CN101332198B - Pharmaceutical use of 6-aryl-3-substituted carbonyl pyridine compound - Google Patents
Pharmaceutical use of 6-aryl-3-substituted carbonyl pyridine compound Download PDFInfo
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- CN101332198B CN101332198B CN2008100630176A CN200810063017A CN101332198B CN 101332198 B CN101332198 B CN 101332198B CN 2008100630176 A CN2008100630176 A CN 2008100630176A CN 200810063017 A CN200810063017 A CN 200810063017A CN 101332198 B CN101332198 B CN 101332198B
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- Prior art keywords
- bimodal
- unimodal
- methoxyphenyl
- compound
- methoxyl group
- Prior art date
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- 238000013459 approach Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
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- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The present invention provides a class 6-aryl-3-substituted carbonyl-pyridine compound and the application of medicinal salt in anti-tumor medicine preparation. By the pharmacological activity test, the compound has obvious activity inhibiting the growth of vitro human chronic medullary archeocyte leukaemia cell strain (K562) and mouse lymph sample tumor cell train (P388D1) and considerable wide spectrum, which can be used for preparing anti-tumor medicines for leukaemia and relevant tumor diseases.
Description
Technical field
The invention belongs to pharmaceutical chemistry and area of pharmacology, particularly, the present invention relates to a class 6-aryl-3-substituted carbonyl-pyridine compounds and their and be used to prepare the purposes of antitumor drug and pharmaceutical composition.
Background technology
According to World Health Organization's report, malignant tumor is the commonly encountered diseases and the frequently-occurring disease of serious threat human health.In the whole world 5,000,000,000 populations, about 9,000,000 examples of annual new cases, dead person reaches 7,000,000 people because of tumor, and the annual trend that also has increase.Drug therapy is occupied critical role in three big therapies of malignant tumor.In the research of antitumor drug, obtained significant development.In recent years, along with molecular weight tumor is learned, the continuous development of molecular pharmacology, and to the illustrating of tumor essence, the drug development process has been quickened in the invention and the application of advanced technologies such as extensive, rapid screening combinatorial chemistry, genetic engineering.In the quite a long period, the conventional cell drug toxicity will be the main body of tumor pharmacother, becomes the focus of paying close attention at present both at home and abroad at the new type antineoplastic medicine of the too many levels effect of mechanism.
Leukemia (leukemia) is commonly called as leukemia, be one of domestic ten big malignant tumor occurred frequently, the malignant disease that belongs to hemopoietic system, comparatively different with cancers in general is, its pathogenesis still is certain class cell abnormality proliferation in bone marrow or other hemopoietic tissue in the hemopoietic tissue, and further invade each viscera tissue in the human body, cause the normal hematopoiesis cell to be suppressed, the symptom of Chan Shenging generally includes fever clinically, hemorrhage, anemia and liver, the situation of spleen and lymphadenectasis, can be divided into acute and chronic leukemia according to the tumor development situation, if classified by paracytic source, individual beamlets is divided into bone marrow and lymph corpuscle leukemia more again again.Acute lymphoblastic (lymphoblast) leukemia is a kind of life-threatening disease, can grow under its normal condition for lymphocytic cell cancerates, and replace the normal cell in the bone marrow rapidly.This type acute lymphoblastic leukemia is the modal malignant tumor of child, accounts for 25% of the whole tumors of child below 15 years old.Involve 3～5 years old child more, also involve teenager, lessly involve the adult.The associating chemotherapy of treatment multiple medications commonly used, the medicine of each dosage is given in a couple of days or several weeks repeatedly.The Combination chemotherapy medication has oral prednisone, weekly vincristine, and vein gives anthracycline antibiotics or asparaginase.Chronic myelocytic (marrow, bone marrow, granulocytic) leukemia is that bone marrow the marrow being invaded by pathogen malignant change of cell produces a large amount of unusual granulocytic a kind of diseases.Primary disease can involve the crowd of any age and sex, but more rare in child below 10 years old.The treatment of chronic lymphocytic leukemia can merge bone marrow transplantation by the high dose chemotherapy and achieve the goal.Hydroxyurea is the most frequently used chemotherapeutics of primary disease as oral medicine.Busulfan is also helpful to primary disease, but because its serious toxic action is general only as the short-term medication.Yet leukocyte has surface antigen, be (the Human Leukocyte Antigen of Human leukocyte antigen, HLA), if do not run into close family members of blood relationship or the close bone marrow donor of other HLA, because repel considering of factor, usually do not advise accepting bone marrow transplantation, and only based on chemotherapy.In the middle of the leukemic medicine of many treatments, the pill Gleevec (being called STI-571 or imatinib again) of the chronic myeloid leukemia of treatment (CML) of U.S. food and UNDCP (FDA) approval listing is evident in efficacy.As if yet the variability of cancerous cell (Heterogeneity) but overcomes the influence that this medicine brings, take this medicine more for a long time, more is easy to generate the JEG-3 to this medical instrument resistance, and this also so once becomes one of problem of the anxious desire solution of scientist.
Except the novel targets of the antitumor action of domestic and international concern and the new type antineoplastic medicine development at the too many levels effect of mechanism, traditional cytotoxicity antitumor drug is still in the treatment of cancer and the common indispensable first-line treatment measure of using of means such as radiotherapy.The task of pharmaceutical chemistry research worker is in this regard: constantly seek the cell toxicant compounds that leukemia cell line is had growth inhibitory activity, as lead compound, strive for finding the anti-cancer agent of more efficient, low toxicities, such as treatment leukemia medicaments from one generation to the next such as the harringtonine of finding, cytosine arabinoside, daunorubicins, and constantly make progress.The industry cell toxicant class antineoplastic new material just under study for action that national cancer institute NCI announces has manyly have been finished clinical experiment nearly or has come into the market, and it is effective to be used for the treatment of mouse leukemia as the RebeccamycinAnalogue (NSC 655649) of Bristol Myers Squibb development; The guanine metabolism agent interfering (NSC 686673) that Glaxo Wellcome releases is used for the treatment of leukemia, t cell lymphoma etc., illustrates that all cell toxicant class anti-leukemia medicine still has market and definite curative effect comparatively widely.
For further new efficient, the wide spectrum cell toxicant type antitumoral compounds of exploration discovery, we have carried out cytotoxic activity research at people and mouse leukemia related neoplasms cell strain to the pyridine compounds and their of the amide groups of the heterocyclic substituted that contains piperazine ring, saturated or unsaturated replacement prepared among the present invention, ester group.
In the current medicament research and development laboratory, primary dcreening operation has the chemical substance of potential anti-leukemia (leukemia) effect, mainly adopts portable mouse leukemia model P388 to detect.But should screening system shortcoming expose gradually, there are certain difference in its result and human body tumor iuntercellular.In order to screen and seek new cancer therapy drug, must develop with the more approaching detection architecture of people's interior tumor cell.Current trend is to be that target cell is measured with the human tumor cell line.In-vitro screening method commonly used comprises the metabolic analysis method of measuring the cellular metabolism ability, measures the viable count method of cell existence and measures the clonal analysis method that cell clone forms ability.Other develop the leukemia cell line pharmacodynamics evaluation model commonly used that and also have P388/ADR, CCRF, CEM, K562, MolT4, HL-60 etc.
The human leukaemia cell is that K562 is equaled to set up from an example is in the pleura transudate of the chronic myelogenous leukemia patient the blast cell crisis in 1975 by Lozzio, has Philadelphia chromosome (Ph).Because of its when being subjected to the inducing of multiple factor, have to red system, so the ability of monokaryon system or megakaryocytic series differentiation is many cell models of studying as cell differentiation.
Summary of the invention
The purpose of this invention is to provide a class and have 6-aryl-3-substituted carbonyl-pyridine compounds and their shown in the structural formula (I) and the application of pharmaceutically useful salt in the preparation antitumor drug thereof.The structural formula of chemical compound (I) is:
Wherein, R
1Be methoxyl group; X is selected from oxygen or nitrogen-atoms; The R group is selected from replacement or unsubstituted hexatomic ring alkyl, replaces or unsubstituted phenyl ring, replaces or unsubstituted aromatic heterocycle, and 2～3 rings connect or the parallel conjugation or the unconjugated cyclic 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 rings, 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 cyclic compound of formation of closing; The substituent group that is used to replace is the alkyl that contains 1～5 carbon, hydroxyl, amino, halogen, nitro, cyano group, or benzyl.
The present invention is used to prepare formula (I) chemical compound of leukemia and related neoplasms medicinal usage, preferably certainly:
I-a.{3-[2-methoxyl group-6-(4-methoxyphenyl) pyridine radicals] } [4-(4-luorobenzyl) piperazinyl] ketone;
I-b.{3-[2-methoxyl group-6-(3-methoxyphenyl) pyridine radicals] } (4-benzhydryl piperazidine base) ketone;
I-c.{3-[2-methoxyl group-6-(3-methoxyphenyl) pyridine radicals] } (1,2,3, the 4-tetrahydro isoquinolyl) ketone;
I-d.1-[2-methoxyl group-6-(3-methoxyphenyl) nicotinoyl] piperidines-4-Methanamide;
I-e.{3-[2-methoxyl group-6-(4-methoxyphenyl) pyridine radicals] } [4-(3, the 4-dichloro benzyl) piperazinyl] ketone;
I-f.{3-[2-methoxyl group-6-(4-methoxyphenyl) pyridine radicals] } (4-cyclohexyl piperazinyl) ketone;
I-g.1-[2-methoxyl group-6-(4-methoxyphenyl) nicotinoyl]-4-(piperidino) piperidines-4-Methanamide;
I-h.{3-[2-methoxyl group-6-(4-methoxyphenyl) pyridine radicals] } [4-(4-fluorophenyl) piperazinyl] ketone;
I-i.2-methoxyl group-6-(4-methoxyphenyl)-N-(p-tolyl) nicotiamide;
I-j.1-[2-methoxyl group-6-(4-methoxyphenyl) nicotinoyl]-the 4-piperidones contracts-1, the 2-diethanol;
I-k.{3-[2-methoxyl group-6-(4-methoxyphenyl) pyridine radicals] } (3,4-indoline-1-yl) ketone;
I-l.{3-[2-methoxyl group-6-(4-methoxyphenyl) pyridine radicals] } [4-(4-fluorophenyl)-1,2,5,6-tetrahydro pyridyl] ketone;
I-m. cis-2-[2-methoxyl group-6-(4-methoxyphenyl) nicotinoyl amido] the naphthenic acid ethyl ester;
I-n.{3-[2-methoxyl group-6-(4-methoxyphenyl) pyridine radicals] } (4-ethyl piperazidine base) ketone;
I-o.{3-[2-methoxyl group-6-(4-methoxyphenyl) pyridine radicals] } (4-phenyl-1,2,5,6-tetrahydro pyridyl) ketone;
I-p.2-methoxyl group-6-(4-methoxyphenyl)-N-phenyl nicotiamide;
I-q.{3-[2-methoxyl group-6-(3-methoxyphenyl) pyridine radicals] } [4-(4-fluorophenyl) piperazinyl] ketone;
I-r.{3-[2-methoxyl group-6-(4-methoxyphenyl) pyridine radicals] } (4-benzhydryl piperazidine base) ketone;
I-s.{3-[2-methoxyl group-6-(4-methoxyphenyl) pyridine radicals] } [4-(2-methoxyphenyl) piperazinyl] ketone;
I-t.2-methoxyl group-6-(4-methoxyphenyl)-N-(2-morpholine ethyl) nicotiamide;
I-u.[2-methoxyl group-6-(4-methoxyphenyl)] nicotinic acid (4-formoxyl-2-methoxyl group) phenyl ester;
I-v.[2-methoxyl group-6-(4-methoxyphenyl)] nicotinic acid (4-formoxyl) phenyl ester;
I-w.[2-methoxyl group-6-(4-methoxyphenyl)] nicotinic acid (4-fluorine) benzyl ester;
I-x.[2-methoxyl group-6-(4-methoxyphenyl)] nicotinic acid Pentamethylene. base ester;
I-y.[2-methoxyl group-6-(4-methoxyphenyl)] the basic ester of nicotinic acid (hexamethylene-2-alkene);
I-z.[2-methoxyl group-6-(4-methoxyphenyl)] nicotinic acid (4-acetoxyl group) butyl ester.
Formula (I) synthetic route that chemical compound adopted that preparation the present invention relates to has following process route feature: utilize the condensation under the effect of condensing agent or derivatization reagent of 6-aryl-2-alkoxyl-Nicotinicum Acidum (compound IV) and organic alcohol, phenol or organic amine to generate Compound I I (acetanisole or meta-methoxy 1-Phenylethanone .).Specifically comprise: when forming amido link; use the synthetic method of amine acidylate commonly used; carboxylic acid and organic amine directly high temperature or mineral acid (as: concentrated sulphuric acid, 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 Bronsted acid, Lewis acid catalysis of carboxylic acid and alcohol or phenol forms, perhaps use Vesley method, DCC and analog 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 ketenes as catalyst, perhaps two activation methods are used; Utilize carboxylic acid and organic alcohol, phenol or organic amine condensation reaction under the effect of condensing agent or derivatization reagent 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; response time 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 naphthyridine ", and DIC is " N, a N-DIC ", and BDP is " diphenyl phosphoester ", and BOP is " blocking special condensing agent ".
Usefulness of the present invention is: test through pharmacologically active, this compounds has the activity of remarkable chronic myelogone leukemia cell line of inhibition In vitro culture people (K562) and mouse lymph sample tumor cell strain (P388D1) growth, can be used as anti-treating leukemia and related neoplasms disease medicament purposes thereof.
The present invention has selected chronic myelogone leukemia cell line of In vitro culture people (K562) and mouse lymph sample tumor cell strain (P388D1) as the pharmacological testing evaluation model.Test is found: the 6-aryl-3-substituted carbonyl-pyridine compounds and their among the present invention is all to have significant growth inhibitory activity for above two kinds of leukemia relevant cells, illustrate that such 6-aryl-3-substituted carbonyl-pyridine compounds and their has the purposes that can expect as anti-treating leukemia related neoplasms disease medicament, finishes the present invention thus.
The specific embodiment
Further specify the present invention below by preparation example and embodiment.Embodiment has provided the synthetic and dependency structure appraising datum 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 (acetanisole):
Methoxybenzene (10.8 grams, 0.1 mole) is dissolved in 150 milliliters of dichloromethane, adds anhydrous chlorides of rase zinc powder (26.8 grams, 0.20 mole) then, drip acetic anhydride (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 facies anhydrous magnesium sulfate drying, filtering and concentrating get the colorless oil crude product, get initial compounds IIa (acetanisole) (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 1-Phenylethanone .):
3-hydroxy acetophenone (13.6 grams, 0.1 mole) is dissolved in 150 milliliters of acetone, adds potassium carbonate 20 gram (0.15 mole) and dimethyl sulfate (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 color grease crude product, get Compound I Ib (meta-methoxy 1-Phenylethanone .) 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-methoxyphenyl)-2H-pyridin-2-ones] preparation:
With sodium metal (2.76 grams, 120 mMs) add in 250 milliliters of ether, drip 1 milliliter of ethanol, drip Compound I Ia (acetanisole) (100 mM) and Ethyl formate (150 mM) 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 cyanoacetamide (12.6 grams, 150 mMs) and water (400 milliliters).After mixture refluxed 8 hours, acidifying with acetic acid was used in cooling, filter xanchromatic solid, after the drying, head product recrystallization from ethanol obtains intermediate compound III a[3-cyano group-6-(4-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-2-methoxypyridine] preparation:
Intermediate compound III a[3-cyano group-6-(4-methoxyphenyl)-2H-pyridin-2-ones] (10 mM) at N, N-dimethylformamide dimethyl acetal (DMFDMA) (1.8 grams, 15 mMs) N, dinethylformamide (50 milliliters) vlil is spent the night, and mixture is to going in the frozen water.Produce 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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl)-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-methoxyphenyl) Nicotinicum Acidum] preparation:
In 100 milliliters of ethanol, the potassium hydroxide solution and midbody compound IVa[3-cyano group-6-(4-the methoxyphenyl)-2-methoxypyridine that add 110 milliliter 30%]: (10 mM), heat up and refluxed 12 hours, be cooled to room temperature, placement is spent the night, filter 2-methoxyl group-6-(4-methoxyphenyl) Nicotinicum Acidum potassium salt, after the careful neutralization of the hydrochloric acid of 6N, with dichloromethane extraction (5 * 150 milliliters), merge organic facies, anhydrous calcium chloride drying, sucking filtration, rotary evaporation is removed dichloromethane, obtains midbody compound Va[2-methoxyl group-6-(4-methoxyphenyl) 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-methoxyphenyl) 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-methoxyphenyl) 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-methoxyphenyl) pyridine radicals] } [4-(4-luorobenzyl) piperazinyl] ketone)
With 100 milligrams of chemical compound Va[2-methoxyl group-6-(4-methoxyphenyl) Nicotinicum Acidum] be dissolved in 5 milliliters the thionyl chloride, be warming up to back flow reaction after 5 hours, after excessive thionyl chloride is removed in decompression, add dry 15 milliliters of dichloromethane 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 dichloromethane, wash (2 * 20 milliliters) with water, the saturated common salt water washing, anhydrous sodium sulfate drying, remove dichloromethane 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 Mass Spectrometry MS (ESI), m/e:436 (M+1)
+
Prepare the formula shown in the following table one (I) chemical 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 chemical compound in the table one:
I-b.{3-[2-methoxyl group-6-(3-methoxyphenyl) pyridine radicals] } (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-methoxyphenyl) pyridine radicals] } (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-methoxyphenyl) nicotinoyl] piperidines-4-Methanamide: faint yellow solid, fusing point: 188～189 ℃ (ethyl alcohol recrystallization), R
f(chloroform/methanol: 10/1) 0.56; Proton nmr spectra
1HNMR (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-methoxyphenyl) pyridine radicals] } [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-methoxyphenyl) pyridine radicals] } (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-methoxyphenyl) nicotinoyl]-4-(piperidino) piperidines-4-Methanamide: 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-methoxyphenyl) pyridine radicals] } [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-methoxyphenyl)-N-(p-tolyl) nicotiamide: 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-methoxyphenyl) nicotinoyl]-the 4-piperidones contracts-1, the 2-diethanol: 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-methoxyphenyl) pyridine radicals] } (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-1.{3-[2-methoxyl group-6-(4-methoxyphenyl) pyridine radicals] } [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-methoxyphenyl) 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-methoxyphenyl) pyridine radicals] } (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 (400MHz, 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-methoxyphenyl) pyridine radicals] } (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-methoxyphenyl)-N-phenyl nicotiamide: 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=8.8Hz, 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-methoxyphenyl) pyridine radicals] } [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-methoxyphenyl) pyridine radicals] } (4-benzhydryl piperazidine base) ketone: white solid, fusing point: 82～83 ℃ (ethyl alcohol recrystallization), R
f(ethyl acetate/petroleum ether: 1/4) 0.40;
1HNMR (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-methoxyphenyl) pyridine radicals] } [4-(2-methoxyphenyl) 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-methoxyphenyl)-N-(2-morpholine ethyl) nicotiamide: white solid, fusing point: 109～110 ℃ (ethyl alcohol recrystallization), R
f(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-methoxyphenyl)] nicotinic acid (4-formoxyl-2-methoxyl group) phenyl ester: white solid, fusing point: 61～63 ℃ (petroleum ether 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-methoxyphenyl)] nicotinic acid (4-formoxyl) phenyl ester white solid: fusing point: 67～69 ℃ (petroleum ether 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-methoxyphenyl)] nicotinic acid (4-fluorine) benzyl ester: white solid, fusing point: 63～65 ℃ (petroleum ether recrystallization), R
f(ethyl acetate/petroleum ether: 1/4) 0.60; Proton nmr spectra
1HNMR (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-methoxyphenyl)] nicotinic acid Pentamethylene. base ester: white solid, fusing point: 64～65 ℃ (petroleum ether recrystallization), R
f(ethyl acetate/petroleum ether: 1/4) 0.63; Proton nmr spectra
1HNMR (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-methoxyphenyl)] the basic ester of nicotinic acid (hexamethylene-2-alkene): white solid, fusing point: 73～74 ℃ (petroleum ether 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-methoxyphenyl)] nicotinic acid (4-acetoxyl group) butyl ester: white solid, fusing point: 72～74 ℃ (petroleum ether 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).
The prepared above-mentioned 6-aryl-3-substituted carbonyl-pyridine compounds and their of the present invention has important biological, in vitro tests shows that this type of chemical compound with pyridine ring structure has growth inhibitory activity for chronic myelogone leukemia cell line of In vitro culture people (K562) and mouse lymph sample tumor cell strain (P388D1), can expect as control related neoplasms disease medicament purposes.
The prepared compound or pharmaceutically acceptable salt thereof of the present invention can combine with adjuvant or carrier pharmaceutically commonly used, prepares the pharmaceutical composition with anticancer usage.Aforementioned pharmaceutical compositions can adopt injection, tablet, capsule, paster, the subcutaneous dosage forms such as burying agent of planting, or other adopt controlled release, slow release formulation and the nanometer formulation of known theory and technology preparation.
Embodiment further specifies the present invention below by pharmacology.Embodiment has provided the part activity data of representative compounds.Mandatory declaration, following pharmacology 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.
Pharmacology embodiment 1:Compound I-x is to the chronic myelogone leukaemia's of people cytotoxic activity
The chronic myelogone leukaemia of people (K562) contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter streptomycin with RPMI 1640 culture medium culturings in the culture medium.Cell is with every hole 1 * 10
4Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO
2Cultivated 24 hours in the incubator of humid air.
The assay method of cell survival rate is with improveing mtt assay.Cell is after 24 hours hatch, and the dimethyl sulfoxide solution of the Compound I-x that will newly join joins in each hole with Concentraton gradient respectively, makes that the ultimate density of chemical compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), continue at 37 ℃ 5%CO again
2Cultivated 3 hours in the incubator of humid air, add 150 microlitre dimethyl sulfoxines in every hole, the MTT crystal Jia Za (formazan) that the vibration dissolving generates, formed Jia Za microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Wherein Compound I-x is to the half-inhibition concentration (IC of K562 cell
50) obtain by dose effect curve.
Experimental result shows, the IC of Compound I-x
50Be 57.9 μ M.
As positive control, DDP is to the 503nhibiting concentration IC of K562 cell with antitumor one line medication cisplatin (DDP) in this test
50Be 18.8 μ M.
This experiment shows that this type of 6-aryl-3-substituted carbonyl-pyridine compounds and their has stronger cytotoxicity to chronic myelogone leukaemia, might develop into the new medicine with the chronic myelogone leukemia of anti-people and related neoplasms effect.
Pharmacology embodiment 2:Compound I-y is to the chronic myelogone leukaemia's of people cytotoxic activity
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 1.
Wherein Compound I-y is to K562 cell 503nhibiting concentration (IC
50) obtain by dose effect curve.The IC of Compound I-y
50Be 65.9 μ M; As positive control, DDP is to the 503nhibiting concentration IC of K562 cell with antitumor one line medication cisplatin (DDP) in this test
50Be 18.8 μ M.
Experiment conclusion: this experiment shows that further this type of 6-aryl-3-substituted carbonyl-pyridine compounds and their has stronger cytotoxicity to the chronic myelogone leukaemia of people, might develop into the new medicine with anti-chronic myelogone leukemia effect and related neoplasms effect.
Pharmacology embodiment 3: Compound I-j is to the chronic myelogone leukaemia's of people cytotoxic activity
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 1.
Wherein Compound I-j is to K562 cell 503nhibiting concentration (IC
50) obtain by dose effect curve.The IC of Compound I-j
50Be 46.2 μ M; As positive control, DDP is to the 503nhibiting concentration IC of K562 cell with antitumor one line medication cisplatin (DDP) in this test
50Be 18.8 μ M.
Experiment conclusion: this experiment shows that further this type of 6-aryl-3-substituted carbonyl-pyridine compounds and their has stronger cytotoxicity to the chronic myelogone leukaemia of people, might develop into the new medicine with anti-chronic myelogone leukemia effect and related neoplasms effect.
Pharmacology embodiment 4: Compound I-x is to the cytotoxic activity of mouse lymph sample tumor
Mouse lymph sample oncocyte (P388D1) contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter streptomycin with RPMI 1640 culture medium culturings in the culture medium.Cell is with every hole 5 * 10
3Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO
2Cultivated 24 hours in the incubator of humid air.
The assay method of cell survival rate is with improveing mtt assay.Cell is after 24 hours hatch, and the dimethyl sulfoxide solution of the Compound I-x that will newly join joins in each hole with Concentraton gradient respectively, makes that the ultimate density of chemical compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), continue at 37 ℃ 5%CO again
2Cultivated 3 hours in the incubator of humid air, add 150 microlitre dimethyl sulfoxines in every hole, the MTT crystal Jia Za (formazan) that the vibration dissolving generates, formed Jia Za microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Wherein Compound I-x is to the half-inhibition concentration (IC of P388D1 cell
50) obtain by dose effect curve.
Compound I-x is to P388D1 cell half-inhibition concentration IC
50Obtain by dose effect curve.Experimental result shows, the IC of Compound I-7
50Be 36.8 μ M.
As positive control, DDP is to the 503nhibiting concentration IC of P388D1 cell with antitumor one line medication cisplatin (DDP) in this test
50Be 7.7 μ M.
This experiment shows that this type of 6-aryl-3-substituted carbonyl-pyridine compounds and their has stronger cytotoxicity to the P388D1 cell, might develop into the new medicine with antiangiogenic quasi-leukemia and related neoplasms effect.
Pharmacology embodiment 5: Compound I-y is to the cytotoxic activity of mouse lymph sample tumor
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 4.
Compound I-y is to P388D1 cell half-inhibition concentration IC
50Obtain by dose effect curve.Experimental result shows, the IC of Compound I-y
50Be 44.7 μ M.
This test with antitumor one line medication cisplatin (DDP) as the 503nhibiting concentration IC of positive control DDP to the P388D1 cell
50Be 7.7 μ M.
This experiment further shows 6-aryl 3-substituted carbonyl-pyridine compounds and their, and the P388D1 cell is had stronger cytotoxicity, might develop into the new medicine with antiangiogenic quasi-leukemia and related neoplasms effect.
Pharmacology embodiment 6: Compound I-j is to the cytotoxic activity of mouse lymph sample tumor
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 4.
Compound I-j is to P388D1 cell half-inhibition concentration IC
50Obtain by dose effect curve.Experimental result shows, the IC of Compound I-j
50Be 46.3 μ M.
As positive control, DDP is to the 503nhibiting concentration IC of P388D1 cell with antitumor one line medication cisplatin (DDP) in this test
50Be 7.7 μ M.
This experiment shows further that again 6-aryl-3-substituted carbonyl-pyridine compounds and their designed among the present invention has stronger cytotoxicity to the P388D1 cell, might develop into the new medicine with antiangiogenic quasi-leukemia and related neoplasms effect.
These 6-aryl-3-substituted carbonyl-pyridine compounds and theirs of the present invention or its officinal salt can with antitumor drug that has now gone on the market such as platinum medicine cisplatin (DDP), camptothecine irinotecan (Irinatecan, CPT-11), the vinca alkaloids medicine loses carbon vincaleucoblastine (Vinorebine, the NVB nvelbine), deoxidation born of the same parents former times class medicine gemcitabine (Gemcitabine, Gemzar, strong selecting), the harringtonine analog derivative, Rebeccamycin Analogue (NSC 655649), guanine metabolism agent interfering (NSC686673), Gleevec etc. unite use, prepare and have tumor growth and suppress active cytotoxicity compositions, can be used for treating tumor disease, especially leukemia and related neoplasms disease thereof.
Claims (2)
1. 6-aryl-3-substituted carbonyl-pyridine compounds and their and officinal salt thereof the application in the preparation antitumor drug, described chemical compound has the structure shown in the formula (I):
It is characterized in that,
Described chemical compound is preparing the application for the treatment of in acute and chronic leukemia, bone marrow and the lymph corpuscle leukemia medicament;
Described chemical compound is selected from:
Methoxyl group-6-(4-methoxyphenyl) nicotinoyl of Compound I-j.1-[2-]-the 4-piperidones contracts-1, the 2-diethanol;
Compound I-x.[2-methoxyl group-6-(4-methoxyphenyl)] nicotinic acid Pentamethylene. base ester;
Compound I-y.[2-methoxyl group-6-(4-methoxyphenyl)] the basic ester of nicotinic acid (hexamethylene-2-alkene).
2. application according to claim 1 is characterized in that: the dosage form of described medicine is selected injection, tablet or capsule for use.
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