WO2018108147A1 - 一种组合、其应用及治疗方法 - Google Patents

一种组合、其应用及治疗方法 Download PDF

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Publication number
WO2018108147A1
WO2018108147A1 PCT/CN2017/116413 CN2017116413W WO2018108147A1 WO 2018108147 A1 WO2018108147 A1 WO 2018108147A1 CN 2017116413 W CN2017116413 W CN 2017116413W WO 2018108147 A1 WO2018108147 A1 WO 2018108147A1
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Prior art keywords
prednisone
odm
enzalutamide
arn
galeterone
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PCT/CN2017/116413
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English (en)
French (fr)
Inventor
戈传生
廖柏松
李文成
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康朴生物医药技术（上海）有限公司
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Priority to PL17881171T priority Critical patent/PL3527210T3/pl
Priority to AU2017376704A priority patent/AU2017376704B2/en
Application filed by 康朴生物医药技术（上海）有限公司 filed Critical 康朴生物医药技术（上海）有限公司
Priority to NZ753549A priority patent/NZ753549B2/en
Priority to JP2019529888A priority patent/JP7048106B2/ja
Priority to KR1020197016757A priority patent/KR102368555B1/ko
Priority to EP17881171.7A priority patent/EP3527210B1/en
Priority to BR112019010559-0A priority patent/BR112019010559B1/pt
Priority to KR1020227006155A priority patent/KR20220028178A/ko
Priority to CA3046869A priority patent/CA3046869C/en
Priority to CN201780076085.3A priority patent/CN110049765B/zh
Priority to RU2019121794A priority patent/RU2731535C1/ru
Priority to ES17881171T priority patent/ES2884064T3/es
Priority to DK17881171.7T priority patent/DK3527210T3/da
Priority to US16/468,385 priority patent/US10933059B2/en
Publication of WO2018108147A1 publication Critical patent/WO2018108147A1/zh
Priority to ZA2019/04328A priority patent/ZA201904328B/en

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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
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    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
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    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • 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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates to a combination, its use and a method of treatment.
  • Prostate cancer is a common malignant tumor of the male reproductive system. According to the World Health Organization's International Agency for Research on Cancer, the number of newly diagnosed prostate cancer patients in the world was 1.1 million in 2012, accounting for 15% of the total number of new cancer cases, making it the second most common cancer among men worldwide. In the United States, the incidence of prostate cancer ranks first among all malignant tumors, and mortality ranks second, second only to lung cancer. Although the incidence of prostate cancer patients in China is much lower than that in Western countries, it has shown a significant growth trend in recent years. It has ranked first in male urinary tumors and found to be mostly in advanced stage.
  • Prostate cancer cells need androgen support, including testosterone, to grow. Therefore, the targeted therapeutic strategy for prostate cancer is mainly directed to the synthesis of androgen and its binding to androgen receptors.
  • Enzalutamide a prostate cancer drug approved by the US FDA in August 2012, is a small molecule androgen receptor antagonist that ultimately inhibits males by competitively inhibiting the binding of androgens to their receptors.
  • the hormone receptor signaling pathway in turn, achieves the effect of treating castration-tolerant prostate cancer.
  • Enzalutamide also has some side effects in clinical research, such as weakness or fatigue, low back pain, diarrhea, joint pain, hot flashes, tissue swelling, musculoskeletal pain, headache, upper respiratory tract infection, dizziness, oppression Spinal cord and cauda equina syndrome, muscle weakness, difficulty sleeping, lower respiratory tract infection, hematuria, tingling, anxiety and high blood pressure.
  • the technical problem to be solved by the present invention is to provide a combination, application and treatment method for improving the efficacy of the existing prostate cancer treatment drugs to achieve better clinical application effects.
  • the combination and treatment method of the present invention is capable of inhibiting the growth of prostate cancer cells more effectively.
  • the present invention provides a combination comprising a benzoheterocyclic compound represented by the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolism thereof One or more of a substance and a prodrug, and an androgen receptor pathway modulator;
  • n1 is 0 or 1;
  • L 1 and L 2 are independently CH 2 , CHD or CD 2 ;
  • X is NH, ND or O
  • R 1 and R 3 are independently H or D;
  • R 2 is H, D or halogen
  • R 4 is H, D, CH 3 , CH 2 D, CHD 2 or CD 3 ;
  • R 5 , R 6 , R 7 , R 8 and R 9 are independently H or D;
  • carbon marked with * is not Symmetric center
  • R 10 is H, D or Wherein R 1 ', R 2 ', R 3 ' and R 4 ' are independently H, D, halogen, cyano, hydroxy, substituted or unsubstituted (C 1 -C 12 )alkyl, substituted or unsubstituted (C 1 -C 12 ) alkoxy, (C 2 -C 20 )heterocycloalkyl, or deuterated (C 2 -C 20 )heterocycloalkyl;
  • the substituent in the substituted (C 1 -C 12 ) alkoxy group is one or more of the following groups: D, halogen, hydroxy, (C 1 -C 12 ) alkoxy, (C 2 -C 20 )heterocycloalkyl, and (C 1 -C 12 )alkyl-substituted (C 2 -C 20 )heterocycloalkyl;
  • the substituent in the substituted (C 1 -C 12 )alkyl group is one or more of the following groups: D, (C 2 -C 20 )heterocycloalkyl, deuterated (C 2 -C) 20 ) heterocycloalkyl, (C 1 -C 12 )alkyl substituted (C 2 -C 20 )heterocycloalkyl, and deuterated (C 1 -C 12 )alkyl substituted (C 2 -C 20 ) a heterocycloalkyl group;
  • n1 is 0, X is NH or ND, and R 10 is H or D, R 2 is F;
  • n1 is 1, R 10 is
  • D represents deuterium-enriched hydrogen
  • H represents non-deuterium-enriched hydrogen
  • the androgen receptor pathway regulators are enzalutamide, ARN-509, ODM-201, VT-464, Orteronel, EPI-001, Andarine, RD162, BMS-641988, CH5137291, flutamide, hydroxyl Flutamide, RU58642, LG120907, LG105, Galeterone, spironolactone, MK-2866, AZD3514, clopidogrel acetate, ORM-15341, bicalutamide, nilutamide, Degarelix, goserelin acetate, One or more of leuprolide acetate, abiraterone, and abiraterone acetate;
  • the androgen receptor pathway modulator is one of the above compounds, the androgen receptor pathway modulator is not bicalutamide, nilutamide, leuprolide acetate, acetate ring Prokalgestrel or spironolactone.
  • the asymmetric center preferably means the (S) configuration carbon, the (R) configuration carbon, or the racemate.
  • the Z is any of the following structures:
  • the Z is any of the following structures: Among them, the carbon marked with * is an asymmetric center, and the definitions of the asymmetric centers, H and D are as described above.
  • the (C 2 -C 20 )heterocycloalkyl group preferably, the deuterated (C 2 -C 20 )heterocycloalkyl group, the (C 1 - a C 12 )alkyl-substituted (C 2 -C 20 )heterocycloalkyl group, and a (C 2 -C 12 )alkyl-substituted (C 2 -C 20 )heterocycloalkyl group as described above
  • the "(C 2 -C 20 )heterocycloalkyl group” independently means "a (C 2 -C 6 )heterocycloalkyl group having a hetero atom of N or O and a hetero atom number of 1-2;
  • the "(C 2 -C 6 )heterocycloalkyl group having a hetero atom of N or O and having 1-2 hetero atoms” is preferably a morpholinyl group (for example) ).
  • the substituted or unsubstituted (C 1 -C 12 )alkyl group preferably, the substituted or unsubstituted (C 1 -C 12 )alkyl group, the (C 1 -C 12 )alkyl group substituted (C 2 -C 20 ) In the (C 2 -C 12 )alkyl-substituted (C 2 -C 20 )heterocycloalkyl group, the "(C 1 -C 12 )alkyl group" described in the heterocycloalkyl group, and the deuterated (C 1 -C 12 )alkyl group Independently (C 1 -C 4 )alkyl; the (C 1 -C 4 )alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl Or a tert-butyl group; the substituted (C 1 -C 12 ) alkyl group is
  • (C 1 -C 12 ) alkoxy group preferably, the (C 1 -C 12 ) alkoxy group, and the substituted or unsubstituted (C 1 -C 12 ) alkoxy group, "(C 1 -C 12 )alkoxy" is independently (C 1 -C 4 )alkoxy; said (C 1 -C 4 )alkoxy is preferably methoxy, ethoxy , n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
  • a pharmaceutically acceptable salt thereof, and a stereoisomer thereof are provided.
  • One or more of the isotopic compounds, metabolites and prodrugs are any of the following compounds: B101, B102, B103, B104, B105, B106, C107, C108, C109, C110, C111, C112, which are pharmaceutically acceptable Salt, and, and its stereoisomers.
  • One or more of the drugs are any of the following compounds: B101, B102, B103, B104, B105, B106, C111, pharmaceutically acceptable salts thereof, and stereoisomers thereof.
  • the androgen receptor pathway modulator is preferably selected from the group consisting of enzalutamide, ARN-509, abiraterone, abiraterone acetate, Galeterone, ODM-201, and ORM-15341. One or more of them.
  • the androgen receptor pathway modulator is more preferably enzalutamide, ARN-509, Galeterone, ODM-201, ORM-15341, abiraterone, abiraterone acetate, Enzalutamide and Galeterone, enzalutamide and abiraterone acetate, enzalutamide and abiraterone, enzalutamide and ODM-201, enzalutamide and ORM-15341, ARN-509 and Galeterone , ARN-509 and abiraterone acetate, ARN-509 and abiraterone, ARN-509 and ODM-201, ARN-509 and ORM-15341, ODM-201 and Galeterone, ODM-201 and abiraterone acetate , ODM-201 and abiraterone, ORM-15341 and Galeterone, ORM-15341 and abiraterone acetate , ODM-201 and
  • the androgen receptor pathway modulator is optimally enzalutamide, ARN-509, Galeterone, ODM-201, abiraterone, abiraterone acetate, enzalutamide And Galeterone, enzalutamide and abiraterone acetate, ARN-509 and Galeterone, ARN-509 and abiraterone acetate, ODM-201 and enzalutamide, ODM-201 and ARN-509, ODM-201 And Galeterone, ODM-201 and abiraterone, or, ODM-201 and abiraterone acetate.
  • the combination of the androgen receptor pathway modulators is: "the benzoheterocyclic compound represented by the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer thereof,
  • One or more of the isotopic compounds, metabolites, and prodrugs are selected from the group consisting of: B101, B102, B103, B104, B105, B106, C107, C108, C109, C110, C111, C112, pharmaceutically acceptable salts thereof And, its stereoisomers; androgen receptor pathway modulators are selected from the group consisting of enzalutamide, ARN-509, abiraterone, abiraterone acetate, Galeterone, ODM-201, and ORM
  • the benzoheterocyclic compound represented by the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolism thereof The combination of one or more of the substance and the prodrug and the androgen receptor pathway modulator is: "the benzoheterocyclic compound represented by the formula (I), a pharmaceutically acceptable salt thereof, One or more of a solvate, a crystal form, a eutectic, a stereoisomer, an isotope compound, a metabolite, and a prodrug are selected from the group consisting of B101, B102, B103, B104, B105, B106, C107, C108, C109, C110, C111, C112, pharmaceutically acceptable salts thereof, and stereoisomers thereof; androgen receptor pathway regulators are enzalutamide, ARN-509, Galeterone, ODM-201, ORM-15341, Bitron, abira
  • the benzoheterocyclic compound represented by the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolism thereof The combination of one or more of the substance and the prodrug and the androgen receptor pathway modulator is: "the benzoheterocyclic compound represented by the formula (I), a pharmaceutically acceptable salt thereof, One or more of a solvate, a crystal form, a eutectic, a stereoisomer, an isotope compound, a metabolite, and a prodrug are selected from the group consisting of B101, B102, B103, B104, B105, B106, C107, C108, C109, C110, C111, C112, pharmaceutically acceptable salts thereof, and stereoisomers thereof; androgen receptor pathway regulators are enzalutamide, ARN-509, Galeterone, ODM-201, abiraterone, acetic acid Abibi
  • the combination of the benzoheterocyclic compound of formula (I) and the androgen receptor pathway modulation is preferably: B101 and enzalutamide, B102 and enoxa Ralamine, B103 and enzalutamide, B104 and enzalutamide, B105 and enzalutamide, B106 and enzalutamide, C111 and enzalutamide, B101 and ARN-509, B102 and ARN-509, B103 and ARN-509, B104 and ARN-509, B105 and ARN-509, B106 and ARN-509, C111 and ARN-509, B101 and Abitron, B102 and Abiton, B103 and Abiraterone, B104 and Abiraterone, B105 and Abiraterone, B106 and Abiraterone, C111 and Abiraterone, B101 and abiraterone acetate, B102 and abiraterone acetate, B103 and abirater
  • the pharmaceutically acceptable salt of the benzoheterocyclic compound represented by the formula (I), and the combination of the androgen receptor pathway regulation are preferably as described in any of the above paragraphs.
  • the only difference is that "the benzoheterocyclic compound represented by the formula (I)” is replaced with "the pharmaceutically acceptable salt of the benzoheterocyclic compound represented by the formula (I)".
  • B101 and enzalutamide are present in the previous paragraph, this paragraph corresponds to the pharmaceutically acceptable salt of B101 and enzalutamide.
  • the stereoisomer of the benzoheterocyclic compound represented by the formula (I), and the combination of the androgen receptor pathway regulation are preferably in any combination of the above paragraphs.
  • the only difference is that the "pharmaceutically acceptable salt of the benzoheterocyclic compound represented by the general formula (I)” is replaced by the "stereoisomer of the benzoheterocyclic compound represented by the general formula (I)” .
  • there is a pharmaceutically acceptable salt of B101 and enzalutamide there is a pharmaceutically acceptable salt of B101 and enzalutamide, and this paragraph corresponds to the stereoisomer of B101 and enzalutamide.
  • the combination may further comprise a hormonal compound which is one or more of prednisone, dexamethasone, dehydroepiandrosterone, iso-androstenone, and megestrol acetate.
  • the hormonal compound is preferably prednisone. Therefore, the combination may include the benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotopic compound thereof, One or more of a metabolite and a prodrug, said androgen receptor pathway modulator, and said hormone compound.
  • the combination of the androgen receptor pathway modulator and the hormonal compound is preferably: Galeterone and prednisone, prednisone and abiraterone acetate, enzalutamide And prednisone, ARN-509 and prednisone, enzalutamide and dexamethasone, enzalutamide and Galeterone and prednisone, enzalutamide and Galeterone and dexamethasone, enzalutamide and ODM -201 and prednisone, enzalutamide and ODM-201 and dexamethasone, enzalutamide and ORM-15341 and prednisone, enzalutamide and ORM-15341 and dexamethasone, enzalutamide And abiraterone acetate and prednisone, enzalutamide and abiraterone acetate and dexamethasone, enzalutamide
  • the combination of the androgen receptor pathway modulator and the hormonal compound is more preferably: Galeterone and prednisone, prednisone and abiraterone acetate, enzalutamide and strong Pine, ARN-509 and prednisone, enzalutamide and Galeterone and prednisone, enzalutamide and ODM-201 and prednisone, enzalutamide and ORM-15341 and prednisone, enzalu Amine and abiraterone acetate and prednisone, enzalutamide and abiraterone and prednisone, ARN-509 and Galeterone and prednisone, ARN-509 and ODM-201 and prednisone, ARN-509 And ORM-15341 and prednisone, ARN-509 and abiraterone acetate and prednisone, ARN-509 and abiraterone and pred
  • the combination of the androgen receptor pathway modulator and the hormone compound is optimally: Galeterone and prednisone, prednisone and abiraterone acetate, enzalutamide and strong Pine, ARN-509 and prednisone, enzalutamide and Galeterone and prednisone, enzalutamide and abiraterone acetate and prednisone, ARN-509 and Galeterone and prednisone, ARN-509 And abiraterone acetate and prednisone, ODM-201 and prednisone, ODM-201 and Galeterone and prednisone, ODM-201 and abiraterone acetate and prednisone, ODM-201 and abiraterone And prednisone, enzalutamide and ODM-201 and prednisone, or, ARN-509 and ODM-201 and prednisone.
  • the benzoheterocyclic compound represented by the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope thereof The combination of one or more of a compound, a metabolite, and a prodrug, the androgen receptor pathway modulator, and the hormone compound is preferably the "general formula (I)
  • One or more of a benzoheterocyclic compound, a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolite, and prodrug thereof are selected from the group consisting of: B101, B102 , B103, B104, B105, B106, C107, C108, C109, C110, C111, C112, pharmaceutically acceptable salts thereof, and stereoisomers thereof; and the androgen receptor pathway regulator and the hormone
  • the combination of compounds is: Galeterone and prednisone, prednisone and a
  • the combination of the benzoheterocyclic compound represented by the formula (I), the androgen receptor pathway modulator, and the hormone compound is more preferably: B101 and Enzalutamide and prednisone, B102 and enzalutamide and prednisone, B103 and enzalutamide and prednisone, B104 and enzalutamide and prednisone, B105 and enzalutamide and strong Pine, B106 and enzalutamide and prednisone, C111 and enzalutamide and prednisone, B101 and ARN-509 and prednisone, B102 and ARN-509 and prednisone, B103 and ARN-509 And prednisone, B104 and ARN-509 and prednisone, B105 and ARN-509 and prednisone, B106 and ARN-509 and prednisone, C111 and ARN-509 and prednisone, B101 and
  • the combination of the pharmaceutically acceptable salt of the benzoheterocyclic compound represented by the general formula (I), the androgen receptor pathway modulator, and the hormonal compound is more preferably
  • the combination of any one of the above paragraphs differs only in that "the benzoheterocyclic compound represented by the formula (I)” is replaced by the “pharmaceutically acceptable salt of the benzoheterocyclic compound represented by the formula (I). ".
  • B101 and enzalutamide and prednisone this paragraph corresponds to the pharmaceutically acceptable salt of B101 and enzalutamide and prednisone.
  • the combination of the stereoisomer of the benzoheterocyclic compound represented by the general formula (I), the androgen receptor pathway modulator, and the hormonal compound is more preferably as described above.
  • the only difference is that the "pharmaceutically acceptable salt of the benzoheterocyclic compound represented by the formula (I)" is replaced by the "steric compound of the benzoheterocyclic compound represented by the formula (I). isomer”.
  • the pharmaceutically acceptable salt of B101 and enzalutamide and prednisone there is a pharmaceutically acceptable salt of B101 and enzalutamide and prednisone, and this paragraph corresponds to the stereoisomer of B101 and enzalutamide and prednisone.
  • the components of the combination may be used simultaneously or separately (eg, sequentially); when the components of the combination are used simultaneously, the components of the combination may be uniformly mixed (ie, the components mixture).
  • the components of the combination may be prepared as a single pharmaceutical composition for simultaneous use, or the components may be separately formulated into individual independent pharmaceutical compositions which may be used simultaneously or separately ( example As used in sequence).
  • the term "component” means a component in the combination of the present invention, that is, a compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope thereof
  • a compound a metabolite, and a prodrug, an androgen receptor pathway modulator, or a hormonal compound.
  • the invention also provides a pharmaceutical composition comprising the combination described above and one or more pharmaceutical excipients.
  • the pharmaceutical composition provided by the present invention may comprise a benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic or stereoisomer thereof.
  • a benzoheterocyclic compound represented by the above formula (I) a pharmaceutically acceptable salt, solvate, crystal form, eutectic or stereoisomer thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer
  • a pharmaceutically acceptable salt represented by the above formula (I)
  • a pharmaceutically acceptable salt solvate, crystal form, eutectic, stereoisomer
  • a body an isotope compound, a metabolite, and a prodrug
  • the above-described androgen receptor pathway modulator the above hormone compound
  • one or more pharmaceutically acceptable excipients comprising the benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer
  • the pharmaceutical excipients may be those excipients widely used in the field of pharmaceutical production.
  • the excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition, and may also provide means for the subject to be dissolved at the desired rate after administration, or to promote the subject's activity after administration of the composition.
  • the ingredients are effectively absorbed.
  • the pharmaceutical excipient can be an inert filler or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
  • the pharmaceutical excipient may include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
  • excipients binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
  • the pharmaceutical composition may consist of the combination and the one or more pharmaceutical excipients.
  • compositions known in the art include, but are not limited to, conventional mixing, dissolving, granulating, emulsifying, pulverizing, encapsulating, embedding, or lyophilizing processes.
  • the pharmaceutical composition of the present invention may be obtained by mixing a benzoheterocyclic compound represented by the formula (I), a pharmaceutically acceptable salt thereof, a solvate, a crystal form, a eutectic, a stereoisomer, an isotope compound, Preparation of one or more of metabolites and prodrugs, androgen receptor pathway modulators, and pharmaceutical excipients.
  • the pharmaceutical composition of the present invention may be prepared by mixing a compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolite, and prodrug thereof.
  • a pharmaceutically acceptable salt solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolite, and prodrug thereof.
  • One or more, androgen receptor pathway modulators, hormonal compounds, and pharmaceutical excipients are prepared.
  • compositions of the present invention may be formulated for administration in any form, including injection (intravenous), mucosa, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion). , injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration.
  • the pharmaceutical compositions of the invention may also be in a controlled release or delayed release dosage form.
  • Solid mouth Examples of pharmaceutical preparations include, but are not limited to, powders, capsules, caplets, soft capsules, pills, and tablets.
  • liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
  • Examples of the formulation for topical administration include, but are not limited to, an emulsion, a gel, an ointment, a cream, a patch, a paste, a foaming agent, a lotion, a drop, or a serum preparation.
  • preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection.
  • Examples of other suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic formulations; aerosols: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and ingots Agent.
  • controlled release dosage form refers to a dosage form in which the rate of release of the therapeutically active ingredient in the pharmaceutical composition is controllable or has a specific delay to control the subject to whom the pharmaceutical composition is administered. The site of treatment of the active ingredient.
  • a controlled release dosage form can contain a controlled release agent such as a sustained release agent (sustained release) and/or a delayed release agent (delayed release).
  • sustained release refers to the prolonged release of a therapeutically active ingredient from a pharmaceutical formulation.
  • delayed release refers to a therapeutically active ingredient from a pharmaceutical composition after the subject has received the composition to reach the desired environment within the subject, or after a particular period of time after the subject has received the administration. Released in such a way that release occurs at a specific location or desired environment.
  • sustained release agent and “delayed release agent” refer to a compound or additive that provides controlled release of a therapeutically active ingredient from a formulation such that release occurs gradually and the time of release is prolonged.
  • the sustained or delayed release agent allows the subject to release the therapeutically active ingredient for a specified period of time after administration of the composition.
  • Controlled release from a controlled release dosage form of a pharmaceutical composition of the invention can be accomplished by a variety of conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • the pharmaceutical composition of the present invention may further comprise an enteric coating to control the release of the active ingredient in the pharmaceutical composition such that it is gradually and continuously released from the composition for a desired period of time, so that the active ingredient can be prolonged Play a therapeutic or preventive role during the time period.
  • enteric coating to control the release of the active ingredient in the pharmaceutical composition such that it is gradually and continuously released from the composition for a desired period of time, so that the active ingredient can be prolonged Play a therapeutic or preventive role during the time period.
  • Non-limiting examples of controlled release agents that can be incorporated into the pharmaceutical compositions of the present invention to provide controlled release compositions include polymers such as hydroxypropyl methylcellulose; gels; permeable membranes; microparticles; liposomes; Ball and its combination. Any of the compositions described herein can be applied to controlled release formulations such as tablets, capsules, soft capsules and caplets.
  • the present invention also provides a combination kit comprising the pharmaceutical composition A and the pharmaceutical composition B;
  • the pharmaceutical composition A includes the benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolism thereof.
  • a pharmaceutically acceptable salt solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolism thereof.
  • the pharmaceutical composition B comprising the above-described androgen receptor pathway modulator and one or more pharmaceutically acceptable excipients.
  • the combination kit can be composed of the pharmaceutical composition A and the pharmaceutical composition B described.
  • the pharmaceutical composition A may be a benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolism thereof. And one or more pharmaceutically acceptable excipients; and the pharmaceutical composition B may be an androgen receptor pathway modulator and one or more pharmaceutically acceptable excipients as described above composition.
  • the "androgen receptor pathway modulator" described in the pharmaceutical composition B and the combination thereof are as described above.
  • the combination kit may further comprise a pharmaceutical composition C comprising the hormonal agent described above and one or more pharmaceutically acceptable excipients.
  • the combination kit may consist of the pharmaceutical composition A, the pharmaceutical composition B, and the pharmaceutical composition C.
  • the pharmaceutical composition C may be composed of the above hormonal drugs and one or more pharmaceutically acceptable excipients.
  • the benzoheterocyclic compound represented by the formula (I) a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer thereof, as described in the pharmaceutical composition A "one or more of a body, an isotope compound, a metabolite, and a prodrug", the "androgen receptor pathway modulator” described in the pharmaceutical composition B, described in the pharmaceutical composition C
  • the hormonal drugs and the combinations they form are as described above.
  • Each of the pharmaceutical compositions in the combination kit can be used simultaneously or separately (e.g., sequentially).
  • the "pharmaceutical excipient" is as defined above.
  • the term "active ingredient” means an active ingredient in the pharmaceutical composition or combination kit of the present invention, that is, a compound of the formula (I), a pharmaceutically acceptable salt thereof, a solvate, a crystal form, a eutectic, One or more of a stereoisomer, an isotope compound, a metabolite, and a prodrug, an androgen receptor pathway modulator, a hormone compound, or a combination thereof.
  • the above combination, the above pharmaceutical composition, or the above-described combination kit can be used for the prevention and/or treatment of prostate cancer.
  • the prostate cancer is preferably castration-resistant prostate cancer.
  • the present invention provides the benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotopic compound thereof, Use of one or more of a metabolite and a prodrug for the preparation of a pharmaceutical composition for preventing and/or treating prostate cancer in combination with an androgen receptor pathway modulator as described above.
  • the present invention provides the benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotopic compound thereof,
  • a metabolite and a prodrug are prepared for use in combination with the above-described androgen receptor pathway modulator, and the above-described hormonal compound for prevention and/or Or use in a pharmaceutical composition for treating prostate cancer.
  • the present invention also provides the above-described androgen receptor pathway modulator, which is prepared by using the benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt, a solvate thereof, a crystal form, Use of one or more of eutectic, stereoisomers, isotopic compounds, metabolites, and prodrugs in combination with a pharmaceutical composition for preventing and/or treating prostate cancer.
  • the present invention also provides the above-described androgen receptor pathway modulator, which is prepared by using the benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt, a solvate thereof, a crystal form, Use of one or more of a eutectic, a stereoisomer, an isotope compound, a metabolite, and a prodrug, and a pharmaceutical composition as described above in combination with a prophylactic and/or therapeutic prostate cancer.
  • the above-described androgen receptor pathway modulator which is prepared by using the benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt, a solvate thereof, a crystal form, Use of one or more of a eutectic, a stereoisomer, an isotope compound, a metabolite, and a prodrug, and a pharmaceutical composition as described above in combination with a prophylactic and/or therapeutic prostate cancer.
  • the present invention also provides the above hormonal compound, which is prepared by using the benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, a solvate, a crystal form, a eutectic, a stereo Use of one or more of an isomer, an isotope compound, a metabolite, and a prodrug, and a combination of the above-described androgen receptor pathway modulators in the prevention and/or treatment of prostate cancer.
  • the above hormonal compound which is prepared by using the benzoheterocyclic compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, a solvate, a crystal form, a eutectic, a stereo Use of one or more of an isomer, an isotope compound, a metabolite, and a prodrug, and a combination of the above-described androgen receptor pathway modulators in the prevention and/or treatment of prostate cancer.
  • One or more of the metabolites and prodrugs, the above-described androgen receptor pathway modulators, and the above hormone compounds may be administered simultaneously or separately (e.g., sequentially).
  • the benzoheterocyclic compound represented by the formula (I) a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotopic compound, metabolite thereof
  • a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotopic compound, metabolite thereof One or more of the prodrugs, the androgen receptor pathway modulators, the hormone compounds, and combinations thereof are as described above.
  • the invention also provides a method of preventing and/or treating prostate cancer comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of the combination described above.
  • the prostate cancer may be castration resistant prostate cancer.
  • the method of preventing and/or treating prostate cancer comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a benzoheterocyclic compound represented by the above formula (I), which is pharmaceutically acceptable One or more of a salt, a solvate, a crystal form, a eutectic, a stereoisomer, an isotope compound, a metabolite, and a prodrug, and a therapeutically or prophylactically effective amount of the above-described androgen receptor pathway modulator .
  • a benzoheterocyclic compound represented by the above formula (I) which is pharmaceutically acceptable
  • a salt, a solvate, a crystal form, a eutectic, a stereoisomer, an isotope compound, a metabolite, and a prodrug and a therapeutically or prophylactically effective amount of the above-described androgen receptor pathway modulator .
  • benzoheterocyclic compound represented by the above formula (I) a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolite, and prodrug thereof
  • a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolite, and prodrug thereof may be administered simultaneously or separately (e.g., sequentially).
  • the method of preventing and/or treating prostate cancer preferably comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a benzoheterocyclic compound represented by the above formula (I).
  • a benzoheterocyclic compound represented by the above formula (I) One or more of its pharmaceutically acceptable salts, solvates, crystal forms, eutectic, stereoisomers, isotopic compounds, metabolites and prodrugs, A therapeutically or prophylactically effective amount of the above-described androgen receptor pathway modulator, and a therapeutically or prophylactically effective amount of the above hormonal compound.
  • benzoheterocyclic compound represented by the above formula (I) a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolite, and prodrug thereof
  • a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolite, and prodrug thereof may be administered simultaneously or separately (for example, sequentially).
  • the isomers, isotopic compounds, metabolites, and prodrugs, the androgen receptor pathway modulators, the hormone compounds, and combinations thereof are as described above.
  • the compound administered to each subject (herein referred to as a benzoheterocyclic compound represented by the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic thereof
  • the therapeutically or prophylactically effective amount of one or more of stereoisomers, isotopic compounds, metabolites and prodrugs, androgen receptor pathway modulators or hormonal compounds is from about 0.005 to about 1000 mg/day, From about 0.01 to about 500 mg/day, from about 0.01 to about 250 mg/day, from about 0.01 to about 100 mg/day, from about 0.1 to about 100 mg/day, from about 0.5 to about 100 mg/day, from about 1 to about 100 mg/day, from about 0.01 to about 50 mg/day, from about 0.1 to about 50 mg/day, from about 0.5 to about 50 mg/day, from about 1 to about 50 mg/day, from about 0.02 to about 25 mg /day or from about 0.05 to about 10 mg / day.
  • a therapeutically or prophylactically effective amount (herein referred to as a benzoheterocyclic compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomeric
  • a prophylactic or therapeutically effective amount of one or more of a conformation, an isotope compound, a metabolite, and a prodrug, an androgen receptor pathway modulator or a hormonal compound is about 0.01, about 0.05, about 0.1, about 0.2, About 0.3, about 0.4, about 0.5, about 0.6, about 0.8, about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60 , about 70, about 80, about 90, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900 or about 1000 mg per day per
  • the benzoheterocyclic compound represented by the formula (I) and the The molar ratio of the androgen receptor pathway modulator can be selected according to the routine in the art, for example, 1:0.0002-1:300, and for example, 1:0.0005-1:222 (1:0.0002, 1:0.0005, 1:0014, 1 : 0.0041, 1:0.01, 1:0.0037, 1:0.11, 1:0.33, 1:1, 1:3, 1:9, 1:27, 1:79, 1:222), and then for example 1:0.1- 1:222.
  • the benzoheterocyclic compound represented by the formula (I) and the amount of the androgen receptor pathway modulator is not particularly limited and may be selected according to the routine in the art, for example, a substance of the benzoheterocyclic compound represented by the formula (I).
  • the amount of the substance may be from 0.01 to 300 ⁇ M, for example from 0.05 to 50 ⁇ M, and for example from 0.05 to 11.11 ⁇ M.
  • the amount of the hormone compound is not special
  • the molar ratio of the hormone compound to the androgen receptor pathway modulator may be 1:0.01-1:100, for example 1:0.1-1:10 (again, for example, 1:0.1, 1 : 1, 2: 1, 1: 10).
  • the amount of the hormone compound is not special
  • the amount of the substance, for example, the hormonal compound and the androgen receptor pathway modulator may be from 0.01 to 300 ⁇ M, for example from 0.05 to 50 ⁇ M, for example from 0.1 to 10 ⁇ M.
  • the components of the combination of the invention When the components of the combination of the invention are administered to a subject to treat or prevent a disease, disorder or condition, the components of the combination may be administered by the same route or by different routes. Administration can be by any of the routes described herein including, but not limited to, oral, inhalation, injection, ocular, mucosal, rectal, emulsion, liposomal, long-term implantation or sustained release methods.
  • the particular route of administration will depend on the therapeutic agent itself and the formulation, as well as the disease, condition or condition to be prevented or treated. In accordance with the present disclosure, one of ordinary skill in the art has a skill level sufficient to determine its route of administration.
  • the components of the combination of the invention may be administered to the subject over a period of time (dose cycle) followed by a period of non-administration of the compound (non-administration cycle).
  • dose cycle a period of time followed by a period of non-administration of the compound
  • non-administration cycle a period of non-administration of the compound
  • the desired number of dosing cycles and non-dosing cycles can be repeated.
  • the desired length and number of administration cycles or non-dosing cycles will depend on the type and/or severity of the disease, condition or condition being treated or prevented, as well as the gender, age, weight and other parameters of the individual subject ( For example, the biological, physical, and physiological conditions of the individual subject, etc.).
  • the components in the combination of the present invention may be administered to the subject simultaneously over a period of time, and may also be administered to the subject sequentially over a period of time.
  • the level of skill of one of ordinary skill in the art in light of the disclosure herein will be sufficient to determine the appropriate length and number of dosing
  • Therapeutic methods described herein can be administered to a subject using the components of the combination of the invention using any suitable method, including injection, transmucosal, oral, inhalation, ocular, rectal, long-term implantation, liposomes. , emulsion or sustained release method.
  • the therapeutically or prophylactically effective amount of each component or active ingredient in a combination, pharmaceutical composition or combination kit of the invention may vary from subject to subject, such as for a particular subject, such as Age, diet, health, etc., seeking treatment or prevention of symptoms or the severity of the disease, condition or condition as well as complications and types, preparations used, and the like.
  • a therapeutically or prophylactically effective amount to be administered to a subject to elicit a desired biological or medical response in the subject may be administered to a subject to elicit a desired biological or medical response in the subject.
  • a synergistic effect can be exerted in the treatment or prevention of any disease, condition or condition, such as prostate cancer.
  • the combination, pharmaceutical composition or combination kit according to the invention may be used alone, or with ultrasound therapy, radiation therapy (abbreviated as radiotherapy) or Radioimmunotherapy or the like may be used in combination with one or more other pharmacologically active therapeutic agents (hereinafter referred to as "other therapeutic agents").
  • other therapeutic agents pharmacologically active therapeutic agents
  • the amount and type of other therapeutic agent will depend on the disease, condition or condition to be treated or prevented; the severity of the disease, condition or condition; factors of the subject to whom the composition is administered, such as age, weight, physical condition Etc.; route of administration, etc.
  • the additional therapeutic agent may be a naturally occurring, semi-synthetic or synthetic compound.
  • the additional therapeutic agent can be a small molecule, such as a synthetic organic or inorganic molecule; or a larger molecule or biomolecule, such as a pharmacologically active protein or nucleic acid.
  • the additional therapeutic agent can be one of a chemotherapeutic agent, an anti-angiogenic drug (also known as an angiogenesis inhibitor), an immunomodulatory agent, an immunotherapeutic agent, a monoclonal antibody, a polyclonal antibody, and a kinase inhibitor. kind or more.
  • chemotherapeutic agent that is, a chemical synthetic drug.
  • Chemotherapeutic agents are currently the main drugs for the treatment of tumors and certain autoimmune diseases. Commonly used are: epirubicin, doxorubicin, daunorubicin, mitomycin, fluorouracil deoxynucleotides and the like.
  • An anti-angiogenic drug inhibits neovascularization by inhibiting proangiogenic growth factors, growth factor receptors, and downstream signaling pathways, thereby inhibiting tumor growth and metastasis, including vascular endothelial growth inhibitors and receptors.
  • Immunomodulators are drugs that enhance, promote and regulate immune function, and have a role in the treatment of immune dysfunction, certain secondary immunodeficiency diseases and certain malignant tumors. According to the function of immunomodulators, they are mainly classified into immunosuppressants and immunopotentiators. The former is used for anti-inflammatory, anti-autoimmune, anti-allergic, anti-graft rejection and anti-tumor, the latter for anti-infective, anti-allergic and anti-tumor.
  • drugs belonging to immunosuppressive agents including antimetabolites (cycloheximide A, azolidine, cyclophosphamide, methotrexate, mycophenolate mofetil, tacrolimus and mirazolabine, etc.) , glucocorticoids, monoclonal antibodies (anti-TNF-alpha/receptors, anti-IFN- ⁇ , and anti-CD25 single Hang, etc.), cytokines IFN- ⁇ , IL-10 and TGF- ⁇ , chemical agents (fluoride Mitt and 5-HT3 receptor antagonists, non-molecular anti-inflammatory drugs, nucleic acids, statin anti-lipids, HMG-CoA reductase inhibitors, plants (Tracile vine, Cordyceps extract FTY720, Qinglingsu and Paxilin, and other biological products (cholera toxin B subunit, sNTB-A-Fc fusion protein, CMV-IkappaBa carrier inhibitor and B7-HI
  • immune enhancers including cytokines (interferon alpha, interferon gamma, thymosin and thymus 5 peptide, G-CSF/GM-CSF, IL-2, IL-12, recombinant human erythropoietin, epidermal cells).
  • cytokines interferon alpha, interferon gamma, thymosin and thymus 5 peptide
  • G-CSF/GM-CSF IL-2
  • IL-12 recombinant human erythropoietin, epidermal cells.
  • growth factors chemokine intercellular adhesion molecule-1, vascular cell adhesion molecule-1, P-selectin and other intercellular adhesion molecules, etc.
  • biological products [IVIG, transfer factor, immune ribonucleic acid, fine Bacteria and its extracts (Bacillus Calmette-Guer and its extracts, defatted and delipidated milk M.
  • vaccae vaccine other bacterial extracts, low calcium reaction V or V antigen LcrV, Vibrio cholerae product Zot and Mycobacterium, etc.] , plant medicines (polysaccharides, saponins and other botanical ingredients, etc.), chemical preparations (levamisole, cimetidine, pidotimod, NS-398 imiprazole, Propagermanium and liposomes, etc.), micronutrients ( Vitamin A/C/D, trace elements iron, zinc, selenium) and others (macrolide antibiotics, aminophylline).
  • Immunotherapy refers to modulating a subject's immune response to produce a desired therapeutic effect.
  • the immunotherapeutic agent refers to modulating the subject's immune system when administered to a subject, sufficient to ultimately reduce symptoms associated with adverse immune responses. Or a drug that ultimately reduces the symptoms caused by increasing the required immune response.
  • a monoclonal antibody refers to an antibody that is highly uniform and uniquely directed against a particular antigenic epitope produced by a single B cell clone.
  • Polyclonal antibodies refer to the use of an antigen-immune receptor comprising multiple antigenic determinants, which stimulates multiple B-cell clones of the body to produce different antibodies against multiple epitopes.
  • kinases are a class of enzymes that transfer a phosphate group from a high-energy donor molecule (such as ATP) to a specific target molecule (the substrate); this process is called phosphorylation; a kinase inhibitor is a class that can be combined. A kinase that reduces its activity.
  • Other therapeutic agents include, but are not limited to, daratumumab, elotuzumab, palbociclib, panobinostat, nivolumab, pembrolizumab, pemetrexed, topotecan (topotecan), doxorubicin, borontezo Rice (bortezomib), gemcitabine, dacarbazine, biaxin, vincristine, azacitidine, CAR-T, rituximab ), trastuzumab, PD-1 inhibitor, PD-L1 inhibitor, HDAC inhibitor, androgen receptor pathway modulator other than the aforementioned androgen receptor pathway modulator, docetaxel One or more of (docetaxel), clofarabine injection, Ublituximab, romidepsin, BTK inhibitor, red blood cell growth hormone, eltrombopag, minocycline, and melphalan.
  • the therapeutically or prophylactically effective amount of the androgen receptor pathway modulator or hormone compound in the pharmaceutical composition or combination kit of the invention may be lower than the administration of the compound of formula (I) of the invention, An effective amount of a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolite or prodrug thereof.
  • the amount, therapeutic or prophylactically effective amount, dose, starting dose and the like of the compound to be administered refer to the amount of a specific compound, for example, specifically a certain benzene represented by the formula (I). a heterocyclic compound, a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolite or prodrug thereof, specific androgen receptor pathway modulator or specific hormone a compound, not a combination of multiple compounds.
  • a therapeutically or prophylactically effective amount of an androgen receptor pathway modulator or a hormonal agent used in the method of the present invention Drug guidance can be found in the patents and published patent applications cited herein and in Wells et al, eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000) and other medical literature.
  • androgen receptor pathway modulator includes androgen inhibitors, androgen receptor inhibitors, androgen biosynthesis inhibitors, and other drugs that affect the androgen receptor pathway.
  • Hormonal is a type of chemical substance that is produced by certain tissues of the normal body and then diffused into the blood, transported by the blood to other tissues of the body, and exerts a special physiological role. Hormonal compounds include synthetic or natural hormonal chemicals.
  • salt, composition, excipient, etc. it is meant that the salt, composition, excipient, and the like are generally non-toxic, safe, and suitable for use by a subject, preferably A mammalian subject, more preferably a human subject.
  • salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, isonicotinic acid Salt, lactate, salicylate, acid citrate, tartrate, oleate, tannic acid, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, gentisinate , fumarate, gluconate, glucuronate, sugar, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, besylate , p-toluenesulfonate and pamoate (ie, 1-1-methylene-bis(2-hydroxy-3-naphthoate)
  • Suitable base salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, barium salts, and diethanolamine salts.
  • Suitable base salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, barium salts, and diethanolamine salts.
  • the term "metabolite” refers to an active substance produced by a change in the chemical structure experienced by a drug molecule in vivo, which is typically a derivative of the aforementioned drug molecule, which may also be chemically modified.
  • polymorph refers to one or more crystal structures formed by the different arrangement of molecules in the lattice space upon crystallization.
  • the term "eutectic” refers to a multi-component system in which one or more API (active pharmaceutical ingredient) molecules and one or more guest (or coformer) molecules are present.
  • the API molecule and the guest (or coformer) molecule can also exist as a solid at room temperature when alone in its pure form (in order to distinguish the eutectic from the solvate or hydrate). Salts in which significant or complete proton exchange occurs between the API molecule and the guest molecule are excluded from this particular definition.
  • the API and co-forms pass hydrogen bonds and possibly other non-covalent Interactions interact. It may be noted that the eutectic itself may form solvates, including hydrates.
  • the guest (or co-form) refers to other physiologically acceptable acid, base, or nonionic compounds.
  • solvate refers to a crystalline form of a compound of formula (I), a pharmaceutically acceptable salt, crystal form, eutectic, stereoisomer, isotope compound, metabolite or prodrug thereof. It also contains one or more solvent molecules that are incorporated into the crystal structure.
  • the solvate may include a stoichiometric or non-stoichiometric amount of solvent, and the solvent molecules in the solvent may be present in an ordered or non-ordered arrangement. Solvates containing non-stoichiometric amounts of solvent molecules may result from the solvate losing at least a portion, but not all, of the solvent molecules.
  • a solvate is a hydrate, meaning that the crystalline form of the compound further comprises water molecules.
  • the term "prodrug” refers to a derivative of a compound comprising a biologically reactive functional group such that under biological conditions (in vitro or in vivo), the bioreactive functional group can be cleaved from the compound or otherwise reacted to provide the Compound.
  • the prodrug is inactive, or at least less active than the compound itself, such that the compound does not exert its activity until it is cleaved from the biologically reactive functional group.
  • the bioreactive functional group can be hydrolyzed or oxidized under biological conditions to provide the compound.
  • a prodrug can comprise a biohydrolyzable group
  • biohydrolyzable groups include, but are not limited to, biohydrolyzable phosphates, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbonates, Biohydrolyzable carbamate and biohydrolyzable ureide.
  • the compound of the formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotopic compound, metabolite or prodrug thereof in the combination of the present invention may contain one or more Symmetric center ("stereoisomer").
  • stereoisomer refers to enantiomers, diastereomers, epimers, endo-exo isomers, steric hindrance All stereoisomers of atropisomers, regioisomers, cis- and trans-isomers, and the like.
  • stereoisomers herein also include “pure stereoisomers” and “enriched stereoisomers” or “racemates” of the various stereoisomers described above. These stereoisomers can be isolated, purified and enriched by asymmetric synthesis or chiral separation methods including, but not limited to, thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc. It is obtained by chiral separation by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds.
  • pure stereoisomer herein is meant a stereoisomer of the compound in question having a mass content of not less than 95% relative to other stereoisomers of the compound.
  • enriched stereoisomer herein is meant that the stereoisomer of the compound in question has a mass content of not less than 50% relative to the other stereoisomers of the compound.
  • racemate herein is meant that the mass of one stereoisomer of the compound in question is equal to the mass content of the other stereoisomers of the compound.
  • D denotes deuterium-enriched hydrogen and H denotes non-deuterium-enriched hydrogen.
  • ⁇ compound means Abundance of cerium at any relevant site in a compound of formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolite or prodrug thereof Greater than its natural abundance at this site (0.0156%).
  • the abundance of enthalpy at any of its associated sites may be in the range of greater than 0.0156% to 100%.
  • An example of a method for obtaining a ruthenium-enriched compound is to synthesize a compound by exchanging hydrogen with hydrazine or enriching the starting material with hydrazine.
  • Non-deuterium enrichment refers to hydrogen in nature, ie in the form of a mixture of H (hydrogen or hydrazine), D ( 2 H or hydrazine) and T ( 3 H or hydrazine) isotopes.
  • isotopic compound means that the compound of the formula (I) of the present invention, a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, metabolite or prodrug thereof contains one or Multiple natural or non-natural abundance of atomic isotopes.
  • Non-natural abundance of atomic isotopes including, but not limited to, hydrazine ( 2 H or D), hydrazine ( 3 H or T), iodine-125 ( 125 I), phosphorus-32 ( 32 P), carbon-13 ( 13 C) Or carbon-14 ( 14 C).
  • the aforementioned isotopic compounds can also be used as therapeutic or diagnostic agents (i.e., in vivo developers), or as research tools. All isotopic variations of the compounds of the invention, whether or not they are radioactive, are included within the scope of the invention.
  • isotopic enrichment refers to a compound of formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotope compound, metabolite, prodrug thereof, Or multiple non-naturally abundant atomic isotopes.
  • “Isotopic enrichment” also refers to a compound of formula (I), a pharmaceutically acceptable salt, solvate, crystal form, eutectic, stereoisomer, isotopic compound, metabolite, or prodrug compound thereof having at least one of Non-natural abundance isotope atom.
  • the term "subject” or “patient” refers to any animal that is or has been administered a compound or composition according to an embodiment of the invention, which is superior to mammals and optimal for humans.
  • the term "mammal” as used herein includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., which are optimal for humans.
  • the terms “subject” and “patient” are used interchangeably herein.
  • treating refers to amelioration, prevention, or reversal of a disease or condition, or at least one discernible symptom thereof, for example, by reducing or stabilizing the symptoms of a cancer or condition.
  • “treating” or “treating” refers to the improvement, prevention, or reversal of at least one measurable physical parameter of a disease or condition being treated that may not be recognized in a mammal.
  • “treating” or “treating” refers to slowing the progression of a disease or condition, or physical, such as the identification of stable symptoms, or physiological, for example, stabilization of body parameters. , or both.
  • “treating” or “treating” refers to delaying the onset of a disease or condition.
  • the combination, pharmaceutical composition, or combination kit is administered as a preventative measure.
  • preventing or “preventing” refers to reducing the risk of obtaining a given disease or condition.
  • the specified combination, pharmaceutical composition or combination kit is administered to the subject as a preventive measure, such as a subject having a family history or predisposition to cancer or an autoimmune disease.
  • therapeutically effective amount refers to an amount of a compound or composition that is capable of causing a tissue system, animal or human to produce a biological or medical response (a researcher, veterinarian, doctor or other clinician is seeking), which may include Reduce the symptoms of the disease or condition being treated.
  • the therapeutically effective amount is an amount effective to treat, ameliorate or prevent cancer, a condition.
  • prophylactically effective amount refers to an amount of an active compound or agent that is capable of inhibiting the onset of a condition in a subject (as sought by a researcher, veterinarian, medical practitioner, or other clinician).
  • a prophylactically effective amount of a compound refers to an amount of the therapeutic agent used alone or in combination with other therapeutically active compounds that provides a therapeutic benefit in the treatment or prevention of a disease, disorder or condition.
  • the structures of the androgen receptor pathway regulators and hormone compounds are as follows:
  • the reagents used in the present invention are all commercially available, and the compounds of the formula (I) and the androgen receptor pathway modulators of the present invention can be readily synthesized by those skilled in the art according to synthetic methods well known in the art or according to published literature or patents.
  • Related patents such as WO2016065980, WO9803502, WO2010056344, WO2012079022, WO2012015986, WO2011100380, WO2014116573, WO2008039489, WO2014110558, WO2014039421, WO2006124118, and the like.
  • the positive progress of the present invention is that the combination of the present invention can more effectively inhibit the growth of prostate cancer cells, and the combined components have a synergistic effect.
  • Test compounds such as B101, B102, B103, B104, B105, B106, C111, androgen receptor pathway regulators, hormones on Vcap cells (androgen receptor-positive prostate cancer cells) (ATCC, Cat. No. CRL-2876)
  • the inhibitory effects of the compounds alone or in combination on proliferation of prostate cancer cells The specific experimental operation is as follows. 5 ⁇ 10 3 Vcap cells per well were inoculated into a 96-well culture plate (Corning, catalog number CLS3903) containing a specific medium and placed at 37 ° C, 5% CO 2 , incubator The culture was carried out for 24 hours.
  • the test compound and the androgen receptor pathway modulator were formulated into a 150 mM stock solution using DMSO (Sigma, Cat. No.
  • the test compound is used alone or in combination with other androgen receptor pathway modulators and/or hormonal compounds to treat the cells.
  • the combination drug is: Enxylamine (Selleck, Cat. No. S1250), ARN-509 (Selleck, Cat. No. S2840), abiraterone acetate (Selleck, catalog number S2246), Galeterone (Selleck, catalogue No.
  • Table 2 Note: Synergistic effect analysis was performed on the experimental data of the combination of B105 and enzalutamide in Table 1. The data in the table shows that there is a strong synergy between the two.
  • Synergistic index of combination therapy (the same below): ⁇ 0.1: strong synergistic effect; 0.1-0.3: strong synergistic effect; 0.3-0.7: synergistic effect; 0.7-0.85: mild synergistic effect; 0.85-0.90: slight synergy ;0.90-1.10: approximation additive; 1.10.10.20: mild antagonism; 1.20-1.45: mild antagonism; 1.45-3.3: antagonism; 3.3-10: strong antagonism; >10: strong antagonism
  • Table 4 Note: Synergistic effect analysis was performed on the experimental data of the combination of C111 and enzalutamide in Table 3. The data in the table shows that there is a strong synergy between the two.
  • Vcap cell viability test compound alone, test compound in combination with enzalutamide, or test compound in combination with ARN-509
  • the cell viability of B101, B105, C111, enzalutamide, and ARN-509 is 65.4%, 72.5%, and 81.0%, respectively. 54.0%, 52.2%.
  • the cell viability was 25.2%, 27.5%, and 35.8%, respectively.
  • the cell viability was 24.3%, 28.0%, and 35.6%, respectively.
  • Vcap cell viability test compound alone, test compound in combination with Galeterone, or test compound in combination with abiraterone acetate
  • the cell viability of B101, B105, C111, Galeterone, and abiraterone acetate are 65.4%, 72.5%, 81.0%, and 62.8, respectively. %, 91.7%.
  • the cell viability was 34.4%, 36.7%, and 47.0%, respectively.
  • the cell viability was 56.6%, 57.1%, and 68.5%, respectively.
  • the effect of the combination drug is outstanding.
  • the cell viability of ODM-201, B101, B105, and C111 is 69.0%, 71.1%, 69.7%, and 72.0%, respectively.
  • the cell viability was 37.1%, 36.6%, and 43.1%, respectively.
  • Vcap cell viability B105 is administered in combination with enzalutamide, ARN-509, prednisone, Galeterone, or abiraterone acetate
  • v refers to the components contained in the combination. A space indicates no such component. The same below.
  • Vcap cell viability C111 in combination with enzalutamide, ARN-509, prednisone, Galeterone, or abiraterone acetate
  • Vcap cell viability B101 was combined with enzalutamide, ARN-509, prednisone, Galeterone, or abiraterone acetate.
  • Vcap cell viability test compound alone, test compound in combination with enzalutamide, or test compound in combination with ARN-509
  • the cell viability of B102, B103, B104, B106, enzalutamide, and ARN-509 are 80.9%, 84.1%, and 77.4, respectively. %, 79%, 65.7%, 70.4%.
  • the cell viability was 41.1%, 42.7%, 41.2%, and 40.5%, respectively.
  • the cell viability was 40.2%, 41.7%, 40.5%, and 41.1%, respectively.
  • the purpose of this experiment was to test the change in the secretion level of PSA (ie, pro-progenitor antigen) in the supernatant of the prostate tumor cell line VCap cells after treatment with the test compound and enzalutamide for 5 days.
  • PSA pro-progenitor antigen
  • VCap cells were treated with 0.5 ⁇ M enzalutamide alone and with 2 test compounds at different concentrations in combination with 0.5 ⁇ M enzalutamide for 5 days, and the PSA levels of each treatment group were determined by electrochemiluminescence immunoassay.
  • the cell culture conditions were: 37 ° C, 5% CO 2 and 95% humidity.
  • FBS fetal calf serum
  • Cells in the exponential growth phase were collected for viable cell counting.
  • the cell suspension was adjusted to 4.17 x 10e4/ml with the above medium.
  • 120 ⁇ l of the cell suspension was added to each well in a 96-well cell culture plate to a final cell concentration of 5000 cells/well.
  • the cells were incubated overnight at 37 ° C in a 5% CO 2 incubator.
  • test compound was dissolved in DMSO to a 10 mM stock solution.
  • a 4x series of gradient dilutions was prepared using stock solutions and DMSO. Then, a 10-fold dilution was made with each dilution of the medium, and a 10-fold solution of enzalutamide was prepared.
  • Each cell was supplemented with enzalutamide and an equal volume of the corresponding test compound solution per well, one for each drug concentration.
  • concentration of enzalutamide used in the final test and the concentration range of the test compound are shown in Table 13.
  • the final concentration of DMSO per well was 0.2%. Incubate for 5 days at 37 ° C in a 5% CO 2 incubator.
  • the supernatant cells of each well were collected, 2000 rpm, centrifuged for 5 minutes, and the supernatant was transferred to a clean EP tube for PSA determination.
  • PSA inhibition rate calculation formula (1-(V sample / V DMSO )) ⁇ 100% calculation.
  • the V sample was the PSA reading of the drug treatment group, and the V DMSO was the PSA average of the solvent control group.
  • Vcap cells were replaced with LNCap cells (androgen receptor-positive prostate cancer cells) (ATCC, catalog number CRL-1740), and the test results were as follows:
  • B105 is administered in combination with enzalutamide, ARN-509, prednisone, Galeterone, or abiraterone acetate
  • v refers to the components contained in the combination. A space indicates no such component. The same below.
  • B101 is administered in combination with enzalutamide, ARN-509, prednisone, Galeterone, or abiraterone acetate
  • v refers to the components contained in the combination. A space indicates no such component.

Abstract

提供了一种组合、其应用及治疗方法。所述组合包含通式（I）所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，以及雄激素受体通路调节剂和/或激素类药物。所述组合和治疗方法能够更有效地抑制前列腺癌细胞的增长。

Description

一种组合、其应用及治疗方法
本申请要求申请日为2016年12月16日的中国专利申请CN201611170723.1的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种组合、其应用及治疗方法。
背景技术
前列腺癌是男性生殖系统常见的恶性肿瘤。据世界卫生组织国际癌症研究机构统计，2012年全球新诊断的前列腺癌患者为110万，约占新增癌症病例总数的15％，成为全球范围内男性第二常见的癌症。在美国，前列腺癌发病率在所有恶性肿瘤中居第一位，死亡率居第二位，仅次于肺癌。中国前列腺癌患者的发病率虽远低于西方国家，但近年来呈显著增长趋势，已在男性泌尿系肿瘤中排名第一，且发现多在晚期。
前列腺癌细胞需要包括睾酮在内的雄激素支持才能生长。因此，前列腺癌的靶向治疗策略主要针对雄激素的合成及其与雄激素受体的结合。例如，2012年8月被美国FDA批准上市的治疗前列腺癌药物恩杂鲁胺(Enzalutamide)是一种小分子雄激素受体拮抗剂，它通过竞争性抑制雄激素与其受体的结合最终抑制雄激素受体信号通路，进而达到治疗去势耐受前列腺癌的效果。
恩杂鲁胺(Enzalutamide)在临床研究中也出现了一些副作用，如虚弱或疲劳、腰背痛、腹泻、关节痛、潮热、组织肿胀、肌肉骨骼疼痛、头痛、上呼吸道感染、头晕、压迫脊髓和马尾神经综合征、肌无力、睡眠困难、下呼吸道感染、血尿、刺痛、焦虑和高血压等。
而对于癌症的治疗，临床上常采用联合用药方式以提高治疗效果，例如多西紫杉醇与强的松联合用于治疗前列腺癌。但是，人们在探索新的联合治疗方案时也会遇到很大挫折，典型的例子之一是，虽然多西紫杉醇与强的松联合可以治疗前列腺癌(Tannock et al.N.Eng.J.Med.(2004),351,1502-1512)，但是，在一项临床研究中，用多西紫杉醇、强的松、来那度胺三者联合的治疗方案却以失败告终(Petrylak et al.Lancet Oncol.(2015)16-4,417-425)。需要同时指出的是，多个II期临床研究结果也表明，来那度胺单独用于治疗前列腺癌的临床效果并不理想(Xing et al.Asian Pac.J.Cancer Prev.(2015)16-9,3969-3972)。因此，探索前列腺癌的联合用药方式以提高疗效、降低毒副作用成为本领域亟需 要解决的技术问题。
发明内容
本发明所要解决的技术问题是为了提高现有的前列腺癌治疗药物的疗效以达到更好的临床应用效果，而提供了一种组合、其应用及治疗方法。本发明的组合和治疗方法能够更有效地抑制前列腺癌细胞的增长。
本发明提供了一种组合，其包含通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，以及雄激素受体通路调节剂；
Figure PCTCN2017116413-appb-000001
通式(I)中，n1为0或1；
L1和L2独立地为CH2、CHD或CD2；
X为NH、ND或O；
R1和R3独立地为H或D；
R2为H、D或卤素；
Z为
Figure PCTCN2017116413-appb-000002
其中，R4为H、D、CH3、CH2D、CHD2或CD3；R5、R6、R7、R8和R9独立地为H或D；用*标注的碳为不对称中心；
R10为H、D或
Figure PCTCN2017116413-appb-000003
其中R1’、R2’、R3’和R4’独立地为H、D、卤素、氰基、羟基、取代或未取代的(C1-C12)烷基、取代或未取代的(C1-C12)烷氧基、(C2～C20)杂环烷基、或、氘代(C2～C20)杂环烷基；
所述的取代的(C1-C12)烷氧基中的取代基为下列基团中的一个或多个：D、卤素、羟基、(C1-C12)烷氧基、(C2-C20)杂环烷基、和、(C1-C12)烷基取代的(C2-C20)杂环烷基；
所述的取代的(C1-C12)烷基中的取代基为下列基团中的一个或多个：D、(C2-C20)杂环烷基、氘代(C2-C20)杂环烷基、(C1-C12)烷基取代的(C2-C20)杂环烷基、和、氘代(C1-C12)烷基取代的(C2-C20)杂环烷基；
当所述的取代的(C1-C12)烷基或所述的取代的(C1-C12)烷氧基中的取代基为多个时，所述的取代基相同或不同；
上述各基团中，所述的(C2-C20)杂环烷基、所述的氘代(C2-C20)杂环烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基、和、所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中，所述的“(C2-C20)杂环烷基”独立地为“杂原子为O、N和S中的一种或多种的(C2-C20)杂环烷基”；
当通式(I)中，n1为0，X为NH或ND，R10为H或D时，R2为F；
当通式(I)中，n1为1时，R10为
Figure PCTCN2017116413-appb-000004
D表示氘富集的氢，H表示非氘富集的氢；
所述的雄激素受体通路调节剂为恩杂鲁胺、ARN-509、ODM-201、VT-464、Orteronel、EPI-001、Andarine、RD162、BMS-641988、CH5137291、氟他米特、羟基氟他胺、RU58642、LG120907、LG105、Galeterone、螺内酯、MK-2866、AZD3514、醋酸环丙氯地孕酮、ORM-15341、比卡鲁胺、尼鲁米特、Degarelix、醋酸戈舍瑞林、醋酸亮丙瑞林、阿比特龙和乙酸阿比特龙酯中的一种或多种；
当所述的雄激素受体通路调节剂为上述化合物中的一种时，所述的雄激素受体通路调节剂不为比卡鲁胺、尼鲁米特、醋酸亮丙瑞林、醋酸环丙氯地孕酮或螺内酯。
所述的组合中，通式(I)中，所述的不对称中心较佳地是指(S)构型碳、(R)构型碳、或者消旋体。
所述的组合中，通式(I)中，较佳地，所述的Z为下列任一结构：
Figure PCTCN2017116413-appb-000005
Figure PCTCN2017116413-appb-000006
Figure PCTCN2017116413-appb-000007
Figure PCTCN2017116413-appb-000008
在一些实施例中，更佳地，所述的Z为下列任一结构：
Figure PCTCN2017116413-appb-000009
其中，用*标注的碳为不对称中心，所述的不对称中心、H和D的定义均如前所述。
通式(I)中，较佳地，所述的(C2-C20)杂环烷基、所述的氘代(C2-C20)杂环烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基、和、所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中，所述的“(C2-C20)杂环烷基”独立地指“杂原子为N或O，杂原子数为1-2个的(C2-C6)杂环烷”基；所述的“杂原子为N或O，杂原子数为1-2个的(C2-C6)杂环烷基”较佳地为吗啉基(例如
Figure PCTCN2017116413-appb-000010
)。
通式(I)中，较佳地，所述的取代或未取代的(C1-C12)烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基、和、所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中，所述的“(C1-C12)烷基”独立地为(C1-C4)烷基；所述的(C1-C4)烷基较佳地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；所述的取代的(C1-C12)烷基较佳地为
Figure PCTCN2017116413-appb-000011
Figure PCTCN2017116413-appb-000012
通式(I)中，较佳地，所述的(C1-C12)烷氧基、和、所述的取代或未取代的(C1-C12)烷氧基中，所述的“(C1-C12)烷氧基”独立地为(C1-C4)烷氧基；所述的(C1-C4)烷氧基较佳地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基。
通式(I)中，所述的
Figure PCTCN2017116413-appb-000013
较佳地为
Figure PCTCN2017116413-appb-000014
Figure PCTCN2017116413-appb-000015
所述的组合中，较佳地，所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种为下列任一化合物：
Figure PCTCN2017116413-appb-000016
Figure PCTCN2017116413-appb-000017
Figure PCTCN2017116413-appb-000018
Figure PCTCN2017116413-appb-000019
Figure PCTCN2017116413-appb-000020
Figure PCTCN2017116413-appb-000021
Figure PCTCN2017116413-appb-000022
Figure PCTCN2017116413-appb-000023
Figure PCTCN2017116413-appb-000024
Figure PCTCN2017116413-appb-000025
Figure PCTCN2017116413-appb-000026
Figure PCTCN2017116413-appb-000027
其药学上可接受的盐、和、其立体异构体。
在所述的组合中，更佳地，所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种为下列任一化合物：B101、B102、B103、B104、B105、B106、C107、C108、C109、C110、C111、C112、其药学上可接受的盐、和、其立体异构体。最佳地，所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种为下列任一化合物：B101、B102、B103、B104、B105、B106、C111、其药学上可接受的盐、和、其立体异构体。
在所述的组合中，所述的雄激素受体通路调节剂较佳地选自恩杂鲁胺、ARN-509、阿比特龙、乙酸阿比特龙酯、Galeterone、ODM-201和ORM-15341中的一种或多种。
在所述的组合中，所述的雄激素受体通路调节剂更佳地为恩杂鲁胺、ARN-509、Galeterone、ODM-201、ORM-15341、阿比特龙、乙酸阿比特龙酯、恩杂鲁胺和Galeterone、恩杂鲁胺和乙酸阿比特龙酯、恩杂鲁胺和阿比特龙、恩杂鲁胺和ODM-201、恩杂鲁胺和ORM-15341、ARN-509和Galeterone、ARN-509和乙酸阿比特龙酯、ARN-509和阿比特龙、ARN-509和ODM-201、ARN-509和ORM-15341、ODM-201和Galeterone、ODM-201和乙酸阿比特龙酯，ODM-201和阿比特龙、ORM-15341和Galeterone、ORM-15341和乙酸阿比特龙酯、或、ORM-15341和阿比特龙。
在所述的组合中，所述的雄激素受体通路调节剂最佳地为恩杂鲁胺、ARN-509、Galeterone、ODM-201、阿比特龙、乙酸阿比特龙酯、恩杂鲁胺和Galeterone、恩杂鲁胺和乙酸阿比特龙酯、ARN-509和Galeterone、ARN-509和乙酸阿比特龙酯、ODM-201和恩杂鲁胺、ODM-201和ARN-509、ODM-201和Galeterone、ODM-201和阿比特龙、或、ODM-201和乙酸阿比特龙酯。
在一些实施例中，所述的“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”和所 述的雄激素受体通路调节剂的组合为：“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”选自：B101、B102、B103、B104、B105、B106、C107、C108、C109、C110、C111、C112、其药学上可接受的盐、和、其立体异构体；雄激素受体通路调节剂选自恩杂鲁胺、ARN-509、阿比特龙、乙酸阿比特龙酯、Galeterone、ODM-201和ORM-15341中的一种或多种。
在一些实施例中，所述的“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”和所述的雄激素受体通路调节剂的组合为：“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”选自B101、B102、B103、B104、B105、B106、C107、C108、C109、C110、C111、C112、其药学上可接受的盐、和、其立体异构体；雄激素受体通路调节剂为恩杂鲁胺、ARN-509、Galeterone、ODM-201、ORM-15341、阿比特龙、乙酸阿比特龙酯、恩杂鲁胺和Galeterone、恩杂鲁胺和乙酸阿比特龙酯、恩杂鲁胺和阿比特龙、恩杂鲁胺和ODM-201、恩杂鲁胺和ORM-15341、ARN-509和Galeterone、ARN-509和乙酸阿比特龙酯、ARN-509和阿比特龙、ARN-509和ODM-201、ARN-509和ORM-15341、ODM-201和Galeterone、ODM-201和乙酸阿比特龙酯，ODM-201和阿比特龙、ORM-15341和Galeterone、ORM-15341和乙酸阿比特龙酯、或、ORM-15341和阿比特龙。
在一些实施例中，所述的“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”和所述的雄激素受体通路调节剂的组合为：“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”选自B101、B102、B103、B104、B105、B106、C107、C108、C109、C110、C111、C112、其药学上可接受的盐、和、其立体异构体；雄激素受体通路调节剂为恩杂鲁胺、ARN-509、Galeterone、ODM-201、阿比特龙、乙酸阿比特龙酯、恩杂鲁胺和Galeterone、恩杂鲁胺和乙酸阿比特龙酯、ARN-509和Galeterone、ARN-509和乙酸阿比特龙酯、ODM-201和恩杂鲁胺、ODM-201和ARN-509、ODM-201和Galeterone、ODM-201和阿比特龙、或、ODM-201和乙酸阿比特龙酯。
在一些实施例中，所述的通式(I)所示的苯并杂环化合物和所述的雄激素受体通路调节的组合较佳地为：B101和恩杂鲁胺、B102和恩杂鲁胺、B103和恩杂鲁胺、B104和恩杂鲁胺、B105和恩杂鲁胺、B106和恩杂鲁胺、C111和恩杂鲁胺、B101和ARN-509、 B102和ARN-509、B103和ARN-509、B104和ARN-509、B105和ARN-509、B106和ARN-509、C111和ARN-509、B101和阿比特龙、B102和阿比特龙、B103和阿比特龙、B104和阿比特龙、B105和阿比特龙、B106和阿比特龙、C111和阿比特龙、B101和乙酸阿比特龙酯、B102和乙酸阿比特龙酯、B103和乙酸阿比特龙酯、B104和乙酸阿比特龙酯、B105和乙酸阿比特龙酯、B106和乙酸阿比特龙酯、C111和乙酸阿比特龙酯、B101和Galeterone、B102和Galeterone、B103和Galeterone、B104和Galeterone、B105和Galeterone、B106和Galeterone、C111和Galeterone、B101和ODM-201、B102和ODM-201、B103和ODM-201、B104和ODM-201、B105和ODM-201、B106和ODM-201、C111和ODM-201、B101和恩杂鲁胺和Galeterone、B102和恩杂鲁胺和Galeterone、B103和恩杂鲁胺和Galeterone、B104和恩杂鲁胺和Galeterone、B105和恩杂鲁胺和Galeterone、B106和恩杂鲁胺和Galeterone、C111和恩杂鲁胺和Galeterone、B101和恩杂鲁胺和乙酸阿比特龙酯、B102和恩杂鲁胺和乙酸阿比特龙酯、B103和恩杂鲁胺和乙酸阿比特龙酯、B104和恩杂鲁胺和乙酸阿比特龙酯、B105和恩杂鲁胺和乙酸阿比特龙酯、B106和恩杂鲁胺和乙酸阿比特龙酯、C111和恩杂鲁胺和乙酸阿比特龙酯、B101和ARN-509和Galeterone、B102和ARN-509和Galeterone、B103和ARN-509和Galeterone、B104和ARN-509和Galeterone、B105和ARN-509和Galeterone、B106和ARN-509和Galeterone、C111和ARN-509和Galeterone、B101和ARN-509和乙酸阿比特龙酯、B102和ARN-509和乙酸阿比特龙酯、B103和ARN-509和乙酸阿比特龙酯、B104和ARN-509和乙酸阿比特龙酯、B105和ARN-509和乙酸阿比特龙酯、B106和ARN-509和乙酸阿比特龙酯、C111和ARN-509和乙酸阿比特龙酯、B101和ODM-201和恩杂鲁胺、B102和ODM-201和恩杂鲁胺、B103和ODM-201和恩杂鲁胺、B104和ODM-201和恩杂鲁胺、B105和ODM-201和恩杂鲁胺、B106和ODM-201和恩杂鲁胺、C111和ODM-201和恩杂鲁胺、B101和ODM-201和ARN-509、B102和ODM-201和ARN-509、B103和ODM-201和ARN-509、B104和ODM-201和ARN-509、B105和ODM-201和ARN-509、B106和ODM-201和ARN-509、C111和ODM-201和ARN-509、B101和ODM-201和Galeterone、B102和ODM-201和Galeterone、B103和ODM-201和Galeterone、B104和ODM-201和Galeterone、B105和ODM-201和Galeterone、B106和ODM-201和Galeterone、C111和ODM-201和Galeterone、B101和ODM-201和阿比特龙、B102和ODM-201和阿比特龙、B103和ODM-201和阿比特龙、B104和ODM-201和阿比特龙、B105和ODM-201和阿比特龙、B106和ODM-201和阿比特龙、C111和ODM-201和阿比特龙、B101和ODM-201和乙酸阿比特龙酯、B102和ODM-201和乙酸阿比特龙酯、B103和ODM- 201和乙酸阿比特龙酯、B104和ODM-201和乙酸阿比特龙酯、B105和ODM-201和乙酸阿比特龙酯、B106和ODM-201和乙酸阿比特龙酯、或者、C111和ODM-201和乙酸阿比特龙酯。
在一些实施例中，所述的通式(I)所示的苯并杂环化合物的药学上可接受的盐、和、所述的雄激素受体通路调节的组合较佳地如上一段任一组合所述，区别仅在于将“通式(I)所示的苯并杂环化合物”替换为“通式(I)所示的苯并杂环化合物的药学上可接受的盐”。例如，上一段中有B101和恩杂鲁胺，则本段对应为B101的药学上可接受的盐和恩杂鲁胺。
在一些实施例中，所述的通式(I)所示的苯并杂环化合物的立体异构体、和、所述的雄激素受体通路调节的组合较佳地如上一段任一组合所述，区别仅在于将“通式(I)所示的苯并杂环化合物的药学上可接受的盐”替换为“通式(I)所示的苯并杂环化合物的立体异构体”。例如，上一段中有B101的药学上可接受的盐和恩杂鲁胺，则本段对应为B101的立体异构体和恩杂鲁胺。
所述的组合还可进一步包含激素类化合物，所述的激素类化合物为强的松、地塞米松、去氢表雄酮、异雄酮和醋酸甲地孕酮中的一种或多种。所述的激素类化合物较佳地为强的松。因此，所述的组合可包含所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，所述的雄激素受体通路调节剂，和，所述的激素类化合物。
所述的组合中，所述的雄激素受体通路调节剂和所述的激素类化合物的组合较佳地为：Galeterone和强的松、强的松和乙酸阿比特龙酯、恩杂鲁胺和强的松、ARN-509和强的松、恩杂鲁胺和地塞米松、恩杂鲁胺和Galeterone和强的松、恩杂鲁胺和Galeterone和地塞米松、恩杂鲁胺和ODM-201和强的松、恩杂鲁胺和ODM-201和地塞米松、恩杂鲁胺和ORM-15341和强的松、恩杂鲁胺和ORM-15341和地塞米松、恩杂鲁胺和乙酸阿比特龙酯和强的松、恩杂鲁胺和乙酸阿比特龙酯和地塞米松、恩杂鲁胺和阿比特龙和强的松、恩杂鲁胺和阿比特龙和地塞米松、ARN-509和地塞米松、ARN-509和Galeterone和强的松、ARN-509和Galeterone和地塞米松、ARN-509和ODM-201和强的松、ARN-509和ODM-201和地塞米松、ARN-509和ORM-15341和强的松、ARN-509和ORM-15341和地塞米松、ARN-509和乙酸阿比特龙酯和强的松、ARN-509和乙酸阿比特龙酯和地塞米松、ARN-509和阿比特龙和强的松、ARN-509和阿比特龙和地塞米松、ODM-201和强的松、ODM-201和地塞米松、ODM-201和Galeterone和强的松、ODM-201和Galeterone和地塞米松、ODM-201和乙酸阿比特龙酯和强的松、ODM-201和乙酸阿比特龙酯和地塞 米松、ODM-201和阿比特龙和强的松、ODM-201和阿比特龙和地塞米松、ORM-15341和强的松、ORM-15341和地塞米松、ORM-15341和Galeterone和强的松、ORM-15341和Galeterone和地塞米松、ORM-15341和乙酸阿比特龙酯和强的松、ORM-15341和乙酸阿比特龙酯和地塞米松、ORM-15341和阿比特龙和强的松、ORM-15341和阿比特龙和地塞米松、Galeterone和地塞米松、或、乙酸阿比特龙酯和地塞米松。
所述的组合中，雄激素受体通路调节剂和所述的激素类化合物的组合更佳地为：Galeterone和强的松、强的松和乙酸阿比特龙酯、恩杂鲁胺和强的松、ARN-509和强的松、恩杂鲁胺和Galeterone和强的松、恩杂鲁胺和ODM-201和强的松、恩杂鲁胺和ORM-15341和强的松、恩杂鲁胺和乙酸阿比特龙酯和强的松、恩杂鲁胺和阿比特龙和强的松、ARN-509和Galeterone和强的松、ARN-509和ODM-201和强的松、ARN-509和ORM-15341和强的松、ARN-509和乙酸阿比特龙酯和强的松、ARN-509和阿比特龙和强的松、ODM-201和强的松、ODM-201和Galeterone和强的松、ODM-201和乙酸阿比特龙酯和强的松、ODM-201和阿比特龙和强的松、ORM-15341和强的松、ORM-15341和Galeterone和强的松、ORM-15341和乙酸阿比特龙酯和强的松、或、ORM-15341和阿比特龙和强的松。
所述的组合中，所述雄激素受体通路调节剂和所述激素类化合物的组合最佳地为：Galeterone和强的松、强的松和乙酸阿比特龙酯、恩杂鲁胺和强的松、ARN-509和强的松、恩杂鲁胺和Galeterone和强的松、恩杂鲁胺和乙酸阿比特龙酯和强的松、ARN-509和Galeterone和强的松、ARN-509和乙酸阿比特龙酯和强的松、ODM-201和强的松、ODM-201和Galeterone和强的松、ODM-201和乙酸阿比特龙酯和强的松、ODM-201和阿比特龙和强的松、恩杂鲁胺和ODM-201和强的松、或、ARN-509和ODM-201和强的松。
在本发明的一些实施例中，所述的“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”、所述雄激素受体通路调节剂和所述激素类化合物的组合较佳地为：所述的“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”选自：B101、B102、B103、B104、B105、B106、C107、C108、C109、C110、C111、C112、其药学上可接受的盐、和、其立体异构体；所述雄激素受体通路调节剂和所述激素类化合物的组合为：Galeterone和强的松、强的松和乙酸阿比特龙酯、恩杂鲁胺和强的松、ARN-509和强的松、恩杂鲁胺和Galeterone和强的松、恩杂鲁胺和乙酸阿比特龙酯和强的松、ARN-509和Galeterone和强的松、ARN-509和乙酸阿比特龙酯和强的松、ODM-201和强的松、ODM-201和Galeterone和强的松、 ODM-201和乙酸阿比特龙酯和强的松、ODM-201和阿比特龙和强的松、恩杂鲁胺和ODM-201和强的松、或、ARN-509和ODM-201和强的松。
在本发明的一些实施例中，所述的通式(I)所示的苯并杂环化合物、所述雄激素受体通路调节剂和所述激素类化合物的组合更佳地为：B101和恩杂鲁胺和强的松、B102和恩杂鲁胺和强的松、B103和恩杂鲁胺和强的松、B104和恩杂鲁胺和强的松、B105和恩杂鲁胺和强的松、B106和恩杂鲁胺和强的松、C111和恩杂鲁胺和强的松、B101和ARN-509和强的松、B102和ARN-509和强的松、B103和ARN-509和强的松、B104和ARN-509和强的松、B105和ARN-509和强的松、B106和ARN-509和强的松、C111和ARN-509和强的松、B101和Galeterone和强的松、B102和Galeterone和强的松、B103和Galeterone和强的松、B104和Galeterone和强的松、B105和Galeterone和强的松、B106和Galeterone和强的松、C111和Galeterone和强的松、B101和ODM-201和强的松、B102和ODM-201和强的松、B103和ODM-201和强的松、B104和ODM-201和强的松、B105和ODM-201和强的松、B106和ODM-201和强的松、C111和ODM-201和强的松、B101和强的松和乙酸阿比特龙酯、B102和强的松和乙酸阿比特龙酯、B103和强的松和乙酸阿比特龙酯、B104和强的松和乙酸阿比特龙酯、B105和强的松和乙酸阿比特龙酯、B106和强的松和乙酸阿比特龙酯、C111和强的松和乙酸阿比特龙酯、B101和恩杂鲁胺和Galeterone和强的松、B102和恩杂鲁胺和Galeterone和强的松、B103和恩杂鲁胺和Galeterone和强的松、B104和恩杂鲁胺和Galeterone和强的松、B105和恩杂鲁胺和Galeterone和强的松、B106和恩杂鲁胺和Galeterone和强的松、C111和恩杂鲁胺和Galeterone和强的松、B101和恩杂鲁胺和乙酸阿比特龙酯和强的松、B102和恩杂鲁胺和乙酸阿比特龙酯和强的松、B103和恩杂鲁胺和乙酸阿比特龙酯和强的松、B104和恩杂鲁胺和乙酸阿比特龙酯和强的松、B105和恩杂鲁胺和乙酸阿比特龙酯和强的松、B106和恩杂鲁胺和乙酸阿比特龙酯和强的松、C111和恩杂鲁胺和乙酸阿比特龙酯和强的松、B101和ARN-509和Galeterone和强的松、B102和ARN-509和Galeterone和强的松、B103和ARN-509和Galeterone和强的松、B104和ARN-509和Galeterone和强的松、B105和ARN-509和Galeterone和强的松、B106和ARN-509和Galeterone和强的松、C111和ARN-509和Galeterone和强的松、B101和ARN-509和乙酸阿比特龙酯和强的松、B102和ARN-509和乙酸阿比特龙酯和强的松、B103和ARN-509和乙酸阿比特龙酯和强的松、B104和ARN-509和乙酸阿比特龙酯和强的松、B105和ARN-509和乙酸阿比特龙酯和强的松、B106和ARN-509和乙酸阿比特龙酯和强的松、C111和ARN-509和乙酸阿比特龙酯和强的松、B101和ODM-201和恩杂鲁胺和强的松、B102和ODM-201和 恩杂鲁胺和强的松、B103和ODM-201和恩杂鲁胺和强的松、B104和ODM-201和恩杂鲁胺和强的松、B105和ODM-201和恩杂鲁胺和强的松、B106和ODM-201和恩杂鲁胺和强的松、C111和ODM-201和恩杂鲁胺和强的松、B101和ODM-201和ARN-509和强的松、B102和ODM-201和ARN-509和强的松、B103和ODM-201和ARN-509和强的松、B104和ODM-201和ARN-509和强的松、B105和ODM-201和ARN-509和强的松、B106和ODM-201和ARN-509和强的松、C111和ODM-201和ARN-509和强的松、B101和ODM-201和Galeterone和强的松、B102和ODM-201和Galeterone和强的松、B103和ODM-201和Galeterone和强的松、B104和ODM-201和Galeterone和强的松、B105和ODM-201和Galeterone和强的松、B106和ODM-201和Galeterone和强的松、C111和ODM-201和Galeterone和强的松、B101和ODM-201和阿比特龙和强的松、B102和ODM-201和阿比特龙和强的松、B103和ODM-201和阿比特龙和强的松、B104和ODM-201和阿比特龙和强的松、B105和ODM-201和阿比特龙和强的松、B106和ODM-201和阿比特龙和强的松、C111和ODM-201和阿比特龙和强的松、B101和ODM-201和乙酸阿比特龙酯和强的松、B102和ODM-201和乙酸阿比特龙酯和强的松、B103和ODM-201和乙酸阿比特龙酯和强的松、B104和ODM-201和乙酸阿比特龙酯和强的松、B105和ODM-201和乙酸阿比特龙酯和强的松、B106和ODM-201和乙酸阿比特龙酯和强的松、或、C111和ODM-201和乙酸阿比特龙酯和强的松。
在一些实施例中，所述的通式(I)所示的苯并杂环化合物的药学上可接受的盐、所述雄激素受体通路调节剂和所述激素类化合物的组合更佳地如上一段任一组合所述，区别仅在于将“通式(I)所示的苯并杂环化合物”替换为“通式(I)所示的苯并杂环化合物的药学上可接受的盐”。例如，上一段中有B101和恩杂鲁胺和强的松，则本段对应为B101的药学上可接受的盐和恩杂鲁胺和强的松。
在一些实施例中，所述的通式(I)所示的苯并杂环化合物的立体异构体、所述雄激素受体通路调节剂和所述激素类化合物的组合更佳地如上一段任一组合所述，区别仅在于将“通式(I)所示的苯并杂环化合物的药学上可接受的盐”替换为“通式(I)所示的苯并杂环化合物的立体异构体”。例如，上一段中有B101的药学上可接受的盐和恩杂鲁胺和强的松，则本段对应为B101的立体异构体和恩杂鲁胺和强的松。
所述组合中的各组分可同时使用或分开使用(例如顺序使用)；当所述组合中的各组分同时使用时，所述组合中的各组分可均匀混合(即各组分的混合物)。
所述组合中的各组分可以制备成一个单一的药物组合物同时使用，也可以将各组分分别制成单个独立的药物组合物，这些单个独立的药物组合物可同时使用或分开使用(例 如顺序使用)。
本发明中，术语“组分”是指本发明组合中的组分，即通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，雄激素受体通路调节剂，或者激素类化合物。
本发明还提供了一种药物组合物，其包含上述的组合和一种或多种药用辅料。
一方面，本发明提供的药物组合物，其可包含上述通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，上述雄激素受体通路调节剂，和，一种或多种药用辅料。
另一方面，本发明提供的药物组合物，其可包含上述通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，上述雄激素受体通路调节剂，上述激素类化合物，和，一种或多种药用辅料。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
所述药物组合物可由所述组合和所述一种或多种药用辅料组成。
本领域已知的制备药物组合物的方法包括但不限于常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。例如，本发明的药物组合物可以通过混合通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，雄激素受体通路调节剂，和药用辅料来制备。或者，本发明的药物组合物可以通过混合通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，雄激素受体通路调节剂，激素类化合物，和药用辅料来制备。
本发明所述的药物组合物可以配制成任何形式用于给药，包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或延迟释放剂型。固体口 服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂、丸剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部给药用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂：如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
在某些实施例中，本发明的药物组合物涉及控释剂型。如本文所用，“控释剂型”指的是一种剂型，其中药物组合物中的治疗活性成分的释放速率可控，或者是具有特定的延迟，以控制接受药物组合物给药的受试者中治疗活性成分的释放部位。一种控释剂型可以包含一种控释剂，如持续释放剂(持续释放)和/或延迟释放剂(延迟释放)。
如本文所用，术语“持续释放”是指治疗活性成分从药物制剂中释放的时间延长。如本文所用，术语“延迟释放”是指受试者接受给药后组合物到达受试者内所需环境后，或受试者接受给药后经过特定时间后，治疗活性成分从药物组合物中释放，使得释放发生在特定部位或所需的环境。
如本文所用，术语“持续释放剂”和“延迟释放剂”是指提供使治疗活性成分从制剂中控制释放的化合物或添加剂，以便释放逐渐发生，并且释放的时间延长。持续或延迟释放剂可使受试者接受组合物给药后治疗活性成分在特定长时间内释放。
从本发明的药物组合物的控释剂型的控制释放可以通过各种条件来实现，这些条件包括但不限于pH值、温度、酶、水或其它生理条件或化合物。本发明的药物组合物可以进一步包含肠溶衣，以控制药物组合物中活性成分的释放，使其在所需的一段时间内从组合物中逐渐和连续地释放，使得该活性成分能在延长的时间期内发挥治疗或预防作用。本领域技术人员根据公开的内容可以熟知那些合适的控释剂、持续和延迟释放剂。可以并入本发明的药物组合物以提供控释组合物的控释剂的非限制性实例包括聚合物，如羟丙基甲基纤维素；凝胶；渗透膜；微粒；脂质体；微球以及其组合。本文所述的任何组合物可适用于控释制剂，如片剂、胶囊、软胶囊和囊片。
再一方面，本发明还提供了一种组合药盒，其包含药物组合物A和药物组合物B；
所述的药物组合物A包括上述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，和，一种或多种药用辅料；所述的药物组合物B包括上述的雄激素受体通路调节剂和一种或多种药用辅料。
所述的组合药盒可由所述的药物组合物A和所述的药物组合物B组成。所述的药物组合物A可由上述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，和，一种或多种药用辅料组成；所述的药物组合物B可由上述的雄激素受体通路调节剂和一种或多种药用辅料组成。较佳地，所述的药物组合物A中所述的“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”、所述的药物组合物B中所述的“雄激素受体通路调节剂”及它们所形成的组合如上所述。
所述的组合药盒还可以包含药物组合物C，所述的药物组合物C包括上述的激素类药物和一种或多种药用辅料。
所述的组合药盒可以由所述的药物组合物A、所述的药物组合物B和所述的药物组合物C组成。所述的药物组合物C可由上述的激素类药物和一种或多种药用辅料组成。较佳地，所述的药物组合物A中所述的“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”、所述的药物组合物B中所述的“雄激素受体通路调节剂”、所述的药物组合物C中所述的激素类药物及它们所形成的组合如上所述。
所述组合药盒中的各个药物组合物可以同时使用或分开使用(例如顺序使用)。
所述组合药盒中，所述的“药用辅料”的定义同上。
本发明中，术语“活性成分”是指本发明药物组合物或组合药盒中的活性成分，即通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，雄激素受体通路调节剂，激素类化合物，或者，它们所形成的上述组合。
上述组合、上述药物组合物、或上述的组合药盒可用于预防和/或治疗前列腺癌。所述的前列腺癌较佳地为去势抵抗性前列腺癌。
再一方面，本发明还提供了上述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，在制备用于和上述的雄激素受体通路调节剂联合预防和/或治疗前列腺癌的药物组合物中的应用。
又一方面，本发明还提供了上述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，在制备用于和上述的雄激素受体通路调节剂、以及上述的激素类化合物联合预防和/ 或治疗前列腺癌的药物组合物中的应用。
本发明还提供了上述的雄激素受体通路调节剂，在制备用于和上述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种联合预防和/或治疗前列腺癌的药物组合物中的应用。
本发明还提供了上述的雄激素受体通路调节剂，在制备用于和上述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种、以及上述的激素类化合物联合预防和/或治疗前列腺癌的药物组合物中的应用。
本发明还提供了上述的激素类化合物，在制备用于和上述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种、以及、上述的雄激素受体通路调节剂联合预防和/或治疗前列腺癌的药物组合物中的应用。
在本发明所述的应用中，上述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，上述的雄激素受体通路调节剂，和，上述激素类化合物可以同时或者分开施用(例如顺序施用)。
在上述的应用中，所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种、所述的雄激素受体通路调节剂、所述的激素类化合物以及它们所形成的组合如上所述。
再一方面，本发明还提供了一种预防和/或治疗前列腺癌的方法，包括向所需患者施用治疗或预防有效量的上述的组合。所述的前列腺癌可为去势抵抗性前列腺癌。
在一个实施例中，所述预防和/或治疗前列腺癌的方法，包括向所需患者施用治疗或预防有效量的上述通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，和，治疗或预防有效量的上述的雄激素受体通路调节剂。
其中，上述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，和，上述的雄激素受体通路调节剂可以同时或者分开施用(例如顺序施用)。
在本发明的一些实施例中，所述的预防和/或治疗前列腺癌的方法较佳地包括向所需患者施用治疗或预防有效量的上述通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，治 疗或预防有效量的上述雄激素受体通路调节剂，以及，治疗或预防有效量的上述激素类化合物。
其中，上述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，上述的雄激素受体通路调节剂，和，上述激素类化合物可以同时或者分开施用(例如顺序施用)。
在所述的预防和/或治疗前列腺癌的方法中，所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种、所述的雄激素受体通路调节剂、所述的激素类化合物以及它们所形成的组合如上所述。
在某些实施方式中，给予每个受试者的化合物(此处是指通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种、雄激素受体通路调节剂或激素类化合物)的治疗或预防有效量为从约0.005至约1000mg/天，从约0.0l至约500mg/天，从约0.0l至约250mg/天，从约0.0l至约100mg/天，从约0.1至约100mg/天，从约0.5至约100mg/天，从约1至约100mg/天，从约0.0l至约50mg/天，从约0.1至约50mg/天，从约0.5至约50mg/天，从约1至约50mg/天，从约0.02至约25mg/天或从约0.05至约l0mg/天。
在某些实施方式中，治疗或预防有效量(此处是指通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种、雄激素受体通路调节剂或激素类化合物的预防或治疗有效量)是约0.01、约0.05、约0.1、约0.2、约0.3、约0.4、约0.5、约0.6、约0.8、约1、约2、约5、约10、约15、约20、约25、约30、约40、约45、约50、约60、约70、约80、约90、约100、约150、约200、约250、约300、约350、约400、约450、约500、约550、约600、约650、约700、约750、约800、约850、约900或约1000mg/每天/受试者。
在本发明所述的组合、药物组合物、组合药盒、应用、或预防和/或治疗前列腺癌的方法中，所述的通式(I)所示的苯并杂环化合物与所述的雄激素受体通路调节剂的摩尔比可根据本领域常规进行选择，例如1:0.0002-1:300，又例如1:0.0005-1:222(1:0.0002、1:0.0005、1:0014、1:0.0041、1:0.012、1:0.0037、1:0.11、1:0.33、1:1、1:3、1:9、1:27、1:79、1:222)，再例如1:0.1-1:222。
在本发明所述的组合、药物组合物、组合药盒、应用、或预防和/或治疗前列腺癌的方法中，所述的通式(I)所示的苯并杂环化合物与所述的雄激素受体通路调节剂的用量不做特殊的限定，可根据本领域常规进行选择，例如通式(I)所示的苯并杂环化合物的物质 的量例如0.001-300μM，又例如0.05-300μM(再例如300.00μM、100.00μM、33.33μM、11.11μM、3.70μM、1.23μM、0.41μM、0.14μM或0.05μM)；雄激素受体通路调节剂的物质的量可以是0.01-300μM，又例如0.05-50μM，又例如0.05-11.11μM。
在本发明所述的组合、药物组合物、组合药盒、应用、或预防和/或治疗前列腺癌的方法中，当还进一步含有激素类化合物时，所述的激素类化合物的用量不做特殊的限定，例如所述的激素类化合物与所述的雄激素受体通路调节剂的摩尔比可以是1:0.01-1:100，例如1:0.1-1:10(又例如1:0.1、1:1、2:1、1:10)。
在本发明所述的组合、药物组合物、组合药盒、应用、或预防和/或治疗前列腺癌的方法中，当还进一步含有激素类化合物时，所述的激素类化合物的用量不做特殊的限定，例如所述的激素类化合物与所述的雄激素受体通路调节剂的物质的量可以分别是0.01-300μM，又例如0.05-50μM，又例如0.1-10μM。
当将本发明的组合中的各组分给予受试者以治疗或预防疾病、病症或病况时，组合中的各组分可通过相同的途径给药，也可通过不同的途径给药。可通过本文描述的任何途径给药，包括但不限于口服、吸入、注射、眼部、粘膜、直肠、乳剂、脂质体、长效植入或持续缓释方法。具体给药途径将依赖于治疗剂本身及制剂，以及需预防或治疗的疾病、病症或病况。根据本公开内容，本领域中一名普通技术人员的技能水平足以确定其给药途径。本发明的组合中的各组分，可以在一段时间(给药周期)内给予受试者，其后是一段不给予化合物的时期(非给药周期)。可以重复所需次数的给药周期和非给药周期。给药周期或者非给药周期的所需长度和次数将取决于正在治疗或预防的疾病、病症或病况的类型和/或严重程度，以及受试者个体的性别、年龄、体重和其他参数(例如，受试者个体的生物学、身体和生理状况等)。在本发明的组合中的各组分，可以在一段时间内同时给予受试者，还可以在一段时间内先后给予受试者。根据本文件公开的内容本领域普通技术人员的技术水平将足以确定给药周期和/或非给药周期的适当长度和次数。
本文所述的治疗方法可使用任何合适的方法将本发明的组合中的各组分给予受试者，包括注射、经粘膜、口服、吸入、眼部、直肠、长效植入、脂质体、乳剂或持续释放方法。
本领域技术人员会认识到，本发明的组合、药物组合物或组合药盒中的各组分或者活性成分的治疗或预防有效量可以随着因素的不同而不同，对于特定受试者，如年龄、饮食、健康等，寻求治疗或预防的症状或疾病、病症或病况的严重程度以及并发症和类型，所用制剂等。根据本发明公开内容，本领域普通技术人员将能够很容易地确定需给予受试者的治疗或预防有效量，以便在受试者中引起期望的生物学或医学响应。
根据本发明的组合、药物组合物或组合药盒中的各组分或者活性成分的联合使用， 可以在治疗或预防任何疾病、病症或病况(例如前列腺癌)中发挥协同作用。
在本文所述的任何方法中，包括但是不限于前述的治疗方法、应用等，根据本发明的组合、药物组合物或组合药物盒可单独使用，或与超声疗法、放射疗法(简称放疗)或放射免疫疗法等配合使用，还可与一种或多种其它具有药理学活性的治疗剂(以下简称“其它治疗剂”)联合使用。其它治疗剂的量和类型将取决于要进行治疗或预防的疾病、病症或病况；疾病、病症或病况的严重程度；接受组合物给药的受试者的因素，如年龄、体重、身体状况等；给药途径等。根据本发明的实施例，其它治疗剂可以是天然存在的、半合成的或合成的化合物。在另一个实施例中，其它治疗剂可以是小分子，如合成的有机或无机分子；或较大的分子或生物分子，例如具有药理活性的蛋白质或核酸。在另一个实施例中，其它治疗剂可以是化疗剂、抗血管生成药物(又称血管生成抑制剂)、免疫调节剂、免疫治疗剂、单克隆抗体、多克隆抗体和激酶抑制剂中的一种或多种。
化疗剂(化学治疗剂)，即化学合成药物。化疗剂是目前治疗肿瘤及某些自身免疫性疾病的主要药物，常用的有：表阿霉素、阿霉素、柔红霉素、丝裂霉素、氟尿嘧啶脱氧核苷酸等。
抗血管生成药物是指通过抑制促血管生成的生长因子、生长因子受体及下游信号通路等抑制新生血管生成，从而抑制肿瘤的生长和转移的发生，主要包括血管内皮生长抑制剂、受体酪氨酸激酶抑制剂、PI3K/AKT/mTOR通路抑制剂、作用于VEGF-A、VEGF-B和胎盘生长因子的重组融合蛋白(例如阿柏西普)、重组人血管内皮抑素等。
免疫调节剂是增强、促进和调节免疫功能的药物，对治疗免疫功能低下，某些继发性免疫缺陷病和某些恶性肿瘤等有一定作用。按照免疫调节剂的功能，主要分为免疫抑制剂和免疫增强剂。前者用于抗炎症、抗自身免疫反应、抗过敏、抗移植排斥反应和抗肿瘤，后者用于抗感染、抗过敏和抗肿瘤。属于免疫抑制剂的药物种类繁多，包括抗代谢药物(环袍菌素A、硫唑漂吟、环磷酰胺、甲氨蝶吟、霉酚酸酯、他克莫司和米唑拉宾等)、糖皮质激素、单克隆抗体(抗TNF-alpha/受体、抗IFN-γ，和抗CD25单杭等)、细胞因子IFN-β、,IL-10和TGF-β、化学制剂(来氟米特和5-HT3受体拮杭剂)、非苗体类抗炎药、核酸类、他丁类抗脂药、HMG辅酶A还原酶抑制剂、植物类(雷公藤、冬虫夏草提取物FTY720、青高素和帕吠琳等)和其他生物制品(霍乱毒素B亚单位、sNTB-A-Fc融合蛋白、CMV-IkappaBa载体抑制剂和B7-HI抑制剂等)。免疫增强剂的品种同样繁多，包括细胞因子(干扰素α、干扰素γ、胸腺肽和胸腺5肽、G-CSF/GM-CSF、IL-2、IL-12、重组人红细胞生成素、表皮细胞生长因子、趋化因子细胞间黏附分子-1、血管细胞黏附分子-1，P-选择素及其他细胞间黏附分子等)、生物制品[IVIG、转移因子、免疫核糖核酸、细 菌及其提取物(卡介苗及其提取物、脱脂脱糖脂母牛分枝杆菌菌苗、其他细菌提取物、低钙反应V或V抗原LcrV，霍乱弧菌的产物Zot和分歧杆菌等)]、植物类药物(多糖、皂苷及其他植物成分等)、化学制剂(左旋咪唑、甲氰咪呱、匹多莫德、NS-398咪啥莫特、Propagermanium和脂质体等)、微量营养素(维生素A/C/D、微量元素铁、锌、硒)和其他(大环内酯类抗生素、氨茶碱)。
免疫治疗指调节受试者的免疫反应，使其产生需要的治疗效果，免疫治疗剂指当给予受试者时，调节该受试者的免疫系统，足以最终减少与不利的免疫反应相关的症状或者最终减轻由于增加所需的免疫反应而导致的症状的药物。
单克隆抗体是指由单一B细胞克隆产生的高度均一、仅针对某一特定抗原表位的抗体。
多克隆抗体是指用一种包含多种抗原决定簇的抗原免疫受体，可刺激机体多个B细胞克隆产生针对多种抗原表位的不同抗体。
在生物化学里，激酶是一类从高能供体分子(如ATP)转移磷酸基团到特定靶分子(受质)的酶；这一过程谓之磷酸化；激酶抑制剂是指一类可以结合激酶并降低其活性的分子。
其它治疗剂包括但不限于：daratumumab、elotuzumab、palbociclib、panobinostat、nivolumab、pembrolizumab、培美曲塞(pemetrexed)、托泊替康(拓扑替康)(topotecan)、阿霉素(doxorubicin)、硼替佐米(bortezomib)、吉西他滨(gemcitabine)、达卡巴嗪(dacarbazine)、克拉霉素(biaxin)、长春新碱(vincristine)、阿糖胞苷(azacitidine)、CAR-T、利妥昔单抗(rituximab)、曲妥珠单抗(trastuzumab)、PD-1抑制剂、PD-L1抑制剂、HDAC抑制剂、除前述雄激素受体通路调节剂以外的雄激素受体通路调节剂、多西他赛(docetaxel)、氯法拉滨注射液、Ublituximab、romidepsin、BTK抑制剂、红血球生长激素、eltrombopag、米诺四环素和美法仑(melphalan)中的一种或多种。
在另一个实施例中，本发明的药物组合物或组合药盒中，雄激素受体通路调节剂或激素类化合物的治疗或预防有效量可低于不给予本发明通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物或前药时的有效量。
本发明中，涉及的所施用的化合物的量、治疗或预防有效量、剂量、起始剂量等均是指具体某一个化合物的量，例如具体地某一个通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物或前药、具体某一个雄激素受体通路调节剂或具体某一个激素类化合物，而非多个化合物的组合。
本发明中方法中所用雄激素受体通路调节剂或激素类药物的治疗或预防有效量和给 药指导可见本文引用的专利和公布的专利申请以及Wells et al,eds.,Pharmacotherapy Handbook,2nd Edition,Appleton and Lange,Stamford,Conn.(2000)；PDR Pharmacopoeia,Tarascon Pocket Pharmacopoeia 2000,Deluxe Edition,Tarascon Publishing,Loma Linda,Calif.(2000)和其它医学文献。
本文所用术语“雄激素受体通路调节剂”包括雄激素抑制剂、雄激素受体抑制剂、雄激素生物合成抑制剂以及其它影响雄激素受体通路的药物。
术语“激素”是由正常机体某些组织产生，然后弥散入血液，由血液循环运输到机体其他组织，发挥特殊生理作用的一类化学物质。激素类化合物包括人工合成的或天然的激素类化学物质。
如本文中所用，当提到具体盐、组合物、辅料等“药学上可接受的”时，是指该盐、组合物、辅料等一般无毒、安全，并且适合于受试者使用，优选哺乳动物受试者，更优选为人受试者。
本文所用术语“药学上可接受的盐”指药学上可接受的有机或无机盐。示例性盐包括但不限于：硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、gentisinate、富马酸盐、葡糖酸盐、葡糖醛酸盐、糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲烷磺酸盐、乙烷磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1-1-亚甲基-双(2-羟基-3-萘甲酸盐))。本发明中所用化合物可与各种氨基酸形成药学上可接受的盐。合适的碱盐包括但不限于铝盐、钙盐、锂盐、镁盐、钾盐、钠盐、锌盐、铋和二乙醇胺盐。药学上可接受的盐的综述见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
如本文所用，术语“代谢物”是指药物分子在体内所经历的化学结构的变化后产生的活性物质，该活性物质一般为前述药物分子的衍生物，其还可被化学修饰。
如本文所用，术语“晶型(polymorph)”是指在结晶时，分子在晶格空间的排列不同而形成的一种或多种晶体结构。
如本文所用，术语“共晶”是指其中存在一种或多种API(活性药物成分)分子和一种或多种客体(或助形成物)分子的多组分体系。在共晶中，当独自为其纯品形式(为了使共晶区别于溶剂化物或水合物)时，API分子和客体(或助形成物)分子在室温下也都可以以固体存在。从这种特定的定义中排除了其中在API分子和客体分子之间发生显著的或完全的质子交换的盐。在共晶中，API和助形成物通过氢键和可能的其他非共价的 相互作用而发生相互作用。可注意到，共晶本身可能形成溶剂化物，包括水合物。客体(或助形成物)是指其他生理上可接受的酸、碱、非离子化合物。
如本文所用，术语“溶剂化物”是指通式(I)化合物、其药学上可接受的盐、晶型、共晶、立体异构体、同位素化合物、代谢物或前药的一种晶体形式，它还包含一种或多种融入晶体结构中的溶剂分子。溶剂化物可包括化学计量量或非化学计量量的溶剂，并且溶剂中的溶剂分子可能以有序或非有序排列的形式存在。含有非化学计量量溶剂分子的溶剂化物可能是溶剂化物至少丢失一部分(但并非全部)溶剂分子得到的。在一个特定实施例中，一种溶剂化物是一种水合物，意味着化合物的结晶形式进一步包括水分子。
如本文所用，术语“前药”是指包含生物反应官能团的化合物的衍生物，使得在生物条件下(体外或体内)，生物反应官能团可从化合物上裂解或以其他方式发生反应以提供所述化合物。通常，前药无活性，或者至少比化合物本身活性低，使得直到将所述化合物从生物反应官能团上裂解后才能发挥其活性。生物反应官能团可在生物条件下水解或氧化以提供所述化合物。例如，前药可包含可生物水解的基团，可生物水解的基团实例包括但不限于可生物水解的磷酸盐、可生物水解的酯、可生物水解的酰胺、可生物水解的碳酸酯、可生物水解的氨基甲酸酯和可生物水解的酰脲。有关前药的综述参见，例如，J.Rautio et al.,Nature Reviews Drug Discovery(2008)7,255-270 and Prodrugs:Challenges和Rewards(V.Stella et al.ed.,Springer,2007)。
本发明的组合中的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物或前药可以含有一个或多个不对称中心(“立体异构体”)。如本文所用，术语“立体异构体”是指对映异构体、非对映异构体、差向异构体(epimers)、内向-外向异构体(endo-exo isomers)、阻转异构体(atropisomers)、位向异构体(regioisomers)、顺式-和反式-异构体等在内的所有立体异构体。本文的“立体异构体”也包括前述各种立体异构体的“纯立体异构体”及“富集立体异构体”或“消旋体”。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。本文的“纯立体异构体”是指所涉化合物的一种立体异构体相对于该化合物的其它种立体异构体的质量含量不低于95％。本文的“富集立体异构体”是指所涉化合物的一种立体异构体相对于该化合物的其它种立体异构体的质量含量不低于50％。本文的“消旋体”是指所涉化合物的一种立体异构体的质量含量与该化合物的其它种立体异构体的质量含量相等。
如本文所用，D表示氘富集的氢，H表示非氘富集的氢。“氘富集”化合物意指在通 式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物或前药的化合物中的任何相关位点处的氘的丰度大于其在该位点处的自然丰度(0.0156％)。因此，在“氘富集”化合物中，其相关位点中的任一者处的氘丰度都可能在大于0.0156％到100％的范围内。获得氘富集化合物的方法的实例是用氘交换氢或者用氘富集起始物质合成化合物。
根据本领域普通技术知识，非氘富集的位点还可以省略符号H。非氘富集是指自然中的氢，即以H(氢或氕)、D(2H或氘)和T(3H或氚)同位素混合物的形式存在的。
本文所用术语“同位素化合物”是指本发明的通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、代谢物或前药中含有一个或多个天然或非天然丰度的原子同位素。非天然丰度的原子同位素包括但不限于氘(2H或D)、氚(3H或T)、碘-125(125I)、磷-32(32P)、碳-13(13C)或碳-14(14C)。前述同位素化合物还可用作治疗或诊断剂(即，体内显影剂)，或研究工具。本发明的化合物的所有同位素变体，无论是否具有放射性，都包括在本发明的范围内。
本文所用术语“同位素富集”是指通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物、前药中含有一个或多个非天然丰度的原子同位素。“同位素富集”也指通式(I)化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物，或前药化合物中至少含有一个非天然丰度同位素原子。
如本文所用，术语“受试者”或“患者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优，人类最优。如本文所用，术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。术语“受试者”和“患者”在本文中可互换使用。在一个实施例中，“治疗”或“正在治疗”是指疾病或病症或其至少一个可辨别症状的改善、预防或逆转，例如通过减少或稳定癌症或病症症状，治疗癌症。在另一个实施例中，“治疗”或“正在治疗”指正在治疗的疾病或病症的至少一个可测量身体参数的改善、预防或逆转，可能并未在哺乳动物中识别所述疾病或病症。然而在另一个实施例中，“治疗”或“正在治疗”是指减慢疾病或病症的进展，或者是身体上的，例如可辨别症状的稳定，或生理学上的，例如，身体参数的稳定，或两者兼而有之。在另一个实施例中，“治疗”或“正在治疗”是指延迟疾病或病症的发作。
在某些实施例中，组合、药物组合物或组合药盒作为预防措施给药。如本文所用，“预防”或“正在预防”是指降低获得给定疾病或病症的风险。在实施例的优选模式中， 将指定组合、药物组合物或组合药盒作为预防措施给予受试者，例如有癌症或自身免疫性疾病家族病史或倾向的受试者。
如本文所用，“治疗有效量”是指能够引起组织系统、动物或人产生生物学或医学反应(研究员、兽医、医生或其他临床医生正在寻求的)的化合物或组合物的量，其可以包括减轻正在治疗的疾病或病症症状。在一个优选实施例中，治疗有效量是有效治疗、改善治疗或预防癌症、病症的量。
术语“预防有效量”是指能够抑制受试者中病症发作(研究员、兽医、医生或其它临床医生所寻求的)的活性化合物或药剂的量。化合物的预防有效量是指治疗剂单独使用或联合其它治疗活性化合物所用的量，其在治疗或预防疾病、病症或病况中能够提供治疗益处。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
如无另外说明，本文所用术语的单数形式“一个”或“一种”也包括复数意义。
如无另外说明，本文使用“或”或“和”指“和/或”。
本文中引用或描述了各种出版物、文章和专利，引用或描述这些参考文献或将其整体并入本文或对之进行的讨论是为了说明本发明的背景，并非是指其中的内容构成了本发明现有技术的一部分。
除非另有定义，本文所用所有技术和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。否则，此处所用的某些术语的含义具有本说明书所设定的含义。
本发明中，所述的雄激素受体通路调节剂和激素类化合物的结构如下：
Figure PCTCN2017116413-appb-000028
Figure PCTCN2017116413-appb-000029
Figure PCTCN2017116413-appb-000030
Figure PCTCN2017116413-appb-000031
本发明所用试剂均市售可得，本发明中式(I)化合物和雄激素受体通路调节剂可由本领域技术人员根据本领域熟知的合成方法，或根据已公开的文献或专利很容易地合成得到，相关的专利例如WO2016065980，WO9803502，WO2010056344，WO2012079022，WO2012015986，WO2011100380，WO2014116573，WO2008039489，WO2014110558，WO2014039421，WO2006124118等。
本发明的积极进步效果在于：本发明的组合能够更有效地抑制前列腺癌细胞的增长，组合的各组分之间具有协同效果。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中如未注明具体条件的实验方法，可按照常规方法和条件，或按照商品说明书选择。
效果实施例1.CTG细胞增殖实验：
体外测试化合物与雄激素受体通路调节剂联用对前列腺癌细胞增殖的抑制作用。
在Vcap细胞(雄激素受体阳性前列腺癌细胞)(ATCC，产品目录号CRL-2876)上测试B101、B102、B103、B104、B105、B106、C111等化合物、雄激素受体通路调节剂、激素类化合物单用或彼此联用对前列腺癌细胞增殖的抑制作用。具体实验操作如下。按每孔5×103个Vcap细胞，接种至含有特定培养基的底透壁白的96-孔培养板(Corning，产品目录号CLS3903)中，置于37℃，5％CO2，培养箱内培养24小时。测试化合物及雄激素受体通路调节剂用DMSO(Sigma，产品目录号276855)配成150mM的储备液，用培养基稀释至所需浓度(DMSO终浓度为0.2％)后加入各孔，2孔/浓度，在37℃，5％CO2培养箱内孵育5天。测试化合物单用或分别与其它雄激素受体通路调节剂和/或激素类化合物等联用处理细胞。联用药物为：恩杂鲁胺(Selleck，产品目录号S1250)，ARN-509(Selleck，产品目录号S2840)，乙酸阿比特龙酯(Selleck，产品目录号S2246),Galeterone(Selleck，产品目录号S2803)，ODM-201(康朴生物医药技术(上海)有限公司)和强的松(Selleck，产品目录号S1622)。每个测试药物的浓度设置见下述实验结果表。之后，每孔加入100μl 
Figure PCTCN2017116413-appb-000032
细胞活性检测试剂(Promega，产品目录号G7570)，在振板机上混匀10分钟，诱导细胞溶解。将96孔板在室温中放置10分钟，使其发光信号稳定。粘贴白色的底膜于培养板底部，使用EnSpire测板。通过Graphpad/Prism和Calcusyn软件进行数据处理，计算每个化合物的平均细胞增殖抑制率或存活率或联合用药的协同作用指数，具体实验结果见表1-12。
表1.Vcap细胞增殖抑制率：B105和恩杂鲁胺联合用药
Figure PCTCN2017116413-appb-000033
Figure PCTCN2017116413-appb-000034
表1注解：不同浓度的B105和恩杂鲁胺单用或联用处理Vcap细胞5天，测定细胞增殖抑制率(％)。联合用药效果突出，例如，B105单用时(浓度为1.23μM)对Vcap细胞的抑制率为26.3％，恩杂鲁胺单用时(浓度为1.23μM)对Vcap细胞的抑制率为30％，两者联用(1.23μM B105加1.23μM恩杂鲁胺)时对Vcap细胞的抑制率则为61.8％。
表2.B105和恩杂鲁胺联合用药的协同作用指数(对表1中联合用药的实验数据进行协同作用效果分析)
Figure PCTCN2017116413-appb-000035
表2注解：对表1中B105和恩杂鲁胺联合用药的实验数据进行协同作用效果分析。表中数据显示二者有较强协同作用。
联合用药的协同作用指数注解(下同)：<0.1:很强协同作用；0.1-0.3:强协同作用；0.3-0.7:协同作用；0.7-0.85:温和协同作用；0.85-0.90:轻微协同作用；0.90-1.10:近似相加作用；1.10-1.20:轻微拮抗作用；1.20-1.45:温和拮抗作用；1.45-3.3:拮抗作用；3.3-10:强拮抗作用；>10:很强拮抗作用
表3.Vcap细胞增殖抑制率：C111和恩杂鲁胺联合用药
Figure PCTCN2017116413-appb-000036
Figure PCTCN2017116413-appb-000037
表3注解：不同浓度的C111和恩杂鲁胺单用或联用处理Vcap细胞5天，测定细胞增殖抑制率(％)。联合用药效果突出，例如，C111单用时(浓度为1.23μM)对Vcap细胞的抑制率为23.4％，恩杂鲁胺单用时(浓度为1.23μM)对Vcap细胞的抑制率为36.8％，两者联用(1.23μM C111加1.23μM恩杂鲁胺)时对Vcap细胞的抑制率则为54.7％。
表4.C111和恩杂鲁胺联合用药的协同作用指数(对表3中C111和恩杂鲁胺联合用药的实验数据进行协同作用效果分析)
Figure PCTCN2017116413-appb-000038
表4注解：对表3中C111和恩杂鲁胺联合用药的实验数据进行协同作用效果分析。表中数据显示二者有较强协同作用。
表5.Vcap细胞存活率：测试化合物单用、测试化合物与恩杂鲁胺联合用药、或、测试化合物与ARN-509联合用药
Figure PCTCN2017116413-appb-000039
表5注解：联合用药效果突出，例如，在1.0μM时，B101、B105、C111、恩杂鲁胺、ARN-509各自单用情况下,细胞存活率分别为65.4％、72.5％、81.0％、54.0％、52.2％。1.0μM的B101、B105、C111分别与1.0μM的恩杂鲁胺联用时，细胞存活率分别为25.2％、27.5％、35.8％。1.0μM的B101、B105、C111分别与1.0μM的ARN-509联用时，细胞存活率分别为24.3％、28.0％、35.6％。
表6.Vcap细胞存活率：测试化合物单用、测试化合物与Galeterone联合用药、或、测试化合物与乙酸阿比特龙酯联合用药
Figure PCTCN2017116413-appb-000040
表6注解：联合用药效果突出，例如，在1.0μM时，B101、B105、C111、Galeterone、乙酸阿比特龙酯各自单用情况下,细胞存活率分别为65.4％、72.5％、81.0％、62.8％、91.7％。1.0μM的B101、B105、C111分别与1.0μM的Galeterone联用时，细胞存活率分别为34.4％、36.7％、47.0％。1.0μM的B101、B105、C111分别与1.0μM的乙酸阿比特龙酯联用时，细胞存活率分别为56.6％、57.1％、68.5％。
表7.Vcap细胞存活率：测试化合物单用或测试化合物与ODM-201联合用药
测试化合物 测试化合物单用 与1μM ODM-201联用
  10μM 1μM 0.1μM 10μM 1μM 0.1μM
ODM-201 75.4％ 69.0％ 90.7％      
B101 65.8％ 71.1％ 81.7％ 32.5％ 37.1％ 43.8％
B105 65.5％ 69.7％ 77.9％ 32.2％ 36.6％ 43.3％
C111 63.3％ 72.0％ 76.3％ 37.2％ 43.1％ 45.9％
表7注解：联合用药效果突出，例如，在1.0μM时，ODM-201、B101、B105、C111各自单用情况下,细胞存活率分别为69.0％、71.1％、69.7％、72.0％。1.0μM的B101、B105、C111分别与1.0μM的ODM-201联用时，细胞存活率分别为37.1％、36.6％、43.1％。
表8.Vcap细胞存活率：B105分别与恩杂鲁胺、ARN-509、强的松、Galeterone、或乙酸阿比特龙酯联合用药
Figure PCTCN2017116413-appb-000041
Figure PCTCN2017116413-appb-000042
Figure PCTCN2017116413-appb-000043
“v”指该组合所含的组分。空格表示无该组分。下同。
表8注解：联合用药抑制细胞生长效果更加突出。例如：1.0μM的恩杂鲁胺与乙酸阿比特龙酯(1.0μM)联用时，细胞存活率为50.7％。1.0μM的恩杂鲁胺与乙酸阿比特龙酯(1.0μM)和B105(1.0μM)联用时，细胞存活率则降低为22.0％。1.0μM的恩杂鲁胺与强的松(1.0μM)和乙酸阿比特龙酯(1.0μM)联用时，细胞存活率为45.9％。1.0μM的恩杂鲁胺与强的松(1.0μM)和乙酸阿比特龙酯(1.0μM)和B105(1.0μM)联用时，细胞存活率则降低为25.9％。
表9.Vcap细胞存活率：C111分别与恩杂鲁胺、ARN-509、强的松、Galeterone、或乙酸阿比特龙酯联合用药
Figure PCTCN2017116413-appb-000044
Figure PCTCN2017116413-appb-000045
表9注解：联合用药抑制细胞生长效果更加突出。例如：1.0μM的恩杂鲁胺与乙酸阿比特龙酯(1.0μM)联用时，细胞存活率为50.7％(表8)。1.0μM的恩杂鲁胺与乙酸阿比特龙酯(1.0μM)和C111(1.0μM)联用时，细胞存活率则降低为40.1％。1.0μM的恩杂鲁胺与强的松(1.0μM)和乙酸阿比特龙酯(1.0μM)联用时，细胞存活率为49.8％。1.0μM的恩杂鲁胺与强的松(1.0μM)和乙酸阿比 特龙酯(1.0μM)和C111(1.0μM)联用时，细胞存活率则降低为35.3％。
表10.Vcap细胞存活率：B101分别与恩杂鲁胺、ARN-509、强的松、Galeterone、或乙酸阿比特龙酯联合用药
Figure PCTCN2017116413-appb-000046
Figure PCTCN2017116413-appb-000047
表10注解：联合用药抑制细胞生长效果更加突出。例如：1.0μM的恩杂鲁胺与乙酸阿比特龙酯(1.0μM)联用时，细胞存活率为50.7％(表8)。1.0μM的恩杂鲁胺与乙酸阿比特龙酯(1.0μM)和B101(1.0μM)联用时，细胞存活率则降低为26.7％。1.0μM的恩杂鲁胺与强的松(1.0μM)和乙酸阿比特龙酯(1.0μM)联用时，细胞存活率为51.3％。1.0μM的恩杂鲁胺与强的松(1.0μM)和乙酸阿比特龙酯(1.0μM)和B101(1.0μM)联用时，细胞存活率则降低为27.2％。
表11.Vcap细胞存活率：测试化合物单用、测试化合物与B101联合用药、或、测试化合物与B105联合用药
Figure PCTCN2017116413-appb-000048
Figure PCTCN2017116413-appb-000049
表12.Vcap细胞存活率：测试化合物单用、测试化合物与恩杂鲁胺联合用药、或、测试化合物与ARN-509联合用药
Figure PCTCN2017116413-appb-000050
表12注解：联合用药效果明显，例如，在1.0μM时，B102、B103、B104、B106、恩杂鲁胺、ARN-509各自单用情况下,细胞存活率分别为80.9％、84.1％、77.4％、79％、65.7％、70.4％。1.0μM的B102、B103、B104、B106分别与1.0μM的恩杂鲁胺联用时，细胞存活率分别为41.1％、42.7％、41.2％、40.5％。1.0μM的B102、B103、B104、B106分别与1.0μM的ARN-509联用时，细胞存活率分别为40.2％、41.7％、40.5％、41.1％。
效果实施例2PSA抑制率实验：
本实验的目的是测试供试化合物与恩杂鲁胺联合处理前列腺肿瘤细胞系VCap细胞5天后，其上清PSA(即前列腺原抗原)分泌水平的改变。
用0.5μM恩杂鲁胺单独，以及用不同浓度的2个供试化合物分别联合0.5μM恩杂鲁胺处理VCap细胞5天，通过电化学发光免疫分析法测定各处理组PSA水平。
实验材料与方法
1、细胞系
肿瘤类型 细胞名称 培养基 处理时间(天)
前列腺癌 VCap DMEM+10％FBS 5
细胞培养条件为：37℃，5％CO2和95％湿度。
2、试剂
1)DMEM培养基(Thermo scientific，产品号：SH30243.01)
2)FBS(胎牛血清)(Gibco，产品号：10099-141)
3)0.25％胰酶-EDTA(Gibco，产品号：25200-072)
4)DMSO(Sigma，产品号：D2650)
5)前列腺特异性抗原试剂(Roche，产品号：04641655190)(太仓市第一人民医院提供)
3、仪器
1)二氧化碳培养箱：SANYO Electric Co.,Ltd.(Japan).(Equipment ID:TAINC0490)
2)显微镜：Chongguang XDS-1B,Chongqing Guangdian Corp.(Chongqing,P.R.China).(Equipment ID:TAMIC0130)
3)冰箱：海尔Z16TXZ(China).(Equipment ID:TAREF0490)
4)电子天平：Mettlertoledo AL104.(Shanghai,China).(Equipment ID:TBBAL0560)
5)全自动电化学免疫分析仪：Roche Cobas e601(太仓市第一人民医院)
4、测定化合物对VCap细胞PSA分泌抑制率
细胞接种
收集处于指数生长期的细胞进行活细胞计数。用上述培养基将细胞悬液调整到4.17×10e4/ml。每孔加120μl细胞悬液于96-孔细胞培养板，最终细胞浓度为5000细胞/孔。将细胞置于37℃，5％CO2孵箱中过夜培养。
加药处理
以DMSO溶解各供试化合物为10mM储存液。用储存液和DMSO制备4×系列梯度稀释液。然后用培养基各稀释制成10倍稀释液，同时配制恩杂鲁胺10倍溶液。每株细胞每孔分别加入恩杂鲁胺以及等体积的供试化合物相应溶液，每个药物浓度各1个复 孔，最终测试所用恩杂鲁胺浓度及供试化合物浓度范围参见表13。每孔DMSO终浓度为0.2％。置于37℃，5％CO2孵箱中培养5天。
检测
药物处理5天后，分别收集各孔细胞上清液，2000转/分，离心5分钟，转移上清液至干净EP管中，做PSA测定。
5、数据分析
PSA抑制率计算公式：(1-(V样品/VDMSO))×100％计算。其中V样品，为药物处理组的PSA读数，VDMSO为溶剂对照组的PSA平均值。
表13 PSA抑制率(％)：0.5μM恩杂鲁胺单独、以及和不同浓度的测试化合物联合用药
Figure PCTCN2017116413-appb-000051
表13注解：0.5μM恩杂鲁胺单用时，对PSA的抑制率为30.7％，0.5μM恩杂鲁胺分别与0.1μM的B105和C111联用后PSA抑制率达到60.4％和52.8％，可见联合用药比恩杂鲁胺单独用药效果明显增强。
效果实施例3
参照效果实施例1的测试方法，替换其中的Vcap细胞为LNCap细胞(雄激素受体阳性前列腺癌细胞)(ATCC，产品目录号CRL-1740)，测试结果如下：
表14.LNCap细胞存活率：测试化合物单用、测试化合物与恩杂鲁胺或测试化合物与ARN-509联合用药
Figure PCTCN2017116413-appb-000052
Figure PCTCN2017116413-appb-000053
表14注解：联合用药效果突出，例如，在1.0μM时，B101、B105、恩杂鲁胺、ARN-509各自单用情况下,细胞存活率分别为63％、61.5％、70.5％、86.7％。1.0μM的B101、B105分别与1.0μM的恩杂鲁胺联用时，细胞存活率分别为34.1％、32％。1.0μM的B101、B105分别与1.0μM的ARN-509联用时，细胞存活率分别为46.3％、44.7％。
表15.LNCap细胞存活率：测试化合物单用、测试化合物与Galeterone或测试化合物与乙酸阿比特龙酯联合用药
Figure PCTCN2017116413-appb-000054
表15注解：联合用药效果突出，例如，在1.0μM时，B101、B105、Galeterone、乙酸阿比特龙酯各自单用情况下,细胞存活率分别为63％、61.5％、79％、90.7％。1.0μM的B101、B105分别与1.0μM的Galeterone联用时，细胞存活率分别为43.6％、40.6％。1.0μM的B101、B105分别与1.0μM的乙酸阿比特龙酯联用时，细胞存活率分别为46.2％、47.9％。
表16.LNCap细胞存活率：B105分别与恩杂鲁胺、ARN-509、强的松、Galeterone、或乙酸阿比特龙酯联合用药
Figure PCTCN2017116413-appb-000055
Figure PCTCN2017116413-appb-000056
“v”指该组合所含的组分。空格表示无该组分。下同。
表16注解：
联合用药抑制细胞生长效果更加突出。1.0μM的恩杂鲁胺与强的松(1.0μM)和乙酸阿比特龙酯(1.0μM)联用时，细胞存活率为56.7％。1.0μM的恩杂鲁胺与强的松(1.0μM)和乙酸阿比特龙酯(1.0μM)和B105(1.0μM)联用时，细胞存活率则降低为28.6％。1.0μM的恩杂鲁胺与强的松(1.0μM)和Galeterone(1.0μM)联用时，细胞存活率为55.7％。1.0μM的恩杂鲁胺与强的松(1.0μM)和Galeterone(1.0μM)和B105(1.0μM)联用时，细胞存活率则降低为26.8％。
表17.LNCap细胞存活率:B101分别与恩杂鲁胺、ARN-509、强的松、Galeterone、或乙酸阿比特龙酯联合用药
Figure PCTCN2017116413-appb-000057
Figure PCTCN2017116413-appb-000058
“v”指该组合所含的组分。空格表示无该组分。
表17注解：
联合用药抑制细胞生长效果更加突出。1.0μM的恩杂鲁胺与强的松(1.0μM)和乙酸阿比特龙酯(1.0μM)联用时，细胞存活率为57.6％。1.0μM的恩杂鲁胺与强的松(1.0μM)和乙酸阿比特龙酯(1.0μM)和B101(1.0μM)联用时，细胞存活率则降低为27.5％。1.0μM的恩杂鲁胺与强的松(1.0μM)和Galeterone(1.0μM)联用时，细胞存活率为53.4％。1.0μM的恩杂鲁胺与强的松(1.0μM)和Galeterone(1.0μM)和B101(1.0μM)联用时，细胞存活率则降低为26.6％。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (18)

  1. 一种组合，其包含通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，以及雄激素受体通路调节剂；
    Figure PCTCN2017116413-appb-100001
    通式(I)中，n1为0或1；
    L1和L2独立地为CH2、CHD或CD2；
    X为NH、ND或O；
    R1和R3独立地为H或D；
    R2为H、D或卤素；
    Z为
    Figure PCTCN2017116413-appb-100002
    其中，R4为H、D、CH3、CH2D、CHD2或CD3；R5、R6、R7、R8和R9独立地为H或D；用*标注的碳为不对称中心；
    R10为H、D或
    Figure PCTCN2017116413-appb-100003
    其中R1’、R2’、R3’和R4’独立地为H、D、卤素、氰基、羟基、取代或未取代的(C1-C12)烷基、取代或未取代的(C1-C12)烷氧基、(C2～C20)杂环烷基、或、氘代(C2～C20)杂环烷基；
    所述的取代的(C1-C12)烷氧基中的取代基为下列基团中的一个或多个：D、卤素、羟基、(C1-C12)烷氧基、(C2-C20)杂环烷基、和、(C1-C12)烷基取代的(C2-C20)杂环烷基；
    所述的取代的(C1-C12)烷基中的取代基为下列基团中的一个或多个：D、(C2-C20)杂环烷基、氘代(C2-C20)杂环烷基、(C1-C12)烷基取代的(C2-C20)杂环烷基、和、氘代(C1-C12)烷基取代的(C2-C20)杂环烷基；
    当所述的取代的(C1-C12)烷基或所述的取代的(C1-C12)烷氧基中的取代基为多个时，所 述的取代基相同或不同；
    上述各基团中，所述的(C2-C20)杂环烷基、所述的氘代(C2-C20)杂环烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基、和、所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中，所述的“(C2-C20)杂环烷基”独立地为“杂原子为O、N和S中的一种或多种的(C2-C20)杂环烷基”；
    当通式(I)中，n1为0，X为NH或ND，R10为H或D时，R2为F；
    当通式(I)中，n1为1时，R10为
    Figure PCTCN2017116413-appb-100004
    D表示氘富集的氢，H表示非氘富集的氢；
    所述的雄激素受体通路调节剂为恩杂鲁胺、ARN-509、ODM-201、VT-464、Orteronel、EPI-001、Andarine、RD162、BMS-641988、CH5137291、氟他米特、羟基氟他胺、RU58642、LG120907、LG105、Galeterone、螺内酯、MK-2866、AZD3514、醋酸环丙氯地孕酮、ORM-15341、比卡鲁胺、尼鲁米特、Degarelix、醋酸戈舍瑞林、醋酸亮丙瑞林、阿比特龙和乙酸阿比特龙酯中的一种或多种；
    当所述的雄激素受体通路调节剂为上述化合物中的一种时，所述的雄激素受体通路调节剂不为比卡鲁胺、尼鲁米特、醋酸亮丙瑞林、醋酸环丙氯地孕酮或螺内酯。
  2. 如权利要求1所述的组合，其特征在于，通式(I)中，所述的不对称中心是指(S)构型碳、(R)构型碳或者消旋体；
    和/或，通式(I)中，所述的(C2-C20)杂环烷基、所述的氘代(C2-C20)杂环烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基、和、所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中，所述的“(C2-C20)杂环烷基”独立地是指“杂原子为N或O，杂原子数为1-2个的(C2-C6)杂环烷基”；
    和/或，通式(I)中，所述的取代或未取代的(C1-C12)烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基、和、所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中，所述的“(C1-C12)烷基”独立地为(C1-C4)烷基；
    和/或，通式(I)中，所述的(C1-C12)烷氧基、和、所述的取代或未取代的(C1-C12)烷氧基中，所述的“(C1-C12)烷氧基”独立地为(C1-C4)烷氧基；
    和/或，通式(I)中，所述的Z为下列任一结构：
    Figure PCTCN2017116413-appb-100005
    Figure PCTCN2017116413-appb-100006
    和/或，通式(I)中，所述的取代的(C1-C12)烷基为
    Figure PCTCN2017116413-appb-100007
    Figure PCTCN2017116413-appb-100008
    和/或，通式(I)中，所述的
    Figure PCTCN2017116413-appb-100009
    为
    Figure PCTCN2017116413-appb-100010
    Figure PCTCN2017116413-appb-100011
  3. 如权利要求2所述的组合，其特征在于，通式(I)中，所述的(C2-C20)杂环烷基、所述的氘代(C2-C20)杂环烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基、和、所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中，当所述的“(C2-C20)杂环烷基”是指杂原子为N或O，杂原子数为1-2个的(C2-C6)杂环烷基时，所述的“杂原子为N或O，杂原子数为1-2个的(C2-C6)杂环烷基”独立地为吗啉基；
    和/或，通式(I)中，所述的取代或未取代的(C1-C12)烷基、所述的(C1-C12)烷基取代的(C2-C20)杂环烷基、和、所述的氘代(C1-C12)烷基取代的(C2-C20)杂环烷基中，当所述的“(C1-C12)烷基”为(C1-C4)烷基时，所述的(C1-C4)烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；
    和/或，通式(I)中，所述的(C1-C12)烷氧基、和、所述的取代或未取代的(C1-C12)烷氧基 中，当所述的“(C1-C12)烷氧基”为(C1-C4)烷氧基时，所述的(C1-C4)烷氧基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基；
    和/或，所述的Z为下列任一结构：
    Figure PCTCN2017116413-appb-100012
  4. 如权利要求3所述的组合，其特征在于，所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种为下列任一化合物：
    Figure PCTCN2017116413-appb-100013
    Figure PCTCN2017116413-appb-100014
    Figure PCTCN2017116413-appb-100015
    Figure PCTCN2017116413-appb-100016
    Figure PCTCN2017116413-appb-100017
    Figure PCTCN2017116413-appb-100018
    Figure PCTCN2017116413-appb-100019
    Figure PCTCN2017116413-appb-100020
    Figure PCTCN2017116413-appb-100021
    Figure PCTCN2017116413-appb-100022
    其药学上可接受的盐、和、其立体异构体；
    较佳地，所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种为下列任一化合物：B101、B102、B103、B104、B105、B106、C107、C108、C109、C110、C111、C112、其药学上可接受的盐、和、其立体异构体。
  5. 如权利要求1～4中任一项所述的组合，其特征在于，
    所述的雄激素受体通路调节剂选自恩杂鲁胺、ARN-509、阿比特龙、乙酸阿比特龙酯、Galeterone、ODM-201和ORM-15341中的一种或多种。
  6. 如权利要求5所述的组合，其特征在于，所述的雄激素受体通路调节剂为恩杂鲁胺、ARN-509、Galeterone、ODM-201、ORM-15341、阿比特龙、乙酸阿比特龙酯、恩杂鲁胺和Galeterone、恩杂鲁胺和乙酸阿比特龙酯、恩杂鲁胺和阿比特龙、恩杂鲁胺和ODM-201、恩杂鲁胺和ORM-15341、ARN-509和Galeterone、ARN-509和乙酸阿比特龙酯、ARN-509和阿比特龙、ARN-509和ODM-201、ARN-509和ORM-15341、ODM-201和Galeterone、ODM-201和乙酸阿比特龙酯，ODM-201和阿比特龙、ORM-15341和Galeterone、ORM-15341和乙酸阿比特龙酯、或、ORM-15341和阿比特龙。
  7. 如权利要求4所述的组合，其特征在于，所述的通式(I)所示的苯并杂环化合物和所述的雄激素受体通路调节的组合为：B101和恩杂鲁胺、B102和恩杂鲁胺、B103和恩杂鲁胺、B104和恩杂鲁胺、B105和恩杂鲁胺、B106和恩杂鲁胺、C111和恩杂鲁胺、B101和ARN-509、B102和ARN-509、B103和ARN-509、B104和ARN-509、B105和ARN-509、B106和ARN-509、C111和ARN-509、B101和阿比特龙、B102和阿比特龙、B103和阿比特龙、B104和阿比特龙、B105和阿比特龙、B106和阿比特龙、C111和阿比特龙、B101和乙酸阿比特龙酯、B102和乙酸阿比特龙酯、B103和乙酸阿比特龙酯、B104和乙酸阿比特龙酯、B105和乙酸阿比特龙酯、B106和乙酸阿比特龙酯、C111和乙酸阿比特龙酯、B101和Galeterone、B102和Galeterone、B103和Galeterone、B104和Galeterone、B105和Galeterone、B106和Galeterone、C111和Galeterone、B101和ODM-201、B102和ODM-201、B103和ODM-201、B104和ODM-201、B105和ODM-201、B106和ODM-201、C111和ODM-201、B101和恩杂鲁胺和Galeterone、B102和恩杂鲁胺和Galeterone、B103和恩杂鲁胺和Galeterone、B104和恩杂鲁胺和Galeterone、B105和恩杂鲁胺和Galeterone、B106和恩杂鲁胺和Galeterone、C111和恩杂鲁胺和Galeterone、B101和恩杂鲁胺和乙酸阿比特龙酯、B102和恩杂鲁胺和乙酸阿比特龙酯、B103和恩杂鲁胺和乙酸阿比特龙酯、B104和恩杂鲁胺和乙酸阿比特龙酯、B105和恩杂鲁胺和乙酸阿比特龙酯、B106和恩杂鲁胺和乙酸阿比特龙酯、C111和恩杂鲁胺和乙酸阿比特龙酯、B101和ARN-509和Galeterone、B102和ARN-509和Galeterone、B103和ARN-509和Galeterone、B104和ARN-509和Galeterone、B105和ARN-509和Galeterone、B106和ARN-509和Galeterone、C111和ARN-509和Galeterone、B101和ARN-509和乙酸阿比特龙酯、B102和ARN-509和乙酸阿比特龙酯、B103和ARN-509和乙酸阿比特龙酯、B104和ARN-509和乙酸阿比特龙酯、B105和ARN-509和乙酸阿比特龙酯、B106和 ARN-509和乙酸阿比特龙酯、C111和ARN-509和乙酸阿比特龙酯、B101和ODM-201和恩杂鲁胺、B102和ODM-201和恩杂鲁胺、B103和ODM-201和恩杂鲁胺、B104和ODM-201和恩杂鲁胺、B105和ODM-201和恩杂鲁胺、B106和ODM-201和恩杂鲁胺、C111和ODM-201和恩杂鲁胺、B101和ODM-201和ARN-509、B102和ODM-201和ARN-509、B103和ODM-201和ARN-509、B104和ODM-201和ARN-509、B105和ODM-201和ARN-509、B106和ODM-201和ARN-509、C111和ODM-201和ARN-509、B101和ODM-201和Galeterone、B102和ODM-201和Galeterone、B103和ODM-201和Galeterone、B104和ODM-201和Galeterone、B105和ODM-201和Galeterone、B106和ODM-201和Galeterone、C111和ODM-201和Galeterone、B101和ODM-201和阿比特龙、B102和ODM-201和阿比特龙、B103和ODM-201和阿比特龙、B104和ODM-201和阿比特龙、B105和ODM-201和阿比特龙、B106和ODM-201和阿比特龙、C111和ODM-201和阿比特龙、B101和ODM-201和乙酸阿比特龙酯、B102和ODM-201和乙酸阿比特龙酯、B103和ODM-201和乙酸阿比特龙酯、B104和ODM-201和乙酸阿比特龙酯、B105和ODM-201和乙酸阿比特龙酯、B106和ODM-201和乙酸阿比特龙酯、或者、C111和ODM-201和乙酸阿比特龙酯。
  8. 如权利要求1～7中任一项所述的组合，其特征在于，所述的组合还包含激素类化合物，所述的激素类化合物为强的松、地塞米松、去氢表雄酮、异雄酮和醋酸甲地孕酮中的一种或多种。
  9. 如权利要求8所述的组合，其特征在于，所述的组合中，所述的雄激素受体通路调节剂和所述的激素类化合物的组合为：Galeterone和强的松、强的松和乙酸阿比特龙酯、恩杂鲁胺和强的松、ARN-509和强的松、恩杂鲁胺和地塞米松、恩杂鲁胺和Galeterone和强的松、恩杂鲁胺和Galeterone和地塞米松、恩杂鲁胺和ODM-201和强的松、恩杂鲁胺和ODM-201和地塞米松、恩杂鲁胺和ORM-15341和强的松、恩杂鲁胺和ORM-15341和地塞米松、恩杂鲁胺和乙酸阿比特龙酯和强的松、恩杂鲁胺和乙酸阿比特龙酯和地塞米松、恩杂鲁胺和阿比特龙和强的松、恩杂鲁胺和阿比特龙和地塞米松、ARN-509和地塞米松、ARN-509和Galeterone和强的松、ARN-509和Galeterone和地塞米松、ARN-509和ODM-201和强的松、ARN-509和ODM-201和地塞米松、ARN-509和ORM-15341和强的松、ARN-509和ORM-15341和地塞米松、ARN-509和乙酸阿比特龙酯和强的松、ARN-509和乙酸阿比特龙酯和地塞米松、ARN-509和阿比特龙和强的松、ARN-509和阿比特龙和地塞米松、ODM-201和强的松、ODM-201和地塞米松、ODM-201和Galeterone和强的松、ODM-201和Galeterone和地塞米松、ODM-201和乙酸阿比特龙酯和强的松、 ODM-201和乙酸阿比特龙酯和地塞米松、ODM-201和阿比特龙和强的松、ODM-201和阿比特龙和地塞米松、ORM-15341和强的松、ORM-15341和地塞米松、ORM-15341和Galeterone和强的松、ORM-15341和Galeterone和地塞米松、ORM-15341和乙酸阿比特龙酯和强的松、ORM-15341和乙酸阿比特龙酯和地塞米松、ORM-15341和阿比特龙和强的松、ORM-15341和阿比特龙和地塞米松、Galeterone和地塞米松、或、乙酸阿比特龙酯和地塞米松。
  10. 如权利要求8所述的组合，其特征在于，所述的通式(I)所示的苯并杂环化合物、所述雄激素受体通路调节剂和所述激素类化合物的组合为：B101和恩杂鲁胺和强的松、B102和恩杂鲁胺和强的松、B103和恩杂鲁胺和强的松、B104和恩杂鲁胺和强的松、B105和恩杂鲁胺和强的松、B106和恩杂鲁胺和强的松、C111和恩杂鲁胺和强的松、B101和ARN-509和强的松、B102和ARN-509和强的松、B103和ARN-509和强的松、B104和ARN-509和强的松、B105和ARN-509和强的松、B106和ARN-509和强的松、C111和ARN-509和强的松、B101和Galeterone和强的松、B102和Galeterone和强的松、B103和Galeterone和强的松、B104和Galeterone和强的松、B105和Galeterone和强的松、B106和Galeterone和强的松、C111和Galeterone和强的松、B101和ODM-201和强的松、B102和ODM-201和强的松、B103和ODM-201和强的松、B104和ODM-201和强的松、B105和ODM-201和强的松、B106和ODM-201和强的松、C111和ODM-201和强的松、B101和强的松和乙酸阿比特龙酯、B102和强的松和乙酸阿比特龙酯、B103和强的松和乙酸阿比特龙酯、B104和强的松和乙酸阿比特龙酯、B105和强的松和乙酸阿比特龙酯、B106和强的松和乙酸阿比特龙酯、C111和强的松和乙酸阿比特龙酯、B101和恩杂鲁胺和Galeterone和强的松、B102和恩杂鲁胺和Galeterone和强的松、B103和恩杂鲁胺和Galeterone和强的松、B104和恩杂鲁胺和Galeterone和强的松、B105和恩杂鲁胺和Galeterone和强的松、B106和恩杂鲁胺和Galeterone和强的松、C111和恩杂鲁胺和Galeterone和强的松、B101和恩杂鲁胺和乙酸阿比特龙酯和强的松、B102和恩杂鲁胺和乙酸阿比特龙酯和强的松、B103和恩杂鲁胺和乙酸阿比特龙酯和强的松、B104和恩杂鲁胺和乙酸阿比特龙酯和强的松、B105和恩杂鲁胺和乙酸阿比特龙酯和强的松、B106和恩杂鲁胺和乙酸阿比特龙酯和强的松、C111和恩杂鲁胺和乙酸阿比特龙酯和强的松、B101和ARN-509和Galeterone和强的松、B102和ARN-509和Galeterone和强的松、B103和ARN-509和Galeterone和强的松、B104和ARN-509和Galeterone和强的松、B105和ARN-509和Galeterone和强的松、B106和ARN-509和Galeterone和强的松、C111和ARN-509和Galeterone和强的松、B101和ARN-509和乙酸阿比特龙酯和强的 松、B102和ARN-509和乙酸阿比特龙酯和强的松、B103和ARN-509和乙酸阿比特龙酯和强的松、B104和ARN-509和乙酸阿比特龙酯和强的松、B105和ARN-509和乙酸阿比特龙酯和强的松、B106和ARN-509和乙酸阿比特龙酯和强的松、C111和ARN-509和乙酸阿比特龙酯和强的松、B101和ODM-201和恩杂鲁胺和强的松、B102和ODM-201和恩杂鲁胺和强的松、B103和ODM-201和恩杂鲁胺和强的松、B104和ODM-201和恩杂鲁胺和强的松、B105和ODM-201和恩杂鲁胺和强的松、B106和ODM-201和恩杂鲁胺和强的松、C111和ODM-201和恩杂鲁胺和强的松、B101和ODM-201和ARN-509和强的松、B102和ODM-201和ARN-509和强的松、B103和ODM-201和ARN-509和强的松、B104和ODM-201和ARN-509和强的松、B105和ODM-201和ARN-509和强的松、B106和ODM-201和ARN-509和强的松、C111和ODM-201和ARN-509和强的松、B101和ODM-201和Galeterone和强的松、B102和ODM-201和Galeterone和强的松、B103和ODM-201和Galeterone和强的松、B104和ODM-201和Galeterone和强的松、B105和ODM-201和Galeterone和强的松、B106和ODM-201和Galeterone和强的松、C111和ODM-201和Galeterone和强的松、B101和ODM-201和阿比特龙和强的松、B102和ODM-201和阿比特龙和强的松、B103和ODM-201和阿比特龙和强的松、B104和ODM-201和阿比特龙和强的松、B105和ODM-201和阿比特龙和强的松、B106和ODM-201和阿比特龙和强的松、C111和ODM-201和阿比特龙和强的松、B101和ODM-201和乙酸阿比特龙酯和强的松、B102和ODM-201和乙酸阿比特龙酯和强的松、B103和ODM-201和乙酸阿比特龙酯和强的松、B104和ODM-201和乙酸阿比特龙酯和强的松、B105和ODM-201和乙酸阿比特龙酯和强的松、B106和ODM-201和乙酸阿比特龙酯和强的松、或、C111和ODM-201和乙酸阿比特龙酯和强的松；
    其中，所述的B101、B102、B103、B104、B105、B106、C107、C108、C109、C110、C111和C112如权利要求4所述。
  11. 一种药物组合物，其包含如权利要求1～10中任一项所述的组合和一种或多种药用辅料。
  12. 如权利要求1～4中任一项所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，在制备用于和如权利要求1、5和6中任一项所述的雄激素受体通路调节剂联合预防和/或治疗前列腺癌的药物组合物中的应用；
    或者，如权利要求1～4中任一项所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种 或多种，在制备用于和如权利要求1、5和6中任一项所述的雄激素受体通路调节剂、以及、如权利要求8所述的激素类药物联合预防和/或治疗前列腺癌的药物组合物中的应用；
    或者，如权利要求1、5和6中任一项所述的雄激素受体通路调节剂，在制备用于和如权利要求1～4中任一项所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种联合预防和/或治疗前列腺癌的药物组合物中的应用；
    或者，如权利要求1、5和6中任一项所述的雄激素受体通路调节剂，在制备用于和如权利要求1～4任一项所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种、以及、如权利要求8所述的激素类药物联合预防和/或治疗前列腺癌的药物组合物中的应用；
    或者，如权利要求8所述的激素类药物，在制备用于和如权利要求1～4中任一项所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种、以及、如权利要求1、5和6中任一项所述的雄激素受体通路调节剂联合预防和/或治疗前列腺癌的药物组合物中的应用。
  13. 如权利要求12所述的应用，其特征在于，所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种、和、所述的雄激素受体通路调节剂所形成的组合如权利要求7所述；
    和/或，所述的雄激素受体通路调节剂、和、所述的激素类化合物所形成的组合如权利要求9所述；
    和/或，所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，所述的雄激素受体通路调节剂，和，所述的激素类化合物所形成的组合如权利要求10所述；
    和/或，所述的前列腺癌为去势抵抗性前列腺癌。
  14. 一种预防和/或治疗前列腺癌的方法，包括向所需患者施用治疗或预防有效量的如权利要求1～10中任一项所述的组合。
  15. 如权利要求14所述的方法，其特征在于，所述的“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”、和、所述的“雄激素受体通路调节剂”同时或者分开施用；
    和/或，所述的“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”、所述的“雄 激素受体通路调节剂”、和、所述的“激素类化合物”同时或者分开施用；
    和/或，所述的前列腺癌为去势抵抗性前列腺癌。
  16. 一种组合药盒，其特征在于，其包含药物组合物A和药物组合物B；
    所述的药物组合物A包括如权利要求1～4中任一项所述的通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种，和，一种或多种药用辅料；
    所述的药物组合物B包括如权利要求1、5和6中任一项所述的雄激素受体通路调节剂和一种或多种药用辅料；
    例如，所述的药物组合物A中所述的“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”、和、所述的药物组合物B中所述的“雄激素受体通路调节剂”所形成的组合如权利要求7所述。
  17. 如权利要求16所述的组合药盒，其特征在于，所述的组合药盒还包含药物组合物C，所述的药物组合物C包括如权利要求8所述的激素类药物和一种或多种药用辅料；
    和/或，所述组合药盒中的各个药物组合物同时使用或分开使用；
    和/或，所述的组合药盒用于预防和/或治疗前列腺癌，较佳地为去势抵抗性前列腺癌。
  18. 如权利要求17所述的组合药盒，其特征在于，所述的药物组合物A中所述的“通式(I)所示的苯并杂环化合物、其药学上可接受的盐、溶剂化物、晶型、共晶、立体异构体、同位素化合物、代谢物和前药中的一种或多种”、所述的药物组合物B中所述的“雄激素受体通路调节剂”、和、所述的药物组合物C中所述的“激素类药物”所形成的组合如权利要求10所述。
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