Note: Descriptions are shown in the official language in which they were submitted.
-- 1 --
P~IARHACE:UTICAL AGI~NT
Technical Field
The present invention relates to a new pharmaceutical agent
and, more particularly, to a new physical form of a substituted
quinoline derivative with valuable pharmacological properties in
antagonising wholly or in part one or more of the actions of the
substances known as angiotensins, and in particular of that known as
angiotensin II (hereinafter referred to as "AII" ) . The invention also
concerns pharmaceutical compositions containing the new physical form
and for use in treating diseases or medical conditions such as
hypertension, congestive heart failure and/or hyperaldosteronism in
warm-blooded animals (including man), as well as in other diseases or
medical conditions in which the renin-angiotensin-aldosterone system
plays a significant causative role. The invention also concerns a
process for the manufacture of the new physical form and the use of
the form in treating one of the afore-mentioned diseases or medical
conditions and for the production of novel pharmaceuticals for use in
such medical treatments.
Background to the Invention
The angiotensins are key mediators of the renin-angiotensin-
aldosterone system, which is involved in the control of homeostasis
and fluid/electrolyte balance in many warm-blooded animals, including
man. The angiotensin known as AII is produced by the action of
angiotensin converting enzyme (ACE) from angiotensin I, itself
produced by the action of the enzyme renin from the blood plasma
protein angiotensinogen. AII is a potent spasmogen especially in the
vasculature and is known to increase vascular resistance and blood
pressure. In addition, the angiotensins are known to stimulate the
release of aldosterone and hence result in vascular congestion and
hypertension via sodium and fluid retention mechanisms. Hitherto
there have been a number of different approaches to pharmacological
intervention in the renin-angiotensin-aldosterone system for
therapeutic control of blood pressure and/or fluid/electrolyte
balance, including, for example, inhibiting the actions of renin or
ACE. However, there remains a continuing need for an alternative
- 2 - ~ r~ '?5
approach because of the side-effects and/or idiosyncratic reactions
associated with any particular therapeutic approach.
It is known in the chemical art that a compound may often
exist in the solid state in one or more different and discrete
physical forms which have different physical properties including
melting point and solubility. This phenomenon is known as
polymorphism. Some of these physical forms may be intrinsically more
stable than others, for example, as a result of the different energies
associated with the crystal lattices involved. It is desirable in the
production of pharmaceutical formulations for medical use that the
active ingredients are in a physical form which is both physically
stable and can be prep~red to reproduclble quality standards
substantially free of impurities and other physical forms. This
latter requirement is especially important because different physical
forms can have markedly different bioavailabilities.
Our European patent application, Publication Number 412,848
describes a series of quinoline derivatives which antagonise the
pharmacological actions of the physiological agent known as
angiotensin II. One such quinoline derivative which is especially
preferred for its angiotensin II antagonist properties is
2-ethyl-4-l(2'-(lD-1,2,3,4-tetrazol-5-yl)-biphenyl-4-yl)methoxy]-
quinoline hydrochloride (shown as chemical structure A hereinafter and
referred to hereinafter as "compound A"). We have now discovered, and
this a basis for our invention, that compound A may be isolated in a
number of different forms, one of which, now referred to as the gamma
form, is particularly useful for pharmaceutical use, for example, by
virtue of its stability.
Disclosure of the Invention
According to the invention there is provided the gamma
crystalline form of the compound A, essentially anhydrous and
substantally free of other physical forms and which form is
characterised by having a melting point which is in the range about
185-192 degrees Celsius (C) and an X-ray powder diffraction pattern
includiDg specific peaks at about 2~ = 8.6, 11.9, 12.4, 14.3, 15.5,
19.0, 19.3, 19.9, 20.3, 22.8, 23.1, 24.3, 25.7, 27.5, 28.7 and 29.4.
It is to be understood that references in this specification
- 3 ~ r~3~
to the gamma crystalline form of the compound A, essentially anhydrous
and substantially free of other physical forms (hereinafter referred
to as the gamma form of compound A), refer to material containing less
than 0.5% by weight of water and in which material at least 95~ by
weight of the compound A is present in that single physical form.
X-ray powder diffraction spectra may be determined in
conventional manner, for example, using a Philips PW1130 X-ray
generator with a broad focus copper tube and approximately 0.5 g of
sample material mounted in a standard Philips pack holder over the
scanning range of 4-40 2~ counting for 4 seconds per point at 0.02
intervals to produce a trace of spacings against intensity for this
range. An X-ray diffraction spectrum of a typical sample of the gamma
crystalline form of the compound A is shown in Figure 1 attached
hereinafter. It will be understood that the 2~ values obtained in
practice may vary slightly from one machine to another and so the
values quoted hereinabove are not to be construed as absolute.
The melting characteristics of samples of the compound A
vary with their purity, degree of hydration and physical form and may
be determined by conventional procedures well known in the art, for
example, by differential scanning calorimetry. The melting point
characteristics of a typical sample of the gamma form of compound A
are given for illustration in Example 3 hereinafter.
The compound A may be obtained by procedures well known in
the chemical art for the production of chemically analogous compounds
such as the procedures described in our aforementioned European patent
application. Typical procedures are described in the accompanying
Examples. Such known procedures tend to give material of different
crystalline form and degree of hydration or solvation than the gamma
form of compound A of the present invention. This can be inferred
from the different physical properties of the forms. Thus, for
example the melting characteristics, X-ray powder spectra and Fourier
transform infra-red spectra are different to those of the gamma form
of compound A of the invention. Many of the procedures for the
production of compound A may give rise to one particular form (now
referred to as the alpha form) which is inherently less
thermodynamically stable than the gamma form of the invention. Thus,
for example, a sample of compound A produced by the general procedure
- 4 - ~ 5
described in Example 25 of the aforesaid European patent application
is obtained as predominantly the alpha form having a melting point
(with decomposition) of about 178-181C and with an X-ray powder
diffraction pattern including strong specific peaks at about 2~ =
7.21, 10.17 and 11.40~. A typical X-ray powder diffraction pattern of
the alpha form of the compound A is shown in Figure 2 hereinafter.
This can be contrasted with the different X-ray diffraction pattern
for a typical sample of the gamma form of compound A of the present
invention which is shown in Figure 1 hereinafter. The gamma form is
intrinsically more stable and has a more compact crystal form than the
alpha form of compound A and is consequently generally preferred for
pharmaceutical purposes.
According to a further feature of the invention there is
provided a process for the preparation of the gamma form of compound A
as defined above, which comprises heating at elevated temperature a
source of compound A in one or more suitable polar organic solvents,
optionally reducing the volume of the resultant solution by partial
evaporation, optionally followed by adding a non-hydroxylic organic
solvent or diluent and then cooling the mixture obtained to about O to
20 degrees Celsius (C).
The source of compound A may typically contain predominantly
the form now known as the alpha form of compound A, for example as may
be obtained by one of the procedures described hereinafter.
Suitable polar organic solvents include, for example,
hydroxylic solvents, such as methanol, ethanol, propanol and
2-methoxyethanol, or a mixture thereof, especially a mixture of
ethanol containing up to about 10% by volume of methanol.
Suitable non-hydroxylic solvents for use as specified in the
above process include7 for example, ethyl acetate and butyl acetate.
The process preferably requires the heating to be carried
out at elevated temperature, for example from about 40 to 130'7C,
conveniently at or about the boiling point of the solvent or solvent
mixture. It will be understood that it is necessary to carry out the
process for sufficient time to permit complete conversion to the gamma
from to occur. In general this will require several hours, preferably
at least 1 to 12 hours, of heating.
One preferred process comprises dissolving the source of
- 5 - ~ q~ 5
compound A by heating in a hydroxylic solvent (especially ethanol) at
or near the boiling point of said solvent, adding another more polar
and lower boiling hydroxylic solvent (especially methanol) and then
removing the lower boiling point solvent by fractional distillation
prior to addition of a suitable non-hydroxylic solvent (especially
ethyl acetate).
Another preferred process comprises heating a source of
compound A in a mixture of ethanol containing up to 10~ by volume of
methanol (conveniently that mixture known in the UK as industrial
methylated spirits) at or near the boiling point of said mixture for
at least 2 hours, followed by cooling to about 0 to 20C.
It will be recognised that the process may be carried
without complete solution of the source of compound A, that is with
the material as a slurry in the polar organic solvent.
The procedure of the invention may optionally be preceded by
a preliminary purification step. This step involves the conversion of
the compound A into its free base form and subsequently into its
sodium salt form which latter is purified by extraction into a
suitable organic solvent mixture and then reconverted into the
hydrochloride salt to give compound A.
By virtue of its specific physical characteristics, the
gamma form of compound A is particularly suitable for incorporation
into pharmaceutical compositions and especially into conventional
solid state pharmaceutical compositions suitable for oral
administration, such as tablets, capsules and powders, which
compositions may be formulated in a conventional manner.
According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises the gamma form
of compound A as defined hereinbefore together with a pharmaceutically
acceptable diluent or carrier.
As stated above, the compound A will have beneficial
pharmacolcgical effects in warm-blooded animals (including man) in
diseases and medical conditions where amelioration of the
vasoconstrictor and fluid retaining properties of the renin-
angiotensin-aldosterone system is desirable, at least in part by
antagonism of one or more of the physiological actions of AII. The
compound A will thus be useful in the treatment of diseases or medical
- 6 - 2~ 5
conditions such as hypertension, congestive heart failure and/or
hyperaldosteronism in warm-blooded animals (including man), as well as
in other diseases or medical conditions in which the
renin-angiotensin-aldosterone system plays a significant causative
role.
The antagonism of one or more of the physiological actions
of AII and, in particular, the antagonism of the interaction of AII
with the receptors which mediate its effects on a target tissue, may
be assessed using one or more of the following, routine laboratory
procedures:
Test A: This in vitro procedure involves the incubation of
the test compound initially at a concentration of 100 micromolar (or
less) in a buffered mixture containing fixed concentrations of
radiolabelled AII and a cell surface membrane fraction prepared from a
suitable angiotensin target tissue. In this test, the source of cell
surface membranes is the guinea pig adrenal gland which is well known
to respond to AII. Interaction of the radiolabelled AII with its
receptors (assessed as radiolabel bound to the particulate membrane
fraction following removal of unbound radiolabel by a rapid filtration
procedure such as is standard in such studies~ is antagonized by
compounds which also bind to the membrane receptor sites and the
degree of antagonism (observed in the test as displacement of
membrane-bound radioactivity) is determined readily by comparing the
receptor-bound radioactivity in the presence of the test compound at
the specified test concentration with a control value determined in
the absence of the test compound. Using this procedure compounds
showing at least 50% displacement of radiolabelled AII binding at a
concentration of 10 4 M are retested at lower concentrations to
determine their potency. For determination of the IC50 ~concentration
for 50% displacement of radiolabelled AII binding), concentrations of
the test compound are ordinarily chosen to allow testing over at least
four orders of magnitude centred about the predicted approximate IC50,
which latter is subsequently determined from a plot of percentage
displacement against concentration of the test compound.
In general, the compound A shows significant inhibition in
Test A at a concentration of 50 micromolar or much less.
Test B: This in vitro test involves the measurement of the
_ 7 _ 2~ ~.~ 5
antagonistic effects of the test compound against AII-induced
contractions of isolated rabbit aorta, maintained in a physiological
salt solution at 37C. In order to ensure that the effect of the
compound is specific to antagonism of AII, the effect of the test
compound on noradrenaline-induced contractions may also be determined
in the same preparation.
In general, the compound A shows significant inhibition in
Test B at a final concentration of 50 micromolar or much less.
Test C: This in vivo test involves using terminally-
anaesthetised or conscious rats in which an arterial catheter has been
implanted under anaesthesia for the measurement of changes in blood
pressure. The AII antagonistic effects of the test compound following
oral or parenteral administration, are assessed against angiotensin
II-induced pressor responses. To ensure that the effect is specific,
the effect of the test compound on vasopressin-induced pressor
responses may also be determined in the same preparation.
The compound A shows specific AII-antagonist properties in
Test C at a dose of 50 mg/kg body weight or much less, without any
overt toxicological or other untoward pharmacological effect.
Test D: This in vivo test involves the stimulation of
endogenous AII biosynthesis in a variety of species including rat,
marmoset and dog by introducing a diet of low sodium content and
giving appropriate daily doses of a saluretic known as frusemide. The
test compound is then administered orally or parenterally to the
animal in which an arterial catheter has been implanted under
anaesthesia for the measurement of changes in blood pressure.
The compound A shows AII-antagonist properties in Test D as
demonstrated by a significant reduction in blood pressure at a dose of
50 mg/kg body weight or much less, without any overt toxicological or
other untoward pharmacological effect.
The compound A will generally be administered to man so
that, for example, a daily oral dose of up to 50 mg/kg body weight
(and preferably of up to 10 mg/kg) or a daily parenteral dose of up to
5 mg/kg body weight tand preferably of up to 1 mg/kg) is received,
given in divided doses as necessary, the precise amount of compound
(or salt) administered and .he route and form of administration
depending on size, age and sex of the person being treated and on the
- 8 - X ~ ~.S
particular disease or medical condition being treated according to
principles well known in the medical arts.
In addition to their aforesaid use in therapeutic mediclne
in humans, the compounds A is also useful in the veterinary treatment
of similar conditions affecting commercially valuable warm-blooded
animals, such as dogs, cats, horses and cattie. In general for such
treatment, the compound A will generally be administered in an
analogous amount and manner to those described above for
administration to humans.
The invention will now be illustrated by the following non-
limiting Examples in which, unless otherwise stated:-
(i) concentrations and evaporations were carried out by rotary
evaporation in vacuo;
(ii) operations were carried out at room temperature, that is in
the range 18-26C;
(iii) yields, where given, are intended for guidance and are not
necessarily the maximum attainable by diligent process development;
(iv) lH NMR spectra were normally determined at 200 MHz in C~Cl3
using tetramethylsilane (TMS) as an internal standard, and are
expressed as chemical shifts (delta values) in parts per million
relative to TMS using conventional abbreviations for designation of
major peaks: s, singlet; m, multiplet; t, triplet; br, broad;
d,doublet; and
(v) products had satisfactory microanalyses.
CHEHICAL STRUCTURE OF COMPOUND A
N ~'~
~=
_ 9 ~ C ~ ~5
Example 1
lThis Example descibes an existing procedure for the preparation of a
source of compound A-l
A solution of 2-ethyl-4-[(2'-(2-tributylstannyl-2H-
1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline in toluene (15
ml), prepared ln situ by refluxing for 90 hours a mixture of
4'-[(2-ethylquinolin-4-yloxy)methyl]biphenyl-2-carbonitrile (0.9 g)
and a solution of tributyltin azide in toluene (15 ml) Ithe latter
prepared by reaction of tributyltin chloride (3.3 g) and sodium azide
(1.13 g) in water (22.5 ml) at ambient temperature for 4 hours,
followed by extraction with toluene and azeotropic removal of water
from the extract to leave a volume of 15 mll, was added slowly over 1
hour to a solution of sodium nitrite (2.5 g) in water (10 ml)
containing lZ% w/v hydrochloric acid (10 ml), maintaining the
temperature of the mixture below 5C. A solution of sulphamic acid
(1.43g) in water (lOml) was then added, maintaining the temperature
below 5C, and the mixture stirred for 1 hour. The resultant
suspended semi-solid was collected by filtration and washed with water
(3 x 10 ml), followed by toluene (10 ml). The semi-solid was then
added to tetrahydrofuran (THF) (40 ml), which caused the product to
dissolve and then crystallise as a white solid. After cooling for one
hour the solid was collected by filtration, washed with THP (5 ml) and
dried to give: 2-ethyl-4-l(2~ 1,2,3,4-tetrazol-5-yl)-
biphenyl-4-yl)methoxy]quinoline hydrochloride; m.p. 179-180C (dec.);
NMR (d6-DMSO): 1.46(t,3H), 3.18(q,2H), 5.68(s,2H), 7.22(d,2H),
7.5-7.8(m,7H), 7.P,3(t,1H), 8.08(t,1H), 8.18(d,1H), 8.32(d,1H).
The starting 4'-[(2-ethylquinolin-4-yloxy)methyl~biphenyl-
2-carbonitrile was obtained as follows:
A mixture of 2-ethyl-4-quinolone (1.73 g), (prepared by a
similar method to that described in Org. Syn., Coll. Vol. III, p.374
and p.593 from aniline and methyl propionylacetate),
4'-bromomethylbiphenyl-2-carbonitrile (3.1 g) and solid potassium
carbonate (1.81 g) in N-methylpyrrolidone (40 ml) were stirred for 36
hours under nitrogen. The mixture was then added dropwise to water
(100 ml) at 15-25"C and stirred for 30 minutes. The suspended solid
was collected by filtration, washed with water, and dried at 60C
under vacuum. The solid was recrystallised from tert-butyl methyl
-10- 2r~ 5
ether to give 4'-[(2-ethylquinolin-4-yloxy)methyll-biphenyl-2-
carbonitrile as a solid (1.9 g), m.p. 151-153C; NMR(CDCl3): 1.4(t,
3H), 2.97(q,2H), 5.35(s,2H), 6.76(s,1H), 7.4-7.6(m, 3H), 7.6-7.8(m,
6H), 8.0(d,lH), 8.25(d, lH).
The starting 4'-bromomethylbiphenyl-2-carbonitrile was
itself obtained as follows:-
(i) 2M Sodium carbonate solution (200 ml) was added to a stirred
mixture of 4-methylphenylboronic acid (30 g), 2-bromobenzonitrile
(36.4 g), palladium (II) chloride (0.4 g), methanol (200 ml) and
toluene (200 ml) at 5C. The temperature rose to approximately 20C
and a solid precipitated. The reaction mixture was then heated at
reflux for 2 hours. The reaction mixture uas allowed to cool and
water (100 ml) was added, followed by diatomaceous earth (5 g). The
mixture was stirred for 15 minutes, then filtered through diatomaceous
earth. The organic phase of the filtrate was separated and washed
with 2M sodium carbonate solution and then water. The organic phase
was then filtered and the filtrate evaporated. The resultant solid
was recrystallised from petroleum ether (b.p. 110-120C) to give
4'-methylbiphenyl-2-carbonitrile which was used without further
purification.
(ii) A mixture of 4'-methylbiphenyl-2-carbonitrile (3.86 g),
N-bromosuccinimide (3.92 g) and azo(bisisobutyronitrile) (0.15 g) in
chlorobenzene (75 ml) was heated at 70C for 3 hours. Further
N-bromosuccinimide (0.3 g) and azo(bisisobutyronitrile) (0.05 g) was
added and the mixture was heated for another 15 minutes. Heating was
stopped and the mixture stirred for 16 hours at ambient temperature.
Water (50 ml) was added and the mixture stirred for 30 minutes and
filtered. The organic phase was separated, washed with water (50 ml)
and dried (MgS04). The solvent was removed by evaporation and the
resultant solid recrystallised from cyclohexane to give
4'-bromomethylbiphenyl-2-carbonitrile (3.~ g) (A) as a solid; NMR
(CDCl3): 4.55(s,2H), 7.4-7.85(m, 8H).
Example Z
[This Example describes the purification of material obtained by an
an~logo~s procedure to that described in Example 1.]
2-Ethyl-4-[(2'-(lH-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)-
~v~ ~5
methoxy]quinoline hydrochloride (50.0 g~, obtained for example asdescribed in Example 1, was slurried in a mixture of methyl t-butyl
ether (125 ml), butanol (175 ml) and 10~ w/v aqueous sodium chloride
solution (150 ml) at 10-12C. A mixture of 10~ w/v aqueous sodium
chloride solution (50 ml), water (25ml) and 48% w/w aqueous sodium
hydroxide solution (20 g) was prepared and added to the slurry,
maintaining the temperature at 10-12C. After mixing, the layers were
separated and the organic phase was added to a mixture of methyl
t-butyl ether (200 ml), butanol (30 ml) and concentrated hydrochloric
acid (23.5 g) at 10C. The reaction mixture was stirred at 10C for
one hour and the purifed 2-ethyl-4-1~2'-(lH-1,2,3,4-tetrazol-5-yl)-
biphenyl-4-yl)methoxylquinoline hydrochloride isolated by filtration.
The solid was washed with methyl t-butyl ether (2 x 100 ml), then
slurried in water (500 ml), collected by filtration and washed with
water (150 ml). It was dried in vacuo at 30 for 16 hours to give
partially hydrated material (46.0g), m.p. 147-50C.
~xample 3
IThis Example describes a typical preparation of the ga~a form of
compound Al
A sample (5.0 g) of 2-ethyl-4-[(2'-(lH-1,2,3,4-tetrazol-
-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride (obtained from
Example 2) was heated to reflux in absolute ethanol (50 ml) and
methanol (40 ml) was added at reflux to achieve solution (about 1
hour). The reaction solution was distilled (about 30 minutes) to
remove 50 ml of distillate and then cooled to ambient temperature.
After stirring for 16 hours, ethyl acetate (50ml) was added and the
mixture stirred at 0-5C for 1 hour. The solid material was collected
by filtration and washed with ethyl acetate (Sml) and dried ln vacuo
at 25C for 64 hours to give the gamma crystalline form of
2-ethyl-4-[(2'-(lEI-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl)methoxyl-
quinoline hydrochloride, as a compact crystalline solid (4.42g), in
essentially anhydrous state, with m.p. 189-191C and X-ray diffraction
as shown in Figure 1 attached hereto. Using differential scanning
calorimetry, this material showed an initial change at 188.8C and a
final change at 192.5C.
This procedure may also be modified by heating a slurry of
;~t s~ 5
- 12 -
2-ethyl-4-[(2'-(lH-1,2,3,4-tetrazol--5-yl)biphenyl-4-yl)methoxy]-
quinoline hydrochloride in a mixture of industrial methylated spirit
(about 5% methanol, 95% ethanol) under reflux for at least two hours,
cooling the slurry to ambient temperature, separating the solid by
filtration, to give the gamma crystalline form of compound A in
essentially anhydrous state and with essentially the same physical
properties as those given above.
Example 4
[This Xxample describes a procedure for the preparation of a source of
compound A which is predominantly the alpha form.l
A mixture of 2-ethyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-
5-yl)biphenyl-4-yl)methoxy]quinoline (A) (930 mg) and a mixture of
ethanol (lOml), methanol (5ml) and concentrated hydrochloric acid
(2 ml) was allowed to stand for 2 hours. Volatile material was
removed by evaporation. The residue was mixed with ethanol (20ml) and
volatile material removed by evaporation. This porocedure was
repeated twice. The resultant residue was triturated with ether
(2 x 30 ml). The ether was decanted off. The solid residue was
dissolved in a mixture of ethyl acetate (40ml) and ethanol (60ml).
The volume of solution was then quickly reduced by about 50% by
partial evaporaticn and then cooled to ambient temperature to give
predominantly the alpha form of 2-ethyl-4-[(2'-(lH-tetrazol-
5-yl)biphenyl-4-yl)methoxylquinoline hydrochloride (160 mg), as a
light crystalline solid, m.p. 179-182C (decomposition). Further
crystalline material (240 mg) of m.p. 177-179C (decomposition) was
obtained by concentrating the mother liquor in vacuo (to about 10 ml
in volume) and then cooling it to about 0-5C. Both samples of
crystalline solid were subsequently shown to be the alpha form by
X-ray diffraction spectroscopy. [A typical X-ray diffraction pattern
for a sample of the alpha form obtained by this procedure is shown in
Figure 2 hereinafter.]
The starting 2-ethyl-4-([2'-(2-triphenylmethyl-2H-tetrazol-
5-yl)biphenyl-4-yl]methoxy)quinoline may be obtained as a solid, m.p.
173-174DC (decomposition); N~R: 1.4(t,3H), 2.96(q,2H), 5.16(s,2H),
6.73(s,1H), 6.9-6.94(m,6H), 7.18-7.32(m,13H), 7.33-7.55(m,4H),
13 ~ ;~ ~ S
7.67(dt,1H), 7.99(m,2H), 8.11(d,1H); microanalysis, found: C,81.1;
H,5-4; N,10-9%; C44H35N50 requires C,81-4; ~,5.4; N~10-8%~ by
alkylating at ambient temperature a solution of the sodium salt of
2-ethyl-4-quinolone (prepared by the method described in Org. Syn.,
1955, Coll. Vol. III, p.374 and p.593) in _,_-dimethylformamide (DMF)
with a solution in DMF of 5-12-(4'-bromomethylbiphenylyl)l-2-
triphenylmethyl-2H-tetrazole (obtained as described in European Patent
0291969).
Example 5
[This Example describes a conventional tablet formulation of the gamma
form of compound A (as defined hereinbefore) suitable for medical or
veterinary administration to warm-blooded animals including humans.
Material mg/tablet
Gamma form of Compound A 5
Croscarmellose sodium 2
Microcrystalline cellulose 16
Lactose 76
Hagnesium stearate
SCS SS36185
19-Jan-1992
