CN110950845B - Formylacetamide azole derivative and application thereof - Google Patents
Formylacetamide azole derivative and application thereof Download PDFInfo
- Publication number
- CN110950845B CN110950845B CN201911147449.XA CN201911147449A CN110950845B CN 110950845 B CN110950845 B CN 110950845B CN 201911147449 A CN201911147449 A CN 201911147449A CN 110950845 B CN110950845 B CN 110950845B
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- derivative
- formylacetamide
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- C07D401/14—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 three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of drug synthesis, and relates to a novel formylacetamidazole derivative, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, a preparation method thereof and a pharmaceutical composition containing the compound. The formylacetamide azole derivative has stronger antifungal effect. The invention provides a formylacetamide azole compound shown in a general formula I, which has the following structural formula,
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a novel formylacetamidazole derivative, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, a preparation method thereof and application thereof in antifungal drugs.
Background
Fungal Infections (IFI) include primarily superficial fungal infections and deep fungal disease infections. Wherein, deep mycosis infection can affect internal tissues and organs besides invading skin and subcutaneous tissues, so that the deep mycosis infection has the characteristics of high mortality rate and high cure difficulty in clinic. In addition, with the clinical extensive use of broad-spectrum antibacterial drugs, immunosuppressants and chemoradiotherapy drugs, the occurrence of drug resistance of pathogenic fungi is more and more frequent. However, there is no effective treatment until now, and once fungal resistance occurs, a complicated dosing scheme is often required, and the treatment risk is multiplied by the poor interaction or compliance of multiple drugs. According to statistics, the number of people who die from infection caused by deep drug-resistant fungi in the world every year is up to 150 thousands, which is close to the death rate caused by tuberculosis.
At present, antifungal drugs widely applied in the market are mainly commercialized antifungal inhibitors developed aiming at CYP51 targets, such as azole compounds, and the inhibitors have the advantages of high selectivity and strong specificity. At present, although CYP51 inhibitors have the advantages of high efficiency and low recurrence rate, the CYP51 inhibitors have the defects of easy generation of drug resistance and high metabolic toxicity. In particular, they all have developed resistance problems that, once they occur, are extremely difficult to overcome. Therefore, the molecular mechanism of pathogenic fungi is deeply researched, and the development of antifungal medicines with novel structure, strong biological activity and low side effect has important research value and profound significance.
The inventor considers the structural characteristics of the CYP51 inhibitor from the molecular structure of the inhibitor, designs and synthesizes a series of novel formylacetamide azole derivatives. In vitro activity screening shows that the compounds have high antifungal and drug-resistant fungal activity.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a formylacetamide azole derivative with a novel structure and application thereof; the invention relates to a formyl acetamide azole derivative with strong anti-candida albicans, candida krusei, candida tropicalis and aspergillus fumigatus effects, in particular to an application in preparing a medicament for treating and preventing pathogenic drug-resistant fungi.
In order to achieve the above object, the present invention provides formylacetamidazole compounds represented by the general formula I
Wherein:
a is 1-phenyl-4-piperidinyl, methylnaphthalene, phenyl, naphthyl, 1,4 benzodioxan, quinolinyl, benzofuranyl, 1,3-benzodioxolyl, 1,3-benzodioxazole, 1,3-benzoxazole, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, biphenyl, ar being optionally substituted with 1 to 4 of the same or different M's;
m is hydrogen or 1-3 selected from halogen, cyano, hydroxyl, nitro, amino, (C) 1 -C 6 ) Alkenyl, (C) 1 -C 6 ) Alkyl radical, C 1 -C 6 ) Alkoxy group, (C) 1 -C 6 ) Alkynyl, optionally hydroxy, amino or halo (C) 1 -C 6 ) Alkyl or (C) 1 -C 6 ) Alkoxy or (C) 1 -C 6 ) Alkylthio, mono-or di (C) 1 -C 6 Alkyl) substituted amino, (C) 1 -C 6 ) Alkylamido, free, salified, esterified and amidated carboxyl, (C) 1 -C 6 ) Alkylsulfinyl, sulfonyl, (C) 1 -C 6 ) Alkoxy group, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkanoyl, carbamoyl, mono-or di (C) 1 -C 6 Alkyl) substituted carbamoyl, (C) 1 -C 3 ) Substituted electron donating or electron withdrawing groups of alkylenedioxy;
x is CH or N atom;
r is an alkane or aryl group.
The invention preferably relates to a formylacetamidazole compound shown in a general formula I and pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein
A is 1-phenyl-4-piperidinyl, methylnaphthalene, phenyl, naphthyl, 1,4 benzodioxan, quinolinyl, benzofuranyl, 1,3-benzodioxolyl, 1,3-benzodioxazole, 1,3-benzoxazole, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, biphenyl, ar being optionally substituted with 1 to 4 of the same or different M's;
m is hydrogen or 1-3 substituents selected from the group consisting of hydroxy, halo, nitro, trifluoromethyl, (C1-C4) alkyl, (C1-C4) alkoxy;
x is CH or N atom;
r is an alkane or aryl group.
The invention preferably relates to the formylacetamidazole compounds shown in the general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein
A is 1-phenyl-4-piperidinyl, methylnaphthalene, phenyl, naphthyl, 1,4 benzodioxane, quinolinyl, benzofuranyl, 1,3-benzodioxolyl, 1,3-benzodioxazole, 1,3-benzoxazole, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, ar is optionally substituted with 1-4 of the same or different M;
m is hydrogen or 1-3 groups selected from hydroxy, halogen, nitro, trifluoromethyl, (C1-C4) alkyl, (C1-C4) alkoxy;
x is CH or N atom;
r is methyl, ethyl, isopropyl, sec-butyl, isopentyl, cyclopropyl, phenyl, or triazolemethyl, and the like.
The invention preferably relates to a formylacetamidazole compound shown in a general formula I and pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof,
wherein
A is 1-phenyl-4-piperidinyl, methylnaphthalene, phenyl, naphthyl, 1,4 benzodioxane, quinolinyl, benzofuranyl, 1,3-benzodioxolyl, 1,3-benzodioxazole, 1,3-benzoxazole, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, ar is optionally substituted with 1-4 of the same or different M;
m is hydrogen or 1-3 substituents selected from the group consisting of hydroxy, halo, nitro, trifluoromethyl, (C1-C4) alkyl, (C1-C4) alkoxy;
x is CH or N atom;
r is methyl, isopropyl, sec-butyl, isopentyl, phenyl or triazolylmethyl.
A compound of the general formula I above, and geometric isomers thereof, or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, selected from:
2- ((1H-imidazol-1-yl) methyl) -N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) -3-oxo-3-phenylpropanamide; 2- ((1H-1,2,4-triazol-1-yl) methyl) -N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) -3-oxo-3-phenylpropanamide;
2- (((1H-imidazol-1-yl) methyl) -N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) -4-methyl-3-oxopentanamide 2- ((1H-1,2,4-triazol-1-yl) methyl) -N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) -4-methyl-3-oxopentanamide;
2- (((1H-imidazol-1-yl) methyl) -N- (naphthalen-2-ylmethyl) -3-oxo-3-phenylpropanamide;
2- (((1H-1,2,4-triazol-1-yl) methyl) -N- (naphthalen-2-ylmethyl) -3-oxo-3-phenylpropanamide.
The corresponding structural formulas of the above 6 compounds are as follows:
the derivatives of formula I above may form pharmaceutically acceptable salts with acids according to methods common in the art to which the invention pertains. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "alkylene" refers to straight or branched chain alkylene; "aryl" refers to an organic group derived from an aromatic hydrocarbon by removal of two hydrogen atoms at one or different positions, such as phenyl, naphthyl; "heteroaryl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, which refers to an organic group having aromatic character and obtained by removing two hydrogen atoms at one or different positions in the ring system, such as thiazolyl, imidazolyl, pyridyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, furyl, thienyl, pyrrolyl, indolyl, benzothiazolyl, oxazolyl, isoxazolyl, naphthyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and the like; "saturated or partially saturated heterocyclyl" refers to a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, such as 2H-1-benzopyran-2-onyl, indoline-2,3-diketonyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiazolinyl, and the like.
The invention can contain the derivative of the formula I, and pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as active ingredients, and the derivative is mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
In-vitro antifungal activity tests show that the derivatives shown in the general formula I have antifungal activity, so that the compounds can be used for preparing medicines for treating and/or preventing fungal diseases such as candida albicans, candida krusei, candida tropicalis, aspergillus fumigatus and the like.
The active compound or the pharmaceutically acceptable salt and the solvate thereof can be used as antifungal medicaments.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way. The compounds of formula I according to the present invention can be prepared by amidation of the corresponding starting material 1-1 according to the method of scheme 1 to prepare intermediates 1-2, addition reaction of the intermediates 1-2 with formaldehyde solution to obtain intermediates 1-3, and substitution reaction of the intermediates with imidazole to obtain the target products 1-4.
According to the derivatives of formula I of the present invention, the main part can be prepared by adding HATU, DIEA and formylacetic acid containing various substituent groups to the corresponding intermediate 1-1 and refluxing in the same manner as in scheme 1 to obtain intermediate 1-2. Then, using ethanol as a solvent, adding 37% formaldehyde solution, stirring at room temperature for 5h, and obtaining the intermediates 1-3 through an addition reaction. Then adding CDI or CDT into acetonitrile solution containing the intermediate 1-3, refluxing for 5 hours, and finally obtaining the target product 1-4. Wherein Ar, M and R in the compound are as defined in the summary of the invention.
When Ar is piperidinyl and M is pyrimidinyl, the key intermediate, the piperidinamines intermediate, is synthesized as follows (scheme 2).
The key intermediate piperidine amine intermediate can be prepared by synthesizing according to the method of a route 2, using 2,4-dichloropyrimidine (2-1) as a starting material to perform substitution reaction with N- (piperidine-4-yl) carbamic acid tert-butyl ester at room temperature to obtain an intermediate 2-2, and using trifluoroacetic acid to remove BOC protection to prepare the key intermediate piperidine amine intermediate 2-3.
The specific implementation mode is as follows:
the following examples are intended to illustrate but not limit the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by Bruker ARX-400, and the mass spectrum is measured by Agilent 1100 LC/MS; all reagents used were analytically or chemically pure.
EXAMPLE 1 preparation of 2- ((1H-imidazol-1-yl) methyl) -N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) -3-oxo-3-phenylpropanamide
Step 1 preparation of tert-butyl (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) carbamate
Dissolving 2,4-dichloropyrimidine (1.0 eq) in DMF, and adding K 2 CO 3 (1.5 eq), adding N- (piperidine-4-yl) carbamic acid tert-butyl ester (1.2 eq) under stirring, reacting at normal temperature for 6 hours, adding ice water after the reaction is completed, separating out solids, and filtering and drying to obtain the required compound.
Step 2 preparation of 1- (2-Chloropyrimidin-4-yl) piperidin-4-amine
Dissolving tert-butyl (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) carbamate (1.0 eq) in a dichloromethane solution, adding excess trifluoroacetic acid (10.0 eq) under ice bath conditions, and adding saturated K 2 CO 3 Adjusting alkali, extracting with dichloromethane, collecting organic layer Na 2 SO 4 And dried overnight. Finally obtaining the required compound by vacuum distillation.
Step 3 preparation of N- (1- (2-Chloropyrimidin-4-yl) piperidin-4-yl) -3-oxo-3-phenylpropanamide
Benzoylacetic acid (1.0 eq) and HATU (1.2 eq) were added separately to a solution in anhydrous DMF. After stirring at room temperature for 2 hours, 1- (2-chloropyrimidin-4-yl) piperidin-4-amine (1.1 eq) and DIEA (4.0 eq) were added, heating was carried out at 75 ℃ for 7 hours, the reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic phase was dried. Na (Na) 2 SO 4 Dry overnight. Finally, the desired compound was obtained by vacuum distillation.
Step 4 preparation of N- (1- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) -2- (hydroxymethyl) -3-oxo-3-phenylpropanamide
N- (1- (2-Chloropyrimidin-4-yl) piperidin-4-yl) -3-oxo-3-phenylpropanamide (1.0 eq) was dissolved in ethanol, and 30mL of 37% formaldehyde solution was added. After stirring at room temperature for 4 hours and completion of the reaction, the organic phase was extracted with ethyl acetate and dried. Na (Na) 2 SO 4 Dry overnight. Finally, the desired compound was obtained by vacuum distillation.
Step 5 preparation of 2- ((1H-imidazol-1-yl) methyl) -N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) -3-oxo-3-phenylpropanamide
Dissolving N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) -3-oxo-3-phenylpropanamide (1.0 eq), CDI (2.0 eq) and imidazole (3.0 eq) in 30mL acetonitrile, refluxing for 6 hours, after completion of the reaction, pouring water, extracting with ethyl acetate three times, and drying the organic phase. Na (Na) 2 SO 4 Dry overnight. Finally, the desired compound was obtained by vacuum distillation.
The yield is 71.4 percent; mp:142.4-145.5 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ8.11–7.97(m,2H),7.90(d,J＝20.5Hz,1H),7.80(d,J＝15.0Hz,1H),7.67(ddt,J＝16.5,13.6,3.1Hz,1H),7.58–7.43(m,2H),7.18(d,J＝15.0Hz,1H),6.88–6.56(m,1H),6.16(d,J＝15.0Hz,1H),5.70(s,1H),4.87–4.56(m,2H),4.43–4.18(m,1H),3.81(p,J＝15.2Hz,1H),3.44(dt,J＝24.9,11.1Hz,2H),3.28(dd,J＝17.9,6.9Hz,1H),2.10–1.86(m,2H),1.82–1.47(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ196.32,168.60,163.89,156.72,156.18,139.84,137.04,132.74,129.14,128.74,128.61,120.63,97.18,54.58,51.32,48.55,47.50,30.70.ESI-MS m/z:439.2[M+H] + ；461.2[M+Na] + ；437.2[M-H] - .
Example 2- ((1H-1,2,4-triazol-1-yl) methyl) -N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) -3-oxo-3-phenylpropanamide;
the yield is 72.3 percent; mp is 145.9-148.2 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ8.77(s,1H),8.39–7.93(m,2H),7.84(dd,J＝40.6,9.2Hz,1H),7.67(ddt,J＝16.5,13.6,3.1Hz,1H),7.56–7.28(m,1H),6.70(s,1H),6.16(d,J＝15.0Hz,1H),5.23(dd,J＝24.7,8.6Hz,1H),4.92–4.73(m,1H),4.37(dd,J＝24.7,8.6Hz,1H),3.83(p,J＝15.2Hz,1H),3.53–3.00(m,2H),2.12–1.86(m,1H),1.74(ddt,J＝24.8,15.2,11.0Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ196.32,168.60,163.89,156.72,156.18,151.75,144.06,137.04,132.74,129.14,128.61,97.18,54.13,52.79,48.55,47.50,30.70.ESI-MS m/z:440.2[M+H] + ；462.2[M+Na] + ；4387.2[M-H] - .
Example 3- (((1H-imidazol-1-yl) methyl) -N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) -4-methyl-3-oxopentanamide;
the yield is 68.7 percent; mp is 143.3-146.7 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ7.92(s,1H),7.80(d,J＝15.0Hz,1H),7.18(d,J＝15.0Hz,1H),6.78(dd,J＝15.0,0.6Hz,1H),6.35(s,1H),6.16(d,J＝15.0Hz,1H),4.39(dd,J＝23.3,12.8Hz,1H),4.26(dd,J＝14.6,11.0Hz,1H),4.14(dd,J＝23.2,12.7Hz,1H),3.72(p,J＝15.2Hz,1H),3.49–3.13(m,4H),2.69–2.33(m,1H),2.04–1.80(m,2H),1.65(ddt,J＝24.8,15.2,11.0Hz,2H),1.04(d,J＝12.8Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ212.74,167.16,163.89,156.72,156.18,139.84,128.74,120.63,97.18,61.33,49.12,48.55,47.50,38.24,30.70,18.56.ESI-MS m/z:405.2[M+H] + ；427.2[M+Na] + ；403.2[M-H] - .
Example 4- ((1H-1,2,4-triazol-1-yl) methyl) -N- (1- (2-chloropyrimidin-4-yl) piperidin-4-yl) -4-methyl-3-oxovaleramide;
the yield is 70.5 percent; mp is 142.8-144.6 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ8.77(s,1H),8.06(s,1H),7.80(d,J＝15.0Hz,1H),6.35(s,1H),6.16(d,J＝15.0Hz,1H),5.14–4.75(m,1H),4.36(dd,J＝24.5,14.7Hz,1H),4.20(t,J＝14.6Hz,1H),3.83(p,J＝15.2Hz,1H),3.49–3.17(m,4H),1.99(tdt,J＝22.0,15.2,11.9Hz,3H),1.69(ddt,J＝24.9,15.2,11.0Hz,2H),1.04(d,J＝12.8Hz,6H). 13 C NMR(101MHz,DMSO-d 6 )δ212.74,167.16,163.89,156.72,156.18,151.75,144.06,97.18,59.13,50.92,48.55,47.50,38.24,30.70,18.56.ESI-MS m/z:406.2[M+H] + ；428.2[M+Na] + ；404.2[M-H] - .
EXAMPLE 5 preparation of 2- (((1H-imidazol-1-yl) methyl) -N- (naphthalen-2-ylmethyl) -3-oxo-3-phenylpropanamide
Step 1 preparation of N- (Naphthalen-2-ylmethyl) -3-oxo-3-phenylpropanamide
Benzoylacetic acid (1.0 eq) and HATU (1.2 eq) were added separately to a solution in anhydrous DMF. After stirring at room temperature for 2 hours, naphthylmethylamine (1.1 eq) and DIEA (4.0 eq) were added, the mixture was heated at 75 ℃ for 7 hours, the reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic phase was dried. Na (Na) 2 SO 4 Dry overnight. Finally obtaining the required compound by vacuum distillation.
Step 2 preparation of 2- (hydroxymethyl) -N- (naphthalen-2-ylmethyl) -3-oxo-3-phenylpropanamide
N- (Naphthalen-2-ylmethyl) -3-oxo-3-phenylpropanamide (1.0 eq) was dissolved in ethanol and 30mL of 37% formaldehyde solution was added. After stirring at room temperature for 4 hours and completion of the reaction, the organic phase was extracted with ethyl acetate and dried. Na (Na) 2 SO 4 Dry overnight. Finally, the desired compound was obtained by vacuum distillation.
Step 3 preparation of 2- (((1H-imidazol-1-yl) methyl) -N- (naphthalen-2-ylmethyl) -3-oxo-3-phenylpropanamide
2- (hydroxymethyl) -N- (naphthalen-2-ylmethyl) -3-oxo-3-phenylpropanamide (1.0 eq), CDI (2.0 eq) and imidazole (3.0 eq) were dissolved in 30mL acetonitrile, reacted for 6 hours under reflux, after completion of the reaction, poured into water, extracted three times with ethyl acetate and the organic phase was dried. Na (Na) 2 SO 4 Dry overnight. Finally, the desired compound was obtained by vacuum distillation.
The yield is 69.4%; mp is 136.3-139.6 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ8.10–7.99(m,2H),7.92(s,1H),7.82–7.57(m,6H),7.57–7.33(m,4H),7.18(d,J＝15.0Hz,1H),6.86–6.72(m,1H),6.61(s,1H),4.91–4.67(m,2H),4.51(s,2H),4.16(dd,J＝29.7,18.6Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ196.32,169.55,139.84,137.04,136.20,133.66,133.02,132.74,129.14,128.90,128.74,128.64,128.61,127.77,127.15,126.71,126.51,126.17,120.63,56.66,47.61,44.33.ESI-MS m/z:384.2[M+H] + ；406.2[M+Na] + ；382.2[M-H] - .
Example 6- (((1H-1,2,4-triazol-1-yl) methyl) -N- (naphthalen-2-ylmethyl) -3-oxo-3-phenylpropanamide;
the yield is 66.8%; mp is 132.6-137.5 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ8.75(s,1H),8.16–7.87(m,3H),7.83–7.32(m,10H),7.22(s,1H),5.25–4.82(m,2H),4.50(s,2H),4.37–4.00(m,1H). 13 C NMR(101MHz,DMSO-d 6 )δ196.32,169.55,151.75,144.06,137.04,136.20,133.66,133.02,132.74,129.14,128.90,128.64,128.61,127.77,127.15,126.71,126.51,126.17,53.64,51.71,44.33.ESI-MS m/z:385.2[M+H] + ；407.2[M+Na] + ；483.2[M-H] - .
Pharmacological study of a portion of the products of the invention
In vitro antifungal Activity test
The compounds of interest were tested for antifungal and antifungal resistance activity, respectively. The in vitro Minimum Inhibitory Concentration (MIC) was determined using standard guidelines described in the national clinical laboratory standards committee (NCCLS). MIC values are defined as the lowest concentration of antibacterial inhibitor that has an inhibitory effect. In the experiment, FLC and terbinafine were selected as positive control drugs; all compounds were dissolved in DMSO and serially diluted into growth medium. And observing the daily growth of the fungus under the culture condition of 35 ℃; the compounds prepared in the above examples were tested for their in vitro antifungal and antifungal resistance, see table 1.
TABLE 1 in vitro antifungal Activity test (MIC, μ g/ml) for the compounds prepared in the examples.
From the test results, it is clear that the compound of the general formula I to be protected has good in vitro antifungal activity, so that the compound of the invention has good industrial application prospect.
The compounds of general formula I of the present invention can be administered alone, but usually are administered in admixture with a pharmaceutically acceptable carrier selected according to the desired route of administration and standard pharmaceutical practice, and their novel use is illustrated below in the context of methods for the preparation of various pharmaceutical dosage forms of the compounds, e.g., tablets, capsules, injections, aerosols, suppositories, films, dripping pills, liniments for external use and ointments, as appropriate.
Example 7: tablet formulation
10g of the compound of claim 1 (in the case of the compound of example a-1) was mixed with 20g of excipients according to a usual pharmaceutical tableting method and compressed into 100 tablets each weighing 300mg.
Example 8: capsule preparation
10g of the compound containing the compound in claim 1 (taking the compound in the embodiment a-1 as an example) is mixed with 20g of auxiliary materials according to the requirement of a pharmaceutical capsule, and then the mixture is filled into empty capsules, wherein each capsule weighs 300mg.
Example 9: injection preparation
Using 10g of the compound containing the compound of claim 1 (exemplified by the compound of example a-1), activated carbon adsorption was carried out according to a conventional pharmaceutical method, and the mixture was filtered through a 0.65 μm microporous membrane and then filled into nitrogen gas bottles to prepare water-filled injecta preparations, each containing 2mL, and 100 bottles in total.
Example 10: aerosol formulation
Dissolving 10g of the compound of claim 1 (example is the compound of example a-1) in propylene glycol, adding distilled water and other additives, and making into 500mL of clear solution.
Example 11: suppository
50 suppositories are prepared by grinding 10g of the compound of claim 1 (example is the compound of example a-1) with appropriate amount of glycerol, mixing well, adding molten glycerogelatin, grinding well, pouring into lubricant-coated moulds
Example 12: film agent
Using 10g of the compound containing the compound of claim 1 (in the case of the compound of example a-1), polyvinyl alcohol, medicinal glycerin, water and the like were swelled under stirring and then dissolved by heating, and then the compound of example 18 was added to the filtrate and dissolved under stirring, and 100 films were formed on a film coating machine.
Example 13: drop pills
10g of the compound containing the compound of claim 1 (taking the compound in example a-1) is mixed with 50g of a matrix such as gelatin and the like, heated, melted and mixed uniformly, and then dropped into low-temperature liquid paraffin to prepare 1000 pills.
Example 14: external liniment
Is prepared from 10g of the compound containing the compound in claim 1 (taking the compound in the example a-1 as an example), 2.5g of auxiliary materials such as emulsifying agent and the like by mixing and grinding according to a conventional pharmaceutical method, and adding distilled water to 200 mL.
Example 15: ointment formulation
Prepared by grinding 10g of the compound of claim 1 (taking the compound of example a-1 as an example) and mixing with 500g of an oily base such as vaseline.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Claims (3)
1. A formylacetamidoazole derivative, wherein the formylacetamidoazole derivative has the following general formula:
wherein:
a is 1-phenyl-4-piperidinyl or methylenenaphthyl;
m is hydrogen or halogen, trifluoromethyl, (C1-C4) alkyl or (C1-C4) alkoxy;
the X is CH or N atom;
and R is methyl, ethyl, isopropyl or phenyl.
2. The formylacetamide azole derivative of claim 1 wherein the derivative is selected from the group consisting of:
3. the use of compounds according to any of claims 1-2 for the preparation of medicaments for the treatment and prophylaxis of fungal diseases.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911147449.XA CN110950845B (en) | 2019-11-21 | 2019-11-21 | Formylacetamide azole derivative and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911147449.XA CN110950845B (en) | 2019-11-21 | 2019-11-21 | Formylacetamide azole derivative and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110950845A CN110950845A (en) | 2020-04-03 |
| CN110950845B true CN110950845B (en) | 2023-04-18 |
Family
ID=69977894
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911147449.XA Active CN110950845B (en) | 2019-11-21 | 2019-11-21 | Formylacetamide azole derivative and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110950845B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112194629B (en) * | 2020-09-18 | 2023-10-24 | 聊城大学 | Phenethyl azole derivative and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541828A (en) * | 2014-12-10 | 2016-05-04 | 沈阳药科大学 | Acylaminoimidazole derivative and use thereof |
| CN107311995A (en) * | 2017-06-07 | 2017-11-03 | 沈阳药科大学 | Three ring isoxazole class derivatives and its preparation method and application |
| CN109232396A (en) * | 2018-11-27 | 2019-01-18 | 聊城大学 | Amide pyridine derivatives and application thereof |
| CN109485607A (en) * | 2018-10-25 | 2019-03-19 | 沈阳药科大学 | β-azole-phenyl ketone derivatives and application thereof |
-
2019
- 2019-11-21 CN CN201911147449.XA patent/CN110950845B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541828A (en) * | 2014-12-10 | 2016-05-04 | 沈阳药科大学 | Acylaminoimidazole derivative and use thereof |
| CN107311995A (en) * | 2017-06-07 | 2017-11-03 | 沈阳药科大学 | Three ring isoxazole class derivatives and its preparation method and application |
| CN109485607A (en) * | 2018-10-25 | 2019-03-19 | 沈阳药科大学 | β-azole-phenyl ketone derivatives and application thereof |
| CN109232396A (en) * | 2018-11-27 | 2019-01-18 | 聊城大学 | Amide pyridine derivatives and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| Combating fluconazole-resistant fungi with novel β-azole-phenylacetone derivatives;Liyu Zhao等;《European Journal of Medicinal Chemistry》;20190913;第183卷;111689 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110950845A (en) | 2020-04-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110352188B (en) | Fluoroallylamine derivatives and use thereof | |
| WO2020198466A1 (en) | Beta adrenergic agonist and methods of using the same | |
| CN109232396B (en) | Amide pyridine derivative and application thereof | |
| CN114340740A (en) | Beta adrenergic agonists and methods of use thereof | |
| JP7398605B2 (en) | FXR small molecule agonists and their preparation methods and uses | |
| AU2470900A (en) | Non-peptide gnrh agents, methods and intermediates for their preparation | |
| CA2661166A1 (en) | Compounds and methods for inhibiting the interaction of bcl proteins with binding partners | |
| CA2694724C (en) | Cyclic inhibitors of carnitine palmitoyltransferase and treating cancer | |
| CN107311995B (en) | Tricyclic isoxazole class derivative and its preparation method and application | |
| JP2013532657A (en) | Cyclic N, N'-diarylthiourea and N, N'-diarylurea-androgen receptor antagonists, anticancer agents, methods for their preparation and uses | |
| TWI832539B (en) | Compounds used as CDK7 kinase inhibitors and their applications | |
| CN109485645B (en) | Benzothiazole derivative and application thereof | |
| CN114516832A (en) | Tubulin inhibitor and preparation method and application thereof | |
| CN111848600A (en) | 2,4, 4-trisubstituted dihydrooxazole derivative and application thereof | |
| CN110950845B (en) | Formylacetamide azole derivative and application thereof | |
| EP3981768A1 (en) | Polymorph of cdk9 inhibitor and preparation method for polymorph and use thereof | |
| CN112194629B (en) | Phenethyl azole derivative and preparation method and application thereof | |
| CN112142673B (en) | Aryl alkene azole derivative and preparation method and application thereof | |
| AU2006309576B2 (en) | Ortho-substituted aniline derivative and antioxidant drug | |
| CN113999211B (en) | Indazole skeleton derivative containing 1,2,3-triazole with specific activity of resisting prostate cancer | |
| WO2022022388A1 (en) | Crystal form a of dezocine derivative, preparation method therefor and use thereof | |
| CN115477608A (en) | Tubulin inhibitor and preparation method and application thereof | |
| CN109485607B (en) | Beta-azole-phenyl ketone derivative and application thereof | |
| CA2956464C (en) | Bisamidinium-based inhibitors for the treatment of myotonic dystrophy | |
| CN111320574B (en) | Aryl amide derivative and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information |
Inventor after: Sun Bin Inventor after: Dong Yue Inventor after: An Yunfei Inventor after: Liu Min Inventor after: Wang Zhengping Inventor after: Han Jun Inventor before: Sun Bin Inventor before: Dong Yue Inventor before: An Yunfei |
|
| CB03 | Change of inventor or designer information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |