O-desmethylvenlafaxine prodrug, its preparation method and application

Abstract

The application discloses an O-desmethylvenlafaxine prodrug and a preparation method and application thereof, relates to the technical field of drug synthesis, and the structural formula of the O-desmethylvenlafaxine prodrug is shown in the following formula: The phenolic hydroxyl in the structure of the O-desmethylvenlafaxine is etherified or carbonated through a substitution reaction, O-desmethylvenlafaxine prodrug is synthesized, the bioavailability of the O-desmethylvenlafaxine can be remarkably improved, and a compound with the prodrug property is screened through a pharmacokinetics test.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, specifically to an O-desmethylvenlafaxine prodrug, its preparation method, and its application. Background Technology

[0002] Venlafaxine (VEN) is a phenethylamine derivative, chemically named (±)-1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)cyclohexanol. Venlafaxine is a dual inhibitor of serotonin (5-HT) and norepinephrine (NE) reuptake (SNRIs), a novel antidepressant with a unique chemical structure and neuropharmacological activity, unlike other antidepressants. Venlafaxine exists in a racemic form; the levorotatory and dextrorotatory isomers have different pharmacological activities. While the dextrorotatory isomer primarily inhibits 5-HT, the levorotatory isomer simultaneously inhibits the reuptake of both 5-HT and NE.

[0003] O-Desmethylvenlafaxine is the active metabolite of the antidepressant venlafaxine. Like venlafaxine, it exerts its pharmacological effects by inhibiting the reuptake of 5-HT and NE, but it has fewer side effects and a wider range of indications. Because O-Desmethylvenlafaxine exposes an additional hydroxyl group, its hydrophilicity is increased, resulting in decreased oral bioavailability and potentially increased pro-systemic side effects from unabsorbed drugs. To improve the bioavailability of O-Desmethylvenlafaxine, synthesizing its prodrugs may effectively increase its bioavailability, improve efficacy, and reduce side effects.

[0004] Prodrugs, also known as pro-drugs or pro-agents, were first proposed by Albert in 1951. Prodrugs are compounds with low or no in vitro activity, but which release their active substance in vivo through enzymatic or non-enzymatic action to exert their pharmacological effects. Currently, many drugs used clinically suffer from the following problems: incomplete oral absorption, thus affecting blood drug concentration; unsatisfactory distribution in vivo, producing undesirable toxic side effects; low water solubility, making them inconvenient to formulate into injections, or precipitation at the injection site causing pain; and some drugs are also metabolized and degraded due to the first-pass effect, shortening their half-life. In some cases, formulation technology can solve some problems, but sometimes it is not entirely satisfactory. The reasons for these problems are all related to the chemical structure of the drug, which is key to determining the drug's physicochemical properties and its binding to receptors to exert its therapeutic effect. Therefore, people appropriately modify the chemical structure of drugs to formulate prodrugs, thereby improving pharmacokinetic behavior and overcoming the above problems to varying degrees. The prodrug approach has become one of the effective ways to develop new drugs, and its application is becoming increasingly widespread and attracting much attention. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing O-demethylvenlafaxine prodrug, which improves the bioavailability of O-demethylvenlafaxine by etherifying or carbonate the phenolic hydroxyl group in the O-demethylvenlafaxine structure and screening for compounds with prodrug properties.

[0006] The technical problem to be solved by this invention is achieved by the following technical solution:

[0007] One objective of this invention is to provide an O-desmethylvenlafaxine prodrug, the structural formula of which is as follows:

[0008] ;

[0009] Where R is , , , , One of them.

[0010] The second objective of this invention is to provide a method for preparing an O-demethylvenlafaxine prodrug, wherein the O-demethylvenlafaxine prodrug is obtained by reacting O-demethylvenlafaxine with a halogenated product through a substitution reaction.

[0011] The reaction equation is as follows:

[0012] ;

[0013] Where R is , , , , One of them;

[0014] The halogenated product is , , One of them; wherein X is one of F, Cl, Br, and I.

[0015] Furthermore, the molar ratio of the O-demethylvenlafaxine to the halide is 1:(1~2).

[0016] Furthermore, the substitution reaction is carried out in the presence of an acid-binding agent, which is an inorganic or organic base.

[0017] Furthermore, the inorganic base includes, but is not limited to, one or more of sodium hydroxide, potassium carbonate, and sodium carbonate; the organic base includes, but is not limited to, one or more of triethylamine, pyridine, and N,N-diisopropylethylamine.

[0018] Furthermore, the amount of the acid-binding agent is 1 to 3 times the molar amount of O-demethylvenlafaxine.

[0019] Furthermore, the reaction solvent for the substitution reaction includes, but is not limited to, one or more of N,N-dimethylformamide, dichloromethane, and isopropanol.

[0020] Furthermore, the substitution reaction is carried out at a temperature of 20-70°C for 2-12 hours.

[0021] A third objective of this invention is to provide the application of the O-desmethylvenlafaxine prodrug in the preparation of antidepressant drugs.

[0022] The beneficial effects of this invention are: by etherifying the phenolic hydroxyl group in the O-demethylvenlafaxine structure through a substitution reaction, this invention synthesizes an O-demethylvenlafaxine prodrug, which can significantly improve the bioavailability of O-demethylvenlafaxine, and compounds with prodrug properties can be screened through pharmacokinetic experiments. Attached Figure Description

[0023] Figure 1 The 1H NMR spectrum of the O-demethylvenlafaxine prodrug synthesized in Example 1;

[0024] Figure 2 The mass spectrum of the O-demethylvenlafaxine prodrug synthesized in Example 1 is shown below.

[0025] Figure 3 The mass spectrum of the O-demethylvenlafaxine prodrug synthesized in Example 2 is shown below.

[0026] Figure 4 The 1H NMR spectrum of the O-demethylvenlafaxine prodrug synthesized in Example 3;

[0027] Figure 5 This is a crystal structure diagram of the O-demethylvenlafaxine prodrug synthesized in Example 3;

[0028] Figure 6 The 1H NMR spectrum of the O-demethylvenlafaxine prodrug synthesized in Example 4;

[0029] Figure 7 The carbon NMR spectrum of the O-demethylvenlafaxine prodrug synthesized in Example 4;

[0030] Figure 8 The 1H NMR spectrum of the O-demethylvenlafaxine prodrug synthesized in Example 5;

[0031] Figure 9 The carbon NMR spectrum of the O-demethylvenlafaxine prodrug synthesized in Example 5;

[0032] Figure 10The blood concentration-time curves of O-desmethylvenlafaxine prodrug and O-desmethylvenlafaxine synthesized in Examples 1-5 are shown. Detailed Implementation

[0033] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below with reference to specific embodiments and illustrations.

[0034] Example 1

[0035]

[0036] O-Desmethylvenlafaxine (0.24 g, 0.9 mmol), sodium hydroxide (0.08 g, 2.0 mmol), and N,N-dimethylformamide (5 mL) were added to a reaction flask and stirred at room temperature for 10 min. Then, 1-iodoethylcyclohexyl carbonate (0.30 g, 1.0 mmol) was added, and the mixture was heated to 40 °C and stirred for 12 h. After the reaction was complete, 20 mL of water was added to the reaction solution, and the mixture was stirred at room temperature for 30 min to crystallize. The mixture was filtered, and the filter cake was dissolved in 5 mL of ethyl acetate. Isopropanol hydrochloride was added dropwise to crystallize the mixture, which was then filtered and dried to obtain cyclohexyl(4-(2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl)phenyl) carbonate hydrochloride, with a yield of 69.6%. 1 HNMR (400 MHz, CDCl3) δ 7.12 (q, J = 8.8 Hz, 4H), 4.79-4.64 (m, 1H), 3.29 (t, J =12.5 Hz, 1H), 3.00 (dd, J = 12.5, 3.2Hz, 1H), 2.32 (s, 6H), 2.30 (d, J 0.96 (dt, J = 13.0, 3.9 Hz, 1H), 0.88 (dt, J =13.0, 3.9 Hz, 1H). MS(ESI) calcd for C 23 H 25 NO4[M+H] + 389.26, found 390.4.

[0037] Example 2

[0038]

[0039] O-Desmethylvenlafaxine (0.24 g, 0.9 mmol), potassium carbonate (0.20 g, 1.4 mmol), and dichloromethane (5 mL) were added to a reaction flask and stirred at room temperature for 10 min. Then, 1-iodoethylcyclohexyl carbonate (0.30 g, 1.0 mmol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, 5 mL of water was added to the reaction solution for extraction. The organic layer was concentrated to dryness, dissolved in 5 mL of ethyl acetate, and crystallized by adding isopropanol hydrochloride. The crystals were filtered and dried to give cyclohexyl(1-(4-(2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl)phenoxy)ethyl) carbonate hydrochloride, with a yield of 51.1%. MS(ESI) calcd for C 25 H 39 NO5[M+H] + 433.28, found 434.3.

[0040] Example 3

[0041]

[0042] O-Desmethylvenlafaxine (0.24 g, 0.9 mmol), potassium carbonate (0.20 g, 1.4 mmol), and isopropanol (5 mL) were added to a reaction flask and stirred at room temperature for 10 min. Then, iodomethyl isopropyl carbonate (0.29 g, 1.2 mmol) was added, and the mixture was heated to 70 °C and stirred for 12 h. After the reaction was complete, 20 mL of water was added to the reaction solution, and the mixture was stirred at room temperature for 30 min to crystallize. The mixture was filtered, and the filter cake was dissolved in 5 mL of ethyl acetate. Isopropanol hydrochloride was added dropwise to crystallize the mixture, which was then filtered and dried to give 4-(2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl)phenyl isopropyl carbonate hydrochloride, with a yield of 74.3%. 1 H NMR (400 MHz, CDCl3) δ7.12 (q, J = 8.3 Hz, 4H), 6.88 (s, br, 1H), 4.97 (p, J = 6.3 Hz, 1H), 3.29 (t, J =12.5 Hz, 1H), 3.00 (dd, J = 12.5, 3.3 Hz, 1H), 2.32 (s, 7H), 1.65-1.78 (m, 3H), 1.49-1.58 (m, 3H), 1.38 (d,J = 6.2 Hz, 6H), 1.34-1.17 (m, 2H), 1.04-0.79 (m, 2H).

[0043] 0.2 g of 4-(2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl)phenyl isopropyl carbonate hydrochloride was dissolved in ethyl acetate and left to stand open at room temperature to slowly crystallize. After 5 days, colorless and transparent needle-like single crystals were obtained. Diffraction intensity data were collected using a RigakuMM007-Saturn724+ small molecule single crystal X-ray diffractometer, and the crystal structure was resolved by the direct method (SHELXS-97). After refinement, the final reliability factor was R=0.0877(2578), wR2=0.2732(4009) (w=1 / σ|F|2), and S=1.084. Test results: Monoclinic crystal system, space group P21 / c, cell parameters: cell length a = 8.7641 (5), cell length b = 8.7641 (6), cell length c = 51.375 (5), cell angle a = γ = 90°, cell angle β = 90°, cell volume V = 3946.1 (7), number of asymmetric units in the cell Z = 8.

[0044] Example 4

[0045]

[0046] O-Desmethylvenlafaxine (0.24 g, 0.9 mmol), potassium carbonate (0.20 g, 1.4 mmol), and dichloromethane (5 mL) were added to a reaction flask and stirred at room temperature for 10 min. Then, iodomethyl isopropyl carbonate (0.29 g, 1.2 mmol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, 5 mL of water was added to the reaction solution for extraction. The organic layer was concentrated to dryness, dissolved in 5 mL of ethyl acetate, and crystallized by adding isopropanol hydrochloride. The crystals were filtered and dried to give (4-(2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl)phenoxy)methyl isopropyl carbonate hydrochloride, with a yield of 55.3%. 1 H NMR (400 MHz, CDCl3)δ 7.07 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.84 (s, br, 1H), 5.74 (s, 2H), 4.98-4.89 (m, 1H), 3.27 (t, J = 12.5 Hz, 1H), 2.96 (dd, J = 12.5, 3.4 Hz,1H), 2.32 (s, 6H), 2.27 (d,J = 3.4 Hz, 1H), 1.81-1.58 (m, 3H), 1.60-1.47 (m,3H), 1.38 (d, J = 6.2 Hz, 1H), 1.31 (d, J = 6.3 Hz, 6H), 1.31-1.23 (m, 1H), 1.01-0.82 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 155.57, 153.64, 135.25, 130.33,120.53, 115.73, 88.43, 74.19, 72.77, 61.16, 51.77, 45.50, 38.09, 31.24, 25.99, 21.71, 21.61, 21.33.

[0047] As can be seen from Examples 1-4, the same reactants yield different reaction products under different reaction conditions (alkaline, reaction temperature). Example 1 yielded a carbonate product at 40°C and under strongly alkaline conditions; Example 2 yielded an ether at room temperature and under weakly alkaline conditions; Example 3 yielded a carbonate product at 70°C and under weakly alkaline conditions; and Example 4 yielded an ether at room temperature and under weakly alkaline conditions.

[0048] Possible mechanisms for carbonate formation (taking Example 3 as an example):

[0049] ;

[0050] Possible mechanisms for ether formation (taking Example 4 as an example):

[0051] .

[0052] Example 5

[0053]

[0054] O-Desmethylvenlafaxine (0.24 g, 0.9 mmol), potassium carbonate (0.20 g, 1.4 mmol), and dichloromethane (5 mL) were added to a reaction flask and stirred at room temperature for 10 min. Then, methyl valerate (0.29 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 2 h. After the reaction was complete, 5 mL of water was added to the reaction solution for extraction. The organic layer was concentrated to dryness, dissolved in 5 mL of ethyl acetate, and crystallized by adding isopropanol hydrochloride. The crystals were filtered and dried to give (4-(2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl)phenoxy)methyl neopentyl ester hydrochloride, with a yield of 66.3%. 1H NMR (400 MHz, DMSO- d 6 ) δ9.45 (s, br,1H),7.32 (d, J = 8.5 Hz, 2H),7.03 (d, J = 8.5 Hz, 2H),5.78 (s, 2H),4.61 (s,1H),3.72-3.60 (m, 1H),3.56-3.43 (m, 1H),3.10 (dd, J = 9.6, 3.6 Hz, 1H),2.68(d, J = 4.7 Hz, 3H),2.60 (d, J = 4.7Hz, 3H),1.68-1.50 (m, 2H),1.48-1.37 (m,3H),1.37-1.28 (m,1H),1.24- 1.17 (m, 2H),1.12 (s, 9H), 1.09-0.95 (m, 2H). 13 C NMR (101 MHz, DMSO-) d 6 ) δ 176.93, 155.92, 133.33, 131.26, 116.38, 85.96, 72.54,58.54, 50.36, 43.78, 43.13, 38.85, 36.55, 33.70, 27.03, 25.73, 21.81, 21.43.

[0055] Example 6

[0056] Twenty-four beagle dogs, weighing 8–14 kg, were randomly divided into six groups of four. The O-desmethylvenlafaxine prodrug synthesized in Examples 1–5 and O-desmethylvenlafaxine were respectively prepared into solutions with purified water (equivalent to 25 mg / mL of O-desmethylvenlafaxine). Each dog was administered 2 mL by gavage, resulting in a dosage of 50 mg (equivalent to O-desmethylvenlafaxine) per dog. The dogs were fasted for 10 h before administration and fed 4 h after administration. Plasma samples were collected at 18 time points before administration and at 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, and 24 h after administration. The samples were placed in vacuum anticoagulant tubes containing EDTA-k2 and centrifuged at 3000 rpm for 10 min to separate the plasma, which was then frozen at -80°C for later analysis. Blood drug concentrations were determined by LC-MS / MS, and the average value was taken. The results are as follows: Figure 1 As shown.

[0057] Record Figure 1 The maximum plasma concentration (C) of each curve max ) and time to peak blood concentration (T) max The area under the curve (AUC) was calculated. Using the AUC of O-desmethylvenlafaxine as a baseline (set as 100%), the AUC increase ratio of the O-desmethylvenlafaxine prodrugs synthesized in Examples 1-5 was calculated, as shown in Table 1.

[0058] Table 1 Pharmacokinetic parameters of each compound

[0059]

[0060] As can be seen from Table 1, since the prodrugs synthesized in Examples 1-5 are almost entirely converted into the active metabolite O-desmethylvenlafaxine after entering the beagle's body through the gastrointestinal tract, the bioavailability of the prodrugs synthesized in Examples 1-5 is higher than that of O-desmethylvenlafaxine. Among them, the AUC of the prodrugs synthesized in Examples 1, 2, and 4 is increased by more than 30%, and the improvement in bioavailability is very significant, showing a clear advantage compared with O-desmethylvenlafaxine.

[0061] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. An O-desmethylvenlafaxine prodrug, the structural formula of which is as follows: in, R is One of them.

2. A method for preparing an O-desmethylvenlafaxine prodrug, characterized in that: The O-demethylvenlafaxine prodrug can be obtained by reacting O-demethylvenlafaxine with a halide. The reaction equation is as follows: Where R is One of them; The halogenated product is One of them; wherein X is one of F, Cl, Br, and I.

3. The method for preparing the O-desmethylvenlafaxine prodrug according to claim 2, characterized in that: The molar ratio of the O-demethylvenlafaxine to the halide is 1:(1-2).

4. The method for preparing the O-desmethylvenlafaxine prodrug according to claim 2, characterized in that: The substitution reaction is carried out in the presence of an acid-binding agent, which is an inorganic or organic base.

5. The method for preparing the O-desmethylvenlafaxine prodrug according to claim 4, characterized in that: The inorganic base is one or more of sodium hydroxide, potassium carbonate, and sodium carbonate.

6. The method for preparing the O-desmethylvenlafaxine prodrug according to claim 4, characterized in that: The organic base is one or more of triethylamine, pyridine, and N,N-diisopropylethylamine.

7. The method for preparing the O-desmethylvenlafaxine prodrug according to claim 4, characterized in that: The amount of the acid-binding agent is 1 to 3 times the molar amount of O-demethylvenlafaxine.

8. The method for preparing the O-desmethylvenlafaxine prodrug according to claim 2, characterized in that: The reaction solvent for the substitution reaction is one or more of N,N-dimethylformamide, dichloromethane, and isopropanol.

9. The method for preparing the O-desmethylvenlafaxine prodrug according to claim 2, characterized in that: The substitution reaction is carried out at a temperature of 20–70°C for 2–12 hours.

10. The use of the O-desmethylvenlafaxine prodrug of claim 1 in the preparation of an antidepressant.

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