CN114957296A - Novel Alzheimer disease detection probe and biological application thereof - Google Patents
Novel Alzheimer disease detection probe and biological application thereof Download PDFInfo
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- CN114957296A CN114957296A CN202110215279.5A CN202110215279A CN114957296A CN 114957296 A CN114957296 A CN 114957296A CN 202110215279 A CN202110215279 A CN 202110215279A CN 114957296 A CN114957296 A CN 114957296A
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Abstract
The invention provides a novel Alzheimer disease detection probe and biological application thereof, and particularly provides a compound shown as the following formula (I), or pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, hydrate or solvate thereof. The compound of the present invention can be used for treating or preventing the nervous system diseases related to acetylcholinesterase, or can be used as an imaging probe for diagnosing the nervous system diseases related to acetylcholinesterase.
Description
Technical Field
The invention belongs to the field of integration of biomolecule detection, imaging and diagnosis and treatment, and particularly relates to a novel Alzheimer disease detection probe based on targeting Abeta and AChE and biological application thereof.
Background
Alzheimer's Disease (AD) is a complex degenerative Disease of the central nervous system, which is clinically manifested as cognitive impairment, disorientation, gradually declining memory, finally loss of thinking ability, motor ability, inability to take care of oneself in life, etc. Among the causes of death in the elderly, AD has become the fourth killer following cardiovascular, tumor and stroke. It is estimated that over 3500 million people worldwide currently suffer from this disease and this figure is expected to double in 2030 and two in 2050, reaching 1.15 million, and the treatment and care of AD has become a major economic burden to society.
The main pathological features of AD patients are the accumulation of β -amyloid (a β) into senile plaques, abnormal accumulation of intracellular Tau protein forming Neuronal Fibrillary Tangles (NFTs) and neuronal death. In recent years, the pathogenesis of AD has been mainly focused on the Α β toxicity hypothesis, which dominates, the cholinergic neuronal hypothesis and the Tau protein hypothesis, which show that the neurotoxicity of Α β aggregates to form amyloid fibrils, and is associated with some proteins including apolipoprotein e (apoe), acetylcholinesterase (AChE), α 1-anticoagulated lactonase and heparin sulfate proteoglycan. Among them, AChE plays a key role in cholinergic transmission in the central nervous system of mammals and may also participate in non-cholinergic mechanisms. Studies have reported that the majority of cortical AChE activity in the brain of AD patients is primarily associated with the amyloid core of senile plaques, rather than the neuritic component found peripherally. AChE directly promotes aggregation of a β peptides to form amyloid fibrils and complexes with small a β peptide fragments, consistent with co-localization sites of a β deposits in the brain of AD patients.
The biomarker is an indicator factor which can be used for objectively determining and evaluating normal physiological or pathological processes, and is an important basis for realizing early diagnosis of AD, disease course monitoring, intervention treatment, curative effect judgment and the like. With the development of genomics and imaging technologies, people have made great progress in diagnostic technologies and biomarkers of AD. In the past decades, people have gradually established a series of body fluid markers (such as cerebrospinal fluid, blood, urine, etc.) and nerve imaging probes (such as brain structure images, functional images, molecular images, etc.). In particular, the development of neuroimaging techniques such as Positron Emission Tomography (PET), single photon emission tomography (SPECT), etc. has made it possible to detect changes in the brain regions resulting from normal aging and early AD in vivo. In combination with positron emitters such as 18F and 11C, PET is sensitive to both mild early brain changes and disease progression. 18F-fluorodeoxyglucose (FDG-PET) imaging probes have been used for imaging of brain glucose metabolism for the course tracking of asymptomatic AD and the detection of preventive therapies. To date, 3A β imaging probes have been approved by the FDA for the diagnosis of AD, such as Florbetapir (18F AV-45), 18F-Flutemetamol, Florbetaben (18F-BAY 94-9172). In addition, some Tau protein PET imaging probes have been developed greatly, such as 18F-THK523, 18F-THK5117, 18F-THK5105, 18F-THK5351, 18F-AV1451(T807) and 11C-PBB3, and the probes provide valuable information for understanding the role of Tau protein in early stage of AD onset. Although these probes clearly reflect the progress of the disease course of AD to some extent, exhibit good diagnostic value and are incorporated into new diagnostic criteria for AD and are used for the diagnosis of clinical AD patients, they have respective disadvantages such as false positive in many patients who are not demented. Therefore, there is a great need for the development of novel, more sensitive diagnostic or integrated diagnostic probes for the diagnosis and treatment of AD.
Disclosure of Invention
Based on the biological characteristics of Abeta peptide and AChE, the invention provides a novel AD detection probe molecule targeting Abeta and AChE, and finds a small molecular probe with high-efficiency and high-selectivity Abeta binding capacity and inhibitory cholinesterase double-target spots, so that different target spots generate a synergistic or complementary effect, a linkage effect is exerted, and the diagnosis or diagnosis and treatment integration of AD is realized.
In a first aspect of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, hydrate or solvate thereof,
wherein the content of the first and second substances,
ar is selected from the group consisting of: substituted or unsubstituted phenyl, or substituted or unsubstituted 5-7 membered aromatic heterocycle; wherein the 5-to 7-membered aromatic heterocyclic ring contains 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen;
x can be CH or N; and when X is CH, the connecting bridge can be positioned on X (H on CH is replaced by the connecting bridge);
the connecting bridge (Linker) can be selected from the following structural fragments:
wherein Y is selected from the group consisting of: - (CH) 2 ) n -、-Ph(CH 2 ) n -、-O-、-Ph(CH 2 ) n -、-NR-、-S-；
p is selected from the group consisting of: 1. 2,3, 4, 5 or 6;
p2 is selected from the group consisting of: 0.1, 2 or 3;
r is selected from the group consisting of: H. substituted or unsubstituted C 1 -C 4 An alkyl group;
wherein:
m is 0, 1,2 or 3;
n is selected from the group consisting of: 0.1, 2 or 3;
x is selected from the group consisting of: (CH) 2 ) p CO or SO 2 Wherein p is 0, 1,2 or 3; is preferably (CH) 2 ) p Or CO, p is preferably 1 or 2;
R 1 selected from the group consisting of: halogen, C1-C6 straight or branched chain alkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxy, mercapto, C2-C6 acyl, sulfonyl, aminosulfonyl, and C2-C6 sulfonyl;
R 3 selected from the group consisting of: substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 3 -C 10 Cycloalkenyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6 -C 12 An aryl group; the R is 1 Wherein the substituent is selected from halogen and C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkoxycarbonyl, halogen-substituted C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, mercapto, sulfonyl, C 6 - C 10 1,2,3, 4 or 5 substituents in aryl and 3-12 membered heterocyclyl which may be the same or different; or at said C 6 -C 12 Two adjacent substituents on the aryl group and carbon atoms on the adjacent aromatic ring form C 3 -C 7 Cycloalkyl radical, C 3 -C 7 Cycloalkenyl or 3-7 membered heterocyclyl; each heterocyclic group independently contains 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen;
R 4 is one or more groups selected from the group consisting of: hydrogen, halogen, C 1 -C 6 Alkyl, C substituted by halogen 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 An alkoxy group;
R 5 and R 6 Each independently selected fromGroup (2): hydrogen, carboxyl, C 1 -C 4 Alkoxycarbonyl and C 1 -C 4 An alkyl group; or R 5 And R 6 Together form C 1 -C 4 An alkylene group;
wherein, the substituted refers to one or more (preferably 1-5) hydrogen atoms on the group being replaced by a substituent selected from the group consisting of: halogen, C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight-chain or branched alkenyl, C 1 -C 6 Straight or branched alkynyl, cyano, nitro, NH 2 、C 1 -C 6 Amino (including linear or branched chain alkyl mono-or di-substituted amino), hydroxyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, C 1 -C 6 Alkoxy, mercapto, C 2 -C 6 Acyl, sulfonyl, aminosulfonyl and C 2 -C 6 Sulfonyl radical, C 5 -C 10 An aromatic group.
In another preferred embodiment, the
Has a structure represented by the following formula:
R 1 、R 2 selected from the group consisting of: halogen, C1-C6 straight or branched chain alkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxy, mercapto, C1-C4 acyl, sulfonyl, aminosulfonyl, and C1-C4 substituted sulfonyl;
m and n are each independently selected from the group consisting of: 0.1, 2 or 3;
and the substituent means that one or more (preferably 1 to 5) hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogen, C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight-chain or branched alkenyl, C 1 -C 6 Straight or branched alkynyl, cyano, nitro, NH 2 、C 1 -C 6 Amino (including linear or branched chain alkyl mono-or di-substituted amino), hydroxyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, C 1 -C 6 Alkoxy, mercapto, C 2 -C 6 Acyl, sulfonyl, aminosulfonyl and C 2 -C 6 Sulfonyl, C 5 -C 10 An aromatic group.
In another preferred embodiment, the
Selected from the group consisting of:
in another preferred embodiment, R is 1 、R 2 Each independently is halogen.
In another preferred embodiment, R is 1 、R 2 Each independently F.
In another preferred embodiment, Ar is selected from the group consisting of: substituted or unsubstituted phenyl, or substituted or unsubstituted 5-7 membered aromatic heterocycle; wherein the 5-to 7-membered aromatic heterocyclic ring contains 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen, and the substituent means that one or more (preferably 1 to 5) hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogen, C 1 -C 4 Straight or branched alkyl, C 1 -C 4 Straight-chain or branched alkenyl, C 1 -C 4 Straight or branched alkynyl, cyano, nitro, NH 2 、C 1 -C 4 Amino (including linear or branched chain alkyl mono-or di-substituted amino), hydroxyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, C 1 -C 4 Alkoxy, mercapto, C 2 -C 4 Acyl, sulfonyl, aminosulfonyl and C 2 -C 4 Sulfonyl, C 5 -C 10 An aromatic group.
In another preferred embodiment, the connecting bridge is selected from the group consisting of:
wherein p1 is selected from the group consisting of: 0.1 or 2.
In another preferred embodiment, the connecting bridge is selected from the group consisting of:
in another preferred embodiment, the compound of formula I is selected from the group consisting of:
in a second aspect of the present invention, there is provided a method for preparing a compound of formula I according to the first aspect of the present invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, hydrate or solvate thereof, wherein the compound of formula I has a structure shown in formula I-1, and the compound is prepared by the following method:
reacting a compound of formula I-a with a compound of formula I-b in an inert solvent to provide a compound of formula I-1;
or
The compound of the formula I has a structure shown in a formula I-2, and is prepared by the following method:
reacting a compound of formula I-c with a compound of formula I-d in an inert solvent to provide a compound of formula I-2.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I as described in the first aspect of the present invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, hydrate or solvate thereof, together with one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents.
In a fourth aspect of the present invention, there is provided a use of a compound of formula I as described in the first aspect of the present invention, or an enantiomer, diastereomer, racemate or mixture thereof, for the preparation of a pharmaceutical composition for the treatment or prevention of a neurological disease associated with acetylcholinesterase, or for the preparation of an imaging probe for the diagnosis of a neurological disease associated with acetylcholinesterase.
In another preferred embodiment, the acetylcholinesterase-related neurological disease is selected from the group consisting of: senile dementia, Alzheimer's disease, Parkinson's disease, epilepsy, or schizophrenia.
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.
Drawings
FIG. 1 is a graph of the effect of Cy series compounds on fluorescence imaging of APP/PS1 transgenic mice brain slices. A: a skin layer; b: hippocampus japonicus.
Detailed Description
Through long-term and intensive research, the inventor sets a novel AD detection probe molecule targeting both Abeta and AChE, and the probe molecule has both high-selectivity Abeta binding capacity and cholinesterase inhibition activity, so that diagnosis or diagnosis and treatment integration of AD can be realized. Based on the above findings, the inventors have completed the present invention.
Term(s)
As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C 1 -C 8 Alkyl represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. Such as C 2 -C 6 The alkenyl group means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. E.g. C 2 -C 6 Alkynyl means straight or branched chain alkynyl having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
As used herein, the term "C 3 -C 8 Cycloalkyl "refers to cycloalkyl groups having 3 to 8 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. It may also be in the form of a double ring, for example a bridged or spiro ring.
As used herein, the term "C 1 -C 6 Alkylamino "refers to a substituted amino group 1 -C 6 The amino substituted by the alkyl can be mono-substituted or di-substituted; for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamino and the like.
As used herein, the term "C 1 -C 6 Alkoxy "means a straight or branched chain alkoxy group having 1 to 6 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy and the like.
As used herein, the term "5-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a saturated or partially saturated cyclic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be monocyclic or may be in the form of a double ring, for example a bridged or spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.
As used herein, the term "C 6 -C 10 Aryl "means an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a single ring or a condensed ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2,4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
Unless specifically stated to be "substituted or unsubstituted", the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, nitrile group, nitro group, hydroxyl group, amino group, C 1 -C 6 Alkyl-amino, C 1 -C 6 Alkyl radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, halo C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkoxy, allyl, benzyl, C 6 -C 12 Aryl radical, C 1 -C 6 alkoxy-C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 Alkynyl-carbonyl, C 2 -C 6 Alkenyl-carbonyl, C 3 -C 6 Cycloalkyl-carbonyl, C 1 -C 6 Alkyl-sulfonyl, and the like.
As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.
Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier, thereby converting with each other. For example, proton tautomers (i.e., proton transmutations) include interconversion by proton shift, such as 1H-indazoles and 2H-indazoles. Valence tautomers include interconversion by recombination of some of the bonding electrons.
As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations of the specific embodiments with other chemical synthetic methods, and equivalents known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.
The solvents used in the present application may be commercially available, the compounds may be artificial or
The software names, and the commercial compounds are under the supplier catalog name.
Novel Alzheimer disease detection probe
The novel Alzheimer's disease detection probe of the invention can be a compound having the following general formula (I) or a salt thereof, wherein the compound comprises an enantiomer, a diastereomer, a racemate or a mixture thereof,
ar can be phenyl, substituted phenyl or 5-7-membered aromatic heterocycle, wherein the substituted phenyl can comprise 1-5 substituents selected from halogen, C1-C6 straight chain or branched chain alkyl, cyano, nitro, amino, C1-C6 straight chain or branched chain alkyl mono-or di-substituted amino, hydroxyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxy, sulfydryl, C1-C4 acyl, sulfonyl, aminosulfonyl and C1-C4 substituted sulfonyl; the 5-7 membered aromatic heterocyclic ring contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, and at least one substituent selected from halogen, C1-C6 straight chain or branched chain alkyl, cyano, nitro, amino, C1-C6 straight chain or branched chain alkyl mono-or di-substituted amino, hydroxyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxy, sulfydryl, C1-C4 acyl and C5-C10 aryl;
x can be C or N;
the connecting bridge (Linker) can be selected from the following structural fragments:
wherein Y can be selected from- (CH) 2 )n-、-Ph(CH 2 ) n-, C1-C6 straight or branched chain alkylene, phenylalkylene;
wherein R is 1 、R 2 Can be selected from halogen, C1-C6 straight chain or branched chain alkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, trifluoromethyl, trifluoroMethoxy, carboxyl, C1-C4 alkoxy, mercapto, C1-C4 acyl, sulfonyl, aminosulfonyl, and C1-C4 substituted sulfonyl;
the above m and n may be integers of 0 to 3.
In a more preferred embodiment of the invention, the compounds of formula I of the invention are preferably the following specific compounds:
process for the preparation of compounds of formula I
The invention provides a preparation method of a compound probe represented by a general formula (I), which is carried out according to the following scheme.
The first scheme is as follows:
step a: 2-bromo-5-formylpyridine, 1-tert-butoxycarbonylpiperazine and K 2 CO 3 Adding the compound F-2 into anhydrous DMSO, heating and stirring to react overnight; the heating condition can be 60-100 ℃.
Step b: adding acetylacetone into anhydrous toluene, slowly adding BF3 Et2O solution into the solution, and reacting at 40-80 deg.C for 2h to obtain compound F-4.
Step c: dissolving F-4 in acetonitrile, and adding glacial acetic acid, tetrahydroisoquinoline and p-dimethylaminobenzaldehyde into the system. Reacting at 40-80 ℃ overnight to obtain a compound F-5.
Step d and e: dissolving F-5 in acetonitrile, and adding glacial acetic acid, tetrahydroisoquinoline and F-2 into the system. Reacting at 40-80 ℃ overnight to obtain a compound F-6.
Step f: dissolving 3-fluoro-4-methyl phenylacetate in anhydrous carbon tetrachloride, adding N-bromosuccinimide and azodiisobutyronitrile into the system, and performing reflux reaction for 2 hours to obtain a compound F-8.
Step g: reacting F-9 in a 50% TFA/DCM system at room temperature, and spin-drying the reaction liquid to obtain the compound F-10.
Step h: dissolving F-10 in DMF, and dissolving K in DMF 2 CO 3 And F-8 is added into the system to react for 8 hours, thus obtaining the compound F-8.
Step i: dissolving F-11 in KOH aqueous solution for reaction to obtain a compound F-12.
Step j: f-12 was dissolved in THF, and F-6, the condensing agent, was added to the system. Reacting at room temperature to obtain the target compound.
Scheme II:
the intermediate F-2 in the scheme I is replaced by F-13 in the scheme, and other synthetic methods are the same as the scheme I.
The third scheme is as follows:
the intermediate F-12 in the first scheme is replaced by F-16 in the scheme, and other synthetic methods are the same as the first scheme.
Pharmaceutical compositions and methods of administration
The compound of the present invention and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment (stabilization, alleviation or cure) of diseases associated with acetylcholinesterase, since the compound of the present invention has excellent inhibitory activity against acetylcholinesterase.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 1-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.
When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents. One or more (2, 3, 4, or more) of such other pharmaceutically acceptable therapeutic agents may be used simultaneously, separately or sequentially with a compound of the invention for the prevention and/or treatment of cytokine and/or interferon mediated diseases.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 1 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
Detection probe imaging method
As described herein, the detection probe compound of the present invention has better targeting effect on both Α β and AChE, and thus can be used for disease course tracking and preventive therapy detection of asymptomatic AD. Thus, the present invention also provides a better tool for early detection and diagnosis of Alzheimer's disease.
The present invention also provides a method for detecting amyloid beta deposits in vitro or in vivo, comprising the steps of:
i) applying an Alzheimer's disease detection probe shown as a formula I to a detection object;
ii) combining the Alzheimer's disease detection probe shown in the formula I with beta-amyloid in the detection object to obtain a sample to be detected;
iii) staining said sample to be tested and then detecting a fluorescent signal in said sample;
iv) generating an image representative of the location and/or amount of the fluorescent signal; and
v) determining the distribution and extent of said amyloid beta deposits in said subject.
The detection probes of the invention can be carried out by conventional administration methods, preferably parenterally. After the administering step and before the detecting step, the detection probes of the invention are allowed to bind to amyloid-beta. For example, when the subject is an intact mammal, the detection probes of the invention will dynamically traverse the mammalian body, contacting various tissues therein. The detection probes of the present invention will bind to amyloid beta once they are contacted with the amyloid beta.
The detection method of the invention preferably comprises the detection and imaging of the fluorescence signal released from the sample by means of, for example, a fluorescence microscope with a photographic function, which detection step can also be understood as the acquisition of signal data.
The "test object" of the present invention may be any human or animal subject. Preferably, the subject of the invention is a mammal. Most preferably the subject is in the whole mammalian body. In a particularly preferred embodiment, the test subject of the present invention is a human.
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. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
The experimental procedures used in the following examples are, unless otherwise specified, conventional: the reagents and biomaterials used in the following examples are commercially available unless otherwise specified.
Example 1 preparation of Cy-3 Compound
(1) Synthesis of F-2
2-bromo-5-formylpyridine (50.0mg,0.27mmol), 1-tert-butoxycarbonylpiperazine (75.1mg, 0.40mmol) and K 2 CO 3 (74.3mg,0.54mmol) was added to 2.0ml of anhydrous DMSO, reacted at 80 ℃ overnight, the reaction solution was spun dry, extracted with ethyl acetate and aqueous system, the organic layer was washed with water and saturated NaCl, respectively, and anhydrous Na 2 SO 4 Drying and concentration gave 61.4mg of a yellow solid in 78.5% yield. ESI-MS: [ M + H ]] + ＝292.15；[M+Na] + ＝314.15。
(2) Synthesis of F-4
Acetylacetone (1.0g,9.98mmol) was added to 2.5ml of anhydrous toluene, and BF was added 3 *Et 2 Slowly adding O solution into the above solution, reacting at 60 deg.C for 2 hr, pouring the reaction solution into ice water, extracting with ethyl acetate, washing the organic layer with water and saturated NaCl, and adding anhydrous Na 2 SO 4 After drying and concentration, 1.0g of pale yellow solid was obtained with a yield of 71%.
(3) Synthesis of F-5
F-4(150.0mg, 1.0mmol) was dissolved in 2.0ml of acetonitrile, and glacial acetic acid (0.1ml), tetrahydroisoquinoline (0.02ml) and p-dimethylaminobenzaldehyde (149.9mg, 1.00mmol) were added to the above system. The reaction was carried out overnight at 60 ℃, and after the solvent was evaporated to dryness, the crude reaction product was separated by flash column chromatography (PE: EA ═ 5:1) to give 59mg of a reddish brown solid in 21% yield. ESI-MS: [ M + Na ]] + ＝302.10；[M+K] + ＝318.10。
(4) Synthesis of F-6
F-5(30.0mg, 0.11mmol) was dissolved in 1.0ml acetonitrile, and glacial acetic acid (20ul), tetrahydroisoquinoline (4.0ul) and F-2(31.3mg, 0.11mmol) were added to the above system. The reaction was carried out overnight at 60 ℃ and, after evaporation of the solvent, the crude reaction product was separated by flash column chromatography (PE: EA: DCM ═ 4:1:1) to give 16.8mg of a dark blue solid in 21% yield. ESI-MS: [ M + H ]] + ＝553.35；[M+Na] + ＝575.40。
(5) Synthesis of F-8
Methyl 3-fluoro-4-methylphenylacetate (100.0mg, 0.55mmol) was dissolved in 15ml of anhydrous carbon tetrachloride, and N-bromosuccinimide (107.0mg, 0.60mmol) and azobisisobutyronitrile (2.7mg, 0.016mmol) were added to the above system, and the mixture was refluxed for 2 hours, and the crude product was separated by flash column chromatography (PE: EA ═ 40:1, containing 1% acetic acid) to obtain 51mg of a yellow solid in a yield of 33%.
(6) Synthesis of F-10
F-9(155mg, 0.38mmol) was reacted in 50% TFA/DCM system at room temperature for 30min, and the reaction was dried by spinning to give 110mg of pale yellow solid, 94.3% yield. ESI-MS: [ M + H ]] + ＝307.16。
(7) Synthesis of F-11
F-10(110mg, 0.38mmol) was dissolved in 2.0ml DMF and K was added 2 CO 3 (265mg, 1.9mmol) and F-8(150mg, 0.57mmol) are added into the system, the reaction is carried out for 8h at 30 ℃, after the solvent is evaporated to dryness, ethyl acetate and a water system are used for extraction, an organic layer is respectively washed by water and saturated NaCl, and anhydrous Na 2 SO 4 Drying and concentration gave 161mg of yellow solid in 87.3% yield.
(8) Synthesis of F-12
Dissolving F-11(161mg, 0.38mmol) in 1N/KOH, reacting at 45 deg.C for 6h, pouring the reaction solution into ice water, adjusting pH to 6.5 with 1M HCl, extracting with DCM, washing the organic layer with water and saturated NaCl, and extracting with anhydrous Na 2 SO 4 Drying and concentration gave 147mg of a pale yellow solid in 81.8% yield.
(9) Synthesis of Cy-3
F-12(100.7mg, 0.21mmol) was dissolved in anhydrous 10.0ml THF and F-6(98.5mg, 0.18mmol), HBTU (80.7mg, 0.21mmol) and DIPEA (44ul, 0.26mmol) were added to the system. After reacting for 2h at room temperature, evaporating the reaction solution to dryness, and using C as a crude reaction product 18 The preparative liquid phase was separated to obtain a total of 41.7mg of Cy-3 as a dark blue powder in a yield of 25.9%. ESI-MS: [ M + H ]] + ＝908；[M+Na] + ＝930。 1 H-NMR(CDCl 3 ,400MHz):δ(ppm)8.25(s,1H),7.96(d,1H,J＝14.7Hz),7.95(d,1H,J＝11.0Hz),7.59(d,1H,J＝15.5Hz),7.49(d,2H,J＝8.8Hz),7.45-7.50(m,1H),7.13(s,1H),7.11(d,2H,J＝9.7Hz),6.96(d,1H,J＝9.4Hz),6.84(s,1H),6.67(d,2H,J＝8.8Hz),6.59(d,1H,J＝15.6Hz),6.43(d,1H,J＝15.0Hz),5.95(s,1H),3.94(s,3H),3.87(s,3H),3.71-3.78(m,10H),3.55(d,2H,J＝9.2Hz),3.27-3.33(m,1H),3.07(s,6H),3.12(m,2H),2.77-2.82(m,2H),2.37-2.47(m,1H),2.07-2.26(m,4H),1.66-1.69(m,1H).
Using a synthesis similar to that described above, with the corresponding substrates, the individual compounds shown in the following tables were obtained:
example 2 inhibition of acetylcholinesterase in vitro by Cy series of Compounds
Determination of cholinesterase Activity by Ellman colorimetry [8] . Mouse cortex homogenate was used as the AChE zymogen, and 0.1mM selective inhibitor of butyrylcholinesterase, tetraisopropyl pyrophosphoroamide (iso-OMPA), was added to the mouse cortex homogenate before enzyme activity assay to exclude the effect of butyrylcholinesterase. The enzyme activity determination procedure was as follows: mu.l of the total enzyme reaction mixture contained 50. mu.l of sodium phosphate buffer (0.1M, pH 7.4), 30. mu.l of thioacetyl choline iodide (2mM, substrate for AChE), 109. mu.l of water, 1. mu.l of compound, 50. mu.l of 3% (w/v) 5,5' -dithio-bis (2-nitrobenzene) and 10. mu.l of proenzyme, and was incubated for 20 minutes at room temperature. After 20 minutes, the reaction was stopped by adding 1ml of 3% (w/v) sodium dodecylsulfate and the colorimetric value of the colored product was determined at 450nm in a spectrophotometer. The activity of the whole enzyme is expressed by percentage of the activity of the enzyme without the inhibitor, and the calculation formula is as follows: the inhibition ratio (% as total enzyme activity OD value-test compound OD value)/total enzyme activity OD value × 100%. The results show the IC of Cy-1 and Cy-4 50 The values are respectively 0.131nM and 1.86nM, both in nanomolar scale, which shows that Cy-1 and Cy-4 have good inhibition effect on mouse cortical acetylcholinesterase.
Example 3Cy series Compounds Effect on brain fluorescence imaging of APP/PS1 transgenic mice
After 12-month-old APP/PS1 mice are anesthetized with chloral hydrate, the whole brains are taken out after being perfused by normal saline heart, and paraffin sections are carried out after being fixed in 4% paraformaldehyde for one week, wherein the sections comprise cortex and hippocampus. Before dyeing, paraffin sections are subjected to xylene dewaxing, alcohol gradient rehydration, distilled water and PBS pretreatment, then are dyed for 20 minutes in a dark place by ThS (positive dyeing agent), and after dyeing is finished, excess dye is removed by washing with 50% alcohol, and the paraffin sections are rinsed for 3 times by PBS. And then, dyeing for 30 minutes in a dark place by using a fluorescent compound, rinsing for 3 times by using PBS after dyeing is finished, finally, adding an anti-quenching agent, sealing a film, and drying in the air. The next day, the effect of the compound on specifically recognizing the Abeta plaque is observed by using a Leica upright fluorescence microscope. The results show that Cy-1, Cy-2, Cy-3 and Cy-4 have better fluorescence signals in the brain slice of APP/PS1 mouse and have a co-localization effect with senile plaques (FIG. 1).
All documents mentioned in this application are incorporated by reference in 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. A compound shown as the following formula I, or pharmaceutically acceptable salt, enantiomer, diastereoisomer, racemate, hydrate or solvate thereof,
wherein the content of the first and second substances,
ar is selected from the group consisting of: substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 7-membered aromatic heterocycle; wherein the 5-to 7-membered aromatic heterocyclic ring contains 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen;
x can be CH or N; and when X is CH, the connecting bridge can be positioned on X;
the connecting bridge (Linker) is selected from the following structural fragments:
wherein Y is selected from the group consisting of: - (CH) 2 ) n -、-Ph(CH 2 ) n -、-O-、-Ph(CH 2 ) n -、-NR-、-S-；
p is selected from the group consisting of: 1. 2,3, 4, 5 or 6;
p2 is selected from the group consisting of: 0.1, 2 or 3;
r is selected from the group consisting of: H. substituted or unsubstituted C 1 -C 4 An alkyl group;
wherein:
m is 0, 1,2 or 3;
n is selected from the group consisting of: 0.1, 2 or 3;
x is selected from the group consisting of: (CH) 2 ) p CO or SO 2 Wherein p is 0, 1,2 or 3; is preferably (CH) 2 ) p Or CO, p is preferably 1 or 2;
R 1 selected from the group consisting of: halogen, C1-C6 straight or branched chain hydrocarbyl, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxy, mercapto, C2-C6 acyl, sulfonyl, aminosulfonyl, and C2-C6 sulfonyl;
R 3 selected from the group consisting of: substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 3 -C 10 Cycloalkenyl radicals, substitutedOr unsubstituted 3-12 membered heterocyclic group, substituted or unsubstituted C 6 -C 12 An aryl group; the R is 1 Wherein the substituent is selected from halogen and C 1 -C 6 Alkyl, halogen substituted C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkoxycarbonyl, halogen-substituted C 1 -C 6 Alkoxy radical, C 2 -C 6 Alkenyl radical, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl, cyano, nitro, amino, hydroxy, hydroxymethyl, carboxy, mercapto, sulfonyl, C 6 -C 10 1,2,3, 4 or 5 substituents in aryl and 3-12 membered heterocyclyl which may be the same or different; or at said C 6 -C 12 Two adjacent substituents on the aryl group and carbon atoms on the adjacent aromatic ring form C 3 -C 7 Cycloalkyl radical, C 3 -C 7 Cycloalkenyl or 3-7 membered heterocyclyl; each heterocyclic group independently contains 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen;
R 4 is one or more groups selected from the group consisting of: hydrogen, halogen, C 1 -C 6 Alkyl, C substituted by halogen 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, halogen substituted C 1 -C 6 An alkoxy group;
R 5 and R 6 Each independently selected from the group consisting of: hydrogen, carboxyl, C 1 -C 4 Alkoxycarbonyl and C 1 -C 4 An alkyl group; or R 5 And R 6 Together form C 1 -C 4 An alkylene group;
wherein, the substituent means that one or more (preferably 1 to 5) hydrogen atoms on the group are replaced by the substituent selected from the following group: halogen, C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight-chain or branched alkenyl, C 1 -C 6 Straight or branched alkynyl, cyano, nitro, NH 2 、C 1 -C 6 Amino (including linear or branched chain alkyl mono-or di-substituted amino), hydroxyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, C 1 -C 6 Alkoxy, mercapto, C 2 -C 6 Acyl, sulfonyl, aminosulfonyl and C 2 -C 6 Sulfonyl radical, C 5 -C 10 An aromatic group.
2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, hydrate or solvate thereof, wherein
Has a structure represented by the following formula:
R 1 、R 2 selected from the group consisting of: halogen, C1-C6 straight or branched chain hydrocarbyl, cyano, nitro, amino, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxy, C1-C4 alkoxy, mercapto, C1-C4 acyl, sulfonyl, aminosulfonyl, and C1-C4 substituted sulfonyl;
m and n are each independently selected from the group consisting of: 0.1, 2 or 3;
and the substituent means that one or more (preferably 1 to 5) hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogen, C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight-chain or branched alkenyl, C 1 -C 6 Straight or branched alkynyl, cyano, nitro, NH 2 、C 1 -C 6 Amino (including linear or branched chain alkyl mono-or di-substituted amino), hydroxyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl, C 1 -C 6 Alkoxy, mercapto, C 2 -C 6 Acyl, sulfonyl, aminosulfonyl and C 2 -C 6 Sulfonyl radical, C 5 -C 10 An aromatic group.
3. A compound of formula I according to claim 1Or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, hydrate or solvate thereof, wherein
Selected from the group consisting of:
4. a compound of formula I according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, hydrate or solvate thereof, wherein Ar is selected from the group consisting of: substituted or unsubstituted phenyl, or substituted or unsubstituted 5-7 membered aromatic heterocycle; wherein the 5-to 7-membered aromatic heterocyclic ring contains 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen, and the substituent means that one or more (preferably 1 to 5) hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: halogen, C 1 -C 4 Straight or branched alkyl, C 1 -C 4 Straight-chain or branched alkenyl, C 1 -C 4 Straight or branched alkynyl, cyano, nitro, NH 2 、C 1 -C 4 Amino (including straight chain or branched chain alkyl mono-substituted or di-substituted amino), hydroxyl, hydroxymethyl, trifluoromethyl, trifluoromethoxy, carboxyl and C 1 -C 4 Alkoxy, mercapto, C 2 -C 4 Acyl, sulfonyl, aminosulfonyl and C 2 -C 4 Sulfonyl radical, C 5 -C 10 An aromatic group.
5. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, hydrate or solvate thereof, wherein the connecting bridge is selected from the group consisting of:
6. a compound of formula I according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, hydrate or solvate thereof, selected from the group consisting of:
7. a process for the preparation of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, hydrate or solvate thereof, wherein the compound of formula I has the structure shown in formula I-1, and wherein the compound is prepared by:
reacting a compound of formula I-a with a compound of formula I-b in an inert solvent to obtain a compound of formula I-1;
or
The compound of the formula I has a structure shown in a formula I-2, and is prepared by the following method:
reacting a compound of formula I-c with a compound of formula I-d in an inert solvent to provide a compound of formula I-2.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, hydrate or solvate thereof, together with one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and/or diluents.
9. Use of a compound of formula I according to claim 1, or enantiomers, diastereomers, racemates or mixtures thereof, for the preparation of a pharmaceutical composition for the treatment or prevention of a neurological disease associated with acetylcholinesterase, or for the preparation of an imaging probe for the diagnosis of a neurological disease associated with acetylcholinesterase.
10. The use of claim 9, wherein the acetylcholinesterase-related neurological condition is selected from the group consisting of: senile dementia, Alzheimer's disease, Parkinson's disease, epilepsy, or schizophrenia.
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| Title |
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| YU ZHOU等: ""Kinetics-Driven Drug Design Strategyfor Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate"", 《J.MED.CHEM.》, vol. 64, pages 1844 - 1855 * |
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