CN114057635A - 2-aryl ureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound and application thereof - Google Patents

2-aryl ureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound and application thereof Download PDF

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CN114057635A
CN114057635A CN202111519088.4A CN202111519088A CN114057635A CN 114057635 A CN114057635 A CN 114057635A CN 202111519088 A CN202111519088 A CN 202111519088A CN 114057635 A CN114057635 A CN 114057635A
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ethyl
methoxyphenoxy
nicotinamide
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ureido
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胡春
李乐瑢
张富荣
文杰
杨小力
王宇航
吴阳灿
刘晓平
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Shenyang Pharmaceutical University
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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Abstract

2-Arylureido-N- [2- (2-methoxyphenoxy) ethyl]A nicotinamide compound and application thereof, belongs to the technical field of medicine, and particularly relates to 2-aryl ureido-N- [2- (2-methoxyphenoxy) ethyl]Nicotinamide compound, prodrug and pharmaceutically active metabolite thereof, stereoisomer of the compound and pharmaceutically acceptable salt thereof, and application of the compound in anti-influenza virus medicines. 2-Arylureido-N- [2- (2-methoxyphenoxy) ethyl]The nicotinamide compound and the acid addition salt suitable for the compound in pharmacy can be combined with the existing medicines or used independently as an influenza virus inhibitor for treating influenza, and particularly has better curative effect on various influenza A.

Description

2-aryl ureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound and application thereof as an anti-influenza virus medicine.
Background
Influenza (flu) is an upper respiratory disease caused by influenza virus (IFV). To date, there are 5 influenza pandemics documented in the literature: spain type H1N1 influenza in 1918; influenza type H2N2 in asia in 1957; influenza type H3N2 in hong kong of china in 1968; avian influenza type H1N1 in 2005; influenza type H1N1 in 2009.
Influenza virus belongs to the family of orthomyxoviridae (orthomyxovoridae), and is a single-stranded, negative-stranded RNA genomic virus. Generally, influenza viruses are classified into the following four types: A. b, C and D. Among them, type a is the most prominent and drastic epidemic of influenza viruses throughout the year, and has become a hot spot for influenza virus research. Influenza viruses contain mainly the following proteins: RNA polymerase (RNA polymerase), Neuraminidase (NA), Hemagglutinin (HA), Nucleoprotein (NP), proton channel protein (M2), Matrix protein 1(Matrix protein, M1), Nuclear Export Protein (NEP) and nonstructural protein 1(non-structural protein 1, NS1) (VON ITZST protein M.the ware acquisition infection: Discovery and degradation of sialidase inhibition. Nature Reviews Drug Discovery,2007,6(12):967 974.). The new influenza virus subtypes are mainly changes around Hemagglutinin (HA) and Neuraminidase (NA). The NP protein and RNA polymerase located in the inner layer are stable and rarely varied. Therefore, anti-influenza virus drugs against the NP protein and RNA polymerase are not susceptible to drug resistance.
NP proteins and RNA polymerases are the major components of the influenza Ribonucleoprotein (RNP) complex (PORTELA A, Digard P. the influenza virus nucleoprotein: a multifunctional RNA-binding protein peptide to virus replication. journal of General Virology,2002,83(4): 723-) 734).
NP is a major structural protein of a virus and contains many functional domains, such as NUclear Localization Signals (NLSs), RNA binding domains, NP-NP binding domains, and PB2 binding domains (HAGIWARA K, KONDOH Y, Ueda A, et al, discovery of novel anti-viral agents directed acquisition of the infectious of the nucleic acids using photo-cross-linked chemical arrays, biochemical and biological Research Communications,2010,394(3): 721-. NP is expressed in large quantities during viral infection and is involved in multiple processes of viral replication. NP is also involved in the initial primer-free synthesis of cRNA during replication of the Viral genome (Newcomb L, Kuo R-L, Ye Q, et al interaction of the Influenza A Viral nucleic acid Protein with the Viral RNA polymers Unsterimed Viral RNA replication. journal of Virology,2009,83(1):29-36.) is an essential component of the Viral replication process.
RNA polymerase also plays an important role in the viral propagation process and is essential for viral RNA replication, transcription and translation. RNA polymerase consists of three protein subunits, polymerase acid Protein A (PA), polymerase basic protein 1 (PB 1) and polymerase basic protein 2 (PB 2). The PA protein subunit has polymerase activity and plays a role of kinase or helicase, the PB1 and PB2 protein subunits have key functions on the extension of viral RNA and the induction of host cell apoptosis, the PB1 protein subunit is responsible for recognizing and cutting a host mRNA 5' end cap structure primer, and the PB2 protein subunit is responsible for catalyzing the extension reaction of a newly synthesized RNA chain. They function in conjunction with each other and play an essential role in the transcriptional replication of influenza viruses.
The highly conserved sequences make NP and RNA polymerase ideal targets for the development of broad-spectrum influenza virus inhibitors. Several studies have shown that influenza virus inhibitors acting on NP and RNA polymerase have potential druggability. Meanwhile, NP and RNA polymerase do not have homologous proteins in mammalian cells, so that the antiviral drug which selectively acts on the NP and RNA polymerase does not have serious toxic and side effects on human bodies.
Nucleozin is a small molecule NP inhibitor (GERRITIZ SW, CIANCI C, KIM S, et al. inhibition of influenza virus replication vitamin a small molecules of the ligand of the formation of high-order nuclear protein oligomers. Proc Natl Acad Sci U S A,2011,108: 15366. sup. 15371.) which can induce the aggregation of nucleoproteins to form large aggregates, antagonize the nuclear entry and nuclear accumulation of nucleoproteins, interfere with the replication and proliferation of viruses, and thus achieve the effective therapeutic effect of influenza. Favipiravir (Favipiravir) has been used as an RNA polymerase inhibitor for the treatment of influenza, and is currently marketed as an antiviral drug only in japan and is still under clinical study in other countries such as the united states. The action mechanism is as follows: favipiravir is converted in vivo into the form of Favipiravir nucleoside triphosphate, competitively inhibits viral RNA polymerase by mimicking Guanosine Triphosphate (GTP), thereby inhibiting viral genome replication and transcription, and exerts antiviral effects (FURUTA Y, TAKAHASHI K, KUNO-MAEKAWA M, et al&Chemotherapy,2005,49(3): 981-. Favipiravir inhibits influenza virus type A, B, C, in which IC is associated with PR/8/34 influenza A virus strain50The value was 1.0. mu. mol. L–1And are effective against both neuraminidase inhibitor-resistant viruses and amantadine-resistant viruses (SIDDEL R, BARNARD D, DAY C, et al. effectiveness of oral administered T-705 on viral affinity influenza A (H5N1) viral infections in micro. antibiotic Agents&Chemotherapy,2007,51(3):845-851.；KISO M,TAKAHASHI K,SAKAI-TAGAWA Y,et al.T-705(favipiravir)activity against lethal H5N1 influenza A viruses.Proceedings of the National Academy of Sciences of the United States of America,2010,107(2):882-887.)。
Disclosure of Invention
The technical problem to be solved by the invention is to provide a 2-aryl ureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound shown in formula I, a prodrug and a pharmaceutically active metabolite thereof, a stereoisomer of the compound and pharmaceutically acceptable salts thereof, and application of the compound in preparing medicines for treating diseases related to influenza.
Figure BDA0003408100610000031
Wherein R is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl and benzyloxy.
Further, R is selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine and benzyloxy.
Still further, the 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound is any one of the following compounds:
2- (3-phenylureido) -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide;
2- [3- (4-methylphenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide;
2- [3- (4-methoxyphenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide;
2- [3- (4-fluorophenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide;
2- [3- (4-chlorophenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide;
2- [3- (4-bromophenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide;
2- [3- (4-benzyloxyphenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide.
The invention also provides a pharmaceutical composition which comprises the 2-aryl ureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound shown in the formula I, a prodrug thereof, a pharmaceutically active metabolite and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
The pharmaceutical composition is used for preparing a medicament for treating influenza virus diseases. For example, using an aqueous saline solution as the carrier, at a pH of 7.4, the pharmaceutical composition is introduced into the bloodstream of the patient as a solution by local bolus injection.
The compounds of the present invention may be administered alone or in combination with adjuvants, such as pharmaceutically acceptable carriers or diluents, in the form of pharmaceutical compositions according to conventional pharmaceutical practice. Routes of administration include oral administration or parenteral, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes.
For oral administration, administration in the form of an aqueous solution or suspension may be used in addition to tablets or capsules. For oral administration, the active pharmaceutical ingredient is combined with an orally acceptable, non-toxic, pharmaceutically acceptable inert carrier to form a pharmaceutical composition, which for oral administration in the form of tablets or capsules comprises lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol; for oral administration in liquid form, carriers include ethanol, glycerol, water and combinations thereof. In addition, pharmaceutically acceptable binders, lubricants, disintegrants and coloring agents may also be added to the pharmaceutical composition. Binding agents include starch, gelatin, natural sugars such as glucose or lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes. The lubricant comprises sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. When aqueous suspensions are used orally, the active ingredient is combined with emulsifying and suspending agents. Sweetening agents or flavoring agents may also be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, the pH of the solution being adjusted and buffered appropriately. For intravenous use, the total concentration of solutes should be controlled to maintain the formulation isotonic.
The 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamides of the invention may also be used in combination with known agents useful in the treatment or prevention of influenza. Preferred combinations include a compound of the invention and an inhibitor of M2 ion channel protein, a compound of the invention and a neuraminidase inhibitor, a compound of the invention and an interferon inducer, a compound of the invention and an antisense oligonucleotide, and a compound of the invention and an inosine monophosphate dehydrogenase inhibitor.
The term "administration" and variations thereof (e.g., "administering" a compound) in reference to the present invention means: introducing a 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound or a prodrug of said compound into an animal system in need of treatment. When 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide or a prodrug thereof is provided in combination with one or more other active agents, "administering" and variations thereof are understood to include the simultaneous and sequential introduction of the 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide or a prodrug thereof and the other agent. Typically, the prodrugs are functional derivatives of 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamides which are readily convertible in vivo into the desired compound. In the present invention, the term "administering" shall encompass the specifically disclosed 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compounds or compounds that may not be specifically disclosed, but which are capable of being converted in vivo to the specified compound after administration to a subject.
When the compounds of the present invention are administered to a human subject, the daily dosage will generally be determined by the prescribing physician, and the dosage will generally vary with the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms. In one exemplary use, a suitable amount of the compound is administered to the mammal being treated. When used for the indicated effects, the oral dosage of the invention will be from about 0.01mg per kg body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably from 0.01 mg/kg/day to 10 mg/kg/day, most preferably from 0.1 mg/kg/day to 5.0 mg/kg/day. For oral administration, the composition is preferably provided in the form of a tablet, wherein the tablet comprises 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500mg of active ingredient, preferably 1mg to 100mg of active ingredient. For intravenous injection, the most preferred dose is 0.1mg/kg/min to 10mg/kg/min during a constant rate infusion. The compound of the present invention or a pharmaceutical composition comprising the compound may be administered in a once-daily dose, or the total daily dose may be divided into two, three or four daily doses. For administration in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The dosage regimen utilizing the compounds of the present invention will be selected in accordance with a variety of factors including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition being treated; the route of administration; renal and hepatic function of the patient; and the particular compound or salt thereof used. The skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
Pharmaceutically acceptable salts of the compounds of the present invention refer to conventional acid addition salts or base addition salts which retain the biological potency and properties of the compounds of formula I and which are formed with suitable non-toxic organic or inorganic acids or bases. Acid addition salts include hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, sulfate, perchlorate, thiocyanate, bisulfate, persulfate, borate, formate, acetate, propionate, valerate, pivalate, hexanoate, heptanoate, octanoate, isooctanoate, undecanoate, laurate, palmitate, stearate, oleate, cyclopropionate, oxalate, malonate, succinate, maleate, fumarate, adipate, azelate, acrylate, strawberry, crotonate, glatironate, itaconate, sorbate, cinnamate, glycolate, lactate, malate, tartrate, citrate, tartrate, mandelate, diphenoxylate, troponate, ascorbate, gluconate, glucoheptonate, mandelate, dibenzolate, trogoplate, ascorbate, gluconate, glucoheptonate, and the like, Glucarate, mannonate, lactobionate, benzoate, phthalate, paraththalate, furoate, nicotinate, isonicotinate, salicylate, acetylsalicylate, caseinate, gallate, caffeate, ferulate, picrate, camphorate, camphorsulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, benzenesulfonate, p-toluenesulfonate, sulfanilate, sulfamate, taurate, 2-hydroxyethanesulfonate, glycinate, alaninate, valine, leucine, isoleucine, phenylalanine, tryptophan, caseinate, aspartate, asparagine, glutamate, lysine, glutamine, methionine, serine, threonine, cysteine, proline, histidine, arginine, and salts thereof, Edetate, pyruvate, alpha-ketoglutarate, alginate, cyclopentanepropionate, 3-phenylpropionate, 3-cyclohexylpropionic acid, 2-naphthoate, 2-naphthalenesulfonate, pamoate, lauryl sulfate, glycerophosphate, lauryl sulfate, pectin oleate, and the like. Base addition salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine salts, and the like, and basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides and the like.
The invention also provides a preparation method of the 2-aryl ureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound shown in the general formula I, which comprises the following steps:
Figure BDA0003408100610000061
wherein R is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen and benzyloxy.
Further, R is selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine and benzyloxy.
The invention has the beneficial effects that: the compound provided by the invention is used for preparing a medicament for inhibiting influenza virus, and is a novel influenza virus inhibitor acting on NP protein and RNA polymerase. Compared with the anti-influenza virus medicaments which are on the market and act on other targets, the influenza virus inhibitor which acts on NP protein and RNA polymerase has stability. The influenza virus inhibitor compound has wide therapeutic effect on influenza.
The compound disclosed by the invention is simple in preparation method and stable in yield, and the prepared compound can be used for preparing a medicine for treating influenza-related diseases.
Detailed Description
The following examples are given to illustrate the present invention. It should be understood, however, that the present invention is not limited to the following examples which are specifically set forth.
Example 1: preparation of 2- (3-phenylureido) -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide
Figure BDA0003408100610000062
Step A: preparation of 2, 3-pyridinedicarboxylic anhydrides
Placing 16.7g (100mmol) of 2, 3-pyridinedicarboxylic acid in a 100mL eggplant-shaped bottle, adding 20.0mL of acetic anhydride, heating and refluxing for 30min, cooling, crystallizing, filtering, drying to obtain 12.4g of 2, 3-pyridinedicarboxylic anhydride pale yellow solid with yield of 83.2 percent, m.p. of 132.6-133.8 ℃. (literature (GRIBBLE G, FLETCHER G, KETCHA D, et al. metallic heterocycles in the synthesis of inflammatory analytes: A new route to the 10H-pyridine [2,3-b ] carboxylic ring system. journal of Organic Chemistry,1989,54(14): 3264; 3269 ])) value: 133-.
And B: preparation of 2-carbamoylpyridine-3-carboxylic acid
13.6g (200mmol) of 25% ammonia water is put into a 100mL eggplant-shaped bottle, 7.46g (50mmol) of 2, 3-pyridinedicarboxylic anhydride is slowly added under the condition of ice-water bath, after stirring for 2.5h, the temperature is raised to 40 ℃, the reaction is continued for 3.5h, after cooling, vacuum pumping is carried out, the pH value is adjusted to about 5 by concentrated hydrochloric acid, a large amount of white solid is precipitated, and after suction filtration and drying, 6.8g of 2-carbamoylpyridine-3-formic acid white solid is obtained, the yield is 81.9%, m.p., 173.1-174.3 ℃ (documents (LIM S., MJ.A.preparation and structural associations of soisomerometric 2, 3-disustulated pyridines.Bullen des Societes Chemicals Belges,1980,89(3): 205.: 205 ℃ C.).
And C: preparation of 2-aminonicotinic acid
Placing 2.4g (60mmol) of sodium hydroxide into a 100mL eggplant-shaped bottle, adding 20mL of water, stirring for dissolving, adding 3.32g (20mmol) of 2-carbamoylpyridine-3-formic acid into the sodium hydroxide solution in batches under the condition of ice-water bath, dropwise adding 17.6g (24mmol) of 10% sodium hypochlorite solution after all solids are dissolved, stirring overnight, heating to 80 ℃, and reacting for 2 hours. The reaction solution is cooled to room temperature, concentrated hydrochloric acid is dripped to adjust the pH value to about 5, light yellow solid is precipitated, and the reaction solution is filtered and dried to obtain 1.0g of 2-aminonicotinic acid light yellow solid with the yield of 36.2 percent, wherein m.p. 306.1-307.2 ℃ (bibins R, HITCHINGS G. Studies on condensed pyridine systems: Synthesis of sodium 4-and 2, 4-substistuted pyridine [2,3-d ] pyridine. journal of the American Chemical Society,1955,77(8): 2256-.
Step D: preparation of 2-amino-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide
2.76g (20mmol) of 2-aminonicotinic acid and 4.58g (24mmol) of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) were put in a 100mL eggplant-shaped bottle, 20mL of DMF was added, and after stirring uniformly, 3.24g (24mmol) of 1-hydroxybenzotriazole (HOBt) and 4.00g (24mmol) of 2- (2-methoxyphenoxy) ethylamine were added, and stirring was carried out at room temperature, and TLC was carried out until the reaction of 2-aminonicotinic acid was completed, and 30mL of water was added, whereby a large amount of solid was precipitated. Suction filtration, water washing and drying are carried out to obtain 4.72g of white powder with the yield of 82%. 155.6-156.4 ℃ in m.p.; IR (KBr, cm)-1)3419,3394,3275,2928,2833,1653,1620,1540,1504,1454,1403,758；1H-NMR(400MHz,CDCl3):δ3.78-3.82(m,2H,NHCH2CH2O),3.85(s,3H,OCH3),4.20(t,2H,NHCH2CH2O),6.33(brs,2H,NH2),6.61(dd,1H,Ar-H,J1＝7.6Hz,J2＝4.8Hz),6.91-6.94(m,3H,Ar-H,NH),6.97-7.02(m,2H,Ar-H),7.67(d,1H,Ar-H,J＝7.6Hz),8.16(d,1H,Ar-H,J＝4.8Hz)；ESI-MS(m/z):288.1([M+H]+)。
Step E: preparation of 2- (3-phenylureido) -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide
1.48g (5mmol) of phosgene in solid formPlacing the mixture into a 250mL eggplant-shaped bottle, adding 20mL of toluene, stirring until the mixture is completely dissolved, adding 15mmol of aniline into a 20mL beaker, adding a proper amount of toluene to dilute and dissolve the aniline, and dropwise adding the toluene solution of aromatic amine into the solid phosgene toluene solution by using a constant-pressure dropping funnel under the condition of ice-water bath for about 30 min. After dripping, heating and refluxing for 6h, cooling, and filtering out solids to obtain an aryl isocyanate toluene solution; 0.57g (2mmol) of 2-amino-N- [2- (2-methoxyphenoxy) ethyl]Placing nicotinamide in 100mL eggplant-shaped bottle, adding 10mL dichloromethane, stirring to dissolve, adding prepared phenyl isocyanate toluene solution, heating to 60 deg.C, and monitoring by TLC until 2-amino-N- [2- (2-methoxyphenoxy) ethyl]Reacting nicotinamide completely, concentrating the reaction solution, cooling, filtering, washing with small amount of ethyl acetate to obtain gray solid, and performing column chromatography [ V (ethyl acetate): V (dichloromethane) ═ 1:6 ]]Separating to obtain 2- (3-phenylureido) -N- [2- (2-methoxyphenoxy) ethyl]Nicotinamide white solid 0.62g, yield 38.2%. m.p. 158.2-159.0 ℃; IR (KBr, cm)-1)3358,3104,2949,2831,1666,1630,1564,1510,1480,1448,743；1H-NMR(400MHz,CDCl3):δ3.82-3.86(m,2H,NHCH2CH2O),3.84(s,3H,OCH3),4.21(t,2H,NHCH2CH2O),6.91-7.07(m,6H,Ar-H),7.09(brs,1H,NH),7.33(t,2H,Ar-H,J＝8.0Hz),7.61(d,2H,Ar-H,J＝7.6Hz),7.89(dd,1H,Ar-H,J1＝7.6Hz,J2＝1.6Hz),8.38(dd,1H,Ar-H,J1＝4.8Hz,J2＝1.6Hz),10.46(s,1H,NH),11.82(s,1H,NH)；ESI-MS(m/z):407.1([M+H]+)。
Example 2: preparation of 2- [3- (4-methylphenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide
Figure BDA0003408100610000081
According to the preparation method of example 1, 0.68g of white solid was obtained with a yield of 40.4%. 161.5-162.2 ℃ in m.p.; IR (KBr, cm)-1)3352,3187,2922,1680,1633,1591,1504,1454,1409,741；1H-NMR(400MHz,CDCl3):δ3.81-3.85(m,2H,NHCH2CH2O),3.84(s,3H,OCH3),4.21(t,2H,NHCH2CH2O),6.91-7.03(m,5H,Ar-H),7.09(brs,1H,NH),7.13(d,2H,Ar-H,J＝8.4Hz),7.49(d,2H,Ar-H,J＝8.4Hz),7.88(dd,1H,Ar-H,J1＝7.6Hz,J2＝1.6Hz),8.37(dd,1H,Ar-H,J1＝4.8Hz,J2＝1.6Hz),10.42(s,1H,NH),11.71(s,1H,NH)；ESI-MS(m/z):421.1([M+H]+)。
Example 3: preparation of 2- [3- (4-methoxyphenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide
Figure BDA0003408100610000091
According to the preparation method of example 1, 0.54g of a white solid was obtained in a yield of 30.9%. 139.9-140.5 ℃ in m.p.; IR (KBr, cm-1)3336,3063,2984,2836,1679,1630,1594,1506,1453,1417,732; 1H-NMR (400MHz, CDCl3) < delta > 3.80(s,3H, OCH3),3.81-3.84(m,2H, NHCH)2CH2O),3.84(s,3H,OCH3),4.21(t,2H,NHCH2CH2O),6.88(d,2H,Ar-H,J＝8.8Hz),6.91-7.03(m,5H,Ar-H),7.08(brs,1H,NH),7.51(d,2H,Ar-H,J＝8.8Hz),7.88(dd,1H,Ar-H,J1＝8.0Hz,J2＝2.0Hz),8.36(dd,1H,Ar-H,J1＝4.8Hz,J2＝1.6Hz),10.41(s,1H,NH),11.61(s,1H,NH)；ESI-MS(m/z):437.2([M+H]+)。
Example 4: preparation of 2- [3- (4-fluorophenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide
Figure BDA0003408100610000092
According to the preparation method of example 1, 1.00g of a white solid was obtained with a yield of 58.9%. m.p. 170.6-171.5 ℃; IR (KBr, cm)-1)3354,3057,2938,1675,1627,1541,1508,1486,1413,741；1H-NMR(400MHz,CDCl3):δ3.82-3.86(m,2H,NHCH2CH2O),3.84(s,3H,OCH3),4.21(t,2H,NHCH2CH2O),6.91-7.04(m,7H,Ar-H),7.13(brs,1H,NH),7.54-7.57(m,2H,Ar-H),7.90(d,1H,Ar-H,J＝8.0Hz),8.37(dd,1H,Ar-H,J1＝4.8Hz,J2＝1.6Hz),10.50(s,1H,NH),11.78(s,1H,NH)；ESI-MS(m/z):425.1([M+H]+)。
Example 5: preparation of 2- [3- (4-chlorophenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide
Figure BDA0003408100610000101
According to the preparation method of example 1, 0.64g of a white solid was obtained in a yield of 36.4%. 182.9-184.1 ℃ in m.p.; IR (KBr, cm)-1)3332,3065,2932,2836,1705,1627,1592,1507,1487,1403,741；1H-NMR(400MHz,CDCl3):δ3.82-3.86(m,2H,NHCH2CH2O),3.85(s,3H,OCH3),4.21(t,2H,NHCH2CH2O),6.91-7.03(m,5H,Ar-H),7.11(brs,1H,NH),7.28(d,2H,Ar-H,J＝8.8Hz),7.57(d,2H,Ar-H,J＝9.2Hz),7.90(dd,1H,Ar-H,J1＝7.6Hz,J2＝1.6Hz),8.38(dd,1H,Ar-H,J1＝5.2Hz,J2＝2.0Hz),10.53(s,1H,NH),11.87(s,1H,NH)；ESI-MS(m/z):441.1([M+H]+)。
Example 6: preparation of 2- [3- (4-bromophenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide
Figure BDA0003408100610000102
According to the preparation method of example 1, 1.10g of a white solid was obtained with a yield of 56.8%. 183.5-184.0 ℃ in m.p.; IR (KBr, cm)-1)3382,3060,2998,2836,1706,1650,1585,1505,1455,1399,737；1H-NMR(400MHz,CDCl3):δ3.81-3.83(m,2H,NHCH2CH2O),3.84(s,3H,OCH3),4.21(t,2H,NHCH2CH2O),6.91-7.03(m,5H,Ar-H),7.16(brs,1H,NH),7.42(d,2H,Ar-H,J＝8.8Hz),7.51(d,2H,Ar-H,J＝8.8Hz),7.90(dd,1H,Ar-H,J1＝7.6Hz,J2＝1.2Hz),8.37(dd,1H,Ar-H,J1＝5.2Hz,J2＝1.6Hz),10.55(s,1H,NH),11.88(s,1H,NH)；ESI-MS(m/z):485.1([M+H]+)。
Example 7: preparation of 2- [3- (4-benzyloxyphenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide
Figure BDA0003408100610000111
According to the preparation method of example 1, 0.62g of a white solid was obtained in a yield of 30.2%. m.p. 178.2-180.0 ℃; IR (KBr, cm)-1)3336,3063,2906,1684,1615,1544,1507,1435,1405,737；1H-NMR(400MHz,CDCl3):δ3.82-3.83(m,2H,NHCH2CH2O),3.85(s,3H,OCH3),4.20(t,2H,NHCH2CH2O),5.05(s,2H,ArCH2O),6.91-7.03(m,7H,Ar-H,NH),7.29-7.33(m,2H,Ar-H),7.38(d,2H,Ar-H,J＝7.6Hz),7.44(d,2H,Ar-H,J＝7.6Hz),7.50(d,2H,Ar-H,J＝8.8Hz),7.90(dd,1H,Ar-H,J1＝7.6Hz,J2＝1.6Hz),8.35(dd,1H,Ar-H,J1＝5.2Hz,J2＝1.6Hz),10.45(s,1H,NH),11.64(s,1H,NH)；ESI-MS(m/z):513.2([M+H]+)。
Example 8: influenza virus ribonucleoprotein complex activation activity test experiment (RNP activation activity test experiment)
Influenza virus ribonucleoprotein complex activation activity assay 293T cells were used as the test cell line. The ribonucleoprotein complex comprises influenza NP and RNA polymerase (including PA, PB1 and PB2 subunits) fragments.
293T cells were first cultured: in a petri dish (diameter 6cm), a culture solution mixed with 1/10T75 was added, and it was checked whether there was enough plasmid for transfection.
Will be 1 × 105Individual 293T cells were seeded overnight in 96-well microtiter plates. 125ng of pcDNA3a-PB1, pcDNA3a-PB2, pcDNA3a-PA, pcDNA3a-NP, pPOL-NS-Luci plasmid and pEGFP were co-transfected into 293T cells and the RNP complex was reconstituted with Lipofectamine 2000 (Invitrogen). 6h after transfection, growth medium containing the test compound was added. After 24h, luciferase activity was determined by Steady-Glo luciferase substrate (Promega). Using VICTOR 3MultThe GFP expression and the emitted fluorescence were read in an ilabel plate reader (Perkin Elmer).
Results (%) of the RNP-activating activity assay were calculated by dividing the luciferase signal (relative luminescence value) containing the test compound by the luciferase signal (relative luminescence value) of the negative control (DMSO). The low RNP activation activity value indicates that the tested compound interacts with RNP and has certain influenza virus inhibition activity. For each compound tested, the experiment was tested at its highest non-cytotoxic concentration.
The experimental results of the RNP activation activity test of part of 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound samples prepared by the method are listed below (N is 3).
Figure BDA0003408100610000121
From the primary screening results of the influenza virus ribonucleoprotein complex activation activity test experiment of the tested target compound, the 2-aryl ureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound provided by the invention has obvious interaction with RNP and has inhibitory activity on influenza virus, wherein the interaction of 2- [ (3-phenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide and RNP is strongest.
Example 9: inhibitory Activity of test Compounds against influenza viruses
A part of target compounds were tested for anti-influenza virus activity by standard plaque assay, using A/WSN/33(H1N1) influenza virus as the test virus strain, the test compounds were dissolved in DMSO, diluted with culture medium to a concentration of 100. mu.M, and dimethylsulfoxide as the blank.
MDCK cells were seeded at a concentration in 96-well cell culture plates in 5% CO2The cells were cultured at 37 ℃ for 24 hours, the culture medium was removed, influenza A/WSN/33(H1N1) virus was inoculated into MDCK cells, and the cells were adsorbed at 37 ℃ for 2 hours, and the virus solution was decanted. Adding 100 mu mol.L-1Each compound was subjected to 3 duplicate wells, and virus control groups were setThe culture was continued at 37 ℃ for 24h (infected virus, without compound), and the number of viral strains in the cells was determined by standard plaque assay on MDCK cells to calculate the virus viability. The survival rate of the virus is (number of the virus strain of the experimental group/number of the virus strain of the virus control group) × 100%.
The inhibitory activity of the compounds of the present invention against influenza virus was measured according to the above-described method, and the results are shown in the following table.
Figure BDA0003408100610000122
Figure BDA0003408100610000131
The screening results of the test experiment of the A/WSN/33(H1N1) influenza virus inhibitory activity of the tested target compound show that the compound can obviously reduce the survival amount of influenza viruses and effectively inhibit the activity of the influenza viruses, wherein the 2- [3- (4-fluorophenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide has the strongest inhibitory activity on the influenza viruses.
In the following formulations, "active ingredient" refers to a compound of formula I, or a salt or solvate thereof.
Example 10: gelatin capsule
Figure BDA0003408100610000132
Example 11: tablet formulation
Figure BDA0003408100610000133
Example 12: tablet formulation
Figure BDA0003408100610000134
The active ingredient, starch and cellulose were passed through a 45 mesh u.s. sieve and mixed thoroughly, the resulting powder was mixed with polyvinylpyrrolidone, then passed through a 14 mesh u.s. sieve, and the granules thus obtained were dried at 50-60 ℃ and passed through an 18 mesh u.s. sieve. The sodium carboxymethylcellulose, the magnesium stearate and the talc are firstly sieved by a 60-mesh U.S. sieve, then added into the granules, mixed and pressed into tablets on a tablet machine.
Example 13: suspending agent
Figure BDA0003408100610000141
The drug is passed through a 45 mesh u.s. screen and mixed with sodium carboxymethylcellulose and syrup to form a uniform paste, the benzoic acid solution, flavoring and coloring agents are diluted with some water and added with stirring, then sufficient water is added to achieve the desired volume.
Example 14: aerosol and method of making
Figure BDA0003408100610000142
The active ingredient is mixed with ethanol and the resulting mixture is added to propellant 22, cooled to 30 ℃ and transferred to a container. The required amount was then added to the stainless steel vessel and diluted with the remaining propellant before the valve assembly was installed.
Example 15: suppository
Figure BDA0003408100610000143
The active ingredient was passed through a 60 mesh u.s. sieve and suspended in a pre-melted saturated fatty acid glyceride compound, and the mixture was poured into a standard 2g cavity suppository mold and cooled.
Example 16: injectable formulations
Figure BDA0003408100610000151
The above solution was administered to the patient by intravenous injection at a rate of about 1 mL/min.
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.

Claims (8)

1. A2-aryl ureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound, a prodrug thereof, a pharmaceutically active metabolite thereof and a pharmaceutically acceptable salt thereof, wherein the 2-aryl ureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound has a structure shown in formula I:
Figure FDA0003408100600000011
wherein R is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halogen, trifluoromethyl and benzyloxy.
2. The 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound of claim 1, a prodrug, a pharmaceutically active metabolite and a pharmaceutically acceptable salt thereof, wherein R in the structural formula I is selected from the group consisting of hydrogen, methyl, methoxy, fluorine, chlorine, bromine and benzyloxy.
3. The 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide according to claim 1, a prodrug, a pharmaceutically active metabolite, and a pharmaceutically acceptable salt thereof, wherein the 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide is selected from the group consisting of:
2- (3-phenylureido) -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide;
2- [3- (4-methylphenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide;
2- [3- (4-methoxyphenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide;
2- [3- (4-fluorophenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide;
2- [3- (4-chlorophenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide;
2- [3- (4-bromophenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide;
2- [3- (4-benzyloxyphenyl) ureido ] -N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide.
4. A pharmaceutical composition comprising a 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound as claimed in any one of claims 1 to 3, a prodrug thereof, a pharmaceutically active metabolite thereof, a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
5. Use of a 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide according to any one of claims 1 to 3, a prodrug thereof, a pharmaceutically active metabolite thereof, and a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of influenza.
6. Use of a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the treatment of influenza virus.
7. The use according to claim 5, wherein the effective amount of 2-arylureido-N- [2- (2-methoxyphenoxy) ethyl ] nicotinamide compound acts on nucleoprotein or RNA polymerase of the influenza virus to inhibit replication of the influenza virus.
8. The use of claim 6, wherein the pharmaceutical composition acts on the nucleoprotein or RNA polymerase of the influenza virus in an amount effective to inhibit replication of the influenza virus.
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