Pharmaceutical Substances Syntheses, Patents, Applications - Part 145 doc

I
Nilutamide
N
1441
f
CH3
POCI,
koo,
+
HNvCH3
-
i
kfc~3 N-CH3
1
oxychloride
nicotinic diethylamine Nikethamide
acid
Reference(s):
DRP 351 085 (Ciba; 1920).
DRP
441 707 (Ciba; 1924).
Fonnulation(s):
drg. 50 mg in comb. (as calcium thiocyanate); powder 150 mg; sol. 250 mg/ml
Trade Name(s):
D: Felsol (Roland)-comb. GB: Coramine (Ciba); wfm
J:
Coramin (Ciba-Geigy-
Zellaforte Plus (Eurim
1:
Miocardina (Croce Takeda)
Pharma)-comb.

Bianca); wfm USA: Coramine (Ciba); wfm
F:
Coramine (Ciba); wfm
Nilutamide
ATC: G03H; L02BB02
(RU-23908)
.
Use: non-steroidal antiandrogen (for
treatment of prostatic carcinoma)
RN: 63612-50-0 MF:
C,,H,,F,N,04 MW: 317.22
LD,,: 200 mg/kg
(M,
p.0.);
195 mg/kg (R, p.0.)
CN:
5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-2,4-imidazolidinedione
3'-trifluoromethyl-
ocetonilide
NO2
2-amino-2-
1
-(3-trifluoromethyl-
cyonopropane 4-nitrophenyl)-4.4-
dimethyl-5-imino-Z-
irnidazolidinone
3-lrifluoromethyl-
4-nitrophenyl
isocyanaie
(I)

Nilutamide
,
.
DOS 2 649 925 (Roussel-Uclaf; appl. 29.10.1976; F-prior. 29.1 0.1975).
US 4 097 578 (Roussel-Uclaf; 28.6.1978; F-prior. 29.10.1975).
synthesis of
3-trifluoromethyl-4-nitrophenyl
isocyanate:
Rouche, H.: Bull. CI. Sci., Acad. R. Belg. (BCSAAF)
13,
346 (1927).
JP
6
725 067 (Japan Bureau of Ind. Techn.; appl. 15.3.1966).
1442
N
Nilvadipine
medical use for the treatment of hormone dependent cancer other than pmsraric cancer:
WO 8 803 404 (Roussel-Uclaf; appl. 3.11 .l987; I-prior. 4.1 1.1986).
Formulatinn(s):
tabl. 50 mg
Trade Name(s):
F:
Anandron (Cassenne)
USA:
Nilandron (Hoechst Marion
Roussel)
Nilvadipine
(FR-34235; Niprodipine)
ATC:

C08CAlO
Use: calcium antagonist, antihypertensive,
antianginal
RN: 75530-68-6
MF:
C19HIYN306 MW: 385.38
LD,,,:
9150 pg/kg (M, i.v.); 1300 mg/kg (M, p.0.);
9650 pglkg
(R,
i.v.); 1560 mglkg (R, p.0.);
3850 pgkg (dog, i.v.); 510 mgikg (dog, p.0.)
CN:
2-cyano-1
.4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedi~arboxylic
acid 3-methyl 5-(1-
methylethyl) ester
3-nitro- isopropyl
benzoldehyde acetoocetate
methyl 3-amino-
4,4-dimethoxy-
crotonote
isopropyl 2-(3-nitro-
benzy1idene)oceto-
acetote
(I)
0,CH3
HCI
5-isopropyl 3-methyl
2-(dimethoxymethyl)-6-

methyl-4-(3-nitropheny1)-
1,4-dihydropyridine-3.5-
dicarboxylote
Reference(s):
DE
2940 833 (Fujisawa; appl. 9.10.1979; GB-prior. 10.10.1978).
US
4 338 322 (Fujisawa; 6.7.1982; GB-prior. 10.10.1978).
US
4 525 478 (Fujisawa; 25.6.1985; GB-prior. 10.10.1978).
Migamal,
A.
et
al.: Chem. Pharm. Bull. (CPBTAL) 34,3071 (1986).
H3C
!
CHO
NH
OH.
(CH3C0)20
'3c'f0~0.cH3
CH30 hydroxylarnine
NO2
H
H3C
N
CN
H~~TH:T:~~
Nimesulide
N

1443
medical use for treatment of arteriosclerosis:
EP
185 283 (Fujisawa; appl. 7.12.1985; GB-prior. 10.12.1984).
medical use for treatment of cerebral dysfunction:
EP
253 173 (Fujisawa; appl. 26.6.1987; J-prior. 1.7.1986,29.6.1987).
Formulation(s):
s. r. cps. 8 mg, 16 mg
Trade Name(s):
D: Escor (Merck)
Nivadil (Klinge)
J:
Nivadil (Fujisawa; 1989)
Nimesulide
ATC: MOlAX17
Use: anti-inflammatory
RN: 51803-78-2 MF:
C,,Hl,N,OSS MW: 308.31 EINECS: 257-431-4
LD,,: 392 mglkg (M, p.0.);
200 mgkg (R, p.0.)
CN:
N-(4-nitro-2-phenoxyphenyl)methanesulfonamide~
2-bramo-1- potassium 2-nitrodiphenyl 2-aminodiphenyl
nitrobenzene phenolote ether ether
(I)
I
Nimesulide
methanesulfonyl 2'-phenaxymethane-
chloride

(11)
sulfonanilide
acetyl
chloride
0
H~~$~~~
2-phenoxy-4-
nitroaniline
(111)
Reference
(s):
US
3 840 597 (Riker; 8.10.1974; prior. 3.7.1972; 24.2.1971, 13.4.1970).
DOS 2 333 643 (Riker; appl. 2.7.1973; USA-prior. 3.7.1972).
synthesis of
2-phenoxy-4-nitroaniline:
DOS 2 842 186 (BASF; appl. 28.9.1978).
McCombie, H.
et
al.:
J. Chem.
Soc.
(JCSOA9) 1931,529.
1444
N
Nimetazepam
synthesis of2-nitrodiphenyl ether:
Suter, C.M.:
J.
Am. Chem. Soc. (JACSAT)

51,
2581 (1929).
Lock,
G.:
Monatsh. Chem. (MOCMB7)
55,
167 (1930).
Formulation(s):
gran. 100 mg; suppos. 200 mg; tabl. 100 mg, 200 mg
Trade
Name(s):
I:
Algolide (Garant) Folid (CT) Nimesil (Lucofarmaco)
Aulin (Boehringer Mannh.; Laider (Esseti) Remov (Piam)
1985) Mesid (Janssen-Cilag) generics
Eudolene (Savio IBN)
Mesulid (Novartis Farma;
Fansidol (NCSN) 1985)
Nimetazepam
ATC: NOSCD
Use: hypnotic, tranquilizer, anticonvulsant,
skeletal muscle relaxant
RN: 201
1-67-8 MF: C,,H,,N303 MW: 295.30 EINECS: 217-931-5
LD,,,: 750 mglkg
(M,
p.0.);
970 mglkg
(R,
p.0.)

CN:
1,3-dihydro-l-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one
1.
HCI. NoNO,
2. ethyl o-benzyl-
ocetoacetote
ethyl phenylpyruvote
4-nitrophenylhydrozone
(1)
HCI or HZSO, KOH, H,O
I
O2N
ethyl 5-nitro-3-
phenylindol-2-
corboxylate
1.
SOC$
7
NH.
dimethyl sulfate
1
-methyl-5-nitro-
3-phenylindol-2-
corboxylic acid
Nimodipine
N
1445
NaBH,,
BF3
.

0(C2H&
I11
-
.
O2N
.
2-aminomethyl-1
-
Nimetozepom
methyl-5-nitro-3-
phenylindole
Rejerence(s):
US 3 652 551 (Surnitomo; 28.3.1972; J-prior. 1.12.1967,9.12.1967, 14.12.1967, 15.12.1967,21.12.1967,
28.12.1967, 10.1.1968, 11.3.1968).
DOS 1811 830
(Sumitorno; appl. 29.11.1968; J-prior.
1.12.1967,9.12.1967,14.12.1967,15.12.1967,21.12.1967,
28.12.1967, 10.1.1968, 11.3.1968).
DOS 1 816 046 (Surnitomo; appl. 20.12.1968; J-prior. 25.12.1967,9.4.1968).
DOS 1817761 (Sumitomo; appl. 29.11.1968; J-prior. 1.12.1967,9.12.1967, 14.12.1967, 15.12.1967,21.12.1967,
28.12.1967, 10.1.1968, 11.3.1968).
DOS 1 817 794 (Sumitomo; appl. 20.12.1968; J-prior. 25.12.1967).
Ihizurni,
K.
et al.: J. Org. Chem. (JOCEAH) 37,4111 (1972).
indole precursor:
US 3 770 767 (Sumitomo; 6.1 1.1973; J-prior. 28.12.1967).
Formulation(s):
tabl. 3 mg, 5 mg
Trade Narne(s):

J: Erirnin (Sumitomo)
Nimodipine
ATC: C08CA06
Use: calcium antagonist, cerebral
RN:
LD,":
CN:
vasodilator
66085-59-4
MF:
C2,H26N207 MW: 418.45 EINECS: 266-127-0
26.2 mgkg (M, i.v.); 940 mg/kg
(M,
p.0.);
5 mag (R, i.v.); 2738 mgkg (R, p.0.);
4 mag (dog, i.v.);
1
gkg (dog, p.0.)
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic
acid 2-methoxyethyl 1-methylethyl
ester
diketene (1)
isopropyl
3-omino-
crotonote
(11)
1446
N
Nimorazole
2-methoxyethyl Nimodipine

2-(3-nitrobenzy1idene)-
ocetoocetate
(lU)
Reference(s):
DOS 2 117 571 (Bayer; appl. 10.4.1971).
DE 2 117 573 (Bayer; prior. 10.4.1971).
US 3 799 934 (Bayer; 26.3.1974; D-prior.
10.4.197 1).
US 3 932 645 (Bayer; 13.1.1976; D-prior. 10.4.197
1).
Meyer,
H.
et al.: Arzneim Forsch. (ARZNAD) 31,407 (1981); 33, 106 (1983).
Formulation(s):
cps. 30 mg; f. c. tabl. 30 mg; vial 10 mgI50 ml
Trade Name(s):
D:
Nimotop (Rayer Vital; GB: Nimotop (Baycr; 1988) USA: Nimotop (Bayer)
1985) I: Nimotop (Bayer Italia)
F: Nimotop (Bayer) Periplum (Italfarmaco)
Nimorazole
(Nitrimidazine)
ATC: POIAB06
Use: chemotherapeutic (trichomonas),
antiprotozoal
RN: 6506-37-2
MF:
C,H,,N,O, MW: 226.24 EINECS: 229-394-4
LD,,,:
1530 mgkg (M, p.0.);

1540 mgkg
(R,
p.o.)
CN:
4-[2-(5-nitro- 1 H-imidazol- l -yl)ethyl]morpholine
2-morpholino- 4-nitro-
ethyl chloride imidozole
sodium salt
Reference(s):
US 3 399 193 (Carlo Erba; 27.8.1968; prior. 4.8.1965).
US 3 458 528 (Merck
&
Co.; 29.7.1969; prior. 7.7.1965, 18.5.1966).
US 3 646 027 (Merck
&
Co.; 29.2.1972; prior. 7.7.1965, 18.5.1966).
Formulatiorz(s):
tabl. 500 mg
Trade Name(s):
D:
Esclama (Pharmacia
&
F:
Naxogyn (Pharmacia
&
GB: Naxogin (Carlo Erba); wfm
IJpjohn) Upjohn) Nulogyl (Bristol); wfm
Nimustine
N
1447

1:
Naxogin (Erba) Sirledi (Cansyth) Sirledi (Inverni della Beffa)
Nimustine
(ACNU)
ATC: LOIAD06
Use: antineoplastic
RN: 42471-28-3 MF:
C,Hl,C1N,02 MW: 272.70 EINECS: 255-838-1
CN:
N-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-N-(2-chloroethyl)-N-nitrosourea
2-chloroethyl 4-ornino-5-
isocyanate ominomethyl-
2-methylpyrimidine
HCI.
NONO*
Reference(s):
DOS 2 257 360 (Sankyo; appl. 20.1 1.1972; J-prior. 20.1
1.1971,4.12.1971,26.7.1972).
US 4 003 901 (Sankyo; 18.1.1977; J-prior. 20.1 1.1971,4.12.1971, 26.7.1972).
Formulation(s):
vial 25 mg, 50 mg
Trade Name(s):
D: ACNU 50 (ASTA Medica
J:
Nidran (Sankyo)
AWD)
Nipradilol
(Nipradolol)
ATC: C07A; C04A
Use: P-antagonist with vasodilating

activity, antihypertensive, antianginal
RN: 81486-22-8 MF:
Cl,H2,N,0, MW: 326.35
LD,,: 68 mgkg (M, i.v.); 461 mglkg (M, p.0.);
144 mgkg (R, i.p.); 78 mglkg (R, i.v.); 1040 mgkg (R, p.0.); 850 mgtkg (R, s.c.);
20 mgkg (dog, i.v.1; >400 mglkg (dog, p.0.)
CN:
3,4-dihydro-8-[2-hydroxy-3-[(l-methylethyl)amino]propoxy]-2H-l-benz.opyran-3-ol
3-nitrate
NoOH
CHO C
N
COOH
2-hydroxy-3- acrylo-
rnethoxybenz- nitrile
aldehyde
V
1448
N
Niridazole
0
CICOOC2H5,
NoN3,
H2S04
I.
ethyl chloroformote
OH
2. nitric ocid
sodium azide
3.4-dihydro-8-(ethoxy-

carbonyloxy)-ZH-1 -benzo-
pyron-3-01 3-nitrote
(II)
3. isopropylamine
I
I
Niprodilol
EP 42 299 (Kowa; appl. 16.6.1981; J-prior. 25.12.1980, 17.6.1980).
US 4 394 382 (Kowa; 19.7.1983; appl. 9.6.1981; J-prior. 25.12.1980, 17.6.1980).
Shiratsuchi,
M.
et al.: Chem. Pharm. Bull. (CPBTAL) 35, 632 (1987).
separation of diastereomeric racemates:
EP 154 51 1 (Kowa; appl. 27.2.1985; J-prior. 29.2.1984).
US
4
727 085 (Kowa; 23.2.1988; appl. 28.8.1985; J-prior. 29.2.1984).
synthesis of enantiomers:
Shiratsuchi,
M.
et al.: Chem. Pharm. Bull. (CPBTAL), 33,2735 (1985); 35,3691 (1987).
synthesis of
3,4-dihydro-2H- 1 -benzopyran-3,s-diol:
JP 59 029 681 (Kowa; appl. 12.8.1982).
Kawamura,
K.
et al.: Chem. Pharrn. Bull. (CPBTAL) 38,2088 (1990).
Formulation(s):
tabl. 3 mg, 6 mg
Trade Name(s):

J: Hypadil(Kowa;1988)
Niridazole
ATC: P02BX02
Use: chemotherapeutic (antischistosomal)
RN: 61-57-4 MF: C6H6N40,S MW: 214.21 EINECS: 200-512-6
LD,,: 2500
mgkg (M, p.0.);
900 mg/kg
(R,
p.0.)
CN:
1-(5-nitr0-2-thiazolyl)-2-imidazolidinone
2-amino- 2-omino-5-
thiozole nitrothiozole
r=\
,4
N
S
two
A
NyS
r
I=(
NO2
NS
2-chloroethyl-
Y
NH2
NH2
isocyonote

Nisoldipine
N
1449
Heference(s):
Lambert, C.R. et al.: Experientia (EXPEAM) 20,452 (1964).
GB
986 562 (Ciba; appl. 22.5.1963; CH-prior. 30.5.1962,23.4.1963).
alternative syntheses:
DAS 2 033 61 1 (Egyt; appl. 7.7.1970; H-prior. 7.7.1969).
DAS 2 117 050 (Egyt; appl. 7.4.1971; H-prior. 16.4.1970).
Formulation(s):
tabl. 100 mg, 500 mg
Trade Name(s):
F:
Ambilhar (Ciba); wfm
Nisoldipine
(Bay-K
5552)
ATC: C02DE; C08CA07
Use: calcium antagonist, antihypertensive,
antianginal
RN: 63675-72-9 MF:
C2,H,N2O6 MW: 388.42 EINECS: 264-407-7
LD,,: 360 pglkg (M, i.v.); 41 1 mglkg (M, p.0.); 384 mgkg (M, s.c.);
1120 pglkg
(R,
i.v.); 1257 mglkg (R, p.0.); 654 mgkg (R, s.c.);
2 mg/kg (dog, i.v.); 400 mgkg (dog, p.0.)
CN:
1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic

acid methyl 2-methylpropyl ester
2-nitro- isobutyl
isobutyl 2-(2-nitro-
benzoldehyde
acetoacetate
benzylidene)acetoacetate
(I)
methyl 3-amino-
crotonate
Nisoldipine
Li
Keference(s):
DOS 2 549 568 (Bayer; appl. 5.11.1975).
US 4 154 839 (Bayer; 15.5.1979; appl. 8.5.1978; D-prior. 5.1 1.1975).
additional synthesis:
ES 539 113 (Ind. y Comercial Quimica; appl. 27.12.1984).
ES 549 302 (Mora Ruedas; appl. 26.1 1.1985).
ES 546 423 (Inke; appl. 31.7.1985).
ES 546 784 (Sune Coma; appl. 9.9.1985).
CS 243 591 (P. Cupka et al.; appl. 25.1.1985).
medical use for treatment of alcoholism:
DOS 3 806 277 (Tropon; appl. 27.2.1988).
medical use for inhibition of opioid tolerance:
JP 61 260 025 (Miles; appl. 12.5.1986; USA-prior. 13.5.1985).
1450
N
Nitrazepam
medical use as saluretic:
DOS 3 212 736 (Bayer; appl. 6.4.1982).
medical use as antiarteriosclerotic:

DOS 3 222 367 (Bayer; appl. 15.6.1982).
Formulation(s):
f.
c. tabl. 5 mg, 10 rng, 20 rng, 30
mg,
40 rng
Trade lYame(s);
D: Baymycard (Bayer Vital1 I: Syscor (Bayer Italia)
J:
Baymycard (Bayer; 1990)
Zeneca; 1990) Zadipina (SrnithKline USA: Sular (Zeneca)
GB: Syscor MR (Bayer) Beecharn)
Nitrazepam
ATC: N05CD02
Use: hypnotic, anticonvulsant
RN:
mo:
CN:
(3
146-22-5 MF: C,,H,,N,O, MW: 281.27 EINECS: 205-665-2
130 mglkg
(M,
i.v.); 550 mglkg (M, p.0.);
825 mglkg (R, p.0.)
1,3-dihydr0-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one
0
pyridine
+
H,c-o'i
HCI

d
NH2
2-amino- glycine ethyl 2-0x0-5-phenyl-
benzophenone ester hydrochloride
(I)
2.3-dihydro-1
H-
HNO,. H2S0,
11
b
2-chloro-5-
nitrobenzo-
02N$-f.
,
Nitrozepam
p-toluene-
sulfomide
sodium salt