Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
  • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
  • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
• • 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
• • 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
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• This invention relates to the field of chemical synthesis, and in particular to compounds and their use as L-type calcium channel blockers or/and acetylcholinesterase inhibitors.
• Alzheimer's disease is a central nervous system degenerative disease characterized by chronic, progressive cognitive impairment and memory impairment.
• the main pathological features are senile plaques, neurofibrillary tangles and neuronal loss, which seriously affect patients. Cognition, memory, language function and personal life ability and emotional personality.
• the more accepted pathology of Alzheimer's disease in the world is "the theory of cholinergic deficiency.” It is said that the loss of choline acetate, a neurotransmitter in the brain of patients, is a key cause of Alzheimer's disease.
• Cholinesterase is a key enzyme in biological nerve conduction. In the cholinergic synapse, the enzyme can degrade acetylcholine, stop the excitatory effects of neurotransmitters on the postsynaptic membrane, and ensure the neural signal in the organism. The normal delivery. However, acetylcholinesterase can catalyze the cleavage reaction of acetylcholine, which leads to the loss of acetylcholine and the failure of nerve signaling, which affects the body's cognitive and memory functions.
• acetylcholinesterase inhibitors are used to inhibit the activity of cholinesterase, delay the hydrolysis of acetylcholine, increase the level of acetylcholine in the synaptic cleft, and achieve the purpose of treating Alzheimer's disease.
• Vascular dementia is an acquired intelligent damage syndrome caused by various cerebrovascular diseases. The clinical manifestations are intelligent decline in memory, calculation, attention and executive function. It is the second only after Alzheimer's disease. The most common cause of dementia. The researchers believe that a mechanism of injury is: Infarction, hypoxic hypoperfusion and hemorrhagic lesions lead to a decrease in brain tissue volume and delayed necrosis of neurons, which in turn leads to impaired acetylcholine nerves in the brain, reduced release of acetylcholine, and progressive memory impairment and cognitive impairment. Social and daily life, activity ability declined. Taking an acetylcholinesterase inhibitor can effectively improve a patient's cognitive function, executive function, and daily living ability.
• a calcium channel antagonist such as nimodipine
• enters the brain tissue the receptor associated with the calcium channel reversibly binds to it, thereby inhibiting the influx of calcium ions into the nerve cells, thereby increasing tolerance to ischemia, dilating the cerebral blood vessels and Improve brain blood supply, protect neurons, and effectively improve cognitive function in patients with vascular dementia.
• the present invention is directed to the development of Alzheimer's disease and vascular dementia with increased calcium influx and reduced acetylcholine release, providing compounds and their use as L-type calcium channel blockers or/and acetylcholinesterase inhibitors.
• the compounds of the present invention have a significant inhibitory effect on L-type calcium channels and acetylcholinesterase.
• the present invention provides the following technical solutions:
• the present invention provides a compound of the formula YLX, wherein Y is selected from the group consisting of a group of formula I, formula II or formula III,
• R 2 and R 3 may be independently selected from nitro, cyano or trifluoromethyl;
• Ar may be selected from an aryl or heteroaryl group, and the C r C 4 position of the aryl or heteroaryl group may be optionally a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, an amino group, a dC 4 alkylthio group, dC 8 alkyl, C 2 -C 8 alkenyl or/and C 2 -C 8 alkynyl substituted.
• R 5 and R 6 are independently selected from hydrogen, dC 8 alkyl, C 2 -C 8 chain Alkenyl or C 2 -C 8 alkynyl;
• R 2 and R 3 may also be independently selected from -COOR 7 or -CONR 7 ; the dC 4 position of Ar may be optionally substituted by -COOR 7 , wherein R 7 may be selected from ( ⁇ -( 8 alkyl, C 2 -C 8 Alkenyl or C 2 -C 8 alkynyl;
• X may be selected from a group having a structure such as any one of the formulae IV to X, and may be bonded to L through any one of R.
• R may be selected from a direct bond, a hydrogen, a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, an amino group, a dC 4 alkylthio group, a dC 12 alkyl group, a C 2 -C 12 alkenyl group or a C 2 - C 12 alkynyl;
• R may also be selected from -NR 5 R 6 or -COOR 7 , wherein R 5 and R 6 may be independently selected from hydrogen, dC 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl, R 7 may be selected from dC 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl;
• L may be selected from a direct bond, a Ci-Ci 2 alkylene group, a C 2 -C 12 subchain group or a C 2 -C 12 alkynylene group.
• R pR 4 and Ar may be independently selected from dC 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl, one or more of which -
• the CH 2 - group may be optionally substituted by -0, -S -, -S0 2 - or / and -NR 5 -, and R 5 may be selected from hydrogen, dC 8 alkyl, C 2 -C 8 alkenyl or c 2 -c 8 alkynyl.
• R 5 and R 6 may be independently selected from dC 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl, which may be optionally phenyl or Substituted phenyl substituents.
• L and R are independently selected from ( ⁇ - 12 alkylene, C 2 -C 12 alkenylene or C 2 -C 12 alkynylene, one or more of them)
• the -CH 2 - group may be optionally -0-, -S-, -S0 2 -, cycloalkylene, arylene, heteroalicyclic, heteroarylene or/and -NR 5 -
• R 5 may be selected from hydrogen, dC 8 alkyl, C 2 -C 8 chain or C 2 -C 8 alkynyl.
• the compound provided by the present invention, Y may also be selected from:
• R 2 and R 3 are independently selected from -COOR 7
• R 4 is a fluorenyl group or an amino group
• X is a structure represented by Formula IV
• L is preferably bonded to the benzene ring of X
• R 7 is preferably selected from C. r C 8 alkyl, C 2 -C 8 chain or C 2 -C 8 alkynyl.
• R 2 and R 3 are independently selected from -COOR 7
• R 4 is a fluorenyl group or an amino group
• X is a structure represented by formula VII
• L is preferably bonded to the benzene ring of X
• R 7 is preferably selected from d. -Cg alkyl, C 2 -C 8 chain or C 2 -C 8 alkynyl.
• R 4 is selected from C r C 4 alkyl
• R 2 and R 3 are independently selected from -COOR 7 and X is as defined in formula VII
• Ar may be selected from phenyl
• C The r C 4 position may be optionally a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, an amino group, -NR 5 R 6 , dC 4 alkylthio group, -COOR 7 , Ci-Cg alkyl group, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl substituted
• R 5 and R 6 may be selected from hydrogen, dC 8 alkyl, C 2 -C 8 chain or C 2 -C 8 alkynyl
• R 7 may be selected From dC 8 alkyl, C 2 -C 8 chain or C 2 -C 8 alkynyl.
• R 3 is -COOCH 3 and X is a structure represented by the formula IV, L is bonded to the benzene ring of X.
• R 3 is -COOCH 3 and X is a structure represented by Formula IX, L is not bonded to the benzene ring of X.
• the compound provided by the present invention and independently selected from C r C 4 alkyl, R 3 may be -COOR 7 , X is as defined in formula IV, formula VII, IX or X, and Ar is selected from phenyl or benzene.
• These rings may have one or more double bonds, but these rings do not have a fully conjugated ⁇ -electron system; unsubstituted heteroalicyclic groups include pyrrolidinyl, piperidino, piperazino, morpholino a thiomorpholino group, a homopiperazino group or the like; a heteroalicyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or two or more, more preferably one or two.
• heteroalicyclic refers to Monovalent heteroalicyclic;
• the compounds provided herein also comprise isomers of the compounds, pharmaceutically acceptable equivalents or mixtures of the two.
• the isomers of the compounds provided herein are those which have the same number and type of atoms and which have the same molecular weight but differ in atomic arrangement and configuration.
• a mixture comprising one or more of stereoisomers, diastereomers, enantiomers, non-racemates, racemates, and the like.
• Isoforms refer to compounds having the same number and type of atoms, the same molecular weight, but different atomic arrangements and configurations; stereoisomers refer to only the arrangement of atoms in space. The same isomer; the diastereomer refers to a stereoisomer that is not mirror image of each other; the diastereomer occurs in a compound having two or more asymmetric carbon atoms, such a compound 2 n optical isomers, where n is the number of asymmetric carbon atoms; enantiomers refer to stereoisomers that are not mirror images of each other; racemates refer to the same aliquot A mixture of individual enantiomers; a non-racemate refers to a mixture of individual enantiomers containing different aliquots.
• a method of separating optical isomers involves the use of an optimally selective chiral column to maximize separation of the enantiomers. It is also possible to react a compound of the invention with an activated form of an optically active acid or a diol or an isocyanate to synthesize a covalent diastereomeric molecule, such as an ester, amide, acetal or ketal, and then use conventional A method such as chromatography, distillation, crystallization or sublimation can separate the synthetic diastereomers and then hydrolyze to release the enantiomerically pure compound. In some cases, since the compound can be a prodrug, it is not necessary to hydrolyze the optically active drug of the parent prior to administration to the patient. Similarly, the optically active compound of the present invention can be obtained using an optically active starting material.
• the compounds of the invention include individual optical isomers as well as racemic or/and non-racemic mixtures.
• the R configuration can be enriched, while in other non-racemic mixtures, the S configuration can be enriched.
• the pharmaceutically acceptable equivalents of the compounds provided herein may comprise one or a mixture of two or more of a pharmaceutically acceptable salt, hydrate, solvate, metabolite, prodrug or isostere. .
• the compounds provided herein are pharmaceutically acceptable equivalents
• pharmaceutically acceptable Accepted salts include the acid or base salts of the compounds provided herein.
• the pharmaceutically acceptable salt has the pharmaceutical activity of the compound and is suitable for both biological and practical applications.
• the compound provided by the present invention is in a pharmaceutically acceptable equivalent, and the pharmaceutically acceptable acid salt may comprise acetate, adipate, alginate, aspartate, benzoate, benzene.
• Acid salt hydrogen sulfate, butyrate, citrate, camphorate, camphorate, cyclopentane propionate, digluconate, lauryl sulfate, ethyl sulphate, Fumarate, glucoheptanoate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrocyanate, hydroiodide, 2-hydroxyethionate, lactic acid Salt, maleate, sulphate, 2-toxin, nicotinate, oxalate, thiocyanate, decyl sulphate and undecanoate.
• the compound provided by the present invention is in a pharmaceutically acceptable equivalent
• the pharmaceutically acceptable basic salt may comprise an ammonium salt, an alkali metal salt such as a sodium and potassium salt, an alkaline earth metal salt such as a calcium salt and a magnesium salt, and an organic compound.
• a salt formed by a base such as a dicyclohexylamine salt, an N-mercapto-D glucosamine salt, and a salt with an amino acid such as arginine and lysine.
• the basic nitrogen-containing group can be quaternized by the following reagents, including lower alkyl halides such as sulfonium, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulphates Salts such as dithiol, diethyl, dibutyl and dipentyl sulfate; long chain compounds such as sulfhydryl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl
• the base compound is phenyl bromide.
• the compounds provided herein are in pharmaceutically acceptable equivalents
• the prodrugs refer to derivatives of the compounds of the invention which require biotransformation, such as metabolism, prior to their pharmacological utility.
• Prodrugs are formulated from substances that improve chemical stability, improve patient acceptance and compliance, improve bioavailability, prolonged duration of action, improve organ selectivity, improve formulation, such as enhanced water solubility, or reduce side effects such as toxicity.
• Prodrugs can be prepared from the compounds of the invention by conventional methods, see BURGER'S MEDICINAL CHEMISTRY AND DRUG CHEMISTRY, 5th Edition, Vol. 1, pp. 172-178, 949-982 (1995).
• the electronic isosteres include bioisosteres.
• bioisosteres In addition to physical similarities, bioisosteres share certain biological properties. Typically, bioisosteres interact with the same recognition sites or broadly produce similar biological effects.
• a metabolite refers to a substance produced by metabolism or by a metabolic process.
• the compound provided by the present invention is specifically:
• Compound 5 5-isopropyl-3-indolyl-2-(4-(diaminoaminodecanoyloxy)phenyl)-6-fluorenyl-4-(1-indolyl-5-nitro- 1H-imidazol-2-yl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 7 3-ethyl-5-mercapto-4-(2-chlorophenyl)-2-((2-(4-(diaminoaminodecanoyloxy))benzyl) Amino)ethoxy)indenyl)-6-mercapto-1 4-dihydropyridine-3,5-dicarboxylate;
• Compound 8 3-(5-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)pentanyl)-5-mercapto-2,6-diindolyl-4 -(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 12 3-(4-(4-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)piperazin-1-yl)phenethyl)-indenyl-2, 6-Dimercapto-4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 15 3-(2-(Diamino)-2-(3-(4-indole-ethyl-decylaminodecanoyloxy)phenyl]indolyl-2,6-diindolyl-4 -(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 16 3-(2-(6-(Diaminoaminodecanoyloxy)-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-5-indenyl-2, 6-Dimercapto-4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 17 3-mercapto-5-(1-(2-((1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)piperidin-4-yl)-2, 6-Dimercapto-4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 19 3-(2-(6-(Diaminoaminodecanoyloxy)-2-mercapto-1,2,3,4-tetrahydroisoquinolin-1-yl)ethyl)-5- Mercapto-2,6-diamidino-4-trinitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 24 3-mercapto-5-(5-((1,2,3,4-tetrahydroacridin-9-yl)amino)-2,6-diindol-4-(3-nitrate Phenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 25 3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-indenyl-2,6-didecyl- 4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 27 3-(10-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)indolyl)-5-indenyl-2,6-didecyl- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 28 3-(2-((2-(6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)thio)ethyl)-indenyl- 2,6-diamidino-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 29 3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-ethyl-2,6-didecyl- 4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 31 3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-isopropyl-2,6-di Mercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 32 3-(5-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)pentyl)-5-indolyl-4-(benzo[c] [l,2,5]oxadiazol-4-yl)-2,6-dimercapto-1 4-dihydropyridine-3,5-dicarboxylate;
• Compound 33 3-(1-(4-(Diaminoaminodecanoyloxy)benzyl)piperidin-4-yl)-5-indolyl-2,6-diindenyl-4-(3-nitrate Phenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 36 3-(4-(2-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)ethyl)cyclohexyl)-5-indenyl-2, 6-Dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 39 3-(6-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)-2-indolylheptan-2-yl)-5-indenyl-2, 6-Dimercapto-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 40 3-ethyl-5-mercapto-2-((2-(6-chloro-1,2,3,4-tetrahydroacridin-9-ylamino)ethoxy) fluorenyl)- 4-(2-chlorophenyl)-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 43 3-ethyl-5-mercapto 2-((2-(di-((3,5,6-tridecylpyrazin-2-yl)indolyl)amino)) Ethoxy)indenyl)-4-(2-chlorophenyl-6-mercapto-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 45 3-mercapto-5-(2-(1-((3,5,6-tridecyl-2-yl)indolyl)piperidin-4-yl)ethyl)-2,6- Dimercapto- 4-(3-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 46 3-mercapto-5-(1-((3,5,6-tridecylpyrazin-2-yl)indolyl)piperidin-4-yl)indolyl-2,6-diindole 4--4-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 48 3-ethyl-5-mercapto-4-(2-chlorophenyl)-6-mercapto-2-((2-(2-(indolyl-((3,5,6-tri) Mercaptopyrazin-2-yl)decylamino)ethylamino)ethoxy)indenyl)-1,4-dihydropyridine-3,5-dicarboxylate;
• Compound 52 3-ethyl-5-mercapto-4-(2-chlorophenyl)-2-((2-(1-(4-indole-ethyl-decylaminodecanoyloxy)phenyl) Ethylamino)ethoxymethyl)-6-fluorenyl-1,4-dihydropyridine-3,5-dicarboxylate;
• the invention also provides the use of the compound as an L-type calcium channel blocker or/and an acetylcholinesterase inhibitor.
• the invention also provides the use of the compound for the manufacture of a medicament for modulating calcium homeostasis, treating cardiovascular disease, stroke or dementia.
• Calcium homeostasis refers to the intrinsic balance of intracellular calcium; cardiovascular disease refers to heart, blood vessel or circulatory diseases; dementia refers to a more serious mental disorder, the patient's brain development is basically mature, intelligent It is also normal, but in the future, it will cause serious damage to the brain due to various harmful factors, causing serious mental retardation.
• Treatment refers to: prevention of diseases in animals susceptible to diseases, disorders or diseases but not yet diagnosed already. The occurrence of a disorder or condition, or the inhibition of a disease, disorder, or condition, that is, preventing its development, relieving a disease, disorder, or condition, that is, causing the disease, disorder, or condition to subside.
• the compound provided by the present invention is used in the preparation of a drug for dementia, and the dementia is Alzheimer's disease or vascular dementia.
• the pharmaceutically acceptable carrier comprises a pharmaceutically acceptable material, composition or vehicle, which may be a liquid or solid filler, diluent, excipient or soluble capsule forming material, carrying or transporting the target compound from An organ or part of the body to another organ or another part of the body.
• a pharmaceutically acceptable material, composition or vehicle which may be a liquid or solid filler, diluent, excipient or soluble capsule forming material, carrying or transporting the target compound from An organ or part of the body to another organ or another part of the body.
• the pharmaceutically acceptable carrier comprises a saccharide, a starch, a cellulose and a derivative thereof, a powdered tragacanth, malt, gelatin, talc, an excipient, an oil, a glycol, a polyol, an ester. , agar, buffer, alginic acid, non-pyrogenic water, isotonic saline, Ringer's solution, ethanol, pH buffer, polyester, polycarbonate, polyanhydride, and others compatible in the composition to be used Non-toxic substances.
• the saccharide may comprise lactose, glucose and sucrose;
• the starch may comprise corn starch, potato starch;
• the cellulose and its derivatives comprise sodium carboxymethyl cellulose, ethyl cellulose and acetic acid Cellulose;
• the excipient may comprise cocoa butter, a wax for suppositories;
• the oil may comprise peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil;
• the glycol may comprise propylene glycol;
• the polyol may comprise glycerin, sorbitol, mannitol, polyethylene glycol; Ethyl oleate, ethyl laurate; buffer contains magnesium hydroxide, aluminum hydroxide.
• the detection of the L-type calcium channel block activity of the compound provided by the present invention shows that the inhibition rate of the compound at 100 nmol/L for the L-type calcium channel is 8.71-35.77%, and the compound of the compound at 1000 nmol/L is L.
• the inhibition rate of the -type calcium channel is 26.43-83.54%;
• the detection of the acetylcholinesterase inhibitory activity of the compound provided by the present invention shows that when the inhibition rate of acetylcholinesterase activity is 50%, the amount of the compound is 16-1470.
• the present invention discloses the use of the compound and the compound as an L-type calcium channel blocker or an inhibitor of acetylcholinesterase activity, and those skilled in the art can learn from the contents of the present article and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
• the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
• the preparation process is as follows:
• the filtrate was concentrated under pressure to obtain a yellow solid, which was purified by silica gel column chromatography, eluting with a gradient of petroleum ether and ethyl acetate in a ratio of 3: 1-1:1 to obtain the compound 1 provided by the present invention. It was a yellow solid, 0.5 g, yield 50%.
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the liquid was purified by silica gel column chromatography, eluting with a gradient of 1% triethylamine, eluting with a gradient of petroleum ether and ethyl acetate in a gradient of 2: 1-1:1.
• the compound provided by the invention 7, 750 mg, yield 54.1%.
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows: Accurately weigh 2.0 g, ie 6.6 mmol of compound S 30, 1.3 g 4- hydroxypiperidine set 11 i.e. 13.2 mmol, 493 mg sodium i.e., 3.3 mmol of transducer i.e., 6.6 mmol and 908 mg of potassium carbonate were dissolved in 30 mL of acetone The reaction was stirred at room temperature for 18 h. After suction filtration, the collected filtrate was dried, concentrated, and purified by silica gel column eluting with eluting system containing 1% triethylamine. The volume ratio of petroleum ether to ethyl acetate in the eluent was 3:1, and S 47 1.9 was obtained. g, yield 89%.
• the pH of the reaction solution is adjusted to about 9 by adding saturated NaHC0 3 , and the organic phase is extracted twice with dichloromethane, and the dichloromethane extract is combined, dried with anhydrous NaSO 4 , concentrated, and purified by silica gel column.
• the elution system of % triethylamine was eluted, and the volume ratio of petroleum ether to ethyl acetate in the eluate was 1:1, and the compound 17 of the present invention, 2.8 g, was obtained in a yield of 74%.
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the compound 25 provided by the present invention was tested and the results were as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the pH of the reaction solution was adjusted to about 9 by adding saturated NaHC0 3 , and extracted twice with dichloromethane, and the dichloromethane extract was combined, dried over anhydrous NaSO 4 , concentrated and purified by silica gel column.
• the elution system of ethylamine was eluted, and the volume ratio of petroleum ether to ethyl acetate in the eluate was 2:1, and the compound 28, 620 mg of the present invention was obtained in a yield of 95%.
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated.
• the mixture was concentrated and purified by silica gel column chromatography, eluting with an elution system containing 1% triethylamine.
• the volume ratio of petroleum ether to ethyl acetate in the eluent was 1: 1 - 1 : 1 ,
• the preparation process is as follows:
• the organic layer was concentrated under reduced pressure and purified by silica gel column chromatography eluting with eluting with 1% triethylamine.
• the volume ratio of petroleum ether to ethyl acetate in the eluent was 1:1-0:
• a yellow oily product was obtained, i.e., the compound provided in the present invention was 34, 1.2 g, and the yield was 92.3%.
• the preparation process is as follows:
• the preparation process is as follows:
• the pH of the reaction solution was adjusted to about 9 by adding saturated NaHC0 3 , extracted twice with dichloromethane, and the dichloromethane extract was combined, dried over anhydrous NaSO 4 , concentrated and purified by silica gel column, using 1% The elution system of ethylamine was eluted, and the volume ratio of petroleum ether to ethyl acetate in the eluate was 3:1, and the compound 36, 53 mg of the present invention was obtained in a yield of 5%.
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the compound 40 provided by the present invention was tested and the results were as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows: Accurately weigh 2-(bromopurinyl)-3,5,6-trimercaptopyrazine 214 mg, about 1 mmol, 4-hydroxymercaptopiperidine 115 mg, about 1 mmol, dissolved in 10 mL acetonitrile Medium, K 2 C0 3 405 mg, approximately 3 mmol, refluxed overnight. Cool to room temperature, dilute the solvent acetonitrile under reduced pressure, add 15 mL of water, dilute chloroform to extract 15 mL x 3 times, dry, distill off dichloromethane under reduced pressure to give crude S 1 ( ) 2 224 mg. The rate is 90%.
• the preparation process is as follows:
• the preparation process is as follows:
• the compound 48 provided by the present invention was tested and the results were as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the compound 50 provided by the present invention was tested and the results were as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the preparation process is as follows:
• the compound 54 provided by the present invention was tested and the results were as follows:
• the calcium current of the rat dorsal root ganglion cells was measured according to the following method, thereby determining the inhibitory activity of the compound provided by the present invention on the L-type calcium ion channel.
• D-MEM/F- 12 Medium, Gibco; fetal bovine serum ie FBS, Gibco; collagenase, Sigma; poly-L-lysine, Sigma; trypsin, Invitrogen; trypsin inhibitor, Sigma; Dorsal root ganglion cell culture medium: 90% D-MEM/F-12, 10% FBS, P/S 100U/mL; Digestive juice, freshly prepared before experiment: 5 mL D-MEM/F-12, 5 mg collagen Enzyme, 2.5 mg trypsin.
• rat dorsal root ganglion cells Two rats, 140 g of Wister rats were decapitated under pentobarbital anesthesia, and the lumbar L4-L6 dorsal root ganglia were quickly separated from the ridge. In PBS; the connective tissue and septum on the ganglion are removed, and the ganglion is cut into several pieces and placed in the digestive juice at 37.
• HPES Hydroxyethylpiperazineethanesulfonic acid
• pH 7.4 was adjusted with CsOH, and the osmotic pressure was 305-310 milliosmoles.
• the pH was adjusted to 7.3 with CsOH and the osmotic pressure was 290-295 milliosmoles.
• the pipette solution is divided into several portions and stored at -20 °C before use.
• Patch Clamp Test The test was performed at room temperature using a whole cell patch clamp technique, controlled by a Multiclamp 700B amplifier, a DigiData 1440 A/DD/A converter, a 1 kHz filter, using Pclamp 10 software.
• the cells tested were continuously passed through a perfusion system - a biological fast solution converter, RSC-160, and a bath solution of 1-2 mL/min. This process was performed under an inverted microscope and the perfusion point was manually inserted. Pull the borosilicate glass capillary (BF150-86-10, Sutter Instrument Co.) using a programmable micropipette maker.
• the pipette end resistance is 2 - 4 ⁇ .
• the voltage control sequence from a holding potential of -60 mV, reaches O mV over 300 ms and then back to -60 mV over 60 ms. This voltage control sequence is repeated every 10 s during the test.
• the test compound is added at a low concentration until the peak current reaches the stable 5 recording points again, and if the peak current has not changed, wait 5 min. Add a high concentration of compound test if necessary. Two cells were tested per compound. Data analysis and curve fitting were performed using Clampfit (V10.2, Molecular Devices), Excel 2003 (Microsoft) and SigmaPlot. Test compound inhibition rate. Calculated as follows:
• Rat brain homogenate was used as an enzyme source for acetylcholinesterase.
• Triton X-100 purchased from Biyuntian; substrate, Ach-S-CL, sigma: ready-to-use, each time PBS is used to prepare 0.1 mol/L stock solution; color developer, DTNB, sigma: with PBS Formulated as a 0.005 mol/L stock solution; Stop solution, 3 % SDS: Prepare a 3 % SDS solution in PBS.
• Vistar rats were purchased from Qinglongshan Farm in Nanjing, Jiangsu Province. Experimental equipment: Homogenizer and Tecan M200 microplate reader.
• Compound working fluid configuration The compound of 0.01 mol/L stock solution was diluted with DMSO to a working concentration of lOOx, from high to low of 1000, 250, 62.5, 15.625, 3.9063, 0.9766, 0.2441, respectively, four times in sequence. Compared to the dilution, a total of seven concentration gradients, unit: mol / L.
• Enzyme working solution is obtained by diluting the brain homogenate supernatant with PBS in a ratio of 1:100.
• Preparation of substrate working solution The substrate of 0.1 mol/L stock solution was diluted to 4 mmol/L with PBS, and the working solution was reserved.
• Procedure Take 96-well plates, add 48 PBS to each well; add 2 - series concentration gradient of the working solution of the compound to each well, and add 2 ⁇ DMSO directly to the positive control group and the negative control group; add 50 cerebral stalks per well.
• Working fluid use a plate shaker to mix the hooks, seal each well with membrane, and incubate at 37 °C for 48 h; add 50 ⁇ 0.005 mol/L color solution to each well; add 50 L substrate working solution per well
• the negative control group was directly added with 50 L of 10 ⁇ PBS, mixed by a plate shaker, and allowed to stand at 37 ° C for 1 h; the absorbance at 412 nm of each well was measured on a Tecan M200 microplate reader.
• Compound configuration According to the sample quality and molecular weight, the compound was configured into a 0.01 mol/L stock solution in DMSO. The concentration of 100 ⁇ compound was prepared: First, the compound stock solution was firstly set to 1000 ⁇ /L, 200 ⁇ /L, 40 ⁇ with DMSO. /L, 8 ⁇ /L, 1.6 ⁇ /L, 0.32 ⁇ /L, concentration gradient of 0.064 ⁇ /L.
• each stock solution is mixed according to the ratio of 200 ⁇ L Amplex Red reagent : 100 Horseradish peroxidas: 100 Choline Oxidase: lO L Ach : 9590 ⁇ 1 Reaction Buffer to obtain 2 working liquid.
• the final concentration of the compound thus obtained is 10 ⁇ /L, 2 ⁇ /L, 0.4 ⁇ /L, 0.08 ⁇ /L, 0.016 ⁇ /L, 0.0032 ⁇ /L, 0.00064 ⁇ /L; Incubation at room temperature 30-45 Min.
• Fluorescence detection Under the Infinite M200 enzyme-labeled detector, the fluorescence value of each well at the excitation wavelength of 540 nm and the emission wavelength of 590 nm was measured.
• the average 0D value of the positive control - the average 0D value of the negative control was used to find the logarithm of the base of the dosing concentration.
• the logarithmic value was plotted on the abscissa and the inhibition rate was plotted on the ordinate.
• the original 6.0 was drawn and a pharmacological fit was fitted.
• the dose-effect relationship is determined by the sigmoid curve, and the drug concentration corresponding to the 50% inhibition rate is obtained, that is, the IC 5 which inhibits the activity of the compound for acetylcholinesterase. value.
• the results of the detection of the compound for acetylcholinesterase inhibitory activity are shown in Table 5.

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