Use of deuterated vitamin A and its derivatives

Abstract

The present invention discloses a novel use of deuterated vitamin A and its derivatives. Specifically, the present invention discloses the use of deuterated vitamin A and its derivatives, such as those represented by formula (I) or formula (II), in the preparation of a drug for treating and / or preventing or alleviating retinal diseases such as juvenile macular degeneration and age-related macular degeneration, which are associated with lipofuscin accumulation, by slowing the formation rate of retinoid dimers. The present invention also discloses the use of a pharmaceutical composition of such compounds in the preparation of a drug for treating and / or preventing or alleviating retinal diseases such as juvenile macular degeneration and age-related macular degeneration, which are associated with lipofuscin accumulation.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to the use of deuterated vitamin A and its derivatives as shown in formula (I) or formula (II) in the preparation of drugs for treating and / or preventing or alleviating retinal diseases related to lipofuscin accumulation by slowing down the formation rate of retinoid dimers. Background Art

[0002] Vitamin A is essential for vision. The visual cycle, also known as the retinoid cycle, is the basis for human vision. Most visual cycles occur in photoreceptors and retinal pigment epithelial (RPE) cells. RPE cells maintain the normal renewal of visual cells and provide the main metabolic enzymes for the visual cycle. Photoreceptors convert light signals into nerve impulses. During this conversion process, the 11-cis-retinal bound to the opsin in rhodopsin undergoes a conformational change under light and is converted into all-trans retinal. This then dissociates from the opsin, generating visual electrical signals that are transmitted to the brain by the optic nerve, forming vision.

[0003] All-trans retinal is a key intermediate in the visual cycle. Its highly reactive nature allows it to condense with phosphatidylethanolamine to form a Schiff base derivative, which then reacts with another molecule of all-trans retinal through different reaction pathways to form retinoid dimers such as N-retinylidene-N-retinylethanolamine (A2E) and all-trans-retinal dimer (ATRdimer). These dimers accumulate in RPE cells, forming the primary component of RPE lipofuscin. Lipofuscin is phototoxic, causing protein and lipid peroxidation, inducing RPE cell apoptosis and damage. Therefore, its harmful accumulation in the retina plays a crucial role in the pathogenesis of retinal diseases such as Stargardt and age-related macular degeneration (AMD). Stargardt disease is caused by a mutation in the transporter ABCA4 gene, which prevents the normal metabolism of lipofuscin. The resulting toxic retinoid dimers cause retinal epithelial cell atrophy, further leading to photoreceptor cell death and loss of central vision. Currently, there are no proven effective drug treatments for Stargardt disease and Advanced Myeloma (AMD), making them a hot area of drug research and development.

[0004] Deuterium (D or 2H) is an isotope of hydrogen with an abundance of 0.015%. Deuterium is non-radioactive, and the carbon-deuterium bond is more stable than the carbon-hydrogen bond. Therefore, deuterated drugs that replace the hydrogen in the active center group with deuterium have a longer half-life and can reduce the therapeutic dose. At the same time, due to the kinetic isotope effect, deuterium will reduce the reaction rate when participating in certain chemical reactions. Therefore, introducing deuterium into specific parts of the compound can slow down the formation of toxic byproducts and thus slow down the occurrence and development of related diseases. ALK-001 (C20-D3-vitamin A) is a deuterated vitamin A derivative in which all three hydrogens at the C20 position are replaced by deuterium. It was developed by Alkeus Pharmaceuticals for the prevention and treatment of retinal diseases such as Stargardt disease and AMD. In wild-type mice (Kaufman Y, Ma L, Washington I. J Biol Chem. 2011, 286, 7958-7965.) and Stargardt disease model mice ((a) Ma L, Kaufman Y, Zhang J, Washington I. J Biol Chem. 2011, 286, 7966–7974. (b) Charbel Issa P, Barnard AR, Herrmann P, Washington I, MacLaren RE. Proc Natl Acad Sci USA. 2015, 112, 8415–8420.), when C20-D3-vitamin A was the sole source of vitamin A intake, the formation of toxic retinoid dimers was reduced by more than half, and fundus autofluorescence was also significantly reduced. ALK-001 is currently undergoing a Phase II clinical trial for Stargardt disease and a Phase III clinical trial for advanced dry AMD. The FDA has granted ALK-001 Breakthrough Therapy Designation and Orphan Drug Designation for the treatment of Stargardt disease. Therefore, the strategy of using deuterated vitamin A derivatives to treat Stargardt and AMD is feasible, laying a solid foundation for the present invention. Building on this foundation, the development of deuterated vitamin A derivatives with novel structures and enhanced efficacy holds great promise and promises significant application prospects. Summary of the Invention

[0005] The present invention provides a novel use of deuterated vitamin A, its derivatives, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for reducing the formation of retinoid dimers in lipofuscin, particularly A2E and ATR dimers. Specifically, the deuterated vitamin A, its derivatives, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, can be used to treat and / or prevent or alleviate retinal diseases associated with lipofuscin accumulation, such as juvenile macular degeneration and age-related macular degeneration.

[0006] The present invention provides the use of deuterated vitamin A and its derivatives or pharmaceutically acceptable salts thereof as represented by formula (I) or formula (II) in the preparation of a medicament for treating and / or preventing or alleviating retinal diseases associated with lipofuscin accumulation, wherein the structure of formula (I) or formula (II) is as follows:

[0007]

[0008] in,

[0009] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, deuterium, tritium, halogen, and C1-C10 alkyl;

[0010] R 7 selected from hydrogen, deuterium, and tritium;

[0011] R 8 is selected from hydrogen, deuterium, tritium, acyl, sulfonyl, and C1-C10 alkyl;

[0012] Preferably,

[0013] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen and deuterium;

[0014] R 7 selected from hydrogen and deuterium;

[0015] R 8 Selected from hydrogen, deuterium, formyl, acetyl, propionyl, palmitoyl.

[0016] The retinal disease associated with lipofuscin accumulation in the present invention is selected from the following group: juvenile macular degeneration and its complications, age-related macular degeneration and its complications, etc.

[0017] The lipofuscin of the present invention is selected from the following group of retinoid dimers: N-retinylidene-N-retinylethanolamine (A2E), all-trans-retinal dimer (ATRdimer), or a combination thereof.

[0018] The present invention also provides a pharmaceutical composition for treating retinal diseases associated with harmful accumulation of lipofuscin. It should be understood that the active ingredient of the pharmaceutical composition includes a compound represented by formula (I) or formula (II) or its crystal form, pharmaceutically acceptable salt, solvate, etc.

[0019] The structural formula (I) or formula (II) described in the present invention can react with an inorganic or organic base to produce a "pharmaceutically acceptable salt", including but not limited to: sodium salt, calcium salt, potassium salt, magnesium salt, manganese salt, iron salt, copper salt, zinc salt, aluminum salt, lithium salt, etc.

[0020] The term "solvate" refers to an association or complex between one or more solvent molecules and the compound of formula (I) or (II) described herein. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0021] The pharmaceutical composition provided by the present invention preferably contains an active ingredient in a weight ratio of 0.001 to 99 wt%, and the preferred ratio is that the deuterated vitamin A and its derivatives represented by the general formula (I) or formula (II) of the present invention as the active ingredient account for 0.1 wt% to 90 wt% of the total weight, and the rest is a pharmaceutically acceptable carrier, diluent, solution or saline solution.

[0022] When necessary, one or more pharmaceutically acceptable carriers may be added to the drug of the present invention, including conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field.

[0023] The pharmaceutical composition of the present invention can be in the form of tablets, pills, capsules, granules, powders, granules, ointments, emulsions, suspensions, injections, microspheres and the like.

[0024] The administration of the pharmaceutical composition of the present invention includes, but is not limited to, oral, topical, transdermal, sublingual, intraocular, intramuscular, parenteral, and intravenous administration, preferably oral administration or injection.

[0025] The present invention also provides the use of a pharmaceutical composition in the preparation of a medicament for treating and / or preventing or alleviating retinal diseases associated with lipofuscin accumulation, such as juvenile macular degeneration and age-related macular degeneration. In particular, the lipofuscin is selected from the group consisting of retinoid dimers: N-retinylidene-N-retinylethanolamine (A2E), all-trans retinal dimer (ATR dimer), or a combination thereof.

[0026] The present invention also provides a pharmaceutical composition of deuterated vitamin A represented by formula (I) or formula (II), its derivatives, or its crystal forms, solvates, and pharmaceutically acceptable carriers for use in treating and preventing retinal diseases such as Stargardt disease and AMD.

[0027] The present invention has the following beneficial effects: the compound or pharmaceutical composition of the present invention can reduce the formation of retinoid dimers in lipofuscin, especially the deuterated vitamin A compound 1e, which has better pharmacodynamic properties than the active metabolite of ALK-001, can better reduce the formation of retinoid dimers A2E and ATRdimer, and is more suitable for the preparation of drugs for the treatment and prevention of retinal diseases such as Stargardt disease and dry AMD. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 Figure 3 is a curve showing the change in the formation of A2E over time from the reaction of all-trans retinal and compound 1a prepared in an example of the present invention with ethanolamine. The compound 1a prepared in an example of the present invention forms A2E 2.3 times slower than all-trans retinal.

[0029] Figure 2 The graph shows the change in the formation of ATR dimer over time by the reaction of all-trans retinal and compound 1a prepared in the embodiment of the present invention with proline. The formation of ATR dimer by compound 1a prepared in the embodiment of the present invention is 1.4 times slower than that by all-trans retinal.

[0030] Figure 3 Figure 3 is a curve showing the change in the formation of A2E over time from all-trans retinal, compounds 1c, 1d, and 1e prepared in the examples of the present invention, and ethanolamine. Among them, compound 1e prepared in the examples of the present invention forms A2E the slowest;

[0031] Figure 4 This is a curve showing the change in the formation of A2E over time by the reaction of compounds 1d and 1e prepared in the examples of the present invention with ethanolamine. Compound 1e prepared in the examples of the present invention forms A2E 2.1 times slower than compound 1d.

[0032] Figure 5 Figure 3 is a curve showing the change in the formation of ATR dimer over time by the reaction of all-trans retinal, compounds 1b, 1c, 1d, and 1e prepared in the examples of the present invention with proline. Among them, compound 1e prepared in the examples of the present invention forms the ATR dimer the slowest;

[0033] Figure 6 This is the curve of the reaction of compounds 1d and 1e prepared in the examples of the present invention with proline to form ATR dimer over time. Among them, the ATR dimer formed by compound 1e prepared in the examples of the present invention is 1.3 times slower than that of 1d;

[0034] Figure 7 Figure 3 is a curve showing the change in the formation of A2E over time from the reaction of all-trans retinal and the compound 1f prepared in the example of the present invention with ethanolamine. The rate of A2E formation from the compound 1f prepared in the example of the present invention is substantially the same as that from all-trans retinal.

[0035] Figure 8 The graph shows the change in the formation of ATR dimer over time when all-trans retinal and compound 1f prepared in the example of the present invention react with proline. The rate of ATR dimer formation by compound 1f prepared in the example of the present invention is substantially the same as that of all-trans retinal. DETAILED DESCRIPTION

[0036] The present invention will be further described in detail below with reference to specific examples and data, but the present invention is not limited to the following examples.

[0037] Example 1: Synthesis of Compound 1a

[0038] The synthetic route is:

[0039]

[0040] Preparation of compound S1:

[0041] In a glove box, a dry reaction flask was added with LiAlD4 (356.1 mg, 8.5 mmol, 99% D). After the reaction flask was removed from the glove box, it was purged three times under argon, and then ether (50 mL) was added. The reaction system was cooled to 0°C in an ice-water bath, and a solution of all-trans retinoic acid (1.5006 g, 5 mmol) in ether (120 mL) was slowly added dropwise. The mixture was then stirred at 0°C for 2 hours. Water (10 mL) was added to quench the reaction, and the organic phase was separated. The aqueous phase was added with 5% potassium hydroxide (100 mL) and filtered through a short column of celite. The column was washed with ethyl acetate (100 mL). The organic phase was separated and the aqueous phase was extracted with ether (20 mL x 3) and washed with water to neutral pH. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain the crude product S1. S1 was used directly in the next step without purification.

[0042] Preparation of compound 1a:

[0043] Under argon atmosphere, the above crude product S1 and dichloromethane (100 mL) were added to a dry reaction flask, and then Na2CO3 (9.5397 g, 90 mmol) and MnO2 (7.8282 g, 90 mmol) were slowly added. The reaction solution was stirred at room temperature for 19 hours, then filtered through a short column of celite, washed with ethyl acetate (15 mL × 3), and the solvent was removed by rotary evaporation. Separation and purification were performed by silica gel column chromatography (eluent: petroleum ether, then petroleum ether / ethyl acetate = 50 / 1, then 40 / 1) to obtain product 1a (344.9 mg, 24% (2 steps)): red liquid; 1 H NMR (400MHz, CDCl3): δ = 7.14 (dd, J1 = 14.8Hz, J2 = 11.6Hz, 1H, = CH), 6.42-6.29 (m, 2H, 2x = CH),6.22-6.12(m,2H,2x=CH),5.97(s,1H,=CH),2.33(s,3H,CH3),2.08-1.98(m,5H,CH2 and CH3),1.72(s,3H,CH3),1.67-1.58(m,2H,CH2),1.51-1.43(m,2H,CH2),1.04(s,6H,2x CH3); 13 C NMR (100MHz, CDCl3): δ = 190.8 (J = 25.7Hz), 154.7, 141.3, 137.7, 137.1, 134.5, 132.5, 130.5, 129.7, 129.4, 128.9, 39.6, 34.3, 33.1, 29.0, 21.7,19.2,13.1,13.0; IR(neat):v=2955,2933,2923,2859,2092,1643,1570,1445,1375,1359,1344,1268,1211,1195,1165,1070,1025cm -1 ;MS (70eV, EI) m / z (%): 285 (M + ,100); HRMS calcd m / z for C 20 H 27 DO[M + ]:285.2197,found:285.2200.

[0044] Example 2: Synthesis of Compounds 1b, 1c, and 1e

[0045] The synthetic route is:

[0046]

[0047] Preparation of compound S2:

[0048] Under argon, 2,2,6,6-tetramethylpiperidine (11.8 mL, density 0.837 g / mL, 9.8766 g, 70 mmol) and THF (70 mL) were added to a dry reaction flask. The flask was cooled to -78°C in a dry ice-acetone bath, and n-butyllithium (2.5 M in hexane, 28.0 mL, 70 mmol) was added dropwise. After the addition was complete, stirring was continued at -78°C for 1 hour, followed by stirring at 0°C for 30 minutes in an ice-water bath (to produce a lithium 2,2,6,6-tetramethylpiperidine solution). A solution of bis[(pinacolato)boryl]methane (19.1414 g, 70 mmol) in THF (140 mL) was added to the reaction flask at 0°C, and stirring was continued at 0°C for 30 minutes. The reaction flask was cooled to -78°C in a dry ice acetone bath, and a solution of β-cyclocitral (8.0101 g, 95% purity, 50 mmol) in THF (50 mL) was added. The reaction solution was stirred at -78°C for 3 hours, and then stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction, water (400 mL) was added, and the mixture was extracted with ethyl acetate (3×300 mL). The organic phases were combined, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The product S2 (12.4276 g, 86%) was obtained by separation and purification by silica gel column chromatography (eluent: petroleum ether, then petroleum ether / ethyl acetate = 30 / 1): a light yellow liquid; 1 HNMR (400MHz, CDCl3): δ = 7.01 (d, J = 18.4Hz, 1H, = CH), 5.42 (d, J = 18.4Hz, 1H, = CH), 2.00 (t, J = 6.2Hz, 2H, CH2) ,1.71(s,3H,CH3),1.63-1.55(m,2H,CH2),1.47-1.41(m,2H,CH2),1.29(s,12H,4xCH3),1.04(s,6H,2xCH3); 13 CNMR (100MHz, CDCl3): δ = 149.5, 139.2, 130.9, 82.9, 39.8, 33.7, 33.1, 28.8, 24.8, 21.6, 19.1; IR (nea t):v=2977,2928,2866,2827,1615,1459,1379,1370,1344,1317,1266,1212,1164,1144,1109,1028cm -1 ;MS (70eV, EI) m / z (%): 276 (M + ,32.02),161(100).

[0049] Preparation of compound S4:

[0050] To a dried reaction flask, Cp*Rh(OAc)2 (178.2 mg, 0.5 mmol), Cu(OAc)2·H2O (599.3 mg, 3.0 mmol), S2 (2.7620 g, 10 mmol), THF (50 mL), S3 (1.0515 g, 15 mmol), THF (50 mL), and H2O (540 μL, 30 mmol) were added in sequence. The reaction flask was capped with a rubber stopper and an air balloon was inserted to keep the reaction system under air. The mixture was stirred in an oil bath at 50°C for 56 hours. The reaction solution was filtered through a silica gel cartridge, washed with ethyl acetate (80 mL), and the solvent was removed by rotary evaporation. Ethyl acetate (10 mL) was added to dilute the mixture, and the mixture was filtered through a silica gel cartridge again, washed with ethyl acetate (80 mL), and the solvent was removed by rotary evaporation. The product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50 / 1, then 30 / 1) to obtain product S4 (1.6202 g, 74%): yellow liquid; 1 HNMR (400MHz, CDCl3): δ = 10.13 (d, J = 8.0Hz, 1H, CHO), 6.74 (d, J = 16.0Hz, 1H, = CH), 6.21 (d, J = 16.4Hz, 1H, = CH), 5.94 (d, J = 8.0Hz, 1H, = C H),2.32(s,3H,CH3),2.05(t,J=6.2Hz,2H,CH2),1.73(s,3H,CH3),1.68-1.59(m,2H,CH2),1.52-1.45(m,2H,CH2),1.05(s,6H,2xCH3); 13 CNMR (100MHz, CDCl3): δ=191.3,155.0,137.0,135.7,135.5,132.7,128.7,39.5,34.2,33.2,28.9,21.7,19.0,12.9; IR(n eat):v=2956,2928,2864,2769,2723,1661,1606,1594,1445,1384,1361,1333,1259,1204,1146,1125,1106,1045,1029cm -1 ;MS (70eV, EI) m / z (%): 218 (M + ,28.07),119(100).

[0051] Preparation of compound S5:

[0052] Under argon, 2,2,6,6-tetramethylpiperidine (905.0 mg, 6.4 mmol) and THF (6.4 mL) were added to a dry reaction flask. The reaction flask was cooled to -78°C in a dry ice-acetone bath, and n-butyllithium (2.5 Minhexane, 2.56 mL, 6.4 mmol) was added dropwise. After the addition was complete, stirring was continued at -78°C for 1 hour, followed by stirring at 0°C for 30 minutes in an ice-water bath (to produce a lithium 2,2,6,6-tetramethylpiperidine solution). A solution of bis[(pinacolato)boryl]methane (1.7170 g, 6.4 mmol) in THF (12.8 mL) was added to the reaction flask at 0°C, followed by stirring at 0°C for 30 minutes. The reaction flask was cooled to -78°C in a dry ice-acetone bath, and a solution of S4 (873.5 mg, 4 mmol) in THF (4 mL) was added. The reaction solution was stirred at -78°C for 2 hours. A saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction, water (20 mL) was added, and the mixture was extracted with ethyl acetate (4×20 mL). The organic phases were combined, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The product was separated and purified by silica gel column chromatography (eluent: petroleum ether, then petroleum ether / ethyl acetate = 50 / 1) to obtain the product S5 (1.1036 g, 81%): a yellow liquid; 1 HNMR (400MHz, CDCl3): δ = 7.41 (dd, J1 = 17.4Hz, J2 = 11.4Hz, 1H, = CH), 6.26 (d, J = 16.0Hz, 1H, = CH), 6.31-6.22 (m, 2H, 2x = CH), 5.56 (d, J = 17.2Hz, 1H ,=CH),2.08-1.97(m,5H,CH2andCH3),1.70(s,3H,CH3),1.67-1.58(m,2H,CH2),1.49-1.43(m,2H,CH2),1.28(s,12H,4xCH3),1.02(s,6H,2xCH3); 13 CNMR (100MHz, CDCl3): δ=145.7,139.6,137.6,137.3,131.7,129.8,128.7,83.1,39.6,34.2,33.1,28.9,24.7,21.7,19.2 ,12.9; IR(neat):v=3431,2976,2928,2865,1718,1669,1616,1601,1576,1472,1456,1379,1362,1338,1271,1142,1105cm -1 ;MS (70eV, EI) m / z (%): 342 (M + ,12.16),129(100).

[0053] Preparation of compound 1b:

[0054] To a dry reaction tube, Cp*Rh(OAc)2 (17.8 mg, 0.05 mmol) and Cu(OAc)2·H2O (59.9 mg, 0.30 mmol) were added sequentially. The reaction tube was protected from light with aluminum foil. S5 (0.5 M THF solution, 2000 μL, 1.0 mmol), S3-d2' (108.4 mg, 1.5 mmol), THF (8 mL), and H2O (54 μL, 3.0 mmol) were then added sequentially. The reaction tube was plugged with a rubber stopper and an air balloon was inserted to keep the reaction system in an air atmosphere. The reaction solution was stirred at room temperature in the dark for 22 hours. The reaction solution was filtered through a short silica gel column, washed with ethyl acetate (40 mL), and the solvent was removed by rotary evaporation. Ethyl acetate (10 mL) was added to dilute the solution, then filtered through a short silica gel column, washed with ethyl acetate (40 mL), and the solvent was removed by rotary evaporation. The product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 40 / 1, then 30 / 1) to obtain product 1b (162.7 mg, 57%): a yellow waxy liquid; 1 HNMR (400MHz, CD3CN): δ = 7.23 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6.42 (d, J = 15.2H z,1H,=CH),6.37(d,J=16.4Hz,1H,=CH),6.23(d,J=11.6Hz,1H,=CH),6.18(d,J=16.4H z,1H,=CH),5.89(s,1H,=CH),2.31-2.27(m,2H,CH2D),2.07-1.98(m,5H,CH3andCH2), 1.71(s,3H,CH3),1.66-1.58(m,2H,CH2),1.52-1.44(m,2H,CH2),1.03(s,6H,2xCH3); 13 CNMR (100MHz, CD3CN): δ = 191.9 (t, J = 25.7Hz), 156.1, 142.0, 138.6, 138.1, 135.7, 133.6, 131.1, 130.6, 130.2, 129.7 (t, J = 3.2Hz), 40.4, 34.9, 33 .7,29.3,22.0,19.9,13.1,13.0(t,J=19.4Hz); IR(neat):v=2951,2926, 2909,2867,2093,1644,1568,1447,1355,1267,1192,1164,1079,1043cm -1;MS (70eV, EI) m / z (%): 286 (M + ,100);HRMScalcdm / zfor C 20 H 26 D2O[M + ]:286.2260,found286.2259.

[0055] Preparation of compound 1c:

[0056] The procedure was the same as for the preparation of compound 1b. Cp*Rh(OAc)2 (17.8 mg, 0.05 mmol), Cu(OAc)2·H2O (60.0 mg, 0.30 mmol), S5 (0.5 M solution in THF, 2000 μL, 1.0 mmol), S3-d2 (108.1 mg, 1.5 mmol), THF (8 mL), and H2O (54 μL, 3.0 mmol) were reacted for 16 hours to give product 1c (156.7 mg, 55%) (eluent: petroleum ether / ethyl acetate = 40 / 1, then 30 / 1): a yellow waxy liquid. 1 HNMR (400MHz, CDCl3): δ = 10.10 (d, J = 8.0Hz, 1H, CHO), 7.14 (dd, J1 = 14.8Hz, J2 =11.6Hz,1H,=CH),6.43-6.29(m,2H,2x=CH),6.22-6.11(m,2H,2x=CH),5.97(d ,J=8.0Hz,1H,=CH),2.29(s,1H,CD2H),2.09-1.99(m,5H,CH3andCH2),1.72(s ,3H,CH3),1.66-1.58(m,2H,CH2),1.51-1.44(m,2H,CH2),1.04(s,6H,2xCH3); 13 CNMR (100MHz, CDCl3): δ=191.1,154.8,141.3,137.6,137.1,134.5,132.5,130.5,129.7,129.4,129.0,39.6,34.2,33.1,28.9, 21.7,19.2,13.0,12.4(quint,J=19.4Hz); IR(neat):v=2956,2925,2861,1655,1569,1447,1375,1353,1265,1194,1161,1107cm -1 ;MS (70eV, EI) m / z (%): 286 (M + ,100);HRMScalcdm / zforC 20 H 26D2O[M + ]:286.2260,found286.2259.

[0057] Preparation of compound 1e:

[0058] The procedure was the same as for the preparation of compound 1b. Cp*Rh(OAc)2 (17.9 mg, 0.05 mmol), Cu(OAc)2·H2O (59.8 mg, 0.30 mmol), S5 (0.5 M solution in THF, 2000 μL, 1.0 mmol), S3-d4 (111.1 mg, 1.5 mmol), THF (8 mL), and H2O (54 μL, 3.0 mmol) were reacted for 22 hours to give product 1e (162.0 mg, 56%) (eluent: petroleum ether / ethyl acetate = 40 / 1, then 30 / 1): a yellow waxy liquid; 1 HNMR (400MHz, CDCl3): δ = 7.14 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6.42-6.30 (m, 2H, 2x = CH), 6.22-6.13 (m, 2H, 2x = CH), 5.97 (s ,1H,=CH),2.08-2.00(m,5H,CH3andCH2),1.72(s,3H,CH3),1.66-1.58(m,2H,CH2),1.51-1.44(m,2H,CH2),1.04(s,6H,2xCH3); 13 CNMR (100MHz, CDCl3): δ = 190.8 (t, J = 26.1Hz), 154.8, 141.3, 137.6, 137.0, 134.5, 132.5, 130.5, 129.7, 129.4, 129.0, 39.6, 34.2, 33.1, 2 8.9,21.7,19.2,13.0,12.4(hept,J=19.3Hz); IR(neat):v=2956,2927,2864,2826,2092,1651,1568,1457,1447,1353,1195,1169,1044cm -1 ;MS (70eV, EI) m / z (%): 288 (M + ,100);HRMScalcdm / zforC 20 H 24 D4O[M + ]:288.2386,found288.2387.

[0059] Example 3: Synthesis of Compound 1d

[0060] The synthetic route is:

[0061]

[0062] Preparation of compound S6:

[0063] Under argon, 1e (578.4 mg, 2 mmol), tert-butyl alcohol (40 mL), and 2-methyl-2-butene (11.9 mL, density 0.662 g / mL, 7.8695 g, 90% purity, 100 mmol) were added sequentially to a dry reaction flask. NaClO2 (1.6299 g, 18 mmol) and NaH2PO4 (1.6809 g, 14 mmol) were dissolved in water (20 mL), and the aqueous solution was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature in the dark for 11 hours, then water (100 mL) was added, extracted with ether (100 mL x 4), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The product was separated and purified by silica gel column chromatography (eluent: petroleum ether / acetone = 10 / 1, then 7 / 1) to obtain crude product S6.

[0064] Preparation of compound 1d:

[0065] The two-step reaction operation is the same as in Example 1.

[0066] S6 (352.6 mg, 1.2 mmol), ether (50 mL), and LiAlH4 (76.2 mg, 2 mmol) were reacted for 2.5 hours to obtain the crude product S7.

[0067] The above S7, dichloromethane (20 mL), Na2CO3 (2.2168 g, 20.9 mmol), and MnO2 (1.8546 g, 21.3 mmol) were reacted for 18 hours to give the product 1d (123.6 mg, 36% (2 steps)) (silica gel was treated with petroleum ether containing 5% by volume triethylamine) (eluent: petroleum ether, then petroleum ether / ethyl acetate = 50 / 1, then 40 / 1): an orange waxy liquid; 1 H NMR (400MHz, CDCl3): δ = 10.10 (d, J = 8.0Hz, 1H, CHO), 7.14 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6. 42-6.30(m,2H,2x=CH),6.22-6.13(m,2H,2x=CH),5.97(d,J=8.4Hz,1H,=CH),2.08-2.00(m,5H,CH3 and CH2),1.72(s,3H,CH3),1.66-1.58(m,2H,CH2),1.51-1.44(m,2H,CH2),1.04(s,6H,2x CH3); 13C NMR (100MHz, CDCl3): δ=191.1,154.7,141.2,137.6,137.0,134.5,132.5,130.5,129.7,129.3,129.0,39.5,34.2,33.1,28.9,21.7, 19.1,12.9,12.3(hept,J=19.3Hz); IR(neat):v=2957,2925,2862,1654,1568,1445,1403,1347,1269,1195,1161,1133,1108,1042cm -1 ;MS (70eV, EI) m / z (%): 287 (M + ,70.1),84(100); HRMScalcd m / z for C 20 H 25 D3O[M + ]:287.2323,found 287.2320.

[0068] Example 4: Synthesis of Compound 1f

[0069] The synthetic route is:

[0070]

[0071] Preparation of compound S8:

[0072] To a dried reaction flask, Cp*Rh(OAc)2 (142.5 mg, 0.4 mmol), Cu(OAc)2·H2O (479.2 mg, 2.4 mmol), S2 (2.2098 g, 8 mmol), THF (40 mL), S3-d2 (865.2 mg, 12 mmol), THF (40 mL), and H2O (432 μL, 24 mmol) were added in sequence. The reaction flask was capped with a rubber stopper and an air balloon was inserted to keep the reaction system under air. The mixture was stirred in a 50°C oil bath for 48 hours. The reaction solution was filtered through a silica gel short column, washed with ethyl acetate (80 mL), and the solvent was removed by rotary evaporation. Ethyl acetate (10 mL) was added to dilute the mixture, and the mixture was filtered through a silica gel short column, washed with ethyl acetate (80 mL), and the solvent was removed by rotary evaporation. The product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 50 / 1, then 30 / 1) to obtain product S8 (1.3374 g, 76%): yellow liquid; 1H NMR (400MHz, CDCl3): δ = 10.13 (d, J = 8.0Hz, 1H, CHO), 6.74 (d, J = 16.0Hz, 1H, = CH), 6.21 (d, J = 16.4Hz, 1H, = CH), 5.94 (d, J = 8.0Hz, 1H, =CH),2.28(s,1H,CD2H),2.05(t,J=6.2Hz,2H,CH2),1.73(s,3H,CH3),1.68-1.59(m,2H,CH2),1.52-1.45(m,2H,CH2),1.05(s,6H,2x CH3); 13 C NMR (100MHz, CDCl3): δ=191.3,155.0,137.0,135.6,135.5,132.7,128.7,39.5,34.2,33.2,28.9,21.7,19.0,12.4(quint,J= 20.3Hz); IR(neat):v=2959,2928,2864,2774,2735,1661,1605,1585,1456,1360,1258,1194,1146,1125,1101,1043,1026cm -1 ;MS(70eV,EI)m / z(%):220(M + ,26.80),121(100); HRMS calcdm / z for C 15 H 20 D2O[M + ]:220.1791,found 220.1790.

[0073] Preparation of compound S9:

[0074] Under argon, 2,2,6,6-tetramethylpiperidine (1.2882 g, 9.12 mmol) and THF (9.1 mL) were added to a dry reaction flask. The flask was cooled to 0°C in an ice-water bath, and n-butyllithium (2.5 mol / L in n-hexane, 3.65 mL, 9.12 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 0°C for 30 minutes in an ice-water bath (to produce a lithium 2,2,6,6-tetramethylpiperidine solution). A solution of bis[(pinacolato)boryl]methane (2.4439 g, 9.12 mmol) in THF (18.2 mL) was added to the flask at 0°C, followed by further stirring at 0°C for 30 minutes. The flask was cooled to -78°C in a dry ice-acetone bath, and a solution of S8 (1.2560 mg, 5.7 mmol) in THF (5.7 mL) was added. The reaction solution was stirred at -78 ° C for 3 hours. A saturated aqueous ammonium chloride solution (6 mL) was added to quench the reaction, water (90 mL) was added, and the mixture was extracted with ethyl acetate (3×60 mL). The organic phases were combined, washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The product was separated and purified by silica gel column chromatography (silica gel was deactivated with 35 wt% water, eluent: petroleum ether) to obtain the product S9 (1.6670 g, 85%): a yellow liquid; 1 HNMR (400MHz, CDCl3): δ = 7.41 (dd, J1 = 17.2Hz, J2 = 11.2Hz, 1H, = CH), 6.26 (d, J = 16.0Hz, 1H, = CH), 6.17-6.05 (m, 2H, 2x = CH), 5.58 (d, J = 17.2Hz, 1H, = CH), 2 .01(t,J=6.0Hz,2H,CH2),1.96(s,1H,CD2H),1.70(s,3H,CH3),1.65-1.57(m ,2H,CH2),1.48-1.43(m,2H,CH2),1.28(s,12H,4xCH3),1.02(s,6H,2xCH3); 13 CNMR (100MHz, CDCl3): δ=145.7,139.6,137.6,137.3,131.7,129.8,128.7,83.1,39.6,34.2,33.1,28.9,24.7,21.7,19.2, 12.4(quint,J=19.4Hz); IR(neat):v=2976,2928,2864,1614,1597,1572,1456,1379,1371,1341,1317,1269,1142,1103cm -1 ;MS (70eV, EI) m / z (%): 344 (M +,90.1),101(100);HRMScalcdm / zforC 22 H 33 D2 11 BO2[M + ]:344.2850,found344.2853.

[0075] Preparation of compound 1f:

[0076] The procedure was the same as for the preparation of compound 1b. Cp*Rh(OAc)2 (17.8 mg, 0.05 mmol), Cu(OAc)2·H2O (59.9 mg, 0.30 mmol), S9 (0.5 M solution in THF, 2000 μL, 1.0 mmol), S3 (105.2 mg, 1.5 mmol), THF (8 mL), and H2O (54 μL, 3.0 mmol) were reacted for 22 hours to give product 1e (148.5 mg, 52%) (eluent: petroleum ether / ethyl acetate = 40 / 1, then 30 / 1): a yellow waxy liquid; 1 HNMR (400MHz, CDCl3): δ = 10.11 (d, J = 8.0Hz, 1H, CHO), 7.14 (dd, J1 = 14.8Hz, J2 =11.6Hz,1H,=CH),6.44-6.29(m,2H,2x=CH),6.22-6.10(m,2H,2x=CH),5.97(d ,J=8.0Hz,1H,=CH),2.33(s,3H,CH3),2.07-1.97(m,3H,CD2HandCH2),1.72(s ,3H,CH3),1.66-1.58(m,2H,CH2),1.50-1.43(m,2H,CH2),1.04(s,6H,2xCH3); 13 CNMR (100MHz, CDCl3): δ=191.1,154.8,141.3,137.6,137.1,134.5,132.5,130.5,129.7,129.4,129.0,39.6,34.3,33.1,28.9, 21.7,19.2,13.1,12.5(quint,J=19.2Hz); IR(neat):v=2959,2924,2862,2762,1655,1574,1447,1385,1159,1132,1109,1043cm -1 ;MS (70eV, EI) m / z (%): 286 (M + ,100);HRMScalcdm / zforC 20 H 26 D2O[M+ ]:286.2260,found286.2263.

[0077] In order to further illustrate the beneficial effects of the present invention, the present invention provides the following examples.

[0078] Example 5: HPLC detection of the effect of compound 1a prepared in Example 1 of the present invention on the formation of two dimers A2E and ATRdimer

[0079] Experimental purpose: To study the effect of deuterated aldehyde group of all-trans-retinal on the formation rate of two dimers in vitro.

[0080] Experimental process:

[0081] (1) HPLC detection of A2E formation rate in vitro

[0082] To a dry brown bottle, add 1a (20.2 mg, 0.071 mmol) or all-trans-retinal (20.2 mg, 0.071 mmol), anhydrous ethanol (5 mL), ethanolamine (2.2 mg), and acetic acid (2.2 mg) in sequence. Cover the bottle and stir at room temperature in the dark. A small amount of the reaction solution was sampled at different time points during the reaction and the A2E content was determined by HPLC, with peak area expressed as the peak area.

[0083] HPLC chromatographic conditions: Chromatographic column: C18 column; mobile phase is acetonitrile and water, gradient elution conditions: 85% acetonitrile (0-11 min, 2 ml / min, containing 0.1% TFA), 95% acetonitrile (12-18 min, 3 ml / min, containing 0.1% TFA); detection wavelength: 445 nm.

[0084] (2) HPLC detection of ATR dimer formation rate in vitro

[0085] To a dry brown bottle, add 1a (10.0 mg, 0.035 mmol) or all-trans-retinal (10.0 mg, 0.035 mmol), anhydrous ethanol (5 mL), L-proline (8.0 mg), and triethylamine (3 μL) in sequence. Cover the bottle and stir at room temperature in the dark. A small amount of the reaction solution was sampled at different time points during the reaction and the ATR dimer content was determined by HPLC, with peak area expressed as the peak area.

[0086] HPLC chromatographic conditions: chromatographic column: C18 column; mobile phase: acetonitrile and water, gradient elution condition: 100% acetonitrile (2.5 ml / min); detection wavelength: 430 nm.

[0087] Concentration-time curves and reaction rate constants were derived using Prism (GraphPad Software).

[0088] Experimental results:

[0089] The results are as follows Figures 1 to 2 The results show that for the formation of A2E, the reaction rate of compound 1a is slower than that of all-trans retinal, and the reaction rate constant ratio k 全反式视黄醛 / k 1a =2.3. Similarly, for the formation of ATRdimer, the reaction rate of compound 1a is slower than that of all-trans retinal, and the reaction rate constant ratio k 全反式视黄醛 / k 1a =1.4. Thus, deuterated substitution of the aldehyde group of all-trans retinal can significantly slow the formation of A2E and ATR dimer, indicating that the compounds of the present invention can reduce the formation of lipofuscin deposits and are therefore suitable for preparing drugs for treating lipofuscin-related retinal diseases such as juvenile macular degeneration and age-related macular degeneration.

[0090] Example 6: HPLC detection of the effects of compounds 1b, 1c, 1d, 1f, and 1e synthesized in the present invention on the formation of two dimers A2E and ATRdimer

[0091] Experimental purpose: To study the effect of different deuterated all-trans retinal on the formation rate of two dimers in vitro.

[0092] The experimental process is the same as that of Example 5 of the present invention.

[0093] Experimental results:

[0094] The results are as follows Figures 3 to 8 The results show that for the formation of A2E, the reaction rate of compound 1e is slower than that of other deuterated compounds and all-trans retinal. The reaction rate constant ratio k of all-trans retinal and compound 1e is 全反式视黄醛 / k 1e =19.0, the reaction rate constant ratio k of compound 1d and compound 1e 1d / k 1e =2.1. Similarly, for the formation of ATRdimer, the reaction rate of compound 1e is slower than that of other deuterated compounds and all-trans retinal. The reaction rate constant ratio k of all-trans retinal and compound 1e is 全反式视黄醛 / k 1e =19.4, the reaction rate constant ratio k of compound 1d and compound 1e 1d / k 1e=1.3. Thus, compound 1e has a strong ability to slow the formation of two dimers, A2E and ATR dimer. Compared with compound 1d, it has a superior ability to slow dimer formation. Therefore, it is more suitable as a compound for reducing the formation of lipofuscin deposits, and further suitable for preparing drugs for treating lipofuscin-related retinal diseases such as juvenile macular degeneration and age-related macular degeneration.

[0095] Although the present invention has been described in detail in the above embodiments, changes and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the present invention are included in the present invention and are protected by the appended claims.

Claims

1. Use of deuterated vitamin A or a pharmaceutically acceptable salt thereof as represented by formula (I) in the preparation of a drug for treating and / or preventing or alleviating retinal diseases associated with lipofuscin accumulation, characterized in that: The structure of formula (I) is shown below: Formula (I); R 1 、R 2 、R 3 are each independently selected from hydrogen; R 4 、R 5 、R 6 are each independently selected from deuterium; The retinal disease is selected from the group consisting of juvenile macular degeneration and age-related macular degeneration.

2. The use according to claim 1, characterized in that The lipofuscin is selected from the following group of retinoid dimers: N -ATV Yellow Base- N - retinylethanolamine, all-trans retinal dimer, or a combination thereof.

3. Use of a pharmaceutical composition in the preparation of a drug for treating and / or preventing or alleviating retinal diseases associated with lipofuscin accumulation, characterized in that: The pharmaceutical composition contains: deuterated vitamin A represented by formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier; the retinal disease is selected from the following group: juvenile macular degeneration and age-related macular degeneration.

4. The use according to claim 3, characterized in that The pharmaceutical composition is in the form of tablets, pills, capsules, granules, powders, granules, pastes, emulsions, suspensions, injections, and microspheres.

5. The use according to claim 3, characterized in that The lipofuscin is selected from the following group of retinoid dimers: N -ATV Yellow Base- N - retinylethanolamine, all-trans retinal dimer, or a combination thereof.

Images