WO2020249117A1 - 抗高血压的多元醇化合物及其衍生物 - Google Patents

抗高血压的多元醇化合物及其衍生物 Download PDF

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WO2020249117A1
WO2020249117A1 PCT/CN2020/095974 CN2020095974W WO2020249117A1 WO 2020249117 A1 WO2020249117 A1 WO 2020249117A1 CN 2020095974 W CN2020095974 W CN 2020095974W WO 2020249117 A1 WO2020249117 A1 WO 2020249117A1
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French (fr)
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李洪林
赵振江
王蕊
沈寅初
付建军
徐玉芳
钱旭红
焦茜
李诗良
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East China University of Science and Technology
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East China University of Science and Technology
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Priority to AU2020289909A priority Critical patent/AU2020289909B2/en
Priority to BR112021014881A priority patent/BR112021014881A2/pt
Priority to US17/424,105 priority patent/US12180146B2/en
Priority to CA3130821A priority patent/CA3130821A1/en
Priority to EP20822935.1A priority patent/EP3906969A4/en
Publication of WO2020249117A1 publication Critical patent/WO2020249117A1/zh
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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Definitions

  • the present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a class of antihypertensive polyol compounds, their derivatives and their applications in the preparation of antihypertensive drugs.
  • Hypertension is the most common cardiovascular disease in the world. Although some hypertensive patients are genetically susceptible, environmental factors are not to be ignored. With the improvement of people's quality of life and changes in eating habits, the incidence of diseases such as hyperlipidemia and atherosclerosis has been increasing, and the incidence of hypertension has gradually increased. Hypertension is the fuse of many diseases, which will increase the risk of coronary heart disease, heart failure and kidney diseases. Therefore, reaching the standard for lowering blood pressure is the key to the treatment of hypertension. The purpose of the treatment of hypertension is to control blood pressure, reduce target organ damage and the incidence and mortality of cardiovascular and cerebrovascular diseases, improve long-term prognosis, and improve the quality of life. To achieve this goal, in addition to improving the lifestyle, medication is also needed.
  • the commonly used clinical antihypertensive drugs can basically be classified into the following categories: namely diuretic antihypertensive drugs, ⁇ -receptor blockers, calcium antagonists (CCB), angiotensin converting enzyme inhibitors (ACEI), Angiotensin II receptor blocker (ARB), alpha receptor blocker.
  • diuretic antihypertensive drugs ⁇ -receptor blockers, calcium antagonists (CCB), angiotensin converting enzyme inhibitors (ACEI), Angiotensin II receptor blocker (ARB), alpha receptor blocker.
  • ACEI angiotensin converting enzyme inhibitors
  • ARB Angiotensin II receptor blocker
  • Pulmonary Arterial Hypertension is another disease that seriously endangers human life.
  • the diagnostic criteria is the mean pulmonary artery pressure (mPAP) ⁇ 25mmHg measured by the right heart catheterization method in the resting state.
  • mPAP mean pulmonary artery pressure
  • the pathogenesis of PAH is caused by many factors, including dysfunction of pulmonary artery endothelial cells (PAEC), abnormal proliferation and remodeling of pulmonary artery endothelial cells and pulmonary artery smooth muscle cells (PASMC), and the formation of in situ thrombus.
  • PAH has a high mortality rate and poor prognosis, with an average survival time of only 2.8 years. It has become a major type of cardiovascular disease that has gradually received attention in Western countries.
  • PAH therapeutic drugs mainly include endothelin receptor antagonists, bosentan, sitaxsentan, ambrisentan, etc., and 5-phosphodiesterase (PDE-5) inhibitors Denafil, tadanafil, vardenafil, etc. and prostacyclin analogues epoprostol, iloprost, treprostinil, etc.
  • PDE-5 inhibitors Denafil, tadanafil, vardenafil, etc.
  • prostacyclin analogues epoprostol, iloprost, treprostinil, etc.
  • the purpose of the present invention is to provide new compounds that can be used as drugs for hypertension, pulmonary hypertension and related diseases.
  • the present invention provides compounds of formula I, or pharmaceutically acceptable salts or esters, prodrugs, optical isomers, stereoisomers or solvates thereof for preparing the prevention or treatment of hypertension or hypertension.
  • X is an absent or substituted or unsubstituted C1-C3 linear or branched alkyl group
  • n is an integer of 0-5, preferably an integer of 1-5;
  • R 1 and R 3 are each 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, wherein m is an integer of 0-5, preferably 0-3, most preferably 1-2; or R 1 and R 3 can be Form a five-membered ring Wherein R 6 is a substituted or unsubstituted C
  • R 2 and R 11 are each 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 C1-C10 linear or branched alkyl, substituted or unsubstituted C1-C10 unsaturated linear or branched alkyl, hydroxyl, substituted or unsubstituted C1 -C10 alkoxy, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted C1-C5 alkyl formyl, substituted or unsubstituted benzoyl, nitro, COOH , Substituted or unsubstituted C1-C5 alkoxyformyl, amino, substituted or unsubstituted C1-C5 alkylamino, substituted or unsubstituted C1-C5 alkylformylamino, substituted or unsubstituted benzoyl Amino, substituted or unsubstituted benzo aromatic
  • the phosphate group is such as As shown, wherein R 5 is selected from substituted or unsubstituted C1-C10 alkyl.
  • the substituted or unsubstituted aminoacetyl group is such as As shown, where R is various amino acid substituents.
  • the compound is represented by formula II,
  • 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 A substituted aminoacetyl group, 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 A substituted aminoacetyl group, or a substituted or unsubstituted monosaccharide, disaccharide or polysaccharide group;
  • R 10 is selected from H, substituted or unsubstituted C1-C10 linear or branched alkyl, substituted or unsubstituted C1-C10 unsaturated linear or branched alkyl, F, Cl, Br, hydroxyl, C1- C3 linear or branched alkoxy, substituted or unsubstituted C1-C5 alkyl formyl, substituted or unsubstituted benzoyl, or substituted or unsubstituted benzo aromatic ring or five-membered heteroatom-containing, Six-membered heterocycle; n is selected from any integer from 0-3.
  • the present invention provides the following compounds, or salts or esters, prodrugs, optical isomers or solvates thereof for the preparation of prevention or treatment of hypertension or hypertension-related diseases or pulmonary hypertension or pulmonary hypertension-related diseases
  • drugs include:
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the hypertension-related diseases include, but are not limited to: stroke (cerebral hemorrhage and cerebral ischemia), hypertensive heart disease, hypertensive nephropathy, hypertensive fundus disease and retinopathy, hypertension Blood pressure lower limb ischemia, etc.;
  • the pulmonary hypertension-related diseases include but are not limited to: idiopathic pulmonary hypertension, cor pulmonale, high altitude heart disease, cardiovascular disease, pulmonary obstruction, fibrotic disorders, and urinary system disorders.
  • the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof,
  • X is an absent or substituted or unsubstituted C1-C3 linear or branched alkyl group
  • n is an integer of 0-5, preferably an integer of 1-5;
  • R 1 and R 3 are each independently 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 alkyl formyl, substituted or unsubstituted benzoyl, substituted or unsubstituted ester, substituted or unsubstituted Substituted or unsubstituted A substituted or unsubstituted aminoacetyl group, a substituted or unsubstituted monosaccharide, disaccharide or polysaccharide group, or a substituted or unsubstituted phosphate group, where m is 0-5, preferably 0-3, most preferably 1-2 Integer; or R 1 and R 3 can form a five-membered ring Wherein R 6
  • R 2 and R 11 are each 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 C1-C10 linear or branched alkyl, substituted or unsubstituted C1-C10 unsaturated linear or branched alkyl, hydroxyl, substituted or unsubstituted C1 -C10 alkoxy, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted C1-C5 alkyl formyl, substituted or unsubstituted benzoyl, nitro, COOH , Substituted or unsubstituted C1-C5 alkoxyformyl, amino, substituted or unsubstituted C1-C5 alkylamino, substituted or unsubstituted C1-C5 alkylformylamino, substituted or unsubstituted benzoyl Amino, substituted or unsubstituted benzo aromatic
  • the phosphate group is such as As shown, wherein R 5 is selected from substituted or unsubstituted C1-C10 alkyl.
  • the substituted or unsubstituted aminoacetyl group is such as As shown, where R is various amino acid substituents.
  • the compound is used to prepare a medicine for preventing or treating hypertension or pulmonary hypertension.
  • the compound is represented by formula II,
  • 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 A substituted aminoacetyl group, 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 A substituted aminoacetyl group, or a substituted or unsubstituted monosaccharide, disaccharide or polysaccharide group;
  • R 10 is selected from H, substituted or unsubstituted C1-C10 linear or branched alkyl, substituted or unsubstituted C1-C10 unsaturated linear or branched alkyl, F, Cl, Br, hydroxyl, C1- C3 linear or branched alkoxy, substituted or unsubstituted C1-C5 alkyl formyl, substituted or unsubstituted benzoyl, or substituted or unsubstituted benzo aromatic ring or five-membered heteroatom-containing, Six-membered heterocycle; n is selected from any integer from 0-3.
  • the compound is a compound selected from the following, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof:
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the compound is used for the preparation of drugs for the prevention or treatment of hypertension or hypertension-related diseases or pulmonary hypertension or pulmonary hypertension-related diseases, or for the prevention or treatment of hypertension or hypertension-related diseases or pulmonary hypertension Or pulmonary hypertension related diseases.
  • the hypertension-related diseases include but are not limited to: stroke (cerebral hemorrhage and cerebral ischemia), hypertensive heart disease, hypertensive nephropathy, hypertensive fundus disease and retinopathy, hypertension Blood pressure lower limb ischemia, etc.;
  • the pulmonary hypertension-related diseases include but are not limited to: idiopathic pulmonary hypertension, cor pulmonale, high altitude heart disease, cardiovascular disease, pulmonary obstruction, fibrotic disorders, and urinary system disorders.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the second aspect, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, or stereoisomer thereof.
  • Body or solvate and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is used to prepare drugs for the prevention or treatment of hypertension or hypertension-related diseases or pulmonary hypertension or pulmonary hypertension-related diseases, or for the prevention or treatment of hypertension or hypertension-related diseases or Pulmonary hypertension or pulmonary hypertension-related diseases.
  • the hypertension-related diseases include but are not limited to: stroke (cerebral hemorrhage and cerebral ischemia), hypertensive heart disease, hypertensive nephropathy, hypertensive fundus disease and retinopathy, hypertension Blood pressure lower limb ischemia, etc.;
  • the pulmonary hypertension-related diseases include but are not limited to: idiopathic pulmonary hypertension, cor pulmonale, high altitude heart disease, cardiovascular disease, pulmonary obstruction, fibrotic disorders, and urinary system disorders.
  • the pharmaceutical composition is an administration form of nebulized inhalation.
  • the present invention provides a method for preventing or treating hypertension or hypertension-related diseases or pulmonary hypertension or pulmonary hypertension-related diseases, which comprises adding a therapeutically effective amount of the compound described in the second aspect, or a pharmaceutically acceptable compound thereof.
  • the accepted salt or ester, prodrug, optical isomer, stereoisomer or solvate or the pharmaceutical composition of the third aspect is administered to a subject in need thereof.
  • Figure 1 shows the therapeutic effect of oral compound 1 on an animal model of hypoxic pulmonary hypertension
  • Figure 2 shows the effect of oral administration of Compound 1 on the reduction of arterial hypertrophy in the lung tissue of rats with hypoxia-induced pulmonary hypertension
  • Figure 3 shows the therapeutic effect of oral compound 1 on monocrotaline-induced pulmonary hypertension animal model
  • Figure 4 shows the effect of oral administration of compound 1 on the reduction of arterial hypertrophy in the lung tissue of rats with monocrotaline-induced pulmonary hypertension
  • Figure 5 shows the therapeutic effect of compound 1 sprayed administration on monocrotaline-induced pulmonary hypertension animal model
  • Figure 6 shows the effect of oral administration of compound 1 by atomization on reducing the degree of arterial hypertrophy in the lung tissue of rats with monocrotaline-induced pulmonary hypertension.
  • C 1-n means that the group has 1-n carbon atoms
  • C 1-10 means that the group has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms
  • C6-C10 means that the group has 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl used herein has the same meaning as commonly understood by those of ordinary skill in the art, and refers to various saturated or unsaturated linear, side chain or cyclic hydrocarbon groups.
  • the alkyl group described herein refers to a lower alkyl group of 1-10 carbon atoms; preferably, it refers to a lower alkyl group of 1-8 carbon atoms; more preferably, it refers to a lower alkyl group of 1 to 6 carbon atoms.
  • Lower alkyl refers to a lower alkyl group of 1-10 carbon atoms; preferably, it refers to a lower alkyl group of 1-8 carbon atoms; more preferably, it refers to a lower alkyl group of 1 to 6 carbon atoms.
  • the alkyl groups described herein include but are not limited to: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl , Heptyl and so on.
  • aryl has the same meaning as commonly understood by those of ordinary skill in the art, and refers to a cyclic conjugated aromatic system; for example, the term “C6-C10 aryl” refers to those with 6 Aromatic ring groups with to 10 carbon atoms, such as phenyl, naphthyl, etc.
  • heteroaryl refers to the ring of a cyclic conjugated aromatic system containing one or more heteroatoms such as N, O or S; for example, pyridyl and pyrazinyl.
  • aminoacetyl as used herein has the conventional meaning understood by those of ordinary skill in the art, that is, an amino-substituted acetyl group.
  • the aminoacetyl group is such as As shown, where R is various amino acid substituents.
  • heterocyclic group refers to a saturated or partially unsaturated non-aromatic cyclic group, including monocyclic, fused, spiro or bridged rings, wherein the heterocyclic ring has at least one ring selected from O , S or N heteroatoms as ring members.
  • heterocyclic group refers to a saturated or unsaturated 5- or 6-membered cycloalkyl group containing 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen in the ring, such as dioxane Pentyl etc.
  • halogen refers to F, Cl, Br or I.
  • substituted refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent.
  • the specific substituents may be the substituents correspondingly described in the foregoing, or may be specific substituents appearing in each embodiment. Therefore, in the present invention, the substituents in the general formula (I) or (II) may each independently be the corresponding group in the specific compound in the embodiment; that is, the present invention includes the above general formula (I) or (II)
  • the combination of the substituents in) also includes the combination of the partial substituents shown in the general formula (I) or (II) and other specific substituents appearing in the examples.
  • a substituted group may have a specific substituent at any substitutable position of the group, and the substituent may be the same or different in each position.
  • a cyclic substituent such as a heterocyclic group, may be connected to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, for example, two rings have a common carbon atom.
  • the substituents are for example (but not limited to): C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group , Aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino, C 1-8 alkoxy, nitro , Cyano, mercapto, amino, etc.
  • the hydrogen atoms on the alkyl group and the aryl group are substituted by an amino group, a halogen group or other groups to become groups belonging to the above definitions.
  • the present invention provides a series of novel compounds with therapeutic effects on hypertension and non-arterial hypertension. These compounds have different mechanisms from existing therapeutic drugs.
  • the present invention provides a compound represented by the following formula I or II, or a pharmaceutically acceptable salt or ester, prodrug, optical isomer, stereoisomer or solvate thereof,
  • the compounds of the present invention can prepare pharmaceutically acceptable salts or esters, prodrugs, optical isomers, stereoisomers or solvates thereof.
  • the compound of the present invention can be reacted with an inorganic acid or an organic acid to form a conventional pharmaceutically acceptable salt.
  • the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc.
  • the organic acids include 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 Acid, hexanoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic
  • optical isomers or stereoisomers obtained by resolution of the compounds of the present invention also fall within the protection scope of the present invention.
  • the present invention also provides a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition optionally includes pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmaceutically acceptable salt thereof in a safe and effective amount and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • “Pharmaceutically acceptable excipients or carriers” refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as emulsifiers
  • wetting agents such as sodium lauryl sulfate
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods 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.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectant, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and gly
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, spray and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage when administered is a pharmaceutically effective dosage.
  • the compounds and pharmaceutical compositions of the present invention can be administered via oral, nasal, skin, lung, or gastrointestinal tract. The most preferred is oral administration, one-time administration or divided administration. Regardless of the method of administration, the individual's optimal dose should be determined based on the specific treatment. Usually start with a small dose and gradually increase the dose until the most suitable dose is found.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • the compound of the present invention is preferably in a form suitable for atomized administration.
  • the present invention provides a series of novel compounds with therapeutic effects on hypertension and non-arterial hypertension.
  • the compound of the present invention has a different mechanism from the existing drugs for the treatment of hypertension and non-arterial hypertension, so it is possible to develop new drugs for the treatment of hypertension and non-arterial hypertension.
  • the compounds of the present invention can be prepared according to conventional routes or methods, and can also be obtained according to the methods or routes described herein.
  • Test drug the compound of the present invention. The dose of all compounds was uniformly set at 200 mg/kg.
  • the blood pressure changes before and after the administration are detected, and the antihypertensive effect is judged based on the SBP reduction of ⁇ 20mmHg compared with the base value after the administration is effective; at the same time, the heart rate changes before and after the administration are detected.
  • Heart rate with mean ⁇ standard deviation Indicates that the two-sample equal variance paired t test was used to compare the changes of heart rate before and after medication, and P ⁇ 0.05 was the standard of statistically significant difference.
  • the positive drug metoprolol hydrochloride has the best blood pressure lowering effect.
  • SBP reduces blood pressure by more than 20mmHg at most of the recorded time points, and the lowest value of blood pressure reduction is 3 hours after administration; While lowering blood pressure, it also significantly slows down heart rate. 6 hours after administration, the average heart rate is slowed by 46 beats/min. This feature of both blood pressure reduction and heart rate slowing is in line with the pharmacological effects of ⁇ -blockers.
  • the second compound with antihypertensive effect is 1-(3-ethylphenyl)-1,2-ethylene glycol, before and after administration, 1-(3-ethylphenyl)-1,2-ethylene glycol
  • the duration of blood pressure reduction is similar to that of the positive drug Metoprolol Hydrochloride.
  • the maximum blood pressure reduction effect is also 3 hours after administration, but the blood pressure reduction amplitude is slightly lower than that of the positive drug Metoprolol Hydrochloride; in addition, 1-(3-ethyl
  • the effect of phenyl)-1,2-ethylene glycol on the heart rate is the opposite of that of the positive drug Metoprolol Hydrochloride. It can significantly accelerate the heart rate while lowering blood pressure.
  • the compound of the present invention is dissolved in physiological saline as the tested drug, and the administration methods used in the experiment include gavage and inhalation.
  • the positive drugs in the experiment are selected according to different animal models and experimental requirements.
  • the body weight of the rats was weighed every 3 days to observe the growth of the rats.
  • a hypoxic and low-pressure environment was used to establish an animal model of pulmonary hypertension in SD rats.
  • compound 1 was given by intragastric administration to detect the pulmonary artery hemodynamics and right heart hypertrophy index RVHI to determine whether compound 1 can improve hypoxic pulmonary hypertension. effect.
  • mice (purchased from Shanghai Sipuer-Bikai Experimental Animal Co., Ltd.), male, weighing 180-200g, were bred in an artificially controlled animal room with light and darkness for 12 hours each at a temperature of 20-25°C and relative humidity It is 50-60%, free to ask for food and water.
  • the mice were randomly divided into groups according to the experimental requirements, and they were kept separately in squirrel cages, with 3 to 4 rats in each cage. All relevant operations of animal experiments are in compliance with the provisions of China's "Guidelines for the Management and Use of Laboratory Animals".
  • hypoxic PAH model was established by placing SD male rats in a fully-automatically regulated low-pressure hypoxic chamber (atmospheric pressure of about 50 kPa, oxygen concentration of 10%) for 8 hours a day for 28 days.
  • the rats in the blank control group were kept in a normoxic environment.
  • the experimental rats of hypoxic PAH model were divided into 8 groups, namely blank control group, model group, Sidenafil (25mg/kg) group, compound 1 (10mg/kg) group, compound 1 (25mg/kg) group, For compound 1 (50 mg/kg) group, compound 1 (100 mg/kg) group and compound 1 (200 mg/kg) group, the concentration in parentheses of the group name represents the administration concentration of the compound and the drug.
  • Sidenafil is often used as a positive drug. It can reduce the pulmonary artery pressure in rats and reduce the right ventricular hypertrophy and vascular remodeling. In this experiment, 25mg/kg Sidenafil was used as the positive drug.
  • the positive drugs Sidenafil and Compound 1 were both dissolved in physiological saline and formulated into solutions of different concentrations according to different dosing concentrations.
  • the rats were continuously administered for 28 days with a dosing volume of 5ml/kg.
  • the rats in the control and model groups were administered The corresponding volume of saline solution is administered by gavage. See Table 5 for specific grouping.
  • the Powerlab biological information acquisition and processing system was started, and the right heart catheter filled with 0.2% heparin sodium (Beijing Soleibao Technology Co., Ltd.) normal saline was connected to the pressure transducer and then zeroed for standby. After injecting 20% urethane (Shanghai Yuanye Biotechnology Co., Ltd.) solution into the abdominal cavity of the rat for anesthesia, the right neck hair was shaved and the right jugular vein was isolated and exposed. The right heart catheter enters the right jugular vein of the rat, enters the right atrium through the superior vena cava, and reaches the right ventricle through the atrioventricular valve. After the typical right ventricular waveform appears and stabilizes for a while, the waveform is recorded, and then it passes through the Powerlab biological information acquisition and processing system (ADInstruments) Read the pressure value.
  • ADInstruments Powerlab biological information acquisition and processing system
  • RV right ventricle
  • LV+S left ventricle and interventricular septum
  • the positive drug sildenafil can improve the remodeling of the right ventricle and effectively reduce the value of RV/(LV+S) (P ⁇ 0.001). It is suggested that when the doses of compound 1 are 100mg/kg and 200mg/kg, gavage can improve the increase of pulmonary artery pressure in hypoxia-induced pulmonary hypertension rats after 28 treatment.
  • MCT monocrotaline
  • mice (purchased from Shanghai Sipuer-Bikai Experimental Animal Co., Ltd.), male, weighing 180-200g, were bred in an artificially controlled animal room with light and darkness for 12 hours each at a temperature of 20-25°C and relative humidity It is 50-60%, free to ask for food and water.
  • the mice were randomly divided into groups according to the experimental requirements, and they were kept separately in squirrel cages, with 3 to 4 rats in each cage. All relevant operations of animal experiments are in compliance with the provisions of China's "Guidelines for the Management and Use of Laboratory Animals".
  • Both the positive drugs Selexipag and Compound 1 were administered by gavage.
  • Selexipag and compound 102 were dissolved in 0.5% CMC-Na solution, and the rats were continuously administered for 21 days with a dosage volume of 5 mg/kg.
  • the rats in the control and model groups were given the corresponding volume of CMC-Na solution by gavage. See Table 7 for the specific grouping situation.
  • the RVSP and mRVP of the blank control group were 32.43 ⁇ 2.78mmHg and 7.56 ⁇ 2.52mmHg, respectively.
  • the RVSP and mPAP of rats increased (P ⁇ 0.001, P ⁇ 0.05).
  • the pulmonary vascular pressure of rats was higher than that of the blank control group, but the RVSP and mRVP were significantly lower than those of the untreated model group (P ⁇ 0.001, P ⁇ 0.05).
  • the experiment set up a selexipag positive drug control group (compared with the model group RVSP: P ⁇ 0.001, mRVP: P ⁇ 0.05), suggesting that when the dose of compound 1 is 100mg/kg, there is improvement field after gavage treatment 21
  • RVSP model group
  • mRVP mRVP
  • FIG. 3C shows that the RVHI 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).
  • the RVHI of rats was 0.31 ⁇ 0.059, which was significantly lower than that of the untreated model group (P ⁇ 0.05).
  • 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, after treatment 21 by gavage, it has the effect of relieving right heart hypertrophy caused by pulmonary hypertension.
  • MCT monocrotaline
  • mice (purchased from Shanghai Sipuer-Bikai Experimental Animal Co., Ltd.), male, weighing 180-200g, were bred in an artificially controlled animal room with light and darkness for 12 hours each at a temperature of 20-25°C and relative humidity It is 50-60%, free to ask for food and water.
  • the mice were randomly divided into groups according to the experimental requirements, and they were kept separately in squirrel cages, with 3 to 4 rats in each cage. All relevant operations of animal experiments are in compliance with the provisions of China's "Guidelines for the Management and Use of Laboratory Animals".
  • the second experiment was divided into 5 groups, which were the control group, the model group, the positive control Tyvaso (1.62 ⁇ g/kg) group, the compound 1 (10mg/kg) group and the compound 1 (30mg/kg) group.
  • normal saline was injected subcutaneously into the back of the neck of the blank control group of rats, and monocrotaline (Chengdu Purifa Biotechnology Co., Ltd.) solution was injected in the other groups at a dose of 60 mg/kg.
  • the administration method of Compound 1 and Tyvaso is nebulized inhalation.
  • the compound is first dissolved in physiological saline, and then the solution is made into an aerosol with a nebulizer to be inhaled into the mouth and nose of rats.
  • the rats in the control group and the model group only inhaled the aerosol made of physiological saline.
  • the rats were continuously administered for 28 days, and the concentration in the parentheses of the group name represents the administered concentration of the compound. See Table 9 for specific grouping. After the administration, the determination of pulmonary vascular hemodynamics and RVHI was the same as the experimental method in Example 1.
  • the RVSP and mRVP of the blank control group were 29.78 ⁇ 2.12mmHg and 6.78 ⁇ 1.15mmHg, respectively.
  • the RVSP and mPAP of rats increased (P ⁇ 0.01, P ⁇ 0.001).
  • the pulmonary vascular pressure of rats was higher than that of the blank control group, but the RVSP was significantly lower than that of the untreated model group (P ⁇ 0.05, P ⁇ 0.01), and after compound 1 spray treatment, mRVP also showed the same trend.
  • the experiment set up a Tyvaso positive drug control group (compared with the model group RVSP: P ⁇ 0.05, mRVP: P ⁇ 0.05), suggesting the use of compound 1 for aerosol administration.
  • the dose is 10mg/kg and 30mg/kg, it has Improve the phenomenon of monocrotaline-induced pulmonary artery pressure increase in pulmonary hypertension rats.
  • the RVHI of the blank control group and the model group were 0.182 ⁇ 0.028 and 0.396 ⁇ 0.056, respectively.
  • the right heart hypertrophy index of the model group was significantly increased (P ⁇ 0.01).
  • the RVHI of the two groups of rats decreased to 0.235 ⁇ 0.026 and 0.204 ⁇ 0.035, respectively, which was significantly lower than that of the untreated model group (P ⁇ 0.05, P ⁇ 0.01).
  • the right heart hypertrophy index of the positive control drug Tyvaso treatment group was 0.197 ⁇ 0.031, which was significantly lower than that of the model group (P ⁇ 0.01). It is suggested that the use of compound 1 for aerosol administration, when the dosage is 10mg/kg and 30mg/kg, has the effect of relieving the right heart hypertrophy caused by pulmonary hypertension.

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Abstract

本发明提供式I所示化合物、或其药学上可接受的盐或酯、前药、光学异构体、立体异构体或溶剂合物。本发明的化合物能够用于制备预防或治疗高血压或高血压相关疾病或肺动脉高压或肺动脉高压相关疾病的药物。本发明的化合物与现有的治疗高血压和肺动脉高压的药物具备不同的机理，从而为开发高血压和肺动脉高压治疗药物奠定了全新的物质基础。

Description

抗高血压的多元醇化合物及其衍生物 技术领域
本发明涉及药物化学领域；具体来说，本发明涉及涉及一类抗高血压的多元醇化合物、其衍生物以及它们在制备抗高血压药物中的应用。
背景技术
高血压是世界上最常见的心血管疾病，虽然部分高血压病人有遗传易感性，但是环境因素是不可忽视的致病因素。随着人们生活质量的改善和饮食习惯的改变，高血脂、动脉粥样硬化等疾病的发病率不断提高，高血压发病率也逐渐提高。高血压是多种疾病的导火索，会使冠心病、心力衰竭及肾脏的疾病的发病风险增高。因此，降压达标是高血压治疗的关键。高血压的治疗目的是控制血压，降低靶器官损害和心脑血管病的发病率、病死率，改善长期预后，提高生活质量。要达到此目的，除改善生活方式外，还需采取药物治疗。
目前，临床常用于的抗高血压药物基本上可归结为以下几类：即利尿降压药、β受体阻滞药、钙拮抗药(CCB)、血管紧张素转换酶抑制剂(ACEI)、血管紧张素II受体阻滞剂(ARB)、α受体阻滞剂。上述药物虽可有效减低血压，但存在明显的副作用，例如水、电解质紊乱，哮喘、心率减慢，性功能减退等；此外病人常常会出现药物依赖，一旦停药，血压会马上反弹等等。
肺动脉高压(Pulmonary Arterial Hypertension,PAH)是另一种严重危及人生命安全的疾病。其诊断标准为在静息状态下，通过右心导管法检测所得的平均肺动脉压力(mPAP)≥25mmHg。PAH的发病由多种因素所致，包括肺动脉内皮细胞(PAEC)的功能紊乱、肺动脉内皮细胞及肺动脉平滑肌细胞(PASMC)的异常增殖、重构以和原位血栓的形成。PAH死亡率高、预后差，平均存活时间仅为2.8年，在西方国家已成为逐渐得到重视的一大类心血管疾病。在PAH的发生和发展过程中，内皮素(ET-1)、NO和前列环素等通路起到了重要的作用。针对这三个靶点，目前上市的PAH治疗药物主要有内皮素受体拮抗剂波生坦、西他生坦、安贝生坦等，5-磷酸二酯酶(PDE-5)抑制剂西地那非、他达那非、伐地那非等和前列环素类似物依前列醇、伊洛前列素、曲前列素等。尽管这些药物对PAH病情的发展起到一定的缓解作用，但患者通常进行性地病情恶化，有研究表明患病人群5年的生存率仍然仅为50％左右。此外，许多PAH患者往往因为长期服药而要负担高额的药物费用，病情严重者还需要通过多种药物联合治疗来达到控制病情的目的，这种情况给患者和社会带来的经济压力更加沉重，严重降低了患者的治愈率。因此，发现具有抑制甚至逆转肺动脉高压发展的新靶点药物对于改善PAH患者的预后并提高其生活质量具有重要意义。
因此，研究开发高血压、肺动脉高压及其相关疾病的治疗药剂依然具有极其重要的临床意义和应用前景。
发明内容
本发明的目的在于提供新的能够用作高血压、肺动脉高压及其相关疾病的药物的化合物。
在第一方面，本发明提供式I所示化合物、或其药学上可接受的盐或酯、前药、光学异构体、立体异构体或溶剂合物在制备预防或治疗高血压或高血压相关疾病或肺动脉高压或肺动脉高压相关疾病的药物中的用途，
Figure PCTCN2020095974-appb-000001
式中，
X为不存在或者取代或未取代的C1-C3直链或支链烷基；
n为0-5的整数，优选1-5的整数；
R 1和R 3各自独立选自H、D、取代或未取代的C1-C10烷基、取代或未取代的-(CH 2CH 2O) mH、取代或未取代的苄基、取代或未取代的苯基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、取代或未取代的氨基乙酰基、取代或未取代的
Figure PCTCN2020095974-appb-000002
取代或未取代的
Figure PCTCN2020095974-appb-000003
取代或未取代的单糖、二糖或多糖基或取代或未取代的磷酸酯基，其中m为0-5、优选0-3、最优选1-2的整数；或者R 1和R 3可形成五元环
Figure PCTCN2020095974-appb-000004
其中R 6为取代或未取代的C1-C5烷基；
R 2和R 11各自独立选自H、D、羰基、取代或未取代的C1-C10烷基、取代或未取代的苯基、CH 2OR 7；R 7选自H、取代或未取代的C1-C10烷基、取代或未取代的单糖、二糖或多糖基；
R 4选自H、D、取代或未取代的C1-C10直链或支链烷基、取代或未取代的C1-C10不饱和直链或支链烷基、羟基、取代或未取代的C1-C10烷氧基、卤素、取代或未取代的苄基、取代或未取代的苯基、取代或未取代的C1-C5烷基甲酰基，取代或未取代的苯甲酰基、硝基、COOH、取代或未取代的C1-C5烷氧甲酰基、氨基、取代或未取代的C1-C5烷基氨基、取代或未取代的C1-C5烷基甲酰氨基、取代或未取代的苯甲酰氨基、取代或未取代的苯并芳香环或含杂原子的五元、六元杂环。
在优选的实施方式中，所述磷酸酯基如
Figure PCTCN2020095974-appb-000005
所示，其中R 5选自取代或未取代的C1-C10烷基。
在优选的实施方式中，所述取代或未取代的氨基乙酰基是如
Figure PCTCN2020095974-appb-000006
所示，其中R为各种氨基酸取代基。
在具体的实施方式中，所述化合物如式II所示，
Figure PCTCN2020095974-appb-000007
式中，
R 8选自H、取代或未取代的C1-C10烷基、取代或未取代的苄基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、取代或未取代的氨基乙酰基、或取代或未取代的单糖、二糖或多糖基；
R 9选自H、取代或未取代的C1-C10烷基、取代或未取代的苄基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、取代或未取代的氨基乙酰基、或取代或未取代的单糖、二糖或多糖基；
R 10选自H、取代或未取代的C1-C10直链或支链烷基、取代或未取代的C1-C10不饱和直链或支链烷基、F、Cl、Br、羟基、C1-C3直链或支链烷氧基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、或取代或未取代的苯并芳香环或含杂原子的五元、六元杂环；n选自0-3的任意整数。
在具体的实施方式中，本发明提供以下化合物、或其盐或酯、前药、光学异构体或溶剂合物在制备预防或治疗高血压或高血压相关疾病或肺动脉高压或肺动脉高压相关疾病的药物中的用途：
Figure PCTCN2020095974-appb-000008
Figure PCTCN2020095974-appb-000009
Figure PCTCN2020095974-appb-000010
Figure PCTCN2020095974-appb-000011
Figure PCTCN2020095974-appb-000012
在具体的实施方式中，所述化合物是
Figure PCTCN2020095974-appb-000013
Figure PCTCN2020095974-appb-000014
在具体的实施方式中，所述高血压相关疾病包括但不限于：脑中风(脑出血及脑缺血)、高血压性心脏病、高血压性肾病、高血压性眼底病变及视网膜病变、高血压性下肢缺血等；
所述肺动脉高压相关疾病包括但不限于：特发性肺动脉高压、肺源性心脏病、高原性心脏病、心血管疾病、肺阻塞、纤维变性病症、泌尿系统病症。
在第二方面，本发明提供式I所示化合物、或其药学上可接受的盐或酯、前药、光学异构体、立体异构体或溶剂合物，
Figure PCTCN2020095974-appb-000015
式中，
X为不存在或者取代或未取代的C1-C3直链或支链烷基；
n为0-5的整数，优选1-5的整数；
R 1和R 3各自独立H、D、取代或未取代的C1-C10烷基、取代或未取代的-(CH 2CH 2O) mH、取代或未取代的苄基、取代或未取代的苯基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、取代或未取代的酯基、取代或未取代的
Figure PCTCN2020095974-appb-000016
取代或未取代的
Figure PCTCN2020095974-appb-000017
取代或未取代的氨基乙酰基、取代或未取代的单糖、二糖或多糖基或取代或未取代的磷酸酯基，其中m为0-5、优选0-3、最优选1-2的整数；或者R 1和R 3可形成五元环
Figure PCTCN2020095974-appb-000018
其中R 6为取代或未取代的C1-C5烷基；
R 2和R 11各自独立选自H、D、羰基、取代或未取代的C1-C10烷基、取代或未取代的苯基、CH 2OR 7；R 7选自H、取代或未取代的C1-C10烷基、取代或未取代的单糖、二糖或多糖基；
R 4选自H、D、取代或未取代的C1-C10直链或支链烷基、取代或未取代的C1-C10不饱和直链或支链烷基、羟基、取代或未取代的C1-C10烷氧基、卤素、取代或未取代的苄基、取代或未取代的苯基、取代或未取代的C1-C5烷基甲酰基，取代或未取代的苯甲酰基、硝基、COOH、取代或未取代的C1-C5烷氧甲酰基、氨基、取代或未取代的C1-C5烷基氨基、取代或未取代的C1-C5烷基甲酰氨基、取代或未取代的苯甲酰氨基、取代或未取代的苯并芳香环或含杂原子的五元、六元杂环。
在优选的实施方式中，所述磷酸酯基如
Figure PCTCN2020095974-appb-000019
所示，其中R 5选自取代或未取代的C1-C10烷基。
在优选的实施方式中，所述取代或未取代的氨基乙酰基如
Figure PCTCN2020095974-appb-000020
所示，其中R为各种氨基酸取代基。
在优选的实施方式中，所述化合物用于制备预防或治疗高血压或肺动脉高压的药物。
在具体的实施方式中，所述化合物如式II所示，
Figure PCTCN2020095974-appb-000021
式中，
R 8选自H、取代或未取代的C1-C10烷基、取代或未取代的苄基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、取代或未取代的氨基乙酰基、或取代或未取代的单糖、二糖或多糖基；
R 9选自H、取代或未取代的C1-C10烷基、取代或未取代的苄基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、取代或未取代的氨基乙酰基、或取代或未取代的单糖、二糖或多糖基；
R 10选自H、取代或未取代的C1-C10直链或支链烷基、取代或未取代的C1-C10不饱和直链或支链烷基、F、Cl、Br、羟基、C1-C3直链或支链烷氧基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、或取代或未取代的苯并芳香环或含杂原子的五元、六元杂环；n选自0-3的任意整数。
在具体的实施方式中，所述化合物是选自以下的化合物、或其药学上可接受的盐或酯、 前药、光学异构体、立体异构体或溶剂合物：
Figure PCTCN2020095974-appb-000022
Figure PCTCN2020095974-appb-000023
Figure PCTCN2020095974-appb-000024
Figure PCTCN2020095974-appb-000025
在优选的实施方式中，所述化合物是
Figure PCTCN2020095974-appb-000026
Figure PCTCN2020095974-appb-000027
在优选的实施方式中，所述化合物用于制备预防或治疗高血压或高血压相关疾病或肺动脉高压或肺动脉高压相关疾病的药物，或用于预防或治疗高血压或高血压相关疾病或肺动脉高压或肺动脉高压相关疾病。
在优选的实施方式中，所述高血压相关疾病包括但不限于：脑中风(脑出血及脑缺血)、高血压性心脏病、高血压性肾病、高血压性眼底病变及视网膜病变、高血压性下肢缺血等；
所述肺动脉高压相关疾病包括但不限于：特发性肺动脉高压、肺源性心脏病、高原性心脏病、心血管疾病、肺阻塞、纤维变性病症、泌尿系统病症。
在第三方面，本发明提供一种药物组合物，所述药物组合物包含第二方面所述的化合物、或其药学上可接受的盐或酯、前药、光学异构体、立体异构体或溶剂合物，和药学上可 接受的载体或赋形剂。
在优选的实施方式中，所述药物组合物用于制备预防或治疗高血压或高血压相关疾病或肺动脉高压或肺动脉高压相关疾病的药物，或用于预防或治疗高血压或高血压相关疾病或肺动脉高压或肺动脉高压相关疾病。
在优选的实施方式中，所述高血压相关疾病包括但不限于：脑中风(脑出血及脑缺血)、高血压性心脏病、高血压性肾病、高血压性眼底病变及视网膜病变、高血压性下肢缺血等；
所述肺动脉高压相关疾病包括但不限于：特发性肺动脉高压、肺源性心脏病、高原性心脏病、心血管疾病、肺阻塞、纤维变性病症、泌尿系统病症。
在具体的实施方式中，所述药物组合物是雾化吸入的给药形式。
在第四方面，本发明提供一种预防或治疗高血压或高血压相关疾病或肺动脉高压或肺动脉高压相关疾病的方法，包括将治疗有效量的第二方面所述的化合物、或其药学上可接受的盐或酯、前药、光学异构体、立体异构体或溶剂合物或第三方面所述药物组合物给予有此需要的对象。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了口服化合物1对低氧性肺动脉高压动物模型的治疗作用；
图2显示了口服化合物1对低氧致肺动脉高压大鼠肺组织中小动脉肥厚程度的减轻作用；
图3显示了口服化合物1对野百合碱诱导肺动脉高压动物模型的治疗作用；
图4显示了口服化合物1对野百合碱致肺动脉高压大鼠肺组织中小动脉肥厚程度的减轻作用；
图5显示了化合物1雾化给药对野百合碱诱导肺动脉高压动物模型的治疗作用；和
图6显示了口服化合物1雾化给药对野百合碱致肺动脉高压大鼠肺组织中小动脉肥厚程度的减轻作用。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现一系列对于高血压和非动脉高压具有治疗效果的全新化合物，这些化合物与现有的治疗药物具备不同的机理，从而开发高血压和非动脉高压治疗药物奠定了全新的物质基础。在此基础上完成了本发明。
术语定义
本文所用的关于化合物的基团、取代基或结构的术语具有本领域技术人员理解相同的含义。为清晰起见，对本说明书中用到的术语定义如下。
在本文中，“一”、“一个”、“一种”或“一类”是指包括其所修饰对象的复数形式，即，“一”、“一个”、“一种”或“一类”是指最少一个/种/类或一个/种/类或一个/种/类以上。
在本文中，形如“C 1-n”的表述是指基团具有1-n个碳原子，例如，“C 1-10”的表述指基团具有1、2、3、4、5、6、7、8、9或10个碳原子；同样地，“C6～C10”是指基团具有6、7、8、9或10个碳原子。
本文所用的术语“烷基”与本领域普通技术人员通常理解的含义相同，是指各种饱和或不饱和的直链的、带侧链的或环状的碳氢基团。例如，本文所述的烷基是指1-10个碳原子的低级烷基；优选地，是指1-8个碳原子的低级烷基；更优选地，是指1-6个碳原子的低级烷基。在具体的实施方式中，本文所述的烷基包括但不限于：甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基等等。
本文所用的术语“芳基”与本领域普通技术人员通常理解的含义相同，是指环状共轭芳香系统；例如，术语“C6-C10芳基”是指在环上不含杂原子的具有6至10个碳原子的芳香族环基，如苯基、萘基等。而本文所用的术语“杂芳基”是指在环状共轭芳香系统的环中含有一个或一个以上的如N、O或S的杂原子；例如吡啶基、吡嗪基。
本文所用的术语“氨基乙酰基”具有本领域普通技术人员理解的常规含义，即，氨基取代的乙酰基。在具体的实施方式中，所述氨基乙酰基如
Figure PCTCN2020095974-appb-000028
所示，其中R为各种氨基酸取代基。
本文所用的术语“杂环基”是指饱和或部分不饱和的非芳香性环状基团，包括单环、并环、螺环或桥环，其中所述杂环具有至少1个选自O、S或N的杂原子作为环成员。例如，“5或6元杂环基”是指在环上含有1～3个选自氧、硫或氮的杂原子的饱和或不饱和的5或6元环烷基，例如二氧杂环戊基等。
本文所用的术语“卤素”是指F、Cl、Br或I。
基于本发明的教导以及本领域的公知常识，本领域技术人员可以知晓本发明的化合物以及上述所定义的各种取代基还可以进一步被取代，例如被C1-6烷基、C1-6烷氧基、卤素、硝基、氨基、苯基、羟基等取代，只要所预期的取代基的组合是稳定的或化学上可实现的取代基组合。
本文所用的术语“取代”是指特定基团上的一个或多个氢原子被特定的取代基所替代。特定的取代基可以是前文中相应描述的取代基，也可以是各实施例中出现的具体取代基。因此，在本发明中，通式(I)或(II)中的取代基可以各自独立地为实施例中具体化合物中的相应基团；即，本发明包括上述通式(I)或(II)中各取代基的组合，也包括通式(I)或(II)中所示部分取代基与实施例中出现的其它具体取代基的组合。
除非特别说明，某个被取代的基团可以在该基团的任何可取代位点上具有一个特定的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环基，可以 与另一个环相连，例如环烷基，从而形成螺二环系，例如，两个环具有一个共用碳原子。所述取代基例如(但并不限于)：C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C 1-8醛基、C 2-10酰基、C 2-10酯基、氨基、C 1-8烷氧基、硝基、氰基、巯基、氨基等。在具体的实施方式中，烷基和芳基上的氢原子被氨基、卤素或其它基团取代即成为属于上述各定义中的基团。
为了方便以及符合常规理解，术语“任意取代的”、“任选取代的”或“取代或未取代的”只适用于能够被取代基所取代的位点，而不包括那些化学上不能实现的取代。
本发明的化合物
本发明提供了一系列对于高血压和非动脉高压具有治疗效果的全新化合物，这些化合物与现有的治疗药物具备不同的机理。
在具体的实施方式中，本发明提供下式I或II所示化合物、或其药学上可接受的盐或酯、前药、光学异构体、立体异构体或溶剂合物，
Figure PCTCN2020095974-appb-000029
通式中的各取代基如上所述。
在本发明的化合物的基础上，本领域技术人员可以其制成药学上可接受的盐或酯、前药、光学异构体、立体异构体或溶剂合物。例如，可以将本发明的化合物与无机酸或有机酸反应形成常规的可药用盐。所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括各种氨基酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者将本发明的化合物与无机碱形成钠盐、钾盐、钙盐、铝盐或铵盐；或者与有机碱形成甲胺盐、乙胺盐或乙醇胺盐。
由于本发明的化合物中存在手性碳原子，因此，通过将本发明化合物拆分获得的光学异构体或立体异构体也落在本发明的保护范围内。
在本发明的化合物或其药学上可接受的盐或酯、前药、光学异构体、立体异构体或溶剂合物的基础上，本发明还提供包含本发明化合物的药物组合物，所述药物组合物任选包含药学上可接受的赋形剂。
在具体的实施方式中，本发明的药物组合物包含安全有效量范围内的本发明化合物或其药学上可接受的盐以及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。
“药学上可以接受的赋形剂或载体”是指：一种或多种相容性固体或液体填料或凝胶物 质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2020095974-appb-000030
Figure PCTCN2020095974-appb-000031
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、娇味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推 进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量。本发明的化合物和药物组合物可通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服，一次性服用或分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。在具体的实施方式中，本发明的化合物优选采用适合雾化给药的形式。
本发明的优点：
1.本发明提供了一系列对于高血压和非动脉高压具有治疗效果的全新化合物；和
2.本发明的化合物与现有的治疗高血压和非动脉高压的药物具备不同的机理，从而有可能开发全新的高血压和非动脉高压治疗药物。
以下结合具体实施案例对本发明的技术方案进一步描述，但以下实施案例不构成对本发明的限制，所有依据本发明的原理和技术手段采用的各种施用方法，均属于本发明范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例
部分化合物制备方法
本发明的化合物可以按照常规路线或方法制备得到，也可以按照本文中描述的方法或路线获得。
合成部分：
实施例1.化合物1的合成
Figure PCTCN2020095974-appb-000032
1.化合物1.3的合成
将镁屑(2.2g，90mmol)置于250mL三口反应瓶中，加一粒碘，将化合物1.1(15g，82mmol)溶于无水四氢呋喃120mL中，通过恒压滴液漏斗将化合物1的四氢呋喃溶液滴10mL 到含镁屑的反应瓶中，用电吹风加热引发反应，待反应开始后，再将剩余的110mL化合物1.1的四氢呋喃溶液慢慢滴入。滴加结束后，回流反应3.5小时，最后得到化合物1.2的四氢呋喃溶液。
在冰浴下，将化合物1.2的四氢呋喃溶液滴加到苄氧乙醛(12g，80mmol)的无水四氢呋喃80mL溶液中，滴加结束后，升至室温反应1小时，然后加入饱和氯化铵水溶液萃灭反应。最后，将四氢呋喃除去，并用乙酸乙酯萃取，无水硫酸钠干燥，过柱纯化(PE:EA＝10:1)得目标化合物12.4g，两步产率为59.6％。 1H NMR(400MHz,DMSO):δ7.36-7.15(m,8H),7.09(d,J＝7.6Hz,1H),5.38(d,J＝4.4Hz,1H),4.74-4.70(m,1H),4.51(s,2H),3.53-3.44(m,2H),2.61(q,J＝7.6,2H),1.19(t,J＝7.6,3H).LC-MS:255.30(M-H) -.
2.化合物1的合成
将化合物1.3(12.4g，48.4mmol)溶于乙醇70mL，并加入10％钯碳2.43g，置换空气，加H 2，38℃搅拌3小时。反应结束后，将溶剂除去，过柱纯化(PE:EA＝5:1)得目标化合物6.42g，产率为79％。 1H NMR(400MHz,CDCl 3):δ7.28-7.12(m,4H),4.78(dd,J 1＝8.0Hz,J 2＝3.6Hz,1H),3.74-3.62(m,2H),2.64(q,J＝7.6Hz,2H),1.23(t,J＝7.6Hz,3H).LC-MS:165.10(M-H) -.
实施例2.化合物2的合成
Figure PCTCN2020095974-appb-000033
1.化合物2.6的合成
将镁屑(0.17g，7mmol)置于50mL三口反应瓶中，加1粒碘，将化合物2.4(1g，6.4mmol)溶于无水四氢呋喃12mL中，通过恒压滴液漏斗将化合物4的四氢呋喃溶液滴2mL到反应瓶中，用电吹风加热引发反应，待反应开始后，再将剩余的10mL化合物2.4的四氢呋喃溶液慢慢滴入。滴加结束后，回流反应3.5小时，最后得到化合物2.5的四氢呋喃溶液。
在冰浴下，将化合物2.5的四氢呋喃溶液滴加到苄氧乙醛(0.97g，6.4mmol)的无水四氢呋喃8mL溶液中，滴加结束后，升至室温反应1小时，然后加入饱和氯化铵水溶液萃灭反应。最后，将四氢呋喃除去，并用乙酸乙酯萃取，无水硫酸钠干燥，过柱纯化(PE:EA＝10:1)得目标化合物0.98g，两步产率为67.6％。 1H NMR(400MHz,DMSO):δ7.37-7.22(m,10H),5.41(d,J＝4.0Hz,1H),4.78-4.74(m,1H),4.51(s,2H),3.51-3.48(m,2H).LC-MS:227.30(M-H) -.
2.化合物2的合成
将化合物2.6(0.9g，4mmol)溶于乙醇10mL，并加入10％钯碳0.2g，置换空气，加H 2，38℃搅拌3小时。反应结束后，将溶剂除去，过柱纯化(PE:EA＝5:1)得目标化合物0.24g，产率为45％。 1H NMR(400MHz,DMSO):δ7.34-7.28(m,4H),7.24-7.20(m,1H),5.24(d,J＝4.4Hz,1H),4.74(t,J＝6Hz,1H),4.55(q,J＝6Hz,1H),3.43(t,J＝6Hz,2H).LC-MS:137.10(M-H) -.
实施例3.化合物3的合成
Figure PCTCN2020095974-appb-000034
1.化合物3.9的合成
将镁屑(0.33g，13.8mmol)置于100mL三口反应瓶中，加1粒碘，将化合物3.7(2g，11.7mmol)溶于无水四氢呋喃20mL中，通过恒压滴液漏斗将化合物3.7的四氢呋喃溶液滴3mL到反应瓶中，用电吹风加热引发反应，待反应开始后，再将剩余的17mL化合物7的四氢呋喃溶液慢慢滴入。滴加结束后，回流反应3.5小时，最后得到化合物3.8的四氢呋喃溶液。
在冰浴下，将化合物3.8的四氢呋喃溶液滴加到苄氧乙醛(1.74g，11.6mmol)的无水四氢呋喃14mL溶液中，滴加结束后，升至室温反应1小时，然后加入饱和氯化铵水溶液萃灭反应。最后，将四氢呋喃除去，并用乙酸乙酯萃取，无水硫酸钠干燥，过柱纯化(PE:EA＝10:1)得目标化合物0.95g，两步产率为34％。 1H NMR(400MHz,DMSO):δ7.34-7.04(m,9H),5.34(d,J＝4.0Hz,1H),4.73-4.69(m,1H),4.51(s,2H),3.52-3.43(m,2H),2.28(s,3H).LC-MS:241.30(M-H) -.
2.化合物3的合成
将化合物3.9(0.9g，3.8mmol)溶于乙醇10mL，并加入10％钯碳0.2g，置换空气，加H 2，38℃搅拌3小时。反应结束后，将溶剂除去，过柱纯化(PE:EA＝5:1)得目标化合物0.28g，产率为50％。 1H NMR(400MHz,CDCl 3):δ7.26-7.09(m,4H),4.76(dd,J 1＝8.0Hz,J 2＝3.6Hz,1H),3.72-3.59(m,2H),3.09(s,2H),2.34(s,3H).LC-MS:151.10(M-H) -.
实施例4.化合物4的合成
Figure PCTCN2020095974-appb-000035
1.化合物4.12的合成
将镁屑(0.31g，12.9mmol)置于100mL三口反应瓶中，加1粒碘，将化合物4.10(2g，10.9mmol)溶于无水四氢呋喃20mL中，通过恒压滴液漏斗将化合物10的四氢呋喃溶液滴3mL到反应瓶中，用电吹风加热引发反应，待反应开始后，再将剩余的17mL化合物4.10的四氢呋喃溶液慢慢滴入。滴加结束后，回流反应3.5小时，最后得到化合物11的四氢呋喃溶液。
在冰浴下，将化合物4.11的四氢呋喃溶液滴加到苄氧乙醛(1.62g，10.8mmol)的无水四氢呋喃14mL溶液中，滴加结束后，升至室温反应1小时，然后加入饱和氯化铵水溶液萃灭反应。最后，将四氢呋喃除去，并用乙酸乙酯萃取，无水硫酸钠干燥，过柱纯化(PE:EA＝10:1)得目标化合物1g，两步产率为36％。 1H NMR(400MHz,DMSO):δ7.35-7.14(m,9H),5.33(d,J＝4.0Hz,1H),4.74-4.70(m,1H),4.51(s,2H),3.52-3.43(m,2H),2.57(q,J＝7.6Hz,2H),1.16(t,J＝7.6Hz,3H).LC-MS:255.30(M-H) -.
2.化合物4的合成
将化合物4.12(0.9g，3.5mmol)溶于乙醇10mL，并加入10％钯碳0.2g，置换空气，加H 2，38℃搅拌3小时。反应结束后，将溶剂除去，过柱纯化(PE:EA＝5:1)得目标化合物0.24g，产率为37％。 1H NMR(400MHz,CDCl 3):δ7.20-7.10(m,4H),4.72(dd,J 1＝8.0Hz,J 2＝3.6Hz,1H),3.66-3.55(m,2H),2.59(q,J＝7.6Hz,2H),2.46(s,2H),1.15(t,J＝7.6Hz,3H).LC-MS:165.10(M-H) -.
实施例5.化合物5的合成
Figure PCTCN2020095974-appb-000036
1.化合物5.15的合成
将镁屑(0.31g，12.9mmol)置于100mL三口反应瓶中，加1粒碘，将化合物5.13(2g，10.9mmol)溶于无水四氢呋喃20mL中，通过恒压滴液漏斗将化合物5.13的四氢呋喃溶液滴3mL到反应瓶中，用电吹风加热引发反应，待反应开始后，再将剩余的17mL化合物5.13的四氢呋喃溶液慢慢滴入。滴加结束后，回流反应3.5小时，最后得到化合物5.14的四氢呋喃溶液。
在冰浴下，将化合物5.14的四氢呋喃溶液滴加到苄氧乙醛(1.62g，10.8mmol)的无水四氢呋喃14mL溶液中，滴加结束后，升至室温反应1小时，然后加入饱和氯化铵水溶液萃灭反应。最后，将四氢呋喃除去，并用乙酸乙酯萃取，无水硫酸钠干燥，过柱纯化(PE:EA＝10:1)得目标化合物1.4g，两步产率为50％。 1H NMR(400MHz,DMSO):δ7.44-7.42(m,1H),7.35-7.25(m,5H),7.19-7.12(m,3H),5.33(d,J＝4.4Hz,1H),5.01-4.97(m,1H),4.55-4.47(m,2H),3.51-3.40(m,2H),2.66(m,2H),1.15(t,J＝7.6,3H).LC-MS:255.30(M-H) -.
2.化合物5的合成
将化合物5.15(1.2g，4.7mmol)溶于乙醇15mL，并加入10％钯碳0.3g，置换空气，加H 2，38℃搅拌3小时。反应结束后，将溶剂除去，过柱纯化(PE:EA＝5:1)得目标化合物0.43g，产率为47％。 1H NMR(400MHz,DMSO):δ7.41-7.14(m,4H),5.14(d,J＝4.0Hz,1H),4.81-4.76(m,2H),3.37(q,J＝7.6Hz,2H),1.16(t,J＝7.6Hz,3H).LC-MS:165.10(M-H) -.
6.化合物6的合成
Figure PCTCN2020095974-appb-000037
1.化合物6.18合成
将镁屑(0.31g，12.9mmol)置于100mL三口反应瓶中，加1粒碘，将化合物6.16(2g，8.5mmol)溶于无水四氢呋喃20mL中，通过恒压滴液漏斗将化合物16的四氢呋喃溶液滴3mL到反应瓶中，用电吹风加热引发反应，待反应开始后，再将剩余的17mL化合物6.16的四氢呋喃溶液慢慢滴入。滴加结束后，回流反应3.5小时，最后得到化合物6.17的四氢呋喃溶液。
在冰浴下，将化合物6.17的四氢呋喃溶液滴加到苄氧乙醛(1.28g，8.5mmol)的无水四氢呋喃14mL溶液中，滴加结束后，升至室温反应1小时，然后加入饱和氯化铵水溶液萃灭反应。最后，将四氢呋喃除去，并用乙酸乙酯萃取，无水硫酸钠干燥，过柱纯化(PE:EA＝10:1) 得目标化合物0.9g，两步产率为32％。 1H NMR(400MHz,DMSO):δ7.38-7.02(m,9H),5.33(d,J＝4.4Hz,1H),4.75-4.70(m,1H),4.47(s,2H),3.56-3.49(m,2H).LC-MS:307.30(M-H) -.
2.化合物6合成
将化合物6.18(0.85g，2.8mmol)溶于乙醇10mL，并加入10％钯碳0.23g，置换空气，加H 2，38℃搅拌3小时。反应结束后，将溶剂除去，过柱纯化(PE:EA＝5:1)得目标化合物0.2g，产率为33％。 1H NMR(400MHz,DMSO):δ7.35-7.29(m,1H),7.19-7.13(m,2H),7.02-6.98(m,1H),5.34(d,J＝4Hz,1H),4.70(t,J＝6Hz,1H),4.51(q,J＝5.6Hz),3.40(t,J＝6Hz,2H).LC-MS:217.10(M-H) -.
实施例7.化合物7的合成
Figure PCTCN2020095974-appb-000038
1.化合物7.21合成
将镁屑(0.31g，12.9mmol)置于100mL三口反应瓶中，加1粒碘，将化合物7.19(2g，11.7mmol)溶于无水四氢呋喃20mL中，通过恒压滴液漏斗将化合物19的四氢呋喃溶液滴3mL到反应瓶中，用电吹风加热引发反应，待反应开始后，再将剩余的7.17mL化合物7.19的四氢呋喃溶液慢慢滴入。滴加结束后，回流反应3.5小时，最后得到化合物7.20的四氢呋喃溶液。
在冰浴下，将化合物7.20的四氢呋喃溶液滴加到苄氧乙醛(1.76g，11.7mmol)的无水四氢呋喃14mL溶液中，滴加结束后，升至室温反应1小时，然后加入饱和氯化铵水溶液萃灭反应。最后，将四氢呋喃除去，并用乙酸乙酯萃取，无水硫酸钠干燥，过柱纯化(PE:EA＝10:1)得目标化合物1.32g，两步产率为47.2％。 1H NMR(400MHz,DMSO):δ7.44-7.14(m,9H),5.36(d,J＝4.4Hz,1H),4.71-4.67(m,1H),4.50(s,2H),3.50-3.41(m,2H).LC-MS:245.30(M-H) -
2.化合物7合成
将化合物7.21(1.3g，5.4mmol)溶于乙醇10mL，并加入10％钯碳0.23g，置换空气，加H 2，38℃搅拌3小时。反应结束后，将溶剂除去，过柱纯化(PE:EA＝5:1)得目标化合物0.2g，产率为33％。 1H NMR(400MHz,DMSO):δ7.37-7.31(m,1H),7.18-7.12(m,2H),7.06-7.01(m,1H),5.39(d,J＝4.4Hz,1H),4.77(t,J＝5.6Hz,1H),4.56(q,J＝5.6Hz),3.43(t,J＝6Hz,2H).LC-MS:155.10(M-H) -.
实施例8.化合物8的合成
Figure PCTCN2020095974-appb-000039
1.化合物8.24的合成
将镁屑(0.57g，22.2mmol)置于100mL三口反应瓶中，加1粒碘，将化合物8.22(4g，21.5mmol)溶于无水四氢呋喃40mL中，通过恒压滴液漏斗将化合物8.22的四氢呋喃溶液滴5mL到反应瓶中，用电吹风加热引发反应，待反应开始后，再将剩余的35mL化合物8.22的四氢呋喃溶液慢慢滴入。滴加结束后，回流反应3.5小时，最后得到化合物8.23的四氢呋喃溶液。
在冰浴下，将化合物8.23的四氢呋喃溶液滴加到苄氧乙醛(3.21g，21.5mmol)的无水四氢呋喃30mL溶液中，滴加结束后，升至室温反应1小时，然后加入饱和氯化铵水溶液萃灭反应。最后，将四氢呋喃除去，并用乙酸乙酯萃取，无水硫酸钠干燥，过柱纯化(PE:EA＝10:1)得目标化合物4g，两步产率为63.6％。 1H NMR(400MHz,DMSO):δ7.35-7.14(m,9H),5.33(d,J＝4.0Hz,1H),4.74-4.70(m,1H),4.51(s,2H),3.73(s,3H),3.52-3.43(m,2H).LC-MS:257.30(M-H) -.
2.化合物8的合成
将化合物8.24(3.5g，13.6mmol)溶于乙醇30mL，并加入10％钯碳0.69g，置换空气，加H 2，38℃搅拌3小时。反应结束后，将溶剂除去，过柱纯化(PE:EA＝5:1)得目标化合物1.42g，产率为62.3％。 1H NMR(400MHz,DMSO):δ7.23(t,J＝8Hz,1H),6.91(d,J＝7.6Hz,2H),6.80-6.77(m,1H),5.24(d,J＝4.4Hz,1H),4.73(t,J＝5.6Hz,1H),4.53(q,J＝4.8Hz,1H),3.73(s,3H),3.43-3.36(m,2H).LC-MS:167.10(M-H) -.
实施例9.化合物9的合成
Figure PCTCN2020095974-appb-000040
1.化合物9.26的合成
将对异丙基苯胺(4g，29.6mmol)溶于二氯甲烷(40ml)中，并在冰浴下，将NBS(5.8g，32.6mmol)分批多次加入二氯甲烷溶液中，然后将反应温度升到室温，反应进行1小时结束。纯化后得产物4.6g，产率74％。 1H NMR(400MHz,CDCl 3):δ7.28(d,J＝1.6Hz,1H),6.98(dd,J 1＝1.6Hz,J 2＝1.6Hz,1H),6.71(d,J＝8Hz,1H),3.76(s,2H),2.79(m,1H),1.20(d,J＝6.8Hz,6H).LC-MS:214.10(M+H) +.
2.化合物9.27合成
将化合物9.26(2g，9.3mmol)溶于乙酸(10mL)，水(4mL)和浓HCl(1mL)的混合溶液中，然后在冰浴下将NaNO 2(0.78g，11.2mmol)的水溶液(2mL)逐滴加入到上述混合溶液中。反应进行半小时后，在冰浴下，将所得反应混合液滴加入50％的H 3PO 2的水溶液(12mL)中，滴加结束后继续反应8小时，然后将反应温度升至25摄氏度反应3天。反应结束后，过柱纯化。得到产物1.4g，产率75.3％ 1H NMR(400MHz,DMSO):δ7.42(s,1H),7.37-7.34(m,1H),7.25(d,J＝4.8Hz,2H),1.20(d,J＝6.8Hz,6H).LC-MS:199.20(M+H) +.
3.化合物9.29合成
将镁屑(0.17g，7.1mmol)置于100mL三口反应瓶中，加1粒碘，将化合物9.27(1.3g，7.5mmol)溶于无水四氢呋喃12mL中，通过恒压滴液漏斗将化合物9.27的四氢呋喃溶液滴2mL到反应瓶中，用电吹风加热引发反应，待反应开始后，再将剩余的10mL化合物9.27的四氢呋喃溶液慢慢滴入。滴加结束后，回流反应3.5小时，最后得到化合物9.28的四氢呋喃溶液。
在冰浴下，将化合物9.28的四氢呋喃溶液滴加到苄氧乙醛(0.98g，7.1mmol)的无水四氢呋喃10mL溶液中，滴加结束后，升至室温反应1小时，然后加入饱和氯化铵水溶液萃灭反应。最后，将四氢呋喃除去，并用乙酸乙酯萃取，无水硫酸钠干燥，过柱纯化(PE:EA＝10:1)得目标化合物1g，两步产率为56％。 1H NMR(400MHz,DMSO):δ7.36-7.15(m,8H),7.09(d,J＝8Hz,1H),5.38(d,J＝4Hz,1H),4.74-4.70(m,1H),4.51(s,2H),3.53-3.44(m,2H),2.83-2.76(m,1H),1.20(d,J＝7.6Hz,6H).LC-MS:271.30(M+H) +.
4.化合物9合成
将化合物9.28(1g，3.6mmol)溶于乙醇10mL，并加入10％钯碳0.19g，置换空气，加H 2，38℃搅拌3小时。反应结束后，将溶剂除去，过柱纯化(PE:EA＝5:1)得目标化合物g，产率为。 1H NMR(400MHz,CDCl 3):δ7.19-7.04(m,4H),4.69(d,J＝4.0Hz,1H),3.64-3.52(m,2H),3.22(s,2H),2.83-2.76(m,1H),1.15(d,J＝7.6Hz,6H).LC-MS:179.10(M-H) -.
实施例10.化合物10的合成
Figure PCTCN2020095974-appb-000041
1.化合物10.30的合成(羰基的保护)
取对溴苯乙酮(5g，25.4mmol)于100mL三口瓶中，加甲苯60mL做为溶剂，加入乙二醇(10g,161.3mmol),对甲苯磺酸(1g，5mmol)，升温至130℃，回流分水16h。反应结束后加盐水搅拌，静止分层，取有机相，无水硫酸钠干燥，过柱色谱层析得到化合物3g。产率48％。 1H NMR(400MHz,CDCl 3):δ7.49-7.44(m,2H),δ7.37-7.34(m,2H),4.05(m,2H),3.77-3.73(m,2H),1.62(s,3H).LC-MS:242.10(M-H) -.
2.化合物10.32的合成
将镁屑(0.31g，12.9mmol)置于100mL三口反应瓶中，加1粒碘，将对溴苯缩乙二酮(2.5g，10.4mmol)溶于无水四氢呋喃20mL中，通过恒压滴液漏斗将乙二酮的四氢呋喃溶液滴3mL到反应瓶中，用电吹风加热引发反应，待反应开始后，再将剩余的17mL四氢呋喃溶液慢慢滴入。滴加结束后，回流反应3.5小时，最后得到格氏试剂的四氢呋喃溶液。
在冰浴下，将缩乙二酮的四氢呋喃溶液滴加到苄氧乙醛(1.5g，10mmol)的无水四氢呋喃14mL溶液中，滴加结束后，升至室温反应1小时，然后加入饱和氯化铵水溶液萃灭反应。最后，将四氢呋喃除去，并用乙酸乙酯萃取，无水硫酸钠干燥，过柱纯化(PE:EA＝10:1)得目标化合物0.8g，两步产率为25％。 1H NMR(400MHz,CDCl 3):δ7.44-7.29(m,10H),4.9 0(dd,J＝8.8Hz,3.2Hz,1H),4.57(q,J＝12Hz,2H),3.98(t,J＝6Hz,2H),3.71(t,J＝6Hz,2H),3.60(dd,J＝8Hz,3.2Hz),3.39(t,J＝8Hz,1H),1.62(s,3H).LC-MS:313.20(M-H) -.
3.化合物10.33的合成(脱苄基反应)
将化合物(0.75g，2.4mmol)溶于乙醇10mL，并加入10％钯碳0.23g，置换空气，加H 2，38℃搅拌3小时。反应结束后，将溶剂除去，过柱纯化(PE:EA＝2:1)得目标化合物0.2g，产率为29％。 1H NMR(400MHz,DMSO):δ7.35-7.29(m,4H),5.23(d,J＝4Hz,1H),4.74(t,J＝6Hz,1H),4.54-4.49(m,1H),3.98-3.94(m,2H),3.43(t,J＝6.8Hz,2H),1.53(s,3H).LC-MS:223.10(M-H) -.
4.化合物10合成
取化合物(0.18g，0.8mmol)加入乙醇10mL，盐酸5d，50℃反应15h。加水，DCM萃取，有机相加无水硫酸钠干燥，过柱色谱层析得到0.06g。产率40％。 1H NMR(400MHz,DMSO):δ7.91(d,J＝8.4Hz,2H),7.49(d,J＝8.4Hz,2H),5.42(d,J＝4Hz,1H),4.80(t,J＝6Hz,1H),4.63(q,J＝5.6Hz,1H),3.46(t,J＝6Hz,2H),2.56(s,3H).LC-MS:181.10 (M+H) +.
实施例11.化合物11(D)的合成
Figure PCTCN2020095974-appb-000042
1.3-乙烯基苯基环氧乙烷(B)的合成
氮气保护下将叔丁醇钾(2.214g,0.02mol)、THF(2ml)、DMSO(12ml)逐滴加入含有三乙烯基苯甲醛(A,1.215g,0.009mol)、三甲基碘化硫(2.118g,0.011mol)、THF(8ml)、DMSO(15ml)的三口烧瓶中，冰浴下反应12h。反应过程中用TLC监测反应进度。反应结束用二氯甲烷萃取，有机层用无水硫酸钠干燥，最后用柱层析分离(PE:EA＝150:1)，得3-乙烯基苯基环氧乙烷(B)0.755g(56％)。 1H NMR(DMSO,400MHz):δ7.43-7.21(m,4H),6.77(dd,J＝10.817.7Hz,1H,),5.83(d,J＝17.7Hz,1H),5.29(d,J＝10.8Hz,1H),3.93(dd,J＝2.7,4.0Hz,1H),3.13(dd,J＝4.0,5.5Hz,1H,),2.88(q,J＝2.7Hz,1H).
2.3-(1-羟基-2-苯甲酰氧基乙基)苯乙烯(C)的合成
氮气保护下将苯甲酸(1.22g,10.0mmol)、碘化四丁铵(0.369g,1.0mmol)、3-乙烯基苯基环氧乙烷(B，1.46g,10.0mmol)溶于5mL DMF，100℃反应12h.。反应过程中用TLC监测反应进度。反应结束用二氯甲烷萃取，有机层用无水硫酸钠干燥，最后用柱层析分离(PE:EA＝10:1)，得3-(1-羟基-2-苯甲酰氧基乙基)苯乙烯(C)0.818g(30.47％). 1H NMR(DMSO,400MHz):δ7.33-7.95(m,9H),6.78(dd,J＝10.9,17.6Hz,1H),5.85(d,J＝17.6Hz,1H),5.78(d,J＝4.6Hz,1H),5.27(d,J＝10.9,1H),4.96(q,J＝4.6,1H),4.34(d,J＝5.7Hz,2H).
3.化合物11(D)的合成
将3-(1-羟基-2-苯甲酰氧基乙基)苯乙烯(C，0.20g,0.745mmol)、氢氧化钠(0.043g,1.08mmol)溶于4ml甲醇中，回流反应2h后加入1ml H 2O。反应过程中用TLC监测反应进度。反应结束用二氯甲烷萃取，有机层用无水硫酸钠干燥，最后用柱层析分离(PE:EA＝1:1)，得3-(1,2-二羟乙基)苯乙烯(D)0.07g(57.2％)。 1H NMR(CDCl3,400MHz):δ7.12-7.29(m,4H),6.65(dd,J＝11.1,17.7Hz,1H),5.69(d,J＝17.7Hz,1H),5.19(d,J＝11.1Hz,1H),4.71(dd,J＝3.3,8.3Hz,1H),3.65(m,2H),3.07(s,2H).MS(EI):164.1.
实施例12.化合物30的合成
Figure PCTCN2020095974-appb-000043
将化合物1(1.66g，0.01mol)溶于DCM 7mL，加入浓硫酸1滴，微微加热后反应开始放热反应。反应结束后，在加入溶剂20mL，碳酸氢钠溶液洗涤，干燥浓缩过柱纯化(PE:EA＝10:1)得目标化合物2.00g，产率为80％。 1H NMR(400MHz,CDCl 3):δ7.21-7.00(m,4H),4.75(dd,J 1＝8.0Hz,J 2＝3.6Hz,1H),3.72-3.60(m,2H),2.66(q,J＝7.6Hz,2H),2.21(s,3H)，2.10(s,3H)，1.25(t,J＝7.6Hz,3H).LC-MS:251.17(M+H) +.
实验例13.抗高血压活性测试
在本实施例中，按照本领域常规的试验操作测试了本发明的化合物对自发性高血压大鼠(SHR)血压是否有降低作用以及对心率有何影响。
受试药物：本发明的化合物。所有化合物剂量统一设定为200mg/kg。
其它试剂、试验动物和仪器：本实施例用到的所有其它试剂和仪器均是可商品化购得的试剂和仪器。
在测试中，检测给药前后的血压变化，降压效果判断以给药后与基础值比较SBP降低≧20mmHg为有效；同时检测给药前后的心率变化。
统计分析：
心率以均数±标准差
Figure PCTCN2020095974-appb-000044
表示，用两样本等方差配对t检验比较用药前后心率变化，以P<0.05为具有统计学显著性差异标准。
实验结果
相比之下，阳性药盐酸美托洛尔降压效果最好，给药后SBP降低大部分记录时间点血压降低超过20mmHg，血压降低最低值在给药后3小时；盐酸美托洛尔在降低血压的同时又显著地减慢心率作用，给药后6小时平均心率减慢46次/分，这种既有血压降低又有心率减慢的特点符合β受体阻断药的药理作用。
其次有降压作用的化合物是1-(3-乙基苯基)-1,2-乙二醇，给药前后比较，1-(3-乙基苯基)-1,2-乙二醇的降压持续时间与阳性药盐酸美托洛尔相似，最大降压作用也是在给药后3h，但降压幅度略低于阳性药盐酸美托洛尔；此外，1-(3-乙基苯基)-1,2-乙二醇对心率的影响与阳性药盐酸美托洛尔正好相反，在降压的同时有明显的加快心率的作用。
表1.几种化合物给药前后对SHR血压和心率的影响(6h M±SD)n＝8
Figure PCTCN2020095974-appb-000045
Figure PCTCN2020095974-appb-000046
其他化合物降低血压和加快心率的作用实验结果，见表2，表3，表4。
表2.几种化合物给药后SHR血压动态变化及给药前后差值(SBP，mmHg)n＝8
Figure PCTCN2020095974-appb-000047
表3.化合物给药后SHR心率动态变化及给药前后差值(次/分)n＝8
Figure PCTCN2020095974-appb-000048
Figure PCTCN2020095974-appb-000049
表4、化合物给药后SHR血压动态变化及给药前后差值(SBP，mmHg)n＝8
Figure PCTCN2020095974-appb-000050
Figure PCTCN2020095974-appb-000051
Figure PCTCN2020095974-appb-000052
实施例14.肺动脉高压测试
本实施例研究了本发明化合物对PAH模型鼠的治疗作用。实验对SD大鼠使用低压低氧和皮下注射野百合碱建立PAH的动物模型。在PAH模型鼠造模期间持续给药，造模完成后测量大鼠右心室压并保留心、肺器官，分别用来计算右心室的肥厚指数和观察肺部血管的形态变化。然后对SHR自发性高血压模型大鼠单次给药，监测其血压在给药后8小时内的变化。
本发明化合物作为受测试药物溶于生理盐水，实验中使用到的给药方式有灌胃和吸入两种。实验中阳性药根据不同的动物模型和实验要求选择。每隔3天对大鼠的体重进行一次称量，观察大鼠生长情况。
1.口服化合物1对低氧性肺动脉高压动物的治疗作用
1)实验目的
使用低氧低压环境建立SD大鼠的肺动脉高压动物模型，同时灌胃给予化合物1进行治疗，检测大鼠肺动脉血流动力学和右心肥厚指标RVHI，判断化合物1是否具有改善低氧肺动脉高压的效果。
2)实验动物和实验方法
SD大鼠(购自上海西普尔-必凯实验动物有限公司)，雄性，体重180-200g，饲养在人工控制的光照、黑暗各12小时的动物房中，温度为20～25℃，相对湿度为50～60％，可自由索取食物和水。老鼠按照实验要求随机分组，按分组分开在鼠笼中饲养，每笼3～4只大鼠。所有动物实验的相关操作都符合中国《实验动物管理和使用指南》的规定。
低氧性PAH模型的建立是将SD雄性大鼠置于全自动调节的低压低氧舱中(大气压约50kPa，氧浓度10％)，每天8小时，持续28天。空白对照组大鼠则饲养在常氧环境中。
低氧性PAH模型的实验大鼠共分为8组，分别为空白对照组、模型组、Sidenafil(25mg/kg)组、化合物1(10mg/kg)组、化合物1(25mg/kg)组、化合物1(50mg/kg)组、化合物1(100mg/kg)组和化合物1(200mg/kg)组，分组名称的括号中的浓度代表化合物和药物的给药浓度。在低氧诱导的PAH实验中，Sidenafil常用来作为阳性药物，它能够降低大鼠的肺动脉压，并减轻其右心室肥厚和血管重构，本实验用25mg/kg Sidenafil作为阳性药。阳性药Sidenafil和化合物1均溶于生理盐水，按不同的给药浓度配成不同浓度的溶液，对大鼠持续给药28天，给药容积为5ml/kg，对照和模型组的大鼠给对应体积的生理盐水溶液，给药方式均为灌胃。具体分组情况见表5。
给药结束后，启动Powerlab生物信息采集与处理系统，将充盈0.2％肝素钠(北京索莱宝科技有限公司)生理盐水的右心导管连接压力换能器后校零备用。向大鼠腹腔注射20％的乌拉坦(上海源叶生物科技有限公司)溶液进行麻醉后，剃去右颈部毛发并分离暴露出右颈静脉。右心导管自大鼠右颈静脉进入，经上腔静脉进入右心房，通过房室瓣到达右心室，待出现典型的右心室波形并稳定片刻后记录波形，然后通过Powerlab生物信息采集与处理系统(ADInstruments)读出压力值。
压力测量结束后，取出导管，立即解剖大鼠并取出心肺组织。分离出右心室(RV)以及左心室和室间隔(LV+S)，称重并计算右心肥厚指数，右心肥厚指数RVHI＝RV/(LV+S)。分离出肺右下部肺叶组织，浸泡于4％的多聚甲醛(Sigma)中固定1周左右后制作厚度为3μm的石蜡切片，然后进行苏木素-伊红(武汉谷歌生物科技有限公司)染色。每组大鼠肺组织石蜡切片HE染色完成后，置于倒置显微镜(Nikon TS100)下观察，每张切片分别取5条肺动脉在200×视野下拍照记录。使用Image-pro plus 6.0软件对直径为100～300μm的肺中小动脉进行分析，计算管壁厚度占血管外径的百分比(WT％)和管壁面积占血管总面积的百分比(WA％)。
表5.低氧性肺动脉高压模型大鼠分组情况
Figure PCTCN2020095974-appb-000053
3)实验结果
实验结果示于图1和2，其中：
(1)由图1A，图1B可得，间接性低压低氧的PAH模型中，正常鼠(RVSP平均值为29.76±2.48mmHg，mRVP平均值为8.16±1.45mmHg)与模型鼠(RVSP平均值为75.46±2.57mmHg，mRVP平均值为26.12±2.37mmHg)比较差异明显，且P<0.001，说明本实验中成功建立PAH模型。当对低氧诱导的大鼠口服不同剂量的化合物1治疗28天后发现，当化合物1剂量为10mg/kg、25mg/kg、50mg/kg时大鼠的肺血管压力与模型组相比无明显下降。而化合物1剂量100mg/kg和200mg/kg时，大鼠的RVSP和mRVP明显低于未用药的模型组(化合物1 100mg/kg：P<0.01,P<0.05；化合物1 200mg/kg：P<0.001,P<0.01)。实验并设西地那非阳性药对照组(与模型组相比RVSP：P<0.001，mRVP：P<0.01)，提示当AH001的剂量为100mg/kg和200mg/kg时，经灌胃给药治疗28后具有改善低氧诱导肺动脉高压大鼠肺动脉压力增高的现象。
(2)由图1C可得，低氧型PAH模型中，模型鼠与正常组大鼠比较RV/(LV+S)值显著升高(P<0.001)，说明持续低压低氧能导致SD大鼠右心重构增厚变厚。当对低氧诱导的大鼠口服不同剂量的化合物1治疗28天后发现，当化合物1剂量为10mg/kg、25mg/kg、50mg/kg 时大鼠的RVHI与模型组相比无明显下降。而化合物1剂量100mg/kg和200mg/kg时，大鼠的右心肥厚情况与模型组相比则明显好转(P<0.01,P<0.001)。阳性药西地那非能改善右心室的重构，有效降低RV/(LV+S)值(P<0.001)。提示当化合物1的剂量为100mg/kg和200mg/kg时，经灌胃给药治疗28后具有改善低氧诱导肺动脉高压大鼠肺动脉压力增高的现象。
(3)由图1D和图2可得，长期低氧使模型组大鼠肺中小动脉明显增厚，其肺小动脉的中膜厚度(2×MT/ED)比明显增加(P<0.001vs.Control)。对比模型组，当化合物1剂量为10mg/kg、25mg/kg、50mg/kg时大鼠肺血管重构的情况并未减轻。而化合物1剂量100mg/kg和200mg/kg时，大鼠的中膜厚度比与模型组相比则明显好转(P<0.05,P<0.001)。实验并设西地那非阳性药对照组，经西地那非干预21天后，肺小动脉肥厚情况明显减轻(P<0.001vs.Model)。提示当化合物1的剂量为100mg/kg和200mg/kg时，经灌胃给药治疗28后具有减轻低氧致肺动脉高压大鼠肺组织中小动脉肥厚的作用。
表6.化合物1及系列化合物低氧性肺动脉高压模型大鼠的实验结果
Figure PCTCN2020095974-appb-000054
Figure PCTCN2020095974-appb-000055
2.口服本发明化合物对野百合碱诱导肺动脉高压动物的治疗作用
1)实验目的
使用皮下注射野百合碱(MCT)建立SD大鼠的肺动脉高压动物模型，同时灌胃给予化合物1进行治疗，检测大鼠肺动脉血流动力学和右心肥厚指标RVHI，判断口服化合物1是否具有改善野百合碱诱导肺动脉高压的作用。
2)实验动物和实验方法
SD大鼠(购自上海西普尔-必凯实验动物有限公司)，雄性，体重180-200g，饲养在人工控制的光照、黑暗各12小时的动物房中，温度为20～25℃，相对湿度为50～60％，可自由索取食物和水。老鼠按照实验要求随机分组，按分组分开在鼠笼中饲养，每笼3～4只大鼠。所有动物实验的相关操作都符合中国《实验动物管理和使用指南》的规定。
实验过程中将SD大鼠随机分为4组：空白对照组、肺动脉高压模型组、Selexipag(1mg/kg)治疗组和化合物1(100mg/kg)组，每组6只，分组名称括号中的浓度代表化合物的给药浓度。其中Selexipag是日本新药株式会社发现、合成的新型口服长效前列环素受体激动剂。实验第一天于空白对照组大鼠的颈背部皮下注射生理盐水，其余各组均注射野百合碱(成都普瑞法生物科技有限公司)溶液，剂量为60mg/kg。阳性药Selexipag和化合物1均采用灌胃方式给药。Selexipag和化合物102溶于0.5％的CMC-Na溶液中，对大鼠持续给药21天，给药容积为5mg/kg，对照组和模型组大鼠灌胃给对应体积的CMC-Na溶液。具体分组情况见表7。
给药结束后，肺血管血流动力学和RVHI的测定同实施例1中实验方法。
表7.野百合碱致肺动脉高压模型大鼠分组情况(口服)
Figure PCTCN2020095974-appb-000056
3)实验结果
(1)由图3A和图3B可得，空白对照组大鼠的RVSP和mRVP分别为32.43±2.78mmHg、7.56±2.52mmHg。而经野百合碱诱导形成肺动脉高压后，大鼠的RVSP和mPAP均有所上升(P<0.001,P<0.05)。经化合物1(100mg/kg,po)治疗后，大鼠的肺血管压力均高于空白对照组大鼠，但RVSP和mRVP明显低于未用药的模型组(P<0.001,P<0.05)。实验并设selexipag阳性药对照组(与模型组相比RVSP：P<0.001，mRVP：P<0.05)，提示当化合物1的剂量为100mg/kg时，经灌胃给药治疗21后具有改善野百合碱致肺动脉高压大鼠 肺动脉压力增高的现象。
(2)由图3C可得空白对照组大鼠和模型组大鼠的RVHI分别为0.20±0.021和0.46±0.045，模型组的右心肥厚指数明显升高(P<0.001)。经化合物1(100mg/kg,po)治疗后，大鼠的RVHI为0.31±0.059，明显低于未用药的模型组(P<0.05)。同时阳性对照药selexipag治疗组的右心肥厚指数为0.27±0.026，与模型组相比显著性降低(P<0.05)。提示当化合物1的剂量为100mg/kg时，经灌胃给药治疗21后具有缓解肺动脉高压所致的右心肥厚作用。
(3)由图3D和图4可得，经野百合碱后，肺动脉高压模型组大鼠在经野百合碱造模肺中小动脉明显增厚，其肺小动脉的中膜厚度(2×MT/ED)比明显增加(P<0.01)。对比模型组，化合物1(100mg/kg,po)给药组大鼠肺组织肺中小动脉肥厚病理变化显著减轻(P<0.01)。实验并设selexipag阳性药对照组，经selexipag干预21天后，肺小动脉肥厚情况明显减轻(P<0.05vs.Model)。提示当化合物1的剂量为100mg/kg时，经灌胃给药治疗21后具有减轻野百合碱致肺动脉高压大鼠肺组织中小动脉肥厚的作用。
表8.口服化合物1及系列化合物治疗MCT-PAH大鼠的实验结果
Figure PCTCN2020095974-appb-000057
3.化合物1雾化给药对野百合碱诱导肺动脉高压动物的治疗作用
1)实验目的
使用皮下注射野百合碱(MCT)建立SD大鼠的肺动脉高压动物模型，同时采用化合物1雾化吸入的给药方式进行治疗，检测大鼠肺动脉血流动力学和右心肥厚指标RVHI，判断化合物1以雾化吸入的给药方式进行治疗时是否具有改善野百合碱诱导肺动脉高压的作用。
2)实验动物和实验方法
SD大鼠(购自上海西普尔-必凯实验动物有限公司)，雄性，体重180-200g，饲养在人工控制的光照、黑暗各12小时的动物房中，温度为20～25℃，相对湿度为50～60％，可自由索取食物和水。老鼠按照实验要求随机分组，按分组分开在鼠笼中饲养，每笼3～4只大鼠。所有动物实验的相关操作都符合中国《实验动物管理和使用指南》的规定。
第二次实验分为5组，分别为对照组、模型组、阳性对照Tyvaso(1.62μg/kg)组、化合物1(10mg/kg)组和化合物1(30mg/kg)组。实验第一天于空白对照组大鼠的颈背部皮下注射生理盐水，其余各组均注射野百合碱(成都普瑞法生物科技有限公司)溶液，剂量为60mg/kg。化合物1和Tyvaso给药方式为雾化吸入，先将化合物溶于生理盐水中，再用雾化仪把溶液制成气溶胶给大鼠口鼻吸入。对照组和模型组的大鼠只吸入由生理盐水制成的气溶胶。对大鼠持续给药28天，分组名称括号中的浓度代表化合物的给药浓度。具体分组情况见表9。给药结束后，肺血管血流动力学和RVHI的测定同实施例1中实验方法。
表9.野百合碱致肺动脉高压模型大鼠分组情况(雾化吸入)
Figure PCTCN2020095974-appb-000058
3)实验结果
(1)由图5A和图5B可得，空白对照组大鼠的RVSP和mRVP分别为29.78±2.12mmHg、6.78±1.15mmHg。而经野百合碱诱导形成肺动脉高压后，大鼠的RVSP和mPAP均有所上升(P<0.01,P<0.001)。经化合物1(10mg/kg和30mg/kg)雾化吸入治疗后，大鼠的肺血管压力均高于空白对照组大鼠，但RVSP明显低于未用药的模型组(P<0.05,P<0.01)，而经化合物1雾化治疗后，mRVP也呈现相同的趋势。实验并设Tyvaso阳性药对照组(与模型组相比RVSP：P<0.05，mRVP：P<0.05)，提示使用化合物1进行雾化给药，当剂量为10mg/kg和30mg/kg时，具有改善野百合碱致肺动脉高压大鼠肺动脉压力增高的现象。
(2)由图5C可得空白对照组大鼠和模型组大鼠的RVHI分别为0.182±0.028和0.396±0.056，模型组的右心肥厚指数明显升高(P<0.01)。经化合物1(10mg/kg和30mg/kg)雾化吸入治疗后，两组大鼠的RVHI分别降至为0.235±0.026和0.204±0.035，明显低于未用药的模型组(P<0.05,P<0.01)。同时阳性对照药Tyvaso治疗组的右心肥厚指数为0.197±0.031， 与模型组相比显著性降低(P<0.01)。提示使用化合物1进行雾化给药，当剂量为10mg/kg和30mg/kg时，具有缓解肺动脉高压所致的右心肥厚作用。
(3)由图5D和图6可得，经野百合碱后，肺动脉高压模型组大鼠在经野百合碱造模肺中小动脉明显增厚，其肺小动脉的中膜厚度(2×MT/ED)比明显增加(P<0.01)。对比模型组，经化合物1(10mg/kg和30mg/kg)雾化吸入治疗后，大鼠肺组织肺中小动脉肥厚病理变化显著减轻(P<0.05,P<0.01)。实验并设Tyvaso阳性药对照组，经Tyvaso吸入21天后，肺小动脉肥厚情况明显减轻(P<0.001vs.Model)。提示使用化合物1进行雾化给药，当剂量为10mg/kg和30mg/kg时，具有减轻野百合碱致肺动脉高压大鼠肺组织中小动脉肥厚的作用。
表10.雾化吸入化合物1及系列化合物治疗MCT-PAH大鼠的实验结果
Figure PCTCN2020095974-appb-000059
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 式I所示化合物、或其药学上可接受的盐或酯、前药、光学异构体、立体异构体或溶剂合物在制备预防或治疗高血压或高血压相关疾病或肺动脉高压或肺动脉高压相关疾病的药物中的用途，
    Figure PCTCN2020095974-appb-100001
    式中，
    X为不存在或者取代或未取代的C1-C3直链或支链烷基；
    n为0-5的整数，优选1-5的整数；
    R 1和R 3各自独立选自H、D、取代或未取代的C1-C10烷基、取代或未取代的-(CH 2CH 2O) mH、取代或未取代的苄基、取代或未取代的苯基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、取代或未取代的氨基乙酰基、取代或未取代的
    Figure PCTCN2020095974-appb-100002
    取代或未取代的
    Figure PCTCN2020095974-appb-100003
    取代或未取代的单糖、二糖或多糖基或取代或未取代的磷酸酯基，其中m为0-5、优选0-3、最优选1-2的整数；或者R 1和R 3可形成五元环
    Figure PCTCN2020095974-appb-100004
    其中R 6为取代或未取代的C1-C5烷基；
    R 2和R 11各自独立选自H、D、羰基、取代或未取代的C1-C10烷基、取代或未取代的苯基、CH 2OR 7；R 7选自H、取代或未取代的C1-C10烷基、取代或未取代的单糖、二糖或多糖基；
    R 4选自H、D、取代或未取代的C1-C10直链或支链烷基、取代或未取代的C1-C10不饱和直链或支链烷基、羟基、取代或未取代的C1-C10烷氧基、卤素、取代或未取代的苄基、取代或未取代的苯基、取代或未取代的C1-C5烷基甲酰基，取代或未取代的苯甲酰基、硝基、COOH、取代或未取代的C1-C5烷氧甲酰基、氨基、取代或未取代的C1-C5烷基氨基、取代或未取代的C1-C5烷基甲酰氨基、取代或未取代的苯甲酰氨基、取代或未取代的苯并芳香环或含杂原子的五元、六元杂环。
  2. 如权利要求1所述的用途，其特征在于，所述化合物如式II所示，
    Figure PCTCN2020095974-appb-100005
    式中，
    R 8选自H、取代或未取代的C1-C10烷基、取代或未取代的苄基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、取代或未取代的氨基乙酰基、或取代或未取代的单糖、二糖或多糖基；
    R 9选自H、取代或未取代的C1-C10烷基、取代或未取代的苄基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、取代或未取代的氨基乙酰基、或取代或未取代的单糖、二糖或多糖基；
    R 10选自H、取代或未取代的C1-C10直链或支链烷基、取代或未取代的C1-C10不饱和直链或支链烷基、F、Cl、Br、羟基、C1-C3直链或支链烷氧基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、或取代或未取代的苯并芳香环或含杂原子的五元、六元杂环；n选自0-3的任意整数。
  3. 以下化合物、或其盐或酯、前药、光学异构体或溶剂合物在制备预防或治疗高血压或高血压相关疾病或肺动脉高压或肺动脉高压相关疾病的药物中的用途：
    Figure PCTCN2020095974-appb-100006
    Figure PCTCN2020095974-appb-100007
    Figure PCTCN2020095974-appb-100008
    Figure PCTCN2020095974-appb-100009
  4. 如权利要求3所述的用途，其特征在于，所述化合物是
    Figure PCTCN2020095974-appb-100010
    Figure PCTCN2020095974-appb-100011
    Figure PCTCN2020095974-appb-100012
  5. 如权利要求1-4中任一项所述的用途，其特征在于，所述高血压相关疾病包括但不限于：脑中风(脑出血及脑缺血)、高血压性心脏病、高血压性肾病、高血压性眼底病变及视网膜病变、高血压性下肢缺血等；
    所述肺动脉高压相关疾病包括但不限于：特发性肺动脉高压、肺源性心脏病、高原性心脏病、心血管疾病、肺阻塞、纤维变性病症、泌尿系统病症。
  6. 式I所示化合物、或其药学上可接受的盐或酯、前药、光学异构体、立体异构体或溶剂合物，
    Figure PCTCN2020095974-appb-100013
    式中，
    X为不存在或者取代或未取代的C1-C3直链或支链烷基；
    n为0-5的整数，优选1-5的整数；
    R 1和R 3各自独立H、D、取代或未取代的C1-C10烷基、取代或未取代的-(CH 2CH 2O) mH、取代或未取代的苄基、取代或未取代的苯基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、取代或未取代的酯基、取代或未取代的
    Figure PCTCN2020095974-appb-100014
    取代或未取代的
    Figure PCTCN2020095974-appb-100015
    取代或未取代的氨基乙酰基、取代或未取代的单糖、二糖或多糖基或取代或未取代的磷酸酯基，其中m为0-5、优选0-3、最优选1-2的整数；或者R 1和R 3可形成五元环
    Figure PCTCN2020095974-appb-100016
    其中R 6为取代或未取代的C1-C5烷基；
    R 2和R 11各自独立选自H、D、羰基、取代或未取代的C1-C10烷基、取代或未取代的苯基、CH 2OR 7；R 7选自H、取代或未取代的C1-C10烷基、取代或未取代的单糖、二糖或多糖基；
    R 4选自H、D、取代或未取代的C1-C10直链或支链烷基、取代或未取代的C1-C10不饱和直链或支链烷基、羟基、取代或未取代的C1-C10烷氧基、卤素、取代或未取代的苄基、取代或未取代的苯基、取代或未取代的C1-C5烷基甲酰基，取代或未取代的苯甲酰基、硝基、COOH、取代或未取代的C1-C5烷氧甲酰基、氨基、取代或未取代的C1-C5烷基氨基、取代 或未取代的C1-C5烷基甲酰氨基、取代或未取代的苯甲酰氨基、取代或未取代的苯并芳香环或含杂原子的五元、六元杂环。
  7. 如权利要求6所述的化合物，其特征在于，所述化合物如式II所示，
    Figure PCTCN2020095974-appb-100017
    式中，
    R 8选自H、取代或未取代的C1-C10烷基、取代或未取代的苄基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、取代或未取代的氨基乙酰基、或取代或未取代的单糖、二糖或多糖基；
    R 9选自H、取代或未取代的C1-C10烷基、取代或未取代的苄基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、取代或未取代的氨基乙酰基、或取代或未取代的单糖、二糖或多糖基；
    R 10选自H、取代或未取代的C1-C10直链或支链烷基、取代或未取代的C1-C10不饱和直链或支链烷基、F、Cl、Br、羟基、C1-C3直链或支链烷氧基、取代或未取代的C1-C5烷基甲酰基、取代或未取代的苯甲酰基、或取代或未取代的苯并芳香环或含杂原子的五元、六元杂环；n选自0-3的任意整数。
  8. 选自以下的化合物、或其药学上可接受的盐或酯、前药、光学异构体、立体异构体或溶剂合物：
    Figure PCTCN2020095974-appb-100018
    Figure PCTCN2020095974-appb-100019
    Figure PCTCN2020095974-appb-100020
    Figure PCTCN2020095974-appb-100021
  9. 一种药物组合物，所述药物组合物包含权利要求6-8中任一项所述的化合物、或其药学上可接受的盐或酯、前药、光学异构体、立体异构体或溶剂合物，和药学上可接受的载体或赋形剂。
  10. 如权利要求9所述的药物组合物，其特征在于，所述药物组合物是雾化吸入的给药形式。
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