WO2010015652A2 - Composés thiazole utilisés comme activateurs de la guanylate cyclase soluble - Google Patents

Composés thiazole utilisés comme activateurs de la guanylate cyclase soluble Download PDF

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Publication number
WO2010015652A2
WO2010015652A2 PCT/EP2009/060145 EP2009060145W WO2010015652A2 WO 2010015652 A2 WO2010015652 A2 WO 2010015652A2 EP 2009060145 W EP2009060145 W EP 2009060145W WO 2010015652 A2 WO2010015652 A2 WO 2010015652A2
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WIPO (PCT)
Prior art keywords
methyl
oxy
thiazol
phenyl
piperidinecarboxylic acid
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PCT/EP2009/060145
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English (en)
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WO2010015652A3 (fr
Inventor
Anne Marie Jeanne Bouillot
Nerina Dodic
Francoise Jeanne Gellibert
Olivier Mirguet
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Smithkline Beecham Corporation
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Priority claimed from GB0814494A external-priority patent/GB0814494D0/en
Priority claimed from GB0818455A external-priority patent/GB0818455D0/en
Priority claimed from GB0818555A external-priority patent/GB0818555D0/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO2010015652A2 publication Critical patent/WO2010015652A2/fr
Publication of WO2010015652A3 publication Critical patent/WO2010015652A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds, pharmaceutical compositions containing them, to their use in medicine, and to processes for their preparation.
  • the present invention relates to compounds which, when administered to a patient, activate soluble guanylate cyclase (sGC) and to the use of such compounds for the activation of sGC in patients for a therapeutic effect.
  • sGC soluble guanylate cyclase
  • sGC is a member of a family of related enzymes which share homologous catalytic domains but are activated in different ways.
  • This family includes the adenylate cyclases, a class of membrane bound enzymes that convert ATP to cAMP, which are regulated by G proteins, and the membrane-bound guanylate cyclases that make cyclic guanosine monophosphate (cGMP) in response to hormone signals via an extracellular ligand binding domain.
  • cGMP cyclic guanosine monophosphate
  • the active enzyme contains one heme unit in a heterodimer arrangement, composed of one alpha and one beta-subunit.
  • Several subtypes of subunits have been described, which differ from each other with respect to sequence and tissue-specific distribution.
  • the subtypes alpha-1 and beta-1 are thought to be mainly expressed in the brain and the lung but have also been shown to be expressed in heart, kidney, liver, skeletal muscle, placenta, colon, uterus, prostate, spleen, pancreas, platelets and isolated blood vessels.
  • Alpha-2 subunits have been detected in the brain, placenta, uterus and pancreas, while beta-2 subunits seem to be expressed in the liver and kidney.
  • the enzyme is thought to be a principal receptor for the ubiquitous signalling molecule, nitric oxide (NO), forming a NO-sGC-cGMP signal transduction axis. It is believed that soluble guanylate cyclase is a heme sensor protein that selectively binds NO at the heme iron, which activates the enzyme to convert guanosine triphosphate (GTP) to cGMP. It is thought that cGMP subsequently mediates a number of important physiological processes, including smooth muscle relaxation and neurotransmission.
  • NO ubiquitous signalling molecule
  • soluble guanylate cyclase is a heme sensor protein that selectively binds NO at the heme iron, which activates the enzyme to convert guanosine triphosphate (GTP) to cGMP. It is thought that cGMP subsequently mediates a number of important physiological processes, including smooth muscle relaxation and neurotransmission.
  • cGMP is a critical component involved in the regulation of various (patho)physiological processes, for example in cardiovascular, respiratory, gastrointestinal, urogenital, nervous and immune systems including, neuronal excitability and particularly smooth muscle tone, thereby controlling, among other things, blood pressure, gastro-intestinal motility and genital erection.
  • novel compounds of the invention are activators of sGC and consequently may have application in the treatment of one or more diseases or conditions, which include: cardiovascular diseases and conditions, such as angina (including stable and unstable angina pectoris), low cardiac output, cerebral ischemia, cardiac ischemia, myocardial infarction, coronary reperfusion injury, arterial hypertension (including pulmonary arterial hypertension), congestive heart failure (for example due to systolic and/or diastolic cardiac dysfunction, low cardiac output or high systemic vascular resistance), heart failure with preserved ejection fraction, acute heart failure syndromes (AHFS), cardiac hypertrophy, acute coronary syndrome, thromboses (including arterial or venous thrombosis), atherosclerosis, peripheral vascular disease, glomerulonephritis, restenosis (for example following percutaneous vascular intervention, vascular angioplasty or stent placement), Raynaud's disease, vascular complications of diabetes or of obesity, stroke, hereditary cerebral haemorrhage, endothelial
  • cardiovascular hypertension including pulmonary arterial hypertension
  • cardiac ischemia myocardial infarction
  • congestive heart failure for example due to systolic and/or diastolic cardiac dysfunction, low cardiac output or high systemic vascular resistance
  • cardiac hypertrophy acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome and restenosis (for example following percutaneous vascular intervention, vascular angioplasty or stent placement).
  • a particular disease or condition for which the compounds of the invention may be useful is congestive heart failure. Another particular disease or condition for which the compounds of the invention may be useful is peripheral vascular disease. Another particular disease or condition for which the compounds of the invention may be useful is arterial hypertension (also known as systemic hypertension). Another particular disease or condition for which the compounds of the invention may be useful is pulmonary arterial hypertension. Another particular disease or condition for which the compounds of the invention may be useful is angina.
  • the present invention provides a compound of formula (I)
  • R 1 and R 2 are independently selected from hydrogen, halo, Ci -4 alkoxy, CF 3 and OCF 3 ;
  • R 3 represents hydrogen, fluoro, chloro or R 4a and R 4b each independently represent hydrogen, CF 3 or halo;
  • R 5 represents a group Z-X; wherein Z is absent or represents (CH 2 ) 2 or O; and X represents
  • J and L both represent CH, or one of J and L represents CH and the other represents N; when both J and L represent CH, R 6 represents hydrogen, halo, CF 3 , C 1-4 alkyl or C 1-4 alkoxy in a meta or ortho position relative to the R 7 substituent and R 7 represents hydrogen, halo, CF 3 , OCF 3 , C 1-4 alkyl, C 1-4 alkoxy, CH 2 OH, CN, CONR 8 R 9 or CO 2 H; or when one of J or L represents N, R 6 represents hydrogen or halo in a meta or ortho position relative to the R 7 substituent and R 7 represents hydrogen, halo, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, CH 2 OH, CN, CONR 8 R 9 or CO 2 H; and R 8 and R 9 are independently selected from hydrogen and C 1-4 alkyl.
  • alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, means a straight or branched alkyl containing at least 1 , and at most 4, carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropyl, and t-butyl.
  • alkoxy refers to a straight or branched alkoxy group containing the specified number of carbon atoms.
  • C 1-4 alkoxy means a straight or branched alkoxy group containing at least 1 , and at most 4, carbon atoms.
  • alkoxy as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, or 2-methylprop-2-oxy.
  • halo refers to the elements fluorine, chlorine, bromine and iodine. In an embodiment halo represents bromine, fluorine and chlorine. In a further embodiment halo represents fluorine and chlorine.
  • R 1 and R 2 are independently selected from hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, CF 3 , OCF 3 or OCH 3 .
  • R 1 represents hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, CF 3 , OCF 3 or OCH 3 .
  • R 2 represents hydrogen, methyl, fluoro or OCF 3 .
  • R 1 is in a para position relative to the -OCH 2 - linker.
  • R 2 is in an ortho position relative to the -OCH 2 - linker.
  • R 1 is in a para position relative to the -OCH 2 - linker and R 2 is in an ortho position relative to the - OCH 2 - linker.
  • R 1 is in an ortho position relative to the bond linking to the thiazole ring.
  • R 2 is in a meta position relative to the -OCH 2 - linker.
  • R 1 represents hydrogen and R 2 represents hydrogen, methyl or CF 3 , in a further embodiment with R 2 in an ortho position relative to the -OCH 2 - linker.
  • R 2 represents hydrogen and R 1 represents hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, methoxy, CF 3 or OCF 3 , in a further embodiment with R 1 in a para position relative to the -OCH 2 - linker.
  • R 1 represents fluoro and R 2 represents fluoro, in a further embodiment with R 1 in a para position relative to the -OCH 2 - linker and R 2 in an ortho position relative to the -OCH 2 - linker.
  • R 1 represents hydrogen and R 2 represents methyl, in a further embodiment with R 2 in a meta position relative to the -OCH 2 - linker.
  • R 1 represents fluoro and R 2 represents hydrogen, in a further embodiment with R 1 in an ortho position relative to the bond linking to the thiazole ring.
  • R 2 represents hydrogen and R 1 represents hydrogen, methyl, ethyl, fluoro, chloro or CF 3 , with R 1 in a para position relative to the -OCH 2 - linker.
  • R 3 represents hydrogen. In a further embodiment R 3 represents methyl. In a further embodiment R 3 represents chloro.
  • R 4a and R 4b each independently represent hydrogen, C 1-4 alkyl, C 1-4 alkoxy or halo.
  • R 4a represents hydrogen.
  • R 4b represents hydrogen, methyl, methoxy, propoxy, fluoro or chloro.
  • R 4a represents hydrogen and R 4b represents hydrogen, methyl, methoxy, propoxy, fluoro or chloro.
  • R 4a represents hydrogen and R 4b represents methyl.
  • Z is absent.
  • R 6 is in a meta-position relative to the R 7 substituent.
  • J and L both represent CH.
  • J represents N and L represents CH.
  • J represents CH and L represents N.
  • J and L both represent CH and R 6 represents hydrogen, halo, CF 3 , C- ⁇ alkoxy or C 1-4 alkyl in a meta or ortho position relative to the R 7 substituent.
  • CH and R 6 represents hydrogen, halo, CF 3 or C 1-4 alkyl in a meta position relative to the R 7 substituent.
  • CH and R 6 represents C 1-4 alkoxy in an ortho position relative to the R 7 substituent.
  • CH and R 6 represents hydrogen, methyl, chloro or CF 3 in a meta position relative to the R 7 substituent.
  • J and L both represents CH and R 6 represents methoxy in an ortho position relative to the R 7 substituent.
  • one of J and L represents N and R 6 represents hydrogen or chloro in a meta or ortho position relative to the R 7 substituent.
  • R 7 represents hydrogen, halo, CN, OCF 3 , CF 3 , C ⁇ alkoxy, CH 2 OH, CONR 8 R 9 or CO 2 H; wherein R 8 and R 9 are independently selected from hydrogen and C 1-4 alkyl.
  • R 7 represents hydrogen, fluoro, chloro, CN, CF 3 , OCF 3 , methoxy, CH 2 OH, CO 2 H, CO 2 NH 2 or CO 2 N(CH 3 ),.
  • J and L both represent CH, R 6 represents hydrogen and R 7 represents hydrogen, fluoro, chloro, methoxy, CN, CF 3 , CH 2 OH, CO 2 H, CO 2 NH 2 or CO 2 N(CH 3 ) 2 .
  • R 7 represents CF 3 and R 6 represents halo, C 1-4 alkyl or CF 3 .
  • R 7 represents CF 3 and R 6 represents chloro, methyl or CF 3 .
  • J and L both represent CH, R 7 represents CN and R ,6 1 represents C 1-4 alkyl.
  • J and L both represent CH, R 7 represents CN and R b represents methyl.
  • J and L both represent CH, R 6 represents CF 3 and R 7 represents C 1-4 alkoxy. In an embodiment J and L both represent CH, R 6 represents CF 3 and R 7 represents methoxy. In an embodiment J and L both represent CH, R 6 represents methoxy and R 7 represents hydrogen.
  • J and L both represent CH, R 6 represents hydrogen and R 7 represents CF 3 .
  • one of J and L represents N and the other represents CH, R 7 represents CF 3 and R 6 represents halo. In an embodiment one of J and L represents N and the other represents CH, R 7 represents CF 3 and R 6 represents chloro. In an embodiment J represents N, L represents CH, R 7 represents CF 3 and R 6 represents halo. In an embodiment J represents N, L represents CH, R 7 represents CF 3 and R 6 represents chloro.
  • one of J and L represents N and the other represents CH, R 7 represents C 1- 4 alkoxy and R 6 represents hydrogen. In an embodiment one of J and L represents N and the other represents CH, R 7 represents methoxy and R 6 represents hydrogen. In an embodiment J represents CH, L represents N, R 7 represents methoxy and R 6 represents hydrogen.
  • J and L represents N and the other represents CH, R 6 represents halo and R 7 represents CN.
  • J represents N and L represents CH, R 6 represents halo and R 7 represents CN.
  • J represents N and L represents CH, R 6 represents chloro and R 7 represents CN.
  • Salts of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable.
  • salts having non-pharmaceutically acceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.
  • Solvates of the compounds of formula (I) and solvates of the salts of the compounds of formula (I) are included within the scope of the present invention.
  • the term "solvate” refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solute in this invention, a compound of formula (I) or a salt thereof
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid.
  • the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
  • a salt may be readily prepared by using a desired acid or base as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • Suitable pharmaceutically acceptable salts can include acid addition salts or base addition salts and will be apparent to those skilled in the art.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic acid such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric or phosphoric acid; or with a suitable organic acid such as succinic, maleic, malic, mandelic, formic, acetic, propionic, hexanoic, fumaric, glutamic, lactic, citric, tartaric, benzoic, salicylic, aspartic, benzenesulfonic, p- toluenesulfonic, methanesulfonic, ethanesulfonic or naphthalenesulfonic acid.
  • a suitable inorganic acid such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric or phosphoric acid
  • a pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine, N-methyl-D-glucamine triethylamine, triethanolamine, choline, arginine, lysine or histidine.
  • a suitable inorganic or organic base including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine, N-methyl-D-glucamine triethylamine, triethanolamine, choline, arginine, lysine or histidine.
  • suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of the carboxylic acid moiety that is present in the compound of formula (I). Since the compounds of formula (I) can include a carboxylic acid moiety together with one or more basic nitrogen atom(s) they have the possibility to also form internal salts, which salts are also included within the scope of the present invention.
  • pharmaceutically acceptable metal salts for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts
  • pharmaceutically acceptable metal salts of the carboxylic acid moiety that is present in the compound of formula (I). Since the compounds of formula (I) can include a carboxylic acid moiety together with one or more basic nitrogen atom(s) they have the possibility to also form internal salts, which salts are also included within the scope of the present invention
  • polymorphs of a compound of the invention are also included within the scope of the invention.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
  • compounds of the invention as activators of sGC, may be useful in the treatment of a disease or condition which is mediated by sGC activity.
  • the invention provides a compound of the invention as defined above for use in therapy; in an embodiment the therapy is human therapy.
  • the invention provides the use of a compound of the invention for the manufacture of a medicament for treating a disease or condition mediated by sGC activity.
  • the invention provides a compound of the invention for use in the treatment of a disease or condition mediated by sGC activity.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, in association with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
  • the carrier, diluent and/or excipient must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • the invention provides a method of treatment of a disease or condition which is mediated by the activity of sGC such as one or more of the diseases described above, for example arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, acute coronary syndrome, atherosclerosis, peripheral vascular disease or restenosis, comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of the invention, or of a pharmaceutical composition comprising a compound of the invention.
  • sGC such as one or more of the diseases described above, for example arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, acute coronary syndrome, atherosclerosis, peripheral vascular disease or restenosis
  • the invention provides a method of treatment of cardiorenal syndrome or hepatorenal syndrome comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of the invention, or of a pharmaceutical composition comprising a compound of the invention.
  • the compounds of the invention may also be used in combination with other therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
  • a compound of the invention or a pharmaceutically acceptable derivative thereof When a compound of the invention or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
  • the compounds of the present invention may for example be used in combination with antihypertensive drugs such as diuretics (for example epitizide, bendroflumethiazide, chlortalidone, chlorthiazide, hydrochlorthiazide, indapamide, metolazone), ACE inhibitors (such as benzapril, captopril, enalapril, fosinopril, lisinopril, preindopril, quinapril, ramipril, trandopril), angiotensin receptor blockers (such as candesartan, irbesartan, losartan, telmisartan, valsartan), calcium channel inhibitors (such as amlodipine, felodipine, isradapine, nifedipine, niimodipine, nitrendipine, diltiazem, verapamil), ⁇ -adrenergic receptor antagonists (such
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • either the compound of the invention or the second therapeutic agent may be administered first.
  • the combination may be administered either in the same or different pharmaceutical composition.
  • references herein to "treatment” extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
  • the compound of the invention may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
  • the compound of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with one or more standard pharmaceutical excipients, carriers or diluents, according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired preparation.
  • compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
  • compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate
  • Suppositories typically contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions of the invention may be formulated, for administration to mammals including humans, by any route, and include those in a form adapted for oral, topical or parenteral administration.
  • the compositions may, for example, be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • the invention provides a pharmaceutical composition for oral administration such as an oral suspension or liquid, for example an aqueous based fluid formulation, or a solid dosage formulation such as a tablet or capsule.
  • a pharmaceutical composition for oral administration such as an oral suspension or liquid, for example an aqueous based fluid formulation, or a solid dosage formulation such as a tablet or capsule.
  • compositions may contain from 0.1 % by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will typically contain from 5-1000 mg of the active ingredient.
  • the optimal quantity and spacing of individual doses of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each suitably provided in substantially pure form, for example at least 60% pure, for example at least 75% pure, for example at least 85%, for example at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds typically contain at least 1%, for example at least 5%, for example from 10 to 59% of a compound of the invention.
  • Compounds of general formula (I) may be prepared according to reaction scheme 1 by saponification of compounds of formula (II) in a presence of base such as NaOH or LiOH in a suitable solvent such as ethanol at 40 0 C or reflux.
  • base such as NaOH or LiOH
  • suitable solvent such as ethanol at 40 0 C or reflux.
  • Compounds of formula (II) may be prepared according to reaction scheme 2 by reacting compounds of formula (III) and compound of formula (IV) in the presence of base such as potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile or acetone at reflux.
  • base such as potassium carbonate or cesium carbonate
  • a suitable solvent such as acetonitrile or acetone at reflux.
  • Compounds of formula (III) may be prepared according to reaction scheme 3 by reacting the alpha bromo ketone of formula (V) and ethyl 1-(aminocarbonothioyl)-4-piperidinecarboxylate (Vl) in a suitable solvent such as ethanol or DMF at reflux, or under microwave conditions in ethanol at 120 0 C.
  • a suitable solvent such as ethanol or DMF at reflux, or under microwave conditions in ethanol at 120 0 C.
  • the compound of formula (VIII) may be prepared according to reaction scheme 4b.
  • compounds of formula (VII) may be prepared from the corresponding methyl derivatives of formula (Vila) according to Scheme 4b.
  • the compound of formula (Vila) where R 1 is ethyl and R 2 is hydrogen may be prepared as described in WO2005019151.
  • Compounds of formula (Vila) where R 1 is propyl and R 2 is hydrogen may be prepared from the corresponding 4-propyl-anisole by (i) bromination in the position ortho to the methoxy group and (ii) conversion of the bromine to a boronic acid group by standard methods. Analogous processes may be used to prepare other compounds of formula (Vila) where R 1 is C 1-4 alkyl and R 2 is as defined above. For example, 2-bromo-4,6-dimethyl phenol is commercially available from Bionet.
  • Compounds of formula (Vila) where R 1 is H and R 2 is ethyl, isopropyl or t-butyl may be prepared from the corresponding 2-ethyl-anisole, 2-isopropyl-anisole or 2-t-butyl-anisole, by
  • compounds of general formula (V) which are not commercially available may be prepared according to reaction scheme 5 by reacting the alkyl ketone of formula (IX) with a suitable brominating agent such as copper (II) bromide in a suitable solvent such as a mixture of EtOAc and chloroform or a bromine polymer supported reagent in THF.
  • a suitable brominating agent such as copper (II) bromide
  • a suitable solvent such as a mixture of EtOAc and chloroform or a bromine polymer supported reagent in THF.
  • compounds of formula (IXa) may be prepared according to reaction scheme 6 starting from (i) the commercially available 4-(trifluoromethyl)phenol with methyl iodide in a solvent such as acetonitrile at reflux with a suitable base such as potassium carbonate, followed by (ii) reaction with acetic anhydride in trifluorosulfonic acid at 30 0 C, and (iii) demethylation using boron tribromide in a suitable solvent such as DCM at -8O 0 C.
  • a solvent such as acetonitrile at reflux with a suitable base such as potassium carbonate
  • the compound of formula (Vl) may be prepared according to reaction scheme 7 in two steps by first reacting fluorenylmethyloxycarbonyl chloride and potassium thiocyanate in a suitable solvent such as ethyl acetate, to afford the non isolated 9H-fluoren-9-ylmethyl isothiocyanatidocarbonate, followed by reaction with ethyl 4-piperidinecarboxylate in a suitable solvent such as chloroform.
  • the compound of formula (X) may be prepared according to reaction schemes 8 to 10.
  • the compound of formula (Xa) may be prepared according to reaction scheme 8, starting from reduction of the carboxylic acid of formula (Xl) using borane dimethyl sulphide in THF at 75°C, followed by bromation of alcohol (XII) with phosphorus tribromide in dichloromethane at room temperature.
  • the compound of formula (Xb) may be prepared according to reaction scheme 9.
  • the alcohol of formula (Xl) can be also prepared from esterification of the carboxylic acid of formula (X) using sulphuric acid in methanol at reflux, followed by reduction of (XII) with lithium aluminium hydride in THF at 0 0 C.
  • the borolane derivative of formula (XV) may be prepared by reacting the compound of formula (Xl) with bis(pinacolato)diboron with Pd(dppf)CI 2 (N) and potassium acetate in a suitable solvent such as 1 ,4-dioxane at reflux.
  • Compound (Xb) may be finally obtained from compound (XV) by bromination with phosphorus tribromide in DCM at 0 0 C.
  • the compound of formula (Xc) may be prepared according to reaction scheme 10, starting from alkylation of the benzaldehyde of formula (XVIa) using a base such as sodium hydride in a suitable solvent, such as THF/DMF followed by reduction of the aldehyde (XVIb) with sodium borohydride in methanol at room temperature. Bromination of the alcohol with phosphorus tribromide in dichloromethane at room temperature provides the compound (Xc).
  • R 5 represents a group Z-X wherein Z is absent
  • compound (IVa) may be prepared according to reaction scheme 1 1 , namely by Suzuki reaction from the alcohol of formula (XV) and the corresponding halo derivative of formula (XVII), for example reacting with palladium tetrakis with a base such as cesium carbonate in a suitable solvent such as DME at reflux, followed by bromination, for example with phosphorus tribromide in DCM at 0 0 C.
  • reaction scheme 1 1 namely by Suzuki reaction from the alcohol of formula (XV) and the corresponding halo derivative of formula (XVII), for example reacting with palladium tetrakis with a base such as cesium carbonate in a suitable solvent such as DME at reflux, followed by bromination, for example with phosphorus tribromide in DCM at 0 0 C.
  • Certain compounds of formula (XVII) are commercially available, for example: wherein hal represents Br or Cl, J represents N, R 6 represents H, and R 7 represents CN, CF 3 , COOH, Cl or OMe (Aldrich, Fluka or Acros); wherein hal represents Cl, J represents N, R 6 represents Cl, and R 7 represents CF 3 (Aldrich); wherein J represents CH, hal represents F, R 6 represents H, F, Cl, OMe, Me, or CF 3 , and R 7 represents CN or COOH (Aldrich, Acros, Apin).
  • Other compounds of formula (XVII) may be prepared by standard methods well-known to the person skilled in the art.
  • compound (IVa) may also be prepared according to reaction scheme 12, namely by Suzuki reaction from the alcohol of formula (XII) and the corresponding boronic acid derivative of formula (XVIII), for example reacting with palladium tetrakis with a base such as cesium carbonate in a suitable solvent such as DME at reflux followed by bromination with phosphorus tribromide in DCM at O 0 C.
  • compounds of formula (XIX) may be prepared from reaction of a compound of formula (III) with the corresponding alkylating reagent of formula (X) in the presence of a base such as potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile or acetone at reflux.
  • a base such as potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile or acetone at reflux.
  • Suzuki coupling with the corresponding boronic acid of formula (XVIII) using palladium tetrakis with a base such as cesium carbonate in a suitable solvent such as DME at reflux provides the compound of formula (Na).
  • compounds of formula (XX) may be prepared from alkylation of a compound of formula (III) with the corresponding alkylating reagent of formula (Xb) in the presence of base such as potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile or acetone at reflux.
  • base such as potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile or acetone at reflux.
  • Compounds of formula (IVb) may be prepared according to reaction scheme 16 by reacting the commercially available aldehyde of formula (XX) and the compound of formula (XXI) in the presence of base such as cesium carbonate in a suitable solvent such as DMF at 85°C.
  • the aldehyde function of compounds of formula (XXII) may be reduced down to the corresponding alcohol function of compounds of formula (XXIII) in the presence of reducing agent such as lithium aluminium hydride in a suitable solvent such as THF at room temperature.
  • reducing agent such as lithium aluminium hydride
  • a suitable solvent such as THF at room temperature.
  • compounds of formula (IVb) may be prepared from compounds of formula (XXIII) in the presence of a brominating agent such as phosphorus tribromide in a suitable solvent such as DCM at room temperature.
  • Phenol derivatives of formula (XXI) are commercially available or may be prepared by standard methods well-known to the person skilled in the art.
  • Compounds of formula (NIb) where R 3 represents fluoro or chloro may be prepared according to reaction scheme 17 by reacting compounds of formula (Ilia) where R 3 represents hydrogen in the presence of a halogenating agent, such as Selectfluor in a suitable solvent such as DMF, or N-chlorosuccinimide in a suitable solvent such as acetonitrile at 60 0 C.
  • a halogenating agent such as Selectfluor in a suitable solvent such as DMF, or N-chlorosuccinimide in a suitable solvent such as acetonitrile at 60 0 C.
  • Certain compounds of formula (XXIV) are commercially available.
  • Other compounds of formula (NIV) may be prepared by methods as described in Tetrahedron (2007), 63(23), 5088-5094 or in Journal of Organic Chemistry (2007), 72(1 ), 144-149 or may be prepared by standard methods well-known to the person skilled in the art.
  • (XXVI) (4-phenethyl)benzyl aldehyde is commercially available (from Alfa or ABCR).
  • Other compounds of formula (XXVI) may be prepared by methods as described in Tetrahedron Letters, 1999, 40(11 ), 2075-2078 or in Tetrahedron Letters, 2006, 62(51 ), 11925-11932, or may be prepared by standard methods well-known to the person skilled in the art.
  • MS mass spectra
  • MS mass spectra
  • Fluorenylmethyloxycarbonyl chloride (1 Kg, 3.86 mol; in 5 batches, 200g * 5) was dissolved in anhydrous ethyl acetate (300ml * 5). This solution was added dropwise to a suspension of dry potassium thiocyanate (82.6 g * 5, 4.25 mol) in anhydrous ethyl acetate (1.5 L * 5) at 0 0 C under N 2 atmosphere. The solution was allowed to warm to RT and stirred overnight. The reaction was monitored by thin layer chromatography.
  • the crude product was used for the subsequent step without futher purification.
  • Fluorenylmethyloxycarbonyl isothiocyanate, intermediate 7, (1.08 Kg, 3.86 mol, in 5 batches, 200g * 5) was dissolved in chloroform (1.5 L * 5) and a solution of commercially available piperidine-4-carboxylic acid ethyl ester (133.7 g * 5, 4.25 mol) in chloroform was added. Then the mixture was stirred at RT for 3 hours. The mixture was concentrated in vacuo and residue was washed with Et 2 O, filtered and the solid was dissolved in dichloromethane (1.5 L * 5) then piperidine (329.1 g * 5, 19 mol) was added. The mixture was stirred at RT overnight. The reaction mixture was concentrated.
  • LiAIH 4 (30 g, 0.79 moL) was dissolved in THF (500 ml_), and the mixture was cooled to O 0 C.
  • Example 1 1-[4-(2- ⁇ [(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy ⁇ -5-methylphenyl)- 1 ,3-thiazol-2-yl]-4-piperidinecarboxylic acid.
  • Example 2 was prepared by an analogous method to that described for Example 6 starting from the corresponding ester.
  • Example 38 1 -[5-chloro-4-(2- ⁇ [(4'-cyano-4-biphenylyl)methyl]oxy ⁇ phenyl)-1 ,3-thiazol-2-yl]- 4-piperidinecarboxylic acid
  • Example 41 1 - ⁇ 5-methyl-4-[2-( ⁇ [4'-(methyloxy)-4-biphenylyl]methyl ⁇ oxy)phenyl]-1 ,3- thiazol-2-yl ⁇ -4-piperidinecarboxylic acid
  • Example 2 was prepared by an analogous method to that described for Example 6 starting from the corresponding ester.
  • Example 55 1- ⁇ 4-[5-methyl-2-( ⁇ [3-methyl-4'-(trifluoromethyl)-4- biphenylyl]methyl ⁇ oxy)phenyl]-1 ,3-thiazol-2-yl ⁇ -4-piperidinecarboxylic acid-2- aminoethanol (1 :1)
  • Example 54 The compound was recrystallized from a mixture of acetonitrile and methanol to give the title compound sodium 1- ⁇ 4-[5-methyl-2-( ⁇ [3-methyl-4'- (trifluoromethyl)-4-biphenylyl]methyl ⁇ oxy)phenyl]-1 ,3-thiazol-2-yl ⁇ -4-piperidinecarboxylate as a white solid (70 mg, 0.119 mmol). Most of the compound was dissolved in the filtrate. The compound had the same analytical data as was obtained for Example 54. The following Example was prepared by a method analogous to that described for Example 54 but using lithium hydroxide as base.
  • Example 55 The following Example was prepared by a method analogous to that described for Example 55.
  • Example 2 was prepared by an analogous method to that described for Example 6 starting from the corresponding ester.
  • Example 2 was prepared by an analogous method to that described for Example 1 starting from the corresponding ester.
  • Example 1 The following Examples were prepared by a method analogous to that described for Example 1 but in some cases sodium hydroxide was used instead of lithium hydroxide (or by a method analogous to that described for Example 6 in the case of Example 87; or by a method analogous to that described for Example 54 in the case of Example 82; or by a method analogous to that described for Example 81 for Example 86) starting from the corresponding ester.
  • Example 2 was prepared by an analogous method to that described for Example 6 starting from the corresponding ester.
  • soluble guanylate cyclase can be tested in an assay based on measuring the fluorescent polarisation (FP) signal of fluorescently labelled cGMP.
  • FP fluorescent polarisation
  • cGMP displaces the interaction giving rise to a decrease in polarisation and FP signal which can be equated to enzyme activity.
  • Compounds are incubated with human sGC, anti- cGMP antibody, the GTP substrate and fluorescently labelled cGMP. After a period of one hour the assay is stopped with the addition of EDTA and after a further hour the assay is read.
  • Human sGC is thawed and resuspended in assay buffer (10OmM TRIS, 1 OmM MgCI 2 , 0.2mM Tween 20, pH7.4, containing 1 :100 dilution of sheep anti-cGMP) to give final concentration of 1 nM in the well.
  • assay buffer (10OmM TRIS, 1 OmM MgCI 2 , 0.2mM Tween 20, pH7.4, containing 1 :100 dilution of sheep anti-cGMP) to give final concentration of 1 nM in the well.
  • a substrate solution is prepared containing GTP and 8-fluo-cGMP in de-ionized water to a final concentration of 25 ⁇ M and 5OnM respectively.
  • Assay plates containing 5 ⁇ l_ of various test compounds and of a standard agonist (50 ⁇ M -5OnM) in 1 % DMSO as 6 point, four fold dilutions across a 96 well plate are used in the assay.
  • the plate also contains 6 wells of DMSO (1 %) to produce high control and a cGMP standard curve (14nM to 10 ⁇ M) to convert FP data to cGMP concentration.
  • 25 ⁇ l_ of enzyme mix and 20 ⁇ l of substrate mix described above are added to each well of the plate.
  • Samples are mixed on an orbital shaker and then incubated at room temperature for 1 hour. After this incubation period 5 ⁇ l of 0.5M EDTA is added to all wells and the plates are incubated for a further hour at room temperature prior to reading the FP signal in an appropriate reader.
  • FP data are converted to cGMP concentrations and then fitted using ActivityBase software.
  • the activity of a test compound is determined as the pEC500 value which is the concentration able to increase by 5- fold basal cGMP.
  • the compounds of Examples 1 to 90 were tested in the assay described above and gave pEC500 values of greater than 5.0. In an embodiment the compounds of the invention give a pEC500 value of ⁇ 6.0 when tested in this assay. In a further embodiment the compounds of the invention give a pEC500 value of ⁇ 7.0 when tested in this assay.
  • the compounds 1 - ⁇ 5-methyl-4-[2-( ⁇ [4-(2-phenylethyl)phenyl]methyl ⁇ oxy)phenyl]-1 ,3-thiazol-2-yl ⁇ - 4-piperidinecarboxylic acid and 1-(4- ⁇ 5-(1-methylethyl)-2-[( ⁇ 3-methyl-4'-[(trifluoromethyl)oxy]-4- biphenyly ⁇ methy ⁇ oxylpheny ⁇ -i ⁇ -thiazol ⁇ -yl ⁇ -piperidinecarboxylic acid were also prepared by analogous methods to those described above. These two compounds were tested in the assay described above and gave pEC500 values of ⁇ 5.0 i.e. below the detectable limit of the assay.

Abstract

L'invention porte sur des composés de la formule (I) dans laquelle R1 et R2 sont choisis indépendamment entre hydrogène, halo, C1-4alkyle, C1-4alcoxy, CF3 et OCF3; -Y- représente la formule (IA) R3 représente hydrogène, fluoro, chloro ou C1-4alkyle; R4a et R4b représentent chacun indépendamment hydrogène, C1-4alkyle, C1-4alcoxy, CF3 ou halo; et R5 représente a groupe Z-X; où Z est absent ou représente (CH2)2 ou O; et X représente la formule (IB) où: J et L représentent tous deux CH, ou J ou L représente CH et l'autre représente N; lorsque J et L représentent tous deux CH, R6 représente hydrogène, halo, CF3, C1-4alkyle ou C1-4alcoxy dans une position méta ou ortho par rapport au substituant R7 et R7 représente hydrogène, halo, CF3, OCF3, C1-4alkyle, C1-4alcoxy, CH2OH, CN, CONR8R9 ou CO2H; ou lorsque J ou L représente N, R6 représente hydrogène ou halo dans une position méta ou ortho par rapport au substituant R7 et R7 représente hydrogène, halo, CF3, C1-4alkyle, C1-4alcoxy, CH2OH, CN, CONR8R9 ou CO2H; et R8 et R9 sont choisis indépendamment entre hydrogène et C1-4alkyle; ou sur des sels de ce dernier qui activent la guanylate cyclase soluble (sGC), sur des compositions pharmaceutiques les contenant, sur leur utilisation en médecine, et sur des procédés de préparation de ces derniers.
PCT/EP2009/060145 2008-08-07 2009-08-05 Composés thiazole utilisés comme activateurs de la guanylate cyclase soluble WO2010015652A2 (fr)

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Cited By (20)

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WO2011130515A1 (fr) * 2010-04-14 2011-10-20 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Arylthiazolyl pipéridines et composés associés comme modulateurs de la production de protéine de neurone moteur de survie (smn)
WO2012073038A3 (fr) * 2010-12-01 2012-07-19 University Of Sheffield Composés et leurs procédés de préparation
WO2013025425A1 (fr) * 2011-08-12 2013-02-21 Boehringer Ingelheim International Gmbh Activateurs de guanylate cyclase soluble
EP2594270A2 (fr) 2011-11-18 2013-05-22 BIP Patents Utilisation de stimulateurs de la sGC ou d'activateurs de la sGC, seuls et en combinaison avec des inhibiteurs de PDE5 pour le traitement de la sclérose systémique (Ssc)
US8455638B2 (en) 2007-09-06 2013-06-04 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
US8461348B2 (en) 2008-04-04 2013-06-11 Takeda Pharmaceutical Company Limited Heterocyclic derivative and use thereof
US8507512B2 (en) 2009-02-26 2013-08-13 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
CN103304506A (zh) * 2013-06-07 2013-09-18 陕西师范大学 含氟苯并噁唑类液晶化合物的制备方法
US8569339B2 (en) 2011-03-10 2013-10-29 Boehringer Ingelheim International Gmbh Soluble guanylate cyclase activators
US8906904B2 (en) 2012-09-07 2014-12-09 Boehringer Ingelheim International Gmbh Alkoxy pyrazoles as soluble guanylate cyclase activators
US9353090B2 (en) 2014-07-22 2016-05-31 Boehringer Ingelheim International Gmbh Heterocyclic carboxylic acids as activators of soluble guanylate cyclase
US9365574B2 (en) 2010-05-27 2016-06-14 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
WO2018069148A1 (fr) 2016-10-11 2018-04-19 Bayer Pharma Aktiengesellschaft Combinaison contenant des activateurs gcs et des antagonistes du récepteur des minéralocorticoïdes
WO2019081456A1 (fr) 2017-10-24 2019-05-02 Bayer Aktiengesellschaft Utilisation d'activateurs et de stimulateurs de sgc comprenant une sous-unité bêta2
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)
WO2019211081A1 (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 déficiences cognitives
WO2019219672A1 (fr) 2018-05-15 2019-11-21 Bayer Aktiengesellschaft Benzamides à substitution 1,3-thiazol-2-yl pour le traitement de maladies associées à la sensibilisation de fibres nerveuses
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
WO2020148379A1 (fr) 2019-01-17 2020-07-23 Bayer Aktiengesellschaft Procédés permettant de déterminer si un sujet est apte à être traité avec un agoniste de guanylyle cyclase soluble (sgc)
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

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WO2009071504A1 (fr) * 2007-12-03 2009-06-11 Smithkline Beecham Corporation Pyridines 2,6-disubstituées comme activateurs de la guanylate cyclase soluble

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EP0288758A2 (fr) * 1987-04-09 1988-11-02 Bayer Ag Dihydropyridinamides, procédé pour leur préparation et leur utilisation comme médicaments
WO1998049152A1 (fr) * 1997-04-25 1998-11-05 Smithkline Beecham Corporation Inhibiteurs de proteases
WO2009071504A1 (fr) * 2007-12-03 2009-06-11 Smithkline Beecham Corporation Pyridines 2,6-disubstituées comme activateurs de la guanylate cyclase soluble

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8455638B2 (en) 2007-09-06 2013-06-04 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
US8461348B2 (en) 2008-04-04 2013-06-11 Takeda Pharmaceutical Company Limited Heterocyclic derivative and use thereof
US8507512B2 (en) 2009-02-26 2013-08-13 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
WO2011130515A1 (fr) * 2010-04-14 2011-10-20 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Arylthiazolyl pipéridines et composés associés comme modulateurs de la production de protéine de neurone moteur de survie (smn)
US9365574B2 (en) 2010-05-27 2016-06-14 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
WO2012073038A3 (fr) * 2010-12-01 2012-07-19 University Of Sheffield Composés et leurs procédés de préparation
US8569339B2 (en) 2011-03-10 2013-10-29 Boehringer Ingelheim International Gmbh Soluble guanylate cyclase activators
US8815857B2 (en) 2011-08-12 2014-08-26 Boehringer Ingelheim International Gmbh Soluble guanylate cyclase activators
JP2014525401A (ja) * 2011-08-12 2014-09-29 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 可溶性グアニル酸シクラーゼ活性化因子
WO2013025425A1 (fr) * 2011-08-12 2013-02-21 Boehringer Ingelheim International Gmbh Activateurs de guanylate cyclase soluble
EP2594270A2 (fr) 2011-11-18 2013-05-22 BIP Patents Utilisation de stimulateurs de la sGC ou d'activateurs de la sGC, seuls et en combinaison avec des inhibiteurs de PDE5 pour le traitement de la sclérose systémique (Ssc)
USRE46886E1 (en) 2012-09-07 2018-06-05 Boehringer Ingelheim International Gmbh Alkoxy pyrazoles as soluble guanylate cyclase activators
US8906904B2 (en) 2012-09-07 2014-12-09 Boehringer Ingelheim International Gmbh Alkoxy pyrazoles as soluble guanylate cyclase activators
JP2015527394A (ja) * 2012-09-07 2015-09-17 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 可溶性グアニル酸シクラーゼ活性化因子としてのアルコキシピラゾール
CN103304506B (zh) * 2013-06-07 2015-05-20 陕西师范大学 含氟苯并噁唑类液晶化合物的制备方法
CN103304506A (zh) * 2013-06-07 2013-09-18 陕西师范大学 含氟苯并噁唑类液晶化合物的制备方法
US9353090B2 (en) 2014-07-22 2016-05-31 Boehringer Ingelheim International Gmbh Heterocyclic carboxylic acids as activators of soluble guanylate cyclase
WO2018069148A1 (fr) 2016-10-11 2018-04-19 Bayer Pharma Aktiengesellschaft Combinaison contenant des activateurs gcs et des antagonistes du récepteur des minéralocorticoïdes
WO2019081456A1 (fr) 2017-10-24 2019-05-02 Bayer Aktiengesellschaft Utilisation d'activateurs et de stimulateurs de sgc comprenant une sous-unité bêta2
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)
WO2019211081A1 (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 déficiences cognitives
WO2019219672A1 (fr) 2018-05-15 2019-11-21 Bayer Aktiengesellschaft Benzamides à substitution 1,3-thiazol-2-yl pour le traitement de maladies associées à la sensibilisation de fibres nerveuses
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
WO2020148379A1 (fr) 2019-01-17 2020-07-23 Bayer Aktiengesellschaft Procédés permettant de déterminer si un sujet est apte à être traité avec un agoniste de guanylyle cyclase soluble (sgc)
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

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