TW200306808A - Use of inhibitors of the sodium-dependent chloride/bicarbonate exchanger for the treatment of thrombotic and inflammatory disorders - Google Patents

Abstract

Inhibitors of the cellular sodium-dependent chloride/bicarbonate exchangers show an inhibiting effect on the secretion of von-Willebrand factor. These inhibitors can therefore be employed for the treatment of thrombotic and inflammatory disorders.

Description

Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200306808 A7 B7 V. Description of the Invention (1) The present invention relates to sodium-dependent chloride / bicarbonate exchanger inhibitors used in human and veterinary medicine to prevent and treat blood via blood. The use of von-Willebrand factor in acute or chronic conditions, this inhibitor can therefore be used to treat thrombosis and inflammatory conditions. 5 Sodium-dependent chloride / bicarbonate exchanger (NCBE) inhibitors are known (EP 0 855 392, EP 1 097 140). NCBE inhibitors are suitable because they can inhibit the cell Na + -dependent C17HCCV exchange mechanism. After the prevention and treatment of arrhythmias, infarctions and angina pectoris and is commonly used for cardioprotection, especially after ischemia and reperfusion events, these 10 NCBE inhibitors are available because of their potential protective effects in pathological hypoxia and ischemia. For the treatment of all acute or chronic injuries caused by ischemia or diseases caused mainly or secondaryly by it, other potential indications that may be used are the protection of organ transplanted tissues, renal failure, and protection of the central nervous system from ischemia-induced injuries , Treatment of shock states, diseases caused by hyperplasia15 including cancer, fibrosis, organ hypertrophy and hyperplasia, respiratory drive injury, etc. However, the use of NCBE inhibitors for the treatment of thrombosis disclosed in previous techniques is related to NCBE inhibition alone The agent protects the tissue from the damage caused by ischemia, rather than preventing thrombosis by itself. 20 The mechanism of action of NCBE inhibitors during acute ischemic events includes reducing sodium / hydrogen exchanger (NHE) activation as a result of intracellular acidification and causing increased sodium ion inflow in tissues with acute hypoperfusion. Delay the situation of tissue sodium overload, because sodium and calcium ions are combined and transported in the heart tissue, which prevents fatal heart cells from becoming excessively negative. The paper size applies the Chinese National Standard (CNS) A4 specification (210x 297 mm)

200306808 A7 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention (2) Charge. In addition, NCBE inhibitors can inhibit or delay the re-assay of cells by preventing the inflow of bicarbonate. Accordingly, when blood flow is normal and healthy, of course, as expected, no protective effect of NCBE inhibitors against these acute events was found. 5 Previous techniques revealed that multiple substances intervene in the interaction of coagulation factors and thus cause the coagulation cascade to stop. Similarly, by developing multiple principles of action, instead of inhibiting thrombus formation, it causes dissolution (decomposition) of already formed thrombus. Part of the various junctions involved in the connection of these principles of action have been introduced into medicine to prevent thrombosis, such as derivatives of vitamin K family (leaf 10 green quinone), factors VIII and factor IX, platelet aggregation inhibitors such as acetamidine Salicylic acid, persantin, and azatripifine, anticoagulants such as heparin and heparin. The hemagglutination cascade can be mechanically divided into two paths described by: exogenous 15 20 endogenous

VII + TF XII-► Xlla

> Xa platelet aggregation thrombin prothrombin fibrinogen + fibrin -4-

This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm). The Intellectual Property Bureau of the Ministry of Economy, Employees' Cooperatives, Printed Clothes, 200306808 A7 B7 V. Invention Description (3) It is called endogenous level exogenous pathway, These individuals eventually converge under factor X activation and lead to the production of thrombin and subsequent fibrin. In the medical use of this blood coagulation inhibitor, it is important that the coagulation inhibition effect is not too strong or complete, it will inhibit the formation of micro-gold 5 plugs and micro-coagulation, which are required for life and must occur continuously In the case of microtrauma, due to individual response differences at a specific time, the degree of inhibition of coagulation may only be adjusted inaccurately, and this degree must be carefully monitored as much as possible. If these many small coagulation processes that occur permanently are inhibited, there are High risk of excessive bleeding (hemophilia). 10 Disadvantages of existing known medical agents on the market involved as inhibitors during coagulation events are therefore high-risk bleeding complications, and the risk of fatal bleeding is particularly present in high-dose thrombolytic medical procedures, such as acute myocardial infarction or The medical process of pulmonary embolism, therefore, there is an urgent need for medical agents that, despite overdose, are not accompanied by an increased risk of bleeding. 15 Many known anticoagulant substances work by exhibiting effects on platelets and thrombocytes, and inhibit their function or activation. The endothelium also obviously plays an important role in coagulation events. Based on this, Most of the von-Willebrand's factor (vWF) is manufactured in endothelial cells and is fixed (continuously) secreted into the circulating blood so as to ensure the required blood clotting in the blood. A considerable amount of manufactured vWF is stored in weighing scales. It is within the cytoplasmic granules of the Weibel-Palade body and is released by stimulation of endothelial cells when needed. If endothelial cells cannot produce vWF and deliver it to the blood, the result is a well-known hereditary vWF-dependent disease vonWillebrand- Jiirgens syndrome, which is characterized in that the paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm)

200306808 Δ7 Α7 Β7 V. Description of the invention (4) Bleeding that can hardly be stopped. In recent years, it has been known that the disease caused by the increase in v \ VF concentration in the blood can cause, for example, the tendency to increase blood coagulation and inflammation. Therefore, Kampuken et al. According to a large number of studies, in his paper "Elevated factor VIII levels and the risk of 5 thrombosis" (Arterioscler.'Thromb. Vase. Biol. 21 (5): 731, 738 (2001)), the amount of vWF in the blood was increased There is a clear correlation with the increased rate of thrombotic disorders. Factor VIII and vWF form a complex of prerequisites required for blood coagulation, which can establish high levels of von Willebrand factor (vWF) and vWF-bound factor VIII in blood. Thrombin formation risk factors, but antithrombotic agents that antagonize the combination of vWF and factor Vin stabilization may also have disadvantages, because in the event of overdose, a dangerous tendency to substantially inhibit blood clotting and bleeding must be expected. When trying to find effective compounds for the treatment of acute or chronic diseases caused by an increase in the amount of νοη 15 Willebrand factor in the blood, it has now been found that the use of a compound according to the present invention can inhibit the release of von Willebrand factor from endothelial cells, and the compound of the present invention can inhibit A large amount of pH-dependent vWF accumulated during ischemia was released. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs in view of the normal and essential secretion of normal p Η which occurs in the blood, 20 It is known to be about 7.4, and part of the VWF is stored in the Weibel-Palade body. When falling, vWF release is delayed and reduced, and when the pH is decreased, the cell granulation effect of the Weibel-Palade body filled with vWF is inhibited. Accordingly, in the case of acidosis, the Weibel-Palade body is significantly increased and therefore vWF extensively gathers in the endothelium-6- This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200306808 Δ7 A7 B7 V. Description of the invention (5) Cells and reduce the essence and stimulation of vWF secretion. Observation by staining method and quantitative measurement in the supernatant prove that this acidosis state with a apparent pH drop below 7 occurs, for example, in tissue ischemia, which is equivalent to a reperfusion state when rebasing and endothelial cell stimulation, In a very short period of time, 5 cytokinesis occurs, thus cavitating the Weibel-Palade body (WPB), which results in a large release of prothrombin risk factors. In addition to vWF, the Weibel-Palade body also stores a membrane-permeable protein, P-selectin (Wagner, D.D. 1993, Thromb. Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs.

Haemost ·, 70: 105-110), P-selectin is located in the vesicle membrane and is incorporated into the cell membrane of endothelial cells after the fusion of the vesicle 10 (cell granulation), which means that each Weibel-Palade Somatic cell degranulation not only leads to increased vWF release, but also increases p-selectin expression in endothelial cell membranes. Examples show that VWF secretion during acidosis and subsequent reperfusion (quantitatively measured by ELISA). 15 The immunofluorescence data on the Weibel-Palade body confirm that the measured vWF is therefore not only a marker of increased (increased vWF secretion) or decreased (decreased VWF secretion) thrombotic tendency (via increased platelet aggregation), but also a marker of A direct marker for increasing or decreasing the expression of P-selectin. P-selectin is used as a basis for white blood cells and their initial inflammatory response (Vestweber, D., Blanks, JE. 1999, Physiol. Rev., 79: 181 -213; Issekutz, AC ·, Issekutz, TB 2002, J.

Immunol., 168: 1934-1939), with a wide range of pathophysiological significance and confirmation of ischemia / reperfusion disorder, thrombosis and atherosclerosis (Massberg, S., et al., 1998, Blood, 92: 507- 515; Kita, T ·, et al ·, 2001, This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200306808 A7 B7 V. Description of invention (6)

Ann. Ν · Υ · Acad · Sci ·, 947: 199-205), in addition to being a marker of inflammation and an initiator of inflammation, P-selectin has a significant role in the spread of cancer (Varki, A ·, Varki , NM 2001, Braz J Med Med Res 34: 711-717) and various inflammations (arthritis) of the joints (Veihelmann, 5 A. et al., 1999, Microcirculation, 6: 281- 290; Mclnnes, IB., Et al., 2001, J. Immunol., 167: 4075-4082) also play an important role, and based on this, the mode of action of the substance disclosed here has also been found to be useful as a medical agent All P-selectin-related disorders described above. The present invention therefore relates to cell sodium-dependent chloride / bicarbonate 10 exchanger inhibitors for the manufacture of medicaments for the prevention and treatment of acute and chronic diseases caused by increasing the amount of von Willebrand factor in blood and / or increasing the expression of P-selectin. Applications for chronic conditions. The invention also relates to the compound of formula I R13 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

N 20 and / or all stereoisomeric forms of the compounds of the formula I and / or mixtures of these forms in any proportion and / or physiologically tolerable salts of the compounds of the formula I are used in the manufacture of medicaments for the prevention and treatment by increasing blood For the application of von Willebrand factor amount and / or increase of P-selectin expression in acute and chronic diseases, this paper size is applicable to Chinese National Standard (CNS) A4 specification (210x297 mm) A7 200306808 V. Description of invention (7) The symbols have the following meanings: X is equal to

R9 ^ R12 'Z,

R11, Ni, R10, R (l) are hydrogen, alkanes containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms CaH2a-phenyl, in which the phenyl moiety is unsubstituted or selected from the group F, C1, Br, J; 1, 2 or 3; CF3 methyl, methoxy, hydroxyl or NR (19) R (20) is substituted by a group; R (19) and R (20) are independently η or an alkyl group containing 丨, 2, 3, or * carbon atoms; R, a is 0, 1 or 2; or R (1) 疋 contains 1, 2, 3, 4, 5, 6, 7, 8 or 9;

CbHn-heteroaryl, wherein the heteroaryl moiety is unsubstituted or 1, 2, or 3 are the same or different and are selected from f, Cl, Br τ ητ:,, cf3, CH3, fluorenyloxy, hydroxyl, or NR (21) R (22) group substitution · R (21) and R (22) are each independently fluorene or a radical containing 1, 2 3 formula, 4 4 atoms; b is 0, 1 or 2; Or R (l) is -CcH2c-Cycloxazone containing 3, 4, 5, 6, or 7 carbon atoms; c is 0, 1 or 2;

R (2) and R (3) are hydrogen, F, Cl, Br, independently of each other; [, CF -9- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 200306808 A7 B7 V. Description of the invention (8) CN, -N〇2, CH2OR (23), CO-R (24) or 0-R (25); R (23) is hydrogen or contains 1, 2, 3, 4, 5, 6 Alkyl group of 7 or 8 carbon atoms; R (24) is hydrogen, 5 alkyl group of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, OR (26) or phenyl Where phenyl is an unsubstituted or 1, 2 or 3 identical or different group selected from F, Cl, Br, I, CF3, fluorenyl, fluorenyl, hydroxyl, or NR (27) R (28) Substitution; R (27) and R (28) are independently Η or an alkyl group containing 1, 2, 3, or 4 carbon atoms; 10 R (26) is hydrogen or 1, 2, 3, 4, 5 R, 25, 7, 7 or 8 carbon atoms; R (25) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms or phenyl, where phenyl is Unsubstituted or substituted with 1, 2 or 3 groups which are the same or different and are selected from the group consisting of F, Cl, Br, I, CF3, methyl, fluorenyl 15oxy, hydroxyl or NR (29) R (30); R ( 29) and R (30) are each independently fluorene or an alkyl group containing 1, 2, 3 or 4 carbon atoms; Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R (25) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, which is unsubstituted or treated by 1, 2 or 3 identical or different 20 selected from the group consisting of F, Cl, Br, I, CF3, CH3, methoxy, hydroxyl or NR (31) R (32); R (31) and R (32) each other Independently is fluorene or an alkyl group containing 1, 2, 3, or 4 carbon atoms; or R (2) and R (3) are independently of each other containing 1, 2, 3, 4, 5, 6, 7, or 8 -10- This paper size applies to China National Standard (CNS) A4 (210x297 mm) A7 200306808 B7 V. Description of the invention (9) Alkyl group with 3 carbon atoms, 3, 4, 5, 6 or 7 carbons Atomic cycloalkyl, or -CdH2d-phenyl, where the phenyl moiety is unsubstituted or is the same or different from 1, 2 or 3 selected from F, Cl, Br, I, CF3, methyl, and oxo Hydroxy, hydroxy or NR (33) R (34) has 5 generations; R (33) and R (34) are independently Η or an alkyl group containing 1, 2, 3 or 4 carbon atoms; d is 0, 1 or 2; or R (2) and R (3) are each independently -CeH2e-heteroaryl containing 1, 2, 3, 4, 5, 6, 7, 8 10 or 9 carbon atoms, Where the heteroaryl moiety is Unsubstituted or substituted with 1, 2 or 3 groups which are the same or different and are selected from F, C1, Br, I, CF3, CH3, methoxy, hydroxyl or NR (35) R (36); R (35) And R (36) is independently Η or an alkyl group containing 1, 2, 3 or 4 carbon atoms; e is 0, 1 or 2; or R (2) and R (3) are independently -SOf-R (37); printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy, R (37) is an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, containing 3, 4 , A cycloalkyl group of 5, 6, or 7 carbon atoms, or -20 CgH2g-phenyl, wherein the phenyl moiety is unsubstituted or is selected from the group consisting of F, Cl, and B through 1, 2 or 3 identical or different , I, CF3, fluorenyl, fluorenyl, hydroxy, or NR (38) R (39); R (38) and R (39) are independently fluorene or contain 1, 2, 3, or 4 Carbon atom burning base; -11- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200306808 Alkane of 7 carbon atoms to 7 carbon atoms Printed by A7, Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs B7 V. Description of the invention (10 f is 0, 1 or 2; g is 0, 1 or 2; R (4) is hydrogen, containing 1, 2, 3, 4, 5, 6, 7 ring base, 1-naphthalene base 2-naphthyl, -CiHy cycloalkyl containing 3, 4, 5, 7 or 5, wherein phenyl # is unsubstituted or is the same or not as 1, 2 or 3 @ ^ 自 S 1 , 2, 3, 4, 5, 6, 7, or 8 carbon atoms alkyl, F, C1, Br, I, CF3, SOjR (48), OR (49), NR (50) R (51), -CN, -N02 * CO-R (52) group substitution; 10 i is 0, 1 or 2; R (48) is an alkyl group containing 1, 2, 3 or 4 carbon atoms or NR (53) R (54); R (53) and R (54) are each independently hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; 15 j is 0, 1 or 2; R (49) is hydrogen or Alkyl groups containing 1, 2, 3 or 4 carbon atoms; R (50) and R (51) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; R (52) is Hydrogen, a 20 alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms or OR (55); R (55) is hydrogen, containing 1, 2, 3, 4, 5, 6 An alkyl group of 7, 7 or 8 carbon atoms; or R (4) and R (6) —from which the carbon atom containing it is a cycloalkyl or alkoxy group containing 3, 4, 5, 6, or 7 carbon atoms ; .12-

This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200306808 A7 B7 V. Description of the invention (η) R (5), R (6), R (7) and R (8) are independent of each other Is hydrogen, F, CF3, 0-R (56), an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and 3, 4, 5, 6, or 7 carbon atoms Cycloalkyl, or CkH2k-phenyl, in which the phenyl moiety is unsubstituted or is the same or different from F, Cl, Br, I, CF3, methyl, methoxy Group, hydroxy or NR (57) R (58) substitution; R (57) and R (58) are each independently hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; k is 0, 1 or 2; 10 R (56) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 The same or different substituents selected from the group consisting of F, Cl, B1 \ I, CF3, methyl, methoxy, hydroxyl, or NR (59) R (60); R (59) and R (60) are independently of each other Hydrogen or 15 carbon atoms containing 1, 2, 3, or 4 carbon atoms; printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R (56) is 1, 2, 3, 4, 5, 6, 7, 8 Or a heteroaryl group of 9 carbon atoms, which Unsubstituted or substituted with 1, 2 or 3 groups which are the same or different and are selected from the group consisting of F, Cl, Bi, I, CF3, CH3, methoxy, hydroxyl or NR (61) R (62); 20 R ( 61) and R (62) are independently Η or an alkyl group containing 1, 2, 3, or 4 carbon atoms; R (5) and R (7) together form a second bond with the carbon atom There are radicals R (6) and R (8), where R (4), R (6) and R (8) are the same as the above definitions; R (9) is a group containing 1, 2, 3, 4, 5, 6 , Alkyl groups of 7 or 8 carbon atoms, -13- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200306808 A7 B7 V. Description of the invention (12) Contains 2, 3, 4, 5 , An alkenyl group of 6, 7, or 8 carbon atoms, or -ciH2i.IrA; Π is 0 or 2; and I is 0, 1, 2, 3, or 4, wherein when II is 2, I is not 0 or 5 1; R (10) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms Alkenyl, mm is 0 or 2; and 10 m 疋 0, 1, 2, 3, or 4, wherein when mm is 2, m is not 0 or 1; R (ll) and R (12) are independent of each other Is hydrogen or an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; Z is a carbonyl group Sulfofluorenyl; 15 A and B are each independently 1. an aryl group containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably phenyl, 1-naphthyl or 2-naphthyl; printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs; 2. A base under the meaning of 1, which is the same or different from 1,2,3,4,5 Carbonyl, 6, 7, or 8 carbon atoms, F, Cl, Br, I, CF3, SOnR (63), OR (64), NR (65) R (66), -CN, -N02 Or CO-R (67) substitution; 3. Heteroaryl groups containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms; -14- This paper size applies Chinese national standards (CNS) A4 specification (210x297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200306808 A7 B7 V. Description of the invention (13) 4. The base under the definition of 3 is the same or Different substituents selected from the group consisting of F, Cl, B1, I, CF3, CH3, methoxy, hydroxyl or NR (68) R (69); 5. containing 3, 4, 5, 6, or 7 carbon atoms Cycloalkyl; 5 6.OR (70); or 7.0-R (71); η is 0, 1 or 2; R (70) and R (71) are independently 1 · hydrogen; 10 2. containing 1 , 2, 3, 4, 5, An alkyl group of 6, 7, or 8 carbon atoms; 3.-C0H20-00-phenyl, where 〇〇 is 0 or 2; and 〇 is 0, 1, 2, 3, or 4, where 〇 was At 2 o, 0 is not 0 or 1; 15 4. A group under the definition of 3, in which the phenyl moiety is selected from 1, 2, 3, 4, 5, 6, Alkyl groups of 7 or 8 carbon atoms, F, Cl, B *, I, CF3, SOpR (72), OR (73), NR (74) R (75), -CN, -N02 or C. -R (76) group substitution; or 20 5. alkenyl group containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R (63) and R (72) independently of each other contain 1, Alkyl or NR (77) R (78) of 2, 3 or 4 carbon atoms; R (67) and R (76) are independently of each other hydrogen, containing 1, 2, 3, 4, 5, 6, 7 Or an alkyl group of 8 carbon atoms or OR (89); -15- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Printed clothing of the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200306808 A7 B7 V. Description of the invention (14) R (89) is hydrogen or a burning group containing 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 each other is hydrogen or an alkyl group containing 1, 2, 3 5 or 4 carbon atoms; p is independently of 0, 1 or 2; R (13), R (14) and R (15) are independent of each other Ground is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, F, Cl, Br, I, CF3, -CN, -N02, SOq-R (79), CO-R (80) or 0-10 R (81); q is independently 0, 1 or 2; R (79) is 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms An alkyl or phenyl group which is unsubstituted or is selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl or 15 NR (82) R ( 83); R (82) and R (83) are each independently a gas or an alkyl group containing 1, 2, 3, or 4 carbon atoms; R (80) is hydrogen, containing 1, 2, 3, Alkyl or OR (84) with 4, 5, 6, 7, or 8 carbon atoms; 20 R (84) is hydrogen or contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms R (81) is hydrogen, an alkyl or phenyl group containing 1, 2, 3, 4, 5, 0 '7 or 8 carbon atoms, which is unsubstituted or is the same or Differently selected from F, Cl, Br, I, CF3, methyl, methoxy, and hydroxy-16-I Paper sizes are applicable to China National Standard (CNS) A4 specifications (21〇 × 2 ^ 7 ^ 5 " 7 "-' '

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 200306808 A7 B7 V. Description of the invention (15) or NR (82) R (83); Y is a covalent bond, CR (16) R (17), C 〇, S, S〇2, 0 or NR (18); R (16) is hydrogen or -〇R (85); 5 R (85) is hydrogen, containing 1, 2, 3, 4, 5, 6, Alkyl or C0-R (86) with 7 or 8 carbon atoms; R (86) is an alkyl or phenyl group with 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms Unsubstituted or substituted by 1, 2 or 3 groups of the same or different 10 groups selected from F, Cl, B *, I, CF3, fluorenyl, fluorenyl or hydroxy; R (17) is hydrogen or contains 1, An alkyl group of 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R (18) is hydrogen, an alkyl group of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, CO-R (87) or S〇2R (88); 15 R (87) and R (88) are independently of each other alkyl groups containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms , A cycloalkyl or phenyl group containing 3, 4, 5, 6, or 7 carbon atoms which is unsubstituted or is the same or different from 1, 2 or 3 selected from F, Cl, Br, I, CF3, and A Radical, methoxy or substituted by radical. 20 The present invention also relates to the use of a compound of formula I for the manufacture of a medicament for the prevention and treatment of acute and chronic conditions caused by increasing the amount of von Willebrand factor in blood and / or increasing the expression of P-selectin in blood, wherein the significance B · 疋X is -17-

This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 200306808 Δ7 Α7 Β7 V. Description of Invention (16) R2

5 R (l) is an alkyl or phenyl group containing 1, 2, 3 or 4 carbon atoms which is unsubstituted or substituted with a group selected from F, Cl, CF3, methyl or methoxy; R (2) and R (3) are independently hydrogen, F, Cl, CF3, -CN, CO-R (24), or 〇-R (25); 10 R (24) is hydrogen, containing 1, 2, An alkyl, OR (26) or phenyl group of 3 or 4 carbon atoms which is unsubstituted or substituted with a group selected from F, Cl, CF3, methyl or methoxy; R (26) is hydrogen, Fluorenyl or ethyl; R (25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, phenyl, 15 of which is unsubstituted or substituted with one selected from F, Cl, CF3, fluorenyl or A methoxy group is substituted; or R (25) is a heteroaryl group which is unsubstituted or substituted with a group selected from F, C1, CF3, CH3 or methoxy; or R (2) and R (3 ) Are each independently an alkane group containing 1, 2, 3, or 4 carbon atoms, a cycloalkyl group containing 3, 4, 5, 6, or 7 carbon atoms; or R (2) and R (3) each other Is independently phenyl which is unsubstituted or substituted with a group selected from F, Cl, CF3, fluorenyl or fluorenyl; or R (2) and R (3) each independently contains 1, 2, Of 3, 4, 5, 6, 7, 8 or 9 carbon atoms An aryl group which is unsubstituted or substituted with one system selected -18-

This paper size applies to China National Standard (CNS) A4 (210x297 mm) A7 B7 200306808 5. Description of the invention (17) Substitution of F, Cl, CF3, CH3 or methoxy groups; or R (2) and R ( 3) independently of each other are -SOrR (37); R (37) is an alkyl or phenyl group containing 1, 2, 3, or 4 carbon atoms, which is unsubstituted or substituted by one selected from F, Cl, CF3, 5 group substitution of methyl or methoxy; f is 0 or 2; R (13), R (14) and R (15) are each independently hydrogen, methyl, F, C1, CF3, -CN, S 〇2-R (79), Co-R (80) or 〇-R (81); R (79) and R (81) are each independently 10 alkane containing 1, 2, 3 or 4 carbon atoms Or phenyl is unsubstituted or substituted with a group selected from F, C1, CF3, CH3, or fluorenyl; R (80) is hydrogen, fluorenyl, or OR (84); R (84) is hydrogen Or an alkyl group containing 1, 2, 3 or 4 carbon atoms; Y is a covalent bond or a methylene group. 15 The present invention also relates to all stereoisomeric forms of the compound of formula II R2 and / or the compound of formula II and / or mixtures of these forms in any ratio and / or physiologically tolerable salts of the compound of formula -19-

Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives. This paper is printed in accordance with the Chinese National Standard (CNS) A4 (210x297 mm) 200306808 A7 B7. Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Employee Consumer Cooperatives. Manufacture of pharmaceuticals for the prevention and treatment of acute and chronic conditions caused by increasing the amount of von Willebrand factor in blood and / or increasing the expression of P-selectin, where the symbol has the following meaning: 5 R1 is hydrogen, containing 1, 2, 3 , 4, 5, 6, 7, or 8 carbon atoms alkyl or -CaH2a-phenyl which are unsubstituted or selected from 1-3, including F, Cl, Bι :, I, CF3, fluorenyl, Alkoxy, hydroxyl and NR (8) R (9) group substitution; R (8) and R (9) are independently fluorene or (CVQ) alkyl; 10 a is 0, 1 or 2; or R1 Is a heteroaryl group, which is unsubstituted or substituted with 1-3 groups selected from the group consisting of F, Cl, Br, I, CF3, CH3, methoxy, hydroxyl and NR (10) R (11); R (10) and R (ll) are independently fluorene or (CVC4) alkyl; 15 b is 0, 1 or 2; or R1 is -CdH2d- (C3-C7) _cycloalkyl; d is 0,1 Or 2; R2 and R3 are independently hydrogen, 氢, ( 1, 31 *, 1, € 3, -CN, -N02, CH2OR17, CO-R6, or 0-R7; 20 R17 is hydrogen or contains 1, 2, 3, 4, 5, 6, 7, or 8 Alkyl group of 6 carbon atoms; R6 is hydrogen, alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, OR30 or phenyl group which is unsubstituted or selected by 1-3 Including F, Cl, Beta *, I, CF3, fluorenyl, fluorenyloxy, hydroxyl and -20- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Α7 Β7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200306808 V. Description of the invention (19) NR (31) R (32) is replaced by a base; R (31) and R (32) are independently Η or (CrC4) Alkyl; R30 is hydrogen or alkyl containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; 5 R7 is hydrogen, containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms alkyl, phenyl which are unsubstituted or selected from 1-3 including F,

Cl, Br, I, CF3, methyl, fluorenyloxy, hydroxyl and NR (12) R (13) group substitution; R (12) and R (13) are independently fluorene or (CVCJ alkyl group); or 10 R7 is (C ^ Cq) -heteroaryl, which is unsubstituted or 1-3 selected from the group consisting of F, Cl, Br, I, CF3, CH3, fluorenyloxy, hydroxyl, and NR (14) R (15) group substitution; R (14) and R (15) are independently fluorene or (CrC4) alkyl; or R2 and R3 are independently of each other containing 1, 2, 3, 4, 5, 6, 7 Or an alkyl group of 15 15 carbon atoms, a cycloalkyl group containing 3, 4, 5, 6, or 7 carbon atoms or -CgH2g-phenyl which is unsubstituted or selected from 1-3 including F, Cl , Bι ·, I, CF3, methyl, methoxy, hydroxyl, and NR (18) R (19) group substitution; R (18) and R (19) are independently fluorene or ((VC4) alkyl ; 20 g is 0, 1 or 2; or R2 and R3 are heteroaryl groups, which are unsubstituted or 1-3 selected from the group consisting of F, Cl, B1 *, I, CF3, CH3, methoxy, Hydroxyl and NR (20) R (21) group substitution; R (20) and R (21) are independently fluorene or (CVC4) alkyl group; -21- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

200306808 A7 B7 V. Description of the invention (20) 1 is 0, 1 or 2; or R2 and R3 are SOn-R22; η is 0, 1 or 2; R22 is 1, 2, 3, 4, 5, 6 , An alkyl group of 7 or 8 carbon atoms, 5 a cycloalkyl group containing 3, 4, 5, 6, or 7 carbon atoms or _ (: 汨 25_phenyl group which is unsubstituted or 1-3 selected Substituting from groups including F, Cl, Br, I, CF3, methyl, fluorenyloxy, hydroxyl, and NR (34) R (35); R (34) and R (35) are independently η or (CrC4 ) Alkyl; or 10 s is 0, 1 or 2; R4 and R5 are independently of each other hydrogen, alkyl containing 丨, 2, 3, 4, 5, 6, 7, or 8 carbon atoms,?, (: 1, 31 \ 1, 〇3, -0 ^, -N〇2, SOp-R16, CO-R23 or 0-R24; p is 0, 1 or 2; 15 R16 is 1, 2, 3, 4 Alkyl or phenyl of 5, 6, 7, or 8 carbon atoms which are unsubstituted or selected from 1-3 including F, C1

Br, I, CF3, methyl, methoxy, hydroxyl, and nR (26) R (27) substitution; Employees' cooperation in intellectual property bureau of the Ministry of Economic Affairs, printed R (26) and R (27) independently of each other Is η or (CrC4) alkyl; or 20 R23 is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms or OR25; R24 is hydrogen, containing 1, 2, 3 An alkyl or phenyl group of 4, 5, 6, 7, or 8 carbon atoms which is unsubstituted or is selected from the group consisting of F,

Cl, Bx ·, I, CF3, methyl, fluorenyloxy, hydroxyl and -22- This paper size is applicable to China National Standard (CNS) A4 (210x297 public love) 200306808 A7 B7 V. Description of the invention (21) NR ( 28) R (29) group substitution; R (28) and R (29) are independently fluorene or (Ci-C4) alkyl. The invention also relates to the use of a compound of formula Η for the manufacture of a medicament for the prevention and treatment of acute and chronic conditions caused by increasing the amount of von Willebrand factor in blood and / or increasing the expression of 5 P-selectin, wherein the symbols have the following meanings: R (l) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms or -CaH2a_phenyl, wherein the phenyl moiety is unsubstituted or 3 identical or different groups selected from the group consisting of F, Cl, Br, I, 10 CF3, methyl, fluorenyloxy, hydroxyl, or NR (8) R (9); R (8) and R (9) each other Is independently hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; a is 0, 1 or 2; or R (l) is 1, 2, 3, 4, 5, 6, 7, 8 Or -15 CbH2b-heteroaryl of 9 carbon atoms, in which the heteroaryl moiety is unsubstituted or is the same or different through 1, 2, or 3 and is selected from the group consisting of F, Cl, Br, I, CF3, CH3, Substituted by ethoxy, hydroxy or NR (10) R (11); R (10) and R (11) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs are hydrogen or contain 1, 2, 3 or Carbon atom of 4 carbon atoms; b is 0, 1 or 2; or R (l) is 3, 4, 5, 6 or 7 carbons -CdH2d-cycloalkyl; d is 0, 1 or 2; R (2) and R (3) are independently hydrogen, F, Cl, Br, I, CF3, -23- Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 200306808 A7 B7 V. Description of invention (22) CN, -N02, CH2〇R (17), Co-R (6) or 0-R ( 7); R (17) is hydrogen or an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R (6) is hydrogen, containing 1, 2, 3, 4, 5 , Alkyl group of 6, 7, or 8 carbon atoms, OR (30) or phenyl which is unsubstituted or is the same or different through 1, 2 or 3 and is selected from the group consisting of F, Cl, Br, I, CF3, Methyl, methoxy, hydroxy or NR (31) R (32) substitution; R (31) and R (32) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms ; 10 R (30) is hydrogen or an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R (7) is hydrogen, containing 1, 2, 3, 4, 5, Alkyl group of 6, 7, or 8 carbon atoms, or phenyl group which is unsubstituted or is the same or different through 1, 2 or 3 and is selected from the group consisting of F, Cl, B1, I, CF3, methyl, methoxy 15 group, hydroxy or NR (12) R (13) substitution; R (12) and R (13) are independently hydrogen or An alkyl group of 1, 2, 3, or 4 carbon atoms; or R (7) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, which contains 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbons Atomic heteroaryl, which is unsubstituted or is the same or different through 1, 2 or 3 and is selected from the group consisting of F, Cl, B *, I, CF3, CH3, methoxy, hydroxy, or NR (14) R (15) radical substitution; R (14) and R (15) are independently hydrogen or a radical containing 1, 2, 3 or 4 carbon atoms; or R (2) and R (3) are independent of each other Is containing 1, 2, 3, 4, 5, 6, 7, or 8 -24- ~ ----------------------------- -------A paper size is applicable to China National Standard (CNS) A4 (210x297 mm) 200306808 B7 ------- V. Description of the invention (23) Burning group with 3 carbon atoms, containing 3 , 4, 5, 6, or 7 carbon atom ring alkyl groups or -CgH2g-phenyl, wherein the phenyl moiety is unsubstituted or is the same or different through 1, 2, or 3 selected from the group consisting of ρ, cl, Br , I, CF3, fluorenyl, methoxy, hydroxy, or group 5 of Nr (18) R (19); R (18) and R (19) are each independently hydrogen or containing 丨, 2, 3, or 4 A carbon atom; g is 0, 1, or 2; or R (2) and R (3) are -CiH2i-heteroaryl of 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, wherein the heteroaryl moiety is unsubstituted or is the same as that of 1, 2 or 3 Differently selected from the group consisting of ρ, ci Br I, CF3, CH3, fluorenyloxy, hydroxyl, or NR (20) R (21); R (20) and R (21) are independently hydrogen or 2, 3 or 4 carbon atoms of 15 atoms; 1 is 0, 1 or 2; or R (2) and R (3) are SOn-R22; η is 0, 1 or 2; Intellectual Property Bureau of the Ministry of Economic Affairs R (22) printed by employee consumer cooperative is a 20-base burner containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and a naphthene containing 3, 4, 5, 6, or 7 carbon atoms This group is unsubstituted or is selected from the group consisting of F, Cl, Br, I, CF3, fluorenyl, methoxy, hydroxyl, or NR (34) R (35 ) Group substitution; R (34) and R (35) are independently of each other hydrogen or containing 1, 2, 3 or 4 carbon atoms -25- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200306808 V. Description of the invention (24) Burning base of the child; s is 0, 1 or 2; R (4) is SOP-R (16); p Yes 0, 1 2; 5 R (16) is an alkyl or phenyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. It is unsubstituted or selected by 1, 2 or 3 same or different Substituting from groups including F, Cl, Br, I, CF3, fluorenyl, fluorenyl, hydroxyl, or NR (26) R (27); R (26) and R (27) are independently hydrogen or contain 1 , 2, 3 or 4 carbon atoms. The invention also relates to the use of a compound of formula II for the manufacture of a medicament for the prevention and treatment of acute and chronic conditions caused by increasing the amount of von Willebrand factor in blood and / or increasing the expression of P-selectin, wherein the symbol has the following meaning: 15 R (l) is an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, a -CdH2d-cycloalkyl group containing 3, 4, 5, 6, or 7 carbon atoms, and d is equal to 0, 1 or 2, or -CaH2a-phenyl, wherein the phenyl moiety is unsubstituted or is the same or different through 1, 2, or 3 and is selected from the group consisting of F, C1, Βι ·, I, CF3, methyl, 20-substituent substitution of ethoxy, hydroxy or NR (8) R (9); R (8) and R (9) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; a Is 0, 1 or 2; R (2) is hydrogen, F, Cl, Br, I, 〇-R (7) or SnR (22); -26-

This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 200306808 Δ7 Α7 Β7 V. Description of the invention (25 10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 R (7) is hydrogen, containing 1 , 2, 3, 4, 5, 6, 7, or 8 carbon atoms alkyl, or phenyl which is unsubstituted or is the same or different via 1, 2, or 3 and is selected from the group consisting of F, Cl, Br, I , CF3, fluorenyl, methoxy, hydroxyl or NR (12) R (13); R (12) and R (13) are independently of each other · is hydrogen or contains 1, 2, 3 or 4 carbons Atom alkyl group; η is 0, 1 or 2; R (22) is an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, containing 3, 4, 5, 6, or 7 carbon atom cycloalkyl or -CsH2s-phenyl which is unsubstituted or is the same or different through 1, 2 or 3 selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, Substituted by a radical or a radical of NR (34) R (35); R (34) and R (35) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; s is 0, 1 Or 2; R (3) is hydrogen, -CN or Co-R (6); R⑹ is hydrogen, an alkyl group containing U 2, 3, 4, 5, 6, 7, or 8 carbon atoms or OR (30 ); R (30) is hydrogen or containing !, An alkyl group of 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R (4) is SOp-R (16); p is 0, 1 or 2; R (16) is 1, 2, 3, 4 5 6 7 弋 q γ, 5, 6, 7, or 8 carbon atoms alkyl or phenyl group which is unsubstituted or via u 2 or 3 same or different -27- This paper size applies to China Standard (CNS) A4 mm

200306808 A7 B7 V. Description of the invention (26) selected from the group consisting of F, Cl, Br, I, CF3, fluorenyl, methoxy, hydroxyl or NR (26) R (27); R (26) and R (27) independently of each other are hydrogen or an alkyl group containing 1, 2, 3, or 4 carbon atoms; 5 and physiologically tolerable salts thereof. The invention also relates to the use of a compound of formula II for the manufacture of a medicament for the prevention and treatment of acute and chronic conditions caused by increasing the amount of von Willebrand factor in blood and / or increasing the expression of P-selectin, wherein the symbol has the following meaning: 10 R (l) is -CaH2a-phenyl, wherein the phenyl moiety is unsubstituted or is the same or different from 1 or 2 selected from the group consisting of F, Cl, Br, CF3, methyl, methoxy, hydroxyl, or NR ( 8) R (9) group substitution; R (8) and R (9) are independently hydrogen or methyl; a is 0 or 1; 15 R (2) is F, Cl, B * or I, especially Is C1; or OR (7); R (7) is an alkyl group containing 1, 2, 3, or 4 carbon atoms; R (3) is Co-R (6); R (6) is hydrogen; economic The Ministry of Intellectual Property Bureau's consumer cooperation, the company printed R (4) is S02R (16), R (16) is equal to an alkyl group containing 1, 2, 3 or 4 carbon atoms. The present invention also relates to the use of the compound of formula II above, wherein the groups R (l), R (2), R (3) and R (4) have the above definitions, and the biphenyl substituent is connected as formula la or lb, More preferably, it is la. -28- tzhang scale applies Chinese National Standard (CNS) A4 specification (210x297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200306808 A7 A7 B7 V. Description of the invention (27)

The invention also relates to compounds of formula II and / or all stereoisomeric forms of compounds of formula II and / or mixtures of these forms in any ratio and / or physiologically tolerable salts of compounds of formula 11 for use in the manufacture of pharmaceuticals for prevention And the treatment of acute and chronic conditions caused by increasing the amount of von Willebrand factor in the blood and / or increasing the expression of P-selectin by 10 plus, the symbol has the following meaning: R (l) is hydrogen, containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms alkyl or -CaH2a-phenyl, in which the phenyl moiety is unsubstituted or is the same or different through 1, 2, or 3 and is selected from the group consisting of F, Cl, and β *, I, 15 CF3, fluorenyl, fluorenyl, hydroxy, or NR (8) R (9); R (8) and R (9) are independently hydrogen or contain 1, 2, 3 or An alkyl group of 4 carbon atoms; a is 0, 1 or 2; or R (l) is -20 CbH2b-heteroaryl containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms Group in which the heteroaryl moiety is unsubstituted or is the same or different via one, two or three selected from the group consisting of F, Cl, Br, I, CF3, fluorenyl, fluorenyl, hydroxyl, or NR (10) R (11) radical substitution; R (10) and R (ll) are each independently hydrogen or Contains 1, 2, 3 or 4 carbon atoms -29-

This paper size applies to China National Standard (CNS) A4 (210x 297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 200306808 A7 B7 V. Description of the invention (28) alkyl of the child; b is 0, 1 or 2 Or R (l) is -CdH2d-cycloalkyl containing 3, 4, 5, 6, or 7 carbon atoms; d is 0, 1 or 2; 5 R (2) and R (3) are independently of each other t ^ F'CUBiUCF ;,-CN, -N02, CH2OR (17), CO-R (6) or 0-R (7), 0- (an elongation group containing 2, 3 or 4 carbon atoms)- 0-R (17) or NR (50) R (51); R (17) is hydrogen or a 10-alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R (6 ) Is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, OR (30), or benzyl, which is unsubstituted or is the same or different via 1, 2, or 3 Selected from the group consisting of F, Cl, B *, I, CF3, methyl, methoxy, hydroxyl, or NR (31) R (32); 15 R (31) and R (32) are independently hydrogen Or a radical containing 1, 2, 3, or 4 carbon atoms; R (30) is hydrogen or an alkyl radical containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R (50) And R (51) are independently of each other-(20 alkyl groups containing 2, 3 or 4 carbon atoms) -〇-R (52); R (52) Hydrogen or an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and R (7) is hydrogen, containing 1, 2, 3, 4, 5, 6, 7, or 8 carbons Atom alkyl or phenyl which is unsubstituted or 1, 2, or 3 identical or -30- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

Printed by the Intellectual Property Bureau's Consumer Cooperatives, Ministry of Economic Affairs, 200306808 A7 B7 V. Description of the Invention (29) Differently selected from F, Cl, Br, I, CF3, fluorenyl, methoxy, hydroxyl, or NR (12) R (13 ); R (12) and R (13) are independently hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; or 5 R (7) is 1, 2, 3, 4 A heteroaryl group of 5, 6, 7, 8, 8 or 9 carbon atoms, which is unsubstituted or is the same or different through 1, 2 or 3 and is selected from the group consisting of F, Cl, B *, I, CF3, CH3, Methoxy, hydroxyl or NR (14) R (15) substitution; R (14) and R (15) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; Or R (2) and R (3) are independently of each other alkyl groups containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and containing 3, 4, 5, 6, or 7 carbon atoms Cycloalkyl or -CgH2g-phenyl, in which the phenyl moiety is unsubstituted or is the same or different from 1, 2 or 3 selected from the group consisting of F, Cl, Br, 15 I, CF3, fluorenyl, and methoxy Group, hydroxy or NR (18) R (19) substitution; R (18) and R (19) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; g is 0, 1 or 2; or 20 R (2) And R (3) are each independently -QKbr heteroaryl containing 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, wherein the heteroaryl moiety is unsubstituted or substituted by 1 , 2 or 3 groups which are the same or different and are selected from the group consisting of F, Cl, B *, I, CF3, CH3, methoxy, hydroxyl or NR (20) R (21); -31- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)

Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs on 200306808 A7 B7 V. Description of the Invention (30) R (20) and R (21) are independently of each other hydrogen or a burning group containing 1, 2, 3 or 4 carbon atoms; 1 is 0, 1 or 2; or R (2) and R (3) are each independently Son-R22; 5 η is 0, 1 or 2; R (22) is a group containing 1, 2, 3, 4 , 5, 6, 7, or 8 carbon atoms alkyl, cycloalkyl containing 3, 4, 5, 6, or 7 carbon atoms or -CsH2s-phenyl which are unsubstituted or substituted by 1, 2 or 3 The same or different substituents selected from the group consisting of F, Cl, Br, I, CF3, fluorenyl, methoxy, 10 hydroxyl, or NR (34) R (35); R (34) and R (35) are independent of each other Ground is hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; s is 0, 1 or 2; R (4) and R (5) are independently of each other hydrogen, containing 1, 2, 3, 4 , 5, 6, 7, 15 or 8 carbon atoms alkyl, F, Cl, Br, I, CF3, -CN, -N02, SopR (16), CO-R (23), 0-R ( 24) or 0- (alkylene group containing 2, 3 or 4 carbon atoms) -0-R (33); p is 0, 1 or 2; R (16) is 1, 2, 3, 4, Alkyl 20 or phenyl of 5, 6, 7 or 8 carbon atoms which is unsubstituted or selected from 1, 2 or 3 same or different Including F, Cl, B *, I, CF3, fluorenyl, fluorenyl, hydroxy, or NR (26) R (27) substitution; R (26) and R (27) are independently hydrogen or contain 1 , 2, 3, or 4 carbon atom alkyl groups; or -32- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

200306808 Α7 Β7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (M 10 15 R (23) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms OR (25); R (25) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R (24) is hydrogen, containing 1, 2, 3, —Alkyl or phenyl group of 4, 5, 6, 7, or 8 carbon atoms which is unsubstituted or is the same or different through 1, 2, or 3 and is selected from the group consisting of F, Cl, Br, I, CF3, methyl , Methoxy, hydroxyl or NR (28) R (29) substitution; R (28) and R (29) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; R (33) is hydrogen or an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; provided that at least one of the groups R (2) or R (3) is 0- (inclusive) , Alkylene of 3, 4 or 4 carbon atoms) -0-R (17) or NR (50) R (51). The present invention also relates to the following formula 4 '-[5-fluorenyl-4- (2- Methoxyethoxy) -2-phenyl-1-imidazolylfluorenyl] -3'-methanesulfonylbiphenyl-2-sulfonylamine wax 20

Or the following formula 4 ’-{[Mentyl (σsphen-2-yl lutein acid) amine group] fluorenyl group] · _3’ -methyrite yellow

This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) A7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200306808 B7 V. Description of the invention (32) Biphenyl-2-pentanoic acid amine moon green ° = s \

It is used in the manufacture of pharmaceuticals for the prevention and treatment of acute 10 and chronic conditions caused by increasing the amount of von Willebrand factor in blood and / or increasing the expression of P-selectin. The invention also relates to compounds of formula III

II

N and / or all stereoisomeric forms of compounds of formula III and / or the physiological tolerance of compounds of formula III in any proportion and / or mixtures of these forms 20 salts for the manufacture of medicaments for prevention and treatment The use of von Willebrand factor and / or increasing P-selectin expression in acute and chronic conditions, where the symbol has the following meaning: R (l) is 1. Contains 1, 2, 3, 4, 5, 6, 7 Or an alkyl group with 8 carbon atoms; -34- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

200306808 V. Description of the invention (33 group, J: S alkyl alkane 3 ·-:;, carbon atom alkenyl; or A,, AU or 12 4 * -CnH2n-nn-Y nn is 0 or 2 ; And η is 0, 1, 2, 3, or 4 JL Φ ^

Yes. Or 1; Ge 4 'where "…, η; 5 · -CnH2n_nn-Y 10 15 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 nn is 0 or 2; and η 疋 1,2, 3, or 4, where When the rib is 2, η is not in which 1, 2 or 3 hydrogen atoms in the divalent radical -CnH2n_nn- are independently substituted with each other by the following groups: 1. Contains 6, 7, 8, 9, 10, 11, 12 An aryl group of 13 or 14 carbon atoms is more preferably a phenyl group, a 1-naphthyl group or a 2-naphthyl group; 2. an amino group; 3. NR (22) R (23); 5. COOR (16); 6. An alkyl group containing 1, 2, 3 or 4 end atoms; 7. (C6-C14) -aryl- (CVC4) -alkylfluorenyl, preferably phenylethyl- R (2) is 1. Hydrogen; This paper size applies Chinese National Standard (CNS) A4 specification (210x297 public love). Alkane of 3, 6, 7, or 8 carbon atoms 3, containing 1, 2 3 Α ε ^ ^,,,, 6, 7 or alkane of 4 carbon atoms 48; ', all to all hydrogen atoms are replaced by fluorine ; Jindian, 3, 4, 5, 6, 7, 8, 9, 10, U, or alkenyl with 12 stone antiatoms; 5. containing 2, 3 4 sf \ nc,,, 6 Alkynyl 7 or 8 carbon atoms group;

6. · _CnH2n_nn-Z nn is 0 or 2; and 10 15 is printed by the Intellectual Property Agency of the Ministry of Economic Affairs, 2011 疋, 1, 2, 3, or 4, where n is not 0 or 1 when nn is 2;

7 · -CnH2n-nn-Z nn is 0 or 2; and η is 1, 2, 3, or 4, where n is 2, 2, or 3 among the divalent radicals -CnH2n_nn- The hydrogen atoms are independently substituted by the following groups: L An aryl group containing 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms, preferably phenyl, 1-naphthyl, or 2-naphthalene Group, · 2. Amine group; 3. NR (22) R (23); 4. (Ci_C4) -Aceto group; 5. COOR (16); 6. · Containing 1, 2, 3 or 4 carbon atoms Alkyl; -36- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 200306808 A7 B7 Printed invention description printed by employee consumer cooperative of Intellectual Property Bureau of Ministry of Economy (35) R (3) and R ( 4) independently of each other are hydrogen or alkyl groups containing 1, 2, 3, 4, 5, η or 8 carbon atoms; R (5), R (6) and R (7) are independently of each other hydrogen, Alkyl, F, Cl, B ^ with 1, 2, 3, 4 5, 6, 7, or 8 carbon atoms; [5 CF3, -CN, -N02, SoqR (8), (: 0- 11 (21) or 〇R (10); R (8) is an alkyl group NR (11) R (12) or phenyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms It is unsubstituted or is selected from the group consisting of F, Cl , Br, I, CF3, methyl 10 ethoxy, hydroxyl or NR (11) R (12) group substitution; R (9) and R (21) are each independently hydrogen, containing 1, 2, 3, Alkyl or OR (13) of 4, 5, 6, 7, or 8 carbon atoms; R (l0) is hydrogen, optionally substituted with (CrCO-alkoxy containing 1, 2, 3, 4, 5 , 6, 7, or 8 carbon atoms alkyl; or phenyl which is 15 unsubstituted or 1, 2, or 3 identical or different selected from the group consisting of F,

Cl, Br, I, CF3, fluorenyl, methoxy, hydroxyl, or NR (11) R (12) group substitution; R (ll), R (12), R (19), and R (20) are independent of each other Ground is hydrogen, an alkyl group containing 1, 2, 3 or 4 carbon atoms or (CVC4) -alkylfluorenyl group, preferably 20 is ethyl group; R (13) is hydrogen or containing 1, 2, 3, 4 , 5, 6, 7, or 8 carbon atoms; X is carbonyl, -CO-NH-, -CO-CO- or sulfonyl; Y and Z are -37 independently of each other National Standard (CNS) A4 specification (210x297 mm)

200306808

5 ο 11 5 11 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 • 3 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms, preferably phenyl, 1- Naphthyl or naphthyl; 2. A base according to the definition of 1, which is the same or different from 1, 2, 3, 4, 5, 6, 7, or 8 Carbon atom alkyl group, aryl group containing 6, 7, 8, 9, 1 (K 11 12, 13, or 14 carbon atoms) is more preferably phenyl, n-nyl or 2-naphthyl, F, Cl, Br , I, CF3 sqqR (18), OR (16), NR (19) R (20), -CN, N02 or CO-R (9), or two of them together form a fused Heterocyclyl, preferably fluorenedioxy; 3. heteroaryl containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms; 4. a radical as defined by 3, which It is substituted by 1, 2 or 3 groups which are the same or different and are selected from the group consisting of F, Cl, Br, I, CF3, CH3, methoxy, hydroxyl or NR (11) R (12); Cycloalkyl of 5, 6, 7, 8, 9, or 10 carbon atoms, preferably cyclopropyl, cyclopentyl, cyclohexyl, 1,2,3,4-tetrahydronaphthyl or hydrobenzyl ; 6. Based on the definition of 5, which contains 6 Aryl groups of 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms are more preferably substituted by phenyl, 1-naphthyl or 2-naphthyl groups; 7. 〇-R (14); 8.0 -R (17); 9.-S〇2-R (14); -38-

This paper size applies to China National Standard (CNS) A4 specifications (210x 297 public love) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 200306808 Α7 __________ Β7 V. Description of the invention (37) 10. Aromatic alkyl, more suitable Is phenyl-ch2-c0-; or 11 · heterocyclyl; R (14) and R (17) are independently 1 · gas; 5 2 · containing 丨, 2, 3, 4, 5, 6, Alkyl groups of 7 or 8 carbon atoms; 3. Alkenyl groups of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; 4 * -CnH2n_nn " • phenyl 10 ηη is 0 or 2; and η is 1, 2, 3, or 4, where η is not 1 when ηη is 2; 5. A base according to the definition of 4, wherein the phenyl moiety is the same as 丨, 2 or 3 Or differently selected from alkyl groups containing 2, 3, 4, 5, 6, 15, 7 or 8 carbon atoms, F, C1, Br, J, cF3, SOqR (15), OR (16), NR (11) R (12), -CN, N02 or CO-R (9) group substitution; or R (15) and R (18) are independently of each other containing 丨, 2, 3 or 4 carbon atoms One, all 1, 2, 3, or 4 carbon atoms, one or all of the 20 hydrogen atoms are replaced by fluorine, preferably CF3, or NR (11) R (12); R (16) is 1. hydrogen ; 2 .Sulfur radicals containing 1, 2, 3 or 4 carbon atoms; 3. · (2, 3, or 4 carbon atoms) substituted with (CVC4) -sulphuroxy-39- This paper size applies to Chinese national standards ( CNS) A4 specification (210 X 297 public love) " a '----

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 200306808 A7 B7 V. Description of the invention (38) Atomic base; 4. Alkyl groups containing 1, 2, 3 or 4 carbon atoms in which one to all hydrogen atoms are replaced by fluorine CF3 is preferred; 5. Aryl groups containing 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon 5 atoms are more preferably phenyl, 1-naphthyl, or 2-naphthyl; 6. The base according to the definition of 5, which is substituted by 1, 2 or 3 groups which are the same or different and are selected from the group consisting of F, Cl, Br, I, CF3, NR (19) R (20), -CN, N02; R ( 22) and R (23) are each independently hydrogen or CO-OR (24); 10 R (24) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms Or -CnH2n-phenyl, n is equal to 1, 2, 3, or 4; q is independently 0, 1, or 2 from each other. The invention also relates to compounds of formula IV

20 and / or all stereoisomeric forms of compounds of formula IV and / or mixtures of these forms in any proportion and / or physiologically tolerable salts of compounds of formula IV for the manufacture of medicaments for prevention and treatment by increasing blood For the application of von Willebrand factor and / or increasing the expression of P-selectin in acute and chronic diseases, the symbols have the following meanings: -40- This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm)

200306808 A7 B7 V. Description of the invention (39) R (l) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, 1-naphthyl, 2-naphthyl, -CaH2a-cycloalkenyl or -CaH2a-phenyl group containing 3, 4, 5, 6, or 7 carbon atoms, wherein the phenyl moiety is unsubstituted or 1-3 selected from the group consisting of 1, 2, Alkyl groups of 3, 4, 5, 6, 5, 7 or 8 carbon atoms, F, Cl, B \ I, CF3, SonR (ll), OR (17), NR (8) R (9), -CN, NO] or CO-R (22) group substitution; R (11) is an alkyl group containing 1, 2, 3 or 4 carbon atoms or NR (20) R (21); 10 R (20) And R (21) is independently argon or an alkyl group containing 1, 2, 3, or 4 carbon atoms; R (17) is hydrogen or an alkyl group containing 1, 2, 3, or 4 carbon atoms; R ( 8) and R (9) are independently of each other hydrogen or an alkyl group containing 1, 2, 3, or 4 carbon atoms; 15 R (22) is hydrogen, containing 1, 2, 3, 4, 5, 6, 7 Or an alkyl group of 8 carbon atoms or OR (30); R (30) is argon, a burning group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; an employee of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the consumer cooperative a is 0, 1 or 2; 20 η is 0, 1 or 2; or R (l) and R (3) together with the carbon atom containing 3, 4, 5 A cycloalkyl or fluorenyl group of 6 or 7 carbon atoms; R (2), R (3), R (4), and R (5) are each independently hydrogen, f, CF3, 0-R (10), Contains -41- with 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200306808 A7

V. Description of the invention (40) Alkenyl, ring grafting group containing 3, 4, 5, 6, or 7 carbon atoms,

CgH2g-phenyl, in which the phenyl moiety is unsubstituted or 1-3 selected from the group consisting of F, Cl, Br, I, Cp3 methyl, methoxy, marginal or NR (18) R (19) R (18) and R (19) are each independently hydrogen or an alkyl group containing 2, 3, or 4 carbon atoms; g is 0, 1 or 2; R (10) is hydrogen, An alkynyl group, phenyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, which is unsubstituted or selected from 1-3, including F, 10 Cl, Br, I, CF3, Fluorenyl, fluorenyl, substituted by a radical or NR (12) R (13); R (12) and R (13) are independently of each other hydrogen or an alkane containing one, two, three, or four carbon atoms Or R (10) is a hetero 15 aryl group containing 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, which is unsubstituted or is selected from 1-3 F, C1

Br, I, CF3, methyl, methoxy, hydroxy or nr (14) R (15); R (14) and R (15) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy Hydrogen or an alkyl group containing 丨, 2, 3, or 4 carbon atoms; or 20 R (2) and R (4)-the second bond between the carbon atom and R (3) and R ( 5), where R (l), R (3), and R (5) are the same as defined above; R (6) and R (7) are independently hydrogen,? , € 1, 31 *, 1, 0? 3, -CN, -N〇2, SOp-R (16), CO-R (23) or 0-R (24); R (23) is hydrogen, containing -42 of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) 200306808 A7 B7 V. Description of the invention (41) Alkyl or OR (25); R (25) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R (24) is hydrogen, containing 1, 2, 5 alkyl or phenyl groups of 3, 4, 5, 6, 7 or 8 carbon atoms which are unsubstituted or are selected from the group consisting of F,

Cl, Br, I, CF3, fluorenyl, methoxy, hydroxy or NR (28) R (29) substitution; R (28) and R (29) are fluorene or contain 1, 2, 3 or 4 Carbon atom alkyl; R (16) is an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, 10 phenyl, which is unsubstituted or selected from 1-3 Including F,

Cl, Br, I, CF3, methyl, methoxy, hydroxyl or NR (26) R (27) substitution; R (26) and R (27) are fluorene or contain 1, 2, 3 or 4 Alkyl of carbon atoms; ρ is 0, 1 or 2. 15 The present invention also relates to the stereoisomeric forms of the compound of Formula IV and / or the compound of Formula IV, the Intellectual Property Bureau of the Ministry of Economic Affairs, the Consumer Cooperative Printing Department, and / or the mixture of these forms in any proportion and / or the physiology of the compound of Formula IV Tolerance salts are used in the manufacture of pharmaceuticals for the prevention and treatment of acute and chronic conditions caused by increasing the amount of von Willebrand factor in blood and / or increasing the expression of P-selectin. The 20 symbol has the following meaning: R (l ) Is fluorenyl, ethyl, 1-naphthyl, 2-naphthyl, cycloalkyl or phenyl containing 3, 4, 5, 6, or 7 carbon atoms. It is unsubstituted or is selected from one including Alkyl group with 1, 2, 3 or 4 carbon atoms, F, ci, CF3, S02R (11), OR (17), NR (8) R (9) or CO- -43- This paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Employee Cooperatives 200306808 A7 B7 V. Description of the invention (42) Substituting by R (22); R (ll) is Fluorenyl or dimethylamino; R (17) is hydrogen, methyl or ethyl; R (8) and R (9) are each independently hydrogen, fluorenyl or ethyl; 5 R (22) is hydrogen or An alkyl group of 1, 2, 3 or 4 carbon atoms; or R (l) and R (3) —from which the carbon atom is a cycloalkyl group containing 3, 4, 5, 6 or 7 carbon atoms Or R (2) and R (4) are hydrogen; or the second bond between R (2) and R (4) and the carbon atom bears the groups R (3) and 10 R (5 ); R (3) and R (5) are each independently hydrogen, CF3, 0-R (10), an alkyl or phenyl group containing 1, 2, 3, or 4 carbon atoms, which are unsubstituted or 1 substituent selected from the group consisting of F, Cl, CF3, methyl, methoxy, hydroxyl, or NR (18) R (19); 15 R (18) and R (19) are independently hydrogen, 曱R or 10; R (l0) is hydrogen, an alkyl or phenyl group containing 1, 2, 3, or 4 carbon atoms, which is unsubstituted or selected from the group consisting of F, Cl, CF3, methyl , Methoxy, hydroxy, or NR (12) R (13); R (12) and R (13) are independently hydrogen, fluorenyl, or ethyl; or 20 R (10) contains 1, A heteroaryl group of 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted or is selected from the group consisting of F, C1, CF3, CH3, fluorenyloxy, hydroxyl, or diaryl Methylamine substituents; R (6) and R (7) are independently hydrogen, F, Cl, CF3 , S02-CH3, -44- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

A7 200306808 B7 V. Description of the invention (43) Co-R (23) or O-R (24); R (23) is hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; R (24 ) Is hydrogen, an alkyl or phenyl group containing 1, 2, 3, or 4 carbon atoms. It is unsubstituted or is selected from the group consisting of F, Cl, CF3, methyl, 5 methoxy, hydroxyl, or NR. (28) Substitution of R (29); R (28) and R (29) are hydrogen, methyl, or ethyl. In particular, the use of a compound of formula IV in which the biphenyl ring is connected to a compound of the formula R4.

N 10 15 and ceramide is in position 2. The above compounds 疋 are known and can be prepared according to the disclosure of, for example, Ep 0 855 392 2P 1 097 140, EP 1 097 141. EP 1076 65U £? 1053 224 or EP 0 903 339. Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives. The base and the base can be linear or branched. This also applies to the formulas CaH2a, CbH2b, CdH2d, < The alkynyl group can also be straight or branched when it is substituted or present in other groups, such as in an alkoxy or alkylthio group or in a fluorinated alkynyl group. Cycloalkyl also refers to a ring substituted with alkyl. Examples of silks containing 1, 2, 3, 4, 5, 6, 7, or 8 yelling atoms -45- 200306808 A7 V. Description of the invention 44 5 10 15 20 Yes ... fluorenyl, ethyl, iL propyl, n Butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, second butyl, third butyl, The third fluorenyl group is derived from a divalent group such as methylene, ^ -ethyl, 1,1-ethyl, 1, M-propyl, L2-propyl, 2,2-propyl ???, 3-propenyl, propenyl, 1,5-propenyl, 2,2-dimethyl], 3-propenyl, 1,6-hexyl and the like are examples of alkylene. Cycloalkyl groups containing 3, 4, 5, 6, or 7 carbon atoms are especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, but they can also be substituted by containing 1, 2, 3 Or alkyl substitution of 4 carbon atoms, 'methylcyclohexyl and 2,3-dimethylcyclopentyl are examples of substituted cycloalkyl. Heterofluorenyl groups containing U 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms refer to, in particular, radicals derived from phenyl or naphthyl, in which "or more ch radicals are substituted by N and / Or at least two adjacent groups are substituted with $ NH or 0 (to form a five-membered aromatic ring), it may also be at one of the condensed sites of a bicyclic group (such as indolyl) or both atoms are nitrogen atom. Heteroaryl is especially succinyl, thienyl, pyrrolyl, imidyl, pyrazolyl, triazolyl, tetrazolyl, pyrazolyl, isoxazolyl, thia. Sorryl, isofluorenyl, aziridinyl, pyridinyl, pyrimidinyl, tammyl, glutamyl, sialyl, 4phenyl, isoisopropyl, phthaloyl, phenyl, Amidazolyl, fluorenyl, nitrogen-containing heterocyclic groups containing 1, 2, 3, 4, 5 6 7 8 or 9 carbon atoms refer to especially aromatic systems or 3- ° pyridyl, 1- , 2-, 4-, or 5-taste sigma group, 4-bit 5 pyrazolyl, 1,2,3-triazol-1-, -4-, or 5-yl, 丨, 2, 'trisial · i 一 埤 算 线 2--3. -46- This paper size is applicable to Chinese National Standard (CNS) A4 (210x297 mm) 200306808 Α7 Β7 5. Description of the invention (45 :) 5 10 15 Intellectual Property Bureau, Ministry of Economic Affairs Employee Consumer Cooperative printed 20 or -5-yl, 1- or 5-tetrazolyl, 2, 4_ or 5-oxazolyl, 3_, 'or 5-isohumazolyl, 1,2,3-hm Diazol 4- or 5-yl, 1,2,4-fluorenediazole_3_ or -5-yl, 1,3,4-fluorenediazole or -5-yl, 2'cardiol or thiazolyl, > , Deuterated or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-diadiazol-3- or -5-yl, fluorene 52,3 · thia Diazole-cardiol or -5-yl, 2_, oxal or 'lipidyl, 2' 4 '5- or 6-pyrimidyl, 3- or oxidyl, Pyryl, 1, 2-, 3-, 4, 5-, 6- or 7-indolyl, L, 2, ', or 5 benzylidene, 1, 3, 4, 5, 5, or 7-port-inducing base, ^, 4, 5-, 6, 7- or fluorenyl, BU, 3, 4, 5_, 6, 7_2-, 4.n 5-, 6-. 3-, 4- , 5-, 6-, 7- or 8-fluorenyl, 2, 3 gastric, 5, 6, or 8- humenyl, 1-, 4, 5, 6, 7-, or 8-phthaloyl. Particularly preferred nitrogen-containing heterocyclic groups are pyrrolyl, imidazolyl, fluorenyl, pyrazolyl, pyridyl, pyrargyl, pyrimidinyl, and daphthyl. Sigma refers to 2- and 3-thienyl, and furanyl refers to 2- and 3-furyl. Mono-substituted phenyl can be substituted at positions 2, 3, or 4, and di-substituted at positions 2, 3 , 2,4,2,5,2,6,3,4, or 3,5, three substitutions at positions 2,3,4,2,3,5,2,3,6,2,4,5,2 , 4,6 or 3,4,5, the corresponding descriptions also apply to nitrogen-containing heterocycles or thienyl. If the radicals are di- or tri-substituted, the substituents may be the same or different. The invention also relates to the use of the above-mentioned compounds of formulae I, II, III and IV in combination with a sodium / hydrogen exchanger inhibitor. The present invention also relates to the combination of the above-mentioned compounds of formulas I, II, 111, and 1 ¥ -47- This paper size applies the Chinese National Standard (CNS) A4 specification (21〇χ 297 public love) 200306808 A7 B7 Column sodium / hydrogen exchanger inhibitor

^ ΝΗ 2 α

N Ya NH2 〇 NH0 h3c.〇2s ^-^ Y Ύ

This paper size applies to the Chinese National Standard (CNS) A4 (210 x 297 mm) 200306808 Δ7 Α7 Β7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

ν / Ν 丫 νη2 Ν Η. N = <

Cl Ν Η. JL _ νη2ο ^ Ο Ν Η, Ν = < Ν Η 〇 or and / or all stereoisomeric forms of the above compounds and / or these forms 10 mixtures in any ratio and / or the physiology of the above compounds Tolerant salts are used in the manufacture of pharmaceuticals for the prevention and treatment of acute and chronic conditions caused by increasing the amount of von Willebrand factor in the blood and / or increasing the expression of P-selectin. The present invention also relates to the compounds of the above formula I, II, III and IV in combination with card 15 cariporide H-0QS-CHr H 'O NH2 20 for the manufacture of pharmaceuticals for prevention and treatment by increasing the amount of von Willebrand factor in the blood and And / or use of increasing P-selectin expression in acute and chronic conditions. The invention also relates to 4 '-[5-fluorenyl-4- (2-methoxyethoxy

This paper size applies to Chinese National Standard (CNS) A4 specifications (210 x 297 mm) A7 200306808 B7 _ V. Description of the invention (48) Benzyl-1-imidazolylmethyl] -3'-methanesulfonylbiphenyl- 2-sulfoamidonitrile combined with Kalibo is used in the manufacture of pharmaceuticals for the prevention and treatment of acute and chronic conditions caused by increasing the amount of von Willebrand factor in blood and / or increasing the expression of P-selectin.

5 The above compounds are known and can be based on, for example, EP 0 416 499, EP 0 556 673, EP 0 589 336, EP 0 622 356, EP 0 699 666, EP 0 708 088, EP 0 719 766, EP 0 726 254, EP 0 787 728, EP 0 972 767, DE 19529612, DE 19601303, WO 99 00379 or Ding Kawamoto et al., Eur. J. Pharmacol. 10 420 (2001), 1-8. Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs' Consumer Consumption Cooperative when the above compounds can have non-paraisomeric or paraisomeric forms and lead to their mixture in a selected synthesis, which can be separated into pure stereoisomers. Chromatography on palm-like supporting substances as needed, or if the racemic compounds mentioned above can form salts, through non-isomeric formation of 15 crystals and optically active base or acid as an adjuvant Constituent salts, suitable for solid phase separation of palmar isomers by thin-layer or column chromatography. Examples are modified Shixi gum branches (known as Pirkle phase) and high molecular weight carbohydrates. For example, triethyl cellulose, after proper derivation known to those skilled in the art, can be used for the purpose of analysis by gas chromatography 20 on the opposite solid phase, for the separation of racemic carboxylic acids. Palm isomers are non-palladium isomerized salts of different solubility using bases that are usually commercially available with optical activity. Examples of bases are (-)-nicotine, (+)-, and p-phenylethyl Amine, quinine base, L-lysine or L- and D-spermine, The insoluble components are separated by solids, and the non-palladium isomers that are relatively easy to dissolve are from -50 to this standard. Applicable to China National Standard (CNS) A4 (21 × 297). 200306808 Δ7 Α7 Β7 Intellectual Property of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperatives V. Description of the Invention (49) Mother liquor is deposited, and pure palmar isomers are obtained from non-palm palmar isomers obtained from this method. Optically active acids for racemic compounds of formula I containing test groups such as amine groups such as (+)-camphor-10 sulfonic acid, D- and L-tartaric acid, D- and L-lactic acid and (+) and 5 (- ) Mandelic acid is converted into pure palmar isomers, and palmitic compounds containing alcohol or amine functional groups can also be converted into corresponding vinegars with appropriate activation or N-protected palmar isomeric pure amino acids as required. Or an acid amine, or conversely, a para-isomeric pure amino acid protected with a carboxyl group to para-carboxylic acid is converted to amidine or a para-isomeric pure hydroxycarboxylic acid such as lactic acid is converted to the corresponding 10 Palmitic esters, which can then be used in the form of amino acids or alcohols that are produced in pure isomeric form Chiral, for separation of the isomers of the palm via crystallization method or a chromatography on a suitable stationary phase and the separation of isomers, subsequent elimination of the chiral part via suitable method. The acidic or basic products of the above compounds may exist in the form of their salts. 15 Formulas or free forms are preferred, and are preferably pharmacologically suitable salts, such as alkali metal or alkaline earth metal salts, or hydrochloride, bromate , Sulfates, hemisulfates, all possible phosphates, and salts of amino acids, trona or carboxylic acids. Pharmacologically tolerable salts are prepared from the above-mentioned compounds 20 which can form salts in a manner known per se, including their stereoisomeric forms, carboxylic acids and hydroxamic acids with basic reagents such as hydroxides , Carbonates, bicarbonates, alkoxides and ammonia or organic bases such as trimethylamine or triethylamine, ethanolamine or triethanolamine or basic amino acids such as lysine, ornithine or arginine, suitable alkali metals Alkaline earth metal or substituted ammonium salt if necessary, -51- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

200306808 A7B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (50) The above compounds containing basic groups can also be prepared as stable acid addition salts with strong acids. Inorganic and organic acids are suitable for this purpose. , Such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluene acid, 4-bromobenzenesulfonic acid, cyclohexylaminosulfonic acid, trifluoromethylsulfonic acid, 5 bend , Oxalic acid, tartaric acid, succinic acid, or trifluoroacetic acid. The sulfonium sulfonates of the above compounds are particularly preferred. Due to their pharmacological properties, the above compounds are suitable for the prevention and treatment of acute and chronic conditions caused by increasing the amount of von Willebrand factor in the blood and / or increasing the expression of P-selectin. 10 These include thrombotic disorders caused by ischemic states and subsequent reperfusion, such as thrombosis in acute myocardial, bowel, or cerebral infarction; thrombotic conditions that occur during or after surgery; pulmonary edema; increased rates of chronic obstruction to blood flow Occurrence of deep venous thrombosis, especially in lower limbs, such as prolonged lying or sitting, and during ischemia and subsequent reperfusion, 15 inflammation disorders that occur during vasculitis (e.g., associated with autoimmune disease or connective tissue disease ). These also include conditions caused by increased expression of P-selectin, such as initial inflammation; but also prevent and treat atherosclerosis; and prevent and treat cancer; and joint inflammation and joint disorders such as rheumatoid arthritis 20 . The medicament of the present invention can be administered orally, by inhalation, rectally or percutaneously, or by subcutaneous, intra-articular, intraperitoneal or intravenous injection, and oral administration is preferred. The present invention also relates to a method for producing a medicament, which comprises adapting -52- the paper size to the Chinese National Standard (CNS) A4 specification (210x297 mm)

V. Description of the invention (51) 10 to Sha One of the above compounds, a pharmaceutically suitable and physiologically tolerable carrier, and other suitable active ingredients as required, and added excipients are converted into a suitable administration form. The above compounds are mixed with additives suitable for this purpose, such as _, stabilizers or inert diluents, and converted into suitable administration forms such as tablets, coated tablets, two-piece capsules, water, alcohol by conventional methods. Or oil-based suspensions or aqueous or oil-based solutions', examples of inert carriers that can be used are gum arabic, oxidized town, carbomagnesium, osmium potassium, cerose, glucose or starch, especially corn starch. Prepared as dry or wet granules, examples of suitable oil-based carriers or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. 15 For subcutaneous, abdominal, or sedative assistance, if necessary, the active compound is converted into a solution, suspension, or emulsion with a substance suitable for this purpose, such as a dissolving agent, emulsifier, or other excipient. Examples of suitable solvents are physiological table salts. Water or alcohols-such as ethanol, propanol, glycerol, and sugar solutions such as glucose or mannitol solutions, or mixtures of different solvents mentioned above. Conventional adjuvants such as carriers, disintegrating agents, adhesives, coating agents, bulking agents, glidants or lubricants, flavoring agents, sweeteners and dissolving agents can also be used. It is carbonated carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, lake, 20 powders, glue and its derivatives, animal and vegetable oils such as cod liver oil, sunflower oil. Glycols and solvents such as sterile water and monotic and polyhydric alcohols such as glycerol. The above compounds are more suitable for the production of a one-person Shangle product in Huadan Kailuan JL and the use of one of the above compounds containing a defined dose of the above-mentioned compound as an active ingredient -53 · 200306808 A7 B7 5. (52) copies of the invention description, in The dosage for oral administration for this purpose is from 0.01 mg / kg / day to 25.0 mg / kg / day, preferably from 0.01 mg / kg / day to 5.0 mg / kg / day. The parenteral dose is from 0.001 Mg / kg / day to 5 mg / kg / day, preferably 0.001 mg / kg / day to 2.5 mg / kg 5 kg / day. In severe cases, the dose can be increased, and a smaller dose is sufficient. In many cases, these data are relevant to adults weighing approximately 75 kg. The above compounds can be used alone or in combination with anticoagulants, platelet inhibitors or fibrinolytic agents, and can be co-administered, such as 10 and factor Xa inhibitors, standard heparin, low molecular weight heparin such as enoxaparin, dow Dalteparin, certroparin, parnaparin or tinzaparin, direct thrombus inhibitors such as hirudin, aspirin, fibrinogen receptor antagonists, streptococcal kinases , Urokinase and / or group 15 plasminogen activator (tPA). Unlike the previously described effects of nano-dependent chloride / biacid exchanger inhibitors on platelet aggregation, the above compounds also show an inhibitory effect on the excessive release of von Willebrand factor. The new | page principle of antithrombotic action is The decisive and beneficial way is different from the antithrombotic effect principle described previously20, in which a) it only affects the ischemic tissue of the subsequent reperfusion phase, and other cells that are not affected by ischemia (pre-ischemia) will remain completely unaffected Are affected, and b) there is no need to worry about any dangerous bleeding complications during the dissolution therapy. -54- This paper size is in accordance with China National Standard (CNS) A4 (210x297 mm). Designed and printed by the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the employee consumer cooperative 200306808 A7 A7 B7 V. Description of the invention (53) The examples illustrate the invention in more detail. The following examples demonstrate the effect of extracellular poisoning (PHex = 6.4) and are specific inhibitors of sodium-dependent chloride / bicarbonate exchangers released by intracellular pH (pHi) and von Willebrafid factor (vWF), All 5 examples were performed using human umbilical vein endothelial cells (HUVEC), and these included primary cell cultures isolated from the umbilical vein. For the following examples, the cells were in gelatinized glass Petri dishes (to measure intracellular proton concentration) or in cell Petri dishes (12-well Petri dishes, Falcon, New Jersey, USA; measure vWF release) after the first pass. 10 Cultivation. Example 1:

Measuring intracellular pH Printed to measure intracellular proton concentration (ρΗ〇, add pH-sensitive fluorescent dye BCECF-AM (2 ', 7'_bis (carboxyethyl) to HUVECs) ) -5 (6) -15 ene-based fluorescein). Deltascan fluorometer (PTI, Hamburg) was used in subsequent fluorescence measurements. This measurement system mainly includes a UV light source, a single filter, and proton extraction. And Felix and Oscar software suite (PTI, Hamburg) are used to report the BCECF (proportion) after 20% excitation at a wavelength of 439.5 nm (pH-independent) and 490 nm (pH-sensitivity) through a computer-controlled system. Measure the radiation ratio and find the pH after calibration. Specify the measured cells to control the temperature and partial pressure of carbon dioxide in the system during continuous perfusion. For reperfusion stimulation, set the experimental conditions at 37 ° C and set the system Inflation and reperfusion make the carbon dioxide partial pressure be 5% or 10%. In the experiment, use sodium bicarbonate to slow down -55- This paper size applies Chinese National Standard (CNS) A4 specification (210x297). 200306808 Δ7 Α7 Β7 Ministry of Economy Wisdom Printed by the Production Cooperative Consumer Cooperative. V. Description of the invention (54) Washing pHex 6.4 Initial culture for 60 minutes to stimulate respiratory metabolic acidosis, then change the initial reperfusion to sodium bicarbonate buffer pH 7.4 and use 10 micromolar concentration tissue Amine was used as a reperfusion stimulus. These control experiments were performed with 5 NCBE inhibitors 4 '-[5-methylfluorenyl-4- (2-methoxyethoxy) -2- Phenyl-1-imidazolyl fluorenyl] -3'-methylsulfonylbiphenyl-2-sulfonylaminonitrile (hereinafter referred to as Compound 1) and NHE inhibitor in experimental reperfusion buffer comparison. The results of each test are summarized in Tables 1 and 2. 10 Table 1: Intracellular pH under extracellular acidosis (pHi (acidosis)) for at least 15 minutes under controlled conditions (CO) Table 1: pH; (acid Poisoning) 6.53 ± 0.02 (mean soil SEM) pHi (CO) 7 · 23 ± 0 · 02 (mean soil SEM) SEM is the standard deviation of the mean value. Extracellular acidosis leads to persistent intracellular during acidosis After acidification, the pH of intracellular acidosis is substantially the same as the extracellular pH (for extracellular acidosis, pHex = 6.4). The reperfusion of experimental buffer, control buffer (NHE) and control buffer (CO) containing caliper wave, from the measurement during the first 30 seconds after reperfusion, acidosis was found to be the largest in the second half of 20 to 60 minutes. Time of pHi change. Table 2: -56- This paper size applies to China National Standard (CNS) A4 (210x297 mm)

A7 200306808 B7 V. Description of the invention (55) △ ρΗί, _ / 2 [5] time ▲ ^ ___ —) (mean soil SEM) CO 18 soil 1.5 NHE 190 ± 2.9 Compound 1 + Kalibo 450 ± 32.7 Example 2 Measurement of vWF release after reperfusion was measured in a Heraeus Heracell incubator, which allowed the calculation of umbilical vein endothelial cells in a controlled physiological situation (temperature 37 ° C, relative humidity 100%, 5 pC02 fixed at 5%) and quickly Change different cell culture media. The cells are poisoned with an acid medium (pH 6.4, the components include: medium M199 w / Earle's & amino acid, w / L-glutamic acid, w / o NaHC03, w / o Hepes + 0.084 g NaHC03 / liter) or pH standard medium (pH 10 7 · 4, ingredients include: medium M199 w / Earle's & amino acid, w / L- Valley Intellectual Property Bureau, employee property cooperation, printed amino acid, w / o NaHC〇3 , W / o Hepes + 2.200 g NaHCCV)) After initial culture for 1, 3 or 48 hours, the supernatant should be taken out before reperfusion. The night samples were measured for vWF in the case of acidosis (vWFaeid () Sls) and the control group. Concentration, when stimulating reperfusion, change the medium to ρΗ7.4 · medium (15 parts: medium M199 w / Earle's & amino acid, w / L-glutamic acid, w / 0 NaHC〇3, w / o Hepes + 2.200 g NaHC03 / liter + 10 micromolar histamine), in which the above-mentioned NCBE inhibitor compound 1 at a concentration of 10 micromolar was added to the same medium but no corresponding inhibitor was added as a control group. -57-This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 200306808 A7 B7 V. Description of the invention (56) The VWF concentration is determined by using the sample taken from the supernatant, which uses a specific antibody via ELISA The method (enzyme-linked immunoabsorption assay) was completed, and the vWF content of standard human plasma (Behring, Marburg) was calculated using international standards (2nd International Standard 87/718; National Institute for Biological Standards and Control, 5 London). Table 3: After 15 minutes of incubation, the VWF concentration of the cell supernatant was measured under the condition of acidosis (vWFaeidc) sis and the control group (vWFe0). The vWF concentration in the control group was set to 100%. 10 Table 3: vWFC0 100% vWFacid () sis (essential) 46 ± 1.1% vWFaeidQsis (stimulation, histamine 50 micromolar concentration) 52 ± 2.5% In the essential secretion and stimulation of Weibel-Palade body secretion, Acidosis caused a significant decrease in VWF secretion, and vWF secretion was reduced by a factor of 2 compared to control cells during the period of acidosis (pHex = 6.4). Employees ’cooperation and publication of the Intellectual Property Bureau of the Ministry of Economic Affairs, Table 4: vWF secretion was measured during 10 minutes of reperfusion under stimulation. The vWF secretion (vWFc.) Of 15 pairs of cells and cells was set to 100 ° / 〇, acid poisoning. The vWF concentration (vWFacid () sls) of cells during reperfusion and the concentration of 10 micromolar acidic cells in the presence of the above compound 1 during reperfusion (vWFcl) are expressed relative to the control group. 20 Table 4: -58- ----------- This paper size applies to China National Standard (CNS) A4 (21 × 297 mm) Printed by the Employees ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 200306808 A7 B7 V. Description of the invention (57) vWFC0 100% V WF acidosis 193 ± 8.0% VWFcl 157 ± 18% During the reperfusion period, vWF secretion increased by a factor of two. Blocking the NCBE transporter with the above compound 1 reduced the increase by about 50%. VWF is secreted and therefore approaches control values. These examples show the presence of extracellular acidosis during, for example, intracellular deficiency that results in intracellular acidosis, resulting in reduced (essential and irritating) vWF secretion, subsequent reperfusion and stimulation of endothelial cells resulting in rapid intracellular rebasing At the same time, increase the increased vWF secretion, delay the rebasification with the above compound 1, reduce the increased vWF secretion and therefore possible thrombosis. The data show that the intracellular pH is determined by measuring the extracellular pH and then by measuring the intracellular pH. Endothelial cell secretion, by inhibiting rebasification, can significantly reduce known endothelial cell activation during the reperfusion phase, as well as concerns about rethrombosis (vWF secretion) and inflammation associated with it. -59- This paper size applies to China National Standard (CNS) A4 (210x 297 mm)

Claims (5)

200306808 A8 B8 C8 D8, patent application scope 1. A cell sodium-dependent gaseous / bicarbonate exchanger inhibitor for the manufacture of drugs for prevention and treatment by increasing the amount of von Willebrand factor in the blood and / or increasing P-selection Of acute or chronic conditions caused by the expression of vegetin. 5 2. Application according to item Γ of the scope of the patent application, wherein at least one compound of the formula I and / or all stereoisomeric forms of the compound of the formula I and / or mixtures of these forms in any proportion and / or the compound of the formula I are used Physiologically tolerable salts act as inhibitors of cell-dependent chloride / bicarbonate exchangers, where the symbol has the following meaning: 10 X equals Or R12 R9 ^ Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, R (l) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, or -CaH2a-phenyl, of which phenyl Part is unsubstituted or substituted with 1, 2 or 3 groups which are the same or different and are selected from F, Cl, Br, I, CF3, fluorenyl, fluorenyloxy, hydroxyl or NR (19) R (20); 20 R (19) and R (20) are independently Η or an alkyl group containing 1, 2, 3 or 4 carbon atoms; a is 0, 1 or 2; or R (l) is 1, 2 -CbH2b-heteroaryl group with 3, 4, 5, 6, 7, 8 or 9 carbon atoms, in which the heteroaryl part is unsubstituted or -60-This paper size applies Chinese National Standard (CNS) A4 Specifications (210 x 297 mm) 8 8 8 8 AB c D 200306808 VI. Patent application scope 1, 2 or 3 same or different selected from F, Cl, Br, I, CF3, CH3, methoxy, hydroxyl or NR (21) R (22) group substitution; R (21) and R (22) are independently Η or an alkyl group containing 1, 2, 3 or 4 carbon atoms; 5 b is 0, 1 or 2 Or R (l) is -CeH2e-cycloalkyl having 3, 4, 5, 6, or 7 carbon atoms; c is 0, 1 or 2; R (2) and R (3) are independently of each other hydrogen , F, Cl, Br, I CF3, -CN, -N〇2, CH2OR (23), CO-R (24) or 〇-R (25); 10 R (23) is hydrogen or contains 1, 2, 3, 4, 5, An alkyl group of 6, 7 or 8 carbon atoms; R (24) is argon, an alkyl group of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, OR (26) or phenyl, Where phenyl is an unsubstituted or 1, 2 or 3 identical or different group selected from F, Cl, Br, I, CF3, 15 methyl, methoxy, hydroxyl or NR (27) R (28) Replacement; R (27) and R (28) are independently tritium or a radical containing 1, 2, 3, or 4 carbon atoms; the consumer cooperation of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the agency R (26) is hydrogen Or an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; 20 R (25) is hydrogen, containing 1, 2, 3, 4, 5, 6, 7, or 8 carbons Atomic alkyl or phenyl, where phenyl is unsubstituted or is the same or different from 1, 2 or 3 selected from F, Cl, Br, I, CF3, methylmethoxy, hydroxyl or NR (29) R (30) is substituted by base; R (29) and R (30) are independently Η or contain 1, 2, 3 or 4 carbon atoms -61-t paper size is applicable to China National Standard (CNS) A4 specifications ( 210 x297 mm) 200306808 A8 B8 C8 D8 VI. Application Alkyl group; or R (25) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, which is unsubstituted or via u 2 or 3 The same or different substituents selected from the group consisting of NR (31) R (32); R (31) and R (32) are independently η or an alkyl group containing 丨, 2, 3 or 4 carbon atoms; or 10 15 Consumption cooperation of employees of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by the society 20 R (2) and R (3) are independent of each other, including 2, 3, 4, 5, 6, and 6? Or an alkyl group of 8 carbon atoms, a cycloalkyl group containing 3, 4, 5, 6, or 7 carbon atoms, or a -CdH2d-phenyl group, wherein the phenyl moiety is unsubstituted or 1, 2, or 3 The same or different substituents selected from ρ, ci, Br, I, CF3, methyl, methoxy, hydroxyl, or nr (33) R (34); R (33) and R (34) are independently of each other η or an alkyl group containing 1, 2, 3 or 4 carbon atoms; d is 0, 1 or 2; or R (2) and R (3) are independently of each other containing 1, 2, 3, 4, 5, -CeH2e-heteroaryl group of 6, 7, 8 or 9 carbon atoms, in which the heteroaryl moiety is unsubstituted or is selected from the group consisting of F, C1, Br, I, CF3 through 1, 2 or 3 identical or different , CH3, methoxy, hydroxyl, or NR (35) R (36); R (35) and R (36) are independently Η or an alkyl group containing 1, 2, 3, or 4 carbon atoms ; E is 0, 1, or 2; or -62-This leaflet scale is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) 200306808 A8 B8 C8 D8____ Six, the scope of patent application R (2) and R (3) Independent of each other is -SOrR (37); R (37) is an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and containing 3, 4, 5, 6, or 7 carbon atoms Atomic ring radical, or _ CgH2g-phenyl, in which the phenyl moiety is unsubstituted or is selected from the group consisting of F, Cl, Br, I, CF3, fluorenyl, fluorenyl, hydroxy, or NR (38 ) R (39) radical substitution; R (38) and R (39) are independently Η or a radical containing 1, 2, 3 or 4 carbon atoms; f is 0, 1 or 2; 10 g is 0, 1 or 2; R (4) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, a 1-naphthyl group, a 2-dichloro group, containing 3, 4 -CJif cycloalkyl, or -CjHf phenyl of 5, 6, 6 or 7 carbon atoms, in which the phenyl moiety is unsubstituted or is selected from the group consisting of 1, 15 2 through 1, 2 or 3 identical or different Alkyl groups of 3, 4, 5, 6, 7, or 8 carbon atoms, F, C1, Br, I, CF3, SojR (48), OR (49), NR (50) R (51),- CN, -N02, or CO-R (52); i is 0, 1, or 2; printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R (48) is one containing 1, 2, 3, or 4 carbon atoms Alkyl or 20 NR (53) R (54); R (53) and R (54) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; j is 0, 1 or 2 R (49) is hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; -63-this paper Applicable to China National Standard (CNS) A4 specification (210x297 mm) 200306808 A8 B8 C8 D8_ VI. Patent application scope R (50) and R (51) are independently hydrogen or contain 1, 2, 3 or 4 carbons Atomic group; R (52) is hydrogen, alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms or OR (55); 5 R (55) is hydrogen, containing 1 An alkyl group of 2, 2, 3, '4, 5, 6, 7, or 8 carbon atoms; or R (4) and R (6) together with a carbon atom containing 3, 4, 5, 6, or Cycloalkyl or alkynyl of 7 carbon atoms; R (5), R (6), R (7), and R (8) are independently 氲, F, CF3, 0-10 R (56), containing Alkyl groups of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, cycloalkyl groups of 3, 4, 5, 6, or 7 carbon atoms, or -CkH2k-phenyl, of which phenyl Some are unsubstituted or substituted with 1, 2 or 3 groups which are the same or different and are selected from F, Cl, Br, I, CF3, fluorenyl, methoxy, hydroxyl or NR (57) R (58); 15 R (57) and R (58) are independently of each other hydrogen or a burning group containing 1, 2, 3 or 4 carbon atoms; k is 0, 1 or 2; printed by R, Consumer Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs (56) is hydrogen, containing 1, 2, 3, 4, 5 Alkyl group of 6, 7, or 8 carbon atoms, or phenyl group which is unsubstituted or 1, 2, or 3 same 20 or different is selected from F, Cl, B1, I, CF3, fluorenyl, methoxy Group, hydroxy or NR (59) R (60) substitution; R (59) and R (60) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; R (56) It is a hybrid containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms -64-This paper size applies to China National Standard (CNS) A4 (210x297 mm) A8 B8 C8 D8 Economy Printed by the Consumer Cooperative of the Ministry of Intellectual Property Bureau 200306808 VI. The scope of patent application for aryl is unsubstituted or selected from 1, 2 or 3 identical or different selected from F, CU, L CF3, CH3, methoxy, Substituted by a group or a group of NR (61) R (62); R (61) and R (62) are each independently η or an alkyl group containing 5, 2, 3, or 4 carbon atoms; I, R (5) and R (7) —the second bond between the carbon atom and the group r (6) and R (8) 'where R (4), R (6) and R (8) are the same As defined above; R (9): an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms Alkenyl, _ 10 C1H21-11-A; II is 0 or 2; and I is 0, 1, 2, 3, or 4, where when II is 2, I is not 0 or 1; R (lO) is hydrogen and contains 1 15 alkyl, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, alkenyl containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms,-, mm is 0 or 2 And m is 0, 1, 2, 3, or 4, wherein when mm is 2, m is not 0 or 1; 20 R (ll) and R (12) are independently of each other hydrogen or containing 丨, 2, 3, An alkyl group of 4, 5, 6, 7, or 8 carbon atoms; Z is a carbonyl group or a sulfonyl group; A and B are independently of each other 1. containing 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms -65-This paper size applies to China National Standard (CNS) A4 (210 X 297 public love) 200306808 A8 B8 C8 D8 t. The aryl group in the scope of patent application is preferably phenyl, 1-naphthyl or 2-naphthyl; 2. A group under the definition of 1, which is the same or Differently selected from alkyl groups containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, F, Cl, B1, I, CF3, SOnR (63), OR (64), 5 NR ( 65) R (66), -CN, -N02 or CO-R (67) group substitution; 3. Heteroaryl groups containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms 4. A radical under the definition of 3, which is selected from the group consisting of F, Cl, Br, I, CF3, CH3, fluorenyl, or NR (68) R ( 69); 5. Cycloalkyl groups containing 3, 4, 5, 6, or 7 carbon atoms; 6. 〇R (70); or 7.0-R (71); 15 η is 0, 1 or 2 R (70) and R (71) are independently 1. Hydrogen; printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy 2. Containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms垸 phenyl; 2000 is 0 or 2; and 0 is 0, 1, 2, 3, or 4, where when 00 is 2, 0 is not 0 or 1; 4. a group under the definition of 3, wherein benzene The base part is selected by the same or different options. Self-contained 1, 2, 3, 4, 5, 6, 7, or 8 -66-This paper size applies to China National Standard (CNS) A4 specifications (21〇X 297 public love) 200306808 A8 B8 C8 D8___ Six, apply for a patent Alkyl, F, Cl, Br, I, CF3, SOpR (72), OR (73), NR (74) R (75), -CN, -N〇2 * CO-R (76) Radical substitution; or 5. Alkenyl groups containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms; 5 R (63) and R (72) independently of each other contain 1, 2, 3, or 4 Alkyl or NR (77) R (78); R (67) and R (76) are independently of each other hydrogen, containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms Alkyl or OR (89); R (89) is argon or a 10-alkyl group containing 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) are independently argon or contain 1, 2 , Alkyl groups of 3, or 4 carbon atoms; p is 0, 1 or 2 independently of each other; 15 R (13), R (14) and R (15) are independently of each other hydrogen, containing 1, 2, 3, Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of 4, 5, 6, 7, or 8 carbon atoms, alkyl, F, Cl, Br, I, CF3, -CN -N02, SOq-R (79), CO-R (80), or 〇-R (81); q is independently 0, 1 or 2; 20 R (79) is 1, 2, 3, 4, An alkyl or phenyl group of 5, 6, 7 or 8 carbon atoms which is unsubstituted or is the same or different from 1, 2 or 3 selected from F, Cl, Br, I, CF3, methyl, methoxy , Hydroxyl or NR (82) R (83); R (82) and R (83) are independently hydrogen or contain 1, 2, 3, or 4 carbon atoms -67-This paper is applicable to China Standard (CNS) A4 specification (210 x 297 public love) 200306808 Printed by A8 B8 C8 D8 of the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives, the patent application scope; R (80) is hydrogen, containing 1, 2, Alkyl or OR (84) of 3, 4, 5, 6, 7, or 8 carbon atoms; R (84) is hydrogen or one of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms 5 alkyl; R (81) is hydrogen, an alkyl or phenyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; it is unsubstituted or the same through 1, 2 or 3 Or different substituents selected from the group consisting of F, Cl, B1, I, CF3, methyl, methoxy, hydroxyl, or NR (82) R (83); 10 Y is a covalent bond, CR (16) R (17 ), CO, S, S〇2, 0, or NR (1 8); R (16) is hydrogen or -OR (85); R (85) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms or CO-R ( 86); 15 R (86) is an alkyl or phenyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms which is unsubstituted or is the same or different via 1, 2 or 3 A substituent selected from the group consisting of F, Cl, Bt *, I, CF3, methyl, methoxy, or hydroxyl; R (17) is hydrogen or contains 1, 2, 3, 4, 5, 6, 7, or 8 carbons Atomic 20 alkyl groups; R (18) is hydrogen, alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, CO-R (87) or S02R (88); R ( 87) and R (88) are independently of each other alkyl groups containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and -68 containing 3, 4, 5, 6, or 7 carbon atoms -This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200306808 Printed by A8, B8, C8, D8, Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics, “Cycloalkyl or phenyl for patent application, which are unsubstituted or selected from 1, 2 or 3 identical or different selected from F, Cl, Beta , I, CF3, methyl, methoxy or hydroxy group substitution. 3. Application according to item 1 or 2 of the scope of patent application, wherein at least 5 compounds of formula I are used as cell-dependent chloride / bicarbonate Exchanger inhibitor, where is defined as: X is R2 R (l) is an alkyl or phenyl group containing 1, 2, 3 or 4 carbon atoms which is unsubstituted or substituted with a group 15 selected from F, Cl, CF3, methyl or methoxy; R (2) and R (3) are independently hydrogen, F, Cl, CF3, -CN, CO-R (24), or 0-R (25); R (24) is hydrogen, containing 1, 2, 3 Or an alkyl group of 4 carbon atoms, OR (26) or phenyl which is unsubstituted or substituted with a group selected from F, Cl, CF3, methyl20 or methoxy; R (26) is hydrogen , Methyl or ethyl; R (25) is hydrogen, an alkyl group containing 1, 2, 3 or 4 carbon atoms, phenyl which is unsubstituted or substituted by one selected from F, Cl, CF3, methyl or Substituted by ethoxy groups; or -69-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200306808 Printed clothing A8 B8 C8 D8 s of the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the scope of patent application R (25) is heteroaryl, which is unsubstituted or is selected from one selected from F, Cl, CF3, CH3 or methoxy Or R (2) and R (3) are independently an alkyl group having 1, 2, 3, or 4 carbon atoms, or a cycloalkyl group having 3, 4, 5, 6, or 7 carbon atoms ; Or 5 R (2) and R (3) are independently phenyl groups which are unsubstituted or substituted with a group selected from F, Cl, CF3, fluorenyl or methoxy; or R (2) and R (3) are independently of each other heteroaryl groups containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which are unsubstituted or substituted with one selected from F, Cl, CF3, CH3 Or a alkoxy group substitution; or 10 R (2) and R (3) are independently -SOrR (37); R (37) is an alkyl or benzene group having 1, 2, 3, or 4 carbon atoms Is unsubstituted or substituted with a group selected from F, Cl, CF3, methyl or methoxy; f is 0 or 2; 15 R (13), R (14) and R (15) are independent of each other Ground is hydrogen, methyl, F, C1, CF3, -CN, S02-R (79), CO-R (80) or 0_R (81); R (79) and R (81) are independently , 2, 3, or 4 carbons Atomic alkyl or phenyl is unsubstituted or substituted with a group selected from F, C1, CF3, CH3 or methoxy; 20 R (80) is hydrogen, methyl or OR (84); R ( 84) is hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; Y is a covalent bond or a fluorenylene group. 4. Application according to items 1 to 3 of the scope of patent application, in which at least one compound of formula II is used -70-This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200306808 A8 B8 C8 D8 VI. Patent application scope R2 All stereoisomeric forms of compounds of Formula II printed by the Consumer Cooperative of the Ministry of Economic Affairs and the Intellectual Property Bureau and / or mixtures of these forms in any ratio and / or physiologically tolerable salts of compounds of Formula II as cell sodium dependent Chloride / bicarbonate exchanger inhibitors, 10 where the symbol has the following meaning: R1 is fluorene, a calcined group containing 1, 2, 3, 4, 5, 6, 7, or 8 atom-blocking atoms or -CaH2a-benzene It is unsubstituted or substituted with 1-3 groups selected from the group consisting of F, Cl, Br, I, CF3, fluorenyl, methoxy, hydroxyl and NR (8) R (9); 15 R (8 ) And R (9) are independently fluorene or (CVC4) alkyl; a is 0, 1 or 2; or R1 is heteroaryl, which is unsubstituted or selected from 1-3 including F, Cl , Br, I, CF3, CH3, methoxy, hydroxyl and NR (10) R (11) group substitution; 20 R (10) and R (ll) are independently fluorene or (CVC4) alkyl; b Is 0, 1 or 2; or R1 is -CdH2d- (C3-C7) -cycloalkyl; d is 0, 1 or 2; R2 and R3 are independently hydrogen, F, Cl, Br *, I, CF3 、--71-This paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm) 200306 808 Α8 Β8 C8 D8 VI. Patent application scope CN, -N〇2, CH2OR17, C0-R6 or 0-R7; R17 is hydrogen or contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms Alkyl; R6 is hydrogen, an alkane containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, 5 radical, OR30, or phenyl which is unsubstituted or is selected from 1-3 including F, Cl, Br, I, CF3, fluorenyl, fluorenyloxy, hydroxyl, and NR (31) R (32) substituents; R (31) and R (32) are independently fluorene or (CVC4) alkane R30 is hydrogen or an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R7 is hydrogen, containing 1, 2, 3, 4, 5, 6, 7, or 8 Alkyl, phenyl of carbon atoms which are unsubstituted or 1-3 selected from the group consisting of F, Cl, Br ·, I, CF3, fluorenyl, fluorenyl, hydroxyl and NR (12) R (13 ); 15 R (12) and R (13) are independently fluorene or (CVC4) alkyl; or R7 is (CrC9) -heteroaryl, which is unsubstituted or 1-3 selected Substituting from F, Cl, Br, I, CF3, CH3, methoxy, hydroxyl and NR (14) R (15); R (14) and R (15) printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy ) Are independent of each other Or ((VC4) alkyl; or 20 R2 and R3 are independently of each other alkyl groups containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, containing 3, 4, 5, 6, or 7 A carbon alkyl cycloalkyl or -CgH2g-phenyl which is unsubstituted or selected from 1-3 including F, Cl, Br, I, CF3, methyl, fluorenyloxy, hydroxyl and NR (18) Substitution of R (19); -72-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 200306808 A8 B8 C8 D8 VI. Patent application scope R (18) and R (19) each other Is independently fluorene or (CrC4) alkyl; g is 0, 1 or 2; or R2 and R3 are -CiH2r (CrC9) -heteroaryl, which is unsubstituted or selected from 1-3 including F, Cl, Br, I, CF3, CH3, methoxy-5, hydroxy and NR (20) R (21) substitution; R (20) and R (21) are independently fluorene or (C "C4) alkane 1 is 0, 1 or 2; or R2 and R3 are SOn-R22; η is 0, 1 or 2; 10 R22 is one containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms Alkyl, cycloalkyl containing 3, 4, 5, 6, or 7 carbon atoms or -CsH2s-phenyl which is unsubstituted or selected from 1-3 including F, Cl, Br, I, CF3, Fluorenyl, methoxy, And NR (34) R (35); 15 R (34) and R (35) are independently fluorene or (CrC4) alkyl; or s is 0, 1, or 2; Intellectual Property Bureau, Ministry of Economic Affairs Printed by employee consumer cooperatives R4 and R5 are independently of each other hydrogen, alkyl groups containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, fluorene, (: 1 ,; 81 :, 1, € ? 3, -0 > 1, -N〇2, SOp-R16, CO-R23 or 0-R24; 20 p is 0, 1 or 2; R16 is 1, 2, 3, 4, 5, 6, 7 Or an alkyl or phenyl group of 8 carbon atoms which is unsubstituted or 1-3 selected from the group consisting of F, C1, Bι, I, CF3, methyl, methoxy, hydroxyl and NR (26) R (27) base substitution; -73-This paper size applies the Chinese National Standard (CNS) A4 regulations (210x297 mm) 200306808 A8 B8 C8 D8 6. The scope of patent application R (26) and R (27) are independent of each other R23 Is hydrogen, containing 1, 2, or OR25; OR25 is hydrogen, containing 1, alkyl; site is fluorene or ((Vc4) alkyl; 3, 4, 5, 6, 7, or 8 carbon atoms alkane 2 Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of the Intellectual Property Bureau of the Ministry of Economy, 3, 4, 5, 6, 7, or 8 carbon atoms. R24 is hydrogen, containing K 2, 3, 4, 5, 6, 7 8 atom-blocking alkyl or phenyl groups which are unsubstituted or ㈤3 selected from the group consisting of F, Cl, Br, I, CF3, $, methyllactyl, meridian, and NR (28) R (29 ) Groups are substituted for 'R (28) and R (29) independently of each other or (Cl_C0 alkyl. 5. According to the fourth paragraph of the patent application, where at least one compound of formula II is used as a cell sodium-dependent gaseous 7 bicarbonate exchanger inhibitor, wherein the symbol has the following meaning: R (l) is hydrogen , An alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, or -CaH2a-phenyl, in which the phenyl moiety is unsubstituted or is the same or different via 1, 2, or 3 Send from including F, Cl, I, CF3, methyl, methoxy, substituted by a group of the group $ NR (8) R (9); R (8) and R (9) are independently of each other or Carbonyl containing 1, 2, 3 or 4 carbon atoms, 20 a is 0, 1 or 2; or R (l) is 1, 2, 3, 4, 5, 6, 7, 8 or 9 charcoal -CbH2b-heteroaryl of the atom, in which the heteroaryl moiety is unsubstituted or is the same or different from 1, 2 or 3 selected from the group consisting of F, Cl, Br, I, CF3, CH3, methoxy, and hydroxyl Or NR (l〇) R (ll) base substitution; ίο 15 -74 This paper size applies to China National Standard (CNS) A4 (210x297 mm) 8 8 8 AB c D Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Yi 200306808, patent application scope R (10) and R (ll) are independently hydrogen or An alkyl group of 1, 2, 3 or 4 carbon atoms; b is 0, 1 or 2; or R (l) is a -CdH2d-cycloalkyl group containing 3, 4, 5, 6 or 7 carbon atoms, 5 d is 0, 1, or 2; R (2) and R (3) are independently of each other hydrogen, tritium, € 1, 31 *, 1, € [3, -CN, -NO〗, CH2OR (17), CO -R (6) or 0-R (7); R (17) is hydrogen or an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; 10 R (6) is hydrogen , An alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, OR (30) or phenyl which is unsubstituted or is the same or different via 1, 2 or 3 and is selected from the group consisting of F, Cl, Bi *, I, CF3, methyl, fluorenyloxy, hydroxyl or NR (31) R (32) group substitution; R (31) and R (32) are independently hydrogen or contain 1, 2, 3 or 4 carbon atoms and 15-membered alkyl groups; R (30) is hydrogen or an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R (7) is hydrogen , An alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, or a benzyl group which is unsubstituted or is the same or 20 differently selected from the group consisting of F, Cl , Bι *, I, CF3, fluorenyl, fluorenyloxy, hydroxyl, or NR (12) R (13); R (12) and R (13) are independently hydrogen or contain 1 Alkyl group of 2, 3 or 4 carbon atoms; or R (7) is a hetero-75 containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms-This paper is for Chinese country Standard (CNS) A4 size (210x297 mm) 200306808 Α8 Β8 C8 D8 VI. Patent application scope aryl, which is unsubstituted or is the same or different from 1, 2 or 3 selected from the group consisting of F, Cl, Beta *, I, CF3, CH3, methoxy, hydroxyl Or NR (14) R (15) group substitution; R (14) and R (15) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; or 'R (2 ) And R (3) are independently of each other alkyl groups containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and cycloalkyl groups containing 3, 4, 5, 6, or 7 carbon atoms Or -CgH2g-phenyl, wherein the phenyl moiety is unsubstituted or is the same or different via 1, 2, or 3 selected from the group consisting of F, Cl, Br, 10 I, CF3, methyl, methoxy, hydroxy, or NR (18) R (19) group substitution; R (18) and R (19) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms;. G is 0, 1 or 2 ; Or 15 R (2) and R (3) are-heterocyclic groups containing 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, in which the heterocyclic group portion is unsubstituted Or one, two, or three identical or different selected from the group consisting of F, Cl, Br, I, CF3, CH3, methoxy, hydroxyl, or NR (2 0) a radical substitution of R (21); 20 R (20) and R (21) are each independently hydrogen or an alkyl group containing 1, 2, 3, or 4 soil atoms; 1 is 0, 1 or 2; or R (2) and R (3) are Son-R22; η is 0, 1 or 2; -76-This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200306808 Intellectual Property Bureau, Ministry of Economic Affairs Printed by employee consumer cooperatives A8 B8 C8 D8 々, patent application scope R (22) is an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, containing 3, 4, 5, 6 Or a cycloalkyl group of 7 carbon atoms or -CsH2s-phenyl which is unsubstituted or is the same or different through 1, 2 or 3 selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy , 5 hydroxyl or NR (34) R (35) substitution; R (34) and R (35) are each independently hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; s is 0, 1 or 2; R (4) is SOp-R (16); 10 p is 0, 1 or 2; R (16) is one containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms Alkyl or phenyl which is unsubstituted or is the same or different via one, two or three selected from the group consisting of F, Cl, Br, I, CF3, fluorenyl, fluorenyl, hydroxy, or NR (26) R (27 ); 15 R (26) And R (27) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms. 6. Application according to item 4 or 5 of the scope of patent application, wherein at least one compound of formula II is used as a cell sodium-dependent chloride / bicarbonate exchanger inhibitor, wherein the symbol has the following meaning: 20 R (l) is containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms alkyl groups, -CdH2cr cycloalkyl groups containing 3, 4, 5, 6, or 7 carbon atoms, d is equal to 0, 1, or 2, Or -CaH2a-phenyl, in which the phenyl moiety is unsubstituted or is the same or different through 1, 2, or 3 and is selected from the group consisting of F, C1, Br, I, CF3, fluorenyl, fluorenyl, hydroxyl, or NR (8) R (9) -77-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 200306808 Printed by A8, B8, C8, D8 of the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, and applied for the replacement of the patent scope; R (8) and R (9) are independently hydrogen or one containing 1, 2, 3, or 4 carbon atoms A) 0; 1 or 2; 5 R (2) is hydrogen, F, Cl, Bi *, I, 0-R (7) or SnR (22); R (7) is hydrogen, containing An alkyl group of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, or a phenyl group which is unsubstituted or is the same or different via 1, 2, or 3 and is selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl or NR (12) R (13) group substitution; 10 R (12) and R (13) are independently hydrogen or contain 1, 2, 3 or 4 Carbon alkyl groups; η is 0, 1 or 2; R (22) is an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, containing 3, 4, 5, 6 Or a cycloalkyl group of 7 carbon atoms or -15 CsH2s-phenyl which is unsubstituted or is the same or different through 1, 2 or 3 and is selected from the group consisting of F, Cl, Beta *, I, CF3, fluorenyl, fluorene Oxygen, hydroxyl or NR (34) R (35) substitution; R (34) and R (35) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; 20 s is 0, 1 or 2; R (3) is hydrogen, -CN CO-R (6); R (6) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms or OR (30); R (30) is hydrogen or -78 with 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms-This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 200306808 Printed by A8, B8, C8, D8 of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economics, the scope of patent application is burned; R (4) is SOP-R (16); p is 0, 1 or 2; R (16) is 1 Alkyl 5, or Phenyl of 2, 2, 3, 4, 5, 6, 7, or 8 carbon atoms which are unsubstituted or are the same or different via 1, 2, or 3 and are selected from the group consisting of F, Cl, Br, I , CF3, fluorenyl, fluorenyl, hydroxyl, or NR (26) R (27); R (26) and R (27) are independently hydrogen or contain 1, 2, 3, or 4 carbon atoms Its burning base. 10 7. Application according to claims 4 to 6 of the scope of patent application, wherein at least one compound of formula II is used as a cell sodium-dependent chloride / bicarbonate exchanger inhibitor, wherein the symbol has the following meaning: R (l) is- CaH2a-phenyl, where the phenyl moiety is unsubstituted or is the same or different from 1 or 2 selected from the group consisting of F, Cl, Br, CF3, methyl, 15 methoxy, hydroxyl, or NR (8) R ( 9); R (8) and R (9) are independently hydrogen or methyl; a is 0 or 1; R (2) is F, Cl, B ** or I, especially C1; or R (7); R (7) is an alkyl group containing 1, 2, 3 or 4 carbon atoms; 20 R (3) is CO-R (6); R (6) is hydrogen; R (4) is So2R (16), R (16) is equal to an alkyl group containing 1, 2, 3 or 4 carbon atoms. 8. Application according to claims 4 to 7 in the scope of patent application, wherein the formula II compound -79- This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200306808 A8 B8 C8 D8 6. The scope of patent application has the following definitions, based on R (l), R (2), R (3) and R (4) It has the definition according to item 4 of the scope of patent application, and the biphenyl substituent is connected as shown in formula la or Ib, preferably la Printed by the Employees ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 9. Application according to items 4 to 8 of the scope of patent application, wherein at least 10 compounds of formula II are used as inhibitors of cell sodium-dependent chloride / bicarbonate exchangers, where The symbol has the following meanings: R (l) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms or -CaH2a-phenyl, in which the phenyl moiety is unsubstituted Or substituted with 1, 2 or 3 groups which are the same or different and are selected from the group consisting of f, ci, Br, I, 15 CL, fluorenyl, methoxy, hydroxyl or NR (8) R (9); R (8) And R (9) are each independently hydrogen or an alkyl group containing 丨, 2, 3, or 4 carbon atoms; a is 0, 1 or 2; or R (l) is 1, 2, 3, 4, 5 _ CbHn-heteroaryl group of 6, 6, 7, 8 or 9 carbon atoms, wherein the heteroaryl moiety is unsubstituted or is the same or different through 1, 2 or 3 selected from the group consisting of ^ 〇, valence, l 曱Group's methoxy group, substituted with a group or a group such as hydrazone; R (10) and R (ll) are independently of each other hydrogen or contain 2, 3 or 4 carbon atoms -80- 200306808 A8 B8 C8 D8 VI. Burning group for patent application; b is 0, 1 or 2; or R (l) is -CdH2d-cycloalkyl containing 3, 4, 5, 6, or 7 carbon atoms; d is 0, 1, or 2; 5 R (2) and R (3) are independently hydrogen, ytterbium, (^ 1, 31 \ 1, 0? 3,-CN, -N02, CH2OR (17), CO -R (6) or 0-R (7), CK is an alkylene group containing 2, 3 or 4 carbon atoms) -0-R (17) or NR (50) R (51); R (17) is Hydrogen or 10 alkyl groups containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; R (6) is hydrogen, containing 1, 2, 3, 4, 5, 6, 7, or 8 Carbon atom, alkynyl, OR (30) or phenyl which is unsubstituted or is the same or different through 1, 2 or 3 and is selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, and hydroxyl Or NR (31) R (32); 15 R (31) and R (32) are each independently hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; R (30) is hydrogen Or burned bases containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R (50) and R (51) are independent of each other-(including 20 alkyl groups of 2, 3 or 4 carbon atoms:)-0-11 (52); R (52) is hydrogen or contains 1, 2, 3, 4, 5, 6, 7 or 8 A carbon atom; R (7) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, or a phenyl group which is unsubstituted or substituted by 1, 2 or 3 identical or -81-This paper size applies Chinese National Standard (CNS) A4 (210x297 mm) A8 B8 C8 D8 Printed by Employee Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 200306808 Six. The scope of patent application is different from F , Cl, B1 ·, I, CF3, methyl, fluorenyloxy, hydroxyl or NR (12) R (13) group substitution; R (12) and R (13) are independently hydrogen or contain 1, 2 , 3 or 4 carbon atoms; or 5 R (7) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is unsubstituted or Substituted by 1, 2 or 3 groups which are the same or different and are selected from the group consisting of F, Cl, Bi *, I, CF3, CH3, methoxy, hydroxyl or NR (14) R (15); R (14) and R (15) independently of each other are hydrogen or an alkyl group containing 1, 2, 3, or 4 carbon atoms; or R (2) and R (3) are independently of each other containing 1, 2, 3, 4, 5 , 6, 7, or 8 carbon atoms alkyl, cycloalkyl containing 3, 4, 5, 6, or 7 carbon atoms or -CgH2g-phenyl, where the phenyl moiety is Substituted or substituted with 1, 2 or 3 groups which are the same or different and are selected from the group consisting of F, Cl, Br, 15 I, CF3, methyl, methoxy, hydroxyl or NR (18) R (19); R ( 18) and R (19) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; g is 0, 1 or 2; or 20 R (2) and R (3) are independent of each other Is a -QHy heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, where the heteroaryl moiety is unsubstituted or is the same or different via 1, 2 or 3 It is selected from the group consisting of F, Cl, B1, I, CF3, CH3, methoxy, hydroxyl, or NR (20) R (21); -82-This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200306808 Printed by A8 B8 C8 D8 of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 6. The scope of patent applications R (20) and R (21) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; 1 is 0, 1 or 2; or R (2) and R (3) are each independently Son-R22; 5 η is 0, 1 or 2; R (22) is a group containing 1, 2, 3, 4 , 5, 6, 7, or 8 carbon atoms alkyl, cycloalkyl containing 3, 4, 5, 6, or 7 carbon atoms or -CsH2s-phenyl which are unsubstituted or substituted by 1, 2 or 3 The same or different substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, 10 hydroxyl, or NR (34) R (35); R (34) and R (35) are independent of each other Ground is hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; s is 0, 1 or 2; R (4) and R (5) are independently of each other hydrogen, containing 1, 2, 3, 4 , 5, 6, 7, 15 or 8 carbon atoms alkyl, F, Cl, Br, I, CF3, -CN, -N02, SOp-R (16), CO-R (23), 0-R ( 24) or 0- (alkylene group containing 2, 3 or 4 carbon atoms) -〇-R (33); P is 0, 1 or 2; R (16) is 1, 2, 3, 4, Alkyl 20 or phenyl of 5, 6, 7 or 8 carbon atoms which is unsubstituted or 1, 2, or 3 The same or different is selected from the group consisting of F, Cl, B *, I, CF3, fluorenyl, methoxy, hydroxyl, or NR (26) R (27); R (26) and R (27) are independent of each other Is hydrogen or an alkyl group containing 1, 2, 3, or 4 carbon atoms; or -83-This paper size applies to China National Standard (CNS) A4 (210x297 mm) 200306808 A8 B8 C8 _ D8 Patent application scope R (23) is hydrogen, alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms or OR (25); R (25) is hydrogen , An alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; 5 R (24) is hydrogen, containing 1, 2, 3, 4, 5, 6, 7, or 8 carbons Atom alkyl or phenyl which is unsubstituted or is the same or different via 1, 2, or 3 and is selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, hydroxyl, or NR (28) R (29) group substitution; R (28) and R (29) are independently of each other hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; R (33) is hydrogen or 1, 2 Alkyl groups of 3, 4, 5, 6, 7, or 8 carbon atoms, with the limitation that at least one of the R (2) or R (3) groups is 0- (containing 2, 3 or 4 carbon atoms (Alkylene) -0-R (17) or NR (50) R (51). 15 1〇 · According to the application of the scope of application for patents Nos. 4 to 9 in which 4'- Intellectual Property Bureau of the Ministry of Economic Affairs employee consumer cooperatives printed clothing [5_ 甲 醯 基 -4- (2-methoxyethoxy ) -2-phenyl-1-imidazolylmethyl l 3'-fluorenylsulfonylbiphenyl-2-sulfonylaminonitrile or 4 '-{[benzyl (thiophene-2-sulfonyl) amine Methyl] fluorenyl} -3'-fluorenylsulfenylbiphenyl-2-sulfonamidonitrile as a cell sodium-dependent chloride / bicarbonate exchanger inhibitor. 20 11. Application according to item 1 of the scope of patent application, wherein at least one is used III 〇84-Compound of formula III This paper is in accordance with Chinese National Standard (CNS) A4 (210x297 mm). 200306808 VI. Application for patents 10 15 Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs Consumer Cooperatives 20 A8 B8 C8 D8 and / Or all stereoisomeric forms of the compound of formula III and / or the physiological tolerance of these compounds in any proportion and / or the compound of formula m " accepting salts as cell sodium-dependent chloride / bicarbonate exchangers Inhibitors, where the symbols have the following meanings: R⑴ is 1. an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; 2. containing 1, 2, 3, 4, 5, 6 , Alkyl groups of 7 or 8 carbon atoms, in which one to all of the hydrogen atoms are replaced by fluorine; 3. alkenyl groups of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms ;or 4. -CnH2n-nn-Y nn is 0 or 2; and η is 0, 1, 2, 3, or 4, where when the dish is 2, η is not 0 or 1; 5. ~ CnH2n.nn " Y nn Is 0 or 2; and η 疋 1, 2, 3, or 4, wherein when Yang is 2, η is not wherein 1, 2, or 3 hydrogen atoms in the divalent group -CnH2n_nn- are independently substituted with : 1. An aryl group containing 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms, preferably a phenyl group, a 1-naphthyl group, or a 2-naphthyl group; 2. an amino group; 3. NR (22) R (23); -85-This paper size is applicable to China National Standard (CNS) A4 (210x297) 200306808 6. Scope of patent application 104. Burning base; 5.C00R (16); 6. Alkyl group containing 1, 2, 3 or 4 carbon atoms; WCVCu) -aryl- (CVC + burning base, compared with Preferably it is phenylethenyl; R (2) is 1. hydrogen; 2. an alkyl group containing 1, 2, 3, 4, 5, 0, 7 or 8 carbon atoms; 3. containing 1, 2, 3 Alkyl groups of 4, 5, 6, 7, or 8 carbon atoms in which one to all of the hydrogen atoms are substituted with fluorine; 4. containing 2, 3, 4, 5, 6, 7, 8, 9, 10, n, or Alkenyl group with 12 carbon atoms; 5. Alkynyl group with 2, 3, 4, 5, 6, 7, or 8 carbon atoms; 15 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 20 6 · -CnH2n_nn-Z nn is 0 or 2; and η is 0, 1, 2, 3, or 4, where q is 0 or 1 when addition is 2; 7. -CnH2n-nn-Z nn is 0 or 2; and 11 疋 1, 2, 3, or 4, where 不是 is not 1, ^ is not 1; wherein u 2 or 3 chlorine atoms in the divalent group -CnH2n_nn- are independently substituted with each other by the following groups ... Contains 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon sources -86 This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm 200306808 A8 B8 C8 D8 Six, The aryl group in the scope of the patent application is preferably phenyl, 1-naphthyl or 2-naphthyl; 2. Amino group; 3. NR (22) R (23); Alkyl ester group; 5. COOR (16); 6. Alkyl groups containing 1, 2, 3 or 4 carbon atoms; R (3) and R (4) are independently of each other hydrogen or containing 1, 2, 3, 4, 5, Alkyl groups of 6, 7, or 8 carbon atoms; R (5), R (6), and R (7) are independently of each other hydrogen, containing 1, 2, 3, 4, 10 5, 6, 7, or 8 Carbon atom group, F, Cl, Br, I, CF3, -CN, -N02, SOq-R (8), C0-R (21) or 0-R (10); R (8) contains 1 Alkyl, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, NR (11) R (12) or phenyl are unsubstituted or are selected by the same or different Substituting from groups including F, Cl, Br, I, CF3, fluorenyl, methoxy, hydroxyl, or NR (11) R (12); R (9) and R (21) are independently hydrogen and contain 1 Alkyl or OR (13) of 2, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; printed clothing R (10) of the consumer cooperative of employees of the Intellectual Property Bureau of the Ministry of Economic Affairs is hydrogen, and if necessary (C1 -C4) -alkyl substituted with alkoxy, containing 1 2 20 3, 4, 5, 6, 7, or 8 carbon atoms; or phenyl which is unsubstituted or is the same or different by 1, 2 or 3 Selected from the group consisting of jp Cl, Br, I, CF3, methyl, fluorenyl, substituted with a group or a group of NR (11) R (12); R (ll) R (12), R (19) and R (20) independently of one another are hydrogen, containing u -87 - This applies China National Standard Paper Scale (CNS) A4 size (210x297 mm) 200306808 A8 B8 Alkyl or (C "c4) -alkylfluorenyl groups of 2, 3 or 4 carbon atoms, preferably ethenyl groups; R (13) fluorinated hydrogen or containing !, 2, 3, 4, 5, 6, 7 Or an alkyl group of 8 carbon atoms; X is a few groups, -CO-NH, -CO-CO-, or sulfonyl; Y and Z are independently of each other h containing 6, 7, 8, 9, 10, 11, An aryl group of 12, 13 or 14 carbon atoms, preferably a phenyl group, a 1-naphthyl group or a 2-naphthyl group; 2. A group according to the definition of 1, which is the same as 丨, 2, 3, * or 5 Or differently selected from the group consisting of an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, an alkyl group containing 6, 7, 8, 9, 10, 11, U, 13 or 14 carbon atoms Aryl is more preferably phenyl, 1β naphthyl or 2-naphthyl, f, ci, Br, I, CF3, soqR (18), oR (i6), NR (19) R (20),- CN, N02 or CO-R (9) group substitution, or two of them together to form a fused heterocyclic group, more preferably methylenedioxy; 3. containing 1, 2, 3, 4, 5, Heteroaryl groups of 6, 7, 8 or 9 carbon atoms; printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 4. A base defined according to 3, which is the same or different from 丨, 2 or 3 and is selected from the group consisting of F, Cl, Br, I, CF3, CH3, methoxy Group, hydroxy or NR (11) R (12) substitution; 5. Cycloalkyl containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably cyclopropyl, cyclo Amyl, cyclohexyl, ^ 2,3,4-tetrahydronaphthyl or hydroindenyl; This paper size applies to China National Standard (CNS) A4 specifications (210x297 public love) 200306808 A8 B8 C8 D8 6. Application for patent scope 6 · A base as defined by 5, which is preferably an aryl group containing 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms, which is preferably a phenyl, 1-naphthyl or 2-naphthyl group. Group substitution; 7.〇-R (14); 5 8.0-R (17); 9.-S02-R (14); i. · Arylalkylfluorenyl, preferably phenyl-CH2-CO-; Or 11 · heterocyclyl; R (14) and R (l7) are independently 10 1 · hydrogen; 2 · alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; 3. Dilute group containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; 4.-CnH2n_nn-phenylnn is 0 or 2; and 'n is " ^, 2, 3 or 4, where ηη is 2, η is not 1; clothing printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Bases as defined in 4, where the phenyl moiety is 1, 2, or 3 20 The same or different is selected from the group consisting of alkyl groups containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, F, Cl, Br, I, CF3, SoqR (15), OR (16) , NR (11) R (12), -CN, No2 or C0-R (9); or R (15) and R (18) are independently 1, 2, 3 or 4 -89 of carbon atom-This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 200306808 A8 B8 C8 -------- D8 VI. Patent application scope Alkyl, including U 2, 3 Or one of the four carbon atoms, the hydrogen atom of the food part is replaced by fluorine, preferably cf3, or NR (11) R (12); R (16) is 1. hydrogen; 5 2 · containing 丨, 2 , 3 or 4 carbon atoms alkyl; 3_ (Cl-C4) -alkoxy substituted alkyl groups containing 丨, 2, 3 or 4 broken atoms; 4 · S !, 2, 3 or 4 A carbon atom of which the _ to the hydrogen atom of the food portion is replaced by fluorine, preferably cF3; 10 5 · aryl containing 6, 7, 8, 9, 10, 屮 12, 13, or 14 broken atoms is more suitable Is a phenyl group, a naphthyl group or a 2-naphthyl group; 6. A group according to the definition of 5, which is the same as or different from τ, 2 or 3 and is selected from the group including F, Cl, Br, I, CF3, NR 19) of R (20), -CN, N02 15 R (22) and R (23) are each independently nitrogen or c0_r (24); R (24) is hydrogen, containing 1, 2, 3, 4, 5, 6, 7, or An alkyl group of 8 carbon atoms or -CnH2n-phenyl, η is equal to 1, 2, 3 or 4; q is independently 0, 1 or 2 each other. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 12. According to the application of the scope of patent application No. 1, which uses at least 20 compounds of formula IV This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 200306808 A8 B8 C8 D8_ VI. Patent application scope and / or all stereoisomeric forms of the compound of formula IV and / or these forms in any The mixture of the ratios and / or physiologically tolerable salts of the compound of formula IV is used as a cell sodium-dependent chloride / bicarbonate exchanger inhibitor, wherein the symbol has the following meaning: 5 R (l) is hydrogen, containing 1, 2 , 3, 4, 5, 6, 7, or 8 carbon atoms alkyl, 1-naphthyl, 2-naphthyl, -CaH2a-cycloalkyl containing 3, 4, 5, 6, or 7 carbon atoms or -CaH2a-phenyl, wherein the phenyl moiety is unsubstituted or 1-3 selected from the group consisting of alkyl, F, Cl containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms , Beta, I, CF3, 10 SOnR (ll), OR (17), NR (8) R (9), -CN, No2, or CO-R (22); R (ll) is Alkyl or NR (20) R (21) containing 1, 2, 3 or 4 carbon atoms; R (20) and R (21) are independently hydrogen or contain 1, 2, 3 or 4 carbon atoms 15 subunits; R (17) is hydrogen or an alkyl group containing 1, 2, 3, or 4 carbon atoms; R (8) and R (9) are independently hydrogen Alkyl groups containing 1, 2, 3, or 4 carbon atoms; printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R (22) is hydrogen, containing 1, 2, 3, 4, 5, 6, 7, or 8 carbons Atomic 20 alkyl or OR (30); R (30) is hydrogen, an alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; a is 0, 1 or 2; η Yes 0, 1 or 2; or -91-This paper size applies to Chinese National Standard (CNS) A4 (210x297 mm) 200306808 8 8 8 8 AB c D Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Patent scope R (l) and R (3) —from which the carbon atom is a cycloalkyl or fluorenyl group containing 3, 4, 5, 6, or 7 carbon atoms; R (2), R (3) , R (4) and R (5) are independently of each other hydrogen, F, CF3, 0-R (10), a 5 alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms , A cycloalkyl group containing 3, 4, 5, 6, or 7 carbon atoms, -CgH2g-phenyl, in which the phenyl moiety is unsubstituted or selected from 1-3, including F, Cl, Bι *, I, CF3, fluorenyl, fluorenyl, hydroxy, or NR (18) R (19) substituents; R (18) and R (19) are independently hydrogen or contain 1, 2, 3, or 4 carbons Base of the original 10 seeds; g 〇, 1 or 2; R (10) is hydrogen, an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and a phenyl group which is unsubstituted or having 1-3 Selected from the group consisting of F, Cl, B *, I, CF3, fluorenyl, fluorenyl, hydroxy, or 15 NR (12) R (13); R (12) and R (13) are independently hydrogen Or an alkyl group containing 1, 2, 3, or 4 carbon atoms; or R (10) is a heteroaryl group containing 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms, which Is unsubstituted or substituted with 1-3 groups selected from the group consisting of F, C1, 20 Br, I, CF3, fluorenyl, fluorenyloxy, hydroxyl, or NR (14) R (15); R (14) and R (15) is independently of each other hydrogen or an alkyl group containing 1, 2, 3, or 4 carbon atoms; or R (2) and R (4) —the second bond between the carbon atom and the group R (3) and -92-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 200306808 A8 B8 C8 D8 VI. Patent application scope R (5), where R (l), R (3) and R (5) are the same as the above definitions; R (6) and R (7) are independently hydrogen , 卩, 0: 1, 61 \ 1, 〇3, -CN, -N〇2, SOP-R (16), CO-R (23) or 0-R (24); R (23) is hydrogen , A 5 alkyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms or OR (25); R (25) is hydrogen, containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R (24) is hydrogen, an alkyl or phenyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. It is unsubstituted or substituted by 1 -3 substituents selected from the group consisting of F, 10 Cl, B *, I, CF3, fluorenyl, fluorenyloxy, hydroxyl, or NR (28) R (29); R (28) and R (29) are Η Or an alkyl group containing 1, 2, 3, or 4 carbon atoms; R (16) is an alkyl group, phenyl group containing 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; Substituted or substituted with 1-3 groups selected from the group consisting of F, 15 Cl, Bi, I, CF3, fluorenyl, methoxy, hydroxyl, or NR (26) R (27); R (26) and R ( 27) is fluorene or an alkyl group containing 1, 2, 3 or 4 carbon atoms; P is 0, 1 or 2. Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs for consumer cooperation and social printing 13. According to the application of the scope of patent application No. 12, which uses at least 20 compounds of formula IV, where the symbols have the following meanings: R (l) is fluorenyl, ethyl , 1-naphthyl, 2-naphthyl, cycloalkyl or phenyl containing 3, 4, 5, 6, or 7 carbon atoms which are unsubstituted or selected from 1 including 1, 2, 3, or 4 carbon atoms alkyl, F, Cl, CF3, SO2R (11), OR (17), NR (8) R (9) or CO-93-This standard applies to Chinese national standards (CNS ) A4 specification (210 x 297 mm) 200306808 A8 B8 C8 D8 VI. Patent application scope ~ R (22) substitution of substituents; R (n) is methyl or dimethylamino; R (17) is hydrogen, Fluorenyl or ethyl; R (8) and R (9) are each independently hydrogen, methyl or ethyl; 5 R (22) is hydrogen or an alkyl group containing 1, 2, 3 or 4 carbon atoms; Or R (l) and R (3) —from which the carbon atom is a cycloalkyl or alkoxy group containing 3, 4, 5, 6, or 7 carbon atoms; R (2) and R (4) are Hydrogen; or the second bond between R (2) and R (4) and the carbon atom bears the groups R (3) and 10 R (5); R (3) and R (5) are independent of each other Hydrogen, CF3, OR (IO), an alkyl or phenyl group containing 1, 2, 3 or 4 carbon atoms which are unsubstituted or substituted by 1 selected from the group consisting of F, Cl, CF3, methyl, and methoxy , Hydroxy or NR (18) R (19) substituents; 15 R (18) and R (19) are each independently hydrogen, methyl or ethyl; R (l0) is hydrogen and contains 1,2 Alkyl or phenyl of 3, 4 or 4 carbon atoms which are unsubstituted or substituted by a group selected from the group consisting of F, Cl, CF3, methyl, methoxy, hydroxyl or NR (12) R (13) Replaced by; printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R (12) and R (13) are independently hydrogen, methyl or ethyl; or 20 R (10) contains 1,2,3,4,5 A heteroaryl group of 6, 6, 8, 8 or 9 carbon atoms which is unsubstituted or substituted with a substituent selected from the group consisting of F, C1, CF3, CH3, methoxy, hydroxyl or dimethylamino ; R (6) and R (7) are independently of each other hydrogen, F, Cl, CF3, S〇2-CH3, -94-This paper size is applicable to China National Standard (CNS) A4 (210x297 mm) 200306808 Αδ Β8 C8 D8 VI. Application scope of patents C0-R (23) or 0-R (24); R (23) is hydrogen or contains 1, 2, 3 or 4 carbon atoms An alkyl group; R (24) is hydrogen, an alkyl group containing 1, 2, 3 or 4 carbon atoms or a phenyl group which is unsubstituted or is selected from the group consisting of F, Cl, CF3, methyl, 5 Substituted by methoxy, hydroxy or NR (28) R (29); R (28) and R (29) are hydrogen, amidino or ethyl. 14. Application according to claims 1 to 13 in which the compounds of formulae I, II, III and IV are combined with sodium / rhenium exchanger inhibitors to manufacture pharmaceuticals for prevention and treatment by increasing the amount of von Willebrand factor in the blood and / 10 Or increase acute or chronic conditions caused by P-selectin expression. 15. Application according to item 14 of the patent application, in which a compound selected from the following is used 15 -N .NH2 Ύ ΝΗ0 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 2 Η This paper size applies to China National Standard (CNS) A4 (210x297 mm) 〇 NH, Or the Intellectual Property Office of the Ministry of Economic Affairs 20 and / or all stereoisomeric forms of the above compounds and / or mixtures of these forms in any ratio and / or physiologically tolerable salts of the above compounds as sodium / nitrogen exchanger inhibitors. This paper size applies to China National Standard (CNS) A4 specification (21〇X 297 public love), which combines the formula ί, Π, 200306808 Α8 Β8 C8 D8 VI. Patent application scope III and / or IV compounds and card force Wave (cariporide) 17. Application according to claims η to a in the scope of patent application, wherein 4'_〇 曱 醯 phenyl-4- (2-methoxyethoxy) -2-phenyl + imidazolylmethyl] -3 is used in combination -Methocarbamyl biphenyl-2-Luteinate amine wax and Kalibo. 10 18. Application according to one or more of items 1 to 17 of the scope of the patent application, wherein the disorder is a thrombotic disorder caused by an ischemic state and subsequent reperfusion, such as a thrombus in an acute myocardial, bowel or cerebral infarction; during or during surgery Subsequent thrombotic disorders; pulmonary edema; deep venous thrombosis that occurs at an increased rate after long-term obstruction of blood flow, especially in lower limbs, such as 15 during prolonged lying or sitting, and during ischemia and subsequent reperfusion 2. Inflammatory disorders that occur during vasculitis such as those associated with spontaneous immune disease or connective tissue disease, or initial inflammatory reactions, prevention and treatment of atherosclerosis, Intellectual Property Bureau of the Ministry of Economic Affairs, employee consumer cooperative printing disease, prevention and treatment of cancer or joint treatment Inflammation and joint disorders such as rheumatoid arthritis. 20 I9. Application according to one or more of items 1 to 16 of the scope of the patent application, in which the compounds and anticoagulants, platelet inhibitors of aggregation or fibrinolytic agents mentioned in the scope of the application of the scope of patents 1 to 16 are used in combination. 20. The application according to item 19 of the scope of the patent application, wherein the additional agent is selected from factor Xa inhibitors, standard heparin, and low molecular weight heparin, such as Yi-97-This paper applies Chinese National Standard (CNS) A ^^ ~ ' 200306808 A8 B8 C8 _D8_ VI. Scope of patent application Enoxaparin, dalteparin, certroparin, parnaparin or tinzaparin, direct thrombus inhibitors such as leech Serotonin, aspirin, fibrinogen receptor antagonist, streptococcal kinase, urokinase and / or group 5 plasminogen activator. 21. Application according to one or more of items 1 to 16 of the scope of the patent application, wherein the medicament is administered orally, inhaled, rectally or percutaneously or subcutaneously, intra-articularly, intraperitoneally or intravenously. Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 8 9 This paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) 200306808 (I). The designated representative of this case is: Figure (None) (II) 2. Brief description of the representative symbols of the components in this representative diagram: If there is a chemical formula in this case, please disclose the chemical formula that can best show the features of the invention: Yi O ', page 2-1