RU2848695C2 - Antihypertensive polyol compound and its derivative - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: group of inventions relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof, as well as the compounds listed below, for the prevention or treatment of arterial hypertension or pulmonary hypertension. Use of a compound of formula I or a pharmaceutically acceptable salt thereof for the prevention or treatment of arterial hypertension or pulmonary hypertension:

wherein X is absent; n is an integer of 0-5; each of R₁ and R₃ is independently selected from H, C1-C2 alkylformyl, unsubstituted or substituted with O or NH₂; each R₂ is independently selected from H, carbonyl, unsubstituted C1-C10 alkyl; R₄ is selected from H, unsubstituted C1-C10 alkyl, unsubstituted unsaturated C2 alkyl, hydroxyl, unsubstituted C1 alkoxy, halogen, unsubstituted C1 alkylformyl; R₁₁ selected from H. Use of the following compounds or their salts for the prevention or treatment of the above-mentioned diseases:

EFFECT: drug for preventing or treating arterial hypertension or pulmonary hypertension.

4 cl, 6 dwg, 10 tbl, 14 ex

Description

Field of technology

The present invention relates to the field of pharmaceutical chemistry; in particular, the present invention relates to an antihypertensive polyol compound, its derivatives and their use for the production of antihypertensive drugs.

State of the art

Hypertension is the most common cardiovascular disease worldwide. Although some patients with hypertension have a genetic predisposition, environmental factors are also significant pathogenic factors. As quality of life improves and dietary habits change, the incidence of conditions such as hyperlipidemia, atherosclerosis, and the like steadily increases, and the incidence of hypertension is gradually increasing. Hypertension is a contributor to various diseases, increasing the risk of developing coronary heart disease, heart failure, and kidney disease. Therefore, lowering blood pressure is key to treating hypertension. The goal of hypertension treatment is to control blood pressure, reduce target organ damage, cardiovascular disease incidence, and mortality, and improve long-term prognosis and quality of life. To achieve this goal, in addition to lifestyle improvements, drug therapy is also necessary.

Currently, widely used antihypertensive drugs are divided into the following types: diuretic antihypertensive drugs, beta-blockers, calcium antagonists (CCBs), angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor blockers (ARBs), and alpha-blockers. Although these drugs can effectively reduce hypotension, they have significant side effects, such as fluid and electrolyte imbalances, asthma, decreased heart rate, sexual dysfunction, etc. Furthermore, patients often suffer from drug dependence, and blood pressure will immediately recover after discontinuing the drug.

High pulmonary pressure (PAH) is another disease that seriously threatens human life safety. The diagnostic criterion for PAH is a resting mean pulmonary artery pressure (MPP) of ≥25 mmHg, as determined using a right heart catheter. The onset of PAH is caused by a variety of factors, including pulmonary artery endothelial cell (PAEC) dysfunction, abnormal proliferation and remodeling of pulmonary artery endothelial cells and pulmonary artery smooth muscle cells (PASMCs), and in situ thrombus formation. PAH is a disease with high mortality, poor prognosis, and a median survival time of only 2.8 years and has become a major class of cardiovascular diseases in Western countries. Pathways such as endothelin (ET-1), NO, and prostacyclin (prost) play an important role in the onset and development of PAH. For these three targets, currently available PAH therapeutic agents primarily include endothelin receptor antagonists (bosentan, tambosentan, and bubebactam), phosphodiesterase 5 (PDE5) inhibitors (sildenafil, taddenafil, and valenafil), and alprost analogs (Ealprost, Iloprost, and Triprost). Although these drugs have a certain alleviating effect on the progression of PAH, the disease typically worsens in patients. Studies show that the 5-year survival rate for patients remains only approximately 50%. Furthermore, many PAH patients typically incur high drug costs due to long-term administration, and patients with severe disease also require a combination of multiple drugs to combat the disease, which places greater economic pressure on patients and society and significantly reduces the cure rate. Therefore, it is important to find new targeted drugs that can suppress or even reverse the progression of pulmonary hypertension to improve the prognosis and quality of life of patients with PAH.

Thus, research and development of therapeutic agents for the treatment of hypertension, pulmonary hypertension and related diseases may still have extremely great clinical significance and application prospects.

Brief description of the invention

The object of the present invention is to provide a new compound that can be used as a drug for the treatment of hypertension, pulmonary hypertension and related diseases.

In a first aspect of the present invention there is provided the use of a compound of formula I or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof for the preparation of a medicament for the prevention or treatment of hypertension or diseases associated with hypertension, or pulmonary hypertension or diseases associated with pulmonary hypertension,

Where

X is absent or represents substituted or unsubstituted linear or branched C1-C3 alkyl;

n is an integer 0-5, preferably an integer 1-5;

each of R ₁ and R ₃ is independently selected from H, D, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted -(CH ₂ CH ₂ O) _m H, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted C1-C5 alkylformyl, substituted or unsubstituted benzoyl, substituted or unsubstituted aminoacetyl, substituted or unsubstituted , substituted or unsubstituted , a substituted or unsubstituted monosaccharide, disaccharide or polysaccharide group, or a substituted or unsubstituted phosphate group, where m is an integer of 0-5, preferably 0-3, most preferably 1-2; or R ₁ and R ₃ may form a five-membered ring , where R ₆ is substituted or unsubstituted C1-C5 alkyl;

each R ₂ and R ₁₁ is independently selected from H, D, carbonyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted phenyl, CH ₂ OR ₇ ; R ₇ is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted monosaccharide, disaccharide or polysaccharide group;

R ₄ is selected from H, D, substituted or unsubstituted linear or branched C1-C10 alkyl, substituted or unsubstituted unsaturated linear or branched C1-C10 alkyl, hydroxyl, substituted or unsubstituted C1-C10 alkoxy, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted C1-C5 alkylformyl, substituted or unsubstituted benzoyl, nitro, COOH, substituted or unsubstituted C1-C5 alkoxyformyl, amino, substituted or unsubstituted C1-C5 alkylamino, substituted or unsubstituted C1-C5 alkylcarboxamido, substituted or unsubstituted benzoylamino, substituted or unsubstituted benzoaromatic ring, or a five-membered or six-membered heterocyclic rings containing heteroatoms.

According to a preferred embodiment, the phosphate group is as shown in , where R ₅ is selected from substituted or unsubstituted C1-C10 alkyl.

According to a preferred embodiment, the substituted or unsubstituted aminoacetyl is as shown in , where R represents various amino acid substituents.

According to a specific embodiment, said compound is represented by formula II,

(II)

Where

R ₈ is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C5 alkylformyl, substituted or unsubstituted benzoyl, substituted or unsubstituted aminoacetyl, or a substituted or unsubstituted monosaccharide, disaccharide, or polysaccharide group;

R ₉ is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C5 alkylformyl, substituted or unsubstituted benzoyl, substituted or unsubstituted aminoacetyl, or a substituted or unsubstituted monosaccharide, disaccharide, or polysaccharide group;

R ₁₀ is selected from H, substituted or unsubstituted linear or branched C1-C10 alkyl, substituted or unsubstituted unsaturated linear or branched C1-C10 alkyl, F, Cl, Br, hydroxyl, linear or branched C1-C3 alkoxy, substituted or unsubstituted C1-C5 alkylformyl, substituted or unsubstituted benzoyl or substituted or unsubstituted benzoaromatic ring or a five-membered or six-membered heterocyclic ring containing heteroatom(s); and n is any integer selected from 0-3.

In a particular embodiment of the present invention, there is provided the use of the following compounds or a salt or ester, prodrug, optical isomer or solvate thereof for the preparation of a medicament for the prevention or treatment of hypertension or diseases associated with hypertension, or pulmonary hypertension or diseases associated with pulmonary hypertension:

According to a specific embodiment, said compound is

In specific embodiments, diseases associated with hypertension include, but are not limited to, cerebral apoplexy (cerebral hemorrhage and cerebral ischemia), hypertensive heart disease, hypertensive nephropathy, hypertensive fundus lesions and retinal lesions, hypertensive lower limb ischemia, and the like;

Diseases associated with pulmonary hypertension include, but are not limited to, idiopathic pulmonary hypertension, pulmonary heart disease, plateau heart disease, cardiovascular disease, pulmonary obstruction, fibrotic disorders, and urinary disorders.

According to a second aspect of the present invention, there is provided a compound of formula I or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof,

(I)

Where

X is absent or represents substituted or unsubstituted linear or branched C1-C3 alkyl;

n is an integer 0-5, preferably an integer 1-5;

each of R ₁ and R ₃ is independently selected from H, D, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted -(CH ₂ CH ₂ O) _m H, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted C1-C5 alkylformyl, substituted or unsubstituted benzoyl, substituted or unsubstituted ester group, substituted or unsubstituted , substituted or unsubstituted , a substituted or unsubstituted aminoacetyl, a substituted or unsubstituted monosaccharide, disaccharide or polysaccharide group, or a substituted or unsubstituted phosphate group, where m is an integer of 0-5, preferably 0-3, most preferably 1-2; or R ₁ and R ₃ may form a five-membered ring , where R ₆ is substituted or unsubstituted C1-C5 alkyl;

each of R ₂ and R ₁₁ is independently selected from H, D, carbonyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted phenyl, CH ₂ OR ₇ ; R ₇ is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted monosaccharide, disaccharide or polysaccharide group;

R ₄ is selected from H, D, substituted or unsubstituted linear or branched C1-C10 alkyl, substituted or unsubstituted unsaturated linear or branched C1-C10 alkyl, hydroxyl, substituted or unsubstituted C1-C10 alkoxy, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted C1-C5 alkylformyl, substituted or unsubstituted benzoyl, nitro, COOH, substituted or unsubstituted C1-C5 alkoxyformyl, amino, substituted or unsubstituted C1-C5 alkylamino, substituted or unsubstituted C1-C5 alkylcarboxamido, substituted or unsubstituted benzoylamino, substituted or unsubstituted benzoaromatic ring, or a five-membered or six-membered heterocyclic rings containing heteroatoms.

According to a preferred embodiment, the phosphate group is as shown in , where R ₅ is selected from substituted or unsubstituted C1-C10 alkyl.

According to a preferred embodiment, the substituted or unsubstituted aminoacetyl is as shown in , where R represents various amino acid substituents.

According to a preferred embodiment, said compound is used to produce a medicament for preventing or treating hypertension or pulmonary hypertension.

According to a specific embodiment, said compound is represented by formula II,

Where

R ₈ is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C5 alkylformyl, substituted or unsubstituted benzoyl, substituted or unsubstituted aminoacetyl, or a substituted or unsubstituted monosaccharide, disaccharide, or polysaccharide group;

R ₉ is selected from H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C5 alkylformyl, substituted or unsubstituted benzoyl, substituted or unsubstituted aminoacetyl, or a substituted or unsubstituted monosaccharide, disaccharide, or polysaccharide group;

R ₁₀ is selected from H, substituted or unsubstituted linear or branched C1-C10 alkyl, substituted or unsubstituted unsaturated linear or branched C1-C10 alkyl, F, Cl, Br, hydroxyl, linear or branched C1-C3 alkoxy, substituted or unsubstituted C1-C5 alkylformyl, substituted or unsubstituted benzoyl or substituted or unsubstituted benzoaromatic ring or a five-membered or six-membered heterocyclic ring containing heteroatom(s); and n is any integer selected from 0-3.

According to a specific embodiment, said compound is selected from the following compounds or a salt or ester, prodrug, optical isomer or solvate thereof:

According to a preferred embodiment, said compound is

According to a preferred embodiment, said compound is used to produce a medicament for preventing or treating hypertension or diseases associated with hypertension, or pulmonary hypertension or diseases associated with pulmonary hypertension, or is used to prevent or treat hypertension or diseases associated with hypertension, or pulmonary hypertension or diseases associated with pulmonary hypertension.

According to a preferred embodiment, diseases associated with hypertension include, but are not limited to, cerebral apoplexy (cerebral hemorrhage and cerebral ischemia), hypertensive heart disease, hypertensive nephropathy, hypertensive fundus lesions and retinal lesions, hypertensive lower limb ischemia, and the like;

Diseases associated with pulmonary hypertension include, but are not limited to, idiopathic pulmonary hypertension, pulmonary heart disease, plateau heart disease, cardiovascular disease, pulmonary obstruction, fibrotic disorders, and urinary disorders.

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound according to the second aspect or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof and a pharmaceutically acceptable carrier or excipient.

According to a preferred embodiment, said pharmaceutical composition is used to prepare a medicament for preventing or treating hypertension or diseases associated with hypertension, or pulmonary hypertension or diseases associated with pulmonary hypertension, or is used to prevent or treat hypertension or diseases associated with hypertension, or pulmonary hypertension or diseases associated with pulmonary hypertension.

According to a preferred embodiment, diseases associated with hypertension include, but are not limited to, cerebral apoplexy (cerebral hemorrhage and cerebral ischemia), hypertensive heart disease, hypertensive nephropathy, hypertensive fundus lesions and retinal lesions, hypertensive lower limb ischemia, and the like;

Diseases associated with pulmonary hypertension include, but are not limited to, idiopathic pulmonary hypertension, pulmonary heart disease, plateau heart disease, cardiovascular disease, pulmonary obstruction, fibrotic disorders, and urinary disorders.

According to specific embodiments, said pharmaceutical composition is in the form for aerosol inhalation administration.

In a fourth aspect, the present invention provides a method for preventing or treating hypertension or diseases associated with hypertension, or pulmonary hypertension or diseases associated with pulmonary hypertension, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the second aspect or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof, or a pharmaceutical composition according to the third aspect.

It should be understood that the above-described technical features of the present invention and the various technical features described in detail below (e.g., embodiments) can be combined with each other within the scope of the present invention to obtain a new or preferred technical solution that will not be specifically indicated herein.

Description of drawings

FIG. 1 shows the therapeutic effect of orally administered compound 1 on an animal model of low-oxygen pulmonary hypertension;

FIG. 2 shows the reducing effect of orally administered compound 1 on the level of medium and small artery hypertrophy in the lung tissue of a rat with high pulmonary arterial pressure caused by low oxygen content;

FIG. 3 shows the therapeutic effect of orally administered compound 1 on an animal model of monocrotaline-induced pulmonary hypertension;

FIG. 4 shows the reducing effect of orally administered compound 1 on the level of medium and small artery hypertrophy in the lung tissues of a rat with high pulmonary arterial pressure induced by monocrotaline;

FIG. 5 shows the therapeutic effect of compound 1 administered by nebulization in an animal model of monocrotaline-induced pulmonary hypertension; and

FIG. 6 shows the reducing effect of oral compound 1 administered by nebulization on the level of medium and small artery hypertrophy in the lung tissues of rats with high pulmonary arterial pressure induced by monocrotaline.

Methods for carrying out the invention

The present inventors have unexpectedly discovered a series of new compounds with therapeutic effects on hypertension and pulmonary hypertension. The mechanism of action of these compounds differs from existing therapeutic agents, creating an entirely new basis for the development of therapeutic agents for the treatment of hypertension and pulmonary hypertension. Based on the above findings, the present invention has been completed.

Terms

Terms used herein relating to compounds, substituents, or structures have the same meanings as those understood by one skilled in the art. For clarity, the terms used herein are defined as follows.

As used herein, the term "a" or "an" includes plural forms of the modified subject matter, i.e., "a" or "an" refers to "at least one" or "one/more".

As used herein, expressions such as "C _1-n " refer to a group containing 1-n carbon atoms, for example, the expression "C _1-10 " refers to a group containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; similarly, "C6-C10" refers to a group containing 6, 7, 8, 9, or 10 carbon atoms.

As used herein, the term "alkyl" has the same meaning as commonly understood by one of skill in the art and refers to various saturated or unsaturated linear, pendant, or cyclic hydrocarbon radicals. For example, alkyl as described herein refers to lower alkyl containing from 1 to 10 carbon atoms; preferably, lower alkyl containing from 1 to 8 carbon atoms; more preferably, lower alkyl containing from 1 to 6 carbon atoms. According to a particular embodiment, alkyl as described herein includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, etc.

As used herein, the term "aryl" has the same meaning as commonly understood by those skilled in the art and refers to a cyclic conjugated aromatic system. For example, the term "C6-C10 aryl" refers to an aromatic ring group containing 6 to 10 carbon atoms but no heteroatom in the ring, such as phenyl, naphthyl, and the like. As used herein, the term "heteroaryl" refers to a cyclic conjugated aromatic system containing one or more heteroatoms, such as N, O, or S; for example, pyridyl and pyrazinyl.

As used herein, the term "aminoacetyl" has the generally accepted meaning understood by those skilled in the art, i.e., amino-substituted acetyl. According to a specific embodiment, aminoacetyl is shown in , where R represents various amino acid substituents.

As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated non-aromatic cyclic group containing a monocyclic, fused, spiro, or bridged ring, wherein the heterocyclic ring contains at least one heteroatom selected from O, S, or N as a ring member. For example, "5- or 6-membered heterocyclyl" refers to a saturated or unsaturated 5- or 6-membered cycloalkyl containing from 1 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen in the ring, such as dioxolyl, etc.

In this document, the term "halogen" refers to F, Cl, Br, or I.

Based on the concept of the present invention and the common knowledge in the art, it will be understood by one skilled in the art that the compounds of the present invention, as well as the various substituents defined above, may be further substituted, for example substituted with C1-6 alkyl, C1-6 alkoxy, halogen, nitro, amino, phenyl, hydroxyl, etc., provided that the combination of substituents desired is a stable or chemically achievable combination of substituents.

As used herein, the term "substituted" means that one or more hydrogen atoms in a particular group are replaced with particular substituents. A particular substituent may be a substituent previously described herein, or may be a particular substituent present in various embodiments. Thus, in the present invention, each substituent in general formula (I) or (II) may independently represent the corresponding group in a particular compound in one embodiment; that is, the present invention includes a combination of each substituent in general formula (I) or (II) described above, and also includes a combination of a portion of the substituents presented in general formula (I) or (II) and other particular substituents present in one embodiment.

Unless otherwise specifically stated, a substituted group may have a specific substituent at any substitutable center of the group, which may be the same or different at different centers. A cyclic substituent such as heterocyclyl may be linked to another ring such as cycloalkyl to form a spirobicyclic ring system, for example, two rings having a common carbon atom. Such a substituent includes, but is not limited to, _C1-8 alkyl, _C2-8 alkenyl, _C2-8 alkynyl, _C3-8 cycloalkyl, 3-12-membered heterocyclyl, aryl, heteroaryl, halogen, hydroxy, carboxyl (-COOH), _C1-8 aldehyde group, _C2-10 acyl, _C2-10 ester group, amino, _C1-8 alkoxy, nitro, cyano, mercapto, amino and the like. In a specific embodiment, the hydrogen atom in the alkyl and aryl is replaced by amino, halogen, or other groups, thereby becoming a group within each of the above definitions.

For convenience and in accordance with generally accepted understanding in the art, the terms "optionally," "optionally substituted," or "substituted or unsubstituted" apply only to centers that can be substituted by substituents and do not refer to those that are chemically unattainable.

Compounds according to the invention

The present invention provides a series of entirely new compounds that have a therapeutic effect on hypertension and pulmonary hypertension, having mechanisms of action different from existing therapeutic drugs.

According to a specific embodiment of the present invention, there is provided a compound of formula I or II, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof,

(I); (II)

The substituents in the general formula are described as indicated above.

The compounds of the present invention can be prepared by one skilled in the art as a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer, or solvate. For example, the compounds of the present invention can react with an inorganic or organic acid to form common pharmaceutically acceptable salts. The inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc., and the organic acid includes various amino acids, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, hexanoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid and the like; or the compound according to the present invention forms sodium, potassium, calcium, aluminum or ammonium salts with an inorganic base or forms methylamine, ethylamine or ethanolamine salts with an organic base.

Due to the presence of chiral carbon atoms in the compounds of the present invention, optical isomers or stereoisomers obtained by resolution of the compounds of the present invention are also within the scope of the present invention.

Based on the compound of the present invention or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof, the present invention also provides a pharmaceutical composition containing the compound of the present invention and, optionally, a pharmaceutically acceptable excipient.

According to a specific embodiment, the pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier in a safe and effective amount. A "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects.

A "pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid excipients or gels that are suitable for human use and must be of sufficient purity and low toxicity. As used herein, the term "compatibility" means that the components of the composition and the compound of the present invention can be mixed with each other without significantly reducing the effectiveness of said compound. Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. Tween®), wetting agents (e.g. sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free raw water, etc.

The administration of the compound or pharmaceutical composition according to the present invention is not particularly limited, and typical routes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is combined with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) adhesives, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, such as glycerol; (d) disintegrating agents, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) dissolution retarding agents, such as paraffin; (f) absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. For capsules, tablets, and pills, the dosage form may also contain a buffer.

Solid dosage forms such as tablets, pills, capsules, pellets, and granules can be prepared using coatings and shell materials, such as casings and other materials known in the art. They may contain opacifying agents, and the active compound(s) in such compositions can be released in a delayed manner in a specific part of the gastrointestinal tract. Examples of suitable encapsulating components include polymeric materials and wax-based materials. The active compound can also be microencapsulated with one or more of the excipients described above, if desired.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compounds, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof, etc.

In addition to the said inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfuming agents.

In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, microcrystalline cellulose, methanol, aluminum and agar or mixtures thereof, etc.

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

Dosage forms of the compound of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed with a physiologically acceptable carrier and any preservative, buffer, or propellant (if necessary) under sterile conditions.

The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the administered dose is a pharmaceutically effective amount. The compound and pharmaceutical composition of the present invention can be administered via the oral, nasal, cutaneous, pulmonary, or gastrointestinal routes, preferably orally, in a single or divided dose. Regardless of the route of administration, the optimal dosage for an individual should be determined based on the specific treatment. Typically, the dosage is gradually increased from a low dosage until a suitable dosage is found. The specific dosage should take into account factors such as the route of administration, the patient's health condition, and the like, which are within the skill of the art. In a specific embodiment, the compound of the present invention is preferably in a form suitable for administration by nebulization.

Advantages of the invention

1. The present invention provides a series of new compounds that have a therapeutic effect on hypertension and pulmonary hypertension; and

2. The mechanisms of action of the compounds of the present invention for the treatment of hypertension and pulmonary hypertension are different from existing drugs, and this potentially allows for the development of new therapeutic drugs for the treatment of hypertension and pulmonary hypertension.

The technical solution according to the present invention will be further described below in conjunction with specific embodiments, but the following embodiments do not limit the present invention. All various methods of application adopted in accordance with the principles and technical means of the present invention are within the scope of the present invention. Experimental methods in the following examples, in which specific conditions are not specified, generally comply with generally accepted conditions or conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

Examples

Method for obtaining compounds

The compounds of the present invention can be prepared according to conventional routes or methods, and can also be prepared according to the methods or routes described herein.

Synthesis:

Example 1. Synthesis of compound 1

1. Synthesis of compound 1.3

Magnesium powders (2.2 g, 90 mmol) were placed in a 250 mL three-necked reaction flask, a crystal of iodine was added, compound 1.1 (15 g, 82 mmol) was dissolved in 120 mL of anhydrous tetrahydrofuran, and 10 mL of a solution of Compound 1 in tetrahydrofuran was added dropwise into the reaction flask containing magnesium powders through a constant-pressure dropping funnel. The reaction was initiated using a hair dryer, and then, after the reaction started, the remaining 110 mL of a solution of Compound 1.1 in tetrahydrofuran was slowly added dropwise. After the addition, the reaction mixture was refluxed for 3.5 hours, resulting in a solution of compound 1.2 in tetrahydrofuran.

In an ice bath, a solution of Compound 1.2 in tetrahydrofuran was added dropwise to 80 mL of a solution of benzyloxyacetaldehyde (12 g, 80 mmol) in anhydrous tetrahydrofuran. After the addition, the temperature of the solution was raised to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, tetrahydrofuran was removed, and the resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified using a column (PE:EA = 10:1) to obtain 12.4 g of the title compound in a two-step yield of 59.6%. ¹ H NMR (400 MHz, DMSO): δ 7.36-7.15 (m, 8 H), 7.09 (d, J = 7.6 Hz, 1 H), 5.38 (d, J = 4.4 Hz, 1 H), 4.74-4.70 (m, 1 H), 4.51 (s, 2 H), 3.53-3.44 (m, 2 H), 2.61 (q, J =7.6, 2 H), 1.19 (t, J =7.6, 3 H). LC-MS: 255.30 (MH) ^- .

2. Synthesis of compound 1

Compound 1.3 (12.4 g, 48.4 mmol) was dissolved in 70 mL of ethanol, 10% palladium on carbon (2.43 g) was added, air was replaced with _H2 , and the reaction system was stirred for 3 h at 38°C. After completion of the reaction, the solvent was removed and the residue was purified by column (PE:EA = 5:1) to obtain 6.42 g of the target compound in 79% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.28-7.12 (m, 4 H), 4.78 (dd, J ₁ = 8.0 Hz, J ₂ = 3.6 Hz, 1 H), 3.74-3.62 (m, 2 H), 2.64 (q, J = 7.6 Hz, 2 H), 1.23 (t, J = 7.6 Hz, 3 H). LC-MS: 165.10 (MH) ^- .

Example 2. Synthesis of compound 2

1. Synthesis of compound 2.6

Magnesium powders (0.17 g, 7 mmol) were placed in a 50 mL three-necked reaction flask, a small crystal of iodine was added, compound 2.4 (1 g, 6.4 mmol) was dissolved in anhydrous tetrahydrofuran (12 mL), 2 mL of Compound 4 in tetrahydrofuran solution was added dropwise into the reaction flask using a constant pressure dropping funnel, the reaction was initiated using a hair dryer, and the remaining 10 mL of Compound 2.4 in tetrahydrofuran solution was slowly added dropwise after the reaction was initiated. After the addition, the reaction mixture was refluxed for 3.5 hours, resulting in a solution of Compound 2.5 in tetrahydrofuran.

In an ice bath, a solution of Compound 2.5 in tetrahydrofuran was added dropwise to 8 mL of a solution of benzyloxyacetaldehyde (0.97 g, 6.4 mmol) in anhydrous tetrahydrofuran. After the addition, the temperature of the solution was raised to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, tetrahydrofuran was removed, and the resulting residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by a column (PE:EA = 10:1) to obtain 0.98 g of the title compound in a two-step yield of 67.6%. ¹ H NMR (400 MHz, DMSO): δ 7.37-7.22 (m, 10 H), 5.41 (d, J = 4.0 Hz, 1 H), 4.78-4.74 (m, 1 H), 4.51 (s, 2 H), 3.51-3.48 (m, 2 H). LC-MS: 227.30 (MH) ^- .

2. Synthesis of compound 2

Compound 2.6 (0.9 g, 4 mmol) was dissolved in ethanol (10 mL), 10% palladium on carbon (0.2 g) was added, air was replaced with H ₂ , and the reaction mixture was stirred for 3 h at 38 °C. After completion of the reaction, the solvent was removed, and the resulting residue was purified by column (PE:EA = 5:1) to obtain 0.24 g of the target compound in 45% yield. ¹ H NMR (400 MHz, DMSO): δ 7.34-7.28 (m, 4 H), 7.24-7.20 (m, 1 H), 5.24 (d, J = 4.4 Hz, 1 H), 4.74 (t, J = 6 Hz, 1 H), 4.55 (q, J = 6 Hz, 1 H), 3.43 (t, J = 6 Hz, 2 H). LC-MS: 137.10 (MH) ^- .

Example 3. Synthesis of compound 3

1. Synthesis of compound 3.9

Magnesium powders (0.33 g, 13.8 mmol) were placed in a 100 mL three-necked reaction flask, a small crystal of iodine was added, compound 3.7 (2 g, 11.7 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), a solution of compound 3.7 in tetrahydrofuran (3 mL) was added dropwise into the reaction bottle using a constant-pressure dropping funnel, the reaction was initiated using an electric hair dryer, and the remaining solution of compound 7 in tetrahydrofuran (17 mL) was slowly added dropwise after the reaction started. After the addition, the reaction mixture was refluxed for 3.5 hours, resulting in a solution of compound 3.8 in tetrahydrofuran.

A solution of compound 3.8 in tetrahydrofuran was added dropwise to a solution of benzyloxyacetaldehyde (1.74 g, 11.6 mmol) in anhydrous tetrahydrofuran (14 mL) in an ice bath. After the addition, the temperature of the reaction mixture was raised to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, tetrahydrofuran was removed, and the resulting residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by a column (PE:EA = 10:1) to obtain 0.95 g of the target compound in a two-step yield of 34%. ¹ H NMR (400 MHz, DMSO): δ 7.34-7.04 (m, 9 H), 5.34 (d, J = 4.0 Hz, 1 H), 4.73-4.69 (m, 1 H), 4.51 (s, 2 H), 3.52-3.43 (m, 2 H), 2.28 (s, 3 H). LC-MS: 241.30 (MH) ^- .

2. Synthesis of compound 3

Compound 3.9 (0.9 g, 3.8 mmol) was dissolved in ethanol (10 mL), and 10% palladium on carbon (0.2 g) was added, air was replaced with _H2 , and the reaction system was stirred for 3 h at 38 °C. After completion of the reaction, the solvent was removed and the residue was purified by column (PE:EA=5:1) to obtain 0.28 g of the title compound in 50% yield. ¹ H NMR (400 MHz, _CDCl3 ): δ 7.26-7.09 (m, 4 H), 4.76 (dd, J1 =8.0 Hz, J2 =3.6 Hz, 1 H), 3.72-3.59 (m, ₂ H), 3.09 (s, 2 H), _2.34 (s, 3 H). LC-MS: 151.10 (MH) ^- .

Example 4. Synthesis of compound 4

1. Synthesis of compound 4.12

Magnesium powders (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction flask, a small crystal of iodine was added, compound 4.10 (2 g, 10.9 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), a solution of the compound in tetrahydrofuran (3 mL) was added dropwise into the reaction bottle using a constant-pressure dropping funnel, and the reaction was initiated with an electric hair dryer. The remaining 17 mL of the solution of compound 4.10 in tetrahydrofuran was slowly added dropwise after the reaction started. After the addition, the reaction mixture was refluxed for 3.5 hours, resulting in a solution of compound 11 in tetrahydrofuran.

A solution of compound 4.11 in tetrahydrofuran was added dropwise to a solution of benzyloxyacetaldehyde (1.62 g, 10.8 mmol) in anhydrous tetrahydrofuran (14 mL) in an ice bath. After the addition, the temperature of the reaction mixture was raised to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, tetrahydrofuran was removed, and the resulting residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column purification (PE:EA = 10:1) to obtain 1 g of the target compound in a two-step yield of 36%. ¹ H NMR (400 MHz, DMSO): δ 7.35-7.14 (m, 9 H), 5.33 (d, J = 4.0 Hz, 1 H), 4.74-4.70 (m, 1 H), 4.51 (s, 2 H), 3.52-3.43 (m, 2 H), 2.57 (q, J = 7.6 Hz, 2 H), 1.16 (t, J = 7.6 Hz, 3 H). LC-MS: 255.30 (MH) ^- .

2. Synthesis of compound 4

Compound 4.12 (0.9 g, 3.5 mmol) was dissolved in ethanol (10 mL), 10% palladium on carbon (0.2 g) was added, air was replaced with _H2 , and the reaction system was stirred for 3 h at 38 °C. After completion of the reaction, the solvent was removed, and the resulting residue was purified by a column (PE:EA = 5:1) to obtain 0.24 g of the target compound in 37% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.20-7.10 (m, 4 H), 4.72 (dd, J ₁ = 8.0 Hz, J ₂ = 3.6 Hz, 1 H), 3.66-3.55 (m, 2 H), 2.59 (q, J = 7.6 Hz, 2 H), 2.46 (s, 2 H), 1.15 (t, J = 7.6 Hz, 3 H). LC-MS: 165.10 (MH) ^- .

Example 5. Synthesis of compound 5

1. Synthesis of compound 5.15

Magnesium powders (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction flask, a small crystal of iodine was added, compound 5.13 (2 g, 10.9 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), a solution of compound 5.13 in tetrahydrofuran (3 mL) was added dropwise into the reaction bottle using a constant pressure dropping funnel, the reaction was initiated using a hair dryer, and the remaining 17 mL of compound 5.13 in tetrahydrofuran solution was slowly added dropwise after the reaction started. After the addition, the reaction mixture was refluxed for 3.5 hours, and as a result, a solution of Compound 5.14 in tetrahydrofuran was obtained.

In an ice bath, a solution of compound 5.14 in tetrahydrofuran was added dropwise to a solution of benzyloxyacetaldehyde (1.62 g, 10.8 mmol) in anhydrous tetrahydrofuran (14 mL). After the addition, the temperature of the reaction mixture was raised to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, tetrahydrofuran was removed, and the residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column purification (PE:EA = 10:1) to obtain 1.4 g of the target compound in a two-step yield of 50%. ¹ H NMR (400 MHz, DMSO): δ 7.44-7.42 (m, 1 H), 7.35-7.25 (m, 5 H), 7.19-7.12 (m, 3 H), 5.33 (d, J = 4.4 Hz, 1 H), 5.01-4.97 (m, 1 H), 4.55-4.47 (m, 2 H), 3.51-3.40 (m, 2 H), 2.66 (m, 2 H), 1.15 (t, J = 7.6, 3 H). LC-MS: 255.30 (MH) ^- .

2. Synthesis of compound 5

Compound 5.15 (1.2 g, 4.7 mmol) was dissolved in ethanol (15 mL), and 10% palladium on carbon (0.3 g) was added, air was replaced with _H2 , and the reaction system was stirred for 3 h at 38 °C. After completion of the reaction, the solvent was removed and the resulting residue was purified by column (PE:EA=5:1) to give 0.43 g of the title compound in 47% yield. ¹ H NMR (400 MHz, DMSO): δ 7.41-7.14 (m, 4 H), 5.14 (d, J =4.0 Hz, 1 H), 4.81-4.76 (m, 2 H), 3.37 (q, J =7.6 Hz, 2 H), 1.16 (t, J =7.6 Hz, 3 H). LC-MS: 165.10 (MH) ^- .

6. Synthesis of compound 6

1. Synthesis of compound 6.18

Magnesium powders (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction flask, a small crystal of iodine was added, compound 6.16 (2 g, 8.5 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), a solution of compound 16 in tetrahydrofuran (3 mL) was added dropwise to the reaction bottle using a constant-pressure dropping funnel, and the reaction was initiated with an electric hair dryer. The remaining 17 mL of the solution of compound 6.16 in tetrahydrofuran was slowly added dropwise after the reaction started. After the addition, the reaction mixture was refluxed for 3.5 hours, resulting in a solution of compound 6.17 in tetrahydrofuran.

A solution of compound 6.17 in tetrahydrofuran was added dropwise to a solution of benzyloxyacetaldehyde (1.28 g, 8.5 mmol) in anhydrous tetrahydrofuran (14 ml) in an ice bath. After the addition, the temperature of the reaction system was raised to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, tetrahydrofuran was removed, and the resulting residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified using a column (PE:EA = 10:1) to obtain 0.9 g of the target compound in 32% yield. ¹ H NMR (400 MHz, DMSO): δ 7.38-7.02 (m, 9 H), 5.33 (d, J = 4.4 Hz, 1 H), 4.75-4.70 (m, 1 H), 4.47 (s, 2 H), 3.56-3.49 (m, 2 H). LC-MS: 307.30 (MH) ^- .

2. Synthesis of compound 6

Compound 6.18 (0.85 g, 2.8 mmol) was dissolved in ethanol (10 mL), 10% palladium on carbon (0.23 g) was added, air was replaced with _H2 , and the reaction system was stirred for 3 h at 38°C. After completion of the reaction, the solvent was removed, and the residue was purified by column (PE:EA = 5:1) to obtain 0.2 g of the target compound in 33% yield. ¹ H NMR (400 MHz, DMSO): δ 7.35-7.29 (m, 1 H), 7.19-7.13 (m, 2 H), 7.02-6.98 (m, 1 H), 5.34 (d, J = 4 Hz, 1 H), 4.70 (t, J = 6 Hz, 1 H), 4.51 (q, J = 5.6 Hz), 3.40 (t, J = 6 Hz, 2 H). LC-MS: 217.10 (MH) ^- .

Example 7. Synthesis of compound 7

1. Synthesis of compound 7.21

Magnesium powders (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction flask, a small crystal of iodine was added, compound 7.19 (2 g, 11.7 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), a solution of compound 19 in tetrahydrofuran (3 mL) was added dropwise into the reaction bottle using a constant-pressure dropping funnel, and the reaction was initiated with an electric hair dryer. The remaining 7.17 mL of the solution of compound 7.19 in tetrahydrofuran was slowly added dropwise after the reaction started. After the addition, the reaction mixture was refluxed for 3.5 hours, resulting in a solution of compound 7.20 in tetrahydrofuran.

A solution of compound 7.20 in tetrahydrofuran was added dropwise to a solution of benzyloxyacetaldehyde (1.76 g, 11.7 mmol) in anhydrous tetrahydrofuran (14 ml) in an ice bath. After the addition, the temperature of the reaction system was raised to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, tetrahydrofuran was removed, and the resulting residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified using a column (PE:EA = 10:1) to obtain 1.32 g of the target compound in a yield of 47.2%. ¹ H NMR (400 MHz, DMSO): δ 7.44-7.14 (m, 9 H), 5.36 (d, J = 4.4 Hz, 1 H), 4.71-4.67 (m, 1 H), 4.50 (s, 2 H), 3.50-3.41 (m, 2 H). LC-MS: 245.30 (MH) ^-

2. Synthesis of compound 7

Compound 7.21 (1.3 g, 5.4 mmol) was dissolved in ethanol (10 mL), 10% palladium on carbon (0.23 g) was added, air was replaced with _H2 , and the reaction mixture was stirred for 3 h at 38 °C. After completion of the reaction, the solvent was removed, and the residue was purified by column (PE:EA = 5:1) to obtain 0.2 g of the target compound in 33% yield. ¹ H NMR (400 MHz, DMSO): δ 7.37-7.31 (m, 1 H), 7.18-7.12 (m, 2 H), 7.06-7.01 (m, 1 H), 5.39 (d, J = 4.4 Hz, 1 H), 4.77 (t, J = 5.6 Hz, 1 H), 4.56 (q, J = 5.6 Hz), 3.43 (t, J = 6 Hz, 2 H). LC-MS: 155.10 (MH) ^- .

Example 8. Synthesis of compound 8

1. Synthesis of compound 8.24

Magnesium powders (0.57 g, 22.2 mmol) were placed in a 100 mL three-necked reaction flask, a small crystal of iodine was added, compound 8.22 (4 g, 21.5 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), a solution of compound 8.22 in tetrahydrofuran (5 mL) was added dropwise into the reaction bottle using a constant-pressure dropping funnel, and the reaction was initiated with an electric hair dryer. The remaining 35 mL of compound 8.22 in tetrahydrofuran solution was slowly added dropwise after the reaction started. After the addition, the reaction mixture was refluxed for 3.5 hours, resulting in a solution of compound 8.23 in tetrahydrofuran.

A solution of compound 8.23 in tetrahydrofuran was added dropwise to a solution of benzyloxyacetaldehyde (3.21 g, 21.5 mmol) in anhydrous tetrahydrofuran (30 mL) in an ice bath. After the addition, the temperature of the reaction system was raised to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, tetrahydrofuran was removed, and the resulting residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified using a column (PE:EA = 10:1) to obtain 4 g of the target compound in a yield of 63.6%.¹H NMR (400 MHz, DMSO): δ 7.35-7.14 (m, 9 H), 5.33 (d,J= 4.0 Hz, 1 H), 4.74-4.70 (m, 1 H), 4.51 (s, 2 H), 3.73 (s, 3H), 3.52-3.43 (m, 2 H). LC-MS: 257.30 (M-H)^-.

2. Synthesis of compound 8

Compound 8.24 (3.5 g, 13.6 mmol) was dissolved in ethanol (30 mL), 10% palladium on carbon (0.69 g) was added, air was replaced with _H2 , and the reaction mixture was stirred for 3 h at 38 °C. After completion of the reaction, the solvent was removed, and the residue was purified by column (PE:EA = 5:1) to obtain 1.42 g of the target compound in 62.3% yield. ¹ H NMR (400 MHz, DMSO): δ 7.23 (t, J = 8 Hz, 1 H), 6.91 (d, J = 7.6 Hz, 2 H), 6.80-6.77 (m, 1 H), 5.24 (d, J = 4.4 Hz, 1 H), 4.73 (t, J = 5.6 Hz, 1 H), 4.53 (q, J = 4.8 Hz, 1 H), 3.73 (s, 3H), 3.43-3.36 (m, 2 H). LC-MS: 167.10 (MH) ^- .

Example 9. Synthesis of compound 9

1. Synthesis of compound 9.26

p -Isopropylaniline (4 g, 29.6 mmol) was dissolved in dichloromethane (40 mL), and NBS (5.8 g, 32.6 mmol) was added to the dichloromethane solution portionwise on an ice bath. The reaction temperature was raised to room temperature, and the reaction was complete after 1 h. After purification, 4.6 g of product were obtained in 74% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.28 (d, J = 1.6 Hz, 1 H), 6.98 (dd, J ₁ = 1.6 Hz, J ₂ = 1.6 Hz, 1 H), 6.71 (d, J = 8 Hz, 1 H), 3.76 (s, 2 H), 2.79 (m, 1 H), 1.20 (d, J = 6.8 Hz, 6 H). LC-MS: 214.10 (M+H) ⁺ .

2. Synthesis of compound 9.27

Compound 9.26 (2 g, 9.3 mmol) was dissolved in a mixed solution of acetic acid (10 mL), water (4 mL), and concentrated HCl (1 mL), and 2 mL of an aqueous solution of NaNO₂(0.78 g, 11.2 mmol) was added dropwise to the above mixed solution in an ice bath. After half an hour, the resulting reaction mixture was added dropwise to a 50% aqueous solution of H₃PO₂(12 ml) in an ice bath. After the addition, the reaction was continued for 8 hours, and then the reaction temperature was raised to 25 degrees Celsius for 3 days. After completion of the reaction, the reaction mixture was purified using a column to obtain 1.4 g of product with a yield of 75.3%.¹H NMR (400 MHz, DMSO): δ 7.42 (s, 1H), 7.37-7.34 (m, 1H), 7.25 (d, J= 4.8 Hz, 2 H), 1.20 (d,J= 6.8 Hz, 6 H). LC-MS: 199.20 (M+H)⁺.

3. Synthesis of compound 9.29

Magnesium powders (0.17 g, 7.1 mmol) were placed in a 100 mL three-necked reaction flask, a small crystal of iodine was added, compound 9.27 (1.3 g, 7.5 mmol) was dissolved in anhydrous tetrahydrofuran (12 mL), a solution of compound 9.27 in tetrahydrofuran (2 mL) was added dropwise into the reaction bottle using a constant-pressure dropping funnel, and the reaction was initiated with an electric hair dryer. The remaining 10 mL of the solution of compound 9.27 in tetrahydrofuran was slowly added dropwise after the reaction started. After the addition, the reaction mixture was refluxed for 3.5 hours, resulting in a solution of compound 9.28 in tetrahydrofuran.

A solution of compound 9.28 in tetrahydrofuran was added dropwise to a solution of benzyloxyacetaldehyde (0.98 g, 7.1 mmol) in anhydrous tetrahydrofuran (10 mL) in an ice bath. After the addition, the temperature of the reaction system was raised to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, tetrahydrofuran was removed, and the resulting residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified using a column (PE:EA = 10:1) to obtain 1 g of the target compound in 56% yield. ^1H NMR (400 MHz, DMSO): δ 7.36-7.15 (m, 8 H), 7.09 (d, J = 8 Hz, 1 H), 5.38 (d, J = 4 Hz, 1 H), 4.74-4.70 (m, 1 H), 4.51 (s, 2 H), 3.53-3.44 (m, 2 H), 2.83-2.76 (m, 1 H), 1.20 (d, J = 7.6 Hz, 6 H). LC-MS: 271.30 (M+H) ⁺ .

4. Synthesis of compound 9

Compound 9.28 (1 g, 3.6 mmol) was dissolved in ethanol (10 mL), 10% palladium on carbon (0.19 g) was added, air was replaced with H ₂ , and the reaction mixture was stirred for 3 h at 38 °C. After completion of the reaction, the solvent was removed and the residue was purified by column (PE:EA = 5:1) to obtain g of the title compound in 10% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.19-7.04 (m, 4 H), 4.69 (d, J = 4.0 Hz, 1 H), 3.64-3.52 (m, 2 H), 3.22 (s, 2 H), 2.83-2.76 (m, 1 H), 1.15 (d, J = 7.6 Hz, 6 H). LC-MS: 179.10 (MH) ^- .

Example 10. Synthesis of compound 10

1. Synthesis of compound 10.30 (carbonyl protection)

p-Bromoacetophenone (5 g, 25.4 mmol) was placed in a 100 ml three-necked flask, toluene (60 ml) was added as a solvent, ethylene glycol (10 g, 161.3 mmol) was added andp-toluenesulfonic acid (1 g, 5 mmol), the temperature was raised to 130°C, and the reaction mixture was refluxed for 16 h. After completion of the reaction, brine was added, the mixture was stirred, and the layers were allowed to separate. The organic phase was collected, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain 3 g of the compound in 48% yield.¹H NMR (400 MHz, CDCl₃):δ7.49-7.44 (m, 2 H), δ 7.37-7.34 (m, 2 H), 4.05 (m, 2 H), 3.77-3.73 (m, 2 H), 1.62 (s, 3 H). LC-MS: 242.10 (M-H)^-.

2. Synthesis of compound 10.32

Magnesium powders (0.31 g, 12.9 mmol) were placed in a 100 mL three-necked reaction flask, a small crystal of iodine was added, 4-bromobenzene ethylene ketal (2.5 g, 10.4 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), a solution of the ketal in tetrahydrofuran (3 mL) was added dropwise to the reaction bottle using a constant-pressure dropping funnel, and the reaction was initiated with an electric hair dryer. The remaining 17 mL of the tetrahydrofuran solution was slowly added dropwise after the reaction started. After the addition, the reaction mixture was refluxed for 3.5 hours, resulting in a solution of the Grignard reagent in tetrahydrofuran.

A solution of the ketal in tetrahydrofuran was added dropwise to a solution of benzyloxyacetaldehyde (1.5 g, 10 mmol) in anhydrous tetrahydrofuran (14 ml) in an ice bath. After the addition, the temperature of the reaction system was raised to room temperature for 1 hour, and then a saturated aqueous solution of ammonium chloride was added to quench the reaction. Finally, tetrahydrofuran was removed, and the resulting residue was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified using a column (PE:EA = 10:1) to obtain 0.8 g of the target compound in 25% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.44-7.29 (m, 10 H), 4.9 0 (dd, J = 8.8 Hz, 3.2 Hz, 1 H), 4.57 (q, J = 12 Hz, 2 H), 3.98 (t, J = 6 Hz, 2 H), 3.71 (t, J = 6 Hz, 2 H), 3.60 (dd, J = 8 Hz, 3.2 Hz), 3.39 (t, J = 8 Hz, 1 H), 1.62 (s, 3 H). LC-MS: 313.20 (MH) ^- .

3. Synthesis of compound 10.33 (debenzylation)

The compound (0.75 g, 2.4 mmol) was dissolved in ethanol (10 mL), 10% palladium on carbon (0.23 g) was added, air was replaced with _H2 , and the reaction mixture was stirred for 3 h at 38 °C. After completion of the reaction, the solvent was removed, and the residue was purified by column (PE:EA = 5:1) to obtain 0.2 g of the target compound in 29% yield. ¹ H NMR (400 MHz, DMSO): δ 7.35-7.29 (m, 4 H), 5.23 (d, J = 4 Hz, 1 H), 4.74 (t, J = 6 Hz, 1 H), 4.54-4.49 (m, 1 H), 3.98-3.94 (m, 2 H), 3.43 (t, J = 6.8 Hz, 2 H), 1.53 (s, 3 H). LC-MS: 223.10 (MH) ^- .

4. Synthesis of compound 10

The resulting compound (0.18 g, 0.8 mmol) was collected, 10 ml of ethanol, and hydrochloric acid were added over 5 days. The reaction was carried out at 50°C for 15 h. Water was added, and the resulting mixture was extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 0.06 g of product in 40% yield. ¹ H NMR (400 MHz, DMSO): δ 7.91 (d, J = 8.4 Hz, 2 H), 7.49 (d, J = 8.4 Hz, 2 H), 5.42 (d, J = 4 Hz, 1 H), 4.80 (t, J = 6 Hz, 1 H), 4.63 (q, J = 5.6 Hz, 1 H), 3.46 (t, J = 6 Hz, 2 H), 2.56 (s, 3 H). LC-MS: 181.10 (M+H)+.

Example 11. Synthesis of compound 11(D)

1. Synthesis of 3-vinylphenylethylene oxide (B)

Under a protective nitrogen atmosphere, potassium tert-butoxide (2.214 g, 0.02 mol), THF (2 mL), and DMSO (12 mL) were added dropwise to a three-necked flask containing trivinylbenzaldehyde ( A , 1.215 g, 0.009 mol), trimethylsulfur iodide (2.118 g, 0.011 mol), THF (8 mL), and DMSO (15 mL). The reaction was carried out in an ice bath for 12 h. TLC was used to monitor the reaction progress during the reaction. After completion of the reaction, the reaction mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and finally purified by column chromatography (PE:EA = 150:1) to obtain 0.755 g of 3-vinylphenylethylene oxide ( B ) (56%). ¹ H NMR (DMSO, 400 MHz): δ 7.43-7.21 (m, 4H), 6.77 (dd, J=10.8 17.7 Hz, 1H), 5.83 (d, J= 17.7 Hz, 1H), 5.29 (d, J=10.8 Hz, 1H), 3.93 (dd, J=2.7, 4.0 Hz, 1H), 3.13 (dd, J= 4.0, 5.5 Hz, 1H), 2.88 (q, J=2.7 Hz, 1H).

2. Synthesis of 3-(1-hydroxy-2-benzoyloxyethyl)styrene (C)

Under a protective nitrogen atmosphere, benzoic acid (1.22 g, 10.0 mmol), tetrabutylammonium iodide (0.369 g, 1.0 mmol) and 3-vinylphenylethylene oxide ( B , 1.46 g, 10.0 mmol) were added to 5 ml of DMF. The reaction was carried out at 100 °C for 12 h. During the reaction, TLC was used to monitor the reaction progress. After completion of the reaction, the reaction mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and finally purified by column chromatography (PE:EA = 10:1) to give 3-(1-hydroxy-2-benzoyloxyethyl)styrene ( C ) 0.818 g (30.47%). ¹ H NMR (DMSO, 400 MHz): δ 7.33-7.95 (m, 9H), 6.78 (dd, J=10.9, 17.6 Hz, 1H), 5.85 (d, J=17.6 Hz, 1H), 5.78 (d, J=4.6 Hz, 1H), 5.27 (d, J=10.9, 1H), 4.96 (q, J=4.6, 1H), 4.34 (d, J=5.7 Hz, 2H).

3. Synthesis of compound 11(D)

3-(1-Hydroxy-2-benzoyloxyethyl)styrene ( C , 0.20 g, 0.745 mmol) and sodium hydroxide (0.043 g, 1.08 mmol) in 4 ml of methanol were refluxed for 2 h. And then 1 ml of _H2O was added. During the reaction, TLC was used to monitor the reaction progress. After the completion of the reaction, the reaction mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and finally purified by column chromatography (PE:EA=1:1) to obtain 0.07 g of 3-(1,2-dihydroxyethyl)styrene ( D ) (57.2%). ¹ H NMR (CDCl3, 400 MHz): δ 7.12-7.29 (m, 4H), 6.65 (dd, J=11.1, 17.7 Hz, 1H), 5.69 (d, J=17.7 Hz, 1H), 5.19 (d, J=11.1 Hz, 1H), 4.71 (dd, J= 3.3, 8.3 Hz, 1H), 3.65 (m, 2H), 3.07 (s, 2H). MS (IE): 164.1.

Example 12. Synthesis of compound 30

Compound 1 (1.66 g, 0.01 mol) was dissolved in 7 mL of DCM, 1 drop of concentrated sulfuric acid was added, and the exothermic reaction was initiated by gentle heating. After completion of the reaction, 20 mL of solvent was added, washed with sodium bicarbonate solution, dried, concentrated, and purified using a column (PE:EA = 10:1) to obtain 2.00 g of the target compound in 80% yield. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.21-7.00 (m, 4 H), 4.75 (dd, J ₁ = 8.0 Hz, J ₂ = 3.6 Hz, 1 H), 3.72-3.60 (m, 2 H), 2.66 (q, J = 7.6 Hz, 2 H), 2.21 (s, 3 H), 2.10 (s, 3 H), 1.25 (t, J = 7.6 Hz, 3 H). LC-MS: 251.17 (M+H) ⁺ .

Example 13 Test for antihypertensive activity

In this example, it was tested whether the compound of the present invention has a lowering effect on the blood pressure of spontaneously hypertensive rats (SHR) and an effect on the heart rate, in accordance with generally accepted experimental procedures in the art.

Test drugs: compounds according to the present invention. The dosage of each compound was uniformly set at 200 mg/kg.

Other reagents, test animals and instruments: All other reagents and instruments used in this example are commercially available reagents and instruments.

In this study, changes in blood pressure were determined before and after administration, and compared with the baseline value, a decrease in systolic blood pressure (SBP) ≥ 20 mmHg after administration was assessed as an effective antihypertensive effect; and at the same time, changes in heart rate were determined before and after administration.

Statistical analysis:

Heart rate was expressed as mean ± standard deviation. The changes in heart rate before and after administration were compared using a paired t-test for two samples with equal variance, and P < 0.05 was considered the standard for statistically significant difference.

Experimental results

By comparison, the positive drug metoprolol hydrochloride exhibited the greatest blood pressure-lowering effect. After administration, blood pressure decreased by more than 20 mmHg at most time points, with the lowest blood pressure value recorded 3 hours after administration. Metoprolol hydrochloride can significantly slow heart rate while lowering blood pressure. Six hours after administration, the average heart rate decreased by 46 beats/min. This pattern of both blood pressure reduction and heart rate slowing is consistent with the pharmacological effects of a β-receptor blocker.

Secondly, 1-(3-ethylphenyl)-1,2-ethylene glycol was a compound with antihypertensive effect. Before and after administration, the duration of the antihypertensive effect of 1-(3-ethylphenyl)-1,2-ethylene glycol was similar to that of the positive drug metoprolol hydrochloride, and the maximum antihypertensive effect was also observed 3 hours after administration, but the amplitude of the blood pressure decrease was slightly lower than that of the positive drug metoprolol hydrochloride. In addition, the effect of 1-(3-ethylphenyl)-1,2-ethylene glycol on heart rate was directly opposite to that of the positive drug metoprolol hydrochloride, that is, it can significantly increase the heart rate while decreasing blood pressure.

TABLE 1. Effect of selected compounds on blood pressure and heart rate of SHR before and after administration (6 h M ± SD) n = 8 Connection number Group (structure) Dosage (mg/kg) Blood pressure (SBP, mmHg) Difference in mmHg Heart rate (bpm) Difference (bpm) Initial level After administration Initial level After administration Metoprolol hydrochloride 200 186±7.87 164±7.85 23 328±24.5 282±21.3 -46 connection 4 200 184±14.7 181±13.2 3 345±42.2 346±43.4 1 connection 1 200 192±7.98 174±4.01 18 356±46.4 368±25.5 12 connection 12 200 187±11.9 181±8.80 6 333±44.0 336±49.5 3 connection 13 200 190±13.2 178±11.2 12 319±21.0 329±27.7 10

The results of experiments assessing the effect of other compounds on lowering blood pressure and increasing heart rate are presented in Table 2, Table 3 and Table 4.

TABLE 2. Dynamic changes in SHR arterial pressure after administration of some compounds and the difference before and after administration (SBP, mmHg) n=8 Group Time after administration (h) 0 1 2 3 4 5 6
Metoprolol hydrochloride 186±7.24 166±6.39 164±4.50 161±9.15 163±13.7 164±15.9 168±8.78 Difference 20 22 25 24 23 18
Compound 4 184±14.7 182±11.6 178±10.8 177±10.9 180±15.80 184±16.0 186±17.7 Difference 3 7 8 5 1 -1
Compound 1 192±7.98 176±9.55 172±7.36 169±4.07 173±7.15 175±5.61 180±6.66 Difference 16 20 23 19 17 11
Compound 12 187±11.9 184±10.6 182±10.4 183±9.90 178±6.61 182±7.25 184±12.1 Difference 3 5 4 9 5 3
Compound 13 190±13.2 186±12.4 178±12.0 171±13.1 176±11.4 180±11.9 176±10.1 Difference 3 12 19 14 10 14

TABLE 3. Dynamic changes in heart rate SHR after administration and the difference before and after administration (beats/min) N = 8 Group Time after administration (h) 0 1 2 3 4 5 6
Metoprolol hydrochloride 328±24.5 283±24.4 283±23.1 279±22.3 280±23.0 285±24.0 288±28.5 Difference -44 -45 -49 -48 -43 -40
Compound 4 345±42.2 347±42.6 349±49.7 349±48.3 345±45.1 338±39.7 341±46.9 Difference 2 4 4 0 -6 -4
Compound 1 356±46.4 348±39.3 380±34.1 385±31.5 385±30.4 372±28.5 373±31.3 Difference -9 23 28 28 16 17
Compound 12 333±44.0 328±47.6 342±46.9 348±53.2 336±54.5 331±51.0 336±52.7 Difference -5 8 15 3 -3 3
Compound 13 319±21.0 325±24.2 332±38.9 335±43.8 334±45.8 329±39.5 320±43.1 Difference 6 14 17 15 10 2

TABLE 4. Dynamic changes in arterial pressure SHR after administration and the difference before and after administration (SBP, mmHg) n = 8 Group Time after administration (h) 0 1 2 3 4 5 6 Compound 2 185±7.25 169±6.39 167±4.50 166±9.15 166±13.7 165±15.3 170±8.77 Difference 16 18 19 19 20 15 Compound 3 188±14.5 180±11.6 178±10.9 177±13.9 180±15.80 186±16.0 186±17.7 Difference 18 10 11 8 2 2 Compound 7 193±7.90 177±9.56 172±7.36 171±4.07 173±6.18 175±5.63 180±7.61 Difference 16 21 22 20 18 13 Compound 6 189±11.2 184±10.9 180±12.4 180±7.80 183±6.56 182±8.29 188±13.2 Difference 5 9 9 6 7 1 Compound 8 194±13.5 188±12.4 181±12.7 176±11.1 176±10.3 180±11.3 186±10.4 Difference 0 6 13 18 18 14 8 Compound 5 189±8.42 169±6.32 174±4.56 171±9.34 173±13.66 174±15.9 178±8.48 Difference 20 15 18 16 15 11 Compound 9 194±11.4 192±11.6 188±12.1 177±12.3 180±12.85 184±16.0 186±17.8 Difference 2 6 17 14 10 8 Compound 10 192±7.98 186±9.54 182±7.36 179±4.07 183±7.65 185±5.64 190±6.54 Difference 6 10 13 9 7 2 Compound 11 189±8.9 184±10.8 182±10.4 183±9.90 178±6.21 182±7.45 184±9.5 Difference 5 7 6 11 7 5 Connection 1-1 190±13.2 176±12.4 168±12.0 161±13.1 166±11.4 170±11.9 186±10.1 Difference 0 14 22 29 24 20 14 Connection 1-2 186±7.24 176±6.39 164±4.50 161±9.15 163±13.7 174±15.9 178±8.78 Difference 10 22 25 23 12 8 Compound 1-3 186±7.24 168±6.39 165±4.50 163±9.15 163±13.7 164±15.9 168±8.78 Difference 18 21 23 23 22 18 Compound 14 184±14.7 182±11.6 178±10.8 177±10.9 18±15.80 184±16.0 186±17.7 Difference 3 7 8 5 1 -1 Compound 15 190±7.98 176±9.55 172±7.36 169±4.07 173±7.15 175±5.61 180±6.66 Difference 14 18 21 17 15 10 Compound 16 183±11.9 174±10.6 172±10.4 173±9.90 168±6.61 172±7.25 174±12.1 Difference 9 11 10 15 11 9 Compound 17 195±13.2 186±12.4 188±12.0 181±13.1 186±11.4 180±11.9 186±10.1 Difference 0 9 7 14 9 15 9 Compound 18 192±7.24 176±6.39 174±4.50 171±9.15 173±13.7 174±15.9 178±8.78 Difference 16 18 21 19 18 14 Compound 19 194±14.7 182±11.6 178±10.8 177±10.9 181±15.80 184±16.0 186±17.7 Difference 12 16 17 13 10 8 Connection 20 192±7.98 186±9.55 182±7.36 189±4.07 183±7.15 185±5.61 190±6.66 Difference 6 10 3 9 7 2 Compound 21 195±11.9 184±10.6 182±10.4 183±9.90 178±6.61 182±7.25 184±12.1 Difference 11 13 12 17 13 11 Compound 22 198±8.20 187±6.39 184±4.69 171±12.14 173±13.7 174±15.9 178±8.78 Difference 11 14 26 25 24 20 Compound 23 196±6.28 186±6.39 187±4.66 181±9.15 183±13.7 178±15.9 178±8.78 Difference 10 9 15 13 18 18
Connection 30 193±4.39 189±7.54 188±3.69 185±10.11 183±9.66 188±14.9 188±8.64 Difference 4 5 8 20 5 5 Compound 25 199±7.09 191±6.64 189±7.77 186±8.18 184±4.56 187±14.2 188±5.55 Difference 8 10 11 15 12 11

Example 14 Pulmonary hypertension test

In this example, the therapeutic effect of compounds according to the present invention in a mouse model of PAH is investigated. During the experiment, SD rats were exposed to hypobaric hypoxia and given a subcutaneous injection of monocrotaline to create an animal model of PAH. The administration was continued during the creation of the mouse model of PAH. After completion of the model, the rats' right ventricular pressure was measured, and the heart and lungs were preserved and used to calculate the right ventricular hypertrophy index and observe morphological changes in the pulmonary blood vessels. A single administration was then performed in rats with a spontaneously hypertensive model of SHR, and changes in blood pressure were monitored for 8 hours after administration.

A compound of the present invention was dissolved in saline as the test drug. The routes of administration used in the experiment included gavage and inhalation. The positive drugs used in the experiment were selected based on the various animal models and experimental requirements. Rats' body weights were determined every 3 days, and their growth was monitored.

1. Therapeutic effect of oral compound 1 on animals with hypoxic pulmonary hypertension

1) The purpose of the experiment

An animal model of pulmonary hypertension in SD rats was established under hypoxic and low pressure conditions, and compound 1 was simultaneously administered via gavage for treatment. The pulmonary artery hemodynamics and right heart hypertrophy index (RVHI) of rats were measured to determine whether compound 1 has an ameliorating effect on hypoxic pulmonary hypertension.

2) Experimental animal and experimental method

Male SD rats (purchased from Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.) weighing 180–200 g were raised in a controlled-breeding facility with a 12-hour light/dark cycle at 20–25°C and 50–60% relative humidity. They were provided with ad libitum access to food and water. Rats were randomly divided into groups according to experimental requirements and housed individually in cages with 3–4 rats per cage. All relevant animal experimental procedures complied with the provisions of the Guide for the Care and Use of Laboratory Animals of China.

A hypoxic PAH model was created by placing male SD rats in a fully automatically controlled low-pressure hypoxic chamber (atmospheric pressure approximately 50 kPa, oxygen concentration 10%) for 8 hours per day for 28 days. Rats in the empty control group were maintained in an environment with normal oxygen levels.

The experimental rats of hypoxic PAH model were divided into 8 groups, namely: blank control group, model group, Sidenafil (25 mg/kg) group, compound 1 (10 mg/kg) group, compound 1 (25 mg/kg) group, compound 1 (50 mg/kg) group, compound 1 (100 mg/kg) group, and compound 1 (200 mg/kg) group. The concentration in parentheses in the group name represents the administered concentration of the compound or drug. In hypoxia-induced PAH experiments, Sidenafil is often used as a positive drug, which can reduce pulmonary artery pressure in rats and reduce right ventricular hypertrophy and vascular remodeling. In this experiment, 25 mg/kg Sidenafil was used as a positive drug. Both active ingredients, Sidenafil and Compound 1, were dissolved in saline and prepared as solutions of varying concentrations for administration. Rats were administered continuously for 28 days at a dose of 5 ml/kg. Rats in the control and model groups were administered the corresponding volume of saline via gavage. The specific group distribution is shown in Table 5.

After completion of the injection, the POWERLAB biological data acquisition and processing system was started, and a right heart catheter filled with 0.2% sodium heparin (Beijing Solo Technology Co. Ltd.) in saline was connected to a pressure sensor and then zero-calibrated for use. After 20% urethane solution (Shanghai Yuanye Biotechnology Co., Ltd.) was injected into the rats' abdomen for anesthesia, the hair on the right side of the neck was shaved, and the right jugular vein was isolated and exposed. The right heart catheter was inserted into the rat's right jugular vein, penetrated the right atrium through the superior vena cava, and reached the right ventricle through the atrioventricular valve. After a typical right ventricular signal appeared and stabilized for a while, the signal was recorded and the pressure value was then read by the Powerlab biological data acquisition and processing system (ADInstruments).

After measuring the pressure, the catheter was removed, and the rat was immediately dissected to collect the heart and lung tissues. The right ventricle (RV) and left ventricle and interventricular septum (LV+S) were separated and weighed, and the right heart hypertrophy index (RVHI =RV/(LV+S)) was calculated. The lung lobe tissue from the right lower lung was separated, soaked in 4% paraformaldehyde (Sigma) for about 1 week to obtain a 3-μm-thick paraffin section, and then stained with hematoxylin and eosin (Wuhan Guge Biotechnology Co., Ltd.). After completing the HE staining of the paraffin sections of the lung tissues of rats in each group, these sections were observed under an inverted microscope (Nikon TS100), and 5 pulmonary arteries were taken from each section and fixed in a 200× field of view. To analyze small pulmonary arteries with a diameter of 100-300 μm, Image-pro plus 6.0 software was used, and the percentage of wall thickness to the outer diameter of the blood vessel (WT%) and the percentage of wall area to the total area of the blood vessel (WA%) were calculated.

TABLE 5. Distribution of rats with hypoxic pulmonary hypertension model by groups

Group number Distribution into groups Number of rats Route of administration Number of doses 1 Control group 6 Introduction through a gastric tube once a day 2 Model group 6 Introduction through a gastric tube once a day 3 Sidenafil group (25 mg/kg) 6 Introduction through a gastric tube once a day 4 Compound group 1 (10 mg/kg) 6 Introduction through a gastric tube once a day 5 Compound group 1 (25 mg/kg) 6 Introduction through a gastric tube once a day 6 Compound group 1 (50 mg/kg) 6 Introduction through a gastric tube once a day 7 Compound group 1 (100 mg/kg) 6 Introduction through a gastric tube once a day 8 Compound group 1 (200 mg/kg) 6 Introduction through a gastric tube once a day

3) Experiment results

The results of the experiment are shown in Fig. 1 and 2, where:

(1) From Figure 1A and Figure 1B, it can be seen that in the PAH model resulting from indirect hypobaric hypoxia, there was a significant difference between normal rats (the mean right ventricular systolic pressure (RVSP) was 29.76±2.48 mmHg and the mean right ventricular pressure (mRVP) was 8.16±1.45 mmHg) and model rats (the mean RVSP was 75.46±2.57 mmHg and the mean mRVP was 26.12±2.37 mmHg), and P < 0.001, indicating that the PAH model was successfully established in this experiment. When different doses of compound 1 were orally administered to treat hypoxia-induced rats for 28 days, it was found that when the doses of compound 1 were 10 mg/kg, 25 mg/kg and 50 mg/kg, there was no significant decrease in the pulmonary vascular pressure of the rats compared with the model group. However, when the doses of compound 1 were 100 mg/kg and 200 mg/kg, the RVSP and mRVP of the rats were significantly lower than those of the untreated model group (compound 1 100 mg/kg: P < 0.01, P <0.05; compound 1 200 mg/kg: P < 0.001, P < 0.01). In this experiment, a positive control group of sildenafil was also established (compared with the model group in the case of RVSP: P < 0.001, mRVP: P < 0.01). It is suggested that when the doses of AH001 were 100 mg/kg and 200 mg/kg, and after intragastric administration for 28 days of treatment, the increase in pulmonary artery pressure in rats with hypoxia-induced pulmonary hypertension could be improved.

(2) It can be seen from Figure 1C that in the hypoxic PAH model, the RV/(LV+S) value of the model rats was significantly higher than that of normal rats (P < 0.001), indicating that chronic low pressure and hypoxia can lead to the remodeling and thickening of the right heart in SD rats. After different dosages of compound 1 were orally administered to treat hypoxia-induced rats for 28 days, it was found that when the dosages of compound 1 were 10 mg/kg, 25 mg/kg and 50 mg/kg, there was no significant decrease in RVHI in the rats compared with the model group. However, when the dosages of compound 1 were 100 mg/kg and 200 mg/kg, the right heart hypertrophy of the rats was significantly improved compared with the model group ( P < 0.01, P < 0.001). The positive effect of sildenafil on right ventricular remodeling was demonstrated, as well as its ability to effectively reduce RV/(LV+S) (P < 0.001). It is suggested that, when the doses of compound 1 were 100 mg/kg and 200 mg/kg, and after intragastric administration for 28 days, the increase in pulmonary artery pressure in rats with hypoxia-induced pulmonary hypertension could be improved.

(3) It can be seen from Figure 1D and Figure 2 that long-term hypoxia resulted in significant thickening of small pulmonary arterioles in the model group, and the relative media thickness (2 × media thickness (MT)/outer diameter (ED)) of small pulmonary arteries was significantly increased ( P < 0.001 compared with the control). Compared with the model group, when the dose of compound 1 was 10 mg/kg, 25 mg/kg and 50 mg/kg, the pulmonary vascular remodeling in rats was not reduced. However, when the doses of compound 1 were 100 mg/kg and 200 mg/kg, the relative media thickness of rats was significantly improved compared with the model group ( P < 0.05, P < 0.001). It is suggested that when the doses of compound 1 were 100 mg/kg and 200 mg/kg, and after intragastric administration for treatment for 28 days, hypoxia-induced small artery hypertrophy in the lung tissue of rats with pulmonary hypertension could be reduced.

2. Therapeutic effect of oral administration of the compound according to the present invention on animals with pulmonary hypertension induced by monocrotaline

1) The purpose of the experiment

Monocrotaline (MCT) was administered by subcutaneous injection to create an animal model of pulmonary hypertension in SD rats. Compound 1 was simultaneously administered via gavage for treatment. Pulmonary artery hemodynamics and the right heart hypertrophy index (RVHI) were measured in rats to determine whether oral administration of Compound 1 ameliorated monocrotaline-induced pulmonary hypertension.

2) Experimental animals and experimental methods

Male SD rats (purchased from Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.) weighing 180–200 g were raised in a controlled-breeding facility with a 12-hour light/dark cycle at 20–25°C and 50–60% relative humidity. They were provided with ad libitum access to food and water. Rats were randomly divided into groups according to experimental requirements and housed individually in cages with 3–4 rats per cage. All relevant animal experimental procedures complied with the provisions of the Guide for the Care and Use of Laboratory Animals of China.

During the experiment, SD rats were randomly divided into 4 groups: blank control group, pulmonary hypertension model group, Selexipag (1 mg/kg) treatment group, and Compound 1 (100 mg/kg) group, 6 rats in each group, and the concentration in parentheses represents the administered concentration of the compound, wherein Selexipag is a new long-acting oral prostacyclin receptor agonist discovered and synthesized by Japan New Drug Co., Ltd. On the first day of the experiment, saline was administered by subcutaneous injection into the scruff of the neck of the rats in the blank control group, and the rats in the other groups were administered monocrotaline solution (Chengdu Purifa Biotechnology Co., Ltd.) at a dosage of 60 mg/kg by injection. Both positive drugs, Selexipag and Compound 1, were administered through a gastric tube. Selexipag and compound 102 were dissolved in 0.5% sodium carboxymethylcellulose (SMC-Na) solution. Rats were administered 5 mg/kg continuously for 21 days. Rats in the control and model groups were administered the corresponding volume of SMC-Na solution via gavage. The specific group distribution is shown in Table 7.

After administration, pulmonary vascular hemodynamics and RVHI were determined according to the same experimental method as in Example 1.

TABLE 7. Distribution of rats with monocrotaline-induced pulmonary hypertension model (oral administration of the drug) by groups Group number Distribution into groups Number of rats Route of administration Number of injections 1 Control group 6 introduction through a gastric tube once a day 2 Model group 6 introduction through a gastric tube once a day 3 Selexipag group (1 mg/kg) 6 introduction through a gastric tube Twice a day 4 Compound group 1 (100 mg/kg) 6 introduction through a gastric tube once a day

3) Experiment results

(1) It can be seen from Figure 3A and Figure 3B that RVSP and mRVP of the blank control group were 32.43±2.78 mmHg and 7.56±2.52 mmHg, respectively. After pulmonary hypertension was induced by monocrotaline, RVSP and mPAP of rats increased ( P < 0.001, P < 0.05). After treatment with compound 1 (100 mg/kg, p.o.), the pulmonary vascular pressure of rats was higher than that of the blank control group, but RVSP and mRVP were significantly lower than that of the untreated model group ( P < 0.001, P < 0.05). In this experiment, a positive drug selexipag control group was also established (compared with the model group, RVSP: P < 0.001, mRVP: P < 0.05). It was suggested that when the dose of compound 1 was 100 mg/kg and after intragastric administration for treatment for 21 days, the increase in pulmonary artery pressure in rats with monocrotaline-induced pulmonary hypertension could be improved.

(2) It can be seen from Figure 3C that the RVHI indices of the blank control group and the model group were 0.20±0.021 and 0.46±0.045, respectively, and the right heart hypertrophy index of the model group was significantly increased ( P < 0.001). After treatment with compound 1 (100 mg/kg, p.o.), the RVHI in rats was 0.31±0.059, which was significantly lower than that of the untreated model group ( P < 0.05). Meanwhile, the right heart hypertrophy index of the positive control drug selexipag treatment group was 0.27±0.026, which was significantly lower than that of the model group ( P < 0.05). It is suggested that when the dose of compound 1 is 100 mg/kg and after intragastric administration for treatment for 21 days, right heart hypertrophy caused by pulmonary hypertension can be reduced.

(3) It can be seen from Figure 3D and Figure 4 that in the rats with monocrotaline-induced pulmonary hypertension model, arterioles were significantly thickened and the relative media thickness (2× MT/ED) of pulmonary arterioles was significantly increased ( P < 0.01). Compared with the model group, the pathological changes of arteriolar hypertrophy in the lung tissue of rats in the compound 1 (100 mg/kg, p.o.) group were significantly reduced ( P < 0.01). In the said experiment, a positive drug control group of selexipag was also established. After exposure to selexipag for 21 days, pulmonary arteriolar hypertrophy was significantly reduced (P < 0.05 compared with the model group). It is suggested that when the dose of compound 1 is 100 mg/kg and after intragastric administration for treatment for 21 days, arterial hypertrophy in the lung tissue of rats with monocrotaline-induced pulmonary hypertension can be reduced.

TABLE 8. Experimental results for orally administered Compound 1 and a number of compounds for the treatment of rats with MKT-LAH Distribution of experimental animals into groups RVSP / mmHg mPAP/mmHg RVHI 2 × MT/ED Control group 32.43±2.78 7.56±2.52 0.20±0.021 0.26±0.059 Model group 50.06±5.28 19.87±3.35 0.46±0.045 0.39±0.024 selexipag group (1 mg/kg, p/o) 35.67±2.89 8.78±1.98 0.27±0.026 0.30±0.086
Compound group 1 (100 mg/kg, p/o) 39.72±3.46 9.21±2.69 0.31±0.059 0.27±0.062
Compound 7 (100 mg/kg, p/o) 42.31±2.78 15.67±2.70 0.33±0.058 0.27±0.045
Compound 8 (100 mg/kg, p/o) 45.97±3.49 16.47±3.07 0.33±0.037 0.31±0.052
Compound 5 (100 mg/kg, p/o) 44.32±2.12 15.76±2.71 0.35±0.048 0.29±0.054
Compound 16 (100 mg/kg, p/o) 48.89±6.64 16.74 ± 3.08 0.320± 0.031 0.32 ±0.066 Compound 30 (100 mg/kg, p/o) 44.38±2.89 16.21 ± 1.29 0.245 ± 0.032 0.31 ± 0.021

3. Therapeutic effect of compound 1 administered by nebulization in animals with monocrotaline-induced pulmonary hypertension

1) The purpose of the experiment

An animal model of pulmonary hypertension in SD rats was created using subcutaneous injection of monocrotaline (MCT). For treatment, compound 1 was administered via aerosol inhalation. Pulmonary artery hemodynamics and the right heart hypertrophy index (RVHI) were studied to determine whether compound 1 administered via aerosol inhalation ameliorated monocrotaline-induced pulmonary hypertension.

2) Experimental animal and experimental method

Male SD rats (purchased from Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.) weighing 180–200 g were raised in a controlled-breeding facility with a 12-hour light/dark cycle at 20–25°C and 50–60% relative humidity. They were provided with ad libitum access to food and water. Rats were randomly divided into groups according to experimental requirements and housed individually in cages with 3–4 rats per cage. All relevant animal experimental procedures complied with the provisions of the Guide for the Care and Use of Laboratory Animals of China.

In the second experiment, the rats were divided into 5 groups, namely, the control group, the model group, the Tivazo positive control group (1.62 μg/kg), the compound 1 group (10 mg/kg), and the compound 1 group (30 mg/kg). On the first day of the experiment, saline was administered by subcutaneous injection into the scruff of the neck of the rats in the blank control group, while the other groups were administered a monocrotaline solution (Chengdu Purifa Biotechnology Co., Ltd.) by injection at a dosage of 60 mg/kg. Compound 1 and Tivazo were administered by aerosol inhalation, that is, the compound was first dissolved in saline, and then the solution was prepared as an aerosol using a nebulizer to penetrate the mouth and nose of the rats by inhalation. The rats in the control group and the model group inhaled only the aerosol prepared from saline. Rats were administered the compound continuously for 28 days, and the concentration in parentheses in the group name represents the administered compound concentration. The specific group distribution is shown in Table 9. After administration, pulmonary vascular hemodynamics and RVHI were determined in the same way as for the experimental method in Example 1.

TABLE 9. Distribution of rat models of pulmonary hypertension induced by monocrotaline (aerosol inhalation of the drug) by groups Group number Distribution into groups Number of rats Route of administration Number of injections 1 Control group 6 Aerosol inhalation once a day 2 Model group 6 Aerosol inhalation once a day 4 Tivazo group (1.62 mcg/kg) 6 Aerosol inhalation Four times a day 5 Compound group 1 (10 mg/kg) 6 Aerosol inhalation once a day 6 Compound group 1 (30 mg/kg) 6 Aerosol inhalation once a day

3) Experiment results

(1) From Figure 5A and Figure 5B, it can be seen that the RVSP and mRVP of the blank control group were 29.78±2.12 mmHg and 6.78±1.15 mmHg, respectively. After pulmonary hypertension was induced by monocrotaline, the RVSP and mPAP of rats increased (P < 0.01, P < 0.001). After compound 1 (10 mg/kg and 30 mg/kg) was administered by aerosol inhalation for treatment, the pulmonary vascular pressure of rats was higher than that of the blank control group, but RVSP was significantly lower than that of the untreated model group ( P < 0.05, P < 0.01). While after compound 1 was administered by aerosol inhalation for treatment, mRVP also showed the same trend. In this experiment, a control group of the positive drug Tivazo was also established (compared to the model group RVSP: P < 0.05, mRVP: P < 0.05). It was suggested that the increase in pulmonary artery pressure in rats with monocrotaline-induced pulmonary hypertension could be improved by administering compound 1 by aerosol inhalation at doses of 10 mg/kg and 30 mg/kg.

(2) It can be seen from Figure 5C that the RVHI of the rats in the blank control group and the model group was 0.182±0.028 mmHg and 0.396±0.056 mmHg, respectively. The right heart hypertrophy index in the model group was significantly increased ( P < 0.01). After administration of compound 1 (10 mg/kg and 30 mg/kg) by aerosol inhalation for treatment, the RVHI indices of the two groups of rats decreased to 0.235±0.026 and 0.204±0.035, respectively, which were significantly lower than that of the untreated model group ( P < 0.05, P < 0.01). At the same time, the right ventricular hypertrophy index in the positive control drug Tivazo treatment group was 0.197±0.031, which was significantly lower than that of the model group ( P < 0.01). It was suggested that when compound 1 was administered by aerosol inhalation at doses of 10 mg/kg and 30 mg/kg, right heart hypertrophy caused by pulmonary hypertension could be reduced.

(3) It can be seen from Figure 5D and Figure 6 that after establishing the model using monocrotaline, the small arteries of the rats in the pulmonary hypertension model group were significantly thickened, and the relative media thickness of the small pulmonary arteries (2 × MT/ED) was significantly increased ( P < 0.01). Compared with the model group, after administering compound 1 (10 mg/kg and 30 mg/kg) by aerosol inhalation for treatment, the pathological changes of pulmonary arteriolar hypertrophy in the lung tissues of rats were significantly reduced ( P < 0.05, P < 0.01). In the said experiment, a positive drug control group, Tivazo, was also established. After administering Tivazo by inhalation for 21 days, the pulmonary arteriolar hypertrophy was significantly reduced ( P < 0.001 compared with the model group). It was suggested that small artery hypertrophy in the lung tissue of rats with monocrotaline-induced pulmonary hypertension was reduced by administration of compound 1 by aerosol inhalation at doses of 10 mg/kg and 30 mg/kg.

TABLE 10. Experimental results for compound 1 and a number of compounds administered by aerosol inhalation for the treatment of rats with MKT-LAH

Distribution of experimental animals into groups RVSP / mmHg mPAP/mmHg RVHI 2 × MT/ED Control group 29.78±2.12 6.78 ± 1.15 0.182 ± 0.028 0.275±0.017 Model group 55.23±6.94 20.88 ± 2.68 0.396 ± 0.056 0.485±0.025 Tivazo Group
(1.62 mcg/kg, ing.) 34.61±3.69 10.54 ± 2.14 0.197 ± 0.031 0.275±0.042
Compound 1 (10 mg/kg, ing.) 35.92±3.74 11.46 ± 2.48 0.235 ± 0.026 0.335±0.034 Compound 1
(30 mg/kg, ing.) 31.18±4.62 8.06 ± 2.59 0.204 ± 0.035 0.319±0.035
Compound 7
(30 mg/kg, ing.) 44.61±2.96 12.45 ± 2.41 0.267 ± 0.013 0.375±0.024
Compound 8
(30 mg/kg, ing.) 45.92 ± 3.47 14.16 ± 3.84 0.306 ± 0.027 0.353 ± 0.043
Compound 5
(30 mg/kg, ing.) 40.18±4.62 11.06 ± 2.95 0.324 ± 0.053 0.390 ± 0.038
Compound 16
(30 mg/kg, ing.) 41.44±2.03 14.76 ± 1.98 0.290 ± 0.054 0.357 ±0.032
Compound 30 (30 mg/kg, ing.) 46.04±3.27 16.00 ± 3.44 0.273 ± 0.043 0.402 ± 0.034

All documents referenced in this application are incorporated herein by reference as if each document were individually incorporated by reference. It should also be understood that those skilled in the art may make various changes or modifications after reading the above concept of the present invention, which are also within the scope defined by the appended claims.

Claims (14)

1. The use of a compound of formula I or a pharmaceutically acceptable salt thereof for the prevention or treatment of arterial hypertension or pulmonary hypertension, where X is absent; n is an integer 0-5; each of R ₁ and R ₃ is independently selected from H, C1-C2 alkylformyl, unsubstituted or substituted by O or NH ₂ ; each R ₂ is independently selected from H, carbonyl, unsubstituted C1-C10 alkyl; R ₄ is selected from H, unsubstituted C1-C10 alkyl, unsubstituted unsaturated C2 alkyl, hydroxyl, unsubstituted C1 alkoxy, halogen, unsubstituted C1 alkylformyl; R ₁₁ is selected from H. 2. The use according to paragraph 1, where n is 1. 3. Use of the following compounds or their salts for the prevention or treatment of arterial hypertension or pulmonary hypertension: 4. The use according to claim 3, wherein said compound is