EP1476154A2 - Verwendung von inhibitoren des natrium-abhängigen chlorid-bicarbonat-austauschers zur behandlung von thrombotischen und inflammatorischer erkrankungen - Google Patents

Verwendung von inhibitoren des natrium-abhängigen chlorid-bicarbonat-austauschers zur behandlung von thrombotischen und inflammatorischer erkrankungen

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Publication number
EP1476154A2
EP1476154A2 EP03706428A EP03706428A EP1476154A2 EP 1476154 A2 EP1476154 A2 EP 1476154A2 EP 03706428 A EP03706428 A EP 03706428A EP 03706428 A EP03706428 A EP 03706428A EP 1476154 A2 EP1476154 A2 EP 1476154A2
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EP
European Patent Office
Prior art keywords
carbon atoms
alkyl
hydrogen
phenyl
substituted
Prior art date
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EP03706428A
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German (de)
English (en)
French (fr)
Inventor
Hans-Jochen Lang
Heinz-Werner Kleemann
Stefan Werner Schneider
Hans Oberleithner
André NIEMEYER
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Sanofi Aventis Deutschland GmbH
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Aventis Pharma Deutschland GmbH
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Publication of EP1476154A2 publication Critical patent/EP1476154A2/de
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the use of inhibitors of the sodium-dependent chloride-bicarbonate exchanger in human and veterinary medicine for the prevention and treatment of acute or chronic diseases caused by increased blood levels of von Willebrand factor.
  • the inhibitors can therefore be used to treat thrombotic and inflammatory diseases.
  • NCBE cellular sodium-dependent chloride-bicarbonate exchanger
  • NCBE inhibitors can be used Their potential protective effects against pathological hypoxic and ischemic situations can be used for the treatment of all acute or chronic damage caused by ischemia or diseases primarily or secondarily induced.Tissue protection for organ transplants, kidney failure, protection against ischemically induced damage to the central nervous system are further potential indications , Treatment of shock, proliferation-induced diseases including cancer, fibrotic diseases, organ hypertrophies and hyperplasias, respiratory disruption, etc. can.
  • the use of the NCBE inhibitors for the treatment of thromboses described in the prior art relates exclusively to the protective effect of the NCBE inhibitors against the destruction of the tissue affected by the ischemia and in no way to the prevention of thrombus formation per se.
  • the effective mechanism of action of the NCBE inhibitors in acute ischemia is that they reduce the increased sodium ion influx which arises in acutely deficient tissue through activation of the sodium / hydrogen exchanger (NHE) as a result of intracellular acidification. This will delay the situation of tissue sodium overload. Since sodium and calcium ion transport are coupled in the heart tissue, the life-threatening calcium overload of the heart cells is prevented.
  • the blocking of the bicarbonate influx prevents or retards the re-alkalinization of the cell interior under NCBE inhibitors.
  • the prior art describes numerous classes of substances which intervene in the interaction of the coagulation factors and thus bring the coagulation cascade to a standstill. Numerous active principles have also been developed which do not suppress thrombus formation, but rather cause the dissolution (lysis) of thrombi which have already formed. Some of these principles of action, which intervene at various switching points in the cascade mentioned, were introduced into therapy for preventing thrombogenesis, such as derivatives of the vitamin K group (phylloquinones), factor VIII and factor IX preparations, platelet aggregation inhibitors such as acetylsalicylic acid, dipyridamole and ticlopidine, Anticoagulants such as heparins or heparinoids.
  • the blood coagulation cascade can be mechanistically divided into two paths, as shown in the diagram below.
  • vWF von Willebrand factor
  • the compounds used according to the invention inhibit the release of the von Willebrand factor from the endothelial cells.
  • the compounds according to the invention inhibit the massive pH-dependent release of the vWF accumulated in ischemia.
  • the transmembrane protein P-selectin is also stored in the Weibel-Palade bodies (Wagner, DD 1993, Thromb. Haemost, 70: 105-110).
  • the P-selectin sits in the vesicle membrane and is built into the plasma membrane of the endothelial cell after vesicle fusion (exocytosis). Every Weibel-Palade body exocytosis thus not only leads to an increased release of vWF, but also to an increased P-selectin expression in the Endothelial cell membrane.
  • the vWF secretion (quantitative measurement by means of ELISA) is shown under acidosis, as well as during a subsequent reperfusion. At the same time, these quantitative measurements are supported by immunofluorescence data from the Weibel-Palade bodies.
  • the measured vWF is not only a marker for increased (increase in vWF secretion) or decreased (decrease in vWF secretion) tendency to thrombosis (via the increase in aggregation of the platelets), but also a direct marker for an increased or decreased P-selectin expression in the endothelial cell membrane.
  • P-selectin serves as an anchor for leukocytes and thus the initial inflammatory reaction (Vestweber, D., Blanks, JE 1999, Physiol. Rev., 79: 181-213; Issekutz, AC, Issekutz, TB 2002, J. Immunol., 168 : 1934 to 1939).
  • the 'pathophysiological significance is varied and has for ischemia / Reperfusionsrawen, thrombosis and atherosclerosis (Mass Berg, S., et al, 1998, Blood, 92: 507-515; Kita, T., et ah, 2001, Ann NY Acad.. Be., 947: 199-205).
  • P-selectin As an inflammation marker and initiator of inflammation, it plays an essential role in the process of cancer spreading (Varki, A., Varki, NM 2001, Braz. J. Med. Biol. Res. 34: 711-717) , as well as during different joint inflammations (arthritis) (Veihelmann, A. et al, 1999, Microcirculation, 6: 281-290; Mclnnes, IB, et al., 2001, J. Immunol., 167: 4075-4082).
  • the mode of action of the substances described here can thus also be used as a therapeutic agent for all of the above-mentioned P-selectin-associated diseases.
  • the invention therefore relates to the use of inhibitors of the cellular sodium-dependent chloride-bicarbonate exchanger for the production of medicaments for the prophylaxis and therapy of acute or chronic diseases which are caused by increased blood levels of the von Willebrand factor and / or increased expression of the P-selectin. caused.
  • the invention further relates to the use of compounds of the formula
  • R (1) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or -C a H 2a -phenyl, where the phenyl part is unsubstituted or substituted and has 1, 2 or 3 identical or different radicals from the series F, Cl, Br, I, CF3,
  • R (21) and R (22) independently of one another.
  • R (23) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
  • R (24) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, OR (26) or phenyl; where phenyl is unsubstituted or substituted with 1, 2 or 3 identical or different radicals from the group F, Cl, Br, I, CF3, methyl, methoxy, hydroxy or NR (27) R (28);
  • R (26) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • R (25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or
  • phenyl where phenyl is unsubstituted or substituted with 1, 2 or 3 identical or different radicals from the series F, Cl, Br, I, CF3, methyl, methoxy, hydroxy or NR (29) R (30); , R (29) and R (30) independently of one another
  • R (33) and R (34) independently of one another
  • heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, the heteroaryl part being unsubstituted or substituted by 1, 2 or 3 identical or different radicals from the F series , Cl, Br, I, CF3,
  • R (37) alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl with 3, 4, 5,
  • CO-R (52); i zero, 1 or 2;
  • R (48) alkyl with 1, 2, 3 or 4 carbon atoms or NR (53) R (54);
  • R (49) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; R (50) and R (51) independently of one another
  • R (52) is hydrogen, alkyl having 1, 2,3,4,5,6,7 or 8 carbon atoms or OR (55);
  • R (55) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or R (4) and R (6) together with the carbon atom bearing them, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or fluorenyl;
  • Phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or different radicals from the series F, Cl, Br, I, CF3, Methyl, methoxy, hydroxy or NR (59) R (60); R (59) and R (60) independently of one another
  • R (61) and R (62) independently of one another
  • R (5) and R (7) together form a second bond between the carbon atoms bearing the radicals R (6) and R (8), where R (4), R (6) and R (8) are as defined above ;
  • R (9) alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alkenyl with 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or -C
  • II zero or 2; and I zero, 1, 2, 3 or 4; where I is not zero or 1 when II is 2;
  • ⁇ m ⁇ 2m-mm B, mm zero or 2; and m zero, 1, 2, 3 or 4; where m is non-zero or 1 when mm is 2;
  • aryl having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;
  • radical as defined under 1. which is composed of 1, 2 or 3 identical or different radicals from the alkyl series having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br , I, CF 3 , SO n R (63), OR (64), NR (65) R (66), -CN, - NO 2 or CO-R (67);
  • n zero, 1 or 2;
  • R (70) and R (71) independently of one another
  • alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • R (80) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
  • R (84) is hydrogen or alkyl of 1, 2, 3, 4, 5, 6, 7 or 8
  • R (81) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or different radicals from the F series, Cl, Br, I,
  • Y is a covalent bond, CR (16) R (17), CO, S, SO 2 , O or NR (18), R (16) is hydrogen or -OR (85);
  • R (85) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or.
  • R (17) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
  • R (18) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, CO-R (87) or SO 2 R (88);
  • the invention further relates to the use of compounds of the formula I for the manufacture of a medicament for the prophylaxis and therapy of acute or chronic diseases which are caused by increased blood levels of the von Willebrand factor and / or increased expression of the P-selectin, in which:
  • R (1) alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which is unsubstituted or substituted by a radical from the series F, Cl, CF3, methyl or methoxy;
  • R (24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, OR (26) or
  • Phenyl which is unsubstituted or substituted by a radical from the series F, Cl, CF3, methyl or methoxy;
  • R (26) is hydrogen, methyl or ethyl;
  • R (25) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms, phenyl which is unsubstituted or substituted by a radical from the series
  • Phenyl which is unsubstituted or substituted by a radical from the series F, Cl, CF3, methyl or methoxy; or
  • Heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is unsubstituted or substituted with a radical from the series F, Cl, CF3, CH3 or methoxy; or
  • R (37) alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which is unsubstituted or substituted by a radical from the series F, Cl, CF3, methyl or methoxy; f zero or 2;
  • R (13), R (14) and R (15) independently of one another are hydrogen, methyl, F, Cl, CF 3 , -CN, SO 2 -R (79), CO-R (80) or OR (81); R (79) and R (81) independently of one another
  • R (80) is hydrogen, methyl or OR (84);
  • R (84) is hydrogen or alkyl with 1, 2, 3, or 4
  • ⁇ is a covalent bond or methylene.
  • the invention further relates to the use of compounds of the formula II
  • R (1) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -C a H 2a phenyl, where phenyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, hydroxy and NR (8) R (9); R (8) and R (9) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; a zero, 1 or 2; or
  • R (10) and R (11) independently of one another are hydrogen or alkyl having 1, 2,
  • R (2) and R (3) independently of one another are hydrogen, F, Cl, Br, I, CF 3 , -CN, -NO 2 ,
  • R (17) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, R (50) and R (51) independently of one another - (alkylene having 2, 3 or 4 carbon atoms - atoms) -OR (52);
  • R (52) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • R (6) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, OR (30) or phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, hydroxy and NR (31) R (32);
  • R (31) and R (32) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
  • R30 is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • R (7) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, phenyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, hydroxy and NR (12) R (13); ,
  • R (12) and R (13) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R (7) heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, where heteroaryl is unsubstituted or substituted with 1 - 3 substituents selected from the group consisting of F, Cl, Br , I, CF3, CH3, methoxy, hydroxy and NR (14) R (15);
  • R (14) and R (15) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or
  • R (2) and R (3) independently of one another are alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or -CgH2g- Phenyl, in which phenyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, hydroxy and NR (18) R (19);
  • R (18) and R (19) independently of one another are hydrogen or alkyl having 1, 2,
  • Heteroaryl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, CF3, methyl, methoxy, hydroxy and NR (20) R (21);
  • R (20) and R (21) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; I zero, 1 or 2; or
  • R (34) and R (35) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; s zero, 1 or 2;
  • R (90) and R (91) independently of one another are hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or
  • the invention further relates to the use of compounds of formula II for the manufacture of a medicament for the prophylaxis and therapy of acute or chronic diseases caused by increased blood levels of the von Willebrand factor and / or increased expression of the P-selectin, in which the symbols have the following meanings:
  • R (1) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -C a H 2a phenyl, the phenyl part being unsubstituted or substituted by 1, 2 or 3 identical or various residues from the series F, Cl, Br, I, CF3, methyl, methoxy,
  • R (8) and R (9) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; a zero, 1 or 2; or
  • Heteroaryl part is unsubstituted or substituted with 1, 2 or 3 identical or different radicals from the series F, Cl, Br, I, CF3, methyl, methoxy,
  • R (10) and R (11) independently of one another are hydrogen or alkyl having 1, 2,
  • R (2) and R (3) independently of one another hydrogen, F, Cl, Br, I, CF 3 , -CN, -NO 2l CH 2 OR (17), CO-R (6) or OR (7);
  • R (17) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • R (6) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, OR (30) or phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or different radicals the series F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy or NR (31) R (32);
  • R (31) and R (32) independently of one another are hydrogen or alkyl having 1, 2,
  • R (30) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • R (7) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or different radicals from the F series, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy or NR (12) R (13);
  • R (12) and R (13) independently of one another hydrogen or alkyl having 1, 2,. 3 or 4 carbon atoms; or
  • R (14) and R (15) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or
  • R (2) and R (3) independently of one another alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or -C q H2 q -phenyl, the
  • Phenyl part is unsubstituted or substituted with 1, 2 or 3 identical or different radicals from the series F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy or NR (18) R (.19);
  • R (18) and R (19) independently of one another are hydrogen or alkyl with 1, 2 ,.
  • R (2) and R (3) independently of one another —C
  • R (20) and R (21) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
  • R (2) and R (3) independently of one another SO n -R (22); n zero, 1 or 2; R (22) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or -C 3 H2s-phenyl which is unsubstituted or is substituted with 1, 2 or 3 identical or different radicals from the series F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy or
  • R (26) and R (27) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms.
  • the invention further relates to the use of compounds of formula II for the manufacture of a medicament for the prophylaxis and therapy of acute or chronic diseases which are caused by increased blood levels of the von Willebrand factor and / or increased expression of the P-selectin in which the symbols have the following meanings:
  • R (2) is hydrogen, F, Cl, Br, I, OR (7) or SO n -R (22);
  • R (7) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or different radicals from the F series, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy or NR (12) R (13);
  • R (12) and R (13) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; n zero, 1 or 2;
  • R (22) alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms or -C S H2 S phenyl which is unsubstituted or is substituted with 1, 2 or 3 identical or different radicals from the series F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy or NR (34) R (35);
  • R (3) is hydrogen, -CN, or CO-R (6);
  • R (6) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
  • R (30) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • R (91) hydrogen, R (90) SO p -R (16), p zero, 1 or 2;
  • the invention further relates to the use of compounds of formula II for the manufacture of a medicament for the prophylaxis and therapy of acute or chronic diseases which are caused by increased blood levels of the von Willebrand factor and / or increased expression of the P-selectin in which the symbols have the following meanings:
  • R (8) and R (9) independently of one another are hydrogen or methyl; a zero or 1;
  • R (7) alkyl having 1, 2, 3 or 4 carbon atoms
  • R (6) and R (91) are hydrogen; R (90) SO 2 R (16) with R (16) equal to alkyl having 1, 2, 3 or 4 carbon atoms.
  • the invention further relates to the above-mentioned use of the compounds of
  • R (1), R (2), R (3) and R (90) are as defined above.
  • the invention further relates to the use of compounds of the formula II and / or all stereoisomeric forms of the compounds of the formula II and / or mixtures of these forms in any ratio, and / or the physiologically tolerable salts of the compounds of the formula II for the preparation of a medicament for prophylaxis and therapy of acute or chronic diseases caused by increased blood levels of the von Willebrand factor and / or increased expression of the P-selectin, in which the symbols have the following meanings:
  • R (1) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -C a H2 a -phenyl, the phenyl part being unsubstituted or substituted by 1, 2 or 3 identical or various residues from the series F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy or NR (8) R (9);
  • R (8) and R (9) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; a zero, 1 or 2; or
  • Heteroaryl part is unsubstituted or substituted with 1, 2 or 3 identical or different radicals from the series F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy or NR (10) R (11); R (10) and R (11) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; b zero, 1 or 2; or R (1) -CdH2d cycloalkyl having 3, 4, 5, 6 or 7 C atoms; d zero, 1 or 2; R (2) and R (3) independently of one another are hydrogen, F, Cl, Br, I, CF 3 , -CN, -NO 2 ,
  • R (17) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • R (6) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, OR (30) or
  • Phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or different radicals from the series F, Cl, Br, I, CF 3 , methyl,
  • R (31) and R (32) independently of one another
  • R (30) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • R (50) and R (51) independently of one another - (alkylene with 2, 3, or 4 C-
  • R (52) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • R (7) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or different radicals from the F series, Cl, Br, I, CF 3 , methyl, methoxy,
  • R (12) and R (13) independently of one another are hydrogen or alkyl having 1, 2,
  • R (14) and R (15) independently of one another are hydrogen or alkyl having 1, 2,
  • R (2) and R (3) independently of one another are alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or -C 8 H 2g -phenyl, the phenyl part being unsubstituted or substituted by 1, 2 or 3 identical or different radicals from the series F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy or NR (18) R (19) ;
  • R (18) and R (19) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; g zero, 1 or 2; or R (2) and R (3) independently of one another C
  • R (20) and R (21) independently of one another are hydrogen or alkyl having 1, 2,
  • R (2) and R (3) independently of one another SO n -R (22); n zero, 1 or 2;
  • R (90) and R (91) independently of one another hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, Cl, Br, I, CF 3 , -CN, -NO2 , SO p -R (16), CO-R (23), OR (24) or
  • R (26) and R (27) independently of one another are hydrogen or alkyl having 1, 2,
  • R (23) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
  • R (25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • R (24) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or different radicals from the series F, Cl , Br, I, CF 3 , methyl, methoxy, hydroxy or NR (28) R (29); R (28) and R (29) independently of one another
  • R (33) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; with the proviso that at least one of the radicals R (2) or R (3) is O- (alkylene with 2, 3 or 4 carbon atoms) -O-R (17) or NR (50) R (51).
  • Another object of the invention is the use of 4 '- [5-formyl-4- (2-methoxy-ethoxy) -2-phenyl-1-imidazolylmethyl] -3'-methylsulfonylbiphenyl-2-sulfonylcyanamide, the following formula
  • the invention further relates to the use of compounds of the formula III
  • R (101) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • Hydrogen atoms are replaced by fluorine; 3. alkenyl with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; or 4. -C ⁇ H2n-nn -Y > nn zero or 2; and n is zero, 1, 2, 3 or 4; where n is non-zero or 1 when nn is 2;
  • aryl having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;
  • R (102) 1. hydrogen
  • alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, in which one to all hydrogen atoms are replaced by fluorine;
  • -C n H2n-nn _z > nn Nu H or 2; and n is 1, 2, 3 or 4, where n is not 1 when nn is 2; where 1, 2 or 3 hydrogen atoms in the divalent radical -C n H 2 n-nn- are independently replaced by a radical from the series
  • aryl having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;
  • R (10) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms optionally substituted with (-C-C 4 ) alkoxy; or phenyl which is unsubstituted or substituted with 1, 2 or 3 identical or different radicals from the series F, Cl, Br, I, CF 3 , methyl, methoxy, hydroxy or NR (11) R (12);
  • R (13) is hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; XA carbonyl, -CO-NH-, -CO-CO- or sulfonyl;
  • aryl having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably phenyl, 1-naphthyl or 2-naphthyl;
  • a radical as defined under 1. with 1, 2, 3, 4 or 5 identical or different radicals from the alkyl series. with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, aryl with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably phenyl, 1-naphthyl or 2-Naphthyl, F, Cl, Br, I, CF 3 , SO q R (18), OR (16), NR (19) R (20), -CN, NO 2 or CO-R (9) ;. or where two residues together form a fused heterocyclyl residue, preferably methylenedioxy.
  • Cycloalkyl with 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms preferably cyclopropyl, cyclopentyl, cyclohexyl. 1, 2,3,4-tetrahydronaphthyl or indanyl;
  • arylalkylcarbonyl preferably phenyl-CH ⁇ -CO-; or
  • alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • nn zero or 2; and n is zero, 1, 2, 3 or 4; where n is non-zero or 1 when nn is 2;
  • a radical as defined under 4. the phenyl part being substituted by 1, 2 or 3 identical or different radicals from the series alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F , Cl, Br, I, CF 3 , SO q R (15), OR (16), NR (11) R (12), -CN, -NO 2 or CO- R (9); or
  • Alkyl with 1, 2, 3 or 4 carbon atoms alkyl with 1, 2, 3 or 4 carbon atoms, in which one to all hydrogen atoms are replaced by fluorine, preferably CF 3 , or NR (11) R (12);
  • R (16) 1. hydrogen, 2. alkyl having 1, 2, 3 or 4 carbon atoms,
  • aryl with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms preferably phenyl, 1-naphthyl or 2-naphthyl;
  • R (22) and R (23) independently of one another are hydrogen or CO-OR (24); R (24) hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -C n H2 n -
  • the invention further relates to the use of compounds of the formula IV
  • R (111) hydrogen, alkyl with 1, 2,3,4,5,6,7 or 8 carbon atoms, 1 -naphthyl, 2-
  • R (11) alkyl with 1, 2, 3 or 4 carbon atoms or NR (20) R (21);
  • R (20) and R (21) independently of one another are hydrogen or alkyl with 1, 2, 3 or
  • R (17) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms
  • R (8) and R (9) independently of one another are hydrogen or alkyl having 1, 2, 3 or 4
  • R (22) is hydrogen, alkyl having 1, 2,3,4,5,6,7 or 8 carbon atoms or OR (30);
  • R (30) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; a zero, 1 or 2; n zero, 1 or 2; or
  • R (111) and R (113) together with the carbon atom carrying them cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or fluorenyl;
  • R (112), R (113), R (114) and R (115) independently of one another hydrogen, F, CF 3 , O-R (10), alkyl with 1, 2,3,4,5,6,7 or 8 carbon atoms, cycloalkyl with 3, 4, 5, 6 or 7 carbon atoms, -CgH2g-phenyl, the phenyl part being unsubstituted or substituted by 1 to 3 substituents from the group F, Cl, Br, I, CF. 3 , methyl, methoxy, hydroxy or NR (18) R (19); , R (18) and R (19) independently of one another are hydrogen or alkyl having 1, 2, 3 or
  • R (10) is hydrogen, alkyl with 1, 2,3,4,5,6,7 or 8 carbon atoms, phenyl which is unsubstituted or substituted with 1-3 substituents from the group
  • R (12) and R (13) independently of one another are hydrogen or alkyl with 1,2,3 or
  • R (15); R (14) and R (15) independently of one another are hydrogen or alkyl
  • R (112) and R (114) together form a second bond between the carbon atoms bearing the radicals R (113) and R (115), where R (111), R (113), R (115) are as defined above;
  • R (116) and R (117) independently of one another are hydrogen, F, Cl, Br, I, CF 3 , -CN, -NO 2 , SO p -R (16), CO-R (23) or OR (24) ;
  • R (23) is hydrogen, alkyl having 1, 2,3,4,5,6,7 or 8 carbon atoms or OR (25);
  • R (25) is hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
  • R (24) is hydrogen, alkyl having 1, 2,3,4,5,6,7 or -8 C atoms or phenyl which is unsubstituted or substituted by 1-3 substituents from the group F, Cl, Br, I , CF 3 , methyl, methoxy, hydroxy or NR (28) R (29);
  • R (28) and R (29) are H or alkyl having 1, 2, 3 or 4 carbon atoms;
  • R (16) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, phenyl which is unsubstituted or substituted by 1-3 substituents from the group F, Cl, Br, I, CF 3 .
  • the invention further relates to the use of compounds of the formula IV and / or all stereoisomeric forms of the compounds of the formula IV and / or mixtures of these forms in any ratio, and / or the physiologically tolerable salts of the compounds of the formula IV for the preparation of a medicament for prophylaxis and therapy of acute or chronic diseases caused by increased blood levels of the von Willebrand factor and / or increased expression of the P-selectin, in which the symbols have the following meaning:
  • R (111) is methyl, ethyl, 1-naphthyl, 2-naphthyl, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or phenyl which is unsubstituted or substituted by a substituent from the group alkyl having 1, 2, 3 or 4 carbon atoms, F, Cl, CF 3 , SO 2 R (11), OR (17), NR (8) R (9), or CO-R (22); R (11) methyl or dimethylamino; R (17) is hydrogen, methyl or ethyl;
  • R (8) and R (9) independently of one another are hydrogen, methyl or
  • R (22) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or R (111) and R (113) together with the carbon atom bearing them cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or fluorenyl;
  • R (112) and R (114) are hydrogen; or R (112) and R (114) together form a second bond between the carbon atoms carrying the radicals R (113) and R (115);
  • R (113) and R (115) independently of one another are hydrogen, CF 3 , OR (10), alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which is unsubstituted or substituted by a substituent from the group F, Cl , CF 3 , methyl, methoxy, hydroxy or NR (18) R (19);
  • R (18) and R (19) independently of one another are hydrogen, methyl or ethyl;
  • R (10) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which is
  • R (23) is hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms
  • R (24) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which is unsubstituted or substituted by 1 substituent from the group F, Cl, CF 3 , methyl, methoxy, hydroxy or NR (28) R (29);
  • R (28) and R (29) independently of one another are hydrogen, methyl or ethyl.
  • compounds of formula IV are also used in which the biphenyl ring as in compounds of the following formula is linked and the sulfonylcyanamide group is located at the 2 position.
  • Alkyl residues and alkylene residues can be straight-chain or branched. This also applies to the alkylene radicals of the formulas C a H 2a , C b H 2b , CdH 2d , C g H 2 g, and C
  • Cycloalkyl is also understood to mean alkyl-substituted rings.
  • alkyl radicals with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms are: methyl, ethyl, n-propyl, n-butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, isopentyl, Neopentyl, isohexyl, 3-methylpentyl, sec-butyl, tert-butyl, tert-pentyl.
  • the divalent residues derived from these residues e.g. B.
  • methylene 1, 1-ethylene, 1, 2-ethylene, 1,1- ' propylene, 1, 2-propylene, 2,2-propylene, 1, 3-propylene, 1, 4-butylene, 1, 5 -Pentylene, 2,2-dimethyl-1, 3-propylene, 1, 6-hexylene, etc. are examples of alkylene radicals.
  • Cycloalkyl radicals with 3, 4, 5, 6 or 7 carbon atoms are in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, but they can also be substituted, for example, by alkyl with 1, 2, 3 or 4 carbon atoms.
  • 4-Methylcyclohexyl and 2,3-dimethylcyclopentyl may be mentioned as examples of substituted cycloalkyl radicals.
  • Heteroaryl with 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms is understood to mean in particular residues which are derived from phenyl or naphthyl in which one or more CH groups have been replaced by N and / or in which at least two adjacent CH groups (to form a five-membered aromatic ring) have been replaced by S, NH or O.
  • one or both atoms of the condensation site of bicyclic radicals can also be N atoms.
  • Heteroaryl includes, in particular, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyi, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolylinyl, isololinyl, isololinyl, isololinyl, isololinyl, isololinyl, isololinyl, isolazolyl, vinyl, quinolyl, vinyl.
  • Aromatic systems 1, 2 or 3 pyrrolyl, 1, 2, 4 or 4 are particularly suitable as N-containing heterocycles having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1, 2,3-triazol-1-, -4- or 5-yl, 1, 2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1, 2,3-oxadiazol-4- or 5-yl, 1, 2,4-oxadiazol-3-or 5-yl, 1, 3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1, 3,4-thiadiazol-2- or -5-yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-thiadiazol-4- or 5-yl, 2-, 3- or
  • N-containing heterocycles pyrrolyl, imidazolyl, quinolyl, pyrazolyl, pyridyi, pyrazinyl, pyrimidinyl and pyridazinyl are particularly preferred.
  • Thienyl represents both 2- and 3-thienyl.
  • Furyl stands for 2- and 3-furyl.
  • Monosubstituted phenyl radicals can be substituted in the 2-, 3- or 4-position, disubstituted in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5 Position, trisubstituted in the 2,3,4-, 2,3,5-, 2,3,6- 2,4,5-, 2,4,6- or 3,4,5-position.
  • the substituents can be the same or different.
  • the invention further relates to the use of the above-mentioned compounds of the formulas I, II, III and IV in combination. with inhibitors of the sodium-hydrogen exchanger.
  • the invention further relates to the use of the abovementioned compounds of the formulas I, II, III and IV in combination with inhibitors of the sodium hydrogen exchanger from the following group of active compounds
  • Another object of the invention is the use of the compounds of
  • Another object of the invention is the use of 4 '- [5-formyl-4- (2-methoxy-ethoxy) -2-phenyl-1-imidazolylmethyl] -3'-methylsulfonyl-biphenyl-2-sulfonylcyanamide in combination with cariporides for the manufacture of a medicament for the prophylaxis and therapy of acute or chronic diseases caused by increased blood levels of the von Willebrand factor and / or increased expression of the P-selectin.
  • the separation into the pure stereoisomers is possible either by chromatography on an optionally chiral support material or, if the racemic compounds mentioned above are capable of salt formation, by fractional crystallization the diastereomeric salts formed with an optically active base or acid as auxiliary.
  • Modified silica gel supports so-called Pirkle phases
  • high-molecular carbohydrates such as triacetyl cellulose are suitable as chiral stationary phases for the separation of enantiomers by thin-layer or column chromatography.
  • gas chromatographic methods on chiral stationary phases can also be used for analytical purposes.
  • the differently soluble solvents are mixed with an optically active, usually commercially available base such as (-) - nicotine, (+) - and (-) - phenyethylamine, quinine bases, L-lysine or L- and D-arginine diastereomeric salts formed, the heavier soluble component isolated as a solid, the more soluble diastereomer separated from the mother liquor, and the pure enantiomers obtained from the diastereomeric salts obtained in this way.
  • racemic compounds of the formula I which contain a basic group such as an amino group
  • optically active acids such as (+) - camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L- Convert lactic acid and (+) and (-) - mandelic acid into the pure enantiomers.
  • chiral compounds which contain alcohol or amine functions with correspondingly activated or optionally N-protected enantiomerically pure amino acids in the corresponding esters or amides, or conversely chiral carboxylic acids with carboxy-protected enantiomerically pure amino acids in the amides or with enantiomerically pure hydroxycarboxylic acids such as lactic acid transfer the corresponding chiral ester.
  • the chirality of the amino acid or alcohol residue introduced in enantiomerically pure form can be used to separate the isomers by separating the diastereomers now present by crystallization or chromatography on suitable stationary phases and then cleaving off the chiral part of the molecule carried along using suitable methods.
  • Acidic or basic products of the above-mentioned compounds can be in the form of their salts or in free form.
  • the production of physiologically compatible salts from the abovementioned compounds capable of salt formation, including their stereoisomeric forms, is carried out in a manner known per se.
  • the carboxylic acids and hydroxamic acids form with alkaline reagents such as hydroxides, carbonates, hydrogen carbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine or triethanolamine or also basic amino acids, for example lysine, omithine or arginine, stable alkali metal, alkaline earth metal or, if appropriate substituted ammonium salts.
  • alkaline reagents such as hydroxides, carbonates, hydrogen carbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine or triethanolamine or also basic amino acids, for example lysine, omithine or arginine, stable alkali metal, alkaline earth metal or, if appropriate substituted ammonium salts.
  • Both inorganic and organic acids such as hydrogen chloride, hydrogen bromide, sulfur, phosphorus, methanesulfone, benzenesulfone, p-toluenesulfone, 4-bromobenzene sulfone, cyclohexylamidosulfone, trifluoromethylsulfone, vinegar and oxal come for this -, Tartaric, succinic or trifluoroacetic acid in question.
  • Methanesulfonic acid salts of the abovementioned compounds are particularly preferred.
  • the above-mentioned compounds are suitable for the prophylaxis and therapy of acute or chronic diseases which are caused by increased blood levels of the von Willebrand factor and / or increased expression of the P-selectin.
  • thrombotic diseases that are provoked by ischemic conditions with subsequent reperfusion; such as thrombosis in acute myocardial, mesenteric or even cerebral infarction; thrombotic diseases that occur during or after surgical interventions; pulmonary emboli; deep venous thrombosis, such as that which occurs after a prolonged restriction of the blood circulation, in particular of the lower extremities, for example after prolonged lying or sitting, as well as inflammatory diseases such as that during ischemia and subsequent reperfusion, during vasculitis (e.g. as part of an autoimmune disease or Collagenosis).
  • the medicaments according to the invention can be administered by oral, inhalative, rectal or transdermal application or by subcutaneous, intra-articular, intraperitoneal or intravenous injection. Oral application is preferred.
  • the invention also relates to a method for producing a medicament, which is characterized in that at least one of the abovementioned compounds is brought into a suitable dosage form with a pharmaceutically suitable and physiologically tolerable carrier and, if appropriate, other suitable active ingredients, additives or auxiliaries.
  • the abovementioned compounds are mixed with the additives suitable for this purpose, such as carriers, stabilizers or inert diluents, and brought into suitable dosage forms by the customary methods, such as tablets, dragées, push-fit capsules, aqueous alcoholic or oily suspensions or aqueous or oily solutions.
  • the additives suitable for this purpose such as carriers, stabilizers or inert diluents, and brought into suitable dosage forms by the customary methods, such as tablets, dragées, push-fit capsules, aqueous alcoholic or oily suspensions or aqueous or oily solutions.
  • inert carriers such.
  • the preparation can take place both as dry and as moist granules.
  • Vegetable or animal oils such as sunflower oil or cod liver oil, are suitable as oily carriers or solvents.
  • the active compounds are, if desired, brought into solution, suspension or emulsion with the suitable substances, such as solubilizers, emulsifiers or other auxiliaries.
  • suitable substances such as solubilizers, emulsifiers or other auxiliaries.
  • solvents such.
  • physiological saline or alcohols e.g. As ethanol, propanol, glycerol, and also sugar solutions such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.
  • customary auxiliaries such as carriers, disintegrants, binders, coatings, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers.
  • Magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as sterile are common additives Water and monohydric or polyhydric alcohols such as glycerin.
  • the above-mentioned compounds are preferably prepared as pharmaceutical preparations in dosage units and administered, each unit containing as active constituent, a 'particular dose of the above compounds.
  • the dosage can also be increased in severe cases. In many cases, however, lower doses are sufficient.
  • These figures refer to an adult weighing approximately 75 kg.
  • the above-mentioned compounds can be used alone or in combination with anticoagulant, platelet aggregation-inhibiting or fibrinolytic active substances.
  • the co-application can take place, for example, with factor Xa inhibitors, standard heparin, low molecular weight heparins such as enoxaparin, dalteparin, certroparin, parnaparin or tinzaparin, direct thrombin inhibitors such as hirudin, aspirin, fibrinoge ⁇ receptor antagonists, streptokinase, urokinase tas and / or activator (T) ,
  • the cells were cultured either on gelatinized glass plates (measurement of the intracellular proton concentration) or on cell culture plates (12-well culture plates, Falcon, New Jersey, USA; measurement of the vWF release) after the first passage.
  • HUVECs were loaded with the pH-sensitive fluorescent dye BCECF-AM (2 ', 7'-bis (carboxyethyl) - 5 (6) -carboxyfluorescein).
  • BCECF-AM 2 ', 7'-bis (carboxyethyl) - 5 (6) -carboxyfluorescein.
  • a Deltascan Spectrofluorometer (PTI, Hamburg) was used for the subsequent measurement of the fluorescence.
  • This measuring system essentially consists of a UV light source, a monochromator, a photon detector and the software packages Felix and Oscar (PTI, Hamburg) for controlling the system via a computer.
  • the ratio of the measured emissions of the BCECF was recorded and the pH value was determined after calibration.
  • the measuring chamber is constructed in such a way that the parameters of temperature and the carbon dioxide partial pressure of the system are checked with continuous perfusion.
  • the test conditions were set to 37 ° C. and a carbon dioxide partial pressure of 5% or 10% by gassing the system and perfusate. In the experiment, it was first pre-incubated for 60 minutes with sodium bicarbonate buffer pH ex 6.4 in order to simulate respiratory-metabolic acidosis.
  • Table 1 Intracellular pH during an extracellular acidosis (pHj (acidosis)) of at least 15 minutes or under control conditions (Co).
  • pHj extracellular acidosis
  • SEM is the standard deviation from the mean
  • Extracellular acidosis resulted in intracellular acidification that persisted throughout the duration of the acidosis.
  • Table 2 Reperfusion with test buffer containing the above-mentioned compound 1 and cariporide, control buffer containing cariporide (NHE) and control buffer (Co). From the measured values within the first 30 seconds after reperfusion, the time until the half-maximum pHj change after 60 minutes of acidosis was determined. Table 2:
  • Said cells were initially acidotic with medium (6.4 pH of the constituents: Medium M199 w / Earle's & Amino Acids, w / L-Glutamine, w / o NaHCO3, w / o Hepes + 0,084g NaHCO 3/1) or pH standard medium (pH 7.4 from the constituents: medium M199 w / Earle's & amino Acids, w / L-glutamine, w / o NaHCO3, w / o Hepes + 2,200g NaHCO 3/1) for a , three or 48 hours.
  • medium 6.4 pH of the constituents: Medium M199 w / Earle's & Amino Acids, w / L-Glutamine, w / o NaHCO3, w / o Hepes + 0,084g NaHCO 3/1
  • pH standard medium pH 7.4 from the constituents: medium M199 w / Earle's & amino Acid
  • vWF concentration The samples taken from the supernatant were used to determine the vWF concentration.
  • An ELISA procedure enzyme-linked immunosorbent assay was used for this purpose using specific antibodies.
  • the vWF content of standard human plasma (Behring, Marburg) is based on an international standard (2 nd International Standard 87/718; National Institute for Biological Standards and Control, London) converted.
  • Table 3 vWF concentration in the cell supernatant measured under acidic (vWF az i dos e) and under control conditions (vWF C0 ) after a 15 minute incubation period. The vWF concentration under control conditions is set to 100%. Table 3:
  • vWF secretion was measured during a 10 minute reperfusion period with stimulation.
  • the vWF secretion of the control cells (vWF C0 ) was set to 100%.
  • the vWF concentration during reperfusion preazidotischer cells (vWFazi d ose) and the vWF concentration during reperfusion preazidotischer cells in the presence of 10 .mu.M of the abovementioned compound 1 (vWFv 1) were indicated as relative values to the control values.

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EP03706428A 2002-02-14 2003-02-05 Verwendung von inhibitoren des natrium-abhängigen chlorid-bicarbonat-austauschers zur behandlung von thrombotischen und inflammatorischer erkrankungen Withdrawn EP1476154A2 (de)

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DE10206354 2002-02-14
PCT/EP2003/001100 WO2003068224A2 (de) 2002-02-14 2003-02-05 Verwendung von inhibitoren des natrium-abhängigen chlorid-bicarbonat-austauschers zur behandlung von thrombotischen und inflammatorischer erkrankungen

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