CN100528872C - Tetrahydro-proto-berberine compounds, their preparing method, composition and use - Google Patents

Tetrahydro-proto-berberine compounds, their preparing method, composition and use Download PDF

Info

Publication number
CN100528872C
CN100528872C CNB2006100293845A CN200610029384A CN100528872C CN 100528872 C CN100528872 C CN 100528872C CN B2006100293845 A CNB2006100293845 A CN B2006100293845A CN 200610029384 A CN200610029384 A CN 200610029384A CN 100528872 C CN100528872 C CN 100528872C
Authority
CN
China
Prior art keywords
compound
acid
proto
tetrahydro
berberines
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CNB2006100293845A
Other languages
Chinese (zh)
Other versions
CN1900075A (en
Inventor
杨玉社
丁宇
孙佩华
莫骄
金国章
嵇汝运
镇学初
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Priority to CNB2006100293845A priority Critical patent/CN100528872C/en
Publication of CN1900075A publication Critical patent/CN1900075A/en
Priority to PCT/CN2007/001734 priority patent/WO2008014661A1/en
Application granted granted Critical
Publication of CN100528872C publication Critical patent/CN100528872C/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Psychiatry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides tetrahydro protoberberine compounds as shown and their pharmaceutically acceptable inorganic or organic salts, crystallized hydrates, solvates and medicinal compositions. The present invention also provides their preparation process and application in preparing medicine for treating neurological diseases, especially dopamine acceptor related neurological diseases.

Description

Tetrahydro-proto-berberine compound, its preparation method and composition thereof and purposes
Technical field
The present invention relates to pharmaceutical chemistry and chemotherapy field, be specifically related to the synthetic of tetrahydro-proto-berberine compound and preparation treatment nervous system disorders medicine particularly with the application of Dopamine Receptors related neural systemic disease pharmaceutical field.
Background technology
Nervous system disorders is one of contemporary society's pandemic, however many nervous system disorderss effectively treated as yet clinically, particularly schizophrenia is a kind of serious mental disorder, its clinical treatment obtains satisfied the solution far away.In the last few years, neuroscientists use animal and patient's working memory operation [Working Memory Task] test and reflection pallium prefrontal lobe (PFC) function the short-term memory experiment [Castner, S.A.Science 2000,287:2020; Abi-Dargham, A.The J Neurosciences.2002,22,3708], and utilize positron emission tomography figure (PET) test clinically, proved the D of patient 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 the dopamine D in the inboard prefrontal cortex of brain (mPFC medical PrefrontalCortex) 1The function of receptors downward modulation, hypopallium district (Subcorticalregions) is as the dopamine D in midbrain ventral tegmental area (VTA, Ventral Tegmental 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 (Jin GZ.TiPS, 2002,23:4).
Reported first compound of Tetrahydro-proto-berberines class (THPBs) Stopholidines (l-SPD) such as Jin nation's chapter are first known D of having 1Excitement and D 2The lead drug of antagonism dual function (JinGZ.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, really has non-classical tranquilizer characteristic, might become a class novel anti schizophrenia drug.Chinese patent CN115318 discloses preparation method and use left-handed and the suitable suitability for industrialized production of dextrorotation chloro Si Kuli quinoline.Chinese patent CN1603324 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.
The invention provides compound of Tetrahydro-proto-berberines class, synthetic method and the purposes of a class formation novelty, this compounds has D1 excitement-D2 and blocks double pharmacological action, can be applicable to preparation treatment nervous system disorders medicine particularly with Dopamine Receptors related neural systemic disease pharmaceutical field.
Summary of the invention
One of purpose of the present invention provides as shown in the formula compound of Tetrahydro-proto-berberines class shown in (I) and pharmaceutically acceptable inorganic or organic salt thereof, crystalline hydrate, solvate and their pharmaceutical composition:
Figure C20061002938400101
(I)
In the formula (I)
R 1And R 3Represent the C of straight chain or side chain independently of one another 1-4Alkyl;
R 2And R 4Represent hydrogen independently of one another;
R 5Represent halogen, nitro or amino;
R 6Represent hydrogen;
The configuration of 14 carbon atoms can be R type, S type or raceme.
Another object of the present invention provides has compound of Tetrahydro-proto-berberines class shown in the above-mentioned formula (I) and pharmaceutically acceptable inorganic or organic salt thereof, the three kinds of preparation methods and their pharmaceutical composition of crystalline hydrate, solvate.
Another purpose of the present invention provides the application of the compound of Tetrahydro-proto-berberines class shown in the above-mentioned formula (I) as prodrug.
The present invention also provides has acceptable inorganic or organic salt on compound of Tetrahydro-proto-berberines class shown in the above-mentioned formula (I) and the pharmacology thereof, crystalline hydrate, solvate, prodrug and their pharmaceutical composition preparation treatment nervous system disorders medicine particularly with the application of Dopamine Receptors related neural systemic disease pharmaceutical field.
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, being that 14 alkyl is good with carbonatomss such as methyl, ethyl, propyl group, sec.-propyl, butyl, for better, is the best with methyl, ethyl with methyl, ethyl and propyl group.
The group that " aryl " expression has aromaticity is good with the aryl of 6-14 carbon atom, is in particular phenyl, tolyl, xylyl, xenyl, naphthyl, indenyl, anthryl, phenanthryl, and better is phenyl or naphthyl, the best be phenyl.
" alkyl of replacement ", " aryl of replacement ", " benzyl of replacement " represent respectively above-mentioned " alkyl ", " aryl ", " benzyl " can randomly be selected from halogen atom, alkyl, alkoxyl group, acyloxy ,-OH ,-NH 2, NO 2The group of ,-NHAc replaces.
" acceptable salt on the pharmacology " 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 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 acid, Phenylsulfonic acids, with salt that acidic amino acid became such as aspartic acid, L-glutamic acid.
In compound of Tetrahydro-proto-berberines class shown in the formula of the present invention (I) and the preparation intermediate thereof, representative compound is as follows:
1,3-methoxyl group-4-benzyloxy-ω-nitrostyrolene (1);
2,3-methoxyl group-4-benzyloxy-phenylethylamine (2);
3,2-chloro-4-benzyloxy-5-hydroxyl-toluylic acid (3);
4, N-(3 '-methoxyl group-4 '-benzyloxy styroyl)-2-chloro-4-benzyloxy-5-hydroxyl-phenylacetamide (4);
5, N-(3 '-methoxyl group-4 '-benzyloxy styroyl)-2-chloro-4-benzyloxy-5-methylamino ethoxy acyl-oxygen base-phenylacetamide (5);
6,1-(2 '-chloro-4 '-benzyloxy-5-methylamino ethoxy acyl-oxygen base) benzyl-6-methoxyl group-7-benzyloxy-3,4-dihydro-isoquinoline hydrochloride (6);
7,1-(2 '-chloro-4 '-benzyloxy-5-hydroxyl) benzyl-6-methoxyl group-7-benzyloxy-1,2,3,4-tetrahydroisoquinoline (7);
8, (±)-2,10-benzyloxy-3-methoxyl group-9-hydroxyl-12-chlorine Tetrahydro-proto-berberines (8);
9, (±)-2,10-benzyloxy-3,9-dimethoxy-12-chlorine Tetrahydro-proto-berberines (9);
10, (±)-2,10-dihydroxyl-3,9-dimethoxy-12-chlorine Tetrahydro-proto-berberines (10);
11, (±)-2,10-dihydroxyl-3,9-dimethoxy-12-bromine Tetrahydro-proto-berberines (11);
12, (±)-2,10-dihydroxyl-3,9-dimethoxy-12-fluorine Tetrahydro-proto-berberines (12);
13, (±)-2,10-dihydroxyl-3,9-dimethoxy-12-nitro Tetrahydro-proto-berberines (13);
14, (±)-2,10-dihydroxyl-3,9-dimethoxy Tetrahydro-proto-berberines (14);
15, (14S, 2 ' S)-2,10-benzyloxy-3-methoxyl group-9-(N-p-toluenesulfonyl pyrroles-2 '-formyl) Oxy-1 2-chlorine Tetrahydro-proto-berberines (15);
16, (14R, 2 ' S)-2,10-benzyloxy-3-methoxyl group-9-(N-p-toluenesulfonyl pyrroles-2 '-formyl) Oxy-1 2-chlorine Tetrahydro-proto-berberines (16);
17, (S)-(-)-2,10-benzyloxy-3-methoxyl group-9-hydroxyl-12-chlorine Tetrahydro-proto-berberines (17);
18, (R)-(+)-2,10-benzyloxy-3-methoxyl group-9-hydroxyl-12-chlorine Tetrahydro-proto-berberines (18);
19, (S)-(-)-2,10-benzyloxy-3,9-dimethoxy-12-chlorine Tetrahydro-proto-berberines (19);
20, (R)-(+)-2,10-benzyloxy-3,9-dimethoxy-12-chlorine Tetrahydro-proto-berberines (20);
21, (S)-(-)-2,10-dihydroxyl-3,9-dimethoxy-12-chlorine Tetrahydro-proto-berberines (21);
22, (R)-(+)-2,10-dihydroxyl-3,9-dimethoxy-12-chlorine Tetrahydro-proto-berberines (22);
23, (±)-2,10-dihydroxyl-3, the amino Tetrahydro-proto-berberines (23) of 9-dimethoxy-12-;
Compound of Tetrahydro-proto-berberines class shown in the formula according to the present invention (I) can prepare with following three kinds of reaction schemes.
Reaction scheme 1 is as follows:
Reagent and reaction conditions: a) HOSU, DCC, CH 2Cl 2, r.t.; B) Et 3N, benzene, ClCOOEt; C) POCl 3, benzene refluxes; D) NaBH 4, CH 3OH; E) 37%HCHO, H 2O, CH 3OH refluxes; F) THF, CH 2N 2, 3days; G) concentrated hydrochloric acid/ethanol refluxes;
Reaction scheme is one preparation method be described in detail as follows:
The preparation of compound 2: reference literature (a.A.I.Meyeres﹠amp; Joseph Guiles, Heterocycles, 1989,28 (1), 295-301.b.Paul W.Ford, Mathew R.Narbut, Jack Belli, and Bradley S.Davidson, J.Org.Chem., 1994,59 (20), 5955-5960) preparation.
The preparation of compound 3: reference literature (B Hegedus, Helv.Chim.Acta., 1963,46 (7), 2604-2612.) make.
The preparation of compound 4: be prepared into Acibenzolar with N-hydroxy-succinamide (NHS/HOSU) and toluylic acid compounds 3, be added dropwise to the productive rate (70-90%) that phenylethylamine 2 promptly can be good again and make amidated products 4.This method shows remarkable advantages in the preparation of this compounds, simple to operate, the reaction conditions gentleness, and product is used purifying hardly.The activation of compound 3 carboxyls also can be made other active ester or mixed acid anhydrides, the solvent that reaction is adopted is inert solvents such as methylene dichloride, chloroform, benzene, toluene, tetrahydrofuran (THF), dioxane, ether, temperature of reaction 0-100 ℃, reaction times 0.1-72 hour, thick product with methyl alcohol, ethanol, Virahol, ethyl acetate, chloroform, methylene dichloride, benzene, normal hexane or wherein two or more components by the mixed solvent recrystallization of suitable ratio composition.Optimum reaction conditions is in the methylene dichloride, room temperature reaction 0.1-24 hour, and thick product ethyl alcohol recrystallization;
The preparation of compound 5: compound 4 makes compound 5 through the protection to phenolic hydroxyl group.Reaction solvent can use inert solvents such as benzene, toluene, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, ether, preferably uses benzene, toluene.This reaction is generally carried out in the presence of acid acceptor, and the acid acceptor that is preferred for this reaction comprises mineral alkali such as sodium bicarbonate, yellow soda ash, salt of wormwood etc.; Organic bases such as triethylamine, diisopropylethylamine, pyridine, N, accelerine, N, N-dimethyl aminopyridine, 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene (DBU) etc.With ethanol, methyl alcohol, Virahol, ethyl acetate, chloroform, methylene dichloride, benzene, normal hexane or the mixed solvent recrystallization formed in suitable ratio of two or more components wherein, preferably use ethanol, methyl alcohol, ethyl acetate; Routine is used for can being easy to remove of organic chemistry filed and is difficult for any protecting group of the structure of decomposition goal compound after reaction, can be used as phenolic hydroxyl group protecting group suitable among this preparation method.The object lesson that can be used for the protecting group of this purpose comprises formyl radical, ethanoyl, trifluoroacetyl group, benzoyl, p-toluenesulfonyl, methoxycarbonyl, ethoxy carbonyl, isobutoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl is to methoxyl group benzyloxy base carbonyl etc.;
Compound 6 and 7 preparation: compound 5 condensation under suitable condition closes ring and can obtain compound 6, and condensing agent can be phosphorus oxychloride, tribromo oxygen phosphorus, Vanadium Pentoxide in FLAKES etc., and reaction solvent can be benzene, toluene, acetone, acetonitrile etc.Compound after the phenolic hydroxyl group protection can be removed protecting group by methods such as hydrolysis, solvolysis or reduction according to the relevant nature of protecting group, forms compound 7;
The preparation of compound 8: the hydrochloride of compound 7 and 37% formalin carry out the Mannich cyclization, make 8.The solvent that Mannich reaction is adopted is a methyl alcohol, ethanol, water or two kinds appropriate combination wherein, temperature of reaction from room temperature to reflux all can, optimum for refluxing.Recrystallization solvent with ethanol, methyl alcohol, Virahol, acetone, ethyl acetate, chloroform, methylene dichloride, benzene, toluene, normal hexane or wherein two or more components by the mixed solvent of suitable ratio composition;
Compound 9 and 10 preparation: obtain compound 9 after the conventional diazomethane methylating reagent of compound 8 usefulness methylates, back hydrolysis can obtain 10 under acidic conditions then, used acid can be the hydrochloric acid of suitable concentration, phosphoric acid, sulfuric acid, Glacial acetic acid, trifluoroacetic acid etc. in the reaction, solvent is ethanol, methyl alcohol, Virahol, acetone, water etc., and optimal conditions is concentrated hydrochloric acid and ethanol.
R 1, R 2, R 3, R 4, R 5And R 6, before the definition.
Reaction scheme two is described in detail as follows:
Figure C20061002938400171
Reagent and reaction conditions: a) Me 2SO 4, K 2CO 3, acetone; B) HNO 3(conc.), AcOH c) EtOH, reflux; D) i.POCl 3, benzene; Ii.NaBH 4, MeOH; E) conc.HCl-EtOH refluxes; F) Pd/C, H 2.
The preparation of compound 24: the reference literature method (J.Org.Chem., 1979,44 (3), 407-409)
The preparation of compound 25: 24 with conventional alkylating reagent methyl-sulfate, methyl iodide, diazomethane, trifluoromethane sulfonic acid methyl esters or other alkylating reagent etc., alkylation obtains 25 under the effect of organic bases or mineral alkali.Reaction solvent can be used methyl alcohol, acetone, and dioxane, ether, tetrahydrofuran (THF), methyl-sulphoxide, N, dinethylformamide, chloroform, methylene dichloride etc. preferably use acetone, methyl alcohol, tetrahydrofuran (THF).The mineral alkali that is used for this reaction can be a sodium hydroxide, potassium hydroxide, hydrated barta, potassium hydride KH, sodium hydride, potassium tert.-butoxide, salt of wormwood, yellow soda ash or the like, the organic bases that is used for this reaction can be a 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., preferred compound 24 methylate in salt of wormwood with methyl-sulfate and obtain compound 25;
The preparation of compound 26: 25 obtain nitration product 26 under the nitrating agent effect of routine.Temperature of reaction 0-40 ℃, reaction times 0.1-24 hour, nitration reagent can be the mixture etc. of mixture, iron nitrate, ethyl nitroacetate, concentrated nitric acid and Glacial acetic acid of mixture, Sodium Nitrite and the vitriol oil of mixture, saltpetre and the vitriol oil of different ratios mixture, different concns nitric acid, SODIUMNITRATE and the vitriol oil of the vitriol oil and concentrated nitric acid, and what be preferred for this reaction is the mixture of concentrated nitric acid and Glacial acetic acid;
The preparation of compound 27: compound 26 obtains 27 with compound 2 condensation reactions.Temperature of reaction 0-100 ℃, reaction times 0.1-48 hour.The solvent that reaction is adopted can use ethanol, methyl alcohol, acetonitrile, benzene, toluene, ethyl acetate, chloroform, methylene dichloride, acetone, tetrahydrofuran (THF) etc., preferably uses ethanol, benzene;
The preparation of compound 28: compound 27 condensation under suitable condition closes ring, can obtain compound 28 through reduction.Condensing agent can be phosphorus oxychloride, tribromo oxygen phosphorus, Vanadium Pentoxide in FLAKES etc., reaction solvent can be benzene, toluene, acetone, acetonitrile etc., reductive agent can be sodium borohydride, POTASSIUM BOROHYDRIDE etc., the solvent that reaction is adopted can use acetonitrile, benzene, toluene, ethyl acetate, chloroform, methylene dichloride, acetone, tetrahydrofuran (THF) etc., preferably uses benzene, toluene; The visible embodiment 28 of optimal conditions;
The preparation of compound 13: similar with the preparation method of compound 10, make compound 13;
The preparation of compound 23: compound 13 catalytic hydrogenation reduction under suitable condition obtains 23.The catalyzer of catalytic hydrogenation can be selected 10% or 5% palladium carbon or other catalyzer that contains palladium for use, or Raney-Ni, or other contains the catalyzer of palladium or nickel; Preferred catalyzer is 10% palladium carbon.Solvent can be selected the mixed solvent of methylene dichloride and low alkyl alcohol such as methyl alcohol, ethanol, Virahol etc., glacial acetic acid for use; Best is the mixed solvent or the glacial acetic acid of methyl alcohol and methylene dichloride.Reaction times all can from 0.1 hour to no longer absorbing hydrogen.Temperature of reaction from room temperature to 40 ℃ all can, room temperature preferably.Reaction pressure from normal pressure to tens normal atmosphere all can, optimum condition is a normal pressure.
Reaction scheme 3 preparation methods are (with R 5=Cl product is an example) be described in detail as follows:
Figure C20061002938400201
Reagent and reaction conditions: a) oxalyl chloride; NaOH, 4-butyl ammonium hydrogen sulfate, tetrahydrofuran (THF), HPLC splits; B) 20%KOH, EtOH; C) CH 2N 2, THF; D) HCl/EtOH refluxes
The preparation of compound 15 and compound 16: (±)-2; 10-benzyloxy-3-methoxyl group-9-hydroxyl-12-chloro-Tetrahydro-proto-berberines 8 becomes ester with the acyl chlorides that is generated by suitable chiral acid under the alkali effect; separate a pair of diastereomer (14S of generation through HPLC; 2 ' S)-2; 10-benzyloxy-3-methoxyl group-9-(N-p-toluenesulfonyl pyrroles-2 '-formyl) Oxy-1 2-chloro-Tetrahydro-proto-berberines 15 and (14R; 2 ' S)-2,10-benzyloxy-3-methoxyl group-9-(N-p-toluenesulfonyl pyrroles-2 '-formyl) Oxy-1 2-chloro-Tetrahydro-proto-berberines 16.Acid can be any suitable optically active organic acid that has, and this reacts preferred L-proline(Pro) and become ester with compound 8 under the effect of sodium hydroxide and phase-transfer catalyst 4-butyl ammonium hydrogen sulfate after the acidylate in sulfur oxychloride;
The preparation of compound 17 and compound 18: compound 15 and 16 back hydrolysis under alkaline condition can obtain (S)-(-)-2 accordingly, 10-benzyloxy-3-methoxyl group-9-hydroxyl-12-chloro-Tetrahydro-proto-berberines 17 and (R)-(+)-2,10-benzyloxy-3-methoxyl group-9-hydroxyl-12-chloro-Tetrahydro-proto-berberines 18, used alkali can be yellow soda ash, salt of wormwood, cesium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide etc. in the reaction, solvent is ethanol, methyl alcohol, Virahol, acetone, water etc., and optimal conditions is potassium hydroxide and ethanol;
The preparation of compound 19 and compound 20: the preparation method of compound 17 and 18 reference compounds 9 obtains (S)-(-)-2,10-benzyloxy-3,9-dimethoxy-12-chloro-Tetrahydro-proto-berberines 19 and (R)-(+)-2,10-benzyloxy-3,9-dimethoxy-12-chloro-Tetrahydro-proto-berberines 20;
The preparation of compound 21 and compound 22: (S)-(-)-2,10-benzyloxy-3,9-dimethoxy-12-chloro-Tetrahydro-proto-berberines 19 and (R)-(+)-2,10-benzyloxy-3, the preparation method of 9-dimethoxy-12-chloro-Tetrahydro-proto-berberines 20 reference compounds 10 obtains (S)-(-)-2,10-dihydroxyl-3,9-dimethoxy-12-chloro-Tetrahydro-proto-berberines 21 and (R)-(+)-2,10-dihydroxyl-3,9-dimethoxy-12-chloro-Tetrahydro-proto-berberines 22.
The structural formula of representative compounds sees Table 1.
Figure C20061002938400221
Figure C20061002938400231
Figure C20061002938400251
Pharmacology test
The present invention also provides the action characteristic of compound of Tetrahydro-proto-berberines class to dopamine D 1, D2 acceptor.
One. compound of Tetrahydro-proto-berberines class is measured the avidity of dopamine D 1, D2 acceptor:
1, test method: during D1 receptors bind competitive assay, with different concns (10 -5M～10 -11M) this series compound and positive control medicine (-)-SPD and radioactive ligand [3H] SCH23390 (D1-Selective) and the expressed D1 receptor protein of a certain amount of transfection insect cell (Sf9 cell) are added in the reaction tubes, after 60min is hatched in 30 ℃ of water-baths, put termination reaction in the ice.On Millipore cell sample collector, after process GF/C glass fiber filter paper filters and dries, place the 0.5ml test tube, add the 500ul liquid scintillation solution, counting is measured intensity of radioactivity.
D2 receptors bind competitive assay is the same, but the isotropic substance receptor-ligand uses [3H] Spiperone (D2-Selective).
2, test materials: acceptor makes up and cell culture material: intestinal bacteria E.coli.DH5 α bacterial strain; Insect viruses transfer vector pVL1393 plasmid; BaculoGold linearizing baculovirus DNA is available from PharMingen company; MkD1R cDNA; RD2R cDNA; Fall army worm isolated cells SF9 (Spodoptetra Frugiperda 9); Various restriction enzymes, Taq archaeal dna polymerase, T4 ligase enzyme etc. are available from TakaRa company; Plasmid purification, glue recovery, PCR product purification test kit are available from Shanghai China Shun Bioisystech Co., Ltd; The LB substratum; Insect cell substratum TNM-FH.
Receptors bind experiment material: isotropic substance aglucon [3H] SCH23390 (85.0Ci/mmol), [3H] Spiprone (77.0Ci/mmol) is available from Amersham company; (+) Butaclamol is available from RBI company; The GF/C glass fiber filter paper is available from Whatman company; Liquid scintillation solution.
Test-compound all earlier with the DMSO dissolving, is diluted to respective concentration (10 with distilled water then -5M～10 -11M), test-results sees Table 2.
Two. compound of Tetrahydro-proto-berberines class is to the mensuration of d1 dopamine receptor agonism characteristic, with the change of cAMP level as the index of medicine to the effect of DA receptor subtype.
Test method: the variation according to cAMP amount in the born of the same parents after the detection administration judges that compound of Tetrahydro-proto-berberines class is to the D1 receptor agonism, hatch the HEK293 cell 40min of stably express D1 acceptor with the serum-free medium that contains 100uM IBMX after, 37 ℃ of reactions of the different pharmaceutical 10min that adds various concentration, the 1M HClO of adding 100ul precooling 4,, add 20ul 2M K in 4 ℃ of termination reaction 1hr 2CO 3Neutralization reaction, the centrifugal 15min of 3000rpm abandons KClO 4Precipitation is got the detection that a certain amount of supernatant liquor is made cAMP.Positive control drug is Dopamine and l-SPD, and test-results sees Table 3.
Three. compound of Tetrahydro-proto-berberines class is to the mensuration of d2 dopamine receptor retardation characteristic:
Test method: each medicine dissolution is in the serum-free F12 training liquid that contains 100uM IBMX, behind the Chinese hamster ovary celI 10min of 37 ℃ of preincubate stably express D2 acceptors, add 10uMForskolin and 10uM Dopamine reaction 10min more simultaneously, add the 1MHClO of 100ul precooling 4,, add 20ul 2M K in 4 ℃ of termination reaction 1hr 2CO 3Neutralization reaction, the centrifugal 15min of 3000rpm abandons KClO 4Precipitation is got the detection that a certain amount of supernatant liquor is made cAMP.Positive control drug is Haloparidol and l-SPD, and test-results sees Table 4.
Table 2 part representative compounds is to the avidity measurement result of dopamine D 1, D2 acceptor
# represents that the maximum concentration of medicine does not have the obvious suppression effect yet
Table 3 part representative compounds is to the measurement result of d1 dopamine receptor agonism characteristic
The medicine numbering EC50(nM) ±SEM(nM) MAX STI *(％) ±SEM(％)
10 33.88 14.83 93.87 8.43
11 47.60 9.86 93.19 4.18
12 31.50 12.89 107.63 4.62
13 26.65 11.84 81.13 5.19
14 26.53 7.73 109.15 3.28
21 16.56 1.90 88.06 3.21
Dopamine 35.07 7.16 97.10 3.34
L-SPD 22.98 5.55 100.00 2.05
*Max Stimulation is the maximum value that produces cAMP behind the exciting D1 acceptor of this medicine, and data relay changes per-cent into, is 100% with L-SPD.
Table 4 part representative compounds is to the measurement result of d2 dopamine receptor retardation characteristic
The medicine numbering EC50±SEM
10 1.90±1.09uM
11 -
12 5.03±4.18uM
13 -
14 2.64±1.00uM
21 0.55±0.25uM
Haloparidol 7.33±1.80nM
L-SPD 4.38±1.18uM
As seen from the above, the compound of Tetrahydro-proto-berberines class of being tested has the avidity similar or stronger with L-SPD to dopamine D 1, D2 acceptor, and medicine L-SPD the strong 1-9 of avidity times to the D1 acceptor shone in 13,12,11,10,21 comparisons as compound.Particularly the retardation of 21 pairs of D2 acceptors of compound is stronger 9 times than L-SPD.The pharmacology test result shows that The compounds of this invention has the exciting and D2 retardance dual function of potent D1.So, the present invention also provide have acceptable inorganic or organic salt, crystalline hydrate, solvate and their pharmaceutical composition on compound of Tetrahydro-proto-berberines class shown in the above-mentioned formula (I) and the pharmacology thereof can be used for preparing treatment nervous system disorders medicine particularly with the medicine of Dopamine Receptors related neural systemic disease.
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 400MHz nmr determination; Optically-active is measured by Perkin-Elmer 241MC type or the automatic polarimeter of P-1030 (A012360639) type; Chemical shift is represented with δ (ppm); Separation is the 200-300 order with silica gel.
Embodiment 1:3-methoxyl group-4-benzyloxy-ω-nitrostyrolene (compound 1)
Reference literature (a.A.I.Meyeres﹠amp; Joseph Guiles, Heterocycles, 1989; 28 (1), 295-301.b.Paul W.Ford, Mathew R.Narbut; Jack Belli, and Bradley S.Davidson, J.Org.Chem.; 1994,59 (20), 5955-5960); from vanillin food grade,1000.000000ine mesh; with bromobenzyl, salt of wormwood refluxes in acetone and obtains the product of benzyl protection, and this product refluxes in Glacial acetic acid with Nitromethane 99Min., ammonium acetate and generates 3-methoxyl group-4-benzyloxy-ω-nitrostyrolene (1).M.P.117-119℃. 1HNMR(CDCl 3)：δ7.95(d，1H，J＝13.7Hz)，7.52(d，1H，J＝13.5Hz)，7.45-7.31(m，5H)，7.11-7.02(m，2H)，6.92(d，1H，J＝8.5Hz)，5.22(s，2H)，3.93(s，3H)。
Embodiment 2:3-methoxyl group-4-benzyloxy-phenylethylamine (compound 2)
Under the argon shield; (12.0g 0.32mol) is suspended in and anticipates in the anhydrous tetrahydrofuran (THF) (250ml) compound 1 (28.5g Lithium Aluminium Hydride; 0.10mol) be dissolved in anhydrous tetrahydrofuran (THF) (250ml); stir down, the latter is slowly splashed in the suspension liquid of front, the anti-backflow of a control speed is too violent; dropwising post-heating refluxed 2 hours; stir under room temperature and spend the night, the frozen water cooling is stirred and is slowly splashed into H down successively 2O (12ml), 15% sodium hydroxide solution (12ml), H 2O (36ml), the dregs that forms filters, filter cake is washed it repeatedly with acetone, filtrate decompression concentrates the back and dissolves with ether (100-150ml), wash diethyl ether solution after three times with the salt of wormwood drying, be evaporated to driedly, 188-196 ° of cut collected in vacuum (2mmHg) underpressure distillation, and the oily matter that obtains (19.0g) solidifies soon and is compound 2.Yield: 73.9%.mp 59-61℃；TLC Rf＝0.54(1∶4 MeOH∶CH 2Cl 2，I 2)； 1H NMR(CDCl 3)：δ7.42-7.27(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，J＝6.7Hz)，1.41(br，2H)。
Embodiment 3:2-chloro-4-benzyloxy-5-hydroxyl-toluylic acid (compound 3)
From 3, the 4-Dihydroxy benzaldehyde begin reference literature (B Hegedus, Helv.Chim.Acta., 1963,46 (7), 2604-2612.) make.mp 100-102℃； 1H NMR(CDCl 3)：δ7.42-7.36(m，5H)，6.90-6.87(m，2H)，6.74(dd，1H，J＝2.1，8.1Hz)，5.69(br，1H)，5.09(s，2H)，3.56(s，2H)。
Embodiment 4:N-(3 '-methoxyl group-4 '-benzyloxy styroyl)-2-chloro-4-benzyloxy-5-hydroxyl-benzene Ethanamide (compound 4)
Compound 3 (0.7g; 2.3mmol) be dissolved in methylene dichloride (25ml); under the nitrogen protection; to wherein adding N-hydroxy-succinamide (NHS/HOSu) (0.27g; 2.3mmol) and DCC (0.47g, 2.3mmol), stirring reaction 3 hours; generate the white casse thing; stopped reaction, filtering solids DCU drips in filtrate and is dissolved with compound 2 (0.63g; 2.3mmol) methylene dichloride (25ml) solution; continued stirring reaction 23 hours under the room temperature, it is inferior to give a baby a bath on the third day after its birth with 10% dilute hydrochloric acid and saturated sodium bicarbonate aqueous solution successively, the Anhydrous potassium carbonate drying; filtering and concentrating, ethyl alcohol recrystallization get compound 4 (0.85g).Yield: 61.6%.mp 130-132℃； 1HNMR(CDCl 3)：δ7.40-7.27(m，10H)，6.87(s，1H)，6.80(s，1H)，6.74(d，1H，J＝8.2Hz)，6.62(d，1H，J＝1.8Hz)，6.51(dd，1H，J＝1.8，8.2Hz)，5.37(br，1H)，5.08(s，2H)，5.04(s，2H)，3.81(s，3H)，3.51(s，2H)，3.43(dd，2H，J＝6.7，13.3Hz)，2.66(t，2H，J＝6.7Hz)。
Embodiment 5:N-(3 '-methoxyl group-4 '-benzyloxy styroyl)-2-chloro-4-benzyloxy-5-methylamino ethoxy Acyloxy-phenylacetamide (compound 5)
Compound 4 (0.65g, 1.2mmol) and triethylamine (0.25g 2.5mmol) is dissolved in the benzene (40ml) together, under 5-10 ℃, the dropping Vinyl chloroformate (0.3ml, 3.1mmol), stirring at room 2 hours, isolate the benzene layer, wash with water successively, 5% dilute hydrochloric acid is washed, washing, anhydrous sodium sulfate drying, the resistates of filtering and concentrating gets white crystal with ethyl alcohol recrystallization and is compound 5 (0.65g).Yield: 86.6%.mp 117-118℃；TLC Rf＝0.71(1∶2.5 Acetone∶PE)； 1HNMR(CDCl 3)：δ7.43-7.29(m，10H)，7.08(s，1H)，6.99(s，1H)，6.76(d，1H，J＝8.1Hz)，6.66(d，1H，J＝2.0Hz)，6.53(dd，1H，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＝6.9Hz)，1.30(t，3H，J＝7.2Hz)。
Embodiment 6: hydrochloric acid 1-(2 '-chloro-4 '-benzyloxy-5-methylamino ethoxy acyl-oxygen base) benzyl-6-methoxyl group -7-benzyloxy-3,4-dihydro-isoquinoline (compound 6)
Compound 5 (1.23g, 2mmol) be dissolved in the exsiccant benzene (9ml), add new phosphorus oxychloride (4ml) of steaming, be warming up to backflow, stirring reaction 2.5 hours, stopped reaction, the cooling back adds sherwood oil (100ml), and refrigeration is spent the night, remove liquid substance with tipping, the solid that is attached to bottle wall embathes three times with sherwood oil, with hot methanol (30ml) dissolving, separates out yellow particle in the storing, add ether again, (need 100ml approximately) till the dropping of ether no longer produces muddiness, when refrigerator cold-storage was some, the brilliant compound 6 (1.2g) that gets was assembled in filter.Yield: 94.7%.mp216-217℃(decomp.)； 1H NMR(CDCl 3)：δ7.33-7.29(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＝7.6Hz)，1.25(t，3H，J＝7.1Hz)。
Embodiment 7:1-(2 '-chloro-4 '-benzyloxy-5-hydroxyl) benzyl-6-methoxyl group-7-benzyloxy -1,2,3,4-tetrahydroisoquinoline (compound 7)
(1.32g 2mmol) is dissolved in methyl alcohol (60ml) to compound 6, and the frozen water cooling down, (0.75g 20mmol), is warming up to backflow slowly to add sodium borohydride, stirring reaction 2 hours removes solvent under reduced pressure, thin up, be neutralized to pH constant (about 6～7) with potassium dihydrogen phosphate, solids is with chloroform extraction, and extracting solution washing back anhydrous sodium sulfate drying filters, remove chloroform under reduced pressure, remaining pale solid is through column chromatography (MeOH: CH 2Cl 2=1: 20) purifying gets compound 7 (1.0g).Yield: 93.1%.mp 196-198℃(decomp.)； 1HNMR(DMSO-d6)：δ7.45-7.29(m，10H)，7.03(s，1H)，6.79(s，1H)，6.64(s，1H)，6.63(s，1H)，5.08(s，2H)，4.93(s，2H)，3.88(dd，1H，J＝4.2，9.4Hz)，3.71(s，3H)，3.03(m，1H)，2.93(dd，1H，J＝4.2，13.4Hz)，2.78-2.75(m，1H)，2.68(dd，1H，J＝9.4，13.4Hz)，2.59-2.57(m，2H)。
Embodiment 8:(±)-2,10-benzyloxy-3-methoxyl group-9-hydroxyl-12-chloro-Tetrahydro-proto-berberines (compound 8)
Compound 7 (0.3g, 5.8mmol) be suspended in chloroform (6ml), add appropriate hydrochloric acid-methanol solution, jolting makes the solid dissolving, decompression is spin-dried for solvent, and resistates is dissolved in methyl alcohol (13ml), adds 37% formalin (7ml), add entry (5ml) again, room temperature was placed two days, steamed and removed methyl alcohol, and resistates adds the sodium bicarbonate aqueous solution neutralization, with chloroform extraction three times, the saturated common salt washing, washing, anhydrous sodium sulfate drying, filtering and concentrating, resistates obtains clear crystal with recrystallizing methanol and is compound 8 (0.2g).Yield: 65.2%.mp 178-180℃； 1H NMR(CDCl 3)：δ7.48-7.28(m，10H)，6.88(s，1H)，6.80(s，1H)，6.66(s，1H)，5.62(br，1H)，5.16(dd，2H，J＝3.0Hz)，5.07(s，2H)，4.20(d，1H，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，1H，J＝10.6，16.5Hz)。
Embodiment 9:(±)-2,10-benzyloxy-3,9-dimethoxy-12-chloro-Tetrahydro-proto-berberines (is changed Compound 9)
Compound 8 (180mg, 0.34mmol) be dissolved in tetrahydrofuran (THF) (3ml), to the diazomethane diethyl ether solution that wherein drips prepared fresh (with the preparation of 2g nitrosomethylurea), room temperature was placed 3 days, carefully remove solvent and unnecessary reactant under reduced pressure, (EtOAc: PE=1: 4) separation obtains compound 9 (120mg) through column chromatography.Yield: 64.9%.mp 149-151℃； 1H NMR(00MHz，CDCl 3)：δ7.48-7.28(m，10H)，6.92(s，1H)，6.65(s，1H)，6.79(s，1H)，5.17(d，2H，J＝2.4Hz)，5.08(d，2H，J＝5.6Hz)，4.21(d，1H，J＝15.9Hz)，3.89(s，3H)，3.87(s，3H)，3.50-3.44(m，2H)，3.19-3.09(m，3H)，2.70-2.59(m，2H)，2.51(dd，1H，J＝11.3，16.6Hz)。
Embodiment 10:(±)-2,10-dihydroxyl-3,9-dimethoxy-12-chloro-Tetrahydro-proto-berberines (is changed Compound 10)
Concentrated hydrochloric acid (3ml) and ethanol (6ml) are mixed, to wherein add compound 9 (30mg, 0.055mmol), be warming up to backflow, stirring reaction is after 4 hours, stopped reaction, remove solvent and excess reactant, the ammoniacal liquor alkalization with 10%, solution becomes clarification, with ethyl acetate extraction 3 times, merge the organic phase washing, anhydrous sodium sulfate drying filters, remove solvent under reduced pressure, resistates is through column chromatography (CH 3OH: CH 2Cl 2=1: 80) purifying obtains 10 (10mg).Yield: 50.0%.mp 200℃(decomp.)； 1H NMR(CD 3OD)：δ6.82(s，1H)，6.77(s，1H)，6.68(s，1H)，4.17(d，1H，J＝15.7Hz)，3.82(s，3H)，3.80(s，3H)，3.53-3.49(m，2H)，3.38(dd，1H，J＝4.1，16.8Hz)，3.23-3.19(m，1H)，3.07-3.02(m，1H)，2.72-2.59(m，2H)，2.50(dd，1H，J＝10.4，16.8Hz).
Compound (11)-(14) make with similar approach:
Embodiment 11:(±)-2,10-dihydroxyl-3,9-dimethoxy-12-bromo-Tetrahydro-proto-berberines (is changed Compound 11)
Compound 11 is a white crystal, MP 200-202 ℃ (decomp.), 1H NMR (CD 3OD): δ 7.01 (s, 1H), 6.77 (s, 1H), 6.68 (s, 1H), 4.17 (d, 1H, J=15.9Hz), 3.83 (s, 3H), 3.81 (s, 3H), 3.53-3.47 (brm, 2H), 3.34 (dd, 1H, J=4.2,16.6Hz), 3.24-3.19 (m, 1H), 3.06 (m, 1H), 2.72-2.59 (m, 2H), 2.49 (dd, 1H, J=11.4,16.6Hz).
Embodiment 12:(±)-2,10-dihydroxyl-3,9-dimethoxy-12-fluoro-Tetrahydro-proto-berberines (is changed Compound 12)
Compound 12 is the grey crystal, MP 223-225 ℃ (decomp.), 1HNMR (DMSO-d 6): δ 9.62 (brs, 1H), 8.76 (s, 1H), 6.72 (s, 1H), 6.65 (s, 1H), 6.55 (d, 1H, J=10.6Hz), 4.05 (d, 1H, J=14.7Hz), 3.73 (s, 3H), 3.69 (s, 3H), 3.33 (brm, 2H), 3.20-3.10 (brm, 2H), 2.90 (brm, 1H), 2.62-2.43 (m, 2H), 2.30 (dd, 1H, J=11.7,14.8Hz).
Embodiment 13:(±)-2,10-dihydroxyl-3,9-dimethoxy-12-nitro-Tetrahydro-proto-berberines (compound 13)
The preparation method of compound 13 reference compounds 10 is from (±)-2,10-benzyloxy-3, and 9-dimethoxy-12-nitro-Tetrahydro-proto-berberines 28 obtains, yield:81.5%, MP＞200 ℃ (decomp.), 1H NMR (DMSO-d 6): δ 10.25 (brs, 1H), 8.77 (s, 1H), 7.51 (s, 1H), 6.71 (s, 1H), 6.66 (s, 1H), 4.10 (d, 1H, J=14.8Hz), 3.88 (s, 3H), 3.45 (s, 3H), 3.33 (brm, 3H), 3.09 (brm, 1H), 2.90 (brm, 1H), 2.71 (brm, 1H), 2.59 (brm, 1H), 2.44 (brm, 1H).
Embodiment 14:(±)-2,10-dihydroxyl-3,9-dimethoxy-Tetrahydro-proto-berberines (compound 14)
Compound 14 is a white crystal, MP 129-131 ℃ (decomp.), 1HNMR (DMSO-d 6): δ 9.13 (s, 1H), 8.73 (s, 1H), 6.70 (m, 3H), 6.64 (s, 1H), 4.06 (d, 1H, J=15.7Hz), 3.73 (s, 3H), 3.71 (s, 3H), 3.40 (brm, 3H), 3.17 (m, 2H), 2.90 (m, 1H), 2.55 (m, 2H).
Embodiment 15 and 16:(14S, 2 ' S)-2, (N-is to toluene sulphur for 10-benzyloxy-3-methoxyl group-9- Acyl pyrroline-2 '-formyl) Oxy-1 2-chloro-Tetrahydro-proto-berberines (compound 15) and (14R, 2 ' S)- 2,10-benzyloxy-3-methoxyl group-9-(N-p-toluenesulfonyl pyrroles-2 '-formyl) Oxy-1 2-chloro- Tetrahydro-proto-berberines (compound 16)
(150mg 0.56mmol) is dissolved in methylene dichloride (10ml) to the L-proline(Pro), and ice bath drips oxalyl chloride (5ml) down, and stirring is spent the night, and is evaporated to the dried acyl chlorides that obtains, to wherein adding tetrahydrofuran (THF) (3ml); Compound 8 (260mg, 0.5mmol), sodium hydroxide powder (50mg, 1.25mmol) and 4-butyl ammonium hydrogen sulfate (0.6mg) be dissolved in tetrahydrofuran (THF) (5ml) together, following aforementioned solution of room temperature is added in the solution of back (about 0.5 hour), continue to stir 2.5 hours, the TLC monitoring reaction finishes, and helps filter with silica gel, and filtrate concentrates back column chromatography (CH 2Cl 2: EtOAc=10: 1) oily matter is a pair of diastereomer (-)-(14S, 2 ' S)-15 and (-)-(14R, 2 ' S)-16.
(-)-(14S，2′S)-15：
[α] D 25＝-85.2°(c＝0.1，CH 3CN)
1H NMR(CHCl 3)：δ7.78-7.74(m，2H)，7.42-7.29(m，12H)，7.00(s，1H)，6.76(s，1H)，6.65(s，1H)，5.18(d，2H，J＝3.3Hz)，5.01(s，2H)，4.10(d，1H，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：
[α] D 25＝-89.1°(c＝0.1，CH 3CN)
1H NMR(CHCl 3)：δ7.79(d，2H，J＝8.4Hz)，7.46(d，2H，J＝8.4Hz)，7.42-7.25(m，10H)，6.96(s，1H)，6.79(s，1H)，6.68(s，1H)，5.22(d，2H，J＝3.4Hz)，4.98(s，2H)，4.10(d，1H，J＝15.8Hz)，3.94(s，3H)，3.20-3.45(m，6H)，2.70-2.84(m，3H)，2.69(m，3H)，2.44(s，3H)，1.93-2.10(m，3H)。
Embodiment 17:(S)-(-)-2,10-benzyloxy-3-methoxyl group-9-hydroxyl-12-chloro-tetrahydrochysene is former little Bark of a cork tree alkali (compound 17)
Compound 15 (21mg) is dissolved in 1: 1 20% potassium hydroxide and alcohol mixeding liquid (5ml), reflux and stirred 4 hours, stopped reaction, after the conventional processing, column chromatography (EtOAc: PE=1: 4) compound (S)-17 (8mg).mp 127-130℃；[α] D 25＝-130°(c＝0.12，CH 3CN)； 1H NMR(CHCl 3)：δ7.48-7.28(m，10H)，6.88(s，1H)，6.79(s，1H)，6.66(s，1H)，5.62(br，1H)，5.16(d，2H，J＝2.9Hz)，5.06(s，2H)，4.20(d，1H，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)，2.51(m，1H)。
Embodiment 18:(R)-(+)-2,10-benzyloxy-3-methoxyl group-9-hydroxyl-12-chloro-tetrahydrochysene is former little Bark of a cork tree alkali (compound 18)
Compound 16 is a raw material, prepares compound 18 with the method that is similar to compound 17.mp 128-129℃；[α] D 25＝+130°(c＝0.12，CH 3CN)； 1H NMRCHCl 3)：δ7.48-7.28(m，10H)，6.87(s，1H)，6.80(s，1H)，6.64(s，1H)，5.66(br，1H)，5.16(d，2H，J＝2.7Hz)，5.06(s，2H)，4.20(d，1H，J＝15.8Hz)，3.88(s，3H)，3.48-3.43(m，2H)，3.22-3.09(m，3H)，2.69-2.60(m，2H)，2.51(m，1H)。
Embodiment 19:(S)-(-)-2,10-benzyloxy-3, the 9-dimethoxy-former barberry of 12-chloro-tetrahydrochysene Alkali (compound 19)
Compound 17 is a raw material, prepares compound 19 with the method that is similar to compound 9.m.p.113-115℃；[α] D 25＝-149°(c＝0.08，CH 3CN)； 1H NMRCHCl 3)：δ7.48-7.28(m，10H)，6.92(s，1H)，6.79(s，1H)，6.64(s，1H)，5.17(d，2H，J＝3.0Hz)，5.07(s，2H)，4.21(d，1H，J＝15.8Hz)，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)，2.51(m，1H)。
Embodiment 20:(R)-(+)-2,10-benzyloxy-3, the 9-dimethoxy-former barberry of 12-chloro-tetrahydrochysene Alkali (compound 20)
Compound 18 is a raw material, prepares compound 20 with the method that is similar to compound 9.m.p.114-115℃；[α] D 25＝+131°(c＝0.08，CH 3CN)； 1H NMR(CHCl 3)：δ7.48-7.28(m，10H)，6.92(s，1H)，6.79(s，1H)，6.64(s，1H)，5.17(d，2H，J＝2.9Hz)，5.07(s，2H)，4.22(d，1H，J＝15.8Hz)，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)，2.51(m，1H)。
Embodiment 21:(S)-(-)-2,10-dihydroxyl-3,9-dimethoxy-12-chloro-Tetrahydro-proto-berberines (compound 21)
Compound 19 is a raw material, prepares compound 21 with the method that is similar to compound 10.m.p.166℃(decomp.)；[α] D 25＝-287°(c＝0.090，CH 3OH)； 1HNMR(CD 3OD)：δ6.82(s，1H)，6.76(s，1H)，6.68(s，1H)，4.17(d，1H，J＝15.7Hz)，3.82(s，3H)，3.80(s，3H)，3.53-3.49(m，2H)，3.38(dd，1H，J＝4.1，16.8Hz)，3.23-3.19(m，1H)，3.07-3.02(m，1H)，2.72-2.59(m，2H)，2.51(dd，1H，J＝10.4，16.8Hz)。
Embodiment 22:(R)-(+)-2,10-dihydroxyl-3,9-dimethoxy-12-chloro-Tetrahydro-proto-berberines (compound 22)
Compound 20 is a raw material, prepares compound 22 with the method that is similar to compound 10.m.p.166℃(decomp.)；[α] D 25＝+285°(c＝0.095，CH 3OH)； 1HNMR(CD 3OD)：δ6.82(s，1H)，6.77(s，1H)，6.68(s，1H)，4.17(d，1H，J＝15.8Hz)，3.82(s，3H)，3.80(s，3H)，3.53-3.50(m，2H)，3.38(dd，1H，J＝4.1，16.8Hz)，3.23-3.19(m，1H)，3.07-3.03(m，1H)，2.72-2.59(m，2H)，2.50(dd，1H，J＝10.4，16.8Hz)。
Embodiment 23:(±)-2,10-dihydroxyl-3,9-dimethoxy-12-amino-Tetrahydro-proto-berberines (compound 23)
Under the room temperature, compound 13 is dissolved in the Glacial acetic acid, after normal pressure under 5% the Pd-C catalysis is inhaled hydrogen reduction, through routine handle get final product compound 23.Yield: 94.5%.mp127-130℃(decomp.)； 1HNMR(CD 3OD)：δ6.83(s，1H)，6.70(s，1H)，6.28(s，1H)，4.30(d，1H，J＝15.4Hz)，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＝1.7，16.1Hz)，1.94(s，2H)。
Embodiment 24:7-benzyloxy-8-methoxyl group-3-oxo-isochroman (compound 25)
7-benzyloxy-8-hydroxyl-3-oxo-isochroman 24[J.Org.Chem., 1978,43 (10), 1992] (2.7g, 10mmol) (2.8g 20mmol) is mixed together in acetone (100ml) with the Anhydrous potassium carbonate powder, (2ml 20mmol), is warming up to backflow to drip methyl-sulfate, stirring reaction 6 hours, stopped reaction, cooled and filtered, filter cake is with the acetone thorough washing, be concentrated into dried, resistates column chromatography (EtOAc: PE=1: 6) obtain colorless oil 25 (2.7g).Yield: 95.1%; 1H NMR (CDCl 3): δ 7.45-7.34 (m, 5H), 6.93 (d, 1H, J=8.2Hz), 6.85 (d, 1H, J=8.2Hz), 5.40 (s, 2H), 5.12 (s, 2H), 3.91 (s, 3H), 3.62 (s, 2H).
Embodiment 25:5-nitro-7-benzyloxy-8-methoxyl group-3-oxo-isochroman (is changed Compound 26)
7-benzyloxy-8-methoxyl group-3-oxo-isochroman 25 (1.4g, 5mmol) be dissolved in the Glacial acetic acid (30ml), be cooled to when just not solidifying,, fully stir to wherein dripping concentrated nitric acid (5ml), rose to stirring at room 1 hour, pour in the frozen water (200ml) after reaction finishes, solids is washed organic phase with ethyl acetate extraction, dry concentrating, (EtOAc: PE=1: 6) purifying obtains compound 26 (1.46g) to column chromatography.Yield: 98.7%.mp 132-134℃； 1HNMR(400MHz，CDCl 3)：δ7.79(s，1H)，7.40(m，5H)，5.42(s，2H)，5.19(s，2H)，4.14(s，2H)，4.04(s，3H)。
Embodiment 26:N-(3 '-methoxyl group-4 '-benzyloxy styroyl)-2-nitro-4-benzyloxy-5-hydroxyl Base-6-methylol-phenylacetamide (compound 27)
5-nitro-7-benzyloxy-8-methoxyl group-3-oxo-isochroman 26 (329mg, 1mmol) with 3-methoxyl group-4-benzyloxy-phenylethylamine 2 (0.51g, 2mmol) be dissolved in the ethanol (25ml), be warming up to backflow, stirring reaction 20 hours, stopped reaction, remove solvent under reduced pressure, resistates dissolves with methylene dichloride, successively with 1N hydrochloric acid and twice of washing, anhydrous sodium sulfate drying, (Acetone: PE=1: 4) purifying obtains compound 27 (576mg) with ethanol-sherwood oil recrystallization or column chromatography after the filtering and concentrating.Yield: 98.4%.mp 95-98℃； 1H-NMR(CDCl 3)：δ7.61(s，1H)，7.45-7.30(m，10H)，6.81(d，1H，J＝8.1Hz)，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＝7.0Hz)。
Embodiment 27:(±)-2,10-benzyloxy base-3, the 9-dimethoxy-former barberry of 12-nitro-tetrahydrochysene Alkali (compound 28)
Compound 27 (2g; 3.4mmol) be dissolved in the dry toluene (15ml); add the new phosphorus oxychloride (3.3ml that steams; 45mmol); under the nitrogen protection, be warming up to backflow, stirring reaction 3 hours; stopped reaction; steaming desolventizes, and resistates is dissolved in methyl alcohol (50ml), and the ice bath cooling carefully adds sodium borohydride (2.8g down in batches; 74mmol); stirring reaction spends the night under the room temperature then, after reacting completely, adds entry (20ml) cancellation; stir after 30 minutes again toward wherein pouring water (100ml) into; with dichloromethane extraction several times, anhydrous sodium sulfate drying, filtering and concentrating; (Acetone: PE=1: 4) separation and purification obtains compound 28 (0.9g), yield: 47.8% to column chromatography.mp 132-134℃(decomp.)； 1H NMR(CDCl 3)：δ7.71(s，1H)，7.48-7.31(m，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，2H)，3.21-3.04(brm，4H)，2.75-2.60(m，2H)。

Claims (10)

1, acceptable inorganic or organic salt on the compound of Tetrahydro-proto-berberines class shown in the class formula (I) or its pharmacology,
Figure C2006100293840002C1
Wherein, R 1And R 3Represent the C of straight chain or side chain independently of one another 1-4Alkyl;
R 2And R 4Represent hydrogen independently of one another;
R 5Represent halogen, nitro or amino;
R 6Represent hydrogen;
The configuration of 14 carbon atoms is R type, S type or raceme.
2, according to acceptable inorganic or organic salt on the compound of Tetrahydro-proto-berberines class of claim 1 or its pharmacology, acceptable salt is the salt that the compound of Tetrahydro-proto-berberines class shown in the formula (I) 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, Phenylsulfonic acid, aspartic acid or L-glutamic acid on the wherein said pharmacology.
3, according to acceptable inorganic or organic salt on the compound of Tetrahydro-proto-berberines class of claim 1 or its pharmacology, wherein said compound is selected from one of following compounds:
(±)-2,10-dihydroxyl-3,9-dimethoxy-12-chlorine Tetrahydro-proto-berberines;
(±)-2,10-dihydroxyl-3,9-dimethoxy-12-nitro Tetrahydro-proto-berberines;
(±)-2,10-dihydroxyl-3, the amino Tetrahydro-proto-berberines of 9-dimethoxy-12-;
(S)-(-)-2,10-dihydroxyl-3,9-dimethoxy-12-chlorine Tetrahydro-proto-berberines;
(R)-(+)-2,10-dihydroxyl-3,9-dimethoxy-12-chlorine Tetrahydro-proto-berberines;
(±)-2,10-dihydroxyl-3,9-dimethoxy-12-bromine Tetrahydro-proto-berberines; With
(±)-2,10-dihydroxyl-3,9-dimethoxy-12-fluorine Tetrahydro-proto-berberines.
4, the preparation method of acceptable inorganic or organic salt on a kind of compound of Tetrahydro-proto-berberines class of claim 1 or its pharmacology, reaction scheme is as follows:
Figure C2006100293840003C1
R 1, R 2, R 3, R 4, R 5And R 6, define as claim 1,
Reactions steps is as follows:
(a) compound 3 is made Acibenzolar, generate 4 with 2 reactions then;
(b) compound 4 makes compound 5 through the protection to phenolic hydroxyl group;
(c) compound 5 under proper condition condensation close ring and obtain compound 6;
(d) according to the character of protecting group, protecting group is removed, formed compound 7 by hydrolysis, solvolysis or reduction;
(e) hydrochloride of compound 7 and 37% formalin carry out the Mannich cyclization, make compound 8;
(f) compound 8 usefulness alkylating reagents carry out obtaining compound 9 behind the alkanisation;
(g) compound 9 recirculation water under acidic conditions solves compound 10;
(h) selectively, according to a conventional method, compound 8,9 or 10 and equivalent or suitably excessive acid-respons obtain corresponding salt.
5, the preparation method of acceptable inorganic or organic salt on a kind of compound of Tetrahydro-proto-berberines class of claim 1 or its pharmacology, reaction scheme is as follows:
Figure C2006100293840005C1
R 1, R 2, R 3, R 4And R 6Define as claim 1 R 5Be nitro or amino, reactions steps is as follows:
(a) compound 24 usefulness alkylating reagents alkanisation under the alkali effect obtains compound 25;
(b) compound 25 obtains compound 26 under the nitrating agent effect;
(c) compound 26 obtains compound 27 with compound 2 condensations;
(d) compound 27 encircles the condensation pass under proper condition, obtains compound 28 through reduction;
(e) compound 28 recirculation water under acidic conditions solves compound 13;
(f) compound 13 under proper condition catalytic hydrogenation reduction obtain compound 23;
(g) selectively, according to a conventional method, compound 28,13 or 23 and equivalent or suitably excessive acid-respons obtain corresponding salt.
6, the preparation method of acceptable inorganic or organic salt on a kind of compound of Tetrahydro-proto-berberines class of claim 1 or its pharmacology, reaction scheme is as follows:
Figure C2006100293840006C1
Reactions steps is as follows:
(a) compound 8 becomes ester with the acyl chlorides that is generated by suitable chiral acid under the alkali effect, separates obtaining compound 15 and 16 through HPLC;
(b) compound 15 and 16 recirculation water under alkaline condition solves corresponding compounds 17 and 18;
(c) obtain corresponding compounds 19 and 20 after compound 17 and 18 usefulness methylating reagents methylate;
(d) compound 19 and 20 recirculation water under acidic conditions solves corresponding compounds 21 and 22;
(e) selectively, according to a conventional method, compound 17～21 and equivalent or suitable excessive acid-respons obtain corresponding salt.
7, with the compound of following chemical formulation:
Figure C2006100293840007C1
8, a kind of pharmaceutical composition comprises as acceptable inorganic or organic salt on the compound of Tetrahydro-proto-berberines class of the claim 1 of activeconstituents or its pharmacology, and acceptable accessories.
9, the acceptable inorganic or application of organic salt in preparation treatment nervous system disorders medicine on the compound of Tetrahydro-proto-berberines class of claim 1 or its pharmacology.
10, application according to claim 9, wherein said nervous system disorders are the nervous system disorders relevant with Dopamine Receptors.
CNB2006100293845A 2006-07-26 2006-07-26 Tetrahydro-proto-berberine compounds, their preparing method, composition and use Expired - Fee Related CN100528872C (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CNB2006100293845A CN100528872C (en) 2006-07-26 2006-07-26 Tetrahydro-proto-berberine compounds, their preparing method, composition and use
PCT/CN2007/001734 WO2008014661A1 (en) 2006-07-26 2007-05-29 Tetrahydroprotoberberine compounds, their manufacture, medicinal composition and uses.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CNB2006100293845A CN100528872C (en) 2006-07-26 2006-07-26 Tetrahydro-proto-berberine compounds, their preparing method, composition and use

Publications (2)

Publication Number Publication Date
CN1900075A CN1900075A (en) 2007-01-24
CN100528872C true CN100528872C (en) 2009-08-19

Family

ID=37656093

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB2006100293845A Expired - Fee Related CN100528872C (en) 2006-07-26 2006-07-26 Tetrahydro-proto-berberine compounds, their preparing method, composition and use

Country Status (2)

Country Link
CN (1) CN100528872C (en)
WO (1) WO2008014661A1 (en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100528872C (en) * 2006-07-26 2009-08-19 中国科学院上海药物研究所 Tetrahydro-proto-berberine compounds, their preparing method, composition and use
CN101037436B (en) * 2007-04-18 2010-08-11 中国科学院上海药物研究所 L-stepholidine (l-SPD) derivatives, preparation method and usage thereof
CN101921229B (en) * 2009-06-17 2012-08-08 中国科学院上海药物研究所 Synthesis method of stepholidine or derivative optical isomer thereof and intermediate thereof
CN102234276B (en) * 2010-04-28 2013-04-17 中国科学院上海药物研究所 Preparation method of optical isomer of stepholidine or its derivative and intermediate used in the method
CN102796096B (en) * 2011-05-27 2016-09-14 中国科学院上海药物研究所 Hexahydro dibenzo [a, g] quinolizine compounds, its preparation method, pharmaceutical composition and application thereof
US9526721B2 (en) * 2011-08-05 2016-12-27 James Jackson MILLER Tetrahydroprotoberbine compounds and uses thereof in the treatment of neurological, psychiatric and neurodegenerative diseases
CN103387583B (en) 2012-05-09 2018-04-13 中国科学院上海药物研究所 Diaryl simultaneously [a, g] quinolizine class compound, its preparation method, pharmaceutical composition and its application
JP6733449B2 (en) * 2016-09-15 2020-07-29 株式会社ツムラ Method for producing berberine alkaloid
CN109384780B (en) * 2017-08-14 2022-04-08 中国科学院上海药物研究所 Tetrahydro-protoberberine compounds, preparation method, application and pharmaceutical composition thereof
CN115260185A (en) * 2022-08-02 2022-11-01 杨征 Deuterated derivatives of corydaline and stepholidine and preparation method thereof
CN115477647A (en) * 2022-10-26 2022-12-16 山西医科大学 Berberine fumarate crystal form, preparation method, composition and application thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1045442C (en) * 1994-07-20 1999-10-06 中国科学院上海药物研究所 Levo- and dextro-rotary chloroscouriline (tetrahydroprotoberberines) and application thereof
CN100345848C (en) * 2003-09-29 2007-10-31 中国科学院上海药物研究所 Leavo halogenated salt and its preparation process and use
CN1900076B (en) * 2005-07-08 2011-06-22 中国科学院上海药物研究所 Tetrahydro proto-berberine compounds, and their preparing method and use
CN100528872C (en) * 2006-07-26 2009-08-19 中国科学院上海药物研究所 Tetrahydro-proto-berberine compounds, their preparing method, composition and use

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
a chemical genetic screen identifies inhibitors ofregulatednuclear export of a forkhead transcription factorinpten-deficient tumor cells. tweeny et al.cancer cell,Vol.4 No.6. 2003
a chemical genetic screen identifies inhibitors ofregulatednuclear export of a forkhead transcription factorinpten-deficient tumor cells. tweeny et al.cancer cell,Vol.4 No.6. 2003 *
characteristics of tetrahydroprotoberberines on dopamineD1and D2 receptors in calf striatum. guo，xiang，et，al.中国药理学报，第18卷第3期. 1997
characteristics of tetrahydroprotoberberines on dopamineD1and D2 receptors in calf striatum. guo,xiang,et,al.中国药理学报，第18卷第3期. 1997 *
protoberberine alkaloids. structuresofaequaline,coramine,discretinine, and schefferine. einar brochmann hanssen et al.J. Org. Chem.,Vol.42 No.22. 1977
protoberberine alkaloids. structuresofaequaline,coramine,discretinine,and schefferine. einar brochmann hanssen et al.J.Org.Chem.,Vol.42 No.22. 1977 *
protopine alkaloids in horse urine. paul m wynne et al.J. charomatography B,Vol.811 . 2004
racemic2,10-dibenzyloxy-12-chloro-3,9-dimethoxy-5,8,13,13a-tetrahydro-6H-dibenzo[a,g]quinolizine. yu ding et al.acta cryst.,Vol.E61 . 2005
synthesis of stepholidine. rajeswari et al.collection czechoslov.chem. commun.,Vol.42 . 1977
the alkaloids of stephania glabra. a direct chemicalcorrelationof the absolute configuration ofsomebenzyltetrahydroisoquinoline,proaporphine, andaporphinealkaloids. anew protoberberine alkaloid. cava et al.J. org. Chem.,Vol.33 No.7. 1968
total synthesis of discretamine andstepholidine. einar brochmann hanssen et al.J. Org. Chem.,Vol.42 No.19. 1977

Also Published As

Publication number Publication date
WO2008014661A1 (en) 2008-02-07
CN1900075A (en) 2007-01-24

Similar Documents

Publication Publication Date Title
CN100528872C (en) Tetrahydro-proto-berberine compounds, their preparing method, composition and use
AU2018232071B2 (en) Hepatitis B virus surface antigen inhibitor
ES2948192T3 (en) Heteroaromatic compounds and their use as dopamine D1 ligands
JP5746219B2 (en) 5-Alkynyl-pyrimidine
CA2762680C (en) Methyl sulfanyl pyrmidmes useful as antiinflammatories, analgesics, and antiepileptics
CA2908098A1 (en) Mk2 inhibitors and uses thereof
KR20170063590A (en) Novel compounds
CN105518005A (en) Tricyclic pyrido-carboxamide derivatives as ROCK inhibitors
CA2942522A1 (en) 5,5-dioxo-11h-benzo[c][2,1]benzothiazepine derivatives and their use as mu-opioid receptor agonists
AU2017208119B2 (en) 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine dopamine D3 ligands
BR112019026955A2 (en) dihydro-pyrrole-pyridine derivatives
JP2020530483A (en) Tetrahydroprotoberberine compound, its production method, use and pharmaceutical composition
CN104411696A (en) Cyclohexane-1,2'-naphthalene-1',2"-imidazole compounds and their use as BACE inhibitors
CN103923079A (en) Preparation method of apixaban intermediate
CA3188104A1 (en) Compositions for modulating splicing
CN101870696B (en) N-aryl piperazine derivative having double activity of dopamine D2 and 5-HT2a
CA2872883A1 (en) Heteroaryl compounds and methods of use thereof
JP7051855B2 (en) Protein kinase regulator
JP5940729B2 (en) Diallylo [a, g] quinolizine compound, process for producing the same, pharmaceutical composition and application thereof
Hussenether et al. Synthesis of 5‐phenyl‐5, 6, 7, 8‐tetrahydro‐1, 6‐naphthyridines and 5‐phenyl‐6, 7, 8, 9‐tetrahydro‐5H‐pyrido [3, 2‐c] azepines as potential D1 receptor ligands
TW202241413A (en) Pyrazoloquinazoline compound, and preparation method therefor and use thereof
KR20040034996A (en) Improved method for the preparation of risperidone
RU2330020C2 (en) NEW DERIVATIVES OF AMINOPYRIDINE AS ANTAGONISTS mGIuR5
IE883136L (en) Ó(2)-adreno receptor antagonists
PL184412B1 (en) Novel derivatives of oxazoloquinolinone, method of obtaining them and pharmaceutic preparation containing such derivatives

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20090819

Termination date: 20110726