EP1368335A2 - Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques - Google Patents

Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques

Info

Publication number
EP1368335A2
EP1368335A2 EP02701292A EP02701292A EP1368335A2 EP 1368335 A2 EP1368335 A2 EP 1368335A2 EP 02701292 A EP02701292 A EP 02701292A EP 02701292 A EP02701292 A EP 02701292A EP 1368335 A2 EP1368335 A2 EP 1368335A2
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
chain
straight
branched
substituted
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Withdrawn
Application number
EP02701292A
Other languages
German (de)
English (en)
Inventor
Cristina Alonso-Alija
Michael Härter
Michael Hahn
Josef Pernerstorfer
Stefan Weigand
Johannes-Peter Stasch
Frank Wunder
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer AG
Bayer Healthcare AG
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 AG, Bayer Healthcare AG filed Critical Bayer AG
Publication of EP1368335A2 publication Critical patent/EP1368335A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to new chemical compounds which also stimulate soluble guanylate cyclase via a novel mode of action which does not involve the heme group of the enzyme, their production and their use as medicaments, in particular as medicaments for the treatment of cardiovascular diseases.
  • Cyclic guanosine monophosphate is one of the most important cellular transmission systems in mammalian cells. Together with nitrogen monoxide (NO), which is released from the endothelium and transmits hormone-like and mechanical signals, it forms the NO / cGMP system.
  • NO nitrogen monoxide
  • the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triposphate (GTP).
  • GTP guanosine triposphate
  • the previously known representatives of this family can be divided into two groups according to structural features and the type of ligand: the particulate guanylate cyclases that can be stimulated by natriuretic peptides and the soluble guanylate cyclases that can be stimulated by NO.
  • the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer, which is part of the regulatory center. This is of central importance for the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. Hem-free preparations, on the other hand, cannot be stimulated by NO. CO is also able to attack the central iron atom of the heme, whereby the stimulation by CO is significantly less than that by NO.
  • guanylate cyclase plays a decisive role in different physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion and neuronal signal transmission as well as in diseases , which are based on a disturbance of the above-mentioned processes.
  • the NO / cGMP system can be suppressed, which leads to Examples include high blood pressure, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, thrombosis, stroke and myocardial infarction.
  • a NO-independent treatment option for such diseases aimed at influencing the cGMP signal path in organisms is a promising approach due to the expected high efficiency and few side effects.
  • the previously known stimulators of soluble guanylate cyclase stimulate the enzyme either directly via the heme group (carbon monoxide, nitrogen monoxide or diphenyliodonium hexafluorophosphate) by interaction with the iron center of the heme group and a resulting conformational change that leads to an increase in enzyme activity (Gerzer et al., FEBS Lett. 132 (1981), 71), or via a heme-dependent mechanism that is independent of NO, but too potentiates the stimulating effect of NO or CO (e.g. YC-1, Hoenicka et al., J. Mol. Med. (1999) 14; or that in WO 98/16223, WO 98/16507 and WO 98/23619 described pyrazole derivatives).
  • NO or CO e.g. YC-1, Hoenicka et al., J. Mol. Med. (1999) 14; or that in WO 98/16223, WO 98/
  • Fatty acids such as B. arachidonic acid, prostaglandin endoperoxides and fatty acid hydroperoxides on the soluble guanylate cyclase could not be confirmed (see e.g. Hoenicka et al., J. Mol. Med. 77 (1999), 14).
  • the enzyme still shows a detectable catalytic basal activity, i.e. cGMP is still formed.
  • the remaining catalytic basal activity of the heme-free enzyme cannot be stimulated by any of the known stimulators mentioned above.
  • protoporphyrin IX A stimulation of heme-free soluble guanylate cyclase by protoporphyrin IX has been described (Ignarro et al., Adv. Pharmacol. 26 (1994), 35).
  • protoporphyrin IX can be regarded as facial expressions for the NO-heme adduct, which is why the addition of protoporphyrin IX to the soluble guanylate cyclase should lead to the formation of a structure of the enzyme corresponding to the soluble guanylate cyclase which is stimulated by NO. This is also through the
  • the compounds according to the invention are able to stimulate both the heme-containing and the heme-free form of the soluble guanylate cyclase.
  • the stimulation of the enzyme with these new stimulators is via a heme-independent path, which is also demonstrated by the fact that the new stimulators on the heme-containing enzyme on the one hand show no synergistic effect with NO and on the other hand the effect of these new stimulators is not affected by Hem-dependent inhibitor of soluble guanylate cyclase, lH-l, 2,4-oxadiazol- (4,3a) -quinoxalin-l-one (ODQ).
  • EP-A-0 345 068 describes, inter alia, the aminoalkanecarboxylic acid (1) as an intermediate in the synthesis of GABA antagonists:
  • WO 93/00359 describes the aminoalkanecarboxylic acid (2) as an intermediate in peptide synthesis and its use as an active ingredient for treating diseases of the central nervous system:
  • Row S, N and / or O is fused, or a partially unsaturated or aromatic heterocycle having 1 to 9 carbon atoms and up to 3
  • V is absent, O, NR 4 , NR 4 CONR 4 , NR 4 CO, NR 4 SO 2 , COO, CONR 4 or S (O) 0 ,
  • o 0, 1 or 2
  • Q is missing, straight chain or branched alkylene, straight chain or branched
  • Means alkenediyl or straight-chain or branched alkynediyl each having up to 12 carbon atoms, each of which has one or more groups from O, S (O) p , NR 5 , CO, NR 5 SO 2 or CONR 5 can contain, and can be substituted one or more times by halogen, hydroxy or alkoxy with up to 4 carbon atoms, optionally any two atoms of the above chain to form a three- to eight-membered ring can be connected to one another,
  • R 5 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, which can be substituted by halogen or alkoxy having up to 4 carbon atoms,
  • R 6 is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, straight-chain or branched haloalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
  • R 8 , R 9 , R 11 and R 12 independently of one another are hydrogen, straight-chain or branched alkyl, straight-chain or branched alkenyl having up to 8 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, arylalkyl with 8 to 18
  • R denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn can be substituted one or more times by halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,
  • R 10 is hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to 12 carbon atoms, aryl having 6 to 10 carbon atoms, an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and or denotes O or cycloalkyl having 3 to 8 carbon atoms, which may optionally further be substituted by halogen, hydroxy, CN, NO 2 , NH 2 , NHCOR 7 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms;
  • aryl with 6 to 10 carbon atoms, a saturated carbocycle with 6 to 10 carbon atoms, an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O can be substituted, which can also be bonded via N, which is directly or via a group from O, S, SO, SO 2 , NR 7 , SO 2 NR 7 , CON, straight-chain or branched alkylene, straight-chain or branched alkenediyl , straight-chain or branched alkyloxy, straight-chain or branched oxyalkyloxy, straight-chain or branched sulfonylalkyl, straight-chain or branched thioalkyl, each with up to 8
  • Carbon atoms can be bonded and one to three times by straight-chain or branched alkyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy, carbonylalkyl or straight-chain or branched alkenyl, each with up to 6 Carbon atoms, halogen, SR 6 , CN, NO 2 , NR 8 R 9 , CONR 15 R 16 or NR 14 COR 17 can be substituted,
  • R 15 , R 16 independently of one another are hydrogen, straight-chain or branched
  • R 17 is hydrogen, straight-chain or branched alkyl with up to 12
  • Haloalkyl or haloalkoxy can be substituted with up to 6 carbon atoms
  • the cyclic radicals can be fused with an aromatic or saturated carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O,
  • C 6 - alkoxy, NR 19 R 20 , cycloalkyl with 3 to 8 carbon atoms can carry, straight-chain or branched haloalkyl, straight-chain or branched alkoxy, or alkoxycarbonyl with up to 4 carbon atoms each, CN, NO 2 , NR 19 R 20 , SR 17 , SO 2 R 17 , cycloalkyl with 3 to 8 carbon atoms, haloalkoxy haloalkoxy with up to 6 carbon atoms,
  • Cycloalkoxy with up to 14 carbon atoms CONH 2 , CONR 17 R 17 , SO 2 NH 2 , SO 2 NR 17 R 17 , alkoxyalkoxy with up to 12 carbon atoms, NHCOOR 17 , NHCOR 17 , NHSO 2 R 17 , NHCONH 2 , OCONR 17 R 17 , OSO 2 R 17 , C 2 -i 2 -alkenyl or C ⁇ .i 2 -alkynyl means
  • R 19 and R 20 independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, m represents an integer from 1 to 4,
  • W denotes straight-chain or branched alkylene with up to 6 carbon atoms or straight-chain or branched alkenediyl with up to 6 carbon atoms, each of which can contain a group from O, S (O) q , NR 21 , CO or CONR 21 , or CO, NHCO or OCO means
  • q 0, 1 or 2
  • U denotes straight-chain or branched alkyl having up to 4 carbon atoms
  • A is aryl with 6 to 10 carbon atoms or an aromatic heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, which may be one to three times by halogen, straight-chain or branched alkyl, straight-chain or branched Haloalkyl, straight-chain or branched alkoxy, haloalkoxy or alkoxycarbonyl with up to 4 carbon atoms, CN, NO 2 or NR 22 R 23 can be substituted, in which
  • R and R each independently represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, carbonylalkyl or sulfonylalkyl.
  • R 2 means tetrazolyl, COOR 24 or CONR 25 R 26 ,
  • R 24 is hydrogen, alkyl of 1 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms
  • R 25 and R 26 each independently represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO 2 R 27 , or R 25 and R 26 together represent a five- or six-membered ring form, which can contain N or O,
  • R 27 denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being one or more times by halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6
  • X denotes straight-chain or branched alkylene with up to 12 carbon atoms or straight-chain or branched alkenediyl with up to 12 carbon atoms, each of one to three groups from O, S (O) r , NR 28 , CO or
  • CONR 29 may contain aryl or aryloxy having 6 to 10 carbon atoms, the aryl radical in turn being able to be substituted one or more times by halogen, CN, NO, alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms, optionally two random atoms of the above chains are connected to one another by an alkyl chain to form a three- to eight-membered ring, embedded image in which
  • r 0, 1 or 2
  • R 28 represents hydrogen, alkyl having 1 to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
  • R 29 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
  • n 1 or 2;
  • R 1 means tetrazolyl, COOR 30 or CONR 31 R 32 ,
  • R 30 is hydrogen, alkyl of 1 to 8 carbon atoms or cycloalkyl of 3 to 8 carbon atoms
  • R 31 and R 32 each independently represent hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO 2 R 33 ,
  • R means straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn can be substituted one or more times by halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms,
  • radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;
  • V is absent, O, NR 4 , NR 4 CONR 4 , NR 4 CO, NR 4 SO 2 , COO, CONR 4 or S (O) 0 ,
  • R 4 independently of any further radical R 4 which may be present, denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or arylalkyl having 7 to 18 carbon atoms, the aryl radical can in turn be substituted one or more times by halogen, alkyl, alkoxy having up to 6 carbon atoms,
  • Q is absent, straight-chain or branched alkylene, straight-chain or branched alkenediyl or straight-chain or branched alkynediyl each having up to 12 carbon atoms, each of which means one or more groups of O, S (O) p , NR 5 , CO, NR 5 SO 2 or CONR 5 can contain, and can be substituted one or more times by halogen, hydroxy or alkoxy with up to 4 carbon atoms, optionally any two atoms of the above chain can be connected to form a three- to eight-membered ring,
  • R 5 is hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, which can be substituted by halogen or alkoxy having up to 4 carbon atoms,
  • p 0, 1 or 2
  • Y is hydrogen, NR 8 R 9 , aryl with 6 to 10 carbon atoms, an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O or straight-chain or branched cycloalkyl with 3 to 8 carbon atoms, which can also be bonded via N, the cyclic radicals in each case one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched Haloalkyl, straight-chain or branched haloalkoxy each having up to 8 carbon atoms, straight-chain or branched cycloalkyl having 3 to 8 carbon atoms, halogen, hydroxy, CN, SR 6 , NO 2 , NR 8 R 9 , NR 7 COR 10
  • NR 7 CONR 7 R 10 or CONR ⁇ R 12 can be substituted, embedded image in which
  • R 6 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, straight-chain or branched haloalkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
  • R 7 independently of any further radical R 7 which may be present, denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
  • R 8 , R 9 , R 11 and R 12 independently of one another are hydrogen, straight-chain or branched alkyl, straight-chain or branched alkenyl with up to
  • R 13 denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being used one or more times by halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms can be substituted
  • R 10 is hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to
  • Haloalkyl or haloalkoxy can be substituted with up to 6 carbon atoms
  • Haloalkyl, straight-chain or branched haloalkoxy, carbonylalkyl or straight-chain or branched alkenyl having in each case up to 6 carbon atoms, halogen, SR 6, CN, NO 2, NR 8 R 9, CONR l5 R 16 or NR 14 COR 17 may be substituted,
  • R 14 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
  • R 15 , R 16 independently of one another are hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, cycloalkyl having 3 to 8 carbon atoms or a radical of the formula SO 2 R 18 ,
  • R 18 denotes straight-chain or branched alkyl having up to 4 carbon atoms or aryl having 6 to 10 carbon atoms, the aryl radical in turn being substituted one or more times by halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms can
  • R 17 is hydrogen, straight-chain or branched alkyl with up to 12
  • 3 heteroatoms from the series S, N and / or O or cycloalkyl with 3 is up to 8 carbon atoms, which may optionally be further substituted by halogen, CN, NO 2 , alkyl, alkoxy, haloalkyl or haloalkoxy having up to 6 carbon atoms;
  • Carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O can be fused
  • R 3 denotes hydrogen, halogen, straight-chain or branched alkyl, straight-chain or branched haloalkyl or straight-chain or branched alkoxy each having up to 4 carbon atoms,
  • n an integer from 1 to 4,
  • W denotes straight-chain or branched alkylene or straight-chain or branched alkenediyl each having up to 4 carbon atoms
  • A is phenyl or an aromatic heterocycle having 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O, which may be one to three times by halogen, straight-chain or branched alkyl, straight-chain or branched haloalkyl or straight-chain or branched alkoxy with up to 4 carbon atoms, can be substituted,
  • R 2 means COOR 24
  • X denotes straight-chain or branched alkylene with up to 8 carbon atoms or straight-chain or branched alkenediyl with up to 8 carbon atoms, each of one to three groups from phenyl, phenyloxy, O, CO
  • R 29 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,
  • n 1 or 2;
  • R 1 means COOR 30 ,
  • R, 30 is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms.
  • radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;
  • V is absent, O, S or NR 4 means
  • R represents hydrogen or methyl
  • cyclic radicals are each one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy each having up to 4 carbon atoms, straight-chain or branched cycloalkyl having 3 to 6 carbon atoms, F, CI, Br, I, NO 2 , SR 6 , NR 8 R 9 , NR 7 COR 10 or CONR ⁇ R 12 substituted could be,
  • R denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or straight-chain or branched haloalkyl having up to 4 carbon atoms,
  • R 7 denotes hydrogen, or straight-chain or branched alkyl having up to 4 carbon atoms
  • R 8 , R 9 , R 11 and R 12 independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl, where the phenyl radical is monosubstituted to triple by F, CI Br, hydroxy, methyl, ethyl, n - Propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, Methoxy, ethoxy, amino, acetylamino, NO 2 , CF 3 , OCF 3 or CN may be substituted, or two substituents from R 8 and R 9 or R 11 and R 12 may be linked to form a five- or six-membered ring, which can be interrupted by O or N,
  • R 14 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or cycloalkyl having 3 to 8 carbon atoms,
  • R 17 is hydrogen, straight-chain or branched alkyl having up to 12 carbon atoms, straight-chain or branched alkenyl having up to
  • Butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO 2 , CF 3 , OCF 3 or CN may be substituted;
  • R 3 represents hydrogen, methyl or fluorine
  • n an integer from 1 to 4,
  • W denotes CH 2 , -CH 2 CH 2 -, CH 2 CH 2 CH 2)
  • CH CHCH 2 ,
  • A is phenyl, pyridyl, thienyl or thiazolyl, which is optionally one to three times by methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, CF 3 , methoxy, Ethoxy, F, CI, Br can be substituted,
  • R 2 means COOR 24
  • R 24 is hydrogen or straight-chain or branched alkyl with up to 4
  • X denotes straight-chain or branched alkylene with up to 8 carbon atoms or straight-chain or branched alkenediyl with up to 8 carbon atoms, each of which may contain one to three groups from phenyl, phenyloxy, O, CO or CONR 30 ,
  • R 30 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms
  • n 1 or 2;
  • R 1 means COOR 35 ,
  • R 35 is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms.
  • radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;
  • the cyclic radicals in each case one to three times by straight-chain or branched alkyl, straight-chain or branched alkenyl, straight-chain or branched alkynyl, straight-chain or branched alkoxy, straight-chain or branched alkoxyalkoxy, straight-chain or branched haloalkyl, straight-chain or branched haloalkoxy with in each case up to 4 carbon atoms, straight-chain or branched cycloalkyl with 3 to 6 carbon atoms, F, CI, Br, I, NO 2 , SR 6 , NR 8 R 9 , NR 7 COR 10 or CONR n R 12 can be substituted, embedded image in which
  • R 6 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or straight-chain or branched haloalkyl having up to 4 carbon atoms,
  • R 7 denotes hydrogen, or straight-chain or branched alkyl having up to 4 carbon atoms
  • R 8 , R 9 , R 11 and R 12 independently of one another are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl, where the phenyl radical is monosubstituted to triple by F, CI Br, hydroxy, methyl, ethyl, n - Propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl,
  • R 10 is hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or phenyl, where the phenyl radical is monosubstituted to triple by F, Cl Br, hydroxy, methyl, ethyl, n-propyl, i-propyl, n-butyl, see -Butyl, i-butyl, t-butyl,
  • Methoxy, ethoxy, amino, acetylamino, NO 2 , CF 3 , OCF 3 or CN may be substituted;
  • R 17 is hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, straight-chain or branched alkenyl having up to
  • Butyl, i-butyl, t-butyl, methoxy, ethoxy, amino, acetylamino, NO 2 , CF 3 , OCF 3 or CN may be substituted;
  • the cyclic radicals can be fused with an aromatic or saturated carbocycle with 1 to 10 carbon atoms or an aromatic or saturated heterocycle with 1 to 9 carbon atoms and up to 3 heteroatoms from the series S, N and / or O,
  • R represents hydrogen, methyl or fluorine
  • n an integer from 1 to 2
  • W -CH 2 - or -CH 2 CH 2 - means
  • A is phenyl, which is optionally one to three times by methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, CF 3 , methoxy, ethoxy, F, CI, Br can be substituted
  • R 2 means COOR 24 embedded image in which
  • R 24 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • R 30 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,
  • n 1 or 2;
  • R 1 means COOR 35 ,
  • R 35 is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms.
  • radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;
  • Y is phenyl which is substituted by a radical selected from the group consisting of 2-phenylethyl, cyclohexyl, 4-chlorophenyl, 4-methoxyphenyl,
  • R 3 represents hydrogen, methyl or fluorine
  • n an integer from 1 to 2
  • A means phenyl
  • R 2 means COOH, where R 2 is in the 4-position to the rest U,
  • X means (CH 2 )
  • R 1 means COOH. Also particularly preferred according to the present invention are compounds in which
  • radicals V and W can be bonded to any carbon atom or to any nitrogen atom of a ring which may be present;
  • Q means CH 2 O which is bonded to Z via its carbon atom
  • Y is phenyl which is substituted by a radical selected from the group consisting of 2-phenylethyl, cyclohexyl, 4-chlorophenyl, 4-methoxyphenyl, 4-trifmormethylphenyl, 4-cyanophenyl, 4-chlorophenoxy, 4-methoxyphenoxy, 4-trifluoromethylphenoxy, 4-cyanophenoxy, 4-methylphenyl, 4-tert-butylphenyl, 4-carboxyphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2,4-dichlorophenyl is selected,
  • R 3 represents hydrogen, methyl or fluorine
  • n an integer from 1 to 2
  • A means phenyl
  • R means COOH, where R2 is arranged in 4 position to the rest U,
  • R 1 means COOH.
  • the compounds of the general formula (I) according to the invention can also be present in the form of their salts. In general, 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.
  • 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.
  • particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic 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.
  • Sodium, potassium, magnesium or calcium salts as well as 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.
  • the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner, for example by racemate resolution or chromatographic separation.
  • Double bonds present in the compounds according to the invention can be in the eis or trans configuration (Z or E form).
  • the substituents generally have the following meaning:
  • Alkyl generally represents a straight-chain or branched hydrocarbon radical having 1 to 20 carbon atoms.
  • Alkylene generally stands for a straight-chain or branched hydrocarbon bridge with 1 to 20 carbon atoms.
  • methylene ethylene
  • ethylene ethylene
  • Alkenyl 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. Examples include allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl, isoheptenyl, octenyl and isooctenyl.
  • Alkynyl generally represents a straight-chain or branched hydrocarbon radical having 2 to 20 carbon atoms and one or more, preferably with one or two triple bonds. Examples include ethynyl, 2-butynyl, 2-pentynyl and 2-hexynyl.
  • Alkenediyl generally represents a straight-chain or branched hydrocarbon bridge with 2 to 20 carbon atoms and one or more, preferably with one or two, double bonds.
  • Alkenediyl generally represents a straight-chain or branched hydrocarbon bridge with 2 to 20 carbon atoms and one or more, preferably with one or two, double bonds.
  • Alkindiyl generally represents a straight-chain or branched hydrocarbon bridge with 2 to 20 carbon atoms and one or more, preferably with one or two triple bonds. Examples include ethyne-1,2-diyl, propyne-1,3-diyl, l-butyne-1,4-diyl, l-butyne-1,3-diyl, 2-butene-1,4-diyl.
  • Acyl generally represents straight-chain or branched lower alkyl having 1 to 9 carbon atoms, which is 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. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohex oxy, heptoxy, isoheptoxy, octoxy or iso-octoxy.
  • alkoxy and “alkyloxy” are used synonymously.
  • Alkoxyalkyl generally represents an alkyl radical having up to 8 carbon atoms which is substituted by an alkoxy radical having up to 8 carbon atoms.
  • Alkyl here generally represents a straight-chain or branched hydrocarbon radical having 1 to 13 carbon atoms. Examples include the following alkoxycarbonyl 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.
  • 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.
  • 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.
  • heterocycle generally represents a saturated, unsaturated or aromatic 3- to 10-membered, for example 5- or 6-membered, heterocycle which can contain up to 3 heteroatoms from the series S, N and or or and which in the case of a nitrogen atom can also be bound via this.
  • heterocycle includes: oxadiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, piperazinyl,
  • Thiazolyl, furyl, oxazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl and tetrahydropyranyl are preferred.
  • heteroaryl (or "hetaryl”) stands for an aromatic heterocyclic radical.
  • heterocycle structures shown in the present application only one bond to the neighboring group is indicated, for example in the heterocycle structures which are suitable for Y, the bond to the unit Q. Independently of this, however, these heterocycle structures can carry further substituents as indicated.
  • the present invention further relates to a process for the preparation of the compounds of the formula (I), characterized in that
  • E either represents a leaving group which is substituted in the presence of a base or is an optionally activated hydroxy function
  • E either represents a leaving group which is substituted in the presence of a base or is an optionally activated hydroxy function
  • E either represents a leaving group which is substituted in the presence of a base or is an optionally activated hydroxy function
  • Va stands for O or S
  • E either represents a leaving group which is substituted in the presence of a base or is an optionally activated hydroxy function:
  • R ⁇ and R 2 b each independently represent CN or COO Alk, where Alk represents a straight-chain or branched alkyl radical having up to 6 carbon atoms,
  • M represents an aryl or heteroaryl radical, a straight-chain or branched alkyl, alkenyl or alkynyl radical or cycloalkyl radical or an arylalkyl, an arylalkenyl or an arylalkynyl radical,
  • the compounds of the formula (I) can also be prepared on a solid phase, such as a polystyrene resin, particularly preferably a commercially available Wang polystyrene resin.
  • the resin is initially dissolved in a swollen like dimethylformamide (DMF).
  • the corresponding carboxylic acid serving as the starting compound is then bound to the resin by standard methods.
  • the carboxylic acid can be bound to the resin in the presence of a base such as pyridine or 4-dimethylaminopyridine (DMAP) and a reagent which activates the carboxyl unit, such as an acid halide, for example dichlorobenzoyl chloride, in a solvent such as dimethylformamide (DMF).
  • a base such as pyridine or 4-dimethylaminopyridine (DMAP)
  • DMAP 4-dimethylaminopyridine
  • a reagent which activates the carboxyl unit such as an acid halide, for example dichlorobenzoyl chloride
  • reaction mixture is left to stir for at least 2 hours, preferably 12 hours, particularly preferably about 24 hours, at room temperature and normal pressure, the carboxylic acid being used in excess, preferably in a two to three-fold excess, with respect to the loading of the solid phase.
  • the carboxylic acid bound to the resin can be derivatized without having to be separated from the resin beforehand.
  • a corresponding 4-aminobenzoic acid or 4-formylbenzoic acid derivative can be attached to the resin, then via successive reductive amination reactions, as described below for the preparation of the compounds of the formula (II), (IV) and (VI) a compound of the formula (VUI) are reacted, which can then be converted into the target compounds on the solid phase analogously to process [D].
  • the resin is split off after the desired structure of the target compound on the solid phase in a conventional manner in an acidic environment.
  • the product separated from the resin can, after removal of any solvents which may be present, be purified by known purification processes, such as, for example, chromatographic processes.
  • purification processes such as, for example, chromatographic processes.
  • Preferred solvents for the processes according to the invention are conventional organic solvents which do not change under the reaction conditions or water.
  • ethers such as diethyl ether, butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or hydrocarbons such as benzene, toluene, xylene or petroleum ether, or amides such as dimethylformamide or hexamethylphosphorium triamide, or 1,3-dimethyl-2-imidazole are preferably used for the process according to the invention -on, 1, 3-dimethyl-tetrahydro- pyrimidin-2-one, acetonitrile, ethyl acetate or dimethyl sulfoxide can be used. It is of course also possible to use mixtures of the abovementioned solvents.
  • the bases preferred for the processes according to the invention comprise basic compounds conventionally used for basic reactions.
  • Alkali metal hydrides such as sodium hydride or potassium hydride, or alkali metal alcoholates such as sodium methoxide, sodium ethanolate, potassium methoxide, potassium ethanolate or potassium t-butoxide, or carbonates such as sodium carbonate, cesium carbonate or potassium carbonate or amides such as sodium amide or lithium diisopropylamide, or organolith such as phenyllithium, butyllithium or methyl lithium or sodium hexamethyldisilazane can be used.
  • Processes A to C according to the invention can preferably be carried out in acetonitrile in each case by reaction of the compounds (II) and (UT), (TV) and (V) or (VI) and (VII) in the presence of a base such as sodium carbonate, Et 3 N, DABCO , K 2 CO 3 , KOH, NaOH or NaH can be carried out.
  • the reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 70 ° C.
  • the reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
  • the reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 90 ° C.
  • the reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
  • a compound of the formula (I) is prepared by nucleophilic substitution of a leaving group E in the compound of the formula (LX) by the hydroxyl or thiol function of the compound of the formula (Vi ⁇ ).
  • the following leaving groups E are, for example: halogen, tosylate, mesylate, or a hydroxyl function activated by reagents such as diisopropylazodicarboxylate / PPh 3 (Mitsonobu reaction).
  • a compound of the formula (I) is reacted by reacting a compound of the formula (XI) which contains a substitutable group L with a compound of the group (XII) in the presence of a palladium compound and, if appropriate, a reducing agent and other additives represented in basic medium.
  • the reaction formally represents a reductive coupling of the compounds of the formulas (XI) and (XII), as described, for example, in LS Hegedus, Organometallics in Synthesis, M. Schlosser, Ed., Wiley & Sons, 1994.
  • substitutable group L in the compounds of the formula (XI) for example a halogen radical such as Br or I or a conventional leaving group such as a triflate radical can be used.
  • a palladium (II) compound such as Cl 2 Pd (PPh 3 ) 2 or Pd (OAc) 2 or a palladium (O) compound such as Pd (PPh 3 ) 4 or Pd 2 (dba) 3 can be used as the palladium compound become.
  • a reducing agent such as triphenylphosphine or other additives such as Cu (I) Br, NBu 4 NCl, LiCl or Ag 3 PO 4 can also be added to the reaction mixture (cf. T Jeffery, Tetrahedron lett. 1985, 26, 2667-2670; T. Jeffery, J. Chem. Soc, Chem. Commun. 1984, 1287-1289; S. Bräse, A. deMejiere in "Metal-catalyzed cross-coupling reactions", Ed. F. Diederich, PJ Stang , Wiley-VCH,
  • the reaction is carried out in the presence of a conventional base such as Na 2 CO 3 , NaOH or triethylamine.
  • Suitable solvents are the organic solvents mentioned above, ethers such as dimethoxyethane being particularly preferred.
  • the reaction can generally be in one Temperature range from -20 ° C to + 90 ° C, preferably from 0 ° C to + 90 ° C.
  • the reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
  • the first step of process G thus proceeds analogously to process D, with compounds of the formula (XIH) being reacted with the alcohols or thiols of the formula (XIII) here instead of the compounds of the formula (IX).
  • the unsaturated compounds of the formula (XIV) are thus obtained, which can be converted into the compounds of the formula (I) by conventional hydrogenation processes.
  • Process G can be carried out in one of the above-mentioned organic solvents. Ethyl acetate is preferred.
  • the reaction can generally be carried out in a temperature range from -20 ° C. to + 90 ° C., preferably from 0 ° C. to + 90 ° C.
  • the reaction can be carried out at normal pressure, elevated or reduced pressure (for example in a range from 0.5 to 5 bar). In general, the reaction is carried out at normal pressure.
  • the new compounds of the formula II, IV and VI can be obtained in a generally known manner by the following methods: by reaction of amines of the formulas (XV), (XVI) and (XV ⁇ )
  • radicals R 2 , R 3 , m, V, Q, U, W, X, Y and A have the meanings given above;
  • Ua, Wa and Xa have the meaning of U, W and X, but are shortened by one carbon unit, and
  • T represents hydrogen or a -CC alkyl function, which can also be linked to Ua or Xa to form a cycle, and the other radicals are as defined above,
  • Va O or S
  • the other residues are as defined above.
  • (Ilb) is obtained, for example, by first reacting (XVa) with (XVIII) to form a Schiff base and then reducing it with common reducing agents, such as NaBH, H 2 / Pd / C etc., or directly under the conditions of a reductive one
  • a compound of formula (XXIII) can be obtained from the compound of formula (IIc) thus obtained by protecting the amino function (see also T.W. Greene, P.G.M.
  • an N-protecting group as in (XXII) can be introduced and removed using standard methods (cf. TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, second edition, New York, 1991).
  • the protective group can be introduced by reacting the amine with tert-butyl pyrrocarbonate in polar or non-polar solvents at 0 ° C to 25 ° C.
  • the protecting group can be split off to (Ila) using numerous acids, such as, for example, HC1, H 2 SO 4 or CF 3 COOH, at from 0 ° to 25 ° C. (cf. literature cited above).
  • 4-chloromethylbiphenyl compounds which carry a further substituent in the 4'-position can be obtained by coupling 4- (B (OH) 2 - Ph-CHO with the corresponding bromophenyl compounds substituted in the 4-position in the presence of palladium catalysts, such as for example Pd (PPh 3 ) or PdCl 2 (PPh3) 2 and sodium carbonate to the corresponding biphenyl Compounds and subsequent reduction to alcohol with NaBH 4 and conversion to the corresponding chloride with SOCl 2 are prepared.
  • palladium catalysts such as for example Pd (PPh 3 ) or PdCl 2 (PPh3) 2
  • the compounds can also be prepared by generally known methods, e.g. by reacting an alcohol with a chlorination reagent, e.g. Thionyl chloride or sulfuryl chloride can be produced (see e.g. J. March, Advanced Organic Chemistry, fourth edition, Wiley, 1992, page 1274 or the literature cited therein).
  • a chlorination reagent e.g. Thionyl chloride or sulfuryl chloride
  • Amines of the formula (XV) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (cf., for example, Tetrahedron 1997, 53, 2075; J. Med. Chem. 1984, 27, 1321; WO97 / 29079; J. Org. Chem. 1982, 47, 5396).
  • these compounds can be selected from the corresponding halide compounds and in particular chloride compounds in which a W'-Hal group is used instead of the W-NH 2 radicals of the compounds of the formula (XV), where W 'is a radical W shortened by one C atom, by substitution of the halide residue by a cyano group to obtain the corresponding nitrile compounds and reduction of the nitrile group or by reaction of corresponding aldehyde compounds in which instead of the residues W-NH 2 of the compounds of the formula (XV) there is a group W'-CHO, where W represents a radical W shortened by one carbon atom, can be obtained with nitromethane and subsequent reduction.
  • W'-Hal group is used instead of the W-NH 2 radicals of the compounds of the formula (XV)
  • a few exemplary synthetic routes for the amines of the formula (XV) are listed below, the reagents indicated generally representing only one of several possibilities.
  • a reduction reaction from aldehyde to alcohol groups, substitution of alcohol groups by halogen groups, substitution of halogen functions by nitrile groups, or reductions of nitrile groups to corresponding amino groups can be carried out with all reactants conventionally used for such reactions (cf. e.g. the corresponding chapter in March, Advanced Organic Chemistry, Wiley, 3 , ed., 1985).
  • the radicals given have the same meaning as defined above.
  • the corresponding hydroxycarboxylic acids or hydroxycarnonic esters can also be used instead of the hydroxyaldehydes become.
  • the conversion of the primary hydroxyl group into the nitrile group can also be carried out via the corresponding bromide, mesylate, tosylate or acetate instead of via the corresponding halide.
  • This process can be used, for example, starting from 2-hydroxynaphth-1-aldehyde, 1-hydroxymethyl-2-methoxynaphthalene or one of the following commercially available or literature-known hydroxyaldehydes:
  • the 2-cyanomethyl-3-hydroxypyridine is also according to Desideri et al, J. Heterocycl.
  • Amines of the formula (XVI) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (cf., for example, J. Am. Chem. Soc. 1982, 104, 6801; Chem. Lett. 1984, 1733; J. Med Chem. 1998, 41, 5219; DE-2059922).
  • Amines of the formula (XVII) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (see, for example, J. Org. Chem. 1968, 33, 1581; Bull. Chem. Soc. Jpn. 1973, 46, 968 ; J. Am. Chem. Soc. 1958, 80, 1510; J. Org. Chem. 1961, 26, 2507; Synth. Commun. 1989, 19, 1787).
  • Amines of the formulas (XV), (XVI) and (XVII) can also be according to generally known
  • Carbonyl compounds of the formula (XVIII) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature (see e.g. J. Med. Chem. 1989, 32, 1277; Chem. Ber. 1938, 71, 335; Bull. Soc. Chim. Fr. 1996, 123, 679).
  • Carbonyl compounds of the formula (XIX) are commercially available, known from the literature, or can be synthesized in analogy to processes known from the literature,
  • Carbonyl compounds of the formula (XX) are commercially available, known from the literature, or can be synthesized analogously to processes known from the literature
  • Carbonyl compounds of the formulas (XVIII), (XIX) and (XX) can also be prepared by generally known methods, e.g. by oxidation of alcohols, the reduction of acid chlorides, or the reduction of nitriles (see e.g. J.
  • the compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity.
  • the compounds according to the invention in particular the compounds of the general formula (I), lead to vascular relaxation, platelet aggregation inhibition and to a reduction in blood pressure and to an increase in the coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular increase in cGMP.
  • cardiovascular diseases such as, for example, for the treatment of high blood pressure and heart failure, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, of arrhythmias, for the treatment of thromboembolic diseases 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), percutaneous transluminal coronary angioplasties (PTCA), bypass and for the treatment of arteriosclerosis, fibrotic diseases such as liver fibrosis and diseases of the pulmonary fibrosis or pulmonary fibrosis system, for example, of the uterine fibrosis or pulmonary fibrosis system, for example, of the asthma or pulmonary fibrosis system Prostate hypertrophy, erectile dysfunction, female sexual dysfunction and incontinence as well as for the treatment of glaucoma.
  • thromboembolic diseases and ischemia such as myocardial infar
  • the compounds described in the present invention are also active compounds for combating diseases in the central nervous system which are characterized by disorders of the NO / cGMP system.
  • 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, beverages and addictive substances.
  • the active ingredients are also suitable for regulating cerebral blood flow and are therefore effective means of combating migraines.
  • the compounds according to the invention in particular the compounds of the general formula (I), can likewise be used to combat painful conditions.
  • the compounds according to the invention have anti-inflammatory activity and can therefore be used as anti-inflammatory agents.
  • Rabbits are anesthetized or killed by intravenous injection of thiopental sodium (approx. 50 mg / kg,) and exsanguinated.
  • the saphenous artery is removed and divided into 3 mm wide rings.
  • the rings are individually mounted on a triangular pair of hooks made of 0.3 mm special wire (Remanium®) that is open at the end.
  • Each ring is placed in 5 ml organ baths with 37 ° C warm, carbogen-gassed Krebs-Henseleit solution of 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; Bovine serum albumin: 0.001%.
  • 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 line recorders. Contractions are induced by adding phenylephrine.
  • the substance to be examined is added in increasing doses in each further run and the level of the contraction achieved under the influence of the test substance is compared with the level of the contraction achieved in the last previous run. From this, the concentration is calculated, which is necessary to achieve the contraction achieved in the pre-control Reduce 50% (IC 50 ).
  • the standard application volume is 5 ⁇ l.
  • the DMSO proportion in the bath solution corresponds to 0.1%.
  • Stasch Purified soluble guanylyl cyclase expressed in a baculovirus / Sf9 System: Stimulation by YC-1, nitric oxide, and carbon oxide. J. Mol. Med. 77 (1999): 14-23.
  • the heme-free guanylate cyclase was obtained by adding Tween 20 to the sample buffer (0.5% in the final concentration).
  • the activation of the sGC by a test substance is given as n-fold stimulation of the basal activity.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, include the inventive
  • the active ingredient can optionally also be present in microencapsulated form in one or more of the carriers mentioned above.
  • the therapeutically active compounds in particular the 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 to be available.
  • 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 one or more according to the invention
  • Active ingredients preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg body weight.
  • BABA n-butyl acetate / n-butanol / glacial acetic acid / phosphate buffer pH 6
  • the mixture is heated to reflux for five hours. After cooling, it is acidified with dilute hydrochloric acid and briefly heated again (5 minutes). Then it is made alkaline with sodium hydroxide solution and extracted with ether. The organic extract is dried over anhydrous sodium sulfate. After filtering and spinning in, 14.2 g of a yellow waxy solid are obtained, which is only approx.
  • the toluene is then removed on a tot evaporator and the residue is taken up in methanol.
  • the methanolic solution is mixed with ice cooling with 2.34 g (61.77 mmol) of solid sodium borohydride. After stirring for 30 minutes at room temperature, the mixture is neutralized with 5% sodium dihydrogenphosphate solution, diluted with water and extracted with ether. The organic phase is over
  • the crude product obtained is purified by column chromatography (dichloromethane / methanol acetic acid 100: 10: 1.5) and 325 mg (1.01 mmol, 10% yield) of a colorless oil are obtained.
  • Solvent B 0.3g HC1 (30%) / ll water gradient: A / B 2/98 to 95/5 within 2.5 min
  • UV detector DAD 208-400 nm

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne l'utilisation de composés de formule (I) et de ses sels et stéréoisomères, dans la production de médicaments servant à traiter des maladies cardio-vasculaires.
EP02701292A 2001-03-07 2002-02-22 Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques Withdrawn EP1368335A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10110750A DE10110750A1 (de) 2001-03-07 2001-03-07 Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften
DE10110750 2001-03-07
PCT/EP2002/001891 WO2002070510A2 (fr) 2001-03-07 2002-02-22 Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques

Publications (1)

Publication Number Publication Date
EP1368335A2 true EP1368335A2 (fr) 2003-12-10

Family

ID=7676478

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02701292A Withdrawn EP1368335A2 (fr) 2001-03-07 2002-02-22 Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques

Country Status (7)

Country Link
US (2) US20040082798A1 (fr)
EP (1) EP1368335A2 (fr)
JP (1) JP4535679B2 (fr)
AU (1) AU2002234645A1 (fr)
CA (1) CA2439756C (fr)
DE (1) DE10110750A1 (fr)
WO (1) WO2002070510A2 (fr)

Families Citing this family (232)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100074949A1 (en) 2008-08-13 2010-03-25 William Rowe Pharmaceutical composition and administration thereof
DE10109859A1 (de) * 2001-03-01 2002-09-05 Bayer Ag Neuartige Aminodicarbonsäurederivate
DE10110747A1 (de) * 2001-03-07 2002-09-12 Bayer Ag Substituierte 2,6-Diamino-3,5-dicyano-4-aryl-pyridine und ihre Verwendung
DE10216145A1 (de) * 2002-04-12 2003-10-23 Bayer Ag Verwendung von Stimulatoren der löslichen Guanylatcyclase zur Behandlung von Glaukom
WO2004108681A1 (fr) 2003-06-06 2004-12-16 Fibrogen, Inc. Composes heteroaryliques contenant de l'azote et leur utilisation dans l'augmentation de l'erythropoietine endogene
TWI372050B (en) * 2003-07-03 2012-09-11 Astex Therapeutics Ltd (morpholin-4-ylmethyl-1h-benzimidazol-2-yl)-1h-pyrazoles
US7276608B2 (en) * 2003-07-11 2007-10-02 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives as cannabinoid receptor modulators
PL1651612T3 (pl) 2003-07-22 2012-09-28 Astex Therapeutics Ltd Związki 3,4-pochodne 1h-pirazolu i ich zastosowanie jako kinazy zależne od cyklin (cdk) i modulatory kinazy syntazy glikogenu-3 (gsk-3)
US7696210B2 (en) 2004-06-17 2010-04-13 Wyeth Gonadotropin releasing hormone receptor antagonists
MXPA06014797A (es) 2004-06-17 2007-02-16 Wyeth Corp Procesos para preparacion de antagonistas de receptor de hormona que libera gonadotropina.
CA2810655C (fr) 2004-06-24 2013-12-10 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs de cassette de liaison a l'atp
US8354427B2 (en) * 2004-06-24 2013-01-15 Vertex Pharmaceutical Incorporated Modulators of ATP-binding cassette transporters
US7868037B2 (en) 2004-07-14 2011-01-11 Ptc Therapeutics, Inc. Methods for treating hepatitis C
US7772271B2 (en) 2004-07-14 2010-08-10 Ptc Therapeutics, Inc. Methods for treating hepatitis C
JP2008506702A (ja) 2004-07-14 2008-03-06 ピーティーシー セラピューティクス，インコーポレーテッド Ｃ型肝炎を治療するための方法
US7781478B2 (en) 2004-07-14 2010-08-24 Ptc Therapeutics, Inc. Methods for treating hepatitis C
WO2006019832A1 (fr) 2004-07-22 2006-02-23 Ptc Therapeutics, Inc. Thienopyridines utilisees pour traiter l'hepatite c
DE102004042607A1 (de) * 2004-09-03 2006-03-09 Bayer Healthcare Ag Substituierte Phenylaminothiazole und ihre Verwendung
US20070225318A1 (en) * 2004-09-20 2007-09-27 Biolipox Ab Pyrazole Compounds Useful In The Treatment Of Inflammation
EP1814866A2 (fr) * 2004-11-23 2007-08-08 Wyeth a Corporation of the State of Delaware Antagonistes du recepteur d'hormone de liberation de gonadotropine
US7825256B2 (en) 2004-12-01 2010-11-02 Kalypsys, Inc. Inducible nitric oxide synthase dimerization inhibitors
US8110573B2 (en) 2004-12-30 2012-02-07 Astex Therapeutics Limited Pyrazole compounds that modulate the activity of CDK, GSK and aurora kinases
BRPI0606455A (pt) 2005-01-21 2008-03-11 Astex Therapeutics Ltd compostos farmacêuticos
MX2007008810A (es) 2005-01-21 2007-11-21 Astex Therapeutics Ltd Compuestos farmaceuticos.
US7538113B2 (en) 2005-02-18 2009-05-26 Wyeth 4-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
US7534796B2 (en) 2005-02-18 2009-05-19 Wyeth Imidazo[4,5-b]pyridine antagonists of gonadotropin releasing hormone receptor
US7582634B2 (en) 2005-02-18 2009-09-01 Wyeth 7-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor
US20060189619A1 (en) * 2005-02-24 2006-08-24 Wyeth 3-({4-[2-(4-Tert-butylphenyl)-1h-benzimidazol-4-yl]piperazin-1-yl}methyl)pyrido[2,3-b]]pyrazi ne compounds
US7531542B2 (en) 2005-05-18 2009-05-12 Wyeth Benzooxazole and benzothiazole antagonists of gonadotropin releasing hormone receptor
US7582636B2 (en) 2005-05-26 2009-09-01 Wyeth Piperazinylimidazopyridine and piperazinyltriazolopyridine antagonists of Gonadotropin Releasing Hormone receptor
US20060281768A1 (en) * 2005-06-10 2006-12-14 Gaul Michael D Thienopyrimidine and thienopyridine kinase modulators
TW200800911A (en) * 2005-10-20 2008-01-01 Biolipox Ab Pyrazoles useful in the treatment of inflammation
DE102005050497A1 (de) 2005-10-21 2007-04-26 Bayer Healthcare Ag Difluorphenol-Derivate und ihre Verwendung
DE102005050377A1 (de) * 2005-10-21 2007-04-26 Bayer Healthcare Ag Heterocyclische Verbindungen und ihre Verwendung
DE102005050376A1 (de) 2005-10-21 2007-05-31 Bayer Healthcare Ag Dicarbonsäure-Derivate und ihre Verwendung
DE102005050498A1 (de) 2005-10-21 2007-06-06 Bayer Healthcare Aktiengesellschaft Cyclopropylessigsäure-Derivate und ihre Verwendung
DE102005050375A1 (de) 2005-10-21 2007-04-26 Bayer Healthcare Ag Tetrazol-Derivate und ihre Verwendung
EP1943234A1 (fr) * 2005-10-31 2008-07-16 Biolipox AB Utilisation de triazoles comme inhibiteurs de la lipoxygenase
TW200732320A (en) * 2005-10-31 2007-09-01 Biolipox Ab Pyrazoles useful in the treatment of inflammation
WO2007052000A1 (fr) * 2005-11-01 2007-05-10 Biolipox Ab Utilisation de pyrazoles dans le traitement de l'inflammation
CN101374849A (zh) * 2005-12-24 2009-02-25 沃泰克斯药物股份有限公司 作为abc转运蛋白调控剂的喹啉-4-酮衍生物
BRPI0620960A2 (pt) 2005-12-28 2011-11-29 Vertex Pharmaceuticals Incorporated formas sólidas de n-[2,4-bis(1,1-dimetiletil)-5-hidroxifenil]-1,4-didro-4- oxiquinolina-3- carboxamida
EP1968579A1 (fr) 2005-12-30 2008-09-17 Astex Therapeutics Limited Composes pharmaceutiques
EP2476669A1 (fr) 2006-01-27 2012-07-18 Fibrogen, Inc. Composants de cyanoisoquinoline et procédés d'utilisation correspondants
JP5111491B2 (ja) 2006-04-04 2013-01-09 フィブロジェン， インコーポレイテッド ピロロ−およびピラゾロ−ピリミジン化合物、およびそれらの使用方法
DE102006024024A1 (de) 2006-05-23 2007-11-29 Bayer Healthcare Aktiengesellschaft Substituierte Arylimidazolone und -triazolone sowie ihre Verwendung
EP2043635A2 (fr) * 2006-06-29 2009-04-08 Astex Therapeutics Limited Combinaisons pharmaceutiques
JP5523829B2 (ja) 2006-06-29 2014-06-18 アステックス、セラピューティックス、リミテッド 複合薬剤
ES2376771T3 (es) * 2006-08-21 2012-03-16 Genentech, Inc. Compuestos aza-benzofuranilo y métodos de utilización
AU2007286807B2 (en) * 2006-08-21 2013-03-21 Genentech, Inc. Aza-benzothiophenyl compounds and methods of use
DE102006042143A1 (de) * 2006-09-08 2008-03-27 Bayer Healthcare Aktiengesellschaft Neue substituierte Bipyridin-Derivate und ihre Verwendung
DE102006044696A1 (de) 2006-09-22 2008-03-27 Bayer Healthcare Ag 3-Cyano-5-thiazaheteroaryl-dihydropyridine und ihre Verwendung
DE102006056739A1 (de) * 2006-12-01 2008-06-05 Bayer Healthcare Ag Substituierte 4-Amino-3,5-dicyano-2-thiopyridine und ihre Verwendung
DE102006056740A1 (de) * 2006-12-01 2008-06-05 Bayer Healthcare Ag Cyclisch substituierte 3,5-Dicyano-2-thiopyridine und ihre Verwendung
DE102007009494A1 (de) 2007-02-27 2008-08-28 Bayer Healthcare Ag Substituierte 4-Aryl-1, 4-dihydro-1,6-naphthyridinamide und ihre Verwendung
DE102007015035A1 (de) 2007-03-29 2008-10-02 Bayer Healthcare Ag Substituierte Dibenzoesäure-Derivate und ihre Verwendung
DE102007015034A1 (de) 2007-03-29 2008-10-02 Bayer Healthcare Ag Lactam-substituierte Dicarbonsäuren und ihre Verwendung
DE102007019691A1 (de) 2007-04-26 2008-10-30 Bayer Healthcare Ag Verwendung von acyclisch substituierten Furopyrimidin-Derivaten zur Behandlung der pulmonalen arteriellen Hypertonie
DE102007019690A1 (de) 2007-04-26 2008-10-30 Bayer Healthcare Ag Verwendung von cyclisch substituierten Furopyrimidin-Derivaten zur Behandlung der pulmonalen arteriellen Hypertonie
DE102007026392A1 (de) 2007-06-06 2008-12-11 Bayer Healthcare Ag Lösungen für die Perfusion und Konservierung von Organen und Geweben
DE102007027799A1 (de) 2007-06-16 2008-12-18 Bayer Healthcare Ag Substituierte Furopyrimidine und ihre Verwendung
DE102007027800A1 (de) 2007-06-16 2008-12-18 Bayer Healthcare Ag Substituierte bicyclische Heteroaryl-Verbindungen und ihre Verwendung
MX2009013952A (es) 2007-06-28 2010-01-28 Novartis Ag Moduladores de calicreina 7.
DE102007035367A1 (de) 2007-07-27 2009-01-29 Bayer Healthcare Ag Substituierte Aryloxazole und ihre Verwendung
DE102007036076A1 (de) 2007-08-01 2009-02-05 Bayer Healthcare Aktiengesellschaft Dipeptoid-Produgs und ihre Verwendung
DE102007042754A1 (de) 2007-09-07 2009-03-12 Bayer Healthcare Ag Substituierte 6-Phenylnikotinsäuren und ihre Verwendung
DE102007051762A1 (de) 2007-10-30 2009-05-07 Bayer Healthcare Ag Substituierte Pyrrolotriazine und ihre Verwendung
DE102007054786A1 (de) 2007-11-16 2009-05-20 Bayer Healthcare Ag Trisubstituierte Furopyrimidine und ihre Verwendung
DE102007061756A1 (de) 2007-12-20 2009-06-25 Bayer Healthcare Ag Substituierte 4-Aminopyrimidin-5-carbonsäuren und ihre Verwendung
DE102007061757A1 (de) 2007-12-20 2009-06-25 Bayer Healthcare Ag Substituierte 2-Phenylpyrimidin-5-carbonsäuren und ihre Verwendung
DE102007061764A1 (de) 2007-12-20 2009-06-25 Bayer Healthcare Ag Anellierte Cyanopyridine und ihre Verwendung
DE102007061763A1 (de) * 2007-12-20 2009-06-25 Bayer Healthcare Ag Substituierte azabicyclische Verbindungen und ihre Verwendung
DE102007061766A1 (de) 2007-12-20 2009-06-25 Bayer Healthcare Ag 4-(4-Cyano-2-thioaryl)-dihydropyrimidinone und ihre Verwendung
DE102008052013A1 (de) 2008-10-17 2010-04-22 Bayer Schering Pharma Aktiengesellschaft 4-(4-Cyano-2-thioaryl)-dihydropyrimidinone und ihre Verwendung
DE102008022521A1 (de) 2008-05-07 2009-11-12 Bayer Schering Pharma Aktiengesellschaft 1,4-Diaryl-pyrimidopyridazin-2,5-dione und ihre Verwendung
DE102008007400A1 (de) 2008-02-04 2009-08-06 Bayer Healthcare Ag Substituierte Furane und ihre Verwendung
DE102008013587A1 (de) 2008-03-11 2009-09-17 Bayer Schering Pharma Aktiengesellschaft Heteroaryl-substituierte Dicyanopyridine und ihre Verwendung
JP5432890B2 (ja) * 2008-04-04 2014-03-05 武田薬品工業株式会社 複素環誘導体及びその用途
WO2009143992A1 (fr) * 2008-05-29 2009-12-03 Bayer Schering Pharma Aktiengesellschaft Dicyanopyridines substituées par du 2-alcoxy et leur utilisation
DE102008030207A1 (de) 2008-06-25 2009-12-31 Bayer Schering Pharma Aktiengesellschaft Substituierte 7-Sulfanylmethyl-, 7-Sulfinylmethyl- und 7-Sulfonylmethyl-Indole und ihre Verwendung
DE102008030206A1 (de) 2008-06-25 2009-12-31 Bayer Schering Pharma Aktiengesellschaft 3-Cyanoalky- und 3-Hydroxyalkyl-Indole und ihre Verwendung
AR072297A1 (es) * 2008-06-27 2010-08-18 Novartis Ag Derivados de indol-2-il-piridin-3-ilo, composicion farmaceutica que los comprende y su uso en medicamentos para el tratamiento de enfermedades mediadas por la sintasa aldosterona.
DE102008039083A1 (de) 2008-08-21 2010-02-25 Bayer Schering Pharma Aktiengesellschaft Substituierte 5-Aminopyrazole und ihre Verwendung
DE102008039082A1 (de) 2008-08-21 2010-02-25 Bayer Schering Pharma Aktiengesellschaft Azabicyclisch-substituierte 5-Aminopyrazole und ihre Verwendung
DE102008054205A1 (de) 2008-10-31 2010-05-06 Bayer Schering Pharma Aktiengesellschaft Verwendung von Helium-Sauerstoff-Gasgemischen zur Behandlung der pulmonalen arteriellen Hypertonie
JP5649584B2 (ja) 2008-11-14 2015-01-07 フィブロジェン インコーポレイテッド Ｈｉｆヒドロキシラーゼ阻害剤としてのチオクロメン誘導体
DE102008060967A1 (de) 2008-12-06 2010-06-10 Bayer Schering Pharma Aktiengesellschaft Substituierte Phenylsulfonyltriazolone und ihre Verwendung
DE102008062566A1 (de) 2008-12-16 2010-06-17 Bayer Schering Pharma Aktiengesellschaft Aminosäureester-Prodrugs und ihre Verwendung
DE102008062567A1 (de) 2008-12-16 2010-06-17 Bayer Schering Pharma Aktiengesellschaft Dipeptoid-Prodrugs und ihre Verwendung
DE102009004197A1 (de) 2009-01-09 2010-07-15 Bayer Schering Pharma Aktiengesellschaft Heterocyclisch anellierte Diaryldihydropyrimidin-Derivate und ihre Verwendung
DE102009006602A1 (de) 2009-01-29 2010-08-05 Bayer Schering Pharma Aktiengesellschaft Alkylamino-substituierte Dicyanopyridine und deren Aminosäureester-Prodrugs
DE102010001064A1 (de) 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft Substituierte 2-Acetamido-5-Aryl-1,2,4-triazolone und deren Verwendung
DE102009013642A1 (de) 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft Substituierte Phenylalaninderivate und deren Verwendung
US8476442B2 (en) 2009-03-20 2013-07-02 Vertex Pharmaceutical Incorporated Process for making modulators of cystic fibrosis transmembrane conductance regulator
DE102009016553A1 (de) 2009-04-06 2010-10-07 Bayer Schering Pharma Aktiengesellschaft Sulfonamid- und Sulfoximin-substituierte Diaryldihydropyrimidinone und ihre Verwendung
DE102009028929A1 (de) 2009-08-27 2011-07-07 Bayer Schering Pharma Aktiengesellschaft, 13353 Heterocyclisch-substituierte 2-Acetamido-5-Aryl-1,2,4-triazolone und deren Verwendung
EP2539326B1 (fr) 2010-02-27 2017-05-03 Bayer Intellectual Property GmbH Aryltriazolone liée à un bis-aryle et son utilisation
DE102010020553A1 (de) 2010-05-14 2011-11-17 Bayer Schering Pharma Aktiengesellschaft Substituierte 8-Alkoxy-2-aminotetralin-Derivate und ihre Verwendung
CN103038232B (zh) 2010-05-26 2016-01-20 阿德弗里奥药品有限责任公司 单独的和与PDE5抑制剂相组合的sGC刺激剂、sGC活化剂用于治疗系统性硬化症(SSc)的用途
DE102010030187A1 (de) 2010-06-16 2011-12-22 Bayer Schering Pharma Aktiengesellschaft 4-Cyan-2-sulfonylphenyl)pyrazolyl-substituierte Pyridinone und Pyrazinone und ihre Verwendung
EP2687210A1 (fr) 2010-06-25 2014-01-22 Bayer Intellectual Property GmbH Stimulateurs et activateurs de la guanylate cyclase soluble pour leur utilisation dans le traitement de la drépanocytose et de la conservation des substituts sanguins
DE102010030688A1 (de) 2010-06-30 2012-01-05 Bayer Schering Pharma Aktiengesellschaft Substituierte Dicyanopyridine und ihre Verwendung
HUE031710T2 (en) 2010-07-14 2017-07-28 Novartis Ag IP receptor agonist heterocyclic compounds
DE102010040187A1 (de) 2010-09-02 2012-03-08 Bayer Schering Pharma Aktiengesellschaft Substituierte N-Phenethyl-triazolonacetamide und ihre Verwendung
US20120058983A1 (en) 2010-09-02 2012-03-08 Bayer Pharma Aktiengesellschaft Adenosine A1 agonists for the treatment of glaucoma and ocular hypertension
DE102010040924A1 (de) 2010-09-16 2012-03-22 Bayer Schering Pharma Aktiengesellschaft Substituierte Phenylacet- und Phenylpropanamide und ihre Verwendung
US8802700B2 (en) 2010-12-10 2014-08-12 Vertex Pharmaceuticals Incorporated Modulators of ATP-Binding Cassette transporters
AR087020A1 (es) 2011-07-01 2014-02-05 Bayer Ip Gmbh Polipeptidos de fusion de relaxina y usos de los mismos
JP2014529293A (ja) 2011-07-08 2014-11-06 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ レラキシンを放出する融合タンパク質およびその使用
US8883819B2 (en) 2011-09-01 2014-11-11 Irm Llc Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
WO2013105061A1 (fr) 2012-01-13 2013-07-18 Novartis Ag Dihydropyrido [2,3-b]pyrazines fusionnées comme agonistes des récepteurs ip pour le traitement de l'hypertension artérielle pulmonaire (hap) et des troubles connexes
WO2013105057A1 (fr) 2012-01-13 2013-07-18 Novartis Ag Pyrroles fondus utilisés comme agonistes du récepteur ip pour le traitement de l'hypertension artérielle pulmonaire (htap) et des troubles associés
WO2013105058A1 (fr) 2012-01-13 2013-07-18 Novartis Ag 7,8-dihydropyrido[3,4-b]pyrazines utilisées comme agonistes du récepteur ip pour le traitement de l'hypertension artérielle pulmonaire (htap) et des troubles associés
WO2013105066A1 (fr) 2012-01-13 2013-07-18 Novartis Ag Sels d'un agoniste du récepteur ip
US9115129B2 (en) 2012-01-13 2015-08-25 Novartis Ag Substituted pyrido[2,3-B]pyrazines as IP receptor agonists
US20150005311A1 (en) 2012-01-13 2015-01-01 Novartis Ag IP receptor agonist heterocyclic compounds
MX2014010253A (es) 2012-02-27 2014-11-12 Vertex Pharma Composicion farmaceutica y administraciones de la misma.
CN104470899B (zh) 2012-03-09 2017-12-26 菲布罗根有限公司 作为hif羟化酶抑制剂的4‑羟基‑异喹啉化合物
WO2013144191A1 (fr) 2012-03-29 2013-10-03 Bayer Intellectual Property Gmbh 2-amino-3-cyanopyridines substituées utilisées comme inhibiteurs de l'échange sodium-calcium et leurs utilisations dans le cas de maladies cardiovasculaires
UA112897C2 (uk) 2012-05-09 2016-11-10 Байєр Фарма Акцієнгезелльшафт Біциклічно заміщені урацили та їх застосування для лікування і/або профілактики захворювань
US8883823B2 (en) 2012-07-16 2014-11-11 Fibrogen, Inc. Crystalline forms of a prolyl hydroxylase inhibitor
PL3470397T3 (pl) 2012-07-16 2022-06-20 Fibrogen, Inc. Postacie krystaliczne inhibitora hydroksylazy prolilowej
EP3219706A1 (fr) 2012-07-16 2017-09-20 Fibrogen, Inc. Procédé de fabrication de composés d'isoquinoline
SI2875003T1 (sl) * 2012-07-20 2017-03-31 Bayer Pharma Aktiengesellschaft Nove 5-aminotetrahidrokinolin-2-karboksilne kisline in njihova uporaba
US9387203B2 (en) 2012-07-20 2016-07-12 Bayer Pharma Aktiengesellschaft Substituted aminoindane- and aminotetralinecarboxylic acids and the use thereof
ES2694297T3 (es) 2013-01-24 2018-12-19 Fibrogen, Inc. Formas cristalinas de ácido {[1-ciano-5-(4-clorofenoxi)-4-hidroxi-isoquinolina-3-carbonilo]-amino}-acético
EP2956455B1 (fr) 2013-02-13 2017-05-17 Novartis AG Composes heterocycliques a activite agoniste sur le recepteur ip
US9073921B2 (en) 2013-03-01 2015-07-07 Novartis Ag Salt forms of bicyclic heterocyclic derivatives
WO2015011086A1 (fr) 2013-07-25 2015-01-29 Bayer Pharma Aktiengesellschaft Stimulateurs de sgc ou activateurs de sgc et inhibiteurs de pde5 en combinaison avec un autre traitement pour la thérapie de la fibrose kystique
UY35735A (es) 2013-09-16 2015-04-30 Bayer Pharma AG Trifluorometilpirimidinonas disustituidas y su uso
JP2016532721A (ja) 2013-10-07 2016-10-20 バイエル ファーマ アクチエンゲゼルシャフト 環状チエノウラシルカルボキサミドおよびその使用
CA2927420A1 (fr) * 2013-10-15 2015-04-23 Toa Eiyo Ltd. Derive d'acide 4-aminomethylbenzoique
CN105873919A (zh) 2013-11-08 2016-08-17 拜耳医药股份有限公司 作为类糜蛋白酶抑制剂的取代的尿嘧啶
EP3066098A1 (fr) 2013-11-08 2016-09-14 Bayer Pharma Aktiengesellschaft Uraciles substitués et leur utilisation
JP2017501164A (ja) 2013-12-19 2017-01-12 バイエル ファーマ アクチエンゲゼルシャフト 置換されたピペリジニルテトラヒドロキノリン類
US20160318866A1 (en) 2013-12-19 2016-11-03 Bayer Pharma Aktiengesellschaft Substituted bipiperidinyl derivatives
JP2017503778A (ja) 2013-12-19 2017-02-02 バイエル ファーマ アクチエンゲゼルシャフト アドレナリン受容体α２Ｃ拮抗薬としての置換されたビピペリジニル誘導体
JOP20200052A1 (ar) 2013-12-19 2017-06-16 Bayer Pharma AG بيبريدينيل تتراهيدرو كوينولينات مستبدلة واستخدامها كمعضدات مستقبل أدريني ألفا- 2c
WO2015150350A1 (fr) 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Acides cyclopentanecarboxyliques à disubstitution 2,5 pour traiter des maladies des voies respiratoires
CA2944617A1 (fr) 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Derives chiraux d'acide cyclopentanecarboxylique a disubstitution 2,5 et leur utilisation
WO2015150363A1 (fr) 2014-04-03 2015-10-08 Bayer Pharma Aktiengesellschaft Acides cyclopentanecarboxyliques à disubstitution 2,5 et leur utilisation
US10112926B2 (en) 2014-04-24 2018-10-30 Novartis Ag Amino pyridine derivatives as phosphatidylinositol 3-kinase inhibitors
WO2015162459A1 (fr) 2014-04-24 2015-10-29 Novartis Ag Dérivés aminés de pyrazine utilisables en tant qu'inhibiteurs de la phosphatidylinositol 3-kinase
KR20160141856A (ko) 2014-04-24 2016-12-09 노파르티스 아게 포스파티딜이노시톨 3-키나제 억제제로서의 피라진 유도체
TW201625601A (zh) 2014-07-02 2016-07-16 諾華公司 噻吩－２－基－吡啶－２－基－１ｈ－吡唑－４－羧酸衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途
TW201625584A (zh) 2014-07-02 2016-07-16 諾華公司 茚滿及吲哚啉衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途
TW201625586A (zh) 2014-07-02 2016-07-16 諾華公司 環己烯－１－基－吡啶－２－基－１ｈ－吡唑－４－羧酸衍生物及其作為可溶性鳥苷酸環化酶活化劑之用途
US10059707B2 (en) 2014-08-01 2018-08-28 Bayer Pharma AG Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro- 1-6-naphthyridine-3-carbox-amide and the purification thereof for use as an active pharmaceutical ingredient
WO2016037954A1 (fr) 2014-09-09 2016-03-17 Bayer Pharma Aktiengesellschaft N,2-diarylquinoline-4-carboxamides substitués et utilisation desdits n,2-diarylquinoline-4-carboxamides substitués comme anti-inflammatoires
WO2016046157A1 (fr) 2014-09-24 2016-03-31 Bayer Pharma Aktiengesellschaft Dérivés de pyridobenzazépine et de pyridobenzazocine inhibant le facteur xia
EP3204358B1 (fr) 2014-10-07 2018-09-19 Vertex Pharmaceuticals Incorporated Co-cristaux de modulateurs du régulateur de conductance transmembranaire de la mucoviscidose
EP3215498B1 (fr) 2014-11-03 2018-08-22 Bayer Pharma Aktiengesellschaft Dérivés de phényltriazole à substitution hydroxyalkyle et utilisations associées
WO2016113205A1 (fr) 2015-01-13 2016-07-21 Bayer Pharma Aktiengesellschaft Pentafluoréthylpyrimidinones substituées et leur utilisation
UY36586A (es) 2015-03-26 2016-10-31 Bayer Pharma AG Heterociclilmetiltienouracilos y uso de los mismos
AU2016258847A1 (en) 2015-05-06 2017-11-16 Bayer Pharma Aktiengesellschaft The use of sGC stimulators, sGC activators, alone and combinations with PDE5 inhibitors for the treatment of Digital Ulcers (DU) concomitant to Systemic Sclerosis (SSc)
CN113712969A (zh) 2015-07-23 2021-11-30 拜耳制药股份公司 可溶性鸟苷酸环化酶的刺激剂和/或活化剂及其用途
SI3337800T1 (sl) 2015-08-21 2019-08-30 Bayer Pharma Aktiengesellschaft, Postopek priprave (4S)-4-(4-ciano-2-metoksifenil)-5-etoksi-2,8-dimetil-1,4-dihidro- 1-6-nafthiridin-3-karboksamida in njegovo čiščenje, za uporabo kot aktivna farmacevtska učinkovina
WO2017081044A1 (fr) 2015-11-13 2017-05-18 Bayer Pharma Aktiengesellschaft 4-(4-cyano-2-thioaryle)-dihydropyrimidinones destinées au traitement de plaies chroniques
WO2017097671A1 (fr) 2015-12-10 2017-06-15 Bayer Pharma Aktiengesellschaft Dérivés de perhydropyrrolo[3,4-c]pyrrole substitués et leur utilisation
WO2017097792A1 (fr) 2015-12-10 2017-06-15 Bayer Pharma Aktiengesellschaft Dérivés de 2-phényl-3-(pipérazinométhyl)imidazo[1,2-a]pyridine utilisés comme bloqueurs des canaux task-1 et task-2 pour traiter des troubles respiratoires liés au sommeil
WO2017153235A1 (fr) 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-3-aryl-1-naphthamides substitués et leur utilisation
WO2017153234A1 (fr) 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-2-arylchinolin-4-carboxamides substitués et leur utilisation
WO2017153231A1 (fr) 2016-03-09 2017-09-14 Bayer Pharma Aktiengesellschaft N-cyclo-2-arylisochinolinon-4-carboxamides substitués et leur utilisation
TW201806943A (zh) 2016-05-03 2018-03-01 拜耳製藥股份有限公司 經醯胺取代之苯基三唑衍生物及其用途
US10526314B2 (en) 2016-05-03 2020-01-07 Bayer Aktiengesellschaft Hydroxyalkyl-substituted heteroaryltriazole derivatives and uses thereof
US10525041B2 (en) 2016-05-03 2020-01-07 Bayer Pharma Aktiengesellschaft Fluoroalkyl-substituted aryltriazole derivatives and uses thereof
WO2017191105A1 (fr) 2016-05-03 2017-11-09 Bayer Pharma Aktiengesellschaft Dérivés d'aryltriazole à substitution amide et leurs utilisations
WO2017191117A1 (fr) 2016-05-03 2017-11-09 Bayer Pharma Aktiengesellschaft Antagonistes du récepteur v1a destinés à une utilisation dans le traitement de maladies rénales
US9988367B2 (en) 2016-05-03 2018-06-05 Bayer Pharma Aktiengesellschaft Amide-substituted pyridinyltriazole derivatives and uses thereof
US10800746B2 (en) 2016-05-03 2020-10-13 Bayer Pharma Aktiengesellschaft Oxoalkyl-substituted phenyltriazole derivatives and uses thereof
JOP20170113B1 (ar) 2016-05-09 2023-03-28 Bayer Pharma AG مركبات 5، 6، 7، 8-رباعي هيدرو [1، 2، 4] تريازولو [4، 3-أ] بيريدين 3(2h)-ون مستبدلة ومركبات 2، 5، 6، 7-رباعي هيدرو-3h-بيرولو [2، 1-ج] [1، 2، 4] تريازول-3-ون واستخداماتها
EP3481823B1 (fr) 2016-07-11 2020-10-28 Bayer Pharma Aktiengesellschaft Amides de l'acide 1-pyridyl-naphthyridin-3-carboxylique substitués en position 7, et leur utilisation
JOP20190005A1 (ar) 2016-07-20 2019-01-20 Bayer Ag مركبات ديازاهيترو ثنائية الحلقة مستبدلة واستخداماتها
WO2018041771A1 (fr) 2016-09-02 2018-03-08 Bayer Pharma Aktiengesellschaft Thiéno-uraciles substitués par un groupe (1-méthylcyclopropyl)méthyle et leur utilisation
EP3296298A1 (fr) 2016-09-14 2018-03-21 Bayer Pharma Aktiengesellschaft 1-aryl-naphtyridin-3-ylcarboxamides substitués en position 7 et leur utilisation
JOP20190045A1 (ar) 2016-09-14 2019-03-14 Bayer Ag مركبات أميد حمض 1- أريل-نفثيريدين-3-كربوكسيليك مستبدلة في الموضع 7 واستخدامها.
CA3037642A1 (fr) 2016-09-23 2018-03-29 Bayer Aktiengesellschaft Thieno-uraciles a substitution n 3 -cyclique et leur utilisation
JP7237823B2 (ja) 2016-10-11 2023-03-13 バイエル ファーマ アクチエンゲゼルシャフト Ｓｇｃアクチベーターとミネラルコルチコイド受容体アンタゴニストとを含む組合せ
JOP20190080A1 (ar) 2016-10-14 2019-04-11 Bayer Pharma AG مركبات مشتقة من 6-(1h-بيرازول-1-يل) بيريميدين-4- أمين مستبدل واستخداماتها
US10927098B2 (en) 2016-10-20 2021-02-23 Bayer Pharma Aktiengesellschaft Hydroxyalkyl-substituted triazole derivatives and uses thereof
EP3338803A1 (fr) 2016-12-21 2018-06-27 Bayer Pharma Aktiengesellschaft Formes pharmaceutiques comprenant des inhibiteurs de canaux de task-1 et task-3 et leur utilisation pour le traitement des troubles respiratoires
EP3338764A1 (fr) 2016-12-21 2018-06-27 Bayer Pharma Aktiengesellschaft Formes pharmaceutiques comprenant des inhibiteurs de canaux de task-1 et task-3 et leur utilisation pour le traitement des troubles respiratoires
JOP20190148A1 (ar) 2016-12-21 2019-06-18 Bayer Pharma AG أشكال جرعات صيدلية تحتوي على مثبطات قنوات task-1 و task-3 واستخدامها لمعالجة الاضطرابات التنفسية
JOP20190141A1 (ar) 2016-12-21 2019-06-12 Bayer Pharma AG أشكال جرعات صيدلية تحتوي على مثبطات لقناة task-1 و task-3 واستخدامها في معالجة اضطراب تنفسي
AU2018219283B2 (en) 2017-02-08 2022-05-19 Bristol-Myers Squibb Company Modified relaxin polypeptides comprising a pharmacokinetic enhancer and uses thereof
BR112019021136A2 (pt) 2017-04-10 2020-07-21 Bayer Aktiengesellschaft n-ariletil-2-arilquinolina-4-carboxamidas substituídas e uso das mesmas
TWI770157B (zh) 2017-04-10 2022-07-11 德商拜耳廠股份有限公司 經取代之n-芳基乙基-2-胺基喹啉-4-甲醯胺及其用途
JOP20190284A1 (ar) 2017-06-14 2019-12-11 Bayer Pharma AG مركبات إيميدازوبيريميدين مستبدلة بديازا ثنائي الحلقة واستخدامها للمعالجة من اضطرابات التنفس
WO2018227427A1 (fr) 2017-06-14 2018-12-20 Bayer Aktiengesellschaft Dérivés de diazépane pontés substitués et leur utilisation
JP7065951B2 (ja) 2017-09-22 2022-05-12 ジュビラント エピパッド エルエルシー Ｐａｄ阻害剤としての複素環式化合物
CA3076476A1 (fr) 2017-10-18 2019-04-25 Jubilant Epipad LLC Composes imidazo-pyridine a utiliser en tant qu'inhibiteurs de pad
CR20200176A (es) 2017-10-24 2020-07-24 Bayer Pharma AG Profármacos de derivados de triazol sustituido y sus usos
US20210253557A1 (en) 2017-10-24 2021-08-19 Bayer Pharma Aktiengesellschaft Substituted triazole derivatives and uses thereof
WO2019081456A1 (fr) 2017-10-24 2019-05-02 Bayer Aktiengesellschaft Utilisation d'activateurs et de stimulateurs de sgc comprenant une sous-unité bêta2
EP3700899A1 (fr) 2017-10-24 2020-09-02 Bayer Pharma Aktiengesellschaft Dérivés de triazole substitués et utilisations associées
WO2019081291A1 (fr) 2017-10-24 2019-05-02 Bayer Aktiengesellschaft Promédicaments de dérivés de triazole substitués, et utilisations de ceux-ci
WO2019081299A1 (fr) 2017-10-24 2019-05-02 Bayer Pharma Aktiengesellschaft Dérivés de triazole substitués par une amine et utilisations associées
WO2019081303A1 (fr) 2017-10-24 2019-05-02 Bayer Pharma Aktiengesellschaft Dérivés de triazole substitués et utilisations associées
EP3700900A1 (fr) 2017-10-24 2020-09-02 Bayer Aktiengesellschaft Dérivés de triazole substitués et utilisations associées
CA3080677A1 (fr) 2017-11-06 2019-05-09 Jubilant Prodel LLC Derives de pyrimidine utilises en tant qu'inhibiteurs de l'activation de pd1/pd-l1
CA3081775A1 (fr) 2017-11-07 2019-05-16 Bayer Aktiengesellschaft 2,4-dihydro-3h-1,2,4-triazol-3-ones substituees et leur utilisation
MX2020005363A (es) 2017-11-24 2020-10-01 Jubilant Episcribe Llc Compuestos heterociclicos como inhibidores de prmt5.
EP3498298A1 (fr) 2017-12-15 2019-06-19 Bayer AG Utilisation de stimulateurs sgc et d'activateurs sgc seuls ou en combinaison avec des inhibiteurs pde5 pour le traitement de troubles osseux, y compris l'ostéogénèse imparfaite (oi)
MX2020009517A (es) 2018-03-13 2021-01-20 Jubilant Prodel LLC Compuestos biciclicos como inhibidores de la interaccion/activacio n de pdl/pd-l1.
EP3553082A1 (fr) 2018-04-12 2019-10-16 Bayer Aktiengesellschaft Anticorps greffés de peptide natriurétique du cerveau
EP3553081A1 (fr) 2018-04-12 2019-10-16 Bayer Aktiengesellschaft Anticorps greffés de peptide natriurétique auriculaire
EP3553079A1 (fr) 2018-04-12 2019-10-16 Bayer Aktiengesellschaft Anticorps greffés de peptide natriurétique de type c
CA3098475A1 (fr) 2018-04-30 2019-11-07 Bayer Aktiengesellschaft Utilisation d'activateurs de la gcs et de stimulateurs de la gcs pour le traitement de deficiences cognitives
JOP20200287A1 (ar) 2018-05-15 2020-11-09 Bayer Ag بنزاميدات مستبدلة بـ 3،1- ثيازول-2- يل للمعالجة من أمراض مصاحبة لتحسس الألياف العصبية
BR112020021612A2 (pt) 2018-05-17 2021-01-26 Bayer Aktiengesellschaft derivados substituídos de di-hidropirazolo pirazina carboxamida
JP7457658B2 (ja) 2018-05-22 2024-03-28 ▲広▼▲東▼▲東▼▲陽▼光▲薬▼▲業▼有限公司 フェニル置換ジヒドロナフチリジン化合物及びその使用
EP3574905A1 (fr) 2018-05-30 2019-12-04 Adverio Pharma GmbH Procédé d'identification d'un sous-groupe de patients souffrant de dcssc qui bénéficie d'un traitement comportant des stimulateurs sgc et des activateurs sgc à un degré supérieur à celui d'un groupe de contrôle
CA3120775A1 (fr) 2018-11-27 2020-06-04 Bayer Aktiengesellschaft Procede de fabrication de formes pharmaceutiques contenant des inhibiteurs des canaux task-1 et task-3 et leur utilisation pour le traitement de troubles respiratoires
US20220128561A1 (en) 2019-01-17 2022-04-28 Bayer Aktiengesellschaft Methods to determine whether a subject is suitable of being treated with an agonist of soluble gyanylyl cyclase (sgc)
WO2020164008A1 (fr) 2019-02-13 2020-08-20 Bayer Aktiengesellschaft Procédé de préparation de microparticules poreuses
WO2020165031A1 (fr) 2019-02-15 2020-08-20 Bayer Aktiengesellschaft Dérivés isochinolin-pipéridinylméthanone substitués
CN114793434A (zh) 2019-10-18 2022-07-26 加利福尼亚大学董事会 作为用于治疗病原性血管病症的药剂的3-苯基磺酰基-喹啉衍生物
CN112707854B (zh) 2019-10-25 2022-03-15 年衍药业(珠海)有限公司 吡咯酰胺类化合物及其用途
AR120404A1 (es) 2019-11-06 2022-02-09 Bayer Ag CARBOXAMIDAS HETEROCÍCLICAS SUSTITUIDAS COMO ANTAGONISTAS DE LOS RECEPTORES a₂C ADRENÉRGICOS
WO2021094208A1 (fr) 2019-11-12 2021-05-20 Bayer Aktiengesellschaft Antagonistes d'imidazo pyrimidine ep3 substitués
WO2021094209A1 (fr) 2019-11-12 2021-05-20 Bayer Aktiengesellschaft Dérivés de pyrrolo triazine carboxamide substitués en tant qu'antagonistes du récepteur de la prostaglandine ep3
WO2021094210A1 (fr) 2019-11-12 2021-05-20 Bayer Aktiengesellschaft Dérivés de pyrazine carboxamide substitués utilisés en tant qu'antagonistes du récepteur de la prostaglandine ep3
CA3170507A1 (fr) 2020-02-21 2021-08-26 Universiteit Maastricht Utilisation d'un stimulateur de guanylate cyclase soluble (sgc) ou d'une combinaison d'un stimulateur de sgc et d'un activateur de sgc dans des conditions dans lesquelles le groupe heme de sgc est oxyde ou sgc est deficient en heme
EP4110396A1 (fr) 2020-02-26 2023-01-04 Universiteit Maastricht Combinaison thérapeutique pour le traitement de l'ischémie cérébrale et ladite combinaison thérapeutique destinée à être utilisée dans le traitement de l'ischémie cérébrale
WO2022112213A1 (fr) 2020-11-30 2022-06-02 Bayer Aktiengesellschaft Formes cristallines de 3-[[3-(4-chlorophényl)-5-oxo-4-((2s)-3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1h-1,2,4-triazol-1-yl]méthyl]-1-[3- (trifluorométhyl)pyridin-2-yl]-1h-1,2,4-triazole-5-carboxamide
EP4011873A1 (fr) 2020-12-10 2022-06-15 Bayer Aktiengesellschaft Acides carboxyliques de pyrazolo pipéridine substitués
EP4011874A1 (fr) 2020-12-10 2022-06-15 Bayer Aktiengesellschaft Acides carboxyliques de pyrazolo pipéridine substitués
CN115175681A (zh) 2020-12-10 2022-10-11 拜耳公司 sGC活化剂用于治疗眼科疾病的用途
AU2021393988A1 (en) 2020-12-10 2023-06-22 Bayer Aktiengesellschaft Substituted pyrazolo piperidine carboxylic acids
EP4259618A1 (fr) 2020-12-10 2023-10-18 Bayer Aktiengesellschaft Acides pyrazolylpipéridine carboxyliques substitués
CN113563250B (zh) * 2021-07-28 2023-07-07 南华大学 一种苯甲酸色胺衍生物及其制备与应用
WO2023237577A1 (fr) 2022-06-09 2023-12-14 Bayer Aktiengesellschaft Activateurs de guanylate cyclase soluble destinés à être utilisés dans le traitement de l'insuffisance cardiaque à fraction d'éjection préservée chez les femmes

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5464853A (en) * 1993-05-20 1995-11-07 Immunopharmaceutics, Inc. N-(5-isoxazolyl)biphenylsulfonamides, N-(3-isoxazolyl)biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin
US5981573A (en) * 1996-02-07 1999-11-09 Banyu Pharmaceutical Co., Ltd. N,N-disubstituted amic acid derivatives
TR200102561T2 (tr) * 1999-03-01 2002-02-21 Pfizer Products Inc. Tiroid alıcı ligantları olarak oksamik asitler ve türevleri
FR2794742B1 (fr) * 1999-06-11 2005-06-03 Sanofi Synthelabo Nouveaux derives du benzene, un procede pour leur preparation et les compositions pharmaceutiques les contenant

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO02070510A3 *

Also Published As

Publication number Publication date
WO2002070510A2 (fr) 2002-09-12
US20040082798A1 (en) 2004-04-29
JP4535679B2 (ja) 2010-09-01
US7705043B2 (en) 2010-04-27
CA2439756A1 (fr) 2002-09-12
CA2439756C (fr) 2011-01-11
JP2004529111A (ja) 2004-09-24
AU2002234645A1 (en) 2002-09-19
DE10110750A1 (de) 2002-09-12
WO2002070510A3 (fr) 2003-01-30
US20070179139A1 (en) 2007-08-02

Similar Documents

Publication Publication Date Title
EP1368335A2 (fr) Nouveaux derives d'acide aminodicarbonique presentant des proprietes pharmaceutiques
EP1368300A1 (fr) Derives d'acide aminodicarboxylique
EP1216225B1 (fr) Nouveaux derives d'acide aminodicarboxylique presentant des proprietes pharmaceutiques
EP1216223B1 (fr) Derives d'acide dicarboxylique a proprietes pharmaceutiques
EP1368302B1 (fr) Nouveaux derives d'acide aminodicarboxylique
WO2001019776A2 (fr) Nouveaux derives d'acide dicarboxylique presentant des proprietes pharmaceutiques
DE19943639A1 (de) Dicarbonsäurederivate mit neuartigen pharmazeutischen Eigenschaften
EP1368303B1 (fr) Derives d'acide aminodicarboxylique a substitution halogene servant d'agents pharmaceutiques pour le traitement de maladies cardio-vasculaires
EP1368301B1 (fr) Derives d'acide aminodicarboxylique a halogenation de chaine laterale servant d'agents pharmaceutiques pour le traitement de maladies cardio-vasculaires
EP0358118A1 (fr) Phénylamides - procédé pour leur préparation ainsi qu'un médicament contenant ces composés

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20031007

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER HEALTHCARE AG

RBV Designated contracting states (corrected)

Designated state(s): DE ES FR GB IT

17Q First examination report despatched

Effective date: 20061027

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER SCHERING PHARMA AG

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER SCHERING PHARMA AKTIENGESELLSCHAFT

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER PHARMA AKTIENGESELLSCHAFT

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20110901