1-amide-1, 2-dihydrophthalazine compound as well as preparation method and application thereof

Abstract

The invention discloses a 1-amide-1, 2-dihydrophthalazine compound as well as a preparation method and application thereof, the 1-amide-1, 2-dihydrophthalazine compound has a chemical structure as shown in a formula (1): # imgabs0 #, in the formula, a substituent group R1 represents aryl and alkyl; r2 represents aryl or alkyl; the technical route for preparing the 1-amide-1, 2-dihydrophthalazine compound is simple to operate, concise in route and relatively high in yield, the used reagents are common reagents and can be suitable for large-scale preparation, and the compound can also be applied to preparation of a staphylococcus aureus growth inhibitor, can inhibit the growth of staphylococcus aureus, and has a good application prospect. And a basis can be provided for research of novel antibacterial drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a 1-amide-1,2-dihydrophthalazine compound and a preparation method and application thereof. Background Art

[0002] Phthaloazines, as an important nitrogen-containing heterocyclic skeleton, have received extensive attention in the medicinal chemistry community in the past two decades. Numerous studies on their chemical properties have shown that the introduction of structural diversity can improve their effectiveness in a variety of biological activities, such as antibacterial, anticancer, antiepileptic, antihypertensive, cardiotonic, antidiabetic, analgesic, antipsychotic, antithrombotic, vasodilatory, anti-inflammatory, antitrypanosomal, antileishmanial, asthma, chronic obstructive pulmonary disease, etc.

[0003] At present, the core chemical skeletons of many commercially available drugs and drug candidates in therapeutic areas are phthalazines. For example, the antihypertensive drug hydralazine, the antihistamine azathionine, the vascular endothelial growth factor receptor (VEGFR) inhibitor vatalanib, etc. In view of the wide range of applications and pharmacological activities of the phthalazine skeleton, structural modification of it may expand the scope and intensity of pharmacological activities, and thus discover new drugs with higher efficacy and lower side effects. As important active molecules, phthalazine derivatives can be synthesized in a variety of ways through metal-catalyzed cyclization reactions, coupling reactions or addition reactions, but the existing synthetic routes have problems such as the difficulty in obtaining the starting materials and metal catalysts used, and low yields. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides a 1-amide-1,2-dihydrophthalazine compound and a preparation method and application thereof. The compound can inhibit the growth of Staphylococcus aureus, has simple synthesis reaction conditions, high yield, and can be prepared in large quantities.

[0005] In order to solve the above technical problems, the present invention provides a technical solution: a 1-amide-1,2-dihydrophthalazine compound, characterized in that it has a chemical structure of formula (1):

[0006]

[0007] Among them, the substituent R 1 Represents aromatic group or alkyl group; R 2 Represents aryl and alkyl.

[0008] Furthermore, the substituent R 1represents phenyl, methyl, ethyl, propyl, tert-butyl, benzyl, 1-chloropropyl, 1-methylethyl acetate, propoxy, isobutoxy, pentyloxy, cyclopentyloxy, 3,3,3-trichloropropoxy, chloromethoxy, allyloxy, benzyloxy, phenoxy, 9-fluorenylmethoxy;

[0009] R 2 It represents tert-butyl, 4-ethylphenyl, 2,6-dimethylphenyl, cyclopentyl, benzyl, 1-cyclohexenylethyl.

[0010] Furthermore, the 1-amide-1,2-dihydrophthalazine compounds have the following structures 1a-1x:

[0011]

[0012] In order to solve the above technical problems, another technical solution provided by the present invention is: according to the above-mentioned method for preparing 1-amide-1,2-dihydrophthalazine compounds, it is characterized in that the following reaction route is adopted for preparation:

[0013]

[0014] Among them, the substituent R 1 Represents aromatic group or alkyl group; R 2 Represents aryl and alkyl.

[0015] Furthermore, phthalazine, an acyl chloride, and an isocyanide are dissolved in an organic solvent at room temperature, reacted at -2°C to 0°C for 3-5 hours, and sodium bicarbonate is added to quench the reaction. The mixture is extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified to obtain 1-amide-1,2-dihydrophthalazine compounds 1a-1x.

[0016] Further, the acyl chloride refers to benzoyl chloride, acetyl chloride, propionyl chloride, butyryl chloride, tert-butyryl chloride, phenylacetyl chloride, 4-chlorobutyryl chloride, 2-acetoxyisobutyryl chloride, propyl chloroformate, isobutyl chloroformate, amyl chloroformate, cyclopentyl chloroformate, 2,2,2-trichloroethyl chloroformate, chloromethyl chloroformate, allyl chloroformate, benzyl chloroformate, phenyl chloroformate, 9-fluorenylmethyl chloroformate;

[0017] The isocyanide refers to tert-butyl isocyanide, 4-ethylphenyl isocyanide, 2,6-dimethylphenyl isocyanide, cyclohexyl isocyanide, phenylethyl isocyanide, 1-(2-isocyanoethyl)cyclohex-1-ene, and methyl isocyanoacetate;

[0018] The organic solvent refers to dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, tetrahydrofuran, and 1,4-dioxane.

[0019] In order to solve the above technical problem, another technical solution provided by the present invention is: use of the above-mentioned 1-amide-1,2-dihydrophthalazine compound in the preparation of a Staphylococcus aureus growth inhibitor.

[0020] The beneficial effects of the present invention are:

[0021] The technical route for preparing 1-amide-1,2-dihydrophthalazine compounds in the present application is simple to operate, has a concise route, and has a high yield. The reagents used are all commonly used reagents, and are suitable for large-scale preparation. Antibacterial activity tests show that the series of 1-amide-1,2-dihydrophthalazine compounds synthesized by the present invention can inhibit the growth of Staphylococcus aureus, and allow the introduction of multiple functional groups into the entire skeleton, which provides a new skeleton for the discovery of antibacterial drugs, can be used as a lead compound for subsequent development and research, and has a broad application prospect.

[0022] In order to make the above and other purposes, features and advantages of the present invention more obvious and easy to understand, preferred embodiments are given below and described in detail with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only one of the drawings of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0024] Figure 1 This is a graph showing the antibacterial activity test results of some 1-amide-1,2-dihydrophthalazine compounds. DETAILED DESCRIPTION

[0025] Embodiments of the present invention will be described in detail below with reference to the accompanying drawings. Although certain embodiments of the present invention are shown in the accompanying drawings, it should be understood that the present invention can be implemented in various forms and should not be construed as being limited to the embodiments described herein, which are instead provided for a more thorough and complete understanding of the present invention. It should be understood that the drawings and embodiments of the present invention are only for exemplary purposes and are not intended to limit the scope of protection of the present invention.

[0026] Example

[0027] The 1-amide-1,2-dihydrophthalazine compound described in formula (1) is prepared according to the following reaction route:

[0028]

[0029] Among them, the substituent R 1Represents aromatic group or alkyl group; R 2 Represents aryl and alkyl.

[0030] The specific steps are: dissolving phthalazine, an acyl chloride and an isocyanide in an organic solvent at room temperature, reacting at -2°C to 0°C for 3-5 hours, preferably at 0°C for 4 hours, adding sodium bicarbonate to quench the reaction, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating, and purifying with a column to obtain 1-amide-1,2-dihydrophthalazine compounds 1a-1x.

[0031] Wherein, the acyl chloride refers to benzoyl chloride, acetyl chloride, propionyl chloride, butyryl chloride, tert-butyryl chloride, phenylacetyl chloride, 4-chlorobutyryl chloride, 2-acetoxyisobutyryl chloride, propyl chloroformate, isobutyl chloroformate, pentyl chloroformate, cyclopentyl chloroformate, 2,2,2-trichloroethyl chloroformate, chloromethyl chloroformate, allyl chloroformate, benzyl chloroformate, phenyl chloroformate, 9-fluorenylmethyl chloroformate;

[0032] The isocyanide refers to tert-butyl isocyanide, 4-ethylphenyl isocyanide, 2,6-dimethylphenyl isocyanide, cyclohexyl isocyanide, phenylethyl isocyanide, 1-(2-isocyanoethyl)cyclohex-1-ene, and methyl isocyanoacetate;

[0033] The organic solvent refers to dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, tetrahydrofuran, 1,4-dioxane; the organic solvent is preferably dichloromethane or tetrahydrofuran.

[0034] The reaction route is:

[0035]

[0036] Among them, the substituent R 1 Represents aromatic group or alkyl group; R 2 Represents aryl and alkyl.

[0037] The structures of 1-amide-1,2-dihydrophthalazine compounds 1a-1x are shown below:

[0038]

[0039] The term "aromatic group" can also be referred to as "aryl group", which should include carbocyclic aromatic ring groups with carbon atoms ranging from C6 to C 10 Aromatic groups, such as phenyl (C6), fluorenyl (C 10 ) group.

[0040] The synthesis method of compounds 1a-1x is:

[0041] Synthesis of compound 1a

[0042] Phthaloazine (195 mg, 1.5 mmol), benzoyl chloride (252 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1a (428 mg, 85%). 1 H NMR (400MHz, CDCl3) δ7.74-7.69(m,2H),7.66-7.62(s,1H),7.54-7.33(m,7H),6.43(s,1H),6.23(s,1H),1.30(s,9H)ppm.

[0043] Synthesis of compound 1b

[0044] Phthaloazine (195 mg, 1.5 mmol), acetyl chloride (140 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1b (331 mg, 81%). 1 H NMR (400MHz, CDCl3) δ7.57(s,1H),7.49-7.39(m,2H),7.32-7.29(m,2H),6.12-6.05(m,2H),2.43(s,3H),1.27(s,9H)ppm.

[0045] Synthesis of compound 1c

[0046] Phthaloazine (195 mg, 1.5 mmol), propionyl chloride (166 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1c (342 mg, 80%). 1 H NMR (400MHz, CDCl3) δ7.58(s,1H),7.51-7.28(m,4H),6.17-6.00(m,2H),2.97-2.87(m,1H),2.77-2.66(m,1H),1.34-1.19(m,12H)ppm.

[0047] Synthesis of compound 1d

[0048] Phthaloazine (195 mg, 1.5 mmol), butyryl chloride (191 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1d (351 mg, 78%). 1 H NMR (400MHz, CDCl3) δ7.57(s,1H),7.51-7.44(m,1H),7.43-7.37(m,1H),7.33-7.27(m,2H),6.23-6.0 0(m,2H),2.96-2.85(m,1H),2.73-2.62(m,1H),1.79-1.66(m,2H),1.27(s,9H),1.05-0.98(m,3H)ppm.

[0049] Synthesis of compound 1e

[0050] Phthaloazine (195 mg, 1.5 mmol), tert-butyryl chloride (216 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1e (338 mg, 75%). 1 H NMR (400MHz, CDCl3) δ7.56(s,1H),7.49-7.28(m,4H),6.20-5.95(m,2H),1.41(s,9H),1.26(s,9H)ppm.

[0051] Synthesis of compound 1f

[0052] Phthaloazine (195 mg, 1.5 mmol), phenylacetyl chloride (277 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1f (371 mg, 79%). 1 H NMR (400MHz, CDCl3) δ7.61 (s, 1H), 7.46-7.24 (m, 9H), 6.09 (s, 1H), 6.00 (s, 1H), 4.30 (d, J = 14.0Hz, 1H), 4.01 (d, J = 14.0Hz, 1H), 1.13 (s, 9H) ppm.

[0053] Synthetic compound 1g

[0054] Phthaloazine (195 mg, 1.5 mmol), 4-chlorobutyryl chloride (252 mg, 1.8 mmol), tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain 1 g (373 mg, 74%) of the target product. 1 H NMR(400MHz, CDCl3)δ7.58(s,1H),7.51-7.39(m,2H),7.35-7.29(m,2H),6.11-6.02(m,2H),3. 66(d,J=6.8Hz,2H),3.18-3.08(m,1H),2.93-2.83(m,1H),2.28-2.14(m,2H),1.27(s,9H)ppm.

[0055] Synthesis of compound 1h

[0056] Phthaloazine (195 mg, 1.5 mmol), 2-acetoxyisobutyryl chloride (297 mg, 1.8 mmol), tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1h (340 mg, 63%). 1 H NMR(400MHz, CDCl3)δ9.70(s,1H),9.01-8.97(m,1H),7.87(s,1H),7.78-7.71(m ,2H),7.60-7.55(m,1H),1.98(s,3H),1.72(s,3H),1.62(s,3H),1.57(s,9H)ppm.

[0057] Synthesis of compound 1i

[0058] Phthaloazine (195 mg, 1.5 mmol), propyl chloroformate (220 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1i (376 mg, 79%). 1 H NMR(400MHz, CDCl3)δ7.66(s,1H),7.52-7.26(m,4H),5.91(s,1H),5.81(s,1 H),4.38-4.23(m,2H),1.85-1.74(m,2H),1.26(s,9H),1.05-0.92(m,3H)ppm.

[0059] Synthesis of compound 1j

[0060] Phthaloazine (195 mg, 1.5 mmol), isobutyl chloroformate (247 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1j (431 mg, 87%). 1 H NMR(400MHz, CDCl3)δ7.68(s,1H),7.51-7.28(m,4H),5.91(s,1H),5.81(s,1H), 4.13(d,J=7.2Hz,2H),2.14-2.04(m,1H),1.26(s,9H),0.99(d,J=7.2Hz,6H)ppm.

[0061] Synthesis of compound 1k

[0062] Phthaloazine (195 mg, 1.5 mmol), amyl chloroformate (275 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1k (428 mg, 83%). 1 H NMR(400MHz, CDCl3)δ7.67(s,1H),7.51-7.28(m,4H),5.94(s,1H),5.82(s,1H),4.42- 4.27(m,2H),1.84-1.72(m,2H),1.44-1.34(m,2H),1.27(s,9H),0.96-0.87(m,3H)ppm.

[0063] Synthesis of compound 1l

[0064] Phthaloazine (195 mg, 1.5 mmol), cyclopentyl chloroformate (268 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 11 (449 mg, 87%). 1H NMR(400MHz, CDCl3)δ7.67(s,1H),7.51-7.26(m,4H),5.90(s,1H),5.78(s,1H),5.3 3(s,1H),2.09-1.92(m,2H),1.90-1.74(m,4H),1.69-1.54(m,2H),1.27(s,9H)ppm.

[0065] Synthesis of compound 1m

[0066] Phthaloazine (195 mg, 1.5 mmol), 2,2,2-trichloroethyl chloroformate (381 mg, 1.8 mmol), tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1m (492 mg, 81%). 1 H NMR (400MHz, CDCl3) δ7.77(s,1H),7.55-7.42(m,3H),7.35-7.32(m,1H),5.95-5.77(m,2H),5.10-4.91(m,2H),1.26(s,9H)ppm.

[0067] Synthesis of compound 1n

[0068] Phthaloazine (195 mg, 1.5 mmol), chloromethyl chloroformate (232 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1n (417 mg, 86%). 1 H NMR (400MHz, CDCl3) δ7.69(s,1H),7.54-7.32(m,4H),6.07-5.86(m,3H),5.83(s,1H),1.28(s,9H)ppm.

[0069] Synthesis of compound 1o

[0070] Phthaloazine (195 mg, 1.5 mmol), allyl chloroformate (217 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1o (364 mg, 77%). 1H NMR (400MHz, CDCl3) δ7.68(s,1H),7.52-7.28(m,4H),6.08-5.98(m,1H),5.91(s,1H),5.82(s ,1H),5.42(d,J=17.2Hz,1H),5.30(d,J=14.4Hz,1H),4.84(d,J=6.0Hz,1H),1.27(s,9H)ppm.

[0071] Synthesis of compound 1p

[0072] Phthaloazine (195 mg, 1.5 mmol), benzyl chloroformate (307 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1p (447 mg, 85%). 1 H NMR (400MHz, CDCl3) δ7.67(s,1H),7.51-7.26(m,9H),6.00-5.66(m,2H),5.50-5.25(m,2H),1.19(s,9H)ppm.

[0073] Synthesis of compound 1q

[0074] Phthaloazine (195 mg, 1.5 mmol), phenyl chloroformate (283 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1q (479 mg, 91%). 1 H NMR (400MHz, CDCl3) δ7.74(s,1H),7.49-7.39(m,4H),7.36-7.19(m,5H),6.09(s,1H),5.91(s,1H),1.26(s,9H)ppm.

[0075] Synthesis of compound 1r

[0076] Phthaloazine (195 mg, 1.5 mmol), 9-fluorenylmethyl chloroformate (466 mg, 1.8 mmol), and tert-butyl isocyanide (150 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, and the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1r (547 mg, 80%). 1H NMR (400MHz, CDCl3) δ7.79-7.68(m,5H),7.50-7.29(m,8H),6.05-5.70(m,2H ),4.67-4.60(m,1H),4.56-4.46(m,1H),4.44-4.37(m,1H),1.25(m,9H)ppm.

[0077] Synthesis of compound 1s

[0078] Phthaloazine (195 mg, 1.5 mmol), 9-fluorenylmethyl chloroformate (466 mg, 1.8 mmol), and 4-ethylphenylisocyanate (238 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1s (555 mg, 74%). 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),7.93-7.72(m,6H),7.57-7.28(m,9H),7.16-7. 10(m,2H),6.10(s,1H),4.53-4.33(m,3H),2.57-2.52(m,2H),1.16-1.10(m,3H)ppm.

[0079] Synthesis of compound 1t

[0080] Phthaloazine (195 mg, 1.5 mmol), 9-fluorenylmethyl chloroformate (466 mg, 1.8 mmol), and 2,6-dimethylphenylisocyanate (236 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1t (582 mg, 76%). 1 H NMR(400MHz,DMSO-d6)δ9.78(s,1H),7.93-7.73(m,6H),7.62-7.31(m,7H),7.06- 6.97(m,3H),6.16(s,1H),4.56-4.48(m,1H),4.45-4.36(m,2H),1.96(s,6H)ppm.

[0081] Synthesis of compound 1u

[0082] Phthaloazine (195 mg, 1.5 mmol), 9-fluorenylmethyl chloroformate (466 mg, 1.8 mmol), and cyclohexyl isocyanate (171 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1u (601 mg, 83%). 1 H NMR (400MHz, CDCl3) δ7.85-7.59(m,5H),7.52-7.25(m,8H),6.20-5.62(m,2H),4.71-4.28(m,3H), 3.79-3.48(m,1H),1.82-1.69(m,2H),1.64-1.47(m,3H),1.31-1.21(m,2H),1.17-0.98(m,3H)ppm.

[0083] Synthesis of compound 1v

[0084] Phthaloazine (195 mg, 1.5 mmol), 9-fluorenylmethyl chloroformate (466 mg, 1.8 mmol), and phenethyl isocyanate (212 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1v (425 mg, 58%). 1 H NMR (400MHz, CDCl3) δ7.78-7.63(m,5H),7.50-7.37(m,5H),7.34-7.27(m,3H),7.2 0-7.06(m,5H),6.48(s,1H),6.00(s,1H),4.60-4.44(m,2H),4.41-4.26(m,3H)ppm.

[0085] Synthetic compound 1w

[0086] Phthaloazine (195 mg, 1.5 mmol), 9-fluorenylmethyl chloroformate (466 mg, 1.8 mmol), 1-(2-isocyanoethyl)cyclohex-1-ene (243 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1w (651 mg, 74%). 1H NMR (400MHz, CDCl3) δ7.82-7.62(m,5H),7.53-7.28(m,8H),6.12-5.69(m,2H),5.37-5.18(s,1H),4.66-4.47(m,2H), 4.44-4.32(m,1H),3.35-3.06(m,2H),2.14-1.95(m,2H),1.94-1.86(m,2H),1.84-1.73(m,2H),1.56-1.40(m,4H)ppm.

[0087] Synthetic compound 1x

[0088] Phthaloazine (195 mg, 1.5 mmol), 9-fluorenylmethyl chloroformate (466 mg, 1.8 mmol), methyl isocyanoacetate (179 mg, 1.8 mmol) were dissolved in dichloromethane (10 mL) and reacted at 0°C for 4 hours. Sodium bicarbonate was added to quench the reaction, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified by column to obtain the target product 1x (583 mg, 82%). 1 H NMR (400MHz, CDCl3) δ7.84-7.63(m,5H),7.53-7.28(m,8H),6.67(m,1H),6.0 6(m,1H), 4.76-4.46(m,2H), 4.45-4.33(m,1H), 3.95(s,2H), 3.65(m,3H)ppm.

[0089] The following is an activity test of some of the compounds 1a-1x prepared by the present invention:

[0090] Experimental Materials

[0091] Preparation of the drug: 1-Amide-1,2-dihydrophthalazine compounds were prepared by the preparation method described in the above examples. Before use, they were prepared into a 3.2 mM stock solution with cell-grade DMSO, and then diluted with LB broth to the required concentration.

[0092] Preparation of culture medium

[0093] Preparation of solid culture medium: Weigh a certain amount of LB agar solid powder as needed, dissolve it in distilled water, sterilize it at 121℃ and high temperature and high pressure for 30 minutes, transfer it to a sterile culture dish while it is still hot, cool and solidify naturally, and store it in a 4℃ refrigerator for later use.

[0094] Preparation of liquid culture medium: Weigh a certain amount of LB broth solid powder as needed, dissolve it in distilled water, sterilize it at 121℃ under high temperature and high pressure conditions for 30 minutes, cool it to room temperature, and store it in a 4℃ refrigerator for later use.

[0095] Experimental methods

[0096] Activation of strains: The experimental strain (Staphylococcus aureus ATCC 25923) was inoculated onto LB solid medium using the plate streak method, and the medium was inverted in a constant temperature incubator and cultured at 37°C for 24 hours.

[0097] Bacterial strain subculture: Use an inoculation loop to pick 3-5 colonies of the same morphology from the LB solid culture medium, inoculate them into a shake tube containing 4-5 mL of LB liquid culture medium, place the shake tube in a shaker at 37°C, 150 rpm, and culture the bacteria to the logarithmic growth phase (6-8h) for use.

[0098] Preparation of bacterial suspension: Prepare the test bacteria into 0.5 MCF bacterial suspension using LB broth medium, containing approximately 1-5*106 CFU / mL.

[0099] Drug dilution: Add 100 μL LB medium to each well of the 2nd to 11th columns of the 96-well plate, add 190 μL LB medium to the wells in the first column, take 10 μL of drug and add it to the wells in the first column, mix by pipetting up and down, and perform two-fold gradient dilution, starting from the first column and then diluting in turn to make the drug concentration in each well decrease. The 11th column is used as a growth control, containing only culture medium and bacterial solution, without drugs. The 12th column is a blank control, containing only culture medium, without bacterial solution and drugs.

[0100] Inoculate bacteria: Add 100 μL of the prepared bacterial suspension to each well except the blank control well, so that the final bacterial count in each well is about 5*10 5 CFU / mL

[0101] Bacterial culture: Put the lid on the 96-well plate and place it in an incubator at 37°C for 24 hours.

[0102] Result observation: Use an enzyme marker to detect the absorbance at a wavelength of 600nm to determine the growth of bacteria. The lowest drug concentration that completely inhibits bacterial growth is the minimum inhibitory concentration (MIC).

[0103] Experimental results: See the results Figure 1 The results showed that some 1-amide-1,2-dihydrophthalazine compounds had an inhibitory effect on the growth of Staphylococcus aureus, suggesting that this series of derivatives has potential antibacterial effects and can be used to prepare inhibitors of Staphylococcus aureus growth.

[0104] The above description of the various embodiments tends to emphasize the differences between the various embodiments. The same or similar aspects can be referenced to each other, and for the sake of brevity, this application will not go into details.

[0105] Note that the above are only preferred embodiments of the present invention and the technical principles used. Those skilled in the art will understand that the present invention is not limited to the specific embodiments herein, and that various obvious changes, readjustments and substitutions can be made by those skilled in the art without departing from the scope of protection of the present invention. Therefore, although the present invention has been described in more detail through the above embodiments, the present invention is not limited to the above embodiments, and may include more other equivalent embodiments without departing from the concept of the present invention, and the scope of the present invention is determined by the scope of the appended claims.

Claims

1. A 1-amide-1,2-dihydrophthalazine compound, characterized in that: It has the chemical structure of formula (1): Among them, the substituent R 1 Represents aromatic group or alkyl group; R 2 Represents aryl and alkyl.

2. A 1-amide-1,2-dihydrophthalazine compound according to claim 1, characterized in that: The substituent R 1 represents phenyl, methyl, ethyl, propyl, tert-butyl, benzyl, 1-chloropropyl, 1-methylethyl acetate, propoxy, isobutoxy, pentyloxy, cyclopentyloxy, 3,3,3-trichloropropoxy, chloromethoxy, allyloxy, benzyloxy, phenoxy, 9-fluorenylmethoxy; R 2 It represents tert-butyl, 4-ethylphenyl, 2,6-dimethylphenyl, cyclopentyl, benzyl, 1-cyclohexenylethyl.

3. A 1-amide-1,2-dihydrophthalazine compound according to claim 2, characterized in that: The 1-amide-1,2-dihydrophthalazine compounds have the following structures 1a-1x:

4. A method for preparing a 1-amide-1,2-dihydrophthalazine compound according to any one of claims 1 to 3, characterized in that Prepared by the following reaction route: Among them, the substituent R 1 Represents aromatic group or alkyl group; R 2 Represents aryl and alkyl.

5. The method for preparing a 1-amide-1,2-dihydrophthalazine compound according to claim 4, characterized in that: Phthaloazine, an acyl chloride, and an isocyanide are dissolved in an organic solvent at room temperature, reacted at -2°C to 0°C for 3-5 hours, and sodium bicarbonate is added to quench the reaction. The mixture is extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified to obtain 1-amide-1,2-dihydrophthalazine compounds 1a-1x.

6. The method for preparing a 1-amide-1,2-dihydrophthalazine compound according to claim 5, characterized in that: The acyl chloride refers to benzoyl chloride, acetyl chloride, propionyl chloride, butyryl chloride, tert-butyryl chloride, phenylacetyl chloride, 4-chlorobutyryl chloride, 2-acetoxyisobutyryl chloride, propyl chloroformate, isobutyl chloroformate, pentyl chloroformate, cyclopentyl chloroformate, 2,2,2-trichloroethyl chloroformate, chloromethyl chloroformate, allyl chloroformate, benzyl chloroformate, phenyl chloroformate, 9-fluorenylmethyl chloroformate; The isocyanide refers to tert-butyl isocyanide, 4-ethylphenyl isocyanide, 2,6-dimethylphenyl isocyanide, cyclohexyl isocyanide, phenylethyl isocyanide, 1-(2-isocyanoethyl)cyclohex-1-ene, and methyl isocyanoacetate; The organic solvent refers to dichloromethane, 1,2-dichloroethane, acetonitrile, toluene, tetrahydrofuran, and 1,4-dioxane.

7. Use of a 1-amide-1,2-dihydrophthalazine compound according to any one of claims 1 to 3 in the preparation of a Staphylococcus aureus growth inhibitor.

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