Note: Descriptions are shown in the official language in which they were submitted.
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POLYMORPHIC N-[3-[[2-(3,4-DIMETHOXYPHENYL) ETHYL] AMINO] PROPYL] ~-NITRO
BENZAMIDE HY
DROCHLORIDE
This invention relates to a novel pharmaceutical, to a process for the
preparation of the
pharmaceutical and to the use of the pharmaceutical in medicine.
S International Patent Application, Publication Number WO 96/13479 discloses
certain compounds of formula (A):
RZ R,
X- Z- N-A -Ar
R~
4
(A)
or a salt thereof, or a solvate thereof, characterised in that:
Ar represents substituted or unsubstituted aryl, wherein the optional
substituents are
selected from alkyl, hydroxy or alkoxy or, if attached to adjacent carbon
atoms any two
substituents together with the carbon atoms to which they are attached may
form a fused
heterocyclic ring of five to six atoms wherein one, two or three of the said
atoms are
oxygen or nitrogen;
A represents a C1-4 n-alkylene group wherein each carbon is optionally
substituted by 1
or 2 C 1-6 alkyl groups;
R1 represents hydrogen, alkyl, alkenyl or cycloalkyl;
one or two of the group of R2, R3 and R4 represents nitro the remaining
members of the
group of R2, R3 and R4 represent hydrogen;
X represents a -CO-NH- moiety; and
Z represents C2_4 n-alkylene group wherein each carbon is optionally
substituted by 1 or
2 C1-6 alkyl groups.
Example 2 of WO 96/13479 is the hydrochloride salt, N-[3-[[2-(3,4-
dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide hydrochloride
(hereinafter also
referred to as 'the Hydrochloride'), the disclosed melting point of which is
141-2°C.
It has now been discovered that N-[3-[[2-(3,4-
dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide hydrochloride exists in a
novel
polymorphic form which form is particularly suitable for bulk preparation and
handling
and is also indicated to have superior formulation properties. This novel
polymorphic
form can be prepared by an efficient, economic and reproducible process
particularly
suited to large scale preparation.
The novel polymorphic form also has useful pharmaceutical properties and is
considered to be a useful anti-arrhythmic agent having combined Class
III/Class IV anti-
arrhythmic properties, therefore showing an improved pharmacological profile
over pure
class III anti-arrhythmic agents, in particular showing a low proarrhythmic
potential,
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WD 01/27071 CA 02386845 2002-04-08 pCT/GB00/03847
readily restoring the contractile function of the ischaemic myocardium. It is
considered to
be particularly useful for the treatment of atrial or ventricular cardiac
arrhythmias.
Accordingly, the present invention provides a novel polymorphic form of N-[3-
[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide hydrochloride
S (hereinafter also referred to as 'Compound (I)') characterised in that it:
(l) provides a solid state nuclear magnetic resonance spectrum containing
chemical
shifts substantially as represented in Table I; and/or
(ii) provides an X-ray powder refraction (XRPD) pattern substantially as
represented
in Table II; and/or
(iii) provides an infra red spectrum substantially as illustrated in Figure
(I).
The present invention encompasses Compound (I) isolated in a purified form or
in
an impure form, such as when admixed with other materials, for example the
known form
of the Hydrochloride or any other material.
Preferably, Compound (I) is in a purled form, especially a crystalline form.
The invention also provides a process for preparing the novel polymorphic form
of N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide
hydrochloride,
characterised in that N-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-4-
nitrobenzamide hydrochloride is crystallized from acetonitrile and thereafter
the
acetonitrile removed.from the product.
Preferably the acetonitrile is removed by drying, suitably in vacuo.
The crystals are preferably dried at an elevated temperature, for example at
60°C
and over an extended period, usually greater than 12 hours for example 36
hours.
Crystallisation and any recrystallisation is generally carried out at low to
ambient
temperature, suitably at ambient temperature.
Suitably the Hydrochloride is dissolved in acetonitrile at an elevated
temperature,
for example the reflux temperature of the solvent. Conveniently,
crystallisation is
initiated by allowing the solution to cool to ambient temperature.
In a preferred form of the process, Compound (I) is prepared from a solution
of
the Hydrochloride in acetonitrile at an elevated temperature such as
60°C, allowing the
product to crystallise on cooling and thereafter drying the resulting product
in vacuo at
60°C. Purification of Compound (I) is also suitably effected by
recrystallization of
impure Compound (I) using this last mentioned procedure.
The Hydrochloride is prepared according to known procedures such as those
disclosed in WO 96/13479. The disclosures of WO 96/13479 are incorporated
herein by
3 S reference.
As used herein, the term "cardiac arrhythmia" relates to any variation from
the
normal rhythm of heart beat, including, without limitation, sinus arrhythmia,
premature
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WO 01/27071 CA 02386845 2002-04-08 pCT/GB00/03847
heartbeat, heartblock, fibrillation, flutter, tachycardia, paroxysmal
tachycardia and
premature ventricular contractions.
As mentioned above the compound of the invention has useful therapeutic
properties: The present invention accordingly provides Compound (I) for use as
an active
therapeutic substance.
More particularly, the present invention provides Compound (I) for use in the
treatment of and/or prophylaxis of arrhythmia, especially cardiac arrhythmia
such as
ventricular arrhythmia, and also ischaemic rhythm disorders.
Compound (I) may be administered her se or, preferably, as a pharmaceutical
composition also comprising a pharmaceutically acceptable Garner.
Accordingly, the present invention also provides a pharmaceutical composition
comprising Compound (I) and a pharmaceutically acceptable carrier therefor.
Compound (I) is normally administered in unit dosage form.
An amount effective to treat the disorder hereinbefore described depends upon
such factors as the efficacy of a Compound (I) chosen, the nature and severity
of the
disorders being treated and the weight of the mammal. However, a unit dose
will
normally contain 0.1 to 500 mg for example 2 to 50 mg, of the compound of the
invention. Unit doses will normally be administered once or more than once a
day, for
example 2,3,4,5 or 6 times a day, more usually 2 to 4 times a day, such that
the total daily
dose is normally in the range, for a 70 kg adult of 0.1 to 2500 mg, more
usually 1 to 1000
mg, for example 1 to 200 mg, that is in the range of approximately 0.02 to 3
mglkg/day,
more usually 0.1 to 3 mg/kg/day, for example 0.15 to 2 mg/kg/day.
At the above described dosage range, no toxicological effects are indicated
for the
compounds of the invention.
In such treatment, the active compound may be administered by any suitable
route, e.g. by the oral, parenteral or topical routes. For such use, the
compound will
normally be employed in the form of a pharmaceutical composition in
association with a
human or veterinary pharmaceutical carrier, diluent and/or excipient, although
the exact
form of the composition will naturally depend on the mode of administration.
Compositions are prepared by admixture and are suitably adapted for oral,
parenteral or topical administration, and as such may be in the form of
tablets, capsules,
oral liquid preparations, powders, granules, lozenges, pastilles,
reconstitutable powders,
injectable and infusable solutions or suspensions, suppositories and
transdermal devices.
Orally administrable compositions are preferred, in particular shaped oral
compositions,
since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit
dose,
and contain conventional excipients such as binding agents, fillers, diluents,
tabletting
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WO 01/27071 PCT/GB00/03847
agents, lubricants, disintegrants, colourants, flavourings, and wetting
agents. The tablets
may be coated according to well known methods in the art.
Suitable fillers for use include cellulose, mannitol, lactose and other
similar
agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch
derivatives
such as sodium starch glycollate. Suitable lubricants include, for example,
magnesium
stearate. Suitable pharmaceutically acceptable wetting agents include sodium
lauryl
sulphate.
Solid oral compositions may be prepared by conventional methods of blending,
filling, tabletting or the like. Repeated blending operations may be used to
distribute the
active agent throughout those compositions employing large quantities of
fillers. Such
operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily
suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as
a dry product
for reconstitution with water or other suitable vehicle before use. Such
liquid
preparations may contain conventional additives such as suspending agents, for
example
sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
carboxymethyl cellulose,
aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for
example
lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may
include edible
oils), for example, almond oil, fractionated coconut oil, oily esters such as
esters of
glycerine, propylene glycol, or ethyl alcohol; preservatives, for example
methyl or propyl
p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or
colouring
agents.
For parenteral administration, fluid 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 suspended or dissolved.
Parenteral
solutions are normally prepared by dissolving the active compound in a vehicle
and filter
sterilising before filling into a suitable vial or ampoule and sealing.
Advantageously,
adjuvants such as a local anaesthetic, preservatives and buffering agents are
also
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 active compound is suspended in the vehicle instead of being dissolved and
sterilised
by exposure to ethylene oxide before suspending in the sterile vehicle.
Advantageously, a
surfactant or wetting agent is included in the composition to facilitate
uniform
distribution of the active compound.
For topical administration, the composition may be in the form of a
transdermal
ointment or patch for systemic delivery of the compound and may be prepared in
a
conventional manner, for example, as described in the standard textbooks such
as
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'Dermatological Formulations' - B.W. Barry (Drugs and the Pharmaceutical
Sciences -
Dekker) or Harrys Cosmeticology (Leonard Hill Books).
In addition such compositions may contain further active agents such as
anti-hypertensive agents and diuretics.
As is common practice, the compositions will usually be accompanied by written
or printed directions for use in the medical treatment concerned.
As used herein the term 'pharmaceutically acceptable' embraces compounds,
compositions and ingredients for both human and veterinary use: for example
the term
'pharmaceutically acceptable salt' embraces a veterinarily acceptable salt.
The present invention further provides a method for the treatment and/or
prophylaxis of arrhythmia, especially cardiac arrhythmia such as ventricular
arrhythmia,
and also ischaemic rhythm disorders in a human or non-human mammal which
comprises
administering an effective, non-toxic, amount of Compound (I) to a human or
non-human
mammal in need thereof.
Conveniently, the active ingredient may be administered as a pharmaceutical
composition hereinbefore defined, and this forms a particular aspect of the
present
invention.
In the treatment and/or prophylaxis of arrhythmia and/or ischaemic arrhythmia
disorders Compound (I) may be taken in doses, such as those described above.
Similar dosage regimens are suitable for the treatment and/or prophylaxis of
non-human mammals.
In a further aspect the present invention provides the use of Compound (I) for
the
manufacture of a medicament for the treatment of arrhythmia, especially
cardiac
arrhythmia such as ventricular arrhythmia, and also ischaemic rhythm
disorders.
No adverse toxicological effects are indicated when Compound (I) is
administered
in the above mentioned dosage ranges.
The following Examples illustrate the invention but do not limit it in any
way.
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WO 01/27071 CA 02386845 2002-04-08 pCT/GB00/03847
Example 1
Preparation of a novel polymorphic form N-[3-[[2-(3,4-
dimethoxyphenyl)ethyl]amino]propyl]-4-nitrobenzamide, hydrochloride
(Compound (I))
The Hydrochloride was prepared as disclosed in Example 2 of WO 96/13479.
173g of crude Hydrochloride was dissolved at reflux in 1.3 liter of
acetonitrile.
The solution was then allowed to cool to room temperature over two hours
during which
time crystallisation occurred. The resulting crystals were filtered off,
washed with
acetonitrile (1L), dried under vacuum (0.5 Torr) at 60°C for 12 hours
and then for a
further period of 24 hours under the same conditions (0.5 Torr, 60°C)
to afford 125.6 g of
Compound (I) m.p. 156°C displaying by HPLC a main peak of 99.8% with
the main
impurity < 0.1%. Total yield (synthesis + purification) 59.9%.
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SPECTROSCOPIC DATA
(A) Solid State NMR
The 90.SSMHz 13C CP-MAS NMR spectrum chemical shifts are tabulated in
Table I. Data were recorded at ambient temperature and 10 kHz spinning
frequency, on a Bruker AMX360WB spectrometer.
Table I
C13 Chemical shifts (ppm)
28.8 33.4 36.0 49.1 54.6 57.6 107.2 112.7 120.5
126.3 127.9 131.7 137.3 146.8 148.9 164.5
(B) X-Ray Powder Diffraction (XRPD)
A summary of the XRPD angles characteristic of the Compound (I ) is given in
Table II.
A PW1710 X-ray powder diffractometer (Cu X-ray source) was used to generate
the spectrum using the following acquisition conditions:
Tube anode: Cu
Generator tension: 40 kV
Generator current: 30 mA
Start angle: 3.5 °2A
End angle: 35.0 °20
Step size: 0.005 °20
Time per step: 0.25 s
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WO 01/27071 CA 02386845 2002-04-08 pCT/GB00/03847
Table II
XRPD Diffraction Angles
Diffraction Angle
(°28)
8.7
14.4
18.0
20.7
22.2
22.7
23.9
24.3
24.9
26.6
28.1
29.2
30.8
31.4
32.0
34.0
_g_
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(C) Infra Red spectrum
The infrared absorption spectrum of a mineral oil dispersion of Compound (I)
was
obtained using a Perkin-Elmer PE2000 spectrometer at 2 cm-1 resolution.
Figure (I)
s~.o
so
~o
so
%T 40
20
0.0
4000.0 3000 2000 1500 1000 450.0
cm-1
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