Pharmaceutical Substances Syntheses, Patents, Applications - Part 11 pps

Amobarbital
A
101
Amobarbital
(Amylobarhitone)
ATC: N05CA02
Use: hypnotic
RN: 57-43-2 MF: C,,H,,N,O,
MW:
226.28 EINECS: 200-330-7
LD,,: 345 mg/kg (M, p.0.);
250 mg/kg (R, p.0.);
58 mgkg (dog, i.v.)
CN:
5-ethyl-5-(3-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione
monosodium
salt
RN: 64-43-7 MF: C,,H,,N,NaO, MW: 248.26 EINECS: 200-584-9
LDs,: 505 m@g (M, pa);
128 mg/kg (R, i.v.); 275 mglkg (R, p.0.);
75 mgkg (dog, i.v.); 99 mgkg (dog, p.0.)
0
0,CH3
I.
NODC~H,
'w.,-Br
O-CH,
2.
H3c*Br
CH3. NoOCZHS
0

0
I
ethyl
bromide
isopentyl
bromide
diethyl
malonote
diethyl
ethylrnalonate
diethyl
e-ethyl-
a-isapentylmalonate
(I)
Amobarbital
u
Reference(s):
GB
191 008 (E. Layraud; 1922; F-prior. 192
1).
US 1 856 792 (Eli Lilly; 1932; prior. 1929).
Formulation(s):
tabl. 15 mg, 30 mg,
50
mg, I00 mg
Trade
Name(s):
D: Ansudoral (Basothem)-
comb.; wfrn
Jalonac

(Riihm Pharma)-
comb.; wfrn
Metrotonin (Temm1er)-
comb.; wfm
Stadadorm Tabl. (Stada);
wfm
F:
Binoctal (Houd6)-comb.;
wfm
Carlytkne amobarbital
(Dedieu)-comb.; wfm
Methxane (Ga1lier)-
comb.; wfrn
Nardyl (Vemin)-comb.;
wfrn
Noctadiol (Millot-Solac)-
comb.; wfrn
Supponoctal (Houd6)-
comb.; wfrn
Tensophoril (Syn1ab)-
comb.; wfrn
ViscCralgine comprimCs
(Riom)-comb.; wfrn
GR:
Amytal(F1ynn)
Sodium Amytal (Flynn)
Tuinal
(Flynn)-comb.
1:
Amobarb (Tariff.

lntegrativo)
J:
Amytal (Yamanouchi)
Isomytal (Nippon
Shinyaku)
USA: Amytal (Lilly)
Amytal Sodium (Lilly)
Tuinal (Lilly)
102
A
Amodiaquine
Amodiaquine
ATC: POlBA06
Use: antimalarial
RN: 86-42-0 MF:
C2,H,,C1N3O MW: 355.87 EINECS: 201-669-3
LD,,,: 550 mglkg (M, p.0.)
CN:
4-[(7-chloro-4-quinolinyl)amino]-2-[(diethylamino)methyl]phenol
dihydrochloride dihydrate
RN: 69-44-3 MF: C2,H22C1N30 2HC1 2H20 MW: 464.82 EINECS: 200-706-0
4.7-dichloro- 4-ominophenol
quinoline
(cf. chloroquine
synthesis)
formaldehyde diethylomine
7-chloro-4-(4-hydroxy-
phenylomino)quinoline
(I)
Amodioquine

US
2 474 821 (Parke Davis; 1949; prior. 1945).
Burckhalter, J.F. et al.: J. Am. Chem. Soc. (JACSAT)
68,
1894 (1946).
Fonnulation(s):
tabl. 200 mg (as dihydrochloride dihydrate)
Trade Name(s):
F: Flavoquine (Roussel GB: Camoquin (Parke Davis);
Diamant) wfm
USA: Camoquin (Parke Davis);
wfm
Amorolfine
ATC: DOlAE16
Use: topical antimycotic
RN: 78613-35-1 MF: C2,H,N0
MW:
317.52
CN:
cis-(f)-4-[3-[4-(1,1-dimethylpropyl)phenyl]-2-methylpropyl]-2,6-dimethylmorpholine
hydrochloride
RN: 78613-38-4 MF: C,,H3SN0. HCl
MW:
353.98
4-tert-omyl- propion-
benzoldehyde aldehyde
4-tert-omyl-a-methyl-
cinnomoldehyde
(I)
Amosulalol

A
103
H
cis-2,6-dimethyl- Arnorolfine
rnorpholine
Reference(s):
DE
2 752 135 (Hoffmann-La Roche; appl. 22.1 1.1976).
EP
24
334
(Hoffrnann-La Roche; appl. 7.8.1980; CH-prior. 17.8.1979, 29.5.1980).
antirnycotic nail varnish:
EP
389 778 (Hoffmann-La Roche; appl. 15.2.1990; CH-prior. 9.1 1.1989, 24.2.1989).
Formulation(s):
cream 0.25
%,
sol. 5
%
Trade
Name(s):
D:
Loccryl (Roche)
GB:
Loceryl (Roche; 1992 as
J:
Pekiron (Kyorin)
F:
Loceryl (Roche) hydrochloride)

Amosulalol
(YM-W538)
ATC: CO2CB
Use:
a-
and P-adrenoceptor blocker,
antihypertensive
RN: 85320-68-9 MF:
Cl,H,N,05S MW: 380.47
CN:
(+)-5-[1-hydroxy-2-[[2-(2-methoxyphenoxy)ethyl]amino]ethyl]-2-methylbe~enesulfonamide
monohy drochloride
RN: 70958-86-0 MF: Cl,H,N,05S
.
HCI MW: 416.93
Guoiacol 1,2-dibromo-
(2-rnethoxy- ethane
phenol)
3-amino-4-methyl-
acetaphenone
5-acetyl-2-methyl-
benzenesulfanornide
5-[[N-[2-(2-rnethoxyphenoxy)ethyl]-
benzylarnino]ocetyl]-2-methyl-
benzenesulfonomide
104
A
Amoxapine
H,.
Pd-C

0
I
Amosulalal
I
Reference(s):
DOS 2 843 016 (Yamanouchi; appl. 3.10.1978; J-prior.
12.10.1977,26.10.1977,23.12.1977,21.6.1978).
GB
2 006 772 (Yamanouchi; appl. 12.10.1978; J-prior. 12.10.1976, 26.10.1977, 23.12.1977, 21.6.1978).
synthesis of I:
Augstein,
1.
et al.:
J.
Med. Chem. (JMCMAR)
8,
365 (1965).
synthesis of 11:
EP 162 404 (Seitetsu Kagaku; appl. 14.5.1985; J-prior. 15.5.1984, 18.9.1984, 3.4.1985).
synthesis of
14~-amosulalol:
Arima,
H.;
Tamazawa, K.: J. Labelled Compd. Radiopham. (JLCRD4) 20,803 (1983)
Formulation(s):
tabl. 10 mg
Trade Name(s):
J: Lowgan (Yamanouchi;
1988 as hydrochloride)
Amoxapine

ATC: N06AA17
Use: antidepressant
RN: 14028-44-5 MF: C,,H&lN,O MW: 313.79 EINECS: 237-867-1
LD,,: 122 mglkg (M, i.p.); 112 mgkg (M, p.0.)
CN:
2-chloro-l l-(l-piperaztnyl)dibenzo[b,fl[l
,410xazepine

2.
H,.
Pd-C
___,
H
0
1.
1
-chloro-2-nitro- ethyl
benzene chloroformate
4-chlorophenal 2-(4-chlora-
phenaxy)anilins
1
-ethoxycarbanyl
piperazine
1
Amoxapine
Amoxicillin
A
105
Referencefs):
US 3 681 357 (American Cyanamide; 16.5.1972; prior. 20.5.1966).

US 3 444 169 (American Cyanamide; 13.5.1969; prior. 17.1.1966).
GB 1 177 956 (American Cyanamide; prior. 23.12.1966).
GB 1 192 812 (American Cyanamide; USA-prior. 20.5.1966).
DE
1 645 954 (American Cyanamide; appl. 17.1 .l967; USA-prior. 17.1.1966).
GB 1 157 957 (American Cyanamide; prior. 15.9.1965).
US 3 663 696 (American Cyanamide; 16.5.1972; prior. 28.2.1964, 20.5.1966,22.7.1970).
Schmutz,
J.
et al.: Helv. Chim. Acta (HCACAV) 50,245 (1967).
Schmutz, J. et al.: Chim. Ther. (CHTPBA) 2,424 (1967).
preparation of
2-(4-ch1orophenoxy)aniline:
DE
216 642 (Bayer; 1908).
Wassrnundt, F.W.; Pedemonte, R.P.:
J.
Org. Chern. (JOCEAH) 60 (16), 4991 (1995).
Formulation(s):
sol. 5
%;
sol. 5
%;
tabl. 25 mg, 50 mg, 100 mg, 150 mg
Trade Namefs):
F:
DCfanyl (Wyeth-Lederle)
1:
Amoxan (Lederle; 1981) USA: Asendin (Lederle Labs.;
GB: Asendis (Wyeth) 1980)

Amoxicillin
(Amoxycillin)
ATC: JOlCA04
Use: a'ntibiotic
RN: 26787-78-0 MF: C16H,,N305S
MW:
365.41 EINECS: 248-003-8
LD,,:
>25 gkg (M, p.0.);
>15
gkg
(R, p.0.)
CN:
[2S-[2a,5a,6~(S*)]]-6-[[amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-l-
azabicyclo[3.2.0]heptane-2-carboxylic
acid
sodium D(-)-a-(4-hydroxy- ethyl chloroformote
arnino)acetote
(DANE solt; cf.
ampicillin, method
HO
~o'oncH3
COOH
1.
(CH,),sicl. N(C2H5)3.
H"O-CH,
CH,O
CH3
1.
trimethyl-

chlorosilone
D-a-(4-hydroxyphenyl)-a-(2-
6-amino-
methoxycarbonyl-1 -methyl-
penicillonic acid (11)
etheny1amino)acetic acid
anhydride with monoethyl
carbonate (I)
106
A
Arnoxicillin
Arnoxicillin
trirnethyl-
chlorosilane
6-orninopenicillanic
acid trirnethylsilyl ester
(111)
D(-)-2-(4-hydraxypheny1)-
glycyl chloride hydrachlaride
arnoxicillin trirnethylsilyl ester
(IV)
Reference(s):
"racemic arnoxicillin":
US 3 674 776 (Beecham; 4.7.1972; prior. 23.8.1968).
GB 1 241 844 (Beecham; appl. 18.8.1969; prior. 23.8.1968).
DE 1 942 693 (Beecham; appl. 18.8.1969; GB-prior. 23.8.1968).
GB 978 178 (Beecham; appl. 2.11.1962; valid from 25.10.1963).
US
3 192 198 (Beecham; 29.6.1965; GB-prior. 2.11.1962).
amoxicillin:

Long, A.A.W. et al.: J. Chem. Soc. C (JSOOAX) 1971,1920.
US 3 674 776 (Beecham; 4.7.1972; appl. 18.8.1969; GB-prior. 23.8.1968).
DOS 1 942 693 (Beecham; appl. 21.8.1969; GB-prior. 23.8.1968).
GB 1 241 844 (Beecham; appl. 23.8.1968; valid from 20.8.1969).
a
US 4 128 547 (Gist-Brocades; 5.12.1978; NL-prior. 6.9.1977).
GB 1 339 605 (Beecham; appl. 1.4.1971; valid from 28.3.1972).
preparation of "DANE salt":
DE 2 400 489
(Upjohn Co.; appl. 5.1.1974; USA-prior. 12.1.1973).
US 3 904 606 (Upjohn Co.; prior. 12.1.1973).
Dane, E. et al.: Angew. Chem. (ANCEAD) 76,342 (1964).
Dane,
E.
et al.: Chem. Ber. (CHBEAM) 98,789 (1965).
b
DAS 2 61 1 286 (Bristol-Myers; appl. 17.3.1976; USA-prior. 17.3.1975).
preparation
of
D(-)-2-(4-hydroxypheny1)glycyl
chloride hydrochloride:
CA 1 024 507 (Bristol Myers Co.; appl. 16.1.1974; USA-prior. 18.1.1973)
Amoxicillin
A
107
alternative syntheses:
US 4 053 360 (Bristol-Myers; 11.10.1977; GB-prior. 5.6.1974, 19.3.1975).
DOS 2 454 841 (Archifar; appl. 19.1 1.1974; I-prior. 17.5.1974).
DOS 2 755 903 (Dobfar; appl. 15.12.1977; I-prior. 16.12.1976).
GB 1 535 291 (Bristol-Myers; appl. 5.3.1976; USA-prior. 17.3.1975).

US
4
098 796 (Novo; 4.7.1978; appl. 7.6.1976).
BE 867 414 (Antibioticos S.A.; appl. 24.5.1978; E-prior. 4.6.1977).
microbiologic acylation of
6-APA
with methyl
D-a-(4-hydroxypheny1)-glycinate
hydrochloride by means
of
Aphanocladium aranearum (ATCC 20453):
US
4
073 687 (Shionogi; 14.2.1978; J-prior. 14.5.1975).
sodium salt:
GB 1 543 317 (Beecham; valid from 4.8.1976; prior. 27.9.1975).
DOS 2 729 112 (Beecham; appl. 28.6.1977; GB-prior. 7.7.1976).
trihydrate:
DAS 2 61 1 286 (Bristol-Myers; appl. 17.3.1976; USA-prior. 17.3.1975).
DOS 2 732 528 (Bristol-Myers; appl. 19.7.1977; GB-prior. 20.7.1976).
water soluble salts with arginine or lysine:
GB
I
504 767 (Beecham; valid from 23.8.1976; prior. 2.7.1975,30.9.1975; 3.1 1.1975).
GB
1
539 510 (Beecham; valid from 23.8.1976; prior. 23.8.1975,30.9.1975, 3.1 1.1975).
"amorphous" amoxicillin:
DAS 2 112 634 (Beecham; appl. 16.3.1971; GB-prior. 16.3.1970).
,fomulation,for injection solutions:

GB 1 532 993 (Beecham; appl. 7.3.1975; valid from 9.2.1976).
0-acetylamoxicillin:
US
4
053 360 (Bristol-Myers; 11.10.1977; GB-prior. 5.6.1974, 19.3.1975).
Fomulation(s): syrup 500 mg/5 ml, 2.5
%,
5
%,
10
%;
tabl. 500 mg, 750 mg, 1 g
Trade Name(s):
D:
Amagesan (Pharbita)
Amoxi-Diolan (Engelhard)
Amoxillat (Azupharma)
Amoxypen (Grunenthal)
Augmentan (SmithKline
Beecham; 1982)-comb.
Clamoxyl (SmithKline
Beecham; 1974)
dura AX (durachemie)
Flanamox (Wolff)
Sigamopen (Kytta-
Siegfried)
F:
Agram (Inava)
Amodex (Bouchara)
Amophar (Dakota)

Amoxine (Negma)
Augmentin (SmithKline
Beecham; 1984)-comb.
Bactox (Innotech
International)
Bristamox (Bristol-Myers
Squibb)
Ciblor (1nava)-comb.
Clamoxyl (SmithKline
Beecham; 1974)
-
Flemoxine (Yamanouchi
Pharma)
Gramidil (EG Labo)
Hiconcil (Bristol-Myers
Squibb)
Zamocilline (Zambon)
GB:
Amoran (Eastern)
Amoxil (Bencard; 1972)
Augmentin (SmithKline
Beecham; 1984)-comb.
Galenamox (Galen)
I: Alfamox (Alfa
Wassermann)
Am-73 (Medici)
Amoflux (Lampugnani)
Amox (Salus Research)
Amoxina
(Magis)

Amoxipen (Metapharma)
Cabermox (Caber)
Ibiamox (IBI; as trihydrate)
Isimoxin (ISI)
Mopen (Firma)
Pamocil (Farma Uno)
Simoxil (Herdel)
Sintopen (Mitim)
Velamox (SmithKline
Beecham)
Zimox (Carlo Erba)
generics and numerous
combination preparations
J: Amolin (Takeda)
Clamoxyl (SmithKline
Beecham; 1975)
Delacillin (Sankyo)
Efpenix
(Toyo Jozo)
Hiconcil (Bristol)
Himinomax (Kaken)
Pacetocin (Kyowa)
Sawacillin (Fujisawa)
Widecillin (Meiji)
generics
USA: Amoxil (SmithKline
Beecham; 1974)
Wymox (Wyeth-Ayerst;
1978)
FX

108
A
Amphetaminil
Amphetaminil
Use: psychotonic
(Amfetaminil)
RN: 17590-01-
1
MF: C17H,,N2 MW: 250.35 EINECS: 241-560-8
LDS,,: 182 mgkg
(M,
p.0.);
37.6 mgkg (R,
p.0.)
CN:
cr-[(l-methy1-2-phenylethyl)amino]benzeneacetonitrile
2-amino-
1
-
sodium benzaldehyde Amphetaminil
phenylpropane cyanide
Reference(s):
AT 223 606 (Dr.
H.
Voigt;
appl.
25.4.1961;
valid
from 15.3.1962).
Klosa,

J.: J.
Prakt. Chem. (JPCEAO) 20,275 (1963).
Formulation(s): amp. 20 mg, 60 mg
Trade Name(s):
D: AN
1
(Voigt); wfm
Ton-0, (Voigt)-comb.; wfm
Vit-0, (Voigt)-comb.; wfm
Amphotericin
B
ATC: AOlAB04; GOlAA03; J02AAOI
Use: fungicidal antibiotic
RN: 1397-89-3 MF: C,,H7,NO17
MW:
924.09 EINECS: 215-742-2
LD,,: 1200 pg/kg
(M,
i.v.);
>8
gkg
(M,
p.0.);
1600 pgkg (R,
i.v.);
>5 g/kg
(R,
p.0.);
6 mg/kg (dog,
i.v.)

CN: [lR-
(lR*,3S*,5R*,6R*,9R*,l lR*, 15S*,16R*,17R*,I
8S*,l9E,21E,23E,25E,27E929E,3
1
E,33R*,35S*,36R*,37
S*)]-33-[(3-amino-3,6-dideoxy-~-~-mannopyranosyl)oxy]-l,3,5,6,9,11,17,37-octahydroxy-15,16,18-
trimethyl-13-oxo-14,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,3
1-heptaene-36-carboxylic
acid
1
Amphotericin
8
Ampicillin
A
109
Fementatively from
Streptomyces nodosus.
Reference(s):
US
2 908 61 1 (Olin Mathieson; 1959; prior. 1954).
Formulation(s):
caramels 10 mg; cream 30 mg/g; ointment 30 mg/l g; powder 50 mg; susp. 100 mg, 500 mg;
tabl. 10 mg, 100 mg; liposome-encapsulated amphotericin B in a complex with dimyristoyl
phosphatidylcholine and dimyristoyl phosphatidylglycerol, vials 20 ml
Trade Name(s):
D: AmBisome (NeXstar;
1999)
Ampho-Moronal (Bristol-
Myers Squibb)
Amphotericin B zur

Infusion (Bristol-Myers
Squibb)
Mysteclin (Bristol-Myers
Squibb)-comb.
F: Amphocycline (Bristol-
Myers Squibb)-comb.
Fungizone (Squibb) USA:
GB: Abelcet (Liposome Co.)
Ambisone (NeXstar)
Amphicol (Zeneca)
Fungilin
r (Squibb)
Fungizone (Squibb)
I: Fungilin (Mead Johnson)
Fungizone (Bristol-Myers
Squibb)
J: Fungizone (Bristol-Myers
Squibb-Sankyo)
Abelect Injection
(Liposome Co.)
Amphotec for Injection
(Sequus)
Fungizone (Bristol-Myers
Squibb, Oncology/
Immunology)
Ampicillin
ATC: JOlCAOI; SOlAA19
Use: antibiotic
RN: 69-53-4 MF: C16HlyN304S MW: 349.41 EINECS: 200-709-7
LD,,: 4600mgkg (M, i.v.); >5 g/kg

(M,
p.0.);
6200 mgkg (R, i.v.)
CN:
[2S-[2a,5a,6~(S*)]]-6-[(aminophenylacetyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-
azabicyclo[3.2.0]heptane-2-carboxylic
acid
trihydrate
RN: 7177-48-2 MF: C,,HIyN30,S
.
3H20 MW: 403.46
LD,,: 15.2 gkg (M, p.0.);
10 gfkg
(R,
p.o.1
monosodium salt
RN: 69-52-3 MF: Cl,H,,N3Na04S MW: 37 1.39 EINECS: 200-708-
1
LD,,: >5314 mg/kg (M,R, p.0.)
monopotassium salt
RN: 23277-71-6 MF: C,,H1,KN3O4S MW: 387.50 EINECS: 245-550-4
0
N(C2H5)3
___,
CI>O~CH~
triethyl-
K
0
amine
D(-)-Cbo-phenylglycine ethyl chloro- 0-Cbo-phenylglycine

formote (1) anhydride with monoethyl
carbonate
(11)
I1
+
H-N
0
-T
I
penicillanic acid (UI)
Cbo-am~icillin sodium salt (IV)
I
Ampicillin
D(-)-a-phenylglycine
chloride hydrochloride
D(-)-phenylglycine
methyl N-(2-methoxycorbonyl-1 -methyl-
sodium salt
ocetoocetate
etheny1)-D(-)-phenylglycine
sodium salt
(V)
1.
1
,
pyridine
2.111,
NaHC03
v
+

Reference(s):
a
GB 893 049 (Beecham; appl. 6.10.1958, 12.5.1959).
GB 902 703 (Beecham; valid from 19.5.1961; prior. 25.8.1960).
US 2 985 648 (Beecham; 23.5.1961; GB-prior. 6.10.1958).
DAS 1 139 844 (Beecham; appl. 6.10.1959; GB-prior.
6.10.1958, 12.5.1960).
DE
1
156 078 (Beecham; appl. 29.5.1961; GB-prior. 25.8.1960).
b
US 3 140 282 (Bristol-Myers; 7.7.1964; appl. 5.3.1962).
c
GB 991 586 (Beecham; appl. 28.2.1963, 3.12.1963; valid from 13.2.1964).
alternati~~e syntheses:
DE 1 168 910 (Beecham; appl. 3.7.1962; GB-prior. 21.7.1961).
US
3
144 445 (American Home; 11.8.1964; appl. 26.12.1962).
DAS 1 445 506 (Bristol-Myers; appl. 24.10.1963; USA-prior. 29.10.1962).
DAS
1
545 534 (Astra; appl. 4.3.1965; S-prior. 6.3.1964).
DAS 2 029 195 (Yamanouchi; appl. 13.6.1970; J-prior. 16.6.1969).
DAS 1 800 698 (American Home Products; appl. 2.10.1968; USA-prior. 2.10.1967).
DOS 2 755 903 (Dobfar; appl. 15.12.1977; I-prior. 16.12.1976).