CN114105986A - Aromatic condensed ring diketone compound and preparation method and application thereof - Google Patents

Aromatic condensed ring diketone compound and preparation method and application thereof Download PDF

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CN114105986A
CN114105986A CN202111472410.2A CN202111472410A CN114105986A CN 114105986 A CN114105986 A CN 114105986A CN 202111472410 A CN202111472410 A CN 202111472410A CN 114105986 A CN114105986 A CN 114105986A
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钱旭红
杨青
邵旭升
袁鹏涛
李忠
徐晓勇
倪新烔
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East China University of Science and Technology
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Abstract

The invention relates to an aromatic condensed ring diketone compound and a preparation method and application thereof, wherein the compound has a structural formula shown as a formula I. Compared with the prior art, the aromatic fused ring diketone compound has the chitinase (such as corn borer chitinase OfChi-h, caenorhabditis elegans chitinase CeCht1, human chitotriose chitinase HsChit1 and the like) inhibitory activity, and the aromatic fused ring diketone compound shows the inhibitory activity on Asian corn borer, human beings, caenorhabditis elegans, aspergillus fumigatus, serratia marcescens chitinase and the like through evaluation and research on the inhibitory effect and selectivity of the compound, so that the aromatic fused ring diketone compound has wide application scenes in the fields of biology and biochemistry.

Description

Aromatic condensed ring diketone compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of chitinase inhibitors, and relates to an aromatic fused ring diketone compound as well as a preparation method and application thereof.
Background
Chitin is an important component of insect exoskeleton and midgut peritrophic membrane, nematode egg shell and fungal cell wall, and is accompanied with synthesis and degradation of chitin in insect molting, nematode hatching and molting and fungal growth processes. The GH18 family chitinase is a key enzyme for hydrolyzing chitin, and plays an indispensable role in bacterial nutrition absorption, fungal cell wall remodeling, nematode ovalization and insect molting. Chitinase, which is involved in insect or nematode molting, causes insect or nematode molting failure and death, and thus chitinase is considered as an important target for developing pesticides.
The human body expresses two chitinases and various chitinase proteins, wherein HsChit1 is related to pulmonary fibrosis, clinical and pharmacological researches find that HsChit1 can be used as a target for treating specific pulmonary fibrosis, and the chitinase AMCase can be used as a target for anti-asthma medicaments. In recent years, with the development of biology and biochemistry, the crystal structures of chitinases OfChi-h and OfChtI, nematode chitinase CeCht1, human chitinase HsChit1, AMCase and Serratia marcescens chitinase SmChiA from corn borer are analyzed, and an important basis is provided for the reasonable design of small-molecule chitinase inhibitors.
Therefore, the chitinase inhibitor is developed aiming at different targets, and has important application prospect in the fields of agriculture and medicine.
Disclosure of Invention
The invention aims to provide an aromatic condensed ring diketone compound and a preparation method and application thereof. The compound has wide application prospect in the aspects of inhibiting and controlling agricultural pests, being used for specific pulmonary fibrosis, resisting fungal infection, inhibiting bacterial growth and the like.
The purpose of the invention can be realized by the following technical scheme:
an aromatic condensed ring diketone compound, which has a structural formula shown in formula I:
Figure BDA0003392996510000021
wherein:
x represents a substituent at any one or more positions on the pyridine ring, and each substituent is independently selected from one of the following groups: H. halogen, cyano, nitro, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted C5-C7Cycloalkenyl, substituted OR unsubstituted phenyl, substituted OR unsubstituted naphthyl, substituted OR unsubstituted 5-OR 6-membered heterocyclyl, substituted OR unsubstituted 8-to 12-membered heteroaromatic bicyclic ring system, ORa、SRa、C(O)Rb、C(O)ORa、NRaRb、S(O)2Ra(ii) a Preferably, X represents a substituent at any one or two positions on the pyridine ring, and each substituent is independently selected from one of the following groups: H. methyl, ethyl, propyl, cyclopropyl, n-butyl, tert-butyl, halogen, cyano, nitro, methoxy; more excellentOptionally, X represents a substituent at any position on the pyridine ring, and X is selected from one of the following groups: H. methyl, ethyl, propyl, cyclopropyl, n-butyl, tert-butyl, halogen.
M is a single bond, or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms, said alkylene group being a linear or branched alkylene group; preferably, M is a single bond, or a substituted or unsubstituted alkylene group having 1 to 5 carbon atoms.
Y is selected from one of the following groups: H. halogen, cyano, nitro, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted C5-C7Cycloalkenyl, substituted OR unsubstituted phenyl, substituted OR unsubstituted naphthyl, substituted OR unsubstituted 5-OR 6-membered heterocyclyl, substituted OR unsubstituted 8-to 12-membered heteroaromatic bicyclic ring system, ORa、SRa、C(O)Rb、C(O)ORa、NRaRb、S(O)2Ra(ii) a Preferably, Y is selected from one of the following groups: halogen, cyano, nitro, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted C5-C7A cycloalkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted indolyl group, a substituted or unsubstituted morpholine ring, a substituted or unsubstituted piperazine ring, a substituted or unsubstituted 5-or 6-membered heterocyclic group, a substituted or unsubstituted 8-to 12-membered heteroaromatic bicyclic ring system.
Further, Ra、RbEach independently selected from one of the following groups: H. substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C7CycloalkanesRadical, substituted or unsubstituted C5-C7Cycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-or 6-membered heterocyclyl, substituted or unsubstituted 8-to 12-membered heteroaromatic bicyclic ring systems.
Further, X, M, Y, Ra、RbWherein said substitution is by one or more of the following groups: halogen, cyano, nitro, R ', OR ', Si (R ')3、NR'R"、C(O)R'、C(O)OR'、C(O)NR'R"、SR'、S(O)mR1、S(O)2NR'R"、OC(O)R1、OC(O)NR'R"、OS(O)2R1、OS(O)2NR'R"、N(R2)C(O)R1、N(R2)C(O)NR'R"、N(R2)S(O)2R1、N(R2)S(O)2NR' R "; preferably, X, M, Y, said substitution is by one or more of the following groups: halogen, cyano, nitro, amino, methoxy, methylthio, C1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6A haloalkynyl group. m is 1 or 2.
Further, R', R "are each independently selected from one of the following groups: H. c1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6Haloalkynyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted C5-C7Cycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocyclyl, substituted or unsubstituted 8-to 12-membered heteroaromatic bicyclic ring system;
R1selected from one of the following groups: c1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6Haloalkynyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted C5-C7A cycloalkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted 5-or 6-membered heterocyclyl group, a substituted or unsubstituted 8-to 12-membered heteroaromatic bicyclic ring system;
R2selected from one of the following groups: H. c1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6Haloalkynyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted C5-C7Cycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-or 6-membered heterocyclyl, substituted or unsubstituted 8-to 12-membered heteroaromatic bicyclic ring systems.
Further, R', R1、R2Wherein said substitution is by one or more of the following groups: halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6Halogenated alkynyl, hydroxy C1-C4Alkyl, OR3、NR3R4、C(O)R3、C(O)OR3、C(O)NR3R4、SR3、S(O)mR5、S(O)2NR3R4、OC(O)R5、OC(O)NR3R4、OS(O)2R5、OS(O)2NR3R4、N(R6)C(O)R5、N(R6)C(O)NR3R4、N(R6)S(O)2R5、N(R6)S(O)2NR3R4(ii) a m is 1 or 2.
Go toStep (d) R3、R4、R6Each independently selected from one of the following groups: H. c1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6Halogenated alkynyl, C1-C6An alkyloxy group;
R5selected from one of the following groups: c1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6A haloalkynyl group.
A preparation method of aromatic condensed ring diketone compounds comprises the following steps:
1) reacting the compound of the formula A with diethyl malonate to obtain a compound of a formula B;
2) reacting the compound shown in the formula B with phosphorus oxychloride to obtain a compound shown in the formula C;
3) reacting the compound shown in the formula C with ammonia water to obtain a compound shown in a formula D;
4) reacting the compound of the formula E with methyl cyanoacetate to obtain a compound of a formula F;
5) reacting the compound of formula D with the compound of formula F to obtain a compound of formula G;
6) reacting the compound of the formula G with N, N-dimethylformamide dimethyl acetal to obtain the aromatic condensed ring diketone compound;
the structural formulas of the compound of the formula A, the compound of the formula B, the compound of the formula C, the compound of the formula D, the compound of the formula E, the compound of the formula F and the compound of the formula G are respectively as follows:
Figure BDA0003392996510000041
an application of aromatic condensed ring diketone compound in preparing chitinase inhibitor. The aromatic condensed ring diketone compound can also be used for preventing and treating diseases taking chitinase as a target spot, used for specific pulmonary fibrosis, asthma, resisting fungal infection, inhibiting bacterial growth and the like, and used for controlling the growth of lepidoptera pests and hatching nematode eggs. Especially for inhibiting the activity of family 18 chitinase, the compound being used at a final concentration of not less than 10 μ M in inhibiting the activity of family 18 chitinase.
An aromatic fused ring diketone derivative is based on the aromatic fused ring diketone compound, and the derivative is an optical isomer, a cis-trans isomer, a pharmaceutically acceptable salt or a solvate of a compound shown in a formula I.
A chitinase inhibitor based on the aromatic fused ring diketone compound, wherein the inhibitor comprises one or more of a compound shown in the formula I, an optical isomer of the compound shown in the formula I, a cis-trans isomer of the compound shown in the formula I, a pharmaceutically acceptable salt of the compound shown in the formula I and a solvate of the compound shown in the formula I.
The aromatic condensed ring diketone compound has a rigid plane structure and a plurality of hydrogen bond acceptors and donors, wherein the rigid plane structure can generate pi-pi accumulation with aromatic amino acid residues exposed in solution in a chitinase binding pocket, and the hydrogen bond acceptors (such as carbonyl oxygen atoms) and the hydrogen bond donors can generate direct or water-mediated hydrogen bond with amino acid in the binding pocket, so that the chitinase inhibition effect is generated.
Compared with the prior art, the invention has the following characteristics:
1) the aromatic fused ring diketone compound has the chitinase (such as corn borer chitinase OfChi-h, caenorhabditis elegans chitinase CeCht1, human chitotriose chitinase HsChit1 and the like) inhibitory activity, and the evaluation and research on the inhibitory effect and selectivity of the compound can show the inhibitory activity on Asian corn borer, human beings, caenorhabditis elegans, aspergillus fumigatus and serratia marcescens chitinases, so that the compound has wide application scenes in the fields of biology and biochemistry.
2) The results of data obtained by the inhibition activity of the inhibitor, including inhibition percentage and inhibition constant determination, show that the structure shows wide inhibition activity and shows certain inhibition activity on OfChi-h, OfChtI, CeCht1, HsChit1, AmCase, AfChiB1 and SmChiA.
3) Particularly, the inhibition rates of the compound I-2 in the corresponding table to OfChi-h, CeCht1, HsChit1 and SmChiA are all over 90 percent, and the compound I-2 inhibits K of the chitinase OfChi-h of the ostrinia nubilalisiK at 58nM for human HsChit1i295nM, K against Serratia marcescens SmChiAiWas 126 nM.
Drawings
FIG. 1 is a test chart of the inhibitory activity of I-2 on Asiatic corn borer chitinase OfChi-h;
FIG. 2 is a test chart of the inhibitory activity of I-2 on human chitotriose chitinase HsChit 1;
FIG. 3 is a test chart of I-2 inhibitory activity against Serratia marcescens chitinase;
FIG. 4 is a test chart of the inhibitory activity of I-28 on Asiatic corn borer chitinase OfChi-h.
Detailed Description
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The term "C1-C6Alkyl "means a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
The term "C2-C6Alkenyl "means a straight or branched chain alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
The term "C2-C6Alkynyl "refers to straight or branched chain alkynyl groups having 2 to 6 carbon atoms, such as ethynyl, propynyl, or the like.
The term "C3-C7Cycloalkyl "refers to a cyclic alkyl group having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.
The term "C5-C7Cycloalkenyl "refers to a cyclic alkenyl group having 5 to 7 carbon atoms with one or more double bonds, such as cyclopentenyl, cyclohexenyl, cycloheptenyl, 1, 3-cyclohexadienyl, 1, 4-cyclohexadienyl, or the like.
The term "C1-C4Alkoxy "means a straight or branched chain alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.
The term "halogen" refers to fluorine, chlorine, bromine, or iodine. The term "halogenated" refers to a group substituted with one or more of the above halogen atoms, which may be the same or different, such as trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, or the like.
The term "ring" or "ring system" refers to a carbocyclic or heterocyclic ring.
The term "heterocycle" means that at least one of the atoms forming the skeleton of the heterocycle is not carbon, and is nitrogen, oxygen or sulfur. Typically, the heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens, and/or no more than 2 sulfurs. Unless otherwise indicated, the heterocyclic ring may be a saturated, partially unsaturated, or fully unsaturated ring. In a preferred embodiment of the invention, 1 to 4 heteroatoms independently selected from N, S, and O are contained in the heterocycle.
The term "ring system" refers to fused rings where two or more rings are joined together.
The term "5-or 6-membered heterocyclic group" means a five-or six-membered ring containing one or more hetero atoms selected from nitrogen, oxygen or sulfur, for example, pyridyl, thiazolyl, isothiazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, pyrimidinyl, tetrahydrofuryl, 4, 5-dihydrothiazol-2-yl, 2-cyanoimino-4-oxy-1, 3-thiazolidin-3-yl, 2-cyanoimino-4-oxy-1, 3-thiazinan-3-yl, oxazolyl, isoxazolyl, 1H-tetrazolyl, 1H-1,2, 3-triazolyl, 4H-1,2, 4-triazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, tetrazolyl, or the like.
The term "heterocyclic ring system" refers to a ring system in which at least one ring in the ring system is heterocyclic.
The term "heteroaromatic ring system" refers to systems in which at least one ring in the ring system is aromatic.
The term "8-to 12-membered heteroaromatic bicyclic ring system" or "8-to 14-membered heteroaromatic bicyclic or tricyclic ring system" may be selected from the group consisting of: benzofuran, benzo [ b ] thiophene, indole, quinoline, isoquinoline, 1H-indazole, 1H-benzo [ d ] imidazole, benzo [ d ] thiazole, benzo [ d ] oxazole, benzo [ d ] isoxazole, benzo [ d ] [1,2,3] thiadiazole, 2, 3-dihydroimidazo [1,2-a ] pyridine, quinazoline, quinoxaline, cinnoline, phthalazine, 1, 8-naphthyridine, 4,5,6, 7-tetrahydrobenzo [ b ] thiophene, benzo [ b ] thiophene-1, 1-dioxane, 8H-indeno [2,1-b ] thiophene, 7, 8-dihydro-6H-cyclopenta [4,5] thieno [2,3-d ] pyrimidine, 3,5,6, 7-tetrahydro-4H-cyclopenta [4,5] thieno [2,3-d ] pyrimidin-4-one, spiro [ indoline-3, 2'- [1,3] dioxolane ] -2-one, spiro [ indoline-3, 2' - [1,3] dioxane ] -2-one, indoline-2, 3-dione, or the like.
The term "alkyl" refers to a group derived from an alkane molecule by the removal of one hydrogen atom; the term "alkylene" refers to a group of an alkane molecule lacking two hydrogen atoms. Similarly, "alkenylene", "alkynylene", "cycloalkylene", "cycloalkenylene", "phenylene", "naphthylene", "heterocyclylene" or "heteroarylene bicyclic or tricyclic ring system" are defined analogously.
Unless specifically stated to be "substituted or unsubstituted", the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6Halogenated alkynyl, hydroxy C1-C4Alkyl, OR3、NR3R4、C(O)R3、C(O)OR3、C(O)NR3R4、SR3、S(O)mR5、S(O)2NR3R4、OC(O)R5、OC(O)NR3R4、OS(O)2R5、OS(O)2NR3R4、N(R6)C(O)R5、N(R6)C(O)NR3R4、N(R6)S(O)2R5Or N (R)6)S(O)2NR3R4Etc., wherein R is3、R4、R5、R6As defined above, m is 1 or 2.
The inert solvent refers to various solvents which do not react with the raw materials, including various straight, branched or cyclic alcohols, ethers or ketones, alkyl halides, 1, 4-dioxane, acetonitrile, tetrahydrofuran, N-Dimethylformamide (DMF), Dimethylsulfoxide (DMSO), and the like.
The compounds of the present invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included within the scope of the invention. The present invention includes all isomeric forms of the compounds.
Pharmaceutical compositions and methods of administration:
the compounds of formula I of the present invention can be used in pharmaceutical compositions comprising a safe and effective amount of a compound of formula I of the present invention, an antibiotic or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" ofBy "herein is meant that the components of the composition are capable of being admixed with and with the compounds of the present invention without significantly diminishing the pharmaceutical effectiveness of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0003392996510000081
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be packaged alone or in combination with other polypeptide antibiotics and other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the pharmaceutical composition is administered to a mammal (e.g., human) in need of treatment, wherein the administration is a pharmaceutically acceptable and effective dose, and the daily dose for a human of 60kg body weight is usually 1-2000mg, preferably 5-500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention is described in detail below with reference to the figures and specific embodiments. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
Example (b):
the aromatic condensed ring diketone compound is prepared by the following method,
Figure BDA0003392996510000101
the method comprises the following steps: reacting the compound of the formula A with diethyl malonate at the temperature of 110-130 ℃ in a solvent-free or inert solvent, after the reaction is finished, filtering the obtained solid, washing a filter cake by using ethanol, and drying in vacuum to obtain a compound of the formula B;
step two: to a round bottom flask containing 20mL of N, N-Dimethylformamide (DMF) was added phosphorus oxychloride (POCl) under ice-bath conditions3) (30mmol), stirring for 40min under an ice bath condition, dissolving 10mmol of the compound shown in the formula B in 20ml of DMF, slowly adding the solution into a flask, heating to 80 ℃ after the addition is finished, reacting for 1h, finishing TLC tracking reaction, cooling the temperature of the reaction solution to room temperature, pouring the reaction solution into ice water, stirring for 30min, performing suction filtration, washing with water, and drying in an infrared oven to obtain a compound shown in the formula C;
step three: weigh formula C compound 10mmol into 100mL round bottom flask, add 20mL ethanol, 3mL ammonia (25% -28%), stir reaction at 70 ℃ for 2h, TLC trace reaction to completion. Cooling the reaction liquid to room temperature, carrying out suction filtration to obtain a yellow crude product, washing a filter cake with absolute ethyl alcohol, and separating by column chromatography (AcOEt: PE ═ 1:1) to obtain a compound shown in the formula D;
step four: methyl cyanoacetate (1.0-1.2equiv.) was added to the corresponding amine (compound of formula E) (1.0equiv.) and stirred at room temperature. After 0.5-12h, white solid is separated out, a solid product is obtained by suction filtration, a filter cake is washed by cooled ether and dried to obtain a white solid product, a solid compound is not separated out in part of reaction, and the compound of the formula F can be obtained by column chromatography with the yield of 72-93%;
step five: adding 10% of alkali into the compound of the formula D and the compound of the formula F in an inert solvent, stirring and reacting for 10min-2h at 70 ℃, separating out a large amount of solids, cooling to room temperature after TLC tracking reaction is finished, performing suction filtration to obtain solids, washing a filter cake with cold ethanol, and drying in an infrared oven to obtain a compound of the formula G;
step six: weighing 1mmol of the compound of the formula G, adding the compound of the formula G into 5mL of DMFDMA, reacting for 10min-1H, separating out a large amount of solid, tracking the reaction by TLC, cooling to room temperature, adding 2mL of ethanol, carrying out suction filtration to obtain solid, washing a filter cake by using the ethanol, and drying in an infrared oven to obtain the compound of the formula H, namely the aromatic condensed ring diketone compound.
Wherein, the process conditions of the above-mentioned production method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, and the like are not limited to the above specific examples.
The specific synthesis of the series of compounds will be briefly described below by taking the synthesis example of compound I-2.
Synthesis of 2-hydroxy-9-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one:
Figure BDA0003392996510000111
weighing 2-amino-3-methylpyridine (10.8g, 100mmol) and diethyl malonate (16g, 100mmol) in a 250ml round-bottom flask, reacting at 110 ℃ for 12h, cooling to room temperature, and performing suction filtration to obtain the compoundWhite solid, washing the filter cake with cooled absolute ethyl alcohol, and drying in an infrared oven to obtain 16.2g of white solid, wherein the yield is about 91 percent, and the product can be directly used for the next reaction.1H NMR(400MHz,DMSO-d6)δ2.48(s,3H),5.44(s,1H),7.20(t,J＝7.0Hz,1H),7.87(d,J＝6.8Hz,1H),8.84(d,J＝6.8Hz,1H),11.52(brs,1H)ppm。
Synthesis of 2-chloro-9-methyl-4-oxo-4H-pyrido [1,2-a ] pyrimidine-3-carbaldehyde:
Figure BDA0003392996510000112
under ice-bath conditions, POCl was added to a round bottom flask containing 20mL of DMF3(30mmol), stirring for 40min under ice bath, dissolving 10mmol of compound in 20ml DMF, slowly adding into a flask, heating to 80 ℃ after the addition is finished, reacting for 1h, tracking the reaction by TLC, cooling the temperature of the reaction liquid to room temperature, pouring into ice water, stirring for 30min, filtering, washing with water, and drying in an infrared oven. Recrystallizing the dried solid with ethanol to obtain 2-chloro-9-methyl-4-oxo-4H-pyrido [1,2-a ]]Pyrimidine-3-carbaldehyde in a yield of 78%,1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.04(d,J＝6.9Hz,1H),8.24(d,J＝7.1Hz,1H),7.58(t,J＝7.0Hz,1H),2.53(s,3H)。
synthesis of 2-amino-9-methyl-4-oxo-4H-pyrido [1,2-a ] pyrimidine-3-carbaldehyde:
Figure BDA0003392996510000121
weighing 2-chloro-9-methyl-4-oxo-4H-pyrido [1,2-a ]]Pyrimidine-3-carbaldehyde (2.223g,10mmol) was placed in a 100mL round bottom flask, 20mL ethanol, 3mL ammonia (25% -28%) was added, the reaction was stirred at 70 ℃ for 2h, and the reaction was followed by TLC to completion. Cooling the reaction liquid to room temperature, carrying out suction filtration to obtain a yellow crude product, washing a filter cake by using absolute ethyl alcohol, and separating by using column chromatography (AcOEt: PE ═ 1:1) to obtain a white solid product, namely the 2-amino-9-methyl-4-oxo-4H-pyrido [1,2-a ]]Pyrimidine-3-carbaldehyde with a yield of 42%,1H NMR(400MHz,Chloroform-d)δ10.32(s,1H),9.13(s,1H),8.80(d,J＝7.1Hz,1H),7.59(d,J＝6.8Hz,1H),6.87(t,J＝7.0Hz,1H),5.74(s,1H),2.43(s,3H)ppm。
synthesis of 2-cyano-N- (pyridin-3-ylmethyl) acetamide:
Figure BDA0003392996510000122
weighing 1.08g of 3-aminomethyl pyridine and 1.2g of methyl cyanoacetate, reacting for 4 hours at room temperature, tracking the reaction by TLC, concentrating the obtained liquid to obtain PE, EA and 2:1, performing column chromatography to obtain a white solid with the yield of 81.2 percent,1H NMR(400MHz,CDCl3)δ8.54–8.46(m,2H),7.66(dt,J＝7.8,1.9Hz,1H),7.29-7.26(m,2H),4.47(d,J＝5.9Hz,2H),3.43(s,2H)ppm。
synthesis of 2-amino-N- (3-pyridylmethyl) -10-methyl-5-oxo-5H-pyrido [1,2-a:2',3' -d ] pyrimidine-3-carboxamide:
Figure BDA0003392996510000123
weighing 2-amino-9-methyl-4-oxo-4H-pyrido [1,2-a ]]Placing 203mg of pyrimidine-3-formaldehyde and 175mg of 2-cyano-N- (pyridine-3-ylmethyl) acetamide in a 50mL round-bottom flask, adding 10mL of 10% NaOH ethanol solution, reacting for 20min, precipitating a large amount of solid, cooling to room temperature, performing suction filtration, washing with ethanol, and drying to obtain 2-amino-N- (3-pyridylmethyl) -10-methyl-5-oxo-5H-pyrido [1,2-a:2',3' -d ]]Pyrimidine-3-carboxamide, yield: 78.6%, a pale yellow solid,1H NMR(400MHz,DMSO-d6)δ＝9.49(t,J＝5.8Hz,1H),8.86(s,1H),8.68(d,J＝6.8Hz,1H),8.64–8.56(d,J＝1.6Hz 1H),8.48(dd,J＝4.8,1.6Hz,1H),8.00(s,2H),7.77(d,J＝7.8Hz,1H),7.69(d,J＝6.8Hz,1H),7.39(dd,J＝7.6,4.8Hz,1H),6.99(t,J＝7.0Hz,1H),4.50(d,J＝5.6Hz,2H),2.45(s,3H)ppm.
synthesis of Compound I-2:
Figure BDA0003392996510000131
weighing 2-amino-N- (3-pyridylmethyl) -10-methyl-5-oxo-5H-pyrido [1,2-a:2',3' -d ]]360mg of pyrimidine-3-formamide is added into 5mL of N, N-dimethylformamide dimethyl acetal (DMFDMA) and reacts for 10min at 110 ℃, a large amount of solid is separated out, 2mL of ethanol is added after the mixture is cooled to room temperature, the mixture is filtered by suction and washed by 2mL of ethanol to obtain a compound I-2, a yellow-green solid, the yield is 67.3%,1H NMR(400MHz,DMSO-d6)δ9.56(t,J＝5.8Hz,1H),8.93(s,1H),8.74(d,J＝7.1Hz,1H),8.64(s,1H),8.53(d,J＝3.8Hz,1H),7.88(d,J＝7.9Hz,1H),7.78(d,J＝6.7Hz,1H),7.48(dd,J＝7.8,4.9Hz,1H),7.08(t,J＝7.0Hz,1H),4.52(d,J＝5.7Hz,2H),2.47(s,3H)ppm。
other compounds can be synthesized in a similar manner using the corresponding starting materials according to the general synthesis scheme, with the nuclear magnetic data shown in the table below.
TABLE 1 Structure of aromatic fused ring diketones and nuclear magnetism thereof
Figure BDA0003392996510000132
Figure BDA0003392996510000141
Figure BDA0003392996510000151
Figure BDA0003392996510000161
Figure BDA0003392996510000171
Figure BDA0003392996510000181
Figure BDA0003392996510000191
Figure BDA0003392996510000201
Figure BDA0003392996510000211
Figure BDA0003392996510000221
The enzymes OfChi-h, OfChtI, CeCht1, HsChit1, AmCase, AfChiB1, SmChiA used in the examples refer to the following references:
Liu,T.,Chen,L.,Zhou,Y.,Jiang,X.,Duan,Y.,&Yang,Q.(2017).Structure,catalysis,and inhibition of OfChi-h,the lepidoptera-exclusive insect chitinase.Journal of Biological Chemistry,292(6),2080-2088.
Chen,L.,Zhou,Y.,Qu,M.,Zhao,Y.,&Yang,Q.(2014).Fully deacetylated chitooligosaccharides act as efficient glycoside hydrolase family 18chitinase inhibitors.Journal of Biological Chemistry,289(25),17932-17940.
Chen,Q.,Chen,W.,Kumar,A.,Jiang,X.,Janezic,M.,Zhang,K.Y.,&Yang,Q.(2021).Crystal Structure and Structure-Based Discovery of Inhibitors of the Nematode Chitinase Ce Cht1.Journal of Agricultural and Food Chemistry,69(11),3519-3526.
Schüttelkopf,A.W.,Andersen,O.A.,Rao,F.V.,Allwood,M.,Rush,C.L.,Eggleston,I.M.,&van Aalten,D.M.(2011).Bisdionin C A Rationally Designed,Submicromolar Inhibitor of Family 18Chitinases.ACS medicinal chemistry letters,2(6),428-432.
the inhibition rate test method comprises the following steps:
the test compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a 10mM stock solution.
Reaction system: the reaction system contained an appropriate amount of chitinase and 20. mu.M MU- (GlcNAc) in a total volume of 100. mu.L2、2％(v/v)DMSO、10mM NaH2PO4、10mM Na2HPO4(pH 6.0) and various concentrations of inhibitors.
At 30 ℃, the chitinase to be detected and the corresponding compound are firstly incubated for 10min, and then a substrate MU- (GlcNAc) is added2After the reaction was continued for 20min, 100. mu.L of 0.5M sodium carbonate solution was added to terminate the reaction, and the fluorescence intensity was measured by a microplate reader (Tecan Infinite 200Pro) at an excitation wavelength of 360nm and an emission wavelength of 440 nm. Fluorescence intensity of the experimental group is denoted as FEThe fluorescence intensity of the negative control group containing no substrate was designated as FNThe fluorescence intensity of the positive control group without the compound was designated as FPBlank control fluorescence intensity is denoted FBThe inhibitory activity was calculated by the following formula.
Inhibition rate ═ 1- (F)E-FN)/(FP-FB)]×100％
Inhibition constant KiDetermination of the value:
the inhibitory activity of the compounds at different concentrations was determined at three different substrate concentrations, with the reciprocal of the reaction rate as ordinate and the compound concentration as abscissa, and K of the compound was calculated by the Dixon plots methodiThe value is obtained.
TABLE 2 inhibitory Activity of aromatic fused Ring diketones against different chitinases at 10. mu.M concentration
Figure BDA0003392996510000231
Figure BDA0003392996510000241
Figure BDA0003392996510000251
Figure BDA0003392996510000261
Figure BDA0003392996510000271
FIG. 1 is a test chart of the inhibitory activity of I-2 on Asiatic corn borer chitinase OfChi-h, and FIG. 1 shows that K of I-2 on Asiatic corn borer chitinase OfChi-hiWas 58 nM.
FIG. 2 is a graph showing the test of the inhibitory activity of I-2 on human chitotriose chitinase HsChit1, and FIG. 2 shows that K of I-2 on human chitotriose chitinase HsChit1iAt 295 nM.
FIG. 3 is a graph showing the test of I-2 inhibitory activity against Serratia marcescens chitinase, and FIG. 3 shows K of I-2 on Serratia marcescens chitinaseiWas 126 nM.
FIG. 4 is a test chart of the inhibitory activity of I-28 on Asiatic corn borer chitinase OfChi-h, and FIG. 4 shows K of I-28 on Asiatic corn borer chitinase OfChi-hiWas 65 nM.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.

Claims (10)

1. An aromatic condensed ring diketone compound is characterized in that the structural formula of the compound is shown as a formula I:
Figure FDA0003392996500000011
wherein:
x represents a substituent at any one or more positions on the pyridine ring, and each substituent is independently selected from one of the following groups: H. halogen, cyano, nitro, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted C5-C7Cycloalkenyl, substituted OR unsubstituted phenyl, substituted OR unsubstituted naphthyl, substituted OR unsubstituted 5-OR 6-membered heterocyclyl, substituted OR unsubstituted 8-to 12-membered heteroaromatic bicyclic ring system, ORa、SRa、C(O)Rb、C(O)ORa、NRaRb、S(O)2Ra；
M is a single bond, or a substituted or unsubstituted alkylene group having 1 to 10 carbon atoms, said alkylene group being a linear or branched alkylene group;
y is selected from one of the following groups: H. halogen, cyano, nitro, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted C5-C7Cycloalkenyl, substituted OR unsubstituted phenyl, substituted OR unsubstituted naphthyl, substituted OR unsubstituted 5-OR 6-membered heterocyclyl, substituted OR unsubstituted 8-to 12-membered heteroaromatic bicyclic ring system, ORa、SRa、C(O)Rb、C(O)ORa、NRaRb、S(O)2Ra。
2. The aromatic fused ring diketone compound as claimed in claim 1, wherein R isa、RbEach independently selected from one of the following groups: H. substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C2-C6Alkenyl, substituted or unsubstituted C2-C6Alkynyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted C5-C7Cycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-or 6-membered heterocyclyl, substituted or unsubstituted 8-to 12-membered heteroaromatic bicyclic ring systems.
3. The aromatic fused ring diketones according to claim 2, wherein X, M, Y, R is represented bya、RbWherein said substitution is by one or more of the following groups: halogen, cyano, nitro, R ', OR ', Si (R ')3、NR'R"、C(O)R'、C(O)OR'、C(O)NR'R"、SR'、S(O)mR1、S(O)2NR'R"、OC(O)R1、OC(O)NR'R"、OS(O)2R1、OS(O)2NR'R"、N(R2)C(O)R1、N(R2)C(O)NR'R"、N(R2)S(O)2R1、N(R2)S(O)2NR' R "; m is 1 or 2.
4. The aromatic fused ring diketone compound according to claim 3,
r 'and R' are each independently selected from one of the following groups: H. c1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6Haloalkynyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted C5-C7Cycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocyclyl, substituted or unsubstituted 8-to 12-membered heteroaromatic bicyclic ring system;
R1selected from one of the following groups: c1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6Haloalkynyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted C5-C7A cycloalkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted 5-or 6-membered heterocyclyl group, a substituted or unsubstituted 8-to 12-membered heteroaromatic bicyclic ring system;
R2selected from one of the following groups: H. c1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6Haloalkynyl, substituted or unsubstituted C3-C7Cycloalkyl, substituted or unsubstituted C5-C7Cycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-or 6-membered heterocyclyl, substituted or unsubstituted 8-to 12-membered heteroaromatic bicyclic ring systems.
5. The aromatic fused ring diketone compound according to claim 4, wherein R', R "are1、R2Wherein said substitution is by one or more of the following groups: halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6Halogenated alkynyl, hydroxy C1-C4Alkyl, OR3、NR3R4、C(O)R3、C(O)OR3、C(O)NR3R4、SR3、S(O)mR5、S(O)2NR3R4、OC(O)R5、OC(O)NR3R4、OS(O)2R5、OS(O)2NR3R4、N(R6)C(O)R5、N(R6)C(O)NR3R4、N(R6)S(O)2R5、N(R6)S(O)2NR3R4(ii) a m is 1 or 2.
6. The aromatic fused ring diketone compound according to claim 5,
R3、R4、R6each independently selected from one of the following groups: H. c1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6Halogenated alkynyl, C1-C6An alkyloxy group;
R5selected from one of the following groups: c1-C6Alkyl radical, C1-C6Haloalkyl, C2-C6Alkenyl radical, C2-C6Haloalkenyl, C2-C6Alkynyl, C2-C6A haloalkynyl group.
7. A method for producing the aromatic fused ring diketones according to any one of claims 1 to 6, comprising the steps of:
1) reacting the compound of the formula A with diethyl malonate to obtain a compound of a formula B;
2) reacting the compound shown in the formula B with phosphorus oxychloride to obtain a compound shown in the formula C;
3) reacting the compound shown in the formula C with ammonia water to obtain a compound shown in a formula D;
4) reacting the compound of the formula E with methyl cyanoacetate to obtain a compound of a formula F;
5) reacting the compound of formula D with the compound of formula F to obtain a compound of formula G;
6) reacting the compound of the formula G with N, N-dimethylformamide dimethyl acetal to obtain the aromatic condensed ring diketone compound;
the structural formulas of the compound of the formula A, the compound of the formula B, the compound of the formula C, the compound of the formula D, the compound of the formula E, the compound of the formula F and the compound of the formula G are respectively as follows:
Figure FDA0003392996500000031
8. use of a aromatic fused ring diketone compound as claimed in any one of claims 1 to 6 in the preparation of a chitinase inhibitor.
9. An aromatic fused ring diketone derivative based on the aromatic fused ring diketone compound as claimed in any one of claims 1 to 6, wherein the derivative is an optical isomer, a cis-trans isomer, a pharmaceutically acceptable salt or a solvate of the compound of formula I.
10. A chitinase inhibitor based on the aromatic fused ring diketones as claimed in any of claims 1 to 6, wherein the inhibitor comprises one or more of the compounds of formula I, optical isomers of the compounds of formula I, cis-trans isomers of the compounds of formula I, pharmaceutically acceptable salts of the compounds of formula I, solvates of the compounds of formula I.
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