Note: Descriptions are shown in the official language in which they were submitted.
2036091
Merck Patent Gesellschaft
mit beschr~nkter Haftung
D a r m s t a d t
Pharmaceutical composition
S ~he invention relates to a new pharmaceutical
composition containing bisoprolol and/or one of its
physiologically acceptable salts and a potassium channel
activator.
This new composition acts to lower blood pressure
and can also be used for ~reating asthma, disturbances of
peripheral blood flow, heart failure and/or angina
pectoris.
The object of the invention was to provide new
medicaments in the form of pharmaceutical compositions
which have better properties than known medicaments which
can be used for the ~ame purposes.
This object has been achieved by the discovery of
the new composition. Bisoprolol = (+)-1-p-~2-isopropoxy-
ethoxymethyl)-phenoxy-3-isopropylamino-2-propanol is
disclosed in German Offenlegungsschrift 2,645,710. The
preferred salts of bisoprolol are
the hydrochloride and the hemifumarate.
EP-A2-0,323,745 has already described pharmaceut-
ical products which contain combinations of potassium
channel activators with ~-receptor blockers. However,
bisoprolol is not mentioned among the ~-receptor blockers
specified therein. Compared with the products specified
therein, the present new compositions are distinguished
by high ~1-selectivity and a long duration of action.
Potassium channel activators are describPd, for
example, in EP-A-0,205,292, EP-A-0,214,818,
EP-A-0,250,077, GB-A-1,489,879, EP-A-0,112,776,
EP-A-0,273,262, EP-A-0,277,612, EP-A-0,277,612,
EP-A-0,340,718 and EP-A-0,346,724.
Preferred potassium channel activators are those
of the formula I
2 2~3 6 0
R6 R5-Z
~X~
~ 0~
R7 \ Rl
in which
X-Y is =CH-CHRa-, =CR4-CR3A- or =CH-CA(OA)-, and, if
the radical R5 is neither completely nor parti-
ally hydrogenated, also =C4-CHR3_ or
=CH-CH(OA)-,
R1 is A,
R2 and R8 are each H or A,
R1 and R2 together are also alkylene with 3-6 C atoms
R3 is OH, or OAc,
R4 is H,
R3 and R4 together are also a bond,
R5 is a pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, oxo-dihydro-pyridyl, oxo-dihydro-
pyridazinyl, oxo-dihydro-pyrimidinyl, oxo-
dihydro-pyrazinyl, 3H- or 5H-2-pyrrolinon-1-yl,
2H-1-isoquinolinon-2-yl, 2H-l-phthalazinon-2~
yl, 3H-4-quinazolinon-3-yl, or lH-2-thio-
pyridon-l-yl radical, each of which is
- unsubstituted or substituted once or twice by
A, F, Cl, Br, I, OH, OA, OAc, NO2, NH2, AcNH,
HOOC and/or AOOC, it also being possible for
these radicals to be completely or partially
hydrogenated,
R6 and R7 are each H, A, HO, AO, CHO, ACO, ACS, HOOC,
AOOC, AO-CS, ACOO, A-CS-O, hydroxyalkyl,
mercaptoalkyl, NO2, NH2, NHA, NA2, CN, F, Cl,
Br, I, CF3, ASO, ASO2, AO-SO, AO-SO2, AcNH,
AO-CO-NH, H2NSO, HANSO, A2NSO, H2NSO2, HANSO2,
A2NSO2, H2NCO, HANCO, A2NCO, H2NCS, HANCS, A2NCS,
ASONH, ASO2NH, AOSONH, AOSO2NH, ACO-alkyl,
nitroalkyl, cyanoalkyl, A-C(=NOH) or
A-C(=NNH2),
Z is a bond, O, S or NH,
3 2036091
R7 is also pyridyl, pyridazinyl, pyrimidinyl or
pyrazinyl,
A is alkyl with 1-6 C atoms (where several
groups A can, independently of one another, be
different alkyl groups),
-alkyl- is alkylene with 1-6 C atoms and
Ac is alkanoyl with 1-8 C atoms or aroyl with 7-11
C atoms,
and/or one of the physiologically acceptable salts
thereof.
Some of the compounds of the formula I are known
(compare, for example, EP-A-0,273,262).
Preferred compounds of the formula I are those in
which the radicals Rl and R2 are each CH3, the radical R7
is H and/or the radical R6 is CN, with the radical R6
preferably being in the 6 position. The group X-Y is
preferably =CR4-CR3A- [especially =CH-C(OH)A- or =C=CA-]
or else, if the radical R5 is neither completely nor
partially hydrogenated, =CR4-CHR3- (especially =CH-CHOH-
or =C=CH-).
The group R5-Z is preferably lH-2-pyridon-1-yl,
2-hydroxy-4-pyridyloxy, 6-hydroxy-3-pyridazinyloxy,
1,6-dihydro-1-methyl- or 1,6-dihydro-1-ethyl-6-oxo-3-
pyridazinyloxy.
Specific preferred compounds of the ~ormula I are
2,2-dimethyl-4-(lH-2-pyridon-1-yl)-6-cyano-3-chromanol
~Ia), especially its (3S,4R~ enantiomer, 2,2-dimethyl-4-
(lH-2-pyridon-1-yl)-6-cyano-2H-chromene (Ib), 2,2-di-
methyl-4-(6-hydroxy-3-pyridazinyloxy)-6-cyano-3-chrom-
anol, especially its (3S,4R) enantiomer, 2,2,3-trimethyl-
4-(6-hydroxy-3-pyridazinyloxy)-6-cyano-3-chromanol,
especially its (3S,4R) enantiomer, 2,2-dimethyl-4-
(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyloxy~-6-cyano-3-
chromanol (Ic), especially its (3S,4R) enantiomer, 2,2,3-
trimethyl-4-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl-
oxy)-6-cyano-3-chromanol, especially its (3S,4R)
enantiomer.
It is remarkable that the action of the said
potassium channel activators in lowering blood press~re
2036091
-- 4 --
is distinctly enhanced by concurrent administration of
bisoprolol. The action of the combination is greater than
can be expected after estimation of the action of the
individual components. This (synergistic) effect can be
found, for example, in standard tests on anaesthetized or
conscious rats, dogs, cats, monkeys or minipigs, for
example by methods as described in EP-A2-0,323,745.
The new pharmaceutical composition can be pre-
pared by converting bisoprolol and/or one of its physio-
logically acceptable salts and (at least) one potassiumchannel activator, preferably a compound of the
formula I, together with at least one solid, liquid or
semi-liquid vehicle or auxiliary into a suitable dosage
form. The compositions obtained in this way can be used
as medicaments in human or veterinary medicine, espe-
cially for lowering blood pressure. Suitable vehicles are
organic or inorganic substances which are suitable for
enteral (for example oral, sublingual or rectal), parent-
eral or topical (for example transdermal) administration
and do not react with the new compounds, for example
water, vegetable oils, benzyl alcohols, polyethylene
glycols, glycerol triacetate and other fatty acid glycer-
ides, gelatin, soya lecithin, carbohydrates such as
lactose or starch, magnesium stearate, talc or cellulose.
Used f~r oral administration are, in particular, tablets,
coated tablets, capsules, syrups, solutions or drops, for
rectal administration are suppositories, for parenteral
administration are solutions, preferably oily or aqueous
solutions, as well as suspensions, emulsions or implants,
and for topical administration are ointments, creams or
plasters. The active substances can also be freeze-dried
and the resulting lyophilisates used, for example, for
preparing in~ection products. The compositions can be
sterilized and/or contain auxiliaries such as preserv-
atives, stabilizers and/or wetting agents, emulsifiers,salts to influence the osmotic pressure, buffer substanc-
es, colorants and/or flavourings. They can also contain
other active substances, for example other substances
acting ~o lower blood pressure, or diuretics.
2036091
- 5 -
The composition~ according to the invention are
used for lowering blood pressure and/or for controlling
diseases. They are, as a rule, administered for the
therapy and/or prophylaxis of asthma, disorders of the
cardiovascular system, especially congestive heart
failure, angina pectoris, peripheral or cerebral vessel
disorders and pathological states a~sociated with high
blood pressure, in analogy to known substances acting to
lower the blood pressure, e~pecially the ~-receptor
blockers or the potassium channel activators themselves.
The dosages of the compounds of the formula I or the
salts thereof are preferably between about 0.1 mg and
50 mg, especially 0.2 and 10 mg, very particularly
preferably between 0.1 and 5 mg, per dosage unit.
Bisoprolol is preferably used in dosages between about 1
and about 100 mg, especially between ~ and 20 mg, per
dosage unit. The daily dosage of the compounds of the
formula I or the salts thereof is preferably between
about 0.001 and 1, in particular between 0.002 and
0.2 mg/kg of body weight, and those of bisoprolol are
preferably between about 0.02 and 0.2 mg/kg of body
weight. The specific dose for each particular patient
depends, however, on a wide variety of factors, for
example on the activity of the specific compound em-
ployedj the age, body weight, general state of health,
sex, the diet, the time and route of administration, the
rate of elimination, drug combination and severity of the
particular disease for which the therapy is applied. Oral
administration is preferred.
The components of the new pharmaceutical composi-
tion are preferably administered in combination. However,
they can also be administered singly, concurrently or
successively.
Example 1: Tablets
A mixture of 20 g of Ia, 100 g of bisoprolol
hemifumarate, 4 kg of lactose, 1.2 kg of potato starch,
0.2 kg of talc and 0.1 kg of magnesium stearate is
compressed in a customary manner to give tablets such
that each tablet contains 1 mg of Ia and 5 mg of
2036091
- 6 -
bisoprolol hemifumarate.
Example 2: Coated tablets
Tablets are compressed in analogy to Example A
and then coated in a conventional manner with a coating
composed of sucrose, potato starch, talc, tragacanth and
colorant.
Example 3: Capsules
A screened mixture of 30 g of Ib, 100 g of
bisoprolol hemifumarate and 6 kg of lactose is used to
fill hard gelatin capsules in a customary manner such
that each capsule contains 0.3 mg of Ib and l mg of
bisoprolol hemifumarate.
Example D: Ampoules
A solution of 2 g of Ic and 20 g of bisoprolol
hemifumarate in 30 l of double-distilled water is fil-
tered sterile, dispensed into ampoules, freeze-dried
under sterile conditions and sealed sterile. Each ampoule
contains 0.1 mg of Ic and 1 mg of bisoprolol
hemifumarate.
