NZ280887A - Benzoylguanidines; preparation and medicaments - Google Patents

Benzoylguanidines; preparation and medicaments

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Publication number
NZ280887A
NZ280887A NZ280887A NZ28088796A NZ280887A NZ 280887 A NZ280887 A NZ 280887A NZ 280887 A NZ280887 A NZ 280887A NZ 28088796 A NZ28088796 A NZ 28088796A NZ 280887 A NZ280887 A NZ 280887A
Authority
NZ
New Zealand
Prior art keywords
group
hydrogen
methyl
phenoxy
zero
Prior art date
Application number
NZ280887A
Inventor
Heinz-Werner Kleemann
Hans-Jochen Lang
Jan-Robert Schwark
Andreas Weichert
Wolfgang Scholz
Udo Albus
Original Assignee
Hoechst Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19502795A external-priority patent/DE19502795A1/en
Priority claimed from DE1995104805 external-priority patent/DE19504805A1/en
Application filed by Hoechst Ag filed Critical Hoechst Ag
Publication of NZ280887A publication Critical patent/NZ280887A/en

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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/40—Acylated substituent nitrogen atom
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    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
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    • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/16—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/30—Isothioureas
    • C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
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    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • 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
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    • 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
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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  • Chemical & Material Sciences (AREA)
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  • 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)
  • Pyridine Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Quinoline Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number £80887 <br><br> 0 <br><br> New Zealand No. 280887 International No. PCT/ <br><br> TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION <br><br> Priority dates: 30.01.1995;14.02.1995; <br><br> Complete Specification Filed: 25.01.1996 <br><br> Classification^) C07C277/08; C07C279/22; C07C303/40; C07C311/29,64; C07C317/46; C07C323/25; C07C381/10; C07C335/32; C07D213/70,42; C07D215/36; C07D233/54.02; C07D235/28; C07C317/28; A61K31/44,18,415,47 <br><br> Publication date: 24 October 1997 <br><br> Journal No.: 1421 <br><br> new zealand patents act 1953 <br><br> COMPLETE SPECIFICATION <br><br> Title of Invention: <br><br> Basically-substituted benzoylguanidines, a process for preparing them, their use as a medicament or diagnostic agent, and a medicament containing them <br><br> NO DRAWINGS <br><br> Name, address and nationality of applicant(s) as in international application form: <br><br> HOECHST AKTIENGESELLSCHAFT, Joint Stock Company of D-65926 Frankfurt am Main, Federal Republic of Germany <br><br> 280887 <br><br> Patents Form 5 <br><br> N.Z. No. <br><br> NEW ZEALAND <br><br> Patents Act 1953 <br><br> COMPLETE SPECIFICATION <br><br> BASICALLY-SUBSTITUTED BENZOYLGUANIDINES. A PROCESS FOR PREPARING THEM. THEIR USE AS A MEDICAMENT OR DIAGNOSTIC AGENT. AND A MEDICAMENT CONTAINING THEM <br><br> We, HOECHST AKTIENGESELLSCHAFT, a Joint Stock Company existing under the laws of the Federal Republic of Germany of, D-65926 Frankfurt am Main, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- <br><br> .1- r <br><br> •"1VED <br><br> - 1 - (Followed by 1A) <br><br> 28088 <br><br> — la - <br><br> Hoechst Aktiengesellschaft HfflH flB/'J? CH!I7 Jk Description <br><br> Basically-substituted benzoylguanidines, a process for preparing them, their use as a medicament or diagnostic 5 agent, and a medicament containing them <br><br> The invention relates to benzoylguanidines of the formula (I) <br><br> R(1) <br><br> r ( 2 ) r ( 5 ) <br><br> nh <br><br> -VrY <br><br> r (4) 0 "hj r(3&gt; " 2 <br><br> in which: <br><br> one of the three substituents R(l), R(2) and R(3) is 10 R(6)-A-B-D-; <br><br> R(6) is a basic protonatable radical, i.e. an amino group -NR(7)R(8), an amidino group R(7)R(8)N-C[=N-R(9)]- or a guanidino group r(7| r(10) <br><br> r(a) <br><br> R(9)/N <br><br> R(7) , R(8) , R(9) and R(10) are, 15 independently of each other, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; <br><br> or <br><br> R(7) and R(8) are, <br><br> together ' CaH2a; 20 a is 4, 5, 6 or 7; <br><br> where, when a = 5, 6 or 7, a methylene group of the group CaH2a can be replaced <br><br> - 2 <br><br> 280 887 <br><br> by a heteroatom group O, SOm or NR(ll), <br><br> or <br><br> R(8) and R(9) or R(9) and R(10) or R(7) and <br><br> R(10) are a group C^; <br><br> x is 2, 3, 4 or 5; <br><br> where, when x = 3, 4 or 5, a methylene group of the group can be replaced by a heteroatom group O, SOm or MR(11); <br><br> m is zero, 1 or 2; <br><br> R(ll) is hydrogen or methyl; <br><br> is a basic heteroaromatic ring system having <br><br> 1-9 carbon atoms; <br><br> is CbH2i,; <br><br> b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; <br><br> where, in the group CbH2b, one or two methylene groups can be replaced by one of the groupings selected from the group consisting of -O-, -CO-, -CH[OR(20) ] -, -SOm-, -NR(20)-, -NR(20)-CO-, -NR(20)-CO-NH-, -NR(20)-C0-NH-S02- <br><br> -r(20)n-s- <br><br> II <br><br> I NR(19 ) 1 bb and -SOaa[NR(19)]bb-; <br><br> and where, in the group CbH2b, a methylene group can be replaced by -CH-R(99), where R(99), together with R(7), forms a pyrrolidine or piperidine ring; <br><br> aa is 1 or 2; <br><br> bb is 0 or 1; <br><br> aa + bb =2; <br><br> R(19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms <br><br> 28088 <br><br> R(20) is hydrogen or methyl; <br><br> B is a phenylene or naphthylene radical <br><br> R(12) R(12) <br><br> ip- <br><br> B(t J) <br><br> M IS) <br><br> R(12) and R(13) are, <br><br> independently of each other, hydrogen, 5 methyl, P, CI, Br, I, CP3 or -SOw-R(14); <br><br> R(14) is methyl or NR(15)R(16); <br><br> R(15) and R(16) are, <br><br> independently of each other, hydrogen or alkyl having 1, 2, 3 or 10 4 carbon atoms; <br><br> w is zero, 1 or 2; <br><br> D is -CdH2d-Xf-; <br><br> d is zero, 1, 2, 3 or 4; <br><br> X is -0-, -CO-, -CH[OR(21)]-, -SOm- or 15 -NR(21)-; <br><br> f is zero or 1; <br><br> R(21) is hydrogen or methyl; <br><br> m is zero, 1 or 2; <br><br> and in each case the other two of the substituents R(l) 20 and R(2) and R(3) are, <br><br> independently of each other, hydrogen, F, CI, Br, I, -CN, - (C-L-Cg) -alkyl, - (C2-C8)-alkenyl, -NR(35)R(36) or R(17)-CgH2g-Zh-; <br><br> g is zero, 1, 2, 3 or 4; <br><br> 25 h is zero or 1; <br><br> R(35) and R(36) are, <br><br> independently of each other, hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; <br><br> or <br><br> 30 R(35) and R(36) are. <br><br> 2 8 0 8 8 7 <br><br> - 4 - <br><br> together, 4-7 methylene groups of which one CH2 group can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl; <br><br> Z is -0-, -CO-, -SOv-, -NR(18)-, -NR(18)-CO-, -NR(18)-CO-NH- or -NR(18)-S02-; <br><br> R(18) is hydrogen or methyl; <br><br> v is zero, 1 or 2; <br><br> R (17) is cycloalkyl having 3, 5 or 6 <br><br> carbon atoms, or CkF2k4.1-f k is 1, 2 or 3, <br><br> or <br><br> R(17) is pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, <br><br> which is not substituted or is substituted by 1-4 substituents selected from the group consisting of F, CI, Br, X, -CN, (C2-C8) -alkanoyl, (C2-C8)-alkoxy-carbonyl, formyl, carboxyl, -CF3, methyl and. methoxy; <br><br> or <br><br> R(17) is - (C3-C8)-cycloalkyl or phenyl, <br><br> which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F and CI, -CF3, methyl, hydroxyl, methoxy, -NR(37)R(38) , CH3S02- and H2N02S-; <br><br> R(37) and R(38) are hydrogen or -CH3; <br><br> R(4) and R(5) are, <br><br> independently of each other, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR(32) , -NR(33)R(34) or -CrF2r4-1; <br><br> R (32), R(33) and R(34) are, <br><br> independently of each other, hydrogen or alkyl having 1, 2 or 3 carbon atoms; <br><br> r is 1, 2, 3 or 4; <br><br> and the pharmacologically tolerated salts thereof. <br><br> Compounds of the formula I are preferred in which: <br><br> \ \1 <br><br> &gt;- 280 8 8 7 <br><br> - 5 - <br><br> R(l) ia hydrogen/ F, CI, -(Cx-C4)-alkyl, - (C2-C4)-alkenyl, -NR(35)R(36) or R(17) -CgH2g-Zh- ; <br><br> R(35) and R(36) are, <br><br> Independently of each other, hydrogen, methyl 5 or ethyl; <br><br> or <br><br> R(35) and R(36) are, <br><br> together, 4-5 methylene groups of which one CH2 group can be replaced by oxygen, -S-, -NH-10 or -NCH3; <br><br> R(17) is cycloalkyl having 5 or 6 carbon atoms, or C^F^^i; <br><br> k is 1, 2 or 3, <br><br> g is zero, 1, 2, 3 or 4; <br><br> 15 h is zero or 1; <br><br> Z is -0-, -CO-, -SOv-, -NR(18)-, -NR(18)-CO-, -NR(18)-CO-NH- or -NR(18)-S02-; <br><br> R(18) is hydrogen or methyl; <br><br> v is zero, 1 or 2; <br><br> 20 or, if g and h are zero, <br><br> R(17) is pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, <br><br> which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, CI, 25 (C2-C5)-alkanoyl, (C2-Cs)-alkoxycarbonyl, <br><br> formyl, earboxyl, -CF3, methyl and methoxy; <br><br> or <br><br> R(17) is - (C3-C8)-cycloalkyl or phenyl, 30 which is not substituted or is sub stituted by 1-2 substituents selected from the group consisting of F and CI, -CF3, methyl, methoxy, -NR(37)R(38), CH3S02- and HjN02S-; 35 R(37) and R(38) are, <br><br> independently of each other, <br><br> hydrogen or -CH3; <br><br> one of the substituents R(2) and R(3) is R(6)-A-B-D; <br><br> li <br><br> fi ~ C ^ <br><br> - 6 <br><br> 28 0 8 87 <br><br> R(6) is -NR(7)R(8), an amidino group R(7)R(8)N-C[=N-R(9)]- or a guanidino group <br><br> R(7j R(10) <br><br> K.) -V- <br><br> R(9)^H <br><br> 10 <br><br> 15 <br><br> 20 <br><br> 25 <br><br> 30 <br><br> or <br><br> R(6) is A is <br><br> •:£r\ <br><br> \?&gt; <br><br> R(7), R(8) / R(9) and R(10) are independently of each other, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; <br><br> or <br><br> R(7) and R(8) are, <br><br> together, CJHj,; <br><br> x is 4,5,6 or 7; <br><br> where, when x = 5, 6 or 7, a methylene group of the group can be replaced by a heteroatom group O, SOm or MR(11); <br><br> R(ll) is hydrogen or methyl; <br><br> or <br><br> R(8) and R(9) are, <br><br> together, C^ax; <br><br> is 2, 3, 4 or 5; <br><br> where, when x = 3, 4 or 5, a methylene group of the group C„Hax can be replaced by a heteroatom group O, NR(11); <br><br> m is zero, 1 or 2; <br><br> SO„ or m <br><br> imidazolyl, pyridyl, isoquinolinyl; <br><br> quinolinyl or cbH2b' <br><br> is 1, 2, 3, 4 or 5, <br><br> where, in the group CbH2b, one or two methylene groups can be replaced by <br><br> - 7 - <br><br> 280887 <br><br> one of the groupings selected from the group consisting of -O-, -CO-, -CH[OR(20)]-, -SOm-, NR(20), -NR(20)-CO-, -NR(20)-CO-NH-, 5 -NR(20)-C0-NH-S02-, <br><br> ii° &gt;" <br><br> -r ( 20)n-s~ <br><br> II <br><br> t NR(19 ) 1 bb and -SOaa[NR(19) ]bb-; <br><br> and where, in the group CbH2b, a methylene group can be replaced by -CH-R(99), where R(99), together 10 with R(7) , forms a pyrrolidine or piperidine ring; <br><br> aa is 1 or 2; <br><br> bb is 0 or 1; <br><br> aa + bb = 2; <br><br> 15 R(19) is hydrogen or alkyl having 1, <br><br> 2, 3 or 4 carbon atoms R(20) is hydrogen or methyl; <br><br> B is a phenylene or naphthylene radical r( 12) r(12) <br><br> R(13) <br><br> R(12) and R(13) are, <br><br> 20 independently of each other, hydrogen, methyl, <br><br> F, CI, CF3 or -S02-R(14); <br><br> R(14) is methyl or NR(15)R(16); <br><br> R(15) and R(16) are, <br><br> independently of each other, 25 hydrogen or alkyl having 1, <br><br> 280 8 8 7 <br><br> - 8 - <br><br> 2, 3 or 4 carbon atoms; <br><br> D is -CdH2d-Xf-; <br><br> d is zero, 1, 2, 3 or 4; <br><br> X is -O-, -CO-, -CH[OR(21)]-, -SOm- or 5 -NR(21)-; <br><br> £ is zero or 1; <br><br> R(21) is hydrogen or methyl; <br><br> m is zero, 1 or 2; <br><br> and in each case the other of the radicals R(2) and R(3) 10 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, CI or CF3; <br><br> R(4) and R(5) are, <br><br> independently of each other, hydrogen, alkyl having 15 1, 2 or 3 carbon atoms, F, CI or -CF3; <br><br> and the pharmacologically tolerated salts thereof. <br><br> Compounds of the formula I are particularly preferred in which: <br><br> R(1) is hydrogen, F, CI, alkyl having 1, 2, 3 or 4 carbon 20 atoms, -NR(35)R(36) or R(17)-CgH2g-Zh-; <br><br> g is zero, 1, 2, 3 or 4; <br><br> h is zero or 1; <br><br> Z is -0-, -CO-, -SOv-, -NR(18)-, -NR(18)-CO-, -NR(18)-CO-NH- or -NR(18)-S02-; 25 R(18) is hydrogen or methyl; <br><br> v is zero, 1 or 2; R (17) is cycloalkyl having 5 or 6 carbon atoms, or CF3-; <br><br> or, if g and h are zero, <br><br> 3 0 R(17) is pyrrol-1-yl, <br><br> which is not substituted or is substituted by 1-2 substituents selected from the group consisting of F, Cl, (C2-C5) -alkanoyl, (C2-C5) -alkoxycarbonyl, 35 -CF3 and methyl; <br><br> or <br><br> R(17) is - (C5-C6) -cycloalkyl or phenyl, <br><br> which is not substituted or <br><br> - 9 - <br><br> 28088 <br><br> substituted by a substituent which is selected from the group consisting of F and CI, -CF3, methyl, CH3S02- and H2N02S-; <br><br> R(35) and R(36) are, 5 independently of each other, hydrogen, <br><br> methyl or ethyl; <br><br> or <br><br> R(35) and R(36) are, <br><br> together, 4-5 methylene groups of which 10 one CH2 group can be replaced by oxygen, <br><br> -S-, -NH- or -NCH3; <br><br> one of the substituents R(2) and R(3) is <br><br> R(6)-A-B-D-; <br><br> R(6) is -NR(7)R(8), an amidino group R(7)R(8)N-15 C[=N-R(9)]- or a guanidino group <br><br> R(7| R(t0) <br><br> «&lt;•) <br><br> R(9)^M <br><br> R(7) is hydrogen &gt;r alkyl having 1, 2, 3 or 4 carbon atoms; <br><br> R(8), R(9) and R(10) are, <br><br> 2 0 independently of each other, <br><br> hydrogen, methyl or ethyl; <br><br> or <br><br> R(7) and R(8) are, <br><br> together, CaH2a; 25 a is 4 or 5; <br><br> where, when a = 5, a methylene group of the group CaH2a can be replaced by NR(11), <br><br> 3 0 R(ll) is hydrogen or methyl; <br><br> or <br><br> R(6) is imidazolyl or pyridyl? <br><br> - 10 <br><br> 2808 <br><br> is CbH2b; <br><br> is 1, 2, 3, 4 or 5, <br><br> where, in the group CbH2b, one or two methylene groups can be replaced by one of the groupings selected from the group consisting of -CO-, -CH[OR(20)]-, -NR(20)-CO-, <br><br> I <br><br> - r ( 2 0 ) n -s - <br><br> °&gt;oo <br><br> INR(19 ) 1 bb <br><br> -SOaa[NR(19)]bb and -S02-; <br><br> and where, in the group C2bH2b, a 10 methylene group can be replaced by <br><br> -CH-R(99), where R(99), together with R(7), forms a pyrrolidine or piperidine ring; <br><br> aa is 1 or 2; 15 bb is 0 or 1; <br><br> aa + bb = 2; <br><br> R(19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms R(20) is hydrogen or methyl; 20 or, if b is 2, 3, 4 or 5, <br><br> a carbon atom in CbH2b can be replaced by a grouping -O-, -S-, -NR(20)-, -NR(20)-CO- or -NR(20)-CO-NH-; 6 is a phenylene radical, <br><br> r(i2) <br><br> r(13) <br><br> 25 <br><br> R(12) and R(13) are, <br><br> 280 887 <br><br> - 11 - <br><br> independently of each other, hydrogen, <br><br> methyl, F, CI, CF3 or -S02R(14); <br><br> R(14) is methyl or NH2; <br><br> D is -CH2-, -0-, -CO-, -SOm- or -NR(21)-; 5 m is zero or 2; <br><br> R(21) is hydrogen or methyl; <br><br> and in each case the other of the radicals R(2) and R(3) <br><br> is hydrogen; <br><br> 10 R(4) and R(5) are, <br><br> independently of each other, hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, CI or -CF3; <br><br> and the pharmaceutically tolerated salts thereof. <br><br> Compounds of the formula X are very particularly pre-15 ferred in which <br><br> R(1) is hydrogen, F, CI, alkyl having 1, 2, 3 or 4 carbon atoms, -NR(35) R(36) or R&lt;17)-CgH2g-Zh-; <br><br> g is zero or 1; <br><br> h is zero or 1; <br><br> 20 Z is -O-, -CO-, -NR (18) -CO-, -NR (18)-CO-NH- or <br><br> -NR(18)-S02-; <br><br> R(18) is hydrogen or methyl; <br><br> or, if g is 1; <br><br> Z is -S02-; <br><br> 25 R(17) is CF3-; <br><br> R(35) and R(36) are, <br><br> independently of each other, hydrogen, methyl or ethyl; <br><br> or <br><br> 30 R(35) and R(36) are, <br><br> together, 4-5 methylene groups of which one CH2 group can be replaced by oxygen, -S-, -NH-or -NCH3; <br><br> one of the substituents R(2) and R(3) is 35 R (6) -A-B-O-; _. .... <br><br> R(6) is -NR(7)R(8) or a guanidino group /C ' ' \ <br><br> / f • <br><br> &lt;' ** <br><br> ii ^ 'S-j1 <br><br> c., <br><br> \ ^ ^ -v V1" <br><br> "* V * £ C <br><br> - 12 - <br><br> 280887 <br><br> R(7| «&lt;io) «&lt;•&gt; <br><br> Ms) <br><br> R (7) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; <br><br> R(8), R(9) and R(10) are, 5 independently of each other, hydrogen, <br><br> methyl or ethyl; <br><br> or <br><br> R(7) and R(8) are, <br><br> together, CaH2a; <br><br> 10 a is 4 or 5; <br><br> where, when a = 5, a methylene group of the group CaH2a can be replaced by -NH- or -NCH3-, <br><br> or <br><br> 15 R(6) is imidazolyl; <br><br> A is CbH2b; <br><br> b is 1, 2, 3 or 4; <br><br> where, in the group CbH2b, one or two methylene groups can be replaced by one <br><br> 2 0 of the groupings selected from the group consisting of -CO-, <br><br> ii0'" <br><br> -R(20)N-S- <br><br> INR(19 ) ] bb <br><br> -SOaa[NR(19)]bb- and -S02-, <br><br> and where, in the group CbH2b, a methylene group can be replaced by -CH-R(99), where 25 R(99) , together with R(7) , can form a <br><br> 10 <br><br> - 13 <br><br> 280887 <br><br> pyrrolidine or piperidine ring; <br><br> or, if b is 2, 3 or 4, <br><br> a methylene group in the group CbH2b can be replaced by a grouping -O- or -S-; aa is 1 or 2; <br><br> bb is 0 or 1; <br><br> aa + bb = 2; <br><br> R(19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms R(20) is hydrogen or methyl; is a phenylene radical, <br><br> R(U) <br><br> jb- <br><br> R (1 3) <br><br> R(12) and R(13) are, <br><br> hydrogen; <br><br> and in each case the other of the radicals R(2) and R(3) 15 is hydrogen; <br><br> R(4) and R(5) are hydrogen; <br><br> and the pharmacologically tolerated salts thereof. <br><br> 20 Particular preference is given to a compound which is selected from the group consisting of <br><br> 4- [4-N- (dimethylaminoethyl) methylsulf amoyl] phenoxy-3 -trifluoromethylbenzoylguanidine dihydrochloride; 4-[4-(4-methylpiperazinosulfonyl)phenoxy]-3 -trifluoro-25 methylbenzoylguanidine dihydrochloride; <br><br> 4-[4-(2-pyrrolidineethylaminosulfonyl)phenoxy]-3-trifluoromethylbenzoylguanidine dimaleate; 4- [4-(2-piperidineethylaminosulfonyl)phenoxy] -3-trifluoromethylbenzoylguanidine dimaleate; 30 4- [4-(N-dimethylamino-n-propyl)sulfamoyl]phenoxy-3- <br><br> 30 <br><br> 2 8 0 8 8 7 <br><br> - 14 - <br><br> trifluoromethylbenzoylguanidine; <br><br> 4- [4- (N-dimethylaminoethyl) sulfamoyl]phenoxy-3-trifluoro-me thylbenzoylguanidine; <br><br> 4 - (4- imidosulf amoyl) phenoxy-3 - trifluoromethylbenzoyl -guanidine; <br><br> 3 - trif luoromethyl - 4 - (4-N-me thylimidosulf amoyl) -phenoxybenzoylguanidine; <br><br> 3-methyl-4- [4-(l-methylpiperazin-4-ylsulfonyl)phenoxy]-benzoylguanidine; <br><br> 4 - (4-guanidinosulf onyl) phenoxy-3 - trif luorome thylbenzoyl -guanidine; <br><br> 4- [4- (2 -imidazolylthioacetyl) phenoxy] -3-methylsulfonyl-benzoylguanidine dihydrochloride; <br><br> 4 - [4 - (N,N# -dimethyl-S- isothiouronylacetyl)phenoxy] -3- <br><br> me thy 1 sul f ony lbenz oy lguanidine dihydrochloride; <br><br> 4- [4- (2-benzimidazolylthioacetyl)phenoxy]-3-methyl- <br><br> sulfonylbenzoylguanidine dihydrochloride; <br><br> 4- [4- (2-N-imidazolyl~l-hydroxyethyl) phenoxy] -3-methyl- <br><br> sulfonylbenzoylguanidine dihydrochloride; <br><br> 4- [4- (N,N-dimethylglycylamino)phenoxy] -3-methylsulfonyl- <br><br> benzoylguanidine dihydrochloride; <br><br> 4-[4-(N,N-diethylaminoethyl)aminosulfonylphenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride; <br><br> 4- [4- (4 - imi da zolyl ethyl) aminosulf onylphenoxy] -3-methyl-sulfonylbenzoylguanidine dihydrochloride; 4- [4- {3-N-imidazolyl-1-propyl) aminosulf onylphenoxy] -3-methy1sulfonylbenzoylguanidine dihydrochloride; 4- [4- (1-methyl-2-pyrrolidinylethyl) aminosulf onylphenoxy] -3 -methylsulf onylbenzoylguanidine dihydrochloride; 4- [4- (N-piperidinoethyl) aminosulf onylphenoxy] -3 -methylsulf onylbenzoylguanidine dihydrochloride; 4-[4-(2-dimethylaminoethyl)sulfonylmethylphenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride; 4-[4-(2-dimethylaminoethyl)sulfonylmethylphenoxy]-3-trifluoromethylbenzoylguanidine dihydrochloride. <br><br> The indicated allcyl radicals can be either straight-chain or branched. <br><br> "-'V\ <br><br> 280887 <br><br> - 15 - <br><br> A basic heteroaromatic ring system having 1-9 carbon atoms is understood to mean, in particular, radicals which are derived from cyclopentyl, phenyl or naphthyl and in which one or more CH groups is/are replaced by N. Heteroaryl is, in particular, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, quinolyl and isoquinolyl. Halogen is F, CI, Br or I. <br><br> If the compounds of the formula I contain centers of asymmetry, formula I describes both the individual optical antipodes and also their possible enantiomeric mixtures. <br><br> The invention furthermore relates to a process for preparing a compound I, which comprises reacting a compound of the formula II <br><br> «(*) 0 <br><br> in which R(l) to R(5) have the given meaning and L is a leaving group which can readily be substituted nucleo-philically, with guanidine, and, where appropriate, converting the product into a pharmacologically tolerated salt. <br><br> The activated acid derivatives of the formula II, in which L is an alkoxy, preferably a methoxy group, a phenoxy group, phenylthio, methylthio, or a 3-pyridyloxy or 2-pyridylthio group, or a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained, in a known manner, from the underlying carbonyl chlorides (formula II, L = CI), which, for their part, can in turn be prepared, in a known manner, from the under lying carboxylic acids (formula II, L = OH), for example using <br><br> 28088 <br><br> - 16 - <br><br> thionyl chloride. <br><br> In addition to the carbonyl chlorides of the formula II (L = Cl) , other activated acid derivatives of the formula II can also be prepared, in a known manner, directly from 5 the underlying benzoic acid derivatives (formula II, L = OH) , for example the methyl esters of the formula II where L = OCH3 by treatment: with gaseous HC1 in methanol, the imidazolides of the formula II by treatment with carbonyl diimidazole [L = 1-imidazole, Staab, Angew. 10 Chem. Int. Ed. Engl. 1, 351 - 367 (1962)], the mixed anhydrides II using ClCOOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, and benzoic acids can also be activated with dicyclohexyl-carbodiimide (DCC) or with 0[(cyano(ethoxycarbonyl)-15 methylene) amino] -1,1, 3,3-tetramethyluronium tetrafluoro-borate ("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 preparing activated carboxylic acid deriva-20 tives of the formula II can be found in J. March, Advanced Organic Chemistry, Third Edition (John Wiley &amp; Sons, 1985), p. 350, where the source references are cited. <br><br> An activated carboxylic acid derivative of the formula II 25 is reacted with guanidine, in a known manner, in a protic or aprotic polar, but inert, organic solvent. Methanol, isopropanol or THF have proved to be of value in the reaction of the methyl benzoate (II, L = OME) with guanidine at temperatures of from 20 °C to the boiling 3 0 point of the solvents. Most reactions of compounds II with salt-free guanidine were advantageously carried out in aprotic inert solvents such as THF, dimethoxyethane, dioxane or isopropanol. However, water can also be employed as a solvent in the reaction of II and guanidine 35 when a base is used. <br><br> If L = Cl, the reaction is advantageously carried out <br><br> 28088 <br><br> - 17 - <br><br> with the addition of an acid-capturing agent, for example in the form of excess guanidine, in order to bind the hydrohalic acid. <br><br> Some of the underlying benzoic acid derivatives are known. They are prepared, using methods which are known from the literature, by, for example, converting the finished radical R (6)-A-B-CdH2d-Xf-, or a precursor thereof, by halogen exchange, into a benzoic acid derivative of the formula III <br><br> or ' <br><br> I I I <br><br> 10 in which the substituent R' has the meaning of a lower alkyl radical, for example methyl or ethyl, and R" is halogen. The reactions are described in the literature, for example as a nucleophilic substitution reaction, as a free-radical Ullmann reaction or as palladium-catalyzed 15 reactions. <br><br> The introduction of the benzenesulfonamide derivatives which are substituted in the phenyl moiety by sulfur, oxygen or nitrogen nucleophiles is achieved using methods, which are known from the literature, of 20 nucleophilic substitution on the aromatic moiety. Halides and trif luorome thanesulfonates have proved to be of value, in this substitution, as leaving group on the benzoic acid derivative. The reaction is advantageously carried out in a dipolar aprotic solvent, such as DMF or 25 TMU, at a temperature of from 0°C to the boiling point of the solvent, preferably from 80°C to the boiling point of the solvent. An alkali metal salt or alkaline earth metal salt possessing an anion of high basicity and low nucleo-philicity, for example K2C03 or CsC03, advantageously <br><br> ► 28088 <br><br> serves as acid-capturing agent. <br><br> Most of the R(6}-A-B-CdH2d-Xf- compounds used as precursors are known and some of them are also commercially available as reagents. They are prepared by methods which 5 are known from the literature and with which the person skilled in the art is familiar. <br><br> Some substituents can successfully be introduced into the 4 and 5 positions by methods which are known from the literature, namely palladium-mediated cross-coupling of 10 aryl halides with, for example, organostannanes, organo-boronic acids or organoboranes or organocopper or organo-z inc c ompounds. <br><br> In general, benzoylguanidines I are weak bases and cam. <br><br> bind acid with the formation of salts. Suitable acid 15 addition salts are salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, ascorbates, acetates, phosphates, methylsulfonates and p-toluenesulfonates. <br><br> 20 The compounds I are substituted acylguanidines. <br><br> The best known representative of the acylguanidines is the pyrazine derivative amiloride, which is used in therapy as a potassium-sparing diuretic. A large number of other amiloride-type compounds are described in the 25 literature, for example dimethylamiloride or ethylisopropylamiloride. <br><br> 28088 <br><br> NH <br><br> \ /C\ <br><br> &lt;T NH NH <br><br> II I <br><br> R ' ^Cv <br><br> \.,/ ^|s|^ <br><br> 'N' <br><br> I <br><br> R ' ' <br><br> 'NH <br><br> Amiloride: R',R" = H Dimethylamiloiide: R',R" =&gt; CH3 <br><br> Ethylisopropylt*miloride: R' = C2H5, and R" = CH(CH3)2 <br><br> Moreover, tests are known, which suggest that amiloride 5 has antiarrhythmic properties (Circulation 79, 1257 to 1263 (1989)). However, militating against its widespread use as an antiarrythmic is the fact that this effect is only weakly expressed and is accompanied by hypotensive and saluretic activity, and these side-effects are 10 undesirable in the treatment of disturbances of cardiac rhythm. <br><br> Experiments on isolated animal hearts have also suggested that amiloride has antiarrhythmic properties (Eur. Heart J. 9 (suppl. 1): 167 (1988) (book of abstracts)). Thus, 15 it has been found that artificially induced ventricular fibrillation in rat hearts can be completely suppressed by amiloride. In this model, the abovementioned amiloride derivative ethylisopropylamiloride was even more potent than amiloride itself. <br><br> 20 US Patent 5 091 394 (HOE 89/F 288) describes benzoylguanidines which carry only a hydrogen atom in the position corresponding to the radical R(l) and in which none of the substituents has the meaning of R(5)-A-B-D-. European Laid-Open Application 0 556 674 A (HOE 92/F 034) 25 proposes 3,5-substituted benzoylguanidines in which, however, the substituent R(2) does not have the meaning <br><br> 280 <br><br> 20 - <br><br> of R(5)-A-B-D-, which is claimed in accordance with the present invention. <br><br> US Patent 3 780 027 claims acylguanidines which are structurally similar to the compounds of the formula I 5 and which are derived from commercially available loop diuretics, such as bumetanide. Accordingly, these compounds are reported to have powerful salidiuretic activity. <br><br> It was surprising, therefore, that the novel compounds 10 have no undesirable, disadvantageous salidiuretic properties but, nevertheless, have a very good antiarrhythmic activity against arrhythmias as they occur, for example, in connection with oxygen deficiencies. Due to their pharmacological properties, the compounds are out-15 standingly suitable for use, as antiarrhythmic pharmaceuticals having a cardioprotective component, for the prophylaxis and treatment of infarction and for the treatment of angina pectoris, in which context they also preventively inhibit, or reduce greatly, the 20 pathophysiological processes associated with the development of ischemically induced damage, in particular when ischemically induced cardiac arrhythmias are triggered. Due to their protective activity against pathological hypoxic and ischemic situations, the novel compounds of 25 the formula I can, owing to inhibition of the cellular Na+/H+ exchange mechanism, be used as pharmaceuticals for treating all acute or chronic damage which is triggered by ischemia or for treating diseases which are directly or colaterally induced thereby. This applies to their use 30 as pharmaceuticals for surgical interventions, for example in connection with organ transplants, where the compounds can be used for the projection of the organs in the donor before and during their removal, for the protection of removed organs, for example during their 35 treatment with, or storage in, physiological bathing fluids, and also during their transfer into the recipient organism. Equally, the compounds are valuable protective <br><br> 28088 <br><br> - 21 - <br><br> pharmaceuticals when angioplastic surgical interventions are carried out, for example on the heart or on peripheral blood vessels. In correspondence with their protective activity against ischemia-indxiced damage, the 5 compounds are also suitable as pharmaceuticals for the treatment of ischemias of the nervous system, in particular of the central nervous system, where they are suitable, for example, for the treatment of stroke or of brain edema. Moreover, the compounds of the formula I 10 according to the invention are also suitable for the treatment of forms of shock, for example allergic, cardiogenic, hypovolemic and bacterial shock. <br><br> Moreover, the compounds of the formula I according to the invention are distinguished by a powerful inhibitory 15 action on cell proliferation, for example fibroblast cell proliferation 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 direct or collateral <br><br> 2 0 cause, and they can therefore be used as antiathero- <br><br> sclerotics, agents against diabetic late complications, cancers, fibrotic disorders, such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, organ hypertrophies and hyperplasias, in particular in prostatic hyperplasia 25 or prostatic hypertrophy. <br><br> The compounds according to the invention are valuable inhibitors of the cellular sodium/proton antiporter (Na+/H+ exchanger), which is elevated in a large number of diseases (essential hypertension, atherosclerosis, <br><br> 3 0 diabetes and the like) even in those cells which are readily accessible to measurements, such as in erythrocytes, thrombocytes or leucocytes. The compounds according to the invention are therefore suitable as outstanding and simple scientific tools, for example in 35 their use as diagnostics for determining, and distinguishing between, particular forms of hypertension, and also of atherosclerosis, diabetes, proliferative dis- <br><br> 28088 <br><br> - 22 <br><br> orders and the like. Moreover, the compounds of the formula I are suitable for preventive therapy for preventing the genesis of hypertension, for example of essential hypertension. <br><br> 5 In addition to a strongly inhibitory effect on the Na+/H+ exchanger the solubility in water of the compounds according to the invention is significantly improved in contrast to the known compounds. They are therefore much better suited to intravenous administration. <br><br> 10 Pharmaceuticals which contain a compound I can be administered orally, parenterally, intravenously, rectally or by inhaling, the preferred way of administration depending on the particular symptom of the disease. The compounds I can be used by themselves or together with 15 pharmaceutical auxiliaries, and they can be employed both in veterinary medicine and human medicine. <br><br> A person skilled in the art knows, on the basis of his expert knowledge, which auxiliaries are suitable for the desired pharmaceutical fozmulation. Auxiliaries which can 20 be used in addition to solvents, gel formers, bases for suppositories, tableting auxiliaries, and other excipi-ents for active substances are, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor improvers, preservatives, solubilizers or colorants. <br><br> 25 For an oral dosage form, the active compounds together with the suitable additives, such as carriers, stabilizers or inert diluents, are mixed and formulated by customary methods to give suitable dosage forms, such as tablets, sugar-coated tablets, hard gelatin capsules, or 30 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. Dry granules or moist granules cam be used for the preparation. 35 Examples of oily carriers or examples of solvents are <br><br> 28088 <br><br> 23 - <br><br> vegetable or animal oils, such as sunflower oil or cod liver oil. <br><br> For subcutaneous or intravenous administration, the active compounds, if desired together with the substances 5 which are customary for this purpose, such as solubil-izers, emulsifiers or other auxiliaries, are dissolved, suspended or emulsified. Examples of suitable solvents are: water, physiological saline solution or alcohols, for example ethanol, propanol, glycerol, and also sugar 10 solutions, such as glucose or mannitol solutions, or else a mixture of the various solvents which have been mentioned above. <br><br> Pharmaceutical formulations which are suitable for administration in the form of aerosols or sprays are, for 15 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. <br><br> If required, the formulation can also contain other 20 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. <br><br> 25 The dose of the active substance of the formula X 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 30 and individual responsiveness of the mammal to be treated. <br><br> 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 <br><br> 23088 <br><br> 24 - <br><br> 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 exeunple up to 4 single doses per day. In particular, for 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. <br><br> List of abbreviations: <br><br> 10 <br><br> AIBN <br><br> a,a-azobisisobutyronitrile <br><br> Bn benzyl <br><br> brine saturated aqueous solution <br><br> ch2ci2 <br><br> dichloromethane <br><br> DC1 <br><br> desorption chemical ionizaf <br><br> 15 <br><br> DIP <br><br> diisopropyl ether <br><br> DMA <br><br> dimethylacetamide <br><br> DME <br><br> dime thoxyethane <br><br> DMP <br><br> N, N- dime thy 1 f ormamide <br><br> EA <br><br> ethyl acetate (EtOAc) <br><br> 20 <br><br> EI <br><br> electron impact <br><br> eq equivalent <br><br> ES <br><br> electrospray ionization <br><br> Et ethyl <br><br> FAB <br><br> fast atom bombardment <br><br> 25 <br><br> HEP <br><br> n-heptane <br><br> HOAc acetic acid <br><br> Me methyl <br><br> MeOH <br><br> methanol <br><br> mp melting point <br><br> 30 <br><br> MTB <br><br> methyl tert-butyl ether <br><br> NBS <br><br> N-bromosuccinimide <br><br> NMP <br><br> N-methylpyrro1idone <br><br> RT <br><br> room temperature <br><br> THF <br><br> tetrahydrofuran <br><br> 35 <br><br> TMU <br><br> N,N,N' ,N' - tetramethylurea <br><br> CNS <br><br> central nervous system <br><br> 280887 <br><br> - 25 - <br><br> Experimental Section <br><br> General protocol for preparing benzoylguanidines (I) Variant A: from benzoic acids (XI/ L = OH) <br><br> 0.01 mol of the benzoic acid derivative of the formula II 5 is dissolved or suspended in 60 ml of anhydrous THF and 1.78 g (0.011 mol) of carbonyl diimidazole are then added. After the mixture has been stirred at RT for 2 hours, 2.95 g (0.05 mol) of guanidine are introduced into the reaction solution. After the mixture has been 10 stirred overnight, the THF is distilled off under reduced pressure (rotary evaporator), water is added, the pH is adjusted to from 6 to 7 with 2 N HCl and the corresponding benzoyl guanidine (formula I) is filtered off. The benzoylguanidines thus obtained can be converted into the 15 corresponding salts by treatment with aqueous, methanolic or ethereal hydrochloric acid or other pharmacologically tolerated acids. <br><br> General protocol for preparing benzoylguanidines (I) Variant B: from alkyl benzoates (II, L = 0-alkyl) <br><br> 20 5 mmol of the alkylbenzoate of the formula II and 25 mmol of guanidine (free base) are dissolved in 15 ml of isopropanol or suspended in 15 ml of THF and the mixture is boiled under reflux until conversion is complete (monitoring by thin layer chromatography) (typical 25 reaction time, from 2 to 5 h). The solvent is distilled off under reduced pressure (rotary evaporator) and the residue is taken up in 300 ml of EA and this solution is washed 3 x with 50 ml of NaHC03 solution on each occasion. It is dried over Na2S04 and the solvent is 30 distilled off in vacuo; the residue is chromatographed on silica gel using a suitable eluent, e.g. EA/MeOH, 5:1. (Salt formation, cf. Variant A) <br><br> Example 1: 4-^-AminosulfonylJphenoxy-S-trifluoromethyl-benzoylguanidine <br><br> - 26 - <br><br> 28088 <br><br> oA T T <br><br> o NH. <br><br> a) Methyl 4-fluoro-3-trifluoromethylbenzoate <br><br> 5 g of 4-f luoro-3-trif luoromethylbenzoic acid and 9 ml of S0C12 are stirred at 60 °C for 8 h in 50 ml of MeOH. The volatile constituents are then removed in vacuo and 5.1 g 5 are obtained of a colorless oil which is subjected to further use without purification. <br><br> Rf (EA/MeOH 10:1) - 0.74 MS (DCI) 223 (M + H)+ <br><br> b) Methyl 4-(4-aminosulfonyl)phenoxy-3-trifluoromet'hyl-benzoate <br><br> 10 890 mg of fluoride a) , 690 mg of 4-hydroxybenzene-sulfonamide and 1.1 g of K2C03 are stirred at 120 °C for 2 h in 5 ml of DMF. The mixture is allowed to cool to RT, 100 ml of brine are added and the whole is extracted 3 x with 50 ml of EA on each occasion. The organic phase is 15 dried over Na2S04 and the solvent is removed in vacuo. 1.2 g of a colorless oil are obtained. <br><br> Rf (MTB) =0.45 MS (DCI) 376 (M + H)+ <br><br> c) 4-(4-Aminosulfonyl)phenoxy-3-trifluoromethyl-benzoylguanidine <br><br> 20 550 mg of methyl ester 1 b) are guanylated in accordance with Variant B. 170 mg of an amorphous powder are obtained. <br><br> Rf (EA/MeOH 10:1) = 0.50 MS (ES) 403 (M + H)+ <br><br> is converted into the hydrochloride. <br><br> 25 mp &gt; 270 °C <br><br> Example 2: 4-[4-(N-t-Butylimido-N'-t-butyl) sulfamoyl] -3-trifluoromethylbenzoylguanidine dihydrochloride <br><br> - 27 - <br><br> 28088 <br><br> h * c <br><br> »rr hsCTH <br><br> CHS \^CH* <br><br> h,c ch a) 4-Fluorobenzenesulfonic acid N,N'-bis-t-butylimidoam-ide <br><br> 10.3 ml of bromine are added to 900 ml of t-butylamine at -30 °C. The mixture is allowed to warm to -5 °C and 6.6 5 ml of 4-fluorothiophenol are added. The mixture is warmed to RT and then stirred at this temperature for 4 h. It is subsequently poured onto 600 g of ice, and 500 ml of EA are added; this mixture is washed 3 x with 100 ml of a saturated aqueous solution of Na2S03 on each occasion. 10 The organic phase is now concentrated in vacuo and the residue is taken up once again with 500 ml of EA; this solution is washed 3 x with 200 ml of a 0.6 M aqueous solution of KH2P04 on each occasion. The organic phase is then stirred for 1 h together with 100 ml of a 2 N 15 aqueous solution of HC1 and the EA phase is then separated off. The aqueous phase is adjusted to pH 9 with Na2C03 and extracted 3 x with 200 ml of EA on each occasion. The organic phases are dried over Na2S04 and the solvent is removed in vacuo. 6.4 g of a colorless oil are 20 obtained. <br><br> Rf (DIP) =0.46 MS (DCI): 287 (M + H)+ <br><br> b) 4-Hydroxybenzenesulfonic acid N,N'-bis-t-butylimidoamide <br><br> 2.9 g of 4-fluorobenzenesulfonic acid N,N'-bis-t-25 butyl imidoamide and 3.4 g of CsOH (monohydrate) are stirred at 160-170 °C for 8 h in 25 ml of TMU. The mixture is then allowed to cool to RT, 100 ml of water and 50 ml of a saturated aqueous solution of NaHC03 are <br><br> 28088 <br><br> added and the whole is extracted 3 x with 100 ml of EA on each occasion. The organic phases are dried over Na2S04 and the solvent Is removed in vacuo. Chromatography on silica gel using EA/HEP 1:1 yields 700 mg of a colorless 5 oil. <br><br> Rf (MTB/DIP 1.1) - 0.27 MS (EI): 285 (M + H) + <br><br> c) Methyl 4-[4- (N-t-Butylimido-N'-t-butyl) sulf-amoyl] -phenoxy-3 -1ri fluoromethylbenzoate <br><br> 600 mg of 4-hydroxybenzenesulfonic acid N,N'-bis-t-10 butylimidoamide, 468 mg of methyl 4-fluoro-3-trifluoro-methylbenzoate and 2.1 g of Cs2C03 are stirred at 160 °C for 1.5 h in 10 ml of TMU. The mixture is allowed to cool to RT, 100 ml of a saturated aqueous solution of NaHC03 are added and the whole is extracted 3 x with 100 ml of 15 EA on each occasion. The organic phases are dried over Na2S04 and the solvent is removed in vacuo. Chromatography on silica gel using DIP yields 400 mg of a colorless oil. <br><br> Rf (DIP) =0.28 MS (ES): 487 (M + H)+ <br><br> 20 d) 4-[4-(N-t-Butylimido-N'-t-butyl)sulfamoyl]phenoxy-3-trifluoromethylbenzoylguanidine <br><br> 300 mg of methyl 4- [4- (N-1-butylimido-N' -t-butyl) sulfamoyl]-3-trifluoromethylbenzoate and 182 mg of guanidine are reacted in 10 ml of isopropanol in accord-25 ance with the general protocol for preparing benzoylguanidines, Variant B. 120 mg of a colorless oil are obtained. <br><br> Rf (EA) = 0.24 MS (FAB): 587 (M + H)+ <br><br> mp (dihydrochloride) = 165 - 168 °C. <br><br> 30 Example 3: 4-[4-N-(Dimethylaminoethyl)methylsulfamoyl]-phenoxy- 3 - trif luoromethylbenzoylguanidine dihydrochloride <br><br> - 29 - <br><br> 280887 <br><br> ch ch <br><br> 'S'sxy ii <br><br> 0 <br><br> a) Methyl 4-phenoxy-3 -trifluoromethylbenzoate <br><br> 15 g of methyl 4-chloro-3-trifluoromethylbenzoate, 5.9 g of phenol and 17.4 g of K2C03 are stirred at 110 °C for 14 h in 100 ml of DMF. The mixture is allowed to cool to 5 RT, is diluted with 1 1 of EA, and is then washed 2 x with 200 ml of water on each occasion, 2 x with 200 ml of a 0.1 N aqueous solution of NaOH on each occasion, and 2 x with 3 00 ml of a saturated aqueous solution of NaCl on each occasion. The organic phase is dried over Na2S04 and 10 the solvent is removed in vacuo. Chromatography on silica gel using EA/HEP 1:8 yields 11 g of a colorless oil. Rf (EA/HEP 1:8) = 0.24 MS (DCI): 297 (M + H)+ <br><br> b) 4-Phenoxy-3-trifluoromethylbenzoic acid <br><br> 11 g of methyl 4-phenoxy-3-trifluoromethylbenzoate are 15 dissolved in 200 ml of MeOH, 41 ml of a 1 N aqueous solution of NaOH are added and the mixture is stirred at RT for 24 h. The MeOH is then removed in vacuo, and the remaining mixture is diluted with 1 1 of water and the whole adjusted to a pH of 2 with an aqueous solution of 20 HC1; the precipitate is then filtered off. The latter is air-dried for 48 h, resulting in 9.2 g of sin amorphous solid. <br><br> Rf (EA) = 0.10 MS (DCI): 283 (M + H)+ <br><br> c) 4-(4-Chlorosulfonyl)phenoxy-3-trifluoromethylbenzoic 25 acid <br><br> 1 g of 4-phenoxy-3-trifluoromethylbenzoic acid is dissolved in 15 ml of CHC13, and 710 fil of chlorosulfonic acid are added dropwise. The mixture is stirred at RT for 3 h and the solvent is then removed in vacuo. 50 g of ice <br><br> 28088 <br><br> 30 <br><br> and 50 ml of water are then added, and the mixture is stirred for 10 minutes and the precipitate then filtered off. 0.96 g of an amorphous solid are obtained. <br><br> 5 d) 4-[4-N-(Dimethylaminoethyl)methylsulfamoyl]phenoxy-3-trifluoromethylbenzoic acid <br><br> 475 mg of 4-(4-chlorosulfonyl)phenoxy-3-trifluoromethylbenzoic acid are dissolved in 10 ml of acetone, and 160 fil of trimethylethylenediamine and 350 fil of 10 triethylamine are added. The mixture is stirred at RT for 2 h, after which it is diluted with 100 ml of water and the acetone is removed in vacuo. The remaining mixture is adjusted to pH =&gt; 6-7 with a 0.1 N aqueous solution of HCl and then extracted 6 x with 100 ml of EA on each 15 occasion. The organic phases are dried over Na2S04 and the solvent is removed in vacuo. 330 mg of an amorphous solid are obtained. <br><br> 20 e) Methyl 4- [4-N- (Dimethylaminoethyl)methylsulfamoyl] -phenoxy-3-trifluoromethylbenzoate <br><br> 330 mg of 4- [4-N- ( dime thylamino ethyl) methyl sulf amoyl] -phenoxy-3-trif luoromethylbenzoic acid and 1 ml of S0C12 are heated under reflux for 8 h in 10 ml of MeOH. The 25 volatile constituents of the mixture are removed in vacuo, the residue is taken up with 100 ml each of a saturated aqueous Na2C03 solution and 100 ml of EA and extracted 3 x with 100 ml of EA on each occasion. The organic phases are dried over Na2S04 and the solvent is removed in vacuo. 30 Chromatography of the residue on silica gel using EA/MeOH 2:1 yields 150 mg of a colorless resin. <br><br> Rf (EA/MeOH 1:1) = 0.30 MS (EI): 461 (M + H)+ <br><br> f) 4- [4-N-(Dimethylaminoethyl)methylsulfamoyl]phenoxy-3-trifluoromethylbenzoylguanidine 35 140 mg of methyl 4-[4-N-(dimethylaminoethyl)methyl-sulfamoyl]phenoxy-3-trifluoromethylbenzoate and 90 mg of <br><br> Rf (DIP 2 % HOAc) = 0.3 8 <br><br> MS (EI): 381 (M + H)+ <br><br> Rf (CH2Cl2/Me0H/H0Ac/H20 8:4:1:1) = 0.42 <br><br> MS (EI): 447 (M + H)+ <br><br> 28088 <br><br> 31 - <br><br> guanidine are reacted in 3 ml of isopropanol in accordance with the general protocol for preparing benzoylguanidines, Variant B. 130 mg of an amorphous solid are obtained. <br><br> 5 Rf (EA/MeOH 1:1) - 0.12 MS (EI): 488 (M + H)+ <br><br> mp (dihydrochloride) a 203 °C <br><br> The title compounds of Examples 4-8 were synthesized in analogy with Example 3: <br><br> Example 4: 4-[4-(4-Methylpiperazinosulfonyl)phenoxy]-3-10 trifluoromethylbenzoylguanidine dihydrochloride ch c r j i hc i <br><br> • fYrii Hei o 0 nh- <br><br> Rf (EA/MeOH 1:1) a 0.15 MS (EI): 486 (M + H)+ <br><br> mp (dihydrochloride) &gt; 250 °C <br><br> Example 5: 4-[4-(2-Pyrrolidineethylaminosulfonyl)-phenoxy]-3-trifluoromethylbenzoylguanidine dimaleate <br><br> 0 OH <br><br> 15 Rf (CH2Cl2/Me0H/H0Ac/H20 8:4:1:1) <br><br> =0.37 MS (FAB): 500 (M + H)+ <br><br> Example 6 : 4- [4- (2-Piperidineethylaminosulfonyl) phenoxy] -3-trifluoromethylbenzoylguanidine dimaleate <br><br> 280887 <br><br> - 32 - <br><br> O <br><br> CF <br><br> tljOUy rf <br><br> 0 OH <br><br> ,NH. <br><br> •T- XT' <br><br> 0 OH <br><br> Rf (CH2Cl2/Me0H/H0Ac/H20 8:4:1:1) <br><br> = 0.40 MS (FAB): 514 (M + H)+ <br><br> Example 7: 4- [4-(N-Dimethylamino-n-propyl)sulf-amoyl] phenoxy-3-tri fluoromethylbenzoylguanidine <br><br> (ch3)2n« <br><br> -N II H <br><br> 5 Rf (EA/MeOH 1:1) = 0.06 <br><br> MS (EI): 488 (M + H)+ <br><br> Example 8: 4-[4-(N-Dimethylaminoethyl) sulf amoyl] phenoxy -3 -trifluoromethylbenzoylguanidine cf ch <br><br> 'N' <br><br> I <br><br> ch <br><br> " <br><br> nOr" <br><br> 0 nh nh. <br><br> Rf (EA/MeOH 1:1) = 0.17 MS (EI): 474 (M + H)+ <br><br> Example 9: 4- (4-Imidosulfamoyl)phenoxy-3-trifluoromethyl- <br><br> 28088 <br><br> - 33 <br><br> bexizoylguanidine ii nk a) 4- [4- (N-t-Butylimido-N' - t-butyl) sulfamoyl]phenoxy-3-trifluoromethylbenzoic acid <br><br> 7.9 g of methyl 4 - [4-(N-t-butylimido-N'-t-5 butyl) sulfamoyl]phenoxy-3-trifluoromethylbenzoate (Example 2 c) are dissolved in 100 ml of MeOH, and 40 ml of a 2 N aqueous solution of NaOH are added. The mixture is boiled under reflux for 3 h, the MeOH is removed in vacuo and the residue is taken up in a mixture composed 10 of 100 ml of water and 100 ml of EA. 500 ml of a saturated aqueous solution of NaH2P04 are added and the whole is extracted 3 times with 200 ml of EA on each occasion. The organic phases are dried over Na2S04 and the solvent is removed in vacuo. 7.2 g of white crystals are 15 obtained. <br><br> Rf (MTB) = 0.25 MS (ES): 473 (M + H)+ <br><br> mp a 200 ° C <br><br> b) 4- (4-Imidosulf amoyl) phenoxy-3-trifluoromethylbenzoic acid <br><br> 20 6.6 g of 4 - [4 - (N-t-butylimido-N' - t -butyl) sulfsunoyl] phenoxy-3 - trif luoromethylbenzoic acid are dissolved in 140 ml of anhydrous CH2Cl2, 3.7 ml of trif luorome thanesulfonic acid are added and the mixture is stirred at RT for 24 h. It is then stirred into 1 1 of 25 a 0.66 M aqueous solution of KH2P04, and the methylene chloride phase is separated off and extracted 3 times with 300 ml of EA on each occasion. The combined organic phases are dried over Na2S04 and the solvents are removed in vacuo. 6.7 g are obtained of a viscous oil which is 30 used without further purification. <br><br> 34 <br><br> 28088 <br><br> Rf (EA/MeOH 5:1) = 0.21 <br><br> MS (ES): 361 (M + H)+ <br><br> c) Methyl 4-(4-imidosulfamoyl)phenoxy-3-trifluoro-methylbenzoate and d) Methyl 4-(4-N-methylimidosulfamoyl)phenoxy-3- <br><br> 5 trifluoromethylbenzoate <br><br> 6.7 g of 4-(4-imidosulfamoyl)phenoxy-3-trifluoromethyl-benzoic acid are dissolved in 100 ml of MeOH, 20 ml of a 2 N solution of (trimethylsilyl) diazomethane in HEP are added dropwise, and the mixture is stirred at RT for 6 h. 10 200 ml of a 20 % aqueous solution of acetic acid are then added and the whole is stirred for 30 minutes. 200 ml of EA are then added and this mixture is then extracted 9 times with 100 ml of a 1 N aqueous solution of HC1 on each occasion. The aqueous phase is then adjusted to a pH 15 of 10 with Na2C03 and extracted 3 times with 200 ml of EA on each occasion. The organic phases are dried over Na2S04 and the solvent is removed in vacuo. The residue is chromatographed on silica gel using EA/HEP 1:1 and 1.2 g of Product c) are obtained in addition to 890 mg of 20 Product d), with both products being oils. <br><br> c) Rf (EA) =0.32 MS (ES) : 375 (M + H)+ <br><br> d) Rf (EA) =0.38 MS (ES) : 389 (M + H)+ <br><br> e) 4-(4-Imidosulfamoyl)phenoxy-3-trifluoromethyl-benzoylguanidine <br><br> 25 220 mg of methyl 4- (4-imidosulfamoyl)phenoxy-3-trifluoromethylbenzoate and 174 mg of guanidine are reacted in 10 ml of THF in accordance with Variant B of the general protocol for preparing benzoylguanidines. 80 mg of colorless crystals are obtained following chromatography 30 on silica gel using EA/MeOH 5:1. <br><br> R£ (EA/MeOH 5:1) = 0.22 MS (ES): 402 (M + H)+ <br><br> Mp = 156°C <br><br> Example 10: 3-Trifluoromethyl-4-(4-N-methylimidosulf amoyl)phenoxybenzoylguanidine <br><br> 35 <br><br> o nh2 <br><br> nh <br><br> 490 mg of methyl 4-(4-N-methylimidosulf amoyl) phenoxy-3 -trif luoromethylbenzoate (Example 9 d) and 373 mg of guanidine are reacted in 20 ml of THF in accordance with Variant B of the general protocol for preparing benzoylguanidines. 370 mg of colorless crystals are obtained following chromatography on silica gel using EA/MeOH 5:1. R£ (EA/MeOH 5:1) = 0.33 MS (ES): 416 (M + H)+ <br><br> mp (dihydrochloride) = 233 °C <br><br> The title compound of Example 11 was synthesized from methyl 3-methyl-4-phenoxybenzoate in analogy with Example 3: <br><br> Example 11: 3-Methyl-4-(4-(l-methylpiperazin-4-yl-sulfonyl)phenoxy)benzoylguanidine a) Methyl 3-methyl-4-phenoxybenzoate <br><br> 3.4 g of methyl 4-fluoro-3-methylbenzoate, 2.4 g of phenol and 19.5 g of Cs2C03 are stirred at 160 °C for 20 minutes in 100 ml of NMP. The mixture is poured into 400 ml of a saturated aqueous solution of NaHC03 and the whole is diluted with 400 ml of water and extracted 3 times with 200 ml of MTB on each occasion. The organic <br><br> II <br><br> 0 nh2 <br><br> 0 <br><br> - 36 - <br><br> 28088 <br><br> phases are dried over Na2S04 and the solvent is removed in vacuo. Chromatographing the residue on silica gel using EA/HEP 1:4 yields 2.0 g of a colorless oil. R£ (EA/HEP 1:4) ■&gt; 0.33 MS (EI): 243 (M + H)+ <br><br> The title compound of Example 12 is synthesized in analogy with Example 9: <br><br> Example 12: 3-Methylsulfonyl-4-(4-imidosulf amoyl)phenoxy-benzoylguanidine h <br><br> Rf (EA/MeOH 5:1) - 0.24 MS (ES): 412 (M + H)+ <br><br> 10 Example 13: 4-(4-Guanidinosulfonyl)phenoxy-3-trifluorome thy lb en z oylguani dine a) 4-(4-Hydroxysulfonyl)phenoxy-3-trifluoromethylbenzoic acid <br><br> 13 . 5 g of 4-phenoxy-3-trifluoromethylbenzoic acid 15 (Example 3 b) are dissolved in 150 ml of CHC13, 3.3 ml of chlorosulfonic acid are added dropwise at RT and the mixture is subsequently stirred for 3 h. The solvent is removed in vacuo, 300 g of ice and 100 ml of water are added, and the mixture is stirred for 10 minutes. 400 ml 20 of a saturated aqueous solution of NaCl which has been cooled to 0 °C are then added and the mixture is stirred <br><br> 28088 <br><br> - 37 - <br><br> at 0 °C for a further 15 minutes and the precipitate is filtered off with suction. It is dried in vacuo at 40 °C resulting in 16.5 g of a white solid which is subjected to further use without purification. <br><br> 5 b) 4-(4-Chlorosulfonyl)phenoxy-3-trifluoromethylbenzoyl chloride <br><br> 14.0 g of 4-(4-hydroxysulfonyl)phenoxy-3-trifluoromethyl-benzoic acid and 1 ml of DMF are dissolved in 250 ml of S0C12 and this solution is heated under reflux for 8 h. 10 Approximately half of the excess S0C12 is then removed in vacuo and the solution is added dropwise to 1 kg of ice. The mixture is extracted 3 times with 500 ml of CH2C12 on each occasion and the organic phases are dried over MgS04 and the solvent is removed in vacuo. 18.0 g are obtained 15 of an oil which is used without further purification. Rf (DIP/2 % HOAc) = 0.51 <br><br> c) 3-Hydroxypyridyl 4-[4-(3-pyridyloxy)sulfonyl]phenoxy-3-trifluoromethylbenzoate <br><br> 18.0 g of 4-(4-chlorosulfonyl)phenoxy-3-trifluoromethyl-20 benzoyl chloride are dissolved in 150 ml of acetone, 3.7 g of 3-hydroxypyridine and 11.0 g of K2C03 are added and the reaction mixture is stirred at RT for 3 h. It is then poured into 500 ml of water and the whole is extracted 3 times with 300 ml of EA on each occasion. The organic 25 phases are dried over Na2S04, the solvent is removed in vacuo and the residue is chromatographed on silica gel using MTB/2 % HOAc. 8.0 g of a yellowish oil are obtained. <br><br> Rf (MTB/2 % HOAc) «= 0.29 MS (FAB): 517 (M + H) + <br><br> 30 d) 4-(4-Guanidinosulfonyl)phenoxy-3-trifluoromethyl benzoylguanidine <br><br> 3.0 g of 3-hydroxypyridyl 4-[4-(3-pyridyloxy)sulfonyl]-phenoxy-3-trifluoromethylbenzoate and 3.4 g of guanidine are dissolved in 10 ml of i-propanol and this solution is 35 heated under reflux for 3 h. The solvent is removed in vacuo and the residue is taken up in 400 ml of water; the <br><br> 280887 <br><br> - 38 - <br><br> solution is adjusted to pH 8 with an aqueous solution of HC1 and stirred at RT for 2 h. The precipitate is filtered off and chromatographed on silica gel using EA/MeOH 5:1. 272 mg of an amorphous solid are obtained. Rf (EA/MeOH 5:1) = 0.33 MS (ES): 445 (M + H)+ <br><br> Example 14: 3-Methylsulfonyl-4-[4-(2-dimethylaminoethyl)-phenoxy]benzoylguanidine bis-methanesulfonate <br><br> 14 a) 5-Carboxy-2-fluorobenzenesulfinic acid 15.6 g (0.124 mol) of sodium sulfite are dissolved at 10 70 °C in 120 ml of water. While maintaining the same temperature, 23.8 g (0.1 mol) of. 4-fluoro-3-chloro-sulfonylbenzoic acid and 10 N NaOH are added simultaneously and in portions in such a manner that the pH is maintained between 9 and 10 (exothermic reaction). The 15 mixture is stirred at 70 °C for a further 3 hours, is subsequently left to stir for a further 15 minutes together with activated charcoal and is then filtered. The filtrate is adjusted to pH 0 - 1 with concentrated hydrochloric acid while cooling externally and the 20 crystalline 5-carboxy-2-fluorobenzenesulfinic acid is filtered off. Colorless crystals, <br><br> m.p.: 167 - 170 °C. <br><br> 14 b) 5-Carboxy-2-fluorobenzenesulfinic acid disodium salt <br><br> 2 5 is obtained by introducing 17.2 g (0.084 mol) of carboxy-2-fluorobenzenesulfinic acid into a stirred solution of 6.72 g (0.168 mol) of NaOH in a mixture composed of 150 ml of methanol and 30 ml of water: after removing suspended material by filtration, the solvent is <br><br> 28088 <br><br> distilled off and the residue is crystallized with acetone. <br><br> Colorless crystalline substance, m.p.: &gt; 320 °C. <br><br> 14 c) Methyl 4-fluoro-3-methylsulfonylbenzoate 5 30 g (0.21 mol) of methyl iodide are added to a suspension of 15 g (0.06 mol) of 5-carboxy-2 - f luorobenzene-sulfinic acid disodium salt in 80 ml of dry DMF and the mixture is stirred at 60 °C for 6 hours; the solvent is distilled off and water is added to the residue. This 10 mixture is stirred for 30 min. while cooling with ice and the precipitate is filtered off. <br><br> Colorless crystalline substance, <br><br> m.p.: 102-105 °C. <br><br> 14 d) Methyl 3-methyl sulf onyl-4-[4-(2-dimethyl amino-15 ethyl)phenoxy]benzoate <br><br> 4.64 g (0.02 mol) of methyl 4-fluoro-3-methylsulfonyl-benzoate are added to a mixture composed of 60 ml of dimethylacetamide, 3.6 g (0.022 mol) of N,N-dimethyl-2-(4-hydroxyphenyl) ethyl amine and 9.08 g (0.066 mol) of 20 powdered, anhydrous K2C03, and the suspension is stirred at 90 °C for 4 hours. After distilling off the solvent and adding water to the residue, the latter mixture is extracted several times with ethyl acetate; the combined organic phases are then concentrated under reduced 25 pressure and the substance is obtained as a yellow, oily liquid. <br><br> 14 e) Preparation of 3-methylsulfonyl-4-[4-(2-dimethylaminoethyl)phenoxy]benzoic acid hydrochloride 1.88 g (0.005 mol) of methyl 3-methylsulfonyl-4-[4-(2-30 dimethylaminoethyl) phenoxy] benzoate are boiled under reflux for 5 hours in 40 ml of half-concentrated hydrochloric acid, after which the aqueous hydrochloric acid is distilled off and the residue is crystallized with acetone. <br><br> 35 Colorless crystalline substance, m.p.: 246 - 248 °C. <br><br> 280887 <br><br> - 40 <br><br> 14 f) 3-Methylsulfonyl-4-[4-(2-dimethylaminoethyl)-phenoxy]benzoylguanidine is obtained, in analogy with the protocol given in Variant A, from 3-methyl sulf onyl-4-[4-(2-dimethylamino-5 ethyl)phenoxy]benzoic acid at a pH of between 7 and 8. Colorless crystals, m.p.: 214 - 218 °C. <br><br> 3-Methylsulfonyl-4- [4- (2-dimethylaminoethyl) phenoxy] -benzoylguanidine bis-methanesulfonate is obtained, in analogy with the protocol given in 10 Variant A, from 3-methylsulfonyl-4- [4-(2-dimethylaminoethyl) phenoxy]benzoylguanidine by treating it with 2.5 eg of methanesulfonic acid in ethanol. <br><br> Colorless solid, <br><br> m.p.; 102 °C. <br><br> 15 Example 15: 4-[4-(2-Dimethylaminoethyl)thiomethyl-phenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride x 2 HC I <br><br> H jC o <br><br> 15 a) Preparation of 4-(2-dimethylaminoethyl)-thiomethylpheno1 <br><br> A mixture composed of 200 mg of p-toluenesulfonic acid, 20 14.1 g (0.1 mol) of 2-dimethylaminoethylmercaptan hydrochloride and 12.4 g (0.1 mol) of 4-hydroxybenzyl alcohol in 250 ml of toluene is boiled, under reflux for about 5 hours, on a Kutscher and Steudel water separator, the solvent is then driven off and the residue is dis-25 solved in methanol after which this solution is filtered. After concentrating once again, the residue is crystallized from acetone, the crystalline product is filtered <br><br> 28088 <br><br> - 41 - <br><br> off and the slightly hygroscopic mass is dried over NaOH while excluding air. <br><br> m.p.: 134 - 140 °C. <br><br> 15 b) Methyl 4-[4-(2-dimethylaminoethyl)thiomethyl-phenoxy]-3-methylsulfonylbenzoate <br><br> A mixture composed of 3.48 g (0.015 mol) of 4-(2-dimethylaminoethyl)thiomethylphenol, 40 ml of anhydrous tetramethylurea, 6.8 g (0.049 mol) of anhydrous powdered K2C03 and 3.48 g (0.015 mol) of methyl 4-fluoro-3-methylsulf onylbenzoate is stirred at 90 - 100 °C for 6 hours, the solvent is distilled off and the residue is taken up in water. After extracting with ethyl acetate, and drying and concentrating the combined organic phases, the desired product is obtained as an oil. <br><br> 15 c) 4-[4-(2-Dimethylaminoethyl)thiomethylphenoxy]-3-methylsulfonylbenzoic acid hydrochloride is obtained, in analogy with the protocol described in Example 14 d), by hydrolyzing methyl 4-fluoro-3-methyl-sulfonylbenzoate in 20 % HCl. <br><br> Colorless to pale-yellow crystalline substance, <br><br> m.p.: 179 - 185 °C. <br><br> 15 d) 4- [4-(2-Dimethylaxainoethyl) thiomethylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride is obtained, in analogy with the protocol described in Example 14 e), from 4-[4-(2-dimethylaminoethyl)-thiomethylphenoxy]-3-methylsulfonylbenzoic acid hydrochloride. <br><br> Hygroscopic substance, m.p.: 230 °C. <br><br> Example 16: 4-[4-(2-Dimethylaminoethylthio)phenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride <br><br> 28088 <br><br> 42 <br><br> hjc —n <br><br> 2 <br><br> hsc 0 <br><br> o nh2 <br><br> 16 a) N,N-Dimethyl-2-(4-hydroxyphenylthio) ethylamine 17.28 g (0.11 mol) of 2-dimethylaminoethyl chloride hydrochloride, and then 19.38 g (0.15 mol) of ethyl diisopropylamine, are added, under an atmosphere of 5 protective gas (argon), to a solution ct 12.6 g (0.1 mol) of 4-mercaptophenol in 100 ml of anhydrous DMF, and the reaction mixture is heated at 110 °C for 12 hours while stirring with a magnet. After the solvent has been distilled off, water is added to the residue and this 10 mixture is adjusted to pH 8-9 with 2 N NaOH; the amorphous precipitate is extracted several times with ethyl acetate and the combined organic phases are dried over sodium sulfate. The solvent is distilled off and the residue is subjected to column chromatography on silica 15 gel, being eluted with a mixture composed of 8 parts of ethyl acetate and 1 part of methanol. <br><br> Colorless crystals, <br><br> m.p. 108 - 110 °C. <br><br> 16 b) Methyl 4-[4-(2-dimethylaminoethylthio)phenoxy]-3-20 methylsulfonylbenzoate is obtained as a yellow oil, in analogy with the protocol described in 14 d), by reacting N,N-dimethyl-2-(4-hydroxyphenylthio)ethylamine with methyl 4-fluoro-3-methylsulfonylbenzoate, with DMF being used as the 25 reaction medium in place of dimethylacetamide. <br><br> Yellow oily liquid. <br><br> 16 c) 4-[4-(2-Dimethylaminoethylthio)phenoxy]-3-methyl- <br><br> 28088 <br><br> sulfonylbenzoic acid <br><br> 6.8 g of methyl 4- [4-(2-dimethylaminoethylthio)phenoxy] -3-methylsulfonylbenzoate are boiled, under reflux conditions for 5 hours, in 10 ml of glacial acetic acid and 70 ml of half-concentrated HC1. After the solvent has been distilled off, the desired substance is obtained as an amorphous solid which does not have a defined melting point. <br><br> 16 d) 4-[4-(2-Dimethylaminoethylthio)phenoxy]-3-methyl-sulfonylbenzoylguanidine dihydrochloride is obtained in analogy with the protocol given in Variant A. <br><br> Colorless solid, <br><br> Decomposition point: 160 °C with foaming. <br><br> Example 17: 4-[4-(2-Dimethylaminoethylsulfonyl)phenoxy] 3 -methylsulfonylbenzoylguanidine dihydrochloride <br><br> H3C <br><br> x 2 H C I <br><br> 17 a) 4-[4-(2-Dimethylaminoethylsulfonyl)phenoxy]-3-methylsulfonylbenzoic acid <br><br> 6.9 g (0.028 mol) of 3-chloroperbenzoic acid are added, in portions at 5-10 °C, to a solution of 3.8 g (0.008 mol) of 4-[4-(2-dimethylaminoethyl thio) phenoxy] -3-methylsulfonylbenzoic acid in 50 ml of glacial acetic acid and the mixture is stirred at RT for 12 hours. After having added water, the precipitate of 3-chlorobenzoic acid is filtered off and further impurities are extracted from the filtrate using ethyl acetate. The aqueous phase is concentrated and the amorphous residue is crystallized <br><br> 44 <br><br> 280887 <br><br> with ethyl acetate. <br><br> Colorless crystals, <br><br> m.p.: 167 - 171 °C <br><br> 17 b) 4-[4-(2-Dimethylaminoethylsulfonyl)phenoxy]-3-5 methylsulfonylbenzoylguanidine dihydrochloride is obtained, in analogy with the protocol given in Variant A, from 4-[4-(2-dimethylaminoethylsulfonyl)-phenoxy]-3-methylsulfonylbenzoic acid in TMU as the reaction medium. The dihydrochloride is crystallized with 10 methanol. <br><br> Colorless crystals, <br><br> m.p.: 233 - 240 °C (decomposition). <br><br> Example 18: 4-[(4-Quanidinocarbonyl)phenoxy]-3-methyl-sulfonylbenzoylguanidine dihydrochloride <br><br> HjH' <br><br> 0 1H <br><br> 2 <br><br> 15 18 a) 4-(4-Carboxyphenoxy)-3-methylsulfonylbenzoic acid By reacting ethyl 4-hydroxybenzoate with methyl 4-fluoro-3-methylsulfonylbenzoate in analogy with the protocol given under 14 d), methyl 4-(4-ethoxycarbonylphenoxy)-benzoate is obtained as a colorless to pale-yellow oil 2 0 which is hydrolyzed, without any further purification steps, in analogy with the manner indicated In protocol 16 c) , to give 4-(4-carboxyphenoxy)-3-methylsulfonylbenzoic acid. <br><br> Colorless crystals, <br><br> 25 m.p.: 272 - 275 °C. <br><br> 18 b) 4-[(4-Quanidinocarbonyl)phenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride <br><br> 280887 <br><br> - 45 - <br><br> is obtained, in analogy with the protocol described in Variant A, by reacting 0.74 g (0.0022 mol) of (4-carboxy-phenoxy)-3-methylsulfonylbenzoic acid with 0.78 g (0.0048 mol) of carbonyldiimidazole and 1.55 g (0.026 mol) of guanidine in DMA. <br><br> Colorless crystals, <br><br> m.p.: 252 °C (decomposition). <br><br> Example 19: 4-[4-(2-Dimethylaminoethyl)thiomethylphenoxy] -3 -trifluoromethylbenzoylguanidine dihydrochloride x 2 HC I <br><br> 19 a) Methyl 4-[4-(2-dimethylaminoethyl)thiomethylphenoxy] -3-trifluoromethylbenzoate is obtained, in analogy with the protocol described in Example 15 b), from 4-(2-dimethylaminoethyl)-thiomethylphenol and methyl 4-fluoro-3-trifluoromethylbenzoate, in DMU as the reaction medium, as an amorphous, oily product. <br><br> 19 b) 4-[4-(2-Dimethylaminoethyl)thiomethylphenoxy]-3-trifluoromethylbenzoic acid is obtained, in analogy with the protocol described in Example 14 d) , by acid hydrolysis of methyl 4- [4- (2-dimethylaminoethyl)thiomethylphenoxy]- 3 -trifluoromethylbenzoate. <br><br> Colorless, hygroscopic crystals, <br><br> m.p.: 158 - 168 °C (decomposition). <br><br> 19 c) 4-[4-(2-Dimethylaminoethyl)thiomethylphenoxy]-3-trifluoromethylbenzoylguanidine dihydrochloride <br><br> 46 <br><br> 280887 <br><br> is obtained, in analogy with the protocol described in Variant A, from 4-[4-(2-dimethylaminoethyl)thiomethylphenoxy] -3-trif luoromethylbenzoic acid in TMU as the reaction medium. Amorphous, strongly hygroscopic solid, decomposition at 80 - 85 °C. <br><br> Example 20 s 4-[4-(2-Dimethylaminoethylthio)phenoxy]-3 -trifluoromethylbenzoylguanidine dihydrochloride <br><br> 20 a) Methyl 4-[4-(2-dimethylaminoethylthio)phenoxy]-3-trifluoromethylbenzoate is obtained, in analogy with the protocol described in Example 15 b), from 4-(2-dimethylaminoethylthio) phenol and methyl 4-fluoro-3-trifluoromethylbenzoate, in DMU as the reaction medium, as an amorphous, oily product. <br><br> 20 b) 4-[4-(2-Dimethylaminoethylthio)phenoxy]-3-tri-fluoromethylbenzoic acid is obtained, in analogy with the protocol described in Example 14 d) , by acid hydrolysis of methyl 4-[4-(2-dimethylaminoethylthio) phenoxy] -3 -trifluoromethylbenzoate. The desired 4-[4-(2-dimethylaminoethyl thio) phenoxy] -3-trifluoromethylbenzoic acid is crystallized with acetone. <br><br> Colorless crystals, <br><br> m.p. 174 - 182 °C (decomposition) <br><br> 20 c) 4- [4-(2-Dimethylaminoethyl thio) phenoxy]-3-tri-fluoromethylbsiizoylguanidine dihydrochloride is obtained, in analogy with the protocol described in Variant A, from 4-[4-(2-dimethylaminoethyIthio)phenoxy]- <br><br> h3c—n <br><br> 2 <br><br> 280887 <br><br> - 47 - <br><br> 3-trif luoromethylbenzoic acid in THF as the reaction medium. <br><br> Amorphous, hygroscopic crystalline solid, <br><br> m.p.: 240 °C. <br><br> Example 21: 3-Trifluoromethyl-4-[4-(2-dimethylaminoethyl )phenoxy]benzoylguanidine dihydrochloride x 2 HCl <br><br> 21 a) 4-Chloro-3-trifluoromethylbenzoic acid The Grignard compound is initially prepared from 100 g of 5-bromo-2-chlorobenzotrifluoride and 10.2 g of magnesium 10 in 600 ml of diethyl ether. A stream of 60 g of anhydrous C02 is then passed into this solution at RT. 500 ml of a saturated aqueous solution of NaHS04 are added dropwise and the phases are separated; further extraction takes place with 2 x 100 ml of diethyl ether. The organic phase 15 is extracted 3 x with 300 ml of 1 N NaOH on each occasion, and the aqueous phase is then washed 3 x with 100 ml of diethyl ether on each occasion. The aqueous phase is now brought to pH 2 with HCl and diluted to 4 1 with water. The product is filtered off with suction and dried 20 in vacuo. <br><br> 75 g of white powder. <br><br> Rf (MTB 2 % HOAc) = 0.68 <br><br> 21 b) Methyl 4-chloro-3-trifluoromethylbenzoate 75 g of 4-chloro-3-trif luoromethylbenzoic acid are 25 dissolved in 500 ml of MeOH, and 75 ml of S0C12 are added dropwise. The mixture is boiled under reflux for 5 h and the volatile constituents are then removed in vacuo. The residue is taken up in 1 1 of EA and this solution is washed with 500 ml of a saturated aqueous solution of <br><br> 48 <br><br> 28088 <br><br> Na2C03. The organic phase is then dried over Na2S04, the solvent is removed in vacuo and the product is distilled in vacuo. <br><br> b.p. 94 °C (2 torr) <br><br> 21 c) Methyl 4-[4-(2-dimethylaminoethyl)phenoxy]-3-trifluoromethylbenzoate <br><br> 1.9 g of methyl 4-chloro-3-trifluoromethylbenzoate, 1.3 g of 4-(2-dimethylamino) ethylphenol and 7.8 g of Cs2C03 10 are stirred, at 140 °C for 5 h, in 50 ml of tetramethylurea. The mixture is allowed to &lt;vool and 3 00 ml of a saturated aqueous solution of NaHC03 and 150 ml of water are then added and the whole is extracted 3 x with 100 ml of EA on each occasion. The organic phases 15 are dried over Na2S04 and the solvent is then removed in vacuo. Chromatography using acetone/water 10:1 yields 2.0 g of a colorless oil. <br><br> Rf (acetone/water 10:1) = 0.15 MS (DCI): 368 (M + H)+ <br><br> 20 21 d) 4-[4-(2-Dimethylaminoethyl)phenoxy]-3-trifluoromethylbenzoylguanidine <br><br> 2.0 g of methyl 4-[4-(2-dimethylaminoethyl)phenoxy]-3-trifluoromethylbenzoate are guanylated with 1.6 g of guanidine in 60 ml of isopropanol in accordance with 25 Variant B. The crude product is converted into the dihydrochloride and recrystallized from 1,2-dimethoxy-ethane/water 9 : 1. <br><br> m.p. (free base): 164 °C <br><br> m.p. (dihydrochloride): 236 °C MS (DCI): 395 (M + H)+ <br><br> 30 Solubility of the dihydrochloride in water, 49 mg/ml (pH = 5.3) <br><br> 5 Rf (DIP) = 0.49 <br><br> MS (DCI) : 239 (M + H)+ <br><br> Example 22: 4-£"4-( 2-N , N-Dime thylamino ) eth^l^phenoxy- 3-sulfamoylbenzoylguanidine bis-methanesulfonate <br><br> - 49 - <br><br> 2808 <br><br> x 2 CHjSOjH <br><br> h2no2s is obtained, in analogy with the protocol described in Variant A, from 4-[4- (2-dimethylaminoethyl)phenoxy] -3-sulfamoylbenzoic acid in dimethylacetamide or N-methyl-pyrrolidone as the reaction medium. Amorphous, 5 hygroscopic, crystalline solid, <br><br> m.p.: 183 °C. <br><br> a) Methyl 4-[4-(2-dimethylaminoethyl)phenoxy]-3 -sulf amoy lbenzoate is obtained by heating 0.011 mol of N,N-dimethyl-2-(4-hydroxyphenyl)ethylamine, 0.033 mol of <br><br> 10 potassium carbonate (ground) and 0.01 mol of methyl 4-fluoro-3-sulfamoylbenzoate at 90-100 °C for 5 hours in 40 ml of dimethylacetamide. After the solvent has been distilled off, the residue is stirred with water and the brown amorphous product Is treated with ethyl acetate; <br><br> 15 the crystalline precipitate is filtered off and the solvent is distilled off from the filtrate. Amorphous oily product. <br><br> b) 4-[4-(2-Dimethylaminoethyl)phenoxy]-3-sulfamoylbenzoic acid <br><br> 20 is obtained by hydrolyzing 0.0066 mol of the corresponding methyl ester (a) for 5 hours in 60 ml of boiling half-concentrated hydrochloric acid. After the aqueous hydrochloric acid has been evaporated off in vacuo, the residue is treated with acetone and the precipitate is <br><br> 25 filtered off. The solvent is distilled off and the desired benzoic acid is obtained. Softening point from 60 °C. <br><br> 50 <br><br> 280887 <br><br> Example 23: 3-Chloro-4- [4- (2-dimethylaminoethyl)phenoxy] -5-methylsulfonylbenzoylguanidine bis-methanesulfonate is obtained, in analogy with the protocol described in Variant A, from 3-chloro-4-[4-(2-dimethylaminoethyl)-phenoxy]-5-methylsul£onylbenzoic acid in dimethylacetamide or N-methylpyrrolidone as the reaction medium. Hygroscopic crystalline solid, <br><br> m.p.: 200 °C. <br><br> a) Methyl 3-chloro-4- [4- (2-dimethylaminoethyl)phenoxy] - 5-methylsulfonylbenzoate is obtained, in analogy with Example 22 a), by reacting methyl 3,4-dichloro-5-methylsulfonylbenzoate with N,N-dimethyl-2-(4-hydroxyphenyl) ethylamine. Amorphous, oily substance. <br><br> b) 3-Chloro-4-[4-(2-dimethylaminoethyl)phenoxy]-5-methyl-sulfonylbenzoic acid is obtained in analogy with Example 22 a). Crystalline solid, <br><br> Decomp. 238 - 244 °C. <br><br> Example 24: 4-[(4-Guanidinocarbonyl)phenoxy]-3-methyl-sulfonylbenzoylguanidine <br><br> 0 <br><br> .N^NH2 <br><br> o nh2 <br><br> x 2 CHjSOjH <br><br> h2n h2n <br><br> ^n&lt;^-nh2 o nh2 <br><br> 280887 <br><br> - 51 - <br><br> Is obtained, as the salt-free base from Example 18, by-treating 4-[(4-guanidinocarbonyl(phenoxy]-3-methyl-sulfonylbenzoylguanidine dihydrochloride with triethylamine in DMF. <br><br> Colorless crystalline solid, m.p.: 237 °C <br><br> Example 25: 4-[4-(2-N-Imidazolyl-1-oxoethyl)phenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride o nh2 <br><br> is obtained, in analogy with the protocol described in Variant A, from4-[4-(2-N-imidazolyl-l-oxoethyl)phenoxy]-3-methylsulfonylbenzoic acid in dry dimethylacetamide or N-methylpyrrolidone as the reaction medium. Colorless crystalline solid, decomp.: 255 °C. <br><br> a) 4-(4-Chloroacetylphenoxy)-3-methylsulfonylbenzoic acid 0.02 mol of 3-methylsulfonyl-4-phenoxybenzoic acid is introduced, in portions and at 0-5 °C, into a mixture composed of 0.08 mol of chloroacetyl chloride, 16 g of anhydrous aluminum chloride and 150 ml of 1,2-dichloro-ethane and the mixture is stirred at room temperature for 2 hours and then at 40-45 °C for 2 hours. After having been left to stand overnight, the reaction mixture is poured, while stirring, into ice water and the crystalline precipitate is filtered off, washed with water and dried. Yellow crystals, m.p.: 184-187 °C. <br><br> b) 4-[4-(2-N-Imidazolyl-1-oxoethyl)phenoxy]-3-methyl-sulfonylbenzoic acid <br><br> A solution of 0.005 mol of 4-(4-chloroacetylphenoxy)-3-methylsulfonylbenzoic acid (25 a) in 25 ml of anhydrous DMF is stirred with 0.0225 mol of imidazole at 60 °C for <br><br> - 52 - <br><br> 28088 <br><br> 4 hours and the solvent Is then distilled off. After the amorphous residue has been treated with water, and the pH has been adjusted to pH 2-3 with 2 N hydrochloric acid, the mixture is stirred for one hour and the crystalline precipitate is filtered off. Crystals, decomp. 2"\5-241 °C. <br><br> Example 26: 4-[4-(2-Imidazolylthioacetyl)phenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride <br><br> x 2 HC I NH <br><br> o NH <br><br> is obtained, in analogy with the protocol described in 10 Variant A, from 4-[4-(2-imidazolylthioacetyl)phenoxy]-3-methylsulfonylbenzoic acid in a mixture composed of 50 ml of THF and 10 ml of dimethylacetamide as the reaction medium. Colorless crystalline solid, <br><br> m.p.: 220 °C. <br><br> 15 a) 4-[4-(2-Imidazolylthioacetyl)phenoxy]-3-methyl-sulfonylbenzoic acid is obtained by reacting 4-(4-chloro-acetylphenoxy) - 3-methylsulfonylbenzoic acid (Example 25 a) and 1 mol of 2-mercapto imidazole in 20 ml of acetone and briefly heating to boiling point. The mixture 2 0 is stirred at room temperature for approximately 5 days and the crystalline precipitate is filtered off. <br><br> Decomp.: 202 - 205 °C. <br><br> Example 27: 4-[4-(4,5-Dihydro-2-imidazolylthioacetyl)-phenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride <br><br> 280887 <br><br> - 53 - <br><br> is obtained, in analogy with the protocol described in Variant A, from 4-[4-(4,5-dihydro-2-imidazolylthioacety-1)phenoxy]-3-methylsulfonylbenzoic acid in a mixture composed of 50 ml of THF and 10 ml of dimethylacetamide as the reaction medium. <br><br> Colorless crystalline solid, m.p.: 210 °C. a) 4-[4-(4,5-Dihydro-2-imidazolylthioacetyl)phenoxy]-3-methylsulfonylbenzoic acid is prepared, in analogy with Protocol 26 a), by reacting 4-(4-chloroacetylphenoxy)-3-me thy 1 sulf onylbenzoic acid (Example 25 a) with 2-mercapto-4,5-dihydroimidazole. Decomp.: 305-310 °C. <br><br> Example 28 : 4-[4-(N,N#-Dimethyl-S-isothiouronylacetyl)-phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride is obtained, in analogy with the protocol described in Variant A, from 4-[4-(N,N'-dimethyl-S-isothiouronyl-acetyl) phenoxy] -3-methylsulfonylbenzoic acid in a mixture composed of 50 ml of THF and 10 ml of dimethylacetamide as the reaction medium. <br><br> Colorless crystalline solid, <br><br> m.p.: 150 °C. <br><br> a) 4-[4-(N,N'-Dimethyl-S-isothiouronylacetyl)phenoxy]-3- <br><br> - 54 - <br><br> 28088 7 <br><br> methylsulfonylbenzoic acid is obtained, in analogy with protocol 26 a), by reacting 4-(4-chloroacetylphenoxy)-3-methylsulfonylbenzoic acid (Example 25 a) with N,N' -dimethylthiourea at room temperature . Colorless crystals. <br><br> Decomp.; 185-190 °C. <br><br> Example 29: 4-[4-(2-Benzimidazolylthioacetyl)phenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride <br><br> 0 nh2 <br><br> is obtained, in analogy with the protocol described in Variant A, from 4-[4-(2-benzimidazolylthioacetyl)-phenoxy]-3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid, m.p.: 228 °C. <br><br> a) 4-[4-(2-Benzimidazolylthioacetyl)phenoxy]-3-methyl-sulfonylbenzoic acid is obtained, in accordance with protocol 26 a), by reacting 4-(4-chloroacetylphenoxy)-3-methylsulfonylbenzoic acid (Example 25 a) with 2-mercaptobenzimidazole in DMF. <br><br> m.p.: 182 °C. <br><br> Example 30: 4-[4-(2-Pyridylthioacetyl)phenoxy]-3-methylsulf onylbenzoylguanidine dihydrochloride <br><br> 280 <br><br> 55 <br><br> 0 <br><br> HCl o NH2 <br><br> is obtained, in analogy with the protocol described in Variant A, from 4-[4-(2-pyridylthioacetyl)phenoxy]-3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid, <br><br> m.p.: 203 °C. <br><br> a) 4-[4-(2-Pyridylthioacetyl)phenoxy]-3-methylsulfonylbenzoic acid is obtained, in analogy with protocol 26 a) , by reacting 4-(4-chloroacetylphenoxy)-3-methylsulfonylbenzoic acid (Example 25 a) with 2-mercaptopyridine. m.p.: 194-196 °C. <br><br> Example 31: 4- [4- (2-Quinolylthioacetyl)phenoxy] -3-methyl-sulfonylbenzoylguanidine dihydrochloride is obtained, in analogy with the protocol described in Variant A, from 4-[4-(2-quinolylthioacetyl)phenoxy]-3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid, m.p.: 192 °C. <br><br> a) 4- [4-(2-Quinolylthioacetyl)phenoxy]-3-methylsulfonyl-benzoic acid is prepared, in analogy with Protocol 26 a) , by reacting 4-(4-chloroacetylphenoxy)-3-methylsulfonyl- <br><br> 0 <br><br> x 2 HCl nh2 <br><br> 2808 <br><br> - 56 - <br><br> benzoic acid (Example 25 a) with 2-mercaptoquinoline in DMF. m.p. 210-214 °C. <br><br> Example 32 s 4- [4- (2-N-Imidazolyl-1-hydroxyethyl)phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride is obtained, in analogy with the protocol described in Variant A, from 4-[4-(2-N-imidazolyl-1-hydroxyethyl)-phenoxy]-3-methylsulfonylbenzoic acid in dimethylacetamide or N-methylpyrrolidine as the reaction medium. Colorless crystalline solid, <br><br> decomposition point: 260 °C. <br><br> a) 4- [4- (2-N-Imidazolyl-1-hydroxyethyl)phenoxy] -3-methylsulfonylbenzoic acid is obtained by reducing 0.0034 mol of 4-[4-(2-N-imidazolyl-1-oxoethyl)phenoxy]-3-methylsulfonylbenzoic acid with 0.0068 mol of sodium boro-hydride in 40 ml of ethanol. After distilling off the solvent, treating the residue with water and adjusting the pH to 4 with 2 N HCl, the mixture is stirred for a few hours at room temperature and the crystals are filtered off. <br><br> m.p. 240-248 °C. <br><br> oh x 2 HCl <br><br> ^Y"NH2 <br><br> 0 nhj <br><br> Example 33: 3-Methylsulfonyl-4-(4-sulfamoylphenoxy)-benzoylguanidine hydrochloride <br><br> 2808 <br><br> 57 <br><br> hcl h2n02s nh2 <br><br> o nh2 <br><br> is obtained, in analogy with the protocol described in phenoxy)benzoic acid in dimethylacetamide as the reaction medium. Colorless crystalline solid, <br><br> 5 decomposition point: 267 °C. <br><br> a) 3-Methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid is obtained by reacting 0.03 mol of 4-phenoxy-3-methylsulfonylbenzoic acid with 0.15 mol of chlorosulfonic acid 10 in 60 ml of methylene chloride ac 0 - 5 °C and subsequently stirring the mixture at room temperature for 4 hours. After the mixture has been treated with ice water, the methylene chloride phase is separated off, washed with water and dried over magnesium sulfate, and 15 the solvent is then distilled off. Crystals, <br><br> m.p.: 167 - 170 °C. <br><br> b) 3-Methylsulfonyl-4-(4-sulfamoylphenoxy)benzoic acid is obtained by reacting 3-methylsulfonyl-4-(4-chloro-sulfonylphenoxy)benzoic acid with an aqueous concentrated <br><br> 20 solution of ammonia at room temperature for 24 hours, distilling off the ammonia and acidifying the aqueous solution to pH 1-2 with 2 N HCl. The crystals are filtered off, washed with water and dried. Colorless crystalline substance. <br><br> Variant A, from 3-methylsulfonyl-4-(4-sulfamoyl <br><br> 25 m.p. 240 - 245 °C. <br><br> Example 34 : 4-[4-(l-Hydroxy-2-(2-pyridylthio)ethyl)-phenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride <br><br> 2808 <br><br> - 58 - <br><br> OH <br><br> x 2 HC I <br><br> nh2 <br><br> o nh2 <br><br> is obtained, in analogy with the protocol described in Variant A, from 4-[4-(l-hydroxy-2-(2-pyridylthio)ethyl)-phenoxy]-3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid, m.p.: 116 °C. <br><br> a) 4-[4-(l-Hydroxy-2-(2-pyridylthio)ethyl)phenoxy]-3-methylsulfonylbenzoic acid is obtained in analogy with Example 32 a). Colorless crystalline substance, m.p.: 169-174 °C. <br><br> Example 35: 4-[4-(l-Hydroxy-2-(2-benziridazolylthio)-ethyl)phenoxy]- 3-methy1sulfonylbenzoylguanidine dihydrochloride is obtained, in analogy with the protocol described in Variant A, from 4- [4- (l-hydroxy-2- (2-benzixnidazolylthio) -ethyl)phenoxy]-3-methylsulfonylbenzoic acid in dimethylacetamide as the reaction medium. Colorless crystalline solid, <br><br> m.^.. : 213 °C. <br><br> OH <br><br> x 2 HCl <br><br> 0 NH2 <br><br> a) 4 -[4-(l-Hydroxy-2-(2-benzimidazolylthio)ethyl)-phenoxy]-3-methylsulfonylbenzoic acid <br><br> 28 088 7 <br><br> 59 <br><br> is obtained in analogy with Example 32 a) . Colorless crystalline substance, <br><br> m.p.: 186 - 188 °C. <br><br> Example 36: 4-[4-(l-Hydroxy-2-(2-quinolylthio)ethyl)-phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride is obtained, in analogy with the protocol described in Variant A, from 4- [4- (l-hydroxy-2- (2-quinolylthio) ethyl) -phenoxy]-3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid, m.p.: 180 °C. <br><br> a) 4- [4-(l-Hydroxy-2-(2-quinolylthio)ethyl)phenoxy]-3-methylsulfonylbenzoic acid is obtained, in analogy with Example 32 a) , from 4- [4- (2-quinolylthioacetyl)phenoxy] -3-methylsulfonylbenzoic acid (Example 31 a) . <br><br> Colorless crystalline substance. <br><br> Example 37 : 4- [4- (N,N-Dimethylglycylamino)phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride oh x 2 HCl nh2 <br><br> 0 nh2 <br><br> CH5—N <br><br> nh2 <br><br> x 2 HCl <br><br> 0 nh2 <br><br> is obtained, in analogy with the protocol described in Variant A, from4- [4-(N,N-dimethylglycy7.amino)phenoxy] -3- <br><br> 28088 <br><br> methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid, <br><br> m.p.: 223 °C. <br><br> a) 3-Methylsulfonyl-4-(4-nitrophenoxy)benzoic acid is 5 prepared by reacting 0.02 mol of 3-methylsulfonyl-4-phenoxybenzoic acid with 0.96 ml of 100 % nitric acid at -10 °C in a mixture composed of 8 ml of acetic anhydride and 4 ml of glacial acetic acid. After the mixture has been stirred at this temperature for 1.5 hours, it is 10 then stirred at room temperature for 24 hours and at 40 °C for a further 6 hours. It is then poured into ice water and the amorphous, oily product is crystallized with water by stirring. Yellow crystalline substance, m.p.: 140-150 °C. <br><br> 15 b) 4-(4-Aminophenoxy)-3-methylsulfonylbenzoic acid is obtained by catalytically hydrogenating 3-methylsulfonyl-4- (4-nitrophenoxy)benzoic acid (Example 37 a) with Raney nickel in methanol under standard pressure until hydrogen uptake is complete. A homogeneous, amor-20 phous oil is obtained after evaporating off the solvent. <br><br> c) N,N-Dimethylglycineimidazolide hydrochloride is obtained by reacting N, N-dime thy lglycine hydrochloride with carbonyldiimidazole in anhydrous dimethylacetamide, from which the product separates out. The mixture is 25 subjected to further reaction without any additional working-up steps. <br><br> d) 4-[4-(N,N-Dimethylglycylamino)phenoxy]-3-methyl-sulfonylbenzoic acid is obtained by reacting N,N-dimethylglycineimidazolide hydrochloride (Example 37 c) 30 with 4-(4-aminophenoxy)-3-methylsulfonylbenzoic acid (Example 37 b) by means of stirring at room temperature for 5 hours in dimethylacetamide. The solvent is distilled off, the pH is adjusted to 1-2 with HCl and the mixture is extracted with ethyl acetate. The aqueous 35 phase is distilled off and the residue is treated with <br><br> 280887 <br><br> methanol. After the Insoluble material has been filtered off, the desired compound is obtained as a colorless oil. <br><br> Example 38: 4-[4-(N,N-Dlethylaminoethyl) aminosulfonylphenoxy] -3-methyl sulf onylbenzoylguanidine dihydrochloride is obtained, in analogy with the protocol described in Variant A, from 4-[4- (N,N-diethylaminoethyl) aminosulf onylphenoxy]-3-methylsulfonylbenzoic acid in anhydrous dimethylacetamide as the reaction medium. Colorless, crystalline solid, <br><br> m.p.: 206 °C. <br><br> a) 4- [4- (N,N-Diethylaminoethyl) aminosulf ony lphenoxy] -3-methylsulfonylbenzoic acid is obtained by reacting 0.05 mol of 3-methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid (Example 33 a) with 0.06 mol of N, N-diethyl amino ethylamine in the presence of excess triethylamine (approximately 0.015 mol) in methanol as the reaction medium. After the solvent mixture has been distilled off, the residue is treated with a little water and the mixture is adjusted to pH 4 - 5. The crystalline precipitate is filtered off. <br><br> m.p.: 263 - 268°C. <br><br> Example 39 : 4- [4- (l-Methyl-4-piperazino) sulf ony lphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride <br><br> 28088 <br><br> 62 <br><br> 0 <br><br> 0 <br><br> x 2 HCl <br><br> CHs02S <br><br> ^N^NH2 o nh2 <br><br> is obtained, in analogy with the protocol described in Variant A, £rom4-[4-(l-methyl-4-piperazino)sulfonylphenoxy] -3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid, <br><br> Decomp.: 234-244 °C. <br><br> a) 4-[4-(1-Methyl-4-piperazino)sulfonylphenoxy]-3-methylsulfonylbenzoic acid is obtained by reacting methyl-sulfonyl-4- (4-chlorosulfonylphenoxy)benzoic acid (Example 33 a) with N-methylpiperazine in analogy with Example 38 a). <br><br> Colorless crystals, <br><br> Decomp.: 287 - 292 °C. <br><br> Example 40: 4-[4-(4-Imidazolylethyl)aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride <br><br> /^N <br><br> x 2 hcl <br><br> 0 nh2 <br><br> is obtained, in analogy with the protocol described in Variant A, from 4-[4-(4-imidazolylethyl)aminosulfonylphenoxy] -3 -methylsulfonylbenzoic acid in dimethyl- <br><br> 280887 <br><br> 63 - <br><br> acetamide as the reaction medium. Colorless crystalline solid, <br><br> m.p.: 264 °C. <br><br> a) 4-[4-(4-Imidazolylethyl)aminosulfonylphenoxy]-3-5 methylsulfonylbenzoic acid is obtained, in analogy with Example 38 a), by reacting methylsulfonyl-4-(4-chloro-sulfonylphenoxy)benzoic acid (Example 33 a) with histamine. Colorless, amorphous solid, <br><br> Decomp. 2 65 °C. <br><br> 10 Example 41: 4 - [4 - (3 -N-Imidazolyl-1-propyl) aminosulf ony lphenoxy] - 3 -methylsulf onylbenzoylguanidine dihydrochloride <br><br> X 2 HCl <br><br> N^NH2 <br><br> 0 NH, <br><br> is obtained, in analogy with the protocol described in Variant A, from 4-[4-(3-N-imidazolyl-1-propyl)amino-15 sulf ony lphenoxy] -3-methylsulfonylbenzoic acid in THF as the reaction medium. Colorless crystalline solid, Decomp.: 257 °C. <br><br> a) 4- [4- ( 3-N-Imidazolyl-1-propyl) aminosulf ony lphenoxy] - 3-methylsulfonylbenzoic acid 20 is obtained, in analogy with Example 38 a), by reacting methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid (Example 33 a) with 1-(3-aminopropyl) imidazole. Colorless amorphous solid, <br><br> m.p.: 250 °C. <br><br> 25 Example 42: 4-[4-(l-Methyl-2-pyrrolidinylethyl)amino- <br><br> - 64 - <br><br> 280887 <br><br> sul£onylphenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride <br><br> / <br><br> CH <br><br> ch3o2s is obtained, in analogy with the protocol described in Variant A, from4-[4-(l-methyl-2-pyrrolidinylethyl)amino-5 sulfonylphenoxy]-3-methylsulfonylbenzoic acid in dimethylacetamide as the reaction medium. Colorless crystalline solid, <br><br> m.p.: 254 °C. <br><br> a) 4-[4-(1-Methyl-2-pyrrolidinylethyl)aminosulfonyl- <br><br> 10 phenoxy]-3-methylsulfonylbenzoic acid is obtained, in analogy with Example 38 a) , by reacting methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid (Example 33 a) with 2-(2-aminoethyl)-1-methylpyrrolidine. m.p. 242 - 247 °C. <br><br> 15 Example 43: 4-[4-(N-Morpholinoethyl)aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride <br><br> P <br><br> ch3o2s x 2 NCI N^NH2 <br><br> is obtained, in analogy with the protocol described in <br><br> 65 <br><br> 280887 <br><br> Variant A, from 4-[4-(N-morpholinoethyl)aminosulfonyl-phenoxy]-3-methylsulfonylbenzoic acid in dimethylacetamide as the reaction medium. Colorless crystalline solid, <br><br> m.p.: 272 °C. <br><br> a) 4-[4-(N-Morpholinoethyl)aminosulfonylphenoxy]-3-methy1sulfonylbenzoic acid is obtained, in analogy with Example 38 a), by reacti7jg methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid (Example 33 a) with N- (2-aminoethyl)morpholine. Colorless crystalline compound, <br><br> m.p. 220-224 °C. <br><br> Example 44: 4- [4-N-Piperidinoethyl)aminosulfonylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride is obtained, in analogy with the protocol described in Variant A, from 4-[4-(N-piperidinoethyl)aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in anhydrous dimethylacetamide as the reaction medium. Colorless crystalline solid, <br><br> m.p.: 266 °C. <br><br> a) 4-[4-(N-Piperidinoethyl)aminosulfonylphenoxy]-3-methylsulfonylbenzoic acid is obtained, in analogy with Example 38 a), by reacting methylsulfonyl-4-(4-chlorosulfonylphenoxy)benzoic acid (Example 33 a) with N- (2-aminoethyl)piperidine. Colorless crystalline substance. <br><br> x 2 HCl o nh2 <br><br> 66 <br><br> 28088 <br><br> m.p.: 271-273 °C. <br><br> Example 45: 4- [4- (2-Pyridylethyl) aminosulf onylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride is obtained, in analogy with the protocol described in Variant A, from 4-[4-(2-pyridylethyl)aminosulfonylphenoxy] -3-methylsulfonylbenzoic acid in anhydrous dimethylacetamide as the reaction medium. Colorless crystalline solid, <br><br> m.p.: 257 °C. <br><br> a) 4-[4-(2-Pyridylethyl)aminosulfonylphenoxy]-3-methylsulfonylbenzoic acid is obtained, in analogy with Example 38 a), by reacting methylsulfonyl-4-(4-chloro-sulf ony lphenoxy) benzoic acid (Example 33 a) with 2-(aminoethy1)pyridine. Colorless crystals, <br><br> m.p. 268-270 °C. <br><br> x 2 HCl <br><br> 0 nh2 <br><br> Example 46: 4-[4-(2-Dimethylaminoethyl)sulfonylmethylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride <br><br> - 67 - <br><br> 280887 <br><br> x 2 HCl nh2 <br><br> nh2 <br><br> is obtained by peracid oxidation, in analogy with the protocol described in Example "4", from 4- [4-(2-dimethylaminoethyl) thiomethylphenoxy]-3-methylsulf onylbenzoylguanidine dihydrochloride (Example 15). Colorless crystals, <br><br> m.p.: 245 °C. <br><br> Example 47: 4-[4-(2-Dimethylaminoethyl)sulfonylmethyl-phenoxy] -3 -trifluoromethylbenzoylguanidine dihydrochloride is obtained by peracid oxidation, in analogy with the protocol described in Example 17, from 4-[4-(2-dimethylaminoethyl) thiomethylphenoxy]-3-trifluoromethylbenzoylguanidine dihydrochloride (Example 19). <br><br> Colorless crystals, m.p. 140 °C. <br><br> Pharmacological data: <br><br> 0 nh2 <br><br> x 2 HC I <br><br> Inhibition of the rabbit erythrocyte Na+/H+ exchanger <br><br> 28 0 i <br><br> - 68 - <br><br> New Zealand White rabbits (Ivanovas) were given a standard diet containing 2 % cholesterol for six weeks in order to activate Na+/H+ exchange and thus to render it possible to use flame photometry to determine the influx 5 of Na+ into the erythrocytes via Na+/H+ exchange. Blood was removed from the aural arteries and rendered incoagulable by adding 25 IU of potassium heparin. A part of each sample was used for determining the hematocrit in duplicate by means of centrifugation. Aliquots of in each 10 case 100 fil were used for measuring the starting content of Na+ in the erythrocytes. <br><br> In order to determine the amiloride-sensitive sodium influx, 100 fil of each blood sample were in each case incubated, at pH 7.4 and 37 °C, in 5 ml of a hyperosmolar 15 salt/sucrose medium (mmol/1: 140 NaCl, 3 KC1, 150 sucrose, 0.1 ouabain, 20 tris-hydroxymethylaminomethane). After that, the erythrocytes were washed three times with an ice-cold MgCl2/ouabain solution (mmol/1: 112 MgCl2, 0.1 ouabain) and hemolyzed in 2.0 ml of distilled water. 20 The intracellular content of sodium was determined by flame photometry. <br><br> The net influx of Na+ was calculated from the difference between the initial sodium values and the sodium content of the erythrocytes following incubation. The amiloride-25 inhibitable sodium influx was given by the difference in the sodium content of the erythrocytes following incubation with and without 3 x 10"4 mol/1 amiloride. The same procedure was followed when using the novel compounds. <br><br></p> </div>

Claims (1)

  1. <div class="application article clearfix printTableText" id="claims"> <p lang="en"> 280887<br><br> - 69 -<br><br> Results<br><br> Inhibition of the Na+/H+ exchanger:<br><br> Exsuaple<br><br> IC50 (/unol/1)<br><br> 1<br><br> 0.8<br><br> 2<br><br> 0.32<br><br> 3<br><br> 0.05<br><br> 4<br><br> 0.082<br><br> 5<br><br> 0.3<br><br> 6<br><br> 0.1<br><br> 7<br><br> 0.06<br><br> 8<br><br> 0.005<br><br> 9<br><br> 0.1<br><br> 14<br><br> 0.05<br><br> 15<br><br> 0.01<br><br> 16<br><br> 0.16<br><br> 17<br><br> 1<br><br> 18<br><br> 0.2<br><br> 19<br><br> 0.008<br><br> 20<br><br> 0.04<br><br> 21<br><br> 0.014<br><br> 28<br><br> 0.12<br><br> 32<br><br> 0.44<br><br> 33<br><br> 0.20<br><br> 46<br><br> 0.09<br><br> 47<br><br> 0.07<br><br> 10<br><br> 15<br><br> 20<br><br> 25<br><br> 28088<br><br> - 70 -<br><br> WHAT WE CLAIM IS: HOB 0 D/r 007 K Bu i o.P<br><br> 1. A compound of the formula I<br><br> R(i)<br><br> Rt3)^VvNHi 1<br><br> R(4) 0 MH2<br><br> In which:<br><br> one of the three substituents R(l), R(2) and R(3) is R(6) -A-B-D-;<br><br> R(6) is a basic protonatable radical, i.e.<br><br> an amino group -NR(7)R(8), an amidino group R(7)R(8)N-C[»N-R(9)] - or a guanidino group<br><br> R(7| B &lt;10)<br><br> Ms)<br><br> 10 R(7) , R(8) , R(9) and R(10) are,<br><br> independently of each other, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;<br><br> or<br><br> 15 R(7) and R(8) are,<br><br> together, CaH2a;<br><br> a is 4, 5, 6 or 7;<br><br> where, when a = 5, 6 or 7, a methylene group of the group CaH2a 20 can be replaced by a heteroatom group O, SOm or NR(ll),<br><br> or<br><br> R (8) and R(9) or R(9) and R(10) or R(7)<br><br> and R(10) are<br><br> - 71 -<br><br> a group Cjaax; 2 B 0 8 8 7<br><br> x is 2, 3, 4 or 5;<br><br> where, when x « 3, 4 or 5, a methylene group of the group 5 CgHjx can be replaced by a heteroatom group 0, S0m or NR(ll) 7 m is zero, 1 or 2; R(11) is hydrogen or methyl;<br><br> 10 or<br><br> R(6) is a basic heteroaromatic ring system having 1-9 carbon atoms;<br><br> A is CbH2b;<br><br> b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 15 10;<br><br> where, in the group CbH2b, one or two methylene groups can be replaced by one of the groupings selected from the group consisting 20 of -O-, -CO-, -CH[OR(20)]-, -SOm-,<br><br> -NR ( 2 0) -, -NR (2 0 ) -CO-, -NR(20)-CO-NH-, -NR(20)-C0-NH-S02-<br><br> i^0)"<br><br> -R(20)N-S-II<br><br> (NR ( 1 9 ) I bb<br><br> 25<br><br> 30<br><br> and -SOaa[NR(19)]bb-;<br><br> and where, in the group CbH2b, a methylene group can be replaced by<br><br> -CH-R(99), where R(99), together with R(7), forms a pyrrolidine or piperidine ring;<br><br> aa is 1 or 2;<br><br> bb is 0 or 1;<br><br> aa + bb « 2;<br><br> R(19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms<br><br> 28 0887<br><br> 72 -<br><br> B<br><br> R(12)<br><br> R(20) is hydrogen or methyl; is a phenylene or naphthylene radical<br><br> R( 12)<br><br> R(13)<br><br> R&lt;13)<br><br> 10<br><br> 15<br><br> 20<br><br> 25<br><br> 30<br><br> R(12) and R(13) are,<br><br> independently of each other, hydrogen, methyl, F, Cl, Br, I, CF3 or -SOw-R(14);<br><br> R(14) is methyl or NR(15)R(16); R(15) and R(16) are,<br><br> independently of each other, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; w is zero, 1 or 2; D is -CdH2d-Xf-;<br><br> d is zero, 1, 2, 3 or 4;<br><br> X is -O-, -CO-, -CH[OR(21)]-, -SOm-<br><br> or -NR(21)-;<br><br> f is zero or 1;<br><br> R(21) is hydrogen or methyl; m is zero, 1 or 2;<br><br> and in each case the other two of the substituents R(1) and R(2) and R(3) are,<br><br> independently of each other, hydrogen, F, Cl, Br, I, -CN, - (C-L-Cg) -alkyl, - (C2-C8)-alkenyl, -NR (35) R (36) or R (17) -CgH2g-Zh- ;. g is zero, 1, 2, 3 or 4;<br><br> h is zero or 1;<br><br> R (35) and R(36) are,<br><br> independently of each other, hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;<br><br> - 73 -<br><br> 280 8 8 7<br><br> or<br><br> R(35) and R(36) are,<br><br> together, 4-7 methylene groups of which one CH2 group can be replaced by oxygen, -S-, -NH-, -NCH3 or -N-benzyl;<br><br> Z is -O-, -CO-, -SOv-, -NR(18)-,<br><br> -NR(18)-CO-, -NR(18)-CO-NH- or -NR(18)-S02-;<br><br> R(18) is hydrogen or methyl;<br><br> v is zero, 1 or 2;<br><br> R (17) is cycloalkyl having 3, 5 or<br><br> 6 carbon atoms, or CleF2]H.i_;<br><br> k is 1, 2 or 3,<br><br> or<br><br> R(17) is pyrrol-l-yl, pyrrol-2-yl or pyrrol-3-yl,<br><br> which is not substituted or is substituted by 1-4 substituents selected from the group consisting of F, Cl, Br, X, -CN, (C2-C8)-alkanoyl, (C2-C8)-alkoxycarbonyl, formyl, carboxyl, -CF3, methyl and methoxy;<br><br> or<br><br> R(17) is - (C3-C8)-cycloalkyl or phenyl,<br><br> which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F and Cl, -CF3, methyl, hydroxyl, methoxy, -NR(37)R(38), CH3S02- and H2N02S-;<br><br> R(37) and R(38) are hydrogen or -CH3;<br><br> R(4) and R(5) are,<br><br> independently of each other, hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, -OR (32), -NR (33) R (34) or -CrF2r+1;<br><br> R(32) , R(33) and R(34) are, ^<br><br> ' «• ^<br><br> independently of each other, hydrogejl -'<br><br> // K<br><br> \ \ 1 V<br><br> I 2 8 0 8 8 7<br><br> - 74 -<br><br> or alkyl having 1, 2 or 3 carbon atoms; r is 1/ 2, 3 or 4;<br><br> and the pharmacologically tolerated salts thereof.<br><br> 2. A compound of the formula I as claimed in claim 1, 5 wherein:<br><br> R(l) is hydrogen, P, Cl, - (C1-C4)-alkyl, -(C2-C4)-alkenyl, -NR(35)R(36) or R(17) -CgH2g-Zh-;<br><br> R(35) and R(36) are,<br><br> independently of each other, hydrogen, 10 methyl or ethyl;<br><br> or<br><br> R(35) and R(36) are,<br><br> together, 4-5 methylene groups of which one CH2 group can be replaced by 15 oxygen, -S-, -NH- or -NCH3;<br><br> R (17) is cycloalkyl having 5 or<br><br> 6 carbon atoms, or CkF2Jc+1_;<br><br> k is 1, 2 or 3,<br><br> g is zero, 1, 2, 3 or 4;<br><br> 20 h is zero or 1;<br><br> Z is -0-, -CO-, -SOv-, -NR(18)-,<br><br> -NR(18)-CO-, -NR(18)-CO-NH- or -NR(18)-S02- ;<br><br> R(18) is hydrogen or methyl; 25 v is zero, 1 or 2;<br><br> or, if g and h are zero,<br><br> R(17) is pyrrol-l-yl, pyrrol-2-yl or pyrrol-3-yl, which is not substituted or is substituted by 1 - 2 substituents 3 0 selected from the group consisting of<br><br> F, Cl, (C2-C5) -alkanoyl, (C2-C5)-alkoxy-carbonyl, formyl, carboxyl, -CF3, methyl and methoxy;<br><br> or<br><br> 35 R(17) is - (C3-C8)-cycloalkyl or phenyl,<br><br> which is not substituted or is' ,; v x substituted by 1-2 substituents.'<br><br> j! r-4 .<br><br> \r. 0^V&lt;<br><br> 280 8 87<br><br> selected from the group consrstlng o£ F and Cl, -CF3, methyl, methoxy, -NR(37)R(38), CH3S02- and H2N02S-;<br><br> R(37) and R(38) are,<br><br> Independently of each other, hydrogen or -CH3;<br><br> one of the substituents R(2) and R(3) Is R(6)-A-B-D;<br><br> R(6) is -NR(7)R(8), an amidino group R(7)R(8)N-C[«N-R(9)] - or a guanidino group<br><br> R(7 j «(10)<br><br> "(3) ■^Y"V R(9)/M<br><br> R(7), R(8), R(9) and R(10) are independently of each ether, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;<br><br> or<br><br> R(7) and R(8) are,<br><br> together, CaH2a;<br><br> a is 4,5,6 or 7;<br><br> where, when a = 5, 6 or 7, a methylene group of the group CaH2a can be replaced by a heteroatom group O, SOm or NR(11);<br><br> R(ll) is hydrogen or methyl;<br><br> or<br><br> R(8) and R(9) are,<br><br> together, C„H2x'<br><br> * is 2, 3, 4 or 5; ' where, when x = 3, 4 or 5, a methylene group of the group C„H2x can bo replaced by a<br><br> 28088<br><br> 76 -<br><br> heteroatom group 0, S0m or NR(11);<br><br> m Is zero, 1 or 2;<br><br> or<br><br> 5 R(6) is imidazolyl, pyridyl, quinolinyl or isoquinolinyl;<br><br> A is CbH2b;<br><br> b is 1, 2, 3, 4 or 5,<br><br> where. In the group CbH2b, one or 10 two methylene groups can be replaced by one of the groupings selected from the group consisting Of -0-, -CO-, -CH[OR(20)]-, -SOm- , N R ( 2 0 ) , - N R ( 2 0 ) - CO-, 15 -NR(20) -CO-NH-,<br><br> -NR(20)-C0-NH-S02-,<br><br> ,V<br><br> 0)o«<br><br> -R ( 2 0 ) N-S-<br><br> II<br><br> I N R ( 1 9 ) lbb an^d -SOaa [NR(19) ] bb-;<br><br> and where, in the group CbH2b, a methylene group can be replaced by 20 -CH-R(99), where R(99), together with R(7), forms a pyrrolidine or piperidine ring;<br><br> aa is 1 or 2;<br><br> bb is 0 or 1; 25 aa + bb =2;<br><br> R(19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms R(20) is hydrogen or methyl;<br><br> B is a phenylene or naphthylene radical<br><br> 28088<br><br> - 77 -<br><br> *(12)<br><br> r(i2)<br><br> "(I J)<br><br> «('5)<br><br> (12) and R(13) are,<br><br> independently of each other, hydrogen, methyl, P, Cl, CP3 or -S02-R(14); R(14) is methyl or NR(15)R(16); R(15) and R(16) are,<br><br> independently of each other, hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; D is ~C&lt;jH2d-X£-;<br><br> and in each case the other of the radicals R(2) and R(3) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl or CP3;<br><br> R(4) and R(5) are,<br><br> independently of each other hydrogen, alkyl having 1, 2 or 3 carbon atoms, F, Cl, or -CF3.<br><br> A compound of the formula I as claimed in claim 1 or 2, wherein:<br><br> R(1) is hydrogen, F, Cl, alkyl having 1, 2, 3 or 4 carbon atoms, -NR(35)R(36) or R(17)-CgH2g-Zh-; g is zero, 1, 2, 3 or 4;<br><br> h is zero or 1;<br><br> d is zero, 1, 2, 3 or 4; X is -0-, -CO-, -CH[OR(21)]-, -SOm or -NR(21)-; £ is zero or 1;<br><br> R(21) is hydrogen or methyl; m is zero, 1 or 2;<br><br> 280 887<br><br> - 78 -<br><br> Z is -O-, -CO-, -SOv-, -NR(18)-,<br><br> -NR(18)-CO-, -NR(18)-CO-NH- or<br><br> -NR(18)-S02- ;<br><br> R(18) is hydrogen or methyl;<br><br> v is zero, 1 or 2;<br><br> R(17) is cycloalkyl having 5 or<br><br> 6 carbon atoms, or CP3-;<br><br> or, i£ g and h are zero,<br><br> R(17) is pyrrol-l-yl,<br><br> which is not substituted or is substituted by 1 - 2 substituents selected from the group consisting o£ F, Cl, (C2-C5) -alkanoyl , ( C 2 - C 5 ) -alkoxycarbonyl, -CF3 and methyl;<br><br> or<br><br> R(17) is - (C5-C6)-cycloalkyl or phenyl,<br><br> which is not substituted or is substituted by a substituent which is selected from the group consisting of F and Cl, -CF3, methyl, CH3S02- and H2N02S-;<br><br> R(35) and R(36) are,<br><br> independently of each other, hydrogen,<br><br> methyl or ethyl;<br><br> or<br><br> R(35) and R(36) are,<br><br> together, 4-5 methylene groups of which one CH2 group can be replaced by oxygen, -S-, -NH- or -NCH3;<br><br> one of the substituents R(2) and R(3) is<br><br> R(6) -A-B-D-;<br><br> R(6) is -NR(7)R(8) , an amidino group R(7)R(8)N-C [«N-R(9) ] - or a guanidino group<br><br> V.<br><br> \\<br><br> ^ * *<br><br> V \^-<br><br> * c c *■).<br><br> • •<br><br> 280887<br><br> R(7|<br><br> "(«) /M^li<br><br> R(10)<br><br> R(9)'<br><br> R(7) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;<br><br> R(8), R(9) and R(10) are, 5 independently of each other,<br><br> hydrogen, methyl or ethyl;<br><br> or<br><br> R(7) and R(8) are,<br><br> together, CaH2a; 10 a is 4 or 5;<br><br> where, when a = 5, a methylene group of the group C#H2a can be replaced by NR(11),<br><br> 15 R(ll) is hydrogen or methyl;<br><br> or<br><br> R(6) is imidazolyl or pyridyl;<br><br> A is CbH2b;<br><br> b is 1, 2, 3, 4 or 5, 20 where, in the group CbH2b, one or two methylene groups can be replaced by one of the groupings selected from the group consisting of -CO-, -CH[OR(20) ] - , 25 -NR(20)-CO-,<br><br> ,v<br><br> °)o«<br><br> R(20)N-S-<br><br> INR(19 ) I bb<br><br> -SO0NR(19)]hh and -SO,-;<br><br> bb<br><br> 80<br><br> 28088<br><br> and where, in the group C2bH2b, a methylene group can be replaced by -CH-R(99), where R(99), together with R(7), forms a pyrrolidine or piperidine ring;<br><br> aa is 1 or 2;<br><br> bb is 0 or 1;<br><br> aa + bb » 2;<br><br> R(19) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms R(20) is hydrogen or methyl;<br><br> or, if b is 2, 3, 4 or 5,<br><br> a carbon atom in CbH2b can be replaced by a grouping -0-, -S-, -NR(20)-, -NR(20)-CO- or NR(20)-CO-NH-;<br><br> B<br><br> is a phenylene radical<br><br> R («2)<br><br> r(15)<br><br> R(12) and R(13) are,<br><br> independently of each other, hydrogen, methyl, P, Cl, CP3 or -S02R(14);<br><br> R(14) is methyl or NH2;<br><br> D is -CH2-, -0-, -CO-, -SOm- or -NR(21)-;<br><br> m is zero or 2;<br><br> R(21) is hydrogen or methyl;<br><br> and in each case the other of the radicals R(2) and R(3) is hydrogen;<br><br> R(4) and R(5) are,<br><br> independently of each other, hydrogen, alkyl<br><br> 280 8 8 7<br><br> - 81 -<br><br> having 1/ 2 or 3 carbon atoms, F, Cl or -CF3.<br><br> 4. A compound of the formula I as claimed in at least one o£ claims 1-3, wherein:<br><br> R(1) is hydrogen, F, Cl, alkyl having 1, 2, 3 or 5 4 carbon atoms, -NR(35)R(36) or<br><br> R (17)-CgH2g-Zh-;<br><br> g is zero or 1;<br><br> h is zero or 1;<br><br> Z is -0-, -CO-, -NR(18)-CO-, -NR(18)-<br><br> 10 CO-NH- or -NR(18)-S02-;<br><br> R(18) is hydrogen or methyl;<br><br> or, if g is 1;<br><br> Z is -S02-;<br><br> R(17) is CF3-;<br><br> 15 R(35) and R(36) are,<br><br> independently o£ each other, hydrogen,<br><br> methyl or ethyl;<br><br> or<br><br> R(35) and R(36) are,<br><br> 20 together, 4-5 methylene groups of which one CH2 group cam. be replaced by oxygen, -S-, -NH- or -NCH3;<br><br> one o£ the substituents R(2) and R(3) is R(6)-A-B-0-;<br><br> 25 R(6) is -NR(7)R(8) or a guanidino group<br><br> R(7j R ( t 0 )<br><br> .(.) -v rhK"<br><br> R(7) ia hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;<br><br> R(8), R(9) and R(10) are, 30 independently of each other/'<br><br> hydrogen, methyl or ethyl; (//Vr<br><br> ^ c-<br><br> * e c<br><br> - 82<br><br> 28088<br><br> or<br><br> R(7) and R(8) are,<br><br> together, CaH2a;<br><br> a is 4 or 5;<br><br> 5 where, when a ■ 5, a methylene group o£ the group CaH2a can be replaced by -NH- or -NCH3-,<br><br> or*<br><br> R(6) is imidazolyl;<br><br> 10 A is CbH2b;<br><br> b is 1, 2, 3 or 4;<br><br> where, in the group CbH2b' one or two methylene groups can be replaced by one of the groupings 15 f- selected from the group consisting of -CO-,<br><br> -R(20)N-S-<br><br> II<br><br> IMR( 19) 1^<br><br> -SOaa[NR(19)]bb- and -SOa-, -And where, in the group CbH2b, a methylene group can be replaced by 20 -CH-R(99), where R(99), together with R(7), can form a pyrrolidine or piperidine ring;<br><br> or, if b is 2, 3 or 4,<br><br> a methylene group in the group 25 CbH2b can be replaced by a grouping<br><br> -0- or -S-;<br><br> aa is 1 or 2;<br><br> bb is 0 or 1;<br><br> aa + bb • 2;<br><br> 30 R(19)is hydrogen or allcyl having<br><br> 1, 2, 3 or 4 carbon atoms R(20) is hydrogen or merChyl;<br><br> - 83 - 2 8 0 8 8 7<br><br> B is a phenylene radical,<br><br> R(I2)<br><br> R(1 J)<br><br> R(12) and R(13) are,<br><br> hydrogen;<br><br> and in each case the other o£ the radicals R(2) and 5 R (3) is hydrogen;<br><br> R(4) and R(5) are hydrogen.<br><br> 5. A compound of the formula I as claimed in claim 1, 10 which is selected from the group consisting of 4- [4-<br><br> N- (dimethylaminoethyl) methylsulf amoyl] phenoxy-3-trifluoromethylbenzoylguanidine dihydrochloride; 4- [4- (4-methylpiperazinosulfonyl)phenoxy]-3-trifluoromethylbenzoylguanidine dihydrochloride; 15 4-[4-(2-pyrrolidineethylamlnosulfonyl)phenoxy]-3-<br><br> tr i fluoromethylbenzoylguanidine dimaleate; 4- [4-(2-piperidineethylaminosulfonyl)phenoxy] -3-trifluoromethylbenzoylguanidine dimaleate; 4- [4- (N-dimethylamino-n-propyl) sulfamoyl]phenoxy-3-20 trifluoromethylbenzoylguanidine;<br><br> 4-[4-(N-dimethylaminoethyl)sulfamoyl]phenoxy-3-trifluoromethylbenzoylguanidine;<br><br> 4- (4- ixnidosulf amoyl) phenoxy-3 -trif luoromethylbenzoylguanidine ;<br><br> 25 3 -trifluoromethyl-4-(4-N-methylimidosulf amoyl) -<br><br> phenoxybenzoylguanidine;<br><br> 3-methyl-4- [4-(l-methylpiperazin-4-ylsulfonyl)-phenoxy]benzoylguanidine;<br><br> 4 - (4 -guanidinosulf onyl) phenoxy - 3 - trif luoromethyl -30 benzoylguanidine;<br><br> 4-[4-(2-imidazolylthioacetyl)phenoxy]-3-methyl^<br><br> 1 «• c.<br><br> - 84<br><br> 2 8 0 8 8 7<br><br> sulfonylbenzoylguanidine dihydrochloride;<br><br> 4- [4- (N/N' -dimethyl-S- i so thi our onyl acetyl) phenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride; 4- [4-(2-benzimidazolylthioacetyl)phenoxy]-3-methyl-sulfonylbenzoylguanidine dihydrochloride; 4- [4- (2-N-imidazolyl-1-hydroxyethyl) phenoxy] - 3-methylsulfonylbenzoylguanidine dihydrochloride; 4- [4- (N/N-dimethy'lglycylamino)phenoxy] -3-methylsulf onylbenzoylguanidine dihydrochloride; 4- [4- (N/N-diethylaminoethyl) aminosulf ony lphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride; 4- [4-(4-imidazolylethyl)aminosulfonylphenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride; 4- [4- (3-N-i.Tnidazolyl-l-propyl) aminosulf ony lphenoxy] -<br><br> 3-methylsulfonylbenzoylguanidine dihydrochloride;<br><br> 4-[4-(1-methyl-2-pyrrolidinylethyl)aminosulfonylphenoxy ] - 3-methy1sulfonylbenzoylguanidine dihydrochloride;<br><br> 4- [4- (N-piperidinoethyl)aminosulfonylphenoxy]-3-methylsulfonylbenzoylguanidine dihydrochloride; 4- [4- (2-dimethylaminoethyl) sulf onylmethylphenoxy] -3-methylsulfonylbenzoylguanidine dihydrochloride; 4- [4- (2-dimethylaminoethyl) sulf onylmethylphenoxy] -3-trifluoromethylbenzoylguanidine dihydrochloride.<br><br> A process for preparing a compound X as claimed in claim 1, which comprises reacting a compound of the formula IX<br><br> R(1)<br><br> R(3)<br><br> R(+)<br><br> "tVl<br><br> I I<br><br> in which R(l) to R(5) have the given meaning and L is a leaving group which can readily be substituted nucleophilically, ,f l -a.<br><br> V \ "<br><br> - 85 -<br><br> 280 8 8 7<br><br> with guanidine,<br><br> and, where appropriate, converting the product into a pharmacologically tolerated salt.<br><br> 7. The use o£ a compound I as claimed in claim 1 for 5 preparing a medicament for treating arrhythmias.<br><br> 10 8. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment or prophylaxis of cardiac infarction.<br><br> 9 • The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment or prophy-15 laxis of angina pectoris.<br><br> 10. The use of a compound I as claimed in claim 1 for preparing a medicament for the treatment or prophylaxis of ischemic conditions of the heart.<br><br> 11. The use of a compound I as claimed in claim 1 for 20 preparing a medicament for the treatment or prophylaxis of ischemic conditions of the peripheral and central nervous system and of stroke.<br><br> 12. The use of a compound 1 as claimed in claim 1 for preparing a medicament for the treatment or prophy-<br><br> 25 laxis of ischemic conditions of peripheral organs and limbs.<br><br> 13. The use of a compound 1 as claimed in claim 1 for preparing a medicament for the treatment of states of shock.<br><br> 3 0 14. The use of a compound I as claimed in claim 1 £cvf^<br><br> - 85 - 2 8 0 8 8 7<br><br> preparing a medicament for use in surgical operations and organ transplants.<br><br> 15. The use of a compound X as claimed in claim 1 for preparing a medicament for the preservation and storage of transplants for surgical procedures.<br><br> 15 • The use of a compound X as claimed in claim 1 for preparing a medicament for the treatment of diseases in which cell proliferation represents a primary or secondary cause.<br><br> 10<br><br> 17. The use of a compound X as claimed in claim 1 for 15 preparing a scientific tool for inhibiting the<br><br> NaVH* exchanger, for diagnosing hypertension and proliferative diseases.<br><br> 18. a medicine which contains an effective quantity of a compound X as claimed in one or more of claims 1<br><br> 20 to 4.<br><br> 19. A compound of the formula I according to claim 1 substantially as as herein described or exemplified.<br><br> 20. A process according to claim 6 substantially as herein described or exemplified.<br><br> 21. Use according to any one of claims 7 to 17 substantially as herein described or exemplified.<br><br> 22. A medicine according to claim 18 substantially as herein described or exemplified. V<br><br> HOECHST AKTIENGESELLSCHAFT By Their Attorneys '{^ HENRY HUGHES f!<br><br> Peri<br><br> </p> </div>
NZ280887A 1995-01-30 1996-01-25 Benzoylguanidines; preparation and medicaments NZ280887A (en)

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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
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US6291425B1 (en) * 1999-09-01 2001-09-18 Guilford Pharmaceuticals Inc. Compounds, methods and pharmaceutical compositions for treating cellular damage, such as neural or cardiovascular tissue damage
DE19951418A1 (en) * 1999-10-26 2001-05-03 Merck Patent Gmbh Process for the preparation of N- (4,5-bismethanesulfonyl-2-methyl-benzoyl) guanidine, hydrochloride
DE10024319A1 (en) * 2000-05-17 2001-11-22 Merck Patent Gmbh New bis-acylguanidine compounds are subtype-1 cellular sodium ion-proton antiporter inhibitors useful e.g. for treating arrhythmia, angina pectoris, infarction and insulin-independent diabetes mellitus
DE10046993A1 (en) * 2000-09-22 2002-04-11 Aventis Pharma Gmbh Substituted cinnamic acid guanidides, process for their preparation, their use as a medicament and medicament containing them
DE10338554A1 (en) * 2003-08-22 2005-03-31 Aventis Pharma Deutschland Gmbh Pentafluorosulfanylphenyl-substituted benzoylguanidines, process for their preparation, their use as a medicament or diagnostic agent, and medicament containing them
US7297817B2 (en) * 2004-04-13 2007-11-20 Cephalon France Thio-substituted arylmethanesulfinyl derivatives
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