CN1163263A - Substituted diaryl dicarboxylic diguanidine, and its preparing method, use as medicine or diagnostic reagent and medicine containing it - Google Patents

Substituted diaryl dicarboxylic diguanidine, and its preparing method, use as medicine or diagnostic reagent and medicine containing it Download PDF

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CN1163263A
CN1163263A CN 97102088 CN97102088A CN1163263A CN 1163263 A CN1163263 A CN 1163263A CN 97102088 CN97102088 CN 97102088 CN 97102088 A CN97102088 A CN 97102088A CN 1163263 A CN1163263 A CN 1163263A
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group
hydrogen
radicals
separate
methyl
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H·W·克里曼
J·布伦德尔
J·R·施瓦尔克
A·威彻特
H·J·兰格
U·阿尔布斯
W·舒尔茨
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Hoechst AG
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Hoechst AG
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Abstract

Diaryldicarboxylic acid diguanidides of the formula I in which R(1) to R(10) have the meanings indicated in the claims, are suitable as antiarrhythmic pharmaceuticals having a cardioprotective component for infarct prophylaxis and infarct treatment and also for the treatment of angina pectoris. They also inhibit, in a preventive manner, the pathophysiological processes in the formation of ischemically induced damage, in particular in the elicitation of ischemically induced cardiac arrhythmias.

Description

Substituted diaryl dicarboxylic two guanidines, its preparation method is as the application of medicine or diagnostic reagent and the medicine that contains it
Diaryl dicarboxylic-two guanidine that the present invention relates to Chemical formula 1 with and pharmacopedics on the salt that is fit to:
Wherein:
Radicals R (1), R (2), R (3), one among R (4) and the R (5) is-CO-N=C (NH 2) 2
Other radicals R (1) and R (5) are separate hydrogen, have the alkyl of 1,2,3 or 4 C-atoms, F, Cl ,-OR (32) ,-NR (33) R (34) or CF 3R (32), R (33) and R (34) are separate hydrogen or the alkyl with 1,2,3 or 4 C-atoms;
Other radicals R (2) and R (4) are separate hydrogen, F, Cl, Br, I, OH ,-CN, CF 3,-CO-N=C (NH 2) 2, have the alkyl of 1,2,3,4,5,6,7 or 8 C-atoms, have 2,3,4,5, the alkenyl of 6,7 or 8 C-atoms or-(CH 2) mR (14); M is zero, 1 or 2; R (14) is-(C 3-C 8)-cycloalkyl or phenyl, it is not substituted or by by F and Cl, CF 3, methyl, methoxyl group and-1-3 substituting group selecting in the group that NR (15) R (16) forms replace; R (15) and R (16) be hydrogen or-CH 3
Or other radicals R (2) and R (4) be separate pyrroles-1-base, pyrroles-2-base, or pyrroles-3-base, and it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 8)-alkanoyloxy, (C 2-C 8)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 3, methyl, 1-4 the substituting group of selecting in the group that methoxyl group is formed replaces;
Or other radicals R (2) and R (4) are R (22)-SO 2-, R (23) R (24) N-CO-, R (28)-CO-or R (29) R (30) N-SO 2R (22) and R (28) be separate methyl or-CF 3R (23), R (24), R (29) and R (30) they are separate hydrogen or methyl;
Or other radicals R (2) and R (4) be separate-OR (35) or-NR (35) R (36); R (35) and R (36) are separate hydrogen or have 1,2,3,4, the alkyl of 5 or 6 C-atoms; Or R (35) and R (36) be common 4-7 methylene group, one of them CH 2-Ji can pass through oxygen ,-S-,-NH-,-NCH 3Or-displacement of N-phenmethyl;
Other radicals R (3) is a hydrogen, SR (25), OR (25) ,-NR (25) R (26) ,-CR (25) R (26) R (27); R (25) is a hydrogen, has the alkyl or phenyl of 1,2,3,4,5,6,7 or 8 C-atoms, and it is not substituted or by by F, Cl, CF 3, CH 3, methoxyl group, hydroxyl, amino, 1-3 the substituting group of selecting in the group that methylamino-and dimethylamino are formed replaces; Or R (25) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3, CH 3, methoxyl group, hydroxyl, amino, 1-3 the substituting group of selecting in the group that methylamino-and dimethylamino are formed replaces; R (26) and R (27) are separate that explained as R (25) or hydrogen or have 1,2,3,4,5, the alkyl of 6,7 or 8 C-atoms;
Radicals R (6), R (7), R (8), one among R (9) and the R (10) is-CO-N=C (NH 2) 2
Other radicals R (6) and R (10) are separate hydrogen, have the alkyl of 1,2,3 or 4 C-atoms, F, Cl ,-OR (132) ,-NR (133) R (134) or CF 3R (132), R (133) and R (134) are separate hydrogen or the alkyl with 1,2,3 or 4 C-atoms;
Other radicals R (7) and R (9) are separate hydrogen, F, Cl, Br, I, OH ,-CN, CF 3,-CO-N=C (NH 2) 2, have the alkyl of 1,2,3,4,5,6,7 or 8 C-atoms, have 2,3,4,5, the alkenyl of 6,7 or 8 C-atoms or-(CH 2) MmR (114); Mm is zero, 1 or 2; R (114) is-(C 3-C 8)-cycloalkyl or phenyl, it is not substituted or by by F and Cl ,-CF 3, methyl, methoxyl group and-1-3 substituting group selecting in the group that NR (115) R (116) forms replace; R (115) and R (116) be hydrogen or-CH 3
Or other radicals R (7) and R (9) be separate pyrroles-1-base, pyrroles-2-base or pyrroles-3-base, and it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 8)-alkanoyloxy, (C 2-C 8)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 3, 1-4 the substituting group of selecting in the group that methyl and methoxyl group are formed replaces;
Or other radicals R (7) and R (9) are R (122)-SO 2-, R (123) R (124) N-CO-, R (128)-CO-or R (129) R (130) N-SO 2R (122) and R (128) be separate methyl or-CF 3R (123), R (124), R (129) and R (130) they are separate hydrogen or methyl;
Or other radicals R (7) and R (9) be separate-OR (135) or-NR (135) R (136); R (135) and R (136) are separate hydrogen or have 1,2,3,4, the alkyl of 5 or 6 C-atoms; Or R (135) and R (136) be common 4-7 methylene group, one of them CH 2-Ji can pass through oxygen ,-S-,-NH-,-NCH 3Or-displacement of N-phenmethyl;
Other radicals R (8) is a hydrogen, SR (125) ,-OR (125) ,-NR (125) R (126) or-CR (125) R (126) R (127); R (125) is a hydrogen, has the alkyl or phenyl of 1,2,3,4,5,6,7 or 8 C-atoms, and it is not substituted or by by F, Cl, CF 3, CH 3, methoxyl group, hydroxyl, amino, 1-3 the substituting group of selecting in the group that methylamino-and dimethylamino are formed replaces; Or R (125) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3, CH 3, methoxyl group, hydroxyl, amino, 1-3 the substituting group of selecting in the group that methylamino-and dimethylamino are formed replaces; R (126) and R (127) they be separate that explained as R (125) or hydrogen or have l, 2,3,4,5, and the alkyl of 6,7 or 8 C-atoms;
A is not for existing ,-NR (11)-CO-, and NR (12)-CO-NR (13)-,-NR (17)-CO-NR (18)-SO 2-,-NR (19)-SO 2-,-SO 2-NR (19)-SO 2-,-SO 2-NR (19)-CO-,-O-CO-NR (19)-SO 2-or-CR (20)=CR (21)-; R (11), R (12), R (13), R (17), R (18), R (19), R (20) and R (21) they are separate hydrogen or the alkyl with 1,2,3,4,5,6,7 or 8 C-atoms.
Preferably the compound of formula 1 with and pharmacopedics on the salt that is fit to, wherein:
Radicals R (1), R (2), R (3), one among R (4) and the R (5) is-CO-N=C (NH 2) 2
Other radicals R (1) and R (5) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl ,-OR (32) ,-NR (33) R (34) or CF 3R (32), R (33) and R (34) they are separate hydrogen or methyl;
Other radicals R (2) and R (4) are separate hydrogen, F, Cl, Br, I, OH, CF 3,-CO-N=C (NH 2) 2, have the alkyl of 1,2,3 or 4 C-atoms, have 2,3 or 4 C-atoms alkenyl or-(CH 2) mR (14); M is zero, 1 or 2; R (14) is-(C 3-C 6)-cycloalkyl or phenyl, it is not substituted or by by F and Cl ,-CF 3, 1-2 the substituting group of selecting in the group that methyl and methoxyl group are formed replaces;
Or other radicals R (2) and R (4) be separate pyrroles-1-base, pyrroles-2-base or pyrroles-3-base, and it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
Or other radicals R (2) and R (4) are separate R (22)-SO 2-, R (28)-CO-or R (29) R (30) N-SO 2-; R (22) and R (28) be separate methyl or-CF 3, R (29) and R (30) are separate hydrogen or methyl;
Or other radicals R (2) and R (4) be separate-OR (35) or-NR (35) R (36); R (35) and R (36) are separate hydrogen, methyl or ethyl; Or R (35) and R (36) be common 4-5 methylene group, one of them CH 2-Ji can pass through oxygen ,-S-,-NH-or-NCH 3-displacement;
Other radicals R (3) is a hydrogen ,-SR (25), OR (25) ,-NR (25) R (26) ,-CR (25) R (26) R (27); R (25) is a hydrogen, has the alkyl of 1,2,3 or 4 C-atoms, phenyl, and it is not substituted or by by F, Cl, CF 3, CH 3, 1-2 the substituting group of selecting in the group that methoxyl group and dimethylamino are formed replaces; Or R (25) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3, CH 3, 1-2 the substituting group of selecting in the group that methoxyl group and dimethylamino are formed replaces; R (26) and R (27) are separate hydrogen or the alkyl with 1,2,3 or 4 C-atoms;
Radicals R (6), R (7), R (8), one among R (9) and the R (10) is-CO-N=C (NH 2) 2
Other radicals R (6) and R (10) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl ,-OR (132) ,-NR (133) R (134) or CF 3R (132), R (133) and R (134) they are separate hydrogen or methyl;
Other radicals R (7) and R (9) are separate hydrogen, F, Cl, Br, I, OH, CF 3,-CO-N=C (NH 2) 2, have the alkyl of 1,2,3 or 4 C-atoms, have 2,3 or 4 C-atoms alkenyl or-(CH 2) MmR (114); Mm is zero, 1 or 2; R (114) is-(C 3-C 6)-cycloalkyl or phenyl, it is not substituted or by by F and Cl ,-CF 3, 1-2 the substituting group of selecting in the group that methyl and methoxyl group are formed replaces;
Or other radicals R (7) and R (9) be separate pyrroles-1-base, pyrroles-2-base or pyrroles-3-base, and it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
Or other radicals R (7) and R (9) are separate R (122)-SO 2-, R (128)-CO-or R (129) R (130) N-SO 2-; R (122) and R (128) be separate methyl or-CF 3R (129) and R (130) are separate hydrogen or methyl;
Or other radicals R (7) and R (9) be separate-OR (135) or-NR (135) R (136); R (135) and R (136) are separate hydrogen, methyl or ethyl; Or R (135) and R (136) be common 4-5 methylene group, one of them CH 2-Ji can pass through oxygen ,-S-,-NH-or-NCH 3Displacement;
Other radicals R (8) is a hydrogen ,-SR (125) ,-OR (125) ,-NR (125) R (126) or-CR (125) R (126) R (127); R (125) is a hydrogen, has the alkyl or phenyl of 1,2,3 or 4 C-atoms, and it is not substituted or by by F, Cl, CF 3, CH 3, 1-2 the substituting group of selecting in the group that methoxyl group and dimethylamino are formed replaces; Or R (125) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3, CH 3, 1-2 the substituting group of selecting in the group that methoxyl group and dimethylamino are formed replaces; R (126) and R (127) are separate hydrogen or the alkyl with 1,2,3 or 4 C-atoms;
A is not for existing ,-NR (11)-CO-, and-NR (12)-CO-NR (13)-,-NR (17)-CO-NR (18)-SO 2-;-NR (19)-SO 2-;-SO 2-NR (19)-SO 2-,-SO 2-NR (19)-CO-,-O-CO-NR (19)-SO 2-or-CR (20)=CR (21)-; R (11), R (12), R (13), R (17), R (18), R (19), R (20) and R (21) they are separate hydrogen or the alkyl with 1,2,3 or 4 C-atoms;
Particularly preferably be formula 1 compound with and pharmacopedics on the salt that is fit to, wherein:
Radicals R (1), R (2), R (3), one among R (4) and the R (5) is-CO-N=C (NH 2) 2
Other radicals R (1) and R (5) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl ,-OR (32) ,-NR (33) R (34) or CF 3R (32), R (33) and R (34) they are separate hydrogen or methyl;
Other radicals R (2) and R (4) are separate hydrogen, F, Cl, OH, CF 3,-CO-N=C (NH 2) 2, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
Or other radicals R (2) and R (4) are R (22)-SO 2-; R (22) be methyl or-CF 3
Or other radicals R (2) and R (4) be separate-OR (35) or-NR (35) R (36); R (35) and R (36) are separate hydrogen, methyl or ethyl;
Other radicals R (3) is a hydrogen ,-SR (25) ,-OR (25) ,-NR (25) R (26) or-CR (25) R (26) R (27); R (25) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; Or R (25) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; R (26) and R (27) are separate hydrogen or methyl;
Radicals R (6), R (7), R (8), one among R (9) and the R (10) is-CO-N=C (NH 2) 2
Other radicals R (6) and R (10) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl ,-OR (132) ,-NR (133) R (134) or CF 3R (132), R (133) and R (134) they are separate hydrogen or methyl;
Other radicals R (7) and R (9) are separate hydrogen, F, Cl, OH, CF 3,-CO-N=C (NH 2) 2, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 3And methyl;
Or other radicals R (7) and R (9) are R (122)-SO 2-; R (122) be methyl or-CF 3
Or other radicals R (7) and R (9) be separate-OR (135) or-NR (135) R (136); R (135) and R (136) are separate hydrogen, methyl or ethyl;
Other radicals R (8) is a hydrogen ,-SR (125) ,-OR (125) ,-NR (125) R (126) or-CR (125) R (126) R (127); R (125) is a hydrogen, has the alkyl or phenyl of 1,2,3 C-atoms, and it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; Or R (125) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; R (126) and R (127) are separate hydrogen or methyl;
A is not for existing ,-NR (11)-CO-, and-NR (12)-CO-NR (13)-,-NR (17)-CO-NR (18)-SO 2-,-NR (19)-SO 2-,-SO 2-NR (19)-SO 2-,-SO 2-NR (19)-CO-,-O-CO-NR (19)-SO 2-or-CR (20)=CR (21)-; R (11), R (12), R (13), R (17), R (18), R (19), R (20) and R (21) they are separate hydrogen, methyl or ethyl.
Particularly preferably be fully formula 1 compound with and pharmacopedics on the salt that is fit to, wherein:
Radicals R (1), R (2), R (3), one among R (4) and the R (5) is-CO-N=C (NH 2) 2
Other radicals R (1) and R (5) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl or CF 3
Other radicals R (2) and R (4) are hydrogen, OH, CF 3,-CO-N=C (NH 2) 2, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 3And methyl;
Other radicals R (3) is a hydrogen ,-OR (25) or CR (25) R (26) R (27); R (25) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; Or R (25) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; R (26) and R (27) are separate hydrogen or methyl;
Radicals R (6), R (7), R (8), one among R (9) and the R (10) is-CO-N=C (NH 2) 2
Other radicals R (6) and R (10) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl, or CF 3
Other radicals R (7) and R (9) are hydrogen, OH, CF 3,-CO-N=C (NH 2) 2, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
Other radicals R (8) is a hydrogen ,-OR (125) or-CR (125) R (126) R (127); R (125) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; Or R (125) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; R (126) and R (127) are separate hydrogen or methyl;
A is not for existing ,-NR (11)-CO-, and-NR (12)-CO-NR (13)-,-NR (17)-CO-NR (18)-SO 2-,-NR (19)-SO 2-,-SO 2-NR (19)-SO 2-,-SO 2-NR (19)-CO-,-O-CO-NR (19)-SO 2-or-CR (20)=CR (21)-; R (11), R (12), R (13), R (17), R (18), R (19), R (20) and R (21) they are separate hydrogen or methyl.
Especially particularly preferably be formula 1 compound with and pharmacopedics on the salt that is fit to, wherein:
Radicals R (1), one among R (3) and the R (5) is-CO-N=C (NH 2) 2
Other radicals R (1) and R (5) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl or CF 3
R (2) and R (4) are hydrogen, OH, CF 3, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
Other radicals R (3) is a hydrogen ,-OR (25) or-CR (25) R (26) R (27); R (25) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; Or R (25) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; R (26) and R (27) are separate hydrogen or methyl;
Radicals R (6), one among R (8) and the R (10) is-CO-N=C (NH 2) 2
Other radicals R (6) and R (10) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl or CF 3
R (7) and R (9) are hydrogen, OH, CF 3, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkyl group, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
Other radicals R (8) is a hydrogen ,-OR (125) or-CR (125) R (126) R (127); R (125) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; Or R (125) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; R (126) and R (127) are separate hydrogen or methyl;
A is not for existing ,-NR (11)-CO-, and-NR (12)-CO-NR (13)-,-NR (17)-CO-NR (18)-SO 2-,-NR (19)-SO 2-,-SO 2-NR (19)-SO 2-,-SO 2-NR (19)-CO-,-O-CO-NR (19)-SO 2-or-CR (20)=CR (21)-; R (11), R (12), R (13), R (17), R (18), R (19), R (20) and R (21) they are separate hydrogen or methyl.
Fully particular preferred is formula 1 compound with and pharmacopedics on the salt that is fit to, wherein:
Radicals R (1), R (2), R (3), one among R (4) and the R (5) is-CO-N=C (NH 2) 2
Other radicals R (1) and R (5) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl or CF 3
Other radicals R (2) and R (4) are hydrogen, OH, CF 3,-CO-N=C (NH 2) 2, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
Other radicals R (3) is a hydrogen ,-OR (25) or-CR (25) R (26) R (27); R (25) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; Or R (25) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; R (26) and R (27) are separate hydrogen or methyl;
Radicals R (6), R (7), R (8), one among R (9) and the R (10) is-CO-N=C (NH 2) 2
Other radicals R (6) and R (10) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl or CF 3
Other radicals R (7) and R (9) are hydrogen, OH, CF 3,-CO-N=C (NH 2) 2, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
Other radicals R (8) is a hydrogen ,-OR (125) or-CR (125) R (126) R (127); R (125) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; Or R (125) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 3A substituting group of selecting in the group of forming replaces; R (126) and R (127) are separate hydrogen or methyl;
A is-NR (11)-CO-,-NR (12)-CO-NR (13)-and ,-NR (17)-CO-NR (18)-SO 2-,-NR (19)-SO 2-,-SO 2-NR (19)-SO 2-,-SO 2-NR (19)-CO-,-O-CO-NR (19)-SO 2-or-CR (20)=CR (21)-; R (11), R (12), R (13), R (17), R (18), R (19), R (20) and R (21) they are separate hydrogen or methyl.
Described alkyl group can be straight chain or branched.
For (C 1-C 9)-heteroaryl is appreciated that the group for being derived out by phenyl or naphthyl, one or more therein CH-bases are by the N displacement and/or have at least two adjacent CH-bases (forming one five yuan aromatic ring) to pass through S, NH or O displacement, 1 of condensation position that in addition may bicyclic radicals or 2 atoms (as at the indolizine base) are the N-atoms.
Be considered to particularly furyl, thienyl, pyrryl, imidazolyl as heteroaryl, pyrazolyl, triazolyl, tetrazyl ， oxazolyl isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indyl, indazolyl, quinolyl, isoquinolyl, 2, the 3-phthalazinyl, quinoxalinyl, quinazolyl, cinnolinyl.
If substituent R (1) to the R (10) is contained one or more asymmetric centers, then these can be separate both can be that S also can be the R configuration.Compound can be used as optically-active (with divide) isomer, as diastereomer, exists as racemoid or as their mixture, and carbon-to-carbon double bond both can be that cis also can be trans combination.
The present invention relates to a preparation method of compound 1 in addition, it is characterized in that, with the compound and the guanidine reaction of formula 11,
Figure A9710208800241
Wherein R (1 ') regards to R (1) to the illustrated meaning of R (10) on R (10 ') has, wherein substituent R (1 ') have at least to the R (5 ') one and have at least to the R (10 ') in substituent R (6 ')-individual be described COL-base, wherein L is the leavings group of an easy nucleophilic substitution.
The activation of Chemical formula 11 acid derivative, wherein L is an alkoxyl group, preferably methoxyl group or phenoxy group, a thiophenyl, methylthio group, 2-pyridine sulfenyl, or a nitrogen heterocyclic, preferably 1-imidazolyl, be to be fit to the carboxyl acyl chloride (formula 11 of the method for having known from the basis, L=Cl) obtain, and this compound can (formula 11 L=OH) be for example made with thionyl (two) chlorine by the carboxylic acid on basis with known method.
Other activatory acid derivative of formula 11 also can directly (formula 11 L=OH) be made, and for example has L=OCH by the diaryl dicarboxylic derivative with known method except the carboxyl acyl chloride of formula 11 (L=Cl) 3The methyl esters of formula 11 handle in methyl alcohol with gasiform HCl, the imidazoles thing of formula 11 is handled [L=1-imidazolyl, Staab, Angew, Chem Int.Ed.Engl 1,351-367 (1962)] with the phosphinylidyne diimidazole, blended acid anhydride 11 is used Cl-COOC 2H 5Or tolylsulfonyl chlorination thing in the presence of the triethylamine in an inert solvent, also can use dicyclohexylcarbodiimide (DCC) or with O[(cyano group (ethoxycarbonyl) methylene radical) amino]-1,1,3, and 3-tetramethyl-urea-a tetrafluoro borate (" TO-TU ") activation diaryl dicarboxylic [Proceedings of the 21.European PeptideSymposium, Peptides 1990, Editors E.Giralt and D.Andreu, Es-com, Leiden, 1991].The method that is fit to of the activatory carboxylic acid derivative of a series of preparation formula 11 is at citing document J.March, Advanced Organic Chemistry, Third Edition (John Wiley ﹠amp; Sons, 1985), explanation is arranged in the 350th page.
The activation of formula 1 carboxylic acid derivative and guanidine but to transform be to finish in a kind of proton or non-proton polar organic solvent inert with known method, to this at diaryl dicarboxylic dimethyl ester (11, methyl alcohol when L=OMe) transforming with guanidine, Virahol or THF (tetrahydrofuran (THF)) prove suitable at 20 ℃ between the boiling point of these solvents.Be to be adapted in the inert solvent as THF in the great majority of compound 11 and salt-free guanidine transform, glycol dimethyl ether carries out in dioxane or the Virahol, and water also can be used as solvent and is utilized.
When L=Cl, be fit to add a kind of acid neutralizing agent (S  uref  nger), for example come in conjunction with haloid acid with the form of excessive guanidine.
At the phenyl position with sulphur-, oxygen-or the importing of the compound that replaces of nitrogen nucleophile be by on the document known on the derivative of diaryl-carboxylic-dialkyl the method for nucleophilic substitution finish.Halogen ion and trifluoromethayl sulfonic acid root prove suitable as the leavings group on the derivative of diaryl dicarboxylic in this metalepsy.In a dipolar non-proton solvent, as DMF or TMU, 0 ℃ of temperature to the boiling point of solvent, preferably 80 ℃ of temperature to the boiling point of solvent are handled and are fit to.Suitable as acid neutralizing agent with anionic an alkali metal salt or the alkaline earth salt with a high alkalinity and slight nucleophilicity, for example a K 2CO 3Or C 5CO 3
Alkyl-or the importing of aryl substituent be to finish by known method on the document, i.e. aryl halide and for example organic zinc compound, organic stannane, the cross coupling effect that the palladium of organic boronic or organo-borane transmits.
Diaryl dicarboxylic-two guanidine 1 is generally weak base and can forms salt by combined acid.As the salt of the acid that is fit on all pharmacology of acid salt all at the row of consideration, for example halogenide, particularly hydrochloride, xitix, lactic acid salt, vitriol, Citrate trianion, tartrate, acetate, phosphoric acid salt, mesylate, tosilate.
At U.S. Patent application specification sheets 5091394 (HOE89/F288) with in European open source literature 0556674 (HOE92/F034) benzoylguanidines has been described, diaryl dicarboxylic-two guanidine has not been described.Illustrated among the WO94/26709 (PCT/JP94/00786) in position between benzoylguanidines and gone into a benzene nucleus as the possibility of substituent R (2) (except many other possibilities); and this second benzene nucleus can also (except many other possibilities) carry a guanidine radicals as substituting group, but these compound known still can not be satisfactory for many possibility of its application.
Because being particularly suitable as the anti-arrhythmic that has the Cardioprotective composition, their pharmacological characteristics is used for infraction prevention and infraction treatment and anginal treatment by compound of the present invention; and they can also prophylactically suppress and obviously alleviate the damage of being brought out by local asphyxia, particularly the pathophysiological process of the ARR generation that is caused by local asphyxia.Because they are for the protective effect of pathologic anoxic and local asphyxia situation, according to formula 1 compound of the present invention because pair cell Na +/ H +The inhibition of exchanging mechanism can be used as medicine and is used for all acute or chronic injuries that cause by local asphyxia or former or the secondary disease that causes thus; this relates to their application as the surgical operation medicine; for example when organ transplantation; this compound is used in to be won before the organ and wins in the organ process protection to organ in the donor; protection for the organ under winning; for example be used for processing and the storage of organ in the physiology water-bath; and also can be applied in the process that organ is transplanted to acceptor, this compound when carrying out the angioplasty operation for example heart and around blood vessel be of great value medicine equally with provide protection.The protective effect of the damage that causes for local asphyxia according to them, these compounds also are suitable as the ischemic medicine of treatment neural system, particularly central nervous system, and for example they are fit to for the treatment of apoplexy or cerebral edema.Equally also be suitable for the treatment of shock state in addition according to formula 1 compound of the present invention, for example allergic, cardiogenic (circulation) hypovolemic and bacteroidal shock.
Pass through it for cell proliferation according to formula 1 compound of the present invention in addition, for example for inoblast cell proliferation with for the powerful restraining effect of level and smooth blood vessel muscle cell multiplication, it is loomed large, therefore consider the valuable therapeutical agent of formula 1 compound as some diseases, this class disease causes hyperplasia owing to former or secondary reason, so can be used as antiatherosclerotic, the anti-diabetic late complication, anticancer disease, anti-fibroplasia disease such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, the medicine of organ hypertrophy and organ pipe hyperplasia, particularly hyperplasia of prostate and prostatomegaly.
According to compound of the present invention is the sodium-proton-antiporter (Na of cell +/ H +Exchanger) effective inhibitor, this Na +/ H +Exchanger is at numerous disease (essential hypertension, atherosclerosis, diabetes etc.) and also raise in these cells, measures to be easy to accomplish, for example in red corpuscle thrombocyte or white corpuscle.Therefore be suitable as remarkable and simple science tools according to compound of the present invention, for example they are used for determining and difference hypertension as diagnostic reagent, atherosclerosis, diabetes, the particular form of proliferative disease etc.Formula 1 compound is suitable for stoping hypertensive generation in addition, for example the prophylactic treatment of essential hypertension.
Comparing with most of compound known to demonstrate according to compound of the present invention water-solublely has one significantly to improve.Therefore they are more suitable for intravenously administrable.
According to compound of the present invention compare with the compound of known good water solubility be owing to its biological preferably available property and preferably pharmacokinetics loom large.
The medicine that contains compound 1 can per os, without stomach and intestine, intravenous, rectum or use by inhalation, preferable methods depends on the phenotype of disease at that time, compound 1 can be independent or come together to use with the subsidiary material of lid Lun Shi pharmacopedics, this is not only in veterinary science and is in physianthropy.Which subsidiary material is fit to for desired formula of medicine, and this expertise according to them for the expert is very familiar, except solvent, gel former, the suppository basis, tablet subsidiary material and other bioactive substance carrier are outer can also be used as antioxidant, dispersion agent, emulsifying agent, foam-expelling agent, correctives, preserving agent, solution medium or staining agent.Then can be for a kind of per os type of service with active compound and to this additional substances that is fit to, as carrier substance, stablizer or inert diluent mix and make suitable form of medication by method commonly used, as tablet, drageeing, capsule, water quality, solution alcohol or butyrous.Can use as gum arabic magnesium oxide, magnesiumcarbonate, potassiumphosphate, lactose, glucose or starch, particularly corn starch as inert support.The preparation of medicine can be made exsiccant or moist granula.Can consider as vegetables oil or animal oil as butyrous carrier substance or as solvent, as Trisun Oil R 80 or Oils,glyceridic,cod-liver.
For subcutaneous or intravenous administration be with active compound under desired situation with to this commonly used material such as solution medium, emulsifying agent or other auxiliary substance are made solution, suspension or emulsion, can consider as water, physiological saline or alcohol, for example ethanol as solvent, propyl alcohol, glycerol also has sugar soln such as glucose-or sweet dew (sugar) alcoholic solution in addition, or by a kind of mixture of the different solvent compositions of having mentioned.
For the pharmaceutical formulation with the form of medication of aerosol or spraying is the solution that is fit to formula 1 active substance, suspension or emulsion are in a kind of pharmacy in the unsuspecting solvent, as particularly ethanol or water, or the mixture of these solvents, prescription can also contain the subsidiary material such as the tensio-active agent of other pharmacopedics, emulsifying agent and stablizer and a kind of propelling gas as required.The concentration that this preparation generally contains active substance is about 0.1 to 10, particularly about 0.3 to 3 weight %
The dosage of the active substance of formula 1 is relevant with the action intensity and the acting duration of applied compound with administration number of times; In addition with the kinds of Diseases that will treat and degree and with the mammiferous sex of being treated, at the age, body weight is relevant with individual sensitivity.
Patient's formula 1 compound average every day of total dose at about 75 kilogram weights is at least the 0.001mg/kg body weight, and preferable is to be at least the 0.01mg/kg body weight, and to being up to the 10mg/kg body weight, preferable is to the highest 1mg/kg body weight.In the acute attack of disease, such as after directly suffering from myocardial infarction, also can give higher dosage, and at first be that repeatedly administration is essential, for example give four medicines every day.When intravenous administration, can be essential down to 100mg every day at care unit particularly such as blocking patient at one.
The abbreviation word table
AIBN ∝, ∝-Diisopropyl azodicarboxylate
The Bn benzyl; Phenmethyl
The saturated NaCl aqueous solution of Brine
CH 2Cl 2Methylene dichloride
DCl desorb-chemi-ionization
The DIP diisopropyl ether
The DMA N,N-DIMETHYLACETAMIDE
The DME glycol dimethyl ether
DMF N, dinethylformamide
EE ethyl acetate (EtOAc)
The El electronic impulse
The eq equivalent
Es stream of electrons-ionizing event
The Et ethyl
FAB fast atom bombardment(FAB) (irradiation)
The HEP normal heptane
HOAC acetic acid
The Me methyl
MeOH methyl alcohol
The mp fusing point
The MTB methyl tertiary butyl ether
NBS N-bromo-succinimide
The NMP N-Methyl pyrrolidone
The RT room temperature
The THF tetrahydrofuran (THF)
TMU N, N, N ', N '-tetramethyl-urea
Tol toluene
The ZNS central nervous system
Experimental section
The regulae generales of preparation diaryl dicarboxylic-two guanidine
(1) by benzene dicarboxylic acid-dialkyl (11, the L=O-alkyl)
The guanidine (free alkali) of the benzene dicarboxylic acid-dialkyl of the formula 11 of 5mmol and 50mmol is dissolved in the 5ml Virahol, and boiling under refluxing (according to active 5 minutes to the 10 hours type reaction time of the carbonyl of carboxylic acid derivative) is until complete reaction (thin layer control).Draw with the dilution of 150ml water and with product subsequently.In case of necessity on silica gel with a kind of suitable eluent, for example use EE/MeOH5: 1 or carry out chromatographic analysis at 10: 1 with acetone.
Embodiment 1:3-(4-guanidine radicals carbonyl) phenyl-benzoylguanidines
A.3-(4-formyl radical) phenyl-ethyl benzoate
3.4g 3-bromo-benzoic acid ethyl ester, 170mg palladium (II), 390mg triphenyl phosphine, 2.5g 4-formyl radical phenyl-boron dihydroxide, the Na of the 2N of 15ml 2CO 3The aqueous solution, 90ml toluene and 25ml ethanol is boiling 2 hours in backflow under argon.Add 150ml NaH-CO subsequently 3Saturated aqueous solution and with the EE extraction 3 times that at every turn be 150ml.Pass through Na 2SO 4Make it dry and also in a vacuum solvent is removed, carrying out chromatographic analysis at silica gel at 1: 8 with EE/HEP provides 2.4g white crystals, mp81 ℃.Rf(DIP)＝0.55????????????MIS(DCI)：255(M+H) +
B.3-(4-ethoxy carbonyl) phenyl-ethyl benzoate
2.4g 3-(4-formyl radical) phenyl-ethyl benzoate is dissolved in the 190ml ethanol and at room temperature adds 2.3g NaCN and 1.1ml Glacial acetic acid.Draw a transparent solution after 15 minutes, at room temperature with 18.9g MnO 2Join in this solution.At room temperature stirred 7 hours, throw out is leached, filtrate is injected into the saturated Na of 300ml 2CO 3Extract 3 times with 300ml EE in the aqueous solution and at every turn, pass through Na 2CO 3Make it dry, solvent is removed in a vacuum, carrying out chromatographic analysis at silica gel at 1: 4 with EE/HEP provides 2.5g colourless oil.Rf(DIP)＝0.59?????????????MS(ES)：299(M+H) +
C.3-(4-guanidine radicals carbonyl) phenyl-benzoylguanidines
1.1g reacting according to the regulae generales for preparing diaryl dicarboxylic-two guanidine, 3-(4-ethoxycarbonyl) phenyl-ethyl benzoate obtains the colourless crystallization of 760mg, mp113 ℃ of Rf (acetone 10: 1)=0.21 MS (FAB): 325 (M+H) +
The title compound of embodiment 2 is synthetic with method similar to Example 1:
Embodiment 2:2-(4-guanidine radicals carbonyl) phenyl-benzoylguanidines
Figure A9710208800311
Mp283 ℃ of Rf (acetone 10: 1)=0.25 MS (FAB): 325 (M+H) +
Embodiment 3:4-(4-guanidine radicals carbonyl) phenylsulfamoyl-benzoylguanidines
A.4-sulphonamide-ethyl benzoate
20g 4-sulphonamide-phenylformic acid is dissolved in the 500ml ethanol, splashes into 36ml SOCl 2And boiling 5 hours on refluxing.Volatile fraction is removed in a vacuum subsequently, with saturated Na 2CO 3The aqueous solution transfers to 9 and each with 200ml EE extraction 3 times with pH.Pass through Na 2SO 4Make it dry, solvent is removed in a vacuum and can be obtained the colourless crystallization of 21g, mp108 ℃.Rf(DIP)＝0.24??????????MS(DCl)：230(M+H) +
B.4-(4-ethoxycarbonyl) phenylsulfamoyl-ethyl benzoate
1.1g 4-sulphonamide-ethyl benzoate, 840mg 4-ethyl fluoro benzoate and 4.9gCs 2CO 3In 10ml NMP, stirred 10 hours, make it then at room temperature to cool off, add 200ml EE and each with 100ml water washing 3 times at 130 ℃.Pass through Na 2SO 4Make it dry and solvent is removed in a vacuum.Carry out chromatographic analysis at silica gel at 1: 1 with EE/HEP 2.6g is provided colourless oil.Rf(EE/HEP?1∶1)＝0.38??????MS(DCI)：378(M+H) +
C.4-(4-guanidine radicals carbonyl) phenylsulfamoyl-benzoylguanidines
2.5g (4-(4-ethoxycarbonyl) phenylsulfamoyl-ethyl benzoate reacts (10 hours reaction times) according to the regulae generales of preparation diaryl dicarboxylic-two guanidine, can obtain the unbodied white solid of 560mg.Rf (acetone 10: 1)=0.16 MS (FAB): 446 (M+H) +
The title compound of embodiment 4 be according to the regulae generales of preparation diaryl dicarboxylic-two guanidine by biphenyl-4,4 '-dicarboxylic acid-dimethyl ester is synthetic.
Embodiment 4: biphenyl-4,4 '-dicarboxylic acid-two guanidine Rf (acetone 10: 1)=0.09 MS (FAB): 325 (M+H) +
Embodiment 5:4[3-(guanidine radicals carbonyl) phenyl amino carbonylamino sulphonyl]-benzoylguanidines A) 4-ethoxycarbonyl aminosulfonyl-methyl benzoate
6.0g 4-aminosulfonyl-methyl benzoate and 7.7g K 2CO 3The 5.3ml methyl-chloroformate is injected in boiling 5 minutes under refluxing then in the anhydrous DME of 100ml, and continues under refluxing boiling 2 hours, makes it cooling, draws solid, and with the NaH-SO of 100ml 4Saturated aqueous solution and 200ml water are told product by stirring, draw product and carry out drying at 50 ℃ in a vacuum, mp146 ℃ of Rf of 7.1g colourless crystallization (EE) 0.41 MS (DCl): 288 (M+H) +
B) 4-ethoxycarbonyl aminosulfonyl-phenylformic acid
The NaOH aqueous solution of 6g 4-ethoxycarbonyl aminosulfonyl-methyl benzoate and 42ml 1n at room temperature stirred in the MeOH of 50ml 24 hours.Solvent is removed in a vacuum, is absorbed in the 100ml water, adjusts pH to 1-2 and draws product with the HCl aqueous solution of dilution.Dry in a vacuum, obtain mp:189 ℃ of Rf of 5.5g colourless crystallization (DIP/2%HOAc)=0.28 MS (Es): 274 (M+H) +
C) 4-[3-(hydroxycarbonyl group) phenylamino carbonylamino sulphonyl]-phenylformic acid
2g 4-ethoxycarbonyl aminosulfonyl-phenylformic acid and 1g 3-benzaminic acid be boiling 10 hours under refluxing in the 50ml dry toluene, and solvent is removed in a vacuum, obtains the 2.8g raw product, then it is directly further used.
D) 4-[3-(guanidine radicals carbonyl) phenylamino carbonylamino sulphonyl]-benzoylguanidines
1.4g 4-[3-(hydroxycarbonyl group) phenylamino carbonylamino sulphonyl]-phenylformic acid and 1.4g carbonyl dimidazoles be dissolved in the mixture of the anhydrous THF of a 60ml and dry DMF and at room temperature stirred 24 hours, add the 2.5g guanidine then, and at room temperature continue to stir 24 hours, solvent is removed in a vacuum, product is suspended in the 100ml water, and the HCl aqueous solution with dilution transfers to 7 with pH then, and at room temperature stirs 1 hour, with product sucking-off and dry in a vacuum, obtain the 820mg colourless crystallization.Mp:207 ℃ of Rf (CH 2Cl 2/ MeOH/ water/HOAc 8: 4: 1: MS (Es): 447 (M+H) 1)=0.56 +
Pharmacology data
The erythrocytic Na of rabbit +/ H +The inhibitor of exchanger
White New Zealand rabbit (Ivanovas) obtains a kind of standard diet 6 time-of-weeks that contain 2% cholesterol, to activate Na +/ H +-exchange and can measure with the flame spectrometric analysis method like this and pass through Na +/ H +Exchange Na +Enter erythrocytic influx, blood is taked by arteria auricularis and is come anti-freezing by 251E potassium-heparin, and the part of each sample is used for by twice hematocrit of centrifugal mensuration, is that the aliquots containig of 100 μ l is used to measure red corpuscle Na at every turn +Initial content
In order to measure the sodium-influx of ammonia chloro-sensitivity, is (mmol/l:140NaCl, 3KCl, 150 sucrose in the salt-sucrose-medium of a kind of high osmotic pressure of 5ml with each blood sample 100 μ l at each, 0.1 ouabain, 20 3-hydroxymethyl aminomethane) be to hatch under 7.4 and 37 ℃ at pH.Then with red corpuscle with ice-cold MgCl 2-ouabain-solution (mmol/l:112MgCl 2, 0.1 ouabain) and washing 3 times and in 2.0ml distilled water, make it haemolysis.Measure endoerythrocytic sodium content with flame spectrometric analysis.
Na +-net inflow amount by erythrocytic sodium-initial content and the difference of erythrocyte sodium content after hatching calculate.Sodium-influx that ammonia chlorine suppresses is to add and do not adding ammonia chlorine 3 * 10 by red corpuscle 4The difference of the erythrocyte sodium content after mol/l is hatched draws.According to compound of the present invention also is in this way to handle.
The result
Na +/ H +The restraining effect of exchanger
Embodiment ????1C50μmol/l
????1 ????1.5
????2 ????5.0
????3 ????1.5
????4 ????2.0
????5 ????10

Claims (19)

  1. The diaryl dicarboxylic of Chemical formula 1-two guanidine with and pharmacopedics on the salt that is fit to:
    Figure A9710208800021
    Wherein
    Radicals R (1), R (2), R (3), one among R (4) and the R (5) is-CO-N=C (NH 2) 2
    Other radicals R (1) and R (5) are separate hydrogen, have the alkyl of 1,2,3 or 4 C-atoms, F, Cl ,-OR (32) ,-NR (33) R (34) or CF 3R (32), R (33) and R (34) are separate hydrogen or the alkyl with 1,2,3 or 4 C-atoms;
    Other radicals R (2) and R (4) are separate hydrogen, F, Cl, Br, I, OH ,-CN, CF 3,-CO-N=C (NH 2) 2, have the alkyl of 1,2,3,4,5,6,7 or 8 C-atoms, have 2,3,4,5, the alkenyl of 6,7 or 8 C-atoms or-(CH 2) mR (14); M is zero, 1 or 2; R (14) is-(C 3-C 8) cycloalkyl or phenyl, it is not substituted or by by F and Cl ,-CF 3, methyl, methoxyl group and-1-3 substituting group selecting in the group that NR (15) R (16) forms replace; R (15) and R (16) are hydrogen or CH 3
    Or other radicals R (2) and R (4) be separate pyrroles-1-base, pyrroles-2-base or pyrroles-3-base, and it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 8)-alkanoyloxy, (C 2-C 8)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 3Methyl, 1-4 the substituting group of selecting in the group that methoxyl group is formed replaces;
    Or other radicals R (2) and R (4) are R (22)-SO 2-, R (23) R (24) N-CO-, R (28)-CO-or R (29) R (30)-N-SO 2R (22) and R (28) be separate methyl or-CF 3R (23), R (24), R (29) and R (30) they are separate hydrogen or methyl;
    Or other radicals R (2) and R (4) be separate-OR (35) or-NR (35) R (36); R (35) R (36) is separate hydrogen or has 1,2,3,4, the alkyl of 5 or 6 C-atoms; Or R (35) and R (36) be common 4-7 methylene group, one of them CH 2-Ji can pass through oxygen ,-S-,-NH-,-NCH 3Or-displacement of N-phenmethyl;
    Other group (3) is a hydrogen ,-SR (25) ,-OR (25) ,-NR (25) R (26) ,-CR (25) R (26) R (27); R (25) is a hydrogen, has the alkyl or phenyl of 1,2,3,4,5,6,7 or 8 C-atoms, and it is not substituted or by by F, Cl, CF 3, CH 3, methoxyl group, hydroxyl, amino, the 1-3 that selects in the group that methylamino-and dimethylamino an are formed substituting group replaces; Or R (25) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3, CH 3, methoxyl group, hydroxyl, amino, 1-3 the substituting group of selecting in the group that methylamino-and dimethylamino are formed replaces; R (26) and R (27) are separate that explained as R (25) or hydrogen or have 1,2,3,4,5, the alkyl of 6,7 or 8 C-atoms;
    Radicals R (6), R (7), R (8), one among R (9) and the R (10) is-CO-N=C (NH 2) 2
    Other radicals R (6) and R (10) are separate hydrogen, have the alkyl of 1,2,3 or 4 C-atoms, F, Cl ,-OR (132) ,-NR (133) R (134) or CF 3R (132), R (133) and R (134) are separate hydrogen or the alkyl with 1,2,3 or 4 C-atoms;
    Other radicals R (7) and R (9) are separate hydrogen, F, Cl, Br, I, OH ,-CN, CF 3,-CO-N=C (NH 2) 2, have the alkyl of 1,2,3,4,5,6,7 or 8 C-atoms, have 2,3,4,5, the alkenyl of 6,7 or 8 C-atoms or-(CH 2) MmR (114); Mm is zero, 1 or 2; R (114) is-(C 3-C 8)-cycloalkyl or phenyl, it is not substituted or by by F and Cl, CF 3, methyl, methoxyl group and-1-3 substituting group selecting in the group that NR (115) R (116) forms replace; R (115) and R (116) be hydrogen or-CH 3
    Or other radicals R (7) and R (9) be separate pyrroles-1-base, pyrroles-2-base or pyrroles-3-base, and it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 8)-alkanoyloxy, (C 2-C 8)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 3, 1-4 the substituting group of selecting in the group that methyl and methoxyl group are formed replaces;
    Or other radicals R (7) and R (9) are R (122)-SO 2-, R (123) R (124) N-CO-, R (128)-CO-or R (129) R (130)-N-SO 2R (122) and R (128) be separate methyl or-CF 3R (123), R (124), R (129) and R (130) they are separate hydrogen or methyl;
    Or other radicals R (7) and R (9) be separate-OR (135) or-NR (135) R (136); R (135) and R (136) are separate hydrogen or have 1,2,3,4, the alkyl of 5 or 6 C-atoms; Or R (135) and R (136) be common 4-7 methylene group, one of them CH 2-Ji can pass through oxygen ,-S-,-NH-,-NCH 3Or-displacement of N-phenmethyl;
    Other radicals R (8) is a hydrogen ,-SR (125) ,-OR (125) ,-NR (125) R (126)-CR (125) R (126) R (127); R (125) is a hydrogen, has the alkyl or phenyl of 1,2,3,4,5,6,7 or 8 C-atoms, and it is not substituted or by by F, Cl, CF 3, CH 3, methoxyl group, hydroxyl, amino, the 1-3 that selects in the group that methylamino-and dimethylamino an are formed substituting group replaces; Or R (125) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3, CH 3, methoxyl group, hydroxyl, amino, 1-3 the substituting group of selecting in the group that methylamino-and dimethylamino are formed replaces; R (126) and R (127) are separate that explained as R (125) or hydrogen or have 1,2,3,4,5, the alkyl of 6,7 or 8 C-atoms;
    A is not for existing ,-NR (11)-CO-, and-NR (12)-CO-NR (13)-,-NR (17)-CO-NR (18)-SO 2-,-NR (19)-SO 2-,-SO 2-NR (19)-SO 2-,-SO 2-NR (19)-CO-,-O-CO-NR (19)-SO 2-or-CR (20)=CR (21)-; R (11), R (12), R (13), R (17), R (18), R (19), R (20) and R (21) they are separate hydrogen or the alkyl with 1,2,3,4,5,6,7 or 8 C-atoms.
    2. by formula 1 compound of claim 1, it is characterized in that, wherein:
    Radicals R (1), R (2), R (3), one among R (4) and the R (5) is-CO-N=C (NH 2) 2
    Other radicals R (1) and R (5) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl-OR (32) ,-NR (33) R (34) or CF 3R (32), R (33) and R (34) they are separate hydrogen or methyl;
    Other radicals R (2) and R (4) are separate hydrogen, F, Cl, Br, I, OH, CF 3,-CO-N=C (NH 2) 2, have the alkyl of 1,2,3 or 4 C-atoms; Have 2,3 or 4 C-atoms alkenyl or-(CH 2) mR (14); M is zero, 1 or 2; R (14) is-(C 3-C 6)-cycloalkyl or phenyl, it is not substituted or by by F and Cl ,-CF 3, 1-2 the substituting group of selecting in the group that methyl and methoxyl group are formed replaces;
    Or other radicals R (2) and R (4) be separate pyrroles-1-base, pyrroles-2-base or pyrroles-3-base, and it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
    Or other radicals R (2) and R (4) are separate R (22)-SO 2-, R (28)-CO-or R (29) R (30) N-SO 2-; R (22) and R (28) be separate methyl and-CF 3R (29) and R (30) are separate hydrogen or methyl;
    Or other radicals R (2) and R (4) be separate-OR (35) or-NR (35) R (36); R (35) and R (36) are separate hydrogen, methyl or ethyl; Or R (35) and R (36) be common 4-5 methylene group, one of them CH 2-Ji can pass through oxygen ,-S-,-NH-or-NCH 3Displacement;
    Other radicals R (3) is a hydrogen ,-SR (25) ,-OR (25) ,-NR (25) R (26) ,-CR (25) R (26) R (27); R (25) is a hydrogen, has the alkyl of 1,2,3 or 4 C-atoms, phenyl, and it is not substituted or by by F, Cl, CF 3, CH 3, 1-2 the substituting group of selecting in the group that methoxyl group and dimethylamino are formed replaces; Or R (25) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3, CH 3, 1-2 the substituting group of selecting in the group that methoxyl group and dimethylamino are formed replaces; R (26) and R (27) are separate hydrogen or the alkyl with 1,2,3 or 4 C-atoms;
    Radicals R (6), R (7), R (8), one among R (9) and the R (10) is-CO-N=C (NH 2) 2
    Other radicals R (6) and R (10) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl ,-OR (132) ,-NR (133) R (134) or CF 3R (132), R (133) and R (134) they are separate hydrogen or methyl;
    Other radicals R (7) and R (9) are separate hydrogen, F, Cl, Br, I, OH, CF 3,-CO-N=C (NH 2) 2, have the alkyl of 1,2,3 or 4 C-atoms, have 2,3 or 4 C-atoms alkenyl or-(CH 2) MmR (114); Mm is zero, 1 or 2; R (114) is-(C 3-C 6) cycloalkyl or phenyl, it is not substituted or by by F and Cl ,-CF 3, 1-2 the substituting group of selecting in the group that methyl and methoxyl group are formed replaces;
    Or other radicals R (7) and R (9) be separate pyrroles-1-base, pyrroles-2-base or pyrroles-3-base, and it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
    Or other radicals R (7) and R (9) be separate, R (122)-SO 2, R (128)-CO-or (129) R (130) N-SO 2-; R (122) and R (128) be separate methyl or-CF 3R (129) and R (130) are separate hydrogen or methyl;
    Or other radicals R (7) and R (9) be separate-OR (135) or-NR (135) R (136); R (135) and R (136) are separate hydrogen, methyl or ethyl; Or R (135) and R (136) be common 4-5 methylene group, one of them CH 2-Ji can pass through oxygen ,-S-,-NH-or-NCH 3Displacement;
    Other radicals R (8) is a hydrogen ,-SR (125) ,-OR (125) ,-NR (125) R (126) or-CR (125) R (126) R (127); R (125) is a hydrogen, has the alkyl or phenyl of 1,2,3 or 4 C-atoms, and it is not substituted or by by F, Cl, CF 3, CH 3, 1-2 the substituting group of selecting in the group that methoxyl group and dimethylamino are formed replaces; Or R (125) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3, CH 3, 1-2 the substituting group of selecting in the group that methoxyl group and dimethylamino are formed replaces; R (126) and R (127) are separate hydrogen or the alkyl with 1,2,3 or 4 C-atoms;
    A is not for existing ,-NR (11)-CO-, and-NR (12)-CO-NR (13)-,-NR (17)-CO-NR (18)-SO 2-,-NR (19)-SO 2-,-SO 2-NR (19)-SO 2-,-SO 2-NR (19)-CO-,-O-CO-NR (19)-SO 2-or-CR (20)=CR (21)-; R (11), R (12), R (13), R (17), R (18), R (19), R (20) and R (21) they are separate hydrogen or the alkyl with 1,2,3 or 4 C-atoms.
  2. 3. press formula 1 compound of claim 1 or 2, wherein:
    Radicals R (1), R (2), R (3), one among R (4) and the R (5) is-CO-N=C (NH 2) 2
    Other radicals R (1) and R (5) are separate hydrogen, have the alkyl F of 1,2 or 3 C-atom, Cl ,-OR (32) ,-NR (33) R (34) or CF 3R (32), R (33) and R (34) they are separate hydrogen or methyl;
    Other radicals R (2) and R (4) are separate hydrogen, F, Cl, OH, CF 3,-CO-N=C (NH 2) 2, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
    Or other radicals R (2) and R (4) are R (22)-SO 2-; R (22) be methyl or-CF 3
    Or other radicals R (2) and R (4) be separate-OR (35) or-NR (35) R (36); R (35) and R (36) are separate hydrogen, methyl or ethyl;
    Other radicals R (3) is a hydrogen ,-SR (25) ,-OR (25) ,-NR (25) R (26) or-CR (25) R (26) R (27); R (25) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; Or R (25) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; R (26) and R (27) are separate hydrogen or methyl;
    Radicals R (6), R (7), R (8), one among R (9) and the R (10) is-CO-N=C (NH 2) 2
    Other radicals R (6) and R (10) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl ,-OR (132) ,-NR (133) R (134) or CF 3R (132), R (133) and R (134) they are separate hydrogen or methyl;
    Other radicals R (7) and R (9) are separate hydrogen, F, Cl, OH, CF 3,-CO-N=C (NH 2) 2, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
    Or other radicals R (7) and R (9) are R (122)-SO 2-; R (122) be methyl or-CF 3
    Or other radicals R (7) and R (9) be separate-OR (135) or-NR (135) R (136); R (135) R (136) is separate hydrogen, methyl or ethyl;
    Other radicals R (8) is a hydrogen ,-SR (125) ,-OR (125) ,-NR (125) R (126) or-CR (125) R (126) R (127); R (125) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; Or R (125) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; R (126) and R (127) are separate hydrogen or methyl;
    A is not for existing ,-NR (11)-CO-, and-NR (12)-CO-NR (13)-,-NR (17)-CO-NR (18)-SO 2-,-NR (19)-SO 2-,-SO 2-NR (19)-SO 2-,-SO 2-NR (19)-CO-,-O-CO-NR (19)-SO 2-or-CR (20)=CR (21)-; R (11), R (12), R (13), R (17), R (18), R (19), R (20) and R (21) they are separate hydrogen, methyl or ethyl.
  3. 4. by at least one formula 1 compound in the claim 1 to 3, wherein:
    Radicals R (1), R (2), R (3), one among R (4) and the R (5) is-CO-N=C (NH 2) 2
    Other radicals R (1) and R (5) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl or CF 3
    Other radicals R (2) and R (4) are hydrogen, OH, CF 3,-CO-N=C (NH 2) 2, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
    Other group (3) is a hydrogen ,-OR (25) or-CR (25) R (26) R (27); R (25) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; Or R (25) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; R (26) and R (27) are separate hydrogen or methyl;
    Radicals R (6), R (7), R (8), one among R (9) and the R (10) is-CO-N=C (NH 2) 2
    Other radicals R (6) and R (10) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl, or CF 3
    Other radicals R (7) and R (9) are hydrogen, OH, CF 3,-CO-N=C (NH 2) 2, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
    Other group (8) is a hydrogen ,-OR (125) or-CR (125) R (126) R (127); R (125) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; Or R (125) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; R (126) and R (127) are separate hydrogen or methyl;
    A is not for existing ,-NR (11)-CO-, and-NR (12)-CO-NR (13)-,-NR (17)-CO-NR (18)-SO 2-,-NR (19)-SO 2-,-SO 2-NR (19)-SO 2-,-SO 2-NR (19)-CO-,-O-CO-NR (19)-SO 2-or-CR (20)=CR (21)-; R (11), R (12), R (13), R (17), R (18), R (19), R (20) and R (21) they are separate hydrogen or methyl.
  4. 5. by at least one formula 1 compound in the claim 1 to 4, wherein:
    Radicals R (1), one among R (3) and the R (5) is-CO-N=C (NH 2) 2
    Other radicals R (1) and R (5) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl or CF 3
    R (2) and R (4) are hydrogen, OH, CF 3, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 3And methyl, 1-2 the substituting group of selecting in the group that methoxyl group is formed replaces;
    Other radicals R (3) is a hydrogen ,-OR (25) or-CR (25) R (26) R (27); R (25) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom; It is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; Or R (25) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; R (26) and R (27) are separate hydrogen or methyl;
    Radicals R (6), one among R (8) and the R (9) is-CO-N=C (NH 2) 2
    Other radicals R (6) and R (10) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl, or CF 3
    R (7) and R (9) are hydrogen, OH, CF 3, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
    Other group (8) is a hydrogen ,-OR (125) or-CR (125) R (126) R (127); R (125) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; Or R (125) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; R (126) and R (127) are separate hydrogen or methyl;
    A is not for existing ,-NR (11)-CO-, and-NR (12)-CO-NR (13)-,-NR (17)-CO-NR (18)-SO 2-,-NR (19)-SO 2-,-SO 2-NR (19)-SO 2-,-SO 2-NR (19)-CO-,-O-CO-NR (19)-SO 2-or-CR (20)=CR (21)-; R (11), R (12), R (13), R (17), R (18), R (19), R (20) and R (21) they are separate hydrogen or methyl.
  5. 6. by at least one formula 1 compound in the claim 1 to 4, wherein:
    Radicals R (1), R (2), R (3), one among R (4) and the R (5) is-CO-N=C (NH 2) 2
    Other radicals R (1) and R (5) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl, or CF 3
    Other radicals R (2) and R (4) are hydrogen, OH, CF 3,-CO-N=C (NH 2) 2, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
    Other group (3) is a hydrogen ,-OR (25) or-CR (25) R (26) R (27); R (25) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; Or R (25) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; R (26) and R (27) are separate hydrogen or methyl;
    Radicals R (6), R (7), R (8), one among R (9) and the R (10) is-CO-N=C (NH 2) 2
    Other radicals R (6) and R (10) are separate hydrogen, have the alkyl of 1,2 or 3 C-atom, F, Cl, or CF 3
    Other radicals R (7) and R (9) are hydrogen, OH, CF 3,-CO-N=C (NH 2) 2, having the alkyl or the pyrroles-1-base of 1,2,3 or 4 C-atoms, it is not substituted or by by F, Cl, Br, I ,-CN, (C 2-C 5)-alkanoyloxy, (C 2-C 5)-alkoxy carbonyl, formyl radical, carboxyl ,-CF 31-2 the substituting group of selecting in the group of forming with methyl replaces;
    Other group (8) is a hydrogen ,-OR (125) or-CR (125) R (126) R (127); R (125) is a hydrogen, has the alkyl or phenyl of 1,2 or 3 C-atom, and it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; Or R (125) is-(C 1-C 9)-heteroaryl, it is not substituted or by by F, Cl, CF 3And CH 31 substituting group selecting in the group of forming replaces; R (126) and R (127) are separate hydrogen or methyl;
    A is not for existing ,-NR (11)-CO-, and-NR (12)-CO-NR (13)-,-NR (17)-CO-NR (18)-SO 2-,-NR (19)-SO 2-,-SO 2-NR (19)-SO 2-,-SO 2-NR (19)-CO-,-O-CO-NR (19)-SO 2-or-CR (20)=CR (21)-; R (11), R (12), R (13), R (17), R (18), R (19), R (20) and R (21) they are separate hydrogen or methyl.
  6. 7. press the preparation method of formula 1 compound of claim 1, it is characterized in that, with formula 11 compounds and guanidine reaction,
    Wherein R (1 ') has in claim 1 for R (1) to the illustrated meaning of R (10) to R (10 '), wherein have one and have at least one to be described COL-base in substituent R (6 ') to the R (5 ') at least in substituent R (1 ') to R (10 '), wherein L is the leavings group of an easy nucleophilic substitution.
  7. 8. the compound 1 by claim 1 is used to make a kind of treatment because the medicine of the disease that the local asphyxia state causes.
  8. 9. the compound 1 by claim 1 is used to make the ARR medicine of a kind of treatment.
  9. 10. treat ARR method, it is characterized in that, will add auxiliary commonly used by an effective dose of the compound 1 of claim 1 and with a kind of suitable form of medication administration.
  10. 11. be used to make the medicine of a kind of treatment or prevention myocardial infarction by the compound 1 of claim 1.
  11. 12. the compound 1 by claim 1 is used to make a kind of anginal medicine for the treatment of or prevent.
  12. 13. be used to make the medicine of a kind of treatment or prevention cardiac ischemia state by the compound 1 of claim 1.
  13. 14. be used to make around a kind of treatment or the prevention and the medicine of central nervous system local asphyxia state and apoplexy by the compound 1 of claim 1.
  14. 15. be used to make the medicine of a kind of treatment or prevention peripheral organ and four limbs local asphyxia state by the compound 1 of claim 1.
  15. 16. the compound 1 by claim 1 is used to make a kind of medicine for the treatment of shock state.
  16. 17. be used to make a kind of medicine that uses when surgical operation and the organ transplantation by the compound 1 of claim 1.
  17. 18. the compound 1 by claim 1 is used to make a kind of medicine of preserving and preserve graft for surgical operation.
  18. Treat some diseases 19. be used to make a kind of medicine by the compound 1 of claim 1, reason owing to former or secondary in these diseases produces hyperplasia, therefore this medicine can be used as anti-congee sample arteriosclerosis, the anti-diabetic late complication, anticancer disease, anti-fibrosis disease such as pulmonary fibrosis, hepatic fibrosis or renal fibrosis, the medicine of prostatomegaly.
  19. 20. medicine is characterized in that it contains a effective content by one of claim 1 to 6 or multinomial formula 1 compound.
CN 97102088 1996-01-31 1997-01-28 Substituted diaryl dicarboxylic diguanidine, and its preparing method, use as medicine or diagnostic reagent and medicine containing it Pending CN1163263A (en)

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DE19603425.6 1996-01-31
CN 97102088 CN1163263A (en) 1996-01-31 1997-01-28 Substituted diaryl dicarboxylic diguanidine, and its preparing method, use as medicine or diagnostic reagent and medicine containing it

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