阅读说明：本技术 Wnk激酶抑制剂在预防和/或治疗高原病中的用途 (Use of WNK kinase inhibitors for the prevention and/or treatment of altitude disorders ) 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/或治疗高原病中的用途,特别是WNK463在预防和/或治疗高原肺水肿、高原性心脏病中的用途。本申请的发明人经试验发现,WNK激酶抑制剂(特别是WNK463)对模拟高原环境(特别是海拔5500米的高原环境)大鼠的肺损伤显示出较好的保护作用,其具有开发成防治高原病(特别是高原肺水肿或高原性心脏病)的药物的潜在价值。(The invention discloses application of a WNK kinase inhibitor in prevention and/or treatment of altitude diseases, in particular application of WNK463 in prevention and/or treatment of altitude pulmonary edema and altitude heart diseases. The inventor of the application finds that WNK kinase inhibitors (particularly WNK463) show a good protective effect on lung injury of rats simulating plateau environment (particularly plateau environment with an altitude of 5500 meters), and have potential value for developing drugs for preventing and treating altitude diseases (particularly high altitude pulmonary edema or altitude heart disease).)

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 a altitude disease, 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, or a salt thereofSubstituted 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;

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 claim 1, wherein the high altitude disease is high altitude pulmonary edema or high altitude heart disease.

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

8. The use according to any one of claims 1 to 6, 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 a hyperglycemic condition.

9. 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 altitude sickness, and especially application of WNK463 in preparation of a product for preventing and/or treating altitude pulmonary edema and altitude heart disease.

Background

The plateau refers to an area with an altitude of more than 3000m, including mountains and plateaus. The plateau air is thin, the atmospheric pressure is low, and the oxygen partial pressure is low. It is easy to make people lack oxygen. The disease caused by the failure of adaptation to the high altitude hypoxic environment is called altitude sickness (mountain sickness). China is a mountainous country, and has a plurality of big mountains and plateaus, and the total area of the areas with the altitude of more than 3000m is 1/6. People who live on plains or stay at a plateau for a short period of time can develop altitude diseases. The disease is generally divided into two major categories, acute and chronic. Acute altitude disease refers to acute hypoxia or disease occurring at the beginning of the plateau and is classified into mild (or benign) and severe (or malignant) depending on its severity. Mild immediate response or acute altitude response; heavy duty is divided into: acute altitude disease of brain type (also known as altitude coma or altitude cerebral edema), acute altitude disease of lung type (also known as altitude pulmonary edema), and mixed type (i.e. the comprehensive manifestations of lung type and brain type). The chronic altitude disease refers to a person who has a disease in the upper half of the year before the plateau or has persistent symptoms of the original acute altitude disease, but a few of the plateau population may also have the disease, including plateau heart disease, plateau erythrocytosis, plateau hypertension, plateau hypotension or mixed diseases (in the three types of the disease, namely the plateau erythrocytosis, the plateau hypertension and the plateau heart disease, two types exist at the same time, and the disease is called mixed type.

In recent years, with the improvement of plateau medical care means, great progress is made in the prevention and treatment of the diseases, but the truly effective protective medicine does not obtain the consensus of the international society. Therefore, the search for new preventive and therapeutic drugs becomes an important task in the research of high altitude medicine.

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 a product for preventing and/or treating altitude diseases.

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 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, 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 halogenAnd (4) element.

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 altitude sickness of the invention comprises acute altitude sickness and chronic altitude sickness generated in the altitude environment.

Specifically, the plateau environment is a plateau environment with an altitude of 2500m or more, and particularly a plateau environment with an altitude of 5500m or more.

Specifically, the acute altitude diseases include: high altitude pulmonary edema, high altitude cerebral edema, or mixed type diseases with abnormal symptoms of brain and lung.

Specifically, the chronic altitude diseases include: a mixed disease exists in two types of three types of the high original heart disease, the high altitude erythrocytosis, the high altitude hypertension, the high altitude hypotension or the high altitude erythrocytosis, the high altitude hypertension and the high original heart disease.

In one embodiment of the present invention, the altitude disorder is high altitude pulmonary edema.

In another embodiment of the present invention, the above-mentioned altitude disease is a high altitude heart disease.

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

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

In particular, for the above uses, WNK kinase inhibitors, altitude disorders and products have the above definitions of the 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, in the above pharmaceutical composition, the WNK kinase inhibitor is combined with one or more other active ingredients for preventing and/or treating altitude sickness, wherein the WNK kinase inhibitor and the active ingredients can be formulated for simultaneous, separate or sequential administration (simultaneousness).

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 a altitude disease, which comprises the step of administering an effective amount of a WNK kinase inhibitor or the above-described pharmaceutical composition of the present invention to a subject in need thereof.

Specifically, in the above method, the WNK kinase inhibitor, the pharmaceutical composition, and the altitude sickness 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.

The inventor of the application finds that WNK kinase inhibitors (particularly WNK463) show a good protective effect on lung injury of rats simulating plateau environment (particularly plateau environment with an altitude of 5500 meters), and have potential value for developing drugs for preventing and treating altitude diseases (particularly high altitude pulmonary edema or altitude heart disease).

Drawings

FIG. 1 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. 2 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. 3 shows the change in PAAT of the rats of 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 CO change in the rats of 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. 5 shows the variation of IVSd in the individual groups of rats, p<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.

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.