WO2020068846A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

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Publication number
WO2020068846A1
WO2020068846A1 PCT/US2019/052722 US2019052722W WO2020068846A1 WO 2020068846 A1 WO2020068846 A1 WO 2020068846A1 US 2019052722 W US2019052722 W US 2019052722W WO 2020068846 A1 WO2020068846 A1 WO 2020068846A1
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WO
WIPO (PCT)
Prior art keywords
propan
pyrazol
oxy
pyrimidin
mixture
Prior art date
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PCT/US2019/052722
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English (en)
Inventor
Nobuyuki Matsunaga
Yasufumi Miyamoto
Junya Shirai
Takashi Nakahata
Zeyu SHIOKAWA
Tomohiro Okawa
Akito SHIBUYA
Original Assignee
Heterocyclic Compound
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Application filed by Heterocyclic Compound filed Critical Heterocyclic Compound
Publication of WO2020068846A1 publication Critical patent/WO2020068846A1/fr

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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
    • A61P9/06—Antiarrhythmics
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to a heterocyclic compound having a calcium/calmodulin-dependent protein kinase II
  • CaMKII (sometimes to be abbreviated as "CaMKII” in the present specification) inhibitory action, which is expected to be useful as an agent for the prophylaxis or treatment of cardiac diseases (particularly catecholaminergic polymorphic
  • ventricular tachycardia postoperative atrial fibrillation, heart failure, fatal arrhythmia
  • Cardiac diseases include heart failure, arrhythmia, myocardial infarction, angina, valvular heart disease and the like, and they are high-mortality diseases.
  • cardiac diseases include heart failure, arrhythmia, myocardial infarction, angina, valvular heart disease and the like, and they are high-mortality diseases.
  • the symptoms are improved by control of each risk factor and symptomatic therapy.
  • the satisfaction with treatment remains low level, and there is now no definitive therapy.
  • CaMK Ca 2+ /calmodulin-dependent protein kinase
  • the CaMK family includes CaMKII, and four isoforms (a, b, g and d) exist as CaMKII.
  • CaMKII a and CaMKII b are expressed mainly in cerebral tissue, and CaMKII g and CaMKII d are expressed in many tissues including heart.
  • CaMKII is activated by amino acid- modification due to oxidative stress or hyperglycemia, in addition to the binding of calcium-calmodulin complex.
  • CaMKII regulates cell functions by phosphorylation of a transcription factor which is a substrate, a protein that plays a function in organelle uptake/excretion of Ca 2+ , a protein that regulates contract and relax of muscles, a channel that regulates an intracellular ion concentration, and the like, due to its kinase activation.
  • Non-Patent Documents 1-4 Some documents suggest that CaMKII plays a harmful role in progress of cardiac disease conditions. Expression and activity of CaMKII are increased in heart of human patient or animal with heart failure. In transgenic mouse overexpressing CaMKII d in heart, onsets of cardiac hypertrophy and heart failure are reported (Non-Patent Document 4) . By studies using an inhibitor by a
  • Non-Patent Documents 5-7 For catecholaminergic polymorphic ventricular tachycardia,
  • Non-Patent Document 8 proposes a method for treating cardiac diseases including heart failure, cardiac hypertrophy, myocardial infarction and cardiac arrhythmia.
  • Non-Patent Document 9 CaMKII exacerbating action on growth or metastasis of a certain type of cancer is suggested.
  • therapeutic effect on acute renal failure, intimal hypertrophy, hepatic fibrosis, stroke, pain, rheumatoid arthritis and the like by CaMKII inhibition are also indicated (Non-Patent Documents 10-15) .
  • medicament for a CaMKII selective inhibitor because they have a low kinase selectivity to CaMKII, or they are not suitable for oral administration or chronic administration.
  • Patent Document 1 describes that a compound represented by the following formula (I) :
  • Patent Document 2 describes that a compound represented by the following formula (I) :
  • Patent Document 3 describes that a compound represented by the following formula (I) :
  • each symbol is as defined in Patent Document 3, is a mGluR (metabotropic glutamate receptors) 5 modulator and useful for the treatment or prophylaxis of diseases or conditions in which mGluR5 is involved (e.g., pain disorder, anxiety, depression, Alzheimer's disease, Parkinson's disease, etc . ) .
  • mGluR metalabotropic glutamate receptors
  • Patent Document 4 describes that a compound represented by the following formula (I) :
  • Patent Document 5 describes that a compound represented by the following formula (I) : [0016]
  • each symbol is as defined in Patent Document 5, is a kinase (p38 kinase, etc.) inhibitor and useful for reduction of ischemic cell death (particularly reduction of traumatic neuronalcell death) .
  • a kinase p38 kinase, etc.
  • Patent Document 1 WO 2013/157540
  • Patent Document 2 WO 2013/052394
  • Patent Document 3 WO 2005/021529
  • Patent Document 4 WO 2002/024681
  • Patent Document 5 WO 2002/011724
  • Non-Patent Document 1 European Journal of Heart Failure, vol.16, p .1292-1300
  • Non-Patent Document 2 Circulation Research, vol.84, p.713-721
  • Non-Patent Document 3 Molecular Endocrinology, vol.17, p.183- 192
  • Non-Patent Document 4 Circulation Research, vol.92, p.912-919
  • Non-Patent Document 5 Proceedings of the National Academy of Sciences, vol.106, p.2342-2347
  • Non-Patent Document 6 Circulation Research, vol.112, p.935-944
  • Non-Patent Document 7 Nature, vol.502, p.372-376
  • Non-Patent Document 8 Journal of Molecular and Cellular
  • Non-Patent Document 9 Oncotarget, vol.20, p .11725-11734
  • Non-Patent Document 10 Arterioscler Thromb Vase Biol vol .28, p .441-447
  • Non-Patent Document 11 Cell Calcium, vol.45, p.284-292
  • Non-Patent Document 12 J Clin Invest, vol.119, p.2925-2941
  • Non-Patent Document 13 J Biol Chem, vol.285, p.20675-20682
  • Non-Patent Document 14 J Pharmacol Exp Ther, vol.325, p.267- 275
  • Non-Patent Document 15 BMC Musculoskelet Disord, vol.30, p.61
  • An object of the present invention is to provide a compound having a CaMKII inhibitory action, which is expected to be useful as an agent for the prophylaxis or treatment of cardiac diseases (particularly catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, fatal arrhythmia) and the like.
  • the present inventors have conducted intensive studies in an attempt to solve the above-mentioned problems and found that the compounds mentioned below have a CaMKII inhibitory action, and therefore, is expected to be useful as an agent for the prophylaxis or treatment of cardiac diseases (particularly catecholaminergic polymorphic ventricular tachycardia,
  • the present invention provides the
  • a medicament comprising the compound or salt of the above- mentioned [ 1 ] .
  • a method of inhibiting calcium/calmodulin-dependent protein kinase II in a mammal which comprises administering an effective amount of the compound or salt of the above-mentioned [1] to the mammal.
  • a method for the prophylaxis or treatment of cardiac diseases in a mammal which comprises administering an
  • ventricular tachycardia postoperative atrial fibrillation, heart failure and fatal arrhythmia.
  • ventricular tachycardia postoperative atrial fibrillation, heart failure and fatal arrhythmia.
  • a compound having a superior CaMKII inhibitory action which is expected to be useful as an agent for the prophylaxis or treatment of cardiac diseases (particularly catecholaminergic polymorphic
  • ventricular tachycardia postoperative atrial fibrillation, heart failure, fatal arrhythmia
  • heart failure fatal arrhythmia
  • examples of the salt include metal salts, ammonium salts, salts with organic base, salts with inorganic acid, salts with organic acid, and salts with basic or acidic amino acid.
  • the metal salt include alkali metal salts such as sodium salts, potassium salts and the like; alkali earth metal salts such as calcium can be produce salts, magnesium salts, barium salts and the like; and aluminum salts.
  • salts with organic base include salts with trimethylamine , triethylamine, pyridine, picoline, 2 , 6-lutidine, ethanolamine , diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'- dibenzylethylenediamine and the like.
  • salts with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and the like.
  • Preferable examples of the salts with basic amino acid include salts with arginine, lysine, ornithine and the like.
  • Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. Among them, a pharmaceutically acceptable salt is preferable.
  • examples of the salt include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt etc.) and the like, ammonium salt etc.
  • examples of the salt include salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • Compound A contains isomers such as tautomers, optical isomers, stereoisomers, position isomers and rotational isomers, any of isomers or mixture are also encompassed in Compound A. Further, when Compound A contains an optical isomer, the optical isomer separated from the racemate is encompassed in Compound A.
  • Compound A can be obtained in the crystal form. Either single crystalline form or crystalline mixture can be
  • Compound A can be a pharmaceutically acceptable co crystal or a co-crystal salt.
  • the co-crystal or co-crystal salt as used herein means a crystalline material composed of two or more unique solids at room temperature, each of which has distinctive physical characteristics such as structure, melting point, and heats of fusion, hygroscopicity, solubility, and stability.
  • a co-crystal or a co-crystal salt can be produced according to co-crystallization method known per se.
  • Compound A may be a solvate (e.g., a hydrate) or a non solvate and both are encompassed in Compound A.
  • Compounds labeled with or substituted by isotopes are also encompassed in Compound A.
  • the compound labeled with or substituted by isotopes can be used as, for example, a tracer used for
  • PET Positron Emission Tomography
  • Compound A can be produced according to the methods described in the below-mentioned Examples.
  • the starting compound and/or production intermediate for Compound A may form a salt. While the salt is not particularly limited as long as the reaction can be performed, examples thereof include those similar to the salts optionally formed by Compound A and the like, and the like.
  • isomerization occurs, for example, according to a conventional separation means such as extraction, recrystallization, distillation, chromatography and the like to obtain a pure compound.
  • the corresponding pure isomer can also be obtained by isomerizing a double bond using heating, an acid catalyst, a transition metal complex, a metal catalyst, a radical catalyst, light irradiation, a strong base catalyst and the like, according to the method described in Shin Jikken Kagaku Kouza 14 (The Chemical Society of Japan ed. ) , pages 251 to 253, 4th Edition Jikken Kagaku Kouza 19 (The Chemical
  • Compound A contains a stereoisomer depending on the kind of a substituent, and each stereoisomer and a mixture thereof are encompassed in the present invention.
  • Compound A may be a hydrate or a non-hydrate.
  • Compound A can be synthesized by performing deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, reaction of carbon chain extension, halogenation reaction, substituent exchange reaction, coupling reaction, reductive amination, nucleophilic addition reaction by a carbo anion, Grignard reagent and deoxofluorination reaction singly or two or more thereof in combination.
  • the objective product is obtained as a free form by the above-mentioned reaction, it can be converted to a salt according to a conventional method, or when the objective product is obtained as a salt, it can be converted to a free form or other salt according to a conventional method.
  • the thus-obtained Compound A can also be isolated and purified from a reaction mixture according to a known method such as phase transfer, concentration, solvent extraction, distillation, crystallization, recrystallization, chromatography and the like .
  • the thus-obtained Compound A, other reaction intermediate therefor and starting compounds thereof can be isolated and purified from a reaction mixture according to a method known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column
  • a salt of Compound A can be produced according to a method known per se .
  • Compound A when Compound A is a basic compound, it can be produced by adding an inorganic acid or organic acid, or when Compound A is an acidic compound, by adding an organic base or inorganic base.
  • each optical isomer and a mixture thereof are encompassed in the scope of the present invention, and these isomers can be subjected to optical resolution or can be produced respectively, according to a method known per se, if desired.
  • Compound A may be a prodrug.
  • a prodrug of Compound A invention means a compound which is converted to Compound A with a reaction due to an enzyme, an gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to Compound A with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound which is converted to Compound A by hydrolysis etc. due to gastric acid, etc.
  • a prodrug for Compound A may be a compound obtained by subjecting an amino group in Compound A to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in Compound A to an eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-l, 3- dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert- butylation, etc.); a compound obtained by subjecting a hydroxy group in Compound A to an acylation, alkylation,
  • phosphorylation or boration e.g., a compound obtained by subjecting an hydroxy group in Compound A to an acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation, etc.
  • a compound obtained by subjecting a carboxyl group in Compound A to an esterification or amidation e.g., a compound obtained by subjecting a carboxyl group in Compound A to an ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification,
  • the prodrug of Compound A may be a compound that converts to Compound A under physiological conditions as described in Development of Pharmaceutical Products, vol . 7, Molecule Design, 163-198, Hirokawa Shoten (1990) .
  • Compound A or a prodrug thereof (to be abbreviated as the compound of the present invention) is superior in vivo kinetics (e.g., plasma drug half-life, intracerebral transferability, metabolic stability), shows low toxicity (e.g., more superior as a medicament in terms of acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity etc.) .
  • the compound of the present invention is directly used as a medicament or a pharmaceutical composition mixed with a pharmaceutically acceptable carrier or the like to be orally or parenterally administered to mammals (e.g., humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep and goats) in safety.
  • mammals e.g., humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep and goats
  • parenteral include intravenous, intramuscular, subcutaneous, intra
  • intrarectal, intravaginal , intraperitoneal and intratumor administrations administration to the vicinity of tumor etc. and direct administration to the lesion.
  • the compound of the present invention has a superior CaMKII inhibitory action, it is expected to be useful for the prophylaxis or treatment of, for example, cardiac diseases (cardiac hypertrophy, acute heart failure and chronic heart failure including congestive heart failure, cardiomyopathy, angina, myocarditis, atrial/ventricular arrhythmia, tachycardia, myocardial infarction, etc.),
  • cardiac diseases cardiac hypertrophy, acute heart failure and chronic heart failure including congestive heart failure, cardiomyopathy, angina, myocarditis, atrial/ventricular arrhythmia, tachycardia, myocardial infarction, etc.
  • myocardial ischemia myocardial ischemia, venous insufficiency, post-myocardial infarction transition to heart failure, hypertension, cor pulmonale, arteriosclerosis including atherosclerosis
  • aneurysm aneurysm, coronary arterial sclerosis, cerebral arterial sclerosis, peripheral arterial sclerosis, etc.
  • vascular thickening vascular thickening/occlusion and organ damages after intervention
  • percutaneous coronary angioplasty, stent placement, coronary angioscopy, intravascular ultrasound, coronary thrombolytic therapy, etc. vascular thickening/occlusion and organ damages after intervention
  • bone disorders nonmetabolic bone disorders such as bone fracture, refracture, bone malformation/spondylosis deformans, osteosarcoma, myeloma, dysostosis and scoliosis, bone defect, osteoporosis, osteomalacia, rickets, osteitis fibrosis, renal osteodystrophy, Paget's disease of bone, myelitis with
  • inflammatory diseases diseases (diabetic complication such as retinopathy, nephropathy, nerve damage, macroangiopathy etc.; arthritis such as chronic rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitis etc.; inflammation after surgery/trauma; reduction of swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory enteric diseases such as Crohn's disease, ulcerative colitis etc.; meningitis; inflammatory eye diseases; inflammatory pulmonary diseases such as pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis etc, and the like) , allergic diseases (allergic rhinitis, conjunctivitis, gastrointestinal allergy, pollen allergy, anaphylaxis, etc.), drug dependence, neurodegenerative diseases (Al) rhinitis, conjunctivitis, gastrointestinal allergy, pollen allergy, anaphylaxis, etc.
  • dementia disturbed memory, disturbed consciousness, amnesia, anxiety symptoms, nervous symptoms, unpleasant condition, mental disorders (depression, epilepsy, alcohol dependency, etc.), ischemic peripheral circulatory disorder, deep-vein thrombosis, occlusive peripheral circulatory disorder,
  • arteriosclerosis obliterans ASO
  • occlusive thromboangiitis diabetes (type 1 diabetes, type 2 diabetes, pregnancy diabetes etc.)
  • diabetic complications nerve damage, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia, diabetic hyperosmolar diabetic coma, infectious diseases, diabetic gangrene, xerostomia, deterioration in hearing, cerebrovascular damage, peripheral circulatory disorder, etc.
  • urinary incontinence obesity, hyperlipidemia, hypercholesterolemia, diabetes, impaired glucose tolerance, hyperuricemia, hyperkalemia, hypernatremia etc.
  • metabolic syndrome vesceral obesity syndrome, male or female sexual dysfunction and the like
  • cerebrovascular damage asymptomatic cerebrovascular damage, transient cerebral ischemia attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction, etc.
  • cerebral edema cerebral circulatory disturbance, recurrence and aftereffects of cerebrovascular damages
  • kidney diseases neurodegenerative diseases, neurological symptoms, mental symptoms, subjective symptoms, impairment of activities of daily living, etc.
  • kidney diseases nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, diabetic
  • nephropathy nephrotic syndrome
  • hypertensive nephrosclerosis complications of dialysis, organ damage including nephropathy by irradiation, etc.), erythrocytosis/hypertension/organ damage/vascular thickening after transplantation s rej ection after transplantation, ocular disorders (glaucoma, ocular hypertension, etc.), thrombosis, multiple organ failure, endothelial dysfunction, hypertensive tinnitus, other
  • cancer metastases cancer metastases, endocrine disorders (Addison's disease, Cushing's syndrome, pheochromocytoma, primary
  • gynecological disorders menopausal disorders, pregnancy toxemia, endometriosis, uterine fibroid, ovarian diseases, mammary gland diseases, sexually transmitted diseases, etc.
  • diseases caused by environmental/occupational factor e.g., radiation damage, damage from ultraviolet/infrared/laser beam, altitude sickness etc.
  • infectious diseases viral infectious diseases of, for example, cytomegalovirus, influenza virus and herpesvirus, rickettsial infectious diseases, bacterial infectious diseases, etc.
  • toxemia septicemia, septic shock, endotoxic shock, gram-negative septicemia, toxin shock
  • ear nose throat diseases Meniere's disease, tinnitus, dysgeusia, vertigo, balance disorder, deglutition disorder etc.
  • cutaneous diseases keloid, hemangioma, psoriasis, etc.
  • dialysis hypotension myasthenia gravis
  • systemic diseases such as chronic fatigue syndrome, and the like, particularly cardiac diseases (particularly
  • mammals e.g., humans, monkeys, cats, pigs, horses, bovines, mice, rats, guinea pigs, dogs, rabbits etc . .
  • the concept of prophylaxis of cardiac diseases include treatment of prognosis of myocardial infarction, angina attack, cardiac bypass surgery, thrombolytic therapy, coronary revascularization and the like, and the concept of treatment of cardiac diseases include suppress of progress or severity of heart failure (including both contractile failure HFrEF, and heart failure HFpEF with maintained ejection fraction), and maintenance of cardiac function when performing non-drug therapies (e.g., an implantable defibrillator, resection of cardiac sympathetic nerve, catheter ablation, cardiac
  • pacemaker intra aortic balloon pumping, auxiliary artificial heart, Batista operation, cell transplantation, gene therapy, heart transplantation and the like) for severe heart
  • prognosis survival rate, readmission rate, cardiac event rate etc.
  • the dose of the compound of the present invention varies depending on the administration route, symptom and the like, when, for example, the compound is orally administered to a patient with cardiac disease (adult, body weight 40 - 80 kg, for example, 60 kg), it is, for example, 0.001 - 1000 mg/kg body weight/day, preferably 0.01 - 100 mg/kg body weight/day, more preferably 0.1 - 10 mg/kg body weight/day. This amount can be administered in 1 to 3 portions per day.
  • a medicament containing the compound of the present invention can be used alone or as a pharmaceutical composition containing the compound of the present invention and a
  • a medicament containing the compound of the present invention can be safely administered in the form of, for example, tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal and the like) , pill, powder, granule, capsule (including soft capsule, microcapsule) , troche, syrup, liquid, emulsion, suspension, release control preparation (e.g., immediate- release preparation, sustained-release preparation, sustained- release microcapsule), aerosol, film (e.g., orally
  • disintegrating film oral mucosa-adhesive film
  • injection e.g., subcutaneous injection, intravenous injection,
  • intramuscular injection intraperitoneal injection
  • drip infusion transdermal absorption type preparation
  • ointment lotion
  • adhesive preparation e.g., rectal suppository, vaginal suppository
  • pellet e.g., nasal preparation, pulmonary preparation (inhalant) , eye drop and the like, orally or parenterally (e.g., intravenous, intramuscular,
  • compositions As the aforementioned “pharmaceutically acceptable carrier”, various organic or inorganic carriers conventionally used as preparation materials (starting materials) can be used.
  • excipient, lubricant, binder, disintegrant and the like are used for solid preparations, and solvent, solubilizing agent, suspending agent, isotonicity agent, buffer, soothing agent and the like are used for liquid preparations.
  • preparation additives such as preservative,
  • antioxidant colorant, sweetening agent and the like can also be used.
  • excipient examples include lactose, sucrose, D- mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binding agent examples include crystalline cellulose, white sugar, D-mannitol, dextrin,
  • hydroxypropylcellulose hydroxypropylmethylcellulose
  • polyvinylpyrrolidone starch
  • sucrose gelatin
  • methylcellulose carboxymethylcellulose sodium and the like.
  • disintegrant examples include starch,
  • carboxymethylcellulose carboxymethylcellulose calcium, sodium carboxymethyl starch, L-hydroxypropylcellulose and the like.
  • solvent examples include water for injection, alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizing agent examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium
  • suspending agent examples include surfactants such as stearyl
  • hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone,
  • isotonic agent examples include glucose, D- sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • buffering agent examples include buffer solutions such as phosphates, acetates, carbonates, citrates and the like .
  • Examples of the soothing agent include benzyl alcohol and the like.
  • preservative examples include p-oxybenzoates , chlorobutanol , benzyl alcohol, phenylethyl alcohol,
  • antioxidant examples include sulfite, ascorbic acid, a-tocopherol and the like.
  • the pharmaceutical composition varies according to the dosage form, administration method, carrier and the like, it can be produced according to a conventional method by adding the compound of the present invention in a proportion of generally 0.01 - 100% (w/w) , preferably 0.1 - 95% (w/w) , of the total amount of the preparation.
  • the compound of the present invention When the compound of the present invention is applied to each of the above-mentioned diseases, it can be used in appropriate combination with a pharmaceutical agent
  • ACE angiotensin converting enzyme
  • angiotensin II receptor antagonists e.g., losartan, candesartan cillexetil, valsartan, termisartan, irbesartan, forasartan and the like
  • angiotensin II receptor antagonist/NEP inhibitor combination agent e.g., losartan, candesartan cillexetil, valsartan, termisartan, irbesartan, forasartan and the like
  • b receptor antagonists e.g., propranolol, nadolol, timolol, nipradilol, bunitorolol, indenolol, penbutolol, carteolol, carvedilol, pindolol, acebutolol, atenolol,
  • chlorpropamide glyclopyramide, acetohexamide, tolazamide, glibenclamide , glybuzole and the like; biguanides such as metformin hydrochloride, buformin hydrochloride and the like; a-glucosidase inhibitors such as voglibose, acarbose and the like, insulin sensitizers such as pioglitazone , troglitazone and the like; SGLT2 inhibitors such as ipragliflozin,
  • arrhythmia for example, it can be used concurrently with other antiarrhythmic drugs (e.g., sodium channel blockers such as flecainide, quinidine, procainamide, disopyramide, ajmaline, cibenzoline, lidocain,
  • sodium channel blockers such as flecainide, quinidine, procainamide, disopyramide, ajmaline, cibenzoline, lidocain,
  • diphenylhydantoin mexiletine, propafenone, pilsicainide, phenytoin and the like
  • potassium channel blockers such as amiodarone and the like
  • calcium channel blockers such as verapamil, diltiazem and the like, and the like
  • non-drug therapies e.g., an implantable
  • the compound can be used in combination with antithrombotics (e.g., anticoagulants such as heparin sodium, heparin calcium, warfarin and the like; thrombolytic agents such as urokinase and the like; anti-platelet drugs such as aspirin, sulfinpyrazone (anturan) , dipyridamole (persantin) , ticropidine (panaldine) , cilostazol (pletal) , clopidogrel and the like; and the like) , angiotensin converting enzyme
  • antithrombotics e.g., anticoagulants such as heparin sodium, heparin calcium, warfarin and the like; thrombolytic agents such as urokinase and the like; anti-platelet drugs such as aspirin, sulfinpyrazone (anturan) , dipyridamole (persantin) , ticropidine (panaldine) , c
  • HMG-CoA reductase inhibitors such as pravastatine, fluvastatine, cerivastatine, atorvastatine and the like; fibrate drugs such as sinfibrate, clofibrate
  • coronary vessel reconstructive surgery such as PTCA
  • the compound in chronic rheumatoid arthritis, can be used in combination with non-steroidal antiinflammatory agents (e.g., acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenine, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine , epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesilate, camostat mesilate, ulinastatine, colchicine, probenecid, sulfinpyrazone, benzbromarone, all
  • non-steroidal antiinflammatory agents e.g.
  • dexamethasone hexestrol, methimazole, betamethasone
  • fluocinoloneacetonide prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone ,
  • infliximab D2E7, CDP-571, PASS TNF-a, soluble TNF-a receptor, TNF-a binding protein, anti-TNF-a antibody and the like
  • cyclooxygenase inhibitors e.g., salicylic acid derivatives such as celecoxib, rofecoxib, aspirin and the like, MK-663, valdecoxib, SC-57666, tiracoxib, S-2474, diclofenac,
  • the compound of the present invention in combination with biological products (e.g.: antibody, vaccine preparation and the like) when applying to the above-mentioned respective diseases, and it is also possible to apply the compound in combination with a gene therapy and the like as a combination therapy.
  • biological products e.g.: antibody, vaccine preparation and the like
  • a gene therapy and the like as a combination therapy.
  • antibody and vaccine preparation for example, vaccine preparation to angiotensin II, vaccine preparation to CETP, CETP antibody, TNF a antibody, antibody to other cytokine, amiloid b vaccine preparation, type 1 diabetes vaccine (DIAPEP-277 of Peptor Ltd.
  • anti-HIV antibody HIV vaccine preparation and the like
  • antibody and vaccine preparation to cytokine renin- angiotensin enzyme and products thereof
  • antibody and vaccine preparation to enzyme and protein involved in blood lipid metabolism antibody and vaccine preparation to enzyme and protein involved in blood coagulation-fibrinolytic system
  • antibody and vaccine preparation to protein involved in glucose metabolism and insulin resistance and the like can be
  • a combined use with biological products involved in growth factors such as GH, IGF and the like is possible.
  • a gene therapy for example, a treatment method using a gene relating to cytokine, renin-angiotensin enzyme and products thereof, G protein, G protein-coupled receptor and phosphorylation enzyme thereof, a therapeutic method using a DNA decoy such as NFKB decoy and the like, a therapeutic method using antisense, a therapeutic method using a gene relating to enzyme and protein involved in blood lipid metabolism (e.g., gene relating to metabolism, excretion and absorption of cholesterol or triglyceride or HDL-cholesterol or blood phospholipid, and the like) , a therapeutic method using a gene relating to enzyme and protein (e.g., growth factors such as HGF, VEGF and the like, and the like) involved in
  • angiogenetic therapy aiming at obstruction of peripheral vessel and the like
  • a therapeutic method using a gene relating protein involved in glucose metabolism and insulin resistance, antisense to cytokine such as TNF-a and the like, and the like can be mentioned.
  • various organ regeneration methods such as heart regeneration, kidney regeneration, pancreas regeneration, blood vessel regeneration and the like, cell transplantation therapy using bone marrow cells (bone marrow mononuclear cell, bone marrow mesenchymal stem cell and the like) , and artificial organs (artificial blood vessels and cardiac muscle cell sheet) using tissue engineering.
  • the dose can be reduced as compared to single
  • the drug to be combined with the compound of the present invention can be selected according to the condition of patients (mild case, severe case and the like) ,
  • the period of treatment can be set longer by selecting a concomitant drug having different action and mechanism from the compound of the present invention
  • a sustained treatment effect can be designed by selecting a concomitant drug having different action and mechanism from the compound of the present invention
  • the administration time of the compound of the present invention and the concomitant drug is not restricted, and the compound of the present invention or a pharmaceutical composition thereof and the concomitant drug or a
  • composition thereof can be administered to an administration subject simultaneously, or may be administered at different times.
  • the dosage of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on an administration subject, administration route, disease, combination and the like.
  • the administration mode of the concomitant drug of the present invention is not particularly restricted, and it is sufficient that the compound of the present invention and the concomitant drug are combined in administration. Examples of such
  • administration mode include the following methods:
  • the combination agent of the present invention exhibits low toxicity.
  • the compound of the present invention or (and) the aforementioned concomitant drug can be combined with a pharmacologically acceptable carrier according to the known method to prepare a pharmaceutical composition such as tablets (including sugar-coated tablet and film-coated tablet) , powders, granules, capsules (including soft capsule) , liquids, injections, suppositories, sustained-release agents, etc.
  • a pharmaceutical composition such as tablets (including sugar-coated tablet and film-coated tablet) , powders, granules, capsules (including soft capsule) , liquids, injections, suppositories, sustained-release agents, etc.
  • These compositions can be administered safely orally or non-orally (e.g., topical, rectal, intravenous administration etc.). Injection can be administered intravenously,
  • Examples of the pharmacologically acceptable carriers usable for the production of a combination agent of the present invention various organic or inorganic carrier substances conventionally used as preparation materials can be mentioned.
  • solid preparations for example, excipient, lubricant, binder and disintegrant can be used.
  • liquid preparations for example, solvent, solubilizing agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like can be used.
  • an appropriate amount of conventional preservative, antioxidant, colorant, sweetening agent, adsorbent, wetting agent and the like can be used as appropriate .
  • excipient examples include lactose, sucrose, D- mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binding agent examples include crystalline cellulose, white sugar, D-mannitol, dextrin,
  • disintegrant examples include starch,
  • carboxymethylcellulose carboxymethylcellulose calcium, sodium carboxymethyl starch, L-hydroxypropylcellulose and the like.
  • solvent examples include water for injection, alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizing agent examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium
  • suspending agent examples include surfactants such as stearyl triethanolamine, sodium lauryl sulfate,
  • laurylaminopropionic acid lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate and the like;
  • hydrophilic polymers such as polyvinyl alcohol,
  • methylcellulose hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; and the like.
  • isotonic agent examples include glucose, D- sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • buffering agent examples include buffer solutions such as phosphates, acetates, carbonates, citrates and the like .
  • Examples of the soothing agent include benzyl alcohol and the like.
  • preservative examples include p-oxybenzoates , chlorobutanol , benzyl alcohol, phenylethyl alcohol,
  • antioxidant examples include sulfite, ascorbic acid, a-tocopherol and the like.
  • the mixing ratio of the compound of the present invention to the concomitant drug in the combination agent of the present invention can be appropriately selected depending on an administration subject, administration route, diseases and the like .
  • the content of the compound of the present invention in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to about 100 wt%, preferably from about 0.1 to about 50 wt%, further preferably from about 0.5 to about 20 wt%, based on the preparation.
  • the content of the concomitant drug in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to about 100 wt%, preferably from about 0.1 to about 50 wt%, further preferably from about 0.5 to about 20 wt%, based on the preparation.
  • the content of additives such as a carrier and the like in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 1 to about 99.99 wt%, preferably from about 10 to about 90 wt%, based on the preparation.
  • concomitant drug are separately formulated into preparations, the contents thereof are similar to the above.
  • room temperature generally means about 10°C to about 35°C.
  • the ratios indicated for mixed solvents are volume mixing ratios, unless otherwise specified.
  • % means wt%, unless otherwise specified.
  • the elution in column chromatography in Example was performed under observation by TLC (Thin Layer Chromatography) .
  • TLC Thin Layer Chromatography
  • 6OF254 manufactured by Merck was used as a TLC plate, and the solvent used as an elution solvent for column chromatography was used as a developing solvent.
  • a UV detector was adopted.
  • silica gel column chromatography NH means use of aminopropylsilane-bonded silica gel, and Diol means use of 3- ( 2 , 3-dihydroxypropoxy) propylsilane-bonded silica gel.
  • C18 means use of octadecyl-bonded silica gel.
  • the ratios indicated for elution solvents are volume mixing ratios, unless otherwise specified .
  • MS was measured by LC/MS. As ionization method, ESI method or APCI method was used. The data indicates actual measured value (found) . Generally, molecular ion peaks are observed, and may be observed as a fragment ion. In the case of a salt, a molecular ion peak or fragment ion peak of free form is generally observed.
  • the unit of sample concentration (c) for optical rotation ( [a] D) is g/100 mL . Elemental analysis value (Anal.) was described as calculated value (Calcd) and actual measured value (Found) .
  • the peak by powder X-RAY diffraction in Example means the peak measured using Cu Ka-ray as a source by Ultima IV (Rigaku Corporation, Japan) at room temperature.
  • the measurement conditions are as follows .
  • Electric pressure/Electric current 40 kV/50 mA
  • CDCI3 deuterochloroform
  • APCI atmospheric pressure chemical ionization, atmospheric pressure chemical ionization
  • IPE diisopropyl ether
  • Pd (PPh 3 ) 4 tetrakis (triphenylphosphine) palladium (0)
  • Pd2 (dba) 3 Tris (dibenzylideneacetone) dipalladium (0)
  • the mixture was quenched with saturated aqueous ammonium chloride solution at 0°C and diluted with ethyl acetate .
  • the mixture was filtered through Celite, and the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was suspended in ethyl acetate (50 mL) , the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate/hexane, MeOH/ethyl acetate) and purified by silica gel column
  • reaction mixture was partitioned between ethyl acetate and water.
  • organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (179 mg) .
  • the mixture was stirred at 0°C for 1 hr.
  • the mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution at 0°C and extracted with ethyl acetate.
  • the organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound.
  • the obtained oil was used for next reaction without purification.
  • Diisopropyl azodicarboxylate (4.48 g) was added to a suspension of ethyl l-acetyl-3-hydroxy-lH-pyrazole-4- carboxylate (3.32 g) , propan-2-ol (2.00 g) and
  • triphenylphosphine (5.24 g) in toluene (50 mL) at room
  • reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution.
  • the organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a mixture of the title compound and tert-butyl 6- ⁇ 4- [ (benzyloxy) carbonyl] -3- (propan-2-yloxy) -1H- pyrazol-l-yl ⁇ -2-azaspiro [ 3.3 ] heptane-2-carboxylate .
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution.
  • the organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane and MeOH/ethyl acetate) and preparative HPLC (water/CHaCN containing 0.1% TFA) .
  • the desired fractions were concentrated under reduced pressure.
  • the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution.
  • the organic layer was separated, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (22.2 mg ) .
  • reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution.
  • the organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (68.0 mg) .
  • reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution.
  • the organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (124 mg) .
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution.
  • the organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (33.5 mg) .
  • reaction mixture was partitioned between ethyl acetate and water.
  • organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (MeOH/ethyl acetate and ethyl acetate/hexane) to give the title compound (106 mg) .
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution.
  • the organic layer was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (MeOH/ethyl acetate and ethyl acetate/hexane) and preparative HPLC (water/CH3CN containing 0.1% TFA) .
  • This product was repeatedly purified by silica gel column chromatography (ethyl acetate/hexane and then MeOH/ethyl acetate) to give the title compound (0.3 mg) .

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Abstract

La présente invention concerne un composé ayant une action inhibitrice de CaMKII, qui est supposé être utile en tant qu'agent pour la prophylaxie ou le traitement de maladies cardiaques (en particulier la tachycardie ventriculaire polymorphe catécholaminergique, la fibrillation auriculaire postopératoire, l'insuffisance cardiaque, l'arythmie fatale) et analogues. La présente invention concerne des composés décrits dans des exemples, ou un sel de ceux-ci.
PCT/US2019/052722 2018-09-25 2019-09-24 Composé hétérocyclique WO2020068846A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11130752B2 (en) 2018-09-25 2021-09-28 Cardurion Pharmaceuticals, Llc Aminopyrimidine compound

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US20090181991A1 (en) * 2005-11-03 2009-07-16 Irm Llc Compounds and compositions as protein kinase inhibitors
US8530480B2 (en) * 2007-09-04 2013-09-10 The Scripps Research Institute Substituted pyrimidinyl-amines as protein kinase inhibitors
US9187453B2 (en) * 2012-03-28 2015-11-17 Takeda Pharmaceutical Company Limited Heterocyclic compound
US9212173B2 (en) * 2012-05-03 2015-12-15 Genentech, Inc. Pyrazole aminopyrimidine derivatives as LRRK2 modulators
US20170239264A1 (en) * 2014-08-21 2017-08-24 Pfizer Inc. Aminopyrimidinyl compounds
WO2018183112A1 (fr) * 2017-03-27 2018-10-04 Cardurion Pharmaceuticals, Llc Composé hétérocyclique

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Publication number Priority date Publication date Assignee Title
US20090181991A1 (en) * 2005-11-03 2009-07-16 Irm Llc Compounds and compositions as protein kinase inhibitors
US8530480B2 (en) * 2007-09-04 2013-09-10 The Scripps Research Institute Substituted pyrimidinyl-amines as protein kinase inhibitors
US9187453B2 (en) * 2012-03-28 2015-11-17 Takeda Pharmaceutical Company Limited Heterocyclic compound
US9212173B2 (en) * 2012-05-03 2015-12-15 Genentech, Inc. Pyrazole aminopyrimidine derivatives as LRRK2 modulators
US20170239264A1 (en) * 2014-08-21 2017-08-24 Pfizer Inc. Aminopyrimidinyl compounds
WO2018183112A1 (fr) * 2017-03-27 2018-10-04 Cardurion Pharmaceuticals, Llc Composé hétérocyclique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11130752B2 (en) 2018-09-25 2021-09-28 Cardurion Pharmaceuticals, Llc Aminopyrimidine compound
EP3856188A4 (fr) * 2018-09-25 2022-02-23 Cardurion Pharmaceuticals, LLC Composé d'aminopyrimidine

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