WO2009068652A1 - Pyridines 2, 6-disubstituées et pyrimidines 2, 4-disubstituées en tant qu'activateurs de guanylate cyclase soluble - Google Patents

Pyridines 2, 6-disubstituées et pyrimidines 2, 4-disubstituées en tant qu'activateurs de guanylate cyclase soluble Download PDF

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WO2009068652A1
WO2009068652A1 PCT/EP2008/066444 EP2008066444W WO2009068652A1 WO 2009068652 A1 WO2009068652 A1 WO 2009068652A1 EP 2008066444 W EP2008066444 W EP 2008066444W WO 2009068652 A1 WO2009068652 A1 WO 2009068652A1
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Prior art keywords
compound
formula
trifluoromethyl
carboxylic acid
pharmaceutically acceptable
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PCT/EP2008/066444
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English (en)
Inventor
Thierry Boyer
Nerina Dodic
Brian Evans
Barrie Edward Kirk
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Priority claimed from GB0723507A external-priority patent/GB0723507D0/en
Priority claimed from GB0812924A external-priority patent/GB0812924D0/en
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of WO2009068652A1 publication Critical patent/WO2009068652A1/fr
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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.
  • the novel compounds 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 dysfunction,
  • 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 novel compounds may be useful is congestive heart failure. Another particular disease or condition for which the novel compounds may be useful is peripheral vascular disease. Another particular disease or condition for which the novel compounds may be useful is arterial hypertension (also known as systemic hypertension). Another particular disease or condition for which the novel compounds may be useful is pulmonary arterial hypertension. Another particular disease or condition for which the novel compounds may be useful is angina.
  • the present invention provides a compound of formula (I)
  • n 1 or 2; each R 1 independently represents halo or trifluoromethyl; wherein halo represents fluoro, chloro or bromo;
  • R 2 represents hydrogen or C 1-3 alkyl
  • X represents N or CH; wherein -Z- represents a group selected from:
  • R 3 represents trifluoromethyl or Ci -3 alkyl
  • R 4 ⁇ represents hydrogen, trifluoromethyl or Ci_ 3 alkyl
  • -Z- can additionally represent a group selected from:
  • alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms.
  • alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms.
  • alkyl means a straight or branched alkyl containing at least 1 , and at most 3, carbon atoms and examples include methyl, ethyl, n-propyl, and isopropyl.
  • pharmaceutically acceptable means a compound which is suitable for pharmaceutical use.
  • each R 1 independently represents halo.
  • n represents 2 and both R 1 groups independently represent halo.
  • n represents 2 and both R 1 groups represent chloro.
  • each R 1 independently represents trifluoromethyl. In an embodiment n represents 2 and both R 1 groups represent trifluoromethyl. In an embodiment n represents 1 and the R 1 group represents trifluoromethyl.
  • R 1 group(s) together with the phenyl ring to which they are attached represent 2,3-dichlorophenyl, 3,4-dichlorophenyl, or 3,5-dichlorophenyl.
  • R 1 group(s) together with the phenyl ring to which they are attached represent 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, or 4-bromo-3-fluorophenyl.
  • R 1 group(s) together with the phenyl ring to which they are attached represent 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, or 3,5-bis(trifluoromethyl)phenyl.
  • R 1 group(s) together with the phenyl ring to which they are attached represent 3,4-dichlorophenyl.
  • R 1 group(s) together with the phenyl ring to which they are attached represent 3-trifluoromethylphenyl.
  • R 2 represents hydrogen or methyl
  • X represents CH and R 2 represents hydrogen or methyl. In an embodiment X represents N and R 2 represents hydrogen.
  • R 3 represents trifluoromethyl
  • R 4 represents hydrogen or methyl.
  • Z represents the pyrazole group illustrated above.
  • Z represents the pyrazole group illustrated above, X represents CH or N, R 2 represents hydrogen, R 3 represents trifluoromethyl and the R 1 group(s) together with the phenyl ring to which they are attached represent 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5- dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, 4-bromo-3-fluorophenyl, A- trifluoromethylphenyl, 3-trifluoromethylphenyl, or 3,5-bis(trifluoromethyl)phenyl.
  • Z represents the pyrrole group illustrated above.
  • Z represents the pyrrole group illustrated above, X represents CH or N, R 2 represents hydrogen or methyl, R 4 represents hydrogen or methyl, and the R 1 group(s) together with the phenyl ring to which they are attached represent 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5- dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, 4-bromo-3-fluorophenyl, A- trifluoromethylphenyl, 3-trifluoromethylphenyl, or 3,5-bis(trifluoromethyl)phenyl; in an embodiment the R 1 group(s) together with the phenyl ring to which they are attached represent 3,4-dichlorophenyl.
  • Z represents the thiophene group illustrated above.
  • Z represents the thiophene group illustrated above
  • X represents CH or N
  • R 2 represents hydrogen
  • the R 1 group(s) together with the phenyl ring to which they are attached represent 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl, 3- chloro-4-fluorophenyl, 4-bromo-3-fluorophenyl, 4-trifluoromethylphenyl, 3- trifluoromethylphenyl, or 3,5-bis(trifluoromethyl)phenyl; in an embodiment the R 1 group(s) together with the phenyl ring to which they are attached represent 3-trifluoromethylphenyl.
  • Z represents the piperidine group illustrated above.
  • X represents CH
  • R 2 represents hydrogen
  • the R 1 group(s) together with the phenyl ring to which they are attached represent 2,3- dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4- fluorophenyl, 4-bromo-3-fluorophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, or 3,5-bis(trifluoromethyl)phenyl.
  • Z represents the phenoxy group illustrated above.
  • Z represents the phenoxy group illustrated above
  • X represents CH
  • R 2 represents hydrogen
  • the R 1 group(s) together with the phenyl ring to which they are attached represent 2,3- dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4- fluorophenyl, 4-bromo-3-fluorophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, or 3,5-bis(trifluoromethyl)phenyl.
  • a compound of formula (I) as defined above selected from: 1-(6-(3,4-dichlorophenyl)-pyridin-2-yl)-pyrrole-3-carboxylic acid;
  • 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 or associated solvents 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.
  • Also included within the scope of the invention are solvates (including hydrates) of salts of the compounds of formula (I).
  • 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 suitable organic acid such as succinic, maleic, malic, mandelic, formic, acetic, propionic, hex
  • 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 ammonia, 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 ammonia, 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 (including zwitterionic salts), which salts are also included within the scope of the present invention.
  • the carboxylic acid function attached to the group Y may be a suitable candidate for pro-drug functionality, for example by formation of appropriate esters or amides.
  • certain moieties known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in "Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of formula (I)-
  • a compound of formula (I) (whether in solvated or unsolvated form) or a pharmaceutically acceptable salt thereof (whether in solvated or unsolvated form) defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "a compound 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.
  • a compound of the invention as an activator of sGC, may be useful in the treatment of a disease or condition which is mediated by sGC activity.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, together with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
  • the carrier(s), diluent(s) and/or excipient(s) must each be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • a pharmaceutical composition comprising a) 0.1 mg to 1000 mg of a compound of the invention and b) 0.1g to 2g of one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
  • 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 a pharmaceutical composition as defined above for use in therapy; in an embodiment the therapy is human therapy. According to a further aspect the invention provides a compound of the invention or a pharmaceutical composition as defined above for use in the treatment of a disease or condition mediated by sGC activity.
  • the invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.
  • the invention provides a compound of the invention or a pharmaceutical composition as defined above for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.
  • the invention provides the use of a compound of the invention for the preparation of a medicament for treating a disease or condition mediated by sGC activity.
  • the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.
  • the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.
  • the invention provides a method of treatment of a disease or condition which is mediated by the activity of sGC, in an embodiment arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome 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 as defined above.
  • sGC in an embodiment arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis
  • the invention provides a method of treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease 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.
  • a compound 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.
  • each compound may differ from that when the compound is used alone.
  • 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.
  • the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • references herein to "treat”, “treating” or “treatment” extend to prevention of recurrence of symptoms (whether mild, moderate or severe) and to 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. 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 age and the condition of the patient and will be ultimately at the discretion of the attendant physician, 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.
  • Each dosage unit for oral administration typically contains for example from 0.5 to 250 mg (and for parenteral administration contains for example from 0.05 to 25 mg) of a compound of the invention calculated as the compound of formula (I).
  • a compound of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 1000 mg, for example between 1 mg and 500 mg, e.g. between 5 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, for example between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of formula (I) or a salt thereof calculated as the compound of formula (I), the compound of the invention being administered 1 to 4 times per day, for example 1 to 2 times a day.
  • a compound of the invention may be administered once a day.
  • a compound of the invention will be administered for a period of continuous therapy, for example for a week or more.
  • 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.
  • R 1 , R 2 , R 3 , X, and n are as defined above and P represents a carboxylic acid protecting group, for example Ci -6 alkyl or benzyl, such that together with the carboxylic acid residue an ester is formed.
  • P represents a carboxylic acid protecting group, for example Ci -6 alkyl or benzyl, such that together with the carboxylic acid residue an ester is formed.
  • Suitable protecting groups and deprotection methods are, for example given in T. W. Greene, 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 1991 ).
  • Alkyl ester carboxylic acid protection can be removed, for example, by treatment with mineral base such a potassium hydroxide at an elevated temperature such as reflux in a suitable solvent, for example an alcohol such as ethanol.
  • R 2 , R 3 , X and P' are as defined above and L is halo, such as chlorine or bromine, with a compound of formula (IV) wherein R 1 and n are as defined above.
  • the reaction is typically carried out under nitrogen in a suitable solvent, such as dioxan and water, in the presence of a base, such as sodium carbonate, and a suitable catalyst, such as tetrakis(triphenylphosphine)palladium(0) or trans dichloro(tricyclohexylphosphine)palladium(l l) at elevated temperature, suitably 100 0 C.
  • a suitable solvent such as dioxan and water
  • a base such as sodium carbonate
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium(0) or trans dichloro(tricyclohexylphosphine)palladium(l l) at elevated temperature, suitably 100 0 C.
  • R 3 and P' are as defined above and R 6 is C h alky!.
  • the reaction is typically carried out by adding a solution of compound (Vl) in a suitable solvent (for example anhydrous tetrahydrofuran; adding dropwise under nitrogen at -15 0 C) to a solution of compound (V) in a suitable solvent (for example anhydrous tetrahydrofuran) followed by stirring at room temperature, suitably for between 4 to 24 hours.
  • a suitable solvent for example anhydrous tetrahydrofuran
  • R 2 , X and L are as defined above and L' is a halogen atom, such as chlorine or bromine.
  • L' is a halogen atom, such as chlorine or bromine.
  • R 1 , R 2 , R 4 , X, and n are as defined above and P represents a carboxylic acid protecting group, for example C 1-6 alkyl or benzyl, such that together with the carboxylic acid residue an ester is formed.
  • R 2 , R 4 , X and P' are as defined above and L is halo, such as chlorine or bromine, with a compound of formula (VIII) wherein R 4 is defined above.
  • the reaction is typically carried out under nitrogen in a suitable solvent, such as dioxane and water, in the presence of a base, such as tripotasium phosphate or sodium carbonate, and a suitable catalyst, such as [1 ,1 '-Bis(diphenylphosphino)ferrocene] dichloropalladium(ll) or tetrakis(triphenylphosphine)palladium(0) at elevated temperature, suitably 100 0 C up to 150 0 C.
  • a suitable solvent such as dioxane and water
  • a base such as tripotasium phosphate or sodium carbonate
  • a suitable catalyst such as [1 ,1 '-Bis(diphenylphosphino)ferrocene] dichloropalladium(ll) or tetrakis(triphenylphosphine)palladium(0) at elevated temperature, suitably 100 0 C up to 150 0 C.
  • Compounds of formula (HIB) may be prepared by reaction of a compound of formula (VII), wherein R 2 , X and L are as defined above and L' is a halogen atom, such as chlorine or bromine, with a compound of formula (VIII) wherein R 4 and P' are as defined above.
  • the reaction is typically carried out in a suitable solvent, such as DMF, in the presence of a base, such as sodium carbonate or cesium carbonate, at elevated temperature, suitably 100 0 C up to 130 0 C.
  • a suitable solvent such as DMF
  • a base such as sodium carbonate or cesium carbonate
  • Compounds of formula (IC) wherein Z represents the thiophene group and X represents CH as defined above can be prepared by reaction of 5-carboxy-thiophene-2-boronic acid with a compound of formula (NIC).
  • the reaction is typically carried out under nitrogen in a suitable solvent, such as dimethoxyethane and water, in the presence of a base, such as sodium carbonate and a suitable catalyst, such as tetrakis(triphenylphosphine) palladium(O) at elevated temperature, suitably 100 0 C.
  • R 1 and n are as defined above and P represents a carboxylic acid protecting group, for example Ci_s alkyl, such that together with the carboxylic acid residue an ester is formed.
  • P represents a carboxylic acid protecting group, for example Ci_s alkyl, such that together with the carboxylic acid residue an ester is formed.
  • Compounds of formula (ND) may be prepared by reaction of compounds of formula (IX), lic acid protecting group, for example Ci -6 alkyl,
  • R 1 , R 2 , X, and n are as defined above and P represents a carboxylic acid protecting group, for example C 1-6 alkyl or benzyl, such that together with the carboxylic acid residue an ester is formed.
  • Compounds of formula (NE) may be prepared by reaction of a compound of formula (NIE), wherein R 2 , X and L are as defined above and L is a halogen atom, such as chlorine or bromine, with a compound of formula (IV) wherein R 1 and n are as defined above.
  • NAME Compounds of formula (NIE) may be prepared by reaction of a compound of formula (Xl), wherein P is defined above, with a compound of formula (VII) wherein R 2 , X and L are as defined above and L' is a halogen atom, such as chlorine or bromine.
  • the reaction is typically carried out in a suitable solvent, such as dimethylformamide, in the presence of a base, such as cesium carbonate, at elevated temperature, suitably 12O 0 C.
  • a suitable solvent such as dimethylformamide
  • a base such as cesium carbonate
  • R 1 , R 2 and n are as defined above, and P represents a carboxylic acid protecting group, for example C 1-6 alkyl or benzyl, such that together with the carboxylic acid residue an ester is formed.
  • P represents a carboxylic acid protecting group, for example C 1-6 alkyl or benzyl, such that together with the carboxylic acid residue an ester is formed.
  • Compounds of formula (NF) can be prepared by reaction of compounds of formula (IMF) wherein R 2 , L and P are defined above, with a compound of formula (IV) wherein R 1 and n are as defined above.
  • Compounds of formula (IMF) may be prepared by reaction of a compound of formula (XIII), wherein P is defined above, with a compound of formula (VII) wherein X represents CH, and wherein R 2 and L are as defined above and L' is a halogen atom, such as chlorine or bromine.
  • the reaction is typically carried out in a suitable solvent, such as DMF, in the presence of a base, such as sodium carbonate or cesium carbonate, at elevated temperature, suitably 100 0 C up to 130 0 C.
  • a suitable solvent such as DMF
  • a base such as sodium carbonate or cesium carbonate
  • LCMS Liquid Chromatography Mass Spectroscopy
  • Method A LCMS was conducted using a Waters ZQ mass spectrometer operating in positive ion or negative ion electrospray mode, mass range 100-1000 amu.
  • UV wavelength 215- 330nm
  • column 3.3cm x 4.6mm ID, 3 ⁇ m ABZ+PLUS
  • flow rate 3ml/min
  • injection volume 5 ⁇ l.
  • Solvent A 95% acetonitrile + 5% of a 1% v/v solution of formic acid in water.
  • Solvent B 0.1% v/v solution of formic acid in 1 OmM aqueous ammonium acetate.
  • the preparative column used was typically a Supelcosil ABZplus (10cm x 2.12cm internal diameter; particle size 5 ⁇ m); UV detection wavelength: 200-320nm; flow rate: 20ml/min; injection volume: 0.5ml.
  • Solvent A 0.1% v/v solution of formic acid in water.
  • Solvent B 95% acetonitrile + 5% of a 1 % v/v solution of formic acid in water
  • Method B the mass spectra (MS) were recorded on a micromass ZQ-LC mass spectrometer using electrospray positive ionisation [ES+ve to give MH + molecular ion] or electrospray negative ionisation [ES-ve to give (M-H) " molecular ion] modes.
  • Analytical HPLC was conducted on a X-terra MS C18 column (3 x 30 mm internal diameter, particule size 2,5 ⁇ m), eluting with 0,01 M ammonium acetate in water (solvent A) and 100% acetonitrile using the following elution gradient: 0-4 minutes, 5 to 100% B; 4-5 minutes, 100%B at a flow rate of 1 ,1 mL/min at 40 0 C.
  • LC-HRMS Liquid Chromatography - High-resolution mass spectroscopy
  • Analytical HPLC was conducted on a LUNA 3u C18 column (30 x 3 mm internal diameter, particule size 2,5 ⁇ m). eluting with 0,01 M ammonium acetate in water (solvent A) and 100% acetonitrile (solvent B) using the following elution gradient: 0-0,5 minutes, 5%B; 0,5-3,5 minutes, 5 to 100%B; 3,5-4 minutes, 100%B; 4-4,5 minutes, 100 to 5%B; 4,5-5,5 minutes, 5%B at a flowrate of 1 ,3 mL/min with a temperature of 40 0 C.
  • MS mass spectra
  • Ethyl (2Z)-3-(ethyloxy)-2-(trifluoroacetyl)-2-propenoate (Aldrich, 1.32g, 0.0055 mol) was added in a solution of ethanol (25 ml) to a solution of 2-bromo-6-hydrazinopyridine (D5, 0.94g, 0.005 mol) in ethanol (25 ml) containing diisopropylethylamine (0.92 ml, 0.0055 mol) at -2O 0 C over a 30 minute period.
  • the solution was allowed to slowly warm to room temperature and stirred for a further 2 hours.
  • the orange solution was evaporated to an orange-red gum.
  • Example 1 1 -f6-(3,4-dichlorophenyl)-2-pyridinvn-5-(trifluoromethyl)-1 H-pyrazole-4- carboxylic acid
  • Ethyl 1-(6-bromo-2-pyridinyl)-5-(trifluoromethyl)-1/-/-pyrazole-4-carboxylate (D6, 100mg, 0.275mmol) and 4-(trifluoromethyl)phenylboronic acid (Aldrich, 52mg, 0.275mmol) were stirred in dioxan (1.5ml). A solution of sodium carbonate (58mg, 0.549mmol) in water (1.5ml) was added and the solution degassed with nitrogen. Tetrakis(triphenylphosphine)palladium (0) (20mg) was added and the mixture stirred and heated at 100 0 C for 18 hours, under nitrogen.
  • Example 3 Using a similar procedure to that of Example 2, using the appropriately substituted phenylboronic acid (all available from Aldrich with the exception of 4-bromo-3-fluorophenyl boronic acid which is available from Lancaster Synthesis Ltd), the following Examples 3 to 9 were prepared.
  • Example 6 1 -f6-r3.5-bis(trifluoromethyl)phenvn-2-pyridinyl)-5-(trifluoromethyl)-1 H- pyrazole-4-carboxylic acid
  • Example 8 1 -f6-(4-bromo-3-fluorophenyl)-2-pyridinvn-5-(trifluoromethyl)-1 H- pyrazole-4-carboxylic acid
  • Example 10 1 -f6-(3,4-dichlorophenyl)-4-methyl-2-pyridinvn-5-(trifluoromethyl)-1 H- pyrazole-4-carboxylic acid
  • Example 16 1 -r2-(3,4-dichlorophenyl)-4-pyrimidinvn-5-(trifluoromethyl)-1H-pyrazole-4- carboxylic acid
  • soluble guanylate cyclase sGC
  • FP fluorescence polarisation
  • 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 a 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 a 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 18 gave pEC500 values of greater than 5.
  • the compounds of the invention give a pEC500 value of ⁇ 5.5 when tested in this assay.
  • the compounds of the invention give a pEC500 value of ⁇ 6 when tested in this assay.

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Abstract

L'invention porte sur des composés représentés par la formule (I) : dans laquelle n représente 1 ou 2; les R1 représentent chacun indépendamment halo ou trifluorométhyle; où halo représente fluoro, chloro ou bromo; R2 représente hydrogène ou alkyle en C1-3; X représente N ou CH; où -Z- représente un groupe choisi parmi : (formule) où R3 représente trifluorométhyle ou alkyle en C1-3; et R4 représente hydrogène, trifluorométhyle ou alkyle en C1-3; à la condition que, si Z représente un groupe thiophène et X représente N, R2 ne puisse pas représenter alkyle en C1-3; et lorsque X représente CH, -Z- puisse en outre représenter un groupe choisi parmi (formule), ou des sels de ceux-ci qui activent la guanylate cyclase soluble (sGC). L'invention porte également sur des compositions pharmaceutiques contenant ces composés, sur l'utilisation de ces composés en médecine et sur des procédés permettant de les préparer.
PCT/EP2008/066444 2007-11-30 2008-11-28 Pyridines 2, 6-disubstituées et pyrimidines 2, 4-disubstituées en tant qu'activateurs de guanylate cyclase soluble Ceased WO2009068652A1 (fr)

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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
WO2010015653A1 (fr) * 2008-08-07 2010-02-11 Smithkline Beecham Corporation Dérivés de pyrimidine comme activateurs de guanylate cyclase soluble
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