CN118515629A - Substituted benzoyl piperazine compound and application thereof - Google Patents

Substituted benzoyl piperazine compound and application thereof Download PDF

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CN118515629A
CN118515629A CN202410271622.1A CN202410271622A CN118515629A CN 118515629 A CN118515629 A CN 118515629A CN 202410271622 A CN202410271622 A CN 202410271622A CN 118515629 A CN118515629 A CN 118515629A
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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
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    • 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
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    • 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
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    • 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
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    • 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

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Abstract

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

Description

Substituted benzoyl piperazine compound and application thereof
The application is a divisional application of the following original divisional application: the application date is 11/24/2020, the application number is 202210949547.0, and the application name is a substituted benzoyl piperazine compound and application thereof; this original divisional application is a divisional application of the following parent application: the application date is 11/24/2020, the application number is 202011329548.2, and the application name is a substituted benzoyl piperazine compound and application thereof. The application relates to a re-filing application of an original filing application according to the examination opinion about the singleness problem in the first examination opinion notice of the original filing application.
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a substituted benzoyl piperazine compound and application thereof.
Background
The antibacterial effect of natural products is widely focused, and the natural products become research hot spots for searching antifungal new drugs and lead compounds thereof in recent years due to the characteristics of novel structure, strong biological activity and low toxicity. Gallic acid (GALLIC ACID), also known as gallic acid or gallic acid, i.e. 3,4, 5-trihydroxybenzoic acid, is an organic acid present in plants such as gallnut, lacquer tree, tea, etc. The literature reports that it has antibacterial, antiviral, antitumor, etc. effects. Based on the above, series of substituted benzoyl piperazine compounds are designed and synthesized, and the individual and synergistic antifungal effects of the compounds are evaluated, so that a foundation is provided for further research and development of antifungal medicines.
Disclosure of Invention
The first object of the invention is to provide a substituted benzoyl piperazine compound.
The second object of the invention is to provide an application of the substituted benzoyl piperazine compound in preparing antifungal medicines.
In order to achieve the above 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 pharmaceutically acceptable salt thereof, which has the following structural general formula:
R 1、R2、R3、R4、R5 is independently selected from hydrogen, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and halogen;
X is selected from C or N;
y is selected from one of the following groups:
R6、R7、R8、R9、R10、R11、R12、R13、R14、R15 Each independently selected from hydrogen, hydroxy, halogen (fluorine, chlorine, bromine, iodine), C1-C10 alkyl, C1-C10 alkoxy.
More preferably, the substituted benzoyl piperazine compound is one of the following structures:
r 1、R2、R3、R4、R5 is independently selected from hydrogen, hydroxyl and C1-C10 alkoxy;
R6、R7、R8、R9、R10、R11、R12、R13、R14、R15 Each independently selected from hydrogen, hydroxy, halogen (fluorine, chlorine, bromine, iodine), C1-C10 alkyl, C1-C10 alkoxy.
More preferably, the substituted benzoylpiperazine compound comprises:
R 1、R2、R3 is hydroxy at the same time, and R 4、R5 is hydrogen at the same time;
or, R 1、R2 is hydroxy at the same time and R 3、R4、R5 is hydrogen at the same time;
Or, R 2、R3 is hydroxy at the same time and R 1、R4、R5 is hydrogen at the same time;
Or, R 2、R3、R4 is hydroxy at the same time and R 1、R5 is hydrogen at the same time;
Or, R 2 is methoxy, and R 1、R4、R5、R3 is hydrogen at the same time;
Further preferably, the substituted benzoylpiperazine compound comprises:
R6、R7、R8、R9、R10、R11、R12、R13、R14、R15 Each independently selected from hydrogen, fluorine, chlorine.
Most preferably, the substituted benzoylpiperazine compound is one of the following structures:
The third aspect of the invention provides an application of the substituted benzoyl piperazine compound or the medicinal salt thereof in preparing antifungal medicines.
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 the following components: hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid; preferred organic acids include: formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1, 5), asiatic 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, diethyl acetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids.
By adopting the technical scheme, the invention has the following advantages and beneficial effects:
The substituted benzoyl piperazine compound has better antifungal activity, especially to drug-resistant candida albicans, and has obvious effect when being singly used. In addition, when the compound pesticide is combined with fluconazole, fungi which are originally resistant to the azole can be sensitized to the azole, the dosage of the azole is reduced, the curative effect of the azole is improved, and the synergistic effect is achieved.
Detailed Description
In order to more clearly illustrate the present invention, the present invention will be further described with reference to preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and that this invention is not limited to the details given herein.
The materials used in the examples of the present invention are as follows: bruker SPECTMSPIN AC-P300 (Bruker, switzerland) was used; AC-P600 nmr (Bruker, switzerland); agilent 6120 LC-MS coupled mass spectrometer (Agilent Co., USA); silica gel plate GF254 (plummet yellow sea chemistry, china); a dark box type ultraviolet analyzer (model ZF-20D); a rotary evaporator (Buchi Rotavapor R-3 model); SHB-III circulating type multipurpose vacuum pump; vacuum drying oven (DZF-6021 type); ultrasonic cleaners (KQ-500E type); reagents (analytically pure) and raw materials used in the experiments were purchased from An Naiji reagent limited, carboline technologies limited, pichia medicine technologies limited, exploration platforms, etc.
Example 1
Preparation of Compound 1B-1:
3,4, 5-trimethoxybenzoic acid (compound 1) (100.0 mg,0.5 mmol) was placed in a 100ml round bottom flask, dissolved by adding DCM (10.0 ml, dichloromethane), then 1- (2-chlorophenyl) piperazine (120.0 mg,0.6 mmol), DCC (124.0 mg,0.6mmol, N' -dicyclohexylcarbodiimide), DMAP (244.0 mg,2.0 mmol) were added sequentially and stirred at room temperature for 6h, the solution was observed to become cloudy by clarification, and TLC detection (DCM: meOH=10:1) was performed after the reaction was completed. Filtration, evaporation of the filtrate under reduced pressure, and recrystallization from 95% EtOH gave Compound 1A-1 (111.0 mg, yield: 56%).
Placing compound 1A-1 (100.0 mg,0.3 mmol) in a 100ml round bottom three-mouth bottle, adding anhydrous DCM (10.0 ml) under the protection of anhydrous anaerobic argon, dropwise adding DCM solution (6.0 ml,3.0 mmol) of BBr 3 at a constant speed of two drops per second at the temperature of minus 30 ℃, stirring overnight after the dropwise adding, moving the reaction device to room temperature, detecting by TLC (DCM: meOH=10:1), adding 100.0ml of water for quenching after the reaction is finished, stirring for 1h at room temperature, then observing whether solid is precipitated or not, filtering if solid is precipitated, and placing a filter cake in an oven for drying; if no solid is precipitated, EA is extracted three times, the organic phases are combined, dried over anhydrous sodium sulfate, and the organic phase is evaporated to dryness and recrystallized from DCM or EtOH to give compound 1B-1.
Example 2
Preparation of Compound 1B-2:
1- (2-chlorophenyl) piperazine used in example 1 was replaced with 1- (3-chlorophenyl) piperazine (120.0 mg,0.6 mmol), and other reference example 1 gave compound 1A-2 (123.0 mg, yield: 61%). Preparation of Compound 1B-2 reference was made to the preparation of Compound 1B-1 in example 1.
Example 3
1- (2-Chlorophenyl) piperazine used in example 1 was replaced with 1- (2, 3-dichlorophenyl) piperazine (140.0 mg,0.6 mmol), and other reference example 1 gave compounds 1A-3 (107.0 mg, yield: 58%). Preparation of Compound 1B-3 reference was made to the preparation of Compound 1B-1 in example 1.
Example 4
3,4, 5-Trimethoxybenzoic acid (Compound 1) (100.0 mg,0.5 mmol) was placed in a 100ml round bottom flask, DMF (10.0 ml) was added to dissolve it, then 4,4' -difluorodibenzopiperazine (173.0 mg,0.6 mmol), pyBOP (312.2 mg,0.6 mmol) and DIEA (1.0 ml,2.0 mmol) were added sequentially, stirred for 4h at room temperature after addition, TLC detection (DCM: meOH=10:1) was performed, and the reaction was completed. 100.0ml of water was added thereto to quench, and the mixture was stirred at room temperature for 1 hour to examine whether or not a solid precipitated, and the solid precipitated was filtered, and the cake was dried in an oven and recrystallized from 95% EtOH to give Compound 1A-4 (118.0 mg, yield: 60%).
Preparation of Compound 1B-4 reference was made to the preparation of Compound 1B-1 in example 1.
Example 5
3,4, 5-Trimethoxybenzoic acid (Compound 1) (100.0 mg,0.5 mmol), N-Boc-piperazine (150.0 mg,0.6 mmol), pyBOP (312.2 mg,0.6 mmol) and DIEA (1.0 ml,2.0 mmol) were added and stirred at room temperature for 4h after the addition was complete, and TLC detection (DCM: meOH=10:1) was performed. 100.0ml of water was added to quench, stirred at room temperature for 1h, filtered and the cake recrystallized from 95% EtOH to give intermediate a. The product was weighed, dissolved in hydrochloric acid-ethyl acetate solution in an equivalent ratio of 1:3, stirred at room temperature, checked by TLC (DCM: meoh=10:1), filtered after the reaction was completed and recrystallized from 95% etoh to give intermediate b.
Intermediate b (140.0 mg,0.5 mmol), 2, 3-dichlorobenzoic acid (115.0 mg,0.6 mmol), pyBOP (312.2 mg,0.6 mmol) and DIEA (1.0 ml,2.0 mmol) gave compound 1A-5121.0mg (yield: 59%) as compound 1A-4.
Preparation of Compound 1B-5 reference example 1 was made to the preparation of Compound 1B-1.
Example 6
The 2, 3-dichlorobenzoic acid used in example 5 was replaced with 3, 4-dichlorobenzoic acid (115.0 mg,0.6 mmol), and compound 1A-6 (115.0 mg, yield: 58%) was obtained according to other reference example 5. Preparation of Compound 1B-6 reference was made to the preparation of Compound 1B-1 in example 1.
Example 7
The 2, 3-dichlorobenzoic acid used in example 5 was replaced with 3,4, 5-trifluorobenzoic acid (110.0 mg,0.6 mmol), and other reference example 5 gave compound 1A-7 (120.0 mg, yield: 65%). Preparation of Compound 1B-7 reference was made to the preparation of Compound 1B-1 in example 1.
Example 8
2, 3-Dichlorobenzoic acid used in example 5 was replaced with trans-cinnamic acid (100.0 mg,0.6 mmol), and Compound 1A-8 (116.0 mg, yield: 59%) was obtained according to other reference example 5. Preparation of Compound 1B-8 reference was made to the preparation of Compound 1B-1 in example 1.
Example 9
Replacement of 2, 3-dichlorobenzoic acid used in example 5 with phenoxyacetic acid (100.0 mg,0.6 mmol) gave compound 1A-9 (130.0 mg, yield: 75%) with other reference to example 5. Preparation of Compound 1B-9 reference was made to the preparation of Compound 1B-1 in example 1.
Example 10
2, 3-Dichlorobenzoic acid used in example 5 was replaced with 2, 4-Dichlorophenoxy acetic acid (135.0 mg,0.6 mmol), and Compound 1A-10 (109.0 mg, yield: 58%) was obtained according to other reference example 5. Preparation of Compounds 1B-10 reference was made to the preparation of Compounds 1B-1 in example 1.
Example 11
Compound c (163.0 mg,0.6 mmol) was placed in a 100ml round bottom flask and dissolved by adding DMF (10.0 ml), then 3,4, 5-trimethoxybenzoic acid (compound 1) (100.0 mg,0.5 mmol) was added in sequence, pyBOP (312.2 mg,0.6 mmol) was added, DIEA (1.0 ml,2.0 mmol) was added, stirring was carried out for 2h at room temperature after addition was complete, TLC detection (DCM: meOH=10:1) was carried out, and the reaction was completed. 100.0ml of water was added thereto to quench, and the mixture was stirred at room temperature for 1 hour to examine whether or not a solid precipitated, and the solid precipitated was filtered, and the cake was dried in an oven and recrystallized from 95% EtOH to give 1A-11 (138.0 mg, yield: 78%).
Preparation of Compound 1B-11 reference was made to the preparation of Compound 1B-1 in example 1.
Example 12
2,3, 4-Trimethoxybenzoic acid (Compound 4) (100.0 mg,0.5 mmol), 1- (2-chlorophenyl) piperazine (120.0 mg,0.6 mmol), DCC (124.0 mg,0.6 mmol), DMAP (244.0 mg,2.0 mmol), and Compound 1C-1 (102.0 mg, yield: 48%) were obtained in the same manner as in example 1.
Compound 1C-1 (100.0 mg,0.3 mmol), BBr 3 in DCM (6.0 ml,3.0 mmol), was prepared as compound 1B-1 in example 1 to give compound 1D-1.
Example 13
1- (3-Chlorophenyl) piperazine (120.0 mg,0.6 mmol) was used instead of 1- (2-chlorophenyl) piperazine used in example 12, and other reference example 12 gave 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
1- (2, 3-Dichlorophenyl) piperazine (140.0 mg,0.6 mmol) was used in place of 1- (2-chlorophenyl) piperazine used in example 12, and other reference example 12 gave compound 1C-3 (109.0 mg, yield: 50%).
Preparation of Compound 1D-3 reference example 12 was made to the preparation of Compound 1D-1.
Example 15
2,3, 4-Trimethoxybenzoic acid (Compound 4) (100.0 mg,0.5 mmol), 4' -difluorodibenzopiperazine (173.0 mg,0.6 mmol), pyBOP (312.2 mg,0.6 mmol), DIEA (1.0 ml,2.0 mmol), compound 1C-4 (117.0 mg, yield: 58%) was obtained in the same manner as in example 4 as 1A-4.
Preparation of Compound 1D-4 reference example 12 was made to the preparation of Compound 1D-1.
Example 16
2,3, 4-Trimethoxybenzoic acid (Compound 4) (100.0 mg,0.5 mmol), N-Boc-piperazine (150.0 mg,0.6 mmol), pyBOP (312.2 mg,0.6 mmol), DIEA (1.0 ml,2.0 mmol), were taken in the same manner as intermediate b of example 5 to give intermediate e.
Intermediate e (140.0 mg,0.5 mmol), 2, 3-dichlorobenzoic acid (115.0 mg,0.6 mmol), pyBOP (312.2 mg,0.6 mmol), DIEA (1.0 ml,2.0 mmol) was weighed out, and 1C-5 (135.0 mg, yield: 79%) was obtained in the same manner as in 1A-4 of example 4.
Preparation of Compound 1D-5 reference example 12 preparation of Compound 1D-1.
Example 17
3, 4-Dichlorobenzoic acid (115.0 mg,0.6 mmol) was used in place of 2, 3-Dichlorobenzoic acid used in example 16, and Compound 1C-6 (124.0 mg, yield: 68%) was obtained according to other reference example 16.
Preparation of Compound 1D-6 reference example 12 was made to the preparation of Compound 1D-1.
Example 18
3,4, 5-Trifluorobenzoic acid (110.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 16, and other reference example 16 gave 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
Trans-cinnamic acid (100.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 16, and compound 1C-8 (130.0 mg, yield: 78%) was obtained according to other reference example 16.
Preparation of Compound 1D-8 reference example 12 was made to the preparation of Compound 1D-1.
Example 20
The 2, 3-dichlorobenzoic acid used in example 16 was replaced with phenoxyacetic acid (100.0 mg,0.6 mmol), and Compound 1C-9 (139.0 mg, yield: 75%) was obtained according to other reference example 16.
Preparation of Compounds 1D-9 reference example 12 preparation of Compound 1D-1.
Example 21
2, 4-Dichlorophenoxy acetic acid (135.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 16, and Compound 1C-10 (125.0 mg, yield: 70%) was obtained according to other reference example 16.
Preparation of Compounds 1D-10 reference example 12 preparation of Compound 1D-1.
Example 22
Intermediate C (163.0 mg,0.6 mmol), 2,3, 4-trimethoxybenzoic acid (compound 4) (100.0 mg,0.5 mmol), pyBOP (312.2 mg,0.6 mmol), DIEA (1.0 ml,2.0 mmol) was weighed out to give 1C-11 (134.0 mg, yield: 70%) as compound 1A-4.
Preparation of Compound 1D-11 reference example 12 was made to the preparation of Compound 1D-1.
Example 23
3, 4-Dimethoxybenzoic acid (Compound 5) (100.0 mg,0.5 mmol), 1- (2-chlorophenyl) piperazine (120.0 mg,0.6 mmol), pyBOP (312.2 mg,0.6 mmol), DIEA (1.0 ml,2.0 mmol), and Compound 1A-4 were prepared to give 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), gave 2B-1 as compound 1B-1 in example 1.
Example 24
1- (3-Chlorophenyl) piperazine (120.0 mg,0.6 mmol) was used instead of 1- (2-chlorophenyl) piperazine used in example 23, and other reference example 23 gave compound 2A-2 (121.0 mg, yield: 60%).
Preparation of Compound 2B-2 reference example 23 was made to the preparation of Compound 2B-1.
Example 25
1- (2, 3-Dichlorophenyl) piperazine) (140.0 mg,0.6 mmol) was used instead of 1- (2-chlorophenyl) piperazine used in example 23, and other reference example 23 gave 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
4,4' -Difluorobenzopiperazine (173.0 mg,0.6 mmol) was used in place of 1- (2-chlorophenyl) piperazine used in example 23, and other reference example 23 gave 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
3, 4-Dimethoxybenzoic acid (Compound 5) (100.0 mg,0.5 mmol), N-Boc-piperazine (150.0 mg,0.6 mmol), pyBOP (312.2 mg,0.6 mmol), DIEA (1.0 ml,2.0 mmol), and Compound 1A-4 were recrystallized from 95% EtOH to give intermediate g.
Intermediate g (125.0 mg,0.5 mmol), 2, 3-dichlorobenzoic acid (115.0 mg,0.6 mmol), pyBOP (312.2 mg,0.6 mmol), DIEA (1.0 ml,2.0 mmol), 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
3, 4-Dichlorobenzoic acid (115.0 mg,0.6 mmol) was used in place of 2, 3-Dichlorobenzoic acid used in example 27, and Compound 2A-6 (112 mg, yield: 70%) was obtained according to other reference example 27.
Preparation of Compound 2B-6 reference example 23 was made to the preparation of Compound 2B-1.
Example 29
3,4, 5-Trifluorobenzoic acid (110.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 27, and other reference example 27 gave compound 2A-7 (126.0 mg, yield: 66%).
Preparation of Compound 2B-7 reference example 23 was made to the preparation of Compound 2B-1.
Example 30
Trans-cinnamic acid (100.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 27, and compound 2A-8 (104.0 mg, yield: 50%) was obtained according to other reference example 27.
Preparation of Compound 2B-8 reference example 23 was made to the preparation of Compound 2B-1.
Example 31
Phenoxyacetic acid (100.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 27, and compound 2A-9 (130.0 mg, yield: 66%) was obtained according to other reference example 27.
Preparation of Compound 2B-9 reference example 23 was made to the preparation of Compound 2B-1.
Example 32
2, 4-Dichlorophenoxy acetic acid (135.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 27, and compound 2A-10 (116.0 mg, yield: 60%) was obtained according to other reference example 27.
Preparation of Compound 2B-10 reference example 23 was made to the preparation of Compound 2B-1.
Example 33
2, 3-Dimethoxybenzoic acid (Compound 6) (100.0 mg,0.5 mmol), 1- (2-chlorophenyl) piperazine (120.0 mg,0.6 mmol), pyBOP (312.2 mg,0.6 mmol), DIEA (1.0 ml,2.0 mmol), and Compound 1A-4 of example 4 were synthesized to give 2C-1 (116.0 mg, yield: 65%).
A solution of 2C-1 (100.0 mg,0.3 mmol) BBr 3 in DCM (6.0 ml,3.0 mmol) was weighed out and the procedure was as for compound 1B-1 in example 1 to give 2D-1.
Example 34
1- (3-Chlorophenyl) piperazine (120.0 mg,0.6 mmol) was used instead of 1- (2-chlorophenyl) piperazine used in example 33, and other reference example 33 gave compound 2C-2 (113.0 mg, yield: 60%).
Preparation of Compound 2D-2 reference example 33 preparation of Compound 2D-1.
Example 35
1- (2, 3-Dichlorophenyl) piperazine (140.0 mg,0.6 mmol) was used in place of 1- (2-chlorophenyl) piperazine used in example 33, and other reference example 33 gave compound 2C-3 (136.0 mg, yield: 77%).
Preparation of Compound 2D-3 reference example 33 preparation of Compound 2D-1.
Example 36
4,4' -Difluorobenzopiperazine (173.0 mg,0.6 mmol) was used in place of 1- (2-chlorophenyl) piperazine used in example 33, and other reference example 33 gave 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
2, 3-Dimethoxybenzoic acid (Compound 6) (100.0 mg,0.5 mmol), N-Boc-piperazine (150.0 mg,0.6 mmol), pyBOP (312.2 mg,0.6 mmol), DIEA (1.0 ml,2.0 mmol), the same procedure as in example 4 was followed to give intermediate i.
Intermediate i (150.0 mg,0.5 mmol), 2, 3-dichlorobenzoic acid (compound 5) (115.0 mg,0.6 mmol), pyBOP (312.2 mg,0.6 mmol), DIEA (1.0 ml,2.0 mmol) was weighed out to give 2C-5 (129.0 mg, yield: 70%) as compound 1A-4 in example 4.
Preparation of Compound 2D-5 reference example 33 preparation of Compound 2D-1.
Example 38
3,4, 5-Trifluorobenzoic acid (110.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 35, and other reference example 35 gave compound 2C-7 (114.0 mg, yield: 72%).
Preparation of Compound 2D-7 reference example 33 was made to the preparation of Compound 2D-1.
Example 39
Trans-cinnamic acid (100.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 35, and compound 2C-8 (126.0 mg, yield: 66%) was obtained according to other reference example 35.
Preparation of Compound 2D-8 reference example 33 was made to the preparation of Compound 2D-1.
Example 40
2, 4-Dichlorophenoxy acetic acid (135.0 mg,0.6 mmol) was used in place of 2, 3-dichlorobenzoic acid used in example 35, and compound 2C-10 (123.0 mg, yield: 60%) was obtained according to other reference example 35.
Preparation of Compound 2D-10 reference example 33 preparation of Compound 2D-1.
Example 41
Synthesis method of compound (4- (2, 3-dichlorophenyl) piperazin-1-yl) (3-methoxyphenyl) methanone (3B-3)
3-Methoxybenzoic acid (Compound 9) (100.0 mg,0.65 mmol), 1- (2, 3-dichlorophenyl) piperazine (139.0 mg,0.8 mmol), pyBOP (416.3 mg,0.8 mmol), DIEA (1.0 ml,2.0 mmol), and Compound 1A-4 of 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
Example 42
Pharmacological test materials and methods
Instrument and reagent: a Multiskan MK3 type enzyme-labeled detector (manufactured by Labsystems, finland) was used; SW-CT-IF ultra-clean bench (sutake air technologies, inc.); inverted microscopes (AMERSHAM PHARMACIA products); microsampler (Finnish FINNPETTE product); 96 well cell culture plates (danish Nunclon product); MJX intelligent mould incubator (Ningbo Jiangnan instruments Co.); a water-proof electrothermal constant temperature incubator (Shanghai inspired medical equipment factory); THZ-82A bench-top constant temperature shaker (Shanghai Zhou medical equipment works).
Fluconazole (Fluconazole, FLC) injection (5 ml:0.2g; pfizer, U.S. Pat.; co., ltd.); dimethyl sulfoxide (DMSO, chinese national chemical reagent limited); baicalein (BE, an Naiji, reagent limited); gallic acid (GA, adamas Co.).
Test strain: drug-resistant candida albicans (c.albicans 901, c.albicans 904) are obtained from the long-sea hospital flora preservation center and are subjected to biological and morphological identification. All the tested strains are subjected to the culture on a culture medium of Saccharopolyster agar (SDA) in a cutting mode, the monoclonal cutting and activating are carried out again after the culture is carried out for 2 weeks at the constant temperature of 30 ℃, the monoclonal Saccharopolyster agar slant obtained after the secondary activation is selected, and after the culture method is adopted for culture, the culture is preserved in a refrigerator at the temperature of 4 ℃ for standby.
Culture solution
1. Saccharum dextrose agar solid medium (SDA)
Composition of glucose agar media (SDA) of Save (g/L): glucose (40.0 g), peptone (10.0 g) and agar (15.0 g), regulating pH value of the culture medium to 7.0+/-0.1, heating, stirring, dissolving in 900.0ml of sterile triple distilled water, fixing volume to 1.0L, sterilizing at 121 ℃ under high pressure for 20min, cooling to about 30 ℃, transferring to a sterile culture dish, and preserving in a refrigerator at 4 ℃ for standby.
RPMI 1640 liquid Medium
RPMI-1640 liquid Medium (g/L): the morpholine propane sulfonic acid (17.25 g), RPMI 1640 (5.0 g) and NaHCO 3 (1.0 g) are heated, stirred and dissolved in 450.0ml of sterile triple distilled water, the volume is fixed to 500.0ml, the solution is micro-filtered and sub-packaged in 250.0ml triangular flasks through a micro-porous filter membrane of 0.22 mu m, and the solution is preserved in a refrigerator at the temperature of 4 ℃ for standby.
YEPD culture solution
YEPD broth (g/L): peptone (20.0 g), glucose (20.0 g) and yeast extract (10.0 g) are heated, stirred and dissolved in 900.0ml of sterile triple distilled water, the volume is fixed to 1.0L, the high pressure sterilization is carried out for 20min at 121 ℃, the cooling is carried out to about 30 ℃, and the mixture is transferred to a sterile culture dish and stored in a refrigerator at 4 ℃ for standby.
Experimental method
Strain activation: inoculating a small amount of frozen bacteria liquid at-80 ℃ with an inoculating loop onto sterile SDA culture medium at 4 ℃ for preservation in a refrigerator, culturing in a 30 ℃ incubator for 48 hours, and returning to the 4 ℃ refrigerator for preservation.
Preparation of fungal suspensions: before the experiment, activated candida albicans is picked from a sterile SDA culture medium which is preserved and used at the temperature of 4 ℃ by an inoculating loop, inoculated into 1.0ml of sterile YEPD liquid culture solution, and subjected to shaking and activating culture for 16 hours at 200rpm in a 30 ℃ incubator, so that fungi are in the later period of exponential growth phase. The bacterial liquid is sucked into 1.0ml of sterile YEPD culture liquid by a liquid-transferring gun, the method is repeated, the fungi are activated and cultured again for 16 hours, the number of the fungi is calculated by a blood cell counting plate, the fungi can be diluted by a sterile RPMI-1640 liquid culture medium, and the concentration of the bacterial liquid is regulated to be in the range of 1 multiplied by 10 3-5×103 CFU/ml.
Preparation of a drug-sensitive reaction plate: sterile RPMI 1640 liquid medium (100.0 μl) was added to each row of wells 1 of a sterile 96-well plate as a blank; test compound solution (40.0. Mu.l) and bacterial solution (160.0. Mu.l) were sequentially added to well No. 2; bacterial liquid (100.0 μl) was added to wells 3-12, wherein no drug was added to wells 12 and only bacterial liquid (100.0 μl) was added as a positive control. The final drug concentration per well was made 64.0, 32.0, 16.0, 8.0, 4.0, 2.0, 1.0, 0.5, 0.25 and 0.125 μg/ml by dilution at ratio 2-11 Kong Yici, respectively, where the DMSO content was all below 1.0%. The final concentration of fluconazole solution was 8.0. Mu.g/ml, and MIC values were obtained for the test compound in combination with fluconazole (8.0. Mu.g/ml). Under the same conditions, a batch of quality control bacteria drug sensitive plates are required to be prepared, and all the drug sensitive plates are cultured for 24 hours at the temperature of 30 ℃ in an incubator.
Determination of Minimum Inhibitory Concentration (MIC): the OD value of each well of the drug sensitive plate cultured at constant temperature was measured at 620nm by an enzyme-labeled analyzer. Wherein the OD of the positive control well No. 12 is about 0.2. And then, in contrast to the above, the OD value of each other hole is reduced by more than 80%, and the corresponding lowest concentration is the MIC value (80% of the minimum drug concentration in which the fungal growth is inhibited). If the MIC value of the drug is not within the measurement range, the following rule is followed: when the MIC value is lower than the minimum concentration of 0.125. Mu.g/ml, the MIC value is calculated to be ". Ltoreq.0.125. Mu.g/ml", and when the MIC value exceeds the maximum concentration of 64.0. Mu.g/ml, the MIC value is calculated to be "> 64.0. Mu.g/ml". Repeating the parallel operation for three times, wherein the adopted MIC value can be accurately repeated or the two MIC values are different by one concentration unit, and the MIC value is taken as a relatively high concentration; if the MIC values differ by more than two concentration units in the test, the above procedure needs to be repeated until the requirements are met.
Quality control bacteria: the experiment reference adopts candida parapsilosis ATCC18062 as quality control bacteria, and MIC value reference value: FLC:0.25-1.0 mug/ml; amB:0.5-2.0 mug/ml. Each experiment uses the strain as a reference, and when the MIC value is actually measured within the range, the experiment operation is accurate, and the result is reliable. Therefore, only when the experimental strain and the control strain grow well under the same condition, the experiment is confirmed to be successful, and the result is reliable.
Drug efficacy evaluation of combination drug: the experiment refers to the evaluation of the combined effect of two drugs by using the partial inhibitory concentration index (FICI) specified by the M27-A3 and M38-A2 standard test of CLSI. The partial inhibitory concentration index (fractional inhibitory concentration index, FICII) is used as a main parameter of the interaction mode of two drugs of the combined drug and can be used for explaining the interaction mode of antifungal drugs. Calculation formula of FICI index: FICI index = MIC (group a combination)/MIC (group a alone) +mic (group B combination)/MIC (group B alone) (the value of twice the maximum concentration was used to calculate the FICI when the MIC 80 value was above the detection ceiling). The latest standard adopted by the current foreign journal: when the FICI is less than or equal to 0.5, the two medicines act synergistically; when FICI is less than or equal to 1 and is 0.5, two medicines are used the action is additive; when FICI is 1 to less than or equal to 4, the two medicines act independently; both drugs act as antagonism when FICI > 4.
Antifungal activity of the compound and structure-activity relationship: the target compounds prepared in examples 1 to 41 were tested for their individual effects in vitro and for their synergistic fluconazole resistance against drug resistant candida albicans, and the results are shown in table 2.
TABLE 2 test results of the combination of the target compound and fluconazole against drug-resistant Candida albicans Activity
a Acting on drug resistant candida albicans 901 in combination with fluconazole (FLC, 8.0 μg/ml); b Acting on drug resistant candida albicans 904 in combination with fluconazole (FLC, 8.0 μg/ml).
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-6、1D-7、1B-8、1D-8、2D-8、1B-9、1D-9、1B-10、1D-10、2D-10、) showed drug-resistant fungal activity alone (MIC <128.0 μg/ml), with compound (2D-2, 2D-10) showing the strongest single drug-resistant fungal activity, MIC = 2.0 μg/ml. A total of 37 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-6、1D-7、1B-8、1D-8、2D-8、1B-9、1D-9、1B-10、1D-10、2D-10、2B-1、2B-2、2B-3、2B-5、2D-5、2B-6、1B-7、2B-7、2D-7、2B-8、1B-11、1D-11) showed synergistic antimycotic activity with fluconazole, with compound (2D-5,2B-5,1B-10) showing the strongest synergistic fluconazole antimycotic activity, mic=0.5 μg/ml, fici=0.066. In addition, 2 target compounds (1B-10, 1D-10) showed additive activity.
The foregoing description is only illustrative of the preferred embodiment of the present invention, and is not to be construed as limiting the invention, but is to be construed as limiting the invention to any and all simple modifications, equivalent variations and adaptations of the embodiments described above, which are within the scope of the invention, may be made by those skilled in the art without departing from the scope of the invention.

Claims (8)

1. A substituted benzoyl piperazine compound or its medicinal salt is characterized by having the following structural general formula:
R 1、R2、R3、R4、R5 is independently selected from hydrogen, hydroxy, C1-C10 alkyl, C1-C10 alkoxy and halogen;
X is selected from C or N;
y is selected from one of the following groups:
R6、R7、R8、R9、R10、R11、R12、R13、R14、R15 Each independently selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, C1-C10 alkoxy.
2. The substituted benzoylpiperazine compound or its pharmaceutically acceptable salt according to claim 1, wherein the substituted benzoylpiperazine compound is one of the following structures:
r 1、R2、R3、R4、R5 is independently selected from hydrogen, hydroxyl and C1-C10 alkoxy;
R6、R7、R8、R9、R10、R11、R12、R13、R14、R15 Each independently selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, C1-C10 alkoxy.
3. The substituted benzoylpiperazine compound or its pharmaceutically acceptable salt according to claim 2, wherein, in the substituted benzoylpiperazine compound:
R 1、R2、R3 is hydroxy at the same time, and R 4、R5 is hydrogen at the same time;
or, R 1、R2 is hydroxy at the same time and R 3、R4、R5 is hydrogen at the same time;
Or, R 2、R3 is hydroxy at the same time and R 1、R4、R5 is hydrogen at the same time;
Or, R 2、R3、R4 is hydroxy at the same time and R 1、R5 is hydrogen at the same time;
Or, R 2 is methoxy, and R 1、R4、R5、R3 is hydrogen at the same time.
4. A substituted benzoylpiperazine compound or its pharmaceutically acceptable salt according to claim 3, wherein ：R6、R7、R8、R9、R10、R11、R12、R13、R14、R15 of the substituted benzoylpiperazine compounds are each independently selected from hydrogen, fluorine, chlorine.
5. The substituted benzoylpiperazine compound or its pharmaceutically acceptable salt according to claim 4, wherein the substituted benzoylpiperazine compound is one of the following structures:
6. Use of a substituted benzoylpiperazine compound, hydrate, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, in the manufacture of an antifungal medicament.
7. Use of a substituted benzoylpiperazine compound, hydrate, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, in the preparation of a synergistic fluconazole antifungal medicament.
8. The use according to claim 6 or 7, wherein the fungus is candida albicans.
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