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    • 专利摘要:
    The present invention relates to compounds of formula (I) Formula I In the above formula, Each radical is as defined in the claims. The compound may be used for a wide range of diseases such as cardiac infarction, angina pectoris, diseases caused by ischemia, impaired breathing, ischemic symptoms of the heart, ischemic symptoms and seizures of the peripheral and central nervous system, ischemic symptoms of peripheral organs and limbs, cell proliferation Used for the treatment and / or prevention of diseases of primary or secondary cause, for the treatment of sprained conditions during surgical insertion and organ transplantation, or as a drug for the preservation and storage of the implant to be used for surgical insertion. Is an inhibitor of sodium-dependent bicarbonate / chloride ion exchanger.
    公开号:KR20010043304A
    申请号:KR1020007012268
    申请日:1999-04-30
    公开日:2001-05-25
    发明作者:바이헤르트안드레아스；랑한스요헨；페트리슈테판；슈바르크얀-로베르트；클레만하인츠-베르너；파버자비네；얀젠한스-빌리
    申请人:로버트 흐라이탁, 미쉘 베스트；아벤티스 파마 도이칠란트 게엠베하；
    IPC主号:
    专利说明:

    Substituted sulphonyl cyanamides, method for producing same and their use as medicament
    The present invention relates to compounds of formula (I) and physiologically acceptable salts thereof:
    In the above formula,
    X is ego;
    R (1) is hydrogen; Alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; Or -C a H 2a -phenyl
    [Wherein the phenyl moiety is unsubstituted or one, two or three identical from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy and NR (19) R (20) Or substituted by different radicals,
    R (19) and R (20) are independently of each other H or alkyl of 1, 2, 3 or 4 carbon atoms,
    a is 0, 1 or 2], or
    R (1) is —C b H 2b -heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms
    Wherein the heteroaryl moiety is unsubstituted or one, two or three from the group consisting of F, Cl, Br, I, CF 3 , CH 3 , methoxy, hydroxy and NR (21) R (22) Substituted by the same or different radicals,
    R (21) and R (22) are independently of each other H or alkyl of 1, 2, 3 or 4 carbon atoms,
    b is 0, 1 or 2], or
    R (1) is —C c H 2c -cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, where c is 0, 1 or 2;
    R (2) and R (3) are independently of each other hydrogen, F, Cl, Br, I, CF 3 , -CN, -NO 2 , CH 2 OR (23), CO-R (24) or OR (25) )
    [Where R (23) is hydrogen or alkyl of 1, 2, 3, 4, 5, 6, 7 or 8,
    R (24) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8, OR 26 or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , Substituted by one, two or three identical or different radicals from the group consisting of one to three substituents from the group consisting of methyl, methoxy, hydroxy and NR (27) R (28), R (27) and R (28) are independently of each other H or alkyl of 1, 2, 3 or 4, R (26) is hydrogen or of 1, 2, 3, 4, 5, 6, 7 or 8 Alkyl),
    R (25) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8, or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , methyl, me Is substituted by one, two or three identical or different radicals from the group consisting of oxy, hydroxy and NR (29) R (30), wherein R (29) and R (30) are independently of each other H or Or alkyl having 1, 2, 3 or 4 carbon atoms, or
    R (25) is unsubstituted or one, two or three identical from the group consisting of F, Cl, Br, I, CF 3 , CH 3 , methoxy, hydroxy and NR (31) R (32) Heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, wherein R (31) and R (32) are independently of each other H or 1, 2, 3 or 4 alkyl); or
    R (2) and R (3) are independently of each other alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or -C d H 2d -phenyl
    [Wherein the phenyl moiety is unsubstituted or one, two or three identical from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy and NR (33) R (34) Or substituted by different radicals,
    R (33) and R (34) are independently of each other H or alkyl of 1, 2, 3 or 4 carbon atoms,
    d is 0, 1 or 2], or
    R (2) and R (3) independently of one another are -C e H 2e -heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms
    [Wherein the heteroaryl moiety is unsubstituted or one, two or three from the group consisting of F, Cl, Br, I, CF 3 , CH 3 , methoxy, hydroxy and NR (35) R (36) Substituted by the same or different radicals,
    R (35) and R (36) are independently of each other H or alkyl of 1, 2, 3 or 4 carbon atoms,
    e is 0, 1 or 2], or
    R (2) and R (3) are each independently of the other -SO f -R (37)
    [Wherein R (37) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or -C g H 2g -phenyl, wherein the phenyl moiety is unsubstituted or is selected from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy and NR (38) R (39) Substituted by 3, 2 or 3 same or different radicals, R (38) and R (39) are independently of each other H or alkyl of 1, 2, 3 or 4, f is 0, 1 or 2 And g is 0, 1 or 2);
    R (4) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8, 1-naphthyl, 2-naphthyl, -C i of 3, 4, 5, 6 or 7 carbon atoms H 2i -cycloalkyl, or —C i H 2i -phenyl
    [Wherein the phenyl moiety is unsubstituted or has 1, 2, 3, 4, 5, 6, 7 or 8 alkyl, F, Cl, Br, I, CF 3 , SO j R (48), OR (49) Is substituted by one, two or three identical or different radicals from the group consisting of NR (50) R (51), -CN, -NO 2 and CO-R (52),
    i is 0, 1 or 2,
    R (48) is alkyl having 1, 2, 3 or 4 carbon atoms or NR (53) R (54),
    R (53) and R (54) are independently of each other hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    j is 0, 1 or 2,
    R (49) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    R (50) and R (51) are independently of each other hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    R (52) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 or OR (55),
    R 55 is hydrogen or alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or
    R (4) and R (6) together with the carbon atoms accompanying them are cycloalkyl or fluorenyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (5), R (6), R (7) and R (8) are independently of each other hydrogen, F, CF 3 , OR (56), carbon number 1, 2, 3, 4, 5, 6, 7 or Alkyl of 8, cycloalkyl of 3, 4, 5, 6 or 7 or -C k H 2k -phenyl
    [Wherein the phenyl moiety is unsubstituted or one, two or three identical from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy and NR (57) R (58) Or substituted by different radicals,
    R (57) and R (58) are independently of each other hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    k is 0, 1 or 2,
    R (56) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8, or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , methyl, me Substituted by one, two or three identical or different radicals from the group consisting of oxy, hydroxy and NR (59) R (60), wherein R (59) and R (60) are independently of each other hydrogen or Or alkyl having 1, 2, 3 or 4 carbon atoms, or
    R (56) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the heteroaryl is unsubstituted or substituted with F, Cl, Br, I, CF 3 , CH 3 , me Substituted by one, two or three identical or different radicals from the group consisting of oxy, hydroxy and NR (61) R (62), wherein R (61) and R (62) are independently of each other hydrogen or Or alkyl having 1, 2, 3 or 4 carbon atoms;
    R (5) and R (7) together are the second bond between the carbon atoms accompanying the radicals R (6) and R (8), where R (4), R (6) and R (8) are As defined above;
    R (9) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or -C l H 2l-ll -A
    [Wherein ll is 0 or 2 and l is 0, 1, 2, 3 or 4; when ll is 2, l is not 0 or 1];
    R (10) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl of 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or -C m H 2m -mm -B
    [Where mm is 0 or 2 and m is 0, 1, 2, 3 or 4; when mm is 2, m is not 0 or 1];
    R (11) and R (12) are independently of each other hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
    Z is carbonyl or sulfonyl;
    A and B are independent of each other
    1. aryl having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;
    2. Alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br, I, CF 3 , SO n R (63), OR (64), NR (65) R ( 66), a radical as defined in 1, substituted by one, two or three identical or different radicals from the group consisting of —CN, —NO 2 and CO—R 67;
    3. heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;
    4. Substitution by one, two or three identical or different radicals from the group consisting of F, Cl, Br, I, CF 3 , CH 3 , methoxy, hydroxy and NR (68) R (69) Radicals as defined in 3;
    5. cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
    6. O-R 70; or
    7. O-R 71;
    n is 0, 1 or 2;
    R (70) and R (71) are independent of each other
    1. hydrogen;
    2. alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
    3. -C o H 2o-oo -phenyl wherein oo is 0 or 2 and o is 0, 1, 2, 3 or 4; when oo is 2, o is not 0 or 1;
    4. Phenyl residues are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br, I, CF 3 , SO p R (72), OR (73), NR (74) A radical as defined in 3 which is substituted by one, two or three identical or different radicals from the group consisting of R (75), -CN, -NO 2 and CO-R (76); or
    5. alkenyl of 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
    R (63) and R (72) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms or NR (77) R (78);
    R (67) and R (76) are independently of each other hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 or OR (89);
    R (89) is hydrogen or alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
    R (64), R (65), R (66), R (68), R (69), R (73), R (74), R (75), R (77) and R (78) Independently of one another are hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    p is 0, 1 or 2 independently of each other;
    R (13), R (14) and R (15) are independently of each other hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8, F, Cl, Br, I, CF 3 , -CN, -NO 2 , SO q -R (79), CO-R (80) or OR (81)
    [Wherein q is 0, 1 or 2 independently of each other,
    R (79) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , methyl, methoxy, Substituted by one, two or three identical or different radicals from the group consisting of hydroxy and NR (82) R (83), wherein R (82) and R (83) are independently of each other hydrogen or carbon atoms , 2, 3 or 4 alkyl)
    R (80) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 or OR (84),
    R (84) is hydrogen or alkyl of 1, 2, 3, 4, 5, 6, 7 or 8,
    R (81) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8, or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , methyl, me Oxy, hydroxy and NR (82) R (83) are substituted by one, two or three identical or different radicals);
    Y is CR (16) R (17), CO, S, SO 2 , O, NR (18);
    R (16) is hydrogen or -OR (85)
    [Wherein R (85) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 or CO-R (86),
    R (86) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , methyl, methoxy and Is substituted by one, two or three identical or different radicals from a group consisting of hydroxy);
    R (17) is hydrogen or alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
    R (18) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, CO-R (87) or SO 2 R (88), wherein R (87) and R (88) ) Is independently of each other alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl (unsubstituted or substituted with F, Cl , Is substituted by one, two or three identical or different radicals from the group consisting of Br, I, CF 3 , methyl, methoxy and hydroxy).
    Preferred compounds of formula (I)
    X ego;
    R (1) is hydrogen; Alkyl having 1, 2, 3 or 4 carbon atoms; Or -C a H 2a -phenyl
    [Wherein the phenyl moiety is unsubstituted or substituted by one, two or three identical or different radicals from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy, a Is 0 or 1], or
    Carbon number, wherein R (1) is unsubstituted or substituted by one, two or three identical or different radicals from the group consisting of F, Cl, Br, I, CF 3 , CH 3 , methoxy and hydroxy 1, 2, 3, 4, 5, 6, 7, 8 or 9 heteroaryl, or
    R (1) is —C c H 2c -cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, where c is 0 or 1;
    R (2) and R (3) are independently of each other hydrogen, F, Cl, Br, I, CF 3 , -CN, -NO 2 , CH 2 OR (23), CO-R (24) or OR (25 )
    [Wherein R (23) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,
    R (24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR (26) or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy Substituted by one, two or three identical or different radicals from the group consisting of R (26) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,
    R (25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or is selected from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy One, two or three of the same or different radicals), or
    R 25 is unsubstituted or substituted by 1, 2 or 3 identical or different radicals from the group consisting of F, Cl, Br, I, CF 3 , CH 3 and methoxy , 3, 4, 5, 6, 7, 8 or 9 heteroaryl; or
    R (2) and R (3) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or -C d H 2d -phenyl
    [Wherein the phenyl moiety is unsubstituted or substituted by one, two or three identical or different radicals from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy, d Is 0 or 1], or
    R (2) and R (3) are, independently of each other, unsubstituted or one, two or three identical from the group consisting of F, Cl, Br, I, CF 3 , CH 3 , methoxy and hydroxy Or heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, substituted by different radicals, or
    R (2) and R (3) are independently of each other -SO f -R (37)
    [Wherein R (37) is alkyl having 1, 2, 3 or 4 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or -C g H 2g -phenyl, wherein the phenyl moiety is unsubstituted or one, two or three identical from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy Substituted by different radicals, f is 0, 1 or 2, and g is 0 or 1);
    R (4) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, 1-naphthyl, 2-naphthyl, -C i H 2i -cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, or- C i H 2i -phenyl
    [Wherein the phenyl moiety is unsubstituted or has 1, 2, 3, 4, 5, 6, 7 or 8 alkyl, F, Cl, CF 3 , SO j R (48), OR (49), NR (50 Is substituted by one, two or three identical or different radicals from the group consisting of R (51), -CN and CO-R (52),
    i is 0, 1 or 2,
    R (48) is alkyl having 1, 2, 3 or 4 carbon atoms or NR (53) R (54),
    R (53) and R (54) are independently of each other hydrogen, methyl or ethyl,
    j is 0 or 2,
    R (49) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    R (50) and R (51) are independently of each other hydrogen, methyl or ethyl,
    R (52) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms or OR (55),
    R 55 is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms; or
    R (4) and R (6) together with the carbon atoms accompanying them are cycloalkyl or fluorenyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (5), R (6), R (7) and R (8) are each independently hydrogen, F, CF 3 , OR (56), alkyl having 1, 2, 3 or 4 carbon atoms, 3, 4 carbon atoms , 5, 6 or 7 cycloalkyl or -C k H 2k -phenyl
    [Wherein the phenyl moiety is unsubstituted or substituted by one, two or three identical or different radicals from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy,
    k is 0 or 1,
    R 56 is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or is selected from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy One, two or three of the same or different radicals), or
    R (56) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the heteroaryl is unsubstituted or substituted with F, Cl, Br, I, CF 3 , CH 3 , me Is substituted by one, two or three identical or different radicals from the group consisting of oxy and hydroxy), or
    R (5) and R (7) together are the second bond between the carbon atoms accompanying the radicals R (6) and R (8), where R (4), R (6) and R (8) are As defined above;
    R (9) is alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, or -C 1 H 2l-ll -A
    [Wherein ll is 0 or 2 and l is 0, 1, 2 or 3; when ll is 2, l is not 0 or 1];
    R (10) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, alkenyl of 2, 3 or 4 carbon atoms, or -C m H 2m-mm- B
    [Where mm is 0 or 2 and m is 0, 1, 2 or 3; when mm is 2, m is not 0 or 1];
    R (11) and R (12) are independently of each other hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    Z is carbonyl or sulfonyl;
    A and B are independent of each other
    1. phenyl;
    2. 1, 2 from the group consisting of alkyl, F, Cl, CF 3 , SO n R (63), OR (64), —CN and CO-R (67) having 1, 2, 3 or 4 carbon atoms Radicals as defined in 1, substituted by 3 or 3 same or different radicals;
    3. 1-naphthyl or 2-naphthyl;
    4. substituted by one, two or three identical or different radicals from the group consisting of alkyl, F, Cl, CF 3 , CH 3 , methoxy and hydroxy having 1, 2, 3 or 4 carbon atoms, Radicals as defined in 3;
    5. heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;
    6. substituted by one, two or three identical or different radicals from the group consisting of alkyl, F, Cl, CF 3 , CH 3 , methoxy and hydroxy having 1, 2, 3 or 4 carbon atoms, Radicals as defined in 5;
    7. cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
    8. O-R 70; or
    9. O-R 71;
    n is 0, 1 or 2;
    R (70) and R (71) are independent of each other
    1. hydrogen;
    2. alkyl having 1, 2, 3 or 4 carbon atoms;
    3. -C o H 2o-oo -phenyl wherein oo is 0 or 2 and o is 0, 1, 2 or 3; when oo is 2, o is not 0 or 1;
    4. The phenyl moiety consists of alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF 3 , SO p R (72), OR (73), -CN, -NO 2 and CO-R (76) Radicals as defined in 3, substituted by one, two or three identical or different radicals from the group; or
    5. alkenyl having 2, 3 or 4 carbon atoms;
    R (63) and R (72) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms or NR (77) R (78);
    R (67) and R (76) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms or O-alkyl having 1, 2, 3 or 4 carbon atoms;
    R (64) and R (73) are independently of each other hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    p is independently from each other 0, 1 or 2;
    R (13), R (14) and R (15) are independently of each other hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF 3 , -CN, SO q -R (79), CO -R (80) or OR (81)
    [Where q is 0, 1 or 2,
    R (79) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or from 1, 2 from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy Or substituted by three same or different radicals),
    R (80) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms or OR (84),
    R (84) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    R (81) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or one from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy, Two or three identical or different radicals are substituted);
    Y is CR (16) R (17), CO, S, SO 2 , O or NR (18);
    R (16) is hydrogen or -OR (85)
    [Where R (85) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or COR (86),
    R (86) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or from 1, 2 or 3 from the group consisting of F, Cl, CF 3 , methyl and methoxy Substituted by the same or different radicals;
    R (17) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    R (18) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, COR (87) or SO 2 R (88), wherein R (87) and R (88) are independently of each other C1, 2, Alkyl of 3 or 4, cycloalkyl of 3, 4, 5, 6, 7 or 8, or phenyl, which is unsubstituted or from the group consisting of F, Cl, Br, I, CF 3 , methyl and methoxy Dogs, two or three are substituted by the same or different radicals), and a physiologically acceptable salt thereof.
    Preferred compounds of formula (I)
    X ego;
    R (1) is hydrogen; Alkyl having 1, 2, 3 or 4 carbon atoms; Or phenyl
    Wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy; or
    R 1, unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , CH 3 , methoxy and hydroxy, having 1, 2, 3, 4, 5, 6, 7, 8 Or heteroaryl of 9, or
    R (1) is cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (2) and R (3) are independently of each other hydrogen, F, Cl, CF 3 , -CN, -NO 2 , CO-R (24) or OR (25)
    [Where R (24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR (26) or phenyl, wherein phenyl is unsubstituted or substituted with F, Cl, CF 3 , methyl, methoxy and hydroxy Substituted by a substituent from the group consisting of R (26) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,
    R (25) is hydrogen, alkyl of 1, 2, 3 or 4, or phenyl, wherein phenyl is unsubstituted or substituted by a substituent from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy Is substituted), or
    R (2) and R (3) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or phenyl, wherein phenyl is unsubstituted or substituted by substituents from a group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy; or
    R (2) and R (3) are independently of each other, substituted or unsubstituted on one, two or three identical or different radicals from the group consisting of F, Cl, CF 3 , CH 3 , methoxy and hydroxy Substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 heteroaryl;
    R (2) and R (3) are independently of each other -SO f -R (37)
    [Wherein R (37) is alkyl having 1, 2, 3 or 4 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or phenyl, wherein phenyl is unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy, and f is 0 or 2;
    R (4) is methyl, ethyl, 1-naphthyl, 2-naphthyl, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, or -C i H 2i -phenyl, wherein i is 0 or 1 ] Or
    R (4) and R (6) together with the carbon atoms accompanying them are cycloalkyl or fluorenyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (5) and R (7) are independently of each other hydrogen or fluorine, or a second bond between carbon atoms carrying radicals R (6) and R (8);
    R (6) and R (8) are independently of each other hydrogen, F, CF 3 , OR (56), alkyl having 1, 2, 3 or 4 carbon atoms or -C k H 2k -phenyl
    [Wherein the phenyl moiety is unsubstituted or substituted by one, two or three identical or different radicals from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy,
    k is 0 or 1,
    R (56) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or one from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy, Substituted by two or three identical or different radicals), or
    R (56) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein heteroaryl is unsubstituted or is substituted with F, Cl, CF 3 , CH 3 , methoxy and hydroxy Is substituted by one, two or three identical or different radicals from the group consisting of
    R (9) is alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, or -C l H 2l-ll -A wherein ll is 0 or 2, and l is 0, 1, 2 or 3; when ll is 2, l is not 0 or 1];
    R (10) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, alkenyl of 2, 3 or 4 carbon atoms, or -C m H 2m-mm -B, where mm is 0 or 2, and m is 0, 1, 2 or 3; when mm is 2, m is not 0 or 1];
    R (11) and R (12) are independently of each other hydrogen or methyl;
    Z is carbonyl or sulfonyl;
    A and B are independent of each other
    1. phenyl;
    2. 1, 2 from the group consisting of alkyl of 1, 2, 3 or 4 carbon atoms, F, Cl, CF 3 , SO 2 R (63), OR (64), -CN and CO-R (67) Radicals as defined in 1, substituted by 3 or 3 same or different radicals;
    3. 1-naphthyl or 2-naphthyl;
    4. a radical as defined in 3, substituted by a radical from the group consisting of alkyl, F, Cl, CF 3 , CH 3 , methoxy and hydroxy having 1, 2, 3 or 4 carbon atoms;
    5. heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;
    6. radicals as defined in 5, substituted by radicals from the group consisting of F, Cl, CF 3 , CH 3 , methoxy and hydroxy;
    7. cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (63) is alkyl having 1, 2, 3 or 4 carbon atoms;
    R (67) is alkyl having 1, 2, 3 or 4 carbon atoms or O-alkyl having 1, 2, 3 or 4 carbon atoms;
    R (64) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    R (13), R (14) and R (15) are independently of each other hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF 3 , -CN, SO q -R (79), CO -R (80) or OR (81)
    [Where q is 0 or 2,
    R (79) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or from 1, 2 from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy Or substituted by three same or different radicals),
    R (80) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms or OR (84),
    R (84) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    R (81) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or one from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy, Two or three identical or different radicals are substituted);
    Y is CR (16) R (17), CO, S, SO 2 , O or NR (18);
    R (16) is hydrogen or -OR (85)
    [Where R (85) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or COR (86),
    R (86) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy] Is;
    R (17) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    R (18) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, COR (87) or SO 2 R (88), wherein R (87) and R (88) are independently of each other C1, 2, Alkyl of 3 or 4, cycloalkyl of 3, 4, 5 or 6, or phenyl, which is unsubstituted or substituted by radicals from the group consisting of F, Cl, Br, I, CF 3 , methyl and methoxy ) Is a compound of Formula I and a physiologically acceptable salt thereof.
    Particularly preferred compounds of formula I are
    X ego;
    R (1) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl
    Wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy], or
    Of 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein R (1) is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , CH 3 and methoxy Heteroaryl
    R (1) is cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (2) and R (3) are independently of each other hydrogen, F, Cl, CF 3 , -CN, CO-R (24) or OR (25)
    [Where R (24) is hydrogen, alkyl of 1, 2, 3 or 4, OR (26) or phenyl, wherein phenyl is unsubstituted or is selected from the group consisting of F, Cl, CF 3 , methyl and methoxy Substituted by a radical of R (26) is hydrogen, methyl or ethyl)
    R (25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy Or
    R (25) of 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , CH 3 and methoxy Heteroaryl] or
    R (2) and R (3) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy], or
    R (2) and R (3), independently of one another, are unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , CH 3 and methoxy, having 1, 2, 3, 4, 5 , Heteroaryl of 6, 7, 8 or 9, or
    R (2) and R (3) are independently of each other -SO f -R (37)
    [Where R (37) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy ) And f is 0 or 2;
    R (4) is methyl, ethyl, 1-naphthyl, 2-naphthyl, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, or phenyl,
    R (4) and R (6) together with the carbon atoms accompanying them are cycloalkyl or fluorenyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (5) and R (7) are independently of each other hydrogen or a second bond between carbon atoms carrying the radicals R (6) and R (8);
    R (6) and R (8) are independently of each other hydrogen, CF 3 , OR (56), alkyl or phenyl having 1, 2, 3 or 4 carbon atoms
    [Wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy,
    R 56 is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy Or
    R (56) is a heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the heteroaryl is unsubstituted or consists of F, Cl, CF 3 , CH 3 and methoxy Is substituted by a radical from);
    R (9) is alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, or -C l H 2l-ll -A wherein ll is 0 or 2, and l is 0, 1, 2 or 3; when ll is 2, l is not 0 or 1];
    R (10) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, alkenyl of 2, 3 or 4 carbon atoms, or -C m H 2m-mm -B, where mm is 0 or 2, and m is 0, 1, 2 or 3; when mm is 2, m is not 0 or 1];
    R (11) and R (12) are independently of each other hydrogen or methyl;
    Z is carbonyl or sulfonyl;
    A and B are independent of each other
    1. phenyl;
    2. Substituted by a radical from the group consisting of alkyl, F, Cl, CF 3 , SO 2 R (63), OR (64), -CN and CO-R (67) having 1, 2, 3 or 4 carbon atoms Radicals as defined in 1;
    3. 1-naphthyl or 2-naphthyl;
    4. a radical as defined in 3, substituted by a radical from the group consisting of alkyl, F, Cl, CF 3 , CH 3 and methoxy having 1, 2, 3 or 4 carbon atoms;
    5. heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;
    6. radicals as defined in 5, substituted by radicals from the group consisting of F, Cl, CF 3 , CH 3 and methoxy;
    7. cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (63) is alkyl having 1, 2, 3 or 4 carbon atoms;
    R (64) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    R (67) is alkyl having 1, 2, 3 or 4 carbon atoms or O-alkyl having 1, 2, 3 or 4 carbon atoms;
    R (13), R (14) and R (15) are independently of each other hydrogen, methyl, F, Cl, CF 3 , -CN, SO 2 -R (79), CO-R (80) or OR (81 )
    [Where R (79) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy )ego,
    R (80) is hydrogen, methyl or OR (84),
    R (84) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    R (81) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , methyl and methoxy Is;
    Y is CR (16) R (17), CO, S or SO 2 ;
    R (16) is hydrogen or -OR (85)
    [Where R (85) is hydrogen, methyl or COR (86),
    R (86) is methyl, cyclopentyl, cyclohexyl, or phenyl, wherein phenyl is unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , methyl and methoxy;
    Are compounds of formula I wherein R (17) is hydrogen or methyl and physiologically acceptable salts thereof.
    Particularly preferred compounds of formula I are
    X ego;
    R (1) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy;
    R (2) and R (3) are independently of each other hydrogen, F, Cl, CF 3 , -CN, CO-R (24) or OR (25)
    [Where R (24) is hydrogen, alkyl of 1, 2, 3 or 4, OR (26) or phenyl, wherein phenyl is unsubstituted or is selected from the group consisting of F, Cl, CF 3 , methyl and methoxy Substituted by a radical of R (26) is hydrogen, methyl or ethyl)
    R (25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy Or
    R (25) is heteroaryl which is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , CH 3 and methoxy], or
    R (2) and R (3) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms,
    R (2) and R (3) are, independently of one another, phenyl unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , methyl and methoxy, or
    R (2) and R (3) are, independently of each other, heteroaryl unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , CH 3 and methoxy, or
    R (2) and R (3) are independently of each other -SO f -R (37)
    [Where R (37) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy ) And f is 0 or 2;
    R (13), R (14) and R (15) are independently of each other hydrogen, methyl, F, Cl, CF 3 , -CN, SO 2 -R (79), CO-R (80) or OR (81 )
    [Wherein R (79) and R (81) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or consists of F, Cl, CF 3 , methyl and methoxy Is substituted by a radical from a group),
    R (80) is hydrogen, methyl or OR (84),
    R (84) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    Y is methylene and a physiologically acceptable salt thereof.
    Preferred compounds are compounds of formula (I) and physiologically acceptable salts thereof, wherein Y is methylene and X, R13, R14 and R15 are as defined above. Preference is also given to compounds of the formula I in which R (13), R (14) and R (15) are hydrogen in each case and physiologically acceptable salts thereof.
    Both alkyl and alkenyl may be straight or branched chain, independently of one another.
    Examples of alkyl radicals having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, isopentyl, neopentyl, Isohexyl, 3-methylpentyl, secondary-butyl, tert-butyl, tert-pentyl.
    Examples of alkenyl radicals are vinyl, 1-propenyl, allyl, butenyl, 3-methyl-2-butenyl.
    Cycloalkyl also means an alkyl-substituted ring.
    Cycloalkyl radicals are, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, which may for example be substituted by alkyl having 1, 2, 3 or 4 carbon atoms. Examples of substituted cycloalkyl radicals that may be mentioned are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.
    Aryl groups having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms are, for example, phenyl, naphthyl, biphenyl, anthryl or fluorenyl, 1-naphthyl, 2- Naphthyl and especially phenyl are preferred.
    Heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, in particular, has one or more CH groups replaced by N and / or two or more adjacent CH groups replaced by S, NH or O ( Radicals derived from phenyl or naphthyl). In addition, one or two atoms of the condensation site of the bicyclic radical may also be a nitrogen atom (as in indolizinyl).
    Heteroaryls are, in particular, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl , Pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnaolinyl.
    Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
    The present invention includes all stereoisomeric forms of the compounds of formula (I). The asymmetric centers contained in the compounds of formula (I) may all have an S configuration or an R configuration independently of one another. The present invention includes all possible enantiomers and diastereomers as well as mixtures of two or more stereoisomeric forms, for example mixtures of all ratios of enantiomers and / or diastereomers. Accordingly, the present invention relates to enantiomers in enantiomerically pure form, racemate form, and mixtures of two enantiomers in all proportions, as left-handed and preferential optical cognates. In the presence of cis / trans isomerism, the present invention relates to both cis and trans forms and mixtures of these forms in all proportions. If desired, individual stereoisomers may be prepared by conventional methods, such as by chromatography or crystallization, by using stereochemically homogeneous starting materials in the synthesis, or by dividing the particular mixture by stereoselective synthesis. Can be. If desired, derivatization may be carried out before the stereoisomer is separated. Stereoisomeric mixtures may be separated at the compound stage of formula (I) or at the intermediate stage during the synthesis process. In the presence of a mobile hydrogen atom, the present invention also encompasses all tautomeric forms of the compounds of formula (I).
    If the compound of formula (I) contains at least one acidic or basic group, the invention also relates to the corresponding physiologically or toxicologically acceptable salts, in particular pharmaceutically available salts. Thus, compounds of formula (I) containing acidic groups may be present on these groups and according to the invention, for example, may be used as alkali metal salts, alkaline earth metal salts or ammonium salts. Examples of such salts are sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia, or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids. There may be compounds of formula (I) containing at least one basic, ie, group capable of adding protons, in the form of acid addition salts with inorganic or organic acids which are physiologically acceptable according to the invention, for example hydrogen chloride, hydrogen bromide, Phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pi It can be used as a salt with melic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isnicotinic acid, citric acid, adipic acid and the like. When the compound of the formula (I) simultaneously contains an acidic group and a basic group in the molecule, the present invention also includes internal salts or betaines (zwitterions) in addition to the salt forms described. Salts can be obtained from compounds of formula I by conventional methods known to those skilled in the art, for example by combining organic or inorganic acids or bases in certain solvents or dispersants, or by anion exchange or cation exchange It can be obtained from other salts. The present invention is also not directly suitable for use as a medicament because of its low physiological tolerance, but includes all salts of the compounds of formula (I) which are suitable as intermediates for the preparation of chemical reactions or physiologically acceptable salts, for example. do. Physiologically acceptable salts of compounds of formula I mean organic and inorganic salts thereof, as described, for example, in Remington's Pharmaceutical Sciences (17th Edition, page 1418 (1985)). And in view of chemical stability and solubility, especially sodium, potassium, calcium and ammonium salts are preferred for acidic groups; in particular hydrochloride, sulfate, phosphate, or carboxylate or sulfonic acid salts, for example acetic acid, citric acid, benzoic acid, male Acids, fumaric acid, tartaric acid and p-toluenesulfonic acid are preferred for the basic group.
    The invention further relates to all solvates of compounds of formula (I), for example adducts with hydrates or alcohols, and also derivatives of compounds of formula (I), for example esters, and prodrugs and activities. Contains metabolites.
    The invention also relates to a process for preparing the novel compounds of formula (I) and their physiologically acceptable salts thereof, including reacting a compound of formula (II) with a cyanogen bromide:
    In the above formula,
    The radicals are as defined above.
    The reaction is a bipolar aprotic solvent, such as acetonitrile, DMA, which is stable against cyanogen bromide using a strong auxiliary base that is not extremely nucleophilic, such as K 2 CO 3 or Cs 2 CO 3 . Run in TMU or NMP. Suitable reaction temperatures are from 0 ° C. to the boiling point of the solvent used and temperatures of 60 to 120 ° C. are preferred.
    X Sulfonamide derivatives of Formula II may be prepared by reacting a compound of Formula III with a compound of Formula IV:

    In the above formula,
    Y, R (13), R (14) and R (15) are as defined above,
    G is, for example, CH 2 Cl, CH 2 Br, CH 2 OH, CH 2 OMs,
    Sulfonamide groups are described in J. Med. Chem. 1995, 38, 2357; Nucleophilic substitution or Mitsunobu reaction, it is advantageous to be present in a protected form, for example as a dimethylaminomethylene derivative.
    Methods for the preparation of compounds of formula IV are described in particular in EP-A 253310, EP-A 324377, US 5482957 and in J. Pat. Med. Chem. 1995, 38, 2357-2377.
    X Sulfonamide derivatives of formula (II) wherein, for example, G is-(CO) R (8) and Y, R (8), R (13), R (14) and R (15) are as defined above. Obtained via the Wittig reaction of a compound of formula III with phosphorane containing radicals R (4) and / or R (5) and / or R (6). Such Beatig reactions are known to those skilled in the art and are described, for example, in Org. Synth. 1960, 40, 66; J. Org. Chem. 1963, 28, 1128 and Org. Synth. Coll. Vol. 5 1973, 751.
    X The sulfonamide derivatives of formula (II) are, for example, prepared by amines by reductive amination with NaBH 3 CN (Synthesis 1975, 135), followed by reaction with an acid chloride R (9) -Z-Cl to give G Available through the compound of formula III, which is formyl. When R (11) and R (12) are not hydrogen, it is necessary to introduce related radicals. This does not react the imine passed through reductive amination with a specific reducing agent, but with organometallic compounds, such as Grignard compounds or alkyllithium compounds, which carry radicals R (11) or radicals R (12), By reaction in a manner known to the skilled person.
    Compounds of formula (III), wherein Y is as defined above, may be prepared by in situ reactions, for example, by in situ reactions having aryl halides substituted under Pd (O) catalysis by methods known to those skilled in the art [ Y = methylene] [see; J. Org. Chem. 1977, 42, 1821; J. Org. Chem. 1988, 53, 5789] can be prepared by methods known in the art by allowing suitable aryl derivatives to be obtained, for example, substituted by methyl, carboxylic esters, formyl, allowing the radicals G mentioned above to be obtained. Can be. The corresponding aryllithium derivatives are reacted with substituted benzaldehydes or benzoyl chlorides to yield substituted diphenylmethane or benzophenone derivatives [Y = C (R (16) R (17), CO].] The ether and thioether derivatives The preparation of [Y = O, S, SO 2 ] is usually carried out by nucleophilic substitution of sulfonamide-activated halobenzenes with phenolates or thiophenolates, the latter being a continuous oxidation reaction, for example meta- Conversion to the corresponding sulfonyl compound by oxidation with chloroperbenzoic acid Pd (O) -catalyzed reaction of aniline with aryl halides (J. Org. Chem. 1996, 61, 1133), or Through the reaction of acyl aniline with an aryl halide in the presence of potassium carbonate and copper iodide (J. Org. Chem. 1978, 26, 4975), Phenylamine [Y = NR (18)] can also be Can.
    The compounds of formula (I) according to the invention are suitable as inhibitors of sodium-dependent bicarbonate / chloride exchangers (NCBEs) or inhibitors of sodium / bicarbonate symporters.
    EP-A 855392 describes imidazole derivatives having biphenylsulfonylcyanamide side chains as NCBE inhibitors.
    EP-A 903339 and DE 19804251.5 propose biphenylsulfonylcyanamide derivatives substituted as NCBE inhibitors.
    Compounds similar to the compounds of formula I according to the invention are described in US Pat. Nos. 5,482,957 and 5,604,251 as well as in EP-A 479479, which are described as hypotensive angiotensin II antagonists. However, they do not have the sulfonylcyanamide side chains which are always present according to the invention. Imidazolbiphenyl derivatives are also described in WO9523792, WO9523791, EP-A 465368, EP-A 648763. Known compounds are angiotensin II receptor antagonists of subtype AT1, the action of which is not present in the compounds of formula (I) according to the invention or only at a slight extent.
    The present invention also provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of diseases caused by ischemic symptoms;
    The use of a compound of formula (I) for the manufacture of a medicament for treating or preventing heart infarction;
    The use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of angina;
    The use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of ischemic symptoms of the heart;
    The use of a compound of formula (I) for the manufacture of a medicament for the treatment or prevention of ischemic symptoms and seizures of the peripheral and central nervous system;
    The use of a compound of formula (I) for the manufacture of a medicament for treating or preventing ischemic symptoms of peripheral organs and members;
    The use of a compound of formula I for the manufacture of a medicament for the treatment of condition;
    The use of a compound of formula (I) for the manufacture of a drug for use in surgical operations and organ transplantation;
    The use of a compound of formula (I) for the manufacture of a medicament for the preservation and storage of the implant for surgical intervention;
    Has the use to prepare drugs for the treatment of diseases in which cell proliferation is the primary or secondary cause; The use of a compound of formula (I) for the preparation of atherosclerosis, the treatment of late diabetes complications, the treatment of carcinomatous disorders, the treatment of fibrosis, such as pulmonary fibrosis, liver fibrosis or renal fibrosis, the treatment of prostate hyperplasia;
    The use of a compound of formula (I) to prepare a medicament for treating impaired respiratory mobility; And
    A pharmaceutical comprising an effective amount of a compound of formula (I).
    For example, inhibition of cellular Na + -dependent Cl − / HCO 3 − exchange mechanisms of compounds of formula I according to the present invention which are potentially linked to each other, important for treating diseases arising in the case of oxygen-deficient symptoms. Because of the antiarrhythmic properties, the compounds of formula (I) are suitable as arrhythmia therapeutic agents with cardioprotective components for the prevention of infarction and for the treatment of infarction and for treating angina, which are also particularly ischemic induction in the formation of ischemic induced damage. Pathophysiological processes in the induction of isolated cardiac arrhythmias are inhibited or significantly reduced in a prophylactic manner.
    Due to pathological hypoxic and their potential protective effect on ischemic situations, the compounds of formula (I) according to the invention the intracellular Na + - dependent Cl - / HCO 3 - inhibition of the exchange mechanism, or ischemia or This 1 The sodium / bicarbonate symphote as a medicament for the treatment of any acute or chronic damage caused by secondary or secondary induced disease can be used. They can protect organs that are acutely or chronically inadequately supplied with oxygen by reducing or preventing ischemic induced damage, and therefore, in thrombosis, vasospasm, atherosclerosis or surgical inserts (eg, liver and kidneys). In transplantation, the compound protects the donor's organs before and during removal and thereby protects the removed organs, for example, during treatment or storage thereof in physiological bathing fluid and during transplantation into the recipient body. Or as a medicament in chronic or acute renal failure. Compounds of formula (I) are also potentially useful agents with protective action, for example when performing angiogenic surgical insertions on the heart and peripheral vessels. Corresponding to their potential protective action against ischemic induced damage, the compounds are also suitable as medicaments for treating ischemia of the nervous system, especially the central nervous system, wherein the compound is for example a seizure or It can be used to treat brain edema. Furthermore, the compounds of the formula (I) according to the invention are also suitable for treating allergic, cardiac, hemolytic and bacterial shock forms, for example.
    Because of the potentially potent inhibitory action on cell proliferation, eg, fibroblast proliferation and vascular smooth muscle cell proliferation, the compounds of formula (I) are atherosclerosis because they are suitable as useful therapeutics for diseases in which cell proliferation is the primary or secondary cause. It can be used as an agent for treating atherosclerosis, for treating late complications of diabetes, for treating carcinoma disorders, for treating fibrotic disorders such as pulmonary fibrosis, liver fibrosis or renal fibrosis, for treating organ hypertrophy and hyperplasia, especially prostatic hyperplasia or prostatic hyperplasia.
    Inhibitors of intracellular Na + -dependent Cl − / HCO − exchangers or inhibitors of sodium / bicarbonate symphoters have been found to be able to stimulate the respiratory tract through increased chemical sensitivity of the respiratory chemokines. These chemokines are involved to a considerable extent in maintaining orderly respiratory activity. They are activated in the body by hypoxia, a decrease in pH and an increase in CO 2 (excess carbonate) to regulate the respiratory fraction. During sleep, breathing is particularly susceptible to interference and much of it depends on the activity of chemoreceptors.
    Improving respiratory mobility as a result of stimulating the chemoreceptor with a substance that inhibits Na + -dependent Cl − / HCO 3 − exchange results in improved respiration in the following clinical symptoms and diseases: impaired central respiratory mobility (eg : Central apnea sleep, sudden infant death, postoperative hypoxia), muscle-related breathing disorders, respiratory disorders after long-term ventilation, respiratory disorders during adaptation to alpine zones, obstructive sleep, and apnea sleep, acute and chronic lung diseases and hypoxia And diseases in the form of mixed with excess carbon.
    Agents containing a compound of formula (I) may be administered orally, parenterally, intravenously, rectally or by inhalation, with the preferred method of administration being dependent upon the particular symptoms of the disease. The compounds of formula (I) can be used on their own or in combination with pharmaceutical adjuvants in both veterinary medicine and human medicine.
    Those skilled in the art are well aware of the adjuvants suitable for the desired pharmaceutical formulation based on their expertise. In addition to solvents, gel-forming agents, suppository bases, tablet aids and other active compound excipients, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor modifiers, preservatives, solubilizers or colorants can be used.
    In the case of oral dosage forms, the active compound is mixed with suitable additives, for example excipients, stabilizers or inert diluents, and suitable dosage forms, for example tablets, coated tablets, hard capsules, by conventional methods Made from aqueous, alcoholic or oily solvents. Inert excipients that can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. It can be prepared herein as anhydrous and wettable granules. Possible oily excipients or solvents are, for example, vegetable or animal oils, for example sunflower oil or cod liver oil.
    In the case of subcutaneous or intravenous administration, the active compound is optionally made into a solvent, suspending agent or emulsion with conventional substances, for example solubilizers, emulsifiers or other auxiliaries. Suitable solvents are, for example, water, saline or alcohols, for example ethanol, propanol, glycerol, and additionally also sugar solutions such as glucose or mannitol solutions, or mixtures of the various solvents mentioned. .
    Pharmaceutical formulations suitable for administration in the form of aerosols or sprays are, for example, solvents, suspensions of the active compounds of formula (I) in pharmaceutically acceptable solvents such as, in particular, ethanol or water, or mixtures of such solvents Agent or emulsion.
    If desired, the formulation may contain other pharmaceutical adjuvants such as surfactants, emulsifiers and stabilizers, and also propellants. Such formulations usually contain the active compound at a concentration of about 0.1 to 10, in particular about 0.3 to 3% by weight.
    The dosage and frequency of administration of the active compound of formula (I) to be administered depends on the efficacy and duration of action of the compound used; The type and severity of the disease to be treated; And the sex, age, weight and individual responsiveness of the mammal to be treated. On average, in a patient weighing approximately 75 kg, the daily dose of the compound of formula I is 0.001 mg / kg body weight or more, preferably 0.01 mg / kg body weight to 10 mg / kg body weight or less, preferably 1 mg / kg body weight to be. If the disease develops acutely, for example, immediately after cardiac infarction, a higher dose may be required, especially a greater number of times, for example up to four times a day. In particular, for intravenous administration, for example, for infarct patients in intensive care wards, up to about 200 mg per day may be necessary.
    The compounds of formula (I) can be used as sole active compounds or in combination with other pharmacologically active compounds.
    Compounds of formula (I) and / or physiologically acceptable salts thereof may be used in combination with other pharmacologically active compounds for treating or preventing the above-mentioned symptoms, in particular for the treatment of cardiovascular disorders, to achieve advantageous therapeutic effects. Preferred are combinations with inhibitors of sodium / hydrogen exchangers (NHEs) and / or active substances from other classes of cardiovascular active compounds.
    The invention additionally comprises a) a combination of an NCBE inhibitor of Formula I and / or a physiologically acceptable salt thereof with a NHE inhibitor and / or a physiologically acceptable salt thereof; b) a combination of an NCBE inhibitor of Formula I and / or a physiologically acceptable salt thereof with an active substance from another class of cardiovascular active compounds and / or a physiologically acceptable salt thereof; And c) active substances and / or physiologically acceptable from the NCBE inhibitor of Formula I and / or physiologically acceptable salts thereof and NHE inhibitors and / or physiologically acceptable salts thereof and other classes of cardiovascular active compounds. To a salt thereof.
    Active compounds known and identified as NHE inhibitors are guanidine derivatives, preferably acylguanidines, in particular Edward J. Cragoe, Jr., "DIURETICS, Chemistry, Pharmacology and Medicine", J. WILEY & Sons (1983). ), 303-341 or the NHE inhibitor mentioned in EP 98115754.8.
    Suitable NHE inhibitors are for example US 5292755, US 5373024, US 5364868, US 5591754, US 5516805, US 5559153, US 5571842, US 5641792, US 5631293, EP-A 577024, EP-A 602522, EP-A 602523 , EP-A 603650, EP-A 604852, EP-A 612723, EP-A 627413, EP-A 628543, EP-A 640593, EP-A 640588, EP-A 702001, EP-A 713864, EP-A 723956 Benzoylguanidine as described in EP-A 754680, EP-A 765868, EP-A 774459, EP-A 794171, EP-A 814077, EP-A 869116; Ortho-substituted benzoylguanidine as described in EP-A 556673, EP-A 791577, EP-A 794172; Ortho-amino-substituted benzoylguanidine as described in EP-A 690048; Isoquinoline as described in EP-A 590455; Benzo-fused five-membered ring heterocycle as described in EP-A 639573; Diacyl-substituted guanidines as described in EP-A 640587; Acylguanidine as described in US 5547953; Phenyl-substituted alkyl- or alkenylcarbonylguanidines with perfluoroalkyl groups, as described in US Pat. No. 5,567,734, EP-A 688766; Heteroaroylguanidine as described in EP-A 676395; Bicyclic heteroaroylguanidine as described in EP-A 682017; Indenoylguanidine as described in EP-A 738712; Benzyloxycarbonylguanidine as described in EP-A 748795; Phenyl-substituted alkenylcarbonylguanidines with fluorophenyl groups, as described in EP-A 744397; Substituted cinnamoylguanidine as described in EP-A 755919; Sulfonimideamides as described in EP-A 771788; Benzenedicarbonyldiguanidine as described in EP-A 774458, EP-A 774457; Diarylcarbonyldiguanidine as described in EP-A 787717; Substituted thiophenylalkenylcarbonylguanidines as described in EP-A 790245; Bis-ortho-substituted benzoylguanidine as described in EP-A 810207, substituted 1- or 2-naphthylguanidine as described in EP-A 810205 and EP-A 810206; Indanilidineacetylguanidine as described in EP-A 837055; Phenyl-substituted alkenylcarbonylguanidines as described in EP-A 825178; Aminopiperidylbenzoylguanidine as described in EP-A 667341; Heterocycleoxybenzylguanidine as described in EP-A 694537; Ortho-substituted benzoylguanidine as described in EP-A 704431; Ortho-substituted alkylbenzylguanidines as described in EP-A 699660; Ortho-substituted heterocyclylbenzoylguanidine as described in EP-A 699666; Ortho-substituted 5-methylsulfonylbenzoylguanidine as described in EP-A 708088; Ortho-substituted 5-alkylsulfonylbenzoylguanidine with 4-amino substituents, as described in EP-A 723963; Ortho-substituted 5-alkylsulfonylbenzoylguanidines with 4-mercapto substituents, as described in EP-A 743301; 4-sulfonyl- or 4-sulfinylbenzylguanidine as described in EP-A 758644; Alkenylbenzoylguanidine as described in EP-A 760365; Benzoylguanidine with fused cyclic sulfones as described in DE 19548708; Benzoyl-, polycyclic aroyl- and heteroaroylguanidines as described in WO 9426709; 3-aryl / heteroarylbenzoylguanidine as described in WO 9604241; 3-phenylbenzoylguanidine with a basic amide in the 5-position, as described in WO 9725310; 3-dihalothienyl- or 3-dihalophenylbenzoylguanidine with basic substituents at the 5-position, as described in WO 9727183; 3-methylsulfonylbenzoylguanidine with specific amino substituents at the 4-position, as described in WO 9512584; Amylolide derivatives as described in WO 9512592; 3-methylsulfonylbenzoylguanidine with specific amino substituents at the 4-position, as described in WO 9726253; Indoloylguanidine as described in EP-A 622356 and EP-A 708091; Indoloylguanidine with a fused additional ring system, as described in EP 787728; Methylguanidine derivatives as described in WO 9504052; 1,4-benzoxazinoylguanidine as described in EP-A 719766; 5-bromo-2-naphthoylguanidine as described in JP 8225513; Quinoline-4-carbonylguanidine with a phenyl radical at the 2-position, as described in EP-A 726254; Cinnamoylguanidine as described in JP 09059245; Propenoylguanidine with naphthalene substituents, as described in JP 9067332; Propenoylguanidine with indole substituents, as described in JP 9067340; Or heteroaryl-substituted acryloylguanidine as described in WO 9711055; And physiologically acceptable salts thereof.
    Preferred NHE inhibitors are compounds highlighted as preferred in the publications mentioned. Particularly preferred compounds are copper lead (HOE642), HOE 694, EMD 96785, FR 168888, FR 183998, SM-20550, KBR-9032, and physiologically acceptable salts thereof. The most preferred compound is another physiologically acceptable salt of the carrier, or N- (4-isopropyl-3-methanesulfonylbenzoyl) guanidine.
    Examples of classes of active compounds with cardiovascular activity that may be advantageously combined with NCBE inhibitors or additionally in combination with NCBE inhibitors and NHE inhibitors include beta-receptor blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, Angiotensin receptor blockers, loop diuretics, thiazide diuretics, calcium-avoidant diuretics, aldosterone antagonists, such as those used to lower blood pressure, and increased cardiac glycosides or other contractile forces in the treatment of heart failure and congestive heart failure. Agents as well as arrhythmia drugs of the class I-IV, nitrates, K ATP openers, K ATP blockers, inhibitors of veratridine-activateable sodium channels, and the like. Thus, for example, the following are suitable: beta-blockers propanolol, atenolol, metoprolol; Calcium antagonist diltiazem hydrochloride, verapamil hydrochloride, nifedipine; ACE inhibitor captopril, enalapril, ramipril; Trandolapril, quinapril, spirapril, preferably ramipril or trandolapril; Angiotensin II receptor antagonist losartan, valsartan, telmisartan, eprosartan, tasosartan, candesartan, irbesartan; Loop diuretics furosemide, pyretanide, torasemide; Thiazide diuretics hydrochlorothiazide, metolazone, indamide; Potassium-avoidant diuretics amylolide, triamterene, spironolactone; Cardiac glycoside dioxins, digtoxins, stropantin; Arrhythmia treatments amiodarone, sotalol, bretyllium, flecainide; Nitrate glyceryl trinitrate; K + (ATP) opener chromakalim, remakalim, nocorandil, pinacyldyl, nioxidil; Inhibitors of veratridine-activateable Na + channels.
    Blockers of non-inactivated sodium channels (veratridine-activateable sodium channels) are examples of particularly advantageous combination components with NCBE inhibitors of formula (I). Combinations of NCBE inhibitors with blockers of non-inactivated sodium channels (veratridine-activateable sodium channels) are suitable for infarction and re-infarction prevention and treatment of infarction, and also for treating angina and ischemically induced cardiac arrhythmias, Suitable for the inhibition of anemia and the development and maintenance of ventricular fibrillation, the combination of an NCBE inhibitor of formula (I) with a blocker of non-inactivated sodium channel is also a pathophysiological process in the formation of ischemic induced damage. Is inhibited or significantly reduced in a prophylactic manner. Because of their increased protective action against pathological hypoxic and ischemic situations, a combination of NCBE inhibitors of formula I and blockers of non-inactivated sodium channels can be used, which is responsible for all acute or chronic conditions caused by ischemia. It is the result of significantly inhibiting Na + influx into cells as a medicament for treating damage or a disease primarily or secondaryly induced thereby. This relates, for example, to their use as a medicament for surgical insertion in organ transplantation, wherein the combination of an NCBE inhibitor of formula I with a blocker of non-inactivated sodium channel is present before the donor's organ And the organs thus removed can be used to protect, for example, during storage in physiological sap and during implantation into the recipient's body. Combinations of NCBE inhibitors of formula I with blockers of non-inactivated sodium channels are also useful agents with protective action, for example when performing angiogenic surgical insertions into the heart and peripheral blood vessels. Corresponding to their protective action against ischemic induced damage, the combination of a NCBE inhibitor of formula I with a blocker of non-inactivated sodium channel is also a medicament for treating ischemia of the nervous system, in particular the central nervous system. Suitable, wherein these combinations are suitable for treating seizures or cerebral edema. Moreover, the combination of the novel NCBE inhibitor of formula I with a blocker of non-inactivated sodium channel is also suitable for treating, for example, allergic, cardiac, bleeding and bacterial shock forms.
    In addition to administration as a fixed combination, the present invention also provides for the treatment of the diseases described above, in parallel with the addition of an active agent from an NHE inhibitor and / or another class of cardiovascular active compounds , Separately or sequentially.
    The invention additionally provides a) NCBE inhibitors of Formula I and NHE inhibitors and / or physiologically acceptable salts thereof; b) NCBE inhibitors of formula I and additionally active substances and / or physiologically acceptable salts thereof from another class of cardiovascular active compounds; Or c) a pharmaceutical preparation comprising an NCBE inhibitor of Formula I, an NHE inhibitor and additionally an active substance from another class of cardiovascular active compounds and / or physiologically acceptable salts thereof.
    Through combination administration, the effect of one combination component can be exerted by each other component, ie the action and / or duration of action of the new combination or agent is the action and / or duration of action of each individual component. Stronger and lasts longer (synergistic effect). As such, combination administration reduces the dosage of each combination component as compared to individual administration. Thus, novel combinations and formulations are advantageous in that the amount of active compound to be administered can be significantly reduced and undesirable side effects are eliminated or significantly reduced.
    The present invention further provides, in each case, with instructions for the use of these active compounds in combination for the simultaneous or separate or sequential administration in the treatment or prevention of the above-mentioned symptoms, a) NCBE of Formula I Inhibitors and NHE inhibitors and / or physiologically acceptable salts thereof; b) NCBE inhibitors of formula I and additionally active substances and / or physiologically acceptable salts thereof from another class of cardiovascular active compounds; Or c) a commercial pack comprising a pharmaceutically active compound comprising an NCBE inhibitor of Formula I, an NHE inhibitor, and additionally an active substance from another class of cardiovascular active compounds and / or physiologically acceptable salts thereof It is about.
    The pharmaceutical preparations according to the invention can be prepared, for example, by thoroughly mixing the individual components as powders or by dissolving the individual components in a suitable solvent such as a lower alcohol and then removing the solvent.
    The weight ratio of NCBE inhibitor to NHE inhibitor or cardiovascular activity in the novel combinations and formulations is conveniently from 1: 0.01 to 1: 100, preferably from 1: 0.1 to 1:10.
    The novel combinations and preparations contain these active compounds in total, preferably from 0.5 to 99.5% by weight, in particular from 4 to 99% by weight.
    When used in accordance with the invention in mammals, preferably humans, the dosages of the various active compound components vary, for example, in the range of 0.001 to 100 mg / kg / day.
    List of abbreviations:
    BCECF: 2 ', 7'-bis- (2-carboxyethyl) -5,6-carboxyfluorescein
    Bn: Benzyl
    CH 2 Cl 2 : Dichloromethane
    DCl: Desorption Chemical Ionization
    DIP: diisopropyl ether
    DMA: Dimethylacetamide
    DME: Dimethoxyethane
    DMF: N, N-dimethylformamide
    EA: ethyl acetate (EtOAc)
    EI: electronic shock
    eq: equivalent
    ES: Electrospray Ionization
    ESneg: Electrospray, Negative Ionization
    Et: ethyl
    EtOH: Ethanol
    FAB: Fast Atomic Bombardment
    Fmoc: 9-fluorenylmethoxycarbonyl
    HEP: n-heptane
    HOAc: acetic acid
    Me: methyl
    MeOH: Methanol
    mp: melting point
    MTB: methyl tert-butyl ether
    NCBE: Sodium-dependent chloride / bicarbonate exchanger
    NHE: Sodium / Hydrogen Exchanger
    NMP: N-methylpyrrolidone
    RT: room temperature
    THF: tetrahydrofuran
    TMU: N, N, N ', N'-tetramethylurea
    Tol: Toluene
    CNS: central nervous system
    Example
    General procedure for the preparation of sulfonylcyanamide from sulfonamides
    The sulfonamide starting material is dissolved in 10 ml / mmol of anhydrous acetonitrile, 3 molar equivalents of K 2 CO 3 in acetonitrile and 1 molar equivalent of a 5N solution of BrCN are added dropwise and the mixture is allowed to complete the conversion (typical reaction time). Is 10 minutes to 6 hours). The reaction mixture is then chromatographed on silica gel without further workup.
    Example 1:
    Ethyl 2-butyl-5-methylsulfanyl-3- [4- (3'-cyanoaminosulfonylbenzyl) benzyl] -3H-imidazole-4-carboxylate
    Composite path:
    a) 3-bromo-N-dimethylaminomethylenebenzenesulfonamide
    20.3 g of 3-bromobenzenesulfonamide are reacted with 57 ml of dimethylformamide dimethyl acetal for 3 days in 120 ml of DMF under RT. After aqueous workup, the white precipitate is filtered off. The product is dried at 50 ° C. in vacuo to give 20.5 g of a colorless solid. mp 122 ° C., MS (ES): 291 (M + H) +
    b) methyl 4- [3- (dimethylaminomethylenesulfamoyl) benzyl] benzoate
    3.5 g of 3-bromo-N-dimethylaminomethylenebenzenesulfonamide (1a) in 80 ml of DMF at 0.1 ml of 0.1 equivalent of Pd (II) acetate, 0.2 equivalent of triphenylphosphine and 0.12 equivalent of copper (I) iodide In the presence of 3 equivalents of zinc reagent of methyl 4-bromomethylbenzoate is cross-linked for 3 hours. After aqueous workup, the solvent is removed in vacuo and the residue is chromatographed on silica gel: colorless solid 4.1 g, mp 36-37 ° C., MS (ES): 361 (M + H) +
    c) reduced to 1.2 g of lithium aluminum hydride in THF 140 ml for 0.5 h at 0 ° C. and refluxed for 2 h to give 4- (3-sulfamoylbenzyl) benzyl alcohol from 1 g) 3.0 g. After aqueous workup, 1.47 g of a colorless solid are obtained. m.p. 113-115 ° C.
    d) 4- [3- (dimethylaminomethylenesulfamoyl) benzyl] benzyl alcohol is obtained from 1.7 g of 1c) similarly to reaction procedure 1a). Colorless crystals 1.98 g, mp 92 ° C., MS (ES): 333 (M + H) +
    e) in situ [reaction with 1 equivalent of methanesulfonyl chloride in the presence of 2 equivalents of triethylamine in methylene chloride for 2 hours at 0 ° C., followed by continuous stirring for 1 hour at RT followed by evaporation of the solvent 0.7 g]] 4- [3- (dimethylaminomethylenesulfamoyl) benzyl] benzyl methanesulfonate prepared in ethyl 2-butyl-5- in the presence of 6 equivalents of potassium carbonate in 18 ml of DMF at 60 ° C. for 16 hours. Methylsulfanyl-3H-imidazole-4-carboxylate (J. Med. Chem. 1995, 38, 2357) Ethyl 2-butyl-5-methylsulfanyl-3- [4 by nucleophilic substitution with 2 equivalents -(3-dimethylaminomethylenesulfamoylbenzyl) benzyl] -3H-imidazole-4-carboxylate is obtained. Purification by aqueous work-up and successive column chromatography yielded 0.31 g of a colorless oil. MS (ES): 557 (M + H) +
    f) 1e) 0.3 g of ethyl 2-butyl-5-methylsulfanyl-3- [4- (3-sulfaylbenzyl) benzyl]-by hydrolysis of 0.3 g under reflux for 2 hours with 1 ml of semi-concentrated hydrochloric acid in 1 ml of glacial acetic acid 3H-imidazole-4-carboxylate is obtained. Water was added and successive drying yielded 0.27 g of a colorless resin. MS (ES): 502 (M + H) +
    g) Similar to the general procedure, 1f) ethyl 2-butyl-5-methylsulfanyl-3- [4- (3'-cyanoaminosulfonylbenzyl) benzyl] -3H-imidazole-4 by cyanating 0.17 g 0.1 g of carboxylate is obtained as a colorless solid (resin). mp 62 ° C., MS (ES): 527 (M + H) +
    Example 2:
    Ethyl 2-butyl-5-methylsulfanyl-3- [3- (3'-cyanoaminosulfonylbenzyl) benzyl] -3H-imidazole-4-carboxylate
    Composite path:
    a) Crosslinking-coupling 3.1 g of 1a) starting from 3 equivalents of methyl 3-bromomethylbenzoate to yield methyl 3- [3- (dimethylaminomethylenesulfamoyl) benzyl] benzoate : Colorless solid 3.05 g, mp 95 ° C., MS (ES): 361 (M + H) +
    b) Similarly to process 1c), 1.9 g of 3- (3-sulfamoylbenzyl) benzyl alcohol is obtained from 2.97 g of 2a) as a colorless solid by reduction with lithium aluminum hydride. mp 94 ° C., MS (Cl): 277 (M) +
    c) Similarly to reaction procedure 1a), 1.41 g of 3- [3- (dimethylaminomethylenesulfamoyl) benzyl] benzyl alcohol is obtained from 1.39 g of 2b) as colorless crystals. mp 99-100 ° C., MS (ES): 333 (M + H) +
    d) ethyl 2-butyl-5- by nucleophilic substitution of 3- [3- (dimethylaminomethylenesulfamoyl) benzyl] benzyl methanesulfonate prepared in situ [2c) from 0.28 g similarly to process 1e) 0.15 g of methylsulfanyl-3- [3- (3-dimethylaminomethylenesulfamoylbenzyl) benzyl] -3H-imidazole-4-carboxylate is obtained as a colorless resin. MS (ES): 557 (M + H) +
    e) Similar to process 1f), ethyl 2-butyl-5-methylsulfanyl-3- [3- (3-sulfamoylbenzyl) benzyl] -3H-amidazole-4-carboxyl by hydrolysis of 0.15 g of 2d) 0.13 g of a rate is obtained as colorless crystals. mp 49 ° C., MS (ES): 502 (M + H) +
    f) Similar to the general procedure, 2e) ethyl 2-butyl-5-methylsulfanyl-3- [3- (3'-cyanoaminosulfonylbenzyl) benzyl] -3H-imidazole-4 by cyanating 0.12 g 0.07 g of -carboxylate is obtained as a colorless solid (resin). mp 172-174 ° C., MS (ES): 527 (M + H) +
    Example 3:
    2-phenyl-4-formyl-5-chloro-3- [3- (3'-cyanoaminosulfonylbenzyl) benzyl] -3H-imidazole
    Composite path:
    a) Similar to process 1e), but using 0.72 g of 5-chloro-4-formyl-2-phenyl-3H-imidazole (Chem. Pharm. Bull. 1976, 24 (5), 960) 2-phenyl-4-formyl-5-chloro-3- [3- by nucleophilic substitution of 3- [3-dimethylaminomethylenesulfamoyl) benzyl] benzyl methanesulfonate prepared in a reaction system [2c) from 0.58 g] 0.19 g of (3-dimethylaminomethylenesulfamoylbenzyl) benzyl] -3H-imidazole is obtained as a colorless oil. MS (ES): 521 (M + H) +
    b) Colorless crystals of 2-phenyl-4-formyl-5-chloro-3- [3- (3-sulfamoylbenzyl) benzyl] -3H-imidazole by hydrolysis of 0.17 g 2a) similarly to process 1f) 0.13 g is obtained. mp 83-85 ° C., MS (ES): 466 (M + H) +
    c) Similar to the general procedure, 3b) 2-phenyl-4-formyl-5-chloro-3- [3- (3'-cyanoaminosulfonylbenzyl) benzyl] -3H-imidazole by cyanating 0.13 g 0.08 g is obtained as a colorless solid. mp 75 ° C., MS (ES): 491 (M + H) +
    Example 4:
    2- [4- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) benzenesulfonyl] -benzenesulfonyl cyanamide
    a) 2-p-tolylsulfanylbenzenesulfonamide
    3.0 g 2-chlorobenzenesulfonamide, 2.0 g thiocsol and 6.5 g K 2 CO 3 are stirred in 30 ml of DMF at 100 ° C. for 6 hours and then at 120 ° C. for 13 hours. The reaction mixture is poured into 200 ml of water and extracted with 500 ml of EA. The organic phase is then extracted with 100 ml of saturated aqueous Na 2 CO 3 solution. It is dried over MgSO 4 and the solvent is removed in vacuo. Chromatography on silica gel using DIP afforded 1.4 g of white crystals. mp 122-124 ° C.
    R f (DIP) = 0.36 MS (ES): 280 (M + H) +
    b) N-dimethylaminomethylene-2-p-tolylsulfanylbenzenesulfonamide
    1.4 g of 2-p-tolylsulfanylbenzenesulfonamide is stirred in 10 ml of dimethoxymethyldimethylamine for 2 hours at RT. The reaction mixture is then poured into 500 ml of water, stirred continuously for 2 hours, the product is suction filtered and then dried under vacuum. 1.6 g of white crystals are obtained. m.p. 151 ° C.
    R f (MTB) = 0.28 MS (DCl): 335 (M + H) +
    c) N-dimethylaminomethylene-2- (toluene-4-sulfonyl) benzenesulfonamide
    1.5 g of N-dimethylaminomethylene-2-p-tolylsulfanylbenzenesulfonamide is dissolved in 50 ml of CH 2 Cl 2 and treated with 2.6 g of m-chloroperbenzoic acid at 0 ° C. The mixture is continuously stirred for 3 h at RT, then treated with 100 ml of saturated aqueous Na 2 SO 3 solution and stirred for 5 more minutes at RT. It is diluted with 150 ml of CH 2 Cl 2 and washed twice with 50 ml of saturated aqueous Na 2 CO 3 solution each time. It is dried over MgSO 4 and the solvent is removed in vacuo. 1.5 g of white crystals are obtained. mp 178 ° C.
    R f (EA) = 0.44 MS (ES): 367 (M + H) +
    d) 2- (4-bromomethylbenzenesulfonyl) -N-dimethylaminomethylenebenzenesulfonamide
    1.5 g of N-dimethylaminomethylene-2- (toluene-4-sulfonyl) benzenesulfonamide, 0.74 g of NBS and 20 mg of benzoyl peroxide are refluxed in 15 ml of chlorobenzene for 2 hours. Cooling the reaction mixture was washed twice with which then, with saturated aqueous Na 2 CO 3 solution and then washed once with 20ml of saturated aqueous Na 2 CO 3 solution was diluted with 50ml toluene 100ml. It is dried over MgSO 4 and the solvent is removed in vacuo. 1.6 g of an amorphous solid are obtained, which are further reacted without further purification.
    R f (EA) = 0.44 MS (ES): 445 (M + H) +
    e) 2- [4- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) benzenesulfonyl] -N-dimethylaminomethylenebenzenesulfonamide
    1.6 g of 2- (4-bromomethylbenzenesulfonyl) -N-dimethylaminomethylenebenzenesulfonamide, 680 mg of 5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde and 1.4 g of K 2 CO 3 Stir for 15 days at RT in 15 ml anhydrous DMF. The reaction mixture is then diluted with 200 ml of EA and washed three times with 50 ml of saturated aqueous Na 2 CO 3 solution each time. It is dried over MgSO 4 and the solvent is removed in vacuo. Chromatography on silica gel using MTB yields 240 mg of a colorless oil.
    R f (MTB) = 0.08 MS (ES): 571 (M + H) +
    f) 2- [4- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) benzenesulfonyl] benzenesulfonamide
    230 mg of 2- [4- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) benzenesulfonyl] -N-dimethylaminomethylenebenzenesulfonamide in 3 ml of EtOH and 3 ml of saturated aqueous HCl solution Reflux for 2 hours. The reaction mixture is cooled and poured into 10 ml of water and the product is filtered off. Chromatography on silica gel using MTB yields 151 mg of an amorphous solid.
    R f (MTB) = 0.41 MS (ES): 516 (M + H) +
    g) 2- [4- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) benzenesulfonyl] benzenesulfonyl cyanamide
    56 [mu] l of a 5M solution of BrCN in 145 mg of 2- [4- (4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl) benzenesulfonyl] benzenesulfonamide, 117 mg K 2 CO 3 and acetonitrile Was refluxed in 2 ml of anhydrous acetonitrile for 90 minutes. The reaction mixture is cooled and chromatographed with EA / MeOH (10: 1) to afford 90 mg of an amorphous solid.
    R f (EA / MeOH 10: 1) = 0.27 MS (ES): 541 (M + H) +
    Pharmacological data:
    Inhibition of Na + -dependent Cl − / HCO 3 Exchanger (NCBE) in Human Endothelial Cells
    Human endothelial cells (ECV-304) were isolated from the culture flasks with trypsin / EDTA buffer (0.05 / 0.02% in phosphate buffer) and after centrifugation (100 g, 5 min), buffered salt solution [mmol / l: 115 NaCl, 20 NH 4 Cl, 5 KCl, 1 CaCl 2 , 1 MgSO 4 , 20 N- (2-hydroxyethyl) -piperazine-N = -2-ethanesulfonic acid (HEPES), 5 glucose and bovine serum albumin 1 g / l; pH 7.4]. This cell suspension is incubated with 5 μM BCECF acetoxymethyl ester at 37 ° C. for 20 minutes. The cells were then washed and sodium- and bicarbonate-free buffer solution (mmol / l: 5 HEPES, 133.8 choline chloride, 4.7 KCl, 1.25 MgCl 2 , 0.97 K 2 HPO 4 , 0.23 KH 2 PO 4 , 5 glucose resuspend in pH 7.4).
    For subsequent fluorescence measurements in a FLIPR (Fluorescent Image Plate Reader), 100 μl of the cell suspension containing 20,000 cells in each case is added to each pipette of each well of a 96-well microtiter plate and the microtiter plate is centrifuged. (100 g, 5 min). In FLIPR, in each case 100 μl of buffer solution is then removed from the further prepared microtiter plates and pipetted into each of the 96 wells of the measurement plate. In this case, for the 100% control, ie the recovery of intracellular pH (pH i ) via NCBE was determined in bicarbonate- and sodium-containing buffer solution containing 50 μM HOE 642 (mmol / l: 5 HEPES, 93.8 NaCl, 40 NaHCO 3 , 4.7 KCl, 1.25 CaCl 2 , 1.25 MgCl 2 , 0.97 Na 2 HPO 4 , 0.23 NaH 2 PO 4 , 5 glucose; pH 7.4). For the 0% control, i.e. without any pH i recovery, a bicarbonate-free, sodium-containing buffer solution (mmol / l: 5 HEPES, 133.8 NaCl, 4.7 KCl, 1.25 CaCl 2) also added 50 μM HOE 642 , 1.25 MgCl 2 , 0.97 Na 2 HPO 4 , 0.23 NaH 2 PO 4 , 5 glucose; pH 7.4). The compounds of formula I according to the invention are added in sodium- and bicarbonate-containing solutions of various concentrations.
    After adding the buffer solution to the dye-loaded acidified cells located on the measurement plate, an increase in fluorescence intensity corresponding to an increase in pH i is determined in each well of the microtiter plate. In this case record the kinetics at 35 ° C. over 2 minutes. The increase in fluorescence intensity for different concentrations of the compounds according to the invention relates to two controls, from which the inhibitory action of the substance is determined.
    result
    Residual Activity of NCBE at Inhibitor Concentration of 10 μM
    ExampleResidual activity (%) One11.1 235.2 324.3
    权利要求:
    Claims (13)
    [1" claim-type="Currently amended] Compounds of formula (I) and physiologically acceptable salts thereof.
    Formula I

    In the above formula,
    X is ego;
    R (1) is hydrogen; Alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; Or -C a H 2a -phenyl
    [Wherein the phenyl moiety is unsubstituted or one, two or three identical from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy and NR (19) R (20) Or substituted by different radicals,
    R (19) and R (20) are independently of each other H or alkyl of 1, 2, 3 or 4 carbon atoms,
    a is 0, 1 or 2], or
    R (1) is —C b H 2b -heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms
    Wherein the heteroaryl moiety is unsubstituted or one, two or three from the group consisting of F, Cl, Br, I, CF 3 , CH 3 , methoxy, hydroxy and NR (21) R (22) Substituted by the same or different radicals,
    R (21) and R (22) are independently of each other H or alkyl of 1, 2, 3 or 4 carbon atoms,
    b is 0, 1 or 2], or
    R (1) is —C c H 2c -cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, where c is 0, 1 or 2;
    R (2) and R (3) are independently of each other hydrogen, F, Cl, Br, I, CF 3 , -CN, -NO 2 , CH 2 OR (23), CO-R (24) or OR (25) )
    [Where R (23) is hydrogen or alkyl of 1, 2, 3, 4, 5, 6, 7 or 8,
    R (24) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8, OR 26 or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , Substituted by one, two or three identical or different radicals from the group consisting of one to three substituents from the group consisting of methyl, methoxy, hydroxy and NR (27) R (28), R (27) and R (28) are independently of each other H or alkyl of 1, 2, 3 or 4, R (26) is hydrogen or of 1, 2, 3, 4, 5, 6, 7 or 8 Alkyl),
    R (25) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8, or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , methyl, me Is substituted by one, two or three identical or different radicals from the group consisting of oxy, hydroxy and NR (29) R (30), wherein R (29) and R (30) are independently of each other H or Or alkyl having 1, 2, 3 or 4 carbon atoms, or
    R (25) is unsubstituted or one, two or three identical from the group consisting of F, Cl, Br, I, CF 3 , CH 3 , methoxy, hydroxy and NR (31) R (32) Heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, wherein R (31) and R (32) are independently of each other H or 1, 2, 3 or 4 alkyl); or
    R (2) and R (3) are independently of each other alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or -C d H 2d -phenyl
    [Wherein the phenyl moiety is unsubstituted or one, two or three identical from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy and NR (33) R (34) Or substituted by different radicals,
    R (33) and R (34) are independently of each other H or alkyl of 1, 2, 3 or 4 carbon atoms,
    d is 0, 1 or 2], or
    R (2) and R (3) independently of one another are -C e H 2e -heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms
    [Wherein the heteroaryl moiety is unsubstituted or one, two or three from the group consisting of F, Cl, Br, I, CF 3 , CH 3 , methoxy, hydroxy and NR (35) R (36) Substituted by the same or different radicals,
    R (35) and R (36) are independently of each other H or alkyl of 1, 2, 3 or 4 carbon atoms,
    e is 0, 1 or 2], or
    R (2) and R (3) are each independently of the other -SO f -R (37)
    [Wherein R (37) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or -C g H 2g -phenyl, wherein the phenyl moiety is unsubstituted or is selected from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy and NR (38) R (39) Substituted by 3, 2 or 3 same or different radicals, R (38) and R (39) are independently of each other H or alkyl of 1, 2, 3 or 4, f is 0, 1 or 2 And g is 0, 1 or 2);
    R (4) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8, 1-naphthyl, 2-naphthyl, -C i of 3, 4, 5, 6 or 7 carbon atoms H 2i -cycloalkyl, or —C i H 2i -phenyl
    [Wherein the phenyl moiety is unsubstituted or has 1, 2, 3, 4, 5, 6, 7 or 8 alkyl, F, Cl, Br, I, CF 3 , SO j R (48), OR (49) Is substituted by one, two or three identical or different radicals from the group consisting of NR (50) R (51), -CN, -NO 2 and CO-R (52),
    i is 0, 1 or 2,
    R (48) is alkyl having 1, 2, 3 or 4 carbon atoms or NR (53) R (54),
    R (53) and R (54) are independently of each other hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    j is 0, 1 or 2,
    R (49) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    R (50) and R (51) are independently of each other hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    R (52) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 or OR (55),
    R 55 is hydrogen or alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or
    R (4) and R (6) together with the carbon atoms accompanying them are cycloalkyl or fluorenyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (5), R (6), R (7) and R (8) are independently of each other hydrogen, F, CF 3 , OR (56), carbon number 1, 2, 3, 4, 5, 6, 7 or Alkyl of 8, cycloalkyl of 3, 4, 5, 6 or 7 or -C k H 2k -phenyl
    [Wherein the phenyl moiety is unsubstituted or one, two or three identical from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy and NR (57) R (58) Or substituted by different radicals,
    R (57) and R (58) are independently of each other hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    k is 0, 1 or 2,
    R (56) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8, or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , methyl, me Substituted by one, two or three identical or different radicals from the group consisting of oxy, hydroxy and NR (59) R (60), wherein R (59) and R (60) are independently of each other hydrogen or Or alkyl having 1, 2, 3 or 4 carbon atoms, or
    R (56) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the heteroaryl is unsubstituted or substituted with F, Cl, Br, I, CF 3 , CH 3 , me Substituted by one, two or three identical or different radicals from the group consisting of oxy, hydroxy and NR (61) R (62), wherein R (61) and R (62) are independently of each other hydrogen or Or alkyl having 1, 2, 3 or 4 carbon atoms;
    R (5) and R (7) together are the second bond between the carbon atoms accompanying the radicals R (6) and R (8), where R (4), R (6) and R (8) are As defined above;
    R (9) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or -C l H 2l-ll -A
    [Wherein ll is 0 or 2 and l is 0, 1, 2, 3 or 4; when ll is 2, l is not 0 or 1];
    R (10) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl of 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or -C m H 2m -mm -B
    [Where mm is 0 or 2 and m is 0, 1, 2, 3 or 4; when mm is 2, m is not 0 or 1];
    R (11) and R (12) are independently of each other hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
    Z is carbonyl or sulfonyl;
    A and B are independent of each other
    1. aryl having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;
    2. Alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br, I, CF 3 , SO n R (63), OR (64), NR (65) R ( 66), a radical as defined in 1, substituted by one, two or three identical or different radicals from the group consisting of —CN, —NO 2 and CO—R 67;
    3. heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;
    4. Substitution by one, two or three identical or different radicals from the group consisting of F, Cl, Br, I, CF 3 , CH 3 , methoxy, hydroxy and NR (68) R (69) Radicals as defined in 3;
    5. cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
    6. O-R 70; or
    7. O-R 71;
    n is 0, 1 or 2;
    R (70) and R (71) are independent of each other
    1. hydrogen;
    2. alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
    3. -C o H 2o-oo -phenyl wherein oo is 0 or 2 and o is 0, 1, 2, 3 or 4; when oo is 2, o is not 0 or 1;
    4. Phenyl residues are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br, I, CF 3 , SO p R (72), OR (73), NR (74) A radical as defined in 3 which is substituted by one, two or three identical or different radicals from the group consisting of R (75), -CN, -NO 2 and CO-R (76); or
    5. alkenyl of 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
    R (63) and R (72) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms or NR (77) R (78);
    R (67) and R (76) are independently of each other hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 or OR (89);
    R (89) is hydrogen or alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
    R (64), R (65), R (66), R (68), R (69), R (73), R (74), R (75), R (77) and R (78) Independently of one another are hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    p is 0, 1 or 2 independently of each other;
    R (13), R (14) and R (15) are independently of each other hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8, F, Cl, Br, I, CF 3 , -CN, -NO 2 , SO q -R (79), CO-R (80) or OR (81)
    [Wherein q is 0, 1 or 2 independently of each other,
    R (79) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , methyl, methoxy, Substituted by one, two or three identical or different radicals from the group consisting of hydroxy and NR (82) R (83), wherein R (82) and R (83) are independently of each other hydrogen or carbon atoms , 2, 3 or 4 alkyl)
    R (80) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 or OR (84),
    R (84) is hydrogen or alkyl of 1, 2, 3, 4, 5, 6, 7 or 8,
    R (81) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8, or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , methyl, me Oxy, hydroxy and NR (82) R (83) are substituted by one, two or three identical or different radicals);
    Y is CR (16) R (17), CO, S, SO 2 , O, NR (18);
    R (16) is hydrogen or -OR (85)
    [Wherein R (85) is hydrogen, alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 or CO-R (86),
    R (86) is alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , methyl, methoxy and Is substituted by one, two or three identical or different radicals from a group consisting of hydroxy);
    R (17) is hydrogen or alkyl of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
    R (18) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, CO-R (87) or SO 2 R (88), wherein R (87) and R (88) ) Is independently of each other alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl (unsubstituted or substituted with F, Cl , Is substituted by one, two or three identical or different radicals from the group consisting of Br, I, CF 3 , methyl, methoxy and hydroxy).
    [2" claim-type="Currently amended] The method of claim 1,
    X ego;
    R (1) is hydrogen; Alkyl having 1, 2, 3 or 4 carbon atoms; Or -C a H 2a -phenyl
    [Wherein the phenyl moiety is unsubstituted or substituted by one, two or three identical or different radicals from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy, a Is 0 or 1], or
    Carbon number, wherein R (1) is unsubstituted or substituted by one, two or three identical or different radicals from the group consisting of F, Cl, Br, I, CF 3 , CH 3 , methoxy and hydroxy 1, 2, 3, 4, 5, 6, 7, 8 or 9 heteroaryl, or
    R (1) is —C c H 2c -cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, where c is 0 or 1;
    R (2) and R (3) are independently of each other hydrogen, F, Cl, Br, I, CF 3 , -CN, -NO 2 , CH 2 OR (23), CO-R (24) or OR (25 )
    [Wherein R (23) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,
    R (24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR (26) or phenyl, wherein phenyl is unsubstituted or is substituted with F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy Substituted by one, two or three identical or different radicals from the group consisting of R (26) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,
    R (25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or is selected from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy One, two or three of the same or different radicals), or
    R 25 is unsubstituted or substituted by 1, 2 or 3 identical or different radicals from the group consisting of F, Cl, Br, I, CF 3 , CH 3 and methoxy , 3, 4, 5, 6, 7, 8 or 9 heteroaryl; or
    R (2) and R (3) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or -C d H 2d -phenyl
    [Wherein the phenyl moiety is unsubstituted or substituted by one, two or three identical or different radicals from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy, d Is 0 or 1], or
    R (2) and R (3) are, independently of each other, unsubstituted or one, two or three identical from the group consisting of F, Cl, Br, I, CF 3 , CH 3 , methoxy and hydroxy Or heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, substituted by different radicals, or
    R (2) and R (3) are independently of each other -SO f -R (37)
    [Wherein R (37) is alkyl having 1, 2, 3 or 4 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or -C g H 2g -phenyl, wherein the phenyl moiety is unsubstituted or one, two or three identical from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy Substituted by different radicals, f is 0, 1 or 2, and g is 0 or 1);
    R (4) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, 1-naphthyl, 2-naphthyl, -C i H 2i -cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, or- C i H 2i -phenyl
    [Wherein the phenyl moiety is unsubstituted or has 1, 2, 3, 4, 5, 6, 7 or 8 alkyl, F, Cl, CF 3 , SO j R (48), OR (49), NR (50 Is substituted by one, two or three identical or different radicals from the group consisting of R (51), -CN and CO-R (52),
    i is 0, 1 or 2,
    R (48) is alkyl having 1, 2, 3 or 4 carbon atoms or NR (53) R (54),
    R (53) and R (54) are independently of each other hydrogen, methyl or ethyl,
    j is 0 or 2,
    R (49) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    R (50) and R (51) are independently of each other hydrogen, methyl or ethyl,
    R (52) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms or OR (55),
    R 55 is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms; or
    R (4) and R (6) together with the carbon atoms accompanying them are cycloalkyl or fluorenyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (5), R (6), R (7) and R (8) are each independently hydrogen, F, CF 3 , OR (56), alkyl having 1, 2, 3 or 4 carbon atoms, 3, 4 carbon atoms , 5, 6 or 7 cycloalkyl or -C k H 2k -phenyl
    [Wherein the phenyl moiety is unsubstituted or substituted by one, two or three identical or different radicals from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy,
    k is 0 or 1,
    R 56 is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or is selected from the group consisting of F, Cl, Br, I, CF 3 , methyl, methoxy and hydroxy One, two or three of the same or different radicals), or
    R (56) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the heteroaryl is unsubstituted or substituted with F, Cl, Br, I, CF 3 , CH 3 , me Is substituted by one, two or three identical or different radicals from the group consisting of oxy and hydroxy), or
    R (5) and R (7) together are the second bond between the carbon atoms accompanying the radicals R (6) and R (8), where R (4), R (6) and R (8) are As defined above;
    R (9) is alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, or -C 1 H 2l-ll -A
    [Wherein ll is 0 or 2 and l is 0, 1, 2 or 3; when ll is 2, l is not 0 or 1];
    R (10) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, alkenyl of 2, 3 or 4 carbon atoms, or -C m H 2m-mm- B
    [Where mm is 0 or 2 and m is 0, 1, 2 or 3; when mm is 2, m is not 0 or 1];
    R (11) and R (12) are independently of each other hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    Z is carbonyl or sulfonyl;
    A and B are independent of each other
    1. phenyl;
    2. 1, 2 from the group consisting of alkyl, F, Cl, CF 3 , SO n R (63), OR (64), —CN and CO-R (67) having 1, 2, 3 or 4 carbon atoms Radicals as defined in 1, substituted by 3 or 3 same or different radicals;
    3. 1-naphthyl or 2-naphthyl;
    4. substituted by one, two or three identical or different radicals from the group consisting of alkyl, F, Cl, CF 3 , CH 3 , methoxy and hydroxy having 1, 2, 3 or 4 carbon atoms, Radicals as defined in 3;
    5. heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;
    6. substituted by one, two or three identical or different radicals from the group consisting of alkyl, F, Cl, CF 3 , CH 3 , methoxy and hydroxy having 1, 2, 3 or 4 carbon atoms, Radicals as defined in 5;
    7. cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
    8. O-R 70; or
    9. O-R 71;
    n is 0, 1 or 2;
    R (70) and R (71) are independent of each other
    1. hydrogen;
    2. alkyl having 1, 2, 3 or 4 carbon atoms;
    3. -C o H 2o-oo -phenyl wherein oo is 0 or 2 and o is 0, 1, 2 or 3; when oo is 2, o is not 0 or 1;
    4. The phenyl moiety consists of alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF 3 , SO p R (72), OR (73), -CN, -NO 2 and CO-R (76) Radicals as defined in 3, substituted by one, two or three identical or different radicals from the group; or
    5. alkenyl having 2, 3 or 4 carbon atoms;
    R (63) and R (72) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms or NR (77) R (78);
    R (67) and R (76) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms or O-alkyl having 1, 2, 3 or 4 carbon atoms;
    R (64) and R (73) are independently of each other hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    p is independently from each other 0, 1 or 2;
    R (13), R (14) and R (15) are independently of each other hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF 3 , -CN, SO q -R (79), CO -R (80) or OR (81)
    [Where q is 0, 1 or 2,
    R (79) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or from 1, 2 from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy Or substituted by three same or different radicals),
    R (80) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms or OR (84),
    R (84) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    R (81) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or one from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy, Two or three identical or different radicals are substituted);
    Y is CR (16) R (17), CO, S, SO 2 , O or NR (18);
    R (16) is hydrogen or -OR (85)
    [Where R (85) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or COR (86),
    R (86) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or from 1, 2 or 3 from the group consisting of F, Cl, CF 3 , methyl and methoxy Substituted by the same or different radicals;
    R (17) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    R (18) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, COR (87) or SO 2 R (88), wherein R (87) and R (88) are independently of each other C1, 2, Alkyl of 3 or 4, cycloalkyl of 3, 4, 5, 6, 7 or 8, or phenyl, which is unsubstituted or from the group consisting of F, Cl, Br, I, CF 3 , methyl and methoxy Dogs, two or three identical or different radicals), and physiologically acceptable salts thereof.
    [3" claim-type="Currently amended] The method according to claim 1 or 2,
    X ego;
    R (1) is hydrogen; Alkyl having 1, 2, 3 or 4 carbon atoms; Or phenyl
    Wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy; or
    R 1, unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , CH 3 , methoxy and hydroxy, having 1, 2, 3, 4, 5, 6, 7, 8 Or heteroaryl of 9, or
    R (1) is cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (2) and R (3) are independently of each other hydrogen, F, Cl, CF 3 , -CN, -NO 2 , CO-R (24) or OR (25)
    [Where R (24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR (26) or phenyl, wherein phenyl is unsubstituted or substituted with F, Cl, CF 3 , methyl, methoxy and hydroxy Substituted by a substituent from the group consisting of R (26) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms,
    R (25) is hydrogen, alkyl of 1, 2, 3 or 4, or phenyl, wherein phenyl is unsubstituted or substituted by a substituent from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy Is substituted), or
    R (2) and R (3) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or phenyl, wherein phenyl is unsubstituted or substituted by substituents from a group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy; or
    R (2) and R (3) are independently of each other, substituted or unsubstituted on one, two or three identical or different radicals from the group consisting of F, Cl, CF 3 , CH 3 , methoxy and hydroxy Substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 heteroaryl;
    R (2) and R (3) are independently of each other -SO f -R (37)
    [Wherein R (37) is alkyl having 1, 2, 3 or 4 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or phenyl, wherein phenyl is unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy, and f is 0 or 2;
    R (4) is methyl, ethyl, 1-naphthyl, 2-naphthyl, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, or -C i H 2i -phenyl, wherein i is 0 or 1 ] Or
    R (4) and R (6) together with the carbon atoms accompanying them are cycloalkyl or fluorenyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (5) and R (7) are independently of each other hydrogen or fluorine, or a second bond between carbon atoms carrying radicals R (6) and R (8);
    R (6) and R (8) are independently of each other hydrogen, F, CF 3 , OR (56), alkyl having 1, 2, 3 or 4 carbon atoms or -C k H 2k -phenyl
    [Wherein the phenyl moiety is unsubstituted or substituted by one, two or three identical or different radicals from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy,
    k is 0 or 1,
    R (56) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or one from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy, Substituted by two or three identical or different radicals), or
    R (56) is heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein heteroaryl is unsubstituted or is substituted with F, Cl, CF 3 , CH 3 , methoxy and hydroxy Is substituted by one, two or three identical or different radicals from the group consisting of
    R (9) is alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, or -C l H 2l-ll -A wherein ll is 0 or 2, and l is 0, 1, 2 or 3; when ll is 2, l is not 0 or 1];
    R (10) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, alkenyl of 2, 3 or 4 carbon atoms, or -C m H 2m-mm -B, where mm is 0 or 2, and m is 0, 1, 2 or 3; when mm is 2, m is not 0 or 1];
    R (11) and R (12) are independently of each other hydrogen or methyl;
    Z is carbonyl or sulfonyl;
    A and B are independent of each other
    1. phenyl;
    2. 1, 2 from the group consisting of alkyl of 1, 2, 3 or 4 carbon atoms, F, Cl, CF 3 , SO 2 R (63), OR (64), -CN and CO-R (67) Radicals as defined in 1, substituted by 3 or 3 same or different radicals;
    3. 1-naphthyl or 2-naphthyl;
    4. a radical as defined in 3, substituted by a radical from the group consisting of alkyl, F, Cl, CF 3 , CH 3 , methoxy and hydroxy having 1, 2, 3 or 4 carbon atoms;
    5. heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;
    6. radicals as defined in 5, substituted by radicals from the group consisting of F, Cl, CF 3 , CH 3 , methoxy and hydroxy;
    7. cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (63) is alkyl having 1, 2, 3 or 4 carbon atoms;
    R (67) is alkyl having 1, 2, 3 or 4 carbon atoms or O-alkyl having 1, 2, 3 or 4 carbon atoms;
    R (64) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    R (13), R (14) and R (15) are independently of each other hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF 3 , -CN, SO q -R (79), CO -R (80) or OR (81)
    [Where q is 0 or 2,
    R (79) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or from 1, 2 from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy Or substituted by three same or different radicals),
    R (80) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms or OR (84),
    R (84) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    R (81) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or one from the group consisting of F, Cl, CF 3 , methyl, methoxy and hydroxy, Two or three identical or different radicals are substituted);
    Y is CR (16) R (17), CO, S, SO 2 , O or NR (18);
    R (16) is hydrogen or -OR (85)
    [Where R (85) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or COR (86),
    R (86) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy] Is;
    R (17) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    R (18) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, COR (87) or SO 2 R (88), wherein R (87) and R (88) are independently of each other C1, 2, Alkyl of 3 or 4, cycloalkyl of 3, 4, 5 or 6, or phenyl, which is unsubstituted or substituted by radicals from the group consisting of F, Cl, Br, I, CF 3 , methyl and methoxy ] And a physiologically acceptable salt thereof.
    [4" claim-type="Currently amended] The method according to any one of claims 1 to 3,
    X ego;
    R (1) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl
    Wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy], or
    Of 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein R (1) is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , CH 3 and methoxy Heteroaryl
    R (1) is cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (2) and R (3) are independently of each other hydrogen, F, Cl, CF 3 , -CN, CO-R (24) or OR (25)
    [Where R (24) is hydrogen, alkyl of 1, 2, 3 or 4, OR (26) or phenyl, wherein phenyl is unsubstituted or is selected from the group consisting of F, Cl, CF 3 , methyl and methoxy Substituted by a radical of R (26) is hydrogen, methyl or ethyl)
    R (25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy Or
    R (25) of 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , CH 3 and methoxy Heteroaryl] or
    R (2) and R (3) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms; Cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms; Or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy], or
    R (2) and R (3), independently of one another, are unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , CH 3 and methoxy, having 1, 2, 3, 4, 5 , Heteroaryl of 6, 7, 8 or 9, or
    R (2) and R (3) are independently of each other -SO f -R (37)
    [Where R (37) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy ) And f is 0 or 2;
    R (4) is methyl, ethyl, 1-naphthyl, 2-naphthyl, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, or phenyl,
    R (4) and R (6) together with the carbon atoms accompanying them are cycloalkyl or fluorenyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (5) and R (7) are independently of each other hydrogen or a second bond between carbon atoms carrying the radicals R (6) and R (8);
    R (6) and R (8) are independently of each other hydrogen, CF 3 , OR (56), alkyl or phenyl having 1, 2, 3 or 4 carbon atoms
    [Wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy,
    R 56 is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy Or
    R (56) is a heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein the heteroaryl is unsubstituted or consists of F, Cl, CF 3 , CH 3 and methoxy Is substituted by a radical from);
    R (9) is alkyl having 1, 2, 3 or 4 carbon atoms, alkenyl having 2, 3 or 4 carbon atoms, or -C l H 2l-ll -A wherein ll is 0 or 2, and l is 0, 1, 2 or 3; when ll is 2, l is not 0 or 1];
    R (10) is hydrogen, alkyl of 1, 2, 3 or 4 carbon atoms, alkenyl of 2, 3 or 4 carbon atoms, or -C m H 2m-mm -B, where mm is 0 or 2, and m is 0, 1, 2 or 3; when mm is 2, m is not 0 or 1];
    R (11) and R (12) are independently of each other hydrogen or methyl;
    Z is carbonyl or sulfonyl;
    A and B are independent of each other
    1. phenyl;
    2. Substituted by a radical from the group consisting of alkyl, F, Cl, CF 3 , SO 2 R (63), OR (64), -CN and CO-R (67) having 1, 2, 3 or 4 carbon atoms Radicals as defined in 1;
    3. 1-naphthyl or 2-naphthyl;
    4. a radical as defined in 3, substituted by a radical from the group consisting of alkyl, F, Cl, CF 3 , CH 3 and methoxy having 1, 2, 3 or 4 carbon atoms;
    5. heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;
    6. radicals as defined in 5, substituted by radicals from the group consisting of F, Cl, CF 3 , CH 3 and methoxy;
    7. cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
    R (63) is alkyl having 1, 2, 3 or 4 carbon atoms;
    R (64) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    R (67) is alkyl having 1, 2, 3 or 4 carbon atoms or O-alkyl having 1, 2, 3 or 4 carbon atoms;
    R (13), R (14) and R (15) are independently of each other hydrogen, methyl, F, Cl, CF 3 , -CN, SO 2 -R (79), CO-R (80) or OR (81 )
    [Where R (79) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy )ego,
    R (80) is hydrogen, methyl or OR (84),
    R (84) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms,
    R (81) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , methyl and methoxy Is;
    Y is CR (16) R (17), CO, S or SO 2 ;
    R (16) is hydrogen or -OR (85)
    [Where R (85) is hydrogen, methyl or COR (86),
    R (86) is methyl, cyclopentyl, cyclohexyl, or phenyl, wherein phenyl is unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , methyl and methoxy;
    And a physiologically acceptable salt thereof, wherein R (17) is hydrogen or methyl.
    [5" claim-type="Currently amended] The method according to any one of claims 1 to 4,
    X ego;
    R (1) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy;
    R (2) and R (3) are independently of each other hydrogen, F, Cl, CF 3 , -CN, CO-R (24) or OR (25)
    [Where R (24) is hydrogen, alkyl of 1, 2, 3 or 4, OR (26) or phenyl, wherein phenyl is unsubstituted or is selected from the group consisting of F, Cl, CF 3 , methyl and methoxy Substituted by a radical of R (26) is hydrogen, methyl or ethyl)
    R (25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy Or
    R (25) is heteroaryl which is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , CH 3 and methoxy], or
    R (2) and R (3) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms,
    R (2) and R (3) are, independently of one another, phenyl unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , methyl and methoxy, or
    R (2) and R (3) are, independently of each other, heteroaryl unsubstituted or substituted by radicals from the group consisting of F, Cl, CF 3 , CH 3 and methoxy, or
    R (2) and R (3) are independently of each other -SO f -R (37)
    [Where R (37) is alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or substituted by a radical from a group consisting of F, Cl, CF 3 , methyl and methoxy ) And f is 0 or 2;
    R (13), R (14) and R (15) are independently of each other hydrogen, methyl, F, Cl, CF 3 , -CN, SO 2 -R (79), CO-R (80) or OR (81 )
    [Wherein R (79) and R (81) are independently of each other alkyl having 1, 2, 3 or 4 carbon atoms, or phenyl, wherein phenyl is unsubstituted or consists of F, Cl, CF 3 , methyl and methoxy Is substituted by a radical from a group),
    R (80) is hydrogen, methyl or OR (84),
    R (84) is hydrogen or alkyl of 1, 2, 3 or 4 carbon atoms;
    A compound of formula (I) wherein Y is methylene and a physiologically acceptable salt thereof.
    [6" claim-type="Currently amended] A compound of formula (I) and / or a physiologically acceptable salt thereof as claimed in any one of claims 1 to 5 for use as a medicament.
    [7" claim-type="Currently amended] A pharmaceutical formulation comprising an effective amount of a compound of formula (I) as claimed in any one of claims 1 to 5 and / or a physiologically acceptable salt thereof.
    [8" claim-type="Currently amended] 8. The pharmaceutical formulation of claim 7, further comprising an effective amount of an NHE inhibitor and / or an active substance from another cardiovascular class of active compound, and / or physiologically acceptable salts thereof.
    [9" claim-type="Currently amended] A compound of formula (I) as claimed in any one of claims 1 to 5 and / or a physiologically acceptable salt thereof for use as an inhibitor of sodium-dependent bicarbonate / chloride exchanger (NCBE).
    [10" claim-type="Currently amended] Cardiac infarction, angina pectoris, diseases caused by ischemic symptoms, impaired respiratory mobility, ischemic symptoms of the heart, ischemic symptoms and seizures of the peripheral and central nervous system, ischemic symptoms of peripheral organs and limbs, cell proliferation may be primary or secondary Claims 1 to 5 for use in the treatment and / or prophylaxis of diseases of primary cause, for the treatment of shock conditions, for use in surgical operations and organ transplantation, or for the preservation and storage of implants for surgical procedures. A compound of formula (I) and / or a physiologically acceptable salt thereof as claimed in claim 1.
    [11" claim-type="Currently amended] A compound of formula (I) as claimed in any one of claims 1 to 5 and / or a physiologically acceptable salt thereof for use in the treatment and / or prophylaxis of cancer.
    [12" claim-type="Currently amended] The method according to claim 7 or 8, wherein the disease caused by heart infarction, angina pectoris, ischemic symptoms, impaired respiratory mobility, ischemic symptoms of the heart, ischemic symptoms and seizures of the peripheral and central nervous system, ischemic symptoms of peripheral organs and limbs, cells Agents for the treatment and / or prophylaxis of diseases in which proliferation is the primary or secondary cause, for the treatment of shock conditions, for surgical operations and organ transplants, or for the preservation and storage of implants for surgical procedures. Pharmaceutical preparations.
    [13" claim-type="Currently amended] The pharmaceutical formulation of claim 7 or 8 for use in the treatment and / or prevention of cancer.
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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:
    1998-05-06|Priority to DE19820064.1
    1998-05-06|Priority to DE19820064A
    1999-04-30|Application filed by 로버트 흐라이탁, 미쉘 베스트, 아벤티스 파마 도이칠란트 게엠베하
    1999-04-30|Priority to PCT/EP1999/002940
    2001-05-25|Publication of KR20010043304A
    优先权:
    申请号 | 申请日 | 专利标题
    DE19820064.1|1998-05-06|
    DE19820064A|DE19820064A1|1998-05-06|1998-05-06|Substituted sulfonylcyanamides, process for their preparation and their use as a medicament|
    PCT/EP1999/002940|WO1999057102A1|1998-05-06|1999-04-30|Substituted sulphonyl cyanamides, method for producing same and their use as medicament|
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