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CN114539204A - Blood brain barrier high permeability hexokinase inhibitor and synthesis method and application thereof - Google Patents

Blood brain barrier high permeability hexokinase inhibitor and synthesis method and application thereof Download PDF

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CN114539204A
CN114539204A CN202210288278.8A CN202210288278A CN114539204A CN 114539204 A CN114539204 A CN 114539204A CN 202210288278 A CN202210288278 A CN 202210288278A CN 114539204 A CN114539204 A CN 114539204A
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袁增强
廖亚金
宋梦文
潘瑞远
李硕硕
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Nanjing Angkeli Medicine Technology Innovation Research Institute Co ltd
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Fujian Jinlan Houpu Biotechnology Co ltd
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Abstract

The invention discloses a blood brain barrier high permeability hexokinase inhibitor, a synthesis method and application thereof. Wherein the inhibitor has a structure shown in formula I. The compound of the invention can solve the problems of low bioavailability and difficult blood brain barrier permeation due to the large polarity of benserazide molecules and a plurality of phenolic hydroxyl groups. Therefore, the inhibitor has remarkably improved cell permeability and bioavailability, so that the inhibitor can penetrate through a blood brain barrier to achieve the effect of treating Alzheimer disease, Parkinson disease and multiple sclerosis, and has wide application prospect in the field of central nervous system diseases.

Description

Blood brain barrier high permeability hexokinase inhibitor and synthesis method and application thereof
Technical Field
The invention relates to the field of biomedicine, in particular to a blood brain barrier high permeability hexokinase inhibitor and a synthesis method and application thereof.
Background
Hexokinase (HK) is the first rate-limiting enzyme in glycolysis and has the major function of catalyzing glucose to glucose-6-phosphate, thereby providing a substrate for the production of glucose-1, 6-diphosphate. There are 4 major subtypes of HK in mammalian cells, HK1, HK2, HK3 and HK4, respectively. There are some differences in the function of each of these different subtypes of HK, such as the phosphorylation of glucose to glucose-6-phosphate mediated primarily by HK1 and HK2 in human and mouse cells. Researchers have also screened multiple inhibitors against different subtypes of HK, some inhibiting only one of HK selectively, and some inhibiting all HK simultaneously.
Pyruvate Kinase (PKM) is the second key rate-limiting enzyme in the glycolytic pathway by catalyzing the dehydrogenation of phosphoenolpyruvate to Pyruvate. Two subtypes, PKM1 and PKM2, are known in mammals. Pyruvate kinase inhibitors can act by inhibiting PKM activity and the formation of PKM multimers. At present, the PKM inhibitor has been reported in the aspect of treating tumors, and the report has not been seen in the research field of treating central nervous system diseases.
Therefore, there is still a need for an inhibitor with high blood-brain barrier permeability, which can effectively inhibit the activity of hexokinase and pyruvate kinase.
The information in this background is only for the purpose of illustrating the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art that is known to a person skilled in the art.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides an inhibitor which can inhibit the activity of hexokinase and pyruvate kinase so as to treat central nervous system diseases. Specifically, the present invention includes the following.
In a first aspect of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof,
Figure BDA0003560695110000021
wherein:
R1selected from H, Me2NCO、O(CH2CH2)2NCO、COCHX2Wherein X is halogen;
R2and R3Each independently selected from Me2NCO、O(CH2CH2)2NCO、COCHX2Or R is2And R3Together form a compound selected from CMe (OR)4) CH (OEt), CPh (OMe).
A compound of formula I according to the invention, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, preferably, R4Selected from H, substituted or unsubstituted C1-C7 alkyl.
The compound of formula I according to the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, preferably, the R1、R2And R3The groups of (a) are the same or different.
In a second aspect of the present invention, there is provided a process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, according to the first aspect, which comprises the step of reacting a compound of formula II in the presence of a catalyst and hydrogen,
Figure BDA0003560695110000022
wherein R is5And R6Each independently selected from H, substituted or unsubstituted C1-12 alkyl, and phenyl;
R7selected from H, Me2NCO、O(CH2CH2)2NCO、COCHX2Wherein X is halogen.
In a third aspect of the invention, there is provided a compound of formula II, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof,
Figure BDA0003560695110000031
wherein R is5And R6Each independently selected from H, substituted or unsubstituted C1-12 alkyl, and phenyl;
R7selected from H, Me2NCO、O(CH2CH2)2NCO、COCHX2Wherein X is halogen.
In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula I according to the first aspect, or a compound of formula II according to the third aspect, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, and optionally one or more pharmaceutically acceptable carriers and/or excipients;
preferably, the composition further comprises an active;
preferably, the active substance is a diagnostic, prophylactic and/or therapeutic agent.
In a fifth aspect of the invention, there is provided the use of a compound of formula I according to the first aspect, or a compound of formula II according to the third aspect, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition;
preferably, the disease or condition comprises a central nervous system disease;
preferably, the disease or condition comprises: alzheimer's disease, Parkinson's disease, multiple sclerosis.
According to the use of the present invention, preferably, the compound is capable of improving blood-brain barrier permeability.
According to the use of the invention, preferably, the compound is capable of modulating hexokinase and/or pyruvate kinase activity.
In a sixth aspect of the invention, there is provided a method of selectively inhibiting hexokinase and/or pyruvate kinase activity in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I according to the first aspect, or a compound of formula II according to the third aspect, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, or a pharmaceutical composition according to the fourth aspect.
The invention designs and synthesizes a plurality of compounds based on a formula I and a formula II and derivatives thereof, and surprisingly discovers that the compounds have improved blood brain barrier permeability, and repeated experiments prove that the compounds can effectively inhibit the enzyme activities of HK2 and PKM2, and the content of effective active ingredients generated by metabolism in brain tissues after oral administration is obviously higher than that of active ingredients directly administered benserazide, thereby providing great convenience for treating diseases related to the central nervous system.
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FIG. 1 shows the results of the enzymatic activity test of HK2 inhibited by benserazide and its derivatives. In A in FIG. 1, the broken lines represent DMSO, TM3-1, Benz, TM1, and TM4 in this order from top to bottom.
FIG. 2 shows the result of the PKM2 enzyme activity inhibition test of benserazide and its derivatives.
FIG. 3 shows the results of detecting the content of benserazide and its derivatives in brain tissue.
FIG. 4 shows that the benserazide derivative TM4 improves the clinical symptoms of multiple sclerosis model mice.
FIG. 5 is a mass spectrum of TM 3.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that the upper and lower limits of the range, and each intervening value therebetween, is specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control. Unless otherwise indicated, "%" is percent by weight.
Any intermediate products obtained during the synthesis of the present invention and the product of the desired compound can be determined by known means by those skilled in the art, including, but not limited to, High Performance Liquid Chromatography (HPLC), Mass Spectrometry (MS), or gas chromatography-mass spectrometry (GC-MS). And further by, for example1H、13C and various two-dimensional Nuclear Magnetic Resonance (NMR) techniques characterize the molecular structure of any compound in the preparation process.
The compounds of formula (I), compounds of formula (II), compounds of formula (III) and intermediates used in the preparation may be purified and isolated according to various well-known methods, such as crystallization or chromatography.
The compounds of the invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base functionality of the compounds of the invention with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Likewise, basic nitrogen-containing groups may be quaternized with: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long chain halides such as decyl, dodecyl, tetradecyl and octadecyl chlorides, bromides and iodides; arylalkyl halides such as benzyl bromide and phenethyl bromide and others. Thus obtaining a product that is soluble or dispersible in water or oil. Examples of acids which may be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as oxalic, maleic, succinic and citric acids.
Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the invention by reacting the carboxylic acid-containing moiety of the compounds of the invention with a suitable base, such as the hydroxide, carbonate and bicarbonate salts of a pharmaceutically acceptable metal cation, or ammonia or an organic primary, secondary or tertiary amine.
Pharmaceutically acceptable salts also include, but are not limited to, cations based on alkali or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like, as well as non-toxic quaternary ammonium and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, ethylammonium, and the like. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
The process for preparing a pharmaceutically acceptable salt of a compound of formula (I), a compound of formula (II) or a compound of formula (III) is not particularly limited, and may be prepared, for example, by one or more of the following three processes:
(i) by reacting a compound of formula (I), a compound of formula (II) or a compound of formula (III) with a desired acid or base;
(ii) removing the acid or base labile protecting group by a suitable precursor derived from a compound of formula (I), a compound of formula (II) or a compound of formula (III) or by ring opening a suitable cyclic precursor using the desired acid or base; or
(iii) By converting a compound of formula (I), a compound of formula (II) or a salt of a compound of formula (III) into another salt via reaction with a suitable acid or base or by means of a suitable ion exchange column.
The term "hydrate, solvate, isomer, complex or prodrug" as used herein has the meaning commonly understood in the art and is intended to indicate that the compounds of the present invention can exist in, for example, amorphous (amorphous), crystalline, unsolvated or solvated forms.
The term "prodrug" as used herein is a pharmacologically inert chemical derivative that is converted in vivo to an active drug molecule for therapeutic effect. Prodrugs include, but are not limited to, compounds that can be oxidized, reduced, aminated, de-aminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrated, alkylated, dealkylated, acylated, deacylated, phosphorylated, and/or dephosphorylated to yield the active compound.
The term "alkyl" generally refers to saturated branched and straight-chain alkyl groups having a carbon chain length of 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, and still more preferably 1 to 6 carbon atoms. Representative alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, (cyclohexyl) methyl, cyclopropylmethyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. The term "alkyl" excludes "cycloalkyl" unless otherwise indicated.
The term "substituted" as used herein, unless otherwise indicated, means that the group it modifies may be optionally substituted with 1 to 5 (typically 1, 2 or 3) substituents selected from: C1-C4 alkyl, carboxyl, halogen, C1-C4 alkoxy, cyano, nitro, amino, hydroxyl, aldehyde, C1-C6 acyl, hydroxymethyl, halogen substituted C1-C4 alkyl (e.g., trifluoromethyl), C1-C10 thioalkyl (e.g., pentafluorothiomethyl), C1-C10 thioalkoxy (e.g., pentafluorothiomethoxy), halogen substituted C1-C4 alkoxy (e.g., trifluoromethoxy), mercapto and C1-C4 acyl.
The term "group" refers to any portion of a compound.
The term "inhibitor" refers to an inhibitory molecule, e.g., a molecule that is used to reduce, block, prevent, delay activation, inactivate, desensitize, or down-regulate, e.g., a gene, protein, ligand, receptor, or cell. Inhibitors may also be defined as molecules that reduce, block or inhibit the activity of HK2 and PKM 2.
The term "composition" is intended to encompass a product in which the specified amounts of each of the specified ingredients are present, as well as any product which results, directly or indirectly, from combination of the specified amounts of each of the specified ingredients.
Unless otherwise indicated, configurations, element symbols, dashes, solid and dashed wedge lines, and the like in the structural formulae shown herein have the definitions customary in the art.
Formula (II)ICompound (I)
In the compounds of the formula I according to the invention, R1Selected from H, Me2NCO、O(CH2CH2)2NCO、COCHX2Wherein X is halogen; r2And R3Each independently selected from Me2NCO、O(CH2CH2)2NCO、COCHX2Or R is2And R3Together form a compound selected from CMe (OR)4) CH (OEt), CPh (OMe). Preferably, R2And R3Is not hydrogen. Also preferably, R2And R3Together forming a pentaketal-like structure.
In a particular embodiment, when R1＝O(CH2CH2)2NCO，R2,R3＝CMe(OCH3) Has the structure shown in the following formula (sometimes referred to herein as "TM 1"):
Figure BDA0003560695110000071
in a particular embodiment, when R1＝H，R2,R3＝CMe(OCH3) Has the structure shown in the following formula (sometimes referred to herein as "TM 2"):
Figure BDA0003560695110000072
in a particular embodiment, when R1＝Me2NCO，R2,R3＝CMe(OCH3) Has the structure shown in the following formula (sometimes referred to herein as "TM 3-1"):
Figure BDA0003560695110000081
in a particular embodiment, when R1＝H，R2,R3Ch (oet) has the structure shown below (sometimes referred to herein as "TM 4"):
Figure BDA0003560695110000082
in a particular embodiment, when R1＝H，R2,R3Cph (ome) has the structure shown by the formula (sometimes referred to herein as "TM 5"):
Figure BDA0003560695110000083
in a particular embodiment, when R1＝Me2NCO，R2,R3Cph (ome) has the structure shown by the formula (sometimes referred to herein as "TM 6"):
Figure BDA0003560695110000084
in a particular embodiment, when R1＝O(CH2CH2)2NCO，R2,R3Cph (ome) has the structure shown by the formula (sometimes referred to herein as "TM 7"):
Figure BDA0003560695110000085
in a particular embodiment, when R1＝COCHCl2，R2,R3Cph (ome) has the structure shown by the formula (sometimes referred to herein as "TM 8"):
Figure BDA0003560695110000091
in a particular embodiment, when R1＝COCHCl2，R2,R3＝CMe(OCH3) Has the structure shown in the following formula (sometimes referred to herein as "TM 9"):
Figure BDA0003560695110000092
in a particular embodiment, when R1＝Me2NCO，R2,R3Ch (oet) has the structure shown below (sometimes referred to herein as "TM 10"):
Figure BDA0003560695110000093
in a particular embodiment, when R1＝O(CH2CH2)2NCO，R2,R3Ch (oet) has the structure shown below (sometimes referred to herein as "TM 11"):
Figure BDA0003560695110000094
in a particular embodiment, when R1＝COCHCl2，R2,R3Ch (oet) has the structure shown below (sometimes referred to herein as "TM 12"):
Figure BDA0003560695110000095
in a particular embodiment, when R1,R2,R3＝COCHCl2Has the structure shown in the following formula (sometimes referred to herein as "TM 13"):
Figure BDA0003560695110000096
in a particular embodiment, when R1,R2,R3＝O(CH2CH2)2NCO has the structure shown below (sometimes referred to herein as "TM 14"):
Figure BDA0003560695110000101
in a particular embodiment, when R1,R2,R3＝Me2NCO is of the formulaThe structure shown (sometimes referred to herein as "TM 15"):
Figure BDA0003560695110000102
synthesis method
In order to achieve specific protection and avoid interference of residual amino and hydroxyl of serine, the invention takes 2,3, 4-trihydroxybenzaldehyde as a raw material and is designed from the beginning, and the synthetic route is shown as follows.
Figure BDA0003560695110000103
Or by the following synthetic route:
Figure BDA0003560695110000104
or by the following synthetic route:
Figure BDA0003560695110000111
wherein R is1、R2Each independently selected from H, substituted or unsubstituted C1-12 alkyl, preferably C1-4 alkyl, and phenyl;
R3selected from H, Me2NCO、O(CH2CH2)2NCO、COCHX2Wherein X is halogen.
Specifically, the synthesis method of the invention comprises the following steps:
reaction of serine methyl ester hydrochloride with hydrazine hydrate in an alcohol solvent affords amine-transesterified compound IM1 serine hydrazide hydrochloride. The reaction time is 12-72h, preferably 24-72 h.
In an inert solvent, the compound S4 and the 3, 4-position phenolic hydroxyl group on the S3 are subjected to ketal formation under the action of an acid as a catalyst to form a compound IM3, and then the 2-position phenolic hydroxyl group in the compound IM3 is subjected to esterification reaction with acyl chloride or an analogue thereof to obtain a compound IM4 with protected 2,3, 4-position hydroxyl groups.
The compound IM4 and IM1 are subjected to condensation reaction in an alcohol solvent, so as to prepare the compound shown in the formula II.
The compound of the formula II is hydrogenated under the action of a catalyst and hydrogen, so that the benserazide derivative with protected three hydroxyl groups at the 2,3 and 4 positions is prepared.
In further embodiments, the synthetic methods of the invention comprise:
the compound IM1 and IM3 are subjected to condensation reaction in an alcohol solvent to form a compound TM3 ', and the compound TM 3' is subjected to hydrogenation reaction under the action of a catalyst and hydrogen, so that the benserazide derivative with protected hydroxyl at the 3, 4-position is prepared.
In further embodiments, the synthetic methods of the invention comprise:
the phenolic hydroxyl of the compound S3 forms ester with acyl chloride or analogues thereof, and reacts with the compound IM1 in alcohol solvent to form the benserazide derivative TM 2' with protected three-position hydroxyl.
In the present invention, the acid chloride or the like means a substituted acid chloride, and specific examples thereof include, but are not limited to, 4-morpholino acid chloride, dimethylcarbamoyl chloride, and the like.
In the present invention, the acid catalyst is preferably p-toluenesulfonic acid or a hydrate thereof, and the reaction temperature of trihydroxybenzaldehyde in the solvent is 80-130 ℃, preferably 100-120 ℃.
In the present invention, the alcohol solvent is preferably a lower alcohol solvent. Examples of alcohol solvents include, but are not limited to: methanol, ethanol, n-propanol, 2-butanol, 2-propanol, 2-butanol and n-butanol.
In the invention, the intermediate product is reacted by carbon-nitrogen double bond to generate single bond by catalyst, the catalyst is palladium-carbon, and the ratio of the intermediate product to the catalyst is 1:0.05-1, preferably 1: 0.08-0.3. The reaction time is 2-24h, preferably 2-12 h.
In the process of the present invention, the various starting materials for the reaction are those which are accessible to the skilled worker on the basis of their prior knowledge, or which can be prepared by methods known from the literature or which are commercially available. The intermediates, starting materials, reagents, reaction conditions and the like used in the reaction scheme may be appropriately changed according to the knowledge of those skilled in the art. Alternatively, other derivatives of formula I, formula II or formula III not specifically recited herein may also be synthesized by one skilled in the art according to the methods described herein.
It will be appreciated by those skilled in the art that other steps or operations, such as purification or alcoholic solution washing steps to increase yield, and further optimization and/or improvement of the process of the present invention, may be included before, after, or between the steps of the preparation process of the present invention, as long as the objectives of the present invention are achieved.
Pharmaceutical composition
The invention provides a composition comprising a compound of formula I, or a compound of formula II, or a compound of formula III, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, as described herein, and optionally one or more pharmaceutically acceptable carriers and/or excipients;
optionally, the composition further comprises an active substance, preferably the active substance is a diagnostic, prophylactic and/or therapeutic agent. Examples of therapeutic agents include, but are not limited to, hexokinase and/or pyruvate kinase inhibitors.
The pharmaceutical excipients are not particularly limited, and can be used in the pharmaceutical composition of the present invention as long as they can be added to form an effective, stable and safe formulation. The pharmaceutical composition of the present invention, in the form of a pharmaceutical preparation, may be any pharmaceutically acceptable dosage form including: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, pills, powders, ointments, pellets, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches. The formulations of the present invention, preferably oral dosage forms, are: capsule, tablet, oral liquid, granule, pill, powder, pellet, and unguent.
The pharmaceutical composition of the present invention, its preparation for oral administration, may contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and the tablet may be coated if necessary.
Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous carriers (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerin, propylene glycol or ethyl alcohol; preservatives, for example p-hydroxybenzyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
For injections, liquid unit dosage forms are prepared containing the pharmaceutical compositions of the present invention and a sterile carrier. Depending on the carrier and concentration, the pharmaceutical composition may be suspended or dissolved. Solutions are generally prepared by dissolving the active substance in a carrier, filter sterilising before filling it into a suitable vial or ampoule and then sealing. Adjuvants such as a local anaesthetic, preservatives and buffering agents may also be dissolved in the vehicle. To improve its stability, the pharmaceutical composition can be frozen after filling into vials and the water removed under vacuum.
The pharmaceutical composition of the present invention, when being prepared into a medicament, can be optionally added with a suitable pharmaceutically acceptable carrier selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, EDTA disodium, calcium sodium EDTA, monovalent alkali metal carbonates, acetates, phosphates or aqueous solutions thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and derivatives thereof, alginates, gelatin, polyvinylpyrrolidone, glycerol, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid-based materials, kaolin, talc, calcium stearate, magnesium stearate, and the like.
Use of
The invention provides a plurality of medical applications of the compound of formula I, the compound of formula II, the compound of formula III, or the pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, or the pharmaceutical composition.
As used herein, unless otherwise indicated, the terms "subject" and "patient" are used interchangeably herein to refer to any animal that may require the pharmaceutical compositions or medicaments described herein for treatment and/or prevention. Subjects and patients thus include, but are not limited to: primates (including humans), canines, felines, murines, and other mammalian subjects. Preferably, the patient is a human.
In the present invention, the term "treatment" refers to both therapeutic treatment and prophylactic or preventative measures, the object of which is to prevent or slow down (lessen) the progression of an undesired physiological change or disorder, such as a disease of the central nervous system. Beneficial or desired clinical results include, but are not limited to, results, whether detectable or undetectable, including alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total). "treatment" also means an extended life span compared to the life span expected when not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those susceptible to the condition or disorder, or those in need of prevention of the condition or disorder.
The term "preventing" as used herein includes avoiding the occurrence of a disease, condition, or disorder and/or delaying the onset of a disease, condition, or disorder. Avoidance of occurrence, delay of onset, or reduced risk of any statistically significant (p ≦ 0.05) as measured by controlled clinical trials may be considered prevention of a disease, disorder, or disorder. Subjects suitable for prophylaxis include those at increased risk of a disease, condition or disorder as identified by genetic or biochemical markers.
The term "effective amount" as used herein means an amount of a drug or pharmaceutical agent that elicits the biological or pharmacological response in a tissue, system, animal or human that is being sought, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means an amount that causes improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a decrease in the rate of progression of a disease or condition, as compared to a corresponding subject not receiving that amount. The term also includes within its scope an amount effective to enhance normal physiological function. In general, an effective amount herein will vary depending on various factors, such as the given drug or compound, pharmaceutical formulation, route of administration, type of disease or disorder, subject being treated, and the like, but can nevertheless be routinely determined by one of skill in the art. An effective amount of a compound of the present invention or a pharmaceutical composition thereof can be easily determined by a person skilled in the art through conventional methods known in the art. In general, the dosage of a compound of formula I, or a compound of formula II, or a compound of formula III, of the present invention for use in a mammal, particularly a human, can be from 0.001 to 1000mg/kg body weight/day, for example from 0.01 to 100mg/kg body weight/day, from 0.01 to 10mg/kg body weight/day, respectively.
The terms "administration" and "administering" are used interchangeably to refer to a compound of the invention, a pharmaceutical composition comprising the same, which is in contact with a subject, cell, tissue, organ or biological fluid when applied to the subject, cell, tissue, organ or biological fluid, for example. In the case of cells, administration includes contacting a compound of the invention, a pharmaceutical composition comprising the same, with a cell (e.g., in vitro or ex vivo) and contacting a compound of the invention, a pharmaceutical composition comprising the same, with a fluid, wherein the fluid is in contact with the cell.
In the present invention, the disease, disorder or disorder may be a disease, disorder or disorder related to the immune system, cardiovascular system, endocrine system, gastrointestinal tract, renal system, hepatic system, metabolic system, respiratory system, central nervous system, or may be cancer or other malignancy.
According to the invention, the compound can improve the blood brain barrier permeability, and solves the problems that benserazide is large in molecular polarity, has a plurality of phenolic hydroxyl groups, is low in bioavailability and is difficult to permeate the blood brain barrier. The compound of the invention has obviously improved cell permeability and bioavailability, thereby achieving the effect of treating Alzheimer disease, Parkinson disease and multiple sclerosis by penetrating blood brain barrier.
The disease, condition or disorder is responsive to inhibition of hexokinase and/or pyruvate kinase activity. The term "hexokinase and/or pyruvate kinase activity inhibition" refers to a complete or partial reduction of the enzymatic activity of hexokinase and/or pyruvate kinase.
Example 1
The synthetic route of this example is as follows:
Figure BDA0003560695110000161
preparation of compound IM 1: reacting serine methyl hydrochloride with hydrazine hydrate in methanol solvent for 2 days to obtain a compound IM1,1H NMR(400MHz,D2O)δ3.83(dt,J＝5.6,4.1Hz,1H),3.74–3.73(m,1H),3.71–3.70(m,1H),3.68(d,J＝0.6Hz,1H),3.67(d,J＝0.6Hz,1H),3.65(d,J＝0.6Hz,1H),3.64(d,J＝0.6Hz,1H).
preparation of compound IM 2: trimethyl orthoacetate (80mmol) as solvent, p-toluenesulfonic acidMonohydrate (4mmol) as a catalyst, 2,3, 4-trihydroxybenzaldehyde (40mmol) and trimethyl orthoacetate were refluxed for 2 days in a round-bottomed flask at 110 ℃ to precipitate a solid, the product was suction-filtered and washed with the filtrate to give a white solid, 3.18g was weighed, the yield was 38%, compound IM2 was obtained,1H NMR(400MHz,CHLOROFORM-D)δ11.03–10.89(m,1H),9.80–9.68(m,1H),7.48–7.05(m,1H),6.64–6.43(m,1H),3.48–2.91(m,3H),1.89–1.76(m,3H).
compound IM3 was prepared by weighing 4.2g (20mmol) of IM2 into a 100ml round bottom flask, adding 2.02g of triethylamine solution as an acid-binding agent in one equivalent, adding DCM20ml, reacting in an ice bath, adding 99g of 4-morpholinocarbonyl chloride in one equivalent, dropwise adding, esterifying with IM2, dropping off 15min, removing the ice-water bath, continuing to react at room temperature for 3 days, stopping the reaction, adding DCM20ml in the same volume, extracting with water for three times, drying with anhydrous sodium sulfate overnight, monitoring by TLC plates that a small amount of IM2 did not react completely, determining by TLC that the eluent ratio of the column separation was PE: ETOAC 5:1, performing dry sampling, separating the product IM3 by column chromatography, collecting 13-16 bottles of column-eluted liquid, rotary steaming, weighing 4.6g, and obtaining yield 71.2%. The amount of the compound IM3 was,1H NMR(400MHz,CHLOROFORM-D)δ9.90(s,1H),7.51–7.30(m,1H),6.85–6.74(m,1H),3.74(ddd,J＝49.0,28.5,6.3Hz,8H),3.35–3.31(m,3H),1.88–1.82(m,3H).
preparation of TM 3': 4.2g of the column-passed product IM3 was put into a flask and condensed with 2.02g of serine hydrazide hydrochloride in a methanol solution (20ml), and the mixture was stirred at room temperature for 2 days, whereby the reaction was changed from a pale yellow transparent solution to a white turbid solution with time, and a white solid was precipitated. And (3) post-reaction treatment: filtering, washing with methanol, recrystallizing the filtered mother liquor, weighing the solid 2.0g, the yield is 34.48%, obtaining the compound TM 3',1H NMR(400MHz,DMSO-D6)δ12.15–11.87(m,1H),8.28(dd,J＝20.3,8.1Hz,2H),8.08(d,J＝15.8Hz,1H),7.48(dd,J＝16.8,8.4Hz,1H),6.96(d,J＝8.4Hz,1H),5.60–5.45(m,1H),3.79–3.55(m,8H),3.37(d,J＝30.1Hz,2H),3.32(s,1H),3.21(d,J＝8.0Hz,3H),1.86–1.68(m,3H).
preparation of TM 3: adding 1g of TM 3' and dissolving with 50ml of methanol, reacting with hydrogen for 5 hours under the condition of 5 atmospheric pressures and palladium carbon (0.1 time) as a catalyst, carrying out suction filtration on reaction mother liquor by using kieselguhr, removing the palladium carbon, carrying out rotary evaporation, pulping by using a small amount of ethyl acetate, and carrying out suction filtration to obtain light yellow powder, weighing 820mg, wherein the yield is 82%, and the TM3 mass spectrum is shown in figure 5.
Example 2
The synthetic route of this example is as follows:
Figure BDA0003560695110000171
preparation of compound IM 1: reacting serine methyl hydrochloride with hydrazine hydrate in methanol solvent for 2 days to obtain a compound IM1,1H NMR(400MHz,D2O)δ3.83(dt,J＝5.6,4.1Hz,1H),3.74–3.73(m,1H),3.71–3.70(m,1H),3.68(d,J＝0.6Hz,1H),3.67(d,J＝0.6Hz,1H),3.65(d,J＝0.6Hz,1H),3.64(d,J＝0.6Hz,1H).
preparation of compound IM 2: trimethyl orthoacetate is used as a solvent, paratoluenesulfonic acid monohydrate (4mmol) is used as a catalyst, 2,3, 4-trihydroxybenzaldehyde (40mmol) and trimethyl orthoacetate are subjected to reflux reaction in a round-bottom flask at 110 ℃ for 2 days, a solid is precipitated, the product is filtered by suction and washed by using filtrate to obtain a white solid, 3.18g is weighed, the yield is 38 percent, and a compound IM2 is obtained,1H NMR(400MHz,CHLOROFORM-D)δ11.03–10.89(m,1H),9.80–9.68(m,1H),7.48–7.05(m,1H),6.64–6.43(m,1H),3.48–2.91(m,3H),1.89–1.76(m,3H).
weighing 4.2g (20mmol) of IM2, adding 2.02g of triethylamine solution as an acid-binding agent with one equivalent weight into a 100ml round-bottom flask, adding 20.24 g of DCM, placing the mixture on an ice bath for reaction, adding 2.15g of dimethylcarbamoyl chloride with one equivalent weight, dropwise adding the dimethylcarbamoyl chloride, carrying out esterification reaction with the IM2, finishing the dropping for 15min, removing the ice water bath, continuing the reaction for 3 days at room temperature, stopping the reaction, adding 20ml as the same volume as the DCM, extracting the mixture for three times by using water, drying the mixture overnight by using anhydrous sodium sulfate, monitoring by a TLC point plate to find that a small amount of IM2 is not completely reacted, determining by TLC that the eluent ratio of the separation of the column is PE: ETOAC 5:1, carrying out the dry sampling to obtain the product IM3, collecting 8-10 bottles of eluent passing through the column, carrying out rotary evaporation and weighing 1g, and obtaining the yield of 17.8%.
Preparation of TM 3-1': 1g of the column-passed product IM3-2 and 0.56g of serine hydrazide hydrochloride were put into a methanol solution (20ml) and condensed with stirring at room temperature for 3 days, and the reaction was changed from a pale yellow transparent solution to a white turbid solution with time to precipitate a white solid. And (3) post-reaction treatment: filtration, washing with methanol, recrystallization of the filtered mother liquor, weighing 1.06g of solid, gave a yield of 81.5%.1H NMR(500MHz,DMSO)δ11.79–11.38(m,1H),8.20(s,1H),7.20–7.11(m,1H),6.76(dd,J＝8.6,3.3Hz,1H),5.57(d,J＝30.8Hz,1H),4.49(d,J＝31.1Hz,1H),3.97–3.74(m,3H),3.35(d,J＝50.1Hz,3H)3.07(dd,J＝23.3,7.9Hz,3H),2.91(d,J＝8.8Hz,3H),1.11(m,2H).
Example 3
The synthetic route of this example is as follows:
Figure BDA0003560695110000191
preparation of compound IM 1: reacting serine methyl hydrochloride with hydrazine hydrate in methanol solvent for 2 days to obtain a compound IM1,1H NMR(400MHz,D2O)δ3.83(dt,J＝5.6,4.1Hz,1H),3.74–3.73(m,1H),3.71–3.70(m,1H),3.68(d,J＝0.6Hz,1H),3.67(d,J＝0.6Hz,1H),3.65(d,J＝0.6Hz,1H),3.64(d,J＝0.6Hz,1H).
preparation of compound IM 4: triethyl orthoformate (80mmol) is poured into 50ml toluene, 0.1 time of p-toluenesulfonic acid monohydrate is weighed as a catalyst and refluxed for 30min at 110 ℃, 2,3,4 trihydroxybenzaldehyde (40mmol) is added into a reaction bottle and continuously refluxed for 19h in inert gas, suction filtration is carried out, the supernatant is subjected to rotary evaporation and sample mixing, column separation (PE: EtoAc ═ 30:1) is carried out to obtain white solid, and the white solid is washed, dried and weighed to obtain 3.1g, and the yield is 37%. To obtain the compound IM4, namely,1H NMR(600MHz,CDCl3)δ11.03–10.92(m,1H),9.73(d,J＝22.0Hz,1H),7.21–7.17(m,1H),6.99(s,1H),6.73–6.62(m,1H),3.82–3.72(m,2H),1.47–1.06(m,3H).
preparation of compound TM 4': 2.1g of (10mmol) IM4 was condensed with 1.56g serine hydrazide hydrochloride in methanol solution (20ml), and stirred at room temperature for 1 day, the reaction changed from a pale yellow transparent solution to a white turbid solution with time, and a white solid precipitated. And (3) post-reaction treatment: filtering, washing with methanol, recrystallizing the filtered mother liquor, weighing 0.9g of solid, the yield being 30.4%, obtaining TM 4',1H NMR(600MHz,DMSO)δ8.53–8.04(m,1H),7.32(t,J＝19.5Hz,1H),7.23–7.00(m,1H),6.65(dd,J＝28.0,8.3Hz,1H),5.58(dd,J＝26.9,21.9Hz,1H),4.07–3.51(m,1H),3.33(s,2H),1.39–0.94(m,3H).
example 4
This example is an experiment in which benserazide derivatives TM1, TM3-1 and TM4 inhibited the activity of HK2 enzyme.
Cultured HEK293T cells (10cm dish) were digested and centrifuged to collect the cells, and then inhibitory effect of benserazide and its derivatives on the enzymatic activity of HK2 was examined using HK2 enzymatic activity assay kit (cat No. MAK091, Sigma). The method comprises the following steps: firstly, cells are lysed by HK Assay buffer in a 1.3ml kit, then the cells are centrifuged for 10min at 13000Xg and 4 ℃, and supernatant is taken and subpackaged into 6 centrifugal tubes of 1.5 ml; secondly, respectively adding DMSO, benserazide and benserazide derivatives TM1, TM3-1 and TM4 into 6 centrifuge tubes, wherein the final concentration is 200 mu M, and uniformly mixing; thirdly, preparing 800 mul of enzyme activity detection reaction system according to the following table, adding the enzyme activity detection reaction system into a white 96-hole plate, wherein each hole is 50 mul, and simultaneously arranging 3 blank holes;
Figure BDA0003560695110000201
and fourthly, adding the cell lysate added with the benserazide and the derivative thereof into the holes of a 96-hole white board added with an enzyme activity detection reaction system according to three repeated holes for each treatment, shaking and uniformly mixing, immediately reading the CD450 absorbance once by using an enzyme-labeling instrument, and detecting once every 2 minutes until the OD450 value of the DMSO treatment group reaches about 1.
As shown in FIG. 1, firstly, the enzyme activity curve shows that benserazide and its derivatives have inhibitory effect on the enzyme activity of HK2, wherein TM4 can completely inhibit the enzyme activity of HK2 at a concentration of 200. mu.M (FIG. 1A); in addition, the effect of TM1 and TM4 at the same concentration in inhibiting the enzymatic activity of HK2 was due to benserazide (fig. 1A and B).
Example 5
This example is an experiment in which benserazide derivatives TM1, TM3-1 and TM4 inhibited PKM2 enzyme activity.
Cultured HEK293T cells (10cm dish) were digested and centrifuged to collect the cells, and then inhibitory effect of benserazide and its derivatives on the enzymatic activity of HK2 was detected using PKM2 enzymatic activity detection kit (cat No. MAK072, Sigma). The method comprises the following steps: firstly, cells are lysed by PKM Assay buffer in a 1.3ml kit, then the cells are centrifuged for 10min at 15000xg 4 ℃, and supernatant is taken and subpackaged into 6 1.5ml centrifuge tubes; secondly, respectively adding DMSO, benserazide and benserazide derivatives TM1, TM3-1 and TM4 into 6 centrifuge tubes, wherein the final concentration is 200 mu M, and uniformly mixing; thirdly, preparing 800 mul of enzyme activity detection reaction system according to the following table, adding the enzyme activity detection reaction system into a white 96-hole plate, wherein each hole is 50 mul, and simultaneously arranging 3 blank holes;
Figure BDA0003560695110000211
and fourthly, adding the cell lysate added with the benserazide and the derivative thereof into the holes of a 96-hole white board added with an enzyme activity detection reaction system according to three repeated holes for each treatment, shaking and uniformly mixing the cells, immediately reading the CD570 absorbance once by using an enzyme-labeling instrument, and detecting the cells once every 2 minutes until the OD570 value of the DMSO treatment group reaches about 1.
As shown in FIG. 2, firstly, the enzyme activity curve shows that both benserazide and its derivatives have inhibitory effect on the enzyme activity of PKM2, wherein the effect of TM4 inhibiting the enzyme activity of PKM2 at the same concentration is due to benserazide (FIG. 2).
Example 6
This example shows the measurement of the drug concentration in brain tissue after oral administration of benserazide derivatives TM1, TM3-1 and TM 4.
30 wild type c57 mice, 10 weeks old, were randomly assigned to 5 groups of 6 mice: solvent group (vehicle), benserazide group (Benz), benserazide derivative TM1 group, benserazide derivative TM3-1 group and benserazide derivative TM4 group. Each mouse was gavaged with solvent, benserazide and its derivatives at a dose of 100mg/kg in groups. Taking 3 mice per group for killing after 2h administration, taking brain tissue after heart perfusion, grinding the brain tissue by a grinder after weighing, extracting micromolecule compounds in the tissue by perchloric acid, and detecting the benserazide content in the brain tissue by liquid chromatography analysis. The remaining 3 mice per group were sacrificed 24h after dosing and brain tissue was removed for testing.
The detection method comprises the following steps: HPLC-MS measurement of the content of benserazide derivatives TM1, TM3-1 and TM4 in brain tissue.
Firstly, a preparation method of a matrix-containing sample comprises the following steps: taking 100 mu L of mouse brain tissue homogenate, placing the homogenate in 800 mu L of methanol, vortexing for 5min, centrifuging for 5min at 14000rpm, transferring the supernatant into a new EP tube, and volatilizing the solvent in a concentrator at 40 ℃. Add 700ng/mL standard 20. mu.L, add 60. mu.L methanol/water (70: 30). Vortex for 2min, centrifuge at 14000rpm for 5min, and sample the supernatant.
② sample without matrix: clean EP tubes were taken, standard was added as above, and 60. mu.L of methanol/water (70:30) was added for the same treatment as above.
Measuring a standard curve: preparing standard solutions with concentrations of 100, 250, 500, 1000, 2500 and 5000ng/mL with methanol-water (70:30), weighing 100 μ L of brain homogenate (1:4) to 1.5mL of EP tube, adding 10 μ L of the standard with the above concentrations, adding 800 μ L of methanol, shaking for 5min, and centrifuging at 14000rpm for 10 min. Transferring supernatant to a new EP tube, centrifuging at 40 deg.C to concentrate and volatilize solvent, adding 100 μ L70% methanol into residue, vortexing for 2min, centrifuging at 14000rpm for 5min, removing supernatant and injecting sample.
Fourthly, measuring the content of benserazide derivatives TM1, TM3-1 and TM4 in the sample: the whole mouse brain was taken out and 0.9% sodium chloride solution was added in a proportion of 1.5 mL. g-1 to prepare a homogenate of mouse brain tissue. Centrifuging at 13000Xg for 7min at 4 deg.C, sucking 200 μ L supernatant, adding 800 μ L methanol, shaking for 60s, centrifuging at 10000 Xg for 10min at 4 deg.C, sucking 750 μ L supernatant, rotary steaming, adding 50 μ L methanol for redissolving, shaking for 60s, centrifuging at 10000 Xg at 4 deg.C for 10min, and collecting 20 μ L supernatant, and analyzing by LC-MS/MS.
As shown in FIG. 3, the content of benserazide in brain tissue was significantly increased after 2h administration, and the content of benserazide in brain tissue of mice administered with TM1, TM3-1 and TM4 was significantly higher than that of the benserazide administered directly, wherein TM4 had the strongest blood-brain barrier permeability. After 24h of administration, the content of benserazide in brain tissue of mice administered with TM4 was still significantly higher than that of the benserazide group. The results show that the designed and synthesized benserazide derivative has better blood brain barrier permeability, wherein the derivative TM4 has the best effect.
Example 7
This example shows the effect of orally administering the benserazide derivative TM4 in the treatment of multiple sclerosis.
The experimental steps are as follows: 40 female mice (strain C57, age 6-8 weeks, purchased from Witonglihua) weighing approximately 16g were randomly divided into 2 groups of 20 mice each. Preparing an EAE model: one group is a non-model group, and the other group is a model group. The preparation method of the model comprises the following steps: mice were injected subcutaneously with 100 μ l of emulsified and homogenized MOG35-55Polypeptide and Freund's complete adjuvant (MOG)35-55Final polypeptide concentration was 2mg/ml), and pertussis toxin was injected once each day and 48 h. Clinical scoring was performed daily, with scoring criteria: 1 minute, tail paralysis; 2 minutes, paralysis of the tail and single hind limb; 3 minutes, paralysis of the tail and both hind limbs; quadriplegia with paralysis of the tail and hind limbs, accompanied by flexion of the spine; mice died in 5 points. ③ administration: according to the literature, mice develop disease sequentially from day 10 after molding, so in this example, administration is started from day 7 after molding. The non-model group and the model group were randomly divided into two groups, 4 mice in total, namely: solvent control group, simple administration group, solvent model group and administration model group. The administration mode is that benserazide derivative TM4 is firstly prepared into 100mg/ml by DMSO, then PEG300 with 4 times DMSO volume is added and mixed evenly, then Tween-80 with 0.5 time DMSO volume is added and mixed evenly, finally physiological saline with 4.5 times volume is added and mixed evenly, and then the mixture is administered by intragastric administration with the administration dose of 100 mg/kg. The solvent control group and the solvent model group were each gavaged with an equal volume of solvent every day. Daily clinical scores were recorded continuously until day 30 post-molding.
The results are shown in fig. 4, in which neither the solvent control group nor the drug-only group had developed disease, and the clinical score was always 0. The onset of the vehicle and administration models continued at 9 days and peaked at 17 days after onset. Administration model group clinical scores were significantly lower than the solvent model group and recovery rates were significantly faster than the solvent model group after administration of the benserazide derivative TM 4. These results indicate that the benserazide derivative TM4 can significantly improve clinical symptoms in EAE model mice.
While the present invention has been described with reference to exemplary embodiments, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. Various modifications or changes may be made to the exemplary embodiments without departing from the scope or spirit of the present invention. The scope of the invention should be accorded the broadest interpretation so as to encompass all modifications and equivalent structures and functions.

Claims (10)

1. A compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof,
Figure FDA0003560695100000011
wherein:
R1selected from H, Me2NCO、O(CH2CH2)2NCO、COCHX2Wherein X is halogen;
R2and R3Each independently selected from Me2NCO、O(CH2CH2)2NCO、COCHX2Or R is2And R3Together form a compound selected from CMe (OR)4) CH (OEt), CPh (OMe).
2. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, wherein R is4Selected from H, substituted or unsubstituted C1-C7 alkyl.
3. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, wherein R is1、R2And R3The groups of (a) are the same or different.
4. A process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, according to any one of claims 1 to 3, comprising the step of reacting a compound of formula II or III in the presence of a catalyst and hydrogen,
Figure FDA0003560695100000012
wherein R is5And R6Each independently selected from H, substituted or unsubstituted C1-12 alkyl, and phenyl;
R7selected from H, Me2NCO、O(CH2CH2)2NCO、COCHX2Wherein X is halogen.
5. A compound of formula II, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof,
Figure FDA0003560695100000021
wherein R is5And R6Each independently selected from H, substituted or unsubstituted C1-12 alkyl, and phenyl;
R7selected from H, Me2NCO、O(CH2CH2)2NCO、COCHX2Wherein X is halogen.
6. A pharmaceutical composition, characterized in that it comprises a compound of formula I according to any one of claims 1 to 3, or a compound of formula II according to claim 5, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, and optionally one or more pharmaceutically acceptable carriers and/or excipients;
preferably, the composition further comprises an active;
preferably, the active substance comprises a diagnostic, prophylactic and/or therapeutic agent.
7. Use of a compound of formula I according to any one of claims 1-3, or a compound of formula II according to claim 5, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, in the manufacture of a medicament for the treatment and/or prevention of a disease or disorder;
preferably, the disease or condition comprises a central nervous system disease;
preferably, the disease or condition comprises: alzheimer's disease, Parkinson's disease, multiple sclerosis.
8. Use according to claim 7, wherein said compound is capable of increasing blood-brain barrier permeability.
9. Use according to claim 7, wherein the compound is capable of modulating hexokinase and/or pyruvate kinase activity.
10. A method of selectively inhibiting hexokinase and/or pyruvate kinase activity in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I according to any one of claims 1-3, or a compound of formula II according to claim 5, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, complex or prodrug thereof, or a pharmaceutical composition of claim 6.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms
WO2013055922A1 (en) * 2011-10-11 2013-04-18 Vaccinex, Inc. Use of semaphorin-4d binding molecules for modulation of blood brain barrier permeability
CN108069946A (en) * 2016-11-08 2018-05-25 威尚（上海）生物医药有限公司 With the substituted quinazoline compound through blood-brain barrier ability

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090163545A1 (en) * 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms
WO2013055922A1 (en) * 2011-10-11 2013-04-18 Vaccinex, Inc. Use of semaphorin-4d binding molecules for modulation of blood brain barrier permeability
CN108069946A (en) * 2016-11-08 2018-05-25 威尚（上海）生物医药有限公司 With the substituted quinazoline compound through blood-brain barrier ability

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