CN103626692A - 3,5-diaryl-ylidene piperidone derivatives and application thereof in preparing blood glucose-reducing and fat-reducing medicine - Google Patents
3,5-diaryl-ylidene piperidone derivatives and application thereof in preparing blood glucose-reducing and fat-reducing medicine Download PDFInfo
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- C07D213/00—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
- 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
- C07D213/62—Oxygen or sulfur atoms
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- C07D213/68—One oxygen atom attached in position 4
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- C07D405/00—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
- 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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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention relates to the technical field of medicines, and provides 3,5-diaryl-ylidene piperidone derivatives and pharmacologically acceptable salts or hydrates thereof. The chemical structural formula of the 3,5-diaryl-ylidene piperidone derivatives and pharmacologically acceptable salts or hydrates thereof is as shown in a general formula I. The 3,5-diaryl-ylidene piperidone derivatives and pharmacologically acceptable salts or hydrates thereof have a remarkable inhibition effect on PTP1B (protein tyrosine phosphates 1b), and can be used for preparing hypoglycemic medicines, fat-reducing medicines and or health-care products for treating and preventing diabetes mellitus and obesity.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a class 3, the two aryl methene phenylpiperidines ketone derivatives of 5-, and preparing the medicine of hypoglycemic, lipopenicillinase, treatment or prevent diabetes, obesity or the application in healthcare products.
Background technology
Protein tyrosine phosphatase is a kind of posttranslational modification mode 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 tyrosine phosphatases, PTPs) regulate.PTPs is the important member in signal transduction pathway, in the developing of human health and disease, plays keying action.
Protein-tyrosine-phosphatase 1B (protein tyrosine phosphatase1B, PTP1B) is purified and the protein-tyrosine-phosphatase of definite biological property the earliest.The insulin sensitivity reduction that diabetes and obesity are all accompanied by insulin sensitivity tissue is insulin resistant, experimental evidence shows at present, PTP1B plays important negative regulation effect to the phosphorylation level of insulin receptor and substrate thereof, by suppressing the activity of PTP1B, contribute to improve the susceptibility of peripheral tissues to Regular Insulin.Genetics evidence shows, the mouse of PTP1B genetically deficient can maintain normal physiological status, and can improve to the control of blood sugar and to the food-induced obesity of high lipid and have certain resistivity.Two pieces of bibliographical informations with milestone significance there is the mouse susceptibility higher to having of Regular Insulin of PTP1B defect; can improve significantly the controllability to blood sugar, and the obesity of diet induced is had to obvious restraining effect (Elchebly M.et al.Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase1B gene.Science1999; 283:1544-8.; Klaman LD.et al.Increased energy expenditure decreased adiposity and tissue-specific insulin sensitivity in protein-tyrosine phosphatase1B defcient mice.Mol Cell Biol2000; 20:5479-89.).And PTP1B antisense oligonucleotide can significantly reduce the expression of PTP1B enzyme level; thereby make glucose level normalizing; raising is to the susceptibility of Regular Insulin (Zinker BA et.al.; PTP1B antisense oligonucleotide lowers PTP1B protein; normalizes blood glucose, and improves insulin sensitivity in diabetic mice.Proc Natl Acad Sci USA2002; 99:11357-62.; Gum RJ et al., Reduction of protein tyrosine phosphatase1b increases insulin-dependent signaling in ob/ob mice.Diabetes2003; 52:21-8).Therefore, PTP1B is an effectively drug target for the insulin resistant class diseases such as treatment diabetes and obesity, finds in the treatment of high reactivity inhibitor for diseases such as diabetes and obesity with the property of medicine and has broad application prospects.
Up to the present, there are a small amount of document or patent to disclose antitumor, anti-inflammatory (Swagatika Das et.al., Europ J Med Chem, 2013, the 64:321-328 of having of the two aryl methene phenylpiperidines ketone derivatives of 3,5-; 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, two piperidin-4-one-analogues of 5-and preparation method thereof and application ", publication number CN103044322A).In aforesaid Chinese patent application CN201310032627.0, disclose a kind ofly 3,5-bis-(2,6-phenyl-dihalide methylene radical)-piperidin-4-one-analog derivative has 11 β-HSD1 restraining effect.
It is new 3 that the art is devoted to find always, and the two aryl methene phenylpiperidines ketone derivatives of 5-, can have the activity that suppresses PTP1B, are developed further into medicine or healthcare products into hypoglycemic, lipopenicillinase, treatment or prevent diabetes, obesity.
Summary of the invention
The object of the invention is to be to provide a class new 3, acceptable salt or hydrate in the two aryl methene phenylpiperidines ketone derivatives of 5-and pharmacology thereof, another object of the present invention is to provide that above-claimed cpd is hypoglycemic in preparation, reducing blood-fat, prevention or treatment hyperlipidaemia, the medicine of diabetes or the application in healthcare products.
The invention provides a class 3, acceptable salt or hydrate in the two aryl methene phenylpiperidines ketone derivatives of 5-and pharmacology thereof, 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-methylenedioxyphenyl; Or the phenyl of the replacement of showing 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, acceptable salt in the pharmacology 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.
Of the present invention 3, acceptable hydrate in the pharmacology of the two aryl methene phenylpiperidines ketone derivatives of 5-, can be its monohydrate, dihydrate.
Preferred compound of the present invention is as follows:
(3E, 5E)-3, two (3,4-dichlorobenzene the methylene radical)-piperidin-4-one-s of 5-,
(3E, 5E)-3, two (4-trifluoromethyl the α-tolylene)-piperidin-4-one-s of 5-,
(3E, 5E)-3, two (4-bromobenzene the methylene radical)-piperidin-4-one-s of 5-,
(3E, 5E)-3, two (2,4 dichloro benzene the methylene radical)-piperidin-4-one-s of 5-,
(3E, 5E)-3, two (2-the naphthyl methylene)-piperidin-4-one-s of 5-,
(3E, 5E)-3, two (2-chlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (3-chlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (4-chlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (3,4-(methylenedioxy) the α-tolylene)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (2,6-dichlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (4-trifluoromethyl the α-tolylene)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (3,4-dichlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (2,4 dichloro benzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (4-bromobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (thiophene-2-methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3,5-double styrene methylene radical-N-methyl piperidine-4-ketone,
(3E, 5E)-1-ethanoyl-3,5-double styrene methylenepiperidines-4-ketone,
(3E, 5E)-1-ethanoyl-3, two (2-naphthyl methylene) piperidin-4-one-s of 5-,
(3E, 5E)-1-ethanoyl-3, two (2, the 6-dichlorobenzene methylene radical) piperidin-4-one-s of 5-,
(3E, 5E)-1-propionyl-3, two (2,4 dichloro benzene methylene radical) piperidin-4-one-s of 5-,
(3E, 5E)-1-propionyl-3, two (furans-2-methylene radical) piperidin-4-one-s of 5-,
(3E, 5E)-1-((E)-3-(3-bromophenyl) allyl aldehyde radical-3, two (thiophene-2-methylene radical) piperidin-4-one-s of 5-,
(3E, 5E)-1-((E)-3-(4-trifluoromethyl) allyl aldehyde radical-3,5-double styrene methylenepiperidines-4-ketone,
(3E, 5E)-1-cinnamoyl-3, two (the 4-anisole methylene radical) piperidin-4-one-s of 5-,
(3E, 5E)-1-((E)-3-(3-bromophenyl) allyl aldehyde radical-3, two (the 3-fluorobenzene methylene radical) piperidin-4-one-s of 5-, or
(3E, 5E)-1-((E)-3-(4-trifluoromethyl) allyl aldehyde radical-3, two (the 3-fluorobenzene methylene radical) piperidin-4-one-s of 5-.
It is above-mentioned 3 that the present invention also provides, and the synthetic route of the two aryl methene phenylpiperidines ketone derivatives of 5-is as follows:
Adopting piperidone or N-methylpiperidone is raw material, and in 10%～50%NaOH solution/ethanol, reaction (a) obtains segment bounds I compound.At anhydrous pyridine, in 0 degree to room temperature reaction, (b) obtains N acyl substituted product to the formula I compound (being R=H) wherein being obtained by piperidone reaction with various acyl chlorides.Acyl chlorides is by commercially available corresponding acid and SOCl
2back flow reaction is prepared and is obtained.
Disclosed in this invention 3, the two aryl methene phenylpiperidines ketone derivatives of 5-, adopt and carry out screening active ingredients from the gst fusion protein (PTP1B and CDC25B) of expression in escherichia coli purifying.Result shows that general formula I compounds of the present invention all has obvious PTP1B restraining effect when concentration is 20 μ g/ml.In preferred compound 1～37 of the present invention and pharmacology thereof, acceptable salt or hydrate can be used for preparing medicine or the healthcare products of ofhypoglycemic medicine, fat-reducing medicament, treatment and prevent diabetes, obesity.
It is above-mentioned 3 that the present invention also provides, and in the two aryl methene phenylpiperidines ketone derivatives of 5-and pharmacology thereof, acceptable salt or hydrate are being prepared protein-tyrosine-phosphatase 1B(PTP1B) application in inhibitor.
It is above-mentioned 3 that the present invention also provides, acceptable salt or hydrate is hypoglycemic in preparation, reducing blood-fat, prevention or treatment hyperlipidaemia, the medicine of diabetes or the application in healthcare products in the two aryl methene phenylpiperidines ketone derivatives of 5-and pharmacology thereof.
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 available obtaining maybe can be prepared by literature method.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer.
Embodiment 1:(3E, 5E)-3, the preparation of two (3,4-dichlorobenzene the methylene radical)-piperidin-4-one-s of 5-
Get 4-piperidone hydrochloride 134mg, 3,4-dichlorobenzaldehyde 383mg, joins in 8ml ethanol, then adds 20%NaOH2ml, in stirring at room.TLC follows the tracks of reaction (generally approximately needing 12～36h) extremely substantially completely.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)-3, the preparation of two (4-trifluoromethyl the α-tolylene)-piperidin-4-one-s of 5-
Divided by 4-piperidone and 4-trifluoromethylated benzaldehyde, be outside raw material, 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)-3, the preparation of two (4-bromobenzene the methylene radical)-piperidin-4-one-s of 5-
Take 4-piperidone and 4-brooethyl phenyl aldehyde is raw material, and 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)-3, the preparation of two (2,4 dichloro benzene the methylene radical)-piperidin-4-one-s of 5-
Divided by 4-piperidone and 2,4 dichloro benzene formaldehyde, be outside raw material, 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)-3, the preparation of two (2-the naphthyl methylene)-piperidin-4-one-s of 5-
Divided by 4-piperidone and 2-naphthaldehyde, be outside raw material, 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)-3, the preparation of two (2-chlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and 2-chlorobenzaldehyde, be outside raw material, 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)-3, the preparation of two (3-chlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and 3-chlorobenzaldehyde, be outside raw material, 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)-3, the preparation of two (4-chlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and 4-chlorobenzaldehyde, be outside raw material, 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)-3, the preparation of two (3,4-(methylenedioxy) the α-tolylene)-N-methyl piperidine-4-ketone (CHS286) of 5-
Divided by N-methyl-4-piperidone and piperonylaldehyde, be outside raw material, 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)-3, the preparation of two (2,6-dichlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and 2,6-dichlorobenzaldehyde, be outside raw material, 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)-3, the preparation of two (4-trifluoromethyl the α-tolylene)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and 4-trifluoromethylated benzaldehyde, be outside raw material, 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)-3, the preparation of two (3,4-dichlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and 3,4-dichlorobenzaldehyde, be outside raw material, 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)-3, the preparation of two (2,4 dichloro benzene the methylene radical)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and 2,4 dichloro benzene formaldehyde, be outside raw material, 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)-3, the preparation of two (4-bromobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and 4-bromobenzaldehyde, be outside raw material, 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)-3, the preparation of two (thiophene-2-methylene radical)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and 2 thiophene carboxaldehyde, be outside raw material, 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)-3, the preparation of 5-double styrene methylene radical-N-methyl piperidine-4-ketone
Divided by N-methyl-4-piperidone and phenylacrolein, be outside raw material, 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)-1-ethanoyl-3, the preparation of 5-double styrene methylenepiperidines-4-ketone
Get (3E, 5E)-3,5-toluylene methylenepiperidines-4-ketone 300mg, joins in 8ml pyridine, then adds diacetyl oxide 1ml, is heated to 60 degree reaction 2h.Then question response liquid cooling is but poured in the frozen water of 100ml afterwards, stirs, and filters, and 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)-1-ethanoyl-3, the preparation of two (2-naphthyl methylene) piperidin-4-one-s of 5-
Divided by (3E, 5E)-3, two (2-naphthyl methylene) piperidin-4-one-s of 5-are outside raw material, and 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)-1-ethanoyl-3, the preparation of two (2, the 6-dichlorobenzene methylene radical) piperidin-4-one-s of 5-
Divided by (3E, 5E)-3,5-bis-(2,6-dichlorobenzene methylene radical) piperidin-4-one-is outside raw material, and 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)-1-propionyl-3, the preparation of two (2,4 dichloro benzene methylene radical) piperidin-4-one-s of 5-
Divided by (3E, 5E)-(3E,5E)-3,5-bis(2,4-dichlorobenzylidene)piperidin-4-one and propionic anhydride, be outside raw material, 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)-1-propionyl-3, the preparation of two (furans-2-methylene radical) piperidin-4-one-s of 5-
Divided by (3E, 5E)-3,5-bis-(furans-2-methylene radical) piperidin-4-one-is outside raw material, and all the other are with embodiment 20.Yellow solid, fusing point ℃, 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-((E)-3-(3-bromophenyl) allyl aldehyde radical-3, the preparation of two (thiophene-2-methylene radical) piperidin-4-one-s of 5-
3-bromo-cinnamic acid 1g, joins 5ml SOCl
2middle backflow 2h, the excessive SOCl of pressure reducing and steaming
2, stand-by.
(3E, 5E)-3 under nitrogen protection, 5-bis-(thiophene-2-methylene radical) piperidin-4-one-300mg joins in new system anhydrous pyridine, then under 0 degree, adds 3-cinnamyl bromide acyl chlorides 222mg, in room temperature reaction 3h.Then reaction solution is poured in 100ml water, filtered, 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-((E)-3-(4-trifluoromethyl) allyl aldehyde radical-3, the preparation of 5-double styrene methylenepiperidines-4-ketone
Divided by (3E, 5E)-3,5-toluylene methylenepiperidines-4-ketone and 4-trifluoromethyl cinnamic acid are outside raw material, and 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)-1-cinnamoyl-3, the preparation of two (the 4-anisole methylene radical) piperidin-4-one-s of 5-
With (3E, 5E)-3,5-bis-(4-anisole methylene radical) piperidin-4-one-(CHS63) and cassia bark acyl chlorides are raw material, and all the other are with embodiment 22, yellow solid, fusing point 196-198 ℃, 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-((E)-3-(3-bromophenyl) allyl aldehyde radical-3, the preparation of two (the 3-fluorobenzene methylene radical) piperidin-4-one-s of 5-
Divided by (3E, 5E)-(3E,5E)-3,5-bis(3-fluorobenzylidene)piperidin-4-one and 3-bromo-cinnamic acid, be outside raw material, 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-((E)-3-(4-trifluoromethyl) allyl aldehyde radical-3, the preparation of two (the 3-fluorobenzene methylene radical) piperidin-4-one-s of 5-
Divided by (3E, 5E)-(3E,5E)-3,5-bis(3-fluorobenzylidene)piperidin-4-one and 4-trifluoromethyl cinnamic acid, be outside raw material, 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)-3, the preparation of two (2,6-dichlorobenzene the methylene radical)-piperidin-4-one-s of 5-
Divided by 4-piperidone and 2,6-dichlorobenzaldehyde, be outside raw material, 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)-3, the preparation of two (2-bromobenzene the methylene radical)-piperidin-4-one-s of 5-
Divided by 4-piperidone and o-bromobenzaldehye, be outside raw material, 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)-3, the preparation of two (furans-2-methylene radical)-piperidin-4-one-s of 5-
Divided by 4-piperidone and 2 furan carboxyaldehyde, be outside raw material, 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)-3, the preparation of two (5-hydroxymethylfurans-2-methylene radical)-piperidin-4-one-s (CHS74) of 5-
Divided by 4-piperidone and 5-hydroxymethyl-furfural, be outside raw material, all the other are with embodiment 1.Yellow solid, yield 12%.
Embodiment 31:(3E, 5E)-3, the preparation of two (the bromo-6-fluorobenzene of 2-the methylene radical)-piperidin-4-one-s of 5-
With reference to CN103044322A method, take the fluoro-6-bromobenzaldehyde of 4-piperidone and 2-as raw material preparation, column chromatography for separation compound.
Embodiment 32:(3E, 5E)-3, the preparation of two (4-anisole the methylene radical)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and aubepine, be outside raw material, all the other are with embodiment 1.
Embodiment 33:(3E, 5E)-3, the preparation of two (4-fluorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and 4-fluorobenzaldehyde, be outside raw material, all the other are with embodiment 1.
Embodiment 34:(3E, 5E)-3, the preparation of two (2-bromobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and 2-bromobenzaldehyde, be outside raw material, all the other are with embodiment 1.
Embodiment 35:(3E, 5E)-3, the preparation of two (5-hydroxymethylfurans-2-methylene radical)-N-methyl piperidine-4-ketone of 5-
Divided by N-methyl-4-piperidone and 5-hydroxymethyl-furfural, be outside raw material, all the other are with embodiment 1.
Embodiment 36 (3E, 5E)-3, the preparation of the two thenylidene-piperidin-4-one-s of 5-
Divided by 4-piperidone and thiophenecarboxaldehyde, be outside raw material, all the other are with embodiment 1.
Embodiment 37: the PTP1B restraining effect experiment of compound
Compound disclosed in this invention is adopted to the inhibition active testing (Chen et al., Eur J Med Chem2013,69:399-412) that carries out with the following method PTP1B.The protein tyrosine phosphatase esterase PTP1B that is used for screening is the gst fusion protein from expression in escherichia coli purifying.Adopt ultraviolet substrate pNPP, observe different compounds 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 can directly monitor the variation of 405nm place photoabsorption to observe variation and the inhibition situation of compound to it of enzymic activity.First calculate unit time optical absorption intensity in the enzyme initial velocity phase increment (unit: mO.D./min), with this, represent the initial velocity of enzyme, then according to formula 1 calculation sample to the inhibiting rate of enzymic activity (%Inhibition).
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 of the present invention (the compound sequence number in table 1 is corresponding one by one with embodiment 1～36) to the restraining effect of PTP1B as table 1.
Table 1 compound of the present invention at 20 μ g/ml to the inhibiting rate of PTP1B (%)
Visible, 1～26 couple of PTP1B of preferred compound of the present invention has remarkable restraining effect, can be used for preparing medicine or the healthcare products of ofhypoglycemic medicine, fat-reducing medicament, treatment and prevent diabetes, obesity.
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 modification being equal to or replacement under the prerequisite without prejudice to the invention spirit, and the modification that these are equal to or replacement are all included in the application's claim limited range.
Claims (6)
1. a class 3, acceptable salt or hydrate in the two aryl methene phenylpiperidines ketone derivatives of 5-and pharmacology thereof, 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-methylenedioxyphenyl; Or the phenyl of the replacement of showing 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.
2. according to the class 3 shown in claim 1, acceptable salt or hydrate in the two aryl methene phenylpiperidines ketone derivatives of 5-and pharmacology thereof, it is characterized in that, in pharmacology, acceptable salt is its hydrochloride, vitriol, phosphoric acid salt, hydrobromate, maleate, fumarate, tartrate, succinate, lactic acid salt, tosilate, salicylate, or oxalate.
3. according to the class 3 shown in claim 1, acceptable salt or hydrate in the two aryl methene phenylpiperidines ketone derivatives of 5-and pharmacology thereof, is characterized in that, in pharmacology, acceptable hydrate is its monohydrate or dihydrate.
4. according to the class 3 shown in claim 1, acceptable salt or hydrate in the two aryl methene phenylpiperidines ketone derivatives of 5-and pharmacology thereof, is characterized in that, described compound is:
(3E, 5E)-3, two (3,4-dichlorobenzene the methylene radical)-piperidin-4-one-s of 5-,
(3E, 5E)-3, two (4-trifluoromethyl the α-tolylene)-piperidin-4-one-s of 5-,
(3E, 5E)-3, two (4-bromobenzene the methylene radical)-piperidin-4-one-s of 5-,
(3E, 5E)-3, two (2,4 dichloro benzene the methylene radical)-piperidin-4-one-s of 5-,
(3E, 5E)-3, two (2-the naphthyl methylene)-piperidin-4-one-s of 5-,
(3E, 5E)-3, two (2-chlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (3-chlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (4-chlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (3,4-(methylenedioxy) the α-tolylene)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (2,6-dichlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (4-trifluoromethyl the α-tolylene)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (3,4-dichlorobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (2,4 dichloro benzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (4-bromobenzene the methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3, two (thiophene-2-methylene radical)-N-methyl piperidine-4-ketone of 5-,
(3E, 5E)-3,5-double styrene methylene radical-N-methyl piperidine-4-ketone,
(3E, 5E)-1-ethanoyl-3,5-double styrene methylenepiperidines-4-ketone,
(3E, 5E)-1-ethanoyl-3, two (2-naphthyl methylene) piperidin-4-one-s of 5-,
(3E, 5E)-1-ethanoyl-3, two (2, the 6-dichlorobenzene methylene radical) piperidin-4-one-s of 5-,
(3E, 5E)-1-propionyl-3, two (2,4 dichloro benzene methylene radical) piperidin-4-one-s of 5-,
(3E, 5E)-1-propionyl-3, two (furans-2-methylene radical) piperidin-4-one-s of 5-,
(3E, 5E)-1-((E)-3-(3-bromophenyl) allyl aldehyde radical-3, two (thiophene-2-methylene radical) piperidin-4-one-s of 5-,
(3E, 5E)-1-((E)-3-(4-trifluoromethyl) allyl aldehyde radical-3,5-double styrene methylenepiperidines-4-ketone,
(3E, 5E)-1-cinnamoyl-3, two (the 4-anisole methylene radical) piperidin-4-one-s of 5-,
(3E, 5E)-1-((E)-3-(3-bromophenyl) allyl aldehyde radical-3, two (the 3-fluorobenzene methylene radical) piperidin-4-one-s of 5-, or
(3E, 5E)-1-((E)-3-(4-trifluoromethyl) allyl aldehyde radical-3, two (the 3-fluorobenzene methylene radical) piperidin-4-one-s of 5-.
5. a class 3 as claimed in claim 1, acceptable salt or the application of hydrate in preparing protein-tyrosine-phosphatase 1B inhibitor in the two aryl methene phenylpiperidines ketone derivatives of 5-and pharmacology thereof.
6. a class 3 as claimed in claim 1, acceptable salt or hydrate is hypoglycemic in preparation, reducing blood-fat, prevention or treatment hyperlipidaemia, the medicine of diabetes or the application in healthcare products in the two aryl methene phenylpiperidines ketone derivatives of 5-and pharmacology thereof.
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| CN103936667A (en) * | 2014-03-31 | 2014-07-23 | 中山大学 | Novel 3, 5-bis(aryl-methyne)-1-methylpiperidine-4-ketone compound as well as synthetic method and application thereof in preparation of anti-cancer medicines |
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| 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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