Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL COMPOUNDS
This invention relates to compounds having pharmacological activity,
processes for their preparation, to compositions containing them and to their
use in the
S treatment of CNS disorders.
EPA 0 021 580 and EPA 0 076 072 describe sulphonamide derivatives which
are disclosed as having antiarrhythmic activity. A structurally distinct class
of
compounds has now been discovered, which have been found to have SHT6 receptor
antagonist activity. SHT6 receptor antagonists are believed to be of potential
use in
the treatment of certain CNS disorders such as anxiety, depression, epilepsy,
obsessive compulsive disorders, migraine, Alzheimers disease (enhancement of
cognitive memory), sleep disorders, feeding disorders such as anorexia and
bulimia,
panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine
and
benzodiazepines, schizophrenia) and also disorders associated with spinal
trauma
and/or head injury such as hydrocephalus. Compounds of the invention are also
expected to be of use in the treatment of certain GI (gastrointestinal)
disorders such as
IBS (Irritable Bowel Syndrome).
The present invention therefore provides, in a first aspect, a compound of
formula (I) or a salt thereof:
O RZ _ R4
C
~R~~ ~n
Rs Re
(I)
wherein:
P is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered
heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen,
nitrogen
or sulphur;
A is a single bond, a C 1 _6alkylene or a C 1 _6alkenylene group;
R 1 is halogen, C 1 _6alkyl optionally substituted by one or more halogen
atoms,
C3_6cycloalkyl, COC 1 _6alkyl, C 1 _6alkoxy, OCF3, hydroxy, hydroxyC 1
_6alkyl,
hydroxyC 1 _6alkoxy, C 1 _6alkoxyC 1 _6alkoxy, C 1 _6alkanoyl, nitro, amino, C
1 _
6alkylamino or diC 1 _6alkylamino, cyano or R 1 is phenyl, naphthyl, a
bicyclic
heterocyclic ring or is a S to 7-membered heterocyclic ring each containing 1
to 4
heteroatoms selected from oxygen, nitrogen or sulphur;
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n is 0, 1, 2, 3, 4, 5 or b:
R2 is C 1 _6 alkyl or aryl C 1 _6 alkyl;
R3 is a group RS or together with RS forms a group (CH2)20 or (CH2)30 or R3 is
linked to R2 to form a group (CH2)2 or (CH2)3;
S R4 is -X(CH2)p-R6 where X is a single bond, CH2, O, NH or N-C 1 _6alkyl and
p is 0
to 6 and R6 is an optionally substituted S- to 7-membered heterocyclic ring
containing
1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R6 is NR~R8
where
R~ and R8 are independently hydrogen, C 1 _6 alkyl or aryl C 1 _6 alkyl; and
RS is hydrogen, halogen, C 1 _6alkyl, C3_6cycloalkyl, COC 1 _6alkyl, C 1
_6alkoxy,
hydroxy, hydroxyC 1 _6alkyl, hydroxyC 1 _6alkoxy, C 1 _6alkoxyC 1 _6alkoxy, C
1 _
6alkanoyl, nitro, trifluoromethyl, cyano or aryl.
C 1-6 Alkyl groups, whether alone or as part of another group, may be straight
chain or branched. As used herein the term aryl includes phenyl and naphthyl.
When P is a bicyclic heterocyclic ring suitable examples include
I S benzothiophene, quinoline or isoquinoline. Suitable S to 7-membered
heterocyclic
rings include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl,
oxazolyl,
thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl,
pyrimidyl,
pyrrolidinyl and pyrazinyl. The heterocyclic rings can be linked to the
remainder of
the molecule via any suitable carbon atom or, when present, a nitrogen atom.
Suitable
substituents for these rings include RS groups as defined above.
Preferably P is phenyl, thiophene, benzothiophene or naphthyl.
Preferably A is a single bond, an ethyl or -CH=CH- group. Most preferably A
is a single bond.
When RI is a S-7 membered heterocyclic or bicyclic hetcrocyclic ring suitable
2S examples include those given within the description of group P. Preferably
RI is
halogen or C 1 _4 alkyl optionally substituted by one or more halogens, for
example
methyl or CF3.
Preferably n is 0, 1, 2 or 3, particularly 1 or 2.
Preferably R2 is C 1 _6 alkyl, in particular methyl or ethyl.
Suitably R3 is a group RS or together with RS forms a group (CH2)20 or
(CH2)30 or R3 is linked to R2 to form a group (CH2)2 or (CH2)3. It will be
appreciated that when R3/RS groups are linked together the two groups must be
attached to adjacent carbon atoms of the phenyl ring. Preferably R3 is a group
RS in
particular hydrogen.
3S Preferably R4 is meta with respect to the carboxamide linkage. Preferably X
is a bond, p is 0 and R6 is an optionally substituted S- to 7-membered
heterocyclic
ring. The heterocyclic rings can be linked to the remainder of the molecule
via a
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carbon atom or, when present, a nitrogen atom. Optional substituents for these
rings,
which can be present on carbon and/or nitrogen atoms, include
C1-6alkyl, in particular methyl. More preferably R4 is an optionally
substituted
piperazine. Most preferably R4 is N-methylpiperazine or piperazine.
Preferably RS is C1-6alkoxy, most preferably methoxy. Preferably RS is para
with respect to the amide group.
Particular compounds of the invention include:
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-N-methyl-4-phenylbenzamide,
4-Bromo-N-ethyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-
methylbenzamide,
4-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-N-
propylbenzamide,
4-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3,N-d imethylbenzamide,
Naphthalene-2-carboxylic acid N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)-N
methyl amide,
3-Chlorobenzo[b]thiophene-2-carboxylic acid-N-[4-methoxy-3-(4-methylpiperazin-
1-
yl)phenyl]-N-methyl amide,
3-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-N-methylbenzamide,
3,4-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)-N-methylbenzamide,
3-Bromothiophene-2-carboxylic acid-N-[4-methoxy-3-(4-methylpiperazin-1-
yl)phenyl]-N-methyl amide,
4-tert Butyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)-N-methylbenzamide,
4-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-N-methylbenzamide,
3,4-Dichloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-N-methylbenzamide,
3-Chlorobenzo[b]thiophene-2-carboxylic acid N-(4-methoxy-3-piperazin-1-
ylphenyl)-
N-methyl amide
and pharmaceutically acceptable salts thereof.
The compounds of the formula (I) can form acid addition salts with acids, such
as conventional pharmaceutically acceptable acids, for example malefic,
hydrochloric,
hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic,
tartaric
and methanesulphonic.
Compounds of formula (I) may also form solvates such as hydrates, and the
invention also extends to these forms. When referred to herein, it is
understood that
the term 'compound of formula (I)' also includes these forms.
Certain compounds of formula (I) are capable of existing in stereoisomeric
forms including diastereomers and enantiomers and the invention extends to
each of
these stereoisomeric forms and to mixtures thereof including racemates. The
different
stereoisomeric forms may be separated one from the other by the usual methods,
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any given isomer may be obtained by stereospecific or asymmetric synthesis.
The
invention also extends to any tautomeric forms and mixtures thereof.
The present invention also provides a process for the preparation of a
compound of formula (I) or a pharmaceutically acceptable salt thereof, which
process
comprises the coupling of a compound of formula (II):
~A-COL
~R~ ~ ~n
(II)
in which R1, n, P, and A are as defined in formula (I) or protected
derivatives thereof
and L is a leaving group with a compound of formula (III):
R2 Ra
I -
N
H
R3 Rs
(nI)
in which R2, R3, R4 and RS are as defined in formula (I) or protected
derivatives
thereof and optionally thereafter:
~ removing any protecting groups,
~ forming a pharmaceutically acceptable salt.
Suitable leaving groups include halogen, in particular chloro. The reaction of
a compounds of formulae (II) and (III) is carried out by mixing the two
reagents
together, optionally in an inert solvent such as dichloromethane.
Those skilled in the art will appreciate that it may be necesary to protect
certain groups. Suitable protecting groups and methods for their attachment
and
removal are conventional in the art of organic chemistry, such as those
described in
Greene T. W. 'Protective groups in organic synthesis' New York, Wiley ( 1981
).
Compounds of formulae (II) and (III) are commercially available or may be
prepared according to known methods or analogous to known methods.
Pharmaceutically acceptable salts may be prepared conventionally by
reaction with the appropriate acid or acid derivative.
Compounds of formula (I) and their pharmaceutically acceptable salts have
SHT6 receptor antagonists are believed to be of potential use in the treatment
of
certain CNS disorders such as anxiety, depression, epilepsy, obsessive
compulsive
disorders, migraine, Alzheimers disease and enhancement of cognitive memory,
sleep
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disorders (including disturbances of Circadian Rhythym), feeding disorders
such as
anorexia and bulimia, panic attacks, withdrawal from drug abuse such as
cocaine,
ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders
associated
with spinal trauma and/or head injury such as hydrocephalus. Compounds of the
invention are also expected to be of use in the treatment of certain GI
disorders such
as IBS
Thus the invention also provides a compound of formula (I) or a
pharmaceutically acceptable salt thereof, for use as a therapeutic substance,
in
particular in the treatment or prophylaxis of the above disorders.
The invention further provides a method of treatment or prophylaxis of the
above disorders, in mammals including humans, which comprises administering to
the
sufferer a therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
In another aspect, the invention provides the use of a compound of formula
(I} or a pharmaceutically acceptable salt thereof in the manufacture of a
medicament
for the treatment or prophylaxis of the above disorders.
The present invention also provides a pharmaceutical composition, which
comprises a compound of formula (I) or a pharmaceutically acceptable salt
thereof,
and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by
admixture, suitably at ambient temperature and atmospheric pressure, is
usually
adapted for oral, parenteral or rectal administration and, as such, may be in
the form
of tablets, capsules, oral liquid preparations, powders, granules, lozenges,
reconstitutable powders, injectable or infusable solutions or suspensions or
suppositories. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and
may contain conventional excipients, such as binding agents, fillers,
tabletting
lubricants, disintegrants and acceptable wetting agents. The tablets may be
coated
according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily
suspension, solutions, emulsions, syrups or elixirs, or may be in the form of
a dry
product for reconstitution with water or other suitable vehicle before use.
Such liquid
preparations may contain conventional additives such as suspending agents,
emulsifying agents, non-aqueous vehicles (which may include edible oils),
preservatives, and, if desired, conventional flavourings or colourants.
For parenteral administration, fluid unit dosage forms are prepared utilising
a
compound of the invention or pharmaceutically acceptable salt thereof and a
sterile
vehicle. The compound, depending on the vehicle and concentration used, can be
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either suspended or dissolved in the vehicle. In preparing solutions, the
compound
can be dissolved for injection and filter sterilised before filling into a
suitable vial or
ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic,
preservatives and buffering agents are dissolved in the vehicle. To enhance
the
stability, the composition can be frozen after filling into the vial and the
water
removed under vacuum. Parenteral suspensions are prepared in substantially the
same
manner, except that the compound is suspended in the vehicle instead of being
dissolved, and sterilization cannot be accomplished by filtration. The
compound can
be sterilised by exposure to ethylene oxide before suspension in a sterile
vehicle.
Advantageously, a surfactant or wetting agent is included in the composition
to
facilitate uniform distribution of the compound.
The composition may contain from 0.1 % to 99% by weight, preferably from
10 to 60% by weight, of the active material, depending on the method of
administration.
The dose of the compound used in the treatment of the aforementioned
disorders will vary in the usual way with the seriousness of the disorders,
the weight
of the sufferer, and other similar factors. However, as a general guide
suitable unit
doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2
to 5
mg; and such unit doses may be administered more than once a day, for example
two
or three a day, so that the total daily dosage is in the range of about 0.5 to
100 mg; and
such therapy may extend for a number of weeks or months.
When administered in accordance with the invention, no unacceptable
toxicological effects are expected with the compounds of the invention.
The following Examples illustrate the preparation of compounds of the
invention.
Example 1
N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-N-methyl-4-phenylbenzamide
A solution of biphenyl-4-carboxylic acid chloride in acetone (2ml) was added
to a
solution of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-N-methylamine (1
equivalent) in acetone and the mixture stood overnight at room temperature.
The
resultant crystalline solid was filtered off and washed with acetone, then
diethyl ether,
to afford the title compound as the hydrochloride salt. MS: m/z = 416 (MH+).
The following compounds were prepared in a similar manner from an N-alkyl-N-[4-
methoxy-3-(4-methylpiperazin-1-yl)phenyl]amine and the appropriate carboxylic
acid
chloride:
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MS (MH+)
4-Bromo-N-ethyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-446/448
methylbenzamide (E2)
4-Bromo-N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-460/462
N-propylbenzamide (E3)
4-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3,N-432/434
dimethylbenzamide (E4)
Naphthalene-2-carboxylic acid N-[4-methoxy-3-(4-methylpiperazin-1-390
yl)phenyl]-N-methyl amide (ES)
3-Chlorobenzo[b]thiophene-2-carboxylic acid N-[4-methoxy-3-(4-430/432
methylpiperazin-1-yl)phenyl]-N-methyl amide (E6)
3-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-N-418/420
methylbenzamide (E7)
3,4-Dichloro-N-[4-methoxy-3-{4-methylpiperazin-1-yl)phenyl]-N-408/410
methylbenzamide (E8)
3-Bromothiophene-2-carboxylic acid N-[4-methoxy-3-(4-424/426
methylpiperazin-1-yl)phenyl]-N-methyl amide (E9)
4-tert Butyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-N-396
methylbenzamide (E10)
4-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-N-418/420
methylbenzamide (E11)
Example 12
3,4-Dichloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-N-methylbenzamide (E12)
S A solution of 1-chloroethylchloroformate (1.12mmol), 3,4-dichloro-N-[4-
methoxy-3-
(4-methylpiperazin-1-yl)phenyl]-N-methylbenzamide (E8) (0.22mmol) and
diisopropylethylamine (1.14mmo1) in 1,2-dichloroethane (2m1) was refluxed for
12h.
The solution was concentrated to a residue which was re-dissolved in methanol
and
refluxed for 6h. The mixture was concentrated, and the residue partitioned
between
dichloromethane and aqueous sodium bicarbonate solution. The organic layer was
dried, concentrated to a residue and purified by column chromatography on
silica gel
using a methanol/dichloromethane solvent gradient. The hydrochloride salt of
the
title compound (E12) was prepared by dissolving the pure material from
chromatography in acetone/dichloromethane and acidifying with ethereal HC1.
MH+ 393/395/397.
Example 13
3-Chlorobenzo[b[thiophene-2-carboxylic acid N-(4-methoxy-3-piperazin-1-
ylphenyl)-N-methyl amide (E13)
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The title compound was prepared from 3-chlorobenzo[b]thiophene-2-carboxylic
acid
[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]methyl amide (E6) according to the
method described for Example 12. MH+ 415/417.
Method for assay of 5-HT6 antagonistic activity:
The test compounds were dissolved in polyethylene glycol:dimethyl sulphoxide (
1:1 )
at 1 or IOmM and diluted to O.lmM using SmM tris buffer (pH 7.7 @
25°C).
Dissolution was assisted by addition of 0.02m1 SM HCl plus heating to
40°C and
sonication for 10 minutes. Serial dilutions of drugs in the same buffer were
carried
out using either a TECAN 5052 or Biomek 2000 Workstation. Samples of the
diluted
test compounds (O.OSmI) were mixed with O.OSml of radio-ligand [3H]-LSD
prepared
in the incubation buffer, and 0.4m1 of a suspension of a preparation of the
washed
membranes of HeLa_SHT6 cells {acquired from Dr. D. Sibley, NIH, Bethesda, see
Ref 1 )(see Table 1 ), also in the incubation buffer. The details of the
incubation
conditions for each assay are shown in Table 2. The incubation buffer was SOmM
Trizma (Sigma, UK) pH7.7 @ 25°C, 4mM MgCl2.
After incubation at 37°C, the mixtures were filtered using a Packard
Fiitermate in
Packard TopCount format. Filters were washed with 4 x Iml aliquots of ice-cold
incubation buffer. Filters were dried and impregnated with 0.04m1 of
Microscint 20
(Packard). IC50 values were estimated from the counts per minute using a four
parameter logistic curve fit within EXCEL (2). Ki values were calculated using
the
method of Cheng and Prusoff (3). pICSp and pKi are the negative 1og10 of the
molar
ICSO and Ki respectively.
Table 1 Details of the methods used to prepare membranes for binding assays
1st spin / resuspensionIncubation protein conc.cells /ml
1, 2 ,3 in in stored
resuspension before finalstored aliquotsaliquots
cells/ml spin
7 x 10 Yes 20min at 4mg/ml ~ 1.0 x
37C 10~
Table 2 Summary of receptor binding assay conditions
proteinradio-ligand Specific Non-SpecificKd (nM)
[vH]-LSD Activity
(ug/ (nM) (Ci/mmol) Definition
sample)
40 2.0 83 Methiothepin3.1
References
1. MONSMA, F.J., SHEN, Y., WARD, R.P., HAMBLIN, M.W., SIBLEY, D.R..
1993. Cloning and expression of a novel serotonin receptor with high affinity
for
tricyclic psychotropic drugs. Mol. Pharmacol., 43, 320-327.
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WO 98/27058 PCT/EP97107160
2. BOWEN, W.P., JERMAN, J.C.. 1995. Nonlinear regression using spreadsheets.
Trends in Pharmacol. Sci., 16, 413-417.
3. CHENG, Y.C., PRUSSOF, W.H.. 1973. Relationship between inhibition constant
(Ki) and the concentration of inhibitor which causes 50% inhibition (IC50) of
an
enzymatic reaction. Biochem. Pharmacol., 92, 881-894.
The compounds of Examples all showed good selective 5-HT6 receptor antagonist
activity, having pKi values above 7.0 at human cloned 5-HT6 receptors.
9
