elastase inhibitors and their application in disease treatment

Abstract

This invention belongs to the pharmaceutical field and relates to an elastase inhibitor and its application in disease treatment. Specifically, it relates to a compound of formula (I), a pharmaceutical composition comprising compound (I), and its application in disease treatment. The compound of formula (I) of this invention has an inhibitory effect on elastase and can be used to treat or prevent diseases caused by the action of elastase, including systemic inflammatory response syndrome (SIRS) with acute lung injury (ALI) / acute respiratory distress syndrome (ARDS).

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and more specifically to the use of a compound, composition, and other substances that inhibit elastase activity in the treatment of diseases. These diseases are caused by the action of elastase, including systemic inflammatory response syndrome (SIRS) with acute lung injury (ALI) / acute respiratory distress syndrome (ARDS). Background Technology

[0002] Human neutrophil elastase (NE) plays a crucial role in various inflammatory responses, tissue damage and remodeling (such as pneumonia), adult respiratory distress syndrome, pulmonary fibrosis, acute and chronic lung injury, pulmonary edema, arteriosclerosis, scleroderma, and other pathological processes. It also promotes viral and bacterial invasion and cancer cell metastasis. Studies on inflammatory mechanisms show that an imbalance between this enzyme and its endogenous inhibitors can lead to tissue matrix degradation and worsening inflammation. Currently, research on using NE inhibitors to treat these types of inflammatory diseases is extensive abroad, and the first marketed drug targeting NE inhibition, sivelestat sodiumhydrate, has been successfully developed, thus promoting the research and development of NE inhibitors.

[0003] Cevelexostat sodium, chemical name: N-{2-[4-(2,2-dimethylpropionyloxy)benzenesulfonylamino]benzoyl}aminoacetic acid, with the following structural formula (see patent EP0347168B for its structure and preparation method), is the world's first NE-specific inhibitor developed by Ono Pharmaceutical Co., Ltd. of Japan and first launched in Japan in 2002. Its indication is to improve acute lung injury (ALI) accompanied by systemic inflammatory response syndrome (SIRS). It is also currently the first novel anti-inflammatory enzyme inhibitor officially approved by the National Medical Products Administration of China for improving systemic inflammatory response syndrome (SIRS) with acute lung injury (ALI) / acute respiratory distress syndrome (ARDS), selectively inhibiting neutrophil elastase (NE).

[0004]

[0005] The use of neutrophil elastase inhibitors (NEIs) to treat the aforementioned diseases, especially those accompanied by systemic inflammatory response syndrome (SIRS) with acute lung injury (ALI) / acute respiratory distress syndrome (ARDS), is currently a hot research topic. Therefore, the development of highly effective and low-toxicity neutrophil elastase inhibitors has significant commercial value and practical implications. Summary of the Invention

[0006] The first object of this invention is to provide a compound of formula (I):

[0007]

[0008] in,

[0009] R1 and R2 are independently selected from hydrogen and C. 1-6 Alkyl group, -A-R4;

[0010] R3 can be selected from tert-butylcarbonyl or benzyloxycarbonyl;

[0011] A is a phenyl group;

[0012] R4 is -SO2NH2 or -CONH2.

[0013] In a preferred embodiment of the present invention, in the compound of formula (I): R1 and R2 are independently selected from hydrogen, methyl, ethyl, propyl, and -A-R4;

[0014] More preferably, R1 and R2 are independently selected from methyl, ethyl, and propyl;

[0015] More preferably, R1 is hydrogen, and R2 is selected from methyl, ethyl, propyl, -A-R4;

[0016] More preferably, R3 is selected from tert-butylcarbonyl;

[0017] A more preferred R4 is -CONH2.

[0018] As a preferred embodiment of the present invention, formula (I) is a compound as follows:

[0019]

[0020]

[0021] This invention provides a method for preparing a compound of formula (I), the method of which is as follows:

[0022]

[0023] Compound (Ia) is synthesized by reacting with an amine or a salt of an amine in an inert organic solvent (e.g., dichloromethane) in the presence of an organic or inorganic base (e.g., triethylamine) to form an amide bond.

[0024] A second object of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The carrier is a pharmaceutically acceptable excipient, such as one or more of the following: an inert diluent, a proppant, a lubricant, a disintegrant, a stabilizer, an isotonic buffer, a suspending agent, a sweetener, a flavoring agent, a fragrance, a preservative, an aqueous solvent, a non-aqueous solvent, a suspension medium, an emulsifier, a dispersant, a solubilizer, etc. The composition can be administered by inhalation in the form of a solution, suspension, or inhaler; or orally in the form of tablets, capsules, granules, etc.; or rectally or transdermally in the form of a suppository; or in the form of an injection.

[0025] The solid compositions of the present invention for oral administration include compressed tablets, capsules, dispersible powders, and granules. In such solid compositions, one or more active compounds are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, or magnesium metasilicate. The composition may also contain substances other than inert diluents, such as lubricants like magnesium stearate, disintegrants like calcium cellulose glycolate, stabilizers like lactose, and solubilizers like glutamic acid and asparagine. If desired, tablets or pills can be formulated as gastric-coated or enteric-coated tablets or pills, such as sugar-coated gelatin-coated, hydroxypropyl cellulose-coated, or hydroxypropyl methylcellulose- or phthalate-coated tablets or pills, using two or more layers. Oral compositions may also include capsules containing absorbable substances such as gelatin.

[0026] Liquid compositions intended for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, and syrups containing inert diluents commonly used in the art, such as distilled water or ethanol. In addition to inert diluents, such compositions may also contain adjuvants, such as wetting agents and suspending agents, as well as sweeteners, flavoring agents, aromatizers, and preservatives.

[0027] Other compositions for oral administration include spray compositions that can be prepared by known methods and contain one or more active compounds. In addition to inert diluents, such compositions may also contain stabilizers such as sodium bisulfite and isotonic buffers such as sodium chloride, sodium citrate, or citric acid.

[0028] Injectable preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of aqueous solvents or suspensions are distilled water for injection and physiological saline solutions. Examples of non-aqueous solvents or suspensions are propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), alcohols (e.g., ethanol), and Tween 80. These compositions may also include adjuvants, such as preservatives, wetting agents, emulsifiers, dispersants, and stabilizers (e.g., lactose) and solubilizers (e.g., glutamic acid and asparagine). They may be sterilized, for example, by filtering through a bacterial retention filter, by incorporating a disinfectant into the composition, or by radiation. They may also be manufactured as sterile solid compositions that can be dissolved immediately in sterile water or certain other sterile injectable media before use.

[0029] A third objective of this invention is the use of the compounds or pharmaceutical compositions of this invention as medicines for the treatment or prevention of diseases caused by the action of elastase, including but not limited to: systemic inflammatory response syndrome (SIRS) with acute lung injury (ALI) / acute respiratory distress syndrome (ARDS).

[0030] Terminology Explanation

[0031] In this invention, "alkyl" refers to a saturated alkane having 1 to 6 carbon atoms, such as a straight-chain alkane or a branched-chain alkane; specific alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, etc. The alkyl groups described in this invention may be unsubstituted or optionally substituted by one or more substituents.

[0032] In the substituent -A-R4, -A-R4 is a phenyl group that is ortho-substituted, meta-substituted, or para-substituted. Detailed Implementation

[0033] The embodiments of this invention are provided for understanding the invention, and the scope of the invention is not limited to the following embodiments. Unless otherwise specified, the compounds, reagents, etc. used in the embodiments of this invention are all purchased from qualified suppliers.

[0034] Example 1

[0035] 4-(N,N-dimethylaminosulfonyl)phenyl neopentanoate:

[0036]

[0037] In a 100 mL three-necked flask, 2.2 g of dimethylamine hydrochloride and 10 mL of dichloromethane were added, stirred, and cooled to 5 °C. Then, 5.5 g of triethylamine was added, and at T = 5 °C, a mixed solution of 4-(chlorosulfonyl)phenyl neopentanoate and DCM (5 g of 4-(chlorosulfonyl)phenyl neopentanoate and 10 mL of dichloromethane) was added dropwise. The reaction was monitored by LC-MS. 20 mL of water was added, stirred, and the mixture was separated. The organic phase was concentrated to dryness to obtain 4.9 g of 4-(N,N-dimethylaminosulfonyl)phenyl neopentanoate. HPLC purity: 99.6%.

[0038] 1 H NMR (400MHz, CDCl3) δ1.34(s,9H),2.68(s,6H),7.22-7.26(t,2H),7.76-7.78(d,2H).

[0039] Example 2

[0040] 4-(N-(2-carbamoylphenyl)aminosulfonyl)phenyl neopentanoate:

[0041]

[0042] In a 100 ml three-necked flask, 2 g of 2-aminobenzamide and 20 ml of dichloromethane were added and stirred at room temperature. Then, 4.88 g of 4-(chlorosulfonyl)phenyl neopentanoate was added, followed by dropwise addition of 1.78 g of triethylamine at room temperature. The reaction was monitored by LC-MS. 20 ml of water was added, and after stirring, a solid precipitated. The mixture was filtered, and the filter cake was slurried with 10 ml of water for 0.5 h. The mixture was then filtered again, washed with 20 ml of water, and dried to obtain 2.7 g of 4-(N-(2-aminocarbamoylphenyl)aminosulfonyl)phenyl neopentanoate. The HPLC purity was 99.4%.

[0043] 1 H NMR(400MHz,DMSO-d6)δ1.27(s,9H),7.07-7.15(m,1H),7.26-7.35(m,2H), 7.49(dtd,2H),7.75-7.86(m,3H),7.88(s,1H),8.35(s,1H),12.29(s,1H);

[0044] Following the preparation methods of Examples 1 or 2 above, 4-(chlorosulfonyl)phenyl neopentanoate was reacted with the corresponding amine or amine salt to prepare compounds of Examples 3-7 and 9-10. Compound of Example 8 was synthesized according to the method of patent EP0347168B. Its structural formula is as follows:

[0045]

[0046]

[0047] Activity test

[0048] Test of the inhibitory activity of the compounds of this invention against human neutrophil elastase

[0049] Assay method: Neutrophil elastase has relatively high specificity for the substrate Suc-Ala-Pro-Ala-pNA (succinyl-alanyl-proly-alanyl-pnitroanilide). The p-nitroaniline released in the reaction was quantitatively detected by spectrophotometry.

[0050] The reaction mixture consisted of a 1 mM Suc-Ala-Pro-Ala-pNA solution (dissolved in N-methylpyrrolidone to a concentration of 100 mM, then 1 / 100 of the solution was added to the reaction mixture), 0.1 M tris-hydrochloric acid (pH 8.0) buffer, 0.2 M sodium chloride aqueous solution, sample solutions of the compounds of the present invention at various concentrations, and elastase solution, forming a final volume of 1.0 mL. The mixture was incubated at 37°C for 30 min. Then, 100 μL of 50% acetic acid was added to the reaction mixture to terminate the reaction. The absorbance at 405 nM was measured using a Spectramax spectrophotometer to determine the release of p-nitroaniline. No compounds of the present invention were added to the control group. The inhibition rate was calculated using the following formula, and the half-maximal inhibitory concentration (IC50) was fitted based on the inhibition rates of different compound concentrations. 50 value.

[0051]

[0052] Table 1. Inhibitory activity of compounds against elastase

[0053]

[0054]

[0055] Experimental results show that the compounds of this invention have an inhibitory effect on elastase.

Claims

1. A compound of the following formula:

2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

3. Use of a pharmaceutical composition of claim 2 for the manufacture of a human neutrophil elastase inhibitor.

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