CN102993197B - Tropinone derivative and its preparation method and application - Google Patents
Tropinone derivative and its preparation method and application Download PDFInfo
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- CN102993197B CN102993197B CN201210579131.0A CN201210579131A CN102993197B CN 102993197 B CN102993197 B CN 102993197B CN 201210579131 A CN201210579131 A CN 201210579131A CN 102993197 B CN102993197 B CN 102993197B
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Abstract
The invention belongs to the preparation field of compound, specifically provide tropinone derivative and its preparation method and application.The structural formula of tropinone derivative and pharmacy acceptable salt thereof as shown in general formula I, wherein, R
2be selected from the alkyl of 1-6 carbon, the aromatic base of a 1-20 carbon, the heterocycle of a 1-20 carbon, amino group; X is selected from alkyl, the aromatic base of a 1-20 carbon, the heterocycle of a 1-20 carbon of 1-6 carbon, methylsulfonyl, p-toluenesulfonyl or
, wherein R
1be selected from the alkyl of 1-6 carbon, the aromatic base of a 1-20 carbon, the heterocycle of a 1-20 carbon.Described tropinone derivative may be used for the medicine preparing treatment type ii diabetes.
Description
Technical field
The preparation field of new compound of the present invention, relates to tropinone derivative and its preparation method and application.
Background technology
World Health Organization's statistics of 2011 shows, the diabetic subject in the whole world has reached 3.66 hundred million people, wherein most genus type ii diabetes, and about 4,600,000 people die from this disease and complication thereof every year.The key agents being used for treating diabetes at present has sulfourea, thiazolidinediones and metformin.But for many patients, these medicines are difficult to maintain blood sugar a normal level.Therefore, invent a kind of newtype drug to have very important significance to treat diabetes.
Alkaloid (Alkaloids) be mainly a class source of students in plant in amino acid, nitrogenous and nitrogen-atoms in ring texture, there is the secondary metabolite of notable biological activity.Tropane alkaloid (Tropanealkaloids) is the alkaloid that a class contains special tropane backbone chemical structure.Most tropane alkaloid has very strong biology and pharmacologically active.Such as, the morphine composition in opium can ease pain, Cocaine can cough-relieving, coromegine in belladonna can spasmolysis.Tropinone (Tropinone) is also one
tropaneclass
biological alkali, be often used as an intermediate to synthesize the tropane alkaloid of various kind, as
coromeginevitriol.
By carrying out structural modification and transformation to the molecule of known excellent activity, being the very important means of one of synthesizing better bioactive molecule, is also an effective way of new drug research, and its research difficulty is relatively low, risk is little, success ratio is high.Few about tropinone derivative relevant report at present, there is one section of document (YaoxueXuebao (1994), 29 (3), 185-94.) tropinone derivative shown in such as shown in formula II and III to be applied to the research of neuroleptic by report as benzamide compound.And in prior art, tropinone derivative is not applied to the correlative study of antidiabetic medicine.
R:3,4,5-trimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4-Dimethoxyphenyl; 2-methoxyl group-4-chloro-phenyl-
A: ethanoyl; Benzoyl
B:3,4,5-trimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4-Dimethoxyphenyl; 2,3-Dimethoxyphenyl
Summary of the invention
The present invention is intended to the tropinone from being easy to get, and by modifying its structure, synthesize a series of tropinone derivative, this tropinone derivative is inhibited to DPP IV, may be used for the medicine preparing treatment type ii diabetes.
For achieving the above object, technical scheme of the present invention is:
Tropinone derivative and pharmacy acceptable salt thereof, structure is as shown in formula I:
Wherein, R
2be selected from the alkyl of 1-6 carbon, the aromatic base of a 1-20 carbon, the heterocycle of a 1-20 carbon or amino group; X is selected from alkyl, the aromatic base of a 1-20 carbon, the heterocycle of a 1-20 carbon of 1-6 carbon, methylsulfonyl, p-toluenesulfonyl or
wherein R
1be selected from the alkyl of 1-6 carbon, the aromatic base of a 1-20 carbon, the heterocycle of a 1-6 carbon; Described alkyl comprises and has substituent alkyl and alkyl ring, and described aromatic base comprises and has substituent aromatic base, and wherein, substituting group is selected from F, Cl, Br, I, NO
2, CF
3, amino group, the alkyl of a 1-6 carbon, the aromatic base of a 1-20 carbon, one or more in the alkoxyl group of a 1-6 carbon and the ester group of 1-6 carbon;
Described heterocycle comprises containing heteroatomic alkyl ring and aromatic nucleus, and wherein heteroatoms is N, O or S.
Preferred technical scheme is: R
2be selected from and have substituent phenyl group, wherein, substituting group is selected from F, Cl, Br, I, NO
2, CF
3, amino group, the alkyl of a 1-6 carbon, one or more in the alkoxyl group of a 1-6 carbon and the ester group of 1-6 carbon; X is
wherein R
1be selected from the aromatic base of the alkyl of 1-6 carbon, a 1-20 carbon.
Preferred technical scheme is: R
2be selected from and there is substituent phenyl group; X is
wherein R
1be selected from the alkyl of 1-6 carbon, phenyl or there is substituent phenyl group; Wherein, substituting group is all selected from F, Cl, Br, I, NO
2, CF
3, amino group, one or more in methyl and methoxyl group.
More preferably: R
2be selected from and have substituent phenyl group, wherein, substituting group is selected from F, Cl, Br, I, NO
2, CF
3, amino group, one or more in methyl and methoxyl group; X is
wherein R
1be selected from the alkyl or phenyl of 1-6 carbon.
Preferably include following particular compound further again, below name by
be set to tropane:
3-(2,3-dichloro-benzoyl) amino-6-benzoyloxy tropane;
3-(4-oil of mirbane formyl) amino-6-benzoyloxy tropane;
3-(3-trifluoromethylbenzoyl) amino-6-benzoyloxy tropane;
3-(3-(3-chloro-phenyl-) urea groups)-6-benzoyloxy tropane;
3-(3-(4-tolyl) urea groups)-6-benzoyloxy tropane;
3-Nai Ji-6-benzoyloxy tropane;
3-(3-Bromophenacyl) amino-6-benzoyloxy tropane;
3-(4-chlorobenzoyl) amino-6-acetoxyl group tropane;
3-(2,4,6-trimethylbenzoyl) amino-6-acetoxyl group tropane;
3-(3-(4-chloro-phenyl-) urea groups)-6-acetoxyl group tropane;
3-(4-oil of mirbane formyl) amino-6-acetoxyl group tropane.
The synthetic route of tropinone derivative described in the application as shown in Figure 1.
The application of described tropinone derivative in preparation treatment type ii diabetes medicine.
Compared with prior art, advantage of the present invention is: first tropinone derivative is applied to anti-diabetic biological activity test, and through finding the Inhibition test of DPP IV (DPP-IV): some compound shows restraining effect to DPPIV, and having two compound inhibiting rates more than 30%, this tropinone derivative may be used for the medicine preparing treatment type ii diabetes.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of tropinone derivative described in the application;
Embodiment
Below by drawings and Examples, the present invention is described in further detail, but the present invention is not only confined to following examples.
The synthesis of embodiment 1 Genipin derivative
1.1 instruments and reagent
Nuclear magnetic resonance spectrum adopts Brucker400MHz ADVANCE DMX500 type nmr determination, and (TMS is interior mark, CDC1
3for solvent); ESI mass spectrum adopts Esquire600 (German Brucker) mass spectrograph to measure.
Column chromatography silica gel is 200-300 order (Haiyang Chemical Plant, Qingdao), and chemical reagent is domestic analytical reagent, without being further purified before using.
The preparation of 1.2 tropinone things
Compound 1(is shown in accompanying drawing 1) preparation: in 250mL there-necked flask, add 5.00g6-hydroxyl tropinone successively, 50mL methylene dichloride, 3mL triethylamine, under nitrogen protection, under condition of ice bath, drip Benzoyl chloride 5mL, reaction stirred overnight at room temperature.The desolventizing of decompression rotary evaporation, residue post layer, analyses to obtain yellow solid 7.68g, yield 92%.
Compound 2(is shown in accompanying drawing 1) preparation: add 4g6-hydroxyl tropinone in 250mL there-necked flask successively, 100mL methylene dichloride, 3mL triethylamine and 40mg DMAP, stir lower instillation 3mL Ac2O after dissolving completely, under room temperature, reaction is spent the night.TLC confirms that reaction terminates, extraction into ethyl acetate, anhydrous sodium sulfate drying, and the desolventizing of decompression rotary evaporation, residue column chromatography, obtains yellow oily liquid 4.1g, productive rate 80%.
Compound 3 or 4(are shown in accompanying drawing 1) preparation: add 1.5g compound 1 or 2 in 100mL there-necked flask and be dissolved with in the ethanol solution 50mL of ammonia; nitrogen protection reaction is spent the night; TLC confirms that raw material reaction is complete; add 600mg sodium borohydride, after 3h, reaction terminates, and ammoniacal liquor quencher is reacted; the desolventizing of decompression rotary evaporation; residue column chromatography, obtains 1g product 3 or 4, and productive rate is respectively 60% and 65%.
Target compound 5 or 6(are shown in accompanying drawing 1) preparation method: in 10mL single port bottle, add intermediate 3 or 4(1mmol), methylene dichloride (5mL), drips triethylamine (1.1mmol) under stirring, acyl chlorides (1.1mmol), 1h is reacted under room temperature, after reaction terminates, add saturated sodium bicarbonate quencher, extract 3 times with methylene dichloride (10mL), organic phase saturated common salt water washing, anhydrous sodium sulfate drying, the desolventizing of decompression rotary evaporation, obtains final product after residue column chromatography.All target compounds all pass through
1the structural characterization of H NMR and ESI-MS is in table 1.
Table 1 target compound
1h NMR and ESI-MS data
Wherein, compound 5a is: 3-(2,3-dichloro-benzoyl) amino-6-benzoyloxy tropane;
Compound 5b is: 3-(4-oil of mirbane formyl) amino-6-benzoyloxy tropane;
Compound 5c is: 3-(3-trifluoromethylbenzoyl) amino-6-benzoyloxy tropane;
Compound 5d is: 3-(3-(3-chloro-phenyl-) urea groups)-6-benzoyloxy tropane;
Compound 5e is: 3-(3-(4-tolyl) urea groups)-6-benzoyloxy tropane;
Compound 5f is: 3-Nai Ji-6-benzoyloxy tropane;
Compound 5g is: 3-(3-Bromophenacyl) amino-6-benzoyloxy tropane;
Compound 6a is: 3-(4-chlorobenzoyl) amino-6-acetoxyl group tropane;
Compound 6b is: 3-(2,4,6-trimethylbenzoyl) amino-6-acetoxyl group tropane;
Compound 6c is: 3-(3-(4-chloro-phenyl-) urea groups)-6-acetoxyl group tropane;
Compound 6d is: 3-(4-oil of mirbane formyl) amino-6-acetoxyl group tropane.
Embodiment 2 tropinone derivative anti-diabetic biological activity assay
Inhibitors of dipeptidyl IV is novel antidiabetic drug deeply concerned at present.Research shows, inhibitors of dipeptidyl IV can promote β cell uelralante, increases the synthesis of β insulin inside cells, the secretion of glucagon suppression simultaneously, and can not hypoglycemic event be there is, side effect is less, in treatment type ii diabetes, have extraordinary prospect.
2.1 experiment reagent
Rosiglitazone (Sigma, R2408)
TransIT-293 transfection reagent (Mirus, MIR2706)
Methyl-sulphoxide (Sigma, Cat.No.154938-1L, Lot.No.52396AK)
384-well plate(384-magnetic separator) (Greiner, 781080)
DPP IV (Sigma, Cat#D4943, Lot#080M1723)
Dipeptidyl peptidase IV – sphaeroprotein
tMproteolytic enzyme (Promega, Cat#G8351, Lot#320119)
384 orifice plates (PerkinElmer, OptiPlate-384, White Opaque384-well)
Before experiment, testing compound 100% methyl-sulphoxide is dissolved into 10mM.
2.2 DPP IV Inhibition test
2.2.1 experimental design and process:
(1) before the use, by DPP IV-sphaeroprotein
tMdamping fluid in test kit dissolves and balances to room temperature, by lyophilized fluorescein detection reagent balance to room temperature;
(2) with the resuspended substrate of 110 μ L ultrapure water, the substrate storage liquid that concentration is 10mM is mixed with;
(3) with DPP IV-sphaeroprotein
tMthe resuspended fluorescein detection reagent of damping fluid 50mL in test kit;
(4) DPP IV-sphaeroprotein is prepared
tMreagent: by 100 μ L DPP IV-sphaeroprotein
tMsubstrate in test kit adds 50mL fluorescein detection reagent resuspended in step 3, and vortex mixes, and in this system, the concentration of substrate is 20 μMs;
(5) with before, by DPP IV-sphaeroprotein
tMdetection reagent is placed in room temperature 30-60 minute;
(6) pH of the preparation of stock solution: 10mM is the tris buffer (adding 0.1% bovine serum albumin) of 8.0; The solution allocation (storing solution of 10mM is dissolved in 100% methyl-sulphoxide) of 3 μMs of Xi Talieding; The buffered soln of configuration DPP IV 2ng/mL; Configure the compound solution (storing solution of 10mM is dissolved in 100% methyl-sulphoxide) of 3 μMs
(7) preparation of sample is tested: positive control matter sample (10 μ L DPP IV+1 μ L Xi Talieding); Maximum value working sample (10 μ L DPP IV+1 μ L are blank); Test compound sample (10 μ L DPP IV+1 μ L compound);
(8) centrifugal 10 seconds of 1000rpm, vibrates 30 seconds, then equilibrium at room temperature 15 minutes;
(9) more centrifugal 10 seconds, vibrate 30 seconds, mixing;
(10) react after 5 minutes, read plate with Envision multiple labeling detector.
2.2.2 experimental data
Experimental standard is qualified, Z-factor>0.7, Max/min>60, and positive compound sitagliptin (Sitagliptin) inhibiting rate reaches 100%.Experimental data is in table 2:
2.2.3 experimental result
Table 2 experimental data
Experimental data in analytical table 2 shows DPP IV, and in table 2, compound all demonstrates certain restraining effect, and has the inhibiting rate of two compounds more than 30%, namely has certain pharmaceutical activity.
2.3 anti-diabetic activity test results
Synthesized compound is to PPAR
γall there is no significant activation, illustrate that the mechanism of action of the type compound is not for this acceptor.But the major part in this compound shows restraining effect to DPPIV, the inhibiting rate of two test compounds is wherein more than 30%.Clinical study shows, DPP-IV inhibitor effectively can be improved the obstacle of islet function and improve type ii diabetes patient to glycemic control.Effectively do not keep on a diet to those and the patient of hypomotility, DPP-IV inhibitor demonstrates the curative effect of good monotherapy.If in conjunction with N1,N1-Dimethylbiguanide, thiazole, the antidiabetic drugs such as Regular Insulin carry out elements addition, and effect also clearly.
Claims (3)
1. tropinone derivative is preparing the application in inhibitors of dipeptidyl IV, and described tropinone derivative structure is as shown in formula I:
Wherein, R
2be selected from and have substituent phenyl group, wherein, substituting group is selected from NO
2, CF
3in one or more; X is
wherein R
1be selected from the alkyl or phenyl of 1-6 carbon.
2. apply according to claim 1, it is characterized in that, described tropinone derivative is selected from following particular compound, below name by
be set to tropane:
3-(4-oil of mirbane formyl) amino-6-benzoyloxy tropane;
3-(3-trifluoromethylbenzoyl) amino-6-benzoyloxy tropane;
3-(4-oil of mirbane formyl) amino-6-acetoxyl group tropane.
3. tropinone derivative is preparing the application in inhibitors of dipeptidyl IV, and described tropinone derivative is selected from following particular compound, below name by
be set to tropane:
3-(3-(3-chloro-phenyl-) urea groups)-6-benzoyloxy tropane;
3-naphthyl-6-benzoyloxy tropane;
3-(3-(4-chloro-phenyl-) urea groups)-6-acetoxyl group tropane.
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| CN104311550B (en) * | 2014-09-12 | 2017-02-01 | 河南普瑞制药有限公司 | Preparation method of 6-hydroxytropinone |
| CN104592245B (en) * | 2014-12-31 | 2017-02-22 | 上海北卡医药技术有限公司 | Spiroketal derivative and preparation method and application thereof |
| CN105924436A (en) * | 2016-05-19 | 2016-09-07 | 中国科学院昆明植物研究所 | Tropinone derivative and drug composition thereof and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB774858A (en) * | 1954-10-20 | 1957-05-15 | Sandoz Ltd | Tropane and -Î-tropane derivatives and process for preparation thereof |
| US5006533A (en) * | 1986-08-30 | 1991-04-09 | Boehringer Ingelheim Gmbh | Certain 3-bromo-2,6-dimethoxybenzamides and pharmaceutical use thereof |
| CN1830445A (en) * | 2000-05-26 | 2006-09-13 | 辉瑞大药厂 | Tropane derivatives having therapy using, compounds and polymorph thereof |
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2012
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB774858A (en) * | 1954-10-20 | 1957-05-15 | Sandoz Ltd | Tropane and -Î-tropane derivatives and process for preparation thereof |
| US5006533A (en) * | 1986-08-30 | 1991-04-09 | Boehringer Ingelheim Gmbh | Certain 3-bromo-2,6-dimethoxybenzamides and pharmaceutical use thereof |
| CN1830445A (en) * | 2000-05-26 | 2006-09-13 | 辉瑞大药厂 | Tropane derivatives having therapy using, compounds and polymorph thereof |
Non-Patent Citations (2)
| Title |
|---|
| 糖尿病治疗药研发新进展;黄胜炎;《上海医药》;20090810;第30卷(第8期);第376页右栏第3-5段 * |
| 褚国华等.苯甲酰胺类抗精神病药物的研究:6β-羟基,乙酰氧基和苯甲酰氧基-3α及β-托品烷衍生物的合成.《药学学报》.1994,第29卷(第3期),第186页Scheme 1,第187页Scheme 2,第192页表2. * |
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Effective date of registration: 20170110 Address after: Kaiyuan Road 410100 in Hunan province Changsha City Economic and Technological Development Zone No. 1318 Patentee after: Herbalife Lei Shuo (Hunan) Natural Products Co. Address before: Liuyang City, Hunan province 410329 Changsha Biomedical Park Branch Center Room 8102 Patentee before: Top pharmaceutical & Chemical (Changsha) Co., Ltd. Patentee before: Herbalife Lei Shuo (Hunan) Natural Products Co. |