WO2008014661A1

WO2008014661A1 - Tetrahydroprotoberberine compounds, their manufacture, medicinal composition and uses.

Info

Publication number: WO2008014661A1
Application number: PCT/CN2007/001734
Authority: WO
Inventors: Yushe Yang; Yu Ding; Peihua Sun; Jiao Mo; Guozhang Jin; Ruyun Ji; Xuechu Zhen
Original assignee: Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Priority date: 2006-07-26
Filing date: 2007-05-29
Publication date: 2008-02-07
Also published as: CN1900075A; CN100528872C

Abstract

The present invention affords tetrahydroprotoberberine compounds listed as formula (I) and their pharmaceutically acceptable inorganic or organic salts, crystallized hydrates, solvates and medicinal compositions. In the formula (I), R1, R2, R3 and R4 represent H, lined or branched chain C1-4 alkyl, cyclopropyl, cyclopropyl methyl, methoxyl methyl, methoxycarbonylmethyl, aryl, benzyl, allyl, or substituted aryl or benzyl. R5 and R6 represent H, halogen, OH, SH, NO2, NH2, substituted or non-substituted lined or branched C1-4 alkyl. The configuration of C-14 is R, S or its racemate. The present invention also provides their preparation process and application in preparing medicine for treating neurological diseases, especially dopamine receptor related neurological diseases.

Description

FIELD OF THE INVENTION The present invention relates to the field of medicinal chemistry and chemotherapeutics, and in particular to the synthesis of a class of tetrahydroprotoberberoids and their The invention relates to the application of the medicament for treating diseases of the nervous system, in particular to the dopamine receptor-related nervous system diseases. BACKGROUND OF THE INVENTION Neurological diseases are one of the epidemic diseases in contemporary society. However, many neurological diseases have not been effectively treated clinically, especially schizophrenia is a serious mental illness, and its clinical treatment is far from satisfactory. In recent years, neuroscientists have used animal and patient working memory tasks to test and reflect short-term memory experiments of the cerebral cortex prefrontal (PFC) function [Castner, SA Science 2000, 287: 2020; Abi-Dargham, A The J Neurosciences. 2002, 22, 3708], and clinical use of positron emission tomography (PET) tests, demonstrated that patient PFC receptor dysfunction is associated with negative symptoms, subcortical structures (NAc, VTA, etc.) The 0 ₂ receptor hyperfunction is associated with positive symptoms [Okubo, Y. Nature.l997, 385:634; Abi-Dargham, A. Eur Psychiatry 2005; 20:15], while the PET test indicates that 5HU† PFC does not The key role [Okubo, Y. Life sciences 2000; 66: 2455]. Therefore, it is suggested that the new etiology of schizophrenia is due to the down-regulation of dopamine receptor function in the mPFC medical Prefrontal Cortex, while the subcortical regions such as the midbrain ventral tegmental area (VTA, Ventral Tegmental Area and dopamine D ₂ receptors in the nucleus accumbens (NAc, Nucleus Accumbens) are hyperactive. Based on this theory, a drug with both dual effects of agonism and D ₂ antagonism should have It may become a new class of antipsychotic drugs with great development prospects (Jin GZ. TiPS, 2002, 23: 4). Jin Guozhang et al. reported for the first time that tetrahydroprotoberberines (THPBs) quintolide (I-SPD) is the first lead drug known to have dual effects of agonism and D ₂ antagonism (Jin GZ. TiPS, 2002, 23 : 4). Clinical utility has initially shown that it is effective against both positive and negative symptoms, has a better effect on negative symptoms, and has non-classical stabilizer properties, and may become a new class of anti-schizophrenia drugs. Chinese patent CN115318 discloses a synthesis method suitable for industrial production of levorotatory and dextrorotatory chlorsulosin and its use. Chinese patent CN1603324 discloses various salts of levofloxacin, which has anti-schizophrenia effect, and particularly mesylate significantly improves the water solubility and stability of levodeskulin. The invention provides a novel structure of tetrahydrogen d, a ruthenium compound, a synthesis method and a use thereof, and the compound has the dual pharmacological action of D1 agonistic-D2 block, and can be applied to the preparation of a medicament for treating diseases of the nervous system, especially with dopamine. Receptor-related neurological disease drug field. SUMMARY OF THE INVENTION One object of the present invention is to provide a tetrahydroprotoberberine compound represented by the following formula (I), and a pharmaceutically acceptable inorganic or organic salt thereof, a crystalline hydrate, a solvate thereof and a pharmaceutical combination thereof Object:

(I) In the formula (I), R ₂ , R ₃ and a C _M alkyl group representing a hydrogen, a straight chain or a branched chain, a cyclopropyl group, a cyclopropyl group, a methoxy group, a methoxycarbonyl group, an aryl group, Benzyl, allyl, or substituted aryl or benzyl;

R ₅ , represents hydrogen, halogen, hydroxy, decyl, nitro, amino, substituted or unsubstituted straight or branched d- ₄ alkyl or other suitable alkyl;

The configuration of the 14-position carbon atom may be R type, S type or racemate; the present invention will = methyl, = = = hydrogen, and R ₅ = halogen excluded. Another object of the present invention is to provide a preparation method of the tetrahydroprotoberberine compound represented by the above formula (I), and a pharmaceutically acceptable inorganic or organic salt thereof, a crystalline hydrate and a solvate thereof, and Their pharmaceutical compositions. Still another object of the present invention is to provide a tetrahydroprotoberberoid compound represented by the above formula (I) as a prodrug. The present invention also provides a tetrahydroprotoberberine compound having the above formula (I) and a pharmacologically acceptable inorganic or organic salt thereof, a crystalline hydrate, a solvate, a prodrug and a pharmaceutical composition thereof The invention relates to the application of the medicament for treating diseases of the nervous system, in particular to the dopamine receptor-related nervous system diseases. The invention is described in detail below. Unless otherwise stated, the terms used herein have the following definitions:

'3⁄43⁄4基" means a saturated or unsaturated, substituted or unsubstituted linear, branched alkane chain, specifically exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert-butyl Base, pentyl, isopentyl, neopentyl, tert-amyl, 1-methylbutyl, 2-methylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-decylpentyl, 2-methylbutyl, 1,1-dimethylbutyl, 1,2-didecylbutyl, 1,3-dimethylbutylate, 2,3-dimethyl Butyl, 3,3-didecylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl Base, 1-ethylberhydrylpropyl, 1-ethyl-2-mercaptopropyl, and the like. Among these groups, methyl, ethyl, propyl, isopropyl, butyl, etc. are preferably 1-4, and more preferably methyl, ethyl or propyl. The sulfhydryl group and the ethyl group are the best.

"Aryl" means an aromatic group, preferably 6 to 14 aryl groups, specifically phenyl, tolyl, diphenyl, biphenyl, naphthyl, anthracenyl , fluorenyl, phenanthryl, more preferred is benzene «Caiji, the best is phenyl.

"Substituted alkyl", "substituted aryl", "substituted benzyl" respectively denotes that H", "aryl", "benzyl" are optionally selected from a halogen atom, an alkyl group, an alkane, Substituents of acyl, -OH, -Li ₂ , N0 ₂ , -HAc are substituted.

The "pharmaceutically acceptable salt" specifically includes a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, and formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid. , fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, ^^xanic acid and other organic acids, and aspartic acid, glutamic acid and other acidic acids The salt formed. In the tetrahydroprotoberberine compound represented by the formula (I) of the present invention and a preparation intermediate thereof, representative compounds are as follows:

1, 3-methoxy-4-benzyloxy-ω-nitrostyrene (1);

2, 3-decyloxy-4-benzyloxy-phenylethylamine (2);

3. 2-Chloro-4-benzyloxy-5-hydroxy-phenylacetic acid (3); 4. N-(3,-Methoxy-4,-benzyloxyphenethyl)-2-chloro-4-benzyloxy-5-hydroxy-phenylacetamide

(4);

5, Ν-(3'-methoxy-4,-benzyloxyphenethyl)-2-chloro-4-benzyloxy-5-ethoxycarbonyloxy-phenylacetamide (5);

6. 1-(2,-Chloro-4,-benzyloxy-5-ethoxycarbonyloxy)benzyl-6-methoxy-7-benzyloxy-3,4-dihydroisoquinoline Hydrochloride (6);

7. 1-(2,-Chloro-4,-benzyloxy-5-hydroxy)benzyl-6-methoxy-7-benzyloxy-1,2,3,4-tetrahydroisoquinoline ( 7);

8, (±)-2,10-dibenzyloxy-3-decyloxy-9-hydroxy-12-chlorotetrahydroprotoberberine (8);

9, (±)-2,10-dibenzyloxy-3,9-dimethoxy-12-chlorotetrahydroprotoberberine (9);

10, (士) -2,10-dihydroxy-3,9-dimethoxy-12-chlorotetrahydroprotoberberine (10);

11. (±)-2,10-dihydroxy-3,9-dimethoxyoxy-12-bromotetrahydroprotoberberine (11);

12, (±)-2,10-dihydroxy-3,9-dimethoxyoxy-12-fluorotetrahydroprotoberberine (12);

13, (士) -2,10-dihydroxy-3,9-dimethoxy-12-nitrotetrahydroprotoberberine (13);

14, (士) -2,10-dihydroxy-3,9-dimethoxytetrahydroprotoberberine (14);

15. (14&2,5 2,10-Dibenzyloxy-3-decyloxy-9-(indole-p-xanthionyl-2-,-formyl)oxy-12-chlorotetrahydroprotoberberine (15);

16. (14^2'^- 2,10-Dibenzyloxy-3-decyloxy-9-(indolyl-p-xylylpyrrole-2,-formyl)oxy-12-chlorotetrahydrogen Berberine (16);

17. OS)-(-)-2,10-Dibenzyloxy-3-decyloxy-9-hydroxy-12-chlorotetrahydroprotoberberine 18, (R)-(+)-2,10-dibenzyloxy-3-decyloxy-9-hydroxy-12-chlorotetrahydroprotoberberine

(18);

19. (5 (-)-2,10-Dibenzyloxy-3,9-dimethoxy-12-chlorotetrahydroprotoberberine (19);

20, (R)-(+)-2,10-dibenzyloxy-3,9-dimethoxyoxy-12-chlorotetrahydroprotoberberine (20);

21, (5)-(-)-2,10-dihydroxy-3,9-dimethoxy-12-chlorotetrahydroprotoberberine (21);

22. (R)-(+)-2,10-Dihydroxy-3,9-dimethoxyoxy-12-chlorotetrahydroprotoberberine (22);

23, (±)-2, 10-dihydroxy-3,9-dimethoxy-12-aminotetrahydroprotoberberine (23); tetrahydroprotoberberine according to formula (I) of the present invention The class of compounds can be prepared by the following three reaction routes. The reaction route 1 is as follows:

Reagents and reaction conditions: a) HOSU, DCC, CH ₂ Cl _2j rt; b) Et ₃ N, benzene, ClCOOEt; c) P0C1 ₃ , benzene, Reflux; d) NaBH ₄ , CH ₃ OH; e) 37% HCHO, H ₂ 0, CH ₃ OH, reflux; f) THF, CH ₂ N ₂ , 3days; g) concentrated salt / ethanol, reflux; A preparation method is described in detail as follows: Preparation of Compound 2: References (a. AIMeyeres & Joseph Guiles, Heterocycles, 1989, 28(1), 295-301. b. Paul W. Ford, Mat ew R. Narbut, Jack Belli , and Bradley S. Davidson, J. Org. Chem., 1994, 59(20), 5955-5960). Preparation of Compound 3: Prepared by reference (B Hegedus, Helv. Chim. Acta., 1963, 46(7), 2604-2612.). Preparation of Compound 4: Preparation of an activated ester with N-hydroxysuccinimide (NHS/HOSU) and phenylacetic acid compound 3, followed by dropwise addition of phenethylamine 2, which can be obtained in good yield (70-90%). Amidation product 4. This method shows significant advantages in the preparation of such compounds, the operation is simple, the reaction conditions are mild, and the product is hardly purified. The activation of the carboxyl group of the compound 3 can also be carried out as other active esters or mixed acid anhydrides. The solvent used in the reaction is an inert solvent such as dichloromethane, chloroform, benzene, toluene, tetrahydrofuran, dioxane or diethyl ether, and the reaction temperature is 0-100°. C, the reaction time is 0.1-72 hours, and the crude product is composed of decyl alcohol, ethanol, isopropanol, ethyl acetate, chloroform, dichloromethane, benzene, n-hexane or two or more components thereof in an appropriate ratio. The mixed solvent was recrystallized. The optimum reaction conditions are dichlorosilane, the reaction is carried out at room temperature for 0.1 to 24 hours, and the crude product is recrystallized from ethanol; Preparation of Compound 5: Compound 4 is obtained by protecting phenolic hydroxyl group to obtain Compound 5. As the reaction solvent, an inert solvent such as benzene, toluene, dichloromethane, chloroform, tetrahydrofuran, dioxane or diethyl ether can be used, and benzene or benzene is preferably used. The reaction is generally carried out in the presence of an acid acceptor, and the acid acceptor preferably used in the reaction includes an inorganic base such as sodium hydrogencarbonate, sodium carbonate, carbonic acid. Potassium, etc.; such as triethylamine, diisopropylethylamine, pyridine, hydrazine, hydrazine-dimethylaniline, hydrazine, hydrazine-dimercaptoaminopyridine, 1,8-diazabicyclo[5, 4,0]undec-7-ene (DBU) and the like. Recrystallization from ethanol, methanol, isopropanol, ethyl acetate, chloroform, dichloromethane, benzene, n-hexane or a mixed solvent of two or more of them in a suitable ratio, preferably using ethanol, decyl alcohol , Ethyl acetate; any protecting group conventionally used in the field of organic chemistry which can be easily removed after the reaction and which does not easily decompose the target compound, can be used as a suitable phenolic hydroxyl protecting group in the preparation method. Specific examples of the protecting group which can be used for this purpose include formyl group, acetyl group, trifluoroacetyl group, benzoyl group, p-toluenesulfonyl group, decyloxycarbonyl group, ethoxycarbonyl group, isobutoxycarbonyl group, tert-butyl group Oxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, etc.; Preparation of compounds 6 and 7: Compound 5 can be condensed under appropriate conditions to give compound 6, and the condensing agent can be phosphorus oxychloride. The phosphorus oxybromide, the phosphorus pentoxide, etc., and the reaction solvent may be benzene, toluene, acetone, acetonitrile or the like. The phenolic hydroxyl group-protected compound can be removed by hydrolysis, solvolysis, or reduction according to the relevant properties of the protecting group to form compound 7; Preparation of compound 8: Compound 7 hydrochloride and 37% furfural The aqueous solution was subjected to Mannich cyclization, and 8 was obtained. The solvent used in the Mannich reaction is methanol, ethanol, water or a suitable combination of the two, and the reaction temperature is from room temperature to reflux, and is preferably reflux. The recrystallization solvent is a mixed solvent of ethanol, methanol, isopropanol, acetone, ethyl acetate, chloroform, dichloromethane, benzene, toluene, n-hexane or a combination of two or more of them in a suitable ratio; Preparation of 10 and 10: Compound 8 is thiolated with a conventional diazomethane thiolation reagent to obtain compound 9, and then refluxed under acidic conditions to obtain 10, and the acid used in the reaction may be a suitable concentration of hydrochloric acid or phosphoric acid. , sulfuric acid, acetic acid, trifluoroethane Acid, etc., the solvent is ethanol, decyl alcohol, isopropanol, acetone, water, etc., and the optimum conditions are concentrated hydrochloric acid and ethanol. , , R ₅ and before definition. Reaction route 2 is described in detail as follows:

23 Reagents and reaction conditions: a) Me ₂ S0 ₄ , K ₂ C0 ₃ , acetone; b) HN0 ₃ (conc.), AcOH c) EtOH, reflux; d) i.POCl ₃ , benzene; ii. NaBH ₄ , MeOH; e) conc.HCl-EtOH, reflux; f) Pd/C, H ₂ . Preparation of compound 24: Reference method (J. Org. Chem., 1979, 44(3), 407-409) Compound 25 Preparation: 24 with conventional alkylating reagents such as dimethyl sulfate, iodonane, diazane, methyl trifluoromethanesulfonate or other alkylating agents, etc., in organic or inorganic Alkylation under the action of a base gives 25. The reaction solvent may be methanol, acetone, dioxane, diethyl ether, tetrahydrofuran, disulfoxide, hydrazine, hydrazine-dimercaptocarboxamide, chloroform, dichloromethane or the like, preferably acetone, decyl alcohol or tetrahydrofuran. The inorganic base used in the reaction may be sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium hydride, sodium hydride, potassium t-butoxide, potassium carbonate, sodium carbonate, etc., and the organic base used in the reaction may be three. Ethylamine, diisopropylethylamine, pyridine, hydrazine, hydrazine-dimercaptoaniline, hydrazine, hydrazine-dimercaptoaminopyridine, 2,6-di-tert-butyl-4-mercaptopyridine, 1,8- Diazabicyclo[5,4,0]undec-7-ene (DBU), etc., preferably compound 24 is thiolated with dinonyl sulfate in potassium carbonate to give compound 25; Preparation of compound 26: 25 in conventional The nitration product 26 is obtained by the action of a nitrating reagent. The reaction temperature is 0-40 ° C, and the reaction time is 0.1-24 hours. The nitration reagent can be a mixture of different ratios of concentrated sulfuric acid and concentrated nitric acid, a mixture of different concentrations of nitric acid, sodium nitrate and concentrated sulfuric acid, and a mixture of potassium nitrate and concentrated sulfuric acid. , a mixture of sodium nitrite and concentrated sulfuric acid, a mixture of ferric nitrate, ethyl nitroacetate, concentrated nitric acid and acetic acid, etc., preferably used in the reaction is a mixture of concentrated nitric acid and acetic acid; Preparation of compound 27: Compound 26 Condensation with compound 2 gives 27. The reaction temperature is 0-100 ° C and the reaction time is 0.1-48 hours. The solvent used for the reaction may be ethanol, decyl alcohol, acetonitrile, benzene, toluene, ethyl acetate, chloroform, dichloromethane, acetone, tetrahydrofuran or the like, preferably ethanol or benzene; preparation of compound 28: compound 27 under appropriate conditions Under the hydrazine ring, compound 28 can be obtained by reduction. The condensing agent may be phosphorus oxychloride, 'phosphonium bromide, pentoxide, etc., and the reaction solvent may be benzene, toluene, acetone, acetonitrile, etc., and the reducing agent may be sodium borohydride or potassium borohydride. The solvent can be used acetonitrile, benzene, toluene, ethyl acetate, chloroform, dichloromethane, acetone, tetrahydrofuran, etc., preferably using benzene, toluene; optimum conditions can be seen in Example 28; Preparation of Compound 13: Similarly to the preparation of Compound 10, Compound 13 was obtained; Preparation of Compound 23: Compound 13 was subjected to catalytic hydrogenation reduction under appropriate conditions to afford 23. Catalytic hydrogenation catalysts may be selected from 10% or 5% palladium on carbon or other palladium-containing catalysts, or Raney-Ni, or other catalysts containing palladium or nickel; the preferred catalyst is 10% palladium on carbon. The solvent may be selected from a mixed solvent of dichloromethane and a lower alkyl alcohol such as methanol, ethanol, isopropanol or the like, and acetic acid; preferably a mixed solvent of decyl alcohol and dichloromethane or acetic acid. The reaction time can be from 0.1 hour to no longer absorbing hydrogen. The reaction temperature may be from room temperature to 40 ° C, preferably room temperature. The reaction pressure can be from atmospheric pressure to several tens of atmospheric pressures, and the optimum condition is atmospheric pressure. The preparation method of Reaction Scheme 3 (taking R ₅ = C1 product as an example) is described in detail as follows:

(S)-(-)-21 (R)-(+)-22

Reagents and reaction conditions: a) oxalyl chloride; NaOH, tetrabutylammonium hydrogen sulfate, tetrahydrofuran, HPLC resolution; b) 20% KOH, EtOH; c) CH ₂ N ₂ , THF; d) HCl/EtOH, reflux compound Preparation of 15 and Compound 16: (±)-2,10-Dibenzyloxy-3-methoxy-9-hydroxy-12-chloro-tetrahydroprotoberberine 8 and formed from a suitable chiral acid The acid chloride is formed by the action of a base Ester, separated by HPLC to form a pair of diastereomers (14 & 2,S 2,10-dibenzyloxy-3-decyloxy-9-(N-p-toluenesulfonylpyrrole-2,-A Acyl)oxy-12-chloro-tetrahydroprotoberberine 15 and (1 ⁴ R, ² ,<S)-2,10-dibenzyloxy-3-methoxy- ⁹ _(N-pair ^ acylpyrrole _ ² ,-formyl) oxy-12-chloro-tetrahydroprotoberberine 16. The acid may be any suitable optically active organic acid, and the preferred reaction is valine in thionyl chloride After acylation, compound 8 is esterified with sodium hydroxide and phase transfer catalyst tetrabutylammonium hydrogen sulfate; Preparation of compound 17 and compound 18: Compounds 15 and 16 are hydrolyzed under basic conditions to obtain corresponding (5)-(-)-2,10-dibenzyloxy-3-decyloxy-9-hydroxy-12-chloro-tetrahydroprotoberberine 17 and (R)-(+)-2, 10-dibenzyloxy-3-methoxy-9-hydroxy-12-chloro-tetrahydroprotoberberine 18, the base used in the reaction may be sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, hydrogen hydroxide Potassium, sodium hydroxide, etc., the solvent is ethanol, methanol, isopropanol, acetone, water, etc., the optimum conditions are potassium hydroxide and ethanol; Preparation of 19 and Compound 20: Compounds 17 and 18 were prepared according to the method of Preparation of Compound 9 to give (S)-(-)-2,10-dibenzyloxy-3,9-dimethoxy-12-chloro-tetrahydro Protoberberine 19 and (R)-(+)-2,10-dibenzyloxy-3,9-dimethoxyoxy-12-chloro-tetrahydroprotoberberine 20; Compound 21 and Compound 22 Preparation: (5)-(-)-2, 10-dibenzyloxy-3,9-dimethoxyoxy-12-chloro-tetrahydroprotoberberine 19 and (R)-(+)-2, 10-Dibenzyloxy-3,9-dimethoxyoxy-12-chloro-tetrahydroprotoberberine 20 is prepared according to the method for preparing compound 10 (SK-)-2,10-dihydroxy-3,9- Dimethoxy-12-chloro-tetrahydroprotoberberine 21 and (i?)-(+)-2,10-dihydroxy-3,9-dimethoxy-12-chloro-tetrahydrogen Scopolamine 22. The structural formula of representative compounds is shown in Table 1.

9ΐ

^C.100/Z,00ZN3/X3d Ϊ99 0/800Ζ ΟΛ\

Pharmacological Tests The present invention also provides the action characteristics of tetrahydroprotoberberine-like compounds on dopamine D1, D2 receptors.

―. Determination of the affinity of tetrahydroprotoberberine compounds for dopamine D1 and D2 receptors:

1. Test method: In the D1 receptor binding competition experiment, different concentrations (10_ ⁵ M ~ 10- ^Π的 ) of this series of compounds and positive control drugs (-) -SPD and radioligand [3HJSCH23390 ( Dl -Selective And a certain amount of D1 receptor protein expressed by transfected insect cells (Sf cells) was added to the reaction tube, and after incubation for 60 min in a water bath at 30 ° C, the reaction was terminated in water. On a Millipore cell sample collector, after GF/C glass fiber filter paper was drawn and dried, placed in a 0.5 ml test tube, and 500 ul of liquid scintillation fluid was added to measure the radiation intensity.

The D2 receptor binding competition experiment is the same as above, but the isotope receptor ligand uses [3H]Spiperone ( D2 -Selective ) ₀

1. Test materials: Receptor construction and cell culture materials: Escherichia coli E. coli. DH5a; strain; insect virus transfer vector pVL1393 broad granule; BaculoGold linearized baculovirus DNA, purchased from PharMingen; mkDIR cDNA; rD2R cDNA; Spodoptetra Frugiperda 9; various restriction enzymes, Taq DNA polymerase, T4 ligase, etc. were purchased from TakaRa; plasmid purification, gel recovery, and PCR product purification kits were purchased from Shanghai. Huaying Biotechnology Co., Ltd.; LB medium; insect cell culture medium TNM-FH. Receptor binding assay materials: Isotope ligand [3H]SCH23390 (85.0 Ci/mmol), [3H]Spiprone (77.0 Ci/mmol) was purchased from Amersham; (+) Butaclamol was purchased from RBI; GF/C glass fiber filter paper Purchased from Whatman; liquid scintillation fluid. The test compounds were first dissolved in DMSO, and then diluted to the corresponding concentration with double distilled water (1 (Τ ⁵ Μ~ 10- ^Π Μ ), the test results are shown in Table 2. II. Tetrahydroprotozoal compound to dopamine D1 The determination of receptor agonistic properties, the change of cAMP level as an indicator of the effect of drugs on DA receptor subtypes. Test method: According to the change of intracellular cAMP amount after drug administration, the tetrahydroprotoberberine compound was judged. For D1 receptor agonism, HEK293 cells stably expressing D1 receptor were incubated with serum-free medium containing lOOuM IBMX for 40 min, then various concentrations of different drugs were added at 37 °C for 10 min, and lOOul pre-cooled 1 M HC10 _{4 was added} . The reaction was terminated at 4 ° C for 1 hr, neutralized by adding 20 ul of 2 M K ₂ CO ₃ , centrifuged at 3000 rpm for 15 min, and the KC10 ₄ precipitate was discarded. A certain amount of the supernatant was taken for cAMP detection. The positive control drugs were Dopamine and /-SPD. The test results are shown in Table 3. - III. Determination of dopamine D2 receptor blockade characteristics by tetrahydroprotoberberine compounds: Test method: Each drug was dissolved in serum-free F12 medium containing lOOuM IBMX, 37 ° C pre-incubation of CHO cells stably expressing D2 receptor After lOmin, add 10uM Forskolin and 10uM Dopamine to react for 10 min, force lOOul pre-cooled 1M HC10 ₄ , stop reaction at ₄ ° C for ₁ hr, add 20 ul 2M K ₂ C0 _{3 to} neutralize the reaction, centrifuge at 3000 rpm for 15 min, discard KC10 ₄ Precipitation, take a certain amount of supernatant for cAMP detection. The positive control drugs are Haloparidol and /-SPD, the test results are shown in Table 4. Table 2 Determination of the affinity of some representative compounds for dopamine D1, D2 receptors

# indicates that the highest concentration of the drug has no obvious inhibitory effect. Table 3 Determination of agonistic properties of dopamine D1 receptor by some representative compounds

* Max Stimulation is the maximum cAMP produced by the drug after stimulating the Dl receptor, converted to a percentage in the data, with a -SPD of 100%. Table 4 Determination of Dopamine D2 Receptor Blocking Properties by Representative Compounds Drug No. EC50 ± SEM

10 1.90 ± 1.09 uM

11

12 5.03 ± 4,18 uM 13

14 2.64 1.00 um uM

21 0.55 士 0.25 uM

Haloparidol 7.33 ± 1.80 nM

Z-SPD 4.38 ± 1.18 uM

^; Seen from the above, the tested compounds Tetrahydroprotoberberines dopamine Dl, D2 receptor and - SPD similar or greater affinity, such as compounds 13, 12, 11, 10, 21 to control drug Z - The affinity of SPD for the D1 receptor is 1-1 times stronger. In particular, the blocking effect of Compound 21 on the D2 receptor was 9 times stronger than that of L-SPD. Pharmacological test results indicate that the compounds of the present invention have potent D turbulence and D2 blockade. Therefore, the present invention also provides a tetrahydroprotoberberine compound having the above formula (I), and a pharmacologically acceptable inorganic or organic salt thereof, a crystalline hydrate, a solvate thereof, and a pharmaceutical composition thereof, which are useful for A medicament for treating a neurological disease drug, particularly a disease associated with a dopamine receptor-related nervous system. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further illustrated by the following examples, but these examples are in no way intended to limit the invention. In all the examples, the melting point was measured by a MEL-TEMP melting point apparatus, the thermometer was not corrected; ^-NMR was measured by a Varian Mercury Plus 400 MHz nuclear magnetic resonance apparatus; and the optical rotation was measured by a Perkin-Elmer 241MC type or P-1030 (A012360639) type automatic polarimeter. Chemical shifts are expressed as δ (ppm); silica gels for separation are both 200-300 mesh. Example 1: 3-Methane-4-benzyloxy-ω-nitrostyrene compound 1) References (a. AIMeyeres & Joseph Guiles, Heterocycles, 1989, 28(1), 295-301. b.Paul W. Ford, Mathew R. Narbut, Jack Belli, and Bradley S. Davidson, . Org. Chem., 1994, 59(20), 5955-5960), starting from vanillin, with Benzyl bromide, potassium carbonate is refluxed in acetone to give a benzyl protected product which is refluxed with nitromethane and ammonium acetate in glacial acetic acid to give 3-methoxy-4-benzyloxy-omega-nitrostyrene (1). MP 117- 119 °C . toMRCCDClB): S7.95(d, IH, J=13.7Hz) ₅ 7.52(d, IH, J=13.5Hz), 7.45- 7.31 (m, 5H), 7.11-7.02(m , 2H), 6.92 (d, IH, J = 8.5 Hz), 5.22 (s, 2H), 3.93 (s, 3H). Example 2: 3-Methoxy-4-benzyloxy-phenylethylamine [Compound 2] Lithium tetrahydroaluminum (12.0 g, 0.32 mol) was suspended in pre-treated anhydrous tetrahydrofuran (250 ml) under argon atmosphere. Compound 1 (28.5 g, O.10 mol) was dissolved in anhydrous tetrahydrofuran (250 ml), and the mixture was slowly added dropwise to the preceding suspension under stirring to control the drip rate to prevent the reflux from being too intense. After completion, the mixture was heated to reflux for 2 hours, and then stirred at room temperature overnight, cooled with ice water, and slowly added dropwise H ₂ 0 (12 ml), 15% sodium hydroxide solution (12 ml), H ₂ 0 (36 ml). The formed turbidity was filtered, and the filter cake was washed with acetone repeatedly. The filtrate was concentrated under reduced pressure and then dissolved with diethyl ether (100-150 ml). The mixture was washed three times with diethyl ether, and then evaporated to dryness. ) 188 - 196 were collected by distillation under reduced pressure. The fraction was obtained, and the obtained oil (19.0 g) was solidified to give Compound 2. Yield: 73.9%. Mp 59-61 °C; TLC i?/ = 0.54 (1:4 MeOH: CH ₂ Cl ₂ , I ₂ ) ; ^! H NMR (CDC1 ₃ ) : 57.42-7.27 (m, 5H), 6.81-6.62 (m , 3H), 5.12(s, 2H), 3.82(s, 3H), 2.93(t, 2H, J=6.7Hz), 2.65(t, 2H,

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's)9S'£ '(HZ ^e s)60''(HIc^q)69'S X V8 ⁽ VZ=f 3⁄4ΐ 'PPJ i XHZ '∞) 8·9-06·9 m ⁽ ^91' L- ZY LQ l7C.l00/.00ZN3/X3d Ϊ99 0/800Ζ OAV J=8.1Hz), 6.66(d, 1H, J=2.0Hz), 6.53(dd ₅ 1H ₅ J=2.0, 8.1Hz), 5.41(br, 1H), 5.11(s, 2H), 5.08(s, 2H), 4.26(q, 2H, J=7.2Hz), 3.84(s, 3H), 3.55(s, 2H), 3.45(dd, 2H, J=6.9, 12.8Hz), 2.69(t, 2H, J =6.9 Hz), 1.30 (t, 3H, J = 7.2 Hz). Example 6: 2,-Chloro-4,-benzyloxy-5-ethoxycarbonyloxy)benzyl-6-methoxy-7-benzyloxy-3,4-dihydroisoquinoline hydrochloride (Compound 6) Compound 5 (1.23 g, ² mmol) was dissolved in dry benzene (9 ml), freshly distilled phosphorus oxychloride (4 ml) was added, and the mixture was warmed to reflux. The reaction was stirred for 2.5 hours, and the reaction was stopped. Petroleum ether (100 ml), refrigerated overnight, the liquid substance was removed by pouring, the solid adhered to the bottle wall was washed three times with petroleum ether, dissolved in hot sterol (30 ml), yellow particles were precipitated, and diethyl ether was added. Until the dropwise addition of diethyl ether no longer caused turbidity (about 100 ml), when the water tank was refrigerated for several times, the compound was crystallized to obtain compound 6 (1.2 g). Yield: 94.7%. Mp 216-217 ° C (decomp.); ^ NMRCCDCls): 67.33-7.29 (m, 10H), 7.13 (s, 1H), 7.12 (s, 1H), 6.98 (s, 1H), 6.75 (s, 1H) ), 5.03(s, 2H), 4.97(s, 2H), 4.67(s, 2H), 4.19(q, 2H, J=7.1Hz), 3.94 (m, 5H), 3.01(t, 2H, J= 7.6 Hz), 1.25 (t, 3H, J = 7.1 Hz). Example 7: 2'-Chloro-4,-benzyloxy-5-hydroxy)benzyl-6-valent oxy-7-benzyloxy-1,2,3,4-tetrahydroisoquinoline (compound) 7) Compound 6 (1.32 g, 2 mmol) was dissolved in decyl alcohol (60 ml), and the mixture was cooled with ice water, and sodium borohydride (0.75 g, 20 mmol) was slowly added, and the mixture was warmed to reflux, and the mixture was stirred for 2 hr. Dilute with water, neutralize with potassium dihydrogen phosphate solution until the pH is unchanged (about 6~7). The solid is extracted with chloroform. The extract is washed with water and dried with anhydrous sodium sulfate, filtered, and then evaporated to remove chloroform. purification of compound 7 (1.0g): purified by column chromatography _{_{(CH 2 Cl 2 = 1:20 MeOH}} ). Yield: 93.1%. Mp 196 - 198 ° C (decomp.); ^ NMRC DMSO-de): Δ7.45- 7.29(m, 10H), 7.03(s, IH), 6.79(s, IH), 6.64(s, IH), 6.63(s, IH), 5.08(s, 2H), 4.93(s ₅ 2H), 3.88 (dd, IH, J=4.2, 9.4 Hz), 3.71 (s, 3H), 3.03 (m, IH), 2.93 (dd, 1H, J=4.2, 13.4 Hz), 2.78-2.75 (m) , IH), 2.68 (dd, 1H, J=9.4, 13.4 Hz), 2.59-2.57 (m, 2H). Example 8: (±)-2,10-dibenzyloxy-3-methoxy-9-hydroxy-12-chloro-tetrahydroprotoberberine (Compound 8) Compound 7 (0.3 g, 5.8 mmol) The solution was suspended in chloroform (6 ml), and an appropriate amount of hydrochloric acid-decanol solution was added thereto, and the solid was dissolved by shaking, and the solvent was evaporated to dryness. The residue was dissolved in decyl alcohol (13 ml), and then added to a 37% aqueous solution of furfural (7 ml), and then added. The mixture was stirred at room temperature for 2 days. Recrystallization gave a colorless crystal which was Compound 8 (0.2 g). Yield: 65.2%. Mp 178 - 180°C ; 3⁄4 NM (CDC1 ₃ ): 07.48-7.28 (m, 10Η), 6.88(s, IH), 6.80(s, IH), 6.66(s, IH), 5.62(br, 1H) , 5.16(dd, 2H, J=3.0Hz), 5.07(s, 2H), 4.20(d, IH, J=15.7Hz), 3.89(s, 3H), 3.48-3.43(m, 2H), 3.22- 3.09 (m, 3H), 2.69-2.60 (m, 2H), 2.51 (dd, IH, J = 10.6, 16.5 Hz). Example 9: (±V2,10-dibenzyloxy-3,9-dimethoxy-12-chloro-tetrahydroprotoberberine (Compound 9) Compound 8 (180 mg, 0.34 mmol) was dissolved in tetrahydrofuran ( 3 ml), freshly prepared diazomethane ether solution (prepared with 2 g of nitrosomethylurea) was added dropwise thereto, and allowed to stand at room temperature for 3 days, and the solvent and excess reaction were evaporated under reduced pressure. :PE = 1 : 4) Compound 9 (120 mg) was obtained. Yield: 64.9%. mp 149 - 151 ° C; ^l R NMR (00 MHz, CDC1 ₃ ): 67.48-7.28 (m, 10H), 6.92 (s , IH), 6.65(s, IH), 6.79(s, 1H), 5.17(d, LZ

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'HZ t£Ll00/L00ZKD/13d I99W0/80(^ OAV Compound 12 is a gray crystal, MP 223-225 °C (decomp.), 1H MR (DMSO-d ₆ ): 69.62 (brs, IH), 8.76 (s, IH), 6.72 (s, IH), 6.65 (s , IH), 6.55 (d, IH, J = 10.6 Hz), 4.05 (d, IH, J = 14.7 Hz), 3.73 (s, 3H), 3.69 (s ₅ 3H), 3.33 (brm, 2H), 3.20 -3.10 (brm, 2H), 2.90 (brm, lH), 2.62-2.43 (m, 2H), 2.30 (dd, 1H ₅ J = 11.7, 14.8 Hz). Example 13: (Soil 2,10-dihydroxy-3,9-dimethoxy-12-nitro-tetrahydroprotoberberine (Compound 13) Compound 13 Reference compound 10 was prepared from (±)- 2,10-Dibenzyloxy-3;9-dimethoxyoxy-12-nitro-tetrahydroprotoberberine 28 was obtained, yield: 81.5%, MP >200 ° C (decomp.), 3⁄4 NMR ( DMSO-d ₆ ): 510.25 (brs, IH), 8.77 (s, IH), 7.51 (s, IH), 6.71 (s, IH), 6.66 (s, IH), 4.10 (d, IH, J=14.8) Hz), 3.88(s, 3H), 3.45(s, 3H), 3.33(brm, 3H), 3.09(brm, IH), 2.90(brm, 1H), 2.71(brm, IH), 2.59(brm, IH ), 2.44 (brm, 1H). Example 14: (s) -2,10-dihydroxy-3,9-dimethoxy-tetrahydroprotoberberine (Compound 14) Compound 14 as white crystal, MP 129-131 ° C (decomp.) , ^! NMR (DMSO-d ₆ ): 59.13 (s, IH), 8.73 (s, IH), 6.70 (m, 3H), 6.64 (s, IH), 4.06 ( d, IH, J = 15.7 Hz), 3.73 (s, 3H), 3.71 (s, 3H) ₅ 3.40 (brm, 3H), 3.17 (m, 2H), 2.90 (m, 1H), 2.55 (m, 2H) Examples 15 and 16: (14 & 2,^- 2,10-dibenzyloxy-3-methoxy-9-(^-p-methylxanylpyrrole-2,-nonanoyl)oxy -12-chloro-tetrahydroprotoberberine (compound 15) and (14R,2,S)-2,10-dibenzyloxy-3- Oxy-9-oxime p-toluoylpyrrole-2,-formyl)oxy-12-chloro-tetrahydroprotoberberine (compound 16) -proline (150 mg, 0.56 mmol) dissolved in dichloro Decane (10ml), drip in water bath Oxalyl chloride (5 ml), stirred overnight, concentrated to dryness to dryness afforded acid chloride, toluene (3 ml); Compound 8 (260 mg, 0.5 mmol), sodium hydroxide powder (50 mg, 1.25 mmol) and tetrabutyl hydrogen sulfate Ammonium (0.6 mg) - dissolved in tetrahydrofuran (5 ml), the solution was added to the latter solution at room temperature (about 0.5 hour), stirring was continued for 2.5 hours, the reaction was completed by TLC, filtered with silica gel, and the filtrate was concentrated. Chromatography (CH ₂ Cl ₂ : EtOAc = 10:1) gave the oil as a pair of diastereomers (-)-(14&2'5)-15 and (-) - (14R, VS)-16 .

(-)-(145,2'5)-15:

[c] _D ²⁵ = - 85.2° (c = 0.1, CH ₃ CN)

^ NMRCCHCls): 57.78-7.74 (m ₅ 2H), 7.42-7.29 (m, 12H), 7.00 (s, IH), 6.76 (s, IH), 6.65 (s, IH), 5.18 (d, 2H, J =3.3Hz), 5.01(s, 2H), 4.10(d, IH, J=15.9Hz), 3.91(s, 3H), 3.22-3.43(m, 6H), 2.90(m, 3H), 2.64(m , 3H), 2.37(s, 3H), 1.95- 2.08(m, 3H).

(-)-(14R, 2'S)-16:

[ ] _Ό ²⁵ = - 89.1° (c = 0.1, CH ₃ CN)

^{_{! H NMR (CHC1 3):}} 57.79 (d 5 2H, J = 8.4Hz), 7.46 (d, 2H, J = 8.4Hz), 7.42-7.25 (m, 10H), 6.96 (s, IH), 6.79 ( s, IH), 6.68(s, IH), 5.22(d, 2H, J=3.4Hz), 4.98(s, 2H), 4.10(d, IH, J=15.8Hz) ₃ 3.94(s, 3H) ₅ 3.20-3.45 (m, 6H), 2.70-2.84 (m, 3H), 2.69 (m ₅ 3H), 2.44 (s, 3H), 1.93- 2.10 (m, 3H). Example 17: ^- -)-2,10-dibenzyloxy-3-methyl-l--9-hydroxy-12-chloro-tetrahydroprotoberberine Compound 17) Compound 15 (21 mg) was dissolved in A 1:1 mixture of 20% potassium hydroxide and ethanol (5 ml) was stirred at reflux for 4 hours to stop the reaction. After workup, column chromatography (EtOAc:PE=l:4) Compound (5)-(-)-17 (8 mg) was obtained. Mp 127—130°C; [c] _D ³ = - 130° (c = 0.12, CH ₃ CN); ^ NMRCCHCls): 7.48-7.28 (m, 10H), 6.88 (s, IH), 6.79 (s, IH), 6.66(s, IH), 5.62(br, 1H), 5.16(d, 2H, J=2.9Hz), 5.06(s, 2H), 4.20(d, IH, J=15.7Hz), 3.88( s, 3H), 3.48-3.43 (m, 2H), 3.22-3.09 (m, 3H), 2.69-2.60 (m, 2H), 2.5 l (m, 1H). Example 18: O-(+)-2,10-dibenzyloxy-3-methoxy-9-hydroxy-12-chloro-tetrahydroprotoberberine (Compound 18) Compound 16 was used as a starting material to resemble Compound 18 was obtained by the method of Compound 17. Mp 128-129 °C; [o;] _D ²⁵ = +130° (c = 0.12, CH ₃ CN); ^! H NMR(CHC1 ₃ ): 67.48-7.28 (m, 10H), 6,87 (s, 1H), 6.80(s, IH), 6.64(s, IH), 5.66(br ₅ IH), 5.16(d, 2H, J=2.7Hz), 5.06(s, 2H), 4.20(d, IH, J = 15.8 Hz), 3.88 (s, 3H), 3.48-3.43 (m, 2H), 3.22-3.09 (m, 3H), 2.69-2.60 (m, 2H), 2.5 l (m, 1H). Example 19: SH-)-2,10-Dibenzyloxy-3,9-dimethoxy-12-chloro-tetrahydroprotoberberine (Compound 19) Compound 17 is a starting material, similar to Compound 9 The compound was prepared by the method. Mp 113-115 ° C ; [o;] _D ²⁵ = - 149. (c = 0.08, CH ₃ CN); ^J H NMR (CHC1 ₃ ): δ 7. 48-7.28 (m, 10H), 6.92 (s, IH), 6.79 (s, IH), 6.64 (s, 1H), 5.17(d, 2H, J=3.0Hz), 5.07(s, 2H), 4.21(d, IH, J=15.8Hz), 3.88(s ₅ 3H), 3.87(s, 3H), 3.50-3.44(m , 2H), 3.19-3.09 (m, 3H), 2.70-2.59 (m, 2H), 2.51 (m, 1H). Example 20: (RW+V2J0-dibenzyloxy-3,9-dimethoxy-12-chloro-tetrahydroprotoberberine (Compound 20) Compound 18 was prepared as a starting material, similar to the compound 9 hydrazine method. Compound 20 was obtained. mp 114-115 ° C; [a] _D ²⁵ = +131° (c = 0.08, CH ₃ CN); 3⁄4 NMR (CHC1 ₃ ): 57.48-7.28(m, 10H), 6.92(s, IH), 6.79 (s, IH), 6.64 (s, IH), 5.17(d, 2H, J=2.9Hz), 5.07(s, 2H), 4.22 (d ₅ IH, J = 15.8 Hz), 3.88 (s, 3H), 3.87 (s, 3H), 3.50-3.44 (m, 2H), 3.19-3.09 (m, 3H), 2.70-2.59 (m, 2H) ), 2.5 l (m, 1H). Example 21: (^)-(-)-2,10-Dihydroxy-3,9-dimethoxy-12-chloro-tetrahydroprotoberberine (Compound 21) Compound 19 is a raw material similar to The compound 21 was prepared by the method of Compound 10. Mp 66 ° C (decomp.) ; [a;] _D ²⁵ = - 287 ° (c = 0.090, C3⁄4OH); 3⁄4 NMR (CD ₃ OD): 66.82 (s, IH), 6.76 (s, IH), 6.68 ( s, IH), 4.17(d, IH, J=15.7Hz), 3.82(s, 3H), 3.80(s, 3H), 3.53-3.49(m, 2H), 3.38(dd, IH, J=4.1, 16.8 Hz), 3.23-3.19 (m, IH), 3.07-3.02 (m, IH), 2.72-2.59 (m, 2H), 2.51 (dd, IH, J = 10.4, 16.8 Hz). Example 22: (? +V2,10-dihydroxy-3,9-dimethoxy-12-chloro-tetrahydroprotoberberine (Compound 22) Compound 20 was prepared as a starting material in a similar manner to Compound 10. Compound 22 was obtained. mpl 66 ° C (decomp.); [a] _D ²⁵ = +285 ° (c = 0.995, CH ₃ OH); ^J H NMR (CD ₃ OD): 66.82 (s, IH), 6.77 (s , IH), 6.68(s, IH), 4.17(d, IH, J= 15.8Hz), 3.82(s, 3H), 3.80(s, 3H), 3.53-3.50(m, 2H), 3.38(dd, IH, J=4.1, 16.8Hz), 3.23-3.19(m, IH), 3.07-3.03(m, IH), 2.72-2.59(m, 2H), 2.50(dd, IH, J=10.4, 16.8Hz) Example 23: (士-2,10-Dihydroxy-3,9-dimethoxyoxy-12-amino-tetrahydroprotoberberine (Compound 23) Compound 13 was dissolved in aqueous acetic acid at room temperature, After normal pressure hydrogenostatic reduction under 5% Pd-C catalysis, compound 23 can be obtained by conventional treatment. Yield: 94.5%. mp 127-130 ° C (decomp.); ¹ H NMR (CD ₃ OD): 56.83 (s, 1H), 6.70 (s, 1H), 6.28 (s, 1H), 4.30 (d, 1H, J = 15.4 Hz) , 3.83(s, 3H), 3.72(s, 3H), 3.88-3.68(m, overlap, 2H), 3.39(brm, 1H), 3.26-3.18 (brm, 2H), 2.94-2.76(brm, 2H) , 2.47 (dd, 1H, J = 1.7, 16.1 Hz), 1.94 (s, 2H). Example 24: 7-Benzyloxy-8-methyl-l--3-oxo-isochroman (Compound 25)

7-Benzyloxy-8-hydroxy-3-oxo-isochroman 24 [J. Org. C em., 1978, 43(10) ₅ 1992] (2.7 g, 10 mmol) and anhydrous Potassium carbonate powder (2.8 g, 20 mmol) was mixed with acetone (100 ml), dimethyl sulfate (2 ml, 20 ramol) was added dropwise, the temperature was raised to reflux, and the reaction was stirred for 6 hours, the reaction was stopped, filtered, and filtered. The acetone was washed with EtOAc (EtOAc)EtOAc. Yield: 95.1%; 3⁄4 M (CDC1 ₃ ): 67.45-7.34 (m, 5H), 6.93 (d, 1H, J = 8.2 Hz), 6.85 (d, 1H, J = 8.2 Hz), 5.40 (s, 2H), 5.12(s, 2H), 3.91(s,

Example 25: 5-Nitro-7-benzyloxy-8-methyl-l--3-oxo-isochroman (Compound 26)

7-Benzyloxy-8-methoxy-3-oxo-isochroman 25 (1.4 g, 5 mmol) was dissolved in glacial acetic acid (30 ml), cooled to just when it was not solidified, The mixture was stirred for 1 hour. PE = 1:6) Purification gave compound 26 (1.46 g). Yield: 98.7%. Mp 133-134 ° C; ^l H NMR (400 MHz ₅ CDC1 ₃ ): 57.79 (s, 1H), 7.40 (m, 5H), 5.42 (s, 2H), 5.19 (s, 2H), 4.14 (s, 2H) ), 4.04(s, 3H). Example 26: N-(3,-Methoxy-4,-benzyloxyphenethyl 2-nitro-4-benzyloxy-5-hydroxyl -6-hydroxymethyl-phenylacetamide (Compound 27)

5-nitro-7-benzyloxy-8-methoxy-3-oxo-isochroman 26 (329 mg, 1 mmol) and 3-decyloxy-4-benzyloxy-phenylethyl The amine 2 (0.5 lg, 2 mmol) was dissolved in ethanol (25 ml), and the mixture was warmed to reflux. The reaction was stirred for 20 hr, and the reaction was stopped. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed twice with 1 N hydrochloric acid and water. Drying with anhydrous sodium sulfate, concentrating by filtration and purifying by ethanol- petroleum ether recrystallization or column chromatography (Acetone: PE = 1:4) affords compound 27 (576 mg). Yield: 98.4%. Mp 95-98 ° C; 3⁄4-NMR (CDC1 ₃ ): S7.61 (s, 1H), 7.45-7.30 (m, 10H), 6.81 (d, 1H, J = 8.1 Hz), 6.74 (d, 1H) , J=1.9Hz), 6.66(dd, 1H, J=1.9, 8.1Hz), 6.22(brt, 1H), 5.16(s, 2H), 5.12(s, 2H), 4.79(s, 2H), 4.04 (s, 3H), 3.85 (s, 3H), 3.79 (s, 2H), 353 (m, 2H), 2.76 (t, 2H, J = 7.0 Hz). Example 27: (±V2,10-dibenzyloxy-3,9-dimethoxyoxy-12-nitro-tetrahydroprotoberberine (Compound 28) Compound 27 (2 g, 3.4 mmol) was dissolved in Add dry distilled toluene (15 ml), add fresh distilled phosphorus oxychloride (3.3 ml, 45 nunol), heat under nitrogen to reflux, stir the reaction for 3 hours, stop the reaction, distill off the solvent, and dissolve the residue in decyl alcohol (50 ml) After cooling with water, carefully add 2.8 g of sodium borohydride, 74 mmol), and then stir the reaction at room temperature overnight. After completion of the reaction, the mixture was quenched with water (20 ml), stirred for 30 minutes, and then poured into water (100 ml). The extract was extracted several times with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (Acetone: PE = 1:4) to give compound 28 (0.9 g), yield: 47.8%. Mp 132-134 ° C (decomp.); ^l R NMR (CDC1 ₃ ): 67.71 (s, 1H), 7.48-7.31 (m ₅ 10H), 6.78 (s, 1H), 6.65 (s, 1H), 5.23 (brs, 4H), 4.27(d, 1H, J=14.8Hz), 3.98(s, 3H), 3.88(s, 3H), 3.54-3.43(brm ₅ 2H), 3.21-3.04(brm, 4H), 2.75-2.60 (m, 2H:).

Claims

Claim

1. A tetrahydroprotoberberine compound represented by the formula (I), and a pharmacologically acceptable inorganic or organic salt thereof, a crystalline hydrate, a solvate thereof,

Wherein, R ₂ , and C _M alkyl, cyclopropyl, cyclopropylmethyl, anthracenyl, methoxycarbonylmethyl, aryl, benzyl, allylic, representing hydrogen, straight or branched chain a aryl or benzyl group; or a substituted aryl group;

R ₅ , representing hydrogen, halogen, hydroxy, decyl, nitro, amino, substituted or unsubstituted straight or branched C _M alkyl;

The configuration of the 14-position carbon atom may be R type, S type or a racemate; the above compound does not include 1? and is a methyl group, R ₂ , and are hydrogen, and R ₅ is a halogen.

The tetrahydroprotoberberine compound according to Claim 1 or a pharmacologically acceptable inorganic or organic salt, crystalline hydrate or solvate thereof, wherein said aryl group is a aryl group of 6 to 14 carbon atoms base.

The tetrahydroprotoberberine compound according to claim 1 or a pharmacologically acceptable inorganic or organic salt, crystalline hydrate or solvate thereof, wherein said substituted alkyl group, The alkyl, aryl or benzyl group in the substituted aryl or benzyl group is optionally selected from the group consisting of a halogen atom, a fluorenyl group, an alkane group, an acyl group, an -OH group, a -2⁄4 group, a NO ₂ group, a -NHAc group. Ears and generations.

The tetrahydroprotophyrin compound according to Claim 1 or a pharmacologically acceptable inorganic or organic salt, crystalline hydrate or solvate thereof, wherein said pharmacologically acceptable salt is and includes hydrochloric acid, Inorganic acids of hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, including citric acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, An organic acid of citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, or fulvic acid, or a salt of an acidic amino acid including aspartic acid or glutamic acid. ,

The tetrahydroprotoberberine compound according to claim 1 or a pharmacologically acceptable inorganic or organic salt, crystalline hydrate or solvate thereof, wherein the compound is selected from the following compounds:

(±)-2,10-dibenzyloxy-3-decyloxy-9-hydroxy-12-chlorotetrahydroprotoberberine; (±)-2,10-dibenzyloxy-3,9- Dimethoxy-12-chlorotetrahydroprotoberberine; (±)-2, 10-dihydroxy-3,9-dimethoxy- 12-chlorotetrahydrogen, decyl; (±)-2 , 10-dihydroxy-3,9-dimethoxy-12-nitrotetrahydroprotoberberine; (±)-2, 10-dihydroxy-3,9-dimethoxy- 12-aminotetra Hydrogen', alkaloid; 5)-(-)-2,10-dibenzyloxy-3-methoxy-9-hydroxy-12-chlorotetrahydroprotoberberine; (R)-(+ -2,10-dibenzyloxy-3-methoxy-9-hydroxy-12-chlorotetrahydroprotoberberine; (-(-)-2,10-dibenzyloxy-3,9- Dimethoxy-12-chlorotetrahydroprotoberberine; (R)-(+)-2,10-dibenzyloxy-3,9-dimethoxy-12-chlorotetrahydroprotoberberine ; (S)-(-)-2, 10-dihydroxy-3,9-dimethoxy-12-chlorotetrahydrogen 'J, alkaloid;

(R)-(+)-2,10-dihydroxy-3,9-dimethoxyoxy-12-chlorotetrahydroprotoberberine;

(±)-2, 10-dihydroxy-3,9-dimethoxy- 12-bromotetrahydrogen ', saponin;

(±)-2,10-dihydroxy-3,9-dimethoxyoxy-12-fluorotetrahydroprotoberberine;

(±)-2, 10-dihydroxy-3,9-dimethoxytetrahydrogenogen 'J, citrate;

(±)-2,10-Dibenzyloxy-3,9-dimethoxy-12-nitro-tetrahydroprotoberberine.

A method for producing a tetrahydroprotoberberine compound according to claim 1 and a pharmacologically acceptable inorganic or organic salt, crystalline hydrate or solvate thereof, wherein the reaction route is as follows:

R ₃ , , R ₅ and R6 are defined as claim 1, and the reaction steps are as follows:

(a) compound 3 is made into an activated ester, and then reacted with 2 to form 4; (b) compound 4 is protected by a phenolic hydroxyl group to obtain compound 5;

(c) compound 5 is condensed under appropriate conditions to give compound 6;

(d) according to the nature of the protecting group, the protective group is removed by hydrolysis, solvolysis or reduction to form compound 7;

(e) the hydrochloride salt of compound 7 and a 37% aqueous solution of formaldehyde are subjected to Maraiich cyclization to obtain compound 8;

(f) compound 8 is alkylated with an alkylating reagent to give compound 9;

(g) compound 9 is hydrolyzed under acidic conditions to give compound 10;

(h) Alternatively, in a conventional manner, compound 8, 9 or 10 is reacted with an equivalent or an appropriate excess of the acid to obtain the corresponding salt; compound 8, 9 or 10 is recrystallized from a different solvent to give the corresponding crystalline hydrate, Solvate.

A method for producing a tetrahydroprotoberberine compound according to claim 1 or a pharmacologically acceptable inorganic or organic salt, crystalline hydrate or solvate thereof, wherein the reaction route is as follows:

, R ₂ , R ₃ , R ₅ and Re, as defined in claim 1,

The reaction steps are as follows:

(a) compound 24 is alkylated with an alkylating agent under the action of a base to give compound 25;

(b) compound 25 is obtained by the action of a nitrating reagent;

(c) compound 26 is condensed with compound 1 to give compound 27;

(d) compound 27 is condensed under appropriate conditions, and reduced to give compound 28;

(e) compound 28 is hydrolyzed under acidic conditions to give compound 13;

(f) compound 13 under suitable conditions catalytic hydrogenation reduction to give compound 23; (g) Alternatively, compound 28, 13 or 23 is reacted with an equivalent or an appropriate excess of the acid to obtain the corresponding salt in a conventional manner; Compound 28, 13 or 23 is recrystallized from a different solvent to give the corresponding crystalline hydrate, Solvate.

(S)-(-)-21 (R)-(+)-22 The reaction steps are as follows:

(a) Compound 8 is esterified with an acid chloride formed from a suitable chiral acid under the action of a base, and is isolated by HPLC to give compounds 15 and 16;

(b) Compounds 15 and 16 are reflux-hydrolyzed under basic conditions to give the corresponding compounds 17 and 18;

(c) Compounds 17 and 18 are methylated with a methylating reagent to give the corresponding compounds 19 and 20;

(d) Compounds 19 and 20 are hydrolyzed under acidic conditions to give the corresponding compounds 21 and 22;

(e) Alternatively, in a conventional manner, compounds 17-21 are reacted with an equivalent or an appropriate excess of the acid to obtain the corresponding salt; Compounds 17-21 are recrystallized from different solvents to give the corresponding crystalline hydrate, solvent. Things.

9. A compound represented by the following chemical formula:

(14S, 2'S)-15 (14R, 2'S)-16

A pharmaceutical composition comprising, as an active ingredient, the tetrahydroprotoberberine compound of claim 1 and a pharmacologically acceptable inorganic or organic salt thereof, a crystalline hydrate, a solvate thereof, and pharmaceutically acceptable Accessories.

11. Use of the tetrahydroprotoxin compound of claim 1 as a prodrug.

The use of the tetrahydroprotoberberine compound of claim 1 or a pharmacologically acceptable inorganic or organic salt, crystalline hydrate or solvate thereof for the manufacture of a medicament for the treatment of a nervous system disorder.

13. The use according to claim 12, wherein the neurological disease is a neurological disease associated with a dopamine receptor.