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CN107868060B - 2- [3- (4-morpholinyl) propylamino ] -3-aryl-4-quinolinone compounds and application thereof - Google Patents

2- [3- (4-morpholinyl) propylamino ] -3-aryl-4-quinolinone compounds and application thereof Download PDF

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CN107868060B
CN107868060B CN201711017644.1A CN201711017644A CN107868060B CN 107868060 B CN107868060 B CN 107868060B CN 201711017644 A CN201711017644 A CN 201711017644A CN 107868060 B CN107868060 B CN 107868060B
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morpholinyl
propylamino
quinazolinone
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influenza
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CN107868060A (en
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金辄
胡春
唐文萍
王丹妮
张富荣
张庆光
张开开
邵鹏柱
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Shenyang Pharmaceutical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4

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Abstract

The invention belongs to the technical field of medicines, and relates to 2- [3- (4-morpholinyl) propylamine]-3-aryl-4-quinolinone derivatives and their use. 2- [3- (4-morpholinyl) propylamino]-3-aryl-4-quinolinone derivatives, including stereoisomers and pharmaceutically applicable salts of the compounds, and the structural general formula is as follows: wherein R is as described in the claims and specification. 2- [3- (4-morpholinyl) propylamino group of the present invention]The (E) -3-aryl-4-quinolinone derivatives and the pharmaceutically applicable acid addition salts of the compounds can be used together with the existing medicines or independently as influenza virus inhibitors for treating influenza, and particularly have better curative effect on various influenza A.

Description

2- [3- (4-morpholinyl) propylamino ] -3-aryl-4-quinolinone compounds and application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to a 2- [3- (4-morpholinyl) propylamino ] -3-aryl-4-quinolinone compound, a preparation method thereof and application thereof in preparation of anti-influenza virus medicines.
Background
Influenza virus belongs to the genus Influenza virus (Influenza virus) of the family orthomyxoviridae, and is an RNA virus. Based on the difference in antigenicity between influenza virus Nucleoprotein (NP) and Neuraminidase (NA), they can be classified into A, B, C (also called A, B, C) three types (PALESE P, YoungJ. variation of influenza A, B, and C viruses. science,1982,215(4539): 1468-. Among them, type A is the most prominent and drastic influenza virus epidemic of all times, and has a wide host range, and can be isolated in human, poultry, pig and horse. Among these, Influenza viruses capable of infecting birds are also known as Avian Influenza Viruses (AIV). All avian influenza viruses found so far belong to the influenza a virus. Therefore, influenza a virus has now become a hot spot for the study of influenza virus. The new influenza virus subtypes are mainly caused by changes of Hemagglutinin (HA) and Neuraminidase (NA) surrounding the virus envelope, and NP protein and RNA polymerase in the inner layer are stable and have few variations. Therefore, anti-influenza virus drugs directed against this target are less likely to develop resistance.
NP is abundantly expressed during viral infection, is involved in multiple processes of viral replication, and is a major component of the influenza Ribonucleoprotein (RNP) complex that undergoes transcription and viral genome replication. It serves as the major structural protein of the virus and contains many functional domains, such as NUclear Localization Sequences (NLSs), RNA binding domain, NP-NP binding domain and PB2 binding domain (HAGIWARA K, KONDOH Y, Ueda A, et al, discovery of novel anti-viral agents direct acquisition of the infectious said viral NUclear proteins using photo-cross-linked chemical arrays, biochemical and Biophysical Research Communications,2010,394(3): 721-. NP not only wraps the viral genome, it also forms homooligomers to maintain a stable RNP structure (PORTELA A, Digard P. the influenza virus nuclear protein: a multifunctional RNA-binding protein viral replication. journal of General Virology,2002,83(4): 723-734). 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.
In the propagation process of viruses, RNA polymerase also plays an important role, and is essential for viral RNA replication, transcription and translation. The RNA polymerase comprises 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 throughout 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.
The compounds of the present invention are influenza virus inhibitors acting on NP and RNA polymerases and are useful for inhibiting influenza viruses. Because of the large amount of anti-influenza virus drugs, viral strains that develop resistance to these drugs account for an increasing proportion of these drugs. However, the influenza virus inhibitor is not affected by virus variation and has stability. Such influenza virus inhibitor compounds have a wide range of therapeutic effects including: treating hyperpyrexia, inhibiting cough, and relieving sore throat, watery nasal discharge, and muscular pain.
Disclosure of Invention
The invention aims to provide a compound shown as a formula I, a prodrug, a pharmaceutically active metabolite thereof, a stereoisomer of the compound and pharmaceutically acceptable salts thereof, and application of the compound in preparing a medicament for treating diseases related to influenza, wherein the diseases related to the influenza are influenza viruses, particularly influenza A.
Figure BDA0001446825190000021
Wherein R may be independently selected from hydrogen, C1-C4 alkyl, halogen, C1-C4 alkoxy or benzyloxy.
Further, R may be independently selected from hydrogen, methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy or benzyloxy.
Further, R may be independently selected from hydrogen, 2-methyl, 4-fluoro, 4-chloro, 4-bromo, 2-methoxy, 4-benzyloxy.
The invention preferably relates to the following compounds, prodrugs thereof, pharmaceutically active metabolites thereof, and stereoisomers of the compounds and pharmaceutically acceptable salts thereof,
2- [3- (4-morpholinyl) propylamino ] -3- (4-methylphenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3-phenyl-4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (2-methylphenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (4-fluorophenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (4-chlorophenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (4-bromophenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (4-benzyloxyphenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (4-methoxyphenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (2-methoxyphenyl) -4-quinazolinone.
The invention also provides a compound of formula I, a prodrug thereof, a pharmaceutically active metabolite thereof, and a pharmaceutical composition of a stereoisomer of the compound, a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The present invention also contemplates pharmaceutical compositions comprising a pharmaceutically acceptable carrier and any of the compounds specifically disclosed herein. The invention also relates to a process for preparing the composition of the invention. The invention also relates to processes and intermediates useful for preparing the compounds and pharmaceutical compositions of the invention.
The compounds of the present invention, their prodrugs, pharmaceutically active metabolites, as well as stereoisomers of the above compounds and pharmaceutically acceptable salts thereof, may be administered alone or preferably in pharmaceutical compositions in combination with pharmaceutically acceptable carriers or diluents, optionally in accordance with conventional pharmaceutical practice, with known adjuvants. The compounds are administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes.
In tablets for oral use, commonly used carriers include lactose and corn starch, as well as lubricating agents such as magnesium stearate. For oral administration in capsule form, useful diluents include lactose and dried corn starch. For oral route use of the therapeutic compounds according to the invention, the selected compound may be administered, for example, in the form of a tablet or capsule, or as an aqueous solution or suspension. For oral administration in the form of tablets or capsules, the active pharmaceutical ingredient can be combined with an orally-administrable, non-toxic, pharmaceutically-acceptable inert carrier, such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral pharmaceutical ingredient may be combined with any orally acceptable, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, suitable binders, lubricants, disintegrating agents and coloring agents may be added to the mixture. Suitable binders 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 and the like. Suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. When aqueous suspensions are used orally, the active ingredient may be combined with emulsifying and suspending agents. Certain sweetening 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 compounds of the invention can also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds of the invention may also be administered by using monoclonal antibodies as individual carriers, wherein the compound molecules are conjugated. The compounds of the invention may also be coupled to soluble polymers as carriers for the drug of interest. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyl-ethylaspartamide-phenol or polyethyleneoxide-polylysine substituted with palmitoyl groups. In addition, the compounds of the present invention may be coupled to a class of biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
The compounds of the present invention may also be used in combination with known agents useful in the treatment or prevention of: high fever, cough, sore throat, watery nasal discharge, muscle pain, and the like, which are accompanied by severe pneumonia, and may even cause failure of various organs such as heart, kidney, and the like, resulting in death. Combinations of the presently disclosed compounds with agents useful in the treatment or prevention of the diseases disclosed herein are also within the scope of the invention. Such agents include the following: m2 ion channel protein inhibitors, neuraminidase inhibitors, hemagglutinin receptor domain blockers, interferon inducers, antisense oligonucleotides, inosine monophosphate dehydrogenase inhibitors, and pharmaceutically acceptable salts and mixtures thereof. A preferred combination is a compound of the invention and an inhibitor of the M2 ion channel protein. Another preferred combination is a compound of the invention and a neuraminidase inhibitor. Another preferred combination is a compound of the invention and an interferon inducer. Another preferred combination is a compound of the invention and an antisense oligonucleotide. Another preferred combination is a compound of the invention and an inosine monophosphate dehydrogenase inhibitor.
An "M2 ion channel protein inhibitor" is a compound that inhibits fusion and uncoating of viruses by interfering with the activity of the M2 ion channel, resulting in the inability of the virus to proceed through the replication cycle and, thus, to die. The target of action of the neuraminidase inhibitor is the neuraminidase on the surface of the influenza virus, and the inhibitor can inhibit mature viruses from escaping from host cells, change the accumulation and release of the influenza viruses in the host cells, and inhibit the propagation of the influenza viruses in human bodies. Neuraminidase catalyzes the cleavage of sialic acid residues at the ends of the carbohydrate side chains on host cells and virions, hemagglutinin and neuraminidase, and facilitates the isolation and diffusion of newly formed virions from infected cells, and thus the diffusion of virions from the infected respiratory mucosa to surrounding tissues. "hemagglutinin receptor domain blockers", hemagglutinin is the major structural protein on the surface of influenza virions and plays an important role in mediating viral infections. The alumino-silicate receptor on the surface of the host cell membrane mediates the entry of the virus into the host cell and lyses the cell membrane, and infection with influenza virus is initiated by binding of the cellular receptor to the virus, thus preventing such binding and blocking infection with the virus. Jeon et al designed novel aptamers that bind directly to the receptor binding domain of viral hemagglutinin and ultimately prevent cell-virus interaction. Oligonucleotides are used as monoclonal antibody substitutes and are considered to be the only drugs having diagnostic and therapeutic effects, and may be developed as a novel anti-influenza virus drug. The interferon inducer can specifically inhibit fusion of influenza virus lipid envelope and host cell, block virus replication, penetrate into cell nucleus and directly inhibit synthesis of virus DNA and RNA, and has preventing and treating effects on A, B type influenza. "antisense oligonucleotide" has been widely used for the inhibition of specific gene expression, and has been an important position in research as a potential drug for treating influenza virus. In the research, the antisense oligonucleotide is found to have higher inhibition effect on the initiation codon of PB2 but weaker inhibition effect on PB1 when used for inhibiting four fragments PB1.PB2, PA and NP in an influenza virus genome, so that the antisense oligonucleotide shows higher inhibition activity and sequence specificity. The inosine monophosphate dehydrogenase inhibitor has broad-spectrum antiviral activity, has strong effect on RNA viruses of cell culture, and is sensitive to A, B influenza viruses. Clinical tests show that the ribavirin is developed in 1973 in China, and the clinical tests show that the ribavirin can prevent and treat A, B influenza, can accelerate fever reduction and shorten the course of disease by adopting a mode of nasal drop and buccal tablets or nasal spray administration.
The term "administration" and variations thereof with respect to the compounds of the present invention (e.g.: the "administration" compound) means: introducing the compound or prodrug of the compound into an animal system in need of treatment. When a compound of the invention or a prodrug thereof is provided in combination with one or more other active agents, "administering" and variations thereof are understood to include both simultaneous and sequential introduction of the compound or prodrug thereof and the other agent. The present invention includes within its scope prodrugs of the compounds of the present invention. Typically, such prodrugs are functional derivatives of the compounds of the present invention which are readily convertible in vivo into the desired compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the use of a specifically disclosed compound or a compound that may not be specifically disclosed, but which is capable of being converted in vivo to the specified compound following administration to a patient in order to treat the various disorders described. Conventional methods for selecting and preparing suitable prodrug derivatives are incorporated herein by reference. Metabolites of these compounds include active substances produced upon introduction of the compounds of the present invention into a biological environment.
The invention also encompasses pharmaceutical compositions useful for treating influenza viral diseases, treatment comprising administering a therapeutically effective amount of a compound of the invention, with or without a pharmaceutically acceptable carrier or diluent. Suitable compositions of the invention include aqueous solutions containing a compound of the invention and a pharmaceutically acceptable carrier, such as saline, at a pH of at least about 7.4. The solution may be introduced into the bloodstream of the patient by a local bolus injection.
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 compositions are preferably provided in the form of tablets containing 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 the active ingredient for adjusting the dosage to the symptoms of the patient to be treated. The medicament generally comprises from about 0.01mg to about 500mg of the active ingredient, preferably from about 1mg to about 100mg of the active ingredient. For intravenous injection, the most preferred dose will be about 0.1mg/kg/min to about 10mg/kg/min during a constant rate infusion. The compounds of the present invention 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 compounds of the present invention can be used in combination with other agents useful in the treatment of influenza viruses. The individual components of such combinations can be administered separately or simultaneously at different times during the course of therapy in divided form or in single combination. The invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly. The compounds of the invention, together with other compounds useful in the treatment of the influenza context, in principle include any combination with any pharmaceutical composition useful in the treatment of diseases associated with influenza virus function.
The invention may therefore also comprise the use in combination with a second agent, wherein the second agent is selected from: m2 ion channel protein inhibitor, neuraminidase inhibitor, hemagglutinin receptor domain blocker, interferon inducer, antisense oligonucleotide, inosine monophosphate dehydrogenase inhibitor.
The compounds of the present invention can be used in combination with other agents useful in the treatment of influenza. Each component of such a combination can be administered separately at different times during the course of therapy or simultaneously in divided or single combination forms. The invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly. It is to be understood that the scope of combinations of the compounds of the present invention with other agents useful for treating influenza includes in principle any combination with any pharmaceutical composition that can be used for treating influenza-related diseases.
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.
In the methods of the present invention, the compounds described in detail herein are capable of forming the active ingredient in admixture with suitable pharmaceutically acceptable diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with regard to the intended form of administration, i.e., oral tablets, capsules, elixirs, syrups and the like, and in accordance with conventional pharmaceutical practice.
Pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts formed from inorganic or organic acids. Conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid and the like. Pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from the compounds of the present invention which contain an acidic or basic moiety by conventional chemical methods. In general, salts of basic compounds can be prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess amount of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, salts of acidic compounds can be synthesized by reaction with a suitable inorganic or organic base.
The compounds of the present invention can be prepared according to the following general scheme using appropriate materials and are further illustrated by the following specific examples. Various known variations of the conditions and methods of the following preparative procedures can also be used to prepare these compounds. All temperatures are degrees celsius unless otherwise indicated.
The following reaction schemes describe the preparation of several representative examples of the invention.
Figure BDA0001446825190000071
Reaction scheme
Wherein R may be independently selected from hydrogen, C1-C4 alkyl, halogen, C1-C4 alkoxy and benzyloxy. Further, R may be independently selected from hydrogen, methyl, ethyl, halogen, methoxy, ethoxy or benzyloxy. Further, R may be independently selected from hydrogen, 2-methyl, 4-fluoro, 4-chloro, 4-bromo, 2-methoxy, 4-benzyloxy.
The compound disclosed by the invention is simple in preparation method and stable in yield, and the prepared compound can be used for better treating influenza-related diseases.
Detailed Description
The present invention is described in detail by the following examples. 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- (4-morpholinyl) propylamino ] -3- (4-methylphenyl) -4-quinazolinone
1.48g (0.01mol) of phthalic anhydride was put into an eggplant-shaped flask, 4.38g (0.025mol) of ammonia water was added dropwise in an ice-water bath, and after completion of the addition, the mixture was stirred in an ice-water bath for 3 hours and then stirred at 40 ℃ for 3.5 hours. Slightly cooling, pumping out ammonia gas from the solution, adjusting the pH value to 2, separating out a large amount of white solid, cooling, performing suction filtration, washing with cold water for 2 times, and drying to obtain an intermediate 2-carbamoylbenzoic acid with the yield of 70.03%. m.p. 194 ℃ and 196 ℃ and EI-MS (M/z) 165([ M)]+)。
2.0g (0.05mol) of sodium hydroxide is added into an eggplant-shaped flask, a small amount of water is added until the sodium hydroxide is completely dissolved, 1.65g (0.01mol) of intermediate 2-carbamoylbenzoic acid is added, and a small amount of water is supplemented, so that the intermediate 2-carbamoylbenzoic acid is completely dissolved. Under the cooling of ice bath, 22.5g (0.015mol) of 10 percent sodium hypochlorite solution is dropwise added, after the dropwise addition is finished, the mixture is stirred overnight in ice bath, stirred for 4 hours at the temperature of 80 ℃, cooled, the pH value is adjusted to 2, a large amount of brick red solid is separated out, filtered and dried to obtain an intermediate 2-aminobenzoic acid, the yield is 55.07 percent, m.p. is 143-]+)。
Adding 1.37g (0.01mol) of intermediate 2-aminobenzoic acid into a large amount of anhydrous ethanol, adding 4mL of concentrated sulfuric acid, refluxing and stirring for 3 hours, supplementing 4mL of concentrated sulfuric acid, refluxing and stirring overnight, cooling, adjusting the pH value of the system to 8 by using a saturated sodium carbonate aqueous solution, extracting by ethyl acetate for 3 times, combining organic phases, washing by using a saturated sodium chloride aqueous solution for 2 times, drying an organic layer, evaporating to remove a solvent to obtain intermediate 2-aminobenzoic acid ethyl ester, wherein the yield is 40.43%, and EI-MS (M/z):165([ M/z ] (yield is 40.43%)]+)。
2.0g of bis (trichloromethyl) carbonate was weighed out and dissolved in 10mL of dry toluene, and a toluene solution containing 2.14g (0.02mol) of p-methylaniline was added dropwise in ice bath, and a large amount of off-white insoluble matter was immediately formed. After the dropwise addition, the mixture was stirred in an ice bath for 40min, and the mixture was refluxed and stirred for 5 hours, whereby insoluble substances disappeared and the solution became a brown transparent liquid. Cooling overnight, filtering, and retaining the filtrate to obtain methyl phenyl isocyanate which can be directly used in the next reaction without further treatment, EI-MS (M/z):133([ M/z)]+)。
Adding the methyl phenyl isocyanate obtained in the last step and 1.67g (0.01mol) of ethyl 2-aminobenzoate into a flask, refluxing and stirring for 5h, naturally cooling, precipitating a large amount of white solid, performing suction filtration, washing with toluene, and drying to obtain 2- [ (4-methylphenyl) ureido]Ethyl benzoate, 2.42g of white powder, yield 81.10%, EI-MS (M/z):298([ M ]]+)。
2.98g of 2- [ (4-methylphenyl) ureido]Ethyl benzoate, 40mL of absolute ethyl alcohol and 3.03g of triethylamine are sequentially added into an eggplant-shaped flask, and the mixture is refluxed for 2 hours and naturally cooled to precipitate a large amount of white solid. Suction filtration, washing with ice and anhydrous ethanol, and drying to give 3- (4-methylphenyl) -2,4- (1H,3H) quinazolinedione as a white powder 1.82g, yield 72.27%, EI-MS (M/z):252([ M/z)]+)。
2.52g of 3- (4-methylphenyl) -2,4- (1H,3H) quinazolinedione was added to a flask, 30.66g of phosphorus oxychloride was added, reflux was carried out for 8H, the solvent was distilled off, the remaining oily substance was dissolved in methylene chloride, and column chromatography was carried out to give 2-chloro-3- (4-methylphenyl) -4-quinazolinone as a white powder (1.26 g, yield 46.55%), EI-MS (M/z):270([ M/z) ([ M ])]+)。
0.27g of 2-chloro-3- (4-methylphenyl) -4-quinazolinone, 0.15g N- [ 3-aminopropyl (3-aminopropyl)]Morpholine, 0.303g triethylamine and 3mL n-butanol are added into an eggplant-shaped flask, and the mixture is refluxed for 6 hours, naturally cooled and solid is separated out. Filtering, washing and drying to obtain 2- [3- (4-morpholinyl) propylamine]-3- (4-methylphenyl) -4-quinazolinone, 0.18g of white powder, yield 48.17%, m.p.:103-105 ℃; ESI-MS (M/z) 379.1([ M + H)]+)；1H NMR(400MHz,CDCl3)δ8.11(dd,J1＝7.9Hz,J2＝1.2Hz,1H),7.65–7.55(m,1H),7.39(dd,J1＝8.1Hz,J2＝3.6Hz,3H),7.17(dd,J1＝16.2Hz,J2＝7.7Hz,3H),4.65(s,1H),3.68–3.37(m,6H),2.45(s,3H),2.32(t,J＝6.6Hz,6H),1.72(p,J＝6.6Hz,2H),1.58(s,1H),1.25(s,1H)；IR:(KBr,cm-1):3308.2(s),3057.7(s),2945.0(s),2815.4(s),1682.9(s),1575.6(s),1501.8(s),1119.4(s),817.2(m),697.7(m)。
Example 2: preparation of 2- [3- (4-morpholinyl) propylamino ] -3-phenyl-4-quinazolinone
According to the procedure of example 1, 0.16g of a yellow powder was obtained in 45.19% yield. m.p. 129-131 ℃. ESI-MS (M/z):365.2([ M + H)]+)；1H NMR(400MHz,CDCl3)δ8.12(d,J＝7.7Hz,1H),7.69–7.49(m,3H),7.42–7.26(m,2H),7.17(t,J＝7.5Hz,1H),4.58(s,1H),3.53(dd,J1＝10.8Hz,J2＝5.7Hz,5H),2.31(t,J＝6.5Hz,5H),1.72(p,J＝6.7Hz,2H),1.25(s,3H),1.02–0.76(m,1H)；IR:(KBr,cm-1):3264.3(s),3057.4(s),2919.1(s),2816.0(s),1679.1(s),1565.3(s),1497.6(s),1115.5(s),769.2(m),696.2(m)。
Example 3: preparation of 2- [3- (4-morpholinyl) propylamino ] -3- (2-methylphenyl) -4-quinazolinone
According to the procedure of example 1, 0.19g of a yellow powder was obtained in a yield of 50.02%. m.p. 102-. ESI-MS (M/z) 379.1([ M + H)]+)；1H NMR(400MHz,CDCl3)δ8.13(d,J＝7.1Hz,1H),7.70–7.56(m,1H),7.51–7.34(m,4H),7.25–7.11(m,2H),4.54(s,1H),3.52(dd,J1＝11.0Hz,J2＝5.6Hz,6H),2.31(t,J＝6.3Hz,6H),2.15(s,3H),1.79–1.65(m,2H)；IR:(KBr,cm-1):3431.3(s),3059.7(s),2951.5(s),2811.6(s),1682.6(s),1580.4(s),1474.8(s),1117.4(s),765.6(m),654.4(m)。
Example 4: preparation of 2- [3- (4-morpholinyl) propylamino ] -3- (4-fluorophenyl) -4-quinazolinone
According to the procedure of example 1, 0.20g of a yellow powder was obtained in a yield of 51.23%. 147-. ESI-MS (M/z) 383.1([ M + H)]+)；1H NMR(400MHz,CDCl3)δ8.12(dd,J1＝7.9Hz,J2＝1.2Hz,1H),7.74–7.53(m,1H),7.42(d,J＝8.2Hz,1H),7.31(dd,J1＝8.3Hz,J2＝3.9Hz,4H),7.19(t,J＝7.5Hz,1H),4.53(t,J＝5.1Hz,1H),3.56(dt,J1＝12.2Hz,J2＝5.6Hz,6H),2.34(dd,J1＝7.9Hz,J2＝3.4Hz,6H),1.75(p,J＝6.7Hz,2H)；IR:(KBr,cm-1):3261.1(s),3066.4(s),2957.8(s),2813.3(s),1677.1(s),1579.8(s),1496.5(s),1117.2(s),769.3(m),640.3(m)。
Example 5: preparation of 2- [3- (4-morpholinyl) propylamino ] -3- (4-chlorophenyl) -4-quinazolinone
According to the procedure of example 1, 0.17g of a yellow powder was obtained in a yield of 42.78%. m.p. 160 ℃ and 162 ℃. ESI-MS (M/z) 399.2([ M + H)]+)；1H NMR(400MHz,CDCl3)δ8.13(d,J＝7.9Hz,1H),7.72–7.54(m,1H),7.41(d,J＝8.1Hz,1H),7.31(dd,J1＝8.4Hz,J2＝4.0Hz,4H),7.18(t,J＝7.6Hz,1H),4.54(s,1H),3.53(dt,J1＝11.6Hz,J2＝5.6Hz,6H),2.34(dd,J1＝7.6Hz,J2＝3.8Hz,6H),1.76(p,J＝6.6Hz,2H)；IR:(KBr,cm-1):3263.2(s),3065.7(s),2930.5(s),2812.7(s),1675.2(s),1580.6(s),1497.3(s),1119.0(s),765.4(m),645.1(m)。
Example 6: preparation of 2- [3- (4-morpholinyl) propylamino ] -3- (4-bromophenyl) -4-quinazolinone
According to the procedure of example 1, 0.22g of a yellow powder was obtained in 48.98% yield. m.p. 184-. ESI-MS (M/z):443.1([ M + H)]+)；1H NMR(400MHz,CDCl3)δ8.12(d,J＝7.8Hz,1H),7.71–7.53(m,1H),7.43(d,J＝8.0Hz,1H),7.32(dd,J1＝8.2Hz,J2＝3.8Hz,4H),7.18(t,J＝7.2Hz,1H),4.52(s,1H),3.55(dt,J1＝12.0Hz,J2＝5.6Hz,6H),2.33(dd,J1＝8.0Hz,J2＝3.6Hz,6H),1.75(p,J＝6.7Hz,2H)；IR:(KBr,cm-1):3262.7(s),3064.8(s),2956.9(s),2814.2(s),1675.6(s),1578.5(s),1501.7(s),1115.6(s),770.2(m),638.6(m)。
Example 7: preparation of 2- [3- (4-morpholinyl) propylamino ] -3- (4-benzyloxyphenyl) -4-quinazolinone
According to the procedure of example 1, 0.23g of a white powder was obtained in 47.78% yield. m.p. 96-98 ℃. ESI-MS (M/z):471.2([ M + H)]+)；1H NMR(400MHz,CDCl3)δ8.11(dd,J1＝7.9Hz,J2＝1.3Hz,1H),7.65–7.55(m,1H),7.42(dd,J1＝15.1Hz,J2＝7.7Hz,6H),7.25–7.19(m,2H),7.16(dt,J1＝4.5Hz,J2＝2.6Hz,3H),5.12(s,2H),4.63(t,J＝5.4Hz,1H),3.54(dt,J1＝12.2Hz,J2＝5.5Hz,6H),2.49–2.13(m,6H),1.73(p,J＝6.7Hz,2H)；IR:(KBr,cm-1):3527.1(s),3036.1(s),2917.8(s),2850.2(s),1679.5(s),1566.4(s),1506.0(s),1118.2(s),739.7(m),654.1(m)。
Example 8: preparation of 2- [3- (4-morpholinyl) propylamino ] -3- (4-methoxyphenyl) -4-quinazolinone
According to the procedure of example 1, 0.18g of a white powder was obtained in a yield of 45.11%. m.p. 143-145 ℃. ESI-MS (M/z):395.2([ M + H)]+)；1H NMR(400MHz,CDCl3)δ8.10(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.71–7.56(m,1H),7.42(d,J＝8.2Hz,1H),7.30(dd,J1＝8.4Hz,J2＝4.0Hz,4H),7.19(t,J＝7.3Hz,1H),4.52(s,1H),3.82(s,3H),3.54(dt,J1＝11.8Hz,J2＝5.6Hz,6H),2.32(dd,J1＝7.9Hz,J2＝3.6Hz,6H),1.74(p,J＝6.7Hz,2H)；IR:(KBr,cm-1):3259.6(s),3062.5(s),2961.4(s),2811.2(s),1679.7(s),1576.5(s),1494.5(s),1119.6(s),771.2(m),642.8(m)。
Example 9: preparation of 2- [3- (4-morpholinyl) propylamino ] -3- (2-methoxyphenyl) -4-quinazolinone
According to the procedure of example 1, 0.16g of a yellow powder was obtained in a yield of 40.10%. m.p. 152-. ESI-MS (M/z):395.2([ M + H)]+)；1H NMR(400MHz,CDCl3)δ8.11(d,J＝7.1Hz,1H),7.69–7.57(m,1H),7.52–7.36(m,4H),7.26–7.12(m,2H),4.56(s,1H),3.85(s,3H),3.55(dd,J1＝11.4Hz,J2＝5.6Hz,6H),2.34(t,J＝6.4Hz,6H),1.79–1.65(m,2H)；IR:(KBr,cm-1):3435.4(s),3056.2(s),2952.4(s),2814.2(s),1679.4(s),1581.2(s),1477.5(s),1115.6(s),768.8(m),652.3(m)。
Example 10: influenza virus ribonucleoprotein complex activity test experiment (RNP activity test experiment)
Influenza virus ribonucleoprotein complex activity test experiments 293T cells were used as test cell lines. Nucleozin is taken as an activity control drug. 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). 6 hours after transfection, growth medium with ready-to-use compound was added. After 24 hours, luciferase activity was measured by Steady-Glo luciferase substrate (Promega). GFP expression and emitted fluorescence were read using a VICTOR 3 Multilabel plate reader (Perkin Elmer).
Results (%) of the RNP activity test experiment 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 activity value indicates that the tested compound interacts with RNP and has certain influenza virus inhibitory activity. For each compound tested, the experiment was tested at its highest non-cytotoxic concentration.
The results of the RNP activity test experiments for some samples are tabulated below (n-3):
Figure BDA0001446825190000101
Figure BDA0001446825190000111
as can be seen from the preliminary screening results of the influenza virus ribonucleoprotein complex activity test experiment of the tested target compound, although the test results of the examples are inferior to the positive control drug Nucleozin, the test results of the examples still have certain interaction with RNP and have influenza virus inhibitory activity.
In the following formulations, "active ingredient" means a compound of formula 1, or a salt or solvate thereof.
Example 11: gelatin capsule
Figure BDA0001446825190000112
Example 12: tablet formulation
Figure BDA0001446825190000113
Example 13: tablet formulation
Figure BDA0001446825190000114
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 14: suspending agent
Figure BDA0001446825190000121
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 15: aerosol and method of making
Figure BDA0001446825190000122
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 16: suppository
Figure BDA0001446825190000123
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 17: injectable formulations
Figure BDA0001446825190000124
The above solution was administered to the patient by intravenous injection at a rate of about 1mL per minute.
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 (10)

1. 2- [3- (4-morpholinyl) propylamino ] -3-aryl-4-quinazolinone compound or pharmaceutically acceptable salt with general formula (I):
Figure DEST_PATH_IMAGE001
wherein,
r is independently selected from hydrogen, C1-C4 alkyl, halogen, C1-C4 alkoxy or benzyloxy.
2. The compound or pharmaceutically acceptable salt of claim 1:
wherein R is independently selected from hydrogen, methyl, ethyl, halogen, methoxy, ethoxy or benzyloxy.
3. The compound or pharmaceutically acceptable salt of claim 1:
wherein R is independently selected from hydrogen, 2-methyl, 4-fluoro, 4-chloro, 4-bromo, 2-methoxy, 4-methoxy or 4-benzyloxy.
4. The compound or pharmaceutically acceptable salt of claim 1, selected from:
2- [3- (4-morpholinyl) propylamino ] -3- (4-methylphenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3-phenyl-4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (2-methylphenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (4-fluorophenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (4-chlorophenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (4-bromophenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (4-benzyloxyphenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (4-methoxyphenyl) -4-quinazolinone;
2- [3- (4-morpholinyl) propylamino ] -3- (2-methoxyphenyl) -4-quinazolinone.
5. A pharmaceutical composition comprising as active ingredient a compound or pharmaceutically acceptable salt according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or diluent.
6. Use of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of a disease associated with influenza.
7. Use of the pharmaceutical composition of claim 5 for the manufacture of a medicament for the treatment of a disease associated with influenza.
8. The use according to claim 6 or 7, wherein the influenza-associated disease is an influenza virus.
9. The use of claim 8, wherein: the compound or pharmaceutically acceptable salt of any one of claims 1-4 in an amount effective to act on nucleoprotein or RNA polymerase of influenza virus to inhibit replication of influenza virus.
10. Use according to claim 8, characterized in that: the pharmaceutical composition of claim 5 in an amount effective to act on nucleoprotein or RNA polymerase of influenza virus to inhibit replication of influenza virus.
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