combinations: with estrogenes for treatment of osteoporosis: WO 9 214 474 Norwich Easton Pharmaceuticals; appl.. with parathyroid hormone for treatment of osteoporosis: WO 9 607 418 P
Trang 1Tiludronate disodium T 2041
tetroisopropyl
methylenedi-
phosphonote
1 12N oq HCI
2 oq NoOH
1 -
tetroisopropyl (4-chloro phenylthio)methylenedi- phosphonote (1)
ONa
HO-P-ONa
II
0
Tiludronote disodium
Ohnishi, H.; Nakamura, T.; Tsurukami, H.; Murakami, H.; Abe, M.; Barbier, A,: Bone Miner (BOMIET) 25 (Suppl I), Abstr 1 1 (1994)
synthesis:
EP 100 718 (Sanofi; appl 25.7.1983; F-prior 29.7.1982)
monohydrate of the disodium salt:
EP 582 515 (Elf Sanofi; appl 3.8.1993; F-prior 5.8.1992)
pharmaceutical preparations:
WO 9 617 616 (Sanofi; appl 5.12.1995; F-prior 6.12.1994)
WO 9 641 618 (Sanofi Winthrop; appl 4.6.1996; USA-prior 8.6.1995)
pharmaceutical compositions:
W 0 9 530 421 (Ciba-Geigy AG; appl 16.1 1.1995; GB-prior 4.5.1994)
JP05 105 632 (Meiji Seika Kaisha; appl 27.4.1993; J-prior 6.6.1991)
EP 336 851 (Sanofi; appl 11.10.1989; F-prior 7.4.1988)
combinations:
with estrogenes for treatment of osteoporosis:
WO 9 214 474 (Norwich Easton Pharmaceuticals; appl 3.9.1992; USA-prior 26.2.1991)
WO 9 414 455 (Merck & Co.; appl 7.7.1994; USA-prior 23.1 2.1992)
with parathyroid hormone for treatment of osteoporosis:
WO 9 607 418 (Procter and Gamble Company; appl 14.3.1996; USA-prior 9.9.1994)
WO 9 607 417 (Procter and Gamble Company; appl 14.3.1996; USA-prior 9.9.1994)
with growth hormone secretagogues for treatment of osteoporosis:
W09 511 029 (Merck & Co.; appl 27.4.1995; USA-prior 19.10.1993)
Formulation(s): tabl 200 mg, 240 mg (as sodium salt hemihydrate)
Trade Name(s):
D: Skelid (Sanofi Winthrop) F: Skelid (Sanofi Winthrop) USA: Skelid (Sanofi)
Trang 22042 T Timepidium bromide
Use: antispasmodic, anticholinergic RN: 35035-05-3 MF: C,,H2,BrNOS2 MW: 400.41
LD,,,: 12 mglkg (M, i.v.); 713 mgkg (M, p.0.);
7 mglkg (R, i.v.); 1213 mglkg (R, p.0.)
CN: 3-(di-2-thienylmethylene)-5-methoxy-1,1-dimethylpiperidinium bromide
1 CH30H HCI
CuSO,, Cu 3 H Raney-Ni
sulfate
5 - b r o m o -
nicotinic acid
methyl N-methyl-5- methoxynipecotate (1)
1 HCI
'0
-
magnesium
bromide
Reference(s):
US 3 764 607 (Tanabe Seiyaku; 9.10.1973; appl 3.6.1971; J-prior 11.6.1970)
FR 2 100 750 (Tanabe Seiyaku; appl 28.4.1972; J-prior 11.6.1970)
DOS 2 128 808 (Tanabe Seiy-aku; appl 9.6.1971; J-prior 11.6.1970)
Kawazu, M et al.: J Med Chem (JMCMAR) 15,914 (1972)
Formulation(s): cps 30 mg; vial 7.5 mg
Trade Name(s):
I : Mepidium (Recordati; J: Sesden (Tanabe Seiyaku;
Use: neuroleptic, antipsychotic RN: 57648-21-2 MF: C22H,4FN,0S MW: 397.52 EINECS: 260-880-9
LD,,,: 500 mglkg (M, p.0.);
>I 2.1 mglkg (R, i.v.); 232 mglkg (R, p.0.);
20 m g k g (dog, i.v.1; 85 mglkg (dog, p.0.)
CN: 4-[4-(2,3-dihydro-2-thioxo- 1 H-benzimidazol-1 -yl)- 1 -piperidinyl]- 1 -(4-fluoropheny1)- 1-butanone
Trang 3Timolol T 2043
4-chloro-4'-iluoro- ethylene
butyrophenone glycol
(cf haloperidol
synthesis)
*
carbon disufide
H
4-(2-nitro-
anilina)-
piperidine (n)
1 Timiperone
1 Hz, Roney-Ni
2 C S 2 KOH
NO2
Referencefs):
DOS 2 526 393 (Daiichi Seiyaku; appl 13.6.1 975)
US 3 963 727 (Daiichi Seiyaku; 15.6.1976; J.-prior 6.6.1975)
Sato, M et al.: J Med Chem (JMCMAR) 21, 11 16 (1978)
alternative syntheses:
Sato, M ; Arimoto, M.: Chem Pharm Bull (CPBTAL) 30,719 (1982)
Trade Narnefs):
J : Tolopelon (Daiichi
Seiyaku; 1984)
- -
SOlEDOl Use: beta blocking agent, antiglaucoma agent, antianginal, antiarrhythmic RN: 26839-75-8 MF: C,,H,,N,O,S MW: 316.43 EINECS: 248-032-6
CN: @)-]-[(I ,I-dimethylethyl)amino]-3-[[4-(4-morpholiny1)- 1,2,5-thiadiazol-3-yl]oxy]-2-propanol
Trang 42044 T Timolol
maleate
RN: 26921-17-5 MF: C,3H,N40,S C4H404 MW: 432.50
3.4-dichlaro- rnorpholine 3-chloro-4- 3-hydroxy-4-
1,2,5-thiadiazole (I) thiadiazole (11)
epichlorohydrin
rocemote resolution with
(+)-tortark acid
N _ _ _ _ _ _ _ ,
OHC<OH + IIl H*, Pd-C
OH
C H 3
isopropylidene-
D-glyceroldehyde
Reference(s):
US 3 619 370 (C E Frosst & Co.; 9.11.1971; appl 21.4.1969)
DOS 1 925 956 (C E Frosst & Co.; appl 21.5.1969; USA-prior 21.4.1969)
DOS 1 925 954 (C E Frosst & Co.; appl 21.5.1969; USA-prior 21.4.1969)
US 3 655 663 (C E Frosst & Co.; 11.4.1972; appl 21.4.1969; prior 22.5.1968) DAS 1 925 956 (C E Frosst & Co.; appl 21.5.1969; USA-prior 22.5.1968, 21.4.1969) DOS 1 925 955 (C E Frosst & Co.; appl 21.5.1969; USA-prior 21.4.1969)
US 3 657 237 (C E Frosst & Co.; 18.4 1972; appl 21.4.1969)
US 3 718 647 (C E Frosst & Co.; 27.2.1973; USA-prior 21.4.1969, 16.8.1971)
US 3 729 469 (C E Frosst & Co.; 24.4.1973; prior 22.5.1968, 21.4.1969,9.9.1971)
US 3 812 182 (C E Frosst & Co.; 21.5.1914; piorL21.4.19~9,16.8.1971 1&6.LP73L
Trang 5Timonacic T 2045
alternative synthesis:
US 4 145 550 (Merck Sharp & Dohme; 20.3.1979; prior 7.8.1975, 8.2.1977, 21.9.1977)
0-acyl-derivatives:
US 3 891 639 (Merck Sharp & Dohme; 24.6.1975; appl 19.4.1973)
US 4011 217 (Merck Sharp & Dohme; 8.3.1977; appl 26.2.1975; prior 19.4.1973)
combinations with diuretics:
US 4 178 374 (Merck & Co.; 11.12.1979; prior 16.8.1974,3.3.1975, 21.10.1976, 10.4.1978)
GB 1 495 034 (Merck & Co.; appl 11.8.1975; USA-prior 16.8.1974, 3.3.1975)
medical use for treatment of glaucoma:
GB 1 524 405 (Merck & Co.; appl 23.9.1976; USA-prior 26.9.1975)
Fonulation(s): eye drops 1 mg/ml, 2.5 mg/ml, 5 mglml, 1 mg/ml (as maleate); tabl 5 mg, 10 mg, 20 mg (as
maleate); tabl 25 mg in comb with hydrochlorothiazide
Trade Name(s):
D: Arutimol (Chauvin
ankerpharm)
Chibro-Timoptol (Chibret;
1979)
dispatim (CIBA Vision)
duratimol (durachemie)
Moducrin (Merck Sharp &
Dohme; 1978)-comb
Timo-COMOD
(Ursapharm)
Timo E D 0 (Mann)
Timohexal (Hexal)
Timolol-ratiopharm
(ratiopharm)
Timomann (Mann)
Tim-Ophthal (Winzer)
Timosine (Chibret)
Timo-Stulln (Pharma
Stulln)
F: Digaol (Leurquin)
Gaoptol (Eurphta)
Moducren (Merck Sharp & I:
Dohme-Chibret)-comb
Nyolol (CIBA Vision Ophthalmics) Ophtim (ThCa) Timabak (ThCa) Timacor (Merck Sharp &
Dohme-Chibret) Timoptol (Merck Sharp &
Dohme-Chibret) numerous combination
GB: Betim (Leo; as maleate) USA:
Blocadren (Merck Sharp &
Dohme; 1974) Glaucol (Baker Norton) Moducren (Morson)-comb
Prestim (Leo)-comb
Timoptol (Merck Sharp &
Dohme)
Blocadren (Merck Sharp & Dohme)
Cusimolol (Alcon) Droptimol (Farmigea) Equiton (Bruschettini)- comb
Oftimolo (Farm~la) Timicon (Merck Sharp & Dohme)-comb
Timoptol (Merck Sharp & Dohme)
Timoptol (Merck-Banyu) Blocadren (Merck Sharp & Dohme; 1983)
Timolide (Merck Sharp & Dohme; 1981)
Timoptic (Merck Sharp & Dohme; 1978)
generics
Timonacic
(Thiazolidincarbonsaure)
ATC: A05 Use: liver therapeutic, choleretic RN: 444-27-9 MF: C4H7N02S MW: 133.17 EINECS: 207-146-6
LD,,: 400 mglkg (M, p.0.);
875 mg/kg (R, p.0.)
CN: 4-thiazolidinecarboxylic acid
arginine salt
RN: 57631-15-9 MF: C4H7N02S C6HI4N4O, MW: 307.38
L-cysteine forrnoldehyde ( Tirnonocic I
Trang 62046 T Tinazoline hydrochloride
Reference(s):
FR-M 3 184 (Sogespar; appl 4.2.1963)
Formulation(s): drinking amp 100 mg (as arginine salt); tabl 400 mg
Trade Name(s):
F: Hkpalidine (Riker- Tiadilon (Dexo; as arginine Tiazolidin (Solvay Pharma)
Thiohiline (Riker); wfm I: Sulfile (Poli)
Use: vasoconstrictor, nasal decongestant RN: 55107-60-3 MF: C , , H I I N , S ~ HCI MW: 253.76
CN: 3-[(4,5-dihydro-IH-imidazol-2-yl)thio]-1 H-indole rnonohydrochloride
tinaznline
RN: 62882-99-9 MF: CIIHllN3S MW: 217.30
ethylene
diomine
ethylene- thiourea
tinomline hydriodide (I)
ion exchange (Amberlite IRA 400)
I
I Tinazoline hydrochloride I
DOS 2 427 207 (Ciba-Geigy; appl 6.5.1974; CH-prior 14.6.1973)
Nagarajan, N et al.: Indian J Chem (IJOCAP) 20B, 672 (1981)
synthesis of ethylenethiourea:
DOS 2 703 31 2 (Bayer, appl 27.1.1977)
Trade Nume(s):
I N : Varsyl (Ciba-Geigy; 1988)
Use: chemotherapeutic (trichomonas), antiprotozoal, antiamebia RN: 19387-91-8 MF: CRH,,N,04S MW: 247.28 EINECS: 243-014-4
LD,,,: >250 mglkg (M i.v.); 3200 mglkg (M, p.0.);
>250 mglkg (R, i.v.); 2710 mglkg (R, p.0.)
CN: 1 -[2-(ethylsulfo1~yl)ethyI]-2-methyl-5-nitro-lH-imidazole
Trang 7Tinoridine T 2047
p-toluenesulfonyl 2-(ethylsulfonyl)
chloride ethanol
2-methyl-5-
nitroirnidozole
2-(ethylsulfonyl)ethyl p-toluenesulfonote (I)
Tinidozole
Reference(s):
US 3 376 31 1 (Pfizer; 2.4.1968; appl 5.8.1966; prior: 26.10.1964)
DAS 1 745 780 (Pfizer; appl 8.2.1967; USA-prior 5.8.1966)
Miller, M.W et al.: J Med Chem (JMCMAR) 13, 849 (1970)
Formulation(s): f c tabl 1 g
Trade Name(s):
D: Simplotan (Pfizer; 1971) I: Fasigin N (Pfizer) USA: Fasigyn (Pfizer); wfm F: Fasigyne 500 (Pfizer) Trimonase (Tosi-Novara) Simplotan (Pfizer); wfm GB: Fasigyn (Pfizer; 1982) J: Fasigyn (Pfizer Taito)
Use: analgesic, anti-inflammatory RN: 24237-54-5 MF: C,7H2,N202S MW: 316.43 EINECS: 246-102-0
LD,,: 5.4 g k g (M, p.0.);
>10.2 glkg (R, p.0.)
CN: 2-amino-4,5,6,7-tetrahydro-6-(phenylmethyl)th1eno[2,3-]pyridine-3-carboxylic acid ethyl ester
monohy drochloride
RN: 25913-34-2 MF: C,7H2,N202S HC1 MW: 352.89 EINECS: 247-342-9
LD,,,: 1601 mgkg (M, p.0.);
1200 mgkg (R, p.0.)
A
S O d H , C2H50H
1 -benzyl-4- ethyl cyono
piperidone ocetote
Tinoridine
DE 1 812 404 (Yoshitomi; appl 3.12.1968; J-prior 4.12.1967)
US 3 563 997 (Yoshitomi; 16.2 1971; J-prior 4.12.1967)
Formulation(s): cps 50 mg, 100 mg (as hydrochloride)
Trang 82048 T Tiocarlide
Trade Name(s):
J : Nonflamin (Yoshitomi)
Tiocarlide
(Thiocarlide)
ATC: J04AD02 Use: tuberculostatic, leprostatic
RN: 91 0-86- 1 MF: C23H32N202S MW: 400.59 EINECS: 213-006-5
CN: N,hr-bis[4-(3-methylbutoxy)phenyl]thiourea
isopentyl 4-nilrophenol 4-isopentyloxy- 1 -
aniline (I)
Re&rence(s):
US 2 703 815 (Ciba; 1955; appl 1951)
Trade Name(s):
Pharma); wfm
Use: anticoagulant
RN: 22619-35-8 MF: C22H,6C1204S M W : 447.34 EINECS: 245-132-1
CN: 3-[3-(4-chlorophenyl)-I-(5-chloro-2-thienyl)-3-hydroxypropyl]-4-hydroxy-2H-l-ben~opyran-2-one
CHO
~)5
CI
-+I
4-hydroxy-
4'-chloro- 2-chlaro-5-
acetophenone thiophene-
carboxoldehyde
Trang 91"
Tioconazole T 2 0 4 9
AI[O-CH(CH3)2]3, isoproponol
b oluminum isopropylote
Tioclomorol
Reference(s):
ZA 6 707 267 (Lipha; appl 7.8.1968; F-prior 13.1 1.1967; 13.12.1966)
Formulation(s): tabl 4 mg
Trade Name(s):
F: Apegmone (Lipha SantC)
Use: antimycotic, topical antifungal RN: 65899-73-2 MF: C,,H,3C13N,0S MW: 387.72 EINECS: 265-973-8
LD,,: 1870 mgkg (M, p.0.);
770 mglkg (R, p.0.)
CN: 1-[2-[(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl]-lH-imidazole
1 -(2,4-dichloro- 2-chloro-3-
phenyl)-2- (chloromethyl)
(1H-imidazol-1 -yl)- thiophene
ethanol
(cf miconozole
synthesis)
DE 2 619 381 (Pfizer; appl 30.4.1976; GB-prior 30.4.1975)
US 4 062 996 (Pfizer; 13.12.1977; appl 30.4.1976; GB-prior 30.4.1 975)
Formulation(s): cream 10 mglg; lotion 10 mglg; ointment vaginal 6.5 %; powder 1 g1100g; spray 1 g1100g
Trade Name(s):
D: Mykontral (LAW) Trosyd (Pfizer; 1986) J: Trosy (Taito Pfizer; 1984) Trosyl (Pfizer); wfm GB: Trosyl (Pfizer; 1988) USA: Vagistat (Bristol-Myers F: Gyno-Trosyd (Pfizer; 1986) I: Trosyd (Roerig) (Irbi) Squibb)
Trang 102050 T Tioguanine
Tioguanine
(Thioguanine)
ATC: LOlBB03 Use: antineoplastic
RN: 154-42-7 MF: C,H,NSS MW: 167.20 EINECS: 205-827-2
LD,,,: 160 mglkg (M, p.0.)
CN: 2-amino-l,7-dihydro-6H-purin-6-thione
S
p2s5 phosphorus pentosulfide
Refirence(s):
US 2 697 709 (Burroughs Wellcome; 1954; GB-prior 1951)
US 2 884 667 (Burroughs Wellcome; 1959; prior 1955)
US 2 800 473 (Burroughs Wellcome; 1957; appl 1955)
US 3 019 224 (Burroughs Wellcome; 1962; appl 1955)
US 3 132 144 (Burroughs Wellcome; 5.5.1964; appl 10.7.1959)
Elion, G.B.; Hitchings, G.H.: J Am Chem Soc (JACSAT) 77, 1676 (1955)
Formulation(s): tabl 40 mg
Trade Name(s):
D: Thioguanh-Wellcome 1: Thioguanine Wellcome USA: Thioguanine Tablo~d
GB: Lanvis (Glaxo Wellcome)
Tiomesterone
(Thiomesterone)
ATC: A14 Use: anabolic, androgen
RN: 2205-73-4 MF: C2,H3,04S2 MW: 450.66 EINECS: 218-614-4
CN: (1 a , 7 a , 17P)-1,7-bis(acety1thio)- 17-hydroxy- 17-methylandrost-4-en-3-one
17p-hydroxy-17-methyl- thioocetic Tiornesterone
5 0 x 0 - 1.4,6-androstotriene acid
Reference(sJ:
US 3 087 942 (Merck AG; 30.4.1963; D-prior 29.10.1960)
Kramer, J.M et al.: Chem Ber (CHREAM) 96,2803 (1963),
starting material:
GB 854 343 (British Drug Houses; valid from 4.3.1959; prior 13.3.1958)
Formulation(s): 15 mg, 30 mg