Pharmaceutical Substances Syntheses, Patents, Applications - Part 6 doc

Alcuronium chloride
A
Trade Name(s):
D:
Delonal (Essex Pharma; GB: Modrasone (Dominion;
J:
Almeta (Shionogi)
1985) 1986) USA: Aclovate (Glaxo Wellcome;
\
F:
Aclosone (Schering- I: Legederm (Schering- 1986)
Plough) Plough; 1988)
Alcuronium chloride
ATC: M03AAOl
Use: muscle relaxant
RN: 15180-03-7 MF: C44H50CIZN402 MW: 737.82 EINECS: 239-229-8
LD,,:
610 pglkg (M, i.p.); 240 pglkg (M, i.v.); 38500 pglkg (M, p.0.); 610 pglkg (M, s.c.);
270 pgkg
(R,
i.p.); 27600 pglkg (R, p.0.); 280 pglkg (R, s.c.)
CN:
[iR-(la,3aS*,lOa,l
la~,12a,14aS*,19aa,20ba,21a,22a~,23E,26]-2,3,11,1
la,13,14,22,22a-octahydro-
23,26-bis(2-hydroxyethylidene)-l ,
12-di-2-propenyl-1OH,19aH,20bH,21H-1,21:
10,12-diethano-
dipyrrolo[3,2-~3',2'-f1[1,5]diazocino[3,2,1-jk:7,6,5-j'k']dicarbazolium
dichloride
iodide

Wieland-Gumlich aldehyde
(degradation product of strychnine)
IRA-400
(CI form)
A
N(b)-ollyl-heminortoxi-
ferine iodide
(1)
diollylnortoxiferin diiodide
(11)
Alcuronium chloride
52
A
Aldosterone
Reference(s):
US 3 080 373 (Roche; 5.3.1963; F-prior. 29.8.1960).
Karrer,
P.
et al.: Angew. Chem. (ANCEAD)
70,
644 (1958).
Formulation(s): amp. 5 ml, 10 ml(1 mg/ml); inj. sol. 10 mg/2 ml
Trade Name(s):
D:
Alloferin Amp. (Roche) GB: Alloferin (Roche); wfm USA: Alloferin (Roche); wfm
F: Allofkrine (Roche); wfm J: Dialferin (Roche)
Aldosterone
ATC:
Use:
RN: 52-39-1 MF: C2,H2,0, MW: 360.45 EINECS: 200-139-9

CN: (1 1
p)-
11,21-dihydroxy-3,20-dioxopregn-4-en-18-a1
&
nH3
-I, nitrosyl pyridine,
&
Me
H
'cH3
H
H
chloride
H
H
0
/
0
/
21
-0-ocetyl-1 1-0-nitrosyl-
corticosterone
(I)
H02AAO1
mineralocorticoid
bosic soponificotion
-
21
-0-ocetyloldosterone
(II)

Reference(s):
Aldosterone
Barton, D.H.R.; Beaton, J.M.: J. Am. Chem. Soc. (JACSAT),
82,
2641 (1960).
starting material:
The Merck Index, 25 13 (Rahway 1976).
alternative syntheses:
US 3 002 972 (Ciba; 3.10.1961; appl. 28.1 1.1958; CH-prior. 5.12.1957).
US 3 014 029 (Ciba; 19.12.1961; appl. 16.6.1959; CH-prior. 18.6.1958).
US 3 049 539 (Wisconsin Alumni Res. Found.; 14.8.1962; appl. 29.7.1957).
Wettstein, A. et al.: Helv. Chim. Acta (HCACAV)
44,
502 (1961).
Reichstein, T. et a].: Helv. Chim. Acta (HCACAV)
38,
1432 (1957).
review:
Fieser, L.F.; Fieser, M.: Steroide p. 766
ff,
Verlag Chemie, Weinheim 1961.
Alendronate sodium
A
53
total synthesis:
Johnson, P.S. et al.:
J.
Am. Chem. Soc. (JACSAT) 80,2585 (1958).
Blickenstaff, R.T.; Ghosh, A.C.; Wolf, G.C.: Total Synthesis of Steroids (Organic Chemistry Vol. 30) p. 187
ff,

Academic Press, New York, London 1974.
Formulation(s):
tabl. 500 mg, 750 mg
Trade Name(s):
D: Aldocorten (Ciba); wfm USA: Aldocortin (Burroughs
GB:
Aldocorten (Ciba); wfm Wellcome); wfm
I:
Sinsurrene Forte (Parke Electrocortin (Ciba-Geigy);
Davis)-comb. wfm
Alendronate sodium
ATC: M05BA04
Use: treatment of osteoporosis
RN:
121268-17-5 MF: C,H,,NNaO,P,. 3H20 MW: 325.12
LD,,: >4 glkg (dog, p. 0.)
CN:
(4-Amino-1-hydroxybutylidene)bis[phosphonic
acid] monosodium salt trihydrate
acid
RN: 66376-36-1 MF: C,H,,NO,P, MW: 249.10
anhydrous monosodium
salt
RN:
1293 18-43-0 MF: C4HI2NNaO,P2 MW: 271.08
y-ominobutyric acid
1.
140°C.
50
psi.

20h.
0
379;
HCI
Alendronote sodium
I
Reference(s):
WO 9 506 052 (Merck
&
Co.; USA-prior. 25.8.1993).
WO 9 533 756 (Merck
&
Co.; appl. 2.6.1995; USA-prior. 6.6.1994).
US 5 510 517 (Merck
&
Co.; 2.3.1995; USA-prior. 25.8.1993).
DE 3 016 289 (Henkel KG; D-prior. 28.4.1980).
BE896 453 (1st. Gentili s.
p.
a.; appl. 14.4.1983; I-prior. 15.4.1982, 16.2.1983).
BE903 513 (1st. Ccntili s. p. a.; appl. 25.10.1985; I-prior. 29.10.1984).
EP
494 844 (1st. Gentili s.
p.
a.; appl. 2.1.1992; I-prior. 8.1.1991).
US 4 621 077 (1st. Gentili s. p. a,; 8.6.1984; I-prior. 15.4.1982).
US 5 019 651 (Merck
&
Co.; 27.12.1991; USA-prior. 20.6.1990).
US 4 922 007 (Merck

&
Co.; 1.5.1990; USA-prior. 9.6.1989).
alternative process for
the
production of
alendronate:
WO 9 834 940 (Apotcx Inc.; CA-prior. 11.2.1997).
Formulation(s):
amp. 5 mg, 10 mg; tabl. 5 mg, 10 mg, 40 mg (as sodium salt)
54
A
Alfacalcidol
Trade
Name(s):
D: Fosamax (Merck Sharp
&
Alendros (Gentili) 'Teiroc (Teijin)
Dohme) Dronal (Sigmatau) USA: Fosamax (Merck Sharp
&.
GB: Fosamax (Merck Sharp
&
Fosamax (Merck Sharp
&
Dohme; 1993)
Dohme)
Dohme)
I:
Adronat (Neopharmed)
J:
Onclast (Banyu)

Alfacalcidol
ATC:
AI
ICCO~
(la-Hydroxycholecalciferol;
la-Hydroxy-vitamin
D,)
Use:
vitamin D-derivative
RN: 41294-56-8 MF: C,,H,O,
MW:
400.65 EINECS: 255-297-1
LD,,:
440
g/kg (M, p.0.);
340 g/kg (R, p.0.)
CN:
(la,3~,5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-l,3-diol
CH3
KOC(CH,),
potassium
tert-butylote
0
3-0x0-1.4.6-cholestatriene
3-0x0-1.5.7-cholestotriene
(I)
NoBH.,
sodium
borohydride
3-chloroper-

benzoic acid
lithium
aluminum
la-hydroxyprovitomin
4
(U1)
Alfadolone acetate
A
55
Alfocolcidoi
Reference(s):
US 3 929 770 (Wisconsin Alumni Res.; 30.12. 1975; J-prior. 3.12.1973).
alternative syntheses:
Holick, M.F. et al.: Science (Washington, D.C.) (SCIEAS)
180,
190 (1973).
Barton, D.H.R. et al.: J. Am. Chem. Soc. (JACSAT) 95,2748 (1973)
Fiirst, A. et al.: Helv. Chim. Acta (HCACAV) 56, 1708 (1973).
US 3 966 777 (Yeda Res.
&
Devel.; 29.6.1976; IL-prior. 22.10.1974).
DOS 2 259 661 (Wisconsin Alumni Res.; appl. 1.12.1972; USA-prior. 2.12.1971).
BE 877 356 (Wisconsin Alumni Res.; appl. 28.6.1979; USA-prior. 15.1.1979, 21.5.1979).
GB 1 553 321 (Merck
&
Co.; valid from 30.6.1977; USA-prior. 1.7.1976).
.
DOS 2 923 953 (Upjohn; appl. 13.6.1979; USA-prior. 19.6.1978).
total synthesis:
Harrison, R.G. et al.: Tetrahedron Lett. (TELEAY) 1973, 3649.

synthesis of intermediates:
US 4 046 760 (Merck
&
Co., 6.9.1977; prior. 1.7.1976).
pharmaceutical formulation:
JP-appl. 78 136 512 (Chugai; appl. 28.4.1977).
US 4 164 569 (Chugai; 14.8.1979; J-prior. 8.4.1977)
use as anti-inflammatory:
FX
2 389 377 (J. Brohult, appl. 6.5.1977).
Formulation(s):
amp. 0.001 mg, 0.002 mg; cps. 0.001 mg, 0.0025 mg, 1 mg; inj. 2 yglml
Trade Name(s):
D: Bondiol (Gry) One Alpha (Leo) Diseon (Smith Kline
&
Eins Alpha (Leo) I: Dediol (Rhhe-Poulenc French)
-
F: Un-Alfa (Leo) Rorer) J: Alfarol (Chugai)
GB: Alfa D (Berk)
Alfadolone acetate
(Alphadolone acetate)
ATC: NOlA
Use: anesthetic (intravenous)
RN: 23930-37-2 MF:
C23H3405 MW: 390.52 EINECS: 245-942-5
LD5,,: >30 mglkg (rabbit, i.v.)
CN:
(3a,5a)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione
alfadolone
RN: 14107-37-0 MF: C2,H320,

MW:
348.48 EINECS: 237-961-2
LD,,,: 59 mgkg (M,
i.v.)
56
A
Alfaxalone
-
ride etherote
alfaxalone
(I)
lead tetraacetate
(4.
v.)
Alfodolane ocetote
Br
0
Br2.HBr. CH,OH
I
H3C4&, acetone
bromine patossium acetate
Reference(s):
DE 2 030 402 (Glaxo; appl. 19.6.1970; GB-prior. 20.6.1969; 11.6.1970).
ZA 703 861 (Glaxo; appl. 8.6.1970; GB-prior. 20.6.1969)
(alternative synthesis).
Browne, P.A.; Kirk, D.N.: J. Chem. Soc. (JCSOA9)
1969,
1653.
Formulalion(s):
amp. 0.5 mglml

Trade Name(s):
D:
Aurantex (Glaxo)-comb.; GB: Althesin (G1axo)-comb.;
wfm wfm
F:
Alfatesine (G1axo)-comb.;
I:
Althesin (G1axo)-comb.;
wfm wfm
Alfaxalone
(Alphaxalone)
ATC: NOlAXO5
Use: anesthetic (intravenous)
RN: 23930-19-0 MF: C2,H3,0, MW: 332.48
LDso:
430 mdkg
(M,
i.p.); 36.9 mglkg
(M,
i.v.); 880 mgikg (M, p.0.); 5220 mglkg (M,
s.c.);
1
16 mdkg (R, i.p.); 19.4 mglkg (R, i.v.); 297
mglkg
(R, p.0.); >2200 mgkg (R, s.c.);
9.36 mgkg (rabbit, i.v.)
CN:
(3o?,5a)-3-hydroxypregnane-l1,20-dione
acetate
RN: 51267-69-7 MF: C23H3404 MW: 374.52

Rhizopus nigricans
progesterone
11
u-hydroxypragesterone
Alfaxalone
A
57
Cr03. HOAc
I
la-hydroxy-5a-pregnone-
3,20-dione
(I)
pregnone
(U)
H2lrCI6, P(OCH3)3. (CH&HOH
(Henbest reduction)
u
b
hexochloro- trimethyl
iridic phosphite
acid
Alfoxalone
1
1
-oxotigogenin
(from
hecogenin)
1.
TOSCI
,

pyridine
2.
0
H~C~
OK
,
DMF
v
-
1.
HZ. Pd-C
2. NoOH
___*
11
-20-dioxo-3p-hydroxy-
5a-pregnane
(V)
Alfaxolone ocetote
1
a
Browne, P.A.; Kirk, D.N.: J.
Chem.
Soc.
C
(JSOOAX)
1969,
1653.
b
Naaata.
W.

et al.: Helv.
Chim.
Acta (HCACAV)
42.
1399 (1959).
5
8
A
Alfentanil
medical use:
DE 2 030 402 (Glaxo; appl. 19.6.1970; GB-prior. 20.6.1969, 11.6.1970).
Formulation(s): amp. 5 ml, 10 ml, 0.3
%
Trade Natne(s):
J: Alphadione (Shin Nihon
Jitsugyo)
Alfentanil
ATC: NOlAH02
Use: analgesic, short-time anesthetic (for
basal narcosis)
RN: 71195-58-9 MF: C2,H32N,03 MW: 416.53
CN:
N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-l-yl)ethyl]-4-(methoxymethyl)-4-pipe~dinyl]-N-
phenylpropanamide
monohydrochloride
RN: 69049-06-5 MF: C21H32N,03
.
HCl MW: 452.99 EINECS: 273-846-3
monohydrochloride monohydrate
RN: 70879-28-6 MF: C2,H32N,0,

.
HC1. H20 MW: 471.00
ethyl sodium
isocyanate azide
chloroethone
(1)
p
H0vCH3
.
HCI
0
+
ON,
+
HCN
A
11
0
I
-benzyl-4- aniline hydrogen
piperidane
cyanide
propionic
anhydride
Alfuzosin
A
59
Alfentonil
L
Reference(s):

GB
1
598 872 (Janssen; appl. 3.5.1978; USA-prior. 5.5.1977).
DOS
2
819 873 (Janssen; appl. 5.5.1978; USA-prior. 5.5.1977, 13.3.1978).
17s 4 167 574 (Janssen; 11.9.1979; appl. 25.10.1978; prior. 13.3.1978).
Forrnulution(s):
amp. 500
pglml;
inj. sol.
I
mgl2 ml, 5 mg/lO ml; intensive care inj.
5
mgtml
Trade Nutne(s):
D: Rapifen (Janssen-Cilag; GB: Rapifen (Janssen-Cilag;
1983) 1983)
F:
Rapifen (Janssen-Cilag) USA: Alfenta (Janssen; 1987)
Alfuzosin
ATC: C02CA; G04CBOl
Use: antihypertensive, a,-antagonist,
treatment
6f benign prostatic
hypertrophy
RN:
81403-80-7
MF:
C,,HnN504

MW
389.46
CN:
(+)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazalinyl)methylamino]propyl]tetrahydro-2-furancarboxamide
monohydrochloride
RN:
81403-68-1
MF:
C19H27N504. HCI
MW
425.92
3.
NH,
OHCaO-CH~
*No3
,
OHC~~'~~:
,
,
.
I12N~-~~3
0-CH,
O2N
02N
0-CH~
perrnongonate
3,4-dirnethoxybenz-
aldehyde
(veratroldehyde)
0 0

Fe,
CH,COOH
b
H2N%-"3
I.
won urea
+
HNW-CHJ
HzN
0-CH3
OAN
/
0-CH3
H
2-amino-4.5-di-
rnethoxybenzomide
60
A
Algestone acetophenide
CI
POCI,
II
NW-C'~
ClhN 0-CH,
4-amino-2-chloro-
6,7-dimethoxy-
quinazoline (111)
triethylarnine
0 0
'

"i
~COOH
+
-
@oAo-cH3
CH~
bnr
3-(methylomino)-
tetrohydrofuran- ethyl
2-corboxylic acid chloroformote
proponenitrile
N-tetrahydrofuroyl-
ethylomine
(N)
hydrofuroyl-trime-
thylenediomine (V)
Reference(s):
US 4 315 007 (Synthelabo; 9.2.1982; F-prior. 6.2.1978, 29.12.1978).
DE 290 445 (Synthelabo; appl. 16.8.1979; F-prior. 6.2.1978,29.12.1978).
Manoury,
P.M.
et al.: J. Med. Chem. (JMCMAR)
29,
19 (1986).
isoomyl alcohol
v
+
111
synthesis of
6,7-dimethoxyquinazoline-2,4-dione:

Althuis, T.H.; Hess, H.J.: J. Med. Chem. (JMCMAR)
20,
146 (1977).
Nb-CH3
d#Mr*N
0-CHI
C"3
Alfuzosin
Formulation(s):
tabl. 2.5 mg (as hydrochloride)
Trade Name(s):
D: Urion (Byk Gulden) Xatral (SynthClabo; 1989) Xatral (Synthelabo)
Uroxatral (Synthelabo) GB: Xatral (Lorex)
F: Urion (Zambon) I: Mittoval (Schering)
Algestone acetophenide
ATC: DlOAX; G03DA
(Alfasone acetophenide; Alphasone acetophenide) Use: antiacne, progestogen
RN: 24356-94-3 MF:
C2,H3,04 MW: 448.60 EINECS: 246-195-8
CN:
[16a(R)]-16,17-[(l-phenylethylidene)bis(oxy)]pregn-4-ene-3,2O-dione
dgestone
RN: 595-77-7 MF: C2,H3,0, MW: 346.47 EINECS: 209-869-2