buchlerwappenblauklein.jpg (23122 Byte)

                               .
buchlerschriftzugblau.jpg (2897 Byte)
Buchler GmbH
D-38110 Braunschweig
Harxb
Ütteler Strasse 3
Tel.  ++ 49  5307  93121
eMail:
himstedt@buchler-gmbh.com
and   
 wedde@buchler-gmbh.com

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bilogicallyactivebalken.jpg (4585 Byte)
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qu.
Today most of the following active ingredients can be traced back to the
framework  of  3-quinuclidinone.  The  new  quinuclidines Quincorine (QCI)
and Quincoridine (QCD) are enantiopure and of course higher functionalized.

Comparisonbutton.gif (2897 Byte)

QCI and QCD are excellent building blocks for the
development of new sophisticated active ingredients.

.e quinic acid

S T R U C T U R E -  /   E F F E C T-   R E L A T I O N S H I P
of some selected biologically active quinunclidine compounds

Structure

Name

Application

Reference

tabellenmolekuel01.gif (1235 Byte)

3-Quinuclidinone
methyliodide;
N-methyl-3-
oxoquinuclidinium
iodide

L9039 Quireston
potent inhibitor of
high-affinity choline
uptake (HAchU) in
synaptosomes; acetyl-
choline synthesis
inhibitor; weak pene-
tration of biological
membranes.
Latoxan

tabellenmolek�l02.gif (1242 Byte)

N-methyl-3-hydroxy-
quinuclidinium
iodide

L 9036 Quirestol
potent inhibitor of
high-affinity choline
uptake (HAChU) in
synaptosomes, bicyclic
inhibitor of Choline;
acetylcholine synthesis
inhibitor; weak pene-
tration of biological
membranes

Latoxan

tabellenmolek�l03.gif (1297 Byte)

3-Quinuclidinyl
acetat hydrochloride

Aceclidine
hydrochloride
eyedrops,hypo-
tensive, cholinergic
Laboratori
Mag S.p.A.

tabellenmolek�l04.gif (1491 Byte)a

3-Quinucliny
benzoat
hydrochloride

Benzoclidin
hydrochloride,
Oxylidin (um)
Oksilidin, Oxilidin

antihypertensive,
sedative
Negwer-No.
4029-00

tabellenmolek�l05.gif (1587 Byte)

3-Quinuclidinyl
benzilat

code-name
US-Army: BZ

incapacitating agent in chemical
warfare, desorientation, hallu-
cination, confused state,
high-
affinity muscarinic antagonist
see also
J. Med. Chem. 1995, 38,
1711

tabellenmolek�l07.gif (1671 Byte)

N-methyl-3-
[(Cyclohexylhydroxy
-phenylacetyl)oxy]
quinuclidinium
bromide

 

Droclinium bromide,
LM 204

anticholinergic, antiulcer agent

Negwer No:
8884-00

CFM-Co.
Farmaceutica
Milanese S.p.A.

Laboratori
Mag S.p.A.

Sifavitor S.p.A.

tabellenmolek�l06.gif (1692 Byte)

N-methyl-3-
quinuclidinyl benzilat bromide

Clidinium bromide,
Quarzan (bromide):
Ro 2-3773

anticholinergic, spasmolytic Negwer No:
9236-00

tabellenmolek�l08.gif (1674 Byte)

alpha-Methyl-alpha-
phenylbenzene-

acetic acid
quinuclidin-
3-yl ester hydro-
chloride


Aprolidine
anticholinergic Negwer No:
8940-00

Structure

Name

Application

Reference

tabellenmolek�l09.gif (1622 Byte)

[R-(R*,R*)]alpha-
(Hydroxymethyl)-
alpha-phenyl-1H-

Imidazole-1-acetic
acid quinuclidine-
3-yl ester

Sepatropate,
UK-88060
bronchodilator, antichonlinergic Negwer No:
7194-00

tabellenmolek�l010.gif (1586 Byte)

M3 muscarinic
antagonist,
useful as a
preventive or remedy
for urologic diseases,
respiratory diseases or
digestive diseases

Yamanouchi
Pharmaceutical Co.

patent
WO96/20194

tabellenmolek�l011.gif (1597 Byte)
cholesterol-lowering agent,
potent activity of inhibiting
squalene synthase without
any side effects

Yamanouchi
Pharmaceutical
Co.

patent
WO96/26938

tabellenmolek�l012.gif (1606 Byte)

(R*,R*)-()-3-
[6,11-Dihydro-
2-methyl-benzo[b,e]
thiepin-11-yl)oxy]
quinuclidine



VUFB-17088
antihistaminic Negwer No: 8938-00

tabellenmolek�l013.gif (1601 Byte)

(R*,R*)-()-3-
[2-Chloro-6,11-
dihydrobenzo

[b,e]thiepin-
11-yl)oxy]
quinuclidine


VUFB - 17089

antidepressant Negwer No:
8273-00

tabellenmolek�l014.gif (1335 Byte)

Spiro (quinuclidine-
3,5`-oxazolidin)-2`-
on
for treatment of
schizophrenia
depressions,
sleeplessness,

anxiety, Alzheimer
disease, intellectual
impairment, neurotic
depressions
Astra AB



patent
PCT-WO
96 06 098

tabellenmolek�l015.gif (1346 Byte)

cis-2-Methylspiro
(1,3-oxathiolane-
5,3`)quinuclidine


AF 102 B

muscarinic agonist,
phase III of clinical
trials (Alzheimer�s)

see also Spiro-
oxathiolane quinuclidines for
treatment of xerostomia

EP 689863 A1 960103

see also Spiro-oxathiolane
quinuclidines for treatment
of Sjoegren`s syndrome

EP 578511 A1 940112

Heterocycles
1994
, 38, 1889


Ishihara Sangyo
Kaisha, Ltd.

patent
EP 683168 A1
950519

tabellenmolek�l016.gif (1299 Byte)

2`-Methylspiro
[quinuclidine -3,4`
-[1,3] dioxalane
muscarinic agonist
Kabi Pharmacia
AB
Uppsala
Sweden


J. Med. Chem.
1992, 35, 1541

Structure

Name

Application

Reference

tabellenmolek�l017.gif (1297 Byte)

3-(2-Furanyl)
quinclidin-2-ene
antimuscarinic
Pharmacia
& Upjohn AB
Uppsala Sweden


J. Med. Chem.
1997
, 40,

3804 - also
J. Med. Chem.
1995
, 38, 473

tabellenmolek�l018.gif (1409 Byte)

3-(2,3-Dihydro-
benzofuran-
2-yl) quinuclidine
antimuscarinic
Pharmacia
& Upjohn AB
Uppsala Sweden



Chirality 1998

tabellenmolek�l019.gif (1493 Byte)

3-(4-(6-methyl-
pyridazin-3-yl)
phenyl)
quinuclidine-3-ol
squalen synthase inhibitor,
inhibitor of cholestorol biosynthesis,
hypercholerstorol�mie, return to
normality of high blood fat value
Zeneca Ltd GB
patent
PCT-WO
9 324 486

Zeneca see
also

Biochemical
Pharmacology

1996
, 51, 14777

tabellenmolek�l020.gif (1507 Byte)

3-Hydroxy-3-
(4-chinolin-
6-yl) phenyl
quinuclidine
squalen synthase
inhibitor, artherio-
sclerosis, decreasing of
serum cholestorol
Rhne-Poulenc
Rorer Pharma-

ceuticals Inc.
USA

patent

PCT-WO
95 31458

tabellenmolek�l021.gif (1452 Byte)

squalen synthase inhibitor, inhibition
of cholestorol biosynthesis, treatment
of artheriosclerosis, hyper-

cholestorl�mie, isch�mie
Zeneca Ltd GB
patent
PCT-WO
95 35295

see also
J. Med. Chem.
1996, 39, 2971

tabellenmolek�l022.gif (1426 Byte)

3-[2-(2-allyl-4-
(2-ethoxycarbony-
lethyl)
phenyl)ethynyl]
quinuclidin-3-ol

squalen synthase
inhibitor,
inhibition of
cholestorol biosynthesis

Zeneca
Pharmaceuticals
GB

Bioorganic &
Medicinal
Chemistry
Letters
1997
, 7, 597

tabellenmolek�l023.gif (1372 Byte)

1,2,4-Triazine quinuclidine high affinity muscarinic
partial agonist
SmithKline
Beecham
Pharmaceuticals

Bioorganic & Medicinal
Chemistry Letters

1994
, 4, 1411

tabellenmolek�l024.gif (1386 Byte)

3-(3-Methyl-1,2,4-
triazol-1-yl)
quinuclidine
muscarinic agonist /
antagonist, also 1,2,3
triazols and tetrazols
SmithKline
Beecham
Pharmaceuticals

J..Med. Chem.
1992
, 35, 128

Structure

Name

Application

Reference

tabellenmolek�l025.gif (1468 Byte)

methylated
1,2,4- oxadiazole
quinuclidine /
methylated 1,2,4-
thiadiazole
quinuclidine
muscarinic agonist /
antagonist
Merck Sharp
Dohme GB

J. Chem. Soc.
Chem. Commun.

1991
, 760

tabellenmolek�l026.gif (1350 Byte)

potential application
for treatment of
irritable bowel
syndrome
Lilly Research
USA

J. Med. Chem.

1997, 40, 538
        .
Eur. J. Med. Chem
1996, 31, 221

tabellenmolek�l027.gif (1487 Byte)

3-Quinuclidinyl
diphenyl carbinol

Fencarol

Quifenadine

antihistaminic and
antiallergic agent,

glutamate solutions
for injections

Olaine Chemical-
Pharmaceutical
Plant

2114 Olaine
Latvia

patent:
RU 2045268 C1 951010 tsentr po
Khimii
Lekarstvennykh
Sredstv, Russia

see also
Izobreteniya

1995
, 28, 127

tabellenmolek�l028.gif (1516 Byte)

10(3-Quinuclidinyl methyl)-phenothiazine)

Mequitazine

antihistaminic,
sedative,anti-
depressant, allergic
diseases, hayfever,
conjuctiva catarrh,
nettle rash, Quincke-
oedema, itch

see also preparation
of phenotiazine
derivatives

patent:
JP 04169583 A2
920617

Yodogawa
Phamaceutical
Co., Ltd. Japan
             
   .

Negwer No:
7671-00

Asahi Chemical Industry Co. Ltd., Japan

Sumika Fine Chemicals Co. Ltd. Japan

Rh�ne-Poulenc Rorer France, GB

tabellenmolek�l029.gif (1265 Byte)

[R-(Z)]-(+)-a-
(quinuclidin-3-yl)
-
a-(methoximino)
acetonitril

(SB 202026)

selective muscarinic M1
agonist, currently in
phase III clinical trials
for the treatment of
senile dementia of
the Alzheimer
type (SDAT)
SmithKline
Beecham
Pharmaceuticals

J. Med.Chem.
1997, 40, 4265

J. Chem. Soc.
 Chem. Commun.

1994
, 2189

tabellenmolek�l030.gif (1433 Byte)

3-(3-Hexyloxy-
pyrazin -2-ylsulfanyl) quinuclidine
centrally active
muscarinic agent
American Home
Products Cor-
poration USA

patent
US005512574A

tabellenmolek�l031.gif (1436 Byte)

3(R)-[2-
(6-trifluoromethyl
pyrazin)yl]
quinuclidine
treatment of neurological and
mental illnesses whose clinical
manifestations are due to
cholinergic deficiency,
and for lowering
intraocular pressure.
Merck Sharp
Dohme GB

patent
US005384408A

see also:
Lilly research
J. Med. Chem.
1995
, 38, 3469

tabellenmolek�l032.gif (1402 Byte)

(3R)-3-
(6-chloropyrazin-
2-yl)

quinuclidine

selective muscarinic
agonist
Merck Sharp Dohme GB

J.Chem. Soc. Perkin Trans  

1995, 1, 641

Structure

Name

Application

Reference

tabellenmolek�l033.gif (1529 Byte)

substance P antagonist treatment
of gastrointestinal disorders, central
nervous system disorders, asthma,
pain, migraine, emesis, urinary
incontinence
Pfizer Pharma-
ceuticals Inc.
USA
 



patent
WO 95/02595

tabellenmolek�l034.gif (1568 Byte)

CP-96,345 selective nonpeptide
antagonist for the
human neurokinin NK1
receptor,

useful in the treat-
ment of inflammatory
disorders, central
nervous system
disorders, asthma,
pain, migraine.

treatment or
prevention of eye
disorder (glaucoma,
ocular hypertension,
miosis, excess of
lacrimation, hyperemia
and breakdown of the
blood aqueous barrier)

Merck Research
USA

Merck Sharp
Dohme GB

Pfizer Pharma-
ceuticals Inc. USA

patent
WO 94/26740

patent
WO 96/14845

Bioorganic &
Medicinal Chemistry
Letters
1995,
7, 1345
          .
J.  Med. Chem
1995, 38, 934

see also Merck
Research USA

European
Journal of
Pharmacology

1997, 325, 253
     .
Bioorganic & 
Medicinal 
Chemistry 
Letters
1993,
3, 1361

tabellenmolek�l035.gif (1529 Byte)

Palonosetron 5-HT3 receptor
antagonist

anti-emetic in
cancer chemotherapy

Syntex USA

1996

tabellenmolekul036.gif (1642 Byte)

N-(quinuclidin-
3-yl)-4-amino-
3-chloro-
1,8-naphthalimid
high affinity
5-HT3 receptor
antagonist,
5-HT4 receptor
agonist
Syntex USA

Bioorganic
& Medicinal
Chemistry Letters

1993
, 3, 1375

tabellenmolekul037.gif (1569 Byte)

N-(quinuclidin-
3-yl)-2-(1-methyl-
1H-indol-3-yl)
-2-oxo-
acetamide
high affinity
5-HT3 receptor partial
agonist, with a pKi
at
5-HT3
receptors in
rat brain of 9.6 � 0.2,
and greater than 1000-fold
selectivity over a wide range of
other neurotransmitter receptors
Syntex USA

Roche Bioscience

Bioorganic & Medicinal Chemistry Letters
1995, 5, 1853

tabellenmolek�l038.gif (1618 Byte) (R)-3-(6-Chloro-
1-isopropyl-
benzimidazole-
4-carboxamido)
quinuclidine
high affinity
ligand for the (R)-zacopride binding site
(pKi 9.84 � 0.42)
Roche Bioscience
USA

Bioorganic & 
Medicinal
Chemistry 
Letters

1996, 6, 477

tabellenmolekul039.gif (1477 Byte)

Z-2-[3`chlorophenyl) methylene]-3-
quinuclidinone hydrochloride

L9038 Penetran Cl

inhibitor of high-affinity
choline uptake (HAChU) in synaptosomes; acetylcholine
synthesis inhibitor;
good penetration of
biological membranes.
Latoxan
France

tabellenmolekul040.gif (1579 Byte)

1,6-Hexamethylene-
bis-(3-benzyl-
quinuclidinium) chloride
tetrahydrate

L 9041 Diquine

nicotinic cholinoreceptor antagonist at the neuromuscular junction; curare-like ganglioblocker.

Curare-form competitive anti-
depolarizing muscle relaxant
used for muscle relaxation and
controlled breathing under
narcosis during surgical
operations. Can be used
for tracheal intubation.
                
.

Latoxan France

Structure

Name

Application

Reference

tabellenmolekul041.gif (1493 Byte)

[2-(4-Amino-5-
chloro-2-metho-
xybenzoxy)
ethyl-
quinuclidinium
bromide
high affinity 5-HT4-receptor agonist Sanofi Midy
France

J. Med. Chem. 1997, 40, 608

tabellenmolekul042.gif (1638 Byte)

treatment of migraine,
headache, diarrhoea,
Alzheimer disease,
schizophrenia,
depressions, anxiety,
mania, gastrointestinal
disorders, addiction to
alcohol and drugs
Synth�labo SA
France 1998

patent
FR 2719842

tabellenmolek�l043.gif (1694 Byte)

1-(3-(10,11-
Dihydro-5H-
dibenz[b,f]
azepin-5-yl-1-
propyl)-3-
quinuclidinium-
carboxylate
use for the clinical treatment of
painful, hyperalgesic and/or
inflammatory conditions in which
C-fibers play a patho-physiological
role by elicting neurogenic pain or
inflammation, use for treatment
of insulin resistance in non-insulin-
dependent diabetes mellitus (NIDDM).
Novo Nordisk A/S Denmark

patent
WO 96/31498

tabellenmolek�l044.gif (1343 Byte)

3-Ethoxycarbonyl quinuclidine hydrochloride

L 9064 Ethoquine

AChR agonist,
rigid bicyclic analog
of Ach and ARECOLINE.
Good penetration of
biological membranes.
Weak muscarinic
agonist, weak
nicotinic antagonist
Latoxan France

tabellenmolek�l045.gif (1684 Byte)

Quinine antimalarial, analgesic, antipyretic Buchler GmbH
Braunschweig
Germany

tabellenmolek�l045.gif (1684 Byte)

Quinidine cardiac depressant (antiarrhythmic) Buchler GmbH
Braunschweig
Germany

tabellenmolek�l047.gif (1425 Byte)

2,2,6,6-tetramethyl quinuclidine hydrobromide

L 9044 Temechine

neuronal nicotinic
AChR antagonist without action
on skeleton muscle innervation,
hypotensive, selectively blocks
autonomic ganglia, the adrenal medulla, carotid glomerules, good penetration of biological membranes.
Latoxan France

tabellenmolek�l048.gif (1406 Byte)

1,2,2,6,6-penta-
methyl
quinuclidinium
iodide

L 9045 Quirestine (Imechine)

nicotinic AChR
antagonist, potent short-acting
ganglioblocker. Short-acting
hypotensive used in surgery for
obtaining hypotension of the
desired level and duratio. In
contrast to Arphonad has no
histamine-like activity and direct
vasodilatory action. Less toxic than
Arphonad. In clinical practise besides
surgery is used for treatment of
pulmonary or cervical edemas and
cronical hypertension caused
by acute renal deficiency. Marked
absence of tachicardia and
prolongation of myorelaxant
action of other drugs.
              .
Latoxan France

Structure

Name

Application

Reference

quinine • quinic acid  • cinchona alkaloids • quinuclidines QCI   QCD

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balkenobenkurz.jpg (5798 Byte)


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