Two novel syntheses of the histamine H3 antagonist thioperamide

Tetrahedron

Vol. 51. No. 48, pp. 13447-13454, 1995 Copyright 0 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 004~4020/95 $9.50+0.00

Pergamon 1-O

0040-4020(95)0088

Two Novel Syntheses

Jos H.M.

of the Histamine

Lange’, Aalt van

Solvay

Duphar

Henri

C. Wals,

de Kuilen

Research

P.O. Box 900.1380

Adri

and Jack

Laboratories.

Ha Antagonist

van den A.J.

den

Department

DA Weesp,

Thioperamide

Hoogenband, Hartog

of Medicinal

Chemistry,

The Netherlands

Abstract: The previously described route for the synthesis of the histamine H3 antagonist thioperamide 3 has been improved considerably. Furthermore, two straightforward novel synthetic routes towards 3 are described herein. The last synthetic route (Scheme 3) is preferable as it is very suitable for the production of multigram quantities of thioperamkfs 3.

Introduction The receptors.

neurotransmitter In addition

presynaptic,

histamine

research

receptor

(H3)

into the role of the histamine

both a selective

In order models,

histamine

agonist

was

in depth

3 was

4 as is depicted

multiple histamine

discovered

H3 receptor

(R)-u-methylhistamine

10 explore

thioperamide

isonicotinate

1 has

to the two postsynaptic

needed

in cell to cell communication,

receptor more

in physiological

in gram

of a selective quantties.

1. We started

types,

recently

2 and a selective

the potential

in Scheme

functions

since

by the group and pathological

antagonist

histamine

Thioperamide3 with the optimisation 13441

known

years

of Schwartz’. conditions

thioperamide2

H3 antagonist 3 can

mediated

thirty

H2),

Crucial

a third,

for further

was the description

of

3.

in various

be prepared

of this route.

by various

(HI,

Two

pharmacological

in nine steps laborious

from

reaction

ethyl steps

1344s

were

J. H. M. LANGE

improved

in our

straightforward

Results

routes

towards

As we were

thioperamide

not entirely

3 were

satisfied

with

the outcome

of this

improved

route,

more

developed.

and dIscussIon

Thioperamide 1. In the

first

ester

4 was

been

converted

in pyridine

ketone

to afford6

thiol 9 in a moderate

derivative

10 in only

modifications the presence

yield. yield.

30 % yield.

of the reaction of Raney

yield

procedure*

of the pyrfdyl

the catalyst

at 50 psi at room temperature,

The final step consisted

tosylate latter

group

was removed8

laborious

for two hours

in 10 was replaced

of the addition

3

-

’

CO,Et

B

which

with

in aqueous

3

-

COCH,

with p-

7 gave provided8

in our hands by refluxing

piperidine

thioperamide

CH,

by slight

reductive

with PtO2

TocCl

CH”

-

NaOAc

4

7

1. KOEt

7-

Q-QH

2. HCI

.HCI

.2 HCI

9

10

S

n 10

c,’ .2 HCI

2.

NCS o-

Scheme

ii

3

1

as

11 in high yield.

3 in 62 % yield.

-

8

the the

the thiol 9 in

The original

acid and water

4-substituted

H,NOH.HCI ’

of acetic

to 11 to afford

4-

nitric acid to give the 4-imidazolyl

10 in 90 % yield.

the corresponding

reacted

isothiocyanate

considerably

gave

into

of the tosyloxim

not be improved

in a mixture

in Scheme

decarboxylation

6 and subsequently

potassium

could

smoothly

isothiocyanate

4 as is outlined

subsequent

rearrangement6p7

was improved

which

afforded

of cyclohexyl

N’

2 H,O+

reaction

by a reduction

1 NaOEV EtOAc

N’

amine

this conversion

isonicotinate

and

into the oxim

7. Neber

of the

of this

However,

from ethyl reaction

5 was converted5

The mercapto

The

in ethanol

moiety

ketone

Reaction

conditions.

Nickel

in nine steps

a condensation

the corresponding

8 in quantitative

imidazolyl

prepared via

Fj4 in 75 % yield. The methyl

choride

a-amino

3 has previously3

step,

acetylpyridine tosyl

laboratory.

et al.

n

13449

Two novel syntheses of thioperamide

However, laborious

steps.

consists

we were

not entirely

Therefore,

a novel

Lithiation

yield,

it is very

stage

of the synthetic

straigmorward

Removal 14 gave

by t-BuLi

of the t-Boc group

route

improved

towards

by the reaction

to optimise

even

lower

route,

thioperamide

as it still contains

some

3 was

which

developed

yields

with l-t-Boc-4-piperidone10

the yield of this reaction (8-10

%). Afthough

of the imidazole

and concomitant

tetrahydropyridine

of a catalytic

The dihydrogen

described

of this

moiety

were

13 afforded

not successful.

the conversion

(and a subsequent

the

For example,

of 12 into 14 has a low deprotectfve

step

in a later

is required.

the corresponding

the presence

straightforward

Attempts

gave

outcome

2.

as no protection

route)

the

12, followed

14 in 20 % yield.

of n-BuLi

with

more

in Scheme

of 4-bromo-(iH)-imidazoleg

piperidine

replacement

yield.

and

of five steps as is depicted

protected

satisfied

amount

chloride

acid-catalyzed

dehydratation

15 in 97 % yield.

of Pt02

at a pressure

salt 11 was converted

of the 4-hydroxy

Hydrogenation

of the double

of 50 psi, to give

into its free base

form

piperidine bond

the 4-piperidinyl+imidazofe and eventually

derfvatke

was performed

in

11 in 83 %

into the thioperamfde

3 as

above.

1 excess n-BuLi, MF.

-78%

NCOs-t-Bu

13

12

14

15

3 H,O*

Hd9

15

F,‘ p

HOAc

1 OH-

NH

Y=

~

g&y3 N ti

.2 HCI 2

H

NCS o-

3

11

Scheme

The piperidone

crucial

step

in our synthetic

building

block

13. There

it is known”

that imicfazolyl

C4 anions,

in the absence by using

reaction

of 4-bromo-(lH)-im.kfazole gave

electrophiles, Secondly,

unprotected

piperfdone

is the

generated

groups’

derivatives,

the electrophilicity

addition

reaction

factors

which

with

lithium

orthoformate,

2*13 is much

more

group

Many

iodide

or dimethyl

must

researchers

imidazoles’

by quenching

attempts

contain

of 12 and

the

Firstly,

less stable

have

dealt with this

5. It was reported’

the lfthiated

to quench

sulfide,

be high enough

form

of the thermodynamically

diffiiult.

followed

However,

such as 13 and I-benzyfCpiperidone, of the carbonyl

the dilkhiated

for the low yield that was found.

12 or protected

naphtalenide,

methyl

between account

on C2, but generation

4-bromo-(lH)-imidazolei4

(lH)-imidazol-4-yldiphenylmethanl.

such as DMF. Methyl

C5. Therefore,

are readily

of C2 protecting

problem

benzophenone

efther

anions

route

are two complicating

2

intermediate

the intem-rediate

with

4 that wfth other

failedId. enolisable

to avoid

hydrogen competing

atoms side

at C3 and

reactions,

for

J. H. M. LANCE

13450

example,

the

electrophilic

occurrence

In the case

where

I-benzyl-4-piperidone

I-benzyl-4-piperidone,

These the case

results

has the additional Interestingly,

prompted

benzyWpipertdone piperidone

between

the

dilithiated

as the electrophile, other

unidentified

piperidones the rationale

intermediate

and

the

(enolised)

removable

under

2-bromopyridine

that

route,

acidic

This

is a Grignard-type

give a higher

prompted

of the

reactive

was

formed,

carbonyl

which

than

the

than

group

is,

(which

in 13.

2-lithiopyridine

with i-

The use of I-ten-butoxycatbonyl-4-

yietd in this reaction,

imidazole

group

the resulting

yield.

moiety

(t-Boc)

as N-protecting

and quenched

the development

coupling”

a more

conditions)

straightforward

coupling

of products

the tert-butoxycarbonyl

in a modest

2 is more

viz. the

possess

with n-BuLi

might

in Scheme

in this

a mixture products.

for applying

I-benzyl-4-(2-pyridyl)piperidin-4-01

unsatisfactory.

the key step

piperidone

easily

reacted

route

step

13 were

formed

of 1-benzyWpiperidone,

the synthetic the key

piperidone

of being

to give

13 instead

Obviously,

This

et ali6

used

and some

use N-protected

to

advantage

Schwartz

was

imidazole

in 1 -benzyl-4-piperidone.

upscale

exchange

substrate.

contained

route,

of hydrogen-lithium

et al.

too.

original

building

route.

block

of the route which

of dimethylsulfamoyl-protected

However,

12 with

the

attempts

t-Eloc

to

protected

is depicted

in Scheme

3. In this

iodoimidazole

derivative

19 with

13. I2 KI

Q

F$:

I.

Na2So,

NaOH

.

y-J

I

c’=2N:

EIOH, Hz0

iI

Et3N, MeCN

Ii

16

dO,NMe,

ii

17

18

1 EtMgBr, CH2C12

19

HCI,

w

95

% >

2

0

13

20 Scheme

lodination the published

of imidazole procedure18.

the monoprotected

imidazole’

protected

piperidone’

Concerted

removal

was converted

4,5-diiodo-(1

the

3, according

previously two

17, which

protection

of 19 with ethyl

the addition

magnesium

20 in 50 % yield.

moiety,

the t-Boc

to Scheme

2.

described

straightforward

group

route

for

novel

synthetic

the

was reduced

of the imidazole

product

of the dimethylsulfamoyl

Furthermore,

H)-imidazole

dimethylsuffamoyl

7 19. Treatment

o 13 gave

to thioperamide

In conclusion, considerably.

16 afforded Subsequent

3

bromide,

and elimination

synthesis routes

18 by

atom smoothly

afforded

followed

by the addition

of t-Boc

gave

of thioperamide towards

to 4(5)-iodoimidazole

nitrogen

3 are

tetrahydropyridine

15 which

3 has

been

improved

herein.

The

described

last

13451

Two novel syntheses of thioperamide

synthetic

route

(Scheme

3) is preferable

as it is very suitable

for the production

of muttigram

quantities

of thioperamide

3.

Acknowledgements

The

colleagues

of the Structure

Analysis

Department

are gratefully

on a Mettler

FP62

acknowledged

for supplying

the spectroscopic

data.

Experimental

sectlon

All melting recorded

were

on a Nicolet

shape and

points

determined

60SX

spectrometer

of the IR absorptions f3C-NMR

spectra

tetramethylsilane

absorptions

multiplet,

br = broad. 4000

used for flash 60 F-254 lamp,

THF

TLC

material, was

syringes

quadnrpole

mass

(Merck)

taken

were

by distillation

used

mixture

from

LiAIH4.

of the thiol 9 (1.0

was heated

at reflux

with ethanol

The combined

(3x).

of an ethanolic diethyl

ether

mixture

ethanol

hydrogen was

converted

added

MHz,

13C:

IS double

fragment

mixtures

chromatography reagent

100

s = sharp.

MHz)

standard.

focussing

(TLC).

TLC

with

The shape/multiplicity

mass

of

q = quartet,

spectrometer

m = or with

Silica gel 60 (Merck)

as volume/volume.

(characteristic

The

‘H-NMR

spectrometer,

t = triplet,

ions are reported.

is shown

are reported.

b = broad,

d = doublet,

spots

Precoated

were

for amines).

was

dried

visualised

All yields

on molsieves

was

silica gel with an UV

refer

to isolated,

(4A).

Glass

equipment

and

overnight to afford

% aq.) = 100/i;

I2 vapor).

‘H-NMR

(D20):

in ethanol (TLC

(50 ml) was analysis

were

solution

concentrated

(containing precipitate

in vacua

Raney

Nickel

that the reaction

The Raney

approximately was filtered

added

showed

Nickel

precipitate

to give an oily residue 4 equivalents

to give

10a~ls

(3.0 g). The was complete was washed (0.75

g). After

of HCI) and evaporation as a white

solid,

which

in was

11.

to a solution

in vacua

(s, 1H). 13C-NMR

fractions

and the formed

was evaporated

mmol)

and filtered.

(25 % aq.) = 87.5/12/0.5)).

dihydrochloridea~lg

(0.3 g) was added

was hydrogenated

g, 5.64

chloride

to compound

4-(4-piperidyl)-(lH)-imidazole PtO2

Concept

Dichloromethane

for two hours

Rf 0.3 (CH2CL2/EtOH/NH40H

vacua,

400

were

10

within two hours;

immediately

(fH:

red spectra

absorptions

broad,

acid as the internal

Only significant

Dragendorff

characteristic

vb = very

s = singlet,

with a Kratos

for thin layer

with

dihydrochioridea

To a suspension

addition

propionic

The ratio of solvent

spraying

Only

lnfra

oven-dried.

4-(4-pyridyl)-(llI)-imidazole

resulting

400

abbreviations:

spectrometer.

chromatography.

or after

AM

and are uncorrected.

and are unoptimised.

dried were

on a Bruker

were

detector.

abbreviations:

salt of 3-trimethylsilyl

spectra

plates

a MCT-B

by the following

Mass

vapor

with

by the following

recorded

is given

column

iodine

purified

were

or the sodium

the NMR

a Finnigan

is given

apparatus

11 of 10 (0.55

at approximately pure 11 (0.47 (D20):

g) in acetic

acid (12.5

50 psi. The catalyst

g, 83 %) as a whfte

6 1.93 (m, 2H), 2.32

6 30.1 (t), 32.6 (d), 46.3 (t), 117.6

solid,

was removed

(d), 138.4

(5 ml) and the resuiting

by filtration

mp 300 oC (dec.).

(m, 2H), 3.20

(d), 136.4

ml) and water

(hyflo).

The filtrate

Rf 0.1 (MeOH/NH40H(25

(m, 3H), 3.56 (m, 2H), 7.34 (s, lH), (s).

8.65

I3452

J. H. M.

LANGE

4-/4-(4-hydroxy-l-tert-butoxycarbonyl)piperidyl]-(lM)-imidorole

To a solution

of 4-bromo-(I

ml of a 2.5 M solution was stirred (10.83

for 1.5 hour

g. 54.4 mmol)

at room

temperature.

Na2S04

and

Subsequently, mmol, 3150

at lo-15

After

acidification in vacua,

the crystalline

material

(vb), 1690

crystals,

(b), 1680

MS (El): mk267

with

(M+),

with

A solution resulting

water

(lml),

lH),

A solution 24 hours

at 50 psi at room

acetate

(50 ml) and acetic

(20.9

ml, 62.6

solution

was stirred

a solution solution dried

149 (M+).

(DMSO/CDC13=4/l):

requires

was allowed over

(br S, IH).

to attain

Na2S04, ether;

fiitered

at room

room

of acetic

from

a mixture

mp 287-288

of a catalytic crude

amount

product

temperature

Found:

stirred

for 40 hours

recrystallised

(acetic

3.90

a&

(86

to room

(b), 2950

(m, 2H),

(vb).

6.35 (m,

149.0953.

7.10 (d, J-1 Ct5H26N4C5S1

temperature and

(20 ml) was hydrogenated The

resulting from

for

mixture

a mixture

was of ethyl

(mp 300 OC. dec.).

(220

ml), ethyl

in a nitrogen

cooled

The

pure

to - 78 OC. After

solution

20 (10.56

1.84 (m, 2H). Hz, IH),

bromide

The

dropwise

resulting addition

of

(110 ml), the resulting

was washed

g, 50 % yield)

(aqueous after

1.93 (dt, J=5 HZ, J=l2

7.85 (d, J=l

requires

magnesium

atmosphere.

in dry dichloromethane

overnight.

NH4CI)

crystallisation Hz, 2H), 2.62

Hz, 1H). MS (El): (m/z)

374

374.1624.

15

(90 ml) was added

(4 ml)),

added

g, 62.6 mmol)

to afford

dihydrochloride

ml)/water

at 95 OC.

20

6 1.47 (s, 9H),

(m, 2H),

374.1622.

HCI solution

at 95 oC, cooled

1.68 (m,

acid (20 ml) and

v 3145

recrystallised

in dry dichloromethane

and stirred in vacua

(CDC13)

4-(4-(1.25.6~tetrohydropyridyl))-(lH)-imidazole

aqueous

v

(br s, IH).

for 40 hours

requires

of Pt02.

was

crystals

and subsequently

13 (12.46

2.88 (s. 6H), 3.31 (br 1. 2H),

To a concentrated

C8HIlN3

acid (40 ml) and water

was dropwisely

temperature

IH-NMR

317.299.273.255.108.57.

g, 5.43

IR (KBr):

11.90

of acetic

OC. IR (KBr):

149.0948.

g, 88 %) as white

mmol)

ether)

and concentrated

mp 143-6 oC).

ml).

267.1583.

HCI (15 ml) was heated

crystals,

The resulting

g, 56.9

in diethyl

for 30 minutes

14 (1.45

Hz, IH),

over

(10

6 1.41 (s, 9H),

7.50 (d, J=l

C13H2,N303

134, 119. Found:

in the presence in vacua.

(17.14

3 M solution

overnight drying

acetonitrile

6 2.78 (m, 2H), 3.53 (t, J=6 Hz, 2H), 3.94

in a mixture

of N-tert-butoxycarbonyl-4-piperidone

(diisopropyl

(M?

mmol;

from

(3x),

11

temperature

of 1917

13

(25 % aq.) = 85/15/l.

(br s, IH),

aqueous

(D20):

acid (50 ml) to give 11 (5.00

solution

(30

solution

was stirred

CH2Cl2

to give the adduct

I-(dinlethylsu[famoyl)-4-[4-(4-hydroxy-I-tert-butoxycorbonyl)piperidyl~-(lH)-imi~zole

To a stirred

mixture with

recrystallised

and dried

and recrystallised

97 %) as white

‘H-NMR

n-BuLi

15

in vacua

MS (El): (m/z)

was evaporated

extraction

was

‘H-NMR 6.86

267.1593.

in concentrated

dihydrochloride

and the resufting

ether

4.77 (br s, IH),

was evaporated

of 15 (5.65 g. 25.5 mmol)

and the filtrate

with diethyl

added

The resulting

of N-tert-butoxycarbonyl-4-piperidone

NH4CI,

material

dihydrochloride

15 (1.61 g, 7.25 mmol,

filtered

crude

Found:

(s), 795 (s). 630 (s) cm-‘.

4-(4-piperidyl)-(IH)-itnidazole

aqueous

(b), 635 (s) cm-‘.

3.64 (m, 2H).

g. 7.49 mmol)

7.54 (s, 1H). 8.75 (s. IH).

with a syringe

atmosphere.

OC. Rf 0.5 (CH2C12/MeOH/NH40H

192,166,148,111,57.

mixture

to afford

1590 (s). 1090

added

washed

(b), 1370 (s). 1170

of 14 (2.00

reaction

to -70 OC. A solution

resulting

was

in dry THF (40 ml) was slowfy

at -70 OC in a nitrogen

saturated

the

4-[4-(1,2,5,6-tetrahydropyridyl)]-(IHj-imidozole

The

again

mp 189.5-190

3.21 (m, 2H),

g, 27.2 mmol)

a syringe

OC and cooled

concentration

1.84 (m, 2H),

12 (4.00

75 mmol)

in THF (40 ml) was gradually

20 %) as white

2H),

14

H)-imidazole

in hexane.

ef al

20 (11.97

and concentrated subsequently

g, 32.0 mmol). in vacua.

washed

with

The resulting

The resulting

solid

acetic

and

acid

solution material diethyl

was was ether,

Two

respectively,

to give pure

(1.52 g, mp 290-l

I5 (4.13

novel

g; mp 291-2

syntheses

OC). Crystallisation

To a solution The

of NaOH resulting in vacua.

ml, 25.7 mmol)

was added.

The

NMR IH),

which

was

2.

kindly

and

Arrang,

6 1.10 (m, 1H)

M.; Schwartz,

J.M.;

Garbarg,

M.; Lancelot,

197840;

Chem. Abstr.

Emmert.

W. Ber 1941,74,

Garbarg,

Compound Meer

7.

Neber,

8.

Schunack.

9.

Stensio,

K.E.; Wahlberg,

Hyroyuki,

0.; Nakamizo,

P.W.;

Burgard, W.Arch.

M. Chem. Pharm.

Tertov,

B. lfeterocycles

Compound

3 showed Vrije

(m, 4l-l)

292.1724.

with some

by 40 hours from

mp 160-162

identical

spectral

Universiteit,

7.13 (d, J=7-8 C15H24N4S1

at room

a mixture

solid,

1.49 (m, 2H),

methanol.

of acetonitrile

data

Hz, lH),

The

(40 ml)

with

Netherlands.

1.64-1.94

7.52 (s, IH),

and

179 OC). Rf 0.15

in comparison

Amsterdam,

1.61 (m, IH),

(3.53

temperature

OC (ii3

for

The filtrate

ml) and cyclohexylisothiocyanate

was crystallised

g, 62 %) as a white

B.; Kahn, B.A.;

J.C. Nature J.C.;

a

IH-

(m. 6H), 2.80 (m,

11.0-12.5

(m, 1H). MS

292.1722.

requires

1963.302,

832.

Lecomte,

J.M.;

Pollar,

H.; Robba,

J.; Lecomte,

J.M.;

Robba,

M.; Schunack,

W.; Schwartz,

J.C.

M.;

Schwartz,

J.C. Ear. Pat. Appl. 1986,

EP

106,84602r.

available

and lt formed

H.; Veldstra.

H. &cl.

the starting

point in our synthesis,

Trav. Chim. Pays-Bus

1973,

72, 236.

1973,306,934. K.; Wahren,

R. Acta Chem. Stand. Seer. E 1973,

N.; Takai.

1985,2J.

A.J.; Chadwick,

H.; Teranishi,

M; Kubo,

K.; Shuto,

27, 2179.

K.; Kasuya,

Y.; Shigenobu,

K.; Hashikami,

417.

D.J. Tetrohedron

N. J. Chem. Sot. Perkin

Bessonov,

Kotenko.

l.V. USSR.

Perkin

(200

and stirred

Bull. 1983,31,3186.

Zn&i

Abstr.

and washed

mmol)

A. Ann. Chem. 1932,493,281. Pharm.

TovarnYe

Kirk.

of I5

1018.

5 is commercially

van der. S.; Kofman.

14.

throperamide

, 1.17-1.34

M.; Lancelot, 1987,

6.

Iddon.

portion

117.

5.

13.

another

11 (4.80 g, 21.4

at 50 OC followed

dr. H. Timmerman,

Found:

Garbarg,

4.

Carpenter.

by filtration

in dry acetonitrile

4.69 (m 2H), 6.75 (s, lH),

J.M.;

J.M.;

Iddon,

afforded

notes

Arrang,

12.

(65 ml) was added

for 2 hours

(3.86

by Prof.

3.

11.

crude20

= 90/10/0.5).

1987.327,

15.

The

292 (M+), 258, 151, 141,95.

Arrang,

was stirred

% aq.)

Nature

10.

removed

was

was dissolved

supplied

3.02 (m, 2H), 4.21 (m, IH),

References

1.

(NaCI)

residue

in vacua.

(CDCl3/DMSO=4II)

(El): (mlz)

in methanol

(80 ml) to give thioperamide

(EtOAc/MeOH/NH40H(25 sample

liquor

3 (Thioperamide)

g, 47 mmol)

The mixture

evaporated

and ethylacetate

(1.88

precipitate

was concentrated

subsequently

of the mother

OC; 80 % total yield).

3-[d-(1 -~cyclohexylaminorhioxo~thyl)piperidyl)~ole

30 minutes.

13453

of thioperamide

V.V.;

1986,42,

Koshchienko,

1981. 47, 107; Chem. Abstr. Pat. SU 941364:

2351,

Trans. I 1987,1445. Y.V. USSR. 1982,

From:

Pal. SU 891664;

96, 199690k.

Otkrytiya

Tertov,

Izobrer

Prom.

A.R.;

Slawinski,

From:

Orksyrjya

fzobrer

B.A.; Koshchienko,

Y.V.,

Obrazrsy

Tovarnye

Znaki

J.J.;

Brunner,

F.; Gorun,

Prom.

Obrazrsy

Bessonov,

1982,

V.V.;

25. 110; Chem.

1983,98,5389Ov.

K.L. 1. Hererocyc[ic Trans. 1989,

1139.

Chem. 1985, Kutzma.

22, 57. Katriizky,

L.V.; Tumbull

Jr, S.P. Synthesis

1991.

1021.

Vollinga,

R.C.;

S. J. Chem. Sot. Menge,

W.M.P.B.;

13454

J.

Timmerman.

16.

H. Reel. Truv. Chin

Menge.

W.M.P.B.;

Ganellin,

C.R.;

Timmerman. Jayes,

Chem. Convnun. Turner,

18.

Pauli,

H.; Arauner,

R.M.: Lindell.

R.H.;

Finnegan,

Compound Durant.

Res. 1993,3, Durant, Angel,

SD.;

P.M.: Henrick.

Y.S.;

123. Vollinga,

R.C.; de Koning,

Tertiuk,

W.; Arrang,

J.M.;

J.P.; Jansen,

Defontaine,

N.; Schwartz,

F.P.; leurs.

R.;

Dyer,

Hamill.

J.C. Collecr.

Czech.

Durant.

Kahn,

G.J.;

118. 33. Dickens,

K.; Gwston.

P.G. /. Org. Chem. 1981,46, building

S.; El-Assadi, Kahn,

block

in the current Hoss,

WO

~ppl.

was contaminated

1993,

EP 591,026;

by a minor

amount

R.L.;

B.J.;

Harrow,

T.A.;

Bible,

e.g.:

Kahn,

A.M.;

1781. pharmaceutical

W.; Messer,

93 20.062;

J. Eur. Pal. Appf. 1994,

G.; PurCefl. T. Eur. Par. Appl. 1994, thioperamide

J.P.;

A.A.;

A.M. PTCInt.

A.M. PTC inr. Appt. 1993,

T.; Schoemaker,

5739.

Chem. 1928,

an important

Ghodsi-Hovsepian,

1.; Purcell,

The crude

lI2.

Ley. S.V. 1. Org. Chem. 1991,.X

E. J. Prakr.

428.

G.J.;

S.; DefOSSe, 20.

D.; Khalaf,

11 constitutes G.J.;

1993.

H. J. Med. Chem. 1994.37,332.

1991,56,2448.

17.

19.

Pays-BOS

H. M. LANGE et al.

W.S.;

WO 93 20.061; C&m.

EP 591,027;

Absfr.

research. Frederickson,

Chem. Absrr. 1994, 1994,

Chem. Absfr.

Chem. Abstr. of its sodium

R.C.A.

120, 107079m. 1994.

1994,121,35609z. salt.

(Received in UK I5 September 1995; revised 6 October 1995; accepted 12 October 1995)

Med. Chem.

120, 107018k. Jegham,

121. 94029.

Jegham,

S.;