Note: Descriptions are shown in the official language in which they were submitted.
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REDUCED PARTICLE SIZE FORM OF 1-(6-CHLORONAPHTH-2- YLSULPHONYL) -~[4-
(4PYRIDYL) BENZOYL]
PIPERAZINE
The invention relates to pharmaceutically-acceptable salts of 1-(6-
chloronaphth-
2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine and reduced particle sized
forms of either
the compound or a pharmaceutically-acceptable salt thereof; which possess
antithrombotic
and anticoagulant properties and accordingly are useful in methods of
treatment of humans or
animals. The invention also relates to processes for the preparation of
pharmaceutically-
acceptable salts of the above compound and reduced particle size forms
thereof, to
pharmaceutical compositions containing them and to their use in the
manufacture of
medicaments for use in the production of an antithrombotic or anticoagulant
effect in humans.
The antithrombotic and anticoagulant effect produced by the compounds of the
invention is believed to be attributable to their strong inhibitory effect
against the activated
coagulation protease known as Factor Xa. Factor Xa is one of a cascade of
proteases involved
in the complex process of blood coagulation. The protease known as thrombin is
the final
protease in the cascade and Factor Xa is the preceding protease which cleaves
prothrombin to
generate thrombin.
Certain compounds are known to possess Factor x:a inhibitory properties and
the
field has been reviewed by R.B. Wallis, Current Opinion in Therapeutic
Patents, 1993, I 173-
1179. Thus it is known that two proteins, one known as antistatin and the
other known as tick
anticoagulant protein (TAP), are specific Factor Xa inhibitors which possess
antithrombotic
properties in various animal models of thrombotic disease.
It is also known that certain non-peptidic compounds possess Factor Xa
inhibitory
properties. Of the low molecular weight inhibitors mentioned in the review by
R.B. Wallis,
all possessed a strongly basic group such as an amidinophenyl or
amidinonaphthyl group.
We have now found that 1-(6-chloronaphth-2-ylsulphonyl)-4-
[4-(4-pyridyl)benzoyl]piperazine (hereinafter referred to as (:ompound 1 )
possesses Factor Xa
inhibitory activity at concentrations which do not inhibit, or which inhibit
to a lesser extent,
the enzyme thrombin which is also a member of the blood coagulation enzymatic
cascade.
The trifluoroacetic acid addition salt of Compound 1 is disclosed as Example 7
of
PCT Application No. GB97/03033.
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Compound 1 possesses activity in the treatment or prevention of a variety of
medical
disorders where anticoagulant therapy is indicated, for example in the
treatment or prevention
of thrombotic conditions such as coronary artery and cerebro-vascular disease.
Further
examples of such medical disorders include various cardiovascular and
cerebrovascular
conditions such as myocardial infarction, the formation of atherosclerotic
plaques, venous or
arterial thrombosis, coagulation syndromes, vascular injury (including
reocclusion and
restenosis following angioplasty and coronary artery bypass surgery, thrombus
formation after
the application of blood vessel operative techniques or after general surgery
such as hip
replacement surgery, the introduction of artificial heart valves or on the
recirculation of
blood), cerebral infarction, cerebral thrombosis, stroke, cerebral embolism,
pulmonary
embolism, ischaemia and angina (including unstable angina).
Compound I is also useful as an inhibitor of blood coagulation in an ex-vivo
situation such as, for example, the storage of whole blood or other biological
samples
suspected to contain Factor Xa and in which coagulation is detrimental.
We have found that Compound 1, i.e. the free base, has limited aqueous
solubility
and limited bioavailabilty when dosed orally. We have investigated
pharmaceutically-
acceptable salts of Compound 1 and also solid forms of both Compound 1 and
pharmaceutically-acceptable salts of Compound 1 with reduced particle size to
try to improve
upon the physical properties of Compound 1.
Our investigations have shown that pharmaceutically-acceptable salts of
Compound
l and reduced particle sized forms of Compound 1, and pharmaceutically-
acceptable salts
thereof, show improved physical properties. In particular the pharmaceutically-
acceptable
salts of Compound 1 showed improved physical properties such as aqueous
solubility and oral
bioavailabilty. In particular the reduced particle size form of a
pharmaceutically-acceptable
salt of Compound 1 showed an improved aqueous dissolution rate, oral
bioavailabilty, and
reduction in the variability in oral bioavailabilty when compared to Compound
1.
Accordingly provided in the present invention is:
(a) a reduced particle size form of a pharmaceutically-acceptable salt or a
solvate
thereof of Compound 1;
(b) a reduced particle size form of Compound 1 or a solvate thereof; and
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(c) a pharmaceutically-acceptable salt of Compound 1 or a solvate thereof.
As used hereinafter the term "a Compound of the invention" refers to either
one of
features (a), (b) or (c) described above.
By the use of the term "reduced particle size" we refer to solid Compound l,
or a
pharmaceutically-acceptable salt thereof, or a solvate of either thereof,
reduced by suitable
processing techniques to a solid of smaller particle size and, consequently,
greater surface
area. Any number of processing techniques known in the pharmaceutical field
may be used to
reduce solid particle size, such as grinding, milling and micronising,
reference should be made
to Remington: The Science and Practise of Pharmacy, 19'" F?d., pages 1598-
1602, for a more
exhaustive review.
The range of particle sizes preferred in this invention start from, in
increasing
preference, moderately fine powder, fine powder, very fine powder, microfine
powder to,
most preferably, superfine powder.
The above references to particle sizes are taken from the British
Pharmacopoeia 1993,
Volume II, Appendix XVII B, A193, and are reproduced below for reference.
Moderately fine powder
A powder all the particles of which pass through a sieve with a nominal mesh
aperture of
355~m and not more than 40.0% by weight pass through a sieve with a nominal
mesh
aperture of 250p.m.
Fine powder
A powder all the particles of which pass through a sieve with a nominal mesh
aperture of
180~m and not more than 40.0% by weight pass through a sieve with a nominal
mesh
aperture of 125~m.
Very fine powder
A powder all the particles of which pass through a sieve with a nominal mesh
aperture of
125~m and not more than 40.0% by weight pass through a sieve with a nominal
mesh
aperture of 45p,m.
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Microfine powder
A powder of which not less than 90% by weight of the particles pass through a
sieve with a
nominal mesh aperture of 45~m.
Superfin~owder
A powder of which not less than 90% by weight of the particles pass through a
sieve with a
nominal mesh aperture of l Op,m.
The particular sieves to be used in determining the particle size are
described in British
Pharmacopoeia 1993 Volume II, Appendix XVIIB, A193-A194, which part is
incorporated
herein by reference.
Pharmaceutically-acceptable salts may be formed by reacting the basic moiety
of
Compound 1 with any one of a number of pharmaceutically-acceptable organic or
inorganic
acids and precipitating the salt from solution. A preferred pharmaceutically-
acceptable salt of
Compound 1 is the hydrochloride salt. In a more preferred from the chloride
salt of
Compound 1 is solvated, preferably hydrated, and in particular the hemihydrate
form is
preferred.
A feature of the invention is a Compound of the invention, as described above,
for
use in medical therapy.
According to a further feature of the invention there is provided a
pharmaceutical
composition which comprises a Compound of the invention, as described above,
in
association with a pharmaceutically-acceptable diluent or carrier.
The composition may be in a form suitable for oral use, for example a tablet,
capsule, aqueous or oily solution, suspension or emulsion; for topical use,
for example a
cream, ointment, gel or aqueous or oily solution or suspension; for nasal use,
for example a
snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a
suppository; for
administration by inhalation, for example as a finely divided powder such as a
dry powder, a
microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for
example a tablet
or capsule; or for parenteral use (including intravenous, subcutaneous,
intramuscular,
intravascular or infusion), for example a sterile aqueous or oily solution or
suspension. In
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general the above compositions may be prepared in a conventional manner using
conventional excipients.
The amount of a Compound of the invention, as described above that is combined
with one or more excipients to produce a single dosage form will necessarily
vary depending
upon the host treated and the particular route of administration. For example,
a formulation
intended for oral administration to humans will generally contain, for
example, from 0.5 mg
to 2 g of active agent compounded with an appropriate and convenient amount of
excipient(s) which may vary from about S to about 98 percent by weight of the
total
composition. Dosage unit forms will generally contain about 1 mg to about 500
mg of an
active ingredient.
The invention also includes the use of a Compound of the invention, as
described
above in the production of a medicament for use in:-
(i) producing a Factor Xa inhibitory effect;
(ii) producing an anticoagulant effect;
(iii) producing an antithrombotic effect;
(iv) treating a Factor Xa mediated disease or medical condition;
(v} treating a thrombosis mediated disease or medical condition;
(vi) treating coagulation disorders; and/or
(vii) treating thrombosis or embolism involving Factor Xa mediated
coagulation.
The invention also includes a method of producing an effect as defined
hereinbefore or treating a disease or disorder as defined hereinbefore which
comprises
administering to a warm-blooded animal requiring such treatment an effective
amount of
form of a Compound of the invention, as described above.
The size of the dose for therapeutic or prophylactic purposes of a form of a
Compound of the invention, as described above, will naturally vary according
to the nature
and severity of the medical condition, the age and sex of the animal or
patient being treated
and the route of administration, according to well known principles of
medicine. In using a
Compound of the invention it will generally be administered so that a daily
oral dose in the
range, for example, 0.1 to 50 mg/kg body weight/day is received, given if
required in divided
doses. In general lower doses will be administered when a parenteral route is
employed, for
example a dose for intravenous administration in the range, for example, 0.01
to 10 mg/kg
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body weight/day will generally be used. Preferred oral daily doses include,
for example, 0.1
to 10 mg/kg body weight/day. In general a preferred dose range for either oral
or parenteral
administration would be 0.01 to 10 mg/kg body weight/day.
Compound 1 may conveniently be prepared by reacting
(4-pyridyl)benzoic acid, or a reactive derivative thereof, for example the
acylchloride
derivative, with 1-(6-chloronaphth-2-ylsulphonyl)piperazine, or a salt
thereof, for example,
the hydrochloride salt. The reaction is conveniently carried out in the
presence of a suitable
base such as, for example, an alkali or alkaline earth metal carbonate,
aIkoxide, hydroxide or
hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide,
potassium
butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium
hydride, or
an organometallic base such as an alkyl-lithium, for example n-butyl-lithium,
or a
dialkylamino-lithium, for example lithium di-isopropylamide, or, for example,
an organic
amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-
dimethylaminopyridine,
triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene. The reaction is
also preferably
1 S carried out in a suitable inert solvent or diluent, for example methylene
chloride, chloroform,
carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, N,N-
dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide or
acetone, and at a
temperature in the range, for example, -78° to 150°C,
conveniently at or near ambient
temperature.
Processes for the preparation of the two intermediates above, as well as for
Compound 1, may be found in PCT application number PC'T/GB97/03033.
Compound 1 or a Compound of the invention may be administered as a sole
therapy or they may be administered in conjunction with other
pharmacologically active
agents such as a thrombolytic agent, for example tissue plasminogen activator
or derivatives
thereof or streptokinase. The compounds of the invention may also be
administered with, for
example, a known platelet aggregation inhibitor (for example aspirin, a
thromboxane
antagonist or a thromboxane synthase inhibitor), a known hypolipidaemic agent
or a known
anti-hypertensive agent.
The dissolution rates of material were tested in analagous methods as
described in the
Britsih Pharmacopoeia 1998 Appendix XIID A189-A191.
The invention will now be illustrated in the following Examples.
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Example 1
Preparation of 1-(6-chloronaphth-2-ylsulphon~)-4-14-I(4 p
ridyl)benzoyllpinerazine
hydrochloride from free base:
Free base 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine
(54.8g) was dissolved in dichloromethane (800m1) and a solution of HCl in
ethyl acetate ( 50
ml of 3.1 M, 1.1 eq.) was added with stirring; the mixture was stirred for
lhour, giving a
copious precipitate. The solvent was removed in vacuo and the resulting
colourless solid dried
under a high vacuum. To the solid was added hot methanol (2.51), the
suspension was brought
to reflux (complete solution at this stage), filtered, and the volume then
reduced on a steam
bath until crystallisation started to occur; the solution was removed from the
steam bath and
allowed to crystallise to give 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-
pyridyl)benzoyl]piperazine as the hydrochloride salt hemihydrate, 46.6g as a
colourless
crystalline solid.
M.p. 250°C
'H NMR(d6-DMSO): 2.9 - 3.2 (broad s, 4H), 3.3 - 3.8 (broad s, 4H), 7.4 (d,
2H), 7.7 (m, 3H),
7.8 (m, 3 H), 8.2 (d, 1 H), 8.3 (m, 2H), 8.5 (s, 1 H), 8.7 (d, 2H)
Microanalysis, found: C, 57.9; H, 4.5; N, 7.7; S, 6.2; Cl, 13..0 %;
C26H23N303C1S. 1.0 HCI.
0.5 H20 requires: C, 58.0; H, 4.7; N, 7.8; S, 6.0; Cl, 13.2
Mass spectrum (+ ive ESP) m/z 492/494 (M+H+).
Example 2
Preparation of Reduced Particle Size Form of Example 1
The hemihydrate hydrochloride salt of compound 1 (Example 1 ) was fed at a
controlled
rate into a fluid energy mill (microniser), in which the salt was subjected to
self attrition
caused by high energy streams of gas. The particles produced were continuously
classified,
with the fines collected via a filter.
The solid produced was measured as "Superfine Powder" (Reference: British
Pharmacopoeia
1993 Vo.2 Appendix A193).
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_g_
Example 3
Illustrative pharmaceutical dosage forms suitable for presenting a Compound of
the
invention for therapeutic or prophylactic use include the following tablet and
capsule
formulations, which may be obtained by conventional procedures well known in
the art of
pharmacy and are suitable for therapeutic use in humans:
(a) Tablet I
m /tablet
Compound Z* 1.0
Lactose Ph. Eur. 93.25
Croscarmellose sodium 4.0
Maize starch paste (5% w/v aqueous 0.75
paste)
Magnesium Stearate 1.0
(b) Tablet II m /tablet
1 S Compound Z* SO
Lactose Ph. Eur 223.75
Croscarmellose sodium 6.0
Maize starch 15.0
Polyvinylpyrrolidone (5% w/v aqueous 2.25
paste)
Magnesium stearate 3.0
(c) Tablet III m /tg ablet
Compound Z* 100
Lactose Ph. Eur. 182.75
Croscarmellose sodium 12.0
Maize starch paste (5% w/v aqueous paste) 2.25
Magnesium stearate 3.0
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(d) Capsule
m~apsule
Compound Z* 10
Lactose Ph. Eur. 488.5
Magnesium stearate 1.5
Note
* The active ingredient Compound Z is a Compound of the invention, as
described above.
The tablet compositions (a) - (c) may be enteric coated by conventional means,
for example,
with cellulose acetate phthalate.
15
25
