WO2021203779A1 - 治疗肺动脉高压的化合物及其应用 - Google Patents

治疗肺动脉高压的化合物及其应用 Download PDF

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WO2021203779A1
WO2021203779A1 PCT/CN2021/000082 CN2021000082W WO2021203779A1 WO 2021203779 A1 WO2021203779 A1 WO 2021203779A1 CN 2021000082 W CN2021000082 W CN 2021000082W WO 2021203779 A1 WO2021203779 A1 WO 2021203779A1
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李洪林
王蕊
焦茜
赵振江
朱丽丽
李诗良
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华东理工大学
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • Pulmonary arterial hypertension refers to the most common type of pulmonary vascular disease in which the mean pulmonary artery pressure (mPAP) of the right heart catheter (mPAP) ⁇ 25 mmHg measured in a resting state, which is 30 mmHg during exercise.
  • mPAP mean pulmonary artery pressure
  • mPAP right heart catheter
  • hemodynamic characteristics and clinical diagnosis and treatment strategies it can be divided into five categories: 1Arterial pulmonary hypertension; 2Pulmonary hypertension caused by left heart disease; 3Pulmonary hypertension caused by hypoxia and/or lung disease; 4Chronic thromboembolic pulmonary hypertension; 5Pulmonary hypertension caused by multiple mechanisms and/or unknown mechanisms.
  • This disease is a relatively serious disease, with low survival rate, poor prognosis, difficult clinical treatment and other problems, and it has seriously threatened human life and health.
  • CTEPH patients are classified into grades I to IV based on the WHO functional classification that represents the severity of symptoms.
  • Class I No symptoms during daily physical activity
  • Class II Comfortable at rest, but symptoms occur during general physical activity, and daily activities are slightly restricted
  • Class III Can be asymptomatic at rest, but appear after light activity Symptoms, obvious limitation of daily activities
  • Grade IV Pulmonary hypertension makes the patient unable to withstand any physical activity, signs of right heart failure, breathing difficulties and/or fatigue may occur at rest, and any physical activity will aggravate the symptoms.
  • prostacyclin drugs epoprostol, beraprostacyclin
  • endothelin receptor antagonists bosentan, macitentan
  • phosphodiesterase- 5 Inhibitors phosphodiesterase- 5 Inhibitors
  • vascular remodeling is considered to be the main cause of PAH, so anti-vascular remodeling is considered to be a more promising therapeutic method.
  • sGC stimulators and agonists have attracted much attention due to their unique ways of action. Lioxigar is the first new type of sGC stimulant developed by Bayer in Germany.
  • TKI tyrosine kinase inhibitors
  • Imatinib imatinib
  • statins are endogenous cholesterol synthesis inhibitors that act on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Previous studies have shown that multiple statins are used alone [Kao, PN (2005). "Simvastatin treatment of pulmonary hypertension: an observational case series.” Chest 127(4): 1446-1452] or with tadalafil [Girgis , RE, D. Li, et al.
  • Rosiglitazone is a highly selective agonist of Peroxisome proliferator activated receptor (PPARy)! J, clinically used as an insulin sensitizer to treat type 2 diabetes. Because PPAR Y plays an important role in the pathogenesis of PAH, the effect of rosiglitazone in improving PAH is gradually known to everyone [Crossno, JT, Jr.; Garat, CV; Reusch, J.
  • the object of the present invention is to provide a compound with pulmonary hypertension therapeutic activity; specifically, the compound of the present invention can treat, reduce or alleviate pulmonary hypertension, right heart hypertrophy caused by pulmonary hypertension, and pulmonary arterial hypertension. Pulmonary arteriole hypertrophy and abnormal proliferation of pulmonary artery smooth muscle cells.
  • the present invention provides the use of proton pump inhibitor compounds in the preparation of drugs for the treatment of pulmonary hypertension and related diseases.
  • the pulmonary hypertension-related diseases include but are not limited to: pneumonia, inflammatory disorders, inflammatory bowel disease, cardiovascular disease, kidney disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disorders, urinary disorders Systemic diseases and neurological diseases.
  • the proton pump inhibitor compound is a compound represented by formula I or a compound represented by formula II Where Ring A is a 5-membered or 6-membered aromatic ring or heteroaromatic ring; n is an integer of 0-3;
  • Ri is selected from: H, substituted or unsubstituted ( ⁇ _ 6 alkyl group, a substituted or unsubstituted Cw alkoxy, substituted or unsubstituted 5- or 6-membered aryl or heteroaryl group, halogen, amino, nitro Group, hydroxyl group;
  • Ring B is a 5-membered or 6-membered aromatic ring or a 5-membered or 6-membered heteroaromatic ring containing 1-2 heteroatoms selected from N, 0 or S;
  • R 2 is selected from: H, substituted or unsubstituted Q- 6 alkyl, substituted or unsubstituted Q- 6 alkoxy, substituted or unsubstituted Q- 6 alkylthio, morpholinyl, NR 4 R 5 , wherein R 4 and R 5 are each independently selected from H or substituted or unsubstituted Q- 6 alkyl; m is an integer of 0-4;
  • R 3 is selected from: H, substituted or unsubstituted Cl-6 alkyl; In the formula II,
  • C ring is selected from 6-10 membered aromatic ring or heteroaromatic ring;
  • R 9 is selected from: H, halogen, substituted or unsubstituted Cu 6 alkyl, RuR ⁇ NCw acyl, wherein R u and R 12 are each independently selected from H or substituted or unsubstituted Cp 3 alkyl; o is 0- An integer of 3;
  • Y is selected from: S0 2 , NR 13 , 0, wherein R 13 is selected from H or substituted or unsubstituted Q_ 3 alkyl; q is an integer of 0-2;
  • Ring D is a 5-membered or 6-membered aromatic ring or a 5-membered or 6-membered heteroaromatic ring or heterocyclic ring containing 1-2 heteroatoms selected from N, 0 or S; Rio is selected from: halogen, substituted or unsubstituted Q_ 6 alkyl, substituted or unsubstituted Q_ 6 alkoxy, substituted or unsubstituted 6-10 membered aryl or heteroaryl or heterocyclic group, NR 14 R 15 , wherein R 14 and R 15 are each independently selected from H, substituted or unsubstituted alkyl group or a substituted or unsubstituted CM Q_ 6 the ester group; p is an integer of 1-4.
  • Formula I in Formula I,
  • Ring A is a benzene ring, a pyridine ring or a thiophene ring; n is 0, 1 or 2;
  • Ri is selected from: H, substituted or unsubstituted Alkoxy, substituted or unsubstituted pyrrolyl, or two form a 4-6 membered heterocyclic ring containing heteroatoms selected from N, 0 or S;
  • Ring B is a benzene ring or a pyridine ring
  • R 2 is selected from: substituted or unsubstituted Q_ 3 alkyl, substituted or unsubstituted Alkoxy, substituted or unsubstituted Q_ 3 alkylthio, morpholinyl, NR 4 R 5 -wherein R 4 and R 5 are each independently a substituted or unsubstituted CM alkyl group, or two R 2 form a group containing optional A 4-6 membered heterocyclic ring of two heteroatoms from N, 0 or S; m is 1, 2 or 3;
  • 11 3 is 11, or R 3 and R 2 form a substituted or unsubstituted 6-8 carbocyclic ring.
  • the compound is selected from the following group:
  • the compound is represented by the following formula 1-1: 1-1 where
  • Ri is selected from: H, substituted or unsubstituted Alkoxy group, a substituted or unsubstituted alkyl Q_ 3;, 117 and 118 are independently selected from: H, substituted or unsubstituted Q_ 3 alkoxy group, a substituted or unsubstituted CM alkyl.
  • the compound is selected from the following group: In a specific embodiment, in Formula II,
  • Ring C is selected from the group consisting of phenyl, pyridoxyl, pyridoxyl or benzimidazolyl;
  • R 9 is selected from: H, F, substituted or unsubstituted Cu 3 alkyl, RnR ⁇ NCw acyl, wherein R u and R 12 are each independently selected from substituted or unsubstituted Q 3 alkyl;
  • Y is selected from: S0 2 , NH or 0; q is 0 or 1;
  • Ring D is selected from: pyrrolyl, pyrimidinyl, phenyl, chromanyl;
  • R 10 is selected from: F, substituted or unsubstituted Cu 3 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted tetrahydroisoquinolinyl, NR 14 R 15 , wherein R 14 and R 15 are each independently selected from H, substituted or unsubstituted ester group Q_ 3; p is 1, 2 or 3.
  • the compound is selected from the following group:
  • the present invention provides a compound represented by formula 1-2, Where
  • Ring B is phenyl or pyrazinyl
  • R 2 is selected from: H, substituted or unsubstituted C M alkyl, substituted or unsubstituted Q 3 alkoxy, morpholinyl, or two R 2s to form a 4-6 membered heterocyclic ring containing two 0s; m is 1, 2 or 3.
  • the compound is selected from the following group:
  • the present invention also provides the compound described in the first aspect for the treatment of pulmonary hypertension and related diseases.
  • the pulmonary hypertension-related diseases include but are not limited to: pneumonia, inflammatory disorders, inflammatory bowel disease, cardiovascular disease, kidney disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disorders, urinary disorders Systemic diseases and neurological diseases.
  • the present invention provides a method for treating pulmonary hypertension and related diseases, the method comprising administering a therapeutically effective amount of the compound described in the first aspect to a patient in need of treatment of pulmonary hypertension and related diseases.
  • the pulmonary hypertension-related diseases include but are not limited to: pneumonia, inflammatory disorders, inflammatory bowel disease, cardiovascular disease, kidney disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disorders, urinary disorders Systemic diseases and neurological diseases.
  • the present invention provides a medicament containing the compound described in the first aspect for the treatment of pulmonary hypertension and related diseases.
  • the pulmonary hypertension-related diseases include but are not limited to: pneumonia, inflammatory disorders, inflammatory bowel disease, cardiovascular disease, kidney disease, diabetes, glaucoma, obesity, osteoporosis, fibrotic disorders, urinary disorders Systemic diseases and neurological diseases.
  • Figure 1 shows the effect of dexlansoprazole on RVSP, mPAP and RVHI in rats with monocrotaline-induced pulmonary hypertension
  • Figure 1A is RVSP: pulmonary artery systolic pressure
  • Figure 1B is mPAP: mean pulmonary artery pressure
  • Figure 1C is RVHI: right ventricular hypertrophy index
  • Figure 2 shows the lungs of a rat with dextrolansolaw versus monocrotaline-induced pulmonary hypertension
  • arteriole remodeling Figure 2A is the H&E staining image of the lung
  • Figure 2B is the WT% : the thickness of the middle pulmonary arterioles as a percentage of the outer diameter of the blood vessel
  • Figure 2C is the WA%: the area of the middle pulmonary arterioles accounts for the wall area Percentage of total blood vessel area
  • Figure 3 shows the effect of esomeravamagnesium, voronolazan fumarate, pumaravail and lan
  • the aromatic ring may be optionally substituted with 1-4 (for example, 1, 2, 3, or 4) substituents selected from the group consisting of halogen, C M aldehyde, Cw alkyl, cyano, nitro , Amino, hydroxy, hydroxymethyl, halogen-substituted alkyl (such as trifluoromethyl), carboxy, C M alkoxy, ethoxyformyl, N (CH 3 ) and C M acyl, etc., heterocyclic group or Heteroaryl, etc.
  • the term "5-membered or 6-membered heteroaromatic ring" means that at least one of the atoms forming the aromatic ring skeleton is not carbon, but nitrogen, oxygen, or sulfur, etc.
  • a heterocyclic ring contains no more than 4 nitrogens , No more than 2 oxygens and/or no more than 2 sulfurs.
  • heterocycles can be saturated, partially unsaturated or fully unsaturated rings.
  • Cp 6 alkyl refers to having 1-6 A straight or branched chain alkyl group with three carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
  • Central oxy refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy Group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group or similar groups.
  • alkylthio refers to a group obtained by replacing the oxygen atom in an alkoxy group with a sulfur atom.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • halogenated refers to a group substituted with one or more of the same or different halogen atoms, such as trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, or similar groups.
  • Q_ 3 acyl refers to the group represented by RC(O)-, where R is H, Q_ 2 alkyl; similarly, the term “C M Ester group "refers to a QC (0) -0 - group, in which Q is H or alkyl Q_ 5 proton pump inhibitor compounds described herein and their use in the prevention and treatment of pulmonary hypertension.”
  • Proton “Pump inhibitor” has the meaning conventionally understood by those skilled in the art; that is, it exists on the biofilm and actively transports H + membrane proteins against the electrochemical potential difference of H on both sides of the membrane ( ⁇ #[ + ). Stomach.
  • H + -K + ATPase proton pump
  • H + protons
  • K + K + into the gastric parietal cells.
  • protons proton pump inhibitors
  • common clinical proton pump inhibitors include omeprazole, Lansolaw, pantoprazole, rabeprazole and esmelawa, etc.
  • the proton pump inhibitor compound of the present invention is a compound represented by formula I or a compound represented by formula II: In the formula, C ring, R 9 , o, Y, q, D ring, R 1() and p are as defined above. In a specific embodiment, the proton pump inhibitor compound of the present invention is a compound selected from the following group:
  • the present invention provides lansoprazole or dexlansoprazole as the prevention and/or treatment of pulmonary hypertension.
  • the structural formulas of the lansoprazole and dexlansolaw are shown below
  • the present invention also provides various derivatives of lansoprazole as drugs for preventing and/or treating pulmonary hypertension.
  • the present invention provides the compound represented by the following formula 1-2 as a medicine for preventing and/or treating pulmonary hypertension, 1-2 where
  • Ring B, R 2 and m are as described above.
  • the compound represented by formula II is the following compound: Based on the compounds of the present invention, those skilled in the art can make them into pharmaceutically acceptable salts. For example, 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 acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc.
  • the organic acid includes 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 ise
  • the structural formula described in the present invention is intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers): for example, containing asymmetric centers The R and S configuration of the double bond, the (Z) and (E) isomers of the double bond, etc. Therefore, the individual stereochemical isomers of the compounds of the present invention or their enantiomers, diastereomers or geometric Mixtures of isomers (or conformational isomers) are within the scope of the present invention.
  • the proton pump inhibitor compound of the present invention can prevent and/or treat pulmonary hypertension and related diseases
  • the pulmonary hypertension is manifested by the phenomenon of increased pulmonary artery pressure, thickening of small pulmonary arteries, etc.
  • pulmonary hypertension-related diseases include but are not limited to: pneumonia, inflammatory diseases, inflammatory bowel disease, and cardiovascular disease , Nephropathy, diabetes, glaucoma, obesity, osteoporosis, fibrotic disorders, urinary system disorders and neurological disorders, etc.
  • the proton pump inhibitor compounds of the present invention and their pharmaceutically acceptable salts
  • the present invention also provides a pharmaceutical composition containing the proton pump inhibitor compound, and the pharmaceutical composition optionally contains pharmaceutically acceptable excipients.
  • the drug of the present invention includes a safe and effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • the "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 each component of 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).
  • the administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include, but are not limited to, oral and inhalation preparations.
  • 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) humectants, 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; (1) accelerated absorption Agents, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • the dosage form may also contain buffering agents.
  • 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 It is a well-known material 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 a microcapsule form 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.
  • the composition may also contain 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.
  • the compounds 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 at the time of administration is the effective dosage considered pharmaceutically.
  • the compounds and pharmaceutical compositions of the present invention can be administered via oral or gastrointestinal routes. It is most preferably taken orally, taken in one time or taken in divided doses. Regardless of the method of administration, the individual's optimal dosage 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. Of course, 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.
  • dexlansoprazole has the following effects in the prevention and/or treatment of pulmonary hypertension drugs:
  • Each dose of dexlansolawine significantly reduces the pulmonary artery pressure in rats with pulmonary hypertension caused by monocrotaline, and inhibits the hypertrophy of small pulmonary arteries;
  • the present invention proves for the first time that a proton pump inhibitor compound, such as dexlansolaw, has the effect of treating monocrotaline-induced pulmonary hypertension in rats, and can be used to prepare a therapeutic drug for pulmonary hypertension;
  • a proton pump inhibitor compound such as dexlansolaw
  • the structure of the drug of the present invention is significantly different from that of known pulmonary hypertension drugs, which can lay a new material foundation for the view of pulmonary hypertension drugs.
  • the present invention will be further explained below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.
  • the experimental methods that do not indicate specific conditions in the following examples are usually based on conventional conditions. Or in accordance with the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and parts by weight.
  • the experimental materials and reagents used in the following examples can be obtained from commercial channels unless otherwise specified. Example 1.
  • the purpose of the experiment was to establish an animal model of pulmonary hypertension by subcutaneously injecting monocrotaline, and at the same time administer the proton pump inhibitor dexlansolaw for treatment, to detect rat pulmonary artery hemodynamics and right heart hypertrophy index RVHI, to judge dexlansolar The efficacy of azole.
  • mice Male SD rats weighing 200-230 g (purchased from Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.), feeding conditions: constant temperature 22 ⁇ 2 ° C, constant humidity 55 ⁇ 5%, light The light and dark are 12 h/day, and the food and water are free for 24 h.
  • SD rats were randomly divided into 6 groups: blank control group, pulmonary hypertension model group, selexipag treatment group, dexlansolaw (Annaiji Chemical Co., Ltd.) low-dose and medium-dose And high-dose treatment group, each group has 6 animals.
  • the Powerlab biological information collection and processing system After the administration, start the Powerlab biological information collection and processing system, connect the prefabricated right heart catheter, fill with 0.2% heparin sodium (Beijing Solebold Technology Co., Ltd.) solution, and then the pressure is 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.
  • heparin sodium Beijing Solebold Technology Co., Ltd.
  • 20% urethane Shanghai Yuanye Biotechnology Co., Ltd.
  • RV right ventricle
  • LV+S left ventricle and interventricular septum
  • RVSP right ventricular systolic pressure
  • mPAP right ventricular mean pressure
  • the right heart hypertrophy index of the blank control group and model group rats were 0.196 ⁇ 0.022 and 0.430 ⁇ 0.044, respectively.
  • the right heart hypertrophy index of the model group was significantly increased (p ⁇ 0.001).
  • the right ventricular hypertrophy index of each dose of dexlansolaw in the treatment group was higher than that of the blank control group, but was significantly lower than that of the untreated model group.
  • Ratio;? ⁇ 0.01) meanwhile, the right heart hypertrophy index of the selexipag treatment group was 0.296 ⁇ 0.027, which was significantly lower than that of the model group (p ⁇ 0.01). It is suggested that dexlansoprazole can relieve the right heart hypertrophy caused by pulmonary hypertension.
  • the purpose of the experiment was to establish an animal model of pulmonary hypertension by subcutaneously injecting monocrotaline, and at the same time give the proton pump inhibitor esomerazole magnesium for treatment, to detect the pulmonary artery hemodynamics and right heart hypertrophy indexes in rats, and to judge Esomera Wow the medicinal effect of magnesium.
  • mice Male SD rats weighing 200-230 g are kept under constant temperature 22 ⁇ 2 ° C, constant humidity 55 ⁇ 5%, light and dark for 12 h/day, and 24 h free intake of food and water.
  • SD rats were randomly divided into 4 groups: blank control group, pulmonary hypertension model group, selexipag-positive drug (1 mg/kg, bid) treatment group, esomerazole magnesium (10 mg/kg, qd) Treatment group, 6 animals in each group.
  • normal saline was injected subcutaneously into the back of the neck of the control group of rats, and monocrotaline solution was injected into the other groups at a dose of 60 mg/kg.
  • the positive drug and esomerazole magnesium were administered continuously for 21 days from the day of modeling (the dosage is 0.5 ml/100 g body weight, intragastric administration), the blank control group and model group were given corresponding volumes of solvent according to body weight.
  • start the Powerlab biological information acquisition and processing system connect the prefabricated right heart catheter, fill the heparin sodium solution, and zero the pressure for use. After injecting 20% urethane solution into the abdominal cavity of the rat for anesthesia, the right neck hair was shaved and the right jugular vein was separated and exposed.
  • RVSP right ventricular systolic pressure
  • mPAP mean right ventricular pressure
  • the experiment set up a selexipag positive drug control group (RVSP: p ⁇ 0.001 compared with the model group, mPAP: 0.001), suggesting that esomeprazole magnesium can improve the increase of pulmonary artery pressure in rats with monocrotaline-induced pulmonary hypertension.
  • the right heart hypertrophy index of the blank control group and model group rats were 0.190 ⁇ 0.045 and 0.382 ⁇ 0.085, respectively.
  • the right heart hypertrophy index of the model group was significantly increased (p ⁇ 0.001).
  • the right heart hypertrophy index of the esomeprazole magnesium treatment group was higher than that of the blank control group, but was significantly lower than the untreated model group (p ⁇ 0.01).
  • the right heart hypertrophy index of the selexipag treatment group was 0.271 ⁇ 0.068. Significantly lower than the model group (p ⁇ 0.01). It is suggested that Esomerazole magnesium can relieve the right heart hypertrophy caused by pulmonary hypertension.
  • the purpose of the experiment was to establish an animal model of pulmonary hypertension by subcutaneously injecting monocrotaline, and at the same time give proton pump inhibitor voronolazan fumarate for treatment, to detect rat pulmonary artery hemodynamics and right heart hypertrophy indexes, and to determine fumaric acid The medicinal effect of Vonuolazan.
  • mice Male SD rats weighing 200-230 g are kept under constant temperature 22 ⁇ 2 ° C, constant humidity 55 ⁇ 5%, light and dark for 12 h/day, and 24 h free intake of food and water.
  • SD rats were randomly divided into 4 groups: blank control group, pulmonary hypertension model group, selexipag positive drug (1 mg/kg, bid) treatment group, vornorazan fumarate (10 mg/kg, qd) ) Treatment group, 6 rats in each group.
  • normal saline was injected subcutaneously into the back of the neck of the blank control group of rats, and monocrotaline solution was injected into the other groups at a dose of 60 mg/kg.
  • the positive drug and voronolazan fumarate were administered continuously for 21 days from the day of modeling (dosage 0.5 ml/100 g body weight, intragastric administration), the blank control group and model group were given corresponding volumes of solvent according to body weight.
  • start the Powerlab biological information acquisition and processing system connect the prefabricated right heart catheter, fill the heparin sodium solution, and zero the pressure for use. After injecting 20% urethane solution into the abdominal cavity of the rat for anesthesia, the right neck hair was shaved and the right jugular vein was separated and exposed.
  • RVSP right ventricular systolic pressure
  • mPAP mean right ventricular pressure
  • the experiment set up a selexipag positive drug control group (compared with the model group RVSP: ⁇ ⁇ 0.001, mPAP: 0.001), suggesting that voronolazan fumarate can improve the increase of monocrotaline-induced pulmonary artery pressure in rats with pulmonary hypertension.
  • the purpose of the experiment was to establish an animal model of pulmonary hypertension by subcutaneously injecting monocrotaline, and at the same time give the proton pump inhibitor pramalazole for treatment, to detect the pulmonary artery hemodynamics and right heart hypertrophy indexes in rats, and to determine the drug of pulmonary valine effect.
  • mice Male SD rats weighing 200-230 g are kept under constant temperature 22 ⁇ 2 ° C, constant humidity 55 ⁇ 5%, light and dark for 12 h/day, 24 h free intake of food and water.
  • SD rats were randomly divided into 4 groups: blank control group, pulmonary hypertension model group, selexipag positive drug (1 mg/kg, bid) treatment group, and pramalava (10 mg/kg, qd) treatment group , 6 in each group.
  • normal saline was injected subcutaneously into the back of the neck of the blank control group of rats, and monocrotaline solution was injected into the other groups at a dose of 60 mg/kg.
  • the positive drug and pramalazole were administered for 21 consecutive days from the day of modeling (the dosage is 0.5 ml/100 g Body weight, intragastric administration), blank control group and model group were given corresponding volumes of solvent according to body weight.
  • start the Powerlab biological information acquisition and processing system connect the prefabricated right heart catheter, fill the heparin sodium solution, and zero the pressure for use.
  • 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.
  • RV right ventricle
  • LV + S left ventricle and interventricular septum
  • RVSP right ventricular systolic pressure
  • mPAP mean right ventricular pressure
  • the experiment also set up a selexipag positive drug control group (compared with the model group, RVSP: p ⁇ 0.001, mPAP: ⁇ ⁇ 0.001), suggesting that pramalazole can improve the increase of monocrotaline-induced pulmonary artery pressure in rats with pulmonary hypertension.
  • the right heart hypertrophy index of the blank control group and model group rats were 0.190 ⁇ 0.045 and 0.382 ⁇ 0.085, respectively.
  • the right heart hypertrophy index of the model group was significantly increased (p ⁇ 0.001).
  • the right ventricular hypertrophy index of the pramalawa treatment group was higher than that of the blank control group, but was significantly lower than that of the untreated model group (p ⁇ 0.001).
  • the right ventricular hypertrophy index of the selexipag treatment group was 0.271 ⁇ 0.068, which is similar to that of the model group. Significantly lower than the group (p ⁇ 0.01).
  • pramalazole has the effect of relieving right heart hypertrophy caused by pulmonary hypertension.
  • the purpose of the experiment was to establish an animal model of pulmonary hypertension by subcutaneously injecting monocrotaline, and at the same time administer dexlansoprazole derivative 119 for treatment, detect the pulmonary artery hemodynamics and right heart hypertrophy indexes in rats, and determine the dexlansoprazole-derived The efficacy of ⁇ 119.
  • mice Male SD rats weighing 200-230 g are kept under constant temperature 22 ⁇ 2 ° C, constant humidity 55 ⁇ 5%, light and dark for 12 h/day, 24 h free food and water. During the experiment, SD rats were randomly divided into 4 groups: blank control group, pulmonary hypertension model group, selexipag positive drug (1 mg/kg, bid) treatment group, 119 (10 mg/kg, qd) treatment group, each group 6 only. On the first day of the experiment, normal saline was injected subcutaneously into the back of the neck of the blank control group of rats, and monocrotaline solution was injected into the other groups at a dose of 60 mg/kg.
  • the positive drug and 119 were administered for 21 consecutive days from the day of modeling (the dosage is 0.5 mL/100 g body weight, Stomach administration), the blank control group and the model group were given corresponding volumes of solvent according to body weight.
  • start the Powerlab biological information acquisition and processing system connect the prefabricated right heart catheter, fill the heparin sodium solution, and zero the pressure for use.
  • 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.
  • the waveform is recorded, and then it passes through the Powerlab biological information acquisition and processing system Read the pressure value.
  • the catheter was taken out, the rat was dissected immediately, and the heart and lung tissues were taken out.
  • RV right ventricle
  • LV + S left ventricle and interventricular septum
  • Separate the right heart hypertrophy index, right heart hypertrophy index ⁇ /; ⁇ + 3).
  • Separate the right lower lung lobe tissue immerse it in 4% paraformaldehyde and fix it for about 1 week, make a 3 pm paraffin section, and then perform hematoxylin-eosin staining.
  • the right ventricular systolic pressure (RVSP) and mean right ventricular pressure (mPAP) of the blank control group were 31.44 ⁇ 2.30 mmHg and 10.88 ⁇ 2.09 mmHg, respectively.
  • RVSP and mPAP were 31.44 ⁇ 2.30 mmHg and 10.88 ⁇ 2.09 mmHg, respectively.
  • the pressure in the dexlansoprazole derivative 119 treatment group was higher than that of the blank control group, but the RVSP was significantly lower than that of the untreated model group (p ⁇ 0.01), and mPAP was also present.
  • the experiment set up a selexipag positive drug control group (compared with the model group RVSP: ⁇ 0.001, mPAP: /? ⁇ 0.001), suggesting that dexlansoprazole derivative 119 can improve monocrotaline-induced pulmonary hypertension in rats with increased pulmonary artery pressure Phenomenon.
  • the right heart hypertrophy index of the blank control group and model group rats were 0.190 ⁇ 0.045 and 0.382 ⁇ 0.085, respectively, and the right heart hypertrophy index of the model group increased significantly (p ⁇ 0.001).
  • the right ventricular hypertrophy index of compound 119 is still higher than that of the blank control group, but is significantly lower than that of the untreated model group ( ⁇ ⁇ 0.05).
  • the right ventricular hypertrophy index of the selexipag treatment group is 0.271 ⁇ 0.068, which is significant compared with the model group Decrease in sex (p ⁇ 0.01). It is suggested that the dexlansolava derivative 119 has the effect of relieving the right heart hypertrophy caused by pulmonary hypertension.
  • Table 5 Comparison of hemodynamic indexes, right heart hypertrophy indexes and pulmonary arteriolar hypertrophy indexes in each experimental group Example 6. The effect of proton pump inhibitors on cell proliferation
  • MTT method to detect PDGF-BB-induced PASMC proliferation After digestion and resuspension, PASMCs that have grown to a confluent state are evenly spread in a transparent 96-well plate, with 5000 cells per well, and placed in a cell incubator overnight. On the second day, the old medium was discarded and all replaced with serum-free DMEM medium to normalize the growth rate of the cells. After 24 h, groups were given dexlansoprazole stimulation. The grouping settings are: normal group (model group), PDGF-BB group, PDGF-BB+rightlansolava 10 pM group, PDGF-BB+rightlansolava 50 pM group and PDGF-BB+rightlansolava 100 nM Group.
  • mice Male SD rats (Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.), 8 weeks old, were randomly divided into 6 groups, namely normoxia group, hypoxia model group, hypoxia +5 mg/ kg dexlansoprazole group, hypoxia + 10 mg/kg dexlansoprazole group, hypoxia + 20 mg/kg dexlansoprazole group and hypoxia + 10 mg/kg sildenafil group, each Group of 8 each.
  • normoxia group hypoxia model group
  • hypoxia +5 mg/ kg dexlansoprazole group hypoxia + 10 mg/kg dexlansoprazole group
  • hypoxia + 20 mg/kg dexlansoprazole group hypoxia + 10 mg/kg sildenafil group
  • Rats in the normoxia group were kept in a normoxia (21% 02) environment for 4 weeks, and the animals in the other 3 groups were kept in a low-pressure and hypoxic chamber (an environment with a simulated altitude of 5500 m, 02 concentration was 10%), daily Hypoxia was 8 hours and continued hypoxia for 4 weeks. Drug intervention was performed while hypoxia was induced.
  • the normoxia group and hypoxia model group were given a mixed solution of (1% DMSO+19% PEG 400+80% normal saline) by intragastric administration, hypoxia+10 mg/kg sidium
  • the nafil group was given sildenafil solution at a concentration of 2 mg/mL by gavage, and the other 3 groups were given dexlansolar at a concentration of 1 mg/mL, 2 mg/mL, and 4 mg/mL by gavage.
  • Wow solution continued administration for 4 weeks.
  • the Powerlab biological information acquisition and processing system (AD Instruments, Australia) was started, and a PE 50 catheter filled with 0.2% heparin sodium normal saline was connected to the pressure transducer for use.
  • the rats were injected intraperitoneally 20% urethane anesthesia, shave the right neck hair and separate and expose the right jugular vein.
  • the PE50 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 a typical right ventricular waveform appears and stabilizes for a period of time, the RVSP and mRVP are recorded and analyzed.
  • the left lung of the rat was taken out and fixed in 4% poly formic acid for 1 week, and lung tissue of appropriate size was cut out to make paraffin sections. Place the H&E stained sections under a microscope for observation.
  • Each section is randomly selected with a diameter of 50-300
  • the small arteries of the lung were photographed and saved.
  • Fig. 5A and Fig. 5B show that the RVSP of rats reared under normoxia is 40.27 ⁇ 2.34 mmHg, while the average RVSP of rats in the model group after exposure to hypoxia for 28 days is 71.09 ⁇ 3.29 mmHg, which is higher than normal. Compared with the group, it was significantly higher (P ⁇ 0.001).
  • High-dose dexlansoprazole (20 mg/kg) can reduce rat RVSP to 57.57 ⁇ 3.96 mmHg (p ⁇ 0.05).
  • high-dose dexlansolaw (20 mg/kg) can also reduce mRVP to 21.20 ⁇ 1.53 mmHg (p ⁇ 0.05).
  • Sildenafil is a PDE-5 inhibitor, used as a positive control drug in this experiment to inhibit the increase in right ventricular pressure caused by hypoxia.
  • FIG. 5D and Figure 5E statistically analyze the WT% and WA% of each group of pulmonary arteries.
  • the analysis shows that the WT% and WA% of the model group are (50.17 ⁇ 4.15)% and (72.38 ⁇ 4.54)%, respectively, which are significantly higher than the normal group (p ⁇ 0.05).
  • the average WT% and WA% values of rats at a dose of 20 mg/kg of dexlansolaw were reduced to (36.57 ⁇ 1.97)% and (57.08 ⁇ 12.16)% respectively after 28 days, which significantly inhibited pulmonary vascular remodeling. (p ⁇ 0.05).
  • Example 8 The effect of dexlansolaw on treatment of pulmonary hypertension in mice induced by SU5416 combined with chronic hypoxia
  • mice Male C57BL/6 mice, 6-8 weeks old, were randomly divided into 4 groups, namely, normoxia group, normoxia + dexlansolaw (10 mg/kg) group, SU5416/low Oxygen (SuHy) group and SuHy+dexlansoprazole (10 mg/kg) group, with 10 rats in each group.
  • the three groups of mice were treated as follows: (1) The normoxic group: The mice were kept in a normoxic (21% 02) environment for 4 weeks, and the blank solvent was injected weekly, and the blank solution was given daily by gavage after 2 weeks.
  • mice were kept in a low-pressure and hypoxic chamber (10% 02) for 4 weeks, and SU5416 solution (20 mg/kg, sc) was subcutaneously injected every week, and a blank was given by gavage after 2 weeks of hypoxia. Solution;
  • SuHy + dexlansolaw (10 mg/kg) group mice are kept in a low-pressure hypoxic chamber for 4 weeks, and SU5416 solution (20 mg/kg, sc) is injected subcutaneously every week, hypoxia 2 A week later, the dexlansoprazole solution was given by gavage.
  • mice After the mice were exposed to SU5416 and hypoxic environment for 4 weeks, they were anesthetized by intraperitoneal injection of pentobarbital (30 mg/kg) and passed through the trachea The catheter is mechanically ventilated. After the mouse has opened the chest, a 1.2 F pressure sensor ((Millar Instruments, USA) is carefully inserted from the apex of the right ventricle, a stable right ventricular pressure is recorded through the Powerlab biological information acquisition and processing system, and RVSP is calculated. After the right ventricular pressure measurement is completed , Take out the catheter, immediately dissect the rat or mouse and take out the heart, absorb the blood in it with filter paper.
  • a 1.2 F pressure sensor (Millar Instruments, USA) is carefully inserted from the apex of the right ventricle, a stable right ventricular pressure is recorded through the Powerlab biological information acquisition and processing system, and RVSP is calculated. After the right ventricular pressure measurement is completed , Take out the catheter, immediately dissect the rat or
  • RV right ventricular wall
  • LV+S left ventricle and ventricular septum

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Abstract

本发明首次发现了质子泵抑制剂及其衍生物在治疗肺动脉高压中的新用途。本发明采用野百合碱诱导大鼠肺动脉高压模型，血小板衍生物生长因子-BB{Platelet-derived growth factcr，PDGF-BB)诱导肺动脉平滑肌细胞(Pulmonary Arterial Smooth Muscle Cell，PASMC)的异常增殖，发现右兰索拉唑等质子泵抑制剂及其衍生物能够降低肺动脉压力，减轻肺中小动脉增厚、抑制PASMC的异常增殖，从而实现了治疗肺动脉高压.

Description

治 疗肺动脉 高压的化 合物及 其应用 技术领域 本发明涉及药物化学领域； 具体地说， 本发明涉及具备肺动脉高压治疗活性的质子泵 抑制剂类化合物及其衍生物及其在治疗肺动脉高压中的应用。 背景技术 肺动脉高压 (Pulmonary arterial hypertension， PAH)是指在静息状态下测得右心导管平 均肺动脉压 (mPAP) ^ 25 mmHg, 在运动时为 30 mmHg的一类最常见的肺血管疾病。 以 肺动脉压力进行性增高、 肺血管重构为病理特点， 临床表现为呼吸困难、 活动耐量减低、 乏 力、心绞痛、晕厥等。根据病理表现、血流动力学特征以及临床诊治策略可将其分为五大类: ①动脉性肺动脉高压; ②左心疾病所致肺动脉高压; ③缺氧和 /或肺部疾病引起的肺动脉高压； ④慢性血栓栓塞性肺动脉高压； ⑤多种机制和 /或不明机制引起的肺动脉高压。该疾病是比较 严重的一种疾病， 具有生存率低、 预后不良， 临床治疗困难等问题， 己严重威胁人类的生命 健康。 基于代表症状严重性的 WHO功能分级将 CTEPH患者分为 I〜 IV级。 I级： 日常体力 活动没有症状； II级： 在静息时是舒适的， 但进行一般体力活动出现症状， 日常活动轻微受 限； III级： 在静息时可以无症状， 但轻微活动后出现症状， 日常活动明显受限； IV级： 肺 动脉高压使患者不能承受任何体力活动，有右心衰竭的体征，休息时可能有呼吸困难和 /或疲 乏， 任何体力活动都会使症状加重。 目前，临床上治疗 PAH的药物主要有三类：前列环素类药物 (依前列醇，贝前列环素 )， 内皮素受体拮抗剂 (波生坦， 马西替坦)， 磷酸二酯酶 -5抑制剂 (西地那非等 )， 可通过舒张 血管来缓解病情， 但效果不佳， 死亡率依旧很高。 近年来， 血管重构被视为是导致 PAH的 主要原因，因此抗血管重构被认为是较有潜力的治疗方法。其中 sGC刺激剂和激动剂由于其 作用途径的独特性而备受关注。利奥西呱是德国拜耳开发的首个新一类 sGC刺激剂，于 2013 年被美国食品药物管理局 (FDA)批准上市， 用于治疗 PAH和慢性血栓栓塞性肺动脉高压， 是第一个用于多病因的抗肺动脉高压药物。 尽管 PAH治疗药物的研发取得了实质性进展， 但患者的预后仍不理想 除了上述药物， 临床实践中还发现一些针对其他适应症开发的药物具有改善 PAH的作 用。 如酪氨酸激酶抑制剂 (Tyrosine kinase inhibitors， TKI)伊马替尼 (Imatinib)主要用于治疗慢 性髓性白血病和恶性胃肠道间质肿瘤。 但研宄表明伊马替尼能够逆转 PAH动物模型的疾病发 展 ［Schermuly, R. T_, E. Dony, et al. (2005). "Reversal of experimental pulmonary hypertension by PDGF inhibition." J Clin Invest 115(10): 2811-2821］ o继伊马替尼之后， 索拉菲尼 (Sorafenib)、 尼 洛替尼 (Nilotinib)等 TKI也被研宄用于治疗 PAH, 在临床试验中同样能够改善 PAH患者的病 f青 ［Klein, M.; Schermuly, etc., Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation 2008, 118 (20), 2081-2090］。 与这些 TKI不同的是， Bcr-Abl激酶抑制剂达沙替尼 ODasatinib)却被发现在临床应用中有可能增加 PAH出现几率。 他汀类药物是内源性胆固醇合 成抑制剂， 作用于 3 -羟基 -3 -甲基戊二酰辅酶 A (HMG-CoA)还原酶。 既往研究结果显示多种他 汀类药物单独使用 ［Kao, P. N. (2005). "Simvastatin treatment of pulmonary hypertension: an observational case series." Chest 127(4): 1446-1452］或与他达拉非 ［Girgis, R. E., D. Li, et al.
(2003). ’’Atenuation of chronic hypoxic pulmonary hypertension by simvastatin." Am J Physiol Heart Circ Physiol 285(3): H938-945］等 PAH特异性药物联合使用时能够改善 PAH动物的血流 动力学、肺血管和右心肥厚等。罗格列酮是过氧化物酶增殖物激活受体 (Peroxisome proliferator activated receptor， PPARy)高选择性的激动齐！ J， 临床上作为胰岛素增敏剂治疗 2型糖尿病。由于 PPARY在 PAH发病过程起重要作用，罗格列酮改善 PAH的作用逐渐为大家所识 ［Crossno, J. T., Jr.; Garat, C. V.; Reusch, J. E_; Morris, K. G_; Dempsey, E. C.; McMurtry, I. F.; Stenmark, K. R.; Klemm， D. J” Rosiglitazone atenuates hypoxia-induced pulmonary arterial remodeling. American journal of physiology. Lung cellular and molecular physiology 2007, 292 (4)， L885-97］。 文献也报道过罗格列酮对低氧诱导的肺动脉高压大鼠 mPAP和红细胞压积的改善作用 ［Crossno, J. T., Jr.; Garat, C. V_; Reusch, J. E.; Morris, K. G.; Dempsey, E. C.; McMurtry, I. F.; Stenmark, K. R.; Klemm, D. J., Rosiglitazone atenuates hypoxia-induced pulmonary arterial remodeling. American journal of physiology. Lung cellular and molecular physiology 2007, 292 (4), L885-97］。 但是这些药物均尚未批准用于治疗 PAH这一适应症。 综上所述， 研发作为治疗肺动脉高压的药物具有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一种具备肺动脉高压治疗活性的化合物； 具体地说， 本发明的 化合物能够治疗、 减轻或缓解肺动脉高压、 肺动脉高压所致的右心肥厚、 肺动脉髙压所致的 肺中小动脉肥厚以及肺动脉平滑肌细胞的异常增殖。 在第一方面， 本发明提供质子泵抑制剂类化合物在制备治疗肺动脉高压及其相关疾病 的药物中的用途。 在优选的实施方式中， 所述肺动脉高压相关疾病包括但不限于： 肺炎、 炎性病症、 炎 性肠病、 心血管疾病、 肾病、 糖尿病、 青光眼、 肥胖、 骨质疏松、 纤维变性病症、 泌尿*** 病症及神经病症。 在具体的实施方式中， 所述质子泵抑制剂类化合物是式 I所示化合物或式 II所示化合 物
Figure imgf000003_0001
式中, A环是 5元或 6元芳环或杂芳环； n是 0-3的整数；
Ri选自： H、 取代或未取代的（^_6烷基、 取代或未取代的 Cw烷氧基、 取代或未取代的 5元或 6元芳基或杂芳基、 卤素、 氨基、 硝基、 羟基；
B环是 5元或 6元芳环或含 1-2个选自 N、 0或 S的杂原子的 5元或 6元杂芳环；
R2选自： H、 取代或未取代的 Q_6烷基、 取代或未取代的 Q_6烷氧基、 取代或未取代的 Q_6烷硫基、 吗啉基、 NR4R5, 其中 R4和 R5各自独立选自 H或取代或未取代的 Q_6烷基； m 是 0-4的整数；
R3选自： H、 取代或未取代的 Cl-6烷基;
Figure imgf000004_0001
II 式中，
C环选自 6-10元芳环或杂芳环;
R9选自： H、 卤素、 取代或未取代的 Cu6烷基、 RuR^NCw酰基， 其中 Ru和 R12各自 独立选自 H或取代或未取代的 Cp3烷基； o是 0-3的整数；
Y 选自： S02、 NR13、 0， 其中 R13选自 H或取代或未取代的 Q_3烷基； q是 0-2的整数；
D 环是 5元或 6元芳环或含 1-2个选自 N、0或 S的杂原子的 5元或 6元杂芳环或杂环； Rio选自： 卤素、 取代或未取代的 Q_6烷基、 取代或未取代的 Q_6烷氧基、 取代或未取 代的 6-10元芳基或杂芳基或杂环基、 NR14R15, 其中 R14和 R15各自独立选自 H、 取代或未取 代的 CM烷基或取代或未取代的 Q_6酯基； p是 1-4的整数。 在具体的实施方式中， 在式 I中，
A 环是苯环、 吡啶环或噻吩环； n是 0、 1或 2;
Ri选自： H、 取代或未取代的
Figure imgf000004_0002
烷氧基、 取代或未取代的吡咯基， 或者两个 形成 含有选自 N、 0或 S的杂原子的 4-6元杂环；
B 环是苯环或吡啶环；
R2选自： 取代或未取代的 Q_3烷基、 取代或未取代的
Figure imgf000004_0003
烷氧基、取代或未取代的 Q_3 烷硫基、 吗啉基、 NR4R5- 其中 R4和 R5各自独立为取代或未取代的 CM烷基， 或者两个 R2 形成含有选自 N、 0或 S的两个杂原子的 4-6元杂环； m 是 1、 2或 3 ;
113为11， 或者 R3与 R2形成取代或未取代的 6-8碳环。 在具体的实施方式中， 所述化合物选自下组：
Figure imgf000005_0001
Figure imgf000006_0003
在具体的实施方式中， 所述化合物如下式 1-1所示：
Figure imgf000006_0001
1-1 式中，
Ri选自： H、 取代或未取代的
Figure imgf000006_0002
烷氧基、 取代或未取代的 Q_3烷基； 、 117和118独立选自： H、 取代或未取代的 Q_3烷氧基、 取代或未取代的 CM烷基。 在具体的实施方式中， 所述化合物选自下组：
Figure imgf000006_0004
在具体的实施方式中， 在式 II中，
C环选自苯基、 批陡基、 咪哇并批陡基或苯并咪哇基；
R9选自： H、 F、 取代或未取代的 Cu3烷基、 RnR^NCw酰基， 其中 Ru和 R12各自独 立选自取代或未取代的 Q_3烷基；
Y选 自： S02、 NH或 0; q是 0或 1 ;
D环选自： 吡咯基、 嘧啶基、 苯基、 苯并二氢吡喃基；
R10选自： F、 取代或未取代的 Cu3烷基、 取代或未取代的苯基、 取代或未取代的四氢 异喹啉基、 NR14R15, 其中 R14和 R15各自独立选自 H、 或取代或未取代的 Q_3酯基； p是 1、 2或 3。 在具体的实施方式中， 所述化合物选自下组：
Figure imgf000007_0002
在第二方面， 本发明提供式 1-2所示化合物，
Figure imgf000007_0001
式中，
B环是苯基或吡哇基；
R2选自： H、 取代或未取代的 CM烷基、 取代或未取代的 Q_3烷氧基、 吗啉基， 或者两 个 R2形成含有两个 0的 4-6元杂环； m 是 1、 2或 3。 在具体的实施方式中， 所述化合物选自下组：
Figure imgf000008_0001
在第三方面， 本发明还提供第一方面所述的化合物， 用于治疗肺动脉高压及其相关疾 病。 在优选的实施方式中， 所述肺动脉高压相关疾病包括但不限于： 肺炎、 炎性病症、 炎 性肠病、 心血管疾病、 肾病、 糖尿病、 青光眼、 肥胖、 骨质疏松、 纤维变性病症、 泌尿*** 病症及神经病症。 在第四方面， 本发明提供肺动脉高压及其相关疾病的治疗方法， 所述方法包括将治疗 有效量的第一方面所述化合物给予需要治疗肺动脉高压及其相关疾病的患者。 在优选的实施方式中， 所述肺动脉高压相关疾病包括但不限于： 肺炎、 炎性病症、 炎 性肠病、 心血管疾病、 肾病、 糖尿病、 青光眼、 肥胖、 骨质疏松、 纤维变性病症、 泌尿*** 病症及神经病症。 在第五方面， 本发明提供一种包含第一方面所述的化合物用于治疗肺动脉高压及其相 关疾病的药物。 在优选的实施方式中， 所述肺动脉高压相关疾病包括但不限于： 肺炎、 炎性病症、 炎 性肠病、 心血管疾病、 肾病、 糖尿病、 青光眼、 肥胖、 骨质疏松、 纤维变性病症、 泌尿*** 病症及神经病症。 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显示了右兰索拉唑对野百合碱所致的肺动脉高压大鼠 RVSP、 mPAP和 RVHI的影 响 （图 1A为 RVSP: 肺动脉收缩压； 图 1B为 mPAP: 肺动脉平均压； 图 1C为 RVHI: 右心 肥厚指数）； 图 2显示了右兰索拉哇对野百合碱致肺动脉高压大鼠肺小动脉重构的影响 （图 2A为肺 部 H&E 染色图； 图 2B为 WT% : 肺中小动脉管壁厚度占血管外径的百分比； ， 图 2C为为 WA% ： 肺中小动脉管壁面积占血管总面积的百分比 图 3显示了埃索美拉哇镁、 富马酸沃诺拉赞、 普马拉哇和兰索拉哇衍生物 119对野百 合碱所致的肺动脉高压大鼠 RVSP、 mPAP和 RVHI的影响 （图 3A为 RVSP：肺动脉收缩压; 图 3B为 mPAP: 肺动脉平均压； 图 3C为 RVHI: 右心肥厚指数； 图 4显示了右兰索拉唑对 PDGF-BB诱导的 PASMC增殖的影响； 图 5显示了右兰索拉唑治疗低氧诱导大鼠肺动脉高压的效果； 图 6显示了右兰索拉唑治疗 SU5416联合慢性低氧诱导的小鼠肺动脉高压的效果。 具体实施方式 发明人经过广泛而深入的研宄， 出乎意料地发现属于质子泵抑制剂的一系列化合物， 这些化合物能够治疗、 减轻或缓解肺动脉高压、 肺动脉高压所致的右心肥厚、 肺动脉高压所 致的肺中小动脉肥厚以及肺动脉平滑肌细胞的异常增殖，从而能够用作治疗肺动脉高压及其 所致疾病的药物。 在此基础上完成了本发明。 基团定义 在本文中， 基团的定义与本领域技术人员常规理解的相同。 为清晰起见对其中的一些 基团定义如下： 在本文中， “5元或 6元芳环”是指含有 5或 6个碳原子的环状芳族基团， 例如苯基。 芳环可任选地被 1-4个 （例如， 1、 2、 3或 4个）选自以下的取代基取代： 卤素、 CM醛基、 Cw 烷基、 氰基、 硝基、 氨基、 羟基、 羟甲基、 卤素取代的烷基（例如三氟甲基）、 羧基、 CM 烷氧基、 乙氧甲酰基、 N（CH3）和 CM酰基等、 杂环基或杂芳基等。 术语 “5元或 6元杂芳环”是指形成芳环骨架的原子中至少一个原子不是碳， 而是氮、 氧 或硫等。 通常， 杂环包含不超过 4个氮、 不超过 2个氧和 /或不超过 2个硫。 除非另外指明， 杂环可以是饱和的、 部分不饱和的或完全不饱和的环。 术语 “Cp6烷基”是指具有 1-6个碳原子的直链或支链烷基， 例如甲基、 乙基、 丙基、 异 丙基、 丁基、 异丁基、 仲丁基、 叔丁基、 或类似基团。 术语 “Ci_6院氧基”指具有 1-6个碳原子的直链或支链焼氧基， 例如甲氧基、 乙氧基、 丙 氧基、 异丙氧基、 丁氧基、异丁氧基、仲丁氧基、 叔丁氧基或类似基团。类似地， “烷硫基” 是指烷氧基中的氧原子被硫原子取代得到的基团。 术语 “卤素 ”指氟、 氯、 溴、 或碘。 术语“卤代的 ”指被相同或不同的一个或多个上述卤原 子取代的基团， 例如三氟甲基、 五氟乙基、 七氟异丙基、 或类似基团。 术语 “Q_3酰基 ”是指 R-C（O）-所示基团， 其中 R为 H、 Q_2烷基； 类似地， 术语 “CM 酯基”是指 Q-C(0)-0 -所示基团， 其中 Q为 H或 Q_5烷基。 质子泵抑制剂类化合物及其在预防和治疗肺动脉高压中的用途 本文所述的“质子栗抑制剂 ”具有本领域技术人员常规理解的含义； S卩，存在于生物膜上， 逆着膜两侧 H的电化学势差 (△#[+)而主动运输 H+的膜蛋白。胃 H+-K+ ATP酶 (质子泵)的功 能是泵出 H+ (质子)， 使之进入胃粘膜腔， 提高胃内的酸度， 作为交换， 将 K+泵入胃壁细胞。 所谓的“质子泵抑制剂”能够与 H+-K+ ATP酶共价结合， 不可逆地使之失活， 因而能够用作 抑制胃酸分泌的药物。 目前临床上常见的质子泵抑制剂类有奥美拉唑、兰索拉哇、泮托拉哇、 雷贝拉唑和艾司奥美拉哇等。 然而， 本发明人出乎意料地发现质子栗抑制剂类化合物能够治疗肺动脉高压及其相关 疾病。 在具体的实施方式中， 本发明的质子栗抑制剂类化合物是式 I所示化合物或式 II所示 化合物：
Figure imgf000010_0001
式中， C环、 R9、 o、 Y、 q、 D环、 R1()和 p如上文所定义。 在具体的实施方式中， 本发明的质子栗抑制剂类化合物是选自下组的化合物:
Figure imgf000010_0002
Figure imgf000011_0001
在优选的实施方式中， 本发明提供兰索拉唑或右兰索拉唑作为预防和 /或治疗肺动脉高 压的药物， 所述兰索拉唑和右兰索拉哇的结构式如以下所示
Figure imgf000012_0001
在以上发现的基础上， 本发明还提供了兰索拉唑的各种衍生物作为预防和 /或治疗肺动 脉高压的药物。 例如， 本发明提供以下式 1-2所示化合物作为预防和 /或治疗肺动脉高压的药 物，
Figure imgf000012_0002
1-2 式中，
B环、 R2、 m如上文所述。 在具体的实施方式中，
Figure imgf000012_0003
在优选的实施方式中， 式 II所示化合物是以下化合物:
Figure imgf000012_0004
在本发明的化合物的基础上， 本领域技术人员可以将其制成药学上可接受的盐。 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。 除非特别说明， 本发明所描述的结构式意在包括所有的同分异构形式（如对映异构， 非 对映异构和几何异构体（或构象异构体）： 例如含有不对称中心的 R、 S构型， 双键的（Z）、 （E） 异构体等。 因此， 本发明化合物的单个立体化学异构体或其对映异构体、 非对映异构体或几 何异构体（或构象异构体）的混合物都属于本发明的范围。 本发明的药物组合物以及给药方法 本发明的质子泵抑制剂类化合物能够预防和 /或治疗肺动脉高压以及相关的疾病。 所述 的肺动脉高压表现为肺动脉压力升高、 肺中小动脉增厚等现象。 本领域技术人员知晓， 肺动 脉高压相关疾病包括但不限于： 肺炎、 炎性病症、 炎性肠病、 心血管疾病、 肾病、 糖尿病、 青光眼、 肥胖、 骨质疏松、 纤维变性病症、 泌尿***病症及神经病症， 等等。 有鉴于此， 在本发明的质子泵抑制剂类化合物及其药学上可接受的盐的基础上。 本发 明还提供了包含所述质子泵抑制剂类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。 本领域技术人员应该理解， 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 吐温 ⑧）、 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、 吸入制剂。 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***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； ⑴ 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。 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， 利用野百合碱所致的大鼠肺动脉高压模型作为动物模型， 本发 明人初步确定了右兰索拉唑的剂量为 5 - 20 mg/kg， 连续给药 21天， 口服。 在具体的实施方式中，右兰索拉唑在预防和 (或)治疗肺动脉高压药物的用途中具有以下 效果：
(1) 右兰索拉哇各剂量显著降低野百合碱所致肺动脉高压大鼠的肺动脉压力，抑制肺中 小动脉肥厚；
(2) 右兰索拉唑各剂量显著抑制血小板衍生物生长因子 -BB (Platelet derived growth factor-BB, PDGF-BB)(20 ng/mL)诱导的大鼠原代肺动脉平滑肌细胞的异常增殖。 本发明的主要优点：
1. 本发明首次证实， 质子泵抑制剂类化合物， 例如右兰索拉哇具有治疗野百合碱致大 鼠肺动脉高压的作用， 可以用于制备肺动脉高压的治疗药物；
2. 本发明的药物与己知的肺动脉高压治疗药物的结构明显不同， 从而能够为肺动脉高 压治疗药物的看法奠定了全新的物质基础。 下面结合具体实施例， 进一步阐述本发明。 应理解， 这些实施例仅用于说明本发明而 不用于限制本发明的范围。 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，否则百分比和份数是重量百分比和重量份数。 以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。 实施例 1.苯并咪哇类质子泵抑制剂衍生物的合成
Figure imgf000015_0001
将胡椒醇 (0.5 g， 3.3 mmol)和无水 DCM放于 50 mL反应瓶中，氩气保护，在冰浴下滴加 二氯亚砜 (0.782 mg， 6.6 mmol)， 在冰浴下搅拌 10分钟后， 常温搅拌 1.5小时， 反应完成， 旋 干溶剂和剩余的二氯亚砜，石油醚过柱，得到黄色油状液体 430 mg，产率为 76.9%。 GC-MS: m/z: 170.0o
(2) 2-((苯并 [1,3] 氧环戊烷 -5 -甲基)-巯基) -1 -氢-苯并咪哇
H
。\ CC NaOH
CI H JC0 h
EtOH, reflux Q ；VsjCXo > 先将 NaOH(174 mg, 4.4 mmol)溶解在乙醇中， 60°C搅拌 30分钟，加入上步产物 (370 mg， 2.2 mmol)和 2 -巯基苯并咪唑 (325 mg， 2.2 mmol)， 升温回流， 反应逐渐析出固体， 4小时后反 应完成， 抽滤， 少量乙醇洗涤， 烘千， 得到白色固体 570 mg, 产率为 92.5%
'H NMR (400 MHz, DMSO-J6) 8 12.54 (s, 1H)， 7.53-7.37 (m, 2H), 7.13-7.11 (m, 2H), 7.02 (d, J= 1.6 Hz, 1H), 6.93-6.91 (m, 1H), 6.83 (d, J= 8 Hz, 1H), 5.98 (s, 2H), 4.49 (s, 2H)。 LC-MS: m/z: 285.10 (M+H)+ o
(3) 2-((苯并［1,3］二氧环戊院 -5 -甲基)-亚砜) -1-氢-苯并咪唑
Figure imgf000015_0002
取上步产物 (464 mg, 1.63 mmol)溶于 DCM中， 冰浴下搅拌， 滴加氧化剂 (338 mg, 1.96 mmol), 冰浴下搅拌 30分钟， 室温搅拌 2小时， 反应完成， 加碳酸钠中和， 搅拌 30分钟， 抽滤， 旋干滤液过柱。 得到白色固体 410 mg， 产率为 83.7%。 lR NMR (400 MHz, DMSO- ) 5 12.54 (s, 1H), 7.53-7.37 (m, 2H), 7.13-7.11 (m, 2H), 7.02 (d, J= 1.6 Hz, 1H), 6.93-6.91 (m, 1H), 6.83 (d, J= 8 Hz, 1H), 5.98 (s, 2H), 4.49 (s, 2H)。 LC-MS: m/z: 301.10 (M+H)+ o 2. 化合物 120的合成
2-（（苯并［1 ,3］二氧环戊烷 -4 -甲基） -亚砜）- 1 -氢-苯并咪哇
Figure imgf000016_0001
*H NMR (400 MHz, DMSO- ) 5 13.50 (s, 1H), 7.65-7.63 (m, 2H), 7.32-7.28 (m, 2H), 6.87 (dd, J\= 0.8 Hz, J2= 6.8 Hz, 1H), 6.75 (t, J= 8 Hz, 1H), 6.64 (dd, J\= 1.2 Hz, J2 — 6.8 Hz, 1H), 5.70 (d, J= 4 Hz, 2H), 4.62-4.44 (m, 2H)。 LC-MS: m/z: 301.10 (M+H)+。
3.化合物 121的合成
4-（2-（（（l苯并咪哇）-2 -亚砜）甲基）苯基）吗啉
Figure imgf000016_0002
'H NMR (400 MHz, DMSO- ) S 7.60 (s, 1H), 7.38-7.30 (m, 3H), 7.27-7.16 (m, 3H), 7.06 (t, J= 7.6 Hz, 1H), 4.86 (d, J= 12.4 Hz, 1H), 4.49 (d, J= 12.8 Hz, 1H), 3.88-3.66 (m, 4H), 2.85-2.73 (m, 4H)。
4
Figure imgf000016_0003
（1） 1-（3 -三氟甲基苄基）-卩比唑 -4 -乙酸乙酯
Figure imgf000016_0004
将 3 -三氟甲基 -1-苄基氯 (1.04 g， 5.35 mmol)、 4 -吡唑甲酸乙酯 (0.5 g， 3.57 mmol)和碳酸铯
(3.49 g, 10.70 mmol)放于 100 mL反应瓶中加乙腈溶解， 室温反应 4小时， 析出固体， 抽滤， 滤液旋干。 得到白色固体 980 mg， 产率为 92.2%。
'H NMR (400 MHz, DMSO- ) S 8.55 (s, 1H), 7.91 (s, 1H), 7.73 (d, J 8.4 Hz, 2H), 7.46 (d, J 8 Hz, 2H), 5.50 (s, 2H), 4.22 (q, J 12 Hz, 2H), 1.27 (t, 6.8 Hz, 3H)。 GC-MS: m/z: 298.10。
(2) 1-(3 -三氟甲基
Figure imgf000017_0001
将上步产物 (488 mg, 1.6 mmol)放于 25 mL两口瓶中加无水 THF溶解， 氩气保护， 冰浴 下滴加锂错氢 (75 mg, 2.1 mmol)， 缓慢升至室温， 反应 5小时， 反应完成， 加水萍灭反应， DCM 萃取， 旋干滤液， 抽滤， 滤液旋干。得到油状液体 256 mg， 产率为 61.1%。 LC-MS: m/z: 257.10 (M+H)+ o
(3) 1-(3 -三氟甲基苄基) -吡唑 -4 -乙基氯
Figure imgf000017_0002
将醇产物 (256 mg， 1 mmol)和氯仿放于 50 mL反应瓶中，氩气保护，在冰浴下滴加二氯 亚砜 (238 mg, 2 mmol), 在冰浴下搅拌 10分钟后， 回流搅拌 2小时， 反应完成， 旋干溶剂和 剩余的二氯亚砜， 得到黄色油状液体 272 mg， 产率为 98.5%。 直接投于下一步。
(4) 2-(((1 -(3-(三氟甲基)苯基)- 1 -吡唑 )-4 -甲基)巯基 )- 1 -苯并咪哇
Figure imgf000017_0003
先将 NaOH (80 mg， 1.9 mmol)溶解在乙醇中， 60°C搅拌 30分钟，加入上步产物 (272 mg, 0.98 mmol)和 2 -巯基苯并咪哇 (148 mg, 0.98 mmol), 升温回流， 反应逐渐析出固体， 4小时 后反应完成， 抽滤， 少量乙醇洗涤， 旋干， 过柱， 得到白色固体 237 mg, 产率为 62.4%。
'H NMR (400 MHz, DMSO-J6) 8 7.51 (s, 1H), 7.47-7.45 (m, 4H), 7.37 (s, 1H), 7.21-7.18 (m, 2H), 7.12 (d， J二 8 Hz, 2H), 5.20 (s, 2H), 4.38 (s, 2H)。 LC-MS: m/z: 389.15 (M+H)+。
(5) 2-(((l-(3-(三氟甲基)苯基 )-1 -吡挫 )-4 -甲基)亚砜 )-1 -苯并咪唑
Figure imgf000017_0004
取上步产物 (237 mg, 0.61 mmol)溶于 DCM中， 冰浴下搅拌， 滴加氧化剂 (126 mg， 0.73 mmol)， 冰浴下搅拌 30分钟， 室温搅拌 4小时， 反应完成， 加碳酸钠中和， 搅拌 30分钟， 抽滤， 旋干滤液过柱。 得到白色固体 180 mg, 产率为 72.2%。
]H NMR (400 MHz, DMSO-t/6) 5 7.64-7.61 (m, 5H), 7.28-7.18 (m, 5H), 5.34 (s, 2H),
4.60-4.36 (m, 2H)。 LC-MS: m/z: 405.15 (M+H)+。 实施例 2.质子泵抑制剂右兰索拉哇对肺动脉高压动物的治疗作用
1. 实验目的 通过皮下注射野百合碱建立肺动脉高压动物模型， 同时给予质子泵抑制剂右兰索拉哇 进行治疗， 检测大鼠肺动脉血流动力学和右心肥厚指标 RVHI, 判断右兰索拉唑的药效。
2. 实验动物和实验方法 体重 200-230 g的雄性 SD大鼠 (购自上海西普尔-必凯实验动物有限公司)， 饲养条件： 恒温 22 ± 2°C， 恒湿 55 ± 5%， 光照明暗各 12 h/天， 24 h自由摄食饮水。 实验过程中将 SD 大鼠随机分为 6组： 空白对照组、 肺动脉高压模型组、 赛乐西帕 (selexipag)治疗组、 右兰索 拉哇 (安耐吉化学有限公司)低剂量、 中剂量和高剂量治疗组， 每组 6只。 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 60 mg/kg。 Selexipag (1 mg/kg, bid)和右兰索拉挫 (5、 10、 20 mg/kg, qd)自造模当日起连续给药 21天 (给药量为 0.5 ml/100g体重， 灌胃给药)， 空白对照组和模 型组按体重给予相应体积的溶剂。 给药结束后，启动 Powerlab生物信息采集与处理***，连接预制的右心导管，充盈 0.2% 肝素钠 (北京索莱宝科技有限公司)溶液后压力校零备用。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*** (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 =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 3 (im的石错 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 x 视野下拍照记录。 使用 Image - pro plus 6.0软件对直径为 100〜 300 (im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%)。
3. 实验结果
(1) 由图 1 A、 B可得， 空白对照组大鼠的右心室收缩压 (RVSP)和右心室平均压 (mPAP) 分别为 21.74 ± 4.95mmHg、 8.85 ± 1.90mmHg。 而经野百合碱诱导形成肺动脉高压后， 大鼠 的 RVSP和 mPAP均明显上升 0? < 0.⑻ l,p < 0.001)。兰索拉哇各剂量治疗组的压力均高于空 白对照组大鼠，但明显低于未用药的模型组 (与模型组相比 RVSP: ;? < 0.05，/7 < 0.01,^ < 0.01， mPAP： /? < 0.01，;? < 0.001，/? < 0.001)。右兰索拉哇 10 mg/kg和 20 mg/kg治疗组的效果接近， 均优于 5 mg/kg剂量的治疗组。 实验并设 selexipag阳性药对照组 (与模型组相比 RVSP： p < 0.01， mPAP： p < 0.001), 提示右兰索拉哇 (5 mg/kg、 10 mg/kg、 20 mg/kg)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 1 C可得空白对照组大鼠和模型组大鼠的右心肥厚指数分别为 0.196 ± 0.022和 0.430 ± 0.044, 模型组的右心肥厚指数明显升高 (p < 0.001)。右兰索拉哇各剂量治疗组的右心 肥厚指数均高于空白对照组大鼠， 但明显低于未用药的模型组， 在剂量为 20 mg/kg时呈现 显著性差异 (与模型组相比; ? < 0.01), 同时 selexipag治疗组的右心肥厚指数为 0.296 ± 0.027, 与模型组相比显著性降低 (p < 0.01)。提示右兰索拉唑具有缓解肺动脉高压所致的右心肥厚作 用。
(3) 由图 2A可得，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， WT % 和 WA% (图 2B和图 2C)相比空白对照组有明显的升高 (p < 0.001, 0.001)。 对比模型组， 右兰索拉哇各剂量给药组大鼠肺组织肺中小动脉肥厚病理变化减轻， WT %和 WA%下降 (与 模型组相比 WT% : < 0.05,^ < 0.05,/? < 0.01 , WA%： /? < 0.05,/? < 0.05,;? < 0.001)。 实验并 设 selexipag阳性药对照组 (与模型组相比 WT % : p < 0.001， WA%： ^ < 0.001), 提示右兰索 拉哇 (5 mg/kg、 10 mg/kg、 20 mg/kg)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 1. 各实验组血流动力学指标、 右心肥厚指标和肺中小动脉肥厚指标的比较
Figure imgf000019_0001
实施例 3.质子泵抑制剂埃索美拉哇镁对肺动脉高压动物的治疗作用
1. 实验目的 通过皮下注射野百合碱建立肺动脉高压动物模型， 同时给予质子泵抑制剂埃索美拉哇 镁进行治疗， 检测大鼠肺动脉血流动力学和右心肥厚指标， 判断埃索美拉哇镁的药效。
2. 实验动物和实验方法 体重 200-230 g的雄性 SD大鼠， 饲养条件为恒温 22 ± 2°C， 恒湿 55 ± 5%， 光照明暗各 12 h/天， 24 h自由摄食饮水。 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阳性药 (1 mg/kg， bid)治疗组、 埃索美拉哇镁 (10 mg/kg， qd)治疗组， 每 组 6只。 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 碱溶液，剂量为 60 mg/kg。阳性药和埃索美拉哇镁自造模当日起连续给药 21天 (给药量为 0.5 ml/100 g体重， 灌胃给药)， 空白对照组和模型组按体重给予相应体积的溶剂。 给药结束后， 启动 Powerlab生物信息采集与处理***， 连接预制的右心导管， 充盈肝 素钠溶液后压力校零备用。 向大鼠腹腔注射 20%的乌拉坦溶液进行麻醉后， 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***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 =RV/(LV+S)。
3. 实验结果
(1) 空白对照组大鼠的右心室收缩压 (RVSP)和右心室平均压 (mPAP)分别为 31.44 ± 2.30mmHg、 10.88 ± 2.09mmHg。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 < 0.001)。 埃索美拉哇镁治疗组的压力均高于空白对照组大鼠， 但明显 低于未用药的模型组 (RVSP: p < 0.01 , mPAP： /? < 0.05)。 实验并设 selexipag阳性药对照组 (与 模型组相比 RVSP: p < 0.001 , mPAP：
Figure imgf000020_0001
0.001), 提示埃索美拉唑镁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) 空白对照组大鼠和模型组大鼠的右心肥厚指数分别为 0.190 ± 0.045和 0.382 ± 0.085, 模型组的右心肥厚指数明显升高 (p < 0.001)。 埃索美拉唑镁治疗组的右心肥厚指数高 于空白对照组大鼠，但明显低于未用药的模型组 (p < 0.01)， 同时 selexipag治疗组的右心肥厚 指数为 0.271 ± 0.068, 与模型组相比显著性降低 (p < 0.01)。 提示埃索美拉哇镁具有缓解肺动 脉高压所致的右心肥厚作用。 表 2. 各实验组血流动力学指标、 右心肥厚指标和肺中小动脉肥厚指标的比较
Figure imgf000020_0002
实施例 4.质子泵抑制剂富马酸沃诺拉赞对肺动脉高压动物的治疗作用
1. 实验目的 通过皮下注射野百合碱建立肺动脉高压动物模型， 同时给予质子泵抑制剂富马酸沃诺 拉赞进行治疗， 检测大鼠肺动脉血流动力学和右心肥厚指标， 判断富马酸沃诺拉赞的药效。
2. 实验动物和实验方法 体重 200-230 g的雄性 SD大鼠， 饲养条件为恒温 22 ± 2°C， 恒湿 55 ± 5%， 光照明暗各 12 h/天， 24 h自由摄食饮水。 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阳性药 (1 mg/kg, bid)治疗组、 富马酸沃诺拉赞 (10 mg/kg， qd)治疗组， 每组 6只。 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 合碱溶液， 剂量为 60 mg/kg。 阳性药和富马酸沃诺拉赞自造模当日起连续给药 21天 (给药量 为 0.5 ml/100 g体重， 灌胃给药)， 空白对照组和模型组按体重给予相应体积的溶剂。 给药结束后， 启动 Powerlab生物信息采集与处理***， 连接预制的右心导管， 充盈肝 素钠溶液后压力校零备用。 向大鼠腹腔注射 20%的乌拉坦溶液进行麻醉后， 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***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 =RV/(LV + S)。
3. 实验结果
(1) 空白对照组大鼠的右心室收缩压 (RVSP)和右心室平均压 (mPAP)分别为 31.44 ± 2.30 mmHg 、 7.776 ± 1.89 mmHg。 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 < 0.001)。 富马酸沃诺拉赞治疗组的压力均高于空白对照组大鼠， 但 明显低于未用药的模型组 (RVSP:
Figure imgf000021_0001
0.001， mPAP： /7 < 0.01)。 实验并设 selexipag阳性药对 照组 (与模型组相比 RVSP: ^ < 0.001 , mPAP： 0.001)， 提示富马酸沃诺拉赞具有改善野 百合碱致肺动脉高压大鼠肺动脉压力增高的现象。
(2) 空白对照组大鼠和模型组大鼠的右心肥厚指数分别为 0.190 ± 0.045和 0.382 ± 0.085 , 模型组的右心肥厚指数明显升高 (p < 0.001)。 富马酸沃诺拉赞治疗组的右心肥厚指数 高于空白对照组大鼠， 但明显低于未用药的模型组 (p < 0.001)， 同时 selexipag治疗组的右心 肥厚指数为 0.271 ± 0.068, 与模型组相比显著性降低 (p < 0.01)。 提示富马酸沃诺拉赞具有缓 解肺动脉高压所致的右心肥厚作用。 表 3. 各实验组血流动力学指标、 右心肥厚指标和肺中小动脉肥厚指标的比较
Figure imgf000021_0002
实施例 5.质子泵抑制剂普马拉唑对肺动脉高压动物的治疗作用
1. 实验目的 通过皮下注射野百合碱建立肺动脉高压动物模型， 同时给予质子栗抑制剂普马拉唑进 行治疗， 检测大鼠肺动脉血流动力学和右心肥厚指标， 判断普马拉哇的药效。
2. 实验动物和实验方法 体重 200-230 g的雄性 SD大鼠， 饲养条件为恒温 22 ± 2°C， 恒湿 55 ± 5%, 光照明暗各 12 h/天， 24 h自由摄食饮水。 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阳性药 (1 mg/kg， bid)治疗组、 普马拉哇 (10 mg/kg, qd)治疗组， 每组 6 只。 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溶 液， 剂量为 60 mg/kg。 阳性药和普马拉唑自造模当日起连续给药 21天 (给药量为 0.5 ml/100 g 体重， 灌胃给药)， 空白对照组和模型组按体重给予相应体积的溶剂。 给药结束后， 启动 Powerlab生物信息采集与处理***， 连接预制的右心导管， 充盈肝 素钠溶液后压力校零备用。 向大鼠腹腔注射 20%的乌拉坦溶液进行麻醉后， 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***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 =RV/(LV + S)。
3. 实验结果
(1) 空白对照组大鼠的右心室收缩压 (RVSP)和右心室平均压 (mPAP)分别为 31.44 ± 2.30 mmHg 、 7.776士 1.89 mmHg。 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 < 0.001)。 普马拉哇治疗组的压力均高于空白对照组大鼠， 但明显低 于未用药的模型组 (RVSP: p < 0.01 , mPAP： < 0.05)。 实验并设 selexipag阳性药对照组 (与 模型组相比 RVSP: p < 0.001， mPAP： ^ < 0.001), 提示普马拉唑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) 空白对照组大鼠和模型组大鼠的右心肥厚指数分别为 0.190 ± 0.045和 0.382 ± 0.085 , 模型组的右心肥厚指数明显升高 (p < 0.001)。 普马拉哇治疗组的右心肥厚指数高于空 白对照组大鼠， 但明显低于未用药的模型组 (p < 0.001)， 同时 selexipag治疗组的右心肥厚指 数为 0.271 ± 0.068, 与模型组相比显著性降低 (p < 0.01)。 提示普马拉唑具有缓解肺动脉高压 所致的右心肥厚作用。 表 4. 各实验组血流动力学指标、 右心肥厚指标和肺中小动脉肥厚指标的比较
Figure imgf000022_0001
实施例 6.右兰索拉唑衍生物 119对肺动脉高压动物的治疗作用
1. 实验目的 通过皮下注射野百合碱建立肺动脉高压动物模型， 同时给予右兰索拉哇衍生物 119进 行治疗， 检测大鼠肺动脉血流动力学和右心肥厚指标， 判断右兰索拉唑衍生物 119的药效。
2、 实验动物和实验方法 体重 200-230 g的雄性 SD大鼠， 饲养条件为恒温 22 ± 2°C， 恒湿 55 ± 5%, 光照明暗各 12 h/天， 24 h自由摄食饮水。 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阳性药 (1 mg/kg， bid)治疗组、 119(10 mg/kg, qd)治疗组， 每组 6只。 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溶液， 剂 量为 60 mg/kg。 阳性药和 119自造模当日起连续给药 21天 (给药量为 0.5 mL/100 g体重， 灌 胃给药)， 空白对照组和模型组按体重给予相应体积的溶剂。 给药结束后， 启动 Powerlab生物信息采集与处理***， 连接预制的右心导管， 充盈肝 素钠溶液后压力校零备用。 向大鼠腹腔注射 20%的乌拉坦溶液进行麻醉后， 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***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=^¥/;¥ + 3)。 分离出 肺右下部肺叶组织， 浸泡于 4%的多聚甲醛中固定 1周左右后制作厚度为 3 pm的石蜡切片， 然后进行苏木素 -伊红染色。每组大鼠肺组织石蜡切片 HE染色完成后， 置于倒置显微镜下观 察， 每个切片分别取 5条肺动脉在 200 x视野下拍照记录。使用 Image - pro plus 6.0软件对直 径为 100 ~ 300 pm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%)。
3. 实验结果
(1) 空白对照组大鼠的右心室收缩压 (RVSP)和右心室平均压 (mPAP)分别为 31.44 ± 2.30 mmHg 、 10.88 ± 2.09 mmHg。 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, 0.001)。 右兰索拉唑衍生物 119治疗组的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 < 0.01), mPAP也呈现。 实验并设 selexipag阳性药 对照组 (与模型组相比 RVSP: < 0.001， mPAP： /? < 0.001)， 提示右兰索拉唑衍生物 119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) 空白对照组大鼠和模型组大鼠的右心肥厚指数分别为 0.190 ± 0.045和 0.382 ± 0.085， 模型组的右心肥厚指数明显升局 (p < 0.001)。 化合物 119的右心肥厚指数尚于空白对 照组大鼠， 但明显低于未用药的模型组 (^ < 0.05)， 同时 selexipag治疗组的右心肥厚指数为 0.271 ± 0.068, 与模型组相比显著性降低 (p < 0.01)。 提示右兰索拉哇衍生物 119具有缓解肺 动脉高压所致的右心肥厚作用。 表 5. 各实验组血流动力学指标、 右心肥厚指标和肺中小动脉肥厚指标的比较
Figure imgf000023_0001
实施例 6.质子泵抑制剂对细胞增殖的影响
1. 大鼠原代 PASMC的培养
4 - 5周龄 SD大鼠， 腹腔注射 10%水合氯醛麻醉， 在 75%酒精中浸泡消毒后， 于安全 柜中开胸后， 取出完整心肺至于冷的 D-Hanks中清洗 2 - 3次。 分离出一段肺动脉， 去除血 管周围组织和血管外膜。纵向剖开肺动脉去除血管内膜。然后在 3.5 cm的培养皿中用眼科手 术剪将血管剪成 1mm3左右的小块并分散。将培养皿翻转（即有细胞的一面朝上），放入 37°C、 5% C02环境的培养箱中干涸 30分钟。 30分钟后取出培养皿并正置，慢慢加入 2 mL含 20% 胎牛血清的 DMEM（高糖型）培养基。 之后， 将培养皿移入细胞培养箱中静置 3天不动， 每隔 3天换液， 至细胞生长至融合状态后传代。 取 3-6代的细胞进行实验。
2. MTT法检测 PDGF-BB诱导的 PASMC增殖 将长至融合状态的 PASMC经消化、 重悬后均匀铺于透明的 96孔板中， 每孔 5000个细 胞， 置于细胞培养箱中过夜。 第二日弃去旧培养基， 全部更换为不含血清的 DMEM培养基， 使细胞的生长速率归一化。 24 h后， 分组加入右兰索拉唑刺激。分组设置为： 正常组（模型组）、 PDGF-BB组、 PDGF-BB+右兰索拉哇 10 pM组、 PDGF-BB+右兰索拉哇 50 pM组和 PDGF-BB+ 右兰索拉哇 100 nM组。 其中正常组（模型组）加入不含化合物的 DMEM培养基， 其余各组分 别加入含不同浓度右兰索拉哇的培养基和终浓度为 20 ng/mL的 PDGF-BB o 48 h后向各孔中分 别加入浓度为 5 mg/mL的 MTT溶液 10 pL， 在 37°C环境下静置 4 h后， 吸除原来的培养基并 加入 150 二甲亚砜， 振荡均匀后， 使用多功能酶标仪（BioTek公司）， 在 490 nm吸光值下读 数》
3. 实验结果 由图 4得， 只加入 PDGF-BB的 PASMC的增殖速率是对照组的 1.5倍， 而在加入 100 HM 、 50 pM和 10 pM浓度的右兰索拉唑后， PASMC的增殖速率是对照组 1.15倍、 1.28倍 和 1.35倍， 说明右兰索拉哇对 PDGF-BB诱导的 PASMC的增殖具有抑制作用。 实施例 7右兰索拉哇治疗低氧诱导大鼠肺动脉高压的效果
1. 实验目的 通过建立低氧诱导的肺动脉高压动物模型评价右兰索拉唑（（R）-Lansoprazole, Dexlansoprazole, Dlan）治疗后大鼠肺动脉血流动力学和右心肥厚指标 RVHI的改善情况， 从 而判断右兰索拉唑改善肺动脉高压的效果。
2. 实验动物和实验方法 雄性 SD大鼠（上海西普尔-必凯实验动物有限公司）， 8周龄， 随机分为 6组， 即常氧组、 低氧模型组、 低氧 +5 mg/kg右兰索拉唑组、 低氧 +10 mg/kg右兰索拉唑组、 低氧 +20 mg/kg 右兰索拉哇组和低氧 +10 mg/kg西地那非组，每组各 8只。其中常氧组大鼠置于常氧（21% 02） 环境中饲养 4周， 其余 3组的动物饲养于低压低氧舱（模拟海拔 5500 m高度的环境， 02浓 度为 10%）中， 每天低氧 8 h， 持续低氧 4周。 在低氧诱导的同时进行药物干预， 其中常氧组 和低氧模型组灌胃给予（1% DMSO+19% PEG 400+80%生理盐水）的混合溶液，低氧 +10 mg/kg 西地那非组灌胃给与浓度为 2 mg/mL的西地那非溶液， 其余 3组则相应灌胃给与浓度为 1 mg/mL、 2 mg/mL和 4 mg/mL的右兰索拉哇溶液， 持续给药 4周。 给药结束后， 启动 Powerlab生物信息采集与处理***（AD Instruments, Australia）, 将充 盈 0.2%肝素钠生理盐水的 PE 50导管连接压力换能器后备用。 给药结束后， 大鼠腹腔注射 20%乌拉坦麻醉， 剃去右颈部毛发并分离暴露出右颈静脉。 PE 50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一段时间 后， 记录并分析 RVSP和 mRVP。 同时取出大鼠的左肺固定于 4%多聚甲酸 1周后，截取适当大小的肺组织制作石蜡切片。 将 H&E 染色后的切片置于显微镜下观察， 每张切片随机选取直径为 50-300
Figure imgf000025_0001
的肺中小动 脉拍照并保存。 用 Image pro plus 6.0软件分析每个血管的内径和外径， 并计算血管壁厚比 WT%=(血管外径-血管内径 )/血管外径 x 100和血管面积比 WA%=血管中膜面积 /血管面积 X100。
3. 实验结果
(1) 图 5A和图 5B的结果显示饲养于常氧环境下大鼠的 RVSP为 40.27 ± 2.34 mmHg, 而暴露于低氧环境 28天后模型组大鼠 RVSP平均值为 71.09 ± 3.29 mmHg， 与正常组相比明 显升高 (P < 0.001)。高剂量右兰索拉唑 (20 mg/kg)可使大鼠 RVSP降低至 57.57 ± 3.96 mmHg(p < 0.05)。同时高剂量的右兰索拉哇 (20 mg/kg)还可降低 mRVP至 21.20 ± 1.53 mmHg(p < 0.05)。 西地那非是一种 PDE-5抑制剂，在本实验中作为阳性对照药可以抑制低氧引起的右心室压力 升高。
(2) 图 5C的 H&E染色结果显示慢性低氧导致大鼠肺动脉管腔狭小、 管壁增厚明显。 而经高剂量右兰索拉哇 (20 mg/kg)和西地那非治疗的大鼠， 肺动脉增厚的情况有明显减轻。
(3) 图 5D和图 5E统计分析了各组肺动脉的 WT%和 WA%。分析可得，模型组的 WT% 和 WA% 分别为 (50.17 ± 4.15)%和 (72.38土 4.54)%， 显著高于正常组 (p < 0.05)。 而 20 mg/kg剂 量的右兰索拉哇千预 28天后大鼠的平均 WT%和 WA%值分别降低至 (36.57 ± 1.97)%和 (57.08 ± 12.16)%, 明显抑制了肺血管重构 (p < 0.05)。 实施例 8右兰索拉哇治疗 SU5416联合慢性低氧诱导的小鼠肺动脉高压的效果
1. 实验目的 通过建立 SU5416 (Semaxinib, 司马沙尼， CAS 204005-46-9)联合慢性低氧诱导的小鼠 肺动脉高压动物模型评价右兰索拉唑治疗后小鼠肺动脉血流动力学和右心肥厚指标 RVHI的 改善情况， 从而判断右兰索拉哇改善肺动脉高压的效果。
2. 实验动物和实验方法 雄性 C57BL/6小鼠， 6-8周龄， 随机分为 4组， 即常氧组、常氧 +右兰索拉哇 (10 mg/kg) 组、 SU5416/低氧 (SuHy)组和 SuHy+右兰索拉唑 (10 mg/kg)组， 每组 10只。 对三组小鼠进 行如下处理， (1) 常氧组： 小鼠置于常氧 (21% 02)环境中饲养 4周， 每周注射空白溶剂， 2 周后每日灌胃给与空白溶液； (2) SuHy组： 小鼠置于低压低氧舱 (10% 02)中饲养 4周， 每周 皮下注射 SU5416溶液 (20 mg/kg, sc)， 低氧 2周后灌胃给与空白溶液； (3)SuHy+右兰索拉哇 (10 mg/kg)组： 小鼠置于低压低氧舱中饲养 4周， 每周皮下注射 SU5416溶液 (20 mg/kg, sc), 低氧 2周后灌胃给与右兰索拉唑溶液。 小鼠暴露于 SU5416和低氧环境 4周后， 腹腔注射戊巴比妥 (30 mg/kg)麻醉， 通过气管 导管进行机械通气。 小鼠开胸后将 1.2 F压力传感器 ((Millar Instruments, USA)自右心室尖小 心置入， 通过 Powerlab生物信息采集与处理***记录一段稳定的右心室压力， 计算 RVSP。 右心室压力测量结束后， 取出导管， 立即解剖大鼠或小鼠并取出心脏， 用滤纸吸净其 中血液。 分离出右心室壁 (RV)以及左心室和室间隔 (LV+S)， 称重并计算右心肥厚指数 =RV/(LV+S)。 同时取出小鼠鼠的肺组织固定于 4%多聚甲醛 1周后， 截取适当大小的肺组织制作石蜡 切片。 将 H&E染色后的切片置于显微镜下观察， 每张切片随机选取直径为 50-300 pm的肺 中小动脉拍照并保存。
3. 实验结果 ⑴ 图 6A和 6B显示 SU5416联合慢性低氧诱导 4周后小鼠的 RVSP达到 34.76 ± 2.37 mmHg ， 与常氧对照组的 RVSP (16.24 ± 1.07 mmHg)相比明显升高 (p < 0.001)， 同时出现明显 的右心肥厚 (p < 0.001)。 与模型组相比， 右兰索拉哇 (10 mg/kg, po)持续给药 14天后可使小鼠 RVSP 下降至 22.50 ± 1.94 mmHg (p < 0.01)， 使 RV/(LV+S)由 (0_40 ± 0.02)下降至 (0.30士 0.02)
(p < 0.01)。 (2) 图 6C说明 SU5416联合慢性低氧导致小鼠肺动脉管壁增厚， 而经右兰索拉唑 (10 mg/kg和 20 mg/kg)治疗后肺动脉增厚的情况有明显减轻。 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

权 利 要 求
1. 质子泵抑制剂类化合物在制备治疗肺动脉高压及其相关疾病的药物中的用途。
2. 如权利要求 1所述的用途， 其特征在于， 所述质子泵抑制剂类化合物是式 I所示化 合物或式 II所示化合物
Figure imgf000027_0001
式中，
A环是 5元或 6元芳环或杂芳环； n是 0-3的整数；
R!选自： H、 取代或未取代的
Figure imgf000027_0002
烷基、 取代或未取代的 Ci6烷氧基、 取代或未取代的 5元或 6元芳基或杂芳基、 卤素、 氨基、 硝基、 羟基；
B环是 5元或 6元芳环或含 1-2个选自 N、 0或 S的杂原子的 5元或 6元杂芳环；
R2选自： H、 取代或未取代的 Q_6烷基、 取代或未取代的 CM烷氧基、 取代或未取代的 Q_6烷硫基、 吗啉基、 NR4R5, 其中 和 R5各自独立选自 H或取代或未取代的 Q_6烷基； m 是 0-4的整数；
R3选自： H、 取代或未取代的 C1-6烷基；
Figure imgf000027_0003
式中，
C环选自 6-10元芳环或杂芳环；
R9选自： H、 卤素、 取代或未取代的
Figure imgf000027_0004
烷基、 RUR^NCM酰基， 其中 Ru和 R12各自 独立选自 H或取代或未取代的 Q_3烷基； o是 0-3的整数；
Y 选自： S02、 NR13、 0， 其中 R13选自 H或取代或未取代的 CM烷基； q是 0-2的整数；
D环是 5元或 6元芳环或含 1-2个选自 N、0或 S的杂原子的 5元或 6元杂芳环或杂环; R10选自： 卤素、 取代或未取代的
Figure imgf000027_0005
烷基、 取代或未取代的 CK6烷氧基、 取代或未取 代的 6-10元芳基或杂芳基或杂环基、 NR14R,5. 其中 R14和 R15各自独立选自 H、 取代或未取 代的 Ci_6烷基或取代或未取代的 Cp6酯基； p是 1-4的整数。
3. 如权利要求 2所述的用途， 其特征在于， 在式 I中，
A 环是苯环、 吡啶环或噻吩环； n是 0、 1或 2;
R!选自： H、 取代或未取代的 CU6烷氧基、 取代或未取代的吡咯基， 或者两个 形成 含有选自 N、 0或 S的杂原子的 4-6元杂环；
B环是苯环或吡啶环；
R2选自： 取代或未取代的 Q_3烷基、 取代或未取代的 CU3烷氧基、 取代或未取代的 烷硫基、 吗啉基、 NR4R5, 其中 R4和 R5各自独立为取代或未取代的 CM烷基， 或者两个 R2 形成含有选自 N、 0或 S的两个杂原子的 4-6元杂环； m 是 1、 2或 3;
R3为 H， 或者 113与112形成取代或未取代的 6-8碳环。
4. 如权利要求 3所述的用途， 其特征在于， 所述化合物选自下组：
Figure imgf000028_0001
Figure imgf000029_0001
式中， 选自： H、 取代或未取代的 CM烷氧基、 取代或未取代的
Figure imgf000029_0002
烷基；
R6、 117和118独立选自： H、 取代或未取代的 Ci_3烷氧基、 取代或未取代的 Cw烷基。
6. 如权利要求 5所述的用途， 其特征在于， 所述化合物选自下组：
Figure imgf000029_0003
Figure imgf000030_0001
7. 如权利要求 2所述的用途， 其特征在于， 在式 II中，
C环选自苯基、 吡啶基、 咪唑并吡啶基或苯并咪唑基；
R9选自： H、 F、 取代或未取代的 CU3烷基、 RuR^NC^酰基， 其中 Ru和 R12各自独 立选自取代或未取代的 Q_3烷基； Y选 自： S02、 NH或 0; q是 0或 1 ;
D环选自： 吡咯基、 嘧啶基、 苯基、 苯并二氢吡喃基；
Rio选自： F、 取代或未取代的 Q_3烷基、 取代或未取代的苯基、 取代或未取代的四氢 异喹啉基、 NR14R15， 其中 R14和 R15各自独立选自 H、 或取代或未取代的 Q_3酯基； p是 1、 2或 3。
8. 如权利要求 7所述的用途， 其特征在于， 所述化合物选自下组：
Figure imgf000030_0002
9. 式 1-2所示化合物，
Figure imgf000031_0001
1-2 式中，
B环是苯基或吡唑基；
R2选自： H、 取代或未取代的 Q_3烷基、 取代或未取代的 Q_3烷氧基、 吗啉基， 或者两 个 R2形成含有两个 0的 4-6元杂环； m 是 1、 2或 3。
10. 如权利要求 9所述的化合物， 其特征在于， 所述化合物选自下组：
Figure imgf000031_0002
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