Yakugaku Kenkyu (YKKKA8) 37,23 (1966); C.A. (CHABAS) 65, 15320 (1966). t % Formulation(s): amp. 50 mgJ5 ml for inf I 1 Tmde Namefs): D: Dopacard (Ipsen Pharma; F: Dopacard (IpsenBlotech) GB: Dopacard (Speywood; as f as hydrochloride) hydrochloride) 1 Dornase alfa f (rhDNase) ATC: R05CB 13 Use: cystic fibrosis therapeutic RN: 143831-71-4 MF: unspecified MW: unspecified CN: deoxyribonuclease (human clone 18-1 protein moiety reduced) Domase alfa is produced by genetically engineered Chinese Hamster ovary cells containing DNA encoding for thenative human proJein deoxyribunuclease I. It is purified by tangentral flow filtration and column chromatography. Reference(s): WO 9 007 572 (Genentech; appl. 12.7.1990; USA-prior. 23 12.1988, 8.12.1989). Shak, S. et al.: Proc. Natl. Acad. Sci. USA (PNASA6) 87(23), 9188 (1990). Formulation(s): amp. 2.5 mgl2.5 ml Tmde Namefs): D: Pulmozyme (Roche) GB: Pulmozyme (Roche) USA: Pulmozyme (Genentech) Donolamide (L-671152; MK-507) ATC: SOlECO3 Use: antiglaucoma, topical carbonic anhydrase inhibitor RN: 120279-96-1 MF: CI0Hl6N2O4S3 MW: 324.45 CN: (4S-trans)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide bans-base RN: 120279-89-2 MF: C10H,,N,04S3 MW: 324.45 708 D Dorzolamide manohy drochloride RN: 130693-82-2 MF: C,,H,,N2O4S3. HCl MW: 360.91 maleate (1:l) RN: 147600-19-9 MF: C,,H,,N2O4S3. C4H404 MW: 440.52 crotonic ocid 4H-thieno[2,3-b]- thiopyran (21) Z-thiophene- thiol COOH chloride 3-(2-thienyl- . 2. tin@') thio)butanoic chloride acid (I) thiopyron-2-sulfonic ocid oxone, H3C \IPC*I!-NH~ S s CH,Oti sodium II 0 0 OH 0 borohydride 5.6-dihydro-4-hydroxy- 6-methyl-4H-thieno- [2.3-blthiopyran-2- sulfonarnide 7,7-dioxide (IV) 1. Tos-CI, pyridine 2.column chiomatogrophy, seporation of the trans isomer + H2N-CH3 b V ethylamine 0 resolution with di-p-toluoyi-D-tartaric ocid 1 -propon01 b 0 H*I,CH3 (V) Darzalomide Dorzolamide D 709 1 CIS0,H o,\ /p o,\ ,p 2 Pa5 H3cp + H3C-CN H3c'"'03 3 NH, i b VII Ritter OH reaction HNKCH3 @ preparation of the optically active thienothiopyran intermediate 6 CH, K 0 @) stereoselective synthesis of intermediate I 2-thiophene- (+)-(R)-B- thiol lithium methyl- salt propiolactone (S)-3-(2-thienyl- thio)butanoic acid Reference(s): a US 4 797 413 (Merck & Co.; appl. 10.1.1989; USA-prior. 12.12.1984, 19.9.1985, 14.5.1986). b EP 617 037 (Merck & Co.; appl. 17.3.1994; USA-prior. 22.3.1993, 10.2.1994). c JP 06 107 666 (Kanegafuchi Chern.; appl. 19.4.1994; J-prior. 28.9.1992). d US 4 968 815 (Merck & Co.; appl. 6.1 1.1990; USA-prior. 16.4.1990). US 4 968 814 (Merck & Co.; appl. 6.11.1990; USA-prior. 18.4.1990). combination with calcium antagonists: W09 323 082 (Alcon Lab.; appl. 12.5.1993; USA-prior. 13.5.1992). cotnbination with P-adrenergic antagonists: EP509 752 (Merck & Co.; appl. 14.4.1992; USA-prior. 17.4.1991, 13.2.1992). EP457 586 (Merck & Co.; appl. 16.5.1991; USA-prior. 17.5.1990). EP 375 319 (Merck & Co.; appl. 18.12.1989; USA-prior. 19.12.1988). Formulation(s): eye drops 22.3 rng/ml (as hydrochloride) Trade Name(s): D: Trusopt (Chibret) GB: Trusopt (Merck Sharp & USA: Trusopt (Merck; 1995 as Dohrne; as hydrochloride) hydrochloride) 710 D Dosulcpin Dosulepin (Dothiepin) ATC: N06AA16 Use: antidepressant, thymoleptic RN: 113-53-1 MF: C,,H,,NS MW: 295.45 EINECS: 204-031-2 LD,,,: 3 1 mgkg (M, Lv.) CN: 3-dibenzo[b,e]thiepin-1 l(6H)-ylidene-N,N-dimethyl-I-propanamine hydrochloride RN: 897-15-4 MF: C,,H2,NS . HCI MW: 331.91 EINECS: 212-978-8 LD,,: 29.2 mglkg (M, i.v.); 209 mglkg (M, p.0.); 24 mglkg (R, i.v.); 260 mglkg (R, p.0.) polyphosphoric acid _____+ 11-0x0-6.1 l-di- magnesium chloride hydrodibenzo- [b-elthiepin RE 618 591 (Spofa; appl. 6.6.1962; CS-prior. 8.6.1961). Forn~ulation(s): cps. 25 mg, 50 mg, 75 mg.; sup. 25 mg Trade Nume(s): D: Idom (Kanoldt) GB: Prothiaden (Knoll; as F: Proth~aden (Knoll, as hydrochloride) hydrochloride) I: Protiaden (Roots Italia) Doxapram ATC: R07ABOl Use: central respiratory stimulant RN: 309-29-5 MF: C2,H3,N202 MW: 378.52 EINECS: 206-216-3 LD?,,: 268 mglkg (M, i.p.1 CN: 1-ethyl-4-[2-(4-morpholinyl)ethyl]-3,3-diphenyl-2-pyrrnlidinone monohydrochloride monohydrate RN: 7081 -53-0 MF: C2,H7,N,O, . HCI . H20 MW: 432.99 LD,,,: 85 mglkg (M, i.v.); 270 mglkg (M, p.0.); 72 mglkg (R, i.v.); 261 mg/kg (R, p.0.); 40 mglkg (dog, i.v.); 150 mgtkg (dog, p.0.) . 5-chloro- 1-[ 1-[ 3-( 2,3-dihydro-2-oxo-1H-benzimidazo-l-yl)propyl ]-4 -piperidinyl ]-1 ,3-dihydro-2H- benzirnidazol-2-one 704 D Domvcridone r + KOCN 4 potassium cyonote (11) ethyl 4-amino-. thiopyron-2-sulfonic ocid oxone, H3C IPC*I!-NH~ S s CH,Oti sodium II 0 0 OH 0 borohydride 5.6-dihydro-4-hydroxy- 6-methyl-4H-thieno- [2.3-blthiopyran- 2- sulfonarnide 7,7-dioxide. dihydrochloride RN: 8648 4-9 1-5 MF: C,,H,,N,O, .2HCI MW: 429.43 0 Ad HOOC 0 hornoveratrylarnine chlaride monoethyl adipate ethyl 6-0 x 0-6 -[ 2-( 3,4-dimethoxy- 6-0 x 0-6 -[ 2-( 3.4-dimethoxy- phenyl)ethylarnino]hexanoote