WO2010037257A1 - 一类新型苯并氮杂卓类化合物及其制备方法和用途 - Google Patents
一类新型苯并氮杂卓类化合物及其制备方法和用途 Download PDFInfo
- Publication number
- WO2010037257A1 WO2010037257A1 PCT/CN2009/001068 CN2009001068W WO2010037257A1 WO 2010037257 A1 WO2010037257 A1 WO 2010037257A1 CN 2009001068 W CN2009001068 W CN 2009001068W WO 2010037257 A1 WO2010037257 A1 WO 2010037257A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- acid
- group
- pharmaceutically acceptable
- receptor
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
Definitions
- the present invention relates to a class of benzazepine compounds which have activity against dopamine receptors, dopamine D 2 receptors, serotonin 1A receptors, serotonin 2A receptors, and processes for their preparation, and Therefore, it can be applied to a variety of therapeutic fields, especially for the treatment of diseases of the central nervous system, such as schizophrenia, depression, anxiety, Parkinson's disease, and dyskinesia and nerves caused by anti-Parkinson's disease/schizophrenia drugs. Protection and so on.
- diseases of the central nervous system such as schizophrenia, depression, anxiety, Parkinson's disease, and dyskinesia and nerves caused by anti-Parkinson's disease/schizophrenia drugs. Protection and so on.
- Dopamine is an important catechin neurotransmitter in mammals and regulates various physiological functions.
- the peripheral dopamine system plays an important role in regulating cardiovascular function, controlling catechol release and hormone secretion, digestive function, and gastrointestinal motility.
- the central dopamine system is thought to be associated with a range of central degenerative diseases (such as Parkinson's disease, Huntington's disease, schizophrenia, etc.) and mental disorders.
- Dopamine acts through dopamine receptors (DD 2 , D 3 , D 4 , D 5 ).
- Dopamine receptor belongs to the G-protein coupled receptor family and is divided into And D 5 subtypes, which specifically bind to the benzazepine series of compounds and activate adenylate cyclase, causing an increase in cAMP.
- the D 2 class includes three subtypes of D 2 , D 3 , and D 4 , which are activated to inhibit the activity of adenylate cyclase and reduce cAMP levels.
- Dopamine receptors are the most widely distributed receptor subtypes in the mammalian brain. Receptors are most distributed in the caudate nucleus, putamen, and nucleus accumbens, and they also have a certain distribution in the presynaptic terminals of glutamate conduction.
- the dopamine D 2 receptor is the second highest dopamine receptor, highly concentrated in the caudate putamen, optic tract and pituitary gland, and a small amount in the thalamus, ventral cap, etc. Dopamine D 2 receptors are involved in the regulation of human mental state and ideology. 2, serotonin receptor
- Serotonin (5-HT) is also an important central neurotransmitter that plays an important role in a range of physiological functions and is thought to be involved in pain sensation, feeding behavior, sexual behavior, emotion, sleep, memory, and the like.
- 5-HT synthesis, storage, membrane uptake and metabolism together with the 5-HT receptor constitute the 5-HT nervous system.
- the 5-HT receptor can be classified into at least 7 types and 16 subtypes. Except that the 5-HT 3 receptor belongs to the ligand-gated iontophore receptor, the rest belong to the G-protein coupled receptor family.
- the 5-HTi receptor includes five subtypes (5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 1E , 5-HT 1F ), and the 5-HT 2 receptor includes three subtypes ( 5-HT 2A , 5-HT 2B , 5-HT 2C ).
- Parkinson's disease also known as paralysis agitans
- the clinical manifestations include four major features: static tremor, slow movement, decreased exercise, muscle rigidity and posture balance disorder.
- the onset age is more common in 50-60 years old.
- dopamine receptor agonists especially dopamine D ⁇ D 2 receptor agonists, are one of the effective means of treating Parkinson's disease.
- dopamine D 2 receptor agonists are mainly used to treat early Parkinson's disease or in advanced and levodos Ba He is used to reduce the conventional dose of levodopa, or to alleviate side effects such as dyskinesia and fluctuations in efficacy caused by long-term medication.
- drugs include ergots, such as Bromocriptine, Pergolide, Cabergoline, Lisuride, and non-ergoline, such as Ropinirole.
- 5-HT 1A receptor agonists have been shown to have anti-dyskinetic effects.
- the 5-HT 1A receptor agonist sarizotan can alleviate dyskinesia in the murine and monkey PD models, and It has been tested on PD patients and has better anti-dysmotility effects.
- An object of the present invention is to provide a novel class of benzazepine compounds represented by the formula (I), or a stereoisomer, a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof.
- Another object of the invention is to provide a process for the preparation of such compounds.
- a further object of the present invention is to provide a pharmaceutical use of such compounds, which compounds generally have dopamine 1 receptor activity, and their dopamine D 2 receptor activity is reported for the first time; such compounds also have 5-HT 1A , 5 -HT 2A receptor activity; thus, such compounds have utility in the preparation of diseases for the treatment of central nervous system, especially schizophrenia, depression, anxiety, Parkinson's disease and anti-Parkinson's disease/schizophrenia The dyskinesia or neuroprotection caused by the drug I.
- the present invention provides a benzazepine compound represented by the following formula (I): a stereoisomer thereof, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
- a hydrogen, a halogen, a hydroxyl group, a C1-C12 radical, a C1-C12 hydrocarbyloxy group or a C1-C12 hydrocarbylamino group said hydrocarbyl group being a saturated or unsaturated linear, branched or cyclic hydrocarbon group, and optionally Substituted by halogen or a 5- or 6-membered aryl group containing 0-3 oxygen atoms; for example: hydrogen, fluorenyl, trifluoromethyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, Tert-butyl, allyl, propargyl, cyclopropyl, cyclobutyl, cyclopropenyl, cyclobutylhydrazine, benzyl, phenethyl, styryl,
- R 2 is hydrogen, unsubstituted or halogen, C 1 -C6 alkoxy, saturated or unsaturated straight substituted with 0-3 of a five- or six-membered aromatic or aliphatic heterocyclic ring selected from oxygen, nitrogen and sulfur atoms A chain or branched C1-C10-based, cyclic C3-C10 hydrocarbon group or a C1-C6 acyl group.
- R 3 is unsubstituted or halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C4 alkylamino or nitrile substituted phenyl, biphenyl, naphthyl or containing 1-3 a five- or six-membered heteroaryl selected from oxygen and sulfur; for example: phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nonylphenyl, 4-nonyloxyphenyl, 4- Hydroxyphenyl, 4-aminophenyl, 4-nonylaminophenyl, 4-diphenylphenyl, 4-cyanophenyl, 4-biphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-decylphenyl, 3-decyloxyphenyl,
- R 2 is hydrogen or a C1-C10 alkyl group
- R 3 is unsubstituted or halogen, C 1 -C 6 hydrocarbyl or C 1 -C 6 alkoxy substituted phenyl or naphthyl. More preferably,
- Ri is the meta position of the benzene ring and is hydrogen or a C 1 -C3 alkyl group
- R 2 is hydrogen or a C1-C3 alkyl group
- R 3 is phenyl, nonylphenyl, decyloxyphenyl, chlorophenyl, fluorophenyl or 2-naphthyl.
- the present invention provides a method for producing a benzazepine compound represented by the formula (I), which is any one of the following two methods.
- a benzazepine compound represented by the formula (I) which is any one of the following two methods.
- the ground cover is substituted with a 5- or 6-membered aryl group containing 0-3 oxygen atoms;
- R 2 is hydrogen, unsubstituted or halogen, C1-C6 alkoxy, containing 0-3 selected from oxygen, nitrogen and sulfur five- or six-membered aromatic or aliphatic heterocyclic ring atoms, saturated or unsaturated, linear or branched C 1 -C 10 hydrocarbon group, C3
- an amino group of 3,4-dimethoxyoxyphenethylamine is used to attack a substituted phenyl oxirane to obtain an amino alcohol compound.
- the amino alcohol compound is cyclized to form a benzo seven-membered ring compound under the catalysis of concentrated sulfuric acid in the presence of trifluoroacetic acid as a solvent.
- the benzo seven-membered ring compound can selectively undergo bromination reaction at the 6 position under the action of Br 2 and glacial acetic acid as a solvent.
- the obtained 6-bromo compound is subjected to Suzuki coupling with a series of R 3 -substituted boric acid in the presence of 2N Na 2 CO 3 aqueous solution, Pd(PPh 3 ) 4 to obtain a compound in which the 6-position is coupled with R 3 .
- the compound can be removed by the action of boron tribromide, and the bis-methoxy protecting group at the 7-position is removed to obtain the target compound; or reacted with the halogenated substance R 2 X to obtain an N-substituted compound, N-
- the substituted compound can be obtained by the action of boron tribromide to obtain the target compound.
- Suzuki coupling occurs with a series of R 3 -substituted boric acids in the presence of Pd(OAc) 2 , P(o-Tol) 3 , K 3 P0 4 and DMF as a solvent to obtain 6-position and R. 3 coupled compounds.
- the 6-position compound coupled with R 3 is removed by the action of boron tribromide, and the bis-methoxy protecting group at the 7-position is removed to obtain the target compound.
- the compound represented by the formula (I) contains a chiral center, and thus a stereoisomer may exist.
- the present invention includes R or S single stereoisomers of the compound represented by the general formula (I) and a mixture thereof.
- the present invention also includes a pharmaceutically acceptable salt of the compound represented by the general formula (I).
- inorganic acids such as hydrochloric acid, hydrobromic acid, acid or phosphoric acid
- organic carboxylic acids eg citric acid (citric acid), lactic acid, malic acid, gluconic acid, tartaric acid, adipic acid, acetic acid, succinic acid, Non-toxic with fumaric acid, ascorbic acid and itaconic acid, or with organic sulfonic acids (eg sulfonic acid, benzenesulfonic acid, etc.) Acid addition salt.
- the present invention also provides a compound represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof or a pharmaceutical composition comprising the same for preventing or Treatment of diseases associated with dopamine DD 2 receptor, serotonin 1 A receptor or serotonin 2A receptor, especially diseases of the central nervous system such as schizophrenia, depression, anxiety, Parkinson's disease and Movement disorders and neuroprotection caused by anti-Parkinson's disease/schizophrenia drugs.
- diseases associated with dopamine DD 2 receptor, serotonin 1 A receptor or serotonin 2A receptor especially diseases of the central nervous system such as schizophrenia, depression, anxiety, Parkinson's disease and Movement disorders and neuroprotection caused by anti-Parkinson's disease/schizophrenia drugs.
- the invention also encompasses any of the novel intermediates disclosed herein.
- Figure 1 shows the effect of compound l ib on dyskinesia caused by levodopa.
- Phenyloxirane (8.01 g, 6.62 mmol) and 3,4-dimethoxyoxyphenethylamine (10 g, 5.52 mmol) were dissolved in acetonitrile and refluxed at 90 ° C for 24 hours.
- the resulting yellow mixture was dried with EtOAc (EtOAc) After the mother liquor was concentrated, column chromatography was carried out to obtain a compound 1 10.40 g (62.6%) o
- the synthesis step of Compound 8 is referred to the synthesis of Compound 3.
- the receptor-positive drug SCH-23390 and the test compound, reference compounds SKF38393 and SKF83959 were dissolved in DMSO to 0.01 mol/L, and diluted to 100 mol/L with deionized water.
- the receptor protein was expressed on the membrane after 48-72 hours.
- the cells were centrifuged at 1000 rpm for 5 min, and the supernatant was discarded.
- the cells were collected and stored in a -20 G C refrigerator. Resuspend with Tris-Cl (pH 7.4) during the experiment.
- Receptor competition combined experiment Add 20 ⁇ and 160 ⁇ receptor protein of test compound and isotope ligand to the reaction tube, so that the final concentration of test compound and positive drug is 10 mol/L, incubate in 30 ° ⁇ water bath After 50 111, immediately transfer to the ice bath to terminate the reaction; on a microporous cell sample collector, rapidly filter through GF/B glass fiber filter paper, and use eluent (50 mM Tris-HCl, H 7.4) 3 ml x 3 times Dry in a microwave oven for 8 to 9 minutes, transfer the filter paper into a 0.5 ml centrifuge tube, and add 500 ⁇ L of fat-soluble scintillation fluid. The light was allowed to stand for more than 30 min, and the radioactivity was measured by counting. The percent inhibition of each compound to isotope ligand binding is calculated as follows: where cpm is the isotope count per minute.
- Inhibition rate (I %) (total combined tube cpm - compound cpm ) / (total combined tube cpm - non-specific combined tube cpm ) ⁇ 100%
- the D 2 receptor-positive drug spiperone and the test compound were dissolved in DMSO to 0.01 mol/L and diluted to 100 mol/L with deionized water.
- the receptor protein was expressed on the membrane after 48-72 hours.
- the cells were centrifuged at 1000 rpm for 5 min, and the supernatant was discarded.
- the cells were collected and stored in a -20 G C refrigerator. Resuspend with Tris-Cl (pH 7.4) during the experiment.
- Receptor competition combined experiment Add 20 ⁇ and 160 ⁇ receptor protein of test compound and isotope ligand to the reaction tube, so that the final concentration of test compound and positive drug is 10 mol/L, incubate in 30 ° ⁇ water bath After 50 111, immediately transfer to the ice bath to terminate the reaction; on a microporous cell sample collector, rapidly filter through GF/B glass fiber filter paper, and use eluent (50 mM Tris-HCl, H 7.4) 3 ml x 3 times Dry in a microwave oven for 8 to 9 minutes, transfer the filter paper into a 0.5 ml centrifuge tube, and add 500 ⁇ L of fat-soluble scintillation fluid. The light was allowed to stand for more than 30 min, and the radioactivity was measured by counting. Calculate the percentage inhibition of isotopic ligand binding by each compound according to the following formula:
- Inhibition rate (I %) (total combined tube cpm - compound cpm ) / (total combined tube cpm - non-specific combined tube cpm ) ⁇ 100%
- the 5-HT 1A receptor positive drug 5-hydroxytryptamine was dissolved in deionized water to 0.01 mol/L; the test compound was dissolved in DMSO to 0.01 mol/L, and then diluted to 100 4 mol/dise with deionized water. L.
- 5-111 ⁇ receptor isotopic ligand 8-OH-DPAT 5-111 ⁇ receptor isotopic ligand 8-OH-DPAT; GF/C glass fiber filter paper; Sex scintillation fluid; 5-HT 1A receptor protein expressed by HEK-293 cells.
- the crude sieve was used to determine the competitive inhibition rate of [ 3 H] 8-OH-DPAT binding to 5-HT 1A receptor in each compound ⁇ / L concentration; the compound with inhibition rate higher than 90% was subjected to a series of concentrations of receptor binding.
- the half-inhibition amount (IC 5 Q, inhibition of 50% [1H] 8-OH-DPAT concentration of the compound required for binding to the 5-HT 1A receptor) was determined.
- Two sets of tubes were tested per concentration and each compound was tested twice independently.
- the positive drug spiperone and the test compound were dissolved in DMSO to 0.01 mol/L and then diluted to 100 mol/L with deionized water.
- HEK-293 cells were transfected with a plasmid vector containing the 5-HT 2A receptor protein gene, using calcium phosphate transfection method, and cultured from the transfected cells through a medium containing G418, and selecting cell orders. Cloning and radionuclide binding experiments finally resulted in stable cell lines stably expressing the 5-HT 2A receptor protein.
- HEK-293 cells were infected with recombinant viruses containing the above various genes. After 48-72 hours, the receptor protein was expressed in a large amount on the membrane. The cells were centrifuged at 1000 rpm for 5 min, and the culture solution was discarded. The cells were collected and stored at -20 °. C refrigerator spare. Tris-HCl reaction buffer (pH 7.7) was used in the experiment. Resuspend.
- Receptor competition combined experiment Add 10 ⁇ and 80 ⁇ receptor protein of test compound and isotope ligand to the reaction tube, so that the final concentration of test compound and positive drug is 10 mol/L, incubate in 37° ⁇ water bath. After 1 5 111, immediately transfer to the ice bath to terminate the reaction; on a microporous cell sample collector, pass through GF/B glass fiber filter paper for rapid filtration, and use an eluent (50 mM Tris-HCl, H 7.7) 3 mlx3 Then, use a microwave oven for 8 to 9 minutes to dry, transfer the filter paper into a 0.5 ml centrifuge tube, and add 500 ⁇ L of fat-soluble scintillation fluid. The light was allowed to stand for more than 30 min, and the radioactivity was measured by counting. Calculate the percentage inhibition of isotopic ligand binding by each compound according to the following formula:
- Inhibition rate (I %) (total combined tube cpm - compound cpm ) / (total combined tube cpm - non-specific combined tube cpm ) ⁇ 100%
- the compound was subjected to two separate tubes per experiment and three separate experiments were performed.
- NT The activity of this receptor was not tested; NA: Inactive.
- the activity of the compound 5a-5e on the receptor is either maintained or increased compared to the reference compound SKF 38393.
- the affinity of the compound 5b to the receptor is about 10-fold higher; while the compounds 11a and lib are compared with the reference compound SKF 83959, not only the activity of the receptor is maintained, but also the D 2 receptor is shown to be high. Affinity, this has never been reported in this class of compounds.
- the compounds of the present invention have certain activities of 5-111 ⁇ and 5-HT 2A , showing broad biological activity and good application prospects of such compounds.
- Levodopa was dissolved in sterile saline at a concentration of 6 mg/ml and 15 mg/ml benserazide was added.
- Compound l ib was dissolved in DMSO, diluted to 1 mg/ml with physiological saline, and the final DMSO concentration was
- PD model preparation Rats were anesthetized with chloral hydrate (300 mg/kg, ip) and fixed in the brain. On the stereo locator. Previously used as a starting point, 6-OHDA was injected into the central forebrain bundle (MFB) according to coordinates (mm) to destroy the substantia nigra: anterior (AP), -2.5; side-open (L), +2.0; dorsoventral (DV) , -8.5. This experiment destroyed the left side of the substantia nigra. 6-OHDA was dissolved in artificial cerebrospinal fluid containing 0.05% vitamin C at a concentration of 2 ⁇ ⁇ / ⁇ 1. The injection volume per rat was 8 ⁇ ⁇ /4 ⁇ l.
- the injection speed was 1 ⁇ /min, and the micro syringe stayed for 2 minutes after the injection, and then slowly pulled out.
- 25 mg/kg (ip) of desipramine was administered 30 minutes before the 6-OHDA injection to prevent the loss of 6-OHDA by the adrenergic neurons.
- the wound was sutured after surgery, and 50,000 units of penicillin (ip) were administered and placed in a clean cage.
- the rats were placed in a 50 cm diameter pot. After 10 to 20 minutes, subcutaneous injection of 0.2 mg/kg apomorphine was performed, and the contralateral rotation was counted.
- a PD model that was rotated more than 20 turns to the opposite side within 5 minutes was considered a successful PD model for subsequent experiments.
- Levodopa-induced dyskinesia PD rats were given levodopa 6 mg/kg (ip) once a day for 21 days. The dyskinesia was evaluated with an abnormal involuntary movement (AIM) score.
- AIM abnormal involuntary movement
- results were expressed as meani se (mean standard error), and t-test was performed. A p-value of less than 0.05 was considered statistically significant.
- Rats induced significant dyskinesia over 21 days. On day 22, rats were given lib 1 mg/kg or vehicle (solvent control) and levodopa was given 15 minutes later for AIM score. It was found that compound lib significantly attenuated dyskinesia caused by levodopa (Fig. 1. *p ⁇ 0.05o n 9).
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Psychology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
一类新型苯并氮杂卓类化合物及其制备方法和用途 技术领域
本发明涉及一类苯并氮杂卓类化合物及其制备方法, 这些化合物具有 对多巴胺1^受体、 多巴胺 D2受体、 5-羟色胺 1A受体、 5-羟色胺 2A受体 的活性,并因此可应用于多种治疗领域,尤其是治疗中枢神经***的疾病, 例如精神***症、 抑郁症, 焦虑症、 帕金森氏症以及抗帕金森氏病 /精神分 裂症药物引起的运动障碍及神经保护等。
背景技术
1、 多巴胺 D^ D2受体
多巴胺是哺乳动物体内重要的儿茶朌胺类神经递质, 对多种生理功能 均有调控作用。 外周多巴胺***对调控心血管***功能、 控制儿茶朌胺释 放和激素分泌、 消化功能及胃肠道运动有着重要的功能。 中枢多巴胺*** 则被认为与一系列的中枢退行性疾病(如帕金森氏症、 亨廷顿舞蹈病、精神 ***症等)和精神紊乱有关。
多巴胺是通过多巴胺受体 (D D2、 D3、 D4、 D5)发挥作用的。 多巴胺 受体属于 G-蛋白偶联受体家族, 分为
和 D5两种亚型, 它们特异性地与苯并氮杂卓类( benzazepine ) 系列化合物结 合, 并激活腺苷酸环化酶, 引起 cAMP的升高。 D2类包括 D2、 D3、 D4三 种亚型, 它们被激活后抑制腺苷酸环化酶的活性, 降低 cAMP水平。
多巴胺 受体是哺乳动物大脑中分布最为广泛的受体亚型。 受体 在尾状核、 壳核、 伏核中分布最多, 其在谷氨酸传导的突触前末梢也有一 定分布。多巴胺 D2受体是第二个含量最高的多巴胺受体, 高度集中在尾壳 核、 视束和脑垂体, 少量表达在丘脑、 腹侧被盖部等。 多巴胺
D2受 体都参与了人的精神状态和意识形态等的调节。
2、 5-羟色胺受体
5-羟色胺 (5-HT)也是一种重要的中枢神经递质, 在一系列的生理功能 中发挥了重要的作用, 被认为与痛觉、 摄食行为、 性行为、 情感、 睡眠、 记忆等有关。 5-HT的合成、储存、膜摄取及代谢与 5-HT受体共同构成 5-HT 神经***。 根据氨基酸序列、 基因结构、 与其偶连的第二信使和药理学表 征, 5-HT受体至少可以分为 7类, 16种亚型。 除了 5-HT3受体是属于配 基-门控离子通受体外, 其余属于 G-蛋白偶联受体家族。 其中 5-HTi受体 包括 5种亚型 (5-HT1A、 5-HT1B、 5-HT1D、 5-HT1E、 5-HT1F ), 5-HT2受体 包括 3种亚型 (5-HT2A、 5-HT2B、 5-HT2C )。
3、 多巴胺受体、 5-羟色胺受体和帕金森氏症、 精神***症
帕金森氏症 (Parkinson's disease, PD)又名震颤麻療 (paralysis agitans), 是一种常见的中老年人神经***变性疾病。 临床表现为静止性震颤、 动作 迟緩、 运动减少、 肌强直和姿势平衡障碍 4大主要特征, 起病年龄多见于 50 ~ 60岁。 研究表明多巴胺受体激动剂, 尤其是多巴胺 D^ D2受体激动 剂是治疗帕金森氏症的有效手段之一。 具有多巴胺 受体活性的化合物, 如麦角灵 CY208243及其类似物 dihydrexidine, dinasoline等表现出良好的 抗帕金森活性;多巴胺 D2受体激动剂主要用来治疗早期帕金森病或在晚期 与左旋多巴合用以减少左旋多巴这一常规用药剂量, 或緩解长期用药带来 的运动障碍及疗效波动等副作用。 这类药物包括麦角类, 如溴隐亭 ( Bromocriptine ), 培高利特 ( Pergolide )、 卡麦角林 ( Cabergoline )、 利舒 脲 (Lisuride ) 等和非麦角碱类, 如罗皮尼罗 ( Ropinirole )、 吡贝地尔 ( Piribedil )、 莫达菲尼( Modafmil )、 普拉克索 ( Pramipexole )、 阿朴*** ( Apomorphine )等; 运动障碍(dyskinesia )是帕金森氏病治疗中出现的 常见副作用。 5-HT1A受体激动剂已被证明有抗运动障碍作用。 例如 5-HT1A 受体激动剂沙立佐坦 (Sarizotan ) 能减轻鼠和猴 PD模型的运动障碍, 且
已经在 PD病人上进行试验并有较好抗运动障碍效果。
众多实验证明, 5-羟色胺受体在精神***症、 抑郁症、 焦虑症的发生、 发展和治疗中有着重要的作用。 而具有多巴胺和 5-羟色胺活性的药物是目 前抗抑郁药的主要选择, 如丁螺环酮 ( Buspirone )、 坦度螺酮 ( Tandospirone )、 吉旅隆 ( Gepirone )、 扎螺酮 ( Zalospirone ) 等。 另夕卜, 作用于多巴胺和 5-羟色胺受体的药物在其他精神障碍疾病的治疗中也有着 重要的作用。
发明内容
本发明的一个目的是提供通式( I )表示的一类新型苯并氮杂卓类化合 物或其立体异构体、 药学上可接受的盐或药学上可接受的溶剂合物。
本发明的另一目的是提供该类化合物的制备方法。
本发明的又一目的是提供该类化合物的医药用途, 这类化合物通常具 有多巴胺1^受体活性, 其多巴胺 D2受体活性属首次报道; 这类化合物同 时还具有 5-HT1A、 5-HT2A受体活性; 由此, 该类化合物具有在制备治疗中 枢神经***疾病中的用途, 尤其是精神***症、 抑郁症、 焦虑症、 帕金森 氏症和抗帕金森氏病 /精神***症药物 I起的运动障碍或神经保护等。
本发明提供如下通式( I )表示的苯并氮杂卓类化合物或其立体异构体、 药学上可接受的盐或药学上可接受的溶剂合物。
为氢、 卤素、 羟基、 C1-C12经基、 C1-C12烃基氧基或 C1-C12烃 基氨基, 所述的烃基为饱和或不饱和的直链、 支链或环状烃基, 且非必需 地被卤素或含 0-3个氧原子的五元或六元芳基取代; 例如: 氢, 曱基, 三 氟曱基, 乙基, 正丙基, 异丙基, 丁基, 异丁基, 叔丁基, 烯丙基, 炔丙 基, 环丙基, 环丁基, 环丙曱基, 环丁曱基, 苄基, 苯乙基, 苯乙烯基,
2-氟乙基, 3-氟丙基, 2-曱氧基乙基, 顺或反式 -3-碘-烯丙基, 3,4-二氯-苯 基乙基, 3-呋喃曱基, 2-呋喃曱基, 3-四氢呋喃曱基或 2-四氢呋喃曱基, 氟, 氯, 溴, 碘, 羟基, 曱氧基, 乙氧基, 异丙氧基, 曱基氨基, 乙基氨 基, 异丙基氨基等。
R2为氢, 未取代或卤素、 C 1 -C6烷氧基、 含 0-3个选自氧、 氮和硫原 子的五元或六元芳香或脂肪杂环取代的饱和或不饱和的直链或支链的 C1-C10经基、 环状的 C3-C10烃基或 C1-C6的酰基。 例如: 氢, 曱基, 三 氟曱基, 乙基, 正丙基, 异丙基, 丁基, 异丁基, 叔丁基, 正戊基, 正己 基, 正庚基, 正辛基, 烯丙基, 炔丙基, 2-氟乙基, 3-氟乙基, 2-曱氧基 乙基, 3-呋喃曱基, 乙酰基, 丙酰基, 三氟乙酰基, 环丙基, 环丁基, 环 戊基等。
R3为未取代或者卤素、羟基、 C1-C6烃基、 C1-C6烷氧基、氨基、 C1-C4 烷基氨基或腈基取代的苯基、 联苯基、 萘基或含 1-3个选自氧和硫原子的 五元或六元杂芳基; 例如: 苯基, 4-氯苯基, 4-氟苯基, 4-曱基苯基, 4- 曱氧基苯基, 4-羟基苯基, 4-氨基苯基, 4-曱基氨基苯基, 4-二曱 苯基, 4-腈基苯基, 4-联苯基, 3-氯苯基, 3-氟苯基, 3-曱基苯基, 3-曱氧基苯基,
3-羟基苯基, 3-氨基苯基, 3-曱基氨基苯基, 3-二曱氨基苯基, 3-腈基苯基, 3-联苯基, 2-氯苯基, 2-氟苯基, 2-曱氧基苯基, 2-羟基苯基, 苯基, 2-曱基氨基苯基, 2-二曱氨基苯基, 2-腈基苯基, 2-联苯基, 2-萘基, 1-萘 基, 2-呋喃, 2-噻喻, 2-吡咯, 3-呋喃, 3-噻喻, 3-吡咯等。
优选地,
通式(I ) 中:
为氢或 C1-C12烷基;
R2为氢或 C1-C10烷基;
R3为未取代或者卤素, C 1 -C6烃基或 C 1 -C6烷氧基取代的苯基或萘基。 更优选地,
通式(I ) 中:
Ri的位置为苯环的间位, 且为氢或 C 1 -C3的烷基;
R2为氢或 C1-C3的烷基;
R3为苯基、 曱基苯基、 曱氧基苯基、 氯苯基、 氟苯基或 2-萘基。
本发明提供通式(I )表示的苯并氮杂卓类化合物的制备方法, 为下述 两种方法中的任意一种。其中, 为氢、 卤素、羟基、 C1-C12烃基、 C1-C12 烃基氧基或 C1-C12烃基氨基, 所述的烃基为饱和或不饱和的直链、 支链 或环状烃基,且非必需地被 素或含 0-3个氧原子的五元或六元芳基取代; R2为氢, 未取代或卤素、 C1-C6烷氧基、 含 0-3个选自氧、 氮和硫原子的 五元或六元芳香或脂肪杂环取代的饱和或不饱和的直链或支链的 C 1 -C 10 烃基、 环状的 C3-C10烃基或 C1-C6的酰基; R3为未取代或者卤素、 羟基、 C1-C6烃基、 C1-C6烷氧基、 氨基、 C1-C4烷基氨基或腈基取代的苯基、 联苯基、 萘基或含 1-3个选自氧和硫原子的五元或六元杂芳基。
具体如下:
方法一:
首先, 3,4-二曱氧基苯乙胺的氨基进攻 1^取代的苯基环氧乙烷, 得到 氨基醇化合物。 然后, 该氨基醇化合物在三氟醋酸为溶剂时的浓硫酸的催 化下成环形成苯并七元环化合物。 该苯并七元环化合物在 Br2的作用下, 冰醋酸为溶剂时可以选择性地在 6位发生溴化反应。 得到的 6-溴代物与一 系列的 R3取代的硼酸在 2N Na2C03水溶液, Pd(PPh3)4存在下,发生 Suzuki 偶联, 得到 6-位与 R3偶联的化合物。 该化合物可以在三溴化硼的作用下, 7,8-位的双曱氧基保护基被脱除, 得到目标化合物; 或者与卤代物 R2X作 用, 得到 N-取代的化合物, N-取代的化合物在三溴化硼的作用下, 可得目 标化合物。
方法二:
首先, 3,4-二曱氧基苯乙胺和 取代的苯基环氧乙烷发生反应, 得到 氨基醇化合物。 然后, 该氨基醇化合物在三氟醋酸为溶剂时的浓硫酸的催 化下选择性成环形成苯并七元环化合物。 得到的苯并七元环化合物再选择 性地在 6位发生溴化反应。 得到的 6-溴代化合物在曱醛水溶液, 曱酸的存 在下发生 N-曱基化反应, 或者与卤代物 R2X反应, 得到 N-取代化合物。 该类化合物与一系列的 R3取代的硼酸在 Pd(OAc)2、 P(o-Tol)3、 K3P04存在 下, DMF为溶剂时, 发生 Suzuki偶联, 得到 6-位与 R3偶联的化合物。 6- 位与 R3偶联的化合物在三溴化硼的作用下, 7,8-位的双曱氧基保护基被脱 除, 从而得到目标化合物。
通式(I )表示的化合物含有一个手性中心, 因此可存在立体异构体。 本发明包括通式(I )表示的化合物的 R或 S单个立体异构体及它们的混 合物。
本发明也包括通式(I )表示的化合物的药学上可接受的盐。 例如与无 机酸如盐酸、 氢溴酸、 酸或磷酸, 与有机羧酸(例如: 柠檬酸(枸橼酸)、 乳酸、 苹果酸、 葡糖酸、 酒石酸, 己二酸、 醋酸、 琥珀酸、 富马酸、 抗坏 血酸和衣康酸等)或与有机磺酸(例如: 曱磺酸、 苯磺酸等)形成的无毒
酸加成盐。
本发明也提供了应用通式(I )表示的化合物或其立体异构体、 药学上 可接受的盐或药学上可接受的溶剂合物或者包含这种物质的药物组合物, 用以预防或治疗与多巴胺 D D2受体, 5-羟色胺 1 A受体或 5-羟色胺 2A 受体相关的疾病, 尤其是中枢神经***的疾病, 例如精神***症、抑郁症、 焦虑症,帕金森氏症和抗帕金森氏病 /精神***症药物引起的运动障碍以及 神经保护等。
本发明也包含这里公布的任何一种新的中间体。
附图说明
图 1为化合物 l ib对左旋多巴引起的运动障碍的影响。
具体实施方式
下面结合具体实施例对本发明作进一步阐述, 但不限制本发明。
制备实施例
1H-NMR用 Varian MercuryAMX300型仪测定; MS用 VG ZAB-HS或 VG-7070型仪测定, 除注明外均为 EI源 (70ev ); 所有溶剂在使用前均经 过重新蒸馏,所使用的无水溶剂均是按标准方法干燥处理获得; 除说明外, 所有反应均是在氮气保护下进行并 TLC跟踪,后处理时均经饱和氯化钠水 溶液洗涤和无水硫酸钠干燥过程; 产品的纯化除说明外均使用硅胶 ( 200-300 目)柱色 i普法; 其中硅胶(200〜300 目) 由青岛海洋化工厂生 产, GF254薄层硅胶板由烟台江友硅胶开发有限公司生产。
化合物 5a-5e的制备
化合物 3的制备可参考文献方法( Ross, S. T.; Franz, R. G.; Gallagher, G., Jr.; Brenner, M.; Wilson, J. W.; DeMarinis, R. M.; Hieble, J. P.; Sarau, H. M. J. Med. Chem. 1987, 30, 35-40; Weinstock, J.; Ladd, D. L.; Wilson, J. W.; Brush, C. K.; Yim, N. C. F.; McCarthy, M. E.; Tobia, P. E.; Hahn, R. A. J. Med. Chem. 1986, 29, 2315-2325 ) 。
苯基环氧乙烷(8.01 g, 6.62 mmol )和 3,4-二曱氧基苯乙胺( 10 g, 5.52 mmol )溶解在乙腈中, 90°C下回流反应 24小时。得到的黄色混合物,旋干, 用***重结晶得到白色化合物 1。 母液浓缩后柱层析分离共得到化合物 1 10.40 g ( 62.6% )o
化合物 1 (10.40 g, 3.45 mmol)溶于约 50 mL三氟醋酸( TFA ) 中, 向其中力入2.5 mL浓硫酸。 混合物在 100°C下回流反应 3小时后旋干溶剂, 得到的残余物用 4N NaOH水溶液中和至碱性, 乙酸乙酯萃取混合物 3次。 得到的有机相水洗, 盐水洗, 无水硫酸钠干燥, 过滤, 旋干溶剂后得到黄 色液体化合物 2 (8.5 g, 86.9 %)。
化合物 2 (1.9 g, 7.06 mmol) 的 30 mL醋酸和盐酸溶液 (醋酸:浓盐酸 =10: 1)在室温搅拌 10分钟, 然后将 Br2 (0.7 mL, 13.6 mmol)緩慢加入其中。
得到的溶液室温搅拌 3.5小时, 然后旋掉部分溶剂。得到的剩余物中加入 4N NaOH水溶液中和至碱性, CH2C12萃取 3次。 得到的有机相水洗, 盐水洗, 无水硫酸钠干燥,过滤,浓缩后柱层析分离,得到黄色液体化合物 3 (1.357 g, 53.2%)。 1H-NMR (300 MHz, CDC13): 7.36 (m, 2H), 7.26 (m, 1 H), 7.13 (d, J = 7.5 Hz, 2H), 6.40 (s, 1H), 4.31 (dd, J = 2.7, 6.7 Hz, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 3.48 (dd, J = 7.2, 13.8 Hz, 1H), 3.38 (dd, J = 3.0, 13.8 Hz, 1H), 3.23 (m, 1H), 3.15 (m, 1H), 2.94 (m, 2H), 2.71 (b, 1H)。
化合物 3 (100 mg, 0.28 mmol) , 苯硼酸 (45 mg, 0.36 mmol), Pd(PPh3)4 (27 mg, 0.02 mmol) , LiCl (15 mg, 0.28 mmol)置于 25 mL烧瓶中, 抽真空, N2保护, 向其中加入 0.5 mL Na2C03水溶液和 5 mL 曱苯和乙醇的混合溶剂 (曱苯:乙醇 =4: 1)。 得到的黄色混合物在 100°C下回流反应 36小时, 然后倒入 水中, 乙酸乙酯萃取 3次。 得到的有机相水洗, 盐水洗, 无水石克酸钠干燥, 过滤,浓缩后柱层析分离,得到黄色液体化合物 4a(40 mg, 35.2%)。 1H-NMR (300 MHz, CDC13): 7.40 (m, 5H), 7.26 (m, 5H), 6.47 (s, 1H), 4.33 (d, J = 5.7 Hz, 1H), 3.70 (s, 3H), 3.51 (s, 3H), 3.43 (m, 2H), 2.81 (m, 2H), 2.59 (m, 2H), 2.26 (b, 1H); 13C-雇 R (75MHz, CDC13): 150.1 , 144.8, 142.2, 139.6, 137.9, 137.0, 132.4, 129.9, 129.8, 128.6, 128.2, 127.8, 126.7, 126.3, 113.6, 60.4, 55.6, 53.5, 52.6, 47.6, 33.9; MS(EI-LR): 359(M+); MS (EI-HR): 理论值 359.1885 (M+) , 实测值 359.1902 (M+)。
化合物 4a (40 mg, 0.36 mmol)置于 8 mL CH2C12中, -78°C下搅拌半小 时, 然后向其中加入 BBr3 (1 M在 CH2C12) 溶液 6 mL。 低温搅拌半小时后 移至常温搅拌 20小时, 然后将反应体系置于 -78 °C下搅拌 30分钟后, 加入 6mL曱醇淬灭, 低温搅拌半小时后移至室温搅拌过夜。 旋干溶剂, 加入曱 醇, 旋干。 重复该操作数次。 制备薄层板分离得到灰色固体化合物 5a (14 mg, 30.6%)。 mp 198-205 °C ; 1H NMR (300 MHz, CD3OD) δ 7.45 (m, 4H), 7.28
(m, 6H), 6.29 (s, 1H), 4.63 (t, J= 5.4 Hz, 1H), 3.68 (m, 2H), 3.28 (m, 1H), 2.90 (m, 3H); 13C NMR (75 MHz, CD3OD) δ 145.5, 143.5, 142.2, 139.2, 134.5, 132.1, 131.9, 131.8, 130.7, 130.0, 129.9, 129.0, 128.8, 117.0, 51.8, 47.7, 47.5, 28.6; EI-MS m/z: 331 (M+); 元素分析: 理论值 C22H21N02'2HBr'2H20: C, 49.93; H, 5.14; N, 2.65. 实测值: C, 49.93; H, 5.30; N, 2.38。
根据相似的步骤可以得到化合物 5b, 5c, 5d和 5e。
5b: mp 180-184°C ; 1H NMR (300 MHz, CD3OD) δ 7.44 (m, 2H), 7.32 (m, 4H), 7.18 (m, 1H), 7.01 (m, 2H), 6.28 (d, J = 7.2 Hz, 1H), 4.61 (t, J = 5.4 Hz, 1H), 3.66 (m, 2H), 3.25 (m, 1H), 2.93 (m, 2H), 2.77 (m, 1H), 2.38 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 145.5, 143.4, 142.3, 142.2, 139.7, 139.1, 134.5, 134.4, 132.5, 132.4, 132.2, 130.7, 129.9, 129.5, 129.0, 128.9, 128.8, 117.0, 116.9, 51.8, 51.7, 47.8, 47.7, 47.5, 28.6, 22.0; EI-MS m/z: 345 (M+); 元素分 析: 理论值 C23H23NO2 0.75HBr2.0H2O: C, 62.48; H, 6.33; N, 3.17. 实测值: C, 62.77; H, 6.29; N, 2.95。
5c: mp 203 -205 °C ; 1H NMR (300 MHz, CD3OD) δ 7.44 (m, 4H), 7.25 (m, 5H), 6.29 (s, 1H), 4.59 (brs, 1H), 3.64 (brs, 2H), 3.22 (m, 1H), 2.93 (m, 2H), 2.71 (m, 1H); 13C NMR (75 MHz, CD3OD) δ 145.4, 143.5, 142.4, 138.0, 134.8,
134.6, 133.6, 133.5, 130.7, 130.0, 129.9, 129.1, 128.9, 117.2, 52.0, 48.1, 47.5, 29.0; EI-MS m/z: 365 (M+);元素分析:理论值 C22H2。C! O2 0.85HBr 0.75H2O: C, 58.96; H, 5.03; N, 3.13. 实测值: C, 58.95; H, 5.07; N, 2.94„
5d: mp >210°C ; 1H NMR (300 MHz, CD3OD) δ 7.45 (m, 2H), 7.29 (m, 7H), 6.30 (s, 1H), 4.64 (brs, 1H), 3.68 (brs, 2H), 3.25 (m, 1H), 2.96 (m, 2H), 2.76 (m, 1H); 13C NMR (75 MHz, CD3OD) δ 165.2, 162.7, 145.4, 143.6, 142.3, 135.3, 134.7, 133.8, 133.7, 133.6, 130.9, 130.7, 129.9, 129.2, 128.9, 117.1,
116.7, 116.5, 51.8, 47.8, 47.4, 28.8; EI-MS m/z: 349 (M^); 元素分析: 理论值
C22H20FNO2 1.0HBr0.75H2O: C, 59.54; H, 5.11; N, 3.16. 实测值: C, 59.66; H: 5.19; N, 2.98 o
5e: mp 215-217°C ; 1H NMR (300 MHz, CD3OD) δ 7.81 (m, 4H), 7.46 (m, 4H), 7.33 (m, 4H), 6.33 (s, 1H), 4.64 (t, J = 5.1 Hz, 1H), 3.64 (m, 2H), 3.23 (m, 1H), 2.86 (m, 3H); 13C NMR (75 MHz, CD3OD) δ 145.5, 143.7, 142.3, 136.8, 136.7, 135.7, 135.4, 134.6, 134.5, 133.6, 132.0, 131.2, 130.7, 130.6, 130.1, 129.9, 129.4, 129.2, 129.1, 129.0, 127.8, 127.6, 123.9, 117.1, 51.8, 47.8, 47.5, 28.8; EI-MS m/z: 381 (M+); 元素分析: 理论值 C26H23NO2'1.25HBrl .0H2O: C, 62.38; H, 5.29; N, 2.80. 实测值: C, 62.50; H, 5.36; N, 2.48。
化合物 11a和 lib的制备
化合物 8的合成步骤参考化合物 3的合成。 1H NMR (300 MHz, CDC13) δ 7.24 (m, 1 H), 7.07 (d, J = 12 Hz, 1 H), 6.93 (m, 2 H), 6.42 (s, 1 H), 4.26 (dd, J = 2.4, 6.9 Hz, 1 H), 3.84 (s, 3 H), 3.68 (s, 3 H), 3.39 (m, 2 H), 3.17 (m, 2 H), 2.93 (m, 2 H), 2.34 (s, 3 H), 2.07 (brs, 1 H)。
向化合物 8 ( 400 mg, 1.06 mmol )的曱酸溶液中加入 2.5 mL 37%的曱 醛水溶液, 100°C下搅拌反应 6 小时。 然后旋掉部分曱酸, 得到的残余物 用 2 N NaOH水溶液中和至碱性。 混合物用 CH2C12萃取 2次, 得到的有机 相水洗, 盐水洗, 无水^ ^酸钠干燥。 过滤, 旋干溶剂, 得到的残余物柱层 析分离得到化合物 9 ( 360 mg, 86.75% )0 1H NMR (300 MHz, CDC13) δ 7.26 (m, 1 H), 7.08 (d, J = 8.1 Hz, 1 H), 6.98 (m, 2 H), 6.24 (s, 1 H), 4.34 (d, J= 8.1 Hz, 1 H), 3.81 (s, 3 H), 3.59 (s, 3 H), 3.38 (m, 1 H), 3.14 (m, 2 H), 2.84 (m, 2 H), 2.35 (s, 3 H), 2.34 (s, 3 H), 2.28 (m, 1 H)。
化合物 9 ( 100 mg, 0.26 mmol ), 3-曱基苯硼酸( 70 mg, 0.51 mmol ), Pd(OAc)2 ( 12 mg, 0.53 mmol ), P(o-Tol)3 ( 60 mg, 0.20 mmol ), K3P04 ( 544 mg, 2.56 mmol )的 DMF溶液在 N2保护下, 120°C下搅拌过夜。 然后将得 到的混合物浓缩, 浓缩产物溶于 CHC13中, 有机相水洗, 盐水洗, 无水石克 酸钠干燥。过滤,旋干溶剂,得到的残余物柱层析分离得到 66 mg粗品 10a。
66 mg化合物 10a置于 9 mL CH2C12中, -78°C下搅拌半小时, 然后向 其中加入 BBr3 (l M, CH2C12为溶剂) 溶液 5 mL。 低温搅拌半小时后移至 常温搅拌过夜, 然后将反应体系置于 -78 V下搅拌 30分钟后, 加入 10 mL 曱醇淬灭, 低温搅拌半小时后移至室温搅拌 2小时。 浓缩, 加入曱醇, 旋 干。 重复该操作数次。 制备薄层板分离得到白色固体 11a ( 25 mg, 两步收 率为 21.6% )。 1H NMR (300 MHz, CDC13 + CD3OD) δ 7.38-7.32 (m, 1 H), 7.28-7.18 (m, 2 H), 7.11-6.97 (m, 5 H), 6.13 (s, 1 H), 4.46 (d, J = 9.0 Hz, 1 H), 3.42-3.34 (m, 1H), 3.05-2.94 (m, 2 H), 2.72 (dd, J = 6.9, 15.6 Hz, 1 H), 2.48 (s, 3 H), 2.40 (d, J = 3.3 Hz, 3 H), 2.35 (s, 3 H), 1.34 (t, J = 7.2 Hz, 2 H); 13C NMR (100 MHz, CDC13 +CD30D) δ 142.1, 141.9, 140.0, 138.1, 138.0, 136.5, 135.4, 130.7, 130.4, 129.1, 129.0, 128.9, 128.4, 128.3, 128.2, 127.9, 127.2, 127.1, 126.8, 125.2, 114.3, 62.2, 56.6, 46.6, 45.9, 29.4, 28.6, 21.1 , 21.0; EI-MS
m/z: 373(M+); 元素分析: 理论值 C24H25NO2'0.65HBr 1.5H20: C, 66.27; H, 6.82; N, 3.09. 实测值: C, 66.32; H, 6.90; N, 3.21 0
采用同样的合成步骤可以得到化合物 llb。 1H NMR (300 MHz, CDC13 + CD3OD) δ 7.82-7.71 (m, 3 H), 7.59 (s, 1 H), 7.39 (dd, J = 3.0, 6.0 Hz, 2 H), 7.22 (dd, J = 1.2, 8.1 Hz, 1 H), 7.12 (t, J = 7.5 Hz, 1 H), 6.97-6.87 (m, 3 H), 6.05 (s, 1 H), 4.27 (d, J= 9.3 Hz, 1 H), 3.18 (d, J= 12.0 Hz, 1 H), 2.76-2.54 (m: 4 H), 2.27 (s, 3 H), 2.23-2.14 (m, 4 H); 13C NMR (100 MHz, CDCI3+CD3OD) δ 142.6, 141.8, 140.0, 138.1, 136.0, 134.4, 134.2, 133.2, 132.3, 129.8, 129.0, 128.9, 128.7, 128.4, 128.1, 127.8, 127.7, 127.5, 127.4, 127.1, 126.02, 125.96, 125.8, 125.2, 114.5, 62.6, 56.7, 47.3, 46.2, 29.4, 29.2, 21.0; EI-MS m/z: 409 (M+);元素分析: 理论值 C28H27NO2'0.25HBr 1.0H2O: C,75.11 ; H, 6.58; N, 3.13。 实测值: C, 75.08; H, 6.42; N, 2.920 试验实施例
通过下面的药理试验阐述本发明所包括的化合物在多巴胺 D2受 体, 5-羟色胺 1A受体, 5-羟色胺 2A受体上的活性及其潜在应用。
一、 受体亲和力
1、 多巴胺 受体
( 1 ) 药物配制:
受体阳性药物 SCH-23390和受试化合物,参考化合物 SKF38393和 SKF83959用 DMSO溶解至 0.01mol/L, 用去离子水稀释至 100 mol/L。
( 2 ) 实验材料:
0 受体同位素配基 [3H] SCH23390, 购自 Amersham公司; (+ )布他 拉莫(Butaclamol ), 购自 RBI公司; GF/B玻璃纤维滤纸, 购自 Whatman 公司; 脂溶性闪烁液。 Tris由吉泰科技有限公司分装。
( 3 ) 细胞:
HEK-293 细胞, 经 48-72 小时后受体蛋白在膜上大量表达, 将细胞 lOOOrpm 离心 5 min后弃上清, 收集胞体, 存放于 -20GC冰箱保存。 实验 时用 Tris-Cl(pH 7.4) 重新混悬。
( 4 ) 实验方法:
受体竟争结合实验: 将待测化合物与同位素配基各 20 μΐ及 160 μΐ受 体蛋白加入反应试管中, 使受试化合物及阳性药物终浓度均为 10 mol/L, 30°〇水浴孵育50 111 后, 即刻移至冰浴终止其反应; 在微孔细胞样品收集 器上,经过 GF/B玻璃纤维滤纸快速抽滤,并用洗脱液 (50 mM Tris-HCl, H 7.4) 3 mlx3次, 用微波炉 8〜9 min烘干, 将滤纸移入 0.5 ml离心管中, 加 入 500 μΐ脂溶性闪烁液。 避光静置 30 min以上, 计数测定放射性强度。 按 以下公式计算各化合物对同位素配基结合的抑制率百分率: 其中, cpm为 每分钟同位素计数。
抑制率 (I %)= (总结合管 cpm -化合物 cpm ) / (总结合管 cpm -非特 异结合管 cpm ) χ 100%
粗筛抑制率高于 95%的化合物进行一系列浓度的受体结合试验, 确定 半数抑制量(IC5。与各受体结合所需化合物浓度)。 每浓度测定两副管, 每 个化合物进行两次独立试险。
2、 多巴胺 D2受体
( 1 ) 药物配制:
D2受体阳性药螺哌隆(spiperone ) 和受试化合物用 DMSO 溶解至 0.01mol/L, 用去离子水稀释至 100 mol/L。
( 2 ) 实验材料:
[3H]Spiperone( 118.0 Ci/mmol ),购自 Amersham公司;( + )Butaclamol, 购自 RBI公司; GF/B玻璃纤维滤纸, 购自 Whatman公司; 脂溶性闪烁液。
Tris由吉泰科技有限公司分装。
( 3 ) 细胞:
HEK-293 细胞, 经 48-72 小时后受体蛋白在膜上大量表达, 将细胞 lOOOrpm 离心 5 min后弃上清, 收集胞体, 存放于 -20GC冰箱保存。 实验 时用 Tris-Cl(pH 7.4) 重新混悬。
( 4 ) 实验方法:
受体竟争结合实验: 将待测化合物与同位素配基各 20 μΐ及 160 μΐ受 体蛋白加入反应试管中, 使受试化合物及阳性药物终浓度均为 10 mol/L, 30°〇水浴孵育50 111 后, 即刻移至冰浴终止其反应; 在微孔细胞样品收集 器上,经过 GF/B玻璃纤维滤纸快速抽滤,并用洗脱液 (50 mM Tris-HCl, H 7.4) 3 mlx3次, 用微波炉 8〜9 min烘干, 将滤纸移入 0.5 ml离心管中, 加 入 500 μΐ脂溶性闪烁液。 避光静置 30 min以上, 计数测定放射性强度。 按 以下公式计算各化合物对同位素配基结合的抑制率百分率:
抑制率 (I %)= (总结合管 cpm -化合物 cpm ) / (总结合管 cpm -非特 异结合管 cpm ) χ 100%
粗筛抑制率高于 95%的化合物进行一系列浓度的受体结合试验, 确定 半数抑制量(IC5。与各受体结合所需化合物浓度)。 每浓度测定两副管, 每 个化合物进行两次独立试险。
3、 5-羟色胺 1 A受体
( 1 ) 药物配制:
5-HT1A受体阳性药物 5-羟色胺( 5-hydroxytryptamine )用去离子水溶 解至 0.01mol/L; 受试化合物用 DMSO溶解至 0.01mol/L, 然后均用去离子 水稀释至 100 4mol/L。
( 2 ) 实验材料:
5-111^受体同位素配基 8-OH-DPAT; GF/C玻璃纤维滤纸; 脂溶
性闪烁液; HEK-293细胞表达的 5-HT1A受体蛋白。
( 3 ) 实验方法:
粗筛测定每个化合物 ΙΟμιηοΙ/L浓度对 [3H] 8-OH-DPAT与 5-HT1A受体 结合的竟争抑制率; 抑制率高于 90%的化合物进行一系列浓度的受体结合 试验, 确定半数抑制量(IC5Q, 抑制 50%[1H] 8-OH-DPAT与 5-HT1A受体结 合所需化合物浓度)。 每浓度测定两副管, 每个化合物进行两次独立试验。
4、 5-羟色胺 2A受体
( 1 ) 药物配制:
阳性药 spiperone和受试化合物均用 DMSO溶解至 0.01 mol/L,然后用 去离子水稀释至 100 mol/L。
( 2 ) 实验材料:
a、 5-HT2A细胞转染:
本实验用含有 5-HT2A受体蛋白基因的质粒载体转染 HEK-293细胞, 使用磷酸钙转染法, 并从转染后的细胞中, 通过含 G418的培养液培养, 以及挑选细胞单克隆和放射性培基结合实验,最终获得能稳定表达 5-HT2A 受体蛋白的稳定细胞株。
b、 受体结合实验材料:
同位素配基 [3H] Ketanserin (酮色林)(67.0Ci/mmol ),购自 PerkinElmer 公司; ( + ) spiperone , 购自 RBI公司; GF/B玻璃纤维滤纸, 购自 Whatman 公司; Tris进口分装; PPO、 POPOP购自上海试剂一厂; 脂溶性闪烁液。 Beckman LS-6500型多功能液体闪烁计数仪。
(3) 实验方法:
用含以上各种基因的重组病毒分别感染 HEK-293细胞, 48-72小时后 受体蛋白在膜上大量表达, 将细胞 1000 rpm离心 5 min后弃培养液, 收集 胞体, 保存于 -20 °C冰箱内备用。 实验时用 Tris-HCl反应緩冲液(pH 7.7 )
重新混悬。
受体竟争结合实验: 将待测化合物与同位素配基各 10 μΐ及 80 μΐ受体 蛋白加入反应试管中, 使受试化合物及阳性药物终浓度均为 10 mol/L, 37°〇水浴孵育 1 5 111 后, 即刻移至冰浴终止其反应; 在微孔细胞样品收集 器上,经过 GF/B玻璃纤维滤纸快速抽滤,并用洗脱液 (50 mM Tris-HCl, H 7.7) 3 mlx3次, 用微波炉 8〜9 min烘干, 将滤纸移入 0.5 ml离心管中, 加 入 500 μΐ脂溶性闪烁液。 避光静置 30 min以上, 计数测定放射性强度。 按 以下公式计算各化合物对同位素配基结合的抑制率百分率:
抑制率 (I %)= (总结合管 cpm -化合物 cpm ) / (总结合管 cpm -非特 异结合管 cpm ) χ 100%
化合物每次实验做两副管, 进行三次单独实验。
5、 试验结果
本发明中化合物 5a-e, 11 a-b的药理结果如表一和表二所示。
表一、 化合物 5a-e, 11 a-b的抑制率列表
NT: 没有测试该受体的活性; NA: 无活性。
由表一和表二可以看出, 化合物 5a-5e与参考化合物 SKF 38393相比 较, 对 受体的活性或是保持, 或是提高。 其中化合物 5b对 受体的亲 和力有约 10倍的提高;而化合物 11a和 lib与参考化合物 SKF 83959相比 较, 不但对 受体的活性得到了保持, 而且对 D2受体显示出了很高的亲 和力, 这是这类化合物中从未有过报道的。 除此之外, 本发明中的化合物 还具有一定的 5-111^和 5-HT2A的活性, 显示了这类化合物广泛的生物活 性和很好的应用前景。
二、化合物 lib对帕金森氏病药物左旋多巴引起运动障碍 (dyskinesia) 的研究
( 1 ) 药物配制:
左旋多巴溶于无菌生理盐水, 浓度为 6 mg/ml,加入 15 mg/ml苄丝肼。 化合物 l ib溶于 DMSO, 用生理盐水稀释到 1 mg/ml, 最后 DMSO浓度为
1%。
( 2 ) 实验材料:
雄性 SD大鼠( 200 ~ 250g ), 购自上海斯莱克实验动物公司。 6-OHDA ( 6-羟多巴胺)、 地昔帕明、 阿朴***购自 Sigma公司。 水合氯醛购自上海 化学试剂有限公司。 左旋多巴购自广西凌云制药厂, 苄丝肼购自湖北黄冈 金维康制药厂。
( 3 ) 实验方法:
PD模型制作: 大鼠用水合氯醛(300 mg/kg, ip )麻醉后, 固定在脑
立体定位仪上。 以前囟为起点, 按坐标 (mm)将 6-OHDA注射到中央前 脑束(MFB)以损毁黑质: 前后(AP), -2.5; 旁开(L), +2.0; 背腹(DV), -8.5。 本实验损毁左侧黑质。 6-OHDA溶解在含 0.05%维生素 C的人工脑 脊液中, 浓度为 2 μδ/μ1。 每只大鼠注射量为 8 μβ /4 μ1。 注射速度 1 μΐ/min, 注射完后微量注射器停留 2分钟, 然后緩慢拔出。 在 6-OHDA注射前 30 分钟给予 25 mg/kg (ip ) 地昔帕明, 防止去曱肾上腺素能神经元摄取 6-OHDA而损伤。 术后缝合伤口, 给予 5万单位青霉素(ip), 置于干净鼠 笼中饲养。 手术三周后, 将大鼠置于一直径 50 cm盆中, 适应 10~20分钟 后, 皮下注射 0.2 mg/kg阿朴***, 记数其向对侧旋转情况。 5分钟内向对 侧旋转大于 20转视为成功的 PD模型, 用于后续的实验。
左旋多巴诱导运动障碍: PD大鼠给予左旋多巴 6 mg/kg ( ip ), 每天一 次, 连续给药 21天。 运动障碍用异常不随意运动 (AIM)评分评价。
结果用 meani se (平均值士标准误)表示, 进行 t检验, p值小于 0.05 被认为有统计学意义。
(4)试验结果:
大鼠经 21 天诱导明显的运动障碍。 第 22 天, 给予大鼠化合物 lib 1 mg/kg或 vehicle (溶剂对照), 15分钟后给予左旋多巴, 进行 AIM评分。 结果发现化合物 lib能显著减轻左旋多巴引起的运动障碍(图 1。 * p<0.05o n=9)。
Claims
1、 一类如下通式(I )表示的苯并氮杂卓类化合物或其立体异构体、 药学上可接受的盐或药学上可接受的溶剂合物:
为氢、 卤素、 羟基、 C1-C12经基、 C1-C12烃基氧基或 C1-C12烃 基氨基, 所述的烃基为饱和或不饱和的直链、 支链或环状烃基, 且非必需 地被 素或含 0-3个氧原子的五元或六元芳基取代;
R2为氢, 未取代或者卤素、 C1-C6烷氧基、 含 0-3个选自氧、 氮和硫 原子的五元或六元芳香或脂肪杂环取代的饱和或不饱和的直链或支链的 C1-C10烃基、 环状的 C3-C10烃基或 C1-C6的酰基;
R3为未取代或者卤素、羟基、 C1-C6烃基、 C1-C6烷氧基、氨基、 C1-C4 烷基氨基或腈基取代的苯基、 联苯基、 萘基或含 1-3个选自氧和硫原子的 五元或六元杂芳基。
2、 根据权利要求 1 所述的苯并氮杂卓类化合物或其立体异构体、 药 学上可接受的盐或药学上可接受的溶剂合物, 其特征在于, 通式(I ) 中: 为氢或 C1-C12烷基;
R2为氢或 C1-C10烷基;
R3为未取代或者卤素、 C 1 -C6烃基或 C 1 -C6烷氧基取代的苯基或萘基。
3、 根据权利要求 2 所述的苯并氮杂卓类化合物或其立体异构体、 药 学上可接受的盐或药学上可接受的溶剂合物, 其特征在于, 通式(I ) 中:
Ri的位置为苯环的间位, 且为氢或 C 1 -C3的烷基;
R2为氢或 C1-C3的烷基;
R3为苯基、 曱基苯基、 曱氧基苯基、 氯苯基、 氟苯基或 2-萘基。
4、 根据权利要求 3 所述的苯并氮杂卓类化合物或其立体异构体、 药 学上可接受的盐或药学上可接受的溶剂合物,其特征在于,所述化合物为:
5、 根据权利要求 1-4 任意一项所述的苯并氮杂卓类化合物或其立体异构 体、 药学上可接受的盐或药学上可接受的溶剂合物, 其特征在于, 所述药 学上可接受的盐是该化合物与盐酸、 氢溴酸、 硫酸或磷酸的无机酸, 或
与柠檬酸、 乳酸、 苹果酸、 葡糖酸、 酒石酸, 己二酸、 醋酸、 琥珀酸、 富马酸、 抗坏血酸或衣康酸的有机羧酸, 或者与曱磺酸或苯磺酸的有机磺 酸形成的无毒酸加成盐。
6、 权利要求 1所述的通式(I )表示的苯并氮杂卓类化合物或其立体 异构体、 药学上可接受的盐或药学上可接受的溶剂合物的制备方法, 其特 征在于, 为下述两种方法中的任意一种:
方法一:
首先, 3,4-二曱氧基苯乙胺的氨基进攻 1^取代的苯基环氧乙烷, 得到氨基 醇化合物; 然后, 该氨基醇化合物在三氟醋酸为溶剂时的浓硫酸的催化下 成环形成苯并七元环化合物; 该苯并七元环化合物在 Br2的作用下, 冰醋 酸为溶剂时选择性地在 6位发生溴化反应;得到的 6-溴代物与 R3取代的硼 酸在 Na2C03水溶液, Pd(PPh3)4存在下, 发生 Suzuki偶联, 得到 6-位与 R3 偶联的化合物; 该化合物在三溴化硼的作用下, 7,8-位的双曱氧基保
护基被脱除, 得到目标化合物; 或者与卤代物 R2X作用, 得到 N-取 代的化合物, N-取代的化合物在三溴化硼的作用下, 可得目标化合物; 方法二:
首先, 3,4-二曱氧基苯乙胺和 取代的苯基环氧乙烷发生反应, 得到 氨基醇化合物; 然后, 该氨基醇化合物在三氟醋酸为溶剂时的浓硫酸的催 化下选择性成环形成苯并七元环化合物; 得到的苯并七元环化合物再选择 性地在 6位发生溴化反应; 得到的 6-溴代化合物在曱醛水溶液, 曱酸的存 在下发生 N-曱基化反应, 或者与卤代物 R2X反应, 得到 N-取代化合物; 该类化合物与 R3取代的硼酸在 Pd(OAc)2、 P(o-Tol)3、 K3P04存在下, DMF 为溶剂时, 发生 Suzuki偶联, 得到 6-位与 R3偶联的化合物; 6-位与 R3偶 联的化合物在三溴化硼的作用下, 7,8-位的双曱氧基保护基被脱除, 从而 得到目标化合物;
上述 Ri、 R2和 R3的定义与权利要求 1相同。
7、 权利要求 1所述的通式(I )表示的苯并氮杂卓类化合物或其立体异构 体、 药学上可接受的盐或药学上可接受的溶剂合物在制备预防或治疗与多 巴胺 受体、 多巴胺 D2受体、 5-羟色胺 1 A受体或 5-羟色胺 2A受体
相关的疾病的药物中的用途。
8、 根据权利要求 7所述的用途, 其特征在于, 所述的与多巴胺 1^受 体、 多巴胺 D2受体、 5-羟色胺 1A受体或 5-羟色胺 2A受体相关的疾病为 中枢神经***的疾病。
9、 根据权利要求 8 所述的用途, 其特征在于, 所述的中枢神经*** 的疾病包括: 精神***症、 抑郁症、 焦虑症, 帕金森氏症或抗帕金森氏病 /精神***症药物引起的运动障碍以及神经保护。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200810200262.7 | 2008-09-23 | ||
CN200810200262A CN101684096A (zh) | 2008-09-23 | 2008-09-23 | 一类新型苯并氮杂卓类化合物及其制备方法和用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010037257A1 true WO2010037257A1 (zh) | 2010-04-08 |
Family
ID=42047508
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2009/001068 WO2010037257A1 (zh) | 2008-09-23 | 2009-09-22 | 一类新型苯并氮杂卓类化合物及其制备方法和用途 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN101684096A (zh) |
WO (1) | WO2010037257A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102276531A (zh) * | 2011-05-30 | 2011-12-14 | 扬子江药业集团广州海瑞药业有限公司 | 一种甲磺酸非诺多泮的制备方法 |
CN102895233B (zh) * | 2012-09-04 | 2015-06-24 | 苏州大学 | 苯并氮杂卓类化合物在制备预防或治疗癫痫的药物中的应用 |
CN114053256B (zh) * | 2020-07-30 | 2023-07-18 | 中国科学院上海药物研究所 | 一种预防和治疗精神障碍性疾病的化合物及其应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4265889A (en) * | 1978-05-05 | 1981-05-05 | Smithkline Corporation | 6-Lower alkyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines |
US4359464A (en) * | 1976-11-17 | 1982-11-16 | Smithkline Beckman Corporation | 3-Furylmethyl-6-halo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines and antihypertensive use thereof |
CN1341102A (zh) * | 1999-02-17 | 2002-03-20 | 色奈斯有限公司 | 多巴胺d1受体***化合物 |
CN101253153A (zh) * | 2005-09-01 | 2008-08-27 | 伊莱利利公司 | 作为5-HT<sub>2c</sub>受体激动剂的6-取代的2,3,4,5-四氢-1H-苯并[d]氮杂䓬 |
-
2008
- 2008-09-23 CN CN200810200262A patent/CN101684096A/zh active Pending
-
2009
- 2009-09-22 WO PCT/CN2009/001068 patent/WO2010037257A1/zh active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4359464A (en) * | 1976-11-17 | 1982-11-16 | Smithkline Beckman Corporation | 3-Furylmethyl-6-halo-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines and antihypertensive use thereof |
US4265889A (en) * | 1978-05-05 | 1981-05-05 | Smithkline Corporation | 6-Lower alkyl-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines |
CN1341102A (zh) * | 1999-02-17 | 2002-03-20 | 色奈斯有限公司 | 多巴胺d1受体***化合物 |
CN101253153A (zh) * | 2005-09-01 | 2008-08-27 | 伊莱利利公司 | 作为5-HT<sub>2c</sub>受体激动剂的6-取代的2,3,4,5-四氢-1H-苯并[d]氮杂䓬 |
Non-Patent Citations (3)
Title |
---|
DATABASE CA 8 July 1989 (1989-07-08), SEEMAN, PHILIP ET AL.: "Dopamine D1 and D2 receptor selectivities of agonists and antagonists.", retrieved from STN Database accession no. 111:545 * |
MIYAURA, NORIO ET AL.: "Palladium-catalyzed cross-coupling reactions of organoboron compounds.", CHEM. REV., vol. 95, no. 7, November 1995 (1995-11-01), pages 2457 - 2483 * |
ZHANG, JING ET AL.: "Synthesis of 6-substituted 1-phenylbenzazepines and their dopamine D' receptor activities.", BIOORG. MED. CHEM., vol. 16, no. 21, 1 November 2008 (2008-11-01), pages 9425 - 9431 * |
Also Published As
Publication number | Publication date |
---|---|
CN101684096A (zh) | 2010-03-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI374141B (en) | Spiro-oxindole compounds and their uses as therapeutic agents | |
JP4311770B2 (ja) | アミノメチル−2,3,8,9−テトラヒドロ−7H−1,4−ジオキシノ[2,3−e]−インドール−8−オンおよびその誘導体 | |
US5302599A (en) | Therapeutically useful heterocyclic indole compounds | |
TWI492947B (zh) | 5-ht受體調節劑及其使用方法 | |
JP2008525524A (ja) | アリールスルホンアミドモジュレーター | |
TWI402272B (zh) | 作為血清素5-HT2c受體配位體之噻吩基及吡咯基氮呯及其用途 | |
WO2005047286A1 (ja) | スピロ複素環化合物 | |
TW201035055A (en) | Substituted 5,6-dihydro-6-phenylbenzo[f]isoquinolin-2-amine compounds | |
TW200813064A (en) | Purinone derivatives as HM74A agonists | |
BRPI0517211B1 (pt) | Composto, composição farmacêutica e seu uso | |
CA2583353A1 (en) | Thienopyridinone compounds and methods of treatment | |
CN113748112A (zh) | 用于制造(2s,3s,4s,5r,6s)-3,4,5-三羟基-6-(((4ar,10ar)-7-羟基-1-丙基-1,2,3,4,4a,5,10,10a-八氢苯并[g]喹啉-6-基)氧基)四氢-2h-吡喃-2-甲酸的方法 | |
JP5010594B2 (ja) | βアドレナリン受容体キナーゼ1のインヒビターとしてのピラゾロピリジン誘導体 | |
RU2489432C2 (ru) | ТРИАЗОЛО[1,5-a]ХИНОЛИНЫ В КАЧЕСТВЕ ЛИГАНДОВ РЕЦЕПТОРА АДЕНОЗИНА А3 | |
CN111606928A (zh) | 一种氮杂环二酮化合物及其制备方法 | |
EP1057814B1 (en) | Tetrahydrobenzindole derivatives | |
JP2010521521A (ja) | セロトニン5−ht6受容体の調節に応答する障害の治療に好適なアゼチジン化合物 | |
JP2010520917A (ja) | 肥満治療用三環式イソキノリン誘導体 | |
WO2010037257A1 (zh) | 一类新型苯并氮杂卓类化合物及其制备方法和用途 | |
TW201038267A (en) | Heterocyclic compounds as MEK inhibitors | |
PT1831227E (pt) | Proteínas buganina modificadas, citotoxinas e métodos e utilizações das mesmas | |
US9271980B2 (en) | Deuterium-enriched pyrimidine compounds and derivatives | |
TW201910327A (zh) | 治療疼痛及疼痛相關病症之新型丙胺衍生物 | |
CN108727416B (zh) | 三环杂芳香体系酰胺衍生物及其制备和用途 | |
WO2007120596A1 (en) | DIHYDRO[1,4]DIOXINO[2,3-e]INDAZOLE DERIVATIVES AS 5-HYDROXYTRYPTAMINE-6 LIGANDS |
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: 09817171 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 09817171 Country of ref document: EP Kind code of ref document: A1 |