Imidazole derivatives with biphenylsulfonyl substitution, method for preparing them and their use as

专利摘要:
The present invention relates to compounds of formula I, wherein the substituents have the meanings indicated in the specification. The compounds of the present invention exhibit excellent antiarrhythmic properties and contain cardioprotective compounds. They prophylactically inhibit or strongly reduce the pathophysiological effects arising in ischemic diseases, particularly ischemic heart arrhythmias. In addition, the compound shows a strong inhibitory effect on cell proliferation. Formula I
公开号:KR20010071957A
申请号:KR1020017000752
申请日:1999-07-10
公开日:2001-07-31
发明作者:클레만하인츠-베르너；랑한스요헨；슈바르크얀-로베르트；페트리슈테판；바이헤르트안드레아스
申请人:로버트 흐라이탁, 미쉘 베스트；아벤티스 파마 도이칠란트 게엠베하；
IPC主号:

专利说明:

TECHNICAL FIELD The present invention relates to a biphenylsulfonyl-substituted imidazole derivative, a process for producing the same, and a use thereof as a drug or diagnostic agent.
[1] The present invention relates to compounds of the general formula (I), or a physiologically acceptable salt thereof,
[2]
[3] In this formula,
[4] R 1 is hydrogen, alkyl of 1 to 8 carbon atoms or -C _a H _2a -phenyl wherein the phenyl moiety is fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR 8 R 9, Are each independently hydrogen or alkyl of 1 to 4 carbon atoms, and a is 0, 1, or 2, or is hydrogen,
[5] R 1 is -C _b H _2b -heteroaryl having 1 to 9 carbon atoms wherein the heteroaryl moiety is fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR 10 R 11 wherein R 10 and R 11 are 2 or 3 identical or different radicals from the group consisting of hydrogen or alkyl of 1 to 4 carbon atoms, and b is 0, 1 or 2,
[6] R1 is -C _d H _2d -cycloalkyl having 3 to 7 carbon atoms, wherein d is 0, 1 or 2;
[7] R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, CF ₃ , -CN, -NO ₂ , CH ₂ OR 17, CO-R 6, O- -O-R17 or NR50R51 wherein R17 is hydrogen or alkyl of 1 to 8 carbon atoms; R6 is hydrogen, alkyl, OR30 with 1 to 8 carbon atoms (wherein, R30 is hydrogen or alkyl of 1 to 8 carbon atoms), or F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR31R32 ( Wherein R31 and R32 are each independently hydrogen or alkyl of 1 to 4 carbon atoms; and R < 2 > is phenyl which is unsubstituted or substituted with 1, 2 or 3 of the same or different radicals from the group consisting of R < R50 and R51 are each independently - (alkylene of 2 to 4 carbon atoms) -O-R52 (wherein R52 is hydrogen or alkyl of 1 to 8 carbon atoms); R7 is hydrogen, C 1 -C 8 alkyl, or F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR12R13 (wherein, R12 and R13 are each independently hydrogen or alkyl of 1 to 4 carbon atoms a) with or phenyl which is unsubstituted or substituted with one, two or three identical or different radicals from the group consisting of, R7 is F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR14R15 (wherein, R14 and R15 are each independently hydrogen or alkyl of 1 to 4 carbon atoms, or a heteroaryl having 1 to 9 carbon atoms which is unsubstituted or substituted by 1, 2 or 3 same or different radicals from the group consisting of
[8] R2 and R3 are each independently a C 1 -C 8 alkyl, cycloalkyl having 3 to 7-alkyl, or -C _g H _2g - phenyl [wherein the phenyl moieties are fluorine, chlorine, bromine, iodine, CF _3, methyl, methoxy 2 or 3 of the same or different radicals from the group consisting of halogen, hydroxy, or NR18R19, wherein R18 and R19 are each independently hydrogen or alkyl of from 1 to 4 carbon atoms; g is 0, 1 or 2,
[9] R2 and R3 are each independently a carbon number of 1 to 9, -C _l H _2l - heteroaryl [wherein the heteroaryl moiety is F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR20R21 (wherein, R20 and R21 are each independently hydrogen or alkyl of 1 to 4 carbon atoms; l is 0, 1 or 2,
[10] R 2 and R 3 are each independently SO _n -R 22 wherein n is 0, 1 or 2; R22 is cycloalkyl or C _S -C _2S C 1 -C 8 alkyl, having from 3 to 7 carbon atoms of the phenyl [wherein, C _S -C _2S-phenyl is F, Cl, Br, I, CF _3, methyl, methoxy , Hydroxyl or NR34R35 wherein R34 and R35 are each independently hydrogen or alkyl of 1 to 4 carbon atoms, s is 0, 1 or 2, 1 or 2;
[11] R4 and R5 are each independently hydrogen, alkyl of 1 to 8 carbon atoms, F, Cl, Br, _{I, CF 3, -CN, -NO 2} , SO P -R16, CO-R23, O-R24 or O- ( Alkyl having 2 to 4 carbon atoms) -O-R33 (wherein p is 0, 1 or 2; R16 is C1-alkyl or phenyl to 8 [wherein the phenyl is F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR26R27 (wherein R26 and R27 are each independently hydrogen or C 1 -C 2, or 3 identical or different radicals from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, heteroaryl, R23 is hydrogen, alkyl having 1 to 8 carbon atoms or OR25 wherein R25 is hydrogen or alkyl having 1 to 8 carbon atoms; R24 is hydrogen, alkyl or phenyl group having 1 to 8 carbon atoms [wherein the phenyl is F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR28R29 (wherein R28 and R29 are hydrogen or carbon atoms are each independently 1 to 4 alkyl), or is unsubstituted or substituted with one, two or three identical or different radicals from the group consisting of And R < 33 > is hydrogen or alkyl having 1 to 8 carbon atoms, provided that at least one of the radicals R2 or R3 is O- (alkylene having 2 to 4 carbon atoms) -O-R17 or NR50R51.
[12] Preferred compounds of formula I are those, or physiologically acceptable salts thereof,
[13] R1 is hydrogen or alkyl having 1 to 4 carbon atoms, -C _a H _2a of phenyl [wherein the phenyl moieties are fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl or NR8R9 (wherein R8 and R9 are each independently Is hydrogen or methyl), or a is 0 or 1, or is hydrogen or methyl,
[14] Wherein R 1 is a radical selected from the group consisting of fluorine, chlorine, bromine, CF ₃ , CH ₃ , methoxy, hydroxyl or NR 10 R 11 (wherein R 10 and R 11 are each independently hydrogen or methyl) 1 to 9 heteroaryl,
[15] R1 is -C _d H _2d -cycloalkyl having 3 to 7 carbon atoms, wherein d is 0 or 1;
[16] R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, CF ₃ , -CN, -NO ₂ , CH ₂ OR 17, CO-R 6, -O- O-R17 or NR50R51 wherein R17 is hydrogen or alkyl of 1 to 4 carbon atoms; R6 is hydrogen, alkyl, OR30 group having 1 to 4 carbon atoms (wherein, R30 is hydrogen or alkyl of 1 to 4 carbon atoms), or phenyl; wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl Or NR31R32, wherein R31 and R32 are each independently hydrogen or methyl, or is substituted or unsubstituted with one or two of the same or different radicals; R7 is hydrogen, alkyl or phenyl group having 1 to 4 carbon atoms [wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR12R13 (wherein, R12 and R13 is hydrogen or methyl, each independently) 1 or 2 of the same from the group consisting of, or is unsubstituted or substituted with a different radical], or, or R7 is a heteroaryl group having 1 to 9 carbon atoms; wherein heteroaryl is F, Cl, Br, CF _3, methyl, methoxy , Hydroxyl or NR14R15, wherein R14 and R15 are each independently hydrogen or methyl, or is substituted or unsubstituted with one or two identical or different radicals; R50 and R51 each independently represent - (alkylene having 2 or 3 carbon atoms) -O-R52 (wherein R52 is hydrogen or alkyl having 1 to 4 carbon atoms)
[17] R2 and R3 are each independently C 1 -C 4 alkyl, cycloalkyl, or -C _g H _2g of 3 to 7 carbon atoms [wherein the phenyl moieties are fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl or NR18R19, wherein R18 and R19 are each independently hydrogen or methyl, and g is 0 or 1;
[18] Heteroaryl of R2 and R3 is a group having 1 to 9 each independently [wherein heteroaryl is F, Cl, Br, CF _3, methyl, methoxy, hydroxyl, or NR20R21 (wherein R20 and R21 are each independently hydrogen or Lt; / RTI > is methyl, or is substituted or unsubstituted with a radical from the group consisting of &
[19] Each of R2 and R3 independently represents a SO _n -R22 {wherein, n is 0, 1 or 2; R22 is cycloalkyl or -C _s H _2s C 1 -C 4 alkyl, 3 to 7 carbon atoms of the phenyl [wherein the phenyl moieties are fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR34R35 (wherein , R34 and R35 are each independently hydrogen or methyl); s is 0 or 1;
[20] R4 and R5 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, F, Cl, _{Br, CF 3, -CN, -NO 2} , SO P -R16, CO-R23, O-R24 or O- (C2- Or-3-alkylene) -O-R33, wherein p is 0, 1 or 2; Consisting of R16 is alkyl or phenyl, [C 1 to 4 wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR26R27 (wherein, R26 and R27 is hydrogen or methyl, each independently) Lt; / RTI > is unsubstituted or substituted with one or two identical or different radicals from the group; R23 is hydrogen, alkyl having 1 to 4 carbon atoms or OR25, wherein R25 is hydrogen or alkyl having 1 to 4 carbon atoms; R24 is hydrogen, alkyl or phenyl group having 1 to 4 carbon atoms [wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR28R29 (wherein, R28 and R29 is hydrogen or methyl, each independently) ≪ / RTI > is unsubstituted or substituted with one or two identical or different radicals from the group consisting of < RTI ID = 0.0 > And R < 33 > is hydrogen or alkyl having 1 to 4 carbon atoms, provided that at least one of the radicals R2 or R3 is O- (alkylene having 2 or 3 carbon atoms) -O-R17 or NR50R51.
[21] Particularly preferred compounds of formula I are those, or physiologically acceptable salts thereof,
[22] Wherein R 1 is hydrogen, alkyl having 1 to 4 carbon atoms or phenyl wherein the phenyl is fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl or NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen or methyl, ≪ / RTI > is unsubstituted or substituted by a radical from the group consisting of &
[23] R1 is made of a heteroaryl group having 1 to 9 carbon atoms; wherein heteroaryl is F, Cl, Br, CF _3, methyl, methoxy, hydroxyl, or NR10R11 (wherein, R10 and R11 is hydrogen or methyl, each independently) Substituted or unsubstituted radicals from the group,
[24] R1 is cycloalkyl having 3 to 7 carbon atoms;
[25] R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, CF ₃ , -CN, -NO ₂ , CO-R 6, O-R 7, O-CH ₂ -CH ₂ -O- is hydrogen, alkyl, OR30 having 1-4 carbon atoms [wherein, R30 is hydrogen or alkyl of 1 to 3 carbon atoms or phenyl; wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl or NR31R32, wherein R31 and R32 are each independently hydrogen or methyl; R7 is hydrogen, alkyl or phenyl group having 1 to 4 carbon atoms [wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR12R13 (wherein, R12 and R13 is hydrogen or methyl, each independently) a substituted or unsubstituted by a radical from the group consisting of - or, R7 is heteroaryl [having 1 to 9 carbon atoms, where the heteroaryl is F, Cl, Br, CF _3, methyl, methoxy, hydroxyl, or NR14R15 (wherein , R < 14 > and R < 15 > are hydrogen or methyl); R17 is methyl or ethyl; R50 and R51 are each independently -CH ₂ -CH ₂ -O-R52 (wherein, R52 is methyl or ethyl)} or,
[26] R2 and R3 are each independently a cycloalkyl or phenyl-C 1 -C 4 alkyl, C 3 -C 7 [wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR18R19 (R18 and R19 Are each independently hydrogen or methyl), or a group of the formula < RTI ID = 0.0 >
[27] Heteroaryl of R2 and R3 is a group having 1 to 9 each independently [wherein heteroaryl is F, Cl, Br, CF _3, methyl, methoxy, hydroxyl, or NR20R21 (wherein R20 and R21 are each independently hydrogen or Lt; / RTI > is methyl, or is substituted or unsubstituted with a radical from the group consisting of &
[28] R2 and R3 are each independently SO _n -R 22 wherein n is 0 or 2; R22 is cycloalkyl or phenyl; wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR34R35 (wherein R34 and R35 of the group having 1 to 4 carbon alkyl, 3 to 7 carbon atoms of are each independently Lt; / RTI > is hydrogen or methyl), or is substituted or unsubstituted with one or two identical or different radicals from the group consisting of
[29] R4 and R5 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, F, _{Cl, CF 3, -CN, -NO 2} , SO P -R16, CO-R23, O-R24 or O-CH ₂ -CH ₂ -O-R < 33 > wherein p is 0 or 2; R23 is hydrogen, alkyl having 1 to 4 carbon atoms or OR25 wherein R25 is hydrogen or alkyl having 1 to 3 carbon atoms; R24 is hydrogen, alkyl or phenyl group having 1 to 4 carbon atoms [wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR28R29 (wherein, R28 and R29 is hydrogen or methyl, each independently) ≪ / RTI > is substituted or unsubstituted with a radical from the group consisting of < RTI ID = 0.0 > Consisting of R16 is alkyl or phenyl, [C 1 to 4 wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR26R27 (wherein, R26 and R27 is hydrogen or methyl, each independently) Substituted or unsubstituted radicals from the group; R33 is one or more of methyl or ethyl}, provided only radicals R2 or R3 is _{O-CH 2 -CH 2 -O-} R17 , or NR50R51.
[30] Most preferred compounds of formula I are those, or physiologically acceptable salts thereof,
[31] R1 is an alkyl or phenyl group having 1 to 4 carbon atoms or (wherein the phenyl radical is substituted or non-substituted ring is in the from the group consisting of F, Cl, CF _3, methyl or methoxy),
[32] R1 is a heteroaryl group having 1 to 9 carbon atoms or (wherein heteroaryl is radical of a substituted or unsubstituted ring is from the group consisting of F, Cl, CF _3, methyl or methoxy),
[33] R1 is cycloalkyl having 3 to 7 carbon atoms;
[34] R2 and R3 are each independently H, F, _{Cl, CF 3, -CN, CO-} R6, O-R7, O-CH 2 -CH 2 -O-CH 3 or NR50R51 [wherein, R6 is hydrogen, C1- to the 4-alkyl, OR30 (where R30 is hydrogen, methyl or ethyl), or phenyl, and (wherein the phenyl radical substituted or is switched to the from the group consisting of F, Cl, CF _3, methyl or methoxy) ; R7 is hydrogen, alkyl or phenyl group having 1 to 4 carbon atoms (wherein the phenyl is unsubstituted or substituted by radicals from the group consisting of F, Cl, CF _3, methyl or methoxy), or, R7 is a group having a carbon number of 1 to 9 heteroaryl (wherein heteroaryl is F, Cl, CF _3, methyl or methoxy radical substituted or non-substituted ring is in the from the group consisting of a) and; R 50 and R 51 are -CH ₂ -CH ₂ -O-CH ₃ ,
[35] R2 and R3 are each independently a cycloalkyl or phenyl group having 1 to 4 carbon alkyl, 3 to 7 carbon atoms (where the phenyl is unsubstituted or substituted by radicals from the group consisting of F, Cl, CF _3, methyl or methoxy Or,
[36] R2 and R3 are each a C 1 -C 9 heteroaryl independently or (where the heteroaryl radical is substituted or non-substituted ring is in the from the group consisting of F, Cl, CF _3, methyl or methoxy),
[37] R2 and R3 are each independently SO _n -R 22 wherein n is 0 or 2; R22 is C 1 -C 4 alkyl or phenyl (wherein phenyl is fluorine, chlorine, CF _3, methyl or methoxy is unsubstituted or substituted by one or two identical or different radicals from the group consisting of a) and;
[38] R4 and R5 are each independently hydrogen, methyl, F, _{Cl, CF 3, -CN, SO 2} -R16, CO-R23, O-R24 or _{O-CH 2 -CH 2 -O-} CH 3 [ where, R16 It is C 1 -C 4 alkyl or phenyl, and (wherein the phenyl is fluorine, chlorine, CF _3, methyl or methoxy radical substituted or non-substituted ring is in the from the group consisting of a); R23 is hydrogen, methyl or OR25, wherein OR25 is hydrogen, methyl or ethyl; R24 is hydrogen, alkyl or phenyl group having 1 to 4 carbon atoms (wherein the phenyl radical substituted or is switched to the from the group consisting of F, Cl, CF _3, methyl or methoxy); provided that, with the proviso that the radical R2 or R3 is one or more of the _{O-CH 2 -CH 2 -O-} CH 3 , or NR50R51.
[39] In addition, preferred compounds are those, or physiologically acceptable salts thereof,
[40] R1 is alkyl of 1 to 8 carbon atoms, -C _d H _2d having a carbon number of 3 to 7 -cycloalkyl (where, d is 0, 1 or 2) or -C _a H _2a - phenyl [wherein the phenyl moieties are fluorine, 2, or 3 identical or different substituents from the group consisting of hydrogen, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen or alkyl of 1 to 4 carbon atoms, Substituted or unsubstituted with different radicals; a is 0, 1 or 2;
[41] R2 is O- (alkylene having 2 to 4 carbon atoms) -O-R17 or NR50R51 wherein R17 is hydrogen or alkyl having 1 to 8 carbon atoms; R50 and R51 are each independently - (alkylene of 1 to 8 carbon atoms) -O-R52, wherein R52 is hydrogen or alkyl of 1 to 8 carbon atoms;
[42] R3 is hydrogen, -CN or CO-R6 wherein R6 is hydrogen, alkyl of 1 to 8 carbon atoms or OR30 wherein R30 is hydrogen or alkyl of 1 to 8 carbon atoms;
[43] R4 is hydrogen, chlorine, fluorine, bromine, iodine, SO _P -R16 or _{O-CH 2 -CH 2 -O-} R33 { where, p is 0, 1 or 2; R16 is C1-alkyl or phenyl to 8 [wherein the phenyl is F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR26R27 (wherein R26 and R27 are each independently hydrogen or C 1 -C 4 >); R33 is methyl or ethyl;
[44] R5 is hydrogen.
[45] In addition, preferred compounds are the compounds and physiologically acceptable salts thereof:
[46] R1 is -C _a H _2a - consisting of phenyl [wherein the phenyl moieties are fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl or NR8R9 (wherein R8 and R9 are each independently hydrogen or methyl) Lt; / RTI > is unsubstituted or substituted by one or two identical or different radicals from the group, and a is 0 or 1;
[47] R2 is O- (alkyl of 2 to 4 carbon atoms) -O-R17 or NR50R51 wherein R17 is alkyl of 1 to 4 carbon atoms, in particular methyl; R50 and R51 are each independently - (alkylene of 2 to 4 carbon atoms) -O-R52, wherein R52 is alkyl having 1 to 4 carbon atoms, in particular methyl;
[48] R3 is CO-R6, wherein R6 is hydrogen;
[49] R4 is SO ₂ R16 (wherein, R16 is alkyl, especially methyl of 1 to 4 carbon atoms), or _{O-CH 2 -CH 2 -O-} CH 3 , and;
[50] R5 is hydrogen.
[51] Particularly preferred compounds of formula I are those, wherein R ₂ is O-CH ₂ -CH ₂ -O-R 17 or NR 50 R 51 wherein R 17 is alkyl of 1 to 4 carbon atoms, in particular methyl; R50 and R51 are -CH ₂ -CH ₂ -O-R52 (wherein, R52 is alkyl, especially methyl of 1 to 4 carbon atoms), and; Gt ;, R < 3 >, R < 4 > and R < 5 > are as defined above, or a physiologically acceptable salt thereof.
[52] The preferred compounds of formula I are those wherein the radicals R1, R2, R3, R4 and R5 are as defined above and the biphenyl substituents are represented by formula Ia, Ib, Ic, Id, Ie, If, Ig, Lt; / RTI > is a compound or a physiologically acceptable salt thereof, wherein < RTI ID = 0.0 >
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62] Also preferred are compounds of formula I, wherein the radicals R1, R2, R3, R4 and R5 are as defined above, and the radicals R4 and R5 are attached to a biphenyl substituent as formula Ij, or a physiologically acceptable salt thereof to be.
[63]
[64] Alkyl radicals and alkylene radicals can be straight-chain or branched. It may also be applied to alkylene radicals of the formulas C _a H _2a , C _b H _2b , C _d H _2d , C _g H _2g and C ₁ H _2l . In addition, the alkyl radicals and alkylene radicals may be substituted or may be straight-chain or branched when included in other radicals such as, for example, alkoxy radicals, alkylmercapto radicals or fluorinated alkyl radicals.
[65] It is also understood that cycloalkyl means an alkyl-substituted ring.
[66] Examples of the alkyl radical having 1 to 8 carbon atoms include methyl, ethyl, n-propyl, n-butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, isopentyl, neopentyl, Butyl, tert-butyl, and tert-pentyl. Propylene, 1, 2-propylene, 1, 3-propylene, 1, 4-butylene, 1 , 5-pentylene, 2,2-dimethyl-1,3-propylene, 1,6-hexylene, and the like are examples of alkylene radicals.
[67] Cycloalkyl radicals having 3 to 7 carbon atoms are especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, but may be substituted, for example, by alkyl of 1 to 4 carbon atoms. Examples of substituted cycloalkyl radicals may be mentioned as 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.
[68] Heteroaryl of 1 to 9 carbon atoms is especially phenyl or naphthyl having one or more CH groups replaced by N and / or two or more adjacent CH groups substituted by S, NH or O (with a 5-membered aromatic ring) ≪ / RTI > In addition, one or all of the condensation sites of the acyclic radical (such as indolizinyl) may be a nitrogen atom.
[69] Heteroaryl is especially furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, Pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, and cinnolinyl. N-containing heterocycles having from 1 to 9 carbon atoms are especially preferred for aromatic heterocyclic groups such as 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 1, 3-or 5-yl, 1- or 5-thiazolyl, 1, -Tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- Thiazolyl, 3-, 4-or 5-iso-thiazolyl, oxadiazolyl, Thiadiazol-2-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazole- 3- or 4-pyridinyl, pyrazinyl, 1-, 2-, 3- or 4-pyrimidinyl, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-, 6 -, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7- or 8- Salinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl.
[70] Particularly preferred N-containing heterocycles are pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl. Thienyl is both 2- and 3-thienyl. Furyl is 2- and 3-furyl.
[71] The monosubstituted phenyl radical may be substituted in the 2-, 3- or 4-position, or in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- Or may be trisubstituted at the 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-position have. N-containing heterocycle or thiophene radical. In the case of the bi- or tricyclic ring of radicals, the substituents may be the same or different.
[72] Where the compounds of formula I contain one or more acidic or basic groups or one or more basic heterocycles, the invention relates to corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically useful salts. Thus, compounds of formula (I) having an acidic group, such as one or more COOH groups, can be prepared, for example, by reacting an alkali metal salt such as an alkali metal salt such as calcium or magnesium salt, Salts with organic amines) or amino acids. Also, compounds of formula (I) having one or more basic (i.e., protonizable) groups or containing one or more basic heterocyclic rings may be used in the form of, for example, hydrochlorides, phosphates, sulfates, methanesulfonates, May be used in the formation of physiologically acceptable acid addition salts thereof with inorganic or organic acids such as lactate, maleate, fumarate, maleate, gluconate, and the like.
[73] Where the compound of formula I contains both acidic and basic groups simultaneously in the molecule, the present invention may include an internal salt, also referred to as betaine, in addition to the salt forms described above. Salts may be obtained from other salts by conventional methods such as, for example, mixing the compounds of formula I with acids or bases in a solvent or dispersant, or alternatively by anion exchange. Physiologically acceptable salts of the compounds of formula I are also understood to mean organic and inorganic salts as described, for example, in Remington's Pharmaceutical Sciences (17th edition, pages 1418 (1985)) do. For the physiological and chemical stability and solubility, sodium, potassium, calcium and ammonium salts are preferred for the acidic group, and among the basic groups, hydrochloric acid, sulfuric acid, phosphoric acid or carboxylic acid or acetic acid, citric acid, benzoic acid, Salts of sulfonic acids such as tartaric acid and p-toluenesulfonic acid are preferred.
[74] When appropriately substituted, the compounds of formula I may exist in stereoisomeric forms. When the compounds of formula I contain one or more asymmetric centers, they may each independently have the S configuration or the R configuration. The present invention encompasses all possible stereoisomers such as, for example, enantiomers or diastereomers, and mixtures of two or more stereoisomers such as enantiomers and / or diastereomers in all ratios. Thus, the invention relates to mixtures or racemic forms of enantiomers, enantiomers, enantiomers and enantiomers, enantiomerically pure forms, and two enantiomers in different ratios, for example. Where cis / trans isomerization is present, the present invention relates to both cis and trans forms and mixtures of these forms. If necessary, the individual stereoisomers can be prepared, for example, by stereoselective synthesis, in accordance with conventional methods for the resolution of the mixture. In the presence of mobile hydrogen atoms, the present invention encompasses all tautomeric forms of the compounds of formula (I).
[75] The invention also relates to a process for the preparation of compounds of formula I and to processes for the preparation of compounds of formula II, which can be prepared by known methods essentially analogous to the compounds of formula II (see J. Med. Chem. 1995. 38, 2357) Lt; RTI ID = 0.0 > cyanogen bromide < / RTI > The reaction is carried out in the presence of a non-nucleophilic strong auxiliary base such as K ₂ CO ₃ or Cs ₂ CO _{3 in an} amphoteric aprotic solvent (such as acetonitrile, DMA, TMU or NMP) stable to cyanogen bromide, Lt; / RTI > Suitable reaction temperatures are from 0 ° C to the boiling point of the solvent used, preferably from 60 ° C to 120 ° C.
[76]
[77] In this formula,
[78] The radicals are as defined above.
[79] The introduction of the substituents R2 or R3, which is alkoxyalkoxy, is carried out on a compound of formula II wherein R2 is a binuclear leaving group, preferably fluorine, chlorine or bromine, and R3 is a formyl, or R3 is a binuclear leaving group, , Chlorine or bromine, and R < 2 > is formyl. It is advantageous for the nucleophile to use an alkali metal salt of an alcohol, preferably sodium, potassium or cesium salt, in the alcohol as a solvent. The reaction temperature is a temperature between 0 ° C and the boiling point of the alcohol, and a temperature between 40 ° C and the boiling point of the alcohol is preferable.
[80] The introduction of the substituents R2 or R3, which is bis (alkoxyallyl) amino, is carried out on a compound of formula (II) wherein R2 is a binuclear leaving group, preferably fluorine, chlorine or bromine, Is carried out by a nucleophilic aromatic substituent on a compound of formula (II), preferably fluorine, chlorine or bromine, and R < 2 > is formyl. The nucleophile uses an alkali metal salt of bis (alkoxyallyl) amine or amine, preferably lithium, sodium, potassium or cesium salt, in an amphoteric solvent. Suitable solvents are THF, DMF, tetramethylurea, N-methylpyrrolidone and hexamethylphosphoramide. The reaction temperature is a temperature between 0 占 폚 and the boiling point of the solvent, and a temperature between 40 占 폚 and the boiling point of the solvent is preferable.
[81] The introduction of the substituent R4 is preferably carried out in the following toluene derivative III.
[82]
[83] In this formula,
[84] Hal is a leaving group suitable for Suzuki reaction, preferably bromine or iodine.
[85] SO ₂ by chlorosulfonated - the introduction of the alkyl radicals are to be found in reference: J. Med. Chem. 1997, 40, 2017 or J. Org. Chem. (1991), 56 (16), 4974-6.
[86] All reactions for the synthesis of compounds of formula I are well known to the person skilled in the art and are described in Houben-Weyl, Methoden der organischen Chemie [Methods of organic chemistry], Thieme-Verlag, Stuttgart or Organic Reactions, John Wiley &Amp; Sons, New York], or may be performed under similar standard conditions. Depending on the conditions in each case, it is possible to temporarily block specific action groups by introduction of a protective group to avoid side effects, and then to remove them again, or first to form a precursor from the desired action group generated in the next step Use of functional groups may be advantageous or necessary in the synthesis of compounds of formula (I). Such synthetic schemes and suitable protecting groups or precursors in each case are well known to those skilled in the art. The resulting compounds of formula I may optionally be purified by conventional purification methods, for example by recrystallization or chromatography. The starting materials for the preparation of compounds of formula (I) are commercially available or can be prepared by analogous methods to the literature.
[87] The present invention also relates to the use of a compound of formula I and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease caused by ischemic symptoms;
[88] The invention also relates to the use of a compound of formula I and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of myocardial infarction;
[89] The invention further relates to the use of a compound of formula I and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of angina pectoris;
[90] The invention further relates to the use of a compound of formula I and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of ischemic symptoms of the heart;
[91] The invention also relates to the use of a compound of formula I and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of peripheral and central nervous system and ischemic symptoms of seizures;
[92] The invention also relates to the use of a compound of formula I and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of ischemic symptoms of peripheral tissues and limbs;
[93] The invention also relates to the use of a compound of formula I and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of a shock condition;
[94] The invention also relates to the use of a compound of formula (I) and / or a physiologically acceptable salt thereof for the manufacture of a medicament for use in surgery and organ transplantation;
[95] The invention further relates to the use of a compound of formula I and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the preservation and storage of implants for surgical operations;
[96] Also for the use of a compound of formula I and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease which is the first or second cause of cell proliferation; And to the use thereof for producing an agent for the production of anti-atherosclerotic agents and late diabetes complications, carcinoma diseases, fibrotic diseases (such as pulmonary fibrosis, liver fibrosis or renal fibrosis) or prostate hyperplasia;
[97] The invention also relates to the use of a compound of formula I and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of impaired respiratory motion;
[98] The invention also relates to pharmaceutical preparations comprising an effective amount of a compound of formula I and / or a physiologically acceptable salt thereof.
[99] The compounds of formula (I) according to the invention are suitable as inhibitors of sodium-dependent bicarbonate / chloride exchange (NCBE) or sodium / bicarbonate symporters.
[100] Compounds analogous to compounds of formula (I) according to the present invention are described in U.S. Pat. Nos. 5,482,957 and 5,604,251. However, they do not have the sulfonyl cyanamide side chain always present according to the present invention. Imidazole derivatives as angiotensin II antagonists are described in WO 9523792, WO 9523791, US 5391732 and EP-A 648763. The known compounds are angiotensin II receptor antagonists of the subtype AT1 which have no activity or only a slight activity in the compound I of the present invention.
[101] In the early EP-A 855392, imidazole derivatives having a biphenylsulfonyl cyanamide side chain are proposed as NCBE inhibitors. The novel imidazole derivatives having the bipyridyl sulfonyl cyanamide side chain described in the present invention have specific substituents R2 and R3 on the imidazole ring and are useful not only for high availability as a cellular Na ⁺ -dependent bicarbonate / chloride exchange inhibitor, but also for improved bioavailability .
[102] The compounds of formula I according to the invention exhibit very good antiarrhythmic properties which are important, for example, in the treatment of diseases arising in the case of oxygen deficiency symptoms. Due to its pharmacological properties, the compounds of formula (I) are eminently suitable as antiarrhythmic agents with a cardioprotective component for the treatment of infarction and infarction and for the treatment of angina, and also for the formation of ischemia-induced damage, Lt; RTI ID = 0.0 > and / or < / RTI > significantly reduces the pathophysiological action. Due to their protective action against pathological hypoxic and ischemic symptoms, the compounds of formula (I) of the present invention result in intracellular Na ⁺ -dependent Cl ^- / HCO ₃ ^- exchange mechanism (NCBE) or sodium / bicarbonate symporter , And can be used as a medicament for the treatment of all acute or chronic injuries due to ischemia or diseases induced primarily or secondary therefrom. They protect organs with an acute or chronic deficiency of oxygen supply by reducing or preventing ischemically induced damage and are thus useful for the treatment of thrombosis, vasospasm, atherosclerosis or surgical intervention such as kidney or liver organ transplantation Can be used to protect donor ' s organs prior to and during removal, for example, to protect organs that have been removed during treatment or during storage thereof in a physiological bath fluid and during transplantation into recipient ' s body). Or as a medicament in chronic or acute renal failure.
[103] In addition, the compounds of formula I are useful medicaments having protective activity when performing angioplasty interventions such as, for example, in the heart or peripheral vascular beds. Corresponding to its protective action against ischemically induced damage, the compounds are also suitable as agents for the treatment of ischemic disorders of the nervous system, particularly the CNS, and are suitable, for example, for the treatment of seizures or brain edema. In addition, the compounds of formula (I) according to the invention are suitable for the treatment of shock formation, for example allergic, cardiogenic, hypolipidemic and bacterial shock.
[104] In addition, the compounds of formula (I) according to the present invention are distinguished by strong inhibitory activity in cell proliferation such as fibroblast proliferation and proliferation of vascular smooth muscle cells and glomerular stromal cells. Thus, the compounds of formula I are useful therapeutics for diseases where cell proliferation is the primary or secondary cause and are useful as anti-atherosclerotic agents, late diabetic complications, fibrotic disorders such as cancerous diseases, pulmonary fibrosis, Can be used as agents for diseases, especially tissue hyperplasia and / or hyperplasia, such as prostate hyperplasia or prostate hypertrophy.
[105] The compounds of formula I and their physiologically acceptable salts according to the invention are useful for the treatment and / or prophylaxis of myocardial infarction, angina pectoris, vaginal ischemic symptoms, respiratory disorders, cardiac ischemic symptoms, ischemic symptoms of the peripheral and central nervous system and seizures For use in the preservation and storage of implants for surgical treatment, for use in surgical procedures and organ transplantation, for treatment of shock conditions, for diseases which are primary or secondary causes of cell proliferation, for ischemic symptoms of extremities and limbs, Suitable.
[106] By increasing the drug sensitivity of the respiratory chemical receptor Na ⁺ - dependent Cl ^_ / HCO ₃ ^- exchange inhibitor (NCBE inhibitors) or revealed the sodium / bicarbonate seam Porter. These chemoreceptors are responsible for a considerable extent for maintaining the indicated respiratory activity. They are activated by hypoxia, pH decline and CO ₂ increase (high carbon dioxide) in the body, leading to an accurate adjustment of respiratory volume. During sleep, breathing is particularly susceptible to impairment and is highly dependent on the activity of chemical receptors. Improvement of respiratory motion by stimulation of chemoreceptors with substances that inhibit Na ⁺ -dependent Cl ^- / HCO ₃ ^- exchange induces improved respiration in the following clinical conditions and diseases: central respiratory disturbances such as sleep apnea Acute and chronic pulmonary disease with hypoxia and hypertension, respiratory disturbances during long-term ventilation, respiratory disturbances during adaptation at high altitudes, sleep apnea disorders and mixed forms, hypoxia and hypertension.
[107] The compounds of the formula I according to the invention and the physiologically acceptable salts thereof can be used in the form of a pharmaceutical agent alone, a mixture with another pharmaceutical agent or a pharmaceutical preparation for an animal, preferably a mammal, especially a human being. The present invention also relates to compounds of formula I for use as medicaments and their physiologically acceptable salts, their use in the treatment and prevention of the above-mentioned syndromes, and their preparation. The present invention also relates to pharmaceutical preparations as active gates containing an effective amount of one or more compounds of formula I and / or a physiologically acceptable salt thereof, additionally conventional pharmaceutically innocuous vehicles and excipients. In general, the pharmaceutical preparations contain from 0.1 to 99% by weight, preferably from 0.5 to 95% by weight, of a compound of the formula I and / or a physiologically acceptable salt thereof. The pharmaceutical preparations can be prepared in a manner known per se. To this end, the compound of formula I and / or a physiologically acceptable salt thereof may be combined with one or more solid or liquid pharmaceutical vehicles and / or excipients, if necessary with other pharmaceutically active compounds, ≪ / RTI >
[108] Medicaments containing a compound of formula I and / or a physiologically acceptable salt thereof may be administered orally, parenterally, intravenously, rectally or by inhalation, and the preferred mode of administration depends on the particular indication of the disease. The compounds of formula I can be used alone or in combination with pharmaceutical adjuvants in veterinary and human medicine.
[109] Adjuvants suitable for the desired pharmaceutical formulation are known to those skilled in the art. Antioxidants, dispersants, emulsifiers, defoamers, flavor control agents, preservatives, solubilizing agents or coloring agents may be used in addition to solvents, gel-forming agents, suppository bases, tableting aids and other vehicles.
[110] For oral dosage forms, the active compound is mixed with suitable excipients such as excipients, stabilizers or inert diluents, and may be formulated into tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions, Lt; / RTI > Inert excipients which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, the formulation is formed into dried and wet granules. Suitable oil-in-water vehicles or solvents are vegetable or animal oils, such as, for example, sunflower oil or cod liver oil.
[111] For subcutaneous or intravenous administration, the active compound is introduced as a solution, suspension or emulsion, if desired together with conventional substances such as solubilizing agents, emulsifying agents or further adjuvants. Possible solvents are, for example, water, physiological saline or alcohols (e.g. ethanol, propanol, glycerol) and further sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of various solvents mentioned.
[112] Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active compounds of formula I in a pharmaceutically acceptable solvent such as, for example, ethanol or water, or mixtures thereof.
[113] If desired, the formulations may contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers, and propellants. Such preparations typically contain active compounds in a concentration of about 0.1 to 10, especially about 0.3 to 3% by weight.
[114] The dosage and frequency of administration of the active compound of the compound of formula I administered will depend on the effect of the compound employed and on the duration of the activity and will depend on the nature of the disease being treated and on the severity, sex, age, weight and individual responsiveness of the mammal do. On average, in the case of a patient weighing about 75 kg, the daily dose of the compound of formula I is at least 0.001 mg, preferably 0.01 mg, up to 10 mg, preferably 1 mg, per kg of body weight. If the disease is acute, for example, immediately after myocardial infarction, higher doses may be required, especially more frequent doses, such as four doses per day or less. Especially in the case of intravenous administration, for example in infarction patients, up to 200 mg of concentrated protection unit per day may be required.
[115] In addition, the compounds of formula I and / or the physiologically acceptable salts thereof can be used to reach effective therapeutic activity with other pharmacologically active compounds for the treatment or prevention of the above-mentioned syndromes, in particular for the treatment of cardiovascular diseases have. Sodium / hydrogen exchange (NHE) inhibitors and / or other classes of cardiovascular active compounds.
[116] The invention further relates to a pharmaceutical composition comprising: a) an NCBE inhibitor of the formula I and / or a physiologically acceptable salt thereof having an NHE inhibitor and / or a physiologically acceptable salt thereof; b) an NCBE inhibitor of formula I and / or a physiologically acceptable salt thereof having an active ingredient from another class of cardiovascular active compound; And c) an NCBE inhibitor of formula I having an active ingredient from the group of NHE inhibitors and / or physiologically acceptable salts thereof and other classes of cardiovascular active compounds and / or physiologically acceptable salts thereof and / Lt; / RTI > acceptable salts thereof.
[117] Active compounds that are known and identified as NHE inhibitors include guanidine derivatives such as those described in Edward J. Cragoe, Jr., "DIURETICS, Chemistry, Pharmacology and Medicine", J. WILEY & Sons (1983), 303-341 The acylguanidines as described or the NHE inhibitors mentioned in DE 19737224.4 are preferred.
[118] Suitable NHE inhibitors are described, for example, in U.S. Patents Nos. 5292755, 5373024, 5364868, 5591754, 5516805, 5559153, 5571842, 5641792, 5631293, EP-A A No. 6271313, EP-A 628543, EP-A 605822, EP-A 603650, EP- A No. 640593, EP-A No. 640588, EP-A No. 702001, EP-A No. 713864, EP-A No. 723956, EP-A No. 754680, EP-A No. 765868 , EP-A 774459, EP-A 794171, EP-A 814077, EP-A 869116; Ortho-substituted benzoylguanidines as described in EP-A 556673, EP-A 791577, EP-A 794172; Ortho-amino-substituted benzoylguanidines as described in EP-A 690048; Isoquinoline as described in EP-A-590455; Benzo-fused 5-membered heterocycle as described in EP-A 639573; Diacyl-substituted guanidines as described in EP-A 640587; Acyl guanidine as described in U.S. Patent No. 5547953; Phenyl-substituted alkyl- or alkenylcarboxylic acid guanidines having perfluoroalkyl groups as described in U.S. Patent No. 5,567,734, EP-A 688766; Heteroaroyl guanidines as described in EP-A 676395; Bicyclic heteroaroylguanidines as described in EP-A 682017; indenoylguanidines as described in EP-A 738712; Benzyloxycarbonyl guanidine as described in EP-A 748795; Phenyl-substituted alkenylcarboxylic acid guanidines having a fluorophenyl group as described in EP-A 744397; Substituted cinnamoylguanidines as described in EP-A 755919; Sulfone imidamides as described in EP-A 771788; Benzene dicarboxylic acid diguanidines as described in EP-A 774458, EP-A 774457; Diarylcarboxylic acid diguanidines as described in EP-A 787717; Substituted thiophenylalkenylcarboxylic acid guanidines as described in EP-A 790245; Bis-ortho-substituted benzoylguanidines as described in EP-A 810207; Substituted 1- or 2-naphthylguanidines as described in EP-A 810205 and EP-A 810206; Indanylidene acetyl guanidine as described in EP-A 837055; Phenyl-substituted alkenylcarboxylic acid guanidines as described in EP-A-825178; Aminopiperidylbenzoylguanidines as described in EP-A 667341; Heterocycloxybenzylguanidines as described in EP-A 694537; Ortho-substituted benzoylguanidines as described in EP-A 704431; Ortho-substituted alkylbenzylguanidines as described in EP-A 699660; Ortho-substituted heterocyclylbenzoylguanidines as described in EP-A-699666; Ortho-substituted 5-methylsulfonylbenzoylguanidines as described in EP-A-708088; An ortho-substituted 5-alkylsulfonylbenzoylguanidine having a 4-amino substituent as described in EP-A 723963; An ortho-substituted 5-alkylsulfonylbenzoylguanidine having a 4-mercapto substituent as described in EP-A-743301; 4-sulfonyl- or 4-sulfinylbenzylguanidines as described in EP-A 758644; Alkenylbenzoylguanidines as described in EP-A 760365; Benzoylguanidines having fused cyclic sulfone as described in DE 19548708; Benzoyl-, polycyclic aroyl- and heteroaroylguanidines as described in WO 9426709; 3-aryl / heteroarylbenzoylguanidines as described in WO 9604241; 3-phenylbenzoylguanidine having a basic amide at the 5-position as described in WO 9725310; 3-dihalothienyl- or 3-dihalophenylbenzoylguanidine having a basic substituent at the 5-position as described in WO 9727183; 3-methylsulfonylbenzoylguanidine having a specific amino substituent at the 4-position as described in WO 9512584; Amylolide derivatives as described in WP 9512592; 3-methylsulfonyl-benzoylguanidine having a specific amino substituent at the 4-position as described in WO 9726253; Indoloylguanidines as described in EP-A 622356 and EP-A-708091; Indoloylguanidines having fused additional ring systems as described in EP 787728; Methyl guanidine derivatives as described in WO 9504052; 1,4-benzoxazinoylguanidine as described in EP-A 719766; 5-bromo-2-naphthoylguanidine as described in JP 8225513; 4-carbonylguanidine having a phenyl radical at the 2-position as described in EP-A 726254; Cinnamoylguanidines as described in JP 09059245; Propenoylguanidine having a naphthalene substituent as described in JP 9067332; Propenoyl guanidine having an indole substituent as described in JP 9067340; Or heteroaryl-substituted acrylanguanidines as described in WO 9711055, and physiologically acceptable salts thereof.
[119] Preferred NHE inhibitors are the compounds highlighted in the mentioned publications. Very particularly preferred compounds are the cariporide (HOE642), HOE 694, EMD 96785, FR 168888, FR 183998, SM 20550, KBR-9032 and physiologically acceptable salts thereof. Most preferred are other physiologically acceptable salts of cariporide or N- (4-isopropyl-3-methanesulfonylbenzoyl) guanidine.
[120] Examples of classes of active compounds having cardiovascular activity that can be compounded therapeutically effectively with NCBE inhibitors or in combination with combinations of NCBE inhibitors and NHE inhibitors include, but are not limited to, -Receptor blockers, calcium antagonists, angiotensin- , Angiotensin receptor blockers, loop diuretics, thiazide diuretics, potassium-deficient diuretics, and aldosterone antagonists are used to lower blood pressure, and also in the treatment of heart failure and congestive heart failure, And class IV antiarrhythmics, nitrates, K _APT openers, K _APT blockers, veratridine-activatable sodium channels, and the like. For example, the following are suitable: [beta] -blockers (e.g., propanol, anthanol, methoprolol); Calcium antagonists (e.g., diltiazem hydrochloride, verapamil hydrochloride, nifedipine); ACE inhibitors such as captopril, enalapril, ramipril; transdolafril, quinapril, spirapril, preferably ramipril or trandolapril; Angiotensin II receptor antagonists (eg, rosatan, valsatan, telmisartan, ffosatan, tasosatan, candesartan, irbesartan); Loop diuretics (eg, furosemide, piretanide, toracemide); Thiazide diuretics (eg, hydrochlorothiazide, metolazone, indapamide); Potassium-deficient diuretics (e.g., amiloride, triamterene, spironolactone); (Eg, glycerol trinitrate); K ⁺ (ATP) openers (eg, glycine, glycyrrhetinic acid, Examples of particularly advantageous combination ingredients with NCBE inhibitors include non-inactive sodium channels (veratridine-activated < RTI ID = 0.0 > The combination of a non-inactive sodium channel (a veratridine activatable sodium channel) inhibitor and an NCBE inhibitor is used to prevent infarction and reinfarction and to treat infarction and angina, and to treat ischemic induced cardiac arrhythmia, The combination of an NCBE inhibitor and a non-inactive sodium channel blocker is also suitable for inhibiting the formation and maintenance of ventricular fibrillation and also for preventing the pathophysiological process in the formation of ischemically induced damage . Causes the or significantly reduce pathological hypoxic and due to their protective activity increased for the ischemic symptoms, NCBE inhibitors and non-formulations according to the invention in an inert sodium channels, resulting in restraint of the cells into the Na ⁺ influx of And can be used as a medicament for the treatment of all acute or chronic injuries induced by ischemia or diseases which are primarily or secondarily induced thereby. The present invention relates to the use of the compounds of formula Wherein the combination of an NCBE inhibitor and a non-inert sodium channel blocker is used for the protection of the donor organ prior to and during removal, for example during storage in a physiological bath fluid, and during implantation into the recipient ' s body NCBE inhibitors and non-inactive sodium channel blockers. Is a valuable, safeguarded agent when performing vascular occlusion surveillance in the heart or peripheral blood vessels. Consistent with their protective activity against ischemically induced injury, the combination of NCBE inhibitors and non-inactive sodium channel blockers The mixture is also suitable as a medicament for the treatment of ischemia of the nervous system, especially the central nervous system, and is suitable for the treatment of seizures or cerebral edema. In addition, the combinations according to the invention of NCBE inhibitors and non-inert sodium channel blockers are suitable for the treatment of shock formation such as allergic, cardiogenic, hypovolemic and bacterial shock.
[121] In addition to administration as a fixed combination, the present invention also relates to the use of an NCBE inhibitor of formula I and / or a pharmaceutically acceptable salt thereof together with an additional active ingredient from another class of NHE inhibitors and / or cardiovascular active compounds for the treatment of the above- Or simultaneous, separate or sequential administration of a pharmaceutically acceptable salt thereof.
[122] A) a NCBE inhibitor of the formula I and / or a physiologically acceptable salt thereof and an NHE inhibitor and / or a physiologically acceptable salt thereof; Or b) an NCBE inhibitor of the formula I and / or a physiologically acceptable salt thereof and, in addition, an active substance from another class of cardiovascular active compounds and / or a physiologically acceptable salt thereof; Or c) a medicament comprising an NCBE inhibitor of formula I and / or a physiologically acceptable salt thereof, an NHE inhibitor and, in addition, an active substance from another class of cardiovascular active compounds and / or a physiologically acceptable salt thereof ≪ / RTI >
[123] By way of compound administration, the effect of one compounding ingredient is effected by each of the other ingredients, i.e. the activity and / or the duration of activity of the combination or formulation according to the invention, relative to the activity and / or activity period of the respective individual ingredient It becomes stronger or longer-lasting (synergistic). In the case of compounding administration, it leads to lowering the dose of each compounding component as compared to individual administration. Thus, the formulations and formulations according to the present invention can significantly reduce the amount of active ingredient administered and eliminate or substantially reduce unwanted side effects.
[124] The present invention also relates to pharmaceutical compositions comprising as a pharmaceutically active compound: a) an NCBE inhibitor and an NHE inhibitor of the formula I and / or a physiologically acceptable salt thereof; Or b) additional active substances and / or physiologically acceptable salts thereof from another class of NCBE inhibitors and cardiovascular active compounds of formula I; Or c) an additional active substance and a physiologically acceptable salt thereof from another class of NCBE inhibitors, NHE inhibitors and cardiovascular active compounds of formula I, in each case in the treatment or prevention of the above-mentioned syndromes, The present invention relates to a commercial pack containing instructions for the use of these active compounds in combination for simultaneous, divided or sequential administration in the treatment of diseases.
[125] The pharmaceutical preparations according to the present invention can be prepared, for example, by intimately mixing the respective ingredients as powders, dissolving the respective components in a suitable solvent such as a lower alcohol, and then removing the solvent.
[126] In the formulations and formulations according to the invention, the weight ratio of the NBCE inhibitor to the substance having an NHE inhibitor or cardiovascular activity is from 1: 0.01 to 1: 100, preferably from 1: 0.1 to 1:10.
[127] The formulations and preparations according to the invention preferably contain from 0.5 to 99.5% by weight, in particular from 4 to 99% by weight, of the active compound.
[128] When used in mammals, preferably humans, according to the present invention, the dosage of the various active compound components will vary, for example from 0.001 to 100 mg / kg per day.
[129] Abbreviation
[130] BCECF 2'7'-bis (2-carboxyethyl) -5,6-carboxyfluorescein
[131] CH ₂ Cl ₂ dichloromethane
[132] DCI desorption - chemical ionization
[133] DMF N, N-dimethylformamide
[134] EA ethyl acetate (EtOAc)
[135] EI electron effect
[136] ES Electron Spray Ionization
[137] HEP n-heptane
[138] MeOH Methanol
[139] mp melting point
[140] NCBE Sodium-Dependent Chloride / Bicarbonate Exchange
[141] NHE sodium / hydrogen exchange
[142] RT room temperature
[143] CNS central nervous system
[144] General methods for preparing sulfonyl cyanamide from sulfonamides
[145] The sulfonamide starting materials of anhydrous acetonitrile was dissolved in acetonitrile 10㎖ / mmol, K ₂ CO ₃ and 3mol eq acetonitrile in 5N BrCN solution was added dropwise 1mol equiv., And the mixture to about 10 minutes (typical reaction time when the transition is complete 6 hours). The reaction mixture is then chromatographed on silica gel without further work-up.
[146] Example 1
[147] 4 '- [5-formyl-4- (2-methoxyethoxy) -2-phenylimidazol-1-ylmethyl] -3'-methanesulfonylbiphenyl-2-sulfonylcyanamide
[148]
[149] a) 2-Bromo-5-methylbenzenesulfonyl chloride
[150] 40 g of 4-bromotoluene was slowly introduced into 250 ml of chlorosulfonic acid at -10 캜 under stirring. At this temperature the mixture is stirred for 30 minutes, elevated to 0 < 0 > C and followed by excess ice. The product is filtered off with suction and washed with a small amount of water. Drying with P ₄ O ₁₀ under vacuum affords 63 g of a colorless solid which is applied as the next reaction.
[151] b) 2-Bromo-5-methylbenzenesulfonic acid
[152] 37.6 g of sodium sulfite are dissolved in 500 ml of water and heated to 70 占 폚. At this temperature, 2-bromo-5-methylbenzenesulfonyl chloride is added in portions. The pH of the solution is maintained between pH 9 and pH 10 by adding 10N NaOH aqueous solution at the same time. The mixture is stirred at 70 < 0 > C for 1.5 h, the solution is filtered and adjusted to pH 0 using a saturated aqueous solution of HCl in an ice bath. The mixture is stirred for 30 minutes, then the product is filtered, washed with a small amount of water and dried. 49.6 g of crystals are obtained. Melting point 120 to 122 占 폚. MS (ES): 236 (M + H) < ⁺ & gt ^; .
[153] c) Sodium 2-bromo-5-methylbenzenesulfinate
[154] 49.6 g of 2-bromo-5-methylbenzenesulfonic acid are dissolved in 400 ml of methanol and treated with an equimolar amount of NaOH in 50 ml of water. The mixture is stirred at room temperature for 3 hours, the solution is filtered, and the solvent is removed under vacuum. Finally, the residue is azeotropically removed using 50 ml of toluene. The solid residue is dried under vacuum with P ₄ O ₁₀ and 54.0 g of product are obtained. Melting point 288-290 占 폚 (decomposition).
[155] d) 1-Bromo-2-methanesulfonyl-4-methylbenzene
[156] Sodium 2-bromo-5-methylbenzenesulfinate (54.0 g) is suspended in dry DMF (300 ml) and treated with 45.7 ml of methyl iodide. In this process, the temperature of the solution is raised to 50 ° C. The mixture is stirred at 50 < 0 > C for 3 hours and the DMF is removed under vacuum. The residue is stirred with 500 ml of water, then stirred at 0 ° C for 1 hour, and filtered. The product is washed with water, filtered and recrystallized from 250 ml of HEP 400 ml / EA using activated carbon. 27.0 g of colorless crystals are obtained. Melting point 110 to 114 占 폚. _Rf (EA / HEP 1: 4) = 0.09. MS (DCI): 250 (M + H) < ⁺ & gt ^; .
[157] e) 1-Bromo-4-bromomethyl-2-methanesulfonylbenzene
[158] 9.9 g of 1-bromo-2-methanesulfonyl-4-methylbenzene are dissolved in 100 ml of chlorobenzene, 77 mg of benzoyl peroxide and 7.1 g of N-bromosuccinimide are added and the mixture is refluxed for 1 hour . The solvent is then removed in vacuo, the residue is dissolved in 100 mL of CH ₂ Cl ₂ , and the mixture is washed twice with 50 mL of saturated aqueous Na ₂ CO ₃ solution and once with 50 mL of water. Dry with Na ₂ SO ₄ and remove the solvent under vacuum. The residue was recrystallized from 30 ml of HEP 80 ml / EA to give 6.9 g of a light yellow solid. Melting point 120 to 124 占 폚. _Rf (EA / HEP 1: 2) = 0.38. MS (DCI): 329 (M + H) < ⁺ & gt ^; .
[159] f) 3- (4-Bromo-3-methanesulfonylbenzyl) -5-chloro-2-phenyl-3H-imidazole-
[160] To a solution of 5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde (Cnem. Pharm. Bull. 1976, 24 (5), 960], 1.6 g of 1-bromo-4-bromomethyl-2-methanesulfonylbenzene and 691 mg of K ₂ CO ₃ are stirred at room temperature for 18 hours. The reaction mixture is poured into 300 ml of aqueous NaHCO ₃ solution and extracted three times with 150 ml of EA each time. Dry the extract with Na ₂ SO ₄ and the solvent removed under vacuum. Chromatography on silica gel using EA / HEP 1: 2 afforded 1.2 g of a colorless oil. _Rf (EA / HEP 1: 2) = 0.16 MS (FAB): 454 (M + H) ⁺ .
[161] g) 4 '- (4-Chloro-5-formyl-2-phenylimidazol-l-ylmethyl) -3'-methanesulfonylbiphenyl-2-sulfonic acid tert-
[162] 3-tert-Butyl-2-dihydroxyborane-2 (3 g, -Ylbenzenesulfonamide < / RTI > [J. Med. Chem. 1997, 40, 547], 24 mg of Pd (II) acetate and 56 mg of triphenylphosphine are dissolved in 13 ml of toluene and 3.5 ml of ethanol and 2M aqueous Na ₂ CO ₃ solution is added. The reaction mixture was refluxed for 105 min, then allowed to cool to room temperature, dissolved in half saturated NaHCO ₃ aqueous solution. Each with EA 150㎖ the mixture extracted three times, dried with Na ₂ SO _4, remove the solvent in vacuo. Chromatography on silica gel with EA / HEP 1: 2 afforded 660 mg of a colorless oil. _Rf (EA / HEP 1: 2) = 0.12 MS (ES): 587 (M + H) ⁺ .
[163] h) 4 '- (4-Chloro-5-formyl-2-phenylimidazol-l-ylmethyl) -3'-methanesulfonylbiphenyl-
[164] To a solution of 4'- (4-chloro-5-formyl-2-phenylimidazol-l-ylmethyl) -3'-methane- sulfonylbiphenyl-2-sulfonic acid tert- butylamide in 5.6 ml of trifluoroacetic acid 650 mg is dissolved and 133 아니 of anisole is injected. The mixture is stirred at room temperature for 8 hours and then the volatile components are removed under vacuum. The residue is dissolved again in 20 ml of water three times, and then the water is removed under vacuum. Finally, the residue is suspended two more times in 30 ml each of toluene, and the volatile components are again removed in vacuo. 570 mg of a light yellow solid which is further reacted without purification due to insufficient solubility is obtained. _Rf (EA / HEP 2: 1) = 0.24.
[165] i) Synthesis of 4 '- [5-formyl-4- (2-methoxyethoxy) -2-phenylimidazol- 1 -ylmethyl] -3'-methanesulfonylbiphenyl-
[166] 330 mg of 4 '- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) -3'-methanesulfonylbiphenyl-2-sulfonamide and 250 mg of NaOH were dissolved in 12.5 ml of methoxyethanol Lt; / RTI > for 2 hours. The reaction mixture is then cooled to room temperature, followed by 100 ml of aqueous NaHCO ₃ solution. Each extracted three times with EA 100㎖, dried with Na ₂ SO _4, remove the solvent in vacuo to give 350mg of a colorless oil which is reacted immediately without further purification due to the remarkable instability. R _f (EA / HEP 2: 1) = 0.18.
[167] j) Synthesis of 4'- [5-formyl-4- (2-methoxyethoxy) -2-phenylimidazol-1-ylmethyl] -3'-methanesulfonylbiphenyl-2-sulfonylcyanamide
[168] (5-formyl-4- (2-methoxyethoxy) -2-phenylimidazol-1-ylmethyl] -3'-trifluoromethylpiperidine was prepared in accordance with the general method for the preparation of the sulfonyl cyanamide from 4- Methanesulfonylbiphenyl-2-sulfonamide (reaction time 15 minutes) and chromatography on silica gel with EA / MeOH 1: 5, 90 mg of crystals are obtained. Melting point> 270 ° C. _Rf (EA / MeOH 1: 5) = 0.27 IR (C = N): 2178.1 cm <^-1> MS (FAB): 595 (M + H) <^+> .
[169] Example 2
[170] Chloro-4 '- [5-formyl-4- (2-methoxyethoxy) -2-phenylimidazol- 1 -ylmethyl] -biphenyl-2- sulfonyl cyanamide
[171]
[172] a) 4-Bromo-1-bromomethyl-2-chlorobenzene
[173] 7.1 ml of 4-bromo-2-chlorotoluene was dissolved in 20 ml of chlorobenzene, and the mixture was treated at 130 캜 with a mixture of 9.4 g of N-bromosuccinimide and 200 mg of dibenzoyl peroxide. The mixture is refluxed for 30 minutes, cooled, diluted with 100 mL of CH ₂ Cl ₂ , and washed once with 50 mL each of a saturated aqueous Na ₂ SO ₃ solution and 100 mL of a saturated aqueous NaHCO ₃ solution. Dry with Na ₂ SO ₄ and remove the solvent under vacuum. 11.0 g of a pale yellow oil are obtained. _Rf (EA / HEP 1: 8) = 0.49 MS (DCI): 283 (M + H) ⁺ .
[174] b) 3- (4-Bromo-2-chlorobenzyl) -5-chloro-2-phenyl-3H-imidazole-
[175] To a solution of 4-chloro-5-cumyl-2-phenylimidazole (see Chem. Pharm. Bull. 1976, 24 (5), 960], 5.8 g of K ₂ CO ₃ and 8.0 g of 4-bromo-1-bromomethyl-2-chlorobenzene are stirred at room temperature for 24 hours. The mixture is then diluted with 250 ml of EA and washed once each with 100 ml of water and 100 ml of saturated aqueous NaCl solution. Dry with Na ₂ SO ₄ and remove the solvent under vacuum. Chromatography on silica gel using EA / HEP 1: 4 afforded 2.2 g of a colorless oil. _Rf (EA / HEP 1: 4) = 0.47 MS (ES): 411 (M + H) <^+> .
[176] c) 3'-Chloro-4'- (4-chloro-5-formyl-2-phenylimidazol-l-ylmethyl) biphenyl-2-sulfonic acid tert-
[177] To a solution of 2.2 g of 3- (4-bromo-2-chlorobenzyl) -5-chloro-2-phenyl-3H- imidazole- Ylbenzenesulfonamide (see J. Med. Chem. 1997, 40, 547], 140 mg of triphenylphosphine, 64 mg of Pd (II) acetate and 1.2 g of Na ₂ CO ₃ are dissolved in 30 ml of toluene, 10 ml of ethanol and 10 ml of water and refluxed for 3 hours. After cooling, 200 ml of a saturated aqueous NaHCO ₃ solution is added and the mixture is extracted three times with 200 ml of EA each. And dried over MgSO _4, the solvent was removed under vacuum. Chromatograph on silica gel to give 1.5 g of colorless foam. _Rf (DIP) = 0.25 MS (ES): 542 (M + H) &lt; ⁺ & gt ^; .
[178] d) 3'-Chloro-4'- (4-chloro-5-formyl-2-phenylimidazol-l-ylmethyl) biphenyl-
[179] 1.5 g of 3'-chloro-4 '- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) Dissolved in 10 ml of trifluoroacetic acid, and stirred at room temperature for 24 hours. The volatile components are removed under vacuum, the residues are each dissolved twice in 50 ml of toluene, and the volatile components are removed again under vacuum. 1.5 g of colorless foam is obtained. _Rf (DIP) = 0.15 MS (ES): 486 (M + H) &lt; ⁺ & gt ^; .
[180] e) 3'-Chloro-4 '- [5-formyl-4- (2-methoxyethoxy) -2- phenylimidazol- 1 -yl- methyl] biphenyl-
[181] 280 mg of 3'-chloro-4 '- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) -biphenyl-2-sulfonamide and 230 mg of NaOH were dissolved in methoxyethanol Lt; / RTI &gt; for 3 hours. After cooling, the reaction mixture is dissolved in a semi-aqueous NaHCO ₃ solution and extracted three times with 100 ml of EA each. The extracts were dried with Na ₂ SO ₄ and, the solvent was removed under vacuum. 310 mg of a colorless oil is obtained which further reacts directly without purification. _Rf (EA / HEP 2: 1) = 0.37.
[182] f) Synthesis of 3'-chloro-4 '- [5-formyl-4- (2-methoxyethoxy) -2- phenylimidazol- 1 -yl- methyl] biphenyl-2-sulfonyl cyanamide
[183] Chloro-4'- [5-formyl-4- (2-methoxyethoxy) -2-phenylimidazol-1-ylmethyl) -acetamide was prepared in accordance with the general method for the preparation of the sulfonyl cyanamide from ] Biphenyl-2-sulfonamide (reaction time 1 hour) and chromatography on silica gel with EA / MeOH 1: 5 afforded 63 mg of white crystals. Melting point 195 캜 (decomposition). _Rf (EA / MeOH 1: 5) = 0.33 IR (C = N): 2178.6 cm ~ ¹ MS (ES): 552 (M + H) ⁺ .
[184] Example 3
[185] 4'- [5-formyl-2- (4-isopropylphenyl) -4- (2-methoxyethoxy) imidazol-1-yl-methyl] biphenyl-
[186]
[187] a) Preparation of 4 '- [4-chloro-5-formyl-2- (4-isopropylphenyl) imidazol- 1 -ylmethyl] biphenyl- 2- sulfonic acid dimethylaminomethyleneamide
[188] 5-chloro-2- (4-isopropylphenyl) -3H-imidazole-4-carbaldehyde [Chem. Pharm.Bull. 1976, 24 (5), 960], 1.9 g of 4'-bromomethylbiphenyl-2-sulfonic acid dimethylaminomethyleneamide and 0.69 g of K ₂ CO ₃ are suspended in 25 ml of anhydrous DMF , And stirred at room temperature for 8 hours. Further, 0.38 g of 4'-bromomethylbiphenyl-2-sulfonic acid dimethylaminomethylene amide was added, and the mixture was stirred at room temperature for further 5 hours. The reaction mixture was diluted with 10% NaHCO ₃ aqueous solution and 300㎖, each with 150㎖ EA and extracted three times. The extracts were dried with Na ₂ SO ₄ and, the solvent was removed under vacuum. Chromatography on silica gel with EA / HEP 2: 1 afforded 1.9 g of a colorless crystalline solid. Melting point 177 캜. _Rf (EA / HEP 2: 1) = 0.28 MS (ES): 550 (M + H) ⁺ .
[189] b) Preparation of 4 '- [4-chloro-5-formyl-2- (4-isopropylphenyl) imidazol-1-ylmethyl] biphenyl-
[190] 1.9 g of 4 '- [4-chloro-5-formyl-2- (4-isopropylphenyl) imidazol-1-ylmethyl] -biphenyl-2-sulfonic acid dimethylaminomethylene amide was dissolved in 35 ml of MeOH , 18 ml of aqueous HCl solution are added and the mixture is refluxed for 90 minutes. After cooling, the pH is adjusted to 5 to 6 with 6N aqueous NaOH solution and the precipitated product is filtered. Each is washed three times with 20 ml of water, and the product is dried under vacuum at 60 &lt; 0 &gt; C. 1.4 g of an amorphous solid is obtained. _Rf (EA / HEP 1: 1) = 0.25. MS (ES): 495 (M + H) @ ⁺ .
[191] c) Preparation of 4 '- [4-chloro-5-formyl-2- (4-isopropylphenyl) imidazol-1-ylmethyl] biphenyl-
[192] 198 mg of 4 '- [4-chloro-5-formyl-2- (4-isopropylphenyl) imidazol-1-ylmethyl] -biphenyl-2-sulfonamide and 166 mg of K ₂ CO ₃ were dissolved in 2 ml of anhydrous acetonitrile And 80 [mu] l of 5N BrCN in acetonitrile is injected. The mixture is refluxed for 1 hour. After cooling, the entire reaction mixture is chromatographed on silica gel using 5: 1 EA / MeOH to yield 170 mg of a crystalline solid. Melting point 217-218 占 폚 (decomposition) _Ff (EA / MeOH 5: 1) = 0.38 MS (ES): 520 (M + H) <^+> .
[193] d) Preparation of 4 '- [5-formyl-2- (4-isopropylphenyl) -4-2-methoxyethoxy) imidazol-1-ylmethyl] biphenyl-
[194] 140 mg of 4 '- [4-chloro-5-formyl-2- (4-isopropylphenyl) imidazol-1-ylmethyl] -biphenyl- Dissolve and stir at 90 [deg.] C for 105 minutes. After cooling, the mixture is dissolved in 10% aqueous NaHCO ₃ solution and extracted three times with 100 ml of EA each. Dry with Na ₂ SO ₄ and remove the solvent under vacuum. Chromatography on silica gel using EA / MeOH 10: 1 gives 90 mg of an amorphous solid. _Rf (EA / MeOH 10: 1) = 0.29 MS (ES): 559 (M + H) ⁺ _.
[195] Example 4
[196] 4'- [5-formyl-4- (2-methoxyethoxy) -2-phenylimidazol-1-ylmethyl] -3 '- (2- methoxyethoxy) Cyanamide
[197]
[198] a) 4-Methyl-3- (2-methoxy) ethoxyaniline
[199] 22.0 g of 3-hydroxy-4-methylaniline, 24.9 g of 2-bromomethyl ether and 233 g of Cs ₂ CO ₃ are dissolved in 570 ml of DMF and stirred at 40 ° C for 8 hours. One liter of a 10% aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted six times with 750 ml of EA each time and washed twice with 1 liter of a 10% aqueous solution of sodium hydrogencarbonate. Dry with sodium sulfate and remove the solvent under vacuum. 32.9 g of a yellow oil used as such is obtained. _Rf (EA / HEP 1: 1) = 0.33
[200] b) 4-Methyl-3- (2-methoxy) ethoxybromobenzene
[201] 32.8 g of 4-methyl-3- (2-methoxy) ethoxy aniline is suspended in 660 ml of a semi-aqueous HBr solution, and a solution of 12.5 g of NaNO _{3 in} 25 ml of water is slowly added dropwise at 0 캜. The mixture is then stirred at 0 ° C for 30 minutes and then this solution is slowly added to a solution of 51.9 g of CuBr in 490 ml of a saturated aqueous HBr solution and heated to 50 ° C. The reaction mixture is then slowly heated from 50 &lt; 0 &gt; C to 70 &lt; 0 &gt; C for 6 hours. After cooling, the mixture is extracted four times with 500 ml of ethyl ether each time, washed with 500 ml of a saturated aqueous solution of NaCl and dried over sodium sulfate. Chromatography on silica gel using EA / HEP 1: 8 afforded 15.4 g of a colorless oil. _Rf (EA / HEP 1: 1) = 0.41 MS (DCI): 245 (M + H) <^+> .
[202] c) 4-Bromomethyl-3- (2-methoxy) ethoxybromobenzene
[203] 15.3 g of 4-methyl-3- (2-methoxy) ethoxybromobenzene are dissolved in 300 ml of chlorobenzene, and a mixture of 11.1 g of N-bromosuccinamide and 125 mg of benzoyl peroxide is added thereto in an amount of under reflux. The mixture is refluxed for 24 hours, the solvent is removed in vacuo and the residue is dissolved in 500 mL of CH ₂ Cl ₂ . The mixture is first washed with 200 mL of a saturated aqueous Na ₂ SO ₄ solution and then with 100 mL of a saturated aqueous sodium carbonate solution. Dry with sodium sulfate and remove the solvent under vacuum. Chromatography on silica gel using EA / HEP 1:15 afforded 12.8 g of a light yellow oil. _Rf (EA / HEP 1: 4) = 0.42 MS (DCI): 323 (M + H) ⁺ .
[204] d) 3- [4-Bromo-2- (2-methoxyethoxy) benzyl] -5- chloro-2-phenyl-3H-imidazole-
[205] 970 mg of 4-bromo-1-bromomethyl-2- (2-methoxyethoxy) benzene and 415 mg of K ₂ CO ₃ were dissolved in anhydrous Suspended in 15 ml of DMF, and stirred at room temperature for 15 hours. The mixture is dissolved in 75 ml of a saturated aqueous Na ₂ CO ₃ solution and 75 ml of water and extracted three times with 100 ml of EA each. Dry with Na ₂ SO ₄ and remove the solvent under vacuum. Chromatography on silica gel with EA / HEP 1: 4 afforded 640 mg of a colorless oil. _{F f (EA / HEP 1:} 2) = 0.26 MS (ES): 450 (M + H) +.
[206] e) Preparation of 4 '- (4-chloro-5-formyl-2-phenylimidazol-l-ylmethyl) -3 '-( 2- methoxy-ethoxy) biphenyl- amides
[207] Benzyl] -5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde 620 mg, 2-dihydroxyboryl benzenesulfonic acid 3 (II) acetate and 36 mg of triphenylphosphine are dissolved in 8 ml of toluene and 2 ml of ethanol, and 1.4 ml of a 2N aqueous Na ₂ CO ₃ solution is added. The reaction mixture is refluxed for 4 hours, cooled and then diluted with 75 ml of a saturated aqueous Na ₂ CO ₃ solution and 75 ml of water. Each is extracted three times with 100 ml of EA. The extracts were dried with Na ₂ SO ₄ and, the solvent was removed under vacuum. Chromatography on silica gel with EA / HEP 1: 2 afforded 600 mg of a colorless oil. _Rf (EA / HEP 1: 2) = 0.20 MS (ES): 583 (M + H) <^+> .
[208] f) 4'- (4-Chloro-5-formyl-2-phenylimidazol-l-ylmethyl) -3 '- (2- methoxyethoxy)
[209] 4'- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) -3 '- (2'-methoxyethoxy) biphenyl- Is dissolved in 5 ml of trifluoroacetic acid, and 117 [mu] l of anisole is added. The mixture is stirred at room temperature for 8 hours and then the solvent is removed under vacuum. Chromatograph on silica gel using EA / HEP 1: 1 to give 350 mg of amorphous solid. _{R f (EA / HEP 1:} 1) = 0.27 MS (ES): 527 (M + H) +
[210] g) Synthesis of 4 '- [5-formyl-4- (2-methoxyethoxy) -2-phenylimidazol- 1 -ylmethyl] -3 '-( 2- methoxyethoxy) Sulfonamide
[211] 340 mg of 4 '- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) -3 &apos;-( 2- methoxyethoxy) biphenyl- Dissolved in 13 ml of methoxyethanol, and stirred at 90 캜 for 7 hours. After cooling, the reaction mixture is diluted with 100 ml of a 10% aqueous NaHCO ₃ solution and extracted three times with 100 ml of EA each. The extracts were dried with Na ₂ SO ₄ and, the solvent was removed under vacuum. Chromatography on silica gel with EA / HEP 2: 1 afforded 230 mg of an amorphous solid. _Rf (EA / HEP 2: 1) = 0.33 MS (ES): 566 (M + H) <^+> .
[212] h) Synthesis of 4 '- [5-formyl-4- (2-methoxyethoxy) -2-phenylimidazol- Phenylcyanamide
[213] 4'- [5-formyl-4- (2-methoxyethoxy) -2-phenylimidazol-1-ylmethyl] -3 '- (2- methoxyethoxy) biphenyl- And 154 mg of K ₂ CO ₃ are suspended in 4 ml of anhydrous acetonitrile and 74 μl of 5N BrCN solution in acetonitrile is introduced. The mixture was refluxed for 3 hours, cooled and then the entire reaction mixture was chromatographed on silica gel using EA / MeOH 10: 1 to yield 170 mg of white crystals. Melting point 162 캜. _Rf (EA / MeOH 10: 1) = 0.11 MS (ES): 591 (M + H) <^+> .
[214] Pharmacological data:
[215] Na in human endothelial cells ⁺ - Dependence Cl ^- / HCO ₃^- Exchange (NCBE) inhibitor
[216] Human endothelial cells (ECV-304) were isolated from culture bottles using trypsin / EDTA buffer (0.05 / 0.02% in phosphate buffer), centrifuged (100 g, 5 min) / L: 115 NaCl, 20 NH ₄ Cl, 5 KCl, 1 CaCl ₂ , 1 MgSO ₄ , 20 N- (2-hydroxyethyl) -piperazine-N-2-ethanesulfonic acid (HEPES) 1 g / l bovine serum albumin, pH 7.4). The cell suspension is incubated with 5 [mu] M BCECF-acetoxymethyl ester at 37 [deg.] C for 20 minutes. Then, the cells were washed, and sodium- and bicarbonate-free buffer solution (mmol / ℓ: 5HEPES, 133.8 choline _{chloride, 4.7KCl, 1.25 MgCl 2, 0.97} K 2 HPO 4, 0.23 KH 2 PO 4, 5 glucose; pH 7.4). Subsequently, for fluorescence measurement in a FLIPR (Fluorescence Shape Plate Reader), 100 쨉 l of the cell suspension with 20,000 cells in each case was pipetted per well into 96-well microtiter plates and the microtiter plates were centrifuged (100 g, 5 minutes). In FLIPR, 100 [mu] l of buffer in each case is removed from the additional pretreated microtiter plate and pipetted into each 96 well assay plate. Bicarbonate containing 50μM HOE 642-and sodium-containing buffer solution (mmol / ℓ: 5 HEPES, 93.8 NaCl, 40 NaHCO 3, 4.7 KCl, 1.25 CaCl 2, 1.25 MgCl 2, 0.97 Na 2 HPO 4, 0.23 NaH 2 PO 4 , 5 glucose, pH 7.4) is used for the recovery of intracellular pH (pH _i ) via a 100% control, ie NCBE. 0% control, i.e. pH _i recovery is not at all, and bicarbonate-free, sodium-containing buffer solution (mmol / ℓ: 5 HEPES, 133.8 NaCl, 4.7 KCl, 1.25 CaCl 2, 1.25 MgCl 2, 0.97 Na 2 HPO 4, 0.23 NaH ₂ PO ₄ , 5 glucose; pH 7.4) was similarly added with 50 μM of HOE 642. Various concentrations of sodium- and bicarbonate-containing solutions are added to the compounds according to the invention. After addition of the buffer for dye-loading, the cells in the assay plate are acidified and the increase in fluorescence corresponding to the rise in pH _i in each well of the microtiter plate is measured. In this case, the change is recorded at 35 DEG C for 2 minutes. Increasing the fluorescence of different concentrations of the compounds according to the present invention associated with the two controls and their substrate inhibition activity are measured.
[217] result
[218] Remaining activity (%) of NCBE at the inhibitor concentration of 10 [mu] M
[219] Compound of Example No.One9.8 218.9 329.6 413.5

权利要求:
Claims (15)
[1" claim-type="Currently amended] A compound of formula I or a physiologically acceptable salt thereof.
Formula I

In this formula,
R 1 is hydrogen, alkyl of 1 to 8 carbon atoms or -C _a H _2a -phenyl wherein the phenyl moiety is fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR 8 R 9, Are each independently hydrogen or alkyl of 1 to 4 carbon atoms, and a is 0, 1, or 2, or is hydrogen,
R 1 is -C _b H _2b -heteroaryl having 1 to 9 carbon atoms wherein the heteroaryl moiety is fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR 10 R 11 wherein R 10 and R 11 are 2 or 3 identical or different radicals from the group consisting of hydrogen or alkyl of 1 to 4 carbon atoms, and b is 0, 1 or 2,
R1 is -C _d H _2d -cycloalkyl having 3 to 7 carbon atoms, wherein d is 0, 1 or 2;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, CF ₃ , -CN, -NO ₂ , CH ₂ OR 17, CO-R 6, O- -O-R17 or NR50R51 wherein R17 is hydrogen or alkyl of 1 to 8 carbon atoms; R6 is hydrogen, alkyl, OR30 with 1 to 8 carbon atoms (wherein, R30 is hydrogen or alkyl of 1 to 8 carbon atoms), or F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR31R32 ( Wherein R31 and R32 are each independently hydrogen or alkyl of 1 to 4 carbon atoms; and R &lt; 2 &gt; is phenyl which is unsubstituted or substituted with 1, 2 or 3 of the same or different radicals from the group consisting of R &lt; R50 and R51 are each independently - (alkylene of 2 to 4 carbon atoms) -O-R52 (wherein R52 is hydrogen or alkyl of 1 to 8 carbon atoms); R7 is hydrogen, C 1 -C 8 alkyl, or F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR12R13 (wherein, R12 and R13 are each independently hydrogen or alkyl of 1 to 4 carbon atoms a) with or phenyl which is unsubstituted or substituted with one, two or three identical or different radicals from the group consisting of, R7 is F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR14R15 (wherein, R14 and R15 are each independently hydrogen or alkyl of 1 to 4 carbon atoms, or a heteroaryl having 1 to 9 carbon atoms which is unsubstituted or substituted by 1, 2 or 3 same or different radicals from the group consisting of
R2 and R3 are each independently a C 1 -C 8 alkyl, cycloalkyl having 3 to 7-alkyl, or -C _g H _2g - phenyl [wherein the phenyl moieties are fluorine, chlorine, bromine, iodine, CF _3, methyl, methoxy 2 or 3 of the same or different radicals from the group consisting of halogen, hydroxy, or NR18R19, wherein R18 and R19 are each independently hydrogen or alkyl of from 1 to 4 carbon atoms; g is 0, 1 or 2,
R2 and R3 are each independently a carbon number of 1 to 9, -C _l H _2l - heteroaryl [wherein the heteroaryl moiety is F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR20R21 (wherein, R20 and R21 are each independently hydrogen or alkyl of 1 to 4 carbon atoms; and l is 0, 1 or 2,
R 2 and R 3 are each independently SO _n -R 22 wherein n is 0, 1 or 2; R22 is cycloalkyl or C _S -C _2S C 1 -C 8 alkyl, having from 3 to 7 carbon atoms of the phenyl [wherein, C _S -C _2S-phenyl is F, Cl, Br, I, CF _3, methyl, methoxy , Hydroxyl or NR34R35 wherein R34 and R35 are each independently hydrogen or alkyl of 1 to 4 carbon atoms, s is 0, 1 or 2, 1 or 2;
R4 and R5 are each independently hydrogen, alkyl of 1 to 8 carbon atoms, F, Cl, Br, _{I, CF 3, -CN, -NO 2} , SO P -R16, CO-R23, O-R24 or O- ( Alkyl having 2 to 4 carbon atoms) -O-R33 (wherein p is 0, 1 or 2; R16 is C1-alkyl or phenyl to 8 [wherein the phenyl is F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR26R27 (wherein R26 and R27 are each independently hydrogen or C 1 -C 2, or 3 identical or different radicals from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaryl, heteroaryl, R23 is hydrogen, alkyl having 1 to 8 carbon atoms or OR25 wherein R25 is hydrogen or alkyl having 1 to 8 carbon atoms; R24 is hydrogen, alkyl or phenyl group having 1 to 8 carbon atoms [wherein the phenyl is F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR28R29 (wherein R28 and R29 are hydrogen or carbon atoms are each independently 1 to 4 alkyl), or is unsubstituted or substituted with one, two or three identical or different radicals from the group consisting of And R &lt; 33 &gt; is hydrogen or alkyl having 1 to 8 carbon atoms, provided that at least one of the radicals R2 or R3 is O- (alkylene having 2 to 4 carbon atoms) -O-R17 or NR50R51.
[2" claim-type="Currently amended] 2. A compound according to claim 1, wherein R <1> is alkyl of 1-4 carbon atoms or -C _a H _2a -phenyl, wherein the phenyl moiety is fluorine, chlorine, bromine, CF ₃ , methyl, methoxy, hydroxyl, R8 and R9 are each independently hydrogen or methyl), and a is 0 or 1;
Wherein R 1 is a radical selected from the group consisting of fluorine, chlorine, bromine, CF ₃ , CH ₃ , methoxy, hydroxyl or NR 10 R 11 (wherein R 10 and R 11 are each independently hydrogen or methyl) 1 to 9 heteroaryl,
R1 is -C _d H _2d -cycloalkyl having 3 to 7 carbon atoms, wherein d is 0 or 1;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, CF ₃ , -CN, -NO ₂ , CH ₂ OR 17, CO-R 6, -O- O-R17 or NR50R51 wherein R17 is hydrogen or alkyl of 1 to 4 carbon atoms; R6 is hydrogen, alkyl, OR30 group having 1 to 4 carbon atoms (wherein, R30 is hydrogen or alkyl of 1 to 4 carbon atoms), or phenyl; wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl Or NR31R32, wherein R31 and R32 are each independently hydrogen or methyl, or is substituted or unsubstituted with one or two of the same or different radicals; R7 is hydrogen, alkyl or phenyl group having 1 to 4 carbon atoms [wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR12R13 (wherein, R12 and R13 is hydrogen or methyl, each independently) 1 or 2 of the same from the group consisting of, or is unsubstituted or substituted with a different radical], or, or R7 is a heteroaryl group having 1 to 9 carbon atoms; wherein heteroaryl is F, Cl, Br, CF _3, methyl, methoxy , Hydroxyl or NR14R15, wherein R14 and R15 are each independently hydrogen or methyl, or is substituted or unsubstituted with one or two identical or different radicals; R50 and R51 each independently represent - (alkylene having 2 or 3 carbon atoms) -O-R52 (wherein R52 is hydrogen or alkyl having 1 to 4 carbon atoms)
R2 and R3 are each independently C 1 -C 4 alkyl, cycloalkyl, or -C _g H _2g of 3 to 7 carbon atoms [wherein the phenyl moieties are fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl or NR18R19, wherein R18 and R19 are each independently hydrogen or methyl, and g is 0 or 1;
Heteroaryl of R2 and R3 is a group having 1 to 9 each independently [wherein heteroaryl is F, Cl, Br, CF _3, methyl, methoxy, hydroxyl, or NR20R21 (wherein R20 and R21 are each independently hydrogen or Lt; / RTI &gt; is methyl, or is substituted or unsubstituted with a radical from the group consisting of &
Each of R2 and R3 independently represents a SO _n -R22 {wherein, n is 0, 1 or 2; R22 is cycloalkyl or -C _s H _2s C 1 -C 4 alkyl, 3 to 7 carbon atoms of the phenyl [wherein the phenyl moieties are fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR34R35 (wherein , R34 and R35 are each independently hydrogen or methyl); s is 0 or 1;
R4 and R5 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, F, Cl, _{Br, CF 3, -CN, -NO 2} , SO P -R16, CO-R23, O-R24 or O- (C2- Or-3-alkylene) -O-R33, wherein p is 0, 1 or 2; Consisting of R16 is alkyl or phenyl, [C 1 to 4 wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR26R27 (wherein, R26 and R27 is hydrogen or methyl, each independently) Lt; / RTI &gt; is unsubstituted or substituted with one or two identical or different radicals from the group; R23 is hydrogen, alkyl having 1 to 4 carbon atoms or OR25, wherein R25 is hydrogen or alkyl having 1 to 4 carbon atoms; R24 is hydrogen, alkyl or phenyl group having 1 to 4 carbon atoms [wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR28R29 (wherein, R28 and R29 is hydrogen or methyl, each independently) &Lt; / RTI &gt; is unsubstituted or substituted with one or two identical or different radicals from the group consisting of &lt; RTI ID = 0.0 &gt; R33 is hydrogen or alkyl having 1 to 4 carbon atoms, provided that at least one of the radicals R2 or R3 is O- (alkylene having 2 or 3 carbon atoms) -O-R17 or NR50R51 or a physiologically acceptable A salt thereof.
[3" claim-type="Currently amended] _3. A compound according to claim 1 or 2, wherein R <1> is hydrogen, alkyl having 1 to 4 carbon atoms or phenyl wherein the phenyl is fluorine, chlorine, bromine, CF3, methyl, methoxy, hydroxyl or NR8R9, And R &lt; 9 &gt; are each independently hydrogen or methyl,
R1 is made of a heteroaryl group having 1 to 9 carbon atoms; wherein heteroaryl is F, Cl, Br, CF _3, methyl, methoxy, hydroxyl, or NR10R11 (wherein, R10 and R11 is hydrogen or methyl, each independently) Substituted or unsubstituted radicals from the group,
R1 is cycloalkyl having 3 to 7 carbon atoms;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, CF ₃ , -CN, -NO ₂ , CO-R 6, O-R 7, O-CH ₂ -CH ₂ -O- is hydrogen, alkyl, OR30 having 1-4 carbon atoms [wherein, R30 is hydrogen or alkyl of 1 to 3 carbon atoms or phenyl; wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl or NR31R32, wherein R31 and R32 are each independently hydrogen or methyl; R7 is hydrogen, alkyl or phenyl group having 1 to 4 carbon atoms [wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR12R13 (wherein, R12 and R13 is hydrogen or methyl, each independently) a substituted or unsubstituted by a radical from the group consisting of - or, R7 is heteroaryl [having 1 to 9 carbon atoms, where the heteroaryl is F, Cl, Br, CF _3, methyl, methoxy, hydroxyl, or NR14R15 (wherein , R &lt; 14 &gt; and R &lt; 15 &gt; are hydrogen or methyl); R17 is methyl or ethyl; R50 and R51 are each independently -CH ₂ -CH ₂ -O-R52 (wherein, R52 is methyl or ethyl)} or,
R2 and R3 are each independently a cycloalkyl or phenyl-C 1 -C 4 alkyl, C 3 -C 7 [wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR18R19 (R18 and R19 Are each independently hydrogen or methyl), or a group of the formula &lt; RTI ID = 0.0 &gt;
Heteroaryl of R2 and R3 is a group having 1 to 9 each independently [wherein heteroaryl is F, Cl, Br, CF _3, methyl, methoxy, hydroxyl, or NR20R21 (wherein R20 and R21 are each independently hydrogen or Lt; / RTI &gt; is methyl, or is substituted or unsubstituted with a radical from the group consisting of &
R2 and R3 are each independently SO _n -R 22 wherein n is 0 or 2; R22 is cycloalkyl or phenyl; wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR34R35 (wherein R34 and R35 of the group having 1 to 4 carbon alkyl, 3 to 7 carbon atoms of are each independently Lt; / RTI &gt; is hydrogen or methyl), or is substituted or unsubstituted with one or two identical or different radicals from the group consisting of
R4 and R5 are each independently hydrogen, alkyl of 1 to 4 carbon atoms, F, _{Cl, CF 3, -CN, -NO 2} , SO P -R16, CO-R23, O-R24 or O-CH ₂ -CH ₂ -O-R &lt; 33 &gt; wherein p is 0 or 2; R23 is hydrogen, alkyl having 1 to 4 carbon atoms or OR25 wherein R25 is hydrogen or alkyl having 1 to 3 carbon atoms; R24 is hydrogen, alkyl or phenyl group having 1 to 4 carbon atoms [wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR28R29 (wherein, R28 and R29 is hydrogen or methyl, each independently) &Lt; / RTI &gt; is substituted or unsubstituted with a radical from the group consisting of &lt; RTI ID = 0.0 &gt; Consisting of R16 is alkyl or phenyl, [C 1 to 4 wherein the phenyl is fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl, or NR26R27 (wherein, R26 and R27 is hydrogen or methyl, each independently) Substituted or unsubstituted radicals from the group; Wherein R 33 is methyl or ethyl, provided that at least one of the radicals R 2 or R 3 is O-CH ₂ -CH ₂ -O-R 17 or NR 50 R 51, or a physiologically acceptable salt thereof.
[4" claim-type="Currently amended] Claim 1 to claim 3 Compounds according to any one of the preceding, R1 is alkyl or phenyl (wherein the carbon number of 1 to 4 and the phenyl is unsubstituted or substituted by radicals from the group consisting of F, Cl, CF _3, methyl or methoxy Or,
R1 is a heteroaryl group having 1 to 9 carbon atoms or (wherein heteroaryl is radical of a substituted or unsubstituted ring is from the group consisting of F, Cl, CF _3, methyl or methoxy),
R1 is cycloalkyl having 3 to 7 carbon atoms;
R2 and R3 are each independently H, F, _{Cl, CF 3, -CN, CO-} R6, O-R7, O-CH 2 -CH 2 -O-CH 3 or NR50R51 [wherein, R6 is hydrogen, C1- to the 4-alkyl, OR30 (where R30 is hydrogen, methyl or ethyl), or phenyl, and (wherein the phenyl radical substituted or is switched to the from the group consisting of F, Cl, CF _3, methyl or methoxy) ; R7 is hydrogen, alkyl or phenyl group having 1 to 4 carbon atoms (wherein the phenyl is unsubstituted or substituted by radicals from the group consisting of F, Cl, CF _3, methyl or methoxy), or, R7 is a group having a carbon number of 1 to 9 heteroaryl (wherein heteroaryl is F, Cl, CF _3, methyl or methoxy radical substituted or non-substituted ring is in the from the group consisting of a) and; R 50 and R 51 are -CH ₂ -CH ₂ -O-CH ₃ ,
R2 and R3 are each independently a cycloalkyl or phenyl group having 1 to 4 carbon alkyl, 3 to 7 carbon atoms (where the phenyl is unsubstituted or substituted by radicals from the group consisting of F, Cl, CF _3, methyl or methoxy Or,
R2 and R3 are each a C 1 -C 9 heteroaryl independently or (where the heteroaryl radical is substituted or non-substituted ring is in the from the group consisting of F, Cl, CF _3, methyl or methoxy),
R2 and R3 are each independently SO _n -R 22 wherein n is 0 or 2; R22 is C 1 -C 4 alkyl or phenyl (wherein phenyl is fluorine, chlorine, CF _3, methyl or methoxy is unsubstituted or substituted by one or two identical or different radicals from the group consisting of a) and;
R4 and R5 are each independently hydrogen, methyl, F, _{Cl, CF 3, -CN, SO 2} -R16, CO-R23, O-R24 or _{O-CH 2 -CH 2 -O-} CH 3 [ where, R16 It is C 1 -C 4 alkyl or phenyl, and (wherein the phenyl is fluorine, chlorine, CF _3, methyl or methoxy radical substituted or non-substituted ring is in the from the group consisting of a); R23 is hydrogen, methyl or OR25, wherein OR25 is hydrogen, methyl or ethyl; R24 is hydrogen, alkyl or phenyl group having 1 to 4 carbon atoms (wherein the phenyl radical substituted or is switched to the from the group consisting of F, Cl, CF _3, methyl or methoxy); provided that, with the proviso that the radical R2 or R3 one or more of the _{O-CH 2 -CH 2 -O-} CH 3 or a salt thereof acceptable compound or physiologically NR50R51 of the formula I.
[5" claim-type="Currently amended] The method according to any one of the preceding claims 4, wherein, R1 is an alkyl group having 1 to 8 carbon atoms, -C _d H _2d having a carbon number of 3 to 7 -cycloalkyl (where, d is 0, 1 or 2) or - C _a H _2a -phenyl wherein the phenyl moiety is selected from the group consisting of fluorine, chlorine, bromine, iodine, CF ₃ , methyl, methoxy, hydroxyl or NR 8 R 9 wherein R 8 and R 9 are each independently hydrogen or alkyl of 1 to 4 carbons 2 or 3 of the same or different radicals; a is 0, 1 or 2;
R2 is O- (alkylene having 2 to 4 carbon atoms) -O-R17 or NR50R51 wherein R17 is hydrogen or alkyl having 1 to 8 carbon atoms; R50 and R51 are each independently - (alkylene of 1 to 8 carbon atoms) -O-R52, wherein R52 is hydrogen or alkyl of 1 to 8 carbon atoms;
R3 is hydrogen, -CN or CO-R6 wherein R6 is hydrogen, alkyl of 1 to 8 carbon atoms or OR30 wherein R30 is hydrogen or alkyl of 1 to 8 carbon atoms;
R4 is hydrogen, chlorine, fluorine, bromine, iodine, SO _P -R16 or _{O-CH 2 -CH 2 -O-} R33 { where, p is 0, 1 or 2; R16 is C1-alkyl or phenyl to 8 [wherein the phenyl is F, Cl, Br, I, CF _3, methyl, methoxy, hydroxyl, or NR26R27 (wherein R26 and R27 are each independently hydrogen or C 1 -C 4 &gt;); R33 is methyl or ethyl;
Lt; 5 &gt; is hydrogen, or a physiologically acceptable salt thereof.
[6" claim-type="Currently amended] The method according to any one of claims 1 to 5, R1 is -C _a H _2a - phenyl [wherein the phenyl moieties are fluorine, chlorine, bromine, CF _3, methyl, methoxy, hydroxyl or NR8R9 (wherein R8 and R9 are each independently hydrogen or methyl), and a is 0 or 1;
R2 is O- (alkyl having 2 to 4 carbon atoms) -O-R17 or NR50R51 wherein R17 is alkyl having 1 to 4 carbon atoms; R50 and R51 are each independently - (alkylene of 2 to 4 carbon atoms) -O-R52, wherein R52 is alkyl of 1 to 4 carbon atoms;
R3 is CO-R6, wherein R6 is hydrogen;
R4 is SO ₂ R16 (wherein, R16 is alkyl of 1 to 4 carbon atoms), or _{O-CH 2 -CH 2 -O-} CH 3 , and;
Lt; 5 &gt; is hydrogen, or a physiologically acceptable salt thereof.
[7" claim-type="Currently amended] A compound according to any one of claims 1 to 6, wherein R ₂ is O-CH ₂ -CH ₂ -O-R 17 or NR 50 R 51 wherein R 17 is alkyl of 1 to 4 carbon atoms, R 50 and R 51 are -CH ₂ - CH ₂ -O-R 52, wherein R 52 is alkyl having from 1 to 4 carbon atoms, or a physiologically acceptable salt thereof.
[8" claim-type="Currently amended] 8. A compound according to any one of claims 1 to 7 for use as a medicament, or a physiologically acceptable salt thereof.
[9" claim-type="Currently amended] 7. A pharmaceutical preparation comprising an effective amount of a compound of formula I according to any one of claims 1 to 7 or a physiologically acceptable salt thereof.
[10" claim-type="Currently amended] The pharmaceutical preparation according to claim 9, further comprising an effective amount of an NHE inhibitor and / or another class of active substance of a cardiovascular active compound, and / or a physiologically acceptable salt thereof.
[11" claim-type="Currently amended] 8. A compound of formula I according to any one of claims 1 to 7, or a physiologically acceptable salt thereof, useful as a sodium-dependent bicarbonate / chloride exchange inhibitor.
[12" claim-type="Currently amended] 8. The method according to any one of claims 1 to 7, wherein the disease is selected from the group consisting of myocardial infarction, angina pectoris, diseases caused by ischemic symptoms, respiratory movement disorders, cardiac ischemic symptoms, ischemic symptoms of peripheral and central nervous system, seizures, For use in the preservation and storage of implants for the treatment and / or prophylaxis of diseases in which cell proliferation is the first and second cause, for the treatment of shock conditions, for surgical procedures and organ transplantation, or for surgical treatment, A compound or a physiologically acceptable salt thereof.
[13" claim-type="Currently amended] 8. The use according to any one of claims 1 to 7 for the preparation of a compound of formula I or a physiologically acceptable salt thereof for use as an antiatherosclerotic agent, a late diabetic complication, an autoimmune disease, a fibrotic disease or a hypertrophy and / A pharmaceutically acceptable salt thereof.
[14" claim-type="Currently amended] 11. The method according to claim 9 or 10, wherein the disease is selected from the group consisting of myocardial infarction, angina pectoris, ischemic symptom, respiratory movement disorder, ischemic heart disease, ischemic symptom of peripheral and central nervous system, seizure, A pharmaceutical formulation for use in the preservation and storage of implants for the treatment and / or prevention of diseases which are the first and second cause, the treatment of shock conditions, surgical operations and organ transplantation or surgical treatment.
[15" claim-type="Currently amended] 11. A pharmaceutical formulation according to claim 9 or 10 for use in the preparation of an anti-atherosclerotic agent, an agent for late diabetic complications, cancerous disease, fibrotic disease or hypertrophy and / or hyperplasia.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1998-07-18|Priority to DE19832428A

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1998-07-18|Priority to DE19832428.6

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1999-07-10|Application filed by 로버트 흐라이탁, 미쉘 베스트, 아벤티스 파마 도이칠란트 게엠베하

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1999-07-10|Priority to PCT/EP1999/004887

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2001-07-31|Publication of KR20010071957A

优先权:

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申请号 | 申请日 | 专利标题

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DE19832428A|DE19832428A1|1998-07-18|1998-07-18|New imidazolylmethyl-biphenyl-sulfonylcyanamides, are sodium-dependent bicarbonate/chloride exchanger inhibitors used e.g. for treating cardiovascular disorders such as cardiac infarction|

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DE19832428.6|1998-07-18|

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PCT/EP1999/004887|WO2000003996A1|1998-07-18|1999-07-10|Imidazole derivatives with biphenylsulfonyl substitution, method for preparing them and their use as a drug or diagnostic agent|