CN115703725A - Elastase inhibitors and their use in the treatment of disease - Google Patents
Elastase inhibitors and their use in the treatment of disease Download PDFInfo
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- CN115703725A CN115703725A CN202110930289.7A CN202110930289A CN115703725A CN 115703725 A CN115703725 A CN 115703725A CN 202110930289 A CN202110930289 A CN 202110930289A CN 115703725 A CN115703725 A CN 115703725A
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Abstract
The invention belongs to the field of medicines, and relates to an elastase inhibitor and application thereof in disease treatment. In particular, it relates to compounds of formula (I), pharmaceutical compositions comprising compounds of formula (I) and their use in the treatment of disease. The compound of formula (I) of the present invention has an inhibitory effect on elastase, and is useful for the treatment or prevention of 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
The invention relates to the field of medicines, in particular to a compound with inhibitory activity on elastase, a composition and application in disease treatment. The diseases are diseases caused by the action of elastase, and include Systemic Inflammatory Response Syndrome (SIRS) with Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS).
Background
Human Neutrophil Elastase (NE) plays an important role in various pathological processes of body such as inflammatory reaction, tissue injury remodeling (such as pneumonia), adult respiratory distress syndrome, pulmonary fibrosis, acute (slow) lung injury, pulmonary edema, atherosclerosis, scleroderma and the like, and has the function of promoting the invasion of viruses and bacteria and the metastasis of cancer cells. Studies of the mechanisms of inflammation have shown that imbalance in the balance of this enzyme and its endogenous inhibitors in vivo can lead to degradation of the tissue matrix and worsening of inflammation. At present, the research of treating the inflammatory diseases by using the NE inhibitor abroad is very wide, and the first marketed drug of sevelamer sodium (hydrate) taking NE as a treatment way is successfully developed, so that the research and development of the NE inhibitor are promoted.
Cevimetastat sodium, chemical name: n- {2- [4- (2, 2-dimethylpropionyloxy) benzenesulfonylamino ] benzoyl } aminoacetic acid has the following structural formula, and the structural formula and the preparation method are shown in patent EP0347168B, which is developed and developed by Nippon Hippo pharmaceutical company (Ono), and is the first global NE specific inhibitor which is firstly marketed in Japan in 2002, and is applicable to improvement of Acute Lung Injury (ALI) accompanied with Systemic Inflammatory Response Syndrome (SIRS). Is also currently approved by the first national drug administration officially for the improvement of Systemic Inflammatory Response Syndrome (SIRS) with Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) as a novel anti-inflammatory enzyme inhibitor that selectively inhibits Neutrophil Elastase (NE).
The treatment of the above mentioned diseases, especially the treatment of the associated Systemic Inflammatory Response Syndrome (SIRS) with Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS), with Neutrophil Elastase Inhibitors (NEI) is a hot topic of current research. Therefore, the development of the efficient and low-toxicity neutrophil elastase inhibitor has important commercial value and practical significance.
Disclosure of Invention
It is a first object of the present invention to provide a compound of formula (I):
wherein, the first and the second end of the pipe are connected with each other,
R 1 and R 2 Independently selected from hydrogen, C 1-6 Alkyl, -A-R 4 ；
R 3 Optionally selected from tert-butylcarbonyl and benzyloxycarbonyl;
a is phenyl;
R 4 is-SO 2 NH 2 、-CONH 2 。
As a preferred embodiment of the present invention, in the compounds of formula (I): r is 1 And R 2 Independently selected from hydrogen, methyl, ethyl, propyl, -A-R 4 ；
More preferred R1 and R2 are independently selected from methyl, ethyl, propyl;
more preferred R 1 Is hydrogen, R 2 Optionally selected from methyl, ethyl, propyl, -A-R 4 ；
More preferred R 3 Selected from tert-butylcarbonyl;
more preferred R 4 is-CONH 2 。
As a preferred embodiment of the invention, the formula (I) is the following compound:
the invention provides a preparation method of a compound shown as a formula (I), which comprises the following steps:
the compound of formula (I-a) is synthesized by reacting a compound of formula (I-a) 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.
A second object of the invention is to provide a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The carrier is a pharmaceutically acceptable adjuvant, which may be, for example, one or more of an inert diluent, a proppant, a lubricant, a disintegrant, a stabilizer, an isotonic buffer, a suspending agent, a sweetening agent, a flavoring agent, a perfuming agent, a preservative, an aqueous solvent, a non-aqueous solvent, a suspending medium, an emulsifying agent, a dispersing agent, a solubilizing agent, and the like. The composition can be administered by inhalation in the form of solution, suspension, inhalant, etc.; or orally administered in the form of tablet, capsule, granule, etc.; or rectally in the form of suppositories or transdermally; or in the form of an injection.
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, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or magnesium metasilicate. The composition may also contain other substances in addition to inert diluents, for example lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilisers such as lactose and solubilisers such as glutamic and aspartic acid. If desired, the tablets or pills may be provided as gastric film-coated or enteric film-coated tablets or pills, for example sugar-coated gelatin-coated, hydroxypropyl cellulose-coated or hydroxypropylmethyl cellulose-, phthalate-coated tablets or pills, two or more layers being used. Oral compositions may also include capsules of an ingestible material such as gelatin.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, containing inert diluents commonly used in the art, such as distilled water or ethanol. In addition to inert diluents, such compositions can also include adjuvants, such as wetting and suspending agents, as well as sweetening, flavoring, perfuming and preservative agents.
Other compositions for oral administration include spray compositions, which comprise one or more active compounds, which can be prepared by known methods. In addition to inert diluents, such compositions can also include stabilizers such as sodium bisulfite and isotonic buffers such as sodium chloride, sodium citrate, or citric acid.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of aqueous solvents or suspension media are distilled water for injection and physiological saline solution. Examples of non-aqueous solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil), alcohols (e.g. ethanol), tween 80. These compositions may also include adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing and stabilizing agents (e.g., lactose) and solubilizing agents (e.g., glutamic and aspartic acids). They may be filtered, for example, through a bacteria retaining filter, disinfected by incorporating a disinfectant in the composition or by radiation. They may also be manufactured in the form of sterile solid compositions that are dissolved in sterile water or some other sterile injection medium immediately prior to use.
A third object of the present invention is the use of the compounds or pharmaceutical compositions of the present invention as medicaments 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).
Interpretation of terms
In the present invention, "alkyl" means 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, and the like. The alkyl groups described herein may be unsubstituted or optionally substituted with one or more substituents.
substituent-A-R 4 In, -A-R 4 Is ortho-substituted, meta-substituted or para-substituted phenyl.
Detailed Description
The examples of the present invention are for understanding the present invention, and the scope of the present invention is not limited to the following examples. Unless otherwise indicated, the compounds, reagents, etc. used in the examples of the present invention were purchased from qualified suppliers.
Example 1
4- (N, N-dimethylsulfamoyl) phenyl pivalate:
adding 2.2g of dimethylamine hydrochloride and 10ml of dichloromethane into a 100ml three-necked bottle, stirring, cooling to 5 ℃, adding 5.5g of triethylamine, keeping the T =5 ℃, dropwise adding a mixed solution of 4- (chlorosulfonyl) phenyl pivalate and DCM (5 g of 4- (chlorosulfonyl) phenyl pivalate and 10ml of dichloromethane), sampling LCMS to monitor the reaction, adding 20ml of water, separating after stirring, and concentrating the organic phase until the organic phase is dry to obtain 4.9g of 4- (N, N-dimethylsulfamoyl) phenyl pivalate. HPLC purity 99.6%.
1 H NMR(400MHz,CDCl 3 )δ1.34(s,9H),2.68(s,6H),7.22-7.26(t,2H),7.76-7.78(d,2H).
Example 2
4- (N- (2-carbamoylphenyl) sulfamoyl) phenyl pivalate:
adding 2g of 2-aminobenzamide and 20ml of dichloromethane into a 100ml three-necked bottle, stirring at room temperature, adding 4.88g of 4- (chlorosulfonyl) phenyl pivalate, dropwise adding 1.78g of triethylamine at room temperature, sampling and monitoring the reaction by LCMS (liquid Crystal display System), adding 20ml of water, stirring to separate out a solid, filtering, pulping a filter cake with 10ml of water for 0.5h, filtering, rinsing the filter cake with 20ml of water, and drying to obtain 2.7g of 4- (N- (2-carbamoylphenyl) sulfamoyl) phenyl pivalate. HPLC purity 99.4%.
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)；
The following compounds of examples 3-7 and 9-10 were prepared by reacting 4- (chlorosulfonyl) phenyl pivalate with the corresponding amine or amine salt according to the preparation method of example 1 or example 2. The compound of example 8 was synthesized with reference to the method of patent EP 0347168B. The structural formula is as follows:
activity assay
Testing of the Activity of the Compounds of the invention against human neutrophil elastase
The test method comprises the following steps: neutrophil elastase has relatively high specificity for substrate Suc-Ala-Pro-Ala-pNA (succinyl-alkyl-propyl-pnitroanilide), and uses spectrophotometry to quantitatively detect p-nitroaniline released in the reaction.
The reaction mixture consisted of 1mM Suc-Ala-Pro-Ala-pNA (dissolved in N-methylpyrrolidone to a concentration of 100mM, and then 1/100 amount of the solution was added to the reaction mixture), 0.1M tris-hydrochloric acid (pH 8.0) buffer solution, 0.2M aqueous sodium chloride solution, various concentrations of the compound sample solution of the present invention and elastase solution to make up a mixture solution with a final volume of 1.0ml, and was incubated at 37 ℃ for 30 minutes. The reaction was then stopped by adding 100. Mu.l of 50% acetic acid to the reaction mixture solution, and the p-nitroaniline released from the reaction was measured by reading the absorbance measurement at 405nM using a Spectramax spectrophotometer. The compound of the present invention was not added to the control group. The inhibition was calculated as follows and the half inhibitory concentration IC was fitted to the inhibition of different concentrations of compound 50 The value is obtained.
Inhibitory Activity of the Compounds of Table 1 on Elastase
The experimental result shows that the compound of the invention has an inhibitory effect on elastase.
Claims (10)
1. A compound of formula (I):
wherein the content of the first and second substances,
R 1 and R 2 Independently selected from hydrogen, C 1-6 Alkyl, -A-R 4 ；
R 3 Optionally selected from tert-butylcarbonyl and benzyloxycarbonyl;
a is phenyl;
R 4 is-SO 2 NH 2 、-CONH 2 。
2. A compound of formula (I) as claimed in claim 1: wherein R is 1 And R 2 Independently selected from hydrogen, methyl, ethyl, propyl, -A-R 4 。
3. A compound of formula (I) as claimed in claim 1 or 2: wherein R is 1 And R 2 Independently selected from methyl, ethyl, propyl.
4. A compound of formula (I) as claimed in claim 3: wherein R is 3 Selected from tert-butylcarbonyl.
5. A compound of formula (I) as claimed in claim 1 or 2: wherein R is 1 Is hydrogen, R 2 Optionally selected from methyl, ethyl, propyl, -A-R 4 。
6. The compound of claim 5, of formula (I): wherein R is 3 Selected from tert-butylcarbonyl.
7. The compound of formula (I) according to claim 6: wherein R is 4 is-CONH 2 。
8. A compound of formula (I) according to any one of claims 1-2, which is the following compound:
9. a pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 and a pharmaceutically acceptable carrier.
10. Use of the pharmaceutical composition of claim 9 in the manufacture of a medicament for the treatment or prevention of a disease caused by the action of elastase.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110930289.7A CN115703725A (en) | 2021-08-13 | 2021-08-13 | Elastase inhibitors and their use in the treatment of disease |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110930289.7A CN115703725A (en) | 2021-08-13 | 2021-08-13 | Elastase inhibitors and their use in the treatment of disease |
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| Publication Number | Publication Date |
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| CN115703725A true CN115703725A (en) | 2023-02-17 |
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| CN202110930289.7A Pending CN115703725A (en) | 2021-08-13 | 2021-08-13 | Elastase inhibitors and their use in the treatment of disease |
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