WO1995005823A1 - Utilisation comme medicaments d'esters d'acide 1-4-dihydropyridin dicarboxylique n-alkyles - Google Patents

Utilisation comme medicaments d'esters d'acide 1-4-dihydropyridin dicarboxylique n-alkyles Download PDF

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Publication number
WO1995005823A1
WO1995005823A1 PCT/EP1994/002723 EP9402723W WO9505823A1 WO 1995005823 A1 WO1995005823 A1 WO 1995005823A1 EP 9402723 W EP9402723 W EP 9402723W WO 9505823 A1 WO9505823 A1 WO 9505823A1
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
carbon atoms
compounds
medicaments
alkylated
Prior art date
Application number
PCT/EP1994/002723
Other languages
German (de)
English (en)
Inventor
Siegfried Zaiss
Dieter Neuser
Johannes-Peter Stasch
Siegfried Goldmann
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to JP7507325A priority Critical patent/JPH09501923A/ja
Priority to PL94313116A priority patent/PL313116A1/xx
Priority to KR1019960700944A priority patent/KR960703594A/ko
Priority to AU76135/94A priority patent/AU7613594A/en
Priority to EP94926199A priority patent/EP0714301A1/fr
Publication of WO1995005823A1 publication Critical patent/WO1995005823A1/fr
Priority to BG100367A priority patent/BG100367A/xx
Priority to NO960777A priority patent/NO960777L/no

Links

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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • 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
    • A61P9/10—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 present invention relates to the use of partially known N-alkylated 1,4-dihydropyridinedicarboxylic acid esters as antiatherosclerotic medicaments, in particular their use for restenosis prophylaxis after angioplasty and vascular surgical measures.
  • N-alkylieite 1,4-dihydropyridinedicarboxylic acid esters of the general formula (I) N-alkylieite 1,4-dihydropyridinedicarboxylic acid esters of the general formula (I)
  • R 1 represents hydrogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, halogen or methyl
  • R 2 represents hydrogen, halogen, nitro, hydroxy, trifluoromethyl or methyl
  • R 3 represents hydrogen or cyano
  • R 2 and R 3 together form a condensed benzo ring
  • R 4 and R 5 are the same or different and represent straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by alkoxy having up to 4 carbon atoms,
  • R 6 represents straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 7 carbon atoms
  • 1,2-Trimethyl-4- (4-trifluoromethylphenyl) -1, 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester and 4- (4-chloro-3-trifluoromethylphenyl) -1-cyclopropyl-2 are particularly preferred , 6-dimethyl-1, 4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester in the control of atherosclerosis, in particular for restenosis prophylaxis after angioplasty and vascular surgery.
  • the compounds according to the invention thus show an unforeseeable, valuable pharmacological spectrum of action.
  • the compounds according to the invention inhibit smooth muscle cell proliferation.
  • Vascular wall injuries lead to neointimal cell growth and consequently to a narrowing of the free vascular lumen. This process is the main cause of restenosis problems after vascular opening measures, such as percutaneous angioplasties, endarterectomies or bypass operations.
  • the compounds according to the invention can therefore be used in medicines for the treatment and prophylaxis of residual enosis, e.g. after angioplasty and vascular surgery.
  • the compounds according to the invention can also be used for the treatment of atherosclerosis.
  • a balloon catheter is introduced into the carotid artery, this is inflated and the inside of the blood vessel is injured by moving the catheter [Clowes A.W., et al., Lab. Invest. Vol. 49, No. 3, p. 327, 1983].
  • This damage causes neointimal smooth muscle proliferation, which cause stenoses.
  • the extent of the vasoconstriction in the animals is determined after approximately 2 weeks by histological processing of the blood vessels by measuring the area of the proliferation tissue on vascular cross sections.
  • the compounds according to the invention surprisingly significantly inhibit the vascular constrictions, as can be seen from the table below.
  • the new active ingredients can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, ie in amounts which are sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. if water is used as the diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally or parenterally, in particular perlingually or intravenously.
  • solutions of the active ingredient can be used using suitable liquid carrier materials.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Urology & Nephrology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation comme médicaments anti-athérosclérose, d'esters d'acide 1-4-dihydropyridin dicarboxylique N-alkylés partiellement connus de la formule (I), dans laquelle R1 à R6 ont la notation mentionnée dans la description. L'invention concerne notamment leur utilisation pour assurer la prophylaxie de la resténose après des angioplasties et des interventions chirurgicales vasculaires.
PCT/EP1994/002723 1993-08-27 1994-08-16 Utilisation comme medicaments d'esters d'acide 1-4-dihydropyridin dicarboxylique n-alkyles WO1995005823A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP7507325A JPH09501923A (ja) 1993-08-27 1994-08-16 薬剤としてのｎ−アルキル化された１，４−ジヒドロピリジンジカルボン酸エステル類の使用
PL94313116A PL313116A1 (en) 1993-08-27 1994-08-16 Application of n-alkalated 1,4-dihydropridinocarboxylic esters as drugs
KR1019960700944A KR960703594A (ko) 1993-08-27 1994-08-16 약제로서의 N-알킬화 1,4-디히드로피리딘디카르복실산 에스테르의 용도(Use Of N-Alkylated 1,4-Dihydropyridine Dicarboxylic Acid Esters as Medicaments)
AU76135/94A AU7613594A (en) 1993-08-27 1994-08-16 Use of n-alkylated 1,4-dihydropyridine dicarboxylic acid esters as medicaments
EP94926199A EP0714301A1 (fr) 1993-08-27 1994-08-16 Utilisation comme medicaments d'esters d'acide 1-4-dihydropyridin dicarboxylique n-alkyles
BG100367A BG100367A (en) 1993-08-27 1996-02-19 The use of esters of n-alkylated, 1,4-dihydropyrimidinedicarboxylic acids as medicamentous forms
NO960777A NO960777L (no) 1993-08-27 1996-02-26 Anvendelse av N-alkylerte 1,4-dihydropyridin dikarboksylsyreestere som medikamenter

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4328884A DE4328884A1 (de) 1993-08-27 1993-08-27 Verwendung von N-alkylierten 1,4-Dihydropyridincarbonsäureestern als Arzneimittel
DEP4328884.7 1993-08-27

Publications (1)

Publication Number Publication Date
WO1995005823A1 true WO1995005823A1 (fr) 1995-03-02

Family

ID=6496196

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/002723 WO1995005823A1 (fr) 1993-08-27 1994-08-16 Utilisation comme medicaments d'esters d'acide 1-4-dihydropyridin dicarboxylique n-alkyles

Country Status (13)

Country Link
EP (1) EP0714301A1 (fr)
JP (1) JPH09501923A (fr)
KR (1) KR960703594A (fr)
CN (1) CN1129906A (fr)
AU (1) AU7613594A (fr)
BG (1) BG100367A (fr)
CA (1) CA2170285A1 (fr)
CZ (1) CZ43896A3 (fr)
DE (1) DE4328884A1 (fr)
HU (1) HUT75302A (fr)
NO (1) NO960777L (fr)
PL (1) PL313116A1 (fr)
WO (1) WO1995005823A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19741694A1 (de) * 1997-09-18 1999-04-15 Schering Ag Verwendung Bis-Amin-Oxim-Derivaten und N¶2¶S¶2¶-Komplexderivaten zur Restenoseprophylaxe
WO2003053930A1 (fr) * 2001-12-20 2003-07-03 Bayer Healthcare Ag Derives de 1,4-dihydro-1,4-diphenylpyridine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2854252C (fr) * 2011-11-24 2016-11-29 Lipidart Kutato Fejleszto Es Tanacsado Kft. Derives de 1,4-dihydropyridine ayant une activite modulant hsp

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3222367A1 (de) * 1982-06-15 1983-12-15 Bayer Ag, 5090 Leverkusen Verwendung von 1,4-dihydropyridinen in antiarteriosklerotika und deren herstellung
EP0169009A2 (fr) * 1984-07-17 1986-01-22 FISONS plc Dérivés de dihydropyridine et leur préparation, leur formulation et leur utilisation comme produits pharmaceutiques
EP0451654A2 (fr) * 1990-04-11 1991-10-16 Bayer Ag Utilisation d'esters d'acides de 1,4-dihydropyridine carboxyliques N-alkylés comme médicaments, composés nouveaux et leur procédé de préparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3222367A1 (de) * 1982-06-15 1983-12-15 Bayer Ag, 5090 Leverkusen Verwendung von 1,4-dihydropyridinen in antiarteriosklerotika und deren herstellung
EP0169009A2 (fr) * 1984-07-17 1986-01-22 FISONS plc Dérivés de dihydropyridine et leur préparation, leur formulation et leur utilisation comme produits pharmaceutiques
EP0451654A2 (fr) * 1990-04-11 1991-10-16 Bayer Ag Utilisation d'esters d'acides de 1,4-dihydropyridine carboxyliques N-alkylés comme médicaments, composés nouveaux et leur procédé de préparation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANDREAS M. KNORR: "Influence of nifedipine on experimental arteriosclerosis", CARDIOVASC. DRUGS THER., vol. 4, no. SUP5, 1990, pages 1027 - 1032 *
GIOVANNI SPERTI ET AL.: "Calcium influx modulates DNA synthesis and proliferation in A7r5 vascular smooth muscle cells", EUR.J.PHARMACOL., vol. 206, no. 4, 1992, pages 279 - 284 *
PHILIP D. HENRY: "Anti-atherosclerotic effects of calcium antagonists: A brief review", CLIN.INVEST.MED, vol. 10, no. 6, 1987, pages 601 - 605 *
YON KO ET AL.: "Action of dihydropyridine calcium antagonists on early growth response gene expression and cell growth in vascular smooth muscle cells", J.HYPERTENSION, vol. 11, no. 11, 1993, pages 1171 - 1178 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19741694A1 (de) * 1997-09-18 1999-04-15 Schering Ag Verwendung Bis-Amin-Oxim-Derivaten und N¶2¶S¶2¶-Komplexderivaten zur Restenoseprophylaxe
DE19741694C2 (de) * 1997-09-18 2002-10-31 Schering Ag Verwendung von Komplexen, deren Ligand ein Bis-Amin-Oxim-Derivat oder ein N¶2¶S¶2¶-Derivat und deren Zentralatom ein Radionuklid ist
WO2003053930A1 (fr) * 2001-12-20 2003-07-03 Bayer Healthcare Ag Derives de 1,4-dihydro-1,4-diphenylpyridine
US7199136B2 (en) 2001-12-20 2007-04-03 Bayer Healthcare Ag 1,4-dihydro-1,4-diphenylpyridine derivatives

Also Published As

Publication number Publication date
CA2170285A1 (fr) 1995-03-02
DE4328884A1 (de) 1995-03-02
CN1129906A (zh) 1996-08-28
AU7613594A (en) 1995-03-21
PL313116A1 (en) 1996-06-10
HUT75302A (en) 1997-05-28
JPH09501923A (ja) 1997-02-25
EP0714301A1 (fr) 1996-06-05
HU9600472D0 (en) 1996-04-29
CZ43896A3 (en) 1996-05-15
BG100367A (en) 1996-07-31
NO960777D0 (no) 1996-02-26
KR960703594A (ko) 1996-08-31
NO960777L (no) 1996-04-10

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