Note: Descriptions are shown in the official language in which they were submitted.
WO 93/03725 211 6 ~ 2 4 PCI/CB92/01519
5-HT4 RECEPTOR ANTAGONISTS
This invention relates to the u~e of compounds as 5-HT4 receptor
antagoDists in the treatment of gastrointestinal disorders, CNS disorders
and/or cardiovascular disorders, and to certain novel compounds having
5-H14 receptor antagonist activity.
European Journal of Pharmacology 146 (1988), 187-188, and Naunyn-
Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe a non
classical 5-hydroxytryptamine receptor, now designated the 5-m4
receptor, and that ICS 205-930, which i8 also a 5-HT3 receptor antagonist,
acts as an antagonist at this receptor.
PCT/GB9V00650 (SmithKline and French Laboratories I~mited) describes
the u~e of cardiac 5-HT4 receptor antagonists in the treatment of atrial
arrhyt~mias and fitroke.
Some 5-HT3 receptor antagonists have been disclosed as of potential use
in the treatment of certain aspects of irritable bowel syndrome t&ee
EP-A-189002 (Sandoz Limited) and EP-A-200444 ~Beecham Group p.l.c)].
5-HT3 receptor interaction~ wbich are of potential use in the treatment of
IBS are those associated eitber with the visceral pain and abnormal
perception of sensation aspects of tbis disease, or they are related to tbe
ability of some 5-HT3 receptor antagonists to cause consl ipation in
volunteer~.
Some 5-H'r3 receptor antagonists ha~e been disclosed as of potential use
in the treatment of gastrointestinal disorders associated with upper gut
motili1y [see EP-A-226266 (Glaxo Group Ltd.) and EP-A-189002 (Sandoz -
Limited)3. 6-HT3 receptor antagonists are also well known antiemetics,
such as ondarsetron, granisetron and tropisetron (see Drugs of the Future
1989, 1~ (9) p.875 - E.D. King and G.J. Sanger).
35 EP-A-189002 (Sandoz L~mited) and EP-A-429984 (Nisshin Flour MillingCo., Ltd.) di~lose compounds whi~ are described as 5-HT3 receptor
antagonists usefi~l in the treatment of gastrointestinal disorders.
WO 93/03725 PCI'/GB92/01519
2116G2~ -2- ~
We have now di~covered that certain of t;hese compounds and related
compound~ act as antagoni~t~ at 5-H14 receptors and are of potential use
in the treatment of IBS or atrial arrh~ias and stroke.
5 The compounds of the present invention also have a potential use in the
treatment of CNS disorder~ such as anxiety and/or migraine, in 1 he
treatment of upper gut motility disorders and as antieInetics.
VVhen u~ed herein~ 'treatment' includes prophylaxis as appropnate.
The invention therefore provides the use of a compound of formula (I) or a
pharmaceutically acceptable salt thereof:
X~CO-Y-Z (1~
wherein
X i8 a group of formula (a), (b) or (c):
R~L (a)
R6J~R2
,~ J, o
Rs ~ F~3 -
R~
~ (C)
c
wo93/0372s 2 11 6 () ~ ~ PCr/GB92/01519
wherein
L iB N or CRB wherein R6 iB hydrogen, Cl 6 alkoxy, halogen, Cl~ alkyl or
cyano;
Q is NR1, CH2, 0 or S;
5 WisCHorN;
Ra is hydrogen, halo, Cl 6 alkyl, amino, nitro or Cl 6 alkoxy;
Rb is hydrogen, halo, Cl 6 alkyl or Cl 6 alkoxy;
Rl is hydrogen, Cl lo alkyl, Cw alkenyl, aralkyl, C2 6 alkanoyl or C2 6
alkanoyl Cl 3 alkyl;
10 R2 is Cl 6 alkoxy; and
R3 i8 hydrogen, chloro or fluoro; ~:
R4 is hydrogen,Cl 6 alkyl, amino optionally subs~tuted by a Cl 6 alkyl
group, halo, hydroxy or C1 6 alkoy;
Rs i6 hydrogen, halo, Cl 6 alkyl, Cl 6 alkoxy, nitro, amino or Cl 6
alkylthio; and
R6 is hydrogen, halo, Cl 6 alkyl, Cl 6 alkoxy or amino; ~ ;
Rc is hydrogen, Cl 6 alkoxy, halo or Cl 6 alkyl;
Y is O or NH;
Z is of su~formula (d) or (e):
H2)n~ (d)
` Rd .
)n2 N~ (e)
R~ - :
.:
wherem
nlisO, 1,2,30r4;n2is2,3,40r5; ::
25 q is 0, 1, 2 or 3;
Rd i8 hydrogen, C1 12 alkyl or aralkyl;
R7 and R8 are hydrogen or C1 6 alkyl; and
Rg is hydrogen or C1 1o alkyl; :
in the manufacture of a medicament for use as a 5-HT4 receptor
30 antagonist.
WO 93/03725 PCr/Gs92/01519
2116024
.. q
E~ample~ of alkyl or alkyl containing groups include Cl, C2, C3, C4, Cs,
C6, C7, Cg, Cg, Clo, Cll or C12 branched, straight chained or cyclic alkyl,
a~ appropriate. Cl 4 alkyl groups include methyl, ethyl n- and iso-propyl,
n-, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cycJobutyl,
5 cyclopentyl, cyclohe~grl, cycloheptyl and cyclooctyl. Alkenyl include~ all
suitable ~ralues including E and Z fo~ns.
Aryl includes phenyl and naphthyl optionally ~ub~tituted by one or more
gub~tituents selected from halo, Cl 6 alkyl and Cl 6 alko~
''
Halo inc3udes fluoro, chloro, bromo and iodo.
When Z i5 of su~formula (d), nl i8 preferably 2, 3 or 4 when the azacycle
is attached at the nitrogen atom and nl is preferably 1 when the azacycle
15 i8 attached at a carbon atom, such as the 4-position wheTl q i8 2.
VVhen Z is of sub-~ormula (e), n2 i8 preferably 2, 3 or 4.
R8 and Rg are preferably both alkyl, espec ally one of R8 and Rg is C4 or
20 larger alkyl.
Specific values of Z of particular interest are as follows:
~--~N Bu ~)
--~N ^O ~li)
--N3 aii)
~NMenBu ~Iv)
Tbe invention also provides novel compounds within formula (I) with side
chains (i), (ii), (iii) or (iv).
wO 93~03725 2116 0 2 4 pcrlGB92/o15l9
- 5-
The invention also provides novel compounds within fiormula (I) wherein
X iB of formula (a) wherein L is C-OCH3, C-CH3 or C- Cl, in particular
those wherein the side chain Z i6 of sub-formula (i), (ii), (iii) or (iv).
5 Other values of Z of interest are described with re~erence to the Esamples,
such as those in Example~ 19 onwards. In particular, the side chain of
formula (i) or (ii) i8 replaced by a corresponding side chain wi~h an alkyl
or optionally substituted benzyl N-substituent and/or wherein the 4- -
piperidinyl gro~p is replaced by 3-azetidinyl or 3-pyrrolidinyl.
~:'~
L in formula (a) is favourably C-H, C-CH3, C-Cl or C-OCH3. ;
Q in formula (a) i~ favourably NRl, usually NH or N-methyl.
Rl i8 preferably hydrogen or a methyl or ethyl group.
R2 is preferably methoxy.
R4 iB preferably amino.
R5 i8 preferably halo.
R6 iB preferably hydrogen.
A substituent when halo is selected from fluoro, chloro, bromo and iodo,
preferably chloro. Rb when halo is preferably iodo.
:
Y iB preferably 0.
Particularly suitable esamples of compounds of formula (I) include those
described in the Examples hereinafter and in Example 2 of EP-A-429984.
.
The pharmaceutically acceptable salts of the compounds of the formula (I)
include acid addition salts with conventional acids such as hydrochloric,
35 hydrobromic, boric, phosphoric, sulphuric acids and pha~maceutically
acceptable organic acids such as acetic, tartaric, maleic, citric, succu~ic,
benzoic, ascorbic, methanesulpho~ic, a-keto glutaric, -glycerophosphoric,
and glucose-l-phosphoric acids.
:
WO 93/03725 pcr/GB92/ol~l9
2 1 1 ~ ~3 2 1 - 6 -
Examples of pharmaceutically acceptable salts include quaternary
derivative6 of the compounds of formula (I) BUCh as the compounds
quaternised by compounds RX-T where;n R~ is Cl 6 alkyl, phenyl-Cl 6
5 alkyl or Cs 7 cycloalkyl, and T is a radical corresponding to an anion of an
acid. Suitable e~amples of R,~ include methyl, ethyl and n- and iso-propyl;
a~d benzyl and phenethyl. Suitable examples of T include halide 8uch a6
chloride, bromide and iodide.
10 E~amples of phar~naceutically acceptable salts also include internal salts
such as N-02ides.
The compounds of the formula (I), their pharmaceutically acceptable salts,
(including quaterna~ derivatives and N-o~ides) may also form
15 pharmaceutically acceptable solvates, such as hydrates, which are
included wherever a compound of formula (I) or a salt tbereof i8 herein
referred to.
5-HT4 receptor antagonist activity may be iden~fied accordi~g to
20 standard methods, such as those described hereinafter.
Esampl~s of 5-HT4 receptor antagonists include ICS 20~930
(tropisetron), which is described in the above mentioned patent reference~
and GB 2125398A, R 50 595 (Janssen), whic~ is described in FR76530 and
25 Eur.J. Pharmacol., 1~1 119^125 (1990), and SDZ 205-557, wbich is
described by KH. Buchheit and R. Gamse in Naunyn-S;chmiedeberg's
Ar~h. Pha~macol., ~ (Suppl.), R101 (1991).
In one aspect, the compound of formula (I) is a more potent antagonist at
30 5-HT4 receptors than at 5-H'r3 receptors.
PreferaUy, the 5-HT4 receptor antagonist of formula ;a) is in substantially
pure pharmaceutically acceptable form.
35 The compounds of formula a) may be prepared as descnbed in the
aforeme~tioned patent references, or by analogous methods thereto.
The compounds of the present invention are 5-HT4 receptor antago~ists
wo 93/03725 2 116 0 2 4 PCI/GB92/01519
and it is thus believed may generally be used in the ~eatment or
prophylaxis of gastrointsstinal disorders, cardiovascular disorders and
CNS disorders.
5 They are of potential interest in the treatment of irritable bowel syndrome
(IBS), in particular the diarrhoea aspects of IBS, i.e., these compounds
block the ability of 5-HT to stimulate gut motility via activation of enteric
neurones. In animal models of IBS, this can be conveniently measured as
a reduction of the rate of defaecation. They are also of potential use in the
10 treatment of unnary incontinence which is often associated with IBS.
They may also be of potential use in other gastrointestinal disorders, such
as those associated wîth upper gut motility, and as antiemetics. In
particular, they are of potential use in the treatment of the nausea and
15 gastric symptoms of gastro oesophageal reflu~c disease and dyspepsia.
An~emetic activity îs determined in known animal models of ~-
cytotosic-agent/radiation induced emesis. -~
Specific cardiac 5-HT4 receptor antagonists wbich prevent atrial ~-
20 fibrillation and other atrial arrhythmias associated with 5-HT, would also
be e~cpected to reduce occurrence of stroke (see A.J. Kaumann 1990,
Naumyn-Scbmiedeberg's Arch. Pharmacol. 342, 619-622, for appropriate ~ -
a~ test method). -
25 It is believed that platelet-de~ived 5-HT induces atrial arrhythmias which
encourage atrial fibrillation and atrial disorders are associabed with
6ymptomatic cerebral and sytemic embolism. Cerebral embolism is the
most common cause of ischaemic stroke and the heart the most common ~ -
source of embolic material. Of particular concern i8 the frequency of
30 embolism associated with atrial fibrillation.
An~iolytic activity is likely to be effected via the hippocampus (Dumuis et
al 1988, Mol Pharmacol., 34, 880-887). Activity may be demonstrated in
Etandard animal models, the social interaction test and the X-maze test.
M~graine suf~erers ofte~ undergo situations of an~ciety and emotional -~
stress that precede the appearaDce of headache (Sachs, 1985, Migraine,
Pan Books, London). It has also been observed that during and within 48
WO 93/03725 PCI/GB92/01~519
211602 1 -8- ~
hours of a migraine attack, cyclic AMP levels are considerably increased
in the cerebrospinal ~uid (Welch et al., 1976, Headache 16, 160-167). It i8
believed that a migraine, including tbe prodomal pha~e and the asso~ated
increased levels of cyclic AMP are related to ~timulation of 5-HT4
5 receptor6, and hence that administration of a 5-HT4 antagonist iB of
potential benefit in relieving a migraine attack.
The invention also provides a 5-HT4 antagonist pharmaceutical
composition compri~ing a compound of formula (I), or a pharmaceutically
10 acceptable salt thereof, and a pharmaceutically acceptable carrier.
Such compositions are prepared by admi~cture and are u~ually adspted for
enteral such ss oral, nasal or rectal, or parenteral administrstion, and as
such may be in the form of tablets, capsules, oral liquid preparations,
15 powders, granules, lozenges, reconstitutable powders, nasal sprays,
suppositries, injectable and infi~sable solutions or suspensions.
Sublingual or transdermal administration is also envisaged. Orally
admiDistrable compositions are preferred, since they are more convenient
for general use.
Tablets snd capsule~ for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding age~ts,
filler~, diluents, tabletting agents, lubricants, disintegrants, colourants,
flavourings, and wetting agents. The tablets may be coated according to
25 well known methods in the art, for example ~vith an enteric coating
Suitable fillers for use include cellulose, maImitol, lactose and other
similar agents. Suitable disintegrants include starch,
polyvinylpolypyrrolidone and starch denvatives such as sodium starch
30 glycollate. Suitable lubncants include, for example, magnesium stearate.
Suitable pharmaceutically acceptable wetting agents in~:lude sodium
lauryl sulphate. Oral liquid preparations may be in the form of, for
esample, aqueous or oily suspensions, solutions, emulsion~, syrups, or
35 elisirs, or may be presented as a dry product for reconstitution ~nth water
or other suitable vehicle before use. Su~ liquid preparations may contain
conventio~al additives such as suspending agents, for esample sorbitol,
syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
WO 93/03725 2 11 5 a ~ '1 P~/GB92/OlSl9
9 . -.~
carbo~yl.lethylcellulose, aluminium ~tearate gel or hydrogenated edible
fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
acacia; non-aqueous vehicles (which may include edible oils), for esample,
almond oil, fractionated coconut oil, oily esters such as esters of glycerine,
5 propylene glycol, or ethyl alcohol; preservatives, for example methyl or
propyl p-hydrosybenzoate or sorbic acid, and if desired conventional
flavouring or colouring agents.
~ .
Oral liquid preparations are usually in the form of aqueou6 or oily
10 suspensions, solutions, emulsions, 6yrups, or eli~irs or are presented as a
dry product for reconstitution with water or other suitable vehicle before
use. Such liquid preparations may contain conventional additives ~uch as
suspending agents, emulsifying agents, non-aqueous vehicles ~which may
include edible oils), preservatives, and flavouring or colounng agents.
The oral compositions may be prepared by conventional methods of
blending, filling or tabletting. Repeated Uending operations may be used
to distribute the active agent throughout those compositions employing ;~
large quantities of fillers. Such operations are, of course, conventional in
20 the art.
. .
For parenteral admiI~istration, ~uid unit dose forms are prepared
containing a compound of the present invention and a sterile vehicle. The
compound, depending on the vehicle and the concentration, can be either
25 suspended or dissolved. Parenteral solutions are normally prepared by
dissolving the compound in a vehicle and filter sterilising before filling
i~to a suitable vial or ampoule and sealing Advantageously, adjuvants
such as a local anaesthetic, preservatives and buffering agents are also
di6solved in the vehicle. To enhance the stability, the composition can be
30 frozen af~er filling into the vial and the water removed uIlder vacuum.
Parenteral suspensis are prepared in substantially the 6ame manner
except t}~at the compound is suspended in the vehicle instead of being
dissolved and sterilised by esposure of ethylene oside before suspending
35 in the sterile vehicle. Advantageously, a 6u~ctant or wetting agent i8
in~luded in the composition to facilitate uniform distribution of the
compound of the invention.
wO 93/0372s PCr/GB92/01519
2 1 1 6 0 ~ 4 - 1 o -
The invention further provides a method of treatment or prophyla~is of
i~itable bowel syndrome, gastro-oesophagal reflu~ disease, dyspepsia,
atrial arrhythmias and stroke, anxiety and/or migraille in mammfllB, BUCh
a~ humans, which compri~es the administration of an e~ective amount of
5 a compound of the formula (I) or a pharmaceutically acceptable salt
thereof.
An amount effective to treat the disorders hereinbefore described depends
on the relative efficacies of the compound~ to be administered, the nature
10 and severity of the di~order being treated and the weight of the mammal.
However, a unit dose for a 70 kg adult will normally contain 0.05 to 1000
mg for example 0.5 to 500 mg, of the compound. Unit doses may be
administered once or more than once a day, for esample~ 2, 3 or 4 times a
day, more usually 1 to 3 times a day, that is in the range of approgimately
15 0.0001 to 50 mgA~g/day, more usually 0.0002 to 25 mg/'kglday.
No adverse to~cological effects are indicated within the aforementioned
dosage ranges.
20 The invention also provides a compound of formula (I) or a
pba~maceutically acceptable ~alt thereof for u~e as an active therapeutic
substance, in particular for use in the treatment of irritable bowel
syndrome, gastro oesophagal reflus disease, dyspepsia, atrial arrhythmias
and stroke, an~ciety and/or migraine.
The following Examples illustrate the preparation of compounds of -formula (I); the following descriptions relate to the preparation of side
chain (Z containing) intermediates.
:.-
WO 93/03725 2 1 1 ~ 0 2 4 PCI/GB92/01519
- 1 1 -
.
~ Y Z :.
:
El (a~, O CH2-(1-ethyl-4-piperidyl) :
L~CH,
RalRb = H,
Q = NH.
E2 (b~, R6=H O (CH2)2-(1-piperidyl)
R2 = OMe,
R3-H,
R4=NH2
Rs = Cl.
E3 (b), R6=H NH CH2-(1-ethyl~-piperidyl)
R2 = OMe,
R3 = F, ~:
. 20 R4=NH2
Rs = Cl.
E4 (b), R6=H O SH2-(1-butyl-4-piperidyl)
R2 = OMe,
R3 = H,
R4 = NH2~
Rs = Cl. ~-
':
E5 (as E3) O CH2-(1-butyl-~pipendyl) . -
-
E6 (-~El) ~O CH2~ butyl4-piperidyl)
~ ..
`,:
W6) 93/03725 PCI~/GB92/01~;19
211602~ 12-
~am~ (contd.)
~ Y z
E7 (c),* O CH2~ butyl-4-pipelidyl)
W=CH,
Rc=3-OMe
E8 (c),* O CH2-(1-butyl-4-piperidyl~
W=N
E9 (c),** O CH2-(1-butyl~-pipendyl3
W=N :~
ElO (a), O CH2-(l-butyl-4-piperidyl)
L~N, ;
Ra~b = H,
Q = NMe
Ell (as El) O (CH2)2-(1-homopiperidyl)
El2 (as El) O (CH2)3-(1-piperidyl)
E13 (as El) O (CH2)4-(1-piperidyl)
El4 (a), O (CH2)2-(1-pipendyl)
L=CH,
R~ = 5-Br,
Rb-H
Q ~ NH
* l-~ubstituted
~: ~ 35
**3-substituted
.
W0 93/~3725 2 116 0 2 4 PCr/GB92/01519
- 1 3 - ~-
Eacam~le~ (contd.)
~. Y Z ~
5 E16 (b), O (CH2)2-(1-piperidyl)
R2 = OMe,
R3 = H,
R4 = Me,
R5 =
E16 (a), O (CH2)2-(1-pipendyl)
L = COCH3,
Ra~Rb = H~ :
Q = NH
E17 (a), O (CH2-(1-butyl~-pipendyl)
L=CH,
R~/Rb - H,
Q-CH2 .,:,
E18 ~a), O (CH2)2-(1-piperidyl)
L = CH,
- Ra~Rb = H,
Q=S
~ -
El9 (as E2) O CH2-(1-butyl-3-pyrrolidinyl~
:~ `
E20 (as E1) O CH2-(1-butyl-3-pyrrolidinyl) ~:
30E21 (as E2) O (CH2)2-(1-pentyl-3-pyrrolidinyl)
E22 (asE1) i O ~ (CH2)2-(1-pentyl-3-pyrrolidinyl)
E23 (asE2) O CH2-(hexahydr~1-bul;yl-3-
azepinyl)
WO Q3/0372~ pcr/GB92~olsl9
211~1~2~ -14-
~lml21~ (contd.)
~ Y Z
E24 (a~ E1) O CH~-(hexahydro-1-butyl-3-
azepinyl) -
E26 (as E2) O (CH2)2-(1-butyl-3-piperidyl) ;
E26 (as E1) O (CH2~2-(l-butyl-3-piperidyl)
E27 (as E2) O (CH2)2-(1-butyl~2-pipendyl)
E28 (as E2) O CH2-(l~butyl-3-piperidyl)
:~
E29 (as E1) O CH2-(1-butyl-3-piperidyl)
E30 (as E2) O l-butyl~-piperidyl ~.
E~l (as E2) O CH2-(1-butyl-1,2,5,~
tetrahydropyridyl) - ~
E32 (a), Q (i)
L=CH,
~a~b = H~
Q - NEt
E33 (a), O (i)
L=CH,
RaJRb = H,
Q - NCH
E34 (as E33) O (ii)
E36 ~a~ E2) O C~I2-(1-butyl-3-azetidinyl)
~:
WO 93/03725 211 ~ ~ 2 ~ pcr/GB92/olsl9
- 1 5 -
Q5 (contd.)
~ Y Z ~:
~:
E36 (a), O CH2-(1-butyl-4-piperidyl)
L = C-CH3
Ra~Rb = H, ~:~
Q=NH
E37 (a), O CH2~ butyl-4-piperidyl)
L=C-Cl :
Ra~Rb = H,
Q = NCH3
:
E38 (a), O CH2-(1-butyl-4-pipendyl)
L = C-OCH3 ::
Ra/Rb = H,
Q = NH
E39 (a), NH CH2-(1-butyl~-piperidyl)
L = C-H
Ra/~b = H,
Q=NH
E40 (a), ~H CH2-(1-butyl~-piperidyl)
Ra~b = H
Q=NH
E41 (as E36) O (CH2~(1-piperidyl)
~- E42 (b), R6-H O (i)
R2=OMe,
` R3=Cl, ~-
R4=NH2
'.
:~:
WO 93/03725 PCr/GB92/01~19
211~024 -16-
De~cr~ption 1 (intermediates for Examples 19 and 20)
a) l-Butyl-3-carbomethosypyrrolid-5-one
5 To a cooled solution of butylamine (9.4 ml) in methanol (10 ml) was added,
dropwise, dimethyl itaconate (15g). The reaction mi~ture wa~ stirred at
room temperature overnight. The solvent wa~ evaporated under reduced
pressure to af~ord crude 1-bu~ 3-carbomethoxy-pyrrolidi~-5-one (17.9g).
10 b) 1-Butyl 3-hydroxymethylpyrrolidine
To a stirred slurry of lithium aluminium hydride (4.29g) in diethyl ether
(70 ml) was added 1-butyl-3-carbometho~ypyrrolid-5-one (lOg) in diéthyl
ether (20 ml). The reaction mixture has maintained at reflus for 3h under
15 a nitrogen atmosphere, and stirnng continued overnight at room
temperature. The mixture was cooled and water (4 ml), 10% aqueous
NaOH (6 ml) and water (8 ml) were added seque~tially. Diethyl ether
was added and the misture stirred for lh. The resultant precipitate was
removed by filtration through keiselguhr and the filtrate concentrated
20 u~der reduced pre~sure. Distillation at reduced pressure gave pure 1-
butyl-3-hydrosymethylpyrrolidine (Dl) (5.13g).
.,
lH NMR (CDC13) 250 MHz ~: 3.69 (dd, lH), 3.51 (dd, lH), 2.80 (dt, lH),
2.64 (dd, lH), 2.24-2.53 (m, 5H), 1.92-2.07 (m, lH), 1.60-1.73 (m, lH),
1.2~1.55 (m, 4H), 0.92 (t, 3H). -~
Desc~iption 2 (intermediate for Examples 21 and 22)
30 a) Following the procedures outlined in Description 1, the follo~ving
compound was obtained:
1-pentyl-3-hydro~ymethylpyrrolidine
35 b) 3-Chloromethyl-l-pentylpyrrolidine (6.54g) in ~hloroform (lO ml)
wa~ saturated with hydrogen chlonde and the misture heated to reflus. A
solution of thionyl chloride (5.6 ml) in chloroform (10 ~1) was added
dropwise and stirring continued for lh The reaction mixture was cooled
``'
WO 93/03725 ~ O ~ ~ PCI/GB~2/01519
- 17-
to room temperature and ~tirIing continued overnight. The reaction
mi~ture was concentrated to half-volume and azeotroped with ethanol (2
10 ml). Tbe residue was diluted with water and extracted with diethyl
ether. I~e aqueous phase was basified with 50% aqueous sodium
hydro2~ide and extracted with diethyl ether. The organic phase was
washed with water, dried (Na2S04) and concentrated in vacuo to afford
a~ oil. Distillation under reduced pressure gave pure 3-chloromethyl-1- -
pentylpyrrolidine (5.79g).
A 6tirred solution of 3-chloromethyl-1-pentyl pyrrolidine (5.415g),
tricaprylmethyl smInonium chloride (375 mg), snd sodium cysnide (7.25g)
in water (12.5 ml) was heated at 100C for 24h. The reaction mi~ture
was cooled to room tempersture and extracted with ethyl acetate. The
organic phase was washed with water, dried (Na2S04) and concentrated
15 in vacuo to sfford crude 3-cyanomethyl-1-pentylpyrrolidine (5.04g).
d) A solution of 3-cyanomethyl-1-pentylpyrrolidine (2.982g) in
methanolic HCl (60 ml) was allowed to fitand at room temperature for 16h.
The solvent was removed under reduced pressure, the residue diluted
20 with water, basified with aqueous sodium hydro~nde solu~on and
e~tracted with diethyl ether. The orgaDic phase was washed with water,
dned (Na2S04) filtered and concentrated in vacuo to a~ord crude methyl
3-(1-pentyl pyrrolidino) acetate. Mstillation under reduced pressure
(100C at 0.2 mm Hg) gave tille compound (2.13g).
e) To a ~uspension of lithium aluminium hydride (0.7g) in diethyl
ether (40 ml) was added methyl 3-(1-pentyl pyrrolidino) acetate (1.967g)
under a nit~ogen atmosphere. The mi~ture was heated to reflu~c and
stirnng continued for 4h. The reaction mi~ture was cooled to room
30 temperature and stirring continued overnight. Water (5 ml) was added
dropwise and the resultant precipitate removed by filtration and washed
with dichloromethane. The combined organic filtrate was concentrated in
vacuo to af~ord an oil. Dis~llation under reduced pressure (150C l l.0
mm Hg) gave pure 3-hydroxyethyl-1-pentylpyrrolidine (D2) (1.48g).
lH NMR (250 ~OEIz) (CDC13) ~: 4.18-4.41 (8, lH), 3.52-3.73 (m, 2H), 2.7~
2.85 (m, lH), 2.33-2.52 (m, 6H), 1.92-2.08 (m, lH), 1.45-1.80 (m, 5H), 1.22-
?-38 (m, 4H), 0.88 (t, 3H).
wo 93/03725 pcl/Gs92/olsls
211602 1 -18-
Degcription 3 (inte~nediate for Examples 23 and 24)
a) Hexahydro-l-butyl-azepin-2-one
5 To a solution of hexahydro-1H-azepin-2-one (lOg) i~l dry THF (300 ml) was
added potassium tert-butoxide (9.86g). The reaction mixture was heated
to reflux. 1-Bromobutane (9.45 ml) was added after lh. Stirring was
continued for 2h. The reaction misture was cooled to room temperature
and water (10 ml) added. The solvent was concentrated under reduced
10 pressure and the residue dissolved in et~yl acetate (250 ml) and washed
~nth brine. The organic phase was dried (Na2S04) filtered and
concentrated in vacuo to afford an oil.
Kugelrohr distillation af~orded pure title compound (12.0g).
b) Hesahydr~l-butyl-3-carbosyazepin-2-one
To a solution of hexahydro-1-butylazepin-2-one (6.0g) in dry 1~ (30 ml)
was added lithium diisopropylamide in cyclohexane (1.5M, 23.3 ml) at
20 0C. Stirring was continued at ambient temperature for 30 min. C02
pellets was added to the reaction misture which were subsequently
poured into ice-water (200 ml). The l~IF was concentrated in vacuo and
1 he aqueous phase adjusted to pH2 with 5N HCl. The aqueou~ phase was
ext~acted with chloroform (4 s 200 ml) and the combined organic estracts
25 were d~ied (NaaS04), filtered and concentrated in vacuo to afford an oil.
Elash chromatography on silica u~ing chloroform and ethanol as the
eluant gave pure title compound (1.9Og).
c) He~ahydro-l-buty1-3-hydrosymethylazepine
To a slurrg of lithium aluminium hydride (1.03g) in THF (50 ml) was
added a solution of he~cahydro 1-butyl 3-carboxyl azepin-2-one (1.9Og) in
1~ (50 ml) under a nitrogen atmosphere. Stimng was continued at
ambient temperature for 70h. The reaction mi~ture was heated to reflux
35 for 5h, cooled and quenched by the sequential addition of water (1 ml),
10~6 aqueous NaOH (1~ nd) and water (2~ ml). Stimng was continued at
room temperature for lh. The resultant precipitate was remo ~ed by ;~
filtration and the filtrate concentrated in vacuo to afford an oil. -
WO 93/03725 211 6 Q 2 ~1 PCrJGB92/01519
- 19- .
Kughlerohr distillation gave pure ~tle compound ~D3) (0.76g).
H NMR (CDC13) 250 MHz ~: 4.71 (m, lH~, 3.81 (dd, lH), 3.49-3.57 (m,
lH), 2.70-2.85 (m, 3H), 2.43 (dt, 2H), 2.07-2.30 (m, lH), 1.41-1.90 (m, 9H),
5 1.22-1.37 ~m, 2H), 0.92 (t, 3H).
De~cription 4 (intermediate for E~ampl~s 25 and 26)
10 a) Ethyl 1-buty1-3-pyridylacetateiodide
To a cooled solution of ethyl 3-pyridylacetate (12g) in acetone (50 ml) was
added l-iodobutane (12.90 ml). The reaction mixture was ~tirred at room
temperature overnight and then heated to reflu~. The reaction mi~cture
15 was cooled to room temperature and diethyl ether waæ added. S~rriIlg
waB continued for 15 min. The resultant precipitate was removed by
filtration and dried to afford crude title compound (23.76g).
b) Ethyl-1-buty1~3-piperidylacetat~ -
A solution of ethyl 1^butyl-3-pyridylacetate iodide (21g) in ethanol wa~ -~
hydrogenated over PtO2 (2g) at atmospheric pressure and room
temperature. The catalyst wa~ removed by filtration through keiselguhr
and the filtrate concentrated in vacuo. The residue wa~ dissolved in
25 water, basified from K2C03 and e~tracted with chloroform. The organic
phase svas dried (Na2S04) filtered and concentrated in vacuo to afford
ethyl 1-butyl-3-piperidylacetate (13.6g) as an oiL
c) l-But3~1-3-pipendyletha~ol
To a slurry of litbium alumi~ium hydride (3.51g~ in diethyl ether (50 ml)
wa8 add~d, dropwise, a 801ution of ethyl 1-but~rl-3-piperidyl acetate ~7.0g)
in diethyl ether (50 ml) at 0C under a nitrogen atmosphere. Stir~ing was
continued at smbient temperature for ffOh. The reaction misture was
35 cooled to 0C and treated ~equentially with water (3.5 ml), 10% aqueous
NaOH (5.2 ml) and water (8.7 ml). Stirring was continued for lh. The
precipitate wa~ removed by filtration through Keiselguhr and the filtrate
evaporated under reduced pressure to afford crude product. Vacuum
WO 93/03725 PCI/GB92/0~519
211~02-1 ~
dis~llation gave pure title compound (D4) (4.0g).
lH NMR (CDCI3) 250 MHz ~: 3.59-3.77 (m, 2H), 2.64-2.69 (m, 2H), 2.23-
2.35 (m, 2H), 2.11-1.96 (m, lH), 1.40-1.88 (m, 9H), 1.22-1.38 (m, 2H), 0.98-
1.14 (m, lH), 0.92 (t, 3H).
MH+ 186
De~cription 6 (intermediate for Example 27)
a) Ethyl l-butyl-2-piperidylacetate
To a solution of ethyl lH-piperidyl-2-acetate (8.3g) in ethanol (100 ml) was
added potassium carbonate (14.35g) and 1-bromo butane (11.7 ml). The
reaction mixture was heated to reflux overnight. The reaction mi~cture
was cooled to room temperature and filtered through keiselguhr. The
filtrate was evaporated under reduced pressure to afford an oil. Flash
cbromatography on silica eluting with chloroform and ethanol gave pure
title compound (5.85g). -
b) l-Butyl-2-pipe~idylethanol
Following the procedure ou~ined in Description 4c), ethyl 1-butyl-2-
piperidyl acetate (4.44g) gave the title compound as an oil afl;er kugelrohr
dis~llation (2.27g).
lH NMR (CDC13) 250 MHz ~: 5.45 (m, lH), 3.82-3.94 (m, lH), 3.70-3.80
(m, lH), 3.00-3.09 (m, lH), 2.73-2.85 (m, lH), 2.61-2.72 (m, lH), 2.40-2.52 --
~m, lH), 2.21-2.34 (m, lH), 1.81-1.96 (m, lH), 1.23-1.75 (m, 11H), 0.90 (t,
3H).
`'..
MH+ 186
:
wo 93/0372s 2116 0 2 4 PCI/Gs92/OlSlg
- 21 -
Description 6 (intermediate for E~ample 28)
a) E:thyl-l-buty1-3-piperidyl carbo~ylate
5 Following the procedure ou~lined in description 5a), ethyl-lH-piperidyl 3-
carbo~ylate (15.7g) gave ~tle compound (17.1g).
b) l~Buty1-3-pipe~dylmethanol `~
10 Following the procedure outlined i~ Description 5b), ethyl l-butyl -3-
piperidyl carbox~rlate (17.1g) gave l-butyl 3-pipendinyl methanol (D6)
(3.9g).
lH NMR (250 MHz) (CDC13) ~: 3.38-3.53 (m, 2H), 2.82-3.03 (m, 2~I),
15 2.23-2.34 (m, 2H), 1.98-2.02 (m, lH), 1.36-1.97 (m, 8H), 1.22-1.35 (m, 2H),
0.92 (t, 3H).
Description 7 (intermediate for Esample 30)
a) Dimethyl-2, 2'-butyliminodiethanoate
Methyl acrylate (11.78g) was added dropwise to n-butylamine (6g), at 0C.
The reaction misture wa~ heated to re~u~ for 24h The reaction mi~ture
25 was cooled to room temperature, diluted with ethyl acetate and washed
with water (3x). The organic phase was dried (Na2S04), filtered and
concent~ated u~der reduced pressure to afford an oil. Purificat~on by
kugelrohr distillation gave the title compound (9.95g).
,
30 b) l~Butyl-4piper~done
Potassium te~-buto~ndé (6.82g) was added to a solution of dimethyl-2,2 -
butyl iminodiethanoate (9.95g) in diethyl ether under a nitrogen
atmosphere. The reaction mi~ture was stirred at room temperature
35 overnight. The mixture was estracted into 5N HCl (100 ml) and heated
under reflux for 2h The reaction misture was cooled to room temperature
and e~raporsted under reduced pressure. The residue was basified with
K2C03 and e~tracted unth ethyl acetate. The organic phase was dried
wO 93J03725 pcr/Gs92/ol5l9
2 11 ~ 0 2 4 - 22 -
(Na2S04) filtered and concentrated in vacuo. Flash chromatography on
silica using ethyl acetate as the eluant gave pure 1-butyl-4-pipe~idone
(3.68g).
c) 1-Butyl-4-pipe~idol
To a slurry of lit~ium al=um hydride (0.96g) in diethyl etber (50 ml)
wa~ added 1-butyl~piperidiDone (2.6g) in diethyl ether (50 ml), at 0C -:
under a nitrogen atmosphere. The reaction mi~ture waB stirred ove~ight
at ambient temperature, cooled to 0C and treated sequentially with
water (1.0 ml), 10~b NaOH (1.4 ml) and water (2.4 ml). The misture wa~ ~
stirred at ambient temperature for lh and the precipitate removed by ::
filtra~on through keiselguhr. Tbe filtrate was concentrated under ~-
reduced pres~ure to afford an oil. Purification by vacuum dis~llation gave
1-butyl~-piperidol (D7) (1.98g).
lH NMR (CDC13) 250 MHz ~: 3.61-3.74 (m,l H), 2.71-2.82 (m, 2H), 2.2~
2.34 (m, 2H), 2.0~-2.16 (m, 2H), 1.82-1.95 (m, 3H), 1.38-1.67 (m, 4H), 1.22- -
1.37 (m, 2H), 0.9 (t, 3H).
~scription 8 (interInediate for E~ample 31)
a) Ethyl l~butyl-4-pyridyl carbo~ylate iodide
, :~
Following the procedure ou~lined in Desc iption 4a), ethyl 4-pyridine
carbo~ylate (lOg) gave the title compound (22.2g).
b) Ethyl 2-butyl-(1,2,6,0-tetrahydropiperidyl4-carbo~ylate
To a suspension of sodium borohydride (4.6g) in ethanol (300 ml~, at 0C,
wag added ethyl l-but~yl~pyridyl carboylate iodide (lOg) u~der an
atmosphere of nitrogen. The reaction mi~ture was stirred for 2h at
ambient temperautre. The mi~cture was poured into water and tbe solve~t :~
concentrated under reduced pressure. The residue was estracted into
~hlo~oform and the organic pha~e dried (Na2S04), filtered and
concentrated to afford an oil. Flash chromatography on silica using
c~loroform and ethanol a8 eluant gave pure title compound (2.59g).
WO 93/03725 2 11~ ~ 2 '1 PCI/GB92/Ot51g
- 23 -
c) l-Buty1-(1,~,5,6)-tetl ahydropiperidyl-4-methanol
Following the procedure outlined in Description 4c), ethyl l-butyl-
5 (1,2,5,6~ tetrahydropipelidyl-4-carbo~ylate t2g) gave pure ~tle compouDd
(D8) (630 mg).
lH NMR (CDCl3) 250 MHz ~: 5.59 (8, lH), 3.92 (8, 2H), 2.95 (8, 2H), 2.59
(t,2H), 2.36 -2.50 (m, 2H), 2.10-2.20 (m, 2H), 1.25-1.60 (m, 6H), 0.92 (t,
10 3H).
M+ 169
15 Description 9 (intermediate for E:Eample 35~
a) l-Benzyl 4-chloro-3-hydro:cybutylamine
To a 801u~ion of epichlorohydrin (150ml) in cyclohesane (1l) was added :~
20 benzylamine (240ml). The reaction mixture was stirred at room
temperature for 24h The precipitate w88 removed by filtration, washed
with petrol (bp 60-80~C) and dried (327.7g)
b) l-Benzyl-3-trimethylsilo~yazetidi~e
To a solution of imidazole (112g) and triethyl amine (825ml) in
acetonitrile (1.51~ was added, dropwise chlorotrimethylsilane (203ml) at -
5C uIlder nitrogen. Stirnng was continued at room temperature for
11/2h. 1-benzyl-4-chloro-3-hydroxybutylamine (310g) wa~ added to the
30 reaction and t~e resulting misture heated to re~ux for 72b, with vigorous
stirring. The mixture was cooled to room temperature, toluene (21) was
added and the mi~ture left to stand overDight. The precipitate was
removed by filtration, ~lurned in petrol (bp 60-B0C) (2l) and washed with
water (200ml). The filtrate was concentrated in vacuo and the residue
35 partitioned between water and petrol (bp 60-80C) (1l). The organic
layer~ were dried (MgSO4), filtered and concentrated in uacuo to af~ord
an oil. Purification by vacuum distillation gave l-benzyl-3-trimethylsilo~cy
azetidine (130g) as a colourless oil.
WO 93/03725 PCI~GB92/OtS19
211602~ -24-
c) l-Be~zyl-3-hydro~yazetidine
A solution of l-benzyl-3-trimethylsiloxyazetidine (89g) in cHCI/water
(53/350ml) was stirred vigorously at room temperature for lOmin. The
misture was basified with K2C03 and extracted ~ntb diethyl ether. The -~
ethereal extracts were dried (MgS04), filtered and concentrated in vacuo
to afford l-benzy1-3-hydroxyazetidine (59.6g) as a white solid.
d) l-Benzyl-3-cyanoa~etidine
To a stirred solution of 1-benzyl-3-hydroxyazetidine (B3.1g) and
triethylamine (71ml) in toluene (610ml) and triethylamine (71ml) was
added, dropwise, over 20min methane sulphonyl chloride (39.5ml).
During addition the internal temperature was maintained between O ~nd
5C. On completion of addition stirring was continued for a further
30min. Water (20ml) was added to the reaction misture and the
separated toluene layer removed. The aqueous layer was furt~er
e~acted with toluene (2~100ml). The organic estracts were combined
and washed vri~Lh brine. The organic phase was treated with Adogen 464 -~
(25g) and a solution of sodium cyanide (29.5g) in water (173ml). The
reaction misture was heated to re~ux for ll/2h and allowed to cool to
room temperature. The mixture was transferred to a separato~y funnel
and the aqueous layer removed. The organic phase was washed with
water (3x200ml) and brine (200ml), dried (MgS04), filtered, and
concentrated in vacuo. Distillation of the residue gave pure 1-benzyl-3-
cyanoazetidine (62.9g).
e) Methyl l~benzyl-3-azetidinyl carbo~ylate
To a ~olution of 1-benzy1-3-cyanoazetidine (lOg) in methanol (40ml) wa~ -
added cH2S04 (35ml), dropwise, 80 as to maintain the reaction at a
ma~imum 55C. The reaction mixture was heated to 80C for 2h, cooied
to r.t. and poured into ice (240g3. The mixture was basified with aq.
ammonia and extracted into dichloromethane. The orgaDic phase was
washed with water, dried (Na2S04), filtered and concentrated in vacuo to
a~ord crude title compound (10.18g).
WO 93/03725 211 6 0 2 I PCI/GB92/01519
- 25 -
f) Methyl-lH-3-azetidinyl carboxylate acetate
A ~olution of methyl 1-benzyl-3-azetidi~yl carbsgylate (5.45g) in et~ol
~lOOml) and acetic a~d (6ml) wa~ hydrogenated over 10% Pd/C at 50pBi
5 alld 50C for 6h. The catalyst was removed by filt~ation tbrough
keiselguhr and the filtrate concent~ated in vacuo to af~ord met~yl l-H-3-
azetidinyl carbo~ylate acetate (3.65g).
g) Methyl l-but~l-3-azetidinyl carbosylate
To a ~olution of methyl l-H-3-aze~dinyl carbo~cylate acetate (2.80g) and
triel~hylamiDe ~4.6ml) in dicbloromethane (60ml) wa~ added, drop~e,
butyryl chloride (1.6ml). The reaction mixture was ~tirr~d at ambient
temperature for 70h. The mixture was washed witb water and t~e ::
15 organic phase dried (Na2SO4), filtered and concentrated under reduced
pressure to af~ord crude methyl 1-butyryl-3-azetidinyl carbo~ylate (2.60g).
Buty1-3-hydro~ymethylazetidine
20 To a solution of I,ithium aluminium hydride (2.20g) in dry THF (26ml)
wa~ added a ~olution of methyl 1-butyryl-3-azetidinyl carbos~ylate (3.60g)
iD dry l'HF, st 0C, under a nitrogen atmosphe;e. The reaction mi~ture
was stirred at am~ient temperature o~ren~ight. The reaction was
quenched by sequential addition of water (21/2ml), 10% aq. NaOH (4ml)
25 and water (5ml). Diethyl ether (20ml) was added and stirring continued
for lh The precipitate ~ras removed by filtration through Keiselguhr and
the filtrate concelltrated in vacl~o to afford an oil. Kug~lerobr distillatio~
afforded pure title compound (D9) (1.lg).
1H ~MR 250M~Iz (CDCl3), ~: 3.67 (d,2H3, 3.23-3.47 (m,2H), 2.97-3.08
(m,2H), 2.55-2.68 (m,lH), 2~35-2.7 (m,2H), 1.27-1.38 (m,4H), 0.8~0.98
(m,3H), ~IH+ 144
WO 93/03725 pcr/GB92/ol5l9
21160~
- 26 -
De~c~ption 10 (intermediate for E~ample 4)
1 -Butyl-4-piperidinemethanol
5 A mixture of ethyl isonipecotate (31.4g, 0.2mole), K2CO3 (54g, 0.4mole)
and ~BuBr (27.4g, 0.2mole) in EtOH (400ml) was stirred under reflux for
3 hours. The reaction mixture was allowed to cool, filtered through
keiselguhr and the filtrate concentrated to give a pale yellow oil. This was
dissolved in dry Et20 (200ml) and added dropwise to a suspension of
10 LiA~I4 (20g, 0.26mole) in dry Et2O. The reaction mi~ture was stirred at
room temperature overnight then cooled in an ice bath. Water (20ml) was
carefully added, followed by 20% aq. NaOH ~20ml), followed by water
(60ml). The mi~ture was stirred at room temperature for 30 minute~ then
filtered through keiselguhr. The filtrate was concentrated in vacuo to give
15 a colourless oil (25.0g).
NMR 250MHz (CDC13)
~: 3.48(d,2H), 2.93-2.99(bd,2H), 1.18-2.4(m,14H), 0.9(t,3H) -
~
WO 93/0372~ 21 1 6 0 2 4 PCI/GB92~01519
- 27 -
Preparation of Intermediate Acid for Example 3
a) Methyl-4-acetamido-5-chloro-2-methoxybenzoate (10.9g) was
dissolved in chloroform (40 ml), cooled to -10 C under nitrogen. A three
molar excess of trifluoromethyl hypofluorite was slowly bubbled through
~he stirred, cooled 601ution for 6 hours. A slow posi~ve nitrogen stream
was maintained throughout the reaction. After warming to room
temperature and thoroughly purging with nitrogen, the chloroform was -~-
removed in vacuo.
The residue was chromatographed on silica using chloroform with
increasing amounts of methanol as eluant. Methyl4-acetamido-5-chloro-
3-~uoro-2-metho~ybenzoate was isolated as an off white solid.
1H NMR (CDC13) 250MHz; ~: 7.64 (d, lH), 7.37 (bs, lH), 3.98 (bs, 3H), 3.9
(s, 3H), 2.2 (s, 3H)
b) Methyl-4-acetamido-5-chloro-3-fluor~2-methoxybenzoate (1.89g)
in 25 ml ethanol was treated with a solution of sodium hydroxide (1.15g)
in 15 ml water. The mi~cture was heated under reflux for 16 hours then
cooled. 1ne solvent was removed in vacuo and the residue acidified. The
precipitated solid was collected by filtration to give 1.48g of 4-amino-5-
chloro-3-fluoro-2-methoxybenzoic acid. -
lH NMR (DMS0) 250MHz; ~: 7.49 (d, lH), 6.19 (bs, 2H), 3.80 (s, 3H)
WO 93/03725 PCr/GB92/01519
2116~24 -28-
EYamP1e 1
(1-EthY1-4-PiPeridY1)methYI 1H indO1e-3 CarbO~ (E1)
A suspen~ion of indole-3-carboxylic acid (500 mg, 0.003 mole) in
dichloromethane (50 ml) was treated with osalyl chloride (0.635, 0.005
mole) and two drop6 of dimethylformamide. The mi~ture was stirred at
room temperature for one and a half hours then the solvent wa~ removed
in vacuo. The residue was redissolved in dichloromethane (50 ml) and a :~
601ution oftIiethylamine (612 mg, 0.006 mole) and l-ethyl~-
hydrosymethylpiperidine (430 mg, 0.003 mole) in dichloromethane (20 ml)
wa~ added dropwise. The reaction misture was stirred at room
temperature overnight then washed with aqueous potassium carbonate
solution and water, dried and concentrated to give a gummy solid which
15 was purified by column chromatography on silica gel using chloroform
95%, methanol 5% as eluant to give a white solid 405 mg, mp 135-6C.
lH NMR (250MHz) CDC13; ~: 10.08 (bs, lH), 8.10 - 8.20 (m, lH), 7.76 (d, :
lH), 7.35 - 7.45 (m, lH), 7.20 - 7.28 (m, 2H), 4.20 (d, 2H), 3.0-3.12 (bd,
20 2H), 2.5 (dd, 2H), 1.4-2.10 (m, 7H), 1.10 (t, 3H).
Esample 2
25 4-Amino-5-chloro-2-methosy-(2-(1-piperidyl)ethyl)benzoate (E2)
A solution of 4-amin~3-chlor~2-methosybenzoic acid (2.01g, 0.01 mole) in
acetonitrile (30 ml) was treated with bi~-carbonyldiimidazole (1.62g, 0.01
~ole) and the mi~cture was stirred at room temperature for one and a balf
30 hours. The solvent was removed in vacuo to leave the crude imidazolide.
A ~olution of 1-(2-hydro~yethyl)piperidine (1.29g, 0,01 mole) in dry TE~
(10 ml) under an atmosphere of nitrogen, was cooled in an ice bath n-
Butyllitbium (6.25 ml of 1.6M solution in hesane) was added dropwise
35 and the resulting solution stirred at 0C for 15 minutes.
The imidazolide was dissolved in dry 1~' (20 ml) and the resulting
solution added dropwise to the solution of the lithium alko~cide at 0C.
WO 93/03725 2116 0 ~ 4 PCI/GB92/01519
~9
The reaction mixture was allowed to warm to room temperature and was
~tirred for 3 hours. The solvent was removed in vacuo and the residue
partitioned between chloroform and water. The cblorofo~m was separated,
washed several times with water, dried and concentrated to give a white ~;
5 eolid (recrystallised from ether/petroleum ether) yield 2.6g, mp 135-6C.
lH NMR (250MHz) CDC13; ~: 7.82 (s, lH), 6.30 (8, lH), 4.48 (bs, 2H), 4.38 -~
(t, 2H), 3.82 (8, 3H), 2.72 (t, 2H), 2.45-2.56 (m, 4H), 1.52-1.66 (m, 4H), -
1.40-1.50 (m, 2H).
.
E~ample 3
4-Amino-6-chloro-3-fluoro-2-metho~y-(1-ethyl-4-
15 piperidyl)methylbenzamide (E3)
A solution of 4-amin~5-chloro-3-fluoro-2-metho~cybenzoic acid (210mg, -
0.001 mole) in acetonitrile (15ml) was treated with bis-
carbonyldiimidazole (162mg, 0.001 mole). The misture was stirred at
20 room temperature for one and a half hours.
A ~olution of 1-ethyl-4-aminomethylpiperidine (142 mg, 0.001 mole) in
acetonitrile (10 ml) was added dropwise and the reaction mixture was
stirred at room temperature for 3 hours.
The solvent was removed in vacuo and the residue partitioned between ~ -
chloroform and water. The chlorofo~n layer was removed, washed several
times with water, drièd and concentrated to give a beige solid which was
converted to the hydrochloride salt, 110 mg, mp 208-9C.
lH NMR (250 ~Hz) CDC13 (free base); ~: 7.82 (d, lH), 7.65-7.75 (bt, lH),
4.30 ~bs, 2H), 4.40 (B, 3H), 3.25 ~t, 2H), 2.82-2.95 (bd, 2H), 2.28-2.38 (dd, ~ ;
2H), 1.10-1.90 (m, 7H), 1.0 (t, 3H). -
:.
WO 93/03725 PCI/GB92/01519
211~0~ll 30
Example 4
4-Amino-5-chlor~2-methoxy.(l-butyl4-piperidyl)methyl benzoate
(E4) -
The title compound was prepared from 4-amino-5-chloro-2-
methoxybenzoic acid and 1-butyl4-piperidinemethanol by the method
described for Example 2. It was isolated as a white solid, mp 62-53C.
1H N~IR (250 MHz) CDC13; ~: 7.80 (8, lH), 6.28 (8, lH), 4.42 (bs, 2H), 4.10
(d, 2H), 3.85 (s, 3H), 2.92-3.02 (bd, 2H), 2.35 (m, 2H), 1.20-2.02 (m, 11H),
0.92 (t, 3H).
15 Esample 6
4-Amino-5-chloro-3-fluoro-2-methoy-(1-butyl-4-piperidyl)methyl
benzoate (E5~
20 The title compound was prepared from 4-amino-5-chloro-3-~uoro-2-
methoxybenzoic acid and 1-butyl-4-piperidinemethanol by the method -
described for E~ample 2. It was isolated as a colourless gwn and
converted to the hydrochloride salt, mp 195-7C.
25 lH NMR (250 MHz) CDC13 (free base); ~: 7.62 (d, lH),4.45 (bs, 2H), 4.12
(d, 2H), 3.90 (s, 3H), 2.92-3.15 (bd, 2H), 2.28-2.38 (m, 2H), 1.2~2.00 (m,
l1H), 0.90 (t, 3H).
30 E~ample 6
(1~Bu~ piperidyl)methyl-lH-indole-3-carbosylate (E6)
A ~uspension of indole-3-carboxylic acid (500mg, 0.003 mole) in
35 dichloromethane (50 ml) was treated with oxalyl chloride (0.635g, 0.005
mole) and two drops of dimethylformamide. The misture was stirred at
room temperature for one and a half hour~ then the solvent was remo~red
. ~ in vacuo to leave the acid chloride.
WO 93/0372~; 211 6 0 2 4 PCI/GB92/01519
- 31 -
A solution of 1-butyl-4-piperidinemethanol (513 mg, 0.003 mole) in dry
THF (10 ml) under an atmosphere of nitrogen, was cooled ~n an ice bath.
n-Butyllithium (1.88 ml of 1.6m ~olution in hexane) was added dropwise
and the resulting solution ~tirred at 0C for 15 minutes.
The acid chlo~de was dissolved in dry THF (20 ml) and the solution added
dropwise to the solution of the lithium alko2nde at 0C.
The reaction mixt~e was allowed to warm to room temperature and was
stirred for 3 hours. The solvent was removed in v~cuo and the residue
partitioned between chloroform and water. The chloroform was separated,
washed ~everal times with water, d~ied and concentrated to give a pale
brown gum.
lH NMR (250 MHz) CDC13; o: 9.90 (bs, lH), 8.10-8.18 (m, lH), 7.78 (d,
lH), 7.37-7.46 (m, lH), 7.1~7.28 (m, 2H), 4.19 (d, 2H), 3.05-3.15 (bd, 2H),
2.40-2.49 (m, 2H), 1.20-2.18 (m, 11H), O.90~t, 3H).
Esample 7
3-Metho~y-2-(1-butyl-4piperidyl)methylnaphthoate (E7)
The title compound was prepared from 3-metho~y-2-naphthoic acid and 1-
butyl4-piperidinemethanol by the method described for Example 2. It ~ -
was isolated as a pink solid MP 65-6C.
.
lH NMR (250 MHz) CDCl3; o: 8.28 (s, lH), 7.84 (d, lH), 7.75 (d, lH), 7.51 ` -
(t, lH)f 7.37 (t, lH), 7.19 (8, lH), 4.22 (d, 2H), 3.98 (~, 3H), 3.00 (bd, 2H), - :
2.32-2.40 (m, 2H), 1.24-2.03 (m, 11H), 0.92 (t, 3H).
.::
...
:: :
: "
WO 93/0~725 PCr/GB92/01519
211~02`~ -32- ~
Example 8
(l-Butyl-4-piperidyl)methyl-isoquinoline-1-carbo~ylate ~E8)
5 The title compound was prepared from isoquinoline-1-carbo~ylic acid and
1-butyl-4-piperidine-methanol by the method described for E~ample 2. It
was isolated as a colourless gum.
lH NMR (250 MHz) CDC13; ~: 8.70 (dd, lH), 8.65 (d, lH), 7.88 (dd, lH),
10 7.81 (d, lH), 7.60-7.78 (m, 2H), 4.39 (d, 2H), 3.00 (bd, 2H), 2.28-2.39 (m,
2H), 1.20-2.05 (m, llH), 0.90 (t, 3H).
Esample 9 -
(l-Butyl-4-piperidyl)methyl-isoquinoline-3-carbosylate (E9)
The til~le compound was prepared from isoquinoline-~carbo~cylic acid and
l-butyl4-piperidinemethanol by the method described for Esample 2. It
20 was isolated as a white solid, mp 82-3C.
lH~ (250 MHz) CDC13; ~: 9.38 (s, lH), 8.60 (s, lH), 8.10 (dd, lH), 7.98
(dd, lH), 7.70-7.87 (m, 2H), 4.35 (d, 2H~, 3.00 (bd, 2H), 2.26-2.40 (m, 2H),
1.20-2.05 (m, 11H), 0.91 (t, 3H). -
Esample lO
(l-Butyl-4-piperidyl)methyl-l-methylindazole-3-carbosylate (E10)
The ~tle compound was prepared in a similar man~er to the compound of
E~cample 6, from the 1-methylindazole acid (EP-A-323105)
m.p. 190C. (hydro~hloride salt).
Reference: lU.K Patent 1571278 (SOG D'Etudes Sci. et. Ind. D'Ille
de Fr.)
wo 93/03725 211 6 0 2 ~ PCI/GB92/01519
- 33-
Examples 11 to 14
The following compouIlds were prepared (as hydrochloride salts), in a
similar manner to that described in EP-A-429984.
(l-Homopipe~dyl)ethyl-lH-indole ~-carbosylate (Ell)
m.p. 123-125C
10 ~1-Piperidyl)propyl-lH-indole-3-carbosylats (E12)
m.p. 184-187~C '
(I-Piperidyl)butyl-lH-indole-3-carbosylate (E13)
m.p. 170-173C
(l-Piperidyl)ethyl-6-bromo-lH-indole-3 carbo~y1ate(E14)
20 m.p. 186-188C
E~ample 16
5-Chloro-2-methosy-4-methyl-(2-(l-piperidyl)ethyl)benzoate (E15) "
The title compound was prepared in a similar manner to the compound of
example 2, from 5-c~llor~2-methoxy~-methylbenzoic a~d (J. Chem. Soc.,
1963, p.730), and isolated as the hydrochloride sait, m.p. 185-186C.
:~:
~Esamplé i6
(l-Pipe~idylethyl)-2-methosyindole-3-carbosylate hydrochloride
' 35 (E16)
Following the procedure outlined in GB 2125398A, E~cample A-S, (N-
piperidylethyl)indole-3-carboxylate (0.21g) was conver,ted to the title
WO 93/03725 PCI/GB92~111519
211602Q 34
compound (38mg, 16%). -
lH NMR (CDC13) 250MHz (free base)
o: 9.25(brs,1H), 8.0(d,1H), 7.29(d,1H), 7.25-7.95(m,2H), 4.55(t,2H), -
4.12(6,3H), 2.90(t,2H), 2.67(brs,4H), 1.75-1.6(m,4H), 1.55-1.35(m,2H).
EYamP1e 17
(l-Buty1-4-pipe~dyl)methylindene-1-carbosylate hydroc~loride
(E17)
~:.
A solution of indene-l-carboxylic acid (187mg) (N.H. Cromwell and D.B.
Capps, J. Amer. Chem. Soc., ~, 44448, 1952) in dichloromethane (1Oml)
was treated with oxalyl chloride (lOOmg) and two drops of
dimet}lylformamide. The mixture was stirred at room t~mperature for one
and a half hours then the solvent was removed in vacuo to leave the acid
chloride.
A solution of 1-butyl-4-piperidinemethanol (120mg) in dry THF (5ml)
under an atmosphere of nitrogen, was cooled in an ice bath. n-
Butyllit~ium (0.5ml of 1.6m solution in hexane) was added dropwise and
the resulting solution stirred at 0c for 15 minute~.
The acid chloride was dissolved in dry THF (1Oml) and the solution added
dropwise to the solution of the lithium alkoxide at 0C.
The reaction mi~Lure was allowed to warm to room temperature and was
stirred for 3 hours. The solvent was removed in vacuo and the residue
part;itioned between c~loroform and water. The chloroform was separated,
washed several timës with water, dned and concentrated to giYe a pale
gum which ~Ya~ converted to the hydrochlo~ide salt 120mg, mp 131-3C.
lH NMR (250MHz) CDC13
~: 8.02(d,1H), 7.55-7.45(m,2H), 7.38(t,1H), 7.28(t,1H), 4.21(d,2H),
3.55(d,2H), 3.20(brd,2H), 2.65-1.25(m,13H), 0.95(t,3H).
:
W093/03725 2116 0 2 4 pcr/Gs92/ol519
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Example 18
2~ Piperidyl)ethyl-3~benzothiophene carbosylate (E18)
5 Benzothiophene-3-carbo~cylic acid (J. Matsuki, J. Chem. Soc. Jpn, 1966,
~Z, 18b) (400mg) was heated under reflux with SOC12 (0.7ml) in dry
toluene (15ml) for 30 minutes. The toluene was removed in vacuo and the --
residue dried under high vacuum.
10 l-Piperidineethanol (290mg) was dissolved in dry tl'~!' (5ml) and nBuLi
(1.4ml of 1.6M Soln in hexane) was added. The mixture was ~tirred at
room temperature for 15 minutes then a ~olution of the acid cbloride from
a~ove in d~r THF (10ml) was added. The reaction misture was stirred at
room temperature for 2hrs then the solvent was removed in ~acuo. The
15 residue vas partitioned bet~veen H20 and EtOAc and the EtOAc layer
removed wased several times with H20, dried (MgSO4) and concentrated
to give a pale yellow oil. This was purified by column chromatography on
SiO2 using EtOAc as eluant. The product was isolated as a pale yellow oil
and converted to the hydrochlo~de salt, 30mg mp 192-4C.
~0 , .
H NMR (250MHz) (DMSO) (free base)
:9.70(s,1H), 8.5(dd,1H), 8.12(dd,1H), 7.5(dt,2H), 4.4(t,2H), 2.68(t,2H),
3.28-2.49(m,4H), 1.30-1.55(m,6H).
Esample 19
(l-Bu~y1 3-pyrroli&yl)methyl-4-amino-5-chloro-2- '
30 methosybenzoate hydrochlo~ide (El9)
To a slurry of 4-amino-5-chloro-2-methoxy benzoic acid (l.OOg) in
- acetonit~ile (25 ml) was added bis carbonyl diimidazole (820 mg). The
reac~on mixture was gtirred at ambient temperature for 2h. The solvent
35 was removed in vacuo and the residue dissolved in dichlorometbane and
uashed with water. The organic phase was dried and filtered aIld
concentrated in vacuo. Crystallisation from he~aneldic~loromethane
a~orded the i~termediate imidazolide as a beige solid (9~3 mg).
wo 93/03725 PCr/GB92/OlSlg
2116024 -36-
To a solution of 1-butyl-3-hydroxymethylpyrrolidine (D1) (485 mg) in dry
(THF (20 ml) was added nBuli (1.6M in hexane, 1.92 ml) at 0C under a
I~itrogen atmosphere. Stirring waS continued at amWent temperature for
5 30 min. The imidazolide (776 mg) in 'l'~' (20 ml) was added to the
reaction mi~cture and stirring colltinued for 20h. Water (1ml) was added
and the ~olvent concent~ated in vacuo. The residue was partit;ioned
between chloroform and water. The organic phase was dried (NaS04)
filtered and concentrated in vacl~o to afford crude product. Flash
10 ~hromatography on silica using chloroform and ethanol gave (1-butyl-3-
pyrrolidinyl)methyl-4-~5-chlor~2-methoxy benzoate, whic~ wa~
treated with ethereal HCl to a~ord the title compound ~154 mg).
mp 181-184C.
lH ~MR (CD30D) 400 MHz ~: 7.69 (lH, s), 6.47 (lH, ~), 4.15-4.32 (4H,
m), 3.81 (s, 3H), 3.50-3.59 (lH, m), 3.34-3.41 (2H, m), 3.11-3.16 (3H, m),
2.74-2.83 (lH, m), 2.23-2.34 (lH, m), 1.88-1.99 (lH, m), 1.66-1.75 (2H, m),
1.38-1.48 (2H, m), 0.98 (3H, t)
MH+ 341 (Cl+).
E~ample 20
(l-Butyl-3~pyrrolidinylmethyl)-lH~indole-3-carbosylate
hydrochloride (E20)
To a ~lu2Ty of indole-3-carboxylic acid (l.OOg) in dicbloromethane (20 ml)
30 was added oxalyl chlonde (1.1 ml) and N,N'dimet~yl fo~mamide (2 drops).
The reaction mixture was stirred at ambient temperature for 2h The
solvent was evaporated under reduced pressure to afford crude indole-3
carbonyl chloride (960 mg).
35 To a solution of 1-butyl-3-hydroxymethylpyrrolidine (D1) (SOO mg) in dry
THF (20 ml) was added Buli (1.6M in he~canes, 1.99 ml) at 0C under a
nitrogen atmosphere. Stirring was continued at ambient temperature for
30 min. Indole-3-carbonylchloride (571 mg) in dry THF (10 ml) was added
,
WO 93/03725 211 6 0 2 4 PCr/GB92/01519
- 37 -
to the reaction mixture and stiIring con1;inued for 20h. Water (1 ml~ was
added to the reaction mixture and the solvent concentrated in vacuo. The
residue was partitioned between chlorofolm and water. The organic
phase was dried (NaSO4), filtered and concent~ated in vacuo to afford
5 crude product. Flash chromatography on silica using chlorofonn and
ethanol gave (l-butyl-3-pyrrolidinylmethyl~lH-indole-3-carbo~ylate
which was treated with ethereal HCl to af~ord ~tle compound.
m.p 59-62C
lH NMR (CD3OD) 270 MHz ~: 7.98-8.05 (m, 2H), 7.41-7.48 (m, lH),
7.15-7.26 (m, 2H), 4.28-4.47 (m, 2H), 3.51-3.93 ~m, 2H), 3.42-3.56 (m, lH), -
2.81-3.25 (m, 4H), 2.19-2.47 (m, lH), 1.82-2.16 (m, lH), 1.60-1.80 (m, 2H),
1.34-1.50 (m, 2H), 0.94-1.02 (m, 3H).
M+ 300
Esample 21
(l~Penty1-3-pyrrolidinyl)ethyl 4-amino-6-chloro-2- -
metho~ybenzoate hydrochloride (E21) -~
Following the procedure outlined in Example 19, 3-hydroxymethyl-1-
25 pentyl pyrrolidine (D2) (500 mg) gave the title compound (158 mg).
lH NMR (d6-DMSO) 270 MHz ~: 7.58 (s, lH), 6.47 (s, lH),4.054.22 ~m, -~
2H), 3.74 (s, 3H), 3.58-3.70 (m, lH), 3.36-3.57 (m, lH), 3.21 ~t, 2H), 2.87- ~-
3.12 (m, 3H), 2.68-2.84 (q, lH), 2.28-2.45 (m, lH), 2.03-2.27 (m, lH), 1.51-
30 1.91 (m, 5H), 1.18-1.37 (m, 4H), 0.87 (t, 3H).
M+ 368;(Freebase) -
~ .: . ' ~
WO 93/03725 PCI/GB92/0l519
211602-i -38-
E~ample 22
(l-Pen~ 3-pyrrolidinyl)ethyl-lH~ dole-3-carbo~ylate
hydrochloride (E22)
The ~tle compound wa~ prepared in a similar manner to the compouIld of
E~ample 20.
mp 48-51C
lH NMR (d6-DMSO) 270 MHz ~: 12.05 (bs, lH), 8.08 (d, lH~, 7.9~8.03
(m, lH), 7.45-7.52 (m, lH), 7.14-722 (m, 2H), 4.20-4.33 (m, 2H), 3.42-3.72
~m, 3H), 3.23 (t, lH), 2.90-3.15 (m, 2H), 2.73 (q, lH), 2.35-2.82 (m, lH),
2.06-2.30 (m, lH), 1.49-1.98 (m, 4H), 1.29-1.47 (m, 4H), 0.88 (t, 3H).
M+ 328 (Freebase3
Example 23
(HeYahydro-l-bu~1-3-azepinylmethyl)-4-a~o-5-chloro-2-
methov benzoate (E23)
Following the procedure out~ined in E~a~ple 19, reac~on of he~ahydro 1-
25 butyl-3-hydro~ymet hyl azepine (D3) (500 mg) gave the 1itle compound, as
a ~ee base, (318 mg).
mp 72-75C
30 lH NMR (CDCl3) 250 MHz ~: 7.82 (s, lH), 6.29 (s, lH~, 4.50 (bs, 2H),
3.96 4.18 (m, 2H), 3.84 (s, 3H), 2.83 (dd, lH), 2.61-2.75 (m, 2H), 2.43-2.60
(m, 3H), 2.05-2.20 (m, lH), 1.21-1.86 ~m, 10H), 0.89 (t, 3H). ~ `
WO 93/03725 211 6 0 2 I PCr/GB9U01519
- 39 -
E~ample 24
(Hesahydro-l-butyl-3-azepinylmethyl)-lH-indole-3-c~rbosylate
hydrochloride (E24)
~:
Follo~ving t~e procedure outlined in Example 20, reaction of he~ahydro-l-
butyl 3-hydroxymethyl azepine (D3) (500 mg) gave the ~tle compound ::
(155 mg).
mp 75-78C
H NMR (CDCI3) 250 MHz Free base
~: 9.45 (m, lH), 8.14-8.22 (m, lH), 7.95 (d, lH), 7.40-7.48 (m, lH), 7.22- -
7.31 (m, 2H), 4.10-4.28 (m, 2H), 3.00 (dd, lH), 2.51-2.89 (m, 5H), 2.23-2.48
(m, lH), 1.40-1.94 (m, 8H), 1.18-1.33 (m, 2H), 0.82 (t, 3H). -
MH+ 329 -:
E~ample 25
4-Ami~o-5-Chloro-2-metho~y-(1-butyl-3-piperidyl)ethyl-benzoate
(E25)
Follo~nng the procedure outlined in Example 19, reaction of 1-butyl-3-
piperidyl ethanol (D4) (lg) gave the title compound as a firee base (1.41g).
mp 102-104C
~:
lH NMR (CDCl3) 250 MHz ~: 7.80 (s, lH), 6.28 (s, lH), 4.45 (s, 2H), 4.27 - -
(t, 2Hj, 3.84 (s, 3H), 2.81-2.96 (m, 2H), 2.25-2.33 (m, ZH), 1.40-1.90 (m,
;~ ~ 11H), 1.22-1.48 (m, 2H), 0.92 (t, 3H). ~
M+ 368 :
WO g3/03725 P(~/GB92/01519
211602~ 40
E~ample 26
(l-Buty1-3-piperidylethyl)-lH.indole-3-carbosylate hydrochloride
(E26)
Following the procedure outLined in Example 21, reaction of 1-butyl-3-
piperidyl ethanol (D4) (500 mg~ g~ve the title compound (205 mg).
lH NMR (CDCl3) 250 MHz Free base
~: 10.02 (s, lH), 8.13-8.20 (m, lH), 7.79-7.81 (m, lH), 7.32-7.44 (m, lH),
7.19-7.30 (m, 2H), 4.30-4.47 (m, 2H), 2.92-3.08 (m, 2H), 2.31-2.42 (m, 2H),
1.44-1.98 (m, lOH), 1.21-1.35 (m, 2H), 0.83-1.06 (m, 4H).
15 M+ 328
Esample 27
20 4-Amino-5-chloro-2-metho~y-(1-butyl-2-pipe~idylethyl)-benzoate
(E27)
Follo~ving t~e procedure outlined in E~ample 19, reaction of 1-butyl 2-
piperidyl ethanol (D5) (750 mg) gave the title compound (650 mg).
mp 75-77C
lH NMP~ (CDCl3) 250 MHz o: 7.81 (s, lH), 6.29 (s, lH), 4.48 (s, 2H), 4.19- "
4.35 (m, 2H), 3.82 (s, 3H), 2.77-2.88 (m, lH), 2.22-2.70 (m, 4H), 1.99-2.13
(m, lH), 1.21-1.86 (m, 11H), 0.90 ~t, 3H). -
'~
M+ 36B
,
.
.
WO 93~03725 211 ~ ~) 2 ~ PCI'/GB92/01519
- 41 -
Esample 28
4-~nin~5-chlor~2-methosy-(1-butyl 3-piperidylmethyl)- benzoate
hydrochloride (E28) :
Following the procedure outlined in Example 19, 1-butyl-3-piperidyl
methanol (D6) (500 mg) gave title compound (100 mg). ::
mp 218-221C -
:'
H NMR (CDC13) 250 MHz Free base
~: 7.81 (s, lH), 6.27 (s, lH), 4.46 (8, 2H), 4.00-4.19 (m, 2H~, 3.84 (s, 3H),
2.84-3.06 (m, 2H), 2.29-2.38 (m, 2H), 2.01-2.18 (m, lH), 1.22-1.98 (m,
15 llH), 0.91 (t, 3H).
M+ 354 :
20 E~ample 29
(I-Butyl~3-piperidylmethyl) IH-indole-3-csrbosylate
h~rdrochloride (E29) .
25 Following the procedure outlined in Example 20, 1-butyl 3-pipendyl
methanol (D6) (500 mg) gave pure title compound (36 mg).
lH NMR (CDCl3) 250 MHz - Free base
30 ~: 9.96 (s, lH), 8.17-8.21 (m, lH), 7.90-7.95 (m, lH), 7.3~7.44 (m, lH~,
7.21-7.29 (m, 2H), 4.19 (d, 2H)? 3.12-3.22 (m, lH), 2.95-3.04 (m, lH), 2.31-
2.45 (m, 2H), 2.10-2.30 (m, lH), 1.42-2.06 (m, 6H), 1.03-1.40 (m, 4H~, 0.90 :
(t, 3H).
35 MH+ 315
wo 93/03725 PCr/GB92/015l9
2 1 ~ ~ ~ 2 1 - 42 -
E~:ample 30
4-Amino-5-chloro-2-metho~y-(l~butyl-4-piperidyl)benzoate (E30)
5 Following the procedure ou~ined in Example 19, 1-butyl 4-piperidinol
(D7) (500 mg) gave the title compound (150 mg). -
mp 83-85C
1H NMR (CDC13) 250 MHz ~: 7.80 (s, lH), 6.28 (s, lH), 4.94-5.05 (m, lH),
4.47 (fi, 2H), 3.83 (s, 3H), 2.66-2.81 (m, 2H), 2.29-2.45 (m, 4H), 1.93-2.08
~m, 2H), 1.76-1.90 (m, 2H), 1.43-1.58 (m, 2H), 1.23-1.41 (m, 2H), 0.93 (t, ::
3H).
M+ 340 -
Esample 31
.'~'
20 4-Amino-5-chloro-2-methosy-(1-butyl-1,2,5,~tetrahydro~
py~idylmethyl)benzoate (E31j -`
Foilowing tlle procedure outlined in Example 19, 1-butyl (1,2,5,6)
tetrahydropiperidyl-4-methsnol (D7) (300 mg) gave pure title compound
25 (220 mg).
. .
mp 75-77C ~-
lH NMR (CDC13) 250 MHz 8: 7.83 (8, lH), 6.28 (8, lH), 5.76 (s, lH), 4.63
30 (8, 2H), 4.48 (s, 2H), 3.81(8, 3H), 3.00 (8, 2H), 2.61 (t, 2H), 2.36-2.56 (m,2H), 2.25 (m, 2H), 1.4~2.09 (m, 2H), 1.28-1.41 (m, 2H), 0.93 (t, 3H).
MH+ 353
WO 93/03725 21 1 6 0 2 4 PCl /GB92/01519
- 43 -
E~ample 32
(l-Butyl-4-piperidyl)methyl-1-ethyl-lH-indole-3-carbosylate (E32)
5 A suspension of 1-ethyl indole-3-carboxylic acid (500 mg) in
dichloromethane (50 ml~ was treated with o~calyl chloride (0.635g, 0.005
mole) and two drops of dimethylformamide. The mixture was stirred at
room temperature for 1~ hours then the solvent was removed in vacuo to
leaYe the acid chloride.
A solution of l-butyl-4-piperidinemethanol (513 mg, 0.003 mole) in dry
THF (10 ml) under an atmosphere of nitrogen, was cooled in an ice bath.
n-Butyllithium (1.88 ml of 1.6M solution in hexane) was added dropwise
15 and the resulting solution stirred at 0C for 15 minutes.
The ac d chloride was dissolved in dry THF (20 ml) and the solution added
dropwise to the solution of the lithium alko~de at 0C.
20 The reaction mi~cture was allowed to warm to room temperature and was
s'drred for 3 hours. I~e solvent was removed in vacuo and the residue
partitioned between chloroform and water. The chloroform was separated,
was}ied several times with water, driedand concentrated to give a pale
brown gum which was converted to the hydrochlo~ide salt, mp 158-9C.
lH ~MR (250 MHz) (CDCl3) (firee ba~e)
~: 8.10-8.19 (m, lH), 7.88 (s, lH), 7.2-7.38 (m, 3H), 4.20 (m, 4H), 2.92-3.03
(bd, 2H), 2.28-2.40 (m, 2H), 1.20-2.0 (m, 14H), 0.90 (t, 3H).
WO 93/03725 PCl'/GB92/01519
211~a24 _44
E~ample~ ~3 and ~4
The follo~g compounds were prepared from the colTe~ponding indole
carbo~cylic acid by the method des~ibed for Example 32.
~:~
(l-But3rl-4-piperidyl)methyl-1-methyl-lH-indole-3-carbosylate
(E33) :
.--
mp 187-8C (hydrochloride salt) ~:~
'"'
H NMR (250 MHz) (CDC13) (free base) :
~: 8.10-8.19 (m, lH), 7.88 (8, lH), 7.2-7.38 (m, 3H~, 4.20 (d, 2H), 3.82 (8, ~ .
3H), 2.82-2.98 (bd, 2H), 2.28-2.39 (m, 2H), 1.20-2.18 (m, 11H), 0.90 (t, 3H). ~:"
(l-Cyclohe~ylmethyl 4-piperidyl)methyl-1-methyl-lH-indole 3- ::
carbosylate (E34)
mp 164-5C (hydrochloride ~alt)
H NMR (250 MHz) (CDCl3) (free base)
~: 8.10-8.19 (m, lH), 7.80 (8, lH), 7.22--7.4 (m, 3H), 4.20 (d, 2H), 3.82 (8,
3H), 2.86-2.96 (bd, 2H), 2.12 (d, 2H), 0.8~1.98 (m, 18H).
:..
Esample 35
.
(l-Butyl-3-azetidinylme1 hyl)-4-a~o-5-chloro-2-methosybenzoate
3n (E35) -
Following the procedures outlined above, 1-butyl-3-hydro~cymetbyl
azetidine (D9) (500mg) gsve the title compound (240mg). M+ 326
lH NMR 250MHz, CDCl3, o:7.83 (s,1H), 6.28 (s,1H), 4.50 (bs,2H), 4.33
(d,2H), 3.84 (s,3H), 3.38-3.49 (m,2H), 2.81-3.00 (m,3H), 2.38-2A5 (m,2H),
1.2~1.37 (m,4H), 0.85-0.94 (m,3H) -
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E~ample 36
(N-Butylpiperid-4-ylmethyl)~2~methylindole-3-carbosylate (E36)
5 Following the procedure outlined in E~cample 6 (except that
methyllithium used in place of n-butyllithium), 2-methylindol~3-
carbosylic acid (D1) (950mg) was converted to the ~tle compound (134mg,
8%) mp 128-130C
1H NMR (CHCl3) 200MHz ;
~: 8.1-8.0 (m, lH), 7.38-6.9 (m, 4H), 4.22 (d, 2H), 3.05 (brd, 2H), 2.75 (~, -
3H), 2.5-2.25 (m, 2H), 2.15-1.70 (m, 4H), 1.70-1.16 (m, 7H), 0.92 (t, 3H) -~
Esample 37
(N-Bu1 ylpipefid4-ylme~hyl)-2-chloro-l methylindob 3-carbosylate
hydrochloride (E37)
FollowiDg the procedure outlined in GB 2125398A, Esample A5, N- -
Butylpiperid-4-ylmethyl-1-methyl)indole-3-carbo~ylate (E33) (300mg) was
converted to the title compound (65mg, 15%) mp 238~4QC
25 lH NMR (CDCl3) 200MHz (free base)
~: 8.18-8.05 (m, lH), 7.33-7.20 (m, 3H), 4.24 (d, 2H), 3.77 (s, 3H), 3.05
(brd, 2H), 2.4~2.3 (m, 2H), 2.12-1.7 ~m, 5H), 1.65-1.15 (m, 6H), 0.92 (t,
3H)
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E~ample 38
(N-Butylpiperid-4-ylmethyl) 2-metho~yindole-3-carbosylate
hydrochloride (E38)
Following the procedure outlined in GB 2125398A E~ample A5, (N-
butylpiperid-4-ylmethyl~indole-3-carboxylate (E6) (0.25g) was converted
to the 1itle compouIld (108mg, 36%) mp 168-170C. --
'':
10 lH NMR (CDCl3) 250MHz (free base)
~: 7.95 (d, lH), 7.3-7.05 (m, 3H), 4.20 (d, 2H), 4.07 (s, 3H), 3.07 (brd, 2H),
2.49-2.36 (m, 2H), 2.09 (br t, 2H), 1.99-1.75 (m, 3H), 1.7-1.2 (m, 6H), 0.91
(t, 3H)
E~ample 39
(N-Butylpiperid-4-ylmethyl)indole-3-carbosamide (E39)
To a stirring solution of indo~e-3-carboxylic acid (lg) in dichloromethane
(20ml) at 0C under nitrogen was added oxalyl chloride (0.81 ml) and dry
dimethylformamide (3 drops). After 3 hours, the solvents were
evaporated under reduced pressure. A portion of the residual acid
25 chloride (420mg) was dissolved in dichloromethane (12ml) and added
dropwise to a solution of N-butylpiperid-4-ylmethylamine (40ûmg) in
dicbloromethane 12ml) followed by triethylamine (0.36ml). Af'cer stirnng
at ambient temperature overnight, the reaction mixture was washed with
saturated NaHC03 and the organic phase was dried (Na2S04). The
30 solvent was evaporated under reduced pressure and the residue
recrystallised from ethylacetate to give the title compound (467mg, 64C).
lH NMR (CDCl3) 250MHz
35 ~: 9.29 (br s, lH), 8.05-7.9 (m, lH), 7.81 (d, lH), 7.55-7.4 (m, lH), 7.39 7.2
(m, 2H), 6.28 (br 8, lH), 3.39 (t, 2H), 3.0 (br d, 2H), 2.45-2.25 (m, 2H), 2.1-
`
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1.1 (m, 11H), 0.9 (t, 3H)
Esample 40
a~-Butylpipe~d-4-ylmethyl)-2.methoxyindole.3.carboxamide
hydrochloride (E40)
.
Follovving the procedure outlined in GB 2125398A, Example A5, (N-
10 Butylpiperid-4-ylmethyl)indole-3-carboxamide (E39) (220mg) was
convered to the ~tle compound (230mg, 86~o). Mp 138-144C ;-
lH NMR SCDC13) 250MHz (free base)
15 ~ 9.85 (br s, lH), 8.25 (d, lH), 7.4-7.0 (m, 3H), 6.78 (t, lH), 4.18 (s, 3H),3.35 (t, 2H), 2.98 (br d, 2H), 2.45-2.25 (m, 2H), 1.95 (br t, 2H), 1.82-1.2 (m,
9H), 0.91 (t, 3H)
20 E~ample 41
l-Pipendylethyl-2-methylindole-3-carbo~ylate hydrochloride
(E41)
25 Following the procedure outlined in Example 36, 2-methylindole-3-
carboxylic acid (490 mg) was converted to the title compound (76mg) mp
147-9(~.
lH NMR (CDC13) 200 MHz
~: 8.65(br s,1H), 8.15-8.00(m,1H), 7.35-7.00(m,3H), 4.49(t,2H), 2.82(t,2H),
2.68(s,3H), 2.6-2.45(m,4H), 1.7-1.35(m,6H).
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Esample 42
4-Amino-3,5-dichloro-2-methoxy-(1-butyl-4-piperidyl)methyl
benzoate (E42)
The title compound wa~ prepared from ~amino-3,5-dichloro-2-
methoxybenzoic acid and 1-butyl4-piperidylmetbanol by the methsd
described in Example 2, except that MeLi was used in place of nBuL~. The
product was isolated as the hydrochloride salt.
mp l90-191C
H NMR (200MHz) CDCl3 (free bsse) ~: 7.72(s,1H), 4.9(bs,2H), 4.12(d,2H),
3.85(s,3H), 2.85-3.0(bd,2H), 2.2-2.34(m,2H), 1.2-2.00(m,11H), O.90(t,3H).
.
: .
~ .
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Further compounds of potential use in the inven~ion which were preparedare as follows:
~, ~CO2Y(CH2) nR
a~
r
R1
Ral Rl Y n R m.p.
H Et O 2 l-pipe~idyl 175-177C
H npr O 2 1-piperidyl 198-199C
H nBu O 2 1-pipe~dyl 202-204C
MeO H O 2 1-piperidyl 142-144C
Cl H O 2 1-pipendyl 153.5-154.5C
1 5 ~-
H H O 2 NHBz 233-235C
H H O 4 N(CH3)2 153~C
H H O 2 N(CH3)2 108-9C
H H O 3 N(CH3)2 208-210C
H O 2 N(Et~2 15~7C
H H NH 2 N((~H3)2 194-5C
H ~I NH 2 N(Et)2 97-98C
: 30 H Bz O 2 N(CH3)2 165-166C
H Bz O 4 N(CH3)2 138-9C
~: '
:
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5-HT4 RECE:PTOR ANT~GONIST ACTIVll Y
1) Guinea pig colon
Male guinea-pigs, weighing 250-400g are usea. Longitudinal muscle-
myenteric plexus preparations, appro~mately 3cm long, are obtained from
the di~tal colon region. These are suspended under a 0.5g load in isolated
tissue baths containing Krebs solution bubbled with 5% C02 in 2 and
maintained at 37C. In all experiments, the Krebs solution also contains -~
methiothepin 10-7M and granisetron 10-6M to block effects at 5-HT1,
5-HT2 and 5-HT3 receptors.
After constraction of a simple concentration-response curve with 5-HT,
using 308 contact tiInes and a 15min dosing cycle, a concentration of 5-HT ~-
is selected 80 as to obtain a contraction of the mu~cle approximately 40- ~ -
70% maximum(10~9M approx). The tissue is then alternately dosed every
15min with this concentration of 5-HT and then with an approximately
equi-effective concentration of the nicotine receptor stimulant,
20 dimethylphenylpiperazinium (DMPP). Af~cer obtaining consistent
responses to both ~HT and DMPP, increasing concentrations of a putative
5-HT4 re~eptor antagonist are then added to the bathing solution. The
effects of this compound are then determined as a percentage reduction of
the contractions evoked by 5-HT or by DMPP. From this data, pIGso
25 values are determined, being defined as the -log concentration of
antagonist which reduces the contraction by 50%. A compound which
reduces the response to 5-HT but not to DMPP is believed to act as a
5-HT4 receptor antagonist.
30 - Compounds were generally sctive in the range of` concentrations of the
order of pICso=6 or more, E4 and E7 showing particularly good activity.
.
2) Piglet Atria
35 Compounds were tested in the piglet spontaneous beating screen
(Naunyn-Schmiedeberg's Arch. Pharmacol 342, 619-622). pRg
(-log1o Kg) value for the compounds were generally of the order of 6 or
more, E6 and E16 showing particularly good activity.
W O 93/03725 211 6 0 2 'I PC~r/G B92/01519
3) Rat oe~ophagu~
Rat oesophageal tunica muscularis mucosae i~ set up according to Baxter
5 et. al. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439446 (1991).
The inner smooth muscle tube of the muscularis mucosae is isolated and ~:
mounted fior isometric tension recording in o~zygenated (95% 2/5% C2)
Tyrodes solution at 37~C. All e~penments are perfonned in pargyline pre-
treated preparations (lOO~lM for 15 min followed by washout) and in the :-
10 presence of cocaine (30~1M). Relaxant responses to 5-HT are obtained
after pre-contracting the oesophagus tissue ~vith carbachol (3
4) 6-HT-induced motilit~r in dog gastric pouch
15 Compounds are tested for inhibition in the in vivo method described in
"Stimulation of canine motility by BRL 24924, a new gastric prokinetic `~:
agent", Ber nudez et al, J. Gastrointestinal Motility, 1990, 2(4), 281-286.
,)
