CN117342993A

CN117342993A - Trafarotene salt, pharmaceutical composition and application thereof

Info

Publication number: CN117342993A
Application number: CN202310816048.9A
Authority: CN
Inventors: 李向阳; 孟月垒; 刘骏
Original assignee: Shijiazhuang Dikaiwei Pharmaceutical Technology Co ltd
Current assignee: Shijiazhuang Dikaiwei Pharmaceutical Technology Co ltd
Priority date: 2022-07-05
Filing date: 2023-07-05
Publication date: 2024-01-05

Abstract

The invention discloses a trefoil salt, a pharmaceutical composition and application thereof. The Qu Faluo tin salt is shown as a formula (I) ₀ ) The definition of substituent groups is shown in the specification; the salts are useful in the preparation of medicaments for the treatment of diseases mediated by the biological effects of retinol through modulation of the retinol receptor (RAR).

Description

Trafarotene salt, pharmaceutical composition and application thereof

Technical Field

The invention relates to a trefoil salt, a pharmaceutical composition and application thereof.

Background

The research and development of Retinoids (Retinoids) has been in progress for nearly a hundred years, and the molecular structure of vitamin a (Retinol/Retinol) was awarded by Karrer et al in 1937, while the research of retinoic acid for treating skin diseases by Stuettgen and Kligman et al in the 20 th century, 60 th, brought the dermatology into a brand new era, and developed the third generation classical retinoic acid drugs as one of the three major stones of modern dermatological drugs: the first generation is non-aromatic (non-aromatic) including vitamin a (retinol), all-trans retinoic acid, isotretinoin, etc.; the second generation is monoaromatic (monoaromatic) including avermectin, etc.; the third generation is polyaromatic retinoic acid (polyaromatics), including aromatic retinoic acid, adapalene, tazarotene, bexarotene, etc. Although the retinoic acid compounds have more than 2000 kinds, the clinically used medicines are very limited, and the external medicines have not been developed much for more years.

The distribution of RAR and RXR receptors in different tissues is differential. In the case of skin, RAR-gamma and RAR-alpha are mainly expressed in epidermis, RAR-beta is mainly expressed in dermis, and RAR-alpha is distributed everywhere. In number, 90% of the RARs receptors in the epidermis are RAR-gamma, which is directly involved in terminal differentiation, and thus is also a major target in dermatological external retinoic acid drugs for the treatment of diseases such as acne, e.g. psoriasis.

The us FDA was initially approved in 2019 at 10 for the treatment of acne vulgaris patients 9 and older with 0.005% of the Trifarotene (Qu Faluo statin) cream from Galderma company on the market (trade name Aklief). The drug is the first retinoid approved by the FDA in the united states for 20 years to treat acne vulgaris.

Trifarote (Qu Faluo) is only one dosage form of ointment sold in the market, the application mode is that the ointment is smeared on dry skin every night, in addition, the dosage form can be used for multiple times due to the friction influence of clothes, bedding and the like when being smeared locally in the process of treating skin diseases, especially skin diseases (such as acne) of trunk parts; furthermore, during the use of trefoil (content 0.005%) there is evidence that skin irritation side effects are caused by erythema, desquamation, dryness and stinging/burning.

Disclosure of Invention

The invention relates to a trefoil salt, which greatly increases the agonistic activity and selectivity to RAR-alpha, has high stability, and can be prepared into dosage forms such as spray, patch and the like in the process of preparing a pharmaceutical composition or cosmetics; in addition, the spray and patch dosage forms can increase the convenience of the patient in medication and greatly improve the medication experience of the patient; in addition, it has been unexpectedly found that the compounds of the present invention do not readily enter the blood circulation system upon dermal administration, but that higher concentrations can be achieved in the skin, enabling lower doses to be used, and thus lower skin irritation and other side effects.

The present inventors developedA compound of formula (I) ₀ ) The shown Qu Faluo is a salt of a statin,

formula (I) ₀ ) Wherein R is selected from metal element, amine, amino acid, or organic acid.

The present inventors have developed a Qu Faluo statin salt of formula (I),

in the formula (I), R is selected from metal elements, amine or amino acid; r is R ⁺ Representing the corresponding cation.

In some embodiments of the invention, R is selected from alkali metals, alkaline earth metals, zinc, silver; r is R ⁺ Represents a metal cation, preferably from Li ⁺ 、K ⁺ 、Zn ²⁺ 、Mg ²⁺ 、Ca ²⁺ Or Ag ⁺ 。

In some embodiments of the invention, R is selected from meglumine, ethylenediamine, tromethamine, ethanolamine, diethanolamine, triethanolamine, or piperazine.

In some embodiments of the invention, R is selected from basic amino acids;

in more specific embodiments of the invention, R is selected from L-arginine, D-arginine, L-lysine, D-lysine, L-ornithine, D-ornithine, DL-arginine, DL-lysine, DL-ornithine.

In some aspects of the invention, R is selected from organic acids;

in more specific embodiments of the invention, R is selected from tartaric acid, lactic acid, benzoic acid, ferulic acid, citric acid, tranexamic acid, fumaric acid, salicylic acid.

In more specific embodiments, the Qu Faluo statin salt has the following structure:

in some embodiments of the invention, a method for preparing Qu Faluo statin salt comprises the steps of: reacting Qu Faluo with metal element hydroxide or metal element soluble salt, organic acid, amine or amino acid in a certain proportion in a salifying solvent at a proper temperature to obtain Qu Faluo statin salt;

in some embodiments of the invention, the salification of Qu Faluo with a metal element hydroxide or a metal element soluble salt, an organic acid, an amine or an amino acid is performed in a salifying solvent which is one or a combination of several of water, methanol, ethanol, isopropanol, tertiary butanol, acetone, acetonitrile, ethyl acetate, butyl acetate, isopropyl ether, dichloromethane, chloroform, tetrahydrofuran, more particularly, the salifying solvent is selected from methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, isopropyl ether, dichloromethane, tetrahydrofuran;

in some embodiments of the invention, qu Faluo is reacted with a metal element hydroxide or metal element soluble salt, an organic acid, an amine or an amino acid in a salt forming solvent at a suitable temperature from room temperature to reflux, more particularly at reflux temperature;

in some embodiments of the invention, qu Faluo and organic acid, amine or amino acid are reacted in a salt-forming solvent at a suitable temperature in a certain ratio, wherein the certain ratio is that the mole ratio of the trefoil to the organic acid, amine or amino acid is (1:0.4) to (1:2.0), more specifically, the mole ratio of Qu Faluo to the organic acid, amine or amino acid is (1:0.8) to (1:1.5).

In some embodiments of the invention, the composition comprises Qu Faluo statin salt.

In some embodiments of the invention, the use of a composition comprising Qu Faluo statin salt for the manufacture of a medicament for the treatment of a condition involving the modulation of retinol receptor (RAR) to mediate the biological effects of retinol;

in some embodiments of the invention, the compounds or compositions of the invention are useful for treating diseases mediated by the biological effects of retinol through modulation of retinol receptors (RARs), particularly in dermatological applications;

more particularly, compositions comprising Qu Faluo salts the compositions prepared are directed to dermatological disorders associated with keratosis in the treatment of cell differentiation and proliferation;

further, the composition comprising Qu Faluo statin salt is for use in a dermatological disorder associated with keratosis involving cell differentiation and proliferation selected from the group consisting of acne vulgaris, acne, polymorphonuclear leukocytes, rosacea, nodulocystic acne, acne conglobata, senile acne, and secondary acne;

further, the secondary acne is solar acne, acne related to drug treatment or occupational acne;

more particularly, compositions comprising Qu Faluo salts of the invention are prepared for use in the treatment of dermatological disorders having an inflammatory immune allergic component, with or without a cell proliferative disorder;

further, the skin diseases with inflammatory immune allergic components, with or without cell proliferation disorders, are selected from all forms of psoriasis, skin specific reactivity.

In some embodiments, the invention relates to a cosmetic composition, characterized in that it comprises, in a physiologically acceptable medium, at least one compound as defined in the invention;

more specifically, the concentration of the compound or compounds of the invention is between 0.0001% and 1% by weight, further preferably between 0.0001% and 0.2% by weight, relative to the total weight of the composition.

In some embodiments of the invention, the composition comprising Qu Faluo statin salt is in the form of a solution, spray, emulsion, ointment, emulsion, gel, or patch;

in some embodiments of the invention, the medicament prepared from a pharmaceutical composition comprising Qu Faluo statin salt may be administered by transdermal administration at any part of the body;

transdermal therapeutic application system:

compositions containing a compound of formula (I) or at least one compound of formula (I) as active ingredient are useful for the treatment of diseases mediated by the biological effects of retinol through the modulation of the retinol receptor (RAR), especially in dermatological conditions. These systems may be bandages or patches which contain a matrix layer containing the active substance and an impermeable protective layer. The most preferred system is an active substance reservoir having a permeable bottom facing the skin. By controlling the release rate, the system can stabilize the trefoil at an optimal therapeutic concentration, thereby improving efficacy and reducing Qu Faluo statin side effects.

The trefoil salt can be prepared into spray, patch and other dosage forms in the process of preparing a pharmaceutical composition or cosmetics, and the method can reduce the dosage, thereby reducing side effects such as skin irritation and the like.

The trefoil salt of the invention can increase the convenience of the patient to take medicine when being prepared into a spray and patch dosage form, and greatly improve the medicine taking experience of the patient.

The disclosed compounds have further increased RAR-gamma agonistic activity and selectivity and have high stability.

The compounds disclosed herein have more excellent membrane penetration rates and effects, and are less irritating to the skin.

Furthermore, it was unexpectedly found that the compounds of the present invention were not detected in plasma when administered to the skin, whereas the equimolar Qu Faluo statin had a greater concentration in plasma, indicating that the compounds of the present invention were less likely to enter the blood circulatory system and were safer.

The specific embodiment is as follows:

here, a number of exemplary methods for preparing the compounds of the invention are provided, for example, in the examples below. The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention. Certain compounds of the invention can be used as intermediates for preparing other compounds of the invention.

The Qu Faluo of the initial raw material used in the synthesis process of the compound is self-made; starting materials 4' -hydroxybiphenyl-4-carboxylic acid (starting material 1), 2-tert-butylaniline (starting material 2), meglumine, ethylenediamine, tromethamine, L-arginine, D-arginine, L-lysine, D-lysine, L-ornithine, D-ornithine, DL-arginine, DL-lysine, DL-ornithine, starting material 1 are commercially available; various commonly used dissolving agents and catalysts are commercially available.

Example 1: preparation of starting material Qu Faluo Tine

The synthetic route is as follows:

the preparation method comprises the following steps:

step 1: preparation of intermediate SM 1-1:

starting material 1 (10 g,46.7 mmol) was dissolved in ethanol (200 ml) and sulfuric acid (130 ml) was then added and the reaction was refluxed for 24h. Cooling to room temperature, washing with water, saturated sodium bicarbonate and saturated sodium chloride, respectively, separating the organic phase, concentrating under reduced pressure to dryness to obtain product SM1-1 (9.05 g), yield: 80.0%. [ M+1 ]] ⁺ ＝243.09。

Step 2: preparation of intermediate SM 1-2:

SM1-1 (1.0 g,4.13 mmol) was dissolved in 15ml tetrahydrofuran at 0deg.C, NBS (1.47 g,8.26 mmol) was dissolved in 15ml tetrahydrofuran and added dropwise to the above system in the absence of light for 2h, reacted overnight, and the system water/ethyl acetate was extractedThe organic phase was taken, evaporated to dryness under reduced pressure and purified by column to give product SM1-2 (0.8 g), yield: 60.0%. [ M+1 ]] ⁺ ＝321.00。

Step 3: preparation of intermediate SM 1:

SM1-2 (200 mg,0.63 mmol) and SM1-3 (166 mg,0.693 mmol) were dissolved in 4ml of N, N-dimethylformamide, potassium carbonate (113 mg,0.819 mmol) was added, and nitrogen was purged overnight at 70 ℃. Cooling to room temperature, water quenching, ethyl acetate extraction, washing with 1moL/L hydrochloric acid, and evaporating the organic phase under reduced pressure to dryness to give product SM1 (0.26 g), yield: 87%. [ M+1 ]] ⁺ ＝479.12。

Step 4: preparation of intermediate SM 2-1:

starting material 1 (1.49 g,10 mmol) was dissolved in 20ml of tetrahydrofuran, tetrabutylammonium bromide (4.38 g,9.1 mmol) was added in portions, reacted for 10min at 5 ℃, water was added to the system after TLC detection, extraction was performed 3 times with diethyl ether, the organic phases were combined, washed with saturated sodium bicarbonate, dried and evaporated to dryness under reduced pressure to give product SM2-1 (1.96 g), yield: 86.0%. [ M+1 ]] ⁺ ＝228.03。

Step 5: preparation of intermediate SM 2-2:

NaH (0.63 g,13.17 mmol) was dissolved in 20ml tetrahydrofuran, a solution of SM2-1 (1.0 g,4.39 mmol) in dimethyl sulfoxide was added thereto and stirred at room temperature for 30 minutes, 1, 4-dibromobutane (2.85 g,13.17 mmol) was added thereto, and the reaction was stirred at room temperature for 13 hours and was completed by TLC. Quenching reaction with saturated ammonium chloride, extracting with ethyl acetate, petroleum ether: ethyl acetate=9:1 was purified by column to give product SM2-2 (1.24 g), yield: 69.0%. [ M+1 ]] ⁺ ＝282.08。

Step 6: preparation of intermediate SM 2:

SM2-2 (423 mg,1.5 mmol), pinacol diboronate (457 mg,1.8 mmol), pd (dppf) Cl ₂ (77 mg,0.105 mmol) was dissolved in 1, 4-dioxane (10 ml), potassium acetate (300 mg,3 mmol) was added, and the reaction was carried out overnight at 110℃under nitrogen, and the reaction was complete by TLC, dried directly under reduced pressure, petroleum ether: ethyl acetate=10:1 was purified by column to give product SM2 (0.42 g), yield: 85%. [ M+1 ]] ⁺ ＝330.25。

Step 7: preparation of intermediate ZJT-1:

SM1 (150 mg,0.313 mmol), SM1 (155 mg,0.47 mmol) and tetrakis triphenylphosphine palladium (36 mg,0.0313 mmol) were dissolved in toluene (3 ml), and 2moL/L aqueous potassium carbonate (0.6 ml,1.2 mmol) was added thereto and reacted overnight at 100℃under nitrogen. Cooling to room temperature, filtering with celite, extracting the filtrate with water/ethyl acetate, combining the organic phases, evaporating to dryness under reduced pressure, purifying with column to obtain the product ZJT-1 (0.15 g), yield: 80.0%. [ M+1 ]] ⁺ ＝602.36。

Step 8: preparation of intermediate ZJT-2:

ZJT-1 (100 mg,0.167 mmol) is dissolved in tetrahydrofuran (4 ml), and 1moL/L tetrabutylammonium fluoride tetrahydrofuran solution (0.25 ml,0.25 mmol) is added and reacted at room temperature for 30min. Extraction with water/ethyl acetate, drying of the organic phase over anhydrous sodium sulfate, filtration, drying under reduced pressure, and column purification gave the product ZJT-2 (69.2 mg) in 85.0% yield. [ M+1 ]] ⁺ ＝488.27。

Step 9: preparation of Qu Faluo:

ZJT-2 (200 mg,0.41 mmol) is dissolved in tetrahydrofuran (2 ml), and ethanol is added in sequence

1 ml), an aqueous solution (1 ml) of potassium hydroxide (275 mg,4.9 mmol) was dissolved, and reacted at room temperature for 6 hours. The pH=5 to 6 was adjusted with 1moL/L hydrochloric acid solution, ethyl acetate/water extraction was performed 3 times, the organic phases were combined, evaporated to dryness under reduced pressure, and purified by column to give Qu Faluo statin (162 mg), yield 86.0%. ¹ H NMR(300MHz,CD ₃ OH)δ:8.11-8.08(d,2H),7.75-7.73(d,2H),7.66-7.60(d,3H),7.45(s,1H),7.22-7.19(d,2H),4.16-4.13(t,2H),3.89-3.87(t,2H),3.04(t,4H),1.97(s,4H),1.48(s,9H)。

Example 2: preparation of compound Qu Faluo methyl amine salt (QF-1):

the synthetic route is as follows:

the preparation method comprises the following steps:

qu Faluo (4.59 g,10.0 mmol) was added to a ethanol and water mixed solvent (4:1, V/V,45.0 mL) to which meglumine (2.15 g, 11) was added.0 mmol), heating to reflux and fully dissolving, continuing to reflux for 1.0h, cooling and crystallizing, cooling to room temperature, stirring for 1h, filtering, leaching the obtained filter cake with water, and air-drying the product at 55 ℃ for 2.0h to obtain the compound QF-1 (0.47 g), wherein the yield is 72.5%. ¹ H NMR(CDCl3)：δ8.10(d,J＝6.3Hz,2H)，8.08(d,J＝6.3Hz,2H)，7.75-7.73(m,3H)，7.66(s,2H)，7.20(d,J＝6.5Hz,1H)，4.16-4.13(m,2H)，3.90-3.87(m,3H)，3.78-3.75(m,1H)，3.65-3.62(m,3H)，3.05-3.03(m,4H)，2.90-2.88(m,1H)，2.85(s,3H)，2.67-2.65(m,2H)，1.98-1.97(m,4H)，1.48(s,9H)。

Example 3: preparation of compound Qu Faluo Ding DL-arginine salt (QF-2):

the synthetic route is as follows:

the preparation method comprises the following steps:

qu Faluo (4.59 g,10.0 mmol) was added to a methanol-water mixed solvent (5:1, V/V,45.0 mL), DL-arginine (1.92 g,11.0 mmol) was added thereto, heated to reflux for dissolution, continued to reflux for 1.0h, cooled for crystallization, cooled to room temperature and stirred for 1h, filtered, the resulting filter cake was rinsed with water, and the product was air-dried at 45℃for 1.0h to give Compound QF-2 (3.25 g), yield 51.2%. ¹ H NMR(CDCl3)：δ8.09(d,J＝6.5Hz,2H)，8.06(d,J＝6.2Hz,2H)，7.73-7.70(m,3H)，7.64(s,2H)，7.20(d,J＝6.4Hz,1H)，4.14-4.11(m,2H)，3.88-3.86(m,2H)，3.16–3.14(m,1H)，3.06-3.04(m,2H)，3.03-3.01(m,4H)，1.95-1.92(m,4H)，1.55-1.52(m,4H)，1.46(s,9H)。

Example 4: preparation of compound Qu Faluo Di DL-lysine salt (QF-3):

the synthetic route is as follows:

the preparation method comprises the following steps:

qu Faluo (4.59 g,10.0 mmol) was added to a mixed solvent of acetone and water (4:1, V/V,45.0 mL), DL-lysine (1.62 g,11.0 mmol) was added thereto, heated to reflux, the solution was continuously refluxed for 1.0h, cooled to devitrify, cooled to room temperature and stirred for 1.5h, filtered, the obtained cake was rinsed with water, and the product was air-dried at 45℃for 2.0h to give Compound QF-4 (4.65 g), yield 76.8%.1H NMR (CDCl 3): delta 8.12 (d, j=6.3 hz, 2H), 8.09 (d, j=6.4 hz, 2H), 7.78-7.76 (m, 3H,7.67 (s, 2H), 7.21 (d, j=6.2 hz, 1H), 4.18-4.15 (m, 2H), 3.90-3.87 (m, 2H), 3.79-3.77 (m, 1H), 3.07-3.05 (m, 4H), 3.04-3.02 (m, 2H), 1.99-1.97 (m, 4H), 1.94-1.92 (m, 2H), 1.74-1.72 (m, 2H), 1.56-1.53 (m, 2H), 1.52 (s, 9H).

Example 5: preparation of compound Qu Faluo Tine L-arginine salt (QF-13):

the synthetic route is as follows:

the preparation method comprises the following steps:

qu Faluo (4.59 g,10.0 mmol) was added to ethanol (100.0 mL), heated under reflux, the system was dissolved, an aqueous solution of L (+) -arginine (1.92 g,11.0 mmol) was added thereto, and the reflux was continued for 1.0 hour after the addition was completed; as the reaction proceeds, the system firstly generates solids, then the solids disappear, and finally the system is slowly turbid, and the solids are gradually separated out; cooling for crystallization, cooling to room temperature, stirring for 1h, filtering, leaching the obtained filter cake with ethanol, and air drying the product at 45 ℃ for 1.0h to obtain the compound QF-13 (4.13 g) with the yield of 65.1%. ESI-MS (-) m/z= 458.26. ¹ H NMR(DMSO-d ⁶ )：δ8.09 -8.60(s,3H)，7.95-7.83(m,2H)，7.64-7.52(m,5H)，7.50-7.38(d,2H)，7.15-7.21(s,1H)，4.20-3.98(m,2H)，3.80-3.71(m,2H)，3.65–3.32(m,4H)，3.36-3.24(m,2H)，3.17-3.01(m,2H)，1.95-1.85(m,4H)，1.80-1.55(m,4H)，1.48(s,9H)。

The following examples were synthesized in the same manner as in the above examples.

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Example 12: preparation of Compound Qu Faluo sodium salt of (QF-8):

the synthetic route is as follows:

the preparation method comprises the following steps:

qu Faluo (4.6 g,10 mmol) is added into 50ml ethanol, cooled to 0-10 ℃,10 ml of aqueous solution with 0.44g sodium hydroxide (11 mmol) is dripped into the mixture for carrying out a maintenance temperature reaction, pH 7.5-8.5 is regulated by 1moL/L hydrochloric acid after the reaction is finished, 50ml ethanol is added, natural crystallization, filtration and drying are carried out, and the compound QF-16 (3.95 g) is obtained, and the yield is 82.1%. [ C ₁₉ H ₃₂ NO ₄ +H]＝459.2332。

Example 13: preparation of Compound Qu Faluo potassium salt of Dimethoate (QF-9):

the synthetic route is as follows:

the preparation method comprises the following steps:

referring to the preparation method of example 12, compound QF-9 was prepared by substituting potassium hydroxide for sodium hydroxide. [ C ₁₉ H ₃₂ NO ₄ +H]＝459.2341。

Example 14: preparation of Compound Qu Faluo magnesium salt of the statin (QF-10):

the synthetic route is as follows:

the preparation method comprises the following steps:

the compound QF-8 (2.4 g,5 mmol) is added into 10ml of water, 2ml of water solution dissolved with magnesium chloride (0.25 g,2.6 mmol) is dripped at 20-30 ℃ for reaction for 2h at a maintenance temperature, 50ml of ethanol is added for natural crystallization, filtration and drying are carried out, and the compound QF-10 (1.93 g) is obtained with the yield of 82.1 percent. [ C ₁₉ H ₃₂ NO ₄ +H]＝459.2335。

Example 15: preparation of Compound Qu Faluo tin zinc salt (QF-11):

the synthetic route is as follows:

the preparation method comprises the following steps:

with reference to the preparation of example 14, the compound QF-11, [ C ] was prepared by substituting zinc chloride for magnesium chloride as the starting material ₁₉ H ₃₂ NO ₄ +H]＝459.2337。

Example 16: preparation of Compound Qu Faluo tin silver salt (QF-12):

the synthetic route is as follows:

the preparation method comprises the following steps:

with reference to the preparation of example 14, the compound QF-12, [ C ] was prepared by substituting silver nitrate for magnesium chloride as the starting material ₁₉ H ₃₂ NO ₄ +H]＝459.2341。

Example 17: preparation of compound Qu Faluo, maleic acid salt (QF-16):

the synthetic route is as follows:

the preparation method comprises the following steps:

qu Faluo (2.3 g,5 mmol) of the extract is added to ethanolTo the water (25 mL/5 mL) mixture was added sodium hydroxide (0.2 g) and the system was clarified by heating to 60 ℃. Then, an ethanol solution (1 mL) in which maleic acid (0.6 g,5 mmol) was dissolved was added dropwise to the above system, and a large amount of solids were precipitated under stirring, and after the addition, the mixture was stirred at 60℃for 1 hour; the system temperature is reduced to room temperature, and then the system is filtered, and the filter cake is leached by ethanol and then dried, so that an off-white solid which is the target QF-16 (2.11 g) is obtained, and the yield is 73.3%; ESI-MS (-) m/z=458.24, ESI-MS (+): m/z= 460.26. ¹ H NMR(DMSO-d ⁶ )：δ8.10 -8.01(d,2H)，7.95-7.83(m,2H)，7.72-7.59(m,3H)，7.55-7.38(m,2H)，7.21-7.18(s,1H)，6.03 -5.95(s,2H)，4.91-4.78(s,1H)，4.20-4.03(m,2H)，3.80-3.68(m,2H)，3.05–2.85(m,4H)，1.95-1.85(m,4H)，1.48(s,9H)。

Example 18: preparation of Compound Qu Faluo tranexamic acid salt (QF-17):

the synthetic route is as follows:

the preparation method comprises the following steps:

qu Faluo the (2.3 g,5 mmol) was added to a methanol/water (25 mL/5 mL) mixture, sodium hydroxide (0.2 g) was added, and the system was clarified by heating to 60 ℃. Then, methanol solution (2 mL) dissolved with tranexamic acid (0.79 g,5 mmol) is added dropwise to the system, and the mixture is stirred at 60 ℃ for 1 hour after the addition; the system temperature is reduced to room temperature, and then the system is filtered, and a filter cake is leached by methanol/water (5/1) and dried to obtain a target QF-17 (1.76 g) with the yield of 57.1 percent; ESI-MS (-) m/z=458.26, ESI-MS (+): m/z= 460.28.

Example 19: preparation of compound Qu Faluo statin hydrochloride:

the synthetic route is as follows:

the preparation method comprises the following steps:

qu Faluo the (2.3 g,5 mmol) was added to a mixture of ethanol/20% aqueous sodium hydroxide (20 mL/10 mL) and heated to 60℃and the system was clear. After cooling to room temperature, acidifying the system pH to 2 with hydrochloric acid, stirring the mixture at room temperature for 2 hours, filtering, leaching the filter cake with ethanol/water (1/4), and drying to obtain Qu Faluo statin hydrochloride (1.96 g), yield 79.3%; ESI-MS (-) m/z= 458.22.

Example 20: preparation of Qu Faluo tin cream:

1. composition of prescriptions

2. Preparation process

(1) Preparation of an aqueous phase: taking the prescribed amount of purified water, preheating to 40-50 ℃, weighing the prescribed amount of allantoin, adding, stirring and dissolving; weighing ethanol, propylene glycol and phenoxyethanol, adding, and stirring;

(2) Preparation of an oil phase: weighing the prescription amount MCT, cyclomethicone and isohexadecane, adding and uniformly mixing; adding the API after uniformly stirring, and stirring until dissolving;

(3) Mixing: slowly adding the oil phase into the water phase, and uniformly stirring;

(4) The prescribed amount of the seebeck 305 was added to the mixed solution, and stirring was continued until the solution was in the form of a cream, and then the stirring was stopped.

Example 21: agonist activities of RAR-gamma and RAR-alpha

The compounds were tested for agonist activity on RAR-gamma and RAR-alpha using the HEK-293 cell line (ATCC, cat# CRL-1573), RAR LUCIFERASE REPORTER PLASMID (luciferase reporter plasmid in RAR fire, inc. of Saint Biotech (Shanghai), cat# 11508ES 03).

Cell culture: HEK-293 cells with an anchorage fusion rate of more than 80% in a culture dish were treated with trypsin, and then the cells were inoculated in another culture dish at a proper concentration for culture, and the volume of the culture medium was 10mL. The culture medium is DMEM containing 10% of fetal calf serum, is cultured in a wet environment at 37 ℃ and 5% of carbon dioxide, and is used for the next transfection after being continuously cultured for 72 hours;

FuGENE HD transfection reagent: the preparation of the transfection mixture was carried out according to FuGENE HD transfection kit (purchased from Xinbo biotechnology Co., ltd., product number HD 1000), the tube was vigorously shaken to mix well, and the transfection mixture was left to incubate at room temperature for 15 minutes. Trypsin treatment was used to treat the transfected cells in the previous step, identify cell density, and appropriately dilute the cell suspension to the appropriate volume and density. The appropriate transfection reagent mixture was added and the cell suspension was added to a 96-well plate in an amount of 100. Mu.L per well. Incubating and culturing the 96-well plate for 24 hours under the condition of cell culture in the step 1;

adding a compound to be tested: stock 210 Xcompound was made up with DMSO and diluted to 21 Xcompound solution by adding 9 times the amount of PBS buffer. Adding 5 mu L of 21 Xcompound solution, 37 ℃ and 5% carbon dioxide into each hole, and incubating for 24 hours in a humid environment;

reading a plate: the procedure was followed according to the instructions for the dual luciferase reporter detection system (available from san Biotech (Shanghai) Inc., cat No. 11401ES 76/80), and the plates were left at room temperature for 30 minutes before use, and firefly luciferin was added to each well of the 96-well plates to detect the luminescence intensity of firefly luciferase in an appropriate manner. And adding renilla luciferin, and detecting the luminous intensity of renilla luciferin enzyme.

And (3) data processing: signal = firefly luciferase luminescence intensity/renilla luciferase luminescence intensity, fold activation of agonist = compound signal/baseline signal, baseline signal intensity obtained from DMSO solution without compound. GraphPad Prism processing data to obtain pEC ₅₀ Value, further converted into EC ₅₀ Values.

RAR- γ selection index = RAR- α, EC50 (nM) value/RAR- γ, EC50 (nM) value.

The experimental results of the disclosed compounds are shown in table 1.

TABLE 1 agonistic Activity data for RAR-gamma and RAR-alpha

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The data show that the compounds QF-1, QF-2, QF-3, QF-5, QF-6, QF-7, QF-9, QF-10, QF-11, QF-12, QF-13, QF-14 and QF-15 disclosed by the invention have stronger agonistic activity to RAR-gamma and selectivity to RAR-gamma than the control compound 1 and the control compound 2; the invention discloses compounds QF-16 and QF-17 which have stronger agonistic activity and selectivity to RAR-gamma than control compound 2 and control compound 3; wherein, the agonistic activity of the compound QF-11 and the compound QF-13 to RAR-gamma is 2.4 times and 2.9 times that of the control compound 1 and 2.5 times and 3.2 times that of the control compound 2; the selectivity index of compound QF-11 and compound QF-13 for RAR-gamma is 4.2 times and 5.0 times that of control compound 1, and 3.8 times and 4.6 times that of control compound 2; the agonistic activity of the compound QF-16 and the compound QF-17 on RAR-gamma is more than 2.3 times of that of the control compound 3; the selection index of the compound QF-16 and the compound QF-17 to RAR-gamma is more than 3.5 times that of the control compound 3.

Example 22: aqueous solution stability and photostability test

Room temperature stability test of aqueous solution:

the compounds QF-9, QF-10, QF-11, QF-12, QF-16, QF-17, qu-falatine (control compound 2), qu Faluo-tin hydrochloride (control compound 3) and QF-8 (control compound 1) were taken at 5mg each, respectively, and added to a certain volume of water at 15 ℃ + -2 ℃, vigorously shaken for 30 seconds every 5 minutes, and the dissolution within 30 minutes was observed, as if no solute particles were visible, to be regarded as complete dissolution. After complete dissolution, the mixture was left at room temperature for 5 days, the total impurity area ratio of the compound was determined by HPLC method for 0 and 5 days in solution, and the total impurity area ratio was determined by area normalization method, total impurity growth ratio (%) = (total impurity area ratio for 5 days-total impurity area ratio for 0 day-total impurity area ratio)/total impurity area ratio for 0 day×100%. The results are shown in Table 2.

Light stability test:

placing compounds QF-9, QF-10, QF-11, QF-12, QF-16, QF-17, trefoil (control compound 2), qu Faluo tin hydrochloride (control compound 3) and compound QF-8 (control compound 1) at 5000+ -500 Lx and 90 μw/cm2 ultraviolet at 25deg.C for 5 days; the total impurity conditions of the compound in the solution state are measured by an HPLC method for 0 day and 5 days, the total impurity area occupation ratio is determined by an area normalization method, and the total impurity growth rate (%) = (the total impurity area occupation ratio of 5 days-0 day total impurity area occupation ratio)/the total impurity area occupation ratio of 0 day is multiplied by 100%. The results are shown in Table 3.

TABLE 2 results of 5 day Room temperature stability test of aqueous solutions

TABLE 3 results of 5 day stability test under illumination

The data shows that the aqueous solutions of compounds QF-9, QF-10, QF-11, QF-12 are more stable at room temperature and light stability than Qu Faluo statin and compound QF-8 (Qu Faluo statin sodium salt); the aqueous solutions of compounds QF-16 and QF-17 were more stable at room temperature and light than Qu Faluo statin and trefoil hydrochloride.

Example 23: in vitro test: penetration rate of Qu Faluo and Qu Faluo statins in human skin

The penetration rate of Qu Faluo in human skin was measured in vitro by a modified Franz cell with respect to the penetration rates of the respective salts QF-1, QF-2, QF-3, QF-4, QF-5, QF-8, QF-11. Wherein the human skin is separated from human skin tissue (360-400 μm thick) in front of or behind the thigh region. The receiving solution consisted of 2ml of 2% pH7.4 phosphate buffer (0.2M) and was stirred at 600 rpm. The cumulative total amount of these derivatives and their control drug (Qu Faluo statin) that passed through the skin was measured by specific high performance liquid chromatography. Apparent penetration values of the derivative and Qu Faluo statin through human skin were calculated using either 0.2M1 of a 20% solution of some derivative in 0.2M phosphate buffer ph7.4 or 0.2ml of a 20% solution of trefoil in 0.2M phosphate buffer ph7.4 as donor solution.

The results of the experiments show that the speed of the salt compounds penetrating through human skin is similar to Qu Faluo statin.

Example 24: in vivo experiments: penetration rate and penetration effect of Qu Faluo and Qu Faluo statins in minipigs

Preparing a stock solution:

respectively preparing 0.005% QF-1, QF-3 and QF-8 aqueous solutions with the concentration of 0.002% as stock solutions, and storing at 2-8 ℃.

Experimental animals:

the information of the experimental animals is shown in Table A. The ventilation in the animal house of the experimental animal is good, the air conditioner is arranged, the temperature is kept at 18-26 ℃, the humidity is kept at 40-70%, the experimental animal can eat and drink water freely after 12 hours of illumination. After normal feeding for at least 5 days, pigs with good signs can be selected for the experiment through veterinary examination. Each minipig was marked with an ear tag. The dosing schedule for animal experiments is detailed in Table B.

TABLE A Experimental animal sources and amounts

Table b animal dosing regimen table

Experimental protocol:

feeding can be recovered after the mini pig is dosed for 4 hours, and water can be freely drunk in the experimental process.

ExperimentOn the previous day, the mini-pigs fasted overnight. On the day of the experiment, group A, group B and group C minipigs were each marked with a 20X 20cm area on the back ² The hair is removed and cleaned, and the sampling time points corresponding to 6 are marked respectively. Taking out the self-made cream of the trefoil according to the dose of 1g (self-made, example 17), and carrying out transdermal administration on group A mini-pigs; taking 0.005% QF-1, QF-3, QF-8, 0.002% QF-1, QF-3, QF-8 according to dose of 1mL for transdermal administration to group B and group C minipigs. Binding the animals for about 5 minutes, and covering the administration area with gauze and fixing with waistcoat after the test solution on the skin is basically absorbed.

Group A, group B and group C were given 4-6mg.kg by intravenous injection at 0,1,2,4,8 and 24 hours, respectively ^-1 And (3) carrying out propofol anesthesia, uncovering gauze in a region corresponding to the sampling time point, collecting skin samples with the diameter of 7mm and the depth of 7-8 mm by using a skin biopsy device, and filling wounds to stop bleeding by using a biological dressing. The skin sample is firstly cleaned for 3 times by PBS, the moisture is absorbed by filter paper after the cleaning, then the skin sample is continuously stuck for 10 times by using a clean adhesive tape to remove the stratum corneum, the skin sample is weighed and recorded, is put into a sample collecting tube, is stored in an environment of minus 90 ℃ to minus 60 ℃ and is put under dry ice for transportation.

Taking out the tissue to be homogenized, placing at room temperature, thawing, shearing and uniformly mixing the skin tissue, adding 20% methanol water precooled at 2-8 ℃ according to the weight-volume ratio of 1:20, and homogenizing by using a full-automatic sample rapid grinding instrument or other suitable instruments. 1000. Mu.L of homogenate (if the amount of homogenate is less than 1000. Mu.L, all of the homogenate is collected) is pipetted into a 1.5-mL EP tube and stored in an environment of-90 to-60℃for sample analysis. The skin homogenate sample is stored in a refrigerator at the temperature of minus 90 ℃ to minus 60 ℃ and is used for biological sample analysis.

Analysis results show that the transdermal administration concentrations of the compounds QF-1, QF-3, QF-8 and the trefoil are 0.005% self-made cream, the former reaches the concentration peak more rapidly than the latter, and the drug concentration peak is also improved than the latter; compounds QF-1, QF-3, QF-8 and trefoil self-made cream (0.005%) at a transdermal drug delivery concentration of 0.002% were able to reach the peak drug concentration of the latter in almost the same time. This is an exciting result, and the administration of aqueous solutions formulated as Qu Faluo statin salts can facilitate rapid delivery of Qu Faluo statin to a host to therapeutically effective therapeutic concentrations, and these results also indicate that these salts can be used in a variety of treatments by transdermal administration and that there is a desire to reduce the dosage used.

Example 25: irritation test for dermal administration

Preparing a stock solution:

aqueous solutions of QF-1, QF-3 and QF-8 (control compound 1) were prepared as stock solutions at 0.005% concentration, and stored at 2 to 8 ℃.

Control compound 2: qu Faluo A self-made cream (0.005%).

Experimental animals:

guinea pigs: hartley strain, body weight 300-350 g, day-old 35-45 days, female. Animals are kept in separate cages in an air-conditioning laboratory, the room temperature (24+/-2) DEG C and the relative humidity of 40% -60%, the daily time and day are controlled manually for 12 hours respectively, standard mouse blocks are supplied for free drinking, padding is changed once a day, and the animals are fed for 1 week for standby.

The experimental method comprises the following steps:

the hairiness on two sides of the back vertebral column of the guinea pig is removed 24 hours before the medicine is smeared, and the hairiness on the left side is smeared in a region and the hairiness on the right side is contrasted in a region, and the area of each region is 9cm ² Equal in size. The dehairing 24h examined whether the dehaired skin was damaged by dehairing, such as skin injury, and the guinea pig was not suitable for skin irritation experiments. The method of comparing the two bodies is adopted, and 12 guinea pigs are divided into 3 groups of 4 guinea pigs. The left smearing area of each group of guinea pigs is smeared with 1ml of QF-1, QF-3 and QF-8 solutions with the concentration of 0.005% respectively for a fixed time every day, and the right control area is smeared with 1g Qu Faluo of self-made cream (0.005%) for a fixed time every day; visual observation is carried out before the medicine is smeared every day, the observation is carried out for 7 days continuously, the condition of red spots, edema and the like on the skin of the dehairing area is recorded every day, and scoring is carried out according to the scoring standard. The evaluation criteria are shown in Table C, and the experimental results are shown in Table 5.

Table C skin irritation test scoring criteria

TABLE 4 results of irritation experiments on skin drug delivery

Experimental results show that the skin irritation on the side of the 0.005% concentration QF-1, QF-3 and QF-8 (control compound 1) solution is less than on the side of the Qu Faluo statin self-made cream (0.005% control compound 2), and the skin irritation on the side of the 0.005% concentration QF-1 and QF-3 solution is more significantly reduced than on the side of the 0.005% concentration QF-8 (control compound 1) solution and Qu Faluo statin self-made cream (0.005% control compound 2).

Example 26: in vivo experiments: entry of Qu Faluo and Qu Faluo statins into pig plasma by transdermal administration

Preparing a stock solution:

respectively preparing 0.02% concentration of aqueous solution of trefoil, QF-1, QF-3 and QF-8, and storing at 2-8deg.C as stock solution.

Experimental animals:

the information of the experimental animals is shown in Table D. The ventilation in the animal house of the experimental animal is good, the air conditioner is arranged, the temperature is kept at 18-26 ℃, the humidity is kept at 40-70%, the experimental animal can eat and drink water freely after 12 hours of illumination. After normal feeding for at least 5 days, pigs with good signs can be selected for the experiment through veterinary examination. Each minipig was marked with an ear tag. The dosing regimen for animal experiments is detailed in Table E.

TABLE D Experimental animal sources and amounts

Table e animal dosing regimen table

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Experimental protocol:

The day before the experiment, the mini-pigs fasted overnight. On the day of the experiment, group A and group B minipigs were each marked with a 20X 20cm mark on their backs ² Is used for removing hair and cleaning. 0.02% Qu Faluo, QF-1, QF-3 and QF-8 were taken at a dose of 1mL, and the pigs of groups A and B were given transdermal doses. Binding the animals for about 5 minutes, and covering the administration area with gauze and fixing with waistcoat after the test solution on the skin is basically absorbed. Groups A and B were each prepared by collecting 1mL of whole blood from the jugular vein before and after 0.5,1,2,4,8,12 and 24 hours, respectively. The whole blood sample is placed in an EDTA-K2 test tube for anticoagulation, placed on wet ice, centrifuged (1500-1600 g) for 10min, and plasma is separated. Storing in an environment of-90 to-60 ℃, and placing under dry ice for transportation.

Analysis results show that the trefoil drug can be detected in the blood of a small pig with the transdermal administration concentration of 0.02% Qu Faluo statin solution, while the trefoil drug cannot be detected in the blood of a small pig with the transdermal administration concentration of 0.02% compound QF-1, QF-3 and QF-8 solution, which indicates that the compound of the invention is more difficult to enter the blood circulation system and has higher safety.

Example 27: skin drug delivery pharmacokinetic test for minipigs

Preparing a stock solution:

respectively preparing DMSO (dimethyl sulfoxide) solutions with concentration of 0.65 mu moL/L, namely, a control compound 1, a QF-8 (control compound 2), a Qu Faluo statin hydrochloride (control compound 3), a QF-13, a QF-14, a QF-15, a QF-16 and a QF-17, and storing at 2-8 ℃ as stock solutions.

Experimental animals:

the information of the experimental animals is shown in Table F. The ventilation in the animal house of the experimental animal is good, the air conditioner is arranged, the temperature is kept at 18-26 ℃, the humidity is kept at 40-70%, the experimental animal can eat and drink water freely after 12 hours of illumination. After normal feeding for at least 5 days, pigs with good signs can be selected for the experiment through veterinary examination. Each minipig was marked with an ear tag. The dosing regimen for animal experiments is detailed in Table G.

TABLE F Experimental animal sources and amounts

Table g animal dosing regimen table

Experimental protocol:

The day before the experiment, the mini-pigs fasted overnight. On the day of the experiment, group A and group B minipigs were each marked with a 20X 20cm mark on their backs ² The hair is removed and cleaned, and the sampling time points corresponding to 6 are marked respectively. The DMSO solutions of 0.65 mu moL/L concentration of treprostinil (control compound 1), QF-8 (control compound 2), qu Faluo statin hydrochloride (control compound 2), QF-13, QF-14, QF-15, QF-16 and QF-17 were uniformly smeared and administered in a dose of 1mL, and the animals were fixed for about 5 minutes, and after the test solution on the skin was substantially absorbed, the administration area was covered with gauze and fixed with waistcoat.

Group A and group B were given 4-6mg.kg by intravenous injection at 0,1,2,4,8 and 24 hours, respectively ^-1 And (3) carrying out propofol anesthesia, uncovering gauze in a region corresponding to the sampling time point, collecting skin samples with the diameter of 7mm and the depth of 7-8 mm by using a skin biopsy device, and filling wounds to stop bleeding by using a biological dressing. 1mL of whole blood was collected from the jugular vein at 0.5,1,2,4,8,12 and 24 hours before and after the administration. All-aroundBlood sample is placed in EDTA-K ₂ After anticoagulation in a tube, the tube was placed on wet ice, and plasma was separated after centrifugation (1500 g) for 10min within 30min. The skin sample is firstly cleaned for 3 times by PBS, the moisture is absorbed by filter paper after the cleaning, then the skin sample is continuously stuck for 10 times by using a clean adhesive tape to remove the stratum corneum, the skin sample is weighed and recorded, is put into a sample collecting tube, is stored in an environment of minus 90 ℃ to minus 60 ℃ and is put under dry ice for transportation.

Taking out the tissue to be homogenized, placing at room temperature, thawing, shearing and uniformly mixing the skin tissue, adding 20% methanol water precooled at 2-8 ℃ according to the weight-volume ratio of 1:20, and homogenizing by using a full-automatic sample rapid grinding instrument or other suitable instruments. 1000. Mu.L of homogenate (if less than 1000. Mu.L of homogenate is collected, the whole of the homogenate) is pipetted into a 1.5mL EP tube and stored in an environment of-90 to-60℃for sample analysis. The skin homogenate sample and the plasma sample are stored in a refrigerator at the temperature of-90 to-60 ℃ and are used for biological sample analysis.

LC-MS/MS analysis methods for measuring Qu Faluo statin in skin homogenates and plasma of minipigs were established for concentration determination of biological samples obtained in this experiment. The results of the exposure test in the skin homogenate of the mini-pigs are shown in Table 5, and the results of the drug exposure test in the plasma of the mini-pigs are shown in Table 6.

TABLE 5 results of exposure test in skin homogenates of minipigs

Analysis results show that compared with the compounds QF-8 (control compound 2), qu Faluo statin hydrochloride (control compound 3) and Qu Faluo statin (control compound 1), the QF-8 and the treprostinil hydrochloride reach peak time faster than Qu Faluo statin self-made cream, but the peak drug concentration differences are not obvious; unexpectedly, compared with Qu Faluo (comparative compound 1), the compounds QF-13, QF-14 and QF-15 have peak reaching times advanced by 4 hours, peak reaching concentrations improved by more than 37.1%, and drug concentrations at 24 hours are higher; the compounds QF-13, QF-14 and QF-15 have the same peak time, but the peak concentration is improved by more than 33.0% and the drug concentration is higher at 24 hours compared with QF-8 (control compound 2); QF-16 and QF-17 had the same peak time as Qu Faluo statin hydrochloride (control compound 3), but the peak concentration was increased by 38.0% or more, and the drug concentration at 24 hours was also higher.

TABLE 6 results of drug exposure experiments in pig plasma

Analysis showed that the trefoil drug could not be detected in the small pig blood of compounds QF-13, QF-14, QF-15, QF-16 and QF-17, indicating that the compounds of the invention were more difficult to enter the blood circulation system and higher safety, as the trefoil drug could not be detected in the small pig blood of Qu Faluo (control compound 1), compound QF-8 (control compound 2) and Qu Faluo (control compound 3) equimolar (0.65. Mu. MoL/L) transdermal administration of trefoil (control compound 1), QF-8 (control compound 2), qu Faluo (control compound 3), QF-13, QF-14, QF-16 and QF-17).

While the invention has been described with reference to the preferred embodiments, it is not intended to limit the invention thereto, and it is to be understood that other modifications and improvements may be made by those skilled in the art without departing from the spirit and scope of the invention, which is therefore defined by the appended claims.

Claims

1. A compound of formula (I) ₀ ) The Qu Faluo salt of the present invention is a salt of a statin,

2. The Qu Faluo statin salt according to claim 1,

in the formula (I), R is selected from alkali metal, alkaline earth metal, zinc, silver, amine and amino acid, R ⁺ Representing the corresponding cation.

3. The Qu Faluo statin salt according to claim 2,

R ⁺ represents the corresponding cation selected from Li ⁺ 、K ⁺ 、Zn ²⁺ 、Mg ²⁺ 、Ca ²⁺ Or Ag ⁺ 。

4. The Qu Faluo statin salt according to any of claim 1-2,

r is selected from meglumine, ethylenediamine, tromethamine, ethanolamine, diethanolamine, triethanolamine, or piperazine.

5. The Qu Faluo statin salt according to any of claim 1-2,

r is selected from L-arginine, D-arginine, L-lysine, D-lysine, L-ornithine, D-ornithine, DL-arginine, DL-lysine, and DL-ornithine.

6. The Qu Faluo statin salt according to claim 1,

r is selected from tartaric acid, lactic acid, benzoic acid, ferulic acid, citric acid, tranexamic acid, fumaric acid, and salicylic acid.

7. The Qu Faluo statin salt according to claims 1-6, selected from one of the following compounds:

8. a composition comprising a salt according to claims 1-7.

9. Qu Faluo-salt according to claims 1 to 7 or a composition according to claim 8, characterized in that the composition is in the form of a solution, spray, emulsion, ointment, emulsion, gel or patch for external use.

10. Use of a Qu Faluo statin salt according to claims 1-7 or a composition according to claim 8, characterized in that the medicament being prepared can be administered by transdermal administration at any part of the body.

11. Use of a Qu Faluo statin salt according to claims 1-7 or a composition according to claim 8 for the manufacture of a medicament for the treatment of a condition involving the mediation of the biological effect of retinol by modulation of retinol receptor (RAR).

12. Transdermal therapeutic application system comprising at least one compound according to claims 1 to 7 or containing a composition according to claim 8, for the treatment of diseases mediated by the biological effects of retinol through modulation of retinol receptor (RAR), in particular in dermatological diseases.

13. The use of a Qu Faluo statin salt according to claims 1-7 or a composition according to claim 8 for the manufacture of a medicament for the treatment of dermatological disorders involving keratosis of cell differentiation and proliferation; wherein the "keratosis-related skin disorder involving cell differentiation and proliferation" is selected from the group consisting of acne vulgaris, acne, polymorphonuclear leukocytes, rosacea, nodulocystic acne, acne conglobata, senile acne, and secondary acne; wherein the "secondary acne" is solar acne, acne related to drug treatment or occupational acne.

14. Qu Faluo-salt according to claims 1 to 7 or a composition according to claim 8, relates to the use in the manufacture of a medicament for the treatment of dermatological disorders with an inflammatory immune allergic component, with or without a cell proliferation disorder, characterized in that the dermatological disorders with an inflammatory immune allergic component, with or without a cell proliferation disorder, are selected from all forms of psoriasis, specific reactivity of the skin.

15. Use according to claims 10 to 14, characterized in that the concentration of the compound(s) according to any one of claims 1 to 7 is between 0.0001% and 1%, preferably between 0.0001% and 0.2% by weight relative to the total weight of the composition.