CN106928311A - Limonin derivative, its preparation method and medical usage - Google Patents

Abstract

The present invention relates to medicinal chemistry art, and in particular to the water miscible limonin derivative (I) of a class and (II) and preparation method thereof.Results of pharmacodynamic test proves that compound of the invention has the effects such as treating inflammation, rheumatoid arthritis and pain.

Description

Limonin derivative, its preparation method and medical usage

Technical field

The invention belongs to medicinal chemistry art, and in particular to the water miscible limonin derivative of a class, their preparation Method, and the pharmaceutical composition containing these compounds and its treatment pain and aspect of inflammation purposes.

Background technology

Pain is classified as the fifth-largest vital sign after temperature pulse respiration, blood pressure by modern medicine.Pain is such as Effectively treatment, will have a strong impact on daily quality of life and social stability not in time.Although the research of antalgesic has considerable It is progressive, but be either used for the light, non-steroidal antipyretic-antalgic anti-inflammatory agent of moderate pain, in being still used for, the analgesic of severe pain Agent, suffers from respective side effect and limitation, and being also faced with of having potentially abuses problem.

Rheumatoid arthritis is a kind of common arthritis, and pathogenic factor is not also that very clearly it is a kind of chronic disease, It is the systemic disease based on inflammatory synovitis.The key agents of current clinical treatment rheumatoid arthritis include non-steroidal Anti-inflammatory agent, immunodepressant, biological agent and small molecule targeting medicine.Wherein NSAIDs can relief of symptoms, but drug effect compared with Weak, gastrointestinal side effect is big；Immunodepressant such as methotrexate (MTX) drug effect is clear and definite, persistent, but it is slow to work, and toxicity is big, no Good reaction is more and is difficult to tolerate, and need to for a long time carry out therapeutic drug monitoring；Biological agent such as adalimumab clear curative effect, but price It is expensive, it is difficult to popularize；Such as tropsch imatinib approval listing in 2012 of small molecule targeting medicine, but going deep into and scope with clinical practice Expand, numerous safety issues gradually manifest, Product labelling also has safe black surround to alert, and predominantly increases tumour, infection risk. Therefore, find safely, effectively, the analgesia of Small side effects and anti-inflammatory drug be of great immediate significance and social effect.

Limonoids is highly oxidized tetracyclic triterpenoid, be widely present in the Rutaceaes such as citrus and In Meliaceae plant families.Separated so far to obtain kind of limonoids about more than 300, limonin (limonin) is this Representative in class compound.Research finds that limonin compound has effect at aspects such as analgesia, anti-inflammatory, anticancer, antibacterials, but It is that poorly water-soluble, bioavilability is low, have impact on its clinical practice because its effect is not strong enough.

The content of the invention

The invention discloses the compound of formula I and II, proved through pharmacological evaluation, compound of the invention has preferable Analgesia, anti-inflammatory activity.Therefore, the compound of formula I and II of the invention can be used for clinical remission pain and the work for diminishing inflammation With.

Wherein：

R is represented

R¹Represent H, CH₃、CH₂CH₃、CH₂OH or OH.

X represents CH₂、O、NH、N-CH₃Or N-COCH₃。

R²、R³H or C is represented independently of one another₁~C₆Alkyl.

R⁴Represent H, CH₃, F, Cl or Br.

M=1~5.

R is preferably representedR¹It is preferred that representing H or CH₃, X preferably represents CH₂, O, NH or N-CH₃, m is excellent Choosing=1~4.

R is further preferably representedR²、R³It is preferred that representing C independently of one another₁~C₃Alkyl, m=1~4.

The compound of formula I and II can form acid-addition salts with pharmaceutically acceptable acid, and the acid includes hydrogen chloride, bromine Change hydrogen, sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, butanedioic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, Benzene sulfonic acid, p-methyl benzenesulfonic acid or forulic acid.

Compounds of formula I of the present invention and its pharmaceutically acceptable acid-addition salts (I.A) can be prepared with following method：

Wherein：

By compound III (limonin) through acylated prepare compound IV process, acylating agent used is chloracetyl chloride, 3- chlorpromazine chlorides, 4- chlorobutanoylchlorides, 5-Chlorovaleryl Chloride or 6- chlorine caproyl chlorides, acylating agent can also be acetic anhydride, propionic andydride, butyric acid Acid anhydride, valeric anhydride or caproic anhydride；Catalyst is alchlor or zinc chloride；Solvent is dichloromethane, chloroform, the chloroethenes of 1,2- bis- Alkane, chlorobenzene, nitrobenzene.

The process of prepare compound I is substituted by compound IV, amine used is Wherein R¹Selected from H, CH₃、CH₂CH₃、CH₂OH or OH, X are selected from CH₂、O、NH、N-CH₃Or N-COCH₃, R²、R³Selected from H or C₁~C₆ Alkyl, R⁴Selected from H, CH₃, F, Cl or Br；Acid binding agent be potassium carbonate, sodium carbonate, triethylamine or reactant amine in itself；Solvent is Tetrahydrofuran, acetonitrile, acetone, ethyl acetate, or both mixed solvents any.

The process of acid-addition salts IA is prepared into salt by compound I and acid A, sour A used is hydrogen chloride, hydrogen bromide, sulphur Acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, butanedioic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, P-methyl benzenesulfonic acid or forulic acid；Solvent be ethyl acetate, acetone, tetrahydrofuran, dichloromethane, ethanol, methyl alcohol or isopropanol, or Both mixed solvents any.

Compounds of formula II of the present invention and its pharmaceutically acceptable acid-addition salts (II.A) can be prepared with following method：

Wherein：

By compound V (deoxidation limonin, desoxylimonin) through acylated prepare compound VI process, it is used Acylating agent is chloracetyl chloride, 3- chlorpromazine chlorides, 4- chlorobutanoylchlorides, 5-Chlorovaleryl Chloride or 6- chlorine caproyl chlorides, and acylating agent can also be Acetic anhydride, propionic andydride, butyric anhydride, valeric anhydride or caproic anhydride；Catalyst is alchlor or zinc chloride；Solvent be dichloromethane, Chloroform, 1,2- dichloroethanes, chlorobenzene, nitrobenzene.

The process of prepare compound II is substituted by compound VI, amine used is Wherein R¹Selected from H, CH₃、CH₂CH₃、CH₂OH or OH, X are selected from CH₂、O、NH、N-CH₃Or N-COCH₃, R²、R³Selected from H or C₁~C₆ Alkyl, R⁴Selected from H, CH₃, F, Cl or Br；Acid binding agent be potassium carbonate, sodium carbonate, triethylamine or reactant amine in itself；Solvent is Tetrahydrofuran, acetonitrile, acetone, ethyl acetate, or both mixed solvents any.

Prepare the process of acid-addition salts IIA into salt by compound II and acid A, sour A used be hydrogen chloride, hydrogen bromide, Sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, butanedioic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulphur Acid, p-methyl benzenesulfonic acid or forulic acid；Solvent is ethyl acetate, acetone, tetrahydrofuran, dichloromethane, ethanol, methyl alcohol or isopropyl Alcohol, or both mixed solvents any.

The invention reside in providing a kind of pharmaceutical composition, it include compound I or II of the invention or its salt IA or IIA and pharmaceutically acceptable carrier.

Compound or its salt of the present invention can add pharmaceutically acceptable carrier and be made common pharmaceutical formulation, Such as tablet, capsule, pulvis, syrup, liquor, suspending agent, freeze-dried powder, injection, spices, sweetener, liquid or solid can be added The common medicinal supplementary material such as body filler or diluent.

Compound of the present invention administering mode clinically can be using modes such as oral, injection, external applications.

The present invention includes stereoisomer, hydrate, solvate or the crystallization of the compound of formula I or II simultaneously, it There is same pharmacological effect with compound.Application in treatment pain or anti-inflammatory drugs are prepared.

Part of compounds of the present invention is as follows：

Here is the pharmacological evaluation and result of part of compounds of the present invention：

For convenient drug administration, pharmacological evaluation uses the hydrochloride of I and II class compounds.

Pharmacodynamic experiment proves that the compounds of this invention has anti-inflammatory and analgesic effect.Here be part pharmacodynamics test and As a result：(1) mouse acetic acid twisting experiment

Test method：

ICR mouse, male and female half and half, 18~22g is randomly divided into model group, aspirin group, limonin group, deoxidation lemon Lemon bitter principle group, the compounds of this invention group, every group 8.1 hour pneumoretroperitoneum of each group gastric infusion injects 0.7% acetic acid 0.1mL/ 10g, the acetic acid 0.1mL/10g of model group intraperitoneal injection 0.7%, observes and records mouse writhing number of times in 15 minutes immediately.As a result See Tables 1 and 2.

Writhing number of times inhibiting rate=(model group writhing number of times average-administration group writhing number of times average)/model group writhing time Number average * 100%

The influence of the limonin Derivatives In Mice acetic acid twisting number of times of table 1

Note：^*P<0.05,^**P<0.01vs model groups.

The influence of the deoxidation limonin Derivatives In Mice acetic acid twisting number of times of table 2

Note：^*P<0.05,^**P<0.01vs model groups.

Mouse acetic acid twisting test result indicate that, the abdominal cavity of mouse can be caused after the acetic acid 0.1ml/10g of intraperitoneal injection 0.7% , there is writhing response in pain, and part of compounds of the present invention has obvious inhibiting effect to the writhing response of mouse.Improvedization The analgesic activities of compound increase compared with limonin or deoxidation limonin, generally limonin series derivates activity Higher than deoxidation limonin series derivates, and the compound activity of carbon chain length is better than carbochain in limonin series derivates Short compound, wherein compound I-5HCl, I-6HCl, I-7HCl analgesic activities are far above limonin.

(2) mouse contracting tail experiment

Test method：

ICR male mices, 18~22g is randomly divided into model group, aspirin group, limonin group, deoxidation limonin Each reagent group of group, the compounds of this invention, every group 8.Mouse tail tip 3cm is immersed in 48 DEG C of thermostat water baths, with contracting tail Reflection (rat-tail bounce back out the water surface) is pain reaction indicator, and record rat-tail is put into water-bath to the time (second) reflected by thermally-induced contracting tail As pain reaction threshold value.Contracting tail reflection interval takes pain domain based on its average value twice for survey before administration.Each administration group is filled respectively After stomach, 30 minutes, 60 minutes, 90 minutes, the preclinical change of contracting tail of mouse in 120 minutes, more than 25 after each group gavage are determined Second nonresponder, the threshold of pain is based on 25 seconds.Result is as shown in Figure 1, Figure 2 and Fig. 3.

Mouse contracting tail experimental result is displayed in part of compounds of the invention in the time point of test and can lift mouse contracting tail Pain domain in reaction, shows certain analgesic activities.The effect of generally limonin series compound is better than deoxidation lemon Bitter principle series, and activity is higher when carbon chain lengths are 4 carbon in compound, it is basic with conclusion in the experiment of mouse acetic acid twisting Unanimously.

(3) mice ear experiment

Experimental technique：

ICR male mices, 18~22g is randomly divided into model group, naproxen group, limonin group, the compounds of this invention Group, every group 8.Each group gastric infusion applies dimethylbenzene 25ul and causes scorching, post-tensioning neck execution in 30 minutes after 90 minutes in mouse right ear, uses 8mm card punch punches to ears, takes ear and weighs, and calculates swelling rate (%) and swelling inhibiting rate (%).The results are shown in Table 3 and table 4.

Swelling rate (%)=(auris dextra weight-left ear weight)/left ear weight * 100%

Swelling inhibiting rate (%)=(model group swelling rate-reagent group swelling rate)/model group swelling rate * 100%

The influence of the limonin Derivatives In Mice ear swelling of table 3

Note：^*P<0.05,^**P<0.01vs model groups.

The influence of the deoxidation limonin Derivatives In Mice ear swelling of table 4

Note：^*P<0.05,^**P<0.01vs model groups.

Mice ear experimental result shows that compound of the invention has significant inhibitory action to mice ear.Structure Effect relation is tested with mouse acetic acid twisting and mouse pyrocondensation tail experimental result is basically identical.Wherein compound I-5HCl, I-6 HCl shows stronger anti-inflammatory activity, and higher than positive control naproxen and limonin.

(4) rat assist agent arthritis experiment

Tested according to mouse acetic acid twisting, mouse hot water contracting tail is tested and mice ear experimental result, our selections Compound I-5HCl and I-6HCl have carried out rat assist agent arthritis experiment, further checking is carried out to compound activity and is ground Study carefully.

Experimental technique：

Male Wistar Rats 90, after adaptability is raised 3 days, are randomly divided into 9 groups, every group 10, i.e. blank group, model Group, I-5HCl 200mg/kg groups, I-5HCl 100mg/kg groups, I-5HCl 50mg/kg groups, I-6HCl 200mg/ Kg groups, I-6HCl 100mg/kg groups, I-6HCl 50mg/kg groups, tropsch imatinib 5mg/kg groups.Before modeling, inactivation card is situated between Seedling is sufficiently mixed with incomplete Freund's adjuvant, is made into the complete Freund's adjuvant (CFA) containing inactivated vaccine 10mg/ml.Except blank Each Rat Right metapedes toes injection 0.1ml CFA of outer remaining group of group causes scorching.Modeling starts the administration of each group rat oral gavage on the 21st day, Successive administration 14 days.At regular intervals, the right ankle to each rat surveys swelling situation and changes of weight, the 15th day each group rat Eye socket is taken a blood sample, for detecting TNF-α and IL-6.Result is as follows：

1. toes swelling inhibiting rate

Each group rat measures once its right ankle swelling situation in every three days after giving test-compound, calculates swelling and suppresses Rate, the results are shown in Table 5.

Swelling suppresses percentage=(average swelling rate after average swelling rate-administration before administration) average swelling rate of/model group × 100%

Influences (n=8) of the I-5HCl of table 5 and I-6HCl to the primary parapodum toe swelling of rat

Find out from toes swelling inhibiting rate result, two compounds are swollen to the primary parapodum of rat to be respectively provided with inhibitory activity, and With the rising of dosage, inhibitory activity is also raised, and shows that it has certain dose dependent.From result it is also seen that compound The activity of I-6HCl is slightly above compound I-5HCl.

2. to the influence of rat body weight

A rat body weight is measured every three days after giving test-compound, the change of rat body weight is observed, as a result as schemed 4。

It can be seen that rat before administration the phase when changes of weight it is smaller, from the 5th day backward body weight in rise Trend, illustrates that the health of the rat after compound works takes a turn for the better, and further demonstrating compound has alleviation inflammatory pain Effect.

3. to the influence of rat clinical score

Compound is mainly scored and rat arthritis the influence of rat clinical score by rat body in this experiment Index is showed, and scoring or index explanation clinical state higher are poorer, as a result such as Fig. 5 and Fig. 6.

The whole body scoring that gives rat after test-compound is displayed in figure and arthritis index has declined, illustrate greatly Mouse clinical state takes a turn for the better, and further checking the compounds of this invention has antalgic and inflammation relieving activity.

4. TNF-α and IL-6 assays in serum

Give test-compound each group rat eye socket blood sampling in the 15th day, TNF-α and IL-6 are detected, as a result such as table 6.

TNF-α and IL-6 assays in the serum of table 6

Note：^*p<0.05,^**p<0.01,^***p<0.001vs model groups,^△p<0.05,^△△p<0.01,^△△△p<0.001vs is empty White group

Find out that the TNF-α in rat blood serum upon administration and IL-6 contents have decline from result, point out the two scorching Inflammation factor is probably the important medium that compound plays antalgic and inflammation relieving activity.Specific mechanism needs further research.

(5) mouse hot-plate experiment

The difference of analgesic activities when same compound is administered by different way is investigated using mouse hot-plate experiment.

Experimental technique：

ICR female mices 90,55 (± 0.5) DEG C are heated to by constant water bath box, and female mice is placed on hot plate, with Its foot contact hot plate arrives that to start to lick time of metapedes be the hot plate method threshold of pain (HPPT), rejects HPPT and is more than 30s or less than 5s's Animal, selects standard compliant 70 female mices to be randomly divided into 7 groups, respectively model control group, limonin by body weight 100mg/kg dosage groups, I-5HCl gastric infusion 100mg/kg dosage groups, I-5HCl intravenously administrable 10mg/kg dosage groups, I-6HCl gastric infusion 100mg/kg dosage groups, I-6HCl intravenously administrable 10mg/kg dosage groups.So that first three hot plate is administered The threshold of pain based on the average value of method HPPT, to then stopping to stimulate more than 60s nonresponders, with 60s pain reaction timing, after administration The 30min start recordings threshold of pain time.Threshold of pain increase rate (%)=(threshold of pain-Basic Pain Threshold after administration)/Basic Pain Threshold × 100%, Result such as table 7.

I-5HCl the and I-6HCl mouse hot-plate analgesic experiments of table 7

Note：^*P<0.05,^**P<0.01vs model groups,^△P<0.05,^△△P<Basic Pain Threshold in 0.01vs groups,^◇P<0.05,^◇◇P <0.01vs naproxen groups

In this experiment, we take two kinds of administering modes of gavage and intravenous injection, from experimental result as can be seen that vein The analgesic activities that 10mg/kg dosage is administered are better than the analgesic activities of corresponding oral 100mg/kg dosage.

Limonin insoluble in water, and compound acid adding of the invention is into water-soluble after salt.

Brief description of the drawings

Fig. 1 is effect of -1~I-6 of limonin derivative I of the present invention hydrochlorides to mouse contracting tail

Fig. 2 is the contracting tail effect of -7~I-9 of limonin derivative I of the present invention, I-12~I-13 hydrochlorides to mouse

Fig. 3 is contracting tail of deoxidation limonin derivative I I-2~II-3, II-5~the II-6 hydrochlorides of the present invention to mouse Effect

Fig. 4 is influences of the compounds of this invention I-5HCl and I-6HCl to rat body weight

Fig. 5 is the influence that the compounds of this invention I-5HCl and I-6HCl scores rat body

Fig. 6 is influences of the compounds of this invention I-5HCl and I-6HCl to rat arthritis index

Specific embodiment

Embodiment 1

The preparation of 23- (2- (piperidin-1-yl) acetyl group) limonin (I-1)

23- chloracetyls limonin (IV-1)

Limonin (8g, 17mmol) and dichloromethane (125mL) are added in 250mL three-necked bottles, 0 is cooled under stirring DEG C, alchlor (10.2g, 76.5mmol) is dividedly in some parts, finish, insulated and stirred 20 minutes, dropwise addition chloracetyl chloride (2.2g, 19.5mmol) with the mixed solution of dichloromethane (5mL), drop finishes, and is kept for 0~-5 DEG C react 1 hour, continues to stir then at room temperature Reaction 3 hours, stops reaction, and reaction solution is slowly poured into 100mL frozen water, divides and takes dichloromethane layer, water layer dichloromethane It is extracted twice (100mL × 2), merges organic layer, three times (100mL × 3), saturated common salt is washed with 1mol/L sodium hydrate aqueous solutions Water washing (100mL × 2), anhydrous sodium sulfate drying, suction filtration twice, remove solvent under reduced pressure.Crude product column chromatography (dichloromethane: Methyl alcohol=180:1) purify, obtain light green solid (IV-1) 2.8g, yield 30.2%, m.p.>200℃.¹H NMR(300MHz, CDCl₃) δ 7.62 (s, 1H), 7.24 (s, 1H), 5.50 (s, 1H), 4.77 (d, J=13.1Hz, 1H), 4.55 (s, 2H), 4.46 (d, J=13.0Hz, 1H), 4.03 (s, 2H), 2.99 (dd, J=17.0,3.7Hz, 1H), 2.93-2.79 (m, 1H), 2.68 (d, J=15.7Hz, 1H), 2.58-2.40 (m, 2H), 2.22 (d, J=13.0Hz, 1H), 1.98-1.75 (m, 3H), 1.59-1.51 (m,1H),1.29(s,3H),1.18(s,3H),1.14(s,3H),1.08(s,3H).ESI-MS(m/z):569.2[M+Na]⁺

23- (2- (piperidin-1-yl) acetyl group) limonin (I-1)

In 100mL three-necked bottles add tetrahydrofuran (30mL), potassium carbonate (0.66g, 4.78mmol), KI (0.03g, 0.18mmol), piperidines (0.92g, 10.8mmol), is stirred at room temperature 20 minutes, IV-1 (1.97g, 3.6mmol) is added dropwise and is dissolved in tetrahydrochysene The solution of furans (30mL), drop finishes, and room temperature continues to react 5 hours, TLC detection (dichloromethane:Methyl alcohol=25:1) react complete, Remove solvent under reduced pressure.Residue adds 20mL water, separates out solid, suction filtration, crude product column chromatography (dichloromethane:Methyl alcohol=80:1) Purifying, obtains faint yellow solid (I-1) 1.1g, yield 51.3%, 128 DEG C (charing).¹H NMR(300MHz,CDCl₃)δ7.57(s, 1H), 7.31 (s, 1H), 5.49 (s, 1H), 4.78 (d, J=13.4Hz, 1H), 4.47 (d, J=13.2Hz, 1H), 4.03 (s, 2H), 3.63 (s, 2H), 2.99 (dd, J=16.8,3.5Hz, 1H), 2.94-2.82 (m, 1H), 2.69 (d, J=16.4Hz, 1H), 2.63-2.36 (m, 6H), 2.23 (d, J=13.0Hz, 1H), 1.94-1.78 (m, 3H), 1.69-1.41 (m, 7H), 1.30 (s,3H),1.19(s,3H),1.16(s,3H),1.08(s,3H).ESI-MS(m/z):596.3[M+H]⁺

I-1 (1.0g, 1.68mmol) is dissolved in ethyl acetate (40mL), saturation HCl is slowly added dropwise under ice bath stirring Ethyl acetate solution to pH 2 or so, separate out faint yellow solid, continue to stir 1 hour, suction filtration, gained solid 20mL acetic acid Ethyl ester is beaten, suction filtration, dry faint yellow solid (I-1HCl) 0.9g, yield 85%, m.p.>200℃.¹H NMR (300MHz, DMSO) δ 10.04 (s, 1H), 8.20 (s, 1H), 7.69 (s, 1H), 5.58 (s, 1H), 4.91 (d, J=12.9Hz, 1H), 4.74 (s, 2H), 4.48 (d, J=13.1Hz, 1H), 4.16 (s, 1H), 4.08 (s, 1H), 3.43-3.29 (m, 4H), 3.17-3.05 (m, 1H), 2.75 (d, J=16.6Hz, 1H), 2.65-2.51 (m, 2H), 2.45-2.38 (m, 1H), 2.27 (d, J =12.1Hz, 1H), 1.99-1.57 (m, 9H), 1.45-1.32 (m, 1H), 1.17 (s, 3H), 1.08 (s, 3H), 1.00 (s, 6H).

Embodiment 2

The preparation of 23- (2- (morpholine -4- bases) acetyl group) limonin (I-2)

With compound IV-1 (2.0g, 3.65mmol) and morpholine (0.95g, 10.90mmol) for raw material, the same I- of operating process 1, crude product column chromatography (dichloromethane:Methyl alcohol=90:1) purify, obtain light yellow solid (I-2) 1.2g, yield 54.9%, 146 DEG C (charing).¹H NMR(300MHz,CDCl₃) δ 7.59 (s, 1H), 7.26 (s, 1H), 5.51 (s, 1H), 4.79 (d, J= 13.1Hz, 1H), 4.49 (d, J=13.2Hz, 1H), 4.06 (s, 2H), 3.85-3.73 (m, 4H), 3.70 (s, 2H), 3.00 (dd, J=16.8,3.7Hz, 1H), 2.95-2.79 (m, 1H), 2.78-2.57 (m, 5H), 2.57-2.42 (m, 2H), 2.24 (dd, J=15.8,3.1Hz, 1H), 1.91-1.78 (m, 3H), 1.62-1.46 (m, 1H), 1.32 (s, 3H), 1.20 (s, 3H), 1.17(s,3H),1.10(s,3H).ESI-MS(m/z):598.3[M+H]⁺

With compound I-2 (1.0g, 1.67mmol) for raw material, the same I-1HCl of operating process obtains light yellow solid (I- 2HCl) 0.87g, yield 83%, m.p.>200℃.

Embodiment 3

The preparation of 23- (2- (piperazine -1- bases) acetyl group) limonin (I-3)

With compound IV-1 (2.0g, 3.65mmol) and N- tert-butoxycarbonyl-piperazines (2.73g, 14.6mmol) for raw material, The same I-1 of operating process, crude product column chromatography (dichloromethane:Methyl alcohol=150:1) purify, obtain the faint yellow intermediates of 1.46g.Should Intermediate is dissolved in methyl alcohol (20mL), and the lower methanol solution (20mL) that saturation HCl is added dropwise of ice bath stirring, drop finishes, and room temperature reaction 2 is small When, TLC detection (solvents：Dichloromethane:Methyl alcohol=25:1) react complete, 0~5 DEG C is placed 1 hour, and suction filtration obtains pale yellow colored solid Body (I-3) 0.9g, two steps add up to yield 41.2%, 140 DEG C (charing).¹H NMR(300MHz,CDCl₃)δ7.57(s,1H), 7.25 (s, 1H), 5.49 (s, 1H), 4.77 (d, J=12.7Hz, 1H), 4.47 (d, J=13.4Hz, 1H), 4.03 (s, 2H), 3.68 (s, 2H), 3.06 (s, 4H), 2.97 (dd, J=16.8,3.9Hz, 1H), 2.93-2.81 (m, 1H), 2.78-2.62 (m, 4H), 2.60-2.41 (m, 3H), 2.23 (d, J=12.4Hz, 1H), 2.03-1.76 (m, 3H), 1.62-1.45 (m, 1H), 1.29 (s,3H),1.18(s,3H),1.15(s,3H),1.08(s,3H),0.90–0.82(m,1H).ESI-MS(m/z):597.3[M+ H]⁺

With compound I-3 (0.8g, 1.34mmol) for raw material, the same I-1HCl of operating process obtains light yellow solid (I- 3HCl) 0.69g, yield 81.4%, m.p.>200℃.

Embodiment 4

The preparation of 23- (2- (4- methylpiperazine-1-yls) acetyl group) limonin (I-4)

With compound IV-1 (2.0g, 3.65mmol) and N methyl piperazine (1.64g, 16.42mmol) for raw material, operated The same I-1 of journey, crude product column chromatography (dichloromethane:Methyl alcohol=100:1) purify, obtain yellow solid (I-4) 0.85g, yield 38.2%, 180 DEG C (charing).¹H NMR(300MHz,CDCl₃)δ7.56(s,1H),7.23(s,1H),5.48(s,1H),4.77 (d, J=12.9Hz, 1H), 4.46 (d, J=13.3Hz, 1H), 4.02 (s, 2H), 3.67 (s, 2H), 2.98 (d, J=16.0Hz, 1H),2.92–2.80(m,1H),2.75–2.41(m,9H),2.32(s,3H),2.26–2.04(m,3H),1.97–1.75(m, 3H),1.61–1.44(m,1H),1.29(s,3H),1.17(s,3H),1.14(s,3H),1.07(s,3H).ESI-MS(m/z): 611.3[M+H]⁺

With compound I-4 (0.8g, 1.31mmol) for raw material, the same I-1HCl of operating process obtains light yellow solid (I- 4HCl) 0.68g, yield 80.3%, m.p.>200℃.

Embodiment 5

The preparation of 23- (4- (piperidin-1-yl) bytyry) limonin (I-5)

23- (4- chlorobutyryls) limonin (IV-2)

Limonin (40.0g, 85.01mmol) and dichloromethane (500mL) are added in 1000ml three-necked bottles, stirring declines Temperature is dividedly in some parts alchlor (51.0g, 382.5mmol) to 0 DEG C, finishes, insulated and stirred 20min, and 4- chlorobutanoylchlorides are added dropwise (14.4g, 102.0mmol) and the mixed solution of dichloromethane (15mL), drips and finishes, and is kept for 0~-5 DEG C react 1 hour, then at room Temperature continues stirring reaction 2 hours, stops reaction, and reaction solution is slowly poured into 500mL frozen water, divides and takes dichloromethane layer, water layer Be extracted twice (300mL × 2) with dichloromethane, merge organic layer, with 1mol/L sodium hydrate aqueous solutions wash three times (300mL × 3), saturated aqueous common salt is washed twice (300mL × 2), anhydrous sodium sulfate drying, and suction filtration removes solvent under reduced pressure.Crude product column chromatography (dichloromethane:Methyl alcohol=160:1) purify, obtain light green solid (IV-2) 20.5g, yield 42%, m.p.160~163 DEG C.¹H NMR(300MHz,CDCl₃) δ 7.58 (s, 1H), 7.13 (s, 1H), 5.50 (s, 1H), 4.78 (d, J=12.9Hz, 1H), 4.47 (d, J=13.1Hz, 1H), 4.03 (s, 2H), 3.65 (t, J=6.2Hz, 2H), 3.03 (t, J=7.0Hz, 2H), 2.99-2.80 (m, 2H), 2.68 (d, J=16.7Hz, 1H), 2.59-2.42 (m, 2H), 2.30-2.11 (m, 3H), 1.97-1.76 (m, 3H), 1.54(s,1H),1.30(s,3H),1.19(s,3H),1.15(s,3H),1.08(s,3H).ESI-MS(m/z):597.2[M+ Na]⁺

23- (4- (piperidin-1-yl) bytyry) limonin (I-5)

In 100ml three-necked bottles add IV-2 (2g, 3.48mmol), acetonitrile (50mL), piperidines (1.78g, 20.88mmol) and KI (0.1g, 0.6mmol), heating reflux reaction 48h, TLC (dichloromethane:Methyl alcohol=25:1) detection reaction is complete, subtracts Pressure is evaporated off solvent.Residue adds 50mL water, separates out yellow solid, suction filtration, crude product column chromatography (dichloromethane:Methyl alcohol=60: 1) purify, obtain brown solid (I-5) 0.74g, yield 34%, 150 DEG C (charing).¹H NMR(300MHz,CDCl₃)δ7.56 (s, 1H), 7.13 (s, 1H), 5.47 (s, 1H), 4.76 (d, J=13.1Hz, 1H), 4.46 (d, J=13.1Hz, 1H), 4.03 (d, J=9.1Hz, 2H), 3.08-2.96 (m, 2H), 2.95-2.80 (m, 3H), 2.78-2.56 (m, 6H), 2.52 (d, J= 11.2Hz, 1H), 2.44 (d, J=14.5Hz, 1H), 2.22 (d, J=13.5Hz, 1H), 2.11-1.98 (m, 2H), 1.96- 1.76(m,3H),1.76–1.63(m,4H),1.61–1.42(m,3H),1.28(s,3H),1.16(s,3H),1.13(s,3H), 1.06(s,3H).ESI-MS(m/z):624.3[M+H]⁺

With compound I-5 (0.65g, 1.04mmol) for raw material, the same I-1HCl of operating process obtains white solid (I-5 HCl) 0.51g, yield 74%, m.p.190~193 DEG C.¹H NMR(300MHz,DMSO)δ9.94(s,1H),8.05(s,1H), 7.49 (s, 1H), 5.54 (s, 1H), 4.92 (d, J=12.6Hz, 1H), 4.48 (d, J=13.1Hz, 1H), 4.14 (s, 1H), 4.08(s,1H),3.38–3.30(m,2H),3.20–3.05(m,1H),3.05–2.91(m,4H),2.90–2.79(m,2H), 2.76 (d, J=16.7Hz, 1H), 2.66-2.52 (m, 2H), 2.45-2.39 (m, 1H), 2.27 (d, J=14.4Hz, 1H), 2.04–1.91(m,2H),1.87–1.61(m,9H),1.43–1.32(m,1H),1.17(s,3H),1.09(s,3H),1.00(d, J=3.3Hz, 6H)

Embodiment 6

The preparation of 23- (4- (morpholine -4- bases) bytyry) limonin (I-6)

With compound IV-2 (2.0g, 3.48mmol) and morpholine (1.52g, 17.4mmol) for raw material, the same I- of operating process 5, crude product column chromatography (dichloromethane:Methyl alcohol=80:1) purify, obtain brown solid (I-6) 1.43g, yield 66%, 144 DEG C (charing).¹H NMR(300MHz,CDCl₃) δ 7.55 (s, 1H), 7.08 (s, 1H), 5.49 (s, 1H), 4.77 (d, J=13.0Hz, 1H), 4.46 (d, J=13.2Hz, 1H), 4.03 (d, J=7.7Hz, 2H), 3.68-3.52 (m, 4H), 2.98 (dd, J=16.7, 3.6Hz, 1H), 2.93-2.86 (m, 1H), 2.82 (t, J=6.9Hz, 2H), 2.68 (d, J=17.2Hz, 1H), 2.57-2.47 (m,2H),2.47–2.35(m,6H),2.26–2.18(m,1H),1.97–1.77(m,5H),1.58–1.48(m,1H),1.29 (s,3H),1.18(s,3H),1.14(s,3H),1.07(s,3H).ESI-MS(m/z):626.3[M+H]⁺

With compound I-6 (1.3g, 2.08mmol) for raw material, the same I-1HCl of operating process obtains white solid (I-6 HCl) 1.18g, yield 86%, 200 DEG C (charing).¹H NMR(300MHz,DMSO)δ10.71(s,1H),8.05(s,1H), 7.49 (s, 1H), 5.54 (s, 1H), 4.92 (d, J=13.5Hz, 1H), 4.48 (d, J=12.9Hz, 1H), 4.14 (s, 1H), 4.08(s,1H),3.98–3.88(m,2H),3.82–3.70(m,2H),3.49–3.40(m,2H),3.15–3.02(m,4H), 3.01-2.92 (m, 3H), 2.75 (d, J=16.5Hz, 1H), 2.65-2.52 (m, 2H), 2.45-2.40 (m, 1H), 2.27 (d, J =11.7Hz, 1H), 2.04-1.91 (m, 2H), 1.85-1.63 (m, 3H), 1.31-1.22 (m, 1H), 1.17 (s, 3H), 1.09 (s, 3H), 1.00 (d, J=3.4Hz, 6H)

Embodiment 7

The preparation of 23- (4- (4- methylpiperazine-1-yls) bytyry) limonin (I-7)

With compound IV-2 (2.0g, 3.48mmol) and N methyl piperazine (1.74g, 17.4mmol) for raw material, operated The same I-5 of journey, crude product column chromatography (dichloromethane:Methyl alcohol=80:1) purify, obtain brown solid (I-7) 1.0g, yield 45%, 146 DEG C (charing).¹H NMR(300MHz,CDCl₃) δ 7.55 (s, 1H), 7.08 (s, 1H), 5.49 (s, 1H), 4.77 (d, J= 13.1Hz, 1H), 4.46 (d, J=13.0Hz, 1H), 4.03 (d, J=4.5Hz, 2H), 2.99 (dd, J=16.8,3.7Hz, 1H), 2.93-2.85 (m, 1H), 2.82 (t, J=7.0Hz, 2H), 2.75-2.63 (m, 2H), 2.62-2.35 (m, 10H), 2.31 (s,3H),2.27–2.16(m,2H),1.98–1.74(m,5H),1.60–1.47(m,1H),1.30(s,3H),1.18(s,3H), 1.15(s,3H),1.07(s,3H).ESI-MS(m/z):639.3[M+H]⁺

With compound I-7 (0.9g, 1.4mmol) for raw material, the same I-1HCl of operating process obtains white solid (I-7 HCl) 0.69g, yield 73.1%, m.p.>200℃.

Embodiment 8

The preparation of 23- (4- (pyrroles -1- bases) bytyry) limonin (I-8)

With compound IV-2 (2.0g, 3.48mmol) and pyrrolidines (1.24g, 17.4mmol) for raw material, operating process is same I-5, crude product column chromatography (dichloromethane:Methyl alcohol=60:1) purify, obtain brown solid (I-8) 0.91g, yield 42.9%, M.p.154~156 DEG C.¹H NMR(300MHz,CDCl₃)δ7.59(s,1H),7.21(s,1H),5.49(s,1H),4.77(d,J =13.1Hz, 1H), 4.46 (d, J=13.1Hz, 1H), 4.04 (d, J=9.2Hz, 2H), 3.11-2.78 (m, 10H), 2.69 (d, J=16.0Hz, 1H), 2.56-2.42 (m, 2H), 2.27-2.10 (m, 3H), 2.06-1.96 (m, 4H), 1.91-1.79 (m, 3H),1.61(s,1H),1.29(s,3H),1.18(s,3H),1.14(s,3H),1.06(s,3H).ESI-MS(m/z):610.4 [M+H]⁺

With compound I-8 (0.8g, 1.31mmol) for raw material, the same I-1HCl of operating process obtains light yellow solid (I- 8HCl) 0.55g, yield 64.9%, 190 DEG C (charing).

Embodiment 9

The preparation of 23- (4- (piperazine -1- bases) bytyry) limonin (I-9)

With compound IV-2 (2g, 3.48mmol) and N- tert-butoxycarbonyl-piperazines (5.21g, 27.86mmol) for raw material, behaviour Make the same I-5 of process, crude product column chromatography (dichloromethane:Methyl alcohol=100:1) purify, obtain yellow intermediate 0.92g.By the yellow Intermediate is dissolved in the mixed solvent of methyl alcohol (10mL) and dichloromethane (10mL), the lower methyl alcohol that saturation HCl is added dropwise of ice bath stirring Solution (10mL), drop finishes, room temperature reaction 5 hours, TLC detection (dichloromethane:Methyl alcohol=20:1) react complete, stop reaction, Adjust pH to neutrality, remove solvent under reduced pressure, with dichloromethane (30mL) dissolution residual substance, add water (20mL), divide and take dichloromethane layer, Water layer dichloromethane is extracted twice (20mL × 2), merges organic layer, and saturated aqueous common salt is washed twice (20mL × 2), anhydrous sulphur Sour sodium is dried, and suction filtration removes solvent under reduced pressure.Crude product column chromatography (dichloromethane:Methyl alcohol=60:1) purify, obtain yellow solid (I-9) 0.33g, two steps add up to yield 15.2%, 162 DEG C (charing).¹H NMR(300MHz,CDCl₃)δ7.56(s,1H),7.08 (s, 1H), 5.49 (s, 1H), 4.77 (d, J=13.6Hz, 1H), 4.47 (d, J=11.6Hz, 1H), 4.07 (d, J=34.5Hz, 2H),3.07–2.56(m,9H),2.55–2.30(m,8H),2.29–2.25(m,1H),2.01–1.79(m,5H),1.64–1.51 (m,1H),1.30(s,3H),1.18(s,3H),1.15(s,3H),1.07(s,3H),0.88(brs,1H).ESI-MS(m/z): 625.2[M+H]⁺

With compound I-9 (0.25g, 0.4mmol) for raw material, the same I-1HCl of operating process obtains light yellow solid (I- 9HCl) 0.23g, yield 87.1%, m.p.>200℃.

Embodiment 10

The preparation of 23- (4- (two n-propylamine bases) bytyry) limonin (I-12)

With compound IV-2 (2.0g, 3.48mmol) and di-n-propylamine (2.11g, 20.85mmol) for raw material, operating process Same I-5, crude product column chromatography (dichloromethane:Methyl alcohol=40:1) purify, obtain light yellow solid (I-12) 0.36g, yield 16.2%, 148 DEG C (charing).¹H NMR(300MHz,CDCl₃)δ7.55(s,1H),7.10(s,1H),5.48(s,1H),4.77 (d, J=13.1Hz, 1H), 4.46 (d, J=13.1Hz, 1H), 4.03 (s, 2H), 2.98 (dd, J=16.8,3.7Hz, 1H), 2.93-2.79 (m, 3H), 2.68 (d, J=16.6Hz, 1H), 2.61-2.39 (m, 8H), 2.26-2.18 (m, 1H), 2.02- 1.77(m,5H),1.58–1.41(m,5H),1.29(s,3H),1.17(s,3H),1.14(s,3H),1.07(s,3H),0.87 (t, J=7.3Hz, 6H) .ESI-MS (m/z):640.3[M+H]⁺

With compound I-12 (0.3g, 0.47mmol) for raw material, the same I-1HCl of operating process obtains light yellow solid (I- 12HCl) 0.28g, yield 88.5%, m.p.174~176 DEG C.

Embodiment 11

The preparation of 23- (4- (imidazoles -1- bases) bytyry) limonin (I-13)

With compound IV-2 (2.0g, 3.48mmol) and imidazoles (1.18g, 17.3mmol) for raw material, the same I- of operating process 5, crude product column chromatography (dichloromethane:Methyl alcohol=50:1) purify, obtain gray solid (I-13) 0.27g, yield 12.8%, 150 DEG C (charing).¹H NMR(300MHz,DMSO)δ8.02(s,1H),7.93(s,1H),7.44(s,1H),7.36(s,1H),6.97 (s, 1H), 5.52 (s, 1H), 4.91 (d, J=13.2Hz, 1H), 4.47 (d, J=12.4Hz, 1H), 4.11 (s, 2H), 4.09- 4.02(m,2H),3.19–3.05(m,1H),2.85–2.77(m,2H),2.76–2.70(m,1H),2.66–2.51(m,2H), 2.45-2.39 (m, 1H), 2.27 (d, J=11.7Hz, 1H), 2.09-1.95 (m, 2H), 1.90-1.65 (m, 3H), 1.28- (d, J=4.3Hz, the 6H) .ESI-MS (m/z) of 1.22 (m, 1H), 1.17 (s, 3H), 1.08 (s, 3H), 1.00:607.3[M+H]⁺

With compound I-13 (0.2g, 0.33mmol) for raw material, the same I-1HCl of operating process obtains pale solid (I- 13HCl) 0.18g, yield 85.1%, 196 DEG C (charing).

Embodiment 13

The preparation of 23- (4- (piperidin-1-yl) bytyry) deoxidation limonin (II-2)

23- (4- chlorobutyryls) deoxidation limonin (VI)

Deoxidation limonin V (10g, 22.02mmol) and dichloromethane (140mL) are added in 250ml eggplant-shape bottles,

- 5 DEG C are cooled under stirring, alchlor (14.69g, 110.1mmol) is dividedly in some parts, finished, insulated and stirred 30min, is added dropwise 4- chlorobutanoylchlorides (4.04g, 28.65mmol), and drop finishes, and is kept for 0~-5 DEG C react 1 hour, continues to stir in room temperature Reaction 12 hours is mixed, stops reaction, reaction solution is slowly poured into 150ml frozen water, divided and take dichloromethane layer, water layer dichloromethane Alkane is extracted twice (100mL × 2), merges organic layer, is washed three times (100mL × 3) with 1mol/L sodium hydrate aqueous solutions, saturation food Salt solution is washed twice (100mL × 2), anhydrous sodium sulfate drying, and suction filtration removes solvent under reduced pressure.Crude product column chromatography (petroleum ether: Ethyl acetate=1:1) purify, obtain white solid (VI) 6.48g, yield 52.7%, m.p.136-139 DEG C.¹H NMR (300MHz,CDCl₃) δ 7.65 (s, 1H), 7.19 (s, 1H), 6.86 (s, 1H), 5.03 (s, 1H), 4.68 (d, J=13.3Hz, 1H), 4.57 (d, J=13.3Hz, 1H), 4.11 (s, 1H), 3.65 (t, J=6.2Hz, 2H), 3.04 (t, J=7.1Hz, 2H), 2.97 (dd, J=12.6,4.1Hz, 1H), 2.90-2.76 (m, 1H), 2.67-2.49 (m, 3H), 2.31 (d, J=15.6Hz, 1H),2.25–2.15(m,2H),2.15–2.06(m,1H),1.92–1.80(m,1H),1.61–1.50(m,2H),1.41(s, 3H),1.30(s,3H),1.22(s,3H),1.19(s,3H).ESI-MS m/z:557.2[M-H]^-

23- (4- (piperidin-1-yl) bytyry) deoxidation limonin (II-2)

With compound VI (2.0g, 3.58mmol) and piperidines (1.83g, 21.5mmol) for raw material, the same I-5 of operating process, Crude product column chromatography (dichloromethane:Methyl alcohol=60:1) purify, obtain yellow solid (II-2) 0.88g, yield 40.5%, M.p.139~142 DEG C.¹H NMR(300MHz,CDCl₃)δ7.62(s,1H),7.13(s,1H),6.85(s,1H),5.02(s, 1H), 4.67 (d, J=13.4Hz, 1H), 4.56 (d, J=13.2Hz, 1H), 4.11 (s, 1H), 2.95 (d, J=16.3Hz, 1H),2.89–2.74(m,3H),2.70–2.46(m,3H),2.45–2.30(m,6H),2.30–2.19(m,1H),2.17–2.02 (m,1H),1.99–1.90(m,2H),1.89–1.78(m,1H),1.72–1.55(m,2H),1.55–1.45(m,4H),1.40 (s,5H),1.28(s,3H),1.20(s,3H),1.17(s,3H).ESI-MS m/z:608.4[M+H]⁺

With compound II-2 (0.8g, 1.32mmol) for raw material, the same I-1HCl of operating process obtains light yellow solid (II- 2HCl) 0.64g, yield 75.5%, 178 DEG C (charing).

Embodiment 14

23- (4- (morpholine -4- bases) bytyry) deoxidation limonin (II-3)

With compound VI (2.0g, 3.58mmol) and morpholine (1.87g, 21.5mmol) for raw material, the same I-5 of operating process, Crude product column chromatography (dichloromethane:Methyl alcohol=60:1) purify, obtain light yellow solid (II-3) 0.8g, yield 36.7%, M.p.141~144 DEG C.1H NMR(300MHz,CDCl3)δ7.62(s,1H),7.13(s,1H),6.84(s,1H),5.02(s, 1H), 4.67 (d, J=13.3Hz, 1H), 4.56 (d, J=13.3Hz, 1H), 4.11 (s, 1H), 3.58 (s, 4H), 3.03-2.86 (m,2H),2.86–2.76(m,2H),2.69–2.52(m,3H),2.52–2.35(m,6H),2.34–2.24(m,1H),2.17– 2.02(m,1H),2.00–1.89(m,2H),1.88–1.78(m,1H),1.66–1.48(m,2H),1.39(s,3H),1.28(s, 3H),1.20(s,3H),1.17(s,3H).ESI-MS m/z:632.3[M+Na]⁺

With compound II-3 (0.7g, 1.15mmol) for raw material, the same I-1HCl of operating process obtains light yellow solid (II- 3HCl) 0.62g, yield 83.5%, 198 DEG C (charing).

Embodiment 15

The preparation of 23- (4- (two n-propylamine bases) bytyry) deoxidation limonin (II-5)

With compound VI (2.0g, 3.58mmol) and di-n-propylamine (2.17g, 21.44mmol) for raw material, operating process is same I-5, crude product column chromatography (dichloromethane:Methyl alcohol=60:1) purify, obtain beige solid (II-5) 0.44g, yield 19.7%, M.p.126~128 DEG C.¹H NMR(300MHz,CDCl₃)δ7.64(s,1H),7.18(s,1H),6.84(s,1H),5.02(s, 1H), 4.67 (d, J=12.3Hz, 1H), 4.57 (d, J=12.4Hz, 1H), 4.11 (s, 1H), 3.08-2.74 (m, 4H), 2.72-2.41 (m, 9H), 2.30 (d, J=15.2Hz, 1H), 2.20-2.06 (m, 1H), 2.04-1.81 (m, 3H), 1.71- 1.46(m,6H),1.40(s,3H),1.28(s,3H),1.20(s,3H),1.17(s,3H),0.95–0.84(m,6H).ESI-MS m/z:624.4[M+H]⁺

With compound II-5 (0.35g, 0.56mmol) for raw material, the same I-1HCl of operating process obtains gray solid (II- 5HCl) 0.27g, yield 72.9%, 172 DEG C (charing).

Embodiment 16

The preparation of 23- (4- (imidazoles -1- bases) bytyry) deoxidation limonin (II-6)

With compound VI (2.0g, 3.58mmol) and imidazoles (1.22g, 17.92mmol) for raw material, the same I-5 of operating process, Crude product column chromatography (dichloromethane:Methyl alcohol=60:1) purify, obtain yellow solid (II-6) 0.26g, yield 12.3%, M.p.132~135 DEG C.¹H NMR(300MHz,DMSO)δ8.04(s,1H),7.62(s,1H),7.45(s,1H),7.18(s, 1H), 6.88 (s, 1H), 6.63 (s, 1H), 5.19 (s, 1H), 4.82 (d, J=11.7Hz, 1H), 4.61 (d, J=11.7Hz, 1H),4.11(s,1H),4.06–3.89(m,2H),3.22–3.06(m,1H),2.89–2.73(m,2H),2.71–2.52(m, 3H),2.44–2.25(m,2H),2.22–1.90(m,3H),1.87–1.43(m,3H),1.28(s,3H),1.16(s,3H), 1.13(s,3H),1.00(s,3H).ESI-MS m/z:591.3[M+H]⁺

With compound II-6 (0.2g, 0.34mmol) for raw material, the same I-1HCl of operating process obtains gray solid (II- 6HCl) 0.18g, yield 84.8%, 176 DEG C (charing).

Claims (10)

1. the compound of formula I or II or its pharmaceutically acceptable salt：

Wherein, R is represented

R¹Represent H, CH₃、CH₂CH₃、CH₂OH or OH；X represents CH₂、O、NH、N-CH₃Or N-COCH₃；

R²、R³H or C is represented independently of one another₁~C₆Alkyl；

R⁴Represent H, CH₃, F, Cl or Br；

M=1~5.

2. the compound of claim 1 or its pharmaceutically acceptable salt, wherein R are representedR¹Represent H Or CH₃, X represents CH₂, O, NH or N-CH₃, m=1~4.

3. the compound of claim 1 or its pharmaceutically acceptable salt, wherein R are representedR²、R³Represent independently of one another C₁~C₃Alkyl, m=1~4.

4. the preparation method of the compound of Formula I of claim 1, including：

Wherein the definition of R, m is with claim 1.

5. the preparation method of claim 1 formula of II compounds, including：

Wherein the definition of R, m is with claim 1.

6. the compound or its pharmaceutically acceptable salt of claim 1,2 or 3, wherein pharmaceutically acceptable salt is formula I Or II compounds and the formed salt of following acid：Hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, butanedioic acid, wine Stone acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or forulic acid.

7. a kind of pharmaceutical composition, wherein the compound containing claim 1 or its pharmaceutically acceptable salt and pharmaceutically may be used The carrier of receiving.

8. the purposes of the compound of claim 1 or its pharmaceutically acceptable salt in anti-inflammatory drug is prepared.

9. the compound of claim 1 or its pharmaceutically acceptable salt are preparing the medicine for the treatment of rheumatoid arthritis disease In purposes.

10. the purposes of the compound of claim 1 or its pharmaceutically acceptable salt in analgesic is prepared.