CN111320574B - Aryl amide derivative and application thereof - Google Patents

Aryl amide derivative and application thereof Download PDF

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CN111320574B
CN111320574B CN202010216752.7A CN202010216752A CN111320574B CN 111320574 B CN111320574 B CN 111320574B CN 202010216752 A CN202010216752 A CN 202010216752A CN 111320574 B CN111320574 B CN 111320574B
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孙彬
安云飞
董岳
刘敏
王正平
韩军
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Abstract

The invention belongs to the field of drug synthesis, and relates to a novel aryl amide derivative. The invention relates to a strong antifungal effect of aryl amide derivatives, and also relates to application of the compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparing medicines for treating fungal diseases, in particular to application in preparing medicines for treating and preventing pathogenic and drug-resistant fungi. The invention provides a compound of the general formula,

Description

Aryl amide derivative and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to novel aryl amide derivatives, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, a preparation method of the derivatives and the prodrugs, and application of the derivatives and the pharmaceutically acceptable salts, the hydrates, the solvates or the prodrugs in antifungal drugs.
Background
Fungal Infections (IFI) include primarily superficial fungal infections and deep fungal 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 in pathogenic fungi is more and more frequent. However, no effective treatment is available so far, and once fungal resistance occurs, a complex 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, the antifungal drugs widely used in the market are mainly commercial antifungal inhibitors developed aiming at SE and CYP51 targets, such as allylamines, thioacetamides and azoles, which have the advantages of high selectivity and strong specificity, but have obvious defects in the aspect of coping with fungal drug resistance. At present, SE inhibitors have the problems of low efficiency and high adverse reaction rate besides the existing drug resistance; CYP51 inhibitor has the advantages of high efficiency and low recurrence rate, but has the disadvantages of easy generation of drug resistance and high metabolic toxicity. In particular, the problem of drug resistance which has been developed in all of them is extremely difficult to overcome once it has occurred. The double-target or multi-target medicine can block a plurality of targets in a disease system at the same time, and can effectively prevent drug resistance caused by gene mutation or expression change. Therefore, the deep research on the molecular mechanism of pathogenic fungi and the development of double-target or multi-target antifungal medicines with novel structure, strong biological activity and low side effect have important research value and profound significance.
The inventor considers that the SE inhibitor and the CYP51 inhibitor have common structural characteristics from the molecular structures of the two inhibitors, and designs and synthesizes a series of novel aryl amide derivatives to ensure that the derivatives have double-target characteristics. In vitro activity screening shows that the compounds have higher activity of resisting fungi and drug-resistant fungi.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides an aryl amide derivative with a novel structure and application thereof; the invention relates to a strong antifungal effect of aryl amide derivatives, in particular to application in preparing medicaments for treating and preventing pathogenic candida albicans, candida krusei, candida tropicalis and aspergillus fumigatus.
In order to achieve the above objects, the present invention provides aryl amide compounds represented by general formulas I and II, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
Figure BDA0002424675010000021
wherein:
ar is 2-naphthyl, 1,4 benzodioxan, quinolinyl, benzofuranyl, 1,3 benzodioxolyl, 1,3 benzodioxazole, 1,3 benzoxazole, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, ar is optionally substituted with 1 to 4 identical or different M;
m is hydrogen or a substituent selected from the group consisting of halogen, amino, cyano, hydroxy, nitro, (C1-C6) alkenyl, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkynyl, (C1-C6) alkyl optionally substituted with hydroxy, amino or halo or (C1-C6) alkoxy or (C1-C6) alkylthio, amino substituted with mono or di (C1-C6 alkyl), (C1-C6) alkylamido, free, salified, esterified and amidated carboxy, (C1-C6) alkylsulfinyl, sulfonyl, (C1-C6) alkoxy, (C1-C6) alkyl, (C1-C6) alkanoyl, carbamoyl substituted with mono or di (C1-C6 alkyl), (C1-C3) alkylenedioxy, an donating or withdrawing group;
r is hydrogen, an alkane group or an aromatic group;
R 1 is a 3-pyridyl group, a 4-pyridyl group, a 3-picolyl group, a 4-picolyl group, a phenyl group or a benzyl group.
The invention preferably relates to aryl amide compounds shown in general formulas I and II and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein:
ar is 2-naphthyl, 1,4 benzodioxan, quinolinyl, benzofuranyl, 1,3 benzodioxolyl, 1,3 benzodioxazole, 1,3 benzoxazole, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, ar is optionally substituted with 1 to 4 identical or different M;
m is hydrogen or 1 to 3 groups selected from hydroxy, halogen, nitro, trifluoromethyl, (C1-C4) alkyl, (C1-C4) alkoxy, and possibly also phenyl groups;
r is hydrogen, an alkane group or an aromatic group;
R 1 is a 3-pyridyl group or a 4-pyridyl group or a 3-picolyl group or a 4-picolyl group or a phenyl or benzyl group.
The invention preferably relates to aryl amide compounds shown in general formulas I and II and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof,
wherein:
ar is 2-naphthyl, 1,4 benzodioxan, quinolinyl, benzofuranyl, 1,3 benzodioxolyl, 1,3 benzodioxazole, 1,3 benzoxazole, benzothienyl, indolyl, benzimidazolyl, benzopyrazolyl, ar is optionally substituted with 1 to 4 identical or different M;
m is hydrogen or 1 to 3 groups selected from hydroxy, halogen, nitro, trifluoromethyl, (C1-C4) alkyl, (C1-C4) alkoxy, and possibly also phenyl groups;
r is hydrogen or methyl, isopropyl, sec-butyl, isopentyl, phenyl, benzyl, imidazolylmethyl, triazolylmethyl, or the like;
R 1 is a 3-pyridyl group or a 4-pyridyl group or a 3-picolyl group or a 4-picolyl group or a phenyl or benzyl group.
The compounds of the general formulas I and II, and geometrical isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof are selected from:
(E) -3- (naphthalen-2-yl) -N- (2-oxo-2- (pyridin-3-ylamino) ethyl) acrylamide;
(E) -3- (naphthalen-2-yl) -N- (2-oxo-2- (pyridin-4-ylamino) ethyl) acrylamide;
(E) -3- (naphthalen-2-yl) -N- (2-oxo-2- ((pyridin-3-ylmethyl) amino) ethyl) acrylamide;
(E) -3- (naphthalen-2-yl) -N- (2-oxo-2- ((pyridin-4-ylmethyl) amino) ethyl) acrylamide;
(E) -N- (3- (1H-imidazol-1-yl) -1-oxo-1- (phenylamino) propan-2-yl) -3- (naphthalen-2-yl) acrylamide
(E) -N- (1- (benzylamino) -3- (1H-imidazol-1-yl) -1-oxopropan-2-yl) -3- (naphthalen-2-yl) acrylamide
(E) -N- (3- (1H-imidazol-1-yl) -1-oxo-1- (pyridin-4-ylamino) propan-2-yl) -3- (naphthalen-2-yl) acrylamide;
(E) -N- (3- (1H-imidazol-1-yl) -1-oxo-1- ((pyridin-4-ylmethyl) amino) propan-2-yl) -3- (naphthalen-2-yl) acrylamide;
(E) -2- (2- (naphthalen-2-ylmethylene) hydrazino) -2-oxo-N- (pyridin-3-yl) acetamide;
(E) -2- (2- (naphthalen-2-ylmethylene) hydrazino) -2-oxo-N- (pyridin-4-yl) acetamide;
(E) -2- (2- (naphthalen-2-ylmethylene) hydrazino) -2-oxo-N- (pyridin-3-ylmethyl) acetamide;
(E) -2- (2- (naphthalen-2-ylmethylene) hydrazino) -2-oxo-N- (pyridin-4-ylmethyl) acetamide.
The corresponding structural formulas of the above 12 compounds are as follows:
Figure BDA0002424675010000051
the derivatives of formulae I and II above of the present invention may be combined with an acid to form pharmaceutically acceptable salts according to conventional methods in the art. 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 the general formulae I, ii which may themselves have a weak or even no activity, but which, after administration, are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
"halogen" in the context of 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 ring system refers to an organic group having aromaticity 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, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, and the like; "saturated or partially saturated heterocyclyl" refers to monocyclic or polycyclic ring systems containing one or more heteroatoms selected from N, O, S, such as 2H-1-benzopyran-2-onyl, indoline-2, 3-diketo, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, imidazolidinyl, thiazolinyl, and the like.
The invention can contain the derivatives of the formulas I and II, and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof as active ingredients, and the derivatives are mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers 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 the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, colorants, flavorants, preservatives, solubilizers, bases and the like. 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 formulas I and II have antifungal activity, so that the compounds can be used for preparing medicaments for treating and/or preventing various fungal diseases. In particular to the preparation of the medicine for treating and preventing candida albicans, candida krusei, candida tropicalis and aspergillus fumigatus.
The active compound or the medicinal salt and the solvate thereof can be used as antifungal medicines.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods for their 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. According to the method of the scheme 1, the compound shown in the formula I can be prepared into an intermediate 1-2 by carrying out a Bergenin reaction on a corresponding initial raw material 1-1, the intermediate 1-2 and amino acid methyl ester are subjected to an amidation reaction to obtain an intermediate 1-3, the intermediate 1-4 is hydrolyzed by alkali liquor to obtain an intermediate 1-4, and finally the intermediate and aminomethyl pyridine or aminopyridine are subjected to an amido bond reaction to obtain a target product 1-5.
Figure BDA0002424675010000071
Route 1
According to the derivatives of formula I of the present invention, the main moiety can be prepared from the corresponding intermediate 1-1 by refluxing with malonic acid, pyridine and piperidine to give intermediate 1-2, according to the procedures of scheme 1. Subsequently, the intermediate 1-3 is prepared by amidation reaction by adding EDCI, HOB and the intermediate 1-2 into DMF as solvent, stirring for 2h at room temperature, adding amino acid ester with different substituents and DIEA, and refluxing for about 5 h. And hydrolyzing the intermediate 1-3 by using a 2N-NaOH solution to obtain an intermediate 1-4, finally dissolving the intermediate 1-4 in a DMF solution, adding PyBOP and DIEA, stirring at room temperature for 2 hours, adding 3-picolylamine or 4-picolylamine or 3-pyridylamine or 4-pyridylamine, and refluxing for 6 hours to obtain the target product 1-5. Wherein Ar and M in the compound are as defined in the summary of the invention.
When R is methylimidazolyl or methyltriazoyl, the synthesis of the derivatives of I is as follows (scheme 2).
Figure BDA0002424675010000072
Route 2
Derivatives of formula I according to the invention, derivatives containing an imidazole moiety may be prepared according to the procedure of scheme 2 by refluxing the corresponding intermediate 2-1 with malonic acid, pyridine and piperidine to give intermediate 2-2. Subsequently, EDCI, HOB and the intermediate 2-2 were added into DMF as a solvent, and stirred at room temperature for 2 hours, and serine amino acid methyl ester and DIEA were added thereto, and refluxed for about 5 hours to obtain an intermediate 2-3 by amidation. And then carrying out reflux reaction on the intermediate 2-3 by using CDI or CDT for 5h, introducing azole groups 2-4, hydrolyzing the intermediate 2-4 by using a 2N-NaOH solution to obtain an intermediate 2-5, finally dissolving the intermediate 2-5 in a DMF solution, adding PyBOP and DIEA, stirring at room temperature for 2h, adding aniline or benzylamine or picolyl or pyridylamino, and refluxing for 6h to obtain a target product 2-6. Wherein Ar and M in the compound are as defined in the summary of the invention.
According to the method of the route 3, the compound of the formula II can be prepared by preparing an intermediate 3-2 from a corresponding initial raw material diethyl oxalate 3-1 through a substitution reaction, carrying out a condensation reaction on the intermediate 3-2 and aryl aldehydes with different substituents to obtain the intermediate 3-3, hydrolyzing the intermediate 3-3 with a 2N-NaOH solution to obtain an intermediate 3-4, and finally carrying out a substitution reaction on the intermediate 3-3 and aminomethylpyridine or aminopyridine to obtain a target product 3-5.
Figure BDA0002424675010000081
Route 3
The method comprises the following specific steps: diethyl oxalate 3-1 and hydrazine hydrate are dissolved in C 2 H 5 OH, then the mixture is stirred at room temperature overnight to give intermediate 3-2, the corresponding arylcarboxaldehyde derivative is added toStirring the aqueous solution of the compound 3-2 at room temperature for 5 hours to obtain a key intermediate 3-3, hydrolyzing the intermediate 3-3 by using a 2N-NaOH solution to obtain an intermediate 3-4, finally dissolving the intermediate 3-4 in a DMF solution, adding PyBOP and DIEA, stirring the solution at room temperature for 2 hours, adding 3-picolylamine or 4-picolylamine or 3-pyridylamine or 4-pyridylamine, and refluxing the solution for 6 hours to obtain a target product 3-5.
Detailed Description
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 (E) -3- (naphthalen-2-yl) -N- (2-oxo-2- (pyridin-3-ylamino) ethyl) acrylamide
Step 1 preparation of (E) -3- (naphthalen-2-yl) acrylic acid
Naphthaldehyde (1.0 eq), malonic acid (10.0 eq), 60ML pyridine and 0.02ML piperidine were mixed at reflux overnight. After the reaction is finished, adjusting the pH value to 12 by using a saturated sodium hydroxide solution, extracting by using ethyl acetate, discarding an organic layer, adjusting the pH value of a water layer to 3-4 by using 2N hydrochloric acid, separating out a large amount of white solid, filtering, washing a filter cake by using water until the pH value is neutral, and performing vacuum drying for the next reaction.
Step 2 preparation of (E) - (3- (Naphthalen-2-yl) acryloyl) Glycine methyl ester
(E) -3- (naphthalen-2-yl) acrylic acid (1.0 eq), EDCI (1.2 eq) and HOBt (1.2 eq) were added separately to a solution in anhydrous DMF. After stirring at room temperature for 2 hours, L-glycine methyl ester (1.1 eq) and DIEA (4 eq) were added, and the mixture was heated at 75 ℃ for 7 hours, poured into ice water, extracted with ethyl acetate, and the organic phase was dried. Na (Na) 2 SO 4 Dried overnight. Finally, the desired compound was obtained by vacuum distillation.
Step 3 preparation of (E) - (3- (Naphthalen-2-yl) acryloyl) Glycine
(E) - (3- (naphthalen-2-yl) acryloyl) glycine methyl ester (1.0 eq) was dissolved in 15ml methanol and 30ml of 2N sodium hydroxide solution was added. The reaction mixture was then stirred at 60 ℃ for 7 hours and the progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, methanol was removed by reduced pressure, pH was adjusted to 2-3 with 2N hydrochloric acid, filtered and dried white solid to obtain the desired compound.
Step 4 preparation of (E) -3- (naphthalen-2-yl) -N- (2-oxo-2- (pyridin-3-ylamino) ethyl) acrylamide
PyBOP (1.2 eq) and (E) - (3- (naphthalen-2-yl) acryloyl) glycine (1.0 eq) were added separately to the DMF solution. The mixture was stirred at room temperature for 2 hours, then amino 3-pyridine (1.1 eq) and DIEA (4 eq) were added, heated at 80 ℃ for 7 hours, the reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic phase was Na 2 SO 4 Dry overnight and remove the solvent under vacuum. The resulting solid was dried to give the desired compound. The product was purified by flash column chromatography.
The yield is 73.2 percent; mp is 135.4-138.5 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ9.03(t,J＝5.9Hz,1H),8.67–8.43(m,4H),8.13–7.96(m,4H),7.77–7.58(m,3H),7.39(dd,J＝7.7,4.9Hz,1H),4.39(d,J＝6.0Hz,2H),4.02(d,J＝5.9Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ168.82,167.65,148.31,143.19,140.75,137.24,134.43,134.13,131.83,129.65,129.43,127.93,127.74,127.25,126.94,126.53,125.59,124.17,121.71,44.38.ESI-MS m/z:332.1[M+H] + ；354.1[M+Na] + ；330.0[M-H] - .
Example 2 (E) -3- (naphthalen-2-yl) -N- (2-oxo-2- (pyridin-4-ylamino) ethyl) acrylamide;
the yield is 69.5 percent; mp is 135.9-138.7 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ8.53(d,J＝15.0Hz,2H),8.28(d,J＝14.9Hz,2H),7.77(dddd,J＝14.1,10.1,4.6,2.0Hz,5H),7.58–7.29(m,2H),7.13(d,J＝30.0Hz,1H),6.28(s,1H),6.06(d,J＝30.0Hz,1H),3.92(d,J＝6.4Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ168.83,167.65,149.40,146.11,140.77,134.46,134.11,131.85,129.61,127.93,127.79,127.28,126.92,126.57,125.51,121.72,118.94,44.58.ESI-MS m/z:332.1[M+H] + ；354.1[M+Na] + ；330.0[M-H] - .
Example 3 (E) -3- (naphthalen-2-yl) -N- (2-oxo-2- ((pyridin-3-ylmethyl) amino) ethyl) acrylamide;
the yield is 71.5 percent; mp is 106.9-112.8 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ8.84(s,1H),8.62(s,1H),8.43(s,1H),7.89–7.71(m,5H),7.65(s,1H),7.48(d,J＝30.0Hz,2H),7.29(s,1H),7.15(s,1H),4.47(s,2H),3.92(d,J＝12.4Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ170.13,167.65,148.18,147.68,140.75,135.26,134.47,134.43,134.13,131.83,129.65,127.93,127.74,127.25,126.94,126.53,125.59,124.17,121.71,45.21,44.13.ESI-MS m/z:346.2[M+H] + ；368.1[M+Na] + ；344.1[M-H] - .
Example 4 preparation of (E) -3- (naphthalen-2-yl) -N- (2-oxo-2- ((pyridin-4-ylmethyl) amino) ethyl) acrylamide.
The yield is 73.2 percent; mp is 138.9-142.4 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ8.72(s,1H),8.62(d,J＝2.7Hz,1H),8.50–8.32(m,1H),7.80(dddd,J＝14.1,10.2,4.7,2.0Hz,5H),7.65(dt,J＝14.8,2.9Hz,1H),7.57–7.38(m,2H),7.29(t,J＝15.0Hz,1H),7.15(d,J＝30.2Hz,1H),6.28(s,1H),6.08(d,J＝30.2Hz,1H),4.47(s,2H),3.93(d,J＝8.8Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ170.13,167.65,148.18,147.68,140.75,135.26,134.47,134.43,134.13,131.83,129.65,127.93,127.74,127.25,126.94,126.53,125.59,124.17,121.71,45.21,44.15.ESI-MS m/z:346.2[M+H] + ；368.1[M+Na] + ；344.1[M-H] - .
Example 5 preparation of (E) -N- (3- (1H-imidazol-1-yl) -1-oxo-1- (phenylamino) propan-2-yl) -3- (naphthalen-2-yl) acrylamide.
Step 1 preparation of (E) -3- (naphthalen-2-yl) acrylic acid
Naphthalenecarboxaldehyde (1.0 eq), malonic acid (10.0 eq), 60mL of pyridine, and 0.02mL of piperidine were mixed at reflux overnight. After the reaction is finished, adjusting the pH value to 12 by using a saturated sodium hydroxide solution, extracting by using ethyl acetate, discarding an organic layer, adjusting the pH value of a water layer to 3-4 by using 2N hydrochloric acid, separating out a large amount of white solid, filtering, washing a filter cake by using water until the pH value is neutral, and performing vacuum drying for the next reaction.
Step 2 preparation of (E) - (3- (Naphthalen-2-yl) acryloyl) serine methyl ester
Reacting (E) -3- (naphthalene-2-Yl) acrylic acid (1.0 eq), EDCI (1.2 eq) and HOBt (1.2 eq) were added separately to a solution in anhydrous DMF. After stirring at room temperature for 2 hours, L-serine methyl ester (1.1 eq) and DIEA (4 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 Dried overnight. Finally, the desired compound was obtained by vacuum distillation.
Step 3 preparation of methyl 3 (E) -3- (1H-imidazol-1-yl) -2- (3- (naphthalen-2-yl) acrylamido) propionate
(E) - (3- (naphthalene-2-yl) acryloyl) glycine methyl ester (1.0 eq), CDI (2.0 eq) and imidazole (3.0 eq) were dissolved in 30ml acetonitrile, refluxed for 6 hours, poured into water after the reaction was completed, extracted with ethyl acetate three times, 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 (E) -3- (1H-imidazol-1-yl) -2- (3- (naphthalen-2-yl) acrylamido) propionic acid
Methyl (E) -3- (1H-imidazol-1-yl) -2- (3- (naphthalen-2-yl) acrylamido) propanoate (1.0 eq) was dissolved in 15ml of methanol and 30ml of 2N sodium hydroxide solution was added. The reaction mixture was then stirred at 60 ℃ for 7 hours and the progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, methanol was removed by reduced pressure, pH was adjusted to 2-3 with 2N hydrochloric acid, filtered and dried white solid to obtain the desired compound.
Step 5 preparation of (E) -N- (3- (1H-imidazol-1-yl) -1-oxo-1- (phenylamino) propan-2-yl) -3- (naphthalen-2-yl) acrylamide
PyBOP (1.2 eq) and (E) -3- (1H-imidazol-1-yl) -2- (3- (naphthalen-2-yl) acrylamido) propionic acid (1.0 eq) were added separately to the DMF solution. The mixture was stirred at room temperature for 2 hours, then aniline (1.1 eq) and DIEA (4 eq) were added, heated at 80 ℃ for 7 hours, the reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic phase was Na 2 SO 4 Dry overnight and remove the solvent under vacuum. The resulting solid was dried to give the desired compound. The product was purified by flash column chromatography. The yield is 75.1%; mp is 133.6-135.9 ℃.
1 H NMR(400MHz,DMCO-d 6 )δ8.71(s,1H),8.52(s,1H),7.92(s,1H),7.90–7.68(m,5H),7.68–7.37(m,4H),7.36–7.23(m,2H),7.28–6.99(m,4H),6.78(d,J＝15.0Hz,1H),6.08(d,J＝30.0Hz,1H),5.04(t,J＝12.5Hz,1H),4.67(dd,J＝24.7,12.6Hz,1H),3.97(dd,J＝24.7,12.6Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ170.22,167.10,141.01,139.84,137.33,134.43,134.13,131.83,129.65,128.80,128.74,127.93,127.74,127.25,126.94,126.53,125.59,124.51,122.53,121.67,120.63,51.57,48.68.ESI-MS m/z:346.2[M+H] + ；368.1[M+Na] + ；344.1[M-H] - .ESI-MS m/z:411.2[M+H] + ；433.2[M+Na] + ；409.2[M-H] - .
Example 6 (E) -N- (1- (benzylamino) -3- (1H-imidazol-1-yl) -1-oxopropan-2-yl) -3- (naphthalen-2-yl) acrylamide;
the yield is 73.6 percent; mp is 137.4-139.8 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ8.60(s,1H),8.02–7.69(m,6H),7.60–7.37(m,2H),7.37–6.98(m,7H),6.77(t,J＝7.4Hz,2H),6.08(d,J＝30.2Hz,1H),4.98(t,J＝11.6Hz,1H),4.59(dd,J＝24.7,11.5Hz,1H),4.40(s,2H),3.94(dd,J＝24.7,11.5Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ172.99,167.10,141.01,139.91,139.84,134.43,134.13,131.83,129.65,128.74,128.34,127.93,127.83,127.74,127.35,127.25,126.94,126.53,125.59,122.53,120.63,51.57,49.15,43.99.ESI-MS m/z:425.2[M+H] + ；447.2[M+Na] + ；423.2[M-H] - .
Example 7 (E) -3- (naphthalen-2-yl) -N- (1-oxo-1- ((pyridin-3-ylmethyl) amino) propan-2-yl) acrylamide;
the yield is 64.7 percent; mp is 133.1-135.5 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ8.78(s,1H),8.56(d,J＝15.0Hz,2H),8.49(d,J＝57.5Hz,2H),8.31(d,J＝15.0Hz,2H),8.19–7.70(m,6H),7.64–7.29(m,2H),7.29–7.03(m,2H),6.86–6.64(m,1H),6.08(d,J＝30.2Hz,1H),5.03(t,J＝12.9Hz,1H),4.66(dd,J＝24.7,13.0Hz,1H),3.93(dd,J＝24.7,13.0Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ170.22,167.10,149.33,145.70,141.01,139.84,134.43,134.13,131.83,129.65,128.74,127.93,127.74,127.25,126.94,126.53,125.59,122.53,120.63,119.13,51.57,48.68.ESI-MS m/z:412.2[M+H] + ；434.2[M+Na] + ；410.2[M-H] - .
Example 8 (E) -N- (3- (1H-imidazol-1-yl) -1-oxo-1- ((pyridin-4-ylmethyl) amino) propan-2-yl) -3- (naphthalen-2-yl) acrylamide;
the yield is 64.7 percent; mp is 137.4-141.4 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ8.44(d,J＝15.0Hz,2H),8.11(s,1H),7.97–7.60(m,6H),7.60–7.29(m,2H),7.29–7.00(m,4H),6.78(dd,J＝10.8,4.4Hz,2H),6.08(d,J＝30.2Hz,1H),5.18(s,2H),4.93(t,J＝14.2Hz,1H),4.68(dd,J＝24.7,14.1Hz,1H),3.93(dd,J＝24.7,14.1Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ172.99,167.10,150.46,149.05,141.01,139.84,134.43,134.13,131.83,129.65,128.74,127.93,127.74,127.25,126.94,126.53,125.59,122.79,122.53,120.63,51.57,49.15,43.99.ESI-MS m/z:426.2[M+H] + ；448.2[M+Na] + ；424.2[M-H] - .
EXAMPLE 9 preparation of (E) -2- (2- (naphthalen-2-ylmethylene) hydrazino) -2-oxo-N- (pyridin-3-yl) acetamide
Step 1 preparation of ethyl 2-hydrazino-2-oxoacetate
Diethyl oxalate 1 (3.0 eq) was dissolved in the ethanol solution, and then hydrazine hydrate (1.0 eq) in ethanol solution was slowly added dropwise to the mixed solution. Stir at room temperature overnight. Insoluble white impurities were removed by filtration and the residual mixture was concentrated under reduced pressure to give the desired compound.
Step 2 preparation of (E) -ethyl 2- (2- (naphthalen-2-ylmethylene) hydrazino) -2-oxoacetate
Adding 2-hydrazino-2-oxoethyl acetate (1.5 eq) and naphthaldehyde (1.0 eq) into 30ml of aqueous solution respectively to form mixed solution, stirring for 5 hours at room temperature to generate white solid, performing suction filtration, and collecting the solid, namely the required compound.
Step 3 preparation of (E) -2- (2- (naphthalene-2-methylene) hydrazino) -2-oxyacetic acid
Ethyl (E) -2- (2- (naphthalen-2-ylmethylene) hydrazino) -2-oxoacetate (1.0 eq) was dissolved in 15ml of methanol, and 30ml of 2N sodium hydroxide solution was added. The reaction mixture was then stirred at 60 ℃ for 7 hours and the progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, methanol was removed by reduced pressure, pH was adjusted to 2-3 with 2N hydrochloric acid, filtered and dried white solid to obtain the desired compound.
Step 4 preparation of (E) -2- (2- (naphthalen-2-ylmethylene) hydrazino) -2-oxo-N- (pyridin-3-yl) acetamide PyBOP (1.2 eq) and (E) - (3- (naphthalen-2-yl) acryloyl) glycine (1.0 eq) were added to DMF solution, respectively. The mixture was stirred at room temperature for 2 hours, then amino 3-pyridine (1.1 eq) and DIEA (4 eq) were added, heated at 80 ℃ for 7 hours, the reaction mixture was poured into ice water, extracted with ethyl acetate, the organic phase was dried over Na2SO4 overnight and the solvent was removed in vacuo. The resulting solid was dried to give the desired compound. The product was purified by flash column chromatography.
The yield is 71.1 percent; mp is 136.7-138.2 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ9.74(s,1H),9.07–8.85(m,1H),8.60(t,J＝3.0Hz,1H),8.47(dd,J＝15.0,2.9Hz,1H),8.39–8.25(m,1H),8.08(dt,J＝15.0,3.0Hz,1H),7.94(dd,J＝14.4,3.6Hz,2H),7.88–7.70(m,2H),7.64–7.43(m,2H),7.30(t,J＝15.0Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ165.91,160.12,149.28,148.36,143.48,135.58,134.43,134.13,132.00,130.89,130.05,129.65,127.74,127.25,127.05,126.53,126.16,123.91.ESI-MS m/z:319.1[M+H] + ；341.1[M+Na] + ；317.0[M-H] - .
Example 10 (E) -2- (2- (naphthalen-2-ylmethylene) hydrazino) -2-oxo-N- (pyridin-4-yl) acetamide;
the yield is 70.7 percent; mp is 138.3-141.2 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ9.88(s,1H),8.65–8.52(m,3H),8.47(dd,J＝15.0,2.9Hz,1H),8.31(d,J＝15.0Hz,2H),7.94(dd,J＝14.4,3.6Hz,2H),7.88–7.76(m,2H),7.66–7.37(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.91,160.12,149.28,149.26,145.18,134.43,134.13,130.89,130.05,129.65,127.74,127.25,127.05,126.53,126.16,119.17.ESI-MS m/z:319.1[M+H] + ；341.1[M+Na] + ；317.0[M-H] - .
Example 11 (E) -2- (2- (naphthalen-2-ylmethylene) hydrazino) -2-oxo-N- (pyridin-3-ylmethyl) acetamide;
the yield is 67.5 percent; mp at 139.6-141.7 deg.C. 1 H NMR(400MHz,DMCO-d 6 )δ8.75–8.55(m,2H),8.50–8.32(m,2H),7.94(dd,J＝14.4,3.6Hz,2H),7.89–7.73(m,2H),7.69–7.42(m,4H),7.29(t,J＝14.9Hz,1H),4.23(s,2H). 13 C NMR(101MHz,DMSO-d 6 )δ169.44,160.96,149.28,148.18,147.68,135.26,134.47,134.43,134.13,130.89,130.05,129.65,127.74,127.25,127.05,126.53,126.16,124.17,44.41.ES I-MS m/z:333.1[M+H] + ；355.1[M+Na] + ；331.0[M-H] - .
Example 12 (E) -2- (2- (naphthalen-2-ylmethylene) hydrazino) -2-oxo-N- (pyridin-4-ylmethyl) acetamide;
the yield is 68.6 percent; mp is 138.6-140.8 ℃. 1 H NMR(400MHz,DMCO-d 6 )δ8.60(t,J＝3.0Hz,1H),8.52–8.38(m,3H),7.94(dd,J＝14.4,3.6Hz,2H),7.89–7.75(m,2H),7.65–7.41(m,3H),7.21(d,J＝15.0Hz,2H),5.12(s,2H). 13 C NMR(101MHz,DMSO-d 6 )δ169.44,160.96,150.46,149.28,149.05,134.43,134.13,130.89,130.05,129.65,127.74,127.25,127.05,126.53,126.16,122.79,44.41..ES I-MS m/z:333.1[M+H] + ；355.1[M+Na] + ；331.0[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.
Figure BDA0002424675010000161
Figure BDA0002424675010000171
From the test results, it is clear that the compounds of general formulas I and II to be protected have good in vitro antifungal activity, so that the compounds of the invention have good industrial application prospects.
The compounds of the general formulae I and II of the present invention may be administered alone, but are generally administered in admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice, the following procedures for preparing various pharmaceutical dosage forms of such compounds, e.g., tablets, capsules, injections, aerosols, suppositories, films, drops, liniments and ointments, and the use thereof in the pharmaceutical field are indicated.
Example 13: tablet formulation
10g of the compound of claim 1 (taking the compound of example 1 as an example) is mixed with 20g of auxiliary materials according to a general pharmaceutical tabletting method, and then the mixture is pressed into 100 tablets, wherein each tablet is 300mg.
Example 14: capsule preparation
10g of the compound containing the compound in claim 1 (taking the compound in example 1 as an example) is mixed with 20g of auxiliary materials according to the requirements of pharmaceutical capsules, and then the mixture is filled into hollow capsules, wherein each capsule weighs 300mg.
Example 15: injection preparation
Using 10g of the compound of claim 1 (exemplified by the compound of example 1), adsorbing with activated carbon, filtering through a 0.65 μm microporous membrane, and filling into nitrogen gas bottles to obtain water injection preparations, each containing 2mL, and filling into 100 bottles.
Example 16: aerosol formulation
Dissolving 10g of the compound of claim 1 (in the case of the compound of example 1) in propylene glycol, adding distilled water and other additives, and making into 500mL of clear solution.
Example 17: suppository
50 suppositories are prepared by grinding 10g of the compound of claim 1 (example 1) with the appropriate amount of glycerin, mixing well, adding melted glycerin gelatin, grinding well, pouring into lubricant-coated molds
Example 18: film agent
Using 10g of the compound containing the compound of claim 1 (in example 1), polyvinyl alcohol, medicinal glycerin, water, etc. were swelled under stirring and dissolved under heating, and then filtered through a 80-mesh screen, and the compound of example 18 was added to the filtrate and dissolved under stirring, and 100 films were formed on a film coater.
Example 19: drop pills
10g of the compound containing the compound of claim 1 (taking the compound in example 1 as an example) 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 20: external liniment
Is prepared from 10g of the compound containing the compound in claim 1 (taking the compound in example 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 21: ointment formulations
Prepared by grinding 10g of the compound of claim 1 (taking the compound of example 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 invention.

Claims (5)

1. An arylamide compound characterized by the structural formula selected from:
Figure FDA0004085538770000011
wherein,
ar is 2-naphthyl; m is hydrogen; r is hydrogen or (1H-imidazol-1-yl) methyl; r 1 Is a 3-pyridyl group, a 4-pyridyl group, (pyridin-3-yl) -methyl, (pyridin-4-yl) -methyl, phenyl or benzyl group.
2. The arylamide compound of claim 1, wherein the compound of formula I or ii is selected from the group consisting of:
Figure FDA0004085538770000012
3. a pharmaceutical composition comprising a compound according to any one of claims 1-2 as an active ingredient together with a pharmaceutically acceptable excipient.
4. The use of compounds according to any of claims 1-2 for the preparation of medicaments for the treatment and prophylaxis of fungal diseases.
5. The use of compounds according to any of claims 1-2 for the preparation of medicaments for the treatment and prophylaxis of pathogenic and drug-resistant fungi.
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