WO2025168119A1 - Tetrazole compound, pharmaceutical composition thereof and use thereof - Google Patents

Abstract

Disclosed in the present invention are a tetrazole compound, a pharmaceutical composition thereof and the use thereof. Specifically disclosed in the present invention are compound I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a salt thereof. The compound has one or more of the following advantages: novel structure, good metabolic stability, high bioavailability and effectively alleviating pathological damage caused by pulmonary fibrosis.

Description

Tetrazol compounds, pharmaceutical compositions and applications thereof

This application claims priority to Chinese Patent Application No. 2024101770708, filed on February 8, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application.

Technical Field

The present invention relates to tetrazole compounds, pharmaceutical compositions and applications thereof.

Background Art

Pulmonary fibrosis (PF) is a disease characterized by diffuse pneumonia and alveolar structural disorder, ultimately leading to interstitial pulmonary fibrosis. It is generally believed that the pathogenesis of PF is primarily characterized by persistent damage to alveolar epithelial cells, abnormal activation of fibroblasts, and excessive deposition of extracellular matrix. This leads to varying degrees of inflammation and fibrosis in the alveoli and interstitium, ultimately causing structural damage and functional loss of the lungs.

Idiopathic pulmonary fibrosis (IPF) is the most common and most serious chronic interstitial lung disease of unknown etiology. It manifests clinically as progressive dyspnea accompanied by irritating dry cough. The disease often continues to progress, with a median survival of approximately 3-5 years.

According to statistics, there are 5 million people suffering from IPF worldwide, and with the aggravation of lung damage factors such as environmental pollution, this number is still increasing. Currently, the treatment options for IPF are very limited, and there is no drug that can significantly prolong the patient's survival time. During this period, the patient's quality of life and mental state are seriously affected due to the emergence of multiple complications.

Currently, there are two oral anti-pulmonary fibrosis drugs approved by the U.S. Food and Drug Administration (FDA) and recommended for clinical use: pirfenidone and nintedanib. The anti-pulmonary fibrosis mechanism of pirfenidone (PFD) mainly involves regulating pro-fibrotic cytokines such as transforming growth factor (TGF-β) and platelet-derived growth factor (PDGF), reducing the biological activity of fibroblasts, inhibiting the proliferation of fibroblasts, reducing the expression of collagen fibrils, and the synthesis and accumulation of extracellular matrix. Nintedanib is a small molecule tyrosine kinase inhibitor that can simultaneously block the signal transduction pathways of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), and has anti-fibrotic and anti-inflammatory effects.

While these two marketed drugs can slow the decline in lung function, they cannot reverse disease progression. Furthermore, pirfenidone treatment can cause side effects such as photosensitivity, anorexia, dizziness, and abdominal discomfort. Common adverse reactions with nintedanib include diarrhea, nausea, vomiting, elevated liver enzymes, decreased appetite, and hypertension.

Therefore, developing safe and effective drugs for pulmonary fibrosis has important social and medical significance. We have recently discovered that inhibiting the activity of neurokinin receptor 1 (Tachykinin 1 Receptor) can reduce the production of transforming growth factor-beta (TGF-β) in bronchial epithelial cells. This target has the potential to develop anti-pulmonary fibrosis drugs.

Vofopitant ((2S,3S)-N-{2-Methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl}-2-phenyl-3-piperidinamine), also known as vofopitant or wofopitant, is a potent, selective, and orally active tachykinin NK1 receptor antagonist used as an antiemetic. Currently, there are no reports of vofopitant being used to treat pulmonary fibrosis. Vofopitant also suffers from issues such as low metabolic stability and low bioavailability.

Given the importance of developing novel anti-pulmonary fibrosis drugs, there is an urgent need to develop an anti-pulmonary fibrosis compound with novel structure, good therapeutic effect and excellent pharmacokinetic properties.

Summary of the Invention

The technical problem to be solved by the present invention is to overcome the shortcomings of existing anti-pulmonary fibrosis compounds, such as their relatively simple structure, poor metabolic stability, and low bioavailability. To this end, the present invention provides a tetrazole compound, a pharmaceutically acceptable salt thereof, and uses thereof, which have one or more of the following advantages: novel structure, good metabolic stability, high bioavailability, and effective mitigation of pulmonary fibrosis pathological damage.

The present invention solves the above technical problems through the following technical solutions.

The present invention provides a compound I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of its salt,

In a certain embodiment of the present invention, the compound I is selected from the following structures:

The present invention also provides a pharmaceutical composition comprising a substance D and a pharmaceutical excipient, wherein the substance D is the compound I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of its salt.

The present invention also provides a use of a substance D in the preparation of a drug for treating pulmonary fibrosis, wherein the substance D is the compound I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a salt thereof, or the pharmaceutical composition.

The pulmonary fibrosis is preferably interstitial pulmonary fibrosis or idiopathic pulmonary fibrosis.

The present invention also provides a use of a substance D in the preparation of a drug for treating a disease associated with NK-1R, wherein the substance D is the compound I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a salt thereof, or the pharmaceutical composition;

The NK-1R-related disease is preferably nausea and/or vomiting; more preferably nausea and/or vomiting after chemotherapy.

The present invention also provides a use of a substance D in the preparation of a medicament for treating nausea and/or vomiting, wherein the substance D is the compound I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a salt thereof, or the pharmaceutical composition;

The nausea and/or vomiting is preferably post-chemotherapy nausea and/or vomiting.

The present invention also provides a use of a substance D in the preparation of an NK-1R inhibitor, wherein the substance D is the compound I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a salt thereof, or the pharmaceutical composition.

The present invention also provides a compound A, a salt thereof, a solvate thereof or a solvate of its salt,

The "pharmaceutically acceptable salt" described herein refers to a salt that retains the biological activity of the compound and does not cause toxic side effects. Pharmaceutically acceptable salts include various crystalline forms of different salts and amorphous forms. The pharmaceutically acceptable salts of the tetrazole compounds of the present invention can be generated with inorganic acids or organic acids. The pharmaceutically acceptable salts may impart improved pharmacokinetic properties to the active compound compared to the free form of the active compound. The pharmaceutically acceptable salts may also impart desired pharmacokinetic properties that the active compound did not previously possess, and may even positively affect the efficacy of the active compound relative to its therapeutic activity in the body.

The medicament or pharmaceutical composition of the present disclosure may comprise a pharmaceutically acceptable carrier.

The term "carrier" as used in this disclosure includes acceptable diluents, excipients, adjuvants, vehicles, solubilizing aids, viscosity regulators, preservatives and other known agents used to provide advantageous properties in the final drug or pharmaceutical composition to be administered to a subject.

Pharmaceutical preparations can be prepared by any known method in the pharmaceutical field. In general, the active compound can be uniformly and intimately mixed with a liquid carrier or a solid carrier or both, and then, if necessary, the product is shaped or packaged into the desired preparation.

The medicine or pharmaceutical composition of the present disclosure may also be a formulation for administration by inhalation. When the medicine or pharmaceutical composition of the present disclosure is used for administration by inhalation, it may be in the form of a dry powder, an aqueous solution or suspension, or an aerosol.

The drug or pharmaceutical composition in dry powder form may contain a suitable carrier such as lactose or starch and may be presented in various primary packaging systems (e.g., capsules and vials or blister packs) for use in inhalers or insufflators. The formulation may be packaged for unit dose or multi-dose delivery. In the case of multi-dose delivery, the formulation may be pre-metered or metered at the time of use.

The medicament or pharmaceutical composition of the present disclosure may be in unit dosage form, such as a tablet, capsule, or metered aerosol dose, so that a single dose can be administered to a subject.

The drugs or pharmaceutical compositions of the present disclosure may be administered in a single manner or in combination in a variety of ways, depending on whether local or systemic treatment is desired and the area to be treated. When administered in combination in different dosage forms, the drugs may be administered simultaneously, or they may be administered closely together or widely spaced apart, for example, one dosage form in the morning and another in the evening.

The exact amount of the drug or pharmaceutical composition of the present invention required to obtain a therapeutic effect will vary with the subject, depending on the species, age, weight and overall condition of the subject, the severity of the condition being treated, the specific active agent used, its mode of administration, etc. The dosage range for administration of the drug or pharmaceutical composition of the present invention is large enough to produce a therapeutic effect. The dosage can be adjusted to avoid or alleviate adverse side effects, such as the occurrence of unwanted cross-reactions, allergic reactions, etc. The dosage can vary with the patient's age, condition, sex and degree of disease, route of administration, or whether other drugs are included in the treatment regimen. In the event of any contrary indication, the dosage can be adjusted by a separate physician. The dosage can be varied and can be administered one or more times per day, for one or more days. For a given type of pharmaceutical product, guidelines for suitable dosages can be found in the literature.

In the medicine or pharmaceutical composition disclosed herein, Compounds 1-4 may be the sole active ingredient for treating pulmonary fibrosis, or the medicine or pharmaceutical composition disclosed herein may further contain other active ingredients for treating pulmonary fibrosis. The other active ingredients may be any known active drug for treating pulmonary fibrosis.

When the subject also has other diseases, disorders, or conditions, the drug or pharmaceutical composition of the present disclosure can be administered simultaneously with the drugs for treating these diseases, disorders, or conditions, or can be administered very closely or very far apart in time.

The present invention has been described in detail above, but the above embodiments are merely illustrative in nature and are not intended to limit the present invention. In addition, the present invention is not limited by any theory described in the above prior art or invention summary or the following examples.

Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive progress of the present invention is that: the present invention discloses a tetrazole compound and a pharmaceutically acceptable salt thereof, which has one or more of the following advantages: novel structure, good metabolic stability, high bioavailability, and effective reduction of pathological damage in pulmonary fibrosis.

DETAILED DESCRIPTION

The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR measurements were performed using a Bruker ASCEND-400 NMR spectrometer. The solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform ( _CDC13 ), or deuterated methanol ( _CD3OD ). The internal standard was tetramethylsilane (TMS). Chemical shifts are given in units of ^10-6 (ppm).

MS was measured using a Waters SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6120).

The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from Acros Organics, Sigma-Aldrich Chemical Company, Anage Chemicals, Bid Pharmaceutical Technology Co., Ltd., and other companies.

Unless otherwise specified in the following examples, all reactions were carried out under argon or nitrogen atmosphere.

Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon, such as a 1 L argon or nitrogen balloon.

Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon, such as a 1 L hydrogen balloon.

The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

Example 1 Synthesis of Intermediate A

The synthesis scheme of intermediates A-2 to A-6 refers to patent WO0018403A1.

Synthesis of intermediate A:

Intermediate A-6 (2 mmol) was dissolved in DMF (5 mL), and _K₂CO₃ ( ₃ mmol) and _CD₃I (3 mmol) were added to the solution. The reaction was stirred at room temperature for 2 hours. TLC confirmed complete conversion of the starting material. Under ice-cooling, the reaction was quenched with water (20 mL) and extracted three times with ethyl acetate (15 mL). The organic phases were combined, washed sequentially with water (50 mL) and saturated brine ( ₅₀ mL), dried over _Na₂SO₄ , and concentrated to obtain the crude product. Separation by silica gel column chromatography (PE/EA = 5:1) afforded the product as a white solid.

¹ H NMR(400MHz,d6-DMSO)δ7.23(d,1H),7.62(dd,1H),7.73(d,1H),9.96(s,1H).LC-MS:M/Z(ESI):276.1(M+1)

Example 2 Synthesis of Compound 1 ((2R,3R)-2-phenyl-3-[({2-[(trideuteriomethyl)oxy]-5-[5-(trifluoromethyl)-1,2,3,4-tetraazacyclopentan-1-yl]phenyl}methyl)amino]piperidine)

The synthetic route of compound 1 is as follows:

Preparation of NaBH(OAc) ₃ solution:

Under _N₂ protection, _NaBH₄ (5 mmol) was added to THF (10 mL) and stirred at 0°C for 15 minutes. AcOH (20 mmol) was slowly added dropwise to the reaction solution at 0°C (this addition was exothermic and produced numerous bubbles in the reaction solution; care was taken to control the addition rate). After complete addition, the solution was stirred at 0°C for 15 minutes until no gas was generated. AcOH (20 mmol) was then added, and the reaction solution was brought to room temperature and stirred for 30 minutes to obtain the desired NaBH(OAc) _₃ solution, which was used directly in subsequent reactions.

Preparation of compound 1:

Under _N₂ protection, Intermediate A (1 mmol) and Intermediate B1 (1.05 mmol) were dissolved in dichloromethane (25 mL). AcOH (10 mmol) was added to the reaction solution and stirred at room temperature for 30 minutes. The reaction solution was transferred to a 0°C ice bath and the NaBH(OAc) _₃ solution prepared above was added dropwise. After complete addition, the reaction was returned to room temperature and allowed to react for 18 hours. A plate was then drawn to confirm complete conversion of the starting material. The reaction was transferred to an ice bath _and 2N _Na₂CO₃ solution (50 mL) was slowly added to quench the reaction. A large amount of gas was generated. After stirring until no gas was generated, dichloromethane (25 mL) was added and extracted three times. The organic phases were combined, washed sequentially with water (50 mL) and saturated brine ( ₅₀ mL), dried over _Na₂SO₄ , and concentrated to obtain the crude product. The product was separated by silica gel column chromatography (DCM/MeOH = 20:1) to obtain a colorless to light yellow, transparent oil. LC-MS: M/Z (ESI): 436.1 (M+1)

Example 3 Synthesis of Compound 2 ((2S,3S)-2-phenyl-3-[({2-[(trideuteriomethyl)oxy]-5-[5-(trifluoromethyl)-1,2,3,4-tetraazacyclopentan-1-yl]phenyl}methyl)amino]piperidine)

The synthetic route of compound 2 is as follows:

According to the synthesis method in Example 2, compound 2 was synthesized from intermediate A and intermediate B2.

LC-MS: M/Z (ESI): 436.1 (M+1)

Example 4 Synthesis of Compound 3 ((2S,3R)-2-phenyl-3-[({2-[(trideuteriomethyl)oxy]-5-[5-(trifluoromethyl)-1,2,3,4-tetraazacyclopentan-1-yl]phenyl}methyl)amino]piperidine)

The synthetic route of compound 3 is as follows:

According to the synthesis method in Example 2, compound 3 was synthesized from intermediate A and intermediate B3.

LC-MS: M/Z (ESI): 436.1 (M+1)

Example 5 Synthesis of Compound 4 ((2R,3S)-2-phenyl-3-[({2-[(trideuteriomethyl)oxy]-5-[5-(trifluoromethyl)-1,2,3,4-tetraazacyclopentan-1-yl]phenyl}methyl)amino]piperidine)

The synthetic route of compound 4 is as follows:

According to the synthesis method in Example 2, compound 4 was synthesized from intermediate A and intermediate B4.

LC-MS: M/Z (ESI): 436.1 (M+1)

Example 6 Pharmacodynamics Experiment

The oral drug in this example includes an active pharmaceutical ingredient and a solvent.

The active pharmaceutical ingredients are compounds 1 to 4, with a dosage of 30 mg/kg, and the solvent is water.

Establishment of pulmonary fibrosis model: 6-8 week old C57BL6J male mice (Wei Tonglihua, C57BL/6JNifdc) were selected and adaptively fed for one week. They were divided into a model group (6 mice), a compound 1 treatment group (6 mice), a compound 2 treatment group (6 mice), a compound 3 treatment group (6 mice), a compound 4 treatment group (6 mice), a woflopitam treatment group (6 mice), a nintedanib (nintedanib is a commonly used drug for the treatment of IPF in the prior art) treatment group (6 mice) and a control group (6 mice).

Preparation of bleomycin solution: Prepare bleomycin powder to the desired concentration using sterile PBS.

Non-surgical method for transtracheal instillation of bleomycin into the mouse lungs: Mice were anesthetized with isoflurane and suspended on a surgical board at a 70° angle. Bleomycin was instilled transtracheally using a 200 μL pipette.

On the first day, the model group and each treatment group were instilled with bleomycin solution (1 mg/kg/50 μL) through the trachea, and the control group was treated with an equal amount of normal saline. Treatment began 7 days after modeling and lasted for 14 days, for a total of 21 days.

Preparation and administration of drug solutions of Compounds 1 to 4:

Compounds 1 to 4 were dissolved in water to prepare 30 mg/mL stock solutions. When preparing working solutions, they were diluted 5-fold with autoclaved water to prepare the required volumes. The dose of Compounds 1 to 4 was 30 mg/kg per mouse, and the mice were given the drug by gavage.

Preparation and administration of wolflopitant solution:

Dissolve wolfopitant in water to prepare a 30 mg/mL stock solution. To prepare the working solution, dilute it 5-fold with autoclaved water to the required volume. The dose of wolfopitant per mouse was 30 mg/kg, administered by gavage.

Preparation, Dosage, and Administration of Nintedanib Solution: Dissolve nintedanib in DMSO to prepare a stock solution (40 mg/mL). To prepare the working solution, dilute the stock solution 7-fold with 20% SBE-β-CD saline solution to the required volume and mix thoroughly. Nintedanib was administered to each mouse at a dose of 30 mg/kg by oral gavage.

Evaluation of the effects of compound 1 to compound 4 treatment groups, nintedanib treatment group, and wolflupirtant treatment group on the survival rate and lung injury of mice with pulmonary fibrosis

(1) Compounds 1 to 4 can significantly increase the survival rate of mice with bleomycin-induced pulmonary fibrosis

As shown in Table 1, compared with the control group, all the mice in the model group died; compared with the model group, the compound 1 to 4 treatment groups can significantly increase the survival rate of mice with pulmonary fibrosis, and the survival rate of mice in the wolfuopidem treatment group and the nintedanib treatment group is also improved. As shown in Table 1, all the mice in the model group died, and the survival rate of mice in the compound 1 to compound 4 groups, the wolfuopidem group and the nintedanib group was improved, and the effects of compound 1 to compound 4 were 1.2 times that of the wolfuopidem group and 1.6 times that of the nintedanib group.

Table 1 Survival rates of mice in the control group, model group, compound 1 to compound 4, wolfopitant and nintedanib treatment groups

(2) Treatment with compounds 1 to 4 can reduce the degree of pulmonary fibrosis

MASSON staining: Mouse lung tissue was obtained and fixed in 4% paraformaldehyde for 24 hours, dehydrated with a conventional alcohol gradient, embedded in paraffin, and cut into 5 μm sections for MASSON staining. After clearing with xylene, the sections were mounted with neutral gum. Lung pathological changes were observed under a light microscope and photographed. Pathological images were scored using a modified Ashcroft scale, as shown in Table 2.

The modified Ashcro scale scoring criteria are as follows:

As shown in the scoring results in Table 2, compared with the control group, the degree of pulmonary fibrosis damage in the model group mice was aggravated. The compound 1 to compound 4 treatment groups, the woflopidem treatment group and the nintedanib treatment group could improve the degree of pulmonary fibrosis damage in mice, and the degree of improvement of the pulmonary fibrosis damage in mice by compounds 1 to compound 4 was better than that of the nintedanib group and the woflopidem group.

Table 2 Pulmonary fibrosis severity scores in the control group, model group, compound 1, wolfopitant and nintedanib treatment groups

Example 7 Pharmacokinetic Experiment in Rats

For the pharmacokinetic test in rats, male SD rats (Shanghai Jihui) with a body weight of 200-250 g were used and fasted overnight. Six rats were taken and administered 10 mg/kg of compound 1-4 of the present invention and woflopitant by oral gavage, respectively, with water as the solvent. Blood was collected before administration and 15, 30 minutes, and 1, 2, 4, 6, 8, 10, and 24 hours after administration. 0.2 mL of blood was collected and placed in a labeled EDTA-2K anticoagulant tube. After gently inverting the blood to fully mix the anticoagulant (EDTA-2K), it was immediately placed in wet ice and centrifuged within 1 hour after blood collection to separate the plasma. The centrifugation conditions were set to 4°C, 6800Xg, and 6 minutes. The plasma separated after centrifugation was placed in a labeled EP tube and stored in an ultra-low temperature refrigerator as soon as possible until the sample was analyzed. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software. The results are shown in Table 3.

Table 3 Pharmacokinetic test results in rats

Wherein, _Cmax represents peak concentration, _Tmax represents time to peak concentration, AUC represents area under the plasma concentration-time curve, T1 _/2 represents elimination half-life, and F represents bioavailability.

The experimental results show that compounds 1 to 4 of the present invention exhibit excellent plasma exposure, excellent bioavailability, and excellent pharmacokinetic properties.

Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims (10)

A compound I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of its salt,
The compound I, its pharmaceutically acceptable salt, its solvate, or its solvate of the salt according to claim 1, characterized in that the compound I is selected from the following structures:
A pharmaceutical composition comprising a substance D and a pharmaceutical excipient, wherein the substance D is the compound I according to any one of claims 1 to 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of its salt. A use of a substance D in the preparation of a medicament for treating pulmonary fibrosis, wherein the substance D is the compound I according to any one of claims 1 to 2, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a salt thereof, or the pharmaceutical composition according to claim 3. The use according to claim 4, wherein the pulmonary fibrosis is interstitial pulmonary fibrosis or idiopathic pulmonary fibrosis. A use of a substance D in the preparation of a medicament for treating a disease associated with NK-1R, wherein the substance D is the compound I according to any one of claims 1 to 2, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a salt thereof, or the pharmaceutical composition according to claim 3. The use according to claim 6, wherein the NK-1R-related disease is nausea and/or vomiting; preferably nausea and/or vomiting after chemotherapy. Use of a substance D in the preparation of a medicament for treating nausea and/or vomiting, wherein the substance D is the compound I according to any one of claims 1 to 2, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a salt thereof, or the pharmaceutical composition according to claim 3; The nausea and/or vomiting is preferably post-chemotherapy nausea and/or vomiting. A use of a substance D in the preparation of an NK-1R inhibitor, wherein the substance D is the compound I according to any one of claims 1 to 2, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a salt thereof, or the pharmaceutical composition according to claim 3. a compound A, a salt thereof, a solvate thereof or a solvate of its salt,