Lorazepam
L
1191
Lorazepam
ATC: N05BA06
Use: tranquilizer, anxiolytic
RN: 846-49-1 MF: C,,H,,C12N202 MW: 321.16 EINECS: 212-687-6
LD,,,: 1850 mgkg (M, p.0.);
4500 mgkg (R, p.0.);
>2 dkg (dog, p.0.)
CN:
7-chloro-5-(2-chlorophenyl)-l,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one
Hz OH
,
cl%-OH
OYCI
CI
,
CHJCOOH
-1
hydroxyl-
'I
chloroacetyl
amine
LJ
chloride
2-amino-2'.5-
dichloro-
benzophenone
6-chloro-2- methyl-
chloromethyl-4- amine

(2-chloropheny1)-
quinozoline
3-oxide (1)
(11) acetic
anhydride
US 3 296 249 (American Home Products; 3.1.1967; appl. 4.6.1963; prior. 29.8.1961, 5.3.1962).
US 3 176 009 (American Home Products; 30.3.1965; prior. 5.3.1962).
GB 1 022 642 (American Home; appl. 28.8.1962; USA-prior. 29.8.1961, 5.3.1962).
GB
1 022 644 (American Home; appl. 28.8.1962; USA-prior. 29.8.1961, 5.3.1962).
GB 1 022 645 (American Home; appl. 28.8.1962; USA-prior. 29.8.1961, 5.3.1962).
CB 1 057 492 (American Home; appl. 29.8.1968; addition to CB 1 022 642).
DE 1 445 412 (American Home; appl. 17.8.1962; USA-prior.
29.8.1961,5.3.1962).
DE 1 645 904 (American Home; appl. 17.8.1962; USA-prior. 29.8.1961,5.3.1962).
DE 1 795 509 (American Home; appl. 17.8.1962; USA-prior. 29.8.1961, 5.3.1962).
Fortnulation(s):
amp. 2 mglml, 4 mdml; tabl. 0.5 mg, 1 mg, 2.5 mg
Trade Name(s):
D: Laubeel (Desitin) Punktyl (Krewel
Pro-Dorm (Synthelabo) Meuselbach)
Somagerol (Brenner-Efeka)
Tavor (Wyeth)
1192
L
Lormetazepam
Tolid (Dolorgiet) Lorans (Schiapparelli J: Wypax (Yarnanouchi)
F: Ternesta (Wyeth-Lederle) Searle) USA: Ativan (Wyeth-Ayerst)
GB: Ativan (Wyeth)
Quait (SIT)

I: Control (Bayropharrn) Tavor (Wyeth)
-
Lormetazepam
ATC:
NO~CDO~
Use: tranquilizer, hypnotic
RN: 848-75-9 MF: C16H12C12N202 MW: 335.19 EINECS: 212-700-5
LDso: 1790 mgkg (M, p.0.);
>10 gkg (R, p.0.)
CN:
7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-I-rnethyl-2H-l,4-benzodiazepin-2-0ne
&CI
Lormetozepam
US
3 295 249 (American Home Products; 3.1.1967; prior. 4.6.1963, 5.3.1962, 29.8.1961).
Formulation(s):
cps. 0.5 rng, 1 mg,
2
mg; tabl. 0.5 mg,
1
mg,
2
mg
Trade Name(s):
D: Ergocalm (Brenner-Efeka) F: Noctamide (Schering) I: Minias (Farmades)
Loretam (Wyeth) GB: Loramet (Wyeth); wfm J: Evamyl (Schering)
Noctamid (Asche;
-
Noctamid (Schering); wfm Loramet (Wyeth)
Schering) generics USA: Loramet (Wyeth); wfm

Lornoxicam
(Chlortenoxicam; Ro- 13-9297)
ATC: MOlACO5
Use: anti-inflammatory, nonsteroid
antiphlogistic agent
RN: 70374-39-9 MF:
C,,H,,CIN,0,S2 MW: 371.83
CN:
6-Chloro-4-hydroxy-2-rnethyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide
1,l-dioxide
2.5-dichloro-
3-thiophene-
sulfonylchloride
Losartan potassium
L
1
193
1.
BuLi. THF.
C02
2.
PCI,
0
H
3.
H~C-OH
c,<;:"~3
I
b
-

I1
methyl 2-
CH3 iodoocetote
methyl 5-chloro-
3-(methylsulfomoyl)-
thiophene-
2-corboxylate
methyl 6-chloro-4-
hydroxy-2-methyl-2H-
thieno[2,3-el-1.2-thiozine-
3-corboxylote
l
.l
-dioxide (111)
xylene
I
+
,zN~
+
Lornoxicom
Reference(s):
DE 2 838 85 1 (Hoffman
~n-La Roche; appl. 6.9.1978; LU-prior. 6.
process for the preparation of
5-chloro-3-chlorosulfonyl-2-thiophenecarbolic
esters:
EP 34 072 (CL Pharma A. G.; appl. 7.4.1989; A-prior. 2.5.1988).
pharmaceutical composi~ion containing
lornoxicam
and

disodium EDTA:
WO 9 809 654 (Nycomed Austria GmbH; appl. 1.9.1997; A-prior. 3.9.1996).
Formulation(s):
tabl. 2 mg,
8
mg
Trade Name(s):
D: Telos (Merckle; 1999) GB: Xefo (Nycomed I: Acabel (Formenti)
Amersham)
Losartan potassium
(DuP-753; MK-954)
ATC: C02EXO1; C09CAO1
Use: antihypertensive, angiotensin I1
blocker
RN: 124750-99-8 MF: C22H22C1KN,0 MW: 461 .O1
CN:
2-butyl-4-chloro-l-[[2'-(1H-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol
monopotassium salt
1194
L
Losartan potassium
2-butyl-4-chloro-
5-hydroxymethyl-
imidozole
preporotion of
I
2-methoxy-
benzoyl
chloride
THF

I
H0qiH3
-
90,cH3
ill
CH,
4-tolylmagnesium
NoN3. NH4CI,
OMF.
120 "C
____+
J
h
0
\N
bromide
N,'
O-C,
VH
N=N~o"-f~~3
CI
Losartan
2-omino-2-
methyl-l-
propanol
0
1. HCI
0
2.
SOC12. NH,OH

benzoyl peroxide
3. SOCI, CC14
N-bromo-
succinimide
CH3
WCH,
CH3
2-(4'-methylbiphenyl- 4-methyl-2'-
2-y1)-4,4-dimethyl- cyonobiphenyl
2-oxozoline
(Ill)
Losartan potassium
L
1
195
NoN3
tributyltin chloride
QBr
-
Trt-CI, NaOH
C
N
methyl
PBr ,Trt
N=N
N,'
Y
chloride N=N
2-brorno-
benzonitrile

Trt:
H
C CH,
Y
BuLi, THF
Y
CH3
N=N
triisopropyl 2-(1 -triphenyl-
borote methyl-1H-
'
phenylboronic
acid (V)
"'wCH3
Na2C0,
(Ph,P)+Pd,
80 "C
-VI
p-brornotoluene,
tetrakis(tripheny1-
5-(4'-methyl-1
-1'-
biphenyl-2-yl)-1-
triphenylrnethyl-
1H-tetrozole (VI)
5-(4'-brorno-
rnethyl-l.la-bi-
phenyl-2-yl)-1-
triphenylmethyl-
1

H-tetrazole (VII)
K2C03
DMA.
0-5
"C
d
1
-(triphenyl-
methyl)-5-
(2-brornopheny1)-
1H-tetrazol
(N)
2-butyl-4-chloro-
1 H-irnidazole-5-
carboxaldehyde
(WI)
2-butyl-4-chloro- 1 -[[2'-
(1 -triphenylrnethyl-1 H-
tetrazol-5-yl)-1 ,l'-bi-
phenyl-4-yl]rnethyl]-
1 H-imidazole-5-carbox-
aldehyde
(M)
1196
L
Losartan potassium
1.
NoBH,,
DMA,
H20

2.
HCI
3.
KOH
1x
-
1.
sodium borohydride
ci
'.
Cosorton
potassium
K2CO3,
DMA,
room
temperature
VI*
+
""9
.
Br
p-bromobenzyl
bromide
ci
'-
2-butyl-4-chloro-l-
(4-bromobenzy1)-1H-
irnidozole-5-corbox-
aldehyde
(X)

K2C03,
toluene,
(Ph3P),Pd.75-81
OC
X+V
-
M
Reference(s):
Larsen, R.D. et al.: J. Med. Chem. (JMCMAR) 59 (21), 6391 (1994).
a
EP 324 377 (Du Pont de Nemours; appl. 5.1.1989; USA-prior. 7.1.1988).
Carini, D.J. et al.: J. Med. Chem. (JMCMAR) 34,2525 (1991).
b,c
Smith, G.B. et al.: J. Org. Chem. (JOCEAH) 59, 8151-8156 (1994).
US 5 130 439 (Du Pont de Nemours; 14.7.1992; USA-prior. 18.11.1991).
US 5 310 928 (Du Pont de Nemours; 10.5.1994; USA-prior. 18.11.1991).
polymorphs of
losartan potassium:
WO 9 517 396 (Merck
&
Co.; du Pont de Nemours; appl. 21.12.1994; USA-prior. 23.12.1993).
preparation of
2-butyl-4-chloro-5-hydroxymethylimidazole:
Beoschelli, D.H.; Connor, D.T.: Heterocycles (HTCYAM) 35 (I), 121-124 (1993).
Shy, Y J.; Frey, L.F.; Tschaen, D.M.; Verhoeven, T.R.: Synth. Commun. (SYNCAV) 23 (18), 2623-2630 (1993).
preparation of
4'-bromomethyl-2-cyanobiphenyl
via bromination with
N-bromosuccinimide:
Tanaka, A. et al.: Bioorg. Med. Chem. (BMECEP) 6 (I), 15-30 (1998).

Huang, H.C. et al.: J. Med. Chem. (JMCMAR) 36
(IS), 2172-2181 (1993).
synthesis of intermediate
V:
Lo, Y.S.; Rossano, L.T.; Meloni, D.J.; Moore, J.R.; Lee, Y C; Arneet, J.F.: J. Heterocycl. Chem. (JHTCAD) 32
(1).
355 (1995).
synthesis of intermediate
VIII:
Griffiths, G.H. et al.: J. Org. Chem. (JOCEAH) 64, 8084 (1999).
Griffiths, G.J.: Chimia (CHIMAD) 51 (6), 283 (1997).
combination with e.
g.
lovastatin:
WO 9 526 188 (Merck
&
Co.; appl. 24.3.1995; USA-prior. 29.3.1994).
new form with specijic properties:
WO 9 517 396 (Merck
&
Co., Du Pont; appl. 21.12.1994; USA-prior. 23.12.1993).
Loteprednol etabonate
L
1197
use for treatment of neurodegenerative processes:
WO
9 521 609 (Ciba-Geigy; appl. 26.1.1995; EP-prior. 8.2.1994).
US 5 091 390 (Du Pont de Nemours; appl. 20.9.1990; USA-prior. 20.9.1990).
composition with potassium channel activator:
EP 561 357 (Merck; appl. 16.3.1993; D-prior. 20.3.1992).

composition for direct compression tabl.:
EP 51 1 767 (Merck
&
Co.; appl. 21.4.1992; USA-prior. 29.4.1991).
use for treatment of cardiac and vascular hypertrophy:
DE 4 036 706 (Hoechst; appl. 17.1 1.1990; D-prior. 17.1 1.1990).
Formulation(s):
tabl. 12.5 mg, 25 mg, 50 mg
Trade Narne(s):
D: Lorzaar (MSD
F:
Cozaar (Merck Sharp
&
I:
Losaprex (Merck
&
Co.)
Chibropharm) Dohme-Chibret) USA: Cozaar (Merck
&
Co.;
Lorzaar (MSD
Hyzaar (Merck Sharp
&
1995)
Chibropharm)-comb. with
Dohme-Chibret)-comb. Hyzaar (Merck
&
Co.)-
hydrochlorothiazide GB: Cozaar (Merck Sharp
&

comb. with
Dohme) hydrochlorothiazide
Loteprednol e tabonate
Use: ocular antiinflammatory soft
corticosteroid
RN: 82034-46-6 MF: C,H,,C10, MW: 466.96
CN:
(I
:P,17a)-17-[(Ethoxycarbonyl)oxy]-I
l-hydroxy-3-oxoandrosta-l,4-diene-l7-carboxylic
acid
chloromethyl ester
prednisolone
(q.
v.)
llp.17a-dihydroxy-
3-oxoondrosta-1.4-diene-
17B-carboxylic acid
(I)
ethyl
chloroformate
17a-(ethoxycarbonyloxy)-
1
la-hydroxy-3-oxoandrosta-
1.4-diene-1 7-carboxylic acid
(11)
chloromethyl
iodide
Loteprednol etabonate
1198

L
Lovastatin
Reference(s):
BE 889 563 (Otsuka Pharm. Co. Ltd.; appl. 9.7.1981; USA-prior. 10.7.1980).
oxidation of
prednisolone
with sodium periodate:
Hirschmann et al.: Chem. Ind. (London) (CHINAG) 1958,682
suspension of
loteprednol etabonate:
WO 9 51 1 669 (Pharmos Corp.; USA-prior. 25.10.1993).
US 5 747 061 (Pharmos Corp.; 5.5.1998; USA-prior. 25.10.1993).
Formulation(s):
ophthalmic susp. 0.2% 5 ml, 10 ml, 0.5% 2.5 ml, 5 ml, 10 ml, 15 ml
Trade Name(s):
USA: Alrex (Bausch
&
Lomb Lotemax (Bausch
&
Lomb
Pharm.; 1998) Pharm.)
Lovastatin
(Mevinolin; MK 803; Monakolin-K)
ATC: B04AB; ClOAA02
Use: HMG-CoA-reductase inhibitor,
antihypercholesterolemic
RN: 75330-75-5 MF: C,,H,,O, MW: 404.55
LD,,,: zl glkg (M, p.0.)
CN:
[lS-[la(R*),3a,7P,8P(2S*,4S*),8aP]]-2-methylbutanoic

acid
1,2,3,7,8',8a-hexah~dro-3,7-dimethyl-8-[2-
(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-l-naphthalenyl
ester
Fermentation of
Aspergillus terreus
(ATCC 20541).
Reference(s):
US 4 294 926 (Merck
&
Co.; 13.10.1981, appl. 15.6.1979; prior. 23.1.1980).
US 4 342 767 (Merck
&
Co.; 3.8.1982; prior. 16.6.1980, 15.6.1979, 23.1.1980).
US 4 294 846 (Merck
&
Co.; 13.10.1981; 28.5.1980, 21.9.1979).
US 4 231 938 (Merck
&
Co.; 4.1 1.1980; prior. 15.6.1979).
EP 22 478 (Merck
&
Co.; 13.6.1980; USA-prior. 15.6.1979).
Alberts, A.W. et al.: Proc. Natl. Acad. Sci. USA (PNASA6)
77,
3957 (1980).
Buckland, B. et al.: Novel Microb. Prod. Med. Agric., [Pap. Int. Conf. Biotechnol. Microb. Prod.] 1st
,
1988
(56RDAV), 16 1, Ed. A. L. Demain (Elsevier, Amsterdam).

fermentation of Monascus ruber:
DE 3 006 216 (Sankyo; appl. 20.2.1980; J-prior. 20.2.1979).
US 4 323 648 (Sankyo; 6.4.1982; J-prior. 11.5.1979).
DOS 3 028 284 (Sankyo; appl. 25.7.1980; J-prior. 27.7.1979).
synthesis of intermediates:
JP 59 193 883 (Suntry; appl. 9.3.1983).
JP 59 186 973 (Suntry; appl. 9.3.1983).
JP 59 186 972
(Suntry; appl. 9.3.1983).
Loxapine
L
1199
medical use for the treatment of prostatonzegaly:
JP 56 115 717 (A. Endo; appl. 19.2.1980).
total synthesis:
Quinkert, G. et al.: Synform (SNFMDF)
2,
84, 11 1 (1984) (review).
Majewski, M. et al.: Tetrahedron Lett. (TELEAY)
25,
2101 (1984).
Wovkulich, P.M. et al.: J. Am. Chem. Soc. (JACSAT) 111,2596 (1989).
Clive, D.L. et al.: J. Am. Chem. Soc. (JACSAT) 110,6914 (1988).
Hirama, M.; Iwashita, M.: Tetrahedron Lett. (TELEAY)
24,
181 1 (1983).
new fermentation process:
EP 877 089 (Gist-Brocades; EP-prior. 7.5.1997).
WO 9 837 220 (Gist-Brocades; appl. 20.2.1998; EP-prior. 20.2.1997).
WO 9 837 179 (Gist-Brocades; appl. 20.2.1998; EP-prior. 20.2.1997).

WO 9 736 996 (Gist-Brocades; appl. 21.3.1997; EP-prior. 28.3.1996)
fermentation of Coniothyrium fuckelii:
US 5 409 820 (Apotex; USA-prior. 6.8.1993).
Formulation(s):
tabl. 10 mg, 20 mg, 40 mg
Trade Name(s):
D: Mevinacor (Merck Sharp
&
USA: Mevacor (Merck Sharp
&
Dohme; 1989) Dohme; 1987)
Loxapine
ATC: NOSAH01
Use: neuroleptic, anxiolytic
RN: 1977-10-2 MF: C,,H,,ClN,O MW: 327.82 EINECS: 217-835-3
LD,,: 22 mgkg (M, i.v.); 40 mgkg (M, p.0.);
18 mgkg (R, i.v.); 151 mgkg (R, p.0.)
CN: 2-chloro- 1 1-(4-methyl-1
-piperazinyl)dibenz[bJl[1,4]oxazepine
succinate
(1:l)
RN: 27833-64-3 MF: C,,H,,CIN,O. C4H,04 MW: 445.90 EINECS: 248-682-0
0
pyridine
aOOcl
+
clAi~cH3
___,
NH2
aiHQc,

o
A.
oncH3
2-(4-chlorophen- ethyl
oxy)aniline chloroformate
Reference(s):
US 3 412 193 (American Cyanamid; 19.1 1.1968; appl. 13.12.1965).
Schmutz, J. et a].: Helv. Chim. Acta (HCACAV) 50,245 (1967).
1200
L
Loxoprofen
alternative syntheses:
US 3 546 226 (Dr. A. Wander; 8.12.1970, CH-prior. 30.5.1963,27.9.1963, 13.3.1967,22.3.1967, 9.5.1967,
14.7.1967, 3.1 1.1967).
DE 1 470 426 (Dr. A. Wander; appl. 25.5.1964; CH-prior.
30.5.1963,27.9.1963).
Formulation(s):
cps. 5 mg, 10 mg, 25 mg, 50 mg
Trade Name(s):
F:
Loxapac (Wyeth-Lederle; GB: Loxapac (Wyeth) USA: Loxitane (Lederle; 1975)
1980)
I:
Loxapac (Cyanamid); wfm generic
Loxoprofen
ATC: M01
Use: anti-inflammatory, analgesic
RN: 68767-14-6 MF:
C,SH1803 MW: 246.31
CN:

a-methyl-4-[(2-oxocyclopentyl)methyl]benzeneacetic
acid
sodium
salt
RN: 80382-23-6 ME Cl,H,,NaO, MW: 268.29
LD,,: 740 mgkg (M, i.v.); 3030 mgkg (M, p.0.);
155 mgkg (R, i.v.); 145 mgkg (R, p.0.)
NoOC,H5
KO-CH~
0
ethylote
0
diethyl odipote ethyl 2-0x0-
cyclopentonecorboxylote
(I)
ethyl 2-phenyl- form-
propionate oldehyde
~,"ooH
/
Loxoprofen
Reference(s):
US 4 161 538 (Sankyo; 17.7.1979; J-prior. 5.4.1977).
DOS 2 814 556 (Sankyo; appl. 4.4.1978; J-prior. 5.4.1977).
synthesis of I:
Zupancic, B.G.; Trpin, J.: Monatsh. Chem. (MOCMB7)
98,
369 (1967).
synthesis ofll:
FR
2 134 197 (Lab. Logeais; appl. 26.4.197 1).

Formulation(s):
oral: 3x60 mgld