CA2190693A1 - Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them - Google Patents
Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing themInfo
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- CA2190693A1 CA2190693A1 CA002190693A CA2190693A CA2190693A1 CA 2190693 A1 CA2190693 A1 CA 2190693A1 CA 002190693 A CA002190693 A CA 002190693A CA 2190693 A CA2190693 A CA 2190693A CA 2190693 A1 CA2190693 A1 CA 2190693A1
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- carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
Abstract
Benzenedicarboxylic acid diguanides of the formula I
I
in which R(1) to R(5) have the meanings given in the claims, are useful antiarrhythmic pharmaceuticals having a cardioprotective component, even for the prevention of ischemically induced damage, in particular in the induction of ischemically induced cardiac arrhythmias. As a result of inhibition of the cellular Na+/H+ exchange mechanism, they are used for the treatment of acute or chronic damage caused by ischemia. Moreover, they are distinguished by potent inhibitory action on the proliferation of cells. They are suitable for preventing the genesis of high blood pressure.
I
in which R(1) to R(5) have the meanings given in the claims, are useful antiarrhythmic pharmaceuticals having a cardioprotective component, even for the prevention of ischemically induced damage, in particular in the induction of ischemically induced cardiac arrhythmias. As a result of inhibition of the cellular Na+/H+ exchange mechanism, they are used for the treatment of acute or chronic damage caused by ischemia. Moreover, they are distinguished by potent inhibitory action on the proliferation of cells. They are suitable for preventing the genesis of high blood pressure.
Description
~ Hoechst Ah~iellg~s~ drl HOE ss/F 269 ~ l 9 0 6 9 3 Dr v F
Description 5 Suhstit~ ' benzenedicarboxylic acid diguanides, process for their ,u~:pd~dliu~l,theiruseasa~ediud~e~lordiagnostic,and~ di~.d~e~l containing them The invention relates to be~ ne~iudl~u,~ylic acid diguanides of the~0 formula I
R3~1~",R1 R4~N ~ NHz R5 ~ NH2 in which:
one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) ill each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or4 carbon atoms, F, Cl, Br, I, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
25 R(2) and R(4) i"d~pende, Illy of one another are hydrogen, F, Cl, Br, I, OH, -CN, CF3, -CO-N=C(N~12)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl ha~ring 2, 3, 4, 5, 6, 7 or 8 carbon atoms or ~(CH2)mR(1 4);
m is zero, 1 ol 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or sllhstitl~d by 1 - 3 substituents selected from the group consisting of F
Y ~ ~ 2 ~19~693 and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16) are hydrogen or-CH3;
or~ R(2) and R(4) independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, each of which is uns~ Ih~titl It.od or sl Ih~titllt~d by 1 - 4 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl, 1 0 methoxy;
or R(2) and R(4) i"depellde~ y of one another are R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO or R(29)R(30)N-S02;
R(22) and R(28) independertly of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30) i, Idepellde, ILly of one another are hydrogen or methyl;
20 or R(2) and R(4) i"d~ lde~l~ly of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;
or R(35) and R(36) together are 4 - 7 methylene groups, of which a CH2 group can be replaced by oxygen, -S-, -NH-, -NCH3 or-N-benzyl;
R(3) is hydrogen, -SR(Z5), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl, _ . . , _ .. _ _ . . _ _ . . . . . . .
which is unsllhstitl,tP~I or ~,lhstitlltpd by 1 - 3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
5 or R(25) is-(C~-Cg)-heteroaryl, which is urlcl IhCtitl l'~d or sl Ihstitllt~d by 1 - 3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
R(26) and R(27) i"d~pt:~)de, ILIy of one another are defined as R(25) or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, X-(CH2)y -CF3 or phenyl, which is unsllhstitlltpd or sllhstitlltpd by 1 - 3 substituents selected from the group consisting of F and Cl, -CF3, methyl, methoxy and -NR(6)R(7);
R(6) and R~7) indt:pelldt~ ly of one another are hydrogen or -CH3;
X is a bond or oxygen;
y is zero, 1 or 2;
and their pllal l l ,ac~utically tolerable salts.
Preferred compounds of the formula I are those in which:
one of the radicals R(1), R(2), R(3) and R(4) is -co-N=c(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or4 carbon atoms, F, Cl, Br, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34) ~ ~ 4 2190693 independently of one another are hydrogen or methyl;
R(2) and R(4) independently of one another are hydrogen, F, Cl, Br, I, OH, CF3, -CO-N=(C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or -(CH2)mR(14);
m is zero, 1 Ol 2;
R(14) is-(C3-C6)-cycloalkylorphenyl, which is unsl Ihctitl ~tPd or c, IhCtitlltPd by 1 - 2 substituents selected from the group consisting of F
and Cl, -CF3, methyl and methoxy;
or R(2) and R(4) il,dt:~ellde, Illy of one another are pyrrol-1-yl, pynrol-2-yl or pyrrol-3-yl, which is unsl Ihstitl 1 -' or sllhctitl ~tPd by 1 - 2 substituents selected from the yroup consisting of F, Cl, Br, I, -CN, (C2-Cs)-alkanoyl, (C2-Cs)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl;
or R(2) and R(4) independently of one another are R(22)-SO2-, R(28)-CO)- or R(29)R(30)N-SO2;
R(22) and R(28) i"depende,lLly of one another are methyl or -CF3;
R(29) and F~(30) i"dt:~ellder,lly of one another are hydrogen or methyl;
or R(2) and R(4) independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36) independently of one another are hydrogen, methyl or ethyl;
or ~ ~ 5 2190693 R(35) and R(36) together are 4 - 5 methylene groups, of which a CH2 group can be replaced by oxygen, -S-, -NH- or -NCH3;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, which is unsl Ihstitl ItPd or sl Ihstitl It~Pd by 1 - 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;
or R(25) -is-(C1-Cg~-heteroaryl, which is unsl Ihstitl 1~ ' or sl Ihstitl ~tPd by 1 - 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;
R(26) and R(27) i".lepellde, Illy of one another are hydrogen or alkyl having 1, 2, 3 or 4 carhon atoms;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, CF3 or phenyl, which is urlsl ~hstitl ItPd or sllh~tit~ 1' ' by 1 - 2 substituents selected from the group consisting of F and Cl, -CF3, methyl, methoxy and dimethylamino;
and their plla,l,,aceutically tolerable salts.
Particularly preferred col npounds of the formula I are those in which:
one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R~(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or4 carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34) independently of one another are hydrogen or methyl;
R(2) and R(4) i"d~pellder,lly of one another are hydrogen, F, Cl, OH, CF3, ~ 6 2~906~3 -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsl Ihstitl It~d or c, Ihctitl ItPd by 1 - 2 substituents selected from the group collsisting of F, Cl, Br, I, -CN, (C2-Cs)-alkanoyl, (C2-Cs)-alkoxycarl~onyl, fommyl, carboxyl, -CF3 and methyl;
or R(2) and R(4) i"depender,~ly of one another are R(22)-SO2-;
R(22) is methyl or -CF3;
10 or R(2) and R(4) i"depellde"Lly of cne another are -OR(35) or -NR(35)R(36);
R(35) and R(36) independer tly of one another are hydrogen, methyl or ethyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl, which is uns~ Ihstiti ll_~ or sl Ihstitllt~ by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(25) is -(C1-Cg)heteroaryl, which is unsl Ihstitl It~d or sl Ihstitl l'-d by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
R(26) and R(27) i"depellde"lly of one another are hydrogen or methyl;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3 or phenyl, which is unsllhstitll~ -' or Cllhctitllt~d by 1 - 2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy;
and their pha,l, ,ac~utically tolerable salts.
Very particularly preferred compounds of the fommula I are those in which:
~ 7 2190693 one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) ill each case are:
R(1 ) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3 or methoxy;
R(2) and R(4) independently of one another are hydrogen, OH, CF3, -CO-N =
C(NH2)2, alkyl ha\ling 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is urlcl Ihstitl 1'-1 or .sl IhCtitl ItPd by 1 - 2 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-Cs)-alkano~l, (C2-Cs)- alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl;
R(3) is hydrogen, -OR(25) or-CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl, whicl1 is unsl Ihctitl Itpd or s~ Ihstitl Itpd by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(25) is-(C1-C5)-heteroaryl, which is urlc~ Ihstitlltpd or sl Ihstitl 1' ' by a substituent selected from the group consisting of F, Cl, CF3 and CH3 R(26) and R(27) i"d~pel1de, Illy of one another are hydrogen or methyl;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3 or phenyl, which is urlsllhstitlltPd or sllhstitlltPd by 1 - 2 substituents from the group consisting of F and Cl, -CF3 and methyl;
and their pha""aceutically tolerable salts.
The desiy"dLed alkyl radicals can be either straight-chain or branched.
(C1-Cg)-Heteroaryl is understood as meaning radicals which are derived from phenyl or naphthyl, in which one or more CH groups are replaced by ~ ~ 8 219~693 N and/or in which at least two adjacent CH groups (with formation of a five-"":",L,e,~d aromatic ring) are replaced by S, NH or O. In addition, one or both atoms of the condensation site of bicyclic radicals (as in indolizinyl) can also be N atoms.
Heteroaryl is, in particulalr, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, pl~ dld~illyll quinoxalinyl, quinazolinyl, cinnolinyl.
1û
If one of the substituents R(1) to R(5) contains one or more centers of asymmetry, these can be present independently of one another in either the S or R configuration. The compounds can be present as optical isomers, as ~id~ o",er~, as IdC~llldL~5 or as mixtures thereof.
The invention furthemmore relates to a process for the p,~,d,dlioll of the compounds 1, which comprises reacting compounds of the formula ll R(2~) R(3~) ~ R(1~) O ~ L
R(4~) R(5~) in which R(1') to R(5') have the meanings indicated above for R(1) to R(5), 25 but of which at least one of the substituents R(1') to R(5') is the COL group marked, and in which L is a leaving group which can be easily nucl~ ' 'Iy substituted, with guanidine.
30 The activated acid derivatives of the formula ll, in which L is an alkoxy group, preferably a methoxy group or phenoxy group, a phenylthio, methylthio or 2-pyridylthic group, or a nitrogen he~erocycle, preferably 1-~ ~J 21~693 =~ g imidazolyl, are advantageously obtained in a manner known per se fromthe underlying carbonyl chlorides (formula ll, L = Cl), which for their part can in turn be prepared in a manner known per se from the underlying carboxylic acids (fommula ll, L = OH), for example using thionyl chloride. In 5 addition to the carbonyl chlorides of the fommula ll (L = Cl) further activated acid derivatives of the formula ll can be prepared in a manner known per se directly from the underlying bel~el1e~i~dl ~u~ylic acid derivatives (formula ll, L = OH), such as, for example, the methyl esters of the formula Il where L = OCH3 by treating with gaseous HCI in methanol, the 10 i" l ' ';c'e~ of the formula ll by treating with carbon~ lidd~Ul~ [L = 1-lmidazolyl, Staab, Angew. Chem Int. Ed. Engl. 1,351-307 (1902)], the mixed anhydrides ll with Cl-COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, and also the activation of benzenedi~;d, ~o~ylk, acids using dicyclohexylcarl,odii"~ide (DCC) or using 0-[(cyano)ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate] ("TOTU") [Pl~ceedi"!Js of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991].Anumberofsuitablemethodsforthep,t:pa,dli~.l,of activated carboxylic acid derivatives of the formula ll are indicated under 20 details of source literature in J. March, Advanced Organic Chemistry, Third Edition (John Vviley & Sons, 1985), p. 350.
The reaction of an activated carboxylic acid derivative of the formula I with guanidine is carried out in a manner known per se in a protic or aprotic polar but inert organic solvent. In the case of the reaction of the methyl 25 be"~t:"edica,~oxylates (Il, L = OMe) with guanidine, methanol, isop,upa~
or THF between 20~C and the boiling points of these solvents have proven suitable here. Most reactions of compounds ll with salt-free guanidine were advantageously carried out in inert solvents such as THF, dimethoxyethane, dioxane or isopropanol However, water can also be 30 used as a solvent If L = Cl, the reaction is aclvantageously carried out with addition of an acid ~ 21 90693 scavenger, e.g. in the form of excess guanidine to bind the hydrohalic acid.
The introduction of the compounds sl IhCtitl ItPIi in the phenyl moiety by 5 sulfur, oxygen or nitrogen nucleophiles is carried out by methods known from the literature for the nucleophilic sl Ihstitl Itinl1 of derivatives of dialkyl b~ edi~,dl ~r xylates. In this sl Ih~Ctitl Ition, suitable leaving groups on thebe,~ edi~,a,L,oxylic acid derivative have proven to be halides and triflu~,ul"~Ll,al1esulfonates. The reaction is advantageously carried out in a 10 dipolar aprotic solvent, such as DMF or TMU, at a temperature from 0~C up to the boiling point of the solvent, preferably from 80~C up to the boiling point of the solvent. The acid scavenger used is advantageously an alkali metal or alkaline earth metal salt with an anion of high basicity and low nucleophilicity, for example K2CO3 or CsC03.
The alkyl or aryl substituents are introduced by methods known from theliterature for the palladiul-n-mediated cross-coupling of aryl halides with, forexample, u, ydl lO~il IU compounds, organu~ld, ll Idl 1~5, organoboronic acids or organoboranes.
In general, b~ e~i~,dlL,u,~ylic acid diguanides I are weak bases and can bind acid with formation of salts. Possible acid addition salts are salts of allpl1ar,l~olo~ ly tolerable acids, for example halides, in particular hy~u~,lllolides, ascoiL,dl~:j, lactates, sulfates, citrates, tartrates, acetates, 25 phosphates, methylsl 1'' ldL~s and p-toluenesulfonates.
The Offenlegungsschrift WO 94/26709 describes be~ ledica,~u,~ylic acid diguanides in which, hov/ever, none of the compounds have one of the substituents R(5) claimed here, which corresponds to the R(3) of this 30 Offenlegungsschrift.
Surprisingly, it has been found that the introduction of certain substituents R(1) and/or R(5) ~iy~iriucllllly increases the activity of the compounds and moreover positively affer~ts their pl1d,-,,dcuhi,,etics.
On account of their pl~dl " l~colùy;~l properties, the compounds I are 5 outsldl ,di"y'y suitable as antiarrhythmic pl1arl"~cel Itir,~lc having a ca,~iùpru~ i\/e component for infarct prophylaxis and infarct treatment and for the treatment of angina pectoris, where they also preventively inhibit or greatly decrease the pathophysiological processes in the formation of is~l,e",ic~'ly induced damage, in particular in the induction of 1 û is ~ " li~lly induced cardiac arrythmias. Because ûf their protective actions against pdll loluyiudl 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+/H+ exchange ",eul,a"i:,"" as pharl"~ce, Itir,~lc for the treatment of all acute or chronic damage caused 15 by ischemia or illnesses primarily or secul~dd, ily induced thereby. This relates to their use as ",~.li.,d",el,L~. for surgicai interventions, e.g. in organ ~Idll:,pldllldlioll, where the compounds can be used both forthe protection of the organs in the donor before and during removal, for the protection of removed organs, for example during treatment wi~h or storage thereof in 2û physiological bath fluids, and also during transfer to the recipient's body.
The compounds are also useful pl1al",~rielltir.~1c having a protective action when carrying out anyi~uld~lic surgical interventions, for example on the heart and also on peripheral vessels. In accû,da"~t: with their protective action against is~lle",i~:'y induced damage, the compounds are also 25 suitable as plla" "~ , Itir~lc 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, 3û hypovolemic and bacterial shock.
The compounds of the formula I according to the invention are moreover ~ 21 936~3 distinguished by potent ir~hibitory action on the proliferation of cells, for example fibroblast cell p" ' "rdLioll and the ~,~';' rdliull of vascular smooth muscle cells. The compounds of the formula I are therefore suitable as useful therapeutics for illnesses in which cell pr, ' ' dliDIl is a primary or 5 secondary cause, and can therefore be used as d"tid~l,er,,s,~le,l~i,,~, agents against diabetic late cul~ s, Cdl~ ollld~Us disorders, fibrotic disorders such as pulmonary fibrosis, fibrosis of the liver or fibrosisof the kidney, organ h~el 1, uuhi~s and hype, uldsids, in particular in prostate hyperplasia or prostate hypertrophy.
10 The compounds accordin~ to the invention are effective inhibitors of the cellular sodium-proton an~tiporter (Na+/H+ ex.,l,allger), which is raised in numerous disorders (essential hypertension, dl~,e,uscleru~ ,, diabetes etc.) even in those cells which are easily ~.~ce~ le to measurement, such as, for example, in erythrocytes, platelets or leucocytes. The compounds 15 according to the invention are therefore suitable as outstanding and simple scientific tools, for example in their use as ~iay"o~liu~ for the dt~ r" ,i, Idli and .li,r-r-lllidliull of certain fomms of hjpe,l_"aioll, but also of dlllt:lUscl~lusis, diabetes, proliferative disorders etc. The compounds of the formula I are moreover suitable for preventive therapy for the 20 prevention of the genesis of high blood pressure, for example of essential h~,~el l~l~sion.
Compared with most known compounds, the compounds according to the invention have a siu~ ,iri~a, I~ly improved water solubility. They are therefore25 ~ ily better suited tû i.v. ddl l lil ~i~ll d~ n.
Compared with the known readily water-soluble compounds, the compounds according to tl1e invention are distinguished by their better bioavailability and pharmacokinetics.
PharnlAce~ti~AIc which colltain a compound I can be ad,l,i"i~t~l~d orally, pa,i "l-r~'ly, intravenously, rectally or by inhalation, the preferred type of _ _ _ _ .. . . . . . .
13 2~ 906~3 a l" ,i, liall dLiul, being dependent ûn the particular clinical picture ûf the disûrder. The cûmpûunds I can be used here ûn their ûwn ûr tûgether with ~la""aceutical auxiliaries, for example in veterinary and also in human medicine.
On the basis of his expe~t knowledge, the person skilled in the art is familiar with which auxiliaries are suitable for the desired pha""aceutical formulation. Beside solvents, gelling agents, suppository bases, tablet auxiliaries and other active compound excipients, dl lliU,-i~dll~, 10 di~per~d"~, emulsifiers, antifoams, flavor corrigents, preservatives, so'l l~ ~ or colorants, for example, can be used.
For a form for oral ddl "i, ~ dliul1, the active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers or inert diluents and brought by the customary methods into the suitable 15 ad",i"i:,L,dlion forms, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch.
P~t:pa"lliol1 can in this case take place either as dry or as moist granules.
20 Suitable oily excipients ol solvents are, for example, vegetable or animal oils, such as sunflower oil or fish liver oil.
For subcutaneous or intravenous a l",i"i~lldlioll, lhe active compounds are brought into solution, suspension or emulsion, if desired with the 25 substances customary fol this purpose, such as solubilizers, emulsifiers or other auxiliaries. Possible solvents are, for example: water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, a~-lilioll Iy also sugar solutions such as glucose or mannitol solutions, or alternatively a mixture of the various solvents "~e"li~l~ed.
Pl ,a" "ac~utical fonmulations suitable for a-ll l lil li:,~l d~ in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions .. . ... . .. ... _ .. . ...... .. .. .. . .
~ 14 21 ~0693 of the active compound ~f the formula I in a pharmaceutically d~ JI.
solvent, such as, in particular, ethanol or water, or a mixture of such solvents. If required, the l~ormulation can also contain still other pharmaceutical auxiliarie~ such as surfactants, emulsifiers and stabilizers, 5 as well as a propellant. Such a preparation custolnarily contains the active compound in a concentration from dp~luxillld~ly 0.1 to 10, in particular from app,uxi",dl~ly 0.3 to 3~/O by weight.
The dose of the active compound of the formula I to be a~" ,i"i~ d and 1û the frequency of ad",i"i:,l,dliol1 depend on the potency and duration of action of the compounds used; addi~iul1~lly also on the measure and severity of the illness to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
15 On average, the daily dose of a compound of the formula I in the case of a patient weighing d,upru,~i, lldL~:ly 75 kg is at least 0.001 mg/kg of body weight, preferably at least 0.01 mg/kg of body weight, up to at most 10 mg/kg of body weight, preferably to at most 1 mg/kg of body weight. In acute episodes of the illness, for example i"""~ y affer suffering a 20 cardiac infarct, still higher and especially more frequent doses may also be necessary, e.g. up to 4 individual doses per day. In particular when ad",i, li~tt:l~d i.v., for example in the case of an infarct patient in the intensive care unit, up to 100 mg per day may be necessary.
25 List of abbreviations:
AIBN a,~-azo-bis-isobutyronitrile Bn benzyl Brine saturated aqueous NaCI solution CH2CI2 .liul ,loru, l l~ll ,ane DCI desu",~i~l1 chemical ionization DIP diisopropyl ether DMA dimethyldce:ldl,,ide 2 t 90693 ~ 15 DME dimethoxyethane DMF N,N-dimeth~lru,l"d",ide EA ethyl aceta~e (EtOAc) El electron impact eq equivalent ES electrospray ionisation Et ethyl FAB fast atom bol"L,a,.l"le"L
HEP n-heptane HOAc acetic acid Me methyl MeOH methanol mp melting pOillt MTB methyl tertiary-butyl ether NBS N-bromosuccinimide NMP N-methylpyrrolidone RT room temperature THF tetrahydrofuran TMU N,N,N',N'-tetramethylurea Tol toluene CNS central nervous system E~,e, i" ,t:"Ldl section 25 General procedure for the plt:pdl dLioll of ber,,ene~i.,arL,oxylic acid diguanides (I) from dialkyl benzene.li~alL,oxylates (Il, L = O-alkyl) 5 mmol of the dialkyl ben.~ne~i.,dl LJo~ylate of the fommula (Il) and 50 mmol of guanidine (free base) are dissolved in 5 ml of isup,upanol and boiled 30 under reflux (typical reaction time 5 minutes to 5 h) until reaction is complete (thin-layer checking). The mixture is then diluted with 150 ml of water and the product is lFiltered off with suction. If applup, i ' , it is ~;lllull,dLu~,dphed on silica gel using a suitable eluent, e.g. EA/MeOH 5: 1.
~i 21 9~693 Example 1: 4-Chloro-5-phenyl;~ophll, ' acid diguanide O N~NH2 C~ NHz a) 3-Bromo-2-chloro 5-methylbenzoic acid 25 9 of 2-amino-3-broma-5-methylbenzoic acid are diazotized in 500 ml of 6N aqueous HCI solutiorl at 0~C using 8.3 9 of NaNO2, then the mixture is stirred at RT for 30 minultes and poured in portions onto a warm solution at 40~C of 22 9 of CuCI in 200 ml of a saturated aqueous HCI solution. The mixture is stirred at 40-50~C for 20 minutes, and the precipitate is filtered off with suction, washed with water until it is neutral and dried at 40~C
under reduced pressure. 23.3 9 of pale yellow crystals are obtained, mp 170- 172~C.
Rf (EA/MeOH 5:1) = 0.511 MS (DCI): 249 (M+H)+
b) 5-Bromo4-cl,lo,u;sùpl,ll, ' acid 99 9 of MgSo4 x 7H2O are dissolved in 600 ml of water, then 20 9 of 3-bromo-2-chloro-5-methylbenzoic acid are added, the mixture is warmed to 90~C, then 63 9 of KivlnO4 are added in portions at 90-100~C, and the mixture is stirred under reflux for 2 h. It is then allowed to cool to RT, saturated aqueous Na2SO3 solution is added dropwise until the violet color disappears, the mixture is adjusted to pH = 12 with saturated aqueous Na2CO3 solution and the MnO2 is filtered off with suction. It is washed with saturated aqueous Na2SO3 solution and with hot water, the filtrate is adjusted to pH = 1 with aqueous HCI and the precipitate is filtered off with suction. 13.5 g of a colol less solid are obtained, mp > 275~C.
Rf (DIP/2% HOAc) = 0.18 MS (DCI). 279 (M+H)+
~, 21 90~3 c) Dimethyl 5-bromo-4-~;l,lo,uisopl,ll ' ' 13.5 9 of 5-bromo-4-,.l,loruisopilll~ ' acid are dissolved in 200 ml of MeOH, 20 ml of SOCI2 are added dropwise and the mixture is stirred under reflux for 5 h. The volatile constituents are then removed in vacuo and the residue is dried in a fine vacuum. 14 9 of colourless crystals are obtained, mp 99~C MS (DCI): 307 (M+H)+
d) Dimethyl 4-chloro-5-phenyl;;,ophll,dldl~
3.1 9 of dimethyl 5-bromo-4-chloroisophthalate, 1.2 9 of benzeneboronic acid, 2.1 9 of Na2CO3, 230 mg of Pd(OAc)2 and 500 mg of triphen~ o~.l ,i"e are stirred under reflux for 6 h in 50 ml of toluene and 10 ml of water. The mixture is allowed to cool to RT, and is diluted with 300 ml of toluene and washed 3 times with 100 ml of a saturated aqueous Na2CO3 solution each tilne. The organic phase is dried over Na2SO4, the solvent is removed in vacuo and the residue is then ~ llldlUyld~ ed on silica gel using EA/HEP 1:4. 1.5 9 of a colorless oil are obtained.
Rf (EA/HEP 1:4) = 0.22 MS (DCI): 305 (M+H)+
e) 4-Chloro-5-phenyli~,o~l,ll -' acid diguanide 2.6 9 of potassium teff-butoxide are dissolved in 50 ml of anhydrous DMF
and treated with 2.6 9 of guanidine hydrochloride. The mixture is stirred at RT for 1.5 h, 700 mg of dimethyl 4-chloro-5-pherl~li ,opl l~l laldlt: are added and it is stirred at 1 00'C for 2 h. The mixture is poured onto 1 1 of water, and it is adjusted to pH = 8 with aqueous NaHCO3 solution and aqueous HCI solution and then extracted 3 times with 200 ml of EA each time. The organic phase is dried over Na2SO4 and the solvent is removed in vacuo.
The residue is suspended in 100 ml of water ancl filtered off with suction, then the precipitate is again suspended in 50 ml of EA and filtered off with suction. The product is dried in vacuo and 350 mg of colorless crystals are obtained, mp 235~C (with decomposition).
Rf (acetone/water 10:1) = 0.063 MS (ES): 359 (M+H)+
' ~ 18 2~ 90693 Fl ld~ co~ data:
Inhibition of the Na+tH+ t:X~I~dl~9el of rabbit erythrocytes White New Zealand rabbits (Ivanovas) received a standard diet with 2%
5 .;l loltl~,ul for six weeks in order to activate Na+/H+ exchange and thus to be able to determine the Na+ influx into the erythrocytes via Na+/H+
exchange by flame pllu~u~ , y. The blood was taken from the ear arteries and rendered incoagulable by means of 25 IU of potassium heparin. A part of each sample was used for the duplicate d~ r" ,i"dli~ll of the hematocrit 10 by centrifugation. Aliquots of 1 Oû ul in each case were used to measure the Na+ starting content of the erythrocytes.
In order to detenmine the amiloride-sensitive sodium influx 1 Oû ul of each blood sample were incubated in each case in 5 ml of a hype,us",olar salt-sucrose medium (mmol/l: 140 NaCI 3 KCI 15û sucrose û.1 ouabain 2û tris-hydroxymethyla"",~o",t,~l,alle) at pH 7.4 and 37~C. The erythrocytes were then washed three times with ice-cold MgCI2 ouabain solution (mmol/l: 112 MgCI2 û.1 ouabain) and hemolyzed in 2.û ml of distilled water. The intracellular sodium content was dt:L~II ,)i"ecl by flame 2û photometry.
The net Na+ influx was calculated from the difference between sodium starting values and the sodium content of the erythrocytes after incubation.
The amiloride-inhibitable sodium influx resulted from the difference 25 between the sodium content of the erythrocytes after incubation with and without amiloride 3 x 1 û4 moUI. This procedure was also used in the case of the compounds according to the invention.
~ ~ 21 93693 Results Inhibition of the Na+/H+ exchanger:
Example IC!jo (mmol/l) 1 0.9
Description 5 Suhstit~ ' benzenedicarboxylic acid diguanides, process for their ,u~:pd~dliu~l,theiruseasa~ediud~e~lordiagnostic,and~ di~.d~e~l containing them The invention relates to be~ ne~iudl~u,~ylic acid diguanides of the~0 formula I
R3~1~",R1 R4~N ~ NHz R5 ~ NH2 in which:
one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) ill each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or4 carbon atoms, F, Cl, Br, I, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
25 R(2) and R(4) i"d~pende, Illy of one another are hydrogen, F, Cl, Br, I, OH, -CN, CF3, -CO-N=C(N~12)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl ha~ring 2, 3, 4, 5, 6, 7 or 8 carbon atoms or ~(CH2)mR(1 4);
m is zero, 1 ol 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or sllhstitl~d by 1 - 3 substituents selected from the group consisting of F
Y ~ ~ 2 ~19~693 and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16) are hydrogen or-CH3;
or~ R(2) and R(4) independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, each of which is uns~ Ih~titl It.od or sl Ih~titllt~d by 1 - 4 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl, 1 0 methoxy;
or R(2) and R(4) i"depellde~ y of one another are R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO or R(29)R(30)N-S02;
R(22) and R(28) independertly of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30) i, Idepellde, ILly of one another are hydrogen or methyl;
20 or R(2) and R(4) i"d~ lde~l~ly of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;
or R(35) and R(36) together are 4 - 7 methylene groups, of which a CH2 group can be replaced by oxygen, -S-, -NH-, -NCH3 or-N-benzyl;
R(3) is hydrogen, -SR(Z5), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl, _ . . , _ .. _ _ . . _ _ . . . . . . .
which is unsllhstitl,tP~I or ~,lhstitlltpd by 1 - 3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
5 or R(25) is-(C~-Cg)-heteroaryl, which is urlcl IhCtitl l'~d or sl Ihstitllt~d by 1 - 3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
R(26) and R(27) i"d~pt:~)de, ILIy of one another are defined as R(25) or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, X-(CH2)y -CF3 or phenyl, which is unsllhstitlltpd or sllhstitlltpd by 1 - 3 substituents selected from the group consisting of F and Cl, -CF3, methyl, methoxy and -NR(6)R(7);
R(6) and R~7) indt:pelldt~ ly of one another are hydrogen or -CH3;
X is a bond or oxygen;
y is zero, 1 or 2;
and their pllal l l ,ac~utically tolerable salts.
Preferred compounds of the formula I are those in which:
one of the radicals R(1), R(2), R(3) and R(4) is -co-N=c(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or4 carbon atoms, F, Cl, Br, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34) ~ ~ 4 2190693 independently of one another are hydrogen or methyl;
R(2) and R(4) independently of one another are hydrogen, F, Cl, Br, I, OH, CF3, -CO-N=(C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or -(CH2)mR(14);
m is zero, 1 Ol 2;
R(14) is-(C3-C6)-cycloalkylorphenyl, which is unsl Ihctitl ~tPd or c, IhCtitlltPd by 1 - 2 substituents selected from the group consisting of F
and Cl, -CF3, methyl and methoxy;
or R(2) and R(4) il,dt:~ellde, Illy of one another are pyrrol-1-yl, pynrol-2-yl or pyrrol-3-yl, which is unsl Ihstitl 1 -' or sllhctitl ~tPd by 1 - 2 substituents selected from the yroup consisting of F, Cl, Br, I, -CN, (C2-Cs)-alkanoyl, (C2-Cs)-alkoxycarbonyl, formyl, carboxy, -CF3 and methyl;
or R(2) and R(4) independently of one another are R(22)-SO2-, R(28)-CO)- or R(29)R(30)N-SO2;
R(22) and R(28) i"depende,lLly of one another are methyl or -CF3;
R(29) and F~(30) i"dt:~ellder,lly of one another are hydrogen or methyl;
or R(2) and R(4) independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36) independently of one another are hydrogen, methyl or ethyl;
or ~ ~ 5 2190693 R(35) and R(36) together are 4 - 5 methylene groups, of which a CH2 group can be replaced by oxygen, -S-, -NH- or -NCH3;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, which is unsl Ihstitl ItPd or sl Ihstitl It~Pd by 1 - 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;
or R(25) -is-(C1-Cg~-heteroaryl, which is unsl Ihstitl 1~ ' or sl Ihstitl ~tPd by 1 - 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;
R(26) and R(27) i".lepellde, Illy of one another are hydrogen or alkyl having 1, 2, 3 or 4 carhon atoms;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, CF3 or phenyl, which is urlsl ~hstitl ItPd or sllh~tit~ 1' ' by 1 - 2 substituents selected from the group consisting of F and Cl, -CF3, methyl, methoxy and dimethylamino;
and their plla,l,,aceutically tolerable salts.
Particularly preferred col npounds of the formula I are those in which:
one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R~(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or4 carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34) independently of one another are hydrogen or methyl;
R(2) and R(4) i"d~pellder,lly of one another are hydrogen, F, Cl, OH, CF3, ~ 6 2~906~3 -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsl Ihstitl It~d or c, Ihctitl ItPd by 1 - 2 substituents selected from the group collsisting of F, Cl, Br, I, -CN, (C2-Cs)-alkanoyl, (C2-Cs)-alkoxycarl~onyl, fommyl, carboxyl, -CF3 and methyl;
or R(2) and R(4) i"depender,~ly of one another are R(22)-SO2-;
R(22) is methyl or -CF3;
10 or R(2) and R(4) i"depellde"Lly of cne another are -OR(35) or -NR(35)R(36);
R(35) and R(36) independer tly of one another are hydrogen, methyl or ethyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl, which is uns~ Ihstiti ll_~ or sl Ihstitllt~ by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(25) is -(C1-Cg)heteroaryl, which is unsl Ihstitl It~d or sl Ihstitl l'-d by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
R(26) and R(27) i"depellde"lly of one another are hydrogen or methyl;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3 or phenyl, which is unsllhstitll~ -' or Cllhctitllt~d by 1 - 2 substituents selected from the group consisting of F and Cl, -CF3, methyl and methoxy;
and their pha,l, ,ac~utically tolerable salts.
Very particularly preferred compounds of the fommula I are those in which:
~ 7 2190693 one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) ill each case are:
R(1 ) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3 or methoxy;
R(2) and R(4) independently of one another are hydrogen, OH, CF3, -CO-N =
C(NH2)2, alkyl ha\ling 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is urlcl Ihstitl 1'-1 or .sl IhCtitl ItPd by 1 - 2 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-Cs)-alkano~l, (C2-Cs)- alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl;
R(3) is hydrogen, -OR(25) or-CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl, whicl1 is unsl Ihctitl Itpd or s~ Ihstitl Itpd by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(25) is-(C1-C5)-heteroaryl, which is urlc~ Ihstitlltpd or sl Ihstitl 1' ' by a substituent selected from the group consisting of F, Cl, CF3 and CH3 R(26) and R(27) i"d~pel1de, Illy of one another are hydrogen or methyl;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3 or phenyl, which is urlsllhstitlltPd or sllhstitlltPd by 1 - 2 substituents from the group consisting of F and Cl, -CF3 and methyl;
and their pha""aceutically tolerable salts.
The desiy"dLed alkyl radicals can be either straight-chain or branched.
(C1-Cg)-Heteroaryl is understood as meaning radicals which are derived from phenyl or naphthyl, in which one or more CH groups are replaced by ~ ~ 8 219~693 N and/or in which at least two adjacent CH groups (with formation of a five-"":",L,e,~d aromatic ring) are replaced by S, NH or O. In addition, one or both atoms of the condensation site of bicyclic radicals (as in indolizinyl) can also be N atoms.
Heteroaryl is, in particulalr, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, pl~ dld~illyll quinoxalinyl, quinazolinyl, cinnolinyl.
1û
If one of the substituents R(1) to R(5) contains one or more centers of asymmetry, these can be present independently of one another in either the S or R configuration. The compounds can be present as optical isomers, as ~id~ o",er~, as IdC~llldL~5 or as mixtures thereof.
The invention furthemmore relates to a process for the p,~,d,dlioll of the compounds 1, which comprises reacting compounds of the formula ll R(2~) R(3~) ~ R(1~) O ~ L
R(4~) R(5~) in which R(1') to R(5') have the meanings indicated above for R(1) to R(5), 25 but of which at least one of the substituents R(1') to R(5') is the COL group marked, and in which L is a leaving group which can be easily nucl~ ' 'Iy substituted, with guanidine.
30 The activated acid derivatives of the formula ll, in which L is an alkoxy group, preferably a methoxy group or phenoxy group, a phenylthio, methylthio or 2-pyridylthic group, or a nitrogen he~erocycle, preferably 1-~ ~J 21~693 =~ g imidazolyl, are advantageously obtained in a manner known per se fromthe underlying carbonyl chlorides (formula ll, L = Cl), which for their part can in turn be prepared in a manner known per se from the underlying carboxylic acids (fommula ll, L = OH), for example using thionyl chloride. In 5 addition to the carbonyl chlorides of the fommula ll (L = Cl) further activated acid derivatives of the formula ll can be prepared in a manner known per se directly from the underlying bel~el1e~i~dl ~u~ylic acid derivatives (formula ll, L = OH), such as, for example, the methyl esters of the formula Il where L = OCH3 by treating with gaseous HCI in methanol, the 10 i" l ' ';c'e~ of the formula ll by treating with carbon~ lidd~Ul~ [L = 1-lmidazolyl, Staab, Angew. Chem Int. Ed. Engl. 1,351-307 (1902)], the mixed anhydrides ll with Cl-COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, and also the activation of benzenedi~;d, ~o~ylk, acids using dicyclohexylcarl,odii"~ide (DCC) or using 0-[(cyano)ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate] ("TOTU") [Pl~ceedi"!Js of the 21st European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991].Anumberofsuitablemethodsforthep,t:pa,dli~.l,of activated carboxylic acid derivatives of the formula ll are indicated under 20 details of source literature in J. March, Advanced Organic Chemistry, Third Edition (John Vviley & Sons, 1985), p. 350.
The reaction of an activated carboxylic acid derivative of the formula I with guanidine is carried out in a manner known per se in a protic or aprotic polar but inert organic solvent. In the case of the reaction of the methyl 25 be"~t:"edica,~oxylates (Il, L = OMe) with guanidine, methanol, isop,upa~
or THF between 20~C and the boiling points of these solvents have proven suitable here. Most reactions of compounds ll with salt-free guanidine were advantageously carried out in inert solvents such as THF, dimethoxyethane, dioxane or isopropanol However, water can also be 30 used as a solvent If L = Cl, the reaction is aclvantageously carried out with addition of an acid ~ 21 90693 scavenger, e.g. in the form of excess guanidine to bind the hydrohalic acid.
The introduction of the compounds sl IhCtitl ItPIi in the phenyl moiety by 5 sulfur, oxygen or nitrogen nucleophiles is carried out by methods known from the literature for the nucleophilic sl Ihstitl Itinl1 of derivatives of dialkyl b~ edi~,dl ~r xylates. In this sl Ih~Ctitl Ition, suitable leaving groups on thebe,~ edi~,a,L,oxylic acid derivative have proven to be halides and triflu~,ul"~Ll,al1esulfonates. The reaction is advantageously carried out in a 10 dipolar aprotic solvent, such as DMF or TMU, at a temperature from 0~C up to the boiling point of the solvent, preferably from 80~C up to the boiling point of the solvent. The acid scavenger used is advantageously an alkali metal or alkaline earth metal salt with an anion of high basicity and low nucleophilicity, for example K2CO3 or CsC03.
The alkyl or aryl substituents are introduced by methods known from theliterature for the palladiul-n-mediated cross-coupling of aryl halides with, forexample, u, ydl lO~il IU compounds, organu~ld, ll Idl 1~5, organoboronic acids or organoboranes.
In general, b~ e~i~,dlL,u,~ylic acid diguanides I are weak bases and can bind acid with formation of salts. Possible acid addition salts are salts of allpl1ar,l~olo~ ly tolerable acids, for example halides, in particular hy~u~,lllolides, ascoiL,dl~:j, lactates, sulfates, citrates, tartrates, acetates, 25 phosphates, methylsl 1'' ldL~s and p-toluenesulfonates.
The Offenlegungsschrift WO 94/26709 describes be~ ledica,~u,~ylic acid diguanides in which, hov/ever, none of the compounds have one of the substituents R(5) claimed here, which corresponds to the R(3) of this 30 Offenlegungsschrift.
Surprisingly, it has been found that the introduction of certain substituents R(1) and/or R(5) ~iy~iriucllllly increases the activity of the compounds and moreover positively affer~ts their pl1d,-,,dcuhi,,etics.
On account of their pl~dl " l~colùy;~l properties, the compounds I are 5 outsldl ,di"y'y suitable as antiarrhythmic pl1arl"~cel Itir,~lc having a ca,~iùpru~ i\/e component for infarct prophylaxis and infarct treatment and for the treatment of angina pectoris, where they also preventively inhibit or greatly decrease the pathophysiological processes in the formation of is~l,e",ic~'ly induced damage, in particular in the induction of 1 û is ~ " li~lly induced cardiac arrythmias. Because ûf their protective actions against pdll loluyiudl 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+/H+ exchange ",eul,a"i:,"" as pharl"~ce, Itir,~lc for the treatment of all acute or chronic damage caused 15 by ischemia or illnesses primarily or secul~dd, ily induced thereby. This relates to their use as ",~.li.,d",el,L~. for surgicai interventions, e.g. in organ ~Idll:,pldllldlioll, where the compounds can be used both forthe protection of the organs in the donor before and during removal, for the protection of removed organs, for example during treatment wi~h or storage thereof in 2û physiological bath fluids, and also during transfer to the recipient's body.
The compounds are also useful pl1al",~rielltir.~1c having a protective action when carrying out anyi~uld~lic surgical interventions, for example on the heart and also on peripheral vessels. In accû,da"~t: with their protective action against is~lle",i~:'y induced damage, the compounds are also 25 suitable as plla" "~ , Itir~lc 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, 3û hypovolemic and bacterial shock.
The compounds of the formula I according to the invention are moreover ~ 21 936~3 distinguished by potent ir~hibitory action on the proliferation of cells, for example fibroblast cell p" ' "rdLioll and the ~,~';' rdliull of vascular smooth muscle cells. The compounds of the formula I are therefore suitable as useful therapeutics for illnesses in which cell pr, ' ' dliDIl is a primary or 5 secondary cause, and can therefore be used as d"tid~l,er,,s,~le,l~i,,~, agents against diabetic late cul~ s, Cdl~ ollld~Us disorders, fibrotic disorders such as pulmonary fibrosis, fibrosis of the liver or fibrosisof the kidney, organ h~el 1, uuhi~s and hype, uldsids, in particular in prostate hyperplasia or prostate hypertrophy.
10 The compounds accordin~ to the invention are effective inhibitors of the cellular sodium-proton an~tiporter (Na+/H+ ex.,l,allger), which is raised in numerous disorders (essential hypertension, dl~,e,uscleru~ ,, diabetes etc.) even in those cells which are easily ~.~ce~ le to measurement, such as, for example, in erythrocytes, platelets or leucocytes. The compounds 15 according to the invention are therefore suitable as outstanding and simple scientific tools, for example in their use as ~iay"o~liu~ for the dt~ r" ,i, Idli and .li,r-r-lllidliull of certain fomms of hjpe,l_"aioll, but also of dlllt:lUscl~lusis, diabetes, proliferative disorders etc. The compounds of the formula I are moreover suitable for preventive therapy for the 20 prevention of the genesis of high blood pressure, for example of essential h~,~el l~l~sion.
Compared with most known compounds, the compounds according to the invention have a siu~ ,iri~a, I~ly improved water solubility. They are therefore25 ~ ily better suited tû i.v. ddl l lil ~i~ll d~ n.
Compared with the known readily water-soluble compounds, the compounds according to tl1e invention are distinguished by their better bioavailability and pharmacokinetics.
PharnlAce~ti~AIc which colltain a compound I can be ad,l,i"i~t~l~d orally, pa,i "l-r~'ly, intravenously, rectally or by inhalation, the preferred type of _ _ _ _ .. . . . . . .
13 2~ 906~3 a l" ,i, liall dLiul, being dependent ûn the particular clinical picture ûf the disûrder. The cûmpûunds I can be used here ûn their ûwn ûr tûgether with ~la""aceutical auxiliaries, for example in veterinary and also in human medicine.
On the basis of his expe~t knowledge, the person skilled in the art is familiar with which auxiliaries are suitable for the desired pha""aceutical formulation. Beside solvents, gelling agents, suppository bases, tablet auxiliaries and other active compound excipients, dl lliU,-i~dll~, 10 di~per~d"~, emulsifiers, antifoams, flavor corrigents, preservatives, so'l l~ ~ or colorants, for example, can be used.
For a form for oral ddl "i, ~ dliul1, the active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers or inert diluents and brought by the customary methods into the suitable 15 ad",i"i:,L,dlion forms, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily solutions. Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch.
P~t:pa"lliol1 can in this case take place either as dry or as moist granules.
20 Suitable oily excipients ol solvents are, for example, vegetable or animal oils, such as sunflower oil or fish liver oil.
For subcutaneous or intravenous a l",i"i~lldlioll, lhe active compounds are brought into solution, suspension or emulsion, if desired with the 25 substances customary fol this purpose, such as solubilizers, emulsifiers or other auxiliaries. Possible solvents are, for example: water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, a~-lilioll Iy also sugar solutions such as glucose or mannitol solutions, or alternatively a mixture of the various solvents "~e"li~l~ed.
Pl ,a" "ac~utical fonmulations suitable for a-ll l lil li:,~l d~ in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions .. . ... . .. ... _ .. . ...... .. .. .. . .
~ 14 21 ~0693 of the active compound ~f the formula I in a pharmaceutically d~ JI.
solvent, such as, in particular, ethanol or water, or a mixture of such solvents. If required, the l~ormulation can also contain still other pharmaceutical auxiliarie~ such as surfactants, emulsifiers and stabilizers, 5 as well as a propellant. Such a preparation custolnarily contains the active compound in a concentration from dp~luxillld~ly 0.1 to 10, in particular from app,uxi",dl~ly 0.3 to 3~/O by weight.
The dose of the active compound of the formula I to be a~" ,i"i~ d and 1û the frequency of ad",i"i:,l,dliol1 depend on the potency and duration of action of the compounds used; addi~iul1~lly also on the measure and severity of the illness to be treated and on the sex, age, weight and individual responsiveness of the mammal to be treated.
15 On average, the daily dose of a compound of the formula I in the case of a patient weighing d,upru,~i, lldL~:ly 75 kg is at least 0.001 mg/kg of body weight, preferably at least 0.01 mg/kg of body weight, up to at most 10 mg/kg of body weight, preferably to at most 1 mg/kg of body weight. In acute episodes of the illness, for example i"""~ y affer suffering a 20 cardiac infarct, still higher and especially more frequent doses may also be necessary, e.g. up to 4 individual doses per day. In particular when ad",i, li~tt:l~d i.v., for example in the case of an infarct patient in the intensive care unit, up to 100 mg per day may be necessary.
25 List of abbreviations:
AIBN a,~-azo-bis-isobutyronitrile Bn benzyl Brine saturated aqueous NaCI solution CH2CI2 .liul ,loru, l l~ll ,ane DCI desu",~i~l1 chemical ionization DIP diisopropyl ether DMA dimethyldce:ldl,,ide 2 t 90693 ~ 15 DME dimethoxyethane DMF N,N-dimeth~lru,l"d",ide EA ethyl aceta~e (EtOAc) El electron impact eq equivalent ES electrospray ionisation Et ethyl FAB fast atom bol"L,a,.l"le"L
HEP n-heptane HOAc acetic acid Me methyl MeOH methanol mp melting pOillt MTB methyl tertiary-butyl ether NBS N-bromosuccinimide NMP N-methylpyrrolidone RT room temperature THF tetrahydrofuran TMU N,N,N',N'-tetramethylurea Tol toluene CNS central nervous system E~,e, i" ,t:"Ldl section 25 General procedure for the plt:pdl dLioll of ber,,ene~i.,arL,oxylic acid diguanides (I) from dialkyl benzene.li~alL,oxylates (Il, L = O-alkyl) 5 mmol of the dialkyl ben.~ne~i.,dl LJo~ylate of the fommula (Il) and 50 mmol of guanidine (free base) are dissolved in 5 ml of isup,upanol and boiled 30 under reflux (typical reaction time 5 minutes to 5 h) until reaction is complete (thin-layer checking). The mixture is then diluted with 150 ml of water and the product is lFiltered off with suction. If applup, i ' , it is ~;lllull,dLu~,dphed on silica gel using a suitable eluent, e.g. EA/MeOH 5: 1.
~i 21 9~693 Example 1: 4-Chloro-5-phenyl;~ophll, ' acid diguanide O N~NH2 C~ NHz a) 3-Bromo-2-chloro 5-methylbenzoic acid 25 9 of 2-amino-3-broma-5-methylbenzoic acid are diazotized in 500 ml of 6N aqueous HCI solutiorl at 0~C using 8.3 9 of NaNO2, then the mixture is stirred at RT for 30 minultes and poured in portions onto a warm solution at 40~C of 22 9 of CuCI in 200 ml of a saturated aqueous HCI solution. The mixture is stirred at 40-50~C for 20 minutes, and the precipitate is filtered off with suction, washed with water until it is neutral and dried at 40~C
under reduced pressure. 23.3 9 of pale yellow crystals are obtained, mp 170- 172~C.
Rf (EA/MeOH 5:1) = 0.511 MS (DCI): 249 (M+H)+
b) 5-Bromo4-cl,lo,u;sùpl,ll, ' acid 99 9 of MgSo4 x 7H2O are dissolved in 600 ml of water, then 20 9 of 3-bromo-2-chloro-5-methylbenzoic acid are added, the mixture is warmed to 90~C, then 63 9 of KivlnO4 are added in portions at 90-100~C, and the mixture is stirred under reflux for 2 h. It is then allowed to cool to RT, saturated aqueous Na2SO3 solution is added dropwise until the violet color disappears, the mixture is adjusted to pH = 12 with saturated aqueous Na2CO3 solution and the MnO2 is filtered off with suction. It is washed with saturated aqueous Na2SO3 solution and with hot water, the filtrate is adjusted to pH = 1 with aqueous HCI and the precipitate is filtered off with suction. 13.5 g of a colol less solid are obtained, mp > 275~C.
Rf (DIP/2% HOAc) = 0.18 MS (DCI). 279 (M+H)+
~, 21 90~3 c) Dimethyl 5-bromo-4-~;l,lo,uisopl,ll ' ' 13.5 9 of 5-bromo-4-,.l,loruisopilll~ ' acid are dissolved in 200 ml of MeOH, 20 ml of SOCI2 are added dropwise and the mixture is stirred under reflux for 5 h. The volatile constituents are then removed in vacuo and the residue is dried in a fine vacuum. 14 9 of colourless crystals are obtained, mp 99~C MS (DCI): 307 (M+H)+
d) Dimethyl 4-chloro-5-phenyl;;,ophll,dldl~
3.1 9 of dimethyl 5-bromo-4-chloroisophthalate, 1.2 9 of benzeneboronic acid, 2.1 9 of Na2CO3, 230 mg of Pd(OAc)2 and 500 mg of triphen~ o~.l ,i"e are stirred under reflux for 6 h in 50 ml of toluene and 10 ml of water. The mixture is allowed to cool to RT, and is diluted with 300 ml of toluene and washed 3 times with 100 ml of a saturated aqueous Na2CO3 solution each tilne. The organic phase is dried over Na2SO4, the solvent is removed in vacuo and the residue is then ~ llldlUyld~ ed on silica gel using EA/HEP 1:4. 1.5 9 of a colorless oil are obtained.
Rf (EA/HEP 1:4) = 0.22 MS (DCI): 305 (M+H)+
e) 4-Chloro-5-phenyli~,o~l,ll -' acid diguanide 2.6 9 of potassium teff-butoxide are dissolved in 50 ml of anhydrous DMF
and treated with 2.6 9 of guanidine hydrochloride. The mixture is stirred at RT for 1.5 h, 700 mg of dimethyl 4-chloro-5-pherl~li ,opl l~l laldlt: are added and it is stirred at 1 00'C for 2 h. The mixture is poured onto 1 1 of water, and it is adjusted to pH = 8 with aqueous NaHCO3 solution and aqueous HCI solution and then extracted 3 times with 200 ml of EA each time. The organic phase is dried over Na2SO4 and the solvent is removed in vacuo.
The residue is suspended in 100 ml of water ancl filtered off with suction, then the precipitate is again suspended in 50 ml of EA and filtered off with suction. The product is dried in vacuo and 350 mg of colorless crystals are obtained, mp 235~C (with decomposition).
Rf (acetone/water 10:1) = 0.063 MS (ES): 359 (M+H)+
' ~ 18 2~ 90693 Fl ld~ co~ data:
Inhibition of the Na+tH+ t:X~I~dl~9el of rabbit erythrocytes White New Zealand rabbits (Ivanovas) received a standard diet with 2%
5 .;l loltl~,ul for six weeks in order to activate Na+/H+ exchange and thus to be able to determine the Na+ influx into the erythrocytes via Na+/H+
exchange by flame pllu~u~ , y. The blood was taken from the ear arteries and rendered incoagulable by means of 25 IU of potassium heparin. A part of each sample was used for the duplicate d~ r" ,i"dli~ll of the hematocrit 10 by centrifugation. Aliquots of 1 Oû ul in each case were used to measure the Na+ starting content of the erythrocytes.
In order to detenmine the amiloride-sensitive sodium influx 1 Oû ul of each blood sample were incubated in each case in 5 ml of a hype,us",olar salt-sucrose medium (mmol/l: 140 NaCI 3 KCI 15û sucrose û.1 ouabain 2û tris-hydroxymethyla"",~o",t,~l,alle) at pH 7.4 and 37~C. The erythrocytes were then washed three times with ice-cold MgCI2 ouabain solution (mmol/l: 112 MgCI2 û.1 ouabain) and hemolyzed in 2.û ml of distilled water. The intracellular sodium content was dt:L~II ,)i"ecl by flame 2û photometry.
The net Na+ influx was calculated from the difference between sodium starting values and the sodium content of the erythrocytes after incubation.
The amiloride-inhibitable sodium influx resulted from the difference 25 between the sodium content of the erythrocytes after incubation with and without amiloride 3 x 1 û4 moUI. This procedure was also used in the case of the compounds according to the invention.
~ ~ 21 93693 Results Inhibition of the Na+/H+ exchanger:
Example IC!jo (mmol/l) 1 0.9
Claims (18)
1. A benzenedicarboxylic acid diguanide of the formula I
I
in which:
one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or4 carbon atoms, F, Cl, Br, I, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34) independently of one another are hydrogen or alkyl having 1,
I
in which:
one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or4 carbon atoms, F, Cl, Br, I, -OR(32), -NR(33)R(34) or CF3;
R(32), R(33) and R(34) independently of one another are hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
R(2) and R(4) independently of one another are hydrogen, F, Cl, Br, I, OH, -CN, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -(CH2)mR(14);
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16) are hydrogen or-CH3;
or R(2) and R(4) independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, each of which is unsubstituted or substituted by 1 - 4 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl, methoxy;
or R(2) and R(4) independently of one another are R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO or R(29)R(30)N-SO2;
R(22) and R(28) independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30) independently of one another are hydrogen or methyl;
or R(2) and R(4) independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;
or R(35) and R(36) together are 4 - 7 methylene groups, of which a CH2 group can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
or R(25) is-(C1-C9)-heteroaryl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
R(26) and R(27) independently of one another are defined as R(25) or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, X-(CH2)y-CF3 or phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(6)R(7);
R(6) and R(7) independently of one another are hydrogen or -CH3;
X is a bond or oxygen;
y is zero, 1 or 2, or its pharmaceutically tolerable salts.
2. A compound of the formula I as claimed in claim 1 wherein one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, -OR(32), or -NR(33)R(34) or CF3;
R(32), R(33) and R(34) independently of one another are hydrogen or methyl R(2) and R(4) independently of one another are hydrogen, F, Cl, Br, I, OH, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or -(CH2)mR(14);
m is zero, 1 or 2;
R(14) is -(C3-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F
and Cl, -CF3, methyl and methoxy;
or R(2)and R(4) independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, each of which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl;
or R(2) and R(4) independently of one another are R(22)-SO2-, R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28) independently of one another are methyl or -CF3;
R(29), and R(30) independently of one another are hydrogen or methyl;
or R(2) and R(4) independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36) independently of one another are hydrogen, methyl or ethyl;
or R(35) and R(36) together are 4 - 5 methylene groups, of which a CH2 group can be replaced by oxygen, -S-, -NH- or -NCH3;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;
or R(25) -is -(C1-C9) heteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;
R(26) and R(27) independently of one another are hydrogen or alkyl having 1,2, 3 or 4 carbon atoms;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, CF3 or phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and dimethylamino.
R(2) and R(4) independently of one another are hydrogen, F, Cl, Br, I, OH, -CN, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -(CH2)mR(14);
m is zero, 1 or 2;
R(14) is -(C3-C8)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(15)R(16);
R(15) and R(16) are hydrogen or-CH3;
or R(2) and R(4) independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, each of which is unsubstituted or substituted by 1 - 4 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl, methoxy;
or R(2) and R(4) independently of one another are R(22)-SO2-, R(23)R(24)N-CO-, R(28)-CO or R(29)R(30)N-SO2;
R(22) and R(28) independently of one another are methyl or -CF3;
R(23), R(24), R(29) and R(30) independently of one another are hydrogen or methyl;
or R(2) and R(4) independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36) independently of one another are hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;
or R(35) and R(36) together are 4 - 7 methylene groups, of which a CH2 group can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
or R(25) is-(C1-C9)-heteroaryl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy, hydroxyl, amino, methylamino and dimethylamino;
R(26) and R(27) independently of one another are defined as R(25) or are hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, I, X-(CH2)y-CF3 or phenyl, which is unsubstituted or substituted by 1 - 3 substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and -NR(6)R(7);
R(6) and R(7) independently of one another are hydrogen or -CH3;
X is a bond or oxygen;
y is zero, 1 or 2, or its pharmaceutically tolerable salts.
2. A compound of the formula I as claimed in claim 1 wherein one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, -OR(32), or -NR(33)R(34) or CF3;
R(32), R(33) and R(34) independently of one another are hydrogen or methyl R(2) and R(4) independently of one another are hydrogen, F, Cl, Br, I, OH, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms or -(CH2)mR(14);
m is zero, 1 or 2;
R(14) is -(C3-C6)-cycloalkyl or phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F
and Cl, -CF3, methyl and methoxy;
or R(2)and R(4) independently of one another are pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, each of which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 and methyl;
or R(2) and R(4) independently of one another are R(22)-SO2-, R(28)-CO- or R(29)R(30)N-SO2;
R(22) and R(28) independently of one another are methyl or -CF3;
R(29), and R(30) independently of one another are hydrogen or methyl;
or R(2) and R(4) independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36) independently of one another are hydrogen, methyl or ethyl;
or R(35) and R(36) together are 4 - 5 methylene groups, of which a CH2 group can be replaced by oxygen, -S-, -NH- or -NCH3;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;
or R(25) -is -(C1-C9) heteroaryl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, CF3, CH3, methoxy and dimethylamino;
R(26) and R(27) independently of one another are hydrogen or alkyl having 1,2, 3 or 4 carbon atoms;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, Br, CF3 or phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F
and Cl, -CF3, methyl, methoxy and dimethylamino.
3. A compound of the formula I as claimed in claim 1 or 2, wherein:
one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or-CF3;
R(32), R(33) and R(34) independently of one another are hydrogen or methyl;
R(2) and R(4) independently of one another are hydrogen, F, Cl, OH, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-C5)-alkanoyl, C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 anc methyl;
or R(2) and R(4) independently of one another are R(22)-SO2-;
R(22) is methyl or -CF3;
or R(2) and R(4) independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36) independently of one another are hydrogen, methyl or ethyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(3) is -(C1-C9)heteroaryl which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
R(26) and R(27) independently of one another are hydrogen or methyl;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3 or phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F
and Cl, -CF3, methyl and methoxy.
one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR(32), -NR(33)R(34) or-CF3;
R(32), R(33) and R(34) independently of one another are hydrogen or methyl;
R(2) and R(4) independently of one another are hydrogen, F, Cl, OH, CF3, -CO-N=C(NH2)2, alkyl having 1, 2, 3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F, Cl, Br, I, -CN, (C2-C5)-alkanoyl, C2-C5)-alkoxycarbonyl, formyl, carboxyl, -CF3 anc methyl;
or R(2) and R(4) independently of one another are R(22)-SO2-;
R(22) is methyl or -CF3;
or R(2) and R(4) independently of one another are -OR(35) or -NR(35)R(36);
R(35) and R(36) independently of one another are hydrogen, methyl or ethyl;
R(3) is hydrogen, -SR(25), -OR(25), -NR(25)R(26), -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(3) is -(C1-C9)heteroaryl which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
R(26) and R(27) independently of one another are hydrogen or methyl;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3 or phenyl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F
and Cl, -CF3, methyl and methoxy.
4. A compound of the formula ? as claimed in claim 1, 2 or 3, wherein one of the radicals R(1), R(2), R(3) and R(4) is -CO-N=C(NH2)2;
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3 or methoxy;
R(2) and R(4) independently of one another are hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl having 1,2,3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F
Cl, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxy-carbonyl, formyl, carboxyl, -CF3 and methyl;
R(3) is hydrogen -OR(25) or -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(25) is -(C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, -CF3 and CH3;
R(26) and R(27) independently of one another are hydrogen or methyl;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3 or phenyl, which is unsubstituted or substitued by 1 - 2 substituents selected from the group consisting of F and Cl, -CF3 and methyl.
and the other radicals R(1), R(2), R(3) and R(4) in each case are:
R(1) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3 or methoxy;
R(2) and R(4) independently of one another are hydrogen, OH, CF3, -CO-N=C(NH2)2, alkyl having 1,2,3 or 4 carbon atoms or pyrrol-1-yl, which is unsubstituted or substituted by 1 - 2 substituents selected from the group consisting of F
Cl, Br, I, -CN, (C2-C5)-alkanoyl, (C2-C5)-alkoxy-carbonyl, formyl, carboxyl, -CF3 and methyl;
R(3) is hydrogen -OR(25) or -CR(25)R(26)R(27);
R(25) is hydrogen, alkyl having 1, 2 or 3 carbon atoms or phenyl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, CF3 and CH3;
or R(25) is -(C1-C9)-heteroaryl, which is unsubstituted or substituted by a substituent selected from the group consisting of F, Cl, -CF3 and CH3;
R(26) and R(27) independently of one another are hydrogen or methyl;
R(5) is alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF3 or phenyl, which is unsubstituted or substitued by 1 - 2 substituents selected from the group consisting of F and Cl, -CF3 and methyl.
5. A process for the preparation of a compound I as claimed in claim 1, which comprises reacting a compound of the formula II
II
in which R(1') to R(5') have the meanings indicated above for R(1) to R(5), of which, however, at least one of the substituents R(1') to R(5') is the COL
group marked and in which L is a leaving group which can easily be nucleophilically substituted, with guanidine.
II
in which R(1') to R(5') have the meanings indicated above for R(1) to R(5), of which, however, at least one of the substituents R(1') to R(5') is the COL
group marked and in which L is a leaving group which can easily be nucleophilically substituted, with guanidine.
6. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment of arrhythmias.
7. A method for the treatment of arrhythmias which comprises mixing an efficacious amount of a compound I as claimed in claim 1 with the customary additives and administering in a suitable administering form.
8. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment or prophylaxis of cardiac infarct.
9. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment or prophylaxis of angina pectoris.
10. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment or prophylaxis of ischemic conditions of the heart.
11. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatrnent or prophylaxis of ischemic conditions of the peripheral and central nervous system and of stroke.
12. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment or prophylaxis of ischemic conditions of peripheral organs and members.
13. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment of states of shock.
14. The use of a compound I as claimed in claim 1 for the production of a medicament for use in surgical operations and organ transplantation.
15. The use of a compound I as claimed in claim 1 for the production of a medicament for the preservation and transport of transplants for surgical measures.
16. The use of a compound I as claimed in claim 1 for the production of a medicament for the treatment of illnesses in which cell proliferation is a primary or secondary cause and thus their use as antiatherosclerotics, agents against diabetic late complications, carcinomatous disorders, fibrotic disorders such as pulmonary fibrosis fibrosis of the liver or fibrosis of the kidney and prostate hyperplasia.
17. The use of a compound I as claimed in claim 1 for the production of a scientific tool for the inhibition of the Na+/H+ exchanger, and for the diagnosis of hypertension and proliferative disorders.
18. A pharmaceutical comprising an efficacious amount of a compound I
as claimed in one or more of claims 1 to 4.
as claimed in one or more of claims 1 to 4.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19543194.4 | 1995-11-20 | ||
| DE19543194A DE19543194A1 (en) | 1995-11-20 | 1995-11-20 | New benzene-di:carboxylic acid di:guanidide derivs. |
| DE19624064.6 | 1996-06-17 | ||
| DE1996124064 DE19624064A1 (en) | 1996-06-17 | 1996-06-17 | New benzene-di:carboxylic acid di:guanidide derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2190693A1 true CA2190693A1 (en) | 1997-05-21 |
Family
ID=26020502
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002190693A Abandoned CA2190693A1 (en) | 1995-11-20 | 1996-11-19 | Substituted benzenedicarboxylic acid diguanides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0774458A1 (en) |
| JP (1) | JPH09169719A (en) |
| KR (1) | KR980002018A (en) |
| AR (1) | AR004331A1 (en) |
| AU (1) | AU703352B2 (en) |
| BR (1) | BR9605617A (en) |
| CA (1) | CA2190693A1 (en) |
| CZ (1) | CZ338296A3 (en) |
| HR (1) | HRP960547A2 (en) |
| HU (1) | HUP9603201A3 (en) |
| IL (1) | IL119637A0 (en) |
| MX (1) | MX9605674A (en) |
| NO (2) | NO964905L (en) |
| NZ (1) | NZ299772A (en) |
| PL (1) | PL316438A1 (en) |
| SK (1) | SK148796A3 (en) |
| TR (1) | TR199600916A2 (en) |
| TW (1) | TW353657B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19819548A1 (en) * | 1998-04-30 | 1999-11-04 | Merck Patent Gmbh | Biphenyl derivatives |
| DE10044732A1 (en) * | 2000-09-09 | 2002-03-21 | Mahle Ventiltrieb Gmbh | Roller tappet for an internal combustion engine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE59302959D1 (en) * | 1992-02-15 | 1996-07-25 | Hoechst Ag | 3,5-Substituted benzoylguanidines, with antiarrhythmic effects and inhibitory effects on cell proliferation |
| IL109570A0 (en) | 1993-05-17 | 1994-08-26 | Fujisawa Pharmaceutical Co | Guanidine derivatives, pharmaceutical compositions containing the same and processes for the preparation thereof |
| IL114670A0 (en) * | 1994-08-05 | 1995-11-27 | Fujisawa Pharmaceutical Co | Guanidine derivatives pharmaceutical compositions containing the same and processes for the preparation thereof |
-
1996
- 1996-10-08 PL PL96316438A patent/PL316438A1/en unknown
- 1996-11-07 EP EP96117822A patent/EP0774458A1/en not_active Withdrawn
- 1996-11-18 CZ CZ963382A patent/CZ338296A3/en unknown
- 1996-11-18 AR ARP960105230A patent/AR004331A1/en unknown
- 1996-11-18 AU AU71804/96A patent/AU703352B2/en not_active Ceased
- 1996-11-18 NZ NZ299772A patent/NZ299772A/en unknown
- 1996-11-18 SK SK1487-96A patent/SK148796A3/en unknown
- 1996-11-18 TW TW085114093A patent/TW353657B/en active
- 1996-11-18 TR TR96/00916A patent/TR199600916A2/en unknown
- 1996-11-18 IL IL11963796A patent/IL119637A0/en unknown
- 1996-11-19 JP JP8307831A patent/JPH09169719A/en active Pending
- 1996-11-19 HR HR19624064.6A patent/HRP960547A2/en not_active Application Discontinuation
- 1996-11-19 CA CA002190693A patent/CA2190693A1/en not_active Abandoned
- 1996-11-19 BR BR9605617A patent/BR9605617A/en unknown
- 1996-11-19 NO NO964905A patent/NO964905L/en unknown
- 1996-11-19 KR KR1019960055375A patent/KR980002018A/en not_active Application Discontinuation
- 1996-11-19 HU HU9603201A patent/HUP9603201A3/en unknown
- 1996-11-19 MX MX9605674A patent/MX9605674A/en unknown
- 1996-11-19 NO NO964903A patent/NO964903D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NZ299772A (en) | 1998-12-23 |
| MX9605674A (en) | 1997-05-31 |
| PL316438A1 (en) | 1997-05-26 |
| AU7180496A (en) | 1997-05-29 |
| JPH09169719A (en) | 1997-06-30 |
| HUP9603201A3 (en) | 1997-11-28 |
| KR980002018A (en) | 1998-03-30 |
| NO964903D0 (en) | 1996-11-19 |
| AU703352B2 (en) | 1999-03-25 |
| SK148796A3 (en) | 1997-10-08 |
| HU9603201D0 (en) | 1997-01-28 |
| NO964905L (en) | 1997-05-21 |
| IL119637A0 (en) | 1997-02-18 |
| AR004331A1 (en) | 1998-11-04 |
| TW353657B (en) | 1999-03-01 |
| HRP960547A2 (en) | 1998-02-28 |
| TR199600916A2 (en) | 1997-06-21 |
| BR9605617A (en) | 1998-08-18 |
| EP0774458A1 (en) | 1997-05-21 |
| CZ338296A3 (en) | 1998-05-13 |
| NO964905D0 (en) | 1996-11-19 |
| HUP9603201A2 (en) | 1997-05-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
Effective date: 20011119 |