Pharmaceutical Substances Syntheses, Patents, Applications - Part 27 potx

process for manrifacturing ophthalmic suspensions: pharmaceutical compositions: Formulations: ophth.. dirnethyl sulfate Br benzoic acid dimethoxybenzoate xylene NoOCH3... diethyl o

Brinzolamide B 261

ethyl vinyl

ether

CrO,/H,SO,

acetone

VI -+

Y

(?)-2-(3-bromopropy1)- 4-(1 -ethoxyethoxy)- 3.4-dihydro-2H-thieno- [3.2-el- 1,2-thiazine

1 , l -dioxide

1 BuLi, THF

2 SOz

3 HOSA

O A CH3 0,

Y

C H 3 (VI)

I (+)-I~C~BCI,THF

2 Tos-CI THF

3 H,N-CH,

VII -+

1 (+)-8-chlorodiisopropyl-

compheylborone

2 tosyl chloride

3 ethylamine (VIII)

" 0

3,4-dihydro-2-(3-methoxypropy1)-

4-0~0-2H-thieno[3,2-e]-1,2-thiozine-

6-sulfonornide 1 l-dioxide (VII)

Brinzolornide

I

1H.SH-pyrrolo[l.2-c]-

\\S/NH2 1,3,2-oxazaborole,

2 pyridiniurn perbrornide

B r

0

NaH, THF

3 - b r o m o - l -methoxy- propone (X)

262 B Brinzolamide

ethonol, H20

thioureo

0

3-acetyl-2.5- benzyl

dichlorothiophene chloride

3-acetyl-5-chloro- 2-(benzylthio)- thiophene (XII)

1 CIZ, ethyl acetate

3-(brornoocetyl)-

5-chloro-2-

thiophenesulfonomide (XlIl)

K2C03, DMSO

4-hydroxy-2-(3-rnethoxy- propy1)-2H- thieno[3.2-el- 1,2-thiozine 1.1-dioxide (XV)

XVI

1 trimethyl orthoocetote

3 ethylornine

Reference(s):

Brodimoprim B 263

ophthalmic compositions with prostaglandins:

W O 9 819 680 (Alcon; appl 5.9.1997: USA-prior 1.1 1.1996)

process for manrifacturing ophthalmic suspensions:

pharmaceutical compositions:

Formulation(s): ophth susp 1% in dispensers (2.5,5, 10 and 15 ml)

Trade Name(s):

USA: Azopt (Alcon; 1998)

Brodimoprim

(Ro- 10-5970)

Use: antibacterial

CN: 5-[(4-Bromo-3,5-dimethoxyphenyl)methyl]-2,4-pyrimidinediamine

hydrochloride

0 I 1 NoOH, H 2 0

6H 2 H3c >,0J~3

0

HO OH 1 bromine H C = '0

2 dirnethyl sulfate Br

benzoic acid dimethoxybenzoate

xylene

NoOCH3 CH30H

4-brorno-3.5-dimethoxy- benzoldehyde (11)

I Brodimoprirn

264 B Brodimoprim

dimethyl 2,6-dimethoxy-

terephthalote

1 0 n -

2 S0Clp

3 H, Pd/BaSO,

methyl 4-amino-3.5-di-

methoxybenzoote (V)

a-(rnorpholinornethylene)- hydrocinnornonitrile

H

N , NaOCH3, CH30H

Br

4-bromo-3.5-dimethoxy-

a-(onilinomethylene)-

hydrocinnornonitrile (VII)

Reference(s):

a CA 1 017 743 (Hoffmann-La Roche; CH-prior 8.1 1.1973)

b Kompis, I., Wick A.: Helv Chim Acta (HCACAV) 60 (8), 3025 (1977)

alternative preparation of 4-bromo-3,s-dimethoxybenzaldehyde:

Barknecht, C.F.; Nichols, D.E.: J Med Chem (JMCMAR) 14,370 (1971)

Formulation(s): gran 200 mg; susp 1 %, 50 mg; tabl 200 mg

Trade Name(s):

I : Hyprim (Fisons) Unitrim (Fisons; 1993)

Bromazepam B 265

Bromazepam

?

ATC: N05BA08

Use: tranquilizer

LD,: 879 mg/kg (M, p.0.);

CN: 7-bromo-l,3-dihydro-5-(2-pyridinyl)-2H-1,4-benzodiazepine-2-one

P,OI0 pyridine, A , 3 H20

1 phenyllithiurn

anthrenilamide

and 2-brornopyridine) anthranilonitr~le (from phenyllithiurn 2-(2-orninobenzay1)-

pyridine (I)

acetic anhydr~de 2-(2-acetarnida- 2-(2-acetamido-5-brorno-

benzoy1)pyridine benzoyl)pyndine (11)

H ~ N > ~ " ~ ~ ~

0 oHCI pyridine

b

glycine ethyl ester hydrochloride

I Brornazeparn I

u

? 2 H3C''OQVc~3

2 diethyl oxolate

1 -axide pyruvate 1'-oxide (In)

4-brornophenyl-

hydrozine hydrochloride

ethyl 5-brorno-3- (2-pyridy1)indole- 2-carboxylate 1'-oxide ( N )

266 B Bromazine

5-bromo-3-(2-pyridyl)

indole-2-carbonitrile (V)

1 LiAIH4

2 HCI

2-ominomethyl-5-bromo- 3-(2-pyridyl)indole dihydrochloride

US 3 100 770 (Roche; 13.8.1963; appl 11.8.1961)

US 3 182 065 (Roche; 4.5.1965; appl 9.4.1964; prior 19.4.1963)

US 3 182 066 (Roche; 4.5.1965; appl 9.4.1964; prior 19.4.1963)

US 3 182 067 (Roche; 4.5.1965; appl 9.4.1964)

modijed methods:

DAS 2 233 483 (Roche; appl 7.7.1972; GB-prior 8.7.1971,7.10.1971)

DOS 2 252 378 (Roche; appl 25.10.1972; CH-prior l8.ll.1971)

alternative synthesis of 2-(2-amino-5-bromobenzoy1)pyridine:

DAS 2 256 614 (Roche; appl 17.1 1.1972)

DAS 1 813 241 (Roche; appl 6.12.1968; J-prior 8.12.1967, 9.12.1967, 12.12.1967, 25.4.1968)

combination with sulpiride:

DAS 2 342 214 (Roche; appl 21.8.1973; CH-prior 21.9.1972)

Trade Name(s):

Bromazine

(Bromdiphenhydramine)

CN: 2-[(4-bromophenyl)phenylmethoxy]-N,N-dimethylethanamine

hydrochloride

LD,,: 63 m g k g (M, i.v.); 366 mglkg (M, p.0.);

55 mglkg (R, i.v.); 602 mglkg (R, p.0.);

21 mglkg (dog, i.v.)

Bromelain B 267

FH3

xoH CCI,, 2 H ~ - ~ ~ c H ~ ,

Br 2-dimethylomino-

\

bsnzhydrol hydryl bromide

Reference (s):

GB 670 622 (Parke Davis; appl 1948; CH-prior 1947)

Trade Name(s):

Bromelain

(Bromelin)

LD,,,: 30 mgkg (M, i.v.); >10 g k g (M, p.0.);

>I0 g k g (R, p.0.)

A concentrate of proteolytic enzymes derived from Ananas comosus Merr

proteolytic enzyme (glycoprotein)

relative molecular mass = 33000

By extraction from pineapple stems with water and precipitation with acetone or ammonium sulfate

Reference(s):

Heinicke, R.M.: Science (Washington, D.C.) (SCIEAS) 118,753 (1953)

US 3 002 891 (Pineapple Research Inst Hawai; 3.10.1961; appl 12.12.1958)

purification:

U S 2 950 227 (Schering AG: 1960; prior 1956,1959)

Trade Name(s):

Mulsal (Mucos)-comb

2 6 8 B Bromfenac sodium

Bromfenac sodium

(AHR-10282)

sesquihydrate

free acid

tert-butyl hypo- chlorite

ethyl ?-(methyl thio)acetate

7-(4-bromabenzoy1)-

3-(rnethylthb-2.3-

dihydro-1 H-

indol-2-one (I)

1 Raney-Ni THF

2 NaOH

_*

Bromfenac sadium I

US 4 568 695 (Robins Co.; USA-prior 7.12.1983)

Welsh, D.A et al.: J Med Chem (JMCMAR) 27, 1379-1388 (1984)

Trade Name(s):

USA: Duract (Wyeth-Ayerst)

Bromhexine

(Bromexina)

CN: 2-amino-3,5-dibromo-N-cyclohexyl-N-methyIbenzenemethanmine

monohydrochloride

6 g/kg (R, p.0.)

Bromindione B 269

2-nitrobsnzyl cyclohexyl- (2 -nitrobenzyl) - N-(2-0rninobenzyl)-

Lmmlds methylamine (cyclohexyl)-methylomine N-cyclohexyl-methylamine (1)

Reference(s):

DE 1 169 939 (Thomae; appl 20.11.1961)

US 3 336 308 (Boehringer Ing.; 15.8.1967; D-prior 14.10.1963)

Keck, J.: Justus Liebigs Ann Chem (JLACBF) 662, 17 1 (1963)

alternative syntheses:

DAS 2 31 1 637 (Thomae; appl 9.3.1973)

DAS 2 365 624 (Thomae; appl 27.3.1973; J-prior 30.3.1972,4.7.1972)

DAS 2 315 310 (Thomae; appl 27.3.1973; J-prior 30.3.l972,4.7.1972)

DAS 2 443 712 (Thomae; appl 12.9.1974)

DOS 2633 518 (Egyt; appl 26.7.1976; H-prior 28.10.1975)

DOS 2412 119 (Huhtam&i; appl 13.3.1974; SF-prior 15.3.1973, 2.7.1973,9.1.1974, 8.2.1974)

use as mucous membrane local anesthetic:

DOS 2 729 786 (Thomae; appl 1.7.1977)

tabl 4 mg, 8 mg, 10 mg, 20 mg

Trade Namers):

Berotec solvens

Bisolvomycin (Boehringer

1ng.)-comb

Bisolvon (Roehringer Ing.)

Bisolvonat (Boehringer

1ng.)-comb

hydrochloride)

Bromindione

(Bromophenindione; Brophenadione)

LD5< 200 mglkg (M, p.0.)

270 B Bromisoval

phtholide 4-bromo- 1 Brornindione /

benzoldehyde

Reference(s):

US 2 847 474 (USV; 1958; appl 1954)

cf also anisindione

Formdation(s): amp 8 mg14 ml

Trade Name(s):

F : Fluidane (Metadier-Tours);

wfrn

LD50: 2 g/kg (M, p.0.);

1 glkg (R, p.0.)

CN: N-(aminocarbony1)-2-bromo-3-mcthylbutananlide

isovaleric acid a-brornoiso-

vaieryl bromide

Bromisovol

L

Reference(s):

DRP 185 962 (Knoll; 1906)

Formulation(s): drg 20 mg, 50 mg

Trade Name(s):

Ventrivcrt Tabletten (Do1orgiet)-comb.; wfrn