HZOZ I ATC: N06BA07 Use: psychostimulant, a,-adrenoceptor agonist treatment of narcolepsy and idiopathic hypcrsomnia 2-diphenylrnethyl- thioacetic acid I I Modafinil 2... use of moda
Trang 1Moclobemide M 1351
Isolation from cultures of Eupenicillium hrefeldianum NRRL 5734
a Amberlite IRA-41 l/pH 10
b Chromatography on DEAE-Sephadex A-25
/ Mizoribine
BE 799 805 (Toyo Jozo; appl 31.1 1.1973; J-prior 21.5.1973)
DOS 2 326 916 (Toyo Jozo; appl 23.5.1973; J-prior 21.5.1973)
Mizuno, K et al.: J Antibiot (JANTAJ) 27,775 (1974)
conrrolled-release formulation:
JP 59 227 817 (Toyo Jozo; appl 7.6.1983)
Formulation(s): f c tabl 10 mg; tabl 10 mg
Trade Narne(s):
J : Bredinin (Toyo Jozo)
Moclobemide
(Ro-11-1163)
RN: 71320-77-9 MF: C,,H,,CIN202 MW: 268.74
LD,,,: 707 m g k g (R, p.0.)
CN: 4-chloro-N-[2-(4-morpholinyl)ethyl]benzamide
benzoyl morpholine (I)
chloride
ATC: N06AG02 Use: antidepressant, reversible nonhydrazide MAO- A-inhibitor, antiparkinsonian
I Moclobemide (
Trang 21352 M Modafinil
ReJerence(s):
DE 2 706 179 (HoCCmann-La Roche; appl 14.2.1977; A-prior 16.2.1976)
GR 1 5 12 194 (Hoffmann-La Roche; appl 24.5.1978; A-prior 16.2.1976, 2.9.1976, 20.4.1977, 17.2.1976, 4.6.1976)
medical use for treatment ~Jcognitive disorders:
IJS 4 906 626 (Hoffmann-La Roche; 6.3.1990; appl 13.1.1989; CH-prior 8.12.1988)
Formulation(s): f c tabl 150 mg, 300 mg; tabl 100 mg, 150 mg 300 mg
Trade Name(s);
D: Aurorix (Roche) F: Moclamine (Produits GB: Manerix (Roche)
Modafinil
(CRL-40476)
RN: 68693-11-8 MF: ClsH,SN02S MW: 273.36
racemate
RN: 11 21 11-49-6 MF: ClsH15N02S MW: 273.36
(+)-form
RN: 11 21 11-47-4 MF: Cl,H15N02S MW: 273.36
(-)-form
RN: 11211 1-43-0 MF: CI5HI5NO2S MW: 273.36
'benzhydrol
1 SOCI,
2 aq NH3
3 HZOZ
I
ATC: N06BA07 Use: psychostimulant, a,-adrenoceptor agonist (treatment of narcolepsy and idiopathic hypcrsomnia)
2-(diphenylrnethyl- thio)acetic acid (I)
I Modafinil
2 (CHJ2SO4 NoHC03
3 aq NH3
Trang 3Reference(s):
DE 2 809 625 (Laboratoire L Lafon; appl 5.10.1978; GB-prior 31.3.1977)
EP 233 106 (Laboratoire L Lafon; appl 19.8.1987; F-prior 3 1.1.1986)
use of modafinil as neuroprotective agent:
EP 462 004 (Laboratoire L Lafon; appl 18.12.1991; F-prior 14.6.1990)
use for treatment of urinary and fecal incontinence:
EP 594 507 (Laboratoire L Lafon; appl 27.4.1994; F-prior 23.1.1992)
use as a brain anti-ischemia:
EP 547 952 (Laboratoire L Lafon; appl 23.6.1993; F-prior 13.12.1991)
use for treatment of sleep apnea and ventilation problems of central origin:
WO 9 500 132 (Laboratoire L Lafon; appl 5.1.1995; F-prior 22.6.1993)
rise for modifying feeding behavior:
WO 9 501 171 (Laboratoire L Lafon; appl 12.1.1995; 30.6.1993)
Formulation(s): tabl 100 mg
Trade Name(s):
F: Modiodal (Lafon)
(CI-925; RS- 10085 (base); RS-10085-197; SPM-925) Use: antihypertensive (ACE inhibitor) RN: 103775-10-6 MF: C27H,4N,07 MW: 498.58
CN: [3S-[2[R*(R*)],3R*]]-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-l-oxopropyl]-l,2,3,4-tetrahydro- 6,7-dimethoxy-3-isoquinolinecarboxylic acid
monohydrochloride
RN: 82586-52-5 MF: CUH,4N207 HC1 MW: 535.04
L-olonine
tert-butyl ester
ethyl 2-brorno- 4-phenylbutonoate
N - [ I (5)-ethoxycorbonyl- 3-phenylpropyl]-L-olonine tert-butyl ester (I)
H3C-Ow~~@
, DCC, HOBt, CH2C12
CF3COOH
benzyl 1,2,3.4-tetrohydro-
8 6.7-dimethoxy-3(S)-iso-
Trang 41354 M Mofebutazone
benzyl 2-[N-[I (S)-ethoxycorbonyl-
3-phenylpropyl]-~-olon~l]-l ,2.3,4-
tetrohydro-6.7-dimethoxy-3(S)-
isoquinolinecorboxylote (111)
1 H2, Pd-C
2 HCI
-
Moexipril
synthesis of the storting material 11:
Hz, (R)-BINAP, rhodium(1) bis(norborn0diene)- 1 NaOH hexofluorophosphote H 3 C - 0 2 HCI
methyl N-benzoyl- 3.4-dimethoxy-L- phenylolanine
1 HCI
(S)-2-amino-3-(3,4-
dimethoxypheny1)-
proponoic acid (N)
Reference(s):
EP 96 157 (Warner-Lambert; appl 1.10.1981; USA-prior 3.10.1980, 20.2.1981)
EP 49 605 (Warner-Lambert; appl 1 lo 1981; USA-prior 3.10.1980)
O'Reilly, N.J et al.: Synthesis (SYNTBF) 7, 550-556 (1990)
US 4 912 221 (Occidental Chemical Corp., appl 27.10.1988)
formulation stabilized with ascorbic acid:
EP 264 887 (Warner-Lambert Co.; appl 19.10.1987; USA-prior 20.10.1986)
Formulation(s): f c tabl 7.5 mg, 15 mg; USA: f c tabl 7.5 mg, 12.5 mg, 15 mg, 25 mg (in comb with
hydrochlorothiazide) (as hydrochloride)
Trade Nume(s):
GB: Perdix (Schwarz) Primoxil (Bayer Italia) Univasc (Schwarz)
Use: antirheumatic, anti-inflammatory analgesic
RN: 2210-63- 1 MF: C,,H,,N,O, MW: 232.28 EINECS: 218-641-1
LD,,,: 600 mglkg (M, i.v.);
1750 mglkg (R, p.0.)
CN: 4-butyl-1-phenyl-3,5-pyrazolidinedione
Trang 5Mofezolac M 1355
sodium salt
RN: 41468-34-2 MF: C,,H,,N,NaO, MW: 254.27
diethyl phenyl-
butylrnolonote hydrozine
GB 839 057 (Comm Farmaceutica Milanese; appl 27.11.1957; I-prior 28.11.1956)
Biichi, J et al.: Helv Chim Acta (HCACAV) 36,75 (1953)
Formulation(s): amp 650 mgl3 ml (as sodium salt); cps 200 mg; drg 150 mg-comb.; f c tabl 300 mg
Trade Name(s):
D: Diadin (Diadin) F: Arcobutina (Silbert et Monbutina (Lafare); wfm
Vasotonin (Merz)-comb I: Chemiartrol (Gazzoni);
wfm
Mofezolac
(N-22)
ATC: M01; NO2 Use: anti-inflammatory, analgesic
RN: 78967-07-4 MF: C,,H,,NO, MW: 339.35 '
LD,,: 1528 m g k g (M, p.0.);
887 m g k g (R, p.0.);
800 m g k g (dog, p.0.)
CN: 3,4-bis(4-methoxypheny1)-5-isoxazoleacetic acid
H 0 \
NH20H CH,OH, NoOH 70 O C
b
H3C-0 0-CH3 H3C-0 0-CH3
deoxyonisoin (I) - deoxyonisoin oxirne (U)
1 n-BuLi THF
-15 to 0 OC
H3C n-BuLi THF
2 H C 0-CH,
H3C-0 0-CH, H3C-0 0-CH,
Trang 61356 M Molindone
methyl
3-methoxyacrylote
methyl 5-axo-4.5- bis(4-methoxypheny1)-3- pentenoote (IU)
Reference(s):
EP 26 928 (CDC Life Sciences Inc.; appl 3.10.1 980; CA-prior 5.10.1979)
synthesis with C1CO2Et instead C02:
JP 02 223 568 (Taiho Pharmaceuticals; appl 20.11.1989; J-prior 2.11.1988)
EP 454 87 1 (Taiho Pharmaceuticals; appl 19.1 1.1990; J-prior 21.1 1.1989)
JP 03 220 180 (Taiho Pharmaceuticals; appl 24.1.1990; J-prior 24.1.1990)
EP 464 21 8 (Taiho Pharmaceuticals; appl 22.1.1991; J-prior 24.1.1990)
transdermal formulations:
JP 05 017 354 (Nichiban KK; appl 3.7.1991; J-prior 3.7.1991)
stable injection solution:
AT 391 415 (Kwizda; appl 26.7.1989; A-prior 26.7.1989)
Trade Name(s):
J: Disopain (Taiho-
Yoshitomi)
Use: tranquilizer, sedative RN: 7416-34-4 MF: C,,H,N202 MW: 276.38
CN: 3-ethyl-l,5,6,7-tetrahydro-2-methyl-5-(4-morpholinylmethyl)-4H-indol-4-one
monohydrochloride
RN: 15622-65-8 MF: C,,H,N2O2 HCI MW: 312.84
LD,,: 670 m g k g (M, p.0.);
261 mglkg (R, p.0.)
HO-N
o<z:: HN02 orti&-0-NO k' 0
CH, cyclohexone-
Trang 7Molsidomine M 1357
3-ethyl-2-methyl- morpholine paraform- Molindone
tetrahydroindol (I)
Reference(s):
DAS 1 545 774 (Endo Labs.; appl 16.10.1965)
US 3 491 093 (Endo Labs.; 20.1.1970; prior 2.3.1964, 3.4.1964, 1 1.5.1966,29.11.1967)
combination with amantadine (antidepressant):
US 4 148 896 (Du Pont; 10.4.1979; appl 22.2.1978)
Formulation(s): sol 20 mg/ml; tabl 5 mg, 10 mg, 25 mg, 50 mg, 100 mg
Trade Name(s):
USA: Moban (Gate)
Use: coronary vasodilator RN: 25717-80-0 MF: C,H,,N404 MW: 242.24 EINECS: 247-207-4
LD,,: 800 m g k g (M, i.v.); 830 m g k g (M, p.0.);
760 mglkg (R, i.v.); 1050 mgtkg (R, p.0.)
CN: 5-[(ethoxycarbonyl)amino]-3-(4-morpholinyl)-1,2,3-oxadiazolium inner salt
+ HCHO + HCN + c -
4-amino- form- hydrogen
morpholine oldehyde cyanide
HN-
I +
Molsidomine
Reference(s):
DAS 1 695 897 (Takeda; appl 1.7.1967; J-prior 4.7.1966)
synthesis of 4-aminomorpholine:
DAS 2 532 124 (Cassella; appl 18.7.1975)
US 3 769 283 (Takeda, 30.10.1973; J-prior 4.7.1966)
Formulation(s): amp 2 mg; s r tabl 8 mg; tabl 1 mg, 2 mg, 4 mg
Trang 81358 M Mometasone furoate
Trade Name(s):
D: Corvaton (Hoechst; 1977) Molsidomine (Heumann; I: Molsidolat (Hoechst;
Molsihexal (Hexal) J: Morial (Takeda; 1972) F: Corvasal (Hoechst; 1983)
Use: topical glucocorticoid, anti- inflammatory
RN: 83919-23-7 MF: C,H3,Cl2O6 MW: 521.44
LD,,,: 300 mglkg (R, LC.)
CN: ( 1 1 P, 16a)-9,2 1 -dichloro- 17-[(2-furanylcarbonyI)oxy]- I 1-hydroxy- 16-methylpregna- l,4-diene-3,20-dione
mometasone
RN: 105102-22-5 MF: C22H28C1204 MW: 427.37
2 HCIO,, CH30H
1 4-dimethylamino-
pyridine
165-methyl-1.4,9(1 1)- 2-furoyl
pregnatriene-l7a.21 -dial- chloride
3.20-dione 21 -acetate
17a.21-dihydraxy-1 &-methyl-
1,4,9(11)-pregnatriene-3.20-
d i m e 17-(2-furoote) (I)
1 CH3S02CI
2 LiCI, DMF
chloride
;;:&o
0 'CI HCIO,
1.3-dichloro-5.5-
dirnethylhydontoin
Mometasone furoate
EP 57 401 (Schering Corp.; appl 25.1.1982; USA-prior 2.2.198 1)
US 4 472 393 (Schering Corp.; 18.9.1984; appl 29.7.1982; prior 2.2.198 1)
Shapiro, E.L et al.: J Med Chem (JMCMAR) 30, 1581 (1987)
cream:
EP 262 681 (Schering Corp.; appl 1.10.1987; USA-prior 2.10.1986)
lotion:
US 4 775 529 (Schering Corp.; 4.10.1988; appl 21.5.1987)
Trang 9Monobenzone M 1359
Formulation(s): cream 0.1 %; lotion 0.1 %; ointment 0.1 % ( 1 mg/g)
Trade Name(s):
D: Ecural (Essex Pharma) I: Altosone (Essex Italia) USA: Elocon (Schering-Plough; GB: Elocon (Schering-Plough) Elocon (Schering-Plough) 1988)
Nasorex (Schering- J: Ecotone (Schering-Plough)
against hyperpigmentation of skin) RN: 103-16-2 MF: C,,H,,O, MW: 200.24 EINECS: 203-083-3
LD,,: >600 m g k g (M, i.p.);
4500 m g k g (R, i.p.)
CN: 4-(pheny1methoxy)phenol
Reference(s):
Schiff, H.; Pellizzari, G.: Justus Liebigs Ann Chem (JLACBF) 221, 365 (1883)
HO KOH C&OH
hydroquinone benzyl bromide
Formulation(s): cream 20 %
aO
Monobenzone
Trade Name(s):
D: Depigman (Hermal); wfm I: Dermochinona (chindin); USA: Benoquin (Elder)
wfm
Montelukast sodium
(MK-476; MK-0476; L-70663 1)
ATC: R03DC03 Use: antiallergic, antiasthmatic, leukotriene antagonist RN: 15 1767-02- 1 MF: C,,H,,ClNNaO,S MW: 608.18
CN: 1-[[[(I R)-1-[3-[(1E)-2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy-l-
methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid sodium salt
acid
RN: 158966-92-8 MF: C,,H,,ClNO,S MW: 586.20
acetic onhydride CI OHC
Trang 101360 M Montelukast sodium
toluene, THF
vinylmagnesium
bromide
Pd(OAc)*, LiOAc DMF
palladium acetate Cl / N, \
methyl 2-bromo-
benzoate
(-)-0-chlorodiisopinocarnpheylborane
THF
b
methyl 2-[3-[3-[(2E)-(7-chloro- quinalin-2-yl)vinyl]phenyl]-3- oxopropyl]benzoote (111)
1 THF, toluene
2 fi p H 3 H3C-8-CI, H3CyNyCH3
0 H3C CH3 toluene, acetonltrile
methylmagnesium
bromide
1 BuLi THF
2 DCHA
2-[l-(mercapto-
methyl)cyclopropyl]-
acetic acid (VI)
1 HOAc
2 NaOH toluene/H20
I Montelukast sodium I