WO2018001232A1 - Dérivé à base d'acide acrylique, procédé de préparation s'y rapportant et utilisation médicale correspondante - Google Patents

Dérivé à base d'acide acrylique, procédé de préparation s'y rapportant et utilisation médicale correspondante Download PDF

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WO2018001232A1
WO2018001232A1 PCT/CN2017/090253 CN2017090253W WO2018001232A1 WO 2018001232 A1 WO2018001232 A1 WO 2018001232A1 CN 2017090253 W CN2017090253 W CN 2017090253W WO 2018001232 A1 WO2018001232 A1 WO 2018001232A1
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group
alkyl
pharmaceutically acceptable
compound
stereoisomer
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PCT/CN2017/090253
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English (en)
Chinese (zh)
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关东亮
盛首一
白骅
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浙江海正药业股份有限公司
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Priority to CN201780038512.9A priority Critical patent/CN109415361B/zh
Publication of WO2018001232A1 publication Critical patent/WO2018001232A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and in particular relates to a novel acrylic derivative, a stereoisomer thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, a process for preparing the same, a pharmaceutical composition containing the same, and the same Use as a therapeutic, especially as an estrogen receptor antagonist or an estrogen receptor alpha downregulator.
  • the estrogen receptor (ER) is a ligand-activated transcriptional regulatory protein that mediates the induction of various biological effects through interaction with endogenous estrogens, including 17 ⁇ -estradiol and Estrone.
  • ER has been found to have two subtypes of estrogen receptor alpha (ER alpha, ESR1 and NR3A) and estrogen receptor beta (ER beta, ESR2 and NR3b).
  • Estrogen receptor alpha and estrogen receptor beta are members of the steroid hormone receptor, which is a member of the nuclear receptor family. Similar to the mechanism of nuclear receptors, ER ⁇ is composed of six functional domains (named AF), a ligand-activated transcription factor, because it binds to a specific ligand, including endogenous estrogen 17 ⁇ .
  • Estradiol (E2) binds to the genomic sequence to form a complex, an estrogen receptor responsive element and a co-regulatory factor, to regulate the transcription of the targeted gene.
  • the ER ⁇ gene is located at 6q25.1 and encodes the 595A protein, resulting in different subtypes depending on the cleavage site and the starting point of transcriptional transcription.
  • the receptor also contains an N-terminal (A/B) domain, a hinge region (D, which links the C and E domains), and a carbon terminus ( F domain).
  • A/B N-terminal domain
  • D which links the C and E domains
  • F domain carbon terminus
  • the binding of estrogen to the receptor can lead to a variety of cellular changes, and its regulatory mechanisms can be divided into two pathways: the genomic and non-genomic pathways.
  • the ER-mediated genomic pathway involves the formation of an estrogen receptor dimer, binding to the ERE in the estrogen-regulated gene promoter, mediating the aggregation of other regulatory proteins to the promoter, and ultimately leading to an increase in the mRNA level of the gene. Or lower.
  • estrogen-mediated non-genomic pathway estrogen can react with estrogen-binding proteins present in or adjacent to the cell membrane of ERs and even cell membranes without ERs.
  • Estrogen's cellular responses through non-genomic pathways can increase intracellular calcium and NO levels, as well as activation of a variety of intracellular kinases, including MAPK, PI3K, PKA, and PKC, which phosphorylate and activate nER.
  • ER and/or progesterone receptors in approximately 70% of breast cancer patients indicates that the growth of this tumor cell is hormone-dependent, and the growth of other tumors such as ovarian cancer and endometrial cancer is also dependent on ER ⁇ .
  • Treatment of these diseases Treatment can inhibit ER signaling in a variety of ways, including antagonizing the binding of ligands and ER, antagonizing or downregulating ER ⁇ , and blocking the synthesis of estrogen.
  • ER ⁇ and ER ⁇ are expressed in endocrine tumors such as adrenal cortical tumors, pancreatic cancer, prostate cancer and thyroid cancer, digestive system tumors such as colon cancer, esophageal cancer, liver cancer and pancreatic cancer, and lung cancer.
  • ESR1 mutation may be one of the causes of drug resistance in patients with metastatic ER-positive breast cancer. (Toy et al., Nat. Genetic 2013, 45: 1439-1445; Li, S. et al Cell Rep. 4, 1116-1130 (2013)).
  • tumor growth has ER-dependent activity, so a mechanism for selectively down-regulating ER ⁇ provides a better method to block ER ⁇ activity and mediate early metastasis and tolerance.
  • Medicinal cancer is a mechanism for selectively down-regulating ER ⁇ provides a better method to block ER ⁇ activity and mediate early metastasis and tolerance.
  • SERD selective estrogen receptor downregulator
  • GDC-0810 and GDC-0927 of Gene Tec respectively, in clinical phase II and Clinical Phase I
  • Azlikon's AZD-9496 in Phase I
  • SERD also discloses a series of patent applications for SERD, including WO2011156518, WO2012037410, WO2015082990, and the like.
  • the estrogen receptor down-regulation in the prior art is still not satisfactory, and in order to obtain better effects and avoid the mechanism of resistance, it is still necessary to study and develop a new estrogen receptor alpha down-regulator.
  • One of the objects of the present invention is to provide an acrylic derivative having an estrogen receptor antagonistic action different from the prior art structure.
  • the invention provides a compound of the formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are each independently selected from a hydrogen atom or a halogen, wherein the halogen is preferably F;
  • R 3 is selected from alkyl, wherein said alkyl group is further substituted with one or more halogen substituents;
  • R 4 is each independently selected from the group consisting of halogen, alkyl, alkoxy, trifluoromethyl, cyano, -C(O)NR 5 R 6 , -C(O)R 7 , -SO 2 R 7 , -C (O)OR 7 or -NR 5 C(O)R 6 , wherein said alkyl or alkoxy group is further further selected from one or more selected from the group consisting of halogen, -C(O)NR 5 R 6 , -C Substituting (O) a substituent of R 7 , -SO 2 R 7 , -C(O)OR 7 or -NR 5 C(O)R 6 ;
  • R 5 is selected from a hydrogen atom or an alkyl group
  • R 6 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, aryl group or heteroaryl group is further further selected from one or more selected from the group consisting of hydroxyl groups, Halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 8 R 9 , -C(O)NR 8 R 9 ,- Substituted by a substituent of C(O)R 10 , -SO 2 R 10 , -C(O)OR 10 or -NR 8 C(O)R 9 ;
  • R 5 and R 6 together with the atoms to which they are attached form a 4- to 8-membered heterocyclic group, wherein said heterocyclic group is further optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, and nitrate.
  • Base cycloalkyl, heterocyclic, aryl, heteroaryl, -NR 8 R 9 , -C(O)NR 8 R 9 , -C(O)R 10 , -SO 2 R 10 , -C( O) substituted with a substituent of OR 10 or -NR 8 C(O)R 9 ;
  • R 7 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further one Or a plurality selected from the group consisting of hydroxyl, halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 8 R 9 , -C(O Substituting a substituent of NR 8 R 9 , -C(O)R 10 , -SO 2 R 10 , -C(O)OR 10 or -NR 8 C(O)R 9 ;
  • R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, haloalkyl, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy Substituted by a substituent of an acid or a carboxylic acid ester;
  • n 1, 2, 3 or 4.
  • the compound of the formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof which is represented by the formula (II) a compound, a stereoisomer, a tautomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 and n are as defined in the formula (I).
  • the compound of the formula (I) or (II), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof wherein:
  • the alkyl group is preferably a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group, most preferably a C 1 -C 3 alkyl group;
  • the alkoxy group is preferably a C 1 -C 10 alkoxy group, more preferably a C 1 -C 6 alkoxy group, most preferably a C 1 -C 3 alkoxy group;
  • the cycloalkyl group is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, most preferably a C 3 -C 6 cycloalkyl group;
  • the heterocyclic group is preferably a C 3 -C 10 heterocyclic group, more preferably a C 5 -C 7 monocyclic heterocyclic group or a C 7 -C 10 bicyclic or tricyclic heterocyclic group;
  • the aryl group is preferably a C 6 -C 10 aryl group, more preferably a phenyl group and a naphthyl group;
  • the heteroaryl group is preferably a 5- to 10-membered heteroaryl group, more preferably a 5- to 6-membered monocyclic heteroaryl group or a 9- to 10-membered bicyclic heteroaryl group.
  • the compound of the formula (I) or (II), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof wherein R 1 and R 2 are each independently It is selected from halogen, wherein the halogen is preferably F.
  • the compound of the formula (I) or (II), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof wherein R 3 is C 1 -C A 4- alkyl group, preferably an isopropyl group, wherein the alkyl group is further substituted by one or more substituents selected from F, Cl, Br or I, preferably F or Cl, more preferably F.
  • the compound of the formula (I) or (II), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof wherein:
  • R 1 and R 2 are each independently selected from halogen, wherein the halogen is preferably F;
  • R 3 is selected from halogen-substituted C 1 -C 4 alkyl, preferably F-substituted C 1 -C 4 alkyl; more preferably fluoroisopropyl;
  • R 4 is C 1 -C 4 alkyl, halogen, alkoxy, trifluoromethyl or cyano.
  • Exemplary compounds of the invention include, but are not limited to, the compounds described in Table 1:
  • Another aspect of the present invention provides a process for the preparation of a compound of the formula (I) or a salt thereof, comprising the steps of:
  • the compound of the formula (Ia) is reacted with the formula (1b) in the presence of palladium acetate and tri-o-tolylphosphine under basic conditions to give a compound of the formula (IB); a compound of the formula (Ic) and a formula (I) Id) compound is reacted under basic conditions to obtain a compound of the formula (IA); a compound of the formula (IA) is reacted with a compound of the formula (IB) under acidic conditions, and further ester hydrolysis is carried out to obtain a compound of the formula (I);
  • X is a halogen, preferably bromine;
  • R a is an alkyl group;
  • R b is a leaving group, preferably a halogen and a sulfonate group, more preferably a Br or mesylate group;
  • the definition of n is as described in the general formula (I).
  • Another aspect of the present invention provides a process for the preparation of a compound of the formula (II) or a salt thereof, comprising the steps of:
  • the compound of the formula (IIa) is reacted with a compound of the formula (Id) under basic conditions to give a compound of the formula (IIA); the compound of the formula (IIA) is reacted with a compound of the formula (IB) under acidic conditions, and further ester hydrolysis is carried out. To obtain a compound of the formula (II);
  • R a is an alkyl group
  • R b is a leaving group, preferably a halogen and a sulfonate group, more preferably a Br or mesylate group
  • R 1 , R 2 , R 3 , R 4 and n The definition is as described in the general formula (I).
  • the reagent for providing acidic conditions is an inorganic acid or an organic acid
  • the inorganic acid is preferably hydrochloric acid, sulfuric acid or phosphoric acid, more preferably hydrochloric acid
  • the organic acid is preferably derived from formic acid or acetic acid, more preferably acetic acid.
  • the basic condition is provided by an organic base or an inorganic base
  • the organic base is preferably selected from the group consisting of diisopropylethylamine, diisopropylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4-di.
  • the methotrexate is more preferably diisopropylamine and triethylamine
  • the inorganic base is preferably selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, more preferably sodium carbonate and sodium hydroxide.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of the formula (I) or (II) The compound or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.
  • the composition optionally further comprises an antioxidant or a metal chelating agent.
  • the present invention provides a compound of the formula (I) or (II), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, which is prepared for use in the preparation for treatment
  • a medicament for estrogen receptor mediated diseases wherein the disease is preferably cancer, wherein the cancer is preferably breast cancer and gynecological cancer, wherein the gynecological cancer is preferably ovarian cancer and endometrium Cancer, wherein the estrogen receptor is preferably an estrogen receptor alpha.
  • the present invention provides a compound of the formula (I) or (II), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a selective estrogen
  • the use in the body downregulation is preferably an estrogen receptor alpha downregulation.
  • the present invention provides a compound of the formula (I) or (II), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, which may be combined with one or A combination of a plurality of other suitable anti-tumor drugs for treating an estrogen receptor-mediated disease, wherein the disease is preferably cancer, wherein the cancer is preferably a breast cancer or a gynecological cancer, wherein the gynecological cancer is preferred An ovarian cancer or an endometrial cancer, wherein the estrogen receptor is preferably an estrogen receptor alpha, wherein the other antitumor drug comprises an alkylating agent, an antimetabolite, a natural product having antitumor activity, and Its derivatives, cytotoxic drugs or blocking immune cell migration drugs.
  • Suitable other antineoplastic agents include alkylating agents (but not limited to nitrogen mustard, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes) such as uraramustine, nitrogen Mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, piperac bromide, quetiapine, busulfan, carmustine, lomustine, stellate, dacabar And temozolomide.
  • alkylating agents but not limited to nitrogen mustard, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes
  • alkylating agents such as uraramustine, nitrogen Mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, piperac bromide, quetiapine, busulfan, carmustine, lomustine, stellate
  • Suitable other anti-tumor drugs include, for example, antimetabolites (including but not limited to folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, fluorouracil , cytarabine, 6-mercaptopurine, 6-thiouracil, fludarabine phosphate, pentastatin and gemcitabine.
  • antimetabolites including but not limited to folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors
  • methotrexate including but not limited to folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors
  • methotrexate including but not limited to folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors
  • Suitable other anti-tumor drugs include, for example, certain natural products having antitumor activity and derivatives thereof (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, etc.), such as vinblastine, vincristine, vinblastine , bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, cytarabine, paclitaxel, pucamycin, deoxycofumycin, Mitomycin-C, L-asparaginase, interferon (especially IFN-a), etoposide and teniposide.
  • certain natural products having antitumor activity and derivatives thereof e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, etc.
  • vinblastine vincristine
  • vinblastine bleomycin
  • actinomycin D actinomycin D
  • daunorubicin doxor
  • cytotoxic drugs including noviben, CPT-11, anastrozole, letrozole, capecitabine and droloxifene, topoisomerase.
  • Inhibitors procarbazine, mitoxantrone, platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; antihormonal therapeutics; folinic acid; tegafur and hematopoietic growth factors Be applicable.
  • anti-tumor drugs include antibody therapeutic drugs such as trastuzumab, antibodies to costimulatory molecules such as CTLA-4, 4-1BB and PD-1 or cytokine antibodies (IL-10, IGF- ⁇ ).
  • Drugs that block immune cell migration such as chemokine receptor antagonists, including CCR2 and CCR4; drugs that enhance the immune system, such as adjuvants or adoptive T cell metastases; anticancer vaccines, including dendritic cells , synthetic peptides, DNA vaccines and recombinant viruses.
  • the present invention provides a method for selectively downregulating an estrogen receptor, which comprises the compound of the formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof Or a pharmaceutical composition thereof, which is in contact with an estrogen receptor, preferably an estrogen receptor alpha.
  • the invention further provides a method of treating an estrogen receptor mediated disease comprising administering a compound of the formula (I) or (II) or a stereoisomer thereof, a tautomer thereof to a subject in need thereof A construct or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  • the estrogen receptor is preferably an estrogen receptor alpha;
  • the estrogen receptor mediated disease is preferably cancer, wherein the cancer is preferably breast cancer and gynecological cancer, the gynecology
  • the cancer is preferably ovarian cancer and endometrial cancer.
  • the present invention also relates to a compound of the formula (I) or (II), or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of estrogen receptor mediated Use of the disease, wherein the disease is cancer, wherein the cancer is preferably breast cancer or gynecological cancer, wherein the gynecological cancer is preferably ovarian cancer or endometrial cancer, wherein the estrogen is affected by The body is preferably an estrogen receptor alpha.
  • chemotherapeutic drugs anti-tumor drugs
  • their dosing standards have been discussed in the standard literature, such as the "physicians desk reference” (PDR, eg1996edition, medical Economics Company, Montvale, NJ), the method of administration of various chemotherapeutic drugs, the disclosure content This is incorporated herein by reference.
  • alkyl as a group or part of a group is meant to include C 1 -C 20 linear or branched aliphatic hydrocarbon group with a chain. It is preferably a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group, and most preferably a C 1 -C 3 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1, 1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait.
  • the alkyl group can be substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially saturated monocyclic, fused, bridged, and spiro carbon ring, ie, includes a monocyclic cycloalkyl, a fused cycloalkyl, a bridged cycloalkyl, and a spirocycloalkyl. It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • “Spirocycloalkyl” means a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing a carbon atom (referred to as a spiro atom), and the ring contains one or more A double bond, but none of the rings have a fully conjugated ⁇ -electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiro, a spiro- or a spirocycloalkyl group, preferably a mono- and bi-spirocycloalkyl group, preferably 4 yuan/5 yuan, 4, depending on the number of common spiro atoms between the rings. Yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan.
  • spirocycloalkyl include, but are not limited to, spiro[4.5]decyl, spiro[4.4]decyl, spiro[3.5]decyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” means 5 to 18 members, an all-carbon polycyclic group containing two or more cyclic structures that share a carbon atom with each other, and one or more rings may contain one or more double bonds, However, none of the rings have a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
  • fused cycloalkyl include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, ten Hydronaphthyl or tetradecafluorophenanyl.
  • “Bridge cycloalkyl” means 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups that are not directly bonded to each other, and one or more rings may contain one or A plurality of double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclic [3.3.1] Mercapto, bicyclo [2.2.2] octyl, (1r, 5r)-bicyclo[3.3.2] fluorenyl.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl and the like.
  • the cycloalkyl group can be optionally substituted or unsubstituted.
  • Heterocyclyl “heterocyclic” or “heterocyclic” are used interchangeably herein to refer to a non-aromatic heterocyclic group wherein one or more of the ring-forming atoms are heteroatoms such as oxygen,
  • the nitrogen, sulfur atom and the like include a monocyclic ring, a fused ring, a bridged ring and a spiro ring, that is, a monocyclic heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group and a spiroheterocyclic group.
  • heterocyclyl includes, but are not limited to, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo- Piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl.
  • the heterocyclic group may be substituted or unsubstituted.
  • “Spiroheterocyclyl” means a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing one atom with each other, and the ring contains one or more double bonds, but no An aromatic system having a fully conjugated ⁇ -electron, wherein one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) m (where m is selected from 0, 1 or 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • spiroheterocyclyl include, but are not limited to, 1,7-dioxaspiro[4.5]fluorenyl, 2-oxa-7-azaspiro[4.4]decyl, 7-oxa Spiro[3.5]decyl and 5-oxaspiro[2.4]heptyl.
  • “Fused heterocyclic group” means an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, and one or more rings may contain one or more double bonds, but none of the rings have complete A conjugated ⁇ -electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindenyl, 3-azabicyclo[3.1.0 Hexyl, octahydrobenzo[b][1,4]dioxine.
  • “Bridge heterocyclyl” means 5 to 14 members, 5 to 18 members, containing two or more cyclic structures, sharing two polycyclic groups which are not directly connected to each other, and one or more rings may be used.
  • bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • fused heterocyclic groups include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo [3.3.2] ⁇ .
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group.
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • Aryl means a carbocyclic aromatic system containing one or two rings wherein the rings may be joined together in a fused manner.
  • aryl includes aryl groups such as phenyl, naphthyl, tetrahydronaphthyl.
  • the aryl group is a C 6 -C 10 aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • the aryl group can be substituted or unsubstituted.
  • the "aryl” may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the parent structure is attached to an aryl ring, non-limiting examples include, but are not limited to:
  • Heteroaryl means an aromatic 5 to 6 membered monocyclic or 9 to 10 membered bicyclic ring which may contain from 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodiazepine Oxacyclopentenyl, benzimidazolyl, fluorenyl, isodecyl, 1,3-dioxo-isoindenyl, quinoly
  • Heteroaryl groups can be substituted or unsubstituted.
  • the heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include, but are not limited to:
  • Alkoxy means a group of (alkyl-O-). Among them, the alkyl group is defined in the relevant definition herein. Alkoxy groups of C 1 -C 6 are preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • Hydrophilicity refers to an -OH group.
  • Halogen means fluoro, chloro, bromo and iodo, preferably chloro, bromo and iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Benzyl refers to -CH 2 - phenyl.
  • Carboxy refers to -C(O)OH.
  • Carboxylic acid ester group means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
  • Sulfonate group means -S(O) 2 O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond. Fixed.
  • substituted or “substituted”, unless otherwise indicated, may be substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane.
  • “Pharmaceutically acceptable salt” refers to certain salts of the above compounds which retain their original biological activity and are suitable for pharmaceutical use.
  • the pharmaceutically acceptable salt of the compound of the present invention may be a metal salt, an amine salt formed with a suitable acid, a metal salt preferably an alkali metal or an alkaline earth metal salt, and suitable acids include inorganic acids and organic acids such as acetic acid, benzenesulfonic acid, Benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionethane, lactic acid, malic acid, maleic acid, mandelic acid, Sulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Particularly preferred are hydrochloric acid, hydrobromic acid
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and Shape agent.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • Figure 1 is a graph showing the growth inhibition of the compound of Example 4 and AZD-9496 in breast cancer MCF-7 tumor-bearing mice in Test Example 7. Rate chart.
  • Mass spectrometry was measured by LC/MS, and the ionization method was ESI or APCI.
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • CD 3 OD Deuterated methanol.
  • the solution in the reaction means an aqueous solution.
  • Lithium aluminum hydride (0.70 g, 18.5 mmol) was dissolved in 24 mL of anhydrous tetrahydrofuran, and (Z)-4- was slowly added in an ice bath.
  • Methyl-3-(2-nitroprop-1-en-1-yl)-1H-indole 1h (1.0 g, 4.6 mmol) 6 mL of a solution in tetrahydrofurane, then heated to reflux for 6 hr.
  • reaction mixture was quenched by the addition of 0.7 mL of water, 0.7 mL of sodium hydroxide (15%) and 1.4 mL of water, and dried over anhydrous magnesium sulfate, filtered, filtered, 4-Methyl-1H-indol-3-yl)propan-2-amine 1i (728 mg, off-white solid), yield: 84%.
  • 2-fluoro-2-methyl-N-(1-(4-methyl-1H-indol-3-yl)propan-2-yl)propan-1-amine 1j (527 mg, 2.0 mmol), methyl (E)-3-(3,5-difluoro-4-formylphenyl)acrylate 1c (454 mg, 2.0 mmol) and acetic acid (0.492 mL, 4.0 mmol) were dissolved in 5 mL of toluene. The mixture was reacted at 80 ° C for 10 hours, cooled to room temperature, and concentrated under reduced pressure.
  • 6-Fluoro-1H-indole-3-carbaldehyde 2a (1.0 g, 6.1 mmol), 14.2 mL of nitroethane, ammonium acetate (235 mg, 3.05 mmol) was dissolved in 6.0 mL of acetic acid under argon atmosphere, 110 The reaction was carried out at ° C for 6 hours. The reaction mixture was concentrated under reduced EtOAc. EtOAc (EtOAc) Z)-6-Fluoro-3-(2-nitroprop-1-en-1-yl)-1H-indole 2b (1.31 g, brown solid), yield: 98%.
  • Lithium aluminum hydride (0.95 g, 23.6 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and (Z)-6-fluoro-3-(2-nitroprop-1-en-1-yl) was slowly added under ice bath.
  • -1H- ⁇ 2b (1.31 g, 5.9 mmol) was dissolved in 10 mL of tetrahydrofuran and then heated to reflux for 6 hours.
  • reaction solution was successively added with 0.95 mL of water, 0.95 mL of sodium hydroxide solution (15%), and 1.8 mL of water to quench the reaction, and anhydrous magnesium sulfate (3.0 g) was stirred for 15 minutes, filtered, and concentrated under reduced pressure to give 1-( 6-Fluoro-1H-indol-3-ylpropan-2-amine 2c (1.20 g, brown oil), yield: 100%.
  • Lithium aluminum hydride (0.90 g, 23.6 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran, and (Z)-5-fluoro-3-(2-nitroprop-1-en-1-yl) was slowly added under ice bath.
  • a solution of -1H-indole 3b (1.30 g, 5.9 mmol) in 10 mL of tetrahydrofuran was then heated to reflux for 6 hours.
  • reaction solution was successively added with 0.90 mL of water, 0.90 mL of sodium hydroxide solution (15%), and 1.8 mL of water to quench the reaction, and anhydrous magnesium sulfate (3.0 g) was stirred for 15 minutes, filtered, and concentrated under reduced pressure to give 1-( 5-Fluoro-1H-indol-3-ylpropan-2-amine 3c (1.18 g, brown oil), yield: 100%.
  • Lithium aluminum hydride (0.95 g, 25.0 mmol) was dissolved in 20 mL of anhydrous tetrahydrofuran, and (Z)-4-fluoro-3-(2-nitroprop-1-en-1-yl)- 1H- ⁇ 4b (1.374 g, 6.20 mmol) was dissolved in 10 mL of tetrahydrofuran and then heated to reflux for 6 hours.
  • reaction solution was successively added with 0.95 mL of water, 0.95 mL of sodium hydroxide solution (15%) and 19 mL of water to quench the reaction, and anhydrous magnesium sulfate (5.0 g) was stirred for 15 minutes, filtered, and the filter cake was washed with tetrahydrofuran (5 mL x 3) The filtrate was concentrated under reduced pressure to give 1-(4-fluoro-1H-indol-3-yl)propan-2-amine 4c (1.20 g, brown oil).
  • TR-FRET Fluorescence resonance energy transfer
  • PV3551 Indirect fluorescent labeling of the receptor by GST linkage to the receptor by detecting the TR-FRET effect between the chromophore (Tb-anti-GST antibody) and the fluorescent ligand (Fluormone ES2) on the fluorescently labeled ER ⁇
  • the weakening is used to evaluate the competitive coordination ability between the test compound and the fluorescent ligand and the receptor.
  • the above compounds were tested on the synthesized compounds using the following sample preparation and test methods.
  • the instrument used was a Beckman Coulter BioPAPTR FRD microfluidic instrument.
  • test compound 120 nL was ultrasonically dispersed into a black small-capacity 384-well assay plate.
  • a 1x ER ⁇ -LBD/Tb-anti-GST antibody complex was prepared in a buffer of ES2 and cultured therein for 20 minutes.
  • test compound prepared on the microplate were transferred to the assay plate using Labcyte Echo550. 120 nL of DMSO solution of each test compound was added to the wells of the assay plate and tested at twelve different concentrations (100, 29.17, 10.42, 2.083, 1, 0.292, 0.104, 0.02083, 0.01, 0.0029, 0.00104, 0.001 ⁇ M). ). The obtained TR-FRET raw fluorescence test data was obtained by means of data processing software such as Origin or Genedata. Each compound employed inhibition concentration IC 50 characterized competing ligand effects of test compounds to the estrogen receptor ER ⁇ . The IC 50 represents the concentration of the test compound estimated when the fluorophore (ES2) and the estrogen receptor are reduced by 50%, and the IC 50 determined is shown in Table 2.
  • MCF-7 human breast cancer cell line
  • MCF-7 cells are used in the recovery experiment from frozen cells (about 5x10 6 th) over use.
  • the MCF-7 frozen cell strain (Sigma D5921) purchased from Sigma was stored in DMEM medium containing 2 mM L-glutamic acid.
  • 5% (v/v) Charcoal/Dextran-treated bovine serum embryo cells were added to the resuscitated MCF-7 cells, and the cell concentration was determined using a Coulter Counter.
  • test compound solution was used for the preparation of different concentrations of test solutions (10 mM, 0.1 mM, 1 ⁇ , 0.01 ⁇ ).
  • concentration of test solutions 10 mM, 0.1 mM, 1 ⁇ , 0.01 ⁇ .
  • concentration of test compound and MCF-7 cell culture medium 40 ⁇ L
  • 20 ⁇ L of 11.1% (v/v) aqueous formaldehyde solution phosphoric acid PBS buffer
  • concentration of formaldehyde in the solution was 3.7% (v /v).
  • the level of estrogen receptor ERa in MCF-7 cells was calculated by measuring the fluorescence emission intensities of the two emission bands at 594 nm (24 hour time point) and 488 nm (5 hour time point) of the well plates by Cellomics Arrayscan. The average fluorescence emission intensity of each cell is positively correlated with the ER ⁇ receptor level of the cell.
  • the obtained raw fluorescence test data is obtained by means of data processing software such as Origin or Genedata.
  • IC 50 refers to the fluorescence emission intensity is reduced to 50% of the average concentration of the maximum fluorescence intensity of the test compound, IC 50 as determined in Table 2 is shown.
  • IC 50 range is 0.1nM ⁇ A ⁇ 10nM.
  • the preferred compounds of the present invention are capable of better coordination with estrogen receptors and have a better down-regulation effect on ER ⁇ .
  • Test Example 3 Competitive binding analysis of estrogen receptor ER ⁇ with preferred compounds of the invention
  • the present invention is of competitive binding interactions between the estrogen receptor ER ⁇ ligand and scope give compound was evaluated using Fluorescece polarization TM (FP) fluorescence polarization techniques.
  • the PolarScreen ER Alpha competitor Assay kit for use in FP-coordination evaluation technology was purchased from Invitrogen (Cat. No. A15883) and consists mainly of fluorophores (Fluormone ES2, Cat. No. P2645) and recombinant human estrogen receptor ER ⁇ ligand domains. (Cat. No. A15674).
  • the design principle of this test is as follows.
  • the estrogen receptor ER ⁇ forms a receptor/fluorophore complex with the fluorophore-containing ligand Fluormone ES2, which generates a highly polarized light signal value ( ⁇ mP) after excitation, and detects the decrease of ⁇ mP.
  • ⁇ mP highly polarized light signal value
  • test compounds were tested as described above using the following sample preparation and test methods:
  • test compound solution was diluted with DMSO in a Labcyte 384-well plate (Cat. No. P-05525) (the first concentration was 33.33 ⁇ M, 3 fold dilution, 10 concentrations);
  • the obtained mP value was fitted to a fitting curve by Graphpad Prism 6.0 processing software.
  • IC 50 Semi inhibitory concentration IC 50 characterized competing test compounds to the estrogen receptor ER ⁇ binding effect.
  • IC 50 represents the concentration of the test compound calculated when the fluorophore (ES2) and estrogen receptor binding decreased by 50%, and the IC 50 determined is shown in Table 3.
  • Preferred compounds of the invention have a better affinity for the estrogen receptor.
  • Test Example 4 The preferred compound of the present invention down-regulates the amount of ER ⁇ protein in MCF-7 cells.
  • the down-regulation of the ER ⁇ protein level by the preferred compounds of the present invention was evaluated by immunofluorescence analysis in human breast cancer cell line MCF-7.
  • the MCF-7 cells used in the experiment were frozen in the presence of 20% fetal bovine serum (FBS, purchased from GIBCO, Cat. No. 10099-141) and 10% DMSO (purchased from Solarbio, item number D8371).
  • FBS fetal bovine serum
  • DMSO 10% DMSO
  • Frozen cells about 2x10 6 th
  • Pen / Step purchased from Gibco, Order number 15140-122
  • the cells were resuspended in DMEM containing 2% Activated charcoal (purchased from Sigma, Cat. No.
  • DMSO dilute a 10 mM test compound solution in a Labcyte 384-well plate with DMSO (3 mM diluted 300-fold to obtain 33.33 ⁇ M as the first concentration, followed by 3-fold dilution, 10 concentrations), and then Echo550 (purchased from Echo, Model 550) Transfer 120 nL to 40 ⁇ L of cell culture medium, the final concentration of DMSO was 0.3%, the first concentration of the test compound was 100 nM, and the cells were centrifuged at 1000 rpm for 1 min at room temperature, and the cells were cultured at 37 ° C in a 5% CO 2 cell incubator overnight.
  • the medium in the cell culture plate was aspirated with Apricot (purchased from Apricot Designs, model PPA-384-E), the cells were washed once with 40 ⁇ L of PBS, and PBS was aspirated, followed by the addition of 40 ⁇ L of a 3.7% (v/v) aqueous solution of formaldehyde (purchased from Sigma, product number F1635, diluted with PBS), the cells were fixed at 25 ° C for 20 minutes; after aspirating the aqueous formaldehyde solution, the cells were washed once with 40 ⁇ L of PBS, and 40 ⁇ L of a final concentration of 0.5% Tween-20 (diluted in PBS) was permeated at 25 ° C for 1 h; After aspirating the permeate, the cells were washed once with PBS-T (PBS containing 0.05% Tween-20), and 25 ⁇ L of ER antibody (purchased from CST, Cat.
  • PBS-T PBS containing 0.05% Tween
  • IC 50 of test compounds characterized downregulation of the estrogen receptor ER ⁇ , and ER ⁇ protein IC 50 refers to the relative fluorescence intensity is reduced to a concentration of 50% relative average maximum fluorescent intensity of test compound as measured by IC 50 Table 4 shows.
  • the preferred compounds of the invention have a good down-regulation effect on the amount of ER ⁇ protein.
  • Test Example 5 Test of ER ⁇ Functional Activity Down-regulation in MCF-7 Cells by Preferred Compounds of the Invention
  • the down-regulation effect of the preferred compound of the present invention on the functional activity of the ER ⁇ protein is in the human breast cancer cell line MCF-7. It was evaluated by immunofluorescence analysis.
  • the MCF-7 cells used in the experiment were frozen in DMEM medium containing 20% fetal bovine serum and 10% DMSO.
  • Frozen cells (approximately 2 ⁇ 10 6 cells) were cultured in DMEM medium containing 10% FBS and 1% Pen/Step after resuscitation, and passaged twice for use in experiments.
  • the cells were resuspended in DMEM containing 10% (v/v) Activated charcoal-treated FBS and 1% Pen/Step, and the cell concentration was measured by a cell counter and diluted to 3.75 ⁇ 10 4 cells/mL with the test medium.
  • IC 50 of test compounds characterized downregulation of the estrogen receptor ER ⁇ , and ER ⁇ protein IC 50 refers to the relative fluorescence intensity is reduced to a concentration of 50% relative average maximum fluorescent intensity of test compound as measured by IC 50 Table 5 shows.
  • the preferred compounds of the invention have a good down-regulation effect on the functional activity of the estrogen receptor ER ⁇ .
  • MCF-7 human breast cancer cell line (purchased at Shanghai Cell Resource Center of Chinese Academy of Sciences)
  • the compound is diluted with DMSO to a final concentration of 10 mM;
  • test compound was diluted with the medium to the corresponding action concentration set, and the cells were added at 25 ⁇ L/well.
  • the final concentration of the compound was started from 1 ⁇ M, 4 times gradient dilution, 9 concentration points;
  • tumor cell growth inhibition rate % [(A c - A s ) / (A c - A b )] ⁇ 100%
  • a c negative control OA (cell + CCK-8 + DMSO)
  • a b positive control OA (medium + CCK-8 + DMSO)
  • Table 6 preferred compounds of the invention IC 50 values for inhibition of MCF-7 cells
  • the preferred compounds of the invention have a significant inhibitory effect on the proliferation of MCF-7 cells.
  • Test Example 7 Test for growth inhibition of MCF-7 tumor-bearing SCID mouse xenografts by preferred compounds of the present invention
  • This test was used to evaluate the growth inhibitory effect of oral administration of test substances on MCF-7 tumor-bearing SCID mice for 21 consecutive days.
  • Solvent 20% PEG400, 80% deionized water
  • test substance Preparation of the test substance: Weigh an appropriate amount of the compound of Example 4 and AZD-9496, dissolve it in PEG400 (20%), dissolve it, add 80% of sterilized deionized water, and shake evenly. The test drug is freshly prepared daily before administration.
  • SCID mice SCID mice, SPF, female, 7-9 weeks old (16-22 grams), 100, purchased from Beijing Huakangkang Biotechnology Co., Ltd., 100 healthy ones for experiment, adapt to the environment Time is 5 to 7 days.
  • MCF-7 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum. Culture in a 37 ° C, 5% CO 2 incubator. Logarithmic growth phase cells were taken before inoculation, washed with 0.25% trypsin and washed with PBS, and the cells were resuspended in serum-free medium to adjust the cell concentration to 7.5 ⁇ 10 ⁇ 7 cells/mL (1:1 Matrigel, Extracellular Matrix Proteins). , 356234, BD).
  • mice were inoculated with 0.2 mL of cell suspension (1.5 x 10 ⁇ 7 cells/mouse) under sterile conditions on the right side of each mouse. Estrogen was administered subcutaneously after inoculation. When the tumor grows to a volume of about 150 to 250 mm 3 , mice with similar tumor volumes and good shape are selected (the shape is as single a sphere as possible, no irregular shape or multiple tumors are gathered together), and 10 mice in each group. 6 animal administration and observation
  • Each group of animals was given a test substance once a day (qd) according to the body weight of the above-mentioned table at a fixed time per day, orally administered (po) for 21 consecutive days, and the animal body weight per day was recorded.
  • V (X 2 Y)/2.
  • Evaluation index of antitumor activity tumor growth inhibition rate TGI (%), relative tumor growth rate T/C (%).
  • TGI (%) (V c - V t ) / V c ⁇ 100.
  • V c is the tumor volume of the model control group
  • V t is the tumor volume of the test subject group.
  • Relative tumor volume V n /V 0 .
  • V 0 is the tumor volume at the time of group administration
  • V n is the tumor volume at the time of measurement.
  • T/C (%) T RTV / C RTV ⁇ 100.
  • T RTV was the treatment group RTV
  • C RTV was the negative control group RTV.
  • TGI% tumor growth inhibition rate of the preferred compound of the present invention against breast cancer MCF-7 tumor-bearing mice is shown in Table 7.
  • TGI% Tumor growth inhibition rate
  • Example 4 of the present invention had a significant inhibitory effect on breast cancer MCF-7 within 21 days, and its TGI% was 29.4-80.4, which was superior to AZD-9496.
  • the tumor growth inhibition rate of the compound of Example 4 and AZD-9496 against breast cancer MCF-7 tumor-bearing mice at a dose of 10 mg/kg is shown in Figure 1.
  • the inhibition rate of the compound of Example 4 on tumor volume is significantly better than that of AZD- 9496.

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Abstract

La présente invention concerne un dérivé à base d'acide acrylique représenté par la formule générale (I), des stéréoisomères et des tautomères correspondants, ou un sel de qualité pharmaceutique correspondant, un procédé de préparation s'y rapportant, une composition pharmaceutique le comprenant et une utilisation correspondante en tant qu'agent thérapeutique, en particulier en tant que régulateur négatif sélectif du récepteur des œstrogènes (SERD). Les définitions de R1, R2, R3 et R4 dans la formule générale (I) sont telles qu'indiquées dans la description.
PCT/CN2017/090253 2016-06-29 2017-06-27 Dérivé à base d'acide acrylique, procédé de préparation s'y rapportant et utilisation médicale correspondante WO2018001232A1 (fr)

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