CN101255134A - Aryl pyridine compounds and medicament uses thereof - Google Patents
Aryl pyridine compounds and medicament uses thereof Download PDFInfo
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Abstract
The invention relates to medicinal chemistry field, more particularly, 6-aryl-3-substituted pyridone derivates with the structure represented by the formula (I) and the pharmaceutical salt thereof, and the invention further relates to a method for preparing the compounds with the structure of the formula I and the pharmaceutical use thereof. The compounds of the invention have the pharmaceutical uses for inhibiting the activity of acetylcholine esterase and preventing and curing senile dementia.
Description
Technical field
The invention belongs to organic chemistry, pharmaceutical chemistry and area of pharmacology, particularly, the present invention relates to have 6-aryl-3-replacement-pyridinone derivatives of preventing and treating the senile dementia effect and its production and use.Through the pharmacologically active test, this compounds has the activity of acetylcholine esterase inhibition, can expect as preventing and treating the senile dementia pharmaceutical use.
Background technology
Research prompting both at home and abroad, with advancing age, the sickness rate of senile dementia will progressively increase, and elderly dementia's sickness rate can reach 80% more than 80 years old.Presenile dementia has become the reason of the 4th death that is only second to heart trouble, malignant tumour and apoplexy.The old man of China more than 60 years old reached 1.2 hundred million, nearly 5,000,000 senile dementia patients at present.Therefore, research control medicine for senile dementia is the urgent problem of current the world of medicine.Because of doctor AloisAlzheimer finds to be called for short AD so this disease of name is Alzheimer ' s disease first, Chinese is called A Ercaimo disease.The cause of disease of senile dementia is with heredity, to increase factors such as age, immunologic dysfunction, infection, poisoning, environment relevant.Its pathogenesis is also not fully aware of at present, and what studies show that AD in a large number is various cause of disease results of interaction, has various pathogenic hypothesis, in the recent period prevailing 4 amyloid hypothesis and the cholinergic hypothesis of mainly containing.
As far back as nineteen sixties, it has been found that cholinergic plays crucial effect in the formation of remembering with in safeguarding.Davies in 1976 and Maloney report AD patient's cholinergic neuron selectivity loss becomes the AD investigator who finds that at first the specificity neurochemistry changes.The damaged research of the cholinergic eighties concentrates on the basal forebrain Mai Neite of cortex neural distribution center (Meynert) nuclear, and finds the structure of its proximity such as the influence that grey albumen is not subjected to progressive degeneration.In addition, the modification cell that is implanted into synthesis of acetyl choline (ACh) can reverse memory and the cognition dysfunction that the basalis nuclear damage causes, shows that there are substantial connection in cholinergic system and AD clinical symptom.The cholinergic hypothesis of memory function disorder is proposed nineteen eighty-two Bartus and co-worker thereof.In cholinergic synapse, acetylcholine transferase choline and acetyl-CoA reaction generate vagusstoff, are stored in the utricule of teleneuron; When neural depolarize, ACh is discharged into from utricule in the gap of cynapse; Arrive the opposite side in gap by diffusion initiatively, the acceptor of bonding nicotine or muscarine, activated receptor and produce the signal conduction; Be bonded in the acetylcholinesterase hydrolysis vagusstoff on neurone surface, the regeneration choline.In the cholinergic model of AD, main damaged synthetic and excretory disorder for vagusstoff, the vagusstoff katabolism that decomposes neurotransmitter does not have influencedly in addition, causes the reduction greatly of cholinergic synapse gap vagusstoff concentration, weakens to the signal of pallium district conduction thereupon.This hypothesis obtains the confirmation of clinical in a large number and data.
Based on AD pathogenetic " cholinergic hypothesis ", if clinical application at present and be in anti-AD drug main in the clinical study in order to improve the ACh level in the cranial nerve, recover the ACh nerve conduction, improve patient's memory, cognition and capacity, delay the development of the state of an illness.Wherein a class medicine is the cholinomimetic thing, mainly contains acetylcholinesterase (AChE) inhibitor and M1 receptor stimulant.Another kind of medicine is the medicine that promotes that ACh discharges in the cranial nerve, mainly comprises M2 receptor antagonist, n receptor agonist, throtropin releasing hormone (TRH) analogue, adenosine (A1) receptor antagonist, 5-HT3 receptor antagonist and potassium, agents of calcium ion channel modulators etc.
Acetylcholinesterase (AChE) is called true property or specificity Pseudocholinesterase again, is positioned at neurocyte, skeletal muscle, unstriated muscle, various body of gland and erythrocyte.ACh keeps certain level the human body memory function is played an important role in brain.The physiological action of AChE in brain is to make acetylcholine hydrolyzation and inactivation rapidly.So acetylcholine esterase inhibition is one of also successful method commonly used of treatment senile dementia.
Though it is more to be in the various kinds of drug of research or clinical evaluation at present, the senile dementia vaccine is also in development and be hopeful to make a breakthrough, but at present the most successful medicine is still acetylcholinesterase depressant, and four medicines of the treatment AD that successively passes through as U.S. FDA are the AChE inhibitor.Tacrine (Tacrine), chemical name 9-amino-1,2,3,4-tetrahydrochysene-bifurcation pyridine is first medicine that is used for the treatment of degenerative brain disorder by the special approval of FDA in 1993.E2020 (donepezil, trade(brand)name Acriept, chemical name 2,3-dihydro-5,6-dimethoxy-2-(1-phenylmethylene piperidin-4-yl) methylene radical-1H-1-ketone) be second medicine being used for the treatment of AD of FDA (FDA) in November, 1996 approval.Go on the market in the U.S. in January, 1997, and go on the market in China in October, 1999, uses in more than 50 countries at present.E2020 is a kind of efficient, highly selective, long lasting AChE inhibitor.The E2020 clinical efficacy is similar to tacrine, but it has that dosage is little, toxicity is low, easy administration, advantage such as cheap.
Rivastigmine (rivestigmine, sharp this bright) is the 3rd an AChE inhibitor that is used for anti-senile dementia disease of FDA approval.It is a vagusstoff selective depressant in a kind of novel false irreversible brain.Untoward reaction to liver will be lower than the above two, and better tolerance, no periphery anticholinesterase activity.The AChE inhibitor of lycoremine (Galanthamine) another treatment AD that to be calendar year 2001 ratified by FDA, its long action time, reversible, the maincenter selectivity is strong, is used for the treatment of light, moderate AD.
The inventor finds that 6-aryl-3-replacement-pyridinone derivatives that the present invention prepares has the activity of the acetylcholine esterase inhibition of certain effect, thereby can expect through being developed further into to preventing and treating the senile dementia pharmaceutical use; Finished the present invention thus.
Summary of the invention
The object of the present invention is to provide a kind of compound with acetylcholine esterase inhibition activity.Particularly, the invention provides a kind of 6-aryl 3-replacement-pyridinone derivatives and pharmacologically acceptable salt thereof shown in the formula (I) that have:
Formula (I)
Wherein, R
1Be methoxyl group; X is selected from oxygen or nitrogen-atoms; The R group is selected from replacement or unsubstituted six-ring alkyl, replaces or unsubstituted phenyl ring, replaces or unsubstituted aromatic heterocycle, and 2～3 rings connect or the parallel conjugation or the unconjugated ring compound of formation of closing; Perhaps X and R merge into and replace or unsubstituted five yuan or hexa-atomic alicyclic ring, replace or unsubstituted five yuan or hexa-member heterocycle, replace or unsubstituted five yuan or hexa-atomic aromatic nucleus, replace or unsubstituted five yuan or hexa-atomic aromatic heterocycle, or 2～3 rings connect or parallel conjugation or the unconjugated replacement or the unsubstituted ring compound of formation of closing; The substituting group that is used to replace is the alkyl that contains 1～5 carbon, hydroxyl, amino, halogen, nitro, cyano group, or benzyl.
The preferred formula of the present invention (I) compound is selected from:
I-a.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(4-luorobenzyl) piperazinyl] ketone;
I-b.{3-[2-methoxyl group-6-(3-p-methoxy-phenyl) pyridyl] } (4-benzhydryl piperazidine base) ketone;
I-c.{3-[2-methoxyl group-6-(3-p-methoxy-phenyl) pyridyl] } (1,2,3, the 4-tetrahydro isoquinolyl) ketone;
I-d.1-[2-methoxyl group-6-(3-p-methoxy-phenyl) nicotinoyl] piperidines-4-methane amide;
I-e.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(3, the 4-dichloro benzyl) piperazinyl] ketone;
I-f.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (4-cyclohexyl piperazinyl) ketone;
I-g.1-[2-methoxyl group-6-(4-p-methoxy-phenyl) nicotinoyl]-4-(piperidino) piperidines-4-methane amide;
I-h.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(4-fluorophenyl) piperazinyl] ketone;
I-i.2-methoxyl group-6-(4-p-methoxy-phenyl)-N-(p-tolyl) niacinamide;
I-j.1-[2-methoxyl group-6-(4-p-methoxy-phenyl) nicotinoyl]-the 4-piperidone contracts-1, the 2-di-alcohol;
I-k.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (3,4-indoline-1-yl) ketone;
I-l.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(4-fluorophenyl)-1,2,5,6-tetrahydro pyridyl] ketone;
I-m. cis-2-[2-methoxyl group-6-(4-p-methoxy-phenyl) nicotinoyl amido] the naphthenic acid ethyl ester;
I-n.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (4-ethyl piperazidine base) ketone;
I-o.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (4-phenyl-1,2,5,6-tetrahydro pyridyl) ketone;
I-p.2-methoxyl group-6-(4-p-methoxy-phenyl)-N-phenyl niacinamide;
I-q.{3-[2-methoxyl group-6-(3-p-methoxy-phenyl) pyridyl] } [4-(4-fluorophenyl) piperazinyl] ketone;
I-r.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (4-benzhydryl piperazidine base) ketone;
I-s.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(2-p-methoxy-phenyl) piperazinyl] ketone;
I-t.2-methoxyl group-6-(4-p-methoxy-phenyl)-N-(2-morpholine ethyl) niacinamide;
I-u.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid (4-formyl radical-2-methoxyl group) phenyl ester;
I-v.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid (4-formyl radical) phenyl ester;
I-w.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid (4-fluorine) benzyl ester;
I-x.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid pentamethylene base ester;
I-y.[2-methoxyl group-6-(4-p-methoxy-phenyl)] the basic ester of nicotinic acid (hexamethylene-2-alkene);
I-z.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid (4-acetoxyl group) butyl ester.
Formula (I) synthetic route that compound adopted that preparation the present invention relates to has following operational path feature: utilize the condensation under the effect of condensing agent or derivatization reagent of 6-aryl-2-alkoxyl group-Nicotinicum Acidum (compound IV) and organic alcohol, phenol or organic amine to generate Compound I I (p-methoxy-acetophenone or meta-methoxy methyl phenyl ketone).Specifically comprise: when forming amido linkage; use the synthetic method of amine acidylate commonly used; carboxylic acid and organic amine directly high temperature or mineral acid (as: vitriol oil, phosphoric acid) or under condensing agent (as: DCC, DCC and DMAP, DIC, active phosphate BDP or BOP) effect condensation form; perhaps acid being derived is carboxylic acid halides, nitration mixture acid anhydride (organic or inorganic acid as: sulfonic acid, phosphoric acid, carbonic anhydride), the active ester with electrophilic alcohol or phenol, active mercaptan or phenolic ester, active amide, and perhaps two activation methods are used.When forming ester, the alcohol commonly used or the esterification process of phenol are used, the condensation under high temperature or protonic acid, Lewis acid catalysis of carboxylic acid and alcohol or phenol forms, perhaps use Vesley method, DCC and analogue evaporation thereof, diethylazodicarboxylate's method, perhaps acid is derived and be carboxylic acid halides, nitration mixture acid anhydride (organic or inorganic acid as: sulfonic acid, phosphoric acid, carbonic anhydride), active ester, active mercaptan or phenolic ester, active amide with electrophilic alcohol or phenol, perhaps use ketene as catalyzer, perhaps two activation methods are used; Utilize the condensation reaction under the effect of condensing agent or derivatization reagent of carboxylic acid and organic alcohol, phenol or organic amine to carry out in the condition that alkali or alkali-free are arranged; general amine acylation reaction solvent is used; as water, water or anhydrous solvent, protic or non-protonic solvent are arranged; organic alcohol in the reaction, phenol or organic amine equivalent are 0.5～2.5 equivalents of acid; practical situation according to reaction; reaction times is dozens of minutes or several days, and general 6～12 hours, range of reaction temperature was-70～150 ℃.Wherein DCC is " dicyclohexylcarbodiimide ", and DMAP is " a 4-Dimethylamino pyridine ", and DIC is " N, a N-DIC ", and BDP is " diphenyl phosphoester ", and BOP is " blocking special condensing agent ".
Embodiment
Further specify the present invention below by preparation example and embodiment.Embodiment has provided synthetic and the dependency structure appraising datum and the part activity data of representative compounds.Mandatory declaration, following embodiment is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Preparation example 1:The preparation of initial compounds IIa (p-methoxy-acetophenone):
Anisole (10.8 grams, 0.1 mole) is dissolved in 150 milliliters of methylene dichloride, adds anhydrous chlorides of rase zinc powder (26.8 grams, 0.20 mole) then, drip diacetyl oxide (15.3 grams, 0.15 mole) down at-15 ℃; After dropwising, reaction slowly was raised to room temperature reaction 7 hours, then reactant was carefully poured in 600 milliliters of frozen water, used ethyl acetate extraction 3 times; Organic phase anhydrous magnesium sulfate drying, filtering and concentrating get the colorless oil crude product, get initial compounds IIa (p-methoxy-acetophenone) (13.1 grams, yield 87%) through too short silica gel column chromatography.White solid, fusing point: 35～38 ℃.Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm) 2.56 (unimodal, 3H, COCH
3), 3.87 (unimodal, 3H, OCH
3), 6.93 (bimodal, 2H, J=8.4Hz, H-3,5), 7.94 (bimodal, 2H, J=8.4Hz, H-2,6).
Preparation example 2:The preparation of initial compounds IIb (meta-methoxy methyl phenyl ketone):
3-hydroxy acetophenone (13.6 grams, 0.1 mole) is dissolved in 150 milliliters of acetone, adds salt of wormwood 20 gram (0.15 mole) and methyl-sulfates (12.6 grams, 0.1 mole); Back flow reaction 10 hours, TLC shows and to react completely, filter, with ethyl acetate filter wash cake, concentrate pale brown look oily matter crude product, get Compound I Ib (meta-methoxy methyl phenyl ketone) through too short silica gel column chromatography, 12.1 grams, yield 81%.Colorless oil.
Preparation example 3:Intermediate compound III a[3-cyano group-6-(4-p-methoxy-phenyl)-2H-pyridin-2-ones] preparation:
With sodium Metal 99.5 (2.76 grams, 120 mmoles) add in 250 milliliters of ether, drip 1 milliliter of ethanol, drip Compound I Ia (p-methoxy-acetophenone) (100 mmole) and ethyl formate (150 mmole) mixture under ice bath, after dropwising, mixture stirred after 15 minutes, be warmed up to room temperature reaction 1 hour, after removing ether under reduced pressure, solid mixture adds malonamide nitrile (12.6 grams, 150 mmoles) and water (400 milliliters).After mixture refluxed 8 hours, acidifying with acetic acid was used in cooling, filter the xanchromatic solid, after the drying, head product recrystallization from ethanol obtains intermediate compound III a[3-cyano group-6-(4-p-methoxy-phenyl)-2H-pyridin-2-ones]: yield 56%, faint yellow solid; Fusing point＞250 ℃; R
f(methylene chloride 20: 1) 0.46; Proton nmr spectra
1H-NMR (400MHz, deuterated dimethyl sulfoxide, δ ppm): 3.82 (unimodal, MeO-4 '), 6.69 (bimodal, 1H, J=7.2Hz, H-5), 7.05 (bimodal, 2H, J=8.4Hz, H-3 ', 5 '), 7.79 (bimodal, 2H, J=8.4Hz, H-2 ', 6 '), 8.06 is (bimodal, 1H, J=7.2Hz, H-4).
Preparation example 4:Intermediate compound III b[3-cyano group-6-(3-p-methoxy-phenyl)-2H-pyridin-2-ones] preparation:
Identical with the method for preparation example 3, be raw material with midbody compound IIb, get intermediate compound III b[3-cyano group-6-(3-p-methoxy-phenyl)-2H-pyridin-2-ones]: yield 51%, faint yellow solid; Fusing point:＞250 ℃; R
f(methylene chloride 20: 1) 0.45.
Preparation example 5:Midbody compound IVa[3-cyano group-6-(4-p-methoxy-phenyl)-2-methoxypyridine] preparation:
Intermediate compound III a[3-cyano group-6-(4-p-methoxy-phenyl)-2H-pyridin-2-ones] (10 mmole) at N, N-dimethylformamide dimethyl acetal (DMFDMA) (1.8 grams, 15 mmoles) N, dinethylformamide (50 milliliters) vlil is spent the night, and mixture is to going in the frozen water.Produce the xanchromatic solid precipitation, filter, with a spot of water washing filter cake, dry must thick product, recrystallization gets midbody compound IVa[3-cyano group-6-(4-p-methoxy-phenyl)-2-methoxypyridine in ethanol]: yield 89%; White solid; Fusing point: 137～138 ℃; R
f(petrol ether/ethyl acetate 3: 1) 0.46; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 3.89 (unimodal, 3H, MeO-4 '), 4.15 (unimodal, 3H, MeO-2), 7.02 (bimodal, 2H, J=8.4Hz, H-3 ', 5 '), 7.36 is (bimodal, 1H, J=8.0Hz, H-5), 7.87 is (bimodal, 1H, J=8.0Hz, H-4), 8.04 is (bimodal, 2H, J=8.4Hz, H-2 ', 6 ').
Preparation example 6:Midbody compound IVb[3-cyano group-6-(3-p-methoxy-phenyl)-2-methoxypyridine] preparation:
Identical with the method for preparation example 5, be raw material with intermediate compound III b, get compound intermediate compound IV b[3-cyano group-6-(3-p-methoxy-phenyl)-2-methoxypyridine]: yield 91%; White solid; Fusing point: 126～128 ℃; R
f(petrol ether/ethyl acetate 3: 1) 0.46; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 3.84 (unimodal, 3H, MeO-3 '), 4.10 (unimodal, 3H, MeO-2), 7.08 is (bimodal, 1H, J=8.0Hz, H-4 '), 7.43 (triplets, 1H, J=8.0Hz, H-5 '), 7.69～7.73 (multimodals, 3H, H-5,2 ', 6 '), 8.21 (bimodal, 1H, J=8.0, H-4).
Preparation example 7:Midbody compound Va[2-methoxyl group-6-(4-p-methoxy-phenyl) Nicotinicum Acidum] preparation:
In 100 milliliters of ethanol, the potassium hydroxide solution and midbody compound IVa[3-cyano group-6-(4-the p-methoxy-phenyl)-2-methoxypyridine that add 110 milliliter 30%]: (10 mmole), heat up and refluxed 12 hours, be cooled to room temperature, placement is spent the night, filter 2-methoxyl group-6-(4-p-methoxy-phenyl) Nicotinicum Acidum sylvite, after the careful neutralization of the hydrochloric acid of 6N, with dichloromethane extraction (5 * 150 milliliters), merge organic phase, Calcium Chloride Powder Anhydrous drying, suction filtration, rotary evaporation is removed methylene dichloride, obtains midbody compound Va[2-methoxyl group-6-(4-p-methoxy-phenyl) Nicotinicum Acidum]: yield 80%; White solid; Fusing point; 186～187 ℃; R
f(methylene chloride 25: 1) 0.42; Proton nmr spectra
1H-NMR (400MHz, deuterated dimethyl sulfoxide, δ ppm): 3.83 (unimodal, 3H, MeO-4 '), 4.03 (unimodal, 3H, MeO-2), 7.06 (bimodal, 2H, J=8.4Hz, H-3 ', 5 '), 7.58 (bimodal, 1H, J=7.6Hz, H-5), 8.10～8.17 (multiplet, 3H, H-4,2 ', 6 '); Carbon-13 nmr spectra
13C NMR (100MHz, deuterated dimethyl sulfoxide, δ ppm): 166.0,161.4,161.1,156.8,142.4,130.0,128.7 (* 2), 114.4 (* 2), 112.1,111.8,55.5,53.5.
Preparation example 8:Midbody compound Vb[2-methoxyl group-6-(3-p-methoxy-phenyl) Nicotinicum Acidum] preparation:
Identical with the method for preparation example 7, be raw material with midbody compound IVb, get midbody compound Vb[2-methoxyl group-6-(3-p-methoxy-phenyl) Nicotinicum Acidum]: yield 86%; White solid; Fusing point: 166～168 ℃; R
f(methylene chloride 25: 1) 0.40.
Embodiment 1:The preparation of Compound I-a ({ 3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(4-luorobenzyl) piperazinyl] ketone)
With 100 milligrams of compound Va[2-methoxyl group-6-(4-p-methoxy-phenyl) Nicotinicum Acidum] be dissolved in 5 milliliters the sulfur oxychloride, be warming up to back flow reaction after 5 hours, after excessive sulfur oxychloride is removed in decompression, add dry 15 milliliters of methylene dichloride and the 0.11 milliliter of triethylamine crossed of no water treatment, stir and add 75 milligrams of 1-(4-luorobenzyl) piperazine down, mixture at room temperature reacted 2 hours, after adding 40 milliliters of dilutions of methylene dichloride, wash (2 * 20 milliliters) with water, the saturated common salt water washing, anhydrous sodium sulfate drying, remove methylene dichloride under reduced pressure, silica gel column chromatography (methylene chloride: 40/1) obtain 116 milligrams of faint yellow solids, fusing point: 128～129 ℃ of (ethanol) separation yield Y=69.4%.R
f(methylene chloride: 20/1): 0.41; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 2.50 (wide unimodal, 4H, H-4 ', 6 '), 3.34 is (wide unimodal, 2H, H-3 ' a, 7 ' a), 3.50 (unimodal, 2H, H-8 '), 3.71 is (wide unimodal, 2H, H-3 ' b, 7 ' b), 3.82 (unimodal, 3H, MeO-4 "), 4.05 (unimodal; 3H, MeO-2), 6.98～7.03 (multiplet, 4H, H-11 ', 13 '; 3 ", 5 "), 7.26～7.34 (multiplet, 3H, H-5,10 '; 14 '), 7.65 (triplet, 1H, J=8.0Hz, H-4), 7.81﹠amp; 8.00 (bimodal, J=8.8Hz, H-2 ", 6 "); Electrospray ionization mass spectrum MS (ESI), m/e:436 (M+1)
+
Prepare the formula shown in the following table one (I) compound according to similar approach with above preparation example and embodiment:
Table one:
OMe representation methoxy (OCH wherein
3); What list below is the physicochemical data of each compound in the table one:
I-b.{3-[2-methoxyl group-6-(3-p-methoxy-phenyl) pyridyl] } (4-benzhydryl piperazidine base) ketone: yellow oil, R
f(chloroform/methanol: 10/1) 0.52; Proton nmr spectra
1H NMR (400MHz, deuterochloroform δ ppm): 2.27～2.56 (multiplet, 4H, H-4 ', 6 '), 3.33 (wide bimodal, 2H, J=20.8Hz, H-3 ' b, 7 ' b), 3.73～3.86 (broad peak, 2H, H-3 ' a, 7 ' a), 3.88 is (unimodal, 3H, MeO-3 "), 4.05 (unimodal, 3H, MeO-2); 4.27 (unimodal, 1H, H-8 '), 6.96 (double doublet, 1H; J=2.8,8.4Hz, H-4 "), 7.21 (triplet, 2H, J=7.2Hz, H-12 ', 18 '), 7.26～7.41 (multiplet, 10H, H-5,10 ', 11 ', 13 ', 14 ', 16 ', 17 ', 19 ', 20 ', 5 "); 7.57～7.65 (multiplet, 3H, H-4,2 ", 6 ").
I-c.{3-[2-methoxyl group-6-(3-p-methoxy-phenyl) pyridyl] } (1,2,3, the 4-tetrahydro isoquinolyl) ketone: faint yellow solid, fusing point: 128～129 ℃ (ethyl alcohol recrystallization), R
f(chloroform/methanol: 10/1) 0.56; Proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 2.91 (wide unimodal, 1H, H-10 ' is b), 3.00 (wide unimodal, 1H, H-10 ' a), 3.53 (wide unimodal, 1H, H-11 ' b), 3.73 (wide unimodal, 1H, H-11 ' a), 3.91 is (unimodal, 3H, MeO-3 "), 4.01 (unimodal, 2H, H-3 '); 4.08 (unimodal, 3H, MeO-2), 6.93 (bimodal, 1H; J=7.2Hz, H-4 "), 6.98 (double doublet, 1H, J=2.0,8.0Hz, H-6 '), 7.14～7.25 (multiplet, 3H, H-5 ', 7 ', 8 '), 7.38～7.45 (multiplets, 2H, H-5 ', 5), 7.62～7.73 (multiplets, 3H, H-4,2 ", 6 ").
I-d.1-[2-methoxyl group-6-(3-p-methoxy-phenyl) nicotinoyl] piperidines-4-methane amide: faint yellow solid, fusing point: 188～189 ℃ (ethyl alcohol recrystallization), R
f(chloroform/methanol: 10/1) 0.56; Proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 1.62～2.01 (multiplet, 4H, H-4 ', 6 '), 2.43 (wide unimodal, 1H, H-5 '), 2.90～3.14 is (wide bimodal, 2H, H-3 ' b, 7 ' b), 3.61 (wide unimodal, 1H, H-3 ' a, 7 ' a), 3.89 (unimodal, 3H, MeO-3 "); 4.07 (unimodal, 3H, MeO-2), 4.75 (wide bimodal, 1H; J=13.2Hz, H-3 ' a, 7 ' a), 5.67 (unimodal; 2H, H-9 '), 6.97 (double doublet, 1H; J=2.8,8.0Hz, H-4 "), 7.37～7.89 (multiplets, 2H, H-5,5 "), 7.59～7.63 (multiplet; 3H, H-4,2 ", 6 ").
I-e.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(3, the 4-dichloro benzyl) piperazinyl] ketone: white solid, fusing point: 82～83 ℃ (ethyl alcohol recrystallization), R
f(ethyl acetate/petroleum ether: 1/3) 0.40; Proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 2.31～2.52 (multiplet, 4H, H-4 ', 6 '), 3.31 (wide unimodal, 2H, H-3 ' b, 7 ' b), 3.48 (unimodal, 2H, H-8 '), 3.82 (wide unimodal, 2H, H-3 ' a, 7 ' a), 3.87 (unimodal, 3H, MeO-4 "), 4.06 (unimodal, 3H; MeO-2), 6.98 (bimodal, 2H, J=8.4Hz, H-3 ", 5 "), 7.17 (bimodal, 1H, J=8.0Hz, H-14 '); 7.33 (bimodal, 1H, J=7.6Hz, H-13 '), 7.39 (bimodal; 1H, J=7.6Hz, H-5), 7.45 (unimodal, 1H; H-10 '), 7.64 (bimodal, 1H, J=7.6Hz, H-4); 8.00 (bimodal, 2H, J=8.4Hz, H-2 ", 6 ").
I-f.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (4-cyclohexyl piperazinyl) ketone: white solid, fusing point: 110～113 ℃ (ethyl alcohol recrystallization), R
f(ethyl acetate/petroleum ether: 1/3) 0.44; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 1.08～1.29 (multiplet, 4H, H-10 ' b, 11 ', 12 ' b), 1.62～1.86 (multiplet, 6H, H-9 ', 10 ' a, 12 ' a, 13 '), 2.29 (wide unimodal, 1H, H-8 '), 2.47～2.63 (multiplets, 4H, H-4 ', 6 '), 3.31 (wide bimodal, 2H, H-3 ' b, 7 ' b), 3.83 (wide unimodal, 2H, H-3 ' a, 7 ' a), 3.87 (unimodal, 3H, MeO-4 "), 4.06 (unimodal; 3H, MeO-2), 6.99 (bimodal, 2H, J=8.8Hz; H-3 ", 5 "), 7.33 (bimodal, 1H, J=7.6Hz; H-5), 7.64 (bimodal, 1H, J=7.6Hz, H-4); 8.00 (bimodal, 2H, J=8.8Hz, H-2 ", 6 ").
I-g.1-[2-methoxyl group-6-(4-p-methoxy-phenyl) nicotinoyl]-4-(piperidino) piperidines-4-methane amide: yellow solid, fusing point: 220 ℃ of (decomposition) (ethyl alcohol recrystallizations), R
f(chloroform/methanol: 10/1) 0.25; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 1.46～1.95 (multiplet, 10H, H-4 ', 6 ', 10 '～12 '), 2.48 (wide unimodal, 2H, H-9 ' b, 13 ' b), 2.54 (wide unimodal, 2H, H-9 ' a, 13 ' a), 3.28 (wide unimodal, 1H, H-3 ' b, 7 ' b), 3.83 is (wide unimodal, 2H, H-3 ' a, 7 ' a), 3.87 (unimodal, 3H, MeO-4 "), 4.06 (unimodal, 3H, MeO-2), 4.57 (wide unimodal; 1H, H-3 ' b, 7 ' b), 5.29 (wide unimodal, 1H; H-15 ' b), 6.90 (wide unimodal, 1H, H-15 ' a), 6.99 (bimodal; 2H, J=8.8Hz, H-3 ", 5 "), 7.33 (bimodal; 1H, J=7.6Hz, H-5), 7.64 (bimodal; 1H, J=7.6Hz, H-4), 8.01 is (bimodal, 2H, J=8.8Hz, H-2 ", 6 ").
I-h.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(4-fluorophenyl) piperazinyl] ketone: white solid, fusing point: 66～67 ℃ (ethyl alcohol recrystallization), R
f(ethyl acetate/petroleum ether: 3/1) 0.35; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 3.06 (wide unimodal, 2H, H-4 ' b, 6 ' b), 3.19 (wide unimodal, 2H, H-4 ' a, 6 ' a), 3.50 (wide unimodal, 2H, H-3 ' b, 7 ' b), 3.88 is (unimodal, 3H, MeO-4 "), 3.98 (wide unimodal, 2H, H-3 ' a; 7 ' a), 4.08 (unimodal, 3H, MeO-2), 6.88～6.92 (multiplet; 2H, H-9 ', 13 '), 6.97～7.01 (multiplet, 4H; H-10 ', 12 ', 3 ", 5 "), 7.36 (bimodal; 1H, J=7.6Hz, H-5), 7.68 (bimodal; 1H, J=7.6Hz, H-4), 8.02 is (bimodal, 2H, J=9.2Hz, H-2 ", 6 ").
I-i.2-methoxyl group-6-(4-p-methoxy-phenyl)-N-(p-tolyl) niacinamide: faint yellow solid, fusing point: 43～44 ℃ (ethyl alcohol recrystallization), R
f(chloroform/methanol: 10/1) 0.48; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 2.35 (s, 3H, Me-6 '), 3.89 (unimodal, 3H, MeO-4 "), 4.27 (unimodal, 3H; MeO-2), 7.01 (bimodal, 2H, J=8.4Hz; H-3 ", 5 "), 7.18 (bimodal, 2H; J=8.0Hz, H-5 ', 7 '), 7.50 (bimodal; 1H, J=8.0Hz, H-5), 7.58 (bimodal; 2H, J=8.4Hz, H-4 ', 8 '), 8.08 (bimodal, 2H, J=8.4Hz, H-2 "; 6 "), 8.60 (bimodal, 1H, J=8.0Hz, H-4), 9.83 (unimodal, 1H, H-2 ').
I-j.1-[2-methoxyl group-6-(4-p-methoxy-phenyl) nicotinoyl]-the 4-piperidone contracts-1, the 2-di-alcohol: yellow oil, R
f(ethyl acetate/petroleum ether: 1/4) 0.35; Proton nmr spectra
1H-NMR (400MHz, deuterated acetone, δ ppm): 1.63～1.81 (multiplet, 4H, H-4 ', 6 '), 3.34 (wide unimodal, 1H, H-3 ' b, 7 ' b), 3.47 (wide unimodal, 1H, H-3 ' b, 7 ' b), 3.78 is (wide unimodal, 1H, H-3 ' a, 7 ' a), 3.87 (unimodal, 3H, MeO-4 "), 3.99 (bimodal, 5H, J=4.4Hz, H-9 '; 10 ', 3 ' a, 7 ' a), 4.06 (unimodal, 3H; MeO-2), 6.99 (bimodal, 2H, J=8.8Hz, H-3 ", 5 "), 7.34 (bimodal, 1H, J=7.6Hz, H-5); 7.64 (bimodal, 1H, J=7.6Hz, H-4), 8.01 (bimodal; 2H, J=8.8Hz, H-2 ", 6 ").
I-k.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (3,4-indoline-1-yl) ketone: faint yellow solid, fusing point: 144～145 ℃ (ethyl alcohol recrystallization), R
f(ethyl acetate/petroleum ether: 1/4) 0.34; Proton nmr spectra
1H-NMR (400MHz, deuterated acetone, δ ppm): 3.05～3.15 (m multiplet, 2H, H-4 '), 3.88 (unimodal, 3H, MeO-4 "), 3.95 (wide unimodal, 2H; H-3 '), 4.08 (unimodal, 3H, MeO-2), 7.00 (bimodal; 2H, J=8.8Hz, H-3 ", 5 "), 7..08 (triplet; 1H, J=7.6Hz, H-7 '), 7.21～7.29 (multiplet; 2H, H-6 ', 8 '), 7.38 (bimodal; 1H, J=7.6Hz, H-5), 7.73 is (bimodal, 1H, J=7.6Hz, H-9 '), 8.04 is (bimodal, 2H, J=8.8Hz, H-2 ", 6 "), 8.33 (bimodal, 1H, J=7.6Hz, H-4).
I-l.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(4-fluorophenyl)-1,2,5,6-tetrahydro pyridyl] ketone: faint yellow solid, fusing point: 114～115 ℃ (ethyl alcohol recrystallization), R
f(chloroform/methanol: 10/1) 0.47; Proton nmr spectra
1H-NMR (400MHz, deuterated acetone, δ ppm): 2.49～2.63 (multiplet, 2H, H-6 '), 3.46～3.88 (multiplet, 2H, H-7 '), 3.98 (unimodal, 3H, MeO-4 "), 4.08 (unimodal, 3H, MeO-2), 4.42 (wide bimodal; 2H, J=12.0Hz, H-3 '), 5.87 (wide unimodal, 0.5H; H-4 ' b), 6.10 (wide unimodal, 0.5H, H-4 ' a), 6.99-7.06 (multiplet; 4H, H-3 ", 5 ", 10 ', 12 '); 7.33-7.38 (multiplet, 3H, H-9 ', 13 '; 5), 7.68 (double doublet, 1H, J=3.2,8.0Hz, H-4), 8.03 (double doublet, 2H, J=3.6,8.8Hz, H-2 ", 6 ").
I-m. cis-2-[2-methoxyl group-6-(4-p-methoxy-phenyl) nicotinoyl amido] the naphthenic acid ethyl ester: white solid, fusing point: 46～47 ℃ (ethyl alcohol recrystallization), R
f(ethyl acetate/petroleum ether: 1/3) 0.38; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 1.24 (triplet, 3H, J=7.2Hz, H-11 '), 1.45～1.76 (multiplet, 6H, H-5 ' b, 6 ', 7 ', 8 ' b), 1.97～2.04 (multiplet, 2H, H-5 ' a, 8 ' a), 2.86 (bimodal, 1H, J=5.2Hz, H-4 '), 3.88 (unimodal, 3H, MeO-4 "), 4.17 (q, 2H; J=7.2Hz, H-10 '), 4.21 (unimodal, 3H, MeO-2); 4.46 (multiplet, 1H, H-3 '), 6.99 (bimodal, 2H; J=8.8Hz, H-3 ", 5 "), 7.43 (bimodal; 1H, J=8.0Hz, H-5), 8.05 (bimodal; 2H, J=8.8Hz, H-2 ", 6 "), 8.50 (bimodal, 1H, J=8.0Hz, H-4), (8.79 unimodal, 1H, J=8.8Hz, H-2 ').
I-n.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (4-ethyl piperazidine base) ketone: yellow solid, fusing point: 79-81 ℃ (ethyl alcohol recrystallization), R
f(ethyl acetate/petroleum ether: 3/1) 0.45; Proton nmr spectra
1H-NMR (400 MHz, deuterated acetone, δ ppm): 1.15 (triplet, 3H, J=7.2Hz, H-9 '), 2.40 (quartet, 2H, J=7.2Hz, H-8 '), 2.51 (wide unimodal, 4H, H-4 ', 6 '), 3.35 (wide unimodal, 2H, H-3 ', 7 '), 3.83 (unimodal, 3H, MeO-4 "), 4.04 (unimodal; 3H, MeO-2), 7.00 (bimodal, 2H; J=8.8Hz, H-3 ", 5 "), 7.30 (bimodal; 1H, J=8.0Hz, H-5), 7.65 (bimodal; 1H, J=8.0Hz, H-4), 8.01 (bimodal; 2H, J=8.8Hz, H-2 ", 6 ").
I-o.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (4-phenyl-1,2,5,6-tetrahydro pyridyl) ketone: faint yellow solid, fusing point: 108～110 ℃ (ethyl alcohol recrystallization), R
f(ethyl acetate/petroleum ether: 1/1) 0.36; Proton nmr spectra
1H-NMR (400MHz, deuterated acetone, δ ppm): 2.52～2.60 (multiplet, 2H, H-6 '), 3.47～3.58 (multiplet, 2H, H-7 '), 3.88 (unimodal, 3H, MeO-4 "), 4.01 (unimodal, 3H, MeO-2), 4.44 (wide unimodal; 2H, H-3 '), 5.93 (unimodal, 0.5H, H-4 ' is b); 6.1 (unimodal, 0.5H, H-4 ' a), 6.99 (double doublet, 2H; J=2.4,8.8Hz H-3 ", 5 "), 7.28 (bimodal, 1H; J=7.2Hz, H-5), 7.34～7.38 (multiplet, 5H, H-9 '; 10 ', 11 ', 12 ', 13 '), 7.68 is (bimodal, 1H, J=7.2Hz, H-4), 8.02 (bimodal, 2H, J=2.4,8.8Hz, H-2 ", 6 ").
I-p.2-methoxyl group-6-(4-p-methoxy-phenyl)-N-phenyl niacinamide: faint yellow oily thing, R
f(chloroform/methanol: 10/1) 0.45; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 3.89 (unimodal, 3H, MeO-4 "); 4.29 (unimodal, 3H, MeO-2), 7.01 (bimodal, 2H; J=8.8 Hz, H-3 ", 5 "), 7.15 (triplet, 1H; J=3.2Hz, H-6 '), 7.39 (triplet, 2H; J=7.6Hz, H-5 ', 7 '), 7.51 (bimodal; 1H, J=8.0Hz, H-5), 7.71 is (bimodal, 2H, J=7.6Hz, H-4 ', 8 '), 8.09 (bimodal, 2H, J=8.8Hz, H-2 "; 6 "), 8.61 (bimodal, 1H, J=8.0Hz, H-4), 9.90 (unimodal, 1H, H-2 ').
I-q.{3-[2-methoxyl group-6-(3-p-methoxy-phenyl) pyridyl] } [4-(4-fluorophenyl) piperazinyl] ketone: white solid, fusing point: 54～55 ℃ (ethyl alcohol recrystallization), R
f(ethyl acetate/petroleum ether: 3/1) 0.35; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 3.07 (wide unimodal, 2H, H-4 ' b, 6 ' b), 3.19 (wide unimodal, 2H, H-4 ' a, 6 ' a), 3.48 (wide bimodal, 2H, J=26Hz, H-3 ' b, 7 ' b), 3.90 (unimodal, 3H, MeO-3 "), 3.98 (wide unimodal, 2H; H-3 ' a, 7 ' a), 4.09 (unimodal, 3H; MeO-2), 6.89～7.02 (multiplet, 5H, H-9 '; 10 ', 12 ', 13 ', 3 "), 7.38～7.44 (multiplet, 2H, H-5,4 "); 7.6～7.65 (multiplet, 2H, H-2 ", 6 "); 7.71 (bimodal, 1H, J=7.6Hz, H-4).
I-r.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (4-benzhydryl piperazidine base) ketone: white solid, fusing point: 82～83 ℃ (ethyl alcohol recrystallization), R
f(ethyl acetate/petroleum ether: 1/4) 0.40;
1H NMR (400MHz, deuterochloroform, δ ppm): 2.28～2.52 (multiplet, 4H, H-4 ', 6 '), 3.35 (wide unimodal, 2H, H-3 ' b, 7 ' b), 3.71～3.86 (wide unimodal, 2H, H-3 ' a, 7 ' a), 3.86 is (unimodal, 3H, MeO-4 "), 4.03 (unimodal, 3H, MeO-2); 4.27 (unimodal, 1H, H-8 '), 6.97 (bimodal, 2H; J=9.2Hz, H-3 ", 5 "), 7.19 (triplet, 2H; J=7.2Hz, H-12 ', 18 '), 7.26～7.31 (multiplet, 5H; H-5,10 ', 14 ', 16 ', 20 '); 7.42 (bimodal, 4H, J=7.2Hz, H-11 ', 13 ', 17 ', 19 '), 7.61 is (bimodal, 1H, J=7.6Hz, H-4), 7.97 is (bimodal, 2H, J=8.8Hz, H-2 ", 6 ").
I-s.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(2-p-methoxy-phenyl) piperazinyl] ketone: white solid, fusing point: 54～55 ℃ (ethyl alcohol recrystallization), R
f(ethyl acetate/petroleum ether: 3/1) 0.35; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 3.04 (wide unimodal, 2H, H-4 ' b, 6 ' b), 3.15 (wide unimodal, 2H, H-4 ' a, 6 ' a), 3.50 (wide bimodal, 2H, J=26Hz, H-3 ' b, 7 ' b), 3.87 (unimodal, 6H, MeO-4 ", 9 '), 4.00 (wide unimodal; 2H, H-3 ' a, 7 ' a), 4.07 (unimodal, 3H; MeO-2), 6.88～7.07 (multiplet, 6H, H-10 ', 11 '; 12 ', 13 ', 3 ", 5 "), 7.35 (bimodal; 1H, J=7.6Hz, H-5), 7.68 (bimodal; 1H, J=7.6Hz, H-4), 8.01 is (bimodal, 2H, J=8.8Hz, H-2 ", 6 ").
I-t.2-methoxyl group-6-(4-p-methoxy-phenyl)-N-(2-morpholine ethyl) niacinamide: white solid, fusing point: 109～110 ℃ (ethyl alcohol recrystallization), Rf (ethyl acetate/petroleum ether: 3/1) 0.35; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform CDCl
3, δ ppm): 2.55 (wide unimodal, 4H, H-7 ', 9 '), (2.62 triplet, 2H, J=6.0Hz, H-4 '), 3.60 (double doublets, 2H, J=6.0,15.2Hz, H-3 '), 3.78 (triplets, 4H, J=4.4Hz, H-6 ', 10 '), 3.88 is (unimodal, 3H, MeO-4 "), 4.22 (unimodal, 2H, MeO-2); 7.00 (bimodal, 2H, J=8.8Hz, H-3 ", 5 "); 7.45 (bimodal, 1H, J=7.6Hz, H-5); 8.06 (bimodal, 2H, J=8.8Hz, H-2 ", 6 "), 8.50 (wide unimodal, H, H-2 '); 8.53 (bimodal, 1H, J=7.6Hz, H-4).
I-u.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid (4-formyl radical-2-methoxyl group) phenyl ester: white solid, fusing point: 61～63 ℃ (sherwood oil recrystallization), R
f(ethyl acetate/petroleum ether: 1/4) 0.65; Proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 3.86 (unimodal, 3H, MeO-4 "), 3.89 (unimodal, 3H; MeO-4 '), 4.09 (unimodal, 3H, MeO-2), 7.10 (bimodal, 2H; J=8.8Hz, H-3 ", 5 "), 7.48 (bimodal, 1H, J=7.6Hz; H-5), 7.66～7.72 (multiplet, 3H, H-5 ', 7 ', 8 '); 8.20 (bimodal, 2H, J=8.8Hz, H-2 ", 6 "), 8.44 (bimodal; 1H, J=7.6Hz, H-4), 10.01 (unimodal, 1H, H-9 ').
I-v.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid (4-formyl radical) phenyl ester white solid: fusing point: 67～69 ℃ (sherwood oil recrystallization), R
f(ethyl acetate/petroleum ether: 1/4) 0.70; Proton nmr spectra
1H NMR (400MHz, CDCl
3, δ ppm): 3.90 (unimodal, 3H, MeO-4 '), 4.20 (unimodal, 3H, MeO-2), 7.20 (bimodal, 2H, J=8.8Hz, H-4 ', 8 '), 7.43 (bimodal, 1H, J=8.4Hz, H-5), 7.44 (bimodal, 2H, J=8.4Hz, H-3 ", 5 "),, 7.97 (bimodal, 2H, J=8.8Hz, H-5 ', 7 '), 8.11 (bimodal, 2H, J=8.4Hz, H-2 ", 6 "), 8.43 is (bimodal, 1H, J=8.0Hz, H-4), 10.03 (unimodal, 1H, H-9 ').
I-w.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid (4-fluorine) benzyl ester: white solid, fusing point: 63～65 ℃ (sherwood oil recrystallization), R
f(ethyl acetate/petroleum ether: 1/4) 0.60; Proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 3.88 (unimodal, 3H, MeO-4 '), 4.15 (unimodal, 3H, MeO-2), 5.32 (unimodal, 2H, H-3 '), 6.99 (bimodal, 2H, J=8.8Hz, H-3 " ' 5 "), 7.06 (bimodal, 2H, J=8.4Hz, H-5 ', 9 '), 7.33 (bimodal, 1H, J=8.0Hz, H-5) 7.35 (bimodal, 2H, J=8.4Hz, H-6 ', 8 '), 8.06 (bimodal, 2H, J=8.8Hz, H-2 ", 6 "), 8.23 (bimodal, 1H, J=8.0Hz, H-4).
I-x.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid pentamethylene base ester: white solid, fusing point: 64～65 ℃ (sherwood oil recrystallization), R
f(ethyl acetate/petroleum ether: 1/4) 0.63; Proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 1.73～1.93 (multiplet, 8H, H-4 ', 5 ', 6 ', 7 '), 3.88 (unimodal, 3H, MeO-4 '), 4.13 is (unimodal, 3H, MeO-2), 5.40 (multiplet, 1H, H-3 '), 6.99 is (bimodal, 2H, J=8.8Hz, H-3 ", 5 "), 7.32 (bimodal, 1H, J=8.0Hz, and H-5) 8.05 (bimodal, 2H, J=8.8Hz, H-2 "; 6 "), 8.16 (unimodal, 1H, J=8.0Hz, H-4).
I-y.[2-methoxyl group-6-(4-p-methoxy-phenyl)] the basic ester of nicotinic acid (hexamethylene-2-alkene): white solid, fusing point: 73～74 ℃ (sherwood oil recrystallization), R
f(ethyl acetate/petroleum ether: 1/4) 0.64; Proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 1.70～1.92 (multiplet, 6H, H-6 ', 7 ', 8 '), 3.88 (unimodal, 3H, MeO-4 '), 4.15 (unimodal, 3H, MeO-2), 5.50 (multiplets, 1H, H-3 '), 5.85 (bimodal, 1H, J=8.0Hz, H-5 '), 6.01 (bimodal, 1H, J=8.0Hz, H-4 '), 6.99 (bimodal, 2H, J=8.8Hz, H-3 ", 5 "), 7.32 is (bimodal, 1H, J=8.0Hz, H-5), 8.04 is (bimodal, 2H, J=8.8Hz, H-2 ", 6 "), 8.10 (unimodal, 1H, J=8.0Hz, H-4).
I-z.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid (4-acetoxyl group) butyl ester: white solid, fusing point: 72～74 ℃ (sherwood oil recrystallization), R
f(ethyl acetate/petroleum ether: 1/4) 0.74;
1H NMR (400MHz, deuterochloroform, δ ppm): 1.84 (bimodal, 4H, J=1.2Hz, H-5 ', 6 '), (2.06 unimodal, 3H, H-10 '), 3.88 (unimodal, 3H, MeO-4 '), 4.15 is (unimodal, 3H, MeO-2), 4.16 (unimodal, 2H, H-7 '), 4.35 (unimodal, 2H, H-4 '), 7.00 (bimodal, 2H, J=8.8Hz, H-3 ", 5 "), 7.34 is (bimodal, 1H, J=8.4Hz, H-5), 8.06 (bimodal, 2H, J=8.8Hz, H-2 ", 6 "), 8.20 (bimodal, 1H, J=8.4Hz, H-4).
Pharmacology embodiment 1:Compound 1-t is to the inhibition experiment of acetylcholine esterase active
Ellman etc. have invented the sensitive testing method of measuring acetylcholine esterase active: with the male Wistar rat sacrificed by decapitation, tell brain rapidly, the separation striatum is also weighed, the 0.05 mol phosphoric acid buffer (pH7.2, about 7 milligrams of albumen/milliliters) that adds 19 times of volumes is used homogenizer homogenate.Get the trial drug that suspension 25 microlitres add 1 milliliter of solvent or 50 μ g/mL, in 37 ℃ of water-baths, incubated in advance 10 minutes.Add 10mM two sulphur-two nitrobenzoic acids (DTNB) 10 microlitres, 405nm wavelength place colorimetric.(with the positive contrast of isocyatic selagine solution).
Compound 1-t that measures thus and positive control selagine are to the restraining effect of AChE as shown in Table 2.
Table two compound 1-t and selagine when 50 μ g/mL to the restraining effect of AChE
| Sample | To AChE inhibiting rate (%) |
| Compound 1-t | 27.6±2.5 |
| Selagine | 65.6±3.7 |
Shown in last table, compound 1-t has certain inhibition activity to acetylcholinesterase, and therefore being hopeful further optimal development becomes the acetylcholinesterase selective depressant.
Pharmacology embodiment 2:Compound 1-s is to the inhibition experiment of acetylcholine esterase active
(1) testing sequence is with pharmacology embodiment 1.
(2) recording compound 1-s percent inhibition to AChE when 50 μ g/mL is 24.9 ± 2.2%, illustrates that compound 1-e has certain inhibition activity equally to acetylcholinesterase.
This type of 6-aryl-3-replacement-pyridinone derivatives of above presentation of results is hopeful to develop into the acetylcholinesterase selective depressant.
Claims (5)
1. one kind has 6-aryl-3-replacement-pyridinone derivatives and the pharmacologically acceptable salt thereof shown in the formula (I):
Wherein, R
1Be methoxyl group; X is selected from oxygen or nitrogen-atoms; The R group is selected from replacement or unsubstituted six-ring alkyl, replaces or unsubstituted phenyl ring, replaces or unsubstituted aromatic heterocycle, and 2～3 rings connect or the parallel conjugation or the unconjugated ring compound of formation of closing; Perhaps X and R merge into and replace or unsubstituted five yuan or hexa-atomic alicyclic ring, replace or unsubstituted five yuan or hexa-member heterocycle, replace or unsubstituted five yuan or hexa-atomic aromatic nucleus, replace or unsubstituted five yuan or hexa-atomic aromatic heterocycle, or 2～3 rings connect or parallel conjugation or the unconjugated replacement or the unsubstituted ring compound of formation of closing; The substituting group that is used to replace is the alkyl that contains 1～5 carbon, hydroxyl, amino, halogen, nitro, cyano group, or benzyl.
2. according to formula (I) compound and the pharmacologically acceptable salt thereof of claim 1, it is characterized in that described compound is selected from following compounds:
I-a.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(4-luorobenzyl) piperazinyl] ketone;
I-b.{3-[2-methoxyl group-6-(3-p-methoxy-phenyl) pyridyl] } (4-benzhydryl piperazidine base) ketone;
I-c.{3-[2-methoxyl group-6-(3-p-methoxy-phenyl) pyridyl] } (1,2,3, the 4-tetrahydro isoquinolyl) ketone;
I-d.1-[2-methoxyl group-6-(3-p-methoxy-phenyl) nicotinoyl] piperidines-4-methane amide;
I-e.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(3, the 4-dichloro benzyl) piperazinyl] ketone;
I-f.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (4-cyclohexyl piperazinyl) ketone;
I-g.1-[2-methoxyl group-6-(4-p-methoxy-phenyl) nicotinoyl]-4-(piperidino) piperidines-4-methane amide;
I-h.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(4-fluorophenyl) piperazinyl] ketone;
I-i.2-methoxyl group-6-(4-p-methoxy-phenyl)-N-(p-tolyl) niacinamide;
I-j.1-[2-methoxyl group-6-(4-p-methoxy-phenyl) nicotinoyl]-the 4-piperidone contracts-1, the 2-di-alcohol;
I-k.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (3,4-indoline-1-yl) ketone;
I-l.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(4-fluorophenyl)-1,2,5,6-tetrahydro pyridyl] ketone;
I-m. cis-2-[2-methoxyl group-6-(4-p-methoxy-phenyl) nicotinoyl amido] the naphthenic acid ethyl ester;
I-n.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (4-ethyl piperazidine base) ketone;
I-o.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (4-phenyl-1,2,5,6-tetrahydro pyridyl) ketone;
I-p.2-methoxyl group-6-(4-p-methoxy-phenyl)-N-phenyl niacinamide;
I-q.{3-[2-methoxyl group-6-(3-p-methoxy-phenyl) pyridyl] } [4-(4-fluorophenyl) piperazinyl] ketone;
I-r.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } (4-benzhydryl piperazidine base) ketone;
I-s.{3-[2-methoxyl group-6-(4-p-methoxy-phenyl) pyridyl] } [4-(2-p-methoxy-phenyl) piperazinyl] ketone;
I-t.2-methoxyl group-6-(4-p-methoxy-phenyl)-N-(2-morpholine ethyl) niacinamide;
I-u.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid (4-formyl radical-2-methoxyl group) phenyl ester;
I-v.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid (4-formyl radical) phenyl ester;
I-w.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid (4-fluorine) benzyl ester;
I-x.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid pentamethylene base ester;
I-y.[2-methoxyl group-6-(4-p-methoxy-phenyl)] the basic ester of nicotinic acid (hexamethylene-2-alkene);
I-z.[2-methoxyl group-6-(4-p-methoxy-phenyl)] nicotinic acid (4-acetoxyl group) butyl ester.
3. compound or their mixture according to claim 1 or 2 is used to prepare the purposes of preventing and treating the senile dementia disease medicament.
4. one kind is used to prepare the pharmaceutical composition of preventing and treating senile dementia, and it contains compound or their mixture and the pharmaceutically acceptable auxiliaries according to claim 1 or 2 as activeconstituents for the treatment of significant quantity.
5. according to the medicine or the pharmaceutical composition of claim 3 and 4, it is characterized in that: the dosage form of described medicine is to adopt injection, tablet or capsule, paster, subcutaneous the planting of different way of administration preparation to bury agent; Or other adopt controlled release, slow release formulation and the nanometer formulation of known theory and technology preparation.
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| CNA2008100609404A CN101255134A (en) | 2008-04-08 | 2008-04-08 | Aryl pyridine compounds and medicament uses thereof |
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| CNA2008100609404A CN101255134A (en) | 2008-04-08 | 2008-04-08 | Aryl pyridine compounds and medicament uses thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009043747A3 (en) * | 2007-10-01 | 2009-07-23 | Hoffmann La Roche | N-heterocyclic biaryl carboxamides as ccr receptor antagonists |
| CN103006647A (en) * | 2013-01-04 | 2013-04-03 | 中国药科大学 | Use of 3-amido-2-pyridone derivative |
| EP2703387A1 (en) * | 2012-08-27 | 2014-03-05 | Biofordrug S.R.L. | Cyclohexyl-substituted piperazine compounds |
| WO2015032280A1 (en) * | 2013-09-06 | 2015-03-12 | 中国中化股份有限公司 | Aryl pyridine (pyrimidine) compound and use thereof |
| CN106542985A (en) * | 2015-09-17 | 2017-03-29 | 宁波杰尔盛化工有限公司 | A kind of preparation method of 3- methoxyacetophenones |
-
2008
- 2008-04-08 CN CNA2008100609404A patent/CN101255134A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009043747A3 (en) * | 2007-10-01 | 2009-07-23 | Hoffmann La Roche | N-heterocyclic biaryl carboxamides as ccr receptor antagonists |
| EP2703387A1 (en) * | 2012-08-27 | 2014-03-05 | Biofordrug S.R.L. | Cyclohexyl-substituted piperazine compounds |
| CN103006647A (en) * | 2013-01-04 | 2013-04-03 | 中国药科大学 | Use of 3-amido-2-pyridone derivative |
| CN103006647B (en) * | 2013-01-04 | 2014-09-10 | 中国药科大学 | Use of 3-amido-2-pyridone derivative |
| WO2015032280A1 (en) * | 2013-09-06 | 2015-03-12 | 中国中化股份有限公司 | Aryl pyridine (pyrimidine) compound and use thereof |
| CN104418800A (en) * | 2013-09-06 | 2015-03-18 | 中国中化股份有限公司 | Aryl pyridine/pyrimidine compound and application thereof |
| CN104418800B (en) * | 2013-09-06 | 2017-06-16 | 沈阳中化农药化工研发有限公司 | Aryl pyrrole (phonetic) pyridine class compound and application thereof |
| CN106542985A (en) * | 2015-09-17 | 2017-03-29 | 宁波杰尔盛化工有限公司 | A kind of preparation method of 3- methoxyacetophenones |
| CN106542985B (en) * | 2015-09-17 | 2019-12-03 | 宁波杰尔盛化工有限公司 | A kind of preparation method of 3- methoxyacetophenone |
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