U.S. patent application number 09/901624 was filed with the patent office on 2001-12-06 for heterocyclically substituted benzoylguanidines, process for their preparation, their use as medicaments or diagnostics, and medicaments comprising them.
Invention is credited to Albus, Udo, Jansen, Hans-Willi, Kleemann, Heinz-Werner, Lang, Hans-Jochen, Weichert, Andreas.
Application Number | 20010049446 09/901624 |
Document ID | / |
Family ID | 7926515 |
Filed Date | 2001-12-06 |
United States Patent
Application |
20010049446 |
Kind Code |
A1 |
Weichert, Andreas ; et
al. |
December 6, 2001 |
Heterocyclically substituted benzoylguanidines, process for their
preparation, their use as medicaments or diagnostics, and
medicaments comprising them
Abstract
Heterocyclically substituted benzoylguanidines of the formula I
1 in which the substituents R(1) to R(4) have the meanings
indicated in the claims. These compounds I are suitable as
antiarrhythmic pharmaceuticals having a cardioprotective component
for infarct prophylaxis and infarct treatment, and also for the
treatment of angina pectoris. They also preventively inhibit the
pathophysiological processes in the formation of ischemically
induced damage, in particular in the elicitation of ischemically
induced cardiac arrhythmias.
Inventors: |
Weichert, Andreas;
(Egelsbach, DE) ; Albus, Udo; (Florstadt, DE)
; Jansen, Hans-Willi; (Niedernhausen, DE) ;
Kleemann, Heinz-Werner; (Bischofsheim, DE) ; Lang,
Hans-Jochen; (Hofheim, DE) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT &
DUNNER LLP
1300 I STREET, NW
WASHINGTON
DC
20005
US
|
Family ID: |
7926515 |
Appl. No.: |
09/901624 |
Filed: |
July 11, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09901624 |
Jul 11, 2001 |
|
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09692317 |
Oct 20, 2000 |
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Current U.S.
Class: |
548/304.4 ;
548/354.1 |
Current CPC
Class: |
C07D 249/08 20130101;
A61P 9/10 20180101; C07D 233/56 20130101; C07D 235/06 20130101;
A61P 3/10 20180101; A61P 25/02 20180101; A61P 3/06 20180101; C07D
231/12 20130101; A61P 37/00 20180101; A61P 13/08 20180101; A61P
9/00 20180101; A61P 35/00 20180101; A61P 25/00 20180101 |
Class at
Publication: |
548/304.4 ;
548/354.1 |
International
Class: |
C07D 235/14; C07D
233/56 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 22, 1999 |
DE |
19950898.4 |
Claims
We claim:
1. A heterocyclically substituted benzoylguanidine of the formula I
4in which: R(1) is --(CF.sub.2).sub.c--CF.sub.3; c is zero, 1, 2 or
3; R(2) is (C.sub.1-C.sub.9)-heteroaryl, linked via C or N, which
is unsubstituted or substituted by 1-3 substituents selected from
the group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy,
hydroxyl, amino, methylamino and dimethylamino; R(3) is H, F, Cl,
Br, I, CN, NO.sub.2 or (C.sub.1-C.sub.8)-alkyl; R(4) is H,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)-alkoxy, F, Cl, Br, I, CN
or --(CF.sub.2).sub.o--CF.sub.- 3; o is zero, 1 or2; or a
pharmaceutically tolerable salt thereof.
2. A compound of claim 1, wherein: R(1) is trifluoromethyl; R(2) is
imidazolyl or benzimidazolyl, linked via C or N, each of which is
unsubstituted or substituted by 1-3 substituents selected from the
group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy, hydroxyl,
amino, methylamino and dimethylamino; R(3) is H, F, Cl or
(C.sub.1-C.sub.4)-alkyl; R(4) is H, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkoxy, F, Cl or CF.sub.3.
3. A compound of claim 1, wherein: R(1) is trifluoromethyl; R(2) is
imidazolyl or benzimidazolyl, linked via N, each of which is
unsubstituted or substituted by 1-3 substituents selected from the
group consisting of F, Cl, CF.sub.3, CH.sub.3 and methoxy; R(3) is
H; R(4) is H, methyl, methoxy, Cl or CF.sub.3.
4. A process for preparing a compound I of claim 1, which comprises
reacting a compound of the formula II 5in which R(1) to R(4) have
the meaning indicated and L is an easily nucleophilically
substitutable leaving group, with guanidine.
5. A method of treating or preventing an illness caused by an
ischemic condition, comprising administering an effective amount of
a compound of claim 1 to a host in need of such treatment or
prevention.
6. A method of treating or preventing cardiac infarct, comprising
administering an effective amount of a compound of claim 1 to a
host in need of such treatment or prevention.
7. A method of treating or preventing angina pectoris, comprising
administering an effective amount of a compound of claim 1 to a
host in need of such treatment or prevention.
8. A method for the treatment or prevention of an ischemic
condition of the heart, comprising administering an effective
amount of a compound of claim 1 to a host in need of each treatment
or prevention.
9. A method for the treatment or prevention of stroke or of an
ischemic condition of the peripheral or central nervous system,
which comprises administering an effective amount of a compound of
claim 1 to a host in need of such treatment or prevention.
10. A method for the treatment or prevention of an ischemic
condition of the peripheral organs or limbs, comprising
administering an effective amount of a compound of claim 1 to a
host need of such treatment or prevention.
11. A method of treating or preventing a state of shock, comprising
administering an effective amount of a compound of claim 1 to a
host in need of such treatment or prevention.
12. A method of protecting a transplant organ during surgical
operation or organ transplantations, comprising administering an
effective amount of a compound of claim 1 to a host in need of such
treatment.
13. A method of preserving or protecting organ transplants for
surgical measures, comprising bringing an effective amount of a
compound of claim 1 into contact with the organ transplant.
14. A method of treating an illness in which cell proliferation is
a primary or secondary cause, comprising administering an effective
amount of a compound of claim 1 to a host in need of such
treatment.
15. A method of treating or protecting a disorder of fat
metabolism, comprising administering an effective amount of a
compound of claim 1 to a host in need of such treatment or
protection.
16. A pharmaceutical composition, comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
Description
[0001] This application claims the benefit of foreign priority
under 35 USC .sctn.119 to German patent application no. 19950898.4,
filed on Oct. 22, 1999, the contents of which are incorporated by
reference herein.
[0002] The invention relates to heterocyclically substituted
benzoylguanidines of the formula I 2
[0003] in which:
[0004] R(1) is --(CF.sub.2).sub.c--CF.sub.3;
[0005] c is zero, 1, 2 or 3;
[0006] R(2) is (C.sub.1-C.sub.9)-heteroaryl, linked via C or N,
which is unsubstituted or substituted by 1-3 substituents selected
from the group consisting of F, Cl, CF.sub.3, CH.sub.3, methoxy,
hydroxyl, amino, methylamino and dimethylamino;
[0007] R(3) is H, F, Cl, Br, I, CN, NO.sub.2 or
(C.sub.1-C.sub.8)-alkyl;
[0008] R(4) is H, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkoxy, F, Cl, Br, I, CN or
--(CF.sub.2).sub.o--CF.sub.3;
[0009] o is zero, 1 or 2;
[0010] and their pharmaceutically tolerable salts.
[0011] Preferred compounds of the formula I are those in which:
[0012] R(1) is trifluoromethyl;
[0013] R(2) is imidazolyl or benzimidazolyl, linked via C or N,
each of which is unsubstituted or substituted by 1-3 substituents
selected from the group consisting of F, Cl, CF.sub.3, CH.sub.3,
methoxy, hydroxyl, amino, methylamino and dimethylamino;
[0014] R(3) is H, F, Cl or (C.sub.1-C.sub.4)-alkyl;
[0015] R(4) is H, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)-alkoxy, F, Cl or CF.sub.3;
[0016] and their pharmaceutically tolerable salts.
[0017] Very particularly preferred compounds of the formula I are
those in which:
[0018] R(1) is trifluoromethyl;
[0019] R(2) is imidazolyl or benzimidazolyl, linked via N, each of
which is unsubstituted or substituted by 1-3 substituents selected
from the group consisting of F, Cl, CF.sub.3, CH.sub.3 and
methoxy;
[0020] R(3) is H;
[0021] R(4) is H, methyl, methoxy, Cl or CF.sub.3;
[0022] and their pharmaceutically tolerable salts.
[0023] (C.sub.1-C.sub.9)-heteroaryl is understood as meaning
radicals which are derived from phenyl or naphthyl, in which one or
more CH groups are replaced by N and/or in which at least two
adjacent CH groups are replaced by S, NH or O (with formation of a
five-membered aromatic ring). In addition, one or both atoms of the
condensation site of bicyclic radicals (such as in indolizinyl) can
also be nitrogen atoms.
[0024] (C.sub.1-C.sub.9)-heteroaryl is in particular furanyl,
thienyl, pyrrolyl, imidazolyl, benzimidazole, pyrazolyl, triazolyl,
tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl,
isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl;
very particularly imidazolyl or benzimidazolyl.
[0025] If one of the substituents R(1) to R(4) contains one or more
asymmetric centers, these can be either of the S or R
configuration. The compounds can be present as optical isomers, as
diastereomers, as racemates or as mixtures thereof.
[0026] The designated alkyl radicals can be either straight-chain
or branched.
[0027] The invention furthermore relates to a process for the
preparation of the compound I, which comprises
[0028] reacting compounds of the formula II 3
[0029] in which R(1) to R(4) have the meaning indicated and L is an
easily nucleophilically substitutable leaving group, with
guanidine.
[0030] The activated acid derivatives of the formula II, in which L
is an alkoxy group, preferably a methoxy group, a phenoxy group, a
phenylthio, methylthio or 2-pyridylthio group, a nitrogen
heterocycle, preferably 1-imidazolyl, are advantageously obtained
in a manner known per se from the underlying carbonyl chlorides
(formula II, L=Cl), which in turn can be prepared in a manner known
per se from the underlying carboxylic acids (formula II, L=OH), for
example using thionyl chloride.
[0031] In addition to the carbonyl chlorides of the formula II
(L=Cl), further activated acid derivatives of the formula II can
also be prepared directly from the underlying benzoic acid
derivatives (formula II, L=OH) in a manner known per se, such as,
for example, the methyl esters of the formula II where L=OCH.sub.3
by treating with gaseous HCl in methanol, the imidazolides of the
formula II by treating with carbonyldiimidazole [L=1-imidazolyl,
Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)], the mixed
anhydrides II using Cl--COOC.sub.2H.sub.5 or tosyl chloride in the
presence of triethylamine in an inert solvent, and also the
activation of benzoic acids using dicyclohexylcarbodiimide (DCC) or
using
O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium
tetrafluoroborate ("TOTU") [Proceedings of the 21st European
Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu,
Escom, Leiden, 1991]. A number of suitable methods for the
preparation of activated carboxylic acid derivatives of the formula
II are indicated stating source literature in J. March, Advanced
Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p.
350.
[0032] The reaction of an activated carboxylic acid derivative of
the formula II with guanidine is carried out in a manner known per
se in a protic or aprotic polar but inert organic solvent.
Methanol, isopropanol and THF from 20.degree. C. up to the boiling
temperature of these solvents have proven suitable here in the
reaction of the methyl benzoates (II, L=OMe) with guanidine. Most
reactions of compounds II with salt-free guanidine were
advantageously carried out in aprotic inert solvents such as THF,
dimethoxyethane and dioxane. However, using a base such as, for
example, NaOH, water can also be used as a solvent in the reaction
of II with guanidine.
[0033] If L=Cl, the reaction is advantageously carried out with
addition of an acid scavenger, e.g. in the form of excess guanidine
for -removing the hydrohalic acid.
[0034] Some of the underlying benzoic acid derivatives of the
formula II are known and described in the literature. The unknown
compounds of the formula II can be prepared by methods known from
the literature. The benzoic acids obtained are reacted to give
compounds I according to the invention according to one of the
process variants described above.
[0035] The introduction of some substituents into the 2, 3, 4 and 5
positions is possible by methods, known from the literature, of
palladium-mediated cross-coupling of aryl halides or aryl triflates
with, for example, organostannanes, organoboronic acids or
organoboranes or organocopper or -zinc compounds.
[0036] In general, benzoylguanidines I are weak bases and can bind
acid with formation of salts. Possible acid addition salts are
salts of all pharmacologically tolerable acids, for example
halides, in particular hydrochlorides, lactates, sulfates,
citrates, tartrates, acetates, phosphates, methylsulfonates,
p-toluenesulfonates.
[0037] European Patents EP 602 523 (HOE 92/F 405) and EP 640 588
(HOE 93/F 254) describe benzoylguanidines of similar constitution,
which also carry fluorinated alkyl substituents in the 5 position
in addition to a multiplicity of other substituents R(1), and can
also carry (C.sub.1-C.sub.9) heteroaryls in the 4 position in
addition to a multiplicity of substituents. However, it was not to
be foreseen that these compounds having fluoroalkyl and hetaryl
substitution especially would display an outstanding action.
[0038] Surprisingly, the compounds according to the invention are
NHE inhibitors which additionally inhibit the noninactivating
sodium channel (veratridine-activatable sodium channel) induced
during ischemia, to which the outstanding action can be attributed.
As a result of their pharmacological properties, the compounds are
outstandingly suitable as antiarrhythmic pharmaceuticals having a
cardioprotective component for infarct prophylaxis and infarct
treatment, and also for the treatment of angina pectoris, where
they also preventively inhibit or greatly decrease the
pathophysiological processes in the formation of ischemically
induced damage, in particular in the elicitation of ischemically
induced cardiac arrhythmias. Because of their protective actions
against pathological hypoxic and ischemic situations, the compounds
of the formula I according to the invention can be used, as a
result of inhibition of the cellular Na.sup.+/H.sup.+ exchange
mechanism, as pharmaceuticals for the treatment of all acute or
chronic damage caused by ischemia or illnesses induced primarily or
secondarily thereby. This relates to their use as pharmaceuticals
for surgical interventions, e.g. in organ transplantations, where
the compounds can be used for the protection of organs in the donor
before and during removal, for the protection of removed organs,
for example during treatment with or storage thereof in
physiological bathing fluids, and also during transfer to the
recipient's body. The compounds are also valuable pharmaceuticals
having a protective action when carrying out angioplastic surgical
interventions, for example on the heart and also on peripheral
vessels. Corresponding to their protective action against
ischemically induced damage, the compounds are also suitable as
pharmaceuticals for the treatment of ischemias of the nervous
system, in particular of the CNS, where they are suitable, for
example, for the treatment of stroke or of cerebral edema.
Moreover, the compounds of the formula I according to the invention
are also suitable for the treatment of forms of shock, such as, for
example, of allergic, cardiogenic, hypovolemic and of bacterial
shock.
[0039] Moreover, the compounds of the formula I according to the
invention are distinguished by strong inhibitory action on the
proliferation of cells, for example fibroblast cell proliferation
and the proliferation of smooth vascular muscle cells. The
compounds of the formula I are therefore suitable as valuable
therapeutics for illnesses in which cell proliferation is a primary
or secondary cause, and can therefore be used as
antiatherosclerotics, agents against diabetic late complications,
carcinomatous diseases, fibrotic diseases such as pulmonary
fibrosis, hepatic fibrosis or renal fibrosis, organ hypertrophy and
hyperplasia, in particular in prostate hyperplasia or prostate
hypertrophy.
[0040] The compounds according to the invention are efficacious
inhibitors of the cellular sodium/proton antiporter
(Na.sup.+/H.sup.+ exchanger), which is raised in numerous diseases
(essential hypertension, atherosclerosis, diabetes etc.) even in
those cells which are easily accessible to measurements, such as,
for example, in erythrocytes, platelets or leukocytes. The
compounds according to the invention are therefore suitable as
excellent and simple scientific tools, for example in their use as
diagnostics for the determination and differentiation of certain
forms of hypertension, but also of atherosclerosis, of diabetes,
proliferative diseases etc. Moreover, the compounds of the formula
I are suitable for preventive therapy for the prevention of the
genesis of high blood pressure, for example of essential
hypertension.
[0041] Pharmaceuticals which contain a compound I can in this case
be administered orally, parenterally, intravenously, rectally or by
inhalation, the preferred administration being dependent on the
particular course of the disease. The compounds I can be used here
on their own or together with pharmaceutical excipients, namely
both in veterinary and in human medicine.
[0042] The person skilled in the art is familiar on the basis of
his/her expert knowledge with excipients which are suitable for the
desired pharmaceutical formulation. In addition to solvents,
gel-forming agents, suppository bases, tablet excipients and other
active compound carriers, it is possible to use, for example,
antioxidants, dispersants, emulsifiers, antifoams, flavor
corrigents, preservatives, solubilizers or colorants.
[0043] For an oral administration form, the active compounds are
mixed with the additives suitable for this, such as vehicles,
stabilizers or inert diluents, and brought by means of the
customary methods into the suitable administration forms, such as
tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic
or oily solutions. Inert carriers which can be used are, for
example, gum arabic, magnesia, magnesium carbonate, potassium
phosphate, lactose, glucose or starch, in particular corn starch.
In this case, preparation can be carried out both as dry and as
moist granules. Possible oily vehicles or solvents are, for
example, vegetable or animal oils, such as sunflower oil or
cod-liver oil.
[0044] For subcutaneous or intravenous administration, the active
compounds, if desired with the substances customary for this such
as solubilizers, emulsifiers or further excipients, are brought
into solution, suspension or emulsion. Suitable solvents are, for
example, water, physiological saline solution or alcohols, e.g.
ethanol, propanol, glycerol, in addition also sugar solutions such
as glucose or mannitol solutions, or otherwise a mixture of the
various solvents mentioned.
[0045] Suitable pharmaceutical formulations for administration in
the form of aerosols or sprays are, for example, solutions,
suspensions or emulsions of the active compound of the formula I in
a pharmaceutically acceptable solvent, such as, in particular,
ethanol or water, or a mixture of such solvents.
[0046] If desired, the formulation can also contain still other
pharmaceutical excipients such as surfactants, emulsifiers and
stabilizers and also a propellant. Such a preparation customarily
contains the active compound in a concentration of approximately
0.1 to 10, in particular from approximately 0.3 to 3, % by
weight.
[0047] The dose of the active compound of the formula I to be
administered and the frequency of administration depend on the
potency and duration of action of the compounds used; additionally
also on the type and severity of the illness to be treated and on
the sex, age, weight and individual responsiveness of the mammal to
be treated.
[0048] On average, the daily dose of a compound of the formula I in
the case of a patient weighing approximately 75 kg is at least
0.001 mg/kg, preferably 0.01 mg/kg, at most 10 mg/kg, preferably 1
mg/kg, of body weight. In the case of acute episodes of the
illness, for example immediately after suffering a cardiac infarct,
even higher and especially more frequent doses may also be
necessary, e.g. up to 4 individual doses per day. In particular in
the case of i.v. administration, for example in the case of an
infarct patient in the intensive care unit, up to 200 mg per day
may be necessary.
EXPERIMENTAL SECTION
General Procedure for the Preparation of Benzoylguanidines (I)
Variant A: from benzoic acids (II, L=OH)
[0049] 1.0 eq of the benzoic acid derivative of the formula II is
dissolved or suspended in anhydrous THF (5 ml/mmol) and then
treated with 1.1 eq of carbonyldiimidazole. After stirring for 2
hours at RT, 5.0 eq of guanidine are introduced into the reaction
solution. After stirring overnight, the THF is distilled off under
reduced pressure (Rotavapor), the residue is treated with water,
the mixture is adjusted to pH 6 to 7 using 2N HCl and the
corresponding benzoylguanidine (formula 1) is filtered off. The
benzoylguandines thus obtained can be converted into the
corresponding salts by treating with aqueous, methanolic or
ethereal hydrochloric acid or other pharmacologically tolerable
acids.
General Procedure for the Preparation of Benzoylguanidines (I)
Variant B: from alkyl benzoates (II, L=O-alkyl)
[0050] 1.0 eq of the alkyl benzoate of the formula II and 5.0 eq of
guanidine (free base) are dissolved in isopropanol or suspended in
THF and heated to reflux (typical reaction time 2 to 5 h) until
conversion is complete (thin-layer checking). The solvent is
distilled off under reduced pressure (Rotavapor), the residue is
taken up in EA and the mixture is washed 3.times. with NaHCO.sub.3
solution. It is dried over Na.sub.2SO.sub.4, the solvent is
distilled off in vacuo and the residue is chromatographed on silica
gel using a suitable eluent, e.g. EA/MeOH 5:1.
[0051] (For salt formation compare variant A)
EXPERIMENTAL SECTION
[0052] Abbreviations
[0053] DCI direct chemical ionization
[0054] DMF N,N-dimethylformamide
[0055] ES+ electrospray ionization
[0056] eq equivalents
[0057] EtOH ethanol
[0058] h hour
[0059] HCl hydrogen chloride
[0060] LM solvent
[0061] MeOH methanol
[0062] NaOH sodium hydroxide solution
[0063] RF reflux
[0064] RT room temperature
[0065] M.P. melting point
[0066] THF tetrahydrofuran
[0067] TMEDA tetramethylethylenediamine
EXAMPLE 1
4-N-Imidazolyl-3-trifluoromethylbenzoylguanidine
Dihydrochloride
[0068] Colorless crystals, m.p. 244-248.degree. C.
[0069] Synthesis Route
[0070] a) 4-N-Imidazolyl-3-trifluoromethylbenzoylguanidine from
4-fluoro-3-trifluoromethylbenzoic acid by activation with 1.2 eq of
carbonyldiimidazole in THF at 50.degree. C. After stirring for 1.5
h, 3 eq of guanidine and 2 eq of imidazole are added, then the
mixture is stirred at 120.degree. C. in DMF for a further 7 h and
then subjected to aqueous work-up. The product precipitates as a
solid and is filtered off with suction,
[0071] m.p. 245-250.degree. C., M.sup.++H=298 (DCI).
[0072] b) 4-N-lmidazolyl-3-trifluoromethylbenzoylguanidine
dihydrochloride from 1 a) using 0.5 N EtOH/HCl at RT; the solid is
filtered off with suction.
EXAMPLE 2
4-N-(4'-Methylimidazolyl)-3-trifluoromethylbenzoylguanidine
Dihydrochloride
[0073] Colorless crystals, m.p. 236.degree. C.
[0074] Synthesis Route
[0075] a) 4-Fluoro-3-trifluoromethylbenzoylguanidine from methyl
4-fluoro-3-trifluoromethylbenzoate by guanidation using 3 eq of
guanidine in THF for 2 h at RF, followed by aqueous work-up and
suction filtration of the solid, m.p. 165.degree. C., M.sup.++H=250
(ES.sup.+).
[0076] b)
4-N-(4'-Methylimidazolyl)-3-trifluoromethylbenzoylguanidine from 2
a) by nucleophilic replacement of the fluorine atom using 2 eq of
4-methylimidazole in the presence of 6 eq of potassium carbonate in
DMF with heating to 100.degree. C. for 10 h. After aqueous work-up,
purification by column chromatography follows,
[0077] M.sup.+H=312 (ES.sup.+).
[0078] c)
4-N-(4'-Methylimidazolyl)-3-trifluoromethylbenzoylguanidine
dihydrochloride from 2 b) using ether/HCl at RT; the solid is
filtered off with suction.
EXAMPLE 3
4-N-(4',5'-Dimethylimidazolyl)-3-trifluoromethylbenzoylguanidine
Dihydrochloride
[0079] Colorless crystals, m.p. 259-262.degree. C., M.sup.++H=326
(ES.sup.+).
[0080] Synthesis Route
[0081] a)
4-N-(4',5'-Dimethylimidazolyl)-3-trifluoromethylbenzoylguanidine
from 2 a) by nucleophilic replacement analogously to 2 b), using
4,5-dimethylimidazole. After aqueous work-up, the solid is filtered
off with suction, m.p. 264.degree. C. (dec.), M.sup.++H=326
(ES.sup.+).
[0082] b) 4-N-(4',5'-Dimethylimidazolyl)-3-trifluoromethyl
benzoylguanidine dihydrochloride from 3 a) by hydrochloride
formation analogously to 2 c).
EXAMPLE 4
4-N-Benzimidazolyl-3-trifluoromethylbenzoylguanidine
Dihydrochloride
[0083] Colorless crystals, m.p. 183.degree. C., M.sup.++H=348
(ES.sup.+).
[0084] Synthesis Route
[0085] a) 4-N-Benzimidazolyl-3-trifluoromethylbenzoylguanidine from
2 a) analogously to 3 a), using benzimidazole. After aqueous
work-up, purification by column chromatography on silica gel using
dichloromethane/methanol (20:1) follows.
[0086] b) 4-N-Benzimidazolyl-3-trifluoromethylbenzoylguanidine
dihydrochloride from 4 a) analogously to 2 c).
EXAMPLE 5
4-N-(5',6'-Dichlorobenzimidazolyl)-3-trifluoromethylbenzoylguanidine
Dihydrochloride
[0087] Colorless crystals, m.p. 226-227.degree. C.
[0088] Synthesis Route
[0089] a) Methyl 4-fluoro-3-trifluoromethylbenzoate from
4-fluoro-3-trifluoromethylbenzoic acid using 1.1 eq of
carbonylbisimidazole in THF and with stirring for 2 h at RT and
subsequent addition of an excess of methanol. After a further 2 h
at RT, an aqueous work-up follows; extraction with ethyl acetate
yields a yellowish oil, M.sup.+H=223 (DCI).
[0090] b)
4-N-(5',6'-Dichlorobenzimidazolyl)-3-trifluoromethylbenzoic acid
from 5 a) analogously to 2b), using 2 eq of
5,6-dichlorobenzimidazole, M.sup.++H=375 (ES.sup.+).
[0091] c)
4-N-(5',6'-Dichlorobenzimidazolyl)-3-trifluoromethylbenzoylguani-
dine from 5 b) by activation with 1 eq of carbonylbisimidazole at
RT for 2 h in DMF, and subsequent addition of 5 eq of guanidine
hydrochloride and 7 eq of N-ethyldiisopropylamine. After stirring
at RT for 1 h, an aqueous work-up follows, the solid is filtered
off with suction,
[0092] M.sup.+H=416 (FAB).
[0093] d)
4-N-(5',6'-Dichlorobenzimidazolyl)-3-trifluoromethylbenzoylguani-
dine dihydrochloride from 5 c) analogously to 2 c).
EXAMPLE 6
4-N-(5',6'-Dimethylbenzimidazolyl)-3-trifluoromethylbenzoylguanidine
Dihydrochloride
[0094] Colorless crystals, m.p. 255.degree. C.
[0095] Synthesis Route
[0096] a)
4-N-(5',6'-Dimethylbenzimidazolyl)-3-trifluoromethylbenzoic acid
from 5 a) by nucleophilic replacement with 2 eq of
5,6-dimethylbenzimidazole in the presence of 3.7 eq of potassium
carbonate in DMF in the course of 2 h at 120.degree. C. Aqueous
work-up, extraction with ether yields an oil, M.sup.++H=335
(ES.sup.+).
[0097] b)
4-N-(5',6'-Dimethylbenzimidazolyl)-3-trifluoromethylbenzoylguani-
dine from 6 a) by guanidation analogously to 2 a) affords a solid
after aqueous work-up,
[0098] m.p. 233.degree. C.
[0099] c)
4-N-(5',6'-DimethylbenzimidazolyI)-3-trifluoromethylbenzoylguani-
dine dihydrochloride from 5 b) analogously to 2 c).
EXAMPLE 7
4-N-(4',5'-Dimethylimidazolyl)-2-methyl-5-trifluoromethylbenzoylguanidine
Dihydrochloride
[0100] Colorless crystals, m.p. 235.degree. C.
[0101] Synthesis Route
[0102] a) Methyl 4-fluoro-2-methyl-5-trifluoromethylbenzoate by
lithiation of 4-fluoro-3-trifluoromethylbenzoic acid with 3 eq of
s-butyllithium in the presence of 2.95 eq of TMEDA at -90.degree.
C. under argon in THF and subsequent reaction with 3 eq of methyl
iodide. The mixture is warmed to RT in the course of 1.5 h and
subjected to aqueous work-up. Extraction with ethyl acetate yields
an oil, which is distilled in a bulb tube in a high vacuum and
obtained as a yellowish oil, M.sup.++H=237(DCI).
[0103] b) 4-Fluoro-2-methyl-5-trifluoromethylbenzoic acid from 7 a)
by hydrolysis with 2N NaOH in MeOH at RT overnight, followed by
aqueous work-up and extraction with ethyl acetate, M.sup.++H=223
(DCI).
[0104] c) 4-Fluoro-2-methyl-5-trifluoromethylbenzoylguanidine from
7 b) by reaction with 1.1 eq of thionyl chloride in toluene with
heating to RF for 1 h. The solvent is then evaporated and the
intermediate acid chloride is reacted at RT in THF with a solution
of 3 eq of guanidine hydrochloride and 5 eq of 2N NaOH in THF.
After aqueous work-up, the solid is filtered off with suction,
[0105] m.p. 175-177.degree. C., M.sup.++H=264 (DCI).
[0106] d)
4-N-(4',5'-Dimethylimidazolyl)-2-methyl-5-trifluoromethylbenzoyl-
guanidine from 7 c) by nucleophilic replacement with 2 eq of
4,5-dimethylimidazole in the presence of 4 eq of potassium
carbonate at 120.degree. C. in DMF in the course of 12 h. Aqueous
work-up, extraction with ethyl acetate and subsequent purification
by column chromatography (silica gel) using
dichloromethane/methanol (20:1) yields a solid,
[0107] m.p. 245.degree. C., M.sup.++H=390 (ES.sup.+).
[0108] e)
4-N-(4',5'-Dimethylimidazolyl)-2-methyl-5-trifluoromethylbenzoyl-
guanidine dihydrochloride from 7 d) analogously to 2 c).
EXAMPLE 8
4-N-Benzimidazolyl-2-methyl-5-trifluoromethylbenzoylguanidine
Dihydrochloride
[0109] colorless crystal, m.p. 199-202.degree. C.
[0110] Synthesis Route
[0111] a) 4-N-Benzimidazolyl-2-methyl-5-trifluoromethylbenzoic acid
from 7 a) by nucleophilic replacement of the fluorine with
benzimidazole analogously to 7 d) and subsequent hydrolysis using
NaOH. Aqueous work-up yields a solid, M.sup.++H=321 (ES.sup.+).
[0112] b)
4-N-Benzimidazolyl-2-methyl-5-trifluoromethylbenzoylguanidine from
8 a) by guanidation analogously to 5 c),
[0113] M.sup.++H=362 (ES.sup.+).
[0114] c)
4-N-Benzimidazolyl-2-methyl-5-trifluoromethylbenzoylguanidine
dihydrochloride from 8 b) by hydrochloride formation analogously to
2 c).
EXAMPLE 9
2-Chloro-4-N-benzimidazolyl-3-trifluoromethylbenzoylguanidine
Dihydrochloride
[0115] colorless crystals, m.p. 193-196.degree. C., M.sup.++H=382
(ES.sup.+).
[0116] Synthesis Route
[0117] a) 2-Chloro-4-fluoro-5-iodobenzoic acid from
2-chloro-4-fluorobenzoic acid by iodination with 1.2 eq of
N-iodosuccinimide in 12 eq of trifluoromethanesulfonic acid at
0.degree. C. for 2 h. The reaction mixture is added to ice/H.sub.2O
and the solid is filtered off with suction, m.p. 160-168.degree.
C., M.sup.++H=300(DCI).
[0118] b) Methyl 2-chloro-4-fluoro-5-iodobenzoate from 9a) by
esterification in MeOH/HCl at RT for 20 h, aqueous work-up and
extraction with ethyl acetate affords a yellow oil, M.sup.++H=315
(DCI).
[0119] c) Methyl 2-chloro-4-fluoro-5-trifluoromethylbenzoate from 9
b) by trifluoromethylation with 2 eq of trifluoroacetic acid
potassium salt and 2.05 eq of copper(I) iodide in DMF for 4 h at
150.degree. C. Aqueous work-up, extraction with ethyl acetate and
subsequent column chromatography on silica gel using
n-heptane/ethyl acetate (9:1) yields a brownish liquid,
[0120] M.sup.++H=257 (DCI).
[0121] d) Methyl
2-chloro-4-N-benzimidazolyl-5-trifluoromethylbenzoate from 9c) by
reaction with 1.1 eq of benzimidazole and 3.2 eq of potassium
carbonate at RT in DMF in the course of 1.5 h. Aqueous work-up and
extraction with ethyl acetate yields an oil, M.sup.++H=355
(FAB).
[0122] e) 2-Chloro-4-N-benzimidazolyl-5-trifluoromethylbenzoic acid
from 9 d) by hydrolysis with 2N NaOH in methanol at RT for 18 h.
Aqueous work-up yields a solid, M.sup.+=341 (ES.sup.+).
[0123] f)
2-Chloro-4-N-benzimidazolyl-5-trifluoromethylbenzoylguanidine from
9 e) by reaction with 2.3 eq of carbonylbisimidazole for 2 h at RT
in THF, subsequent addition of 4 eq of guanidine and stirring for a
further 3 h at RT yields, after aqueous work-up, a solid,
M.sup.++H=382(ES.sup.+).
[0124] g) Hydrochloride formation from 9 f) analogously to 2
c).
EXAMPLE 10
2-Chloro-4-N-(5',6'-dichlorobenzimidazolyl)-5-trifluoromethylbenzoylguanid-
ine Dihydrochloride
[0125] colorless crystals, m.p. 199-200.degree. C.
[0126] Synthesis Route
[0127] a) Methyl
2-chloro-4-N-(5',6'-dichlorobenzimidazolyl)-5-trifluorome-
thylbenzoate from 9 c) analogously to 10 a), but using
5,6-dichlorobenzimidazole, colorless oil, M.sup.+H=423 (FAB).
[0128] b)
2-Chloro-4-N-(5',6'-dichlorobenzimidazolyl)-5-trifluoromethylben-
zoic acid from 10 a) analogously to 9 e), colorless solid,
M.sup.++H 409 (ES.sup.+).
[0129] c)
2-Chloro-4-N-(5',6'-dichlorobenzimidazolyl)-5-trifluoromethyl-be-
nzoylguanidine from 10 b) analogously to 9 f), colorless solid,
M.sup.++H=450 (ES.sup.+).
[0130] d)
2-Chloro-4-N-(5',6'-dichlorobenzimidazolyl)-5-trifluoromethylben-
zoylguanidine dihydrochloride from 10 c) analogously to 2 c).
* * * * *