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CN101037436A - L-stepholidine (l-SPD) derivatives, preparation method and usage thereof - Google Patents

L-stepholidine (l-SPD) derivatives, preparation method and usage thereof Download PDF

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CN101037436A
CN101037436A CNA2007100396174A CN200710039617A CN101037436A CN 101037436 A CN101037436 A CN 101037436A CN A2007100396174 A CNA2007100396174 A CN A2007100396174A CN 200710039617 A CN200710039617 A CN 200710039617A CN 101037436 A CN101037436 A CN 101037436A
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spd
acid
phosphate
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berberines
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镇学初
程建军
郭扬
莫骄
杨玉社
金国章
嵇汝运
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Shanghai Institute of Materia Medica of CAS
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Abstract

本发明涉及具有如通式(Ⅰ)结构的左旋千金藤啶碱(l－SPD)衍生物及其制备方法，所述的l－SPD衍生物及其药理上可接受的盐、结晶水合物、溶剂合物具有脑内多巴胺受体D1激动－D2阻滞双重药理作用，并且具有很好的理化性质和口服生物利用度，可应用于制备治疗人或动物神经系统疾病药物特别是精神分裂症和其它与多巴胺受体相关神经系统疾病的药物。

Figure 200710039617

The present invention relates to L-stephadinine (l-SPD) derivatives having a structure such as general formula (I) and a preparation method thereof, said l-SPD derivatives and pharmacologically acceptable salts, crystalline hydrates, The solvate has dual pharmacological effects of dopamine receptor D1 stimulation-D2 blockade in the brain, and has good physical and chemical properties and oral bioavailability, and can be applied to the preparation of drugs for treating human or animal nervous system diseases, especially schizophrenia and schizophrenia. Other drugs for neurological disorders related to dopamine receptors.

Figure 200710039617

Description

L-spd (l-SPD) derivative, Preparation Method And The Use
Technical field
The present invention relates to the pharmaceutical chemistry field, more specifically, relate to l-spd (l-SPD) derivative, its preparation method with and application in preparation treatment nervous system disorders medicine, particularly the nervous system disorders medicine relevant with Dopamine Receptors.
Background technology
Nervous system disorders is one of contemporary society's pandemic, yet many nervous system disorderss are effectively treated for example drug dependence, pain, dysthymia disorders etc. clinically as yet.Particularly schizophrenia is a kind of serious mental disorder, and its clinical treatment obtains satisfied the solution far away.In the last few years, neuroscientists used short-term memory experiment (Castner, S.A., Science, 2000, the 287:2020 of animal and patient's working memory operation (WorkingMemory Task) test and reflection pallium prefrontal lobe (PFC) function; Abi-Dargham, A., The JNeurosciences, 2002,22:3708), and utilize positron emission tomography figure (PET) test clinically, proved the D of schizophreniac PFC 1Function of receptors is lowly relevant with the negative symptoms generation, the D of structure under the cortex (NAc, VTA etc.) 2Function of receptors hyperfunction relevant (Okubo, Y., Nature, 1997,385:634 with positive symptom; Abi-Dargham, A., EurPsychiatry, 2005,20:15).The PET test then shows 5HT 2ATo PFC do not play a crucial role (Okubo, Y., Life sciences, 2000,66:2455).Therefore, people to propose schizoid new nosetiology be because dopamine D in the inboard prefrontal lobe of brain 1The function of receptors downward modulation, hypopallium district (Subcortical Regions) is as the dopamine D in midbrain ventral tegmental area (VTA, VentralTegmental Area) and the volt diaphragm nuclear (NAc, Nucleus Accumbens) simultaneously 2Receptor function controlling is hyperfunction.Based on this hypothesis, one has D simultaneously 1Excitement and D 2The medicine of the dual function effect of antagonism should become the brand-new antipsychotics of a class and have DEVELOPMENT PROSPECT.
Reported first compound of Tetrahydro-proto-berberines class (THPBs) l-spds (l-SPD, its structural formula is as follows) such as Jin nation's chapter are that first has D 1Excitement and D 2The lead drug of antagonism dual function (Jin GZ, TiPS, 2002,23:4).Clinical efficacy shows that tentatively it is all effective in cure to the positive and negative symptoms, to the negative symptoms better efficacy, has non-classical tranquilizer characteristic really, might become a class novel anti schizophrenia drug.Chinese patent application CN1115318A discloses left-handed and the right side selects chloro Si Kuli quinoline (l-SPD analogue) to be fit to the preparation method and use of suitability for industrialized production, Chinese patent application CN1603324A discloses left-handed halo Si Kuli quinoline various salt, particularly mesylate with antipsychotic effect and has significantly improved the water-soluble and stable of left-handed halo Si Kuli quinoline.
Figure A20071003961700071
Though l-SPD has D 1Excitement and D 2The antagonism double action mechanism, it treats schizoid effect also at animal and tentative confirmation clinically.But l-SPD is water-soluble and fat-soluble all very poor, causes its oral being difficult to absorb, and bioavailability is extremely low.The above-mentioned shortcoming of l-SPD makes it be difficult to become medicine, has limited it and has further developed as medicine.
Summary of the invention
Therefore, the object of the present invention is to provide acceptable salt, crystalline hydrate, solvate on the l-SPD derivative of a class formation novelty or its pharmacology.
Another object of the present invention is to provide the preparation method of above-mentioned l-SPD derivative.
An also purpose of the present invention is to provide acceptable salt, crystalline hydrate or the solvate application in preparation treatment nervous system disorders medicine on above-mentioned l-SPD derivative or its pharmacology.
The invention provides acceptable inorganic or organic salt, crystalline hydrate, solvate on the l-SPD derivative shown in the following general formula (I) or its pharmacology:
Figure A20071003961700081
In the general formula (I), R 1Represent hydrogen; C 1-6The alkyl acyl of straight or branched, for example, ethanoyl, propionyl etc.; Aryl-acyl or can substituted aryl-acyl; C 1-6The alkyl sulphonyl of straight or branched, for example, methylsulfonyl; Aryl sulfonyl or can substituted aryl sulfonyl; Phosphate-based, phosphate or phosphate base;
R 2Represent hydrogen; C 1-6The alkyl acyl of straight or branched, for example, ethanoyl, propionyl; Aryl-acyl or can substituted aryl-acyl; C 1-6The alkyl sulphonyl of straight or branched, for example, methylsulfonyl; Aryl sulfonyl or can substituted aryl sulfonyl; Phosphate-based, phosphate or phosphate base;
And R 1And R 2Be not hydrogen atom simultaneously;
The configuration of 14 carbon atoms can be the R/S type of R type or S type or raceme.
According to the present invention, the invention provides the preparation method of the l-SPD derivative shown in the general formula (I), this method comprises:
Concrete reaction scheme is as follows
Figure A20071003961700091
R wherein 1And R 2Definition as mentioned above, raw material l-SPD can separate acquisition (Chin.J.Physiol.1928:203～208) from the piece root of Root of Japanese Stephania plant.
L-SPD in the presence of acid acceptor with reagent reacts such as acyl chlorides, acid anhydrides, SULPHURYL CHLORIDE or sulphonic acid anhydride, can get corresponding acylations or alkylsulfonyl product, i.e. R 1And R 2Independent respectively is hydrogen, C 1-6The alkyl acyl of straight or branched, aryl-acyl or can substituted aryl-acyl, C 1-6The alkyl sulphonyl of straight or branched, aryl sulfonyl or general formula (I) compound that can substituted aryl sulfonyl, R 1And R 2Be not hydrogen atom simultaneously.
For above-mentioned reaction, reaction solvent can use methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, ether, benzene, toluene, N, inert solvents such as dinethylformamide, dimethyl sulfoxide (DMSO), and preferably use methylene dichloride, chloroform.This reaction available acid acceptor comprises mineral alkali, as sodium bicarbonate, yellow soda ash, salt of wormwood etc.; Organic bases, as triethylamine, Diisopropylamine, diisopropylethylamine, pyridine, N, accelerine, N, N-dimethyl aminopyridine, 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene (DBU) etc.Temperature of reaction from 0 ℃ to the solvent refluxing temperature, the reaction times was from 10 minutes to 48 hours.Product purification can be used methyl alcohol, ethanol, Virahol, ethyl acetate, methylene dichloride, chloroform, benzene, normal hexane, sherwood oil or mixed solvent recrystallization or the column chromatography formed in suitable ratio of two or more components wherein.Utilize the acylating reagent and the l-SPD reaction of different mol ratio; can obtain respectively based on two acidylates (when the mol ratio of acylating reagent and l-SPD more than or equal to 2 the time) or single acidylate (when the mol ratio of acylating reagent and l-SPD smaller or equal to 1 the time) product, can obtain two acidylates or single acylate respectively by column chromatography.
Preparation method of the present invention also further comprises: in the presence of alkali, and l-SPD and conventional phosphorylation agent (BnO) 2POCl, (BnO) 2PN ( iPr) 2, (BnO) 2PN (Et) 2Or other phosphorylation agent reaction, obtain phosphate product, i.e. R 1Be phosphate-based or R 1, R 2Be phosphate-based general formula (I) compound simultaneously; Described phosphate product is transformed into corresponding l-SPD phosphorylated derivative, i.e. R through hydrogenation or other respective handling 1Be phosphate or R 1, R 2Be general formula (I) compound of phosphate simultaneously, concrete reaction scheme is as follows: (Bn is a benzyl)
Figure A20071003961700101
The temperature of reaction of described phosphorylation reaction from 0 ℃ to the solvent refluxing temperature, the reaction times was from 10 minutes to 72 hours; Reaction solvent can use N, dinethylformamide, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, ether, benzene, toluene, and inert solvents such as dimethyl sulfoxide (DMSO), and preferably use N, dinethylformamide, methylene dichloride, ether; The alkali that is used for this reaction can be mineral alkali or organic bases, mineral alkali can be sodium hydride, potassium hydride KH, lithium hydride, sodium hydroxide, potassium hydroxide, hydrated barta, potassium tert.-butoxide, salt of wormwood, yellow soda ash etc., organic bases can be triethylamine, diisopropylethylamine, pyridine, N, accelerine, N, N-dimethyl aminopyridine, 2,6-di-t-butyl-4-picoline, 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene (DBU) etc. is preferentially selected sodium hydride, triethylamine, diisopropylethylamine etc. for use.The product that reaction obtains is the mixture of l-SPD bis phosphoric acid dibenzyl ester and the single phosphate dibenzyl ester of l-SPD, can obtain l-SPD bis phosphoric acid dibenzyl ester or the single phosphate dibenzyl ester of l-SPD respectively by column chromatography for separation.
The single phosphate dibenzyl ester product of l-SPD bis phosphoric acid dibenzyl ester or l-SPD can obtain l-SPD bis phosphoric acid or single phosphoric acid derivatives through catalytic hydrogenation.Catalyzed reaction is carried out at normal temperatures and pressures, and the reaction times was from 10 minutes to 48 hours.The solvent that catalytic hydrogenation is used is methyl alcohol, ethanol, tetrahydrofuran (THF), dioxane, methylene dichloride etc.Catalyzed reaction is used catalyzer such as the palladium-containing catalyst that contains metal, or nickel-containing catalyst, and is preferably the palladium carbon of 1～10wt%.
According to the present invention, above-mentioned preparation method also further comprises: the above-mentioned R that makes 1Be phosphate or R 1, R 2Be general formula (I) compound and the alkali reaction salify of phosphate simultaneously, concrete reaction scheme is as follows:
Figure A20071003961700111
Wherein, M +Be metallic cation, ammonium ion, basic aminoacids etc.
The above-mentioned R that makes 1Be phosphate or R 1, R 2Be general formula (I) compound of phosphate simultaneously, promptly single phosphoric acid or bis phosphoric acid l-SPD derivative and alkali react in appropriate solvent can obtain phosphate derivative.The alkali that salt-forming reaction is fit to comprises organic basess such as mineral alkali such as ammoniacal liquor, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium hydride, calcium hydroxide, calcium oxide, lime carbonate, magnesium hydroxide, magnesium oxide, magnesiumcarbonate or sodium ethylate, sodium methylate, basic aminoacids.The solvent that reaction is fit to is water, alcohol or their mixed solvent.The temperature that reaction is fit to is-20 a ℃～solvent refluxing temperature, and optimum temps is a room temperature.
Press chemically ordinary method, make the l-SPD derivative shown in water or water-containing solvent or the solvent recrystallization general formula (I) can obtain the crystalline hydrate or the solvate of (I) compound.
Acceptable inorganic or organic salt, crystalline hydrate, solvate on l-SPD derivative shown in the general formula provided by the invention (I) and the pharmacology thereof, this compounds has D1 excitement-D2 and blocks double pharmacological action, and have good physico-chemical property and oral administration biaavailability, can be applicable to prepare the particularly medicine of schizophrenia and other and Dopamine Receptors related neural systemic disease of treatment human or animal nervous system disorders medicine.
Description of drawings
Fig. 1 is the chart of the influence of 1 pair of rat spontaneous activity of expression compound.
Fig. 2 is the chart of the influence of expression 1 pair of rat new things identification of compound (cognitive function).
Fig. 3 is the social chart of escaping the influence that is negative symptoms of schizophrenia of 1 pair of rat of expression compound.
Embodiment
Describe the present invention below.
Unless dated especially, term used herein has as giving a definition:
" alkyl " expression is saturated or undersaturated, the straight chain of replacement or non-replacement, the branched alkane hydrocarbon chain, can enumerate particularly as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, the 1-methyl butyl, the 2-methyl-propyl, hexyl, isohexyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, the 2-methyl butyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl etc.In these groups, carbonatomss such as preferable methyl, ethyl, propyl group, sec.-propyl, butyl are 1-4 alkyl, more preferably methyl, ethyl or propyl group, most preferable or ethyl.
" aryl " expression aromatic hydrocarbyl, the aryl of preferred 6-14 carbon atom is in particular phenyl, xenyl, naphthyl, indenyl, anthryl, phenanthryl, more preferably phenyl or naphthyl, most preferably phenyl.
" can substituted alkyl ", " can substituted aryl " represent that respectively the group that above-mentioned " alkyl ", " aryl " can randomly be selected from halogen atom, alkyl, alkoxyl group, acyloxy, hydroxyl, amino, nitro, kharophen replaces.
" pharmacy acceptable salt " can enumerate the salt with mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid particularly, with organic acids and the salt that acidic amino acid became such as aspartic acid, L-glutamic acid such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, ethyl sulfonic acids.Also can with mineral alkali or organic bases salify, as the salt that sodium salt, sylvite, calcium salt, magnesium salts, ammonium salt and various basic aminoacids became.
In the derivative of l-SPD shown in the general formula of the present invention (I), the structural formula of representative compound sees the following form 1:
Table 1
Figure A20071003961700141
Figure A20071003961700151
Figure A20071003961700161
Specific embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment never are any limitation of the invention.Among all embodiment, fusing point is measured with MEL-TEMP fusing point instrument, and thermometer is not proofreaied and correct; 1H-NMR Varian Mercury Plus 300MHz nmr determination; Chemical shift is represented with δ (ppm); Separation is the 200-300 order with silica gel.
Embodiment 1:
14-(S)-2,10-diacetoxy-3,9-dimethoxy Tetrahydro-proto-berberines (compound 1)
L-SPD (3.27g 10mmol) is suspended in the methylene dichloride (100mL), and the adding triethylamine (5.61mL, 40mmol), stirred 5 minutes, and the dropping diacetyl oxide (3.78mL, 40mmol), finished room temperature reaction 2 hours, reaction solution fades to clarification by muddiness, is faint yellow.Stopped reaction, reaction solution is with washing (30mL * 3), and saturated sodium bicarbonate solution is washed (30mL * 3), saturated common salt washing (30mL * 3), anhydrous sodium sulfate drying concentrates, resistates gets light yellow crystal compound 1 (3.45g, 83.9%) with methylene dichloride-sherwood oil recrystallization. 1HNMR(CDCl 3)：δ6.95-6.90(m，3H)，6.72(s，1H)，4.20(d，1H，J＝15.7Hz)，3.82(s，3H)，3.81(s，3H)，3.65-3.50(m，2H)，3.30-3.10(m，3H)，2.95-2.60(m，3H)，2.33(s，3H)，2.32(s，3H)。
Embodiment 2:
14-(S)-2,10-two propionyloxies-3,9-dimethoxy Tetrahydro-proto-berberines (compound 2)
L-SPD (3.27g, 10mmol) be suspended in the methylene dichloride (100mL), and the adding triethylamine (5.61mL, 40mmol), stirred 5 minutes, (5.14mL 40mmol), finished room temperature reaction 2 hours to drip propionic anhydride, aftertreatment similar embodiment 1, the ether recrystallization gets light yellow crystal compound 2 (3.05g, 69.4%). 1HNMR(CDCl 3)：δ6.93-6.88(m，3H)，6.72(s，1H)，4.20(d，1H，J＝15.7Hz)，3.81(s，3H)，3.80(s，3H)，3.65-3.50(m，2H)，3.30-3.10(m，3H)，2.95-2.70(m，3H)，2.62(q，4H，J＝7.5Hz)，1.28(t，6H，J＝7.5Hz)。
Embodiment 3:
14-(S)-2,10-dibenzoyl oxygen base-3,9-dimethoxy Tetrahydro-proto-berberines (compound 3)
L-SPD (327mg, 1mmol) be suspended in the methylene dichloride (30mL), (0.42mL 3mmol), stirred 5 minutes to add triethylamine, drip Benzoyl chloride (0.28mL, 2.4mmol), finished room temperature reaction 2 hours, aftertreatment similar embodiment 1, get light yellow crystal compound 3 (420mg, 78.4%). 1HNMR(CDCl 3)：δ8.27-8.23(m，4H)，7.69-7.62(m，2H)，7.56-7.50(m，4H)，7.09(s，1H)，7.03(d，1H，J＝8.4Hz)，6.96(d，1H，J＝8.4Hz)，6.78(s，1H)，4.28(d，1H，J＝15.8Hz)，3.83(s，3H)，3.81(s，3H)，3.68-3.58(m，2H)，3.37-3.21(m，3H)，3.01-2.92(m，1H)，2.81-2.71(m，2H)。
Embodiment 4:
14-(S)-2,10-two mesyloxies-3,9-dimethoxy Tetrahydro-proto-berberines (compound 4)
(654mg 2mmol) is dissolved in the exsiccant tetrahydrofuran (THF) (25mL) l-SPD, and (1.05mL 7.5mmol), stirred 5 minutes, and (0.39mL, 5mmol), adularescent is muddy in the dropping process occurs, and finishes room temperature reaction 4 hours to drip methane sulfonyl chloride to add triethylamine.Stopped reaction concentrates the back residual solid and adds methylene dichloride (50mL) suspendible, with washing (20mL * 3), saturated sodium bicarbonate solution is washed (10mL * 3), saturated common salt washing (10mL * 3), anhydrous sodium sulfate drying, concentrate, get faint yellow solid compound 4 (780mg, 80.7%). 1HNMR(CDCl 3)：δ7.20(d，2H，J＝8.3Hz)，7.18(s，1H)，6.98(d，1H，J＝8.3Hz)，6.75(s，1H)，4.24(d，1H，J＝15.6Hz)，3.90(s，3H)，3.89(s，3H)，3.64-3.50(m，2H)，3.36-3.12(m，9H)，2.92-2.62(m，3H)。
Embodiment 5:
14-(S)-2-mesyloxy-3,9-dimethoxy-10-hydroxy tetrahydro protoberberine (compound 5), 14-(S)-2-hydroxyl-3,9-dimethoxy-10-mesyloxy Tetrahydro-proto-berberines (compound 6)
(654mg 2mmol) is dissolved in the exsiccant tetrahydrofuran (THF) (25mL) l-SPD, and (0.39mL 2.8mmol), stirred 5 minutes, and (0.16mL, 2mmol), adularescent is muddy in the dropping process occurs, and finishes room temperature reaction 6 hours to drip methane sulfonyl chloride to add triethylamine.Stopped reaction, concentrate the back residual solid and add methylene dichloride (50mL) suspendible, with washing (20mL * 3), saturated sodium bicarbonate solution is washed (10mL * 3), saturated common salt washing (10mL * 3), anhydrous sodium sulfate drying concentrates, resistates is collected R with methylene chloride-methanol (volume ratio 200: 1) column chromatography f0.72 (developping agent is a methylene dichloride: methyl alcohol v/v=20: elutriant 1) concentrates and obtains faint yellow solid compound 6 (215mg, 26.5%); Collect R f0.52 (developping agent is a methylene dichloride: methyl alcohol v/v=20: elutriant 1) concentrates and obtains white solid compound 5 (160mg, 19.7%). 1HNMR(CDCl 3)：
Compound 5: δ 7.19 (s, 1H), 6.86-6.76 (m, 2H), 6.74 (s, 1H), 4.20 (d, 1H, J=15.4Hz), 3.88 (s, 3H), 3.81 (s, 3H), 3.62-3.52 (m, 2H), 3.28-3.12 (m, 6H), 2.94-2.58 (m, 3H).
Compound 6: δ 7.19 (d, 1H, J=8.2Hz), 6.96 (d, 1H, J=8.2Hz), 6.81 (s, 1H), 6.61 (s, 1H), 4.22 (d, 1H, J=16.2Hz), 3.90 (s, 3H), 3.88 (s, 3H), and 3.62-3.48 (m, 2H), 3.36-3.06 (m, 6H), 2.94-2.62 (m, 3H).
Embodiment 6:
14-(S)-2,10-two (two benzyloxy) phosphorus acyloxy-3,9-dimethoxy Tetrahydro-proto-berberines (compound 7), the two benzyloxy phosphorus acyloxy-3 of 14-(S)-2-, 9-dimethoxy-10-hydroxy tetrahydro protoberberine (compound 8)
Under the nitrogen protection, (0.60g 15mmol) is suspended in exsiccant N to 60% sodium hydride, and in the dinethylformamide (20mL), (dinethylformamide (10mL) solution finished stirring at room 1 hour for 1.64g, N 5mmol) to drip l-SPD.Slowly (0.5mol/L 20mL), finished stirring at room 3 hours to the carbon tetrachloride solution of dropping chloro dibenzyl phosphite.Stopped reaction removes solvent under reduced pressure, and resistates is with silica gel column chromatography (chloroform: methyl alcohol v/v=100: 1), collect R f0.71 (developping agent is a methylene dichloride: methyl alcohol v/v=20: elutriant 1) concentrates and obtains faint yellow oily compounds 7 (1.43g, 33.7%); Collect R f0.47 (developping agent is a methylene dichloride: methyl alcohol v/v=20: elutriant 1) concentrates and obtains white foam shape solid chemical compound 8 (0.84g, 28.6%). 1HNMR(CDCl 3)：
Compound 7: δ 7.38-7.30 (m, 20H), 7.14 (d, 1H, J=8.5Hz), 7.02 (s, 1H), 6.77 (d, 1H, J=8.5Hz), 6.65 (s, 1H), 5.22-5.13 (m, 8H), 4.19 (d, 1H, J=15.9Hz), 3.83 (s, 3H), 3.79 (s, 3H), 3.52-3.41 (m, 2H), 3.21-3.03 (m, 3H), 2.75-2.56 (m, 3H).
Compound 8: δ 7.38-7.29 (m, 10H), 7.03 (s, 1H), 6.83 (d, 1H, J=8.3Hz), 6.77 (d, 1H, J=8.3Hz), 6.64 (s, 1H), 5.22-5.14 (m, 4H), 4.19 (d, 1H, J=15.4Hz), 3.82 (s, 3H), 3.78 (s, 3H), 3.57-3.42 (m, 2H), 3.22-3.04 (m, 3H), 2.75-2.54 (m, 3H).
Embodiment 7:
14-(S)-2,10-bisphosphate oxygen base-3,9-dimethoxy Tetrahydro-proto-berberines (compound 9)
(0.85g 1mmol) is dissolved in the mixed solvent of methylene dichloride (5mL) and methyl alcohol (5mL) compound 7, adds 10% palladium carbon (0.21g), the logical hydrogen of normal pressure 4 hours.Filtering palladium carbon, filtrate decompression steam and desolventize, and resistates adds water (50mL) dissolving, and methylene dichloride is washed (10mL * 2), and lyophilize gets white solid compound 9 (0.42g, 86.2%). 1HNMR(D 2O)δ7.24(d，1H，J＝6.6Hz)，7.16(s，1H)，6.97(d，1H，J＝6.6Hz)，6.89(s，1H)，4.34(d，1H，J＝12.8Hz)，3.87(s，3H)，3.73(s，3H)，3.58-3.48(m，2H)，3.36-3.22(m，3H)，3.12-2.84(m，3H)。
Embodiment 8:
14-(S)-3,9-dimethoxy Tetrahydro-proto-berberines-2,10-bisphosphate tetra-na salt (compound 10)
(487mg, 1mmol) with water (10mL) dissolving, (40mg, 1mmol), the stirring and dissolving postlyophilization gets incarnadine solid chemical compound 10 (575mg, 100%) to compound 9 to add sodium hydroxide. 1HNMR(D 2O)δ7.38(d，1H，J＝6.6Hz)，7.16(s，1H)，6.97(d，1H，J＝6.6Hz)，6.89(s，1H)，4.06(d，1H，J＝12.8Hz)，3.84(s，3H)，3.73(s，3H)，3.54-3.28(m，2H)，3.22-2.88(m，3H)，2.76-2.48(m，3H)。
Embodiment 9:
14-(S)-2-hydroxyl-3,9-dimethoxy-10-phosphorus acyloxy Tetrahydro-proto-berberines (compound 11)
Adopt the method identical with embodiment 7, (0.59g 1mmol) is dissolved in the mixed solvent of methylene dichloride (5mL) and methyl alcohol (5mL) compound 8, adds 10% palladium carbon (0.12g), and normal pressure led to hydrogen 4 hours.Filtering palladium carbon, filtrate decompression steam and desolventize, and resistates adds water (50mL) dissolving, and methylene dichloride is washed (10mL * 2), and lyophilize gets faint yellow solid compound 11 (0.34g, 83.5%). 1HNMR(DMSO-d 6)δ7.42(s，1H)，6.97-6.84(m，2H)，6.78(s，1H)，4.43(d，1H，J＝12.0Hz)，3.73(s，3H)，3.64(s，3H)，3.37-3.24(m，2H)，3.02-2.80(m，3H)，2.78-2.56(m，3H)。
Embodiment 10:
14-(S)-10-hydroxyl-3,9-dimethoxy Tetrahydro-proto-berberines-2-phosphate monoester disodium salt (compound 12)
Adopt the method identical with embodiment 8, (407mg's compound 10 1mmol) suspends with water (10mL), and (40mg, 1mmol), the stirring and dissolving postlyophilization must incarnadine solid chemical compound 12 (453mg, 100%) to add sodium hydroxide. 1HNMR(D 2O)δ7.39(s，1H)，7.00(d，1H，J＝8.3Hz)，6.95(d，1H，J＝8.3Hz)，6.86(s，1H，)，4.12(d，1H，J＝15.8Hz)，3.85(s，3H)，3.75(s，3H)，3.50(d，1H，15.8Hz)3.36-3.16(m，3H)，3.11-2.96(m，1H)，2.82-2.56(m，3H)。
Biological experiment
1.14-(S)-2,10-diacetoxy-3,9-dimethoxy Tetrahydro-proto-berberines (compound 1) treatment schizophrenia pharmacodynamic experiment
(1) animal
Get healthy adult Sprague-Dawley rat (200-250g), three one cages are raised in 21 ± 2 ℃ of environment of temperature, (0600h-1800h gives light) normally round the clock, ad lib water inlet.
(2) medicine and administering mode
1-(1-benzyl ring hexyl) piperidines nicotinate (PCP) is dissolved in stroke-physiological saline solution and is made into the 5mg/mL colourless transparent solution, 14-(S)-2,10-diacetoxy-3,9-dimethoxy Tetrahydro-proto-berberines (compound 1) is with a small amount of 1 equivalent sulfuric acid dissolution, distilled water diluting is to pH=4-5, make the 10mg/mL light yellow transparent solution, 4 ℃ of preservations.Press 1mL/kg with the medicine abdominal injection to the rat body.
(3) route of administration and mode
PCP group: every day 1 abdominal injection 5mg/kg PCP, successive administration 14 days, 15-28 days continuous every days, the abdominal injection stroke-physiological saline solution was 1 time;
PCP adds 1 group of compound: once a day continuously every day abdominal injection 5mg/kg PCP, successive administration 14 days played 1 abdominal injection 10mg/kg compound 1 every day on the 15th day, successive administration 14 days;
Control group (physiological saline): every day 1 time, continuous 28 days abdominal injection 1mL/kg stroke-physiological saline solution.
Began the detection of each experimental index on the 29th day.
(4) statistical study
With SPSS11.0 software experimental result is carried out statistical study, comprise one-way analysis of variance (one-way ANOVA) and post hoc Bonferroni test (method that mean compares in twos between group).The P value has been considered to statistical significance less than 0.05.
(1) influence of 1 pair of rat spontaneous activity of compound
In the rat spontaneous activity experiment, the acute 5mg/kg of giving PCP (pretreatment time is 10 minutes) can induce rat spontaneous activity to increase, movable total distance is higher than saline control 6-7 doubly in one hour, and after giving compound 1 (10mg/kg), this high spontaneous activity can be reversed to the control group level fully.As Fig. 1, one-way analysis of variance shows that the total distance between three groups has significant difference (P＜0.001).Analysis revealed between group, the total distance of PCP 5mg/kg group (n=6) rat motor has extremely significantly raise (P＜0.001) than control rats (n=6) separately, and PCP adds 1 group of (n=6) spontaneous activity of compound and compares with giving 5mg/kg PCP group rat separately, and extremely significantly descend (P＜0.001) is arranged.
(2) influence of 1 pair of rat new things identification of compound (cognitive function)
The new object identification index of physiological saline control group is 65.11% (n=11), and chronic PCP 2 week back (PCP group) the new object identification of the rat index decreased to 48.48% (n=8) that give illustrate that PCP causes cognitive function to damage really.PCP adds 1 group of compound (administration group) rat the discrimination index of new things is risen to 58.6% (n=14).As Fig. 2, one-way analysis of variance shows that significant difference (P＜0.01) is arranged between three groups.The new things discrimination index of analysis revealed PCP group has been compared utmost point significance decline (P＜0.01) between group with the saline control group, and the administration group then has significance rising (P＜0.05) than the new things discrimination index of PCP group.This shows that compound 1 can strengthen the animal cognitive function really.
(3) the social escape of 1 pair of rat of compound is the influence of negative symptoms of schizophrenia
As Fig. 3, one-way analysis of variance shows, significant difference (P＜0.01) is arranged the social duration of contact of three groups of rats, analysis revealed between group, there is significance decline (P＜0.05) in the social time of PCP group rat (n=7) than saline control group (n=9), and PCP adds 1 group of (n=9) rat of compound and PCP group rat and compares, and significance rise (P＜0.01) is arranged social duration of contact.PCP adds 1 group of compound and compares with the saline control group and do not have significant difference.This shows that compound 1 can reverse the social activity escape symptom that PCP causes.
Experimental result shows that in the high spontaneous activity model that acute 5mg/kg PCP causes, compound 1 (10mg/kg) reduces the spontaneous activity level of rat to physiological saline control group level; New things defect recognition model and social the escape in the model that chronic 14 days PCP cause, chronic (2 week) gives compound 1 (10mg/kg) and can significantly improve the cognition of rat, increases social duration of contact.
Experimental result shows 14-(S)-2,10-diacetoxy-3,9-dimethoxy Tetrahydro-proto-berberines and other compound of the present invention not only can significantly improve the positive symptom of schizophrenia animal, and, has the particularly effect of schizophrenia and other and Dopamine Receptors related neural systemic disease medicine of treatment human or animal nervous system disorders medicine to the effect that also has clear improvement of negative symptoms, cognitive function.
2.14-(S)-2,10-diacetoxy-3, the experiment of 9-dimethoxy Tetrahydro-proto-berberines (compound 1) metabolic characteristics
The rat vein administration: 3 of healthy SD rats, male, body weight 200～250g, fasting 12h before the administration freely drinks water.14-(S)-2,10-diacetoxy-3,9-dimethoxy Tetrahydro-proto-berberines (compound 1) dissolves (less than cumulative volume 2%) with DMSO earlier with a small amount of, add propylene glycol again, make the 4mg/mL light yellow transparent solution, dosage with 8mg/kg gives compound 1 through the rat tail vein injection, and the administration volume is 2mL/kg.
Rat oral gavage administration: 3 of healthy SD rats, body weight 200～250g.Fasting 12h before the administration freely drinks water.With 14-(S)-2,10-diacetoxy-3,9-dimethoxy Tetrahydro-proto-berberines (compound 1) is made into the suspension of 4mg/mL with 0.5%CMC-Na, irritates stomach respectively with the dosage of 40mg/kg and gives compound 1, and the administration volume is 10mL/kg.
The pharmacokinetics result
Rat gives 14-(S)-2 through vein and filling stomach mode, and 10-diacetoxy-3 all detects less than the original shape medicine behind the 9-dimethoxy Tetrahydro-proto-berberines, and metabolism is l-SPD rapidly.
Rat intravenous injection gives 8mg/kg 14-(S)-2,10-diacetoxy-3, and behind the 9-dimethoxy Tetrahydro-proto-berberines, the t of free l-SPD in the blood plasma 1/2Be 6.80 ± 4.59h; AUC 0-tBe 2160 ± 106ngh/mL; Average retention time MRT is 4.10 ± 1.45h; Clearance rate CL is 48.7 ± 2.44mLmin -1Kg -1Apparent volume of distribution V zBe 4.93 ± 3.02Lkg -1Vdss V SsBe 12.0 ± 4.16Lkg -1L-SPD total amount (free type+mating type) t in the blood plasma after the enzymic hydrolysis 1/2Be 6.17 ± 1.97h; AUC 0-tBe 6843 ± 1179ngh/mL; Average retention time MRT is 3.79 ± 0.97h; Clearance rate CL is 15.6 ± 2.53mLmin -1Kg -1Apparent volume of distribution V zBe 2.26 ± 1.31Lkg -1Vdss V SsBe 3.55 ± 1.14Lkg -1
Rat oral gavage gives 40mg/kg 14-(S)-2,10-diacetoxy-3, and behind the 9-dimethoxy Tetrahydro-proto-berberines, the t of free l-SPD in the blood plasma 1/2Be 4.85 ± 2.87h; AUC 0-tBe 3990 ± 1110ngh/mL; C MaxBe 1329 ± 428ng/mL; T MaxBe 0.50 ± 0.0h; Average retention time MRT is 4.47 ± 0.41h; Clearance rate CL is 139 ± 43.9mLmin -1Kg -1Apparent volume of distribution V zBe 51.0 ± 33.8Lkg -1After the enzymic hydrolysis, l-SPD total amount t in the blood plasma 1/2Be 3.72 ± 1.49h; AUC 0-tBe 12687 ± 2887ngh/mL; C MaxBe 3840 ± 426ng/mL; T MaxBe 0.50 ± 0.0h; Average retention time MRT is 5.23 ± 1.39h; Clearance rate CL is 42.6 ± 9.49mLmin -1Kg -1Apparent volume of distribution V zBe 14.6 ± 8.84Lkg -1
AUC with free l-SPD 0-tCalculate, 14-(S)-2,10-diacetoxy-3, the absolute bioavailability of 9-dimethoxy Tetrahydro-proto-berberines is 36.9%.
AUC with the l-SPD total amount 0-tCalculate, 14-(S)-2,10-diacetoxy-3, the absolute bioavailability of 9-dimethoxy Tetrahydro-proto-berberines is 37.1%.
Control experiment: l-SPD metabolic characteristics
The dosage regimen experimental technique is identical with compound 1.
The pharmacokinetics result
When rat intravenous injection gives 8mg/kg l-SPD, the t of free l-SPD in the blood plasma after the administration 1/2Be 9.22 ± 4.91h; AUC 0-tBe 2230 ± 907ngh/mL; Average retention time MRT is 8.22 ± 4.51h; Clearance rate CL is 66.3 ± 25.0mLmin -1Kg -1Apparent volume of distribution V zBe 3.81 ± 0.26Lkg -1Vdss V SsBe 33.0 ± 20.4Lkg -1L-SPD total amount (free type+mating type) t in the blood plasma after the enzymic hydrolysis 1/2Be 7.50 ± 5.29h; AUC 0-tBe 7370 ± 1585ngh/mL; Average retention time MRT is 7.81 ± 4.16h; Clearance rate CL is 18.7 ± 4.23mLmin -1Kg -1Apparent volume of distribution V zBe 1.35 ± 0.25Lkg -1Vdss V SsBe 9.34 ± 7.07Lkg -1
When rat oral gavage gives 40mg/kgl-SPD, the t of free l-SPD in the blood plasma after the administration 1/2Be 5.34 ± 1.47h; AUC 0-tBe 762 ± 663ngh/mL; C MaxBe 253 ± 283ng/mL; T MaxBe 2.13 ± 3.25h; Average retention time MRT is 6.95 ± 2.11h; Clearance rate CL is 1118 ± 572mLmin -1Kg -1Apparent volume of distribution V zBe 469 ± 186Lkg -1The t of l-SPD total amount (free type+mating type) l-SPD total amount in the blood plasma after the enzymic hydrolysis 1/2Be 14.4 ± 10.4h; AUC 0-tBe 2777 ± 2115ngh/mL; C MaxBe 814 ± 995ng/mL; T MaxBe 1.63 ± 2.25h; Average retention time MRT is 19.1 ± 16.6h; Clearance rate CL is 220 ± 95.3mLmin -1Kg -1Apparent volume of distribution V zBe 275 ± 215Lkg -1
AUC with free l-SPD 0-tCalculate, the absolute bioavailability of l-SPD is 6.83%.
AUC with the l-SPD total amount 0-tCalculate, the absolute bioavailability of l-SPD is 7.54%.
Experimental result shows 14-(S)-2,10-diacetoxy-3,9-dimethoxy Tetrahydro-proto-berberines and other compound of the present invention have overcome l-SPD, and fat-soluble poor (LogD of compound 1 is 2.48 during pH=7.0, and l-SPD is 1.39), oral being difficult to absorbs, the shortcoming that bioavailability is low has obviously improved the metabolism performance of l-SPD, particularly improves very big to the l-SPD bioavailability.The bioavailability of compound 1 has improved more than 5 times than l-SPD, has greatly improved the bioavailability of l-SPD.
Therefore The compounds of this invention has the particularly effect of schizophrenia and other and Dopamine Receptors related neural systemic disease medicine of treatment human or animal nervous system disorders medicine.

Claims (10)

1, acceptable salt, crystalline hydrate or solvate on a kind of l-spd derivative with structure shown in the general formula (I) or its pharmacology:
Figure A2007100396170002C1
Wherein, R 1Represent hydrogen, C 1-6The alkyl acyl of straight or branched, aryl-acyl or can substituted aryl-acyl, C 1-6The alkyl sulphonyl of straight or branched, aryl sulfonyl or can substituted aryl sulfonyl, phosphate-based, phosphate or phosphate base;
R 2Represent hydrogen, C 1-6The alkyl acyl of straight or branched, aryl-acyl or can substituted aryl-acyl, C 1-6The alkyl sulphonyl of straight or branched, aryl sulfonyl or can substituted aryl sulfonyl, phosphate-based, phosphate or phosphate base;
And R 1And R 2Be not hydrogen atom simultaneously.
2, acceptable salt, crystalline hydrate or solvate on l-spd derivative according to claim 1 or its pharmacology is characterized in that, described alkyl is that carbonatoms is 1～4 a alkyl; Described aryl is phenyl, xenyl, naphthyl, indenyl, anthryl or phenanthryl; Described can the replacement for the optional group that is selected from halogen atom, alkyl, alkoxyl group, acyloxy, hydroxyl, amino, nitro, kharophen by substituted aryl.
3, acceptable salt, crystalline hydrate or solvate on l-spd derivative according to claim 1 or its pharmacology is characterized in that described R 1Be hydrogen, ethanoyl, propionyl, benzoyl, methylsulfonyl, (two benzyloxy) phosphoryl, phosphate or phosphate base; Described R 2Be hydrogen, ethanoyl, propionyl, benzoyl, methylsulfonyl, (two benzyloxy) phosphoryl, phosphate or phosphate base.
4, according to acceptable salt on claim 1 or 3 described l-spd derivatives or its pharmacology, crystalline hydrate or solvate, it is characterized in that, described l-spd derivative is 14-(S)-2,10-diacetoxy-3,9-dimethoxy Tetrahydro-proto-berberines, 14-(S)-2,10-two propionyloxies-3,9-dimethoxy Tetrahydro-proto-berberines, 14-(S)-2,10-dibenzoyl oxygen base-3,9-dimethoxy Tetrahydro-proto-berberines, 14-(S)-2,10-two mesyloxies-3,9-dimethoxy Tetrahydro-proto-berberines, 14-(S)-2-mesyloxy-3,9-dimethoxy-10-hydroxy tetrahydro protoberberine, 14-(S)-2-hydroxyl-3,9-dimethoxy-10-mesyloxy Tetrahydro-proto-berberines, 14-(S)-2,10-two (two benzyloxy) phosphorus acyloxy-3,9-dimethoxy Tetrahydro-proto-berberines, the two benzyloxy phosphorus acyloxy-3 of 14-(S)-2-, 9-dimethoxy-10-hydroxy tetrahydro protoberberine, 14-(S)-2,10-bisphosphate oxygen base-3,9-dimethoxy Tetrahydro-proto-berberines, 14-(S)-3,9-dimethoxy Tetrahydro-proto-berberines-2,10-bisphosphate tetra-na salt, 14-(S)-10-hydroxyl-3,9-dimethoxy-2-phosphorus acyloxy Tetrahydro-proto-berberines, or 14-(S)-10-hydroxyl-3,9-dimethoxy Tetrahydro-proto-berberines-2-phosphate monoester disodium salt.
5, according to acceptable salt, crystalline hydrate or solvate on claim 1 or 3 described l-spd derivatives or its pharmacology, it is characterized in that described pharmacy acceptable salt is the salt that the l-spd derivative is become with hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, ethyl sulfonic acid, aspartic acid, L-glutamic acid; Or its sodium salt, sylvite, calcium salt, magnesium salts, ammonium salt and the salt that become with arginine, Methionin, Histidine.
6, the preparation method of acceptable salt, crystalline hydrate or solvate on each described l-spd derivative of a kind of claim 1～5 or its pharmacology; it is characterized in that; l-spd l-SPD in the presence of acid acceptor with acyl chlorides, acid anhydrides, SULPHURYL CHLORIDE or sulphonic acid anhydride reagent react; can get corresponding acylations or alkylsulfonyl product, i.e. R 1And R 2Independent respectively is hydrogen, C 1-6The alkyl acyl of straight or branched, aryl-acyl or can substituted aryl-acyl, C 1-6The alkyl sulphonyl of straight or branched, aryl sulfonyl or general formula (I) compound that can substituted aryl sulfonyl, R 1And R 2Be not hydrogen atom simultaneously;
Perhaps, in the presence of alkali, l-SPD and conventional phosphorylation agent (BnO) 2POCl, (BnO) 2PN ( iPr) 2, or (BnO) 2PN (Et) 2Reaction obtains phosphate product, i.e. R 1Be phosphate-based or R 1, R 2Be phosphate-based general formula (I) compound simultaneously; Described phosphate product is transformed into corresponding l-SPD phosphorylated derivative, i.e. R through hydrogenation or other respective handling 1Be phosphate or R 1, R 2Be general formula (I) compound of phosphate simultaneously; Described l-SPD phosphorylated derivative becomes phosphate derivative with alkali reaction, i.e. R 1Be phosphate base or R 1, R 2Be general formula (I) compound of phosphate base simultaneously.
7, the preparation method of acceptable salt, crystalline hydrate or solvate on l-spd derivative according to claim 6 or its pharmacology is characterized in that,
In acidylate or sulfonylation, described acid acceptor is sodium bicarbonate, yellow soda ash, salt of wormwood, triethylamine, Diisopropylamine, diisopropylethylamine, pyridine, N, accelerine, N, N-dimethyl aminopyridine or 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene;
Reaction solvent is methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, ether, benzene, toluene, N, dinethylformamide, dimethyl sulfoxide (DMSO) or its mixture;
Temperature of reaction from 0 ℃ to the solvent refluxing temperature, the reaction times was from 10 minutes to 48 hours.
8, the preparation method of acceptable salt, crystalline hydrate or solvate on l-spd derivative according to claim 6 or its pharmacology is characterized in that,
In phosphorylation reaction, the temperature of reaction of described phosphorylation reaction from 0 ℃ to the solvent refluxing temperature, the reaction times was from 10 minutes to 72 hours; Reaction solvent is N, dinethylformamide, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, ether, benzene, toluene or dimethyl sulfoxide (DMSO); Described alkali is sodium hydride, potassium hydride KH, lithium hydride, sodium hydroxide, potassium hydroxide, hydrated barta, potassium tert.-butoxide, salt of wormwood, yellow soda ash, triethylamine, diisopropylethylamine, pyridine, N, accelerine, N, N-dimethyl aminopyridine, 2,6-di-t-butyl-4-picoline or 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene;
In hydrogenation, to carry out at normal temperatures and pressures, the reaction times was from 10 minutes to 48 hours, and employing palladium-containing catalyst or nickel-containing catalyst;
In the reaction of described l-SPD phosphorylated derivative and alkali, the alkali that is fit to is ammoniacal liquor, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium hydride, calcium hydroxide, calcium oxide, lime carbonate, magnesium hydroxide, magnesium oxide, magnesiumcarbonate, sodium ethylate, sodium methylate or basic aminoacids; The solvent that reaction is fit to is water, alcohol or their mixed solvent; Temperature of reaction is-20 a ℃～solvent refluxing temperature.
9, acceptable salt, crystalline hydrate or the solvate application in preparation treatment nervous system disorders medicine on each described l-spd derivative of claim 1～5 or its pharmacology.
10, application according to claim 9 is characterized in that, described nervous system disorders is schizophrenia or other and Dopamine Receptors related neural systemic disease.
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WO2016041514A1 (en) * 2014-09-17 2016-03-24 成都贝斯凯瑞生物科技有限公司 Tetrahydroberberine derivatives and application thereof
WO2019034031A1 (en) * 2017-08-14 2019-02-21 中国科学院上海药物研究所 Tetrahydroprotoberberine compound, preparation method therefor and uses thereof, and pharmaceutical composition
US11731965B2 (en) 2017-08-14 2023-08-22 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Tetrahydroprotoberberine compound, preparation method therefor and uses thereof, and pharmaceutical composition
CN112062761A (en) * 2020-09-25 2020-12-11 常州大学 Method for synthesizing berberrubine ester substances
WO2024083146A1 (en) * 2022-10-18 2024-04-25 北京泰德制药股份有限公司 Compound based on orydalmine structure and use thereof
WO2025051134A1 (en) * 2023-09-04 2025-03-13 北京泰德制药股份有限公司 Tetrahydroisoquinoline derivative and use thereof

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