CN110536687B - N-hydroxypyridones compounds and uses thereof - Google Patents
N-hydroxypyridones compounds and uses thereof Download PDFInfo
- Publication number
- CN110536687B CN110536687B CN201880024104.2A CN201880024104A CN110536687B CN 110536687 B CN110536687 B CN 110536687B CN 201880024104 A CN201880024104 A CN 201880024104A CN 110536687 B CN110536687 B CN 110536687B
- Authority
- CN
- China
- Prior art keywords
- compound
- another preferred
- group
- pharmaceutically acceptable
- bicyclo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Abstract
A compound shown as a formula (I), a stereoisomer, a pharmaceutically acceptable salt or a mixture thereof, wherein the compound shown as the formula I, the stereoisomer, the pharmaceutically acceptable salt or the mixture thereof can inhibit nerve cell damage and nerve cell death and can be used for preparing a medicament for treating cerebral apoplexy.
Description
Technical Field
The invention relates to an N-hydroxypyridones compound and application thereof.
Background
Cerebral apoplexy (cerebral stroke), also known as acute cerebrovascular diseases (CVA), or cerebrovascular accident (CVA) is a group of diseases in which cerebral tissues are damaged due to sudden rupture of cerebral vessels or blood circulation disorder caused by vascular occlusion, also known as stroke. Cerebral apoplexy can be divided into cerebral arterial thrombosis and hemorrhagic stroke, wherein cerebral arterial thrombosis is common and accounts for about 87 percent.
Ischemic stroke is nerve injury caused by blood supply disturbance, and the key point for treating stroke is to dredge blood vessels to improve the blood supply of cerebral tissues at ischemic positions and protect nerve cells in an ischemic and anoxic environment, so as to prevent the damage and death of the nerve cells. Currently, the main treatment means in the early stage (within 3-6 hours) of ischemic stroke is thrombolytic therapy, however, many patients cannot arrive at hospital within the optimal time window (within 3 hours) of thrombolytic therapy, and stroke also requires CT (computed tomography) or MRI (Magnetic Resonance Imaging) to exclude hemorrhagic stroke, thus requiring 30 minutes or more. Therefore, patients with acute ischemic stroke have a low chance of receiving thrombolytic therapy.
The nerve protective agent is a medicine for treating nerve injury after acute ischemia or reperfusion, and can protect brain tissues, improve the tolerance of nerve cells to ischemia and hypoxia, accelerate the recovery of nerve functions of patients and obviously improve the prognosis of the patients. Neuroprotective agents have an important role in the middle-to-late and convalescent stages of acute ischemic stroke treatment, especially for patients in post-thrombolytic convalescent stages and for patients who miss the time window for thrombolytic treatment.
At present, the traditional Chinese neuroprotective agent micromolecule stroke treatment medicines only comprise edaravone and butylphthalide, but due to individual difference and the like, not all patients can obtain good curative effect by applying the traditional medicines.
Disclosure of Invention
The invention aims to provide a novel N-hydroxypyridone compound with neuroprotective activity and a novel application of 1-hydroxy-4-methyl-6- (2-bicyclo [2, 1] heptane) -2-pyridone in cerebral apoplexy resistance, and the compounds can be used for preparing novel anti-stroke medicaments.
In a first aspect of the invention, the invention provides a compound shown in formula I, a stereoisomer, a pharmaceutically acceptable salt thereof, or a mixture thereof, which is used for preparing a medicament for treating cerebral apoplexy,
in the formula, R 1 、R 2 Each independently of the other being hydrogen, halogen, C 1 -C 8 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-8 Alkynyl, C 2-8 Alkenyl, benzyl or C 6-10 An aryl group;
R 3 is C 3 -C 8 Monocyclic cycloalkyl of (a); r is bromine, iodine, -C (= O) H or- (CH) 2 ) n NR 4 R 5 (ii) a Or R 3 Is C 7-9 Bridged cycloalkyl, H, halogen, C 1-8 Alkyl radical, C 2-8 Alkynyl or C 2-8 Alkenyl, R is hydrogen, bromine, iodine, -C (= O) H or- (CH) 2 ) n NR 4 R 5 ；
Wherein n is 1,2, 3 or 4 4 、R 5 Independently of each other is hydrogen, C 1 -C 10 Alkyl radical, C 3 -C 8 Monocyclic cycloalkyl of (A), C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 6-10 Aryl or bisaziridine substituted C 5-8 An alkynyl group;
or R, R 1 Together with the attached C form a substituted or unsubstituted C 6-10 Aryl, the substituent on the aryl is H, halogen, C 1-8 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-8 Alkynyl, C 2-8 Alkenyl or benzyl.
In another preferred embodiment, the treatment is inhibition of nerve cell damage or inhibition of nerve cell death.
In another preferred embodiment, the application provides the use of 1-hydroxy-4-methyl-6- (2-bicyclo [2,2,1] heptane) -2-pyridone of the formula or a stereoisomer or a mixture of different configurations thereof or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising the same for the preparation of a medicament for the treatment of stroke or for the treatment of stroke,
the stereoisomer is in an endo isomer (endo isomer) or exo isomer (exo isomer);
the mixture of different configurations includes a mixture of two configurations, an endo configuration (endosomer) and an exomer configuration (exomer).
In another preferred embodiment, R 1 、R 2 Each independently of the other is hydrogen, halogen, C 1 -C 6 Alkyl radical, C 3-6 Cycloalkanes, C 2-5 Alkyne, C 2-5 Alkene, benzyl or phenyl.
In another preferred embodiment, R is bromine, iodine, -C (= O) H or- (CH) 2 ) n NR 4 R 5 (ii) a Wherein n is 1,2, 3 or 4 4 、R 5 Independently of one another are hydrogen, C 1 -C 8 Alkyl radical, C 3 -C 6 Monocyclic cycloalkyl of (2), C 2-5 Alkenyl radical, C 2-5 Alkynyl, phenyl or bisaziridine substituted C 5-8 Alkynyl;
or R, R 1 Taken together with the attached C to form a phenyl group.
In another preferred embodiment, when R and R are 1 When taken together with the attached C to form a phenyl radical, R 2 Is H; r is 3 Is C 3-6 And (3) cycloalkane.
In another preferred embodiment, C 7-9 The bridged cycloalkyl group is selected from: bicyclo [2, 1]]Heptanyl radicals i.e.
Bicyclo [2,2 ] s]The octyl radical is
Bicyclo [4,1,1]The octyl radical is
Bicyclo [3,2,1 ]]The octyl radical is
Bicyclo [3,2 ]]Nonyl radicals being
And bicyclo [3, 1]]Nonyl radicals being
In another preferred embodiment, when R is 3 Is C 7-9 When the compound is a bridged cycloalkane, the compound shown in the formula I is an endo isomer, an exo isomer or a mixture of the endo isomer and the exo isomer. C above 7-9 The bridged cycloalkyl is in an endo (endo isomer) or exo (exo isomer) configuration
In another preferred embodiment, the pharmaceutically acceptable salt is an alkaline earth metal, alkali metal, aluminum, transition metal salt of the compound of formula I, or a salt of the compound of formula I with an organic base selected from: ethanolamine, diethanolamine, N-ethylethanolamine, N-methylethanolamine, triethanolamine, diethylaminoethanol, 2-amino-2-methyl-N-propanol, dimethylaminoisopropanol, tert-butylamine, triisopropanolamine, ethylenediamine, morpholine, piperidine, piperazine, cyclohexylamine, tributylamine, dodecylamine, dimethyldodecylamine, triethylamine benzylamine, dibenzylamine, N-methylpiperazine, 4-methylcyclohexylamine, N-methylmorpholine, methylamine and ethylamine.
In another preferred embodiment, the preferred salt is the ethanolamine salt.
In another preferred embodiment, the preferred salt is
In another preferred embodiment, the compound is:
in a second aspect of the invention, there is provided a compound of formula I, a stereoisomer, a pharmaceutically acceptable salt thereof, or a mixture thereof,
in the formula, R 3 Is C 3 -C 8 Monocyclic cycloalkyl of (A), C 7-9 Bridged cycloalkyl, H, halogen, C 1-8 Alkyl, C2-8 alkynyl, C2-8 alkenyl or benzyl;
R 1 、R 2 each independently of the other being hydrogen, halogen, C 1 -C 8 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-8 Alkynyl, C 2-8 Alkenyl, benzyl or C 6-10 An aryl group;
r is bromine, iodine, -C (= O) H or- (CH) 2 ) n NR 4 R 5 (ii) a Wherein n is 1,2, 3 or 4 4 、R 5 Independently of one another are hydrogen, C 1 -C 10 Alkyl radical, C 3 -C 8 Monocyclic cycloalkyl of (A), C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 6-10 Aryl or bisaziridine substituted C 5-8 An alkynyl group;
or R, R 1 Together with the attached C form a substituted or unsubstituted C 6-10 Aryl, the substituent on the aryl is H, halogen, C 1-8 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-8 Alkynyl, C 2-8 Alkenyl or benzyl. In another preferred embodiment, C 7-9 The bridged cycloalkyl group is attached to the N-hydroxypyridone in such a manner that the carbon on the pyridone ring is attached to the bridgehead carbon or non-bridgehead carbon of the bridged cycloalkyl group by a single carbon-carbon bond.
In another preferred embodiment, R 1 、R 2 Each independently of the other is hydrogen, halogen, C 1 -C 6 Alkyl radical, C 3-6 Cycloalkanes, C 2-5 Alkyne, C 2-5 OlefinsBenzyl or phenyl.
In another preferred embodiment, R is bromo, iodo, -C (= O) H, or- (CH) 2 ) n NR 4 R 5 (ii) a Wherein n is 0, 1,2, 3 or 4 4 、R 5 Independently of one another are hydrogen, C 1 -C 8 Alkyl radical, C 3 -C 6 Monocyclic cycloalkyl of (A), C 2-5 Alkenyl radical, C 2-5 Alkynyl, phenyl or diaziridine substituted C 5-8 Alkynyl;
or R, R 1 Together with the attached C, form a phenyl group.
In another preferred embodiment, when R and R are 1 When taken together with the attached C to form a phenyl radical, R 2 Is H; r 3 Is C 3-6 And (3) cycloalkane.
In another preferred embodiment, C 7-9 The bridged cycloalkyl group is selected from: bicyclo [2, 1]]Heptanyl radicals i.e.
Bicyclo [2,2 ]]The octyl radical is
Bicyclo [4,1,1]The octyl radical is
Bicyclo [3,2, 1]]The octyl radical is
Bicyclo [3,2 ]]Nonyl radicals being
And bicyclo [3,3,1 ]]Nonyl radicals being
In another preferred embodiment, when R is 3 Is C 7-9 When the compound is bridged, the compound shown in the formula I is an inner configurational isomer, an outer configurational isomer or a mixture of the inner configurational isomer and the outer configurational isomer. Above C 7-9 Bridged cycloalkyl is built-inType (endo isomer) or exo-configuration (exo isomer)
In another preferred embodiment, the pharmaceutically acceptable salt is an alkaline earth metal, alkali metal, aluminum, transition metal salt of the compound of formula I, or a salt of the compound of formula I with an organic base selected from: ethanolamine, diethanolamine, N-ethylethanolamine, N-methylethanolamine, triethanolamine, diethylaminoethanol, 2-amino-2-methyl-N-propanol, dimethylamino-isopropanol, tert-butylamine, triisopropanolamine, ethylenediamine, morpholine, piperidine, piperazine, cyclohexylamine, tributylamine, dodecylamine, dimethyldodecylamine, triethylamine benzylamine, dibenzylamine, N-methylpiperazine, 4-methylcyclohexylamine, N-methylmorpholine, methylamine and ethylamine.
In another preferred embodiment, the preferred salt is the ethanolamine salt.
In another preferred embodiment, the preferred salt is
In another preferred embodiment, the compound is:
in a third aspect of the present invention, there is provided a pharmaceutical composition, wherein the pharmaceutical composition comprises:
a compound of the second aspect, a stereoisomer, a pharmaceutically acceptable salt, a carboxylate prodrug thereof, or a mixture thereof; and
a pharmaceutically acceptable carrier.
"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 between the compounds of the present invention without significantly diminishing the pharmaceutical effectiveness of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose andderivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifier (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), and optionally other additives
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
In another preferred embodiment, the carrier is selected from the group consisting of: diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorbent carriers, lubricants, or combinations thereof.
In another preferred embodiment, the pharmaceutical composition is formulated as a solid dosage form or a liquid dosage form, preferably suitable for oral administration.
In another preferred embodiment, the solid dosage forms include capsules, tablets, pills, powders, and granules. In another preferred embodiment, the liquid dosage form comprises a pharmaceutically acceptable emulsion, solution, suspension, syrup, or tincture.
In a fourth aspect of the present invention, there is provided a method for preventing and/or treating stroke by administering the compound of the second aspect, a stereoisomer, a pharmaceutically acceptable salt thereof or a mixture thereof to a subject in need thereof.
In another preferred embodiment, said administration is intravenous administration, intraperitoneal administration, inhalation administration, sublingual administration, rectal administration, intramuscular administration, subcutaneous administration, oral administration.
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. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. For reasons of space, they will not be described in detail.
Drawings
FIG. 1 shows that I-1 decreases rat MCAO: (Middle cerebral artery occlusionMiddle cerebral artery embolism) and improved neurobehavioral functional outcome maps: (A) brain slice TTC staining pattern; (B) statistical map of brain slice damage area; (C) neurobehavioral scoring; the displayed value is the average value of the values, ### p < 0.001 compared to Sham (Sham), * p＜0.05， ** p < 0.01 compared to the model group (Vehicle), n =15 to 18. The dose of edaravone is 10mg/kg, and the dose of CPX is 3mg/kg.
Detailed Description
The inventor of the application researches extensively and deeply, firstly develops an N-hydroxypyridone compound with a novel structure, selects an Oxygen Glucose Deprivation (OGD) model constructed by SH-SY5Y cells to test the nerve cell protective activity, tests the anti-ischemic injury activity by a rat focal cerebral ischemia (MCAO) model by a wire-embolism method, and shows that the compound has good neuroprotective activity, and partial compound shows the anti-ischemic injury activity superior to the existing anti-stroke medicine on an animal model, thereby having good prospect for treating the stroke. On the basis of this, the present invention has been completed.
N-hydroxypyridones
In another preferred embodiment, the N-hydroxypyridones of the invention are compounds of formulae II, III, IV, or stereoisomers, or pharmaceutically acceptable salts, or in vivo degradable carboxylate prodrugs thereof:
in formula II: r is 1 ，R 2 Independently H, cl, br, I, F, C 1-8 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-8 Alkynyl, C 2-8 Alkenyl, benzyl. R 3 Is C 7-9 Bridged cycloalkyl, H, cl, br, I, F, C 1-8 Alkyl radical, C 3-8 Cycloalkyl, C2-8 alkynyl, C2-8 alkenyl, benzyl.
In formula III: r 4 ，R 5 Independently is C 2-8 Alkynyl, bisaziridine substituted C 5-8 Alkynyl, H, cl, br, I, F, C 1-8 Alkyl radical, C 3-8 Cycloalkyl radical, C 1-8 Alkenyl and benzyl. R is 6 ，R 7 Independently H, cl, br, I, F, C 1-8 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-8 Alkynyl, C 2-8 Alkenyl, benzyl. R 8 Is C 7-9 Bridged cycloalkyl, H, cl, br, I, F, C 1-8 Alkyl radical, C 3-8 Cycloalkyl, C 2-8 Alkynyl, C 2-8 Alkenyl, benzyl.
In formula IV: r 9 Is C 7-9 Bridged cycloalkyl radical, C 3-8 A cycloalkyl group; r 10 Is H, cl, br, I, F, C 1-8 Alkyl radical, C 3-8 Cycloalkyl radical, C 2-8 Alkynyl, C 2-8 Alkenyl, benzyl. Numbering carbonyl carbon as 1, nitrogen atom as 2, clockwise from small to large, R 10 The substitution site of (b) may be the 5,6,7,8 position on the isoquinolinone ring.
In another preferred embodiment, R 1 ，R 2 ，R 6 ，R 7 ，R 10 Each independently selected from: H. br, I, methyl.
In another preferred embodiment, R 3 ，R 8 ，R 9 Each independently selected from: cyclohexyl, bicyclo [2,2,1]]And (3) heptane.
In another preferred embodiment, R 4 、R 5 Each independently selected from H, methyl, propyl, isopropyl, cyclopentyl, phenyl, n-heptyl, 5-diazirine-1-heptynyl.
Preparation method
The N-hydroxypyridones of the invention may be prepared by the following route.
Route 1:
route 2:
R 4 ，R 5 each independently is H, methyl, propyl, isopropyl, cyclopentyl, phenyl, n-heptyl, 5-diazirin-1-heptynyl.
Route 3:
use of
The N-hydroxypyridone compound has good neuroprotective activity and good prospect of treating cerebral apoplexy, and can be used for preparing medicines for treating cerebral apoplexy.
Furthermore, 1-hydroxy-4-methyl-6- (2-bicyclo [2,2,1] was found]Heptane) -2-pyridone
Or a stereoisomer or a mixture with different configurations or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing the same have the anti-ischemic injury activity superior to that of the existing anti-stroke drugs on animal models, can inhibit the damage and death of nerve cells and play a role in treating cerebral apoplexy.
1-hydroxy-4-methyl-6- (2-Bicyclo [2, 1] heptane) -2-pyridone, which may also be referred to as 2 (1H) -pyridine, 6-Bicyclo [2.2.1] pt-2-yl-1-hydroxy-4-methyl- (CAS index name), or 6-Bicyclo [2.2.1] pt-2-yl-1-hydroxy-4-methyl-2 (1H) -pyridine.
The structural formula represents two optical isomers, namely I internal configuration (endo isomer) and I external configuration (exo isomer).
Preferably, the compound has an endo isomer and a mixture of endo and exo isomers, and can inhibit nerve cell damage and death to treat cerebral apoplexy.
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 for which specific conditions are not indicated in the following examples are generally carried out according to conventional conditions (e.g.as described in Sambrook et al, molecular cloning: A Laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989)) or according to the conditions as recommended by the manufacturer. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
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. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Example 1
(1) Bicyclo [2,2,1] heptanecarboxylic acid (purchased from alfa aesar) was dissolved in dichloromethane, two equivalents of oxalyl chloride were added, two hundredths of an equivalent of DMF was used as a catalyst to react at room temperature for three hours, and the solvent was distilled off under reduced pressure to obtain a crude product of a-cyclic acid chloride.
(2) Three equivalents of powdered aluminum chloride were dissolved in methylene chloride and a mixture of the A-ring acid chloride and I-a (1: 1) was slowly added dropwise thereto. The reaction was refluxed for five hours until no hydrogen chloride gas was produced. After quenching the reaction with dilute hydrochloric acid, the aqueous phase is extracted with a large amount of dichloromethane, the dichloromethane phase is washed with saturated sodium bicarbonate, dried over magnesium sulfate and the solvent is evaporated to give crude I-b.
(3) Adding the crude I-b product into a mixture (3: 10) of sulfuric acid and acetic acid, reacting for five hours at 100 ℃, adding a large amount of ice blocks to quench the reaction, and then slowly adding sodium bicarbonate solution to quench the reaction. Extracting with ethyl acetate, drying with anhydrous sodium sulfate, evaporating solvent to obtain crude I-c product, and purifying by column chromatography.
(4) Dissolving the crude product I-c in proper amount of toluene, adding two equivalents of tetraphosphorus decasulfide, and carrying out reflux reaction for five hours. Filtering to remove the residual vulcanizing agent, removing the toluene by rotary evaporation, and carrying out column chromatography to obtain I-d.
(5) Dissolving I-d and five equivalents of hydroxylamine hydrochloride in an appropriate amount of pyridine, and carrying out reflux reaction for six hours. Insoluble substances are filtered, pyridine is evaporated, and the crude product of I-1 is obtained after column chromatography purification.
(6) Dispersing and ultrasonically filtering the crude I-1 product obtained in the last step by using petroleum ether with a boiling range of 60-90 ℃, and taking a filter cake, wherein the filter cake is in an I-1 internal configuration (an external configuration product in the filter cake is removed by using solubility difference).
1 H NMR(400MHz，CDCl 3 )：δ6.37(s，1H)，5.99(s，1H)，2.94-3.06(m，1H)，2.48(s，1H)，2.38(s，1H)，2.23(s，3H)，1.89(t，J＝11.0Hz，1H)，1.47-1.77(m，3H)，1.20-1.46(m，4H)；MS(EI)m/z 219.1265(M + ).
Preparing I-1, cooling the residual filtrate to minus 20 ℃, filtering insoluble substances, and concentrating the residual filtrate to obtain I-H. (mixture of internal and external configurations, ratio being determined by the ratio of nuclear magnetic peak areas)
1 H NMR(400MHz，CDCl 3 )：δ6.40(s，0.45H)，6.37(s，0.55H)，6.77(s，0.45H)，5.99(s，0.55H)，3.45-3.55(m，0.45H)，2.94-3.06(m，0.55H)，2.76(s，0.45H)，2.48(s，0.55H)，2.37(s，1H)，2.25(s，1.35H)，2.22(s，1.65H)，1.85-1.97(m，1H)，1.12-1.68(m，7H)；MS(EI)m/z 219.1265(M + ).
Example 2
10g of ciclopirox are dissolved in 100ml of carbon tetrachloride, one equivalent of bromosuccinimide and five percent of azobisisobutyronitrile are added as initiators. The reaction was refluxed for 7h under nitrogen protection, then the system was cooled to 0 ℃ and the insoluble material was filtered. Concentrating the filtrate, and purifying by column chromatography to obtain a crude product. Dispersing the crude product in petroleum ether with boiling range of 60-90 deg.C, ultrasonic treating for 10 min, filtering, washing the filter cake with n-hexane, collecting the filter cake to obtain II-1,8.25g with yield of 60%
1 H NMR(400MHz，CDCl 3 )：δ6.09(s，1H)，2.98(tt，J＝11.5，3.2Hz，1H)，2.34(s，3H)，1.95-2.15(m，2H)，1.83-1.94(m，2H)，1.75-1.93(m，1H)，1.18-1.55(m，5H).
Example 3
The required starting materials, reagents and preparation were the same as in example 2 except that NBS was replaced with NIS, giving II-2,9.1g in 56% yield.
1 H NMR(400MHz，CDCl 3 )：δ6.10(s，1H)，2.97(m，1H)，2.39(s，3H)，1.95-2.15(m，2H)，1.75-1.94(m，3H)，1.10-1.58(m，5H)；MS(EI)m/z 333.0225(M + ).
Example 4
The petroleum ether filtrate from example 2 was cooled to-20 ℃, and the insoluble material was filtered and the filtrate was concentrated to give II-3.
1 H NMR(400MHz，CDCl 3 )：δ6.54(s，1H)，3.55-3.65(m，1H)，2.33(s，3H)，2.10-2.30(m，2H)，1.85-1.95(m，2H)，1.60-1.82(m，2H)，1.18-1.55(m，4H)；MS(EI)m/z 285.0360(M + )..
Example 5
(1) Dissolving 2.85g of II-1 in 100ml of ultra-dry tetrahydrofuran, adding 1.5 equivalents of sodium hydrogen under ice-bath stirring, and cooling the reaction system to seventy eight ℃ below zero after no hydrogen is released. Under the protection of nitrogen, 3 equivalents of n-pentane solution of tert-butyl lithium were slowly added dropwise, and the system gradually turned orange. When the color of the reaction system does not deepen any more, 6 equivalents of DMF are added, and the reaction system is gradually returned to the room temperature.
(2) The reaction was allowed to proceed overnight. For work-up, the reaction was quenched by addition of 50ml of 1N HCl solution with stirring in an ice bath. The tetrahydrofuran layer was separated, the aqueous phase was extracted with 50 × 3ml of ethyl acetate, and the tetrahydrofuran and ethyl acetate phases were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The solution was evaporated to give the crude product. The crude product was isolated and purified by mobile phase silica gel column chromatography with methanol to dichloromethane =1 to 30, 810mg II-4, yield 34%.
1 H NMR(400MHz，CDCl 3 )：δ6.08(s，1H)，3.10-3.25(m，1H)，2.56(s，3H)，2.00-2.10(m，2H)，1.70-1.95(m，3H)，1.15-1.52(m，5H)；MS(ES+)m/z 236.1285([M+1] + ).
Example 6
100mg of II-4 and an equivalent amount of methylamine in methanol were dissolved in 5ml of 1, 2-dichloroethane, and 50. Mu.L of acetic acid was added to react at ordinary temperature for 20 minutes. Then, 1.2 equivalents of sodium triacetoxyborohydride was added and reacted at room temperature overnight. The reaction was quenched by addition of 5ml of saturated brine, the organic phase was separated and the aqueous phase was re-extracted with dichloromethane, the dichloromethane phase and the 1, 2-dichloroethane phase were combined and dried and concentrated to give the crude product. And carrying out column chromatography on the crude product to obtain III-1.
1 H NMR(400MHz，CDCl 3 )：δ8.75-8.98(br s，1H)6.19(s，1H)，4.17(s，1H)，3.35-3.55(br s，1H)，2.65(s，3H)，2.27(s，3H)，1.55-1.95(m，5H)，1.15-1.50(m，5H)；MS(ES+)m/z 251.1758([M+1] + ).
Example 7
The required starting materials, reagents and preparation were the same as in example 6 except that a solution of methylamine in methanol was replaced with n-propylamine, to give III-2.
1 H NMR(400MHz，CDCl 3 )：δ8.95-9.20(br s，1H)，6.18(s，1H)，4.22(s，1H)，3.4-3.6(br s，1H)，2.68-2.86(br s，2H)，2.24(s，3H)，1.45-1.95(m，7H)，1.10-1.40(m，8H)；MS(ES+)m/z 279.2075([M+1] + ).
Example 8
The same procedures as in example 6 were repeated except that the methanolic methylamine solution was replaced with propargylamine, to give III-3.
1 H NMR(400MHz，CDCl 3 )：δ5.98(s，1H)，3.87(s，2H)，3.47(d，J＝2.5Hz，2H)，3.05-2.86(m，1H)，2.30(s，3H)，2.26(s，1H)，2.07-1.96(m，2H)，1.74-1.94(m，3H)，1.56-1.17(m，5H)；MS(ES+)m/z 275.1761([M+1] + ).
Example 9
The required starting materials, reagents and preparation were the same as in example 6 except that a solution of methylamine in methanol was replaced with isopropylamine to give III-4.
1 H NMR(400MHz，CDCl 3 )：δ5.87(s，1H)，3.89(s，2H)，3.19-3.32(m，1H)，2.90-3.10(m，1H)，2.24(s，3H)，1.65-1.97(m，5H)，1.08-1.45(m，11H)；MS(ES+)m/z 279.2074([M+1] + ).
Example 10
The required raw materials, reagents and preparation method were the same as in example 6 except that the methanol solution of methylamine was replaced with n-heptylamine, to obtain III-5.
1 H NMR(400MHz，CDCl 3 )：δ6.15(s，1H)，4.07(s，2H)3.0-3.1(m，1H)，2.97(t，J＝7.7Hz，2H)，2.38(s，3H)，1.65-1.95(m，7H)，1.10-1.45(m，11H)，0.75-0.95(m，5H)；MS(ES+)m/z 335.2700([M+1] + ).
Example 11
The required starting materials, reagents and preparation were the same as in example 6 except that the methanolic methylamine solution was replaced with 3-bisaziridine-6-heptynylamine to give III-6.
1 H NMR(400MHz，CDCl3)δ9.55(s，1H)，6.17(s，1H)，4.13(s，2H)，3.02-3.13(m，1H)，2.85(s，2H)，2.37(s，3H)，2.10-2.25(m，2H)，1.95-2.10(m，4H)，1.74-1.93(m，4H)，1.69(t，J＝7.1Hz，2H)，1.52-1.17(m，5H)；MS(ES+)m/z 357.2292([M+1] + ).
Example 12
The required starting materials, reagents and preparation were the same as in example 6 except that the methanol solution of methylamine was replaced with cyclopentylamine to give III-7.
1 H NMR(400MHz，CDCl 3 )：δ5.93(s，1H)，3.99(s，2H)，3.40-3.60(m，1H)，2.90-3.10(m，1H)，2.29(s，3H)，1.55-2.05(m，9H)，1.15-1.47(m，9H)；MS(ES+)m/z 305.2224([M+1] + ).
Example 13
The same procedures as in example 6 were repeated except that the methanol solution of methylamine was replaced with aniline, to give III-8.
1 H NMR(400MHz，CDCl 3 )δ7.19(t，J＝7.7Hz，2H)，7.11(t，J＝7.2Hz，1H)，6.76(d，J＝7.5Hz，2H)，6.01(s，1H)，4.29(s，2H)，2.90-3.10(m，1H)，2.02(d，J＝12.2Hz，2H)，1.72-1.92(m，3H)，1.15-1.55(m，5H)；MS(ES+)m/z 313.1917([M+1] + ).
Example 14
(1) Dissolving o-iodobenzoic acid in dichloromethane, adding two equivalents of thionyl chloride, reacting at room temperature for three hours by using two hundredth equivalents of N, N-dimethylformamide as a catalyst, and removing the solvent by reduced pressure distillation to obtain a crude o-iodobenzoyl chloride product. Simultaneously adding o-iodobenzoyl chloride and equivalent triethylamine into methanol to react for 20 minutes at room temperature to obtain o-iodobenzoic acid methyl ester.
(2) Methyl o-iodobenzoate and equivalent cyclohexylacetylene were dissolved in a mixture of toluene and triethylamine (5: 1), argon bubbled for ten minutes, then one percent cuprous iodide and one percent PdCl were added 2 (PPh 3 ) 2 Reacting for 4.5h at 40 ℃ under the protection of argon as a catalyst, evaporating the solvent, and carrying out column chromatography to obtain an intermediate IV-M.
(3) IV-M and two equivalents of hydroxylamine hydrochloride, four equivalents of potassium hydroxide were dissolved in methanol and reacted overnight at room temperature. Slowly adding dilute hydrochloric acid to adjust the pH value to 3, extracting the water phase by using dichloromethane, and drying and concentrating the organic phase to obtain a crude product. The crude product was chromatographed on a flow-through phase column with methanol to dichloromethane =1 to 20 to give IV-1.
1H NMR(400MHz，CDCl 3 )δ8.35(d，J＝8.2Hz，1H)，7.63(t，J＝7.4Hz，1H)，7.56(d，J＝8.1Hz，1H)，7.47(t，J＝7.2Hz，1H)，6.45(s，1H)，3.16-3.00(m，1H)，2.16(d，J＝11.5Hz，2H)，1.90(d，J＝11.4Hz，2H)，1.81(d，J＝13.5Hz，1H)，1.61-1.16(m，5H)；MS(EI)m/z 243.1260(M + ).
Example 15
1g of I-1 was dissolved in 4ml of ethyl acetate at sixty degrees Celsius and an equivalent amount of ethanolamine was added. Cooling and filtering, washing a filter cake twice by using a small amount of cold ethyl acetate, and drying to remove the solvent residue to obtain the ethanolamine salt I-1.
1 H NMR(400MHz，CDCl 3 )：δ6.35(d，J＝1.9Hz，1H)，5.99(d，J＝2.1Hz，1H)，3.62(t，J＝4.0Hz，3H)，3.1-3.45(br s，4H)，2.95-3.05(dd，J＝9.0，5.6Hz，1H)，2.87.(t，J＝4.0Hz，3H)，2.47(m，1H)，2.37(m，1H)，2.20(s，3H)，1.88(ddd，J＝12.0，9.0，2.5Hz，1H)，1.45-1.72(m，3H)，1.20-1.45(m，4H).
Example 16
Improvement of SH-SY5Y (human neuroblastoma) cells deprived of oxygen sugar by compound
SH-SY5Y is a human neuroblastoma cell, which has the characteristics of a nerve cell. An Oxygen Glucose Deprivation (OGD) model is a treatment for depriving cultured cells of oxygen, glucose and serum, normal culture conditions are recovered after a period of time, and the cell viability is detected after the cells are continuously cultured for 24 hours. The model simulates clinical cerebral ischemic reperfusion injury, detects the influence of oxygen sugar deprivation on the activity of SH-SY5Y cells by adopting a thiazole blue (MTT) colorimetric method, and preliminarily evaluates whether a compound has a neuroprotective effect, particularly an improvement effect on ischemia-induced injury.
The experimental steps are as follows:
the test compound was dissolved in DMSO to prepare a 10mM stock solution, stored at-20 deg.C and diluted as needed. SH-SY5Y cells were subcultured in MEM/F12 medium containing 10% fetal bovine serum, 100U/ml penicillin and 100U/ml streptomycin. Cells were digested with 0.25% trypsin and suspended in MEM/F12 containing 10% fetal bovine serum. At 3.5X 10 5 cells/mL SH-SY5Y cells were seeded in a volume of 100. Mu.L/well on 96-well plates and placed at a concentration of 5% CO 2 Culturing in a constant temperature incubator at 37 ℃. After SH-SY5Y cells are cultured for 24h, the liquid is changed for one time, and the experiment is carried out after the cells are continuously cultured for 24 h. The cells were rinsed once with sugar-free EBSS balanced salt solution in both the oxygen-deficient and administered groups, then replaced with DMEM (sugar-free) culture solution, the test compound was added to the administered group at the corresponding concentration, and the corresponding solvent control was added to the oxygen-deficient group, and the cells were placed in an anaerobic apparatus (containing 85% N) 2 ，10％H 2 ，5％CO 2 ) And culturing for 2h. Replacing normal control group with DMEM culture solution containing sugar and serum, adding 5% of CO 2 The cells were incubated at 37 ℃ for the same time in an incubator. After 2h, the oxygen-containing plate was taken out from the anaerobic apparatus, and serum and glucose were supplemented to the oxygen-deficient lesion group and the administration group, with a final glucose concentration of 1g/L. After further incubation for 24h, 5mg/mL MTT (100. Mu.L/well) was added and viable cell staining was performed. After 3h incubation, the medium was discarded, DMSO (100. Mu.L/well) was added and shaken on a plate shaker to dissolve it well. OD was measured at 490nm for each group. The oxygen deprivation-induced survival of nerve cells following administration was calculated according to the following formula:
survival = OD administration group/OD normal group × 100%
TABLE 1 evaluation of the efficacy of N-OH pyridinones in the OGD model
Cell viability of normal control group was set asData are shown as a percentage compared to the normal control group as an average of three independent experiments at 100%. Test compounds were tested in two groups, with a model group (OGD) cell viability value of 48.56% for group 1 and 54.92% for group 2. * p＜0.05， ** p＜0.01， *** p < 0.001 compared to the model group (OGD).
The experimental results in table 1 show that the compounds in the previous examples all exhibit protective activity against OGD-injured nerve cells, and the more active ones are taken for further dose-effect relationship studies.
TABLE 2 concentration of N-hydroxypyridones in OGD model-evaluation of drug efficacy
Cell viability was set at 100% for the normal control group and data is shown as a percentage compared to the normal control group as an average of three independent experiments. The cell viability value of the test model group (OGD group) was 54.23%. * p＜0.05， ** p＜0.01， *** p < 0.001 compared to the model group (OGD group).
The test results in Table 2 show that I-1 is superior to IV-1, II-2, II-3, III7 and III5 in effective dose and activity in six compounds tested again.
Example 17
Results of efficacy evaluation of compound according to the present invention in rat middle artery occlusion (MCAO) reperfusion (reperfusion) model:
middle Cerebral Artery (MCA) is a frequently-occurring part of cerebral stroke of people, so that a focal cerebral ischemia model caused by blocking MCA is an animal model widely applied at present, neurobehavioral scores and TTC (2, 3, 5-Triphenoyte-tetrazolium chloride,2,3, 5-Triphenyltetrazole) staining recorded by the model can respectively reflect neurobehavioral injuries caused by cerebral ischemia and cerebral ischemic infarction conditions, and the protective effect of the compound on the cerebral ischemia can be reflected by evaluating the first two indexes. Thus, this method was used to evaluate the in vivo efficacy of the ethanolamine salt of I-1 having the superior activity measured in example 16. Transient middle cerebral artery embolization models are mainly based on Longa, et al; stroke, 1989. The rats are anesthetized by chloral hydrate (400 mg/Kg, i.p.), a median incision is made in the neck, tissues are separated, the bifurcation of the right internal carotid artery and the external carotid artery is exposed, a thin line on the common carotid artery is used as a slipknot, the external carotid artery is ligated, a diagonal incision is cut, a plug wire with a rounded head end is inserted, the plug wire enters the internal carotid artery through the external carotid artery, and the plug wire is pushed along the internal carotid artery until the plug wire is resistant (the plug wire is inserted by about 20-22mm from the bifurcation of the external carotid artery and the internal carotid artery). Cutting off external carotid artery, releasing the artery clamp of common carotid artery, taking out the thrombus after 2h of ischemia to obtain reperfusion, and performing behavioral scoring and 2,3, 5-triphenyltetrazolium chloride staining after 24 h. The results are shown in FIG. 1.
TTC staining results in figure 1 show: the normal brain tissue is stained bright red, the tissue of the infarcted part is stained white, compared with a sham operation group, the solvent control group has obvious infarct on the injured side of the half brain (figure A), when the dosage of the compound I-1 ethanolamine salt is 0.3mg/kg and 1mg/kg, the cerebral infarct area volume of MCAO animals can be obviously reduced (figure B), and 1mg/kg of I-1 can obviously improve the neurobehavioral function of rats (figure C). When the dose of the compound I-1 is 1mg/kg, the cerebral infarction area and the neurological score of experimental animals are lower than those of a group administered with 10mg/kg of the existing drug edaravone (figures B and C), which shows that the compound I-1 has certain advantages in effective dose and drug effect compared with the existing drug edaravone.
The novel N-hydroxypyridone compound provided by the invention has a simple molecular structure and a simple preparation process, and shows strong neuroprotective activity in an SH-SY5Y cell oxygen sugar deprivation model experiment, so that the novel N-hydroxypyridone compound is expected to be developed into a medicament for treating cerebral apoplexy. The invention also relates to a new application of the 1-hydroxy-4-methyl-6- (2-bicyclo [2, 1] heptane) -2-pyridone in treating cerebral apoplexy, and in a transient MCAO model experiment of a rat, the 1-hydroxy-4-methyl-6- (2-bicyclo [2, 1] heptane) -2-pyridone can obviously reduce the cerebral infarction area and improve the neurobehavioral function of the rat, which indicates that the compound is expected to be developed into a medicament for treating cerebral apoplexy.
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 (4)
- Use of 1-hydroxy-4-methyl-6- (2-bicyclo [2,2,1] heptane) -2-pyridone or its ethanolamine salt,
it is characterized by being used for preparing the medicine for treating ischemic stroke. - 2. Use of a compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of ischemic stroke, said compound being:
- 3. a compound or a pharmaceutically acceptable salt thereof, wherein the compound is:
- 4. a pharmaceutical composition, comprising:a compound of claim 3 or a pharmaceutically acceptable salt thereof; anda pharmaceutically acceptable carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2018/080648 WO2019183793A1 (en) | 2018-03-27 | 2018-03-27 | N-hydroxypyridone compound and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110536687A CN110536687A (en) | 2019-12-03 |
| CN110536687B true CN110536687B (en) | 2022-12-16 |
Family
ID=68058537
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201880024104.2A Active CN110536687B (en) | 2018-03-27 | 2018-03-27 | N-hydroxypyridones compounds and uses thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN110536687B (en) |
| WO (1) | WO2019183793A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4957730A (en) * | 1985-12-19 | 1990-09-18 | Hoechst Aktiengesellschaft | Antimycotic nail varnish |
| US5846984A (en) * | 1996-01-19 | 1998-12-08 | The Trustees Of Columbia University In The City Of New York | Use of ciclopirox or a pharmaceutically acceptable salt thereof for inhibiting neuronal cell damage or neuronal cell death |
| CN1480132A (en) * | 2002-05-17 | 2004-03-10 | �����ġ����ղ�ʿ��ѧ����˾ | Protective solution for preventing local ischemic damage |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3157101A (en) * | 2000-01-03 | 2001-07-16 | Manfred Bohn | Preparations for the non-traumatic excision of a nail |
| US9527815B2 (en) * | 2014-06-18 | 2016-12-27 | Biotheryx, Inc. | Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating inflammatory, neurodegenerative, or immune-mediated diseases |
-
2018
- 2018-03-27 CN CN201880024104.2A patent/CN110536687B/en active Active
- 2018-03-27 WO PCT/CN2018/080648 patent/WO2019183793A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4957730A (en) * | 1985-12-19 | 1990-09-18 | Hoechst Aktiengesellschaft | Antimycotic nail varnish |
| US5846984A (en) * | 1996-01-19 | 1998-12-08 | The Trustees Of Columbia University In The City Of New York | Use of ciclopirox or a pharmaceutically acceptable salt thereof for inhibiting neuronal cell damage or neuronal cell death |
| CN1480132A (en) * | 2002-05-17 | 2004-03-10 | �����ġ����ղ�ʿ��ѧ����˾ | Protective solution for preventing local ischemic damage |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110536687A (en) | 2019-12-03 |
| WO2019183793A1 (en) | 2019-10-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100438633B1 (en) | N-(3-benzofuranyl)urea derivatives | |
| KR930011300B1 (en) | Oxindole derivative | |
| JP2024514703A (en) | PARP inhibitor with piperazine structure, its preparation method and its pharmaceutical use | |
| AU2005204369B2 (en) | Azabenzofuran substituted thioureas as inhibitors of viral replication | |
| WO2008016596A2 (en) | Pseudobase benzo [c] phenanthridines with improved efficacy, stability, and safety | |
| KR20200086385A (en) | Cap-dependent endonuclease inhibitors | |
| CN108033964B (en) | Pyridyl imidazobenzodiazepine propionate compound and synthesis and application thereof | |
| AU2003284808A1 (en) | The derivatives of pyridone and the use of them | |
| WO2018133670A1 (en) | Butylphthalide-telmisartan heterocomplex, preparation method and application thereof | |
| JP2017521482A (en) | Amantadine nitrate compound with neuroprotective effect and its preparation and medical application | |
| AU2006263915B2 (en) | Biphenyl and naphthyl-phenyl hydroxamic acid derivatives | |
| CN110536687B (en) | N-hydroxypyridones compounds and uses thereof | |
| CN109956868B (en) | Phenyl carboxylic acid derivatives, preparation method and application thereof | |
| US5719180A (en) | Chroman derivatives having vitamin E-like activities | |
| CN114920710A (en) | Urea derivatives | |
| LT3799B (en) | Process for the preparing thienopyrane derivatives | |
| KR102227100B1 (en) | Donepezil ether palmitate or its pharmaceutically acceptable salt | |
| US5232947A (en) | Oxamic acid compounds and pharmaceutical composition for use in improvement of damaged cerebral functions of brain | |
| CN115160227A (en) | Heterozygote of R-or S-2- (1-acetoxy-n-pentyl) benzoic acid and 4-fluoro-edaravone, and preparation and application thereof | |
| KR20120113886A (en) | Novel compounds as xanthine oxidase inhibitors and pharmaceutical composition containing the same | |
| US11767286B2 (en) | Phenylpropionate compound, preparation method for same, and applications thereof | |
| EP2474550A1 (en) | Derivatives of Englerin for the treatment of cancer | |
| EP1157014B1 (en) | Polycyclic 2-amino-dihydrothiazole systems, method for the production thereof and their utilization as medicament | |
| JP5632368B2 (en) | Thienyl- and furanyl-isoquinolinones and methods for their use | |
| Gadekar et al. | Synthesis and biological activity of pyridoxine analogs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |