Imidazoline spiroquinazolinone compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine and chemical industry, and discloses an imidazoline spiroquinazolinone compound and a preparation method and application thereof.The compound is novel in structure, has an imidazoline and quinazolinone double-ring structure, has multiple active sites and large modifiable space, shows good biological activity application potential, and can be used for preparing a novel compound. The compound has the activity of selectively inhibiting phosphodiesterase 7 (PDE7). Meanwhile, 2-aminoacetophenone, isocyanate and amidine which are low in price and easy to obtain serve as starting raw materials of the compound, a spiro-bicyclic system is directly constructed through one-pot series cyclization, and the preparation method has the advantages that the raw materials are easy to obtain, steps are simple, atom economy is high, the reaction system is green and simple, aftertreatment is simple and convenient, amplification is easy and the like.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical technology, and relates to an imidazoline spiroquinazoline one compound, its preparation method, and its application. Specifically, it relates to a spiro[imidazoline-4,4'-quinazoline]-2'(3'H)-one compound, its preparation method, and its application as a phosphodiesterase inhibitor. Background Technology

[0002] Spiroimidazoline compounds are a class of five-membered nitrogen heterocyclic molecules with a spirocyclic skeleton. Due to their unique stereostructure and broad biological activities (such as antihypertensive, antitumor, and inhibition of β-amyloid precursor protein cleavage enzyme 1), they have received continuous attention in drug development. These compounds show promising clinical application prospects as BACE1 inhibitors (such as GNE-629 and GNE-892), α7 nicotinic acetylcholine receptor ligands, and α-adrenergic agonists.

[0003] Currently, the synthesis of these compounds mainly relies on exocyclic α,β-unsaturated cyclic ketones (such as 1,3-indanedione or pyrazolone) and amidine compounds as raw materials, and cyclization is carried out under conditions such as N-halosuccinimides (such as NIS, NBS), electrochemical redox, or copper bromide catalysis (see Org. Chem. Front., 2018, 5, 2864–2869; Chinese Chem. Lett., 2022, 33, 5128–5131; J. Org. Chem., 2023, 88, 6729–6735, etc.), as shown below.

[0004]

[0005] However, existing methods generally have the following limitations: First, the key precursor cyclic α,β-unsaturated ketones usually require multiple pre-synthesis steps, which makes the commercialization of raw materials difficult and the steps lengthy; second, the reaction has low atom economy, and the post-processing mostly relies on column chromatography purification, which is cumbersome; in addition, due to the limitations of the precursor structure, the skeletal type and structural modification of the obtained spiroimidazole are relatively limited, which restricts its diversity derivatization and drug screening.

[0006] Therefore, developing an efficient synthetic method for spiroimidazolinoids that uses readily available raw materials, has simple steps, high atom economy, simple post-processing, and can achieve structural diversity is of great research significance and application value. Summary of the Invention

[0007] To address the aforementioned problems in the prior art, the primary objective of this invention is to provide an imidazoline-spiroquinazoline ketone compound with the structural formula shown in formula (I). This compound has a novel bicyclic structure of imidazoline and quinazoline ketone, possesses multiple active sites, and offers ample room for structural modification, demonstrating promising potential for bioactive applications.

[0008] This invention, by designing and synthesizing a novel imidazoline spiroquinazoline ketone skeleton as shown in formula (I), cleverly circumvents the dependence of existing technologies on the starting material cyclic α,β-unsaturated ketones. Both the quinazoline ring and the imidazoline ring in this skeleton provide multiple substitution modification sites (R...). 1 ,R 2 ,R 3 Furthermore, the raw materials 2-aminoacetophenone, isocyanate, and amidine all have abundant and readily available commercial derivatives, thus fundamentally enabling simultaneous and diversified modification of spirocyclic, quinazolinone, and imidazoline rings from the source, greatly expanding the structural derivatization space and providing a rich compound library for drug screening based on this framework.

[0009] The second objective of this invention is to provide a method for preparing the above-mentioned imidazoline spiroquinazoline ketone compounds. This method does not require the use of structurally complex cyclic α,β-unsaturated ketone raw materials and has the advantages of readily available raw materials, mild reaction conditions, and simple post-processing.

[0010] A third objective of this invention is to provide the use of the above-mentioned imidazoline spiroquinazoline ketone compounds in the preparation of drugs as phosphodiesterase inhibitors.

[0011] This invention discloses a spiroimidazole quinazolinone compound, the structural formula of which is shown in formula (I):

[0012]

[0013] Among them, R 1 It is selected from C1-C6 alkyl, phenyl, C1-C4 alkylphenyl or substituted phenyl, wherein the substituent in the substituted phenyl is halogen, C1-C4 alkyl, C1-C4 alkoxy, cyano, trifluoromethyl; the number or type of substituent can be one, multiple, or one or more, depending on the number of substituted groups on the benzene ring and the need for structural modification;

[0014] R 2 and R 3 Each is independently selected from phenyl or substituted phenyl groups. The substituents in the substituted phenyl groups are halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, or trifluoromethyl groups. The number or type of substituents can be one, multiple, or one or more, depending on the number of substituted groups on the benzene ring and the structural modification requirements.

[0015] This invention discloses a method for preparing the above-mentioned imidazoline spiroquinazoline ketone compounds. The reaction formula is shown below: an acid catalyst and iodine are added to a solution containing 2-aminoacetophenone (formula II), an isocyanate compound (formula III), and an amidine compound (formula IV). The mixture is stirred at 10°C to 100°C for 1 to 20 hours to obtain the imidazoline spiroquinazoline ketone compound as shown in formula (I).

[0016]

[0017] In one embodiment of the present invention, preferably, the molar ratio of 2-aminoacetophenone of formula (II), isocyanate compound of formula (III), amidine compound of formula (IV), acid catalyst and iodine is 1:(1-3):(1-3):(0.01-0.1):(0.5-2).

[0018] In one embodiment of the present invention, preferably, the acid catalyst is one or more selected from boron trifluoride ether, boron trichloride, tris(pentafluorophenyl)boron, p-toluenesulfonic acid, trifluoromethanesulfonic acid, or trifluoroacetic acid.

[0019] In one embodiment of the present invention, preferably, the acid catalyst is tris(pentafluorophenyl)boron.

[0020] In one embodiment of the present invention, preferably, the reaction solvent used in the reaction is one or more of acetonitrile, tetrahydrofuran, ethanol, dichloroethane or toluene.

[0021] In one embodiment of the present invention, the reaction solvent is preferably acetonitrile.

[0022] In one embodiment of the present invention, a post-processing procedure is also included, which may involve cooling the reaction to -5 to -5°C after the reaction is complete, precipitating a solid, filtering to obtain a crude product, washing it multiple times with a solvent, and drying it to obtain an imidazoline spiroquinazoline ketone compound as shown in formula (I).

[0023] This invention discloses the use of the aforementioned imidazoline spiroquinazoline ketone compounds in the preparation of phosphodiesterase (PDE) inhibitors, including their use as inhibitors of various PDE subtypes, such as PDE1, PDE3, PDE4, and PDE7. In one embodiment of this invention, their use as a PDE7 inhibitor is more preferred.

[0024] In summary, compared with existing technologies, this invention has achieved synergistic breakthroughs: First, in terms of compound structure, a novel "imidazoline spiroquinazoline ketone" skeleton was obtained, fundamentally eliminating the dependence on pre-prepared cyclic ketones; second, in terms of synthetic methods, a concise strategy for constructing spirocyclic compounds using inexpensive raw materials in a one-pot process was developed based on the synthetic logic of this skeleton, achieving efficient expansion of structural diversity; and third, in terms of biological activity, it was found that these compounds still exhibit selective inhibition of phosphodiesterase 7 (PDE7) activity (such as Ida) at nanomolar concentrations. Therefore, this invention provides a class of novel, efficiently synthesized compounds with clear target selectivity, laying a solid foundation for their drug development value.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] This invention discloses an imidazoline-spiroquinazoline ketone compound with a novel structure, possessing a bicyclic structure of quinazoline and spiroimidazoline. This compound exhibits multiple active sites, a large modifiability, and demonstrates good potential for biological applications, particularly its selective inhibition of PDE7. Taking compound Ida as an example, its IC50 for PDE7... 50 The value is 147 nM, while the IC values ​​for PDE1 and PDE4 are... 50 The effective concentrations were 6.04 μM and 12.17 μM, respectively, showing selectivity exceeding 40-fold and 80-fold. Therefore, this class of compounds can be used to prepare selective PDE7 inhibitor drugs. Furthermore, the preparation method of this compound exhibits the following advantages: a) readily available raw materials, simple steps, and high atom economy: using inexpensive and readily available 2-aminoacetophenone, isocyanate, and amidine as starting materials, a spirobicyclic system is directly constructed via a one-pot tandem cyclization process, avoiding the need for pre-preparation of complex cyclic precursors and significantly improving synthetic efficiency and atom economy; b) Green and simple reaction system: no metal catalyst is required, and the preferred catalyst dosage can be as low as 1 mol%, and molecular iodine is used as a mild promoter, conforming to the principles of green synthesis; c) Simple post-processing and easy scale-up: the product often precipitates in solid form during the reaction, requiring only filtration and washing to obtain a high-purity product, eliminating the need for column chromatography purification, making the operation simple, environmentally friendly, and possessing good potential for process scale-up. Attached Figure Description

[0027] Figures 1-3 The 3'-(4-bromophenyl)-1,2-diphenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one of Example 1 of this invention are respectively 1 H NMR spectrum, 13 C NMR spectrum and single-crystal electron diffraction pattern;

[0028] Figures 4-5The 1,2-diphenyl-3'-(p-tolyl)-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one of Example 10 of the present invention are respectively 1 H NMR spectrum and 13 C NMR spectrum;

[0029] Figures 6-7 The 3'-(4-methoxyphenyl)-1,2-diphenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one of Example 11 of this invention are respectively 1 H NMR spectrum and 13 CNMR spectrum;

[0030] Figures 8-9 The 3'-(3,4-dichlorophenyl)-1,2-diphenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one of Example 12 of the present invention are respectively 1 H NMR spectrum and 13 CNMR spectrum;

[0031] Figures 10-11 The 3'-butyl-1,2-diphenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one of Example 13 of this invention 1 H NMR spectrum and 13 C NMR spectrum;

[0032] Figures 12-13 The 1-(4-methoxyphenyl)-3'-phenethyl-2-phenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one of Example 14 of this invention are respectively 1 H NMR spectrum and 13 C NMR spectrum;

[0033] Figures 14-16 The 2-(4-fluoro-3-methylphenyl)-3'-phenethyl-1-phenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one of Example 15 of this invention 1 H NMR spectrum, 13 C NMR spectrum and 19 F NMR spectrum;

[0034] Figures 17-19 The 1,2-bis(3-fluorophenyl)-3'-phenethyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one of Example 16 of this invention 1H NMR spectrum, 13 C NMR spectrum and 19 F NMR spectrum;

[0035] Figure 20-22 The 1-(3-chlorophenyl)-3'-phenethyl-2-(4-(trifluoromethyl)phenyl)-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one of Example 17 of this invention 1 HNMR spectrum, 13 C NMR spectrum and 19 F NMR spectrum;

[0036] Figure 23-24 The 1-(2-bromophenyl)-3'-phenethyl-2-phenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one of Example 18 of this invention 1 H NMR spectrum and 13 C NMR spectrum; Detailed Implementation

[0037] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

[0038] Numerous specific details are set forth in the following description to provide a full understanding of the invention. However, the invention can be practiced in many other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0039] The raw materials used in this invention, such as 2-aminoacetophenone as shown in formula (II), isocyanate compounds as shown in formula (III), and amidine compounds as shown in formula (IV), or acids, solvents, etc., can all be obtained through commercial channels unless otherwise specified.

[0040] Example 1: Preparation of 3'-(4-bromophenyl)-1,2-diphenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one

[0041]

[0042] A 50 mL solution of 2-aminoacetophenone (II, 1.35 g, 10 mmol), phenyl 4-bromoisocyanate (IIIa, 2.38 g, 12 mmol), N-phenylbenzamide (IVa, 2.35 g, 12 mmol), trifluoromethanesulfonic acid (15 mg, 0.1 mmol), and molecular iodine (3.05 g, 12 mmol) in dichloroethane was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and a large amount of yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold dichloroethane (3 × 15 mL). The filter cake was dried to obtain 3'-(4-bromophenyl)-1,2-diphenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Iaa), a yellow solid, 3.72 g, melting point: 189.3-190.7℃, yield: 73%.

[0043] Structural characterization and single-crystal electron diffraction pattern of Iaa, such as Figures 1-3 As shown: 1 H NMR(400MHz, CDCl3)δ8.78(s,1H),7.51–7.36(m,5H),7.34–7.17(m,5H),7.17–6.91(m,5H), 6.70(d,J=8.0Hz,1H), 6.32(d,J=7.6Hz,2H), 4.51(d,J=11.6Hz,1H), 4.31(d,J=11.6Hz,1H); 13 C NMR (100MHz, CDCl3) δ162.7,151.9,141.0,136.4,134.6,132.6,131.8,130.9,130.5,129.4,129.2,128.8, 128.5,128.3,127.4,126.8,124.8,123.8,123.3,122.8,122.3,114.2,86.1,67.0; HRMS(ESI-TOF)m / z[M+H] + calcd forC 28 H 22 BrN4O,509.0972; found 509.0970.

[0044] In Examples 2-9, the effects of catalyst, solvent, temperature, and reaction time on product yield were also investigated. Using II (1.35 g, 10 mmol), IIIa (2.38 g, 12 mmol), and IVa (2.35 g, 12 mmol) as starting materials, product Iaa was obtained after the reaction following the same post-treatment steps as in Example 1, and the yields were calculated, as shown in Table 1. The preferred reaction conditions for preparing this compound are: tris(pentafluorophenyl)boron as catalyst, acetonitrile as solvent, and reaction at 60-80 °C for 12-20 h.

[0045] Table 1

[0046] Example catalyst solvent Temperature (°C) Time (h) Yield (%) Example 2 Tris(pentafluorophenyl)boron dichloroethane 80 12 75 Example 3 p-Toluenesulfonic acid dichloroethane 80 12 63 Example 4 Tris(pentafluorophenyl)boron Tetrahydrofuran 80 12 29 Example 5 Tris(pentafluorophenyl)boron Acetonitrile 80 12 83 Example 6 Tris(pentafluorophenyl)boron Acetonitrile 60 12 84 Example 7 Tris(pentafluorophenyl)boron Acetonitrile 40 12 37 Example 8 Tris(pentafluorophenyl)boron Acetonitrile 60 16 88 Example 9 Tris(pentafluorophenyl)boron Acetonitrile 60 20 87

[0047] Example 2: Preparation of Iaa

[0048] A 50 mL solution of dichloroethane containing II (1.35 g, 10 mmol), IIIa (2.38 g, 12 mmol), IVa (2.35 g, 12 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (3.05 g, 12 mmol) was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and a large amount of yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold dichloroethane (3 × 15 mL). The filter cake was dried to give 3.81 g of yellow solid Iaa, with a yield of 75%.

[0049] Example 3: Preparation of Iaa

[0050] A 50 mL solution of dichloroethane containing II (1.35 g, 10 mmol), IIIa (2.38 g, 12 mmol), IVa (2.35 g, 12 mmol), p-toluenesulfonic acid (17 mg, 0.1 mmol), and molecular weight iodine (3.05 g, 12 mmol) was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and a large amount of yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold dichloroethane (3 × 15 mL). The filter cake was dried to give 3.20 g of yellow solid Iaa, with a yield of 63%.

[0051] Example 4: Preparation of Iaa

[0052] A 50 mL solution of tetrahydrofuran containing II (1.35 g, 10 mmol), IIIa (2.38 g, 12 mmol), IVa (2.35 g, 12 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (3.05 g, 12 mmol) was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and a large amount of yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold tetrahydrofuran (3 × 15 mL). The filter cake was dried to give 1.47 g of yellow solid Iaa, with a yield of 29%.

[0053] Example 5: Preparation of Iaa

[0054] A 50 mL acetonitrile solution of II (1.35 g, 10 mmol), IIIa (2.38 g, 12 mmol), IVa (2.35 g, 12 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (3.05 g, 12 mmol) was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and a large amount of yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 4.22 g of yellow solid Iaa, with a yield of 83%.

[0055] Example 6: Preparation of Iaa

[0056] A 50 mL acetonitrile solution of II (1.35 g, 10 mmol), IIIa (2.38 g, 12 mmol), IVa (2.35 g, 12 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (3.05 g, 12 mmol) was stirred at 60 °C for 12 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and a large amount of yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 4.27 g of yellow solid Iaa, with a yield of 84%.

[0057] Example 7: Preparation of Iaa

[0058] A 50 mL acetonitrile solution of II (1.35 g, 10 mmol), IIIa (2.38 g, 12 mmol), IVa (2.35 g, 12 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (3.05 g, 12 mmol) was stirred at 40 °C for 12 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and a large amount of yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 1.88 g of yellow solid Iaa, with a yield of 37%.

[0059] Example 8: Preparation of Iaa

[0060] A 50 mL solution of acetonitrile containing II (1.35 g, 10 mmol), IIIa (2.38 g, 12 mmol), IVa (2.35 g, 12 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (3.05 g, 12 mmol) was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and a large amount of yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold dichloroethane (3 × 15 mL). The filter cake was dried to give 4.47 g of yellow solid Iaa, with a yield of 88%.

[0061] Example 9: Preparation of Iaa

[0062] A 50 mL acetonitrile solution of II (1.35 g, 10 mmol), IIIa (2.38 g, 12 mmol), IVa (2.35 g, 12 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (3.05 g, 12 mmol) was stirred at 60 °C for 20 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and a large amount of yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 4.42 g of yellow solid Iaa, with a yield of 87%.

[0063] Example 10: Preparation of 1,2-diphenyl-3'-(p-tolyl)-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Iba)

[0064]

[0065] A 50 mL acetonitrile solution of 2-aminoacetophenone (II, 1.35 g, 10 mmol), phenyl 4-methylisocyanate (IIIb, 1.98 g, 10 mmol), N-phenylbenzamide (IVa, 1.96 g, 10 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (3.05 g, 12 mmol) was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and a large amount of yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 1,2-diphenyl-3'-(p-tolyl)-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Iba), a white solid, 3.51 g, melting point: 216.0–217.4 °C, yield: 79%.

[0066] Structural characterization of Iba, such as Figures 4-5 As shown: 1HNMR (400MHz, DMSO-d6) δ9.88(s,1H),7.43–6.89(m,16H),6.28(d,J=7.6Hz,2H),4.52(d,J=12.0Hz,1H),4.21(d,J=12.0Hz,1H),2.23(s,3H); 13 C NMR(100MHz,DMSO-d6)δ161.1,151.3,141.8,137.4,136.1,135.6,130.9,130.4,129.3,129.3,129.0 ,128.9,128.7,127.5,124.7,124.4,123.9,121.9,113.9,86.5,65.9,21.0; HRMS(ESI-TOF)m / z[M+H] + calcd forC 29 H 25 N4O, 445.2023; found 445.2029.

[0067] Example 11: Preparation of 3'-(4-methoxyphenyl)-1,2-diphenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Ica)

[0068]

[0069] An acetonitrile solution (50 mL) of 2-aminoacetophenone (II, 1.35 g, 10 mmol), 4-methoxyphenyl isocyanate (IIIc, 4.47 g, 30 mmol), N-phenylbenzamide (IVa, 3.08 g, 20 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (3.05 g, 12 mmol) was stirred at 60 °C for 16 hours. After the reaction was completed as monitored by TLC, the reaction system was cooled to 0 °C, and a large amount of white solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 3'-(4-methoxyphenyl)-1,2-diphenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazoline]-2'(3'H)-one (Ica), a white solid, 3.82 g, melting point: 187.4-189.3 °C, yield: 83%.

[0070] Structural characterization of Ica, such as Figures 6-7 As shown: 1HNMR(400MHz, CDCl3)δ8.15(s,1H),7.56(s,1H),7.43(d,J=7.2Hz,2H),7.34(dd,J=13.2,7.6Hz,2H),7.29–7.20(m,4H),7.09–7.05(m, 3H),7.03–6.96(m,2H),6.73(d,J=8.0Hz,2H),6.34(dd,J=7.2,1.6Hz,2H),4.51(d,J=11.6Hz,1H),4.37(d,J=11.6Hz,1H),3.77(s,3H); 13 CNMR (100MHz, CDCl3) δ162.4,159.2,152.3,141.3,134.8,130.6,130.0,129.6,129.2,129.2,12 8.6,128.2,126.8,124.5,124.1,123.5,122.5,114.1,86.2,67.0,55.5; HRMS(ESI-TOF)m / z[M+H] + calcdforC 29 H 25 N4O2,461.1972; found461.1978.

[0071] Example 12: Preparation of 3'-(3,4-dichlorophenyl)-1,2-diphenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazoline]-2'(3'H)-one (Ida)

[0072]

[0073] An acetonitrile solution (50 mL) of 2-aminoacetophenone (II, 1.35 g, 10 mmol), 3,4-dichlorophenyl isocyanate (IIId, 2.81 g, 15 mmol), N-phenylbenzamide (IVa, 2.94 g, 15 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (2.03 g, 8 mmol) was stirred at 60 °C for 16 hours. After the reaction was completed as monitored by TLC, the reaction system was cooled to 0 °C, and a large amount of white solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 3'-(3,4-dichlorophenyl)-1,2-diphenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazoline]-2'(3'H)-one (Ida), a white solid, 3.14 g, melting point: 203.2-204.3 °C, yield: 70%.

[0074] Structural characterization of Ida, such as Figures 8-9 As shown:1 HNMR(400MHz, CDCl3)δ8.34(s,1H),7.36(dt,J=13.6,7.6Hz,6H),7.24(dq,J=13.6,7.6,6.4Hz,4H),7.14– 6.98(m,6H),6.74(d,J=8.0Hz,1H),6.28(d,J=7.6Hz,2H),4.49(d,J=11.6Hz,1H),4.39(d,J=11.6Hz,1H); 13 C NMR (100MHz, CDCl3) δ162.5,152.1,141.1,137.3,134.9,130.6,129.6,129.2,129.2,128.9,128.6, 128.3,128.1,126.7,124.5,124.3,123.4,122.5,114.0,86.1,67.2,21.2; HRMS(ESI-TOF)m / z[M+H] + calcd for C 28 H 21 Cl2N4O,499.1087; found499.1080.

[0075] Example 13: Preparation of 3'-Butyl-1,2-diphenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazoline]-2'(3'H)-one (Iea)

[0076]

[0077] A 50 mL acetonitrile solution of 2-aminoacetophenone (II, 1.69 g, 10 mmol), butyl isocyanate (IIIe, 2.97 g, 30 mmol), N-phenylbenzamide (IVa, 5.88 g, 30 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (7.62 g, 5 mmol) was stirred at 60 °C for 16 hours. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0 °C, and a large amount of white solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 2.79 g of 3'-butyl-1,2-diphenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Iea), a white solid with a melting point of 186.1–187.3 °C and a yield of 68%.

[0078] Structural characterization of Iea, such as Figures 10-11 As shown: 1HNMR(400MHz, CDCl3)δ8.58(s,1H),7.69–7.60(m,2H),7.44(t,J=7.6Hz,1H),7.34(t,J=7.6Hz ,2H),7.24–7.12(m,4H),7.07(t,J=7.6Hz,1H),6.97(td,J=7.6,1.2Hz,1H),6.86(d,J=7.6Hz, 2H),6.78(d,J=7.6Hz,1H),4.30–4.15(m,2H),3.72(ddd,J=13.6,9.6,6.0Hz,1H),3.13(ddd,J =13.6,10.0,5.6Hz,1H),1.93–1.78(m,2H),1.36(qd,J=7.6,2.4Hz,2H),0.91(t,J=7.6Hz,3H); 13 C NMR (100MHz, CDCl3) δ162.7,141.7,134.5,130.8,129.9,129.2,129.2,129.1,128.4,126.0,1 24.8,124.4,123.6,122.3,113.6,85.8,68.1,43.0,32.2,20.6,13.9; HRMS(ESI-TOF)m / z[M+H] + calcd for C 26 H 27 N4O, 411.2179; found 411.2170.

[0079] Example 14: Preparation of 1-(4-methoxyphenyl)-3'-phenethyl-2-phenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Ifb)

[0080]

[0081] An acetonitrile solution (50 mL) of 2-aminoacetophenone (II, 1.35 g, 10 mmol), 2-phenylethyl isocyanate (IIIf, 1.47 g, 10 mmol), N-(4-methoxyphenyl)benzamidinium (IVb, 4.52 g, 20 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol) and molecular iodine (2.54 g, 10 mmol) was stirred at 60 °C for 16 hours. After the reaction was completed as monitored by TLC, the reaction system was cooled to 0 °C, and a large amount of white solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 1-(4-methoxyphenyl)-3'-phenethyl-2-phenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Ifb), a white solid, 3.56 g, melting point: 141.3-142.8 °C, yield: 73%.

[0082] Structural representation of Ifb, such as Figures 12-13 As shown: 1 HNMR(400MHz, CDCl3)δ7.95(s,1H),7.71(d,J=7.6Hz,2H),7.46(d,J=7.6Hz,1H), 7.37(t,J=7.6Hz,2H),7.23(dt,J=16.4,7.6Hz,7H),7.04(t,J=7.6Hz,1H),6.86( d,J=8.8Hz,2H),6.78(dd,J=14.4,8.4Hz,3H),4.15(d,J=3.6Hz,2H),4.02–3.89( m,1H),3.77(s,3H),3.46–3.29(m,1H),3.20(ddq,J=18.8,12.4,7.6,6.4Hz,2H); 13 CNMR (100MHz, CDCl3) δ163.3,151.9,139.9,134.2,129.4,129.2,129.0,128.5,128.4,12 6.3,126.2,125.8,122.6,114.5,113.5,68.8,55.5,45.4,36.5; HRMS(ESI-TOF)m / z[M+H] + calcd for C 31 H 28 N4O2,488.2212; found488.2210.

[0083] Example 15: Preparation of 2-(4-fluoro-3-methylphenyl)-3'-phenethyl-1-phenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Ifc)

[0084]

[0085] An acetonitrile solution (50 mL) of 2-aminoacetophenone (II, 1.35 g, 10 mmol), 2-phenylethyl isocyanate (IIIf, 2.21 g, 15 mmol), N-phenyl-(3-methyl-4-fluorophenyl)formamidinium (IVc, 6.84 g, 30 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (2.54 g, 10 mmol) was stirred at 60 °C for 16 hours. After the reaction was completed as monitored by TLC, the reaction system was cooled to 0 °C, and a large amount of white solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 2-(4-fluoro-3-methylphenyl)-3'-phenethyl-1-phenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Ifc), a white solid, 4.31 g, melting point: 203.4-205.1 °C, yield: 88%.

[0086] Structural characterization of Ifc, such as Figures 14-16 As shown: 1 HNMR(400MHz, CDCl3)δ8.81(s,1H),7.35(d,J=8.8Hz,2H),7.24–7.07(m,11H),7.00(t,J=7.6Hz,1H),6.84 (t,J=7.6Hz,3H),4.22–4.11(m,2H),3.97–3.86(m,1H),3.36–3.27(m,1H),3.23–3.07(m,2H),2.30(s,3H); 13 C NMR (100MHz, CDCl3) δ162.1,161.8,161.7,159.7,152.4,141.6,139.9,134.4,131.6,131.5,129.3,129.3,129.2,129.1,128.9,128 .5,128.4,128.2,126.2,126.1,125.2,124.8,124.8,124.0,123.8,122.5,116.0,115.8,113.8,86.3,68.3,45.3,36.5,14.8,14.7; 19 FNMR(376MHz, CDCl3)δ-116.2; HRMS(ESI-TOF)m / z[M+H] + calcdfor C 31 H 28 FN4O,491.2242; found491.2240.

[0087] Example 16: Preparation of 1,2-bis(3-fluorophenyl)-3'-phenethyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Ifd)

[0088]

[0089] An acetonitrile solution (50 mL) of 2-aminoacetophenone (II, 1.35 g, 10 mmol), 2-phenylethyl isocyanate (IIIf, 4.41 g, 30 mmol), N-(3-fluorophenyl)-(3-fluorophenyl)formamidinium (IVd, 3.48 g, 15 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (3.08 g, 12 mmol) was stirred at 60 °C for 16 hours. After the reaction was completed as monitored by TLC, the reaction system was cooled to 0 °C, and a large amount of pale yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 3.16 g of 1,2-bis(3-fluorophenyl)-3'-phenethyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Ifd), a pale yellow solid with a melting point of 197.2-199.6 °C and a yield of 64%.

[0090] The structural representation of Ifd, such as Figures 17-19 As shown: 1 HNMR(400MHz, CDCl3)δ8.85(s,1H),7.59(t,J=8.4Hz,1H),7.45–7.35(m,3H), 7.26–7.16(m,7H),7.04(t,J=7.6Hz,1H),6.95(t,J=8.4Hz,2H),6.90–6.83(m ,3H),4.15(q,J=11.2Hz,2H),3.99–3.87(m,1H),3.34(td,J=13.2,12.0,4.8H z,1H),3.22(td,J=11.6,11.2,5.6Hz,1H),3.11(td,J=12.0,11.6,4.8Hz,1H); 13CNMR (100MHz, CDCl3) δ164.0,163.7,161.7,161.4,161.2,158.9,152.4,139. 8,137.6,137.6,134.4,131.6,131.5,130.3,130.3,129.4,128.9,128.5,126 .3,125.9,125.8,125.7,125.0,125.0,123.7,122.9,122.9,122.6,119.1,118.9,118.3,118.1,116.4,116.2,114.9,114.7,113.9,86.4,68.4,45.4,36.5; 19 F NMR(376MHz, CDCl3)δ-111.5,-115.8; HRMS(ESI-TOF)m / z[M+H] + calcdfor C 30 H 25 F2N4O,495.1991; found495.1990.

[0091] Example 17: Preparation of 1-(3-chlorophenyl)-3'-phenethyl-2-(4-(trifluoromethyl)phenyl)-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Ife)

[0092]

[0093] An acetonitrile solution (50 mL) of 2-aminoacetophenone (II, 1.35 g, 10 mmol), 2-phenylethyl isocyanate (IIIf, 2.21 g, 15 mmol), N-(3-chlorophenyl)-(3-trifluoromethylphenyl)formamidinium (IVe, 2.98 g, 10 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (3.81 g, 15 mmol) was stirred at 60 °C for 16 hours. After the reaction was completed as monitored by TLC, the reaction system was cooled to 0 °C, and a large amount of yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 1-(3-chlorophenyl)-3'-phenethyl-2-(4-(trifluoromethyl)phenyl)-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazoline]-2'(3'H)-one (Ife), a yellow solid, 4.31 g, melting point: 163.2-165.1 °C, yield: 77%.

[0094] Structural characterization of Ife, such as Figures 20-22 As shown: 1HNMR(400MHz, CDCl3)δ8.98(s,1H),7.83(d,J=8.0Hz,2H),7.69(d,J=8.0Hz,2H),7.26(tt,J= 11.6,5.6Hz,4H),7.13(dd,J=11.6,8.0Hz,5H),7.04(t,J=7.6Hz,1H),6.89(d,J=7.6Hz,2H), 6.66(d,J=8.0Hz,1H),4.28–4.11(m,2H),3.91(ddd,J=13.2,10.6,5.6Hz,1H),3.35(td,J=13 .2,12.0,4.6Hz,1H),3.24(td,J=11.6,11.6,5.6Hz,1H),3.11(td,J=12.0,11.6,4.6Hz,1H); 13 C NMR (100MHz, CDCl3) δ160.8,152.3,142.3,139.7,135.1,134.4,133.2,133.0,132.8,130.3,129.6,129.6,128.9,128. 8,128.6,126.4,125.9,125.7,125.7,125.7,125.6,125.4,123.5,123.3,122.6,121.6,114.0,86.5,67.7,45.5,36.4; 19 F NMR(376MHz, CDCl3)δ-63.0; HRMS(ESI-TOF)m / z[M+H] + calcd for C 31 H 25 ClF3N4O,561.1664; found561.1660.

[0095] Example 18: Preparation of 1-(2-bromophenyl)-3'-phenethyl-2-phenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Iff)

[0096]

[0097] An acetonitrile solution (50 mL) of 2-aminoacetophenone (II, 1.35 g, 10 mmol), 2-phenylethyl isocyanate (IIIf, 1.76 g, 20 mmol), N-(2-bromophenyl)-benzomidine (IVf, 5.48 g, 20 mmol), tris(pentafluorophenyl)boron (51 mg, 0.1 mmol), and molecular iodine (6.88 g, 15 mmol) was stirred at 60 °C for 16 hours. After the reaction was completed as monitored by TLC, the reaction system was cooled to 0 °C, and a large amount of yellow solid precipitated. The mixture was filtered, and the filter cake was washed with cold acetonitrile (3 × 15 mL). The filter cake was dried to give 1-(2-bromophenyl)-3'-phenethyl-2-phenyl-1,5-dihydro-1'H-spiro[imidazol-4,4'-quinazolin]-2'(3'H)-one (Iff), a yellow solid, 3.69 g, melting point: 190.2-191.4 °C, yield: 69%.

[0098] Structural representation of Iff, such as Figures 23-24 As shown: 1 HNMR(400MHz, CDCl3)δ8.34(s,1H),7.64(d,J=7.2Hz,3H),7.42(d,J=7.2Hz,1H),7.33(t,J=7.2Hz,3H),7.29–7.18(m,6H),7.10 (dd,J=23.2,7.2Hz,3H),6.84(d,J=8.0Hz,2H),4.61(d,J=31.6Hz,1H),4.01(d,J=45.6Hz,1H),3.84–3.37(m,2H),3.24(s,2H); 13 CNMR (100MHz, CDCl3) δ140.0,133.9,131.0,129.4,129.3,129.1,129.0,128.7, 128.6,128.5,128.4,126.2,124.1,113.6,45.4,36.5; HRMS(ESI-TOF)m / z[M+H] + calcd for C 30 H 25 BrN4O,536.1212; found 536.1207.

[0099] Example 19: Experiment on selective inhibition of phosphodiesterase PDE7 activity

[0100] The half-maximal inhibitory concentration (IC50) was determined. 50 The method of evaluating the inhibitory effect of the compounds of the present invention on phosphodiesterase (PDE) activity was described, wherein IC50 was used. 50 This refers to the concentration of the compound required to inhibit the activity of the enzyme by 50%.

[0101] Enzyme source preparation: The coding genes for human PDE1C, PDE3A, PDE4B2, and PDE7A1 were cloned into a baculovirus vector and expressed in Sf21 insect cells. Cell cultures were collected, centrifuged, and the supernatant was used as crude enzyme solution for direct activity assay.

[0102] Enzyme activity assay: The method described by W.J. Thompson et al. (Advances in Cyclic Nucleotide Research, 1979, 10, 69-92) was followed. The total reaction volume was 100 μL, and the reaction was carried out in a buffer solution containing 20 mM Tris-HCl (pH 7.5) and 10 mM MgCl2. The substrates used were cGMP for PDE1 and cAMP for PDE3, PDE4, and PDE7. The substrate concentrations were set as follows: 0.2 μM for PDE1 and PDE3, 0.25 μM for PDE4, and 50 nM for PDE7. The reaction was incubated at 30 °C. For PDE1 and PDE3, the reaction was terminated after 1 hour of incubation; for PDE4 and PDE7, the reaction was terminated after 10 minutes of incubation. The reaction was terminated by heating in a boiling water bath. The 5'-nucleotides produced were converted into nucleosides by snake venom nucleotide phosphorylase. Finally, the enzyme activity was calculated by determining the content of the generated nucleosides by high performance liquid chromatography (HPLC).

[0103] IC 50 Measurements and Results: To determine the IC50 of this type of compound of the present invention... 50 The compounds were diluted and tested within a specific concentration range. For PDE7, the test concentration range was 0.01 μM to 10 μM, with 5-10 concentration points set; for PDE1, PDE3, and PDE4, the test concentration range was 0.1 μM to 100 μM, with at least 6 concentration points set. The resulting IC50 values... 50 The values ​​are listed in Table 2 below:

[0104] Table 2

[0105]

[0106]

[0107] The above results demonstrate that the compounds of this invention can effectively inhibit PDE7 at micromolar or nanomolar concentrations. In particular, compounds Iaa, Ida, and Ife exhibit IC50 inhibition against PDE7. 50 The values ​​were all below 1 μM, with compound Ida showing the highest activity, IC50. 50 The value was 147 nM. Although its absolute activity was lower than that of known PDE7 inhibitor reference standards, its IC50 was still lower. 50(16 nM)(Spiroquinazolinones as novel, potent, and selective PDE7 inhibitors. Part 1. Bioorg. Med. Chem. Lett., 2004, 14, 4623-4626). However, the compounds of the present invention, such as Ida, exhibit superior PDE7 subtype selectivity. The inhibitory activity of compound Ida against PDE7 (0.147 μM) is significantly higher than that against PDE1 (6.04 μM) and PDE4 (12.17 μM), with selectivity folds exceeding 40-fold and 80-fold, respectively. This result confirms that the compounds of the present invention have selective PDE7 inhibitory activity and can be used clinically as PDE7 inhibitor drugs.

[0108] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not exhaustively describe all details, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification. This specification selects and specifically describes these embodiments to better explain the principles and practical applications of the invention, thereby enabling those skilled in the art to better understand and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.

Claims

1. An imidazoline spiroquinazoline ketone compound, the structural formula of which is shown in formula (I): in, R 1 Selected from C1-C6 alkyl, phenyl, C1-C4 alkylphenyl or substituted phenyl, wherein the substituent in the substituted phenyl is halogen, C1-C4 alkyl or C1-C4 alkoxy; R 2 and R 3 Each is independently selected from phenyl or substituted phenyl groups, wherein the substituents in the substituted phenyl groups are halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, or trifluoromethyl groups.

2. A method for preparing the imidazoline spiroquinazoline one compound as described in claim 1, characterized in that, The reaction is shown below. An acid catalyst and iodine are added to a solution containing 2-aminoacetophenone (Formula II), isocyanate compounds (Formula III), and amidine compounds (Formula IV). The mixture is stirred at 10°C to 100°C for 1 to 20 hours to obtain imidazoline spiroquinazoline ketone compounds as shown in Formula (I).

3. The method for preparing imidazoline spiroquinazoline one compounds according to claim 2, characterized in that, The molar ratio of 2-aminoacetophenone (formula (II)), isocyanate compounds (formula (III)), amidine compounds (formula (IV)), acid catalyst, and iodine is 1:(1-3):(1-3):(0.01-0.1):(0.5-2).

4. The method for preparing imidazoline spiroquinazoline one compounds according to claim 2, characterized in that, The acid catalyst is one or more of boron trifluoride ether, boron trichloride, tris(pentafluorophenyl)boron, p-toluenesulfonic acid, trifluoromethanesulfonic acid, or trifluoroacetic acid.

5. The method for preparing imidazoline spiroquinazoline one compounds according to claim 4, characterized in that, The acid catalyst is tris(pentafluorophenyl)boron.

6. The method for preparing imidazoline spiroquinazoline one compounds according to claim 2, characterized in that, The reaction solvent used is one or more of acetonitrile, tetrahydrofuran, ethanol, dichloroethane, or toluene.

7. The method for preparing imidazoline spiroquinazoline one compounds according to claim 6, characterized in that, The reaction solvent is acetonitrile.

8. The method for preparing imidazoline spiroquinazoline one compounds according to claim 2, characterized in that, It also includes a post-processing step: first, the reaction solution is cooled to -5-5℃, filtered to obtain the crude product, then washed multiple times with solvent, and dried to obtain the imidazoline spiroquinazoline ketone compound as shown in formula (I).

9. The use of the imidazoline spiroquinazoline ketone compound of claim 1 in the preparation of a phosphodiesterase inhibitor drug.

10. The application according to claim 9, characterized in that, The phosphodiesterase mentioned is phosphodiesterase subtype 7.

Images