DE19620509A1 - Use of non-peptide bradykinin antagonist compounds - to treat chronic fibrogenetic liver disease, (liver cirrhosis and liver fibrosis) and acute liver disease, and to prevent complications - Google Patents
Use of non-peptide bradykinin antagonist compounds - to treat chronic fibrogenetic liver disease, (liver cirrhosis and liver fibrosis) and acute liver disease, and to prevent complicationsInfo
- Publication number
- DE19620509A1 DE19620509A1 DE1996120509 DE19620509A DE19620509A1 DE 19620509 A1 DE19620509 A1 DE 19620509A1 DE 1996120509 DE1996120509 DE 1996120509 DE 19620509 A DE19620509 A DE 19620509A DE 19620509 A1 DE19620509 A1 DE 19620509A1
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- hydrogen
- halogen
- alkoxy
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 229940122155 Bradykinin receptor antagonist Drugs 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010069729 Collateral circulation Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 244000166124 Eucalyptus globulus Species 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
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- 229920000954 Polyglycolide Polymers 0.000 description 1
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- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 229920002472 Starch Polymers 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
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- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 150000005350 bicyclononyls Chemical group 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
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- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960003260 chlorhexidine Drugs 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000005048 flame photometry Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- MSWIFFGHKBTPMY-VFUQPONKSA-L magnesium;(e)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O MSWIFFGHKBTPMY-VFUQPONKSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229940100652 nasal gel Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229940071462 oralone Drugs 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000004308 pyranonyl group Chemical group O1C(C(=CC=C1)*)=O 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Classifications
-
- 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
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic 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
- A61K31/435—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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Verwendung nicht-peptidischer Bradykinin-Antagonisten zur Behandlung und Prävention von chronisch-fibrogenetischen Lebererkrankungen, akuten Lebererkrankungen und den damit verbundenen Komplikationen.Use of non-peptide bradykinin antagonists for treatment and Prevention of chronic fibrogenetic liver diseases, acute Liver disease and related complications.
Bradykinin und verwandte Peptide sind potente, Entzündungen und Schmerz erzeugende und vasoaktive, körpereigene Substanzen. Aus EP-A 622 361, US 5,212,182, US 5,216,165, US 5,438,064 und WO 960425 sind substituierte, annellierte Heterobicyclen und ihre Verwendung als Bradykinin-Rezeptor antagonisten und ihre Verwendung als Mittel zur Bekämpfung von Zuständen, die durch Bradykinin vermittelt, ausgelöst oder unterstützt werden, bekannt.Bradykinin and related peptides are potent, inflammation and pain Generating and vasoactive, endogenous substances. From EP-A 622 361, US 5,212,182, US 5,216,165, US 5,438,064 and WO 960425 are substituted, annellated heterobicycles and their use as bradykinin receptor antagonists and their use as agents to combat conditions, that are mediated, triggered or supported by bradykinin.
Überraschenderweise wurde nun gefunden, daß nicht-peptidische Bradykinin- Antagonisten dieses Strukturtyps darüber hinaus geeignete Mittel zur Behandlung von chronisch fibrogenetischen Lebererkrankungen (Leberzirrhose und Leberfibrose), akuten Lebererkrankungen und zur Prävention von Komplikationen, insbesondere zur Prophylaxe bzw. Behandlung der portalen Hypertonie, Dekomensationserscheinungen wie Aszites, Ödembildung, heptaorenales Syndrom, hypertensive Gastro- und Colopathie, Splenomegalie sowie Blutungskomplikationen im Gastrointestinaltrakt durch portale Hypertonie, Kollateralkreislauf und Hyperämie und eine Kardiopathie als Folge einer chronisch hyperdynamen Kreislaufsituation und deren Folgen, sind.Surprisingly, it has now been found that non-peptidic bradykinin Antagonists of this type of structure also suitable means for Treatment of chronic fibrogenetic liver diseases (cirrhosis of the liver and liver fibrosis), acute liver disease and for the prevention of Complications, especially for the prophylaxis or treatment of the portals Hypertension, decompression symptoms such as ascites, edema formation, heptaorenal syndrome, hypertensive gastro- and colopathy, splenomegaly as well as bleeding complications in the gastrointestinal tract due to portal hypertension, Collateral circulation and hyperemia and cardiopathy as a result of one chronic hyper-dynamic circulatory situation and its consequences.
Als Verbindungen eignen sich nicht-peptidische Bradykinin-Antagonisten, die im Modell der CCl₄-induzierten Leberfibrose an der Ratte einen natriuretischen und diuretischen Effekt zeigen.Suitable compounds are non-peptidic bradykinin antagonists, which in the Model of CCl₄-induced liver fibrosis in the rat a natriuretic and show diuretic effect.
Geeignete nicht-peptidische Bradykinin-Antagonisten sind unter anderem die Verbindungen der Formel (I)Suitable non-peptide bradykinin antagonists include those Compounds of formula (I)
in welcher die Symbole folgende Bedeutung haben:in which the symbols have the following meaning:
D 1. ein Rest der Formel (II):D 1. a radical of the formula (II):
2. ein Rest der Formeln (III) bis (VI):2. a radical of the formulas (III) to (VI):
E 1. ein Rest der Formel (VII):E 1. a radical of the formula (VII):
2. Wasserstoff, Halogen, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkylthio, (C₁-C₄)-
Alkoxy, wobei in den letzten 3 Resten 1 oder mehrere
Wasserstoffatome durch Fluor ersetzt sein können;
X¹ Stickstoff oder C-R⁴;
X² Stickstoff oder C-R⁵
X³ Stickstoff oder C-R⁶;
X⁴ Sauerstoff, Stickstoff oder N-R⁷;
R¹, R² sind gleich oder verschieden und stehen für Wasserstoff, Halogen, (C₁-
C₄)-Alkyl und (C₁-C₄)-Alkoxy;
R³ Wasserstoff, Halogen, (C₁-C₆)-Alkyl, (C₆-C₁₂)-Aryl, (C₁-C₃)-Alkyl-(C₆-
C₁₂)-Aryl, (C₃-C₅)-Alkenyl, (C₁-C₄)-Alkoxy, CO₂R¹¹.
R⁴ Wasserstoff, Halogen, (C₁-C₄)-Alkyl, Hydroxy, (C₁-C₄)-Alkylthio, Amino,
(C₁-C₄)-Alkylamino, (C₁-C₄)-Dialkylamino, (C₁-C₄)-Alkoxy, das
gegebenenfalls substituiert ist mit Hydroxy, (C₁-C₄)-Alkoxy, Amino und
(C₁-C₄)-Alkylamino, und (C₆-C₁₂)-Aryl, gegebenenfalls substituiert mit
(C₁-C₄)-Alkyl oder CO₂R¹¹;
R⁵ 1. Wasserstoff oder (C₁-C₄)-Alkyl2. 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;
X¹ is nitrogen or C-R⁴;
X² nitrogen or C-R⁵
X³ is nitrogen or C-R⁶;
X⁴ oxygen, nitrogen or N-R⁷;
R¹, R² are the same or different and represent hydrogen, halogen, (C₁-C₄) alkyl and (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, CO₂R¹¹.
R⁴ is hydrogen, halogen, (C₁-C₄) alkyl, hydroxy, (C₁-C₄) alkylthio, amino, (C₁-C₄) alkylamino, (C₁-C₄) dialkylamino, (C₁-C₄) alkoxy, that is optionally substituted with hydroxy, (C₁-C₄) alkoxy, amino and (C₁-C₄) alkylamino, and (C₆-C₁₂) aryl optionally substituted with (C₁-C₄) alkyl or CO₂R¹¹;
R⁵ 1. hydrogen or (C₁-C₄) alkyl
R⁶ 1. Wasserstoff, Halogen, (C₁-C₄)-Alkyl, Hydroxy, (C₁-C₄)-Alkylthio,
Amino, (C₁-C₄)-Alkylamino, (C₁-C₄)-Dialkylamino, (C₁-C₄)-Alkoxy,
das gegebenenfalls substituiert ist mit Hydroxy, (C₁-C₄)-Alkoxy,
Amino und (C₁-C₄)-Alkylamino, und (C₆-C₁₂)-Aryl, gegebenenfalls
substituiert mit (C₁-C₄)-Alkyl oder CO₂R¹¹;
2. ein Rest der Formel (VIII):R⁶ 1. hydrogen, halogen, (C₁-C₄) alkyl, hydroxy, (C₁-C₄) alkylthio, amino, (C₁-C₄) alkylamino, (C₁-C₄) dialkylamino, (C₁-C₄) alkoxy optionally substituted with hydroxy, (C₁-C₄) alkoxy, amino and (C₁-C₄) alkylamino, and (C₆-C₁₂) aryl optionally substituted with (C₁-C₄) alkyl or CO₂R¹¹;
2. a radical of the formula (VIII):
R⁷ (C₁-C₄)-Alkyl, (C₆-C₁₂)-Aryl, oder (C₁-C₃)-Alkyl-(C₆-C₁₂)-Aryl;
R⁸, R⁹ sind gleich oder verschieden und stehen für Wasserstoff und Halogen;
A (C₁-C₃)-Alkandiyl;
Q O oder NR¹¹;
R¹⁰ ein Rest der Formel (IX)R⁷ (C₁-C₄) alkyl, (C₆-C₁₂) aryl, or (C₁-C₃) alkyl- (C₆-C₁₂) aryl;
R⁸, R⁹ are the same or different and stand for hydrogen and halogen;
A (C₁-C₃) alkanediyl;
QO or NR¹¹;
R¹⁰ is a radical of the formula (IX)
R¹¹, R¹⁴ Wasserstoff oder (C₁-C₄)Alkyl;
G O oder H₂;
R¹² steht bei G=O für Wasserstoff und bei G=H₂ für Wasserstoff oder
R¹⁶CO;
R¹³ ist (C₁-C₄)-Alkyl, (C₃-C₇)-Cycloalkyl, -(CH₂)m-(C₃-C₇)-Cycloalkyl, -(CH₂)m-
CONR¹¹R¹¹, oderR¹¹, R¹⁴ are hydrogen or (C₁-C₄) alkyl;
GO or H₂;
R¹² stands for G = O for hydrogen and for G = H₂ for hydrogen or R¹⁶CO;
R¹³ is (C₁-C₄) alkyl, (C₃-C₇) cycloalkyl, - (CH₂) m - (C₃-C₇) cycloalkyl, - (CH₂) m - CONR¹¹R¹¹, or
m, n sind gleich oder verschieden eine Zahl 0-6;
AA steht für eine Aminosäure wie z. B. Methionin, Alanin, Phenylalanin,
2-Chlorphenylalanin, 3-Chlorphenylalanin, 4-Chlorphenylalanin, 2-Fluor
phenylalanin, 3-Fluorphenylalanin, 4-Fluorphenylalanin, Tyrosin,
o-Methyltyrosin, β-(2-Thienyl)-alanin, Glycin, Cyclohexylalanin, Leucin,
Isoleucin, Valin, Norleucin, Phenylglycin, Serin, Cystein, Aminopropion
säure oder Aminobuttersäure;
Y 1. (C₂-C₆)-Alkendiyl,
2. (C₁-C₈)-Alkandiyl,
3. (C₃-C₁₀)-Cycloalkendiyl,
4. (CH)p-To(CH₂)q-,
wobei 1. bis 4. gegebenenfalls mit einen oder mehreren Resten wie
z. B. O-R¹⁸, NO₂, CN, CO₂R¹¹, SO₃R¹⁸, NR²⁰R²¹, SO₂NR²⁰R²¹,
CONR²⁰R²¹ substituiert sein kann;
T O, NR²¹, oder S;
o ist eine Zahl 0 oder 1;
p, q sind gleich oder verschieden und bedeuten eine Zahl von 0 bis 6;
R¹⁵ 1. Wasserstoff,
2. (C₆-C₁₀)-Aryl,
3. (C₁-C₉)-Heteroaryl,
wobei 2. und 3. gegebenenfalls mit einer oder mehreren Gruppen
substituiert sein können, wie Halogen, CN, NO₂, (C₁-C₆)-Alkyl,
(C₆-C₁₀)-Aryl, (C₂-C₅)-Alkenyl, wobei die letzten drei Reste
gegebenenfalls teilweise oder vollständig mit Halogen substituiert
sein können, (C₁-C₅)-Alkoxy; (C₁-C₅)-Alkylthio, NR ²⁰R²¹, CO₂R¹⁹,
SO₃R¹⁸, SO₂NR²⁰R²¹, SO₂R¹⁸, O-R¹⁸; NR²⁰CO-R¹⁵;
R¹⁶ ist Wasserstoff, (C₁-C₄)-Alkyl, (C₆-C₁ ₂)-Aryl, (C₁-C₄)-Alkyl-(C₆-C₁₂)-Aryl,
Perfluoro-(C₁-C₄)-Alkyl;
R¹⁷ ist Wasserstoff, Halogen, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxy, Perfluoro-(C₁-
C₄)-Alkyl, NO₂, OH, NH₂, CONR¹⁶R¹⁶, NR¹⁶CONR¹⁶R¹⁶;
R¹⁸, R¹⁹, R²⁰ gleich oder verschieden sind und Wasserstoff, (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, oder C(O)-NH-(C₁-C₅)-
Alkyl bedeuten;
R²¹ Wasserstoff, C(O)-O-(C₁-C₅)-Alkyl, C(O)-O-(C₁-C₃)-Alkyl-(C₆-C₁₀)-Aryl;
Z -R¹⁴N-R²²;
R²² steht fürm, n, identical or different, are a number 0-6;
AA stands for an amino acid such as B. 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 1. (C₂-C₆) alkylene diyl,
2. (C₁-C₈) alkanediyl,
3. (C₃-C₁₀) cycloalkenediyl,
4. (CH) p -T o (CH₂) q -,
where 1. to 4. optionally with one or more radicals such as. B. O-R¹⁸, NO₂, CN, CO₂R¹¹, SO₃R¹⁸, NR²⁰R²¹, SO₂NR²⁰R²¹, CONR²⁰R²¹ may be substituted;
TO, NR²¹, or S;
o is a number 0 or 1;
p, q are the same or different and represent a number from 0 to 6;
R¹⁵ 1. hydrogen,
2. (C₆-C₁₀) aryl,
3. (C₁-C₉) heteroaryl,
where 2. and 3. may optionally be substituted with one or more groups, such as halogen, CN, NO₂, (C₁-C₆) alkyl, (C₆-C₁₀) aryl, (C₂-C₅) alkenyl, the latter three radicals may optionally be partially or completely substituted with halogen, (C₁-C₅) alkoxy; (C₁-C₅) alkylthio, NR ²⁰R²¹, CO₂R¹⁹, SO₃R¹⁸, SO₂NR²⁰R²¹, SO₂R¹⁸, O-R¹⁸; NR²⁰CO-R¹⁵;
R¹⁶ is hydrogen, (C₁-C₄) alkyl, (C₆-C₁ ₂) 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, CONR¹⁶R¹⁶, NR¹⁶CONR¹⁶R¹⁶;
R¹⁸, R¹⁹, R²⁰ are the same 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 -R¹⁴N-R²²;
R²² stands for
R²³ (C₁-C₄)-Alkyl,R²³ (C₁-C₄) alkyl,
sowie deren physiologisch verträglichen Salze.and their physiologically tolerable salts.
Alkyl und Alkenyl können geradkettig oder verzweigt sein. Entsprechendes gilt für davon abgeleitete Reste wie z. B. Alkoxy.Alkyl and alkenyl can be straight-chain or branched. The same applies for residues derived from such. B. alkoxy.
Alkenyl steht für einfach oder mehrfach ungesättigte Verbindungen wie z. B. 1,4-Butadienyl, 8,11-Heptadienyl, 8,11,14-Heptatrienyl, Butenyl.Alkenyl stands for mono- or polyunsaturated compounds such as B. 1,4-butadienyl, 8,11-heptadienyl, 8,11,14-heptatrienyl, butenyl.
Entsprechendes gilt für Cycloalkenyl.The same applies to cycloalkenyl.
Cycloalkyl steht für mono- oder bicyclische Verbindungen wie z. B. Cyclopropyl, Cyclopentyl, Cyclohexyl, Bicyclononyl. Entsprechendes gilt für Cycloalkenyl.Cycloalkyl stands for mono- or bicyclic compounds such as. B. cyclopropyl, Cyclopentyl, cyclohexyl, bicyclononyl. The same applies to cycloalkenyl.
(C₆-C₁₂)-Aryl ist beispielsweise Phenyl, Naphthyl oder Biphenylyl, vorzugsweise Phenyl. Entsprechendes gilt auch für davon abgeleitete Reste, wie z. B. Aralkyl.(C₆-C₁₂) aryl is, for example, phenyl, naphthyl or biphenylyl, preferably Phenyl. The same applies to residues derived therefrom, such as. B. Aralkyl.
Halogen (Hal) steht für Fluor, Chlor, Brom oder Jod, vorzugsweise für Chlor oder Fluor.Halogen (Hal) represents fluorine, chlorine, bromine or iodine, preferably chlorine or fluorine.
Unter (C₁-C₉)-Heteroaryl werden Reste verstanden, die sich von Phenyl oder Naphthyl ableiten, in welchen eine oder mehrere CH-Gruppen durch N ersetzt sind und/oder in welchen mindestens zwei benachbarte CH-Gruppen (unter Bildung eines fünfgliedrigen aromatischen Rings) durch S, NH oder O ersetzt sind. Desweiteren können auch ein oder beide Atome der Kondensationsstelle bicyclischer Reste (wie im Indolizinyl) N-Atome sein.Under (C₁-C₉) heteroaryl are understood residues that are phenyl or Derive naphthyl in which one or more CH groups are replaced by N. and / or in which at least two neighboring CH groups (under Formation of a five-membered aromatic ring) replaced by S, NH or O. are. Furthermore, one or both atoms of the condensation point can bicyclic radicals (as in indolizinyl) are N atoms.
Als Heteroaryl gelten insbesondere Furanyl, Thienyl, Pyrrolyl, Imidazolyl, Pyrazolyl, Triazolyl, Tetrazolyl, Oxazolyl, Isoxazolyl, Thiazolyl, Isothiazolyl, Pyridyl, Pyrazinyl, Pyrimidinyl, Pyridazinyl, Indolyl, Indazolyl, Chinolyl, Isochinolyl, Phthalazinyl, Chinoxalinyl, Chinazolinyl, Cinnolinyl, Benzopyranonyl, Coumarinyl, Pyranonyl, Furandionyl.Heteroaryl is especially furanyl, thienyl, pyrrolyl, imidazolyl, Pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl, Isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzopyranonyl, Coumarinyl, pyranonyl, furandionyl.
Unter physiologisch verträglichen Salzen von Verbindungen der Formel (I) versteht man sowohl deren organische als auch anorganische Salze, wie sie in Remington′s Pharmaceutical Sciences (A.R. Gennard Editior, Mack Publishing Co., Easton PA, 17. Auflage, Seite 1418 (1985)) beschrieben sind. Aufgrund der physiologischen und chemischen Stabilität und der Löslichkeit sind saure Gruppen unter anderen Natrium-, Kalium-, Calcium- und Ammoniumsalze bevorzugt; für basische Gruppen sind unter anderem Salze der Salzsäure, Schwefelsäure, Phosphorsäure oder von Carbonsäuren oder Sulfonsäuren, wie z. B. Essigsäure, Zitronensäure, Benzoesäure, Maleinsäure, Fumarsäure, Weinsäure und p-Toluolsulfonsäure bevorzugt.Under physiologically tolerable salts of compounds of the formula (I) one understands both their organic and inorganic salts as described in Remington's Pharmaceutical Sciences (A.R. Gennard Editior, Mack Publishing Co., Easton PA, 17th edition, page 1418 (1985)). Because of the physiological and chemical stability and the solubility are acidic Groups including other sodium, potassium, calcium and ammonium salts prefers; for basic groups include salts of hydrochloric acid, Sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, such as e.g. B. acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, Tartaric acid and p-toluenesulfonic acid are preferred.
Geeignete nicht-peptidische Bradykinin-Antagonisten sind zum Beispiel beschrieben in den Patentanmeldungen EP-A 622 361, US 5,212,182, US 5,216,165, US 5,438,064 und WO 960425.Suitable non-peptide bradykinin antagonists are for example described in patent applications EP-A 622 361, US 5,212,182, US 5,216,165, US 5,438,064 and WO 960425.
Besonders geeignet sind Verbindungen der Formel 1, in weicher bedeuten:Compounds of formula 1 are particularly suitable, in which:
D ein Rest der allgemeinen Formel (X)D is a radical of the general formula (X)
E 1. einen Rest der Formel (XI)E 1. a radical of the formula (XI)
2. Wasserstoff, (C₁-C₄)-Alkyl und (C₁-C₄)-Alkoxy;
R¹, R² sind gleich oder verschieden uns stehen für Wasserstoff, Halogen und
(C₁-C₄)-Alkyl;
R⁴ ist Wasserstoff, (C₁-C₄)-Alkyl, Phenyl und Methoxy;
R⁵ 1. Wasserstoff oder (C₁-C₄)-Alkyl;2. hydrogen, (C₁-C₄) alkyl and (C₁-C₄) alkoxy;
R¹, R² are the same or different and are hydrogen, halogen and (C₁-C₄) alkyl;
R⁴ is hydrogen, (C₁-C₄) alkyl, phenyl and methoxy;
R⁵ 1. hydrogen or (C₁-C₄) alkyl;
R⁶ 1. Wasserstoff und (C₁-C₄)-Alkyl
2. ein Rest der Formel (VIII):R⁶ 1. hydrogen and (C₁-C₄) alkyl
2. a radical of the formula (VIII):
R⁸, R⁹ sind gleich oder verschieden und stehen für Wasserstoff oder Chlor;
A ist -CH₂- oder -CH₂-CH₂-;
R¹⁰ steht für einen Rest der Formel (IX):R⁸, R⁹ are the same or different and stand for hydrogen or chlorine;
A is -CH₂- or -CH₂-CH₂-;
R¹⁰ represents a radical of the formula (IX):
R¹¹, R¹⁴ sind Wasserstoff, Methyl oder Ethyl;
G steht für O oder H₂;
R¹² steht bei G gleich O für Wasserstoff oder bei G gleich H₂ für Wasserstoff
oder R¹⁶CO;
R¹³ ist (C₁-C₄)-Alkyl, Cyclopentyl, Cyclohexyl, -(CH₂)mCONR¹¹R¹¹,R¹¹, R¹⁴ are hydrogen, methyl or ethyl;
G represents O or H₂;
R¹² is G when O is hydrogen or G is H₂ is hydrogen or R¹⁶CO;
R¹³ is (C₁-C₄) alkyl, cyclopentyl, cyclohexyl, - (CH₂) m CONR¹¹R¹¹,
m, n sind gleich oder verschieden eine Zahl 0-2;
AA steht für die Aminosäure Glycin oder Alanin;
Y 1. (C₂-C₅)-Alkendiyl,
2. (C₂-C₄)-Alkandiyl,
3. -(CH₂)p-To-(CH₂)q-;
T steht für O oder S;
o ist eine Zahl 0 oder 1;
p, q sind gleich oder verschieden und bedeuten eine Zahl von 0-2;
R¹⁵ 1. Wasserstoff
2. Phenyl,
3. (C₅-C₉)-Heteroaryl,
wobei 2. und 3. gegebenenfalls mit einer, zwei oder drei Gruppen
substituiert sein können, wie Halogen, NO₂, (C₁-C₃)-Alkyl, (C₁-C₃)-Alkyl,
in dem die H-Atome teilweise oder vollständig durch Halogen ersetzt
sind, (C₁-C₃)-Alkoxy, (C₁-C₃)-Alkylthio, NR²⁰R²¹ und NR²⁰CO-Pyridyl
R¹⁶ ist Wasserstoff, (C₁-C₄)-Alkyl, Phenyl;
R¹⁷ ist Wasserstoff, Halogen, (C₁-C₄)-Alkyl, NO₂, NH₂;
R²⁰ ist Wasserstoff, (C₁-C₄)-Alkyl, Benzyl;
R²¹ ist Wasserstoff, C(O)-O-(C₁-C₅)-Alkyl;
Z ist -R¹⁴-N-R²²
R²²m, n are the same or different, a number 0-2;
AA stands for the amino acid glycine or alanine;
Y 1. (C₂-C₅) alkylene diyl,
2. (C₂-C₄) alkanediyl,
3. - (CH₂) p -T o - (CH₂) q -;
T stands for O or S;
o is a number 0 or 1;
p, q are the same or different and represent a number from 0-2;
R¹⁵ 1. hydrogen
2. phenyl,
3. (C₅-C₉) heteroaryl,
where 2. and 3. may optionally be substituted with one, two or three groups, such as halogen, NO₂, (C₁-C₃) alkyl, (C₁-C₃) alkyl, in which the H atoms are partially or completely replaced by halogen are replaced, (C₁-C₃) alkoxy, (C₁-C₃) alkylthio, NR²⁰R²¹ and NR²⁰CO-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
R²³ (C₁-C₄)-Alkyl,R²³ (C₁-C₄) alkyl,
Besonders geeignet sind auch Verbindungen der Formel (I), in welcher die Symbole die folgende Bedeutung haben:Compounds of the formula (I) in which the Symbols have the following meaning:
D ein Rest der allgemeinen Formel (X)D is a radical of the general formula (X)
E ein Rest der Formel (XI)E is a radical of the formula (XI)
R¹, R² sind gleich oder verschieden uns stehen für Wasserstoff, Halogen und
(C₁-C₄)-Alkyl;
R⁴ Wasserstoff, (C₁-C₄)-Alkyl;
R⁵ Wasserstoff;
R⁶ Wasserstoff;
R⁸, R⁹ sind gleich oder verschieden und stehen für Wasserstoff oder Chlor;
A -CH₂- oder -CH₂-CH₂-;
R¹⁰ ein Rest der Formel (IX):R¹, R² are the same or different and are hydrogen, halogen and (C₁-C₄) alkyl;
R⁴ is hydrogen, (C₁-C₄) alkyl;
R⁵ hydrogen;
R⁶ hydrogen;
R⁸, R⁹ are the same or different and stand for hydrogen or chlorine;
A -CH₂- or -CH₂-CH₂-;
R¹⁰ is a radical of the formula (IX):
R¹⁴ Wasserstoff, Methyl oder Ethyl;
AA steht für die Aminosäure Glycin;
Y 1. (C₂-C₅)-Alkendiyl,
2. (C₂-C₄)-Alkandiyl,
3. -(CH₂)p-To-(CH₂)q-;
T steht für O oder S;
o ist eine Zahl 0 oder 1;
p, q sind gleich oder verschieden und bedeuten eine Zahl von 0-2;
R¹⁵ 1. Wasserstoff
2. Phenyl,
3. (C₅-C₉)-Heteroaryl,
wobei 2. und 3. gegebenenfalls mit einer, zwei oder drei Gruppen
substituiert sein können, wie Halogen, NO₂, (C₁-C₃)-Alkyl, (C₁-C₃)-Alkyl,
in dem die H-Atome teilweise oder vollständig durch Halogen ersetzt
sind, (C₁-C₃)-Alkoxy, NR²⁰R²¹ und NR²⁰CO-Pyridyl;
R²⁰ ist Wasserstoff, (C₁-C₄)-Alkyl, Benzyl;
R²¹ ist Wasserstoff, C(O)-O-(C₁-C₅)-Alkyl;
sowie deren physiologisch verträglichen Salze.R¹⁴ is hydrogen, methyl or ethyl;
AA stands for the amino acid glycine;
Y 1. (C₂-C₅) alkylene diyl,
2. (C₂-C₄) alkanediyl,
3. - (CH₂) p -T o - (CH₂) q -;
T stands for O or S;
o is a number 0 or 1;
p, q are the same or different and represent a number from 0-2;
R¹⁵ 1. hydrogen
2. phenyl,
3. (C₅-C₉) heteroaryl,
where 2. and 3. may optionally be substituted with one, two or three groups, such as halogen, NO₂, (C₁-C₃) alkyl, (C₁-C₃) alkyl, in which the H atoms are partially or completely replaced by halogen are replaced, (C₁-C₃) alkoxy, NR²⁰R²¹ and NR²⁰CO-pyridyl;
R²⁰ is hydrogen, (C₁-C₄) alkyl, benzyl;
R²¹ is hydrogen, C (O) -O- (C₁-C₅) alkyl;
and their physiologically tolerable salts.
Geeignet sind auch die Verbindungen
N-[1-[4-(1,1-Dimethylethyl)phenyl]methyl-4-piperidinyl]-8-methoxy4-[-[4-[[[1-
(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl-amino]-3-
chinolincarboxylamid;
N-[1-[(3-chlorphenyl]methyl-4-piperidinyl]-8-methoxy-4-[[4-[[[1-(phe-nylmethyl)-
4-piperidinyl]amino]carbonyl]phenyl-amino]-3-chinolincarboxylamid;
8-Methoxy-N-[1-(phenyl]methyl-4-piperidinyl-[4-[[4-[[[1-(phenylmethy-l)-4 -
piperidinyl]amino]carbonyl]phenyl-amino]-3-chinolincarboxylamid;
N-[2-(Dimethylamino)ethyl]-8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-
piperidinyl]amino]carbonyl]phenyl-amino]-3-chinolincarboxylamid-trif-luoracetat;
N-[2-(Dimethylamino)ethyl]N-ethyl-8-methoxy-4-[[4-[[[1-(phenylmethyl-)-4-
piperidinyl]amino]carbonyl]phenyl-amino]-3-chinolincarboxylamid;
4-[[4-[[[(3-Cyclopentyl-1-oxopropyl)-[1-[6-(diethylamino)-6-oxo-hexy-l-4-
piperidinylamino]-methylphenyl]-amino]-8-methoxy-N-[1-(phenylmethyl)-4-
piperidinyl]-3-chinolincarboxylamid;
4-[[4-[[(1-Butyl-4-piperidinylamino]methyl]-phenylamino]-8-methoxy-N--[1-
(phenylmethyl)-4-piperidinyl]-3-chinolincarboxylamid;
N-(1-Butyl-4-piperidinyl)-8-methoxy-[[4-[[[1-(phenylmethyl)4-piperid-inyl]aminol
carbonyl]-phenyl]-amino]-3-chinolincarboxylamid;
N-[1-[6-(Diethylamino)-6-oxohexyl-4-piperidinyl-8-methoxy-4-[[4-[[[1--
(phenylmethyl)-4-piperidinyl]-amino]-carbonyl]-phenyl]-amino]-3-
chinolincarboxylamid;
4-[[4-[[(1-B utyl-4-piperidinyl)-(1-oxobutyl)-amino]-methyl]-phenyl]-amino-[8-
methoxy-N-[1-(phenylmethyl)-4-piperidinyl]-3-chinolincarboxylamid;
N-[1-[4-[(Diethylamino)-carbonyl]-phenyl-4-piperidinyl-8-methoxy-4-[-[4-[[[1-
(phenylmethyl)-4-piperidinyl]-amino]-carbonyl]-phenyl]-amino-3-
chinolincarboxylamid;
N-[1-(2-Phenylethyl)-4-piperidinyl]-8-methoxy-4-[[4-[[[1-(phenylmeth-yl)-4-
piperidinyl]-amino]-carbonyl]-phenyl]-amino]-3-chinolincarboxylamid;
4-[[4-[[(1-Butyl-4-piperidinyl)-amino]-carbonyl]-phenyl]-aminol-8-me-thoxy-N-[1-
(phenylmethyl)-4-piperidinyl]-3-chinolincarboxylamid;
8-Methoxy-N-(1-methyl-4-piperidinyl)-4-[ [4-[[[1-(phenylmethyl)-4-piperidinyl]
amino]-carbonyl]-phenyl]-amino]-3-chinolincarboxylamid;
N-[1-[(3-Methoxyphenyl)-methyl]-4-piperidinyl-8-methoxy-4-[[4-[[[1-
(phenylmethyl)-4-piperidinyl]-aminoj-carbonyl]-phenyl]-amino-3-
chinolincarboxylamid;
8-Methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]-amino]-carbonyl]--phenyl]
amino]-1-[[3-(trifluoromethyl)-phenyl]-methyl]-4-piperidinyl]-3-
chinolincarboxylamid; oder
7-Chloro-N-[1-(phenylmethyl)-4-piperidinyl]-4-[[4-[[[1-(phenylmethyl-)-4-
piperidinyl]-amino]-carbonyl]-phenyl]-amino]-3-chinolincarboxylamid;-
sowie deren physiologisch verträglichen Salze.The connections are also suitable
N- [1- [4- (1,1-dimethylethyl) phenyl] methyl-4-piperidinyl] -8-methoxy4 - [- [4 - [[[1- (phenylmethyl) -4-piperidinyl] amino] carbonyl] phenyl-amino] -3-quinoline carboxylamide;
N- [1 - [(3-chlorophenyl] methyl-4-piperidinyl] -8-methoxy-4 - [[4 - [[[1- (phe-nylmethyl) -4-piperidinyl] amino] carbonyl] phenylamino ] -3-quinolinecarboxylamide;
8-Methoxy-N- [1- (phenyl] methyl-4-piperidinyl- [4 - [[4 - [[[1- (phenylmethy-l) -4 - piperidinyl] amino] carbonyl] phenylamino] -3 -quinoline carboxylamide;
N- [2- (Dimethylamino) ethyl] -8-methoxy-4 - [[4 - [[[1- (phenylmethyl) -4-piperidinyl] amino] carbonyl] phenylamino] -3-quinolinecarboxylamide trif-luoroacetate ;
N- [2- (dimethylamino) ethyl] N-ethyl-8-methoxy-4 - [[4 - [[[1- (phenylmethyl -) - 4-piperidinyl] amino] carbonyl] phenylamino] -3-quinolinecarboxylamide ;
4 - [[4 - [[[(3-cyclopentyl-1-oxopropyl) - [1- [6- (diethylamino) -6-oxo-hexy-l-4-piperidinylamino] methylphenyl] amino] -8- methoxy-N- [1- (phenylmethyl) -4-piperidinyl] -3-quinolinecarboxylamide;
4 - [[4 - [[(1-butyl-4-piperidinylamino] methyl] phenylamino] -8-methoxy-N - [1- (phenylmethyl) -4-piperidinyl] -3-quinolinecarboxylamide;
N- (1-butyl-4-piperidinyl) -8-methoxy - [[4 - [[[1- (phenylmethyl) 4-piperidinyl] aminol carbonyl] phenyl] amino] -3-quinoline carboxylamide;
N- [1- [6- (diethylamino) -6-oxohexyl-4-piperidinyl-8-methoxy-4 - [[4 - [[[1-- (phenylmethyl) -4-piperidinyl] amino] carbonyl] -phenyl] amino] -3- quinoline carboxylamide;
4 - [[4 - [[(1-butyl-4-piperidinyl) - (1-oxobutyl) amino] methyl] phenyl] amino- [8-methoxy-N- [1- (phenylmethyl) - 4-piperidinyl] -3-quinolinecarboxylamide;
N- [1- [4 - [(diethylamino) carbonyl] phenyl-4-piperidinyl-8-methoxy-4 - [- [4 - [[[1- (phenylmethyl) -4-piperidinyl] amino] - carbonyl] phenyl] amino-3-quinolinecarboxylamide;
N- [1- (2-phenylethyl) -4-piperidinyl] -8-methoxy-4 - [[4 - [[[1- (phenylmeth-yl) -4-piperidinyl] amino] carbonyl] phenyl] -amino] -3-quinolinecarboxylamide;
4 - [[4 - [[(1-butyl-4-piperidinyl) amino] carbonyl] phenyl] aminol-8-methoxy-N- [1- (phenylmethyl) -4-piperidinyl] -3 -quinoline carboxylamide;
8-Methoxy-N- (1-methyl-4-piperidinyl) -4- [[4 - [[[1- (phenylmethyl) -4-piperidinyl] amino] carbonyl] phenyl] amino] -3-quinoline carboxylamide ;
N- [1 - [(3-methoxyphenyl) methyl] -4-piperidinyl-8-methoxy-4 - [[4 - [[[1- (phenylmethyl) -4-piperidinyl] aminoj-carbonyl] phenyl] -amino-3-quinolinecarboxylamide;
8-Methoxy-4 - [[4 - [[[1- (phenylmethyl) -4-piperidinyl] amino] carbonyl] phenyl] amino] -1 - [[3- (trifluoromethyl) phenyl] methyl ] -4-piperidinyl] -3-quinolinecarboxylamide; or
7-chloro-N- [1- (phenylmethyl) -4-piperidinyl] -4 - [[4 - [[[1- (phenylmethyl -) - 4-piperidinyl] amino] carbonyl] phenyl] amino] -3-quinoline carboxylamide; -
and their physiologically tolerable salts.
Ganz besonders geeignet sind auch die folgenden, in den Tabellen 1-3 aufgelisteten Verbindungen der Beispiele 1-44. The following, in Tables 1-3, are also particularly suitable listed compounds of Examples 1-44.
Die Anwendung kann enteral, parenteral - wie z. B. subkutan, i.m. oder i.v. -, nasal, rektal oder per Inhalation erfolgen. Die Dosierung des Wirkstoffs hängt vom Körpergewicht, Alter und von der Applikationsart ab.The application can be enteral, parenteral - such as. B. subcutaneously, i.m. or i.v. -, nasally, rectally or by inhalation. The dosage of the active ingredient depends on body weight, age and the type of application.
Die pharmazeutischen Präparate der vorliegenden Erfindung werden in an sich bekannten Lösungs-, Misch-, Granulier-, Tabletten- oder Dragierverfahren hergestellt. The pharmaceutical preparations of the present invention are in themselves known solution, mixing, granulating, tablet or coating processes produced.
Zur parenteralen Applikation werden die aktiven Verbindungen oder deren physiologisch verträgliche Salze, gewünschtenfalls mit den pharmazeutisch üblichen Hilfsstoffen, beispielsweise zur Isotonisierung oder pH-Einstellung sowie Lösungsvermittler, Emulgatoren, oder anderen Hilfsstoffen, in Lösung, Suspension oder Emulsion gebracht.For parenteral administration, the active compounds or their physiologically acceptable salts, if desired with the pharmaceutical usual auxiliaries, for example for isotonization or pH adjustment as well as solubilizers, emulsifiers, or other auxiliaries, in solution, Bring suspension or emulsion.
Für die beschriebenen Arzneistoffe ist auch der Einsatz von injizierbaren Retardzubereitungen zur subkutanen oder intramuskulären Anwendung sinnvoll. Als Arzneimittel können z. B. ölige Kristallsuspensionen, Mikrokapseln, Mikropartikel, Nanopartikel oder Implantate verwendet werden, wobei die letzteren aus gewebeverträglichen Polymeren, insbesondere bioabbaubaren Polymeren, wie z. B. auf der Basis von Polymilchsäure-Polyglykolsäure- Copolymeren aufgebaut sein können. Andere denkbare Polymere sind Polyamide, Polyester, Polyacetate oder Polysaccharide.The use of injectables is also necessary for the drugs described Retard preparations for subcutaneous or intramuscular use make sense. As a drug, e.g. B. oily crystal suspensions, microcapsules, Microparticles, nanoparticles or implants are used, the the latter from tissue-compatible polymers, in particular biodegradable Polymers such as B. based on polylactic acid-polyglycolic acid Copolymers can be constructed. Other conceivable polymers are Polyamides, polyesters, polyacetates or polysaccharides.
Für die orale Anwendungsform werden die aktiven Verbindungen mit den dafür üblichen Zusatzstoffen wie Trägerstoffen, Stabilisatoren oder inerten Verdünnungsmitteln vermischt und durch übliche Methoden in geeignete Darreichungsformen gebracht, wie Tabletten, Dragees, Steckkapseln, wäßrige alkoholische oder ölige Suspensionen oder wäßrige alkoholische oder ölige Lösungen. Als inerte Träger können z. B. Gummi arabicum, Magnesia, Magnesiumcarbonat, Kaliumphosphat, Milchzucker, Glucose, Magnesiumstearylflumarat oder Stärke, insbesondere Maisstärke verwendet werden. Dabei kann die Zubereitung von festen Arzneiformen sowohl als Trocken- und Feuchtgranulat erfolgen. Als ölige Trägerstoffe oder Lösungsmittel kommen beispielsweise pflanzliche oder tierische Öle in Betracht, wie Sonnenblumenöl und Lebertran.For the oral application form, the active compounds with the for it usual additives such as carriers, stabilizers or inert Diluents mixed and by suitable methods in suitable Dosage forms brought, such as tablets, coated tablets, capsules, aqueous alcoholic or oily suspensions or aqueous alcoholic or oily Solutions. As inert carriers such. B. gum arabic, magnesia, Magnesium carbonate, potassium phosphate, milk sugar, glucose, Magnesium stearyl fumarate or starch, especially corn starch will. The preparation of solid dosage forms can be used both as Dry and wet granules are made. As an oily carrier or solvent For example, vegetable or animal oils come into consideration, such as Sunflower oil and cod liver oil.
Auch orale Retardzubereitungen oder Zubereitungen mit magensaftresistenten Überzügen sind denkbar. Retardzubereitungen können auf Basis von Fett-, Wachs- oder Polymereinbettungen aufgebaut sein. Möglich sind hierbei auch Mehrschicht- oder Manteltabletten oder Pellets.Oral sustained-release preparations or preparations with gastric juice-resistant Coatings are conceivable. Slow-release preparations can be based on fat, Wax or polymer embeddings can be built up. This is also possible Multilayer or coated tablets or pellets.
Für die beschriebenen Arzneistoffe ist auch eine Applikation auf Schleimhäute zur Erzielung systemisch wirksamer Spiegel sinnvoll. Dies betrifft die Möglichkeit der intranasalen, inhalativen und rektalen Anwendung.For the medicinal substances described there is also an application to mucous membranes useful for achieving systemically effective mirrors. This affects the Possibility of intranasal, inhalation and rectal use.
Für die intranasale Anwendungsform werden die Verbindungen mit den dafür üblichen Zusatzstoffen wie Stabilisatoren oder inerten Verdünnungsmitteln vermischt und durch übliche Methoden in geeignete Darreichungsformen gebracht, wie Pulver, wäßrige alkoholische oder ölige Suspensionen oder wäßrige, alkoholische oder ölige Lösungen. Wäßrigen intranasalen Zubereitungen können Chelatbildner, wie Ethylendiamin-N,N,N′,N′- tetraessigsäure und Puffer wie Essigsäure, Phosphorsäure, Citronensäure, Weinsäure und deren Salze zugefügt werden. Mehrfachdosenbehälter enthalten Konservierungsmittel wie Benzalkoniumchlorid, Chlorbutanol, Chlorhexidin, Sorbinsäure, Benzoesäure, PHB-Ester oder Organoquecksilberverbindungen.For the intranasal form of application, the connections with the are usual additives such as stabilizers or inert diluents mixed and by usual methods in suitable dosage forms brought, such as powder, aqueous alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. Aqueous intranasal Preparations can be chelating agents, such as ethylenediamine-N, N, N ′, N′- tetraacetic acid and buffers such as acetic acid, phosphoric acid, citric acid, Tartaric acid and its salts are added. Multiple can containers included Preservatives such as benzalkonium chloride, chlorobutanol, chlorhexidine, Sorbic acid, benzoic acid, PHB ester or organo mercury compounds.
Die Applikation der Nasallösungen kann mittels Dosierzerstäuber erfolgen oder als Nasaltropfen mit viskositätserhöhendem Anteil bzw. Nasengels oder Nasencremes. Für die inhalative Anwendung können Vernebler oder Druckgas- Packungen unter Verwendung inerter Trägergase benutzt werden.The nasal solutions can be applied using a dosing atomizer or as nasal drops with a viscosity-increasing proportion or nasal gel or Nasal creams. For inhalation use, nebulizers or compressed gas Packs can be used using inert carrier gases.
Zur Applikation von Pulvern zur nasalen oder pulmonalen Inhalation sind spezielle Applikatoren erforderlich.For the application of powders for nasal or pulmonary inhalation special applicators required.
Die wirksame Dosis der Verbindungen der Formel (I) beträgt mindestens 0,01 mg/kg/Tag, vorzugsweise mindestens 0,1 mg/kg/Tag, höchstens 30 mg/kg/Tag, vorzugsweise 0,3 bis 10 mg/kg/Tag Körpergewicht in Abhängigkeit vom Schweregrad der Symptomatik, bezogen auf einen Erwachsenen von 75 kg Körpergewicht. The effective dose of the compounds of formula (I) is at least 0.01 mg / kg / day, preferably at least 0.1 mg / kg / day, at most 30 mg / kg / day, preferably 0.3 to 10 mg / kg / day of body weight depending on Severity of symptoms, based on an adult of 75 kg Body weight.
Wirkung der Verbindung aus Beispiel 6 (= Verbindung A) auf die Urin- und Elektrolytausscheidung an Ratten mit Tetrachlorkohlenstoff-induzierter Leberfibrose.Effect of the compound from Example 6 (= compound A) on the urine and Electrolyte excretion in rats with carbon tetrachloride-induced Liver fibrosis.
An Wistar Ratten (Züchter: Hoechst AG, Kastengrund) mit einem anfänglichen Körpergewicht von 120-150 g wurde, wie von Bickel et al. (J. Hepatol. 1991; 13 (Suppl. 3), S. 26-S. 33) beschrieben, eine Leberfibrose induziert. Dazu erhielten die Tiere zweimal pro Woche Tetrachlorkohlenstoff (CCl₄) in einer Dosis von 1 ml/kg per os für mindestens 6 Wochen. Die Fibrose der Leber wurde über den Kollagengehalt der Leber und Leber-relevante Serumparameter (Bilirubin, ALAT, Gallensäuren) verifiziert.To Wistar rats (breeder: Hoechst AG, Kastengrund) with one initial body weight of 120-150 g was as described by Bickel et al. (J. Hepatol. 1991; 13 (Suppl. 3), p. 26-p. 33), one Induced liver fibrosis. The animals received twice a week Carbon tetrachloride (CCl₄) at a dose of 1 ml / kg per os for at least 6 weeks. The fibrosis of the liver was over the Liver collagen content and liver-relevant serum parameters (bilirubin, ALAT, bile acids) verified.
Im Verlauf der Fibrogenese wurden die Tiere unter Standardbedingungen wie folgt gehalten: Tages-Nacht-Rhythmus (Hellphase von 6.30 bis 18.30), Raumtemperatur 22 ± 2°C und relative Luftfeuchtigkeit 60 ± 10%. Die Tiere erhielten standartisierte Rattenfutter (Altromin® 1321) und Wasser ad libitum.In the course of fibrogenesis, the animals were under standard conditions held as follows: day-night rhythm (light phase from 6.30 to 18.30), room temperature 22 ± 2 ° C and relative humidity 60 ± 10%. The animals received standardized rat food (Altromin® 1321) and water ad libitum.
Zum Zeitpunkt des Diureseversuches hatten die Tiere ein Gewicht zwischen 210 und 260 g erreicht. Futter wurde bereits 16 h vor dem Versuch entzogen und während des gesamten Versuchs vorenthalten. Der freie Zugang zu Wasser war den Tieren noch bis zum eigentlichen Versuchsbeginn gestattet. The animals had a weight at the time of the diuresis experiment reached between 210 and 260 g. Food was already 16 h before Trial withdrawn and withheld throughout the trial. The animals had free access to water until the actual day Start of experiment allowed.
Die Tiere wurden für die Dauer des Diureseversuches in speziellen Diuresekäfigen gehalten. Eine kontrollierte Diurese wurde mit einer orale Gabe von 20 ml Wasser per kg Körpergewicht zum Zeitpunkt 0 h ausgelöst. Die Ausscheidung von Elektrolyten und Urinvolumen wurde in den Sammelperioden von 0-5 und 6-24 h getrennt für jedes Tier ermittelt.The animals were kept in special for the duration of the diuresis trial Diuresis cages held. A controlled diuresis was performed with an oral one Administration of 20 ml water per kg body weight at the time 0 h triggered. The excretion of electrolytes and urine volume was in the collection periods of 0-5 and 6-24 h separately for each animal.
Sieben Tage später wurde der Versuch an den gleichen Tieren erneut durchgeführt unter Gabe von Bradykininantagonisten. Zum Zeitpunkt 0 und 6 h erhielten die Tiere 3 mg/kg Körpergewicht Verbindung A intraperitoneal, gelöst in 5 ml/kg Körpergewicht mit der folgenden Zusammensetzung: DSMO 28%, Ethanol 20%, Aqua bidest 44% und 0,9%ige Kochsalzlösung 8%, pH 5,71.The experiment on the same animals was repeated seven days later performed with bradykinin antagonists. At time 0 and for 6 hours the animals received 3 mg / kg body weight compound A intraperitoneally, dissolved in 5 ml / kg body weight with the following Composition: DSMO 28%, ethanol 20%, Aqua bidest 44% and 0.9% saline 8%, pH 5.71.
Natrium und Kalium wurden flammenphotometrisch bestimmt (Flammenphotometer Eppendorf, Hamburg). Chlorid wurde argentometrisch über potentiometrische Endpunktbestimmung gemessen (Chloridmeter Eppendorf, Hamburg). Die analytischen Ergebnisse wurden zur Berechnung der Urinausscheidung (ml/kg Körpergewicht) und Elektrolytausscheidung (mmol/kg Körpergewicht) herangezogen. Sodium and potassium were determined by flame photometry (Eppendorf flame photometer, Hamburg). Chloride measured argentometrically via potentiometric endpoint determination (Eppendorf chloride meter, Hamburg). The analytical results were to calculate urine output (ml / kg body weight) and Electrolyte excretion (mmol / kg body weight) was used.
Die Ergebnisse sind angegeben als arithmetische Mittel und Standardabweichung (SD). Die statistische Überprüfung erfolgte mit dem nicht-parametrischen Test nach Mann-Whitney.The results are given as arithmetic mean and Standard deviation (SD). The statistical check was carried out with the Mann-Whitney non-parametric test.
Ratten mit Leberfibrose zeigen eine deutliche Erhöhung der Diurese und Salurese nach Behandlung mit nicht-peptidischen Bradykininantagonisten. Als Beispiel sind in der obigen Tabelle experimente Daten mit der Beispielverbindung 6 (Verbindung A) aufgeführt. Es ergibt sich eine deutliche, statistisch signifikante Zunahme der Diurese und Ausscheidung von Natrium und Chlorid.Rats with liver fibrosis show a marked increase in diuresis and Saluresis after treatment with non-peptide bradykinin antagonists. As an example in the table above are experimental data with the Example compound 6 (compound A) listed. There is one significant, statistically significant increase in diuresis and excretion of sodium and chloride.
Das Modell der Tetrachlorkohlenstoff-induzierten Leberfibrose an der Ratte findet als Modell für die Leberzirrhose am Menschen allgemeine Anerkennung. Überschießende Natriumretention ist charakteristisch für die Leberfibrose und Leberzirrhose bei Mensch und Tier und wird als Folge einer tiefgreifenden hämodynamischen Störung betrachtet (Schrier et al., Hepatology 1988; 1151-1157). Diese hämodynamische Störung besteht in einer portalen Hypertonie (Pfortaderhochdruck), die eng verknüpft mit einer überschießenden peripheren Vasodilation vor allem im Splanchnicusgebiet (hyperdyname Kreislaufsituation). Die Ursache der peripheren Vasodilatation war bisher nicht geklärt. Die pathologische Natrium- und Wasserretention verschlechtert ihrerseits die Symptomatik, indem sie z. B. zu Ödembildung und Aszites beiträgt. Die portale Hypertonie ist assoziiert mit inadäquater peripherer Vasodilatation und Natriumretention. Diese werden für Dekompensationserscheinungen bei Leberfibrose und Leberzirrhose verantwortlich gemacht. Diese Dekompensationserscheinungen umfassen nicht nur Symptome wie Ödembildung und Aszites, sondern auch das sogenannte heptaorenale Syndrom (Nierenversagen als Folge einer schweren Lebererkrankung). The model of carbon tetrachloride-induced liver fibrosis in the rat is widely recognized as a model for human cirrhosis. Excessive sodium retention is characteristic of liver fibrosis and Liver cirrhosis in humans and animals and is a result of profound hemodynamic disorder (Schrier et al., Hepatology 1988; 1151-1157). This hemodynamic disorder consists of portal hypertension (Portal vein hypertension), which is closely linked to an excessive peripheral Vasodilation especially in the splanchnic area (hyper-dynamic circulatory situation). The cause of peripheral vasodilation has not yet been clarified. The pathological sodium and water retention in turn worsens the Symptoms by z. B. contributes to edema formation and ascites. The portal Hypertension is associated with inadequate peripheral vasodilation and Sodium retention. These are used for signs of decompensation Liver fibrosis and cirrhosis are held responsible. This Decompensation symptoms do not only include symptoms such as Edema formation and ascites, but also the so-called heptaorenal syndrome (Kidney failure as a result of severe liver disease).
Die starke natriuretische Wirkung von nicht-peptidischen Bradykininantagonisten der Formel (I) bei Ratten mit Leberfibrose und Leberzirrhose ist unerwartet, weil Bradykininantagonisten an gesunden Tieren diese Wirkung nicht zeigen und, im Gegenteil, in besonderen Hypertonie- Modellen sogar zu einer Verminderung der Diurese und Natriumausscheidung führen kann (Madeddu et al., Br. J. Pharmacol. 1992; 106: 380-86; Majima et al., Hypertension 1993; 22, 705-714). Bradykinin kann nämlich in der Niere Salurese und Diurese über vaskuläre und tubuläre Mechanismen stimulieren.The strong natriuretic effects of non-peptide Bradykinin antagonists of formula (I) in rats with liver fibrosis and Cirrhosis of the liver is unexpected because bradykinin antagonists occur in healthy animals do not show this effect and, on the contrary, in special hypertension Models even reduce diuresis and sodium excretion (Madeddu et al., Br. J. Pharmacol. 1992; 106: 380-86; Majima et al., Hypertension 1993; 22, 705-714). Bradykinin can namely in the kidney Stimulate saluresis and diuresis via vascular and tubular mechanisms.
Bradykinin ist ein endogenes Peptid mit stark vasodilatierenden Eigenschaften in verschiedenen Gefäßgebieten. Unsere Ergebnisse zeigen, daß Bradykinin mit seinen stark vasodilatierenden Eigenschaften ein wesentlicher Mediator der exzessiven Natriumretention und pathologischen Vasodillatation ist. Eine verbesserte hämodynamische Situation überkompensiert bei weitem eine mögliche Einschränkung der Natrium- und Wasserausscheidung durch Hemmung der stimulierenden Wirkung endogenen Bradykinins in der Niere, so daß ein therapeutischer Nutzen resultiert.Bradykinin is an endogenous peptide with strong vasodilating properties in different vascular areas. Our results show that bradykinin with its strong vasodilating properties an essential mediator of there is excessive sodium retention and pathological vasodillatation. A improved hemodynamic situation far overcompensates one possible limitation of sodium and water excretion through Inhibition of the stimulating effect of endogenous bradykinins in the kidney, see that therapeutic benefits result.
Somit sind nicht-peptidische Bradykininantagonisten der Formel (I) geeignet für die therapeutische und präventive Behandlung bei chronischen fibrogenetischen Lebererkrankungen (Leberzirrhose und Leberfibrose) und akuten Lebererkrankungen.Thus, non-peptide bradykinin antagonists of formula (I) are suitable for the therapeutic and preventive treatment for chronic fibrogenetic Liver disease (cirrhosis and fibrosis) and acute Liver disease.
Claims (4)
X¹ Stickstoff oder C-R⁴;
X² Stickstoff oder C-R⁵;
X³ Stickstoff oder C-R⁶;
X⁴ Sauerstoff, Stickstoff oder N-R⁷;
R¹, R² sind gleich oder verschieden und stehen für Wasserstoff, Halogen, (C₁- C₄)-Alkyl und (C₁-C₄)-Alkoxy;
R³ Wasserstoff, Halogen, (C₁-C₆)-Alkyl, (C₆-C₁₂)-Aryl, (C₁-C₃)-Alkyl-(C₆-C₁₂)- Aryl, (C₃-C₅)-Alkenyl, (C₁-C₄)-Alkoxy, CO₂R¹¹;
R⁴ Wasserstoff, Halogen, (C₁-C₄)-Alkyl, Hydroxy, (C₁-C₄)-Alkylthio, Amino, (C₁-C₄)-Alkylamino, (C₁-C₄)-Dialkylamino, (C₁-C₄)-Alkoxy, das gegebenenfalls substituiert ist mit Hydroxy, (C₁-C₄)-Alkoxy, Amino und (C₁- C₄)-Alkylamino, und (C₆-C₁₂)-Aryl, gegebenenfalls substituiert mit (C₁-C₄)- Alkyl oder CO₂R¹¹;
R⁵ 1. Wasserstoff oder (C₁-C₄)-Alkyl R⁶ 1. Wasserstoff, Halogen, (C₁-C₄)-Alkyl, Hydroxy, (C₁-C₄)-Alkylthio, Amino, (C₁-C₄)-Alkylamino, (C₁-C₄)-Dialkylamino, (C₁-C₄)-Alkoxy, das gegebenenfalls substituiert ist mit Hydroxy, (C₁-C₄)-Alkoxy, Amino und (C₁-C₄)-Alkylamino, und (C₆-C₁₂)-Aryl, gegebenenfalls substituiert mit (C₁-C₄)-Alkyl oder CO₂R¹¹;
2. ein Rest der Formel (VIII): R⁷ (C₁-C₄)-Alkyl, (C₆-C₁₂)-Aryl, oder (C₁-C₃)-Alkyl-(C₆-C₁₂)-Aryl;
R⁸, R⁹ sind gleich oder verschieden und stehen für Wasserstoff und Halogen;
A (C₁-C₃)-Alkandiyl;
Q O oder NR¹¹;
R¹⁰ ein Rest der Formel (IX) R¹¹, R¹⁴ Wasserstoff oder (C₁-C₄)-Alkyl;
G O oder H₂;
R¹² steht bei G=O für Wasserstoff und bei G=H₂ für Wasserstoff oder R¹⁶ CO;
R¹³ ist (C₁-C₄)-Alkyl, (C₃-C₇)-Cycloalkyl, (CH₂)m-(C₃-C₇)-Cycloalkyl, -(CH₂)m-CONR¹¹R¹¹, oder m, n sind gleich oder verschieden eine Zahl 0-6;
AA steht für eine Aminosäure wie z. B. Methionin, Alanin, Phenylalanin, 2-Chlorphenylalanin, 3-Chlorphenylalanin, 4-Chlorphenylalanin, 2-Fluor phenylalanin, 3-Fluorphenylalanin, 4-Fluorphenylalanin, Tyrosin, o-Methyltyrosin, β-(2-Thienyl)-alanin, Glycin, Cyclohexylalanin, Leucin, Isoleucin, Valin, Norleucin, Phenylglycin, Serin, Cystein, Aminopropionsäure oder Aminobuttersäure;
Y 1. (C₂-C₆)-Alkendiyl,
2. (C₁-C₈)-Alkandiyl,
3. (C₃-C₁₀)-Cycloalkendiyl,
4. -(CH)p-To(CH₂)q-,
wobei 1. bis 4. gegebenenfalls mit einen oder mehreren Resten wie z. B. O-R¹⁸, NO₂, CN, CO₂R¹¹, SO₃R¹⁸, NR²⁰R²¹, SO₂NR²⁰R²¹, CONR²⁰R²¹ substituiert sein kann;
T O, NR²¹, oder S;
o ist eine Zahl 0 oder 1
p, q sind gleich oder verschieden und bedeuten eine Zahl von 0 bis 6;
R¹⁵ 1. Wasserstoff,
2. (C₆-C₁₀)-Aryl,
3. (C₁-C₉)-Heteroaryl,
wobei 2. und 3. gegebenenfalls mit einer oder mehreren Gruppen substituiert sein können, wie Halogen, CN, NO₂, (C₁-C₆)-Alkyl, (C₆- C₁₀)-Aryl, (C₂-C₅)-Alkenyl, wobei die letzten drei Reste gegebenenfalls teilweise oder vollständig mit Halogen substituiert sein können, (C₁- C₅)-Alkoxy; (C₁-C₅)-Alkylthio, NR²⁰R²¹, CO₂R¹⁹, SO₃R¹⁸, SO₂NR²⁰R²¹, SO₂R¹⁸, O-R¹⁸; NR²⁰CO-R¹⁵;
R¹⁶ ist Wasserstoff, (C₁-C₄)-Alkyl, (C₆-C₁₂)-Aryl, (C₁ -C₄)-Alkyl-(C₆-C₁₂)- Aryl, Perfluoro-(C₁-C₄)-Alkyl;
R¹⁷ ist Wasserstoff, Halogen, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxy, Perfluoro-(C₁- C₄)-Alkyl, NO₂, OH, NH₂, CONR¹⁶R¹⁶, NR¹⁶CONR¹⁶R¹⁶
R¹⁸, R¹⁹, R²⁰ gleich oder verschieden sind und Wasserstoff, (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, oder C(O)-NH-(C₁ -C₅)-Alkyl bedeuten;
R²¹ Wasserstoff, C(O)-O-(C₁-C₅)-Alkyl, C(O)-O-(C₁-C₃)-Alkyl-(C₆-C₁₀)-Aryl;
Z -R¹⁴N-R²²;
R²² steht für R²³ (C₁-C₄)-Alkyl, sowie deren physiologisch verträglichen Salze. 2. Use according to claim 1 of a non-peptide bradykinin antagonist of the formula (I) in which the symbols have the following meaning: D 1. a radical of the formula (II): 2. a radical of the formulas (III) to (VI): E 1. a radical of the formula (VII): 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;
X¹ is nitrogen or C-R⁴;
X² is nitrogen or C-R⁵;
X³ is nitrogen or C-R⁶;
X⁴ oxygen, nitrogen or N-R⁷;
R¹, R² are the same or different and represent hydrogen, halogen, (C₁-C₄) alkyl and (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, CO₂R¹¹;
R⁴ is hydrogen, halogen, (C₁-C₄) alkyl, hydroxy, (C₁-C₄) alkylthio, amino, (C₁-C₄) alkylamino, (C₁-C₄) dialkylamino, (C₁-C₄) alkoxy, that is optionally substituted with hydroxy, (C₁-C₄) alkoxy, amino and (C₁-C₄) alkylamino, and (C₆-C₁₂) aryl optionally substituted with (C₁-C₄) alkyl or CO₂R¹¹;
R⁵ 1. hydrogen or (C₁-C₄) alkyl R⁶ 1. hydrogen, halogen, (C₁-C₄) alkyl, hydroxy, (C₁-C₄) alkylthio, amino, (C₁-C₄) alkylamino, (C₁-C₄) dialkylamino, (C₁-C₄) alkoxy optionally substituted with hydroxy, (C₁-C₄) alkoxy, amino and (C₁-C₄) alkylamino, and (C₆-C₁₂) aryl optionally substituted with (C₁-C₄) alkyl or CO₂R¹¹;
2. a radical of the formula (VIII): R⁷ (C₁-C₄) alkyl, (C₆-C₁₂) aryl, or (C₁-C₃) alkyl- (C₆-C₁₂) aryl;
R⁸, R⁹ are the same or different and stand for hydrogen and halogen;
A (C₁-C₃) alkanediyl;
QO or NR¹¹;
R¹⁰ is a radical of the formula (IX) R¹¹, R¹⁴ are hydrogen or (C₁-C₄) alkyl;
GO or H₂;
R¹² stands for G = O for hydrogen and for G = H₂ for hydrogen or R¹⁶ CO;
R¹³ is (C₁-C₄) alkyl, (C₃-C₇) cycloalkyl, (CH₂) m - (C₃-C₇) cycloalkyl, - (CH₂) m -CONR¹¹R¹¹, or m, n, identical or different, are a number 0-6;
AA stands for an amino acid such as B. 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 1. (C₂-C₆) alkylene diyl,
2. (C₁-C₈) alkanediyl,
3. (C₃-C₁₀) cycloalkenediyl,
4.- (CH) p -T o (CH₂) q -,
where 1. to 4. optionally with one or more radicals such as. B. O-R¹⁸, NO₂, CN, CO₂R¹¹, SO₃R¹⁸, NR²⁰R²¹, SO₂NR²⁰R²¹, CONR²⁰R²¹ may be substituted;
TO, NR²¹, or S;
o is a number 0 or 1
p, q are the same or different and represent a number from 0 to 6;
R¹⁵ 1. hydrogen,
2. (C₆-C₁₀) aryl,
3. (C₁-C₉) heteroaryl,
where 2. and 3. may optionally be substituted with one or more groups, such as halogen, CN, NO₂, (C₁-C₆) alkyl, (C₆- C₁₀) aryl, (C₂-C₅) alkenyl, the latter three radicals may optionally be partially or completely substituted with halogen, (C₁-C₅) alkoxy; (C₁-C₅) alkylthio, NR²⁰R²¹, CO₂R¹⁹, SO₃R¹⁸, SO₂NR²⁰R²¹, SO₂R¹⁸, O-R¹⁸; NR²⁰CO-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, CONR¹⁶R¹⁶, NR¹⁶CONR¹⁶R¹⁶
R¹⁸, R¹⁹, R²⁰ are the same 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 -R¹⁴N-R²²;
R²² stands for R²³ (C₁-C₄) alkyl, and their physiologically tolerable salts.
D ein Rest der allgemeinen Formel (X) E 1. einen Rest der Formel (XI) 2. Wasserstoff, (C₁-C₄)-Alkyl und (C₁-C₄)-Alkoxy;
R¹, R² sind gleich oder verschieden uns stehen für Wasserstoff, Halogen und (C₁-C₄)-Alkyl;
R⁴ ist Wasserstoff, (C₁-C₄)-Alkyl, Phenyl und Methoxy;
R⁵ 1. Wasserstoff oder (C₁-C₄)-Alkyl; R⁶ 1. Wasserstoff und (C₁-C₄)-Alkyl
2. ein Rest der Formel (VIII): R⁸, R⁹ sind gleich oder verschieden und stehen für Wasserstoff oder Chlor;
A ist -CH₂- oder -CH₂-CH₂-;
R¹⁰ steht für einen Rest der Formel (IX): R¹¹, R¹⁴ sind Wasserstoff, Methyl oder Ethyl;
G steht für O oder H₂;
R¹² steht bei G gleich O für Wasserstoff oder bei G gleich H₂ für Wasserstoff oder R¹⁶CO;
R¹³ ist (C₁-C₄)-Alkyl, Cyclopentyl, Cyclohexyl, -(CH₂)mCONR¹¹R¹¹, m, n sind gleich oder verschieden eine Zahl 0-2;
AA steht für die Aminosäure Glycin oder Alanin;
Y 1. (C₂-C₅)-Alkendiyl,
2. (C₂-C₄)-Alkandiyl,
3. -(CH₂)p-To-(CH₂)q-;
T steht für 0 oder S;
o ist eine Zahl 0 oder 1;
p, q sind gleich oder verschieden und bedeuten eine Zahl von 0-2;
R¹⁵ 1. Wasserstoff
2. Phenyl,
3. (C₅-C₉)-Heteroaryl,
wobei 2. und 3. gegebenenfalls mit einer, zwei oder drei Gruppen substituiert sein können, wie Halogen, NO₂, (C₁-C₃)-Alkyl, (C₁-C₃)-Alkyl, in dem die H-Atome teilweise oder vollständig durch Halogen ersetzt sind, (C₁- C₃)-Alkoxy, (C₁-C₃)-Alkylthio, NR²⁰R²¹ und NR²⁰CO-Pyridyl
R¹⁶ ist Wasserstoff, (C₁-C₄)-Alkyl, Phenyl;
R¹⁷ ist Wasserstoff, Halogen, (C₁-C₄)-Alkyl, NO₂, NH₂;
R²⁰ ist Wasserstoff, (C₁-C₄)-Alkyl, Benzyl;
R²¹ ist Wasserstoff, C(O)-O-(C₁-C₅)-Alkyl;
Z ist -R¹⁴-N-R²²
R²² R²³ (C₁-C₄)-Alkyl, sowie deren physiologisch verträglichen Salze.3. Use according to claim 2 of a non-peptide bradykinin antagonist of the formula (I), in which the symbols have the following meaning:
D is a radical of the general formula (X) E 1. a radical of the formula (XI) 2. hydrogen, (C₁-C₄) alkyl and (C₁-C₄) alkoxy;
R¹, R² are the same or different and are hydrogen, halogen and (C₁-C₄) alkyl;
R⁴ is hydrogen, (C₁-C₄) alkyl, phenyl and methoxy;
R⁵ 1. hydrogen or (C₁-C₄) alkyl; R⁶ 1. hydrogen and (C₁-C₄) alkyl
2. a radical of the formula (VIII): R⁸, R⁹ are the same or different and stand for hydrogen or chlorine;
A is -CH₂- or -CH₂-CH₂-;
R¹⁰ represents a radical of the formula (IX): R¹¹, R¹⁴ are hydrogen, methyl or ethyl;
G represents O or H₂;
R¹² is G when O is hydrogen or G is H₂ is hydrogen or R¹⁶CO;
R¹³ is (C₁-C₄) alkyl, cyclopentyl, cyclohexyl, - (CH₂) m CONR¹¹R¹¹, m, n are the same or different, a number 0-2;
AA stands for the amino acid glycine or alanine;
Y 1. (C₂-C₅) alkylene diyl,
2. (C₂-C₄) alkanediyl,
3. - (CH₂) p -T o - (CH₂) q -;
T stands for 0 or S;
o is a number 0 or 1;
p, q are the same or different and represent a number from 0-2;
R¹⁵ 1. hydrogen
2. phenyl,
3. (C₅-C₉) heteroaryl,
where 2. and 3. may optionally be substituted with one, two or three groups, such as halogen, NO₂, (C₁-C₃) alkyl, (C₁-C₃) alkyl, in which the H atoms are partially or completely replaced by halogen are replaced, (C₁-C₃) alkoxy, (C₁-C₃) alkylthio, NR²⁰R²¹ and NR²⁰CO-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 R²³ (C₁-C₄) alkyl, and their physiologically tolerable salts.
D ein Rest der allgemeinen Formel (X) E ein Rest der Formel (XI) R¹, R² sind gleich oder verschieden uns stehen für Wasserstoff, Halogen und (C₁-C₄)-Alkyl;
R⁴ Wasserstoff, (C₁-C₄)-Alkyl;
R⁵ Wasserstoff;
R⁶ Wasserstoff;
R⁸, R⁹sind gleich oder verschieden und stehen für Wasserstoff oder Chlor;
A -CH₂- oder -CH₂-CH₂-;
R¹⁰ ein Rest der Formel (IX): R¹⁴ Wasserstoff, Methyl oder Ethyl;
AA steht für die Aminosäure Glycin;
Y 1. (C₂-C₅)-Alkendiyl,
2. (C₂-C₄)-Alkandiyl,
3. -(CH₂)p-To-(CH₂)q-;
T steht für 0 oder S;
o ist eine Zahl 0 oder 1;
p, q sind gleich oder verschieden und bedeuten eine Zahl von 0-2;
R¹⁵ 1. Wasserstoff
2. Phenyl,
3. (C₅-C₉)-Heteroaryl,
wobei 2. und 3. gegebenenfalls mit einer, zwei oder drei Gruppen substituiert sein können, wie Halogen, NO₂, (C₁-C₃)-Alkyl, (C₁-C₃)-Alkyl, in dem die H-Atome teilweise oder vollständig durch Halogen ersetzt sind, (C₁- C₃)-Alkoxy, NR²⁰R²¹ und NR²⁰CO-Pyridyl;
R²⁰ ist Wasserstoff, (C₁-C₄)-Alkyl, Benzyl;
R²¹ ist Wasserstoff, C(O)-O-(C₁-C₅)-Alkyl;
sowie deren physiologisch verträglichen Salze.4. Use according to claim 2 or 3 of a non-peptide bradykinin antagonist of the formula (I), in which the symbols have the following meaning:
D is a radical of the general formula (X) E is a radical of the formula (XI) R¹, R² are the same or different and are hydrogen, halogen and (C₁-C₄) alkyl;
R⁴ is hydrogen, (C₁-C₄) alkyl;
R⁵ hydrogen;
R⁶ hydrogen;
R⁸, R⁹ are the same or different and represent hydrogen or chlorine;
A -CH₂- or -CH₂-CH₂-;
R¹⁰ is a radical of the formula (IX): R¹⁴ is hydrogen, methyl or ethyl;
AA stands for the amino acid glycine;
Y 1. (C₂-C₅) alkylene diyl,
2. (C₂-C₄) alkanediyl,
3. - (CH₂) p -T o - (CH₂) q -;
T stands for 0 or S;
o is a number 0 or 1;
p, q are the same or different and represent a number from 0-2;
R¹⁵ 1. hydrogen
2. phenyl,
3. (C₅-C₉) heteroaryl,
where 2. and 3. may optionally be substituted with one, two or three groups, such as halogen, NO₂, (C₁-C₃) alkyl, (C₁-C₃) alkyl, in which the H atoms are partially or completely replaced by halogen are replaced, (C₁-C₃) alkoxy, NR²⁰R²¹ and NR²⁰CO-pyridyl;
R²⁰ is hydrogen, (C₁-C₄) alkyl, benzyl;
R²¹ is hydrogen, C (O) -O- (C₁-C₅) alkyl;
and their physiologically tolerable salts.
Priority Applications (29)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1996120509 DE19620509A1 (en) | 1996-05-22 | 1996-05-22 | Use of non-peptide bradykinin antagonist compounds - to treat chronic fibrogenetic liver disease, (liver cirrhosis and liver fibrosis) and acute liver disease, and to prevent complications |
| EP97107624A EP0808627A2 (en) | 1996-05-22 | 1997-05-09 | Use of non-peptide bradykinin antagonists for treating and preventing chronic fibrogenetic liver diseases, acute liver diseases and complications thereof |
| US08/858,550 US5786365A (en) | 1996-05-22 | 1997-05-19 | Use of nonpeptide bradykinin antagonists for the treatment and prevention of chronic fibrogenetic liver disorders, acute liver disorders and the complications associated therewith |
| AT97108096T ATE189389T1 (en) | 1996-05-22 | 1997-05-20 | USE OF NON-PEPTIDIC BRADYKININ ANTAGONISTS FOR THE TREATMENT AND PREVENTION OF CHRONIC FIBROGENETIC LIVER DISEASE, ACUTE LIVER DISEASE AND THEIR ASSOCIATED COMPLICATIONS |
| ARP970102136A AR007209A1 (en) | 1996-05-22 | 1997-05-20 | USE OF NON-PEPTIDIC BRADIQUININE ANTAGONISTS FOR THE PREPARATION OF MEDICINES USEFUL FOR THE TREATMENT AND PREVENTION OF CHRONIC HEPATIC AND FIBROGENETIC DISEASES, ACUTE HEPATIC DISEASES AND THE COMPLICATIONS ASSOCIATED WITH THEM |
| CZ971546A CZ154697A3 (en) | 1996-05-22 | 1997-05-20 | Use of non-peptidic antagonists of bradykinin for treating and prevention of chronic fibrogenetic diseases of livers, acute diseases of livers and complications connected therewith |
| SK630-97A SK63097A3 (en) | 1996-05-22 | 1997-05-20 | Use of non-peptide bradykinin antagonists for treatment and prophylaxy of chronic fibrinogen liver diseases, acute liver diseases and complications associated with them |
| EP97108096A EP0808628B1 (en) | 1996-05-22 | 1997-05-20 | Use of non-peptide bradykinin antagonists for treating and preventing chronic fibrogenetic liver diseases, acute liver diseases and complications thereof |
| HU9700913A HUP9700913A1 (en) | 1996-05-22 | 1997-05-20 | Use of non-peptide-type bradiquinine-antagonists for treating and profilacting chronic fibrogenetic liver diseases, acut liver diseases and complications of them |
| DE59701078T DE59701078D1 (en) | 1996-05-22 | 1997-05-20 | Use of non-peptide bradykinin antagonists for the treatment and prevention of chronic fibrogenetic liver diseases, acute liver diseases and the associated complications |
| ES97108096T ES2144291T3 (en) | 1996-05-22 | 1997-05-20 | USE OF NON-PEPTIDIC BRADIQUININE ANTAGONIST AGENTS FOR THE TREATMENT AND PREVENTION OF CHRONIC-FIBROGENETIC HEPATIC DISEASES, ACUTE HEPATIC DISEASES AND COMPLICATIONS LINKED TO THEM. |
| TR97/00392A TR199700392A2 (en) | 1996-05-22 | 1997-05-20 | Use of non-peptic bradykinin antagonists for the treatment and prevention of chronic-fibrogenetic liver diseases, acute liver diseases and their related complications . |
| PT97108096T PT808628E (en) | 1996-05-22 | 1997-05-20 | USE OF BRADIQUININE ANTAGONISTS NOT PREPARED FOR THE PREPARATION OF MEDICINES FOR THE TREATMENT AND PREVENTION OF CHRONIC DISEASES OF FIBROGENETIC SYMPTOMS OF ACUTE FIGURE DISEASES AND RELATED COMPLICATIONS |
| DK97108096T DK0808628T3 (en) | 1996-05-22 | 1997-05-20 | Use of non-peptide bradykinin antagonists for the treatment and prevention of chronic fibrinogenic liver diseases, acute |
| AU23511/97A AU2351197A (en) | 1996-05-22 | 1997-05-20 | Use of nonpeptide bradykinin antagonists for the treatment and prevention of chronic fibrogenetic liver disorders, acute liver disorders and the complications associated therewith |
| IL12086297A IL120862A0 (en) | 1996-05-22 | 1997-05-20 | Use of nonpeptide bradykinin antagonists for the treatment and prevention of chronic fibrogenetic liver disorders acute liver disorders and the complications associated therewith |
| SI9730031T SI0808628T1 (en) | 1996-05-22 | 1997-05-20 | Use of non-peptide bradykinin antagonists for treating and preventing chronic fibrogenetic liver diseases, acute liver diseases and complications thereof |
| HR19639303.5A HRP970278A2 (en) | 1996-05-22 | 1997-05-21 | Use of non-peptide bradykinin antagonists for treating and preventing chronic fibrogenetic liver diseases, acute liver diseases and complications thereof |
| JP13116097A JP4034849B2 (en) | 1996-05-22 | 1997-05-21 | Use of non-peptide bradykinin antagonists for the treatment and prevention of chronic fibrosing liver disease, acute liver disease and related complications |
| NO972311A NO972311L (en) | 1996-05-22 | 1997-05-21 | Use of non-peptidic Bradykinin antagonists for the treatment and prevention of chronic fibrogenetic liver disease, acute liver disease and the associated complications |
| CN97113108A CN1176102A (en) | 1996-05-22 | 1997-05-21 | Use of nonpeptide bradykinin antagonists for treatment and prevention of chronic fibrogenetic liver disorders acute liver disorders and complications associated therewith |
| MXPA/A/1997/003725A MXPA97003725A (en) | 1996-05-22 | 1997-05-21 | Application of nopeptide bradiquinin antagonists for the treatment and prevention of chronic and fibrogenetic hepatic diseases, acute hepatic diseases and the complications associated with the |
| ZA9704415A ZA974415B (en) | 1996-05-22 | 1997-05-21 | Use of nonpeptide bradykinin antagonists for the treatment and prevention of chronic fibrogenetic liver disorders, acute liver disorders and the complications associated therewith. |
| IDP971698A ID18447A (en) | 1996-05-22 | 1997-05-21 | USE OF NONPEPTID BRADYKININ ANTAGONIC MATERIALS FOR TREATMENT AND PREVENTION OF FIBROGENETIC HEART DISORDERS IN CHRONIC EXISTENCE OF ACUTE HEART DISORDERS AND THE COMPLICATIONS CONNECTED TO IT |
| KR1019970019637A KR19980024026A (en) | 1996-05-22 | 1997-05-21 | Use of non-peptide bradykinin antagonists to treat and prevent chronic fibrotic liver disease, acute liver disease and related complications |
| PL97320134A PL320134A1 (en) | 1996-05-22 | 1997-05-22 | Application of non-peptic bradykinin antigenes for obtaining a pharmaceutic agentobtained thereby |
| CA002205780A CA2205780A1 (en) | 1996-05-22 | 1997-05-22 | Use of nonpeptide bradykinin antagonists for the treatment and prevention of chronic fibrogenetic liver disorders, acute liver disorders and the complications associated therewith |
| BR9703367A BR9703367A (en) | 1996-05-22 | 1997-05-22 | Use of a non-peptide bradycin antagonist for the treatment and prevention of chronic fibrogenetic liver diseases acute liver diseases and the complications associated with them |
| GR20000400735T GR3033048T3 (en) | 1996-05-22 | 2000-03-24 | Use of non-peptide bradykinin antagonists for treating and preventing chronic fibrogenetic liver diseases, acute liver diseases and complications thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1996120509 DE19620509A1 (en) | 1996-05-22 | 1996-05-22 | Use of non-peptide bradykinin antagonist compounds - to treat chronic fibrogenetic liver disease, (liver cirrhosis and liver fibrosis) and acute liver disease, and to prevent complications |
| US08/858,550 US5786365A (en) | 1996-05-22 | 1997-05-19 | Use of nonpeptide bradykinin antagonists for the treatment and prevention of chronic fibrogenetic liver disorders, acute liver disorders and the complications associated therewith |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19620509A1 true DE19620509A1 (en) | 1997-11-27 |
Family
ID=26025906
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1996120509 Withdrawn DE19620509A1 (en) | 1996-05-22 | 1996-05-22 | Use of non-peptide bradykinin antagonist compounds - to treat chronic fibrogenetic liver disease, (liver cirrhosis and liver fibrosis) and acute liver disease, and to prevent complications |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE19620509A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998027959A3 (en) * | 1996-12-20 | 1998-08-13 | Boehringer Ingelheim Kg | New aqueous medicament preparations for the production of propellent gas-free aerosols |
| US7470422B2 (en) | 1996-12-20 | 2008-12-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Method for the production of propellant gas-free aerosols from aqueous medicament preparations |
-
1996
- 1996-05-22 DE DE1996120509 patent/DE19620509A1/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998027959A3 (en) * | 1996-12-20 | 1998-08-13 | Boehringer Ingelheim Kg | New aqueous medicament preparations for the production of propellent gas-free aerosols |
| US7470422B2 (en) | 1996-12-20 | 2008-12-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Method for the production of propellant gas-free aerosols from aqueous medicament preparations |
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