20 mg, 40 mg Trade Natnes: I : Perketan Inverni della Serepress Formenti... iodide 100 mg; vial 100 mg Trade Names: D: Alrheumun Bayer Vital; 1975 Orudis RhGne-Poulenc Rorer F: Bi-Pr
Trang 1Ketamine K 1121
starting material:
Kiihn, M.: J Prakt Chem (JPCPAO) 156 (11), 103 (1940)
b AT 198 263 (Synfarma; appl 1955)
Formulation(s): amp 1 gl5 ml; cps 250 mg
Trade Name(s):
Use: analgesic, anesthetic
LD,,: 77 mgkg (M, i.v.)
CN: (f)-2-(2-~hlorophenyI)-2-(methylamino)cyclohexanone
monohydrochloride
RN: 1867-66-9 MF: C,3H,,CIN0 HCI MW: 274.19 EINECS: 217-484-6
2-chloro- cyclopentyl-
benzonitrilc magnesium
bromide
(2-chloro- benzoyl)- cyclopentone
methylamine
Reference(s):
US 3 254 124 (Parke Davis; 31.5.1966; prior 31.7.1961,29.6.1962)
BE 634 208 (Parke Davis; appl 27.6.1963; USA-prior 29.6.1962)
Formulation(s): amp 50 mg/5 ml, 100 mg/2 ml, 500 mg/lO ml; inj 5 mg/ml, 10 mglml, 25 mglml, 50 mglml
(as hydrochloride)
Trade Name(s):
USA: Ketaject (Bristol); wfm
Trang 21122 K Ketanserin
Use: antihypertensive
CN: 3-[2-[4-(4-fluorobenzoy1)- 1-piperidinyllethyll-2,4(1 H,3H)-quinazolinedione
1 -benzyl-4-cyano- 4-fluorophenyl-
piperidine magnesium
bromide
ethyl chloro-
formate (11)
0
ethyl
anthranilate
1 S0Cl2
2 I11
chlaride
0
4-(4-fluarabenzoyl)- piperidine (111)
3-(2-hydraxyethy1)- 2,4(1 H.3H)-quinozo- linedione (N)
EP 13 612 (Janssen; appl 7.1.1980; USA-prior 8.1.1979, 12.10.1979)
US 4 335 127 (Janssen; 15.6.1982; prior 8.1.1979, 12.10.1979)
alternative synthesis:
EP-appl 98 499 (Ravizza; appl 27.6.1983; I-prior 6.7.1982)
Formulation(s): amp 10 mg/2 ml, 50 mgllO ml; tabl 20 mg, 40 mg
Trade Natne(s):
I : Perketan (Inverni della Serepress (Formenti)
Trang 3Ketazolam K 1123
Use: tranquilizer
LD,,: 2 gikg (M, p.0.);
5 gtkg (R, p.0.)
CN: 1I-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[l,3]oxazino~3,2-d][l,4]benzodiazepine-4,7(6H)-
dione
2 NHJ
-+ CI
bromide
2-amino-5- dimethyl 5-chloro-2-
chlarobenzo- sulfate rnethylomino-
diketene (11)
L-2Ez-J
Ketozolam
H3C
Referenceis):
a US 3 575 965 (Upjohn; 20.4.1971; prior 20.10.1969)
b S~muskovicz, J et al.: Tetrahedron Lett (TELEAY) 1971,3665
DOS 1 947 226 (Upjohn; appl 18.9.1969; USA-prior 19.9.1968, 27.3.1969)
Formulariort(s): cps 15 mg, 30 mg, 45 mg
Trade Name(s):
Trang 41124 K Ketobemidone
Ketobemidone
(Cetobemidone)
Use: analgesic
LD,,,: 14 mglkg (M, i.v.);
10 m g k g (R, i.v.)
CN: 1-14-(3-hydroxy phenyl)-1-methyl-4-piperidiny1]-l-propanone
hydrochloride
RN: 5965-49- 1 MF: C,,H2,N02 HCl MW: 283.80
0rMgACH3
-+ 1
4-(3-methoxypheny1)- Ketobemidone
1 -methyl-4-propionyl-
piperidine (I)
Reference(s):
DRP 752 755 (1 G Farben; appl 1942)
alternative synthesis:
Kiigi, H.; ~ i e s c h e r , K.: Helv Chim Acta (HCACAV) 32,2489 (1949)
Formulation(s): amp 2 mg12 ml, 10 mg/lO ml, 5 0 mg150 ml; tabl 5 mg (as hydrochloride)
Trade Name(s):
Ketoconazole ATC: DO 1AC08; GOlAF11; J02AB02
Use: antimycotic RN: 65277-42- 1 M E C2,H2,C12N404 MW: 53 1.44 EINECS: 265-667-4
LD,,: 32 mglkg (M, i.v.); 618 m g k g (M, p.0.);
86 m g k g (R, i.v.); 166 mglkg (R, p.0.);
23.3 mglkg (dog, i.v.); 178 m g k g (dog, p.0.)
CN: cis- 1 -acetyl-4-[4-[[2-(2,4-dichloropheny1)-2-1 H-imidazol-1 -ylmethyl)- l,3-dioxolan-4-
yl]methoxy]phenyl]piperazine
Trang 5Ketoprofen K 1125
-
2.4-dichloro- glycerol cis-2-(2,4-dichloro- *' imidozole
methyl-1.3-dioxolane
1 NaOH
0
NaH
sodium hydride
OH
1 -ocetyl-4-(4-
hydroxypheny1)-
piperazine
Ketoconazole I
Reference (s):
DOS 2 804 096 (Janssen; appl 3 1.1.1978; USA-prior 3 1.1.1977,21.11.1977)
US 4 335 125 (Janssen; 15.6.1982; prior 31.1.1977)
Formulaiion(s): cream 20 mg/g (2 %); shampoo 2 %; sol 20 mgiml; susp 100mg; tabl 200 mg
Trade Name(s):
Use: analgesic, anti-inflammatory RN: 2207 1-1 5-4 MF: C,,H,,O, MW: 254.29 EINECS: 244-759-8
LD,,: 500 mgkg (M, i.v.); 360 mgkg (M, p.0.);
350 mglkg (R, i.v.); 62.4 mglkg (R, p.0.)
CN: 3-benzoyl-a-methylbenzeneacetic acid
lysine saIt
RN: 57469-78-0 MF: Cz2Hz8NzOs MW 4 0 4 8
Trang 61126 K Ketorolac
3-methylbenzo-
phenone
3-bromomethyl- benzophenone
(3-benzoylphenyl)- diethyl carbonate
acetonitrile (I)
Reference(s):
US 3 641 127 (Rh8ne-Poulenc; 8.2.1972; F-prior 27.1.1967)
DE 1 668 648 (Rhhe-Poulenc; appl 26.1.1968; F-prior 27.l.l967),
methyl
alternative syntheses:
Ketoprofen
DOS 2 646 792 (Mitsubishi Petrochemical; appl 16.10.1976; J-prior 23.lO.l975,31.7.1976)
US 4 097 522 (Aziende Chim Riun Angelini Francesco; 27.6.1978; I-prior 5.6.1975) '
DOS 2 744 832 (LEK; appl 5.10.1977; YU-prior 18.10.1976)
DOS 2 744 833 (LEK; appl 5.10.1977; YU-prior 18.10.1976)
DOS 2 744 834 (LEK; appl 5.10.1977; YU-prior 18.10.1976)
iodide
100 mg; vial 100 mg
Trade Name(s):
D: Alrheumun (Bayer Vital;
1975)
Orudis (RhGne-Poulenc
Rorer)
F: Bi-Proftnid (Specia)
KCtum (MCnarini)
Profhid (Specia)
Toprec (ThCraplix)
GB: Ketocid (Trinity)
Orudis (Rhhe-Poulenc
Rorer)
Oruvail (Rh8ne-Poulenc
Rorer)
Powergel (Searle) I: Artrosilene (Dompt; as lysine salt)
Fastum (Menarini) Flexen (Lifepharma) Isok (San Carlo) Ketartrium (Esseti) Ketodol (Drug Research) Ketofen (Delsaz &
Filippini; as lysine salt) Meprofen (AGIPS) Orudis (Rh8ne-Poulenc Rorer)
Profend (Drug Research) Reuprofen (Terapeutico M.R.)
Salient (Biomedica Foscama) Sinketol (Locatelli) J: Capisten (Kissei) Orudis (Hokuriku) USA: Orudis (Wyeth-Ayerst; 1977)
Oruvail (Wyeth-Ayerst)
Use: non-steroidal anti-inflammatory, analgesic
LD,,,: 200 mglkg (M, p.0.)
CN: (+)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-l-carboxylic acid
Trang 7Ketorolac K 1127
tromethamine salt
RN: 74103-07-4 MF: C,,H,,NO, C4H,,N03 MW: 376.41
monosodium salt
succinimide benzamide chloride
pyrrole (I) dimethyl
sulfide
2-(methylthio)- pyrrole
5-benzoyl-2-(methyl- 6.6-dimethyl-5.7-dioxo- 1 -[2-(4.6-dioxo-2.2-dimethyl-
thio)pyrrole (11) spiro[2.5]octone- 1,3-dioxon-5-yl)ethyl]-2-
4.8-dione (111) (rnethy1thio)-5-benzoylpyrrole (N)
2 HCI , CH OH
J
1 3-chloroperbenzoic
acid
2 rnethonol
1 Ketoroloc I
1 KOH CH30H
2 HCI
'
f
dimethyl 5-benzoyl-1,2- dihydro-3H-pyrrolo[l,2-a]- pyrrole-l , l -dicarboxylate (V)
"W""?rCOOH
1 I11 , NOH
2 HCI
4 KOH CH30H
5 HCI
- ,
0 H o
ocid
Trang 81128 K Ketotifen
2-chloro- pyrrole
2-chloro-5- benzoylpyrrole (VI)
I NOH, DMF
CH3
Reference(s):
a,b US 4 347 186 (Syntex; 31.8.1982; appl 20.10.1980)
US 4 458 081 (Syntex; 3.7.1984; appl 11.6.1982; prior 20.10.1980)
c US 4 873 340 (Syntex; 10.10.1989; appl 29.5.1986)
alternarive synthesis:
DE 2 760 330 (Syntex; appl 13.7.1977; USA-prior 14.7.1976, 23.2.1977)
DE 2 731 678 (Syntex; appl 13.7.1977; USA-prior 14.7.1976,23.2.1977)
US 4 087 539 (Syntex; 5.2.1978; appl 23.2.1977; prior 14.7.1976)
US 4 089 969 (Syntex; 16.5.1978; appl 23.2.1977; prior 14.7.1976; 23.2.1977)
US 4 097 579 (Syntex; 27.6.1978; appl 31.3.1977)
Muchowski, J.M et al.: J Med Chem (JMCMAR) 28,1037 (1985)
synthesis of enantiomers:
EP 264 429 (Wisconsin Ala Res Found.; appl 2.4.1987; USA-prior 6.11.1986, 16.4.1986)
Gazman, A et al.: J Med Chem (JMCMAR) 29,589 (1986)
Formularion(s): amp 10 mg, 15 mg, 30 mg; eye drops 0.5 %; suppos 30 mg; tabl 10 mg (as tromethamine
salt)
Trade Name(s):
Use: antiasthmatic, antihistaminic
LDso: 179 mglkg (M, p.0.)
CN: 4,9-dihydro-4-(l-methyl-4-piperidinylidene)-1OH-henzo[4,5]cyclohepta[1,2-b]thiophen-l0-onc
fumarate
Trang 9Ketotifen K 1129
benzoyl peroxide KOH CH30H
- 1
0 ti-bromosuccinimide 0
4-0x0-9.10-dihydro-
4H-benzo[4.5]cyclo-
hepto[l.2-blthiophene
(cf pizotifen
synthesis)
, THF
1 -methylpiperidin-
chloride
9- ond 10-bromo-4-0x0-4H-
benzo[4.5]cyclohepta[1.2-blthiophene (I)
seporotion over silica gel
2N HCI
_,
I Ketotifen 1
Trang 101130 K Khellin
Reference(s):
DAS 2 11 1 071 (Sandoz; appl 9.3.1971; CH-prior 11.3.1970, 31.7.1970)
US 3 682 930 (Sandoz; 8.8.1972; CH-prior I 1.3.1970,3 1.7.1970)
DOS 2 144 490 (Sandoz; appl 6.9.197 1; CH-prior 24.9.1970,4.2.1971)
US 3 749 786 (Sandoz; 8.8.1972; CW-prior 11.3.1970)
alternative syntheses:
DOS 2 302 970 (Sandoz; appl 22.1.1973; CH-prior 24.1.1972)
US 3 960 894 (Sandoz; 1.6.1976; CH-prior 21.1.1972)
US 4 128 549 (Sandoz; 5.12.1978; prior 19.1.1973, 26.7.1974, 27.2.1976,3.2.1977)
medical use as antiasthmatic:
US 4 073 915 (Sandoz; 14.2.1978; CH-prior 20.5.1975)
Formulation(s): cps 1 mg; syrup 0.02 %; tabl 1 mg, 2 mg (as fumarate)
Trade Name(s):
Use: vasodilator
LDs,,: 30.6 mglkg (M, i.v.); 50.8 mglkg (M, p.0.);
34.4 mglkg (R, i.v.); 68.8 mglkg (R, p.0.)
CN: 4,9-dimethoxy-7-methyl-5H-furo[3,2-g][1]benzopyran-5-one
I Khellin
Isolation from ethanolic extracts of fruits of Umbellifera Ammi visnaga
Reference(s):
Spath, E ; Gruber, W.: Ber Dtsch Chem Ges (BDCGAS) 71, 106 (1938)
Abu-Shady, H.; Soine, T.O.: J Am Pharm Assoc (JPHAA3) 41,481 (1952)
total syntheses:
Baxter, R.H et al.: J Chem Soc (JCSOA9) 1949,30
Clarke, J.R.; Robertson, A.: J Am Chem Soc (JACSAT) 71, 362 (1949)
Clarke, J.R.; Robertson, A,: J Chem Soc (JCSOA9) 1949,302
Geissman, T.A.; Halsall, T.G.: J Am Chem Soc (JACSAT) 73, 1280 (1951)
Formulation(s): cps 10 mg, 12 mg; drg 1.25 mg, 10 mg; drops 50 mgl100 ml; ointment 0.1 g1100 g,
0.01 g1100 g; sol 0.025 gll00 ml; suppos 2.5 mg, 5 mg; tabl 25 mg