Pharmaceutical Substances Syntheses, Patents, Applications - Part 10 pps

Aminocaproic acid
A
9
1
5-0x0-l0,ll-dihydro- 5-hydroxy- l0,l 1
-
5-chloro-l0,l
1
-dihydro-5H-
SH-dibenzo[o,d]cyclo- dihydro-5H-di-
dibenzo[a,d]cyclohep(ene
(I)
heptene benzo[a,d]cycloheptene
ethyl 7-aminoheptanoote
I
Amineptine
I
Reference (s):
DOS 2 01 1 806 (Science Union; appl. 12.3.1970; GB-P. 27.3.1969).
US 3 758 528 (Science Union; 11.9.1973; appl. 13.3.1970).
US 3 821 249 (Science Union; 28.6.1974; prior. 13.3.1970, 30.10.1972).
Fomularion(s):
tabl. 100 mg (as hydrochloride)
Trade Name(s):
F:
Survector (Euthtrapic;
1:
Maneon (Poli; 1983)
1978); wfm 1999 Survector (Stroder; 1983)
Aminocaproic acid
ATC: B02AAO1

(Acide aminocaproique; Epsilcapramin)
Use: antifibrinolytic, plasmin inhibitor
RN: 60-32-2 MF:
C6H,,N02 MW: 131.18 EINECS: 200-469-3
LD,,: 4900 mgkg (M, i.v.); 14.3 glkg (M, p.0.);
3300 mgkg (R, i.v.);
>7 glkg (dog, p.0.)
CN: 6-aminohexanoic acid
&-caproloctom
I
Aminocaproic acid
US 2 453 234 (American Enka Corp.; 1948; NL-prior. 1946).
Formularion(s):
inj. flask 250 mglml; syrup 25
%;
tabl. 500 mg
Trade Nanle(s):
D:
Epsilon-Aminocapronsaure
F: Hexalense (Leurquin) Resplamin (Kyorin)
"Roche" (Roche); wfm I: Caprolisin (Malesci) USA: Amicar (Immunex)
Epsilon-Tachostypan
J:
Capusumine (Nichiiko)
(Hormon-Chemie)-comb.; Hemotin (Hokuriku)
wfm
Ipsilon (Daiichi)
92
A
Aminoglutethimide

Aminoglutethimide
ATC: JO4AAO1
Use: antineoplastic (aromatase inhibitor)
RN:
125-84-8 MF: C,,H,,N,O, MW: 232.28 EINECS: 204-756-4
LD,,: 625 mglkg
(M,
i.p.)
CN:
3-(4-aminopheny1)-3-ethyl-2,6-piperidinedione
NO2
glutethimide 2-(4-nitropheny1)-
Aminoglutethimide
(q
v.)
2-ethylglutorimide
(I)
methyl ocrylote
"
l.=
2-phenyl-
butyronitrile
2-(4-nitropheny1)-
butyronitrile
Reference(s):
US 2 848 455 (Ciba; 1958; CH-prior. 1955).
racemate resolution:
Finch, N. et al.: Experientia (EXPEAM)
31,
1002 (1975).

Formulation(s):
tabl. 250 mg
Trade Name(s):
D: Orimeten (Novartis
F:
Orimkthe (Novartis) USA: Cytadren (Novartis)
Pharma)
GB: Orimeten (Novartis)
Rodazol (Novartis Pharma)
I:
Orimeten (Novartis)
Aminophenazone
(Amidophenazon; Amidopyrin; Aminopyrine)
ATC: N02BB03
Use: analgesic, antipyretic, anti-
inflammatory
RN:
58-15-1
MF:
C,,H,,N,O MW: 231.30 EINECS: 200-365-8
LDS,,: 78 mg/kg
(M,
i.v.); 350 mglkg (M, p.0.);
98 mglkg (R, i.v.); 285 mglkg
(R,
p.0.);
121 mglkg (dog, i.v.); 220 mglkg (dog, p.0.)
CN:
4-(dimethylamino)-l,2-dihydro-1,5-dimethyl-2-phenyl-3H-pyrazol-3-one
Aminopromazine

A
93
ascorbate
RN: 23635-43-0 MF: C,,H,,N,O
.
C6H80, MW: 407.42
ethyl acetoacetate phenylhydrazine
.
dimethyl sulfote
(I)
4-amino-2,3-dimethyl-
I
Aminophenarone
I
1 -phenyl-5-~3-
pyrazolone
Referencefs):
DRP 193 632 (E. Scheitlin; 1907).
Ehrhart, Ruschig
I,
171.
Formulation(s):
suppos. 200 mg, 500 mg; tabl. 100 mg, 300 mg
Trade Name(s):
D: Compretten (Cascan); wfm Pyramidon (Hoechst); wfm numerous combination
Dimametten (Hormosan); I: Farmidone (Farmitalia) preparations
wfm
Fugantil (Ghimas)
J:
Neophyllin (Nippon Eisai)

Aminopromazine
(Proquamezine)
Use: antispasmodic
RN: 58-37-7 MF: C,,H,,N,S MW: 327.50 EINECS: 200-378-9
CN:
N,N,Ar,Ar-tetramethy1-3-(1OH-phenothiazin-lO-yl)-l,2-propanediamine
fumarate
(2:l)
RN: 3688-62-8 MF: C1yHZSN3S. 1/2C4H404 MW: 771.06 EINECS: 222-987-9
a:?O
phenothiazine
3. fract. crystallization
of the hydrochlorides
1.
sodium amide
2.
1,3-bis(dimethy1omino)-
2-chloropropane
Arninopromazine
94
A
D-Aminosalicvlic acid
Reference(s):
GB 800 635 (Rh6ne-Poulenc; appl. 1954).
DE 1 034 637 (RhGne-Poulenc; appl. 1955; F-prior. 1954).
Trade Name(s):
D: Lorusil (Bayer); wfm F: Lispamol (Specia); wfm
p-Aminosalicylic acid
(Aminosalylum;
PAS)

ATC: J04AAOI
Use: tuberculostatic
RN: 65-49-6 MF:
C7H7N03 MW: 153.14 EINECS: 200-613-5
LD,,: 3898 mgkg (M, i.v.); 4 glkg (M, p.0.)
CN:
4-amino-2-hydroxybenzoic
acid
calcium salt
(2:l)
RN: 133- 15-3 MF: C14H12CaN206 MW: 344.34 EINECS: 205-095-4
LD,,,: 6500 mgkg (M, p.0.)
monosodium salt
RN: 133- 10-8 MF: C,H,NNaO? MW: 175.12 EINECS: 205-091 -2
qoH
+
CO,
KHC03.
5-
10
atm
NH2
3-amino- carbon
phenol dioxide
Reference(s):
US 2 540 104 (Parke Davis; 195 1
;
prior. 1949).
purijication:
US 2 844 625 (Miles, 1958; appl. 1954).

NH2
p-Aminosalicylic ocid
Fo~-mulation(s):
vial -1 3.49 g (as monosodium salt)
Trade Name(s):
D: Pas-Fatol N (Fatol) GB: Asacol (SmithKline
F:
B-PAS (Salvoxyl-Wander); Beecham)
Salf-Pas (Salf; as sodium
salt)
wfm
Pentasal (Yamanouchi)
J:
PAS Calcium (Sumitomo);
PAS Elbiol
Salofalk (Thames)
wfm
(Pharmacotechnie); wfm
I:
Eupasal sodico (Bieffe
Sanpas Cal. (Sankyo); wfm
Medital; as sodium salt) USA: Paser (Jacobus)
Amiodarone
ATC: COlBDOl
Use: antiarrhythmic
RN: 1951-25-3 MF: C25H2912N03 MW: 645.32 EINECS: 217-772-1
LD,,,: 178mg/kg(M,i.v.);>4g/kg(M,p.o.)
CN:
(2-butyl-3-benzofuranyl)[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone
hydrochloride

RN: 19774-82-4 MF: C2,H2,I2NO,
.
HCI MW: 681.78
0
0
a+
doLcH3
H2N-NHl
0
H20
wCH3
H3C hydrazine
'
hydrate
benzofuron butyric anhydride 2-butyrylbenzofuran 2-butylbenzofuran
(I)
I
0.
CH3 hydrochloride
CH3
4-rnethoxy- 2-butyl-3-(4-methoxy- 2-butyl-3-(4-hydroxy-
benzoyl chloride
benzoy1)-benzofuron benzoyl)-benzofuron
(11)
2-butyI-3-(4-hydroxy-
3,5-diiado-benzayl).
benzofuron
(C"3
"a
Cti-0th

~~''~~3
\
OH P-diethylornina-
ethyl chloride
I
Arniodarone
I
/'o
-
I
Reference(s):
FR
1 339 389 (Labaz; appl. 22.11.1962).
US
3 248 401 (Labaz; 26.4.1966; prior. 24.1 1.1961).
2-butylbenzofuran:
Buu-Hoi', N.P. et al.:
J.
Chem. Soc. (JCSOA9)
1964,
173.
Formulation(s):
inj.
sol. 150 mgl3ml; tabl. 200 mg
Trade Name(s):
D: Cordarex (Sanofi
F:
Cordarone (Sanofi
I:
Winthrop) Winthrop)

Tachydaron (ASTA Medica
GB:
Cordarone
X
(Sanofi USA:
AWD) Winthrop)
Amiodar (Midy)
Cordarone (Sigma-Tau)
Cordarone (Wyeth-Ayerst;
as hydrochloride)
Amiphenazole
ATC: R07A
Use: respiratory stimulant, morphine
antagonist, antidote (barbiturate
poisonings)
RN: 490-55-1 MF:
C9HyN,S MW: 191.26 EINECS: 207-713-8
LD,,,: 400 mglkg (M, p.0.)
CN:
5-phenyl-2,4-thiazolediamine
monohy drochloride
RN: 942-31-4 MF: C,HyN3S. HC1 MW: 227.72 EINECS: 213-389-9
LD,,,: 372 mglkg (M, p.0.)
thiourea a-bromo-
phenylocetonitrile
Reference(s):
Davis, W. et al.: J. Chem. Soc. (JSCOA9) 1955, 3491.
Chase,
B.H.
et al.: J. Chem. Soc. (JSCOA9) 1955,4443.

Formulation(s):
inj. flask 150 mg
Trade Narne(s):
9
/+NH,
N
H2N
Arniphenozole
,
.
D: Daptazile 100 (Nicholas); Daptazile Injektion
GB:
wfm (Nicholas); wfm
Daptazole (Nicholas); wfm
Amitriptyline
ATC: N06AA09
Use: antidepressant
RN: 50-48-6 MF: C,,H,,N MW: 277.41 EINECS: 200-041-6
LD,,,: 16mgkg(M,i.v.); 140mg/kg(M,p.o.);
320 mgtkg (R, p.0.)
CN:
3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-l-propanamine
hydrochloride
RN: 549-18-8 MF: Cz0H2,N
.
HC1 MW: 313.87 EINECS: 208-964-6
LDSo: 21 mgkg (M, i.v.); 140 mgkg (M, p.0.);
14 mgkg (R, i.v.); 240 mgkg (R, p.0.);
>27 mgkg (dog, i.v.)
CH3

dibenzosuberone
(I)
3-dimcthylominopropyl-
5-(3-dimethylominopropyl)-
magnesium chloride
l0,ll
-dihydro-5H-
I
Amitriptyline
Amitriptylinoxide
A
97
I11
cyclopropyl-
magnesium
bromide
5-(3-bromopropylidene)-
10,l
1-dihydro-5H-
dibenzo[o.d]cycloheptene
(IU)
CH3
dimethylomine
Reference(s):
a
GB 858 187 (Hoffmann- .La Roche; appl. 24.3.1959; CH-prior. 3.4.1958).
DE 1 109 166 (Hoffmann-La Roche; appl. 16.3.1959; CH-prior. 3.4.1958).
BE 584 061 (Merck
&
Co.; appl. 27.10.1959; USA-prior. 31.10.1958).

BE 609 095 (Kefalas AIS; appl. 12.10.1961; DK-prior. 12.10.1960).
b
Hoffsommer, R.D. et al.:
J.
Org. Chem. (JOCEAH) 27,4134 (1962).
alternative synthesis:
DAS 1 468 138 (Kefalas; appl.
12.3.1963; GB-prior. 23.3.1962,9.11.1962).
US 3 205 264 (Merck
&
Co.; 7.9.1965; appl. 15.6.1962).
Formulation(s): amp. 56.6 mg; f. c. tabl. 10 mg, 25 mg, 50 mg; drg. 11.32 mg, 28.3 mg; drops 40 mg/l ml;
inj. 50 mg/2 ml; tabl. 25 mg, 50 mg (as hydrochloride)
Trade
Name(s):
D: Amineurin (Neuro Hexal) I:
Limbatril (ICN)
Saroten (Bayer Vital)
F:
Elavil (Merck Sharp
&
Dohme-Chibret)
Laroxyl (Roche)
GB: Lentizol (Parke Davis)
Triptafen (Goldshield)-
comb.
Tryptizol (Morson)
Adepril (Lepetit)
Amilit-ifi (IFI)
Amitript (Formulario Naz.)

Diapatol (Teofarma)-comb.
Laroxyl (Roche)
Limbitryl (Roche)-comb.
Sedans (Ganassini)-comb.
Triptizol (Merck Sharp
&
Dohme)
combination preparations
J: Tryptanol (Merck-Banyu;
as hydrochloride)
USA: Elavil (Zeneca; as
hydrochloride)
Etrafon (Schering)
Limbitrol
(Roche Products;
as hydrochloride)
Triavil (Merck; as
hydrochloride)
generics
Amitriptylinoxide
ATC: N06AA09
Use: antidepressant
RN: 4317-14-0 MF:
C,,H,,NO MW: 293.41
LD,,: 320 mg/kg (M, i.p.); 87 mglkg (M, i.v.); 330 mg/kg (M, p.0.);
120 mgkg (R, i.p.); 25 mg/kg (R, i.v.); 1800 mg/kg (R, p.0.);
330-460 mglkg (rabbit, p.0.);
330 mglkg (dog, p.0.)
CN:
3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-l-propanamine

N-oxide
98
A
Amixetrine
ornitriptyline
I
Arnitriptylinoxide
pH3
+
HO-N,
Br
CH3
5-(3- bromopropy1idene)- N,N-dimethyl-
10.1
1
-dihydro-5H- hydroxylamine
dibenzo[o.d]cycloheptene
(cf.
ornitriptyline synthesis)
Reference(s):
DE 1 243 180 (Dumex; appl. 15.2.1964; GB-prior. 20.2.1963).
FR-M 3 222 (Dumex; appl. 20.2.1964; GB-prior. 20.2.1963).
NL-appl. 6 51 1 947 (Merck
&
Co., appl. 14.9.1965; USA-prior. 14.9 1964).
Fortnulation(s):
tabl. 30 mg, 60 mg, 90 mg, 120 mg
Trade Narne(s):
D: Equilibrin (Rh6ne-Poulenc
Rorer)

Amixetrine
ATC: N06A; R03BB
Use: anticholinergic, antidepressant,
antispasmodic
RN: 24622-72-8 MF: C,,H,NO MW: 261.41
CN:
1-(2-(3-methy1butoxy)-2-phenylethyllpyrrolidine
hydrochloride
RN: 24622-52-4 MF: C,,H,,NO. HCl MW: 297.87 EINECS: 246-365-1
-CH,
tert-butyl
-
codCH3
pyrrolidine
hypobrornite
Br
styrene isoomyl alcohol
a-isoomyloxy-
phenethyl bromide
Reference(s):
DOS
1
81 1 767 (Mauvernay; appl. 29.1 1.1968; F-prior. 15.12.1967).
Amixetrine
Formulation(s):
tabl. 50 mg
Trade Name(s):
F: Somagest (Riom); wfm
Amlexanox
A

99
Amlexanox
(AA-673)
ATC: R03DXO
I
;
R06AX
Use: antiallergic, antiasthmatic
RN.
68302-57-8 MF:
CI,H,,N20,
MW: 198.30
LD,:
2320
mgkg
(M.
p.a
):
10
@g
(R.
p.0.)
CN.
2-amino-7-(
I-methylethyl)-5-0x0-SH-[I
~henzopyrano[2,3-b]pyr1dine-3-carhc~xyl~c
ac~d
2-hydroxy-5-isopropyl- dimelhyl- 6-isopropy-4-0x0-
acetophenone formornide
4H-1

-benzopyran-3-
corboxaldehyde
(I)
n
NHIOH
OVNH
,
DMF
1
-
H3C
hydroxylomine
CN
morpholinc
.
dimethyl-
CHO
CH3
*
formornnde
.
CH3
0
6-ixopropyl-4-oro- 2-amino-6-isopropyl-
4H-
I-
benropyron- 4-0x0-4H- 1-bentopyron-
3-corbonitrila 3-carboxoldehyde
(D)
ethyl

cyonoacetote
I
Amlexanox
1.
pipcridinc
0
2.
H2S0,
+
Ncdo~CH3
F
Refcrerrrr(s):
DOS
2
809 720 (Takeda: appl. 7.3.1978; J-prior. 8.3.1977,20.12.1977)
US
4 143 042
(Takeda;
6.3.1979; J-prior. 8.3.1977, 20.12.1977).
CIS
4
255 576 (Takcda; 10.3.1981; J-prior. 8.3.1977, 10.12.1977).
US
4
299
963 (Takcda; 10.1 1.1981; J-prior. 8.3.1977. 10.12.1977).
Nohara,
A.
ct
al.: J. Mcd. Chcrn. (JMCMAR)

28.559
(1985).
sydiesis
of6-isopropyl-4H-
1
-benxopyran-3-carbonitri1e:
H3C
aNH2
COOH
CHJ
0
US
3
896
1
14
(Takeda Chemical Ind.; appl. 22.7.1975; J-prior. 12.4.1972, 14.4.1072).
DE
2
3
17
898
(Takeda Chemical
Ind.;
appl. 25.10.1973; J-prior. 12.4.1972).
Funn~rlr~rion{s):
cream
5
%o;
tabl. 100 mp

Trade
N(~me(a
):
J:
Solfa (Takeda: 1989) USA: Aphthasol (Block
Drug
Company)
Amlodipine
ATC:
COZDE:
CORCAOI
Use:
calcium antagon~st. antianginal.
antlhypcrtensivc
RN:
88150-42-9
MF:
C,H,,C1N20,
MW:
408.88
CN:
2-i(2-aniinoethoxy
)methyl]-4-i2-c21lorophenyl)-
1,4-di
hydro-6-methyl-3.5-pyridinedicarboxylic
acid
3-
ethyl 5-methyl ester
100
A

Amlodipine
rnaleate
(1:l)
RN: 88150-47-4 MF: C20H,5ClN20, . C4H404 MW: 524.95
ethyl 4-chloro-
ocetooctote
CHO
+&I+
2-chlora-
benzaldehyde
methyl 3-omino-
crotonate
ethyl 4-(2-ozidoethoxy)
ocetoocetote
(1)
3-ethyl 5-methyl 2-[(2-ozido-
ethoxy)methyl]-4-(2-chloropheny1)-
1.4-dihydro-6-methyl-3.5-
pyridinedicarbaxylote
(U)
Arnlodipine
Reference(s):
EP 89 167 (Pfizer; appl. 8.3.1983; GB-prior. 11.3.1982).
EP 599 220 (Lek; appl. 19.11.1993; SI-prior. 26.1 1.1992).
CA 2 188 071 (Apotex; appl. 17.10.1996; NZ-prior. 1.1 1 .l995).
besylate salt:
EP 244 944 (Pfizer; appl. 31.3.1987; GB-prior. 4.4.1986).
racemate resolution:
.
EP 331 315 (Pfizer; appl. 16.2.1989; GB-prior. 27.2.1988).

Arrowsmith, J.E. et
al.:
J. Med. Chem. (JMCMAR)
29,
1696 (1986).
combination with ACE-inhibitors:
WO 9 628 185 (Pfizer; appl. 26.2.1996; USA-prior. 16.3.1 995).
Formulation(s):
cps. 5 mg, 15 mg, 20 mg; tabl. 2.5 mg, 5 mg, 10 mg
Trade Name(s):
D:
Norvasc (Mack, Illert; I: Antacal (Errekappa J: Amlodin (Sumitomo)
Pfizer) Euroter.; 1991)
Norvasc (Pfizer)
F:
Amlor (Pfizer)
Monopina (Bioindustria; USA: Lotrel (Novartis)
GB:
Istin (Pfizer; 1990)
1991) Norvasc (Pfizer; 1991)
Norvasc (Pfizer; 1990)