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WO2010015653A1 - Dérivés de pyrimidine comme activateurs de guanylate cyclase soluble - Google Patents

Dérivés de pyrimidine comme activateurs de guanylate cyclase soluble Download PDF

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Publication number
WO2010015653A1
WO2010015653A1 PCT/EP2009/060146 EP2009060146W WO2010015653A1 WO 2010015653 A1 WO2010015653 A1 WO 2010015653A1 EP 2009060146 W EP2009060146 W EP 2009060146W WO 2010015653 A1 WO2010015653 A1 WO 2010015653A1
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WIPO (PCT)
Prior art keywords
methyl
phenyl
pyrimidin
phenylmethyloxy
carboxylic acid
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.)
Ceased
Application number
PCT/EP2009/060146
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English (en)
Inventor
Anne Marie Jeanne Bouillot
Nerina Dodic
Francoise Jeanne Gellibert
Olivier Mirguet
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.)
SmithKline Beecham Corp
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SmithKline Beecham Corp
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
Priority claimed from GB0814492A external-priority patent/GB0814492D0/en
Priority claimed from GB0817052A external-priority patent/GB0817052D0/en
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of WO2010015653A1 publication Critical patent/WO2010015653A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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, CF 3 and Ci -4 alkyl;
  • one of U and V represents N and the other represents CH;
  • R 3 represents CF 3 or C 1-4 alkyl
  • Z is absent or represents O
  • A represents CH or N; when A represents CH, R 5 is selected from hydrogen, methyl, C 1-4 alkoxy, methoxyC 2 - 3 alkoxy, chloro and fluoro and R 6 represents hydrogen;
  • R 5 and R 6 each represent hydrogen or one of R 5 and R 6 represents hydrogen and the other represents methyl
  • J and L both represent CH, or one represents N and the other represents CH, provided that only one of A, J and L represents N;
  • R 8 represents hydrogen or chloro, fluoro, CF 3 , C 1-4 alkyl or C 1-4 alkoxy in a meta or ortho position relative to the R 9 substituent;
  • R 8 represents hydrogen or halo in a meta or ortho position relative to the R 9 substituent
  • R a represents hydrogen, halo, CF 3 , OCF 3 , C 1-4 -alkyl, C 1-4 -alkoxy, CN, CONR 10 R , CO 2 H or N 3 , wherein R ,10 and R are independently selected from hydrogen and C 1-4 -alkyl;
  • R 1 and R 2 are independently selected from hydrogen, halo, CF 3 or C 1-4 alkyl; one of U and V represents N and the other represents CH;
  • R 3 represents CF 3 or C 1-4 alkyl
  • Z is absent or represents O
  • A, J and L each represent CH; or one of A, J and L represents N and the other two each represents CH; and when A represents CH, R 5 is selected from hydrogen, methyl, C 1-4 alkoxy, methoxyC 2- 3 alkoxy, chloro and fluoro and R 6 represents hydrogen; or when A represents N, R 5 and R 6 each represent hydrogen or one of R 5 and R 6 represents hydrogen and the other represents methyl;
  • R 8 represents hydrogen or chloro, fluoro, CF 3 , C 1- 4 alkyl or C 1-4 alkoxy in a meta or ortho position relative to the R 9 substituent; or when one of J and L represents N, R 8 represents hydrogen or halo in a meta or ortho position relative to the R 9 substituent; and R 9 represents hydrogen, halo, CF 3 , OCF 3 , C 1-4 -alkyl, C 1-4 -alkoxy, CN, CONR 10 R 11 , CO 2 H or N 3 , wherein R 10 and R 11 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.
  • C 1-4 alkyl 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.
  • pharmaceutically acceptable means a compound which is suitable for pharmaceutical use.
  • Y— represents
  • 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 pyridine ring.
  • R 2 is in a meta position relative to the -OCH 2 - linker.
  • R 1 and R 2 do not both represent C 2-4 alkyl.
  • R 1 and R 2 represents the other represents hydrogen
  • R 1 represents C 1-4 alkyl, CF 3 or halo, in a further embodiment with R 1 in a para position relative to the -OCH 2 - linker.
  • R 1 represents methyl, CF 3 , fluoro or chloro, in a further embodiment with R 1 in a para position relative to the -OCH 2 - linker.
  • R 2 represents hydrogen
  • R 1 represents chloro or fluoro and R 2 represents hydrogen, in a further embodiment with R 1 in an ortho position relative to the bond linking to the pyridine ring.
  • R 2 represents chloro or fluoro and R 1 represents hydrogen, in a further embodiment with R 2 in a meta position relative to the -OCH 2 - linker.
  • U represents CH and V represents N.
  • R 1 and R 2 each represent hydrogen. In an embodiment R 1 represents chloro or fluoro and R 2 represents hydrogen. In an embodiment R 1 represents C 1-4 alkyl and R 2 represents hydrogen. In an embodiment R 1 represents methyl and R 2 represents hydrogen. In an embodiment R 1 represents CF 3 and R 2 represents hydrogen.
  • R 3 represents methyl or CF 3 . In a further embodiment R 3 represents CF 3 .
  • Z is absent. In an embodiment Z represents O.
  • A represents CH.
  • R 6 represents hydrogen
  • R 5 represents hydrogen, methyl, methoxy, propyloxy, isopropyloxy, isobutyloxy, methoxyethoxy, fluoro or chloro. In an embodiment, R 5 represents hydrogen, methyl, methoxy or propyloxy.
  • J and L both represent CH. In a further embodiment J represents N and L represents CH. In a further embodiment J represents CH and L represents N.
  • R 8 represents hydrogen or chloro, CF 3 , methyl or methoxy in a meta or ortho position relative to the R 9 substituent. In an embodiment R 8 represents hydrogen or chloro, CF 3 , methyl or methoxy in a meta position relative to the R 9 substituent.
  • J and L both represent CH and R 8 represents hydrogen or chloro, CF 3 , methyl or methoxy in a meta position relative to the R 9 substituent.
  • J represents N and L represents CH and R 8 represents hydrogen, or chloro in a meta position relative to the R 9 substituent.
  • J represents CH and L represents N and R 8 represents hydrogen.
  • R 9 represents hydrogen, halo, CF 3 , OCF 3 , C 1-4 alkyl, C 1-4 alkoxy or CN. In a further embodiment R 9 represents halo, CF 3 , OCF 3 , C 1-4 alkoxy or CN. In a further embodiment R 9 represents chloro, fluoro, CF 3 , OCF 3 , methoxy or CN.
  • R 8 represents hydrogen and R 9 represents methoxy, CN, CF 3 , OCF 3 or fluoro.
  • R 8 represents methyl and R 9 represents CN, methoxy or CF 3 , with R 8 being in a meta position relative to the R 9 substituent.
  • R 8 represents CF 3
  • R 9 represents CN, methoxy or chloro, with R 8 being in a meta position relative to the R 9 substituent.
  • R 8 represents chloro
  • R 9 represents CF 3 , CN or methoxy, with R 8 being in a meta position relative to the R 9 substituent.
  • Separation of the individual enantiomers of the relevant compounds may be carried out by standard methods well-known to the person skilled in the art, for example by chiral chromatography.
  • 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) 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) 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 for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, 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.
  • lsotopic 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 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. It will be recognised by one of skill in the art that 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.
  • step (i) the intermediate compounds of formula (II) can be prepared according to the processes set out in Schemes 2 a anndd 33.
  • 2,4-dichloropyrimidine is commercially available from Aldrich.
  • the compounds of formula (V) wherein R 3 represents CF 3 or CH 3 are commercially available (from Aldrich and Orphachem respectively).
  • the compounds of formula (V) wherein R 3 represents C 2-4 alkyl can be prepared according to the process described in US2005096353 (see Scheme 6 at page 17 and the Examples).
  • Ethyl isonipecotate is commercially available (from Aldrich).
  • the compound of formula (lib) can also be prepared in a solvent such as acetone, CH 3 CN or THF in the presence of a base such as Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 , under reflux.
  • step (ii) the intermediate compounds of formula (III) can be prepared according to the processes set out in Schemes 4, 5 and 6.
  • 2-hydroxyphenyl boronic acid is commercially available (from Aldrich) as is 5-fluoro-2- hydroxyphenyl boronic acid (from Apollo or Combi Blocks).
  • the compounds of formula (NIb) can be prepared from the boronic acids of formula (VIb); these are either commercially available or can be prepared by standard methods well-known to the person skilled in the art.
  • the compound of formula (VIb) where R 1 is ethyl and R 2 is hydrogen may be prepared as described in WO2005019151.
  • Compounds of formula (VIb) where R 1 is propyl in a para position relative to the -OCH 2 - linker 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.
  • 2-hydroxy-phenylboronic acid and 5-methyl-2-methoxy-phenylboronic acid are commercially available from Aldrich.
  • 5-chloro-2-hydroxy-phenylboronic acid, 5-fluoro-2-hydroxy- phenylboronic acid and 5-trifluoromethyl-2-methoxy-phenylboronic acid are commercially available from Combi-blocks.
  • step (iii) the following general synthetic schemes can be used (Schemes 8, 9 and 10).
  • Scheme 9 The synthesis described in Scheme 9 relates to compounds wherein Z is absent and both J and L represent CH or J represents CH and L represents N and is particularly suitable for compounds wherein R 5 represents F or Cl.
  • the subsequent step (iv) may be carried out according to Scheme 11 a.
  • the temperature used in this ester hydrolysis reaction will depend on the nature of the compound and the length of time for which the reaction is performed; this will be well appreciated by the person skilled in the art.
  • ester hydrolysis reaction is instead suitably carried out using LiOH at room temperature to avoid hydrolysis of the cyano group to an amide group.
  • Scheme 13 is particularly suitable to prepare compounds wherein R 9 represents CN, Z is absent or Z represents O.
  • hal' is chloro or bromo if such compounds are commercially available. If not, then the corresponding compound wherein hal' is bromo may be used and may be prepared by standard methods. 2-chloro-5-chloromethylpyridine and 4-bromo-2-fluoro-benzyl bromide are both commercially available (from Aldrich). Other compounds of formula (VIII) may generally be prepared by the following methods (Schemes 14, 15 and 16) or by other standard methods well-known to the person skilled in the art.
  • Scheme 17 is particularly suitable for compounds wherein one of A, J or L represents N.
  • Pathway A is thus typically used where A represents N or L represents N; and pathway B is typically used where J represents N.
  • 2- methoxypyridine-5-boronic acid is available from Aldrich and 2-cyanopyridine-5-boronic acid and 2-trifluoromethylpyridine-5-boronic acid are available from Frontier; other compounds of formula (IX) not commercially available may be prepared by standard methods well-known to the person skilled in the art.
  • Certain compounds of formula (XV) are commercially available, for example: wherein J represents N, R 8 represents H and R 9 represents CN, CF 3 , COOR, Cl or OMe (Aldrich, Fluka or Acros); wherein J represents N, R 8 represents Cl and R 9 represents CF 3 (Aldrich).
  • Other compounds of formula (XV) may be prepared by standard methods well-known to the person skilled in the art.
  • Pathway B is also typically used where J and L both represent CH where hal represents Br.
  • Scheme 18b is particularly suitable.
  • Scheme 18c is particularly suitable.
  • R 35 represents H, Me, OMe.
  • Pathway B is thus typically used for A represents N or for A represents CH and hal represents F and R 5 represents H, Me, or OMe.
  • Phenol derivatives of formula (XIX) are commercially available or may be prepared by standard methods well-known to the person skilled in the art.
  • R 5 represents Cl or F:
  • Certain compounds of formula (XVII) are commercially available, for example: wherein hal represents Br or Cl, J represents N, R 8 represents H, and R 9 represents CN, CF 3 , COOR, Cl or OMe (Aldrich, Fluka or Acros); wherein hal represents Cl, J represents N, R 8 represents Cl, and R 9 represents CF 3 (Aldrich); wherein J represents CH, hal represents F, R 8 represents H, F, Cl, OMe, Me, or CF 3 , and R 9 represents CN or COOR (Aldrich, Acros, Apin).
  • Other compounds of formula (XVII) may be prepared by standard methods well-known to the person skilled in the art.
  • R 5 represents OC 1-4 alkyl or O(CH 2 ) 2 OMe:
  • MS mass spectra
  • MS mass spectra
  • Example 1 1 -(4-(5-methyl-2-(2-methyl-4-(4-cvano-2-methylphenyl)benzyloxy)- phenyl)pyrimidin-2-yl)-piperidine-4-carboxylic acid
  • 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 47 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.

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Abstract

L'invention porte sur des composés représentés par la formule (I) ou sur des sels de ceux-ci qui activent la guanylate cyclase soluble (GCs), sur des compositions pharmaceutiques les contenant, sur leur utilisation dans la fabrication d'un médicament pour le traitement de maladies cardiovasculaires et sur des procédés pour leur fabrication.
PCT/EP2009/060146 2008-08-07 2009-08-05 Dérivés de pyrimidine comme activateurs de guanylate cyclase soluble Ceased WO2010015653A1 (fr)

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US8569339B2 (en) 2011-03-10 2013-10-29 Boehringer Ingelheim International Gmbh Soluble guanylate cyclase activators
WO2014039434A1 (fr) * 2012-09-07 2014-03-13 Boehringer Ingelheim International Gmbh Alcoxypyrazoles comme activateurs de guanylate cyclase soluble
US8815857B2 (en) 2011-08-12 2014-08-26 Boehringer Ingelheim International Gmbh Soluble guanylate cyclase activators
WO2016042536A1 (fr) * 2014-09-19 2016-03-24 Glaxosmithkline Intellectual Property Development Limited Nouveaux activateurs de la guanylate cyclase soluble et leur utilisation
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
US10208018B2 (en) 2014-07-02 2019-02-19 Novartis Ag Indane and indoline derivatives and the use thereof as soluble guanylate cyclase activators
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
US12195448B2 (en) 2020-12-10 2025-01-14 Bayer Aktiengesellschaft Substituted pyrazolo piperidine carboxylic acids

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WO2000027394A1 (fr) * 1998-11-05 2000-05-18 University College London Activateurs de guanylate cyclase soluble
WO2009032249A1 (fr) * 2007-09-06 2009-03-12 Merck & Co., Inc. Activateurs de la guanylate cyclase soluble
WO2009068652A1 (fr) * 2007-11-30 2009-06-04 Smithkline Beecham Corporation Pyridines 2, 6-disubstituées et pyrimidines 2, 4-disubstituées en tant qu'activateurs de guanylate cyclase soluble
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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WO2000027394A1 (fr) * 1998-11-05 2000-05-18 University College London Activateurs de guanylate cyclase soluble
WO2009032249A1 (fr) * 2007-09-06 2009-03-12 Merck & Co., Inc. Activateurs de la guanylate cyclase soluble
WO2009068652A1 (fr) * 2007-11-30 2009-06-04 Smithkline Beecham Corporation Pyridines 2, 6-disubstituées et pyrimidines 2, 4-disubstituées en tant qu'activateurs de guanylate cyclase soluble
WO2009071504A1 (fr) * 2007-12-03 2009-06-11 Smithkline Beecham Corporation Pyridines 2,6-disubstituées comme activateurs de la guanylate cyclase soluble

Cited By (36)

* 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
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
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
KR20150048765A (ko) * 2012-09-07 2015-05-07 베링거 인겔하임 인터내셔날 게엠베하 가용성 구아닐레이트 사이클라제 활성제로서의 알콕시 피라졸
CN104619695A (zh) * 2012-09-07 2015-05-13 勃林格殷格翰国际有限公司 作为可溶性鸟苷酸环化酶活化剂的烷氧吡唑
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
WO2014039434A1 (fr) * 2012-09-07 2014-03-13 Boehringer Ingelheim International Gmbh Alcoxypyrazoles comme activateurs de guanylate cyclase soluble
KR101692707B1 (ko) 2012-09-07 2017-01-04 베링거 인겔하임 인터내셔날 게엠베하 가용성 구아닐레이트 사이클라제 활성제로서의 알콕시 피라졸
EA027244B1 (ru) * 2012-09-07 2017-07-31 Бёрингер Ингельхайм Интернациональ Гмбх Алкоксипиразолы в качестве активаторов растворимой гуанилатциклазы
US10550102B2 (en) 2014-07-02 2020-02-04 Novartis Ag Indane and indoline derivatives and the use thereof as soluble guanylate cyclase activators
US10208018B2 (en) 2014-07-02 2019-02-19 Novartis Ag Indane and indoline derivatives and the use thereof 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
WO2016042536A1 (fr) * 2014-09-19 2016-03-24 Glaxosmithkline Intellectual Property Development Limited Nouveaux activateurs de la guanylate cyclase soluble et leur utilisation
CN106687456B (zh) * 2014-09-19 2019-12-03 葛兰素史密斯克莱知识产权发展有限公司 可溶性鸟苷酸环化酶活化剂及它们的用途
AU2015319724B2 (en) * 2014-09-19 2018-05-10 Glaxosmithkline Intellectual Property Development Limited Novel soluble guanylate cyclase activators and their use
US9938260B2 (en) 2014-09-19 2018-04-10 Glaxosmithkline Intellectual Property Development Limited Soluble guanylate cyclase activators and their use
JP2017527602A (ja) * 2014-09-19 2017-09-21 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ 新規な可溶性グアニル酸シクラーゼ活性剤およびそれらの使用
JP2021155450A (ja) * 2014-09-19 2021-10-07 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited 新規な可溶性グアニル酸シクラーゼ活性剤およびそれらの使用
JP2020105189A (ja) * 2014-09-19 2020-07-09 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ 新規な可溶性グアニル酸シクラーゼ活性剤およびそれらの使用
CN106687456A (zh) * 2014-09-19 2017-05-17 葛兰素史密斯克莱知识产权发展有限公司 新的可溶性鸟苷酸环化酶活化剂及它们的用途
US10472350B2 (en) 2014-09-19 2019-11-12 Glaxosmithkline Intellectual Property Development Limited Soluble guanylate cyclase activators and their use
EA033697B1 (ru) * 2014-09-19 2019-11-18 Glaxosmithkline Ip Dev Ltd Активаторы растворимой гуанилатциклазы и их применение
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)
US12195448B2 (en) 2020-12-10 2025-01-14 Bayer Aktiengesellschaft Substituted pyrazolo piperidine carboxylic acids
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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