WO2014146553A1 - Dérivés de flavanoïdes et leurs utilisations - Google Patents

Dérivés de flavanoïdes et leurs utilisations Download PDF

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WO2014146553A1
WO2014146553A1 PCT/CN2014/073439 CN2014073439W WO2014146553A1 WO 2014146553 A1 WO2014146553 A1 WO 2014146553A1 CN 2014073439 W CN2014073439 W CN 2014073439W WO 2014146553 A1 WO2014146553 A1 WO 2014146553A1
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group
piperidin
butoxy
fluorobenzo
isoxazol
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Chinese (zh)
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陈寅
徐祥清
赵松
于民权
邱印利
张桂森
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Nhwa Pharmaceutical Corp
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Nhwa Pharmaceutical Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to flavonoid derivatives and applications thereof. Background technique
  • Schizophrenia has been an independent disease unit for more than a hundred years.
  • Kraepelin summarized the previous clinical phenomena into a disease called early-onset dementia.
  • Bleuler stated his new ideas and believed that the disease had associations, emotions, The core of obstacles such as will and autism is schizophrenia and has been in use ever since.
  • Schizophrenia is the most serious and most harmful of all mental illnesses.
  • the global incidence is about 1-2%.
  • the lifetime prevalence of patients with schizophrenia is 0.7-0.8%, which is not significantly related to gender, ethnicity, or social boundaries, and the mortality rate is 2-3 times higher than that of the general population.
  • the latest research shows that the social burden of mental illness ranks first in Chinese diseases, exceeding the cardiovascular, respiratory and malignant diseases.
  • Typical anti-schizophrenic drugs (such as chlorpromazine and haloperidol) block the dopamine D 2 receptor and have a good effect on positive symptoms of schizophrenia.
  • adverse reactions such as extrapyramidal reaction (EPS), tardive dyskinesia, and increased prolactin are also caused, and they are ineffective for negative symptoms of schizophrenia.
  • EPS extrapyramidal reaction
  • Atypical anti-schizophrenic drugs represented by clozapine and risperidone, not only have a strong effect on dopamine (D 2 ) receptors, but also have a strong effect on serotonin (5-HT 2A ) receptors.
  • these drugs have great advantages: good effects on positive symptoms of schizophrenia; side effects such as extrapyramidal reaction and tardive dyskinesia are significantly reduced; some atypical anti-schizophrenic drugs Negative symptoms and cognitive impairment have some improvement.
  • the current clinical application of atypical anti-schizophrenic drugs have varying degrees of QT interval prolongation and high prolactin and other adverse reactions]. Therefore, it is very important to find new drugs that can effectively cure schizophrenia and have fewer side effects.
  • the action with the receptor can effectively treat the positive symptoms of schizophrenia.
  • the serotonin system plays an important role in regulating the function of the prefrontal cortex, including mood control, cognitive behavior, and working memory.
  • the pyramidal neurons and GABA interneurons of the prefrontal cortex contain serotonin receptors 5 butyl and 5-HT 2A .
  • the serotonin system plays an important role in regulating the function of the prefrontal cortex, including mood control, cognitive behavior, and working memory.
  • 5-HT 1A and atypical antipsychotic treatment Related can improve negative symptoms and cognitive impairment.
  • the 5-HT 2A receptor is involved in various aspects of perception, mood regulation, and motor control. Blocking the 5-HT 2A receptor normalizes the release of dopamine and acts as an antipsychotic.
  • the compounds of the present invention are capable of significantly improving MK-801-induced high activity and effectively apomorphine-induced climbing symptoms. Moreover, the compounds of the invention have a stronger effect and a greater therapeutic index than Abaperidone. In the acute toxicity study, the mice of the present invention have an LD 5Q greater than 2000 mg/kg, which is higher than Abaperidone (160 mg/kg) and has less acute toxicity. Summary of the invention
  • Another object of the present invention is to provide an application of the above flavonoid derivative for the preparation of a medicament for treating neuropsychiatric diseases.
  • the object of the invention can be achieved by the following measures:
  • Z is a substituted or unsubstituted C 2 ⁇ C 6 alkylene group, the C 2 ⁇ C 6 alkylene group is —(CH 2 ) n —, n is an integer of 2 to 6; or substituted or unsubstituted a C 2 -C 6 alkenylene group, wherein the C 2 ⁇ C 6 alkenylene group means that -(CH 2 ) n - contains a carbon-carbon double bond, wherein n is an integer of 2 to 6;
  • Ri R 2, R 3, R 4 R 5 or R 6 are independently hydrogen, halogen, a C r C 5 Huan, substituted C r to C 5 alkyl;
  • R1 and R2 together may also form together with its attached carbon atoms (: cycloalkyl or heterocycloalkyl, heterocycloalkyl hetero atom is 46 N; substituent group is preferably a C r C 5 alkyl on the ring base;
  • X is CH or
  • Ar is of formula II or formula II I;
  • Q is 0 or S
  • R 7, R 8 or R 9 are each independently hydrogen, halogen, C r C 5 Huan group, substituted C r C alkyl or C r C 5 alkoxy group 5.
  • the substituted 5- alkyl substituent is one or more of a halogen, an amino group or a hydroxyl group; the substituted 5 -alkane The group is further preferably a trifluoromethyl group or a hydroxymethyl group.
  • the alkyl group is a methyl group, an ethyl group, a propyl group, a butyl group, a n-pentyl group, an isopentyl group or a neopentyl group.
  • said flavonoid derivatives of the present invention or a pharmaceutically acceptable salt thereof, said C r C 5 alkoxy group are methoxy, ethoxy, propoxy, butoxy.
  • the halogen is fluorine, chlorine, bromine or iodine.
  • R 2 , R 3 , R 4 R 5 or R 6 are independently hydrogen, chlorine, methyl, or B. Base, propyl, trifluoromethyl or hydroxymethyl.
  • R 7 or independently hydrogen, chlorine, fluorine, methyl, ethyl, trifluoromethyl, A Oxy or ethoxy.
  • the R1 and R2 are common thereto
  • the linked carbon atoms together form a substituted or unsubstituted cyclopentane, cyclohexane or piperidine wherein the substituent is selected from one or more of methyl, ethyl, propyl or butyl.
  • said R1 and R2 together with the carbon atom to which they are attached form an unsubstituted cyclopentane, cyclohexane or piperidine.
  • the flavonoid derivative of the present invention or a pharmaceutically acceptable salt thereof is most preferably selected from any one of the following compounds or a pharmaceutically acceptable salt thereof:
  • the present invention also includes a structural compound of the formula (I) and a salt of each of the above specific compounds, the salt being a pharmaceutically acceptable anionic salt: such as a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, Sulfate or hydrogen sulphate, phosphate or acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, mesylate, gluconate, A saccharide, a benzoate, an ethanesulfonate, a besylate, a p-toluenesulfonate, and the like.
  • a pharmaceutically acceptable anionic salt such as a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, Sulfate or hydrogen sulphate, phosphate or acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, mesylate
  • the general synthesis method for this class of compounds is to first synthesize the parent of the flavonoid and then connect it with a piperazinyl or piperidinyl group through a carbon chain.
  • the present invention provides a pharmaceutical composition comprising a compound of the formula (I), and a pharmaceutically acceptable adjuvant (such as a carrier and/or an excipient, etc.), the pharmaceutical composition comprising the present invention sufficient to produce an antipsychotic effect An antipsychotic composition of the compound.
  • a pharmaceutically acceptable adjuvant such as a carrier and/or an excipient, etc.
  • Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
  • the amount of the compound of the present invention depends on the type and severity of the disease or condition, and also on the characteristics of the subject, such as general health, age, sex, body weight, and drug tolerance. The skilled person is able to determine the appropriate dosage based on these or other factors. Effective dosages of the central nervous system drugs commonly used are well known to the skilled artisan.
  • the total daily dose is usually between about 0.05 mg and 2000 mg.
  • the present invention relates to a pharmaceutical composition which provides from about 0.01 to 1000 mg of active ingredient per unit dose.
  • the composition may be administered by any suitable route, for example, orally in the form of a capsule, parenterally in the form of an injection, topically in the form of a cream or lotion, rectal administration in the form of a suppository, in the form of a patch delivery system. Transdermal administration.
  • the compounds provided herein can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, and the like.
  • Tablets, pills, capsules and the like comprise from about 0.01 to about 99 weight percent of active ingredient and binder such as gelatin, corn starch, gum arabic; excipients such as calcium hydrogen phosphate; disintegrants such as corn starch, potato starch or algae An acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose or lactose.
  • a liquid carrier such as a fat or oil may be contained in addition to the above-mentioned types of raw materials.
  • the compounds provided herein can be combined with sterile aqueous or organic vehicles to form injectable solutions or suspensions.
  • the compounds of formula I may contain a chiral center and thus may exist in different enantiomeric and diastereomeric forms.
  • the present invention relates to all optical isomers and all stereoisomers of the compounds of formula I, as racemic mixtures of such compounds and in the form of the respective enantiomers and diastereomers, and the invention relates to All pharmaceutical compositions and methods of treatment containing or using them are defined.
  • the derivative provided by the present invention and a pharmaceutical composition composed of the derivative can be applied to the preparation of a medicament for treating or preventing a neuropsychiatric disease which is schizophrenia.
  • the present invention relates to the use of said derivatives for the preparation of other diseases of the central nervous system diseases, such as drugs for the treatment of depression, memory disorders and dysfunctional diseases associated with intelligence and learning.
  • 2-methoxyphenylpiperazine hydrochloride was changed to 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride salt, prepared according to the method of Example 1.
  • the target compound 2 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)helix [color full-2-1' - cyclopentamidine]-4-one.
  • Example 3 7- ( 3- (4- (2-methoxyphenyl) piperazine small group) propoxy) helix [color full-2-1,-cyclopentan-4-one (3) replaced by 1,3-dibromopropane 1,4 -Dibromobutane, the title compound 3 was prepared as in Example 1 : 7-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy) helix -2-1'-cyclopentan-4-one.
  • the target compound 4 was prepared by the method of Example 3 by substituting 1,3-dibromopropane for 1,4-dibromobutane. 7-(3-(4-(6-fluorobenzo[d]isoxazole) 3-yl)piperidin-1-yl)propoxy) Helical [chroman-2-1'-cyclopentanyl]-4-one. Melting point: 91-93 °C.
  • 2-methoxyphenylpiperazine hydrochloride was changed to 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, and prepared according to the method of Example 5.
  • Target compound 5 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)helix [color full-2-1'- Cyclohexyl]-4-one.
  • 2-Methoxyphenylpiperazine hydrochloride was changed to 3-trifluoromethylphenylpiperazine hydrochloride, and the target compound 6 was prepared as in Example 5: 7-(4- (4- 3-(Trifluoromethyl)phenyl)piperazin-1-yl)butoxy)helix [chroman-2-1'-cyclohexane]-4-one.
  • Example 10 7-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)helix [chroman-2-1'-cyclohexane]-4-one (10)
  • the title compound 10 was prepared by the method of Example 5 using 1,3-dibromopropane in place of 1,4-dibromobutane. 7-(3-(4-(2-methoxyphenyl)piperazine- 1-Base) Propoxy) Spiral [chroman-2-1'-cyclohexanyl]-4-one.
  • the target compound was prepared by the method of Example 5 by substituting 1,3-dibromopropane for 1,4-dibromobutane, and the title compound 10 was obtained by the method of Example 6: 7-( 3- (4- (6) -Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)helix [chroman-2-1'-cyclohexan]-4-one.
  • Example 12 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 2,2-dimethylchroman- 4-ketone (12) Using acetone instead of cyclopentanone, the title compound 12 was prepared as in Example 2: 7-(4-(4-(6-fluorobenzo[d]isoxazole-3-yl) Piperidin-1-yl)butoxy) 2,2-dimethylchroman-4-one.
  • 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride was replaced with 2-methoxyphenylpiperazine hydrochloride, and prepared according to the method of Example 12.
  • the title compound 13 was obtained: 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy) 2,2-dimethylchroman-4-one.
  • Example 14 7- ( 3- (4- (6-fluorobenzo[d] Isoxazol-3-yl)piperidin-1-yl)propoxy) 2,2-dimethylchroman-4-one (14) Substituting 1,3-dibromopropane for 1,4-dibromo Butane, the title compound 14 was obtained as in Example 12: 7-(3-(4-(6-fluorobenzo[d]isooxazol-3-yl)piperidin-1-yl)propoxy 2,2-dimethylchroman-4-one.
  • the title compound 15 was prepared as in Example 13 by substituting 1,3-dibromopropane for 1,4-dibromobutane. 7-(3-(4-(2-methoxyphenyl)piperazine- 1-yl)propoxy) 2,2-dimethylchroman-4-one.
  • the target compound 16 was prepared by the method of Example 12 using 1,4-bis(bromomethyl)cyclohexane instead of 1,4-dibromobutane. 7-((4-(4- 4-(6-fluoro)) Benzo[d]isoxazol-3-yl)piperidin-1-yl)methyl)cyclohexyl)methoxy) 2,2-dimethylchroman-4-one.
  • the target compound 17 was prepared as in Example 12 by substituting 2-bromoethyl ether for 1,4-dibromobutane. 7-(2-(2-(4-(6-fluorobenzo[d]]) Oxazol-3-yl)piperidin-1-yl)ethoxy)ethoxy) 2,2-dimethylchroman-4-one. Melting point: 128-130°. .
  • Example 21 7-(4-(4-(6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-2-methyl-8-chlorochroman-4-one (21) Using 2-chlororesorcin instead of resorcin, the target compound 21 was prepared as in Example 20: 7-(4-(4-(6-fluorobenzo[d]isoxazole- 3-yl)piperidin-1-yl)butoxy) 2-methyl-8-chlorochroman-4-one.
  • Example 24 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy 6-methylchroman-4-one (24) Using 4-methyl resorcinol instead of resorcin, the target compound 24 was prepared as in Example 22: 7- (4- (4- (6-Fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 6-methylchroman-4-one.
  • Example 25 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 8 -methylchroman-4-one (25) Using 2-methyl resorcinol instead of resorcin, the target compound 25 was prepared as in Example 22: 7-(4-(4-(6-fluoro) Benzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy) 8-methylchroman-4-one.
  • Rats were decapitated, operated on ice, and the cortex was quickly taken. Add 3 ml of buffer (0.05 M Tris-HCI buffer containing 0.1% ascorbic acid, ⁇ eugenin and 4 mM CaCI 2 ) in 4 3-4 s.
  • buffer 0.05 M Tris-HCI buffer containing 0.1% ascorbic acid, ⁇ eugenin and 4 mM CaCI 2
  • Isotope ligand 3 H-8-OH-DPAT (67.0 Ci/mmol), purchased from PerkinElmer; 5-HT, purchased from RBI; GF/C glass fiber filter paper, purchased from Whatman; Tris imported package; PPO POPOP was purchased from Shanghai Reagent No. 1 Plant; fat-soluble scintillation fluid. Beckman LS-6500 multi-function liquid scintillation counter.
  • the prepared membrane was uniformly dispersed by a homogenizer with a suitable amount of buffer, and 15 tubes were mixed into a 100 ml container, and a suitable amount of a buffer solution of 50 ml of the membrane was added thereto for use.
  • Each reaction tube was separately added with radioligand 3 H-8-OH-DPAT 10 ⁇ _ (two parallel tubes were set for each reaction tube, and each tube was placed on ice when the sample was applied).
  • Inhibition rate (I %) (total binding tube cpm - compound cpm) / (total binding tube cpm - non-specific binding tube cpm ) x l00% Compounds were subjected to two separate tubes per experiment, and two separate experiments were performed. The experimental results are shown in Table 2.
  • Rats were decapitated, operated on ice, and the cortex was quickly taken. Add 3 ml of buffer (0.05 M Tris-HCI buffer: 6.05 g of Tris dissolved in 1000 ml of double distilled water and adjusted to pH 7.5 with concentrated HCI).
  • buffer 0.05 M Tris-HCI buffer: 6.05 g of Tris dissolved in 1000 ml of double distilled water and adjusted to pH 7.5 with concentrated HCI.
  • Isotope ligand [ 3 H]- Ketanserin 67.0 Ci/mmol ), purchased from PerkinElmer; Methysergide, purchased from RBI; GF/C glass fiber filter paper, purchased from Whatman; Tris imported package; PPO, POPOP purchased from Shanghai Reagent No. 1; fat-soluble scintillation fluid. Beckman LS-6500 multi-function liquid scintillation counter.
  • Inhibition rate (I %) (total binding tube cpm - compound cpm) / (total binding tube cpm - non-specific binding tube cpm ) x l00% Compounds were subjected to two separate tubes per experiment, and two separate experiments were performed. The experimental results are shown in Table 2.
  • Isotope ligand 3 H-Spiperone (67.0 Ci/mmol), purchased from PerkinElmer; Butaclamol, purchased from RBI; GF/C glass fiber filter paper, purchased from Whatman; Tris imported package; PPO, POPOP from Shanghai reagent One plant; fat-soluble scintillation fluid. Beckman LS-6500 multi-function liquid scintillation counter.
  • Each reaction tube was separately added with a radioactive ligand ⁇ -Spiperone ⁇ (two parallel tubes were set for each reaction tube, and each tube was placed on ice when the sample was applied).
  • Inhibition rate (I %) (total binding tube cpm - compound cpm) / (total binding tube cpm - non-specific binding tube cpm ) x l00% Compounds were subjected to two separate tubes per experiment, and two separate experiments were performed. The experimental results are shown in Table 2.
  • Rats were decapitated, operated on ice, quickly took the rat cerebellum, added homogenate F, mixed with a vortex mixer, centrifuged at 48000 g, 4 ° C for 10 min, discard the supernatant, take the precipitate, and then add the homogenate F Wash, repeat three times of centrifugation, and centrifuge, The supernatant was discarded and the pellet was stored at -80 ° C until use.
  • Isotope ligand 3 H-pyrilamine (67.0 Ci/mmol), purchased from PerkinElmer; promethazine, purchased from RBI; GF/C glass fiber filter paper, purchased from Whatman; Tris imported package; PPO, POPOP purchased from Shanghai reagent One plant; fat-soluble scintillation fluid. Beckman LS-6500 multi-function liquid scintillation counter.
  • the first step firstly prepare the prepared membrane with an appropriate amount of homogenate F, and uniformly disperse it with a homogenizer. Mix 15 tubes into a 100 ml container, add a proper amount of the homogenate to a suspension of 50 ml membrane, and set aside.
  • Step 2 Each reaction tube was separately added to the membrane preparation 100 ⁇ .
  • the third step The total binding tube ( ⁇ ) was added 100 ⁇ _ homogenate F, nonspecific binding tube (NB) was added 100 ⁇ _ promethazine (final concentration of 10- 5 M), each test compound specifically binds tube (SB) was added 100 ⁇ _ test compound (final concentration of 10- 5 M);
  • Step 4 Each reaction tube was separately added with radioligand 3 H- P y r ilami ne l ( ⁇ L (each reaction tube was provided with 2 parallel tubes, and each tube was placed on ice when the sample was applied).
  • Step 5 Incubate each reaction tube at 30 ° C for 60 min. After the reaction is completed, the combined ligand is rapidly filtered by decompression, thoroughly washed with ice-cold test buffer, and the filter is taken out and placed in a 3 ml scintillation cup. 2ml of toluene scintillation fluid and mix well;
  • Step 6 Put the scintillation bottle into the liquid scintillation counter
  • Inhibition rate (I %) (total binding tube cpm - compound cpm) / (total binding tube cpm - non-specific binding tube cpm ) x l00% Compounds were subjected to two separate tubes per experiment, and two separate experiments were performed. The experimental results are shown in Table 2.
  • MK-801 produced by Sigma, USA, preparation method: 0.1% vitamin C is formulated into a 1mg/ml solution; Positive drugs tested: haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone, quetiapine; Tween 80, concentration 10%.
  • mice were randomly divided into a blank group, a model group, a positive control group (risperidone group), and a drug group.
  • the empty group and the model group were given 10% Tween 0.1ml/10g, and the positive control group was given risperidone 0.1mg/kg.
  • the drug group was given the corresponding dose of drugs.
  • the blank group was intraperitoneally injected with 0.1% ascorbic acid 0.1ml/10g
  • the model group, the positive control group (30min) were intraperitoneally injected with MK-801 solution 0.1mg/kg. Thereafter, spontaneous activity of each group of mice was measured within 90 minutes. The results are shown in Table 3.
  • Positive drugs tested haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone, quetiapine; apomorphine, supplied by Sigma, 0.9% before use (containing 0.1% vitamin C) dissolved, ready for use; vitamin C, F20061113, Sinopharm Chemical Reagent Co., Ltd.;
  • the instrument clamps the climbing cage, the stopwatch.
  • KM mice male, weighing 18 ⁇ 22g, were randomly divided into negative control group, model group, positive drug group (risperidone, aripiprazole, ziprasidone, quetiapine, olanzapine, fluoride). Piperidinol, clozapine and compound dose groups (see table below for specific doses), 10 in each group.
  • the negative control group and the model group were given the corresponding solvent double distilled water by gavage
  • the positive drug group was given the corresponding positive drug by intragastric administration (first adding a small amount of acetic acid and then adding double distilled water), and each dose group of the compound was intragastrically administered with the corresponding dose of the compound.
  • the volume of the gavage was 0.1 ml/10 g.
  • apomorphine (1 mg/kg) was injected subcutaneously in a volume of 0.1 ml/10 g. Immediately after the injection of apomorphine, put it into a climbing cage for 5 minutes and observe the 10th-11 after the injection of apomorphine. 20-21, 30-31 minutes of behavior and score, the scoring criteria: four feet scored 0 on the floor; two forefoot scored 1 on the cage; four feet scored 2 on the cage.
  • Example 33 method of catalepsy
  • Test drug haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone
  • Self-made grab bar equipment A stainless steel rod with a diameter of 0.3 cm and a height of 5 cm above the table is placed in the mouse box.
  • mice male and female, weighing 20 ⁇ 24g, were randomly divided into negative control group, model group and positive drug group (risperidone, aripiprazole, ziprasidone, quetiapine, olanzapine). , haloperidol, clozapine) and compound dose groups, 10 in each group.
  • the negative control group and the model group were given the corresponding solvent double distilled water by gavage, and the positive drug group was given the corresponding positive drug by intragastric administration (adding a small amount of acetic acid and then adding double distilled water when dissolved), and each dose group of the compound was intragastrically administered with the corresponding dose of the compound.
  • Sequential method limit experiment KM mice, male and female, were randomly divided into several groups, each group of 2-5, each group of 2000mg/kg and solvent group, administered by 0.2ml/10g. Observe the animal's death within 3 days. (If the animal survives in 3 or more days within 3 days and there is no obvious abnormality in the state of life, continue to observe until the end of the experiment after 7 days. If the animal dies 3 or more in 3 days, the median lethal dose method is used. Determine its LD50.
  • mice were pre-tested by median lethal dose method, male and female, randomly divided into several groups, 4 in each group, respectively, each group of 1500mg/kg, 1000mg/kg, 500mg/kg group and solvent group, according to 0.2ml/10g
  • the drug was administered by gavage and the animals were observed for death within 1-3 days.
  • mice in a single administration had LD 5Q greater than 2000 mg/kg, with aripiprazole (93 mg/kg) and ziprasidone ( > 2000mg/kg) equivalent, higher than risperidone (82.1mg/kg) and Abaperidone (160 mg/kg), with less acute toxicity.
  • Table 2 Inhibition rate of each compound to the receptor (repeated three times, ⁇ SD) No. D 2 Inhibition rate % 5- ⁇ 1 ⁇ Inhibition rate % 5- ⁇ 2 ⁇ Inhibition rate % ⁇ Inhibition rate %
  • Active ingredient (compound of the invention) lOOmg
  • the original auxiliary material has been sieved for 80 mesh, and the prescribed amount of active ingredient, microcrystalline cellulose, lactose, povidone K30 is weighed, added to the high-speed mixing machine, mixed at low speed, uniformly mixed, added with appropriate amount of purified water, low-speed stirring, high-speed cutting Granulation, wet granules 60 Dry at °C for 3h, sieve through 24 mesh, add the prescribed amount of sodium carboxymethyl starch, silica and magnesium stearate, mix thoroughly, and compress by tablet press.
  • the compound of the present invention as an active ingredient is any one of the compound compounds 26.
  • Example 36 capsule (230 mg)
  • Active ingredient (compound of the invention) lOOmg
  • the original auxiliary material has been sieved for 80 mesh, and the active ingredients, lactose, starch and povidone K30 are weighed into the high-speed mixing machine.
  • the mixture is mixed at low speed, and the appropriate amount of purified water is added.
  • the mixture is stirred at a low speed and cut at a high speed.
  • the wet granules were dried at 60 ° C for 3 h, sieved through a 24 mesh sieve, and the prescribed amount of silica and magnesium stearate were added, and the mixture was mixed, and the capsule was filled with a capsule filling machine.
  • the compound of the present invention as an active ingredient is any one of the compound compounds 26.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne le domaine de la chimie pharmaceutique, et en particulier, un dérivé de flavanoïde et son utilisation. L'invention concerne un dérivé de flavanoïde représenté par la formule générale (I) ou un sel pharmaceutiquement acceptable de celui-ci. Ce composé peut être utilisé pour la préparation de médicaments destinés à la prévention ou au traitement de maladies du système nerveux central.
PCT/CN2014/073439 2013-03-18 2014-03-14 Dérivés de flavanoïdes et leurs utilisations Ceased WO2014146553A1 (fr)

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CN106905286B (zh) * 2015-12-23 2020-07-24 江苏恩华药业股份有限公司 一种黄酮类化合物衍生物及其应用
CN106977506B (zh) 2016-01-19 2020-04-24 首都医科大学宣武医院 二氢黄酮衍生物、其制备方法和用途

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