CN109535146B - Antituberculous compound and its preparation method and use - Google Patents
Antituberculous compound and its preparation method and use Download PDFInfo
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- CN109535146B CN109535146B CN201710859051.3A CN201710859051A CN109535146B CN 109535146 B CN109535146 B CN 109535146B CN 201710859051 A CN201710859051 A CN 201710859051A CN 109535146 B CN109535146 B CN 109535146B
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
The invention provides an anti-tuberculosis compound, a preparation method and application thereof. Specifically, the invention provides a compound shown in formula I, or pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition, a preparation method and application thereof in preparing a medicine for treating tuberculosis. The compound of the invention has an action site of Aspartate Semialdehyde Dehydrogenase (ASD), has a new action mechanism, can be used for developing novel anti-drug MTB antituberculosis drugs,
Description
Technical Field
The invention relates to the field of medicines, in particular to an anti-tuberculosis compound and a preparation method and application thereof.
Background
The anti-tuberculosis drugs such as rifampin (rifampin), isoniazid (isoniazid), ethambutol (ethambutol) and the like are widely applied, and the death rate of tuberculosis is greatly reduced. However, with the long-term use of these antitubercular drugs and the improper or irregular administration of these drugs, Single Drug Resistant (SDR), multidrug resistant (MDR) and even extensively resistant (XDR) Mycobacterium Tuberculosis (MTB) emerged. The statistical data show that: 3.7% of patients with newly infected tuberculosis are MDR-TB infected patients, the MDR-TB carrying rate in retreated patients is up to 20%, and the XDR-TB patients in MDR-TB patients are more up to 9.0%. Drug resistance
MTB is continuously generated and spread, the cure rate of tuberculosis is reduced, and the death rate of tuberculosis patients infected with MDR and XDR MTB is greatly improved. Therefore, the appearance and spread of the drug-resistant MTB enable tuberculosis to become a serious infectious disease threatening human health again, and the development of novel drugs for resisting the drug-resistant MTB is urgent.
The research and development of antituberculosis drugs has become a global research hotspot, but the research progress of novel antituberculosis drugs is extremely slow, and the clinical requirement for treating drug-resistant tuberculosis cannot be met, so that clinical experts have a call that tuberculosis is not available for treatment. The lack of new targets available for drug development is a major cause of hindering the development process of anti-tuberculosis drugs, and the lack of targets becomes a bottleneck in the development of anti-tuberculosis drugs. Only limited targets for developing antituberculosis drugs include InhA, EmbAB, DNA gyrase, RNA polymerase and the like, and antituberculosis drugs developed based on these targets are widely used for clinical treatment of tuberculosis. Strains resistant to these drugs are also emerging due to mutations in the target genes. Bedaquiline and Delamanid are only 2 antituberculosis drugs which are successfully developed in the last 50 years, have good inhibition effect on sensitive MTB and drug-resistant MTB, and can effectively treat tuberculosis caused by drug-resistant MTB. They have the common feature that the action mechanism is different from that of the traditional antituberculosis drugs, and the action site is a brand new drug target.
There is a great need in the art to develop anti-tuberculosis compounds that act on new targets.
Disclosure of Invention
The inventor utilizes a self-established screening model of the antitubercular drug targeting Aspartate Semialdehyde Dehydrogenase (ASD) to screen and obtain a drug lead IMB-XMA0038 with obvious antitubercular activity, which can be used as the antitubercular drug lead with a brand new framework structure. The present invention has been completed based on the above findings.
IMB-XMA0038 structure
In a first aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof,
wherein the content of the first and second substances,
R1is a 3-10 membered heterocyclic group;
R2selected from halogen, hydroxy, amino, cyano, nitro, carboxyl, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino, RCO-, RNHCO-, RCONH-, ROCO-, RCOO-, RSO2-and RSO2NH-; wherein said C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino is optionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, nitro, carboxy, C1-6Alkyl radical, C1-6Alkoxy and C1-6Substituted by alkylamino;
each R is independently selected from hydrogen and C1-6An alkyl group; wherein said C1-6Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, nitro, carboxy, C1-6Alkyl radical, C1-6Alkoxy and C1-6Substituted by alkylamino;
x is selected from C, N, O and S;
y is selected from N, O and S;
z is selected from N, O and S.
In some preferred embodiments, said R is1Is a 3-8 membered heterocycloalkyl or 5-6 membered heteroaryl.
In some preferred embodiments, said R is1Is a heterocycloalkyl, heterocyclopentyl, heterocyclohexyl, heterocycloheptyl, 5-membered heteroaryl, or 6-membered heteroaryl, wherein the heteroatom is selected from N, O and S; further preferably, the number of heteroatoms is 1, 2 or 3.
In some preferred embodimentsIn embodiments, the R1Is oxacyclopropyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, thietanyl, oxazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, oxepanyl, azepinyl, thiepinyl, furyl, pyrrolyl, thienyl, oxazolyl, pyrazolyl, thiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, or pyrazinyl.
In some preferred embodiments, said R is2Selected from halogen, hydroxy, amino, cyano, nitro, carboxyl, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino, RCO-, RNHCO-, RCONH-, ROCO-, RCOO-, RSO2-and RSO2NH-; wherein said C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino is optionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, nitro, carboxy, C1-4Alkyl radical, C1-4Alkoxy and C1-4Substituted by alkylamino;
each R is independently selected from hydrogen and C1-4An alkyl group; wherein said C1-4Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, nitro, carboxy, C1-4Alkyl radical, C1-4Alkoxy and C1-4And (3) substituted by alkyl amino.
In some preferred embodiments, said R is2Selected from halogen, cyano, nitro, carboxy, RCO-, RNHCO-, RCONH-, ROCO-, RCOO-, RSO2-and RSO2NH-；
Each R is independently selected from hydrogen and C1-2An alkyl group; wherein said C1-2Alkyl is optionally substituted by one or more groups selected from halogen, hydroxy, amino, cyano, nitro, carboxy, C1-2Alkoxy and C1-2And (3) substituted by alkyl amino.
In some preferred embodiments, R2Is nitro.
In some preferred embodiments, said X is O or S.
In some preferred embodiments, said Y is O or S.
In some preferred embodiments, Z is O or N.
In some preferred embodiments, the compound has the structure shown in formula II:
the atoms and substituents are as defined in the first aspect of the invention.
In some preferred embodiments, the compound has the structure shown in formula III:
the atoms and substituents are as defined in the first aspect of the invention.
In some preferred embodiments, the compound is selected from:
- Λ/- [5- (tetrahydrofuran-2-yl) - [1,3,4] oxadiazol-2-yl ] - (5-nitro-furan-2-yl) carboxamide;
- Λ/- [5- (thiotetrahydropyran-4-yl) - [1,3,4] oxadiazol-2-yl ] - (5-nitro-furan-2-yl) carboxamide;
n- [5- (tetrahydrofuran-2-yl) - [1,3,4] thiadiazol-2-yl ] - (5-nitro-furan-2-yl) carboxamide;
- Λ/- [5- (tetrahydrofuran-2-yl) - [1,3,4] oxadiazol-2-yl ] - (5-nitro-furan-2-yl) thiocarboxamide; and
n- [5- (tetrahydrofuran-2-yl) - [1,3,4] oxadiazol-2-yl ] - (5-nitro-pyrrol-2-yl) carboxamide.
In a second aspect, the present invention provides a process for the preparation of a compound as described in the first aspect, comprising the steps of:
the method comprises the following steps: carrying out nucleophilic substitution reaction on the compound 1 and the compound 2 to obtain a compound 3;
step two: performing ring closure reaction on the compound 3 to obtain a compound 4;
step three: carrying out nucleophilic substitution reaction on the compound 4 and the compound 5 to obtain the compound shown in the formula I;
wherein L is1And L2Leaving groups for nucleophilic substitution are, for example, halogen, alkoxy or-OTs.
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt or solvate thereof, optionally together with one or more pharmaceutically acceptable carriers or excipients.
The medicaments described in the present invention can be used in animals, preferably in mammals, in particular in humans. Typically, the pharmaceutical compositions of the present invention contain 0.1 to 90% by weight of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.
The pharmaceutical compositions of the present invention may be prepared according to methods known in the art. For this purpose, the compounds of the invention, or their pharmaceutically acceptable salts or solvates, may, if desired, be combined with one or more solid or liquid pharmaceutical excipients to form suitable administration forms or dosage forms for human use.
The compounds of the present invention, or pharmaceutically acceptable salts or solvates thereof, may be administered in unit dosage form by a route of administration which may be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oromucosal, dermal, peritoneal or rectal. The administration dosage forms include tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized powder for injection, etc. Can be common preparation, sustained release preparation, controlled release preparation and various microparticle drug delivery systems. In order to prepare the unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets. For making the administration units into pills, a wide variety of carriers well known in the art can be used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc. For making the administration unit into a suppository, various carriers well known in the art can be widely used. As examples of the carrier, there may be mentioned, for example, polyethylene glycol, lecithin, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like. To encapsulate the administration unit, the compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, may be mixed with the various carriers described above, and the resulting mixture may be placed in a hard gelatin capsule or a soft gelatin capsule. The compound or the pharmaceutically acceptable salt or the solvate thereof can be prepared into microcapsules, suspended in an aqueous medium to form a suspension, and also can be filled into hard capsules or prepared into injections for application. For preparing the administration unit into preparations for injection, such as solutions, emulsions, lyophilized powders and suspensions, all diluents commonly used in the art can be used, for example, water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid esters, and the like. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added.
In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparation, if desired.
The dosage of the compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, to be administered depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight and individual response of the patient or animal, the particular compound used, the route of administration and the frequency of administration, etc. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g. two, three or four dosage forms.
The actual dosage levels of each active ingredient in the pharmaceutical compositions of this invention can be varied so that the resulting amount of active compound is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. Dosage levels will be selected with regard to the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is common practice in the art to start doses of the compounds at levels below those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
When used in the above treatment or prophylaxis or other treatment and/or prophylaxis, a therapeutically and/or prophylactically effective amount of one of the compounds of the present invention may be employed in pure form or, where present, in the form of a pharmaceutically acceptable ester or prodrug. Alternatively, the compounds may be administered in a pharmaceutical composition comprising the compound of interest together with one or more pharmaceutically acceptable carriers or excipients. It will be appreciated that the total daily amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors known in the medical arts. For example, it is common in the art to start doses of the compound at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. In general, the dosage of the compounds of formula I of the present invention for use in mammals, especially humans, may be between 0.001 to 1000mg/kg body weight/day, such as between 0.01 to 100mg/kg body weight/day, such as between 0.01 to 10mg/kg body weight/day.
The compounds according to the invention may be effective in the prevention or treatment of various diseases or conditions described herein.
In another aspect, the present invention provides the use of a compound as described in the first aspect, or a pharmaceutically acceptable salt or solvate thereof, as an aspartate semialdehyde dehydrogenase inhibitor.
In some preferred embodiments, the aspartate semialdehyde dehydrogenase is an aspartate semialdehyde dehydrogenase of a mycobacterium.
In some preferred embodiments, the aspartate semialdehyde dehydrogenase is an aspartate semialdehyde dehydrogenase of mycobacterium tuberculosis.
In another aspect, the present invention provides the use of a compound as described in the first aspect, or a pharmaceutically acceptable salt or solvate thereof, for inhibiting mycobacterial activity in vivo/in vitro.
In some preferred embodiments, the mycobacterium is mycobacterium tuberculosis.
In another aspect, the present invention provides the use of a compound as described in the first aspect, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the prevention or treatment of tuberculosis.
In some preferred embodiments, the tuberculosis is pulmonary tuberculosis or extrapulmonary tuberculosis (e.g., osteoarticular tuberculosis, tuberculous meningitis, tuberculous pleuritis, renal tuberculosis, intestinal tuberculosis, etc.).
In another aspect, the invention provides the use of an ASD in the manufacture of a medicament for the prevention or treatment of tuberculosis.
In another aspect, the invention provides the use of an ASD in the screening for a medicament for the prevention or treatment of tuberculosis.
Definition of terms
Unless defined otherwise below, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Reference to techniques used herein refers to techniques commonly understood in the art, including those variations of or alternatives to those techniques that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
As used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine.
As used herein, the term "C1-6Alkyl "refers to a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms. E.g. C1-4Alkyl radical, C1-2Alkyl groups, and the like. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl, and the like.
As used herein, the term "C1-6Alkoxy "means with C1-6A radical formed by the alkyl-O-mode, in which C1-6The alkyl group is as defined above.
As used herein, the term "C1-6Alkylamino means substituted by C1-6A radical formed by the alkyl-NH-mode, in which C1-6The alkyl group is as defined above.
As used herein, the term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group containing at least one heteroatom selected from N, O and S. For example, 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 3-5 membered heterocycloalkyl, 3-4 membered heterocycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and the like. Specific examples include, but are not limited to, oxidopropyl, aziridinyl, oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, thietanyl, oxazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, oxepanyl, azepanyl, thiepinyl, furyl, pyrrolyl, thienyl, oxazolyl, pyrazolyl, thiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrazinyl, and the like.
As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic cyclic group having aromatic character containing at least one heteroatom selected from N, O and S. Such as 5-10 membered heteroaryl, 5-6 membered heteroaryl, and the like. Specific examples include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, quinolinyl, and the like.
As used herein, the term "pharmaceutically acceptable salt" refers to (1) the acidic functional groups (e.g., -COOH, -OH, -SO) present in the compounds of the present invention3H, etc.) with a suitable inorganic or organic cation (base), for example, a salt of a compound of the present invention with an alkali metal or alkaline earth metal, an ammonium salt of a compound of the present invention, and a salt of a compound of the present invention with a nitrogen-containing organic base; and (2) basic functional groups present in the compounds of the invention (e.g., -NH)2Etc.) with a suitable inorganic or organic anion (acid), for example a salt of a compound of the invention with an inorganic or organic carboxylic acid.
Thus, "pharmaceutically acceptable salts" of the compounds of the present invention include, but are not limited to, alkali metal salts, such as sodium, potassium, lithium, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts such as ammonium salts; organic base salts such as tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylamine salt, tris (hydroxymethyl) aminomethane salt; hydrohalic acid salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide and the like; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate and the like; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate and the like; aryl sulfonates such as benzenesulfonate, p-benzenesulfonate and the like; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.; amino acid salts such as glycinate, trimethylglycinate, arginate, ornithine, glutamate, aspartate and the like.
The compounds of the invention may be present in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 preparation of N- [5- (tetrahydrofuran-2-yl) - [1,3,4] oxadiazol-2-yl ] - (5-nitro-furan-2-yl) carboxamide (Compound 1, i.e. IMB-XMA0038)
a) Semicarbazide hydrochloride (11.1g, 0.1mol) was dissolved in 100ml of tetrahydrofuran, triethylamine (20.2g, 0.20mol) was added, cooling was carried out to 0 ℃ and tetrahydrofuran-2-carbonyl chloride (13.4g, 0.1mol) was slowly added dropwise while controlling the internal temperature to be lower than 4 ℃. After the dropwise addition, stirring was continued for 1h at 0 ℃. The solvent was distilled off to give a pale yellow solid which was used directly in the next step.
b) The solid obtained in the previous step is dissolved in 30mL of ethylene glycol dimethyl ether, phosphorus oxychloride (9.3mL, 0.1mol) is added, and the reaction is carried out for 2h at 70 ℃. The solvent was distilled off under reduced pressure, 50mL of water and 200mL of ethyl acetate were added, and the pH was adjusted to 8.0 with saturated sodium carbonate. The ethyl acetate was extracted 3 times (200 mL each), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to give a pale yellow solid which was used directly in the next step.
c) The solid obtained in the previous step was dissolved in 50mL of methylene chloride, and 4-nitrofuran-2-carboxylic acid (12.56g, 0.08mol), 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (45.6g, 0.12mol) was added and stirred at room temperature for 3 hours. 500mL of water was added, extraction was performed with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure, and silica gel column chromatography (5: 1-3: 1) was performed to obtain 13.2g of a pale yellow solid by concentration, with a total yield of 44.9% in three steps.
1HNMR(CDCl3,400MHz)：8.59(s,1H),7.66(d,1H,J＝2.0Hz),7.57(d,1H,J＝2.0Hz),5.03-5.00(m,1H),3.99-3.81(m,2H),2.39-2.31(m,1H),2.02-1.93(m,1H),1.61-1.53(m,1H)；
ESI-MS：295.07[M+H]+,317.08[M+Na]+。
EXAMPLE 2 preparation of N- [5- (Thiotetrahydropyran-4-yl) - [1,3,4] oxadiazol-2-yl ] - (5-nitro-furan-2-yl) carboxamide (Compound 2)
a) Semicarbazide hydrochloride (11.1g, 0.1mol) was dissolved in 100ml tetrahydrofuran, triethylamine (20.2g, 0.20mol) was added, cooling to 0 ℃ and thiotetrahydropyran-4-carbonyl chloride was slowly added dropwise, with the internal temperature being kept below 4 ℃. After the dropwise addition, stirring was continued for 1h at 0 ℃. The solvent was distilled off to give a pale yellow solid which was used directly in the next step.
b) The solid obtained in the previous step is dissolved in 30mL of ethylene glycol dimethyl ether, phosphorus oxychloride (9.3mL, 0.1mol) is added, and the reaction is carried out for 2h at 70 ℃. The solvent was distilled off under reduced pressure, 50mL of water and 200mL of ethyl acetate were added, and the pH was adjusted to 8.0 with saturated sodium carbonate. The ethyl acetate was extracted 3 times (200 mL each), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to give a pale yellow solid which was used directly in the next step.
c) The solid obtained in the previous step was dissolved in 50mL of methylene chloride, and 4-nitrofuran-2-carboxylic acid (12.56g, 0.08mol), 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (45.6g, 0.12mol) was added and stirred at room temperature for 3 hours. 100mL of water was added, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. And (3) evaporating the organic solvent under reduced pressure, performing silica gel column chromatography (petroleum ether: ethyl acetate: 5: 1-3: 1), and concentrating to obtain 12.5g of light yellow solid, wherein the total yield of the three steps is 38.6%.
1HNMR(CDCl3,400MHz)：8.27(s,1H),7.58(d,1H,J＝2.0Hz),7.39(d,1H,J＝2.0Hz),2.93-2.87(m,2H),2.77-2.70(m,3H),2.36-2.29(m,2H),2.10-2.03(m,2H)；
ESI-MS：325.08[M+H]+,347.10[M+Na]+。
EXAMPLE 3 preparation of N- [5- (tetrahydrofuran-2-yl) - [1,3,4] thiadiazol-2-yl ] - (5-nitro-furan-2-yl) carboxamide (Compound 3)
a) Thiourea hydrochloride (12.7g, 0.1mol) was dissolved in 100ml tetrahydrofuran, triethylamine (20.2g, 0.20mol) was added, cooled to 0 ℃ and tetrahydrofuran-2-carbonyl chloride was slowly added dropwise, with the internal temperature controlled below 4 ℃. After the dropwise addition, stirring was continued for 1h at 0 ℃. The solvent was distilled off to give a pale yellow solid which was used directly in the next step.
b) The solid obtained in the previous step is dissolved in 30mL of ethylene glycol dimethyl ether, phosphorus oxychloride (9.3mL, 0.1mol) is added, and the reaction is carried out for 2h at 70 ℃. The solvent was distilled off under reduced pressure, 50mL of water and 200mL of ethyl acetate were added, and the pH was adjusted to 8.0 with saturated sodium carbonate. The ethyl acetate was extracted 3 times (200 mL each), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to give a pale yellow solid which was used directly in the next step.
c) The solid obtained in the previous step was dissolved in 50mL of methylene chloride, and 5-nitrofuran-2-carboxylic acid (12.56g, 0.08mol), 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (45.6g, 0.12mol) was added and stirred at room temperature for 3 hours. 100mL of water was added, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure, and silica gel column chromatography (5: 1-3: 1) was performed to obtain 17.2g of a pale yellow solid by concentration, with a total yield of 55.5% in three steps.
1HNMR(CDCl3,400MHz)：8.64(s,1H),7.66(d,1H,J＝2.0Hz),7.57(d,1H,J＝2.0Hz),5.05-5.02(m,1H),3.98-3.94(m,2H),3.85-3.81(m,2H)；
ESI-MS：311.04[M+H]+,333.06[M+Na]+。
EXAMPLE 4 preparation of N- [5- (tetrahydrofuran-2-yl) - [1,3,4] oxadiazol-2-yl ] - (5-nitro-furan-2-yl) thiocarboxamide (Compound 4)
a) Semicarbazide hydrochloride (11.1g, 0.1mol) was dissolved in 100ml tetrahydrofuran, triethylamine (20.2g, 0.20mol) was added, cooling was carried out to 0 ℃ and tetrahydrofuran-2-carbonyl chloride was slowly added dropwise with the internal temperature being controlled to below 4 ℃. After the dropwise addition, stirring was continued for 1h at 0 ℃. The solvent was distilled off to give a pale yellow solid which was used directly in the next step.
b) The solid obtained in the previous step is dissolved in 30mL of ethylene glycol dimethyl ether, phosphorus oxychloride (9.3mL, 0.1mol) is added, and the reaction is carried out for 2h at 70 ℃. The solvent was distilled off under reduced pressure, 50mL of water and 200mL of ethyl acetate were added, and the pH was adjusted to 8.0 with saturated sodium carbonate. The ethyl acetate was extracted 3 times (200 mL each), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to give a pale yellow solid which was used directly in the next step.
c) The solid obtained in the previous step was dissolved in 50mL of methylene chloride, and 4-nitrofuran-2-thiocarboxylic acid (13.84g, 0.08mol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (45.6g, 0.12mol) was added and stirred at room temperature for 3 hours. 100mL of water was added, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. And (3) evaporating the organic solvent under reduced pressure, performing silica gel column chromatography (petroleum ether: ethyl acetate: 5: 1-3: 1), and concentrating to obtain a light yellow solid 11.3g, wherein the total yield of the three steps is 36.5%.
1HNMR(CDCl3,400MHz)：7.54(d,1H,J＝2.0Hz),6.89(d,1H,J＝2.0Hz),5.03-5.01(m,1H),3.99-3.81(m,2H),2.39-2.31(m,2H),2.02-1.93(m,2H)；
ESI-MS：311.04[M+H]+,333.06[M+Na]+。
EXAMPLE 5 preparation of N- [5- (tetrahydrofuran-2-yl) - [1,3,4] oxadiazol-2-yl ] - (5-nitro-pyrrol-2-yl) carboxamide (Compound 5)
a) Semicarbazide hydrochloride (11.1g, 0.1mol) was dissolved in 100ml tetrahydrofuran, triethylamine (20.2g, 0.20mol) was added, cooling was carried out to 0 ℃ and tetrahydrofuran-2-carbonyl chloride was slowly added dropwise with the internal temperature being controlled to below 4 ℃. After the dropwise addition, stirring was continued for 1h at 0 ℃. The solvent was distilled off to give a pale yellow solid which was used directly in the next step.
b) The solid obtained in the previous step is dissolved in 30mL of ethylene glycol dimethyl ether, phosphorus oxychloride (9.3mL, 0.1mol) is added, and the reaction is carried out for 2h at 70 ℃. The solvent was distilled off under reduced pressure, 50mL of water and 200mL of ethyl acetate were added, and the pH was adjusted to 8.0 with saturated sodium carbonate. The ethyl acetate was extracted 3 times (200 mL each), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to give a pale yellow solid which was used directly in the next step.
c) The solid obtained in the previous step was dissolved in 50mL of dichloromethane, 4-nitropyrrole-2-carboxylic acid (12.48g, 0.08mol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (45.6g, 0.12mol) were added, and the mixture was stirred at room temperature for 3 hours. 100mL of water was added, extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The organic solvent is evaporated under reduced pressure, silica gel column chromatography is carried out (petroleum ether: ethyl acetate: 5: 1-3: 1), and light yellow solid 14.7g is obtained by concentration, and the total yield of the three steps is 50.2%.
1HNMR(CDCl3,400MHz)：9.95(s,1H),8.20(s,1H),7.42(d,1H,J＝2.0Hz),7.15(d,1H,J＝2.0Hz),5.11-5.08(m,1H),3.98-3.94(m,1H),3.85-3.80(m,1H),2.35-2.28(m,1H),2.00-1.92(m,2H),1.69-1.61(m,1H)；
ESI-MS：294.07[M+H]+,316.08[M+Na]+。
Example 6 inhibition of ASD by the Compound of the invention IMB-XMA0038
The measurement principle is as follows:
NADPH in the reaction system has strong light absorption at 340nm of ultraviolet light, while its oxidation product NADP (+) has no light absorption at 340 nm. The progress of the ASD-catalyzed reaction can be monitored by using this property.
The enzyme activity assay system is as follows (reagents are purchased from Sigma Aldrich, and the enzymes LysC and ASD are self-expressed and purified):
| composition (I) | Content (wt.) |
| Tris–HCl(pH 8.0) | 50mM(pH 8.0) |
| MgCl2 | 5mM |
| dithiothreitol | 1mM |
| aspartic acid | 5mM |
| ATP | 1mM |
| NADPH | 0.5mM |
| Lys C | 2U |
| ASD | 0.2U |
| Total volume | 100μL |
The progress of the enzymatic reaction was monitored at 37 ℃ by measuring the change in absorbance of NADPH at 340 nm.
The enzyme activity unit was defined as the amount of enzyme that consumed 1. mu. Mol of NADPH per minute under the above reaction conditions was 1U (the enzyme activity unit of LysC was defined as the amount of enzyme that consumed 1. mu. Mol of ATP per minute under the same conditions was 1U).
The calculation formula is as follows:
U/ml＝(△A340nm/min test-△A340nm/min blank)×V×df/(×d×v)
wherein V is the total volume of the reaction, and is 0.1 mL; df is the dilution factor of the enzyme ASD, 10; is NADPH millimolar extinction coefficient, 6.22 mL/mol/cm; d is the optical path of a 96-well plate, 0.5 cm; v is the ASD volume, 0.02 mL.
The concentration of compound IMB-XMA0038 was 40. mu.g/mL, 20. mu.g/mL, 10. mu.g/mL, 5. mu.g/mL, 2.5. mu.g/mL, 1.25. mu.g/mL, 0.0625. mu.g/mL. The ASD in the positive control group is inactivated by heat shock, and the group with the sample concentration of 0 mu g/mL is used as a negative control group. Each set of 3 replicates.
The enzyme activity inhibition rate was calculated as follows:
wherein An is the light absorption value of the positive control group, As is the light absorption value of the sample group, and Ap is the light absorption value of the negative control group.
IC50Values were calculated using software Graphpad Prism 5.0 software and the analytical method was non-linear regression.
The results show that half Inhibition (IC) of ASD is achieved by compound IMB-XMA003850) 5.25. + -. 0.84. mu.g/mL.
Example 7 inhibitory Effect of the Compound IMB-XMA0038 of the present invention on Mycobacterium tuberculosis in vitro
Experimental methods
Bacteria: in the presence of 10% ADC (BBL)TMMiddlebrook ADC enrich) and 0.05% tween-80 (BDBBL)TM) (all available from BD Co., Ltd. (Becton, Dickinson)&Co.)) is usedTMMiddlebrook 7H9 medium (Cat. No.271310) was inoculated with Mycobacterium tuberculosis Standard strain H37Rv (ATCC27294), cultured with shaking at 37 ℃ to the logarithmic growth phase, 1% inoculated in fresh 7H9 medium (containing ADC and tween-80), and a compound sample (128. mu.g/mL-0.25. mu.g/mL, isoniazid as a positive control) was diluted from the second row using the inoculum with a 2-fold dilution method in a 96-well plate (first row is inoculum, twelfth row is blank medium). The plates were incubated at 37 ℃ for 10 days in a static manner, and the OD600nm light absorption value of the culture broth was determined, taking 99% inhibition of strain growth as its MIC value
The results showed that the Minimal Inhibitory Concentration (MIC) of IMB-XMA0038 against wild Mycobacterium tuberculosis H37Rv (ATCC27294) was 2-5. mu.g/mL.
Example 8 inhibition of Mycobacterium tuberculosis in mice by IMB-XMA0038
Bacteria: a standard strain of Mycobacterium tuberculosis H37Rv (ATCC27294) was inoculated in 7H9 medium (containing ADC and tween-80), shaken at 37 deg.CCulturing under shaking to logarithmic phase, centrifuging at 5000 rpm, washing with non-salt pyrogen-free sterilized water, and concentrating to 3 × 108CFU/ml (McFarland standard, tube #1) was stored at-70 ℃ until use. Thawing the seed before inoculation.
Animals: SPF male BALB/C mice, weight 18-20 g, raise in the air-conditioned room designed for infecting animal model, each cage is no more than 6 mice, the temperature is 21 + -2 deg.C, humidity 55 + -15%, keep 12 hours light/12 hours dark circulation, the animal can obtain food and filtered water conveniently. Animals were acclimated for one week prior to the start of the experiment.
Inoculating the strain: thawing the frozen stock solution, diluting with pyrogen-free 0.9% NaCl sterile water containing 0.01% polysorbate 80 (sterile filtered) to a concentration of 10%6CFU/mL, ultrasonic 2min dispersed colony.
Viable count was performed using a cell count containing 10% OADC (BD, BBL)TMMiddlebrook 7H10agar Medium (BD, Difco) from Middlebrook OADC Enrichment, Cat. No.212240)TMMiddlebrook 7h10agarcat.no.262710), serial dilutions of the bacterial solution were inoculated.
Establishing and treating a mouse tuberculosis model: mice were infected according to the standard protocol of an aerosol infection apparatus (099C A4224InhalationExposure System) at a dose of 50-100 CFU/mouse. 3 mice were sacrificed 3 days and 10 days after infection, and viable lung tissue counts were made. Drug treatment is started on the 10 th day of infection, and the test drug IMB-XMA003825 mg/kg; the positive control drug isoniazid (INH, Sigma) is 25mg/kg, 6 CMC drug-free control groups are simultaneously arranged, and the drug is orally administrated by intragastric gavage for 5 times per week, and 15 doses are totally. Mice from each group were sacrificed 30 days post infection, weighed, dissected under sterile procedures, and lung tissue viable count was performed.
The results show that: compared with a solvent control group, IMB-XMA0038 can reduce the lung bacterial load of mice by 102.32(i.e., 208.93 times), the antitubercular activity was significant.
Example 9 acute toxicity of IMB-XMA0038
Animals: SPF male BALB/C mice, weight 18-20 g, raise in the air-conditioned room designed for infecting animal model, each cage is no more than 6 mice, the temperature is 21 + -2 deg.C, humidity 55 + -15%, keep 12 hours light/12 hours dark circulation, the animal can obtain food and filtered water conveniently. Animals were acclimated for one week prior to the start of the experiment.
Experiment: the administration is carried out by intragastric administration, the administration dose is 500mg/kg, and a CMC drug-free control group is arranged, and each group comprises 6 mice. The mice were observed for behavioral changes within 24 hours after dosing: diet, mental state, lethargy, motor coordination, tremor, convulsions, salivation, urination, defecation, hair-setting reaction, skin color, respiratory rate and death.
The results show that IMB-XMA0038 has low toxicity, and half lethal dose (LD50) >500mg/kg for mice, and shows good selective toxicity.
Reference to the literature
1.Daley CL,Caminero JA.Management of multidrug resistanttuberculosis.Seminars in respiratory and critical care medicine.2013；34(1):44-59.
2.World Health Organization:Global tuberculosis report 2014.2014.
3.Marks SM,Flood J,Seaworth B,Hirsch-Moverman Y,Armstrong L,Mase S,etal.Treatment practices,outcomes,and costs of multidrug-resistant andextensively drug-resistant tuberculosis,United States,2005-2007.Emerg InfectDis.2014；20(5):812-21.
4.Amaral L,Martins M,Viveiros M.Enhanced killing of intracellularmultidrug-resistant Mycobacterium tuberculosis by compounds that affect theactivity of efflux pumps.J Antimicrob Chemother.2007；59(6):1237-46.
5.Banerjee A,Dubnau E,Quemard A,Balasubramanian V,Um KS,Wilson T,etal.inhA,a gene encoding a target for isoniazid and ethionamide inMycobacterium tuberculosis.Science.1994；263(5144):227-30.
6.Cui Z,Li Y,Cheng S,Yang H,Lu J,Hu Z,et al.Mutations in the embC-embA intergenic region contribute to Mycobacterium tuberculosis resistance toethambutol.Antimicrob Agents Chemother.2014；58(11):6837-43.
7.Kumar S,Jena L.Understanding Rifampicin Resistance in Tuberculosisthrough a Computational Approach.Genomics&informatics.2014；12(4):276-82.
8.Taniguchi H.[Molecular mechanisms of multidrug resistance inMycobacterium tuberculosis].Journal of UOEH.2000；22(3):269-82.
9.Ohno H,Kohno S.[Mechanisms of drug-resistance in mycobacteria].Nihon rinsho Japanese journal of clinical medicine.1998；56(12):3023-9.
10.Lakshmanan M,Xavier AS.Bedaquiline-The first ATP synthaseinhibitor against multi drug resistant tuberculosis.J Young Pharm.2013；5(4):112-5.
11.Bedaquiline for multidrug-resistant tuberculosis.Drug andtherapeutics bulletin.2014；52(11):129-32.
While specific embodiments of the invention have been described in detail, it will be appreciated by those skilled in the art that various modifications and alternatives to those details could be developed in light of the overall teachings of the disclosure, and that such modifications are intended to be included within the scope of the disclosure. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (14)
1. A compound of formula III, or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1selected from the group consisting of heterocyclopentyl and heterocyclohexyl, wherein the heteroatom is selected from the group consisting of N, O and S, and the number of heteroatoms is 1 or 2;
R2is nitro;
x is selected from O and S;
y is selected from O and S;
z is selected from N and O;
and said compound is not
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1Is tetrahydrofuranyl, pyrrolidinyl, thiacyclopentyl, oxazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl or thiomorpholinyl.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
- Λ/- [5- (tetrahydrofuran-2-yl) - [1,3,4] oxadiazol-2-yl ] - (5-nitro-furan-2-yl) carboxamide;
- Λ/- [5- (thiotetrahydropyran-4-yl) - [1,3,4] oxadiazol-2-yl ] - (5-nitro-furan-2-yl) carboxamide;
n- [5- (tetrahydrofuran-2-yl) - [1,3,4] thiadiazol-2-yl ] - (5-nitro-furan-2-yl) carboxamide;
- Λ/- [5- (tetrahydrofuran-2-yl) - [1,3,4] oxadiazol-2-yl ] - (5-nitro-furan-2-yl) thiocarboxamide; and
n- [5- (tetrahydrofuran-2-yl) - [1,3,4] oxadiazol-2-yl ] - (5-nitro-pyrrol-2-yl) carboxamide.
4. A process for the preparation of a compound of claim 1, comprising the steps of:
the method comprises the following steps: carrying out nucleophilic substitution reaction on the compound 1 and the compound 2 to obtain a compound 3;
step two: performing ring closure reaction on the compound 3 to obtain a compound 4;
step three: compound 4 and compound
Obtaining the compound shown in the formula III through nucleophilic substitution reaction;
wherein L is1And L2Is a leaving group for nucleophilic substitution reaction.
5. The preparation process of claim 4, wherein the leaving group is selected from the group consisting of halogen, alkoxy, and-OTs.
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, optionally together with one or more pharmaceutically acceptable carriers or excipients.
7. Use of a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as an aspartate semialdehyde dehydrogenase inhibitor.
8. The use of claim 7, wherein the aspartate semialdehyde dehydrogenase is an aspartate semialdehyde dehydrogenase of a mycobacterium.
9. The use of claim 7, wherein the aspartate semialdehyde dehydrogenase is an aspartate semialdehyde dehydrogenase of Mycobacterium tuberculosis.
10. Use of a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting mycobacterial activity.
11. The use of claim 10, wherein the mycobacterium is mycobacterium tuberculosis.
12. Use of a compound as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of tuberculosis.
13. The use of claim 12, wherein the tuberculosis is pulmonary tuberculosis or extrapulmonary tuberculosis.
14. The use of claim 13, wherein the extrapulmonary tuberculosis is selected from the group consisting of osteoarticular tuberculosis, tuberculous meningitis, tuberculous pleuritis, renal tuberculosis, and intestinal tuberculosis.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101208427A (en) * | 2003-05-30 | 2008-06-25 | 米克罗比亚股份有限公司 | Methods and compositions for amino acid production |
| WO2009086303A2 (en) * | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
| CN102725287A (en) * | 2009-12-28 | 2012-10-10 | 一般社团法人创药分子谷项目支援机构 | 1,3,4-oxadiazole-2-carboxamide compound |
| WO2014055634A1 (en) * | 2012-10-02 | 2014-04-10 | Yale University | Identification of small molecule inhibitors of jumonji at-rich interactive domain 1a (jarid1a) and 1b (jarid1b) histone demethylase |
| WO2015187827A1 (en) * | 2014-06-03 | 2015-12-10 | The Trustees Of The University Of Pennsylvania | Novel effective antiviral compounds and methods using same |
-
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- 2017-09-21 CN CN201710859051.3A patent/CN109535146B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101208427A (en) * | 2003-05-30 | 2008-06-25 | 米克罗比亚股份有限公司 | Methods and compositions for amino acid production |
| WO2009086303A2 (en) * | 2007-12-21 | 2009-07-09 | University Of Rochester | Method for altering the lifespan of eukaryotic organisms |
| CN102725287A (en) * | 2009-12-28 | 2012-10-10 | 一般社团法人创药分子谷项目支援机构 | 1,3,4-oxadiazole-2-carboxamide compound |
| WO2014055634A1 (en) * | 2012-10-02 | 2014-04-10 | Yale University | Identification of small molecule inhibitors of jumonji at-rich interactive domain 1a (jarid1a) and 1b (jarid1b) histone demethylase |
| WO2015187827A1 (en) * | 2014-06-03 | 2015-12-10 | The Trustees Of The University Of Pennsylvania | Novel effective antiviral compounds and methods using same |
Non-Patent Citations (2)
| Title |
|---|
| RN：717860-00-9、851909-56-3;STN Registry数据库;《STN Registry》;20050608;第1页 * |
| 吡啶衍生物研究(IX)：N-(1-甲氧羰基)乙基-N-[5-(2-氯吡啶-4-基)-1,3,4-噻二唑-2-基]酰胺的合成及除草活性;车超等;《农药学学报》;20041231;第6卷(第3期);第15-20页 * |
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