25 mg, 100 mg as maleate Trade Names: D: Hexphonal ASTA Medica F: Surmontll Specia Surmontil RhBne-Poulcnc Rorer I: Surmontil RhBne-Poulenc USA: Surmont~l Wyeth-Ayerst Trimipramin-neur
Trang 1Trimipramine 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)
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 m g k g (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, 5 0 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
Rorer) I: Surmontil (RhBne-Poulenc USA: Surmont~l (Wyeth-Ayerst) Trimipramin-neuraxpharm Rorer)
(neuraxpharm)
Trang 22122 T Tripamide
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
1 chlorosul- n thionyl
4-chlorobenzoic
acid
u - '
N H 2 4-chlaro-3-sulf- ornoylbenzoic acid
1 NoN02
2 Zn, CHJCOOH
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 N H 2
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)
JP 7 121 708 (Eisaei; appl 17.8.1967)
Fqrmulation(s); tabl 15 mg
Trade Name(s):
J: Normonal (Eisai; 1982)
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.)
Trang 3Triprolidine 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
Takeda)
PBZ-SR (Geigy); wfm Pyribenzamine (Ciba); wfrn Tripelennamine HCI Tablets (Danbury); wfm
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
-
C H 3 C H 3
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)
Trang 42124 T Tritoaualine
Trade Name(s):
F: Actifed (Warner-Lambert) Pro-Entra (Wellcome-
GB: Sudafed (Warner-Lambert)- Tanabe)
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.);
9 0 m g k g (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
Trang 5Troglitazone T 2125
OH HCI +
CI, 1
/ $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 g k g (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
H 3 C w O H LiAIH4, H * Z H A NaH, THF III
HO HO rnethoxymethyl
(+)-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
H A0 , 0 CI '
(11') p-chloronitro-
benzene
(+)-6-(rnethoxyrnethoxy)-
2.5.7.8-tetrarnethyl-2-
(4-nitrophenoxyrnethyl)-
chrornon (N)
Trang 62126 T Troglitazone
tetromethylchromon (VI)
1 NoN02, H20,
HCI, ocetone
2 HZC'+OvC"3
0
CupO 40 O C
VI _*
2 ethyl acrylote
CH3
NoOH C2H50H THF
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-
Trang 7Troglitazone T 2127
1 HZ Pd-C DMF
2 Clr\O/CH3 ,
NOH, THF
3 H~C-L~ ,H3C 1 H 3 c w, 0 n c H 3
'0-0
methyl vinyl
ketane
2 V , pyridine
H3C
6-hydroxy-2-methoxy-
2,5,7,8-tetramethyl-
chromane (XI)
1 OMF
2 HCI 90 O C
4-bromo-3-methyl- 2-butenyl acetote (XN)
XIV
HO H c K ??
0
4-(p-nitrophenoxy)-3- methyl-2-butenyl ocetate (XV)
Trang 82128 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
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
+ H 3 C r 0 - - 7 + M X pyrrol~dtne
5'-ocetoxy-2'-hydrony-
3.4'6-trimethyi-
ocetophenone
1 NaBH,, C H P H
J N
0 2 Tos-OH, benzene
3 Hz Pd-C CHJOH
CH30
6-acetoxy-2.5.7.8-tetromethyl-
2-(4-nitrophenoxyrnethy1)-
Trang 9Troglitazone T 2129
@ intermediate 11:
s-collidine, -40°C
CH3S,CH3
1 H, Pd
2 HCI
2-methyl-2- viny loxirane
Trang 101
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):
Warner-Lambert); wfm
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)