Title of Invention

BENZOYLGUANIDINE DERIVATIVES

Abstract Benzoylguanidine derivatives of general formula I, wherein (1) R1 denotes C1_8 -alkyl, heteroaryl unsubstituted or 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 NH2 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 NH2 group of a primary or secondary amino group, a trifluoromethyl group, cyano or nitro group or halogen or by a 5- or 6-membered heteroaryl group which may 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 all partial structure by a branched or unbranched C1-4 -alkyl group,:: a branched or unbranched C1-4 -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 mixture's thereof and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
Full Text FORM 2
THE PATENTS ACT 1970
[39 OF 1970]
&
The Patents Rule, 2003
COMPLETE SPECIFICATION
[See Section 10 and Rule 13]
"BENZOYLGUANIDINE DERIVATIVES WITH ADVANTAGEOUS
PROPERTIES, METHOD FOR PRODUCING THEM AND THEIR USE IN THE PRODUCTION OF MEDICAMENTS"
BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG (formerly known as BOEHRINGER INGELHEIM PHARMA KG), a German company of, D-55216 Ingelheim am Rhein, Germany,
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:-

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S018-639pct 204
New benzoylguanidine derivatives with advantageous properties, processes for preparing them and their use in
5 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
10 compositions

wherein 15
R1 denotes C1-8-alkyl,
heteroaryl unsubstituted or mono- or polysubstituted
by a branched or unbranched C1-4-alkyl group, a
20 cycloalkyl group, a branched or unbranched C1-4-alkoxy group, an NH2 group or a primary or secondary amino' group, a, trifluoromethyl group, a cyano or nitro group or halogen,
25 aryl unsubstituted or mono- or polysubstituted by a
branched or unbranched C1-4-alkyl group, a branched or unbranched C1-4-alkoxy group, an NH2 group or a primary or secondary amino group, a trifluoromethyl group, a hydroxy, cyano or nitro group or halogen or
30 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
5 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 C1-4-alkoxy group, an NH2 group or a primaryl or secondary amino group, a trifluoromethyl
10 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
15 salts with pharmacologically acceptable acids.
The preferred compounds for the purposes of the present invention are the compounds of general formula I wherein
20 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

25
The following compounds are particularly preferred:
4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine methanesulphonate
30

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4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3-
10 trifluoromethyl-benzoylguanidine methanesulphonate


C1-4-alkyl or C1-8-alkyl generally denotes a branched or unbranched hydrocarbon group haying 1 to 4 or 8 carbon
20 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:
i
25 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 -
30 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-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless
35 otherwise stated, the preferred hydrocarbon groups are lower alkyl groups having 1 to 4 carbon atoms such as

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methyl, ethyl, propyl, iso-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.
Alkoxy generally denotes a straight-chained or branched
5 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
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, nitrp groups, amino groups and/or one or more halogen atoms, which may be identical or different; the
15 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
20 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.
25
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
30 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.
35 The preferred aralkyl groups - unless otherwise stated -are benzyl, phenethyl and phenylpropyl.

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sulphur and/or up to two nitrogen atoms and which are optionally benzo-condensed are preferred.
Examples of particular heterocyclic systems include:
5 acridinyl, acridonyl, alkylpyridinyl, anthraquinonyl, ascorbyl, azaazulenyl, azabenzanthracenyl, azabenzanthrenyl, azachrysenyl, azacyclazinyl, azaindolyl azanaphthacenyl, azanaphthalenyl, azaprenyl, azatriphenylenyl, azepinyl, azinoindolyl, azinopyrrolyl,
10 benzacridinyl, benzazapinyl, benzofuryl,
benzonaphthyridinyl, benzopyranonyl, benzopyranyl, benzopyronyl; benzoquinolinyl, benzoquinolizinyl, benzothiepinyl, benzothiophenyl, benzylisoquinolinyl, bipyridinyl, butyrolactonyl, caprolactamyl, carbazolyl,
15 carbolinyl, catechinyl, chromenopyronyl, chromonopyranyl, cumarinyl, cumaronyl, decahydroquinolinyl,
decahydroquinolonyl, diazaanthracenyl, diazaphenanthrenyl, dibenzazapinyl, dibenzof-uranyl, dibenzothiphenyl, dichromylenyl, dihydrofuranyl, dihydroisocumarinyl,
20 dihydroisoquinolinyl, dihydropyranyl, dihydropyridinyl, dihydropyridonyl, dihydropyronyl, dihydrothiopyranyl, diprylenyl, dioxanthylenyl, oenantholactamyl, flavanyl, flavonyl, fluoranyl, fluoresceinyl, furandionyl, furanochromanyl, furanonyl, furanoquinolinyl, furanyl,
25 furopyranyl, ;furopyronyl, heteroazulenyl.,
hexahydropyrazinoisoquinolinyl, hydrofuranyl, hydrofuranonyl, hydroindolyl, hydropyranyl, hydropyridinyl, hydropyrrolyl, hydroquinolinyl, hydrothiochromenyl, hydrothiophenyl, indolizidinyl,
30 indolizinyl, indolonyl, isatinyl, isatogenyl,
isobenzofurandionyl, isobenzfuranyl, isochromanyl, isof lavonyl, isoindolinyl , isoindolobenzazapinyl, isoindolyl, isoquinolinyl, isoquinuclidinyl, 1actamy1, lactonyl, maleimidyl, monoazabenzonaphthenyl,
35 naphthalenyl, naphthimidazopyridindionyl,
naphthindolizinedibnyl, naphthodihydropyranyl,

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naphthofuranyl, naphthyridinyl, oxepinyl, oxindolyl, oxolenyl, perhydroazolopyridinyl, perhydroindolyl,
phenanthraqiiinonyl, phthalideisoquinolinyl, phthalimidyl,
i
phthalonyl, jpiperidinyl, piperidonyl, prolinyl, parazinyl,
5 pyranoazinyl, pyranoazolyl, pyranopyrandionyl,
i pyranopyridinyl, pyranoquinolinyl, pyranopyrazinyl,
pyranyl, pyrazolopyridinyl, pyridinethionyl,
pyridinonapHthalenyl, pyridinopyridinyl, pyridinyl,
pyridocolinyl, pyridoindolyl, pyridopyridinyl,
10 pyridopyrimijdinyl, pyridopyrrolyl, pyridoquinolinyl,
pyronyl, pyrrocolinyl,. pyrrolidinyl, pyrrolizidinyl,
pyrrolizinyl', pyrrolodioazinyl, pyrrolonyl,
pyrrolopyrimidinyl, pyrroloquinolonyl, pyrrolyl,
quinacridonyjl, quinolinyl, quinolizidinyl, quinolizinyl,
15 quinolonyl, Iquinuclidinyl, rhodaminyl, spirocumaranyl,
succinimidylj, sulpholanyl, sulpholenyl, tetrahydrof uranyl,
tetrahydroispquinolinyl, tetrahydropyranyl,
tetrahydropyridinyl, tetrahydrothiapyranyl,
tetrahydrothiophenyl, tetrahydrothipyranonyl,
20 tetrahydrothipyranyl, tetronyl, thiaphenyl, thiachromanyl,
thiadecalinyi, thianaphthenyl, thiapyranyl, thiapyronyl,
thiazolopyridinyl, thienopyridinyl, thienopyrrolyl,
thienothiophenyl, thiepinyl, thiochromenyl, thiocumarinyl,
thiopyranyl, triazaanthracenyl, triazinoindolyl,
25 triazolopyriciinyl, tropanyl, xanthenyl, xanthonyl,
xathydrolyl,!adeninyl, alloxanyl, alloxazinyl,
anthranilyl, azabenzanthrenyl, azabenzonaphthenyl,
azanaphthacehyl, azaphenoxazinyl, azapurinyl, azinyl,
azoloazinyl., azolyl, barbituric acid, benzazinyl,
30 benzimidazolethionyl, benzimidazolonyl, benzisothiazolyl,
benzisoxazoiyi, benzocinnolinyl, benzodiazocinyl,
benzodioxolanyl; benzodioxolyl, benzopyridazinyl,
benzothiazepinyl, benzothiazinyl, benzothiazolyl,
benzoxazinyl, benzoxazolinonyl, benzoxazolyl, cinnolinyl,
35 depsidinyl, diazaphenanthrenyl, diazepinyl, diazinyl,
dibenzoxazepinyl, dihydrobenzimidazolyl,

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dihydrobenzothiazinyl, dihydrooxazolyl,
dihydropyridazinyl, dihydropyrimidinyl, dihydrothiazinyl, dioxanyl, dioxenyl, dioxepinyl, dioxinonyl, dioxolanyl, dioxolonyl, dioxopiperazinyl, dipyrimidopyrazinyl,
5 dithiolanyl, dithiolenyl, dithiolyl, flavinyl, furopyrimidinyl, glycocyamidinyl, guaninyl, hexahydropyrazinoi-soquinolinyl, hexahydropyridazinyl, hydantoinyl, hydroimidazolyl, hydroparazinyl, hydropyrazolyl, hydropyridazinyl, hydropyrimidinyl,
10 imidazolinyl, imidazolyl, imidazoquinazolinyl,
imidazothiazolyl, indazolebenzopyrazolyl, indoxazenyl, inosinyl, isoalloxazinyl, isothiazolyl, isoxazolidinyl, isoxazolinonyl, isoxazolinyl, isoxazolonyl, isoxazolyl, lumazinyl, methylthyminyl, methyluracilyl, morpholinyl,
15 naphthimidazolyl, oroticyl, oxathianyl, oxathiolanyl, oxazinonyl, oxazolidinonyl, oxazolidiriyl, oxazolidonyl, oxazolinonyl, oxazolinyl, oxazolonyl, oxazolopyrimidinyl,. oxazolyl, perhydrocinnolinyl, perhydropyrroloazinyl, perhydropyrrolothiazinyl, perhydrothiazinonyl,
20 perimidinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,
phenoxazinyl, phenoxazonyl, phthalazinyl, piperazindionyl, piperazinodionyl, polyquinoxalinyl, pteridinyl, pterinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolidonyl, pyrazolinonyl, parazolinyl, pyrazolobenzodiazepinyl,
25 pyrazolonyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyrazolyl, pyridazinyl, pyridazonyl, pyridopyrazinyl, pyridopyrimidinyl, pyrimidinethionyl, pyrimidinyl, pyrimidionyl, pyrimidoazepinyl, pyrimidopteridinyl, pyrrolobenzodiazepinyl, pyrrolodiazinyl,
30 pyrrolopyrimidinyl, quinazolidinyl, quinazolinonyl,
quinazolinyl, quinoxalinyl, sultamyl", sultinyl, sultonyl, tetrahydrooxazolyl, tetrahydropyrazinyl, tetrahydropyridazinyl, tetrahydroquinoxalinyl, tetrahydrothiazolyl, thiazepinyl, thiazinyl,
35 thiazolidinonyl, thiazolidinyl, thiazolinonyl, thiazolinyl, thiazolobenzimidazolyl, thiazolyl,

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thienopyrimidinyl, thiazolidinonyl, thyminyl, triazolopyrimidinyl, uracilyl, xanthinyl, xylitolyl, azabenzonaphththenyl, benzofuroxanyl, benzothiadiazinyl, benzotriazepinonyl, benzotriazolyl, benzoxadiazinyl,
5 dioxadiazinyl, dithiadazolyl, dithiazolyl, furazanyl,
furoxanyl, hydrotriazolyl, hydroxytrizinyl, oxadiazinyl, oxadiazolyl> oxathiazinonyl, oxatriazolyl, pentazinyl, pentazolyl, pentazinyl, polyoxadiazolyl, sydonyl, tetraoxanyl, tetrazepinyl, tetrazinyl, tetrazolyl,
10 thiadiazinyl, thiadiazolinyl, thiadiazolyl,
thiadioxazinyl, thiatriazinyl, thiatriazolyl, thiatriazolyl, triazepinyl, triazinoindolyl, triazinyl, triazolinedionyl, triazolinyl, triazolyl, trioxanyl, triphenodioxazinyl, triphenodithiazinyl,
15 trithiadiazepinyl, trithianyl or trioxolanyl.
:Compounds of this type are already known from German published application 196 01 303.8.
20 As a result of their effect as inhibitors of cellular NaVH+ 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
25 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
30 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
35 operations, for supporting open heart surgery, for
supporting operations which require the blood supply to

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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
5 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
10 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.
15 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
20 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
25 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
30 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
35 proliferation of cells. Consequently, the compounds are useful drugs in the treatment of diseases in which cell

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proliferation plays a primary or secondary role and may be used as drugs against cancers, benign tumours or for example prostate hypertrophy, atherosclerosis, organ hypertrophy and hyperplasia, fibrotic diseases and late
5 complications of diabetes.
Moreover, compounds of this type are known to have a favourable effect on the blood levels of the serum lipoproteins.
10
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.
15
The active substances according to general formula I may
intravenous, intramuscular or subcutaneous
20 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 suppositor;
25 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 2 0 mg. The above doses may be
30 administered several times a day if necessary.
The following are some examples' of pharmaceutical preparations containing the active substance:
35 Tablets:

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Active substance of general formula I 20.0 mg
Magnesium stearate 1.0 mg
Corn starch 62.0 mg
Lactose 83.0 mg
5 Polyvinylpyrrolidone 1.6 mg
Solution for injection
Active substance of general formula I 0.3 g
10 Sodium chloride 0.9 g
Water for injections ad 100 ml
The solution may be sterilised by standard methods.
15 Aqueous solution for nasal administration or inhalation
Active substance of general formula I. 0.3 g
Sodium chloride 0.9 g
Benzalkonium chloride 0.01 mg
20 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
25 between 2 and 6 urn, it is suitable for administration into the lungs.
Capsules for inhalation
30 The compounds of general formula I are packed into hard gelatin capsules in micronised form (particle size essentially between 2 and 6 µM) , optionally with the addition of micronised carrier substances such as lactose. They are inhaled by means of conventional devices for
35 powder inhalation. Between 0.2 and 20 mg of the active

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5

substance of general formula I and 0 to 40 mg of lactose are packed into each capsule, for example.
Aerosol for inhalation
Active substance of general formula I 1 part
Soya lecithin 0.2 parts
Propellant gas mixture ad 100 parts

10 The preparation is preferably transferred into aerosol
containers with a metering valve, each spray delivering a dose of 0.5 mg. For other dosages in the range specified, preparations containing a larger or smaller proportion of active substance are conveniently used.
15
Ointment (composition g/100 g of ointment)
Active substance of general .formula-1 2 -g
Fuming hydrochloric acid 0.011 g
2 0 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
25 Distilled water ad 100
The ingredients are processed in the usual way to form an ointment.
3 0 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:
35 By reacting 4-(1-piperazinyl)-3-trifluoromethylbenzoic acid esters of general formula II

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5 with a compound of general formula III
R1C(O)Q (III)
wherein Q denotes a leaving group which may be substituted
10 by the piperazine nitrogen, optionally in the presence of adjuvants, preferably carbonyldiimidazole, the resulting benzoic acid derivative of general formula IV

15
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
20 solvent - preferably dimethylformamide - with a guanidine salt - preferably guanidine hydrochloride - and the reaction product is isolated.

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Halogen, unless otherwise stated - denotes fluorine, bromine and iodine, preferably fluorine, chlorine or bromine.
5
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.
10
Accordingly, alkylamino denotes for example methylamino, ethylamino, propylamino, 1-methylene-ethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1,1-dimethylethylamino.
15
Correspondingly, dialkylamino denotes, for example, dimethylamino, diethylamino, dipropylamino, dibutylamino, di- (l-methylethyl)-amino,- di- (1-methylpropyl) amino, di-2 -methylpropylamino, ethylmethylamino, methylpropylamino.
20
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
25 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,
30 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
35 to which another aromatic ring may be fused. 5- and 6-membered aromatic rings which contain an oxygen, a

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The present invention is illustrated by the Examples which
follow:

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Examples:
Methyl 4-fluoro-3-trifiuoromethyl-benzoate
5 35.4 g (170 mmol) of 4-fluoro-3-(trifiuoromethyl)-benzoic acid in 250 ml of methanol are mixed with 68 ml of S0C12, 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
10 ambient temperature and evaporated down in vacuo. The oily residue is taken up in 200 ml of diethylether and extracted with water, saturated NaHC03 solution and again with water. The combined organic phases are dried over magnesium sulphate and evaporated down in vacuo.
15
Yield: 29.0 g (77%)
Methyl 4-(4-benzyl-l-piperazinyl)-3-trifluoromethyl-
benzoate 20
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
25 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
30 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%) 35

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Methyl 4-(1-piperazinyl)-3-trifluoromethyl-benzoate
20.2 g (53.3 mmol) of methyl 4- (4-benzyl-l-piperazinyl)-3-trifluoromethyl-benzoate are dissolved in 200 ml of
5 methanol and combined 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.
10 Yield: 14.85 g (97%)
General method of coupling methyl 4-(1-piperazinyl)-3-trifluoromethyl-benzoate with benzoic acids:
15 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-^or 2 hours at ambient temperature (about 25°C). Then 1.44 g (5 mmol) of methyl
20 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 NaHC03 solution, saturated NaCl solution and water, the organic
25 phases are dried over MgS04 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.
30 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. 5 Yield: 75%
Melting point: 149°C
3. methyl 4-(4-(4-fluorophenylcarbonyl)-1-piperazinyl)-
3-trifluoromethyl-benzoate
10
Column chromatography: ethyl acetate/n-heptane (2:1) . Yield: 77%
4. methyl 4-(4-(2-methoxyphenylcarbonyl)-1-piperazinyl)-
15 3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 79%
20 5. methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 83%
25
6. methyl 4-(4-phenylcarbonyl-1-piperazinyl)-3-
trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1) 30 . Yield: 87%
7. methyl 4-(4-(2-furylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoate
35 Column chromatography: ethyl acetate/n-heptane (2:1) Yield: 75%

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10

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- (1-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)-3-15 trifluoromethyl-benzoate
Column chromatography: ethyl acetate/n-heptane (2:1)
Yield: 73% -
20 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
25 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
30 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
35 pharmacologically acceptable acids into the corresponding salts, the following compounds are obtained (in the

WO 00/17176 - 20 - PCT/EP99/06857
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):
5
1st Example
4-(4-(4-Methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-hydrochloride
10

15
from methyl 4-(4-(3-methoxyphenylcarbonyl)-1-piperazinyl)-
3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1) Yield: 71%
20 Melting point: >200°C
MS: (M+H)+ = 450 (free base)
2nd Example
25 4-(4-(2-Pyrrolylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoylguanidine- methanesulphonate

WO 00/17176 - 21 - PCT/EP99/06857
from methyl 4-(4-(2-pyrrolylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1) Yield: 66%
5 Melting point: 246°C
MS: (M+H)-+ = 409 (free base)
3rd Example
10 4-(4-(4-Fluorophenylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoylguanidine-methanesulphonate

from methyl 4-(4-(4-fluorophenylcarbonyl)-1-piperazinyl)-2 20 3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1)
Yield: 40%
Melting point: 140°C
MS: (M+H)+ = 438 (free base)
25
4th Example
4-(4 -(2-Methoxyphenylcarbonyl)-1-piperazinyl) -3 -trifluoromethyl-benzoylguanidine-hydrochloride


WO 00/17176 - 22 - PCT/EP99/06857
from methyl 4-(4-(2-methoxyphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1) Yield: 71%
5 Melting point: 219°C (decomposition)
MS: (M+H)+ = 450 (free base)
5th Example
10 4-(4-(3-Trifluoromethylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-hydrochloride

from methyl 4-(4-(3-trifluoromethylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate
20 Column chromatography: ethyl acetate/methanol (5:1) Yield: 25%
Melting point: 140°C (decomposition) MS: (M+H)+ = 488.(free base)
25 6th Example
4-(4-Phenylcarbonyl-l-piperazinyl)-3-trifluoromethyl-benzoylguanidine -hydrochloride


WO 00/17176 - 23 - PCT/EP99/06857
from methyl 4-(4-phenylcarbonyl-l-piperazinyl)-3-trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1) Yield: 64%
5 Melting point: 214°C
MS: (M+H)+ = 420 (free base)
7th Example
10 4-(4-(2-Furylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-methanesulphonate

from methyl 4-(4-(2-furylcarbonyl)-1-piperazinyl)-3-20 trifluoromethyl-benzoate
Crystallisation from ether
Yield: 19%
Melting point: 190°C (decomposition)
MS: (M+H)+ = 410 (free base) 25
8th Example
4-(4-(3-Methylphenylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoylguanidine-methanesulphonate
30


WO 00/17176 - 24 - PCT/EP99/06857
from methyl 4-(4-(3-methylphenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate
Crystallisation from methanol/ethyl acetate Yield: 76%
5 Melting point: 199°C
MS: (M+H)+ = 434 (free base)
9th Example
10 4-(4-(4-(1-Pyrrolyl)phenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine-dimethylsulphonate

from methyl 4-(4-(4-(1-pyrryl)phenylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoate Crystallisation from methanol Yield: 48%
25 Melting point: 150oC (decomposition) MS: (M+H)+ = 485 (free base)
10th Example
30 4-{4-(2-Pyridylcarbonyl)-1-piperazinyl)-3-trifluoromethyl-benzoylguanidine -dimethanesulphonate

WO 00/17176 - 25 - PCT/EP99/06857

10 from methyl 4-(4-(2-pyridylcarbonyl)-1-piperazinyl)-3-
trifluoromethyl-benzoate
Column chromatography: ethyl acetate/methanol (5:1)
Yield: 34%
Melting point: 115°C (decomposition) 15 MS: (M+H)+ = 421 (free base)
Pharmacological data
Inhibition of the Na+/H+ exchanger in human intestinal
20 cancer cells (HT-29):
HT-29 cells are incubated in growth medium at 37°C with 5% C02. After 3-5 days the growth medium was removed, the cells were washed and charged with 7.5 µM of BCECF-AM (pH-
25 sensitive fluorescent dye) at 37°C without C02. 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 CaCl2, 5 mM glucose and 15 mM HEPES, pH 7.5.
30
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 KCl, 1 mM MgCl2, 1.8 mM CaCl2, 5 mM glucose and 15 mM MOPS, pH 7.0.
35

WO 00/17176 - 26 - PCT/EP99/06857
The wash medium is removed and control medium is added with or without the test compound.: 120 mM NaCl, 5 mM KCl, 1 mM MgCl2, 1.8 mM CaCl2, 5mM glucose, 15 mM MOPS, pH 7.0.
5 The cells are incubated for 4 minutes at 37°C without C02 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.
10 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 IC50/10-6 mol 1-1
1 0.076
3 0.038
4 0.084
5 0.023
7 0.084
8 0.061
10 0.079
15
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.
20
Pharmacokinetic data:
Male rats weighing about 200 g (not starved) were used for the tests. For intravenous and oral administration the
25 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

WO 00/17176 - 27 - PCT/EP99/06857
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
5 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, 10 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
15 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
20 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).
25

Example F ti/2 (i.v.) ti/2 (P-O.)
2 63 1.3 5.0
3 71 3.1 5.4
5 58 5.4 7.5
Reference is hereby made to the entire contents of the disclosure of German Patent Application No. 198 43 489, from which the present- Patent Application claims priority.

We Claim:
1. Benzoylguanidine derivatives of general formula I,

wherein
(i)
R1 denotes C1-8-alkyl,
heteroaryl unsubstituted or 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 NH2 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 NH2 group of a primary or secondary amino group, a trifluoromethyl group, cyano or nitro group or halogen or by a 5- or 6-membered heteroaryl group which may 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 C1-4 alkoxy group, an NH2 group or a primary-6r 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.

2. Compounds of general formula I as claimed in claim 1, characterized in that
R1 may. denote 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

3. 4- (4- (2-Pyrrolylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-methanesulphonate

4. 4- (4- (4-Fluorophenylcarbonyl) -1-piperazinyl) -3-trifluoromethyl-benzoylguanidine-methanesulphonate

(IV)
5. Pharmaceutical preparation, characterized in that it contains a
compound as claimed in one of claims 1 to 4 and the acid addition salts
thereof together with conventional excipients an carries.


6. Use of compounds as claimed in one of claims 1 to 4 as pharmaceutical compositions.
7. Use of compounds after use of compounds as claimed in claim 6 as pharmaceutical compositions having an inhibitory effect on the Na+/H+ exchange.
8. Use ot compounds of general formula I, the acid addition salts thereof for preparing a medicament for the therapeutic treatment of ischaemias.
9. Benzoylguanidine derivatives of general formula I as herein described in accompanying drawings.
JUNE

Dated this [f* day of February




Documents:

601-MUMNP-2005 FORM 13.pdf

601-mumnp-2005-cancelled page(28-8-2008).pdf

601-MUMNP-2005-CANCELLED PAGES(24-2-2009).pdf

601-MUMNP-2005-CANCELLED PAGES(28-8-2008).pdf

601-MUMNP-2005-CLAIMS(24-02-2009).pdf

601-MUMNP-2005-CLAIMS(28-8-2008).pdf

601-mumnp-2005-claims(amended)-(24-2-2009).pdf

601-mumnp-2005-claims(complete)-(13-6-2005).pdf

601-mumnp-2005-claims(granted)-(18-11-2010).pdf

601-mumnp-2005-claims.doc

601-mumnp-2005-claims.pdf

601-mumnp-2005-correspondence(12-4-2006).pdf

601-MUMNP-2005-CORRESPONDENCE(14-9-2012).pdf

601-MUMNP-2005-CORRESPONDENCE(24-02-2009).pdf

601-MUMNP-2005-CORRESPONDENCE(26-5-2009).pdf

601-MUMNP-2005-CORRESPONDENCE(28-8-2008).pdf

601-mumnp-2005-correspondence(ipo)-(16-1-2009).pdf

601-mumnp-2005-correspondence(ipo)-(18-11-2010).pdf

601-mumnp-2005-correspondence-received-ver-061205.pdf

601-mumnp-2005-correspondence-received-ver-110605.pdf

601-mumnp-2005-descripiton (complete).pdf

601-mumnp-2005-description(complete)-(13-6-2005).pdf

601-MUMNP-2005-DESCRIPTION(COMPLETE)-(24-2-2009).pdf

601-MUMNP-2005-DESCRIPTION(COMPLETE)-(28-8-2008).pdf

601-mumnp-2005-description(granted)-(18-11-2010).pdf

601-mumnp-2005-english transalation(12-4-2006).pdf

601-mumnp-2005-form 13(28-8-2008).pdf

601-mumnp-2005-form 1(13-6-2005).pdf

601-MUMNP-2005-FORM 1(28-8-2008).pdf

601-mumnp-2005-form 13(26-5-2009).pdf

601-mumnp-2005-form 13(28-8-2008).pdf

601-mumnp-2005-form 2(24-2-2009).pdf

601-mumnp-2005-form 2(28-8-2008).pdf

601-mumnp-2005-form 2(complete)-(13-6-2005).pdf

601-mumnp-2005-form 2(granted)-(18-11-2010).pdf

601-MUMNP-2005-FORM 2(TITLE PAGE)-(24-2-2009).pdf

601-MUMNP-2005-FORM 2(TITLE PAGE)-(28-8-2008).pdf

601-mumnp-2005-form 2(title page)-(complete)-(13-6-2005).pdf

601-mumnp-2005-form 2(title page)-(granted)-(18-11-2010).pdf

601-MUMNP-2005-FORM 26(14-9-2012).pdf

601-mumnp-2005-form 3(13-6-2005).pdf

601-MUMNP-2005-FORM 3(28-8-2008).pdf

601-mumnp-2005-form-1.pdf

601-mumnp-2005-form-13(28-8-2008).pdf

601-mumnp-2005-form-18.pdf

601-mumnp-2005-form-2.doc

601-mumnp-2005-form-2.pdf

601-mumnp-2005-form-3.pdf

601-mumnp-2005-form-5.pdf

601-mumnp-2005-form-pct-ipea-409.pdf

601-MUMNP-2005-OTHER DOCUMENTS(28-8-2008).pdf

601-MUMNP-2005-PETITION UNDER RULE 137(28-8-2008).pdf

601-MUMNP-2005-PETITION UNDER RULE 138(28-8-2008).pdf

601-MUMNP-2005-POWER OF AUTHORITY(28-8-2008).pdf

601-mumnp-2005-power of authority(7-3-2006).pdf

601-mumnp-2005-power of authority(9-3-2006).pdf

601-mumnp-2005-specification(amanded)-(28-8-2008).pdf

601-mumnp-2005-wo international publication report(12-4-2006).pdf


Patent Number 244113
Indian Patent Application Number 601/MUMNP/2005
PG Journal Number 47/2010
Publication Date 19-Nov-2010
Grant Date 18-Nov-2010
Date of Filing 13-Jun-2005
Name of Patentee BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG
Applicant Address D-55216 INGELHEIM AM RHEIN
Inventors:
# Inventor's Name Inventor's Address
1 STEFAN-MATTHIAS BLECH MULLERWEG 9 D-8844 WARTHAUSEN
2 ERICH BURGER LEIPZIGSTRASSE 7A D-55411 BINGEN AM RHEIN
3 CHRISTAIN EICKMEIER FUNCHSTRASSE 12 D-65187 WIEBADEN
PCT International Classification Number C07D295/00
PCT International Application Number PCT/EP99/06857
PCT International Filing date 1999-09-16
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 19843489.8 1998-09-22 U.K.