Trimipramine T 21 21 Reference(s): GB 1 345 502 (Parke Davis & Co.; appl. 6.7.1972; GB-prior. 6.7.1972). EP 5 145 (Warner-Lambert Co.; appl. 26.10.198 1; USA-prior. 29.1.1982). lyophilic formulation: JP06 172 177 (Dainippon Pharm.; appl. 10.12.1992; J-prior. 10.12.1992). Formulation(s): vial 25 mg Trade Nume(s): F: Neutrexin (IpsedBiotech) I: Neutrexin (lpsen) GB: Neutrexin (Speywood) USA: Ncutrexin (US Bioscience) Trimipramine ATC: N06AA06 Use: antidepressant RN: 739-7 1-9 MF: CzoHz6Nz MW: 294.44 EINECS: 212-008-3 LD,,: 42 mglkg (M, i.v.); 250 mgtkg (M, p.0.) CN: 10.1 1 -dihydr0-N,N,~-trimethyl-5H-dibenz[b,,flaze~inc-5-~ropanamine maleate (1:l) RN: 521-78-8 MF: CX,Hz6N2. C4H404 MW: 410.51 EINECS: 208-318-3 LD,: 40 mgkg (M, i.v.); 425 rngtkg (M, p.0.); 38 mglkg (R, i.v.); 800 mglkg (R, p.0.) monomesylate RN: 25332-1 3-2 MF: C2,,H2,N2 . CH403S MW: 390.55 EINECS: 246-852-9 2-methylpropyl 10,ll-dihydra-SH- chloride Trimipramine dibenz[b.f]ozepine . Reference(s): FR 1 172 014 (RhGne-Poulcnc; appl. 14.12.l955). Jacob, R.M.; Messer, M.: C. R. Hebd. Seances Acad. Sci. (COREAF) 252, 21 17 (1961). Formulation(s): amp. 25 mglml; cps. 25 mg, 50 mg, 100 mg; drops 5.3 g1100 ml (as monomesylate); f. c. tab1 25 mg; tabl. 25 mg, 100 mg (as maleate) Trade Name(s): D: Hexphonal (ASTA Medica F: Surmontll (Specia) Surmontil (RhBne-Poulcnc AW D) GB: Surmontil (RhBne-Poulenc Rorer) Stangyl (RhGne-Poulenc Rorer) J: Surmontil (Shionogi) Rorer) I: Surmontil (RhBne-Poulenc USA: Surmont~l (Wyeth-Ayerst) Trimipramin-neuraxpharm Rorer) (neuraxpharm) 2122 T Tripamide Tripamide ATC: C02 Use: antihypertensive, diuretic RN: 73803-48-2 MF: C,,H20C1N,0,S MW: 369.87 LD,,,: >5 glkg (M, p.0.); 28 gikg (R, p.0.); 22 gikg (dog, p.o.1 CN: (3aol,4a,7a,7acr)-3-(aminosulfonyl)-4-chloro-N-(octahydro-4,7-methano-2H-isoindol-2-yl)benzamide 2. NU3 S0Cl2 HOOC~CI - m0c-Q-CI - + 1. chlorosul- thionyl n 4-chlorobenzoic acid ionic ocid c -4- u- ' NH2 4-chlaro-3-sulf- ornoylbenzoic acid 1. NoN02 2. Zn, CHJCOOH 1. sodium nitrite . L H 2. zinc endo-hexo- hydro-6,7- methono- isoindoline Reference(s): 2-omino-endo- hexohydro-6.7- rnethonoiso- indoline 4-chloro-3-suli arnoylbenzoyl chloride (I) oQ% Tripomide NH2 US 3 787 440 (Eisai; 22.1.1974; appl. 9.1 1.1971; J-prior. 9.1 1.1970). DOS 2 155 660 (Eisai; appl. 9.1 1.197 1; J-prior. 9.1 1.1970). Nakamura, T. ct al.: J. Labelled Compd. Radiopharm. (JLCRD4) 14, 191 (1978). synthesis of 2-amino-endo-hexahydro-4,7-methanoisoindoline: JP 7 121 708 (Eisaei; appl. 17.8.1967). Fqrmulation(s); tabl. 15 mg Trade Name(s): J: Normonal (Eisai; 1982) Tripelennamine ATC: D04AA04; R06AC.04 Use: antihistaminic RN: 91-81-6 MF: C,,H,,N, MW: 255.37 EINECS: 202-100-1 LD,,,: 23 mglkg (M, i.v.); 152 mglkg (M, p.0.) CN: N,N-dimethyl-N-(phenylmethy1)-N'-2-pyridiny- 1,2-ethanediamine monohy drochloride RN: 154-69-8 MF: CI,H2,N3 . HCI MW: 291.83 EINECS: 205-833-5 LD,,,: 9 mglkg (M, i.v.); 97 mglkg (M, p.0.); 12 mglkg (R, i.v.); 469 mglkg (R, p.0.) Triprolidine T 2123 2-benzylomino- 2-(dimethylamino)- I Tripelennomine I pyridine ethyl chloride Reference(s): US 2 406 594 (Ciba; 1946; prior. 1943). . US 2 502 151 (Rhhe-Poulenc; 1950; F-prior. 1943). Formulation(s): stick 115 mg15.75 g (as hydrochloride) Trade Name(s): D: Azaron Stift (Chefaro) I: Sedilene (Montefarmaco); USA: F: Anachoc (Lipha)-comb.; wfm wfm J: Pyribenzamin (Ciba-Geigy- Takeda) PBZ-SR (Geigy); wfm Pyribenzamine (Ciba); wfrn Tripelennamine HCI Tablets (Danbury); wfm Triprolidine ATC: R06AX07 Use: antihistaminic RN: 486-12-4 MF: ClYHz2N2 MW. 278.40 EINECS: 207-627-0 CN: (E)-2-[1-(4-methylphenyl)-3-(1-pyrrolidinyl)-1-propenyl]pyridine monohydroshloride RN: 550-70-9 MF: C, yH22N2 . HCI MW: 3 14.86 EINECS: 208-985-0 LDso: 21 mglkg (M, i.v.); 495 mglkg (M, p.0.); 840 mglkg (R, p.0.) u UcH, 2. 2-"0-0- ovridine , , 4'-methyl- paraform- pyrrolidine 4'-methyl-3- acetophenone aldehyde pyrrolidino- propiophenone Q seporation by ion exchanger - CH3 CH3 Triprolidine u Reference(s): US 2 712 020 (Burroughs Wellcome; 1955; GB-prior. 1948). US 2 712 023 (Burroughs Wellcome; 1955; GB-prior. 1948). Formulation(s): syrup 1.25 mg15 ml; tabl. 1.25 mg, 2.5 mg (as hydrochloride) 2124 T Tritoaualine Trade Name(s): D: Actifed (Warner-1,ambert)- I: Actidil (Warner-Lambert) USA: Actifed (Warner-Lambert)- comb. I: Entra (Wellcome-Tanabe) comb. F: Actifed (Warner-Lambert) Pro-Entra (Wellcome- GB: Sudafed (Warner-Lambert)- Tanabe) comb. Venen (Tanabe) Tritoqualine ATC: R06AX21 Use: antiallergic RN: 14504-73-5 MF: CxH,,N108 MW: 500.55 LD,,,: >I 5 glkg (M, p.0.); >I 5 glkg (R. p.0.) CN: 7-amino-4,5,6-triethoxy-3-(5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxolo[4,5-g]isoquinolin-5-yl)- l(3 H)-isobenzofuranone cotornine 7-nitro-4.5.6-tri- ethoxyphthalide Tritoqualine Reference(s): DE 1 206 909 (M. Jeanson, Paris; appl. 14.8.1959). Formulation(s); drops 180 mg; tabl. 100 mg Trade Narnefs): D: Inhibostamin (Swiss- Inhibostarnin (Zyma); wtm I: Hypostamin (SIT); wfm Pharma); wfm F: Hypostamine (Promedica) Hypostarnine (Zyma); wfm Trofosfamide (Trophosphamide) ATC: LOIAA07 Use: antineoplastic RN: 22089-22-1 MF: C,Hr,C13N,0,P MW: 323.59 EINECS: 244-770-8 LD,,,: 157 mglkg (M, i.v.); 464 mg/kg (M, p.0.); 90 mgkg (R, i.v.); 202 mglkg (R, p.0.) CN: N,N,3-tris(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide Troglitazone T 2125 OH HCI + CI, 1 P - / $0 C I amine N-(2-chlor0ethyl)-3- N,N-bis(2-chloro- hydroxypropylarnine ethyl)phasphorarnidic hydrochloride dichloride Reference(s): DOS 1 645 921 (ASTA-Werke; appl. 1 1.7.1966). GB 1 188 159 (ASTA-Werke; appl. 11.7.1967; D-prior. 11.7.1966). US 3 732 340 (ASTA-Werke; 8.5.1973; prior. 30.6.1967, 11.9.1970, 14.1.1971). for mu lab ion(.^): f. c. tabl. 50 mg Trade Namc(s): D: Ixoten (ASTA Medica I: Ixoten (Schering); wfm AW D) Troglitazone (CI-991; CS 045; GR-92 132X) ATC: AlOBGOl Use: antidiabetic, insulin enhancer, antioxidant RN: 97322-87-7 MF: C,H2,N05S MW: 441.55 LD,: >5 gkg (R, p.0.) CN: 5-[[4-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-1-benzopyran-2-yl)methoxy]phenyl]methyl-2,4- thiazolidinedione monosodium saIt RN: 97323-06-3 MF: C,H,NNaO, MW: 431.46 CI o/CH3 H3CwOH LiAIH4, HZ.*H A NaH, THF III HO HO rnethoxymethyl '3'3 C"3 chloride (+)-6-hydroxy-2.5,7.8- (+)-6-h~droxy-2.5.7.8- letromethylchroman-2- tstrarnethylchrornon- corboxylic acid (I) 2-ylrnethonol (+)-(I() CH3 CH3 NOH, DMF. '3'WH + flNo2 F benzme HA , 0 0 CI ' CH3 CH3 (11') p-chloronitro- benzene (+)-6-(rnethoxyrnethoxy)- 2.5.7.8-tetrarnethyl-2- (4-nitrophenoxyrnethyl)- chrornon (N) 2126 T Troglitazone tetromethylchromon (VI) 1. NoN02, H20, HCI, ocetone 2. HZC'+OvC"3 0 CupO. 40 OC VI _____* 2. ethyl acrylote CH3 NoOH. C2H50H. THF VII - 2.5.7.8-tetromethylchromon-2-yl)- rnethoxy]phenyl]prapionic acid (vIU) @ starting material I: I. K2C03 2. H3C-Li. 1. sulfolane. 120 "C VIII 2,3,5-trimethyl- hydroquinone (M) thiourea 5'.4',6' trimethyl- 2'3'-dihydroxy- ocetophenone (X) CH3 Troglitazone ethyl 6-hydroxy-5.7.8- trimethyl-4-0x0-4H- chromene-2-corboxylote (XI) Troglitazone T 2127 1. HZ. Pd-C. DMF 2. Clr\O/CH3 , NOH, THF 3. H~C-L~ ,H3C 1 H3cw0ncH3 , - HC '0-0 methyl vinyl ketane 2. V , pyridine H3C CH3 CHJ 0 6-hydroxy-2-methoxy- 2,5,7,8-tetramethyl- chromane (XI) 1. OMF 2. HCI. 90 OC WI + KCN + 1 4-bromo-3-methyl- 2-butenyl acetote (XN) XIV HO H c K ?? 0 4-(p-nitrophenoxy)-3- methyl-2-butenyl ocetate (XV) 2128 T Troglitazone 2-i4-(p-nitrophenoxy)-3- methyl-2-butenyll-3,5.6- trirnethylhydroquinone (XVI) + Q^" CH, CH3 (unprotected N) triphenylphosphine piperidine. 2-methoxyethanol 0 6-benzyioxy-2-(4-forrnyl- 2.4- thioroli- phenoxyrnathyl)-2.5.7.8- dinedione tetrornethylchrornan (XVII) H,. Pd-C 5-[4-(6-benzyloxy-2,5,7,8-tetro- rnethylchrornon-2-ylrnethoxy)- benzylideneJ-2.4-thiazolidine- dione (XVIII) @ olternative synthesis of VI: .I. u *A nNo2 benzene + H3Cr0 7+MX pyrrol~dtne CH30 0 5'-ocetoxy-2'-hydrony- 3.4'6-trimethyi- ocetophenone 1. NaBH,, CHPH JJN02 2. Tos-OH, benzene 3. Hz. Pd-C. CHJOH - VI CH30 6-acetoxy-2.5.7.8-tetromethyl- 2-(4-nitrophenoxyrnethy1)- 4-chromonone (XIX) Troglitazone T 2129 @ intermediate 11: s-collidine, -40°C CH3S,CH3 1. H,. Pd 2. HCI XX + 11 2-methyl-2- viny loxirane 1 2130 T Trolnitrate Re-ferencr(sJ: a Yoshioka, T. et a].: J. Med. Chem. (JMCMAR) 32, 421 (1989). EP 207 581 (Sankyo Co.; appl. 26.2.1986; J-prior. 26.2.1985). aa Witiak, D.T. et al.: J. Med. Chem. (JMCMAR) 18 (9), 934 (1975). EP 139 421 (Sankyo Co.; appl. 28.8.1984; prior. 30.8.1983). US 4 572 912 (Sankyo; 25.2.1986, J-prior. 30.8.1983). ab Scott, J.W. et al.: J. Am. Chem. Soc. (JACSAT) 51,200 (1974). b EP 670 300 (Eisai Chem. Co.; appl. 1.3.1995; J-prior. 2.3.1994). EP 543 346 (LonzatSankyo; appl. 17.1 1.1992; CH-prior. 20.1 1.1991). c EP454 501 (Sankyo Co.; appl. 29.4.1991; J-prior. 27.4.1990). ea DE 3 010 504 (BASF AG; appl. 19.3.1980). eb JP 08 1 19 958 (Kwaray Co.; appl. 18.10.1994). JP 08 119 957 (Kwaray Co.; appl. 18.10.1994). ec JP 01 068 366 (Eisai Co.; appl. 9.9.1987). ed Tanabe, K. et al.: Chem. Lett. (CMLTAG) 5,561 (1985). ef Sakito, Y. et al.: Tetrahedron Lett. (TELEAY) 23 (47), 4953 (1982). EP 65 368 (Sumitorno Chem.; appl. 28.4.1982; J-prior. 30.4.1981). kinetic resolution of intermediate 11: Hyatt, J.A.; Skelton, C.: Tetrahedron: Asymmetry (TASYE3) 8 (4), 523 (1997). preparation of (+)-enantiomer by yeast reductase: WO 9 310 254 (SmithKline Beecham; appl. 19.11.1992; GB-prior. 19.11.1991). Formularion(s): tabl. 100 mg, 200 mg, 300 mg, 400 mg Trade Nume(s): J: Noscal (Sankyo) USA: Rezulin (Parke Davis; Warner-Lambert); wfm Trolnitrate ATC: COlDA09 1 Jse: coronary vasodilator RN: 7077.34- 1 MF: C,H,,N40, MW: 284.18 EINECS: 230-376-3 CN: 2,2',2"-nitrilotrisethanol trinitrate (ester) diphosphate RN: 588-42- 1 MF: C,H,,N@, . 2H3P04 MW: 480.17 EINECS; 209-61 7- 1 LD,,,: lOOmg/kg(M,i.v.); 330mg/kg(M,p.o.); 130 mgkg (R, p.0.) triethanalarnine Rejerence(s): FR 984 523 (J. Metadier; appl. 1949). . 4-bromo-3-methyl- 2-butenyl acetote (XN) XIV HO H c K ?? 0 4-( p-nitrophenoxy )-3 - methyl-2-butenyl ocetate (XV) 2128 T Troglitazone 2-i 4-( p-nitrophenoxy )-3 - methyl-2-butenyll-3,5. 6-. (3aol,4a,7a,7acr )-3 -( aminosulfonyl )-4 -chloro-N-(octahydro-4,7-methano-2H-isoindol-2-yl)benzamide 2. NU3 S0Cl2 HOOC~CI - m0c-Q-CI - + 1. chlorosul- thionyl n 4-chlorobenzoic acid ionic ocid c -4 - u- ' NH2 4-chlaro-3-sulf- ornoylbenzoic. RN: 1450 4-7 3-5 MF: CxH,,N108 MW: 500.55 LD,,,: >I 5 glkg (M, p.0.); >I 5 glkg (R. p.0.) CN: 7-amino-4,5,6-triethoxy- 3-( 5,6,7,8-tetrahydro-4-methoxy-6-methyl-1,3-dioxolo[4,5-g]isoquinolin-5-yl)-