CN118619893A

CN118619893A - PGI2 receptor agonist compounds, pharmaceutical compositions and uses

Info

Publication number: CN118619893A
Application number: CN202410701014.XA
Authority: CN
Inventors: 孙立杰; 孙晓飞; 杨娴; 曹柳; 李磊; 朱树杰; 郭志强; 侯海婷; 陈伟; 左亚茹
Original assignee: Shijiazhuang No 4 Pharmaceutical Co Ltd; Hebei Guolong Pharmaceutical Co Ltd
Current assignee: Shijiazhuang No 4 Pharmaceutical Co Ltd; Hebei Guolong Pharmaceutical Co Ltd
Priority date: 2023-12-27
Filing date: 2024-05-31
Publication date: 2024-09-10

Abstract

The invention belongs to the technical field of chemical medicines, and provides a PGI2 receptor agonist compound shown in a general formula I or pharmaceutically acceptable salts, stable isotope derivatives, isomers and mixtures thereof. Wherein R ₁ and R ₂ are each independently selected from H, C ₁-C₃ alkyl or halogen; z is selected from CR ₇ or N atom, wherein R ₇ is selected from H or C ₁-C₃ alkyl, halogen atom or halogenated C ₁-C₃ alkyl; r ₃ is selected from C ₁-C₃ alkyl, C _3‑C₆ monocyclic cycloalkyl; r ₄ is selected from H, C ₁-C₃ alkoxy or 3-6 membered heteroalicyclic; r ₅ represents OH, OR ₆, OR NHSO ₂R₆, wherein R ₆ represents C _1‑4 alkyl OR C _1‑4 alkyl substituted by halogen; represents a single bond or a double bond. The compound has good affinity to PGI2 receptor and low adverse reaction, and avoids the defects of the existing PGI2 analogues and selapage.

Description

PGI2 receptor agonist compounds, pharmaceutical compositions and uses

Cross Reference to Related Applications

The present application claims priority from chinese patent application CN202311824286.0, whose filing date is 2023, 12, 27, and the present application incorporates the entirety of the above-mentioned chinese patent application.

Technical Field

The invention belongs to the technical field of chemical medicines, and particularly relates to a PGI2 receptor agonist compound, a pharmaceutical composition and application.

Background

Pulmonary Arterial Hypertension (PAH) is a disease characterized mainly by vasospasm, intimal hyperplasia, and remodeling of the pulmonary arterioles. Vascular proliferation and remodeling of the pulmonary arterioles results in progressive increases in pulmonary vascular resistance, ultimately leading to right heart failure until death. PAH has been listed as the third most common cardiovascular disease, with prevalence inferior to hypertension and coronary heart disease, has become a public health care problem that severely threatens human physical and mental health, and is listed by the world health organization as a significant chronic disease detection worldwide.

PGI2 is a substance produced in organisms from arachidonic acid via prostaglandin H2 (PGH 2), and PGI2 deficiency can cause pulmonary hypertension. Currently, PGI2 receptor agonists that have been marketed include epoprostenol, beraprost, iloprost, etc., all of which are PGI2 analogs. However, PGI2 has a very short biological half-life and poor selectivity for the target, and the objective effect is difficult to separate from other effects, so that adverse reactions are liable to occur. Selapage (Selexipag) is currently the only PGI2 agonist without PGI2 skeleton but with good selectivity to PGI2 receptor and definite drug effect, and has been marketed in multiple countries for the treatment of adult pulmonary hypertension. The specific therapeutic effect is stronger and longer than other medicines with similar mechanisms, but the price is high, and the specific therapeutic effect clearly increases the great economic burden for patients with pulmonary arterial hypertension which need to be treated for a long time. In addition, selapage, although having relatively good specificity, still has obvious adverse effects such as headache, facial flushing, nausea, vomiting, etc., and for patients requiring long-term administration, the daily and monthly damage of the body caused by the drug can reduce the health level and the quality of life to different extents.

Disclosure of Invention

In view of the above problems, the invention provides a PGI2 receptor agonist compound, a pharmaceutical composition and application thereof, wherein the compound has good affinity to PGI2 receptors and low adverse reaction, and the defects of the existing PGI2 analogues and selapage are avoided.

In order to achieve the aim of the invention, the invention adopts the following technical scheme:

in a first aspect, the present invention provides a PGI2 receptor agonist compound of formula I or a pharmaceutically acceptable salt, stable isotope derivative, isomer and mixture thereof,

Wherein R ₁ and R ₂ are each independently selected from H, C ₁-C₃ alkyl or halogen;

Z is selected from CR ₇ or N atom, wherein R ₇ is selected from H or C ₁-C₃ alkyl, halogen atom or halogenated C ₁-C₃ alkyl;

R ₃ is selected from C ₂-C₄ alkyl, C _3-C₆ monocyclic cycloalkyl;

R ₄ is selected from H, C ₁-C₃ alkoxy or 3-6 membered heteroalicyclic;

R ₅ represents OH, OR ₆ OR NHSO ₂R₆, wherein R ₆ represents C _1-4 alkyl OR C _1-4 alkyl substituted by halogen; the carboxyl groups form an acid, ester or sulfonamide with R5;

Represents a single bond or a double bond.

An embodiment of the invention relates to compounds of the general formula I above, or pharmaceutically acceptable salts, stable isotope derivatives, isomers and mixtures thereof, wherein Z is an N atom; or Z is a C atom R ₇ selected from H or CH ₃.

In one of the embodiments of the present invention,R ₄ represents a double bond, and is H, and the structural formula is shown as formula II correspondingly:

in the formula II, R ₁ and R ₂ are selected from H, methyl or F; z is an N atom, or Z is CR ₇,R₇ selected from H or CH ₃, more preferably an H atom; r ₃ is selected from isopropyl, ethyl or cyclopropanyl, more preferably isopropyl; r ₅ is selected from OH or NHSO ₂R₆,R₆ is selected from C _1-4 alkyl or C _1-4 alkyl substituted by halogen, R ₆ is more preferably methyl.

One embodiment of the present invention relates to a compound of the above formula I or a pharmaceutically acceptable salt, stable isotope derivative, isomer, and mixture thereof, whereinRepresents a single bond, and the structural formula is shown as formula III:

In formula III, R ₄ is selected from H, C ₁-C₃ alkoxy or 3-6 membered heteroalicyclic, preferably R ₄ is H, methoxy, ethoxy or More preferably R ₄ is H, methoxy or ethoxy.

One embodiment of the present invention relates to compounds of formula I or formula iii above, or pharmaceutically acceptable salts, stable isotope derivatives, isomers, and mixtures thereof, wherein R ₁ and R ₂ are selected from H, methyl or F; r ₃ is selected from isopropyl, ethyl or cyclopropanyl, preferably R ₃ is isopropyl; r ₅ is preferably OH or NHSO ₂CH₃.

An embodiment of the present invention relates to a compound represented by the above general formula (I), wherein the compound is selected from, but not limited to:

or prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers, and mixtures thereof.

The compound disclosed by the invention does not have a PGI2 skeleton, has strong selectivity and affinity to a PGI2 receptor, and has good target selectivity compared with a PGI2 analogue. Experiments prove that the compound has better in vivo efficacy than selapage and lower toxicity than selapage, so the compound can be used as a pulmonary artery high pressure treatment medicament with clinical value and development prospect.

The second aspect of the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent, and as active ingredient the above-mentioned compounds or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof.

The pharmaceutical composition can be any dosage form, and optionally can be conventional dosage forms such as tablets, granules, capsules, powder or injection.

In another aspect, the invention relates to the use of the above-described compounds or pharmaceutically acceptable salts, stable isotope derivatives, isomers and mixtures thereof, and the above-described pharmaceutical compositions for the preparation of a medicament for the treatment of pulmonary hypertension.

Drawings

Fig. 1 is a graph showing the effect of compound and Selexipag intragastric administration on pulmonary artery systolic pressure in example (p.ltoreq.0.001 compared to model control, p.ltoreq.0.01 compared to model control).

Detailed Description

The present invention will be described in further detail with reference to specific embodiments in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.

Terminology

In the process for producing a compound of the present application, "eq" means equivalent weight, and in chemistry means equivalent weight. This concept is critical in stoichiometric and chemical reactions, especially when the molar ratio of the substances is concerned. For example, if 0.3mol (1 eq) of A is used in a certain reaction, and the amount of B is 6 times that of A, i.e., 6eq, then the amount of B used is 1.8mol. This representation helps to make it easier and more accurate in calculating the molar ratio of the substances in the chemical reaction. The "eq" of the application is calculated according to the mole ratio.

The expression "C _x-y" as used herein denotes a range of numbers of carbon atoms, wherein x and y are integers, e.g. C _3-6 cycloalkyl denotes cycloalkyl having 3 to 6 carbon atoms.

"Alkyl" means a saturated straight or branched hydrocarbon group having a number of carbon atoms, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, and the like.

The heteroalicyclic represents a single ring or a fused ring of 1 or more heteroatoms of N, O or S. 3-8 membered heterocyclyl, typically 1 or more heteroatoms of N, O or S, preferably 3-6 membered heterocyclyl containing 1 or more heteroatoms of N, O or S, such as glycidylyl, butylene oxide, piperazino, morpholino, piperidino and derivatives thereof.

For example, morpholino refers to a group having the chemical structure: Piperidino refers to a group having a chemical structure:

"halogen" means fluorine, chlorine, bromine or iodine.

"Isomers" as defined herein refer to compounds having the same molecular formula but differing in the nature or order of their atomic bonding or the spatial arrangement of their atoms. The isomers whose atomic spatial arrangements are different are called "stereoisomers". Stereoisomers include optical isomers, geometric isomers and conformational isomers.

The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers isomers and diastereomers. Methods for preparing and separating optical isomers are known in the art.

The compounds of the invention may also exist as geometric isomers. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around a carbon-carbon double bond, carbon-nitrogen double bond, cycloalkyl or heterocyclic group. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configurations, and substituents around cycloalkyl or heterocycle are designated as cis or trans configurations.

"Isotopes" include all isotopes of atoms occurring in the compounds of the invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, but not limited to ²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³⁵S、¹⁸ F and ³⁶ Cl, respectively. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents in assaying biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.

By "prodrug" is meant that the compounds of the invention may be administered in the form of a prodrug. Prodrugs refer to derivatives of the biologically active compounds of the present invention which are converted under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, etc. (each of which is performed with or without the aid of an enzyme). Examples of prodrugs are the following compounds: wherein the amino group in the compounds of the invention is acylated, alkylated or phosphorylated, such as methylamido, alanylamino, pivaloyloxymethylamino, or wherein the hydroxy group is acylated, alkylated, phosphorylated or converted to a borate, such as acetoxy, fumaryloxy, alanyloxy, or wherein the carboxy group is esterified or amidated. These compounds can be prepared from the compounds of the present invention according to well known methods.

"Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts" refer to salts made with pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also encompasses their corresponding pharmaceutically acceptable salts. Thus, the compounds of the invention containing acidic groups may be present in salt form and may be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts, exemplary including sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines, for example ethylamine, ethanolamine, triethanolamine or amino acids. The compounds according to the invention containing basic groups may be present in the form of salts and may be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention includes, in addition to the salt forms mentioned, also internal salts or betaines. The individual salts can be obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.

"Pharmaceutical composition" refers to a composition comprising one or more of the compounds described herein or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, and mixtures thereof, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

Thus, when referring to a "compound," "compound of the application," or "compound of the application," in the present application, all such compound forms, e.g., pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, and mixtures thereof, are included.

The invention also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) according to the invention can be carried out by the following exemplary methods and examples, which, however, should not be regarded as limiting the scope of the invention in any way. The compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and methods described herein. The product from each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis may be synthesized conventionally according to the literature or purchased.

Reference example 1

Preparation of ethyl 6-isopropylamino-3-ethoxy-hexanoate (noted SM 1) was prepared as follows:

SM1-B preparation: SM1-A (4-isopropylamino-1-n-butanol, 200g,1 eq), boc anhydride (349.3 g,1.05 eq), tetrahydrofuran (1200 ml) were sequentially added to the reaction flask, reacted at room temperature for 2 to 2.5 hours, and concentrated to obtain 353g of compound SM1-B.

SM1-C preparation: to the reaction flask, compound SM1-B (300 g,1 eq) and methylene chloride (1500 ml) were added in this order, the temperature was lowered in an ice bath, dessert-martin reagent (660 g,1.2 eq) was added in portions, the reaction was carried out for 2 to 3 hours under heat insulation, the reaction solution was washed with saturated sodium bicarbonate solution, saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by a silica gel column to obtain 172g of compound SM1-C.

SM1-D: to the reaction flask were successively added triethyl phosphorylacetate (199g, 1.2 eq) and tetrahydrofuran (1300 ml), cooled in an ice bath, sodium hydride (35.6 g,1.2 eq) was added in portions, stirred for 1 to 2 hours, compound SM1-C (170 g,1 eq) was added in portions at 0 to 5 ℃ and allowed to react for 2 to 3 hours, the reaction mixture was quenched by dropwise addition of water, extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by a silica gel column to give 135g of compound SM1-D.

SM1-E: to the reaction flask, compound SM1-D (30 g,1 eq), absolute ethyl alcohol (150 ml) and ice bath were added in order, cooled, sodium hydride (6 g,1.5 eq) was added, the mixture was cooled to room temperature and reacted for 2-3 hours, cooled to 0-10 ℃, quenched with 100ml of water, concentrated to remove most of the ethanol, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness and purified by a silica gel column to give 26.3g of compound SM1-E.

SM1 preparation: SM1-E (25 g, 1 eq) and methylene chloride were added to the flask, a hydrochloric acid/ethanol solution (1.1 eq) was added dropwise at room temperature, and after the addition, the mixture was concentrated to dryness to give 19.4g of SM1.

Example 1

Preparation of 6- { N- [5, 6-bis (4-methylphenyl) pyrazin ] -2-yl-N-isopropylamino } -2-hexenoic acid, compound designated SYN-001, corresponding to formula (1).

The preparation route is as follows:

STEP1: to the reaction flask, compound 1A (4, 4' -dimethylbenzoyl 300g,1 eq), 2-aminoacetamide hydrochloride (209 g,1.5 eq) and methanol (2.0L) were added in this order, the mixture was warmed to reflux, aqueous sodium hydroxide solution (101 g,2eq, 200ml of purified water) was added dropwise, stirred at room temperature for 4 to 5 hours, cooled to room temperature, pH was adjusted to 6 to 7 with hydrochloric acid, filtered, and the cake was rinsed with 300ml of methanol and dried in vacuo to give 320g of compound 1B.

STEP2: to the reaction flask, compound 1B (100 g,1 eq) and phosphorus oxychloride (277.4 g,5 eq) were added sequentially, the temperature was raised to 100-105℃and stirred for 3-5 h under heat preservation, the residual phosphorus oxychloride was removed by vacuum concentration, 200mL of toluene was added, and the concentration was continued to remove the residual phosphorus oxychloride. The reaction mass is added with 100ml of dichloromethane and stirred for dissolution, the reaction mass is added into 1000ml of isopropanol, after dripping, the mixture is stirred for 1 to 3 hours at the temperature of between 0 and 5 ℃, and 90.7g of compound 1C is obtained after filtration and vacuum drying.

STEP3: to the reaction flask, compound 1C (100 g,1 eq) and 4- (isopropylamino) butanol (245 g,5.5 eq) were added sequentially, the temperature was raised to 160-170 ℃, the reaction was continued for 20-30 h under heat preservation, the temperature was lowered to 60-80 ℃, the reaction solution was poured into water (1.0L), ethyl acetate was added for extraction, the organic phase was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by silica gel column to obtain 74g of compound 1D.

STEP4: to the reaction flask, compound 1D (70 g,1 eq) and methylene chloride (700 ml) were added in this order, the temperature was lowered in an ice bath, dessert-martin reagent (152 g,2 eq) was added in portions, the reaction was kept warm for 3 to 5 hours, the reaction solution was washed with saturated sodium bicarbonate solution, saturated sodium chloride aqueous solution was washed, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by a silica gel column to give 21.5g of compound 1E.

STEP5: to the reaction flask were successively added triethyl phosphorylacetate (9 g,1.2 eq) and tetrahydrofuran (130 ml), cooled in an ice bath, sodium hydride (1.34 g,1 eq) was added in portions, stirred for 1h, compound 1E (13 g,1 eq) was added in portions at 0 to 5℃and allowed to react for 2 to 3h at room temperature, 50ml of water was added dropwise to the reaction mixture, the mixture was quenched, extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness, and the residue was purified by a silica gel column to give 13g of compound 1F.

STEP6: to the reaction flask, compound 1F (3 g,1 eq), tetrahydrofuran (30 ml) and purified water (3 ml) were added in this order, sodium hydroxide (1.05 g,4 eq) was added, the mixture was heated to reflux, reacted for 12 to 15 hours, cooled to room temperature, 50ml of water was added, pH was adjusted to 5 to 6 with hydrochloric acid, ethyl acetate was added for extraction, and the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness and purified by a silica gel column to give 1.3g of compound SYN-001.

¹H NMR(500MHz,CDCl₃)：δ：8.019(s,1H),7.366～7.350(m,2H),7.282(s,2H),7.158～7.057(m,5H),5.925～5.894(d,1H),4.714～4.688(m,1H),3.460～3.429(m,2H),2.371～2.332(m,8H),1.918～1.857(m,2H),1.291～1.277(m,6H)ppm.

Example 2

Preparation of 6- [ N- (5, 6-diphenylpyrazin-2-yl) -N-isopropylamino ] -2-hexenoic acid, compound designated SYN-002, corresponds to structural formula (2).

The preparation route is as follows:

The preparation of 6- [ N- (5, 6-diphenylpyrazin-2-yl) -N-isopropylamino ] -2-hexenoic acid was the same as that of example 1 except that the starting material was benzil.

¹H NMR(500MHz,CDCl₃)：δ：8.050(s,1H),7.449～7.430(m,2H),7.366～7.347(m,2H),7.285～7.247(m,6H),7.232～7.211(m,1H),5.920～5.889(m,1H),4.741～4.715(m,1H),3.454～3.422(m,2H),2.354～2.340(m,2H),1.898～1.867(m,2H),1.285～1.272(m,6H)ppm.

Example 3

Preparation of 6- { N- [5, 6-bis (4-methylphenyl) -1,2, 4-triazin ] -2-yl-N-isopropylamino } hexanoic acid, compound designated SYN-003, corresponds to formula (3).

The preparation route is as follows:

STEP1, glacial acetic acid (2.5L), 4' -dimethylbenzoyl (compound 6A;500g, 1 eq), semicarbazide hydrochloride (351 g,1.5 eq) and purified water (1L) are added into a reaction bottle in sequence, stirred evenly and heated to 100-110 ℃. The reaction is carried out for 2 to 3 hours under the heat preservation, the temperature is reduced to 30 to 40 ℃, purified water is added, the mixture is stirred for 0.5 to 1.5 hours at room temperature, the mixture is filtered, a filter cake is added into 3L of ethyl acetate, the mixture is heated to reflux and stirred for 2 to 3 hours, the temperature is reduced to the room temperature, and 523g of intermediate 6B is obtained after the filtration and the vacuum drying.

STEP2, adding phosphorus oxychloride (2L) into a reaction bottle, adding 6B (500 g,1 eq), heating to 80-85 ℃, and stirring to dissolve. Keeping the temperature for reaction for 1 to 1.5 hours, concentrating to remove phosphorus oxychloride, adding 1L of toluene, and continuously concentrating to remove residual phosphorus oxychloride. Methyl tertiary ether was added to the residue and stirred for 1h, filtered and dried under vacuum to give 320g of intermediate 6C.

STEP3, namely, sequentially adding the intermediate 6C (100 g,1 eq) and 4- (isopropylamino) butanol (155.3 g,3.5 eq) into a reaction bottle, heating to 140-160 ℃, carrying out heat preservation reaction for 14-20 h, cooling to room temperature, pouring the reaction liquid into water, adding ethyl acetate for extraction, washing an organic phase with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, concentrating to dryness, and purifying the residue by a silica gel column to obtain 71g of intermediate 6D.

STEP4: to the reaction flask, intermediate 6D (70 g,1 eq) and methylene chloride (700 ml) were added, the temperature was lowered to 0 to 10℃and dess-Martin reagent (152 g,2 eq) was added in portions, followed by reaction at 0 to 10℃for 3 to 5 hours. The reaction was stopped, the reaction solution was washed with saturated sodium bicarbonate solution for 2 times, then with saturated aqueous sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by silica gel column to give 41.3g of intermediate 6E.

STEP5: to the reaction flask were added triethyl phosphorylacetate (27.7 g,1.2 eq) and tetrahydrofuran (400 ml), cooled to 0 to 10 ℃, sodium hydride (4.1 g,1 eq) was added, stirred for 1 to 2 hours, intermediate 6E (40 g,1 eq) was added at 0 to 5 ℃, after the addition was completed, the reaction was allowed to react at room temperature for 2 to 3 hours, 100ml of water was added dropwise to the reaction solution for quenching reaction, most (80% or more) of tetrahydrofuran was removed by concentration, 200ml of ethyl acetate was added to the residue for extraction, the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by silica gel column to obtain 21.3g of intermediate 6F.

STEP6: 21G of intermediate 6F,2.1G of 10% palladium on carbon, absolute ethanol (210 ml), hydrogen substitution, and reaction at room temperature for 5 to 7 hours were added to the reaction flask, palladium on carbon was removed by filtration, and the filtrate was concentrated to dryness to give 20.2G of intermediate 6G.

STEP7: to the reaction flask were successively added intermediate 6G (20G, 1 eq), tetrahydrofuran (200 ml), purified water (20 ml), sodium hydroxide (6.9G, 4 eq), heated to reflux, reacted for 2 to 3 hours, concentrated to remove tetrahydrofuran, added purified water (100 ml) and ethyl acetate (100 ml), stirred evenly, left to stand to separate a liquid, kept a water phase, added hydrochloric acid to adjust pH to 3 to 5, added methyl tert-butyl ether for extraction, and after the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated to dryness under reduced pressure to obtain 16.8G of compound SYN-003.

1H NMR(500MHz,CDCl3)：δ：7.455～7.439(m,2H),7.396～7.380(m,2H),7.146～7.129(m,4H),5.137(m,1H),3.599(m,2H),2.462～2.378(m,8H),1.795～1.735(m,4H),1.527～1.454(m,2H),1.365～1.238(m,6H)ppm.

Example 4

Preparation of 3-ethoxy-6- { N- [5, 6-bis (4-methylphenyl) pyrazin ] -2-yl-N-isopropylamino } hexanoic acid, compound designated SYN-004, corresponding to the formula (4).

To a reaction flask was successively added compound 1F, which was designated as 6- { N- [5, 6-bis (4-methylphenyl) pyrazin ] -2-yl-N-isopropylamino } -2-hexenoic acid ethyl ester, (the preparation method of this compound was the same as "compound 1F" in example 1) (3 g,1 eq), absolute ethyl alcohol (30 ml), ice bath cooling, sodium hydride (0.79 g,3 eq) was added, the mixture was allowed to reflux for 12 to 15 hours, cooled to room temperature, pH was adjusted to 5 to 6 with hydrochloric acid, 30ml of water was added, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, concentrated to dryness, and purified by a silica gel column to give 1.2g of the compound SYN-004.¹H NMR(500MHz,CDCl₃)：δ：8.013(s,1H),7.378～7.366(m,2H),7.350(s,1H),7.090～7.065(m,5H),4.803～4.776(m,1H),3.814～3.792(m,1H),3.594～3.536(m,2H),3.449～3.398(m,2H),2.628～2.461(m,2H),2.348～2.337(m,6H),1.802～1.642(m,4H),1.281～1.268(m,6H),1.212～1.185(t,3H)ppm.

Example 5

Preparation of 3-ethoxy-6- { N- [5, 6-bis (4-methylphenyl) -1,2, 4-triazin ] -2-yl-N-isopropylamino } hexanoic acid, compound designated SYN-005, corresponds to formula (5).

The preparation route is as follows:

STEP1 Compound 6C (30 g,1eq, preparation method is the same as in example 3 compound 6C, which is named 5, 6-di (4-methylphenyl) -3-chloro-1, 2, 4-triazine), SM1 (37.2 g, 1.3eq, preparation method see reference example), potassium carbonate (42 g,3 eq), DMF (1.5L), heating to 80-85 ℃, keeping the temperature for 2-3 h, adding water, extracting with ethyl acetate, concentrating to obtain 43.9g of Compound 7D.

STEP2: to the reaction flask, compound 7D (10 g,1 eq), tetrahydrofuran (100 ml) and purified water (10 ml) were added in this order, sodium hydroxide (2.4 g,3 eq) was added, the mixture was heated to reflux, reacted for 12 to 15 hours, cooled to room temperature, pH was adjusted to 5 to 6 with hydrochloric acid, 100ml of water was added, extraction was performed with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness and purified by a silica gel column to give 4.8g of compound SYN-005.

¹H NMR(500MHz,CDCl₃)：δ：7.451～7.425(m,2H),7.381～7.365(m,2H),7.133～7.117(m,4H),3.835～3.811(m,1H),3.605～3.654(m,4H),2.601～2.573(m,2H),2.384～2.365(m,7H),1.699～1.688(m,4H),1.328～1.315(m,6H),1.210～1.182(t,3H)ppm.

Example 6

Preparation of 3-methoxy-6- { N- [5, 6-bis (4-methylphenyl) pyrazin ] -2-yl-N-isopropylamino } hexanoic acid, compound designated SYN-006, corresponds to structural formula (6).

STEP1: to the reaction flask, compound 1F (3G, 1eq, see compound 1F in example 1), anhydrous methanol (30 ml), ice bath cooling, sodium hydride (0.79G, 3 eq) was added, the reaction was allowed to proceed to room temperature for 3 to 5 hours, water quenching was added to 50ml, ethyl acetate extraction was added, the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and purified by a silica gel column to give 2.1G of compound 4G.

STEP2: to the reaction flask, compound 4G (2G, 1 eq), tetrahydrofuran (30 ml) and purified water (3 ml) were added in this order, sodium hydroxide (0.65G, 4 eq) was added, the mixture was heated to reflux, reacted for 12 to 15 hours, cooled to room temperature, adjusted to pH 5 to 6 with hydrochloric acid, added with 30ml of water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and purified by a silica gel column to give 0.9G of compound SYN-006.

¹H NMR(500MHz,CDCl₃)：δ：8.021(s,1H),7.368～7.352(m,2H),7.278～7.258(m,2H),7.091～7.067(m,4H),4.812(m,1H),3.740～3.716(m,1H),3.428～3.413(m,5H),2.642～2.487(m,2H),2.349～2.338(m,6H),1.784～1.671(m,4H),1.293～1.269(m,6H)ppm.

Example 7

Preparation of 6- [ N- (5, 6-diphenyl-1, 2, 4-triazin) -2-yl-N-isopropylamino ] hexanoic acid, compound SYN-007, corresponding to formula (7).

The preparation of 6- [ N- (5, 6-diphenyl-1, 2, 4-triazin) -2-yl-N-isopropylamino ] hexanoic acid was the same as that of 6- { N- [5, 6-bis (4-methylphenyl) -1,2, 4-triazin ] -2-yl-N-isopropylamino } hexanoic acid (number SYN-003) in example 3, except that the starting material was benzil.

¹H NMR(500MHz,CDCl₃)：δ：7.510～7.493(m,2H),7.475～7.448(m,2H),7.396～7.364(m,1H),7.317～7.269(m,5H),5.141～5.070(m,1H),3.592(m,2H),2.407～2.362(m,2H),1.779～1.707(m,4H),1.506～1.445(m,2H),1.322～1.308(m,6H)ppm.

Example 8

Preparation of 3-ethoxy-6- [ N- (5, 6-diphenylpyrazin-2-yl) -N-isopropylamino ] hexanoic acid, compound designated SYN-008, corresponds to structural formula (8).

To the reaction flask, compound 8F (3 g,1eq, compound 8F of preparation method example 2), absolute ethanol (30 ml), ice bath cooling, sodium hydride (0.84 g,3 eq) was added, the mixture was heated to reflux for 12-15 h, cooled to room temperature, pH was adjusted to 5-6 with hydrochloric acid, 100ml of water was added, extraction was performed with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and purified by silica gel column to give 1.2g of compound SYN-008.

¹H NMR(500MHz,CDCl₃)：δ：8.037(s,1H),7.443～7.226(m,10H),4.785(m,1H),3.790(m,1H),3.545～3.414(m,4H),2.585～2.507(m,2H),1.773～1.661(m,4H),1.278～1.265(m,6H),1.175(t,3H)ppm.

Example 9

Preparation of 6- { N- [5, 6-bis (4-fluorophenyl) pyrazin ] -2-yl-N-isopropylamino } -2-hexenoic acid, compound designated SYN-013, corresponding to structural formula (9).

The preparation route is as follows:

6- { N- [5, 6-bis (4-fluorophenyl) pyrazin ] -2-yl-N-isopropylamino } -2-hexenoic acid was prepared in the same manner as in example 1 except that 1, 2-bis (4-fluorophenyl) ethane-1, 2-dione was used as the starting material.

¹H NMR(500MHz,CDCl₃)：δ：8.062(s,1H),7.413～7.385(m,2H),7.326～7.298(m,2H),7.143～7.084(m,1H),6.981～6.933(m,4H),5.919～5.888(d,1H),4.709～4.683(m,1H),3.455～3.424(m,2H),2.361～2.319(m,2H),1.886～1.840(m,2H),1.297～1.274(m,6H)ppm.

Example 10

Preparation of 6- { N- [5, 6-bis (4-fluorophenyl) pyrazin ] -2-yl-N-isopropylamino } -hexanoic acid, compound designated SYN-010, corresponds to structural formula (10).

STEP1: to the reaction flask, compound 12F (6G, 1eq, see compound 12F of example 9), absolute ethanol 60ml, 10% wet palladium on carbon 0.6G, H2 substitution, reaction at room temperature for 3-4H, removal of palladium on carbon by filtration, and concentration of the filtrate gave 5.8G of compound 13G.

STEP2: to the reaction flask, compound 13G (5G, 1 eq), tetrahydrofuran (50 ml) and purified water (5 ml) were added in this order, sodium hydroxide (1.3G, 3 eq) was added, the mixture was warmed to reflux, reacted for 12 to 15 hours, cooled to room temperature, adjusted to pH 5 to 6 with hydrochloric acid, 100ml of water was added, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and purified by a silica gel column to give 2.3G of compound SYN-010.

¹H NMR(500MHz,CDCl₃)：δ：8.125(s,1H),7.423～7.388(m,2H),7.333～7.298(m,2H),7.194～7.100(m,4H),4.768～4.735(m,1H),3.424(m,2H),2.258～2.220(m,2H),1.658～1.554(m,4H),1.425～1.351(m,2H),1.239～1.164(m,6H)ppm.

Example 11

Preparation of 3-morpholino-6- { N- [5, 6-bis (4-methylphenyl) pyrazin ] -2-yl-N-isopropylamino } hexanoic acid, compound designated SYN-017, corresponding to structural formula (11).

STEP1: compound 1F (3G, 1eq, preparation method same as compound 1F of example 1), 6ml morpholine, heating to 100-105 ℃ to react for 12-15 h, cooling to room temperature, adding ammonium chloride aqueous solution to quench, adding ethyl acetate to extract, drying the organic phase with anhydrous sodium sulfate, concentrating to dryness, purifying by silica gel column to obtain 2.1G compound 5G.

STEP2: to the reaction flask, compound 5G (2G, 1 eq), tetrahydrofuran (30 ml) and purified water (3 ml) were added in this order, sodium hydroxide (0.44G, 3 eq) was added, the mixture was heated to reflux, reacted for 12 to 15 hours, cooled to room temperature, adjusted to pH 5 to 6 with hydrochloric acid, 60ml of water was added, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and purified by a silica gel column to give 1.2G of compound SYN-017.

¹H NMR(500MHz,CDCl₃)：δ：8.013(s,1H),7.339～7.323(m,2H),7.282(m,2H),7.086～7.052(m,4H),4.580～4.554(m,1H),3.748(m,4H),3.460～3.431(m,2H),2.889～2.869(m,1H),2.782～2.759(m,2H),2.555～2.495(m,3H),2.387～2.323(m,7H),1.825～1.605(m,3H),1.332～1.253(m,7H)ppm.

Example 12

Preparation of 3-ethoxy-6- { N- [5, 6-bis (4-methylphenyl) pyrazin ] -2-yl-N-isopropylamino } -N- (p-methylsulfonyl) hexanamide, compound designated SYN-044, corresponding to formula (12).

To the reaction flask, compound SYN-004 (1 g,1 eq), methylene chloride (20 ml), methylsulfonamide (300 mg,1.5 eq), DMAP (308 mg,1.2 eq) and EDCI (284 mg,1.2 eq) were sequentially added, the reaction was refluxed for 2 to 3 hours, cooled to room temperature, the reaction solution was washed with purified water, the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and purified by a silica gel column to obtain 650mg of compound SYN-044.

¹H NMR(500MHz,CDCl₃)：δ：8.013(s,1H),7.292～7.272(m,2H),7.208～7.188(m,2H),7.129～7.066(m,4H),4.769～4.737(m,1H),3.771～3.741(m,1H),3.493～3.459(m,2H),3.183(s,3H),2.434～2.290(m,10H),1.694～1.525(m,4H),1.246～1.229(m,6H),1.092～1.057(t,3H)ppm.

Example 13

Preparation of 6- { N- [5, 6-bis (4-fluorophenyl) pyrazin ] -2-yl-N-isopropylamino } -N- (p-methylsulfonyl) hexanamide, compound designated SYN-046, corresponding to formula (13).

To the reaction flask, compound SYN-010 (1.1 g,1 eq), methylene chloride (20 ml), methylsulfonamide (356 mg,1.5 eq), DMAP (367 mg,1.2 eq), EDCI (574 mg,1.2 eq) were successively added, the reaction was refluxed for 2 to 3 hours, cooled to room temperature, the reaction solution was washed with purified water, the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and purified by a silica gel column to obtain 0.6g of compound SYN-046.

¹H NMR(500MHz,CDCl₃)：δ：8.131(s,1H),7.428～7.392(m,2H),7.337～7.302(m,2H),7.204～7.106(m,4H),4.765(m,1H),3.424(m,2H),3.229(s,3H),2.322～2.285(m,2H),1.632～1.596(m,4H),1.397～1.361(m,2H),1.246～1.229(m,6H)ppm.

Example 14

Preparation of { N- [5, 6-bis (4-methylphenyl) -1,2, 4-triazin ] -2-yl-N-isopropylamino } -2-hexenoic acid, compound designated SYN-018, corresponds to formula (14).

To a reaction flask, compound 6F (5 g,1eq, see example 3), tetrahydrofuran (50 ml), purified water (5 ml), sodium hydroxide (0.87 g,2 eq) were added, the mixture was warmed to reflux, reacted for 12 to 15 hours, cooled to room temperature, pH was adjusted to 5 to 6 with hydrochloric acid, 100ml of water was added, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and purified by a silica gel column to give 3.5g of compound SYN-018.

¹H NMR(500MHz,CDCl₃)：δ：8.062(s,1H),7.368～7.351

(m,2H),7.283～7.268(m,1H),7.143～7.050(m,5H),5.981～5.899(d,1H),4.719～4.690(m,1H),3.453～3.422(m,2H),2.371～2.330(m,8H),1.916～1.855

(m，2H)，1.293～1.278(m，6H)ppm。

Experimental example

1. Target selectivity

The experimental process comprises the following steps: the functional activities of compounds numbered SYN-001、SYN-002、SYN-003、SYN-004、SYN-005、SYN-006、SYN-007、SYN-008、SYN-010、SYN-013、SYN-017、SYN-044、SYN-046 and SYN-018 on the following 8 targets IP, EP1, EP2, EP3, EP4, DP, FP and TP were studied using the methods of HTRF cAMP and HTRF IP1 using HEK cells stably expressing the prostacyclin receptor, and compared with Selexipag (commercially available as selapage).

The experimental results are shown in table 1.

TABLE 1 target selectivity

The above results indicate that: compounds No. SYN-001、SYN-002、SYN-003、SYN-004、SYN-005、SYN-006、SYN-007、SYN-008、SYN-010、SYN-013、SYN-017、SYN-044、SYN-046 and SYN-018 have good agonistic activity on IP receptor and have the same effect as Selexipag. Except for the slight agonistic activity of SYN-001, SYN-002 and SYN-003 on EP1, EP2, EP3, EP4, DP, FP and TP targets, the rest compounds have no agonistic activity on other receptors except IP receptors, and the selectivity is high.

Wherein the chemical structural formula (formula IV) of the selapage active ingredient is shown as follows.

The chemical name is: 2- {4- [ (5, 6-diphenylpyrazin-2-yl) (2-propyl) amino ] butoxy } -N- (methylsulfonyl) acetamide.

ACT-333679 is a metabolite of selapage, and the chemical structural formula is shown as follows.

The chemical name is: 2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetic acid.

The structure of the compound in the embodiment of the application is different from the structure of the butoxyacetamide in the branch chain of the active component of selapage, and the main structure of the branch chain in the embodiment of the application is caproic acid or hexenoic acid or caproic acid sulfonamide. Wherein SYN-001、SYN-002、SYN-003、SYN-004、SYN-005、SYN-006、SYN-007、SYN-008、SYN-010、SYN-013、SYN-017、SYN-044、SYN-046 and SYN-018 have good agonistic activity on IP receptor. Has application prospect in preparing medicines for treating pulmonary artery cancer.

2. Pulmonary arterial hypertension rat pharmacodynamic test

The experimental process comprises the following steps: the monocrotaline 40mg/kg subcutaneous injection is used for model preparation, and normal control animals are injected with sodium chloride injection subcutaneously, and the animals begin to take the injection about 2 hours after the molding agent is administered, 2 times a day for 19 days continuously.

Specifically, the compounds numbered SYN-003, SYN-004, SYN-006, SYN-007, SYN-008, SYN-010, SYN-013 and SYN-017 were suspended in 10wt% DMSO+90wt% NaCl to prepare suspensions, and the suspensions were administered by gavage at an active ingredient dose of 3mg/kg body weight and a dose volume of 5mL/kg.

After 19 days of continuous administration, the mean pulmonary artery pressure of the rats was determined using the right heart catheterization method. As a result of the experiment, see FIG. 1, in which the Model group (Model group) was 10wt% DMSO+90wt% NaCl,5ml/kg body weight was administered by intragastric administration, and the Control group (Control group) was administered by intragastric administration using Selexipag,3mg/kg body weight.

The results show that: the compounds with the numbers of SYN-003, SYN-004, SYN-006, SYN-007, SYN-008, SYN-010, SYN-013 and SYN-017 all obviously reduce the pulmonary arterial pressure of the rat, wherein the pressure reducing effect of SYN-004, SYN-007 and SYN-010 is most obvious.

3. Pulmonary arterial hypertension rat survival rate test

The experimental process comprises the following steps: the monocrotaline 40mg/kg subcutaneous injection is used for model preparation, and normal control animals are injected with sodium chloride injection subcutaneously, and the animals begin to take the injection about 2 hours after the molding agent is administered, 2 times a day for 45 days continuously. Wherein the administration mode is as follows: the compounds numbered SYN-004, SYN-007 and SYN-010 were each suspended in 10wt% DMSO+90wt% NaCl to prepare suspensions for administration by gavage at a body weight of 1mg/kg of the active ingredient. Selexipag is taken as a positive medicine group, and is administrated by lavage according to the body weight of 1mg/kg of active ingredient. The model group adopts normal saline to irrigate the stomach.

Rat survival was recorded. The experimental results are shown in table 2.

TABLE 2 influence of SYN-004, SYN-007, SYN-010 on survival of rats with pulmonary hypertension

Grouping	Number of animals (D0)/animal	Number of remaining animals (D45)/animal	Survival (%)
				Normal control group	10	10	100
Model group	10	3	30
				Selexipag group	10	7	70
SYN-004 group	10	7	70
				SYN-007 group	10	8	80
SYN-010 group	10	7	70

The results show that: selexipag, SYN-004, SYN-007 and SYN-010 can obviously improve the survival rate of rats with pulmonary hypertension.

4. Toxicity comparison

Acute toxicity experiment process: rats were randomly grouped by body weight, 10 animals per group, each given 250, 500, 1000, 2000mg/kg of compound by single gavage, each with a volume of 10ml/kg, and observed for 7 days after administration.

The experimental results are shown in table 3.

TABLE 3 acute toxicity of SYN-003, SYN-004, SYN-005, SYN-007 and SYN-010 rats

The results show that: selexipag rats were orally lethal at about 500mg/kg and non-lethal at 250mg/kg. SYN-003, SYN-004, SYN-005, SYN-007 and SYN-010 showed no death at 1000mg/kg and death at 2000mg/kg, indicating that the toxicity was less than Selexipag.

Genetic toxicity test procedure: the samples SYN-004, SYN-007, SYN-010 and ACT-333679 were diluted to 8 concentrations at a final concentration of 1000. Mu.g/well. 2 wells were treated in parallel by a 6-well plate doping method, negative (DMSO) and positive control were simultaneously set, parallel experiments were performed under the condition of presence or absence of a metabolic activation system (+ -S9), after culturing for 48-72 hours, whether the test sample had precipitation and growth of background bacterial plaque were observed, the number of back mutant colonies per well was counted, and the test results are shown in tables 4-11.

Positive result determination

A result satisfying 1 or 2 of the following criteria may be judged positive:

1) At least on one strain, a dose-dependent increase in the number of revertant colonies occurred with or without metabolic activation, and the number of revertant colonies was 2-fold or more than that of the negative control group.

2) The number of back mutated colonies in one or more dose groups, with or without metabolic activation, increased significantly and can be repeated, with the number of back mutated colonies being 2-fold or more than that in the negative control group.

After the test sample is detected by 2 test strains, as long as one test strain exists, the test sample can be judged to be a mutagen no matter whether the test sample is positive under the condition of adding the S9 mixed solution or not adding the S9 mixed solution.

Negative result determination

If the test results show that the number of the revertant colonies of each test strain has no dose-dependent increment, and the peak value of the number of the revertant colonies of each dose group of all strains does not exceed 2 times that of the negative control group, the test sample can be judged to be a non-mutagenic agent.

The results show that: under the condition of +/-S9, when the final concentration of the ACT-333679 of the TA98 strain and the TA100 strain is more than or equal to 250 mug/hole, non-interference precipitation is observed; SYN-004, SYN-007 and SYN-010 were observed to precipitate out without interference at a final concentration of 1000. Mu.g/well. Under the condition of +/-S9, for TA98 and TA100 strains, when the final concentration of ACT-333679 is more than or equal to 250 mug/hole, the background bacterial plaque is reduced; at a final SYN-010 concentration of 1000 μg/well, a reduction of background plaque was observed; no background plaque abnormality was observed at each of SYN-004 and SYN-007 concentrations. For the TA98 and TA100 strains, under the condition of + -S9, the number of the reverse mutation colonies of each concentration group of SYN-004, SYN-007, SYN-010 and ACT-333679 does not reach 2 times of that of the negative control group, and the concentration-effect relationship does not exist, and the test result is considered to be negative.

Therefore, SYN-004, SYN-007, SYN-010 and ACT-333679 are not genotoxic.

TABLE 4SYN-004 bacterial back-mutation 6-well plate preliminary screening test results (TA 98 Strain)

Remarks:

Background plaque: t0: normal;

test article/control article solubility: p0: normal/no precipitate, P1: non-interfering precipitation under the mirror;

* : the number of revertant colonies of the positive control group was 3 times higher than that of the negative control group.

TABLE 5SYN-004 bacteria back mutation 6 well plate preliminary screening test results (TA 100 Strain)

Remarks:

Background plaque: t0: normal;

TABLE 6SYN-007 reverse mutation of bacteria 6 well plate preliminary screening test results (TA 98 Strain)

Remarks:

Background plaque: t0: normal;

TABLE 7SYN-007 reverse mutation of bacteria 6 well plate preliminary screening test results (TA 100 Strain)

Remarks:

Background plaque: t0: normal;

TABLE 8SYN-010 bacteria back mutation 6 well plate preliminary screening test results (TA 98 Strain)

Remarks:

background plaque: t0: normal, T1: a slight decrease in background plaque;

TABLE 9SYN-010 bacteria back mutation 6 well plate preliminary screening test results (TA 100 Strain)

Remarks:

background plaque: t0: normal, T1: a slight decrease in background plaque;

TABLE 10ACT-333679 bacterial back-mutation 6 well plate preliminary screening test results (TA 98 Strain)

Remarks:

NA: not counted;

Background plaque: t0: normal, T1: background plaque was slightly reduced, T3: background plaque severity decreased, T4: the background plaque disappeared;

^a : the positive drugs are sodium azide (0.4 mug/hole) and 2-amino anthracene (0.6 mug/hole) respectively when S9 is not added and added;

TABLE 11ACT-333679 bacterial back-mutation 6 well plate preliminary screening test results (TA 100 Strain)

Remarks:

NA: not counted;

In conclusion, the application synthesizes a series of new structural compounds which have good affinity to PGI2 receptor and low adverse reaction, and has wide application prospect in preparing medicines for treating pulmonary arterial hypertension.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.

Claims

1. A PGI2 receptor agonist compound shown in a general formula I or pharmaceutically acceptable salts, stable isotope derivatives, isomers and mixtures thereof,

R ₃ is selected from C ₂-C₄ alkyl, C _3-C₆ monocyclic cycloalkyl;

R ₄ is selected from H, C ₁-C₃ alkoxy or 3-6 membered heteroalicyclic;

R ₅ represents OH, OR ₆ OR NHSO ₂R₆, wherein R ₆ represents C _1-4 alkyl OR C _1-4 alkyl substituted by halogen;

Represents a single bond or a double bond.

2. The PGI2 receptor agonist compound of claim 1, or pharmaceutically acceptable salts, stable isotope derivatives, isomers, and mixtures thereof, wherein Z is an N atom; or Z is CR ₇, wherein R ₇ is selected from H or CH ₃.

3. The PGI2 receptor agonist compound according to claim 2, or pharmaceutically acceptable salts, stable isotope derivatives, isomers, and mixtures thereof,Represents a double bond, and R ₄ is H.

4. The PGI2 receptor agonist compound or pharmaceutically acceptable salts, stable isotope derivatives, isomers, and mixtures thereof of claim 2 wherein,R ₄ represents a single bond, selected from H, C ₁-C₃ alkoxy or 3-6 membered heteroalicyclic.

5. The PGI2 receptor agonist compound of claim 4, wherein R ₄ is selected from the group consisting of H, methoxy, ethoxy,

6. The PGI2 receptor agonist compound of any one of claims 2 to 5, wherein R ₁ and R ₂ are selected from H, methyl or F, or pharmaceutically acceptable salts, stable isotope derivatives, isomers and mixtures thereof.

7. A compound according to claim 6, or a pharmaceutically acceptable salt, stable isotope derivative, isomer, and mixture thereof, wherein R ₃ is selected from isopropyl, ethyl, or cyclopropyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt, stable isotope derivative, isomer, and mixture thereof, wherein R ₃ is selected from isopropyl.

9. The compound of claim 6, or a pharmaceutically acceptable salt, stable isotope derivative, isomer, and mixture thereof, wherein R ₅ is selected from OH or NHSO ₂CH₃.

10. A compound according to claim 1, or a pharmaceutically acceptable salt, stable isotope derivative, isomer, and mixtures thereof, selected from the group consisting of:

11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient or diluent and, as active ingredient, a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stable isotope derivative, isomer, and mixture thereof.

12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is in a pharmaceutically acceptable dosage form.

13. The pharmaceutical composition of claim 12, wherein the dosage form comprises a tablet, granule, capsule, powder, or injection.

14. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stable isotope derivative, isomer, mixture thereof or a pharmaceutical composition according to any one of claims 11 to 13 for the manufacture of a medicament for the treatment of pulmonary arterial hypertension.