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WO2018181820A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

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Publication number
WO2018181820A1
WO2018181820A1 PCT/JP2018/013469 JP2018013469W WO2018181820A1 WO 2018181820 A1 WO2018181820 A1 WO 2018181820A1 JP 2018013469 W JP2018013469 W JP 2018013469W WO 2018181820 A1 WO2018181820 A1 WO 2018181820A1
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WIPO (PCT)
Prior art keywords
salt
compound
difluoromethyl
methyl
pyrrolo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2018/013469
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English (en)
Japanese (ja)
Inventor
伸之 松永
藤本　卓也
潤 藤本
幸恵 森本
広行 筧
松尾　孝徳
暢 村木
貴子 内藤
珠蘭 加藤
洋 長袋
泰徳 仁尾
賦 大川原
俊太郎 土屋
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Takeda Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Pharmaceutical Co Ltd filed Critical Takeda Pharmaceutical Co Ltd
Publication of WO2018181820A1 publication Critical patent/WO2018181820A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to phosphodiesterase (PDE) inhibition that may be useful for the prevention and / or treatment of pulmonary hypertension, pulmonary fibrosis, fibrosis in the liver, kidney, skin or heart, nonalcoholic steatohepatitis, diabetic nephropathy and the like.
  • PDE phosphodiesterase
  • the present invention relates to a novel compound that can have an action.
  • Pulmonary hypertension is a disease with an extremely poor prognosis, in which pulmonary vascular resistance increases due to abnormal proliferation, remodeling, contraction, etc. of the myocardium and pulmonary vascular tissue, leading to death due to heart failure as the disease progresses.
  • Pulmonary hypertension is mainly classified into five groups according to the onset mechanism. The first group is pulmonary arterial pulmonary hypertension, the second group is pulmonary hypertension associated with left heart disease, and the third group is Pulmonary hypertension associated with pulmonary disease and / or hypoxemia, group 4 includes chronic thromboembolic pulmonary hypertension, group 5 includes pulmonary hypertension associated with multi-factor mechanisms of unknown details, etc. Are classified respectively.
  • the main therapeutic agents currently used are endothelin receptor antagonists, phosphodiesterase 5 inhibitors, prostacyclin analogs, soluble guanylate cyclase (sGC) stimulators, etc., although some symptoms are improved, but still Prognosis is bad.
  • sGC soluble guanylate cyclase
  • pulmonary arterial hypertension associated with connective tissue disease in the first group and pulmonary hypertension in the third group have advanced fibrosis and poor prognosis, and the development of new therapeutic agents is required. Yes.
  • Pulmonary fibrosis represented by interstitial lung disease, is caused by alveolar epithelial cell damage resulting in excessive production of extracellular matrix components, resulting in alveolar stroma fibrosis and respiratory function. It is known as a fatal disease that decreases.
  • Interstitial lung disease is mainly classified into 9 categories: 1) idiopathic interstitial pneumonia of unknown cause, 2) lung disease of collagen disease and related diseases, 3) drug-induced lung disease, 4) neoplastic lung Diseases are included.
  • Idiopathic Pulmonary Fibrosis is the result of excessive production of extracellular matrix components due to the failure of alveolar epithelial cells, resulting in advanced fibrosis of the alveolar stroma and respiratory It is known as a fatal disease with reduced function. Spotted fibrosis is observed, many fibroblast nests are observed, and in high-resolution tomography (HRCT), the fibrotic and thickened septum is seen as honeycomb lungs, and findings with traction bronchodilation are obtained. Symptoms include dry cough and shortness of breath during exertion, resulting in difficulty breathing. The prognosis from the initial diagnosis is very poor, and the survival rate after 5 years is said to be about 50%.
  • the present invention provides a compound that inhibits PDE (especially PDE4 and PDE5) having a chemical structure different from that of known compounds, and a preventive and / or therapeutic agent for pulmonary hypertension, pulmonary fibrosis and the like comprising the compound.
  • PDE especially PDE4 and PDE5
  • a preventive and / or therapeutic agent for pulmonary hypertension, pulmonary fibrosis and the like comprising the compound.
  • the present invention also relates to a compound that inhibits PDE (especially PDE4 and PDE5) having a chemical structure different from that of a known compound, and fibrosis in the liver, kidney, skin or heart, non-alcoholic steatohepatitis comprising the compound
  • PDE especially PDE4 and PDE5
  • Another object is to provide a preventive and / or therapeutic drug for diabetic nephropathy and the like.
  • the present invention [1] 4- [2- (Cyclopropylmethoxy) -5- (difluoromethyl) phenyl] -N- ⁇ 4-[(N, N-dimethylglycyl) amino] cyclohexyl ⁇ -6-methyl-5H-pyrrolo [3,2-d] pyrimidine-7-carboxamide; 4- (5- (Difluoromethyl) -2- ⁇ [1- (difluoromethyl) cyclopropyl] methoxy ⁇ phenyl) -6-methyl-N- [4- (propionylamino) cyclohexyl] -5H-pyrrolo [3, 2-d] pyrimidine-7-carboxamide; and 4- ⁇ 2-[(3-Fluoropyridin-2-yl) methoxy] -5- (trifluoromethyl) phenyl ⁇ -6-methyl-N- [4- (propionylamino) cyclohexyl]
  • the compound of the present invention may have an excellent PDE (particularly PDE4 and / or PDE5) inhibitory action, including pulmonary hypertension, pulmonary fibrosis, fibrosis in the liver, kidney, skin or heart, nonalcoholic steatohepatitis, diabetic It may be useful as a preventive and / or therapeutic agent for nephropathy and the like.
  • the compound of the present invention 4- [2- (Cyclopropylmethoxy) -5- (difluoromethyl) phenyl] -N- ⁇ 4-[(N, N-dimethylglycyl) amino] cyclohexyl ⁇ -6-methyl-5H-pyrrolo [3, 2-d] pyrimidine-7-carboxamide or a salt thereof; 4- (5- (Difluoromethyl) -2- ⁇ [1- (difluoromethyl) cyclopropyl] methoxy ⁇ phenyl) -6-methyl-N- [4- (propionylamino) cyclohexyl] -5H-pyrrolo [3, 2-d] pyrimidine-7-carboxamide or a salt thereof; and 4- ⁇ 2-[(3-Fluoropyridin-2-yl) methoxy] -5- (trifluoromethyl) phenyl ⁇ -6-methyl
  • the compound of the present invention is 4- [2- (Cyclopropylmethoxy) -5- (difluoromethyl) phenyl] -N- ⁇ trans-4-[(N, N-dimethylglycyl) amino] cyclohexyl ⁇ -6-methyl-5H-pyrrolo [ 3,2-d] pyrimidine-7-carboxamide or a salt thereof; 4- (5- (Difluoromethyl) -2- ⁇ [1- (difluoromethyl) cyclopropyl] methoxy ⁇ phenyl) -6-methyl-N- [trans-4- (propionylamino) cyclohexyl] -5H-pyrrolo [ 3,2-d] pyrimidine-7-carboxamide or a salt thereof; and 4- ⁇ 2-[(3-Fluoropyridin-2-yl) methoxy] -5- (trifluoromethyl) phenyl ⁇ -6-methyl-N- [trans-4- (propion)
  • the compound of the present invention is produced by the method described in the examples.
  • the salt in the compound of the present invention is preferably a pharmacologically acceptable salt.
  • a salt with an inorganic base examples include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and a salt with an organic acid. Salts, salts with basic or acidic amino acids are mentioned.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt.
  • salts with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, 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.
  • Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- And salts with toluenesulfonic acid.
  • Preferable examples of the salt 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.
  • the compound of the present invention may have a PDE (particularly PDE4 and / or PDE5) inhibitory action.
  • the compound of the present invention may have low toxicity, and based on PDE (particularly PDE4 and / or PDE5) inhibitory action, mammals (eg, humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, Pulmonary hypertension (Pulmonary Arterial Hypertension (PAH)), Group 1 'pulmonary vein occlusive disease (PVOD) and / or pulmonary capillary hemangiomatosis (dogs, sheep, goats, etc.) PCH), pulmonary hypertension associated with group 2 left heart disease, pulmonary hypertension associated with group 3 pulmonary disease and / or hypoxemia, group 4 chronic thromboembolic pulmonary hypertension (CTEPH), Pulmonary hypertension associated with multi-factor mechanisms of unknown group details), pulmonary fibrosis (Idiopathic Pulmonary Fibrosis (IPF)), lung path
  • the prognosis can be improved in patients with pulmonary hypertension with fibrotic lesions and in patients with pulmonary fibrosis based on both effects of improving fibrosis and reducing pulmonary artery pressure.
  • the compound of the present invention is expected to be useful for the prevention and / or treatment of nonalcoholic steatohepatitis and diabetic nephropathy.
  • the compound of the present invention can be expected to have low toxicity (for example, it should be superior as a pharmaceutical in terms of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.)
  • mammals for example, humans
  • pharmaceutical compositions sometimes referred to herein as “medicaments of the present invention”
  • Monkeys cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.
  • Parenteral administration includes intravenous, intramuscular, subcutaneous, intraorgan, intrapulmonary, intranasal, intradermal, ophthalmic, intracerebral, rectal, intravaginal, intraperitoneal, intratumoral, proximal to tumor, etc. Administration and direct administration to the lesion.
  • the dose of the compound of the present invention may vary depending on the administration route and symptoms.
  • a patient with pulmonary hypertension and / or pulmonary fibrosis adult, body weight 40 to 80 kg, eg 60 kg
  • about 0.001 to about 1000 mg / kg body weight per day preferably about 0 per day 0.01 to about 100 mg / kg body weight, more preferably about 0.1 to about 10 mg / kg body weight per day.
  • This amount may be administered in 1 to 3 divided doses per day.
  • the pharmaceutical dosage form of the present invention includes tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules) ), Lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, film-forms (eg , Orally disintegrating film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), infusion, transdermal preparation, ointment, lotion Oral, parenteral preparations such as suppositories, patches, suppositories (eg, rectal suppositories, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye
  • “pharmaceutically acceptable carrier” examples include various organic or inorganic carriers conventionally used as starting materials.
  • solid preparations include excipients, lubricants, binders, disintegrants, etc.
  • liquid preparations include solvents, solubilizers, suspending agents, isotonic agents, buffering agents, painlessness. And the like.
  • formulation additives such as preservatives, antioxidants, coloring agents, sweeteners and the like can be used.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light
  • excipients include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.
  • lubricant examples include magnesium stearate, calcium stearate, talc and colloidal silica.
  • Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples include propylmethylcellulose and polyvinylpyrrolidone.
  • disintegrant examples include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.
  • Suitable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone , Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
  • polyvinyl alcohol, polyvinylpyrrolidone Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
  • Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.
  • buffer solutions such as phosphate, acetate, carbonate and citrate.
  • Benzyl alcohol is a preferred example of the soothing agent.
  • Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
  • antioxidant examples include sulfite and ascorbate.
  • the colorant examples include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye) and natural dyes (eg, ⁇ -carotene, chlorophyll, bengara).
  • water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.
  • water-insoluble lake dyes Eg, the aluminum salt of the water-soluble edible tar dye
  • natural dyes eg, ⁇ -carotene, chlorophyll, bengara
  • Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
  • the medicament of the present invention can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
  • the content of the compound of the present invention in the medicament of the present invention varies depending on the dosage form, administration method, carrier and the like. , Preferably about 0.1 to about 95% (w / w).
  • the medicament of the present invention can be produced according to a conventional method by adding the compound of the present invention in such a ratio.
  • the compound of the present invention may be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs).
  • concomitant drug examples include pirfenidone used for idiopathic pulmonary fibrosis, sildenafil which is a PDE5 inhibitor, and the like.
  • Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
  • the amount of each agent can be reduced within a safe range in consideration of the opposite effect of these agents. Thus, the adverse effects that would be caused by these agents can be safely prevented.
  • the dose can be reduced.
  • a drug to be used in combination with the compound of the present invention can be selected.
  • the treatment period can be set longer by selecting a concomitant drug having a different mechanism of action from the compound of the present invention.
  • the therapeutic effect can be sustained.
  • excellent effects such as a synergistic effect can be expected.
  • the combined use of the compound of the present invention and the concomitant drug is referred to as “the combination agent of the present invention”.
  • the administration timing of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are simultaneously administered to the administration subject. Alternatively, administration may be performed with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration mode of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) formulating the compound of the present invention and the concomitant drug separately.
  • the concomitant drug of the present invention can be expected to have low toxicity.
  • the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, For example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc., orally or parenterally (eg, topical , Rectal, intravenous administration, etc.).
  • An injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly into a lesion.
  • Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances commonly used as a pharmaceutical material.
  • a pharmaceutical material for solid preparations, excipients, lubricants, binders, disintegrants and the like can be mentioned.
  • Liquid preparations include solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents and the like. Further, if necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation. For example, it is about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight based on the whole preparation. % By weight, more preferably about 0.5 to about 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, for example, about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, based on the whole preparation, More preferably, it is about 0.5 to about 20% by weight.
  • the content of an additive such as a carrier in the combination agent of the present invention varies depending on the form of the preparation. For example, it is about 1 to about 99.99% by weight, preferably about 10 to about 90% by weight based on the whole preparation. Degree. The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
  • an ESI method or an APCI method was used as the ionization method.
  • the data shows actual values (found).
  • a molecular ion peak is observed, but it may be observed as a fragment ion.
  • a free molecular ion peak or a fragment ion peak is usually observed.
  • the mixture was stirred at room temperature overnight.
  • the mixture was diluted with ethyl acetate, and water and saturated aqueous sodium hydrogen carbonate solution were added at room temperature.
  • the organic layer was separated and the aqueous layer was extracted with ethyl acetate.
  • the combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was suspended in isopropyl acetate, and the resulting precipitate was collected by filtration.
  • the obtained solid was washed with isopropyl acetate to give the title compound (18.31 g).
  • Example compounds are shown in Table 1 below. MS in the table indicates actual measurement.
  • Formulation Example A preparation containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.
  • Example 1 Inhibitory activity was evaluated using PDE4B, PDE4D and PDE5A proteins (BPS Bioscience) produced in Sf9 cells.
  • Assay buffer 50 mM Tris-HCl, 8.3 mM MgCl 2 , 1.7 mM EGTA, 0.1%) containing each PDE in Example 1, Example 2 and Example 3 (10 ⁇ 12 ⁇ 10 ⁇ 5 M) or solvent BSA) for 30 minutes, then [ 3 H] -labeled cAMP or cGMP (PerkinElmer) was added for 60 minutes and PDE4 and 5 inhibitory activity was assessed as radioactivity using a scintillation counter (PerkinElmer) . Based on the inhibitory activity at each concentration, the 50% inhibitory concentration (IC 50 ) value (M) was calculated.
  • IC 50 values for PDE4B, PDE4D and PDE5A in each example are shown in Table 2.
  • the present invention may have an excellent PDE (particularly PDE4 and / or PDE5) inhibitory action, pulmonary hypertension, pulmonary fibrosis, fibrosis in the liver, kidney, skin or heart, non-alcoholic steatohepatitis, diabetes
  • PDE PDE
  • pulmonary hypertension pulmonary hypertension
  • pulmonary fibrosis fibrosis in the liver, kidney, skin or heart
  • non-alcoholic steatohepatitis diabetes
  • compounds that can be useful as preventive and / or therapeutic agents for nephropathy and the like.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un composé qui peut être efficace pour la prévention et/ou le traitement de l'hypertension pulmonaire, de la fibrose pulmonaire, de la fibrose hépatique, rénale, cutanée ou cardiaque, de la stéatohépatite non alcoolique, de la néphropathie diabétique et autres. L'invention concerne un composé, ou un sel correspondant, choisi parmi : le 4-[2-(cyclopropylméthoxy)-5-(difluorométhyl)phényl]-N-{4-[(N,N-diméthylglycyl)amino]cyclohexyl}-6-méthyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide ; le 4-(5-(difluorométhyl)-2-{[1-(difluorométhyl)cyclopropyl]méthoxy}phényl)-6-méthyl-N-[4-(propionylamino)cyclohexyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide ; et le 4-{2-[(3-fluoropyridine-2-yl)méthoxy]-5-(trifluorométhyl)phényl}-6-méthyl-N-[4-(propionylamino)cyclohexyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide.
PCT/JP2018/013469 2017-03-31 2018-03-29 Composé hétérocyclique Ceased WO2018181820A1 (fr)

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JP2017072396A JP2020097527A (ja) 2017-03-31 2017-03-31 複素環化合物

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JP2013503131A (ja) * 2009-08-26 2013-01-31 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング メチルピロロピリミジンカルボキサミド
WO2016191334A1 (fr) * 2015-05-27 2016-12-01 Merck Sharp & Dohme Corp. Dérivés d'imidazo-pyrazinyle utiles à titre d'activateurs de guanylate cyclase solubles
JP2017507140A (ja) * 2014-02-19 2017-03-16 バイエル・ファルマ・アクティエンゲゼルシャフト ３−（ピリミジン−２−イル）イミダゾ［１，２−ａ］ピリジン

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JP2013503131A (ja) * 2009-08-26 2013-01-31 ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング メチルピロロピリミジンカルボキサミド
JP2017507140A (ja) * 2014-02-19 2017-03-16 バイエル・ファルマ・アクティエンゲゼルシャフト ３−（ピリミジン−２−イル）イミダゾ［１，２−ａ］ピリジン
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