Pharmaceutical Substances Syntheses, Patents, Applications - Part 150 pps

50 mg as dihydrochloride Trade Names: D: lnsidon Novartis Pharma I: Insidon Novartis Farma F: Insidon Novartis J: Insidon Geigy-Fujisawa GB: lnsidon Geigy; wfm USA: Ensidon Ciba-Geigy;

Opipramol 0 1491

Trade Name(s):

D: Zofran (Glaxo Wellcome) GB: Zofran (Glaxo Wellcome; J: Zofran (Glaxo-Sankyo,

I: Zofran (Glaxo Wellcome) USA: Zofran (Glaxo Wellcome)

Use: thymoleptic, antidepressant RN: 315-72-0 MF: C2,H2,N30 MW: 363.51 EINECS: 206-254-0

LD,,,: 45 mglkg (M, i.v.); 400 mglkg (M, p.0.);

32 m g k g (R, i.v.); l I1 0 mglkg (R, p.0.)

CN: 4-[3-(5H-dibenz[b,flazepin-5-yl)propyl]- 1 -piperazineethanol

dihydrochloride

RN: 909-39-7 MF: C2,H2,N30 2HCl MW: 436.43 EINECS: 213-000-2

LD,,: 45 m g k g (M, i.v.); 443 mglkg (M, p.0.);

32 m g k g (R, i.v.); 900 mglkg (R, p.0.)

1 sodium amide

2 1 -brorno-3-chloro-

5H-dibenz[b,f]ozepine propane 5-(3-chlorapropyl)-5H-

dibenz[b.f]azepine (I)

Reference(s):

GB 862 297 (Geigy; appl 8.5.1958; CH-prior 9.5.1957)

FR 1 271 971 (Geigy; appl 12.8.1959; CH-prior 13.8.1958)

GB 881 398 (Rh6ne-Poulenc, appl 29.9.1958; valid from 7.9.1959)

DE 1 132 556 (Geigy; appl 12.8.1959; CH-prior 13.8.1958)

DE 1 133 729 (Geigy; appl 8.5.1958; CH-prior 9.5.1957)

Formulation(s): drg 50 mg (as dihydrochloride)

Trade Name(s):

D: lnsidon (Novartis Pharma) I: Insidon (Novartis Farma)

F: Insidon (Novartis) J: Insidon (Geigy-Fujisawa)

GB: lnsidon (Geigy); wfm

USA: Ensidon (Ciba-Geigy); wfm

Orazamide

(AICA-Orotate)

ATC: A05B Use: liver therapeutic

RN: 2574-78-9 MF: C5H4N,04 C,HdN40 MW: 282.22 EINECS: 219-923-7

LD,,,: 600 mglkg (M, i.p.)

CN: 5-amino-1 H-imidazole-4-carboxamide orotate (1 : 1)

1492 0 Orciprenaline

\ N H

Refereme(s):

GB 1 018 117 (Fujisawa; appl 13.3.1963; J-prior 15.3.1962)

US 3 271 398 (Fujisawa; 6.9.1966; J-prior 15.3.1962)

corboxomide

newer method for AICA:

DE 2 160 674 (Sagami; appl 29 l2.1971; J-prior 9.12.1970)

Orozornide

Formulation(s): tabl 100 mg

hydrochloride

Trade Name(s):

D: Aicorat (Mack, Illert.); F: Aicamine (Labaz); wfm J: Aicamin (Fujisawa)

Orciprenaline

(Metaproterenol)

ATC: R03AB03; R03CB03 Use: bronchodilator, antiasthmatic RN: 586-06-1 MF: C,,H,,NO, MW: 211.26 EINECS: 209-569-1

LDs,,: 86 mglkg (M, i.v.); >8130 mgkg (M, p.0.);

67.2 m g k g (R, i.v.); 3370 m g k g (R, p.0.);

30 m g k g (dog, i.v.); 125 mglkg (dog, p.0.)

CN: 5-[1-hydroxy-2-[(1-methylethyl)amino]ethyl]-1,3-benzenediol

sulfate (2:l)

RN: 5874-97-5 MF: CllHI7NO3 1/2H2S04 MW: 520.60 EINECS: 227-539-6

LD,,: 114 mglkg (M, i.v.); 4800 mglkg (M, p.0.);

5538 mgkg (R, p.0.)

0 CH,

K

0

K

0

1 isopropylornine (1)

3',5'-dihydroxy-

2-(isopropylornino)-

Orciprenoline

u

Orgotein 0 1493

Reference(s):

DE 1 275 069 (Boehringer Ing.; appl 15.2.1960)

US 3 341 594 (Boehringer lng.; 12.9.1967; D-prior 15.2.1960)

Formularion(s): amp 0.5 mg; doses aerosol 1.5 mg, 0.75 mg; drops 2 %; inhalation aerosol 750 pghetered

inhalation; syrup 10 mg/5 ml; sol 15 mg; tabl 20 mg (as sulfate)

Trade Name(s):

D: Alupent (Boehringer Ing.) I: Alupent (Boehringer Ing.) USA: Alupent (Boehringer Ing.)

F: Alupent (Boehringer Ing.) J: Alotec (Boehringer- generics

GB: Alupent (Boehringer Ing.) Tanabe)

Use: anti-inflammatory

RN: 9054-89- 1 MF: unspecified MW: unspecified EINECS: 232-771-6

CN: dismutase superoxide

Water soluble protein with a relative molecular mass of ca 32600, which particularly contains copper and zinc bound like chelate (ca 4 gram atoms) and has superoxide-dismutase-activity It is isolated from bovine liver or from hemolyzed, plasma free erythrocytes obtained from bovine blood Purification by manyfold fractionated precipitation and solvolyse methods and definitive separation of the residual foreign proteins by denaturizing heating of the orgotein concentrate in buffer solution to ca 65-70 "C and gel filtration andlor dialysis

Reference(s):

DE 2 101 866 (Diagnostic Data; appl 15.1.1971; USA-prior 16.1.1970)

US 3 579 495 (Diagnostic Data; 18.5.1971 ; prior 13.5.1968, 10.4.1969, 24.4.1970)

US 3 624 251 (Diagnostic Data; 30.1 1.1971; appl 16.1.1970)

US 3 687 927 (Diagnostic Data; 29.8.1972; prior 31.8.1966, 2.8.1967,7.6.1971)

Formulation(s): vial 4 mg, 8 mg

Trade Name(s):

D: Peroxinorm (Griinenthal); Interceptor (Isnardi); wfm Oxinorm (Zambeletti);

I: Artrolasi (Ausonia); wfm Orgoten (Serono); wfm

1494 0 Orlistat

(Tetrahydrolipstatin; Orlipastat; Ro- 18-0647) Use: antiobesity, pancreatic lipase inhibitor

RN: 96829-58-2 MF: C2,Hs3NOs M W : 495.75

CN: N-Formyl-t-leucine [2S-[2a(R*),3.beta.]]-l-[[3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester

I

lipstotin is produced by fermentation o l Streptornyces toxytricini

ethyl 3(R)-(tetrohydro-

pyranyloxy)-6-heptenoate

" ' p I , THF, Et.0 H3C-(CH2)6-p+ 2 BuLi

octyltriphenylphosphoniurn

bromide

DIBAL

toluene C H ~ C ~ ~ fu

d i i s o b ~ t ~ l a l u r n i n u m 0 H C h ( C H 2 ) 6 - C H 3 octanoic acid (nI),

diisopropylamide

9 ,Cl l.Qf,; , pyridine

z.To-O* C~H,OH

3 separation of diastereomers

A l

O H 0 0 by column chromatorophy

1 benzenesulfonyl chloride (CH2),-CH, 2 pyridinium p-toluenesulfonate

Orlistat 0 1495

1 PPh3 DEAD THF

HN,CHO 1 triphenylphosphine

HO

(S)-N-formyl- leucine (VI)

1 CH2C12, cyclohexone

2 LiH-DIBAL

1 KOH CH,OH

,

1 potossium hydroxide

2 benzenesulfonyl

1 Hz, Pd-C, THF

2 V PPh,, DEAD THF

2 (S)-N-formylleucine

(XI)

1496 0 Orlistat

YHa

2 CI-5'-CH3

1 butyllithiurn, diisopropylarnine

2 trirnethylsilyl chloride

QH + J ' J "3 ""2 , 0

H O O C ~ C O O H o boron H 00 C,,+\\~O

L

etherote

hexonone

1 BH THF

1 BH3, THF

2 , tBuPh Si O H - -

3 1 borone

diphenylsilyl

chloride

chloride

1 Li-(CHZ)9-CH,

2 VI1

XV 1 decyllithium , tBuPh Si 'o-(cH~)~~- CH3

2 benzyl

1 HF CH3CN

2 Py2 H,Cr,O, '1-

OHC-

2 pyridinium (CH2) ,0- CH3

dichrornote

3(R)-benzyloxy- tetrodeconol (XVII)

Orlistat 0 1497

the diastereomers are separated by column chromotogrophy

1 HF, CH,CN

?p

1 CI-Tbs

(CH2),-CH3

1 Hz Pd-C 2.VI PPh, DEAD

m

2 (S)-forrnylleucine, triphenylphosphine

finalization of synthesis from the stereoisomer XDC

2 0,

(CH2) 1, - C H 3

1 Hz Pd-C

2 VI , PPh, DEAD

olternotive synthesis of 3(R)-benzyloxytetradecanal XM

0HC-(CH2)g-CH3 + H2C'kM'@r -+ H 2 ~ / d ( ~ ~ 2 ) ,,- CH3

allylmagnesium

1498 0 Orlistat

Z(R)-ocetoxy-2-

phenylocetic ocid

1 KOH CH,OH

(m) (XXIII) the diastereomers are separoted by column chromatography

2 benzyl bromide (XXUI) H~C'M(CH,),~- CH,

1 KOH CH,OH

~ O ~ N - ( ~ C O O H PP~, DEAD K~CO,

b O H

isomerization of unwonted stereoisomer H ~ c / ~ ( c H , ) ~ ~ - CH,

1 X X N KH, THF

2 0, cn30H C H ~ C I ~ , XVII

1 benzyl bromide

2 ozone

LDA, THF O H O H XVII + 111 H ~ ~ ~ + ( c H , ) ~ ~ - CH,

lithium

d i i s o ~ r o ~ v l -

(CH,),-CH, ,

mixture of diastereomers

1 Hz Pd-C.THF

2 Tos-OH, CHCI, H,C

(Jones oxidation)

(mI0

mixture of diastereorners

Orlistat 0 1499

1 XXIII, THF, HMPT

A

2 0 , T o CH2Cl,

xx)[I b o Yn o o

1 benzyl bromide H ~ ~ ~ ~ ( c H ~ ) ~ ~ - c H ~

2 3.4-dihydro-2H-pyron (IOWI) (EH,),-CH,

( m u )

's'~'

1.- ,\ pyridine

1 benzenesulfonyl chloride

2 pyridiniurn p-toluenesultonote

PPh, DEAD

Orlistot

C H 2 DIBAL, toluene

~ ~ c K ~ ~ ) ( - C CHI H

+ x m -b vrrr

2 10 2 diisobutylalurninurn

tert-butyl (R)-3-hydroxy-

tetradeconoote

hydride

THF, -7B°C

tert-butyl (S)-p-toluene-

sulfinylocetate

1 Hg-AI THF, H20

2 Br-(CH2),-CH, , BuLi,

2 hexyl bromide, butyllithium (CHJ-CH,

1 KOH, CH,OH -

1500 0 Orlistat

2 VI PPh3 DEAD, THF

(3

H C

\ ~ ~ ( w ~ ) , ~ - c H ~

methyl (R)-3-hydroxy- a-bromooctanoyl

tetradeconoate (XXXVIII) chloride

a-bramooctanoic acid

7%

Zn Et,O, CI-~~-CH,

XXW(

'3'3 + XW(

zinc, trirnethyl-

silyl chloride

analogously

to method

Reference(s):

a EP 129 748 (Hoffmann-La Roche & Co AG; appl 2.1.1985; CH-prior 22.6.1983)

b Schneider, F.; Barbier, P.: Helv Chim Acta (HCACAV) 70,196 (1987)

synthesis uf3(R)-(tetrahydropyrany1oxy)-6-heptenc acid ethyl ester:

Hirama, M.; Nei, M.: J Am Chem Soc (JACSAT) 104,4251 (1982)

c Widmer, U.; Schneider, F.; Barbier, P.: Helv Chim Acta (HCACAV) 70,1412 (1987)

d Hanessian, S.; Tehim, A,; Chen., P.: J Org Chem (JOCEAH) 58 (27), 7768 (1993)

e Barbier, P.; Schneider, F.: J Org Chem (JOCEAH) 53, 1218 (1988)

f EP 189 577 (Hoffmann-La Roche & Co AG; appl 6.8.1986; CH-prior 21.12.1984)

g EP 524 495 (Hoffmann-La Roche & Co AG; appl 27.1.1993; USA-prior 23.7.1991; 12.3.1992)

,further synrheses of orlistat:

Kocieski, P.; Pons, J.M.: Tetrahedron Lett (TELEAY) 30, 1833 (1989)

Fleming, I.; Lawrence, N.J.: Tetrahedron Lett (TELEAY) 31 (25), 3645 (1990)

Casc-Green, S.C.; Davies, S.G.; Hedgecock, C.J.R.: Synlett (SYNLES) 1991,781

Uskovic, M.R.; Chadka, N.K.; Batcho, A.D.; Tang P.C.; Courtney, L.F.; Cook C.M.; Wovliulich, P.M.: J Org Chem (JOCEAH) 56,4714 (1991)

Formulation(s): cps 120 mg

Trade Nume(s):

D: Xenical (Roche; 1999) GB: Xenical (Roche; 1998)

F: Xenical (Roche; 1998) USA: Xenical (Roche; 1998)