Pharmaceutical Substances Syntheses, Patents, Applications - Part 105 docx

Ibuprofen lysinate
1
1041
GB:
Brufen Retard (Knoll; J:
1969)
Fenbid spansule
(Goldshield)
Motrin (Pharmacia
&
Upjohn)
numerous generics
I: Algofen (Blue Cross)
Antagil (Janssen)
Brufen (Boots
Italia; 1972)
Brufort (Lampugnani)
Dolocyl (Novartis)
Moment (Angelini)
Nurofen (Boots Italia)
generics
Ibuprofen lysinate
Andran (Takata)
Anflagen (Ohta)
Bluton (Morishita)
Brufanic (Teiyo; 1976)
Brufen (Kakenyaku)
Buburone (Towa)
Butylenin (Sanwa)
Daiprophen (Daito)
Donjust-B (Horita)

Epinal (Mitsubishi Yuka)
Epobron (Ono)
Eputes (Kobayashi
Kako)
IB-100 (Hishiyama)
Ibuprocin (Nisshin)
Lamidon (Kowa)
Landelun (Tsuruhara)
Liptan (Kowa)
Manypren (Zensei)
Mynosedin (Toho Yakuhin)
Napacetin (Toyama)
Nobfelon (Toho)
Nobfen (Toho)
Nobgen (Kanebo)
Roidenin (Showa)
Sednafen (Taisho)
generic
USA: Motrin
(McNeil)
Vicoprofen (Knoll)
generics
ATC: MOI
AE;
M02AA
Use: anti-inflammatory, analgesic
RN: 57469-77-9
MF: C,3H1802~C6H14N202 MW: 352.48 EINECS: 260-751-7
LD,,: 299 mgkg (M, p.0.);
841 mg/kg (R, p.0.)

CN: L-lysine
mono[a-methyl-4-(2-methylpropyl)benzeneacetate]
ibuprofen
(9.
v.)
Ibuprofen lysinote
u
Reference(s):
DOS 2 419 317 (Neopharmed; appl. 22.4.1974; I-prior. 22.3.1974).
GB
1
497 044 (SPA Soc. Prodotti Antibiotici; appl. 6.3.1975; prior. 7.3.1974).
Fomulation(s):
eff. tab]. 342 mg;
f.
c. tabl. 250 mg, 500 mg; gel 10
%;
s. r. tabl. 800 mg; suppos. 500 mg; vial
(lyo.) 400 mg
Trade Name(s):
D: Imbun (Merckle); wfm I: Aciril (Delalande Isnardi) Arfen (Lisapharma)
Ibuproxam
ATC: MOlAE13; M02AA
Use: anti-inflammatory
RN: 53648-05-8 MF: C13H,,N02 MW: 221.30 EINECS: 258-683-8
LD,,: >2 g/kg (M, p.0.);
>3 gkg (R, p.0.)
CN:
N-hydroxy-a-methyl-4-(2-methylpropyl)benzeneacetamide
1042

I
Ibutilide fumarate
-
1.
C2H50H.
H,SO,
2.
H2N-OH
2.
hydroxylamine
H3C
ibuprofen
I
Ibuproxam
(4.
v.)
Reference(s):
DOS 2 400 531 (Manetti Roberts; appl. 7.1.1974; I-prior. 8.1.1973, 5.7.1973).
Formulation(s):
ointment 5
9%;
suppos. 600 mg; tabl. 300 mg
Trade
Name(s):
I:
Deflogon (Damor);
wfm
Ibudros (Manetti Roberts)
Ibutilide
fumarate

(U-70226E)
ATC: COIBDO5
Use:
antiarrhythmic
RN: 122647-32-9 MF: C20H36N,0,S
.
1/2C4H404
MW:
885.24
LD,,,:
94.2 rnglkg (R,
i.
v.)
CN:
N-[4-[4-(ethylheptylamino)-l-hydroxybutyl]phenyl]methanesulfonamide
(E)-2-butenedioate (2:l) (salt)
base
RN: 122647-3
1-8
MF:
C,,,H,,N203S MW: 384.59
0
I1
H3C-S-CI
1)
0
methone-
sulfonyl
chloride
aniline

pyridine
10-15
'C
____,
succinic
anhydride
OCC,
OMF,
PH
4-[(methylsulfonyl)omina]-
ethylheptyl-
y-oxobenzenebutanoic acid
(I)
omine
N-ethyl-N-heptyl-y-oxo-4-
[(methylsulfonyl)amino]benzene-
butonomide
(11)
Idarubicin
1
1043
lbutilide furnorote
Reference(s):
EP
164 865 (Upjohn; appl. 1.5.1985; USA-prior. 4.5.1984).
Hester, J.B. et al.: J. Med. Chem. (JMCMAR)
34
(I), 308 (1991).
controlled-release formulation:
WO

9 421 237 (Univ. Michigan; appl. 15.3.1994; USA-prior. 15.3.1993).
Formulation(s):
vial 1 mg/ml
Trade Name(s):
USA:
Corvert (Pharmacia
&
Upjohn)
Idarubicin
ATC: LOlDR06
Use: antineoplastic, anthracycline
RN: 58957-92-9 MF:
C2,Hl7NO, MW: 497.50
LD,,,:
3
mgkg
(M, i.p.);
4
mgkg (M, i.v.); 16 mg/kg (M, p.0.)
CN:
(7S-cis)-9-acetyl-7-[(3-amino-2,3,6-trideoxy ~-lyxo-hexopyranosyl)oxy]-7,8,9,IO-tetrahydro-6,9,11-
trihydroxy-5,12-naphthacenedione
OH
0
AICI,
'c0*
-1
,
Tos-OH
aluminurn ethylene glycol

OH OH O O\cHX
ctloride
OH OH
0
OH
dounomycinone 4-0-dernethyl-
dounornycinone
4-0-dernethyldouno-
mycinone 19-ethylene
acetol (I)
4-0-dernethyl-4-0-(p-
toluenesulfonyl)dauno-
rnycinone 19-ethylene
acetal (11)
1044
1
Idarubicin
4-methoxy-
benzylomine
acid
4-demethoxy-4-(4-methoxy-
benzylomino)daunomycinone
19-ethylene ocetol
1.
F3CCOOH. NaN02
HO
2.
H,P02
_____,
2.

hypophosphorous
OH
OH
0
NH2
acid
OH
OH
0
fermentation
with
S.
peucetius corneus,
S.
coeruleus.
S.
coeruleorubidos
IV
b
1.
HgO. HgBr2. molecular sieve
0.5
nm
4-demethoxy-
dounamycinone
(N)
NH2
ldorubicin
lyxo-hexopyronosyl chloride
Reference(s):

a
US
4 471 052 (Adria; 9.1 1.1984; appl. 18.1.1982).
b
DOS 2 525 633 (Soc. Farmaceutici; appl. 6.9.1975; GB-prior. 16.12.1974).
US 4 046 878 (Soc. Farmaceutici; 9.6.1977; appl. 22.5.1975; GB-prior. 6.12.1974).
alternative synthesis:
Arcamone, F. et al.: Experientia (EXPEAM)
34,
1255 (1978).
synthesis of
4-demethoxydaunomycinone:
EP 328 399 (Farmitalia; appl. 2.10.1989; GB-prior. 2.12.1988).
lyophilisate:
GB 2 165 75
1
(Farmitalia; appl. 22.10.1984).
Formulation(s):
cps. 5 mg, 10 mg, 25 mg; vial 5 mg, 10 mg (as hydrochloride)
Idebenone
1
1045
Trade Name(s):
D: Zavedos (Pharmacia
&
GB: Zavedos (Pharmacia
&
J: ldamycin (Pharmacia
&
Upjohn) Upjohn) Upjohn; as hydrochloride)

F:
Zavedos (Pharmacia SA; as
I:
Zavedos (Pharmacia
&
USA: Idamycin (Pharmacia
&
hydrochloride) Upjohn) Upjohn; as hydrochloride)
Idebenone
ATC: COlEB; N06BX13; N07X
(CV-26
19)
Use: senile dementia therapeutic,
coenzyme Q10 derivative, nootropic
RN: 58186-27-9
MF:
C,,H,,O, MW: 338.44
LD,: >I0
g/kg
(M, p.0.);
10 &/kg
(R,
p.o.1
CN:
2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl-2,5-cyclohexadiene-l,4-dione
3.4.5-trirnethoxy- ethyl 9-chloroforrnyl-
toluene nonanoote
9-(2-hydrory-3.4-dirnelhoxy-
6-methylbenzoyl)nononoic
ocid

(I)
OH
Zn-Hg.
HCI
I
-,
H,c/'
K,[(SO&NOI
COOH
-b
11
zinc omalgom
H3C10
potassium
nitrosodisulfate
1
ldebenone
0
1.
C,H,OH.
HCI
2.
LiAlH
COOH
4
,
0
Reference(s):
DOS 2 519 730 (Takeda; appl. 2.5.1975; J-prior. 2.5.1974).
JP 51 128 932 (Takeda; appl. 10.1 1.1976).

JP 59 039 855 (Takeda; appl.
27.8.1982).
US 4 139 545 (Takeda; 13.2.1979; J-prior. 2.5.1974).
US 4 271 083 (Takeda; 2.6.1981; J-prior. 2.5.1974).
US 4525 361 (Takeda; 13.2.1979; appl. 3.4.1975; J-prior. 2.5.1974).
0
H,C/O
OH
0
medical use for the therapy of ischemic disease:
EP
31 727 (Takeda; appl. 29.12.1980; J-prior. 30.12.1979).
DOS
3
049 039 (Takeda; appl. 24.12.1980; J-prior. 30.1 2.1979).
medical use for treatment of allergic disease:
EP 38 674 (Takeda; appl. 15.4.1981; J-prior. 21.4.1980).
medical use for treatment ofjibrosis:
DOS 3 31 1 922 (Takeda; appl. 31.3.1983; J-prior. 6.4.1982).
Okamoto,
K.
et al.: Chem. Pharm. Bull. (CPBTAL) 33,3745; 3756 (1985).
Goto, G. et al.: Chem. Pharm. Bull. (CPBTAL) 33,4422 (1985).
1046
1
Idoxuridine
alternative synthesis:
EP
21 841 (Takeda; appl. 27.6.1980; J-prior. 28.6.1979).
EP

58 057 (Takeda; appl. 4.2.1982; J-prior. 9.2.1981).
Ebrmulation(s):
drg.
30
rng,
45
mg;
tabl. 30
mg
Trade Name(s):
I:
Daruma (Cyanamid) Mnesis (Takeda)
J:
Avan (Takeda; 1987)
Idoxuridine
ATC: D06BBOl; J05AB02; SO1 ADO1
Use: chemotherapeutic (Herpes simplex)
RN: 54-42-2
MF:
C,H,
,IN20s
MW:
354.10 EINECS: 200-207-8
LD,,,:
1
glkg
(M,
i.p.);
4
glkg

(R, i.p.)
CN: 2'-deoxy-5-iodouridine
5-iodo-
uracil
1
-acetyl-5
iodouracil
acetate
5-iodo-mono-
mercuriurocil
(I)
Tos-0
3.5-di-O-tosyl-2-
deoxyribofuronosyl
chloride
(11)
I
ldoxuridine
I
Idoxuridine
/
Ifenprodil
I
1047
Reference(s):
Chang, P.K.; Welch, A.D.:
J.
Med. Chem. (JMCMAR) 6,428 (1963).
FR
1

336 866 (Roussel-Uclaf; appl. 27.7.1962).
GB
1
024 156 (Roussel-Uclaf; appl. 24.7.1963; F-prior. 27.7.1962).
Formulation(s):
eye drops 0.1
%;
ointment 0.2
%,
0.5
%;
sol.
5
%,
10
%,
40
%
Trade Name(s):
D: ldugalen (Phannagalen) Iduridin (Ferring)
J:
I.D.U. (Sumitorno)
Ophtal (Winzer)
I:
Iducher (Farmigea) USA: Dendrid (Alcon); wfm
Virunguent (Hermal)
Iducol (SIF1)-comb. Herplex (Allergan); wfm
Zostrum (Galderma)
Iduridin (Geymonat) Stoxil (Smith Kline
&

F:
Iduviran (Chauvin) Idustatin (Delalande French); wfm
GB:
Herpid (Yamanouchi) 1snardi)-comb.
Ifenprodil
ATC: C04AX28
Use: cerebral and
peripheral
vasodilator
RN:
23210-56-2 MF: C21H2,N02 MW: 325.45 EINECS: 245-491-4
LDS,: 320 mglkg (M, p.0.)
CN:
a-(4-hydroxyphenyl)-~methyl-4-(phenylmeyl)-l-piperidineethanol
tartrate
(2:l)
RN: 23210-58-4 MF: C2,H2,NO2 1/2C,H606 MW: 800.99 BINECS: 245-493-5
benzyl 4'-hydroxy-
4'-benzyloxy-
chloride propiophenone
propiophenone
Na
CO
,
+#m
=+
8""
4-benzyl-
(11)
piperidine

I
lfenprodil
I
Referencets):
DAS
1
695 772 (Lab. Robert et Carribre; appl. 7.9.1967; F-prior. 27.9.1966).
FR
5 733 M (Lab. Rohert et Carribre; appl. 27.9.1966).
US 3 509 164 (Lab. Robert et Carribre; 28.4.1970; F-prior. 27.9.1966).
Formulation(s):
amp. 5 mgl2 ml; tabl. 20
mg
(as tartrate)
Trude Name(s):
F:
Vadilex (Synthtlabo; 1972) J: Cerocral (Funai; 1979)
Ifosfarnide
ATC: LOIAA06
Use: antineoplastic
RN:
3778-73-2 MF: C,H,,CI,N,O,P MW: 26
1
.O9 EINECS: 223-237-3
LDS,; 338 mg/kg
(M,
i.v.); 1005 mglkg
(M,
p.0.);
190 mglkg (R, i.v.); 143 mglkg (R, p.0.)

CN:
N,3-bis(2-chloroethyI)tetrahydro-WI-1,3,2-oxazaphosphorin-2-amine
2-oxide
P0C13
0
H2N~CI
.HCI
N(C~H5)~
OH
0HCI
,
0.
11
p-CI
N(C2H5)3
,
2-chloroethylornine
hydrochloride
N-(2-chloroethy1)-
lfosfornide
3-hydroxypropylomine
hydrochloride
(cf.
trofosfomide
synthesis)
Reference(s):
DAS 1 645 921 (ASTA-Werke; appl.
1
1.7.1966).
Formulation(s):

vial 200 mg, 500
mg,
I g,
2
g
(dry powder)
Trade Nameis):
D:
Holoxan (ASTA Medica GB: Mitoxana (ASTA Medica) USA: Ifex (Bristol-Myers
AWD)
I:
Holoxan (ASTA Medica) Squibb)
F:
Holoxan (ASTA Medica) J: Ifomide (Shionogl)
Iloprost
(Ciloprost;
E-
1030;
SH-401;
ZK-36374)
ATC: BOlAC11
Use: vasodilator, platelet aggregation
inhibitor
RN: 78919-13-8 MF:
C2,H,204 MW: 360.49
CN:
5-[Hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-l-octen-6-ynyl)-2(1H)-pentalenylidene]pentanoic
acid
(4R)
RN: 74843-30-4 MF: C,,H3,04 MW: 360.49

(4s)
RN: 74843-14-4 MF: C,,H,,O, MW: 360.49
trometamol salt
RN: 73873-87-7
MF:
C2,H43N07
MW:
481.63
Iloprost
I
1049
(-)-Corey loctone
derivative
(cf. dinoprost)
1.
~i/hO4~3
,
THF
0
2.
Tos-OH. toluene
3.
K,CO,. CH3OH
1.
lithium ethyl ocetote
cro,
(n)
I.(()
,
toluene

H~,,O
WEl
-
N(C2H5)3
3.
NaBH,. CH30H
3. CH3COOH, H20, THF
I
+
0
H
@
*
In
1.
Collin's oxidation
1.
DABCO
2.
1
-5-diazobicyclo-
2.
benzoyl chloride
[4.3.0]non-5-ene
(DEN)
1.10s-OH
\
CH3
v
HO

HO OHC
O
(_+)-dimethyl 3-methyl-
'
2-0x0-5-heptynyl-
(no
ethylene
phosphonote
(N)
glycol
1
NoBH,, CH30H
2
K2COJ, CH,OH
3 CH3COOH. H20, THF
,
Tos-OH
-
4
dihydropyron
H3C-CEC
1. NaH. DMSO.
chromatographic separation
2
CH3COOH, H20, THF
YI
+
2.
acetic ocid
4-corboxybutylidene- lloprost

triphenylphosphorane
sodium solt
(VII)
1050
1
Iloprost
preporotion
of
4 corboxybutylidenetriphenylphosphorone
sodium
solt
2.
DMSO.
NOH
B,-COOH
b
VII
1.
triphenylphosphine
5-bromopentonoic
acid
preporotion
of
(?)-dimethyl
3-methyl-2-0x0-5-heptynylphosphanote
1-brorno-2-butyne
diethyl
rnethylmolonote
CH3
LiCI.

DMSO.
A
H3C\
CH
BuLi,
DMSO
vII1
b
c'C,,$b,~~3
N
0
Reference(s):
DE 2 845 770 (Schering AG; D-prior. 19.10.1978)
DE 3 839 155 (Schering AG; D-prior. 17.1 1.1988)
Skuballa, W.; Vorbrueggen, H.: Angew. Chem. (ANCEAD)
93
(12), 1080 (1981)
preparation of
4-carboxybutylidenetriphenylphosphorane
sodium salt:
Martinelli, M.J.: J. Org. Chem. (JOCEAH)
55
(17), 5065 (1990).
Johnson, F.P. et al.: J. Am. Chern. Soc. (JACSAT)
104
(a), 2190 (1982).
Niwa,
H.
et al.: Tetrahedron (TETRAB)
50

(25), 7385 (1994).
preparation of
(+)-dimethyl
3-methyl-2-0x0-5-heptynylphosphonate:
DE
2
729 960 (Schering AG; prior. 30.6.1977).
footnote [6] in: Skuballa, W.; Vorbrueggen,
H.:
Angew. Chem. (ANCEAD)
93
(12), 1080 (1981).
(a-
or (a-selective Wittig reactions in the synthesis of carbacyclins:
Westermann,
J.;
Harre, M.; Hickisch,
K.:
Tetrahedron Lett. (TELEAY)
33
(52), 8055 (1992).
alternative synthesis of
cis-bicyclo/3.3.0]oc~ylidene
derivative:
EP 153 822 (Sagami Chemical Research Center; J-prior. 10.2.1984).
Sodeoka,
M.;
Ogawa,
Y.;
Kirio,

Y.;
Shibasaki, M.: Chem. Pharm. Bull. (CPBTAL)
39
(2), 309 (1991)
Formulation(s):
amp. 50 pg10.5 mi, 100 pg/l ml (as trometamol salt)