Pharmaceutical Substances Syntheses, Patents, Applications - Part 50 doc

Citrulline
C
491
Hepasteril B. compositum, Reducdyn (Nordmark)- F: Thioncycline (Merrel1)-
forte (Fresenius)-comb.;
comb.; wfm comb.; wfm
wfm
Sterofundin-CH (Braun ThioxidrCne (Boltu); wfm
Mederma (Merz)-comb.; Melsungen); wfm
I:
Citiolase (Roussel)
wfm
Tutofusin LC (Pfrimmer);
wfrn
Citrulline
ATC: V03AB99
Use: liver therapeutic
RN:
372-75-8 MF: C6H,,N303 MW: 175.19 EINECS: 206-759-6
CN:
fl-(aminocarbony1)-L-ornithine
malate
(1:l)
RN:
70796-17-7 MF: C6H,,N303. C,H,O, MW: 291.26
@
by
fermentation
o from Socchorornyces genus
L-arginine hydrochloride
b from orniihine

Citrulline
c from Arthrobaciel
Referencefs):
1
Fox,
S.W.: J. Biol. Chem. (JBCHA3) 123,687 (1938).
2a
JP 52 143 288 (Kyowa; appl. 20.5.1976).
2b
JP 50 148 588 (Miura; appl. 23.5.1974).
2c
JP 53 075 387 (~yowa; appl. 13.12.1976).
alternative syntheses:
JP 122 48/67 (Ajinomoto; appl. 1 1.9.1965).
JP 117 58/68 (Kyowa; appl. 15.1 1.1965).
Fox,
S.W.
et
al.: J. Org. Chem. (JOCEAH)
6,
410 (1 941).
crystallization:
JP 7 100 174 (Ajinomoto; appl. 20.1 1.1968).
isolation
from
Citrullus vulgaris
Schrad.:
Wada, M.: Biochem.
Z.
(BIZEA2) 224,420 (1930).

use as liver therapeutic:
FR-M 4 182 (Inst. de Recherche Sci.; appl. 9.3.1965).
FR-M 5 594 (Dimaphar; appl. 1.7.1966).
FR-M 5 703 (Lab. Carriere Carron; appl.
30.8.1965).
FR-M
6
305 (Dimaphar; appl. 15.12.1966).
use as digestant:
FR-M 5 695 (Lab. Carriere Carron; appl. 29.8.1966).
citrulline fumarate:
FR-M
6 306 (Dimaphar; appl. 15.12.1966).
492
C
Cladribine
citrulline maleate:
FR-M
6 443 (Dimaphar; appl. 21 A.1967).
Formulation(s):
amp. 60 mg/15 ml;
drg.
25 mg, 100 mg
Trade Name(s):
D:
Polilevo (Taurus Pharma)- Perifago (Pharmacia
&
Citruplexina (Synthe1abo)-
comb. Upjohn) comb.
F:

Azonutril (Pharmacia
&
Stimol (Biocodex; as Ipoazotal (SIT)-comb.
Upjohn)-comb. malate)
Epurarn (Pharmafarm)-
I:
Biotassina (UCM)-comb.
comb.
Cladribine
(NSC- 105014-F; RWJ-2625
1
;
2-CdA)
RN: 4291-63-8 MF: C,,H,,CIN,O, MW: 285.69
CN:
2-chloro-2'-deoxyadenosine
ATC: LOlBB04
Use: antineoplastic
CH,
2.6-dichloro-
2-deoxy-3.5-di-O-p-
purine
toluayl-a-D-erythro-
pentofuronosyl
chloride
1.
NH3,
CH,OH.
100
OC

2.
chrornatogrophy
.
Clodribine
I
purine
(I)
Cladribine
C
493
guanosine
1.
pyridine.
OMF
k
1.
pentyl nitrite, K2C03,
CH2C12. (C,H,),CCI
2. NH,OH, THF
n
F
OH OH
Z-chloro-
odenosine
pyridine
111
1.3-dichloro-
1
.l.3,3-tetro-
DMAP,

ocetonitrile
+
c'rO~
+.
0-phenyi chloro-
thioformote
1
Bu3SnH.
AIBN,
benzene,
A
2. Bu,N+F THF
Clodribine
1.
tributyltin hydride
2.
tetrobutvlommonium fluoride
.El
2-chloro-2'-0-phenoxy-
thiocorbonyl-3'.5'-0-
(tetroisopropyldisiioxonylene)-
adenosine
(N)
494
C
Clavulanic acid
Refc?rence(s):
a
Kazimierczuk,
Z.

et al.: J. Am. Chem. Soc. (JACSAT) 106,6379-6382 (1984).
EP
173 059 (Univ. Brigham Young; appl. 17.7.1985; USA-prior. 6.8.1984, 15.1.1987).
Christensen, L.F. el al.: J. Med. Chem. (JMCMAR) 15,735 (1972).
b
US 5 208 327 (Ortho Pharm. Corp.; appl. 16.4.1992; USA-prior. 18.12.1991).
compositions for treatment of rheumatoid arthritis:
US
5
310 732 (Scripps Res. Inst.; appl. 19.2.1992; USA-prior. 3.2.1986).
Formulatiort(s):
inj. sol. 10 mg/lO ml
Trade Name( s):
D: Leustatin (Janssen-Cilag) GB: Leustat (Janssen-Cilag)
F:
Leustatine (Janssen-Cilag) USA: Leustatin (Ortho Biotech)
Clavulanic acid
ATC: JOICRO2
Use: P-lactamase inhibitor
RN: 58001 -44-8 MF: C,H,NO, MW: 199. I6 EINECS: 261-069-2
LDS,,:
4 g/kg (M, i.v.); 4526 mg/kg
(M,
p.0.);
7936 rnglkg (R, p.0.)
CN:
[2R-(2a,3Z,5a)]-3-(2-hydroxyethylidene)-7-oxo-4-oxa-l-azabicyclo[3.2.0]heptane-2-carboxylic
acid
monosodium
salt

RN: 57943-81-4 MF: C,H,NNa05
MW:
221.14 EINECS: 261-032-0
LD,,,:
4 glkg (M, i.p.); 4500 rnglkg (M, LC.)
From cultures of
Streptornyces clavuligerns.
Reference(s);
US 4 529 720 (Beecham; 16.7.1985; GB-prior. 2.4.1974).
US 4 367 175 (Glaxo; 4.1.1983; GR-prior. 7.2.1975).
GB 1 508 977 (Beecham; appl.
11.4.1975; GB-prior.
2O.4.l974,2l.6.l974.9.lO.l974,
1
I.
12.1974).
DOS 2 517 316 (Beecham; appl. 18.4.1975; GB-prior. 20.4.1974, 21.6.1974,9.10.1974, 11.12.1974)
DE
2 560 074 (Beecham; appl. 18.4.1975; GB-prior. 20.4.1974, 21.6.1974.9.10.1974, 1 1.12.1974).
pure salts (e.
g.
Nu-,
Li-
and other salts);
US 4 490 294 (Beecham; 25.12.1984; GB-prior. 7.2.1975, 17.3.1975).
US 4 490 295 (Beecham; 25.12.1984; GB-prior. 7.2.1975, 17.3.1975).
GB 1 543 563 (Glaxo; appl. 7.2.1975, 17.3.1975; Compl. Spect. 6.2.1976).
tert-bu~lamine salt:
EP
26 044 (Beecham; appl. 15.8.1980; GB-prior. 24.8.1979).

US 4 454 069 (Beecham; 12.6.1984; GR-prior. 24.8.1979).
various salts:
US 4 367 175 (Glaxo; 4.1.1983; GB-prior. 7.2.1975, 17.3.1975)
esters:
Clebopride
C
495
formularion with
amoxicillin:
EP
8
905 (Beecham; appl. 21.8.1979; GB-prior. 6.9.1978).
US 4 301 149 (Beecham; 17.1 1.1981; GB-prior. 11 .lO.I977).
EP
49 061 (Beecham; appl. 6.9.198
1
;
GB-prior. 27.9.1980).
EP
52 962 (Beecham; appl. 2.1 1.1981; GB-prior. 20.1 1.1980).
GB
2
084 016 (Beecham; GB-prior. 27.9.1980).
formulation with penicillins and cephalosporins:
DOS
2
559 41 1 (Beecham; appl. 18.4.1975; GB-prior.
20.4.1974,21.6.1974,9.10.1974,
11.12.1974).
Fonnulution(s):

drops 12.5 mglml;
f.
c. tabl. 125 mg; tabl. 125 mg; vial 0.1
g,
0.2
g,
0.275 g, 0.6 g, 1.2
g,
2.2
g
(as potassium salt)-comb. with amoxicillin
Trade Name(s):
D: Augmentan (SmithKline
Beecham; 1982)-comb.
with amoxicillin
Betabactyl (SmithKline
Beecham)-comb, with
t~carcillin
F:
Augmentin (Sm~thKline
Beecham; 1984)
I
Ciblor (Inava)
Claventin (SmithKline
Beecham)
GB: Augmentin (SmithKline
Beecham; 1984)-comb.
with amoxicillin
Timentin (SmithKline
Beecham)-comb.

I:
Augmentin (SmithKLine
B. Farm.)-comb.
Clavucar (Smith Kline
&
French)-comb. with
ticarcilline
Clavulin
(Carlo Erba)-
comb.
Neoduplamox (Smith Kline
&
French)-comb:
Timentin (SmithKline
Beecham)-comb. with
ticarcilline
all combination
preparations with
amoxicillin
J:
Augmentin (Beecham-
Meiji)-comb. with
amoxicillin
USA: Augmentin (SmithKline
Beecham: 1984)-comb.
with amoxicillin
Timentin (SmithKline
Beecham)
Clebopride
AT: A03FA06; A04AD

Use: anti-emetic, specific antagonist of
peripheral and central
dopamine
receptors, reversible MAO-inhibitor
RN:
55905-53-8
MF:
CzoHz4CIN,02
MW.
373.88 EINECS: 259-885-9
LD,,: 260 mg/kg (M, i.m.); 40 mglkg (M,
i.p.);
51 mglkg (M, i.v.); 490 mglkg (M, p.0.): 350 mglkg (M, s.c.):
1450 mg/kg (R,
i.m.);
155 mglkg (R, i.p.); 39 mglkg
(R,
i.v.); 2540 mglkg (R, p.0.); 4850 mglkg
(R,
s.c.)
CN:
4-amino-5-chloro-2-methoxy-N-[l-(phenylmethyl)-4-piperidinyl]benzamide
monohydrochloride
RN: 57645-39-3 MF: C2,H2,C1N30,
.
HCI MW: 410.35
LD,,: >I @kg
(M,
pa)
malate

(1:l)
RN: 57645-91-7 MF: C,,Hz4CIN,0z
.
C4H,0S MW: 507.97 EINECS: 260-874-6
LD,: 51 mgtkg
(M,
i.v.); 490 mglkg (M, p.0.);
39 mgkg (R, i.v.); 2540 mglkg (R,
p.0.);
>800 mg/kg
(dog,
p.0.)
2.
CI2, FeCI,
b
1
1,
dimethyl sulfote
HN
CH,
I'
2.
chlorine
0
4-amino-
salicylic acid
4-acetomido
salicylic acid
496
C

Clemastine
F73
CI
CH3
HN CH3
K
0
methyl 2-methoxy-
4-aceiamido-5-
chlorobenzoate
(I)
COOH
2-methoxy-4-
amino-5-chloro-
benzaic acid
(11)
2.
111
NH2
Clebopride
1-benzyl-4-amino-
piperidine
(In)
.
.
DE
2 513 136 (Anphar; appl. 21.3.1975; GB-prior. 21.3.1974).
US
4
138 492 (Anphar; 6.2.1979; appl. 17.3.1975; GB-prior. 21.3.1974).

Prieto,
J.
et al.: J. Pharm. Pharmacol. (JPPMAB)
29,
147 (1977).
alternative synthesis:
JP 63 295 558 (Asahi; appl. 26.5.1987).
JP 63 295 557 (Asahi; appl. 26.5.1987).
synthesis of intermediates:
JP 63 295 559 (Asahi; appl. 26.5.1987).
transdermal patch:
EP 303 445 (Fordonal; appl. 9.8.1988; J-prior. 13.8.1987).
Formulation(s):
amp.
1
mg; sol. 0.5 mg; syrup 0.5 mg; tabl. 0.25 mg, 0.5 mg (as hydrogen maleate)
Trade Name(s):
I: Cleprid (Recordati; 1987) J: Amicos (Banyu; 1985)
Motilex (Guidotti) Clast (Meiji)
Clemastine
(Meclastine)
ATC: D04AA 14; R06AA04
Use: antiallergic, antihistaminic
RN:
15686-51-8 MF: CzIH,,CINO MW: 343.90
CN:
[R-(R*,R*)]-2-[2-[1-(4-chlorophenyl)-l-phenylethoxy]ethyl]-l-methylpyrrolidine
hydrogen fumarate
(1:l)
RN: 14976-57-9 MF: C2,H2,C1N0

.
C4H404 MW: 459.97 EINECS: 239-055-2
LD,,: 43 mgkg (M, i.v.); 730 mglkg (M, p.0.);
82 mgkg (R, i.v.); 3550 mgkg (R, p.0.)
Clemastine
C
497
d
CI
4-chloro- methylmagnesium
(1)
benzophenone chloride
4'-chloro- phenylmognesium
OcetoDhenone bromide
1.
NaH, aylene
I
+
CI
a
\
2.
chromatogr.
with
silica gel
H$j,
CH3
/
\
-

CH3
(+)-2-(2-chloro-
ethyl)-1 -methyl-
pyrrolidine
1.
froctionol crystollizotion of rnoleotes
2.
resolution with
(-)-dibenzoyl-L-tllrtoric
acid
11
b
c'l
mixture
of
4
isomers
(U)
Clemostine
1
Reference(s):
Ebnijther, A.; Weber, H P.: Helv. Chim. Acta (HCACAV)
59,
2462 (1976).
GB
942 152 (Sandoz; appl. 14.12.1960; CH-prior. 19.
I
.l96O, 3.8.1 960, 27.9.1960).
FR-M
1 313 (Sandoz; appl. 13.7.1961).

preparation
of
2-(2-chloroethy1)- 1-methylpyrrolidine
enantiomers:
Vemier, J.M. et al.:
I.
Med. Chern. (JMCMAR)
42
(10). 1684 (1999).
Formul~ion(s):
amp. 2 rngl5 ml; gel 300 mglg (as hydrogen furnarate); syrup 0.5 mg/lO ml; tabl. 1 mg
Trade
Namr(s):
Corto-Tavegil (Novartis
Pharma)-comb.
Tavegil (Novartis
Consumer Health)
Tavkgil (Sandoz); wfm
Tavegil (Nnvartis; as
hydrogen furnarate)
Tavegil (Sandoz)
J: Alagyl (Sawai)
Clemanyl (Kyoritsu
Alusas (Fuso) Yamagata)
Anhistan (Nippon Zoki) Fulurninol (Tatsumi)
Antriptin (Nippon Yakuhin) Fumalestine (Hishiyama)
Batomu (Zensei)
Fumartin
(Torii)
Benanzyl (Isei) Histamedine (Mohan)

Chlonaryl (Ohta)
Inbestan (Maruko)
Kinotomin (Toa Eiyo)
498
C
Clemizole
Lacretin (Tokyo Tanabe) Natarilan (Nippon
Telgin
G
(Takata)
Lecasol (Kaken) Chemiphar)
Trabest (Hoei)
Maikohis (Nihon Yakuhin)
Piloral (Nippon Kayaku) Xolamin (Sanko)
Mallermin-F (Taiyo
Raseltin
(Mamishi) generics and combination
Yakuko)
Reconin (Toy ama)
preparations
Marsthine (Towa)
Romien (Fuji Zoki) USA: Tavist (Dorsey); wfm
Masletenc (Shioe)
Tavegyl (Sandoz-Sankyo) Travist (Sandoz);
wfrn
Clemizole
ATC: R06A
Use: antihistaminic, antiallergic
RN:
442-52-4 MF: C,,H,,CIN, MW: 325.84 EINECS: 207-133-5

CN:
l-[(4-chlorophenyl)methyl]-2-(l-pyrrolidinylmethyl)-1H-benzi~dazole
monohydrochloride
RN: 1163-36-6
MF:
C19H2,CIN,
.
HCI MW: 362.30 EINECS: 214-605-4
LDso: 75 mgkg (M, i.v.); 837 mgkg (M, p.0.);
74 mgkg (R, i.v.); 1950 mgfkg
(R,
p.0.)
1
-chloro- 4-chloro-
2-nitro-
benzylamine
benzene
(1)
pyrralidine Clernizole
Reference(s):
US 2 689 853 (Schering AG; 1954; D-prior. 1950).
alternative syntheses:
DE 980 644 (Schering
AG;
appl. 1950).
DE 901 649 (Schering AG; appl. 1951).
Formulation(s):
cream
10
mgl40 g; suppos. 5 mg

Trade Name(s):
D: Megacillin (Grunentha1)- F. Deliproct (Schering)- Ultraproct (&hering)-
comb. wlth penicillin; wfm comb.; wfm comb.; wfm
Scheriproct (Scherax)- Ultralan (Schering); wfm
I:
Ultraproct (Schenng)-
comb.; wfm Ultraproct (Schering)- comb.
Ultraproct (Scherax)- comb.; wfm
J:
Histacur (Nichidoku)
comb.; wfm
GB:
-
Scheriproct (Schering)-
comb.: wfm
Clenbuterol
C
499
Clenbuterol
ATC: R03AC14;R03CC13
IJse:
bronchodilator
RN:
37148-27-9
MF:
C,2H,8C12N20
MW:
277.20 EINECS: 253-366-0
LD5,:
27.6

mgkg
(M,
i.v.)
CN:
4-amino-3,5-dichloro-a-[[(1,1-dimethylethyl)amino)methyl]benzenemethanol
hydrochloride
RN:
21898-19-1
ME
C,2H,8C12N20. HCI
MW:
313.66
4'-nitro- 2-brorno-4'-nitro-
acetophenone
acetophenone
Hz,
Raney-Ni
0
H
0
CI
I
Clenbuterol
1
500
C
Clidanac
Reference(s):
Keck, J. et al.: Arzneim Forsch. (ARZNAD)
22,

861 (1972).
a
DOS 1 793 416 (Thornae; appl. 5.9.1967).
BE 704 213 (Thornae; appl. 22.9.1967; D-prior. 22.9.1966, 15.2.1967, 2.6.1967).
US 3 536 7 12 (Boehringer Ing.; 27.10.1970; D-prior. 22.9.1966,
15.2.1967, 2.6.1967).
b
DOS 2 157 040 (Thornae; appl. 17.1 1.1971).
DE 1 543 928 (Thornae; appl. 22.9.1966).
alternative syntheses:
DAS 2 354 959 (Thomae; appl. 2.1 1.1973).
Fort?zulation(s):
drops 0.059 mg/ml, 15 mg12 ml; syrup 0.005 rnd5 ml; tabl. 0.01 mg, 0.02 rng (as
hydrochloride)
Trade Name(s):
D: Contraspasrnin (ASTA
I:
Broncodil (Leben's) Prontovent (Salus
Medica AWD)
Clenasma (Biomedica Research)
Spiropent (Boehringer Ing.) Foscarna) Spiropent (Boehringer
Ing,
Spasrno-Mucosolvan
Contrasrnina (Falqui) J: Spiropent (Teijin-Kissei)
(Boehringer
1ng.)-comb. Monores (Valeas)
Clidanac
ATC: MOlAB
Use: non-steroidal anti-inflammatory,
antipyretic

RN: 34148-01-1 MF: Cl,Hl,CI02
MW:
278.78
LD,,,: 41 mglkg (R, p.0.)
CN:
6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-l-carboxylic
acid
1.
Li,
?I
1.
AICI,
&
~.H~c-&~H
2.
H,SO,
3.
HCI. CH
,COOH
*
11
CI
1.
lithium,
1.3-dithiane
phenylcyclo-
J-chloro-
hexone
(I)
propionyl

chloride
5-cyclohexyl-l-
indonane
F'
___*
N-chloro-
succinimide
5-cyclohexyl-
1
-indon-
corboxylic
acid
(11)
Clidonoc
L
TiCI,
CI
0,
1
+
Y
CH,
+
A
c
I
titonium
diethyl
tetrochloride
molonate

dichloromethyl
4-cyclohexyl-
(1~)
methyl
ether benzoldehyde