Novel prostacyclins for the treatment of pulmonary hypertension

Abstract

The present invention relates to a novel prostacyclin for treating pulmonary hypertension. More specifically, the compound of the present invention has a structure represented by formula (I), and the definitions of each group and substituent are as described herein. The compound of the present invention has superior RVSP (right ventricular systolic pressure) and Fulton index compared to treprostinil and its salts. [Formula 1] JPEG2025529392000042.jpg39170

Description

[Technical Field]

[0001] This invention relates to the field of pharmaceuticals, and more particularly to a novel prostacyclin for the treatment of pulmonary hypertension. [Background technology]

[0002] Treprostinil is a drug used to treat pulmonary artery hypertension (PAH). It is a prostacyclin derivative with activity that inhibits platelet aggregation and vasodilation. Approved commercially available dosage forms include injections, inhalations, and oral tablets. The active ingredient for the injection and inhalation formulations is treprostinil sodium salt.

[0003] However, conventional treprostinil sodium salt still has the problem of unsatisfactory therapeutic effects in the treatment of pulmonary arterial hypertension, making the development of more effective drugs for the treatment of pulmonary arterial hypertension an urgent need in this field.

[0004] Ralinepag is a drug currently in Phase III trials for the treatment of pulmonary arterial hypertension, and its structure is as follows: [ka] [Overview of the Initiative]

[0005] The object of the present invention is to provide a compound represented by formula (I), a method for producing the same, and its use in the treatment of pulmonary arterial hypertension.

[0006] One aspect of the present invention provides a compound represented by formula (I), a solvate thereof, or a pharmaceutically acceptable salt thereof. [ka] Here, R1 and R2 are each independently selected from the group consisting of a hydrogen atom, deuterium, halogen atom, hydroxyl group, amino group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C2-C6 alkenyl group, substituted or unsubstituted C2-C6 alkynyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C3-C8 cycloalkyl group, substituted or unsubstituted 4-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl group, and substituted or unsubstituted 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein the substitution is Each is independently substituted with one, two, or three substituents selected from the group consisting of deuterium, halogen atoms, hydroxyl groups, amino groups, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C1-C6 alkoxy groups, C3-C8 cycloalkyl groups, 4-8 membered heterocycloalkyl groups containing one, two, or three heteroatoms selected from N, O, or S, R-substituted or unsubstituted C6-C10 aryl groups, or R-substituted or unsubstituted 5-10 membered heteroaryl groups containing one, two, or three heteroatoms selected from N, O, or S, where R is selected from the group consisting of halogen atoms, hydroxyl groups, C1-C6 alkyl groups, and C1-C6 alkoxy groups. Alternatively, R1 and R2, together with the C to which they are bonded, form a 4-8 membered heterocycloalkyl group containing a C3-C8 monocyclic cycloalkyl group, a C3-C8 crosslinked ring cycloalkyl group, a C7-C10 spirocyclic cycloalkyl group, or one, two, or three heteroatoms selected from N, O, or S. Furthermore, R1 and R2 are not hydrogen atoms at the same time, R3 and R4 are each independently selected from the group consisting of a hydrogen atom, a -(C=O)-C1~C6 alkyl group, a C1~C6 alkyl group, a C1~C6 halogenated alkyl group, a C3~C8 cycloalkyl group, and a C3~C8 halogenated cycloalkyl group. R5 is selected from the group consisting of hydrogen atoms, C1-C6 alkyl groups, C1-C6 halogenated alkyl groups, C3-C8 cycloalkyl groups, C3-C8 halogenated cycloalkyl groups, inorganic metal ions, and thionium ions.

[0007] In another preferred example, R1 is a hydrogen atom, R2 is selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, an R-substituted or unsubstituted C6-C10 aryl group, a substituted C1-C6 alkyl group, a hydroxyl-substituted C1-C6 alkyl group, a C2-C6 alkenyl group, a C3-C8 cycloalkyl group, a 4-8 membered heterocycloalkyl group containing one, two, or three heteroatoms selected from N, O, or S, a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing one, two, or three heteroatoms selected from N, O, or S. R is selected from the group consisting of halogen atoms, C1-C6 alkyl groups, and C1-C6 alkoxy groups.

[0008] In another preferred example, R1 is a hydrogen atom, R2 is a C1-C6 alkyl group.

[0009] In another preferred example, R1 is a hydrogen atom, R2 is selected from the group consisting of methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, neopentyl group, and tert-pentyl group.

[0010] In another preferred example, R1 is a hydrogen atom, R2 is an ethyl group.

[0011] In another preferred example, R1 is H, a halogen atom, a methyl group, or an ethyl group. R2 is selected from the group consisting of a halogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a tert-pentyl group, a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a monofluoroethyl group, a trifluoroethyl group, a difluoroisopropyl group, a hydroxy group-substituted ethyl group, a vinyl group, a propenyl group, an ethynyl group, a propynyl group, a benzyl group, a diphenylmethyl group, a methoxybenzyl group, a monochlorobenzyl group, a phenyl group-substituted ethyl group, and a hydroxy group-substituted benzyl group.

[0012] In another preferred example, R1 and R2 together with the C to which they are attached form a group selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0013] In another preferred example, R3 and R4 are hydrogen atoms.

[0014] In another preferred example, R5 is a hydrogen atom.

[0015] In another preferred example, the inorganic metal ion is Li , Na + , K + , Rb + , Cs + , Mg 2+ , Ca 2+ , Ba 2+ , Zn 2+ , Al 3+ and is selected from the group consisting of.

[0016] In another preferred example, R5 is Na + is.

[0017] In another preferred example, the ammonium ion is an ammonium ion corresponding to a base selected from the group consisting of ammonia, methylamine, ethylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, tert-butylamine, tromethamine, meglumine, morpholine, piperazine, piperidine, pyridine, ethylenediamine, N,N'-dibenzylethylenediamine, proline, phenylalanine, aspartic acid, glutamic acid, and lysine.

[0018] In another preferred example, the ammonium ion is a cation.

[0019] In another preferred example, the pharmaceutically acceptable salt is an alkali metal salt or an alkaline earth metal salt.

[0020] In another preferred example, the pharmaceutically acceptable salt is a salt of the compound selected from the group consisting of lithium salts, sodium salts, potassium salts, cesium salts, magnesium salts, calcium salts, barium salts, zinc salts, and aluminum salts.

[0021] In another preferred example, the pharmaceutically acceptable salt is a salt of the compound selected from the group consisting of lithium salts, sodium salts, potassium salts, and cesium salts.

[0022] In another preferred example, the pharmaceutically acceptable salt is a salt of the compound selected from the group consisting of magnesium salts, calcium salts, barium salts, zinc salts, and aluminum salts.

[0023] In another preferred example, the pharmaceutically acceptable salt is the sodium salt of the compound.

[0024] In another preferred example, the pharmaceutically acceptable salt is a salt produced by the compound with a nitrogen atom-containing organic base.

[0025] In another preferred example, the pharmaceutically acceptable salt is a salt produced by the compound with a base selected from the group consisting of ammonia, methylamine, ethylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, tert-butylamine, tromethamine, meglumine, morpholine, piperazine, piperidine, pyridine, ethylenediamine, N,N'-dibenzylethylenediamine, proline, phenylalanine, aspartic acid, glutamic acid, and lysine.

[0026] In another preferred example, the solvate is a hydrate.

[0027] In another preferred example, the compound has a structure represented by formula (II) or formula (III). [ka] Here, R1, R2, R3, R4, and R5 are as defined above.

[0028] [ka] JPEG0007867314000005.jpg213170JPEG0007867314000006.jpg176170In another preferred example, the compound is selected from the group consisting of:

[0029] Two aspects of the present invention provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of a compound described in one aspect of the present invention, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0030] Three aspects of the present invention provide uses for a compound, a solvate thereof, or a pharmaceutically acceptable salt thereof, described in one aspect of the present invention, used in the manufacture of a pharmaceutical product for the treatment of pulmonary arterial hypertension.

[0031] In another preferred example, the drug is an oral formulation.

[0032] In another preferred example, the dosage of the drug is 5-7 mg / kg / day, preferably 6 mg / kg / day.

[0033] In another preferred example, the drug is used for an application selected from the group consisting of the following: 1) Lower the right ventricular systolic pressure, 2) Lower the Fulton coefficient, 3) Reduce PVR (pulmonary vascular resistance), 4) Treat pulmonary hypertension caused by interstitial lung disease, 5) Treat pulmonary hypertension caused by COPD, 6) Treat idiopathic pulmonary fibrosis.

[0034] Within the scope of the present invention, it should be understood that new or preferred technical solutions can be constructed by combining each of the above technical features of the present invention with each of the technical features specifically described below (e.g., in the examples). Since this is limited to 15 pages, each one will not be described individually here. [Brief explanation of the drawing]

[0035] [Figure 1] This document outlines the technical roadmap for the present invention. [Figure 2] This is a bar graph corresponding to the weight data in Table 1 obtained by the present invention. [Figure 3] This is a bar graph corresponding to the RVSP data in Table 2 obtained by the present invention. [Figure 4] This is a bar graph corresponding to the Fulton coefficient data in Table 3 obtained by the present invention. [Modes for carrying out the invention]

[0036] As a result of diligent research over a long period, the inventors have obtained a novel prostacyclin-based drug with excellent efficacy in treating pulmonary arterial hypertension by optimizing the structure of conventional treprostinyl sodium salt. Specifically, by substitution at the R1 and R2 positions of the compound of formula I (preferably C1-C6 alkyl substitution, more preferably mono-C1-C6 alkyl substitution), a compound of formula (I) with superior RVSP (right ventricular systolic pressure) and superior Fulton coefficient was obtained. Based on this, the inventors have completed the present invention.

[0037] term In this invention, unless otherwise specified, terms used have the general meanings well known to those skilled in the art.

[0038] In this invention, the term "halogen atom" refers to F, Cl, Br, or I.

[0039] In the present invention, "C1-C6 alkyl group" refers to a linear or branched alkyl group containing 1 to 6 carbon atoms, such as a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, neopentyl group, tert-pentyl group, or similar groups. In the present invention, the term "C2-C6 alkenyl group" refers to a linear or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, and includes, but is not limited to, vinyl groups, propenyl groups, butenyl groups, isobutenyl groups, pentenyl groups, and hexenyl groups.

[0040] In the present invention, the term "C2-C6 alkynyl group" refers to a linear or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, and includes, but is not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.

[0041] In the present invention, the term "C3-C8 cycloalkyl group" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0042] In the present invention, the term "C1-C6 alkoxy group" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, and includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. Preferably, it is a C1-C4 alkoxy group.

[0043] In the present invention, the term "heterocyclic group" refers to a 4- to 8-membered heterocyclic group comprising one, two, or three heteroatoms selected from N, O, and S, and includes (but is not limited to) the following groups: [ka]

[0044] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning, and preferably refer to a "C6-C10 aryl group." The term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms that does not contain heteroatoms, such as a phenyl group or a naphthyl group.

[0045] In the present invention, the terms "aromatic heterocycle" and "heteroaryl group" have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. For example, a "5-10 membered heteroaryl group" refers to an aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 3-10 carbon atoms. Examples that are not limited to this include furyl, haphenyl, pitenyl, pyrenyl, pyrrolyl, N-alkylpyrrolyl, pyrimidine, pyrazinyl, imidazolyl, and tetrazolyl groups. The heteroaryl ring is condensed with an aryl group, a heterocyclic group, or a cycloalkyl ring, and the ring bonded to the parent structure is a heteroaryl ring. The heteroaryl group may or may not be substituted.

[0046] In this invention, the term "halogenation" means substitution with a halogen atom.

[0047] In the present invention, the term "substitution" means that one or more hydrogen atoms in a particular group are substituted with a particular substituent. The particular substituent is one of the substituents described above or one of the substituents found in each example. Unless otherwise specified, a substituent has one substituent selected from a particular group at any substituted position on the group, and the substituents may be the same or different at each position. Those skilled in the art should understand that the substituent combinations envisioned by the present invention are stable or chemically feasible combinations. Examples of such substituents include (but are not limited to) halogen atoms, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3-12 membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, and C1-C10 sulfonyl groups.

[0048] In this invention, the terms 1-6 refer to 1, 2, 3, 4, 5, or 6. Other similar terms have similar meanings independently. The term "plural" refers to 2-6, such as 2, 3, 4, 5, or 6.

[0049] The term "ester group" refers to a group having a -C(O)-OR or R:C(O)-O- structure, where R independently represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C6-C10 aryl group, a heteroaryl group, or a heterocyclic group, as defined above.

[0050] When a group exists simultaneously at multiple different positions in a compound, it should be understood that its definition at each position is independent of the others and may be the same or different. In other words, the phrase "selected from the group consisting of the following" has the same meaning as the phrase "each independently selected from the group consisting of the following."

[0051] The term "COPD" refers to chronic obstructive pulmonary disease.

[0052] The Fulton coefficient reflects organ remodeling caused by PAH. Fluctuations in this coefficient indicate the potential of new drugs to reverse the cardiopulmonary structure altered by PAH, meaning they can not only alleviate PAH symptoms (symptomatic treatment) but also reverse or cure PAH (causal treatment). This is a goal that conventional drugs in the field of PAH currently cannot achieve, but which new PAH treatments aim to achieve.

[0053] compound The present invention provides a compound represented by formula I, a solvate thereof, or a pharmaceutically acceptable salt thereof. [ka] Here, each unit is defined as described above.

[0054] In another preferred example, in the compound, any one of R1, R2, R3, R4, or R5 is independently a group corresponding to the specific compound of the present invention.

[0055] As used herein, the term “pharmaceutically acceptable salt” refers to a salt suitable for use as a pharmaceutical product, which is produced by a compound of the present invention with an acid or base. pharmaceutically acceptable salts include inorganic and organic salts. One preferred salt is one produced by a compound of the present invention with an acid. Suitable acids for producing salts include, but are not limited to, amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, and lysine.

[0056] Other preferred salts are salts produced by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts produced by morpholine, piperazine, and lysine, respectively.

[0057] The term "solvate" refers to a compound of the present invention that has coordinated with a solvent molecule to form a complex in a specific proportion. The term "hydrate" refers to a complex formed when a compound of the present invention coordinates with water.

[0058] The present invention also includes cocrystals produced by the compound of the present invention and a suitable compound.

[0059] The compounds of the present invention further include prodrugs of the compound represented by formula (I). The term "prodrug" includes substances that may be biologically active or inactive themselves and, when taken in an appropriate manner, react metabolically or chemically in the human body to be converted into the compound of formula (I), or a salt or solution of the compound of formula (I). The prodrugs include, but are not limited to, forms of the compound such as carboxylic acid esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphate amides, glucosides, ethers, and acetals.

[0060] The examples of the present invention illustrate in more detail the methods for producing the structural compounds of formula (I) of the present invention, but it should be understood that these specific methods are not limiting to the present invention. The compounds of the present invention can also be easily produced by any combination of various synthesis methods described herein or known in the art, such combinations can be readily performed by those skilled in the art to which the present invention belongs.

[0061] Typically, the raw materials and reagents used in the manufacturing process of the compounds of the present invention can all be purchased commercially unless otherwise specified.

[0062] Pharmaceutical composition and method of administration The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound, its solvate, or a pharmaceutically acceptable salt thereof.

[0063] The pharmaceutical composition of the present invention contains the compound of the present invention or its pharmaceutically acceptable amount within a range that is safe and effective.

[0064] The composition includes a salt and a pharmacologically acceptable excipient or carrier. In this context, "safe and effective amount" refers to an amount of the compound sufficient to clearly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1 to 2000 mg of the compound of the present invention per dose, more preferably 10 to 1000 mg per dose. Preferably, the "dose" is a capsule or tablet, and may also be an injection, inhalation, or oral formulation.

[0065] A "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gels that are suitable for human use and require sufficient purity and sufficiently low toxicity. "Compatibility" here means that each component in the composition can be mixed with and among itself with the compounds of the present invention without significantly reducing the pharmaceutically active properties of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol), emulsifiers (e.g., Tween®), humectants (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and water that does not contain pyrogens.

[0066] The aforementioned pharmaceutical composition is in the form of an injection, capsule, tablet, pill, powder, or granule.

[0067] The method of administering the compound or pharmaceutical composition of the present invention is not particularly limited, and typical methods of administration include (but are not limited to) oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), oral and nasal inhalation, anal, vaginal, and topical administration.

[0068] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient, such as a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffer.

[0069] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be manufactured using coating and shell materials such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compound in such compositions is delayed in a portion of the gastrointestinal tract. Examples of embedding components that can be used are polymers and waxes. If necessary, the active compound may also be in microcapsule form with one or more of the above excipients.

[0070] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may also include water or other solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-diols, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof, which are conventionally used in the art.

[0071] In addition to these inert diluents, the composition may also contain auxiliary agents such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0072] In addition to the active compound, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, crystalline cellulose, aluminum methoxide and agar, or mixtures thereof.

[0073] The parenteral injection composition may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for redissolution into sterile injection solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0074] The dosage forms of the compounds of the present invention for topical administration include ointments, powders, tapes, sprays, and inhalants.

[0075] The active ingredient is mixed with a physiologically acceptable carrier under sterile conditions and any preservative, buffer, or propellant as needed.

[0076] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0077] The therapeutic method of the present invention may be administered alone or in combination with other therapeutic means or drugs.

[0078] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dose administered is a pharmaceutically effective dose. For a human weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dose should also take into account factors such as the route of administration and the patient's health condition, all of which are within the scope of a skilled physician's expertise.

[0079] Compared to conventional technology, the present invention has the following main advantages: (1) The compounds described in the present invention have a superior effect in treating pulmonary arterial hypertension. (2) The compounds described in the present invention have better RVSP (right ventricular systolic pressure) and better Fulton coefficient. (3) Compared to Ralinepag (United Therapeutics Corporation) in Phase III trials, the corresponding animal experiment data for the compounds in the present invention are superior to those for Ralinepag. (4) Based on body weight data and clinical observations, no differences were observed in feeding, defecation, activity, or leg strength of the rats in the treatment group compared to the healthy group.

[0080] The present invention will be further described in detail by the following specific examples. It should be understood that these examples are not intended to limit the scope of the present invention, but are used solely for illustrative purposes. Experimental methods in the following examples where specific conditions are not specified generally follow conventional conditions, such as those described in Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or conditions recommended by the manufacturer. Unless otherwise specified, percentages and quantities are calculated by weight.

[0081] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those well known to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. Preferred methods and materials described herein are for illustrative purposes only. [Examples]

[0082] Manufacturing of the Examples II-N or III-N and their corresponding sodium salts, II-N-Na or III-N-Na, are produced according to the following operating program. [ka] Comment: II-N represents compounds such as II-1 and II-2, while III-N represents compounds such as III-1 and III-2.

[0083] Step 1: The starting material (SM1) and tetrahydrofuran were added to the reaction flask and cooled to -65°C. At this temperature, LDA or LiHMDS (1.0-5.0 equivalents) was slowly added dropwise. After the addition was complete, stirring was continued at this temperature for 3 hours. Then, the electrophile (1.0-5.0 equivalents) was added to the reaction system. After the addition was complete, the temperature was slowly raised and the mixture was stirred overnight. The reaction was quenched by adding saturated ammonium chloride aqueous solution to the reaction system, and products II-N-7 or III-N-7 were obtained by conventional extraction, washing, drying, concentration, and column chromatography. The products were analyzed by LC-MS and LC-MS, respectively. 1 The characteristics were evaluated by 1HNMR.

[0084] Of these, the electrophile reagent is selected from the group consisting of the following:

[0085] [Table 1]

[0086] Step 2: II-N-7 was dissolved in ethanol (99.5%), then transferred to a hydrogenation reactor, and hydrogenated overnight with palladium carbon. Palladium carbon was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain product II-N-6 or III-N-6. The products were then analyzed by LC-MS and 1 The samples were characterized by 1HNMR.

[0087] Step 3: II-N-6 was dissolved in ethanol (99.5%) and cooled to -25 to -15°C. Next, an appropriate amount of 2M aqueous sodium hydroxide solution was added, and the mixture was stirred at this temperature for 2 to 4 hours. Then, sodium borohydride (1.0 to 2.0 equivalents) was added at this temperature, and stirring was continued for 4 to 6 hours. Products II-N-5 or III-N-5 were obtained by conventional extraction, washing, drying, concentration, and column chromatography. The products were then analyzed by LC-MS and 1 The characteristics were evaluated by 1HNMR.

[0088] Step 4: II-N-5 or III-N-5 was dissolved in ethanol (99.5%), then 1M dilute hydrochloric acid was added, and the mixture was stirred at room temperature for 2-6 hours. Extraction, washing, drying, concentration, and column chromatography purification were performed to obtain product II-N-4 or III-N-4. The products were then analyzed by LC-MS and column chromatography, respectively. 1 The characteristics were evaluated by 1HNMR.

[0089] Step 5: Diphenylphosphine (5.0-10.0 equivalents) was dissolved in anhydrous tetrahydrofuran, cooled to -25 to -15°C, and n-butyllithium (5.0-10.0 equivalents) was slowly added dropwise. After the addition was complete, stirring was continued at this temperature for 2-4 hours to obtain a tetrahydrofuran solution of lithium diphenylphosphine.

[0090] A separate reaction flask was taken, II-N-4 or III-N-4 was added and dissolved in tetrahydrofuran, and a tetrahydrofuran solution of lithium diphenyl phosphide, prepared at room temperature, was slowly added. After the addition was complete, the reaction system was refluxed overnight. The heating device was removed, the system was cooled, further cooled in an ice bath, and the reaction was quenched with saturated ammonium chloride. The crude product was purified by column chromatography by conventional extraction, washing, drying, filtration, and vacuum concentration to obtain product II-N-3 or III-N-3. The products were then analyzed by LC-MS and 1 The characteristics were evaluated by 1HNMR.

[0091] Step 6: II-N-3 or III-N-3 was dissolved in acetone, then potassium carbonate and bromoacetonitrile (1.5-3.0 equivalents each) were added sequentially, and the mixture was stirred overnight at room temperature. Insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain product II-N-2 or III-N-2. The products were then analyzed by LC-MS and 1 The samples were characterized by 1H NMR.

[0092] Step 7: II-N-2 or III-N-2 was dissolved in tetrahydrofuran, and 20% potassium hydroxide aqueous solution was added sequentially, stirring until hydrolysis was complete. The pH was adjusted to 3-4 with 2M hydrochloric acid, and the crude product was obtained by conventional extraction, washing, drying, filtration, and vacuum concentration. Further purification by column chromatography yielded product II-N or III-N. The products were then analyzed by LC-MS and 1 The characteristics were evaluated by 1HNMR.

[0093] Step 8: II-N or III-N was dissolved in tetrahydrofuran, then an equal volume of solid sodium hydroxide was added and the mixture was stirred overnight. The mixture was concentrated under reduced pressure, and acetonitrile was added to form a slurry. A white solid precipitate was obtained, which was then filtered, washed, and dried to yield the sodium salts II-N-Na or III-N-Na. The products were then analyzed by LC-MS and LC-MS, respectively. 1 The samples were characterized by 1H NMR.

[0094] The characteristic data for each compound obtained by the above-described manufacturing method of the present invention are shown in Tables A, B, and C.

[0095] [Table 2] JPEG0007867314000012.jpg219170JPEG0007867314000013.jpg214170JPEG0007867314000014.j pg223170JPEG0007867314000015.jpg233170JPEG0007867314000016.jpg224170JPEG0007867314 000017.jpg200170JPEG0007867314000018.jpg210170JPEG0007867314000019.jpg210170JPEG00 07867314000020.jpg202170JPEG0007867314000021.jpg224170JPEG0007867314000022.jpg43170

[0096] III-20-6 was produced according to the following procedure, and the remaining intermediates, III-20 and III-20-Na, were produced according to steps 3 to 8 described above. [ka]

[0097] The starting material (SM2), PhBr (1.5 equivalents), tert-butoxide sodium (1.5 equivalents), catalytic amounts of Pd(OAc)2 and XPhos, and the solvent toluene were added to the reaction flask and heated to 80°C and stirred. After the starting materials had disappeared, the mixture was quenched with saturated NaCl aqueous solution, and product III-20-6 was obtained by extraction, drying, filtration, concentration, and column chromatography purification. The products were then analyzed by LC-MS and 1 The samples were characterized by 1H NMR.

[0098] [Table 3] JPEG0007867314000025.jpg78170

[0099] In step 5, products III-21-3 and III-21'-3 were obtained, and from these, steps 6-8 were followed to obtain III-21 and III-21', as well as their respective sodium salts, III-21-Na and III-21'-Na.

[0100] [Table 4] JPEG0007867314000027.jpg200170JPEG0007867314000028.jpg117170

[0101] Performance tests and results Purchase and Pre-breeding Twenty-eight 7-week-old male Sprague-Dawley rats (average weight 200-250g) were purchased from Victoria and kept in an experimental setting for one week after purchase until they reached eight weeks of age (temperature 20-26°C, humidity 30-70%, day-night ratio 1:1).

[0102] Grouping Twenty-eight rats were randomly divided into six groups: a drug treatment group, a positive control group, a negative control group, and a healthy control group, and each group was tagged with an ear tag.

[0103] [Table 5]

[0104] 3. Model creation (1) Preparation of monocrotaline (MCT) solution: Weigh a sufficient amount of MCT, add it to 50 ml of 20% ethanol physiological saline, shake gently and slowly, then transfer it to a 50 ml centrifuge tube, tilt it, and place it in a constant temperature shaker at 37°C and 220 rpm, shaking for 12 to 14 hours until the crystal particles are completely dissolved and no longer visible to the naked eye.

[0105] (2) Injection of MCT solution: The skin on the back of the rat's neck was gently lifted, and the MCT solution was subcutaneously injected at a dose of 60 mg / kg using a 1 ml syringe, which was designated as day 0.

[0106] (3) Healthy controls: The same amount of saline solution was administered using the same method.

[0107] 4. Preparation of experimental drugs (1) Compound 1 and Compound C1 can be directly dissolved in water. Appropriate amounts of each drug were weighed according to concentrations of 0.6 mg / ml and 1.2 mg / ml (dosage groups of 3 mg / kg / day and 6 mg / kg / day), and dissolved by shaking in the corresponding volume of pure water to obtain a clear solution.

[0108] (2) Store in a refrigerator at 4°C, take out before use, leave at room temperature, and then use.

[0109] 5. Administration From day 14, after weighing the rats daily, the corresponding solution (drug or saline) was administered intragastricly according to the grouping protocol until day 27, for a total of 14 days. The intragastric dose was 0.5 ml / 100g, and the rats' body weight and survival data were recorded.

[0110] 6. Measurement of hemodynamics On day 28, the hemodynamic status of the rats was evaluated using a right heart catheter.

[0111] (1) Prepare the PE-50 catheter, pressure transducer, and pressure measurement workstation. Flush the tubing with heparinized saline to ensure there are no air bubbles in the tubing, and then adjust the catheter to zero.

[0112] (2) The rats were continuously anesthetized with 2% isoflurane at a flow rate of 2 L / min, their limbs and incisors were fixed to the operating table, and their heads were facing the operator.

[0113] (3) Prepare the skin of the surgical site on the neck.

[0114] (4) The skin of the neck was cut along the midline, and the skin of the neck was pulled and fixed using hemostatic forceps, and the tissue was separated layer by layer with scissors to expose the right internal jugular vein.

[0115] (5) The internal jugular vein was dissected by blunt separation using hemostatic forceps.

[0116] (6) The distal end of the internal jugular vein was ligated using 4-0 sutures, and the sutures were passed through the proximal end of the internal jugular vein to prepare it for use.

[0117] (7) Using ophthalmic scissors, a V-shaped incision was made in the internal jugular vein, and a PE-50 catheter was inserted from this position. After inserting the catheter, the catheter was secured by ligating the sutures that had been placed beforehand at the proximal end of the internal jugular vein.

[0118] (8) The catheter was advanced to the right atrium and then the right ventricle, and the right atrial pressure and right ventricular pressure were recorded. At least five stable waveforms were recorded at each site, and the five consecutive waveforms were used as segments. Two or more segments were selected, and the right ventricular systolic pressure (RVSP) was calculated.

[0119] (9) The PE-50 catheter was removed, and the examination was completed.

[0120] 7. Sample collection (1) After hemodynamic evaluation was completed, rats were anesthetized by intraperitoneal injection of 10% chloral hydrate at a dose of 0.5 ml / 100 g, and sample collection was started after weighing the rats.

[0121] (2) After opening the abdominal cavity, as much blood as possible was drawn from the inferior vena cava using a 5 ml syringe and placed into an EDTA anticoagulant tube, which was then shaken upside down 6 to 8 times.

[0122] (3) The thoracic cavity was kept open, exposing the lungs and heart.

[0123] (4) The left atrial appendage was incised, and a 5 ml syringe was used to extract a bottle of heparinized saline solution. The needle was then inserted into the right atrial appendage and slowly injected to flush out the pulmonary blood vessels.

[0124] (5) Rat heart, lung, liver, spleen, and kidney tissue were collected, cryopreserved, and fixed with formaldehyde solution.

[0125] 8. Measurement of Fulton coefficient After separating the heart, the non-ventricular parts such as the atria, blood vessels, and valve annulus were excised, and as much thrombus as possible in the ventricles was removed using a mirror. Next, the right ventricle (RV) and left ventricle (LV) + interventricular septum (LV+S) were excised along the boundary between the tensed right ventricle (RV) and interventricular septum (S) using straight shears, all moisture was completely aspirated with gauze, and the weight was weighed separately. The RV / (LV+S), i.e., Fulton coefficient, was calculated.

[0126] [ka]

[0127] The experimental results are as follows:

[0128] body weight 1. Body weight on day 0: The mean body weights of treatment groups 1-6 on day 0 were 347±12.77g, 315±3.63g, 316±4.35g, 330±25.11g, 315±13.50g, and 314±5.35g, respectively. The mean body weight of group 1 was significantly greater than that of groups 2, 3, 5, and 6 (P<0.01), and no significant differences were observed between the groups.

[0129] 2. Body weight on day 14: The mean body weights of treatment groups 1-6 on day 14 were 440±32.61, 428±29.90, 413±15.81, 430±34.15, 406±33.50, and 425±20.48 g, respectively, and no significant differences were observed between the groups.

[0130] 3. Body weight at sample collection: The body weights at sample collection for treatment groups 1-6 were 436±44.27, 440±55.00, 436±9.65, 431±58.03, 406±42.45, and 445±25.06 g, respectively, and no significant differences were observed.

[0131] Note: Due to the total weight limit for compound 1, group 1 was actually administered for 13 days, group 2 for 12 days, and measurements and sample collection were performed on day 27 for both groups. Groups 3-6 were actually administered for 14 days, and measurements and sample collection were performed on day 27 for all of them.

[0132] [Table 6]

[0133] Survival status Due to the total weight limit for compound 1, group 1 was actually administered for 13 days, group 2 for 12 days, and measurements and sample collection were performed on day 27 for both groups; groups 3-6 were actually administered for 14 days, and measurements and sample collection were performed on day 27 for all of them.

[0134] Hemodynamic results The RVSP levels in treatment groups 1-6 were 22±4.36, 41+16.27, 38+8.86, 46+13.45, 63+7.34, and 22+2.41 mmHg, respectively. The RVSP levels in rats in model groups 2-4 were significantly higher than those in the healthy control group, and the RVSP levels in rats treated with compound 1 6 mg / kg decreased to the level of the healthy control group (22±4.36 vs 22+2.41 mmHg, P=0.939).

[0135] [Table 7]

[0136] From Table 2: 1) Experimental drug treatment group: The RVSP in the compound 1 6 mg / kg treatment group was significantly lower than in the 3 mg / kg treatment group (22 ± 4.36 vs 41 ± 16.27 mmHg, P = 0.01), and a difference was observed between the dosage groups.

[0137] 2) Positive control group: Both doses of compound C1, i.e., treprostinyl sodium 5.5-hydrate, at 3 and 6 mg / kg, significantly reduced RVSP in rats, but the levels were higher than in the healthy control group, and there was no significant difference in effect between the two dose groups (38±8.86 vs. 46+13.45 mmHg, P=0.201).

[0138] 3) In the group treated with compound 1 at 6 mg / kg, RVSP in rats was lower than in the group treated with the same dose of treprostinil sodium 5.5 hydrate (22 ± 4.36 vs 38 + 8.86 mmHg, P = 0.013), and the pulmonary vasodilatory effect was superior to that of treprostinil sodium 5.5 hydrate at the same dose.

[0139] Results of the Fulton coefficient The Fulton coefficients for groups 1-6 were 0.25±0.27, 0.37+0.12, 0.37+0.07, 0.38+0.10, 0.61+0.080, and 0.29+0.023, respectively. The Fulton coefficient of the negative control group was significantly higher than that of the healthy control group, and the Fulton coefficient of the drug treatment group was significantly lower than that of the negative control group, but no significant difference was observed compared to the healthy control group.

[0140] [Table 8]

[0141] From Table 3: 1) Experimental drug treatment group: The Fulton coefficient was lower in the compound 1 6 mg / kg treatment group than in the 3 mg / kg treatment group, but no significant difference was observed between the two dose groups (0.25 ± 0.27 vs 0.37 + 0.12, P = 0.06).

[0142] 2) Positive control group: Both doses of compound C1, i.e., treprostinil sodium 5.5-hydrate at 3 and 6 mg / kg, significantly reduced the Fulton coefficient in rat hearts, but it was higher than in the healthy control group, and there was no significant difference in effect between the two dose groups (0.37±0.07 vs 0.38+0.10, P=0.921).

[0143] 3) The Fulton coefficient of rat hearts in the compound 1 6 mg / kg treatment group was lower than that of the treprostinil sodium 5.5 hydrate treatment group at the same dose (0.25 + 0.27 vs 0.37 + 0.07, P = 0.029), and there was no significant difference in the Fulton coefficient of rat hearts in the 3 mg / kg treatment group compared to the treprostinil sodium 5.5 hydrate treatment group at the same dose.

[0144] Furthermore, using the same experimental method as described above, the experimental results for Ralinepag are shown in Tables 4 and 5.

[0145] [Table 9]

[0146] [Table 10]

[0147] All documents described in this invention are cited by reference in this application, just as each document is cited by reference on its own. Furthermore, after reading the above teachings of this invention, those skilled in the art should understand that various changes or modifications can be made to the invention, and that these equivalent forms are also included within the scope defined by the claims attached to this application.

Claims

1. A compound represented by formula (I), its solvate, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Here, R １ and R ２ Each is independently selected from the group consisting of a hydrogen atom, deuterium, halogen atom, hydroxyl group, amino group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C2-C6 alkenyl group, substituted or unsubstituted C2-C6 alkynyl group, substituted or unsubstituted C1-C6 alkoxy group, substituted or unsubstituted C3-C8 cycloalkyl group, substituted or unsubstituted 4-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl group, and substituted or unsubstituted 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and the substitution is each Each is independently substituted with one, two, or three substituents selected from the group consisting of deuterium, halogen atoms, hydroxyl groups, amino groups, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C1-C6 alkoxy groups, C3-C8 cycloalkyl groups, 4-8 membered heterocycloalkyl groups containing one, two, or three heteroatoms selected from N, O, or S, R-substituted or unsubstituted C6-C10 aryl groups, and R-substituted or unsubstituted 5-10 membered heteroaryl groups containing one, two, or three heteroatoms selected from N, O, or S, where R is selected from the group consisting of halogen atoms, hydroxyl groups, C1-C6 alkyl groups, and C1-C6 alkoxy groups. Furthermore, R １ and R ２ At the same time, it is not a hydrogen atom, R ３ and R ４ Each of these is independently selected from the group consisting of a hydrogen atom, -(C=O)-C1-C6 alkyl groups, C1-C6 alkyl groups, C1-C6 halogenated alkyl groups, C3-C8 cycloalkyl groups, and C3-C8 halogenated cycloalkyl groups. R ５ The element is selected from the group consisting of hydrogen atoms, C1-C6 alkyl groups, C1-C6 halogenated alkyl groups, C3-C8 cycloalkyl groups, C3-C8 halogenated cycloalkyl groups, inorganic metal ions, and thionium ions.

2. The compound described in Claim 1, its solvate, or a pharmaceutically acceptable salt thereof, R １ It is a hydrogen atom, R ２ is selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted C1-C6 alkyl group, a hydroxyl group-substituted C1-C6 alkyl, a C2-C6 alkenyl group, a C3-C8 cycloalkyl group, a 4- to 8-membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, a C6-C10 aryl group, and a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, R is selected from the group consisting of halogen atoms, C1-C6 alkyl groups, and C1-C6 alkoxy groups.

3. The compound described in Claim 1, its solvate, or a pharmaceutically acceptable salt thereof, R １ These are H, a halogen atom, a methyl group, and an ethyl group. R ２ The group is selected from the group consisting of halogen atoms, methyl groups, ethyl groups, propyl groups, isopropyl groups, butyl groups, isobutyl groups, tert-butyl groups, neopentyl groups, tert-pentyl groups, trifluoromethyl groups, difluoromethyl groups, monofluoromethyl groups, monofluoroethyl groups, trifluoroethyl groups, difluoroisopropyl groups, hydroxyl-substituted ethyl groups, vinyl groups, propenyl groups, ethynyl groups, propynyl groups, benzyl groups, diphenylmethyl groups, methoxybenzyl groups, monochlorobenzyl groups, phenyl-substituted ethyl groups, and hydroxyl-substituted benzyl groups.

4. R ３ and R ４ The compound according to claim 1, or its solvate, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

5. The inorganic metal ion is Li ＋ Na ＋ _K ＋ , Rb ＋ , Cs ＋ Mg ２＋ Ca ２＋ Ba ２＋ , Zn ２＋ Al ３＋ Selected from the group consisting of, and / or The compound according to claim 1, or its solvate, or a pharmaceutically acceptable salt thereof, characterized in that the ammonium ion is an ammonium ion corresponding to a base selected from the group consisting of ammonia, methylamine, ethylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, tert-butylamine, tromethamine, meglumine, morpholine, piperazine, piperidine, pyridine, ethylenediamine, N,N'-dibenzylethylenediamine, proline, phenylalanine, aspartic acid, glutamic acid, and lysine.

6. The compound according to claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof, characterized in that the compound has a structure represented by formula (II) or formula (III). 【Chemistry 2】 Here, R １ , R ２ , R ３ , R ４ , R ５ This is as defined in claim 1.

7. The compound according to claim 1, or its solvate, or a pharmaceutically acceptable salt thereof, is characterized in that the compound is selected from the group consisting of the following. 【Transformation 3】 【change】 【change】

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound described in claim 1, its solvate, or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof, used in the manufacture of a pharmaceutical product for the treatment of pulmonary arterial hypertension.

10. The pharmaceutical product is characterized by being used for an application selected from the group consisting of the following: the compound according to 9, its solvate, or a pharmaceutically acceptable salt thereof: 1) Lower the right ventricular systolic pressure, 2) Lower the Fulton coefficient, 3) Reduce PVR (pulmonary vascular resistance), 4) Treat pulmonary hypertension caused by interstitial lung disease, 5) Treat pulmonary hypertension caused by COPD, 6) Treat idiopathic pulmonary fibrosis.

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