CN112430223B - Substituted benzoyl piperazine compounds and application thereof - Google Patents

Substituted benzoyl piperazine compounds and application thereof Download PDF

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CN112430223B
CN112430223B CN202011329548.2A CN202011329548A CN112430223B CN 112430223 B CN112430223 B CN 112430223B CN 202011329548 A CN202011329548 A CN 202011329548A CN 112430223 B CN112430223 B CN 112430223B
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substituted benzoyl
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CN112430223A (en
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金永生
高越
易滨
郭良君
王瀚萱
陈矗然
姜远英
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Second Military Medical University SMMU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms

Abstract

The invention discloses a substituted benzoyl piperazine compound or medicinal salt thereof, which has the following structural general formula:

Description

Substituted benzoyl piperazine compounds and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to substituted benzoyl piperazine compounds and application thereof.
Background
The antibacterial action of natural products is generally concerned, and the natural products become research hotspots for searching new antifungal drugs and lead compounds thereof in recent years due to the characteristics of novel structures, strong biological activity and low toxicity. Gallic acid (also called Gallic acid or Gallic acid, i.e. 3,4, 5-trihydroxybenzoic acid) is an organic acid present in plants such as Galla chinensis, rhus verniciflua Stokes, and Camellia sinensis. The documents report that the compound has the effects of resisting bacteria, viruses, tumors and the like. Based on the compound, a series of substituted benzoyl piperazine compounds are designed and synthesized, and the individual and synergistic antifungal effects of the substituted benzoyl piperazine compounds are evaluated, so that a foundation is provided for further research and development of antifungal medicaments.
Disclosure of Invention
The first purpose of the invention is to provide a kind of substituted benzoyl piperazine compound.
The second purpose of the invention is to provide an application of the substituted benzoyl piperazine compound in preparing antifungal drugs.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the first aspect of the invention provides a substituted benzoyl piperazine compound or a medicinal salt thereof, which has the following structural general formula:
Figure BDA0002795362070000011
R 1 、R 2 、R 3 、R 4 、R 5 each independently selected from hydrogen, hydroxyl, C1-C10 alkyl, C1-C10 alkoxy and halogen;
x is selected from C or N;
y is selected from one of the following groups:
Figure BDA0002795362070000012
R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 each independently selected from hydrogen, hydroxyl, halogen (fluorine, chlorine, bromine, iodine), C1-C10 alkyl, C1-C10 alkoxy.
More preferably, the substituted benzoyl piperazine compound is one of the following structures:
Figure BDA0002795362070000021
R 1 、R 2 、R 3 、R 4 、R 5 each independently selected from hydrogen, hydroxyl, C1-C10 alkoxy;
R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 each independently selected from hydrogen, hydroxy, halogen (fluorine, chlorine, bromine, iodine), C1-C10 alkyl, C1-C10 alkoxy.
Preferably, in the substituted benzoyl piperazine compound:
R 1 、R 2 、R 3 simultaneously being hydroxy, R 4 、R 5 And is simultaneously hydrogen;
or, R 1 、R 2 Simultaneously being hydroxy, R 3 、R 4 、R 5 And is simultaneously hydrogen;
or, R 2 、R 3 Simultaneously being hydroxy, R 1 、R 4 、R 5 And is simultaneously hydrogen;
or, R 2 、R 3 、R 4 Simultaneously being hydroxy, R 1 、R 5 And is simultaneously hydrogen;
or, R 2 Is methoxy, R 1 、R 4 、R 5 、R 3 And is simultaneously hydrogen;
more preferably, in the substituted benzoyl piperazine compound:
R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 each independently selected from hydrogen, fluorine, chlorine.
Most preferably, the substituted benzoyl piperazine compound is one of the following structures:
Figure BDA0002795362070000022
Figure BDA0002795362070000031
Figure BDA0002795362070000041
the third aspect of the invention provides an application of the substituted benzoyl piperazine compound or the medicinal salt thereof in preparing antifungal medicaments.
The fourth aspect of the invention provides an application of the substituted benzoyl piperazine compound or the medicinal salt thereof in preparing synergistic fluconazole antifungal medicines.
The fungus is Candida albicans.
The substituted benzoyl piperazine compound can be prepared into a medicinal salt form according to a conventional method.
The medicinal salt of the substituted benzoyl piperazine compound is a salt formed by pharmaceutically acceptable inorganic acid and organic acid, wherein the preferable inorganic acid comprises: hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; preferred organic acids include: formic acid, acetic acid, propionic acid, succinic acid, naphthalenedisulfonic acid (1, 5), sulfinic acid, carbenoxolone, glycyrrhetinic acid, oleanolic acid, crataegolic acid, ursolic acid, corosolic acid, betulinic acid, boswellic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropanoic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids.
Due to the adoption of the technical scheme, the invention has the following advantages and beneficial effects:
the substituted benzoyl piperazine compound has good antifungal activity, and especially has obvious effect on drug-resistant candida albicans when being used alone. Moreover, when the antifungal composition is used together with fluconazole, the original azole-resistant fungi can be sensitized to azole drugs again, the dosage of the azole drugs is reduced, the curative effect of the azole drugs is improved, and the synergistic effect is achieved.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below in connection with preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
The materials used in the examples of the invention are as follows: bruker Spectrmspin AC-P300 (Bruker, switzerland) was used; nuclear magnetic resonance apparatus model AC-P600 (Bruker, switzerland); LC-MS Mass spectrometer model Agilent 6120 (Agilent Corp., USA); silica gel plate GF254 (tabasheer, china); a dark box type ultraviolet analyzer (model ZF-20D); rotary evaporator (Buchi Rotavapor R-3 model); SHB-III circulation type multipurpose vacuum pump; vacuum drying oven (model DZF-6021); ultrasonic cleaner (KQ-500E type); reagents (analytically pure) and raw materials for the experiment are purchased from Annaiji reagent, inc., bailingwei science and technology, inc., bigdai medicine science and technology, inc., exploration platform, etc.
Example 1
Preparation of Compound 1B-1:
Figure BDA0002795362070000051
3,4, 5-Trimethoxybenzoic acid (Compound 1) (100.0mg, 0.5 mmol) was placed in a 100ml round-bottom flask, DCM (10.0 ml, dichloromethane) was added to dissolve it, and then 1- (2-chlorophenyl) piperazine (120.0mg, 0.6 mmol), DCC (124.0mg, 0.6mmol, N' -dicyclohexylcarbodiimide), DMAP (244.0mg, 2.0mmol) were added in this order, and stirred at room temperature for 6 hours, and it was observed that the solution became turbid by clarification, TLC detection (DCM: meOH = 10), and the reaction was completed. Filtration, evaporation of the filtrate under reduced pressure, recrystallization from 95% EtOH to give Compound 1A-1 (111.0 mg, yield: 56%).
Compound 1A-1 (100.0 mg,0.3 mmol) was placed in a 100ml round bottom three-necked flask, anhydrous DCM (10.0 ml) was added under anhydrous and oxygen-free argon shielding, and BBr was added dropwise at a constant rate of two drops per second at a temperature of-30 deg.C 3 After the reaction was completed, the reaction apparatus was moved to room temperature and stirred overnight, and TLC was detected (DCM: meOH = 10) and 100.0ml of water was added to quench the reaction, and the reaction was stirred at room temperature for 1 hour, and then whether or not a solid separated out was observed, and if so, the reaction was filtered through a filter, and the reaction solution was stirred at room temperature for 1 hourFiltering, and drying a filter cake in an oven; and if no solid is separated out, EA is extracted for three times, organic phases are combined, anhydrous sodium sulfate is dried, the organic phases are evaporated to dryness, and the mixture is recrystallized by DCM or EtOH to obtain the compound 1B-1.
Example 2
Preparation of Compound 1B-2:
Figure BDA0002795362070000061
1- (2-chlorophenyl) piperazine used in example 1 was replaced with 1- (3-chlorophenyl) piperazine (120.0 mg,0.6 mmol), and reference example 1 was otherwise repeated to give compound 1A-2 (123.0 mg, yield: 61%). Preparation of Compound 1B-2 reference is made to the preparation of Compound 1B-1 in example 1.
Example 3
Figure BDA0002795362070000062
Compound 1A-3 (107.0 mg, yield: 58%) was obtained by substituting 1- (2, 3-dichlorophenyl) piperazine (140.0 mg,0.6 mmol) for 1- (2-chlorophenyl) piperazine used in example 1 and referring to example 1. Preparation of Compound 1B-3 reference is made to the preparation of Compound 1B-1 in example 1.
Example 4
Figure BDA0002795362070000063
After 3,4, 5-trimethoxybenzoic acid (compound 1) (100.0mg, 0.5mmol) was placed in a 100ml round-bottomed flask, DMF (10.0 ml) was added thereto to dissolve it, and then 4,4' -difluorodipheny piperazine (173.0mg, 0.6 mmol), pyBOP (312.2mg, 0.6 mmol) and DIEA (1.0ml, 2.0mmol) were sequentially added thereto, and after the addition, stirring was carried out at room temperature for 4h and detection by TLC (DCM: meOH = 10). Then, 100.0ml of water was added thereto and the mixture was quenched, stirred at room temperature for 1 hour to observe whether or not a solid precipitated, the solid precipitated was filtered, and the filter cake was dried in an oven and recrystallized with 95% EtOH to obtain Compound 1A-4 (118.0 mg, yield: 60%).
Preparation of Compound 1B-4 reference is made to the preparation of Compound 1B-1 in example 1.
Example 5
Figure BDA0002795362070000064
Figure BDA0002795362070000071
After 3,4, 5-trimethoxybenzoic acid (compound 1) (100.0mg, 0.5mmol), N-Boc-piperazine (150.0mg, 0.6 mmol), pyBOP (312.2mg, 0.6 mmol) and additional DIEA (1.0ml, 2.0mmol) were added, stirring was carried out at room temperature for 4h after the completion of the addition, and tlc detection (DCM: meOH = 10) was carried out until the reaction was completed. Adding 100.0ml of water for quenching, stirring for 1h at room temperature, filtering, and recrystallizing the filter cake with 95% EtOH to obtain intermediate a. Weighing, dissolving the product in a 1.
Intermediate b (140.0mg, 0.5mmol), 2, 3-dichlorobenzoic acid (115.0mg, 0.6 mmol), pyBOP (312.2mg, 0.6 mmol) and DIEA (1.0ml, 2.0mmol) were prepared in the same manner as Compound 1A-4 to obtain Compound 1A-5121.0mg (yield: 59%).
Preparation of Compound 1B-5 reference example 1 was made to the preparation of Compound 1B-1.
Example 6
Figure BDA0002795362070000072
Compound 1A-6 (115.0 mg, yield: 58%) was obtained by substituting 3, 4-dichlorobenzoic acid (115.0 mg,0.6 mmol) for 2, 3-dichlorobenzoic acid used in example 5 and referring to example 5. Preparation of Compound 1B-6 reference example 1 was made to the preparation of Compound 1B-1.
Example 7
Figure BDA0002795362070000073
The 2, 3-dichlorobenzoic acid used in example 5 was replaced with 3,4, 5-trifluorobenzoic acid (110.0 mg,0.6 mmol), and otherwise referred to in example 5, to give compounds 1A-7 (120.0 mg, yield: 65%). Preparation of Compound 1B-7 reference is made to the preparation of Compound 1B-1 in example 1.
Example 8
Figure BDA0002795362070000074
Trans-cinnamic acid (100.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 5, and otherwise referred to in example 5, to give compounds 1A-8 (116.0 mg, yield: 59%). Preparation of Compound 1B-8 reference is made to the preparation of Compound 1B-1 in example 1.
Example 9
Figure BDA0002795362070000081
Phenoxyacetic acid (100.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 5, and otherwise referred to in example 5, to give compounds 1A-9 (130.0 mg, yield: 75%). Preparation of Compound 1B-9 reference is made to the preparation of Compound 1B-1 in example 1.
Example 10
Figure BDA0002795362070000082
Compound 1A-10 (109.0 mg, yield: 58%) was obtained by substituting 2, 4-dichlorophenoxyacetic acid (135.0 mg,0.6 mmol) for 2, 3-dichlorobenzoic acid used in example 5 and otherwise referring to example 5. Preparation of Compound 1B-10 reference is made to the preparation of Compound 1B-1 in example 1.
Example 11
Figure BDA0002795362070000083
Compound c (163.0mg, 0.6mmol) was placed in a 100ml round-bottom flask, DMF (10.0 ml) was added to dissolve it, and then 3,4, 5-trimethoxybenzoic acid (Compound 1) (100.0mg, 0.5mmol), pyBOP (312.2mg, 0.6mmol) and DIEA (1.0ml, 2.0mmol) were sequentially added, and after the addition was completed, stirring was carried out at room temperature for 2h, and detection by TLC (DCM: meOH = 10) was carried out until the reaction was completed. Adding 100.0ml of water for quenching, stirring at room temperature for 1h, observing whether or not a solid precipitates, precipitating a solid, filtering, oven-drying the filter cake, and recrystallizing with 95% EtOH to obtain 1A-11 (138.0 mg, yield: 78%).
Preparation of Compound 1B-11 reference is made to the preparation of Compound 1B-1 in example 1.
Example 12
Figure BDA0002795362070000091
2,3, 4-Trimethoxybenzoic acid (Compound 4) (100.0mg, 0.5mmol), 1- (2-chlorophenyl) piperazine (120.0mg, 0.6mmol), DCC (124.0mg, 0.6mmol), DMAP (244.0mg, 2.0mmol), the same as in 1A-1 of example 1, gave a compound 1C-1 (102.0 mg, yield: 48%).
Compound 1C-1 (100.0mg, 0.3mmol), BBr 3 As a solution of DCM (6.0 ml,3.0 mmol), compound 1D-1 was obtained in the same manner as in compound 1B-1 of example 1.
Example 13
Figure BDA0002795362070000092
Reference example 12 was repeated except for using 1- (3-chlorophenyl) piperazine (120.0 mg,0.6 mmol) instead of 1- (2-chlorophenyl) piperazine used in example 12 to obtain compound 1C-2 (110.0 mg, yield: 54%).
Preparation of Compound 1D-2 reference example 12 was made to the preparation of Compound 1D-1.
Example 14
Figure BDA0002795362070000093
Compound 1C-3 (109.0 mg, yield: 50%) was obtained in reference example 12 except that 1- (2-chlorophenyl) piperazine used in example 12 was replaced with 1- (2, 3-dichlorophenyl) piperazine (140.0 mg,0.6 mmol).
Preparation of Compound 1D-3 reference example 12 was made to the preparation of Compound 1D-1.
Example 15
Figure BDA0002795362070000094
2,3, 4-Trimethoxybenzoic acid (Compound 4) (100.0mg, 0.5mmol), 4' -difluorodibenzylpiperazine (173.0mg, 0.6mmol), pyBOP (312.2mg, 0.6mmol), DIEA (1.0ml, 2.0mmol) in the same manner as in 1A-4 in example 4, to give a compound 1C-4 (117.0 mg, yield: 58%).
Preparation of Compound 1D-4 reference example 12 was made to the preparation of Compound 1D-1.
Example 16
Figure BDA0002795362070000095
Figure BDA0002795362070000101
Intermediate e was obtained by the same method as for intermediate b in example 5, except that 2,3, 4-trimethoxybenzoic acid (compound 4) (100.0 mg,0.5 mmol), N-Boc-piperazine (150.0 mg,0.6 mmol), pyBOP (312.2mg, 0.6 mmol) and DIEA (1.0 ml,2.0 mmol) were used.
Intermediate e (140.0mg, 0.5mmol), 2, 3-dichlorobenzoic acid (115.0mg, 0.6 mmol), pyBOP (312.2mg, 0.6 mmol) and DIEA (1.0ml, 2.0mmol) were weighed out in the same manner as in 1A-4 in example 4 to obtain 1C-5 (135.0 mg, yield: 79%).
Preparation of Compound 1D-5 reference example 12 was made to the preparation of Compound 1D-1.
Example 17
Figure BDA0002795362070000102
Compound 1C-6 (124.0 mg, yield: 68%) was obtained by substituting 3, 4-dichlorobenzoic acid (115.0 mg,0.6 mmol) for 2, 3-dichlorobenzoic acid used in example 16 and making reference to example 16.
Preparation of Compound 1D-6 preparation of Compound 1D-1 in reference example 12.
Example 18
Figure BDA0002795362070000103
Reference example 16 was repeated except for using 3,4, 5-trifluorobenzoic acid (110.0 mg,0.6 mmol) in place of 2, 3-dichlorobenzoic acid used in example 16 to give compound 1C-7 (132.0 mg, yield: 70%).
Preparation of Compound 1D-7 reference example 12 was made to the preparation of Compound 1D-1.
Example 19
Figure BDA0002795362070000104
Instead of 2, 3-dichlorobenzoic acid used in example 16, trans-cinnamic acid (100.0 mg,0.6 mmol) was used in addition to reference example 16 to obtain compound 1C-8 (130.0 mg, yield: 78%).
Preparation of Compound 1D-8 reference example 12 was made to the preparation of Compound 1D-1.
Example 20
Figure BDA0002795362070000111
Phenoxyacetic acid (100.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 16, and reference example 16 was otherwise made to obtain compound 1C-9 (139.0 mg, yield: 75%).
Preparation of Compound 1D-9 preparation of Compound 1D-1 in reference example 12.
Example 21
Figure BDA0002795362070000112
Compound 1C-10 (125.0 mg, yield: 70%) was obtained by substituting 2, 4-dichlorophenoxyacetic acid (135.0 mg,0.6 mmol) for 2, 3-dichlorobenzoic acid used in example 16 and making reference to example 16.
Preparation of Compound 1D-10 preparation of Compound 1D-1 in reference example 12.
Example 22
Figure BDA0002795362070000113
Intermediate C (163.0mg, 0.6 mmol), 2,3, 4-trimethoxybenzoic acid (compound 4) (100.0mg, 0.5mmol), pyBOP (312.2mg, 0.6 mmol) and DIEA (1.0ml, 2.0mmol) were weighed out in the same manner as in Compound 1A-4 to obtain 1C-11 (134.0 mg, yield: 70%).
Preparation of Compound 1D-11 reference example 12 was made to the preparation of Compound 1D-1.
Example 23
Figure BDA0002795362070000114
3, 4-Dimethoxybenzoic acid (Compound 5) (100.0mg, 0.5mmol), 1- (2-chlorophenyl) piperazine (120.0mg, 0.6mmol), pyBOP (312.2mg, 0.6mmol), DIEA (1.0ml, 2.0mmol), the same procedure as for Compound 1A-4, gave Compound 2A-1 (126.0 mg, yield: 71%).
Compound 2A-1 (100.0 mg,0.3 mmol), BBr 3 In DCM (6.0 ml,3.0 mmol), which was prepared in the same manner as Compound 1B in example 1-1 to give 2B-1.
Example 24
Figure BDA0002795362070000121
Compound 2A-2 (121.0 mg, yield: 60%) was obtained by substituting 1- (3-chlorophenyl) piperazine (120.0 mg,0.6 mmol) for 1- (2-chlorophenyl) piperazine used in example 23 and making reference to example 23.
Preparation of Compound 2B-2 reference example 23 was made to the preparation of Compound 2B-1.
Example 25
Figure BDA0002795362070000122
Reference example 23 was repeated except for using 1- (2, 3-dichlorophenyl) piperazine) (140.0 mg,0.6 mmol) instead of 1- (2-chlorophenyl) piperazine used in example 23 to obtain compound 2A-3 (135.0 mg, yield: 72%).
Preparation of Compound 2B-3 reference example 23 was made to the preparation of Compound 2B-1.
Example 26
Figure BDA0002795362070000123
Reference example 23 was repeated except for using 4,4' -difluorobenzylpiperazine (173.0 mg,0.6 mmol) in place of 1- (2-chlorophenyl) piperazine used in example 23 to obtain compound 2A-4 (125.0 mg, yield: 50%).
Preparation of Compound 2B-4 reference example 23 was made to the preparation of Compound 2B-1.
Example 27
Figure BDA0002795362070000124
Figure BDA0002795362070000131
3, 4-Dimethoxybenzoic acid (Compound 5) (100.0mg, 0.5mmol), N-Boc-piperazine (150.0mg, 0.6 mmol), pyBOP (312.2mg, 0.6 mmol), DIEA (1.0ml, 2.0mmol), the same procedure as Compound 1A-4, was recrystallized from 95% EtOH to give intermediate g.
Intermediate g (125.0mg, 0.5mmol), 2, 3-dichlorobenzoic acid (115.0mg, 0.6mmol), pyBOP (312.2mg, 0.6mmol), DIEA (1.0ml, 2.0mmol), the same procedure as for compound 1A-4, gave 2A-5 (128.0 mg, yield: 65%).
Preparation of Compound 2B-5 reference example 23 was made to the preparation of Compound 2B-1.
Example 28
Figure BDA0002795362070000132
Compound 2A-6 (112 mg, yield: 70%) was obtained by referring to example 27 except that 3, 4-dichlorobenzoic acid (115.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 27.
Preparation of Compound 2B-6 reference example 23 was made to the preparation of Compound 2B-1.
Example 29
Figure BDA0002795362070000133
Compound 2A-7 (126.0 mg, yield: 66%) was obtained in referential example 27 except that 3,4, 5-trifluorobenzoic acid (110.0 mg,0.6 mmol) was used instead of 2, 3-dichlorobenzoic acid used in example 27.
Preparation of Compound 2B-7 reference example 23 was made to the preparation of Compound 2B-1.
Example 30
Figure BDA0002795362070000134
Trans-cinnamic acid (100.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 27, and reference was made to example 27 to obtain compound 2A-8 (104.0 mg, yield: 50%).
Preparation of Compound 2B-8 reference example 23 was made to the preparation of Compound 2B-1.
Example 31
Figure BDA0002795362070000135
Phenoxyacetic acid (100.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 27, and reference example 27 was otherwise made to obtain compound 2A-9 (130.0 mg, yield: 66%).
Preparation of Compound 2B-9 reference example 23 was made to the preparation of Compound 2B-1.
Example 32
Figure BDA0002795362070000141
Compound 2A-10 (116.0 mg, yield: 60%) was obtained by substituting 2, 4-dichlorophenoxyacetic acid (135.0 mg,0.6 mmol) for 2, 3-dichlorobenzoic acid used in example 27 and making reference to example 27.
Preparation of Compound 2B-10 reference example 23 was made to the preparation of Compound 2B-1.
Example 33
Figure BDA0002795362070000142
2, 3-Dimethoxybenzoic acid (Compound 6) (100.0mg, 0.5mmol), 1- (2-chlorophenyl) piperazine (120.0mg, 0.6mmol), pyBOP (312.2mg, 0.6mmol), DIEA (1.0ml, 2.0mmol), the same as in the case of the Compound 1A-4 in example 4, gave 2C-1 (116.0 mg, yield: 65%).
2C-1 (100.0mg, 0.3mmol), BBr was weighed 3 Was dissolved in DCM (6.0 ml,3.0 mmol) in the same manner as in the production of Compound 1B-1 in example 1 to obtain 2D-1.
Example 34
Figure BDA0002795362070000143
Reference example 33 was repeated except for using 1- (3-chlorophenyl) piperazine (120.0 mg,0.6 mmol) instead of 1- (2-chlorophenyl) piperazine used in example 33 to obtain compound 2C-2 (113.0 mg, yield: 60%).
Preparation of Compound 2D-2 reference example 33 was made to the preparation of Compound 2D-1.
Example 35
Figure BDA0002795362070000144
Reference example 33 was repeated except for using 1- (2, 3-dichlorophenyl) piperazine (140.0 mg,0.6 mmol) instead of 1- (2-chlorophenyl) piperazine used in example 33 to obtain compound 2C-3 (136.0 mg, yield: 77%).
Preparation of Compound 2D-3 reference example 33 was made to the preparation of Compound 2D-1.
Example 36
Figure BDA0002795362070000145
Instead of 1- (2-chlorophenyl) piperazine used in example 33, 4' -difluorodibenzylpiperazine (173.0 mg,0.6 mmol) and the other reference example 33 were used to obtain compound 2C-4 (126.0 mg, yield: 50%).
Preparation of Compound 2D-4 reference example 33 was made to the preparation of Compound 2D-1.
Example 37
Figure BDA0002795362070000151
2, 3-Dimethoxybenzoic acid (Compound 6) (100.0mg, 0.5mmol), N-Boc-piperazine (150.0mg, 0.6 mmol), pyBOP (312.2mg, 0.6 mmol), DIEA (1.0ml, 2.0mmol), the same procedure as for the compounds 1A-4 in example 4, gave intermediate i.
Intermediate i (150.0mg, 0.5mmol), 2, 3-dichlorobenzoic acid (compound 5) (115.0mg, 0.6 mmol), pyBOP (312.2mg, 0.6 mmol) and DIEA (1.0ml, 2.0mmol) were weighed out, and 2C-5 (129.0 mg, yield: 70%) was obtained in the same manner as in compound 1A-4 of example 4.
Preparation of Compound 2D-5 reference example 33 was made to the preparation of Compound 2D-1.
Example 38
Figure BDA0002795362070000152
Compound 2C-7 (114.0 mg, yield: 72%) was obtained in referential example 35 except that 3,4, 5-trifluorobenzoic acid (110.0 mg,0.6 mmol) was used instead of 2, 3-dichlorobenzoic acid used in example 35.
Preparation of Compound 2D-7 reference example 33 was made to the preparation of Compound 2D-1.
Example 39
Figure BDA0002795362070000153
Trans-cinnamic acid (100.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 35, and reference was made to example 35 to obtain compound 2C-8 (126.0 mg, yield: 66%).
Preparation of Compound 2D-8 reference example 33 was made to the preparation of Compound 2D-1.
Example 40
Figure BDA0002795362070000161
Compound 2C-10 (123.0 mg, yield: 60%) was obtained by substituting 2, 4-dichlorophenoxyacetic acid (135.0 mg,0.6 mmol) for 2, 3-dichlorobenzoic acid used in example 35 and making reference to example 35.
Preparation of Compound 2D-10 reference example 33 was made to the preparation of Compound 2D-1.
EXAMPLE 41
Synthesis method of compound (4- (2, 3-dichlorphenyl) piperazin-1-yl) (3-methoxyphenyl) methanone (3B-3)
Figure BDA0002795362070000162
3-Methoxybenzoic acid (Compound 9) (100.0mg, 0.65mmol), 1- (2, 3-dichlorophenyl) piperazine (139.0mg, 0.8mmol), pyBOP (416.3mg, 0.8mmol), DIEA (1.0ml, 2.0mmol), the same procedure as in Compound 1A-4 in example 4, gave 3B-3 (126 mg, yield: 79%).
The structures, NMR and MS data of the compounds prepared in examples 1 to 41 are shown in table 1:
TABLE 1
Figure BDA0002795362070000163
Figure BDA0002795362070000171
Figure BDA0002795362070000181
Figure BDA0002795362070000191
Figure BDA0002795362070000201
Figure BDA0002795362070000211
Figure BDA0002795362070000221
Figure BDA0002795362070000231
Figure BDA0002795362070000241
Figure BDA0002795362070000251
Figure BDA0002795362070000261
Example 42
Materials and methods for pharmacological experiments
Instruments and reagents: a Multiskan MK3 type enzyme standard detector (product of Finland laboratories) is adopted; SW-CT-IF model ultra-clean bench (Suzhou Antai air technology Co., ltd.); inverted microscope (product of Amersham Pharmacia); microsyringe (Finnpette product of finland); 96-well cell culture plates (product of Nunclon, denmark); MJX type intelligent mould incubator (ningbo south of the Yangtze river instrument factory); a waterproof electric heating constant temperature incubator (Shanghai leap into medical instrument factories); THZ-82A desk type constant temperature oscillator (Shanghai leap into medical instrument factory).
Fluconazole (FLC) injection (specification: 5ml; dimethyl sulfoxide (DMSO, chemical agents ltd, chinese national drug group); baicalein (BE, annagi reagent, inc.); gallic acid (GA, adamas).
The test strains are: drug-resistant candida albicans (c.albicans 901 and c.albicans 904) were obtained and biologically and morphologically identified in the long-sea hospital flora storage center. Activating all tested strains by a Sabouraud's Dextrose Agar (SDA) culture medium, culturing for 2 weeks at a constant temperature of 30 ℃, then activating a monoclonal scratch board again, selecting a monoclonal Sabouraud's dextrose agar culture medium inclined plane obtained after secondary activation, culturing by adopting the culture method, and storing in a refrigerator at 4 ℃ for standby.
Culture solution
1. Sa's glucose agar solid medium (SDA)
Sabouraud dextrose agar medium (SDA) composition (g/L): glucose (40.0 g), peptone (10.0 g) and agar (15.0 g), adjusting the pH value of the culture medium to 7.0 +/-0.1, heating and stirring to dissolve in 900.0ml of sterile triple distilled water, fixing the volume to 1.0L, sterilizing at 121 ℃ for 20min under high pressure, cooling to about 30 ℃, transferring to a sterile culture dish, and storing in a refrigerator at 4 ℃ for later use.
RPMI 1640 liquid Medium
RPMI-1640 liquid medium (g/L): morpholine propanesulfonic acid (17.25 g), RPMI 1640 (5.0 g), naHCO 3 (1.0 g) is heated, stirred and dissolved in 450.0ml of sterile triple distilled water, the volume is constant to 500.0ml, the solution is micro-filtered and subpackaged in a 250.0ml triangular flask by a 0.22 mu m microporous membrane, and the solution is preserved in a refrigerator at 4 ℃ for standby.
YEPD culture solution
YEPD culture solution (g/L): heating peptone (20.0 g), glucose (20.0 g) and yeast extract (10.0 g), stirring, dissolving in 900.0ml sterile triple distilled water, diluting to constant volume of 1.0L, autoclaving at 121 deg.C for 20min, cooling to about 30 deg.C, transferring to sterile culture dish, and storing in refrigerator at 4 deg.C for use.
Experimental methods
Strain activation: and dipping a small amount of-80 ℃ frozen bacteria liquid by using an inoculating ring, inoculating the frozen bacteria liquid on a sterile SDA culture medium for storage at a temperature of 4 ℃ in a refrigerator, culturing the bacteria liquid in an incubator at a temperature of 30 ℃ for 48 hours, and storing the bacteria liquid in the refrigerator at a temperature of 4 ℃ for later use.
Preparation of the fungal suspension: before the experiment, the activated candida albicans is selected from a sterile SDA culture medium stored in a refrigerator at 4 ℃ by using an inoculating loop, inoculated into 1.0ml of sterile YEPD liquid culture solution, and subjected to shaking activation culture at 200rpm in an incubator at 30 ℃ for 16h, so that the fungus is in the later period of exponential growth phase. Sucking the bacteria solution into 1.0ml sterile YEPD culture solution with pipette gun, repeating the above method, activating and culturing for 16 hr, counting fungus number with blood count plate, diluting with sterile RPMI-1640 liquid culture medium, and adjusting bacteria solution concentration to 1 × 10 3 -5×10 3 CFU/ml rangeThe inside is surrounded.
Preparing a drug sensitive reaction plate: sterile RPMI 1640 liquid medium (100.0 μ l) was added to each row of No. 1 well of the sterile 96-well plate as a blank; test compound solution (40.0. Mu.l) and bacterial solution (160.0. Mu.l) were added to well No. 2 in this order; the bacteria solution (100.0. Mu.l) was added to wells 3-12, and the bacteria solution (100.0. Mu.l) alone was added to well 12 as a positive control. The final drug concentration in each well was 64.0, 32.0, 16.0, 8.0, 4.0, 2.0, 1.0, 0.5, 0.25 and 0.125. Mu.g/ml by dilution sequentially through wells No. 2-11, all with DMSO content below 1.0%. The final concentration of the fluconazole solution was 8.0 μ g/ml, and the MIC value of the test compound in combination with fluconazole (8.0 μ g/ml) was obtained. Under the same condition, a batch of drug sensitive plates of quality control bacteria need to be prepared, and all the drug sensitive plates are cultured in a constant temperature box at 30 ℃ for 24h.
Determination of Minimum Inhibitory Concentration (MIC): and measuring the OD value of each hole of the drug sensitive plate cultured under the constant temperature condition by using an enzyme-labeled analyzer at the wavelength of 620 nm. The positive control well 12 had an OD of about 0.2. And comparing with the above value, when the OD value of each other hole is reduced by more than 80%, the corresponding lowest concentration is the MIC value (the minimum drug concentration for inhibiting the growth of 80% fungi). If the MIC value of the drug is not in the measurement range, counting is performed according to the following rule: when the MIC value is lower than the lowest concentration of 0.125. Mu.g/ml, the value is calculated to be ≦ 0.125. Mu.g/ml, and when the MIC value exceeds the highest concentration of 64.0. Mu.g/ml, the value is calculated to be ≦ 64.0. Mu.g/ml. Repeating the parallel operation for three times, and taking a relatively high concentration as an MIC value when the adopted MIC value can be accurately repeated or the difference between the two is one concentration unit; if the MIC values in the test are different by more than two concentration units, the above operation needs to be carried out again until the requirements are met.
Quality control bacteria: the experimental reference adopts candida parapsilosis ATCC18062 as a quality control bacterium, and the MIC value reference value is as follows: FLC:0.25-1.0 μ g/ml; amB:0.5-2.0 μ g/ml. Such strains are used as reference in each experiment, and when the actually measured MIC value is kept in the range, the experimental operation is confirmed to be accurate, and the result is reliable. Therefore, only when the experimental strain and the control strain grow well under the same conditions, the experiment is successful, and the result is reliable.
Evaluation of drug efficacy of combination drug: the combined effect of the two drugs was evaluated in this experiment with reference to the Fractional Inhibitory Concentration Index (FICI) as specified in the M27-A3 and M38-A2 standard tests for CLSI. The fractional inhibitory concentration index (FICII) as a major parameter of the interaction pattern of the two drugs in combination can be used to explain the interaction pattern of antifungal drugs. Calculation formula of FICI index: FICI index = MIC (combination A)/MIC (combination A) + MIC (combination B)/MIC (combination B) (when MIC is used alone) 80 Values above the detection ceiling are used to calculate the FICI at twice the ceiling concentration). The latest standard adopted by current foreign periodicals is as follows: when the FICI is less than or equal to 0.5, the two medicines act as a synergistic effect; 0.5<The two medicines have additive action when the FICI is less than or equal to 1; 1<When the FICI is less than or equal to 4, the two medicines have unrelated functions; when FICI>4, the two drugs act as antagonism.
The antifungal activity of the compound is related to the structure-activity: the target compounds prepared in examples 1 to 41 were tested for their in vitro single action and synergistic fluconazole activity against drug-resistant candida albicans, and the results are shown in table 2.
TABLE 2 combination of target compound and fluconazole results of anti-drug-resistant Candida albicans activity test
Figure BDA0002795362070000271
Figure BDA0002795362070000281
Figure BDA0002795362070000291
a Acts on drug-resistant candida albicans 901 in combination with fluconazole (FLC, 8.0 mug/ml); b combined with fluconazole (FLC, 8.0. Mu.g/ml) to act on drug-resistant Candida albicans 904.
A total of 25 target compounds (1B-1, 1D-1, 2D-1, 1B-2, 1D-2, 2D-2, 1B-3, 1D-3, 2D-3, 1B-4, 1D-4, 2B-4, 1B-5, 1D-5, 1B-6, 1D-7, 1B-8, 1D-8, 2D-8, 1B-9, 1D-9, 1B-10, 1D-10, 2D-10) showed individual anti-drug-resistant fungal activity (MIC <128.0 μ g/ml), with compound (2D-2, 2D-10) showing the strongest individual anti-drug-resistant fungal activity and MIC =2.0 μ g/ml. A total of 37 compounds of interest (1B-1, 1D-1, 2D-1, 1B-2, 1D-2, 2D-2, 1B-3, 1D-3, 2D-3, 1B-4, 1D-4, 2B-4, 1B-5, 1D-5, 1B-6, 1D-7, 1B-8, 1D-8, 2D-8, 1B-9, 1D-9, 1B-10, 1D-10, 2B-1, 2B-2, 2B-3, 2B-5, 2D-5, 2B-6, 1B-7, 2D-7, 2B-8, 1B-11, 1D-11) showed synergistic antifungal activity with fluconazole, wherein compound (2D-5,2b-10610) showed the strongest inhibitory activity against fluconazole = 0.6 g/ml, fic/ml. In addition, 2 target compounds (1B-10, 1D-10) showed addition activity.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (3)

1. A substituted benzoyl piperazine compound or its medicinal salt, characterized by that, said substituted benzoyl piperazine compound is one of the following structures:
Figure FDA0003844188040000011
2. the application of the substituted benzoyl piperazine compound or the medicinal salt thereof in preparing antifungal medicaments is characterized in that the fungus is candida albicans;
the substituted benzoyl piperazine compound is one of the following structures:
Figure FDA0003844188040000012
3. the application of substituted benzoyl piperazine compounds or medicinal salts thereof in preparing synergetic fluconazole antifungal medicines is characterized in that fungi are candida albicans;
the substituted benzoyl piperazine compound is one of the following structures:
Figure FDA0003844188040000021
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