Pharmaceutical Substances Syntheses, Patents, Applications - Part 68 ppsx

Dinoprost
D
671
KOH.
CuBF4 OMSO
-1
0
hc!
C
N
2,4-cyclopenta- 2-chloro-
dienylrnethyl ocrylonitr~le
1
I
benzyl ether
1.
H20. H+
2.
resolution with
(+)-ephedrine
-
11
1.
NaOH
HOOCh
1.
(C4H&SnH. NBN
2. Hz. Pd-C
,
111
OH

1
tr~butylstannone
chloride
1.
Collins' reagent
:o
2. dimethyl 2-oxoheptylphosphonate sodium salt.
dimethoxyethone
(-)-Corey lactone (111)
1.
reagent from limonen and thexylborane.
tert-butyllithium
672
D
Dinoprost
HO
OH
2.
diisobutylolurninurn hydride
('4
'
No+
1.
-cHZ/S\cH3
9'2,-
2.
CH,COOH.
H,,
THF
1.

dirnethylsulfoxide
sodium salt
5-triphenylphosphonio-
pentonecorboxylote
Dinoprost
Corey, E.J. et al.: J. Am. Chem. Soc. (JACSAT) 91,5675 (1969).
Corey, E.J. et a].: J. Am. Chem. Soc. (JACSAT) 92, 397 (1970).
Corey, E.J. et al.: J. Am. Chem.
Soc. (JACSAT) 92,2586 (1970).
Corey, E.J. et al.: J. Am. Chem. Soc. (JACSAT) 93, 1491 (1971).
alternative syntheses:
Fried, J. et al.: J. Am. Chem. Soc. (JACSAT) 94,4342,4343 (1972).
Corey,
E.J.
et a].: Tetrahedron Lett. (TELEAY) 1970,307.
Bundy, G.L. et al.: J. Am. Chem. Soc. (JACSAT) 94,2123 (1972).
Corey, E.J.; Varma, R.K.: J. Am. Chem.
Soc. (JACSAT) 93,73 19 (1971).
Schneider,
W.P.;
Murray, H.C.: J. Org. Chem. (JOCEAH) 38,397 (1973).
Tanouchi, T. et al.: Chem. Lett. (CMLTAG) 1976,739.
NL 6 505 799 (Unilever; 6.5.1965).
DOS 2 145 125
(Upjohn; 9.9.1971
;
USA-prior. 11.9.1970, 2.7.1971).
DOS 2 328 13 1 (Schering AG; 30.5.1973).
US 3 933 892 (Hoffmann-La Roche; 20.1.1976; prior. 18.1.1974, 12.2.1973).
isolation:

GB 1 040 544 (Karolinska Inst.ivalid from 21.2.1963; prior. 19.3.1962).
racemic
prostaglandin Fla:
US 3 933 891 (Upjohn; 20.1.1976; prior. 8.7.1974, 3.10.1973, 17.6.1975, 2.7.1971, 11.11.1970).
US 3 987 083
(Upjohn; 19.10.1976; prior. 6.12.1974, 14.3.1969).
US 3 983 155 (Upjohn; 28.9.1976; prior. 6.12.1974, 14.3.1969).
US 3 983 154
(Upjohn; 28.9.1976; prior. 6.12.1974, 14.3.1969).
US 3 983 153 (Upjohn; 28.9.1976; prior. 6.12.1974, 14.3.1969).
US 3 981 880 (Upjohn; 21.9.1976; prior. 6.12.1974, 14.3.1969).
US 3 980
69
1
(Upjohn; 14.9.1976; prior. 6.12.1974, 14.3.1969).
US 3 959 346 (Upjohn; 25.5.1976; prior. 6.12.1974, 14.3.1969).
tron~etharnine salt:
US 3 657 327 (Upjohn; 18.4.1972; prior. 1.6.1970).
rise for control of conception cyclus:
DOS 1 943 492 (Upjohn; appl. 27.8.1969; USA-prior. 29.8.1968).
review:
Prostaglandin Research (Ed.
P.
CrabbC) p. 1, 121 New York, San Francisco, London 1977.
Dinoprostone
D
673
Formulation(s):
amp. 5 mglml
Trade Name(s):

D:
Minprostin F2, (Pharmacia I: Prostin F2, (Upjohn); wfm Prostarmon-F (Ono)
&
Upjohn) J: Glandinon (Mochida) Zinoprost (Ono)
F:
Prostine F,, (Pharmacia
&
Penacelan-F (Glaxo-Fuji) USA: Prostin F,, (Upjohn); wfm
Upjohn SA) Pronalgon (Upjohn)
GB: Prostin
F2
(Pharmacia
&
Prosmon (Fuji)
Upjohn) Pros tamodin (Kanebo)
Dinoprostone
(Prostaglandin
E,)
ATC: G02AD02
Use: oxytocic, abortifacient
RN: 363-24-6 MF: C20H320s MW: 352.47 EINECS: 206-656-6
LD,: 23.2 mglkg (M,
i.v.); 750 mgkg (M, p.0.);
59.5 mglkg (R, i.v.); 500 mglkg
(R,
p.0.)
CN: (5Z,l
la,13E,15S)-11,15-dihydroxy-9-oxoprosta-5,13-dien-l-oic
acid
1.

Jones
ox~dot~on
(Cr03,
H2SO4.
acetone.
-1
0
OC)
2.
CH3COOH,
H20
b
3
6
0
OH
1.
chrorniurn(Vl)
oxide
Y
'I
pmsloglondin
Fq
9.1
1
-bis
(tetrahydropyranyl
ether)
(cf.
dinoprost

synthesis)
I
Dinoprostone
Reference(s j:
Corey, E.J. et al.: J. Am. Chem. Soc. (JACSAT)
92,
397 (1970).
alternative syntheses:
US
3
948 981 (Upjohn; 6.4.1976; prior. 18.12.1974, 3.10.1973,2.7.1971, 11.9.1970).
Schneider,
W.P.
et al.:
J.
Chem. Soc., Chem. Commun. (JCCCAT)
1973,
254.
Heather, J.B. et a].: Tetrahedron Lett. (TELEAY)
1973,
231 3.
isolation:
GB 1 040 544 (Karlinska Inst.; valid from 21.2.1963; prior. 29.3.1962).
further literature:
cf. dinoprost synthesis
medical use as broncholytic:
ZA
681 055 (American Home Products; appl. 31.1.1968; USA-prior. 20.2.1967).
review:
Prostaglandin Research (Ed. P. CrabbC) p. 1, 121, New York, San Francisco, London 1977.

Formulation(sj:
amp. 0.5 gI0.5 ml, 0.75 mg10.75 ml; rectangular tabl. 0.5 mg; syringe with gel 0.5 mg; vaginal
gel 0.5 mg13 g, 1 mgI3 g, 2 mgI3 g; vaginal tabl. 3 mg
Trade Name(s):
D: Minprostin E2 (Pharmacia F: PrCpidil gel (Pharmacia
&
GB: Prepidil (Pharmacia
&
&
Upjohn) Upjohn SA) Upjohn)
Prepidil Gel (Pharmacia
&
Prostine E, (Pharmacia
&
Propress RS (Ferring)
Upjohn) Upjohn SA)
674
D
Diodone
\
3
Prostm E2 (Pharmac~a
&
J: Prostadiel-E (Taiyo) Prepidll (Pharmacia
&
Up~ohn)
Prostaglandin
E,
(Kaken) Upjohn)
f

I:
Prepidil gel (Upjohn) Prostarmon-E (Ono) Prostin E, (Pharmacia
&
Prostin E, (Upjohn) USA: Cervid~l (Forest) UPJO~~)
:
Diodone
ATC:
~08~~10
(Jodopyracet)
Use: X-ray contrast medium
RN: 101 -29-1 MF: C7H512N03 MW: 404.93 EINECS: 202-932-5
CN:
3,5-diiodo-4-0x0-l(4H)-pyridineacetic
acid
meglumine salt
RN: 3736-90-1 MF: C7Hs12N03. C7H17N05 MW: 600.14
LD,,,: 5900 mgkg
(R,
i.v.)
diethanolamine salt
(1:l)
RN: 300-37-8 MF: C7H,12N0,
.
C4HIlNO2 MW: 510.07 EINECS: 206-089-4
\
LD,,,: 6400 mgkg (M, i.v.);
5400 mgkg (R, i.v.)
morpholine salt
(1:l)
RN: 3737-08-4 MF: C,Hs12N0,. C4H,N0

MW:
492.05
ClvCOOH
"
j50
OC,
0
I+
,f&
NaOH
_____,
lodlne
I
chlamocetic
chloride
CI-
0
mono-
0
acid
chloride
pyridine
1
-(4-pyridy1)-
4(1H)-
$5-diiado-
pyridinium
pyridonc
4(1H)-pyddone
chloride

Reft'rence(s):
DRP 554 702 (E. Koenigs, H. Greiner; 1929).
DRP 579 224 (1.
G.
Farben; 1930).
US 1 993 039 (I. G. Farben; 1935; D-prior. 1931).
GB 517 382 (ICI; appl. 1938).
Formulation(s):
amp. 35
%,
50
%,
70
%
Trade Name(s):
D:
Broncho-Abrodil GB: Umbradil (Astra)-comb.;
I:
Joduron (Bracco); wfm
(Schering); wfm wfm J: Pyraceton (Daiichi)
Diosmin
ATC: C05CA03
Use: antihemorrhagic, vein tonic
RN: 520-27-4
MF:
C2,H,,OI5 MW: 608.55 EINECS: 208-289-7
CN:
7-[[6-O-(6-deoxy-a-~-mannopyranosyl)-~-~-glucopyranosyl]oxy]-5-hydroxy-2-(3-hydroxy-4-
methoxypheny1)-4H-1 -benzopyran-4-one
Reference(s):

Zemplkn,
G.;
BognAr, R.: Ber. Dtsch. Chem.
Ges.
(BDCGAS) 76,452 (1943).
Lorette,
N.B.
et al.: J. Org. Chem. (JOCEAH) 16,930 (1951).
Horowitz, R.M.: J. Org. Chem. (JOCEAH) 21, 1184 (1956).
S
2602 314 (Hommel; appl. 22.1.1976; CH-prior. 16.5.1975).
Fonnulation(s):
cps. 300 mg; cream 4 g/100
g;
tabl. 150 mg
Endium (Labs. Europhta) Daflon (Servier)
Flebosmil (Socopharm) Diosven (CT)
F:
Daflon (Servier) Litosrnil (Evans Medical) Doven (Prophin)
Dio
(Labs.
Scienex) MCdiveine (ElertC) Venosmine (Geymonat)
Diosmil (RhBne-Poulenc Preparation
H
Veinotonic
(Whitehall)
Diovenor
(InnothCra)
I:
Arvenum (Strqder)

ATC:
D04AB
Use: local anesthetic
RN:
101-08-6 MF: CzZHz7N3O4
MW:
397.48 EINECS: 202-913-1
CN:
3-(1-piperidiny1)-l,2-propanediol
bis(pheny1carbamate) (cster)
monohydrochloride
RN:
537-12-2
MF:
CZ2H2,N3O4 . HC1 MW: 433.94 EINECS: 208-659-8
LD,:
890
mglkg
(M,
s.c.)
OCN
phenyl
isocyanate
N-(2,J-dihydroxy- Diperodon
propyl)pipendine
US
2
004
132
0:

H.
Rider; 1935; prior. 1931).
Fonnulation(s):
ointment (comb.)
Rider,
T.H.:
J.
Am. Chem. Soc. (JACSAT)
52,
1528, 21 15 (1930).
676
D
Diphemanil metilsulfate
Trade
Narnefs):
USA:
Diothane (Merrell); wfm Prnctodon (Rowell);
wfm
Diphemanil metilsulfate
ATC:
D11AA
Use: anticholinergic, antispasmodic
RN:
62-97-5
MF:
C2,,HxN
.
CH4O3S
MW:
374.53

EINECS:
200-552-4
LD,,,:
4012
pglkg (M, i.v.);
3
17
mglkg
(M,
p.0.);
5
mg/kg (R, i.v.);
1107
mglkg
(R,
p.0.)
CN:
4-diphenylmethylene-1,l-dimethylpiperidinium
methyl sulfate
4-benzoyl- phenylmognesiurn
I
-methyl-
'
bromide
(I)
piperidine
H3C, ,CH3
0
/?
111

+
H~C'
),s,~,cH,
+
0
dimethyl sulfate
(1V)
Diphernonil rnetilsulfote
ethyl 4-pyridyl-
isonicotinate diphenyl-
corbinol
H
.
PtO
IV
V
2b
11
.
111
-
1
Diphernonil rnetilsulfote
1
Reference(s):
US
2
739 968
(Schering Corp.;
1956;

prior,
1951).
Fornulation(s):
cream
2
%;
tabl.
50
mg,
100
mg
Trade Nanre(s):
F:
~rantal (CCtrane); wfm
I:
Prantal (Schering-Plough)
Diphenadione
D
677
J:
Prantal (Schering- USA: Prantal (Schering); wfm
Shionogi)
Diphenadione
ATC: BOlAAlO
Use: anticoagulant, rodenticide
RN:
82-66-6 MF: C23Hlh03 MW: 340.38 EINECS: 201-434-5
LD,,: 28.3 mgkg (M, pa);
1500 p@g (R, p.0.);
3

mglkg (dog, p.0.)
CN: 2-(diphenylacety1)-1 H-indene- 1,3(2H)-dione
dimethyl
phtholate
1,l
-diphenyl-
acetone
2.
diphenylacetyi
chloride
Referencers):
US 2 672 483 (Upjohn; 1954; prior. 1951)
1
Fonnulafion(s):
tabl. 20 mg, 50 mg
1
Trade
Narne(s):
USA: Dipaxin (Upjohn); wfm
Diphenadione
u
Oiphenodione
1
Diphenhydramine
1
ATC: D04AA32; R06AA02
Use: antihistaminic, anti-emetic, sedative,
antitussive
B
%

RN:
58-73-1 MF: CI7H2,NO MW: 255.36 EINECS: 200-396-7
1
LD,:
29mgkg(M,i.v.);l6Omgkg(M,p.o.);
42 mgkg (R, i.v.); 390 mglkg (R, p.0.)
t
CN:
2-(dipheny1methoxy)-N,N-dimethylethanamine
k
hydrochloride
RN:
147-24-0 MF: C17H2,N0. HCI MW: 291.82 EINECS: 205-687-2
LD,,: 20 mgkg (M, i.v.); 64 mglkg (M, p.0.);
35 mgkg (R, i.v.); 500 mglkg (R, p.0.);
24 mgkg (dog, i.v.)
678
D
Diphenhydramine
3
benzhydryl Z-dimethylamina-
bromide ethanol
Reference(s):
US 2 421 71 4 (Parke Davis
&
Co.; 1947; prior. 1944).
US 2 427 878 (Parke Davis; 1947; appl. 1947).
Diphenhydramine
alternative synthesis:
US 2 397 799 (Geigy; 1946; CH-prior. 1942).

Formulation(s):
drops 12.5 mg; s. r. cps. 30 mg; suppos. 10 mg, 20 mg, 50 mg; syrup 2.67 mglml, 12.5 mglrnl;
tabl. 25 mg, 50 mg (as hydrochloride)
Trade Name(s):
D: Anaestecomp (Ritsert)-
comb.
Benadryl
(Warner-
Lambert)
Betadorm (Woelm)-comb.
Dibenzyl-Rhenix (Pharma
Wernigerode)-comb. F:
Dolestan (Whitehall-Much)
Dolestan (Whitehall-
Much)-comb.
Dormigoa (Scheurich)
Dormutil
(Isis Pharma)
Emesan (Lindopharm)
Halbmond-Tabletten
(Whitehall-Much)
Hevert-Dorm (Hevert)
Lupovalin (Pharma Selz) GB:
Moradorm
(Bouhon)-comb.
nervo OPT (Optimed)
Nytol (Block Drug
Company)
I:
Palacril (Warner-Lambelt)-

comb.
Palmicol (RIAM)
Pheramin (Kanoldt)
Praesidin
(Medoeharm)-
comb.
Reisegold (Whitehall-
Much)-comb.
Reisegold tabs (Whitehall-
Much) J:
S.8 Tabletten (Chefaro)
Sediat (Pfleger)
Sedopretten
(Schoning-
Berlin)
Sedovegan (Wolff)
Valeriana comb. Hevert
(Hevest)-comb.
Visano Cor (Kade)-comb.
Actifed Jour et unit
(Warner-Lambert; as
hydrochloride)-comb.
Butix gel (Labs. Pierre
Fabre
SantC; as
hydrochloride)
Nautamine (SynthClabo)
Onctose hydrocortisone
(Monot; as methyl sulfate)-
comb.

Medinex (Whitehall)
Nytol (Stafford-Miller)
'numerous combination
preparations
Allergan (Bouty)
Asmarectal (Serpero)-
comb.
Benadryl (Parke Davis)-
comb.
Benylin (Parke Davis)-
comb.
Difeni (Formulario
Naz.)
Fluvaleas (Valeas)-comb.
combination preparations
Benadin Salicylate (Kongo;
as salicylate)
Benadol (Taisho)
USA:
Benadozol
(Hokuriku; as
tannate)
Benadozol-S
(Hokunku;
as
salicylate)
Benapon (Danippon)
Benasin (Kanto)
Neo-Restar (Ohta; as
maleate)

Restamin (Kowa)
Restar (Ohta; as salicylate)
Restin (Mohan; as
salicylate)
Reston (Kowa Yakuhin)
Salibena (Fuso; as
salicylate)
Vena (Tanabe)
Venerlon (Sanwa; as
tannate)
Zeresmin (Juzen-
Yarnanouchi;
as
salicylate)
Actifed (Warner-Lambert;
as hydrochloride)
Benadryl (Parke Davis; as
hydrochloride)
Dytuss (Lunsco; as
hydrochloride)
Maximum (Pfizer
Consumer; as
hydrochloride)
Tylenol
(McNeil; as
hydrochloride)
Unisom (Pfizer Consumer;
as hydrochloride)
generics
Diphenoxylate

D
679
Diphenoxylate
ATC: AO~DAOI
Use: antidiarrheal, antiperistaltic
RN:
915-30-0 MF: C30H32N202 MW: 452.60 EINECS: 213-020-1
LD,: 337 mg/kg
(M,
p.0.);
221 mg/kg (R, p.0.)
CN:
1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxy1ic
acid ethyl ester
hydrochloride
RN:
3810-80-8 MF: C3,H3,N2O2. HCI MW: 489.06 EINECS: 223-287-6
LD,: 221 mg/kg (R, p.0.)
4-bromo-2.2-
diphenylbutyronitrile
(from diphenyiaceto-
nitrile and 1,2-
dibromoethane)
ethyl 4-phenyl-
piperidine-4-
carboxylote
Diphenoxylate
2
1.
sodium amide

2.
ethyl
1
-(2-chioroethy1)-
4-phenyl-piperidine-
4-carboxylate
Reference(s):
US
2 898 340 (Janssen; 4.8.1959; NL-prior. 5.7.1957).
US
4
086 234 (Searle; 25.4.1978; appl. 7.1 1.1975).
Fomulation(s):
tabl. 2.5 mg (comb. with 0.025 mg atropine sulfate)
Tmde Narne(s):
D: Reasec (Janssen-Ci1ag)- GB: Lomotil (Sear1e)-comb. USA: Lomotil (Searle; as
comb, with atropine sulfate Tropergen (Norgine)-comb. hydrochloride)
F:
Diarsed (Sanofi Winthrop; I: Reasec (Cilag)-comb. Lonox (Geneva; as
as hydrochloride) hydrochloride)
680
D
Diphenylpyraline
Diphenylp yraline
ATC: R06AA07
Use: antiallergic, antihistaminic
RN: 147-20-6 MF: C,,H,,NO MW: 281.40 EINECS: 205-686-7
LD,,,: 42 mgkg (M, i.v.); 250 mgkg (M, p.0.)
CN:
4-(dipheny1methoxy)-1-methylpiperidine

hydrochloride
RN: 132-18-3 MF: C,,H,,NO. HCl MW: 317.86 EINECS: 205-049-3
LD,,,: 52 mgkg (M, i.v.); 210 mglkg (M, p.0.);
28.8 mglkg (R, i.v.); 698 mglkg (R, p.0.)
4-hydroxy- benzhydryl
1
-methyl- bromide
piperidine
Diphenylpyroline
(cf.
piprinhydrinate)
Referencers):
US 2 479 843 (Nopco Chem. Comp.; 1949; prior. 1948).
DE 934 890 (Promonta; appl. 1951).
Formulation(s):
gel 15 mglg
Trade Namefs):
,
,
D: Arbid (Bayer Vital)-comb.
Perdiphen (Schwabe;
spitzner)-comb.
Proctospre (Hennig)
Tempi1 N (Temm1er)-comb.
Topoderm (gepepharm)-
comb.
F: Belfkne (Roger Bellon);
w fm
GB: Escornade Spansule (Smith
Kline

&
French)-comb.;
wfrn
Histryl (Smith Kline
&
French); wfrn
Lergoban (Riker); wfrn
I:
lpercron (Maggioni)-
comb.; wfm
Pirazone Smit (UCB-
Smith); wfrn
J:
Plokon (Nippon Shinyaku)
USA: Diafen (Riker); wfrn
Hispril (Smith Kline
&
French); wfrn
Dipivefrine
ATC: SOlEA02
Use: antiglaucoma
RN: 52365-63-6 MF:
C,,H,,NO, MW: 351.44
CN:
(+)-2,2-dimethylpropanoic
acid
4-11-hydroxy-2-(methy1amino)ethyll-
1,2-phenylene ester
hydrochloride
RN: 64019-93-8 MF: C,,H2,NOS~ HCI MW: 387.90