CN111825613B - Tetrahydroisoquinoline compounds as selective estrogen receptor down-regulation agent, and synthesis method and application thereof - Google Patents
Tetrahydroisoquinoline compounds as selective estrogen receptor down-regulation agent, and synthesis method and application thereof Download PDFInfo
- Publication number
- CN111825613B CN111825613B CN202010823714.8A CN202010823714A CN111825613B CN 111825613 B CN111825613 B CN 111825613B CN 202010823714 A CN202010823714 A CN 202010823714A CN 111825613 B CN111825613 B CN 111825613B
- Authority
- CN
- China
- Prior art keywords
- compound
- estrogen receptor
- selective estrogen
- regulator
- pharmaceutically acceptable
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention relates to the field of medicines, in particular to a tetrahydroisoquinoline derivative, a preparation method and application thereof in medicines. Compared with the prior art, the compound of the invention has the following advantages besides better SERD activity: the initial safety of the compound is superior to that of the existing tetrahydroisoquinoline SERD compound; animal in vivo experimental data show that the drug substitution parameters AUC and Cmax of the compound are obviously higher than those of the existing tetrahydroisoquinoline SERD compound under the same dosage; ③ the compounds of the present application have a lower risk of hERG safety. The compound has better PK property, so that the compound can be reasonably predicted to be applied to clinic, the effective dose is lower, and the medication safety is higher.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a tetrahydroisoquinoline derivative, a preparation method and a medical application thereof.
Background
The Estrogen Receptor (ER) is a receptor through which endogenous estrogens interactMediates ligand-activated transcriptional regulatory proteins induced by a variety of biological effects. ER comprises two subtypes: ER encoded by different genes respectivelyαAnd ERβ。ERαAnd ERβAt the amino acid level, a high degree of similarity is shown, up to 97% in the DNA binding domain and 56% in the ligand binding domain, however, only 24% of low homology is present at the N-terminus. ER comprises 6 structural domains (A-F) and consists of 4 main functional regions, the functional region of the N-terminal A/B domain has a ligand-independent transcription activation functional region AF-1, AF-1 has constitutive activation activity, the transcription of a target gene is activated through the action of a basal transcription factor, a reactivation factor and other transcription factors, the region has a plurality of phosphorylation sites, and the function of AF-1 depends on protein phosphorylation in literature. The C domain constituting the DNA Binding Domain (DBD) is highly conserved, contains 2 zinc finger domains, and is capable of specifically binding to the target DNA, while it plays an important role in receptor dimerization. The D domain is a hinge region, linking the DBD and the ligand domain (LBD), and is less conserved (homology between two subtypes is only 30%). The C-terminal E domain constitutes a Ligand Binding Domain (LBD) that determines specific binding of ER to ligands such as estrogen, SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor down-regulator), and the like. LBD has ligand-dependent transcriptional activation function area AF-2, and with AF-1 to function in cooperation with ER receptor activation target gene transcription. Meanwhile, LBD has a strong dimerization interface and can still function without a ligand, so that LBD is a key site for receptor dimerization.
ERαMainly distributed in the uterus, ovary, testis, pituitary, kidney, epididymis and adrenal gland, while ERβIt is mainly distributed in prostate, ovary, lung, bladder, brain and blood vessels. Since either full agonists or full antagonists have more serious side effects, the study of selective estrogen receptor modulators, SERMs, has proceeded. By "selective" is meant that the SERM is present in certain tissues such as bone, liver, ER of the cardiovascular systemβAgonists are present in the focal zone and antagonists in other tissues such as the mammary gland. It is atUterus (ER)αMore prominent region) may be an agonist or an antagonist. The currently marketed SERMs include Tamoxifen (Tamoxifen), Raloxifene (Raloxifene), Bazedoxifene (Bazedoxifene), Toremifene (Tormeifene), and the like, but the research finds that the currently marketed SERMs still have serious side effects, such as endometrial hyperplasia, polyps, endometrial cancer and the like caused by long-term administration of Tamoxifen and Toremifene, and the common side effects of Raloxifene include hot flashes, leg pain, breast tenderness, venous embolism and the like. Therefore, research and development of novel compounds remain problems to be solved urgently.
Selective estrogen receptor down-regulators (SERDs) are a class of drugs that block estrogenic activity by inhibiting the function of the two transcriptional activation domains of the estrogen receptor, AF1 and AF2, and are a class of classical antiestrogens (full antagonists). Fulvestrant (Fulvestrant) is considered to be a holoestrogen receptor antagonist and induces ERαImmobilization at the nuclear matrix and through the ubiquitin-proteasome pathway ERαRapid degradation (j.biol.chem.,2006,14, 9607-. Fulvestrant has both antagonism and degradation of ERαThe two functions of (1) have certain curative effect on breast cancer patients who have developed anti-hormone drug resistance (Cur. Med. chem.,2010,17, 902-.
Fulvestrant is the only SERD class of drug currently approved for clinical use for the treatment of ER + breast cancer, but it has poor drug-forming properties, is rapidly metabolized and must be administered by monthly intramuscular injection, which limits effective degradation of ER (-50% ER degradation in clinical samples) compared to complete ER degradation seen in vitro studies.
There is a strong clinical need for drugs that inhibit estrogen receptor activity, down-regulate estrogen receptor expression levels, or induce estrogen receptor degradation to improve the therapeutic efficacy against early, metastatic, or drug-resistant breast cancer or other diseases associated with estrogen receptor overactivity.
WO2014191726A, WO2018077630A by AstraZeneca discloses a series of SERD compounds including the early clinical drugs AZD9496 and AZD 9833:
patent WO2016202161a1 discloses a class of piperidine derivatives, including tetrahydroisoquinoline derivatives, for SERD use; similar SERD-like compounds are also disclosed in patents CN109867659A, WO2017107754A1, WO2017174757A1, WO2018233591A1, WO2018233620A1, WO2019223715A1, WO2019228443A1, EP 1113007. The disclosed selective estrogen receptor down-regulator patent applications also include WO2014165723, WO2014151899, WO2014141292, WO2014135834, WO2014106848, WO2018077630, WO2019057201, WO2019192533, WO2020037203, US10149839, US 6608203.
Selective estrogen receptor down-regulation has shown some therapeutic advantages, but there is still a need to develop more orally available SERDs that allow drug candidates to have more excellent properties, such as better efficacy, less side effects, better pharmacokinetic properties, longer dosing intervals, etc., and thus better use for the prevention or treatment of estrogen receptor related diseases.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a selective estrogen receptor down-regulator compound with better curative effect and lower side effect, and isomers or pharmaceutically acceptable salts thereof.
The technical scheme for solving the technical problems is as follows:
a selective estrogen receptor down-regulator compound, an isomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound has a structural formula shown in formula I:
wherein:
R1is H or halogen;
R2is C1~6Alkyl or C3~8A cycloalkyl group;
R3、R4、R5each independently selected from H, Me, halogen, halomethyl or CH2OH; or R3、R4、R5Any two groups of (a) together with the carbon atoms to which they are commonly attached form a three-or four-membered ring;
x is-C (R)6) -or-N-;
R6is H or halogen;
y is selected from the following structures:
preferably, the selective estrogen receptor down-regulator compound or the pharmaceutically acceptable salt thereof has a structural formula shown in formula I:
wherein:
R1is H or halogen;
R2is C1~4Alkyl or C3~8A cycloalkyl group;
R3、R4、R5each independently selected from H, Me, halogen, halomethyl or CH2OH; or R3、R4、R5Any two groups of (a) together with the carbon atoms to which they are commonly attached form a three-or four-membered ring; the three-membered ring is cyclopropyl or oxirane, and the four-membered ring is cyclobutyl or oxetane;
x is-C (R)6) -or-N-;
R6is H or halogen;
y is selected from the following structures:
preferably, the group-CH in the compounds of the formula I or I-12-C(R3)(R4)(R5) Selected from the following structures:
preferably, R in the compounds of the formula I or I-12Is C1~3Alkyl or C3~8A cycloalkyl group.
In particular, the selective estrogen receptor down-regulator compound is selected from the compounds in table 1:
TABLE 1
A second aspect of the present invention provides a method for synthesizing the above compound, wherein:
(1) carrying out substitution reaction on the compound IA and the compound IB to obtain a compound IC;
(2) cyclizing the compound IC and the compound ID to obtain a compound IE;
(3) hydrolyzing compound IE ester, and separating with chiral column to obtain compound of formula I; the specific reaction formula is as follows:
(1) carrying out substitution reaction on the compound IA and the compound IB to obtain a compound IC;
(2) cyclizing the compound IC and the compound IF to obtain a compound IG;
(3) the compound of the formula I is obtained by carrying out European union substitution reaction and chiral column separation on a compound IG and a compound IH, and the specific reaction formula is as follows:
the remaining substituents are as defined above.
In a third aspect, the present invention provides the use of the above compound, an isomer or a pharmaceutically acceptable salt thereof for the preparation of an estrogen receptor down-regulator.
A fourth aspect of the present invention provides the use of a compound as described above, an isomer thereof or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or condition mediated or dependent on an estrogen receptor. Wherein the estrogen receptor mediated or dependent disease or condition is selected from the group consisting of cancer, Central Nervous System (CNS) deficiencies, cardiovascular system deficiencies, blood system deficiencies, immune and inflammatory diseases, susceptibility to infection, metabolic deficiencies, neurological deficiencies, psychiatric deficiencies, and reproductive deficiencies. Wherein the cancer may be breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumors, ovarian tumors, hemophilia, and leukemia; preferably breast, ovarian, endometrial, prostate or uterine cancer; more preferably breast cancer; the Central Nervous System (CNS) deficiency may be alcoholism or migraine; the cardiovascular system defect can be aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension; the blood system defect may be deep vein thrombosis; the immune and inflammatory diseases can be Graves' disease, arthritis, multiple sclerosis, liver cirrhosis; the infection susceptibility may be hepatitis b, chronic liver disease; the metabolic defect may be cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis; the neurological deficit can be alzheimer's disease, parkinson's disease, migraine, vertigo; the mental deficiency may be anorexia nervosa, Attention Deficit Hyperactivity Disorder (ADHD), dementia, major depressive disorder, psychosis; and the reproductive defect may be menstrual onset age, endometriosis, infertility, or the like.
The active substance can be formed into a composition for treating related diseases in an oral mode in the process of treating diseases. For oral administration, it can be prepared into conventional solid preparations such as tablet, powder or capsule.
The pharmaceutically acceptable salt may be, for example, a metal salt, an alkali metal salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like. Non-limiting examples of metal salts include, but are not limited to, salts of alkali metals, such as sodium, potassium, and the like; salts of alkaline earth metals, such as calcium, magnesium, barium, aluminum and the like. Non-limiting examples of salts with inorganic acids include, but are not limited to, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Non-limiting examples of salts with organic acids include, but are not limited to, salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, malic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
The fifth aspect of the present invention provides a composition, which comprises the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
As described in this application "C1~3Alkyl "means methyl, ethyl, n-propyl or isopropyl; the halogen refers to F, Cl, Br and I; said "C3~8Cycloalkyl "means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.
Compared with the prior art, the compound of the invention has the following advantages besides better SERD activity: the initial safety of the compound is superior to that of the existing tetrahydroisoquinoline SERD compound; animal in vivo experimental data show that the drug substitution parameters AUC and Cmax of the compound are obviously higher than those of the existing tetrahydroisoquinoline SERD compound under the same dosage; ③ the compounds of the present application have a lower risk of hERG safety. The compound has better PK property, so that the compound can be reasonably predicted to be applied to clinic, the effective dose is lower, and the medication safety is higher.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1:
examples 1 to 16 Synthesis of I-1
The synthetic route is as follows:
step 1:
compound IA-1(2.28g,0.01mol) and IB-1(2.24g,0.01mol) were added to 1, 4-dioxane (40mL), N-diisopropylethylamine (DIPEA, 3.87g,0.03mol) was added thereto, and the reaction system was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate/petroleum ether 1/1) to give the objective product IC-1(1.36g, yield 45%). LCMS MS Calcd. 302.4 MS Found 303.2[ M +1 ].
Step 2:
the compound IC-1(500mg,1.65mmol), ID-1(411mg,1.82mmol) and acetic acid (500mg,8.3mmol) were added to toluene (10mL), and the reaction was heated to 80 ℃ under nitrogen and stirred for 12 h. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate/petroleum ether 1/3) to give the objective product IE-1(430mg, yield 51%). LCMS MS Calcd 510.5 MS Found 511.3[ M +1 ].
And step 3:
compound IE-1(400mg,0.78mmol) was dissolved in a mixed solution of tetrahydrofuran (10mL) and water (1mL), and a 10% aqueous solution of lithium hydroxide (LiOH,38mg,1.56mmol) was added dropwise with stirring, after completion of the addition, the reaction was stirred at room temperature for 5 hours. Concentrating the reaction solution under reduced pressure to obtain organic solvent, adding 10% diluted acetic acid to adjust pH to 5-6, extracting with dichloromethane (10mL), and concentrating the organic layer to dryness. The residue was concentrated for chiral preparation (separation conditions: chiral preparative column CHIRALPAK AD, 5.0cm ID,25 cm; mobile phase: n-hexane: ethanol: trifluoroacetic acid: 85: 15: 0.1, flow rate: 60mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the title product I-1(120mg, yield 31%, pale yellow solid). MS m/z (ESI): 496.5 in Calcd, 497.3 in MS Found [ M +1]];1HNMR(400MHz,DMSO-d6):δ=12.10(br,1H),10.58(br,1H),7.45(d,J=13.2Hz,1H),7.35(d,J=8.0Hz,1H),7.13(d,J=8.0Hz,1H),6.94(s,1H),6.76(s,2H),6.27(d,J=13.2Hz,1H),5.19(s,1H),3.22(s,3H),3.11(m,1H),2.25-2.45(m,4H),1.42(d,J=16.0Hz,6H),1.12(d,J=4.0Hz,3H)。
Using a procedure similar to the one described above, the following other compounds of the invention were prepared.
TABLE 2 exemplary derivatives of Compound I-1
Examples 17 to 40
The synthetic route is as follows:
step 1:
compound IA-1(2.28g,0.01mol) and IB-1(2.24g,0.01mol) were added to 1, 4-dioxane (40mL), N-diisopropylethylamine (DIPEA, 3.87g,0.03mol) was added thereto, and the reaction system was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate/petroleum ether 1/1) to give the objective product IC-1(1.36g, yield 45%). LCMS MS Calcd. 302.4 MS Found 303.2[ M +1 ].
Step 2:
the compound IC-1(500mg,1.65mmol), IF-1(383mg,1.82mmol) and acetic acid (500mg,8.3mmol) were added to toluene (10mL), and the reaction was heated to 80 ℃ under nitrogen protection and stirred for 12 h. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate/petroleum ether 1/3) to give the objective product IG-1(493mg, yield 59%). LCMS MS Calcd 505.3, MS Found 506.2[ M +1 ].
And step 3:
compound IG-1(400mg,0.79mmol), IH-1(105mg,0.79mmol), Pd2(dba)3(72mg,0.08mmol), Xantphos (70mg,0.12mmol) and cesium carbonate (516mg,1.58mmol) were dissolved in toluene (10mL) and the reaction was stirred at reflux for 12h under nitrogen. After cooling, the reaction mixture was quenched with water (10mL), extracted with ethyl acetate (20mL) and the organic layer was concentrated to dryness. Concentrating the residue for chiral preparation (separation conditions: chiral preparation column)CHIRALPAK AD, 5.0cm ID,25 cm; mobile phase: n-hexane, ethanol and trifluoroacetic acid at a flow rate of 85: 15: 0.1: 60mL/min), the corresponding fractions were collected and concentrated under reduced pressure to give the title product I-17(123mg, yield 28%, light yellow solid). MS m/z (ESI): 556.6 Calcd, MS Found 557.4[ M +1]];1HNMR(400MHz,DMSO-d6):δ=10.58(br,1H),7.35(d,J=8.0Hz,1H),7.13(d,J=8.0Hz,1H),6.94(s,1H),6.57(s,2H),5.20(s,1H),5.05(br,1H),4.35(m,2H),3.11-3.52(m,9H),2.23-2.45(m,6H),1.45(m,8H),1.11(d,J=4.0Hz,3H)。
The following other compounds of the present invention were prepared using procedures similar to those described above.
TABLE 3 exemplary derivatives of Compounds I-17
And (3) activity test:
the present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention. Test example 1 degradation of ER α by Compounds of the present invention
MCF-7 cells were cultured in DMEM/F-12+ 10% FBS medium. The MCF-7 is re-suspended by DMEM/F-12 culture medium and 10% active carbon treatment FBS, and is inoculated in a 48-well plate at 50000 cells/well for culturing for 22-24 hours, and then a compound to be tested is diluted into the culture medium and added into the 48-well plate; the ER α capture antibody was diluted to 1 μ g/mL with PBS, added to a 96-well plate at 100 μ L/well, sealed and coated overnight at room temperature. The coated 96-well plates were then washed 2 times with PBS, and 110. mu.L/well blocking solution (1% BSA in PBS) was added and blocked for 1 hour at room temperature. The 48-well plate was washed 1 time with PBS, the residual liquid was aspirated off, 60ul of lysis buffer (6M urea, 1mM EDTA, 0.5% Triton X-100, 1mM PMSF, Protease inhibitor cocktail) was added to each well and lysed on ice for 15 minutes, and then diluent (1mM EDTA, 0.5% Triton X-100 in PBS) was added; transferring the lysate after cell dilution into a 96-well sealed plate by 100ul per well, and incubating for 2 hours at room temperature; washing the plate with washing solution (PBST) for 4 times, adding diluted primary antibody, incubating for 1 hour, washing the 96-well plate for 4 times, adding secondary antibody, and incubating for 30 minutes; after washing the plate with washing solution, TMB was added for color development for 15 minutes, and the reaction was stopped with 1M sulfuric acid to read the light absorption at 450 nm.
IC determined by degradation of ER alpha by Compounds of the invention50The values are shown in Table 4.
TABLE 4 IC degradation of ER α by Compounds of the invention50Value of
And (4) conclusion: the compound of the invention has obvious degradation effect on ER alpha.
Test example 2 inhibitory Effect of the Compound of the present invention on MCF-7 cell proliferation
Breast cancer cells MCF-7 were purchased from ATCC and cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100U/ml penicillin, 100. mu.g/ml streptomycin.
The compounds of the invention were prepared in 20mM stock solutions, diluted 1000-fold to final concentration with a 100% DMSO gradient, and then diluted 20-fold in medium containing 10% fetal bovine serum. Culturing for 24 hr, removing culture medium, adding 90 μ L culture medium containing 10% fetal calf serum and 10 μ L drug into each well, adding 10 μ L LDMSO into control group, mixing by gentle shaking, placing blank group containing 100 μ L culture medium, standing at 37 deg.C and 5% CO2Culturing in incubator, adding 50 μ L of mixed Cell Titer-Glo (Promega, G7571) into each well after 72 hr, shaking, mixing, standing at room temperature for 10min, and measuring chemiluminescence signalThe value is obtained. Dose-response curves were generated and IC calculated using GraphPad Prism software50(Table 5).
TABLE 5 IC of inhibitory Activity of the Compounds of the present invention on MCF-7 cell proliferation50Value of
And (4) conclusion: the experimental results in Table 5 show that the compound of the invention has good inhibitory activity on MCF-7 breast cancer cells. Test example 3 pharmacokinetic testing of the Compound of the invention
The pharmacokinetic profile of the compounds of the present invention in rats was studied by measuring the drug concentrations in plasma at different times after gastric gavage of rats with SD rats as test animals and using LC/MS method to measure the drug concentrations in rats after gavage of the compounds of the preferred embodiment of the present invention and AZD9496, AZD9833, WO2016202161, example 44, WO2019228443, example 3 and WO2017174757 compound 173.
SD rat source: shanghai Slek laboratory animals Co., Ltd
The administration mode is single intragastric administration
Administration dose and concentration: 5 mg/kg; 2mg/mL
The preparation prescription is as follows: 0.5% Methelculose
Sampling points are as follows: 5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h.
Preparing a standard curve and a quality control sample: appropriate amount of stock solution is diluted with 50% acetonitrile water to obtain standard working solution of 0.04, 0.10, 0.20, 0.40, 1.00, 2.00 and 4.00. mu.g/mL and quality control working solution of 0.10, 1.00 and 3.00. mu.g/mL. Respectively adding 2.50 mu L of standard curve working solution and quality control working solution into 47.5 mu L of blank rat plasma to prepare quality control samples containing standard curves with the concentrations of substances to be detected of 2.00, 5.00, 10.00, 20.00, 50.00, 100.00 and 200.00ng/mL and quality control samples with the concentrations of 5.00, 50.00 and 150.00ng/mL, respectively adding 200 mu L of acetonitrile (containing internal standard loratadine of 5ng/mL), carrying out vortex oscillation for 3min, centrifuging at 15000rpm and 4 ℃ for 15min, and taking 100 mu L of supernatant to carry out LC-MS/MS analysis. By using8.0 calculate the experimental results.
Preferred compounds of the invention have pharmacokinetic parameters as shown in table 6.
TABLE 6 pharmacokinetic parameters of preferred Compounds
And (4) conclusion: the compounds of the examples of the invention show good pharmacokinetic properties and have obvious pharmacokinetic advantages compared with the comparative examples.
Test example 4 acute toxicity test of the Compound of the present invention
Some of the preferred compounds of the present invention were selected for acute toxicity tests, as well as AZD9496, AZD9833, WO2016202161 example 44, WO2017174757 compound 132 and WO2017174757 compound 173.
(1) Experimental protocol
The toxicity symptoms and death situations of animals after the ICR mice are orally administered with the compound to be tested are observed, and the acute toxicity is compared.
Preparing a solvent: an appropriate amount of sodium Methylcellulose (MC) is weighed, dissolved by ultrapure water to a certain volume, and prepared into 0.5% MC (w/v).
③ administration preparation: the desired test samples were weighed out separately and made up into suspensions of 12.5, 37.5, 75.0 and 100.0mg/mL with 0.5% MC solution.
Fourthly, the administration route: the test article and vehicle control group (0.5% MC) were administered orally.
Fifthly, administration frequency: single administration, with fasting overnight before dosing.
Sixthly, administration volume: 20 mL/kg.
General symptom observation: the day of administration was observed 1 time about 0.5, 1, 2, 4, 6 hours after the first administration; the observation period is 2-6 days, 2 times per day, 1 time in the morning and afternoon.
Observations include, but are not limited to: general condition, behavioral activity, gait posture, eye, mouth, nose, gastrointestinal tract, dermal hair, urogenital tract.
(2) Statistical analysis
Body weight data are expressed as mean ± standard deviation and are compared between groups using the Levene's test and one-way analysis of variance, and if differences are indicated, the Dunnet test is followed.
(3) Results of the experiment
The results are shown in Table 7. In the MTD test, the tolerance of the animals to the drugs is considered, and the dosage is up to the time when the animals die frequently, namely the maximum tolerance.
TABLE 7 acute toxicity test results of single oral administration
Note: MTD is the maximum tolerated dose.
The results show that: the MTD (maximum tolerated dose) of the selected compounds I-1 and the like of the invention is greater than or equal to 2000mg/kg, and the acute toxicity is far lower than that of the compounds of the comparative example.
Test example 5 examination of the Effect of the Compound of the present invention on hERG Current
The experiment adopts the whole-cell patch clamp technology to research the in-vitro inhibition effect of the compound on the hERG potassium channel current, draws a concentration effect curve and provides a basis for evaluating the risk of the compound causing ventricular repolarization toxicity.
After the cells were recovered, the cells were placed in a 5% CO medium (DMEM medium containing 10% fetal bovine serum)2The culture was carried out in an incubator at 37 ℃. And (4) carrying out subculture every other day, after 2 generations of stable subculture, digesting the cells 4-6 hours before the experiment, and planting the cells on 12mm cover glass placed in a 24-well plate. Taking out the cover glass wafer before detection, cleaning the cover glass wafer with extracellular fluid, and soaking the cover glass wafer to be detected.
The test compound was dissolved in DMSO to prepare a stock solution of the test compound at 10 mM. The suspension is diluted to working concentration by extracellular fluid before use.
Using the whole-cell recording mode, each voltage stimulus included the following 5 phases: stage A, keeping the cell membrane clamping potential at-80 mV for 0.5 s; stage B, giving the cells a repolarization voltage of-50 mV for baseline tail current measurement, lasting 0.5 s; stage C, giving the cells a depolarization voltage of +50mV for 2.5 s; stage D, repolarizing to-50 mV to extract the hERG tail current for 4 s; and E stage, restoring the clamping potential to-80 mV for 0.5 s. Each voltage stimulation was repeated at intervals of 10s after completion.
The steady state current values at different concentrations of drug determined by the patch clamp system were analyzed and plotted by software Igor. IC50 was plotted as a fitted curve using Graphpad. The results of the experiment are shown in table 8:
TABLE 8 Effect of preferred Compounds on hERG Current
The results show that: the selected compounds of I-1 and the like of the invention have smaller influence on hERG current than the comparative compounds, and the heart safety risk is lower.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (10)
1. A selective estrogen receptor down-regulator compound or a pharmaceutically acceptable salt thereof, wherein the compound has a structural formula shown in formula I:
wherein:
R1is H or halogen;
R2is C1~6Alkyl or C3~8A cycloalkyl group;
R3、R4、R5each independently selected from H, Me, halogen, halomethyl or CH2OH; or R3、R4、R5Any two groups of (a) together with the carbon atoms to which they are commonly attached form a three-or four-membered ring;
x is-C (R)6) -or-N-;
R6is H or halogen;
y is selected from the following structures:
2. the selective estrogen receptor down-regulator compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the structural formula is shown in formula I-1:
wherein:
R1is H or halogen;
R2is C1~4Alkyl or C3~8A cycloalkyl group;
R3、R4、R5each independently selected from H, Me, halogen, halomethyl or CH2OH; or R3、R4、R5Any two groups of (a) together with the carbon atoms to which they are commonly attached form a three-or four-membered ring; the three-membered ring is cyclopropyl or oxirane, and the four-membered ring is cyclobutyl or oxetane;
x is-C (R)6) -or-N-;
R6is H or halogen;
y is selected from the following structures:
4. the selective estrogen receptor down-regulator compound or the pharmaceutically acceptable salt of claim 1, wherein R in the compound of formula I2Is C1~3Alkyl or C3~8A cycloalkyl group.
6. a method of synthesising a selective estrogen receptor down-regulator compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, comprising the steps of:
(1) carrying out substitution reaction on the compound IA and the compound IB to obtain a compound IC;
(2) cyclizing the compound IC and the compound ID to obtain a compound IE;
(3) hydrolyzing compound IE ester, and separating with chiral column to obtain compound of formula I; the specific reaction formula is as follows:
7. a method of synthesising a selective estrogen receptor down-regulator compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, comprising the steps of:
(1) carrying out substitution reaction on the compound IA and the compound IB to obtain a compound IC;
(2) cyclizing the compound IC and the compound IF to obtain a compound IG;
(3) the compound of the formula I is obtained by coupling substitution reaction and chiral column separation of a compound IG and a compound IH, and the specific reaction formula is as follows:
8. use of a selective estrogen receptor down-regulator compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the preparation of an estrogen receptor down-regulator.
9. Use of a selective estrogen receptor down-regulator compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of a disease or condition mediated or dependent on an estrogen receptor.
10. A composition comprising the selective estrogen receptor down-regulator compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and a pharmaceutically acceptable excipient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010823714.8A CN111825613B (en) | 2020-08-17 | 2020-08-17 | Tetrahydroisoquinoline compounds as selective estrogen receptor down-regulation agent, and synthesis method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010823714.8A CN111825613B (en) | 2020-08-17 | 2020-08-17 | Tetrahydroisoquinoline compounds as selective estrogen receptor down-regulation agent, and synthesis method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111825613A CN111825613A (en) | 2020-10-27 |
CN111825613B true CN111825613B (en) | 2022-02-15 |
Family
ID=72919094
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010823714.8A Active CN111825613B (en) | 2020-08-17 | 2020-08-17 | Tetrahydroisoquinoline compounds as selective estrogen receptor down-regulation agent, and synthesis method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111825613B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021249533A1 (en) * | 2020-06-12 | 2021-12-16 | 江苏先声药业有限公司 | Estrogen receptor modulator compound and use thereof |
CN117813288A (en) * | 2021-07-15 | 2024-04-02 | 西藏海思科制药有限公司 | Arylamino derivative estrogen receptor modulator and use thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1113007A1 (en) * | 1999-12-24 | 2001-07-04 | Pfizer Inc. | Tetrahydroisoquinoline compounds as estrogen agonists/antagonists |
WO2002046164A1 (en) * | 2000-12-07 | 2002-06-13 | Astrazeneca Ab | Therapeutic compounds |
WO2016202161A1 (en) * | 2015-06-16 | 2016-12-22 | 江苏恒瑞医药股份有限公司 | Piperidine derivative and preparation method and pharmaceutical use thereof |
CN109219604A (en) * | 2016-04-08 | 2019-01-15 | 豪夫迈·罗氏有限公司 | Tetrahydroisoquinoline estrogenic agents and application thereof |
CN111499614A (en) * | 2019-01-31 | 2020-08-07 | 江苏恒瑞医药股份有限公司 | Tetrahydroisoquinoline derivatives, preparation method and medical application thereof |
-
2020
- 2020-08-17 CN CN202010823714.8A patent/CN111825613B/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1113007A1 (en) * | 1999-12-24 | 2001-07-04 | Pfizer Inc. | Tetrahydroisoquinoline compounds as estrogen agonists/antagonists |
WO2002046164A1 (en) * | 2000-12-07 | 2002-06-13 | Astrazeneca Ab | Therapeutic compounds |
WO2016202161A1 (en) * | 2015-06-16 | 2016-12-22 | 江苏恒瑞医药股份有限公司 | Piperidine derivative and preparation method and pharmaceutical use thereof |
CN109219604A (en) * | 2016-04-08 | 2019-01-15 | 豪夫迈·罗氏有限公司 | Tetrahydroisoquinoline estrogenic agents and application thereof |
CN111499614A (en) * | 2019-01-31 | 2020-08-07 | 江苏恒瑞医药股份有限公司 | Tetrahydroisoquinoline derivatives, preparation method and medical application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN111825613A (en) | 2020-10-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6695457B2 (en) | 6,7-Dihydro-5H-benzo [7] annulene derivative as estrogen receptor modulator | |
EP2029588A2 (en) | Tetrahydropyrido[3,4-d]pyrimidines and related analogues | |
JP2009536651A (en) | Substituted azaspiro derivatives | |
JP2009506987A (en) | Dipiperazinyl ketone and related analogs | |
CN111825613B (en) | Tetrahydroisoquinoline compounds as selective estrogen receptor down-regulation agent, and synthesis method and application thereof | |
JP2010531364A (en) | Piperazinyloxoalkyltetrahydro-β-carbolines and related analogs | |
WO2021178846A1 (en) | Methods of treating estrogen receptor-associated diseases | |
CN112771046B (en) | Other substituted triazoloquinoxaline derivatives | |
WO2006089076A2 (en) | Thiazole amides, imidazole amides and related analogues | |
CN107814798B (en) | 3-substituted acrylic acid compound and preparation method and application thereof | |
CN108976172A (en) | A kind of 4- pyrimidinediamine micromolecular organic compound and its derivative and its application | |
WO2021139756A1 (en) | Tricyclic tetrahydroisoquinoline derivative, preparation method therefor and application thereof in medicine | |
KR20210136973A (en) | estrogen receptor proteolytic agent | |
KR20180085814A (en) | Preparation of Substituted 5,6-dihydro-6-phenylbenzo [f] isoquinolin-2-amine | |
WO2021083328A1 (en) | Polysubstituted isoindoline compounds, preparation method therefor, pharmaceutical composition thereof and use thereof | |
WO2009100120A2 (en) | Pyridinyl-substituted piperazinyl oxoethyl tetrahydropyrazolopyridines | |
JP7464613B2 (en) | Diarylthiohydantoin compound crystals | |
CN116438177A (en) | Targeted chimeric compounds, pharmaceutical compositions containing same, and preparation methods and uses thereof | |
CN108864080B (en) | Tetracyclic compounds as selective estrogen receptor down-regulating agents and application thereof | |
KR20230133396A (en) | Heteroaryl compounds as RIP2 kinase inhibitors, compositions and uses thereof | |
AU2019343922B2 (en) | Treatment for obesity | |
CN115667241A (en) | TrkA inhibitors | |
CA3170620A1 (en) | Crystal of tricyclic compound acting on crbn protein and preparation method therefor | |
JP2022554385A (en) | WDR5 inhibitors and modulators | |
CN110066271B (en) | Pyrrole derivative, preparation method thereof, pharmaceutical composition and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
CB02 | Change of applicant information |
Address after: 200000 room 216, building 2, No. 1366, Qishen Road, Minhang District, Shanghai Applicant after: Shanghai Xunhe Pharmaceutical Technology Co.,Ltd. Address before: 200000 Shanghai Xunhe Pharmaceutical Technology Co., Ltd., 5 / F, building 2, 1295 chuanqiao Road, Pudong New Area, Shanghai Applicant before: Shanghai Xunhe Pharmaceutical Technology Co.,Ltd. |
|
CB02 | Change of applicant information | ||
GR01 | Patent grant | ||
GR01 | Patent grant |