CN114805141A - 4-guanidinobenzoic acid aryl ester compound and application thereof in resisting SARS-CoV-2 virus - Google Patents

4-guanidinobenzoic acid aryl ester compound and application thereof in resisting SARS-CoV-2 virus Download PDF

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CN114805141A
CN114805141A CN202110113667.2A CN202110113667A CN114805141A CN 114805141 A CN114805141 A CN 114805141A CN 202110113667 A CN202110113667 A CN 202110113667A CN 114805141 A CN114805141 A CN 114805141A
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pentahydroxyhexyl
carbamoyl
guanidinobenzoate
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hydrochloride
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沈建华
左建平
王凯
童贤崑
杨莉
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Shanghai Institute of Materia Medica of CAS
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Abstract

The invention relates to the field of medicinal chemistry, in particular to a 4-guanidino aryl benzoate compound and application thereof in resisting SARS-CoV-2 virus. The invention provides 4-guanidinobenzoic acid aryl ester compounds with a structure shown in a formula (I), a preparation method thereof and application thereof in preparing SARS-CoV-2 virus inhibitors and/or medicines for preventing and treating related diseases caused by SARS-CoV-2.

Description

4-guanidinobenzoic acid aryl ester compound and application thereof in resisting SARS-CoV-2 virus
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a 4-guanidinobenzoic acid aryl ester compound and application thereof in resisting SARS-CoV-2 virus.
Background
From 12 months in 2019, the World Health Organization (WHO) successively outbreaks novel coronavirus pneumonia caused by infection of severe acute respiratory syndrome type 2 coronavirus (SARS-CoV-2, new coronavirus for short) in various countries all over the world, and names the coronavirus pneumonia in the World Health Organization (WHO) as COVID-19. SARS-CoV-2 virus is highly infectious and cryptic (Nature. 2020; 584(7821): 420-. A large number of infected persons have no obvious symptoms or light symptoms, typical clinical symptoms are fever, cough, shortness of breath and other respiratory symptoms, and severely infected persons can cause pneumonia, pulmonary edema, respiratory distress and even death. In addition to lung damage, SARS-CoV-2 attacks multiple organs throughout the body, such as the brain, heart, kidney, liver, spleen, gastrointestinal tract, and causes complications such as stroke, thrombosis, acute kidney injury, gastrointestinal infection (Nat Med. 2020; 26(7): 1017-. By 31/10/2020, SARS-CoV-2 has infected more than 4600 million worldwide and caused nearly 120 million deaths, and the epidemic is still spreading rapidly.
The impact of COVID-19 on human health, economic development, social activities, etc. is difficult to estimate, and global scientists are trying to find and develop vaccines and drugs that can effectively combat SARS-CoV-2 using various means. However, only one drug of Reidcisvir has been approved for the treatment of COVID-19 in some countries and regions until now, but the worldwide largest clinical study on new coronary therapy "solid Trial" conducted by the WHO considers Reidcisvir to be ineffective (reproduced anti viral drugs for COVID-19-internal WHO SOLIDARITY Trial results. medRxiv. doi. org/10.1101/2020.10.15.20209817), and it is seen that the therapeutic effect of Reidcisvir is not very precise. There are several vaccines in phase III clinical trials around the world, but the problems of vaccine protection efficacy, persistence and safety remain to be carefully verified (Nature.2020585 (7823): 20-21.). In addition, since SARS-CoV-2 has the possibility of coexisting with human and undergoing mutation for a long period of time, the necessity of developing various drugs having different mechanisms of action to act against SARS-CoV-2 has been further highlighted.
Biological studies have shown that invasion of new coronaviruses is dependent not only on binding of angiotensin converting enzyme 2(ACE2), a membrane surface receptor of host cells, but also on cleavage activation of spike protein (S protein) of new coronaviruses by type II transmembrane serine protease (TMPRSS2) (cell.2020; 181(2):271-280.e 8.). TMPRSS2 is a transmembrane protein with a catalytic center located extracellularly, and cleaves the S2 subunit of the S protein of the novel coronavirus to expose the fusion peptide, facilitating fusion and entry of the virus into the host cell. In vitro studies have shown that the TMPRSS2 inhibitors camostat (camostat) or nafamostat (nafamostat) are effective in blocking infection of lung cells by SARS-CoV-2 virus (Antichronobacterium Agents Chemothers.2020; 64(6): e 00754-20). On the other hand, histopathological studies have found that cell types coexpressed by the two key proteins ACE2 and TMPRSS2, on which viral entry is dependent, are distributed predominantly in the nasal, pulmonary and intestinal tracts (cell.2020; 181(5):1016-1035. e19.; Nat Med.2020; 26(5): 681-687.). This suggests that inhalant-based drugs that act locally on the respiratory system and target TMPRSS2 may also effectively block the portal of viral entry, greatly reducing the risk of infection in humans.
Therefore, there is an urgent need in the art to develop an inhibitor targeting TMPRSS2 for use against SARS-Cov-2 virus.
Disclosure of Invention
The invention mainly aims to provide an inhibitor for SARS-CoV-2 virus invading somatic cells, in particular to a 4-guanidinobenzoic acid aryl ester compound, a preparation method thereof and application thereof in preparing SARS-CoV-2 virus inhibitor and/or medicines for treating related diseases caused by SARS-CoV-2.
In a first aspect of the invention, the invention provides 4-guanidinobenzoic acid aryl ester compounds and pharmaceutically acceptable salts thereof, which have a structure shown in a formula (I),
Figure BDA0002919974210000021
in the formula (I), the compound is shown in the specification,
a is 6-10 membered aromatic ring or aromatic heterocycle, said aromatic ring, aromatic heterocycle can be substituted by 1-2 substituents selected from alkyl, halogen atom;
b is-N (R) 1 )-；
C is a monosaccharide group;
x is O or NH;
R 1 selected from H, C1-C3 alkyl.
In another preferred embodiment, in formula (I), a is selected from: benzene rings, pyridine, naphthalene rings, quinoline, benzofuran or indole.
In another preferred embodiment, in formula (I), R 1 Is H or methyl.
In another preferred embodiment, in formula (I), C is a hexosyl group.
In another preferred embodiment, in formula (I), C is (2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl.
In another preferred embodiment, the pharmaceutically acceptable salt includes, but is not limited to, hydrochloride, sulfate, hydrobromide, mesylate, nitrate, phosphate, acetate, oxalate, succinate, tartrate, maleate, arginine.
In another preferred embodiment, the pharmaceutically acceptable salt is a hydrochloride salt.
In another preferred embodiment, the compound is selected from the group consisting of: 6- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl-4-guanidinobenzoate hydrochloride, 6- (methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl-4-guanidinobenzoate hydrochloride, 4- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, 4- (methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, 6- (N- ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamimidoyl) naphthalen-2-yl 4-guanidinobenzoate dihydrochloride, 5- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-1-yl 4-guanidinobenzoate hydrochloride, 1-methyl-2- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) -1H-indol-6-yl 4-guanidinobenzoate hydrochloride, 3- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) quinolin-7-yl 4-guanidinobenzoate An acid ester hydrochloride, 6- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) pyridin-3 yl 4-guanidinobenzoate hydrochloride, 1-methyl-3- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) -1H-indol-6-yl 4-guanidinobenzoate hydrochloride, or a combination thereof.
In a second aspect of the invention, there is provided a process for the preparation of a compound according to the first aspect, selected from scheme 1 or 2,
wherein route 1 comprises the steps of:
(S1) condensing the compound shown in the formula (Ia) with HB-C under the action of a condensing agent or/and alkali to generate a compound shown in the formula (Ib);
(S2) hydrogenating the compound shown in the formula (Ib) prepared in the S1 to remove benzyl to generate a compound shown in the formula (Ic);
(S3) condensing the compound shown in the formula (Ic) prepared in the step S2 and 4-guanidinobenzoic acid under the action of a condensing agent or/and a base to generate a compound shown in the formula (I);
the steps are shown as follows:
Figure BDA0002919974210000041
wherein R2 is selected from H, C1-C3 alkyl;
the other substituents are as defined above;
wherein route 2 comprises the steps of:
(T1) condensing the compound shown in the formula (Id) and 4-guanidinobenzoic acid under the action of a condensing agent or/and alkali to generate a compound shown in the formula (Ie);
(T2) preparing the compound shown in the formula (Ie) in the step (T1), and hydrogenating to remove benzyl to generate the compound shown in the formula (If);
(T3) condensing the compound shown in the formula (If) prepared in the step (T2) with HB-C under the action of a condensing agent or/and a base to generate a compound shown in the formula (I);
the steps are shown as follows:
Figure BDA0002919974210000042
wherein each substituent is as defined above.
In another preferred embodiment, the condensing agent is selected from: dicyclohexylcarbodiimide (DCC), 2- (7-azabenzotriazole) -N, N '-tetramethyluronium Hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole (ECDI/HOBt), 2- (1H-benzotriazol L-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate (TBTU), N' -Carbonyldiimidazole (CDI), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP), or a combination thereof.
In another preferred embodiment, the condensing agent is DCC or HATU.
In another preferred embodiment, the base is an organic base.
In another preferred embodiment, the organic base includes, but is not limited to, pyridine (Py), N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP), triethylamine;
in a third aspect of the invention there is provided the use of an active ingredient which is a compound of formula (I) as described in the first aspect or a pharmaceutically acceptable salt thereof,
wherein the active ingredient or formulation is used in the preparation of an inhibitor of SARS-CoV-2 virus; and/or SARS-CoV-2 caused related diseases.
In another preferred embodiment, the disease is selected from: or systemic multiple organ complications such as apoplexy, thrombosis, renal injury, gastrointestinal infection, etc. caused by COVID-19 and SARS-CoV-2 infection, or their combination.
In another preferred embodiment, the disease is COVID-19.
In another preferred embodiment, the active ingredient is selected from: 6- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl-4-guanidinobenzoate hydrochloride, 6- (methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl-4-guanidinobenzoate hydrochloride, 4- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, 4- (methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, 6- (N- ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamimidoyl) naphthalen-2-yl 4-guanidinobenzoate dihydrochloride, 5- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-1-yl 4-guanidinobenzoate hydrochloride, 1-methyl-2- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) -1H-indol-6-yl 4-guanidinobenzoate hydrochloride, 3- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) quinolin-7-yl 4-guanidinobenzoate An acid ester hydrochloride, 6- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) pyridin-3 yl 4-guanidinobenzoate hydrochloride, 1-methyl-3- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) -1H-indol-6-yl 4-guanidinobenzoate hydrochloride, or a combination thereof.
In another preferred embodiment, the formulation is an oral formulation or a non-oral formulation.
In another preferred embodiment, the oral or non-oral formulation comprises: powder, granule, capsule, injection, inhalant, tincture, oral liquid, tablet, buccal tablet, or dripping pill.
In another preferred embodiment, the non-oral formulation is an inhalant.
In a fourth aspect of the invention, there is provided a pharmaceutical composition comprising:
(A) the aryl 4-guanidinobenzoate compound of the first aspect or a pharmaceutically acceptable salt thereof;
(B) a pharmaceutically acceptable carrier, excipient or adjuvant;
in another preferred embodiment, the pharmaceutical composition may further comprise an antiviral drug of another mechanism selected from the group consisting of:
(B1) an RNA-dependent RNA polymerase inhibitor;
(B2) a primary protease inhibitor;
(B3) a papain inhibitor;
(B4) a helicase inhibitor;
(B5) a furin inhibitor;
(B6) cathepsin L inhibitors.
In another preferred embodiment, the RNA-dependent RNA polymerase inhibitor is reed-solomon.
In a fifth aspect of the invention, there is provided a use of the pharmaceutical composition of the fourth aspect for the preparation of an inhibitor of SARS-CoV-2 virus; and/or SARS-CoV-2 caused related diseases.
In a sixth aspect of the present invention, there is provided a method of inhibiting the invasion of SARS-CoV-2 and/or treating a disease associated with SARS-CoV-2, comprising the step of administering to a patient in need thereof a medically effective amount of a compound of the first aspect and pharmaceutically acceptable salts thereof or a pharmaceutical composition of the fourth aspect. In another preferred embodiment, the patient is a SARS-CoV-2 infected patient.
In another preferred embodiment, the patient is a patient with systemic multiple organ complications such as COVID-19, stroke due to SARS-CoV-2 infection, thrombosis, renal injury, gastrointestinal infection, etc.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have made extensive and intensive studies and have unexpectedly found that a 4-guanidinobenzoic acid aryl ester compound is effective against SARS-CoV-2 virus, and have completed the present invention.
Specifically, the invention provides a compound for glycosylation structure modification of TMPRSS2 inhibitor camostat and nafamostat, namely a 4-guanidinobenzoate aryl ester compound, which has a structure shown in a general formula I, shows an effect of remarkably inhibiting SARS-CoV-2 virus invasion on a lung cell model, and can be used for preparing a medicine for preventing or treating novel coronavirus pneumonia and complications thereof caused by SARS-CoV-2 infection.
Term(s) for
As used herein, "the compound of the present invention" and "the active ingredient of the present invention" are used interchangeably and refer to the aryl 4-guanidinobenzoate compound of formula (I) or a pharmaceutically acceptable salt thereof, which is provided by the present invention and is effective in inhibiting SARS-CoV-2 virus.
In the invention, a 'monosaccharide' is defined as a univalent free radical obtained after removing one hydroxyl or aldehyde group from polyhydroxy aldehyde containing 3-6 carbon atoms in a molecular structure; "hexoses" are defined as polyhydroxyaldehydes or polyhydroxyketones containing 6 carbon atoms, including but not limited to glucose, galactose, mannose; "hexosyl" is defined as a monovalent free radical resulting from the removal of one hydroxyl or aldehyde group from a hexose; the monosaccharide radical or the hexosyl radical is linked to the group B in the general formula (I) in a chemically permissible manner;
in the present invention, "aromatic ring" is defined as monocyclic and bicyclic ring systems consisting of 6 to 10 carbon atoms and complying with Huckel's rule, including but not limited to benzene ring, naphthalene ring;
in the present invention, "heteroaromatic ring" is defined as monocyclic and bicyclic ring systems having 6 to 10 ring-forming atoms and containing 1 to 4 heteroatoms (selected from N, O, S) while complying with Huckel's rule, including but not limited to pyridine, pyrimidine, quinoline, indole, benzofuran, benzothiophene;
in the present invention, the "alkyl" includes all branched and straight chain isomers at a specific number of carbon atoms; representative examples include: methyl, ethyl, n-propyl, isopropyl;
in the present invention, the "halogen atom" includes fluorine, chlorine, bromine, iodine;
in the present invention, the "condensing agent" refers to an auxiliary agent which catalyzes the reaction of the carboxylic acid and the phenolic hydroxyl group or amine group upon dehydration to form an ester or amide, and allows the reaction to proceed under mild conditions, and representative examples include, but are not limited to, Dicyclohexylcarbodiimide (DCC), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride/1-hydroxybenzotriazole (ECDI/HOBt), 2- (1H-benzotriazol L-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate (TBTU), N' -Carbonyldiimidazole (CDI), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP); preferably, the condensing agent is DCC or HATU;
in the present invention, the "base" includes organic bases and inorganic bases; examples of organic bases include, but are not limited to, pyridine (Py), N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP), triethylamine, 1, 8-diazabicycloundecen-7-ene (DUB), triethanolamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide; examples of inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, potassium phosphate; in the preparation of the compounds, those skilled in the art can appropriately change and adjust the reaction conditions according to the specific reaction substrates;
active ingredients of the invention
The invention provides a 4-guanidinobenzoic acid aryl ester compound and pharmaceutically acceptable salt thereof, which have a structure shown in a formula (I),
Figure BDA0002919974210000071
in the formula (I), the compound is shown in the specification,
a is 6-10 membered aromatic ring or aromatic heterocycle, said aromatic ring, aromatic heterocycle can be substituted by 1-2 substituents selected from alkyl, halogen atom;
b is-N (R) 1 )-；
C is a monosaccharide group;
x is O or NH;
R 1 selected from H, C1-C3 alkyl.
In another preferred embodiment, in formula (I), a is selected from: benzene rings, pyridine, naphthalene rings, quinoline, benzofuran or indole.
In another preferred embodiment, in formula (I), R 1 Is H or methyl.
In another preferred embodiment, in formula (I), C is a hexosyl group.
In another preferred embodiment, in formula (I), C is (2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl.
In another preferred embodiment, the pharmaceutically acceptable salt includes, but is not limited to, hydrochloride, sulfate, hydrobromide, mesylate, nitrate, phosphate, acetate, oxalate, succinate, tartrate, maleate, arginine.
In another preferred embodiment, the pharmaceutically acceptable salt is a hydrochloride salt.
In another preferred embodiment, the compound is selected from the group consisting of: 6- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl-4-guanidinobenzoate hydrochloride, 6- (methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl-4-guanidinobenzoate hydrochloride, 4- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, 4- (methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, 6- (N- ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamimidoyl) naphthalen-2-yl 4-guanidinobenzoate dihydrochloride, 5- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-1-yl 4-guanidinobenzoate hydrochloride, 1-methyl-2- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) -1H-indol-6-yl 4-guanidinobenzoate hydrochloride, 3- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) quinolin-7-yl 4-guanidinobenzoate An acid ester hydrochloride, 6- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) pyridin-3 yl 4-guanidinobenzoate hydrochloride, 1-methyl-3- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) -1H-indol-6-yl 4-guanidinobenzoate hydrochloride, or a combination thereof;
camostat (camostat) or nafamostat (nafamostat)
Camostat (camostat) or nafamostat (nafamostat) is an inhibitor targeting TMPRSS2 and is clinically used for relieving pancreatitis symptoms and anticoagulation, and the structural formula of the camostat or nafamostat is shown as follows:
Figure BDA0002919974210000091
researchers at the Lai Bunitz Primates institute of Germany found that camostat was effective in blocking SARS-CoV-2 virus invasion cells in both the calu-3 lung cell line and the human primary lung cell model (cell.2020; 181(2):271-280.e 8.); subsequent studies further revealed that compared to camostat and nafamostat, SARS-CoV-2 was more potently inhibited and its activity could reach a low nanomolar level (anticancer Agents Chemother.2020; 64(6): e 00754-20). Based on information published in the us clinical trials database (clinicaltrials. gov), research institutes in several countries including the united states, uk, france, etc. are conducting clinical trials of camostat or nafamostat for treatment of covi-19.
Pharmaceutical composition
In the invention, the compound shown in the general formula (I) is usually used for preparing a medicament in the form of a pharmaceutical composition, and the pharmaceutical composition comprises the compound shown in the general formula (I) and one or more pharmaceutically acceptable auxiliary materials; the pharmaceutically acceptable auxiliary materials comprise pharmaceutically acceptable carriers, excipients, sustained-release agents, odorants, flavoring agents and the like; in the pharmaceutical composition, the compound shown in the general formula (I) is used as an active component, the weight of the compound accounts for 0.1-99.9% of the total weight of the pharmaceutical composition, and the balance is pharmaceutically acceptable auxiliary materials; the pharmaceutical composition can be prepared into various dosage forms such as tablets, capsules, solutions, suspensions, aerosols, dry powders and the like based on the conventional process in the field of pharmaceutical preparation, and can be stored in a suitable disinfecting apparatus and a drug delivery device;
in the present invention, the "effective therapeutic dose" means that a subject treated with the dose is cured, improved, effectively prevented from suffering from a disease, a side effect, or the like, or the incidence thereof is significantly reduced, as compared with a subject not treated with the dose; in addition, it includes effective dose for enhancing normal physiological function;
in the invention, the compound shown in the general formula (I), the salt thereof and the pharmaceutical composition thereof can be used for human and animals; the administration route comprises oral administration, inhalation, transdermal absorption, injection, etc.; in the present invention, the preferred route of administration is inhalation; the compound shown in the general formula (I), the salt thereof and the pharmaceutical composition thereof are used as inhalants when used for preparing medicines; the dosage and frequency of administration should be determined according to the order;
in the invention, the inhalant is a medicament form in which a medicament and a carrier thereof are sprayed by a special device to form droplets, and the droplets are inhaled through the mouth and the nose and reach a respiratory system to play a role; such inhalation dosage forms include, but are not limited to, aerosols, sprays, powders; the inhalants can be produced in the customary manner known to the person skilled in the art of pharmaceutical formulation and are not intended to limit the invention in any way;
in the invention, the compound shown in the general formula (I), the salt thereof and the pharmaceutical composition thereof are used for preventing or treating SARS-CoV-2 virus infection or can be used together with other antiviral mechanism medicaments; such drugs include, but are not limited to, RNA-dependent RNA polymerase inhibitors (e.g., ridivir, faviravir), major protease inhibitors (e.g., lopinavir, ritonavir), papain inhibitors, helicase inhibitors, furin inhibitors, cathepsin L inhibitors;
because the protective efficacy and persistence provided by the current vaccines are not verified, and the risk of SARS-CoV-2 virus infection can be reduced only within a certain period of time and to a certain extent after inoculation, the compound shown in the general formula (I), the salt thereof and the pharmaceutical composition thereof can be continuously used after the vaccine is injected into a human body, so that the protective efficacy is enhanced synergistically, and the infection risk is further reduced;
as SARS-CoV-2 attacks not only the respiratory system but also multiple organs in the whole body such as the brain, heart, kidney, liver, spleen, gastrointestinal tract, and the like, leading to complications such as stroke, thrombus, kidney injury, gastrointestinal infection, etc. (Nat Med.2020; 26(7): 1017-.
The main advantages of the invention include:
(a) the compounds of the present invention have outstanding effect on inhibiting SARS-CoV-2, wherein the salt hydrochloride of 6- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl-4-guanidinobenzoic acid inhibits the EC of SARS-CoV-2 50 The value can even reach 0.006 mu m, and SARS-CoV-2 can be inhibited under extremely low concentration.
(b) The compound of the invention has higher selectivity for SARS-CoV-2, can accurately inhibit the replication of SARS-CoV-2 virus, and has excellent clinical popularization value.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally followed by conventional conditions, such as Sambrook et al, molecular cloning: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Abbreviations
All abbreviations used in this example are listed below:
DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DIPEA: n, N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: n, N-dimethylformamide; HATU: 2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate; py: pyridine; THF: tetrahydrofuran.
Preparation of compounds
Example 1: 6- (((2S,3R,4R,5R) -2,3,4,5, 6-Pentahydroxyhexyl) carbamoyl) naphthalen-2-yl 4-guanidinobenzoic acid ester hydrochloride
(1) Synthesis method A
Figure BDA0002919974210000111
6-hydroxy-2-naphthoic acid (10g, 53.19mmol, 1 equiv.), benzyl chloride (18.5mL, 3 equiv.), potassium carbonate (20g, 3 equiv.), potassium iodide (2.65g, 0.3 equiv.) were placed in 100mL DMF and heated at 80 ℃ with stirring overnight until the reaction was complete. Then putting into cold water, extracting twice with ethyl acetate, combining organic phases, washing twice with salt solution, Na 2 SO 4 After drying, separation was carried out by flash chromatography to obtain 14.47g of a white solid, i.e., intermediate 1-1.
Intermediate 1-1(12.25g, 33.29mmol, 1 eq) was dissolved in THF/MeOH mixed solvent (80/40mL), and 2M aqueous KOH (41.6mL, 2.5 eq) was added slowly, followed by heating at 70 ℃ for 1 h. After cooling, most of the organic solvent was distilled off under reduced pressure, and 100mL of ice-water was added to the residue, followed by adjusting the pH to weakly acidic with 6N-concentrated hydrochloric acid. Filtering and collecting separated precipitate, washing with distilled water for several times, vacuum drying overnight after vacuum pumping to obtain 8.9g white solid, namely the intermediate 1-2; MS (ESI) M/z 277.1[ M-H ]] - 。
Intermediate 1-2(400mg, 1.44mmol, 1 eq.), HATU (602mg, 1.1 eq.)Amount), DIPEA (375. mu.L, 1.5 equiv.) in 10mL DMF, stirred at room temperature for 10min, then added D-glucosamine (261mg, 1 equiv.) and reacted overnight. Adding 10mL of water and 10mL of ethyl acetate into the reaction solution, stirring for 5min, then filtering and collecting the precipitate, and drying in vacuum to obtain 490mg of light red solid, namely the intermediate 1-3; MS (ESI) M/z 442.2[ M + H ]] + 。
Intermediate 1-3(490mg, 1.11mmol, 1 equiv), palladium on carbon catalyst (10% Pd, about 55% water, 100mg) in 20mL of methanol, reduced with hydrogen at normal pressure, stirred at room temperature for 4 h. 20mL of DMF was added, the product was heated to complete dissolution, and the palladium/carbon was removed by filtration while hot. The filtrate was evaporated to dryness, then slurried with methanol, filtered, and dried to obtain 250mg of a yellow solid, i.e., intermediate 1-4. 1 H-NMR(d 6 -DMSO,500MHz)δ10.05(brs,1H),8.39(t,1H,J＝5.5),8.33(s,1H),7.87(d,1H,J＝8.5),7.83(dd,1H,J＝8.5,1.5),7.73(d,1H,J＝8.5),7.17-7.14(m,2H),4.95(s,1H),4.52(s,1H),4.48(s,1H),4.40(s,2H),3.82(m,1H),3.68(m,1H),3.60(m,1H),3.51(m,3H),3.40(m,1H),3.33(m,1H)；MS(ESI):m/z 352.1[M+H] + 。
Intermediate 1-4(140mg, 0.4mmol, 1 equiv.), 4-guanidinobenzoic acid hydrochloride (52mg, 0.6 equiv.), DCC (82mg, 1 equiv.), and DMAP (5mg, 0.1 equiv.) in 2mL pyridine and 1mL DMF, stir at room temperature for 4h, then add 52mg 4-guanidinobenzoic acid hydrochloride and 82mg DCC and continue the reaction overnight. The solvent was evaporated under reduced pressure, 2mL water and 2mL methanol were added to the residue, the insoluble solids were removed by filtration, the filtrate was separated by preparative liquid chromatography, eluted with a gradient of 0% to 15% acetonitrile/water, the desired product fraction was collected, concentrated under reduced pressure to about 1mL, and lyophilized overnight to give 60mg of a white solid, example 1. 1 H-NMR(d 6 -DMSO,500MHz)δ10.26(s,1H),8.58(t,1H,J＝5.5),8.56(s,1H),8.24(d,2H,J＝9.0),8.15(d,1H,J＝9.0),8.05-8.01(m,2H),7.82(d,1H,J＝2.5),7.77(s,4H),7.55(dd,1H,J＝9.0,2.5),7.47(d,2H,J＝8.5),4.95(d,1H,J＝4.5),4.52(d,1H,J＝5.0),4.47(d,1H,J＝5.5),4.40(d,1H,J＝6.5),4.37(t,1H,J＝6.0),3.85(m,1H),3.70(m,1H),3.60(m,1H),3.55(m,1H),3.52(m,2H),3.42(m,1H),3.36(m,1H)；MS(ESI):m/z 513.2[M+H] + ,257.1[M/2+H] + 。
(2) Synthesis method B
Figure BDA0002919974210000121
6-hydroxy-2-naphthoic acid (5g, 26.6mmol, 1 equiv.), benzyl bromide (3.79mL, 1.2 equiv.), sodium bicarbonate (3.35g, 1.5 equiv.) in 50mL DMF was heated with stirring overnight at 50 ℃. Then putting into cold water, extracting twice with ethyl acetate, combining organic phases, washing twice with salt solution, Na 2 SO 4 Drying, and separating with flash chromatography column to obtain 3.7g white solid, i.e. intermediate 1-5; MS (ESI) M/z 277.1[ M-H ]] - 。
Intermediate 1-5(2.78g, 10mmol, 1 eq), 4-guanidinobenzoic acid hydrochloride (3.7g, 1.72 eq), DCC (4.3g, 2.09 eq), and DMAP (122mg, 0.1 eq) in 20mL pyridine and 10mL DMF was stirred at room temperature overnight. The solvent was evaporated to dryness under reduced pressure, 15mL of water and 15mL of methanol were added to the residue, the insoluble solids were removed by filtration, the filtrate was evaporated to dryness again, and then silica gel was mixed and separated by flash chromatography to obtain 1.75g of a white solid, i.e., intermediate 1-6. 1 H-NMR(d 6 -DMSO,500MHz)δ10.16(s,1H),8.76(s,1H),8.31(d,1H,J＝9.0),8.24(d,2H,J＝8.5),8.09(m,2H),7.97(d,1H,J＝1.5),7.78(s,4H),7.59(dd,1H,J＝9.0,2.0),7.55(d,2H,J＝6.5),7.48(d,2H,J＝9.0),7.45(t,2H,J＝6.5),7.39(t,1H,J＝6.5),5.45(s,2H)；MS(ESI):m/z 440.2[M+H] + 。
Intermediates 1-6(0.5g, 1.05mmol, 1 eq) were dissolved in 15mL DMF and palladium on carbon catalyst (10% Pd, dry, 50mg) was added followed by hydrogenation overnight at room temperature under normal pressure and TLC indicated complete reaction. Filtering to remove palladium/carbon, concentrating the filtrate to a small amount, adding 10mL of anhydrous methanol, stirring for 20min, filtering, collecting precipitate, and drying to obtain 0.33g of white solid, namely an intermediate 1-7; MS (ESI) M/z 350.1[ M + H] + 。
Intermediates 1-7(85mg,0.23mmol, 1 eq), D-glucosamine (83mg, 2 eq), DIPEA (80 μ L, 2 eq) were dissolved in 3mL DMF, HATU (131mg, 1.5 eq) was added, then stirred at room temperature for 2 h. Evaporating to dryness under reduced pressure, and subjecting the residue to preparative liquid chromatographyLine separation gave 65mg of a white solid, example 1. 1 H-NMR(CD 3 OD,500MHz)δ8.46(s,1H),8.31(d,2H,J＝8.5),8.08(d,1H,J＝9.0),7.97(m,2H),7.81(d,1H,J＝1.5),7.49-7.46(m,3H),4.03(m,1H),3.87(d,1H,J＝3.5),3.80(m,1H),3.74(m,3H),3.66(m,1H),3.55(dd,1H,J＝13.5,7.0)；MS(ESI):m/z 513.2[M+H] + ,257.1[M/2+H] + 。
Example 2: 6- (methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl 4-guanidinobenzoic acid ester hydrochloride
Figure BDA0002919974210000131
The preparation of example 2 was carried out according to the synthetic methods of intermediates 1 to 7 to example 1, except that meglumine was used as a starting material instead of D-glucosamine, to give example 2 as a white solid. 1 H-NMR(d 6 -DMSO,500MHz, about 1:1 rotamer) δ 10.40(brs,1H),8.24(d,2H, J ═ 8.5),8.10(m,2H),8.03/7.97(2x d,1H, J ═ 8.0),7.91/7.88(2x s,1H),7.82(brs,4H),7.62(m,1H),7.52(m,1H),7.48(d,2H, J ═ 9.0),4.96(d,1H, J ═ 4.0),4.60-4.28(m,4H),4.02/3.90(2x m,1H),3.69-3.42(m,5H),3.29(m,2H),3.06/3.04(2x s, 3H); MS (ESI) M/z 527.2[ M + H [)] + ,264.1[M/2+H] + 。
Example 3: 4- (((2S,3R,4R,5R) -2,3,4,5, 6-Pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoic acid ester hydrochloride
Figure BDA0002919974210000141
The preparation of intermediates 3-1 to example 3 was carried out according to the synthetic procedures of intermediates 1-3 to example 1, except that 4-benzyloxybenzoic acid was used as starting material instead of intermediate 1-2 to give example 3 as a white solid. 1 H-NMR(d 6 -DMSO,500MHz)δ10.40(s,1H),8.48(t,1H,J＝5.5),8.19(d,2H,J＝9.0),7.99(d,2H,J＝9.0),7.84(s,4H),7.46(d,2H,J＝9.0),7.39(d,2H,J＝9.0),4.93(brs,1H),4.52-4.39(m,4H),3.81(m,1H),3.68(m,1H),3.60(m,1H),3.50(m,3H),3.43-3.28(m,2H)；MS(ESI):m/z463.2[M+H] + ,232.1[M/2+H] + 。
Example 4: 4- (methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoic acid ester hydrochloride
Figure BDA0002919974210000142
The preparation of intermediates 4-1 to example 4 was carried out according to the synthetic procedures of intermediates 1-3 to example 1, except that 4-benzyloxybenzoic acid was used instead of intermediate 1-2 and meglumine was used instead of D-glucosamine as starting material to give example 4 as a white solid. 1 H-NMR(d 6 -DMSO,500MHz, about 3:2 rotamers) δ 10.31/10.28(2x s,1H),8.19(d,2H, J ═ 8.5),7.80(s,4H),7.57/7.54(2x d,2H, J ═ 8.0),7.46(d,2H, J ═ 9.0),7.37/7.31(2x d,2H, J ═ 7.5),5.00/4.93(2x d,1H, J ═ 5.0),4.56/4.50(2x d,1H, J ═ 4.0),4.45-4.30(m,3H),3.97/3.88(2x m,1H),3.66-3.41(m,5H),3.38-3.22(m,2H),3.00(s, 3H); MS (ESI) M/z 477.2[ M + H ]] + ,239.1[M/2+H] + 。
Example 5: 6- (N- ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamimidoyl) naphthalen-2-yl 4-guanidinobenzoate dihydrochloride
Figure BDA0002919974210000151
6-hydroxy-2-naphthylimido acid methyl ester hydrochloride (205mg, 0.865mmol, 1 equivalent) and D-glucosamine (156mg, 1 equivalent) were dissolved in 5mL of anhydrous methanol, stirred at room temperature for 4h, and then separated by preparative liquid chromatography, with acetonitrile/water system being mobile phase gradient elution to obtain 150mg of white solid, i.e. intermediate 5-1. 1 H-NMR(d 6 -DMSO,500MHz)δ10.34(s,1H),9.66(s,1H),9.42(s,1H),8.91(s,1H),8.30(s,1H),7.95(d,1H,J＝9.5),7.90(d,1H,J＝8.5),7.68(dd,1H,J＝8.5,2.0),7.26(m,2H),5.29(d,1H),4.63(m,2H),4.59(d,1H),4.44(t,1H,J＝5.5),3.97(m,1H),3.76(m,1H),3.63(m,2H),3.55(m,3H),3.45(m,1H)；MS(ESI):m/z 351.2[M+H] + 。
Example 5 preparation according toExample 1 synthesis method a was performed except that intermediate 5-1 was used as the starting material instead of intermediate 1-4; the crude product is separated by preparative liquid chromatography in 0% to 20% acetonitrile/0.1% HCl-H 2 Gradient elution of O system gave example 5 as an off-white solid. 1 H-NMR(d 6 -DMSO,500MHz)δ10.55(s,1H),9.91(t,1H,J＝5.0),9.62(s,1H),9.13(s,1H),8.53(s,1H),8.24(d,2H,J＝8.5),8.23(d,1H,J＝9.0),8.18(d,1H,J＝9.0),8.03(d,1H,J＝2.0),7.90(s,4H),7.87(d,1H,J＝8.5),7.66(dd,1H,J＝9.0,2.0),7.49(d,2H,J＝9.0),5.34(brs,1H),4.65(m,3H),4.45(brs,1H),4.01(m,1H),3.79(m,1H),3.65(m,2H),3.57(m,3H),3.45(m,1H)；MS(ESI):m/z 512.2[M+H] + ,256.6[M/2+H] + 。
Example 6: 5- (((2S,3R,4R,5R) -2,3,4,5, 6-Pentahydroxyhexyl) carbamoyl) naphthalen-1-yl 4-guanidinobenzoic acid ester hydrochloride
Figure BDA0002919974210000161
The preparation of intermediates 6-1 to example 6 was carried out according to the synthetic methods of intermediates 1-1 to example 1, except that methyl 5-hydroxy-1-naphthoate was used as a starting material instead of 6-hydroxy-2-naphthoic acid. 1 H-NMR(d 6 -DMSO,500MHz)δ10.50(brs,1H),8.51(t,1H,J＝5.5),8.32(d,2H,J＝9.0),8.21(d,1H,J＝8.5),7.92(d,1H,J＝8.5),7.87(s,4H),7.71(dd,1H,J＝7.0,1.0),7.66(dd,1H,J＝8.5,7.5),7.61(dd,1H,J＝8.5,7.5),7.53(d,1H,J＝7.5),7.51(d,2H,J＝8.5),4.91(d,1H,J＝5.0),4.57(d,1H,J＝5.0),4.48(d,1H,J＝5.5),4.40(m,2H),3.87(m,1H),3.74(m,1H),3.62(m,1H),3.54(m,3H),3.42(m,2H)；MS(ESI):m/z 513.2[M+H] + ,257.1[M/2+H] + 。
Example 7: 1-methyl-2- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) -1H-indol-6-yl 4-guanidinobenzoic acid ester hydrochloride
Figure BDA0002919974210000162
Preparation of intermediate 7-1 Synthesis according to intermediate 1-1The preparation method is carried out except that 6-hydroxy-2-indolecarboxylic acid is used as raw material to replace 6-hydroxy-2-naphthoic acid; MS (ESI) M/z 358.2[ M + H ]] + 。
Intermediate 7-1(750mg, 2.1mmol, 1 eq) was dissolved in 5mL dry DMF and cooled in an ice bath, then NaH (60% in mineral oil, 90mg, 1.07 eq) was added and stirred for 10 minutes, methyl iodide (132. mu.L, 1 eq) was added and stirring continued to room temperature and the progress of the reaction was checked by TLC. After the reaction is finished, quenching the mixture by saturated ammonium chloride solution, extracting the mixture twice by ethyl acetate, combining organic phases, washing the organic phases twice by saline solution, and carrying out Na reaction 2 SO 4 Drying, and separating with flash chromatography column to obtain 0.66g white solid, i.e. intermediate 7-2; MS (ESI) M/z 372.2[ M + H ]] + 。
The preparation of intermediates 7-3 to example 7 was carried out according to the synthetic procedures of intermediates 1-2 to example 1, except that starting from intermediate 7-2 instead of intermediate 1-1, example 7 was obtained as a white solid. 1 H-NMR(d 6 -DMSO,500MHz)δ10.12(brs,1H),8.38(t,1H,J＝5.5),8.20(d,2H,J＝8.5),7.01(d,1H,J＝9.0),7.68(s,4H),7.49(d,1H,J＝2.0),7.45(d,2H,J＝8.5),7.15(s,1H),7.01(dd,1H,J＝8.5,2.0),4.89(d,1H,J＝4.5),4.52(d,1H,J＝5.0),4.45(d,1H,J＝6.0),4.38(d,1H,J＝6.5),4.37(t,1H,J＝6.0),3.98(s,3H),3.81(m,1H),3.69(m,1H),3.60(m,1H),3.51(m,3H),3.41(m,1H),3.30(m,1H)；MS(ESI):m/z 516.2[M+H] + ,258.6[M/2+H] + 。
Example 8: 3- (((2S,3R,4R,5R) -2,3,4,5, 6-Pentahydroxyhexyl) carbamoyl) quinolin-7-yl 4-guanidinobenzoic acid ester hydrochloride
Figure BDA0002919974210000171
2-amino-4-bromobenzaldehyde (1g, 5mmol, 1 equiv.), ethyl 3-ethoxyacrylate (0.86mL, 1.1 equiv.), p-toluenesulfonic acid monohydrate (95mg, 0.1 equiv.) were reacted in 30mL of toluene at reflux overnight. The toluene was distilled off under reduced pressure, and the residue was redissolved with 30mL of DCM and then with NaHCO 3 Washing with saturated solution once, anhydrous Na 2 S0 4 Drying, separating with flash chromatography column to obtain 125g of solid, intermediate 8-1; MS (ESI) M/z 280.0[ M + H ]] + ,282.0[M+2+H] + 。
Intermediate 8-1(1.24g, 4.45mmol, 1 eq), bis-pinacolato diboron (1.25g, 1.1 eq), potassium acetate (1.3g, 3eq) and PdCl 2 (dppf) -DCM complex (0.35g, 0.1 eq) in 20mL DMF, N 2 The reaction is heated for 5 hours at 100 ℃ under protection. Cooling, filtering to remove insoluble substances, washing with ethyl acetate, evaporating the solvent under reduced pressure, and separating the residue with flash chromatography column to obtain 0.83g of jelly, namely intermediate 8-2; MS (ESI) M/z 328.2[ M + H ]] + 。
Intermediate 8-2(820mg, 2.5mmol) was dissolved in 20mL THF and placed in an ice bath, and H was added dropwise 2 O 2 The aqueous solution (30% by mass, 0.77mL, 3eq) was added dropwise over 10min and stirred at room temperature for 2 h. Adding excessive sodium thiosulfate saturated solution for quenching, extracting with ethyl acetate twice, washing the organic phase with sodium chloride solution, and adding anhydrous Na 2 S0 4 Drying, and separating with flash chromatography column to obtain 0.46g solid, i.e. intermediate 8-3; MS (ESI) M/z 218.1[ M + H] + 。
Intermediate 8-3(457mg,2.1mmol, 1 eq), benzyl chloride (315. mu.L, 1.3 eq), K 2 CO 3 (435mg,1.5 equiv.) and KI (35mg,0.1 equiv.) were reacted in 15mL of DMF by heating at 60-70 ℃ for 3 hours. Adding into cold water, extracting with ethyl acetate twice, mixing organic phases, washing with saline solution twice, and adding Na 2 SO 4 Drying, and separating with flash chromatography column to obtain 0.42g white solid, i.e. intermediate 8-4; MS (ESI) M/z 308.1[ M + H ]] + 。
Intermediate 8-4(420mg,1.37mmol, 1 eq.) is dissolved in THF/MeOH/H 2 To the O mixed solvent (6/6/2mL), NaOH (164mg,3 equiv.) was added and the reaction was stirred at room temperature for 3 h. Evaporating most of the organic solvent, adding 15mL of ice water into the rest, adjusting the pH value to be about 2 by using 6N hydrochloric acid, separating out a white solid, filtering, collecting, washing for three times, and drying in vacuum to obtain 0.32g of an intermediate 8-5; MS (ESI) M/z 280.1[ M + H ]] + 。
The preparation of intermediates 8-6 to example 8 was carried out according to the synthetic methods of intermediates 1-3 to example 1, except that intermediates8-5 as starting material instead of intermediate 1-2 gave example 8 as a white solid. 1 H-NMR(d 6 -DMSO,500MHz)δ10.40(brs,1H),9.35(d,1H,J＝2.0),8.94(d,1H,J＝2.0),8.81(t,1H,J＝6.0),8.24(m,3H),8.01(s,1H),7.84(s,4H),7.69(dd,1H,J＝9.0,2.5),7.48(d,2H,J＝8.5),4.96(d,1H,J＝5.0),4.54(d,1H,J＝5.0),4.47(d,1H,J＝5.5),4.41(d,1H,J＝7.0),4.38(t,1H,J＝6.0),3.86(m,1H),3.71(m,1H),3.63-3.52(m,4H),3.40(m,2H)；MS(ESI):m/z 514.2[M+H] + ,257.6[M/2+H] + 。
Example 9: 6- (((2S,3R,4R,5R) -2,3,4,5, 6-Pentahydroxyhexyl) carbamoyl) pyridin-3-yl 4-guanidinobenzoic acid ester hydrochloride
Figure BDA0002919974210000191
The preparation of intermediates 9-1 to example 9 was carried out according to the synthetic procedures of intermediates 8-4 to example 8, except that methyl 5-hydroxypicolinate was used as starting material instead of intermediate 8-3 to give example 9 as a white solid. 1 H-NMR(d 6 -DMSO,500MHz)δ10.42(s,1H),8.69(d,1H,J＝2.0),8.59(t,1H,J＝6.0),8.22(d,2H,J＝8.5),8.19(d,1H,J＝8.5),8.02(dd,1H,J＝8.5,2.0),7.86(s,4H),7.47(d,2H,J＝8.5),5.01(d,1H,J＝4.5),4.51(d,1H,J＝5.5),4.48(d,1H,J＝6.5),4.46(d,1H,J＝6.0),4.37(t,1H,J＝5.5),3.77(m,1H),3.66(m,1H),3.59(m,2H),3.51(m,1H),3.46(m,1H),3.41(m,1H),3.31(m,1H)；MS(ESI):m/z 464.2[M+H] + ,232.6[M/2+H] + 。
Example 10: 1-methyl-3- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) -1H-indol-6-yl 4-guanidinobenzoic acid ester hydrochloride
Figure BDA0002919974210000192
6-benzyloxy-1H-indole (1g, 4.48mmol, 1 eq) and pyridine (0.47mL, 1.3 eq) were dissolved in 10mL of dry THF and placed in an ice bath, then trichloroacetyl chloride (1.06g, 1.3 eq) dissolved in 5mL of THF was added dropwise over 1H, and stirred at room temperature overnight. And adding 20mL of ethyl acetate for dilution, washing with dilute hydrochloric acid and common salt water in sequence, drying with anhydrous magnesium sulfate, filtering, and evaporating to dryness to obtain a crude product of the intermediate 10-1, wherein the crude product is directly used for the next reaction.
The intermediate 10-1 was dissolved in 20mL of methanol, and 0.5mL of a 50% aqueous solution of potassium hydroxide was added, followed by refluxing overnight. The methanol was distilled off under reduced pressure and the residue was dissolved in DCM and washed twice with brine, anhydrous Na 2 S0 4 Drying, and separating with flash chromatography column to obtain 0.91g solid, i.e. intermediate 10-2; MS (ESI) M/z282.1[ M + H ]] + 。
The intermediate 10-3 was prepared according to the synthetic method for the intermediate 7-2 except that the intermediate 10-2 was used as a raw material instead of the intermediate 7-1 to obtain 0.8g of the intermediate 10-3; MS (ESI) M/z 296.1[ M + H ]] + 。
Intermediate 10-3(0.8g,2.71mmol, 1 eq.) is dissolved in THF/MeOH/H 2 To the O mixed solvent (9/9/3mL), NaOH (325mg,3 equivalents) was added and the reaction was completed by heating at 60 ℃ for 3 days. Evaporating most of the organic solvent, adding 15mL of ice water into the rest, adjusting the pH value to be about 2 by using 6N hydrochloric acid, separating out a solid, filtering, collecting, washing for three times, and drying in vacuum to obtain 0.61g of an intermediate 10-4; MS (ESI) M/z282.2[ M + H ]] + 。
The preparation of intermediates 10-5 to example 10 was carried out according to the synthetic procedures of intermediates 1-3 to example 1, except that starting from intermediate 10-4 instead of intermediate 1-2, example 10 was obtained as a white solid. 1 H-NMR(d 6 -DMSO,500MHz)δ10.40(s,1H),8.21(d,2H,J＝8.5),8.18(d,1H,J＝8.5),8.10(s,1H),7.91(t,1H,J＝5.5),7.84(s,4H),7.48(d,1H,J＝2.0),7.46(d,2H,J＝9.0),7.05(dd,1H,J＝8.5,2.0),3.83(s,3H),3.77(m,1H),3.68(m,1H),3.60(m,1H),3.51(m,3H),3.41(m,1H),3.27(m,1H)；MS(ESI):m/z 501.2[M+H] + ,251.1[M/2+H] + 。
Example 11: 6- (Ethyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl-4-guanidinobenzoic acid ester hydrochloride
Figure BDA0002919974210000201
Example 11 was prepared according to the synthetic method of example 2, except that instead of meglumine, the starting material was meglumine, giving example 11 as a white solid. MS (ESI) M/z 541.2[ M + H ]] + ,271.1[M/2+H] + 。
Example 12 evaluation of anti-SARS-CoV-2 Virus Activity
12.1 evaluation method
Spike protein (S protein) is the main outer membrane protein of new coronavirus SARS-CoV-2, is responsible for infection and invasion process of virus, and can directly block infection of host cell by inhibiting the function of the protein, thus preventing normal life cycle of virus. Therefore, the novel coronavirus S protein can be used as a drug screening target. The HIV pseudovirus is an infectious virus particle which is artificially constructed in vitro and prepared on a large scale by taking HIV virus as a starting material. In the construction process, membrane protein (GP120/41) coding sequences on HIV genomes are replaced by gene technology to become reporter genes Luciferase (Luciferase), and virus proteins Vpr and Nef are deleted. The modified virus particle has the defects of infection ability and progeny virus production ability. On the basis, the exogenously expressed new coronavirus S protein is integrated on the pseudovirus outer membrane, so that the defective virus can be modified to generate HIV pseudovirus particles with the new coronavirus S protein. The avidity and infectivity of the pseudovirion infected cells is completely determined by the activity of the S protein of the novel coronavirus. The infection capacity of the pseudovirus can be accurately reflected by detecting the level of the reporter gene, so that the pseudovirus is an excellent targeted screening technology.
The experiment screens the inhibitor for blocking the invasion of the new coronavirus S protein into the lung cells of Calu-3. The Calu-3 cells were inoculated one day in advance in a 96-well culture plate, provided with an active plate and a cytotoxic plate, respectively, and placed at 37 ℃ under 5% CO 2 And (5) culturing. The activity assay plate and the cytotoxicity assay plate are added with samples with different dilution concentrations and SARS-CoV-2 pseudovirus suspension according to the same sample adding mode, and a virus control, a cell control and a sample control are set. After further 3 days of culture, the cytotoxic plates were assayed for cell viability using the MTT method. The culture medium was aspirated off from the active plate, 100. mu.L of lysis solution was added to each well, and after lysis for 5 minutes with shaking, each well was lysedThen 100 mu L of Luciferase reaction detection solution is added, and the chemiluminescence value is measured after shaking and incubation for 5 minutes.
Screening results the selective inhibitory activity of the compounds on the invasion of the new coronavirus S protein was evaluated by cytotoxicity and relative infectious activity. Wherein cytotoxicity was measured using MTT method (MTT, OD @570), cell relative survival (viatility,%), and compound cytotoxicity results (toxity 100% -viatility) were calculated with 100% plated cells but no compound control wells. For the multi-concentration detection samples, the standard curve 4 parameter fitting method is adopted to calculate the compound CC 50 Numerical values. In order to detect the activity of the reporter gene Luciferase, after the cultured cells are cracked by using a lysate, an enzyme reaction substrate and a detection reagent are added, a chemiluminescence numerical value is read, and the relative invasion activity of the pseudovirus is calculated. Pseudovirus relative invasion activity (FLuc, RLU) pseudovirus relative invasion activity (infection,%), and pseudovirus inhibitory activity (Inhibition 100% -infection) were calculated based on 100% of plated cells but no compound control wells. For multi-concentration detection samples, calculating EC by adopting a standard curve 4 parameter fitting method 50 Numerical values.
Figure BDA0002919974210000211
12.2 screening results
Using the above method, test screening was performed on the compounds obtained in the foregoing examples 1 to 11, and the results obtained are shown in the following table:
TABLE 1 test screening results for the Compounds obtained in examples 1-11
Compound (I) CC 50 (μM) EC 50 (μM) SI
Example 1 >20 0.006 >3333
Example 2 >20 0.039 >512
Example 3 >20 0.076 >263
Example 4 >20 0.018 >1111
Example 5 >20 0.051 >392
Example 6 >20 0.035 >571
Example 7 >20 0.080 >250
Example 8 >20 0.030 >666
Example 9 >20 0.293 >68
Example 10 >20 0.135 >148
Example 11 >20 0.354 >56
Nafamostat >20 0.013 >1538
Camostat >20 0.222 >90
As can be seen from the screening results, compared with Nafamostat or Camostat, the compound of the general formula (I) obtained by glycosylation modification and aromatic heterocycle replacement has stronger activity for inhibiting SARS-CoV-2 virus from invading lung cells and better selectivity, so that the compound has potential application value in preparing medicaments for preventing or treating COVID-19 and complications thereof.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A4-guanidinobenzoic acid aryl ester compound and a pharmaceutically acceptable salt thereof are characterized by having a structure shown in a formula (I),
Figure FDA0002919974200000011
in the formula (I), the compound is shown in the specification,
a is 6-10 membered aromatic ring or aromatic heterocycle, said aromatic ring, aromatic heterocycle can be substituted by 1-2 substituents selected from alkyl, halogen atom;
b is-N (R) 1 )-；
C is a monosaccharide group;
x is O or NH;
R 1 selected from H, C1-C3 alkyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 6- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl-4-guanidinobenzoate hydrochloride, 6- (methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl-4-guanidinobenzoate hydrochloride, 4- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, 4- (methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, 6- (N- ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamimidoyl) naphthalen-2-yl 4-guanidinobenzoate dihydrochloride, 5- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-1-yl 4-guanidinobenzoate hydrochloride, 1-methyl-2- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) -1H-indol-6-yl 4-guanidinobenzoate hydrochloride, 3- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) quinolin-7-yl 4-guanidinobenzoate An acid ester hydrochloride, 6- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) pyridin-3 yl 4-guanidinobenzoate hydrochloride, 1-methyl-3- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) -1H-indol-6-yl 4-guanidinobenzoate hydrochloride, or a combination thereof.
3. A process for the preparation of a compound according to claim 1, selected from scheme 1 or 2,
wherein route 1 comprises the steps of:
(S1) condensing the compound shown in the formula (Ia) with HB-C under the action of a condensing agent or/and alkali to generate a compound shown in the formula (Ib);
(S2) hydrogenating the compound shown in the formula (Ib) prepared in the S1 to remove benzyl to generate a compound shown in the formula (Ic);
(S3) condensing the compound shown in the formula (Ic) prepared in the step S2 and 4-guanidinobenzoic acid under the action of a condensing agent or/and a base to generate a compound shown in the formula (I);
the steps are shown as follows:
Figure FDA0002919974200000021
wherein R2 is selected from H, C1-C3 alkyl;
the other substituents are as defined above;
wherein route 2 comprises the steps of:
(T1) condensing the compound shown in the formula (Id) and 4-guanidinobenzoic acid under the action of a condensing agent or/and alkali to generate a compound shown in the formula (Ie);
(T2) preparing the compound shown in the formula (Ie) in the step (T1), and hydrogenating to remove benzyl to generate the compound shown in the formula (If);
(T3) condensing the compound shown in the formula (If) prepared in the step (T2) with HB-C under the action of a condensing agent or/and a base to generate a compound shown in the formula (I);
the steps are shown as follows:
Figure FDA0002919974200000022
wherein each substituent is as defined above.
4. Use of an active ingredient or a formulation containing said active ingredient, wherein said active ingredient is a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof,
wherein the active ingredient or formulation is used in the preparation of an inhibitor of SARS-CoV-2 virus; and/or SARS-CoV-2 caused related diseases.
5. Use according to claim 4, characterized in that the active ingredient is selected from: 6- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl-4-guanidinobenzoate hydrochloride, 6- (methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-2-yl-4-guanidinobenzoate hydrochloride, 4- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, 4- (methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, methyl ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) phenyl 4-guanidinobenzoate hydrochloride, 6- (N- ((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamimidoyl) naphthalen-2-yl 4-guanidinobenzoate dihydrochloride, 5- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) naphthalen-1-yl 4-guanidinobenzoate hydrochloride, 1-methyl-2- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) -1H-indol-6-yl 4-guanidinobenzoate hydrochloride, 3- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) quinolin-7-yl 4-guanidinobenzoate An acid ester hydrochloride, 6- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) pyridin-3 yl 4-guanidinobenzoate hydrochloride, 1-methyl-3- (((2S,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl) carbamoyl) -1H-indol-6-yl 4-guanidinobenzoate hydrochloride, or a combination thereof.
6. The use of claim 4, wherein the formulation is an oral formulation or a non-oral formulation.
7. A pharmaceutical composition, comprising:
(A) the aryl 4-guanidinobenzoate compound of claim 1 or a pharmaceutically acceptable salt thereof;
(B) a pharmaceutically acceptable carrier, excipient or adjuvant.
8. The pharmaceutical composition of claim 7, which comprises an antiviral drug of another mechanism selected from the group consisting of the aryl 4-guanidinobenzoate compound of claim 1 and a pharmaceutically acceptable salt thereof:
(B1) an RNA-dependent RNA polymerase inhibitor;
(B2) a primary protease inhibitor;
(B3) a papain inhibitor;
(B4) a helicase inhibitor;
(B5) a furin inhibitor;
(B6) cathepsin L inhibitors.
9. Use of a pharmaceutical composition according to claim 7 for the preparation of an inhibitor of the SARS-CoV-2 virus; and/or SARS-CoV-2 caused related diseases.
10. A method for inhibiting the invasion of SARS-CoV-2 and/or treating a SARS-CoV-2-related disease, comprising the step of administering to a patient in need thereof a medically effective amount of a compound of claim 1 and pharmaceutically acceptable salts thereof or a pharmaceutical composition of claim 7.
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