WO2000021954A1 - Nouveaux pyrazoles heterocycliques methyl-substitues - Google Patents

Nouveaux pyrazoles heterocycliques methyl-substitues Download PDF

Info

Publication number
WO2000021954A1
WO2000021954A1 PCT/EP1999/007202 EP9907202W WO0021954A1 WO 2000021954 A1 WO2000021954 A1 WO 2000021954A1 EP 9907202 W EP9907202 W EP 9907202W WO 0021954 A1 WO0021954 A1 WO 0021954A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon atoms
chain
straight
substituted
branched
Prior art date
Application number
PCT/EP1999/007202
Other languages
German (de)
English (en)
Inventor
Achim Feurer
Alexander Straub
Chantal FÜRSTNER
Johannes-Peter Stasch
Elisabeth Perzborn
Joachim Hütter
Klaus Dembowsky
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 CA002346698A priority Critical patent/CA2346698A1/fr
Priority to EP99950564A priority patent/EP1119566A1/fr
Priority to AU63300/99A priority patent/AU6330099A/en
Priority to JP2000575860A priority patent/JP2002527435A/ja
Publication of WO2000021954A1 publication Critical patent/WO2000021954A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid

Definitions

  • the present invention relates to new heterocyclyl-methyl-substituted pyrazole derivatives, ner processes for their preparation and their use as medicaments, in particular as medicaments for the treatment of cardiovascular diseases.
  • the present invention relates to new heterocyclyl-methyl-substituted pyrazoles of the general formula (I)
  • R 1 represents a 6-membered aromatic heterocycle with up to 3 nitrogen atoms, which may be up to 2 times identical or different by hydrogen, formyl, carboxyl, hydroxy, mercapto, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl, each with up to to to
  • R 4 and R 5 are identical or different and are hydrogen or straight-chain or branched acyl having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, which may be by cycloalkyl having 3 to 6 carbon atoms, hydroxyl, amino or by straight-chain or branched alkoxy, acyl or alkoxycarbonyl, each having up to 5 carbon atoms,
  • R 4 and R 5 together with the nitrogen atom form a 3- to 7-membered saturated or partially unsaturated heterocycle which may optionally additionally contain an oxygen or sulfur atom or a radical of the formula -NR 6 ,
  • R 6 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • R 7 denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR 8 R 9 R 10 , wo ⁇ n
  • R 8 , R 9 and R ! 0 are the same or different and are aryl with 6 to 10 carbon atoms or alkyl with up to 6 carbon atoms,
  • b and b ' are the same or different and represent a number 0, 1, 2 or 3,
  • a represents a number 1, 2 or 3
  • R 11 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • c represents a number 1 or 2
  • R 12 and R 13 are the same or different and is hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally by cycloalkyl
  • R 12 and R 13 together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which can optionally contain a further oxygen atom or a radical -NR 14 ,
  • R 14 is hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula
  • alkenyl or alkynyl have a double or triple bond at the point of attachment to the heterocycle R 1 ,
  • R a and R b are identical or different and are hydrogen or straight-chain or branched acyl having up to 10 carbon atoms, cyclic acyl having 3 to 8 carbon atoms, straight-chain or branched alkyl having up to 10 carbon atoms or cycloalkyl having 3 to 14 carbon atoms, where appropriate by
  • R a and R together with the nitrogen atom form a 3- to 7-membered saturated or partially unsaturated heterocycle, which may be by
  • Hydroxy is substituted and which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR C ,
  • R ° is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • R d denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR e R f R 8 ,
  • R e , R f and R 8 are the same or different and are aryl with 6 to 10 carbon atoms or alkyl with up to 6 carbon atoms,
  • (B) is substituted by a 3- to 14-membered heterocyclic ring which can be saturated or unsaturated and contains 1 to 4 heteroatoms from the series N, O, S, SO, SO 2 and optionally by
  • R h and R 1 may be the same or different and denote hydrogen, straight-chain, branched or cyclic alkyl or acyl having up to 6 carbon atoms
  • R h and R together with the nitrogen atom form a 3- to 7-membered saturated or partially unsaturated heterocycle which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR J ,
  • R j represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • (C) is substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which is imperative by one or more of the following groups
  • O, S, SO, SO 2 which is optionally substituted by halogen, alkyl having up to 6 carbon atoms or alkoxy having up to 6 carbon atoms;
  • R k and R 1 can be hydrogen and the other or both independently of one another are straight-chain or branched acyl having up to 10 carbon atoms, cyclic alkyl having 3 to 14 carbon atoms or R k and R 1 together form a 3- to 7-membered saturated or partially unsaturated heterocycle with the nitrogen atom, which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR m ,
  • R m is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, is substituted
  • (D) is substituted by alkoxy with up to 6 carbon atoms, which in turn is substituted,
  • R p represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • R q and R r straight-chain or branched alkyl having 1 to 10 carbon atoms, cyclic alkyl having 3 to 14 carbon atoms, Aryl with 6 to 10 carbon atoms, which is optionally substituted by halogen, alkyl with 1 to 6 carbon atoms or alkoxy with 1 to 6 carbon atoms, or 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, SO, SO 2 , which if necessary by
  • Halogen, straight-chain or branched alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms is substituted
  • R s and R * may be the same or different and denote hydrogen, straight-chain or branched alkyl having 1 to 14 carbon atoms or cycloalkyl having 3 to 14 carbon atoms,
  • alkyl or cycloalkyl radicals optionally being cycloalkyl having 3 to 6 carbon atoms, hydroxy, Amino, straight-chain or branched alkoxy, acyl or alkoxycarbonyl each having up to 6 carbon atoms,
  • Halogen straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms, alkoxy having 1 to 6 carbon atoms,
  • R s and R * are aryl having 6 to 10 carbon atoms, which may be halogen, straight-chain or branched
  • Alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 14 carbon atoms, alkoxy with 1 to 6 carbon atoms is substituted, and / or
  • R s and R 1 3- to 10-membered saturated, partially unsaturated or completely unsaturated heterocyclyl with 1 to 5 heteroatoms from the series N, O, S; SO, SO 2 , which may be halogen, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 14 carbon atoms. atoms, alkoxy is substituted with 1 to 6 carbon atoms,
  • R s and R together with the nitrogen atom form a 3- to 7-membered saturated or partially unsaturated heterocycle which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR U ,
  • R u is hydrogen or a straight-chain or branched alkyl having up to 4 carbon atoms
  • R v and R w can be the same or different and straight-chain or branched acyl with 7 to 14 carbon atoms, cyclic acyl with 3 to 6 carbon atoms, -SO 2 alkyl with 1 to 4 carbon atoms, hydroxymethyl, hydroxyethyl,
  • R x and RY are identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
  • R z denotes straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms
  • radicals R v and R w can optionally be hydrogen
  • R and R ' represent the same or different straight-chain, branched or cyclic alkyl having up to 8 carbon atoms or aryl having 6 to 10 carbon atoms or benzyl,
  • R 2 and R 3 including the double bond, form a phenyl ring which may be up to 3 times identical or different through formyl,
  • A represents phenyl or a 5- to 6-membered aromatic or saturated heterocycle with up to 3 heteroatoms from the series S, N and / or O, which is optionally up to 3 times identical or different by mercaptyl, Hydroxy, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which is substituted can in turn be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms,
  • d represents a number 0 or 1
  • R 15 and R 16 are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl, each having up to 5 carbon atoms,
  • inventive compounds of the general formula (I) can also be present in the form of their salts.
  • salts with organic or inorganic bases or acids may be mentioned here.
  • Physiologically acceptable salts are preferred in the context of the present invention.
  • Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, ⁇ aphthalenedisulfonic acid, acetic acid. acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
  • metal or ammonium salts of the compounds according to the invention which have a free carboxyl group.
  • Sodium, potassium, magnesium or calcium salts and ammonium salts derived from ammonia, or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.
  • the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates both to the enantiomers or diastereomers and to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • alkyl having up to 20 carbon atoms generally represents a straight-chain or branched hydrocarbon radical having 1 to 20 carbon atoms.
  • Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl and isooctyl, nonyl, decyl, dodeyl, eicosyl.
  • alkenyl having up to 20 carbon atoms generally represents a straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and one or more, preferably one or two, double bonds.
  • alkenyl having up to 20 carbon atoms generally represents a straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and one or more, preferably one or two, double bonds.
  • alkynyl generally represents a straight-chain or branched hydrocarbon radical with 2 to
  • Examples include ethynyl, 2-butynyl, 2-pentynyl and 2-hexynyl.
  • acyl with up to 10 carbon atoms generally represents straight-chain or branched lower alkyl having 1 to 9 carbon atoms which are bonded via a carbonyl group.
  • Examples include: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl and isobutylcarbonyl.
  • alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 14 carbon atoms which is bonded via an oxygen atom.
  • alkoxy generally represents a straight-chain or branched hydrocarbon radical having 1 to 14 carbon atoms which is bonded via an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy, octoxy or isooctoxy.
  • Alkoxycarbonyl can, for example, by the formula
  • Alkyl stands for a straight-chain or branched hydrocarbon radical with 1 to 13 carbon atoms.
  • alkoxy carbo- called onyl radicals methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl or isobutoxycarbonyl.
  • Cycloalkyl generally represents a cyclic hydrocarbon radical having 3 to 8 carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.
  • Examples include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • Halogen in the context of the invention represents fluorine, chlorine, bromine and iodine.
  • Aromatic, saturated and unsaturated heterocycles in the context of the invention generally represent a 3- to 10-membered or 5- to 6-membered heterocycle which has up to 4
  • heteroatoms from the series S, N and / or O Contain heteroatoms from the series S, N and / or O and which can optionally also be bonded via a nitrogen atom.
  • examples include: pyridyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl, pyrimidyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, morpholinyl or piperidyl.
  • Hetaryl stands for an aromatic heterocyclic radical.
  • Cycloalkoxy in the context of the invention is an alkoxy radical whose hydrocarbon radical is a cycloalkyl radical.
  • the cycloalkyl radical generally has up to 8 carbon atoms. Examples include: cyclopropyloxy and cyclohexyloxy.
  • the terms "cycloalkoxy” and “cycloalkyloxy” are used synonymously.
  • Preferred compounds of the general formula (I) according to the invention are those in which
  • R 1 for a radical of the formula stands,
  • R 4 and R 5 are identical or different and denote hydrogen or straight-chain or branched acyl having up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which may be by hydroxyl, amino or by straight-chain or branched alkoxy having up to 3 carbon atoms is substituted, or
  • R 4 and R 5 together with the nitrogen atom represent a morpholine ring or a radical of the formulas
  • R 7 denotes straight-chain or branched acyl having up to 4 carbon atoms
  • b and b ' are the same or different and represent a number 0, 1, 2 or 3,
  • a represents a number 1, 2 or 3
  • R 11 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms
  • alkyl, alkenyl, alkynyl and cycloalkyloxy radicals are optionally substituted and the phenyl radical is necessarily substituted by carboxyl, hydroxyl, mercaptyl, nitro, cyano,
  • R a and R b are the same or different and are hydrogen or straight-chain or branched acyl with up to 6 carbon atoms, cyclic acyl with 3 to 6 carbon atoms, straight means chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, these being optionally by
  • R and R b together with the nitrogen atom form a 3- to 7-membered saturated heterocycle
  • R c is hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms.
  • R d means straight-chain or branched acyl with up to 4 carbon atoms, and or
  • (B) are substituted by a 3- to 8-membered heterocyclic ring which can be saturated or unsaturated and contain 1 to 4 heteroatoms from the series N, O, S and optionally by
  • R h and R may be the same or different and denote hydrogen, straight-chain, branched or cyclic alkyl or acyl having up to 4 carbon atoms
  • R h and R together with the nitrogen atom form a 3- to 7-membered saturated heterocycle which optionally additionally contains an oxygen or sulfur atom or a radical of the formula
  • R J represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • Carbon atoms or alkoxy is substituted with 1 to 6 carbon atoms
  • R k and R 1 can be hydrogen and the other or both independently represent straight-chain or branched acyl having up to 6 carbon atoms, cyclic alkyl having 3 to 8 carbon atoms or R k and R 1 together form a 3- to 7-membered saturated heterocycle with the nitrogen atom, which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR m ,
  • R m denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • (D) are substituted by alkoxy with up to 6 carbon atoms, which in turn is substituted by
  • R n and R ° may be the same or different hydrogen or straight-chain, branched or cyclic alkyl or acyl each having up to 5 carbon atoms, or R n and R ° together with the nitrogen atom are a 3- to 7th form a membered saturated heterocycle which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR P ,
  • R p is hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms
  • R q and R r straight-chain or branched alkyl having 1 to 6 carbon atoms, cyclic alkyl having 3 to 8 carbon atoms,
  • Aryl having 6 to 10 carbon atoms which may be by
  • R s and R l may be the same or different and are hydrogen, straight-chain or branched alkyl having 1 to 10 carbon atoms. atoms or cycloalkyl having 3 to 8 carbon atoms,
  • alkyl or cycloalkyl radicals optionally being cycloalkyl having 3 to 6 carbon atoms, hydroxy,
  • Aryl with 6 to 10 carbon atoms which may be fluorine, chlorine, bromine, straight-chain or branched
  • s and R 1 are aryl having 6 to 10 carbon atoms, which is optionally substituted by fluorine, chlorine, bromine, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1 to 6 carbon atoms,
  • R s and R * are 3- to 8-membered saturated heterocyclyl having 1 to 3 heteroatoms from the series N, O, S; which is optionally substituted by fluorine, chlorine, bromine, straight-chain or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, alkoxy having 1 to 6 carbon atoms,
  • R s and R ' together with the nitrogen atom form a 3- to 7-membered saturated heterocycle which optionally additionally contains an oxygen or sulfur atom or a radical of the formula -NR U ,
  • R u is hydrogen or a straight-chain or branched alkyl having up to 4 carbon atoms
  • R v and R w can be the same or different and straight-chain or branched acyl with 7 to 10 carbon atoms, cyclic acyl with 3 to 6 carbon atoms, -SO 2 alkyl with 1 to 4 carbon atoms, hydroxymethyl, hydroxyethyl, alkoxycarbonyl with up to 5 carbon atoms , Alkoxyalkyl with a total of up to 8 carbon atoms, acyloxymethyl with up to 6 carbon atoms in the acyl radical (preferably pivaloyloxymethyl) or the following radicals
  • R x and Ry are the same or different and are hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms m represents a number 0, 1 or 2 and
  • R z denotes straight-chain or branched alkyl having up to 4 carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl,
  • radicals R v and R w can optionally be hydrogen
  • R and R ' are the same or different straight-chain, branched or cyclic alkyl having up to 6 carbon atoms or aryl
  • R 2 and R 3 including the double bond, form a phenyl ring which may be up to 3 times the same or different by formyl, carboxyl, hydroxy, amino, straight-chain or branched acyl, alkoxy, or
  • Alkoxycarbonyl each with up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl with up to 5 carbon atoms, which in turn are substituted by hydroxy, amino, carboxyl, straight-chain or branched acyl, alkoxy or Alkoxycarbonyl can each be substituted with up to 4 carbon atoms,
  • Pyrimidyl, piperazinyl or pyridyl which is optionally up to 2 times identical or different by hydroxy, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl in each case up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in turn is substituted by hydroxy, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl, each with up to 4 Carbon atoms can be substituted
  • a number means 0 or 1
  • R ' 5 and R 16 are the same or different and are hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms,
  • R 1 for a radical of the formula
  • R 1 optionally up to 2 times the same or different by hydrogen, formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl in each case up to 4 carbon atoms, methylamino, amino, fluorine, chlorine, bromine, cyano, azido or straight-chain or branched alkyl having up to 4 carbon atoms which are in turn substituted by hydroxy, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl, Acylamino can each be substituted with up to 3 carbon atoms,
  • alkenyl or alkynyl have their double or triple bond at the point of attachment to the heterocycle R 1 ,
  • R a and R b are identical or different and are hydrogen or straight-chain or branched acyl having up to 4 carbon atoms, cyclic acyl having 3 to 6 carbon atoms, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, where appropriate by
  • R d straight-chain or branched acyl with up to 3 carbon atoms
  • (B) are substituted by a 5- to 6-membered heterocyclic ring, which can be saturated or unsaturated and contains 1 to 4 heteroatoms from the series N, O, S and optionally by
  • R h and R may be the same or different and denote hydrogen, straight-chain, branched or cyclic alkyl or acyl having up to 3 carbon atoms
  • R h and R together with the nitrogen atom represent a radical of the formula
  • (C) are substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which is imperative by one or more of the following groups
  • Cyano cyclic acyl with 3 to 6 carbon atoms, alkylthio with up to 6 carbon atoms, cyclic alkyl with 3 to 14 carbon atoms, phenyl, which may be by Fluorine, chlorine, alkyl with up to 4 carbon atoms or
  • Alkoxy is substituted with up to 4 carbon atoms
  • O, S which is optionally substituted by fluorine, chlorine, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms,
  • R k and R 1 can be hydrogen and the other or both independently represent straight-chain or branched acyl having up to 4 carbon atoms, cyclic alkyl having 3 to 6 carbon atoms or R k and R 1 together with the nitrogen atom a heterocycle of the formula
  • (D) are substituted by alkoxy with up to 4 carbon atoms, which in turn is substituted by
  • R n and R ° may be the same or different hydrogen or straight-chain, branched or cyclic alkyl or acyl each having up to 4 carbon atoms or R n and R ° together with the nitrogen atom form a heterocycle of the formula -N
  • Phenyl radical is optionally substituted by fluorine, chlorine, alkyl, alkoxy each having 1 to 4 carbon atoms; Heteroarylthio with 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, which is optionally substituted by fluorine, chlorine, straight-chain or branched alkyl or alkoxy having 1 to 4 carbon atoms; are substituted,
  • R q and R r straight-chain or branched alkyl having 1 to 3 carbon atoms, cyclic alkyl having 3 to 6 carbon atoms,
  • Phenyl which is optionally substituted by fluorine, chlorine, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 3 carbon atoms, or 5- to 6-membered hetaryl with 1 to 3 heteroatoms from the series N, O, S, which is optionally substituted by
  • R s and R ' may be the same or different and denote hydrogen, straight-chain or branched alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,
  • alkyl or cycloalkyl radicals optionally being cycloalkyl having 3 to 6 carbon atoms, hydroxyl, amino, straight-chain or branched alkoxy, acyl or
  • Alkoxycarbonyl each with up to 4 carbon atoms, Phenyl which is optionally substituted by fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms;
  • N, O, S which may be fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms,
  • Alkoxy is substituted with 1 to 4 carbon atoms
  • R s and R * are phenyl which is optionally substituted by fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms,
  • R s and R * are 3- to 6-membered saturated heterocyclyl having 1 to 3 heteroatoms from the series N, O, S; which is optionally substituted by fluorine, chlorine, straight-chain or branched alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy having 1 to 4 carbon atoms,
  • R v and R w can be the same or different and hydroxymethyl
  • R x and Ry can be the same or different and represent hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms,
  • R z for straight-chain or branched alkyl having up to 4 carbon atoms, cyclopropyl, cyclopentyl, cyclohexyl or aryl and m represents a number 0, 1 or 2 and
  • radicals R v and R w can optionally be hydrogen
  • R and R ' are the same or different straight-chain, branched or cyclic alkyl having up to 4 carbon atoms or phenyl or benzyl,
  • R 2 and R 3 including the double bond, form a phenyl ring which may be identical or different up to 2 times through formyl, carboxyl, hydroxy, amino, straight-chain or branched acyl, alkoxy, or alkoxycarbonyl, each having up to 4 carbon atoms, Nitro, cyano, fluorine, chlorine,
  • Phenyl or straight-chain or branched alkyl having up to 3 carbon atoms are substituted, which in turn can be substituted by hydroxy, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
  • A represents phenyl or tetrahydropyranyl, tetrahydrofuryl, furyl or pyridyl, which may optionally be up to 2 times identical or different by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms, fluorine, Chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 3 carbon atoms are substituted, that can in turn be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
  • d represents a number 0 or 1
  • R 15 and R 16 are identical or different and are hydrogen or straight-chain or branched alkyl or acyl each having up to 3 carbon atoms,
  • R 1 for a radical of the formula
  • pyrimidyl radical listed above may be up to 2 times identical or different by methyl, ethyl, isopropyl, fluorine, amino, cyano, methoxy, chlorine, hydroxymethyl or by a radical of the formula
  • A represents phenyl, which is optionally substituted by fluorine or cyano
  • D represents triflate or halogen, preferably chlorine or bromine
  • L represents a radical of the formula -SnR 1 TTR 19 , ZnR 2U , iodine or triflate
  • R 17 , R 18 and R 19 are identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms,
  • R 20 represents halogen
  • R 1 has the meaning given above
  • T represents triflate or halogen, preferably chlorine or bromine
  • T represents a radical of the formula SnR 17 R 18 R 19 , ZnR 20 or BR 2, R 22 , wo ⁇ n
  • R 17 ' , R 18' , R ' 9' and R 20 ' have the abovementioned meaning of R 17 , R 18 , R 19 and R 20 and are the same or different with this,
  • R 21 and R 22 are the same or different and are hydroxy, aryloxy having 6 to 10 carbon atoms or straight-chain or branched
  • alkyl or alkoxy each having up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring,
  • R 2 and R 3 have the meaning given above
  • R r represents one of the above-mentioned substituents of the 6-membered aromatic heterocycle R 1
  • R 1 , R 2 , R 3 and / or A are varied or introduced by customary methods, preferably by reduction, oxidation, removal of protective groups and / or by nucleophilic substitution.
  • Inert organic solvents which do not change under the reaction conditions are suitable as solvents for the individual steps of processes [A], [B] and [C].
  • ethers such as diethyl ether or tetrahydrofuran, DME, dioxane, alcohols such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. It is also possible to mix the
  • Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane is particularly preferred.
  • inorganic or organic bases can be used as bases for the processes according to the invention.
  • bases preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or potassium tert .butylate, or organic amines (trialkyl (C r C 6 ) amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.
  • alkali metal hydroxides such as sodium hydroxide or potassium hydroxide
  • alkaline earth metal hydroxides such as barium hydroxide
  • alkali metal carbonates such as sodium carbonate or potassium
  • DBU undec-7-ene
  • pyridine diaminopyridine
  • methylpiperidine methylpiperidine
  • morpholine alkali metals such as sodium and their hydrides such as sodium hydride as bases.
  • sodium and potassium carbonate, triethylamine and sodium hydride are preferred.
  • the base is used in an amount of 1 mol to 5 mol, preferably 1 mol to 3 mol, based on 1 mol of the compound of the general formula (II).
  • the reaction is generally carried out in a temperature range from 0 ° C. to 150 ° C., preferably from + 20 ° C. to + 110 ° C.
  • the reaction can be carried out under normal, elevated or reduced pressure (for example 0.5 to 5 bar). Generally one works at normal pressure.
  • Protonic acids are generally suitable as acids for the cyclization. These preferably include inorganic acids such as hydrochloric acid or sulfuric acid, or organic carboxylic acids with 1-6 C atoms, optionally substituted by fluorine, chlorine and / or bromine, such as acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid, or sulfonic acids with -C ⁇ alkyl radicals or aryl residues such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.
  • inorganic acids such as hydrochloric acid or sulfuric acid, or organic carboxylic acids with 1-6 C atoms, optionally substituted by fluorine, chlorine and / or bromine, such as acetic acid, trifluoroacetic acid, trichloroacetic acid or propionic acid, or sulfonic acids with -C ⁇ alky
  • the catalytic hydrogenation can generally be carried out using hydrogen in water or in inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof, with catalysts such as Raney nickel, palladium,
  • the chlorination is generally carried out using the customary chlorinating agents, for example PC1 3 , PC1 5 , POCl 3 or elemental chlorine. Is preferred within the customary chlorinating agents, for example PC1 3 , PC1 5 , POCl 3 or elemental chlorine. Is preferred within the customary chlorinating agents, for example PC1 3 , PC1 5 , POCl 3 or elemental chlorine. Is preferred within the customary chlorinating agents, for example PC1 3 , PC1 5 , POCl 3 or elemental chlorine. Is preferred within the customary chlorinating agents, for example PC1 3 , PC1 5 , POCl 3 or elemental chlorine. Is preferred within the customary chlorinating agents, for example PC1 3 , PC1 5 , POCl 3 or elemental chlorine. Is preferred within the customary chlorinating agents, for example PC1 3 , PC1 5 , POCl 3 or elemental chlorine. Is preferred within the customary chlorinating agents, for example PC1 3
  • the reductions are generally carried out using reducing agents, preferably those which are suitable for the reduction of carbonyl to hydroxy compounds.
  • the reduction is preferably carried out using complex metal hydrides such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboranate, diisobutylaluminium hydride or lithium aluminum hydride.
  • the reduction is very particularly preferably carried out using diisobutylaluminum hydride and sodium borohydride.
  • the reducing agent is generally used in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, based on 1 mol of the compounds to be reduced.
  • the reduction generally takes place in a temperature range from -78 ° C. to + 50 ° C., preferably from -78 ° C. to 0 ° C. in the case of the DIBAH, from 0 ° C. to room temperature in the case of the NaBH 4
  • the reduction generally proceeds at normal pressure, but it is also possible to work at elevated or reduced pressure.
  • solvents for process [B] are: ethers, such as diethyl ether or tetrahydrofuran, DME, dioxane, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethylene or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric triamide. It is also possible Use mixtures of solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.
  • the reaction is generally carried out in a temperature range from 0 ° C. to 150 ° C., preferably from 110 ° C. to 150 ° C.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at normal pressure.
  • PdCl 2 (P (C 6 H 5 ) 3 ) 2 palladium-bis-dibenzylidene acetone (Pd (dba) 2 ), [l, l'-bis (diphenylphosphino) ferrocene are generally suitable as palladium compounds in the context of the present invention ] -Palladium (II) chloride (Pd (dppf) Cl 2 ) or Pd (P (C 6 H 5 ) 3 ) 4 .
  • Pd (P (C 6 H 5 ) 3 ) 4 is preferred.
  • Process [C] takes place in a temperature range from 55 ° C to 120 ° C, preferably at 80 ° C.
  • either the free amidine base is used.
  • the enamines act as solvents.
  • the amidines are reacted in the form of their salts, preferably hydrochlorides, in the presence of a base, preferably sodium methoxide or potassium tert-butoxide in alcohols, preferably methanol or tert-butanol.
  • the use of the enols is reacted with the free amidine base in an inert solvent, preferably toluene.
  • the process [C] can be carried out at normal, elevated or reduced pressure (for example 0.5 to 5 bar). Generally one works at normal pressure.
  • the amidines of the general formula (VI) are new and therefore a further subject of the invention. They can be prepared by using the compounds of the general formula (VIII)
  • R 2 and R 3 have the meaning given above
  • R 2 and R 3 have the meaning given above
  • bases preferably sodium carbonate.
  • the conversion of the nitrile into the imino ether can be carried out in acid, e.g. with HCl / alcohol mixtures as in basic such as e.g. with methanol sodium methanolate.
  • the pyrimidine is prepared by customary methods.
  • the imino ether can also first be converted into an amidine using ammonia or its salts, and this can be reacted with enamines either as a free base or as a salt.
  • aldehyde equivalents such as e.g. Acetals, aminals, enol ethers, aldehydes or enols can be used.
  • the enamines can e.g. from C-H-acidic compounds such as acetonitrile derivatives by known methods by reaction with dimethylformamide derivatives such as e.g. Bis (dimethylamino) tert-butoxymethane, dialkoxy-dialkylamino-methanes can be produced.
  • C-H-acidic compounds such as acetonitrile derivatives
  • dimethylformamide derivatives such as e.g. Bis (dimethylamino) tert-butoxymethane, dialkoxy-dialkylamino-methanes
  • Alcohols such as methanol or ethanol are suitable as solvents for the reaction of the compounds of the general formulas (IX) -> (X). Methanol is preferred.
  • the reaction takes place in a temperature range from 0 ° C to 40 ° C, preferably at room temperature.
  • the reaction can be carried out at normal, elevated or reduced pressure (for example 0.5 to 5 bar). Generally one works at normal pressure.
  • Inorganic or organic bases are suitable as bases for the release of the free amidine bases from the hydrochlorides (X).
  • X hydrochlorides
  • alkali metal hydroxides such as sodium hydroxide or potassium hydroxide
  • alkaline earth metal hydroxides such as barium hydroxide
  • alkali metal carbonates such as sodium carbonate or potassium carbonate
  • alkaline earth metal carbonates such as calcium carbonate
  • alkali alcoholates such as potassium tert-butoxide.
  • Sodium carbonate and potassium tert-butoxide are preferred.
  • the reaction takes place in a temperature range from 0 ° C to 40 ° C, preferably at room temperature.
  • the reaction can be carried out at normal, elevated or reduced pressure (e.g. 0.5 to 5 bar). Generally one works at normal pressure.
  • the compounds of the formula (VIII) can be prepared by reacting the corresponding 3-cyanoindazoles with compounds of the general formula (XIII)
  • inert solvents preferably with tetrahydrofuran in the presence of a base, preferably sodium hydride.
  • the compounds of the general formula (I) according to the invention lead to vascular relaxation, platelet aggregation inhibition and to a reduction in blood pressure as well as an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP.
  • the compounds of the general formula (I) according to the invention enhance the action of substances which increase the cGMP level, such as EDRF (endothelium derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
  • cardiovascular diseases such as, for example, for the treatment of high blood pressure and cardiac insufficiency, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic disorders and ischemia such as myocardial infarction, stroke, transistoric and Ischemic attacks, peripheral circulatory disorders, prevention of restenoses such as after thrombolysis therapies, percutaneous transluminal angioplasties (PTA), percutaneously transluminal coronary angioplasties (PTCA), bypass and for the treatment of arteriosclerosis and diseases of the genitourinary system such as prostate erectile dysfunction, female prostate hypertrophy Dysfunction and incontinence are used.
  • PTA percutaneous transluminal angioplasties
  • PTCA percutaneously transluminal coronary angioplasties
  • the invention comprises the combination of the invention
  • Organic nitrates and NO donors in the context of the invention are generally substances which are therapeutic via the release of NO or NO species
  • the invention also includes combination with compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP). These are in particular
  • Collagenase solution isolated.
  • the cells were then cultured in culture medium at 37 ° C./5% CO 2 until confluence was reached.
  • the cells were passaged, sown in 24-well cell culture plates and subcultivated until they reached confluence ( ⁇ 2 ⁇ 10 5 cells / well).
  • the culture medium was aspirated to stimulate endothelial guanylate cyclase and the cells were washed once with Ringer's solution. After removing the Ringer's solution, the cells were incubated in stimulation buffer with or without NO donor (sodium nitroprusside, SNP or DEA NO 1 ⁇ M) for 10 minutes at 37 ° C./5% CO 2 .
  • NO donor sodium nitroprusside, SNP or DEA NO 1 ⁇ M
  • test substances final concentration 1 ⁇ M
  • buffer solution was aspirated and 4 ° C stop buffer was added to the cells.
  • the cells were then lysed at -20 ° C for 16 hours.
  • the supernatants containing the intracellular cGMP were then removed and the cGMP concentrations were determined by the cGMP-SPA system (Amersham Buchler, Braunschweig).
  • Rabbits are anesthetized and bled by the blow of the neck.
  • the aorta is removed, adherent tissue is removed, divided into 1.5 mm wide rings and individually pretensioned in 5 ml organ baths at 37 ° C, carbogen gassers
  • Krebs-Henseleit solution with the following composition (mM): NaCl: 119; KC1: 4.8; CaCl 2 x 2 H 2 O: 1; MgSO 4 x 7 H 2 O; 1.4; KH 2 PO 4 : 1.2; NaHCO3: 25; Glucose: 10.
  • the contraction force is recorded with Statham UC2 cells, amplified and digitized via A / D converter (DAS-1802 HC, Keithley Instruments Munich) and recorded in parallel on a line recorder. To create a contraction, phenylephrine is added cumulatively to the bath in increasing concentration.
  • the substance to be examined is examined in increasing doses in each subsequent run and the level of the contraction is compared with the level of the contraction reached in the last previous run. From this the concentration is calculated which is required to reduce the level of the control value by 50% (IC 50 ).
  • the standard application volume is 5 ⁇ l, the DMSO content in the bath solution corresponds to 0.1%.
  • the animals were housed individually in Type III cages positioned on the individual recipient stations and were adapted to a 12 hour light / dark rhythm. Water and feed were freely available.
  • the blood pressure of each rat was recorded every 5 minutes for 10 seconds.
  • the measuring points were combined for a period of 15 minutes and the mean value was calculated from these values.
  • test compounds were dissolved in a mixture of Transcutol (10%), Cremophor (20%), H 2 O (70%) and administered orally using a gavage in a volume of 2 ml / kg body weight.
  • the test doses were between 0.3 - 30 mg / kg body weight.
  • Blood from healthy volunteers of both sexes was used to determine platelet aggregation. 9 parts of blood were added to one part of 3.8% sodium citrate solution as an anticoagulant. The blood was centrifuged at 900 rpm for 20 min. The pH of the platelet-rich plasma obtained was adjusted to pH 6.5 using ACD solution (sodium citrate / citric acid / glucose). The platelets were then centrifuged off and taken up in buffer and centrifuged again. The platelet precipitate was taken up in buffer and 2 mmol / 1 CaCl 2 were additionally added.
  • ACD solution sodium citrate / citric acid / glucose
  • aggregation measurements For the aggregation measurements, aliquots of the platelet suspension with the test substance were incubated at 37 ° C. for 10 min. The aggregation was then triggered by adding collagen in an aggregometer and determined using the turbidometric method according to Born (Born, GN.R., J. Physiol. (London), 168, 178-195, 1963) at 37 ° C.
  • Formula (I) also represents active substances for combating diseases in the central nervous system which are characterized by disorders of the ⁇ O / cGMP system. In particular, they are suitable for eliminating cognitive deficits, for improving learning and memory and for treating Alzheimer's disease. They are also suitable for the treatment of diseases of the central nervous system such as
  • Anxiety tension and depression, central nervous system-related sexual dysfunctions and sleep disorders, as well as for the regulation of pathological disorders in the intake of food, stimulants and addictive substances.
  • the active ingredients are also suitable for regulating cerebral blood flow and are therefore effective means of combating migraines.
  • Formula (I) can be used to combat painful conditions.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain the compounds of the general formula (I) according to the invention and processes for the preparation of these preparations.
  • the active ingredient can optionally also be in microencapsulated form in one or more of the above-mentioned carriers.
  • the therapeutically active compounds of the general formula (I) should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.
  • the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
  • the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per 24 hours, optionally in the form multiple doses to achieve the desired results.
  • a single dose contains the active ingredient (s) according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg body weight.
  • Phosphonic acid ester The solution is first freed from the methanol at 40 ° C. and 20 mbar on a rotary evaporator, then at room temperature in a high vacuum.

Landscapes

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

Abstract

L'invention concerne de nouveaux dérivés du pyrazole hétérocycliques méthyl-substitués, leur procédé de fabrication et leur utilisation comme médicaments, notamment pour le traitement des maladies cardiovasculaires.
PCT/EP1999/007202 1998-10-09 1999-09-29 Nouveaux pyrazoles heterocycliques methyl-substitues WO2000021954A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002346698A CA2346698A1 (fr) 1998-10-09 1999-09-29 Nouveaux pyrazoles heterocycliques methyl-substitues
EP99950564A EP1119566A1 (fr) 1998-10-09 1999-09-29 Nouveaux pyrazoles heterocycliques methyl-substitues
AU63300/99A AU6330099A (en) 1998-10-09 1999-09-29 Novel heterocyclyl-methyl-substituted pyrazoles
JP2000575860A JP2002527435A (ja) 1998-10-09 1999-09-29 新規なヘテロシクリル−メチル置換ピラゾール類

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19846514A DE19846514A1 (de) 1998-10-09 1998-10-09 Neue Heterocyclyl-methyl-substituierte Pyrazole
DE19846514.9 1998-10-09

Publications (1)

Publication Number Publication Date
WO2000021954A1 true WO2000021954A1 (fr) 2000-04-20

Family

ID=7883905

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/007202 WO2000021954A1 (fr) 1998-10-09 1999-09-29 Nouveaux pyrazoles heterocycliques methyl-substitues

Country Status (6)

Country Link
EP (1) EP1119566A1 (fr)
JP (1) JP2002527435A (fr)
AU (1) AU6330099A (fr)
CA (1) CA2346698A1 (fr)
DE (1) DE19846514A1 (fr)
WO (1) WO2000021954A1 (fr)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003004503A1 (fr) * 2001-07-04 2003-01-16 Bayer Healthcare Ag Derives de pyrazolopyridine pontes avec la morpholine
US6693102B2 (en) 2000-11-22 2004-02-17 Bayer Aktiengesellschaft Pyridine-substituted pyrazolopyridine derivatives
WO2004031186A1 (fr) * 2002-09-26 2004-04-15 Bayer Healthcare Ag Derives d'indazole pontes par morpholine
US6903089B1 (en) 2000-11-22 2005-06-07 Bayer Aktiengesellschaft Lactam-substituted pyrazolopyridine derivatives
US6919345B2 (en) 2001-05-11 2005-07-19 Bayer Aktiengesellschaft Sulfonate substituted pyrazol pyridine derivatives
JP2006502119A (ja) * 2002-07-18 2006-01-19 バイエル・ヘルスケア・アクチェンゲゼルシャフト 新規２，５−二置換ピリミジン誘導体
US7105523B2 (en) 2000-11-22 2006-09-12 Bayer Aktiengeselischaft Carbamate-substituted pyrazolopyridine-derivatives
US7115599B2 (en) 2000-11-22 2006-10-03 Bayer Aktiengesellschaft Sulfonamide-substituted pyrazolopyridine compounds
US7173037B2 (en) 2002-05-08 2007-02-06 Bayer Healthcare Ag Carbamate-substituted pyrazolopyridines
DE102007026392A1 (de) 2007-06-06 2008-12-11 Bayer Healthcare Ag Lösungen für die Perfusion und Konservierung von Organen und Geweben
DE102007028320A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
DE102007028406A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
DE102007028319A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
DE102007028407A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
EP2138178A1 (fr) 2008-06-28 2009-12-30 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones pour le traitement de maladie pulmonaire obstructive chronique (MPOC) et/ou de l'asthme
US7645752B2 (en) 2006-01-13 2010-01-12 Wyeth Llc Sulfonyl substituted 1H-indoles as ligands for the 5-hydroxytryptamine receptors
US8293738B2 (en) 2010-05-12 2012-10-23 Abbott Laboratories Indazole inhibitors of kinase
WO2012165399A1 (fr) 2011-05-30 2012-12-06 アステラス製薬株式会社 Composé imidazopyridine
WO2013167669A1 (fr) 2012-05-10 2013-11-14 Bayer Pharma Aktiengesellschaft Anticorps capables de lier au facteur de coagulation xi et/ou à sa forme activée, le facteur xia, et utilisations de ceux-ci
WO2014084312A1 (fr) 2012-11-30 2014-06-05 アステラス製薬株式会社 Composé imidazopyridine
CN103974948A (zh) * 2011-10-06 2014-08-06 拜耳医药股份有限公司 在治疗过度增殖性疾病中用作bub1激酶抑制剂的取代的苄基吲唑
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors
WO2017106175A2 (fr) 2015-12-14 2017-06-22 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement d'un dysfonctionnement du sphincter gastro-intestinal
US9993476B2 (en) 2010-05-26 2018-06-12 Adverio Pharma Gmbh Substituted 5-flouro-1H-pyrazolopyridines and their use
WO2018111795A2 (fr) 2016-12-13 2018-06-21 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de sgc pour le traitement de la motilité œsophagienne
US10350206B2 (en) 2014-09-19 2019-07-16 Bayer Pharma Aktiengesellschaft Benzyl substituted indazoles as BUB1 inhibitors
WO2020014504A1 (fr) 2018-07-11 2020-01-16 Cyclerion Therapeutics, Inc. Utilisation de stimulateurs gcs pour le traitement de maladies mitochondriales

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003076408A2 (fr) * 2002-03-08 2003-09-18 Abbott Laboratories Derives d'indazole qui sont des activateurs de guanylate cyclase soluble
DE10232571A1 (de) * 2002-07-18 2004-02-05 Bayer Ag 4-Aminosubstituierte Pyrimidinderivate
KR20060090801A (ko) * 2003-09-04 2006-08-16 머크 앤드 캄파니 인코포레이티드 고안압증 치료용 안용 조성물
DE102006043443A1 (de) 2006-09-15 2008-03-27 Bayer Healthcare Ag Neue aza-bicyclische Verbindungen und ihre Verwendung
DE102008063992A1 (de) 2008-12-19 2010-09-02 Lerner, Zinoviy, Dipl.-Ing. Neue aliphatisch substituierte Pyrazolopyridine und ihre Verwendung
UY33041A (es) 2009-11-27 2011-06-30 Bayer Schering Pharma Aktienegesellschaft Procedimiento para la preparaciòn de {4,6-diamino-2-[1-(2-fluorobencil)-1h-pirazolo[3,4-b]piridin-3-il]pirimidin-5-il}carbamato de metilo y su purificaciòn para el uso como principio activo farmacèutico
AU2010323227B2 (en) 2009-11-27 2015-11-19 Adverio Pharma Gmbh Method for producing methyl-{4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate and its purification for use thereof as pharmaceutical substance
EA031602B1 (ru) 2011-11-25 2019-01-31 Адверио Фарма Гмбх Способы получения альдегидов
BR112015019571A2 (pt) 2013-02-21 2017-07-18 Adverio Pharma Gmbh formas de {4,6-diamino-2-[1-(2-fluorobenzil)-1h-pirazolo[3,4-b]piridino-3-il]pirimidino-5-il}metilcarbamato de metila
KR102615821B1 (ko) * 2017-04-11 2023-12-21 선샤인 레이크 파르마 컴퍼니 리미티드 불소-치환된 인다졸 화합물 및 이의 용도

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0641564A1 (fr) * 1992-05-21 1995-03-08 Yoshitomi Pharmaceutical Industries, Ltd. Compose de pyrazole condense optiquement actif, pour le traitement de la thrombocytopenie et de l'erythropenie
EP0667345A1 (fr) * 1994-02-14 1995-08-16 Yung Shin Pharm. Ind. Co. Ltd. Dérivés 1-benzyle-3-(aryle substitué) du pyrazole condensée comme agents inhibiteurs de l'aggrégation plaquettaire
DE19642320A1 (de) * 1996-10-14 1998-04-16 Bayer Ag Neue 1-Methyl-heterocyclyl-substituierte Pyrazole
DE19642255A1 (de) * 1996-10-14 1998-04-16 Bayer Ag Verwendung von 1-Benzyl-3-(substituierten-hetaryl) -kondensierten Pyrazol-Derivaten

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0641564A1 (fr) * 1992-05-21 1995-03-08 Yoshitomi Pharmaceutical Industries, Ltd. Compose de pyrazole condense optiquement actif, pour le traitement de la thrombocytopenie et de l'erythropenie
EP0667345A1 (fr) * 1994-02-14 1995-08-16 Yung Shin Pharm. Ind. Co. Ltd. Dérivés 1-benzyle-3-(aryle substitué) du pyrazole condensée comme agents inhibiteurs de l'aggrégation plaquettaire
DE19642320A1 (de) * 1996-10-14 1998-04-16 Bayer Ag Neue 1-Methyl-heterocyclyl-substituierte Pyrazole
DE19642255A1 (de) * 1996-10-14 1998-04-16 Bayer Ag Verwendung von 1-Benzyl-3-(substituierten-hetaryl) -kondensierten Pyrazol-Derivaten

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7291622B2 (en) 2000-11-22 2007-11-06 Bayer Aktiengesellschaft Medical uses of carbamate-substituted pyrazolo-pyridine derivatives
US6693102B2 (en) 2000-11-22 2004-02-17 Bayer Aktiengesellschaft Pyridine-substituted pyrazolopyridine derivatives
US6903089B1 (en) 2000-11-22 2005-06-07 Bayer Aktiengesellschaft Lactam-substituted pyrazolopyridine derivatives
US7105523B2 (en) 2000-11-22 2006-09-12 Bayer Aktiengeselischaft Carbamate-substituted pyrazolopyridine-derivatives
US7115599B2 (en) 2000-11-22 2006-10-03 Bayer Aktiengesellschaft Sulfonamide-substituted pyrazolopyridine compounds
US6919345B2 (en) 2001-05-11 2005-07-19 Bayer Aktiengesellschaft Sulfonate substituted pyrazol pyridine derivatives
US7317016B2 (en) 2001-05-11 2008-01-08 Bayer Aktiengesellschaft Methods of treating medical conditions using sulfonate-substituted pyrazolopyridine derivatives
WO2003004503A1 (fr) * 2001-07-04 2003-01-16 Bayer Healthcare Ag Derives de pyrazolopyridine pontes avec la morpholine
US7173037B2 (en) 2002-05-08 2007-02-06 Bayer Healthcare Ag Carbamate-substituted pyrazolopyridines
JP2006502119A (ja) * 2002-07-18 2006-01-19 バイエル・ヘルスケア・アクチェンゲゼルシャフト 新規２，５−二置換ピリミジン誘導体
US7427617B2 (en) 2002-09-26 2008-09-23 Bayer Healthcare Ag Morpoline-bridged indazole derivatives
WO2004031186A1 (fr) * 2002-09-26 2004-04-15 Bayer Healthcare Ag Derives d'indazole pontes par morpholine
US7645752B2 (en) 2006-01-13 2010-01-12 Wyeth Llc Sulfonyl substituted 1H-indoles as ligands for the 5-hydroxytryptamine receptors
DE102007026392A1 (de) 2007-06-06 2008-12-11 Bayer Healthcare Ag Lösungen für die Perfusion und Konservierung von Organen und Geweben
US9546149B2 (en) 2007-06-08 2017-01-17 Mannkind Corporation IRE-1α inhibitors
US9981901B2 (en) 2007-06-08 2018-05-29 Fosun Orinove Pharmatech, Inc. IRE-1α inhibitors
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors
DE102007028407A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
DE102007028319A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
DE102007028406A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
DE102007028320A1 (de) 2007-06-20 2008-12-24 Bayer Healthcare Ag Substituierte Oxazolidinone und ihre Verwendung
EP2138178A1 (fr) 2008-06-28 2009-12-30 Bayer Schering Pharma Aktiengesellschaft Oxazolidinones pour le traitement de maladie pulmonaire obstructive chronique (MPOC) et/ou de l'asthme
US8293738B2 (en) 2010-05-12 2012-10-23 Abbott Laboratories Indazole inhibitors of kinase
US9993476B2 (en) 2010-05-26 2018-06-12 Adverio Pharma Gmbh Substituted 5-flouro-1H-pyrazolopyridines and their use
US11439642B2 (en) 2010-05-26 2022-09-13 Adverio Pharma Gmbh Substituted 5-fluoro-1H-pyrazolopyridines and their use
US10736896B2 (en) 2010-05-26 2020-08-11 Adverio Pharma Gmbh Substituted 5-fluoro-1H-pyrazolopyridines and their use
WO2012165399A1 (fr) 2011-05-30 2012-12-06 アステラス製薬株式会社 Composé imidazopyridine
CN103974948A (zh) * 2011-10-06 2014-08-06 拜耳医药股份有限公司 在治疗过度增殖性疾病中用作bub1激酶抑制剂的取代的苄基吲唑
US10604532B2 (en) 2011-10-06 2020-03-31 Bayer Intellectual Property Gmbh Substituted benzylindazoles for use as BUB1 kinase inhibitors in the treatment of hyperproliferative diseases
EP2763982B1 (fr) * 2011-10-06 2018-01-10 Bayer Pharma Aktiengesellschaft Benzylindazoles substitués pour l'utilisation en tant qu'inhibiteurs de bub1 kinase dans le traitement de maladies d'hyperprolifération
US10266548B2 (en) 2011-10-06 2019-04-23 Bayer Intellectual Property Gmbh Substituted benzylindazoles for use as Bub1 kinase inhibitors in the treatment of hyperproliferative diseases
US10040866B2 (en) 2012-05-10 2018-08-07 Bayer Pharma Aktiengesellschaft Nucleic acids and host cells expressing antibodies capable of binding to the coagulation factor XIa and uses thereof
US10221247B2 (en) 2012-05-10 2019-03-05 Bayer Pharma Aktiengesellschaft Antibodies capable of binding to the coagulation factor XIa and uses thereof
WO2013167669A1 (fr) 2012-05-10 2013-11-14 Bayer Pharma Aktiengesellschaft Anticorps capables de lier au facteur de coagulation xi et/ou à sa forme activée, le facteur xia, et utilisations de ceux-ci
US9783614B2 (en) 2012-05-10 2017-10-10 Bayer Pharma Aktiengesellschaft Antibodies capable of binding to the coagulation Factor XI and/or its activated form factor Xia and uses thereof
US11046783B2 (en) 2012-05-10 2021-06-29 Bayer Pharma Aktiengesellschaft Antibodies capable of binding to the coagulation factor XIa and uses thereof
WO2014084312A1 (fr) 2012-11-30 2014-06-05 アステラス製薬株式会社 Composé imidazopyridine
US10350206B2 (en) 2014-09-19 2019-07-16 Bayer Pharma Aktiengesellschaft Benzyl substituted indazoles as BUB1 inhibitors
WO2017106175A2 (fr) 2015-12-14 2017-06-22 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement d'un dysfonctionnement du sphincter gastro-intestinal
WO2018111795A2 (fr) 2016-12-13 2018-06-21 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de sgc pour le traitement de la motilité œsophagienne
WO2020014504A1 (fr) 2018-07-11 2020-01-16 Cyclerion Therapeutics, Inc. Utilisation de stimulateurs gcs pour le traitement de maladies mitochondriales

Also Published As

Publication number Publication date
EP1119566A1 (fr) 2001-08-01
CA2346698A1 (fr) 2000-04-20
JP2002527435A (ja) 2002-08-27
DE19846514A1 (de) 2000-04-20
AU6330099A (en) 2000-05-01

Similar Documents

Publication Publication Date Title
WO2000021954A1 (fr) Nouveaux pyrazoles heterocycliques methyl-substitues
EP0944631B1 (fr) Nouveaux derives de pyrazole substitues pour le traitement de maladies cardio-vasculaires
EP1102767B1 (fr) Derives de pyrazole substitues
EP1102768B1 (fr) Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
EP1339714B1 (fr) Nouveaux derives de pyrazolopyridine substitues par sulfonamide
EP1339716B1 (fr) derives de pyrazolopyridine substitues par un lactame
EP0934311B1 (fr) Nouveaux derives de pyrazol heterocyclylmethyle-substitues
DE10057751A1 (de) Neue Carbamat-substituierte Pyrazolopyridinderivate
EP1406908A1 (fr) Derives de pyrazolopyridine pontes avec la morpholine
EP1343786A1 (fr) Nouveaux derives de pyrazolopyridine a substitution pyridine
DE19834045A1 (de) (4-Amino-5-ethylpyrimidin-2-yl)-1-(2-fluorbenzyl)-1H-pyrazolo[3,4-b]pyridin
WO2003086407A1 (fr) Utilisation de stimulateurs de la guanylate cyclase soluble pour traiter le glaucome
EP1525203A1 (fr) Derives de pyrimidine 4-amino substitues
DE10021069A1 (de) Substituiertes Pyrazolderivat
DE10244810A1 (de) Neue Morpholin-überbrückte Indazolderivate
EP0473550A1 (fr) Indolonaphtyridines
WO1990007503A1 (fr) 3-azabicyclo[3.1.1]heptanes substitues, leur production et leur utilisation
DE10122895A1 (de) Neue Lactam-substituierte Pyrazolopyridinderivate
DD296925A5 (de) Verfahren zur herstellung von substituierten 1,4-dihydro-4-oxonaphthyridin-3-carboxylat-verbindungen

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref country code: AU

Ref document number: 1999 63300

Kind code of ref document: A

Format of ref document f/p: F

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1999950564

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2346698

Country of ref document: CA

Ref country code: CA

Ref document number: 2346698

Kind code of ref document: A

Format of ref document f/p: F

Ref country code: JP

Ref document number: 2000 575860

Kind code of ref document: A

Format of ref document f/p: F

NENP Non-entry into the national phase

Ref country code: CA

WWP Wipo information: published in national office

Ref document number: 1999950564

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWE Wipo information: entry into national phase

Ref document number: 09807231

Country of ref document: US

WWW Wipo information: withdrawn in national office

Ref document number: 1999950564

Country of ref document: EP