Dopamine d2 receptor compounds and their use in the treatment of erectile dysfunction

Abstract

This invention belongs to the field of biomedicine. This invention provides a dopamine D2 receptor compound and its application in the treatment of erectile dysfunction. The dopamine D2 receptor compound provided by this invention has excellent biological activity and significant application potential in drugs for the treatment of erectile dysfunction.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, and in particular relates to a dopamine D2 receptor compound and its application in the treatment of erectile dysfunction. Background Technology

[0002] Dopamine is an important catecholamine neurotransmitter that regulates various physiological processes, including cardiovascular and endocrine activities, and plays a key role in modulating a variety of biological behaviors. Dopamine D2 receptors belong to the rhodopsin-like heptaspiral receptor family. Evidence suggests that dopamine D2 receptors have a protective effect in regulating immune imbalances and inflammatory responses. For example, the dopamine D2 receptor agonist LY171555 inhibits the activation of the NLRP3 inflammasome in the substantia nigra of PD mice, thereby reducing MPTP-induced neuronal loss. In an animal model of ischemic stroke, activation of dopamine D2 receptors can alleviate neuroinflammatory responses through αB-crystallin. Furthermore, in allergic encephalomyelitis, this receptor agonist can inhibit dendritic cell-mediated Th17 cell differentiation, thereby alleviating encephalomyelitis and limb paralysis symptoms.

[0003] As research progresses, the role of dopamine D2 receptors is clearly no longer limited to the areas mentioned above. For example, a study has reported a receptor called FR64822 ( Dopamine D2 receptor agonists, which indirectly stimulate dopamine D2 receptors, induce anti-nociceptive activity in mice and rats and promote penile erection in rats. These findings have prompted researchers to focus on the potential of dopamine D2 receptor agonists in treating erectile dysfunction. However, research shows that no related research pipelines have yet advanced to the clinical stage.

[0004] Therefore, developing a novel dopamine D2 receptor agonist compound is of great significance for advancing this field. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a dopamine D2 receptor compound and its application in the treatment of erectile dysfunction. The dopamine D2 receptor compound provided by this invention possesses excellent biological activity and has significant application potential in the treatment of erectile dysfunction.

[0006] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0007] This invention provides a dopamine D2 receptor compound as shown in Formula I, or a pharmaceutically acceptable salt thereof. ;in,

[0008] R1 is a C6-10 aryl group optionally substituted with one or more R1-1 groups or a C5-10 heteroaryl group optionally substituted with one or more R1-2 groups, wherein the heteroatom in the C5-10 heteroaryl group is selected from N, O and S.

[0009] R1-1 and R1-2 are each independently C1-6 alkyl, C3-6 cycloalkyl, or C1-6 alkoxy;

[0010] R2 is a C1-6 alkyl group optionally substituted with one or more R2-1, a C1-6 alkoxy group optionally substituted with one or more R2-2, or a C3-6 cycloalkyl group optionally substituted with one or more R2-3;

[0011] R2-1, R2-2 and R2-3 are each independently F, Cl, C1-6 alkyl, C3-6 cycloalkyl or C1-6 alkoxy;

[0012] R3 is a C6-10 aryl group optionally substituted with one or more R3-1 groups or a C5-10 heteroaryl group optionally substituted with one or more R3-2 groups, wherein the heteroatom in the C5-10 heteroaryl group is selected from N, O and S.

[0013] R3-1 and R3-2 are each independently C1-6 alkyl, C3-6 cycloalkyl, or C1-6 alkoxy.

[0014] In this invention, in R1 and R3, the aryl group of C6-10 is phenyl or naphthyl.

[0015] In this invention, in R1 and R3, the heteroaryl group of C5-10 is furanyl, thiophene, pyridinyl, quinolinyl or isoquinolinyl.

[0016] In this invention, R3-1 and R3-2 are each independently methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0017] In this invention, R3-1 and R3-2 are each independently methoxy or ethoxy.

[0018] In this invention, R1 is quinolinyl or isoquinolinyl, preferably quinolinyl. or Better for .

[0019] In this invention, R2 is a C1-6 alkyl group substituted with one or more fluorine molecules, preferably trifluoromethyl.

[0020] In this invention, R3 is a phenyl group substituted with one or more C1-6 alkoxy groups; preferably, it is... or .

[0021] In this invention, the dopamine D2 receptor compound as shown in Formula I is selected from:

[0022] , , and .

[0023] The present invention also provides the use of the above-mentioned compound in the preparation of a drug for treating erectile dysfunction.

[0024] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0025] The reagents and raw materials used in this invention are all commercially available.

[0026] The positive and progressive effects of this invention are as follows: the dopamine D2 receptor compound provided by this invention has excellent biological activity and has important application potential in drugs for the treatment of erectile dysfunction. Attached Figure Description

[0027] Figure 1 This is the proton NMR spectrum of compound 1, a dopamine D2 receptor.

[0028] Figure 2 This is the proton NMR spectrum of compound 2, a dopamine D2 receptor.

[0029] Figure 3 This is the proton NMR spectrum of compound 3, a dopamine D2 receptor.

[0030] Figure 4 This is the proton NMR spectrum of compound 4, a dopamine D2 receptor. Detailed Implementation

[0031] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0032] Preparation of intermediate compound 4:

[0033]

[0034] first step:

[0035] Under a nitrogen atmosphere, compound 1 (0.5 g, 3.64 mmol) was dissolved in phosphorus oxychloride (10 mL) and refluxed. After the reaction was monitored by TLC, phosphorus oxychloride was recovered under reduced pressure. Then, dichloromethane (50 mL) and saturated sodium bicarbonate aqueous solution (100 mL) were added and stirred thoroughly. The mixture was then allowed to stand and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate to remove the solvent and obtain compound 2 (0.51 g, yield 85.62%).

[0036] m / z = 165.0342 ([M+H] + The theoretical calculated value is 165.0340.

[0037] Step Two:

[0038] Compound 2 (0.51 g, 3.12 mmol) and hydrazine hydrate (0.5 mL) were dissolved in ethanol (20 mL) under a nitrogen atmosphere. The mixture was then stirred and heated to reflux. After the reaction was completed by TLC monitoring, excess solvent and excess hydrazine hydrate were removed under reduced pressure to obtain compound 3 (0.46 g, yield 92.7%). No purification was required, and the reaction could proceed directly to the next step.

[0039] m / z = 161.0944 ([M+H] + The theoretical calculated value is 161.0947.

[0040] Step 3:

[0041] Under a nitrogen atmosphere, compound 3 (0.46 g, 2.89 mmol) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (0.76 g, 3.18 mmol) were added to a reaction flask, followed by ethanol (30 mL). The mixture was heated to reflux until the starting material compound 3 was completely consumed, then sodium hydroxide (0.5 g) was added, and the mixture was heated to reflux for another 2 hours. The solvent was then removed under reduced pressure, and distilled water (20 mL) was added. The mixture was filtered to remove insoluble impurities, and then dilute hydrochloric acid was added to adjust the pH to approximately 5-7. A white flocculent precipitate was formed, which was then filtered and dried to obtain compound 4 (0.48 g, yield 54.7%).

[0042] m / z = 309.0723 ([M+H] + The theoretical calculated value is 309.0720.

[0043] Preparation of intermediate compound 7:

[0044]

[0045] first step:

[0046] At -10°C, compound 5 (1 g, 6.94 mmol) was mixed with 10 mL of water and 2 mL of concentrated hydrochloric acid to prepare solution A. Sodium nitrite (1 g) was then dissolved in water, and the sodium nitrite solution was slowly added dropwise to solution A with rapid stirring. The reaction was allowed to proceed for 4 hours. Stannous chloride (1.5 g, 30 mL water) solution was then added dropwise, and stirring continued. The reaction was monitored by TLC until completion. Sodium hydroxide solution was added to adjust the pH to alkaline, and the mixture was extracted with THF. The extract was concentrated by rotary evaporation, filtered, and dried to obtain compound 6 (0.70 g, yield 63.4%), which proceeded directly to the next reaction step without further purification.

[0047] m / z = 165.0342 ([M+H] + The theoretical calculated value is 165.0340.

[0048] Step Two:

[0049] Under a nitrogen atmosphere, compound 6 (0.46 g, 2.89 mmol) and ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (0.76 g, 3.18 mmol) were added to a reaction flask, followed by the addition of ethanol (30 mL). The mixture was heated to reflux, and TLC was used to monitor the consumption of starting material compound 3. Sodium hydroxide (0.5 g) was added, and the mixture was heated to reflux for another 2 hours. The solvent was then removed under reduced pressure, and distilled water (20 mL) was added. The mixture was filtered to remove insoluble impurities, and then dilute hydrochloric acid was added until a white flocculent precipitate was formed. After filtration and drying, compound 7 (0.58 g, yield 65.6%) was obtained.

[0050] m / z = 309.0724([M+H] + The theoretical calculated value is 309.0720.

[0051] Example 1—Dopamine D2 receptor compound 1:

[0052]

[0053] Compound 4 (50 mg, 0.16 mmol), HOBT (24.2 mg, 0.18 mmol), EDC (27.80 mg, 0.18 mmol), and 1-(2-ethoxyphenyl)piperazine hydrochloride (33.60 mg, 0.16 mmol) were dissolved in DMF (20 mL), stirred overnight at room temperature, and then the solvent was removed by rotary evaporation. Ethyl acetate and saturated brine were added, the mixture was shaken thoroughly, and then allowed to stand for separation. The organic phase was collected, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was then prepared by high performance liquid chromatography to obtain dopamine D2 receptor compound 1 (29.3 mg, yield 36.3%).

[0054] 1H NMR (400 MHz, CDCl3) δ 8.61-8.57 (m, 1H), 8.26-8.23 (m, 1H), 8.15-8.09 (m, 2H), 7.87 (d, 1H), 7.70-7.59 (m, 2H), 6.72-6.58 (m, 4H), 4.16 (q,2H), 3.73 (q, 2H), 3.60 (q, 2H), 3.20 (q, 4H), 1.48 (t, 3H).

[0055] m / z = 497.2030 ([M+H] + The calculated value is 497.2033.

[0056] Example 2—Dopamine D2 receptor compound 2:

[0057]

[0058] Compound 4 (50 mg, 0.16 mmol), HOBT (24.2 mg, 0.18 mmol), EDC (27.80 mg, 0.18 mmol), and 1-(2-methoxyphenyl)piperazine hydrochloride (31.29 mg, 0.16 mmol) were dissolved in DMF (20 mL), stirred overnight at room temperature, and then the solvent was removed by rotary evaporation. Ethyl acetate and saturated brine were added, shaken thoroughly, and allowed to stand for separation. The organic phase was collected, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was prepared by high performance liquid chromatography to obtain dopamine D2 receptor compound 2 (21.4 mg, yield 27.2%).

[0059] 1 H NMR (400 MHz, CDCl3) δ 8.62-8.58 (m, 1H), 8.25-8.21 (m, 1H), 8.14-8.09 (m, 2H), 7.90 (d, 1H), 7.68-7.57 (m, 2H), 6.69-6.62 (m, 4H), 3.90 (s,3H), 3.76 (q, 2H), 3.61 (q, 2H), 3.21 (q, 4H).

[0060] m / z = 483.1864 ([M+H] + The calculated value is 483.1877.

[0061] Example 3—Dopamine D2 receptor compound 3:

[0062]

[0063] Compound 7 (50 mg, 0.16 mmol), HOBT (24.2 mg, 0.18 mmol), EDC (27.80 mg, 0.18 mmol), and 1-(2-ethoxyphenyl)piperazine hydrochloride (33.60 mg, 0.16 mmol) were dissolved in DMF (20 mL), stirred overnight at room temperature, and then the solvent was removed by rotary evaporation. Ethyl acetate and saturated brine were added, the mixture was shaken thoroughly, and then allowed to stand for separation. The organic phase was collected, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was prepared by high performance liquid chromatography to obtain dopamine D2 receptor compound 3 (30.7 mg, yield 38.03%).

[0064] 1 H NMR (400 MHz, CDCl3) δ 9.16-9.14 (m, 1H), 8.92 (d, 1H), 8.19-8.14(m, 1H), 8.07 (s, 1H), 8.05-7.98 (m, 2H), 7.80 (t, 1H), 6.96-6.79 (m, 4H), 4.14 (q, 2H), 3.74 (q, 2H), 3.53 (q, 2H), 3.19 (q, 2H), 1.46 (t, 3H).

[0065] m / z = 497.2036 ([M+H] + The calculated value is 497.2033.

[0066] Example 4—Dopamine D2 receptor compound 4:

[0067]

[0068] Compound 7 (50 mg, 0.16 mmol), HOBT (24.2 mg, 0.18 mmol), EDC (27.80 mg, 0.18 mmol), and 1-(2-methoxyphenyl)piperazine hydrochloride (31.29 mg, 0.16 mmol) were dissolved in DMF (20 mL), stirred overnight at room temperature, and then the solvent was removed by rotary evaporation. Ethyl acetate and saturated brine were added, shaken thoroughly, and allowed to stand for separation. The organic phase was collected, and the solvent was removed under reduced pressure to obtain the crude product. The crude product was prepared by high performance liquid chromatography to obtain dopamine D2 receptor compound 4 (18.90 mg, yield 24.12%).

[0069] 1H NMR (400 MHz, CDCl3) δ 9.18-9.16 (m, 1H), 8.95 (d, 1H), 8.18-8.14(m, 1H), 8.08 (s, 1H), 8.04-7.99 (m, 2H), 7.83 (t, 1H), 6.93-6.80 (m, 4H), 3.88 (t, 3H), 3.64 (q, 2H), 3.53 (q, 2H), 3.17 (q, 4H).

[0070] m / z = 483.1874 ([M+H] + The calculated value is 483.1877.

[0071] Application Example 1—Evaluation of Dopamine D2 Receptor Agonistaltic Activity:

[0072] Dopamine D2 receptor 2 is closely related to G protein-mediated cAMP signaling. Once activated, dopamine D2 receptor can inhibit adenylate cyclase, thereby reducing cAMP levels. Based on this principle, those skilled in the art usually use the detection of intracellular cAMP concentration to evaluate the agonistic activity of compounds on dopamine D2 receptor.

[0073] This invention uses time-resolved fluorescence resonance energy transfer (TR-FRET) technology to detect the effects of the above-mentioned compounds on HEK 293 cells (purchased from Shanghai Ruizhi Chemical Research Co., Ltd.) stably transfected with human dopamine D2 receptor, thereby evaluating the dopamine D2 receptor agonist activity of the compound in HEK 293 cells. The positive control drug is FR64822.

[0074] The experimental protocol was as follows: to evaluate the agonistic activity of the above compounds on the dopamine D2 receptor, specifically, a specific compound was prepared with 8 concentration gradients, 4-fold dilution, and an initial concentration of 10 μM; then, if the experimental objective was not achieved, another 8 concentration gradients were prepared with 4-fold dilution, and an initial concentration of 10 nM was set; then, time-resolved fluorescence resonance energy transfer (TREL) was used for experimental testing.

[0075] Specifically, cAMP was measured using the LANCE Ultra cAMP kit (PerkinElmer). The series of compounds at varying concentrations (100 nL each) were thoroughly mixed with the transfected HEK-293 cell solution (10 μL, 2500 cells / well) and incubated at room temperature for 60 minutes. Then, 4X Eu-cAMP tracer solution (5 μL) and... - After thoroughly mixing with anti-cAMP solution (5 μL), incubate for another 60 minutes, then measure the time-resolved FRET signal at 665 nm using an EnVision multi-label plate reader (PerkinElmer).

[0076] Then, based on the readings measured by EnVision, the agonistic activity of compounds at different concentration gradients on the dopamine D2 receptor was calculated. A four-parameter logic equation was used to fit the dopamine D2 receptor agonistic activity of compounds at different concentration gradients, and the calculated activity was obtained. Values. The experimental results are shown in Table 1.

[0077] Table 1:

[0078]

[0079] In summary, the above experimental results demonstrate that the compounds of this invention exhibit excellent agonistic activity against dopamine D2 receptors.

Claims

1. A dopamine D2 receptor compound or a pharmaceutically acceptable salt thereof, characterized in that, The dopamine D2 receptor compound is selected from the group consisting of: , , and .

2. The use of a dopamine D2 receptor compound as described in claim 1 in the preparation of a medicament for treating erectile dysfunction.

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