Note: Descriptions are shown in the official language in which they were submitted.
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+ , .
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S018-639pct.204
New benzoylguanidine derivatives with advantageous
properties, processes for preparing them and their use in
the production of pharmaceutical compositions
The present invention relates to novel benzoylguanidine
derivatives of general formula I, processes for preparing
them and their use in the preparation of pharmaceutical
compositions
F O
NH2
F / N =~
N H2
N
O
(I)
wherein
R1 denotes C1 .-alkyl,
heteroaryl unsubstituted or mono- or polysubstituted
by a branched or unbranched C1_4-alkyl group, a
cycloalkyl group, a branched or unbranched C1_4-alkoxy
group, an NHZ group or a primary or secondary amino
group, a trifluoromethyl group, a cyano or nitro
group or halogen,
aryl unsubstituted or mono- or polysubstituted by a
branched or unbranched C1_4-alkyl group, a branched or
unbranched C1_4-alkoxy group, an NHz group or a
primary or secondary amino group, a trifluoromethyl
group, a hydroxy, cyano or nitro group or halogen or
by a 5- or 6-membered heteroaryl group which may
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contain one, two, three, four or: five heteroatoms
selected from nitrogen, oxygen and sulphur -
identical to one another or different -
alkylaryl, unsubstituted or mono- or polysubstituted
in the aryl and/or alkyl partial structure by a
branched or unbranched C1_4-alkyl group, a branched or
unbranched C1_, -alkoxy group, an NH2 group or a
primary or secondary amino group, a trifluoromethyl
group, a cyano or nitro group or halogen,
optionally in the form of the individual tautomers or
optionally enantiomers and mixtures thereof and in the
form of the free bases or the corresponding acid addition
salts with pharmacologically acceptable acids.
The preferred compounds for the purposes of the present
invention are the compounds of general formula I wherein
R1 may denote an unsubstituted phenyl ring or a phenyl
ring which is substituted by fluorine or by a methyl,
trifluoromethyl, methoxy group or by a pyrrolyl
group, or
N O
The following compounds are particularly preferred:
4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoylguanidine methanesulphonate
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O NHz
N NH
N
fl
N
FFF
O
X CiH3SO3H
and
4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoylguanidine methanesulphonate
l~ Z
'-N~ 1~NH
N X CH3SO3H
F'I'~F
F
O
C1_4-alkyl or C1_B-alkyl generally denotes a branched or
unbranched hydrocarbon group having 1 to 4 or 8 carbon
atoms, which may optionally be substituted by one or more
halogen atoms, preferably fluorine, which may be identical
to or different from one another. The following
hydrocarbon groups are mentioned by way of example:
methyl, ethyl, propyl, 1-methylethyl (isopropyl), n-butyl,
1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,
1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-
dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-
ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-
methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-
dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-
dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-
ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,
1-ethyl-l-methylpropyl and i-ethyl-2-methylpropyl. Unless
otherwise stated, the preferred hydrocarbon groups are
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lower alkyl groups having 1 to 4 carbon atoms such as
methyl, ethyl, propyl, iso-propyl, n-butyl, 1-
methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.
Alkoxy generally denotes a straight-chained or branched
alkyl group bound via an oxygen atom. A lower alkoxy
group having 1 to 4 carbon atoms is preferred. The
methoxy group is particularly preferred.
Aryl generally denotes an aromatic group having 6 to 10
carbon atoms - including compositions in which the
aromatic group may be substituted by one or more lower
alkyl groups, trifluoromethyl groups, cyano groups, alkoxy
groups, nitro groups, amino groups and/or one or more
halogen atoms, which may be identical or different; the
preferred aryl group is an optionally substituted phenyl
group, whilst the preferred substituents are halogen, such
as fluorine, chlorine or bromine, cyano and hydroxyl; for
the purposes of the present invention fluorine is the
preferred halogen. The aryl substituent - preferably
phenyl - may moreover be substituted with a 5- or 6-
membered heteroaryl group which may contain one, two,
three, four or five heteroatoms from the group comprising
nitrogen, oxygen and sulphur, and again the substituents
may be identical or different.
Aralkyl generally denotes an aryl group having 7 to 14
carbon atoms bound via an alkylene chain, the aromatic
group optionally being substituted by one or more lower
alkyl groups, alkoxy groups, nitro groups, amino groups
and/or one or more halogen atoms, the substituents being
identical or different. Aralkyl groups having 1 to 6
carbon atoms in the aliphatic moiety and 6 carbon atoms in
the aromatic moiety are preferred.
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The preferred aralkyl groups - unless otherwise stated -
are benzyl, phenethyl and phenylpropyl.
Halogen, unless otherwise stated - denotes fluorine,
chlorine, bromine and iodine, preferably fluorine,
chlorine or bromine.
Unless otherwise specified, amino denotes an NH2 function
which may optionally be substituted by one or two
C1_8-alkyl, aryl or aralkyl groups, which may be identical
or different.
Accordingly, alkylamino denotes for example methylamino,
ethylamino, propylamino, 1-methylene--ethylamino,
butylamino, 1-methylpropylamino, 2-methylpropylamino or
1,1-dimethylethylamino.
Correspondingly, dialkylamino denotes, for example,
dimethylamino, diet:hylamino, dipropylamino, dibutylamino,
di-(1-methylethyl)amino, di-(1-methylpropyl)amino, di-2-
methylpropylamino, ethylmethylamino, methylpropylamino.
Cycloalkyl generally denotes a saturated or unsaturated
cyclic hydrocarbon group having 5 to 9 carbon atoms which
may optionally be substituted by a halogen atom or a
number of halogen atoms - preferably fluorine - which may
be identical to or different from one another. Cyclic
hydrocarbon groups having 3 to 6 carbon atoms are
preferred. Examples include cyclopropyl, cyclobutyl,
cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,
cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl,
cyclooctenyl, cyclooctadienyl and cyclononinyl.
Heteroaryl for the purposes of the above definition
generally denotes a 5- to 6-membered ring which may
contain oxygen, sulphur and/or nitrogen as heteroatoms and
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to which another aromatic ring may be fused. 5- and
6-membered aromatic rings which contain an oxygen, a
sulphur and/or up to two nitrogen atoms and which are
optionally benzo-condensed are preferred.
Examples of particular heterocyclic systems include:
acridinyl, acridonyl, alkylpyridinyl, anthraquinonyl,
ascorbyl, azaazulenyl, azabenzanthracenyl,
azabenzanthrenyl, azachrysenyl, azacyclazinyl, azaindolyl,
azanaphthacenyl, azanaphthalenyl, azaprenyl,
azatriphenylenyl, azepinyl, azinoindolyl, azinopyrrolyl,
benzacridinyl, benzazapinyl, benzofuryl,
benzonaphthyridinyl, benzopyranonyl, benzopyranyl,
benzopyronyl, benzoquinolinyl, benzoquinolizinyl,
benzothiepinyl, benzothiophenyl, benzylisoquinolinyl,
bipyridinyl, butyrolactonyl, caprolactamyl, carbazolyl,
carbolinyl, catechinyl, chromenopyronyl, chromonopyranyl,
cumarinyl, cumaronyl, decahydroquino:linyl,
decahydroquinolonyl, diazaanthraceny:l, diazaphenanthrenyl,
dibenzazapinyl, dibenzofuranyl, dibenzothiphenyl,
dichromylenyl, dihydrofuranyl, dihydroisocumarinyl,
dihydroisoquinolinyl, dihydropyranyl, dihydropyridinyl,
dihydropyridonyl, dihydropyronyl, dihydrothiopyranyl,
diprylenyl, dioxanthylenyl, oenantholactamyl, flavanyl,
flavonyl, fluoranyl, fluoresceinyl, furandionyl,
furanochromanyl, furanonyl, furanoquinolinyl, furanyl,
furopyranyl, furopyronyl, heteroazulenyl,
hexahydropyrazinoisoquinolinyl, hydrofuranyl,
hydrofuranonyl, hydroindolyl, hydropyranyl,
hydropyridinyl, hydropyrrolyl, hydroquinolinyl,
hydrothiochromenyl, hydrothiophenyl, indolizidinyl,
indolizinyl, indolonyl, isatinyl, isatogenyl,
isobenzofurandionyl, isobenzfuranyl, isochromanyl,
isoflavonyl, isoindolinyl, isoindolobenzazapinyl,
isoindolyl, isoquiriolinyl, isoquinuclidinyl, lactamyl,
lactonyl, maleimidyl, monoazabenzonaphthenyl,
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naphthalenyl, naphthimidazopyridindionyl,
naphthindolizinedionyl, naphthodihyd:ropyranyl,
naphthofuranyl, naphthyridinyl, oxepinyl, oxindolyl,
oxolenyl, perhydroazolopyridinyl, perhydroindolyl,
phenanthraquinonyl, phthalideisoquinolinyl, phthalimidyl,
phthalonyl, piperidinyl, piperidonyl, prolinyl, parazinyl,
pyranoazinyl, pyranoazolyl, pyranopyrandionyl,
pyranopyridinyl, pyranoquinolinyl, pyranopyrazinyl,
pyranyl, pyrazolopyridinyl, pyridinethionyl,
pyridinonaphthalenyl, pyridinopyridinyl, pyridinyl,
pyridocolinyl, pyridoindolyl, pyridopyridinyl,
pyridopyrimidinyl, pyridopyrrolyl, pyridoquinolinyl,
pyronyl, pyrrocolinyl, pyrrolidinyl, pyrrolizidinyl,
pyrrolizinyl, pyrrolodioazinyl, pyrrolonyl,
pyrrolopyrimidinyl, pyrroloquinolonyl, pyrrolyl,
quinacridonyl, quinolinyl, quinolizidinyl, quinolizinyl,
quinolonyl, quinuclidinyl, rhodaminyl, spirocumaranyl,
succinimidyl, sulpholanyl, sulpholenyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydropyranyl,
tetrahydropyridinyl, tetrahydrothiapyranyl,
tetrahydrothiophenyl, tetrahydrothipyranonyl,
tetrahydrothipyranyl, tetronyl, thiaphenyl, thiachromanyl,
thiadecalinyl, thianaphthenyl, thiapyranyl, thiapyronyl,
thiazolopyridinyl, thienopyridinyl, thienopyrrolyl,
thienothiophenyl, thiepinyl, thiochromenyl, thiocumarinyl,
thiopyranyl, triazaanthracenyl, triazinoindolyl,
triazolopyridinyl, tropanyl, xanthenyl, xanthonyl,
xathydrolyl, adeninyl, alloxanyl, all.oxazinyl,
anthranilyl, azabenzanthrenyl, azaberizonaphthenyl,
azanaphthacenyl, azaphenoxazinyl, azapurinyl, azinyl,
azoloazinyl, azolyl, barbituric acid, benzazinyl,
benzimidazolethionyl, benzimidazolonyl, benzisothiazolyl,
benzisoxazolyl, benzocinnolinyl, benzodiazocinyl,
benzodioxolanyl; benzodioxolyl, benzopyridazinyl,
benzothiazepinyl, benzothiazinyl, benzothiazolyl,
benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinnolinyl,
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depsidinyl, diazaphenanthrenyl, diazepinyl, diazinyl,
dibenzoxazepinyl, dihydrobenzimidazolyl,
dihydrobenzothiazinyl, dihydrooxazolyl,
dihydropyridazinyl, dihydropyrimidinyl, dihydrothiazinyl,
dioxanyl, dioxenyl, dioxepinyl, dioxinonyl, dioxolanyl,
dioxolonyl, dioxopiperazinyl, dipyrimidopyrazinyl,
dithiolanyl, dithiolenyl, dithiolyl, flavinyl,
furopyrimidinyl, glycocyamidinyl, guaninyl,
hexahydropyrazinoisoquinolinyl, hexahydropyridazinyl,
hydantoinyl, hydroimidazolyl, hydroparazinyl,
hydropyrazolyl, hydropyridazinyl, hydropyrimidinyl,
imidazolinyl, imidazolyl, imidazoquinazolinyl,
imidazothiazolyl, indazolebenzopyrazolyl, indoxazenyl,
inosinyl, isoalloxazinyl, isothiazolyl, isoxazolidinyl,
isoxazolinonyl, isoxazolinyl, isoxazolonyl, isoxazolyl,
lumazinyl, methylthyminyl, methyluracilyl, morpholinyl,
naphthimidazolyl, oroticyl, oxathianyl, oxathiolanyl,
oxazinonyl, oxazolidinonyl, oxazolidinyl, oxazolidonyl,
oxazolinonyl, oxazolinyl, oxazolonyl, oxazolopyrimidinyl,
oxazolyl, perhydrocinnolinyl, perhydropyrroloazinyl,
perhydropyrrolothiazinyl, perhydrothiazinonyl,
perimidinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,
phenoxazinyl, phenoxazonyl, phthalazinyl, piperazindionyl,
piperazinodionyl, polyquinoxalinyl, pteridinyl, pterinyl,
purinyl, pyrazinyl, pyrazolidinyl, pyrazolidonyl,
pyrazolinonyl, parazolinyl, pyrazolobenzodiazepinyl,
pyrazolonyl, pyrazolopyrimidinyl, pyrazolotriazinyl,
pyrazolyl, pyridazinyl, pyridazonyl, pyridopyrazinyl,
pyridopyrimidinyl, pyrimidinethionyl, pyrimidinyl,
pyrimidionyl, pyrimidoazepinyl, pyrimidopteridinyl,
pyrrolobenzodiazepinyl, pyrrolodiazinyl,
pyrrolopyrimidinyl, quinazolidinyl, quinazolinonyl,
quinazolinyl, quinoxalinyl, sultamyl, sultinyl, sultonyl,
tetrahydrooxazolyl, tetrahydropyrazinyl,
tetrahydropyridazinyl, tetrahydroquinoxalinyl,
tetrahydrothiazolyl., thiazepinyl, thiazinyl,
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thiazolidinonyl, thiazolidinyl, thiazolinonyl,
thiazolinyl, thiazolobenzimidazolyl, thiazolyl,
thienopyrimidinyl, thiazolidinonyl, thyminyl,
triazolopyrimidinyl, uracilyl, xanthinyl, xylitolyl,
azabenzonaphththenyl, benzofuroxanyl, benzothiadiazinyl,
benzotriazepinonyl, benzotriazolyl, benzoxadiazinyl,
dioxadiazinyl, dithiadazolyl, dithiazolyl, furazanyl,
furoxanyl, hydrotriazolyl, hydroxytrizinyl, oxadiazinyl,
oxadiazolyl, oxathiazinonyl, oxatriazolyl, pentazinyl,
pentazolyl, pentazinyl, polyoxadiazolyl, sydonyl,
tetraoxanyl, tetrazepinyl, tetrazinyl, tetrazolyl,
thiadiazinyl, thiadiazolinyl, thiadiazolyl,
thiadioxazinyl, thiatriazinyl, thiatriazolyl,
thiatriazolyl, triazepinyl, triazinoindolyl, triazinyl,
triazolinedionyl, triazolinyl, triazolyl, trioxanyl,
triphenodioxazinyl, triphenodithiazinyl,
trithiadiazepinyl, trithianyl or trioxolanyl.
Compounds of this type are already known from German
published application 196 01 303.8.
As a result of their effect as inhibitors of cellular
Na'/H' exchange, such compounds may be used as active
ingredients of pharmaceutical compositions or they may be
used as intermediate products for the preparation of such
active ingredients. The compounds according to the
invention are effective against arrhythmias which occur in
hypoxia, for example. They can also be used for diseases
connected with ischaemia (such as cardiac, cerebral,
gastrointestinal - such as mesenterial
thrombosis/embolism, pulmonary, renal ischaemia, ischaemia
of the liver, ischaemia of the skeletal muscle). Such
diseases include for example coronary heart disease,
cardiac infarct, angina pectoris, stable angina pectoris,
ventricular arrhythmias, sub-ventricular arrhythmias,
cardiac insufficiency - and also in support of bypass
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operations, for supporting open heart surgery, for
supporting operations which require the blood supply to
the heart to be interrupted and for supporting heart
transplants - embolism in the pulmonary circulation, acute
or chronic kidney failure, chronic kidney insufficiency,
cerebral infarct, reperfusion damage caused by the
resumption of blood supply to areas of the brain after the
clearing of vascular occlusions and acute and chronic
bleeding disorders in the brain. Here, the compounds
mentioned may also be used in conjunction with
thrombolytic agents such as t-PA, streptokinase and
urokinase.
During reperfusion of the ischaemic heart (e.g. after an
attack of angina pectoris or cardiac infarct) irreversible
damage may occur to cardiomyocytes in the affected region.
The compounds according to the invention have a
cardioprotective activity, inter alia, in such cases.
The prevention of damage to transplants must also be
included under the heading of ischaemia (e.g. for
protecting the transplant such as the liver, kidney, heart
or lung, before, during and after implantation and during
storage of the organs for transplant), which may occur in
connection with transplants. The compounds are also drugs
with a protective effect during angioplastic surgery on
the heart and on the peripheral blood vessels.
In essential hypertension and diabetic nephropathy the
cellular sodium proton exchange is increased. The
compounds according to the invention are therefore
suitable as inhibitors of this exchange in order to
prevent these diseases.
The compounds according to the invention are further
characterised by a powerful inhibitory effect on the
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proliferation of cells. Consequently, the compounds are
useful drugs in the treatment of diseases in which cell
proliferation plays a primary or secondary role and may be
used as drugs against cancers, benigri tumours or for
example prostate hypertrophy, atherosclerosis, organ
hypertrophy and hyperplasia, fibrotic diseases and late
complications of diabetes.
Moreover, compounds of this type are known to have a
favourable effect on the blood levels of the serum
lipoproteins.
It has now been found that, surprisingly, the compounds of
general formula I have the advantage over the
benzoylguanidine derivatives already known from the prior
art, of not only being unexpectedly more effective but
also being suitable for oral administration.
The active substances according to general formula I may
be used as an aqueous injectable solution (e.g. for
intravenous, intramuscular or subcutaneous
administration), as tablets, suppositories, ointments, as
plasters for transdermal application, as aerosols for
inhalation through the lungs or as a nasal spray.
The content of active substance in a tablet or suppository
is between 5 and 200 mg, preferably between 10 and 50 mg.
For inhalation, the individual dose is between 0.05 and
20 mg, preferably between 0.2 and 5 mg. For parenteral
injection, the single dose is between 0.1 and 50 mg,
preferably between 0.5 and 20 mg. The above doses may be
administered several times a day if necessary.
The following are some examples of pharmaceutical
preparations containing the active substance:
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Tablets:
Active substance of general formula I 20.0 mg
Magnesium stearate 1.0 mg
Corn starch 62.0 mg
Lactose 83.0 mg
Polyvinylpyrrolidone 1.6 mg
Sol iti on for i nj .__i on
Active substance of general formula 1 0.3 g
Sodium chloride 0.9 g
Water for injections ad 100 ml
The solution may be sterilised by standard methods.
AQueQUS sol u i on for nasal admi ni st-rat- i nn or i nhal at- i nn
Active substance of general formula 1 0.3 g
Sodium chloride 0.9 g
Benzalkonium chloride 0.01 mg
Purified water ad 100 ml
The above solution is suitable for nasal administration in
a spray or, when used in conjunction with a device which
produces an aerosol having a particle size of preferably
between 2 and 6 m, it is suitable for administration into
the lungs.
Cap,mul .-, for i nhal a i on
The compounds of general formula I are packed into hard
gelatin capsules in micronised form (particle size
essentially between 2 and 6 M), optionally with the
addition of micronised carrier substances such as lactose.
They are inhaled by means of conventional devices for
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powder inhalation. Between 0.2 and 20 mg of the active
substance of general formula I and 0 to 40 mg of lactose
are packed into each capsule, for example.
A_rosol for 'nhala.ion
Active substance of general formula I 1 part
Soya lecithin 0.2 parts
Propellant gas mixture ad 100 parts
The preparation is preferably transferred into aerosol
containers with a metering valve, each spray delivering a
dose of 0.5 mg. For other dosages iri the range specified,
preparations containing a larger or smaller proportion of
active substance are conveniently used.
O;n-m t(composition g/100 g of ointment)
Active substance of general formula I 2 g
Fuming hydrochloric acid 0.011 g
Sodium pyrosulphite 0.05 g
Mixture of equal parts of cetyl alcohol
and stearyl alcohol 20 g
White Vaseline 5 g
Artificial bergamot oil 0.075 g
Distilled water ad 100
The ingredients are processed in the usual way to form an
ointment.
The methods of producing the compounds according to the
invention are generally known from the prior art; thus,
the compounds according to the invention may be obtained
by the following method, for example:
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By reacting 4-(1-piperazinyl)-3-trifluoromethylbenzoic
acid esters of general formula II
FF 0
F O
N 1 'C4Alkyl
H"N
(II)
with a compound of general formula III
R1C(O)Q (III)
wherein Q denotes a leaving group which may be substituted
by the piperazine nitrogen, optionally in the presence of
adjuvants, preferably carbonyldiimidazole, the resulting
benzoic acid derivative of general formula IV
FF 0
F I O
- Alkyl
r N C1 - C4
~ ~ N
O
(IV)
is obtained, which is suspended in a suitable, preferably
anhydrous, solvent, preferably dimethylformamide, and is
mixed with a mixture of a solution or suspension of a base
- preferably sodium hydride in a suitable anhydrous
solvent - preferably dimethylformamide - with a guanidine
salt - preferably guanidine hydrochloride - and the
reaction product is isolated.
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The present invention is illustrated by the Examples which
follow:
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Examples:
Methyl 4-fluoro-3- .ri flliorom +-hyl -bPn oatP
35.4 g (170 mmol) of 4-fluoro-3-(trifluoromethyl)-benzoic
acid in 250 ml of methanol are mixed with 68 ml of SOC12,
whilst cooling with ice, at 5 C within 25 minutes. After
it has all been added, the reaction mixture is refluxed
for a further 3 hours. The reaction solution is cooled to
ambient temperature and evaporated down in vacuo. The
oily residue is taken up in 200 ml of diethylether and
extracted with water, saturated NaHCO3 solution and again
with water. The combined organic phases are dried over
magnesium sulphate and evaporated down in vacuo.
Yield: 29.0 g (77%)
Methyl 4- (4-~yl -l -ipinerazinyl ) -3- ri fl uoromPt-hyl -
b -n .oa
7 g (31.5 mmol) of methyl 4-fluoro-3-trifluoromethyl-
benzoate are dissolved in 60 ml of dry dimethylsulphoxide
(DMSO) and combined with 5.55 g (31.5 mmol) of N-
benzylpiperazine and 4.35 g (31.5 mmol) of potassium
carbonate. The mixture is stirred for 12 hours at 90 C.
After cooling, the reaction mixture is poured into 200 ml
of water and extracted three times with ethyl acetate.
The combined organic phases are washed with water and
saturated sodium chloride solution, dried over magnesium
sulphate and distilled off in vacuo. The residue is
chromatographed on silica gel with a mixture of ethyl
acetate and n-heptane.
Yield: 3.93 g (33%)
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Methy1 4_ (l -~)in rPyl )-3- r; fl uo nrnPt-hyl -hPnznat-a
20.2 g (53.3 mmol) of methyl 4-(4-benzyl-l-piperazinyl)-3-
trifluoromethyl-benzoate are dissolved in 200 ml of
methanol and combiiZed with 2 g of palladium on charcoal
and hydrogenated over a period of 1.4 hours at 70 C under
a hydrogen pressure of 5 bar. The solution is suction
filtered over celite and distilled off in vacuo.
Yield: 14.85 g (97%)
General method of coupling methyl 4-(1-piperazinyl)-3-
trifluoromethyl-benzoate with benzoic acids:
5 mmol of the corresponding carboxylic acid are dissolved
in 30 ml of absolute tetrahydrofuran (THF) and combined
under protective gas at 0 C with 810 mg (5 mmol) of
carbonyldiimidazole and stirred for 2 hours at ambient
temperature (about 25 C). Then 1.44 g (5 mmol) of methyl
4-(1-piperazinyl)-3-trifluoromethyl-benzoate are added and
the mixture is stirred for about another 12 hours. The
solution is evaporated to dryness in vacuo and taken up in
ethyl acetate. After washing with saturated NaHCO3
solution, saturated NaCl solution and water, the organic
phases are dried over MgSO4 and evaporated down in vacuo.
After crystallisation in a suitable solvent or
chromatography on silica gel with a suitable eluant, the
following compounds are obtained.
1. methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl)-
3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1)
Yield: 81%
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2. methyl 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoate
Crystallised from methanol
Yield: 75%
Melting point: 149 C
3. methyl 4-(4-(4-fluorophenylcarbonyl)-1-piperazinyl)-
3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1)
Yield: 77%
4. methyl 4-(4-(2-methoxyphenylcarbonyl)-1-piperazinyl)-
3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1)
Yield: 79%
5. methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1-
piperazinyl)-3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1)
Yield: 83%
6. methyl 4-(4-phenylcarbonyl-l-piperazinyl)-3-
trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1)
Yield: 87%
7. methyl 4-(4-(2-furylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1)
Yield: 75%
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8. methyl 4-(4-(3-methylphenylcarbonyl)-1-piperazinyl)-
3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1)
Yield: 79%
9. methyl 4-(4-(4-(l-pyrryl)phenylcarbonyl)-1-
piperazinyl)-3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1)
Yield: 87%
10. methyl 4-(4-(2-pyridylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1)
Yield: 73%
General method for preparing acyl guanidines from the
corresponding methyl carbonates:
5.09 g (127.2 mmol) of 60% NaH in white oil is washed
twice with ether and decanted off. 200 ml of absolute DMF
are added and 12.15 g (127.2 mmol) of guanidine
hydrochloride are added in small amounts with stirring
under protective gas. After stirring for 1 hour,
21.2 mmol of the corresponding methyl ester are added and
the solution is stirred for a further 2 hours at a
temperature of about 120 C. The reaction mixture is then
allowed to cool to ambient temperature, filtered and the
filtrate is evaporated down in vacuo. After
chromatography on silica gel with a suitable eluant and
conversion with ethereal hydrochloric acid or other
pharmacologically acceptable acids into the corresponding
salts, the following compounds are obtained (in the
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structural formulae which follow, the hydrogen atoms have
been omitted in the interests of clarity, provided that
they are bound to a carbon or nitrogen atom and are not
required for the understanding of the invention):
lst Example
4-(4-(4-Methoxyphenylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoylguanidine-hydrochloride
O NHZ
~N "~'NH
~+
N
I X H 'iI
H~ "~ H.
~ F F
F
0
from methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl)-
3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1)
Yield: 71%
Melting point: >200 C
MS: (M+H)' = 450 (free base)
2nd Example
4-(4-(2-PyrrOlylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoylguanidine-methanesulphonate
OII NH2
NNH
ti /. ~+
L. x 1~H3~7O3H
(I ~ ~
N F .~, F
0
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from methyl 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1)
Yield: 66%
Melting point: 246"C
MS: (M+H)' = 409 (free base)
3rd Example
4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoylguanidine-methanesulphonate
O NH2
UN"-t~NH
F
N
I~ I N J x CH3HO3H
~I F
from methyl 4-(4-(4-fluorophenylcarbonyl)-1-piperazinyl)-
3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1)
Yield: 40%
Melting point: 140 C
MS: (M+H)' = 438 (free base)
4th Example
4-(4-(2-Methoxyphenylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoylguanidine-hydrochloride
O NHZ
N '~NH
N%~
x HCI
~
F ~
O O
H3C
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from methyl 4-(4-(2-methoxyphenylcarbonyl)-l-piperazinyl)-
3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1)
Yield: 71%
Melting point: 219 C (decomposition)
MS: (M+H)' = 450 (free base)
5th Example
4-(4-(3-Trifluoromethylphenylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoylguanidine-hydr.ochloride
O NFil
' ~ ~.
N' NH
N
F
N
F~~ FFx HCI
F 0
from methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1-
piperazinyl)-3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1)
Yield: 25%
Melting point: 140 C (decomposition)
MS: (M+H)' = 488 (free base)
6th Example
4-(4-Phenylcarbonyl-l-piperazinyl)-3-trifluoromethyl-
benzoylguanidine-hydrochloride
O NHZ
N,NH
J! ,r
F
F
II F X HCI
0
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from methyl 4-(4-phenylcarbonyl-l-piperazinyl)-3-
trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1)
Yield: 64%
Melting point: 214 C
MS: (M+H)' = 420 (free base)
7th Example
4-(4-(2-Furylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-
benzoylguanidine-methanesulphonate
O NHZ
N ~~NH
[- i1 J '
O N
F " F F
0 x CH3SO3H
from methyl 4- (4- (2-furylcarbonyl) -1--piperazinyl) -3-
trifluoromethyl-benzoate
Crystallisation from ether
Yield: 19%
Melting point: 190"C (decomposition)
MS: (M+H)' = 410 (free base)
8th Example
4-(4-(3-Methylphenylcarbonyl)-1-piper.azinyl)-3-
trifluoromethyl-benzoylguanidine-methanesulphonate
0 NHz
~ 11 N~NH
N:
F
F
F x CH3SO3H
0
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from methyl 4-(4-(3-methylphenylcarbonyl)-1-piperazinyl)-
3-trifluoromethyl-benzoate
Crystallisation from methanol/ethyl acetate
Yield: 76%
Melting point: 199 C
MS: (M+H)' = 434 (free base)
9th Example
4-(4-(4-(l-Pyrrolyl)phenylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoylguanidine-dimethylsulphonate
N
J,
o~ N,~ X 2 CH3SO3H
N
F, N; ~NH
FT ; ~;
F O NH2
from methyl 4-(4-(4-(l-pyrryl)phenylcarbonyl)-1-
piperazinyl)-3-trifluoromethyl-benzoate
Crystallisation from methanol
Yield: 48%
Melting point: 150 C (decomposition)
MS: (M+H)' = 485 (free base)
10th Example
4-(4-(2-Pyridylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-
benzoylguanidine-dimethanesulphonate
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O N
~
F. N NH
F"
F O NHz
X 2 CH3S03H
from methyl 4-(4-(2-pyridylcarbonyl)-l-piperazinyl)-3-
trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1)
Yield: 34%
Melting point: 115 C (decomposition)
MS: (M+H)' = 421 (free base)
Pharmacological data
Inhibition of the Na'/H' exchanger in human intestinal
cancer cells (HT-29):
HT-29 cells are incubated in growth medium at 37 C with 5%
COz. After 3-5 days the growth medium was removed, the
cells were washed and charged with 7.5 M of BCECF-AM (pH-
sensitive fluorescent dye) at 37 C without CO2. After 30
minutes the cells were washed and acidified with the
following medium: 70 mM choline chloride, 20 mM NH4C1,
1 mM MgCl2, 1.8 mM CaClz, 5 mM glucose and 15 mM HEPES, pH
7.5.
After 6 minutes' incubation at 37 C without C02 the cells
are washed, and incubated for 5 minutes with wash medium:
120 mM choline chloride, 5 mM KC1, 1 mM MgC12, 1.8 mM
CaC17, 5 mM glucose and 15 mM MOPS, pH 7Ø
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The wash medium is removed and control medium is added
with or without the test compound: 120 mM NaCl, 5 mM KC1,
1 mM MgClz, 1.8 mM CaCl2, 5mM glucose, 15 mM MOPS, pH 7Ø
The cells are incubated for 4 minutes at 37 C without COz
and measured fluorimetrically (CytoFluor 2350). The
fluorescence of the dye BCECF is measured at the
excitation wavelengths 485 nm (pH sensitive) and 440 nm
(non-pH sensitive) and at the emission wavelength 530 nm.
The cytoplasmic pH is calculated from the ratio of
fluorescences at 485 and 440 nm. The fluorescence ratio
is calibrated by measuring the fluorescent signal after
equilibration of external and internal pH with nigericin.
Example IC50/10-" mol 1-1
1 0.076
3 0.038
4 0.084
5 0.023
7 0.084
8 0.061
10 0.079
The compounds according to the invention also surprisingly
have very good bioavailability and long half-lives after
oral administration - properties which make them
exceptionally suitable for oral use.
Pharmacokinetic data:
Male rats weighing about 200 g (not starved) were used for
the tests. For intravenous and oral administration the
substances are dissolved in an acidified aqueous solution
(pH 3). Individual bolus injections (0.5 mg/kg i.v.,
2.5 mg/kg p.o.) are injected into the caudal vein
(0.2 ml/200 g) or administered through a cannula into the
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- 27 -
stomach (1 ml/200 g). The solutions administered are
analysed to confirm the dosage given. 0.5 ml aliquots of
blood are taken from the retroorbital venous plexus under
brief halothane anaesthesia with heparinised glass
capillaries according to the following plan:
- after i.v. administration: 5 min, 15 min, 30 min, 1 h,
2 h, 4 h, 6 h, 8 h;
- after oral administration: 15 min, 1 h, 2 h, 4 h, 6 h,
8 h, 24 h, 32 h.
The samples are centrifuged and the plasma is stored at
-20 C until ready to be analysed. Preparation of the
samples is carried out by liquid-liquid extraction with an
internal standard. The plasma extracts are analysed by
reversed phase HPLC, coupled with an electrospray tandem
mass spectrometer.
The pharmacokinetic data is determined from the
corresponding plasma concentrations by compartment-free
analysis using the TopFit program (Heinzel, G.,
Woloszczak, R., Thomann, P. TopFit 2.0 - Pharmacokinetic
and pharmacodynamic data analysis, system for the PC,
Gustav Fischer Verlag, Stuttgart, Jena, New York, 1993).
Example F t12 (i.v.) t12 (p.o.)
2 63 1.3 5.0
3 71 3.1 5.4
5 58 5.4 7.5
