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] The present invention relates to the field of medicine, and more particularly to a novel prostacyclin for treating pulmonary hypertension. [Background technology]

[0002] Treprostinil is a drug used to treat pulmonary artery hypertension (PAH). It is a prostacyclin derivative that inhibits platelet aggregation and vasodilation. Approved marketed dosage forms include injections, inhalants, and oral tablets. The active ingredient for injections and inhalants is treprostinil sodium.

[0003] However, conventional treprostinil sodium salts still have the problem of unfavorable therapeutic effects in the treatment of pulmonary arterial hypertension, and therefore there is an urgent need in the technical field to develop drugs that are more effective in the treatment of pulmonary arterial hypertension.

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

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

[0006] One aspect of the present invention provides a compound represented by formula (I), or a solvate thereof, or a pharmaceutically acceptable salt thereof. [ka] where: R1 and R2 are each independently selected from the group consisting of a hydrogen atom, deuterium, a halogen atom, a hydroxyl group, an amino group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 4-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, a substituted or unsubstituted C6-C10 aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, each independently substituted by one, two or three substituents selected from the group consisting of deuterium, a halogen atom, a hydroxyl group, an amino group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a 4-8 membered heterocycloalkyl group containing one, two or three heteroatoms selected from N, O or S, an R substituted or unsubstituted C6-C10 aryl group, and an R substituted or unsubstituted 5-10 membered heteroaryl group containing one, two or three heteroatoms selected from N, O or S, wherein R is selected from the group consisting of a halogen atom, a hydroxyl group, a C1-C6 alkyl group and a C1-C6 alkoxy group; or R1 and R2 together with the C to which they are attached form a C3-C8 monocyclic cycloalkyl group, a C3-C8 bridged ring cycloalkyl group, a C7-C10 spirocyclic cycloalkyl group, or a 4-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S; and 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, -(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 a hydrogen atom, a C1 to C6 alkyl group, a C1 to C6 halogenated alkyl group, a C3 to C8 cycloalkyl group, a C3 to C8 halogenated cycloalkyl group, an inorganic metal ion, and a thionium ion.

[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, a C2-C6 alkenyl group, a C3-C8 cycloalkyl group, a 4-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, a C6-C10 aryl group, and a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; R is selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, and a C1 to C6 alkoxy group.

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

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

[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 embodiment, the inorganic metal ion is Li + , Na + , K. + , Rb + , Cs + , Mg 2+ , Ca 2+ , Ba 2+ , Zn 2+ , Al 3+ is selected from the group consisting of:

[0016] In another preferred embodiment, 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 embodiment, 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 a sodium salt of the compound.

[0024] In another preferred example, the pharmaceutically acceptable salt is a salt formed from the compound and a nitrogen atom-containing organic base.

[0025] In another preferred example, the pharmaceutically acceptable salt is a salt formed by the compound and 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 embodiment, the solvate is a hydrate.

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

[0028] [ka] JPEG2025529392000006.jpg213170JPEG2025529392000007.jpg176170In another preferred embodiment, the compound is selected from the group consisting of:

[0029] A second aspect of the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds according to one aspect of the present invention, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0030] A third aspect of the present invention provides the use of a compound according to one aspect of the present invention, or a solvate thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating pulmonary arterial hypertension.

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

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

[0033] In another preferred embodiment, the drug is used for an application selected from the group consisting of: 1) Decrease right ventricular systolic pressure, 2) Lower the Fulton coefficient, 3) Reduces 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] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention may be combined with the technical features specifically described below (such as in the examples) to form new or preferred technical solutions. Due to the limited space of 15 pages, we will not describe them one by one here. [Brief explanation of the drawings]

[0035] [Figure 1] 1 shows a technology roadmap of the present invention. [Figure 2] 1 is a bar graph corresponding to the weight data of Table 1 obtained according to the present invention. [Figure 3] 1 is a bar graph corresponding to the RVSP data of Table 2 obtained according to the present invention. [Figure 4] 1 is a bar graph corresponding to the Fulton coefficient data of Table 3 obtained according to the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0036] As a result of extensive and intensive research, the present inventors have optimized the structure of conventional treprostinil sodium salt to obtain a novel prostacyclin-based drug with excellent efficacy in treating pulmonary arterial hypertension. Specifically, substitution (preferably C1-C6 alkyl substitution, more preferably mono-C1-C6 alkyl substitution) at the R1 and R2 positions of the compound of formula (I) has resulted in a compound of formula (I) with improved RVSP (right ventricular systolic pressure) and improved Fulton's coefficient. Based on this, the present inventors have completed the present invention.

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

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

[0039] In the present invention, the term "C1-C6 alkyl group" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as 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, or a similar group. In the present invention, the term "C2-C6 alkenyl group" refers to a straight-chain or branched-chain alkenyl group having 2 to 6 carbon atoms and containing one double bond, including, but not limited to, a vinyl group, a propenyl group, a butenyl group, an isobutenyl group, a pentenyl group, and a hexenyl group.

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

[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, including, but not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.

[0042] In the present invention, the term "C1-C6 alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group. A C1-C4 alkoxy group is preferred.

[0043] In the present invention, the term "heterocyclic group" refers to a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O, S, including (but not limited to) the following groups: [ka]

[0044] In the present invention, the terms "aromatic ring" and "aryl group" have the same meaning, and are preferably "C6-C10 aryl group." The term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and no heteroatoms in the ring, such as a phenyl group or 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 to multiple heteroatoms. For example, a "5- to 10-membered heteroaryl group" refers to an aromatic heterocycle containing one to four heteroatoms selected from oxygen, sulfur, and nitrogen and three to ten carbon atoms. Non-limiting examples include furyl, phenyl, pyrenyl, pyrenyl, pyrrolyl, N-alkylpyrrolyl, pyrimidine, pyrazinyl, imidazolyl, and tetrazolyl groups. The heteroaryl ring is fused to an aryl group, heterocyclic group, or cycloalkyl ring, in which the ring bonded to the parent structure is a heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0046] In the present invention, the term "halogenated" means substituted with a halogen atom.

[0047] In the present invention, the term "substituted" means that one or more hydrogen atoms in a specific group are replaced with a specific substituent. The specific substituents are those listed above or recognized in each Example. Unless otherwise specified, a substituent has one substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents envisioned by the present invention are stable or chemically feasible combinations. Examples of the 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 the present invention, the term 1 to 6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms each independently have similar meanings. The term "plurality" refers to 2 to 6, such as 2, 3, 4, 5 or 6.

[0049] The term "ester group" refers to a group having the structure -C(O)-OR or R:C(O)-O-, where R independently represents hydrogen, 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] It should be understood that when a group is simultaneously present at several different positions on a compound, its definition at each position is independent of each other and may be the same or different, i.e., the term "selected from the group consisting of" has the same meaning as the term "each independently selected from the group consisting of:

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

[0052] The Fulton coefficient reflects organ remodeling caused by PAH. Variation in this coefficient means that new drugs may have the potential to reverse the changes in cardiopulmonary structure caused by PAH, not only alleviating the symptoms of PAH (symptomatic treatment) but also reversing or curing PAH (causal treatment). This is a goal that conventional drugs in the PAH field currently cannot achieve, but which new PAH therapeutics aim to achieve.

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

[0054] In another preferred example, in the compound, any of R1, R2, R3, R4, and R5 is each 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, which is formed by the compound of the present invention with an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. One preferred salt is a salt formed by the compound of the present invention with an acid. Suitable acids for forming 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 formed by the compounds of the present invention with bases, 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 salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed with morpholine, piperazine, and lysine, respectively.

[0057] The term "solvate" refers to a complex formed when a compound of the present invention is coordinated with solvent molecules to form a specific ratio. "Hydrate" refers to a complex formed when a compound of the present invention is coordinated with water.

[0058] The present invention also includes co-crystals formed by compounds of the present invention and suitable compounds.

[0059] The compounds of the present invention also include prodrugs of the compounds represented by formula (I). The term "prodrug" includes compounds that may be biologically active or inactive themselves, and that, when ingested in an appropriate manner, are converted into the compounds of formula (I) or salts or solutions of the compounds of formula (I) through metabolic or chemical reactions in the human body. The prodrugs include, but are not limited to, carboxylate esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfonate esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and other forms of the compounds.

[0060] The examples of the present invention more specifically explain the method for producing the compound of formula (I) of the present invention, but it should be understood that these specific methods do not limit the present invention. The compounds of the present invention can also be easily produced by any combination of various synthetic methods described herein or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains.

[0061] Typically, all of the raw materials and reagents used in the processes for preparing the compounds of the present invention may be purchased commercially, unless otherwise specified.

[0062] Pharmaceutical Compositions and Methods of Administration The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more of the above compounds, or solvates thereof, or pharmaceutically acceptable salts thereof.

[0063] The pharmaceutical composition of the present invention contains the compound of the present invention or its pharmacologically acceptable salt within a safe and effective amount.

[0064] The present invention includes a salt and a pharmacologically acceptable excipient or carrier. The term "safe and effective amount" refers to an amount of the compound sufficient to clearly improve the pathological condition without causing significant side effects. Typically, the pharmaceutical composition contains 1 to 2,000 mg of the compound of the present invention per dose, more preferably 10 to 1,000 mg of the compound of the present invention per dose. Preferably, the "dose" is a capsule or tablet, and may also be an injection, inhalant, or oral formulation.

[0065] A "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and require sufficient purity and sufficiently low toxicity. "Compatible" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without appreciably reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (stearic acid, magnesium stearate, etc.), calcium sulfate, vegetable oils (soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0066] The pharmaceutical compositions are in the form of injections, capsules, tablets, pills, powders and granules.

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

[0068] Oral solid dosage forms include capsules, tablets, pills, powders and granules.In these solid dosage forms, active compound is mixed with at least one conventional inert excipient, such as lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate or their mixtures.For capsules, tablets and pills, dosage forms can also contain buffering agents.

[0069] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art.They can also contain opacifying agents, and the release of the active compound or compounds in such compositions is delayed in a certain part of the digestive tract.The examples of embedding materials that can be used are polymeric materials and wax-based materials.If necessary, active compound can also be made into microencapsulated form with one or more of the above-mentioned excipients.

[0070] Oral liquid dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.In addition to active compounds, liquid dosage forms may contain the inert diluents conventionally used in the art, such as water or other solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-diol, dimethylformamide and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or the mixture of these substances.

[0071] Besides these inert diluents, compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0072] In addition to the active compounds, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar, or mixtures of these substances.

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

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

[0075] The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required.

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

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

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

[0079] Compared with the prior art, the present invention has the following main advantages: (1) The compounds described in this invention have better effects in treating pulmonary arterial hypertension. (2) The compounds described in this invention have better RVSP (right ventricular systolic pressure) and better Fulton index. (3) Compared with Ralinepag (United Therapeutics Corporation) which is in Phase III trials, the corresponding animal experimental data of the compound of the present invention are superior to Ralinepag. (4) Based on the weight data and clinical observations, the feeding, defecation, activity, and leg strength of rats in the treatment group were not different from those in 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 do not limit the scope of the present invention, but are used only to illustrate the present invention. Experimental methods for which specific conditions are not specified in the following examples generally follow conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0081] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are used for illustrative purposes only. [Example]

[0082] Preparation of Examples II-N or III-N and the corresponding sodium salts II-N-Na or III-N-Na are prepared according to the following procedure. [ka] Comment: II-N represents compounds II-1, II-2, etc., and III-N represents compounds III-1, III-2, etc.

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

[0084] wherein the electrophile is selected from the group consisting of:

[0085] [Table 1]

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

[0087] Step 3: II-N-6 was dissolved in ethanol (99.5%) and cooled to -25 to -15°C. An appropriate amount of 2M aqueous sodium hydroxide was then 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. The product II-N-5 or III-N-5 was obtained by conventional extraction, washing, drying, concentration, and column chromatography. The products were analyzed by LC-MS and HPLC, respectively. 1 It was characterized by HNMR.

[0088] Step 4: After dissolving II-N-5 or III-N-5 in ethanol (99.5), 1M diluted hydrochloric acid was added and the mixture was stirred at room temperature for 2-6 hours. After extraction, washing, drying, concentration, and column chromatography purification, II-N-4 or III-N-4 were obtained. The products were analyzed by LC-MS and 1 It was characterized by HNMR.

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

[0090] Another reaction flask was taken, and II-N-4 or III-N-4 was added and dissolved in tetrahydrofuran. A freshly prepared solution of lithium diphenylphosphide in tetrahydrofuran was slowly added at room temperature. After the dropwise addition was completed, the reaction system was refluxed overnight. The heating device was removed, cooled, and further cooled in an ice-water bath. Saturated ammonium chloride was added to quench the reaction. After the usual extraction, washing, drying, filtration, and vacuum concentration, the crude product was purified by column chromatography to obtain product II-N-3 or III-N-3. The products were analyzed by LC-MS and 1 It was characterized by HNMR.

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

[0092] Step 7: II-N-2 or III-N-2 was dissolved in tetrahydrofuran, and 20% aqueous potassium hydroxide solution was added in sequence. The mixture was stirred until hydrolysis was complete. The pH was adjusted to 3-4 with 2M hydrochloric acid, and the crude product was obtained by the usual extraction, washing, drying, filtration, and vacuum concentration. The crude product was further purified by column chromatography to obtain product II-N or III-N. The product was analyzed by LC-MS and 1 It was characterized by HNMR.

[0093] Step 8: II-N or III-N was dissolved in tetrahydrofuran, and then an equal amount of solid sodium hydroxide was added and stirred overnight. The mixture was concentrated under reduced pressure, and acetonitrile was added to form a slurry, resulting in a white solid precipitate. After filtration, washing, and drying, the sodium salts II-N-Na and III-N-Na were obtained. The products were analyzed by LC-MS and HPLC, respectively. 1 It was characterized by 1 H NMR.

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

[0095] [Table 2] JPEG2025529392000013.jpg219170JPEG2025529392000014.jpg214170JPEG2025529392000015.j pg223170JPEG2025529392000016.jpg233170JPEG2025529392000017.jpg224170JPEG2025529392 000018.jpg200170JPEG2025529392000019.jpg210170JPEG2025529392000020.jpg210170JPEG20 25529392000021.jpg202170JPEG2025529392000022.jpg224170JPEG2025529392000023.jpg43170

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

[0097] The starting material (SM2), PhBr (1.5 equivalents), sodium tert-butoxide (1.5 equivalents), catalytic amounts of Pd(OAc)2 and XPhos, and toluene as a solvent were added to a reaction flask, heated to 80 °C, and stirred. After the raw materials disappeared, the reaction mixture was quenched with saturated aqueous NaCl, extracted, dried, filtered, concentrated, and purified by column chromatography to obtain product III-20-6. The products were analyzed by LC-MS and HPLC, respectively. 1 It was characterized by 1 H NMR.

[0098] [Table 3] JPEG2025529392000026.jpg78170

[0099] In step 5, products III-21-3 and III-21'-3 were obtained, respectively, which were subsequently subjected to steps 6 to 8 to give III-21 and III-21', and their respective sodium salts III-21-Na and III-21'-Na.

[0100] [Table 4] JPEG2025529392000028.jpg200170JPEG2025529392000029.jpg117170

[0101] Performance Tests and Results Purchase and preliminary breeding Twenty-eight 7-week-old male Sprague-Dawley rats (average weight 200–250 g) were purchased from Weitong Lihua and were acclimatized for one week after purchase in the experimental facility (temperature 20–26°C, humidity 30–70%, day / night ratio 1:1) until they reached 8 weeks of age.

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

[0103] [Table 5]

[0104] 3. Model Creation (1) Preparation of monocrotaline (MCT) solution: Weigh out a sufficient amount of MCT and add it to 50 ml of 20% ethanolic saline. Shake gently and slowly, then transfer it to a 50 ml centrifuge tube. Tilt the tube and place it in an incubator shaker at 37°C and 220 rpm for 12 to 14 hours until the crystalline particles are no longer visible to the naked eye, allowing it to dissolve completely.

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

[0106] (3) Healthy control: The same amount of saline was injected in the same way.

[0107] 4. Preparation of Experimental Drugs (1) Compound 1 and Compound C1 can be directly dissolved in water. The appropriate amount of drug was weighed according to the concentrations of 0.6 mg / ml and 1.2 mg / ml (3 mg / kg / day and 6 mg / kg / day dose groups), and dissolved in the corresponding volume of pure water by shaking to obtain a clear solution.

[0108] (2) Store in a refrigerator at 4°C, remove from the refrigerator before use, let it cool to room temperature, and then use it.

[0109] 5. Administration From the 14th day, the rats were weighed every day, and then the corresponding solution (drug or saline) was intragastrically administered according to the grouping protocol until the 27th day, for a total of 14 days, with the intragastric administration volume being 0.5 ml / 100 g, and the rats' weight and survival data were recorded.

[0110] 6. Hemodynamic Measurements On day 28, the hemodynamic status of the rats was assessed using a right heart catheter.

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

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

[0113] (3) The skin of the surgical site on the neck was prepared.

[0114] (4) The neck skin was incised along the midline, 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) Blunt separation was performed using hemostatic forceps, and the internal jugular vein was dissected.

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

[0117] (7) A V-shaped incision was made in the internal jugular vein using ophthalmic scissors, and a PE-50 catheter was inserted through this incision. After the catheter was inserted, the suture previously placed at the proximal end of the internal jugular vein was ligated to secure the catheter in place.

[0118] (8) The catheter reached the right atrium and then the right ventricle, recording the right atrial pressure and right ventricular pressure. At least five stable waveforms were recorded at each site, and five consecutive waveforms were segmented. Two or more segments were cut out to calculate the right ventricular systolic pressure (RVSP).

[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 with an intraperitoneal injection of 10% chloral hydrate at a dose of 0.5 ml / 100 g, weighed, and then sample collection was initiated.

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

[0122] (3) The chest 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 tube of heparinized saline solution, which was then inserted into the right atrial appendage and slowly injected to flush out the pulmonary blood vessels.

[0124] (5) Heart, lung, liver, spleen, and kidney tissues were collected from rats, frozen, and fixed in formaldehyde solution.

[0125] 8. Measurement of Fulton coefficient After isolating the heart, non-ventricular parts such as the atria, blood vessels, and valve annulus were removed. A microscope was used to remove as much intraventricular thrombus as possible. Next, the right ventricle (RV) and left ventricle (LV) + interventricular septum (LV+S) were removed along the border of the tensed right ventricle (RV) and interventricular septum (S) by straight cutting. The water was completely aspirated with gauze and the hearts were weighed separately. The Fulton coefficient (RV / (LV+S)) was calculated.

[0126] [ka]

[0127] The experimental results are as follows:

[0128] body weight Body weight on day 1: The mean body weights of treatment groups 1 to 6 on day 0 were 347±12.77, 315±3.63, 316±4.35, 330±25.11, 315±13.50, and 314±5.35 g, 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 to 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 groups.

[0130] 3. Body weight at the time of sampling: The body weight at the time of sampling for administration groups 1 to 6 was 436±44.27, 440±55.00, 436±9.65, 431±58.03, 406±42.45, and 445±25.06 g, respectively, and no significant difference was observed.

[0131] NOTE: Due to the total weight limit for Compound 1, Group 1 was actually administered for 13 days, Group 2 was actually administered for 12 days, and both groups were measured and sampled on day 27. Groups 3–6 were actually administered for 14 days, and both groups were measured and sampled on day 27.

[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 was actually administered for 12 days, and both groups were measured and sampled on Day 27; Groups 3-6 were actually administered for 14 days, and all were measured and sampled on Day 27.

[0134] Hemodynamic results The RVSPs of rats in treatment groups 1 to 6 were 22±4.36, 41±16.27, 38±8.86, 46±13.45, 63±7.34, and 22±2.41 mmHg, respectively. The RVSPs of rats in model-prepared groups 2 to 4 were all significantly higher than those of the healthy control group, and the RVSPs of rats in the compound 1 6 mg / kg treatment group were reduced 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 of the compound 1 6 mg / kg treatment group was significantly lower than that of 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: Compound C1, i.e., treprostinil sodium 5.5-hydrate, at doses of 3 and 6 mg / kg, both significantly reduced the RVSP of rats, but it was higher than that of the healthy control group, and there was no significant difference in the effect between the two dose groups (38±8.86 vs. 46±13.45 mmHg, P=0.201).

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

[0139] Fulton coefficient results The Fulton coefficients for groups 1 to 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 for the negative control group was significantly higher than that of the healthy control group, and the Fulton coefficient for the drug treatment group was significantly lower than that of the negative control group, but no significant differences were observed compared to the healthy control group.

[0140] [Table 8]

[0141] From Table 3: 1) Experimental drug treatment groups: The Fulton coefficient of the compound 1 6 mg / kg treatment group was lower than that of 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: Compound C1, i.e., treprostinil sodium 5.5-hydrate, at doses of 3 and 6 mg / kg significantly reduced the Fulton coefficient of the rat heart, but this was higher than that of the healthy control group, and no significant difference was observed 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 in 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 the Fulton coefficient of rat hearts in the compound 1 3 mg / kg treatment group was not significantly different from that in the treprostinil sodium 5.5 hydrate treatment group at the same dose.

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

[0145] [Table 9]

[0146] [Table 10]

[0147] All documents mentioned in this application are incorporated by reference in their entirety as if each such document were incorporated by reference in its entirety. It should also be understood that, after reading the above teachings of the present invention, one skilled in the art can make various changes or modifications to the present invention, and that equivalent forms thereof are also encompassed within the scope defined by the claims appended hereto.

Claims

1. A compound represented by formula (I), or a solvate thereof, or a pharmaceutically acceptable salt thereof, 【Chemical 1】 where: R １ and R ２ are each independently selected from the group consisting of a hydrogen atom, deuterium, a halogen atom, a hydroxyl group, an amino group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 4-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, a substituted or unsubstituted C6-C10 aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, each independently substituted with one, two or three substituents selected from the group consisting of deuterium, a halogen atom, a hydroxyl group, an amino group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a 4-8 membered heterocycloalkyl group containing one, two or three heteroatoms selected from N, O or S, an R substituted or unsubstituted C6-C10 aryl group, and an R substituted or unsubstituted 5-10 membered heteroaryl group containing one, two or three heteroatoms selected from N, O or S, wherein R is selected from the group consisting of a halogen atom, a hydroxyl group, a C1-C6 alkyl group, and a C1-C6 alkoxy group; Or, R １ , R ２ together with the C to which they are attached form a C3-C8 monocyclic cycloalkyl group, a C3-C8 bridged ring cycloalkyl group, a C7-C10 spirocyclic cycloalkyl group, or a 4-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S; And R １ and R ２ is not a hydrogen atom at the same time, R ３ and R ４ are each independently selected from the group consisting of a hydrogen atom, -(C=O)-C1 to C6 alkyl group, a C1 to C6 alkyl group, a C1 to C6 halogenated alkyl group, a C3 to C8 cycloalkyl group, and a C3 to C8 halogenated cycloalkyl group; R ５ is selected from the group consisting of a hydrogen atom, a C1 to C6 alkyl group, a C1 to C6 halogenated alkyl group, a C3 to C8 cycloalkyl group, a C3 to C8 halogenated cycloalkyl group, an inorganic metal ion, and a thionium ion.

2. R １ 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, an R-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 4-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O or S, a C6-C10 aryl group, and a 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S; R is selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, and a C1 to C6 alkoxy group.

3. R １ is H, a halogen atom, a methyl group, or an ethyl group, R ２ 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.

4. R ３ and R ４ 2. The compound of claim 1, or a solvate thereof, 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＋ and / or The compound according to claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein 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. 2. The compound of claim 1, wherein the compound has a structure represented by formula (II): or a solvate thereof, or a pharmaceutically acceptable salt thereof. 【Chemistry 2】 Here, R １ , R ２ , R ３ , R ４ , R ５ is as defined in claim 1.

7. 2. The compound of claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 【Chemistry 3】 【change】 【change】

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds according to claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

9. 10. The use of the compound of claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating pulmonary arterial hypertension.

10. 10. The use according to claim 9, wherein the pharmaceutical is used for an application selected from the group consisting of: 1) Decrease right ventricular systolic pressure, 2) Lower the Fulton coefficient, 3) Lowering PVR; 4) Treat pulmonary hypertension caused by interstitial lung disease; 5) Treat pulmonary hypertension due to COPD; 6) Treat idiopathic pulmonary fibrosis.

Images