Pharmaceutical Substances Syntheses, Patents, Applications - Part 140 potx

with pentazocine.HC1 as hydrochloride; vial 0.4 mglml, 1 mglml, 10 mglml Trade Names: D: Findol Mundipharma- comb.. with tilidine F: Nalone Serb Narcan Du Pont GB: Narcan Du Pont; as hy

Nalorphine N 1391

monohydrochloride

RN: 58895-64-0 MF: C2,H2,NOq HCI MW: 375.90

(+)-base

RN: 131378-67-1 MF: C2,H2,N03 MW: 339.44

(+)-monohydrochloride

RN: 131712-55-5 MF: C2,H2,NO3 HC1 MW: 375.90

naltrexone

(q v.)

Nolrnefene hydrochloride

Reference(s):

Hahn, F.E et al.: J Med Chem (JMCMAR) 18,259 (1975)

syntltesis of nalmefene from naltrexone:

US 7 421 900 (Nat Inst of Health; appl 28.8.1990; USA-prior 26.10.1989)

US 4 322 426 (Du Pont de N.; appl 30.3.1982; USA-prior 28.4.1980)

US 4 751 307 (Mallinckrodt, Inc.; appl 27.2.1987; USA-prior 17.1 l98S)

EP 140 367 (Key Pharm Inc.; appl 8.5.1985; USA-prior 1.1 1.1983)

use of nalmefene:

US 4 880 813 (Baker Cummins Pharm.; appl 14.1 1.1989; USA-prior 22.7.1988)

WO 8 910 125 (Baker Curnmins Pharm.; appl 2.1 1.1989; USA-prior 27.4.1988)

WO 8 702 586 (Key Pharmaceuticals; appl 7.5.1987; 29.1.1985)

US 4 639 455 (Key Pharmaceuticals; appl 27.1.1987; USA-prior 2.1.1984)

US 4 863 928 (Baker Cummins Pharm.; appl 5.9.1989; USA-prior 4.1.1989)

US 4 877 791 (Baker Cummins Pharm.; appl 31.10.1989; USA-prior 1.1 1 l988)

US 4 923 875 (Baker Cummins Pharm.; appl 8.5.1990; 10.7.1989)

WO 9 218 126 (Baker Cummins Pharm.; appl 29.10.1992; USA-prior 10.4.1991)

WO 9 11 8 605 (Finland; appl 12.12.1991; USA-prior 4.6.1990)

formulariotl:

US 4 51 1 570 (Key Pharmaceuticals; appl 16.4.1985; 28.3.1983)

cornbitzutiorz:

WO 9 5 1 985 (Italy; appl 30.1 1.1995; 1-prior 24.5.1994)

Formulation(s): amp 100 pglml, 2 mg12 ml; syringe 2 mg12 rnl (as hydrochloride)

Trade Name(s):

USA: Revex (Ohmeda)

Use: morphine antagonist RN: 62-67-9 MF: CI9II2,NO3 MW: 311.38 EINECS: 200-546-1

LD,,,: 127 mglkg (M, i.v.); 1 140 mgkg (M, p.0.);

226 mglkg (R, i.v.)

CN: (5a,6a)-7,8-didehydro-4,5-epoxy-17-(2-propenyl)morphinan-3,6-diol

1392 N Naloxone

hydrochloride

RN: 57-29-4 MF: C,yH2,N03 HCI MW: 347.84 EINECS: 200-321 -8

LD,,,: 63 m g k g (M, i.v.);

1 150 m g k g (R, p.0.);

120 mg/kg (dog, i.v.)

hydrobromide

RN: 1041-90-3 MF: C,,HzlN03 HBr MW: 392.29 EINECS: 213-868-2

LD,,,: 260 mg/kg (M, i.p.); 921 mg/kg (M, s.c.)

HO

cyanogenl

bromide

CH3

BrCN

+ H3C' ' 'CH,

;

&

: H

Reference(s):

US 2 364 833 (Merck & Co.; 1944; prior 1941)

US 2 89 1 954 (Merck & Co.; 1959; prior 1951)

Formulation(s): amp 1 mg, 5 mg, 10 mg (as hydrobromide)

Trade Name(s):

D: Lethidrone (Wellcome); GB: Lethidrone (Burroughs USA: Nalline (Merck Sharp &

F: Nalorphine Serb I: Norfin (Lusofarmaco); wfm

(L'Arguenon)

Use: narcotic antagonist RN: 465-65-6 MF: ClyHz1NO4 MW: 327.38 EINECS: 207-365-7

LD,,,: 260 mglkg (M, s.c.)

CN: (5a)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one

hydrochloride

RN: 357-08-4 MF: Cl,Hz,N04 HCl MW: 363.84 EINECS: 206-61 1-0

LD,,,: 90 mgkg (M, i.v.); >1 glkg (M, p.0.);

107 mglkg (R, i.v.); >I glkg (R, p.0.)

Naltrexone N 1393

H3c/0@N 0

b HBr o&N H: A

O H \ c H 3 O H \

oxymorphone

H O B r e C H ,

b

ollyl bromide

14-hydroxydihydro-

norrnorphinone

Noloxone

US 3 254 088 (M J Lewenstein; 31.5.1966; appl 14.3.1961)

DE 1 183 508 (M J Lewenstein; appl 7.3.1962; USAlprior 14.3.1961)

GB 929 287 (Sankyo; appl 9.3.1962; J-prior 14.3.1961)

Formulation(s): amp 0.04 mg/2 ml, 0.4 mglml; cps 4 mg in comb with tilidine (as hydrochloride);

tabl 0.5 mg in comb with pentazocine.HC1 (as hydrochloride); vial 0.4 mglml, 1 mglml,

10 mglml

Trade Name(s):

D: Findol (Mundipharma)-

comb with tilidine

Gruntin (Griinentha1)-

comb with tilidine

Narcanti (Du Pont Pharma)

Tilador (Hexa1)-comb with

tilidine

Tilidin (Isis Puren;

Heumann; Stada; BASF;

ratiopharm; Sax)-comb

Valomerck (Merck)-comb

with tilidine Valoron (Godecke)-comb

with tilidine F: Nalone (Serb) Narcan (Du Pont) GB: Narcan (Du Pont; as hydrochloride) I: Narcan (Crinos) Narcan neonatal (Crinos)

generics J: Naloxone Hydrochloride (Sankyo)

USA: Narcan (Endo; as hydrochloride) Talwin Nx (Sanofi) generics and combination preparations

Use: narcotic antagonist RN: 16590-41-3 MF: C2,H2,NO4 MW: 341.41 EINECS: 240-649-9

LD,,: 551 mg/kg (M, s.c.)

CN: (5a)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymo~hinan-6-one

hydrochloride

RN: 16676-29-2 MF: C20H23N04 HCl MW: 377.87 EINECS: 240-723-0

LD,,: 1100 m g k g (M, p.0.);

1450 mgkg (R, p.0.)

1394 N Nandrolone

DMF, 70 'C, 1 week

+ Br& -*

oxymorphone (1) cyclopropyl-

(cf noloxone methyl

ethylene

glycol

1 LiAIH,

2 NH4CI

cyclopropane-

corbonyl

chloride

Reference(s):

DAS I 795 707 (Endo; appl 19.12.1966; USA-prior 19.1.1966)

FX-M 6 358 (Endo; appl 24.2.1967)

US 3 332 950 (Endo; 25.7.1967; prior 23.3.1963, lSS.1963,6.12.1966)

Formulation(s): tabl 50 mg (as hydrochloride)

Trade Name(s):

D: Nemexin (Du Pont Pharma) GB: Nalorex (Du Pont) Narcoral (Crinos) F: Nalorex (Du Pont) I: Antaxone (Zambon Italia) USA: ReVia (Du Pont)

Use: anabolic RN: 434-22-0 MF: C,*H2,02 MW: 274.40 EINECS: 207-101-0

CN: (17P)-l7-hydroxyestr-4-en-3-one

Nandrolone decanoate N 1395

estradiol dirnethyl sulfate

(9 v.)

Li NH,

I -b

'

I Nandralone

Reference(s):

US 2 698 855 (Organics; 1955; prior 1953)

US 2 774 777 (Syntex; 1956; prior 1952)

Wilds, A.L.; Nelson, N.A.: J Am Chem Soc (JACSAT) 75,5366 (1953)

Djerassi, C et al.: J Am Chem Soc (JACSAT) 76,4092 (1954)

Formularion(s): eye drops 10 mglml (as monosodium sulfate) '

Trade Name(s):

D: Keratyl (Chauvin I: Dynabolon (Crinos); wfm USA: Nortestonate (Upjohn);

F: Keratyl (Chauvin) cyclohexylpropionate)

Use: anabolic RN: 360-70-3 MF: C,,H,03 MW: 428.66 EINECS: 206-639-3

LD,,,: >566 mg/kg (M, i.p.)

CN: (l7P)- 17-[(I -oxodecyl)oxy]estr-4-en-3-one

pyridine

d

Reference(s):

US 2 998 423 (Organon; 29.8.1961; appl 2.2.1959; NL-prior 25.2.1958)

0

&A(cH2)8-cH3

H H

H H

nandralane decanoyl chloride

Formulation(s): amp 25 mglml, 50 mg/ml

Nandrolone decanoate

Trade Name(s):

D: Deca-Durabolin (Organon) F: Deca-Durabolin (Organon); I: Deca-Durabolin (Organon

ankerpharm) GB: Deca-Durabolin (Organon)

(9 v.)

1396 N Nandrolone hexyloxyphenylpropionate

J: Deca-Durabolin (Organon- USA: Deca-Durabolin (Organon)

Sankyo)

Nandrolone hexyloxyphenylpropionate ATC: ~ 1 4 ~ ~ 0 1

Use: anabolic RN: 52279-57-9 MF: C,,H4,04 MW: 506.73 EINECS: 257-810-4

CN: (17~)-17-[3-[4-(hexyloxy)phenyl]-l-oxopropoxy]estr-4-en-3-one

I Nondrolone hexyloxyphenylpropionote (I)

Reference(s):

US 2 904 562 (Leo; 15.9.1959; appl 20.1.1958)

Formulmtion(s): amp 50 mg; susp 50 mgl2 ml

Trade Name(s):

D: Anadur (Bastian-Werk); F: Anador (Logeais); wfm

w fm

RN: 62-90-8 MF: C,H3403 MW: 406.57 EINECS: 200-551-9

LD,,,: > l g/kg (M, i.p.);

595 mg/kg (R, i.p.)

CN: (17~)-17-(1-oxo-3-phenylpropoxy)estr-4-en-3-one

Nandrolone undecylate N 1397

Reference(s):

GB 826 028 (Organon; appl 1956; NL-prior 1955)

US 2 868 809 (Upjohn; 1959; prior 1953)

Fortnulation(s): amp 25 mg

Trade Name(s):

D: Docabolin (Nourypharma)-

comb.; wfrn

Durabolin (Organon); wfrn

Hepa-Obaton

(Nourypharma)-comb.;

wfrn

F: Durabolin (Organon); wfrn

GB: Durabolin (Organon); wfrn

I: Anticatabolin (Falorni);

wfrn Anticatabolin (Nativelle);

wfrn Durabolin (Ravasini); wfrn Norandrol (Panther-Osfa Chemie); wfrn

Norbalin (Bieffe); wfrn Sintabolin (AFI); wfrn

Stenabolin (AFI); wfrn Strabolene (Isola-Ibi); wfrn Superbolin (Labin; wfrn J: Durabolin (Organon- Sankyo)

USA: Durabolin (Organon); wfrn Nandrolin (Tutag); wfrn generics; wfrn

Nandrolone undecylate

(Nandrolone undecanoate)

.ATC: A14ABO1 Use: anabolic RN: 862-89-5 MF: C2,H,,0, MW: 442.68 EINECS: 212-729-3

CN: (17P)-17-[(1-oxoundecyl)oxy]estr-4-en-3-one

Reference(s):

BE 659 440 (N Gueritee; appl 9.2.1965; GB-prior 21.2.1964)

nandrolone undeconoyl chloride

use as anabolic in combination with estradiol esters:

FR-M 3 424 (N Gueritee; appl 27.1.1964)

Nandralone undecylate

alternative synthesis and combination with mineral corticoids:

DOS 2 638 507 (Akzo; appl 26.8.1976; NL-prior 27.8.1975)

(9 v.1

use in combination with vitamin E:

FR-M 7 284 (J M Gastand; appl 7.3.1968)

Formulation(s): inj sol 80.5 mgll ml

Trade Name(s):

F: Dynabolon (Thtramex); Trophoboltne (Th6ramex)- I: Dynabolon (Fournier

1398 N Naphazoline

Use: vasoconstrictor, rhinological therapeutic

RN: 835-31-4 MF: CI4HL4N2 MW: 210.28 EINECS: 212-641-5

LD,,,: 170 mglkg (M, i.v.); 270 mg/kg (M, p.0.)

CN: 4,5-dihydro-2-(l-naphthalenylmethyl)-1H-imidazole

monohydrochloride

RN: 550-99-2 MF: C14H14N2 HCI MW: 246.74 EINECS: 208-989-2

mononitrate

RN: 5144-52-5 MF: C,4H,,N2 HNO, MW: 273.29 EINECS: 225-915-4

LD,,: 13.2 mglkg (M, i.v.); 265 mglkg (M, p.0.);

1260 m g k g (R, p.0.)

HCI

ethylene-

0 4 %

acetonitrile

Reference(s):

US 2 161 938 (Ciba; 1939; D-prior 1934)

Formdation(s): eye drops 0.3 mglml, 1 mg/ml; nasal spray

Trade Name(s):

D: Antistin-Privin (CIBA

Vision)-comb

Piniol (Spitzner; as

hydrochloride)

Privin (Novartis Pharma; as

nitrate)

Proculin (Chauvin

ankerpharm)

Rhinex (Pharma

Wernigerode)

Vistalbalon (Pharm-

Allergan)

numerous generics and

combination preparations

F: Collyres bleus Laiter

(Leurquin)-comb

DCrinox (ThCrabel Lucien

pharma)-comb

Frazoline (Bouchara)- comb

Soframycyne ( R o w e l ) - comb

Xylocai'ne naphthazoline (Astra)-comb

GB: Antistin-Privinc (Ciba)- comb.; wfm

Murine (Abbott); wfm Nomaze (Fisons); wfm Vasocon A (Cooper Vision)-comb.; wfm Vasocon A (Knox)-comb.;

wfrn I: Citroftalmina (SIF1)-comb

Collirio Alfa (Bracco) Deltarinalo (Hoechst Marion Rousse1)-comb

Desamin Same (Savoma) Imidazyl (Recordati) Imizol (Farmigea) Naftazolina (Bruschettini) Pupilla (Alfa Wassermann) Rinazina (Maggioni) Rinazina Senza Sulfamlde (Maggioni)

Virginiana Gocce Verdi (Kelemata)

numerous combination preparations

J: Pnvina (Ciba-Geigy- Takeda; as nitrate) USA: Naphcon (Alcon; as hydrochloride)

Naproxen N 1399

Use: anti-inflammatory, a n t i r h e u m a t i c ,

a n a l g e s i c

RN: 22204-53-1 MF: C,,H,,O, MW: 230.26 EINECS: 244-838-7

LD,,,: 435 mglkg (M, i.v.); 360 mglkg (M, p.0.);

248 mglkg (R, p.o.1;

>I d k g (dog, p.0.)

CN: (S)-6-methoxy-a-methyl-2-naphthaleneacetic acid

sodium salt

RN: 26159-34-2 MF: CI4H,,NaO, MW: 252.25

@ Originol process:

n

AICI,

H C

+

oluminu) 1 \o

6-methoxy-2-naphthyl- acetic acid

hydride

DL-2-(6-methoxy-2-

nophthyl)propionic ocid (VI)

Noproxen

racemote resolution with cinchonidine

@ First large-scole manufacturing process of Syntex:

FH3

1400 N Naproxen

1 Mg, THF

2 ZnCI2, THF

0 NOOH , , Br 4 NOOH

' - 0 3 ethyl 2-bromo-

propionote 2-bromo-&methyl-

oxynaphtholene (VI11)

rocemote resolution with cinchonidine

@ Second large-scale manufacturing process of Syntex:

resolution with N-olkyl-D-glucomine

(mode by reductive

ominotion of D-glucose)

@ Asymmetric hydrogenotion:

I1

2-(6-methoxy-2-

nophthyl)ocrylic acid (K)

@ Zombon process:

propionyl

chloride

2-methoxy-6- propionylnaphtholene (X)

OH 0 ocid cotolyst

X f ,,0#~,~~3 ,

H3C 0 OH

(1,2-aryl shift with