Pharmaceutical Substances Syntheses, Patents, Applications - Part 123 pps

Medazepam
M
1221
Pectite (Kissei)
Pelmain (Sawai)
Radcol (Nippon Universal) Thibrin (Kyowa-Hoei)
Sekinin (Tokyo Hosei) Zeotin (Toa Eiyo)
Medazepam
ATC: N05BA03
Use: tranquilizer, anxiolytic
RN: 2898-12-6
MF:
Cl6H,JlN2
MW:
270.76 EINECS: 220-783-4
LD,,:
475 mgfkg
(M,
p.0.);
900 mglkg
(R,
p.0.)
CN:
7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine
2-amino-5-
chloro-
benzophenone
1. NaH
2. H3C-I
LiAIH,
lithium

olanote
I
Medazepam
glycine
ethyl
ester
I
-
1.
sodium hydride
2.
methyl iodide
H~N-~~~
MgBr
nitrobenzene, K2C03
Cu(CH3COO),
-,
c
1
C
N
ethylenediomine
2,5-dichloro- phenyl- 1 -(2,5-dichloro-
benzonitrile magnesium phenyl)-1-phenyl-
bromide methylimine
4-chloro- p-toluene-
oniline sulfochloride
4-chloro-1 -tosylamino-
benzene
H,c/O\

/P
0//S'Oy~~3
NaOCH3
,
I1
dimethyl
sulfote
1222
M
Medibazine
4-chloro-1 -(N-methyl- 4-chloro-N-
Losylamino)benzene
(It)
methylaniline
N-(4-chloropheny1)- benzoyl
N-methylethylene- chloride
diamine (111)
Reference(s):
a,bUS 3 109 843 (Roche; 5.1 1.1963; appl. 21.6.1962; prior. 28.7.1961).
US
3
131 178 (Roche; 28.4.1964; prior.
28.7.1961,4.12.1961,21.6.1962).
Sternbach, L.H. et al.: J. Org. Chem. (JOCEAH) 28,2456 (1963).
c
DAS 1 934 385 (Sumitomo; appl. 7.7.1969).
d
DAS 1 695 188 (Roche; appl. 23.5.1967; USA-prior. 3.6.1966).
DAS 1 795 81 1 (Roche; appl. 23.5.1967).
alternative syntheses:

US 3 141 890 (Roche; 21.7.1964; prior. 28.7.1961,4.12.1961, 21.6.1962).
US 3 144 439 (Roche; 11.8.1964; prior. 28.7.l961,4.12.l96I, 21.6.1962).
DE
1 445 864 (Roche; appl. 27.7.1962; USA-prior. 28.7.1961).
DOS 2 204 484 (Sumitomo; appl. 31.1.1972; J-prior. 9.2.1971, 6.4.1971,28.5.1971).
DOS 2 217 301 (Sumitomo; appl. 10.4.1972; J-prior. 12.4.1971).
I-demethyl-derivative from
5-chloro-2-(2,3-dioxop~perazino)benzophenone:
DAS 1 906 254 (Sumitomo; appl. 7.2.1969; J-prior. 2.4.1968).
DAS 1 965 980 (Sumitomo; appl. 7.2.1969; J-prior. 2.4.1968).
Formulation(s):
cps. 5 rng, I0 mg; tabl. 2.5 mg, 5 mg, 10 rng
Trade Name(s):
D: Medazepam AWD I: Debrum (Sigma-Tau)- Kobazepam (Nihon
Tabletten (ASTA Medica comb.
Iy akuhin)
AWD) Nobriurn
(Roche) Metonas (Kanto)
Rudotel Tabletten (OPW) J: Azepamid (Taiyo)
Narsis (Sumitomo)
F: Nobriurn (Roche); wfm Cerase (Torii) Nobrium (Nippon Roche)
GB:
Nobrium (Roche); wfm Resmit (Shionogi)
Medibazine
ATC: C01
Use: coronary vasodilator
RN: 53-31-6 MF:
C,,H,,N202 MW: 386.50 EINECS: 200-168-7
LD,,,: 4
1 mgkg (M,

i.v.)
CN:
l-(1,3-benzodioxol-5-ylmethyl)-4-(diphenylmethyl)piperazine
Medifoxamine
M
1223
Reference(s):
US 3 119 826 (Science Union; 28.1.1964; F-prior. 12.4.1961).
1-(3.4-methylenedioxy- benzhydryl
Trade Narne(s):
F:
Vialibran (Servier); wfm
Medibozine
Medifoxamine
benzy1)piperozine chloride
ATC: N06A
Use: antidepressant
RN: 32359-34-5 MF:
C1,H,,N02 MW: 257.33 EINECS: 251-01 1-4
LD,,: 750 mgikg (M, p.0.)
CN:
N,N-dimethyl-2,2-diphenoxyethanamine
fumarate
(1:l)
RN: 16604-45-8 MF: C,,H,,N02. C4H4O4 MW: 373.41 EINECS: 240-657-2
C
I
0
COOH
uoH

+
>COOH
-
0
C
I
"'8
phenol dichloroocetic diphenoxyocetic
ocid acid
(I)
I
+
7
2.
dimethylornine
diphenoxy-N.N-di-
I
Medifoxomine
(
rnethylocetomide
Reference(s):
FR
5 498 (Lab. Gerda; appl. 1966).
Brunet, M.A. et al.: Bull. Soc. Chim. Fr. (BSCFAS), 2000 (1967).
additional synthesis:
FR
2 645 147 (Lab. Rolland; appl. 3.4.1989).
FR
2 601 004 (Lab. Rolland; appl. 7.7.1986).
FR

2 588 553 (Lab. Rolland; appl. 16.10.1985).
EP 226 475 (Lab. Rolland; appl. 22.7.1985).
synthesis of
diphenoxyacetic acid:
Alphen,
J.
van: Recl. Trav. Chim. Pays-Bas (RTCPA3)
46,
144 (1927).
Scheibler,
H.;
Depner, M.:
J.
Prakt. Chem. (JPCEAO)
7,
60 (1958).
DE 561 281 (Chem. Fabrik von Heyden; appl. 1930),
also EP 226 475,
FR
2 601 004.
1224
M
Medrogestone
medical use for treatment of cerebral hypoxia and senility:
FR
2 589 357 (Lab. Rolland; appl. 5.11.1985).
FR
2 583 639 (Lab. Rolland; appl. 24.6.1985).
Formularion(s):
tabl. 50 mg

Trade Name(s):
F: ClCdial (Lipha SantC)
Medrogestone
ATC: G03DB03
Use: progestogen
RN: 977-79-7 MF:
C,,H,,O, MW: 340.51 EINECS: 213-555-0
LD,,,: 850
mglkg (g.p., p.0.)
CN:
6,17-dimethylpregna-4,6-diene-3,20-dione
&
Me
,,vCH3 \~'3
H,C
1
O/
OH
,
CHCI3,
0
'C
peroxyocetic
acid
HO
'
methyl 3@-hydroxy-17a-
rnethyl-ondrost-5-ene-17-
corboxylote
Cr03. H,C-CO-CH3

chromium(VI)
oxide
methylmagnesium
bromide
thionyl
chloride
CI CI
nr
chloronil
(N)*
CH~
Medrogestone
Medroxyprogesterone acetate
M
1225
-
2. methyl
iodide
38-ocetoxy-6-methyl-
20-0x0-5.16-pregnodiene
(from dehydropregnenolone.
onologously to o)
1. Oppenouer oxidation
2.
IV
Reference(s):
a
US 3 133 913 (American Home Products, 19.5.1964; appl. 11.9.1961).
Deghenghi, R.; Gaudry, R.: J. Am. Chem. Soc. (JACSAT) 83,4668 (1961).
starting material:

Plattner, P.A. et al.: Helv. Chim. Acta (HCACAV) 31,603 (1948).
b
Deghenghi, R. et al.: J. Med. Chem. (JMCMAR) 6,301 (1963).
starting material:
Bum, D. et al.: J. Chem. Soc. (JCSOA9) 1957,4092.
alternative syntheses:
US 3 170 936 (American Home Products; 23.2.1965; appl. 7.8.1963).
US 3 210 387 (American Home Products; 5.10.1965; appl. 6.5.1963; CDN-prior. 28.1 1.1962).
Formulation(s):
tabl.
5
mg, 25 mg
Trade Name(s):
D: Presomen (Solvay Prothil (Solvay
I:
Colprone (Wyeth)
Arzneimitte1)-comb. Arzneimittel) USA: Colprone (Ayerst); wfm
F: Colprone (Wyeth-Lederle)
Medroxyprogesterone acetate
ATC: G02B; G03D
Use: antineoplastic, progestogen
RN: 71-58-9 MF: C2,H,,O4 MW: 386.53 EINECS: 200-757-9
LD,,,:
>16 glkg (M, p.0.);
>6.4 g/kg (R, p.0.);
>5 glkg (dog, p.0.)
CN:
(6cr)-17-(acetyloxy)-6-methylpregn-4-ene-3,20-dione
5a.17~-dihydroxy-
3,20-dioxo-6P-methyl-

pregnone
HCI. CHCIJ
-
CH3
17-hydroxy-6~-
methylprogesterone
(I)
I226
M
Medroxv~rogesterone acetate
ocetic
anhydride
(11)
CH3
Medroxyprogesterone ocetote
17-hydroxy- ethylene
progesterone glycol
ocid bromide
Referenceis):
a
US 3 147 290 (Upjohn;
I
.9.1964; appl. 17.5.1961; prior. 23.1 1.1956).
Ellis, B. et a].: J. Chem. Soc. (JCSOA9)
1957,
4092.
starting material: cf literature cited under
a
b
US 3 061 616 (~ocleta Farmaceutici Italia; 30.10.1962; appl. 17.9.1958; GB-prior. 24.4.1958).

DE 1 097 986 (Syntex; appl. 29.8.1957; MEX-prior. 8.9.1956).
Babcock, J.C. et al.: J. Am. Chem.
Soc. (JACSAT) 80,2904 (1958).
starting material:
Bernstein, S. et al.:
J.
Am. Chem. Soc. (JACSAT)
76,
5674 (1954).
The Merck Index, 4756 (Rahway 1976).
alternative syntheses:
DE 1 081 456 (British Drug Houses; appl. 21.8.1958; GR-prior. 13.8.1957).
DE 1 101 415 (Searle; appl. 24.9.1958; USA-prior. 27.9.1957).
US 3 043 832 (Ormonoterapia Richter; 10.7.1962; appl. 28.4.1961; I-prior. 27.2.1961).
review:
Ehrhardt, Ruschig 111,352,
Medrylamine
M
1227
Formulation(s):
amp. 500 mg, 1 g; susp. 500 mg; susp. 150 mglml, 500 mglml; tabl. 2.5 mg, 5 mg, 10 mg, 100
mg, 200 mg, 250 mg, 400 mg, 500 mg
Trade Name(s):
D: Clinofem (Pharmacia
&
Upjohn)-comb.
Clinovir (Pharmacia
&
Upjohn)
Depo-Clinovir (Pharmacia

&
Upjohn)
Farlutal (Pharmacia
&
Upjohn)
MPA (Hexa1)-comb.
F: Depo-Prodasone
(Pharmacia
&
Upjohn)-
comb.
Depo-Provera (Pharmacia
&
Upjohn)
Divina (1nnothCra)-comb.
Farlutal (Pharmacia
&
Upjohn)
Gestoral (Novartis)
Prodasone (Pharmacia
&
Upjohn)
GB: Depo-Provera (Pharmacia
&
Upjohn)
Farlutal (Pharmacia
&
Upjohn)
Provera (Pharmacia
&

Upjohn)
combination preparations
I: Depo-Provera
(Upjohn)
Farlutal (Farmitalia)
Lutoral (Midy)
Provera
(Upjohn)
J:
Hysron (Kyowa)
Provera (Upjohn)
USA: Amen (Carnrick)
Depo-Provera (Pharmacia
&
Upjohn)
Premphase (Wyeth-Ayerst)
Prempro (Wyeth-Ayerst)
Provera (Pharmacia
&
Upjohn)
Medry lamine
ATC: R06
Use: topical antihistaminic
RN: 524-99-2 MF: C1,H2,N02 MW: 285.39 EINECS: 208-368-6
CN:
2-[(4-methoxyphenyl)phenylmethoxy]-N,N-dimethylethanamine
hydrochloride
RN: 6027-00-5 MF: CI~H2,N02. HC1 MW: 321.85 EINECS: 227-888-4
LD,,,: 148 mglkg (M, i.p.)
"c"%

+
~0-~~~3
I
/
CH3
4- methoxy- 2-dimethylamino- Medrylamine
benzhydryl 'ethanol
chlor~de
Reference(s):
US 2 668 856 (UCB; 1954; appl. 1948).
Formulation(s):
ointment 20 mglg (2
%)
(as hydrochloride)
Trade Name(s):
D: Corti-Postafen (UCB)- Postafen Salbe (UCB);
comb.; wfm wfm
Medrysone
ATC: SOlBA08
Use: glucocorticoid
RN:
2668-66-8 MF: C,,H,,O, MW: 344.50 EINECS: 220-208-7
LD,,,: 338 mglkg (R, i.p.)
CN: (6a, 11
P)-
11
-hydroxy-6-methylpregn-4-ene-3,20-dione
1228
M
Mefenamic acid

1.
ethylene glycol, p-toluene-
0
sulfonic acid
CH,
2.
lithium alanate
6a-methyl-l l
-oxo-
progesterone
Medrysane
I
Reference(s):
US 2 864 837 (Upjohn; 1958; prior. 1958).
US
2
968 655 (Upjohn; 1961; prior. 1956).
starting material:
Spero,
G.B.
et al.:
J.
Am. Chem. Soc. (JACSAT)
78,
6213 (1956).
US 2 968 655 (Upjohn; 1961; prior. 1956).
Formulation(s):
eye drops 10 mg; eye ointment 10 mg
Trade Name(s):
D: Ophtocortin (Winzer) generic

Spectramedryn (Pharm-
I:
Medramil (Farmigea)-
Allergan)
comb.
F:
Medryson Faure (CIBA USA: HMS Liquifilm (Allergan);
Vision) wfm
Medrocort (Upjohn); wfm
Mefenamic acid
ATC: MOlAGOl
Use: anti-inflammatory, antirheumatic,
analgesic
RN:
61-68-7
MF:
ClsHl,NO,
MW:
241.29 EINECS: 200-513-1
LD,,,: 96 mglkg (M, i.v.); 525 mglkg (M, p.0.);
112 mgkg (R, i.v.); 740 mgkg (R, p.0.)
CN:
2-[(2,3-dimethylphenyl)amino]benzoic
acid
copper(l1) acetate
potassium 2,3-dimethyl- Mefenamic
acid
2-bromo- aniline
benzoate
Reference($):

US 3 138 636 (Parke Davis; 23.6.1964; appl. 23.6.1960).
DE 1 163 846 (Parke Davis; appl. 22.6.1961; USA-prior. 23.6.1960).
alternative syntheses:
DAS
1
186 073 (Parke Davis; appl. 30.4.1963; CDN-prior. 18.9.1962).
DAS 1 186 074 (Parke Davis; appl. 30.4.1963; CDN-prior. 18.9.1962).
DAS 1 186 870 (Parke Davis; appl. 30.4.1963; CDN-prior. 18.9.1962).
DAS 1 186 871 (Parke Davis; appl. 30.4.1963; CDN-prior.
18.9.1962).
Formulation(s):
cps. 250 mg; powder 500 mg, 1 g; suppos. 125 mg, 500 mg; susp. 50 mg
Mefenorex
M
1229
Trade Narne(s):
D: Parkemed (Parke Davis)
J:
Baphameritin M USA: Ponstan (Parke Davis);
Ponalar (Parke Davis) (Hishiy ama) wfm
F: Ponstyl (Parke Davis) Bonabol (Sawai) Ponstel (Parke Davis)
GB: Meflam (Trinity) Pontal (Parke Davis-
Ponstan (Elan) Sank y 0)
I:
Lysalgo (SIT) Spantac (Uji)
Mefenorex
ATC: A08AA09
Use: appetite depressant
RN: 17243-57-1 MF: C,,H,,ClN MW: 21 1.74 EINECS: 241-279-0
CN:

N-(3-chloropropy1)-a-methylbenzeneethanamine
hydrochloride
RN: 5586-87-8 MF: CI2H&lN
.
HCl MW: 248.20 EINECS: 226-985-9
LD,,: 49 mgkg (M, i.v.); 230 mglkg (M, p.0.);
35 mglkg (R, i.v.); 410 mglkg (R, p.0.)
phenylacetone 3-amino- chloride Mefenorex
1
-proponol
Referencefs):
DE 1 210 873 (Hoffmann-La Roche; appl. 18.3.1959).
Formulation(s):
drg. 40 mg (as hydrochloride)
Trade Narnefs):
D: Rondimen (ASTA Medica F: Incital (Pierre Fabre SantC)
AWD; as hydrochloride) USA: Anexate (Roche); wfm
Mefexamide
ATC: N05C
Use: psychoanaleptic, CNS stimulant
RN: 1227-61-8 MF:
C,SH24N,0, MW: 280.37 EINECS: 214-963-1
LD,,: 168 mglkg (M,
i.v.); 1500 ~glkg (M, p.0.)
CN:
N-[2-(diethylamino)ethyl]-2-(4-methoxyphenoxy)acetamide
monohydrochloride
RN: 3413-64-7 MF: C,,H,N203
.
HCl MW: 316.83 EINECS: 222-304-4

hydroquinone chloroocetic 4-methoxy-
monomethyl acid phenoxyocetic
ether acid
1230
M
Mefloquine
R+rence(s):
Thuillier,
G.;
Rumpf, P.: Bull. Soc. Chim. Fr. (BSCFAS)
1960,
1786.
N,N-diethyl-
For~nulation(s):
amp. 150 mg; tabl. 150 mg
Mefexomide
Trade Narne(s):
F: MCfCxadyne (Anphar); Timodyne (Anphar); wfm
wfm
I:
Perneuron (Crinos); wfm
ethylenediomine
Mefloquine
ATC: POIBAOS
Use: antimalarial
RN: 53230-10-7 MF:
C,,H,$,N,O MW: 378.32
CN:
(R*,S*)-(+)-a-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol
monohydrochloride

RN: 51773-92-3 MF: C,,H,,F,N,O~HCl MW: 414.78 EINECS: 257-412-0
LD,,,:
880 mglkg (R, p.0.)
2-trifluoro-
ethyl
Y,Y.Y-
2.8-bis(trifluoro- 2,B-bis(trifluoro-
methyl- trifluorooceto- methyl)-4-hydroxy- methyl)-4-bromo-
aniline
(I)
acetate quinoline quinoline (11)
n-CIHo-Li
butyl-
lithium
Li
COOH
(from 2-bromo-
2,&bis(trifIuoro- 2,8-bis(trifluoro- pyridine)
methyl)-4-lithio- methyl)-4-quinoline-
quinoline
(Ill)
corboxylic acid
(N)