Novel prostacyclin for treating pulmonary hypertension

Abstract

The invention relates to novel prostacyclin for treating pulmonary hypertension. Specifically, the compound disclosed by the invention has a structure as shown in a formula (I), and the definitions of all groups and substituent groups are described in the specification. Compared with treprostinil and salts thereof, the compound provided by the invention has better RVSP (Right Ventricular Systolic Pressure) and better Full index. # imgabs0 #

Description

A new prostacyclin for the treatment of pulmonary hypertension Technical Field

[0001] The present invention relates to the field of medicine, in particular to a novel prostacyclin for treating pulmonary hypertension. Background Art

[0002] Treprostinil is a drug for the treatment of pulmonary artery hypertension (PAH). It is a prostacyclin derivative with the activity of inhibiting platelet aggregation and vasodilation. Its approved marketing dosage forms include injection, inhalation and oral tablets. The raw material of the injection and inhalation is treprostinil sodium salt.

[0003] However, the existing sodium salt of treprostinil still has the problem of poor efficacy in treating pulmonary hypertension. Therefore, there is an urgent need in the art to develop drugs with better efficacy for treating pulmonary hypertension.

[0004] Ralinepag is a drug currently in Phase III clinical trials for the treatment of pulmonary arterial hypertension. Its structure is as follows:

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide a compound represented by formula (I), a preparation method thereof, and use thereof in treating pulmonary hypertension.

[0007] The first aspect of the present invention provides a compound represented by formula (I), or a solvate thereof, or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] R1 and R2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; The substitutions are each independently substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, hydroxy, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, R substituted or unsubstituted C6-C10 aryl, R substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; R is selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy;

[0010] Or R1, R2 and the C to which they are attached together form a C3-C8 monocyclic cycloalkyl, a C3-C8 bridged ring cycloalkyl, a C7-C10 spirocyclic cycloalkyl, or a 4-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0011] Furthermore, R1 and R2 are not hydrogen at the same time;

[0012] R3 and R4 are each independently selected from the group consisting of hydrogen, -(C=O)-C1-C6 alkyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl;

[0013] R5 is selected from the group consisting of hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, inorganic metal ion, and ammonium ion.

[0014] In another preferred embodiment, R1 is hydrogen;

[0015] R2 is selected from the following groups: halogen, C1-C6 alkyl, halo-substituted C1-C6 alkyl, R-substituted or unsubstituted C1-C6 alkyl substituted by C6-C10 aryl, hydroxy-substituted C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C6-C10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S;

[0016] R is selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 alkoxy.

[0017] In another preferred embodiment, R1 is hydrogen;

[0018] R2 is a C1-C6 alkyl group.

[0019] In another preferred embodiment, R1 is hydrogen;

[0020] R2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, and tert-pentyl.

[0021] In another preferred embodiment, R1 is hydrogen;

[0022] R2 is ethyl.

[0023] In another preferred embodiment, R1 is H, halogen, methyl, or ethyl;

[0024] R2 is selected from the following group: halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, trifluoromethyl, difluoromethyl, monofluoromethyl, monofluoroethyl, trifluoroethyl, difluoroisopropyl, hydroxy-substituted ethyl, vinyl, propenyl, ethynyl, propynyl, benzyl, diphenylmethyl, methoxybenzyl, monochlorobenzyl, phenyl-substituted ethyl, hydroxy-substituted benzyl.

[0025] In another preferred embodiment, R1, R2 and the C to which they are connected together form a group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0026] In another preferred embodiment, R3 and R4 are hydrogen.

[0027] In another preferred embodiment, R5 is hydrogen.

[0028] In another preferred embodiment, the inorganic metal ion is selected from the following group: Li + 、Na + , K + , Rb + 、Cs + Mg 2+ , Ca 2+ 、Ba 2+ 、Zn 2+ 、Al 3+ .

[0029] In another preferred embodiment, R5 is Na + .

[0030] In another preferred embodiment, 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.

[0031] In another preferred embodiment, the ammonium ion is a cation.

[0032] In another preferred embodiment, the pharmaceutically acceptable salt is an alkali metal salt or an alkaline earth metal salt.

[0033] In another preferred embodiment, the pharmaceutically acceptable salt is a salt of the compound selected from the group consisting of lithium salt, sodium salt, potassium salt, cesium salt, magnesium salt, calcium salt, barium salt, zinc salt, and aluminum salt.

[0034] In another preferred embodiment, the pharmaceutically acceptable salt is a salt of the compound selected from the group consisting of lithium salt, sodium salt, potassium salt, and cesium salt.

[0035] In another preferred embodiment, the pharmaceutically acceptable salt is a salt of the compound selected from the group consisting of magnesium salt, calcium salt, barium salt, zinc salt, and aluminum salt.

[0036] In another preferred embodiment, the pharmaceutically acceptable salt is the sodium salt of the compound.

[0037] In another preferred embodiment, the pharmaceutically acceptable salt is a salt formed by the compound and a nitrogen-containing organic base.

[0038] In another preferred embodiment, 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.

[0039] In another preferred embodiment, the solvate is a hydrate.

[0040] In another preferred embodiment, the compound has a structure represented by formula (II) or formula (III):

[0041] wherein R1, R2, R3, R4, and R5 are as defined above.

[0042] In another preferred embodiment, the compound is selected from the following group:

[0043] The second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds described in the first aspect of the present invention, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

[0044] The third aspect of the present invention provides a use of the compound described in the first aspect of the present invention, or a solvate thereof, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating pulmonary arterial hypertension.

[0045] In another preferred embodiment, the drug is an oral preparation.

[0046] In another preferred embodiment, the dosage of the drug is 5-7 mg / kg / day, preferably 6 mg / kg / day.

[0047] In another preferred embodiment, the drug is used for a purpose selected from the group consisting of:

[0048] 1) Reduce right ventricular systolic pressure;

[0049] 2) Reduce the Fulton index;

[0050] 3) Reduce PVR (pulmonary vascular resistance);

[0051] 4) Treatment of pulmonary hypertension caused by interstitial lung disease;

[0052] 5) Treatment of pulmonary hypertension caused by COPD;

[0053] 6) Treatment of idiopathic pulmonary fibrosis.

[0054] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG1 shows the technical route of the present invention.

[0056] FIG2 is a bar graph corresponding to the weight data in Table 1 obtained by the present invention.

[0057] FIG3 is a bar graph corresponding to the RVSP data in Table 2 obtained in the present invention.

[0058] FIG4 is a bar graph corresponding to the Fulton index data in Table 3 obtained in the present invention. DETAILED DESCRIPTION

[0059] After extensive and in-depth research, the inventors have developed a novel prostacyclin drug with enhanced efficacy in treating pulmonary hypertension by optimizing the structure of the existing sodium salt of treprostinil. Specifically, by substituting the R1 and R2 positions of the compound of formula I (preferably C1-C6 alkyl substitutions, more preferably mono-C1-C6 alkyl substitutions), they obtained a compound of formula (I) with enhanced RVSP (right ventricular systolic pressure) and Fulton index. Based on this, the inventors completed the present invention.

[0060] the term

[0061] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0062] In the present invention, the term "halogen" refers to F, Cl, Br or I.

[0063] In the present invention, "C1-C6 alkyl" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.

[0064] In the present invention, the term "C2-C6 alkenyl" refers to a straight chain or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0065] In the present invention, the term "C2-C6 alkynyl" refers to a straight chain or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0066] In the present invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0067] In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-C4 alkoxy group.

[0068] 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 and S, including (but not limited to) the following groups:

[0069] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, 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 phenyl, naphthyl, etc.

[0070] In the present invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning and refer to a heteroaromatic group containing one to multiple heteroatoms. For example, a "5-10 membered heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 carbon atoms. Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0071] In the present invention, the term "halo" means substituted with halogen.

[0072] In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substituents include, but are not limited to, halogen, hydroxyl, carboxyl (—COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

[0073] In the present invention, the term 1-6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings. The term "plurality" refers to 2-6, such as 2, 3, 4, 5 or 6.

[0074] The term "ester group" has a -C(O)-O-R' or R'-C(O)-O- structure, wherein R' independently represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, heteroaryl, heterocyclyl, as defined above.

[0075] It should be understood that when a group is present at multiple different positions in a compound, its definition at each position is independent of each other and may be the same or different. That is, the term "selected from the group:" has the same meaning as the term "each independently selected from the group:".

[0076] The term "COPD" refers to chronic obstructive pulmonary disease.

[0077] The Fulton Index reflects the organ remodeling caused by PAH. Changes in this index suggest that new drugs have the potential to reverse the altered cardiopulmonary structure caused by PAH. This means not only alleviating PAH symptoms (treating the symptoms) but also reversing or even curing PAH (treating the root cause). This is a goal that current PAH drugs cannot achieve, but which new PAH drugs hope to achieve.

[0078] Compound

[0079] The present invention provides a compound represented by formula I, or a solvate thereof, or a pharmaceutically acceptable salt thereof,

[0080] wherein each group is as defined above.

[0081] In another preferred embodiment, in the compound, any one of R1, R2, R3, R4, and R5 is independently a corresponding group in the specific compound of the present invention.

[0082] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed with a compound of the present invention and an acid. Suitable acids for salt formation include, but are not limited to, amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, and lysine.

[0083] Another preferred salt is a salt of the compound of the present invention formed with a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, 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 formed from morpholine, piperazine, and lysine, respectively.

[0084] The term "solvate" refers to a complex formed by the coordination of a compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0085] The present invention also includes co-crystals formed between the compounds of the present invention and compatible compounds.

[0086] In addition, the compounds of the present invention also include prodrugs of the compounds represented by formula (I). The term "prodrug" includes a compound that may be biologically active or inactive, and when administered by appropriate methods, undergoes metabolism or chemical reactions in the human body to convert into a compound of formula (I), or a salt or solution composed of a compound of formula (I). The prodrugs include (but are not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino, carbamate, azo, phosphoramide, glucoside, ether, acetal, and the like forms of the compound.

[0087] It should be understood that the examples of the present invention more specifically describe the preparation methods of the compounds of formula (I) of the present invention, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art.

[0088] Typically, the raw materials and reagents used in the process for preparing the compounds of the present invention can be purchased through commercial channels unless otherwise specified.

[0089] Pharmaceutical compositions and methods of administration

[0090] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more of the compounds, or solvates thereof, or pharmaceutically acceptable salts thereof.

[0091] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg per dose. Preferably, "one dose" is a capsule or tablet, but may also be an injection, inhalant, or oral formulation.

[0092] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0093] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0094] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), oral and nasal inhalation, anal, vaginal and topical administration.

[0095] 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, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In capsules, tablets, and pills, the dosage form may also contain a buffer.

[0096] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0097] 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 contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0098] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0099] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0100] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous 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.

[0101] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0102] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0103] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0104] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will 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.

[0105] Compared with the prior art, the present invention has the following main advantages:

[0106] (1) The compounds of the present invention have better therapeutic effects on pulmonary hypertension;

[0107] (2) The compounds of the present invention have better RVSP (right ventricular systolic pressure) and better Fulton index;

[0108] (3) Compared with Ralinepag (United Therapeutics Corporation), which is in Phase III clinical trials, the corresponding animal experimental data of the compound of the present invention are also better than Ralinepag;

[0109] (4) Based on body weight data and clinical observations, the eating, defecation, activity, and paw strength of the rats in the drug-treated group were no different from those in the healthy group.

[0110] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0111] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0112] Preparation Example

[0113] II-N or III-N and its corresponding sodium salt II-N-Na or III-N-Na are prepared according to the following procedure:

[0114] Note: II-N represents compounds such as II-1 and II-2; III-N represents compounds such as III-1 and III-2.

[0115] Step 1:

[0116] Add the starting material (SM1) and tetrahydrofuran to the reaction flask and cool it to -65 ° C. At this temperature, slowly add LDA or LiHMDS (1.0 to 5.0 equivalents). After the addition is completed, continue stirring at this temperature for 3 hours. Then add the electrophilic reagent (1.0 to 5.0 equivalents) to the reaction system. After the addition is completed, slowly increase the temperature and stir overnight. Add saturated ammonium chloride aqueous solution to the reaction system to quench the reaction. After conventional extraction, washing, drying, concentration, and column chromatography, the product II-N-7 or III-N-7 is obtained. The products are analyzed by LC-MS and 1 Characterization was performed by H NMR.

[0117] Wherein, the electrophilic reagent is selected from the following group:

[0118] Step 2:

[0119] Dissolve II-N-7 or III-N-7 in anhydrous ethanol, transfer to a hydrogenation reactor, add palladium carbon and hydrogenate overnight. Filter to remove palladium carbon, concentrate the filtrate under reduced pressure, and purify the crude product by column chromatography to obtain product II-N-6 or III-N-6. The products are analyzed by LC-MS and 1 Characterization was performed by H NMR.

[0120] Step 3:

[0121] Dissolve II-N-6 or III-N-6 in anhydrous ethanol, cool to -25 to -15°C, then add an appropriate amount of 2M sodium hydroxide aqueous solution and stir at this temperature for 2 to 4 hours. Then add sodium borohydride (1.0 to 2.0 equivalents) at this temperature and continue stirring for 4 to 6 hours. After conventional extraction, washing, drying, concentration, and column chromatography, the product II-N-5 or III-N-5 is obtained. The products are analyzed by LC-MS and 1 Characterization was performed by H NMR.

[0122] Step 4:

[0123] Dissolve II-N-5 or III-N-5 in anhydrous ethanol, then add 1M dilute hydrochloric acid and stir at room temperature for 2-6 hours. After extraction, washing, drying, concentration, and column chromatography purification, product II-N-4 or III-N-4 is obtained. The products are analyzed by LC-MS and 1 Characterization was performed by H NMR.

[0124] Step 5:

[0125] Dissolve diphenylphosphine (5.0-10.0 equivalents) in anhydrous tetrahydrofuran and cool to -25--15°C, slowly add n-butyl lithium (5.0-10.0 equivalents) dropwise, and continue stirring at this temperature for 2-4 hours to obtain a tetrahydrofuran solution of lithium diphenylphosphine.

[0126] Take another reaction bottle, add II-N-4 or III-N-4 and dissolve it in tetrahydrofuran, and slowly add the freshly prepared tetrahydrofuran solution of lithium diphenylphosphine at room temperature. After the addition is completed, the reaction system is refluxed overnight. Remove the heat and cool it and further cool it in an ice water bath, and add saturated ammonium chloride to quench the reaction. After conventional extraction, washing, drying, filtering, and concentration under reduced pressure, the crude product is purified by column chromatography to obtain the product II-N-3 or III-N-3. The products are respectively analyzed by LC-MS and 1 Characterization was performed by H NMR.

[0127] Step 6:

[0128] Dissolve II-N-3 or III-N-3 in acetone, then add potassium carbonate and bromoacetonitrile (1.5 to 3.0 equivalents each) in sequence and stir at room temperature overnight. Filter to remove solid insoluble matter, and directly concentrate the filtrate under reduced pressure. The crude product is purified by column chromatography to obtain product II-N-2 or III-N-2. The products are analyzed by LC-MS and 1 Characterization was performed by H NMR.

[0129] Step 7:

[0130] Dissolve II-N-2 or III-N-2 in tetrahydrofuran, add 20% potassium hydroxide aqueous solution in sequence, and stir until hydrolysis is complete. Adjust the pH value to 3-4 with 2M hydrochloric acid, extract, wash, dry, filter, and concentrate under reduced pressure to obtain a crude product, which is then purified by column chromatography to obtain the product II-N or III-N. The products are analyzed by LC-MS and 1 Characterization was performed by H NMR.

[0131] Step 8:

[0132] Dissolve II-N or III-N in tetrahydrofuran, then add an equivalent amount of sodium hydroxide solid and stir overnight. Concentrate under reduced pressure and add acetonitrile to slurry to obtain a white solid precipitate. Filter, wash and dry to obtain sodium salt II-N-Na or III-N-Na. The products are analyzed by LC-MS and 1 Characterization was performed by H NMR.

[0133] The characterization data of the compounds prepared by the above methods of the present invention are shown in Table A, Table B and Table C.

[0134] Table A

[0135] III-20-6 was prepared according to the following operation, and the remaining intermediates, III-20 and III-20-Na were prepared according to the aforementioned steps 3-8.

[0136] The starting material (SM2), PhBr (1.5 equivalents), sodium tert-butoxide (1.5 equivalents), catalytic amounts of Pd(OAc)2 and XPhos, and solvent toluene were added to the reaction flask and the temperature was raised to 80°C with stirring. After the disappearance of the starting material, the product III-20-6 was obtained by quenching with saturated NaCl aqueous solution, extraction, drying, filtration, concentration, and column chromatography purification. The products were analyzed by LC-MS and 1 Characterization was performed by H NMR.

[0137] Table B

[0138] In step 5, products III-21-3 and III-21'-3 are obtained respectively, and the two products are further subjected to steps 6-8 to obtain III-21 and III-21' and their respective sodium salts III-21-Na and III-21'-Na.

[0139] Table C

[0140] Performance testing and results

[0141] 1. Purchase and pre-adaptation

[0142] Twenty-eight 7-week-old male Sprague-Dawley rats (average weight 200-250 g) were purchased from Weitonglihua and acclimatized at the experimental site for 1 week (temperature 20-26°C, humidity 30-70%, day-night ratio 1:1) until they were 8 weeks old.

[0143] 2. Grouping

[0144] 28 rats were randomly divided into the following 6 groups, including drug treatment group, positive control group, negative control group and healthy control group, and marked with ear tags.

[0145] Note 1: Group 1 and Group 2 are experimental drugs of the treprostinil class (Compound 1 is Compound III-2-Na), Group 3 and Group 4 are positive controls for treprostinil (Compound C1 is treprostinil sodium 5.5 hydrate); Group 5 is the negative control group, and Group 6 is the healthy control group.

[0146] Note 2: The suffix H represents the high-dose group (6 mg / kg); M represents the medium-dose group.

[0147] 3. Modeling

[0148] (1) Preparation of Monocrotaline (MCT) solution: Weigh enough MCT into 50 ml of 20% ethanol-normal saline solution, shake gently and slowly, transfer to a 50 ml centrifuge tube, tilt and place in a constant temperature shaker at 37°C and 220 rpm for 12-14 hours to fully dissolve the MCT until no crystal particles are visible to the naked eye.

[0149] (2) MCT solution injection: Gently lift the skin on the back of the rat's neck and inject MCT solution subcutaneously at a dose of 60 mg / kg using a 1 ml syringe and record it as day 0.

[0150] (3) Healthy controls: The same dose of normal saline was injected using the same method.

[0151] 4. Preparation of experimental drugs

[0152] (1) Compound 1 and Compound C1 can be directly dissolved in water. Appropriate amounts of the drugs were 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 shaken with the corresponding volume of pure water to dissolve them, with the formation of a transparent solution being the standard.

[0153] (2) Store in a refrigerator at 4°C, take out before use, and place at room temperature before use;

[0154] 5. Medication

[0155] Starting from the 14th day, rats were weighed daily and given corresponding solutions (drugs or saline) by gavage according to the grouping scheme until the 27th day, for a total of 14 days; the gavage dose was 0.5 ml / 100 g, and the rat body weight and survival data were recorded.

[0156] 6. Hemodynamic Measurements

[0157] On day 28, the hemodynamic status of the rats was assessed using right cardiac catheterization:

[0158] (1) Prepare the PE-50 catheter, pressure transducer, and pressure measurement workstation; flush the tubing with heparinized saline to ensure there are no bubbles in the tubing; and zero the catheter.

[0159] (2) Rats were anesthetized with 2% isoflurane at a flow rate of 2 L / min, and their limbs and incisors were fixed on the operating table with the head facing the operator;

[0160] (3) Skin preparation of the surgical area of ​​the neck;

[0161] (4) Cut the neck skin along the midline, use hemostatic forceps to pull and fix the neck skin, and use scissors to separate the tissue layer by layer to expose the right internal jugular vein;

[0162] (5) Use hemostatic forceps to perform blunt dissection and free the internal jugular vein;

[0163] (6) Use 4-0 suture to ligate the distal end of the internal jugular vein and pass the suture through the proximal end of the internal jugular vein for later use;

[0164] (7) Use ophthalmic scissors to make a V-shaped incision in the internal jugular vein and insert the PE-50 catheter through this incision. After the catheter is inserted, tie the pre-placed suture at the proximal end of the internal jugular vein to secure the catheter.

[0165] (8) The catheter reaches the right atrium and right ventricle in sequence; right atrial pressure and right ventricular pressure are recorded; at least five stable waveforms are recorded at each location; five continuous waveforms are used as segments, and two or more segments are intercepted to calculate the right ventricular systolic pressure (RVSP);

[0166] (9) Remove the PE-50 catheter and complete the examination.

[0167] 7. Get materials

[0168] (1) After the hemodynamic assessment, rats were anesthetized with an intraperitoneal injection of 10% chloral hydrate at a dose of 0.5 ml / 100 g and weighed before sampling.

[0169] (2) After opening the abdominal cavity, use a 5 ml syringe to draw as much blood as possible from the inferior vena cava into an EDTA anticoagulant tube and shake it upside down 6-8 times;

[0170] (3) Continue opening the chest cavity to expose the lungs and heart;

[0171] (4) Cut open the left atrial appendage, draw a tube of heparinized saline with a 5ml syringe and insert it into the right atrial appendage, and slowly inject to flush the pulmonary blood vessels;

[0172] (5) The rat heart, lung, liver, spleen and kidney tissues were frozen and fixed with formaldehyde solution.

[0173] 8. Fulton Index Measurement

[0174] After isolating the heart, trim away any parts other than the ventricles, such as the atria, blood vessels, and valve annulus. Use forceps to remove any intraventricular thrombus as much as possible. Then, use straight scissors to separate the right ventricle (RV) and left ventricle (LV) plus the interventricular septum (LV+S) along the taut junction of the right ventricle (RV) and interventricular septum (S). Dry with gauze and weigh each. RV / (LV+S), the Fulton index, is calculated.

[0175] The structure of compound C1 is as follows:

[0176] The experimental results are as follows:

[0177] weight

[0178] 1. Body weight on day 0: The average body weights of groups 1-6 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 average body weight of group 1 was significantly greater than that of groups 2, 3, 5, and 6 (P < 0.01), and there was no significant difference between the groups.

[0179] 2. Body weight on the 14th day: The average body weights of groups 1-6 on the 14th day were 440±32.61, 428±29.90, 413±15.81, 430±34.15, 406±33.50, and 425±20.48 g, respectively, with no significant differences among the groups.

[0180] 3. Body weight of samples: The body weight of samples in 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, with no significant differences among the groups.

[0181] Note: Due to the total weight limit of compound 1, group 1 was actually administered for 13 days, and group 2 was actually administered for 12 days. Measurements and samples were taken on the 27th day. Groups 3-6 were actually administered for 14 days. Measurements and samples were taken on the 27th day.

[0182] Table 1 Comparison of body weight changes of rats in each group

[0183] Survival

[0184] Due to the total weight limit of compound 1, group 1 was actually administered for 13 days and group 2 was actually administered for 12 days, with measurements and samples collected on the 27th day; groups 3-6 were actually administered for 14 days, with measurements and samples collected on the 27th day.

[0185] Hemodynamic results

[0186] The RVSP of 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 of rats in modeling groups 2-4 were significantly higher than those in the healthy control group. The RVSP of rats in the compound 1 6 mg / kg treatment group had decreased to the level of the healthy control group (22±4.36 vs 22±2.41 mmHg, P=0.939).

[0187] Table 2 Comparison of RVSP values ​​of rats in each group

[0188] From Table 2 we can see that:

[0189] 1) Experimental drug treatment groups: The RVSP in the compound 1 6 mg / kg treatment group was significantly lower than that in the 3 mg / kg treatment group (22±4.36 vs 41±16.27 mmHg, P=0.01), indicating a significant difference between the two groups.

[0190] 2) Positive control group: Compound C1 (treprostinil sodium 5.5 hydrate) at doses of 3 and 6 mg / kg significantly reduced RVSP in rats, but the RVSP was still higher than that in the healthy control group, and there was no significant difference between the two dose groups (38±8.86 vs 46±13.45 mmHg, P=0.201);

[0191] 3) The RVSP of rats in the compound 1 6 mg / kg treatment group was lower than that in the treprostinil sodium 5.5 hydrate treatment group (22±4.36 vs 38±8.86 mmHg, P=0.013), and the pulmonary vasodilation effect was better than that of the treprostinil sodium 5.5 hydrate at the same dose.

[0192] Fulton Index Results

[0193] The Fulton index of 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 index of the negative control group was significantly higher than that of the healthy control group, while the Fulton index of the drug treatment group was significantly lower than that of the negative control group, and there was no significant difference between the two groups.

[0194] Table 3 Comparison of Fulton index of rats in each group

[0195] From Table 3 we can see that:

[0196] 1) Experimental drug treatment groups: The Fulton index of the compound 1 6 mg / kg treatment group was lower than that of the 3 mg / kg treatment group, but there was no significant difference between the two dose groups (0.25±0.27 vs 0.37±0.12, P=0.06);

[0197] 2) Positive control group: Compound C1, treprostinil sodium 5.5 hydrate, at doses of 3 and 6 mg / kg significantly reduced the Fulton index of rat hearts, but it was still higher than that of the healthy control, and there was no significant difference in the effect between the two dose groups (0.37±0.07 vs 0.38±0.10, P=0.921);

[0198] 3) The cardiac Fulton index of rats 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); the cardiac Fulton index of rats in the 3 mg / kg treatment group was not significantly different from that in the treprostinil sodium 5.5 hydrate treatment group at the same dose.

[0199] In addition, according to the same experimental method as above, for Ralinepag, the corresponding experimental results are shown in Tables 4 and 5.

[0200] Table 4 Comparison of RVSP values ​​of rats in each group

[0201] Table 5 Comparison of Fulton index of rats in each group

[0202] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by formula (I), or a solvate thereof, or a pharmaceutically acceptable salt thereof, in, R1 and R2 are each independently selected from the following group: hydrogen, deuterium, halogen, hydroxyl, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; The substitutions are each independently substituted by 1, 2 or 3 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, R substituted or unsubstituted C6-C10 aryl, R substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S; R is selected from the group consisting of halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy; Or R1, R2 and the C to which they are connected together form a C3-C8 monocyclic cycloalkyl, a C3-C8 bridged ring cycloalkyl, a C7-C10 spirocyclic cycloalkyl, or a 4-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S; Furthermore, R1 and R2 are not hydrogen at the same time; R3 and R4 are each independently selected from the group consisting of hydrogen, -(C=O)-C1-C6 alkyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl; R5 is selected from the following group: hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, inorganic metal ion, ammonium ion.

2. The compound according to claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof, characterized in that: R1 is hydrogen; R2 is selected from the following groups: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkyl substituted or unsubstituted C6-C10 aryl substituted C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, C6-C10 aryl, 5-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S metaheteroaryl; R is selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 alkoxy.

3. The compound according to claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R1 is H, halogen, methyl, ethyl; R2 is selected from the following group: halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, trifluoromethyl, difluoromethyl, monofluoromethyl, monofluoroethyl, trifluoroethyl, difluoroisopropyl, hydroxy-substituted ethyl, vinyl, propenyl, ethynyl, propynyl, benzyl, diphenylmethyl, methoxybenzyl, monochlorobenzyl, phenyl-substituted ethyl, hydroxy-substituted benzyl.

4. The compound according to claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: R3 and R4 are hydrogen.

5. The compound according to claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: The inorganic metal ion is selected from the following group: Li + 、Na + , K + , Rb + , Cs + Mg 2+ , Ca 2+ , Ba 2+ 、Zn 2+ 、Al 3+ ; and / or 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, wherein: The compound has a structure shown in formula (II) or formula (III): wherein R1, R2, R3, R4 and R5 are as defined in claim 1.

7. The compound according to claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the group consisting of:

8. A pharmaceutical composition, characterized in that It comprises a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound according to claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof.

9. Use of the compound according to claim 1, or a solvate thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Used for preparing medicine for treating pulmonary hypertension.

10. The use according to claim 9, characterized in that The drug is used for a purpose selected from the group consisting of: 1) Reduce right ventricular systolic pressure; 2) Reduce the Fulton index; 3) Reduce PVR; 4) Treatment of pulmonary hypertension caused by interstitial lung disease; 5) Treat pulmonary hypertension caused by COPD; 6) Treatment of idiopathic pulmonary fibrosis.

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