Pharmaceutical Substances Syntheses, Patents, Applications - Part 214 pps

Tromantadine T 213 1 Trade Name(s): D: Angitrit (Nordmark); wfm Etamin (Zeria) USA: Metamine (Pfizer); wfm J: Amitolen (Hokuriku) Sedalis (Kayaku) Tromantadine ATC: D06BB02; J05AC03 Use: antiviral RN: 53783-83-8 MF: C,6H28N202 MW: 280.41 EINECS: 258-770-0 CN: 2-[2-(climethylamino)ethoxyl-N-tricyclo[3.3.1. l3z']dec- 1-ylacetamide monohydrochIoride RN: 41544-24-5 MF: C,,H,,N,O, . HC1 MW: 316.87 EINECS: 255-434-5 FH3 0 2-dimethylamino- H2N cIlfNH ethanol H3C/Ne~>NH 0 1 -amino- chloro- 1 -(2-chloroocet- odamontone ocetyl amido)adamontane chloride Tromantodine Reference(s): DOS 1 941 218 (Merz & Co.; appl. 13.8.1969). Peteri, D.; Sterner, W.: Arzneim Forsch. (ANCEAD) 23,577 (1973). Formula~ion(s): cream 10 mg, 100 mg/lO g; gel 10 mg, 100 mg/lO g; ointment 1 % (as monohydrochloride) Trade Name(s): D: Vim-"Merz" (Merz & Co.) Viru-"Merz" Serol (Merz & I: Viruserol (Novartis Co.) Consumer Health) Trometamol ATC: B05BB03; B05XX02 (Tromethamine) Usc: osmotic diuretic RN: 77-86-1 MF: C,H,,NO, MW: 121.14 EINECS: 201-064-4 CN: 2-amino-2-(hydroxymethy1)-1.3-propanediol HZ. Raney-Ni 02N-CHI + HCHO + H~~oOHH , nitro- farm- 2-(hydroxymethy1)- methane aldehyde 2-nitro-1 ,3- propanedial Reference(s): US 2 174 242 (Purdue Res. Found.; 1939; appl. 1937). electrolytic reduction: US 2 485 982 (Commercial Solvents Corp.; 1949; appl. 1944). Trometamol El Formu/ation(s): amp. 7.3 gl20 ml, sol. 34.36 gI100 ml 2 132 T Tropenziline bromide Trade Name(s): D: Elektrolyt-Konzentrat Tris TRIS 36.34 % Braun (BI Thamacktat (Bellon; (THAM) pfrimmer Braun) RhBne-Poulenc Rorer) (Pfrimmcr) F: Almide (Alcon) I: Thamesol (Diaco) THAM-Kohler 3 M Monuril (Zambon) Ulcotris (1SF)-Comb. (Kohler) J: Tham-Set (0tsuka)-comb. Tropenziline bromide ATC: A03; NO7 Use: antispasmodic, parasympathomimetic RN: 143-92-0 MF: C,H,oBrNO, MW: 476.41 EINECS: 205-612-3 CN: 3-[(hydroxydiphenylacetyl)oxy]-6-methoxy-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide methoxy- methyl- dimethyl succinoldehyde omine ocetonedi- corboxylote . No H~C~ 0 rn H~c'~ Hz. Roney-Ni -+ - 11 ethyl benrilote H~C~ 0 rn H~c'~ Hz. Roney-Ni ,,,OH 00 -+ H3c\o@ ethyl benrilote 11 6-methoxyiropinone (I) Reference(s): CH 325 296 (Sandoz; appl. 1954). Stoll, A. et a].: Helv. Chim. Acta (HCACAV) 37,495 (1954); 38, 571 (1955). methyl Trade Name(s): D: Pelerol (Sandoz)-comb.; F: Palerol (Salvoxyl-Wander); wfm wfm Tropenziline bromide bromide Tropicamide T 2133 Tropicamide ATC: SOIFAO6 Use: parasympatholytic, mydriatic RN: 1508-75-4 MF: C17H20N202 MW: 284.36 EINECS: 216-140-2 LD,,,: 565 mgkg (M, p.0.); 865 mgkg (R, p.0.) CN: N-ethyl-a-(hydroxymethyl)-N-(4-pyridinylmethyl)benzeneacetamide NH2 + HCI + yTN 'CH3 + I 0-ocetyltropoyl CH3 chloride ethyl- 4-chloromethyl- N-ethyl-4- amine pyridine pyridine- hydrochloride methanornine Tropicarnide u Reference(s): US 2 726 245 (Hoffmann-La Roche; 1955; CH-prior. 1952). Fonnulation(s): eye drops 5 mglml, 5 mg10.5 ml Trade Name(s): D: Aroclunin (Chauvin Tropicamide Faure Visumidriatic Antif. ankerp harm) (Schering) (Merck Sharp & Dohme)- Mydriaticum Stulln GB: Minims Tropicamide comb (Pharma Stulln) (Chauvin) Visumidriatic Fenil Mydrum (Chauvin Mydriacyl (Alcon) (Pharmec)-comb. ankerpham) I: Tropimil (Farmigea) J: Mydrin (Santen) F: Mydriaticum (Merck Sharp Visumidriatic (Pharmec) USA: Tryptar (Armour); wfm & Dohme-Chibret) Tropisetron (ICS-205930) ATC: A04AA03 Use: antiemetic, antimigraine, 5-HT,- antagonist RN: 89565-68-4 MF: C17H20N202 MW: 284.36 CN: JH-Indole-3-carboxylic acid endo-8-methyl-8-azabicyclo[3.2.l]oct-3-yl ester 2134 T Trospium chloride indole-3- carboxylic ocid (I) indole-3- corbonyl chloride (11) 1.THF 2. BuLi, THF 11 + 0 H H Tropisetron 4 1 ,la-corbonyl- 1 -(1 H-indol-3- diirnidozole y1corbonyl)- 1 H- irnidozole Reference(s): a DE 3 322 574 (Novartis; appl. 23.6.1983; CH-prior. 29.6.1982). a,b BE 901 274 (Sandoz A. G.; appl. 14.12.1984; CH-prior. 23.12.1983) use of serotonin-5-HT-antagoni~ts: DE 3 724 059 (Sandoz-Patent GmbH; appl. 21.7.1987; D-prior. 7.8.1986). b DE 3 445 377 (Sandoz-Patent GmbH; appl. 13.12.1984; CH-prior. 23.12.1983). Langlois, M. et al.: Eur. J. Med. Chem. (EJMCA5) 28, 869 (1993). Formrtlution(s): amp. 2 mg/2 rnl, 5 mg/5 rnl; cps. 5 rng Trade Name(s): D: Navoban (ASTA Medica GB: Navoban (Novartis AWD; Novartis Pharma) Pharma) F: Navoban (Novartis I: Navoban (Novartis Pharma) Pharma) Trospium chloride ATC: A03AB20 Use: anticholinergic, antispasmodic RN: 10405-02-4 MF: C,,H,,CINO, MW: 427.97 EINECS: 233-875-4 LD50: 11.2 mg/kg (M. i.v.); 812 mg/kg (M, p.0.); 15.5 mg/kg(R, i.v.); 1510mg/kg(R, p.0.) CN: (la,3~,5a)-3-[(hydroxydiphcnylacetyl)oxy]spiro[8-azoniabicyclo[3.2.1]octane-8,1'-pyrrolidinium] chloride Trovafloxacin mesilate T 2 135 nortropine 1,4-dibromo- butane a-chlorodiphenyl- acetyl chloride Trospium chloride L Reference(s): DE 1 194 422 (Pfleger; appl. 5.3.1963). Formulation(s): amp. 1.2 mg/2 rnl, 2 mg/2 ml; drg. 15 mg, 20 mg, 30 mg; f. c. tabl. 5 mg; suppos. 0.75 mg, 1 rng Trade Name(s): D: Spasrnex (Pfleger) Spasmo-Urgenili Spasrno-Fyt (Madaus) (Madam)-comb. Spasmo-Rhoival (Byk Trospi-forte (medac) GuldenIByk Tosse) J: Spasmex (Nikken) Trovafioxacin mesilate (CP-992 19; CP-992 19-27) ATC: JOlMA13 Use: antibacterial RN: 147059-75-4 MF: C,,H,,F3N4O,. CH403S MW: 512.47 CN: (1 a,5a,6~)-7-(6-Arnino-3-azabicyclo[3.1 .O]hex-3-yl)-l-(2,4-difluorophenyl)-6-fluoro- l,4-dihydro-4-0x0- 1,8-naphthyridine-3-carboxylic acid monohydrate RN: 193478-08-9 MF: C2,H,,F3N403 . CH401S . H20 MW: 530.48 base RN: 147059-72-1 MF: C,,H,,F3N403 MW: 416.36 hydrochloride RN: 146961-34-4 MF: C2,H,,F3N4O3. IICI MW: 452.82 1. Et,O O 2. thermolysis. -N, + HIChOql - 0 N2 0 N-benzyl- ethyl rnoleimide (I) diazoacetate (11) ethyl (la,5a,6n)-3- benzyl-2,4-dioxo-3- azabicyclo[3.1 .O]hexone- 6-carboxylote (ID) 21 36 T Trovafloxacin mesilate 1. LiAIH4, THF 1. CI-Cbo , dioxone, NaHC03 2. Hz, Pd-C, CHJOH H 2. Jones reagent. acetone I -b H 0/'"''qN b IV H benzyl chloroformote (la,Sa,6a)-3-(benzyl- oxycorbonyl)-3-020- bicyclo[3.l .O]hexone- 6-carboxylic acid (N) N3 2. Hz, Pd-C. CH30H CH3 HH b B~~'"‘Q diphenylphosphoryl azide H ethyl 7-chloro-1-(2.4- difluorophenyl)-6-fluoro- 4-0x0-1,4-dihydro- l,8- nophthyridine-3-corboxylote (W) @ alternative synthesis of N VII + H3C-S03H + separation of diastereorners 0 , H3CAOq ? HN, cbo 2,s- 1 -(benzyloxy- (m dihydro- carbony1)- pyrral 2.5-dihydro- 1H-pyrrole F H H2N,,,, 2 H3c-s03H H.PN ,N F 0 Trovofloxocin rnesilate - Trovafloxacin mesilate T 2 137 NaOH I + N @) alternative synthesis of V H 0 1. BH3. THF H O2N.,,,qN47 2. H,. ~d-c 1 + B~/'No, b p' - IX 0 brornonitro methane 1. Boc\O/Boc, THF. TEA HJ+,,,+;~ 2. HZ. Pd-c. cH30H H"" \ Reference(s): route for trovajloxacin 6P- diastereomer: Vilsmaier, E.; Goerz: Synthesis (SYNTBF) 739 (1998). a US 5 164 402 (Pfizer Inc., 17.1 1.1992; USA-prior. 11.7.1990). Brighty, K.E. et al.: Synlett (SYNLES) 1996, 1097. JP 09 012 546 (Chisso Corp.; appl. 23.6.1995). aa Braish, T.E et al.: Synlett (SYNLES) 1996, 1100 Stille, J.K. et al.: J. Org. Chem. (JOCEAH) 45 (1 I), 2139-2145 (1980) ES 2 095 809 (Quimica Synth.; appl. 27.7.1995). ab EP 818 445 (Pfizer Inc.; appl. 1.7.1997; USA-pr~or. 9.7.1996). starting material VI: US 4 571 396 (Warner Lambert Co.; 18.2.1986; USA-prior. 16.4.1984). US 4 775 668 (Pfizer Inc.; 4.10.1988; USA-prior. 19.8.1986). novel crystal forms: . W09 639 406 (Pfizer Inc.; USA-prior. 6.6.1995). W09 707 800 (Pfizer Inc.; appl. 29.7.1996; USA-prior. 29.8.1995). polymorphs of the prodrug: WO 9 708 191 (Pfizer Inc.; appl. 5.7.1996; USA-prior. 29.8.1995). suspension for oral administration: DE 19 706 978 (U. Posanski; appl. 5.1.1998; D-prior. 21.2.1997). use for treatment of Heliobacter pylori infections: EP 676 199 (Pfizer Inc.; appl. 23.3.1995; USA-prior. 7.4.1994). Formulation(s): tabl. 100 mg, 200 mg (as mesylate); vials, 40 ml, 60 ml with 5 mglml Trade Narne(s): D: Trovan (Pfizer); wfm Turvel (Pfizer); wfm USA: Trovan (Pfizer; 1998); wfm 2138 T Troxerutin - Troxerutin ATC: COSCAO~ Use: vein therapeutic RN: 7085-55-4 MF: C13HJ20L9 MW: 742.68 EINECS: 230-389-4 LDS,,: 27.16 gtkg (R, i.p.) CN: 2-[3,4-bis(2-hydroxyethoxy)phenyl]-3-[[6-0-(6-deoxy-a-~-rnannopyranosy1)-~-~-glucopyranosyl]oxy]- 5-hydroxy-7-(2-hydroxyethoxy)-4H-l-benzopyran-4-one rutaside 2-chloroethonol Troxerutin DAS 1 06 1 327 (Zyma; appl. 30.12.1957; CH-prior. 4.7.1957). GB 833 174 (Zyma S.A.; appl. 27.6.1958; CH-prior. 4.7.1957). synthesis with cthylcne oxide: DAS 1 543 974 (Zyma; appl. 8.10.1966; F-prior. 25.10.1965; CH-prior. 9.3.1966). DAS 1 793 746 (Zyrna; appl. 8.10.1966; F-prior. 25.10.1965). Formulation(s): cps. 300 rng; eye drops 50 mgtml; f. c. drg 300 rng; f. c. tabl. 250 rng, 300 rng; s. r. tabl. 300 rng Trade Name(s): D: Drisi-Ven (Sertiirner) Pherarutin (Kanoldt) Posorutin (Ursapharm) F: Troxerutin-ratiopharrn (ratiopharm) Troxeven (Kreussler) Vastribil (Farmasan) Veno SL 300 (Ursapharrn) GB : . numerous combination preparations Ginkor (Beaufour)-comb. RhCobral (Niverpham) RhCoflux (Niverpharrn) Veinarnitol (Negma) VivCne (Labs. de L' ACrocid) Paroven (Zyma); wfm I: Derrnoangiopan (Abiogen Pharrna)-comb. Ernorril (Po1i)-comb. Flebil (Molteni) Premium (Synthelab0)- comb. Venolen (Farrnacologico Milanese) Troxipide RN: 99777-81-8 MF: C,,H2,N204 MW: 294.35 CN: (k)-3,4,5-trirnethoxy-N-3-piperidinylbenzarnide ATC: A02BXI I Usc: ulcer therapeutic base RN: 30751-05-4 MF: C15H2,N204 MW: 294.35 LDsu: 100 rng/kg (M, i.v.); 2 g/kg (M, p.0.); 21 00 rnglkg (R, p.0.) monohydrochloride RN: 3075 1-03-2 MF: C,SH,,N,04 . HCI MW: 330.8 1 LDso: 300 mglkg (M, i.p.); 2000 mglkg (M, p.0.); 1550 mglkg (M, s.c.); 340 mdkg (R, i.p.); 21 00 mgkg (R, p.0.) 3-amino- 3.4.5-trimethoxy- 3-(3.4.5-trimethoxy- pyridine benzoyl chloride benzamid0)pyridine Reference(s): DOS 1 938 512 (Kyorin; J-prior. 30.6.1969). DOS 1 967 324 (Kyorin; J-prior. 30.6.1969). US 3 647 805 (Kyorin; 7.3.1972; appl. 1 1.7.1969). Irikura, T. et al.: J. Med. Chem. (JMCMAR), 14, 357 (1971). medical use for treatment ofgastritis: EP 254 068 (Kyorin; appl. 25.6.1987; J-prior. 26.6.1986) Form~dation(s): tabl. 50 rng, 100 rng Trade Name(s): J: Aplace (Kyorin; 1986) ATC: N06AX02 Use: antidepressant, essential amino acid RN: 73-22-3 MF: CI,Hl2N2O, MW: 204.23 EINECS: 200-795-6 LD,,: >16 gkg (R, p.0.) CN: L-tryptophan acrolein diethyl ocetomido- molonoie H H~SO, , TB3 + H~C~O ooTCH3 COOH aminoacylase and racemization of N-ocetyl-D-tryptophan 111 b 3-cyano- propian- aldehyde 3-(5-hydantoiny1)- propionaldehyde (N) 5-(3-indoly1rnethyl)- hydantoin aminaocylase 0 0 COOH DL-tryptophan (V) Reference(s1: a Warner, O.T.; Moe, O.A.: J. Am. Chem. Soc. (JACSAT) 70,2765 (1948). b Komachiya, Y. et al.: Nippon Kagaku Kaishi (NKAKB8) 86, 856 (1965). erlzyrnatic rueenlate resolution: Chibata, I. et al.: Bull. Agric. Chem. Soc. Jpn. (BACOAV) 21,58, 304 (1957). purification: US 5 057 615 (Mitsui Toatsu; 15.10.1991; J-prior. 27.6.1989). combination with beta blocking agents: IJS 4 161 530 (Ciba-Gcigy; 17.7.1979; CH-prior. 6.1.1975). GR 1 53 1 091 (Ciba-Gcigy; appl. 5.1.1976; CH-prior. 6.1.1975). Volk, W. et a].: Arzneim Forsch. (ANCEAD) 28 (II), 1798 (1978). newer syntheses for DL-tryptophan: Hengartner, M. et al.: J. Org. Chem. (JOCEAH) 44, 3748 (1979). Fbrtnulation(s): f. c. tabl. 500 mg; tabl. 500 mg Trade Narne(s): D: Ardey tropin (Ardeypharm) Actitonic (Reygagne)- Tryptacin (Arther); wfm Kalma (Fresenius-Praxis) comb.; wfm Tryptacin (Nutrition Lypharm (esparma) GB: Optimax (Merck)-comb. Control Products); wfm numerous combination J: Eltrip (Ono) Tryptophane (Nature's preparations Tryptan (Daigo Eiyo) Bounty); wfm F: Actitonic (Amido; as DL- USA: Trofan (Upsher-Smith); Tryptophane (Solgar); wfm form)-comb.; wfm wfm Tryptoplex (Tyson); wfm . 14705 9-7 5-4 MF: C,,H,,F3N4O,. CH403S MW: 512.47 CN: (1 a,5a,6~ )-7 -( 6-Arnino-3-azabicyclo[3.1 .O]hex-3-yl)-l-(2,4-difluorophenyl )-6 -fluoro- l,4-dihydro- 4-0 x 0- 1,8-naphthyridine-3-carboxylic. 2-[ 3,4-bis(2-hydroxyethoxy)phenyl ]-3 -[ [ 6-0 -( 6-deoxy-a-~-rnannopyranosy1 )-~ -~ -glucopyranosyl]oxy ]- 5-hydroxy- 7-( 2-hydroxyethoxy )-4 H-l-benzopyran-4-one rutaside 2-chloroethonol Troxerutin DAS 1 06. .O]hexone- 6-carboxylic acid (N) N3 2. Hz, Pd-C. CH30H CH3 HH b B~~'"‘Q diphenylphosphoryl azide H ethyl 7-chloro- 1-( 2. 4- difluorophenyl )-6 -fluoro- 4-0 x 0-1 ,4-dihydro- l, 8- nophthyridine-3-corboxylote