Use of nonpeptide bradykinin antagonists for the treatment and prevention of chronic fibrogenetic liver disorders, acute liver disorders and the complications associated therewith
First Claim
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1. A method of treating a patient suffering from chronic fibrogenetic liver disorders (hepatic cirrhosis and hepatic fibrosis) and acute liver disorders and for the prevention of complications, comprising, administering to said patient an effective amount of a nonpeptide bradykinin antagonist or a physiologically tolerable salt thereof.
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Abstract
The invention relates to the use of nonpeptide bradykinin antagonists for the production of pharmaceuticals for the treatment of chronic fibrogenetic liver disorders (hepatic cirrhosis and hepatic fibrosis), acute liver disorders and for the prevention of complications, in particular for the prophylaxis or treatment of portal hypertension, decompensation symptoms such as ascites, edema formation, hepatorenal syndrome, hypertensive gastropathy and colopathy, splenomegaly and hemorrhagic complications in the gastrointestinal tract due to portal hypertension, collateral circulation and hyperemia and a cardiopathy as a result of a chronically hyperdynamic circulatory situation and its consequences.
15 Citations
17 Claims
- 1. A method of treating a patient suffering from chronic fibrogenetic liver disorders (hepatic cirrhosis and hepatic fibrosis) and acute liver disorders and for the prevention of complications, comprising, administering to said patient an effective amount of a nonpeptide bradykinin antagonist or a physiologically tolerable salt thereof.
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3. a radical of the formula (II):
- ##STR81##
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4. 2. a radical of the formulae (III) to (VI):
- ##STR82##
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5. E is 1. a radical of the formula (VII):
- ##STR83##
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6. 2. hydrogen, halogen, (C1 -C4)-alkyl, (C1 -C4)-alkylthio, (C1 -C4)-alkoxy, where in the last 3 radicals 1 or more hydrogen atoms can be replaced by fluorine;
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X1 is nitrogen or C--R4 ; X2 is nitrogen or C--R5 ; X3 is nitrogen or C--R6 ; X4 is oxygen, nitrogen or N--R7 ; R1,R2 are identical or different and are hydrogen, halogen, (C1 -C4)-alkyl or (C1 -C4)-alkoxy; R3 is hydrogen, halogen, (C1 -C6)-alkyl, (C6 -C12)-aryl, (C1 -C3)-alkyl-(C6 -C12)-aryl, (C3 -C5)-alkenyl, (C1 -C4)-alkoxy, CO2 R11 ; R4 is hydrogen, halogen, (C1 -C4)-alkyl, hydroxyl, (C1 -C4)-alkylthio, amino, (C1 -C4)-alkylamino, (C1 -C4)-dialkylamino, (C1 -C4)-alkoxy, which is optionally substituted by hydroxyl, (C1 -C4)-alkoxy, amino or (C1 -C4)-alkylamino, and (C6 -C12)-aryl, optionally substituted by (C1 -C4)-alkyl or CO2 R11 ; R5 is
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7. hydrogen or (C1 -C4)-alkyl ##STR84##
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8. R6 is 1. hydrogen, halogen, (C1 -C4)-alkyl, hydroxyl, (C1 -C4)-alkylthio, amino, (C1 -C4)-alkylamino, (C1 -C4)-dialkylamino, (C1 -C4)-alkoxy, which is optionally substituted by hydroxyl, (C1 -C4)-alkoxy, amino or (C1 -C4)-alkylamino, and (C6 -C12)-aryl, optionally substituted by (C1 -C4)-alkyl or CO2 R11 ;
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2. a radical of the formula (VIII);
##STR85## R7 is (C1 -C4)-alkyl, (C6 -C12)-aryl, or (C1 -C3)-alkyl-(C6 -C12)-aryl;R8,R9 are identical or different and are hydrogen or halogen; A is (C1 -C3)-alkanediyl; Q is O or NR11 ; R10 is a radical of the formula (IX) ##STR86## R11,R14 are hydrogen or (C1 -C4)-alkyl;
G is O or H2 ;R12 is hydrogen if G═
O and hydrogen or R16 CO if G═
H2 ;R13 is (C1 -C4)-alkyl, (C3 -C7)-cycloalkyl, --(CH2)m --(C3 -C7)-cycloalkyl, --(CH2)m --CONR11 R11, or ##STR87## m, n are identically or differently a number 0-6;
AA is an amino acid comprising, methionine, alanine, phenylalanine, 2-chlorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, tyrosine, o-methyltyrosine, β
-(2-thienyl)-alanine, glycine, cyclohexylalanine, leucine, isoleucine, valine, norleucine, phenylglycine, serine, cysteine, aminopropionic acid or aminobutyric acid;Y is
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9. (C2 -C6)-alkenediyl,(C1 -C8)-alkanediyl,(C3 -C10)-cycloalkenediyl,--(CH)p --To --(CH2)q --, where 1. to 4. can optionally be substituted by one or more radicals such as, for example, O--R18, NO2, CN, CO2 R11, SO3 R18, NR20 R21, SO2 NR20 R21, CONR20 R21 ;
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T is O, NR21 or S; o is a number 0 or 1; p,q are identical or different and are a number from 0 to 6; R15 is 1. hydrogen, 2. (C1 -C5)-alkyl, 3. (C6 -C10)-aryl, 4. (C1 -C9)-heteroaryl, where 3. and 4. can optionally be substituted by one or more groups, such as halogen, CN, NO2, (C1 -C6)-alkyl, (C6 -C10)-aryl, (C2 -C5)-alkenyl, where the last three radicals can optionally be partially or completely substituted by halogen, (C1 -C5)-alkoxy;
(C1 -C5)-alkylthio, NR20 R21, CO2 R19, SO3 R18, SO2 NR20 R21, SO2 R18, O--R18 ;
NR20 CO--R15 ;R16 is hydrogen, (C1 -C4)-alkyl, (C6 -C12)-aryl, (C1 -C4)-alkyl-(C6 -C12)-aryl, perfluoro-(C1 -C4)-alkyl; R17 is hydrogen, halogen, (C1 -C4)-alkyl, (C1 -C4)-alkoxy, perfluoro-(C1 -C4)-alkyl, NO2, OH, NH2, CONR16 R16, NR16 CONR16 R16 ; R18, R19, R20 are identical or different and are hydrogen, (C1 -C5)-alkyl, (C3 -C5)-alkenyl, (C6 -C12)-aryl-(C1 -C3)-alkyl, (C3 -C10)-cycloalkyl, (C3 -C10)-cycloalkyl-(C1 -C3)-alkyl, C(O)--O--(C1 -C5)-alkyl, or C(O)--NH--(C1 -C5)-alkyl; R21 is hydrogen, C(O)--O--(C1 -C5)-alkyl, C(O)--O--(C1 -C3)-alkyl-(C6 -C10)-aryl; Z is --R14 N--R22 ; R22 is ##STR88## R23 is (C1 -C4)-alkyl, ##STR89## or its physiologically tolerable salts.
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11. E is 1. a radical of the formula (XI) ##STR91##
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12. 2. hydrogen, (C1 -C4)-alkyl or (C1 -C4)-alkoxy;
- R1,R2 are identical or different and are hydrogen, halogen or (C1 -C4)-alkyl;
R4 is hydrogen, (C1 -C4)-alkyl, phenyl or methoxy; R5 is 1. hydrogen or (C1 -C4)-alkyl;
##STR92##
- R1,R2 are identical or different and are hydrogen, halogen or (C1 -C4)-alkyl;
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13. R6 is 1. hydrogen or (C1 -C4)-alkyla radical of the formula (VIII):
- ##STR93## R8,R9 are identical or different and are hydrogen or chlorine;
A is --CH2 -- or --CH2 --CH2 --;R10 is a radical of the formula (IX);
##STR94## R11,R14 are hydrogen, methyl or ethyl;
G is O or H2 ;R12 is hydrogen if G is equal to O or hydrogen or R16 CO if G is equal to H2 ; R13 is (C1 -C4)-alkyl, cyclopentyl, cyclohexyl, --(CH2)m CONR11 R11, ##STR95## m,n are identically or differently a number 0-2;
AA is the amino acid glycine or alanine;Y is
- ##STR93## R8,R9 are identical or different and are hydrogen or chlorine;
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14. (C2 -C5)-alkenediyl,(C2 -C4)-alkanediyl,--(CH2)p --To --(CH2)q --;
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T is O or S; o is a number 0 or 1; p,q are identical or different and are a number from 0-2; R15 is 1. hydrogen 2. (C1 -C5)-alkyl, 3. phenyl, 4. (C5 -C9)-heteroaryl, where 3. and 4. can optionally be substituted by one, two or three groups, such as halogen, NO2, (C1 -C3)-alkyl, (C1 -C3)-alkyl, in which the hydrogen atoms are partially or completely replaced by halogen, (C1 -C3)-alkoxy, (C1 -C3)-alkylthio, NR20 R21, NR20 CO--(C1 -C5)-alkyl and NR20 CO-pyridyl R16 is hydrogen, (C1 -C4)-alkyl, phenyl; R17 is hydrogen, halogen, (C1 -C4)-alkyl, NO2, NH2 ; R20 is hydrogen, (C1 -C4)-alkyl, benzyl; R21 is hydrogen, C(O)--O--(C1 -C5)-alkyl; Z is --R14 --N--R22 R22 is ##STR96## R23 is (C1 -C4)-alkyl, ##STR97## or its physiologically tolerable salts.
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16. (C2 -C5)-alkenediyl,(C2 -C4)-alkanediyl,
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17. --(CH2)p --To --(CH2)q --;
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T is O or S; o is a number 0 or 1; p,q are identical or different and are a number from 0-2; R15 is 1. hydrogen 2. (C1 -C3)-alkyl, 3. phenyl, 4. (C5 -C9)-heteroaryl, where 3. and 4. can optionally be substituted by one, two or three groups, such as halogen, NO2, (C1 -C3)-alkyl, (C1 -C3)-alkyl, in which the hydrogen atoms are partially or completely replaced by halogen, (C1 -C3)-alkoxy, NR20 R21, NR20 CO-- (C1 -C3)-alkyl or NR20 CO-pyridyl; R20 is hydrogen, (C1 -C4)-alkyl, benzyl; R21 is hydrogen, C(O)--O--(C1 -C5)-alkyl; or its physiologically tolerable salts.
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Specification
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Current AssigneeHoechst Aktiengesellschaft (Sanofi )
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Original AssigneeHoechst Aktiengesellschaft (Sanofi )
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InventorsWirth, Klaus, Heitsch, Holger, Bickel, Martin, Wagner, Adalbert, Hropot, Max
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Primary Examiner(s)Reamer, James H.
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Application NumberUS08/858,550Time in Patent Office435 DaysField of Search514/311, 514/312, 514/313, 514/314US Class Current514/311CPC Class CodesA61K 31/00 Medicinal preparations cont...A61K 31/47 Quinolines; IsoquinolinesA61K 31/4709 Non-condensed quinolines an...A61P 1/16 for liver or gallbladder di...A61P 43/00 Drugs for specific purposes...
