WO2016091042A1 - 吡啶甲酰胺类衍生物、其制备方法及其在医药上的应用 - Google Patents
吡啶甲酰胺类衍生物、其制备方法及其在医药上的应用 Download PDFInfo
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- WO2016091042A1 WO2016091042A1 PCT/CN2015/094164 CN2015094164W WO2016091042A1 WO 2016091042 A1 WO2016091042 A1 WO 2016091042A1 CN 2015094164 W CN2015094164 W CN 2015094164W WO 2016091042 A1 WO2016091042 A1 WO 2016091042A1
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- IUZUNEYDOGGCHP-QFIPXVFZSA-N CCOc1cc(C(NC2CCN(C[C@@H](c(c(C)c3CO4)ccc3C4=O)O)CC2)=O)ncc1C#N Chemical compound CCOc1cc(C(NC2CCN(C[C@@H](c(c(C)c3CO4)ccc3C4=O)O)CC2)=O)ncc1C#N IUZUNEYDOGGCHP-QFIPXVFZSA-N 0.000 description 1
- PJJXLIVFRBOUIZ-NRFANRHFSA-N Cc1c(COC2=O)c2ccc1[C@H](CN(CC1)CCC1NC(c(cc1OC)ncc1C#N)=O)O Chemical compound Cc1c(COC2=O)c2ccc1[C@H](CN(CC1)CCC1NC(c(cc1OC)ncc1C#N)=O)O PJJXLIVFRBOUIZ-NRFANRHFSA-N 0.000 description 1
- OWGFVSKANOGPOX-FQEVSTJZSA-N Cc1c([C@H](CN(CC2)CCC2NC(c(cc2OC(F)F)ncc2C#N)=O)O)ccc2c1COC2=O Chemical compound Cc1c([C@H](CN(CC2)CCC2NC(c(cc2OC(F)F)ncc2C#N)=O)O)ccc2c1COC2=O OWGFVSKANOGPOX-FQEVSTJZSA-N 0.000 description 1
- CTVIBPMEQBNGHL-QFIPXVFZSA-N Cc1c([C@H](CN(CC2)CCC2NC(c(cc2OCCF)ncc2C#N)=O)O)ccc2c1COC2=O Chemical compound Cc1c([C@H](CN(CC2)CCC2NC(c(cc2OCCF)ncc2C#N)=O)O)ccc2c1COC2=O CTVIBPMEQBNGHL-QFIPXVFZSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the present invention relates to a class of pyridine carboxamide derivatives, a process for their preparation and pharmaceutical compositions containing the same, and their use as therapeutic agents, in particular as inhibitors of extrarenal medulla secretory potassium channel (ROMK) And its use in the manufacture of a medicament for the treatment and/or prevention of disorders caused by excessive salt and water retention, including hypertension and heart failure.
- ROMK extrarenal medulla secretory potassium channel
- the renal outer medullary potassium channel is also called inward-rectifying potassium channel 1.1 (Kir1.1).
- the ROMK ion channel can coordinate with the Na+-K+-2Cl-cotransporter NKCC2 (responsible for NaCl transport) to regulate Na+ reabsorption through the membranous membrane conductance of the renal medullary ascending segment (TAL).
- TAL renal medullary ascending segment
- Batter syndrome is an autosomal recessive hereditary disease characterized by massive loss of salt in the kidneys, hypokalemia, and low blood pressure.
- Paramyelocytic hyperplasia is mainly caused by mutation of ROMK or Na + -K + -2Cl - cotransporter, except that hypokalemia caused by rotaside cell hyperplasia caused by ROMK mutation is better than Na + -K + - Parathyroid cell hyperplasia induced by 2Cl - cotransporter mutations is greatly alleviated.
- ROMK suppression function may without causing hypokalemia, effective to inhibit Na + -K + -2Cl - transporter salt reabsorption promoting excretion of urine, functions as a diuretic antihypertensive efficacy.
- a series of compounds of the ROMK inhibitor have been disclosed, including patent applications such as WO2010129379, WO2012058134, WO2012058116, WO2012058134, WO2013066714, WO2013028474, WO2014085210, WO2014018764, WO2014015495, WO2014085210, WO2013039802, WO2013062892 and WO2012058116, but still need to be developed hERG selective compound.
- the invention designs a compound having the structure represented by the general formula (I), increases the polar group, reduces the ClogP on the basis of maintaining the ROMK inhibitory activity, improves the hERG selectivity, and increases the safety.
- R 1 is an alkyl group, wherein the alkyl group is optionally further selected from one of a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group, and a carboxylate group. Substituted by a plurality of substituents;
- R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a cyano group, a nitro group, an alkoxy group, a cycloalkyl group, and a heterocyclic group, wherein the alkyl alkoxy group, cycloalkyl group or heterocyclic group is optionally further Substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid, and carboxylic acid esters;
- R 3 is selected from the group consisting of:
- R 4 or R 5 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a cyano group, a nitro group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
- R 6 is selected from a hydrogen atom, an alkyl group, and a halogen
- n 0, 1, or 2.
- a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 1 is an alkyl group, wherein the alkyl group is optionally further substituted selected from halogen, hydroxy and alkoxy of one or more substituents; R 1 is preferably a C 1-6 alkyl group, more preferably a methyl group, an ethyl group or a propyl group.
- a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 4 is an alkyl group, and R 5 is a hydrogen atom.
- a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (II):
- R 1 , R 2 , R 4 , n are as defined in formula (I).
- a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (III):
- R 1 , R 2 , R 4 , n are as defined in formula (I).
- a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (IV):
- R 1 , R 2 , R 3 , n are as defined in formula (I).
- a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (V):
- R 1 , R 2 , R 4 , n are as defined in formula (I).
- a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (VI):
- R 1 , R 2 , R 4 , n are as defined in formula (I).
- Typical compounds of the invention include, but are not limited to:
- a tautomer a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
- the present invention also provides a compound of the formula (IA) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof. Or a pharmaceutically acceptable salt thereof, as an intermediate for the preparation of a compound of the formula (I):
- R 1 is an alkyl group, wherein the alkyl group is optionally further selected from one of a halogen, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group, and a carboxylate group. Substituted by a plurality of substituents;
- R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogen, a cyano group, a nitro group, an alkoxy group, a cycloalkyl group, and a heterocyclic group, wherein the alkyl group, alkoxy group, cycloalkyl group or heterocyclic group is optionally further Substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, and carboxylate; Can be used to prepare a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or An intermediate of a pharmaceutically acceptable salt;
- n 0, 1, or 2.
- a compound represented by the formula (IA) or a tautomer thereof, internal elimination a compound represented by the formula (IVA), which is a form of a compound of the formula (IVA): a form of a compound of the formula (IVA): a compound, a pharmaceutically acceptable salt, or a mixture thereof;
- a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof a compound represented by IV) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof
- An intermediate wherein: R 1 , R 2 , n are as defined in formula (IA).
- Typical compounds of the compounds of formula (IA) include, but are not limited to:
- a tautomer a meso form, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
- the present invention also provides a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof. a method of form, or a pharmaceutically acceptable salt thereof, the method comprising:
- R 1 -R 3 , n are as defined in the formula (I).
- the invention further relates to a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount such as a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable compound thereof Salts and pharmaceutically acceptable carriers, diluents or excipients.
- the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a ROMK inhibitor.
- the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating or preventing hypertension or heart failure.
- the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or Use of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating or preventing a ROMK-mediated disease, including but not limited to liver cirrhosis, acute and chronic renal insufficiency, nephropathy Syndrome, pulmonary hypertension, cardiovascular disease, myocardial infarction, stroke, cardiac insufficiency, excessive pulmonary tension, atherosclerosis and kidney stones.
- a ROMK-mediated disease including but not limited to liver cirrhosis, acute and chronic renal insufficiency, nephropathy Syndrome, pulmonary hypertension, cardiovascular disease, myocardial infarction, stroke, cardiac insufficiency, excessive pulmonary tension, atherosclerosis and kidney stones.
- the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a ROMK inhibitor.
- the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment or prevention of hypertension or heart failure.
- the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment or prevention of a ROMK-mediated disease, preferably selected from the group consisting of cirrhosis, acute and chronic renal insufficiency, nephrotic syndrome, pulmonary artery Hypertension, cardiovascular disease, myocardial infarction, stroke, cardiac insufficiency, excessive pulmonary tension, atherosclerosis and kidney stones.
- a ROMK-mediated disease preferably selected from the group consisting of cirrhosis, acute and chronic renal insufficiency, nephrotic syndrome, pulmonary artery Hypertension, cardiovascular disease, myocardial infarction, stroke, cardiac insufficiency, excessive pulmonary tension, atherosclerosis and kidney stones.
- the present invention also relates to a method of inhibiting ROMK comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof. Isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
- the invention also relates to a method of treating or preventing hypertension and/or heart failure comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a mesogen thereof , a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
- the present invention relates to a method for treating or preventing a ROMK-mediated disease or condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen thereof, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a
- the pharmaceutical composition is preferably selected from the group consisting of cirrhosis, acute and chronic renal insufficiency, nephrotic syndrome, pulmonary hypertension, cardiovascular disease, myocardial infarction, stroke, cardiac insufficiency, hypertonic tone, arteries. Atherosclerosis and kidney stones.
- the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
- Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture.
- excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc.
- These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
- water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
- hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
- Soft gelatin capsules provide oral preparations.
- the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
- excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols
- the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
- preservatives such as ethylparaben or n-propylparaben
- coloring agents such as ethylparaben or n-propylparaben
- flavoring agents such as sucrose, saccharin or aspartame.
- the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
- the above sweeteners and flavoring agents may be added to provide a palatable preparation.
- These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.
- the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
- the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
- the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
- Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
- the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
- Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
- sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
- the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
- the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
- the active ingredient is dissolved in a mixture of soybean oil and lecithin.
- the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
- the injection or microemulsion can be injected into the bloodstream of the patient by a local injection.
- the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
- a continuous intravenous delivery device can be used.
- An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.
- the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
- the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent.
- sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
- fatty acids such as oleic acid can also be prepared as an injection.
- the compounds of the invention may be administered in the form of a suppository for rectal administration.
- These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
- suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
- the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; additionally, the preferred mode of treatment, such as the mode of treatment, the daily dose of the compound of formula (I) or the type of pharmaceutically acceptable salt It can be verified according to traditional treatment options.
- Alkyl means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, and an alkyl group having 1 to 6 carbon atoms is more preferred.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl , 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Pentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
- lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
- the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle
- alkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl, and carboxylate groups preferably selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl,
- Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 10 The carbon atom, most preferably the cycloalkyl ring contains from 3 to 6 carbon atoms.
- Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene
- the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
- Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
- Spirocycloalkyl means a polycyclic group of 5 to 20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring.
- spirocycloalkyl groups include
- fused cycloalkyl means 5 to 20 members, each ring of the system sharing an adjacent carbon atomous all-carbon polycyclic group with other rings in the system, wherein one or more rings may contain one or more Double keys, but no One ring has a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
- fused cycloalkyl groups include
- Bridge cycloalkyl means 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The ⁇ -electron system of the yoke. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
- bridged cycloalkyl groups include
- the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
- the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, Hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino One or more groups of haloalkyl, hydroxyalkyl, carboxyl and carboxylate groups.
- Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) m ( Wherein m is a hetero atom of 0 to 2, but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
- the heterocyclic ring comprises 3 to 12 ring atoms, wherein 1 to 4 are hetero atoms; more preferably, the heterocyclic ring contains 3 to 10 ring atoms, of which 1 to 3 are hetero atoms; more preferably, the heterocyclic ring contains 5 to 6 ring atoms, of which 1 to 2 are heteroatoms.
- monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
- Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
- “Spiroheterocyclyl” means a polycyclic heterocyclic group of 5 to 20 members in which one atom (referred to as a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m
- the hetero atom (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispirocyclic heterocyclic group or a polyspirocyclic group, preferably a monospiroheterocyclic group and a dispiroheterocyclic group, depending on the number of common spiro atoms between the ring and the ring. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
- Non-limiting examples of spiroheterocyclyl groups include
- “Fused heterocyclyl” refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atoms of a polycyclic heterocyclic group with other rings in the system, and one or more rings may contain one or more a bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
- fused heterocyclic groups include
- “Bridge heterocyclyl” refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, these may contain one or more double bonds, but none of the rings have a complete conjugation A ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- bridged heterocyclic groups include:
- the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:
- the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from an alkyl group, Alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy One or more groups of a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, an amino group, a halogenated alkyl group, a hydroxyalkyl group, a carboxyl group, and a carboxylate group.
- Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably benzene.
- the base and naphthyl are most preferably phenyl.
- the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
- the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro , cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl
- the substituent is preferably selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro , cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclo
- Heteroaryl refers to a 5 to 14 membered aryl group having from 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 5 to 10 yuan.
- the heteroaryl group is preferably 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
- the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:
- the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, Hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, One or more groups of a hydroxyalkyl group, a carboxyl group, and a carboxylate group.
- Alkoxy means -O-(alkyl) and -O-(unsubstituted cycloalkyl) wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
- the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a sulfhydryl group, Hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane
- Haloalkyl means an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
- Hydrophilicity refers to an -OH group.
- Hydroalkyl means an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.
- Halogen means fluoro, chloro, bromo or iodo.
- Carboxy refers to -C(O)OH.
- Carboxylic acid ester group means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
- heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
- Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
- “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and Shape agent.
- the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
- R 1 to R 3 and n are as defined in the formula (I).
- R 1 , R 2 , R 4 , n are as defined in the formula (II).
- R 1 , R 2 , R 4 , n are as defined in formula (III).
- R 1 to R 3 and n are as defined in the formula (I).
- R 1 , R 2 , R 4 , n are as defined in the formula (I).
- R 1 , R 2 , R 4 , n are as defined in formula (I).
- Solvents used include, but are not limited to, acetic acid, methanol, ethanol, acetonitrile, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylacetamide or N, N-dimethylformamide is preferably a non-polar solvent, more preferably acetonitrile.
- FIG. 5 Effect of ROMK inhibitor on serum potassium in SD rats.
- the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
- NMR nuclear magnetic resonance
- MS mass spectrometry
- the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
- DMSO-d 6 dimethyl sulfoxide
- CDCl 3 deuterated chloroform
- CD 3 OD deuterated methanol
- TMS Methylsilane
- chemical shifts are given in units of 10 -6 (ppm).
- the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
- ESI FINNIGAN LCQAd
- Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
- the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
- the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm silica gel plate.
- the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.
- An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
- the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
- the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
- the solution in the reaction means an aqueous solution unless otherwise specified.
- the temperature of the reaction was room temperature unless otherwise specified.
- Room temperature is the most suitable reaction temperature, and the temperature range is from 20 ° C to 30 ° C.
- the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
- TLC thin layer chromatography
- the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
- the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane and acetone
- the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
- 6-chloro-4-ethoxynicotinonitrile 2b (375 mg, 2.05 mmol), 4-aminopiperidine-1-carboxylic acid tert-butyl ester (422 mg, 2.05 mmol), palladium acetate (23 mg, 0.1 mmol) , 1,3-bis(diphenylphosphino)propane (42 mg, 0.1 mmol), triethylamine (0.57 mL, 4.1 mmol) and 20 mL of acetonitrile, three times of carbon monoxide, pressure 10 bar, warmed to 80 ° C, stirring reaction 16 hours. The reaction mixture was filtered, and the filtrate was evaporated to dryness. Pyridine carboxamide) piperidine-1-carboxylic acid tert-butyl ester 2c (645 mg, white solid).
- 6-chloro-4-(2-fluoroethoxy)nicotinonitrile 3a (210 mg, 1.05 mmol), 4-aminopiperidine-1-carboxylic acid tert-butyl ester (216 mg, 1.05 mmol), palladium acetate (12 mg, 0.05 mmol), 1,3-bis(diphenylphosphino)propane (22 mg, 0.05 mmol), triethylamine (0.29 mL, 2.1 mmol) and 20 mL of acetonitrile, three times of carbon monoxide, at a pressure of 10 bar, warmed to The reaction was stirred at 80 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj - tert-butyl formate 3b (140 mg, white solid), yield 34%.
- 2-Bromo-5-chloropyridine 4a (2 g, 10.4 mmol) was dissolved in 40 mL of tetrahydrofuran and added dropwise at -78 °C. 7.8 mL of a 2 M lithium diisopropylamide solution was stirred for 1 hour, triisopropyl borate (2.94 g, 15.6 mmol) was added, stirred for 30 minutes, warmed to room temperature, and the reaction was stirred for 16 hours.
- Test Example 1 Determination of ROMK inhibitory activity of human ROMK and rat (rat) by the compound of the present invention
- Human ROMK/HEK293 cells transfected with human ROMK cDNA (NCBI SEQ ID NO: NM_000220.4) and HEK293 cell line stably expressing ROMK channel
- Rat ROMK/HEK293 cells transfected with rat ROMK cDNA (NCBI SEQ ID NO: NM_017023.1) and HEK293 cell line stably expressing ROMK channel
- HEK293 cell line Cell Bank of Chinese Academy of Sciences, GNHu43
- the inhibitory activity of the compound of the present invention against human ROMK or rat ROMK was measured by the above test, and the measured IC 50 values are shown in Table 1.
- the compound of the present invention has a significant inhibitory effect on the activity of human ROMK or rat ROMK channel, and the compound has high pharmacological effect.
- Test Example 2 Determination of hERG inhibitory activity of the compound of the present invention
- hERG/HEK293 cells transfected with human hERG cDNA (NCBI SEQ ID NO: NM_000238 (RC215928, origene)) and HEK293 cell line stably expressing hERG channel
- the inhibitory activity of the compound of the present invention on hERG was measured by the above test, and the measured IC 50 values are shown in Table 2.
- the compounds of the present invention have a weak inhibitory effect on hERG channel activity and low cardiotoxicity.
- Test Example 3 Effect of electrophysiological manual patch clamp detection on ROMK potassium ion channel
- the purpose of this experiment was to examine the effect of compounds on ROMK potassium ion channels in HEK293 cells in ex vivo experiments.
- the ROMK potassium ion channel was stably expressed on the HEK293 cells of the present invention. After the potassium ion current is stabilized, the effect of the compound on the potassium ion channel can be obtained by comparing the potassium ion current before and after the application of different compound concentrations.
- HEK293 cells Cell Bank of Chinese Academy of Sciences, GNHu43;
- Human ROMK/HEK293 cells transfected with human ROMK cDNA (NCBI SEQ ID NO: NM_000220.4) and HEK293 cell line stably expressing ROMK channel;
- Extracellular fluid NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration);
- intracellular fluid K Aspartate, 130; MgCl 2 , 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH titration);
- the compounds were obtained from Sigma (St. Louis, MO) except for the NaOH and KOH used for acid-base titration. buy.
- Cell culture medium Ham's F12 medium (Invitrogen), 10% (v/v) inactivated fetal bovine serum, 100 ⁇ g/ml hygromycin B, 100 ⁇ g/ml geneticin (Geneticin);
- Micro-manipulation instrument MP-225;
- test compound was dissolved in dimethyl sulfoxide (DMSO) and stored at room temperature. On the day of the test, it was diluted with the extracellular fluid to the following final concentration (3, 10, 30, 100, 300 nM) for testing. The final concentration of DMSO in the test compound was 0.3%.
- DMSO dimethyl sulfoxide
- Human ROMK/HEK293 cells were grown in a Petri dish containing the above cell culture medium, and cultured in an incubator containing 5% CO 2 at 37 °C. 24 to 48 hours prior to electrophysiological experiments, human ROMK/HEK293 cells were transferred to circular glass slides placed in petri dishes and grown under the same culture medium and culture conditions as above. The density of human ROMK/HEK293 cells on each circular slide requires that most cells be independent, individual requirements.
- This experiment used a manual patch clamp system for the recording of whole cell currents.
- a circular slide of surface-grown ROMK/HEK293 cells was placed in an electrophysiological recording cell under an inverted microscope.
- the extracellular fluid was continuously perfused in the recording tank (about 1 ml per minute).
- the experimental procedure uses conventional whole-cell patch clamp current recording techniques. Unless otherwise stated, the experiments were carried out at regular room temperature ( ⁇ 25 ° C).
- the cells were clamped at a voltage of -80 mV.
- the cell clamp voltage was depolarized to +20 mV to activate the ROMK potassium channel, and after 5 seconds it was clamped to -50 mV to eliminate inactivation and generate tail current.
- the tail current peak is used as the value of the ROMK current magnitude.
- the drug to be tested can be superimposed and filled until the inhibition of the ROMK current reaches a steady state.
- the recent three consecutive current recording lines are recombined as a criterion for judging whether or not the state is stable.
- rinse with extracellular fluid until the ROMK current returns to the size before the drug is added.
- One cell can test one or more drugs, or multiple concentrations of the same drug, but need to be flushed with extracellular fluid between different drugs.
- test data was analyzed by HEKA Patchmaster, XLFit and data analysis software provided by Graphpad Prism, see Table 3.
- the compounds of the present invention have a strong inhibitory effect on the potassium channel of ROMK.
- Test Example 4 Effect of electrophysiological manual patch clamp detection on hERG potassium channel
- the purpose of this experiment was to examine the effect of compounds on hERG potassium ion channels in CHO cells in ex vivo experiments.
- the hERG potassium ion channel is stably expressed on the CHO cells of the present invention. After the potassium ion current is stabilized, the effect of the compound on the potassium ion channel can be obtained by comparing the potassium ion current before and after the application of different compound concentrations.
- CHO cell line Sophion Bioscience, Denmark;
- hERG/CHO cells transfected with human hERG cDNA (NCBI SEQ ID NO: NM_000238 (RC215928, origene)) and CHO cell line stably expressing hERG channel;
- Extracellular fluid EC 0.0.0 NaCl-Ringer's solution, NaCl, 145; KCl, 4; CaCl 2 , 2; MgCl 2 , 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration), osmotic pressure ⁇ 305 mOsm;
- Intracellular fluid IC 0.0.0 KCl-Linger's solution, KCl, 120, CaCl 2 , 5.374, MgCl 2 , 1.75; EGTA 5; HEPES, 10; Na-ATP 4; pH 7.25 ( KOH titration), osmotic pressure ⁇ 295mOsm;
- the compounds were purchased from Sigma (St. Louis, MO) except for NaOH and KOH for acid-base titration.
- Cell culture medium Ham's F12 medium (Invitrogen), 10% (v/v) inactivated fetal bovine serum, 100 ⁇ g/ml hygromycin B, 100 ⁇ g/ml geneticin;
- Micro-manipulation instrument MP-225;
- CHO hERG cells were grown in a Petri dish containing the above cell culture medium, and cultured in an incubator containing 5% CO 2 at 37 °C. CHO hERG cells were transferred to circular glass slides placed in petri dishes 24 to 48 hours prior to electrophysiological experiments and grown under the same culture and culture conditions as above. The density of CHO hERG cells on each circular slide requires that most cells be independent, individual requirements.
- This experiment used a manual patch clamp system for the recording of whole cell currents.
- a circular slide with CHO hERG cells grown on it was placed in an electrophysiology recording trough under an inverted microscope.
- the extracellular fluid was continuously perfused in the recording tank (about 1 ml per minute).
- the experimental procedure uses conventional whole-cell patch clamp current recording techniques. Unless otherwise stated, the experiments were carried out at regular room temperature ( ⁇ 25 ° C).
- the cells were clamped at a voltage of -80 mV.
- the cell clamp voltage was depolarized to +20 mV to activate the hERG potassium channel, and after 5 seconds it was clamped to -50 mV to eliminate inactivation and generate tail current.
- the tail current peak is used as the value of the hERG current magnitude.
- the drug to be tested can be superimposed and filled until the inhibitory effect of the drug on the hERG current reaches a steady state.
- the recent three consecutive current recording lines are recombined as a criterion for judging whether or not the state is stable.
- rinse with extracellular fluid until the hERG current returns to the size before the drug is added.
- One cell can test one or more drugs, or multiple concentrations of the same drug, but need to be flushed with extracellular fluid between different drugs.
- test data was analyzed by HEKA Patchmaster, XLFit and data analysis software provided by Graphpad Prism, see Table 4.
- the compounds of the present invention have a weak inhibitory effect on the hERG potassium channel and a low cardiotoxicity.
- Rats were used as test animals, and the concentration of the drug in plasma at different times after administration of the compound of the example by intragastric administration was determined by LC/MS/MS method.
- the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
- 0.1 mL of blood was collected before administration and 0.5, 1, 2, 4, 6, 8, 11, and 24 hours after administration, placed in an EDTA anticoagulation tube, centrifuged at 3500 rpm for 10 minutes, and plasma was separated and stored at -20 °C. 2 hours after administration food.
- the content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method. Plasma samples were analyzed by pretreatment with precipitated proteins.
- Test Example 6 Experimental report on the diuretic effect of ROMK inhibitor on SD rats
- SD male rats were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. (Shanghai, China, certificate number 2008001647752, license SCXK (Shanghai) 2013-0016), purchased 120-130g, 5 / cage Feeding, 12/12 hour light/dark cycle adjustment, temperature 23 ⁇ 1°C constant temperature, humidity 50-60%, free access to water. After the animals were purchased, the experiment was started after 7 days of adaptive feeding.
- the positive control drug structure is as follows:
- Drug doses are calculated on a base basis.
- Grouping n Mode of administration normal group 10 0.5% CMC i.g. single
- Compound 1-0.03mg/kg group 10 0.03mg/kg 150532 i.g. single
- Compound 1-0.1mg/kg group 10 0.1mg/kg 150532 i.g. single
- Positive control drug -0.03mg/kg group 10 0.03mg/kg 153111 i.g. single
- Positive control drug - 0.1mg/kg group 10 0.1mg/kg 153111 i.g. single
- the experimental method was carried out in accordance with the method of the patent (WO2010129379A1). At least adaptively fed SD rats were fasted overnight in metabolic cages, and were weighed into the following groups after randomization: blank control group, compound 1 test group 0.03 mg/kg group and 0.1 mg/kg group, positive The control group was 0.03 mg/kg and the group was 0.1 mg/kg, and 10 rats in each group. Each rat was given a single gavage (ig, 1 ml/kg) of each compound, and the blank group was intragastrically administered with the corresponding solvent. After the gavage, the rats were placed in a general cage, and 25 ml/kg of physiological saline was administered 30 minutes later, immediately afterwards.
- the experimental results showed that compared with the blank control group, the urine volume of the positive control drug 0.03mg/kg group and 0.1mg/kg group increased significantly (P ⁇ 0.05), the urine volume increased by 1.41 times and 1.46 times, respectively, and the compound 1 test drug 0.03
- the urine volume of the mg/kg group and the 0.1 mg/kg group increased significantly (P ⁇ 0.01), and the urine volume increased by 2.76 times and 3.22 times, respectively (see Figure 1); the positive drug and each compound 1 test group had a significant increase in urinary sodium excretion.
- K+ channels can be divided into the following four types: slow (delayed) K+ channel (K channel), fast (early) K+ channel (A channel), Ca2+ activated K+ channel [K (Ca) channel] And four types of inward rectifying K+ channels.
- the family of inwardly rectifying K channels (Kir) is further divided into seven types: Kir1 to Kir7, which have different KCNJ gene codes.
- the renal outer medullary potassium channel (ROMK) is mainly of the Kir1 type. There are at least three subtypes of ROMK channels in the rat kidney: ROMK1, ROMK2 and ROMK3, and ROMK2 is mostly distributed in the medullary sputum.
- ROMK1 and ROMK3 are mainly expressed on the manifold.
- ROMK expressed in the thick segment of the medullary ascending branch regulates the secretion and reabsorption of potassium ions together with the Na/K/Cl transporter.
- ROMK expressed in the cortical collecting tubules regulates the secretion of potassium ions together with the Na/K transporter, blocking
- the ROMK site can promote the secretion of NaCl into the lumen, and does not cause hyperkalemia caused by hyperkalemia. It is a good diuretic research direction for patients with hypertension. This experiment mainly explores the diuretic effect of ROMK inhibitors.
- test compound 1 was very soluble, and there was no delamination.
- the positive control drug had static electricity during the weighing process, which was difficult to weigh, and the agglomeration was not easily dissolved in the initial stage of grinding. Soluble well.
- results also showed that compared with the normal group, a single oral gavage of Compound 1 and a positive control drug had a significant effect on diuretic sodium excretion in rats, and dose-dependent between the doses of the test compound 1 and the positive control drug. .
- test drug compound 1 and the test drug positive control drug had obvious diuretic sodium excretion effect and had no effect on blood potassium; however, the diuretic effect of compound 1 was significantly better than that of the positive control drug, and the pharmacodynamics of each group was dose dependent. .
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- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Gastroenterology & Hepatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
实施例 | hERG IC50(μM) |
1 | 43.7 |
实施例编号 | IC50(nM) |
1 | 18.7 |
实施例编号 | IC50(μM) |
1 | 14.95 |
分组 | n | 给药方式 |
正常组 | 10 | 0.5%CMC(i.g.单次) |
化合物1-0.03mg/kg组 | 10 | 0.03mg/kg 150532(i.g.单次) |
化合物1-0.1mg/kg组 | 10 | 0.1mg/kg 150532(i.g.单次) |
阳性对照药-0.03mg/kg组 | 10 | 0.03mg/kg 153111(i.g.单次) |
阳性对照药-0.1mg/kg组 | 10 | 0.1mg/kg 153111(i.g.单次) |
Claims (16)
- 一种通式(I)所示的化合物:或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式,或其可药用的盐,其中:R1为烷基,其中所述烷基任选进一步被选自卤素、羟基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基和羧酸酯基中的一个或多个取代基所取代;R2选自氢原子、烷基、卤素、氰基、硝基、烷氧基、环烷基和杂环基,其中所述烷基、烷氧基、环烷基或杂环基任选进一步被选自烷基、卤素、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基和羧酸酯基中的一个或多个取代基所取代;R3选自下列基团:R4或R5各自独立地选自氢原子、烷基、卤素、氰基、硝基、烷氧基、环烷基、杂环基、芳基和杂芳基;R6选自氢原子、烷基和卤素;n为0、1或2。
- 根据权利要求1所述的通式(I)所示的化合物,其中R1为烷基,其中所述的烷基任选进一步被选自卤素、羟基和烷氧基中的一个或多个取代基所取代;R1优选为甲基、乙基或丙基。
- 根据权利要求1所述的通式(I)所示的化合物,其中R4为烷基,且R5为氢原子。
- 一种药物组合物,其含有治疗有效量的根据权利要求1~6中任意一项所述的通式(I)所示的化合物以及药学上可接受的载体、稀释剂或赋形剂。
- 根据权利要求1~6中任意一项所述的通式(I)所示的化合物或根据权利要求10所述的药物组合物在制备ROMK抑制剂中的用途。
- 根据权利要求1~6中任意一项所述的通式(I)所示的化合物或根据权利要求10所述的药物组合物在制备治疗或预防高血压和/或心力衰竭的药物中的用途。
- 根据权利要求1~6中任意一项所述的通式(I)所示的化合物或根据权利要求10所述的药物组合物在制备治疗或预防ROMK介导的疾病的药物中的用途,所述的疾病优选选自肝硬化、急性和慢性的肾功能不全、肾病综合症、肺动脉高血压、心血管疾病、心肌梗塞、中风、心功能不全、肺张力过强、动脉粥样硬化和肾结石。
- 一种抑制ROMK的方法,其包括给予所需患者治疗有效量的根据权利要求1~6中任意一项所述的通式(I)所示的化合物或根据权利要求10所述的药物组合物。
- 一种治疗或预防高血压和/或心力衰竭的方法,其包括给予所需患者治疗有效量的根据权利要求1~6中任意一项所述的通式(I)所示的化合物或根据权利要求10所述的药物组合物。
- 一种治疗或预防ROMK介导的疾病或病症的方法,其包括给予所需患者治疗有效量的根据权利要求1~6中任意一项所述的通式(I)所示的化合物或根据权利要求10所述的药物组合物,所述的疾病优选选自肝硬化、急性和慢性的肾功能不全、肾病综合症、肺动脉高血压、心血管疾病、心肌梗塞、中风、心功能不全、肺张力过强、动脉粥样硬化和肾结石。
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CN201580008517.8A CN105980379B (zh) | 2014-12-08 | 2015-11-10 | 吡啶甲酰胺类衍生物、其制备方法及其在医药上的应用 |
JP2017528783A JP6736816B2 (ja) | 2014-12-08 | 2015-11-10 | ピリジンカルボキサミド誘導体、それらの製造方法およびそれらの医薬用途 |
MX2017006536A MX2017006536A (es) | 2014-12-08 | 2015-11-10 | Derivados de piridincarboxamida, su metodo de preparacion y sus usos farmaceuticos. |
CA2966788A CA2966788A1 (en) | 2014-12-08 | 2015-11-10 | Pyridinecarboxamide derivatives, preparation method therefor and pharmaceutical uses thereof |
KR1020177018177A KR20170090477A (ko) | 2014-12-08 | 2015-11-10 | 피리딘카복스아미드 유도체, 그의 제조 방법 및 그의 약학적 용도 |
RU2017121460A RU2694899C9 (ru) | 2014-12-08 | 2015-11-10 | Производные пиридинкарбоксамида, способ их получения и их фармацевтическое применение |
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US16/257,716 US10442794B2 (en) | 2014-12-08 | 2019-01-25 | Processes for preparing pyridine carboxamide derivatives |
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CN (1) | CN105980379B (zh) |
AU (1) | AU2015361614B2 (zh) |
BR (1) | BR112017010645A2 (zh) |
CA (1) | CA2966788A1 (zh) |
MX (2) | MX2017006536A (zh) |
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WO2017184662A1 (en) | 2016-04-20 | 2017-10-26 | Bristol-Myers Squibb Company | Substituted bicyclic heterocyclic compounds |
WO2017211271A1 (zh) | 2016-06-07 | 2017-12-14 | 江苏恒瑞医药股份有限公司 | 一种肾外髓质分泌钾通道抑制剂的可药用盐 |
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WO2019109935A1 (zh) | 2017-12-06 | 2019-06-13 | 江苏恒瑞医药股份有限公司 | 一种肾外髓质分泌钾通道抑制剂的晶型及其制备方法 |
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CN108113988A (zh) * | 2016-11-29 | 2018-06-05 | 江苏恒瑞医药股份有限公司 | 一种romk抑制剂与arb联合在制备治疗和/或预防高血压或心力衰竭的药物中的用途 |
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- 2015-11-10 JP JP2017528783A patent/JP6736816B2/ja not_active Expired - Fee Related
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- 2015-11-10 WO PCT/CN2015/094164 patent/WO2016091042A1/zh active Application Filing
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- 2015-11-10 MX MX2017006536A patent/MX2017006536A/es unknown
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US10442794B2 (en) | 2019-10-15 |
RU2017121460A3 (zh) | 2019-03-28 |
EP3231802A4 (en) | 2018-05-02 |
EP3231802B1 (en) | 2021-05-05 |
JP2017536383A (ja) | 2017-12-07 |
CN105980379B (zh) | 2018-09-07 |
US10364234B2 (en) | 2019-07-30 |
JP6736816B2 (ja) | 2020-08-05 |
US20190152958A1 (en) | 2019-05-23 |
EP3231802A1 (en) | 2017-10-18 |
US20170342059A1 (en) | 2017-11-30 |
MX2020011818A (es) | 2021-01-15 |
US20190152959A1 (en) | 2019-05-23 |
RU2694899C2 (ru) | 2019-07-18 |
TW201620898A (zh) | 2016-06-16 |
KR20170090477A (ko) | 2017-08-07 |
CN105980379A (zh) | 2016-09-28 |
TWI718113B (zh) | 2021-02-11 |
AU2015361614B2 (en) | 2019-11-28 |
RU2017121460A (ru) | 2019-01-10 |
US10759788B2 (en) | 2020-09-01 |
RU2694899C9 (ru) | 2019-08-28 |
BR112017010645A2 (pt) | 2017-12-26 |
AU2015361614A1 (en) | 2017-06-22 |
MX2017006536A (es) | 2017-08-09 |
CA2966788A1 (en) | 2016-06-16 |
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