[go: up one dir, main page]

WO2008014661A1 - Composés de tétrahydroprotoberbérine, leur production, leur composition médicinale et leurs utilisations - Google Patents

Composés de tétrahydroprotoberbérine, leur production, leur composition médicinale et leurs utilisations Download PDF

Info

Publication number
WO2008014661A1
WO2008014661A1 PCT/CN2007/001734 CN2007001734W WO2008014661A1 WO 2008014661 A1 WO2008014661 A1 WO 2008014661A1 CN 2007001734 W CN2007001734 W CN 2007001734W WO 2008014661 A1 WO2008014661 A1 WO 2008014661A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
acid
group
tetrahydroprotoberberine
give
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.)
Ceased
Application number
PCT/CN2007/001734
Other languages
English (en)
Chinese (zh)
Inventor
Yushe Yang
Yu Ding
Peihua Sun
Jiao Mo
Guozhang Jin
Ruyun Ji
Xuechu Zhen
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
Publication of WO2008014661A1 publication Critical patent/WO2008014661A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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

Definitions

  • 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.
  • 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.
  • 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:
  • 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;
  • 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 ⁇ means a saturated or unsaturated, substituted or unsubstituted linear, branched alkane chain, specifically exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • reaction route 2 is described in detail as follows:
  • 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.
  • 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.
  • the reaction solvent may be benzene, toluene, acetone, acetonitrile, etc.
  • 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.
  • 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
  • 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
  • the present invention also provides the action characteristics of tetrahydroprotoberberine-like compounds on dopamine D1, D2 receptors.
  • Test method In the D1 receptor binding competition experiment, different concentrations (10_ 5 M ⁇ 10- ⁇ ⁇ ) 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
  • 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 ( ⁇ 5 ⁇ 10- ⁇ ⁇ ), 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.
  • 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.
  • the positive control drugs are Haloparidol and /-SPD, the test results are shown in Table 4. Table 2 Determination of the affinity of some
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ (ppm); silica gels for separation are both 200-300 mesh.
  • Example 1 3-Methane-4-benzyloxy- ⁇ -nitrostyrene compound 1) References (a. AIMeyeres & Joseph Guiles, Heterocycles, 1989, 28(1), 295-301. b.Paul W. Ford, Mathew R.
  • Example 3 2-Chloro-4-benzyloxy-5-hydroxy-phenylacetic acid (Compound 3) Starting from 3,4-dihydroxybenzaldehyde (B Hegedus, Helv. Chim. Acta., 1963, 46 (7), 2604-2612.). Mp 100-102 ° C; 3 ⁇ 4 NMR (CDC1 3 ): ' ⁇ ' ⁇ )9 '9 '(HI ' s )66'9 '( ⁇ 's)80 '(HOI ⁇ )6Z'L-£VL9 : ( ⁇ ⁇ )3 ⁇ 4] ⁇ [ ⁇ [ ⁇
  • 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.
  • 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.
  • 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).
  • Example 9 ( ⁇ V2,10-dibenzyloxy-3,9-dimethoxy-12-chloro-tetrahydroprotoberberine (Compound 9)
  • Compound 8 180 mg, 0.34 mmol
  • tetrahydrofuran 3 ml
  • diazomethane ether solution prepared with 2 g of nitrosomethylurea
  • Compound 9 120 mg was obtained. Yield: 64.9%.
  • Example 13 (Soil 2,10-dihydroxy-3,9-dimethoxy-12-nitro-tetrahydroprotoberberine (Compound 13)
  • 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
  • Example 17 ⁇ - -)-2,10-dibenzyloxy-3-methyl-l--9-hydroxy-12-chloro-tetrahydroprotoberberine Compound 17)
  • 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.
  • Example 19 SH-)-2,10-Dibenzyloxy-3,9-dimethoxy-12-chloro-tetrahydroprotoberberine (Compound 19)
  • Compound 17 is a starting material, similar to Compound 9
  • 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.
  • 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.
  • 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.
  • 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.

Landscapes

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

Abstract

La présente invention concerne des composés de tétrahydroprotoberbérine de la formule (I) et leurs sels organiques ou inorganiques pharmaceutiquement acceptables, hydrates cristallisés, solvates et compositions médicinales. Dans la formule (I), R1, R2, R3 et R4 représentent H, C1-4 alkyle à chaîne linéaire ou ramifiée, cyclopropyle, cyclopropyle méthyle, méthoxyle méthyle, méthoxycarbonylméthyle, aryle, benzyle, alkyle ou bien aryle ou benzyle substitué. R5 et R6 représentent H, halogène, OH, SH, NO2, NH2, C1-4 alkyle linéaire ou ramifié substitué ou non-substitué. La configuration de C-14 est R, S ou son racémate. La présente invention concerne également leur procédé de préparation et leur utilisation dans la préparation de médicaments destinés au traitement de maladies neurologiques, notamment de maladies neurologiques liées au récepteur de la dopamine.
PCT/CN2007/001734 2006-07-26 2007-05-29 Composés de tétrahydroprotoberbérine, leur production, leur composition médicinale et leurs utilisations Ceased WO2008014661A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB2006100293845A CN100528872C (zh) 2006-07-26 2006-07-26 一类四氢原小檗碱类化合物、其制备方法及其组合物和用途
CN200610029384.5 2006-07-26

Publications (1)

Publication Number Publication Date
WO2008014661A1 true WO2008014661A1 (fr) 2008-02-07

Family

ID=37656093

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2007/001734 Ceased WO2008014661A1 (fr) 2006-07-26 2007-05-29 Composés de tétrahydroprotoberbérine, leur production, leur composition médicinale et leurs utilisations

Country Status (2)

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

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012163179A1 (fr) 2011-05-27 2012-12-06 中国科学院上海药物研究所 Composé d'hexahydrodibenzo[a,g]quinolizine, son procédé de préparation, composition pharmaceutique et son utilisation
WO2013020229A1 (fr) * 2011-08-05 2013-02-14 Miller James Jackson Composés tétrahydroprotoberbines et leurs utilisations dans le traitement de maladies neurologiques, psychiatriques et neurodégénératives
WO2013166862A1 (fr) 2012-05-09 2013-11-14 中国科学院上海药物研究所 Composé diaryl[a, g]quinolizidine, son procédé de préparation, composition pharmaceutique, et leurs utilisations
CN115477647A (zh) * 2022-10-26 2022-12-16 山西医科大学 小檗碱富马酸盐晶型及其制备方法和其组合物与应用

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100528872C (zh) * 2006-07-26 2009-08-19 中国科学院上海药物研究所 一类四氢原小檗碱类化合物、其制备方法及其组合物和用途
CN101037436B (zh) * 2007-04-18 2010-08-11 中国科学院上海药物研究所 左旋千金藤啶碱(l-SPD)衍生物、其制备方法和用途
CN101921229B (zh) * 2009-06-17 2012-08-08 中国科学院上海药物研究所 千金藤啶碱或其衍生物光学异构体的合成方法及其中间体
CN102234276B (zh) * 2010-04-28 2013-04-17 中国科学院上海药物研究所 千金藤啶碱或其衍生物光学异构体的制备方法以及在该方法中使用的中间体
JP6733449B2 (ja) * 2016-09-15 2020-07-29 株式会社ツムラ ベルベリン型アルカロイドの製造方法
JP7100693B2 (ja) * 2017-08-14 2022-07-13 シャンハイ インスティチュート オブ マテリア メディカ，チャイニーズ アカデミー オブ サイエンシーズ テトラヒドロプロトベルベリン系化合物、その製造方法、使用及び医薬組成物
CN115260185B (zh) * 2022-08-02 2024-09-24 杨征 金黄紫堇碱和千金藤啶碱的氘代衍生物及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1115318A (zh) * 1994-07-20 1996-01-24 中国科学院上海药物研究所 左、右旋氯斯库利啉及它们的用途
CN1603324A (zh) * 2003-09-29 2005-04-06 中国科学院上海药物研究所 左旋卤代斯库利啉盐及其制备方法和用途
CN1900076A (zh) * 2005-07-08 2007-01-24 中国科学院上海药物研究所 四氢原小檗碱类化合物及其制备方法和用途
CN1900075A (zh) * 2006-07-26 2007-01-24 中国科学院上海药物研究所 一类四氢原小檗碱类化合物、其制备方法及其组合物和用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1115318A (zh) * 1994-07-20 1996-01-24 中国科学院上海药物研究所 左、右旋氯斯库利啉及它们的用途
CN1603324A (zh) * 2003-09-29 2005-04-06 中国科学院上海药物研究所 左旋卤代斯库利啉盐及其制备方法和用途
CN1900076A (zh) * 2005-07-08 2007-01-24 中国科学院上海药物研究所 四氢原小檗碱类化合物及其制备方法和用途
CN1900075A (zh) * 2006-07-26 2007-01-24 中国科学院上海药物研究所 一类四氢原小檗碱类化合物、其制备方法及其组合物和用途

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
COLLECT. CZECH. CHEM. COMMUM., vol. 42, no. 7, pages 2207 - 2216 *
DATABASE CHEM ABS [online] 1976, TEITEL S. ET AL.: "Preferential removal of a methylenedioxy group from optically active isoquinolines", Database accession no. (86:43874) *
DATABASE CHEM ABS [online] 1977, CHIANG H-C ET AL.: "Total synthesis of (+-)-discretamine and (+-)-stepholidine", Database accession no. (87:152440) *
DATABASE CHEM ABS [online] 1977, CHIANG H-C. ET AL.: "An efficient synthesis of 9,10-substituted protoberberine alkaloid:(+-)-stepholidine", Database accession no. (88:89910) *
DATABASE CHEM ABS [online] 1977, RAJESWARI S. ET AL.: "Studies in protoberberine alkaloids. VIII. Synthesis of (+-)-stepholidine", Database accession no. (87:201844) *
DATABASE CHEM ABS [online] 1984, MCMURTREY K.D. ET AL.: "Kinetics and product distribution in Pictet-Spengler cyclization of tetrahydropapaveroline to tetrahydroprotoberberine alkaloids", Database accession no. (100:139420) *
DATABASE CHEM ABS [online] 1989, XU S. ET AL.: "Effects of tetrahydroprotoberberines on dopamine receptor subtypes in brain", Database accession no. (110:205069) *
HETEROCYCLES, vol. 5, no. 1, pages 85 - 90 *
J. ORG. CHEM., vol. 42, no. 19, pages 3190 - 3194 *
J. ORG. CHEM., vol. 49, no. 5, pages 947 - 948 *
JIN GUOZHANG ET AL: "New chemical dopamine receptor retarder in the brain-tetrahydroprotoberberine", CHINA SCIENCE, vol. B, no. 10, 1985, pages 925 - 930 *
JIN GUOZHANG ET AL: "New pharmacological effects of tetrahydroprotoberberines on dopamine receptor", CHINA SCIENCE FUND, no. 5, 2000, pages 300 - 304 *
TAI-WAN YAO HSUEH TSA CHIH, vol. 28, no. 1-2, pages 111 - 120 *
ZHONGGUO YAOLI XUEBAO, vol. 10, no. 2, pages 104 - 110 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012163179A1 (fr) 2011-05-27 2012-12-06 中国科学院上海药物研究所 Composé d'hexahydrodibenzo[a,g]quinolizine, son procédé de préparation, composition pharmaceutique et son utilisation
EP2716640A4 (fr) * 2011-05-27 2014-04-09 Shanghai Inst Materia Medica Composé d'hexahydrodibenzo[a,g]quinolizine, son procédé de préparation, composition pharmaceutique et son utilisation
JP2014515379A (ja) * 2011-05-27 2014-06-30 上海 インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズ ヘキサヒドロジベンゾ［ａ，ｇ］キノリジン系化合物、その製造方法、医薬品組成物およびその応用
US9359372B2 (en) 2011-05-27 2016-06-07 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Hexahydrodibenzo[a,g]quinolizine compound, preparation method thereof, pharmaceutical composition and use thereof
JP2017019768A (ja) * 2011-05-27 2017-01-26 上海 インスティテュート オブ マテリア メディカ、チャイニーズ アカデミー オブ サイエンシーズＳｈａｎｇｈａｉ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｍａｔｅｒｉａ Ｍｅｄｉｃａ， Ｃｈｉｎｅｓｅ Ａｃａｄｅｍｙ Ｏｆ Ｓｃｉｅｎｃｅｓ ヘキサヒドロジベンゾ［ａ，ｇ］キノリジン系化合物、その製造方法、医薬品組成物およびその応用
WO2013020229A1 (fr) * 2011-08-05 2013-02-14 Miller James Jackson Composés tétrahydroprotoberbines et leurs utilisations dans le traitement de maladies neurologiques, psychiatriques et neurodégénératives
US20150306092A1 (en) * 2011-08-05 2015-10-29 James Jackson MILLER Tetrahydroprotoberbine compounds and uses thereof in the treatment of neurological, psychiatric and neurodegenerative diseases
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
WO2013166862A1 (fr) 2012-05-09 2013-11-14 中国科学院上海药物研究所 Composé diaryl[a, g]quinolizidine, son procédé de préparation, composition pharmaceutique, et leurs utilisations
JP2015515994A (ja) * 2012-05-09 2015-06-04 中国科学院上海薬物研究所 ジアリロ［ａ，ｇ］キノリジン系化合物、その製造方法、医薬品組成物およびその応用
US9751882B2 (en) 2012-05-09 2017-09-05 Kingsound & Partner Diaryl[A, G]quinolizidine compound, preparation method therefor, pharmaceutical composition, and uses thereof
CN115477647A (zh) * 2022-10-26 2022-12-16 山西医科大学 小檗碱富马酸盐晶型及其制备方法和其组合物与应用

Also Published As

Publication number Publication date
CN100528872C (zh) 2009-08-19
CN1900075A (zh) 2007-01-24

Similar Documents

Publication Publication Date Title
WO2008014661A1 (fr) Composés de tétrahydroprotoberbérine, leur production, leur composition médicinale et leurs utilisations
AU2020278140B2 (en) A process for the manufacture of (2S,3S,4S,5R,6S)-3,4,5- trihydroxy-6-(((4aR,10aR)-7-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-6-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid
CN117940432A (zh) 一种喜树碱类化合物、其制备方法和用途
JP2021501191A (ja) Ｗｅｅ１阻害剤としての大環状化合物及びその使用
Zhang et al. Structural manipulation on the catecholic fragment of dopamine D1 receptor agonist 1-phenyl-N-methyl-benzazepines
HK1040398A1 (en) Pyridopyranoazepine derivatives, preparation and therapeutic use
WO2008128431A1 (fr) Dérivés de l-stépholidine (l-spd), leurs procédés de préparation et d'utilisation
CA3219940A1 (fr) Composes heterocycliques et leurs procedes de preparation
WO2012163179A1 (fr) Composé d'hexahydrodibenzo[a,g]quinolizine, son procédé de préparation, composition pharmaceutique et son utilisation
KR100460783B1 (ko) 폴리시클릭 아자인돌 화합물, 이들을 제조하는 방법 및이들을 함유하는 약제 조성물
JPH01311063A (ja) ヘテラ―脂肪族カルボクサミド誘導体、その製造方法、該化合物の中間体および該化合物を含有するロイコトリエン拮抗作用を有する薬学的組成物
CN112168824B (zh) 阿朴菲类化合物的应用
CN1900076B (zh) 四氢原小檗碱类化合物及其制备方法和用途
CN110606850A (zh) 一种3-苯并[4,5]咪唑[1,2-a]吡嗪-1-胺类化合物及其制备方法和应用
AU2002224086B8 (en) Indole derivatives and use thereof in medicines
JP5940729B2 (ja) ジアリロ［ａ，ｇ］キノリジン系化合物、その製造方法、医薬品組成物およびその応用
JP2017193549A (ja) ７β−置換６α，１４α−エテノモルフィナンおよび７β−置換６α，１４α−エタノモルフィナンを調製するための方法
TWI824626B (zh) Ripk1抑制劑的晶型及其酸式鹽和其酸式鹽的晶型
Ortner et al. Planar chiral indoles: synthesis and biological effects of the enantiomers
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
CN111606888B (zh) 吡咯类衍生物及其制备方法与应用
Wang et al. Facile synthetic approach for 5-aryl-9-hydroxypyrano [3, 2-f] indole-2 (8H)-one
CN115611901B (zh) 一种氮杂䓬类化合物或其药学上可接受的盐及其制备方法和应用
CN101560178A (zh) 一种多取代吲哚啉类化合物、其制备方法及医药用途
CN120887891A (zh) 10-芳基吴茱萸碱类衍生物的合成及其抗肿瘤用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07721307

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 07721307

Country of ref document: EP

Kind code of ref document: A1