WO2017170354A1 - 医薬 - Google Patents
医薬 Download PDFInfo
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- WO2017170354A1 WO2017170354A1 PCT/JP2017/012305 JP2017012305W WO2017170354A1 WO 2017170354 A1 WO2017170354 A1 WO 2017170354A1 JP 2017012305 W JP2017012305 W JP 2017012305W WO 2017170354 A1 WO2017170354 A1 WO 2017170354A1
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- pulmonary hypertension
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- tetrahydropyrazolo
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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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- 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
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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
Definitions
- the present invention relates to a medicament for preventing or treating pulmonary hypertension.
- Pulmonary hypertension is a disease with a very poor prognosis, in which pulmonary artery pressure increases due to abnormal growth, remodeling, and contraction of the myocardium and pulmonary vascular tissue, and as the disease progresses, it leads to death due to right heart failure.
- 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
- CaSR Calcium-sensitive receptor
- GPCR G protein-coupled receptor
- Non-Patent Documents 1 to 5 In monocrotaline (MCT) -induced pulmonary hypertension rats and hypoxia-induced pulmonary hypertension (HPH) mice, compound NPS-2143 having an action as a CaSR antagonist produced cardiac hypertrophy, increased right ventricular systolic pressure, It has been reported that myocardial tissue fibrosis and pulmonary vascular remodeling are suppressed (Non-Patent Documents 1 to 5).
- NPS-2143 and Calhex 231 enhance the effect of an existing pulmonary arterial hypertension (PAH) therapeutic agent (PDE5 inhibitor / sildenafil) (Non-patent Document 7).
- PAH pulmonary arterial hypertension
- PDE5 inhibitor / sildenafil pulmonary hypertension
- CaSR pulmonary arterial hypertension
- the present invention provides a medicament for preventing or treating pulmonary hypertension.
- the present inventors have found that a compound selected from the group consisting of Compound A, Compound B, Compound C, and salts thereof is effective in preventing or treating pulmonary hypertension.
- the present invention is based on the above findings.
- pulmonary hypertension can be prevented or treated.
- the medicament of the present invention can be administered orally, and when administered orally, it has fewer side effects (for example, infection) than a parenteral medicament, and has an excellent therapeutic effect on pulmonary hypertension and Prognostic improvement effect is expected, and when used in combination with existing drugs, it has the advantage that it is easy for patients, healthcare workers, and related parties to handle.
- FIG. 1 shows Kaplan-Meier survival curves for each administration group in a rat model of monocrotaline-induced pulmonary hypertension.
- the term “subject” is a mammal, for example, a human.
- “subject with pulmonary hypertension” means a subject suffering from pulmonary hypertension. If the subject is a human, the subject is called a “patient”. If the subject suffering from pulmonary hypertension is a human, the subject is referred to as a “pulmonary hypertension patient”.
- the term “pharmaceutically acceptable salt” means an acid addition salt or a base addition salt that is acceptable when administered to a living body.
- the term “therapeutically effective amount” means an amount that provides a therapeutic effect to a subject, for example, in a subject who has been administered this amount compared to a subject who has not been administered this amount, It means that a symptom or condition of a disease is alleviated, alleviated or eliminated, or its progress is delayed or suppressed.
- the therapeutically effective amount can be appropriately determined by the doctor according to the age, weight, sex, and severity of symptoms of the subject.
- pulmonary hypertension means a state in which the pulmonary artery pressure has increased.
- General “hypertension” means a state in which the blood pressure of blood that is pumped from the left ventricle through the aorta into the body is increased, whereas “pulmonary hypertension” is from the right ventricle to the lungs.
- the pulmonary artery connected to is hypertensive. Pulmonary hypertension develops independently of general hypertension.
- Normal values of pulmonary artery pressure at rest on the pulmonary side are a systolic pressure of about 20 mmHg to about 30 mmHg, a diastolic pressure of about 7 mmHg to about 12 mmHg, and an average pressure of about 10 mmHg to about 15 mmHg.
- pulmonary hypertension The criteria for determining pulmonary hypertension are described in, for example, the Guidelines for Treatment of Pulmonary Hypertension (2012 revised edition) by the Japanese Circulation Society. Diagnosis of pulmonary hypertension in humans is usually made based on pulmonary artery mean pressure (mean PAP) measured by right heart catheterization at rest, and pulmonary hypertension can be diagnosed when the pulmonary artery mean pressure is 25 mmHg or more. it can. Recent developments in echocardiography enable non-invasive estimation of pulmonary artery pressure, and diagnosis of pulmonary hypertension may be made based on the estimated value of pulmonary artery pressure.
- mean PAP mean pressure
- echocardiography enable non-invasive estimation of pulmonary artery pressure, and diagnosis of pulmonary hypertension may be made based on the estimated value of pulmonary artery pressure.
- Pulmonary hypertension is clinically classified into five groups from Group 1 to Group 5 according to the Dana Point classification.
- Group 1 is pulmonary arterial hypertension (PAH)
- Group 2 is pulmonary hypertension associated with left ventricular heart disease
- Group 3 is pulmonary hypertension associated with lung disease and / or hypoxemia
- Group 4 is chronic thromboembolic pulmonary hypertension
- Group 5 is pulmonary hypertension due to complex factors of unknown details.
- the first group pulmonary vein embolic disease and / or pulmonary capillary hemangiomatosis
- the first group newborn prolonged pulmonary hypertension
- the first group of pulmonary arterial hypertension is the most typical pulmonary hypertension, and is roughly divided into idiopathic PAH, hereditary PAH, drug-toxin-induced PAH, and PAH associated with each disease.
- various symptoms associated with pulmonary hypertension such as, for example, reducing pulmonary arterial pressure in the subject (Such as an increase in right ventricular pressure) can be improved.
- a medicament for preventing or treating pulmonary hypertension comprising compounds selected from compounds A, B and C and salts thereof.
- Compound A is represented by the following formula:
- Compound B is represented by the following formula.
- Compound C is represented by the following formula:
- the medicament of the present invention comprises the following pulmonary hypertension: pulmonary arterial pulmonary hypertension; pulmonary hypertension due to pulmonary vein embolism; pulmonary hypertension due to pulmonary capillary hemangiomatosis; Hypertension; pulmonary hypertension with left ventricular systolic failure, left ventricular diastolic dysfunction, valvular disease, or congenital / acquired left ventricular inflow / outflow tract obstruction; chronic obstructive pulmonary disease, interstitial lung disease, restraint Other pulmonary diseases with mixed obstructive and obstructive disorders, sleep breathing disorder, alveolar hypoventilation disorder, chronic exposure at high altitudes, or pulmonary hypertension due to developmental disorders; chronic thromboembolic pulmonary hypertension; blood disorders (chronic) Hemolytic anemia, myeloproliferative disease or splenectomy), systemic disease (sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangio
- Solvates can be formed with solvents such as ethanol and water. Solvates in which the solvent incorporated is water are hydrates. Hydrates include those containing various amounts of water in addition to stoichiometric hydrates.
- Compounds A, B and C and salts thereof may be labeled with isotopes (eg, 3 H, 13 C, 14 C, 18 F, 35 S, 125 I) and the like.
- deuterium converters in which 1 H is converted to 2 H (D) are also encompassed in compounds A, B and C and salts thereof.
- Examples of the salts of compounds A, B and C include salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Can be mentioned.
- Preferable examples of 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, magnesium salt and barium salt; aluminum salt and the like.
- Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like.
- Preferable examples of the salt 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. Of these salts, pharmaceutically acceptable salts are preferred.
- the salt of Compound A can be p-toluenesulfonate (tosylate) (hereinafter also referred to as “Compound A ′”).
- the salt of Compound B can be the hydrochloride salt (hereinafter also referred to as “Compound B ′”).
- the salt of Compound C may be p-toluenesulfonate (tosylate) (hereinafter also referred to as “Compound C ′”).
- a compound selected from Compound A, Compound A ′, Compound B, Compound B ′, Compound C and Compound C ′ can be used for the prevention or treatment of pulmonary hypertension. Therefore, according to the present invention, there is provided a medicament for preventing or treating pulmonary hypertension, comprising a compound selected from Compound A, Compound A ′, Compound B, Compound B ′, Compound C and Compound C ′.
- the pulmonary hypertension can be pulmonary arterial pulmonary hypertension.
- Compound A or Compound A ′ can be used for the prevention or treatment of pulmonary hypertension.
- a medicament for preventing or treating pulmonary hypertension comprising Compound A or Compound A ′ is provided.
- the pulmonary hypertension can be pulmonary arterial pulmonary hypertension.
- compound A ′ can be used for the prevention or treatment of pulmonary hypertension. Therefore, according to the present invention, there is provided a medicament for preventing or treating pulmonary hypertension comprising Compound A ′.
- the pulmonary hypertension can be pulmonary arterial pulmonary hypertension.
- the group consisting of right ventricular pressure, right ventricular systolic pressure, survival rate and cardiac hypertrophy in a subject with pulmonary hypertension comprising compounds selected from compounds A, B and C and salts thereof
- a medicament for improving one or more conditions selected from is provided.
- a medicament for improvement is provided.
- a medicament for improving one or more conditions selected from the group consisting of right ventricular pressure, right ventricular systolic pressure, survival rate, and cardiac hypertrophy in a subject with pulmonary hypertension comprising compound A ′
- a medicament for improving one or more conditions selected from the group consisting of right ventricular pressure, right ventricular systolic pressure, survival rate, and cardiac hypertrophy in a subject with pulmonary hypertension comprising compound A ′
- a medicament is provided.
- the dose varies depending on the administration subject, administration route, disease, symptoms, etc., but for example, when orally administered to a human (body weight of about 50 kg), it is preferably in the range of about 0.1 mg to about 500 mg as Compound A, B or C Can be selected from the range of about 1 mg to about 100 mg, for parenteral administration, the range of about 0.01 mg to about 100 mg, preferably the range of about 0.1 mg to about 10 mg. This amount can be administered in one to several times a day (eg, 1 to 3 times a day).
- the medicament of the present invention may contain a compound selected from Compounds A, B and C and salts thereof and a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials can be used. Excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, dissolution aids It can be formulated as an agent, suspending agent, isotonic agent, buffer, soothing agent and the like. If necessary, formulation additives such as preservatives, antioxidants, stabilizers, colorants, sweeteners and the like can also be used.
- the medicament of the present invention can be a medicament for parenteral administration or oral administration.
- the medicament of the present invention can also be a medicament for oral administration.
- the medicament of the present invention can be used in combination with other drugs such as a therapeutic drug for pulmonary hypertension.
- other drugs such as a therapeutic drug for pulmonary hypertension.
- it can be used in combination with the following drugs.
- Endothelin receptor antagonists Endothelin receptor antagonists such as macitentan, bosentan, ambrisentan
- Prostaglandin preparations Prostaglandin preparations (or prostacyclin preparations such as epoprostenol, beraprost, treprostinil, iloprost, selexipag)
- Phosphodiesterase-5 inhibitors Phosphodiesterase-5 inhibitors such as sildenafil and tadalafil
- Soluble adenylate cyclase stimulators Riociguat and other soluble adenylate cyclase stimulators
- Calcium channel antagonists such as nifedipine, diltiazem and amlodipine Calcium channel antagonists
- Examples of the pharmaceutical compounded or used in combination with the pharmaceutical agent of the present invention include compounds A, B and C and compounds formulated in a single formulation containing a compound and a concomitant drug selected from salts thereof, and compounds A, B and Any of those in which a compound selected from C and salts thereof and a concomitant drug are separately formulated are included.
- these are collectively referred to as the combination agent of the present invention.
- the concomitant agent of the present invention comprises a compound selected from compounds A, B and C and salts thereof and a concomitant drug separately or simultaneously, as they are or with a pharmaceutically acceptable carrier, etc. It can be formulated by a method similar to a medicine containing a compound selected from B and C and salts thereof.
- the daily dose of the concomitant drug of the present invention varies depending on the degree of symptoms; age, sex, body weight, sensitivity difference of administration subject; timing and interval of administration; nature of drug, preparation, type; type of active ingredient, etc. There is no particular limitation.
- the compound selected from the compounds A, B and C and salts thereof and the concomitant drug may be administered at the same time, but after the concomitant drug is administered first, A compound selected from A, B and C and salts thereof may be administered, or a compound selected from compounds A, B and C and salts thereof may be administered first, followed by administration of a concomitant drug. Good.
- the time difference varies depending on the active ingredient, dosage form, and administration method to be administered.
- Examples include a method of administering a compound selected from Compounds A, B and C and salts thereof within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
- a compound selected from Compounds A, B and C and salts thereof is administered first, 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 after administration of the compound.
- the method of administering a concomitant drug within time is mentioned.
- concomitant drug of the present invention comprising simultaneously a compound selected from compounds A, B and C and salts thereof and a concomitant drug
- respective contents of the compound selected from compounds A, B and C and salts thereof and a concomitant drug is usually about 0.01 to 90% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight based on the whole preparation. is there.
- the content of the carrier in the concomitant is usually about 0 to 99.8% by weight, preferably about 10 to 99.8% by weight, more preferably about 10 to 90% by weight, based on the whole preparation. .
- the concomitant drug including the concomitant drug is a compound selected from compounds A, B and C and salts thereof It can be manufactured and used in the same manner.
- the medicament of the present invention may be a solid preparation such as powder, granule, tablet or capsule, or a liquid such as syrup or emulsion.
- the medicament of the present invention can be produced by a conventional method such as mixing, kneading, granulation, tableting, coating, sterilization, emulsification, etc., depending on the form of the preparation. Regarding the production of the preparation, for example, the respective items of the 16th revised Japanese Pharmacopoeia General Rules for Preparations can be referred.
- the medicament of the present invention may be formed into a sustained release agent containing an active ingredient and a biodegradable polymer compound.
- a medicament for preventing or treating pulmonary hypertension in a subject in need thereof comprising a compound selected from compounds A, B and C and salts thereof, and a combination drug, A medicament for use in combination is provided.
- a method for preventing or treating pulmonary hypertension in a subject in need thereof comprising administering to the subject a compound selected from compounds A, B and C and salts thereof.
- a method is provided.
- the pulmonary hypertension to be treated can be any of the diseases or conditions described as the treatment target for the medicament of the present invention.
- the subject can be administered a therapeutically effective amount of the compound.
- a medicament containing the compound selected from the compounds A, B and C and salts thereof may be administered.
- pulmonary hypertension to be treated by the above-mentioned medicine can be any of the diseases or conditions described as the treatment object for the medicine of the present invention.
- a compound selected from the group consisting of compounds A, B and C and salts thereof for use in preventing or treating pulmonary hypertension can be any of the diseases or conditions described as the treatment target for the medicament of the present invention.
- the compound to be administered or the compound contained in the medicament is the tosylate salt of Compound A.
- Example 1 Therapeutic effect of compound A 'on pulmonary hypertension in pulmonary hypertension model animals (right ventricular pressure, right ventricular systolic pressure, right heart hypertrophy, pulmonary artery medial thickness, pulmonary artery occlusion)
- the data in the table shows the mean ⁇ standard deviation.
- RVSP right ventricular systolic pressure
- the data in the table shows the mean ⁇ standard deviation.
- RVSP right ventricular systolic pressure
- the data in the table shows the mean ⁇ standard deviation.
- the data in the table shows the mean ⁇ standard error.
- the data in the table shows the mean ⁇ standard error.
- Example 2 Therapeutic effect (survival rate) of Compound A 'on pulmonary hypertension in pulmonary hypertension model animals
- Fig. 1 shows a Kaplan-Meier survival curve obtained from the above experiment.
- NHE (Na + -H + exchange) protein is an important molecule involved in the pathogenesis of pulmonary hypertension, and it can be applied to various pulmonary hypertension animals induced by monocrotaline and hypoxia. It has been shown by administration of various NHE inhibitor compounds and experiments using knockout animals of NHE (Chen et al., 2001; Huetsch et al., 2016; Huetsch and Shimoda, 2015; Yu et al., 2008) . CHP is an essential cofactor for the localization and function of NHE in the cell membrane (Matsushita et al., 2007; Mishima et al., 2007; Pang et al., 2001). Therefore, whether compound A ′ inhibits the interaction of NHE1-CHP1 was examined.
- This NHE1 microsomal fraction and CHP1 are diluted with assay buffer (25 mM Tris-HCl (pH7.4), 137 mM NaCl, 2.7 mM KCl, 0.1% BSA, 1 mM DTT), and compound A 'is added thereto. did. Then, this was added to Alpha Plate-384 Shallow well (PerkinElmer) by 2 ⁇ L / well and reacted at room temperature for 60 minutes. 2 ⁇ L / well of Acceptor Beads and Donor Beads attached to AlphaScreen FLAG (M2) Detection Kit (PerkinElmer) were added thereto and reacted at room temperature for 60 minutes. Then, ApphaScreen signal intensity was measured using EnSpire Multi-label reader (PerkinElmer). Different concentrations of Compound A ′ (concentration: 50.0 nM to 0.8 nM) were evaluated in this test system.
- assay buffer 25 mM Tris-HCl (pH7.
- a medicament for preventing or treating pulmonary hypertension is provided and useful.
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Abstract
Description
肺高血圧症は、心筋や、肺血管組織の異常な増殖やリモデリング、収縮などにより肺動脈圧が上昇し、病気の進行とともに右心不全を併発して死に至る、予後がきわめて不良な疾患である。現在使われている主な治療薬は、エンドセリン受容体アンタゴニスト、ホスホジエステラーゼ5阻害剤、プロスタサイクリンアナログ、可溶性グアニル酸シクラーゼ(sGC)刺激剤などであるが、一部症状の改善がみられるものの、依然予後が悪い。近年、疾患の病態に複数の分子が関与していることが明らかになり、また、現行の治療薬も単剤での効果が限定的であることから、新しい治療薬の開発が望まれている。
[1]肺高血圧症を予防または治療するための、
(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-メトキシフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-5-(2-フルオロフェニル)-2,7,7-トリメチル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、およびそれらの塩からなる群から選ばれる化合物を含有してなる、医薬。
[2]肺高血圧症が肺動脈性肺高血圧症である、上記[1]記載の医薬。
[3]哺乳動物に対して(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-メトキシフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-5-(2-フルオロフェニル)-2,7,7-トリメチル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、およびそれらの塩からなる群から選ばれる化合物を投与することを特徴とする、該哺乳動物における肺高血圧症の予防または治療方法。
[4]肺高血圧症が肺動脈性肺高血圧症である、上記[3]記載の方法。
[5]肺高血圧症を予防または治療するための、(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-メトキシフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-5-(2-フルオロフェニル)-2,7,7-トリメチル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、およびそれらの塩からなる群から選ばれる化合物。
[6]肺高血圧症が肺動脈性肺高血圧症である、上記[5]記載の化合物。
[7]肺高血圧症の予防または治療剤を製造するための、(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-メトキシフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-5-(2-フルオロフェニル)-2,7,7-トリメチル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、およびそれらの塩からなる群から選ばれる化合物の使用。
[8]肺高血圧症が肺動脈性肺高血圧症である、上記[7]記載の使用。
ヒトにおける肺高血圧症の診断は、通常は、安静時に右心カテーテル検査により実測した肺動脈平均圧(mean PAP)に基づきなされ、肺動脈平均圧が25mmHg以上である場合に肺高血圧症と診断することができる。近年の心エコーの発展により、非観血的に肺動脈圧を推定することが可能になり、肺動脈圧の推定値に基づいて肺高血圧症の診断を行うこともある。
さらに、1Hを2H(D)に変換した重水素変換体も、化合物A、BおよびC並びにこれらの塩に包含される。
無機塩基との塩の好適な例としては、ナトリウム塩、カリウム塩などのアルカリ金属塩;カルシウム塩、マグネシウム塩、バリウム塩などのアルカリ土類金属塩;アルミニウム塩などが挙げられる。
有機塩基との塩の好適な例としては、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ジシクロヘキシルアミン、N,N’-ジベンジルエチレンジアミンなどとの塩が挙げられる。
無機酸との塩の好適な例としては、塩酸、臭化水素酸、硝酸、硫酸、リン酸などとの塩が挙げられる。
有機酸との塩の好適な例としては、ギ酸、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸などとの塩が挙げられる。
塩基性アミノ酸との塩の好適な例としては、アルギニン、リジン、オルニチンなどとの塩が挙げられる。
酸性アミノ酸との塩の好適な例としては、アスパラギン酸、グルタミン酸などとの塩が挙げられる。
これらの塩のなかでも、薬学的に許容し得る塩が好ましい。
本発明の特定の態様では、化合物Aまたは化合物A’を肺高血圧症の予防または治療に用いることができる。従って、本発明によれば、化合物Aまたは化合物A’を含む、肺高血圧症を予防または治療するための医薬が提供される。この特定の態様において、肺高血圧症は、肺動脈性肺高血圧症とすることができる。
本発明の特定の態様では、化合物A’を肺高血圧症の予防または治療に用いることができる。従って、本発明によれば、化合物A’を含む、肺高血圧症を予防または治療するための医薬が提供される。この特定の態様において、肺高血圧症は、肺動脈性肺高血圧症とすることができる。
本発明の特定の態様では、化合物Aまたは化合物Aの塩を含む、肺高血圧症の対象において右心室圧、右心室収縮圧、生存率、および心肥大からなる群から選ばれる1以上の状態を改善するための医薬が提供される。
本発明の特定の態様では、化合物A’を含む、肺高血圧症の対象において右心室圧、右心室収縮圧、生存率、および心肥大からなる群から選ばれる1以上の状態を改善するための医薬が提供される。
薬学的に許容し得る担体としては、製剤素材として慣用の各種有機あるいは無機担体物質が用いられ得、固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤;液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤などとして配合され得る。また必要に応じて、防腐剤、抗酸化剤、安定化剤、着色剤、甘味剤などの製剤添加物を用いることもできる。
(1)エンドセリン受容体拮抗薬
マシテンタン、ボセンタン、アンブリセンタンなどのエンドセリン受容体拮抗薬
(2)プロスタグランジン製剤
エポプロステノール、ベラプロスト、トレプロスチニル、イロプロスト、セレキシパグなどのプロスタグランジン製剤(またはプロスタサイクリン製剤)
(3)ホスホジエステラーゼ-5阻害剤
シルデナフィル、タダラフィルなどのホスホジエステラーゼ-5阻害剤
(4)可溶性アデニル酸シクラーゼ刺激剤
リオシグアトなどの可溶性アデニル酸シクラーゼ刺激剤
(5)カルシウムチャネル拮抗剤
ニフェジピン、ジルチアゼム、アムロジピンなどのカルシウムチャネル拮抗剤
(6)Rhoキナーゼ阻害剤
ファスジルなどのRhoキナーゼ阻害剤
(7)その他
イマニチブ、ソラフェニブなどのチロシンキナーゼ阻害剤、ワーファリン、アスピリンなどの抗凝固剤、フロセミド、スピロノラクトンなどの利尿剤、ドーパミン、ジゴキシンなどの強心薬など
本発明の医薬は、製剤の形態に応じて、例えば、混和、混練、造粒、打錠、コーティング、滅菌処理、乳化などの慣用の方法で製造できる。なお、製剤の製造に関して、例えば第十六改正日本薬局方製剤総則の各項などを参照できる。また本発明の医薬は、有効成分と生体内分解性高分子化合物とを含む徐放剤に成形してもよい。
体重(250g±10%)の雄性Sprague-Dawleyラットに、モノクロタリン(MCT) 50 mg/kg(50% ジメチルスルホキシド溶液)を皮下注射して肺高血圧症ラットモデルを作製した。MCT投与後14日目より14日間にわたり、化合物A’投与群 (投与用量:1 mg/kg, 3 mg/kg, または10 mg/kg)、または対照群として同量の溶媒を連日経口投与した。この実験は各群9匹で実施した(溶媒対照群のみ、12匹用いた)。
MCT投与後28日の時点で生存していたラット(負対照群(モノクロタリン非投与群)、9匹、溶媒対照群、8匹、化合物A' 1 mg/kg投与群、9匹、化合物A' 3 mg/kg投与群、5匹、化合物A' 10 mg/kg投与群、9匹。合計40匹)について、カテーテル検査により、右心室圧(RVP)を測定した。結果を表1に示す。
MCT投与後28日の時点で生存していたラット((負対照群(モノクロタリン非投与群)、9匹、溶媒対照群、8匹、化合物A' 1 mg/kg投与群、9匹、化合物A' 3 mg/kg投与群、5匹、化合物A' 10 mg/kg投与群、9匹。合計40匹))について、カテーテル検査により、右室収縮期圧(RVSP)を測定した。結果を表2に示す。
MCT投与後28日の時点で生存していたラット(負対照群(モノクロタリン非投与群)、9匹、溶媒対照群、8匹、化合物A' 1 mg/kg投与群、9匹、化合物A' 3 mg/kg投与群、5匹、化合物A' 10 mg/kg投与群、9匹。合計40匹))について、肺高血圧症モデルラットの右心室重量(RV)、左心室重量(LV)、および心室中隔重量(S)を測定し、右心肥大の指標としてRV/(LV+S)を求めた。結果を表3に示す。
MCT投与後28日の時点で生存していたラット(負対照群(モノクロタリン非投与群)、9匹、溶媒対照群、8匹、化合物A' 10 mg/kg投与群、9匹)のうち、各群5匹(合計15匹)について、肺高血圧症モデルラットの肺組織切片の組織標本をエラスチカワンギーソン染色法にて調製し、肺動脈の中膜の肥厚を測定した。結果を表4に示す。
MCT投与後28日の時点で生存していたラット(負対照群(モノクロタリン非投与群)9匹、溶媒対照群8匹、化合物A' 10 mg/kg投与群9匹)のうち、各群5匹(合計15匹)について、肺高血圧症モデルラットの肺組織切片の組織標本をエラスチカワンギーソン染色法にて調製し、肺動脈の閉塞を測定した。閉塞の指標には、肺動脈中膜の厚みの2倍を肺動脈の径で割った値を用いた。結果を表5に示す。
体重(230g±10g)の雄性Sprague-Dawleyラットに、モノクロタリン(MCT) 50 mg/kg (50% ジメチルスルホキシド溶液)を皮下注射して肺高血圧症ラットモデルを作製した。MCT投与後14日目より14日間にわたり、化合物A’投与群 (投与用量:1 mg/kg, 3 mg/kg, または10 mg/kg)、または対照群として同量の溶媒を一日一回、連日経口投与した。この実験は各群12匹で実施した。
図1に上記実験から得られたカプランマイヤー生存曲線を示す。
ヒトNHE1とヒトCHP1との相互作用に対する化合物A'の阻害活性の評価は、化学増幅型ルミネッセンスプロキシミティホモジニアスアッセイ(AlphaScreenTM (PerkinElmer))を用いたタンパク質相互作用の測定系で行った。FLAGタグ付きの全長ヒトNHE1 (Accession No. NM_003047)のミクロソーム画分は、ヒト胎児腎細胞由来FreeStyleTM 293細胞で発現させて調製した。また、ビオチン化した全長のヒト CHP1 (Accession No. NM_007236)は、小麦胚芽無細胞翻訳系で発現させて精製した。このNHE1ミクロソーム画分とCHP1とをアッセイバッファー(25 mM Tris-HCl (pH7.4), 137 mM NaCl, 2.7 mM KCl, 0.1 % BSA, 1mM DTT)にて希釈し、そこに化合物A'を添加した。そして、これをAlpha Plate-384 Shallow well(PerkinElmer)に2 μL/wellずつ添加して60分間室温で反応させた。そこにAlphaScreen FLAG(M2) Detection Kit(PerkinElmer)付属のAcceptor BeadsおよびDonor Beadsを各2μL/wellずつ添加して60分間室温で反応させた。その後、EnSpire Multi-label reader(PerkinElmer)を用いてApphaScreenシグナル強度を測定した。この試験系で異なる濃度の化合物A'(濃度:50.0 nM~0.8 nM)を評価した。
表6に結果を示す。
本出願は、日本特許出願2016-063747号(2016年3月28日出願)に基づく優先権を主張しており、この内容はその全体が本明細書に参照として取り込まれる。
Claims (8)
- 肺高血圧症を予防または治療するための、
(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-メトキシフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-5-(2-フルオロフェニル)-2,7,7-トリメチル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、およびそれらの塩からなる群から選ばれる化合物を含有してなる、医薬。 - 肺高血圧症が肺動脈性肺高血圧症である、請求項1記載の医薬。
- 哺乳動物に対して(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-メトキシフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-5-(2-フルオロフェニル)-2,7,7-トリメチル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、およびそれらの塩からなる群から選ばれる化合物を投与することを特徴とする、該哺乳動物における肺高血圧症の予防または治療方法。
- 肺高血圧症が肺動脈性肺高血圧症である、請求項3記載の方法。
- 肺高血圧症を予防または治療するための、(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-メトキシフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-5-(2-フルオロフェニル)-2,7,7-トリメチル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、およびそれらの塩からなる群から選ばれる化合物。
- 肺高血圧症が肺動脈性肺高血圧症である、請求項5記載の化合物。
- 肺高血圧症の予防または治療剤を製造するための、(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-メトキシフェニル)プロピル]-2,7,7-トリメチル-5-フェニル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、(5R)-N-[1-エチル-1-(4-エチルフェニル)プロピル]-5-(2-フルオロフェニル)-2,7,7-トリメチル-4,5,6,7-テトラヒドロピラゾロ[1,5-a]ピリミジン-3-カルボキサミド、およびそれらの塩からなる群から選ばれる化合物の使用。
- 肺高血圧症が肺動脈性肺高血圧症である、請求項7記載の使用。
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JP2021530481A (ja) * | 2018-07-10 | 2021-11-11 | ゾゲニクス インターナショナル リミテッド | 肺高血圧症を有さない患者においててんかんまたはてんかん性脳症を処置するために使用するためのフェンフルラミン |
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JP7002444B2 (ja) | 2022-01-20 |
ES2882175T3 (es) | 2021-12-01 |
EP3437644A4 (en) | 2019-11-27 |
EP3437644A1 (en) | 2019-02-06 |
CA3019091A1 (en) | 2017-10-05 |
US20200306249A1 (en) | 2020-10-01 |
JPWO2017170354A1 (ja) | 2019-02-07 |
EP3437644B1 (en) | 2021-06-30 |
JP2022001585A (ja) | 2022-01-06 |
CN109069510A (zh) | 2018-12-21 |
US11033550B2 (en) | 2021-06-15 |
CA3019091C (en) | 2024-01-02 |
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