阅读说明：本技术 Wnk激酶抑制剂在预防和/或治疗肺动脉高压中的用途 (Use of WNK kinase inhibitors for the prevention and/or treatment of pulmonary hypertension ) 是由 何昆仑 张泽宇 刘春蕾 高晓健 李鑫 李晨 韦清霞 李寒露 于 2019-09-17 设计创作，主要内容包括：本发明公开了WNK激酶抑制剂在预防和/或治疗肺动脉高压中的用途,特别是WNK463在预防和/或治疗肺动脉高压及其并发症中的用途。本申请的发明人经试验发现,WNK激酶抑制剂(特别是WNK463)对野百合碱(MCT)诱导的肺动脉高压模型大鼠的肺循环-右心压力、功能及右心室肥厚等均显示出较好的保护作用,其具有开发成防治肺动脉高压及其并发症的药物的潜在价值。(The invention discloses application of a WNK kinase inhibitor in prevention and/or treatment of pulmonary hypertension, in particular application of WNK463 in prevention and/or treatment of pulmonary hypertension and complications thereof. Through experiments, the inventor of the application finds that WNK kinase inhibitors (particularly WNK463) show good protective effects on pulmonary circulation-right heart pressure, functions, right ventricular hypertrophy and the like of a pulmonary arterial hypertension model rat induced by Monocrotaline (MCT), and have potential values for developing medicines for preventing and treating pulmonary arterial hypertension and complications thereof.)

1. Use of a WNK kinase inhibitor or a pharmaceutical composition comprising a WNK kinase inhibitor in the manufacture of a product for the prevention and/or treatment of pulmonary hypertension and its complications, wherein the WNK kinase inhibitor has the structure of formula I:

wherein R is₁-R₁₃Independently selected from: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR₁₆、-C(O)OR₁₆、-C(O)NR₁₆R₁₇、-CH＝NR₁₆、-CN、-OR₁₆、-OC(O)R₁₆、-S(O)_t-R₁₆、-NR₁₆R₁₇、-NR₁₆C(O)R₁₇、-NO₂、-N＝CR₁₆R₁₇And halogen;

R₁₄and R₁₅Independently selected from: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted aralkylSubstituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR₁₆、-C(O)OR₁₆and-C (O) NR₁₆R₁₇(ii) a Or, R₁₄And R₁₅A substituted or unsubstituted heterocyclic group formed with the nitrogen atom to which both are attached;

R₁₆and R₁₇Independently selected from: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl and halogen;

the pharmaceutical composition comprises the WNK kinase inhibitor and one or more pharmaceutically acceptable auxiliary materials.

2. The use according to claim 1, wherein R is₁-R₁₃Independently selected from: hydrogen, halogen, and substituted or unsubstituted alkyl.

3. The use according to claim 1, wherein R is₁₄Is hydrogen, R₁₅Selected from: hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl.

4. The use according to claim 1, wherein R is₁-R₁₄Are all hydrogen; and/or, said R₁₅Is a tert-butyl group.

5. The use of claim 1, wherein the WNK kinase inhibitor is WNK463 having the formula:

6. the use of any one of claims 1 to 5, wherein the WNK kinase inhibitor is the sole active ingredient in the pharmaceutical composition.

7. Use according to any one of claims 1 to 5, wherein the WNK kinase inhibitor is combined in the pharmaceutical composition with one or more other active ingredients for the prevention and/or treatment of pulmonary hypertension and its complications.

8. Use according to claim 7, characterized in that the other active ingredients are selected from: one or more of a prostacyclin-based drug, an endothelin receptor antagonist, a phosphodiesterase type 5 inhibitor, a soluble guanylate cyclase agonist, a 5-hydroxytryptamine transporter inhibitor, a growth factor inhibitor, and a Rho kinase inhibitor.

9. The use of claim 8, wherein the prostacyclin-based drug is selected from the group consisting of: one or more of beraprost, treprostinil, iloprost, and epoprostenol;

the type 5 phosphodiesterase inhibitor may be selected from: one or more of sildenafil, vardenafil and tadalafil;

the soluble guanylate cyclase agonist is riociguat;

the 5-hydroxytryptamine transporter inhibitor is sarpogrelate.

10. The use according to claim 1, wherein the product is a pharmaceutical, food or nutraceutical product.

Technical Field

The invention relates to the technical field of medicines, in particular to application of a WNK kinase inhibitor in preparation of a product for preventing and/or treating pulmonary hypertension and complications thereof, and especially application of WNK463 in preparation of a product for preventing and/or treating pulmonary hypertension and complications thereof.

Background

Pulmonary Arterial Hypertension (PAH) refers to a hemodynamic and pathophysiological state in which the pulmonary arterial pressure rises above a certain threshold, and the etiology is complex, and is caused by various cardiovascular, pulmonary or pulmonary vascular diseases, which can lead to right heart failure, either as an independent disease, as well as complications, or syndromes. The hemodynamic diagnostic criteria are: under the resting state of sea level, the average pulmonary artery pressure detected by the right heart catheter is more than or equal to 25 mmHg.

Pulmonary hypertension is divided into primary and secondary categories. With the gradual and intensive understanding of pulmonary hypertension, the World Health Organization (WHO) "pulmonary hypertension conference" in 2003 classifies pulmonary hypertension according to etiology, pathophysiology, treatment scheme and prognosis features, which was revised by the american academy of thoracic physicians (ACCP) and the european society for cardiovascular diseases (ESC) in 2004, and has guiding significance for the treatment of patients with pulmonary hypertension. It is generally considered that pulmonary hypertension is detected when the mean pulmonary artery pressure detected by the right heart catheter in a calm state is equal to or greater than 25mmHg (Badesch et al, 2009). Pulmonary hypertension can be classified according to the resting PAPm, the mild is 26-35 mmHg; moderate is 36-45 mmHg; the severity was > 45 mmHg.

Pulmonary hypertension is characterized by pulmonary arteriolar vascular remodeling and pulmonary arterial vascular smooth muscle proliferation as pathological features, and is characterized by increased pulmonary circulation pressure and resistance, which can cause increased right heart load, right heart dysfunction and reduced pulmonary blood flow, thereby causing a series of clinical manifestations; pulmonary hypertension often develops progressively during the course of the disease. In particular to right heart failure caused by strengthening pulmonary artery vascular tension, which is a disease seriously threatening the life and health of human beings.

Pulmonary hypertension is a disease that can be treated, but no specific cure is available at present. The traditional treatment methods comprise oxygen inhalation, heart strengthening, diuresis, calcium channel blocker, anticoagulant adjuvant therapy agent and the like, and mainly play a role in relieving symptoms.

In recent years, the development and popularization of targeted therapeutic drugs (mainly including prostacyclin drugs, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, newly-explored soluble guanylate cyclase agonists, 5-hydroxytryptamine transporter inhibitors, growth factor inhibitors, Rho kinase inhibitors, and the like) and treatment methods such as living lung transplantation greatly improve the prognosis of patients.

Although these drugs can relieve the symptoms of PAH to a certain extent, pulmonary hypertension is still an incurable disease with high mortality, median survival time of patients receiving treatment is only 2.7 years, and pulmonary hypertension still lacks a specific cure method, so that the search for new specific therapeutic drugs is urgent.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides the application of the WNK kinase inhibitor in preparing products for preventing and/or treating pulmonary hypertension and complications thereof.

Specifically, the WNK kinase inhibitor has a structure of general formula I:

wherein R is₁-R₁₃Independently selected from: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted alkeneA group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heterocyclylalkyl group, -COR₁₆、-C(O)OR₁₆、-C(O)NR₁₆R₁₇、-CH＝NR₁₆、-CN、-OR₁₆、-OC(O)R₁₆、-S(O)_t-R₁₆、-NR₁₆R₁₇、-NR₁₆C(O)R₁₇、-NO₂、-N＝CR₁₆R₁₇And halogen;

R₁₄and R₁₅Independently selected from: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR₁₆、-C(O)OR₁₆and-C (O) NR₁₆R₁₇(ii) a Or, R₁₄And R₁₅A substituted or unsubstituted heterocyclic group formed with the nitrogen atom to which both are attached;

R₁₆and R₁₇Independently selected from: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl and halogen.

In one embodiment of the invention, R₁、R₂、R₃、R₁₂And R₁₃Independently selected from: hydrogen, halogen, and substituted or unsubstituted alkyl.

In one embodiment of the invention, R₁、R₂、R₃、R₁₂And R₁₃Are all hydrogen.

In one embodiment of the invention, R₄、R₅、R₆、R₇、R₈、R₉、R₁₀And R₁₁Independently selected from: hydrogen, halogen, and substituted or unsubstituted alkyl.

In one embodiment of the invention, R₄、R₅、R₆、R₇、R₈、R₉、R₁₀And R₁₁Are all hydrogen.

In one embodiment of the invention, R₁₄Is hydrogen.

In one embodiment of the invention, R₁₅Selected from: hydrogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl.

In one embodiment of the invention, R₁₅Selected from: c1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, etc.

In one embodiment of the invention, R₁₅Is a tert-butyl group.

In one embodiment of the present invention, the WNK kinase inhibitor is WNK463, which is N- (tert-butyl) -1- (1- (5- (5- (trifluoromethyl) -1,3, 4-oxadiazol-2-yl) pyridin-2-yl) piperidin-4-yl) -1H-imidazole-5-carboxamide, having the following structural formula:

specifically, the pulmonary hypertension is primary pulmonary hypertension or secondary pulmonary hypertension, such as arterial pulmonary hypertension (e.g., idiopathic pulmonary hypertension, hereditary pulmonary hypertension, pulmonary hypertension due to drugs and poisons, or persistent pulmonary hypertension in newborn), pulmonary hypertension associated with left heart disease (e.g., pulmonary hypertension due to cardiac systolic insufficiency, pulmonary hypertension due to diastolic insufficiency, pulmonary hypertension due to valvular disease), pulmonary hypertension due to lung disease (e.g., pulmonary hypertension due to chronic obstructive pulmonary disease, pulmonary hypertension due to emphysema, or pulmonary hypertension due to pulmonary interstitial disease), pulmonary hypertension due to hypoxemia (e.g., pulmonary hypertension due to sleep apnea syndrome, pulmonary hypertension due to chronic altitude disease such as high-grade heart disease), and chronic thromboembolic pulmonary hypertension, and the like.

Specifically, the above complications of pulmonary hypertension are chronic obstructive emphysema, chronic pulmonary heart disease, right heart failure, etc.

Specifically, the product is a medicine, a food, a health product, and the like.

The invention also provides application of the pharmaceutical composition in preparing a product for preventing and/or treating pulmonary hypertension and complications thereof, wherein the pharmaceutical composition comprises a WNK kinase inhibitor and one or more pharmaceutically acceptable auxiliary materials.

In particular, for the above uses, the WNK kinase inhibitors, pulmonary hypertension and its complications and products have the above definitions of the present invention.

In one embodiment of the present invention, the WNK kinase inhibitor is the only active ingredient in the above pharmaceutical composition.

In another embodiment of the present invention, the above pharmaceutical composition wherein the WNK kinase inhibitor is combined with one or more other active ingredients for the prevention and/or treatment of pulmonary hypertension and its complications, wherein the WNK kinase inhibitor and the active ingredients may be formulated for simultaneous, separate or sequential administration.

In one embodiment of the present invention, the above-mentioned other active ingredients are selected from: one or more of a prostacyclin-based drug, an endothelin receptor antagonist, a phosphodiesterase type 5 inhibitor, a soluble guanylate cyclase agonist, a 5-hydroxytryptamine transporter inhibitor, a growth factor inhibitor, and a Rho kinase inhibitor.

Specifically, the prostacyclin drugs can be selected from: one or more of beraprost (Benapnost), Treprostinil (Treprostinil), Iloprost (Iloprost) and Epoprostenol (Epoprostenol).

In particular, the endothelin receptor antagonist can be selected from: one or more of Bosentan (Bosentan), Ambrisentan (Ambrisentan) and Macitentan (Macitentan).

In particular, the type 5 phosphodiesterase inhibitor may be selected from: sildenafil (Sildenafil), Vardenafil (Vardenafil) and Tadalafil (Tadalafil).

Specifically, the soluble guanylate cyclase agonist may be Riociguat (Riociguat).

Specifically, the 5-hydroxytryptamine transporter inhibitor may be Sarpogrelate (Sarpogrelate).

Specifically, the formulation form of the above-mentioned pharmaceutical composition may be any pharmaceutically acceptable dosage form, such as, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, and the like), pills, powders, granules, capsules (including soft capsules, microcapsules), troches, syrups, liquids, emulsions, suspensions, controlled release formulations (e.g., immediate release formulations, sustained release microcapsules), aerosols, films (e.g., orally disintegrating films, oral mucosa-adhesive films), injections (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), intravenous drip, transdermal absorption preparations, ointments, lotions, adhesive preparations, suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, and the like, Oral or parenteral formulations. In one embodiment of the present invention, the pharmaceutical composition is an oral preparation.

Specifically, the above-mentioned pharmaceutical composition is administered into the body by oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, for example, subcutaneous, intravenous, intramuscular, intrathecal, intraventricular, intrasternal, intracranial or intraperitoneal injection or infusion routes, or by means of an external reservoir. In one embodiment of the present invention, the above pharmaceutical composition is administered orally.

Specifically, the pharmaceutically acceptable auxiliary materials are selected from: solvent, emulsifier, plasticizer, disintegrating agent, filler, binder, sweetener, lubricant, etc.

Specifically, the solvent is one or more selected from water, methanol, ethanol, isopropanol, hydroxypropyl-beta-cyclodextrin, polyethylene glycol-15-hydroxystearate, dichloromethane acetone or ethyl acetate.

Specifically, the emulsifier is one or more of polyethylene glycol oleate, polyvinyl alcohol, glyceryl stearate or tween-80.

Specifically, the plasticizer is one or a combination of two or more of polyethylene glycol, castor oil, glycerin, and sorbitol.

Specifically, the disintegrating agent is one or more of crospovidone, sodium carboxymethylcellulose, sodium starch methylcellulose and low-substituted hydroxypropyl cellulose.

Specifically, the filler is one or a combination of two or more of microcrystalline cellulose, erythritol, sorbitol, mannitol, pregelatinized starch, calcium carbonate, sucrose, and lactose.

Specifically, the binder is one or more of polyvinylpyrrolidone, carbomer, hydroxypropyl cellulose, gelatin, guar gum, sodium hydroxymethyl cellulose, hypromellose, magnesium aluminum silicate, ethyl cellulose, hydroxyethyl cellulose, pregelatinized starch, acacia, polyvinyl alcohol, polyvidone, maltodextrin and sodium alginate.

Specifically, the sweetener is one or more of aspartame, xylitol, Mentholum, herba Menthae essence, acesulfame potassium, stevioside and sucralose.

Specifically, the lubricant may be one or a combination of two or more of talc, calcium hydrogenated stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sodium hydrated silica gel, hydrogenated castor oil, zinc stearate, and magnesium stearate.

The present invention also provides a method for preventing and/or treating pulmonary hypertension and its complications, comprising the step of administering to a subject in need thereof an effective amount of a WNK kinase inhibitor or the above-described pharmaceutical composition of the present invention.

Specifically, in the above methods, the WNK kinase inhibitor, the pharmaceutical composition, the pulmonary hypertension and the complications thereof have the above definitions of the present invention.

In one embodiment of the present invention, the subject is a mammal, particularly a human.

Specifically, the effective amount of the above-mentioned WNK kinase inhibitor depends on many factors including the age, weight, sex, natural health condition, nutritional status, activity intensity of the compound, administration time, metabolic rate, severity of the disease, and subjective judgment of the treating physician, etc.

Through experiments, the inventor of the application finds that WNK kinase inhibitors (particularly WNK463) show good protective effects on pulmonary circulation-right heart pressure, functions, right ventricular hypertrophy and the like of a pulmonary arterial hypertension model rat induced by Monocrotaline (MCT), and have potential values for developing medicines for preventing and treating pulmonary arterial hypertension and complications thereof.

Drawings

FIG. 1 shows the change in survival curves of rats in the model group and the treated group.

FIG. 2 shows the change in mPAP of rats in each group<0.05，**p<0.01，***p<0.001, model group vs control group;^#p<0.05，^##p<0.01，^###p<0.001, treatment vs model group; one-way ANOVA.

FIG. 3 shows the RVSP changes of the rats in each group<0.05，**p<0.01，***p<0.001, model group vs control group;^#p<0.05，^##p<0.01，^###p<0.001, treatment vs model group; one-way ANOVA.

FIG. 4 shows the change in TAPES p for each group of rats<0.05，**p<0.01，***p<0.001, model group vs control group;^#p<0.05，^##p<0.01，^###p<0.001, treatment vs model group; one-way ANOVA.

FIG. 5 shows the variation of RVID of rats in each group<0.05，**p<0.01，***p<0.001, model group vs control group;^#p<0.05，^##p<0.01，^###p<0.001, treatment vs model group; one-way ANOVA.

FIG. 6 shows the RVHI variation of rats in each group<0.05，**p<0.01，***p<0.001, model group vs control group;^#p<0.05，^##p<0.01，^###p<0.001, treatment vs model group; one-way ANOVA.

Detailed Description

Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

In the context of the present invention, the following terms have the meanings as detailed below.

"alkyl" refers to a hydrocarbon chain radical that is straight or branched and free of unsaturation, and that is attached by a single bond to the rest of the molecule. Typical alkyl groups contain 1 to about 12, 1 to about 8, or 1 to about 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and the like. If an alkyl group is substituted with a cycloalkyl group, it is correspondingly a "cycloalkylalkyl" radical, such as cyclopropylmethyl. If an alkyl group is substituted with an aryl group, it is correspondingly an "aralkyl" radical, such as benzyl, benzhydryl or phenethyl. If an alkyl group is substituted with a heterocyclyl group, it is correspondingly a "heterocyclylalkyl" radical.

"alkenyl" refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms, at least one unsaturated bond, and which is attached to the rest of the molecule by a single bond. Typical alkenyl groups contain 2 to about 12, 2 to about 8, or 2 to about 6 carbon atoms. In a particular embodiment, the alkenyl group is vinyl, 1-methyl-vinyl, 1-propenyl, 2-propenyl, or butenyl.

"cycloalkyl" refers to an alicyclic hydrocarbon. Typical cycloalkyl groups contain 1 to 4 single and/or fused rings, and 3 to about 18 carbon atoms, preferably 3 to 10 carbon atoms, such as cyclopropyl, cyclohexyl, or adamantyl. In particular embodiments, the cycloalkyl group contains 3 to about 6 carbon atoms.

"aryl" refers to a monocyclic or polycyclic radical, including polycyclic radicals containing monoaryl groups and/or fused aryl groups. Typical aryl groups contain 1 to 3 mono-or fused rings and 6 to about 18 carbon ring atoms, preferably 6 to about 14 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, phenanthryl or anthracyl radicals.

"heterocyclyl" includes heteroaromatic and heteroalicyclic groups containing 1 to 3 monocyclic and/or fused rings and 3 to about 18 ring atoms. Preferred heteroaromatic and heteroalicyclic groups contain from 5 to about 10 ring atoms. Suitable heteroaryl groups in the compounds of the invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms.

"halogen" or "halo" refers to bromo, chloro, iodo or fluoro.

Any reference herein to a compound is intended to represent such a particular compound, and certain variations or forms thereof. In particular, the compounds referred to herein may have asymmetric centers and thus exist in different enantiomeric or diastereomeric forms. Thus, any given compound referred to herein represents any one of the racemates, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomers or geometric isomers of the double bond may also be present, whereby in some cases the molecule may exist as the (E) -isomer or as the (Z) -isomer (trans and cis isomers). If a molecule contains multiple double bonds, each double bond will have its own stereoisomerism, which may be the same or different from that of the other double bonds of the molecule. In addition, the compounds referred to herein may exist as atropisomers. All stereoisomers of the compounds referred to herein, including enantiomers, diastereomers, geometric isomers and atropisomers, and mixtures thereof, are within the scope of the invention.

Furthermore, any of the compounds referred to herein may exist in tautomeric forms. In particular, the term tautomer refers to one of two or more structural isomers of a compound, which isomers are in equilibrium and may be interconverted. Common tautomeric pairs are enamine-imine, amide-imidic acid, keto-enol, lactam-lactam imide, and the like.

Unless otherwise indicated, the compounds of the present invention also include isotopically-labeled forms, i.e., compounds differing only in the presence of one or more isotopically-enriched atoms. E.g. with replacement of at least one hydrogen atom by deuterium or tritium only, or with enrichment¹³C or¹⁴C instead of at least one carbon, or enriched with¹⁵Compounds of the prior art wherein nitrogen of N replaces at least one nitrogen are included within the scope of the present invention.

In the present invention, the term "pulmonary hypertension" is two distinct diseases from the so-called hypertension. The human heart is divided into a left heart system and a right heart system, and the hypertension in daily life refers to the increase of arterial pressure which is emitted from the left heart system and supplies blood to the whole body; the artery emanating from the right heart system is responsible for supplying blood to the lungs and is called the pulmonary artery, and this increase in arterial pressure is called pulmonary hypertension.

In the present invention, the term "effective amount" refers to a dose that achieves treatment, prevention, alleviation and/or alleviation of the disease or disorder described herein in a subject.

The term "subject" can refer to a patient or other animal, particularly a mammal, e.g., a human, dog, monkey, cow, horse, etc., that receives a composition of the invention to treat, prevent, ameliorate, and/or alleviate a disease or disorder described herein.

The term "treating" includes eradicating, removing, reversing, alleviating, altering, or controlling the disease and/or disorder after its onset.

The term "prevention" refers to the ability to prevent, minimize or make difficult the onset or progression of a disease and/or condition by treatment prior to the onset of the disease and/or condition.

The term "disease and/or disorder" refers to a physical condition of the subject that is associated with the disease and/or disorder of the present invention.

The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.