CN103626692B - The two aryl methene phenylpiperidines ketone derivatives of 3,5-and preparing the application in hypoglycemic medicine - Google Patents
The two aryl methene phenylpiperidines ketone derivatives of 3,5-and preparing the application in hypoglycemic medicine Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
The present invention relates to medical art.The invention provides the two aryl methene phenylpiperidines ketone derivatives of a class 3,5-and pharmacologically acceptable salt or hydrate, the chemical structural formula of this compound is as shown in general formula I.Compound of the present invention has remarkable restraining effect to PTP1B, can be used for preparing ofhypoglycemic medicine, fat-reducing medicament, treatment and prevent diabetes, the medicine of obesity or healthcare products.
Description
Technical field
The present invention relates to medical art, be specifically related to the two aryl methene phenylpiperidines ketone derivatives of a class 3,5-, and prepare the application in hypoglycemic, lipopenicillinase, treatment or prevent diabetes, the medicine of obesity or healthcare products.
Background technology
Protein tyrosine phosphatase is the posttranslational modification mode of a kind of important conditioning signal transduction.The phosphorylation of tyrosine is reversible dynamic process in vivo, its phosphorylation and dephosphorylation are respectively by protein tyrosine kinase (protein tyrosine kinases, PTKs) and protein-tyrosine-phosphatase (protein tyrosinephosphatases, PTPs) regulate.PTPs is the important member in signal transduction pathway, in the developing of human health and disease, play keying action.
Protein-tyrosine-phosphatase 1B (protein tyrosine phosphatase1B, PTP1B) is the protein-tyrosine-phosphatase being purified and determining biological property the earliest.Diabetes and obesity are all along with the insulin sensitivity reduction in insulin sensitive tissues and insulin resistant, current experimental evidence shows, the phosphorylation level of PTP1B to insulin receptor and substrate thereof plays important negative regulation effect, by suppressing the activity of PTP1B, contribute to improving peripheral tissues to the susceptibility of Regular Insulin.Genetic evidence shows, the mouse of PTP1B genetically deficient can maintain normal physiological status, and can improve the control of blood sugar and the obesity food-induced to high lipid has certain resistivity.Two sections have mouse that the bibliographical information of milestone significance has a PTP1B defect and have higher susceptibility to Regular Insulin; the controllability to blood sugar can be improved significantly, and to the obesity of diet induced, there is obvious restraining effect (Elchebly M.et al.Increased insulin sensitivity and obesity resistance in micelacking the protein tyrosine phosphatase1B gene.Science1999; 283:1544-8.; Klaman LD.et al.Increased energy expenditure decreased adiposity andtissue-specific insulin sensitivity in protein-tyrosine phosphatase1B defcient mice.Mol Cell Biol2000; 20:5479-89.).And PTP1B antisense oligonucleotide significantly can reduce the expression of PTP1B enzyme level; thus make normalize blood sugar levels; improve susceptibility (the Zinker BA et.al. to Regular Insulin; PTP1B antisense oligonucleotide lowers PTP1B protein; normalizes blood glucose, and improves insulin sensitivity in diabetic mice.ProcNatl Acad Sci USA2002; 99:11357-62.; Gum RJ et al., Reduction of proteintyrosine phosphatase1b increases insulin-dependent signaling in ob/ob mice.Diabetes2003; 52:21-8).Therefore, PTP1B is the drug target of an effective disease such as class such as insulin resistant such as treatment diabetes and obesity etc., finds in the treatment of high reactivity inhibitor for the disease such as diabetes and obesity with druggability and has broad application prospects.
Up to the present, what have a small amount of document or patent to disclose the two aryl methene phenylpiperidines ketone derivatives of 3,5-has antitumor, anti-inflammatory (Swagatika Das et.al., Europ J Med Chem, 2013,64:321-328; Martina Bazzaro et.al., J Med Chem.2011,54:449-456; Babasaheb Yadav et.al., Bioorg Med Chem, 2010,18:6701 – 6707; PCT patent application WO2012021692A1, denomination of invention is CURCUMIN ANALOGS AND METHODS OF USE THEREOF; Chinese patent application CN201110139209.2, denomination of invention is " the sub-receptor tyrosine kinase inhibitors of novel fibroblast growth factor ", publication number CN102293770A; Chinese patent application CN201310032627.0, denomination of invention is " a kind of (3E, 5E)-3,5-pairs of piperidin-4-one-analogues and preparation method thereof and application ", publication number CN103044322A).Disclose a kind of 3,5-bis-(2,6-phenyl-dihalide methylene radical)-piperidin-4-one-analog derivative in aforesaid Chinese patent application CN201310032627.0 and there are 11 β-HSD1 restraining effect.
The art is devoted to find new 3,5-two aryl methene phenylpiperidines ketone derivatives always, can have the activity suppressing PTP1B, is developed further into the medicine into hypoglycemic, lipopenicillinase, treatment or prevent diabetes, obesity or healthcare products.
Summary of the invention
The object of the invention is be to provide a class new 3, the two aryl methene phenylpiperidines ketone derivatives of 5-and pharmacologically acceptable salt or hydrate, another object of the present invention is to provide that above-claimed cpd is hypoglycemic in preparation, reducing blood-fat, prevention or treatment hyperlipidaemia, application in the medicine of diabetes or healthcare products.
The invention provides the two aryl methene phenylpiperidines ketone derivatives of a class 3,5-and pharmacologically acceptable salt or hydrate, it is characterized in that, the chemical structural formula of this compound is as shown in general formula I:
Wherein R, represents H, methyl, ethyl, propyl group, butyl, ethanoyl, propionyl, butyryl radicals, cinnamyl; 3 '-fluorine cinnamyl; 3 '-chlorine cinnamyl; 3 '-bromine cinnamyl; 3 '-iodine cinnamyl; 4 '-trifluoromethyl cinnamyl;
Ar, represents furyl, 5-hydroxymethylfurans base, thienyl, 2-naphthyl, 2-phenyl vinyl, 3,4-methylenedioxyphenyls; Or the phenyl of the replacement shown as follows:
Wherein, R
1represent H, methoxyl group, fluorine, chlorine, bromine, iodine;
R
2represent H, fluorine, chlorine, bromine, iodine, methoxyl group, hydroxyl;
R
3represent H, fluorine, chlorine, bromine, iodine, methoxyl group, oxyethyl group, propoxy-, hydroxyl, trifluoromethyl;
R
4represent H, fluorine, chlorine, bromine, iodine, methoxyl group, hydroxyl;
R
5represent H, fluorine, chlorine, bromine, iodine, methoxyl group.
Of the present invention 3, the pharmacologically acceptable salt of the two aryl methene phenylpiperidines ketone derivatives of 5-, can be its hydrochloride, vitriol, phosphoric acid salt, hydrobromate, maleate, fumarate, tartrate, succinate, lactic acid salt, tosilate, salicylate, oxalate etc.
The pharmacologically acceptable hydrate of of the present invention 3,5-two aryl methene phenylpiperidines ketone derivatives can be its monohydrate, dihydrate.
Preferred compound of the present invention is as follows:
(3E, 5E)-3,5-pairs of (3,4-dichlorobenzene methylene radical)-piperidin-4-one-s,
(3E, 5E)-3,5-pairs of (4-trifluoromethyl α-tolylene)-piperidin-4-one-s,
(3E, 5E)-3,5-pairs of (4-bromobenzene methylene radical)-piperidin-4-one-s,
(3E, 5E)-3,5-pairs of (2,4 dichloro benzene methylene radical)-piperidin-4-one-s,
(3E, 5E)-3,5-pairs of (2-naphthyl methylene)-piperidin-4-one-s,
(3E, 5E)-3,5-pairs of (2-chlorobenzene methylene radical)-N-methyl piperidine-4-ketone,
(3E, 5E)-3,5-pairs of (3-chlorobenzene methylene radical)-N-methyl piperidine-4-ketone,
(3E, 5E)-3,5-pairs of (4-chlorobenzene methylene radical)-N-methyl piperidine-4-ketone,
(3E, 5E)-3,5-pairs of (3,4-(methylenedioxy) α-tolylene)-N-methyl piperidine-4-ketone,
(3E, 5E)-3,5-pairs of (2,6-dichlorobenzene methylene radical)-N-methyl piperidine-4-ketone,
(3E, 5E)-3,5-pairs of (4-trifluoromethyl α-tolylene)-N-methyl piperidine-4-ketone,
(3E, 5E)-3,5-pairs of (3,4-dichlorobenzene methylene radical)-N-methyl piperidine-4-ketone,
(3E, 5E)-3,5-pairs of (2,4 dichloro benzene methylene radical)-N-methyl piperidine-4-ketone,
(3E, 5E)-3,5-pairs of (4-bromobenzene methylene radical)-N-methyl piperidine-4-ketone,
(3E, 5E)-3,5-pairs of (thiophene-2-methylene radical)-N-methyl piperidine-4-ketone,
(3E, 5E)-3,5-double styrene methylene radical-N-methyl piperidine-4-ketone,
(3E, 5E)-1-ethanoyl-3,5-double styrene methylenepiperidines-4-ketone,
Two (2-naphthyl methylene) piperidin-4-one-of (3E, 5E)-1-ethanoyl-3,5-,
Two (2, the 6-dichlorobenzene methylene radical) piperidin-4-one-of (3E, 5E)-1-ethanoyl-3,5-,
Two (2,4 dichloro benzene methylene radical) piperidin-4-one-of (3E, 5E)-1-propionyl-3,5-,
Two (furans-2-methylene radical) piperidin-4-one-of (3E, 5E)-1-propionyl-3,5-,
(3E, 5E)-1-(two (thiophene-2-methylene radical) piperidin-4-one-of (E)-3-(3-bromophenyl) allyl aldehyde radical-3,5-,
(3E, 5E)-1-((E)-3-(4-trifluoromethyl) allyl aldehyde radical-3,5-double styrene methylenepiperidines-4-ketone,
Two (4-methoxybenzylidene) piperidin-4-one-of (3E, 5E)-1-cinnamoyl-3,5-,
(3E, 5E)-1-(two (3-fluorobenzylidene) piperidin-4-one-of (E)-3-(3-bromophenyl) allyl aldehyde radical-3,5-, or
(3E, 5E)-1-(two (3-fluorobenzylidene) piperidin-4-one-of (E)-3-(4-trifluoromethyl) allyl aldehyde radical-3,5-.
The synthetic route that present invention also offers 3,5-above-mentioned two aryl methene phenylpiperidines ketone derivatives is as follows:
Adopt piperidone or N-methylpiperidone to be raw material, in 10% ~ 50%NaOH solution/ethanol, react (a) obtain segment bounds I.The formula I (i.e. R=H) be wherein obtained by reacting by piperidone and various acyl chlorides obtain N acyl substituted product at anhydrous pyridine in 0 degree to room temperature reaction (b).Acyl chlorides is by commercially available corresponding acid and SOCl
2back flow reaction is prepared and obtains.
Disclosed in this invention 3,5-two aryl methene phenylpiperidines ketone derivatives, adopt from expression in escherichia coli and the gst fusion protein of purifying (PTP1B and CDC25B) carries out screening active ingredients.Result shows general formula I compounds of the present invention all obvious PTP1B restraining effect when concentration is 20 μ g/ml.Preferred compound 1 ~ 37 of the present invention and pharmacologically acceptable salt or hydrate can be used for preparing ofhypoglycemic medicine, fat-reducing medicament, treatment and prevent diabetes, the medicine of obesity or healthcare products.
Present invention also offers above-mentioned 3,5-two aryl methene phenylpiperidines ketone derivatives and pharmacologically acceptable salt or hydrate are preparing protein-tyrosine-phosphatase 1B(PTP1B) application in inhibitor.
Present invention also offers above-mentioned 3,5-two aryl methene phenylpiperidines ketone derivatives and pharmacologically acceptable salt or hydrate is hypoglycemic in preparation, reducing blood-fat, prevention or treatment hyperlipidaemia, application in the medicine of diabetes or healthcare products.
Embodiment
Now in conjunction with the embodiments, the present invention is described in detail, but enforcement of the present invention is not limited only to this.
Agents useful for same of the present invention and raw material all commercially maybe can be prepared by literature method.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.
Embodiment 1:(3E, 5E) preparation of-3,5-two (3,4-dichlorobenzene methylene radical)-piperidin-4-one-s
Get 4-piperidone hydrochloride 134mg, 3,4-dichlorobenzaldehyde 383mg, joins in 8ml ethanol, then adds 20%NaOH2ml, in stirring at room temperature.TLC follows the tracks of reaction to substantially complete (generally about needing 12 ~ 36h).Then reaction solution is poured in 100ml water.Separate out yellow mercury oxide, filter, with ethyl alcohol recrystallization, obtain sterling 210mg, yield 51%.
1H NMR（DMSO-d
6）:3.96(4H,s,-CH
2-);7.45-7.48(2H,dd,J=8.4Hz,J=1.8Hz,Ar-H);7.52(2H,s,=CH-);7.69-7.72(2H,d,J=8.4Hz,Ar-H);7.76-7.77(2H,d,J=1.8Hz,Ar-H)。
Embodiment 2:(3E, 5E) preparation of-3,5-two (4-trifluoromethyl α-tolylene)-piperidin-4-one-s
Be outside raw material divided by 4-piperidone and 4-trifluoromethylated benzaldehyde, all the other are with embodiment 1.Yellow solid, yield 37%.
1H NMR(DMSO-d
6):3.32(4H,s,-CH
2-);7.63(2H,s,=CH-);7.68-7.71(4H,d,J=8.1Hz,Ar-H);7.79-7.82(4H,d,J=8.1Hz,Ar-H)。
Embodiment 3:(3E, 5E) preparation of-3,5-two (4-bromobenzene methylene radical)-piperidin-4-one-s
With 4-piperidone and 4-brooethyl phenyl aldehyde for raw material, method is with embodiment 1.Yellow solid, yield 63%.
1H NMR(DMSO-d
6):3.95(4H,s,-CH
2-);7.42-7.44(4H,d,J=8.4Hz,Ar-H);7.52(2H,s,=CH-);7.64-7.66(4H,d,J=8.4Hz,Ar-H)。
Embodiment 4:(3E, 5E) preparation of-3,5-two (2,4 dichloro benzene methylene radical)-piperidin-4-one-s
Be outside raw material divided by 4-piperidone and 2,4 dichloro benzene formaldehyde, all the other are with embodiment 1.Yellow solid, yield 36%.
1H NMR（DMSO-d
6）:3.85(4H,s,-CH
2-);7.43-7.46(2H,d,J=8.4Hz,Ar-H);7.50-7.53(2H,dd,J=8.4Hz,J=1.8Hz,Ar-H);7.65(2H,s,=CH-);7.76(2H,d,J=1.8Hz,Ar-H)。
Embodiment 5:(3E, 5E) preparation of-3,5-two (2-naphthyl methylene)-piperidin-4-one-s
Be outside raw material divided by 4-piperidone and 2-naphthaldehyde, all the other are with embodiment 1.Yellow solid, yield 57%.
1H NMR（DMSO-d
6）:4.12(4H,s,-CH
2-);7.57-7.65(6H,m,Ar-H);7.79(2H,s,Ar-H);7.94-8.05(6H,m,Ar-H);8.08(2H,s,CH=)。
Embodiment 6:(3E, 5E) preparation of-3,5-two (2-chlorobenzene methylene radical)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and 2-chlorobenzaldehyde, all the other are with embodiment 1.Yellow solid, yield 59%.
1H NMR（CDCl
3）:2.37(3H,s,-CH
3),3.61(4H,s,CH
2-),7.23-7.26(3H,m,Ar-H),7.304-7.32(5H,m,Ar-H),8.00(2H,CH=)。
Embodiment 7:(3E, 5E) preparation of-3,5-two (3-chlorobenzene methylene radical)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and 3-chlorobenzaldehyde, all the other are with embodiment 1.Yellow solid, yield 62%.
1H NMR（CDCl
3）:2.37(3H,s,-CH
3),3.61-3.16(4H,m,-CH
2-),7.46-7.47(2H,m,Ar-H),7.23-7.47(8H,m,Ar-H),8.00(2H,-CH=)。
Embodiment 8:(3E, 5E) preparation of-3,5-two (4-chlorobenzene methylene radical)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and 4-chlorobenzaldehyde, all the other are with embodiment 1.Yellow solid, yield 55%.
1H NMR（CDCl
3）:2.50(3H,s,-CH3),3.75(4H,s,CH
2-),7.33-7.37(4H,d,Ar-H),7.42-7.45(4H,d,Ar-H),7.78(2H,brs,-CH=)。
Embodiment 9:(3E, 5E) preparation of-3,5-two (3,4-(methylenedioxy) α-tolylene)-N-methyl piperidine-4-ketone (CHS286)
Be outside raw material divided by N-methyl-4-piperidone and piperonylaldehyde, all the other are with embodiment 1.Yellow solid, yield 68%.
1H NMR（CDCl
3）:2.49(3H,s,-CH
3),3.75(4H,s,-CH
2-),6.03(4H,s,O-CH
2-O),6.87-6.96(6H,m,Ar-H),7.72(2H,-CH=)。
Embodiment 10:(3E, 5E) preparation of-3,5-two (2,6-dichlorobenzene methylene radical)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and 2,6-dichlorobenzaldehyde, all the other are with embodiment 1.Yellow solid, yield 35%.
1H NMR(CDCl
3):2.32(3H,s,-CH
3);3.40(4H,s,-CH
2-);7.25-7.28(2H,m,Ar-H);7.37-7.39(4H,m,Ar-H);7.72(2H,s,Ar-H)。
Embodiment 11:(3E, 5E) preparation of-3,5-two (4-trifluoromethyl α-tolylene)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and 4-trifluoromethylated benzaldehyde, all the other are with embodiment 1.Yellow solid, yield 11%.
1H NMR(CDCl
3):4.93(4H,s,-CH
2-);7.15-7.18(4H,d,J=8.4Hz,Ar-H);7.40-7.43(4H,d,J=8.4Hz,Ar-H);7.82(2H,s,=CH-)。
Embodiment 12:(3E, 5E) preparation of-3,5-two (3,4-dichlorobenzene methylene radical)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and 3,4-dichlorobenzaldehyde, all the other are with embodiment 1.Yellow solid, yield 35%.
1H NMR(CDCl
3):2.49(3H,s,-CH
3),3.72(4H,s,-CH
2-),7.21-7.24(2H,m,2’-Ar-H),7.47-7.52(4H,m,5’-Ar-H,6’-Ar-H),7.69(2H,-CH=)。
Embodiment 13:(3E, 5E) preparation of-3,5-two (2,4 dichloro benzene methylene radical)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and 2,4 dichloro benzene formaldehyde, all the other are with embodiment 1.Yellow solid, yield 55%.
1H NMR(CDCl
3):2.39(3H,s,-CH
3),3.56(4H,s,-CH
2-),7.92(2H,-CH=),7.15-7.18(2H,d,J=8.4Hz,4’-Ar-H),7.28-7.31(2H,m,3’-Ar-H),7.49(2H,m,6’-Ar-H)。
Embodiment 14:(3E, 5E) preparation of-3,5-two (4-bromobenzene methylene radical)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and 4-bromobenzaldehyde, all the other are with embodiment 1.Yellow solid, yield 68%.
1H NMR(CDCl
3):2.47(3H,s,-CH
3),3.72(4H,s,N-CH
2-),7.73(2H,brs,-CO-CH=),7.24-7.27(4H,d,J=8.4Hz,3’-Ar-H,5’-Ar-H),7.55-7.58(4H,d,J=8.4Hz,2’-Ar-H,6’-Ar-H)。
Embodiment 15:(3E, 5E) preparation of-3,5-two (thiophene-2-methylene radical)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and 2 thiophene carboxaldehyde, all the other are with embodiment 1.Yellow solid, yield 97%.1H NMR:2.60(3H,s,-CH
3);3.83(4H,s,-CH
2-);7.14-7.17(2H,dd,J=5.1Hz,J=1.2Hz,Ar-H);7.33-7.34(2H,d,J=1.2Hz,Ar-H);7.55-7.57(2H,d,J=5.1Hz,Ar-H)，7.94(2H,s,=CH)。
Embodiment 16:(3E, 5E) preparation of-3,5-double styrene methylene radical-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and phenylacrolein, all the other are with embodiment 1.Yield 49%.
1H NMR:2.56(3H,s,-CH
3);3.67(4H,s,-CH
2-);7.00(2H,s,Ar-H);7.31-7.39(9H,m,Ar-H);7.50-7.52(5H,m,Ar-H)。
Embodiment 17:(3E, 5E) preparation of-1-ethanoyl-3,5-double styrene methylenepiperidines-4-ketone
Get (3E, 5E)-3,5-toluylene methylenepiperidines-4-ketone 300mg, join in 8ml pyridine, then add diacetyl oxide 1ml, be heated to 60 degree of reaction 2h.Then question response liquid cooling is but poured in the frozen water of 100ml afterwards, stirs, and filters, obtains yellow solid, yield 71% with ethyl alcohol recrystallization.
1H NMR:2.21-2.26(3H,s,-CH
3);4.62(2H,s,-CH
2-);4.80(2H,s,-CH
2-);6.92-7.55(16H,m,Ar-H and-CH=).
13C NMR:21.36(-CH
3);41.79,45.97(-CH
2-);121.40-143.50(Ar-C and–C=);169.10(-CO-N-);185.54(-CO-).ESI-MS:[2M+Na]
+=762.68。
Embodiment 18:(3E, 5E) preparation of two (2-naphthyl methylene) piperidin-4-one-s of-1-ethanoyl-3,5-
Be outside raw material divided by (3E, 5E)-3,5-two (2-naphthyl methylene) piperidin-4-one-s, all the other are with embodiment 17.Yellow solid, yield 65%.
1H NMR(DMSO-d
6):2.13(3H,s,-CH
3);4.67(2H,s,-CH
2-);4.97(2H,s,-CH
2-);7.522-7.55(2H,m,Ar-H);7.59-7.61(3H,m,Ar-H);7.69-7.71(2H,m,Ar-H);7.85-7.92(3H,m,Ar-H);7.97-8.04(4H,m,Ar-H)8.15(2H,s)。
Embodiment 19:(3E, 5E) preparation of two (2, the 6-dichlorobenzene methylene radical) piperidin-4-one-s of-1-ethanoyl-3,5-
Be outside raw material divided by (3E, 5E)-3,5-bis-(2,6-dichlorobenzene methylene radical) piperidin-4-one-, all the other are with embodiment 17.Yellow solid, yield 82%.
1H NMR:1.83-1.88(3H,s,-COCH
3);4.24(2H,s,-CH
2-);4.46(2H,s,-CH
2-);7.23-7.44(6H,m,Ar-H);7.69(1H,s,-CH=);7.71(1H,s,-CH=).
13C NMR:20.39(-CH
3);42.65(-CH
2-);46.42(-CH
2-);127.76-135.13(Ar-C and–C=);168.59(-CO-N-);184.43(-CO-).ESI-MS:[2M+Na]
+=929.25。
Embodiment 20:(3E, 5E) preparation of two (2,4 dichloro benzene methylene radical) piperidin-4-one-s of-1-propionyl-3,5-
Be outside raw material divided by (3E, 5E)-(3E,5E)-3,5-bis(2,4-dichlorobenzylidene)piperidin-4-one and propionic anhydride, all the other are with embodiment 17.Yellow solid, yield 72%.
1H NMR:0.97-1.02(3H,t,J=7.5Hz,-CH
3);2.08-2.15(2H,q,J=7.5Hz,-CO-CH
2-);4.51(2H,s,-CH
2-);4.71(2H,s,-CH
2-);7.11-7.15(1H,m,Ar-H);7.31-7.34(2H,m,Ar-H);7.37-7.40(1H,m,Ar-H);7.46(1H,s,Ar-H);7.51(1H,s,Ar-H);7.89(2H,s,-CH=)。
Embodiment 21:(3E, 5E) preparation of two (furans-2-methylene radical) piperidin-4-one-s of-1-propionyl-3,5-
Be outside raw material divided by (3E, 5E)-3,5-bis-(furans-2-methylene radical) piperidin-4-one-, all the other are with embodiment 20.Yellow solid, fusing point DEG C, yield 67%.
1H NMR:1.11-1.16(3H,t,J=7.5Hz,-CH
3);2.41-2.49(2H,q,J=7.5Hz,-CO-CH
2-);4.95(2H,s,-CH
2-);5.04(2H,s,-CH
2-);6.53-7.63(8H,m,Ar-H and-CH=).
13C NMR:9.27(-CH
3);26.37(-CO-CH
2-);43.43(-CH
2-);45.92(-CH
2-);112.62-112.70(3-C);117.96-118.37(4-C);121.90,123.42(-CH=);128.00-128.42(5-C);145.61-145.78(-C=);151.70(2-C);172.61(-CO-N-);185.81(-CO-).ESI-MS：[2M+Na]
+=645.44
Embodiment 22:(3E, 5E)-1-(preparation of two (thiophene-2-methylene radical) piperidin-4-one-of (E)-3-(3-bromophenyl) allyl aldehyde radical-3,5-
3-bromo-cinnamic acid 1g, joins 5ml SOCl
2middle backflow 2h, the excessive SOCl of pressure reducing and steaming
2, stand-by.
Under nitrogen protection, (3E, 5E)-3,5-bis-(thiophene-2-methylene radical) piperidin-4-one-300mg joins in brand-new anhydrous pyridine, under 0 degree, then adds 3-cinnamyl bromide acyl chlorides 222mg, in room temperature reaction 3h.Then reaction solution is poured in 100ml water, filter, with ethyl alcohol recrystallization, obtain yellow solid, yield 75%.
1H NMR:5.01(4H,s,-CH
2-);6.84-6.89(1H,d,J=15.6Hz,α-H);7.16-7.27(4H,m,Ar-H);7.43-7.49(4H,m,Ar-H);7.50-7.56(1H,d,J=15.6Hz,β-H);7.65(1H,s,-CH=);7.67(1H,s,-CH=);8.02(2H,s,5-H).ESI-MS：[2M+Na]
+=1015.00
Embodiment 23:(3E, 5E)-1-(preparation of (E)-3-(4-trifluoromethyl) allyl aldehyde radical-3,5-double styrene methylenepiperidines-4-ketone
Divided by (3E, 5E)-3,5-toluylene methylenepiperidines-4-ketone and 4-trifluoromethyl cinnamic acid be outside raw material, all the other are with embodiment 22.Yellow solid, yield 76%.
1H NMR(DMSO-d
6):4.90(2H,s),5.04(2H,s),7.32-7.44(12H,m),7.54-7.60(4H,d J=6.9),7.72-7.74(4H,dJ=6.9),7.89(1H,s,-CH=),7.92(1H,s,-CH=)。
Embodiment 24:(3E, 5E) preparation of two (4-methoxybenzylidene) piperidin-4-one-s of-1-cinnamoyl-3,5-
With (3E, 5E)-3,5-bis-(4-methoxybenzylidene) piperidin-4-one-(CHS63) and cassia bark acyl chlorides for raw material, all the other are with embodiment 22, yellow solid, fusing point 196-198 DEG C, yield 72%.
1H NMR:3.88(6H,s,-OCH
3);4.88(2H,s,-CH
2-);4.97(2H,s,-CH
2-);6.41-6.46(1H,d,J=15.6Hz,α-H);6.99-7.48(13H,m,Ar-H);7.48-7.53(1H,d,J=15.6Hz,β-H);7.81(2H,s,-CH=).
13C NMR:55.38(-OCH
3and-CH
2-);114.39-143.06(Ar-Cand–CH=);160.75(4-C);165.76(-CO-N-);187.17(-CO-).ESI-MS=[2M+H]
+=931.54；[2M+Na]
+=953.19。
Embodiment 25:(3E, 5E)-1-(preparation of two (3-fluorobenzylidene) piperidin-4-one-of (E)-3-(3-bromophenyl) allyl aldehyde radical-3,5-
Be outside raw material divided by (3E, 5E)-(3E,5E)-3,5-bis(3-fluorobenzylidene)piperidin-4-one and 3-bromo-cinnamic acid, all the other are with embodiment 22.Yellow solid, yield 78%.
1H NMR(CDCl
3):4.90(4H,br，s),6.36-6.41(1H,d,J=16.5Hz,α-H);7.04-7.27(9H,m,Ar-H);7.40-7.51(4H,m,Ar-H);7.81(2H,s,-CH=)。
Embodiment 26:(3E, 5E)-1-(preparation of two (3-fluorobenzylidene) piperidin-4-one-of (E)-3-(4-trifluoromethyl) allyl aldehyde radical-3,5-
Be outside raw material divided by (3E, 5E)-(3E,5E)-3,5-bis(3-fluorobenzylidene)piperidin-4-one and 4-trifluoromethyl cinnamic acid, all the other are with embodiment 22.Yellow solid, yield 75%.
1H NMR(CDCl
3):4.85-4.99(4H,br，s),6.44-6.49(1H,d,J=15.6Hz,α-H);7.19-7.26(8H,m,Ar-H);7.43-7.54(5H,m,Ar-H);7.82(2H,s,-CH=)。ESI-MS：[M-H]
-=508.82。
Embodiment 27:(3E, 5E) preparation of-3,5-two (2,6-dichlorobenzene methylene radical)-piperidin-4-one-s
Be outside raw material divided by 4-piperidone and 2,6-dichlorobenzaldehyde, all the other are with embodiment 1.Yellow solid, yield 52%.
1H NMR:1.61(1H,brs,-NH-);3.67(4H,s,-CH
2-);7.20-7.26(2H,t,J=7.5Hz,4-H);7.35-7.37(4H,d,J=7.5Hz,3,5-H);7.60(2H,s,-CH=).
13C NMR:47.65(-CH
2-);128.04(4-C);129.75(3,5-C);130.71(2,6-C);133.20(1-C);134.40(-C=);138.49(-CH=);186.28(-CO-).
Embodiment 28:(3E, 5E) preparation of-3,5-two (2-bromobenzene methylene radical)-piperidin-4-one-s
Be outside raw material divided by 4-piperidone and o-bromobenzaldehye, all the other are with embodiment 1.Yellow solid, yield 56%.
1H NMR:1.63(1H,brs,-NH-);3.96-4.02(4H,s,-CH
2-);7.20-7.37(6H,m,Ar-H);7.64-7.67(2H,d,J=8.1Hz,Ar-H);7.91(2H,s,-CH=).
13C NMR:47.87(-CH
2-);125.22-136.06(Ar-C and-C=);187.49(-CO-).
Embodiment 29:(3E, 5E) preparation of-3,5-two (furans-2-methylene radical)-piperidin-4-one-s
Be outside raw material divided by 4-piperidone and 2 furan carboxyaldehyde, all the other are with embodiment 1.Yellow solid, yield 49%.
1H NMR:1.70-1.77(1H,brs,-NH-);2.89-2.97(2H,s,-CH
2-);4.29(2H,s,-CH
2-);6.52-6.54(2H,dd,J
1=3.3Hz,J
2=1.5Hz,4-H);6.67-6.68(2H,d,J=3.3Hz,3-H);7.51(2H,s,-CH=);7.59(2H,d,J=1.5Hz,5-H).
Embodiment 30:(3E, 5E) preparation of-3,5-two (5-hydroxymethylfurans-2-methylene radical)-piperidin-4-one-s (CHS74)
Be outside raw material divided by 4-piperidone and 5-hydroxymethyl-furfural, all the other are with embodiment 1.Yellow solid, yield 12%.
Embodiment 31:(3E, 5E) preparation of-3,5-two (the bromo-6-fluorobenzylidene of 2-)-piperidin-4-one-s
With reference to CN103044322A method, with 4-piperidone and the fluoro-6-bromobenzaldehyde of 2-for prepared by raw material, column chromatography for separation compound.
Embodiment 32:(3E, 5E) preparation of-3,5-two (4-methoxybenzylidene)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and aubepine, all the other are with embodiment 1.
Embodiment 33:(3E, 5E) preparation of-3,5-two (4-fluorobenzylidene)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and 4-fluorobenzaldehyde, all the other are with embodiment 1.
Embodiment 34:(3E, 5E) preparation of-3,5-two (2-bromobenzene methylene radical)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and 2-bromobenzaldehyde, all the other are with embodiment 1.
Embodiment 35:(3E, 5E) preparation of-3,5-two (5-hydroxymethylfurans-2-methylene radical)-N-methyl piperidine-4-ketone
Be outside raw material divided by N-methyl-4-piperidone and 5-hydroxymethyl-furfural, all the other are with embodiment 1.
The preparation of the two thenylidene-piperidin-4-one-of embodiment 36 (3E, 5E)-3,5-
Be outside raw material divided by 4-piperidone and thiophenecarboxaldehyde, all the other are with embodiment 1.
Embodiment 37: the PTP1B restraining effect experiment of compound
Compound disclosed in this invention is adopted inhibit activities test (Chen et al., Eur J Med Chem2013,69:399-412) carrying out PTP1B with the following method.Protein tyrosine phosphatase PTP1B for screening is from expression in escherichia coli and the gst fusion protein of purifying.Adopt ultraviolet substrate pNPP, observe different compound and the activity of recombinase is suppressed, with the medicinal effect of preliminary assessment compound.The product that the phosphide of PTP1B hydrolysis substrate pNPP obtains has very strong photoabsorption at 405nm place.Therefore the change directly can monitoring the photoabsorption of 405nm place is to observe the change of enzymic activity and compound to its suppression situation.First calculate the increment (unit: mO.D./min) of unit time optical absorption intensity in the enzyme initial velocity phase, represent the initial velocity of enzyme with this, then according to the inhibiting rate (%Inhibition) of formula 1 calculation sample to enzymic activity.
Formula 1:%Inhibition=(vDMSO-vSample)/vDMSO × 100%
Wherein vSample represents the initial velocity of dosing group, and vDMSO represents the initial velocity of DMSO group (not dosing group).
In test, screening pure compound concentration is 20 μ g/ml.Inhibiting rate is more than or equal to 50% and thinks effective.
Compound 1 ~ 36 (Compound numbers in table 1 and embodiment 1 ~ 36 one_to_one corresponding) of the present invention to the restraining effect of PTP1B as table 1.
Table 1 compound of the present invention is at the inhibiting rate (%) of 20 μ g/ml to PTP1B
Visible, preferred compound of the present invention 1 ~ 26 couple of PTP1B has remarkable restraining effect, can be used for preparing ofhypoglycemic medicine, fat-reducing medicament, treatment and prevent diabetes, the medicine of obesity or healthcare products.
Below the preferred embodiment of the invention is illustrated, but the invention is not limited to described embodiment, those of ordinary skill in the art also can make all equivalent modification or replacement under the prerequisite without prejudice to the invention spirit, and these equivalent modification or replacement are all included in the application's claim limited range.
Claims (4)
1. the two aryl methene phenylpiperidines ketone derivatives of a class 3,5-and pharmacologically acceptable salt, it is characterized in that, described compound is:
(3E, 5E)-3,5-pairs of (2,6-dichlorobenzene methylene radical)-N-methyl piperidine-4-ketone,
(3E, 5E)-3,5-pairs of (4-trifluoromethyl α-tolylene)-N-methyl piperidine-4-ketone,
(3E, 5E)-3,5-pairs of (3,4-dichlorobenzene methylene radical)-N-methyl piperidine-4-ketone,
(3E, 5E)-1-ethanoyl-3,5-double styrene methylenepiperidines-4-ketone,
Two (2-naphthyl methylene) piperidin-4-one-of (3E, 5E)-1-ethanoyl-3,5-,
Two (2, the 6-dichlorobenzene methylene radical) piperidin-4-one-of (3E, 5E)-1-ethanoyl-3,5-,
Two (2,4 dichloro benzene methylene radical) piperidin-4-one-of (3E, 5E)-1-propionyl-3,5-,
Two (furans-2-methylene radical) piperidin-4-one-of (3E, 5E)-1-propionyl-3,5-,
(3E, 5E)-1-(two (thiophene-2-methylene radical) piperidin-4-one-of (E)-3-(3-bromophenyl) allyl aldehyde radical-3,5-,
(3E, 5E)-1-((E)-3-(4-trifluoromethyl) allyl aldehyde radical-3,5-double styrene methylenepiperidines-4-ketone,
Two (4-methoxybenzylidene) piperidin-4-one-of (3E, 5E)-1-cinnamoyl-3,5-,
(3E, 5E)-1-(two (3-fluorobenzylidene) piperidin-4-one-of (E)-3-(3-bromophenyl) allyl aldehyde radical-3,5-, or
(3E, 5E)-1-(two (3-fluorobenzylidene) piperidin-4-one-of (E)-3-(4-trifluoromethyl) allyl aldehyde radical-3,5-.
2. according to the class 3 shown in claim 1, the two aryl methene phenylpiperidines ketone derivatives of 5-and pharmacologically acceptable salt, it is characterized in that, pharmacologically acceptable salt is its hydrochloride, vitriol, phosphoric acid salt, hydrobromate, maleate, fumarate, tartrate, succinate, lactic acid salt, tosilate, salicylate, or oxalate.
3. the two aryl methene phenylpiperidines ketone derivatives of a class 3,5-as claimed in claim 1 and pharmacologically acceptable salt preparing the application in protein-tyrosine-phosphatase 1B inhibitor.
4. the application in the medicine of the two aryl methene phenylpiperidines ketone derivatives of a class 3,5-as claimed in claim 1 and pharmacologically acceptable salt, reducing blood-fat hypoglycemic in preparation thereof, prevention or treatment hyperlipidaemia, diabetes or healthcare products.
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| CN105503709B (en) * | 2015-12-10 | 2019-06-14 | 中国广州分析测试中心 | Bis- (aryl methylene) -1- substitution -4- piperidones series compounds of 3,5- and its in the application for preparing anti esophageal cancer drug |
| CN106800547B (en) * | 2017-01-03 | 2019-07-23 | 中国人民解放军第二军医大学 | A kind of disubstituted aryl class compound and its application |
| CN110452163A (en) * | 2019-08-13 | 2019-11-15 | 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 | A kind of application of the preparation method of curcumin derivate and its anti-prostate cancer |
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