Tiopronin T 2051 Trade Name(s): D: Emdabol (Merck); wfm Gerantabol (Merck)-comb.; wfm Tiopronin (Mercamidum) ATC: R05CB12 Use: detoxicant, liver therapeutic, hepatoprotectant, mucolytic RN: 1953-02-2 MF: C,H,NO,S MW: 163.20 EINECS: 217-778-4 LD,,,: 1733 mgkg (M, i.v.); 2330 mglkg (M, p.0.); 1300 mglkg (R, p.0.) CN: N-(2-mercapto- 1 -oxopropy 1)glycine monosodium salt RN: 2015-25-0 MF: C,H,NNaO,S MW: 185.18 LD,,: 2 100 mgkg (M, i.v.) 2-bromo- glycine propionyl bromide N-(2-brornopropionyl)- glycine Reference(s): FR 1491 204 (Santen; appl. 10.8.1962; J-prior. 2.1 1.1961). FR-M 3 081 (Santen; appl. 22.10.1962; J-prior. 2.1 1.1961). GB 1 023 003 (Santen; appl. 14.9.1962). use as mucolytic agent: GB 1 482 651 (Lab. Cassenne; appl. 16.9.1974; USA-prior. 14.9.1973). US 3 857 951 (Lab. Cassenne; 3 I .I 2.1 974; appl. 14.9.1973). against nosotoxicosa: US 3 897 480 (Santen; 29.7.1975; J-prior. 3.10.1972, 11 S.1973). sodium salt: DOS 2 924 231 (P. Gargani; appl. 15.6.1979; I-prior. 16.6.1978). Formulation(s): amp. 100 mg, 250 mg; drg. 100 mg, 250 mg; gran. 150 mg, 350 mg; tabl. 100 mg Trade Name(s): D: Captimer (Fresenius) Thiola (Coop. Farm.) USA: Thiola (Mission) F: Acadione (Cassenne) Thiosol (Coop. Farm.) 1: Mucolysin (Farmila) J: Thiola (Santen) Tiotixene (Thiothixene) ATC: N05AF04 Use: neuroleptic RN: 3313-26-6 MF: C,,H,,N,02S2 MW: 443.64 LD,,: 100 mglkg (M, i.p.); 55 mgkg (R, i.p.) CN: (~-N,N-dimethyl-9-[3-(4-methyl-l-piperazinyl)propylidene]-9H-thioxanthene-2-sulfonamide 2052 T Tiotixene dihydrochloride dihydrate RN: 221 89-3 1-7 MF: C,,H2,N,02S2 .2HC1. 2H20 MW: 552.59 1. SOCI, 2. FH3 H N, QJ"JJso3'" 1. thionyl 9H-thioxonthene OCid 9H-thioxonthene-2- chloride 2-dimethylominosuifonyl- sulfonic acid " dimethy'- 9H-thioxanthene (U) omine (1) 1. C4H9Li 2'H3c&,/c~3 I1 1. butyllithium formaldehyde 2. methyl acetate 9-ocetyl-2-dimethylomino- sulfonyl-9H-thioxonthene barohvdride 1 -methyl- piperozine P0Cl3 phosphoryl chloride / \ \ I I/ 0 (N) Tiotixene Reference(s): US 3 310 553 (Pfizer; 21.3.1967; appl. 26.4.1963; prior. 25.9.1962). DE 1 470 157 (Pfizer; appl. 24.9.1963; ~~~-~rior 25.9.1962; 26.4.1963). Muren, J.F.; Bloom, B.M.: J. Med. Chem. (JMCMAR) 13, 17 (1970). Formulation(s): cps. 1 mg, 2 mg, 4 mg, 5 mg, 10 mg; tabl. 10 mg; vial 4 mg, 10 mg (as hydrochloride) Trade Name(s): D: Orbinamon (Pfizer); wfm I: Navane (Pfizer); wfm USA: Navane (Pfizer); wfm GB: Navane (Pfizer); wfm J: Navane (Taito Pfizer) Tioxolone T 2053 Tioxolone ATC: DlOAB03 Use: antiseborrheic RN: 4991-65-5 MF: C7H,0,S MW: 168.17 EINECS: 225-653-0 CN: 6-hydroxy- 1,3-benzoxathiol-2-one resorcinol ammonium rhodanide 1 Tioxolone I Reference(s): US 2 332 418 (Winthrop; 1943; D-prior. 1938). use: US 2 886 488 (Thomae; 12.5.1959; D-prior. 2.7.1955). Formulation(s): sol. 200 mgllOO g in comb. with 100 mg benzoxonium chloride Trade Name(s): D: Loscon (Ga1derma)-comb. I: Wasacne (IFI); wfm J: Vikura (Eisai) F: GBacnine (Lab. du D'Furt); Wasacne (Wassermann); wfm wfm Tipepidine ATC: R05DB24 Use: antitussive RN: 5169-78-8 MF: CI5Hl7NS2 MW: 275.44 LD,,: 55 mglkg (M, i.v.); 867 mglkg (M, p.0.); 44 mglkg (dog, i.v.) CN: 3-(di-2-thienylmethy1ene)-1-methylpiperidine 4'-hydroxybenzophenone 2-carboxylate (1:l) RN: 31139-87-4 MF: C,sH,7NS2. C,,H,,O, MW: 517.67 EINECS: 250-481-8 LD6 10 g/kg (M, p.0.); 10 g/kg (R, p.o.1 ' citrate RN: 5169-77-7 MF: Cl5Hl7NS2~ xC,H807 MW: unspecified Z-thienyl- 0 H3C 0 0 magnesium bromide ethyl nicotinate dimethyl sulfate - - 2054 T Tiauizium bromide Reference(s): ES 272 195 (A. Gallardo; appl. 20.1 1.1961). (also citrate) further literature see under citrate below 4'-hydroaybenzopherrone-2-carboqlate (hibenzate): JP 17 591 (62') (Tanabe Seiyaku; appl. 27.10.1962; prior. 19.10.1960). GB 924 544 (Tanabe Seiyaku; valid from 7.12.1961; J-prior. 19.12.1960). citmte: Ponomarev, A.A.; Martemjanova, N.I.: Khim. Geterotsikl. Soedin. (KGSSAQ) 1957, 174. SU 176 903 (Ponomarev, Martemjanova; appl. 27.10.1 962). Formulution(s): powder 10 %; syrup 25 mg (as hibenzate); tabl. 10 mg (as citrate) Trade Name($): I: Asverin (ISF); wfm Asverin-H (Tanabe; as Hustopan-Syr. (0hta)- Asverin (Searle); wfm hibenzate) comb. J: Asvenne (Tanabe Seiyaku) Hustopan (0hta)-comb. Tiquizium bromide ATC: A03 Use: antispasmodic RN: 71731-58-3 MF: C,,H,,BrNS2 MW: 410.44 LD,,,: 10.3 mglkg (M, i.v.1; 578 mg/kg (M, p.0.); 11.4 mglkg (R, i.v.); 1177 mglkg (R, p.0.); 14.2 mgkg (dog, i.v.); 662 mgfkg (dog, p.0.) CN: truns-3-(di-2-thienylmethylene)octahydro-5-methyl-2H-quinolizinium bromide SOCI, b I thionyl 2-piperidine- ocrylonitrile 1 -(2-cyonoethyl)- chloride ethanol 2-piperidineethonol F Tiracizine T 2055 ___+ \ 2. methyl - bromide 2-thienyl- magnesium bromide 1 Tiquiiium bromide US 4 205 074 (Hokuriku; 27.5.1980; appl. 1.3.1979; prior. 10.5.1978). DOS 2 820 687 (Hokuriku Pharm.; appl. 11.5.1978; J-prior. 16.5.1977, 9.1 1.1977, 8.12.1977,21.12.1977, 28.2.1978). Koshinaka, E. et al.: Chem. Pharm. Bull. (CPBTAL) 27, 1454 (1979). Trade Name(s): I: Thiaton (Hokuriku; 1984) Tiracizine ATC: COlEBll Use: antiarrhythmic RN: 83275-56-3 MF: C,,H2,N3O, MW: 367.45 CN: [5-[(dimethylamino)acetyl]-l0,1l-dihydro-5H-dibenz[b~azepin-3-yl]carbamic acid ethyl ester monohydrochloride RN: 78816-67-8 MF: C2,H2,N30, . HCI MW: 403.91 LD,: 5.4 mglkg (M, i.v.); 48 mglkg (M, p.0.); 10.9 mglkg (R, i.v.); 78 mglkg (R, p.0.) 1. Fe. NH, 2. KOH + '''fCH3 *NO3. *$SO4 0 , a 3'Cl'O"CH3, , H 3. ethyl O CH, chlorotormate I0,l 1-dihydro-5H- OCetyl 3-nitro-5-acetyl- 10.1 1 - dibenz[b,f]azepine chloride dihydro-5H-dibenz- azepine (I) Reference(s): DE 3 040 085 (VEB Arzneimittelwerk Dresden; appl. 24.10.1980; DDR-prior. 5.1 1 .l97l). FR 2493 314 (VEB Arzneimittelwerk Dresden; appl. 5.1 1.1980). DD 258 224 (VEB Arzneimittelwerk Dresden; appl. 5.3.1987). Skoldinov, A.P. et al.: Khim. Farm. Zh. (KHFZAN) 24,51 (1990). DD 267 630 (VEB Arzneimittelwerk Dresden; appl. 25.5.1987). chloroacetyl Tirocizine chloride 2056 T Tirilazad mesilate alternative synthesis of 3-amino-5-acetyl- l0,lI -dihydro-5H-dibenzlb flazepine: US 3 056 774 (Geigy; 1962; appl. 1959; CII-prior. 1958). Formulation(s): f. c. tabl. 50 mg, 100 mg Trade Nnme(s): D: Bonnecor (Arzneimittelwerk Dresden; 1990); wfm Tirilazad mesilate (U-74006) ATC: N07XXOl Use: lipid peroxidation inhibitor RN: 110101 -67-2 MF: C3,HS2N6O2. CH,03S MW: 720.98 CN: (16a)-21-[4-(2,6-di-l-pyrrolidinyl-4-pyrimidinyl)-l -piperazinyl]-l6-methylpregna-l,4,9(11)-triene-3,20- dione monomethanesulfonate hydrate RN: 11 1793-42-1 MF: C3RH52Nh02. CH403S . H20 MW: 739.00 tirilazad RN: 110101-66-1 MF: C3,H5*Nh02 MW: 624.87 ml CNH C'yy CI H THF, 0-20 OC 3 pyridine. 100 % NyN N YN -1 piperozine C I 2.4,6-trichloro- pyrrolidine 6 4-chloro-2.6- pyrimidine dipyrralidina- pyrimidine [ 1. K2C03. CH3CN. 60 OC * 2. H3C-S03H ,,,cH, - NyN + 2. methanesulfanic acid 6 1-(2,6-dipyrrolidino- 21-iodo-16a-methyl- ,4-pyrimidiny1)- pregna-1,4,9(11)- piperozine (I) triene-3.20-dione CH,-SO,H Tirilozod mesilote Reference(s); WO 8 701 706 (Upjohn Co.; appl. 28.8.1986; USA-prior. 29.7.1986, 12.9.1985). ppppppppp Tirofiban hydrochloride T 2057 use in the treatment of ischemic diseases: WO 9 412 185 (Upjohn Co.; appl. 2.12.1993; J-prior. 3.12.1992). use for chemotherapy: WO 9 21 8 089 (Upjohn Co.; appl. 27.3.1992; USA-prior. 9.4.1991). use for treatment ophthalmic disorders: WO 9 119 482 (Upjohn Co.; appl. 26.12.1991; USA-prior. 12.6.1990). Formulafion(s): amp. 45 mgl30 ml, 105 mgl70 ml; vial 45 mg, 105 mg (as hydrate) Trade Name(s): AU: Freedox (Pharmacia & Upjohn) Tirofiban hydrochloride (L 700462; MK 383) ATC: BOlAC17 Use: platelet aggregation inhibitor, GPIIbI IIIa receptor antagonist RN: 142373-60-2 MF: C2,H3,N2OsS . HCl MW: 477.07 CN: N-(Butylsulfonyl)-O-[4-(4-piperidinyl)butyl]-~-tyrosine hydrochloride monohydrate RN: 150915-40-5 MF: C2,H,,N2OsS . HCl . H,O MW: 495.08 base RN: 144493-65-5 MF: C2,H,6N20sS MW. 440.61 1. BSTFA, A. CH3CN 2. 0 \\SA/\cH3 , pyridine c" \; HO 5. 15% KHSO, 1. N.O-bis(trimethylsily1)- trifluoroocetomide 2. butonesulfonyl L-tyrosine chloride N-(butylsulf0nyl)- L-tyrosine (I) KOH, KI, - 'CH, /s\; = 0 <COOH 4-(4-pyridiny1)- butyl chloride (U) 1. H2. Pd-C, CH,COOH 2. HCI 111 + - HCI H N COOH i Tirofibon hydrochloride 2058 T Tirofiban hydrochloride @ synthesis of mterrnediote 11: Br-CI , THF BuLi, THF 3-brorno-1 -chloro- 44coline propone 2. TOOH EM,, THF , Boc /N 4-pyridine- ocetic acid N-(tert-butyloxy- corbony1)-4-pipe- ridineocetic acid 2. (rnethoxycorbonylmethylene)- N-(tert-butyloxy- triphenylphosphorone methyl 4-[N-(tert-butyl- corbony1)-4-pipe- oxycorbonyl)piperidin-4-yl] ridineethonol (N) but-2-enoate (V) 1. Hz. PIC, ethyl acetate 1. I 2. NaOH 2. NOH, DMF 3. BH, 3. chrornatogrophy 4. PPh3. CBr, 4. HCI, ethyl acetate v * - * 4-[N-(tert-butyloxy- carbony1)piperidin- 4-yl]butyl bromide PPh3, THF 1. Hz. Pd-C (i-PrOZCN)2 2. HCI yoH + 1 - 1 - N / Reference($): a US 5 206 373 (Merck+ Co.; 1.9.1993; USA-prior. 28.2.1992). Chung, J.Y. et al.: Tetrahedron (TETRAB) 49 (26), 5767 (1993). b EP 478 363 (Merck+ Co.; appl. 27.9.1991; USA-prior. 30.8.1990). Egbertson, MS. et al.: J. Med. Chem. (JMCMAR) 37,2537 (1994). c WO 9 316 994 (Merck + Co.; appl. 24.2.1993; USA-prior. 28.2.1992). Tiropramide T 2059 alternative synthesis: US 5 292 756 (Merck + Co.; 8.3.1994; USA-prior. 30.8.1991, 27.9.1990). pharmaceutical compositions: US 5 733 919 (Merck + Co.; 31.3.1998; USA-prior. 23.10.1996). WO 9 715 328 (Merck + Co.; appl. 23.10.1996; USA-prior. 27.10.1995). Formulation(s): sol. for inj. 0.05 mglml, 0.25 mglml; vial 50 ml, 0,25 mglml Trade Name(s): D: Aggrastat (Merck Sharp & USA: Aggrastat (Merck Sharp & Dohme; 1998) Dohmc; 1998) Tiropramide ATC: A03AC05 Use: antispasmodic RN: 55837-29-1 MF: C,,H,,N,O, MW: 467.65 LD,,: 40.5 mglkg (M, i.v.); 550 mgkg (M, p.0.); 33.9 mgkg (R, i.v.); 800 mg/kg (R, p.0.) CN: (+_)-a-(benzoylamino)-4-[2-(diethylamino)ethoxy]-N,N-dipropylbenzenepropanamide hydrochloride RN: 57227-16-4 MF: C,,H,,N,O, , xHC1 MW: unspecified EINECS: 260-634-0 LD,,: 28 mglkg (M, i.v.); 639 mglkg (M, p.0.); 32 mglkg (R, i.v.); 1074 mgkg (R, p.0.) 0 HO DL-tyrosine benzoyl (+)-0,N-dibenzoyltyrosine (I) chloride I. acetone, N(c~H~),, CICOOC~H~ H3CeN-CH3 2. HJC~N-CHJ H 1 2. dipropyiornine (11) IN NaOH. CH,OH. 6 h. ambient temp. II . HO N-benzoyi-DL-tyrosine- dipropylamide (111) 2060 T Tixocortol ~ivalate Reference(s): DOS 2 503 992 (Rotta Research; appl. 31.1 .l975; I-prior. 1.2.1974). US 4 004 008 (Rotta Research; 18.1.1977; I-prior. 1.2.1974). 2-diethylomino- ethyl chloride Formulation(s): amp. 50 mgl3 ml; s. r. cps. 200 mg; suppos. 200 mg; tahl. 100 mg (as hydrochloridc) Tiroprornide Trade Name(s): D: Alfospas (Opfermann) I: Alfospas (Rottapharm) Maiorad (Rotta Research) Tixocortol pivalate ATC: A07EA05; R01AD07 (Tiocortisol pivalate; Tixocortol trimethylacetate) Use: glucocorticoid RN: 55560-96-8 MF: Cz6H,,0sS MW: 462.65 EINECS: 259-706-4 CN: (1 1 P)-2 1-[(2,2-dimethyl-l -oxopropyl)thio]- I1 ,I 7-dihydroxypregn-4-ene-3.20-dione tixocortol RN: 61951-99-3 MF: Cz,H3004S MW: 378.53 I lg, 17-dihydroxy-3.20- 2,2-dimethyl- I Tixocortol pivalote dioxo-21 -iodo-4-pregnene propanethioic (cf. hydrocortisone ocid 21 -phosphate synthesis) Reference(s): DOS 2 357 778 (Jouveinal; appl. 20.1 1.1973; F-prior. 30.5.1973). synthesis of tixocortol: Schaub, R.E.; Weiss, M.J.: J. Org. Chem. (JOCEAH) 26, 1223 (1961). Formulation(s): clysma 250 mg; nasal spray lg1100 g; susp. 1 gllOO g Trade Name(s): D: Tiovalon (Intersan; 1986); Oropivalone-Bacitracine Pivalone NComycine wfm (Jouveina1)-comb. (Jouveina1)-comb. I? Dontopivalone (Jouveina1)- Pivalone Nasale (Jouveinal; Rectovalone (Jouveinal) comb. 1978) Thiovalone (Eurorga)- comb. . glucocorticoid RN: 5556 0-9 6-8 MF: Cz6H,,0sS MW: 462.65 EINECS: 25 9-7 0 6-4 CN: (1 1 P )-2 1-[ (2,2-dimethyl-l -oxopropyl)thio ]- I1 ,I 7-dihydroxypregn-4-ene-3.20-dione tixocortol RN: 6195 1-9 9-3 MF: Cz,H3004S. H3C-S03H ,,,cH, - NyN + 2. methanesulfanic acid 6 1-( 2,6-dipyrrolidino- 21-iodo-16a-methyl- ,4-pyrimidiny1 )- pregna-1,4,9(11 )- piperozine (I) triene-3.20-dione CH,-SO,H Tirilozod. (rnethoxycorbonylmethylene )- N-(tert-butyloxy- triphenylphosphorone methyl 4-[ N-(tert-butyl- corbony1 )-4 -pipe- oxycorbonyl)piperidin-4-yl] ridineethonol (N) but-2-enoate (V) 1. Hz. PIC,