NZ250437A - Heterocyclic benzoylguanidines and medicaments - Google Patents
Heterocyclic benzoylguanidines and medicamentsInfo
- Publication number
- NZ250437A NZ250437A NZ250437A NZ25043793A NZ250437A NZ 250437 A NZ250437 A NZ 250437A NZ 250437 A NZ250437 A NZ 250437A NZ 25043793 A NZ25043793 A NZ 25043793A NZ 250437 A NZ250437 A NZ 250437A
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- methyl
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- hydrogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Cardiology (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Quinoline Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Compositions Of Macromolecular Compounds (AREA)
Abstract
Benzoylguanidines of the formula I <IMAGE> where R(1) is hydrogen, Hal, -NO2, -C IDENTICAL N, -CF3, R(4)-SOm or R(5)R(6)N-SO2-, R(4) and R(5) being alk(en)yl, or CF3, with R(5) also having the meaning of H, R(2) is heteroaryl, or -SR(10), -OR(10), -NR(10)R(11) or -CR(10)R(11)R(12); where R(10) is -CaH2a-heteroaryl, R(11) and R(12) are defined as R(10) or are hydrogen or alkyl, R(3) is defined as R(1) or is alkyl or -X-R(13), where X is oxygen, S or NR(14), and R(13) is H or (cyclo)alkyl, are described. They are obtained from a compound II <IMAGE> by reaction with guanidine. The compounds are outstandingly suitable for use as anti-arrhythmic drugs (medicaments, pharmaceuticals) having a cardioprotective component for the prophylaxis and treatment of infarction and also for the treatment of angina pectoris, the compounds also inhibiting or strongly reducing, in a preventive manner, the pathophysiological processes associated with the occurrence of ischemically-induced damage, in particular in association with the triggering of ischemically-induced cardiac arrhythmias.
Description
New Zealand Paient Spedficaiion for Paient Number £50437
0 4 3 7
f
Priority Date(s):
Patents Form 5
Complete Specification Filed:
Class:
Qty. W W; JrO.7), .y£> §. !.££•.. t^c-i /Q<3
PubRcation Date: .2..Z..F.E.B...199S
P.O. Journal No:
NO DRAWING
N.Z. No.
NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION
SUBSTITUTED BENZOYLGUANIDINES. PROCESS FOR THEIR PREPARATION. THEIR USE AS PHARMACEUTICAL OR DIAGNOSTIC. AND PHARMACEUTICAL CONTAINING THEM
We, HOECHST AKTflENGESELLSCHAFT, a Joint Stock Company existing under the laws of the Federal Republic of Germany, of D-65926 Frankfurt am Main, Federal ^public of Germany, do hereby declare the invention, for which we pray that a patent nvay be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: -
- 1 - (Followed by 1A)
Description
- 1A -
259457
Substituted benzoylguanidines, process for their preparation, their use as pharmaceutical or diagnostic, and pharmaceutical containing • them
The invention relates to benzoylguanidines of the formula I
R(1)
R(2)
0)
in which
*
R(l) = hydrogen, F, CI, Br, I, -N02, -C=N, R(16)-cpH2p-oq (wherein p is 0, 1, 2 or 3, q is 0 or 1, R(16)
is CrF2r+1 and r is 1, 2 or 3) , R(4)—SOm or R(5) R (6)N-S02-, where 10 m is zero, 1 or 2,
R (4) and R(5) are the same or different and are (C,-C8)-alkyl, (Q-Cj-alkenyl, -C^-R (7), or CFj,
n is zero, 1, 2, 3 or 4,
R (7) is (C3-C7) -cycloalkyl, or phenyl which is 15 unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, CI, CF3,
methyl, methoxy and NR(8)R(9) , where R(8) and R(9)
are the same or different and are H or C,-C4-alkyl, and R(5) can also mean H,
»
R(S) is H or (C^-Cj) -alkyl, where R(5) and R(6) 20 together can be 4 or 5 methylene groups, of which one CEj group can be replaced by oxygen, S, NH,
N-CHj or N-benzyl,
R(2) = (Ci-Cj)-heteroaryl which is linked via C or N and which is unsubstituted or substituted by 1-3
/V <•
substituents selected from the group consisting of ,
t!
F, CI, CF3, CH3, methoxy, hydroxy, amino, methyl^ .• ' ;,
amino and dimethylamino; or ^
-SR(10), -OR(10) , -NR(10)R(11), -CR(10)R(11) R(12) ; V rv /
W - 2 -
R(10) =» -CaH,a- (Cj-C,) -heteroaryl which is unsbustituted or substituted by 1-3 substituents selected from the group consisting of F, CI, CF3, CE^ methoxy, hydroxyl, amino, methyl amino and dime thy 1 amino, 5 a is zero, 1 or 2,
R(ll) and R(12) independently o£ one another have the definition given for R(10) or are hydrogen or (Ci-Cj -alkyl,
R (3) has the definition given for R(l) or is (Cj^Cj) -10 alkyl or -X-R(13) in which
X is oxygen, S, NR(14), where R(14) is E or (C1-C3) -alkyl,
R(13) is H, (CirCs)-alkyl, (C3-C8)-cycloalkyl,
-CjjH^-R (15) where b is zero, 1, 2, 3 or 4, it 15 also being possible for R(13T and R(14) together to be 4 or 5 methylene groups and for a CE, group to be replaced by oxygen, S, NE, N-CE3 or N-benzyl, and
R(15) is phenyl which is unsubstituted or substi-20 tuted by 1-3 substituents selected from the group consisting of F, CI, CF3, methyl, methoxy and NR (8) R(9), where R(8) and R(9) are the same or different and are H or (Cj-C4)-alkyl,
with the exception of compounds I in which are simutaneously R(l) is R(4)-SOm or R^NSQj, and R (2) is (Q-C^-heteroaryl,
and, the pharmaceutically acceptable salts thereof.
Preferred compounds of the formula I are those in which:
R(l) = hydrogen, F, CI, -CsN, R(16)-CpH2p-Oq (wherein p is
0, 1, 2 or 3, q is 0 or 1, R(16) is CrF2r+I and r is
1, 2 or 3), R(4)—-SO,,, or R(5)R(6)N-S02-, where m is zero, 1 or 2,
R(4) and R(5) are the same or different and are (C,-C8)-alkyl, (C3--C3E2a-R(7) or -CF3,
n is zero or 1, V
- 2A -
R (7) is (C3-C() -cycloallcyl or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, CI, CF3,
methyl, methoxy and NR(8)R(9), where R(8) and R(9) are the same or different and are H or methyl,
R(5) also having the meaning of H, and R(6) is H or methyl,
I
R(3) ■ hydrogen, methyl, cyano* -CF,, F or CI,
and the remaining radicals are as defined above,
with the exception of compounds I in which are simutaneously R (1) is R(4)-S0m or R^NSOj, and R (2) is (Q-C^-heteroaryl,
and the pharmaceutically acceptable salts thereof. Particularly preferred compounds I are those in which:
R (1) = hydrogen, F, CI, -CsN, •>-CF3, R(4)-S0a or R(5)R(6)N-S02, where m is zero, 1 or 2, R(4) is methyl or CF3, and R(5) and R(6) independently of one another are E or methyl;
R(2) = (Ci-Cj)-heteroaryl which is linked via C or N and which is unsubstituted or substituted by a radical selected from the series consisting of F, CI, CF3, CH3, methoxy and dime thy 1 amino; or -SR (10) , -08(10) , -NR (10 ) R (11) , -CR(10)R(11)R (12);
R(10) is -C^Hj,-(Cj-C,)-heteroaryl, which is unsubstituted or substituted by a radical selected from the series consisting of F, CI, CF3, CH3, methoxy and dime thy 1 amino;
a is zero, 1 or 2, and
R(ll) and R(12) independently of one another are • hydrogen or methyl;
R(3) is methyl, cyano, trifluoromethyl, F, Cl or hydrogen,
with the exception of compounds I in which a|?fe simutaneously> lj^
R(l) is R(4)-SOn orJl^NSOj, and |i5~
R(2) is (Q-Cy-heteroaryl, V
and the pharmaceutically acceptable salts thereof.
0 4
- 3A -
(Ci-Cs) -Heteroaryl is to be understood as meaning, in particular, radicals which are derived from phenyl or naphthyl and in which one or more CE groups are replaced by N and/or in which at least twc adjacent CH groups (while forming a five-membered aromatic ring) are
t
2 5 0 4 3
replaced by 8, NH or O. Moreover, It 1b also possible for one or both atoms of the condensation site of bicyclic radicals (as in indolizihyl) to be N atoms.
Heteroaryl means, in particular, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, guinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, guinazolinyl or cinnolinyl.
If one of the substituents R(l) to R(22) contains one or more asymmetric centers, they can have either the S or the R configuration. The compounds can exist as optical isomers, diastereomers, racemates or mixtures of these.
The alkyl radicals which have been mentioned can be straight-chain or branched.
The invention furthermore relates to a process for the preparation of the compound I, which comprises reacting compounds of the formula II
0
with guanidine, R(l) to R(3) having the abovementioned meaning and L being a leaving group which can readily be substituted by a nucleophile.
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, or a nitrogen heterocycle, preferably 1-imidazolyl, are obtained advantageously in a manner known per se from the carbonyl chlorides (formula II,
2S^ n P "V
J y H s
L ss CI) on which they are based and which, in turn, can be prepared in a manner known per se from the carboxylic acids (formula II, L = OH) on which they are based, for example thionyl chloride.
In addition to the carbonyl chlorides of the formula II (L = CI), other activated acid derivatives of the formula II can also be prepared, in a manner known per se, directly from the benzoic acid derivatives (formula II, L = OH) on which they are based, for example the methyl esters of the formula II where L = OCH3 by treatment with gaseous HCl in methanol, the imidazolides of the formula II by treatment with carbonyl diimidazole [L = imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-3 67 (1962)], the mixed anhydrides II with C1-C00C2HS or tosyl chloride in the presence of triethylamine in an inert solvent, and benzoic acids can be activated with dicyclo-hexylcarbodiimide (DCC) or with 0- [ (cyano(ethoxycar-bonyl)methylene)amino] -1,l,3,3-tetramethyluronium tetra-fluoroborate ("TOTU")[Proceedings of the 21. European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A series of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II can be found in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350, where the references are cited.
An Activated carboxylic acid derivative of the formula I is reacted with guanidine in a manner known per se in a protic or aprotic polar, but inert, organic solvent. Methanol, isopropanol or THF have proven themselves in the reaction of the methyl benzoates (II, L = OMe) with guanidine, the temperatures being 20 to the boiling point of these solvents. In most reactions of compounds II with salt-free guanidine, the process was advantageously carried out in aprotic inert solvents, such as THF, dimethoxyethane or dioxane. Even so, water together with a base such as NaOH, can be used as solvent in the reaction of II and III.
250^37
If L = Cl, the process is carried out advantageously with an addition of an acid scavenger, for example in the form of excess guanidine, to bind the hydrohalic acid.
Some of the basic benzoic acid derivatives of the formula 5 II are known and described in the literature. The unknown compounds of the formula II can be prepared by methods known from the literature, for example by converting 4-(or 5-)halo-3-chlorosulfonylbenzoic acids with ammonia or amines into 3-aminosulfonyl-4-(or -5-)halobenzoic 10 acids, or by converting 4-(or 5-)halo-3-chlorosulfonyl-benzoic acids with a mild reducing agent, such as sodium bisulfite and subsequently alkylating the product to give
3-alkylsulfonyl-4- (or -5-)halobenzoic acids, and reacting the benzoic acids obtained by one of the above-described
process variants to give compounds I according to the invention.
Some substituents can successfully be introduced into the
4- and 5-position by methods which are known from the literature, namely palladium-mediated cross coupling of
aryl halides with, for example, organostannanes, organo-boric acids or organoboranes, or organocopper or organo-zinc compounds.
In general, benzoylguanidines are weak bases and can bind acid with the formation of salts. Suitable acid addition 25 salts are Baits of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates and p-toluenesulfonates.
The compounds I are substituted acylguanidines. The best-30 known representative of the acylguanidines is the pyraz-ine derivative amiloride, which is used in therapy as a potassium-retaining diuretic. A large number of other amiloride-type compounds are described in the literature, for example diemthylamiloride or ethylisopropylamiloride.
0 NH CI II II
N-S/(V\h
R * M i „ NH
R ' '
\
N NH
H
2
Amiloride: R', R" = H Dimethylamiloride: R', R" = CH3 Ethylisopropylaniiloride: R' = CaHs, R" = CH(CH3)2
Moreover, tests are known which suggest that amiloride 5 has antiarrhythmic properties (Circulation 79, 1257-63 (1989) . However, its broad use as cm antiarrhythmic is restricted by the fact that this effect is only weakly pronounced and accompanied by a hypotensive and saluretic activity, and these side effects are undesired in the 10 treatment of cardiac arrhythmias.
Experiments on isolated animal hearts have also suggested that amiloride has antiarrhythmic properties (Eur. Heart J. 9 (suppl. 1): 167 (1988) (book of abstracts). For example, it has been found on rats' hearts that arti-15 ficially induced ventricular fibrillation cam. be suppressed completely by amiloride. In this model, the abovementioned amiloride derivative ethylisopropylamiloride was even more potent than amiloride itself.
US Patent 5,091,394 (HOE 89/F 288) describes benzoyl-20 guanidines which have a hydrogen atom in the position which corresponds to the radical R(l). German Patent Application P 42 04 575.4 corresponding to NZ 245894 and US 5 373024 (HOE 92/F__034) proposes 3,5- substituted benzoylguanidines in which, however, the substituents R(2) and R(3) do not have the meani „ 25 claimed in the present invention. jj^;
ss. -v <\ r r.
? R H ■' ¥ '7
- U - -V O / - 8 -
US Patent 3,780,027 claims acylguanidines whose structure is similar to those of the compounds I and which are derived from commercially available loop diuretics, such as bumetanide. Accordingly, a powerful saluretic activity 5 is reported of these compounds.
It was therefore surprising that the compounds according to the invention have no undesired, disadvantageous saluretic properties, but have a very good activity against arrhythmias as thev occur, for example, in 10 connection with oxygen deficiencies. Due to their pharmacological properties, the compounds are highly suitable for use as antiarrhythmics with a cardioprotective component for the prophylaxis and treatment of cardiac infarctions and for the treatment of angina pectoris, in 15 which context they also preventively inhibit, or reduce greatly, the pathophysiological processes in the formation of ischemia-induced damage, in particular when ischemia-induced cardiac arrhythmias are triggered. Due to inhibition of the cellular Na+/H+ exchange mechanism, 20 the compounds of the formula I according to the invention, which have a protective activity against pathological hypoxic and ischemic situations, can be used as pharmaceuticals for the treatment of all acute or chronic damage triggered by ischemia or for the treatment 25 of directly or collaterally induced diseases. This applies to their use as pharmaceuticals for surgical intervention, for example in connection with organ transplants, where the compounds can be used for the protection of the organs in the donor before and during 30 their removal, for the protection of removed organs, for example in their treatment with, or storage in, physiological baths, and for the transfer into the r<£ci.ir>,4 ent organism. Equally, the compounds are valuable protective pharmaceuticals when angioplastic curative 35 5.J5fctfx-rentioau n.rc carried out, for example on the heart or 021 peripheral blood vessels. Due to their protective acStS.vi 'cy against ischemia-induced damage, the compounds are also suitable as pharmaceuticals for the treatment of
ischemias o£ the nervous system, in particular, the central nervous system, where they are suitable, for example, for the treatment of apoplexes and brain edemas. Moreover, the compounds of the formula I according to the 5 invention are also suitable for the treatment of forms of shock, for example allergic, cardiogenic, hypovolemic and bacterial shock.
Moreover, the compounds of the formula I according to the invention are distinguished by powerful inhibitory action 10 on cell proliferations, for example fibroblast prclifera-tion and proliferation of the smooth vascular muscle cells. This is why the compounds of the formula I are suitable as valuable therapeutic agents for diseases in which cell proliferation is a primary or secondary cause, 15 and they can therefore be used as antiatherosclerotics, agents against diabetic late complication#, cancars, fibrotic disorders, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, organ hypertrophies and hyperplasias, in particular in prostatic hyperplasia or 20 prostatic hypertrophia.
The compounds according to the invsation are valuable inhibitors of the cellular sodium proton antiporter (Na+/H+ exchanger), which is elevated in a large number of diseases (essential hypertension, atherosclerosis, 25 diabetes and the like) wen in those cells which are readily accessible to measurements, such as in erythrocytes, thrombocytes or leukocytes. The compounds according to the invention are therefore f?uitable as outstanding and simple scientific tools, for example in 30 their use as diagnostics for determining* and distinguishing between, certain forms of hypertension, but also of atherosclerosis, diabetes? proliferative disorders and the like. Moreover, the compounds of the formula I are suitable for preventivo therapy for pre-35 venting the genesis of hypertension, such as of essential hypertension.
# 2 5 0 o. 7 7
In contrast to the known compounds, the solubility in water of the compounds according to the invention is significantly improved. They are therefore much better suited to intravenous administration♦
Pharmaceuticals which contain a compound I can be administered orally, parenterally, intravenously, rectally or by inhaling, thia preferred way of administration depending on the particular symptom of the disease. The compounds I can be used by themselves or together with 10 galenic auxiliaries, and they can be employed both in veterinary medicine and human medicine.
A person skilled in the art knows, on the basis ot his expert knowledge, which auxiliaries are suitable for the desired pharmaceutical formulation. Auxiliaries which can 15 be used in addition to solvents, gel formers, bases for suppositories, tableting auxiliaries, and other excipi-ents for active substances are, for example, antioxidants, diepersants, emulsifiers, antifoan-B, flavor improvers, preservatives, solubilizers or colorants,
For an oral dosage form, the active compounds together with the suitable additives, trnch as carriers, stabilizers or in-ert diluents, are mixed and formulated by customary methods to give suitable dosaga forms, such as tablets, sugar-coated tablets, hard gelatin capsules, or 25 aqueous, alcoholic or oily solutions. Inert excipxents which can be used ar«. for example, gum arahic, magnesia, magnesium carbor.s.ta, potassium phosphate, lactose, glucose or starch, in particular maize starch. Dry granules or moist granules cs.n be used for the prepstra-30 tion. Examples of oily excipienta or examples of solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.
For subcutaneous or intravenous administration, the active compounds, if desired together with the substances 35 which are customary for this purpose, such as
2 5 0 4 o 7
- ii -
solubilizers, emulsifiers or other auxiliaries, are dissolved, suspended or emulsified. Examples of suitable solvents are: water, physiological saline or alcohols, for example ethanol, propanol, glycerol, and also sugar 5 solutions, such as glucose or mannitol solutions, or else a mixture of the various solvents which have been mentioned above.
Pharmaceutical formulations which are suitable for administration in the form of aerosols or sprays are, for 10 example, solutions, suspensions or emulsions of the active substance of the formula I in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or else in a mixture of such solvents.
If required, the formulation can also contain other 15 pharmaceutical auxiliaries, such as surfactants, emulsifiers and stabilizers, and a propellent gas. The concentration of active substance in such a preparation is generally from about 0.1 to 10, in particular from about 0.3 to 3 % by weight.
The dose of the active substance of the formula I to be administered and the frequency of administration will depend on the power and duration of action of the compounds used; in addition also on the nature and severity of the disease to be treated and on the sex, age, weight 25 and individual responsiveness of the mammal to be treated.
On average, the daily dosage rate of a compound of the formula I in the case of a patient of approximately 75 kg will be at least 0.001 mg/kg, preferably 0.01 mg/kg, up 30 to not more than 10 mg/kg, preferably 1 mg/kg, of body weight. If the disease is acute, such as immediately after suffering a cardiac infarction, even higher and, in particular, more frequent, doses may be required, for example up to 4 single doses per day. In particular, for 35 intravenous administration, such as in the case of a patient who has suffered an infarction and is under
intensive care, up to 200 mg per day may be required. List of abbreviations:
MeOH
methanol
DMF
N, N-dimethylf ormamide
MBS
N-bromosuccinimide
AIBN
a,a-azobis-isobutyronitrile
EI
electron impact
DCI
desorption chemical ionization
RT
room temperature
EA
ethyl acetate (EtOAc)
DIP
diisopropyl ether
MTB
methyl tert.-butyl ether mp melting point
HEP
n-heptane
DME
dime thoxyethane
FAB
fast atom bombardment
CHaCla dichloromethane
THF
tetrahydrofuran eq equivalent
Experimental part
General protocol for the preparation of benzoylguanidines (I)
Variant As from benzoic acid (II, L - OH)
0.01 M of the benzoic acid derivative of the formula II 25 is dissolved or suspended in 60 ml of anhydrous THF, and 1.78 g (0.011 M) of carbon/ldiimidazole are then added. The mixture is stirred for 2 hours at RT, and 2.95 g (0.05 M) of guanidine are then introduced into the reaction solution. The mixture is stirred overnight, and 30 the THF is then distilled off under reduced pressure (Rotavapor), water is added, the mixture is brought to pH 6 to 7 using 2N HCl, and th« corresponding benzoylguanid-ine (formula I) is removed by filtration. The resulting benzoylguanidines can be converted into the corresponding
0 4
salts by treating them with aqueous, methanolic or etheric hydrochloric acid or other pharmacologically acceptable acids.
General protocol for the preparation of benzoylguanidines (I)
Variant B: from alkyl benzoates (II, L = O-alkyl)
mmol of the alkyl benzoate of the formula II and 25 mmol of guanidine (free base) are dissolved in 15 ml of isopropsmol or suspended in 15 ml of THF, and the solutions, or suspensions, are refluxed until the reaction is complete (control by thin-layer chroEiatography; typical reaction time 2 to 5 hours). The solvent is distilled off under reduced pressure (Rotavapor), the residue is taken up in 300 ml of EE, and the mixture is washed 3 x using in each case 50 ml of NaHC03 solution. The ethyl acetate phase is dried over Na2SC4, the solvent is distilled off in vacuo, and the residue is chromatographed on silica gel using a suitable solvent, for example E3/MeOH 5:1. (Salt formation see Variant A)
Example 1
4-(4-Pyridylthio)-3-methylsulfonylbenzoylguanidine
HjCOjS Y NH2
0
a) Methyl 4-(4-pyridylthio)-3-methylsulfonylbenzoate
6 mmol of methyl 4-chloro-3-methylsulfonylbenzoate, 18 mmol of K2C03 and 6 mmol of 4-pyridylthiol are stirred in 30 ml of (anhydrous) DMF for 1 h at 130°C. The mixture is subsequently poured into 100 ml of saturated aqueous NaHCOj solution, and this is extracted 3 x using 100 ml of E£ The ethyl acetate phase is dried over Na2S04, the
2504 3 7
solvent is removed in vacuo, and th€i residue is chromatographed on silica gel using MTB. Pale yellow crystals, mp 112°C,
Rf(MTB) =0.17 MS (DCI): 324 (M + 1)
b) 4-(4-Pyridylthio)-3-methylsulfonylbenzoylguanidine
3.6 mmol of ester 1 a) and 18.1 mmol of guanidine are reacted in accordance with general protocol B. White crystals, mp 205°C
Rf (EE/MeOH 5:1) = 0.24 MS (DCI): 351 (M + 1)
Example 2
4-(2-Pyridylthio)-3-methylsulfonylbenzoylguanidine
CHjOJS J NH2
0
mp 207°C
Rf (BA/MeOH 5:1) = 0.27 MS (DCI): 351 (M + 1)
Example 3
4-(3-Pyridyloxy)-3-methylsulfonylbenzoylguanidine
HJCOjS [J NHJ
0
a) Methyl 4-(3-pyridyloxy)-3-methylsulfonylbenzoate
2 mmol of methyl 4-chloro-3-methylsulfonylbenzoate, 2 mmol of 3-pyridinol and 6 mmol of R2C03 were stirred in 20 ml of (anhydrous) DMF for 2 h at 130°C. The mixture is
0 4 3 7
^ b -.;f e subsequently poured into 100 ml of saturated aqueous NaHC03 solution and this is extracted 3 x using 100 ml of EA. The ethyl acetate phase is dried over Na2S04, the solvent is removed in vacuo, and the product is further 5 reacted without further purification.
Rf (MTB) = 0.15 MS (DCI): 308 (M + 1)
b) 4-(3-Pyridyloxy)-3-methylsulfonylbenzoic acid
2 mmol o£ ester 3 a) are dissolved in 20 ml of MeOH, and 5 equivalents of 2N aqueous NaOH are added. The solution 10 is stirred for 3 h at RT, 50 ml of 0.3 M aqueous KH2P04 solution are added, and the mixture is extracted 3 x using 50 ml of EA. The ethyl acetate phase is dried over Na2S04 solution, the solvent is removed in vacuo, and the product is further reacted without further purification. 15 Rf (EE/MeOH 5:1) = 0.14 MS (DCI): 294 (M+l)
c) 4-(3-Pyridyloxy)-3-methoxysulfonylbenzoylguanidine
2 mmol of benzoic acid 3 b), 2.2 mmol of carbonyldiimid-azole and 10 mmol of guanidine are reacted in accordance with the general protocol A.
White crystals mp 2C2°C
Rf (EA/MeOH) 5:1) - 0.38 MS (DCI): 335 (M + 1)
The title compounds of Examples 4 to 10 are synthesized analogously to Example 3:
Example 4
4-(2-Pyridyloxy)-3-methylsulfonylbenzoylguanidine
- 16
2 5 (1 4 *
i vy
CHjOjS If NH.
0
t amorphous;
Rf (EA/MeOH 5:1) = 0.41 Example 5
MS (DCI): 335 (M + 1)
4-(4-Pyridyloxy)-3-methylsulfonylbenzoylguanidine
\XX
NH
N
NH2
0
CH302S
amorphous;
Rf (EA/MeOH 3:1) = 0.22
MS (DCI): 335 (M + 1)
Example 6
4- (7-Isoguinolinoxy) -3-methylsul£onylbenzoylguanidiiie
.0,
HjC02S
mp 103 to 105°C Rf (EA/MeOH 5:1) = 0.23
MS (DCI): 385 (M + 1)
Example 7
4- (5-Isoquinolinoxy) -3-methylsulfonyili<sazoylguaiiidine
t
0 4 5 7
- 17
HjC02S
amorphous ;
Rf (EA/toluene/MeOH 3:3:1) = 0.21 MS (DCI): 335 (M 4 1) Example 8
4-(5-Quinolinoxy)-3-methylsulfonylbenzoylguanidine
amorphous;
Rf (EA/MeOH 5:1) = 0.23
MS (DCI) : 385 (M + 1)
Example 9
4-(6-Quinolinoxy)-3-methylsulfonylbenzoylguanidine
A
~ NH
^ ^ M-HjC02S^ f. NH
amorphous;
Rf (EA/toluene/MeOH 3;3:1) = 0.24 MS (DCI): 385 (M + 1)
18
Example 10
4- (8 -Quinolinoxy) -3 -methylsulf onylbenzoylguanidine nh2
nh2
0
amorphous;
Rf (EA/MeOH 5:1) = 0.23
MS (DCI) : 385 (M + 1)
General protocol for the preparation of 4-(l-pyirolo)-benzoic acids:
0.01 mole of a 4-aminobenzoic acid are dissolved in 20 ml glacial acetic acid and then 0.01 mole of 2,5-dimethoxy-tetrahydrofuran are added. The mixture is stirred for 15 minutes at room temperature and for 1 hour while boiling. Then the mixture is allowed to cool and is poured into 200 ml of water. The crystalline precipitation is filtered off, is washed a few times with water and the obtained 4-(l-pyrroio)-benzoic acid is dried in the aii.
The subsequent reaction of a 4-(l-pyrrolo)benzoic acid with guanidine after a preceding activation with carbonyldiimidazol results according to the general protocol A for the preparation of benzoyl guanidines in the corresponding 4-(l-pyrrolo)benzoyl-guanidines respectively their salts:
Example 11:
3,5-<lichloro-4-(i-pyiTolo)benzoyl-guanidine-hydrochloride is prepared according to General protocol A from 3,5-dichloro-4-(l-pyrxolo)benzoic acid, colorless crystals, Fp. 274°C
3,5-dchloro-4-(l-pyrrolo)benzoic acid (Fp. 178 - 181°C) is prepared from 3,5-dimethyl-4-aminobenzoic acid according to the General protocol for the preparation of 4-(l-pyrrolo)-bcnzoic acids.
Example 12:
3-chloro-5-methyl-4-(l-pyrrolo)benzoyl-guanidine-hydrochloride is prepared according to General protocol A from 3-chloro-5-methyl-4-(l-pyrrolo)benzoic acid, colorless crystals, Fp. 236 - 238°C.
3-chloro-5-methyl-4-(l-pyrrolo)benzoic acid pFp« 160 - 162°C, dec.) is prepared from 3-cMoro-5-raethyl-4-aramobenzoic acid according to General protocol for the preparation of
4-( l-pyrrolo)-benzoic acids.
Example 13:
3f5-dimethyl-4-(l-pyrrolo)benzoyl-guanidine-hydrocWoride is prepared according to General protocol A from 3,5-dimethyl-4-(l-pyrrolo)benzoic acid, colorless crystals, Fp. 261 - 263°C
3^-dlraethyl-4-(l-pyiTolo)beD2oic acid (Fp. 197 - 200°C) is obtained from 3,5-dimethyl-4-aminobeozoic acid according to General protocol for the preparation of 4-(l-pyrrolo)-beczoic acids.
General protocol for the preparation of 4-[l-(l,3,4-triazolyl)]beozoic icids
0.01 mole of a methylester of a 4-aminobenzoic acid are suspended in 40 nil boiling phosphoroxichloride (POQ3) while stirring, then 0.044 mole of NjN'-diform/lhydrazine are added and then it is refluxed for 45 minutes. The excess POQ3 is distO-.ed off, and then the residue which is mostly dark and viscous is treated with 200 ml of an aqueous saturated solution of sodium acetate. The precipitation is filtered off and is washed some times with water.
0.01 mole of the obtained 4-[l-(l,3,4-triazolyl)]benzoic acid methylester is hydrolyzed with a boiling mixture of 18 ml of pure acetic acid and 36 ml of 20 per cent aqueous hydrochloric acid for 6 hours; thus, the corresponding 4-[l-(l,3,4-triazolyl)]benzoic acid is obtained.
The subsequent reaction of a 4-[l-(l>3,4-triazolyl)]benzoic add with guanidine after activation with carbonyldiimidazol furnishes the respective 4-[l-(l,3,4-triazolyl)]benzoyl-guanidine respectively their salts according to the General protocol for the preparation of benzoylguanidines.
Example 14:
3^-dibromo-4-[l-(l,3,4-triazolyl)]benzoyl-guanidine-dihydrochloride is obtained according to General protocol A from 3,5-dibromo-4-[l-(l,3,4-triazolyl)]benzoic acid, colorless crystals, Fp. >290°C.
The 3^-dibromo-4-[l-(l^,4-triazolyl)benzoic acid (Fp. 281 - 282*0) is obtained from 3,5-dibromo^-fl-^S^triazolytyJbenzoic acid methylester (Fp: 202 - 204°C) according to the General protocol for the preparation of 4-[l-(l,3,4-triazolyl)]benzoic acids.
Example 15:
4-iimdazolyl-3-trifluoromethyl-benzoylguamdme-dihydrochloride: colorless crystals, Fp. 244 - 48"C, dec.
synthesis:
a) 4-2uoro-3-trifiuoromethyl-beraoylguanidine from 4-fluoro-3-trifluoromethyl-benzoic add and guanidine according to variant A, colorless powder, Fp. 136 - 38°C.
0 A z 7
- 20 - - v V* S' -J /
b) 4«imidazolyl-3-trifluoromethyl-benzoylguanidine-dihydrochloride from a) by heating (120°C) in DMF in the presence of 2 eq imidazole for 7 hours, distilling off the solvent and treating the remainder with water. Formation of the salt according to variant A.
t
(0
in which
R(l) = hydrogen, F, CI, Br, I, -N02, -CsN, R(16)-CpH^-O,
(wherein p is 0, 1, 2 or 3, q is Oor 1, R(16)
is CrF2,+1 and r is 1, 2 or 3) , R(4) —SOm 5 or R{5)R(S)N-S02-, where m is zero, 1 or 2,
R(4) and R(5) are the same or different and are (Q-CgJ-alkyl, (C3-C6)-alkenyl,
-CgHj^-R (7), or CF3,
n is zero, 1, 2, 3 or 4,
R (7) is (C3-C7)-cycloalkyl, or phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, CI, CF3,
methyl, methoxy and NR(8)R(9) , where R(8) and R(9)
are the same or different and are H or CrC4-alkyl, and R(5) can also mean H, 15 R(6) is H or (C^-CJ-alkyl, where R(5) and R(6)
together can be 4 or 5 methylene groups, of which one CHj gxoup can be replaced by oxygen, S, NE,
N-CEj or N-benzyl,
(Cj-Cj) -heteroaryl which is linked via C or S and which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, CI, CF3, CHj, methoxy, hydroxy, amino, methy1-ami.no and dimethyl amino; or ■
/.0- - %
-SR(10), -OR(IO), -»S(10)S( 11/)V ^ '
- CR (10) R (11) R (12) ; fa ,, 'q
V . o*" $
~C,Hjb- (Cj-Cj) -heteroaryl which is unsubstituted or V t, substituted" by 1-3 substituents selected from the "•r-~
group consisting of F, CI, CF3, CH3, methoxy,
Claims (1)
- WHAT WE CLAIM IS: 1. K benzoylguanidine of the formula I R(1 ) R(2) R(3) R (2') 25 R(10) = 9 R 0 /n T " - 22 - ^ V 'i? Q £ hydroxy1, amino, methylaunino and dime thy lamino, a is zero, 1 or 2, R(ll) and R(12) independently of one smother have the definition given for R(10) or are hydrogen or 5 (Cx-C4) -alkyl, R(3) has the definition given for R(l) or is (C^-Cs) -alkyl or -X-R(13) in which X is oxygen, S, NR(14), where R(14) is H or (C^-Cj) -alkyl, 10 R(13) is H, (Cl-Cs)-alkyl, (C3-C8)-cycloalkyl, or "CijHjij-R(15) where b is zero, 1, 2, 3 or 4, it also being possible for R(13) and R(14) together to be 4 or 5 methylene groups and for a group to be replaced by oxygen, S, NH, N-CH3 or N"-15 benzyl, and R(15) is phenyl which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, CI, CF3/ methyl, methoxy and NR(8)R(9), where R(8) and R(9) are the same or different and are H or (CrC4)-alkyl, with the. exception of compounds I in which are simutaneously R(l) is R(4)-SOm or R(5)NS02, and R (2) is (C1-C9)^heteroaryl, and the pharmaceutically acceptable salts thereof. 2.'A compound of the formula I as claimed in claim 1, in which R(l) = hydrogen, F, CI, -CsN, R(16)-CpH2p-Oq (wherein p is 0, 1, 2 or 3, q is 0 or 1, R(16) is C,F2r+1 and r is 1, 2 or 3) , R(4) —SO,,, or 25 ' R(5)R(6)N-S02-, where m is zero, 1 or 2, R(4) and R(5) are the same or different and are (CrCg)-alkyl, (C3-C4)-allceftyl? -CaH2a-R(7) or -CF3/ jf? n is zero or 1, >| & <H) r? A '] 4-3 y - 23 - R (7) is (Cj-C,) -cycloalkyl, or phenyl which is un-30 substituted or substituted by 1-3 substituents selected from the group consisting of F, CI, CF3, methyl, methoxy and NR(8) R(9), where R(8) and R(9) are the same or different and are H or methyl, R(5) also having the meaning of E, and 35 R(6) is H or methyl, R(3) » hydrogen, methyl, cyano, -CF3, F or CI, and the remaining radicals are as defined in claim 1. 3. A compound of the formula I as claimed in claim 1, in which •> 5 R (1) = hydrogen, F, CI, -C=N, -CF3, R{4)-SOa or R(5) R(6)N-SOa, where m is zero, 1 or 2, R(4) is methyl or CF3, and R(5) and P. (6) independently of one another are E or methyl; R(2) = (Cj-C,) -heteroaryl which is linked via C or M and 10 which is unsubstituted or substituted by a radi cal selected from the series consisting of F, CI, CF3, CE], methoxy and dimethylamino; or -SR(10) , -OR(IO) , -NR (10) R {11) , -CR (10) R (11) R (3j2) ; 15 R(10) is -CaEla-(Cv-C9)-heteroaryl, which is unsub stituted or substituted by a radical selected from the series consisting of F, CI, CF3, CH3, methoxy and dimethylamino; a is zero, 1 or 2, and 20 R(ll) and R(12) independently of one another are hydrogen or methyl; R(3) is methyl, cyano, trifluoromethyl, F, CI or hydrogen. 4A process for the preparation of a compound I as claimed in claim 1, which comprises reacting a compound of the formula II in which R(l) to R(3) are as defined in claim 1 and L is a leaving group which can readily be substituted by a nucleophile, with guanidine. 5. The use of a compound I as claimed in claim 1 for the preparation of a pharmaceutical for the treatment " of cardiac arrhythmias. 6. The use of a compound I as claimed in claim 1 for the preparation of a cardioprotective pharmaceutical for the prophylaxis and treatment of infarctions and of angina pectoris. 7. A pharmaceutical for the treatment of cardiac arrhythmias/ of infarction and for cardioprotection, which comprises an effective amount of a compound I as claimed in claim 1. (f~- 8. A compound of the formula I according to rlaim 1 substantially' as herein described or exemplified. [i° - ?5 - 7 9. A process according to claim 4 substantially as herein described or exemplified. 8 HOECHST AKTIENGESELLSCHAIT By their Attorneys HENRY HUGHES LTD Per: / li *-■ $ ^ [{ a. \\ r* V o r -• a" s--
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DE4311800 | 1993-04-09 |
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ID=25921333
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EP (1) | EP0602523B1 (en) |
JP (1) | JP3780004B2 (en) |
AT (1) | ATE146170T1 (en) |
AU (1) | AU672246B2 (en) |
CA (1) | CA2111386C (en) |
DE (1) | DE59304748D1 (en) |
DK (1) | DK0602523T3 (en) |
ES (1) | ES2096840T3 (en) |
FI (1) | FI106856B (en) |
GR (1) | GR3022136T3 (en) |
HU (1) | HU217634B (en) |
NO (1) | NO300590B1 (en) |
NZ (1) | NZ250437A (en) |
TW (1) | TW250479B (en) |
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DE4325822A1 (en) * | 1993-07-31 | 1995-02-02 | Hoechst Ag | Substituted benzoylguanidines, process for their preparation, their use as medicament or diagnostic agent, and medicament containing them |
DE4344550A1 (en) * | 1993-12-24 | 1995-06-29 | Hoechst Ag | Substituted 1-oxo-1,2-dihydro-isoquinolinoyl and 1,1-dioxo-2H-1,2-benzothiazinoylguanidines, processes for their preparation, their use as medicaments or diagnostic agents, and medicaments containing them |
FR2719310B1 (en) * | 1994-04-29 | 1996-07-19 | Hoechst France | New acetaldehyde derivatives, their preparation process and their application. |
DE4421495A1 (en) * | 1994-06-20 | 1995-12-21 | Merck Patent Gmbh | Heterocyclyloxy-benzoylguanidines |
IL114670A0 (en) * | 1994-08-05 | 1995-11-27 | Fujisawa Pharmaceutical Co | Guanidine derivatives pharmaceutical compositions containing the same and processes for the preparation thereof |
DE4430212A1 (en) * | 1994-08-28 | 1996-02-29 | Merck Patent Gmbh | Ortho-substituted benzoic acid derivatives |
DE4430916A1 (en) * | 1994-08-31 | 1996-03-07 | Merck Patent Gmbh | Alkyl benzoylguanidine derivatives |
DE4432106A1 (en) * | 1994-09-09 | 1996-03-14 | Hoechst Ag | Heterocyclic N-oxide-substituted benzoylguanidines, process for their preparation, their use as medicament or diagnostic, medicament containing them and intermediates for their preparation |
DE4437874A1 (en) * | 1994-10-22 | 1996-04-25 | Merck Patent Gmbh | Alkyl 5-methylsulfonylbenzoylguanidine derivatives |
US6057322A (en) * | 1995-01-30 | 2000-05-02 | Hoechst Aktiengesellschaft | Basically-substituted benzoylguanidines, a process for preparing them, their use as a medicament or diagnostic agent, and a medicament containing them |
EP0723956B1 (en) * | 1995-01-30 | 1999-10-13 | Hoechst Aktiengesellschaft | Basically substituted benzoylguanidines, process for their preparation, their use as medicaments or diagnostics as well as medicaments containing them |
DE19502895A1 (en) * | 1995-01-31 | 1996-08-01 | Merck Patent Gmbh | 4-mercapto-benzoylguanidine derivatives |
DE19517848A1 (en) * | 1995-05-16 | 1996-11-21 | Merck Patent Gmbh | Fluorine-containing benzoylguanidines |
EP0765867A1 (en) * | 1995-09-27 | 1997-04-02 | Hoechst Aktiengesellschaft | Substituted benzoyl guanidines, process for their preparation, their use as antiarrhythmics or diagnostic agent as well as pharmaceuticals containing them |
DE19540995A1 (en) * | 1995-11-03 | 1997-05-07 | Hoechst Ag | Substituted sulfonimidamides, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them |
DE19542306A1 (en) * | 1995-11-14 | 1997-05-15 | Hoechst Ag | Sulfonylamino-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them |
PL316439A1 (en) * | 1995-11-20 | 1997-05-26 | Hoechst Ag | Novel substituted derivatives of benzoyloguanidine, method of obtaining them, their application in production of pharmaceutic and diagnostic agents and pharmaceutic agent as such |
DE19546736A1 (en) * | 1995-12-14 | 1997-06-19 | Hoechst Ag | Substituted chromanylsulfonyl (thio) ureas, process for their preparation and their use in the manufacture of pharmaceutical preparations |
DE19738604A1 (en) * | 1997-09-04 | 1999-03-11 | Hoechst Marion Roussel De Gmbh | Use of Na<+>/H<+> exchange inhibitors |
DE19950898A1 (en) * | 1999-10-22 | 2001-04-26 | Aventis Pharma Gmbh | New heteroaryl substituted fluoroalkyl-benzoylguanidine derivatives useful for treatment of e.g. ischemias, cardiac infarction, angina, shock, atherosclerosis, cancer and metabolic disorders |
DE10226462A1 (en) * | 2002-06-13 | 2003-12-24 | Aventis Pharma Gmbh | Fluorinated cycloalkyl-derivatized benzoylguanidines, process for their preparation, their use as medicament, and medicament containing them |
EP1567491A4 (en) * | 2002-11-21 | 2007-09-19 | New York Blood Ct Inc | Compounds for inhibition of hiv infection by blocking hiv entry |
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CZ284456B6 (en) * | 1992-02-15 | 1998-12-16 | Hoechst Aktiengesellschaft | Amino substituted benzylguanidines, process of their preparation and their use for preparing medicaments |
EP0604852A1 (en) * | 1992-12-28 | 1994-07-06 | Hoechst Aktiengesellschaft | 2,4-Substituted 5-(N-substituted-sulfamoyl) benzoylguanidines, as antiarrhythmic agents, inhibitors of the proliferation of cells and inhibitors of sodium-hydrogen exchange |
-
1993
- 1993-10-28 TW TW082108978A patent/TW250479B/zh active
- 1993-12-08 AT AT93119782T patent/ATE146170T1/en not_active IP Right Cessation
- 1993-12-08 ES ES93119782T patent/ES2096840T3/en not_active Expired - Lifetime
- 1993-12-08 EP EP93119782A patent/EP0602523B1/en not_active Expired - Lifetime
- 1993-12-08 DE DE59304748T patent/DE59304748D1/en not_active Expired - Lifetime
- 1993-12-08 DK DK93119782.6T patent/DK0602523T3/en active
- 1993-12-13 AU AU52368/93A patent/AU672246B2/en not_active Ceased
- 1993-12-13 NZ NZ250437A patent/NZ250437A/en unknown
- 1993-12-13 FI FI935578A patent/FI106856B/en active
- 1993-12-14 HU HU9303577A patent/HU217634B/en not_active IP Right Cessation
- 1993-12-14 JP JP31304193A patent/JP3780004B2/en not_active Expired - Fee Related
- 1993-12-14 CA CA002111386A patent/CA2111386C/en not_active Expired - Fee Related
- 1993-12-14 NO NO934604A patent/NO300590B1/en unknown
-
1996
- 1996-12-20 GR GR960403574T patent/GR3022136T3/en unknown
Also Published As
Publication number | Publication date |
---|---|
ATE146170T1 (en) | 1996-12-15 |
EP0602523A1 (en) | 1994-06-22 |
AU5236893A (en) | 1994-06-30 |
DK0602523T3 (en) | 1997-06-02 |
TW250479B (en) | 1995-07-01 |
EP0602523B1 (en) | 1996-12-11 |
FI935578A0 (en) | 1993-12-13 |
JPH06239828A (en) | 1994-08-30 |
NO934604L (en) | 1994-06-16 |
FI935578A (en) | 1994-06-16 |
HU9303577D0 (en) | 1994-04-28 |
CA2111386A1 (en) | 1994-06-16 |
NO934604D0 (en) | 1993-12-14 |
AU672246B2 (en) | 1996-09-26 |
FI106856B (en) | 2001-04-30 |
JP3780004B2 (en) | 2006-05-31 |
ES2096840T3 (en) | 1997-03-16 |
HUT70028A (en) | 1995-09-28 |
GR3022136T3 (en) | 1997-03-31 |
HU217634B (en) | 2000-03-28 |
DE59304748D1 (en) | 1997-01-23 |
CA2111386C (en) | 2006-11-14 |
NO300590B1 (en) | 1997-06-23 |
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