CN111012777A - Application of pyrazolidinyl compound in preparation of preparation for treating dermatitis - Google Patents
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Abstract
The invention relates to a pyrazolidinyl compound, and an application of a pharmaceutically acceptable salt, solvate or hydrate thereof in preparing a preparation for treating dermatitis, wherein the structural formula of the pyrazolidinyl compound is shown as a formula (1):
wherein each X is independently selected from O, S or NR1；R1Is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, -C (O) R, -C (O) OR OR-C (O) NRR2；R2Is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or heteroaralkyl; r is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or heteroaralkyl; y is H, alkyl, alkenyl, alkynyl, cycloalkyl, nitro or halogen; z isH, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, -C (O) R3，‑C(O)OR3，‑C(O)SR3，‑C(O)NR3R4，‑C(S)OR3，‑C(NR1)OR3or-C (NR)1)NR3R4(ii) a n is any integer of 0-5.
Description
Technical Field
The invention relates to the field of biological medicines, and in particular relates to an application of a pyrazolidinyl compound in preparation of a preparation for treating dermatitis.
Background
It is known that dermatitis is a common disease in dermatology, the etiology and pathogenesis of dermatitis are not clear, the etiology is quite complex, most of the dermatitis is caused by allergy, and the dermatitis is caused by the interaction of various internal and external factors. Some dermatitis is not associated with allergy.
The current common treatment of dermatitis involves the identification and prevention of factors that may induce or exacerbate inflammation, as well as good skin care, almost always in combination with the use of drugs suitable for treating the symptoms of the disease. In the drugs, steroid preparations are generally used. However, despite its proven clinical efficacy, steroid-based formulations (e.g. topical corticosteroid formulations) cause a number of side effects, such as excessive thinning of the skin, atrophy, so-called "face-moon" caused by deposits of facial fat, reddening of the skin, hirsutism, stretch marks, and the like. Furthermore, when patients use steroids for a long period of time, their bodies often develop resistance to these drugs and it may even occur that dermatitis symptoms recur in a more aggressive form.
The document "Cancer Res 2007; 67 (19), October 1,2007' and US60738242 disclose that pyrazolidinyl compounds can be used as ubiquitin activating enzyme (E1) inhibitors and applied to the treatment of cancers, and whether the compounds have other new applications or not is still unknown according to the prior published technology.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide an application of a pyrazolidinyl compound in preparation of a preparation for treating dermatitis, and the invention discloses a new application of the pyrazolidinyl compound, which can obviously inhibit an NF-kB signal channel in Hacat cells and inhibit the expression of inflammatory factors in back and serum.
The invention aims to disclose application of a pyrazolidinyl compound, a pharmaceutically acceptable salt, a solvate or a hydrate thereof in preparing a preparation for treating dermatitis, wherein the structural formula of the pyrazolidinyl compound is shown as a formula (1):
wherein each X is independently selected from O, S or NR1；R1Is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, -C (O) R, -C (O) OR OR-C (O) NRR2；R2Is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or heteroaralkyl; r is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or heteroaralkyl;
y is H, alkyl, alkenyl, alkynyl, cycloalkyl, nitro or halogen;
z is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, -C (O) R3，-C(O)OR3，-C(O)SR3，-C(O)NR3R4，-C(S)OR3，-C(NR1)OR3or-C (NR)1)NR3R4；
n is any integer of 0-5.
In the above formula, "C (O)", "C (S)", C (NR)1) Respectively represent C atom and O atom, C atom and S atom, C atom and R containing substituent1Are connected by a double bond.
Further, Y is substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted aralkyl, substituted heteroaralkyl, substituted aryl or substituted heteroaryl, wherein the substituents are halogen, nitro, cyano, alkoxy, thioalkoxy, -NR3R4，-S(O)R5or-S (O)2R5(ii) a Wherein R is3And R4Each independently selected from H, alkyl, aralkyl or aryl; r5Is OH, OR3，NH2Or NHR3。
Preferably, the pyrazolidinyl compound has the structural formula shown in formula (2):
wherein each timeEach X is independently selected from O, S or NR1；R1Is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, -C (O) R, -C (O) OR OR-C (O) NRR2；R2Is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or heteroaralkyl; r is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or heteroaralkyl.
Preferably, in formula (1), X is O and Y is NO2N is 1, Z is halogen OR-C (O) OR3Wherein R is3Is C1-C12Straight or branched chain alkyl.
Preferably, the pyrazolidinyl compound is 4[4- (5-nitro-furan-2-ylmethylene) -3, 5-dioxo-pyrazolidin-1-yl ] -benzoic acid ethyl ester (PYR-41).
Further, the pharmaceutically acceptable salt of the pyrazolidinyl compound is a salt of the pyrazolidinyl compound with an inorganic acid or an organic acid.
Further, a pharmaceutically acceptable solvate or hydrate of the pyrazolidinyl compound is a compound formed by coordinative bond or covalent bond between the pyrazolidinyl compound and a solvent or water.
Furthermore, dermatitis is an inflammation of skin caused by immune disorder, is mainly characterized by erythema, pimple, blister, erosion and exudation of the skin and severe pruritus, has high morbidity, is easy to repeatedly attack, has complex reasons and is difficult to heal after the course of disease is prolonged.
By the scheme, the invention at least has the following advantages:
the invention discloses a new application of a pyrazolidinyl compound, which can obviously inhibit an NF-kB signal channel in HaCat cells and inhibit the expression of inflammatory factors in tissues and serum.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following detailed description is given with reference to the preferred embodiments of the present invention and the accompanying drawings.
Drawings
FIG. 1 is a Western blot to detect the expression of different proteins in the NF- κ B signaling pathway in cells;
FIG. 2 is the surface condition of the mouse skin after 2 times of induction for 48 hours;
FIG. 3 is the surface condition of the mouse skin after 48h induction 4 times;
FIG. 4 is a statistical result of mouse dermatitis scoring, ear swelling and left and right ear weight difference after different induction times in different experimental groups;
FIG. 5 illustrates the effect of topical PYR-41 on DNCB-induced dermatitis;
FIG. 6 is a statistical result of the expression of inflammatory factors in serum of different experimental groups;
FIG. 7 is a statistical result of the expression of inflammatory factors in the dorsal skin of mice in different experimental groups.
Detailed Description
The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
In the following examples, ethyl 4[4- (5-nitro-furan-2-ylmethylene) -3, 5-dioxo-pyrazolidin-1-yl ] -benzoate (PYR-41) was used as an example to verify its use in the preparation of a formulation for the treatment of dermatitis, PYR-41 being commercially available.
In the following examples of the invention, the DNCB solution used was prepared as follows:
the appropriate amount of DNCB was weighed out and placed in an EP tube, the volume of acetone olive oil (4: 1) required was calculated by the mass fraction formula and added to the EP tube and shaken to prepare 7% and 0.2% (W/V) DNCB acetone olive oil solutions.
In animal experiments, 0.1 wt% of PY-41 medicament cream is externally applied topically, and the formula of the cream is as follows:
PY-410.1 g, white vaseline 5g, glyceryl monostearate 5g, stearic acid 10g, ethylparaben, 0.1g, 2, 6-tert-butyl-p-phenol 0.02g, triethanolamine 300 mu L, sodium 12 alkyl sulfonate 0.1g, liquid paraffin 15mL, glycerol 10mL, distilled water 52.2mL, and an appropriate amount of ethanol, wherein the total weight of the mixture is ensured to be 100 g.
The preparation method of the cream comprises the following steps:
a (oil phase): white vaseline, glyceryl monostearate, stearic acid, ethylparaben, 2, 6-tert-butyl-p-phenol and liquid paraffin are respectively weighed or measured and put into a No. 1 beaker, the No. 1 beaker is heated to 80 ℃, and the materials are stirred to be completely dissolved.
B (aqueous phase): distilled water, glycerol, triethanolamine, 12-alkyl sodium sulfonate and a No. 2 beaker are respectively weighed or measured, the No. 2 beaker is heated to 75 ℃, and the materials are stirred to be completely dissolved.
C: dissolving PY-41 in appropriate amount of ethanol, slowly adding A (oil phase) into B (water phase), stirring in the same direction while adding, cooling to 60 deg.C, adding C, and stirring to room temperature to obtain PY-41 medicinal cream.
In the following examples, the mice in the experimental group were male Balb/c mice, 6 weeks old, 20-25 g in weight, purchased from Shanghai Si Rick laboratory animals, Inc., and having a license number of SCXK (Shanghai) 2018-.
Example 1
In vitro cultured HaCaT cells are stimulated for 1h by adding TNF- α, then the cells are treated for 6h by PYR-41, the cells are collected, total RNA is extracted, and the levels of proinflammatory cytokines TNF- α and IL-1 are detected by a Real-time PCR method, and as a result, the PYR-41 can reduce the expression of TNF- α and IL-1 in a dose-dependent manner within the dose range of 0-50 uM.
As shown in figure 1C, the result shows that PYR-41 can inhibit the phosphorylation of p65 by the concentration gradient and reduce the activation level of IKB, and the effect of PYR-41 on reducing the activation level of IKB is more obvious along with the increase of the concentration (figure 1C).
Example 2
Induction of dermatitis and eczema: using hair clipper to keep the back of mouse at least 2X 2cm2The area is shaved. Sensitization was performed one or two days after skin preparation to reduce irritation of skin preparation to the back of mice.
The MFG (compound dexamethasone acetate cream), hereinafter referred to as MFG, has anti-inflammatory and antiallergic effects, so that the MFG is used as an experimental positive medicine group. The first Day of experiment initiation (Day 1) mice were randomly divided into four groups of 5 mice each, namely a Normal group (Normal), a Model control group (Model), an administration group (PY-41), and a positive drug control group (MGF). Mice of the model control group, the administration group and the positive control group are shaved on the backs of the mice, 100 mu L of DNCB solution with 7 percent is smeared on each mouse (50 mu L per time), and a normal control group is smeared with an equal amount of acetone-olive oil solution.
From the 5 th day after sensitization, 10. mu.L of 0.2% DNCB solution was applied to the inner and outer sides of the right ear of each mouse of the model control group, the administration group and the positive control group, and then the mice were challenged, and the normal control group was applied with the same amount of acetone-olive oil solution as the solvent. After that, the cells were challenged every 3 days for a total of 5 times. The administration mode comprises the following steps: the drug is administered for the first time 2 hours before the first excitation, the back of the mouse of the administration group is smeared with 0.5mL of the drug cream, the model control group is smeared with the blank substrate of the cream in the same amount, the positive control group is smeared with the mometasone furoate cream in the same amount, and the drug is administered once a day later until the experiment is finished. For the first challenge, the 7% DNCB solution was diluted with acetone/olive oil solution to 0.2% DNCB solution, and 20. mu.L of 0.2% DNCB solution was added to the right ear of the pipette mouse and the mouse was challenged by dropping 20. mu.L of the solution to the inside and outside of the right ear, i.e., 10. mu.L on one side and 20. mu.L on both sides. The method is activated for each subsequent time.
The dermatitis index was evaluated according to the following criteria:
observing the skin damage condition of the dorsal sensitization area of mice of each experimental group 48 hours after each excitation, and taking a picture; severity of inflammation in skin lesions the dermatitis index score was mainly observed for severity of 4 symptoms: (1) erythema or bleeding, (2) edema, (3) exudation and erosion, (4) keratosis or crusting, mild score 1, moderate score 2, severe score 3, normal score 0, and dermatitis index per mouse is the sum of the 4 scores.
Ear swelling was tested according to the following criteria:
measuring the thickness of the middle parts of two ears of each mouse by using an external micrometer 24 hours after each excitation of each experimental group of mice, and calculating the thickness difference of the left ear and the right ear to represent the ear swelling degree; or removing the left and right ear pieces with a punch (8mm ear tissue punch) after the experiment is finished, weighing the mass on an analytical balance, and calculating the difference between the two ear masses to show the swelling degree of the ears.
FIGS. 2-3 show the dermatitis onset in the dorsal sensitization zone of mice in each experimental group 48h after the 2 nd and 4 th challenge, respectively, and no pathological changes in the skin occurred in the normal control group; the model control group shows obvious inflammatory injuries such as red and swollen back sensitized areas, bleeding points and the like 48 hours after the second ear excitation, the skin damage is gradually serious along with the increase of the excitation times, and eczema symptoms such as bleeding, exudation, keratosis, scabbing and the like appear in sequence; the PY-41 administration group and the positive control group mice have obviously slight skin damage inflammation degree compared with the model group. The results show that PY-41 has a prevention and treatment effect on DNCB-induced chronic eczema by external application.
Fig. 4A shows the results of the dermatitis index scores of the mice in each experimental group, and the results show that: the dermatitis of the mice in the model group gradually worsens along with the increase of the excitation times, and the dermatitis indexes of the mice in the administration group and the positive drug group are obviously lower than those of the mice in the model control group. The result of the detection of the ear swelling degree of the mice in each experimental group shows that the obvious right ear swelling appears 24 hours after the second excitation of the model group, and the ear swelling degree is gradually increased along with the increase of the excitation times; the swelling degree of PY-41 and mice in the positive drug group is obviously slight compared with that of the model group, and the normal control group has no large thickness difference change (figure 4B). The detection of the weight difference between the left ear and the right ear after the experiment further shows that the right ear of the mice in the model group has obvious swelling, and the swelling degree of the right ear of the mice in each administration group is obviously reduced (figure 4C).
The mice are killed 48 hours after the 5 th excitation, the skin tissues of the back sensitization area are taken, pathological sections are prepared after formalin fixation, HE staining is carried out, inflammatory pathological changes of the skin tissues of the ear tissue and the back sensitization area are observed, and the results show that: compared with normal mice, the mice in the model group have obvious right ear swelling, hyperkeratosis of epidermis, thickening of epidermis, infiltration of a large number of inflammatory cells in a dermis layer and obvious expansion of dermal blood vessels; the mice in each administration group have weak right ear swelling, slightly keratinized epidermis and slightly thickened epidermis, and the inflammatory cell infiltration model group in the dermis layer is obviously reduced. The epidermis of the skin tissue of the sensitization area on the back of the model group mouse is thickened and hyperkeratosis, and the dermis is infiltrated by a large number of inflammatory cells; the epidermis of the right ear of each mouse administration group is slightly keratinized, the epidermis is slightly thickened, and the inflammatory cell infiltration model group of the dermis layer is obviously reduced (figure 5).
And (3) performing orbital bleeding, namely removing eyeballs from mouse living bodies, performing orbital bleeding and preparing serum, wherein FIGS. 6A-C are statistical results of expression conditions of inflammatory factors in the serum, and it can be seen that compared with a DNCB group, factors IgE, TNF- α and INF-gamma of the PYR-41+ DNCB group are all reduced, which shows that PYR-41 can inhibit the expression of the inflammatory factors in the serum.
FIGS. 7A-C are statistics of mouse dorsal skin inflammatory factor expression, showing that IL-4, IL-13, and IL-5 were all decreased in PYR-41+ DNCB group compared to DNCB group, indicating that PYR-41 can inhibit the expression of dorsal skin inflammatory factor.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
Claims (8)
1. The application of a pyrazolidinyl compound, a pharmaceutically acceptable salt, a solvate or a hydrate thereof in preparing a preparation for treating dermatitis, wherein the structural formula of the pyrazolidinyl compound is shown as a formula (1):
wherein each X is independently selected from O, S or NR1；R1Is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, -C (O) R, -C (O) OR OR-C (O) NRR2；R2Is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or heteroaralkyl; r is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or heteroaralkyl;
y is H, alkyl, alkenyl, alkynyl, cycloalkyl, nitro or halogen;
z is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, halo, -C (O) R3，-C(O)OR3，-C(O)SR3，-C(O)NR3R4，-C(S)OR3，-C(NR1)OR3or-C (NR)1)NR3R4；
n is any integer of 0-5.
2. The use of claim 1, wherein Y is substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted aralkyl, substituted heteroaralkyl, substituted aryl or substituted heteroaryl, wherein the substituents are halo, nitro, cyano, alkoxy, thioalkoxy, -NR3R4，-S(O)R5or-S (O)2R5(ii) a Wherein R is3And R4Each independently selected from H, alkyl, aralkyl or aryl; r5Is OH, OR3，NH2Or NHR3。
3. Use according to claim 1, characterized in that said pyrazolidinyl compound has the formula (2):
wherein each X is independently selected from O, S or NR1；R1Is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, -C (O) R, -C (O) OR OR-C (O) NRR2；R2Is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or heteroaralkyl; r is H, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or heteroaralkyl.
4. Use according to claim 1, wherein X is O and Y is NO2N is 1, Z is halogen OR-C (O) OR3Wherein R is3Is C1-C12Straight or branched chain alkyl.
5. Use according to claim 1, characterized in that the pyrazolidinyl compound is ethyl 4[4- (5-nitro-furan-2-ylmethylene) -3, 5-dioxo-pyrazolidin-1-yl ] -benzoate.
6. The use according to claim 1, characterized in that the pharmaceutically acceptable salt of the pyrazolidinyl compound is a salt of the pyrazolidinyl compound with an inorganic or organic acid.
7. The use according to claim 1, characterized in that the pyrazolidinyl compound pharmaceutically acceptable solvate or hydrate is a compound formed by coordinative or covalent bonding of the pyrazolidinyl compound with a solvent or water.
8. The use of claim 1, wherein the dermatitis is an inflammation of the skin due to an immune disorder.
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