CN116253743B - (+) -Paeovaitol derivative, pharmaceutical composition thereof, preparation method and application thereof - Google Patents
(+) -Paeovaitol derivative, pharmaceutical composition thereof, preparation method and application thereof Download PDFInfo
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- CN116253743B CN116253743B CN202111513524.7A CN202111513524A CN116253743B CN 116253743 B CN116253743 B CN 116253743B CN 202111513524 A CN202111513524 A CN 202111513524A CN 116253743 B CN116253743 B CN 116253743B
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides (+) -paeoviitol derivatives 1-20 shown in a structural formula (I), a pharmaceutical composition thereof, a preparation method and application thereof, and belongs to the technical field of medicines. Pharmacological experiment results show that the (+) -paeoviitol derivative 1-20 (compound 1-20) or the pharmaceutical composition can be used as a melatonin receptor agonist and can be used for preparing medicines for treating or preventing depression.
Description
Technical Field
The invention belongs to the technical field of medicaments, and particularly relates to (+) -paeoviitol derivatives 1-20 (compounds 1-20) shown in a structural formula (I), a pharmaceutical composition and a preparation method thereof, and application of the derivatives or the pharmaceutical composition as melatonin receptor agonists in preparation of medicaments for treating or preventing depression.
Background
Depression is the most common mental disorder, and the patients have symptoms of low mood, pessimistic despair, no sense of pleasure, sleep disturbance and even suicidal tendency by taking the remarkable and durable low mood as the basic clinical manifestation. Reports issued by the world health organization 2017 show that about 4.3% of people worldwide have depression, with the number of patients reaching 3.22 million, of which China has 5400-9600 ten thousand patients. Modern pharmacological studies suggest that depression is associated with reduced levels of neurotransmitters such as central 5-hydroxytryptamine (5-HT), norepinephrine (NA), dopamine (DA), acetylcholine (ACh) and neuropeptides induced by genetic, psychological, and neuroendocrine factors.
With the continuous and intensive research of the action mechanism of modern pharmacological antidepressant drugs, various novel antidepressant drugs are continuously developed and widely applied to clinic, and mainly comprise: monoamine oxidase inhibitors (monoamine-oxidase inhibitor, MAois), selective NA reuptake inhibitors (NA selective reuptake inhibitors, NARIs), selective 5-HT reuptake inhibitors (5-HT selective reuptake inhibitors, SSRIs), selective NA and 5-HT reuptake inhibitors (NA and 5-HT selective reuptake inhibitors, SNRIs). Tricyclic compounds are used clinically as classical antidepressants, which mainly inhibit reuptake of 5-HT and NA by presynaptic membranes, increase the concentration of 5-HT and NA in synaptic clefts, enhance neurotransmission and produce antidepressant effects. Agomelatine the agomelatine (agomelatine), an agomelatine receptor agonist acting on the melatonin receptor, is widely used for the treatment of depression because of its safety and efficacy. On day 3 and 5 of 2019, the us Food and Drug Administration (FDA) approved nasal spray of esketamine (esketamine) was marketed as a fast acting new antidepressant. The cleavanone acts on the glutamate receptor, possibly plays an anti-depression role by affecting the NMDA receptor function and synaptic plasticity of the brain region, and has the characteristic of quick action. However, esketamine as one isomer of K powder is at risk of being abused and may be addictive for long-term use. In the same year, the FDA approves an intravenous infusion formulation (trade name Zulresolone) of allopregnanolone (Bryanolone) for treating postpartum depression, the drug is the first drug which is the only drug for obtaining postpartum depression indication at present, and the drug acts on synaptic and extrasynaptic GABAA receptors (gamma-aminobutyric acid A type receptors) and can play an anti-depression role after being intravenously injected for 48 hours. The medicine is expensive, the treatment course cost is up to 3.6 ten thousand dollars (about 24 ten thousand yuan of civil coins), and the side effects of overstrain or loss of consciousness of patients are caused.
In conclusion, the antidepressant used clinically at present mainly achieves a certain curative effect by influencing the action of 5-hydroxytryptamine and norepinephrine in brain, but has the defects of slow onset of action, obvious side effect, easy generation of drug resistance, easy rebound after stopping the drug and the like, and cannot meet the treatment requirement.
Radix Paeoniae Rubra is dry root of radix Paeoniae Rubra (Paeonia veitchii) belonging to Paeoniaceae (Paeonia), has effects of promoting blood circulation, removing blood stasis, and dredging collaterals, and can be used as a traditional Chinese medicine in many compounds with effects of dispersing stagnated liver qi for relieving depression. In order to find new antidepressant active ingredients from radix Paeoniae Rubra, the present inventors isolated and identified 60 compounds from early radix Paeoniae Rubra, including a pair of C having 6/5/6/6 four-ring system 19 The novel backbones of the norditerpenes (+) -and (-) -paeoviitol (Organic Letters 2014,16,2,424-427). The inventors have previously completed asymmetric catalytic synthesis of paeoeitol for the first time (Organic Letters 2017,19,3,429-431).
The (+) -paeovaitol derivative 1-20 is obtained by taking (+) -paeovaitol as a raw material through a chemical synthesis method for the first time, and no report about the (+) -paeovaitol derivative 1-20 and no report about the biological activity thereof are found in the prior art.
Disclosure of Invention
The invention aims to provide (+) -paeoviitol derivatives 1-20 (compounds 1-20) shown in a formula (I), a pharmaceutical composition taking the (+) -paeoviitol derivatives as active ingredients, an application of the (+) -paeoviitol derivatives as melatonin receptor agonists in medicines for treating or preventing depression, and a preparation method of the (+) -paeoviitol derivatives.
In order to achieve the above object of the present invention, the present invention provides the following technical solutions:
(+) -paeovitol derivatives 1-20 (compounds 1-20) represented by the following structural formula (I):
the invention also provides a pharmaceutical composition which contains (+) -paeoviitol derivatives 1-20 shown in the formula (I) and a pharmaceutically acceptable carrier or excipient.
The invention also provides application of the (+) -paeoviitol derivative 1-20 shown in the formula (I) in preparing melatonin receptor agonists.
Use of (+) -paeovaitol derivatives 1-20 of formula (I) in the preparation of a medicament for treating or preventing depression.
The invention also provides application of the pharmaceutical composition in preparation of melatonin receptor agonists.
The application of the pharmaceutical composition in preparing medicines for treating or preventing depression.
Wherein the "depression" is according to the "diagnosis and statistics of mental diseases handbook fourth edition (DSM-IV) or International Classification of diseases 10 edition (ICD-10) published by the United states psychiatry, including mental diseases or disorders of different subtypes: 1) Depression (Depression) and affective disorders (Mood disorders) types such as depressive, manic, mixture of Depression and mania, slightly manic; 2) Depression-like disorders (Depressive disorders) such as depression-like disorders, dysthymia; 3) Other affective disorders such as those caused by physical health conditions include subtypes of various mental diseases or disorders characterized by depression and affective disorders due to substances (e.g., addictive drugs) or treatments (e.g., surgery, radiation therapy or chemo-etc.), etc.; 4) Bipolar depression or bipolar disorder includes recurrent depressive and slightly manic, alternately depressive and manic episodes.
The symptoms of depression according to the present invention relate to circadian rhythm disorders, sleep disorders, anxiety disorders, chronic stress, acute stress injury or cognitive function injury or disorder, in addition to those described in the handbook of diagnosis and statistics of mental diseases fourth edition (DSM-IV) or international classification of diseases 10 edition (icd=10).
The invention further provides a preparation method of (+) -paeoviitol derivatives 1-20 (compounds 1-20) shown in the formula (I), which comprises the following steps:
the (+) -paeoviitol is prepared to the compound 1-3 under the action of proper acetylating reagent including acetyl chloride, acetic anhydride, 1-acetyl-1H-1, 2, 3-triazole [4,5-B ] pyridine, etc. The diacetyl- (+) -paeoviitol is prepared into an aldehyde intermediate under the action of an oxidant, the aldehyde intermediate and primary amine or secondary amine are subjected to reductive amination and deacetylation in a proper reaction solvent under the action of a proper reducing agent to obtain the compound 4-20, wherein the proper reaction solvent is dichloromethane or chloroform or methanol or ethanol, and the proper reducing agent is sodium borohydride or sodium triacetyl borohydride or sodium cyanoborohydride.
Also provided is a process for preparing the pharmaceutical composition by first preparing (+) -paeoviitol derivatives 1-20 (compounds 1-20) and then adding any one or any combination of the above (+) -paeoviitol derivatives 1-20 to at least one pharmaceutically acceptable carrier or excipient.
The pharmaceutical composition comprises any one or any combination of the compounds 1-20 shown in the formula (I) and at least one pharmaceutically acceptable carrier or excipient.
The invention provides a pharmaceutical composition which comprises at least one or any combination of compounds 1-20 shown in the formula (I) and a pharmaceutically acceptable carrier or excipient. In the present invention, the pharmaceutically acceptable carrier or excipient is preferably a solid, semi-solid or liquid diluent, filler and pharmaceutical preparation adjuvant. The pharmaceutically acceptable carrier or excipient is not particularly limited, and pharmaceutically acceptable carriers and/or excipients which are well known in the art, nontoxic and inert to human and animals can be selected.
The preparation method of the pharmaceutical composition is not particularly limited, at least one of the compounds 1-20 is directly mixed with a pharmaceutically acceptable carrier or excipient, the mixing process is not particularly limited, and the pharmaceutical composition can be obtained by selecting processes well known in the art.
In the present invention, when the compounds 1 to 20 or the pharmaceutical composition are used as melatonin receptor agonists or drugs, they may be used as such or in the form of pharmaceutical compositions, the content of which in the drugs is preferably 0.1 to 99%; in the pharmaceutical composition, the content of at least one of the compounds 1 to 20 in the pharmaceutical composition is preferably 0.5 to 90%. The pharmaceutical composition of the present invention is preferably used in the form of a unit weight dose. In the present invention, the prepared medicine may be preferably administered in both injection (intravenous injection, intramuscular injection) and oral administration.
Compared with the prior art, the invention has the following advantages: the invention provides a novel (+) -paeoviitol derivative, a pharmaceutical composition taking the (+) -paeoviitol derivative as an active ingredient, and application of the (+) -paeoviitol derivative and the pharmaceutical composition thereof in preparing melatonin receptor agonists and antidepressants, and a preparation method of the (+) -paeoviitol derivative.
Description of the drawings:
FIG. 1 is a schematic representation of the structure of (+) -paeovaitol derivatives 1-20 (compounds 1-20) of the invention.
Detailed Description
For a better understanding of the present invention, the following description will further illustrate the essential content of the present invention with specific examples thereof in conjunction with the accompanying drawings, but the present invention is not limited thereto.
Example 1
Preparation of Compounds 1 and 2:
(+) -paeovaitol (328 mg,1 mmol) was dissolved in 4mL of tetrahydrofuran, 1M sodium hydroxide solution (1 mL,1 mmol) was added thereto, and after stirring at room temperature for 5min, 1-acetyl-1H-1, 2, 3-triazole [4,5-B ] pyridine (162 mg,1 mmol) was added thereto and reacted at room temperature for 30min. The reaction mixture was diluted with 5mL of water, pH was adjusted to neutrality using 1M hydrochloric acid solution, extracted with ethyl acetate (3X 10 mL), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the crude product was separated by silica gel column chromatography (acetone-petroleum ether, 15:85) to give 181mg of Compound 1 in 49% yield, 95mg of Compound 2 in 23% yield.
Structural data for compound 1:
traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,CD 3 OD)δ7.00(s,1H,H-1),6.63(s,1H,H-4),6.42(s,1H,H-15),6.37(s,1H,H-12),5.10(d,J＝3.0Hz,1H,H-8),4.14(d,J＝11.5Hz,1H,H-18a),3.98(d,J＝11.5Hz,1H,H-18b),3.07-3.02(m,1H,H-7),2.24(s,3H,H-19),2.01(s,3H,H-16),1.95(s,3H,-OAc),1.54(d,J＝7.5Hz,3H,H-17)； 13 C NMR(125MHz,CD 3 OD)δ171.8(OAc),159.8(C-11),151.6(C-2),148.0(C-5),144.2(C-14),134.2(C-13),128.4(C-6),126.6(C-10),123.9(C-2),120.9(C-4),118.9(C-15),113.2(C-1),112.2(C-12),91.0(C-8),89.5(C-9),67.1(C-18),33.7(C-7),20.7(OAc),16.7(C-16),16.0(C-19),13.6(C-17).
high resolution mass spectrum (ESI) calculated C 21 H 23 O 6 [M+H] + 371.1495, measured as 371.1503.
Structural data for compound 2:
traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(400MHz,CDCl 3 )δ6.94(s,1H,H-15),6.81(s,1H,H-1),6.56(s,1H,H-4),6.47(s,1H,H-12),5.10(d,J＝3.2Hz,1H,H-8),4.20(d,J＝12.0Hz,1H,H-18a),3.96(d,J＝13.6Hz,1H,H-18a),3.06-3.03(m,1H,H-7),2.28(s,3H,-OAc),2.26(s,3H,-OAc),2.03(s,3H,H-19),2.00(s,3H,H-16),1.55(d,J＝6.8Hz,3H,H-17)； 13 C NMR(100MHz,CDCl 3 )δ169.7(C＝O),169.6(C＝O),158.3(C-11),151.3(C-5),144.5(C-2),142.9(C-14),133.5(C-13),129.0(C-6),127.0(C-10),124.2(C-3)120.0(C-4),119.3(C-1),117.5(C-15),112.0(C-12),89.4(C-8),88.0(C-9),67.1(C-18),32.6(C-7),20.8(OAc),20.7(OAc),16.8(C-19),15.9(C-16),13.1(C-17).
high resolution mass spectrum (ESI) calculated C 23 H 25 O 7 [M+H] + 413.1600, measured as 413.1604.
Example 2
Preparation of compound 3:
(+) -paeoviitol (32.8 mg,0.1 mmol) was dissolved in 1mL of pyridine, and 1mL of acetic anhydride was added thereto with stirring and reacted overnight at room temperature. 10mL of water was added to quench the reaction, extraction was performed with ethyl acetate (3X 10 mL), and the organic phases were combined to wash with 5% HCl solution, saturated sodium bicarbonate and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and the crude product was separated by silica gel column chromatography (ethyl acetate-petroleum ether, 10:90) to give 43mg of the title compound in 94% yield.
Structural data for compound 3:
traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,CDCl 3 )δ6.97(s,1H,H-15),6.80(s,1H,H-1),6.58(s,1H,H-4),6.49(s,1H,H-12),5.02(d,J＝3.0Hz,1H,H-8),4.75(d,J＝14.4Hz,1H,H-18a),4.48(d,J＝13.6Hz,1H,H-18b),3.11-3.09(m,1H,H-7),2.29(s,3H,OAc),2.27(s,3H,OAc),2.09(s,3H,OAc),2.05(s,3H,H-19),2.00(s,3H,H-19),1.56(d,J＝8.4Hz,3H,H-17)； 13 C NMR(100MHz,CDCl 3 )δ170.6(C＝O),169.6(C＝O),169.5(C＝O),158.0(C-11),151.1(C-2),144.5(C-14),143.1(C-5),133.8(C-13),129.1(C-10),126.5(C-6),123.9(C-2),120.1(C-4),119.3(C-1),117.7(C-12),112.0(C-15),89.2(C-8),86.0(C-9),67.1(C-18),32.2(C-7),20.8(OAc),20.8(OAc),20.8(OAc),16.8(C-19),15.9(C-16),13.2(C-17).
example 3
Preparation of Compound 4:
compound 2 (20.6 mg,0.05 mmol) was dissolved in 1mL of dichloromethane (10 mL) under nitrogen, dess-Martin reagent (31.8 mg,0.075mmol,0.75 equiv) was slowly added under ice-bath, the reaction was quenched at room temperature for 4h after the addition, saturated sodium thiosulfate solution was added, dichloromethane extraction was performed, the organic phases were combined, saturated brine was washed, and the solvent was removed by concentration under reduced pressure to give an aldehyde intermediate. The aldehyde obtained was dissolved in 1mL of methylene chloride, 0.075mmol of dimethylamine, 15.9mg of sodium triacetylborohydride (0.075 mmol) and 1. Mu.l of acetic acid were sequentially added thereto with stirring, the reaction was carried out at room temperature for 24 hours, after the completion of the reaction, 1mL of 2M sodium hydroxide solution was added and stirred for 6 hours, the pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, extraction was carried out with ethyl acetate (3X 10 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by concentration under reduced pressure, and the crude product was separated by silica gel column chromatography (triethylamine-ethyl acetate-petroleum ether, 1:30:70) to obtain 12.2mg of the objective compound in 69% yield.
Structural data for compound 3:
traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(400MHz,pyridine-d 5 )δ7.43(s,1H,H-15),7.11(s,1H,H-1),6.81(s,1H,H-4),6.61(s,1H,H-12),5.36(d,J＝2.8Hz,1H,H-8),3.33-3.30(m,1H,H-7),3.22(d,J＝13.6Hz,1H,H-18a),2.94(d,J＝13.6Hz,1H,H-18b),2.36(s,6H,N-Me),2.25(s,3H,H-19),2.19(s,3H,H-16),1.61(d,J＝7.2Hz,3H,H-17)； 13 C NMR(100MHz,pyridine-d 5 )δ153.6(C-11),151.7(C-2),150.5(C-14),147.0(C-5),127.8(C-13),127.7(C-6),126.9(C-10),122.9(C-3),120.1(C-4),112.8(C-1),111.6(C-12),110.7(C-15),89.7(C-8),89.3(C-9),65.9(C-18),47.8(N-Me),32.9(C-7),16.9(C-19),16.1(C-16),13.5(C-17).
high resolution mass spectrum (ESI) calculated C 21 H 26 NO 4 [M+H] + 356.1856, measured as 356.1838.
Example 4
Preparation of compound 5:
14mg of the target compound was obtained in 71% yield by the same procedures as in example 3 except that dimethylamine was changed to diethylamine.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,pyridine-d 5 )δ7.46(s,1H,H-15),7.13(s,1H,H-1),6.82(s,1H,H-4),6.62(s,1H,H-12),5.33(d,J＝2.5Hz,1H,H-8),3.44-3.35(m,2H,H-7,H-18a),3.06(d,J＝14.0Hz,1H,H-18b),2.84-2.77(m,2H,H-1′),2.65-2.58(m,2H,H-1′),2.25(s,3H,H-19),2.19(s,3H,H-16),1.65(d,J＝7.0Hz,3H,H-17),1.00-0.97(m,6H,H-2′)； 13 C NMR(125MHz,pyridine-d 5 )δ153.8(C-11),151.9(C-2),150.7(C-14),147.3(C-5),128.0(C-13),127.3(C-6),127.3(C-10),123.1(C-2),120.3(C-4),113.0(C-1),111.9(C-11),111.0(C-15),90.1(C-8),90.0(C-9),60.7(C-18),46.6(C-1′),33.1(C-2′),17.2(C-19),16.3(C-16),13.8(C-17).
high resolution mass spectrum (ESI) calculated C 23 H 30 NO 4 [M+H] + 384.2169, measured as 384.2146.
Example 5
Preparation of Compound 6:
the desired starting materials, reagents and preparation were the same as in example 3 except that dimethylamine was replaced by dipropylamine, to give 13mg of the title compound in 65% yield.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,pydidine-d 5 )δ7.45(s,1H,H-15),7.14(s,1H,H-1),6.83(s,1H,H-4),6.62(s,1H,H-12),5.33(d,J＝3.0Hz,1H,H-8),3.44-3.40(m,2H,H-7,H-18a),3.06(,J＝13.0Hz,1H,H-18b),2.73-2.65(m,2H,H-1′),2.52-2.48(m,2H,H-1′),2.25(s,3H,H-19),2.18(s,3H,H-16),1.68(d,J＝7.0Hz,3H,H-17),1.45-1.39(m,4H,H-2′),0.82(t,J＝7.0Hz,6H,H-3′)； 13 C NMR(125MHz,pydidine-d 5 )δ153.9(C-11),151.9(C-2),150.7(C-14),147.4(C-5),128.0(C-13),127.3(C-6),127.3(C-6),123.1(C-3),120.3(C-4),113.0(C-1),111.8(C-12),111.0(C-15),90.2(C-8),90.1(C-9),62.1(C-18),59.2(C-1′),33.1(C-7),20.7(C-2′),17.2(C-19),16.4(C-16),13.8(C-17),11.1(C-3′).
high resolution mass spectrum (ESI) calculated C 25 H 34 NO 4 [M+H] + 412.2482, measured as 412.2466.
Example 6
Preparation of compound 7:
the desired starting materials, reagents and preparation method were the same as in example 3, except that dimethylamine was replaced by dibutylamine, to give 13mg of the objective compound in 60% yield.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,pyridine-d 5 )δ7.47(s,1H,H-15),7.14(s,1H,H-1),6.84(s,1H,H-4),6.62(s,1H,H-12),5.36(d,J＝3.0Hz,1H,H-8),3.45-3.41(m,2H,H-7,H-18a),3.11(d,J＝14.5Hz,1H,H-18b),2.78-2.73(m,2H,H-1′),2.59-2.53(m,2H,H-1′),2.25(s,3H,H-19),2.18(s,3H,H-16),1.68(d,J＝7.0Hz,3H,H-17),1.45-1.40(m,4H,H-2′),1.2-1.24(m,4H,H-3′),0.85(t,J＝7.0Hz,6H,H-4′)； 13 C NMR(125MHz,pyridine-d 5 )δ153.8(C-11),151.9(C-2),150.7(C-14),147.4(C-6),128.0(C-13),128.0(C-6),127.3(C-10),123.1(C-3),120.3(C-4),113.0(C-1),111.9(C-12),111.0(C-15),90.2(C-8),90.1(C-9),62.1(C-18),55.9(C-1′),33.1(C-7),29.8(C-2′),20.8(C-3′),17.2(C-19),16.4(C-16),14.3(C-4′),13.8(C-17).
high resolution mass spectrum (ESI) calculated C 27 H 28 NO 4 [M+H] + 440.2795, measured as 440.2787.
Example 7
Preparation of Compound 8:
the desired starting materials, reagents and preparation method were the same as in example 3 except that dimethylamine was changed to morpholine, to give 15mg of the title compound in 75% yield.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,pyridine-d 5 )δ7.59(s,1H,H-15),7.14(s,1H,H-1),6.82(s,1H,H-4),6.62(s,1H,H-12),5.33(d,J＝3.0Hz,1H,H-8),3.68-3.66(m,4H,H-2′),3.37-3.35(m,1H,H-7),3.31(d,J＝14.0Hz,1H,H-18a),2.95(d,J＝14.0Hz,1H,H-18b),2.84-2.80(m,2H,H-1′),2.64-2.60(m,2H,H-1′),2.25(s,3H,H-19),2.20(s,3H,H-16),1.67(d,J＝8.4Hz,H-17)； 1 H NMR(125MHz,pyridine-d 5 )δ153.8(C-11),152.1(C-2),150.8(C-14),147.1(C-5),128.2(C-13),128.0(C-6),127.1(C-10),123.3(C-3),120.4(C-4),113.1(C-1),112.0(C-12),110.9(C-15),90.1(C-8),89.7(C-9),67.3(C-2′),65.6(C-18),56.1(C-1′),33.3(C-3),17.2(C-19),16.4(C-16),13.8(C-17).
high resolution mass spectrum (ESI) calculated C 23 H 28 NO 5 [M+H] + 398.1962, measured as 398.1938.
Example 8
Preparation of Compound 9:
the desired starting materials, reagents and preparation method were the same as in example 3, except that dimethylamine was replaced by tetrahydropyrrole, to give 13mg of the title compound in 71% yield.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,pyridine-d 5 )δ7.44(s,1H,H-15),7.11(s,1H,H-1),6.83(s,1H,H-4),6.61(s,1H,H-12),5.38(d,J＝3.0Hz,1H,H-8),3.39(d,J＝13.5Hz,1H,H-18a),3.31-3.26(m,1H,H-7),3.18(d,J＝13.5Hz,1H,H-18b),2.73-2.62(m,4H,H-1′),2.25(s,3H,H-19),2.20(s,3H,H-16),1.62-1.58(m,7H,H-1′,H-17)； 1 H NMR(125MHz,pyridine-d 5 )δ153.9(C-11),151.9(C-2),150.7(C-14),147.3(C-5),128.1(C-13),127.9(C-6),127.2(C-10),123.2(C-3),120.4(C-4),113.1(C-1),111.9(C-12),111.04(C-15),90.0(C-8),89.2(C-9),63.2(C-18),56.8(C-1′),33.1(C-7),23.3(C-2′),17.2(C-19),16.4(C-17),13.8(C-17).
high resolution mass spectrum (ESI) calculated C 28 H 28 NO 4 [M+H] + 382.2013, measured as 382.2007.
Example 9
Preparation of compound 10:
the same procedures as in example 3 were repeated except for changing dimethylamine to N-methyl homopiperazine, to obtain 13mg of the target compound, and the yield was 62%.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,pyridine-d 5 )δ7.44(s,1H,H-15),7.14(s,1H,H-1),6.83(s,1H,H-4),6.62(s,1H,H-12),5.38(d,J＝3.0Hz,1H,H-8),3.54(d,J＝14.5Hz,1H,H-18a),3.44-3.41(m,1H,H-7),3.17(d,J＝14.5Hz,1H,H-18b),3.08-3.05(m,2H,H-1′),2.97-2.93(m,2H,H-2′),2.50-2.52(m,2H,H-3′,H-5′),2.25(s,3H,H-19),2.25(s,3H,H-6′),2.19(s,3H,H-16),1.75-1.71(m,2H,H-4′),1.68(d,J＝7.0Hz,3H,H-17)； 13 C NMR(125MHz,pyridine-d 5 )δ154.0(C-11),151.9(C-2),150.7(C-14),147.4(C-5),128.1(C-13),128.0(C-6),127.2(C-10),123.1(C-3),120.4(C-4),113.1(C-1),111.9(C-12),111.0(C-15),90.2(C-9),90.0(C-8),64.9(C-18),58.9(C-2′),57.6(C-1′),57.0(C-3′),56.9(C-5′),47.1(C-6′),33.2(C-7),28.3(C-4′),17.2(C-19),16.4(C-16),13.7(C-17).
high resolution mass spectrum (ESI) calculated C 25 H 33 N 2 O 4 [M+H] + 425.2435, measured as 425.2387.
Example 10
Preparation of Compound 11:
the same procedures as in example 3 were repeated except for changing dimethylamine to N-acetylpiperazine, to obtain 10mg of the target compound, and the yield was 52%.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,pyridine-d 5 )δ7.45(s,1H,H-15),7.14(s,1H,H-11),6.82(s,1H,H-4),6.61(s,1H,H-12),5.35(d,J＝3.0Hz,1H,H-8),3.39-3.38(m,1H,H-7),3.33(d,J＝14.0Hz,1H,H-18a),2.96(d,J＝14.0Hz,1H,H-18b),2.89-2.85(m,6H,H-2′,H-1′),2.64-2.62(m,2H,H-1′),2.24(s,3H,H-19),2.19(s,3H,H-16),1.66(d,J＝7.0Hz,3H,H-17)； 13 C NMR(125MHz,pyridine-d 5 )δ153.8(C-11),152.0(C-2),150.8(C-14),147.2(C-5),128.1(C-13),128.0(C-6),127.2(C-10),123.2(C-3),120.4(C-4),113.1(C-1),111.9(C-12),110.9(C-15),90.1(C-8),89.8(C9),65.8(C-18),56.8(C-1′),46.6(C-2′),33.2(C-7),17.2(C-19),16.3(C-16),13.8(C-17).
high resolution mass spectrum (ESI) calculated C 23 H 28 N 2 O 4 [M+H] + 397.2122, measured as 397.2106.
Example 11
Preparation of Compound 12:
the desired starting materials, reagents and preparation method were the same as in example 3, except that dimethylamine was changed to N-methylpiperazine, to give 16mg of the title compound in 78% yield.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(400MHz,CD 3 OD)δ6.73(s,1H,H-15),6.59(s,1H,H-1),6.33(s,1H,H-4),6.27(s,1H,H-12),5.03(d,J＝3.2Hz,1H,H-8),3.14(d,J＝14.0Hz,1H,H-18a),3.07-3.04(m,1H,H-7),2.87-2.84(m,3H,H-18b,H-1′),2.64-2.49(m,6H,H-1′,H-2′),2.28(s,3H,H-3′),2.06(s,3H,H-19),2.01(s,3H,H-16),1.52(d,J＝7.2Hz,3H,H-17)； 13 C NMR(100MHz,CD 3 OD)δ153.3(C-11),149.9(C-2),148.7(C-14),146.6(C-5),127.3(C-13),127.2(C-6),125.8(C-10),122.2(C-3),119.3(C-4),111.9(C-1),110.6(C-12),109.5(C-15),89.5(C-8),89.1(C-9),63.9(C-18),54.9(C-1′),54.2(C-2′),44.6(C-3′),32.5(C-7),15.5(C-19),14.6(C-16),12.4(C-17).
high resolution mass spectrum (ESI) calculated C 24 H 30 N 2 O 4 [M+H] + 411.2278, measured as 411.2248.
Example 12
Preparation of Compound 13:
the desired starting materials, reagents and preparation were the same as in example 3, except that dimethylamine was replaced by N-ethylpiperazine, to give 17mg of the title compound in 79% yield.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,pyridine-d 5 )δ7.45(s,1H,H-15),7.14(s,1H,H-1),6.82(s,1H,H-4),6.62(s,1H,H-12),5.34(d,J＝3.0Hz,1H,H-8),3.41-3.38(m,1H,H-7),3.34(d,J＝13.5Hz,1H,H-18a),2.99(d,J＝13.5Hz,1H,H-18b),2.91-2.89(m,2H,H-1′),2.73-2.71(m,2H,H-1′),2.40-2.34(m,4H,H-2′),2.25(s,3H,H-19),2.24(q,2H,J＝7.5Hz,H-3′),2.19(s,3H,H-16),1.67(d,J＝6.0Hz,3H,H-17),0.98(t,3H,J＝7.5Hz,H-3′)； 13 C NMR(125MHz,pyridine-d 5 )δ153.8(C-11),152.0(C-2),150.8(C-14),147.2(C-5),128.1(C-13),128.0(C-6),127.2(C-10),123.2(C-3),120.4(C-4),113.1(C-1),111.9(C-12),110.9(C-15),90.1(C-8),89.7(C-9),65.9(C-18),55.8(C-1′),53.5(C-2′),52.4(C-3′),33.2(C-7),17.2(C-19),16.3(C-16),13.8(C-17),12.4(C-4′).
high resolution mass spectrum (ESI) calculated C 25 H 32 N 2 O 4 [M+H] + 425.2435, measured as 425.2393.
Example 13
Preparation of compound 14:
the same procedures as in example 3 were repeated except for changing dimethylamine to 1- (2-methoxyphenyl) piperazine, to obtain 15mg of the target compound, and the yield was 61%.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,pyridine-d 5 )δ7.48(s,1H,H-15),7.15(s,1H,H-1),7.07-7.00(m,2H,H-5′,H-7′),6.96-6.93(m,2H,H-6′,H-8′),6.85(s,1H,H-4),6.63(s,1H,H-12),5.37(d,J＝3.0Hz,1H,H-8),3.75(s,3H,OMe),3.43-3.37(m,2H,H-7,H-18a),3.14-3.04(m,7H,H-18b,H-1′,H-2′),2.88-2.85(m,2H,H-1′),2.26(s,3H,H-19),2.20(s,3H,H-16),1.68(d,J＝7.0Hz,3H,H-17)； 13 C NMR(125MHz,pyridine-d 5 )δ153.8(C-11),153.0(C-3′),152.0(C-2),150.8(C-14),147.2(C-5),142.3(C-4′),128.1(C-13),128.0(C-6),127.2(C-10),123.8,123.2(C-8′),122.9(C-3),121.5(C-6′),120.4(C-7′),118.6(C-4′),113.1(C-5′),112.5(C-1),111.9(C-12),111.0(C-15),90.1(C-9),89.7(C-8),65.2(C-18),55.9(C-2′),55.5(OMe),51.1(C-1′),33.2(C-7),17.2(C-19),16.4(C-16),13.8(C-17).
high resolution mass spectrum (ESI) calculated C 30 H 35 N 2 O 5 [M+H] + 503.2540, measured as 503.2506.
Example 14
Preparation of compound 15:
the same procedures as in example 3 were repeated except for changing dimethylamine to 1- (4-methylphenyl) piperazine, to obtain 14mg of the target compound, and the yield was 59%.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,pyridine-d 5 )δ7.49(s,1H,H-15),7.15-7.13(m,3H,H-1,H-5′),6.93(d,J＝9.0Hz,H-4′),6.85(s,1H,H-4),6.63(s,1H,H-15),5.33(d,J＝3.0Hz,1H,H-8),3.44-3.34(m,2H,H-7,H-18a),3.11(d,J＝5.0Hz,4H,H-2′),3.10-2.96(m,3H,H-18b,H-1′),2.82-2.7(m,2H,H-1′),2.26(s,1H,H-19),2.23(s,1H,H-7′),2.20(s,1H,H-16),1.67(d,J＝7.0Hz,H-17)； 13 C NMR(125MHz,pyridine-d 5 )δ153.8(C-11),152.0(C-2),150.8(C-14),149.9(C-3′),147.0(C-5),130.0(C-5′)128.5(C-6′)128.1(C-13),128.0(C-6),127.1(C-10),123.2(C-2),120.4(C-4),116.4(C-4′),113.1(C-1),112.0(C-12),111.0(C-15),90.1(C-8),89.7(C-9),65.0(C-18),55.5(C-2′),49.8(c-1′),33.2(C-7),20.4(C-7′),17.2(C-19),16.4(C-16),13.8(C-17).
high resolution mass spectrum (ESI) calculated C 30 H 35 N 2 O 4 [M+H] + 487.2591, measured as 487.2561.
Example 15
Preparation of Compound 16:
the desired starting materials, reagents and preparation method were the same as in example 3, except that dimethylamine was changed to 1- (4-biphenyl) -piperazine, to give 17mg of the title compound in 63% yield.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(500MHz,pyridine-d 5 )δ7.74-7.69(m,4H,H-8′,H-9′),7.51(s,1H,H-15),7.49-7.45(m,2H,H-5′),7.34-7.31(m,1H,H-10′),7.16(s,1H,H-1),7.08(d,J＝9.0Hz,2H,H-4′),6.86(s,1H,H-2),6.64(s,1H,H-12),5.34(d,J＝3.0Hz,1H,H-8),3.42-3.35(m,2H,H-7,H-18a),3.20-3.18(m,4H,H-2′),3.05-2.97(m,3H,H-18b,H-1′),2.83-2.80(m,2H,H-1′),2.27(s,3H,H-19),2.17(s,3H,H-16),1.69(d,J＝7.0Hz,H-17)； 13 C NMR(125MHz,pyridine-d 5 )δ153.8(C-11),152.1(C-2),151.3(C-3′),150.8(C-14),147.2(C-5),141.3(C-7′),131.7(C-6′),129.3(C-9′),128.1(C-13),128.0(C-6),127.9(C-5′),127.1(C-10),126.8(C-10′),126.7(C-8′),123.3(C-2),120.4(C-4),116.2(C-4′),113.1(C-1),112.0(C-12),111.0(C-15),90.1(C-8),89.7(C-9),65.0(C-18),55.4(C-2′),49.0(C-1′),33.2(C-7),17.2(C-19),16.4(C-16),13.8(C-17).
high resolution mass spectrum (ESI) calculated C 35 H 36 N 2 O 4 [M+H] + 549.2748, measured as 549.2740.
Example 16
Preparation of compound 17:
the desired starting materials, reagents and preparation were the same as in example 3 except that dimethylamine was changed to 1- (3-methylbenzyl) -piperazine, to give 17mg of the title compound in 66% yield.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(400MHz,CD 3 OD)δ7.20-7.06(m,4H,H-5′,H-6′,H-7′,H-8′),6.72(s,1H,H-15),6.58(s,1H,H-1),6.31(s,1H,H-4),6.26(s,1H,H-12),5.01(s,1H,H-8),3.36(s,2H,H-3′),3.34(d,J＝14.0Hz,1H,H-18a),3.11(d,J＝14.0Hz,1H,H-18b),3.05-3.03(m,1H,H-7),2.83-2.79(m,2H,H-1′),2.59-2.55(m,6H,H-1′,H-2′),2.31(s,3H,10′),2.04(s,3H,H-19),1.99(s,3H,H-16),1.50(d,J＝7.2Hz,3H,H-17)； 13 C NMR(100MHz,CD 3 OD)δ153.3(C-11),149.9(C-2),148.7(C-14),146.7(C-5),137.6(C-4′),136.6(C-6′),130.2(C-5′),127.8(C-7′),127.7(C-8′),127.3(C-13),127.2(C-6),126.6(C-9′),125.8(C-10),122.2(C-3),119.3(C-4),111.9(C-1),110.6(C-12),109.5(C-15),89.5(C-8),89.1(C-9),64.0(C-18),62.7(C-3′),54.3(C-1′),53.0(C-2′),32.4(C-7),20.0(C-10′),15.4(C-19),14.5(C-17),12.3(C-17).
high resolution mass spectrum (ESI) calculated C 31 H 36 N 2 O 4 [M+H] + 501.2748, measured as 501.2711.
Example 17
Preparation of compound 18:
the desired starting material, reagents and preparation were the same as in example 3 except that dimethylamine was replaced by 1- (2-pyrimidinyl) piperazine, giving 16mg of the title compound in 69% yield.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(400MHz,pyridine-d 5 )δ8.31(d,J＝4.8Hz,2H,H-4′),6.72(s,1H,H-15),6.57(s,1H,H-1),6.49(t,J＝4.8Hz,1H,H-5′),6.40(s,1H,H-4),6.36(s,1H,H-12),5.08(d,J＝3.2Hz,1H,H-8),3.80-3.75(m,4H,H-2′),3.20(d,J＝14.0Hz,1H,H-18a),3.13-3.10(m,1H,H-7),2.91-2.85(m,2H,H-1′),2.80(d,J＝14.0Hz,1H,H-18b),2.60-2.55(m,2H,H-1′),2.09(s,3H,H-19),2.04(s,3H,H-16),1.51(d,J＝6.8Hz,3H,H-17)； 13 C NMR(100MHz,pyridine-d 5 )δ161.4(C-3′),157.8(C-4′),153.8(C-11),149.1(C-2),148.0(C-14),147.3(C-5),127.5(C-13),127.0(C-6),126.2(C-10),122.1(C-3),119.9(C-4),112.7(C-1),111.5(C-12),110.1(C-15),109.8(C-5′),89.7(C-8),89.1(C-9),64.9(C-18),55.1(C-1′),44.2(C-2′),32.7(C-7),16.5(C-19),15.6(C-16),13.4(C-17).
high resolution mass spectrum (ESI) calculated C 27 H 31 N 4 O 4 [M+H] + 475.2340, measured as 475.2311.
Example 18
Preparation of compound 19:
the same procedures as in example 3 were repeated except for changing dimethylamine to 1- (2-pyrazinyl) piperidine, to give 14mg of the objective compound in 59% yield.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(400MHz,pyridine-d 5 )δ8.07-8.06(m,2H,H-5′,H-6′),7.82(d,J＝2.8Hz,1H,H-4′),6.76(s,1H,H-15),6.59(s,1H,H-1),6.41(s,1H,H-4),6.35(s,1H,H-12),5.06(d,J＝2.8Hz,1H,H-8),3.52-3.50(m,4H,H-2′),3.18(d,J＝14.0Hz,1H,H-18a),3.11-3.05(m,1H,H-7),2.92-2.87(m,2H,H-1′),2.84(d,J＝14.0Hz,1H,H-18b),2.66-2.62(m,2H,H-1′),2.10(s,3H,H-19),2.04(s,3H,H-16),1.51(d,J＝7.2Hz,3H,H-17)； 13 C NMR(100MHz,pyridine-d 5 )δ155.1(C-3′),153.7(C-11),149.5(C-14),148.3(C-2),147.1(C-5),142.0(C-6′),132.4(C-5′),130.6(C-4′),127.4(C-13),127.4(C-6),126.0(C-10),122.4(C-3),119.8(C-4),112.7(C-1),111.4(C-12),110.4(C-15),89.7(C-8),89.0(C-9),64.7(C-18),54.6(C-2′),44.7(C-1′),32.7(C-7),16.6(C-19),15.7(C-16),13.4(C-17).
high resolution mass spectrum (ESI) calculated C 27 H 30 N 4 O 4 [M+H] + 475.2340, measured as 475.2341.
Example 19
Preparation of compound 20:
the desired starting materials, reagents and preparation method were the same as in example 3, except that dimethylamine was changed to quinolizine, to give 12mg of the title compound in 56% yield.
Traits: white powder
1 H-NMR 13 C-NMR data: 1 H NMR(400MHz,pyridine-d 5 )δ7.86(d,J＝9.2Hz,H-5′),7.74(d,J＝8.4Hz,H-7′),7.59(d,J＝8.0Hz,H-7′),7.52(dd,J＝7.2,7.2Hz,1H,H-9′),7.23(dd,J＝7.6,7.2Hz,1H,H-8′),6.91(d,J＝9.2Hz,H-4′),6.75(s,1H,H-15),6.53(s,1H,H-1),6.41(s,1H,H-4),6.35(s,1H,H-12),5.08(d,J＝2.8Hz,1H,H-8),3.70-3.61(m,4H,H-2′),3.14(d,J＝14.0Hz,1H,H-18a),3.11-3.08(m,1H,H-7),2.91-2.86(m,2H,H-1′),2.81(d,J＝14.0Hz,1H,H-18b),2.65-2.60(m,2H,H-1′),2.08(s,3H,H-19),2.04(s,3H,H-16),1.47(d,J＝7.2Hz,3H,H-17)； 13 C NMR(100MHz,pyridine-d 5 )δ157.7(C-3′),153.8(C-11),149.1(C-2),147.9(C-14),147.6(C-5),147.3(C-11′),137.7(C-5′),129.8(C-9′),127.5(C-13),127.3(C-7′),127.2(C-6),126.3(C-10),126.2(C-8′),123.1(C-3),122.6(C-8′),122.3(C-6′),119.8(C-4),112.8(C-4′),111.5(C-1),110.4(C-12),109.9(C-15),89.7(C-8),89.0(C-9),64.6(C-18),55.0(C-1′),45.6(C-2′),32.7(C-7),16.6(C-19),15.6(C-16),13.4(C-17).
high resolution mass spectrum (ESI) calculated C 32 H 34 N 3 O 4 [M+H] + 524.2544, measured as 524.2516.
Example 20
(+) -paeovaitol derivative 1-20 pairs MT of the invention 1 And MT (Mobile terminal) 2 Agonistic activity of the receptor.
1 materials and methods
1.1 materials
Melatonin receptor MT 1 And MT (Mobile terminal) 2 Cell lines used for screening agonist activity correspond to human kidney epithelial cells HEK293-MT respectively 1 And HEK293-MT 2 The method comprises the steps of carrying out a first treatment on the surface of the Cell culture medium containing 10% fetal bovine serum (Dulbecco's Modified Eage Medium, DMEM); a wash-free calcium flux kit.
1.2 instruments
CO 2 Thermo Forma 3310 (usa); inverted biological microscope XD-101 (Nanjing): flexstation 3Benchtop Multi-Mode Microplate Reader (Molecular Devices, sunnyvale, california, USA).
1.3 Experimental procedure
Coating 96 Kong Heibi transparent cell culture plate with matrix BD Matrigel, standing at 37deg.C for 1 hr, collecting supernatant, inoculating corresponding HEK293 cells into 96 Kong Heibi transparent cell culture plate at 4×10 hole density, and adding into CO 2 Culturing in a constant temperature incubator at 37 ℃ with the concentration of 5% for 16-24 h; the original medium was discarded, and 100. Mu.L/well of freshly prepared dye was added and incubated at 37℃for 60min in the absence of light. Preparing a sample to be tested: and preparing samples to be tested with different concentrations. And adding a specific volume of sample to be detected into the cells, wherein the volume of the added sample is 50 mu L/hole, and measuring the agonism of the sample crystal to the melatonin receptor by using a Flexstation 3 multifunctional enzyme-linked immunosorbent assay. The experimental results were analyzed using Graphpad prism 5 software.
2 results
Compounds 11 and 14 were tested against MT at a concentration of 1.0mM 1 And MT (Mobile terminal) 2 The receptor has a certain agonistic activity; compound 16 pair MT 1 The receptor has better excitation effect, and the excitation rate is 56.4%; compound 10 is also directed to MT 1 And MT (Mobile terminal) 2 The receptor has better agonistic activity, and the agonistic rate is 58.9% and 62.2% respectively. Compound 12 pair MT 1 And MT (Mobile terminal) 2 The receptor has strong agonism, and the agonism rate is 95.3% and 74.5% respectively.
Conclusion 3
Experimental results show that compounds 10 and 12 are directed to MT 1 And MT (Mobile terminal) 2 The receptor has an agonism, can be used as a novel melatonin receptor agonist, and can treat or ameliorate central nervous system diseases associated with melatonin receptors.
TABLE 1 Compounds 1-20 vs MT 1 And MT (Mobile terminal) 2 Agonism of receptorsAction
Note that: agomelatine was used as a positive control, and the maximum agonism of Melatonin (MT) was set to 100% and the test concentration of the compound was 1.0mM.
Example 22:
effect of compound 12 on the immobility time of the forced swimming test in mice.
1 materials and methods
Medicine and reagent
Sodium carboxymethylcellulose (CMCNa) and the positive drug fluoxetine were purchased from Saen chemical technology (Shanghai) Inc., and the test drug (Compound 12) was prepared from example 11
Experimental instrument
Xuzhou Bona information technologies Co., ltd XQT mouse forced swimming hardware, any-Maze animal behavior record tracking software in the U.S.
Experimental animal
Kunming mice, SPF grade, weighing 18-20g, were purchased from Bejing Fukang Biotech Co. Animal pass number: SCXK (jing) 2014-0004. The mice were housed in 6 groups per cage, were fed with water ad libitum, received 12h light/12 h darkness each day at room temperature 21±1 ℃, and the animals were started after 7 days of adaptation to the new feeding environment. Fasted for 12 hours before the experiment starts, and the water is freely drunk.
2 experimental procedure
Mice were randomly divided into 7 groups according to weight balance, a blank control group (0.5% CMCNA), a fluoxetine positive control group (20 mg/kg), a compound 12 dose group 1 (5 mg/kg), a compound 12 dose group 2 (10 mg/kg), a compound 12 dose group 3 (20 mg/kg), a compound 12 dose group 4 (40 mg/kg), a compound 12 dose group 5 (80 mg/kg), and 12 animals per group. Forced swimming experiments were performed 24h and 1h after intragastric administration prior to testing. Putting the mice into a glass container with the diameter of 15cm, the height of 25cm and the water depth of 10cm, recording the movement condition of the mice by video shooting at the water temperature of 25+/-1 ℃ for 6min, and counting the immobility time within 4min after the mice by using an Any-Maze behavior tracking software to be used as an anti-depression activity index.
3 results
Compound 12 was able to shorten the immobility time of forced swimming in mice at doses of 10,20,40 and 80mg/kg, and was dose dependent, with the most pronounced activity at doses of 20,40mg/kg, suggesting antidepressant activity.
TABLE 2 Compound 12 forced swim test data results in mice
Example 22:
formulation examples
1. Taking any one or any combination of (+) -paeovaitol derivatives 1-20 (compounds 1-20), dissolving with a small amount of DMSO, adding water for injection conventionally, fine filtering, packaging and sterilizing to obtain injection.
2. Dissolving one or any combination of (+) -paeovitol derivatives 1-20 (compounds 1-20) in a small amount of DMSO, dissolving in sterile water for injection, stirring to dissolve, filtering with sterile suction filter funnel, sterile fine filtering, packaging in An Zeng, freeze drying at low temperature, and sterile sealing to obtain powder for injection.
3. Any one or any combination of (+) -paeovitol derivatives 1-20 (compounds 1-20) is taken, and the weight ratio of the (+) -paeovitol derivatives to the excipient is 9:1, adding excipient according to the proportion, and preparing into powder.
4. Any one or any combination of (+) -paeovitol derivatives 1-20 (compounds 1-20) is taken, and the weight ratio of the (+) -paeovitol derivatives to the excipient is 5:1, adding excipient, granulating and tabletting.
5. Taking any one or any combination of (+) -paeovitol derivatives 1-20 (compounds 1-20), and preparing into oral liquid according to conventional oral liquid preparation method.
6. Any one or any combination of (+) -paeovitol derivatives 1-20 (compounds 1-20) is taken, and the weight ratio of the (+) -paeovitol derivatives to the excipient is 5:1, adding excipient, and making into capsule.
7. Any one or any combination of (+) -paeovitol derivatives 1-20 (compounds 1-20) is taken, and the weight ratio of the (+) -paeovitol derivatives to the excipient is 3:1, adding excipient, and making into capsule.
8. Any one or any combination of (+) -paeovitol derivatives 1-20 (compounds 1-20) is taken, and the weight ratio of the (+) -paeovitol derivatives to the excipient is 5:1, adding excipient according to the proportion, and preparing into granules.
From the above examples, the present invention provides a series of (+) -paeoviitol derivatives, their preparation and use, pharmaceutical compositions and uses thereof. The (+) -paeovaitol derivative provided by the invention is opposite to MT 1 And MT (Mobile terminal) 2 The receptor has a certain agonistic activity, especially the compound 12 can obviously shorten the forced swimming immobility time of mice in the forced swimming experiments of mice, has antidepressant activity, can form a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient, and can be used for treating antidepressant.
The foregoing is merely a preferred embodiment of the invention, and it should be noted that modifications could be made by those skilled in the art without departing from the principles of the invention, which modifications would also be considered to be within the scope of the invention.
Claims (10)
1. (+) -paeovaitol derivatives 1-20 shown in the following structural formula,
2. a process for the preparation of (+) -paeovitol derivatives 1-20 of formula (I) as defined in claim 1, wherein: the method comprises the following steps: preparing the compound 1-3 by (+) -paeoviitol under the action of a proper acetylation reagent, wherein the proper acetylation reagent is acetyl chloride, acetic anhydride, 1-acetyl-1H-1, 2, 3-triazole [4,5-B ] pyridine; the diacetyl- (+) -paeoviitol is prepared into an aldehyde intermediate under the action of an oxidant, the aldehyde intermediate and primary amine or secondary amine are subjected to reductive amination and deacetylation in a proper reaction solvent under the action of a proper reducing agent to obtain the compound 4-20, wherein the proper reaction solvent is dichloromethane or chloroform or methanol or ethanol, and the proper reducing agent is sodium borohydride or sodium triacetyl borohydride or sodium cyanoborohydride.
3. Use of (+) -paeoviitol derivatives 1-20 of the structural formula as claimed in claim 1 for the preparation of melatonin receptor agonists.
4. Use of (+) -paeoviitol derivatives 1-20 of the structural formula as claimed in claim 1 for the preparation of a medicament for the treatment or prophylaxis of depression.
5. The use according to claim 4, characterized in that: the symptoms of depression are circadian rhythm disorders, sleep disorders, anxiety disorders, chronic stress, acute stress injury or cognitive function injury or disorder.
6. A pharmaceutical composition comprising a (+) -paeovaitol derivative 1-20 of the structural formula of claim 1 and a pharmaceutically acceptable carrier or excipient.
7. Use of the pharmaceutical composition of claim 6 for the preparation of a melatonin receptor agonist.
8. Use of the pharmaceutical composition of claim 6 for the preparation of a medicament for the treatment or prevention of depression.
9. The use according to claim 8, characterized in that: the symptoms of depression are circadian rhythm disorders, sleep disorders, anxiety disorders, chronic stress, acute stress injury or cognitive function injury or disorder.
10. A process for the preparation of a pharmaceutical composition according to claim 6, characterized in that it comprises the following steps: preparing the compound 1-3 by (+) -paeoviitol under the action of a proper acetylation reagent, wherein the proper acetylation reagent is acetyl chloride, acetic anhydride, 1-acetyl-1H-1, 2, 3-triazole [4,5-B ] pyridine; the diacetyl- (+) -paeoviitol is prepared into an aldehyde intermediate under the action of an oxidant, the aldehyde intermediate and primary amine or secondary amine are subjected to reductive amination and deacetylation in a proper reaction solvent under the action of a proper reducing agent to obtain a compound 4-20, the proper reaction solvent is dichloromethane or chloroform or methanol or ethanol, and the proper reducing agent is sodium borohydride or sodium triacetyl borohydride or sodium cyanoborohydride; the (+) -paeovaitol derivative 1-20, i.e., any one or any combination of compounds 1-20, described above is then added to at least one pharmaceutically acceptable carrier or excipient.
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| (±)-Paeoveitol, a Pair of New Norditerpene Enantiomers from Paeonia veitchii;Liang, Wen-Juan;;Organic Letters;第16卷(第2期);424-427 * |
| A Total Synthesis of Paeoveitol;Xu, Lun;;Organic Letters;第18卷(第15期);3698-3701 * |
| Biomimetic Total Synthesis of Paeoveitol;Zhang, Yuhan;;Organic Letters;第18卷(第18期);4578-4581 * |
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