CN106432208B - amino dithioformic acid (sulfamoyl) ethyl ester compound and preparation method and application thereof - Google Patents
amino dithioformic acid (sulfamoyl) ethyl ester compound and preparation method and application thereof Download PDFInfo
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a compound shown in a general formula (I) or pharmaceutically acceptable salt or solvate thereof, and also relates to a preparation method of the compound and application of the compound in preparing antitumor drugs.
Description
Technical Field
The invention relates to a compound with anti-tumor activity. In particular to a compound of a general formula (I) and a preparation method thereof, and also relates to an application of the compound of the general formula (I) in the aspect of tumor resistance.
Background
The dithiocarbamates have wide biological activity, especially antitumor activity. For example, Li Ruo et al, in Chinese invention patent application CN200410054686.9, disclose the general formula of such compounds:
Wherein R is2Is selected from- (CH)2)n-R3、-CH2-R4、-(CH2)m-COR5Or- (CH)2)m-COCO2R6。
Through a large number of experimental researches, the inventor of the invention continuously optimizes and reforms on the basis of the general formula, and discovers a novel amino dithioformic acid (sulfamoyl) ethyl ester compound with anti-tumor activity.
disclosure of Invention
In a first aspect of the invention, there is provided a compound having the general formula (I):
Wherein, R, R1、R2And R3One of the following two cases A and B is satisfied:
(A) R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, haloalkyl, and sulfanyl;
R1、R2and R3each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, sulfamoyl, acyl, thioacyl, acyloxy, amido, ureido, sulfinyl, alkylsulfonyl, arylsulfonyl, amino, haloalkyl, carbamoyl, halogen, cyano, isocyano, nitro, nitroso, thiocyano, isothiocyanato, hydrazido, sulfanyl, sulfo, and silyl, optionally substituted with one or more substituents each independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, cycloalkenyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, cycloalkoxy, aryloxy, amino, haloalkyl, carbamoyl, halogen, cyano, isocyano, nitro, nitroso, thiocyano, isothiocyanato, hydrazido, sulfo, and silyl, Heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, cycloalkoxyaryloxy, alkylthio, cycloalkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, acyl, thioacyl, acyloxy, acylamino, ureido, sulfinyl, alkylsulfonyl, arylsulfonyl, haloalkyl, carbamoyl, halogen, cyano, isocyano, nitro, nitroso, thiocyano, isothiocyanato, hydrazido, sulfanyl, sulfo, and silyl; or R1、R2And R3together with the carbon atoms to which they are attached, form a cycloalkyl, aryl, heteroaryl, or heterocyclyl group, optionally having one or more substituents thereon, each of the above substituents is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, acyl, thioacyl, acyloxy, amido, ureido, sulfinyl, alkylsulfonyl, arylsulfonyl, haloalkyl, carbamoyl, halogen, cyano, isocyano, nitro, nitroso, thiocyano, isothiocyanato, hydrazoyl, sulfanyl, sulfo, and silyl; or
(B)R1And R2Are each hydrogen, R3And R together with the carbon and nitrogen atoms to which they are respectively attached form a five-, six-, or seven-membered heterocyclic group optionally having one or more substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclylalkyl, alkoxy, cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, acyl, thioacyl, acyloxy, acylamino, ureido, sulfinyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, a fused benzene ring, a fused heteroaromatic ring, a haloalkyl, carbamoyl, halogen, cyano, isocyano, nitro, nitroso, thiocyano, isothiocyanato, hydrazide, a halogen atom, a cyano group, an aryl group, a heteroaryl group, a fused benzene ring, a fused heteroaromaticA group consisting of alkyl, thioalkyl, sulfo and silyl, said fused phenyl ring, fused heteroaryl ring optionally further substituted with alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, cycloalkoxy, aryloxy, alkylthio, cycloalkylthio, arylthio, alkoxycarbonyl, aryloxycarbonyl, acyl, thioacyl, acyloxy, amido, ureido, sulfinyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, fused phenyl ring, fused heteroaryl ring, haloalkyl, carbamoyl, halogen, cyano, isocyano, nitro, nitroso, thiocyano, isothiocyanato, hydrazido, sulfanyl, sulfo and silyl.
in a preferred embodiment, the compound has a structure represented by the following formula (II) or a structure represented by the following formula (III):
Wherein R is4Represents a substituent optionally present on the phenyl ring, said substituent being as defined in the preceding paragraph;
n is an integer selected from 0 to 5, m is an integer selected from 0, 1, 2; or
In a second aspect of the present invention, there is provided a pharmaceutical composition comprising: a compound according to the first aspect of the invention or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier.
In a third aspect of the invention, a process for the preparation of a compound of formula (I) as defined above, which process comprises the steps of:
(1) reacting 3-aminomethylpyridine with carbon disulfide in the presence of anhydrous phosphate to produce pyridin-3-ylmethylcarbamate; preferably, the anhydrous phosphate is anhydrous potassium phosphate;
(2) Reacting the starting material of formula (M) with 2-chloroethanesulfonyl chloride in the presence of an organic base, preferably triethylamine, to produce an intermediate of formula (Q);
(3) reacting the pyridin-3-ylmethylcarbamate obtained in step (1) with the intermediate of formula (Q) obtained in step (2) to obtain a compound according to any one of claims 1 to 6;
Wherein, R, R1、R2and R3As defined in the first aspect of the invention.
In a fourth aspect of the present invention, there is provided the use of a compound of formula (I) as described above, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of cancer.
In a preferred embodiment of the fourth aspect of the present invention, the tumor is selected from the group consisting of lung cancer, breast cancer, liver cancer, stomach cancer, cervical cancer, colon cancer and epithelial cancer.
Detailed Description
the term "alkyl" as used herein refers to a group consisting of only carbon and hydrogen atoms, and having no unsaturation (e.g., double bonds, triple bonds, or rings), which encompasses a wide variety of possible geometric and stereoisomeric groups. This group is connected to the rest of the molecule by a single bond. By way of non-limiting examples of alkyl groups, mention may be made of the following linear or branched groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and seven further isomers thereof, n-hexyl and sixteen further isomers thereof, n-heptyl and various isomers thereof, n-octyl and various isomers thereof, n-nonyl and various isomers thereof, and n-decyl and various isomers thereof.
The term "cycloalkyl" as used herein refers to a saturated non-aromatic ring system consisting of at least 3 carbon atoms, which may be monocyclic, bicyclic, polycyclic, fused, bridged, or spiro. As non-limiting examples of cycloalkyl groups, the following groups may be cited: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl; and fused, bridged or spiro ring groups formed from two or more of the above-mentioned monocyclic rings via a common side and a common carbon atom.
The term "alkenyl" as used herein refers to a group formed in the presence of one or more double bonds (other than methyl) in the above alkyl group.
the term "cycloalkenyl" as used herein refers to a group formed in the presence of one or more double bonds in the above cycloalkyl group.
The term "alkynyl" as used herein refers to a group formed when one or more triple bonds (other than methyl) are present in the alkyl group described above.
The term "alkoxy" as used herein refers to a group having an oxygen atom attached to the alkyl group and a single bond through the oxygen atom to the rest of the molecule, and encompasses a wide variety of possible geometric and stereoisomeric groups. By way of non-limiting examples of alkoxy radicals, mention may be made of the following linear or branched radicals: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy and its other seven isomers, n-hexoxy and its other sixteen isomers, n-heptoxy and its various isomers, n-octoxy and its various isomers, n-nonoxy and its various isomers, n-decoxy and its various isomers.
The term "aryl" as used herein refers to an aromatic ring system consisting of at least 6 carbon atoms, which may be monocyclic, bicyclic, polycyclic, wherein bicyclic and polycyclic rings may be formed from a single ring by single bond linkages or by fusion. As non-limiting examples of aryl groups, the following groups may be cited: phenyl, naphthyl, anthryl, phenanthryl, indenyl, pyrenyl, perylenyl, azulenyl, pentalenyl, heptalenyl, acenaphthenyl, fluorenyl, phenalenyl, fluoranthenyl, acephenanthrenyl, benzoacenaphthenyl, triphenylenyl, perylene, and the like,Phenyl, tetracenyl, picenyl, pentylphenyl, pentacenyl, tetraphthalenyl, hexylphenyl, hexacenyl, coronenyl, trinaphthyl, heptenyl, heptacene, pyranthryl, lecithin, biphenyl, and binaphthyl.
the term "heteroaryl" as used herein refers to a 5-14 membered aromatic heterocyclic ring system having one or more heteroatoms independently selected from N, O or S, which may be monocyclic, bicyclic, polycyclic, wherein bicyclic and polycyclic rings may be formed from a single ring by single bond linkages or fused. As non-limiting examples of heteroaryl groups, the following groups may be cited: oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl, coumarinyl, pyrazolopyridinyl, pyridopyridazinyl, pyrrolopyridyl, imidazopyridinyl, pyrazolopyridazinyl; and a group formed by the above-mentioned heteroaryl group by a single bond connection or a fusion connection.
The term "heterocyclyl" as used herein, means a non-aromatic 3-15 membered ring system consisting of carbon atoms and heteroatoms independently selected from N, O or S, which ring system may be monocyclic, bicyclic or polycyclic and may be fused, bridged or spirocyclic and may optionally contain one or more double bonds. As non-limiting examples of heterocyclyl groups, the following groups may be mentioned: aza derivativesA group selected from the group consisting of acridinyl, benzodioxolyl, chromanyl, dioxolanyl, dioxaphospholyl, decahydroisoquinolinyl, indanyl, indolinyl, isoindolinylChromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazaazanylBase, octahydroindolyl, octahydroisoindolyl, perhydroazepinePiperazinyl, 4-piperidinonyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, thiazolinyl, thiazolidinyl, thiomorpholinyl sulfoxide, and thiomorpholinyl sulfone.
the term "arylalkyl" as used herein, refers to an alkyl group having one or more hydrogen atoms independently replaced by an aryl group, wherein the aryl and alkyl groups are as defined above.
The term "heteroarylalkyl" as used herein refers to an alkyl group wherein one or more hydrogen atoms are independently replaced by a heteroaryl group, wherein the heteroaryl and alkyl groups are as defined above.
The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine or iodine.
The pharmaceutical composition of the present invention contains the compound of the first aspect of the present invention as an active ingredient. In addition, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, including but not limited to: water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar-agar, pectin, acacia, stearic acid or cellulose lower alkyl ethers, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid ethers, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. The pharmaceutical composition may further comprise one or more pharmaceutically acceptable adjuvants, wetting agents, emulsifying agents, suspending agents, preservatives, tonicity adjusting agents, buffering agents, sweetening agents, flavoring agents, coloring agents or any combination of the foregoing.
The pharmaceutical composition of the present invention can be formulated into any form of preparations, such as capsules, tablets, aerosols, solutions, suspensions, dragees, syrups, emulsions, ointments, pastes, injections, powders, granules, pastes, sustained-release preparations, foams. The drug of the present invention may be formulated into an oral administration preparation, a nasal administration preparation, a pulmonary administration preparation, an buccal preparation, a subcutaneous administration preparation, an intradermal administration preparation, a transdermal administration preparation, a parenteral administration preparation, a rectal administration preparation, a depot administration preparation, an intravenous administration preparation, an intraurethral administration preparation, an intramuscular administration preparation, an intranasal administration preparation, an ophthalmic administration preparation, an epidural administration preparation or a topical administration preparation, according to the administration route.
The "cancer" in the present invention includes various cancers known in the art, including but not limited to: lung cancer, liver cancer, stomach cancer, cervical cancer, colon cancer, breast cancer, leukemia, non-small cell cancer, prostate cancer or repigmoma, brain cancer, skin cancer, bone cancer, lymph cancer, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, duodenal cancer, small intestine cancer, large intestine cancer, pancreatic cancer, renal cancer, genital cancer, and thyroid cancer.
examples
The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
In one exemplary embodiment, the compounds of the present invention are synthesized by the following method, wherein each substituent is as defined in formula (I).
In an exemplary synthesis, 3-aminomethylpyridine is dissolved in dichloromethane, anhydrous potassium phosphate is added, and carbon disulfide is carefully added dropwise. After the reaction is carried out for 30min, the reaction is stopped, and excessive unreacted carbon disulfide and solvent are removed by rotary evaporation for standby. And (3) adding the raw materials M and triethylamine in the formula into another reaction bottle, and carefully dropwise adding 2-chloroethanesulfonyl chloride in an ice bath. Reacting for 30min, mixing with the obtained system for later use, and continuing to react for 6h at room temperature to stop the reaction. Adding the reaction system into water, extracting by using dichloromethane, combining organic layers, drying by using anhydrous sodium sulfate, filtering, concentrating, separating by using silica gel column chromatography to obtain a foamy solid, adding a small amount of ethyl acetate, and recrystallizing by using a cold-hot method to obtain the product.
example 1: 3-Pyridylmethylaminodithiocarboxylic acid- {2- (N-propylamino) sulfonyl } ethyl ester
3-Aminomethylpyridine (0.51mL, 5mmol) was dissolved in 20mL of dichloromethane, anhydrous potassium phosphate (2.12g, 10mmol) was added, and after 10 minutes carbon disulfide (0.75mL, 12.5mmol) was added carefully dropwise. After the reaction is carried out for 30min, the reaction is stopped, and excessive unreacted carbon disulfide and solvent are removed by rotary evaporation for standby. Another reaction flask was charged with propylamine (0.41mL, 5mmol) and triethylamine (2.50mL, 20mmol), and 2-chloroethanesulfonyl chloride (0.52mL, 5mmol) was carefully added dropwise while cooling on ice. Reacting for 30min, mixing with the obtained system for later use, and continuing to react for 6h at room temperature to stop the reaction. The reaction system was added to water (30mL), extracted with dichloromethane (30mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (P: E ═ 1:1 to P: E ═ 1:3) to give a foamy solid, and a small amount of ethyl acetate was added to recrystallize by the cold-hot method to give 0.56g of a white solid, with a yield of 33.6%, melting point 73-74 ℃.
1H NMR(400MHz,CDCl3):δ8.41(s,1H),8.32(s,1H),7.63(m,1H),7.23(m,1H),4.86(d,2H,J＝5.4Hz),3.52(m,2H),3.35(m,2H),3.01(m,2H),1.52(m,2H),0.86(t,3H,J＝7.4Hz).
13C NMR(100MHz,CDCl3):δ196.93,149.03,148.44,136.60,132.72,123.86,51.39,48.09,45.09,28.58,23.52,11.26
HRMS(ESI):calcd for C12H20N3O2S3；m/z([M+H]+)334.07050
Example 2: 3-Pyridylmethylaminodithiocarboxylic acid- {2- (N, N-diethylamino) sulfonyl } ethyl ester
Referring to example 1, substituting diethylamine for propylamine gave a white solid in 48.0% yield and a melting point of 88-90 ℃.
1H NMR(400MHz,CDCl3):δ8.45(m,2H),7.74(m,1H),7.28(m,1H),4.91(m,2H),3.69(m,4H),1.21(m,6H)
13C NMR(100MHz,CDCl3):δ180.69,149.07,148.76,135.76,123.63,110.00,66.30,47.28,47.07,45.38,12.73
HRMS(ESI):calcd for C13H22N3O2S3；m/z([M+H]+)348.08609
Example 3: 3-Pyridylmethylaminodithiocarboxylic acid- {2- (cyclohexylamino) sulfonyl } ethyl ester
Referring to example 1, substituting cyclohexylamine for propylamine gave a pale yellow solid, 38.0% yield, m.p. 136-137 ℃.
1H NMR(400MHz,CDCl3):δ8.37(m,2H),7.64(d,1H,J＝7.8Hz),7.21(m,1H),4.86(s,2H),3.55(m,2H),3.34(m,2H),1.96(m,2H),1.64(m,1H),1.06(m,4H),0.78(m,3H)
13C NMR(100MHz,CDCl3):δ195.99,148.19,147.67,135.43,131.58,122.77,52.07,47.14,33.58,32.11,27.80,24.18,23.88
HRMS(ESI):calcd for C15H24N3O2S3；m/z([M+H]+)374.10252
example 4: 3-Pyridylmethyldithiocarbamic acid- (2-p-cyanobenzylaminosulfonyl) ethyl ester
Referring to example 1, p-cyanobenzylamine was used instead of propylamine to give a white solid in 24.0% yield and a melting point of 66-69 ℃.
1H NMR(400MHz,CDCl3):δ8.50(m,2H),7.77(m,2H),7.69(m,1H),7.58(m,2H),7.37(m,1H),4.86(d,2H,J＝5.5Hz),4.62(s,2H),3.56(m,2H),3.39(m,2H)
13C NMR(100MHz,CDCl3):δ196.09,149.08,148.47,145.41,143.65,135.51,132.28,129.82,123.50,118.73,109.83,47.48,42.23,37.61
HRMS(ESI):calcd for C17H19N4O2S3；m/z([M+H]+)407.06646
Example 5: 3-Pyridinylmethylaminothiocarboxylic acid- (2-p-fluoroanilino sulfonyl) ethyl ester
Referring to example 1, p-fluoroaniline was used in place of propylamine to give a white solid in 18.3% yield and a melting point of 59-61 ℃.
1H NMR(400MHz,CDCl3):δ8.55(s,2H),8.47(m,1H),7.70(d,1H,J＝7.8Hz),7.28(m,5H),7.04(m,2H),4.92(d,2H,J＝4.8Hz),3.66(m,2H),3.48(m,2H)
13C NMR(100MHz,CDCl3):δ196.74,149.08,148.79,136.53,132.30,124.13,124.04,123.89,116.50,116.27,50.98,48.25,28.64
HRMS(ESI):calcd for C15H17FN3O2S3；m/z([M+H]+)386.04614
Example 6: 2- (3, 4-Difluorobenzylsulfonyl) ethyl 3-pyridylmethylaminothioate
referring to example 1, substituting 3, 4-difluorobenzylamine for propylamine gave a white solid in 37.7% yield and a melting point of 156-156 ℃.
1H NMR(400MHz,CDCl3):δ8.50(m,2H),7.94(m,1H),7.70(d,1H,J＝9.6Hz),7.39(m,2H),7.22(m,1H),4.85(d,2H,J＝5.5Hz),4.19(d,2H,J＝6.2Hz),3.49(m,2H),3.34(m,2H)
13C NMR(100MHz,CDCl3):δ196.03,149.07,148.47,135.51,132.72,124.32,123.51,117.45,117.27,116.60,116.43,51.03,47.26,44.80,27.81
HRMS(ESI):calcd for C16H18F2N3O2S3；m/z([M+H]+)418.05237
Example 7: 2- (2, 6-Difluoroanilinosulfonyl) ethyl 3-pyridylmethylaminothioate
Referring to example 1, substituting 2, 6-difluoroaniline for propylamine gave a tan liquid in 11.8% yield.
1H NMR(400MHz,CDCl3):δ8.39(m,2H),7.61(m,1H),7.12(m,2H),6.83(m,2H),4.79(s,2H),3.63(m,2H),3.51(m,2H)
13C NMR(100MHz,CDCl3):δ196.92,158.89,149.06,148.82,136.78,132.89,128.50,123.95,113.67,112.21,53.37,48.05,28.57
HRMS(ESI):calcd for C15H16F2N3O2S3；m/z([M+H]+)404.03660
Example 8: 3-Pyridinemethyldithiocarbamic acid 2- (2, 6-dichloroanilinosulfonyl) ethyl ester
Referring to example 1, substituting 2, 6-dichloroaniline for propylamine gave a red-brown liquid in 12.0% yield.
1H NMR(400MHz,CDCl3):δ8.47(m,2H),7.69(m,2H),7.28(m,3H),7.10(m,1H),4.89(d,2H,J＝5.1Hz),4.15(m,2H),3.63(m,2H),3.60(m,2H)
13C NMR(100MHz,CDCl3):δ196.29,149.03,148.51,136.40,134.80,133.61,130.54,125.91,123.71,122.09,60.35,20.95,14.10
HRMS(ESI):calcd for C15H16Cl2N3O2S3；m/z([M+H]+)435.97762
example 9: 3-Pyridinemethylaminodithiocarboxylic acid- (2-o-chloroanilinosulfonyl) ethyl ester
referring to example 1, substituting 2-chloroaniline for propylamine gave a white solid in 13.5% yield. The melting point is 96-98 ℃.
1H NMR(400MHz,DMSO-d6):δ8.51(m,2H),7.68(d,1H,J＝7.8Hz),7.51(m,2H),7.37(m,2H),7.27(m,1H),4.84(d,2H,J＝5.4Hz),3.62(m,2H),3.48(m,2H)
13C NMR(100MHz,DMSO-d6):δ196.42,149.56,148.97,135.99,134.22,133.19,130.43,129.47,128.36,128.16,128.09,124.00,52.83,47.77,28.30
HRMS(ESI):calcd for C15H17ClN3O2S3；m/z([M+H]+)402.01659
Example 10: 3-Pyridinylmethylaminothiocarboxylic acid- (2-m-bromophenylsulfonyl) ethyl ester
referring to example 1, substituting 3-bromoaniline for propylamine gave a white flocculent solid with a yield of 32.6% and a melting point of 59-61 ℃.
1H NMR(400MHz,CDCl3):δ8.43(m,2H),7.61(m,1H),7.38(m,2H),7.13(m,3H),4.86(m,2H),3.43(m,2H),3.21(m,2H)
13C NMR(100MHz,CDCl3):δ195.55,147.85,147.56,137.37,135.73,131.10,129.99,127.09,126.50,123.00,122.03,117.76,47.24,45.38,20.07
HRMS(ESI):calcd for C15H17ClN3O2S3；m/z([M+H]+)445.06600
Example 11: 3-Pyridinemethylaminodithiocarboxylic acid- (2-p-bromoanilinosulfonyl) ethyl ester
Referring to example 1, substituting propylamine with 4-bromoaniline gave a white solid in 28.6% yield, mp 66-68 ℃.
1H NMR(400MHz,CDCl3):δ8.47(m,2H),8.15(m,1H),7.63(m,2H),7.37(m,2H),7.09(m,2H),4.88(d,2H,J＝5.4Hz),3.43(m,2H),3.17(t,2H,J＝6.7Hz)
13C NMR(100MHz,CDCl3):δ195.62,148.28,147.95,135.60,134.79,132.02,131.75,122.93,122.00,121.17,48.34,47.30,28.68
HRMS(ESI):calcd for C15H17BrN3O2S3；m/z([M+H]+)445.96608
example 12: 3-Pyridylmethyldithiocarbamic acid 2- (N-methyl-p-nitroanilinosulfonyl) ethyl ester
referring to example 1, substituting propylamine with N-methyl-p-nitroaniline gave a yellow solid in 50.1% yield, m.p. 119-121 ℃.
1H NMR(400MHz,DMSO-d6):δ8.50(m,2H),8.25(m,2H),7.68(m,3H),7.37(m,1H),4.82(d,2H,J＝5.5Hz),3.65(m,2H),3.51(m,2H),2.51(s,3H)
13C NMR(100MHz,DMSO-d6):δ195.74,149.06,148.47,147.08,144.41,135.22,132.63,124.45,124.40,123.48,49.75,47.33,37.29,27.47
HRMS(ESI):calcd for C16H19N4O4S3；m/z([M+H]+)427.05629
Example 13: 3-Pyridinemethylaminodithiocarboxylic acid- (2- (2-methyl-6-nitroanilino) sulfonyl) ethyl ester
referring to example 1, substituting propylamine with 2-methyl-6-nitroaniline, a white solid was obtained in 50.1% yield and a melting point of 68-69 ℃.
1H NMR(400MHz,CDCl3):δ8.44(m,2H),8.29(m,1H),8.28(m,1H),7.62(m,2H),7.30(m,1H),7.19(m,1H),7.06(m,1H),4.82(d,2H,J＝5.3Hz),3.58(m,2H),3.56(m,2H),2.24(s,3H)
13C NMR(100MHz,CDCl3):δ195.45,148.74,147.19,146.03,134.95,133.74,130.75,128.56,125.00,122.86,119.35,115.74,51.39,47.33,27.57,17.70
HRMS(ESI):calcd for C16H19N4O4S3；m/z([M+H]+)427.05629
Example 14: 3-Pyridinemethyldithiocarbamic acid- (2- (2, 4-dimethylanilino) sulfonyl) ethyl ester
Referring to example 1, substituting propylamine with 2, 4-dimethylaniline, a white solid was obtained in 22.1% yield, mp 111-113 ℃.
1H NMR(400MHz,CDCl3):δ8.53(m,1H),8.42(s,1H),8.37(m,1H),7.60(d,1H,J＝7.9Hz),7.24(m,1H),6.90(m,2H),4.82(d,2H,J＝5.1Hz),3.59(m,2H),3.43(m,2H),2.24(s,3H),2.21(s,3H)
13C NMR(100MHz,CDCl3):δ195.76,148.23,147.87,135.42,135.34,131.30,131.19,130.91,130.68,126.70,123.17,122.76,50.87,47.19,27.67,19.84,17.27
HRMS(ESI):calcd for C17H22N3O2S3；m/z([M+H]+)396.08687
Example 15: 3-Pyridylmethylaminodithiocarboxylic acid- (2-phenethylaminosulfonyl) ethyl ester
Referring to example 1, substituting phenethylamine for propylamine gave a yellow solid in 27.0% yield, mp 85-87 ℃.
1H NMR(400MHz,CDCl3):δ8.52(m,2H),8.11(s,1H),7.71(d,1H,J＝7.7Hz),7.28(m,5H),4.95(d,2H,J＝5.1Hz),3.57(dd,2H,J＝9.1,6.0Hz),3.45(dd,2H,J＝13.2,6.7Hz),3.36(dd,2H,J＝9.1,6.0Hz),2.93(t,2H,J＝6.9Hz)
13C NMR(100MHz,CDCl3):δ196.93,149.38,149.21,137.76,136.22,132.05,128.93,128.87,126.94,123.79,51.58,48.32,44.51,36.56,28.75
HRMS(ESI):calcd for C17H22N3O2S3；m/z([M+H]+)396.0868
example 16: 3-Pyridinemethylaminodithiocarboxylic acid- (2-mesitylenesulfonyl) ethyl ester
referring to example 1, mesitylene was used instead of propylamine to give a white solid in 20.0% yield, mp 91-94 ℃.
1H NMR(400MHz,CDCl3):δ8.58(m,2H),7.75(d,1H,J＝7.7Hz),7.43(m,1H),6.94(m,2H),4.99(d,2H,J＝5.3Hz),3.68(m,2H),3.51(m,2H),2.33(s,6H),2.26(s,3H)
13C NMR(100MHz,CDCl3):δ196.04,149.07,148.46,137.11,136.24,135.51,132.73,130.97,128.90,123.50,53.63,47.26,27.99,20.72,18.90
HRMS(ESI):calcd for C18H24N3O2S3；m/z([M+H]+)410.10252
Example 17: 3-Pyridinemethylaminodithiocarboxylic acid- (2-p-methylanilinosulfonyl) ethyl ester
referring to example 1, p-methylaniline was used in place of propylamine to give white crystals in 7.6% yield and 108-110 ℃ melting point.
1H NMR(400MHz,CDCl3):δ8.41(s,1H),8.36(m,1H),8.05(s,1H),7.60(m,1H),7.09(m,4H),4.79(s,2H),3.55(dd,2H,J＝8.6,6.0Hz),3.37(dd,2H,J＝8.6,6.0Hz),2.22(s,3H)
13C NMR(100MHz,CDCl3):δ195.76,148.08,147.65,135.50,134.31,132.89,129.85,129.09,124.68,120.83,49.83,47.13,27.60,19.85
HRMS(ESI):calcd for C16H20N3O2S3；m/z([M+H]+)382.07122
example 18: 3-Pyridinylmethylaminothiocarboxylic acid- (2-dianilinosulfonyl) ethyl ester
Referring to example 1, diphenylamine was used in place of propylamine to give a pale yellow solid in 14.0% yield and a melting point of 139-140 ℃.
1H NMR(400MHz,CDCl3):δ8.42(m,2H),8.24(m,1H),7.61(d,1H,J＝7.8Hz),7.19(m,10H),4.83(s,2H),3.89(m,2H),3.71(m,2H)
13C NMR(100MHz,CDCl3):δ196.14,143.96,149.13,143.96,141.17,136.39,130.88,130.45,130.02,130.02,127.86,54.40,48.37,28.17
HRMS(ESI):calcd for C21H22N3O2S3；m/z([M+H]+)444.08647
Example 19: 3-Pyridylmethyldithiocarbamic acid- (2-alpha-naphthylaminosulfonyl) ethyl ester
Referring to example 1, substituting α -naphthylamine for propylamine gave a pale yellow solid, 13.2% yield, m.p. 142-146 ℃.
1H NMR(400MHz,CDCl3):δ8.50(m,2H),8.31(m,1H),7.95(d,1H,J＝7.6Hz),7.84(d,1H,J＝8.1Hz),7.67(d,1H,J＝7.8Hz),7.56(m,4H),7.36(m,1H),4.85(d,2H,J＝5.3Hz),3.65(dd,2H,J＝9.7,5.2Hz),3.51(d,2H,J＝9.6,5.3Hz)
13C NMR(100MHz,CDCl3):δ196.43,149.58,148.95,136.01,134.45,133.19,133.00,130.08,128.51,127.22,126.84,126.80,126.14,123.98,123.80,123.61,51.95,47.79,28.40
HRMS(ESI):calcd for C19H20N3O2S3；m/z([M+H]+)418.07122
Example 20: 3-Pyridylmethyldithiocarbamic acid- (2-o-methoxybenzylaminosulfonyl) ethyl ester
Referring to example 1, substituting propylamine with 2-methoxybenzylamine gave a pale yellow solid, 29.2% yield, m.p. 117-119 ℃.
1H NMR(400MHz,CDCl3):δ8.36(m,2H),7.59(d,1H,J＝7.7Hz),7.20(m,2H),6.91-6.77(m,3H),4.82(s,2H),3.45(dd,2H,J＝13.0,6.2Hz),3.21(m,2H)
13C NMR(100MHz,CDCl3):δ196.95,157.44,149.33,148.91,136.27,132.36,129.86,129.66,124.91,123.71,120.81,110.54,55.41,52.16,48.15,43.65,28.63
HRMS(ESI):calcd for C17H22N3O2S3；m/z([M+H]+)412.08267
example 21: 3-Pyridylmethyldithiocarbamic acid- (2-benzylaminosulfonyl) ethyl ester
referring to example 1, substituting benzylamine for propylamine gave a white needle-like solid with a yield of 19.2% and a melting point of 129-131 ℃.
1H NMR(400MHz,DMSO-d6):δ8.84(m,2H),8.40(d,1H,J＝8.0Hz),8.00(dd,1H,J＝7.8,5.7Hz),7.91(t,1H,J＝6.2Hz),7.34(m,4H),4.98(d,2H,J＝5.4Hz),4.18(d,2H,J＝6.1Hz),3.50(dd,2H,J＝9.4,5.9Hz),3.28(dd,2H,J＝9.3,6.0Hz)
13C NMR(100MHz,DMSO-d6):δ196.95,143.91,141.71,141.44,138.18,136.72,128.34,127.63,127.22,126.58,50.94,46.43,45.94,27.96
HRMS(ESI):calcd for C16H20N3O2S3；m/z([M+H]+)382.07045
Example 22: 3-Pyridylmethyldithiocarbamic acid- {2- [ (4-fluorobenzylamino) sulfonyl ] } Ethyl ester
Referring to example 1, substituting p-fluorobenzylamine for propylamine gave a white solid in 67% yield, m.p. 133-134 ℃.
1H NMR(400MHz,DMSO):δ3.27-3.31(m,2H),3.46-3.50(m,2H),4.16(s,2H),4.84(s,2H),7.14-7.18(m,1H),7.36-7.40(m,3H),7.69-7.71(m,1H),8.46-8.51(m,2H).
13C NMR(100MHz,DMSO):δ28.29,45.58,47.58,51.55,115.48,115.69,124.04,130.09,130.18,133.24,134.88,136.04,148.91,149.45,163.08,196.50.
Anal.Cald for C16H18FN3O2S3:C,48.10；H,4.54；N,10.52；Found:C,47.93；H,4.48；N,10.33.
Example 23: 3-Pyridylmethylaminodithiocarboxylic acid- {2- [ (3, 4-dichlorobenzylamino) sulfonyl ] } Ethyl ester
Referring to example 1, substituting 3, 4-dichlorobenzylamine for propylamine gave a white solid in 72% yield and a melting point of 145-146 ℃.
1H NMR(400MHz,DMSO):δ3.33-3.36(m,2H),3.49-3.51(m,2H),4.18(s,2H),4.84(s,2H),7.32-7.39(m,2H),7.58-7.70(m,3H),8.47-8.51(m,2H).
13C NMR(100MHz,DMSO):δ28.27,45.02,47.57,51.45,124.06,128.36,129.93,130.22,131.02,131.41,133.23,136.05,140.14,148.92,149.45,196.44.
Anal.Cald for C16H17Cl2N3O2S3:C,42.66；H,3.80；N,9.33；Found:C,42.59；H,4.08；N,9.06.
Example 24: 3-Pyridylmethylaminodithiocarboxylic acid- {2- [ (4-methoxybenzylamino) sulfonyl ] } ethyl ester
referring to example 1, substituting 4-methoxybenzylamine for propylamine gave a white solid in 51% yield, m.p. 136-138 ℃.
1H NMR(400MHz,DMSO):δ3.23-3.27(m,2H),3.45-3.49(m,2H),4.12(s,2H),4.86(s,2H),6.88-6.19(m,2H),7.25-7.39(m,3H),7.68-7.77(m,2H),8.49-8.52(m,2H),10.62(bs,1H).
13C NMR(100MHz,DMSO):δ28.34,45.98,47.76,55.56,114.25,124.00,129.51,130.48,133.23,136.01,148.96,149.56,159.00,196.60.
Anal.Cald for C17H21N3O3S3:C,49.61；H,5.14；N,10.21；Found:C,49.52；H,5.08；N,10.21.
Example 25: 3-Pyridylmethyldithiocarbamic acid- {2- [ (2-furanmethylamino) sulfonyl ] } ethyl ester
Referring to example 1, substituting propylamine with 2-furanmethanamine gave a white solid in 51% yield, m.p. 135-137 ℃.
1H NMR(400MHz,DMSO):δ3.22-3.26(m,2H),3.43-3.45(m,2H),4.17(s,2H),4.83(s,2H),6.32-6.40(m,2H),7.36-7.40(m,2H),7.36-7.39(m,1H),7.59-7.70(m,2H),8.47-8.50(m,2H).
13C NMR(100MHz,DMSO):δ28.22,40.53,47.56,51.71,99.92,108.44,111.05,124.04,136.03,143.09,148.90,149.44,151.58,196.47.
HRMS(ESI+)m/z calcd for C14H17N3O3S3(M+H)+,372.0432,found372.0508.
Example 26: 3-Pyridylmethylaminodithiocarboxylic acid- {2- [ (3-pyridylmethylamino) sulfonyl ] } ethyl ester
referring to example 1, substituting 3-pyridylmethylamine for propylamine gave a white solid in 40% yield, m.p. 163-164 ℃.
1H NMR(400MHz,DMSO):δ3.34-3.54(m,4H),4.23(s,2H),4.85(s,2H),7.37-7.40(m,2H),7.69-7.93(m,3H),8.49-8.53(m,4H),10.64(bs,1H).
13C NMR(100MHz,DMSO):δ28.36,44.02,47.77,51.46,123.97,124.01,133.23,134.33,135.98,136.03,148.95,149.41,149.56,196.58.
Anal.Cald for C15H18N4O2S3:C,47.10；H,4.74；N,14.65；Found:C,47.34；H,4.86；N,14.67.
Example 27: 3-Pyridinemethyldithiocarbamic acid- [2- (anilinosulfonyl) ] ethyl ester
Referring to example 1, substituting aniline for propylamine gave a white solid in 57% yield, m.p. 117-118 ℃.
1H NMR(400MHz,DMSO):δ3.34-3.54(m,4H),4.23(s,2H),4.85(s,2H),7.37-7.40(m,2H),7.69-7.93(m,3H),8.49-8.53(m,4H),10.64(bs,1H).
13C NMR(100MHz,DMSO):δ28.15,47.73,50.93,120.38,123.98,124.41,129.71,133.17,135.96,138.36,148.95,149.54,196.31.
HRMS(ESI+)m/z calcd for C15H17N3O2S3(M+H)+,368.0483,found368.0565.
Example 28: 3-Pyridylmethyldithiocarbamic acid- [2- [ N- (quinolin-8-yl) aminosulfonyl ] ] ethyl ester
referring to example 1, substituting propylamine with 8-aminoquinoline gave a pale yellow solid in 13% yield, m.p. 108-109 ℃.
1H NMR(400MHz,CDCl3):δ＝3.53-3.56(m,4H),4.73(d,J＝5.60Hz,2H),7.14-7.18(m,1H),7.43-7.50(m,2H),7.55(d,J＝8.00Hz,2H),7.80(dd,J＝1.20,7.60Hz,1H),8.16(dd,J＝1.60,8.00Hz,1H),8.33(s,1H),8.78(dd,J＝1.60,8.40Hz,1H),8.93(t,J＝4.80Hz,2H),9.05(s,1H).
13C NMR(100MHz,CDCl3):δ＝28.39,48.08,50.79,115.12,122.26,122.76,123.78,127.01,128.42,132.39,133.73,136.30,136.47,138.70,148.73,149.01,149.15,196.40.
HRMS(ESI+)m/z Calcd for C18H19N4O2S3(M+H)+:419.06701,Found:419.06713.
Example 29: 3-Pyridylmethyldithiocarbamic acid- [2- [ N- (4- (morpholin-1-yl) phenyl) aminosulfonyl ] ] ethyl ester
Referring to example 1, substituting 4- (4-morpholinyl) aniline for propylamine gave a white solid in 10% yield, m.p. 147-148 ℃.
1H NMR(400MHz,DMSO-d6):δ＝3.05(t,J＝4.40Hz,4H),3.28-3.32(m,2H),3.50-3.54(m,2H),3.72(t,J＝4.40Hz,4H),4.82(d,J＝5.60Hz,2H),6.90(d,J＝9.20Hz,2H),7.13(d,J＝8.80Hz,2H),7.36-7.39(m,1H),7.68(d,J＝7.60Hz,1H),8.48-8.51(m,2H),9.55(s,1H),10.61(t,J＝5.20Hz,1H).
13C NMR(100MHz,DMSO-d6):δ＝27.22,47.25,48.58,50.01,66.05,115.68,123.18,123.54,128.99,132.76,135.63,148.34,148.49,148.94,195.92.
HRMS(ESI+)m/z Calcd for C19H25N4O3S3(M+H)+:453.10888,Found:453.10870.
Example 30: 3-Pyridylmethyldithiocarbamic acid- [2- [ N- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl ] aminosulfonyl ] ] ethyl ester
Referring to example 1, substituting 3-chloro-4- (pyridin-2-ylmethoxy) aniline for propylamine gave a pale yellow solid in 49% yield, m.p. 67-68 ℃.
1H NMR(400MHz,CDCl3):δ＝3.45(t,J＝7.20Hz,2H),3.64(t,J＝7.20Hz,2H),4.90(d,J＝5.20Hz,2H),5.20(s,2H),6.90(d,J＝9.20Hz,1H),7.15(dd,J＝2.40,8.80Hz,1H),7.22-7.25(m,2H),7.42(d,J＝2.40Hz,1H),7.61(d,J＝7.60Hz,1H),7.66(d,J＝7.60Hz,1H),7.23-7.77(m,1H),8.29(s,1H),8.44(d,J＝4.40Hz,1H),8.54(t,J＝5.20Hz,2H),8.73(t,J＝5.20Hz,1H).
13C NMR(100MHz,CDCl3):δ＝28.85,48.42,51.26,71.67,114.49,121.62,122.66,123.13,123.79,124.00,125.32,130.31,132.88,136.56,137.37,148.97,149.17,149.26,152.24,156.46,196.89.
HRMS(ESI+)m/z Calcd for C21H22ClN4O3S3(M+H)+:509.05426,Found:509.05410.
Example 31: 3-Pyridylmethyldithiocarbamic acid- {2- (4-methylpiperazin-1-yl) sulfonyl } ethyl ester
referring to example 1, substituting N-methylpiperazine for propylamine gave a white solid in 33.6% yield, mp 73-74 ℃.
1H NMR(400MHz,CDCl3):δ8.41(s,1H),8.32(s,1H),7.63(m,1H),7.23(m,1H),4.86(d,2H,J＝5.4Hz),3.52(m,2H),3.35(m,2H),3.01(m,2H),1.52(m,2H),0.86(t,3H,J＝7.4Hz).
13C NMR(100MHz,CDCl3):δ196.93,149.03,148.44,136.60,132.72,123.86,51.39,48.09,45.09,28.58,23.52,11.26
HRMS(ESI):calcd for C12H20N3O2S3；m/z([M+H]+)334.07050
Example 32: 3-Pyridylmethyldithiocarbamic acid- (2- (morpholin-1-yl) sulfonyl) ethyl ester
Referring to example 1, morpholine was used in place of propylamine to give a white solid in 30.7% yield, mp 108-109 ℃.
1H NMR(400MHz,CDCl3):δ8.39(m,2H),7.64(d,1H,J＝7.8Hz),7.22(m,1H),4.86(s,2H),3.67(m,4H),3.54(m,2H),3.33(m,2H),3.27(m,4H)
13C NMR(100MHz,CDCl3):δ196.78,149.21,148.86,136.45,132.40,123.84,66.58,49.45,48.32,45.78,28.29
HRMS(ESI):calcd for C13H20N3O3S3；m/z([M+H]+)362.06613
Example 33: 3-Pyridylmethyldithiocarbamic acid- [2- (4-phenylpiperazin-1-ylsulfonyl) ] ethyl ester
Referring to example 1, substituting propylamine with N-phenylpiperazine gave a white solid in 42% yield, mp 144-146 deg.C.
1H NMR(400MHz,DMSO):δ3.19-3.37(m,8H),3.46-3.57(m,4H),4.85(s,2H),6.80-6.97(m,3H),7.35-7.70(m,3H),7.68-7.70(m,1H),8.49-8.53(m,2H).
13C NMR(100MHz,DMSO):δ28.16,45.59,47.64,48.74,116.60,120.10,124.04,129.50,133.20,136.07,148.92,149.47,150.99,196.50.
Anal.Cald for C19H24N4O2S3:C,52.27；H,5.54；N,12.83；Found:C,52.29；H,5.74；N,12.67.
Example 34: 3-Pyridylmethyldithiocarbamic acid- [2- [ (3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl ] ] ethyl ester
Referring to example 1,2,3, 4-tetrahydroisoquinoline was used instead of propylamine to give a pale yellow solid, yield 41%, m.p. 116-117 ℃.
1H NMR(400MHz,DMSO-d6):δ＝2.90(t,J＝5.60Hz,2H),3.47-3.57(m,6H),4.46(s,2H),4.84(d,J＝5.60Hz,2H),7.15-7.20(m,4H),7.35-7.39(m,1H),7.68-7.71(m,1H),8.48-8.52(m,2H),10.65(s,1H).
13C NMR(100MHz,DMSO-d6):δ＝27.68,28.48,42.96,46.51,47.32,48.71,123.52,126.12,126.29,126.59,128.85,132.19,132.72,133.32,135.59,148.44,149.05,196.03
HRMS(ESI+)m/z Calcd for C18H22N3O2S3(M+H)+:408.08741,Found:408.08735.
example 35: 2- { [4- (quinolin-8-ylsulfonyl) piperazin-1-yl ] sulfonyl } ethyl 3-picolylaminodithioate
Referring to example 1, substituting 8- (piperazin-1-ylsulfonyl) quinoline hydrochloride for propylamine, a pale yellow solid was obtained in 66% yield, m.p. 169-170 ℃.
1H NMR(400MHz,DMSO-d6):δ＝3.28-3.29(m,2H),3.35-3.48(m,10H),4.82(d,J＝5.20Hz,2H),7.38-7.41(m,1H),7.67-7.70(m,2H),7.77(d,J＝8.00Hz,1H),8.31-8.33(m,1H),8.39(dd,J＝1.20,7.60Hz,1H),8.49-8.54(m,3H),9.07(dd,J＝1.60,4.40Hz,1H),10.62(t,J＝5.60Hz,1H).
13C NMR(100MHz,DMSO-d6):δ＝25.57,45.36,45.88,47.28,48.79,122.53,123.52,125.72,128.75,132.58,132.72,134.23,135.59,135.85,136.86,143.16,148.44,149.06,151.45,195.96.
HRMS(ESI+)m/z Calcd for C22H26N5O4S4(M+H)+:552.08676,Found:552.08670.
Example 36: 3-Pyridylmethyldithiocarbamic acid- [2- [ [4- [ (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) sulfonyl ] -1, 4-diazepan-1-yl ] sulfonyl ] ] ethyl ester
Referring to example 1, 1- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-ylsulfonyl) -1, 4-diazepan hydrochloride was used instead of propylamine to give a pale yellow solid in 29% yield and melting point 126-128 ℃.
1H NMR(400MHz,DMSO-d6):δ＝1.80(t,J＝4.80Hz,2H),3.24-3.30(m,4H),3.37-3.51(m,8H),4.32(d,J＝4.00Hz,4H),4.85(d,J＝5.20Hz,2H),7.06(d,J＝8.40Hz,1H),7.25-7.27(m,2H),7.36-7.39(m,1H),7.69(d,J＝7.60Hz,1H),8.48-8.52(m,2H),10.64(s,1H).
13C NMR(100MHz,DMSO-d6):δ＝27.69,29.40,46.71,46.91,47.30,49.12,49.89,49.94,64.03,64.36,115.70,117.77,120.26,123.49,130.86,132.70,135.51,143.46,147.20,148.47,149.08,196.03.
HRMS(ESI+)m/z Calcd for C22H29N4O6S4(M+H)+:573.09699,Found:573.09687.
Example 37: 3-Pyridylmethyldithiocarbamic acid- [2- [ (3, 4-dihydroquinolin-1 (2H) -yl) sulfonyl ] ] ethyl ester
Referring to example 1, substituting 1,2,3, 4-tetrahydroquinoline for propylamine gave a pale yellow solid in 20% yield, m.p. 124-125 ℃.
1H NMR(400MHz,DMSO-d6):δ＝1.90-1.97(m,2H),2.81(t,J＝6.40Hz,2H),3.51-3.59(m,4H),3.71(t,J＝6.00Hz,2H),4.81(d,J＝5.60Hz,2H),7.03-7.06(m,1H),7.15(t,J＝8.00Hz,2H),7.34-7.37(m,1H),7.51(d,J＝8.00Hz,1H),7.66(d,J＝8.00Hz,1H),8.47-8.50(m,2H),10.64(s,1H).
13C NMR(100MHz,DMSO-d6):δ＝22.22,26.40,27.69,46.13,47.30,51.04,121.85,123.51,123.93,126.25,129.31,129.65,132.68,135.52,136.61,148.50,149.10,195.85.
HRMS(ESI+)m/z Calcd for C18H22N3O2S3(M+H)+:408.08741,Found:408.08733.
Example 38: 3-Pyridylmethyldithiocarbamic acid- [2- [ [4- [ (2, 6-difluorophenyl) sulfonyl ] piperazin-1-yl ] sulfonyl ] ] ethyl ester
Referring to example 1, substituting 1- (2, 6-difluorobenzenesulfonyl) piperazine for propylamine gave a pale yellow solid in 36% yield, mp 182-183 ℃.
1H NMR(400MHz,DMSO-d6):δ＝3.24(s,4H),3.32-3.49(m,8H),4.83(d,J＝5.20Hz,2H),7.32-7.40(m,3H),7.68-7.80(m,2H),8.48-8.52(m,2H),10.64(t,J＝5.20Hz,1H).
13C NMR(100MHz,DMSO-d6):δ＝27.58,44.70,45.27,47.31,49.08,113.92,123.51,132.69,135.54,136.42,148.49,149.12,157.44,160.20,195.98.
HRMS(ESI+)m/z Calcd for C19H23F2N4O4S4(M+H)+:537.05702,Found:537.05716.
Test example 1
The activity of the compounds of examples 1-21 and 31-32 of the present invention was determined by the adherent cell MTT method, as follows.
culturing in vitro a liver cancer cell line Bel7402, a prostate cancer cell line PC3, a colon cancer cell line HCT116, a breast cancer cell line MDA-MB-468 and a breast cancer cell line SKBr-3. After the cells had grown to a logarithmic growth phase, the cells were collected, centrifuged at 1000rpm for 5 minutes, the supernatant was discarded, suspended in an appropriate amount of medium, and the cell concentration was adjusted to 3X 104And/ml. The cell suspension was inoculated into a 96-well cell culture plate at 100. mu.l per well, and placed in a cell culture chamber (37 ℃, 5% CO)2) After 24h of medium culture, the drug to be tested (from 10) is added-4～102Eight concentrations were selected in μ M, which were: 1X 10-4μM、1×10-3μM、1×10-2μM、1×10-1μM、1μM、10μM、1×101.5μM、1×102μ M). DMSO (final concentration of 0.5%) was added to the negative control group, and 3 duplicate wells were provided for each group. After 72 hours of incubation in an incubator, 20. mu.l of MTT was added to each well at 5mg/ml, and the mixture was left at 37 ℃ for 3 hours. Mu.l DMSO was added to each well, and the absorbance (OD) was measured at 492nm/620nm with shaking at 37 ℃ for 5 min. IC50 values (in μ M) were calculated using Prism Graphpad statistical software. The results are summarized in table 1 below.
TABLE 1
Test example 2
The activity of the compounds of examples 22-30 and 33-38 was tested in the same manner as in test example 1, except that the oral epithelial cancer cell line KB was used in place of the prostate cancer cell line PC 3. The results are summarized in Table 2 below (only the results of the assay for the colon cancer cell line HCT116 are listed for the compounds in examples 28-30 and 34-38).
TABLE 2
Claims (9)
1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:
Wherein, R, R1、R2and R3One of the following two cases A and B is satisfied:
(A) r is hydrogen, methyl, ethyl or phenyl;
R1、R2and R3each independently selected from the group consisting of hydrogen, methyl, ethyl, furyl, pyridyl, phenyl, substituted phenyl and benzyl, or R1、R2And R3Together with the carbon atom to which they are attached form a phenyl, substituted phenyl, naphthyl, quinolinyl, or cyclohexyl group; the substituted phenyl group has one or more substituents independently selected from the group consisting of cyano, fluoro, chloro, bromo, methoxy, nitro, morpholinyl, pyridylmethoxy and methyl; or
(B)R1And R2Are each hydrogen, R3And R together with the carbon and nitrogen atom to which they are attached respectively form a piperazine ring, optionally substituted with quinolinesulfonyl, difluorobenzenesulfonyl, methyl or phenyl, a piperidine ring, optionally fused with a benzene ring, or a morpholine ring, optionally substituted with ethylenedioxybenzenesulfonyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (II) or formula (III):
wherein R is4Represents a substituent optionally present on the benzene ring, and R4Each independently selected from cyano, fluoro, chloro, bromo, iodo, nitro, C1-4Alkyl radical, C1-4Alkoxy, fused benzene ring, fused pyridine ring, morpholinyl, pyridylmethoxy;
n is an integer selected from 0 to 5, m is an integer selected from 0, 1, 2; or
3. The compound according to claim 1, which is selected from the group consisting of the following compounds (1) to (38), or a pharmaceutically acceptable salt thereof:
(1) 3-pyridylmethylaminodithiocarbamate- {2- (N-propylamino) sulfonyl } ethyl ester;
(2) 3-pyridylmethylaminodithiocarbamate- {2- (N, N-diethylamino) sulfonyl } ethyl ester;
(3) 3-pyridylmethylaminothiocarboxylic acid- {2- (cyclohexylamino) sulfonyl } ethyl ester;
(4) 3-pyridylmethylaminothiocarboxylic acid- (2-p-cyanobenzylsulfonylyl) ethyl ester;
(5) 3-pyridylmethylaminothiocarboxylic acid- (2-para-fluoroanilino sulfonyl) ethyl ester;
(6) 2- (3, 4-difluorobenzylaminosulfonyl) ethyl 3-pyridylmethyldithiocarbamate;
(7) 2- (2, 6-difluoroanilinosulfonyl) ethyl 3-pyridylmethyldithiocarbamate;
(8) 2- (2, 6-Dichloroanilinosulfonyl) ethyl 3-pyridylmethylaminothioate;
(9) 3-pyridylmethylaminodithiocarboxylic acid- (2-o-chloroanilinosulfonyl) ethyl ester;
(10) 3-pyridylmethylaminodithiocarboxylic acid- (2-m-bromophenylsulfonyl) ethyl ester;
(11) 3-pyridylmethylaminodithiocarboxylic acid- (2-p-bromoanilinosulfonyl) ethyl ester;
(12) 2- (N-methyl-p-nitroanilinosulfonyl) ethyl 3-pyridylmethylaminothioate;
(13) 3-pyridylmethylaminodithiocarboxylic acid- (2- (2-methyl-6-nitroanilino) sulfonyl) ethyl ester;
(14) 3-pyridylmethylaminodithiocarboxylic acid- (2- (2, 4-dimethylanilino) sulfonyl) ethyl ester;
(15) 3-pyridylmethylaminothiocarboxylic acid- (2-phenethylaminosulfonyl) ethyl ester;
(16) 3-pyridylmethylaminodithiocarboxylic acid- (2-mesitylanilinosulfonyl) ethyl ester;
(17) 3-pyridylmethylaminothiocarboxylic acid- (2-p-methylanilinosulfonyl) ethyl ester;
(18) 3-pyridylmethylaminothiocarboxylic acid- (2-dianilinosulfonyl) ethyl ester;
(19) 3-pyridylmethylaminothiocarboxylic acid- (2- α -naphthylaminosulfonyl) ethyl ester;
(20) 3-pyridylmethylaminodithiocarboxylic acid- (2-o-methoxybenzylaminosulfonyl) ethyl ester;
(21) 3-pyridylmethylaminothiocarboxylic acid- (2-benzylaminosulfonyl) ethyl ester;
(22) 3-pyridylmethylaminothiocarboxylic acid- {2- [ (4-fluorobenzylamino) sulfonyl ] } ethyl ester;
(23) 3-pyridylmethylaminothiocarboxylic acid- {2- [ (3, 4-dichlorobenzylamino) sulfonyl ] } ethyl ester;
(24) 3-pyridylmethylaminothiocarboxylic acid- {2- [ (4-methoxybenzylamino) sulfonyl ] } ethyl ester;
(25) 3-pyridylmethylaminodithiocarbamate- {2- [ (2-furanmethylamino) sulfonyl ] } ethyl ester;
(26) 3-pyridylmethylaminothiocarboxylic acid- {2- [ (3-pyridylmethylamino) sulfonyl ] } ethyl ester;
(27) 3-pyridylmethylaminodithiocarboxylic acid- [2- (anilinesulfonylamino) ] ethyl ester;
(28) 3-pyridylmethylaminodithiocarboxylic acid- [2- [ N- (quinolin-8-yl) aminosulfonyl ] ] ethyl ester;
(29) 3-pyridylmethylaminodithiocarboxylic acid- [2- [ N- (4- (morpholin-1-yl) phenyl) aminosulfonyl ] ] ethyl ester;
(30) 3-pyridylmethylaminodithiocarboxylic acid- [2- [ N- [ 3-chloro-4- (pyridin-2-ylmethoxy) phenyl ] aminosulfonyl ] ] ethyl ester;
(31) 3-pyridylmethylaminothiocarboxylic acid- {2- (4-methylpiperazin-1-yl) sulfonyl } ethyl ester;
(32) 3-pyridylmethylaminodithiocarboxylic acid- (2- (morpholin-1-yl) sulfonyl) ethyl ester;
(33) 3-pyridylmethylaminodithiocarboxylic acid- [2- (4-phenylpiperazin-1-ylsulfonyl) ] ethyl ester;
(34) 3-pyridylmethylaminodithiocarboxylic acid- [2- [ (3, 4-dihydroisoquinolin-2 (1H) -yl) sulfonyl ] ] ethyl ester;
(35) 2- { [4- (quinolin-8-ylsulfonyl) piperazin-1-yl ] sulfonyl } ethyl 3-picolylaminodithioate;
(36) 3-pyridylmethylaminodithiocarboxylic acid- [2- [ [4- [ (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) sulfonyl ] -1, 4-diazepan-1-yl ] sulfonyl ] ] ethyl ester;
(37) 3-pyridylmethylaminodithiocarboxylic acid- [2- [ (3, 4-dihydroquinolin-1 (2H) -yl) sulfonyl ] ] ethyl ester; and
(38) 3-Pyridylmethyldithiocarbamic acid- [2- [ [4- [ (2, 6-difluorophenyl) sulfonyl ] piperazin-1-yl ] sulfonyl ] ] ethyl ester.
4. a pharmaceutical composition comprising: a compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
5. A process for the preparation of a compound according to any one of claims 1 to 3, said process comprising the steps of:
(1) Reacting 3-aminomethylpyridine with carbon disulfide in the presence of anhydrous phosphate to produce pyridin-3-ylmethylcarbamate;
(2) Reacting a starting material of formula (M) with 2-chloroethanesulfonyl chloride in the presence of an organic base to produce an intermediate of formula (Q);
(3) Reacting the pyridin-3-ylmethylcarbamate obtained in step (1) with the intermediate of formula (Q) obtained in step (2) to obtain a compound according to any one of claims 1 to 3;
Wherein, R, R1、R2And R3As defined in the corresponding claims.
6. The method of claim 5, wherein the anhydrous phosphate is anhydrous potassium phosphate.
7. The process of claim 5, wherein the organic base is triethylamine.
8. Use of a compound according to any one of claims 1 to 3, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for use against tumors.
9. The use of claim 8, wherein the tumor is selected from the group consisting of lung cancer, breast cancer, liver cancer, stomach cancer, cervical cancer, colon cancer and epithelial cancer.
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