CN115521306A - 1,2,3,4-tetrahydro-beta-carboline derivative and preparation method and application thereof - Google Patents

1,2,3,4-tetrahydro-beta-carboline derivative and preparation method and application thereof Download PDF

Info

Publication number
CN115521306A
CN115521306A CN202211172658.1A CN202211172658A CN115521306A CN 115521306 A CN115521306 A CN 115521306A CN 202211172658 A CN202211172658 A CN 202211172658A CN 115521306 A CN115521306 A CN 115521306A
Authority
CN
China
Prior art keywords
tetrahydro
optionally substituted
unsubstituted
compound
carboline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202211172658.1A
Other languages
Chinese (zh)
Other versions
CN115521306B (en
Inventor
杨松
刘洪武
苏闪闪
马思越
李婷
柳立伟
吴志兵
周翔
薛伟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guizhou University
Original Assignee
Guizhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guizhou University filed Critical Guizhou University
Priority to CN202211172658.1A priority Critical patent/CN115521306B/en
Publication of CN115521306A publication Critical patent/CN115521306A/en
Application granted granted Critical
Publication of CN115521306B publication Critical patent/CN115521306B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/12—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, neither directly attached to a ring nor the nitrogen atom being a member of a heterocyclic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/16—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof the nitrogen atom being part of a heterocyclic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P3/00—Fungicides

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Environmental Sciences (AREA)
  • Zoology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Wood Science & Technology (AREA)
  • Plant Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Organic Chemistry (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to 1,2,3,4-tetrahydro-beta-carboline derivatives, a preparation method and application thereof, in particular to 1,2,3,4-tetrahydro-beta-carboline compounds containing 3-aminopropionamide, 2-aminoacetamide, 1,3-propylene diamine and dithiocarbamate substructures, and a preparation method and application thereof. The structural formula of the compound is shown as a formula A. The compound provided by the invention has good inhibition effect on pathogenic plant pathogenic bacteria and plant pathogenic fungi, and has simple preparation method and mild reaction conditions.

Description

1,2,3,4-tetrahydro-beta-carboline derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to 1,2,3,4-tetrahydro-beta-carboline derivatives, a preparation method and application thereof, and especially relates to 1,2,3,4-tetrahydro-beta-carboline compounds containing 3-aminopropionamide, 2-aminoacetamide, 1,3-propylenediamine and dithiocarbamate substructures, and a preparation method and application thereof.
Background
Plant diseases are one of the main factors influencing global agricultural production, seriously influence the yield and quality of agricultural products, not only cause great economic loss, but also threaten human health. Such as bacterial leaf blight of rice, citrus canker, kiwifruit canker, tobacco bacterial wilt, wheat scab, rice sheath blight and the like, can outbreak to different degrees every year, and cause huge economic loss to farmers. The long-term use of traditional bactericides such as thiabendazole, bismerthiazol, streptomycin sulfate, carbendazim and the like not only increases the drug resistance of plant pathogenic bacteria, but also has harmful effects on the ecological environment and the safety of plants. Therefore, the development of novel pesticides having high activity, high selectivity and novel structures is urgently required.
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide 1,2,3,4-tetrahydro- β -carboline derivatives, 1,2,3,4-tetrahydro- β -carboline derivatives as a novel pesticide with high activity and high selectivity, which is prepared by using 1,2,3,4-tetrahydro- β -carboline as a starting material to synthesize a series of 1,2,3,4-tetrahydro- β -carboline compounds containing 3-aminopropionamide, 2-aminoacetamide, 1,3-propylenediamine and dithiocarbamate substructures; the compound has good inhibition effect on pathogenic bacteria of pathogenic plants, and has good inhibition effect on pathogenic bacteria [ such as Xanthomonas oryzae (Xoo), xanthomonas anoppophv.citri, xac), actinidia chinensis (Pseudomonas syringaepv.actandiae, psa) and fungi [ such as Rhizoctonia solani (Rhizoctonia solani) and the like ].
In order to achieve the purpose, the following technical scheme can be adopted:
the invention provides a 1,2,3,4-tetrahydro-beta-carboline derivative or a stereoisomer thereof, or a salt or a solvate thereof, wherein the structural formula of the compound is shown as a formula A,
Figure BDA0003863042070000011
wherein R is selected from any one of the following structures:
Figure BDA0003863042070000012
wherein R is 1 And R 2 One or more of each independently selected from hydrogen, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl, optionally substituted or unsubstituted benzyl; or R 1 And R 2 Joined to form any one of an optionally substituted 4 to 10 membered ring or a heteroatom containing ring of N, O and one or more of S.
In another aspect of the present invention, there is provided a method for preparing the 1,2,3,4-tetrahydro- β -carboline derivative, wherein the method for preparing the compound having the structure a as R includes:
Figure BDA0003863042070000021
a method of making a compound having structure b, wherein R is selected from the group consisting of:
Figure BDA0003863042070000022
a method of making a compound having structure c, wherein R is selected from the group consisting of:
Figure BDA0003863042070000023
a method of making a compound wherein R is selected from structure d comprises:
Figure BDA0003863042070000024
a method of making a compound having structure e, wherein R is selected from the group consisting of:
Figure BDA0003863042070000025
in yet another aspect, the present invention provides a composition comprising the 1,2,3,4-tetrahydro- β -carboline derivative or a stereoisomer thereof or a salt thereof or a solvate thereof described above.
In another aspect, the present invention provides a pharmaceutical composition comprising the 1,2,3,4-tetrahydro- β -carboline derivative or the composition as described above; and diluent or auxiliary materials.
The invention further provides an application of the 1,2,3,4-tetrahydro-beta-carboline derivative or the stereoisomer thereof or the salt thereof or the solvate thereof, the composition or the medicament in preventing and treating agricultural fungi and bacterial diseases.
The beneficial effects of the invention at least comprise:
(1) The 1,2,3,4-tetrahydro-beta-carboline derivative provided by the invention has a good inhibition effect on pathogenic plant pathogenic bacteria, and has a good inhibition effect on pathogenic bacteria [ such as rice bacterial blight, citrus canker, kiwi canker and the like ] and plant pathogenic fungi [ such as rice sheath blight and the like ];
(2) The 1,2,3,4-tetrahydro-beta-carboline derivative provided by the invention is simple in preparation method and mild in reaction conditions.
Detailed Description
The examples are given for the purpose of better illustration of the invention, but the invention is not limited to the examples. Therefore, those skilled in the art can make insubstantial modifications and adaptations to the embodiments described above without departing from the scope of the present invention.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. Unless the context has a significantly different meaning, the singular form of expression includes the plural form of expression. As used herein, it is understood that terms such as "comprising," "having," "including," and the like are intended to refer to the presence of features, numbers, operations, components, parts, elements, materials, or combinations thereof. The terms of the present invention are disclosed in the specification and are not intended to exclude the possibility that one or more other features, numbers, operations, components, parts, elements, materials or combinations thereof may be present or may be added. As used herein, "/" can be interpreted as "and" or "depending on the circumstances.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. E.g. "C 1-10 Alkyl "(or alkylene) groups are intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example "C 1-6 Alkyl "denotes an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
The term "alkenyl" as used in the present invention is intended to include both hydrocarbons of straight or branched chain structure and having one or more carbon-carbon double bonds at any stable point in the chain. E.g. "C 2-6 Alkenyl "(or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenylAlkenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl and the like.
The term "alkynyl" as used herein is intended to include both hydrocarbons of straight or branched chain configuration and having one or more carbon-carbon triple bonds occurring at any stable point in the chain. For example "C 2-6 Alkynyl "(or alkynylene) is intended to include C2, C3, C4, C5 and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom or group is replaced with the designated group of choice, provided that the general valence of the designated atom is not exceeded. If not otherwise stated, substituents are named to the central structure. For example, it is understood that when (cycloalkyl) alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C = C, C = N or N = N). When referring to substitution, especially polysubstitution, it is meant that the multiple substituents are substituted at each position on the indicated group, e.g., dichlorophenyl means 1,2-dichlorophenyl, 1,3-dichlorophenyl, 1,4-dichlorophenyl, and 2,4-dichlorophenyl. Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable to be isolated in useful purity from the reaction mixture and subsequently formulated to form an effective therapeutic agent. Preferably, the compounds described so far do not contain N-halogen, S (O) 2 H or an S (O) H group.
The term "aryl" as used in the present invention refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.
The term "halogen" or "halogen atom" as used in the present invention refers to chlorine, bromine, fluorine and iodine.
The term "haloalkyl" as used herein refers to a substituted alkyl group having one or more halo substituents. For example, "haloalkyl" includes mono-, di-and trifluoromethyl; even if the halo in a haloalkyl group is specified as fluoro, chloro, bromo, iodo, the same refers to a substituted alkyl group having one or more fluoro, chloro, bromo, iodo substituents.
The term "heteroaryl" as used herein refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11 to 14 membered tricyclic groups having at least one heteroatom (O, S or N) in at least one ring, said heteroatom containing ring preferably having 1,2 or 3 heteroatoms selected from O, S and N. The heteroatom-containing heteroaryl groups can contain one or two oxygen or sulfur atoms per ring and/or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. If the other ring is cycloalkyl or heterocyclic, it is additionally optionally substituted with = O (oxygen), as valency permits. Exemplary monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like. Exemplary bicyclic heteroaryls include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.
The term "compound" as used in the present invention is understood to include the free form and salts thereof, unless otherwise specified. "salt" means an acid and/or base salt formed with an inorganic and/or organic acid and a base; in addition, "salts" may include zwitterions (inner salts), such as when the compound of formula I contains a basic moiety, such as an amine or pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, such as separation or purification steps in the preparation process, and are therefore included within the scope of the present invention.
In the present invention, C 1 -C 10 Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and isomers thereof; c 1 -C 10 Alkoxy refers to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy and isomers thereof; c 2 -C 5 Alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl, and isomers thereof.
In the present invention, when a substituent is alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxyl, amino, mercapto, or phosphino, or when such substituent is specifically a specific alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxyl, amino, mercapto, or phosphino, one to three of the above substituents are referred to. Such as methylphenyl refers to phenyl substituted with one to three methyl groups.
The invention provides a 1,2,3,4-tetrahydro-beta-carboline derivative or a stereoisomer thereof, or a salt or a solvate thereof, wherein the structural formula of the compound is shown as a formula A,
Figure BDA0003863042070000041
wherein R is selected from any one of the following structures:
Figure BDA0003863042070000042
wherein R is 1 And R 2 One or more of each independently selected from hydrogen, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl, optionally substituted or unsubstituted benzyl; or R 1 And R 2 Joined to form any one of an optionally substituted 4 to 10 membered ring or a heteroatom containing ring of N, O and one or more of S.
A compound of claim 1, wherein R is 1 And R 2 Each independently selected from hydrogen, optionally substituted or unsubstituted C 1-6 Alkyl, optionally substituted or unsubstituted C 2-6 Alkenyl, optionally substituted or unsubstituted C 5-10 Cycloalkyl, optionally substituted or unsubstituted C 5-10 Aryl, optionally substituted or unsubstituted C 5-10 Heteroaryl, optionally substituted or unsubstituted benzyl; or R 1 And R 2 Are linked to form an optionally substituted 5-to 10-membered ring or a heteroatom-containing ring.
In some embodiments, in the 1,2,3,4-tetrahydro- β -carboline derivative described above, R is 1 And R 2 Each independently selected from hydrogen, methyl, allyl, phenyl, benzyl, fluorobenzyl, chlorobenzyl, trifluoromethylbenzyl, methylbenzyl, methoxybenzyl, 2-furylmethyl or 2-thienylmethyl.
In some embodiments, in the 1,2,3,4-tetrahydro- β -carboline derivative described above, when R is 1 And R 2 When the two groups are connected to form a ring, any one of the following groups is adopted:
Figure BDA0003863042070000051
in some embodiments, the 1,2,3,4-tetrahydro- β -carboline derivative described above may be selected from any of the following structures:
Figure BDA0003863042070000052
Figure BDA0003863042070000061
Figure BDA0003863042070000071
the invention also provides a preparation method of the 1,2,3,4-tetrahydro-beta-carboline derivative, wherein,
a method for preparing a compound having structure a, wherein R is selected from the group consisting of:
Figure BDA0003863042070000072
a method of making a compound having R selected from structure b comprises:
Figure BDA0003863042070000073
a method of making a compound having structure c, wherein R is selected from the group consisting of:
Figure BDA0003863042070000074
a method of making a compound wherein R is selected from structure d comprises:
Figure BDA0003863042070000075
a method of making a compound having structure e, wherein R is selected from the group consisting of:
Figure BDA0003863042070000076
the compounds wherein R is selected from the structures a to e correspond to the compounds represented by the formulae (I) to (V) described above, respectively.
In some embodiments, in the preparation method of 1,2,3,4-tetrahydro- β -carboline derivative, the preparation method of the compound represented by formula (VI) comprises:
Figure BDA0003863042070000081
the preparation method of the compound shown in the formula (VII) comprises the following steps:
Figure BDA0003863042070000082
the preparation method of the compound shown in the formula (VIII) comprises the following steps:
Figure BDA0003863042070000083
the preparation method of the compound shown in the formula (IX) comprises the following steps:
Figure BDA0003863042070000084
in some embodiments, in the preparation method of 1,2,3,4-tetrahydro-beta-carboline derivative,
a method for preparing a compound having structure a, wherein R is selected from the group consisting of:
Figure BDA0003863042070000085
a method of making a compound having structure b, wherein R is selected from the group consisting of:
Figure BDA0003863042070000086
a method of making a compound having structure c, wherein R is selected from the group consisting of:
Figure BDA0003863042070000087
a method of making a compound wherein R is selected from structure d comprises:
Figure BDA0003863042070000088
a method of making a compound having structure e, wherein R is selected from the group consisting of:
Figure BDA0003863042070000091
in yet another aspect, the invention provides a composition, which in some embodiments may include the 1,2,3,4-tetrahydro- β -carboline derivative or a stereoisomer thereof or a salt or solvate thereof described above. Specifically, the compound can be used for preventing and treating fungal and bacterial diseases independently, and can also be combined with other fungicide active ingredients to form a composition for preventing and treating fungal and bacterial diseases.
In yet another aspect, the invention provides a medicament, which in some embodiments may comprise a 1,2,3,4-tetrahydro- β -carboline derivative as described above or a composition as described above; and diluent or auxiliary materials. Specifically, the compound can be added with a diluent or an auxiliary material to prepare various dosage forms to be applied in different use environments.
In some embodiments, the above-mentioned medicament, diluent or adjuvant is suitable for emulsifiable concentrate, powder, wettable powder, granule, aqueous solution, suspension, ultra-low volume spray, soluble powder, microcapsule, smoke agent, aqueous emulsion or water dispersible granule.
The invention further provides an application of the 1,2,3,4-tetrahydro-beta-carboline derivative or the stereoisomer thereof or the salt thereof or the solvate thereof, the composition or the medicament in preventing and treating agricultural diseases.
In some embodiments, the agricultural disease is a bacterial or fungal disease of the plant; in some specific embodiments, the agricultural disease is any one or more of plant leaf blight, plant bacterial wilt, plant canker, plant sheath blight, plant gray mold, plant late blight, plant wilt, and plant root rot; in some embodiments, the agricultural disease is one or more of rice bacterial blight, citrus canker, kiwi canker, tobacco bacterial wilt, cucumber bacterial blight, konjac bacterial blight, grape canker, tomato canker, apple canker, rice sheath blight, tree canker, wheat scab, cucumber gray mold, pepper wilt, rape sclerotinia rot, potato late blight, and blueberry root rot.
In addition, when the 1,2,3,4-tetrahydro- β -carboline derivative, or the stereoisomer thereof, or the salt thereof, or the solvate thereof, or the composition or the medicament is used for controlling agricultural diseases, the derivative or the stereoisomer thereof can be contacted with plants or diseases.
It should be noted that natural products are important resources for creating new pesticides. The natural products not only have various varieties and various biological activities, but also have unique effects, and more importantly, the natural products are easy to degrade or have good environmental compatibility, so the natural products are widely used by people for hundreds of years; however, most natural product compounds are complicated in structure, difficult to synthesize, unstable or very volatile to light, and generally cannot be directly used as pesticides. The 1,2,3,4-tetrahydro-beta-carboline derivative provided by the invention is a 1,2,3,4-tetrahydro-beta-carboline compound serving as a common alkaloid, and is widely present in plants, animals, microorganisms and marine organisms. According to the literature report, the 1,2,3,4-tetrahydro-beta-carboline compound has excellent activities of resisting cancer, sterilizing, resisting virus and the like, and is a hotspot structure in the current drug research and development field. In the field of agricultural chemicals, the agricultural antiviral agent chloroindole hydrazide has been successfully developed. In order to search for high-efficiency antibacterial compounds, 1,2,3,4-tetrahydro-beta-carboline is used as a starting material, 3-aminopropionamide, 2-aminoacetamide, 1,3-propylenediamine and dithiocarbamate substructures are used as connecting chains, nitrogen-containing active fragments are introduced, a series of 1,2,3,4-tetrahydro-beta-carboline compounds containing 3-aminopropionamide, 2-aminoacetamide, 1,3-propylenediamine and dithiocarbamate substructures are synthesized, the biological activity of the compounds is investigated, and important scientific bases are provided for research and development of new pesticides.
5363 the research of biological activity of 1,2,3,4-tetrahydro-beta-carboline compounds progresses as follows:
2014, liu et al [ Liu, y.x.; song, h.j.; huang, y.q.; li, j.r.; zhao, s.; song, y.c.; yang, p.w.; xiao, z.x.; liu, y.x.; li, y.q.; shang, h.; wang, q.m. design, synthesis, and additive, fungicidic, and empirical Activities of Tetrahydro- β -carboline-3-carbohydrazide Derivatives [ J ] j.agricultural.food chem.,2014,62,9987-9999 ] designed and synthesized a series of 1,2,3,4-Tetrahydro- β -carboline-3-carboxylic acid Derivatives and evaluated the biological activity of all target molecules. Research results show that most of compounds show excellent activity on Tobacco Mosaic Virus (TMV), and meanwhile, the compounds are found to have excellent control effect on tobacco mosaic in fields. Meanwhile, the compounds also have certain insecticidal and antifungal activities.
2018, ombiro et al [ Ombiro, G.S.; sawai, t.; noutoshi, y.; matsui, h.; yamamoto, m; toyoda, k.; several 1,2,3,4-tetrahydro- β -carboline compounds were reported by ichino, y.specific growth inhibition of Ralstonia solanacearum, xanthomonas oryzae epv.oryzae, x.campestrispv. Campestris, and clavibacterium microbioensis subsp.microorganisnsis [ J ]. Microbiol.res, 2018, 215, 29-35 ], and their anti-plant pathogen activity was evaluated. The biological activity research result shows that part of the compounds have better growth inhibition effect on plant pathogenic bacteria such as Ralstonia solanacearum, rice leaf blight (Xanthomonas oryzae epv. Oryzae), cruciferous black rot (Xanthomonas campestris pv. Camptosris) and tomato bacterial canker (Clavibacterium micobacterium subsp. Microbacterium) and the like.
2020, liu et al [ Liu, H.W.; ji, q.t.; ren, G.G.; wang, f.; su, f.; wang, p.y.; zhou, x.; wu, z.b.; li, z; yang, S.Antibacterials functions and deployed modes of action of novel1,2,3,4-tetrahydro-β-carboline derivatives that possess an attractive 1,3-diaminopropan-2-ol pattern against rice bacterial blight,kiwifruit bacterial canker,and citrus bacterial canker[J].J.Agric.Food Chem.2020,68(45),12558-12568.]A series of 1,2,3,4-tetrahydro- β -carboline derivatives containing isopropanolamine substructures are reported and evaluated for activity against phytopathogenic bacteria. The biological activity test result shows that most of the synthesized compounds have better inhibition effects on Xanthomonas oryzae (Xao), xanthomonas oryzae (Xanthomonas anopsis.citri) and Actinidia chinensis (Pseudomonas syringaepv.actandiae, psa) and EC of the compounds 50 Most are less than 10. Mu.g/mL.
For a better understanding of the present invention, the following further illustrates the contents of the present invention with reference to specific examples, but the contents of the present invention are not limited to the following examples.
1. Preparation and characterization of Compounds
EXAMPLE 1 preparation of intermediate 2-acryloyl-1,2,3,4-tetrahydro-beta-carboline
1,2,3,4-tetrahydro- β -carboline (2.64g, 15.0mmol), triethylamine (1.84g, 18.0mmol) and 15mLN, N-dimethylformamide were added to a 50mL round-bottomed flask, stirred for 30min under ice salt bath conditions, and then acryloyl chloride (1.54g, 16.5mmol) was dissolved in 5mL anhydrous N, N-dimethylformamide and slowly added, at room temperature overnight. Quenching the reaction by water, extracting by ethyl acetate, washing by saturated ammonium chloride solution, taking an organic phase, drying by anhydrous sodium sulfate, desolventizing, and carrying out column chromatography to obtain 3.11g of yellow solid with the yield of 91.5%. The nuclear magnetic data are as follows: 1 HNMR(400MHz,CDCl 3 )δ8.68(s,1H,-NH),7.45(d,J＝7.7Hz,1H,Ar-H),7.31(d,J＝7.9Hz,1H,Ar-H),7.15(t,J＝7.2Hz,1H,Ar-H),7.09(t,J＝7.4Hz,1H,Ar-H),6.72(dd,J＝16.8,10.6Hz,1H,- 1 CH＝CH 2 ),6.39(d,J＝18.2Hz,1H,-CH 1 ＝ 2 CH),5.79(d,J＝12.0Hz,1H,-CH 1 ＝ 2 CH),4.87(s,2H,-N-CH 2 -),3.86(t,J＝5.6Hz,2H,- 2 CHCH 2 -),2.86(t,J＝5.4Hz,2H,- 2 CHCH 2 -)； 13 CNMR(101MHz,CDCl 3 )δ166.5,136.3,130.2,128.3,127.9,126.8,121.7,119.5,117.8,111.1,107.7,44.4,41.1,22.2。
EXAMPLE 2 preparation of intermediate 3-bromo-1- [4- (4-fluorophenyl) piperazin-1-yl ] propan-1-one
4-fluorophenylpiperazine (0.35g, 2.00mmol), triethylamine (0.25g, 2.40mmol) and 3mL of anhydrous dichloromethane were added to a 25mL round-bottomed flask, and after stirring for 30min under ice salt bath conditions, 3-bromopropionyl chloride (0.37g, 2.10 mmol) was dissolved in 2mL of dichloromethane and slowly added dropwise to the system, and the reaction was continued at room temperature for 30h. Quenching the reaction with water, extracting with dichloromethane, taking an organic phase, drying with anhydrous sodium sulfate, desolventizing, and carrying out column chromatography to obtain 0.35g of white solid with the yield of 57.1%. The nuclear magnetic data are as follows: 1 HNMR(400MHz,CDCl 3 )δ6.97(d,J＝8.3Hz,2H,phenyl-H),6.90(d,J＝4.6Hz,2H,phenyl-H),3.83–3.76(m,2H,piperazine-CH 2 ),3.68(t,J＝7.1Hz,2H,- 2 CHCH 2 -),3.65–3.59(m,2H,piperazine-CH 2 ),3.14–3.04(m,4H,piperazine-CH 2 ),2.96(t,J＝7.1Hz,2H,- 2 CHCH 2 -)； 13 CNMR(101MHz,CDCl 3 )δ168.5,157.7(d, 1 J C-F ＝240.2Hz),147.5(d, 4 J C-F ＝2.2Hz),118.7(d, 3 J C-F ＝7.6Hz),115.8(d, 2 J C-F ＝22.2Hz),50.8,50.4,45.5,41.7,36.3,27.2； 19 FNMR(377MHz,CDCl 3 )δ-123.1。
EXAMPLE 3 preparation of the intermediate 2-Bromoacetyl-1,2,3,4-tetrahydro-beta-carboline
1,2,3,4-tetrahydro- β -carboline (0.35g, 2.00mmol), triethylamine (0.25g, 2.40mmol) and 5mL dichloromethane were added to a 25mL round bottom flask, stirred under ice salt bath for 30min, then bromoacetyl bromide (0.44g, 2.10mmol) was dissolved in 5mL anhydrous dichloromethane and slowly added, and reacted at room temperature for 30h. Quenching the reaction with water, extracting with dichloromethane, taking an organic phase, drying with anhydrous sodium sulfate, desolventizing, and carrying out column chromatography to obtain 0.51g of yellow solid with the yield of 86.5%. The nuclear magnetic data are: 1 HNMR(400MHz,CDCl 3 )δ8.21(s,1H,-NH),7.47(d,J＝7.7Hz,1H,Ar-H),7.33(d,J＝8.0Hz,1H,Ar-H),7.19–7.15(m,1H,Ar-H),7.13–7.09(m,1H,Ar-H),4.78(s,2H,-N-CH 2 -),4.00(s,2H,-COCH 2 -),3.82(t,J＝5.6Hz,2H,- 2 CHCH 2 -),2.94(t,J＝5.3Hz,2H,- 2 CHCH 2 -)； 13 CNMR(101MHz,CDCl 3 )δ166.4,136.3,129.5,126.6,122.0,119.7,117.9,111.1,107.8,45.2,41.1,26.1,21.9。
EXAMPLE 4 preparation of intermediate 1- (3-bromopropyl) -4- (4-fluorophenyl) piperazine
4-fluorophenylpiperazine (0.70g, 4.00mmol), triethylamine (0.49g, 4.80mmol) and 5mL of anhydrous dichloromethane were added to a 25mL round-bottomed flask, stirred for 30min under ice salt bath conditions, and 1,3-dibromopropane (1.67g, 8.00mmol) was slowly added and reacted at room temperature for 30h. The reaction was quenched with water, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, desolventized, and subjected to column chromatography to obtain 0.34g of yellow oil with a yield of 28.2%. The nuclear magnetic data are: 1 HNMR(400MHz,CDCl 3 )δ6.95(d,J＝8.3Hz,2H,phenyl-H),6.89(d,J＝4.6Hz,2H,phenyl-H),3.49(t,J＝6.6Hz,2H,-N- 2 CHCH 2 -),3.17–3.08(m,4H,piperazine-CH 2 ),2.67–2.59(m,4H,piperazine-CH 2 ),2.56(t,J＝7.0Hz,2H,Br- 2 CHCH 2 -),2.08(p,J＝6.7Hz,2H,-CH 2 2 CHCH 2 -)； 13 CNMR(101MHz,CDCl 3 )δ157.2(d, 1 J C-F ＝239.0Hz),147.9(d, 4 J C-F ＝2.0Hz),117.9(d, 3 J C-F ＝7.5Hz),115.5(d, 2 J C-F ＝22.0Hz),56.5,53.3,50.1,31.7,29.9； 19 FNMR(377MHz,CDCl 3 )δ-124.5。
EXAMPLE 5 preparation of the object Compound 3- (tert-butylamino) -1- (1,2,3,4-tetrahydro-beta-carbolin-2-yl-) propan-1-one
2-acryloyl-1,2,3,4-tetrahydro-beta-carboline (0.23g, 1.0 mmol), tert-butylamine (0.08g, 1.05mmol) and 4mL of anhydrous methanol are put into a 15mL reaction bottle, then reacted at 60 ℃, followed by TLC until 2-acryloyl-1,2,3,4-tetrahydro-beta-carboline is completely consumed, and the reaction is finished. The reaction was quenched with 20mL of water, extracted twice with 30mL of dichloromethane, collectedThe organic phase is dried by anhydrous sodium sulfate, desolventized and chromatographed by thin layer chromatography to obtain white solid with the yield of 83.5 percent. The nuclear magnetic data are as follows: 1 HNMR(400MHz,CDCl 3 )δ10.17(s,1H,-NH),7.32(dd,J＝7.2,5.6Hz,2H,Ar-H),7.12(t,J＝7.5Hz,1H,Ar-H),7.06(t,J＝7.4Hz,1H,Ar-H),4.68(s,2H,-N-CH 2 -),3.47(t,J＝5.6Hz,2H,- 2 CHCH 2 -),2.98(t,J＝6.0Hz,2H,- 2 CHCH 2 -),2.66(t,J＝5.9Hz,2H,-COCH 2 2 CH-),2.28(t,J＝4.9Hz,2H,-CO 2 CHCH 2 -),1.19(s,9H,-CH 3 )； 13 CNMR(101MHz,CDCl 3 )δ170.8,136.3,130.3,126.8,126.8,121.3,119.0,117.9,110.9,107.2,51.3,43.5,40.4,37.9,33.7,28.5,21.2。
EXAMPLE 6 preparation of the object compound 1- (4- (4-fluorophenyl) piperazin-1-yl) -3- (1,2,3,4-tetrahydro- β -carbolin-2-yl) propan-1-one
1,2,3,4-tetrahydro-beta-carboline (0.12g, 0.70mmol), 3-bromo-1- [4- (4-fluorophenyl) piperazin-1-yl]Propane-1-one (0.22g, 0.70mmol), potassium carbonate (0.12g, 0.84mmol), potassium iodide (0.01g, 0.07mmol) and 4mL acetonitrile were charged in one pot into a 15mL reaction flask, then reacted at 60 ℃ followed by TLC until 3-bromo-1- [4- (4-fluorophenyl) piperazin-1-yl]The propane-1-ketone is completely consumed, and the reaction is finished. The reaction was quenched with 20mL of water and extracted twice with 30mL of dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate, desolventized, and chromatographed over thin layer chromatography to give 0.21g of white solid with 73.6% yield. The nuclear magnetic data is 1 HNMR(400MHz,CDCl 3 )δ7.92(s,1H,-NH),7.46(d,J＝7.6Hz,1H,Ar-H),7.29(d,J＝7.8Hz,1H,Ar-H),7.13(t,J＝7.5Hz,1H,Ar-H),7.08(t,J＝7.1Hz,1H,Ar-H),6.95(t,J＝8.6Hz,2H,phenyl-H),6.84(dd,J＝9.0,4.5Hz,2H,phenyl-H),3.81–3.76(m,2H,- 2 CHCH 2 -),3.75(s,2H,-N-CH 2 -),3.68–3.62(m,2H,- 2 CHCH 2 -),3.08–2.99(m,6H),2.92(t,J＝5.5Hz,2H,piperazine-CH 2 ),2.84(d,J＝5.1Hz,2H,piperazine-CH 2 ),2.70(t,J＝7.4Hz,2H,-COCH 2 -)； 13 CNMR(101MHz,CDCl 3 )δ170.2,157.7(d, 1 J C-F ＝239.9Hz),147.6(d, 4 J C-F ＝2.1Hz),136.1,131.5,127.2,121.4,119.4,118.7(d, 3 J C-F ＝7.8Hz),118.0,115.7(d, 2 J C-F ＝22.1Hz),110.7,108.3,53.4,51.19,50.8,50.7,50.6,45.7,41.6,31.8,21.4； 19 FNMR(377MHz,CDCl 3 )δ-123.2。
EXAMPLE 7 preparation of the objective Compound 2- (4- (4-fluorophenyl) piperazin-1-yl) -3- (1,2,3,4-tetrahydro- β -carbolin-2-yl) ethan-1-one
2-bromoacetyl-1,2,3,4-tetrahydro-beta-carboline (0.15g, 0.60mmol), potassium carbonate (0.10g, 0.72mmol), potassium iodide (0.01g, 0.06mmol), 4-fluorophenylpiperazine (0.12g, 0.66mmol) and 4mL acetonitrile are put into a 15mL reaction bottle by a one-pot method, and then the reaction is finished after reaction at 60 ℃ and TLC tracking until 2-bromoacetyl-1,2,3,4-tetrahydro-beta-carboline is completely consumed. The reaction was quenched with 20mL of water and extracted twice with 30mL of dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate, desolventized, and subjected to thin layer chromatography to obtain a pale yellow solid with a yield of 76.6%. The nuclear magnetic data are: 1 HNMR(400MHz,CDCl 3 )δ8.62(s,1H,-NH),7.46(d,J＝7.6Hz,1H,Ar-H),7.32(d,J＝7.9Hz,1H,Ar-H),7.14(t,J＝7.5Hz,1H,Ar-H),7.12–7.07(m,1H,Ar-H),6.95(t,J＝8.7Hz,2H,phenyl-H),6.87–6.82(m,2H,phenyl-H),4.81(s,2H,-N-CH 2 -),3.90(t,J＝5.5Hz,2H,- 2 CHCH 2 -),3.41(s,2H,-COCH 2 -),3.15–3.08(m,4H,piperazine-CH 2 ),2.89(t,J＝5.2Hz,2H,- 2 CHCH 2 -),2.74–2.68(m,4H,piperazine-CH 2 )； 13 CNMR(101MHz,CDCl 3 )δ169.1,157.2(d, 1 J C-F ＝238.7Hz),147.8(d, 4 J C-F ＝2.1Hz),136.3,130.19,126.8,121.8,119.5,117.9,117.9(d, 3 J C-F ＝7.3Hz),115.6(d, 2 J C-F ＝22.0Hz),111.1,107.9,61.8,53.2,50.2,44.2,40.8,22.2； 19 FNMR(377MHz,CDCl 3 )δ-124.4；HRMS(ESI)[M+H] + calcdforC 23 H 26 ON 4 F:393.2085,found:393.2083。
EXAMPLE 8 preparation of the title compound 2- (3- (4- (4-fluorophenyl) piperazin-1-yl) propyl) -1,2,3,4-tetrahydro- β -carboline
1,2,3,4-tetrahydro- β -carboline (0.12g, 0.70mmol), 1- (3-bromopropyl) -4- (4-fluorophenyl) piperazine (0.21g, 0.70mmol), potassium carbonate (0.12g, 0.84mmol), potassium iodide (0.01g, 0.07mmol) and 4mL acetonitrile were put into a 15mL reaction flask by one-pot method, reacted at 60 ℃, followed by TLC until 1- (3-bromopropyl) -4- (4-fluorophenyl) piperazine was completely consumed, and the reaction was terminated. The reaction was quenched with 20mL of water and extracted twice with 30mL of dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate, desolventized, and chromatographed over thin layer chromatography to give 0.21g of yellow solid in 76.4% yield. The nuclear magnetic data are: 1 HNMR(400MHz,CDCl 3 )δ8.38(s,1H,-NH),7.43(d,J＝7.5Hz,1H,Ar-H),7.31(d,J＝7.7Hz,1H,Ar-H),7.13–7.08(m,1H,Ar-H),7.08–7.04(m,1H,Ar-H),6.94(t,J＝8.7Hz,2H,phenyl-H),6.83(dd,J＝9.0,4.5Hz,2H,phenyl-H),3.71(s,2H,-N-CH 2 -),3.12–3.05(m,4H,piperazine-CH 2 ),2.89(t,J＝5.5Hz,2H,- 2 CHCH 2 -),2.82(d,J＝5.0Hz,2H,- 2 CHCH 2 -),2.69–2.64(m,2H,- 2 CHCH 2 -),2.63–2.55(m,4H,piperazine-CH 2 ),2.49–2.43(m,2H,-N- 2 CHCH 2 -),1.83(p,J＝6.7Hz,2H,-CH 2 2 CHCH 2 -)； 13 CNMR(101MHz,CDCl 3 )δ157.2(d, 1 J C-F ＝238.9Hz),147.8,136.1,131.1,127.0,121.4,119.3,117.9(d, 3 J C-F ＝7.8Hz),117.8,115.5(d, 2 J C-F ＝22.0Hz),110.9,107.9,56.5,55.7,53.2,51.1,50.2,50.0,29.7,24.2,21.0； 19 FNMR(376MHz,CDCl 3 )δ-124.4。
EXAMPLE 9 preparation of the object Compound 3-oxo-3- (1,2,3,4-tetrahydro- β -carbolin-2-yl) propyl 4- (4-fluorophenyl) piperazine-1-carbonidithiol
Under the ice-bath condition, slowly dropwise adding carbon disulfide (0.21g, 5.00mmol) into a reaction bottle containing 4-fluorophenylpiperazine (0.27g, 1.50mmol) and 4mL tetrahydrofuran, stirring for reaction for 3 hours, adding 2-acryloyl-1,2,3,4-tetrahydro-beta-carboline (0.23g, 1.0mmol) into the reaction system, reacting at 60 ℃, tracking by TLC until the consumption of 2-acryloyl-1,2,3,4-tetrahydro-beta-carboline is complete, and finishing the reaction. Adding 20mL of water to quenchThe reaction was carried out, and the reaction solution was extracted twice with 30mL of dichloromethane, and the organic phase was collected, dried over anhydrous sodium sulfate, desolventized, and subjected to thin layer chromatography to obtain 0.23g of a yellow solid with a yield of 95.8%. The nuclear magnetic data are: 1 HNMR(400MHz,CDCl 3 )δ8.76(s,1H,-NH),7.45(d,J＝7.7Hz,1H,Ar-H),7.31(d,J＝7.9Hz,1H,Ar-H),7.17–7.12(m,1H,Ar-H),7.12–7.06(m,1H,Ar-H),6.95(t,J＝8.7Hz,2H,phenyl-H),6.87(d,J＝4.5Hz,2H,phenyl-H),4.80(s,2H,-N-CH 2 -),3.79(t,J＝5.6Hz,2H,- 2 CHCH 2 -),3.18–3.07(m,4H,piperazine-CH 2 ),2.86(d,J＝12.8Hz,4H,piperazine-CH 2 ),2.78–2.71(m,2H,- 2 CHCH 2 -),2.71–2.62(m,4H,-CO 2 CHCH 2 -)； 13 CNMR(101MHz,CDCl 3 )δ197.2,171.0,157.2(d, 1 J C-F ＝238.9Hz),147.8(d, 4 J C-F ＝2.2Hz),136.2,130.4,126.7,121.7,119.5,117.9(d, 3 J C-F ＝7.9Hz),115.5(d, 2 J C-F ＝22.2Hz),111.1,107.6,54.1,53.3,50.1,44.0,40.6,31.3,22.0； 19 FNMR(377MHz,CDCl 3 )δ-124.4。
nuclear magnetic resonance and high resolution mass spectrometry data for the compounds of table 1
Figure BDA0003863042070000121
Figure BDA0003863042070000131
Figure BDA0003863042070000141
Figure BDA0003863042070000151
Figure BDA0003863042070000161
Figure BDA0003863042070000171
Figure BDA0003863042070000181
Figure BDA0003863042070000191
Figure BDA0003863042070000201
Figure BDA0003863042070000211
Figure BDA0003863042070000221
Figure BDA0003863042070000231
Figure BDA0003863042070000241
Figure BDA0003863042070000251
Figure BDA0003863042070000261
TABLE 2 physicochemical Properties of the target Compounds
Figure BDA0003863042070000262
Figure BDA0003863042070000271
2. Compound application
EXAMPLE 10 EC of Compounds on plant pathogenic bacteria 50
EC 50 (medianffectional concentration) is an important index for evaluating the sensitivity of plant pathogenic bacteria to compounds, and is also an important parameter for setting the concentration of the compounds when researching the action mechanism of target compounds. In the concentration gradient experiment, proper 5 concentrations are set by a double dilution method, finally the inhibition rate of the medicament on plant pathogenic bacteria and the medicament concentration are converted into paired numerical values, a toxicity curve is obtained through SPSS software regression analysis, and EC is calculated 50 。
Testing the effective medium concentration EC of target compound on plant pathogenic bacteria by adopting turbidity method 50 The test subjects were rice bacterial blight (Xoo), citrus canker (Xac) and kiwi canker (Psa). DMSO was dissolved in the medium as a blank control. The specific operation is as follows: 1) Placing the monoclonals of Xoo, xac and Psa (originally cultured in an NA solid culture medium) into an NB culture medium, and carrying out shake culture in a constant temperature shaking table at 28 ℃ and 180rpm until the logarithmic phase is reserved; 2) Agents/compounds were formulated at different concentrations (example: 100. 50, 25, 12.5, and 6.25 μ g/mL) of the toxic NB-containing liquid medium 5mL was added to the test tube, and the OD of the toxic NB-containing sterile NB liquid medium at the corresponding concentration was determined 595 Values (reported as sterile medium OD values); 3) Adding 40 μ L of bacteria solution cultured to logarithmic phase into all the treated test tubes, and shake culturing at 28 deg.C and 180rpm in constant temperature shaking table until CK group OD 595 Measuring OD of the bacteria solution with each concentration on spectrophotometer after the value is 0.6-0.8 595 Values (expressed as OD values of the bacteria-containing medium); 4) The inhibition (%) was calculated using the following formula: corrected OD value = bacteria-containing medium OD value — sterile medium OD value; suppression devicePercent production = [ (corrected contrast medium bacterial liquid OD value-corrected toxin-containing medium OD value)/corrected contrast medium bacterial liquid OD value]×100；
The results of the experiments with the target compounds in Table 1 above are shown in Table 3, following the procedure described above.
TABLE 3 EC of the Compounds on phytopathogenic bacteria 50
Figure BDA0003863042070000272
Figure BDA0003863042070000281
Figure BDA0003863042070000291
EXAMPLE 11 inhibitory Activity of the Compound against phytopathogenic fungi (50. Mu.g/mL)
The hypha growth rate method is also called as a medium-containing method, and is one of the conventional methods for measuring the toxicity of the bactericide. The main principle is that the tested medicament is mixed with the culture medium, and the virulence of the medicament is measured by the growth rate of bacterial colonies on the toxic culture medium. In the present example, gibberella zeae, rhizoctonia solani and plasmodiophora viticola were used as test subjects, and DMSO was used as a blank control. The specific operation is as follows: 1) Weighing a proper amount of medicine according to the test concentration, dissolving the medicine by DMSO (the dosage is not more than 1% of the final toxic culture medium), adding 0.1% Tween 20 solution to a constant volume of 10mL, pouring the constant volume into 90mL of melted PDA culture medium, uniformly mixing, and pouring into 9 culture dishes for later use; 2) Burning and sterilizing a puncher (with the inner diameter of 5 mm), after cooling, punching hypha on the edge of a pre-activated strain, sticking the hypha surface to the center of a toxic culture medium by using an inoculating needle, and after finishing treatment, uniformly culturing at 25 ℃; 3) After the diameter of the colony of the reference substance group grows to 5.5-6.6cm, measuring the diameters of the colony of the reference group and the colony of each medicament treatment group by adopting a cross method; 4) The inhibition (%) was calculated using the following formula: inhibition% = (C-T)/(C-0.5) × 100; wherein C is the colony diameter of the control group, T is the colony diameter of the medicament treatment group, and 0.5 is the diameter of the fungus cake for inoculation.
The results of the experiments with the target compounds in Table 1 above are shown in Table 4, following the procedure described above.
TABLE 4 inhibitory Activity of the Compounds on phytopathogenic fungi (50. Mu.g/mL)
Figure BDA0003863042070000292
In summary, it can be seen from Table 3 that the target compounds were against plant pathogenic bacteria [ e.g., bacterial blight of rice, canker citrus and kiwifruit canker germs ] in the in vitro test]Shows good inhibitory activity. EC of most compounds having benzyl groups in their structure against three pathogenic bacteria 50 All are within 10, especially the EC of compound 42 on rice bacterial blight 50 1.34 μ g/mL, EC of Compound 16 against Sclerotinia citrea 50 3.43 mug/mL; EC of compound 6 on kiwifruit canker pathogen 50 It was 2.86. Mu.g/mL. As can be seen from Table 4, the target compounds also exhibited some inhibitory activity against plant pathogenic fungi. Therefore, the compounds can be used for novel pesticides for resisting plant pathogenic bacteria and fungi, and have extremely high research value.
Finally, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that various changes and modifications may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (10)

1. 1,2,3,4-tetrahydro-beta-carboline derivative or stereoisomer thereof, or salt thereof or solvate thereof, the structural formula of the compound is shown as formula A,
Figure FDA0003863042060000011
wherein R is selected from any one of the following structures:
Figure FDA0003863042060000012
wherein R is 1 And R 2 One or more of each independently selected from hydrogen, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl, optionally substituted or unsubstituted benzyl; or R 1 And R 2 Joined to form any one of optionally substituted 4 to 10 membered rings or a heteroatom containing ring of N, O and one or more of S.
2. The 1,2,3,4-tetrahydro- β -carboline derivative of claim 1, wherein R is 1 And R 2 Each independently selected from hydrogen, optionally substituted or unsubstituted C 1-6 Alkyl, optionally substituted or unsubstituted C 2-6 Alkenyl, optionally substituted or unsubstituted C 5-10 Cycloalkyl, optionally substituted or unsubstituted C 5-10 Aryl, optionally substituted or unsubstituted C 5-10 Heteroaryl, optionally substituted or unsubstituted benzyl; or R 1 And R 2 Are linked to form an optionally substituted 5-to 10-membered ring or a heteroatom-containing ring.
3. The 1,2,3,4-tetrahydro- β -carboline derivative of claim 1, wherein R is 1 And R 2 Each independently selected from hydrogen, methyl, allyl, phenyl, benzyl, fluorobenzyl, chlorobenzyl, trifluoromethylbenzyl, methylbenzyl, methoxybenzyl, 2-furylmethyl or 2-thienylmethyl.
4. The 1,2,3,4-tetrahydro- β -carboline derivative of claim 1, when inR 1 And R 2 When the two groups are connected to form a ring, any one of the following groups is adopted:
Figure FDA0003863042060000013
5. the 1,2,3,4-tetrahydro- β -carboline derivative of claim 1, wherein the compound is selected from any of the following structures:
Figure FDA0003863042060000021
Figure FDA0003863042060000031
6. the method of preparing 1,2,3,4-tetrahydro- β -carboline derivatives of any of claims 1 to 5, wherein R is selected from the group consisting of compounds of structure a, the method comprising:
Figure FDA0003863042060000032
a method of making a compound having R selected from structure b comprises:
Figure FDA0003863042060000041
a method of making a compound having structure c, wherein R is selected from the group consisting of:
Figure FDA0003863042060000042
a method of making a compound wherein R is selected from structure d comprises:
Figure FDA0003863042060000043
a method of making a compound having structure e, wherein R is selected from the group consisting of:
Figure FDA0003863042060000044
7. a composition comprising the 1,2,3,4-tetrahydro- β -carboline derivative of any one of claims 1 to 5 or a stereoisomer thereof or a salt or solvate thereof.
8. A medicament comprising a 1,2,3,4-tetrahydro- β -carboline derivative or a stereoisomer thereof or a salt or solvate thereof according to any one of claims 1 to 5 or a composition according to claim 7; and a diluent or an auxiliary material.
9. The medicament of claim 8, wherein the diluent or excipient is suitable for emulsifiable concentrates, dusts, wettable powders, granules, aqueous solutions, suspensions, ultra-low volume sprays, soluble powders, microcapsules, smoke agents, aqueous emulsions or water dispersible granules.
10. Use of a 1,2,3,4-tetrahydro- β -carboline derivative or a stereoisomer thereof or a salt or solvate thereof according to any one of claims 1 to 5, a composition according to claim 7 or a medicament according to claim 8 or 9 for the control of agricultural fungal and bacterial diseases.
CN202211172658.1A 2022-09-26 2022-09-26 1,2,3, 4-tetrahydro-beta-carboline derivative and preparation method and application thereof Active CN115521306B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211172658.1A CN115521306B (en) 2022-09-26 2022-09-26 1,2,3, 4-tetrahydro-beta-carboline derivative and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202211172658.1A CN115521306B (en) 2022-09-26 2022-09-26 1,2,3, 4-tetrahydro-beta-carboline derivative and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN115521306A true CN115521306A (en) 2022-12-27
CN115521306B CN115521306B (en) 2024-03-26

Family

ID=84699918

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202211172658.1A Active CN115521306B (en) 2022-09-26 2022-09-26 1,2,3, 4-tetrahydro-beta-carboline derivative and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN115521306B (en)

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4663456A (en) * 1985-09-16 1987-05-05 American Home Products Corporation 2-(substituted piperazinylalkyl)β-carbolines useful in treatment of psychological disorders
US4766124A (en) * 1987-02-26 1988-08-23 American Home Products Corporation Beta-carbolin H1-receptor antagonists
US5091432A (en) * 1990-03-28 1992-02-25 Glasky Alvin J 9-substituted hypoxanthine bi-functional compounds and their neuroimmunological methods of use
CN1109870A (en) * 1994-02-03 1995-10-11 合成实验室公司 N-(3-aminopropyl)-N-phenyl-5,6,7,8-tetrahydronaphtalene-2-carboxamide derivative, preparation and application of same
CN1384833A (en) * 1999-10-15 2002-12-11 新疗法公司 Synthesis and methods of use of 9-substituted guanine derivatives
CN102424681A (en) * 2011-10-24 2012-04-25 华东师范大学 Acyl-tetrahydro-beta-carboline compound as well as derivatives, application and preparation method thereof
WO2014207240A1 (en) * 2013-06-28 2014-12-31 Alzprotect Carboline compounds usable in the treatment of neurodegenerative diseases
CN105669666A (en) * 2016-01-08 2016-06-15 华东师范大学 Small molecule compound YF-452 and application thereof in preparation of anti-angiogenesis drugs
WO2016116061A1 (en) * 2015-01-22 2016-07-28 南京明德新药研发股份有限公司 Resorcinol derivative as hsp90 inhibitor
CN108513537A (en) * 2015-09-23 2018-09-07 米纳瓦生物技术公司 The method of the reagent of screening differentiation stem cell
CN110621675A (en) * 2017-03-17 2019-12-27 阿古诺治疗有限公司 Tricyclic compounds for the treatment of proliferative diseases
CN112654354A (en) * 2018-08-16 2021-04-13 菲尼克思药业股份有限公司 1,3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indole derivative compound and application thereof

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4663456A (en) * 1985-09-16 1987-05-05 American Home Products Corporation 2-(substituted piperazinylalkyl)β-carbolines useful in treatment of psychological disorders
US4766124A (en) * 1987-02-26 1988-08-23 American Home Products Corporation Beta-carbolin H1-receptor antagonists
US5091432A (en) * 1990-03-28 1992-02-25 Glasky Alvin J 9-substituted hypoxanthine bi-functional compounds and their neuroimmunological methods of use
CN1109870A (en) * 1994-02-03 1995-10-11 合成实验室公司 N-(3-aminopropyl)-N-phenyl-5,6,7,8-tetrahydronaphtalene-2-carboxamide derivative, preparation and application of same
CN1384833A (en) * 1999-10-15 2002-12-11 新疗法公司 Synthesis and methods of use of 9-substituted guanine derivatives
CN102424681A (en) * 2011-10-24 2012-04-25 华东师范大学 Acyl-tetrahydro-beta-carboline compound as well as derivatives, application and preparation method thereof
WO2014207240A1 (en) * 2013-06-28 2014-12-31 Alzprotect Carboline compounds usable in the treatment of neurodegenerative diseases
WO2016116061A1 (en) * 2015-01-22 2016-07-28 南京明德新药研发股份有限公司 Resorcinol derivative as hsp90 inhibitor
CN108513537A (en) * 2015-09-23 2018-09-07 米纳瓦生物技术公司 The method of the reagent of screening differentiation stem cell
CN105669666A (en) * 2016-01-08 2016-06-15 华东师范大学 Small molecule compound YF-452 and application thereof in preparation of anti-angiogenesis drugs
CN110621675A (en) * 2017-03-17 2019-12-27 阿古诺治疗有限公司 Tricyclic compounds for the treatment of proliferative diseases
CN112654354A (en) * 2018-08-16 2021-04-13 菲尼克思药业股份有限公司 1,3,4, 9-tetrahydro-2H-pyrido [3,4-b ] indole derivative compound and application thereof

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ÁDÁM ANDOR KELEMEN等: "Spiro[pyrrolidine-3, 3′-oxindoles] as 5-HT7 receptor ligands", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 28, pages 2418 *
BEI ZHOU等: "Synthesis and antitumor activity of novel N-substituted tetrahydro-β -carboline –imidazolium salt derivatives", 《ORGANIC & BIOMOLECULAR CHEMISTRY》, vol. 14, pages 9423 - 9430 *
CEGLA, MAREK T.等: "4-Aryl-1-piperazinylalkyl derivatives of 1, 2, 3, 4-tetrahydro-β-carboline ring system. Synthesis and preliminary in vivo studies", 《PHARMAZIE》, vol. 51, no. 12, pages 932 - 936 *
M I N G M I N G Z H A N G等: "S y n t h e s i s a n d S t r u c t u re – A c t i v i t y R e l a t i o n s h i p s o f Te t r a h y d ro - β - c a r b o l i n e D e r i v a t i v e s a s A n t i c a n c e r a n d C a n c e r- c h e m o p re v e n t i v e A g e n t s", 《ANTICANCER RESEARCH》, vol. 38, pages 4425 - 4433 *
MAGID ABOU-GHARBIA等: "Psychotropic Agents: Synthesis and Antipsychotic Activity of Substituted fl-Carbolines", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 30, no. 6, pages 1100 - 1105, XP002536262, DOI: 10.1021/JM00389A022 *
MARIA LUISA BARBACCIA等: "[3HIlMIPRAMINE DISPLACEMENT AND 5HT UPTAKE INHIBITION BY TRYPTOLINE DERIVATIVES: IN RAT BRAIN 5-METHOXYTRYPTOLINE IS NOT THE AUTACOID FOR 13HIIMIPRAMINE RECOGNITION SITES", 《EUROPEAN JOURNAL OF PHARMACOLOGY》, vol. 123, pages 45 - 52, XP023769525, DOI: 10.1016/0014-2999(86)90685-0 *
MARION DONNIER-MARECHAL等: "Carboline- and phenothiazine-derivated heterocycles as potent SIGMA-1 protein ligands", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 89, pages 198 - 206, XP029110639, DOI: 10.1016/j.ejmech.2014.10.053 *
ONGTAO DU等: "Novel deoxyvasicinone and tetrahydro- beta -carboline hybrids as inhibitors of acetylcholinesterase and amyloid beta aggregation", 《BIOORG. MED. CHEM. LETT.》, vol. 30, pages 127659 *

Also Published As

Publication number Publication date
CN115521306B (en) 2024-03-26

Similar Documents

Publication Publication Date Title
US9862702B2 (en) Processes for the preparation of pesticidal compounds
CN109627206B (en) Preparation method and application of carbazolyl isopropanolamine derivatives with chiral centers
CN111454260B (en) 1,2,3,4-tetrahydro-beta-carboline compounds containing isopropanolamine substructure as well as preparation method and application thereof
CN109627205B (en) Preparation method and application of carbazolyl isopropanolamine derivatives
CN112062759B (en) Ethylsulfonyl-containing pyridine-1, 2, 4-oxadiazole substituted benzamide compounds and preparation method and application thereof
CN109535144A (en) A kind of 1,3,4- oxadiazoles thio-ether type compounds and its preparation method and application
CN112592335A (en) Carbazole isopropanol diamine compound containing 1, 2, 3-triazole and preparation method and application thereof
CN110606828A (en) Trifluoromethyl pyridine amide derivative containing chiral thioether structure and application thereof
CN110776548B (en) Acetoxy ursolic acid piperazine compounds containing isopropanolamine substructure as well as preparation method and application thereof
CN111285814B (en) Quinazolinone compound containing hydrazone structural unit or stereoisomer thereof, or salt or solvate thereof
CN113278020A (en) Pityriacitrin alkaloid derivative containing acylthiourea structure and preparation method and application thereof
CN111393359A (en) Pyridine salt-containing N- (cinnamoyl) -N&#39; - (substituted) propyl hydrazide compound and preparation method and application thereof
TWI255265B (en) Substituted tetrahydropyridines
CN114751885B (en) Coumarin compound containing isopropanolamine structure and preparation method and application thereof
CN115521306A (en) 1,2,3,4-tetrahydro-beta-carboline derivative and preparation method and application thereof
WO2019168112A1 (en) Imide derivative and bactericide containing same as active ingredient
CN110483405B (en) Kealiinine derivatives, preparation thereof and application thereof in resisting plant viruses and germs
CN115536543B (en) Triclosan compound containing isopropanolamine structure and preparation method and application thereof
CN112592321A (en) 1, 2, 3-triazole hydrazide or amide compounds and preparation method and application thereof
CN112624962B (en) Carbazolyl isopropanolamine derivatives with double chiral centers and preparation method and application thereof
CN116730852A (en) Substituted phenyl isopropanolamine-containing compound, and preparation method and application thereof
CN109553615A (en) A kind of pyrimidine salt compounds and application thereof
CN110903227B (en) Nitroguanidine compound and preparation and application thereof
CN117903096A (en) Cinnamoyl-substituted unsaturated nitrogen-containing heterocycle-containing oxygen-containing compound, composition, preparation method and application
CN114014777A (en) Compounds containing azobenzene isopropanolamine substructure and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant