• 专利附录
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    • 专利摘要:
    The compound of formula 1 is a very useful substance for the manufacture of a medicament for the prevention and treatment of heart disease, especially arrhythmia, for the treatment of gastric ulcer or diarrhea disease. Formula 1 In Chemical Formula 1, R (1) to R (9) and B are as defined in the claims.
    公开号:KR19990030120A
    申请号:KR1019980039836
    申请日:1998-09-25
    公开日:1999-04-26
    发明作者:요아힘 브렌델；우베 게를라흐；한스 요헨 랑；클라우스 바이트만
    申请人:로버트 흐라이탁, 미쉘 베스트；훽스트 마리온 뤼쎌 도이치란드 게엠베하；
    IPC主号:
    专利说明:

    Sulfonamide-substituted cromanns, methods for their preparation, their use as medicaments and pharmaceutical preparations comprising the same
    The present invention relates to compounds of formula (1), their preparation and especially their use in medicaments.
    In Formula 1 above,
    R (1), R (2), R (3), R (4), R (5), R (6), R (7), R (8), R (9) and B are defined below It is as follows.
    The compound affects potassium channels or I Ks that are opened by cyclic adenosine monophosphate (cAMP), and are for example agents for the prevention and treatment of heart diseases, especially arrhythmias, for the treatment of gastric ulcers or for the treatment of diarrhea diseases. Remarkably suitable as a pharmaceutically active compound.
    In recent years, the class of 4-acylaminochroman derivatives has been intensively studied in the field of pharmacy. The best representative of this class is the chromakalim of formula (II). J. Med. Chem. 1986, 29, 2194].
    Chromakalim and other related 4-acylaminochroman derivatives are compounds that relax the smooth muscle organs, so they are used to relax vascular muscles, lower elevated blood pressure, and relax the airways smooth muscles to treat asthma. All these agents typically act at the cellular (eg smooth muscle cell) level to open certain ATP-sensitive K + channels in the cell. Increasing the negative charge (hyperpolarization) in cells induced by the outflow of K + ions prevents the increase of intracellular Ca 2+ concentration through another mechanism, thereby inhibiting cellular activation, e.g., inducing muscle contraction. do.
    The compounds of formula (1) according to the invention differ from these acylamino derivatives in structure, in particular by acylamino groups being substituted by sulfonylamino functional groups. Chromakalim (Formula 2) and acylamino compound homologues act as openers of the ATP-sensitive K + channel, while compounds of formula (1) according to the invention having a sulfonylamino structure open the K + (ATP) channel. It does not act, but surprisingly it has a strong and specific blocking (blocking) action against K + channels opened by cyclic adenosine monophosphate (cAMP) and is fundamentally different from the K + (ATP) channels mentioned. More recent studies have shown that K + (cAMP) channels identified in colon tissue are very similar to, and may be identical to, I Ks channels identified in cardiac muscle. In fact, the compounds of formula (1) according to the present invention may exhibit strong blocking action against I Ks channels in cardiomyocytes of guinea-pig and also I sk channels expressed in Xenopus oocytes. The compounds according to the invention thus exhibit a pharmacological action with high therapeutic utility in vivo by blocking K + (cAMP) channels or I Ks channels.
    In addition, apart from the above-mentioned chromacalim or acylaminochroman derivatives, there are documents which have a 4-sulfonylaminochroman structure, which differs markedly from the compound of formula 1 according to the present invention in both structure and biological action. It is described in. Therefore, EP-A-315 009 discloses a chroman derivative having a 4-phenylsulfonylamino structure which is excellent in antithrombogenicity and antiallergic property. EP-A-389 861 and JP 01294677 describe chromate derivatives having a 3-hydroxychroman or cyclic 4-sulfonylamino group (e.g., formula 3), which activate the K + (ATP) channel. Acts as a blood pressure lowering agent. EP-A-370 901 describes chromen derivatives having a 4-sulfonylamino group in which the remaining bonds of 3-hydroxychroman or N atoms are covalently bonded to a hydrogen atom, which acts as a CNS. Additional 4-sulfonylaminochroman derivatives are described in the literature. Bioorg. Med. Chem. Lett. 4 (1994), 769-773, N-sulfonamides of benzopyran-related potassium channel openers: conversion of glyburyde insensitive smooth muscle relaxants to potent smooth muscle contractors; FEBS Letters 396 (1996), 271-275, Specific blockade of slowly activating I sk channels by chromanols ....; Pflugers Arch. -Eur. J. Physiol. 429 (1995), 517-530, A new class of inhibitors of cAMP-mediated Cl - secretion in rabbit colon, acting by the reducton of cAMP-activated K + conductance.
    It is an object of the present invention to provide pharmaceutically active compounds for the prevention and treatment of heart diseases, in particular arrhythmia, the treatment of gastric ulcers or diarrhea diseases by blocking K + (cAMP) or I ks channels.
    The present invention relates to compounds of formula 1 and physiologically acceptable salts thereof.
    Formula 1
    In Formula 1 above,
    R (1) and R (2) are independently of each other hydrogen, CF 3 , C 2 F 5 , C 3 F 7 , alkyl of 1 to 6 carbon atoms, or unsubstituted, F, Cl, Br, I, CF 3 Or phenyl substituted with one or two substituents selected from the group consisting of NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino,
    R (1) and R (2) together form an alkylene chain of 2 to 10 carbon atoms,
    R (3) is R (10) -C n H 2n -NR (11)-or R (10) -C n H 2n- {where one CH 2 group in the C n H 2n group is -O-, -CO-, -S-, -SO-, -SO 2- , or -NR (12a)-, wherein R (12a) is hydrogen, methyl or ethyl]; R (10) is hydrogen, methyl, cycloalkyl having 3 to 8 carbon atoms, CF 3 , C 2 F 5 or C 3 F 7 ; n is an integer from 0 to 10; R (11) is hydrogen or alkyl of 1 to 6 carbon atoms; when n is less than 3, R (10) and R (11) together form a bond} or
    R (3) together with R (4) is an alkylene chain of 3 to 8 carbon atoms, wherein one CH 2 group of the alkylene chain is -O-, -CO-, -S-, -SO-, -SO 2 -or -NR (12a)-, wherein R (12a) can be substituted with hydrogen, methyl or ethyl}, and
    R (4) is R (13) -C r H 2r {wherein one CH 2 group of the C r H 2r group is -O-, -CH = CH-, -C≡C-, -CO-,- CO-O-, -O-CO-, -S-, -SO-, -SO 2- , -NR (14)-or -CONR (14)-[where R (14) is hydrogen, 1 to C Alkyl of 3, -C y H 2y -OR (12b) or -C y H 2y -NR (12b) 2 , wherein R (12b) is hydrogen, methyl or ethyl and y is 2 or 3] ego; R (13) is H, CF 3 , C 2 F 5 , C 3 F 7 , cycloalkyl having 3 to 8 carbon atoms, -NR (15) R (16), -CONR (15) R (16), -OR (17), -COOR (17), phenyl or an N-containing heterocycle having 1 to 9 carbon atoms, wherein the phenyl and N-containing heterocycle are unsubstituted or substituted with F, Cl, Br, I, CF 3 , NO 2 Or substituted with one or two substituents selected from the group consisting of CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15) and R (16) are independently of each other hydrogen or alkyl having 1 to 4 carbon atoms; R (15) and R (16) together form 4 or 5 methylene group chains, where one CH 2 group is -O-, -S-, -NH-, -N (CH 3 )-or -N ( Benzyl)-); R (17) is hydrogen, alkyl of 1 to 3 carbon atoms or -C x H 2x OR (12c), wherein R (12c) is hydrogen, methyl or ethyl and x is 2 or 3); r is an integer from 0 to 20},
    One or more substituents of R (5), R (6), R (7) and R (8) may be -YC S H 2S -R (18), thienyl, furyl or an N-containing heterocycle having 1 to 9 carbon atoms. {Wherein thienyl, furyl and N-containing heterocycle are unsubstituted or F, Cl, Br, I, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, methylamino, dimethyl Substituted with one or two substituents selected from the group consisting of amino, ethylamino, diethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; Y is -O-, -CO-, -O-CO-, -S-, -SO-, -SO 2- , -SO 2 -O-, -SO 2 NR (12d)-, -NR (12d) Or -CONR (12d)-, wherein the bond to the benzene nucleus is in each case via the left atom and R (12d) is hydrogen, methyl or ethyl]; s is an integer from 1 to 6; R (18) is a substituent selected from the group consisting of NO 2 , CN, NH 2 , N (methyl) 2 , OH, ethyl, -COOH, -COOmethyl, -COOethyl, -CONH 2 and -CON (methyl) 2 Phenyl substituted with one or two; R (18) is a group consisting of F, Cl, Br, I, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino N-containing heterocycle having 1 to 9 carbon atoms substituted with one or two substituents selected from; R (18) is -OR (19), -SO 2 R (19), -NR (19) R (20), -CONR (19) R (20), where R (19) and R (20) Are independently of each other C t H 2t -R (21) (where t is an integer from 0 to 6; R (21) is hydrogen, CF 3 , C 2 F 5 , C 3 F 7 , carbon atoms of 3 to 8 Cycloalkyl, NR (22) R (23), -OR (24), phenyl, thienyl or N-containing heterocycle having 1 to 9 carbon atoms, wherein phenyl, thienyl and N-containing heterocycle are unsubstituted, One substituent selected from the group consisting of F, Cl, Br, I, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino or Are substituted in two; R (22) and R (23) are independently of each other hydrogen or alkyl of 1 to 3 carbon atoms; R (22) and R (23) together are 4 or 5 methylene group chains, wherein CH 2 groups form -O-, -S-, -NH-, -N (CH 3 )-or -N (benzyl)-); and R (24) can be hydrogen or carbon Is alkyl of 1 to 3).
    The remaining substituents R (5), R (6), R (7) and R (8), not defined above, are, in each case, independently of one another, hydrogen, F, Cl, Br, I, alkyl having 1 to 5 carbon atoms. , Cycloalkyl having 3 to 8 carbon atoms, CN, CF 3 , NO 2 , OR (12e) or NR (12e) R (12f) {where R (12e) and R (12f) are independently of each other hydrogen or 1 carbon To alkyl of 4 to 4; R (9) is hydrogen, OR (12g) or OCOR (12g), where R (12g) is hydrogen or alkyl of 1 to 3 carbon atoms,
    B is hydrogen,
    R (9) and B together form a bond.
    Preferred compounds of formula (1) are
    R (1) and R (2) are independently of each other hydrogen, CF 3 , C 2 F 5 , C 3 F 7 , alkyl of 1 to 6 carbon atoms, or unsubstituted, F, Cl, Br, I, CF 3 Or phenyl substituted with one or two substituents selected from the group consisting of NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino,
    R (1) and R (2) together form an alkylene chain of 2 to 10 carbon atoms,
    R (3) is R (10) -C n H 2n -NR (11)-or R (10) -C n H 2n- {where one CH 2 group in the C n H 2n group is -O-, -CO-, -S-, -SO-, -SO 2- , or -NR (12a)-, wherein R (12a) is hydrogen, methyl or ethyl]; R (10) is hydrogen, methyl, cycloalkyl having 3 to 8 carbon atoms, CF 3 , C 2 F 5 or C 3 F 7 ; n is an integer from 0 to 10; R (11) is hydrogen or alkyl of 1 to 6 carbon atoms; when n is 3 or more, R (10) and R (11) together form a bond} or
    R (3) together with R (4) is an alkylene chain of 3 to 8 carbon atoms, wherein one CH 2 group of the alkylene chain is -O-, -CO-, -S-, -SO-, -SO 2 -or -NR (12a)-, wherein R (12a) can be substituted with hydrogen, methyl or ethyl}, and
    R (4) is R (13) -C r H 2r {wherein one CH 2 group in the C r H 2r group is -O-, -CH = CH-, -C≡C-, -CO-,- CO-O-, -O-CO-, -S-, -SO-, -SO 2- , -NR (14)-or -CONR (14)-[where R (14) is hydrogen, 1 to C Alkyl of 3, -C y H 2y -OR (12b), -C y H 2y -NR (12b) 2 , wherein R (12b) is hydrogen, methyl or ethyl and y is 2 or 3] ego; R (13) is H, CF 3 , C 2 F 5 , C 3 F 7 , cycloalkyl having 3 to 8 carbon atoms, -NR (15) R (16), -CONR (15) R (16), -OR (17), -COOR (17), phenyl or an N-containing heterocycle having 1 to 9 carbon atoms, wherein the phenyl and N-containing heterocycle are unsubstituted or substituted with F, Cl, Br, I, CF 3 , NO 2 Or substituted with one or two substituents selected from the group consisting of CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15) and R (16) are independently of each other hydrogen or alkyl having 1 to 4 carbon atoms; R (15) and R (16) together form 4 or 5 methylene group chains, where one CH 2 group is -O-, -S-, -NH-, -N (CH 3 )-or -N ( Benzyl)-); R (17) is hydrogen, alkyl of 1 to 3 carbon atoms, or -C x H 2x OR (12c), wherein R (12c) is hydrogen, methyl or ethyl and x is 2 or 3); r is an integer from 0 to 20},
    R (6) is -YC S H 2S -R (18), thienyl, furyl or an N-containing heterocycle having 1 to 9 carbon atoms, wherein thienyl, furyl and N-containing heterocycle are unsubstituted or F , Cl, Br, I, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, methylamino, dimethylamino, ethylamino, diethylamino, sulfamoyl, methylsulfonyl and methylsulfonyl Substituted with one or two substituents selected from the group consisting of amino; Y is -O-, -CO-, -O-CO-, -S-, -SO-, -SO 2- , -SO 2 -O-, -SO 2 NR (12d)-, -NR (12d) Or -CONR (12d)-[wherein the bond to the benzene nucleus is in each case via the left atom; R (12d) is hydrogen, methyl or ethyl; s is an integer from 1 to 6; R (18) is a substituent selected from the group consisting of NO 2 , CN, NH 2 , N (methyl) 2 , OH, ethyl, -COOH, -COOmethyl, -COOethyl, -CONH 2 and -CON (methyl) 2 Phenyl substituted with one or two; R (18) is a group consisting of F, Cl, Br, I, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino N-containing heterocycle having 1 to 9 carbon atoms substituted with one or two substituents selected from; R (18) is -OR (19), -SO 2 R (19), -NR (19) R (20), -CONR (19) R (20), where R (19) and R (20) Are independently of each other C t H 2t -R (21) (where t is an integer from 0 to 6; R (21) is hydrogen, CF 3 , C 2 F 5 , C 3 F 7 , carbon atoms of 3 to 8 Cycloalkyl, NR (22) R (23), -OR (24), phenyl, thienyl or N-containing heterocycle having 1 to 9 carbon atoms, wherein phenyl, thienyl and N-containing heterocycle are unsubstituted, One substituent selected from the group consisting of F, Cl, Br, I, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino or Are substituted in two; R (22) and R (23) are independently of each other hydrogen or alkyl of 1 to 3 carbon atoms; R (22) and R (23) together are 4 or 5 methylene group chains, wherein CH 2 groups form -O-, -S-, -NH-, -N (CH 3 )-or -N (benzyl)-); and R (24) can be hydrogen or carbon Is alkyl of 1 to 3).
    R (5), R (7) and R (8) are independently of each other hydrogen, F, Cl, Br, I, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, CN, CF 3 , NO 2 , OR (12e) or NR (12e) R (12f), wherein R (12e) and R (12f) are independently of each other hydrogen or alkyl having 1 to 4 carbon atoms,
    R (9) is hydrogen, OR (12g) or OCOR (12g), where R (12g) is hydrogen or alkyl of 1 to 3 carbon atoms,
    B is hydrogen,
    R (9) and B are the compounds which form a bond together and their physiologically acceptable salts.
    Particularly preferred compounds of formula 1 are
    R (1) and R (2) are independently of each other hydrogen, CF 3 or alkyl of 1 to 6 carbon atoms,
    R (1) and R (2) together form an alkylene chain of 2 to 6 carbon atoms,
    R (3) is R (10) -C n H 2n- {where R (10) is methyl, CF 3 or C 2 F 5 ,
    n is 0, 1 or 2},
    R (4) is R (13) -C r H 2r {wherein one CH 2 group in the C r H 2r group is -O-, -CH = CH-, -C≡C-, -CO-,- CO-O-, -O-CO-, -S-, -SO-, -SO 2- , -NR (14)-or -CONR (14)-[where R (14) is hydrogen, 1 to C Alkyl of 3, -C y H 2y -OR (12b), -C y H 2y -NR (12b) 2 , wherein R (12b) is hydrogen, methyl or ethyl and y is 2 or 3] ego; R (13) is H, CF 3 , C 2 F 5 , cycloalkyl having 3 to 7 carbon atoms, -NR (15) R (16), -CONR (15) R (16), -OR (17),- COOR (17), phenyl or N-containing heterocycle having 1 to 9 carbon atoms, wherein phenyl and N-containing heterocycle are unsubstituted, or are substituted with F, Cl, Br, CF 3 , NO 2 , CN, NH 2 , OH , Substituted with one or two substituents selected from the group consisting of methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15) and R (16) are independently of each other hydrogen or alkyl having 1 to 4 carbon atoms; R (15) and R (16) together form 4 or 5 methylene group chains, where one CH 2 group is -O-, -S-, -NH-, -N (CH 3 )-or -N ( Benzyl)-); R (17) is hydrogen, alkyl of 1 to 3 carbon atoms, or -C x H 2x OR (12c), wherein R (12c) is hydrogen, methyl or ethyl and x is 2 or 3); r is an integer of 1 to 12},
    R (6) is -YC S H 2S -R (18), thienyl, furyl or an N-containing heterocycle having 1 to 9 carbon atoms, wherein thienyl, furyl and N-containing heterocycle are unsubstituted or F , Cl, Br, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, methylamino, dimethylamino, ethylamino, diethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino Substituted with one or two substituents selected from the group consisting of: Y is -O-, -CO-, -O-CO-, -S-, -SO-, -SO 2- , -SO 2 -O-, -SO 2 NR (12d)-, -NR (12d) Or -CONR (12d)-[wherein the bond to the benzene nucleus is in each case via the left atom; R (12d) is hydrogen, methyl or ethyl; s is an integer from 1 to 6; R (18) is phenyl substituted with one or two substituents selected from the group consisting of NH 2 , N (methyl) 2 , OH, ethyl, -COOmethyl, -COOethyl, -CONH 2 and -CON (methyl) 2 ; R (18) is selected from the group consisting of F, Cl, Br, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino N-containing heterocycle having 1 to 9 carbon atoms substituted with one or two substituents; R (18) is -OR (19), -NR (19) R (20), -CONR (19) R (20), where R (19) and R (20) are independently of each other C t H 2t -R (21), where t is an integer from 0 to 6; R (21) is hydrogen, CF 3 , NR (22) R (23), -OR (24), phenyl, thienyl or 1 to carbon atoms N-containing heterocycle of 9 wherein phenyl, thienyl and N-containing heterocycle are unsubstituted or are substituted with F, Cl, Br, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, Substituted with one or two substituents selected from the group consisting of dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (22) and R (23) are independently of each other hydrogen or alkyl of 1 to 3 carbon atoms; (22) and R (23) together may be substituted with 4 or 5 methylene group chains, wherein one CH 2 group may be substituted with -O-, -S-, -NH- or -N (CH 3 )- R (24) is hydrogen or alkyl having 1 to 3 carbon atoms;
    R (5), R (7) and R (8) are independently of each other hydrogen, F, Cl, Br, alkyl having 1 to 5 carbon atoms, CN, CF 3 , NO 2 or OR (12e) {where R ( 12e) is alkyl having 1 to 4 carbon atoms},
    R (9) is hydrogen or OH,
    B is hydrogen,
    R (9) and B are the compounds which form a bond together and their physiologically acceptable salts.
    Very particularly preferred compounds of formula 1 are
    R (1) and R (2) are independently of each other hydrogen, CF 3 or alkyl of 1 or 2 carbon atoms,
    R (1) and R (2) together form an alkylene chain of 2 to 5 carbon atoms,
    R (3) is methyl or ethyl,
    R (4) is R (13) -C r H 2r {wherein one CH 2 group of the C r H 2r group is -O-, -CO-O-, -O-CO-, -NR (14) Or -CONR (14)-, wherein R (14) is hydrogen or alkyl of 1 or 2 carbon atoms; R (13) is hydrogen, CF 3 , -NR (15) R (16), -CONR (15) R (16), -OR (17), -COOR (17), phenyl or N having 1 to 9 carbon atoms -Containing heterocycles wherein phenyl and N-containing heterocycles are unsubstituted or substituted from the group consisting of F, Cl, Br, CF 3 , methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino Substituted with one or two; R (15) and R (16) are independently of each other hydrogen or alkyl having 1 or 2 carbon atoms; R (15) and R (16) together form 4 or 5 methylene group chains, where one CH 2 group may be substituted with -O-, -NH- or -N (CH 3 )- and; R (17) is hydrogen or alkyl of 1 or 2 carbon atoms; r is an integer of 1 to 7},
    R (6) is -YC S H 2S -R (18), thienyl, furyl or an N-containing heterocycle having 1 to 9 carbon atoms, wherein thienyl, furyl and N-containing heterocycle are unsubstituted or F Or substituted with one or two substituents selected from the group consisting of Cl, Br, CF 3 , methyl, methoxy, methylamino, dimethylamino, ethylamino, diethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; Y is -O- or -CONR (12d)-[wherein the bond to the benzene nucleus is through the left atom; R (12d) is hydrogen, methyl or ethyl; s is an integer from 1 to 6; R (18) is phenyl substituted with one or two substituents selected from the group consisting of NH 2 , N (methyl) 2 , OH, —COOmethyl, —COOethyl and —CON (methyl) 2 ; R (18) is selected from the group consisting of F, Cl, Br, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino N-containing heterocycle having 1 to 9 carbon atoms substituted with one or two substituents; R (18) is -OR (19) or -CONR (19) R (20), where R (19) and R (20) are independently of each other C t H 2t -R (21) (where t is Is an integer from 0 to 3; R (21) is hydrogen, CF 3 , NR (22) R (23) or -OR (24), where R (22) and R (23) are independently of each other hydrogen or carbon number 1 Alkyl of from 3 to 3; R (22) and R (23) together are 4 or 5 methylene group chains, where one CH 2 group is -O-, -S-, -NH- or -N (CH 3 Can be substituted with R <->; R (24) is hydrogen, alkyl having 1 or 2 carbon atoms),
    R (5), R (7) and R (8) are hydrogen,
    R (9) is hydrogen or OH,
    B is hydrogen,
    And a physiologically acceptable salt thereof, wherein R (9) and B together form a bond.
    In addition, more particularly preferred compounds of formula (1) are
    R (1) and R (2) are methyl,
    R (3) is methyl or ethyl,
    R (4) is R (13) -C r H 2r {wherein one CH 2 group of the C r H 2r group may be substituted with —O—; R (13) is hydrogen or CF 3 ; r is an integer of 1 to 6},
    R (6) is -YC S H 2S -R (18), thienyl, or an N-containing heterocycle having 1 to 9 carbon atoms, wherein thienyl and N-containing heterocycle are unsubstituted, or F, Cl, Substituted with one or two substituents selected from the group consisting of CF 3 , methyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; Y is -O-; s is an integer from 1 to 6; R (18) is substituted with one or two substituents selected from the group consisting of F, Cl, CF 3 , NO 2 , CN, OH, methyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino, N-containing heterocycle having 1 to 9 carbon atoms; R (18) is -OR (19) or -CONR (19) R (20), where R (19) and R (20) are independently of each other C t H 2t -R (21) (where t is Is an integer from 0 to 3; R (21) is hydrogen, CF 3 , NR (22) R (23) or -OR (24), where R (22) and R (23) are independently of each other hydrogen or carbon number 1 Or alkyl of 2; R (24) is hydrogen, alkyl of 1 or 2 carbon atoms;
    R (5), R (7) and R (8) are hydrogen,
    R (9) is hydrogen,
    And a physiologically acceptable salt thereof, wherein B is hydrogen.
    Alkyl radicals and alkylene radicals may be straight or branched. This also applies to alkylene radicals of the formulas C r H 2r , C t H 2t , C n H 2n and C s H 2s . In addition, alkyl radicals and alkylene radicals may be straight or branched when contained in other radicals such as alkoxy radicals, alkylmercapto radicals or fluorinated alkyl radicals. Examples of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3,3 -Dimethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl. Examples of alkylene radicals include divalent radicals derived from the above alkyl radicals, for example methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 2,2 -Propylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 2,2-dimethyl-1,3-propylene, 1,6-hexylene and the like.
    N-containing heterocycles having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms are, in particular, 1-, 2- or 3-pyrrole, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazole- 1-,-3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isooxazolyl, 1,2,3-oxa Diazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-oxadiazol-2-yl or -5-yl, 2- , 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiazole-3- Or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl , 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8- Quinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-shinolinyl, 2-, 3- , 5-, 6-, 7- or 8-quinoxalinyl or 1-, 4-, 5-, 6-, 7- and 8-phthalazinyl.
    Particularly preferred N-containing heterocycles are pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.
    Thienyl refers to both 2-thienyl and 3-thienyl. Furyl refers to 2-furyl and 3-furyl.
    Monosubstituted phenyl radicals are substituted at the 2-, 3- or 4-position, or at the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-position It may be disubstituted. Also in the case of N-containing heterocycles or thienyl radicals, they may be substituted at the same position correspondingly.
    When the radicals are disubstituted, the substituents can be the same or different.
    When the radicals R (1) and R (2) together are alkylene chains, spiro compounds are present by forming a ring in which these radicals and their carbon atoms share one carbon atom with the six-membered ring of formula (1). When R (9) and B together form a bond, there is a 2H-chromen parent structure. When R (10) and R (11) together form a bond, the group R (10) -C n H 2n -NR (11)-is preferably a nitrogen heterocycle bonded via a nitrogen atom. This nitrogen heterocycle is preferred when R (10) and R (11) together form a bond and the group R (10) -C n H 2n -NR (11)-is a nitrogen heterocycle bonded through a nitrogen atom. Preferably a four-membered ring or a ring larger than a four-membered ring, such as a five-membered ring, a six-membered ring or a seven-membered ring.
    When the compound of formula 1 contains one or more acidic or basic groups, or one or more basic heterocycles, the compounds of the invention also include corresponding, physiologically or toxicologically acceptable salts, in particular pharmaceutically useful salts. do. Thus, compounds of formula (I) that include acidic groups (eg, one or more COOH groups) may be used, for example, as alkali metal salts (preferably sodium or potassium salts), alkaline earth metal salts (eg calcium salts or magnesium salts). ) Or ammonium salts such as salts with ammonia, organic amines or amino acids. In addition, compounds of formula (1) that bear at least one basic group, i.e., a protic group, or contain at least one basic heterocyclic ring, may be used in the form of their physiologically acceptable acid addition salts using inorganic or organic acids (e.g., : Hydrochloride, phosphate, sulfate, methanesulfonate, acetate, lactate, maleate, fumarate, malate, gluconate, etc.). In addition, when the compound of formula 1 contains both an acidic group and a basic group in a molecule, the compound of the present invention contains not only the salt form described above, but also an internal salt, so-called betaine. Salts can be obtained from compounds of formula 1 according to conventional methods, for example by combining with acids or bases in a solvent or dispersant or by anion exchange.
    For suitable substitutions, the compounds of formula 1 may exist in stereoisomeric forms. If the compounds of formula 1 have one or more asymmetric centers, they may have S or R configurations independently of each other. The compounds of the present invention comprise in any desired proportions a mixture of all possible stereoisomers (e.g., enantiomers or diastereomers) and two or more stereoisomeric forms (e.g., enantiomeric and / or diastereomers). . Thus, the present invention is, for example, in the case of a right-rotating optical symmetry and a left-rotating optical symmetry both in the enantioscopically pure form, in the form of a mixture of two enantiomeric stereoisomers of varying proportions or in the form of racemates. It relates to an enantiomeric isomer. When cis / trans isomers are present, the present invention relates to both cis and trans forms and mixtures of these forms. Each stereoisomer can be prepared, if desired, by dissolving the mixture according to conventional methods or by, for example, stereoselective synthesis. The present invention also encompasses all tautomeric forms of the compound of formula (1), where a removable hydrogen atom is present.
    Compounds of formula 1 can be prepared by different chemical methods, which are also included in the present invention. Thus, the compound of formula 1, for example,
    (A) reacting a compound of formula 4 with a sulfonamide of formula 5 or a salt thereof in a manner known per se;
    (B) reacting a compound of formula 6 with a sulfonic acid derivative of formula 7,
    (C) subjecting the compound of formula 8 to an alkylation reaction using an alkylating agent of formula 9 in a manner known per se,
    When positions R (5), R (6), R (7) and R (8) of the compound of the formula (1) are hydrogen, a method (d) for carrying out an electrophilic substitution reaction at one or more of these positions,
    (E) subjecting the compound of formula 10 to an esterification or amidation reaction using a compound of formula 11 or 12,
    (F) subjecting the compound of formula 13 to an alkylation reaction with the compound of formula 14,
    (G) amidating a compound of formula 15 using a compound of formula 16,
    (H) subjecting the compound of formula 17 to an alkylation reaction using a compound of formula 18,
    (I) a coupling reaction of a compound of Formula 19 with a compound of Formula 20,
    (J) reacting a compound of formula 21 with a sulfonamide of formula 5 to obtain chromamanol of formula 22, or
    Obtained by method (k) in which the compound of formula 22 is converted by a removal reaction to give the compound of formula 23.
    In Formula 4 above,
    R (1), R (2), R (5), R (6), R (7), R (8) and R (9) are the same as specified in the formula (1),
    L is a heteronuclear leaving group, in particular Cl, Br, I, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy.
    In Formula 5 above,
    R (3) and R (4) is the same as specified in the formula (1),
    M is hydrogen, preferably a metal equivalent, particularly preferably lithium, sodium or potassium.
    In Formula 6 above,
    R (1), R (2), R (4), R (5), R (6), R (7), R (8) and R (9) are the same as specified in the formula (1).
    In Formula 7, above,
    R (3) is the same as specified in Formula 1,
    W is a heteronuclear leaving group such as fluorine, bromine and 1-imidazolyl, in particular chlorine.
    In Formula 8 above,
    R (1), R (2), R (3), R (5), R (6), R (7), R (8) and R (9) are the same as specified in Formula 1,
    M is the same as specified in the formula (5).
    R (4) -L
    In Formula 9 above,
    R (4) is the same as specified in Formula 1,
    L is the same as specified in the formula (4).
    In Formula 10 above,
    R (1), R (2), R (3), R (5), R (6), R (7), R (8), R (9) and B are the same as specified in Formula 1,
    r 'is 1-9.
    R (13) -C r H 2r -NHR (14)
    R (13) -C r H 2r -OH
    In the above formulas 11 and 12,
    R (13) and R (14) is the same as specified in the formula (1),
    r is 1 to 9.
    In Formula 13 above,
    R (1), R (2), R (3), R (5), R (6), R (7), R (8), R (9) and B are the same as specified in Formula 1,
    r 'is the same as specified in formula (10).
    R (13) -C r H 2r -L
    In Formula 14 above,
    R (13) is the same as specified in the formula (1),
    r is the same as specified in Formula 11,
    L is the same as specified in the formula (4).
    In Formula 15 above,
    R (1), R (2), R (3), R (4), R (5), R (7), R (8), R (9), Y, s and B are specified in Formula 1. Same as bar.
    HNR (19) R (20)
    In Formula 16 above,
    R (19) and R (20) are the same as specified in the formula (1).
    In Formula 17 above,
    R (1), R (2), R (3), R (4), R (5), R (7), R (8), R (9) and B are the same as specified in the formula (1).
    R (18) -C s H 2s -L
    In Formula 18 above,
    R (18) and s are the same as specified in the formula (1),
    L is the same as specified in the formula (4).
    In Formula 19 above,
    R (1), R (2), R (3), R (4), R (5), R (7), R (8), R (9) and B are the same as specified in Formula 1,
    L is the same as specified in the formula (4).
    Het-met
    In Formula 20 above,
    Het is an N-containing heterocycle, thienyl or furyl of 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
    Met is B (OH) 2 , trialkylsilyl, alkali metal cation or organometallic radical which can be easily substituted.
    In Formula 21 above,
    R (1), R (2), R (5), R (6), R (7) and R (8) are the same as specified in the formula (1).
    Formula 5
    In Formula 5 above,
    R (3) and R (4) is the same as specified in the formula (1),
    M is the same as specified above or advantageously is a trialkylsilyl radical (eg trimethylsilyl radical).
    In Formula 22 above,
    R (1) to R (8) are the same as specified in the formula (1).

    In Formula 23 above,
    R (1) to R (8) are the same as specified in the formula (1).
    Method (a) corresponds to the nucleophilic substitution reaction of leaving groups in the reactive bicyclic system of formula (4) with sulfonamides or salts thereof. Because of the higher nucleophilicity and reactivity of the sulfonamides present in the form of salts, when using free sulfonamides (Formula 5, M = H), a base is first applied to the free sulfonamides to form sulfonamide salts (Formula 5, M = Metal ions). When using free sulfonamides (Formula 5, M = H), the sulfonamides can be deprotonated with sulfonamide salts in themselves. Preferably, bases which are not alkylated by themselves or only slightly alkylated (e.g. sodium carbonate, potassium carbonate, stericly strongly inhibited amines such as dicyclohexylamine, N, N-dicyclohexylethylamine) or nucleophilic Other low strong nitrogen bases such as DBU (diazabicycloundeken), N, N ', N-triisopropylguanidine, etc.). However, other commonly used bases for this reaction, such as potassium tert-butoxide, sodium methoxide, alkali metal hydrogencarbonates, alkali metal hydroxides (eg LiOH, NaOH or KOH) or alkaline earth metal hydroxides Rocksides such as Ca (OH) 2 ] may also be used.
    The reaction is preferably a solvent, particularly preferably a polar organic solvent such as dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), tetramethylurea (TMU), hexamethylphosphoramide (HMPA), tetrahydrofuran (THF), dimethoxyethane (DME) or other ethers, or hydrocarbons such as toluene, halogenated hydrocarbons such as chloroform or methylene chloride, and the like. However, it can also be carried out in polar good solvents such as water, methanol, ethanol, isopropanol, ethylene glycol or oligomers thereof, and their corresponding half ethers or ethers thereof. The reaction can also be carried out in a mixture of these solvents. However, the reaction can likewise be carried out without using a solvent. The reaction is preferably carried out in a temperature range of -10 to 140 ° C, particularly preferably 20 to 100 ° C. Also, easily, process (a) can be carried out under the conditions of a phase shift catalysis.
    Compounds of formula (4) are prepared according to methods known from the literature, for example in the corresponding alcohols (Formula 4, L = -OH), hydrogen halide (HL) (L = Cl, Br, I) or inorganic acid halides ( Examples: POCl 3 , PCl 3 , PCl 5 , SOCl 2 or SOBr 2 ), or the corresponding Croman derivatives (Formula 4, L = H), to radical chain initiators (eg in the visible or ultraviolet wavelength range) In the presence of high energy rays) or in the presence of chemical free radical initiators such as azodiisobutylonitrile, using chlorine or bromine atoms or free radical activated halogenating agents such as N-bromosuccinimide (NBS Or SO 2 Cl 2 (sulfuric acid)].
    Process (b) is known per se, often to react the reactive sulfonyl compounds of formula 7, in particular chlorosulfonyl compounds (W = Cl), with the amino derivatives of formula 6 to give the corresponding sulfonamide derivatives of formula 1 Describes the reaction used. Originally, this reaction can be carried out without using a solvent, but this type of reaction is in most cases carried out with a solvent.
    The reaction is preferably carried out using a polar solvent in the presence of a base, advantageously the base itself can be used as the solvent, for example when using triethylamine, especially pyridine and its analogs. Solvents to be used are, for example, water, aliphatic alcohols (e.g. methanol, ethanol, isopropanol, secondary-butanol), ethylene glycol and its monomeric and oligomeric monoalkyl and dialkyl ethers, tetrahydrofuran, di Oxanes and dialkylated amides such as DMF, DMA, TMU and HMPA. In this case, the reaction is carried out at a temperature of 0 to 160 ° C, preferably 20 to 100 ° C.
    The amines of formula (6) are preferably prepared in a manner known from the literature, under relatively elevated temperatures and in autoclaves, under reducing reaction conditions or catalyzed reaction conditions, preferably from the corresponding carbonyl compounds of formula (24), ammonia or Obtained using an amine of formula 25.
    In Formula 24 above,
    R (1), R (2), R (5), R (6), R (7), R (8) and R (9) are the same as specified in the formula (1),
    A is oxygen.
    R (4) -NH 2
    In Formula 25 above,
    R (4) is the same as specified in the formula (1).
    In this reaction, the ketone of formula 24 (A = oxygen) and the amine of formula 25 are condensed on their own, such that Schif base of formula 24 wherein A is R (4) -N =. Is formed, which can be converted immediately to the amine of formula 6 by a reduction reaction, ie without undergoing a previous separation step. However, according to methods known from the literature, a Schiff base (formula 24; wherein A is R (4) -N =) is prepared immediately by condensation reaction from the compound of formula 24 and the compound of formula 25 and After separating them, in a separate step, catalytic hydrogenation using suitable reducing agents (e.g. NaBH 4 , LiAlH 4 , NaBH 3 CN) or in the presence of Raney nickel or new metals (eg palladium) By means of which they can be converted into the compound of formula (6).
    Also advantageously the compound of formula 6, wherein R (4) is hydrogen, is an oxime or oxime ether (Formula 24; wherein A is = N-OR and R is H or alkyl) by methods known from the literature. Or a hydrazone (Formula 24; wherein A is = N-NR 2 and R is for example H or alkyl), for example using a complex metal hydride or a catalytic hydrogenation reaction It can be obtained by reducing. The oximes and hydrazones required for this preferably use hydrazines or derivatives thereof in a manner known per se from ketones of formula 24 (where A is oxygen), e.g. hydroxylamine hydrochloride under dehydration conditions Can be prepared). Particularly advantageously, amination is carried out using a suitable ammonium compound (eg ammonium acetate) in the presence of a suitable reducing agent (eg NaCNBH 3 ) to give a compound of formula 6 wherein R (4) is hydrogen. [Note: J. Am. Chem. Soc. 93, 1971, 2897.
    Alternatively, the reactive compounds of formula (4) wherein R (1), R (2), R (5), R (6), R (7), R (8) and R (9) are as defined in Formula 1 And L is the same as specified in Formula 4, by reacting with ammonium or an amine of Formula 24, wherein R (4) is the same as specified in Formula 1, An amino derivative of 6 can be obtained.
    Process (c) represents a reaction known per se, wherein the sulfonamide of formula (8) or a salt thereof is alkylated using an alkylating agent of formula (9). This reaction is similar to method (a), so the reaction conditions already described in detail in method (a) apply to method (c). For the deprotonation reaction of sulfonamides, preferably not only the bases already mentioned in process (a) but also sodium hydride or phosphazene bases are used.
    The preparation of sulfonamide derivatives of formula (8), wherein M is H, and their precursors have already been described in method (b), wherein R (4) is in each case hydrogen. The alkylating agent of formula (9) is prepared from the process described in the same literature or in the process (a), preferably from the corresponding hydroxy compound (Formula 9, where L is -OH).
    Process (d) is carried out at one or more positions designated by the compounds of formula 1 according to the invention in which R (5) to R (8), wherein R (5) to R (8) in each case is hydrogen] Further chemical conversion to other compounds of Formula 1 by substitution reactions is described.
    Preferred substitution reactions
    1. Aromatic nitration reaction to introduce one or more nitro groups. Some or all of these nitro groups may be reduced to amino groups in subsequent reactions. In addition, amino groups can be converted to other groups in subsequent reactions (eg, Sandmeyer reactions) to introduce, for example, cyano groups.
    2. Aromatic halogenation reaction, especially for introducing chlorine, bromine or iodine.
    3. Chlorosulfonation reactions, for example, to introduce chlorosulfonyl groups which can be converted to other groups (eg sulfonamide groups) in subsequent reactions by acting chlorosulfonic acid.
    4. Friedel-Crafts for introducing acyl radicals or sulfonyl radicals by the action of the corresponding acid chlorides in the presence of Lewis acid, especially anhydrous ammonium chloride, as a Friedel-Crafts catalyst. Acylation reaction.
    Method (e) describes the esterification of a carboxylic acid of formula 10 with an alcohol of formula 12 or an amination reaction with an amine of formula 11. A number of methods have been described in the literature for this reaction. These reactions are particularly advantageously using, for example, dicyclohexylcarbodiimide (DCC) with the addition of hydroxybenzotriazole (HOBT) or dimethylaminopyridine (DMAP), or O- [(Cyano (ethoxycarbonyl) methylene) amino] -1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) can be used to activate the carboxylic acid. However, first, the reactive acid derivative may also be synthesized according to known methods. For example, an acid chloride may be synthesized by reacting a carboxylic acid of formula 10 with an inorganic acid halide (e.g., SOCl 2 ), or an acid imidazoleide may be reacted with carbonyldiimidazole, and thereafter, React with an alcohol of formula 12 or an amine of formula 11 with the addition of an additional base accordingly. Carboxylic acids of formula 10 are obtained according to the methods described in methods (a) to (d), in which case R (4) in each case is -C r ' H 2r' COOH or -C r ' H 2r' in each case COOalkyl, in the case of —C r ′ H 2r ′ COOHalkyl, the ester is then further hydrolyzed.
    Method (f) describes the alkylation of an alcohol of Formula 13 using an alkylating agent of Formula 14. For this purpose, first, a suitable base (e.g. sodium hydride or phosphazene base) is applied to the alcohol to convert it to an alcoholate salt, and then the alcoholate salt is converted to a suitable polar solvent (e.g. Dimethylformamide) in combination with an alkylating agent. It is also possible to deprotonate the alcohol with a salt in itself, and then preferably use a base, such as potassium carbonate, which is not itself alkylated. An alcohol of the formula (13) is obtained according to the process described in processes (a) to (d), in which case R (4) is in each case then -C r ' H 2r' OH or -C r ' H 2r' OR, where R is a suitable protecting group (eg, acetoxy), and, for -C r ' H 2r' OR, thereafter further removes the protecting group. However, the ester of formula 1 described in process (e), wherein R (4) is -C r ' H 2r' COOalkyl, can be reduced by using lithium aluminum hydride, Alcohol can be obtained.
    Method (g) describes the amination reaction of a carboxylic acid of formula (15) with an amine of formula (16), which can be carried out under the reaction conditions shown in process (e). The carboxylic acid of formula (15) is, for example, carried out in the same manner as described in method (h), in which case R (18) is COOH or COOalkyl, in the case of COOalkyl, which then further hydrolyzes the ester .
    Process (h) is an alkylation reaction of a phenol of formula (17) using an alkylating agent of formula (18), which can be carried out under the reaction conditions already described in process (f). The phenols of formula 17 may be carried out by the methods described in processes (a) to (f), in which case R (6) is in each case an OH group or a suitably protected derivative (eg benzyl ether), Subsequently, the protection group is further removed.
    Process (i) describes coupling a aryl halide (e.g. iodide) or an arylalkyl sulfonate (e.g. triflate) of formula (19) using a heterocycle of formula (20) in the presence of a suitable transition metal catalyst and have. Preferably, a heterocycle is used in which the Met group is a boronic acid radical [eg B (OH) 2 ], which means in the sense of the Suzuki coupling reaction, for example palladium tetrakis (triphenylphosphine). ) And a base such as potassium carbonate or cesium carbonate may be reacted with an aryl halide of formula (19). However, heterocycles in which the Met group is, for example, a trialkyltin radical [Stille coupling], a trialkylsilyl radical, a Grignard compound or an organic zinc compound can also be used. Suitable reaction conditions for this type of coupling reaction are described in the literature.
    Method (j) is a nucleophilic ring-opening reaction of epoxide of formula 21 using sulfonamide of formula 5 or a salt thereof. This reaction can be carried out under the same conditions as described in method (a). It has proved particularly advantageous to use free sulfonamides in the presence of a lower substoichiometric amount (eg 20-80%) of the corresponding base (eg sodium hydride). It is also advantageous to use sulfonamide derivatives in which M is a trialkylsilyl radical (eg trimethylsilyl radical), and then it is easy to carry out the reaction in the presence of fluorine (eg tetrabutylammonium fluoride).
    Epoxides of formula 21 can be reacted, for example, with suitable inorganic or organic peroxides (eg H 2 O 2 , m-chloroperbenzoic acid) from the corresponding olefins of formula 26 by methods known from the literature, or Is obtained by, for example, base-catalyzed cyclization of the corresponding bromohydrin, which can be obtained by reaction with N-bromosuccinimide and water.
    In Formula 26 above,
    R (1), R (2), R (5), R (6), R (7) and R (8) are the same as specified in the formula (1).
    Epoxides of formula 21 may also be obtained by oxidation of optically pure olefins of formula 26 in the presence of a chiral Jacobsen catalyst described in the literature. See Tetrahedron Lett. 32, 1991, 5055. The olefins of formula 26 may be prepared by reducing the carbonyl group from the ketone of formula 24, wherein A is oxygen, to an OH functional group, followed by acid-catalyzed removal reactions or suitably substituted aryl propargyls as described in the literature. The ether can be obtained by ring closing reaction by heat. J. Org. Chem. 38 (1973) 3832].
    Method (k) describes the conversion of chromamanol of formula (22) to chromamen of formula (23) by a removal reaction. For this purpose, the chromanol can be dehydrated directly in the presence of an acid or base, or first activated with a hydroxyl group (eg acetylation with acetic anhydride or mesylation with methanesulfonyl chloride). Followed by, for example, heating with DBU (diazabicycloundeken) to effect a base-catalyzed removal reaction.
    Apart from the methods described above, many other approaches to the compounds of formula 1 according to the present invention are contemplated. Thus, for example, the reactions described in the methods (a) to (k) may be combined with each other in different arrangements, or the methods described in the same way may not be the first compounds according to the present invention, wherein the radicals R (1) to R ( 8) does not have the meaning specified above, and then converting it to the compound according to the invention in the final step by simply converting one substituent, for example, an alkylation reaction, an amination reaction, etc. This can be useful.
    For all methods, at certain reaction stages, it may be appropriate to temporarily protect the functional groups in the molecule. Such protection group techniques are well known to those skilled in the art. Methods of selecting protective groups for the groups under consideration and their introduction and removal methods are described in the literature and can be applied in each case, if appropriate, without problems.
    Surprisingly, the compound of formula 1 has a strong and specific blocking action (blocking action) against K + channels opened by cyclic adenosine monophosphate (cAMP) and is fundamentally different from the well known K + (ATP) channels. In addition, the K + (cAMP) channels identified in colon tissue are very similar to and may be identical to the I Ks channels identified in cardiac muscle. In the case of the compound according to the present invention, it can exhibit a strong blocking action on the I Ks channel in the cardiomyocytes of the guinea pig and the I sk channel expressed in Xenopus oocytes. The compound according to the present invention exhibits a pharmacological action with high therapeutic utility in vivo by thus blocking K + (cAMP) channel or I Ks channel, and is remarkable as a pharmaceutically active compound for the treatment and prevention of various syndromes. Is suitable.
    Accordingly, the compound of formula 1 according to the present invention is excellent as a novel active compound class that strongly inhibits stimulated gastric acid secretion. Thus, the compound of formula 1 is an important pharmaceutically active substance for the treatment and prevention of gastric ulcers and intestinal ulcers (eg duodenal ulcers). In addition, since they have a strong effect of inhibiting gastric acid secretion, they are suitable as excellent therapeutic agents for the treatment and prevention of reflux esophagitis.
    In addition, the compound of the formula (1) according to the present invention is excellent in diarrhea inhibitory action, and thus is suitable as a pharmaceutically active substance for the treatment and prevention of diarrhea disease.
    In addition, the compounds of formula 1 according to the invention are suitable as pharmaceutically active substances for the treatment and prevention of heart diseases. The compound can be used for the treatment and prophylaxis of all types of arrhythmias, especially cardiac arrhythmias, which can be eliminated by dislocation maintenance action, especially arrhythmias of the atria, ventricles and ventricles. In particular, the compound can be used for the treatment and prevention of atrial fibrillation, atrial fibrillation and reentry arrhythmia and for the prevention of sudden cardiac arrest by ventricular fibrillation.
    Although many substances with antiarrhythmic activity are already on the market, there are still no compounds that are actually satisfactory with regard to activity, range of use and adverse side effects, and therefore, further development of improved antiarrhythmic drugs was needed. The action of many known, so-called class III antiarrhythmic drugs is based on an increase in myocardial dead time due to prolongation of dislocation maintenance. This is essentially measured by the degree of repolarization of the K + flow exiting the cell through multiple K + channels. Here, the so-called delayed rectifier I K is of particular importance, and there are two subtypes of I K which are rapidly activated I Kr and slowly activated I Ks . The most well known antiarrhythmic drugs of class III (eg dofetilide, d-soltalol) block I Kr predominantly or restrictively. However, these compounds increase the risk of proarrhythmic at low heart rate or normal heart rate, in particular arrhythmias, referred to as torsades de pointes [DM Roden, Current Status]. of Class III Antiarrhythmic Drug Therapy; Am. J. Cardiol. 72 (1993), 44B-49B]. However, when the heart rate is higher or the β-receptor is stimulated, the translocation maintenance action of the I Kr blocker is significantly reduced, because under these conditions, it is more strongly repolarized by I Ks . For this reason, the substances according to the invention which act as I Ks blockers have significant advantages over known I Kr blockers. On the other hand, it has been described that the I Ks channel inhibitory effect and the inhibitory effect of life-threatening cardiac arrhythmias induced by, for example, β-adrenergic hyperstimulation have been correlated [BTJ Colatsky, CH Follmer and CF Starmer, Channel Specificity in Antiarrhythmic Drug Action; Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias, Circulation 82 (1990), 2235-2242; AE Busch, K. Malloy, WJ Groh, MD Varnum, JP Adelman and J. Maylie, The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit I sK channels in xenopus oocytes and I Ks in guinea pig cardiac myocytes, Biochem. Biophys. Res. Commun. 202 (1994), 265-270.
    In addition, the compound is advantageously combined with a contractile promoting (positive metabolic) active substance (such as a phosphodiesterase inhibitor) to have a significant therapeutic effect on cardiac insufficiency, particularly congestive heart failure. Indicates.
    In spite of the therapeutically useful advantages obtained by blocking I Ks , only a few have been described so far to inhibit compounds of this type of delayed rectifier. As is generally accepted, the azinimide material in development is blocking on I Ks but mainly blocking (selectivity 1:10) on I Kr . WO-A-95 / 14470 claims the use of benzodiazepines as selective blockers of I Ks . Additional I Ks blockers are described in the literature. FEBS Letters 396 (1996), 271-275, Specific blockade of slowly activating I sK channels by chromanols ....; Pflugers Arch. -Eur. J. Physiol. 429 (1995), 517-530, A new class of inhibitors of cAMP-mediated Cl - secretion in rabbit colon, acting by the reducton of cAMP-activated K + conductance. However, the efficacy of 3-hydroxychromanol described in this document is lower than the compound of formula 1 according to the present invention.
    Thus, the compounds of formula 1 and physiologically acceptable salts thereof according to the invention can be used in animals, preferably in mammals, in particular in the form of medicaments themselves, mixtures thereof or pharmaceutical preparations. In addition, the present invention provides compounds of formula 1 and physiologically acceptable salts thereof for use as medicaments, their use for the treatment and prevention of the aforementioned syndromes, and agents and K + channels for the treatment and prevention of these syndromes. It relates to their use to prepare a medicament with a blocking action. In addition, the present invention relates to pharmaceutical preparations containing an effective amount of at least one compound of formula (I) and / or a physiologically acceptable salt thereof as an active ingredient, as well as conventional pharmaceutically non-toxic excipients and auxiliaries. . Generally, the pharmaceutical preparation contains 0.1 to 90% by weight of the compound of formula 1 and / or physiologically acceptable salts thereof. The preparation of pharmaceutical preparations can be carried out by methods known per se. To this end, the compounds of formula (1) and / or physiologically acceptable salts thereof are prepared in a suitable dosage form or dosage form with one or more solid or liquid pharmaceutical excipients and / or adjuvants and, if necessary, other pharmaceutically active compounds. It can be mix | blended with and used as a pharmaceutical agent for humans or animals.
    Agents containing a compound of formula 1 and / or a physiologically acceptable salt thereof according to the invention may be oral, parenteral (eg, intravenous, rectal, inhaled) or topical. The preferred method of administration depends on the condition of the individual, for example the particular clinical condition of the disease to be treated.
    Those skilled in the art are familiar with the basic expertise of adjuvants suitable for the desired pharmaceutical formulation. To achieve solvents, gel formers, suppository bases, tablet aids and other active compound excipients, as well as, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, storage effects Preparations, buffering agents or coloring agents can be used.
    In addition, the compound of formula 1 may be combined with other pharmaceutically active compounds to achieve an advantageous therapeutic effect. Thus, in the treatment of cardiovascular diseases, it can advantageously be combined with substances having cardiovascular activity. Advantageous combination ingredients of this type which are beneficial for cardiovascular disease are, for example, other antiarrhythmic drugs, ie class I, class II or class III antivenous drugs (eg I Kr channel blockers (eg dofetilide)), Additionally, hypotensive substances (e.g., ACE inhibitors (e.g. enalapril, captopril, ramipril)), angiotensin antagonists, K + channel activators, α- and β-receptor blockers, sympathomimetics, compounds with adrenergic activity , Na + / H + exchange inhibitors, calcium channel antagonists, phosphodiesterase inhibitors and positively active substances (eg, digitalis glycosides or diuretics). Combinations with substances with antibiotic activity and combinations with anti-ulcer agents such as H 2 anti-antagonists such as ranitidine, cimetidine, pamotidine, etc., are particularly advantageous when administered to treat gastrointestinal diseases. .
    As an oral dosage form, the active compound is mixed with suitable excipients (e.g. excipients, stabilizers or inert diluents) and suitable dosage forms (e.g. tablets, dragees, hard capsules and aqueous, alcoholic or Oily solution). Inert excipients that can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, sugar or starch, in particular corn starch. It can be prepared herein as both dry and wettable particles. Suitable oily excipients or solvents are, for example, vegetable oils or animal oils such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are, for example, water, ethanol, sugar solutions or mixtures thereof. Further excipients for other dosage forms are, for example, polyethylene glycol and polypropylene glycol.
    As a subcutaneous or intravenous dosage form, the active compounds are prepared, if necessary, in solution, suspension or emulsion, together with substances which are customarily used for this purpose (eg solubilizers, emulsifiers or other auxiliaries). In addition, the compound of formula 1 and its physiologically acceptable salts can be lyophilized and the resulting lyophilisate can be used, for example, to prepare injection or infusion formulations. Suitable solvents are, for example, water, physiological saline, alcohols (eg ethanol, propanol and glycerol), sugar solutions (eg glucose solution or mannitol solution) or mixtures thereof.
    Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, compounds of formula 1 or physiologically acceptable in pharmaceutically acceptable solvents (e.g. ethanol, water or mixtures of these solvents). Solution, suspension or emulsion thereof. In addition, if desired, the formulation may contain other pharmaceutical adjuvants (eg, surfactants, emulsifiers, stabilizers and propelants). Such formulations typically contain an active compound at a concentration of about 0.1 to 10% by weight, in particular about 0.3 to 3% by weight.
    The dosage of the active compound of formula 1 or a physiologically acceptable salt thereof depends on the individual condition and is usually applied according to the situation of the individual condition for optimal action. However, of course, the dosage is not only the frequency of administration and the strength and persistence of the activity of the compound used for the treatment or prophylaxis, respectively, but also the nature and extent of the disease to be treated, the sex, age and weight of the person or animal being treated. And individual reactivity. Typically, when administered to a patient weighing about 75 kg, the daily dose of the compound of formula 1 is 0.001 to 100 mg / kg body weight, preferably 0.01 to 20 mg / kg body weight. Dosages may be administered in a single dosage form or divided into several, for example, two, three or four single dosage forms. In particular, parenteral administration (eg, intravenous continuous infusion) by injection or infusion may be advantageous when treating acute cardiac arrhythmias, for example, with a strong therapeutic unit.
    Example
    Abbreviated list DMAN, N-dimethylacetamide DMSODimethyl sulfoxide EAEthyl acetate THFTetrahydrofuran
    Example 1
    N- [6- (3-ethoxypropoxy) -2,2-dimethylchroman-4-yl] -N-ethyl-methanesulfonamide
    a) 2,2-dimethyl-6-hydroxychroman-4-one
    The reaction mixture of 100 g (0.65 mol) of 2,5-dihydroxyacetophenone, 130 ml (1.55 mol) and acetone 290 ml (3.95 mol) in 1 L of acetonitrile is heated at 45 ° C. for 8 hours. The solvent is then removed in vacuo and the residue is dissolved in 1 L of EA. The organic phase is washed twice with dilute hydrochloric acid, stirred with activated carbon and then dried over magnesium sulphate to almost concentrate. After the residue was stirred with petroleum ether and the precipitate was filtered off with suction, 102 g of 2,2-dimethyl-6-hydroxychroman-4-one having a melting point of 158 ° C were obtained.
    b) 6-benzyloxy-2,2-dimethylchroman-4-one
    25.2 g (131.2 mmol) of 6-hydroxy-2,2-dimethylchroman-4-one was mixed in 350 ml of diethyl ketone at room temperature with stirring, followed by addition of 18.0 g (131 mmol) of powdered potassium carbonate, followed by 75 Stir for 30 minutes at < RTI ID = 0.0 > After cooling to 60 ° C., 15.7 ml (131 mmol) of benzyl bromide are added dropwise, the mixture is concentrated in vacuo after 2 hours, the residue is treated with water and the solid is filtered off with suction (37 g, melting point 105-107 ° C.).
    c) 6-benzyloxy-2,2-dimethylchroman-4-one oxime
    11.3 g (40 mmol) of 6-benzyloxy-2,2-dimethylchroman-4-one was heated together with 3.1 g (44 mmol) of hydroxylamine hydrochloride in 27 ml of ethanol and 27 ml of pyridine for 3 hours at 70 ° C. The solvent is concentrated in vacuo and precipitated with water to give 12.5 g of product having a melting point of 105 to 108 ° C. The product is dissolved in EA, dried, concentrated and crystallized with petroleum ether (melting point 118-120 ° C.).
    d) 4-amino-6-benzyloxy-2,2-dimethylchroman
    30 g of 6-benzyloxy-2,2-dimethylchroman-4-one oxime is dissolved in 900 ml of THF / methanol (1: 1), treated with 25 ml of aqueous ammonia, and then in a shaking duck. Hydrogenated using Raney nickel. The catalyst is then suction filtered, the filtrate is concentrated in vacuo, the residue is dissolved in EA, the solution is dried and concentrated, and the residue is crystallized using petroleum ether (22.9 g, melting point 86-88 ° C.). ).
    e) 6-benzyloxy-4- (methylsulfonyl) amino-2,2-dimethylchroman
    4.0 g (14 mmol) of 4-amino-6-benzyloxy-2,2-dimethylchroman were treated with 4.2 ml (30 mmol) of triethylamine in 80 ml of THF at room temperature and the mixture was stirred for 30 minutes and then Treated with 1.95 g (1.3 mL, 17 mmol) of methanesulfonyl chloride while raising to 40 < 0 > C. The mixture is then heated to reflux for 2 hours, left overnight at room temperature, then concentrated in vacuo and the residue is treated with water (4.9 g of product, melting point 162-165 ° C.).
    f) N- [6-benzyloxy-2,2-dimethylchroman-4-yl] -N-ethylmethanesulfonamide
    7.2 g (20 mmol) of 6-benzyloxy-4- (methylsulfonyl) amino-2,2-dimethylchroman are added stepwise to a suspension (80% dispersion) of 0.82 g (27 mmol) of sodium hydride in 60 ml of DMA at 10 ° C. Mix. After stirring for 2 hours at room temperature, 2.2 ml (26.5 mmol) of ethyl iodine are added dropwise while raising the temperature to 32 ° C. The mixture is then heated at 35-40 ° C. for 2 hours, concentrated in vacuo, treated with water, the resinous product dissolved in EA, the solution dried, concentrated and the residue taken up with n-heptane / EA ( Chromatographic analysis on silica gel using 2: 1). Petroleum ether / diisopropyl ether (1: 1) is used to crystallize 6 g of product having a melting point of 104 to 106 ° C. from a suitable fraction.
    g) N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-ethylmethanesulfonamide
    12 g of N- [6-benzyloxy-2,2-dimethylchroman-4-yl] -N-ethylmethanesulfonamide are dissolved in 250 ml of THF / methanol (1: 1) and Pd / carbon in a shaker Hydrogenated using. After terminating the uptake of hydrogen, the catalyst is suction filtered, the filtrate is concentrated and the residue is crystallized using diisopropyl ether (7.7 g, melting point 169-170 ° C.).
    h) 1.5 g (5 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-ethylmethanesulfonamide were added together with 1.38 g (10 mmol) of powdered potassium carbonate in 60 ml of DMA. Heat at 30 ° C. Then, 4 ml of 3-ethoxy-1-bromopropane was added dropwise at 50 to 60 ° C., and then the mixture was heated to 110 ° C. for 2 hours, concentrated after vacuum cooling, and the residue was treated with water and aqueous hydrochloric acid. The mixture is extracted using EA and then the organic phase is dried and concentrated and the oily residue is chromatographed on silica gel using n-heptane / EA (2: 1). 0.9 g of N- [6- (3-ethoxypropoxy-2,2-dimethylchroman-4-yl] -N-ethyl-methanesulfonamide having a melting point of 72 to 74 ° C from a suitable fraction using petroleum ether Crystallize.
    Example 2
    N-ethyl-N- [6- (5-hydroxypentyloxy) -2,2-dimethylchroman-4-yl] methanesulfonamide
    a) ethyl-4- [4- (ethylmethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] valerate
    1.5 g (5 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-ethylmethanesulfonamide (Example 1 g) was added together with 0.7 g of powdered potassium carbonate in 75 ml of DMA. Stir for 30 minutes at < RTI ID = 0.0 > Then 0.8 ml (5 mmol) ethyl-5-bromovaleric acid is added and the mixture is stirred at 120 ° C. for 120 minutes. After the reaction is complete (TLC), the mixture is concentrated in vacuo and treated with ice water and aqueous hydrochloric acid to give crystalline crude product which is then chromatographed on silica gel using n-heptane / EA (2: 1). . Petroleum ether is used to crystallize the appropriate fractions (1.5 g, melting point 65-67 ° C).
    b) 0.35 g (0.8 mmol) of ethyl-4- [4- (ethylmethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] valerate at 1O < 0 > C solution of lithium aluminum hydride 1M in THF 1.6 The reaction is carried out with 35 ml in 35 ml of dry THF (see Example 8).
    After termination with EA and concentration in vacuo, 0.28 g of the title compound is crystallized using petroleum ether (melting point 78-80 ° C.).
    Example 3
    5- [4- (ethylmethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] pentanoic acid (2-methoxyethyl) amide
    0.6 g of ethyl-4- [4- (ethylmethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] valerate (Example 2a) were refluxed in 10 ml of methoxyethylamine for 3 days. Heat. The mixture is then concentrated in vacuo and the residue is chromatographed on silica gel. Petroleum ether is used to crystallize 0.28 g of the title compound (melting point 53-55 ° C.).
    Example 4
    5- [4- (ethylmethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] pentanoic acid (2-hydroxyethyl) amide
    0.2 g of ethyl-4- [4- (ethylmethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] valerate (Example 2a) was 2-hydrogenated at a bath temperature of 90 DEG C for 1 hour. Heat in 4 ml of oxymethylamine. The mixture is then treated with aqueous hydrochloric acid, extracted with EA, dried, concentrated and the residue is crystallized with petroleum ether. 0.16 g of the title compound is obtained (melting point 88 to 90 ° C).
    Example 5
    4- [4- (ethylmethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] -N- (2-hydroxyethyl) butyramide
    a) ethyl 4- [4- (ethylmethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] butyrate
    1.0 g (3.3 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-ethylmethanesulfonamide (Example 1 g) together with 0.455 g of powdered potassium carbonate in 50 ml of DMA Stir at 80-90 ° C. for 30 minutes. 0.71 g (0.55 mL, 3.6 mmol) of ethyl 4-bromobutyrate are then added at 60 ° C. and the mixture is stirred at 115 ° C. for 90 minutes. It was then concentrated in vacuo, treated with water and aqueous hydrochloric acid, then the mixture was dissolved in EA, the solution was dried and concentrated, and the residue was then dried on silica gel using n-heptane / EA (3: 1). Chromatographic analysis (0.74 g, melting point 40-42 ° C.).
    b) 0.2 g of the butyric acid ester is stirred in 4 ml of 2-aminoethanol at a bath temperature of 95 ° C. The pH is then adjusted to 1 with 50% hydrochloric acid while cooling with water, dried and concentrated, then the residue is dried on an oil pump to yield 0.26 g of the title compound on oil.
    Example 6
    2- [4- (ethylmethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] -N- (2-methoxyethyl) acetamide
    a) ethyl 4- [4- (ethylmethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] acetate
    1.8 g (6 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-ethylmethanesulfonamide (Example 1 g) 0.83 g (6 mmol) of powdered potassium carbonate in 80 ml of DMA With stirring at 80-90 ° C. for 30 minutes. Then 0.75 g (6.6 mmol) ethyl bromoacetate is added at 60 ° C. and the mixture is stirred at 110 ° C. for 90 minutes. Water and aqueous hydrochloric acid are added, dissolved in EA, dried and chromatographed on silica gel to yield 2.4 g of an oily product.
    b) In the same manner as in Example 5b, 0.21 g of the above ester and 3 ml of 2-methoxyethylamine are obtained from 0.21 g of an oily title compound.
    Example 7
    2- [4- (ethylmethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] -N- (2-hydroxyethyl) acetamide
    0.23 g of the compound of Example 6a was heated in 3 ml of 2-aminoethanol for 1 hour to give 0.23 g of the oily product, the title compound.
    Example 8
    N-ethyl-N- [6- (2-hydroxyethoxy) -2,2-dimethylchroman-4-yl] methanesulfonamide
    To 0.77 g (2 mmol) of the compound of Example 5a in 80 mL of dry THF was added dropwise 4 mL of a lithium aluminum hydride 1M solution in THF at 0 ° C. The mixture is then further stirred at room temperature for 1 hour, then treated with water and dilute hydrochloric acid, concentrated in vacuo, the residue is extracted using EA, the extract is dried and concentrated, and the residue is diiso Crystallization with propyl ether (0.35 g, melting point 76-78 ° C.) affords an additional 0.3 g of oil from the filtrate.
    Example 9
    N- [6- (2-ethoxyethoxy) -2,2-dimethylchroman-4-yl] -N-ethylmethanesulfonamide
    N-ethyl-N- [6- (2-hydroxyethoxy) -2,2-dimethylchroman-4-yl] methanesulfonamide (Example 8) 2.3 g (6.7 mol) of DMA 50 ml under nitrogen Alkylization is carried out using 0.48 g (about 10 mmol) of NaH (80% dispersion) in the genus and 1.6 mL (about 20 mmol) of ethyl iodide. After completion of the reaction and purification by column chromatography on silica gel 1.0 g of the title compound having a melting point of 73 to 75 ° C. is crystallized from the corresponding fractions using petroleum ether.
    Example 10
    N-ethyl-N- [6-(((4-methoxypyridin-2-yl) methyl) oxy) -2,2-dimethylchroman-4-yl] methanesulfonamide
    0.58 g (1.9 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-ethylmethanesulfonamide (Example 1 g) was added to 0.15 g (5 mmol) of NaH in 40 ml of DMA ( 80%) and at 50 ° C. for 30 minutes. A solution of 0.4 g (2 mmol) of 4-methoxy-2-chloromethylpyridine hydrochloride in 5 ml of DMA is then added dropwise and the mixture is heated at 75 ° C. for 2 hours. After completion of the reaction, it is concentrated in vacuo, the residue is treated with ice water, the mixture is extracted using EA, the extract is dried and concentrated and the residue is crystallized using diisopropyl ether. 0.5 g of product having a melting point of 87-89 ° C is obtained.
    Example 11
    Ethanesulfonic acid [6- (2-hydroxyethoxy) -2,2-dimethylchroman-4-yl] -methylamide
    a) 6-benzyloxy-4- (ethylsulfonyl) amino-2,2-dimethylchroman
    8.5 g (30 mmol) of 4-amino-6-benzyloxy-2,2-dimethylchroman (Example 1d) were treated with 9 mL (65 mmol) of triethylamine with stirring in 150 mL of THF at room temperature and the mixture was After stirring for 30 minutes, the mixture was treated with 3.5 mL (37.5 mmol) of ethanesulfonyl chloride while raising the temperature to 40 ° C. The mixture is then stirred at 45 ° C. for 2 hours and terminated in the same manner as in Example 1e. 8.8 g of product having a melting point of 145 to 149 ° C. are obtained (from water).
    b) N- [6-benzyloxy-2,2-dimethylchroman-4-yl] -N-methylethanesulfonamide
    In the same manner as in Example 1f, 8.6 g (23 mmol) of 6-benzyloxy-4- (ethylsulfonyl) amino-2,2-dimethylchroman was dissolved in a suspension of 1 g (25 mmol) of sodium hydride in 75 ml of DMA at 10 ° C. % Dispersion). After stirring for 2 hours at room temperature, 1.6 ml (25 mmol) methyl iodide is added dropwise while raising the temperature to 40 ° C. The mixture is then heated at 35-40 ° C. for 2 hours, concentrated in vacuo, the residue is treated with water, the resinous product is dissolved in EA, the solution is dried, concentrated and the residue is n-heptane Chromatographic analysis on silica gel using / EA (1: 1). Petroleum ether / diisopropyl ether is used to crystallize 7.4 g of product having a melting point of 91 to 93 ° C. from a suitable fraction.
    c) N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-methylethanesulfonamide
    7.2 g (18.5 mmol) of N- [6-benzyloxy-2,2-dimethylchroman-4-yl] -N-methylethanesulfonamide were dissolved in 150 mL of THF / methanol (1: 1) and shaker. Hydrogenated using Pd / Carbon within. After terminating the uptake of hydrogen, the catalyst is suction filtered, the filtrate is concentrated and the residue is crystallized using diisopropyl ether (5.0 g, melting point 160-162 ° C.).
    d) ethyl 4- [4- (methylethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] -acetate
    In the same manner as in Example 6a, 2.1 g (7 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-methylethanesulfonamide was mixed with powdered potassium carbonate and ethyl bromoacetate in DMA. React with 0.9 mL (8 mmol). After treatment with diisopropyl / petroleum ether, 2.5 g of crystalline product having a melting point of 92 to 94 ° C are obtained.
    e) In the same manner as in Example 8, the title compound is obtained using lithium aluminum hydride from 1.8 g of the above ester compound. 1.3 g of product having a melting point of 89 to 92 ° C. are crystallized from a small amount of diisopropyl ether.
    Example 12
    Ethanesulfonic acid [6- (2-ethoxyethoxy) -2,2-dimethylchroman-4-yl] -N-methylamide
    0.5 g of the compound of Example 11 was reacted with NaH and ethyl iodide in DMA in the same manner as in Example 9. After purification by column chromatography on silica gel, 0.4 g of the title compound having a melting point of 70 to 72 ° C. is crystallized using petroleum ether.
    Example 13
    Methyl 4- [4- (ethanesulfonylmethylamino) -2,2-dimethylchroman-6-yloxymethyl] benzoate
    0.6 g (2 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-methylethanesulfonamide (Example 11c) was reacted with powder potash, followed by 4- in DMA. React with 0.505 g (2.2 mmol) of (methoxycarbonyl) benzyl bromide. 0.72 g of product having a melting point of 86 to 88 ° C. is crystallized using diisopropyl ether.
    Example 14
    4- [4- (ethanesulfonylmethylamino) -2,2-dimethylchroman-6-yloxymethyl] benzoic acid
    0.6 g of the ester of Example 13 is hydrolyzed at 50 ° C. for 1 hour in 50 mL of 1.5 M methanolic NaOH. The mixture is then concentrated in vacuo, the residue is treated with water, the mixture is acidified and THF is added until the solution is clear, then the precipitate is suction filtered, washed and dried. 0.56 g of the title compound is obtained having a melting point of 168 to 170 ° C.
    Example 15
    N- [6- (3-ethoxypropoxy) -2,2-dimethylchroman-4-yl] -N-methylmethanesulfonamide
    a) N- [6-benzyloxy-2,2-dimethylchroman-4-yl] -N-methylmethanesulfonamide
    8.9 g of 6-benzyloxy-4- (methylsulfonyl) amino-2,2-dimethylchroman (Example 1e)
    (25 mmol) is incorporated stepwise into a 1.2 g (30 mmol) suspension (60% dispersion) of sodium hydride in 75 ml of DMA at 10 ° C. After stirring for 2 hours at room temperature, 1.9 ml (30 mmol) of methyl iodide are added dropwise while raising the temperature to 50 ° C. The mixture is then heated at 50 ° C. for 2 hours, concentrated in vacuo, the residue is treated with water, the resinous product is dissolved in EA, the solution is dried, concentrated and the residue is n-heptane / EA. Chromatographic analysis on silica gel using (2: 1). Petroleum ether / diisopropyl ether (1: 1) is used to crystallize 7.4 g of product having a melting point of 114 to 116 ° C. from a suitable fraction.
    b) N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-methylmethanesulfonamide
    7.3 g of N- [6-benzyloxy-2,2-dimethylchroman-4-yl] -N-methylmethanesulfonamide are dissolved in 100 ml of THF / methanol (1: 1) and Pd / Hydrogenated using carbon. After the absorption of hydrogen has ended, the catalyst is suction filtered and the filtrate is concentrated, followed by crystallization of 5.2 g of the title compound having a melting point of 159 to 161 ° C. using diisopropyl ether / petroleum ether.
    c) 0.82 g of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-methylmethanesulfonamide
    (2.5 mmol) is heated at 80 ° C. for 30 minutes with 0.83 g (6 mmol) of powdered potassium carbonate in 60 ml of DMA. 2 ml of 3-ethoxy-1-bromopropane were then added dropwise at 50-60 ° C., the mixture was heated to 110 ° C. for 3 hours and concentrated in vacuo, then cooled and the residue treated with water and aqueous hydrochloric acid. And extract using EA, then extract is concentrated to dryness and the oily residue is chromatographed on silica gel using n-heptane / EA (3: 1). Petroleum ether is used to crystallize 0.74 g of the title compound having a melting point of 61-63 ° C. from a suitable fraction.
    Example 16
    N- [6- (2-hydroxyethoxy) -2,2-dimethylchroman-4-yl] -N- (2-methoxyethyl) methanesulfonamide
    a) N- [6-benzyloxy-2,2-dimethylchroman-4-yl] -N- (2-methoxyethyl) methanesulfonamide
    8.9 g (25 mmol) of 6-benzyloxy-4- (methylsulfonyl) amino-2,2-dimethylchroman (Example 1e) was added to a suspension of 0.54 g (30 mmol) of sodium hydride in 80 ml of DMA at 10 ° C. (60% Dispersion step by step). After stirring for 30 min at 50 ° C., 2.2 ml (22 mmol) of 2-methoxyethyl bromide are added dropwise at room temperature. The mixture is then heated at 110 ° C. for 1 hour and concentrated in vacuo, then the residue is treated with water and aqueous hydrochloric acid, the resinous product is dissolved in EA, the solution is dried and concentrated and the residue is toluene Chromatographic analysis on silica gel using / EA (3: 1). Petroleum ether is used to crystallize 2.2 g of product having a melting point of 66 to 68 ° C. from a suitable fraction.
    b) N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N- (2-methoxyethyl) methanesulfonamide
    6 g of N- [6-benzyloxy-2,2-dimethylchroman-4-yl] -N- (2-methoxyethyl) methanesulfonamide was dissolved in 100 ml of THF / methanol (1: 1) and shaken. Hydrogenation with Pd / carbon in the group. Diisopropyl ether is used to crystallize 4.6 g of crude product having a melting point of 115 to 117 ° C.
    c) ethyl 4- [4-((2-methoxyethyl) methanesulfonylamino) -2,2-dimethylchroman-6-yloxy] acetate
    2.65 g (8.0 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N- (2-methoxyethyl) methanesulfonamide was added to 0.48 g (10 mmol) of NaH in 100 mL of DMA. Heat at 50 ° C. for 30 minutes with (80%). Then, as in Example 6a, 1.1 ml (10 mmol) of ethyl bromoacetate was added dropwise, the mixture was then heated at 100 ° C. for 1 hour, concentrated in vacuo, cooled and the residue treated with water and aqueous hydrochloric acid. The mixture is extracted using EA, the extract is dried, concentrated and the oily residue is chromatographed on silica gel using n-heptane / EA (1: 1). 3.2 g of oily product are obtained.
    d) 2.1 g (5 mmol) of the above ester is reduced in 60 ml of THF using 10 ml of a 1 M solution of lithium aluminum hydride in THF. After column chromatography analysis on silica gel using n-heptane / EA (1: 1), 1.4 g of the title compound having a melting point of 61 to 63 ° C. is obtained using diisopropyl ether.
    Example 17
    N- [6- (2-ethoxyethoxy) -2,2-dimethylchroman-4-yl] -N- (2-methoxyethyl) methanesulfonamide
    0.56 g (1.5 mmol) N- [6- (2-hydroxyethoxy) -2,2-dimethylchroman-4-yl] -N- (2-methoxyethyl) methanesulfonamide (Example 16) Was reacted with NaH and ethyl iodide in DMA in the same manner as in Example 9. After column chromatography analysis on silica gel using n-heptane / EA (1: 1), 0.32 g of an oily product are obtained.
    Example 18
    2- {4- [methanesulfonyl- (2-methoxyethyl) amino] -2,2-dimethylchroman-6-yloxy} -N- (2-methoxyethyl) acetamide
    0.43 g of ethyl 4- [4-((2-methoxyethyl) methanesulfonylamino) -2,2-dimethylchroman-6-yloxy] acetate (Example 16c) was added at 90 DEG C for 1 hour. Heat in 6 ml of methoxyethylamine. 0.42 g of an oily product are obtained in the same manner as in Examples 5b and 6b.
    Example 19
    N- [6- (4-hydroxybutoxy) -2,2-dimethylchroman-4-yl] -N- (2-methoxyethyl) methanesulfonamide
    a) ethyl 4- [4-((2-methoxyethyl) methanesulfonylamino) -2,2-dimethylchroman-6-yloxy] butyrate
    2.0 g (6 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N- (2-methoxyethyl) methanesulfonamide (Example 16b) was prepared in the same manner as in Example 5a. React with potassium carbonate and ethyl 4-bromobutyrate. 2.85 g of oily product are obtained.
    b) 0.6 g (1.35 mmol) of the above ester was reduced in THF using 2 ml of a 1 M solution of lithium aluminum hydride in THF to yield 0.46 g of the title compound, an oily product.
    Example 20
    N- (2-hydroxyethyl) -4- {4- [methanesulfonyl- (2-methoxyethyl) amino] -2,2-dimethylchroman-6-yloxy} butyramide
    0.55 g of ethyl 4- [4-((2-methoxyethyl) methanesulfonylamino) -2,2-dimethylchroman-6-yloxy] butyrate (Example 19a) was added at 90 ° C. for 2 hours. Reaction in 4 ml of aminoethanol yields 0.6 g of an oily product.
    Example 21
    N- [6- (3-ethoxypropoxy) -2,2-dimethylchroman-4-yl] -N- (2-methoxyethyl) -methanesulfonamide
    In the same manner as in Example 1 g, 0.5 g (1.5 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N- (2-methoxyethyl) methanesulfonamide (Example 16b) ) Is reacted with potassium carbonate and 3-ethoxy-1-bromopropane. After column chromatography analysis on silica gel using n-heptane / EA (5: 1), 0.35 g of an oily product are obtained.
    Example 22
    2- [4- (ethanesulfonyl- (1-propyl) amino) -2,2-dimethylchroman-6-yloxy] -N- (2-methoxyethyl) acetamide
    a) N- [6-benzyloxy-2,2-dimethylchroman-4-yl] -N- (1-propyl) ethanesulfonamide
    In the same manner as in Example 11b, 7.5 g (20 mmol) of 6-benzyloxy-4- (ethylsulfonyl) amino-2,2-dimethylchroman (Example 11a) was 0.82 g of sodium hydride in 100 ml of DMA at 10 ° C. (27 mmol) are incorporated stepwise into a suspension (80% dispersion). After stirring for 2 hours at room temperature, 2.4 ml (26.2 mmol) of 1-propyl bromide are added dropwise. After completion, the residue is chromatographed on silica gel using n-heptane / EA (1: 1) and 6.0 g of product having a melting point of 102 to 103 ° C. is crystallized from a suitable fraction using petroleum ether.
    b) N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N- (1-propyl) ethanesulfonamide
    6.0 g of N- [6-benzyloxy-2,2-dimethylchroman-4-yl] -N- (1-propyl) ethanesulfonamide was dissolved in 150 ml of THF / methanol (1: 1), followed by shaking. Hydrogenation with Pd / carbon in the group gives 4.4 g of product (from petroleum ether) with a melting point of 173 to 175 ° C.
    c) ethyl 4- [4-((1-propyl) ethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] acetate
    In the same manner as in Example 6a, 0.72 g (2.2 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-methylethanesulfonamide was reacted with potassium carbonate and ethyl bromoacetate. And 0.47 g of a product having a melting point of 62 to 64 ° C. (from petroleum ether / diisopropyl ether) is obtained.
    d) From 0.15 g of the above ester (using aqueous hydrochloric acid) using 4 ml of 2-methoxyethylamine (1 h at 90 ° C.) (using aqueous hydrochloric acid) as in Example 6b, the title compound had a melting point of 94-95 ° C. Obtained as 0.13 g of phosphorus product.
    Example 23
    2- [4- (ethanesulfonyl- (1-propyl) amino) -2,2-dimethylchroman-6-yloxy] -N- (3-ethoxypropyl) acetamide
    In the same manner as in Examples 5b and 6b, 0.15 g of ethyl 4- [4-((1-propyl) ethanesulfonamino) -2.2-dimethylchroman-6-yloxy] acetate was added to 3-ethoxy-1-propylamine. Reaction (1 hour, 95 ° C.) in 4 ml affords 0.16 g of an oily product.
    Example 24
    Ethyl 2- [4- (ethanesulfonyl- (1-propyl) amino) -2,2-dimethylchroman-6-yloxy] -N- (2-piperidin-1-yl) acetamide
    0.19 g (0.45 mmol) of ethyl 4- [4-((1-propyl) ethanesulfonylamino) -2,2-dimethylchroman-6-yloxy] acetate (Example 22c) was added to N- (2-ethyl The reaction is carried out in 3 ml of amino) piperidine (2 hours, 100 ° C). 0.22 g of the title compound is obtained as a resinous product.
    Example 25
    Ethanesulfonic acid [6- (2-methoxyethoxy-2,2-dimethylchroman-4-yl]-(1-propyl) amide
    0.491 g (1.5 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N- (1-propyl) ethanesulfonamide (Example 22b) was added to NaH and 2-methine in DMA. React with oxyethyl bromide. 0.27 g of the title compound having a melting point of 78 to 80 ° C is obtained from petroleum ether.
    Example 26
    Ethanesulfonic acid (2,2-dimethyl-6-thiophen-2-yl-chroman-4-yl) methylamide
    a) ethanesulfonic acid (2,2-dimethylchroman-4-yl) methylamide (4-amino-2,2-dimethylchromone is obtained from 2-hydroxyacetophenone as in Examples 1a, 1c and 1d) Thereafter, 2.83 g (10 mmol) in the same manner as in Examples 11a and 11b) were dissolved in 16 ml of acetic acid, and a solution of 1.62 g (10 mmol) of iodine chloride in 16 ml of acetic acid was added dropwise. After 4 h at rt, the mixture is concentrated and the residue is treated with methylene chloride. The mixture is washed with sodium bicarbonate solution until neutral, then dried and the solvent is removed in vacuo. The oil thus obtained was purified by column chromatography (eluent heptane / EA 1: 1), and 1.4 g (34%) of ethanesulfonic acid (6-iodo-2,2-dimethylchroman-4-yl) methylamide Is obtained as a solid (melting point 87-92 ° C.).
    b) 410 mg (1 mmol) of ethanesulfonic acid (6-iodo-2,2-dimethylchroman-4-yl) methylamide was dissolved in 5 ml of toluene and 130 mg (1 mmol) of thiophenboronic acid, 40 mg of palladium tetrakis (triphenylphosphine) and 1.1 ml of a 2-mol solution of cesium carbonate are added. The mixture is stirred at 80 ° C. overnight. After removal of the solvent, the residue is dissolved in methylene chloride and washed with water. After drying and removing the solvent, the obtained residue was purified by column chromatography (eluent heptane / ethyl acetate 1: 1), ethanesulfonic acid (2,2-dimethyl-6-thiophen-2-yl-chloro 260 mg (71%) of man-4-yl) methylamide are obtained as an oil.
    Example 27
    N- [6- (3-diethylaminopropoxy) -2,2-dimethylchroman-4-yl] -N-methylmethanesulfonamide
    0.7 g (2.5 mmol) of N- [2,2-dimethyl-6-hydroxychroman-4-yl] -N-methylmethanesulfonamide (Example 15b) was added to phosphazene base in 2 ml of DMA. Butylimino-tri (pyrrolidino) phospharane] 1.6 g (5.2 mmol) was stirred at room temperature for 1 hour. Then 0.48 mg (2.6 mmol) of diethylaminopropylchloride hydrochloride are added and the mixture is heated at 100 ° C. for 8 hours. After the solvent is removed in vacuo, the residue is dissolved in EA and the mixture is washed with water. After drying over magnesium sulfate and chromatographic analysis over a silica gel short column, N- [6- (3-diethylaminopropoxy) -2,2-dimethylchroman-4-yl] -N-methylmethanesulfonamide 0.48 g is obtained as a glassy solid.
    Pharmacological research
    I sK of human, rat or guinea pigs is expressed in xenopus oocytes. To this end, oocytes are first isolated from Xenopus laevis and the follicle cells are removed. Subsequently, in vitro synthesized I sK -encoding RNA is injected into these oocytes. Two to eight days after I sK protein expression, I sK flow is measured in oocytes using the two-microelectrode voltage-clamp technique. Typically, in this case, the I sK channel activates to -10mV with a voltage jump for 15 seconds continuously. The bath is filled with a solution of the following composition: NaCl 96 mM, KCl 2 mM, CaCl 2 1.8 mM, MgCl 2 1 mM, HEPES 5 mM (titration to pH 7.5 with NaOH). These tests are performed at room temperature. Use the following for data acquisition and analysis: Geneclamp amplifiers (Axon Instruments, Foster City, USA) and MacLab D / A converters and software (ADInstruments, Castle Hill, Australia). The material according to the invention is tested by adding to bath solutions of different concentrations. The effect of this substance is calculated as the percentage inhibition of the I sK control flow, which is obtained when no substance is added to the solution. The inhibitory concentration (IC 50 ) for each material is then determined by extrapolating the data using the Hill equation.
    Reference:
    AE Busch, H.-G. Kopp, S. Waldegger, I. Samarzija, H. Suβbrich, G. Raber, K. Kunzelmann, JP Ruppersberg and F. Lang; Inhibition of both exogenously expressed I sK and endogenous K + channels in Xenopus oocytes by isosorbide dinitrate; J. Physiol. 491 (1995), 735-741;
    T. Takumi, H. Ohkubo and S. Nakanishi; Cloning of a membrane protein that induces a slow voltage-gated potassium current; Science 242 (1989), 1042-1045;
    M.D. Varnum, A.E. Busch, C.T. Bond, J. Maylie and J.P. Adelman; The minK channel underlies the cardiac potassium current and mediates species-specific responses to protein kinase; C. Proc, Natl. Acad. Sci. USA 90 (1993), 11528-11532.
    For compounds according to the invention, the IC 50 values below are determined by the methods described using human I sK protein.
    compoundIC 50 [μM] Example 10.43 Example 21.71 Example 36.36 Example 87.43 Example 90.69 Example 10To 8 Example 150.32 Example 17To 1 Example 211.74 Example 22~ 3 Example 232.49 Example 260.38
    According to the present invention, there are provided pharmaceutically active compounds for the prevention and treatment of heart diseases, in particular arrhythmia, the treatment of gastric ulcers or diarrhea, methods for their preparation, their use as medicaments and pharmaceutical preparations comprising the same.
    权利要求:
    Claims (18)
    [1" claim-type="Currently amended] Compounds of Formula 1 and physiologically acceptable salts thereof.
    Formula 1

    In Formula 1 above,
    R (1) and R (2) are independently of each other hydrogen, CF 3 , C 2 F 5 , C 3 F 7 , alkyl of 1 to 6 carbon atoms, or unsubstituted, F, Cl, Br, I, CF 3 Or phenyl substituted with one or two substituents selected from the group consisting of NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino,
    R (1) and R (2) together form an alkylene chain of 2 to 10 carbon atoms,
    R (3) is R (10) -C n H 2n -NR (11)-or R (10) -C n H 2n- {where one CH 2 group in the C n H 2n group is -O-, -CO-, -S-, -SO-, -SO 2- , or -NR (12a)-, wherein R (12a) is hydrogen, methyl or ethyl]; R (10) is hydrogen, methyl, cycloalkyl having 3 to 8 carbon atoms, CF 3 , C 2 F 5 or C 3 F 7 ; n is an integer from 0 to 10; R (11) is hydrogen or alkyl of 1 to 6 carbon atoms; when n is less than 3, R (10) and R (11) together form a bond} or
    R (3) together with R (4) is an alkylene chain of 3 to 8 carbon atoms, wherein one CH 2 group of the alkylene chain is -O-, -CO-, -S-, -SO-, -SO 2 -or -NR (12a)-, wherein R (12a) can be substituted with hydrogen, methyl or ethyl}, and
    R (4) is R (13) -C r H 2r {wherein one CH 2 group of the C r H 2r group is -O-, -CH = CH-, -C≡C-, -CO-,- CO-O-, -O-CO-, -S-, -SO-, -SO 2- , -NR (14)-or -CONR (14)-[where R (14) is hydrogen, 1 to C Alkyl of 3, -C y H 2y -OR (12b) or -C y H 2y -NR (12b) 2 , wherein R (12b) is hydrogen, methyl or ethyl and y is 2 or 3] ego; R (13) is H, CF 3 , C 2 F 5 , C 3 F 7 , cycloalkyl having 3 to 8 carbon atoms, -NR (15) R (16), -CONR (15) R (16), -OR (17), -COOR (17), phenyl or an N-containing heterocycle having 1 to 9 carbon atoms, wherein the phenyl and N-containing heterocycle are unsubstituted or substituted with F, Cl, Br, I, CF 3 , NO 2 Or substituted with one or two substituents selected from the group consisting of CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15) and R (16) are independently of each other hydrogen or alkyl having 1 to 4 carbon atoms; R (15) and R (16) together form 4 or 5 methylene group chains, where one CH 2 group is -O-, -S-, -NH-, -N (CH 3 )-or -N ( Benzyl)-); R (17) is hydrogen, alkyl of 1 to 3 carbon atoms or -C x H 2x OR (12c), wherein R (12c) is hydrogen, methyl or ethyl and x is 2 or 3); r is an integer from 0 to 20},
    One or more substituents of R (5), R (6), R (7) and R (8) may be -YC S H 2S -R (18), thienyl, furyl or an N-containing heterocycle having 1 to 9 carbon atoms. {Wherein thienyl, furyl and N-containing heterocycle are unsubstituted or F, Cl, Br, I, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, methylamino, dimethyl Substituted with one or two substituents selected from the group consisting of amino, ethylamino, diethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; Y is -O-, -CO-, -O-CO-, -S-, -SO-, -SO 2- , -SO 2 -O-, -SO 2 NR (12d)-, -NR (12d) Or -CONR (12d)-, wherein the bond to the benzene nucleus is in each case via the left atom and R (12d) is hydrogen, methyl or ethyl]; s is an integer from 1 to 6; R (18) is a substituent selected from the group consisting of NO 2 , CN, NH 2 , N (methyl) 2 , OH, ethyl, -COOH, -COOmethyl, -COOethyl, -CONH 2 and -CON (methyl) 2 Phenyl substituted with one or two; R (18) is a group consisting of F, Cl, Br, I, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino N-containing heterocycle having 1 to 9 carbon atoms substituted with one or two substituents selected from; R (18) is -OR (19), -SO 2 R (19), -NR (19) R (20), -CONR (19) R (20), where R (19) and R (20) Are independently of each other C t H 2t -R (21) (where t is an integer from 0 to 6; R (21) is hydrogen, CF 3 , C 2 F 5 , C 3 F 7 , carbon atoms of 3 to 8 Cycloalkyl, NR (22) R (23), -OR (24), phenyl, thienyl or N-containing heterocycle having 1 to 9 carbon atoms, wherein phenyl, thienyl and N-containing heterocycle are unsubstituted, One substituent selected from the group consisting of F, Cl, Br, I, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino or Are substituted in two; R (22) and R (23) are independently of each other hydrogen or alkyl of 1 to 3 carbon atoms; R (22) and R (23) together are 4 or 5 methylene group chains, wherein CH 2 groups form -O-, -S-, -NH-, -N (CH 3 )-or -N (benzyl)-); and R (24) can be hydrogen or carbon Is alkyl of 1 to 3).
    The remaining substituents R (5), R (6), R (7) and R (8), not defined above, are, in each case, independently of one another, hydrogen, F, Cl, Br, I, alkyl having 1 to 5 carbon atoms. , Cycloalkyl having 3 to 8 carbon atoms, CN, CF 3 , NO 2 , OR (12e) or NR (12e) R (12f) {where R (12e) and R (12f) are independently of each other hydrogen or 1 carbon To alkyl of 4 to 4; R (9) is hydrogen, OR (12g) or OCOR (12g), where R (12g) is hydrogen or alkyl of 1 to 3 carbon atoms,
    B is hydrogen,
    R (9) and B together form a bond.
    [2" claim-type="Currently amended] The method of claim 1,
    R (1) and R (2) are independently of each other hydrogen, CF 3 , C 2 F 5 , C 3 F 7 , alkyl of 1 to 6 carbon atoms, or unsubstituted, F, Cl, Br, I, CF 3 Or phenyl substituted with one or two substituents selected from the group consisting of NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino,
    R (1) and R (2) together form an alkylene chain of 2 to 10 carbon atoms,
    R (3) is R (10) -C n H 2n -NR (11)-or R (10) -C n H 2n- {where one CH 2 group in the C n H 2n group is -O-, -CO-, -S-, -SO-, -SO 2- , or -NR (12a)-, wherein R (12a) is hydrogen, methyl or ethyl]; R (10) is hydrogen, methyl, cycloalkyl having 3 to 8 carbon atoms, CF 3 , C 2 F 5 or C 3 F 7 ; n is an integer from 0 to 10; R (11) is hydrogen or alkyl of 1 to 6 carbon atoms; when n is 3 or more, R (10) and R (11) together form a bond} or
    R (3) together with R (4) is an alkylene chain of 3 to 8 carbon atoms, wherein one CH 2 group of the alkylene chain is -O-, -CO-, -S-, -SO-, -SO 2 -or -NR (12a)-, wherein R (12a) can be substituted with hydrogen, methyl or ethyl}, and
    R (4) is R (13) -C r H 2r {wherein one CH 2 group in the C r H 2r group is -O-, -CH = CH-, -C≡C-, -CO-,- CO-O-, -O-CO-, -S-, -SO-, -SO 2- , -NR (14)-or -CONR (14)-[where R (14) is hydrogen, 1 to C Alkyl of 3, -C y H 2y -OR (12b), -C y H 2y -NR (12b) 2 , wherein R (12b) is hydrogen, methyl or ethyl and y is 2 or 3] ego; R (13) is H, CF 3 , C 2 F 5 , C 3 F 7 , cycloalkyl having 3 to 8 carbon atoms, -NR (15) R (16), -CONR (15) R (16), -OR (17), -COOR (17), phenyl or an N-containing heterocycle having 1 to 9 carbon atoms, wherein the phenyl and N-containing heterocycle are unsubstituted or substituted with F, Cl, Br, I, CF 3 , NO 2 Or substituted with one or two substituents selected from the group consisting of CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15) and R (16) are independently of each other hydrogen or alkyl having 1 to 4 carbon atoms; R (15) and R (16) together form 4 or 5 methylene group chains, where one CH 2 group is -O-, -S-, -NH-, -N (CH 3 )-or -N ( Benzyl)-); R (17) is hydrogen, alkyl of 1 to 3 carbon atoms, or -C x H 2x OR (12c), wherein R (12c) is hydrogen, methyl or ethyl and x is 2 or 3); r is an integer from 0 to 20},
    R (6) is -YC S H 2S -R (18), thienyl, furyl or an N-containing heterocycle having 1 to 9 carbon atoms, wherein thienyl, furyl and N-containing heterocycle are unsubstituted or F , Cl, Br, I, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, methylamino, dimethylamino, ethylamino, diethylamino, sulfamoyl, methylsulfonyl and methylsulfonyl Substituted with one or two substituents selected from the group consisting of amino; Y is -O-, -CO-, -O-CO-, -S-, -SO-, -SO 2- , -SO 2 -O-, -SO 2 NR (12d)-, -NR (12d) Or -CONR (12d)-[wherein the bond to the benzene nucleus is in each case via the left atom; R (12d) is hydrogen, methyl or ethyl; s is an integer from 1 to 6; R (18) is a substituent selected from the group consisting of NO 2 , CN, NH 2 , N (methyl) 2 , OH, ethyl, -COOH, -COOmethyl, -COOethyl, -CONH 2 and -CON (methyl) 2 Phenyl substituted with one or two; R (18) is a group consisting of F, Cl, Br, I, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino N-containing heterocycle having 1 to 9 carbon atoms substituted with one or two substituents selected from; R (18) is -OR (19), -SO 2 R (19), -NR (19) R (20), -CONR (19) R (20), where R (19) and R (20) Are independently of each other C t H 2t -R (21) (where t is an integer from 0 to 6; R (21) is hydrogen, CF 3 , C 2 F 5 , C 3 F 7 , carbon atoms of 3 to 8 Cycloalkyl, NR (22) R (23), -OR (24), phenyl, thienyl or N-containing heterocycle having 1 to 9 carbon atoms, wherein phenyl, thienyl and N-containing heterocycle are unsubstituted, One substituent selected from the group consisting of F, Cl, Br, I, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino or Are substituted in two; R (22) and R (23) are independently of each other hydrogen or alkyl of 1 to 3 carbon atoms; R (22) and R (23) together are 4 or 5 methylene group chains, wherein CH 2 groups form -O-, -S-, -NH-, -N (CH 3 )-or -N (benzyl)-); and R (24) can be hydrogen or carbon Is alkyl of 1 to 3).
    R (5), R (7) and R (8) are independently of each other hydrogen, F, Cl, Br, I, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, CN, CF 3 , NO 2 , OR (12e) or NR (12e) R (12f), wherein R (12e) and R (12f) are independently of each other hydrogen or alkyl having 1 to 4 carbon atoms,
    R (9) is hydrogen, OR (12g) or OCOR (12g), where R (12g) is hydrogen or alkyl of 1 to 3 carbon atoms,
    B is hydrogen,
    A compound of formula 1 wherein R (9) and B together form a bond.
    [3" claim-type="Currently amended] The method according to claim 1 or 2,
    R (1) and R (2) are independently of each other hydrogen, CF 3 or alkyl of 1 to 6 carbon atoms,
    R (1) and R (2) together form an alkylene chain of 2 to 6 carbon atoms,
    R (3) is R (10) -C n H 2n- {where R (10) is methyl, CF 3 or C 2 F 5 ,
    n is 0, 1 or 2},
    R (4) is R (13) -C r H 2r {wherein one CH 2 group in the C r H 2r group is -O-, -CH = CH-, -C≡C-, -CO-,- CO-O-, -O-CO-, -S-, -SO-, -SO 2- , -NR (14)-or -CONR (14)-[where R (14) is hydrogen, 1 to C Alkyl of 3, -C y H 2y -OR (12b), -C y H 2y -NR (12b) 2 , wherein R (12b) is hydrogen, methyl or ethyl and y is 2 or 3] ego; R (13) is H, CF 3 , C 2 F 5 , cycloalkyl having 3 to 7 carbon atoms, -NR (15) R (16), -CONR (15) R (16), -OR (17),- COOR (17), phenyl or N-containing heterocycle having 1 to 9 carbon atoms, wherein phenyl and N-containing heterocycle are unsubstituted, or are substituted with F, Cl, Br, CF 3 , NO 2 , CN, NH 2 , OH , Substituted with one or two substituents selected from the group consisting of methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (15) and R (16) are independently of each other hydrogen or alkyl having 1 to 4 carbon atoms; R (15) and R (16) together form 4 or 5 methylene group chains, where one CH 2 group is -O-, -S-, -NH-, -N (CH 3 )-or -N ( Benzyl)-); R (17) is hydrogen, alkyl of 1 to 3 carbon atoms, or -C x H 2x OR (12c), wherein R (12c) is hydrogen, methyl or ethyl and x is 2 or 3); r is an integer of 1 to 12},
    R (6) is -YC S H 2S -R (18), thienyl, furyl or an N-containing heterocycle having 1 to 9 carbon atoms, wherein thienyl, furyl and N-containing heterocycle are unsubstituted or F , Cl, Br, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, methylamino, dimethylamino, ethylamino, diethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino Substituted with one or two substituents selected from the group consisting of: Y is -O-, -CO-, -O-CO-, -S-, -SO-, -SO 2- , -SO 2 -O-, -SO 2 NR (12d)-, -NR (12d) Or -CONR (12d)-[wherein the bond to the benzene nucleus is in each case via the left atom; R (12d) is hydrogen, methyl or ethyl; s is an integer from 1 to 6; R (18) is phenyl substituted with one or two substituents selected from the group consisting of NH 2 , N (methyl) 2 , OH, ethyl, -COOmethyl, -COOethyl, -CONH 2 and -CON (methyl) 2 ; R (18) is selected from the group consisting of F, Cl, Br, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino N-containing heterocycle having 1 to 9 carbon atoms substituted with one or two substituents; R (18) is -OR (19), -NR (19) R (20), -CONR (19) R (20), where R (19) and R (20) are independently of each other C t H 2t -R (21), where t is an integer from 0 to 6; R (21) is hydrogen, CF 3 , NR (22) R (23), -OR (24), phenyl, thienyl or 1 to carbon atoms N-containing heterocycle of 9 wherein phenyl, thienyl and N-containing heterocycle are unsubstituted or are substituted with F, Cl, Br, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, Substituted with one or two substituents selected from the group consisting of dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R (22) and R (23) are independently of each other hydrogen or alkyl of 1 to 3 carbon atoms; (22) and R (23) together may be substituted with 4 or 5 methylene group chains, wherein one CH 2 group may be substituted with -O-, -S-, -NH- or -N (CH 3 )- R (24) is hydrogen or alkyl having 1 to 3 carbon atoms;
    R (5), R (7) and R (8) are independently of each other hydrogen, F, Cl, Br, alkyl having 1 to 5 carbon atoms, CN, CF 3 , NO 2 or OR (12e) {where R ( 12e) is alkyl having 1 to 4 carbon atoms},
    R (9) is hydrogen or OH,
    B is hydrogen,
    A compound of formula 1 wherein R (9) and B together form a bond.
    [4" claim-type="Currently amended] The method according to any one of claims 1 to 3,
    R (1) and R (2) are independently of each other hydrogen, CF 3 or alkyl of 1 or 2 carbon atoms,
    R (1) and R (2) together form an alkylene chain of 2 to 5 carbon atoms,
    R (3) is methyl or ethyl,
    R (4) is R (13) -C r H 2r {wherein one CH 2 group of the C r H 2r group is -O-, -CO-O-, -O-CO-, -NR (14) Or -CONR (14)-, wherein R (14) is hydrogen or alkyl of 1 or 2 carbon atoms; R (13) is hydrogen, CF 3 , -NR (15) R (16), -CONR (15) R (16), -OR (17), -COOR (17), phenyl or N having 1 to 9 carbon atoms -Containing heterocycles wherein phenyl and N-containing heterocycles are unsubstituted or substituted from the group consisting of F, Cl, Br, CF 3 , methyl, methoxy, sulfamoyl, methylsulfonyl and methylsulfonylamino Substituted with one or two; R (15) and R (16) are independently of each other hydrogen or alkyl having 1 or 2 carbon atoms; R (15) and R (16) together form 4 or 5 methylene group chains, where one CH 2 group may be substituted with -O-, -NH- or -N (CH 3 )- and; R (17) is hydrogen or alkyl of 1 or 2 carbon atoms; r is an integer of 1 to 7},
    R (6) is -YC S H 2S -R (18), thienyl, furyl or an N-containing heterocycle having 1 to 9 carbon atoms, wherein thienyl, furyl and N-containing heterocycle are unsubstituted or F Or substituted with one or two substituents selected from the group consisting of Cl, Br, CF 3 , methyl, methoxy, methylamino, dimethylamino, ethylamino, diethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; Y is -O- or -CONR (12d)-[wherein the bond to the benzene nucleus is through the left atom; R (12d) is hydrogen, methyl or ethyl; s is an integer from 1 to 6; R (18) is phenyl substituted with one or two substituents selected from the group consisting of NH 2 , N (methyl) 2 , OH, —COOmethyl, —COOethyl and —CON (methyl) 2 ; R (18) is selected from the group consisting of F, Cl, Br, CF 3 , NO 2 , CN, NH 2 , OH, methyl, ethyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino N-containing heterocycle having 1 to 9 carbon atoms substituted with one or two substituents; R (18) is -OR (19) or -CONR (19) R (20), where R (19) and R (20) are independently of each other C t H 2t -R (21) (where t is Is an integer from 0 to 3; R (21) is hydrogen, CF 3 , NR (22) R (23) or -OR (24), where R (22) and R (23) are independently of each other hydrogen or carbon number 1 Alkyl of from 3 to 3; R (22) and R (23) together are 4 or 5 methylene group chains, where one CH 2 group is -O-, -S-, -NH- or -N (CH 3 Can be substituted with R <->; R (24) is hydrogen, alkyl having 1 or 2 carbon atoms),
    R (5), R (7) and R (8) are hydrogen,
    R (9) is hydrogen or OH,
    B is hydrogen,
    A compound of formula 1 wherein R (9) and B together form a bond.
    [5" claim-type="Currently amended] The method according to any one of claims 1 to 4,
    R (1) and R (2) are methyl,
    R (3) is methyl or ethyl,
    R (4) is R (13) -C r H 2r {wherein one CH 2 group of the C r H 2r group may be substituted with —O—; R (13) is hydrogen or CF 3 ; r is an integer of 1 to 6},
    R (6) is -YC S H 2S -R (18), thienyl, or an N-containing heterocycle having 1 to 9 carbon atoms, wherein thienyl and N-containing heterocycle are unsubstituted, or F, Cl, Substituted with one or two substituents selected from the group consisting of CF 3 , methyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; Y is -O-; s is an integer from 1 to 6; R (18) is substituted with one or two substituents selected from the group consisting of F, Cl, CF 3 , NO 2 , CN, OH, methyl, methoxy, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino, N-containing heterocycle having 1 to 9 carbon atoms; R (18) is -OR (19) or -CONR (19) R (20), where R (19) and R (20) are independently of each other C t H 2t -R (21) (where t is Is an integer from 0 to 3; R (21) is hydrogen, CF 3 , NR (22) R (23) or -OR (24), where R (22) and R (23) are independently of each other hydrogen or carbon number 1 Or alkyl of 2; R (24) is hydrogen, alkyl of 1 or 2 carbon atoms;
    R (5), R (7) and R (8) are hydrogen,
    R (9) is hydrogen,
    A compound of formula 1, wherein B is hydrogen.
    [6" claim-type="Currently amended] A compound of formula (1) or a physiologically acceptable salt thereof according to any one of claims 1 to 5 for use as a medicament.
    [7" claim-type="Currently amended] As an active compound, an effective amount of at least one compound of formula (1) according to any one of claims 1 to 6 and / or physiologically acceptable salts thereof, pharmaceutically acceptable excipients and additives and, if desired, A pharmaceutical formulation further comprising one or more other pharmacologically active compounds.
    [8" claim-type="Currently amended] Use of a compound of formula 1 according to any one of claims 1 to 5 and / or physiologically acceptable salts thereof for the preparation of a K + channel blocking agonist for the treatment and prevention of K + channel intervening diseases. .
    [9" claim-type="Currently amended] Use of a compound of formula 1 according to any one of claims 1 to 5 and / or a physiologically acceptable salt thereof for the preparation of a medicament for inhibiting gastric acid secretion.
    [10" claim-type="Currently amended] Use of a compound of formula 1 according to any one of claims 1 to 5 and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of gastric ulcer or intestinal ulcer.
    [11" claim-type="Currently amended] Use of a compound of formula 1 according to any one of claims 1 to 5 and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of reflux esophagitis.
    [12" claim-type="Currently amended] Use of a compound of formula 1 according to any one of claims 1 to 5 and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of diarrheal diseases.
    [13" claim-type="Currently amended] A compound of formula 1 according to any one of claims 1 to 5 and / or physiologically acceptable thereof for the manufacture of a medicament for the treatment or prophylaxis of all types of arrhythmia, including atria, ventricles and ventricular arrhythmias Use of salts.
    [14" claim-type="Currently amended] Use of a compound of formula 1 according to any one of claims 1 to 5 and / or physiologically acceptable salts thereof for the manufacture of a medicament for the treatment or prophylaxis of cardiac arteries which can be eliminated by a translocation maintenance action. .
    [15" claim-type="Currently amended] A compound of formula 1 according to any one of claims 1 to 5 and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of atrial fibrillation or atrial fibrillation Usage.
    [16" claim-type="Currently amended] A compound of formula 1 according to any one of claims 1 to 5 and / or physiologically acceptable for the manufacture of a medicament for the treatment or prevention of reentry arrhythmias or for the prevention of cardiac arrest by ventricular fibrillation. Use of salts thereof.
    [17" claim-type="Currently amended] Use of a compound of formula 1 according to any one of claims 1 to 5 and / or physiologically acceptable salts thereof for the manufacture of a medicament for the treatment of heart failure.
    [18" claim-type="Currently amended] For suppressing stimulated gastric acid secretion, for treating or preventing gastric ulcers, intestinal ulcers, reflux esophagitis, diarrheal diseases, arrhythmias in the atria, ventricles and ventricles, atrial fibrillation and atrial fibrillation, or for ventricular fibrillation Use of a compound of formula 1 according to any one of claims 1 to 5 and / or a physiologically acceptable salt thereof for the manufacture of a medicament for the prevention of cardiac arrest by.
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    同族专利:
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    CZ307198A3|1999-04-14|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1997-09-26|Priority to DE19742508.9
    1997-09-26|Priority to DE19742508A
    1998-09-25|Application filed by 로버트 흐라이탁, 미쉘 베스트, 훽스트 마리온 뤼쎌 도이치란드 게엠베하
    1999-04-26|Publication of KR19990030120A
    优先权:
    申请号 | 申请日 | 专利标题
    DE19742508.9|1997-09-26|
    DE19742508A|DE19742508A1|1997-09-26|1997-09-26|Sulfonamide-substituted chromanes, processes for their preparation, their use as medicaments or diagnostic agents and pharmaceutical preparations containing them|
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